LT4552B - Inhibitors of farnesyl protein transferase - Google Patents
Inhibitors of farnesyl protein transferase Download PDFInfo
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- LT4552B LT4552B LT98-120A LT98120A LT4552B LT 4552 B LT4552 B LT 4552B LT 98120 A LT98120 A LT 98120A LT 4552 B LT4552 B LT 4552B
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Description
Šis išradimas yra susijęs su junginiais, kurie inhibuoja farnezilproteintransferazę ir ras baltymo farnezilinimą, ir todėl jie yra naudingi kaip priešvėžiniai agentai. Šie junginiai taip pat yra naudingi ir nevėžinių susirgimų, susijusių su signalo perdavimo būdais, kurie veikia per ras, ir būdais, susijusiais su kitokiais nei ras baltymais, kuriuos po transliacijos taip pat modifikuoja fermentas farnezilproteintransferazė, gydymui. Šie junginiai taip pat gali veikti kaip kitų preniltransferazių inhibitoriai, ir todėl jie gali būti veiksmingi gydant ligas, susijusias su kitomis baltymų prenil-modifikacijomis.The present invention relates to compounds which inhibit farnesyl protein transferase and find farnesylation of the protein and are therefore useful as anticancer agents. These compounds are also useful for the treatment of non-cancerous signaling pathways that act via ras and those associated with non-ras proteins that are also modified after translation by the enzyme farnesyl protein transferase. These compounds may also act as inhibitors of other prenyltransferases and therefore may be effective in treating diseases associated with other prenyl-modifications of the protein.
Žinduolių ras geno šeima apima tris genus: H-ras, K-ras ir N-ras. Ras baltymai yra rišančių ir hidrolizuojančių GTP baltymų šeima, kuri reguliuoja ląstelių augimą ir diferenciaciją, Normalių ras baltymų per didelio kiekio gaminimasis arba mutacijos, kurios inhibuoja jų GTPazės aktyvumą, gali sukelti nekontroliuojamą ląstelių dalijimąsi.The mammalian ras gene family comprises three genes: H-ras, K-ras and N-ras. Ras proteins are a family of binding and hydrolyzing GTP proteins that regulate cell growth and differentiation. Excessive production of normal ras proteins or mutations that inhibit their GTPase activity can lead to uncontrolled cell division.
Transformuojantis ras aktyvumas priklauso nuo baltymo lokalizacijos plazmos membranos atžvilgiu. Šis membraninis susirišimas vyksta per eilę citozolinių ras baltymų potransliacinių modifikacijų. Pirmoji ir būtina stadija šioje vyksmų sekoje yra šių baltymų farnezilinimas. Reakciją katalizuoja fermentas farnezilproteintransferazė (FPT), o farnezilpirofosfatas (FPP) šioje reakcijoje yra farnezilo grupės donorius. Ras C-gale yra sekos dalis, vadinama “Cys-Aaai-Aaa2-Xaa” boksu (CAAX boksas), kuriame Cys yra cisteinas, Aaa yra alifatinė aminorūgštis, o Xaa yra serinas arba metioninas. Farnezilinimas vyksta CAAX bokso cisteino liekanoje (cys-186), prisijungiant prenilo grupei prie baltymo per tioeterinę jungtį.Transforming ras activity depends on the localization of the protein to the plasma membrane. This membrane binding occurs through a series of post-translational modifications of cytosolic ras proteins. The first and necessary step in this sequence is the farnesylation of these proteins. The reaction is catalyzed by the enzyme farnesyl protein transferase (FPT), and farnesyl pyrophosphate (FPP) is the donor farnesyl group in this reaction. Ras at the C-terminus is a portion of a sequence called "Cys-Aaai-Aaa 2 -Xaa" box (CAAX box), where Cys is cysteine, Aaa is an aliphatic amino acid, and Xaa is serine or methionine. Farnesylation occurs at the cysteine residue (cys-186) of the CAAX boxing by attaching the prenyl group to the protein via a thioether linkage.
Pagal šj išradimą junginiai, kurių formulės I, II, III ir IV:According to the present invention, compounds of formulas I, II, III and IV:
R4, R5 R 4 , R 5
RS,R7 R S , R 7
R1, R2, R3 R 1 , R 2 , R 3
R1, R2, R3 R 1 , R 2 , R 3
IV, jų enantiomerai, diastereomerai ir farmaciškai tinkamos druskos, jų provaistai ir solvatai inhibuoja farnezilproteintransferazę, kuri yra fermentas, dalyvaujantis ras onkogeno ekspresijoje. I-IV formulėse ir išradimo aprašyme, aukščiau duoti simboliai reiškia:IV, their enantiomers, diastereomers and pharmaceutically acceptable salts, their prodrugs and solvates inhibit farnesyl protein transferase, an enzyme involved in the expression of ras oncogene. In the formulas I-IV and in the description of the invention, the above symbols means:
m, n, r, s ir t yra 0 arba 1;m, n, r, s and t are 0 or 1;
p yra O, 1 arba 2;p is O, 1 or 2;
V, W ir X yra pasirinkti iš grupės, susidedančios iš deguonies, vandenilio, R1, R2 arba R3;V, W and X are selected from the group consisting of oxygen, hydrogen, R 1 , R 2 or R 3 ;
Z ir Y yra pasirinkti iš grupės, susidedančios iš CHR9, SO2, SO3, CO, CO2, O, NR10, SO2NR11, CONR12,Z and Y are selected from the group consisting of CHR 9 , SO 2, SO 3, CO, CO 2, O, NR 10 , SO 2 NR 11 , CONR 12 ,
N'N '
II c,CN /CN NII c, CN / CN N
IIII
-C-N — I-C-N - I
R13 R 13
OO
IIII
-N—ΟΙ-N — ΟΙ
R14 R 14
NRisNRis
-SO20-SO 2 0
IIII
-C-N—NI I R16 R17 arba Z gali nebūti;-CN-NI AND 16 R 17 or Z may be absent;
— SO2- N- SO 2 - N
NI I R18 R19 NI AND 18 R 19
O .N R20 R21N .N R22 \\ // -SR6, R7, R9, R10, R11, R12, R13, R14, R15, R16 R17, R18, R19, R20, R21, R22, R24, R25, R26, R27, R28, R29, R30 R31, R32, R33, R34, R35, R36 R37 ir R38 yra pasirinkti iš grupės, susidedančios iš alkilo, arilo arba arilo su pakaitais;O .NR 20 R 21 N. NR 22 \ -S R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 R 31 , R 32 , R 33 , R 34 , R 35 , R 36 R 37 and R 38 is selected from the group consisting of alkyl, aryl or aryl substituted;
R4, R5 yra pasirinkti iš grupės, susidedančios iš vandenilio, halogeno, nitrogrupes, cianogrupes ir U-R23;R 4 , R 5 are selected from the group consisting of hydrogen, halogen, nitro, cyano and UR 23 ;
U yra pasirinktas iš grupės, susidedančios iš sieros, deguonies, NR24, CO, SO, SO2, CO2, NR25CO2, NR26CONR27, NR28SO2, NR29SO2NR30, SO2NR31, NR32CO, CONR33, PO2R34 ir PO3R35 arba U nėra;U is selected from the group consisting of sulfur, oxygen, NR 24 , CO, SO, SO 2, CO2, NR 25 CO 2, NR 26 CONR 27 , NR 28 SO 2, NR 29 SO 2 NR 30 , SO 2 NR 31 , NR 32 CO, CONR 33 , PO2R 34 and PO 3 R 35 or U are absent;
R1, R2 ir R3 yra pasirinkti iš grupės, susidedančios iš vandenilio, alkilo, alkoksikarbonilo, alkilo su pakaitais, alkenilo, alkenilo su pakaitais, alkinilo, alkinilo su pakaitais, aralkilo, cikloalkilo, arilo, arilo su pakaitais, heterociklo, heterociklo su pakaitais, cianogrupes, karboksigrupės, karbamilo (pvz., CONH2) arba karbamilo su pakaitais, pasirinkto iš CONH-alkilas, CONHarilas, CONH-aralkilas, arba turinčio du pakaitus prie azoto atomo, pasirinktus iš alkilo, arilo arba aralkilo;R 1 , R 2 and R 3 are selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, alkenyl substituted, alkynyl, alkynyl substituted, aralkyl, cycloalkyl, aryl, aryl substituted, heterocyclic, heterocyclic substituents, cyano groups, carboxy groups, carbamyl (e.g., CONH 2 ) or carbamyl substituents selected from CONH-alkyl, CONHaryl, CONH-aralkyl, or substituted with two nitrogen atoms selected from alkyl, aryl or aralkyl;
R8 ir R23 yra pasirinkti iš grupės, susidedančios iš vandenilio, alkilo, alkilo su pakaitais, alkenilo, alkenilo su pakaitais, alkinilo, alkinilo su pakaitais, aralkilo, cikloalkilo, arilo, arilo su pakaitais, heterociklo, heterociklo su pakaitais;R 8 and R 23 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkenyl substituted, alkynyl, alkynyl substituted, aralkyl, cycloalkyl, aryl, aryl substituted, heterocyclic, heterocyclic substituted;
bet kurie du iš R1, R2 ir R3 gali būti sujungti tarpusavyje, susidarant cikloalkilo grupei;any two of R 1 , R 2 and R 3 may be joined together to form a cycloalkyl group;
R, S ir T yra pasirinkti iš grupės, susidedančios iš CH2, CO ir CH(CH2)PQ, kurioje Q yra NR36R37, OR38 arba CN; ir A, B, C ir D yra anglis, deguonis, siera arba azotas; su sąlyga, kadR, S and T are selected from the group consisting of CH 2, CO and CH (CH 2 ) P Q wherein Q is NR 36 R 37 , OR 38 or CN; and A, B, C and D are carbon, oxygen, sulfur or nitrogen; provided that
1) kai m yra nulis, V ir W abu negali būti deguonis, arbaWhen m is zero, V and W cannot both be oxygen, or
2) W ir X kartu gali būti deguonis tik tada, jei Z nėra, arba Z yra O, NR10, CHR9,2) W and X together can be oxygen only when Z is absent or Z is O, NR 10 , CHR 9 ,
O — N—C - — N—SO2-O - N - C - - N - SO 2 -
I II I
R14 R15 R 14 R 15
I, II ir V formulėse, o X kartu gali būti deguonis O — N—C - ” — N—SO2- tik tada, jei Y yra O, NR10, CHR9, R14 R15 III ir IV formulėse, arbaIn formulas I, II and V, and X together may be oxygen O - N - C - '- N - SO 2 only if Y is in O, NR 10 , CHR 9 , R 14 R 15 in formulas III and IV, or
3) R23 gali būti vandenilis, išskyrus atvejį, kai U yra SO, SO2, NR25CO2 arba NR28SO2, arba3) R 23 may be hydrogen unless U is SO, SO 2, NR 25 CO2 or NR 28 SO 2 ; or
4) R8 gali būti vandenilis, išskyrus atvejį, kai Z yra SO2, CO2 arba4) R 8 may be hydrogen unless Z is SO 2 , CO 2 or
- N —SO,- N - SO,
O ,NR20 \\ // —S— .O, NR 20 \\ // —S—.
R21 N. N R22 \\ // —S—R 21 N. NR 22 \\ // —S—
R15 R 15
Žemiau duota įvairių terminų, panaudotų šio išradimo aprašyme, apibrėžimai. Šie apibrėžimai taikomi terminams, naudojamiems visame išradimo aprašyme, išskyrus ribotus specifinius atvejus, tiek imant atskirai, tiek ir kaip didesnės grupės dalį.Definitions of the various terms used in the description of the present invention are given below. The following definitions apply to the terms used throughout the specification, except in limited specific cases, either individually or as part of a larger group.
Terminas “alkilas” reiškia tiesiosios arba šakotosios grandinės nepakeistas angliavandenilių grupes, turinčias 1-20 anglies atomų, geriau 1-7 anglies atomus. Išsireiškimas “žemesnysis alkilas” reiškia nepakeistas alkilo grupes, turinčias 1-4 anglies atomus.The term "alkyl" refers to straight or branched chain unsubstituted hydrocarbon groups having from 1 to 20 carbon atoms, preferably from 1 to 7 carbon atoms. The term "lower alkyl" refers to unsubstituted alkyl groups having from 1 to 4 carbon atoms.
Terminas “pakeistas alkilas” reiškia alkilo grupę, kurioje yra, pavyzdžiui, 1-4 pakaitai, tokie kaip halogenas, trifluormetilas, trifluormetoksigrupė, hidroksilas, alkoksigrupė, cikloalkoksigrupė, heterociklooksigrupė, oksogrupė, alkanoilas, ariloksigrupė, alkanoiloksigrupė, aminogrupė, alkilaminogrupė, arilaminogrupė, aralkilaminogrupė, cikloalkilaminogrupė, heterocikloaminogrupė, dipakeisti aminai, kuriuose 2 aminopakaitai yra pasirinkti iš alkilo, arilo arba aralkilo; alkanoilaminogrupė, aroilaminogrupė, aralkanoilaminogrupė, pakeisto alkanoilaminogrupė, pakeisto arilaminogrupė, pakeisto aralkanoilaminogrupė, merkaptogrupė, alkiltiogrupė, ariltiogrupė, aralkiltiogrupė, cikloalkiltiogrupė, hetrociklotiogrupė, alkiltiono grupė, ariltiono grupė, aralkiltiono grupė, alkilsulfoniias, arilsulfonilas, aralkilsulfonilas, sulfonamidogrupė, pvz., SO2NH2, pakeista sulfonamidogrupė, nitrogrupė, cianogrupė, karboksigrupė, karbamilas, pvz., CONH2, pakeistas karbamilas, pvz. CONH-alkilas, CONH-arilas, CONH-aralkilas, arba turintis du pakaitus prie azoto atomo, pasirinktus iš alkilo, arilo arba aralkilo; alkoksikarbonilas, arilas, pakeistas arilas, guanidinogrupė ir heterociklai, tokie kaip indolilas, imidazolilas, furilas, tienilas, tiazolilas, pirolidilas, piridilas, pirimidilas ir pan.The term "substituted alkyl" means an alkyl group containing, for example, 1-4 substituents such as halogen, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocycloxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, aryloxy, amino, , cycloalkylamino, heterocycloamino, disubstituted amines wherein 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoilaminogrupė, substituted alkanoylamino, substituted arylamino, substituted aralkanoilaminogrupė, mercapto, alkylthio, arylthio aralkiltiogrupė, cikloalkiltiogrupė, hetrociklotiogrupė alkylthiono group arylthiono group aralkiltiono group alkilsulfoniias, arylsulfonyl, aralkylsulfonyl sulfonamidogrupė eg., SO 2 NH 2 , substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g., CONH 2 , substituted carbamyl, e.g. CONH-alkyl, CONH-aryl, CONH-aralkyl, or two substituents on a nitrogen atom selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
Kaip minėta aukščiau, jeigu pakaitas dar turi pakaitus, tai jie yra halogenas, alkilas, alkoksigrupė, arilas arba aralkilas.As mentioned above, if the substituent is further substituted, they are halogen, alkyl, alkoxy, aryl or aralkyl.
Terminas “halogenas” arba “Hal” reiškia fluorą, chlorą, bromą ir jodą.The term "halogen" or "Hal" refers to fluorine, chlorine, bromine and iodine.
Terminas “arilas” reiškia monociklinių arba biciklinių aromatinių angliavandenilių grupes, turinčias 6-12 anglies atomų žiede, tokias kaip fenilo, naftilo, bifenilo ir difenilo grupės, ir visose jose gali būti pakaitų.The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having from 6 to 12 carbon atoms in the ring, such as phenyl, naphthyl, biphenyl and diphenyl groups, and may be substituted in all of them.
Terminas “aralkilas” reiškia arilo grupę, prijungtą tiesiogiai per alkilo grupę, tokią kaip benzilas.The term "aralkyl" refers to an aryl group attached directly through an alkyl group such as benzyl.
Terminas “pakeistas arilas” reiškia arilo grupę, kurioje yra, pavyzdžiui,The term "substituted aryl" means an aryl group containing, for example,
1-4 pakaitai, tokie kaip alkilas, pakeistas alkilas, halogenas, trifluormetoksigrupė, trifluormetilas, hidroksilas, alkoksigrupė, cikloalkiloksigrupė, heterociklooksigrupė, alkanoilas, alkanoiloksigrupė, aminogrupė, alkilaminogrupė, aralkilaminogrupė, cikloalkilaminogrupė, heterocikloaminogrupė, dialkilaminogrupė, merkaptogrupė, alkiltiogrupė, cikloalkiltiogrupė alkanoilaminogrupė, hetrociklotiogrupė, ureidogrupė, nitrogrupė, cianogrupė, karboksigrupė, karboksialkilas, karbamilas, alkoksikarbonilas, alkiltionogrupė, ariltionogrupė, alkilsulfonilas, sulfonamidogrupė, ariloksigrupė ir pan. Pakaituose taip pat gali būti pakaitų, tokių kaip halogenas, hidroksilas, alkilas, alkoksigrupė, arilas, pakeistas alkilas arba aralkilas.1-4 substituents, such as alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy cikloalkiloksigrupė, heterociklooksigrupė, alkanoyl, alkanoyloxy, amino, alkylamino aralkilaminogrupė, cikloalkilaminogrupė, heterocikloaminogrupė, dialkylamino, mercapto, alkylthio, alkanoylamino cikloalkiltiogrupė, hetrociklotiogrupė , ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthio, arylthio, alkylsulfonyl, sulfonamido, aryloxy, and the like. The substituents may also be substituted such as halogen, hydroxyl, alkyl, alkoxy, aryl, substituted alkyl or aralkyl.
Terminas “alkenilas reiškia tiesiosios arba šakotosios grandinės angliavandenilių grupes, turinčias 2-20 anglies atomų, geriau 2-15 anglies atomų, ir visų geriausia - 2-8 anglies atomus, turinčias 1-4 dvigubas jungtis.The term "alkenyl" means straight or branched chain hydrocarbon groups having from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, and most preferably from 2 to 8 carbon atoms having from 1 to 4 double bonds.
Terminas “pakeistas alkenilas reiškia alkenilo grupę, kurioje yra, pavyzdžiui, 1-2 pakaitai, tokie kaip halogenas, hidroksilas, alkoksigrupė, alkanoilas, alkanoiloksigrupė, aminogrupė, alkilaminogrupę, dialkilaminogrupė, alkanoilaminogrupė, merkaptogrupė, alkiltiogrupę, alkiltionogrupė, alkilsulfonilas, sulfonamidogrupė, nitrogrupę, cianogrupė, karboksigrupė, karbamilas, pakeistas karbamilas, guanidinogrupė ir hetetociklinė grupė, pvz., indolilas, imidazolilas, furilas, tienilas, tiazolilas, pirolidilas, piridilas, pirimidilas ir pan.The term "substituted alkenyl" means an alkenyl group containing, for example, 1-2 substituents, such as halogen, hydroxyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, mercapto, alkylthio, alkylthio, alkylthio, alkylthio, a cyano group, a carboxy group, a carbamyl, a substituted carbamyl, a guanidino group and a heterocyclic group such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
Terminas “alkinilas reiškia tiesiosios arba šakotosios grandinės angliavandenilių grupes, turinčias 2-20 anglies atomų, geriau 2-15 anglies atomų, ir visų geriausia - 2-8 anglies atomus, turinčias 1-4 trigubas jungtis.The term "alkynyl" refers to straight or branched chain hydrocarbon groups having from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, and most preferably from 2 to 8 carbon atoms having from 1 to 4 triple bonds.
Terminas “pakeistas alkinilas reiškia alkinilo grupę, kurioje yra, pavyzdžiui, pakaitas, toks kaip halogenas, hidroksilas, alkoksigrupė, alkanoilas, alkanoiloksigrupė, aminogrupė, alkilaminogrupę, dialkilaminogrupė, alkanoilaminogrupė, merkaptogrupė, alkiltiogrupę, alkiltionogrupė, alkilsulfonilas, sulfonamidogrupė, nitrogrupę, cianogrupė, karboksigrupė, karbamilas, pakeistas karbamilas, guanidinogrupė ir hetetociklinė grupė, pvz., imidazolilas, furilas, tienilas, tiazolilas, pirolidilas, piridilas, pirimidilas ir pan.The term "substituted alkynyl" means an alkynyl group containing, for example, a substituent such as halogen, hydroxyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, mercapto, alkylthio, alkylthiono, alkylthio, , carbamyl, substituted carbamyl, guanidino, and a heterocyclic group such as imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
Terminas “cikloalkilas” reiškia sočių ciklinių angliavandenilių žiedų sistemas, geriausia turinčias 1-3 žiedus ir 3-7 anglies atomus viename žiede, kurios gali būti kondensuotos su nesočių C3-C7 karbocikliniu žiedu, kuriose gali būti pakaitų. Tokių grupių pavyzdžiais yra ciklopropilas, ciklobutilas, ciklopentilas, cikloheksilas, cikloheptilas, ciklooktilas, ciklodecilas, ciklododecilas ir adamantilas. Pakaitų pavyzdžiais yra viena arba daugiau alklio grupių, kurios aprašytos aukščiau, arba viena arba daugiau aukščiau aprašytų grupių, kaip pakaitų alkilo grupėje.The term "cycloalkyl" refers to saturated cyclic hydrocarbon ring systems, preferably having 1 to 3 rings and 3 to 7 carbon atoms per ring, which may be fused to an unsaturated C 3 -C 7 carbocyclic ring which may be substituted. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more alkyl groups as described above or one or more of the groups described above as alkyl substituents.
Terminai “heterociklas, “heterociklinis” ir “heterociklo-” reiškia pilnai sočią arba nesočią, aromatinę arba nearomatinę ciklinę grupę, pavyzdžiui, kuri yra 4-7-narė monociklinė, 7-11-narė biciklinė arba 10-15-narė triciklinė žiedų sistema, kurioje yra bent vienas heteroatomas bent vieną anglies atomą turinčiame žiede, ir joje gali būti pakaitų. Kiekviename heteroatomą turinčios heterociklines grupės žiede gali būti 1, 2, 3 arba 4 heteroatomai, pasirinkti iš azoto atomų, deguonies atomų ir sieros atomų, ir, esant reikalui, azoto bei sieros heteroatomai gali būti oksidinti, o azoto heteroatomai gali būti kvaternizuoti. Heterociklinė grupė gali būti prijungta prie bet kurio heteroatomo arba anglies atomo.The terms "heterocycle," heterocyclic, "and" heterocyclo "refer to a fully saturated or unsaturated, aromatic or non-aromatic cyclic group, such as a 4-7 membered monocyclic, 7-11 membered bicyclic, or 10-15 membered tricyclic ring system. containing at least one heteroatom in the ring containing at least one carbon atom and optionally substituted. Each heteroatom-containing heterocyclic ring may contain 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally nitrogen and sulfur heteroatoms may be oxidized and nitrogen heteroatoms may be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom.
Monociklinių heterociklinių grupių pavyzdžiais yra pirolidinilas, pirolilas, indolilas, pirazolilas, oksetanilas, pirazolinilas, imidazolilas, imidazolinilas, imidazolidinilas, oksazolilas, oksazolidinilas, izoksazolinilas, izoksazolilas, tiazolilas, tiadiazolilas, tiazolidinilas, izotiazolilas, izotiazolidinilas, furilas, tetrahidrofurilas, tienilas, oksadiazolilas, piperidinilas, piperazinilas, 2-oksopiperazinilas, 2-oksopiperidinilas, 2-oksopirolidinilas, 2oksazepinilas, azepinilas, 4-piperidonilas, piridilas, N-oksopiridilas, pirazinilas, pirimidinilas, piridazinilas, tetrahidrotiopiranilas, tetrahidropiranilas, morfolinilas, tiamorfolinilas, tiamorfolinilsulfoksidas, tetrahidrotiopiranilsulfonas, tiamorfolinilsufonas, 1,3-dioksolanas ir tetrahidro1,1 -dioksotienilas, dioksanilas, izotiazolidinilas, tietanilas, tiiranilas, triazinilas ir triazolilas ir pan.Examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolinyl, oxetanyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolyl , piperazinyl, 2-oxopiperazinyl, 2-oxopyrrolidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxopyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, monomer, , 3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiranyl, triazinyl and triazolyl and the like.
Biciklinių heterociklinių grupių pavyzdžiais yra benzotiazolilas, benzoksazolilas, benzotienilas, chinuklidinilas, chinolinilas, chinolinil-Noksidas, tetrahidroizochinolinilas, izochinolinilas, benzimidazolilas, benzopiranilas, indolizinilas, benzofurilas, chromonilas, kumarinilas, cinolinilas, chinoksalinilas, indazolilas, pirolopiridilas, furopiridinilas (toks kaip furo[2,3-c]piridinilas, furo[3,1 -bjpiridinilas arba furo[2,3-b]piridinilas), dihidroizoindolilas, dihidrochinazolinilas (toks kaip 3,4-dihidro-4oksochinazolinilas), benzizotiazolilas, benzizoksazolilas, benzodiazinilas, benzofurazanilas, benzotiopiranilas, benzotriazolifas, benzpirazolilas, dihidrobenzofurilas, dihidrobenzotienilas, dihidrobenzotiopiranilas, dihidrobenzotiopiranilsulfonas, dihidrobenzopiranilas, indolinilas, izochromanilas, izoindolinilas, naftiridinilas, ftalazinilas, piperonilas, purinilas, piridopiridilas, chinazolinilas, tetrahidrochinolinilas, tienofurilas, tienopiridilas, tienotienilas ir pan.Examples of bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, coumarinyl, coumarinol, , 3-c] pyridinyl, furo [3,1-b] pyridinyl or furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, , benzotriazolif, benzpyrazolyl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purine.
Pakaitų pavyzdžiais yra viena arba daugiau alklio grupių, kurios aprašytos aukščiau, arba viena arba daugiau aukščiau aprašytų grupių, kaip pakaitų alkilo grupėje.Exemplary substituents include one or more alkyl groups as described above or one or more of the groups described above as alkyl substituents.
Taip pat įeina mažesnieji heterociklai, tokie kaip epoksidai ir aziridinai.Also included are smaller heterocycles such as epoxides and aziridines.
Terminas “heteroatomai apima deguonį, sirą ir azotą.The term "heteroatoms" includes oxygen, sir and nitrogen.
“ABC” žiedas ir “ABCD kondensuotas žiedas su diazepino žiedu gali būti monociklinis arba biciklinis, pvz. naftilo arba chinolilo prigimties.The ABC ring and the ABCD fused ring with diazepine ring can be monocyclic or bicyclic, e.g. of naphthyl or quinolyl nature.
I-IV formulių junginiai gali sudaryti druskas, kurias taip pat apima šis išradimas. Pirmenybė teikiama farmaciškai tinkamoms (t.y. netoksiškoms, fiziologiškai priimtinoms) druskoms, nors taip pat naudingos yra ir kitos druskos, pvz. išskiriant arba gryninant šio išradimo junginius.The compounds of formulas I-IV may form salts which are also encompassed by the present invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts, e.g. isolating or purifying the compounds of the present invention.
I-IV formulių junginiai gali sudaryti druskas su šarminiais metalais, tokiais kaip natris, kalis ir litis, su žemės šarminiais metalais, tokiais kaip kalcis ir magnis, su organinėmis bazėmis, tokiomis kaip dicikloheksilaminas, tributilaminas, piridinas, ir aminorūgštimis, tokiomis kaip argininas, lizinas ir pan. Tokias druskas galima gauti, pavyzdžiui, pakeičiant I-IV junginiuose karboksirūgšties protonus (jeigu yra karboksirūgštis) norimu jonu terpėje, kurioje druska iškrenta j nuosėdas, arba vandeninėje terpėje, o po to nugarinant vandenį. Kitas druskas galima gauti šios srities specialistams žinomais būdais.The compounds of formulas I-IV may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine, and amino acids such as arginine, lysine and so on. Such salts may be obtained, for example, by substitution of the protons of the carboxylic acid (if present in a carboxylic acid) with the desired ion in the precipitating medium or in aqueous medium, followed by evaporation of the water. Other salts may be obtained by methods known to those skilled in the art.
I-IV formulių junginiai gali sudaryti druskas su įvairiomis organinėmis ir neorganinėmis rūgštimis. Tokios druskos apima druskas, sudarytas su vandenilio chloridu, hidroksimetansulfonrūgštimi, vandenilio bromidu, metansulfonrūgštimi, sulfato rūgštimi, acto rūgštimi, trifluoracto rūgštimi, maleino rūgštimi, benzensulfonrūgštimi, toluensulfonrūgštimi ir įvairiomis kitomis (pvz., nitratus, fosfatus, boratus, tartratus, citratus, sukcinatus, benzoatus, askorbatus, salicilatus ir pan.). Tokias druskas galima gauti, veikiant I-IV junginius ekvivalentiniu kiekiu rūgšties terpėje, kurioje druska iškrenta j nuosėdas, arba vandeninėje terpėje, o po to nugarinant vandenį.The compounds of formulas I-IV may form salts with various organic and inorganic acids. Such salts include salts formed with hydrochloric, hydroxymethanesulfonic, hydrobromic, methanesulfonic, sulfuric, acetic, trifluoro-acetic, maleic, benzenesulfonic, toluenesulfonic, and citrates, tartrates, , benzoates, ascorbates, salicylates, etc.). Such salts may be obtained by treating compounds I-IV with an equivalent amount of the acid in which the salt is deposited, or in aqueous medium, followed by evaporation of the water.
Be to, gali būti gauti cviterjonai (“vidinės druskos“).In addition, zwitterions ("inner salts") may be obtained.
I-IV formulių junginiai taip pat gali turėti provaisto formas. Bet koks junginys, kuris in vivo gali pavirsti bioaktyviu agentu (t.y. I-IV formulių junginiu) yra provaistas, kurį taip pat apima šis išradimas.The compounds of formulas I-IV may also have prodrug forms. Any compound that can be converted in vivo to a bioactive agent (i.e., a compound of formulas I-IV) is a prodrug also encompassed by the present invention.
Pavyzdžiui, I-IV formulių junginiuose gali būti karboksirūgšties esterio grupė. Karboksirūgšties esteris gali būti patogiai gaunamas, esterinant bet kokią karboksirūgšties funkcinę grupę, esančią aprašytoje žiedinėje struktūroje(se).For example, the compounds of formulas I-IV may contain a carboxylic acid ester group. The carboxylic acid ester may conveniently be obtained by esterification of any carboxylic acid functional group present in the described ring structure (s).
įvairios provaistų formos yra gerai žinomos specialistams. Tokių provaistinių darinių pavyzdžius galima rasti:various forms of prodrugs are well known to those skilled in the art. Examples of such prodrug derivatives include:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) ir Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et ai., (Academic Press, 1985);a) Design of Prodrugs edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et al., (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by KrosgaardLarsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs”, by H. Bundgaard, p. 113-191 (1991);b) A Textbook of Drug Design and Development, edited by KrosgaardLarsen and H. Bundgaard, Chapter 5, Design and Application of Prodrugs, by H. Bundgaard, p. 113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Revievvs, 8, 1-38 (1992);c) H. Bundgaard, Advanced Drug Delivery Revision, 8, 1-38 (1992);
d) H. Bundgaard, et ai., Journal of Pharmaceutical Sciences, 77, 285 (1988); ird) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and
e) N. Kakeya, et ai., Chem. Phar. Bull., 32, 692 (1984),e) N. Kakeya, et al., Chem. Phar. Bull., 32, 692 (1984),
Be to, turi būti suprantama, kad I-IV formulių junginių solvatai (pvz. hidratai) taip pat Įeina i šį išradimą. Solvatų pagaminimo metodai yra žinomi specialistams.In addition, it should be understood that solvates (e.g. hydrates) of the compounds of formulas I-IV are also encompassed by the present invention. Methods for the preparation of solvates are known to those skilled in the art.
Pageidautinos grupėsPreferred groups
Šio išradimo junginiuose pirmenybė yra teikiama tokioms grupėms:Within the compounds of the present invention, the following groups are preferred:
I, II, II ir IV formulių junginiai, kuriuose m yra nulis.Compounds of formulas I, II, II and IV wherein m is zero.
Dar tinkamesni yra I, II, II ir IV formulių junginiai, kuriuose m yra nulis, o n yra vienetas.More preferred are compounds of formulas I, II, II and IV wherein m is zero and n is a unit.
Labiausiai tinkami yra I formulės junginiai, kuriuose m, r, s ir t yra nulis, n yra vienetas, o ABCD yra karbociklinis žiedas, pvz. benzo-žiedas.Most preferred are compounds of formula I wherein m, r, s and t are zero, n is a unit, and ABCD is a carbocyclic ring, e.g. benzo-ring.
Naudingumas ir panaudojimasUtility and utilization
I-IV formulių junginiai yra S-farnezilproteintransferazės inhibitoriai. Todėl jie tinka įvairių vėžio formų gydymui, įskaitant (bet neapsiribojant) tokias:The compounds of formulas I-IV are inhibitors of S-farnesyl protein transferase. Therefore, they are suitable for the treatment of various cancers, including but not limited to:
karcinomą, įskaitant šlapimo, pūslės, krūties, storosios žarnos, inkstų, kepenų, plaučių (Įskaitant mažųjų ląstelių plaučių vėžį), kiaušidžių, prostatos, sėklidžių, kasos, stemplės, skrandžio, tulžies pūslės, kaklo, skydliaukės ir odos (įskaitant žvyninių suregėjusių ląstelių) karcinomą:carcinoma including urinary, bladder, breast, colon, kidney, liver, lung (Including small cell lung cancer), ovarian, prostate, testicular, pancreas, esophagus, stomach, gall bladder, neck, thyroid and skin (including scaly cortex) ) carcinoma:
limfoidinės prigimties hematopoetinius auglius, įskaitant leukemiją, ūmią limfocitinę leukemiją, ūmią limfoblastinę leukemiją, B-ląstelių limfomą, Tląstelių limfomą, Hodkino limfomą, ne Hodkino limfomą, gauruotųjų ląstelių limfomą ir Burketo limfomą;lymphoid haematopoietic tumors including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, non-Hodkin lymphoma, squamous cell lymphoma, and Burkett's lymphoma;
mielininės prigimties hematopoetinius auglius, įskaitant ūmią ir chronišką mielogenines leukemijas, mielodisplastinį sindromą ir promielocitinę leukemiją;hematopoietic tumors of the myelinic nature, including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia;
centrinės ir periferinės nervų sistemos auglius, įskaitant astrocitomą, neuroblastomą, gliomą ir švanomas;tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwanoma;
mezenchiminės kilmės auglius, įskaitant fibrosarkomą, rabdomiosarkomą ir osteosarkomą;tumors of mesenchymal origin, including fibrosarcoma, rhabdomyosarcoma and osteosarcoma;
kitus auglius, įskaitant melanomą, pigmentinę ksenodermiją, keratoaktantomą, seminomą, skydliaukės foliku'ių vėžį ir teratokarcinomą.other tumors including melanoma, xenoderma pigmentation, keratoactantoma, seminoma, thyroid follicular cancer and teratocarcinoma.
I-IV formulių junginiai ypatingai tinka gydymui auglių, kuriuose randasi didelis kiekis ras, tokių kaip storosios žarnos, plaučių ir kasos augliai, ir auglių, kuriuose į auglio išsilaikymą, auglio augimą arba auglio vystymąsi įnašą duoda preniltransferazė. Vartojant kompoziciją, kurioje yra vienas (arba kombinacija) šio išradimo junginių, sumažinamas auglio vystymasis, sumažinama auglio masė arba sukeliama auglio regresija.The compounds of formulas I-IV are particularly suitable for the treatment of tumors with a high content of ras, such as colon, lung and pancreatic tumors, and tumors in which prenyltransferase contributes to tumor survival, tumor growth or tumor development. Administration of a composition comprising one (or a combination) of the compounds of the present invention reduces tumor growth, reduces tumor mass, or causes tumor regression.
I-IV formulių junginiai taip pat gali inhibuoti auglio angiogenezę, ir taip paveikti auglio augimą. Tokios I-IV formulių junginių priešangiogenezinės savybės taip pat gali būti naudingos gydant tam tikras aklumo formas, susijusias su tinklainės vaskuliarizacija.The compounds of formulas I-IV may also inhibit tumor angiogenesis and thus affect tumor growth. Such anti-angiogenic properties of the compounds of Formulas I-IV may also be useful in the treatment of certain forms of blindness associated with retinal vascularization.
I-IV formulių junginiai taip pat gali būti tinkami nevažinių susirgimų, kurie gali būti susiję su signalo perdavimo keliais per ras, pvz., neurofibromatozės, aterosklerozės, plaučių fibrozės, artrito, psoriazės, glomerulonefrito, restenozės po angioplastikos arba kraujagyslių chirurgijos, hipertrofinio rando susidarymo, policistinės inkstų ligos ir endotoksinio šoko, gydymui. I-IV formulių junginiai taip pat gali būti naudingi kaip priešgrybeliniai agentai.Compounds of Formulas I-IV may also be useful in non-malignant disorders that may be involved in signal transduction pathways such as neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation. , polycystic kidney disease and endotoxic shock. The compounds of formulas I-IV may also be useful as antifungal agents.
I-IV formulių junginiai gali sukelti arba inhibuoti apoptozę - fiziologini ląstelių žuvimo procesą, kuris turi kritinę reikšmę normaliam vystymuisi ir homeostazei. Apoptozinių kelių pokyčiai duoda jnašą j jvairių žmogaus ligų patogenezę. I-IV formulių junginiai, kaip apoptozės moduliatoriai, bus naudingi gydant įvairias žmonių ligas, susijusias su apoptozės nukrypimais, įskaitant vėžį (konkrečiau, bet tuo neapsiribojant, folikulines limfomas, karcinomas su p53 mutacijomis, priklausančius nuo hormonų krūties, prostatos ir kiaušidžių auglius, ir priešvėžinius pažeidimus, tokius kaip paprastąją adenominę polipozę), virusines infekcijas (įskaitant, bet neapsiribojant, herpeso virusą, raupų virusą, Epštieno-Baro virusą, Sindbis’o virusą ir adenovirusą), autoimunines ligas (įskaitant, bet neapsiribojant, sisteminę raudonąją vilkligę, imuninį glomerulonefritą, reumatinį artritą, psoriazę, uždegimines žarnyno ligas ir autoimuninį cukrinį diabetą), neurodegeneracinius sutrikimus (įskaitant, bet neapsiribojant, Alchaimerio ligą, su AIDS susijusią demenciją, Parkinsono ligą, amiotrofinę lateralinę sklerozę, pigmentinį retinitą, nugaros raumenų atrofiją ir susijusį su smegenėlėmis išsigimimą), AIDS, mielodisplastinius sindromus, hipoplazinę anemiją, susijusius su išeminiais pažeidimais miokardo infarktus, insultą ir reperfuzinj pažeidimą, aritmiją, aterosklerozę, sukeltas toksinų arba alkoholio kepenų ligas, hematologines ligas (įskaitant, bet neapsiribojant, chronišką anemiją ir hipoplazinę anemiją), kaulų-raumenų sistemos degeneracines ligas (įskaitant, bet neapsiribojant, osteoporozę ir artritą), aspirinui jautrų rinosinusitą, cistinę fibrozę, išsėtinę sklerozę, inkstų ligas, ir vėžinį skausmą.Compounds of formulas I-IV can induce or inhibit apoptosis, a physiological process of cell death that is critical to normal development and homeostasis. Changes in the apoptotic pathways contribute to the pathogenesis of various human diseases. Compounds of Formulas I-IV, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases associated with apoptosis abnormalities, including cancer (more specifically, but not limited to follicular lymphomas, carcinomas with p53, hormone-dependent breast, prostate and ovarian tumors), and antitumor lesions such as plain adenomatous polyposis, viral infections (including, but not limited to, herpes virus, smallpox virus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including but not limited to systemic lupus erythematosus, glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus, neurodegenerative disorders (including, but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, nuggetic retinitis, pigmentosa) cerebellar degeneration), AIDS, myelodysplastic syndromes, hypoplastic anemia associated with ischemic lesions myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin or alcoholic liver disease, hematologic anemia (including but not limited to) musculoskeletal degenerative diseases (including, but not limited to, osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.
I-IV formulių junginiai taip pat gali būti tinkami gydant ligas, susijusias su farneziltransferazės substratais, kitokiais nei ras (pvz., branduolio laminais, transducinu, rodopsinkinaze, cGMP fosfodiesteraze, TC21, fosforilkinaze, Rap2, RhoB, RhoE, PRL1), kuriuos taip pat po transliacijos modifikuoja fermentas farnezilproteintransferazę.Compounds of formulas I-IV may also be useful in the treatment of diseases involving farnesyltransferase substrates other than ras (e.g., nuclear laminates, transducin, rhodopsin kinase, cGMP phosphodiesterase, TC21, phosphoryl kinase, Rap2, RhoB, RhoE, PRL1). shortly after translation, it modifies farnesyl protein transferase enzyme.
I-IV formulių junginiai taip pat gali veikti kaip kitų preniltransferazių (pvz., geranilgeraniltransferazės I ir II) inhibitoriai, ir todėl jie gali būti efektyvūs gydant ligas, susijusias su kitomis baltymų (pvz. rap, rab, rac ir rho genų produktų ir pan.) prenil-modifikacijomis (pvz., geranilgeranilinimas). Pavyzdžiui, jie gali rasti pritaikymą kaip vaistai prieš hepatito delta viruso (HDV) infekcijas, kuris seka iš neseniai gautų duomenų, kad produktyviai virusinei infekcijai yra reikalingas HDV delta antigeno didžiosios izoformos geranilgeranilinimas [J. S. Glen, et ai., Science, 256, 1331 (1992)].The compounds of formulas I-IV may also act as inhibitors of other prenyltransferases (e.g., geranylgeranyltransferase I and II) and therefore may be effective in the treatment of diseases associated with other protein (e.g., rap, rab, rac and rho gene products, etc.). .) prenyl modifications (e.g., geranylgeranylation). For example, they may find application as drugs against hepatitis delta virus (HDV) infections, which follows recent data that geranylgeranylation of the major isoform of HDV delta antigen is required for productive viral infection [J. S. Glen, et al., Science, 256: 1331 (1992)].
Šio išradimo junginiai taip pat gali būti naudingi kombinacijoje su gerai žinomais priešvėžiniais ir citotoksiniais agentais ir gydymo būdais, įskaitant radioterapiją. Jeigu vaisto forma yra dozuota, tokiose kombinacijose šio išradimo junginiai naudojami žemiau nurodytomis dozėmis, o kitas farmaciškai aktyvus agentas naudojamas jo įprastų dozių intervale. I-IV formulių junginiai gali būti naudojami pakaitomis su žinomais priešvėžiniais arba citotoksiniais agentais ir kitais gydymo būdais, įskaitant radioterapiją, jeigu kombinacijos vaisto forma yra nepakankamai veikli.The compounds of the present invention may also be useful in combination with well-known anticancer and cytotoxic agents and treatments, including radiotherapy. When the dosage form is in a dosage form, the combinations of the present invention are used in the following dosage regimens, and the other pharmaceutically active agent is used within its usual dosage range. The compounds of formulas I-IV may be used alternately with known anti-cancer or cytotoxic agents and other therapies, including radiotherapy, if the combination formulation is insufficiently active.
Tyrimai su farneziltransferaze buvo atlikti pagal V. Manne et ai., Drug Development Research, 34, 121-137 (1995). 1-431 pavyzdžiuose aprašyti junginiai inhibavo farneziltransferazę, ir jų IC5o reikšmės yra 0,1 nM - 100 μΜ ribose.Farnesyltransferase assays were performed according to V. Manne et al., Drug Development Research, 34, 121-137 (1995). The compounds described in Examples 1-431 inhibited farnesyltransferase and have IC 50 values in the range of 0.1 nM to 100 μΜ.
Šio išradimo junginių vaistų formos gali būti gaminamos su farmaciniu tirpikliu arba skiedikliu ir skiriamos peroraliniam, intraveniniam, intraperitoniniam, poodiniam, intraabdominaliniam, intraraumeniniam, rektaliniam, vaginaliniam arba vietiniam vartojimui.. Peroralinio vartojimo formose gali būti panaudojamos vaisto lėto išsiskyrimo receptūros, tokios kaip bioskaldomi polimerai arba provaistai. Farmacinės kompozicijos gali būti paverčiamos vaisto formomis klasikiniu būdu, naudojant kietus arba skystus tirpiklius, skiediklius ir priedus, tinkančius norimam vartojimo būdui. Peroraiiniu būdu junginiai gali būti vartojami tablečių, kapsulių, granulių, miltelių ir pan. vaisto formoje. Šie junginiai gali būti skiriami 0,05-200 mg/kg/per dieną dozėmis, geriau mažesnėmis nei 100 mg/kg/per dieną dozėmis, kaip vienkartinė dozė arba kaip į 2-4 dalis padalinta dozė.Dosage forms of the compounds of the present invention may be formulated with a pharmaceutical solvent or diluent for oral, intravenous, intraperitoneal, subcutaneous, intra-abdominal, intravenous, rectal, vaginal or topical administration. For oral administration, slow-release formulations such as biosc or prodrugs. Pharmaceutical compositions may be formulated in a classical manner using solid or liquid solvents, diluents, and additives suitable for the intended route of administration. The compounds may be administered orally in the form of tablets, capsules, granules, powders, and the like. in drug form. These compounds may be administered at a dose of 0.05-200 mg / kg / day, preferably less than 100 mg / kg / day, as a single dose or as a divided dose in 2 to 4 doses.
Gavimo būdasMethod of obtaining
Z, = CO, SO2, CO2, CONR5, SO3, SO2NR5i C(NCN)NR5 stadijaZ, = CO, SO 2 , CO 2 , CONR 5 , SO 3 , SO 2 NR 5i C (NCN) NR 5 Stage
Pirmoji stadija atliekama, veikiant antranilo rūgštį fosgeno, tokio kaip fosgenas arba trifosgenas, ekvivalentu vandens ir organinio tirpiklio mišinyje nuo kambario temperatūros iki 50 °C.The first step is carried out by treating anthranilic acid with an equivalent of phosgene such as phosgene or triphosgene in a water-organic solvent mixture at room temperature to 50 ° C.
stadijastage
Produktas veikiamas aminorūgšties hidrochloridu arba aminorūgšties esterio hidrochloridu piridine aukštesnėje temperatūroje, pageidautina virinant su grįžtamu šaldytuvu. 1 schemos 2 stadija gali būti atliekama per dvi stadijas: izatoinės rūgšties anhidridas kondensuojamas su aminorūgštimi organiniame tirpiklyje, tokiame kaip piridinas, nuo 0 °C iki virimo temperatūros, ir gaura antraniloilaminorūgštis ciklinama standartinėse amidinio ryšio susidarymo sąlygose, pvz., panaudojant HOBt/karbodiimidą organiniame tirpiklyje, tokiame kaip DMF, nuo 0 °C iki kambario temperatūros. Kai kurių 1 schemos junginių 1, kuriuose Ri = halogenas, prekyboje nėra. Tokius 1 schemos junginius 3, 4 arba 5, kuriuose Ri = halogenas, galima pagaminti iš 1 schemos junginių 3, 4 arba 5, kuriuose Ri = vandenilis, juos halogeninant, pavyzdžiui, veikiant bromu organiniame tirpiklyje, tokiame kaip acto rūgštis, nuo 0 °C iki kambario temperatūros. Junginys 3, kuriame Ri yra arilas arba heteroarilas, gali būti pagaminamas iš junginio 3, kuriame Ri yra bromas, jodas arba trifluormetansulfoniloksigrupė, panaudojant paladžio katalizuojamą kopuliavimą su arilo arba heteroarilo metaloido dariniu, tokiu kaip fenilboro rūgštimi, vandens ir organinio tirpiklio mišinyje, pvz. THF/DMF/vanduo, esant bazei, pvz., natrio karbonatui, nuo kambario temperatūros iki 90 °C. (Kitu atveju, 1 schemos junginys, kuriame Ri = arilas arba heteroarilas, yra taip pat pagaminamas iš 5 schemos junginio 2, kuriame Rt yra bromas, jodas arba trifluormetansulfoniloksigrupė, veikiant arilmetaloido dariniu, tokiu kaip fenilboro rūgštimi arba tributilstanilpiridinu, deoksigenintame organiniame tirpiklyje (pvz. THF) arba vandens ir organinio tirpiklio sistemoje, tokioje kaip NaHCO3/toluenas, esant paladžio katalizatoriui, tokiam kaip tetrakis(trifenilfosfin)paladis, nuo kambario temperatūros iki 100 °C. Deblokavus gaunamas norimas junginys). Kitu atveju, toks Suzuki arba Stille kopuliavimas gali būti atliekamas su 1 schemos junginiu 1, arba 1 schemos junginiu 4, arba 1 schemos junginiu 5, kuriuose neacilintas benzodiazepino azotas gali būti blokuojamas, pvz. trifluoracetilo grupe, o po to deblokuojamas. Junginys 3, kuriame Rt yra alkoksigrupė, yra pagaminamas alkilinant atitinkamą hidroksijunginj standartinėmis sąlygomis. Junginys 3, kuriame Rį yra alkilaminoalkiiarilas, yra pagaminamas iš junginio 3, kuriame Rį yra arilaldehidas, redukcinio amininimo būdu standartinėmis sąlygomis.The product is treated with amino acid hydrochloride or amino acid ester hydrochloride pyridine at elevated temperature, preferably refluxing. Step 2 of Scheme 1 can be carried out in two steps: condensation of the isatoic acid anhydride with an amino acid in an organic solvent such as pyridine from 0 ° C to reflux, and the gaura anthranoylamino acid is cyclized under standard amide bond conditions such as HOBt / carbodiimide in a solvent such as DMF from 0 ° C to room temperature. Some of the compounds of Scheme 1 in which Ri = halogen are not commercially available. Compounds 3, 4 or 5 of Scheme 1 wherein Ri = halogen can be prepared from compounds 3, 4 or 5 of Scheme 1 where Ri = hydrogen by halogenation, for example by treatment with bromine in an organic solvent such as acetic acid, from 0 °. C to room temperature. Compound 3 wherein R 1 is aryl or heteroaryl may be prepared from compound 3 wherein R 1 is bromo, iodo or trifluoromethanesulfonyloxy by palladium-catalyzed copulation with an aryl or heteroaryl metalloid derivative such as phenylboronic acid in a mixture of water and an organic solvent, e.g. THF / DMF / water in the presence of a base such as sodium carbonate, from room temperature to 90 ° C. (Alternatively, the compound of Scheme 1 in which R 1 = aryl or heteroaryl is also prepared from the compound of Scheme 5 in which Rt is bromo, iodo or trifluoromethanesulfonyloxy, in a deoxygenated organic solvent (e.g., phenylboronic acid or tributylstanylpyridine). THF) or in a water-organic solvent system such as NaHCO 3 / toluene in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium, from room temperature to 100 ° C. Alternatively, such Suzuki or Stille copulation may be performed with Scheme 1 Compound 1, or Scheme 1 Compound 4, or Scheme 1 Compound 5, wherein the unacylated benzodiazepine nitrogen may be blocked, e.g. trifluoroacetyl group and then deprotected. Compound 3, wherein Rt is an alkoxy group, is prepared by alkylation of the corresponding hydroxy linker under standard conditions. Compound 3 wherein R 1 is alkylaminoalkyl aryl is prepared from reductive amination of compound 3 where R 1 is arylaldehyde under standard conditions.
stadijastage
Po to junginys 3 yra veikiamas redukuojančiu agentu, tokiu kaip ličio aliuminio hidridas arba boranas, inertiniame tirpiklyje, tokiame kaip tetrahidrofuranas, nuo kambario temperatūros iki tirpiklio virimo temperatūros. Jeigu R, arba R2 yra funkcinės grupės, pvz. CO2R, kurias redukuoja, pvz. ličio aliuminio hidridas iki, pvz. CH2OH, tokios grupės bus redukuojamos 3 stadijoje. Junginys 4 arba 6, kuriuose Rį yra CN, gali būti pagaminamas iš junginio 4 arba 6, kuriuose Rį = halogenas, mainų reakcijoje su CuCN inertiniame tirpiklyje, tokiame kaip NMP, aukštesnėje temperatūroje. Junginys 4, kuriame Rį yra CO2H, gali būti pagaminamas iš junginio 4, kuriame Rį = CN, hidrolizės būdu, pvz. šildant su vandeniniu natrio hidroksidų tinkamame tirpiklyje, tokiame kaip etanolis, 100 0 temperatūroje; po to, produktas, kuriame Rį = CONRsRe, gali būti pagaminamas standartinėmis amidinio ryšio gavimo sąlygomis.Compound 3 is then treated with a reducing agent such as lithium aluminum hydride or borane in an inert solvent such as tetrahydrofuran from room temperature to the boiling point of the solvent. If R, or R 2 is a functional group, e.g. CO 2 R which is reduced, e.g. lithium aluminum hydride up to, e.g. CH 2 OH, such groups will be reduced in step 3. Compound 4 or 6, wherein R 1 is CN, can be prepared from compound 4 or 6, where R 1 = halogen, by exchange reaction with CuCN in an inert solvent such as NMP at elevated temperature. Compound 4, wherein R 1 is CO 2 H, can be prepared from hydrolysis of compound 4, wherein R 1 = CN, e.g. heating with aqueous sodium hydroxide in a suitable solvent such as ethanol at 100 ° C; thereafter, the product wherein R R = CONRsRe can be prepared under standard amide bond conditions.
stadijastage
Po to produktas acilinamas arba sulfonilinamas standartinėmis sąlygomis nuo -78 °C iki kambario temperatūros (pvz. veikiant rūgšties halogenanhidridu R3COX, kur X yra Cl arba Br, inertiniame organiniame tirpiklyje, pvz. acetonitrile, arba vandens ir organinio tirpiklio mišinyje, pvz. NaOH/dichloretane; veikiant O-fenilesteriu inertiniame organiniame tirpiklyje, pvz. acetonitrile; veikiant karboksirūgštimi, esant kopuliavimo agentui, pvz. DCC arba EDC, inertiniame organiniame tirpiklyje, tokiame kaip DMF; veikiant halogenformiatu, tokiu kaip etil-, izopropil- arba 4-nitrofenilchlorformiatas, inertiniame organiniame tirpiklyje, tokiame kaip dichlormetanas, nuo 0 °C iki kambario temperatūros, jeigu reikia, esant bazei, tokiai kaip diizopropiletilaminas, susidarant karbamatams, ir kai kurie iš jų, pvz. 4-nitrofeniikarbamatas, veikiami aminu, pvz. Ν,Ν,Ν’-trimetiletilendiaminu, nuo kambario temperatūros iki 110 °C, susidarant karbamidams; veikiant karboksirūgšties anhidridu arba sulfonilanhidridu, tokiu kaip gintaro rūgšties anhidridas arba trifluormetansulfonilanhidridas, inertiniame tirpiklyje, tokiame kaip etilacetatas, dichlormetanas arba piridinas, nuo 0 °C iki kambario temperatūros, jeigu reikia, esant bazei, tokiai kaip diizopropilaminas; veikiant izocianatu inertiniame tirpiklyje, tokiame kaip THF; veikiant karbamilchloridu R5R6NCOX, kur X yra Cl arba Br, inertiniame tirpiklyje, tokiame kaip acetonitrilas, esant bazei, tokiai kaip diizopropiletilaminas/dimetilaminopiridinas; veikiant sulfonrūgšties halogenanhidridu R3SO2X, kur X yra Cl arba Br, vandens ir organinio tirpiklio mišinyje, pvz. NaOH/CH2CI2; veikiant halogensulfonatu ROSO2CI, kur X yra Cl arba Br, .inertiniame tirpiklyje, tokiame kaip CH2CI2; veikiant sulfamoilchloridu R5ReNSO2X, kur X yra Cl arba Br, inertiniame tirpiklyje, tokiame kaip acetonitrilas, esant bazei, tokiai kaip diizopropiletilaminas/dimetil-aminopiridinas; veikiant N-cianotiokarbamidu NH(CN)C(S)NR5R6, esant kopuliavimo reagentui, tokiam kaip karbodiimidas, inertiniame tirpiklyje, tokiame kaip DMF, maždaug kambario temperatūroje; veikiant cianokarbonimidatu, tokiu kaip difenilcianokarbonimidatas, tinkamame tirpiklyje, tokiame kaip DMF, esant bazei, tokiai kaip diizopropiletilaminas, nuo kambario temperatūros iki 80 °C, o po to veikiant aminu, tokiu kaip metilaminas, maždaug kambario temperatūroje). Junginys 5, kuriame R( yra halogenas, pvz. bromas, gali būti pagaminamas iš junginio 5, kuriame R, = H, veikiant halogeninimo agentu, pvz. tetrabutilamonio perbromidu, inertiniame tirpiklyje, tokiame kaip chloroformas, maždaug kambario temperatūroje. Jeigu Ri arba R2 yra CH2OH, acilinimą galima atlikti taip, kad būtų gaunamas diamido, esteris; šis esteris gali būti suskaldytas, pvz. natrio metoksidu metanolyje, ir gautas alkoholis suoksidintas iki rūgšties, pvz. Jones’o reagentu; po to gali būti suskaldytas N1 amidas, pvz. KOH vandeniniame metanolyje, virinant su grįžtamu šaldytuvu, o rūgštis gali būti kopuliuojama su aminais standartinėmis peptidų kopuliavimo sąlygomis, susidarant 1 schemos junginiui 5, kuriame Ri arba R2 yra karboksamidas. Jeigu Ri arba R2 yra CH2O-Prot, apsauginė grupė gali būti pašalinama, pvz. Boc - veikiant rūgštimi, tokia kaip TFA, inertiniame tirpiklyje, tokiame kaip dichlormetanas, susidarant junginiui 5 arba 6, kuriuose Ri arba R2 yra CH2OH. Junginys 5, kuriame Ri arba R2 yra ariloksialkilas, yra pagaminamas iš junginio 5, kuriame R, arba R2 yra CH2OH, paverčiant alkoholio grupę j atskylančią grupę, tokią kaip triflatas, pvz. veikiant triflo rūgšties anhidridų dichlormetane -40 °C temperatūroje ir pakeičiant aralkoksido druska, pvz. dichlormetane nuo -40 °C iki kambario temperatūros. Junginys 5, kuriame Ri arba R2 yra CH2NH2, yra pagaminamas iš junginio 5, kuriame Ri arba R2 yra CH2OH, paverčiant alkoholio grupę j atskylančią grupę, tokią kaip triflatas, pvz. veikiant triflo rūgšties anhidridų dichlormetane -40 °C temperatūroje, ir atliekant pakeitimo reakciją su amoniaku, pvz. dichlormetane nuo -40 °C iki kambario temperatūros. Šis aminas po to gali būti kopuliuojamas su karboksirūgštimis standartinėmis amidinio ryšio sudarymo sąlygomis. Jeigu junginys 5 yra sulfinilintas beta-halogenalkilsulfonilhalogenidu, ši halogenidą galima atskelti baze, tokia kaip diizopropiletilaminas, ir po to prie gauto nesotaus sulfonamido galima prijungti nukleofilus, tokius kaip dimetilaminas arba natrio imidazolatas, reakciją atliekant organiniame tirpiklyje, tokiame kaip THF arba dichlormetanas, nuo kambario temperatūros iki virimo temperatūros. Jeigu junginys 5 yra acilintas arba sulfonilintas acilinimo arba sulfonilinimo agentu, kuriame yra atskylanti grupė, pvz. chloridas arba bromidas, tokia atskylanti grupė gali būti pakeičiama nukleofilais, pvz. aminais, tokiais kaip dimetilaminas arba N-metilpiperazinas, inertiniame tirpiklyje, tokiame kaip THF arba DMF, jeigu reikia, esant bazei, tokiai kaip diizopropiletilaminas, nuo 0 °C iki 110 °C temperatūroje.The product is then acylated or sulfonylated under standard conditions from -78 ° C to room temperature (e.g., by treatment with acid halide R 3 COX where X is Cl or Br, in an inert organic solvent such as acetonitrile, or in a mixture of water and organic solvent, e.g. NaOH / dichloroethane; O-phenyl ester in an inert organic solvent such as acetonitrile; carboxylic acid in the presence of a copolymer such as DCC or EDC; in an inert organic solvent such as DMF; in halogen formate such as ethyl, isopropyl or 4- nitrophenyl chloroformate, in an inert organic solvent such as dichloromethane, from 0 ° C to room temperature, if necessary in the presence of a base such as diisopropylethylamine, to form carbamates, and some of them, such as 4-nitrophenylcarbamate, are treated with an amine, e.g. Ν, Ν'-trimethylethylenediamine, from room temperature to 110 ° C, in the presence of ureas; by the action of a carboxylic acid ride or sulfonyl anhydride such as succinic anhydride or trifluoromethanesulfonyl anhydride in an inert solvent such as ethyl acetate, dichloromethane or pyridine, from 0 ° C to room temperature, if necessary in the presence of a base such as diisopropylamine; treating the isocyanate with an inert solvent such as THF; with a carbamyl chloride R 5 R 6 NHCOX where X is Cl or Br in an inert solvent such as acetonitrile in the presence of a base such as diisopropylethylamine / dimethylaminopyridine; with a sulfonic acid halide anhydride R 3 SO 2 X wherein X is Cl or Br in a mixture of water and an organic solvent, e.g. NaOH / CH 2 Cl 2 ; acting on halosulfonate ROSO 2 Cl, where X is Cl or Br, in an inert solvent such as CH 2 Cl 2 ; with sulfamoyl chloride R 5 in ReNSO 2 X, where X is Cl or Br, in an inert solvent such as acetonitrile in the presence of a base such as diisopropylethylamine / dimethylaminopyridine; with N-cyanothiourea NH (CN) C (S) NR 5 R 6 in the presence of a copolymer such as carbodiimide in an inert solvent such as DMF at about room temperature; treating with a cyanocarbonimidate such as diphenylcyanocarbonimidate in a suitable solvent such as DMF in the presence of a base such as diisopropylethylamine at room temperature to 80 ° C followed by treatment with an amine such as methylamine at about room temperature). Compound 5 wherein R ( is a halogen, e.g. bromine) can be prepared from compound 5 wherein R 1 = H by the action of a halogenating agent such as tetrabutylammonium perbromide in an inert solvent such as chloroform at about room temperature. 2 is CH 2 OH, the acylation can be carried out to give the diamide ester, this ester can be cleaved with e.g. sodium methoxide in methanol and the resulting alcohol oxidized to an acid such as Jones reagent, followed by cleavage with N1 an amide such as KOH in aqueous methanol under reflux, and the acid can be copolymerized with amines under standard peptide copolymer conditions to form compound 5 of Scheme 1 wherein R 1 or R 2 is carboxamide If R 1 or R 2 is CH 2 O-Prot , the protecting group may be removed, e.g., Boc by treatment with an acid such as TFA in an inert solvent such as dichloromethane to form compound 5 or 6 wherein Ri a or R 2 is CH 2 OH Compound 5 wherein R 1 or R 2 is aryloxyalkyl is prepared from compound 5 wherein R 1 or R 2 is CH 2 OH by converting an alcohol group to a leaving group such as triflate, e.g. by treatment with triflic acid anhydrides in dichloromethane at -40 ° C and replacement with an aralkoxide salt, e.g. in dichloromethane from -40 ° C to room temperature. Compound 5 wherein R 1 or R 2 is CH 2 NH 2 is prepared from compound 5 wherein R 1 or R 2 is CH 2 OH by converting an alcohol group to a leaving group such as triflate, e.g. by treatment with triflic acid anhydride in dichloromethane at -40 ° C, and by reaction with ammonia, e.g. in dichloromethane from -40 ° C to room temperature. This amine can then be copolymerized with carboxylic acids under standard amide linkage conditions. If compound 5 is sulfinylated with a beta-haloalkylsulfonyl halide, this halide can be cleaved by a base such as diisopropylethylamine and then attached to the resulting unsaturated sulfonamide by nucleophiles such as dimethylamine or sodium imidazolate, in a reaction with an organic solvent such as to boiling point. If compound 5 is acylated or sulfonylated with an acylating or sulfonylating agent containing a leaving group, e.g. chloride or bromide, such a leaving group may be replaced by nucleophiles, e.g. amines such as dimethylamine or N-methylpiperazine in an inert solvent such as THF or DMF, if necessary in the presence of a base such as diisopropylethylamine, at a temperature from 0 ° C to 110 ° C.
stadijastage
Po to gali būti atliekamas įvairių produktų redukcinis alkilinimas, esant rūgščiai, pvz. acto rūgščiai, redukuojančiam agentui, pvz. NaBH(OAc)3, inertiniame organiniame tirpiklyje, pvz. dichloretane, maždaug kambario temperatūroje. Redukcinį alkilinimą taip pat galima atlikti, panaudojant vandenilį ir katalizatorių, tokį kaip Pd ant anglies, tirpiklyje, tokiame kaip etanolis, esant rūgščiai, tokiai kaip acto rūgštis, maždaug kambario temperatūroje.This can be followed by reductive alkylation of various products in the presence of an acid, e.g. acetic acid, reducing agent, e.g. NaBH (OAc) 3 , in an inert organic solvent, e.g. in dichloroethane at about room temperature. Reductive alkylation can also be carried out using hydrogen and a catalyst such as Pd on carbon in a solvent such as ethanol in the presence of an acid such as acetic acid at about room temperature.
Po to 1 schemos junginys, kuriame Ri = halogenas, gali būti paverčiamas metalo dariniu ir skaldomas, pvz. vandeniu, susidarant junginiui, kuriame Ri = H, arba skaldant anglies dioksidu, susidarant junginiui, kuriame R, = CO2H; ši rūgštis gali būti kopuliuojama su aminais standartinėmis peptidų kopuliavimo sąlygomis, susidarant 1 schemos junginiams, kuriuose Ri yra karboksamidas. 1 schemos junginys, kuriame Ri = halogenas, gali būti paverčiamas metalo dariniu ir skaldomas ketonu, tokiu kaip cikloheksanonas, o po to redukuojamas alkoholis, pvz. su trifluoracto rūgštimi ir natrio borhidridu, susidarant junginiui, kuriame Ri = pvz. cikloheksilas. 1 schemos junginys, kuriame imidazole yra 2dimetilaminometilo grupė, gali būti pagaminamas standartinėmis Manicho sąlygomis. 1 schemos junginys, kuriame Ri = OH, gali būti pagaminamas iš 1 schemos junginio, kuriame R, = OMe, dealkilinant, pvz. veikiant BBr3. 1 schemos junginys, kuriame Ri = arilOalkilas, gali būti pagaminamas iš 1 schemos junginio, kuriame Ri = HOalkilas, pagal Mitsunobu reakciją su arilo alkoholiu. 1 schemos junginys, kuriame R3 = aril-NH2 arba heteroaril-NH2l gali būti pagaminamas iš 1 schemos junginio, kuriame R3 = aril-NO2 arba heteroaril-NO2, redukuojant (pvz. SnCI2) standartinėmis sąlygomis. Šis produktas toliau gali būti acilinamas, sulfonilinamas arba redukciškai amininamas standartinėmis sąlygomis.The compound of Scheme 1 wherein Ri = halogen can then be converted into a metal derivative and cleaved, e.g. water to form a compound wherein R 1 = H or decomposition with carbon dioxide to form a compound wherein R 1 = CO 2 H; this acid can be copolymerized with amines under standard peptide copulation conditions to form compounds of Scheme 1 wherein R 1 is carboxamide. The compound of Scheme 1 wherein Ri = halogen can be converted to a metal derivative and cleaved with a ketone such as cyclohexanone and then reduced to an alcohol, e.g. with trifluoroacetic acid and sodium borohydride to form a compound wherein Ri = e.g. cyclohexyl. The compound of Scheme 1 wherein the imidazole has a 2-dimethylaminomethyl group can be prepared under standard Manich conditions. The compound of Scheme 1 wherein R 1 = OH can be prepared from the compound of Scheme 1 wherein R 1 = OMe by dealkylation, e.g. exposed to BBr 3 . The compound of Scheme 1 in which R 1 = arylOalkyl may be prepared from the reaction of Scheme 1 in which R 1 = HOalkyl by Mitsunobu reaction with an aryl alcohol. The compound of Scheme 1 in which R 3 = aryl-NH 2 or heteroaryl-NH 2 1 can be prepared from the compound of Scheme 1 in which R 3 = aryl-NO 2 or heteroaryl-NO 2 by reduction (e.g. SnCl 2 ) under standard conditions. This product can be further acylated, sulfonylated, or reductively aminated under standard conditions.
schemascheme
= CO, SO2 stadija schemoje pradinė medžiaga redukuojama hidrinimo būdu, esant platinos oksidui. Reakcija atliekama alkoholyje, pvz. etanolyje, maždaug kambario temperatūroje.= CO, SO 2 In the scheme, the starting material is reduced by hydrogenation in the presence of platinum oxide. The reaction is carried out in alcohol, e.g. in ethanol at about room temperature.
ir 3 stadijosand Stage 3
Po to produktas monoacilinamas arba monosulfonilinamas standartinėmis sąlygomis nuo -78 °C iki kambario temperatūros (pvz. veikiant rūgšties halogenanhidridu R2COX, kur X yra Cl arba Br, inertiniame organiniame tirpiklyje, pvz. acetonitrile, arba vandens ir organinio tirpiklio mišinyje, pvz. NaOH/metileno chloride; arba veikiant sulfonilhalogenidu R3SO2X, kur X yra Cl arba Br, organiniame tirpiklyje, pvz. CH2CI2, esant bazei, tokiai kaip trietilaminas). Po to su šiuo produktu atliekama redukcinio alkilinimo reakcija, kaip aprašyta 1 schemos paskutinėje stadijoje.The product is then monoacylated or monosulfonylated under standard conditions from -78 ° C to room temperature (e.g. by treatment with acid halogen R 2 COX where X is Cl or Br, in an inert organic solvent such as acetonitrile, or a mixture of water and organic solvent, e.g. NaOH / methylene chloride; or by reaction with a sulfonyl halide R 3 SO 2 X, where X is Cl or Br, in an organic solvent such as CH 2 Cl 2 in the presence of a base such as triethylamine). This product is then subjected to a reductive alkylation reaction as described in Scheme 1, final step.
scemoje junginys 1 yra blokuojamas tinkama grupe, pavyzdžiui tretbutoksikarbonilo grupe. Ši reakcija vykdoma inertiniame organiniame tirpiklyje, pvz. THF, maždaug kambario temperatūroje. Junginys 2, kuriame Ri yra aminogrupė, gali būti selektyviai acilinamas, pvz. veikiant izobutilchlorformiatu inertiniame tirpiklyje, tokiame kaip metileno chloridas, esant bazei, tokiai kaip diizopropiletilaminas, maždaug kambario temperatūroje. Junginys 2, kuriame Ri yra R5CONH, o kitas Ri yra Br, yra pagaminamas iš junginio, kuriame Ri yra R5CONH, brominant, pvz. tetrabutilamonio tribromidu inertiniame tirpiklyje, tokiame kaip chloroformas, maždaug kambario temperatūroje. Po to junginys 2 veikiamas junginiu, kurio formulė R3COCI, esant piridinui, inertiniame organiniame tirpiklyje, tokiame kaip dichloretanas, nuo 0 °C iki kambario temperatūros. Po to junginys 3 yra deblokuojamas, veikiant, pavyzdžiui, trifluoracto rūgštimi inertiniame organiniame tirpiklyje, tokiame kaip dichloretanas, maždaug kambario temperatūroje. Po to su junginiu 4 atliekama redukcinio alkilinimo reakcija pagal 1 schemoje aprašytas stadijas.in Scheme, compound 1 is blocked with a suitable group, for example tert-butoxycarbonyl. This reaction is carried out in an inert organic solvent, e.g. THF, at about room temperature. Compound 2, wherein R 1 is an amino group, can be selectively acylated, e.g. treating isobutyl chloroformate with an inert solvent such as methylene chloride in the presence of a base such as diisopropylethylamine at about room temperature. Compound 2 wherein R 1 is R 5 CONH and the other R 1 is Br is prepared by bromination of a compound wherein R 1 is R 5 CONH, e.g. tetrabutylammonium tribromide in an inert solvent such as chloroform at about room temperature. Compound 2 is then treated with a compound of formula R 3 COCl in the presence of pyridine in an inert organic solvent such as dichloroethane from 0 ° C to room temperature. Compound 3 is then deprotected by treatment with, for example, trifluoroacetic acid in an inert organic solvent such as dichloroethane at about room temperature. The compound 4 is then subjected to a reductive alkylation reaction according to the steps described in Scheme 1.
schemascheme
schemoje junginys 1 yra veikiamas junginiu, kurio formulė R2COCO2Me, esant organinei rūgščiai, pvz. acto rūgščiai, ir redukuojančiam agentui, tokiam kaip NaCNBH3 arba NaBH(OAc)3, inertinaime organiniame tirpiklyje, tokiame kaip dichloretanas, maždaug kambario temperatūroje. Po to tarpinis junginys deblokuojamas, veikiant, pavyzdžiui, trifluoracto rūgštimi inertiniame organiniame tirpiklyje, pvz. CH2CI2, maždaug kambario temperatūroje ir ciklinamas šildant, pvz. 60 °C temperatūroje, ir susidaro junginys 2. Po to su junginiu 2 atliekama redukcinio alkilinimo reakcija, kaip parodyta 1 schemoje, ir gaunamas junginys 3. Junginys 3 gali būti redukuojamas, pvz. ličio aliuminio hidridu, susidarant junginiui 4, kuris gali būti paverčiamas į junginį 6, kaip aprašyta 12 schemoje. Kitu atveju, junginys 2 yra redukuojamas iki junginio 5, kaip parodyta 1 schemoje, o junginys 5 veikiamas taip, kaip parodyta 1 schemoje.In Scheme I, compound 1 is treated with a compound of formula R 2 COCO 2 Me in the presence of an organic acid, e.g. acetic acid, and a reducing agent such as NaCNBH3 or NaBH (OAc) 3 in an inert organic solvent such as dichloroethane at about room temperature. The intermediate is then deprotected by treatment with, for example, trifluoroacetic acid in an inert organic solvent, e.g. CH 2 Cl 2 at about room temperature and cyclized by heating, e.g. 60 ° C to form compound 2. Compound 2 is then subjected to a reductive alkylation reaction as shown in Scheme 1 to give compound 3. Compound 3 can be reduced, e.g. lithium aluminum hydride to form compound 4, which can be converted to compound 6 as described in Scheme 12. Alternatively, Compound 2 is reduced to Compound 5 as depicted in Scheme 1 and Compound 5 is treated as depicted in Scheme 1.
7y = CO, SO2, CO2, CONR5, SO3, SO2NR5 7 y = CO, SO 2 , CO 2 , CONR 5 , SO 3 , SO 2 NR 5
P rotP rot
schemoje junginys 1 yra blokuojamas, veikiant, pavyzdžiui, trifenilmetilchloridu arba Boc anhidridu inertiniame organiniame tirpiklyje, pvz.In Scheme I, Compound 1 is blocked by treatment with, for example, triphenylmethyl chloride or Boc anhydride in an inert organic solvent, e.g.
acetonitrile arba tetrahidrofurane, nuo kambario temperatūros iki tirpiklio virimo temperatūros. Po to junginys 2 veikiamas junginiu, kurio formulė R4-L, kurioje L yra atskylanti grupė, tokia kaip triflatas, esant bazei, tokiai kaip diizopropiletilaminas, inertiniame organiniame tirpiklyje, tokiame kaip tetrahidrofuranas, nuo -78 °C iki kambario temperatūros. R4 gali būti blokuojanti grupė, pvz. ftalimido, kurią galima atskelti, pvz. hidrazinu. 5 schemos reakcija su R4-L gali būti atliekama su junginiu 1 ir tiesiogaiai gaunamas junginys 3 be bolkavimo/deblokavimo.acetonitrile or tetrahydrofuran, from room temperature to the boiling point of the solvent. Compound 2 is then treated with a compound of formula R 4 -L wherein L is a leaving group such as triflate in the presence of a base such as diisopropylethylamine in an inert organic solvent such as tetrahydrofuran at -78 ° C to room temperature. R 4 may be a protecting group, e.g. phthalimide which can be cleaved e.g. hydrazine. The reaction of Scheme 5 with R 4 -L can be carried out with compound 1 and directly obtain compound 3 without bulging / deprotection.
schemascheme
NCNC
N CO,R H 2 N CO, RH 2
HO. ^S, 'S ΌΗHO. ^ S, 'S ΌΗ
R,R,
Z1 = CO, SO2 Z 1 = CO, SO 2
R, schemoje cianacetilamino rūgštis veikiama ditiandioliu tinkamame tirpiklyje, tokiame kaip etanolis, esant bazėms, tokioms kaip piperidinas ir trietilaminas, nuo kambario temperatūros iki 80 °C. Po to tarpinis junginys ciklinamas tinkamame tirpiklyje, tokiame kaip piridinas, esant katalizatoriui, tokiam kaip piridinio hidrochloridas, aukštesnėje temperatūroje, tokioje kaip 130 °C. Po to junginys 2 veikiamas taip, kaip aprašyta 1 schemoje.In Scheme R, cyanoacetylamino acid is treated with dithiandiol in a suitable solvent such as ethanol in the presence of bases such as piperidine and triethylamine at room temperature to 80 ° C. The intermediate is then cyclized in a suitable solvent such as pyridine in the presence of a catalyst such as pyridine hydrochloride at an elevated temperature such as 130 ° C. Compound 2 is then treated as described in Scheme 1.
schemascheme
Z, = CO, SO2, CO2, CONR5, SO2NR5 u, = co, so2, co2, conr5, so2nr5 schemos junginys 1 redukuojamas (pvz. Fe, SnCI2 arba TiCI3) standartinėmis sąlygomis. Junginys 2 acilinamas arba sulfonilinamas standartinėmis sąlygomis (pvz. veikiant anhidridu ir acilinimo katalizatoriumi, tokiu kaip DMAP, veikiant rūgšties halogenanhidridu, veikiant karboksirūgštimi standartinėmis peptidų kopuliavimo sąlygomis, veikiant alkoksikarbonilchloridu, veikiant izocianatu, veikiant sulfonilhalogenidu arba veikiant sulfamilchloridu) arba atliekama redukcinio alkilinimo reakcija standartinėmis sąlygomis (pvz. veikiant aldehidu ir redukcijos agentu, tokiu kaip NaCNBH3 arba Na(OAc)3BH, organiniame tirpiklyje, tokiame kaip dichloretanas arba DMF, esant rūgščiai, tokiai kaip acto rūgštis, nuo 0 °C iki kambario temperatūros).Z, = CO, SO 2 , CO 2 , CONR 5 , SO 2 NR 5 u, = co, so 2 , co 2 , conr 5 , so 2 nr 5, compound 1 is reduced (e.g. Fe, SnCl 2 or TiCl 3). ) under standard conditions. Compound 2 is acylated or sulfonylated under standard conditions (e.g., anhydride and acylation catalysts such as DMAP, acid halogen anhydride, carboxylic acid, standard peptide copolymer, alkoxycarbonyl chloride, isocyanate, sulfonyl halide or standard sulfamyl) (e.g., by treatment with an aldehyde and a reducing agent such as NaCNBH 3 or Na (OAc) 3 BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at 0 ° C to room temperature).
schemascheme
R4 3 schemos junginys 1 veikiamas etilendiaminu, produktas 2 redukuojamas, selektyviai aciiinamas arba sulfonilinamas, ir atlikus redukcinį alkilinimą, gaunamas junginys 3 taip, kaip parodyta 1 schemoje. Kitu atveju, 8 schemos 1 stadija gali būti atlikta per 2 stadijas, kuriose etilendiaminas yra kondensuojamas su halogeniniu heterociklu arba naudojant grynas medžiagas, arba organiniame tirpiklyje aukštesnėje temperatūroje, ir gauta aminorūgštis ciklinama standartinėmis amidinio ryšio susidarymo sąlygomis, pvz. naudojant HOBt/karbodiimidą organiniame tirpiklyje, tokiame kaip DMF arba piridinas, nuo 0 °C iki kambario temperatūros. Kai kurių 8 schemos junginių 1, kuriuose FG = halogenas, nėra prekyboje. Toks 8 scemos junginys 2, kuriame Ri = halogenas, gali būti pagaminami iš 8 schemos junginio 2, kuriame R, = vandenilis, ji halogeninant, pavyzdžiui, veikiant bromu organiniame tirpiklyje, tokiame kaip acto rūgštis, nuo 0 °C iki kambario temperatūros. Junginys 2, kuriame R, = arilas arba heteroarilas, gali būti pagaminamas iš junginio 2, kuriame Ri yra halogenas arba trifluormetansulfoniloksigrupė, panaudojant standartinius Suzuki arba Stille kopuliavimus, kaip aprašyta 1 schemos 2 stadijoje. Po to produktas redukuojamas, acilinamas arba sulfonilinamas, ir atliekamas redukcinis alkilinimas taip, kaip aprašyta 1 schemoje. Su pačiu 8 schemos junginiu 2 gali būti atlikta redukcinio alkilinimo reakcija, panaudojant imidazolo grupę turintį aldehidą, kaip parodyta 1 schemoje, ir gaunamas norimas junginys.Compound 1 of Scheme R 4 is treated with ethylenediamine, product 2 is reduced, selectively acylated or sulfonylated, and reductive alkylation affords compound 3 as shown in Scheme 1. Alternatively, Scheme 8, Step 1 may be carried out in Step 2, in which ethylenediamine is condensed with a halogen heterocycle, either on its own or in an organic solvent at a higher temperature, and the resulting amino acid cyclized under standard amide bond formation conditions, e.g. using HOBt / carbodiimide in an organic solvent such as DMF or pyridine from 0 ° C to room temperature. Some compounds of Scheme 8 in which FG = halogen are not commercially available. Scheme 8, wherein R 1 = halogen, can be prepared from Scheme 8, compound 2, wherein R 1 = hydrogen, by halogenation, for example by treatment with bromine in an organic solvent such as acetic acid, from 0 ° C to room temperature. Compound 2, wherein R 1 = aryl or heteroaryl, can be prepared from compound 2, wherein R 1 is halogen or trifluoromethanesulfonyloxy, using standard Suzuki or Stille copolymers as described in Scheme 1, Step 2. The product is then reduced, acylated or sulfonylated and subjected to reductive alkylation as described in Scheme 1. Compound 2 of Scheme 8 itself can be subjected to a reductive alkylation reaction using an imidazole-containing aldehyde as shown in Scheme 1 to give the desired compound.
schema (imidazolo aldehidai)scheme (imidazole aldehydes)
Kai kurie imidazolo aldehidai pagaminami tokiu būdu. Su imidazolo grupę turinčiu aldehidu atliekama VVittig’o reakcija, panaudojant trietilfosfonacetato formulės junginį, esant bazei, tokiai kaip natrio hidridas, inertiniame organiniame tirpiklyje, tokiame kaip dimetoksietanas, nuo maždaug 0 °G iki kambario temperatūros. Produktas hidrinamas alkoholyje, pvz. etanolyje, maždaug kambario temperatūroje ir redukuojamas DIBAL, pavyzdžiui dichloretane, maždaug -78 °C temperatūroje. Kitu atveju, kai kurie aminoalkilo grupę turintys imidazolilalkanoliai, pagaminti žinomais būdais (pvz. Buschauer, et ai., Arch. Pharm., 315, 563 (1982)), blokuojami Boc grupe, kaip parodyta 3 schemos 1 stadijoje, ir oksidinami, pvz. Svvern’o sąlygomis.Some imidazole aldehydes are made this way. A Vittig reaction with an imidazole-containing aldehyde is carried out using a compound of the formula triethylphosphonacetate in the presence of a base such as sodium hydride in an inert organic solvent such as dimethoxyethane from about 0 ° C to room temperature. The product is hydrogenated in alcohol, e.g. ethanol at about room temperature and reduced with DIBAL, such as dichloroethane, at about -78 ° C. Alternatively, some aminoalkyl-containing imidazolylalkanols prepared by known methods (e.g., Buschauer, et al., Arch. Pharm., 315, 563 (1982)) are blocked with the Boc group as shown in Scheme 3, Step 1 and oxidized, e.g. . Svvern terms.
schemascheme
schemoje pradinė medžiaga yra veikiama alilmagnio bromidu, esant ličio heksametildisilazidui, inertiniame tirpiklyje, pvz. THF, nuo maždaug -78 °C iki kambario temperatūros. Produktas blokuojamas, pvz. Teoc grupe, vandens ir organinio tirpiklio mišinyje, pvz. vandeniniame dioksane, maždaug kambario temperatūroje. Blokuotas produktas oksidinamas, veikiant pvz. OsO4/NalO4 vandeniniame dioksane maždaug kambario temperatūroje. Po to su šiuo produktu atliekama redukcinio alkilinimo reakcija, kaip parodyta 1 schemoje, ir po to produktas, deblokuojamas tetrabutilamonio fluoridu nuo kambario temperatūros iki 50 °C THF.In the scheme, the starting material is exposed to an aluminum magnesium bromide in the presence of lithium hexamethyldisilazide in an inert solvent, e.g. THF, from about -78 ° C to room temperature. The product is blocked, e.g. Teoc group, in a mixture of water and organic solvent, e.g. in aqueous dioxane at about room temperature. The blocked product is oxidized by the action of e.g. OsO 4 / NalO 4 in aqueous dioxane at about room temperature. This product is then subjected to a reductive alkylation reaction as shown in Scheme 1 and then deprotected with tetrabutylammonium fluoride from room temperature to 50 ° C in THF.
schemascheme
schemoje pradinė medžiaga yra redukuojama pvz. ličio aliuminio hidridu inertiniame organiniame tirpiklyje, pvz. etilenglikolio dimetilo eteryje nuo 0 °C iki tirpiklio virimo temperatūros.in the scheme, the starting material is reduced e.g. lithium aluminum hydride in an inert organic solvent, e.g. ethylene glycol in dimethyl ether from 0 ° C to the reflux temperature of the solvent.
schemascheme
nėra, CO, SO2, CO2, CONRS, SO3, SO2NR5 schemos 1 stadijoje monoblokuotas benzodiazepinas, toks kaip parodyta 3 schemoje, yra kopuliuojamas su, esant reikalui, blokuota imidazolo grupę turinčia karboksirūgštimi, panaudojant standartinius amidinio ryšio sudarymo metodus, tokius kaip izobutilchlorformiatą organiniame tirpiklyje, tokiame kaip THF, nuo -30 °C iki kambario temperatūros. 12 schemos 2 stadijoje gautas amidas redukuojamas, pavyzdžiui, boranu organiniame tirpiklyje, tokiame kaip THF, nuo kambario temperatūros iki tirpiklio virimo temperatūros. 12 schemos junginys 3 gali turėti nitrogrupę, kurią galima redukuoti, pvz. TiCI3, iki aminogrupės, kuri tada gali būti acilinama arba sulfonilinama taip, kaip aprašyta 7 schemoje. 12 schemos 3 stadijoje aminogrupę blokuojanti grupė atskeliama (pvz. Boc atskeliama rūgštimi, tokia kaip TFA, organiniame tirpiklyje, tokiame kaip metileno chloridas). 12 schemos 4 stadijoje gautas junginys yra veikiamas standartinėmis sąlygomis įvairiais aktyviais acilinimo arba sulfonilinimo agentais, susidarant šio išradimo junginiams, tokiems kaip rūgštys karbodiimido reakcijos sąlygomis, arba rūgščių chloranhidridais, susidarant amidams; karbonatais arba chlorformiatais, susidarant karbamatams; karbamilchloridais arba izocianatais, susidarant karbamidams; sulfonilchloridais, susidarant sulfonamidams; halogensulfonatais, susidarant sulfamatams; sulfamoilchloridais, susidarant sulfonilkarbamidams. Kitu atveju, 12 schemos 4 stadijoje gautas junginys standartinėmis redukcinio amininimo sąlygomis yra veikiamas aldehidais, kaip aprašyta 1 schemos 5 stadijoje, susidarant šio išradimo junginiams. Jeigu imidazolo grupė buvo blokuota, tada ji deblokuojama.No, CO, SO 2, CO 2, CONR S, SO 3, SO 2 NR 5 scheme 1 step monoprotected benzodiazepine such as shown in Scheme 3 is coupled with, if necessary, protected by an imidazole group-containing carboxylic acid using standard amide bond of methods such as isobutyl chloroformate in an organic solvent such as THF from -30 ° C to room temperature. In Scheme 12, Step 2, the resulting amide is reduced, for example, with borane in an organic solvent such as THF from room temperature to the reflux temperature of the solvent. Compound 3 of Scheme 12 may have a nitro group which can be reduced, e.g. TiCl 3 , to the amino group, which may then be acylated or sulfonylated as described in Scheme 7. In Scheme 12, Step 3, the amino protecting group is cleaved (e.g., Boc is cleaved with an acid such as TFA in an organic solvent such as methylene chloride). The compound of Scheme 12, Step 4, is treated under standard conditions with various active acylating or sulfonylating agents to form compounds of the present invention, such as acids under the carbodiimide reaction conditions, or acid chloro anhydrides to form amides; carbonates or chloroformates to form carbamates; carbamyl chlorides or isocyanates to form ureas; sulfonyl chlorides to form sulfonamides; halogen sulfonates to form sulfamates; sulfamoyl chlorides to form sulfonylureas. Alternatively, the compound obtained in Step 4 of Scheme 12 is treated with aldehydes under standard reductive amination conditions as described in Scheme 1 Step 5 to form the compounds of the present invention. If the imidazole group is blocked then it is unblocked.
schemascheme
(pvz. Prot = Boc) schemos 1 stadijoje su monoblokuotu benzodiazepinu, tokiu kaip ir 3 schemoje, atliekamas redukcinis alkilinimas, panaudojant imidazolo grupę turinti aldehidą ir redukcijos agentą, tokį kaip NaCNBH3 arba Na(OAc)3BH, organiniame tirpiklyje, tokiame kaip dichloretanas arba DMF, esant rūgščiai, tokiai kaip acto rūgštis, nuo 0 °C iki kambario temperatūros. Po to produktas veikiamas taip, kaip aprašyta 12 schemoje. Produktas 2 gali būti prijungiamas prie kieto pagrindo, pvz. polistireno dervos, ir 1 schemos reakcijos gali būti atliekamos su prie dervos prijungta medžiaga. Atskėlus nuo pagrindo, pvz. veikiant rūgštimi, tokia kaip trifluoracto rūgštis, esant surišikliui, tokiam kaip trietilsilanas, maždaug kambario temperatūroje, gaunamas 1 schemos junginys 6.(e.g. Prot = Boc) in Scheme 1, a monoblocked benzodiazepine such as in Scheme 3 is subjected to reductive alkylation using an imidazole-containing aldehyde and a reducing agent such as NaCNBH 3 or Na (OAc) 3 BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at 0 ° C to room temperature. The product is then treated as described in Scheme 12. Product 2 can be connected to a solid substrate, e.g. polystyrene resins, and the reactions of Scheme 1 can be performed with the resin-bound material. When detached from the base, e.g. treating with an acid such as trifluoroacetic acid in the presence of a binder such as triethylsilane at about room temperature affords Scheme 1 Compound 6.
schemascheme
pvz., 1 arba 3 schema schemos 1 stadijoje atliekama aminobenzenkarboksirūgšties redukcinio amininimo reakcija, panaudojant N-blokuotą aminoaldehidą, standartinėmis sąlygomis, pvz. veikiant hidridiniu reagentu, tokiu kaip natrio triacetoksiborhidridas arba natrio cianborhidridas, tinkamame tirpiklyje, tokiame kaip metileno chloridas'arba metanolis, esant rūgščiai, tokiai kaip acto rūgštis, nuo 0 °C iki maždaug kambario temperatūros. Produktas deblokuojamas, pvz. Boc atskeliamas veikiant rūgštimi, tokia kaip TFA arba HCI, jeigu reikia esant surišikliui, tokiam kaip dimetilsulfidas, tinkamame tirpiklyje, tokiame kaip metileno chloridas arba dioksanas, maždaug kambario temperatūroje, arba Fmoc atskeliamas veikiant antriniu aminu tetrahidrofurane maždaug kambario temperatūroje. Po to produktas ciklinamas standartinėmis amidinio ryšio susidarymo sąlygomis, tokiomis kaip veikiant difenilfosforilazidu organiniame tirpiklyje, tokiame kaip DMF, Po to produktas veikiamas taip, kaip aprašyta 1 schemoje.e.g., Scheme 1 or Scheme 3 is a reductive amination reaction of an aminobenzoic acid using N-blocked aminoaldehyde under standard conditions, e.g. by treatment with a hydride reagent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride or methanol in the presence of an acid such as acetic acid, from 0 ° C to about room temperature. Product is unblocked, e.g. Boc is cleaved by treatment with an acid such as TFA or HCl, if necessary in the presence of a binder such as dimethylsulfide, in a suitable solvent such as methylene chloride or dioxane at about room temperature, or Fmoc is cleaved by treatment with a secondary amine in tetrahydrofuran at about room temperature. The product is then cyclized under standard amide bond formation conditions such as diphenylphosphoryl azide in an organic solvent such as DMF. The product is then treated as described in Scheme 1.
schemascheme
schemos 1 stadijoje benzodiazepindionas sulfonilinamas chlorsulfonrūgštimi, ir gautas sulfonilchloridas kondensuojamas su aminu. Po to produktas veikiamas taip, kaip aprašyta 1 schemoje.In Scheme 1, Scheme 1, the benzodiazepindione is sulfonylated with chlorosulfonic acid, and the resulting sulfonyl chloride is condensed with an amine. The product is then treated as described in Scheme 1.
schemascheme
schemos 1 stadijoje 1 schemos benzodiazepinas gali būti redukciškai alkilinamas dviejose padėtyse, panaudojant imidazolo grupę turintį aldehidą ir redukcijos agentą, tokį kaip NaCNBFfo arba Na(OAc)3BH, organiniame tirpiklyje, tokiame kaip dichloretanas arba DMF, esant rūgščiai, tokiai kaip acto rūgštis, nuo 0 °C iki kambario temperatūros.In Scheme 1, Scheme 1, the benzodiazepine of Scheme 1 can be reductively alkylated at two positions using an imidazole-containing aldehyde and a reducing agent such as NaCNBFfo or Na (OAc) 3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid. 0 ° C to room temperature.
schemos 1 stadijoje 1 schemos benzodiazepinas gali būti veikiamas R3-L inertiniame tirpiklyje, tokiame kaip DMF, THF arba metileno chloridas, esant bazei, tokiai kaip diizopropiletilaminas arba kalio karbonatas, nuo 0 °C iki 100 °C, kur L yra atskylanti grupė, tokia kaip chloridas, bromidas, metansulfonatas, 4-metilbenzensulfonatas arba triflatas, o R3 yra pakeista alkilo grupė, pakeista arilo grupė arba pakeista heterociklinė grupė. Po to šis produktas veikiamas taip, kaip aprašyta 1 schemoje.in Scheme 1, Step 1, the benzodiazepine of Scheme 1 can be treated with R 3 -L in an inert solvent such as DMF, THF or methylene chloride in the presence of a base such as diisopropylethylamine or potassium carbonate, from 0 ° C to 100 ° C, where L is a leaving group, such as chloride, bromide, methanesulfonate, 4-methylbenzenesulfonate or triflate, and R 3 is a substituted alkyl group, a substituted aryl group, or a substituted heterocyclic group. This product is then treated as described in Scheme 1.
schemascheme
CH3 CH 3
NH-ProtNH-Prot
RR
ch3 ch 3
NH-ProtNH-Prot
CH2OAcCH 2 OAc
NH-ProtNH-Prot
CHOCHO
NH-ProtNH-Prot
pvz. 1 arba 3 schemae.g. Scheme 1 or 3
stadijastage
Pirmoji stadija atliekama, veikiant piridiną, turintį blokuotą aminogupę ir metilo grupę, oksidinimo agentu, tokiu kaip vandenilio peroksidas, tinkamame tirpiklyje, tokiame kaip vandeninė acto rūgštis arba trifluoracto rūgštis, nuo kambario temperatūros iki 75 °C.The first step is carried out by treating a pyridine having a protected amino group and a methyl group with an oxidizing agent such as hydrogen peroxide in a suitable solvent such as aqueous acetic acid or trifluoroacetic acid at room temperature to 75 ° C.
stadijastage
Produktas acilinamas acilinimo agentu, tokiu kaip acto rūgšties anhidridas, ir pergrupuojamas šildant nuo kambario temperatūros iki 90 °C tinkamame tirpiklyje, tokiame kaip acto rūgštis.The product is acylated with an acylating agent such as acetic anhydride and regrouped by heating from room temperature to 90 ° C in a suitable solvent such as acetic acid.
stadijastage
Produktas deacilinamas, pvz. vandeniniu NaOH, nuo kambario temperatūros iki 50 °C ir oksidinamas iki aldehido, pvz. MnO2, tinkamame tirpiklyje, tokiame kaip tetrahidrofuranas, maždaug kambario temperatūroje.The product is deacylated, e.g. aqueous NaOH, from room temperature to 50 ° C and oxidized to aldehyde, e.g. MnO 2 in a suitable solvent such as tetrahydrofuran at about room temperature.
stadijastage
Su produktu atliekama redukcinio amininimo reakcija, panaudojant aminorūgšties esterį, standartinėmis sąlygomis, pvz. hidrinant inertiniame tirpiklyje, tokiame kaip metanolis, arba veikiant hidridiniu reagentu, tokiu kaip natrio triacetoksiborhidridas, tinkamame tirpiklyje, tokiame kaip metileno chlorido ir acto rūgšties mišinys, maždaug kambario temperatūroje.The product is subjected to a reductive amination reaction using an amino acid ester under standard conditions, e.g. by hydrogenation in an inert solvent such as methanol or by treatment with a hydride reagent such as sodium triacetoxyborohydride in a suitable solvent such as a mixture of methylene chloride and acetic acid at about room temperature.
stadijastage
Produktas deblokuojamas ir ciklinamas, pvz. veikiant polifosforo rūgštimi, nuo kambario temperatūros iki 100 °C.The product is unblocked and cyclized, e.g. at room temperature to 100 ° C with polyphosphoric acid.
stadijastage
Produktas sulfonilinamas taip, kaip aprašyta 1 schemos 4 stadijoje.The product is sulfonylated as described in Scheme 1, Step 4.
stadijastage
Produktas redukuojamas taip, kaip aprašyta 1 schemos 3 stadijoje. Po to produktas veikiamas taip, kaip aprašyta 1 schemos 5 stadijoje.The product is reduced as described in Scheme 1, Step 3. The product is then treated as described in Scheme 1, Step 5.
R,R,
R, • N CO2HR, • N CO 2 H
Br .NH-Prot schema pvz., 14 schemaBr. NH-Prot Scheme eg Scheme 14
R-,R-,
Pirmoji stadija atliekama, veikiant pirimidiną, turintį halogeną ir karboksigrupę, jei reikia, monoblokuotu diaminu tinkamame tirpiklyje, tokiame kaip vanduo, esant katalizatoriui, tokiam kaip CuSO4, nuo kambario temperatūros iki 100 °C. Po to produktas veikiamas taip, kaip aprašyta 14 schemoje.The first step is carried out by reacting a pyrimidine containing a halogen and a carboxy group, if necessary, with a monoblocked diamine in a suitable solvent such as water in the presence of a catalyst such as CuSO 4 , from room temperature to 100 ° C. The product is then treated as described in Scheme 14.
schemascheme
stadijastage
Pirmoji stadija vykdoma, panaudojant nitrobenzaldehido redukcinį amininimą aminorūgšties esteriu standartinėmis sąlygomis, pvz. veikiant hidridiniu reagentu, tokiu kaip triacetoksiborhidridas, tinkamame tirpiklyje, tokiame kaip metileno chlorido ir acto rūgšties mišinys, maždaug kambario temperatūroje.The first step is carried out using reductive amination of the nitrobenzaldehyde with an amino acid ester under standard conditions, e.g. by reaction with a hydride reagent such as triacetoxyborohydride in a suitable solvent such as a mixture of methylene chloride and acetic acid at about room temperature.
stadijastage
Produktas sulfonilinamas taip, kaip aprašyta 1 schemos 4 stadijoje.The product is sulfonylated as described in Scheme 1, Step 4.
stadijastage
Produkto nitrogrupė redukuojama į aminogrupę standartinėmis sąlygomis, tokiomis kaip reakcija su SnCI2 arba TiCI3. Junginys, kuriame Ri = Br, gali būti pagaminamas iš junginio, kuriame Ri = H, brominant, pavyzdžiui, veikiant tetrabutilamonio perbromidu inertiniame tirpiklyje, tokiame kaip chloroformas, maždaug kambario temperatūroje.The nitro group of the product is reduced to the amino group under standard conditions such as reaction with SnCl 2 or TiCl 3 . The compound wherein Ri = Br can be prepared from the compound wherein Ri = H by bromination, for example by treatment with tetrabutylammonium perbromide in an inert solvent such as chloroform at about room temperature.
stadijastage
Produktas ciklinamas, šildant su CuCN inertiniame tirpiklyje, tokiame kaip N-metilpirolidinonas, nuo kambario temperatūros iki 195 °C. Junginys, kuriame Ri = CN, pagaminamas iš junginio, kuriame Ri = halogenas, tomis pačiomis sąlygomis.The product is cyclized by heating with CuCN in an inert solvent such as N-methylpyrrolidinone from room temperature to 195 ° C. A compound wherein Ri = CN is prepared from a compound wherein Ri = halogen under the same conditions.
stadijastage
Produktas alkilinamas blokuotu (jeigu reikia) imidazolilalkanoliu Mitsunobu sąlygomis. Po to, jeigu reikia, produktas veikiamas taip, kaip aprašyta 5 schemoje.The product is alkylated with blocked (if necessary) imidazolylalkanol under Mitsunobu conditions. Subsequently, if necessary, the product is treated as described in Scheme 5.
schemascheme
schemos junginys 3 gali būti selektyviai redukuojamas, pvz. veikiant redukcijos agentu, tokiu kaip boranas, inertiniame organiniame tirpiklyje, tokiame kaip tetrahidrofuranas, maždaug kambario temperatūroje. Po to atliekama produkto 2 redukcinio amininimo reakcija taip, kaip aprašyta 1 schemoje.Scheme compound 3 may be selectively reduced e.g. acting as a reducing agent such as borane in an inert organic solvent such as tetrahydrofuran at about room temperature. The reductive amination reaction of product 2 is then carried out as described in Scheme 1.
schemascheme
stadijastage
Gali būti pirmiausia atliekamas 20 schemos 4 junginio redukcinis amininimas taip, kaip aprašyta 1 schemos 5 stadijoje.The reductive amination of compound 4 of Scheme 20 may be carried out first as described in Scheme 1, Step 5.
stadijastage
Šio produkto esterintas (jeigu reikia) esteris hidrolizuojamas, pvz. veikiant šarminiu hidroksidų tinkamame tirpiklyje, tokiame kaip vandeninis alkoholis, nuo kambario temperatūros iki tirpiklio virimo temperatūros.The esterified (if necessary) ester of this product is hydrolyzed, e.g. by reaction with an alkaline hydroxide in a suitable solvent such as aqueous alcohol, from room temperature to the boiling point of the solvent.
stadijastage
Produktas ciklinamas standartinėmis amidinio ryšio sudarymo sąlygomis, pvz. veikiant BOP inertiniame tirpiklyje, tokiame kaip DMF, esant bazei (jeigu reikia), tokiai kaip diizopropiletilaminas, maždaug kambario temperatūroje.The product is cyclized under standard amide bond conditions, e.g. with BOP in an inert solvent such as DMF in the presence of a base (if necessary) such as diisopropylethylamine at about room temperature.
N23 schemaSchematic of N23
Rį /Rh /
P rotP rot
R,R,
NU -jį—(CH2)„CO l\TNU - (CH 2 ) CO l \ T
R,R,
Z, = CO, so2, SO2NR5 Z 1 = CO, so 2 , SO 2 NR 5
R, schemos junginys 2 gali būti tiesiogiai deblokuojamas taip, kaip aprašyta 12 schemos 3 stadijoje ir veikiamas taip, kaip aprašyta 12 schemos 4 stadijoje. Kitu atveju, 12 schemos junginys 5 gali būti pagaminamas redukuojant, pvz. ličio aliuminio hidridu arba boranu, 23 schemos junginį 3, kuriame Zi nėra CO.R, Scheme 2 may be directly deprotected as described in Scheme 12, Step 3, and treated as described in Scheme 12, Step 4. Alternatively, compound 5 of Scheme 12 may be prepared by reduction, e.g. lithium aluminum hydride or borane, Scheme 23, compound 3, wherein Zi is not CO.
schemascheme
7., = S02, SO2NR5 schemos junginys 5 gali būti veikiamas imidazolo grupę turinčiu aldehidu ir šarminio metalo cianidu, tokiu kaip NaCN, esant rūgščiai, tokiai kaip acto rūgštis, tinkamame tirpiklyje, tokiame kaip metanolis/acetonitrilas, maždaug kambario temperatūroje, ir gaunamas junginys 2. Junginys 2 gali būti redukuojamas, pvz. ličio aliuminio hidridu, tinkamame tirpiklyje, tokiame kaip eteris, maždaug kambario temperatūroje, ir gaunamas junginys 3. Junginys 3, kuriame Ri yra halogenas, pvz. bromas, gali būti pagaminamas iš junginio 3, kuriame Ri = H, veikiant halogeninimo agentu, pvz. tetrabutilamonio perbromidu, inertiniame tirpiklyje, tokiame kaip chloroformas, maždaug kambario temperatūroje. Gali būti atlikta junginio 3 redukcinio amininimo reakcija standartinėmis sąlygomis, ir gaunamas junginys 4.7., = S0 2 , Compound 5 of Scheme 5 of SO 2 NR 5 can be treated with an imidazole-containing aldehyde and an alkali metal cyanide such as NaCN in the presence of an acid such as acetic acid in a suitable solvent such as methanol / acetonitrile at about room temperature. , and the resulting compound 2. Compound 2 can be reduced, e.g. lithium aluminum hydride in a suitable solvent such as ether at about room temperature to give Compound 3 wherein R 1 is halogen, e.g. bromine may be prepared from compound 3 in which R 1 = H by the action of a halogenating agent, e.g. tetrabutylammonium perbromide in an inert solvent such as chloroform at about room temperature. The reductive amination reaction of compound 3 can be carried out under standard conditions to give compound 4.
schemascheme
schemos 1 stadijoje N-(2-nitroaril)-aminorūgšties esteris, gaunamas veikiant aminorūgšti 1-fiuor-2-nitrobenzenu, o po to esterinant, redukuojamas, pvz. vandeniliu, esant paladžio katalizatoriui, tinkamame tirpiklyje tokiame kaip etilacetatas, maždaug kambario temperatūroje. Gautas aminas ciklinamas į junginį 2 redukcijos sąlygomis. Junginys 2 acilinamas arba sulfoniiinamas taip, kaip aprašyta 1 schemos 4 stadijoje. Junginys 3 redukuojamas, pvz. boranu, tinkamame tirpiklyje, tokiame kaip metanolis, maždaug kambario temperatūroje. Junginys 3, kuriame R, yra halogenas, pvz. bromas, gali būti pagaminamas iš junginio 3, kuriame Ri = H, veikiant halogeninimo agentu, pvz. tetrabutilamonio perbromidu, inertiniame tirpiklyje, tokiame kaip chloroformas, maždaug kambario temperatūroje. Atliekama junginio 4 redukcinio amininimo reakcija su imidazolo grupę turinčiu aldehidu taip, kaip aprašyta 1 schemos 5 stadijoje.in Scheme 1, Scheme 1, the N- (2-nitroaryl) -amino acid ester obtained by treatment of the amino acid with 1-fluoro-2-nitrobenzene followed by esterification is reduced, e.g. hydrogen in the presence of palladium catalyst in a suitable solvent such as ethyl acetate at about room temperature. The resulting amine is cyclized to compound 2 under reduction conditions. Compound 2 is acylated or sulfonylated as described in Scheme 1, Step 4. Compound 3 is reduced, e.g. borane in a suitable solvent such as methanol at about room temperature. Compound 3 wherein R is halogen, e.g. bromine may be prepared from compound 3 in which R 1 = H by the action of a halogenating agent, e.g. tetrabutylammonium perbromide in an inert solvent such as chloroform at about room temperature. Reductive amination of compound 4 with an imidazole-containing aldehyde is carried out as described in Scheme 1, Step 5.
schemascheme
schemos 1 stadijoje junginys 1 veikiamas metileninimo agentu, tokiu kaip Ν,Ν,Ν’,Ν'-tetrametildiaminometanas, tinkamame tirpiklyje, tokiame kaip acto rūgšties anhidridas ir DMF, maždaug kambario temperatūroje. Po to junginys 2 veikiamas 1,2-fenilendiaminu tinkamame tirpiklyje, tokiame kaip toluenas, maždaug 115 °C temperatūroje dehidrinimo sąlygomis, pvz. su Dean-Stark’o gaudykle, pridėjus hidrochinono. Po to junginys 3 redukuojamas ir atliekama redukcinio amininimc reakcija taip, kaip aprašyta 1 schemos 5 stadijoje.In Scheme 1, compound 1 is treated with a methylating agent such as Ν, Ν, Ν ', Ν'-tetramethyldiaminomethane in a suitable solvent such as acetic anhydride and DMF at about room temperature. Compound 2 is then treated with 1,2-phenylenediamine in a suitable solvent such as toluene at about 115 ° C under dehydrogenation conditions, e.g. with a Dean-Stark trap with hydroquinone added. Compound 3 is then reduced and subjected to a reductive amine reaction as described in Scheme 1, Step 5.
Toliau aprašomi šio išradimo darbiniai pavyzdžiai, kurie yra tinkamiausi išradimo įgyvendinimo variantai. Visos temperatūros yra duodamos Celsijaus laipsniais (°C), jeigu nenurodyta kitaip. Šie pavyzdžiai tik iliustruoja išradimą, ir nėra jo apribojimas.The following are working examples of the present invention, which are preferred embodiments of the invention. All temperatures are given in degrees Celsius (° C) unless otherwise stated. These examples are merely illustrative of the invention and are not intended to be limiting thereof.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-1H1,4-benzodiazepinas (hidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (hydrochloride)
A. 1,4-Benzodiazepin-2,5-dionasA. 1,4-Benzodiazepine-2,5-dione
Maišomas izatoinės rūgšties anhidrido (16,4 g, 0,1 mol) ir glicino etilo esterio hidrochlorido tirpalas 40 ml piridino virinamas su grįžtamu šaldytuvu 7 vai. Gauta suspensija šaldoma 0 °C temperatūroje 18 vai. Nuosėdos surenkamos ir plaunamos etanoliu ir eteriu, ir gaunamas junginys A, kuris yra gelsva kieta medžiaga.A stirred solution of isatoic anhydride (16.4 g, 0.1 mol) and glycine ethyl ester hydrochloride in 40 ml of pyridine was refluxed for 7 hours. The resulting suspension is cooled to 0 ° C for 18 hours. The precipitate is collected and washed with ethanol and ether to give compound A, which is a yellowish solid.
B. 2,3,4,5-Tetrahidro-1H-1,4-benzodiazepinas j maišomą ličio aliuminio hidrido (LAH, 3,5 g, 90 mmol) suspensiją THF (100 ml) kambario temperatūroje ir argono atmosferoje dalimis, lėtai sudedamas kietas junginys A (3,5 g, 20 mmol). Sudėjus šj junginį, gauta suspensija virinama su grįžtamu šaldytuvu argono atmosferoje 18 vai., atšaldoma iki 0 °C, ir per lašinamąjį piltuvėlį supilamas NH4OH (5 ml, kone.) ir 30 ml THF mišinys. Gauta suspensija maišoma 1 vai. ir nufiltruojama. Sukoncentravus filtratą vakuume, gaunamas alyvos pavidalo junginys B.B. 2,3,4,5-Tetrahydro-1 H -1,4-benzodiazepine is added slowly to a stirred suspension of lithium aluminum hydride (LAH, 3.5 g, 90 mmol) in THF (100 mL) at room temperature under argon atmosphere. solid compound A (3.5 g, 20 mmol). After addition of this compound, the resulting suspension was refluxed under argon for 18 h, cooled to 0 ° C, and a mixture of NH 4 OH (5 mL, almost) and 30 mL of THF was added via a dropping funnel. The resulting suspension was stirred for 1 h. and filtered off. Concentration of the filtrate in vacuo afforded compound B as an oil.
C. 2,3,4,5-Tetrahidro-4-(1-naftalenilkarbonil)-1H-1,4-benzodiazepinasC. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine
Junginio B (500 mg, 3,37 mmol) ir naftalenkarboksirūgšties fenilo esterio (750 mg, 3,02 mmol) mišinys nedideliame kiekyje acetonitrilo, pridėjus katalitinį kiekį dimetilaminopiridino (DMAP), kaitinamas 110 °C temperatūroje argono atmosferoje 18 vai. Mišinys atšaldomas iki kambario temperatūros. Produktas išskiriamas sparčiosios chromatografijos metodu (1:1 etiIacetatas:heksanai), ir gaunamas junginys C, kuris yra balta kieta medžiaga (520 mg).A mixture of Compound B (500 mg, 3.37 mmol) and naphthalenecarboxylic acid phenyl ester (750 mg, 3.02 mmol) in a small amount of acetonitrile was added with a catalytic amount of dimethylaminopyridine (DMAP) at 110 ° C under argon for 18 h. The mixture is cooled to room temperature. The product was isolated by flash chromatography (1: 1 ethyl acetate: hexanes) to give Compound C as a white solid (520 mg).
D. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (hidrochloridas)D. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride)
Į maišomą junginio C (200 mg, 0,66 mmol) ir 4-formilimidazolo (110 mg, 1,15 mmol) tirpalą dichloretano (2 ml) ir acto rūgšties (1,0 ml) mišinyje iš karto pridedama NaBH(OAc)3 (190 mg). Mišinys maišomas 30 min. ir praskiedžiamas etilacetatu (25 ml), o po to NH4OH (3 ml, kone.). Mišinys maišomas kambario temperatūroje 18 vai. ir supilamas j etilacetato (50 ml) ir sotaus NaHCO3 (50 ml) mišinj. Organinis sluoksnis atskiriamas, o vandeninis sluoksnis ekstrahuojamas etilacetatu (50 ml). Sumaišyti organiniai ekstraktai plaunami sočiu NH4CI tirpalu (50 ml), džiovinami Na2SO4 ir koncentruojami vakuume. Liekana ištirpinama metanolyje (2 ml) ir pridedama 1N HCl tirpalo eteryje (2 ml). Nugarinus tirpiklį vakuume, liekana išdžiovinama vakuume ir gaunamas 1 pavyzdžio junginys, kuris yra gelsva kieta medžiaga (240 mg). MS: (M + H)+383+ To a stirred solution of compound C (200 mg, 0.66 mmol) and 4-formylimidazole (110 mg, 1.15 mmol) in dichloroethane (2 mL) and acetic acid (1.0 mL) was added NaBH (OAc) 3 immediately. (190 mg). The mixture was stirred for 30 min. and diluted with ethyl acetate (25 mL) followed by NH 4 OH (3 mL, almost). The mixture was stirred at room temperature for 18 hours. and poured into a mixture of ethyl acetate (50 mL) and saturated NaHCO 3 (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extracts were washed with saturated NH 4 Cl solution (50 mL), dried over Na 2 SO 4, and concentrated in vacuo. The residue was dissolved in methanol (2 mL) and 1N HCl in ether (2 mL) was added. Evaporation of the solvent in vacuo gave a residue which was dried in vacuo to give Example 1 as a yellowish solid (240 mg). MS: (M + H) + 383 +
Analizė išskaičiuota pagal C24H22N4O -1,75 HCl -2,5 H2O.Analysis calculated for C 24 H 2 2 N 4 O -1.75 HCl -2.5 H 2 O.
Išskaičiuota: C, 58,67; H, 5,90; N, 11,41; Cl, 12,63.Found: C, 58.67; H, 5.90; N, 11.41; Cl, 12.63.
Rasta: C, 58,48; H, 6,10; N, 11,32; Cl, 12,46.Found: C, 58.48; H, 6.10; N, 11.32; Cl, 12.46.
8-Chlor-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftaIeniIkarboniI)-1 H-1,4-benzodiazepinas (hidrochloridas)8-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (hydrochloride)
A. 8-Chlor-1,4- benzodiazepin-2,5-dionasA. 8-Chloro-1,4-benzodiazepine-2,5-dione
7-Chlorizatoinės rūgšties anhidrido (34 g, 0,17 mol) ir glicino etilo esterio hidrochlorido (24 g, 0,17 mol) tirpalas bevandeniame piridine (120 ml) šildomas iki 80 °C 1 vai. ir virinamas su grįžtamu šaldytuvu per naktį. Gauta suspensija maišoma kambario temperatūroje 3 vai. Nuosėdos nufiltruojamos, plaunamos vandeniu, ir išdžiovinus, gaunama 4,4 g junginio A, kuris yra balta kieta medžiaga. Filtratas nugarinamas, gauta kieta medžiaga perplaunama vandeniu ir išdžiovinus gaunama dar 27,2 g junginio A, kuris yra balta kieta medžiaga (bendra išeiga 85 %). MS (M + H) 211.A solution of 7-chloroisatoic acid anhydride (34 g, 0.17 mol) and glycine ethyl ester hydrochloride (24 g, 0.17 mol) in anhydrous pyridine (120 ml) was heated to 80 ° C for 1 h. and refluxed overnight. The resulting suspension was stirred at room temperature for 3 hours. The precipitate was filtered off, washed with water and dried to give 4.4 g of compound A, a white solid. The filtrate is evaporated, the solid obtained is washed with water and dried to give a further 27.2 g of compound A, which is a white solid (85% overall yield). MS (M + H) 211.
B. 8-Chlor-2,3,4,5-tetrahidro-1 H-1,4-benzodiazepinasB. 8-Chloro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
Į junginį A (1,4 g, 6,6 mmol) etilenglikolio dimetileteryje (20 ml) pridedama borano-THF (1,0 M THF, 20 ml). Skaidrus tirpalas virinamas su grįžtamu šaldytuvu 6 vai. Tirpiklis nugarinamas, o liekana veikiama sočiu natrio rūgščiuoju karbonatu. Vandeninis tirpalas ekstrahuojamas metileno chloridu. Organinis tirpalas plaunamas sočiu natrio rūgščiuoju karbonatu ir sočiu NaCl tirpalu, džiovinamas (natrio sulfatu), ir nugarinus, gaunama alyva (1,0 g). Negrynas produktas valomas chromatografiškai (10 % metanolis metileno chloride), ir gaunamas junginys B, kuris yra šiek tiek gelsva kieta medžiaga (0,56 g, 46 %). MS (M + H) 183.To compound A (1.4 g, 6.6 mmol) in ethylene glycol dimethyl ether (20 mL) was added borane-THF (1.0 M THF, 20 mL). The clear solution is refluxed for 6 hours. The solvent is evaporated and the residue is treated with saturated sodium bicarbonate. The aqueous solution was extracted with methylene chloride. The organic solution was washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), and evaporated to give an oil (1.0 g). The crude product was purified by chromatography (10% methanol in methylene chloride) to give Compound B as a slightly yellow solid (0.56 g, 46%). MS (M + H) 183.
C. 8-Chlor-2,3,4,5-tetrahidro-4-(1-naftalenilkarbonil)-1H-1,4benzodiazepinasC. 8-Chloro-2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine
J junginio B (0,154 g, 0,84 mmol) tirpalą metileno chloride (4 ml) ir natrio hidroksidą (1N, 4 ml) 0 °C temperatūroje sulašinamas 1 -naftoilchlorido (0,12 ml, 0,84 mmol) tirpalas metileno chloride (1 ml). Tirpalas maišomas 1 vai., atskiriamas organinis sluoksnis, o vandeninis sluoksnis ekstrahuojamas metileno chloridu. Sumaišyti organiniai sluoksniai džiovinami (natrio sulfatu), ir nugarinamas tirpiklis. Gauta alyva chromatografuojama (silikagelis, 5 % metanolio, 0,5 % amonio hidroksido, 94,5 % metileno chlorido), ir gaunamas junginys C, kuris yra geltona kieta medžiaga (0,26 g, 90 %). MS (M-H) 335.A solution of Compound J (0.154 g, 0.84 mmol) in methylene chloride (4 mL) and sodium hydroxide (1N, 4 mL) at 0 ° C was added dropwise to a solution of 1-naphthoyl chloride (0.12 mL, 0.84 mmol) in methylene chloride (1 mL). The solution is stirred for 1 hour, the organic layer is separated and the aqueous layer is extracted with methylene chloride. The combined organic layers were dried (sodium sulfate) and the solvent was evaporated. The resulting oil was chromatographed (silica gel, 5% methanol, 0.5% ammonium hydroxide, 94.5% methylene chloride) to give Compound C as a yellow solid (0.26 g, 90%). MS (M-H) - 335.
D. 8-Chlor-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (hidrochloridas)D. 8-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride)
D junginys pagaminamas iš junginio C pagal 1 pavyzdyje duotą D junginio gavimo metodiką. Chromatografuojant (silikagelis, 5 % metanolio, 0,5 % amonio hidroksido, 94,5 % metileno chlorido), o po to panaudojant preparatinę HPLC ir pavertus j hidrochlorido druską, gaunamas 2 pavyzdžio junginys, kuris yra nelabai balta kieta medžiaga. Lyd. temp.: 160-162 °C.Compound D is prepared from Compound C according to the procedure for the preparation of Compound D in Example 1. Chromatography (silica gel, 5% methanol, 0.5% ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion to the hydrochloride salt afforded Example 2 as an off-white solid. Lyd. mp: 160-162 ° C.
MS: (M + H)+383+ MS: (M + H) + 383 +
Analizė išskaičiuota pagal C24H21N4OCI -1,85 HCI -2,5 H2O.Analysis calculated for C24H21N4OCI HCI -1.85 -2.5 H 2 O.
Išskaičiuota: C, 59,51; H, 4,76; N, 11,57.Found: C, 59.51; H, 4.76; N, 11.57.
Rasta: C, 59,42; H, 4,84; N, 11,48.Found: C, 59.42; H, 4.84; N, 11.48.
pavyzdysexample
1,2,3,4-Tetrahidro-4-[(3H-imidazol-4-il)metil]-1-(-naftalen-1ilkarbonil)chinoksalinas (dihidrochloridas)1,2,3,4-Tetrahydro-4 - [(3H-imidazol-4-yl) methyl] -1 - (- naphthalen-1-ylcarbonyl) quinoxaline (dihydrochloride)
A, 1,2,3,4-Tetrahidrochinoksalinas j chinoksalino (2,75 g, 21 mmol) tirpalą absoliučiame EtOH (100 ml) pridedama Pt(IV)O2 (Adamso katalizatoriaus, 200 mg), ir mišinys hidrinamas (1 atm.) kambario temperatūroje 6 vai. Mišinys nufiltruojamas per celitą (Celite), ir sukoncentravus filtratą, gaunama 2,74 g junginio A, kuris yra nelabai balta kieta medžiaga (97 %) MS (M + H) 135.A, 1,2,3,4-Tetrahydroquinoxaline To a solution of quinoxaline (2.75 g, 21 mmol) in absolute EtOH (100 mL) was added Pt (IV) O 2 (Adams catalyst, 200 mg) and the mixture hydrogenated (1 atm). .) at room temperature for 6 hours. The mixture was filtered through celite (Celite) and the filtrate concentrated to give 2.74 g of Compound A as an off-white solid (97%) MS (M + H) 135.
B. 1,2,3,4-Tetrahidro-1-(naftalen-1-ilkarbonil)chinoksalinasB. 1,2,3,4-Tetrahydro-1- (naphthalen-1-ylcarbonyl) quinoxaline
J junginio A (1,0 g, 7,45 mmol) ir trietilamino (TEA, 2,1 ml, 14,9 mmol) tirpalą CH2CI2 (100 ml) -78 °C temperatūroje pridedama nafttalenkarboksirūgšties chloranhidrido (1,12 ml, 7,45 mmol). Po 2 vai. šaldymo vonia nuimama, mišinys pamaišomas kambario temperatūroje 1 vai. ir sukoncentruojamas. Liekana gryninama sparčiosios chromatografijos metodu (silikagelis, 95:5:0,1, CHCI3:MeOH:NH4OH), ir gaunamas junginys B, kuris yra nelabai balta kieta medžiaga (2,04 g, 95 %). MS (M+H) 289.To a solution of compound J (1.0 g, 7.45 mmol) and triethylamine (TEA, 2.1 mL, 14.9 mmol) in CH 2 Cl 2 (100 mL) at -78 ° C was added naphthalenecarboxylic acid anhydride (1.12 ml, 7.45 mmol). After 2 or. remove the cooling bath, stir the mixture at room temperature for 1 hour. and concentrate. The residue was purified by flash chromatography (silica gel, 95: 5: 0.1 CHCl 3: MeOH: NH 4 OH) to give compound B, which is an off-white solid (2.04 g, 95%). MS (M + H) 289.
C, 1,2,3,4-Tetrahidro-4-[(3H-imidazol-4-il)metil]-1-(-naftalen-1-ilkarbonil)chinoksalinas (dihidrochloridas)C, 1,2,3,4-Tetrahydro-4 - [(3H-imidazol-4-yl) methyl] -1 - (- naphthalen-1-ylcarbonyl) quinoxaline (dihydrochloride)
C junginys pagaminamas iš junginio B pagal 1 pavyzdyje duotą D junginio gavimo metodiką. Chromatografuojant (silikagelis, 10 % etanolis/etilacetate) gaunama skaidri geltona alyva, kuri paverčiama hidrochloridu, panaudojant 4N HCI dioksane (4 ml, kambario temperatūra, 2 vai); gaunamas 3 pavyzdžio junginys, kuris yra nelabai balta kieta medžiaga. MS: (M + H)+289+ Compound C is prepared from Compound B according to the procedure for Preparation D of Example 1. Chromatography (silica gel, 10% ethanol / ethyl acetate) gives a clear yellow oil which is converted to the hydrochloride using 4N HCl in dioxane (4 mL, room temperature, 2 h); The compound of Example 3 is obtained which is an off-white solid. MS: (M + H) + 289 +
Analizė išskaičiuota pagal C23H2oN40 -1,9 HCI.Analysis calculated for C 23 H 2 O 4 O · 0.9 HCl.
Išskaičiuota; C, 63,10; H, 5,04; N, 12,47.Excluded; C, 63.10; H, 5.04; N, 12.47.
Rasta: C, 63,10; H, 5,39; N, 12,47.Found: C, 63.10; H, 5.39; N, 12.47.
pavyzdysexample
2,3,4,5-Tetrahidro-4-(1H-imidazol-4-il-metil)-1-(1-naftaIenilkarbonil)-1H1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-4- (1H-imidazol-4-yl-methyl) -1- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (dihydrochloride)
A. 2,3,4,5-Tetrahidro-4-[(1,1-dimetiletoksi)-karbonil]-1H-1,4-benzodiazepinas j maišomą 1 pavyzdžio junginio B (300 mg) tirpalą pridedama di-tbutildikarbonato (400 mg). Mišinys maišomas kambario temperatūroje 18 vai., ir reakcija stabdoma, pridedant sotaus NaHCO3 tirpalo. Tirpiklis nugarinamas, o liekana chromatografuojama (sparčioji chromatografija, silikagelis, 1:2 etilacetatas:heksanai). Gaunamas alyvos pavidalo junginys A (350 mg).A. 2,3,4,5-Tetrahydro-4 - [(1,1-dimethylethoxy) carbonyl] -1H-1,4-benzodiazepine is added di-t-butyl dicarbonate (400 mg) to a stirred solution of Example 1 Compound B (300 mg). mg). The mixture was stirred at room temperature for 18 hours and quenched by the addition of saturated NaHCO 3 solution. The solvent was evaporated and the residue was chromatographed (flash chromatography, silica gel, 1: 2 ethyl acetate: hexanes). Obtained as an oil, Compound A (350 mg).
B. 2,3,4,5-Tetrahidro-1-(1-naftalenilkarbonil)-4-[(1,1-dimetiletoksi)karbonil]-1H-1,4-benzodiazepinasB. 2,3,4,5-Tetrahydro-1- (1-naphthalenylcarbonyl) -4 - [(1,1-dimethylethoxy) carbonyl] -1H-1,4-benzodiazepine
J maišomą junginio A (350 mg, 1,4 mmol) tirpalą metileno chloride 0 °C temperatūroje ir argono atmosferoje pridedama 1-naftalenkarboksirūgšties chloranhidrido (0,22 ml, 1,4 mmol), o po to piridino (0,25 ml). Mišinys pamaišomas 2 vai. Po to pridedama sotaus NaHCO3, ir mišinys maišomas 18 vai. kambario temperatūroje. Gautas tirpalas supilamas j metileno chlorido ir sotaus NaHCO3 mišinį. Organinis sluoksnis atskiriamas, plaunamas 10 % HCI (2 x 25 ml), džiovinamas (MgSO4) ir sukoncentravus vakuume, gaunamas alyvos pavidalo junginys B (450 mg, 80 %).To a stirred solution of compound A (350 mg, 1.4 mmol) in methylene chloride at 0 ° C under argon was added 1-naphthalenecarboxylic acid chloro anhydride (0.22 mL, 1.4 mmol) followed by pyridine (0.25 mL). . The mixture is stirred for 2 hours. Then saturated NaHCO 3 and the mixture was stirred for 18 h. at room temperature. The resulting solution was poured into a mixture of methylene chloride and saturated NaHCO 3 . The organic layer was separated, washed with 10% HCl (2 x 25 mL), dried (MgSO 4 ), and concentrated in vacuo to give compound B (450 mg, 80%) as an oil.
C. 2,3,4,5-Tetrahidro-1-(1-naftalenilkarbonil)-1H-1,4-benzodiazepinasC. 2,3,4,5-Tetrahydro-1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine
Junginys B ištirpinamas metileno chlorido ir TFA mišinyje (10 ml, 1:10. Tirpalas maišomas kambario temperatūroje 2 vai. Tirpiklis nugarinamas vakuume, liekana praskiedžiama CHCI3 ir pašarminama 10N NaOH tirpalu. Organinis sluoksnis atskiriamas, džiovinamas (MgSO4) ir sukoncentravus, gaunamas alyvos pavidalo junginys C (310 mg, 92 %).Compound B was dissolved in a mixture of methylene chloride and TFA (10 mL, 1:10). The solution was stirred at room temperature for 2 h. The solvent was evaporated in vacuo, the residue was diluted with CHCl 3 and basified with 10N NaOH. The organic layer was separated, dried (MgSO 4 ) Compound C (310 mg, 92%) as an oil.
D. 2,3,4,5-Tetrahidro-4-(1H-imidazol-4-ilmetil)-1-(1naftaIenilkarbcnil)-1H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys (šiek tiek gelsva kieta medžiaga) pagaminamas iš junginio C pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką.D. Preparation of 2,3,4,5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) as a slightly yellow solid. from compound C according to the procedure for the preparation of compound D as described in Example 1.
Analizė išskaičiuota pagal C24H22N4O -2,0 HCI -1,3 H2O.Analysis calculated for C 24 H 2 2 N 4 O -2.0 HCl -1.3 H 2 O.
Išskaičiuota: C, 60,20; H, 5,60; N, 11,70; Cl, 14,82.Found: C, 60.20; H, 5.60; N, 11.70; Cl, 14.82.
Rasta: C, 60,21; H, 5,60; N, 11,48; Cl, 14,68.Found: C, 60.21; H, 5.60; N, 11.48; Cl, 14.68.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-il-metil)-2-metil-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (hidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -2-methyl-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride)
A. 2-M eti I-1,4-benzodiazepin-3-onasA. 2-M Ethyl-1,4-benzodiazepin-3-one
Junginio A Boc darinys pagaminamas iš 2-amino-N-[(1,1dimetiletoksi)karbonil]fenilmetilamino ir metilpiruvato pagal 1 pavyzdyje aprašytą D junginio sintezės metodiką. Gauta alyva ištirpinama metileno chlorido ir TFA mišinyje (8 ml, 1:1), tirpalas maišomas kambario temperatūroje 1 vai. ir koncentruojamas vakuume. Liekana paskirstoma tarp eterio ir 10 % HCI tirpalo, vandeninis sluoksnis pašarminamas 10N NaOH tirpalu iki pH 11 ir ekstrahuojamas etilacetatu (2 x 50 ml). Sumaišyti organiniai ekstraktai džiovinami MgSO4, ir sukoncentravus, gaunamas junginys A, kuris yra kieta medžiaga (250 mg, 28 %). Lyd. temp.: 149-151 °C. MS (M + H) 177.The Boc derivative of Compound A is prepared from 2-amino-N - [(1,1-dimethylethoxy) carbonyl] phenylmethylamine and methyl pyruvate according to the synthesis procedure for Compound D described in Example 1. The resulting oil was dissolved in a mixture of methylene chloride and TFA (8 mL, 1: 1), and the solution was stirred at room temperature for 1 h. and concentrated in vacuo. The residue was partitioned between ether and 10% HCl, the aqueous layer was basified to pH 11 with 10N NaOH and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over MgSO 4 and concentrated to give Compound A as a solid (250 mg, 28%). Lyd. m.p. 149-151 ° C. MS (M + H) 177.
B. 2-Metil-1,4-benzodiazepinasB. 2-Methyl-1,4-benzodiazepine
Į LAH (160 mg, 4,21 mmol) suspensiją bevandeniame THF (5 ml) kambario temperatūroje sulašinamas junginio A (181 mg, 1,03 mmol) tirpalas. Šis tirpalas virinamas su grįžtamu šaldytuvu 5 vai., atšaldomas iki 0 °C ir praskiedžiamas THF (20 ml). Sulašinamas sotus NaCl tirpalas (0,5 ml), mišinys maišomas kambario temperatūroje 18 vai. ir nufiltruojamas per MgSO4 sluoksnį. Šis MgSO4 sluoksnis perplaunamas etilacetatu, ir sumaišyti filtratai koncentruojami vakuume. Gaunamas junginys B, kuris yra pusiau kieta medžiaga (160 mg, 96 %). MS (M + H) 163.To a suspension of LAH (160 mg, 4.21 mmol) in anhydrous THF (5 mL) is added a solution of Compound A (181 mg, 1.03 mmol) at room temperature. This solution was refluxed for 5 h, cooled to 0 ° C, and diluted with THF (20 mL). Saturated NaCl solution (0.5 mL) was added dropwise and the mixture was stirred at room temperature for 18 hours. and filtered through a MgSO 4 layer. The MgSO 4 layer was washed with ethyl acetate and the combined filtrates concentrated in vacuo. Compound B is obtained which is a semi-solid (160 mg, 96%). MS (M + H) 163.
C. 2-Metil-4-(1-naftalenilkarbonil)-1,4-benzodiazepinasC. 2-Methyl-4- (1-naphthalenylcarbonyl) -1,4-benzodiazepine
Junginys C pagaminamas iš junginio B pagal 2 pavyzdyje aprašytą junginio C gavimo metodiką. Po chromatografijos (sparčioji chromatografija, silikagelis, 1:1 etilacetatas:heksanai) gaunamas junginys C, kuris yra kieta medžiaga. Lyd. temp.: 75 °C. MS (M + H) 317.Compound C is prepared from Compound B according to the procedure described in Example 2 for the preparation of Compound C. Chromatography (flash chromatography, silica gel, 1: 1 ethyl acetate: hexanes) gives compound C as a solid. Lyd. mp: 75 ° C. MS (M + H) 317.
D. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-2-metil-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (hidrochloridas) pavyzdžio junginys (šiek tiek gelsva kieta medžiaga) pagaminamas iš junginio C pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką. Lyd. temp.: 165 °C (putoja). MS (M + H) 397.D. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -2-methyl-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride) Example Compound (slightly yellowish) solid) is prepared from Compound C according to the procedure for the preparation of Compound D as described in Example 1. Lyd. mp: 165 ° C (foam). MS (M + H) 397.
Analizė išskaičiuota pagal C25H24N4O -2,4 HCI -1,0 H2O -0.5 CH3OH. Išskaičiuota: C, 59,12; H, 5,92; N, 10,84; Cl, 16,42.Analysis calculated for C25H24N4O HCl -2.4 -1.0 -0.5 H 2 O CH 3 OH. Found: C, 59.12; H, 5.92; N, 10.84; Cl, 16.42.
Rasta: C, 59,09; H, 5,58; N, 10,48; Cl, 16,28.Found: C, 59.09; H, 5.58; N, 10.48; Cl, 16.28.
pavyzdysexample
2,3,4,5-Tetrahidro-4-(1-naftalenilkarbonil)-1-[[1-(fenilmetil)-1H-imidazol· 5-il]metil]-1H-1,4-benzodiazepinas (hidrochloridas)2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1 - [[1- (phenylmethyl) -1H-imidazol-5-yl] methyl] -1H-1,4-benzodiazepine (hydrochloride)
A. 2,3,4,5-Tetrahidro-4-(1-naftalenilkarbonil)-1-[[1-(trifenilmetil)-1Himidazol-4-il]metil]-1H-1,4-benzodiazepinasA. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1 - [[1- (triphenylmethyl) -1Himidazol-4-yl] methyl] -1H-1,4-benzodiazepine
J 1 pavyzdžio junginio (90 mg, 0,21 mmol) tirpalą acetonitrile (1 ml) kambario temperatūroje ir argono atmosferoje pridedama TEA (0,14 μΙ, 1 mmol), o po to trifenilmetilchlorido (56 mg, 0,2 mmol). Mišinys virinamas su grjžtamu šaldytuvu 2 vai., atšaldomas iki kambario temperatūros ir maišomas vai. Nuosėdos nufiltruojamos, ir sukoncentravus filtratą, gaunamas junginys A (110 mg, 92 %). MS (M + H)+ = 625.To a solution of the compound of Example 1 (90 mg, 0.21 mmol) in acetonitrile (1 mL) at room temperature under argon was added TEA (0.14 μΙ, 1 mmol) followed by triphenylmethyl chloride (56 mg, 0.2 mmol). The mixture is refluxed for 2 hours, cooled to room temperature and stirred in the oven. The precipitate was filtered off and concentrated the filtrate to give Compound A (110 mg, 92%). MS (M + H) <+> = 625.
B. 2,3,4,5-Tetrahidro-4-(1-naftalenilkarbonil)-1-[[1-(fenilmetil)-1Himidazol-5-il]metil]-1 H-1,4-benzodiazepinas (hidrochloridas) j benzilo alkoholio (18 μΙ, 0,18 mmol) tirpalą THF (1 ml) -78 °C temperatūroje, argono atmosferoje pridedama trifluormetansulfonrūgšties anhidrido (30 μΙ, 0,18 mmol) ir DIPEA (35 μΙ, 2 mmol). Po 20 min. sulašinamas junginio A (100 mg, 0,15 mmol) tirpalas THF (1 ml). Mišiniui per 3 vai. leidžiama sušilti iki kambario temperatūros ir maišoma 14 vai. Pridedama acto rūgšties (1,5 ml) ir vandens (1 ml), mišinys pavirinamas su grįžtamu šaldytuvu 30 min., atšaldomas iki kambario temperatūros ir nugarinamas. Liekana ištirpinama chloroforme, tirpalas plaunamas sočiu NaHCO3 tirpalu, džiovinamas (MgSO4) ir koncentruojamas. Liekana chromatografuojama (sparčioji chromatografija, silikagelis, 9:1 CHCI3:MeOH). Grynas produktas ištirpinamas etilacetate, ir per tirpalą leidžiamos HCI dujos 30 sek. Nugarinus gaunamas 6 pavyzdžio junginys (33 mg, bendra išeiga 33 %).B. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1 - [[1- (phenylmethyl) -1Himidazol-5-yl] methyl] -1H-1,4-benzodiazepine (hydrochloride) To a solution of benzyl alcohol (18 μΙ, 0.18 mmol) in THF (1 mL) at −78 ° C was added trifluoromethanesulfonic anhydride (30 μΙ, 0.18 mmol) and DIPEA (35 μΙ, 2 mmol) under argon. After 20 minutes A solution of Compound A (100 mg, 0.15 mmol) in THF (1 mL) was added dropwise. For 3 hours. Allow to warm to room temperature and stir for 14 hours. Acetic acid (1.5 mL) and water (1 mL) were added and the mixture was refluxed for 30 min, cooled to room temperature and evaporated. The residue is dissolved in chloroform, washed with saturated NaHCO 3 solution, dried (MgSO 4 ) and concentrated. The residue was chromatographed (flash chromatography, silica gel, 9: 1 CHCI 3: MeOH). The pure product was dissolved in ethyl acetate and HCl gas was bubbled through the solution for 30 sec. Evaporation afforded Example 6 (33 mg, 33% overall yield).
MS (M + H)+ =473. IR (KBr) 2853, 1630, 1508 cm·1.MS (M + H) <+> = 473. IR (KBr) 2853, 1630, 1508 cm -1 .
pavyzdysexample
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilsulfonil)-1H1,4-benzodiazepinas (hidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylsulfonyl) -1H1,4-benzodiazepine (hydrochloride)
A. 2,3,4,5-Tetrahidro-4-(1-naftalenilsulfonil)-1H-1,4-benzodiazepinasA. 2,3,4,5-Tetrahydro-4- (1-naphthalenylsulfonyl) -1H-1,4-benzodiazepine
Junginys A pagaminamas iš 1 pavyzdžio junginio B ir 1naftalensulfonichlorido pagal 2 pavyzdyje aprašytą junginio C gavimo metodiką. Perkristalinus iš metanolio, gaunamas junginys A, kuris yra kieta medžiaga. Lyd. temp.: 165-166 °C. MS (M+H) 339.Compound A is prepared from Example 1 Compound B and 1-naphthalenesulfonyl chloride according to the procedure described in Example 2 for the preparation of Compound C. Recrystallization from methanol gives compound A, which is a solid. Lyd. mp: 165-166 ° C. MS (M + H) 339.
B. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilsulfonil)1 H-1,4-benzodiazepinas (hidrochloridas) pavyzdžio junginys (balta kieta medžiaga) gaunamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką. Lyd. temp.: 140 °C (putoja).B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylsulfonyl) -1H-1,4-benzodiazepine (hydrochloride) Example compound (white solid) from Compound A according to the procedure for the preparation of Compound D as described in Example 1. Lyd. 140 ° C (foam).
MS (M + H) 419.MS (M + H) 419.
Analizė išskaičiuota pagal G23H22N4O2S -1,5 HCI -1,0 H2O.Analysis calculated for G 23 H 22 N 4 O 2 S -1.5 HCl -1.0 H 2 O.
Išskaičiuota: C, 56,34: H, 5,22; N, 11,43; Cl, 10,85; S, 6,54.Found: C, 56.34: H, 5.22; N, 11.43; Cl, 10.85; S, 6.54.
Rasta: C, 56,70; H, 5,16; N, 11,04; Cl, 10,72; S, 6,54.Found: C, 56.70; H, 5.16; N, 11.04; Cl, 10.72; S, 6.54.
(S)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-3-[2-(metiltio)etil]-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (hidrochloridas) pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš izatoinės rūgšties anhidrido ir L-metionino metilo esterio hidrochlorido pagal reakcijų seką, aprašytą šiems junginiams gauti: 1 pavyzdžio junginiui A; 1 pavyzdžio junginiui B, išskyrus tai, kad tirpikliu buvo naudojamas etilenglikolio dimetilo eteris; 2 pavyzdžio junginiui C; 1 pavyzdžio junginiui D. Lyd. temp.: 78-80 °C.(S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride) Example compound (yellow solid) is prepared from isatoic anhydride and L-methionine methyl ester hydrochloride according to the reaction sequence described for the following compounds: Example 1 Compound A; Compound B of Example 1, except that ethylene glycol dimethyl ether was used as solvent; The compound C of Example 2; For the compound of Example 1, D. Lyd. m.p. 78-80 ° C.
MS (M+H) 457.MS (M + H) 457.
Analizė išskaičiuota pagal C27H28N4OS -1,6 HCI -2,3 H2O.Analysis calculated for C 27 H 28 N 4 OS -1.6 HCl -2.3 H 2 O.
Išskaičiuota: C, 58,28; H, 6,20; N, 10,07; S, 5,76; Cl, 10,19.Found: C, 58.28; H, 6.20; N, 10.07; S, 5.76. Cl, 10.19.
Rasta;Found;
C, 58,02; H, 5,87; N, 12,23; S, 4,95; Cl, 10,27.C, 58.02; H, 5.87; N, 12.23; S, 4.95; Cl, 10.27.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-il-metil)-N-metil-N-fenil-4H-1,4benzodiazepin-4-karboksamidas (hidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -N-methyl-N-phenyl-4H-1,4-benzodiazepine-4-carboxamide (hydrochloride)
A. 2,3,4,5-Tetrahidro-N-metil-N-fenil-4H-1,4-benzodiazepin-4karboksamidasA. 2,3,4,5-Tetrahydro-N-methyl-N-phenyl-4H-1,4-benzodiazepine-4-carboxamide
J maišomą 1 pavyzdžio junginio B (0,5 g, 3,35 mmol) tirpalą THF, esant NaHCO3 (1,68 g, 20 mmol), pridedama N-metil-N-fenilkarbamoilchlorido (480 mg, 2,83 mmol). Mišinys maišomas kambario temperatūroje 18 vai., po to nufiltruojamas. Sukoncentravus filtratą vakuume ir liekaną perkristalinus iš metanolio, gaunamas junginys A, kuris yra balta kieta medžiaga (720 mg, 76 %). Lyd. temp.: 159-160 °C.To a stirred solution of Example 1 Compound B (0.5 g, 3.35 mmol) in THF in NaHCO 3 (1.68 g, 20 mmol) was added N-methyl-N-phenylcarbamoyl chloride (480 mg, 2.83 mmol). . The mixture was stirred at room temperature for 18 hours and then filtered. Concentration of the filtrate in vacuo and recrystallization of the residue from methanol gave compound A as a white solid (720 mg, 76%). Lyd. mp: 159-160 ° C.
B. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-N-metil-N-fenil-4H-1,4benzodiazepin-4-karboksamidas (hidrochloridas) pavyzdžio junginys (balta kieta medžiaga) yra pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką. Lyd. temp.; 145 °C (susitraukia).B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-N-phenyl-4H-1,4-benzodiazepine-4-carboxamide (hydrochloride) Example compound (white solid) ) is prepared from Compound A according to the procedure for the preparation of Compound D as described in Example 1. Lyd. temp .; 145 ° C (shrinks).
MS (M + H) 362.MS (M + H) 362.
Analizė išskaičiuota pagal C21H23N5O -1,8 HCI -1,0 H2O.Analysis calculated for C21H23N5O HCl -1.8 -1.0 H 2 O.
Išskaičiuota: C, 56,67; H, 6,07; N, 15,74; Cl, 14,34.Found: C, 56.67; H, 6.07; N, 15.74; Cl, 14.34.
Rasta: C, 57,08; H, 6,03; N, 15,40; Cl, 14,53.Found: C, 57.08; H, 6.03; N, 15.40; Cl, 14.53.
2-I2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-1H-1,4-benzodiazepin-4il]sulfonil]benzenkarboksirūgšties metilo esteris (hidrochloridas) pavyzdžio junginys (balta kieta medžiaga) yra pagaminamas iš metoksikarbonilbenzensulfonilchlorido ir 2 pavyzdžio junginio B taip, kaip aprašyta reakcijų sekoje tokiems junginiams gauti: 2 pavyzdžio junginiui C; 1 pavyzdžio junginiui D. MS (M + H) 427.2-1,2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepin-4yl] sulfonyl] benzoic acid methyl ester (hydrochloride), the title compound (white solid) is prepared from methoxycarbonylbenzenesulfonyl chloride and Example 2 Compound B as described in the reaction sequence to afford the following compounds: Example 2 Compound C; For Example 1, Compound D. MS (M + H) 427.
Analizė išskaičiuota pagal C2iH22N4O4S -1,1 HCI -1,0 H2O.Analysis calculated for C 2 i H 22 N 4 O 4 S -1.1 HCl -1.0 H 2 O.
Išskaičiuota: C, 56,04; H, 5,22; N, 11,56; S, 6,62; Cl, 8,05.Found: C, 56.04; H, 5.22; N, 11.56; S, 6.62. Cl, 8.05.
Rasta: C, 52,20; H, 5,11; N, 10,40; S, 7,20; Cl, 8,09.Found: C, 52.20; H, 5.11; N, 10.40; S, 7.20; Cl, 8.09.
7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-2-metil-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (hidrochloridas)7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -2-methyl-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride)
A. 7-Brom-1,4-benzodiazepin-2,5-dionasA. 7-Bromo-1,4-benzodiazepine-2,5-dione
Junginys A buvo pagamintas iš 6-bromizatoinės rūgšties anhidrido pagal 1 pavyzdyje aprašytą junginio A gavimo metodiką.Compound A was prepared from 6-bromoacetic acid anhydride according to the procedure for preparation of Compound A described in Example 1.
B. 7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenūkarbonil)-1H-1,4-benzodiazepinas (hidrochloridas) pavyzdžio junginys (kieta medžiaga) buvo pagamintas iš junginio A taip kaip aprašyta reakcijų sekoje tokiems junginiams gauti: 2 pavyzdžio junginiui B; 2 pavyzdžio junginiui C; 1 pavyzdžio junginiui D. Atikus šio junginio chromatografiją (5 % metanolio, 0,5 % amonio hidroksido, 94,5 % metileno chlorido), o po to dar preparatinę HPLC ir pavertus jį hidrochlorido druska, gaunamas 11 pavyzdžio junginys. Lyd. temp.: 160-162 °C.B. Example compound 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (hydrochloride) (solid) was prepared from Compound A as described in the reaction sequence to afford the following compounds: Example 2 Compound B; The compound C of Example 2; Example 1 Compound D. Chromatography of this compound (5% methanol, 0.5% ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion to the hydrochloride salt afforded Example 11. Lyd. mp: 160-162 ° C.
MS (M + H) 461.MS (M + H) 461.
Analizė išskaičiuota pagal C24H2iBrN4O -1,5 HCI.Analysis calculated for C 24 H 2 iBrN 4 O · 1.5 HCl.
Išskaičiuota: C, 55,86; H, 4,39; N, 10,86.Found: C, 55.86; H, 4.39; N, 10.86.
Rasta: C, 55,84; H, 4,49; N, 10,71.Found: C, 55.84; H, 4.49; N, 10.71.
pavyzdysexample
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftaleniikarbonil)-7fenil-1H-1,4-benzodiazepinas (hidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -7-phenyl-1H-1,4-benzodiazepine (hydrochloride)
A. 7-Fenil-1,4-benzodiazepin-2,5-dionas pavyzdžio junginio A (0,834 g, 3,1 mmol) tirpalas 20 ml 1:1 DMF:THF degazuojamas azotu. Pridedama paladžio tetrakistrifenilfosfino. Po pusės valandos pridedama bevandenio natrio karbonato (0,37 g, 3,5 mmol) tirpalo vandenyje (6 ml) ir fenilboro rūgšties (1,00 g, 8,3 mmol). Suspensija maišoma kambario temperatūroje per naktį, paskui 80-90 °C temperatūroje 2 dienas. Ši suspensija nufiltruojama. Nuosėdos plaunamos vandeniu ir etilacetatu, ir gaunamas junginys A, kuris yra šiek tiek pilka kieta medžiaga (0,65 g, 84 %). LC-MS (M + H)+ 253.A. A solution of 7-phenyl-1,4-benzodiazepine-2,5-dione compound A (0.834 g, 3.1 mmol) in 20 mL of 1: 1 DMF: THF is degassed with nitrogen. Palladium tetrakistriphenylphosphine is added. After half an hour, a solution of anhydrous sodium carbonate (0.37 g, 3.5 mmol) in water (6 mL) and phenylboronic acid (1.00 g, 8.3 mmol) was added. The suspension was stirred at room temperature overnight, then at 80-90 ° C for 2 days. The suspension is filtered. The precipitate was washed with water and ethyl acetate to give Compound A as a slightly gray solid (0.65 g, 84%). LC-MS (M + H) + 253.
B. 7-Fenil-1,4-benzodiazepinas j 11 pavyzdžio junginio A (0,62 g, 2,5 mmol) suspensiją THF pridedama LAH THF (1,0 M THF, T ml). Ši suspensija maišoma 3 vai. ir virinama su grįžtamu šaldytuvu 2 vai. Atšaldžius iki kambario temperatūros, pridedama natrio hidroksido (1 N, 5 ml), o po to 10 ml sotaus natrio kalio tartrato. Vandeninis tirpalas ekstrahuojamas metileno chloridu. Organinė fazė džiovinama (natrio sulfatu) ir nugarinama. Gauta alyva gryninama chromatografijos metodu (10 % metanolis metileno chloride), ir gaunamas junginys B, kuris yra gelsva kieta medžiaga (0,46 g, 58 %). LC-MS (M + H) + 225.B. 7-Phenyl-1,4-benzodiazepine To a suspension of Example 11 Compound A (0.62 g, 2.5 mmol) in THF was added LAH THF (1.0 M THF, T mL). The suspension is stirred for 3 hours. and boil under reflux for 2 hours. After cooling to room temperature, sodium hydroxide (1 N, 5 ml) was added followed by 10 ml of saturated sodium potassium tartrate. The aqueous solution was extracted with methylene chloride. The organic phase is dried (sodium sulfate) and evaporated. The resulting oil was purified by chromatography (10% methanol in methylene chloride) to give Compound B as a yellowish solid (0.46 g, 58%). LC-MS (M + H) + 225.
C. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-7-fenil-1H-1,4-benzodiazepinas (hidrochloridas) pavyzdžio junginys (kieta medžiaga) pagaminamas iš junginio B pagal aprašytą reakcijų seką tokiems junginiams gauti: 2 pavyzdžio junginiui C; 1 pavyzdžio junginiui D. Atikus šio junginio chromatografiją (5 % metanolio, 0,5 % amonio hidroksido, 94,5 % metileno chlorido), o po to dar preparatinę HPLC ir pavertus jį hidrochlorido druska, gaunamas 12 pavyzdžio junginys. Lyd. temp.: 158-160 °C.C. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (hydrochloride) Example compound (solid) prepared from Compound B according to the reaction sequence described to give the following compounds: Example C; Example 1 Compound D. Chromatography of this compound (5% methanol, 0.5% ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion to the hydrochloride salt afforded Example 12. Lyd. mp: 158-160 ° C.
MS (M + H) 459.MS (M + H) 459.
Analizė išskaičiuota pagal C30H26N4O -2,0 HCIO,58H2O.Analysis calculated for C30H26N4O -2.0 HCIO, 58H 2 O.
Išskaičiuota: C, 66,50; H, 5,42; N, 10,34. ·Found: C, 66.50; H, 5.42; N, 10.34. ·
Rasta: C, 66,56; H, 5,64; N, 10,00.Found: C, 66.56; H, 5.64; N, 10.00.
2,3,4,5-Tetrahidro-1-(1H-imidazol-2-ilmetil)-4-(1-naftalenilkarbonil)-1H1,4-benzodiazepinas (hidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-2-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (hydrochloride)
J 1 pavyzdžio junginio C (50 mg, 0,085 mmol) tirpalą dichioretane (5 ml) pridedama 2-imidazolkarboksaldehido (33 mg, 0,34 mmol), NaBH(OAc)3 (72 mg, 0,34 mmol) ir ledinės acto rūgšties (0,2 ml). Mišinys maišomas 16 vai. Pridedama sotaus vandeninio natrio rūgščiojo karbonato tirpalo (0,5 ml), ir tirpalas sausai nugarinamas. Liekana ištirpinama mišinyje (50/50) iš 0,1 % TFA metanolyje ir 0,1 % TFA vandenyje ir supilama į YMC C18 kolonėlę (S-5, ODS 30x250 mm). Gryninimas HPLC metodu atliekamas tokiomis sąlygomis: tirpiklis A: 0,1 % TFA 90 % vandens ir 10 % metanolio tirpale; tirpiklis B; 0,1 % TFA 90 % metanolio ir 10 % vandens tirpale: 10-90 % B tirpale A per 30 min. Frakcijos, kuriose yra didžiausia smailė, supilamos kartu, ir po jų liofilizacijos gaunama balta kieta medžiaga. Pridedama 1M HCI (6 ml), ir tirpalas sukoncentruojamas iki stiklo pavidalo medžiagos. Pakartojus šią stadiją, gaunama 25 mg (66 %) 13 pavyzdžio baltos, stiklo pavidalo kietos medžiagos.To a solution of compound C (50 mg, 0.085 mmol) in Example 1 in dichloroethane (5 mL) was added 2-imidazolecarboxaldehyde (33 mg, 0.34 mmol), NaBH (OAc) 3 (72 mg, 0.34 mmol) and glacial acetic acid. (0.2 mL). The mixture is stirred for 16 hours. Saturated aqueous sodium bicarbonate solution (0.5 ml) is added and the solution is evaporated to dryness. The residue was dissolved in a mixture (50/50) of 0.1% TFA in methanol and 0.1% TFA in water and applied to a YMC C18 column (S-5, ODS 30x250 mm). Purification by HPLC is carried out under the following conditions: solvent A: 0.1% TFA in 90% water and 10% methanol; solvent B; 0.1% TFA in 90% methanol and 10% water: 10-90% B in solution A over 30 min. The highest peak fractions are pooled and lyophilized to give a white solid. 1M HCl (6 mL) was added and the solution was concentrated to a glass. Repeat this step to obtain 25 mg (66%) of Example 13 as a white glassy solid.
MS (M + H)+383.MS (M + H) + 383.
1H-BMR (CD3OD, 270 MHz) 6 8,11(2H, m), 7,7-7,1 (10H, m), 6,71 (0,5H, t, J=7,05 Hz), 6,07 (0,5H, d, J=7,05 Hz), 5,01(1 H, m), 4,7-4,0 (2H, m), 3,6-3,4 (4H, m), 3,1(1H,m). 1 H-NMR (CD 3 OD, 270 MHz) δ 8.11 (2H, m), 7.7-7.1 (10H, m), 6.71 (0.5H, t, J = 7.05 Hz), 6.07 (0.5H, d, J = 7.05Hz), 5.01 (1H, m), 4.7-4.0 (2H, m), 3.6-3, 4 (4H, m), 3.1 (1H, m).
2,3,4,5-Tetrahidro-1-[3-(1H-imidazol-2-il)propil]-4-(1-naftalenilkarbonil)1H-1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- [3- (1H-imidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) 1H-1,4-benzodiazepine (dihydrochloride)
A. 3-[imidazol-2-iI]-propenkarboksirūgšties etilo esteris j šaldomą (0 °C) natrio hidrido (1,86 g, 45,8 mmol, 60 % dispersija mineralinėje alyvoje, prieš tai perplauta THF ir išdžiovinta N2) tirpalą 1,2dimetoksietane (DME, 20 ml) per 15 min. sulašinamas trietilfosfonacetatas (12 g, 54,1 mmol), ištirpintas DME (10 ml). Tirpalas maišomas 1 vai. kambario temperatūroje, po to pridedama 2-imidazolacetaldehido (4 g, 41,6 mmol) 20 ml DME. Tirpalas maišomas ir virinamas su grįžtamu šaldytuvu (85 °C) 15 min., po to atvėsinama iki 60 °C ir laikoma 1 vai. Šaldant, tirpalas sukoncentruojamas iki 1/2 pradinio tūrio ir nufiltruojamas. Kieta medžiaga perkristalinama iš metanolio, etilacetato ir heksanu mišinio, ir gaunama 5,1 g (74 %) junginio A, kuris yra balta kristalinė medžiaga. MS (M + H)+ 167.A. Ethyl 3- [imidazol-2-yl] -propionic acid ethyl ester into cooled (0 ° C) sodium hydride (1.86 g, 45.8 mmol, 60% dispersion in mineral oil, washed with THF and dried over N 2 ). solution in 1,2-dimethoxyethane (DME, 20 mL) over 15 min. triethylphosphonacetate (12 g, 54.1 mmol) dissolved in DME (10 mL) was added dropwise. The solution is stirred for 1 hour. at room temperature, followed by the addition of 2-imidazoleacetaldehyde (4 g, 41.6 mmol) in 20 mL of DME. The solution was stirred and refluxed (85 ° C) for 15 minutes, then cooled to 60 ° C and held for 1 hour. Upon cooling, the solution is concentrated to 1/2 initial volume and filtered. The solid was recrystallized from a mixture of methanol, ethyl acetate and hexanes to give 5.1 g (74%) of compound A as a white crystalline solid. MS (M + H) + 167.
B. 3-[imidazol-2-il]-propankarboksirūgšties etilo esterisB. 3- [Imidazol-2-yl] -propionic acid ethyl ester
Junginio A (4,01 g, 24,2 g) tirpalas absoliučiame etanolyje (100 ml, pašildytas, kad medžiaga ištirptų) hidrinamas, naudojant Pd/C (0,5 g), kambario temperatūroje 16 vai. Vakuume pašalinus H2, katalizatorius atskiriamas nufiltruojant per celito sluoksnį. Sukoncentravus filtratą vakuume, gaunama 4,0 g (100 %) junginio B, kuris yra balta kristalinė medžiaga. MS (M + H)+ 169+.A solution of Compound A (4.01 g, 24.2 g) in absolute ethanol (100 mL, heated to dissolve) was hydrogenated using Pd / C (0.5 g) at room temperature for 16 h. After removal of H 2 in vacuo, the catalyst is separated by filtration through a pad of celite. Concentration of the filtrate in vacuo afforded 4.0 g (100%) of Compound B as a white crystalline solid. MS (M + H) < + > 169 + .
C. 3-[N-Trifenilmetil-imidazol-2-il]-propankarboksirūgšties etilo esterisC. Ethyl 3- [N-triphenylmethyl-imidazol-2-yl] -propionic acid
Junginys C pagaminamas iš junginio B pagal 6 pavyzdyje aprašytą junginio A gavimo metodiką, tirpikliu panaudojant metileno chloridą. Po vandeninio tirpalo apdorojimo ir perkristalinimo iš etilacetato ir heksanu mišinio, gaunamas junginys C, kuris yra balta kristalinė medžiaga. MS (M + H)+ 411+.Compound C is prepared from Compound B according to the procedure described in Example 6 for the preparation of Compound A using methylene chloride as solvent. Treatment of the aqueous solution and recrystallization from a mixture of ethyl acetate and hexane affords compound C, which is a white crystalline solid. MS (M + H) + 411 + .
D. 3-[N-Trifenilmetil-imidazol-2-il]propanalisD. 3- [N-Triphenylmethylimidazol-2-yl] propanal
Maišomas junginio C (300 mg, 0,73 mmol) tirpalas dichlormetane (3 ml) atšaldomas iki -78 °C ir švirkštu j jj suleidžiamas prieš tai atšaldytas (-70 °C) 1M DIBAL tirpalas dichlormetane (0,73 mmol, 0,73 ml). Pamaišius 1 vai. dar pridedama prieš tai atšaldyto (-70 °C) DIBAL tirpalo (0,3 ml, 0,3 mmol). Pamaišius dar 2 vai., pridedama sotaus NH4CI tirpalo (10 ml), o po to 0,1 N HCI (20 ml). Pamaišius 5 min., pridedama metileno chlorido (30 ml). Atskiriami sluoksniai, ir vandeninis sluoksnis plaunamas metileno chloridu. Sumaišyti organiniai sluoksniai džiovinami MgSO4, nufiltruojama ir sukoncentravus gaunama 266 mg (99 %) junginio D, kuris yra balta kieta medžiaga. 1H-BMR (CD3OD, 270 MHz) δ 9,4 (1H, s), 7,38 (10H, m), 7,05 (7H, m), 2,7-2,2 (4H, m).A stirred solution of Compound C (300 mg, 0.73 mmol) in dichloromethane (3 mL) is cooled to -78 ° C and a pre-cooled (-70 ° C) 1M DIBAL solution in dichloromethane (0.73 mmol, 0, 73 ml). After stirring for 1 hour. additional pre-cooled (-70 ° C) DIBAL solution (0.3 mL, 0.3 mmol) was added. After stirring for a further 2 h, saturated NH 4 Cl solution (10 mL) was added followed by 0.1 N HCl (20 mL). After stirring for 5 min, methylene chloride (30 mL) was added. The layers were separated and the aqueous layer was washed with methylene chloride. The combined organic layers were dried over MgSO 4 , filtered, and concentrated to give 266 mg (99%) of Compound D as a white solid. 1 H-NMR (CD 3 OD, 270 MHz) δ 9.4 (1H, s), 7.38 (10H, m), 7.05 (7H, m), 2.7-2.2 (4H, m).
E. 2,3,4,5-Tetrahidro-1-[3-(1-trifenilmetilimidazol-2-il)propil]-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinasE. 2,3,4,5-Tetrahydro-1- [3- (1-triphenylmethylimidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine
Junginys E buvo pagamintas iš junginio D ir 1 pavyzdžio junginio C pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką, maišant 16 vai. Po chromatografijos (sparčioji chromatografija, silikagelis, 9:1 metileno chloridas: metanolis) gaunamas stiklo pavidalo junginys E (74 %). MS (M + H)+ 653,3.Compound E was prepared from Compound D and Example 1 Compound C according to the procedure described in Example 1 for the preparation of Compound D with stirring for 16 hours. Chromatography (flash chromatography, silica gel, 9: 1 methylene chloride: methanol) affords E (74%) as a glass. MS (M + H) + 653.3.
F. 2,3,4,5-Tetrahidro-1-[3-(1H-imidazol-2-il)propil]-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (dihidrochloridas)F. 2,3,4,5-Tetrahydro-1- [3- (1H-imidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)
Junginio E (110 mg, 0,18 mmol) TFA (5 ml), metileno chlorido (5 ml) ir trietilsilano (0,1 ml) mišinys maišomas 2 vai. kambario temperatūroje ir sukoncentruojamas. Maišant į liekaną pridedama heksanų, ir mišinys nudekantuojamas. Liekana ištirpinama mišinyje, susidedančiame iš 0,1 % TFA metanolyje ir 0,1 % TFA vandenyje (50/50), supilama j YMC C18 kolonėlę (S-5, ODS 30x250 mm), ir gryninimas HPLC metodu atliekamas tokiomis sąlygomis: tirpiklis A: 0,1 % TFA 90 % vandens ir 10 % metanolio mišinyje; tirpiklis B: 0,1 % TFA 90 % metanolio ir 10 % vandens mišinyje; 0-100 % B tirpiklyje A per 30 min. Frakcijos, kuriose yra didžiausia smailė, supilamas kartu ir liofilizuojamos iki alyvos pavidalo liekanos. Pridedama 1M vandeninio HCI (6 ml), ir tirpalas sukoncentruojamas iki stiklo pavidalo liekanos. Pakartojus šią stadiją, gaunama 50 mg (84 %) 14 pavyzdžio medžiagos, kuri yra balta kieta medžiaga.A mixture of E (110 mg, 0.18 mmol) in TFA (5 mL), methylene chloride (5 mL), and triethylsilane (0.1 mL) was stirred for 2 h. at room temperature and concentrated. Hexane is added to the residue while stirring and the mixture is decanted. The residue is dissolved in a mixture of 0.1% TFA in methanol and 0.1% TFA in water (50/50), applied to a YMC C18 column (S-5, ODS 30x250 mm) and purified by HPLC under the following conditions: solvent A 0.1% TFA in a mixture of 90% water and 10% methanol; solvent B: 0.1% TFA in a mixture of 90% methanol and 10% water; 0-100% B in solvent A over 30 min. The highest peak fractions are pooled and lyophilized to an oily residue. 1M aqueous HCl (6 mL) was added and the solution was concentrated to a glass residue. Repeat this step to obtain 50 mg (84%) of Example 14 as a white solid.
MS (M + H)+411.MS (M + H) + 411.
1H-BMR (CD3OD, 300 MHz) δ 8,05-7,95 (2H, m), 7,6-7,05 (12H, m), 6,71 (0,5H, m), 6,02 (0,5H, m), 4,4 (2H, m), 3,6-3,0 (8H, m), 2,2-2,0 (2H, m). 1 H-NMR (CD 3 OD, 300 MHz) δ 8.05-7.95 (2H, m), 7.6-7.05 (12H, m), 6.71 (0.5H, m), 6.02 (0.5H, m), 4.4 (2H, m), 3.6-3.0 (8H, m), 2.2-2.0 (2H, m).
1-[3-Amino-3-(1H-imidazol-2-il)propil]-2,3,4.5-tetrahidro-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (trihidrochloridas)1- [3-Amino-3- (1H-imidazol-2-yl) propyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)
A. N-[2-(trimetilsilil)etoksimetil]imidazolasA. N- [2- (Trimethylsilyl) ethoxymethyl] imidazole
J NaH (2,1 g, 51 mmol, 60 % dispersija mineralinėje alyvoje, perplauta heksanais) ir DMF (60 ml) mišinį mažomis porcijomis pridedama imidazolo (3,0 g, 44 mmol). Mišinys maišomas N2 atmosferoje 1 vai., po to sulašinamasImidazole (3.0 g, 44 mmol) was added in small portions to a mixture of NaH (2.1 g, 51 mmol, 60% dispersion in mineral oil, washed with hexanes) and DMF (60 mL). The mixture is stirred under N 2 for 1 h, then added dropwise
2-(trimetilsilil)etoksimetilchloridas (SEM-CI). Mišinys maišomas 1 vai., ir reakcija stabdoma vandeniu (5 ml). Mišinys supilamas į vandenį (80 ml) ir ekstrahuojamas etilacetatu. Organinis sluoksnis plaunamas sočiu vandeniniu NH4CI, sočiu NaCl, džiovinamas (MgSO4), nufiltruojamas, ir sukoncentravus gaunama 6,3 g (72 %) junginio A, kuris yra skaidrus skystis. MS (M + H)+ 199.2- (trimethylsilyl) ethoxymethyl chloride (SEM-CI). The mixture was stirred for 1 h and quenched with water (5 mL). The mixture was poured into water (80 mL) and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NH4Cl, saturated aqueous NaCl, dried (MgSO 4), filtered and concentrated to provide 6.3 g (72%) of Compound A, which is a clear liquid. MS (M + H) + 199.
B. N-[2-(trimetilsilil)etoksimetil]imidazol-2-karboksaldehidas j atšaldytą (-40 °C) junginio A (3,0 g, 15,1 mmol) mišinj THF (75 ml) supilamas n-BuLi tirpalas heksane (2,5M, 6,4 ml, 15,1 mmol). Po 15 min. pridedama DMF (1,4 ml, 18,1 mmol), ir mišinys maišomas 3 vai., o po to pridedama sotaus vandeninio NH4CI (30 ml). Mišinys ekstrahuojamas etilacetatu, organinė fazė plaunama sočiu vandeniniu NH4CI, sočiu NaCl, džiovinama MgSO4, nufiltruojama, ir sukoncentravus gaunama 3,1 g junginio B (92 %), kuris yra gelsva alyva. MS (2M + H)+ 453,2.B. N- [2- (Trimethylsilyl) ethoxymethyl] imidazole-2-carboxaldehyde in n-BuLi in hexane was added to a cooled (-40 ° C) mixture of Compound A (3.0 g, 15.1 mmol) in THF (75 mL). (2.5M, 6.4 mL, 15.1 mmol). After 15 minutes DMF (1.4 mL, 18.1 mmol) was added and the mixture was stirred for 3 h before saturated aqueous NH 4 Cl (30 mL) was added. The mixture is extracted with ethyl acetate, the organic phase is washed with saturated aqueous NH 4 Cl, saturated NaCl, dried over MgSO 4 , filtered, and concentrated to give 3.1 g of compound B (92%) as a yellowish oil. MS (2M + H) + 453.2.
C. 1-Amino-1-[N-[2-(trimetilsilil)etoksimetil]imidazol-2-il]-but-3-enas j atšaldytą (-78 °C) junginio B (1,22 g, 5,4 mmol) mišinj THF (10 ml) Ar atmosferoje švirkštu suleidžiamas prieš tai atšaldytas (-78 °C) ličio bistrimetilsililamido tirpalas THF (1M, 5,6 ml, 5,6 mmol). Mišinys sušildomas iki -20 °C ir laikomas 1 vai., po to vėl atšaldomas iki -78 °C. J ši mišinj švirkštu suleidžiamas prieš tai atšaldytas (-78 °C) alilmagnio bromido tirpalas (1M, etilo eteryje, 7,45 ml, 7,45 mmol). Šis mišinys sušildomas iki kambario temperatūros ir Ar atmosferoje maišomas 16 vai. Mišinys skaldomas 1N vandeniniu NaOH (20 ml) ir ekstrahuojamas etilo eteriu. Organinis sluoksnis plaunamas sočiu NaCl, džiovinamas MgSO4, nufiltruojamas, ir sukoncentravus gaunama geltona liekana. Ši liekana chromatografuojama per sparčiosios chromatografijos silikagelio kolonėlę (5x20 cm), eliuuojant metileno chlorido ir metanolio (9:1) mišiniu, o po to amonio hidroksido, metanolio ir chloroformo (1:5:94) mišiniu. Gaunama 0,55 g (38 %) junginio C, kuris yra oranžinis skystis. MS (M + H)+ 267.C. 1-Amino-1- [N- [2- (trimethylsilyl) ethoxymethyl] imidazol-2-yl] -but-3-ene to cooled (-78 ° C) compound B (1.22 g, 5.4) mmol) in THF (10 mL) A solution of lithium bistrimethylsilylamide in THF (1M, 5.6 mL, 5.6 mmol) was pre-cooled by syringe under Ar atmosphere. The mixture was warmed to -20 ° C and held for 1 h, then cooled again to -78 ° C. A pre-cooled (-78 ° C) solution of aluminum magnesium bromide (1M, in ethyl ether, 7.45 mL, 7.45 mmol) is added to this mixing syringe. The mixture was warmed to room temperature and stirred under Ar for 16 h. The mixture was quenched with 1N aqueous NaOH (20 mL) and extracted with ethyl ether. The organic layer was washed with saturated NaCl, dried over MgSO 4 , filtered, and concentrated to a yellow residue. This residue is chromatographed on a silica gel flash column (5 x 20 cm), eluting with a mixture of methylene chloride and methanol (9: 1) followed by a mixture of ammonium hydroxide, methanol and chloroform (1: 5: 94). 0.55 g (38%) of C is obtained, which is an orange liquid. MS (M + H) + 267.
D. 1-[(Trietilsilil)etoksikarbonilamino]-1-[N-[2trimetilsilil)etoksimetil]imidazol-2-il]-but-3-enasD. 1 - [(Triethylsilyl) ethoxycarbonylamino] -1- [N- [2-trimethylsilyl) ethoxymethyl] imidazol-2-yl] -but-3-ene
Į maišomą junginio C (450 mg, 1,7 mmol) suspensiją vandenyje (2 ml) pridedama TEA (0,32 ml, 2,3 mmol) tirpalo dioksane (2 ml), o po to 2(trietilsilil)etoksikarbonilsukcinimido. Mišinys maišomas kambario temperatūroje 16 vai. Pridedama etilo eterio (30 ml) ir 1N vandeninio KHSO4 (30 ml). Atskiriami sluoksniai, ir vandeninis sluoksnis plaunamas etilo eteriu. Sumaišyti organiniai sluoksniai džiovinami MgSO4, nufiltruojama ir koncentruojama. Liekana chromatografuojama per sparčiosios chromatografijos silikagelio kolonėlę (5x20 cm), eliuuojant metileno chlorido ir metanolio (9:1) mišiniu. Gaunama 531 mg (84 %) stiklo pavidalo junginio D. MS (M + H)+ 412.To a stirred suspension of Compound C (450 mg, 1.7 mmol) in water (2 mL) was added a solution of TEA (0.32 mL, 2.3 mmol) in dioxane (2 mL) followed by 2 (triethylsilyl) ethoxycarbonyl succinimide. The mixture was stirred at room temperature for 16 hours. Ethyl ether (30 mL) and 1N aqueous KHSO 4 (30 mL) were added. The layers were separated and the aqueous layer was washed with ethyl ether. The combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue is chromatographed on a silica gel flash column (5 x 20 cm), eluting with a mixture of methylene chloride and methanol (9: 1). 531 mg (84%) of D. is obtained in the form of a glass. MS (M + H) + 412.
E. 3-[(Trietilsilil)etoksikarbonilamino]-3-[N-[2trimetilsilil)etoksimtil]imidazol-2-il]-propanalisE. 3 - [(Triethylsilyl) ethoxycarbonylamino] -3- [N- [2-trimethylsilyl) ethoxymethyl] imidazol-2-yl] -propanal
Į maišomą junginio D mišinj dioksane (5 ml) ir vandenyje (5 ml) pridedama natrio perjodato (94 mg, 0,37 mmol) ir osmio tetroksido (2 mg ištirpinti 0,5 ml vandens ir 0,5 ml dioksano). Mišinys maišomas 18 vai. Pridedama metileno chlorido, atskiriami sluoksniai ir vandeninis sluoksnis plaunamas metileno chloridu. Sumaišyti organiniai sluoksniai džiovinami MgSO4, nufiltruojama ir koncentruojama. Liekana chromatografuojama per sparčiosios chromatografijos silikagelio kolonėlę (5x20 cm), eliuuojant metileno chlorido ir metanolio (9:1) mišiniu. Gaunama 90 mg (90 %) stiklo pavidalo junginio E.Sodium periodate (94 mg, 0.37 mmol) and osmium tetroxide (2 mg dissolved in 0.5 mL water and 0.5 mL dioxane) were added to a stirred mixture of Compound D in dioxane (5 mL) and water (5 mL). The mixture is stirred for 18 hours. Methylene chloride is added, the layers are separated and the aqueous layer is washed with methylene chloride. The combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue is chromatographed on a silica gel flash column (5 x 20 cm), eluting with a mixture of methylene chloride and methanol (9: 1). 90 mg (90%) of compound E are obtained in the form of a glass.
F. 1-[[(Trietilsilil)etoksikarbonilamino]-3-(1(trimetilsilil)etoksimetilimidazol-2-il]propil]-2,3,4,5-tetrahidro-4-(1 naftalenilkarboniI)-1H-1,4-benzodiazepinasF. 1 - [[(Triethylsilyl) ethoxycarbonylamino] -3- (1- (trimethylsilyl) ethoxymethylimidazol-2-yl] propyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4 benzodiazepine
Junginys F pagaminamas iš junginio E ir 1 pavyzdžio junginio C pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką, maišant 16 vai. Po chromatografijos (sparčioji chromatografija, silikagelis, 9:1 metileno chloridas: metanolis) gaunamas stiklo pavidalo junginys F (44 %). MS (M + H)+ 700.Compound F is prepared from Compound E and Example 1 Compound C according to the procedure for Preparation Compound D described in Example 1 with stirring for 16 hours. Chromatography (flash chromatography, silica gel, 9: 1 methylene chloride: methanol) affords F (44%) as a glass. MS (M + H) + 700.
G. 1-[3-Amino-3-(1H-imidazol-2-il]propil]-2,3,4,5-tetrahidro-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (trihidrochloridas)G. 1- [3-Amino-3- (1H-imidazol-2-yl] propyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)
Į junginio F (20 mg, 0,029 mmol) tirpalą TFA (3 ml) pridedama tetrabutilamonio fluorido (44 mg, 0,17 mmol), ir tirpalas šildomas 50 °C temperatūroje 16 vai. Atšaldžius, tirpiklis nugarinamas vakuume, o liekana ištirpinama mišinyje, susidedančiame iš 0,1 % TFA metanolyje ir 0,1 % TFA vandenyje (50/50) ir supilama į YMC C18 kolonėlę (S-5, ODS 30x250 mm). Gryninimas HPLC metodu atliekamas tokiomis sąlygomis: tirpiklis A: 0,1 % TFA 90 % vandens ir 10 % metanolio mišinyje; tirpiklis B: 0,1 % TFA 90 % metanolio ir 10 % vandens mišinyje; 0-100 % B tirpiklyje A per 30 min. Frakcijos, kuriose yra didžiausia smailė, supilamas kartu ir liofilizuojamos iki alyvos pavidalo liekanos. Pridedama 1M vandeninio HCI (6 ml), ir tirpalas sukoncentruojamas iki baltos kietos medžiagos. Pakartojus šią stadiją, gaunama 9 mg (58 %) 15 pavyzdžio medžiagos, kuri yra balta kieta medžiaga.To a solution of compound F (20 mg, 0.029 mmol) in TFA (3 mL) was added tetrabutylammonium fluoride (44 mg, 0.17 mmol) and the solution was heated at 50 ° C for 16 h. After cooling, the solvent was evaporated in vacuo and the residue was dissolved in a mixture of 0.1% TFA in methanol and 0.1% TFA in water (50/50) and applied to a YMC C18 column (S-5, ODS 30x250 mm). Purification by HPLC is carried out under the following conditions: solvent A: 0.1% TFA in a mixture of 90% water and 10% methanol; solvent B: 0.1% TFA in a mixture of 90% methanol and 10% water; 0-100% B in solvent A over 30 min. The highest peak fractions are pooled and lyophilized to an oily residue. 1M aqueous HCl (6 mL) was added and the solution was concentrated to a white solid. Repeat this step to give 9 mg (58%) of Example 15 as a white solid.
MS (M + H)+425.MS (M + H) < + >
1H-BMR (CD3OD, 270 MHz) δ 8,05-7,95 (2H, m), 7,7-7,05 (10H, m), 6,71 (0,5H, m), 6,02(0,5H, m), 4,4 (2H, m), 4,0 (1H, m), 3,6-3,0 (7H, m), 2,9 (1H, m). 1 H-NMR (CD 3 OD, 270 MHz) δ 8.05-7.95 (2H, m), 7.7-7.05 (10H, m), 6.71 (0.5H, m), 6.02 (0.5H, m), 4.4 (2H, m), 4.0 (1H, m), 3.6-3.0 (7H, m), 2.9 (1H, m) .
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-3-metil-4-(1nafta!enilkarbonil)-1H-1,4-benzodiazepinas (hidrochloridas) pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš izatoinės rūgšties anhidrido ir D,L-alanino etilo esterio hidrochlorido pagal 8 pavyzdyje aprašytą metodiką. Lyd. temp.: 180-185 °C.2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-methyl-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride) Example Compound (yellow solid) ) is prepared from isatoic anhydride and D, L-alanine ethyl ester hydrochloride according to the procedure described in Example 8. Lyd. mp: 180-185 ° C.
MS (M + H)+ 397.MS (M + H) < + > 397.
Analizė išskaičiuota pagal C25H24N4O -1,3 HCI-1,3H2O.Analysis calculated for C25H24N4O-HCl -1.3 1.3H 2 O.
Išskaičiuota: C, 64,26; H, 6,02; N, 11,99; Cl, 9,86.Found: C, 64.26; H, 6.02; N, 11.99; Cl, 9.86.
Rasta: C, 64,33; H, 5,82; N, 11,70; Cl, 9,65.Found: C, 64.33; H, 5.82; N, 11.70; Cl, 9.65.
(S)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)’3-[2-(metiltio)etil]-4-(1naftalenilmetil)-1H-1,4-benzodiazepinas (hidrochloridas) j etilenglikolio dimetilo eterio (bevandenis, 20 ml) ir ličio aliuminio hidrido (17 mg, 0,45 mmol) suspensiją argono atmosferoje 0 °C temperatūroje lėtai sudedamas junginio 8 (75 mg, 0,15 mmol) mišinys etilenglikolio dimetilo eteryje. Mišiniui leidžiama sušilti iki kambario temperatūros, pamaišoma 30 min. ir virinama su grįžtamu šaldytuvu (85 °C) 18 vai. Mišinys atšaldomas iki 0 °C, ir reakcija stabdoma pridedant iš eilės tetrahidrofurano ir vandens (po 1 ml) mišinio, vandeninio natrio hidroksido (2 ml, 1N) ir vandens (1 ml). Susidariusios nuosėdos nufiltruojamos, ir vakuume sukoncentravus filtratą, gaunama gintaro pavidalo alyva. Ši medžiaga ištirpinama metanolyje (2 ml), paveikiama vandenilio chlorido tirpalu (1 ml, bevandenis, 2M, eteryje), ir sukoncentravus vakuume, gaunamas 17 pavyzdžio junginys, kuris yra geltona kieta medžiaga. Lyd. temp.: 115-120 °C.(S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylmethyl) -1H-1,4-benzodiazepine (hydrochloride) to a suspension of ethylene glycol dimethyl ether (anhydrous, 20 mL) and lithium aluminum hydride (17 mg, 0.45 mmol) under argon at 0 ° C was slowly added a mixture of compound 8 (75 mg, 0.15 mmol) in ethylene glycol dimethyl ether . The mixture was allowed to warm to room temperature and stirred for 30 min. and reflux (85 ° C) for 18 hours. The mixture was cooled to 0 ° C and quenched by successive addition of a mixture of tetrahydrofuran and water (1 mL), aqueous sodium hydroxide (2 mL, 1N) and water (1 mL). The precipitate formed is filtered off and the filtrate is concentrated in vacuo to give an amber oil. This material was dissolved in methanol (2 mL), treated with a solution of hydrochloric acid (1 mL, anhydrous, 2M, in ether) and concentrated in vacuo to afford Example 17 as a yellow solid. Lyd. mp: 115-120 ° C.
MS (M + H)+ 443.MS (M + H) + 443.
Analizė išskaičiuota pagal C27H30N4S -2,4 HCI -2,6 H2O.Analysis calculated for C27H30N4S HCI -2.4 -2.6 H 2 O.
Išskaičiuota; C, 56,21; H, 6,57; N, 9,71; Cl, 14,75. Rasta: C, 56,20; H, 6,55; N, 9,85; Cl, 14,81.Excluded; C, 56.21; H, 6.57; N, 9.71; Cl, 14.75. Found: C, 56.20; H, 6.55; N, 9.85; Cl, 14.81.
pavyzdysexample
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-9-metil-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys (gelsva kieta medžiaga) pagaminamas iš 8metilizatoinės rūgšties anhidrido ir glicino etilo esterio hidrochlorido pagal aprašytą reakcijų seką tokiems junginiams gauti: 1 pavyzdžio junginiui A, virinant su grįžtamu šaldytuvu 16 vai.; 17 pavyzdžio junginiui, išskyrus tai, kad tirpikliu naudojamas THF; virinant su 1-naftalenkarboksirūgšties 4nitrofenilesteriu toluene, esant DMAP; 1 pavyzdžio junginiui D.2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -9-methyl-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (yellowish solid) prepared from 8-methylsilicic acid anhydride and glycine ethyl ester hydrochloride according to the reaction sequence described to give the following compounds of Example 1 by boiling under reflux for 16 hours; The compound of Example 17, except that THF is used as a solvent; boiling with 4-nitrophenyl ester of 1-naphthalenecarboxylic acid in toluene in the presence of DMAP; For Example 1, Compound D.
MS (M + H)+ 397.MS (M + H) < + > 397.
Analizė išskaičiuota pagal C25H24N4O -2 HCI.Analysis calculated for C25H24N4O -2 HCl.
Išskaičiuota: C, 63,96; H, 5,58; N, 11,93.Found: C, 63.96; H, 5.58; N, 11.93.
Rasta: C, 62,83; H, 5,77; N, 11,13.Found: C, 62.83; H, 5.77; N, 11.13.
pavyzdysexample
2,3,4,5-Tetrahidro-4-(1H-imidazol-4-ilmetil)-9-metil-1-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys pagaminamas iš 9-metil-2,3,4,5-tetrahidro-1,4benzodiazepino pagal aprašytą reakcijų seką tokiems junginiams gauti: 4 pavyzdžio junginiui A; kopuliuojama su 1-naftalenkarboksirūgšties chloranhidridų, naudojant trietilaminą metileno chloride: Boc atskeliamas 4N HCl dioksane; 1 pavyzdžio junginiui D; chromatografavimas (silikagelis, sparčioji chromatografija, 9/1 CHCI3/CH3OH), po to apdorojus 1M HCi eteryje ir ištrynus su eteriu, gaunamas 19 pavyzdžio junginys, kuris yra geltona kieta medžiaga.2,3,4,5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -9-methyl-1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example compound is prepared from 9-methyl -2,3,4,5-tetrahydro-1,4-benzodiazepine according to the reaction sequence described for the preparation of the following compounds: Compound A of Example 4; coupled with chloro-anhydrides of 1-naphthalenecarboxylic acid using triethylamine in methylene chloride: Boc is cleaved in 4N HCl in dioxane; Example 1 for compound D; Chromatography (silica gel, flash chromatography, 9/1 CHCl 3 / CH 3 OH) followed by treatment with 1M HCl in ether and purification with ether afforded Example 19 as a yellow solid.
MS (M + H)+397.MS (M + H) < + > 397.
1H-BMR (270 MHz, CD3OD) δ 9,12-8,9 (m, 1H), 8,5-8,23 (m, 1H), 8,1-7,9 (m, 1 H-NMR (270 MHz, CD 3 OD) δ 9.12-8.9 (m, 1H), 8.5-8.23 (m, 1H), 8.1-7.9 (m,
3H), 7,9-7,0 (m, 7H), 5,7-5,28 (m, 1H), 4,85-4,1 (m, 3H), 4,0-3,05 (m, 4H), 2,92,55 (m, 1H), 1,9-1,75 (s, 3H).3H), 7.9-7.0 (m, 7H), 5.7-5.28 (m, 1H), 4.85-4.1 (m, 3H), 4.0-3.05 ( m, 4H), 2.92,55 (m, 1H), 1.9-1.75 (s, 3H).
1-[[2-(2-Aminoetil)-1H-imidazol-4-il]metil]-2,3,4,5-tetrahidro-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (trihidrochloridas)1 - [[2- (2-Aminoethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)
A. [2-(2-[[(1,1-dimetil)-etoksikarbonil]amino]etil)-1-[(1,1-dimetil)etoksikarbonil]-imidazol-4-il]metanolis [2-(2-Aminoetil)-1H-imidazol-4-il]metanolio hidrochloridas buvo pagamintas taip, kaip aprašyta (Buschauer, et ai., Arch. Pharm., 315, 563 (1982)). Į 1,0 g šios negrynintos medžiagos (laikoma, kad yra 4,7 mmol) suspensiją 10 ml DMF pridedama 2 ml (14,1 mmol) trietilamino, ir suspensija maišoma 0,5 vai. Po to j reakcijos mišinį pridedama 3,1 g (14,1 mmol) BOC anhidrido ir maišoma kambario temperatūroje per naktį. Reakcijos mišinys nugarinamas iki sausos liekanos, ir ši liekana chromatografuojama sparčiosios chromatografijos būdu per 100 cm3 silikagelio kolonėlę. Eliuuojama etilacetatu ir gaunama 1,27 g (3,7 mmol, 79 %) junginio A, kuris yra klampi geltona alyva.A. [2- (2 - [[(1,1-Dimethyl) -ethoxycarbonyl] amino] ethyl) -1 - [(1,1-dimethyl) ethoxycarbonyl] -imidazol-4-yl] methanol [2- (2 -Aminoethyl) -1H-imidazol-4-yl] methanol hydrochloride was prepared as described (Buschauer, et al., Arch. Pharm., 315, 563 (1982)). To a suspension of 1.0 g of this crude material (considered 4.7 mmol) in 10 mL of DMF was added 2 mL (14.1 mmol) of triethylamine and the suspension was stirred for 0.5 h. Thereafter, 3.1 g (14.1 mmol) of BOC anhydride were added to the reaction mixture and stirred at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is subjected to flash chromatography over a 100 cm 3 silica gel column. Elution with ethyl acetate gave 1.27 g (3.7 mmol, 79%) of Compound A as a viscous yellow oil.
B. [2-(2-[[(1,1-dimetil)-etoksikarbonil]amino]etil)-1-[(1,1-dimetil)etoksikarbonil]-imidazol-4-il]karboksaldehidasB. [2- (2 - [[(1,1-Dimethyl) ethoxycarbonyl] amino] ethyl) -1 - [(1,1-dimethyl) ethoxycarbonyl] -imidazol-4-yl] carboxaldehyde
J 1,2 g (3,5 mmol) junginio A tirpalą 10 ml chloroformo pridedama 0,9 g (10 mmol) mangano dioksido. Reakcijos mišinys šildomas 50 °C temperatūroje, intensyviai maišant. Po 1, 2 ir 4 vai. šildymo vis pridedama po 0,3 g MnO2. Išlaikius 6 vai. 50 °C temperatūroje, mišinys atvėsinamas iki kambario temperatūros ir be jokio apdorojimo chromatografuojamas sparčiosios chrpmatografijos būdu per 150 cm3 silikagelio kolonėlę. Eliuuojama 50 % etilacetatu heksane ir gaunama 673 mg (57 %) junginio B, kuris yra balta kristalinė medžiaga.To a solution of 1.2 g (3.5 mmol) of Compound A in 10 ml of chloroform is added 0.9 g (10 mmol) of manganese dioxide. The reaction mixture was heated at 50 ° C with vigorous stirring. After 1, 2 there are 4 or. 0.3 g of MnO 2 were added after heating. After 6 hours At 50 [deg.] C., the mixture is cooled to room temperature and subjected to flash chromatography on a 150 cm <3> silica gel column without elution. Elution with 50% ethyl acetate in hexane afforded 673 mg (57%) of Compound B as a white crystalline solid.
C. 1-[[2-(2-Aminoetil)-1H-imidazol-4-il]metil]-2,3,4,5-tetrahidro-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (trihidrochloridas)C. 1 - [[2- (2-Aminoethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) )
Atliekama 1 pavyzdžio junginio C redukcinio amininimo reakcija junginiu B pagal 1 pavyzdyje aprašytą junginio D sintezės metodiką. Gauta alyva chromatografuojama sparčiosios chromatografijos būdu (silikagelis, 50 % etilacetatas heksanuose), ir gaunamas baltų putų pavidalo junginio C bisBoc analogas. Šios medžiagos 94 mg (0,15 mmol) tirpalas 3 ml 4N HCIdioksane maišomas kambario temperatūroje 3 vai. Nugarinus tirpikli, gaunama baltų putų pavidalo liekana, kuri gryninama HPLC metodu per YMC S5 ODS (30x250 mm) kolonėlę. Naudojamas gradientinis eliuavimas nuo 0 iki 100 % tirpiklio B (A: 10 % metanolis:vanduo + 0,1 % TFA, B: 10 % vanduo:metanolis + 0,1 % TFA), ir gaunama alyvos pavidalo liekana, kuri paverčiama jos HCl druska, pridedant metanolinio HCl ir nugarinant tirpiklj. Nuo liekanos nugarinamas metanolis dar du kartus, ir gaunama 53 mg (0,10 mmol, 66 %) 20 pavyzdžio junginio, kuri yra balta kieta medžiaga. Lyd. temp.: 165 °C.The reductive amination reaction of compound C of Example 1 with compound B is carried out according to the procedure for the synthesis of compound D as described in Example 1. The resulting oil is subjected to flash chromatography (silica gel, 50% ethyl acetate in hexanes) to give a white foam analogue of compound C, bisBoc. A solution of this material (94 mg, 0.15 mmol) in 3 mL of 4N HCl in dioxane was stirred at room temperature for 3 h. Evaporation of the solvent gave a white foam which was purified by HPLC on a YMC S5 ODS (30 x 250 mm) column. A gradient elution of 0 to 100% solvent B (A: 10% methanol: water + 0.1% TFA, B: 10% water: methanol + 0.1% TFA) is used to give an oil residue which is converted into its HCl. salt by adding methanolic HCl and evaporating the solvent. The residue was stripped of methanol twice more to give 53 mg (0.10 mmol, 66%) of Example 20 as a white solid. Lyd. mp: 165 ° C.
MS (M + H)+ 426.MS (M + H) < + >
Analizė išskaičiuota pagal C26H27N5O -3 HCI.Analysis calculated for C26H27N5O -3 HCl.
Išskaičiuota: C, 58,38; H, 5,65; N, 13,09.Found: C, 58.38; H, 5.65; N, 13.09.
Rasta: C, 59,01; H, 6,15; N, 13,03.Found: C, 59.01; H, 6.15; N, 13.03.
1-[[2-(2-Aminometil)-1H-imidazol-4-il]metil]-2,3,4,5-tetrahidro-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (trihidrochloridas) pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš chloracetonitrilo ir 1 pavyzdžio junginio C pagal 20 pavyzdyje aprašytą metodiką; lyd. temp.: 155-160 °C.Example 1 - [[2- (2-Aminomethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) Compound (white solid) is prepared from chloroacetonitrile and Compound C of Example 1 according to the procedure described in Example 20; melt mp: 155-160 ° C.
MS (M + H)+ 412,MS (M + H) + 412,
Analizė išskaičiuota pagal C25H25N5O -3 HCI.Analysis calculated for C25H25N5O -3 HCl.
Išskaičiuota: C, 57,65; H, 5,42; N, 13,45.Found: C, 57.65; H, 5.42; N, 13.45.
Rasta: C, 57,41; H, 5,18; N, 13,17.Found: C, 57.41; H, 5.18; N, 13.17.
pavyzdysexample
N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)1H-1,4-benzodiazepin-8-il]acetamidas (dihidrochloridas)N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) 1H-1,4-benzodiazepin-8-yl] acetamide (dihydrochloride)
A. 2-[2-[[(1,1-Dimetil)-etoksikarbonil]amino]etilamino]-4-nitrobenzenkarboksirūgštis į 2-[[(1,1-dimetil)-etoksikarbonil]amino]acetaldehido (6,0 g, 38 mmol), 4-nitroantranilo rūgšties (3,8 g, 19 mmol) ir acto rūgšties (2,0 ml) tirpalą metanolyje (150 ml) dalimis pridedama natrio cianborhidrido (2,3 g, 38 mmol). Mišinys maišomas kambario temperatūroje 16 vai., koncentruojamas vakuume, skaldomas 1N HCI (100 ml) ir ekstrahuojamas CH2CI2 (3x100 ml). Sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojama ir koncentruojama vakuume. Liekana gryninama sparčiosios chromatografijos metodu (19/1/0,05 CHCI3/MeOH/AcOH) ir gaunamas junginys A (4,4 g, 72 %), kuris yra kieta medžiaga. MS: (M + H)+ 326.A. 2- [2 - [[(1,1-Dimethyl) -ethoxycarbonyl] amino] ethylamino] -4-nitrobenzoic acid to 2 - [[(1,1-dimethyl) -ethoxycarbonyl] amino] acetaldehyde (6.0 g) , 38 mmol), a solution of 4-nitroanthranilic acid (3.8 g, 19 mmol) and acetic acid (2.0 mL) in methanol (150 mL) was added portionwise to sodium cyanoborohydride (2.3 g, 38 mmol). The mixture was stirred at room temperature for 16 h, concentrated in vacuo, quenched with 1N HCl (100 mL) and extracted with CH 2 Cl 2 (3 x 100 mL). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by flash chromatography (19/1 / 0.05 CHCl 3 / MeOH / AcOH) to give Compound A (4.4 g, 72%) as a solid. MS: (M + H) + 326.
B. 2-[(2-amino]etilamino]-4-nitrobenzenkarboksirūgštis j junginį B (2,8 g, 8,6 mmol) kambario temperatūroje pridedama bevandenio HCI dioksane (4M, 20 ml, 80 mmol), ir mišinys maišomas 2 vai. Tirpalas koncentruojamas vakuume, ir ištrynus liekaną su dietilo eteriu, gaunamas junginys B (2,1 g, 84 %), kuris yra kieta medžiaga. MS: (M + H)+ 226.B. 2 - [(2-Amino] ethylamino] -4-nitrobenzoic acid to compound B (2.8 g, 8.6 mmol) at room temperature was added to anhydrous HCl in dioxane (4M, 20 mL, 80 mmol) and the mixture was stirred for 2 h. Concentrate the solution in vacuo and purify the residue with diethyl ether to give Compound B (2.1 g, 84%) as a solid, MS: (M + H) + 226.
C. 8-Nitro-2,3-dihidro-1 H-1,4-benzodiazepin-5-onas j junginio B (1,0 g, 3,4 mmol) tirpalą DMF (12 ml) kambario temperatūroje pridedama difenilfosforilazido (1,1 ml, 5,0 mmol). Mišinys maišomas 10 min., pridedama N-metilmorfolino (1,3 ml, 12 mmol), ir mišinys maišomas kambario temperatūroje 5 vai. Po to reakcija stabdoma 10 % LiCI / 10 % NaHCO3 (100 ml), ir vandeninis tirpalas ekstrahuojamas etilacetatu (5x50 ml). Sumaišyti organiniai ekstraktai plaunami 10 % LiCI (2x60 ml), džiovinami (MgSO4), nufiltruojama ir koncentruojama vakuume. Liekana trinama su petrolio eteriu ir dietilo eteriu, ir gaunamas junginys C (0,42 g, 61 %), kuris yra kieta medžiaga. MS: (M+CH3CN + H)+ 249.C. 8-Nitro-2,3-dihydro-1H-1,4-benzodiazepin-5-one To a solution of compound B (1.0 g, 3.4 mmol) in DMF (12 mL) was added diphenylphosphorylazide (1) at room temperature. , 1 mL, 5.0 mmol). The mixture was stirred for 10 min, N-methylmorpholine (1.3 mL, 12 mmol) was added and the mixture was stirred at room temperature for 5 h. The reaction was then quenched with 10% LiCl / 10% NaHCO 3 (100 mL) and the aqueous solution was extracted with ethyl acetate (5 x 50 mL). The combined organic extracts were washed with 10% LiCl (2x60 mL), dried (MgSO 4 ), filtered, and concentrated in vacuo. The residue was triturated with petroleum ether and diethyl ether to give Compound C (0.42 g, 61%) as a solid. MS: (M + CH 3 CN + H) + 249.
D. 8-Nitro-2,3,4,5-tetrahidro-1 H-1,4-benzodiazepinasD. 8-Nitro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
J junginio C (0,42 g, 2,0 mmol) tirpalą THF (5 ml) 0 °C temperatūroje sulašinamas borano dimetilsulfidas (10 M, 1,2 ml, 12 mmol). Mišinys sušildomas iki kambario temperatūros ir virinamas su grįžtamu šaldytuvu 2 vai. Po to mišinys atšaldomas iki 0 °C, atsargiai pridedama metanolio (10 ml), ir tirpalas prisotinamas bevandeniu HCl. Mišinys virinamas su grįžtamu šaldytuvu 1 vai., sukoncentruojamas vakuume ir liekana trinama su dietilo eteriu. Gaunamas junginys D (0,34 g, 65 %), kuris yra kieta medžiaga. MS: (M + H)+ 194.A solution of Compound C (0.42 g, 2.0 mmol) in THF (5 mL) was added dropwise at 0 ° C to borane dimethyl sulfide (10 M, 1.2 mL, 12 mmol). The mixture is warmed to room temperature and refluxed for 2 hours. The mixture was then cooled to 0 ° C, methanol (10 mL) was carefully added, and the solution was saturated with anhydrous HCl. The mixture was refluxed for 1 h, concentrated in vacuo and the residue triturated with diethyl ether. Compound D (0.34 g, 65%) was obtained as a solid. MS: (M + H) < + > 194.
E. 8-Nitro-2,3,4,5-tetrahidro-4-(1-naftalenilkarbonil)-1H-1,4benzodiazepinasE. 8-Nitro-2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine
Junginys E pagaminamas iš junginio D ir 1-naftalenkarboksirūgšties chloranhidrido pagal 2 pavyzdyje aprašytą junginio C sintezės metodiką, maišant 16 vai. MS: (M + CH3CN + H)+ 389.Compound E is prepared from compound D and 1-naphthalenecarboxylic acid anhydride according to the procedure described in Example 2 for the synthesis of compound C with stirring for 16 hours. MS: (M + CH 3 CN + H) + 389.
F. 2,3,4,5-Tetrahidro-1-(1 H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-8-nitro-lH-1,4-benzodiazepinasF. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8-nitro-1H-1,4-benzodiazepine
Junginys F pagaminamas iš junginio E pagal 1 pavyzdyje aprašytą junginio D sintezės metodiką, išskyrus tai, kad tirpikliu yra naudojamas metanolis, o laisva bazė naudojama sekančioje reakcijoje. MS (M + H)+ 428.Compound F is prepared from Compound E according to the procedure described in Example 1 for the synthesis of Compound D, except that the solvent is methanol and the free base is used in the following reaction. MS (M + H) < + >
G. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-8-amino-1H-1,4-benzodiazepinas j junginio F (0,13 g, 0,29 mmol) tirpalą etanolio, vandens ir kone. HCI (500/50/1) mišinyje (26 ml) kambario temperatūroje pridedama geležies miltelių (0,15 g, 2,6 mmol). Mišinys virinamas su grįžtamu šaldytuvu 3 vai., atšaldomas iki kambario temperatūros, nufiltruojamas ir filtratas sukoncentruojamas vakuume, Liekana ištirpinama CH2CI2 (100 ml), plaunama 1N NaOH (100 ml) ir vandeninis sluoksnis vėl ekstrahuojamas CH2CI2 (2x100 ml). Sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojama, ir sukoncentravus vakuume, gaunamas junginys G (0,60 g, 52 %), kuris yra kieta medžiaga. Junginys G naudojamas be papildomo gryninimo.G. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8-amino-1 H -1,4-benzodiazepine, Compound F (0.13 g, 0.29 mmol) in ethanol, water and nearly. To a mixture of HCl (500/50/1) (26 mL) was added iron powder (0.15 g, 2.6 mmol) at room temperature. The mixture was refluxed for 3 h, cooled to room temperature, filtered and the filtrate concentrated in vacuo, the residue was dissolved in CH 2 Cl 2 (100 mL), washed with 1N NaOH (100 mL) and the aqueous layer was re-extracted with CH 2 Cl 2 (2x100 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated in vacuo to give G (0.60 g, 52%) as a solid. Compound G is used without further purification.
H. N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepin-8-il]acetamidas (dihidrochloridas)H. N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] acetamide (dihydrochloride)
Į junginio G (0,050 g, 0,13 mmol) ir acto rūgšties anhidrido (0,024 ml, 0,25 mmol) tirpalą CH2CI2 (2 ml) kambario temperatūroje pridedama 4dimetilaminopiridino (0,005 g). Mišinys maišomas 16 vai., reakcija stabdoma 10 % NaHCO3 (1 ml) ir MeOH (0,50 ml), ir maišoma kambario temperatūroje 15 min. Mišinys praskiedžiamas vandeniu (5 ml), ir tirpalas ekstrahuojamas CH2CI2 (3x50 ml). Sumaišyti organiniai ekstraktai džiovinami (MgSO4), filtruojama ir koncentruojama vakuume. Liekana gryninama sparčiosios chromatografijos metodu (19/1/0,01 CHCI3/MeOH/NH4OH), ir reikiamos frakcijos koncentuojamos vakuume. Liekana ištirpinama MeOH (5 ml), paveikiama 1N HCI (2 ml), filtruojama per miliporinj filtrą ir po liofiiizacijos gaunamas 22 pavyzdžio junginys (0,018 g, 32 %), kuris yra kieta medžiaga. MS (M + H)+ 440.To a solution of compound G (0.050 g, 0.13 mmol) and acetic anhydride (0.024 mL, 0.25 mmol) in CH 2 Cl 2 (2 mL) was added 4-dimethylaminopyridine (0.005 g) at room temperature. The mixture was stirred for 16 h, quenched with 10% NaHCO 3 (1 mL) and MeOH (0.50 mL), and stirred at room temperature for 15 min. The mixture was diluted with water (5 mL) and the solution was extracted with CH 2 Cl 2 (3x50 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (19/1 / 0.01 CHCl 3 / MeOH / NH 4 OH) and the required fractions concentrated in vacuo. The residue was dissolved in MeOH (5 mL), treated with 1N HCl (2 mL), filtered through a millipolar filter, and lyophilized to give Example 22 (0.018 g, 32%) as a solid. MS (M + H) + 440.
Analizė išskaičiuota pagal C26H25N5O2 -2,0 HCI -1,16 CH3OH.Analysis calculated for C26H25N5O2 -1.16 HCI -2.0 CH 3 OH.
Išskaičiuota: C, 59,35; H, 5,80; N, 12,74.Found: C, 59.35; H, 5.80; N, 12.74.
Rasta: C, 59,35; H, 5,81; N, 12,22.Found: C, 59.35; H, 5.81; N, 12.22.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-1Hpirido[2,3-e]-1,4-diazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-pyrido [2,3-e] -1,4-diazepine (trihydrochloride)
A. 2,3,4,5-Tetrahidro-1H-pirido[2,3-e]-1,4-diazepin-5-onasA. 2,3,4,5-Tetrahydro-1H-pyrido [2,3-e] -1,4-diazepin-5-one
2-Chlornikotinamido (4,0 g, 25,5 mmol) tirpalas etilendiamine (25 ml) virinamas su grįžtamu šaldytuvu 24 vai. J šį tirpalą pridedama 5N NaOH (5,1 ml, 25,5 mmol), ir mišinys koncentruojamas vakuume. Negryna medžiaga chromatografuojama (silikagelis, 5-20 % CH3OH/CHCI3), ir gaunamas junginys A (339 mg, 8 %), kuris yra gelsva kieta medžiaga. MS (M + H + CH3CN)+ 205.A solution of 2-chloronicotinamide (4.0 g, 25.5 mmol) in ethylenediamine (25 mL) was refluxed for 24 h. To this solution was added 5N NaOH (5.1 mL, 25.5 mmol) and the mixture was concentrated in vacuo. The crude material was chromatographed (silica gel, 5-20% CH3OH / CHCl3) to give Compound A (339 mg, 8%) as a yellowish solid. MS (M + H + CH 3 CN) + 205.
B, 2,3,4,5-Tetrahidro-1H-pirido[2,3-e3-1,4-diazepinas į junginio A (100 mg, 0,61 mmol) tirpalą sausame toluene (15 ml) pridedama diizobutilaliuminio hidrido (1M heksanuose, 3,1 ml, 3,1 mmol). Mišinys virinamas su grįžtamu šaldytuvu 36 vai. Po 12 ir po 24 vai. vėl pridedama DiBAH (kiekvieną kartą po 3,1- ml). Po 36 vai. reakcijos mišinys atvėsinamas iki kambario temperatūros, ir reakcija stabdoma metanoliu. Susidaro klampus gelis, kuris ištirpinamas 1N HCI. Mišinys ekstrahuojamas EtOAc (15 ml), ir atskiriamas organinis sluoksnis. Vandeninis sluoksnis pašarminamas 5N NaOH ir ekstrahuojamas 10 % i-PrOH/CH2Cl2 (5x15 ml). Organiniai sluoksniai sumaišomi, džiovinami Na2SO4 ir sukoncentravus vakuume, gaunamas junginys B (79 mg, 87 %), kuris naudojamas nevalytas. MS (M + H + CH3CN)+ 191.B, 2,3,4,5-Tetrahydro-1 H -pyrido [2,3-b] -1,4-diazepine is added to a solution of compound A (100 mg, 0.61 mmol) in dry toluene (15 mL) with diisobutylaluminum hydride ( 1M in hexanes, 3.1 mL, 3.1 mmol). The mixture is refluxed for 36 hours. After 12 and after 24 or. DiBAH is added again (3.1 ml each). After 36 or so. the reaction mixture is cooled to room temperature and quenched with methanol. A viscous gel is formed which is dissolved in 1N HCl. The mixture was extracted with EtOAc (15 mL) and the organic layer was separated. The aqueous layer was basified with 5N NaOH and extracted with 10% i-PrOH / CH 2 Cl 2 (5 x 15 mL). The organic layers were combined, dried over Na 2 SO 4 and concentrated in vacuo to give Compound B (79 mg, 87%) which was used crude. MS (M + H + CH 3 CN) + 191.
C. 2,3,4,5-Tetrahidro-4-(1-naftalenilkarbonil)-1H-pirido[2,3-e]-1,4diazepinas j junginio B (79 mg, 0,53 mmol), 1-naftalenkarboksirūgšties (115,5 mg, 0,67 mmol), EDC (128,4 mg, 0,67 mmol) ir HOBt (90,5 mg, 0,67 mmol) tirpalą bevandeniame DMF (2 ml) pridedama diizopropiletilamino (0,1 ml, 0,67 mmol). Po 3 vai. reakcijos mišinys praskiedžiamas EtOAc (5 ml) ir plaunamas 10 % LiCI. Organinis sluoksnis plaunamas 1N HCI ir atskiriamas. Vandeninis sluoksnis pašarminamas 5N NaOH ir ekstrahuojamas EtOAc (5x5 ml). Šie penki organiniai sluoksniai sumaišomi, džiovinami Na2SO4 ir koncentruojami. Negryna medžiaga chromatografuojama (silikagelis, 0-5 % CH3OH/CHCI3), ir gaunamas junginys C (96 mg, 60 %), kuris yra rusva alyva. MS (M + H + CH3CN)+ 345.C. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1H-pyrido [2,3-e] -1,4-diazepine, Compound B (79 mg, 0.53 mmol), 1-naphthalenecarboxylic acid (115.5 mg, 0.67 mmol), EDC (128.4 mg, 0.67 mmol) and HOBt (90.5 mg, 0.67 mmol) in anhydrous DMF (2 mL) were added diisopropylethylamine (0.1 ml, 0.67 mmol). After 3 or. the reaction mixture was diluted with EtOAc (5 mL) and washed with 10% LiCl. The organic layer was washed with 1N HCl and separated. The aqueous layer was basified with 5N NaOH and extracted with EtOAc (5x5 mL). The five organic layers were combined, dried over Na 2 SO 4, and concentrated. The crude material was chromatographed (silica gel, 0-5% CH 3 OH / CHCl 3 ) to give Compound C (96 mg, 60%) as a brown oil. MS (M + H + CH 3 CN) + 345.
D. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-pirido[2,3-e]-1,4-diazepinas (trihidrochloridas) j junginio C (30 mg, 0,10 mmol) ir 4-formilimidazolo (14,5 mg, 0,50 mmol) tirpalą dichloretane (0,5 ml) ir acto rūgštyje (0,25 ml) pridedama NaBH(OAc)3 (29,7 mg, 0,14 mmol). Mišinys maišomas kambario temperatūroje 12 vai. ir 80 °C temperatūroje 12 vai. Vėl pridedama 4formilimidazolo (14,5 mg, 0,50 mmol) ir NaBH(OAc)3 (30 mg, 0,14 mmol), ir reakcijos mišinys šildomas 80 °C temperatūroje dar 24 vai. Reakcijos mišinys atvėsinamas iki kambario temperatūros, praskiedžiamas EtOAc (2 ml) ir pridedama NH4OH (kone., 2 ml). Pamaišius 3 vai., pridedama NaHCO3 (sotus tirpalas, 3 ml) ir dar EtOAc (5 ml). Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas EtOAc (3x5 ml). Organiniai sluoksniai sumaišomi ir plaunami NH4CI (sotus tirpalas, 5 ml), džiovinami Na2SO4 ir sukoncentruojami vakuume. Negryna medžiaga ištirpinama metanolyje (2 ml) ir gryninama HPLC metodu (YMC S5 ODS 30x250 mm kolonėlė, tirpiklis A: 10 % MeOH/H2O pagal masę/0,1 % TFA, tirpiklis B: 90 % MeOH/H2O pagal masę/0,1 % TFA, gradientas: 0-100 % B tirpiklyje A per 60 min. 25 ml/min. greitis, kontroliuojama esant 220 nm bangos ilgiui). Frakcijos, kuriose yra produktas, sumaišomos, koncentruojamos vakuume, liekana ištirpinama 1ND. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-pyrido [2,3-e] -1,4-diazepine (trihydrochloride) a solution of compound C (30 mg, 0.10 mmol) and 4-formylimidazole (14.5 mg, 0.50 mmol) in dichloroethane (0.5 mL) and acetic acid (0.25 mL) was added NaBH (OAc) 3 ( 29.7 mg, 0.14 mmol). The mixture was stirred at room temperature for 12 hours. and at 80 ° C for 12 hours. 4-Formylimidazole (14.5 mg, 0.50 mmol) and NaBH (OAc) 3 (30 mg, 0.14 mmol) were added again and the reaction mixture was heated at 80 ° C for a further 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (2 mL) and NH 4 OH (almost 2 mL) was added. After stirring for 3 h, NaHCO 3 (saturated solution, 3 mL) and EtOAc (5 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3x5 mL). The organic layers were combined and washed with NH 4 Cl (saturated solution, 5 mL), dried over Na 2 SO 4, and concentrated in vacuo. The crude material was dissolved in methanol (2 mL) and purified by HPLC (YMC S5 ODS 30x250 mm column, solvent A: 10% MeOH / H 2 O w / w 0.1% TFA, solvent B: 90% MeOH / H 2 O mass / 0.1% TFA, gradient: 0-100% B in Solvent A over 60 min at 25 mL / min, controlled at 220 nm). The fractions containing product are mixed, concentrated in vacuo, and the residue is dissolved in 1N
HCI ir liofilizuojama, vėl ištirpinama vandenyje ir liofilizuojama. Gaunamas 23 pavyzdžio junginys, kuris yra pūkų pavidalo kieta medžiaga (4 mg, 8 %). 1H-BMR (CD3OD, 400 MHz) δ 8,87 (d, J, = 1,3, 0,5H), 8,70 (d, J, = 1,3 0,5H), 8.06 (dd, J, = 1,7, J2 = 5,6, 0,5H), 7,96 (d, J, = 6,8, 0,5H), 7,83-7,91 (m, 2,5H), 7,60 (d, Ji = 1,3, 0,5H), 7,52 (dd, J, = 1,7, J2 = 7,3, 0,5H), 7,34-7,49 (m, 4H), 7,26 (dd, J, = 1,3, J2 = 7,6, 0,5H), 7,11 (dd, J, = 1,3, J2 = 7,1,0,5H), 7,05 (dd, Ji = 5,6, J2 = 7,3, 0,5H), 6,57 (d, J, = 7,3, 0,5H), 6,52 (dd, J, = 5,6, J2 = 7,7, 0.5H), 5,01 (d, J, = 1,3, 1H), 4,95 (d, Ji = 1,3, 1H), 4,39-4,57 (m, 1,5H), 4,084,13 (m, 1H), 3,88-3,94 (m, 1H), 3,53-3,65 (m, 1,5H), 3,42-3,45 (m, 1H); MS (M + H)+384.HCl and lyophilized, redissolved in water and lyophilized. Example 23 is obtained as a fluffy solid (4 mg, 8%). 1 H-NMR (CD 3 OD, 400 MHz) δ 8.87 (d, J 1 = 1.3, 0.5H), 8.70 (d, J 1 = 1.3 0.5H), 8.06 ( dd, J 1 = 1.7, J 2 = 5.6, 0.5H), 7.96 (d, J 1 = 6.8, 0.5H), 7.83-7.91 (m, 2 , 5H), 7.60 (d, J 1 = 1.3, 0.5H), 7.52 (dd, J 1 = 1.7, J 2 = 7.3, 0.5H), 7.34- 7.49 (m, 4H), 7.26 (dd, J 1 = 1.3, J 2 = 7.6, 0.5H), 7.11 (dd, J 1 = 1.3, J 2 = 7,1,0,5H), 7.05 (dd, Ji = 5.6, J 2 = 7.3, 0.5H), 6.57 (d, J = 7.3, 0.5H) 6.52 (dd, J = 5.6, J 2 = 7.7, 0.5H), 5.01 (d, J = 1.3, 1H), 4.95 (d, Ji = 1 , 3, 1H), 4.39-4.57 (m, 1.5H), 4.084.13 (m, 1H), 3.88-3.94 (m, 1H), 3.53-3.65 (m, 1.5H), 3.42-3.45 (m, 1H); MS (M + H) < + > 384.
pavyzdysexample
2,3,4,5-Tetrahidro-1-(1 H-imidazol-4-ilmetiI)-4-(1-naftalenilkarbonil)-1 Hnafto[2,3-e]-1,4-diazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-naphtho [2,3-e] -1,4-diazepine (dihydrochloride)
A. 2H-3,1-Naftoksazin-2,4(1H)-dionas j ledu šaldomą 25 g (10,7 mmol) 80 % 2-amino-3naftalenkarboksirūgšties ir 2,5 g (8,5 mmol) trifosgeno suspensiją 70 ml acetonitrilo argono atmosferoje sulašinama 0,35 ml (25 mmol) trietilamino. Maišoma tol, kol ledo vonios temperatūra pasiekia kambario temperatūrą ir po to per naktį maišoma kambario temperatūroje. Tada j gautą suspensiją pridedama 2 ml metanolio ir maišoma dar valandą. Nufiltravus kietą medžiagą, gaunama 2,5 g (priimama, kad išeiga yra 100 %) junginio A, kuris yra rusvi milteliai.A. 2H-3,1-Naphthoxazine-2,4 (1 H) -dione in a ice-cooled suspension of 25 g (10.7 mmol) of 80% 2-amino-3-naphthalenecarboxylic acid and 2.5 g (8.5 mmol) of triphosgene. of acetonitrile under argon was added dropwise 0.35 mL (25 mmol) of triethylamine. Stir until the ice bath reaches room temperature and then stir overnight at room temperature. 2 ml of methanol are then added to the resulting suspension and stirred for an additional hour. Filtration of the solid gave 2.5 g (assuming a 100% yield) of Compound A, which was a brownish powder.
B. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1 H-nafto[2,3-e]-1,4-diazepinas (dihidrochloridas) pavyzdžio junginys (nelabai balta amorfinė kieta medžiaga) pagaminamas iš junginio A pagal reakcijų seką tokiems junginiams gauti: 1 pavyzdžio junginiui A, virinama 10 vai; 2 pavyzdžio junginiui B, išskyrus tai, kad tirpikliu naudojamas THF, o produkto:bornano kompleksas suskaldomas virinant su vandeniniu HCI; 2 pavyzdžio junginiui C, išskyrus tai, kad chromatografijoje naudojamas 50 % etiiacetatas heksane; 1 pavyzdžio junginiui D, ir produktas gryninamas preparatine HPLC (YMC S5 ODS (30x250 mm kolonėlė, gradientinis eliuavimas nuo 40 iki 100 % tirpiklio B (A: 10 % metanolis:vanduo + 0,1 % TFA, B: 10 % vanduo:metanolis + 0,1 % TFA) ir paverčiamas HCI druska, veikiant HCI-MeOH.B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-naphtho [2,3-e] -1,4-diazepine (dihydrochloride) Example compound (off-white amorphous solid) is prepared from Compound A according to the reaction sequence to give Compound A of Example 1, boiling for 10 hours; Compound B of Example 2, except that THF is used as solvent and the product: bornan complex is cleaved by boiling with aqueous HCl; Compound C of Example 2, except that 50% ethyl acetate in hexane was used for chromatography; Example 1 Compound D, and the product was purified by preparative HPLC (YMC S5 ODS (30 x 250 mm column, gradient elution 40 to 100% solvent B (A: 10% methanol: water + 0.1% TFA, B: 10% water: methanol) + 0.1% TFA) and converted to the HCl salt with HCl-MeOH.
Analizė išskaičiuota pagal C28H24N4O -1,5 HCI -0,25 H2O.Analysis calculated for C 28 H 24 N 4 O -1.5 HCl -0.25 H 2 O.
Išskaičiuota: C, 68,39; H, 5,33; N, 11,39.Found: C, 68.39; H, 5.33; N, 11.39.
Rasta: C, 68,41; H, 5,46; N, 11,31.Found: C, 68.41; H, 5.46; N, 11.31.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-8nitro-1H-1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8nitro-1H-1,4-benzodiazepine (dihydrochloride)
Į 22 pavyzdžio junginio E (0,50 g, 1,43 mmol), 4-formilimidazolo (0,41 g, 4,3 mmol) ir AcOH (4 ml) tirpalą CH2CI2 (4 ml) pridedama natrio triacetoksiborhidrido (0,91 g, 4,3 mmol). Pamaišius 15 vai., mišinys praskiedžiamas CH2CI2 (10 ml), NH4OH (5 ml) ir NaHCO3 (5 ml) ir maišoma 30 min. Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CH2CI2 (2x50 ml). Sumaišyti organiniai sluoksniai džiovinami MgSO4, nufiltruojama ir koncentruojama. Produktas gryninamas, chromatografuojant per silikagelio kolonėlę, eliuuojamą 19/1 CHCI3/CH3OH, ir gaunamas 25 pavyzdžio junginys (0,52 g, 85 %), kuris yra gelsva kieta medžiaga. (25 pavyzdžio junginys yra taip pat ir 22 pavyzdžio junginys F).To a solution of Example 22 Compound E (0.50 g, 1.43 mmol), 4-formylimidazole (0.41 g, 4.3 mmol) and AcOH (4 mL) in CH 2 Cl 2 (4 mL) was added sodium triacetoxyborohydride ( 0.91 g, 4.3 mmol). After stirring for 15 h, the mixture was diluted with CH 2 Cl 2 (10 mL), NH 4 OH (5 mL) and NaHCO 3 (5 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 ( 2 x 50 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated. The product was purified by chromatography on a silica gel column eluting with 19/1 CHCl 3 / CH 3 OH to give Example 25 (0.52 g, 85%) as a yellowish solid. (The compound of Example 25 is also the compound F of Example 22).
MS (M + H)+ 428.MS (M + H) < + >
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-8amino-1H-1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8amino-1H-1,4-benzodiazepine (dihydrochloride)
J 25 pavyzdžio junginio (0,10 g, 0,23 mmol) tirpalą AcOH/H2O (2 ml, 1:1) pridedama 16 % vandeninio TiCI3 (2 mi). Pamaišius 15 min., reakcijos mišinys pašarminamas 1N NaOH ir NaHCO3 ir maišomas 30 min. Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCI3/CH3OH (9/1). Sumaišyti organiniai sluoksniai džiovinami MgSO4, nufiltruojama ir sukoncentravus gaunama 0,92 g (73 %) 26 pavyzdžio junginio. 20 mg šios medžiagos mėginys veikiamas 1M HCI eteryje (2 ml). Susidaro gelsva kieta medžiaga, kuri keletą kartų trinama su eteriu, išdžiovinama vakuume, ir gaunamas 26 pavyzdžio junginys (23 mg), kuris yra gelsva kieta medžiaga. (26 pavyzdžio junginys taip pat yra ir 22 pavyzdžio junginys G).To a solution of Example 25 (0.10 g, 0.23 mmol) in AcOH / H 2 O (2 mL, 1: 1) was added 16% aqueous TiCl 3 (2 mL). After stirring for 15 min, the reaction mixture was basified with 1N NaOH and NaHCO 3 and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl 3 / CH 3 OH (9/1). The combined organic layers were dried over MgSO 4 , filtered, and concentrated to give 0.92 g (73%) of Example 26. A 20 mg sample of this material is treated with 1M HCl in ether (2 mL). A yellowish solid is formed which is triturated several times with ether, dried in vacuo to give Example 26 (23 mg) as a yellowish solid. (The compound of Example 26 is also the compound of Example 22, G).
MS(M + H)+ 398.MS (M + H) < + > 398.
N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)1 H-1,4-benzodiazepin-8-il]benzamidas (dihidrochloridas) į 26 pavyzdžio junginio (0,042 g, 0,10 mmol) tirpalą CH2CI2 (1 ml) ir trietilaminą (0,01 g, 0,016 ml) 0 °C temperatūroje pridedama benzoilo chlorido (0,016 g, 0,013 ml). Pamaišius 2 vai., mišinys praskiedžiamas NaHCO3 (2 ml) ir CHCI3 (10 ml). Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCI3 (2x20 ml). Sumaišyti organiniai sluoksniai džiovinami MgSO4, nufiltruojama ir koncentruojama. Liekana gryninama per sparčiosios chromatografijos slilikagelio kolonėlę, eliuuojant CHCI3/CH3OH (9/1). Produktas veikiamas 1M HCI eteryje (2 ml). Susidaro gelsva kieta medžiaga, kuri keletą kartų trinama su eteriu, išdžiovinama vakuume, ir gaunamas 27 pavyzdžio junginys (0,015 g, 28 %), kuris yra gelsva kieta medžiaga.N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] benzamide (dihydrochloride) To a solution of Example 26 (0.042 g, 0.10 mmol) in CH 2 Cl 2 (1 mL) and triethylamine (0.01 g, 0.016 mL) at 0 ° C was added benzoyl chloride (0.016 g, 0.013 mL). After stirring for 2 h, the mixture was diluted with NaHCO 3 (2 mL) and CHCl 3 (10 mL). The layers were separated and the aqueous layer was extracted with CHCl 3 (2 x 20 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with CHCl 3 / CH 3 OH (9/1). The product was treated with 1M HCl in ether (2 mL). A yellowish solid is formed which is triturated several times with ether, dried in vacuo to give Example 27 (0.015 g, 28%) as a yellowish solid.
MS (M + H)+ 502.MS (M + H) + 502.
IR: (KBr): 3434, 2930, 1611, 1508, 1424, 1263 cm'1.IR: (KBr) 3434, 2930, 1611, 1508, 1424, 1263 cm @ -1 .
pavyzdysexample
N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)1 H-1,4-benzodiazepin-8-il]cikloheksanamidas (dihidrochloridas) pavyzdžio junginys pagaminamas iš 26 pavyzdžio junginio ir cikloheksankarboniichlorido pagal 27 pavyzdyje aprašytą metodiką. Negrynas produktas veikiamas tiesiogiai HCI/eteryje. Geltona kieta medžiaga, kuri susidaro keletą kartų trinant su eteriu, išdžiovinama vakuume ir gaunamas 28 pavyzdžio junginys, kuris yra geltona kieta medžiaga. Išeiga 90 %. MS (M + H)+ 508.Example of N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] cyclohexanamide (dihydrochloride) The compound is prepared from the compound of Example 26 and cyclohexanecarbonyl chloride according to the procedure described in Example 27. The crude product is exposed directly to HCl / ether. The yellow solid, which is formed by repeated trituration with ether, is dried in vacuo to give Example 28 as a yellow solid. Yield 90%. MS (M + H) + 508.
IR: (KBr): 3434, 2930, 1611, 1508, 1424, 1263 cm'1.IR: (KBr) 3434, 2930, 1611, 1508, 1424, 1263 cm @ -1 .
2,3,4,5-Tetrahidro-1-[2-(1H-imidazol-4-il)etil]-4-(1-naftalenilkarbonil)-1H1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (dihydrochloride)
A. 2,3,4,5-Tetrahidro-1-[1-okso-2-(1-trifenilmetil-imidazol-4-il)etil]-4[(1,1-dimetiletoksi)karbonil]-1H-1,4-benzodiazepinasA. 2,3,4,5-Tetrahydro-1- [1-oxo-2- (1-triphenylmethyl-imidazol-4-yl) -ethyl] -4 - [(1,1-dimethylethoxy) carbonyl] -1H-1 , 4-Benzodiazepine
Į 250 mg (0,68 mmol) N-trifenilmetil-4-imidazolacto rūgšties ir 94 μΙ (0,68 mmol) trietilamino tirpalą 3 ml THF -30 °C temperatūroje argono atmosferoje sulašinama 97 μΙ (0,75 mmol) izobutilchlorformiato. Pamaišoma 10 min., ir pridedamas 253 mg (1,02 mmol) 4 pavyzdžio junginio A tirpalas 1 ml THF. Sušilęs iki kambario temperatūros mišinys maišomas 7 vai., po to praskiedžiamas etilacetatu. Tirpalas plaunamas sočiu NaCl, sočiu NaHCO3, vėl sočiu NaCl, džiovinamas (MgSO4) ir koncentruojamas. Gauta alyva chromatografuojama sparčiosios chromatografijos metodu (silikagėlis, 75 % etil acetatas :heksanai), ir gaunama 195 mg (0,33 mmol, 48 %) junginio A, kuris yra balta putų pavidalo kieta medžiaga.To a solution of 250 mg (0.68 mmol) of N-triphenylmethyl-4-imidazolactic acid and 94 μΙ (0.68 mmol) of triethylamine in 3 mL of THF at -30 ° C was added 97 μΙ (0.75 mmol) of isobutyl chloroformate. Stir for 10 min and add a solution of 253 mg (1.02 mmol) of Example 4 Compound A in 1 mL THF. After warming to room temperature, the mixture was stirred for 7 h, then diluted with ethyl acetate. The solution was washed with saturated NaCl, saturated NaHCO 3 , again with saturated NaCl, dried (MgSO 4 ) and concentrated. The resulting oil was subjected to flash chromatography (silica gel, 75% ethyl acetate: hexanes) to give 195 mg (0.33 mmol, 48%) of Compound A as a white foamy solid.
B. 2,3,4,5-Tetrahidro-1-[2-(1H-imidazol-4-il)etil]-4-(1,1-dimetiIetoksi)karbonil]-1H-1,4-benzodiazepinasB. 2,3,4,5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1,1-dimethylethoxy) carbonyl] -1H-1,4-benzodiazepine
J 100 mg (0,17 mmol) junginio A tirpalą 1 ml THF argono atmosferoje pridedama 1 ml (1 mmol) 1M borano THF. Kai nustoja putoti, mišinys pašildomas 60 °C temperatūroje 1 vai. ir atvėsinamas iki kambario temperatūros. Pridedama kone. HCI (0,5 ml), tirpalas pašildomas 60 °C temperatūroje 1 vai. ir nugarinamas iki sausos liekanos. Ši liekana praskiedžiama vandeniu, tirpalas plaunamas du kartus etilacetatu, pašarminamas, lašinant 40 % KOH vandenyje, ir ekstrahuojamas metileno chloridu (3x). Sumaišyti metileno chlorido ekstraktai plaunami sočiu NaCl (2x), džiovinami (MgSO4) ir nugarinus tirpikli, gaunama 39 mg klampios alyvos. Ši medžiaga chromatografuojama sparčiosios chromatografijos metodu (silikagėlis, CHCI3:MeOH:NH4OH 80:20:2), ir gaunama 16 mg (0,066 mmol, 40 %) alyvos pavidalo junginio B.To a solution of 100 mg (0.17 mmol) of Compound A in 1 mL of THF under argon was added 1 mL (1 mmol) of 1M borane in THF. When the foaming ceases, the mixture is heated to 60 ° C for 1 hour. and cooled to room temperature. Comes with machine. HCl (0.5 mL), warm to 60 ° C for 1 h. and evaporated to dryness. The residue was diluted with water, washed twice with ethyl acetate, basified with 40% KOH in water and extracted with methylene chloride (3x). The combined methylene chloride extracts were washed with saturated NaCl (2x), dried (MgSO 4 ) and evaporated to give 39 mg of a viscous oil. This material was subjected to flash chromatography (silica gel, CHCl 3 : MeOH: NH 4 OH 80: 20: 2) to give 16 mg (0.066 mmol, 40%) of compound B as an oil.
C. 2,3,4,5-Tetrahidro-1-[2-(1H-imidazol-4-il)etil]-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (dihidrochioridas)C. 2,3,4,5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)
Junginys C pagaminamas iš junginio B (30 mg, 0,12 mmol) pagal 23 pavyzdyje aprašytą junginio C gavimo metodiką, maišant 18 vai. Mišinys nugarinamas iki sausos liekanos, liekana chromatografuojama sparčiosios chromatografijos metodu (silikagelis, 10 % metanolis:chloroformas) ir gaunama 33 mg medžiagos, kuri gryninama preparatinės HPLC metodu per YMC S5 ODS (30x250 mm) kolonėlę. Panaudojus gradientinį eliuavimą nuo 30 iki 100 % tirpiklio B (A: 10 % metanolis:vanduo + 0,1 % TFA, B: 10 % vanduo:metanolis + 0,1 %TFA), gaunama skaidri stiklo pavidalo liekana, kuri paverčiama HCI druska, veikiant HCI-MeOH; gaunama 20 mg (0,04 mmol, 36 %) 29 pavyzdžio junginio, kuris yra kieta putų pavidalo medžiaga.Compound C is prepared from Compound B (30 mg, 0.12 mmol) according to the procedure for preparation of Compound C described in Example 23 with stirring for 18 hours. The mixture is evaporated to dryness, and the residue is chromatographed on flash silica gel (10% methanol: chloroform) to give 33 mg of material which is purified by preparative HPLC over a YMC S5 ODS (30 x 250 mm) column. A gradient elution of 30 to 100% solvent B (A: 10% methanol: water + 0.1% TFA, B: 10% water: methanol + 0.1% TFA) gives a clear glassy residue which is converted to the HCl salt with HCl-MeOH; 20 mg (0.04 mmol, 36%) of Example 29 is obtained which is a solid foam.
MS (M + H)+ 397.MS (M + H) < + > 397.
Analizė išskaičiuota pagal C25H24N4O ·2 HCI -1,5 H2O.Analysis calculated for C25H24N4O · HCl 2 -1.5 H 2 O.
Išskaičiuota: C, 60,48; H, 5,89; N, 11,28.Found: C, 60.48; H, 5.89; N, 11.28.
Rasta: C, 60,69; H, 5,63; N, 11,12.Found: C, 60.69; H, 5.63; N, 11.12.
2,3,4,5-Tetrahidro-1-[2-(1H-imidazol-4-il)etil]-4-(1-naftalenilkarbonil)-7fenil-1H-1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
A. 2,3,4,5-Tetrahidro-4-[(1,1-dimetiletoksi)karbonil]-7-fenil-1H-1,4benzodiazepinas j 12 pavyzdžio junginio B (5,2 g, 23 mmol) tirpalą THF (50 ml) pridedama di-tret-butildikarbonato (6,1 g, 28 mmol). Mišinys maišomas kambario temperatūroje 2 vai, ir koncentruojamas vakuume. Liekana gryninama sparčiosios chromatografijos metodu (silikagelis, etilacetatas) ir gaunamas alyvos pavidalo junginys A (5,7 g, 91 %). MS: (M+H)+ 325.A. 2,3,4,5-Tetrahydro-4 - [(1,1-dimethylethoxy) carbonyl] -7-phenyl-1H-1,4-benzodiazepine in Example 12 Compound B (5.2 g, 23 mmol) in THF (50 mL) was added di-tert-butyl dicarbonate (6.1 g, 28 mmol). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate) to give compound A as an oil (5.7 g, 91%). MS: (M + H) + 325.
B. 2,3,4,5-Tetrahidro-1-[2-(1H-imidazol-4-il)etil]-4-(1naftalenilkarbonil)-7-fenil-1H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys pagaminamas iš junginio A pagal tokią 3 stadijų metodiką, naudojamą šiems junginiams gauti: 29 pavyzdžio junginiui A; 29 pavyzdžio junginiui B, virinant su grįžtamu šaldytuvu 4 vai. ir borano perteklių suskaldant lašinant metanolį: 3 pavyzdžio junginiui B, maišant kambario temperatūroje 2 vai. ir chromatografuojant sparčiosios chromatografijos metodu per silikagelį, eliuuojant 10 % metanoliu chloroforme, o po to preparatinės HPLC metodu (YMC S5 ODS (30x250 mm) kolonėlė: gradientinis eliuavimas nuo 40 iki 100 % tirpiklio B (A: 10 % metanolis:vanduo + 0,1 % TFA, B: 10 % vanduo:metanolis + 0,1 % TFA); skaidri stiklo pavidalo liekana paverčiama HCI druska, veikiant HCI-MeOH; gaunamas 30 pavyzdžio junginys, kuris yra putų pavidalo kieta medžiaga.B. Example of 2,3,4,5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) Compound A is prepared from Compound A according to the following 3-step procedure used to prepare the following compounds: Compound A of Example 29; Example 29 Compound B under reflux for 4 hours. and excess borane by decomposition with methanol: Compound B of Example 3 under stirring at room temperature for 2 hours. and flash chromatography on silica gel eluting with 10% methanol in chloroform followed by preparative HPLC (YMC S5 ODS (30 x 250 mm) column: gradient elution from 40 to 100% solvent B (A: 10% methanol: water + 0). 1% TFA, B: 10% water: methanol + 0.1% TFA), the clear glass residue is converted to the HCl salt by treatment with HCl-MeOH to give Example 30 as a foamy solid.
MS (M + H)+ 473.MS (M + H) + 473.
Analizė išskaičiuota pagal C3iH28N4O -2,15 HCI -1H2O.Analysis calculated for C 2 iH 8N 3 O 4 -2.15 HCl -1 H 2 O.
Išskaičiuota: C, 65,44; H, 5,69; N, 9,85.Found: C, 65.44; H, 5.69; N, 9.85.
Rasta: C, 65,56; H, 5,26; N, 9,40.Found: C, 65.56; H, 5.26; N, 9.40.
7-Brom-2,3,4,5-tetrahidro-1-[2-(1H-imidazol-4-il)etil]-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys pagaminamas iš 7-brom-1,4-benzodiazepino (pagaminto pagal 11 pavyzdyje aprašytą junginio B sintezės metodiką) pagal metodikas, naudojamas tokiems junginiams gauti: 4 pavyzdžio junginiui A; 29 pavyzdžio junginiui A, maišant 2 vai. ir chromatografijoje naudojant etilacetatą; 29 pavyzdžio junginiui B, redukuojant boranu, virinama su grjžtamu šaldytuvu 3 vai., veikiama HCI 60 °C temperatūroje 2 vai. ir chromatografijoje naudojamas chloroformas: metanolis: NH4OH (90:10:1); 23 pavyzdžio junginiui C, chromatografuojama per silikagelį, naudojant 20 % metanolį chloroforme, ir preparatine HPLC, naudojant 40-100 % B gradientą, MS (M + H) + 475.Example 7 7-Bromo-2,3,4,5-tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) is prepared. from 7-bromo-1,4-benzodiazepine (prepared according to the synthesis procedure for compound B described in Example 11) according to the procedures used to obtain the following compounds: Compound A of Example 4; Example 29 to compound A with stirring for 2 hours. and ethyl acetate for chromatography; Example 29 Compound B, under borane reduction, was refluxed for 3 hours and treated with HCl at 60 ° C for 2 hours. and chloroform used in chromatography: methanol: NH 4 OH (90: 10: 1); Compound C of Example 23 was chromatographed on silica gel with 20% methanol in chloroform and preparative HPLC using a 40-100% gradient B, MS (M + H) + 475.
Analizė išskaičiuota pagal C25H23N4OBr -2 HCI -0,35 H2O.Analysis calculated for C 25 H 23 N 4 OBr -2 HCl -0.35 H 2 O.
Išskaičiuota: C, 55,41; H, 4,67; N, 9,79.Found: C, 55.41; H, 4.67; N, 9.79.
Rasta: C, 55,55; H, 4,53; N, 10,00.Found: C, 55.55; H, 4.53; N, 10.00.
1-[[1-(2-Aminoetil)-1H-imidazol-5-il]metil]-2,3,4,5-tetrahidro-4-(1naftalenilkarbonil)-7-fenil-1H-1,4-benzodiazepinas (trihidrochloridas)1 - [[1- (2-Aminoethyl) -1H-imidazol-5-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1 H -1,4-benzodiazepine (trihydrochloride)
A. 1-[[1-[(1,1-Dimeti!etoksi)-karbonil]-1 H-imidazol-4-il]metil]-2,3,4,5tetrahidro-4-(1 -naftalenilkarbčnil)-7-fenil-1 H-1,4-benzodiazepinasA. 1 - [[1 - [(1,1-Dimethylethoxy) carbonyl] -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) - 7-phenyl-1H-1,4-benzodiazepine
150 mg (0,33 mmol) 12 pavyzdžio junginio, 144 mg (0,66 mmol) di-tbutildikarbonato ir 5 mg dimetilaminopiridino tirpalas 2 ml metileno chlorido maišomas argono atmosferoje per naktį. Neapdorotas mišinys chromatografuojamas sparčiosios chromatografijos metodu (silikagelis, 50 % etilacetatas heksanuose), ir gaunama 142 mg (0,25 mmol, 77 %) junginio A, kuris yra balta putų pavidalo medžiaga.A solution of 150 mg (0.33 mmol) of Example 12, 144 mg (0.66 mmol) of di-t-butyl dicarbonate and 5 mg of dimethylaminopyridine in 2 mL of methylene chloride was stirred under argon overnight. The crude mixture was subjected to flash chromatography (silica gel, 50% ethyl acetate in hexanes) to afford 142 mg (0.25 mmol, 77%) of Compound A as a white foam.
B. 1-[[1-(2-(N-ftalimidoetil)-1H-imidazol-5-il]metil]-2,3,4,5-tetrahidro4-(1-naftalenilkarbonil)-7-fenil-1H-1,4-benzodiazepinasB. 1 - [[1- (2- (N-Phthalimidoethyl) -1H-imidazol-5-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1 H- 1,4-Benzodiazepine
J ledu šaldomą 0,5 g (2,6 mmol) N-hidroksietilftalimido ir 315 μΙ (3,9 mmol) piridino tirpalą 5 ml metileno chlorido argono atmosferoje sulašinamas 527 μΙ (3,1 mmol) trifluormetansulfonrūgšties anhidrido tirpalas 5 ml metileno chlorido. Šaldant maišoma dar 0,5 vai., po to kambario temperatūroje -1 vai. Susidaro daug purių nuosėdų. Reakcijos mišinys hidrolizuojamas, pridedant ledo, ir maišoma 10 min. Organinis sluoksnis plaunamas 5 % NaHSO4 ir sočiu NaCl, džiovinamas (MgSO4), ir nugarinus tirpikli, gaunama 615 mg (1,9 mmol, 73 %) trifluormetansulfonato, kuris yra balta kieta medžiaga. Šio trifluormetansulfonato 44 mg (0,13 mmol) ir 75 mg (0,13 mmol) junginio A tirpalas 1,5 ml metileno chlorido maišomas per naktį argono atmosferoje. Neapdorotas mišinys chromatografuojamas sparčiosios chromatografijos metodu (silikagelis, etilacetatas, po to 10 % metanolis chloroforme), ir gaunama 41 mg (0,065 mmol, 50 %) junginio B, kuris yra balta putų pavidalo medžiaga.A solution of 0.5 g (2.6 mmol) of N-hydroxyethylphthalimide and 315 μΙ (3.9 mmol) of pyridine in 5 mL of methylene chloride under argon was added dropwise to a solution of 527 μ 3 (3.1 mmol) of trifluoromethanesulfonic anhydride in 5 mL of methylene chloride. Stirring is continued for another 0.5 h, followed by -1 h at room temperature. A large amount of friable sediment forms. The reaction mixture was hydrolyzed by adding ice and stirred for 10 min. The organic layer was washed with 5% NaHSO 4 and saturated NaCl, dried (MgSO 4 ), and evaporated the solvent to give 615 mg (1.9 mmol, 73%) of trifluoromethanesulfonate as a white solid. A solution of this trifluoromethanesulfonate (44 mg, 0.13 mmol) and 75 mg (0.13 mmol) of Compound A in 1.5 mL of methylene chloride was stirred overnight under argon. The crude mixture was subjected to flash chromatography (silica gel, ethyl acetate followed by 10% methanol in chloroform) to give 41 mg (0.065 mmol, 50%) of Compound B as a white foam.
C. 1-[[1-(2-Aminoetil)-1H-imidazol-5-il]metil]-2,3,4,5-tetrahidro-4-(1naftalenilkarbonil)-7-fenil-1 H-1,4-benzodiazepinas (trihidrochloridas) mg (0,095 mmol) junginio C ir 100 μΙ hidrazino tirpalas 0,5 ml metanolio maišomas per naktį argono atmosferoje. Gautos nuosėdos nufiltruojamos, ir skaidrus bespalvis filtratas chromatografuojamas preparatinės HPLC metodu per YMC S5 ODS (30x250 mm) kolonėlę. Panaudojus gradientinį eliuavimą nuo 25 iki 100 % tirpiklio B (A: 10 % metanolis:vanduo + 0,1 % TFA, B: 10 % vanduo:metanolis + 0,1 % TFA), gaunama balta kieta medžiaga, kuri paverčiama HCI druska, veikiant HCIMeOH, ir gaunama 11 mg (0,18 mmol, 19 %) 32 pavyzdžio junginio, kuris yra amorfinė gelsva kieta medžiaga.C. 1 - [[1- (2-Aminoethyl) -1H-imidazol-5-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1, A solution of 4-benzodiazepine (trihydrochloride) mg (0.095 mmol) in Compound C and 100 μΙ hydrazine in 0.5 mL methanol was stirred overnight under argon. The resulting precipitate is filtered off and the clear colorless filtrate is chromatographed on preparative HPLC over a YMC S5 ODS (30 x 250 mm) column. A gradient elution of 25 to 100% solvent B (A: 10% methanol: water + 0.1% TFA, B: 10% water: methanol + 0.1% TFA) gives a white solid which is converted to the HCl salt, HCl MeOH to give 11 mg (0.18 mmol, 19%) of Example 32 which is an amorphous yellowish solid.
MS (M + H)+ 502.MS (M + H) + 502.
1H-BMR (270 MHz, CD3OD, rotamerų/konformerų mišinys): δ 3,00 (1H, m), 1 H-NMR (270 MHz, CD 3 OD, rotamer / conformer mixture): δ 3.00 (1H, m),
3,43 (2H, m), 3,57 (2H, m), 4,09 (1H, m), 4,20 (1H, m), 4,50 (1H, m), 4,59 (1H,3.43 (2H, m), 3.57 (2H, m), 4.09 (1H, m), 4.20 (1H, m), 4.50 (1H, m), 4.59 (1H ,
m), 4,72 (2H, m), 5,02 (1H, m), 6,09 (1H, s), 7,03 (1H, m), 7,22-8,05 (13H, m), 9,12 ir 9,18 (1H, m).m), 4.72 (2H, m), 5.02 (1H, m), 6.09 (1H, s), 7.03 (1H, m), 7.22-8.05 (13H, m) ), 9.12 and 9.18 (1H, m).
IR (KBr): 764, 781, 1144, 1487, 1510, 1609, 2924, 3418 cm'1.IR (KBr): 764, 781, 1144, 1487, 1510, 1609, 2924, 3418 cm @ -1 .
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-1H-1,4-benzodiazepin4-karboksirūgštis (fenilmetilo esteris)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine, 4-carboxylic acid (phenylmethyl ester)
A. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-[(1,1-dimetiletoksi)karbonil]-7-fenil-1 H-1,4-benzodiazepinasA. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] -7-phenyl-1H-1,4-benzodiazepine
J 30 pavyzdžio junginio A (4,6 g, 14 mmol) ir 4-formilimidazolo (2,7 g, 28 mmol) tirpalą 1:1 metileno chloride/AcOH (40 ml) kambario temperatūroje pridedama natrio triacetoksiborhidrido (4,5 g, 21 mmol). Mišinys maišomas kambario temperatūroje 16 vai. ir koncentruojamas vakuume. Liekana ištirpinama metileno chloride (100 ml) ir 1/1 1N NaOH/NH4OH (100 ml), ir mišinys maišomas kambario temperatūroje 16 vai. Atskiriamas organinis sluoksnis, ir vandeninis sluoksnis ekstrahuojamas metileno chloridu (3x50 ml). Sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojama ir koncentruojama vakuume. Išgryninus liekaną sparčiosios chromatografijos metodu (19/1 CHCI3/MeOH), gaunamas junginys A (5,7 g, 100 %), kuris yra kieta medžiaga. MS: (M + H)+ 405.A solution of Example 30 Compound A (4.6 g, 14 mmol) and 4-formylimidazole (2.7 g, 28 mmol) in 1: 1 methylene chloride / AcOH (40 mL) was treated with sodium triacetoxyborohydride (4.5 g) at room temperature. 21 mmol). The mixture was stirred at room temperature for 16 hours. and concentrated in vacuo. The residue was dissolved in methylene chloride (100 mL) and 1/1 1N NaOH / NH 4 OH (100 mL) and the mixture was stirred at room temperature for 16 h. The organic layer was separated and the aqueous layer was extracted with methylene chloride (3 x 50 mL). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (19/1 CHCl 3 / MeOH) afforded Compound A (5.7 g, 100%) as a solid. MS: (M + H) + 405.
B. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-1H-1,4benzodiazepinas į junginį A (2,0 g, 5,0 mmol) pridedama bevandenio HCI (4M, 20 ml, 80 mmol) dioksane. Mišinys maišomas kambario temperatūroje 4 vai. ir koncentruojamas vakuume. Liekana ištirpinama vandenyje (10 ml) ir pridedama 1N NaOH (15 ml). Tirpalas ekstrahuojamas metileno chloridu (4x75 ml), sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojama ir sukoncentravus vakuume, gaunamas junginys B (1,45 g, 97 %), kuris yra kieta medžiaga. MS: (M + H)+ 305.B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine, to compound A (2.0 g, 5.0 mmol) was added with anhydrous HCl (4M, 20 mL, 80 mmol) in dioxane. The mixture was stirred at room temperature for 4 hours. and concentrated in vacuo. The residue was dissolved in water (10 mL) and 1N NaOH (15 mL) was added. The solution was extracted with methylene chloride (4 x 75 mL), the combined organic extracts dried (MgSO 4 ), filtered and concentrated in vacuo to give Compound B (1.45 g, 97%) as a solid. MS: (M + H) + 305.
C. 2,3,4,5-T etrahidro-1-(1 H-imidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepin-4-karboksirūgštis (fenilmetilo esteris) j junginio B (0,2 M, 1,0 ml, 0,16 mmol ) tirpalą DMF pridedama pnitrofenilbenzilkarbonato (0,04 g, 0,16 mmol). Mišinys maišomas kambario temperatūroje 3 vai., praskiedžiamas etilacetatu (50 ml) ir plaunamas 10 % LiCI (50 ml). Vandeninis sluoksnis ekstrahuojamas etilacetatu (2x50 ml). Organinės frakcijos sumaišomos, plaunamos 10 % LiCI (2x50 ml), džiovinamos (MgSO4), nufiltruojama ir koncentruojama vakuume. Išgryninus liekaną sparčiosios chromatografijos metodu (19/1/0,05C. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine-4-carboxylic acid (phenylmethyl ester) in Compound B (O, To a solution of 2 M, 1.0 mL, 0.16 mmol) in DMF was added pnitrophenylbenzyl carbonate (0.04 g, 0.16 mmol). The mixture was stirred at room temperature for 3 h, diluted with ethyl acetate (50 mL) and washed with 10% LiCl (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic fractions were combined, washed with 10% LiCl (2 x 50 mL), dried (MgSO 4 ), filtered and concentrated in vacuo. After purification of the residue by flash chromatography (19/1 / 0.05)
CHCb/MeOH/AcOH), gaunamas 33 pavyzdžio junginys (0,07 g, 93 %), kuris yra balta kieta medžiaga.CHCl 3 / MeOH / AcOH) to give Example 33 (0.07 g, 93%) as a white solid.
MS (M + H)+ 439.MS (M + H) + 439.
Analizė išskaičiuota pagal C27H26N4O2 0,05 H2O.Analysis calculated for C27H26N4O2 0.05 H 2 O.
Išskaičiuota: C, 72,52; H, 6,08; N, 12,53.Found: C, 72.52; H, 6.08; N, 12.53.
Rasta: C, 72,51; H, 5,85; N, 12,47.Found: C, 72.51; H, 5.85; N, 12.47.
pavyzdys eexample e
NN
HH
NN
O OCF3 O OCF 3
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-4-[2(trifluormetoksi)benzoil]-1H-benzodiazepinas2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- [2- (trifluoromethoxy) benzoyl] -1H-benzodiazepine
J o-trifluormetoksibenzenkarboksirūgštj (0,021 g, 0,10 mmol) kambario temperatūroje pridedamas HOAt (0,014 g, 0,10 mmol) tirpalas DMF (0,5 ml). J ši mišinj pridedamas 33 pavyzdžio junginio B (0,2 M, 0,50 ml, 0,16 mmol) tirpalas DMF ir diizopropilkarbodiimidas (DIC, 0,013 ml, 0,10 mmol, 1,0 ekv.), ir mišinys maišomas kambario temperatūroje 16 vai. Mišinys gryninamas jonų mainų chromatografijos metodu per kietos fazės ekstrakcijos kolonėlę, naudojant tokią operacijų seką:A solution of HOAt (0.014 g, 0.10 mmol) in DMF (0.5 mL) was added at room temperature to the o-trifluoromethoxybenzoic acid (0.021 g, 0.10 mmol). To this mixture was added a solution of Example 33 Compound B (0.2 M, 0.50 mL, 0.16 mmol) in DMF and diisopropylcarbodiimide (DIC, 0.013 mL, 0.10 mmol, 1.0 equiv.), And the mixture was stirred at room temperature. at 16 hours. The mixture is purified by ion-exchange chromatography over a solid phase extraction column using the following sequence of operations:
1) Varian'o kietos fazės ekstrakcijos kolonėlė (1,5 g, SCX katijonitas) kondicionuojama 10 ml MeOH/CH2CI2;1) Varian solid phase extraction column (1.5 g, SCX cation exchanger) is conditioned with 10 mL MeOH / CH 2 Cl 2 ;
2) mišinys suleidžiamas j kolonėlę, naudojant 10 ml švirkštą, kad būtų palaikomas pastovus sistemos slėgis;2) Inject the mixture into the column using a 10 ml syringe to maintain a constant system pressure;
3) kolonėlė plaunama 3x7,5 ml MeOH/CH2CI2 (1:1);3) washing the column with 3x7.5 mL of MeOH / CH 2 Cl 2 (1: 1);
4) kolonėlė plaunama 1x 7,5 ml 0,01 N amoniako MeOH;4) washing the column with 1x 7.5 mL of 0.01 N ammonia in MeOH;
5) kolonėlė eliuuojama' 7,5 ml 1,0 N amoniako MeOH, ir eliuatas renkmas j pasvertą rinktuvą.5) Elute the column with 7.5 mL of 1.0 N ammonia in MeOH and collect the eluate on a weighed collector.
Tirpalas, kuriame yra produktas, koncentruojamas Savant Speed Vac sistema (maždaug 2 mm Hg, 20 vai.). Liekana ištirpinama CH3CN (1 ml) ir vandens (1 ml) mišinyje ir liofilizuojama; gaunamas 34 pavyzdžio junginys (0,42 g, 85 %), kuris yra baltas liofiliatas.The solution containing the product is concentrated using the Savant Speed Vac system (approximately 2 mm Hg, 20 hours). The residue is dissolved in a mixture of CH 3 CN (1 ml) and water (1 ml) and lyophilized; Example 34 (0.42 g, 85%) is obtained which is a white lyophilisate.
MS (M + H)+493.MS (M + H) < + > 493.
Analizė išskaičiuota pagal C27H23N4O2F3-0,68 H2O.Analysis calculated for C 2 7 H 23 N 4 O 2 F 3 -0.68 H 2 O.
Išskaičiuota: C, 64,25; H, 4,86; N, 11,29. Rasta: C, 64,24; H, 4,83; N, 11,40.Found: C, 64.25; H, 4.86; N, 11.29. Found: C, 64.24; H, 4.83; N, 11.40.
1,2,3,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-N-metil-N,7-difenil-4H-1,4benzodiazepin-4-karboksamidas (dihidrochloridas)1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-N, 7-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (dihydrochloride)
A. 7-Fenil-1,2,3,5-tetrahidro-N-metil-N-fenil-4H-1,4-benzodiazepin-4karboksamidas j maišomą 115 mg (0,5 mmol) 12 pavyzdžio junginio B, 3 ml CH2CI2 ir 2,5 ml 1N NaOH mišinį 0 °C temperatūroje per 3 min. supilamas 94 mg (0,55 mmol) N-metil-N-fenilkarbamilchlorido tirpalas 1,5 ml CH2CI2. Po 1,5 vai. reakcijos mišinys praskiedžiamas CH2CI2 ir vandeniu, ir atskiriami sluoksniai. Vandeninis sluoksnis ekstrahuojamas CH2CI2 (2x), sumaišyti organiniai sluoksniai džiovinami (Na2SO4), ir sukoncentravus gaunama 177 mg (99 %) stiklo pavidalo junginio A.A. 7-Phenyl-1,2,3,5-tetrahydro-N-methyl-N-phenyl-4H-1,4-benzodiazepine-4-carboxamide in stirring 115 mg (0.5 mmol) of Example 12 Compound B in 3 mL CH 2 Cl 2 and 2.5 mL of 1N NaOH at 0 ° C for 3 min. a solution of 94 mg (0.55 mmol) of N-methyl-N-phenylcarbamyl chloride in 1.5 mL of CH 2 Cl 2 was added . After 1.5 or. the reaction mixture is diluted with CH 2 Cl 2 and water and the layers are separated. The aqueous layer was extracted with CH 2 Cl 2 (2x), the combined organic layers dried (Na 2 SO 4 ), and concentrated to give 177 mg (99%) of compound A as a glass.
B. 1,2,3,5-Tetrahidro-1-(1 H-imidazol-4-ilmetil)-N-metil-N,7-difenil-4H1,4-benzodiazepin-4-karboksamidas (dihidrochloridas) pavyzdžio junginys pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D sintezės metodiką. Chromatografiškai išgryninus (silikagelis, 7 % metanolio, 0,5 % amonio hidroksido, 93 % metileno chlorido) ir po to pavertus hidrochlorido druska, gaunamas miltelių pavidalo 35 pavyzdžio junginys; lyd. temp.; 97-102 °C.B. 1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-N, 7-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (dihydrochloride) from compound A according to the synthesis procedure for compound D described in Example 1. Chromatographic purification (silica gel, 7% methanol, 0.5% ammonium hydroxide, 93% methylene chloride) followed by conversion to the hydrochloride salt gave the powdered compound of Example 35; melt temp .; 97-102 ° C.
MS (M + H)+ 438+.MS (M + H) < + > 438 + .
Analizė išskaičiuota pagal C27H27N5O -1,2 HCI · 0,75 H2O · 0,25 C4H10O. Išskaičiuota: C, 65,51; H, 6,32; N, 13,64; Cl, 8,29.Analysis calculated for C 27 H 27 N 5 O · 1.2 HCl · 0.75 H 2 O · 0.25 C 4 H 10 O. Calculated: C, 65.51; H, 6.32; N, 13.64; Cl, 8.29.
Rasta: C, 65,55; H, 5,98; N, 13,50; Cl, 8,42.Found: C, 65.55; H, 5.98; N, 13.50; Cl, 8.42.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftaleniIkarbonil)-7-(1pi pe ridi ni Isulf oni I) -1H-1,4-benzodiazepinas (monohidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -7- (1-pyridine Isulfonyl) -1H-1,4-benzodiazepine ( monohydrochloride)
A. 2,3,4,5-Tetrahidro-7-(1-piperidinilsuIfonil)-1H-1,4-benzodiazepin2,5-dionasA. 2,3,4,5-Tetrahydro-7- (1-piperidinylsulfonyl) -1H-1,4-benzodiazepine-2,5-dione
Maišomas 1 pavyzdžio junginio A (400 mg, 2,3 mmol) tirpalas 10 ml chlorsulfato rūgšties šildomas 100 °C temperatūroje 6 vai. Tirpalas supilamas j ledo ir vandens mišinį. Vandeninė suspensija ekstrahuojama etilacetatu. Sumaišyti organiniai ekstraktai džiovinami ir filtruojami. Filtratas sumaišomas su piperidinu (0,2 ml) 0 °C temperatūroje. Reakcija vykdoma 30 min. Gautas tirpalas plaunamas 10 % HCI, sočiu NH4CI tirpalu, džiovinamas iš koncentruojamas. Liekana trinama su eteriu, ir gaunamas junginys A, kuris yra balta kieta medžiaga (250 mg, 34 %). (M-H)' 322.A stirred solution of Example 1 Compound A (400 mg, 2.3 mmol) in 10 mL of chlorosulfonic acid was heated at 100 ° C for 6 h. Pour the solution into a mixture of ice and water. The aqueous suspension is extracted with ethyl acetate. The combined organic extracts were dried and filtered. The filtrate was mixed with piperidine (0.2 mL) at 0 ° C. The reaction was run for 30 min. The resulting solution was washed with 10% HCl, saturated NH 4 Cl solution, dried and concentrated. The residue was triturated with ether to give Compound A as a white solid (250 mg, 34%). (MH) '322.
B. 2,3,4,5-Tetrahidro-7-(1-piperidinilsulfonil)-1H-1,4-benzodiazepinasB. 2,3,4,5-Tetrahydro-7- (1-piperidinylsulfonyl) -1H-1,4-benzodiazepine
J maišomą LAH (200 mg, 5 mmol) suspensiją glime dalimis pridedama junginio A (185 mg, 0,57 mmol). Sudėjus junginį, mišinys šildomas 80 °C temperatūroje argono atmosferoje 4 vai. Po to mišinys atšaldomas iki 0 °C ir pridedama etilacetato (20 ml), o po to NH4OH (0,3 ml) tirpalo. Mišinys maišomas kambario temperatūroje 18 vai. Susidariusi suspensija nufiltruojama. Sukoncentravus filtratą, gaunamas junginys B, kuris yra alyva (90 mg, 53 %). (M-H)'295.To a stirred suspension of LAH (200 mg, 5 mmol) was added compound A (185 mg, 0.57 mmol) in portions. After compounding, the mixture was heated at 80 ° C under argon for 4 h. The mixture was then cooled to 0 ° C and ethyl acetate (20 mL) was added followed by NH 4 OH (0.3 mL). The mixture was stirred at room temperature for 18 hours. The resulting suspension is filtered. Concentration of the filtrate gave compound B which was an oil (90 mg, 53%). (MH) 295.
C. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1' naftalenilkarbonil)-7-(1-piperidinilsulfonil)-1H-1,4-benzodiazepinas (monohidrochloridas) pavyzdžio junginys pagaminamas iš junginio B, panaudojant 2 stadijų metodiką, aprašytą 2 pavyzdžio junginiui C gauti, o po to 1 pavyzdžio junginiui D gauti.C. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1'-naphthalenylcarbonyl) -7- (1-piperidinylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride) Example 2 is prepared from Compound B using the 2-step procedure described for Example 2, Compound C, followed by Example 1, for Compound D.
MS (M + H)+ 530+.MS (M + H) < + > 530 + .
Analizė išskaičiuota pagal C29H3iN5O3S -1,1 HCI · 0,2 tolueno · 0,5 C4H10O. Išskaičiuota: C, 62,22; H, 6,27; N, 11,20; S, 5,13; Cl, 6,23.Analysis calculated for C 2 9H3iN 5 O 3 S · HCl -1.1 · 0.2 toluene 0.5 C4H10O. Found: C, 62.22; H, 6.27; N, 11.20; S, 5.13; Cl, 6.23.
Rasta: C, 62,38; H, 6,45; N, 11,18; S, 5,23; Cl, 6,29.Found: C, 62.38; H, 6.45; N, 11.18; S, 5.23; Cl, 6.29.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-7pi ri d i η-2-i l-1 H-1,4-benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-pyridazole-2-yl-1H-1,4-benzodiazepine (trihydrochloride) )
A. 2,3,4,5-Tetrahidro-1-(1-trifenilmetil-imidazol-4-iImetil)-4-(1naftalenilkarbonil)-7-brom-1 H-1,4-benzodiazepinas į 11 pavyzdžio junginio (6,83 mmol, 3,15 g) ir trietilamino (34 mmol, 4,7 ml) tirpalą acetonitrile (100 ml) pridedama trifenilmetilchlorido (6,83 mmol, 1,9A. 2,3,4,5-Tetrahydro-1- (1-triphenylmethyl-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-bromo-1H-1,4-benzodiazepine into the compound of Example 11 (6). , 83 mmol, 3.15 g) and triethylamine (34 mmol, 4.7 mL) in acetonitrile (100 mL) were added triphenylmethyl chloride (6.83 mmol, 1.9 mL).
g), ir reakcijos mišinys maišomas 2 vai. Gautas homogeninis geltonas tirpalas sukoncentruojamas sumažintame slėgyje, ir išgryninus liekaną sparčiosios chromatografijos metodu, gaunama 3,9 g (81 %) junginio A, kuris yra balta kieta medžiaga. MS (M + H)+ 703.g), and the reaction mixture is stirred for 2 hours. The resulting homogeneous yellow solution was concentrated under reduced pressure and purified by flash chromatography to give 3.9 g (81%) of Compound A as a white solid. MS (M + H) + 703.
B. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-7piridin-2-il-1H-1,4-benzodiazepinas (trihidrochloridas)B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7pyridin-2-yl-1H-1,4-benzodiazepine (trihydrochloride)
Junginio A (0,28 mmol, 200 mg), 2-(fr/-n-butilstanil)piridino (1,4 mmol,Compound A (0.28 mmol, 200 mg), 2- (tert-butylstanyl) pyridine (1.4 mmol,
520 mg) ir Pd(PPh3)4 (40 mg, 0,034 mmol) mišinys degazuotame THF (3 ml) šildomas 75 °C temperatūroje 18 vai. Reakcijos mišinys atvėsinamas iki kambario temperatūros, praskiedžiamas 30 ml MeOH ir veikiamas 2,0 ml TFA. Mišinys pamaišomas 12 vai., koncentruojamas, gryninamas preparatinės HPLC metodu, ir pavertus j HCl druską, gaunama 46 mg (30 % abi stadijos) 37 pavyzdžio junginio, kuris yra geltona kieta medžiaga.A mixture of 520 mg) and Pd (PPh 3 ) 4 (40 mg, 0.034 mmol) in degassed THF (3 mL) was heated at 75 ° C for 18 h. The reaction mixture was cooled to room temperature, diluted with 30 mL of MeOH and treated with 2.0 mL of TFA. The mixture was stirred for 12 h, concentrated, purified by preparative HPLC and converted to the HCl salt to afford 46 mg (30% of both steps) of Example 37 as a yellow solid.
MS (M + H)+ 460+.MS (M + H) + 460 + .
Analizė išskaičiuota pagal C29H25N5O -3,09 HCl.Analysis calculated for C29H25N5O -3.09 HCl.
Išskaičiuota: C, 60,07; H, 4,95; N, 12,24.Found: C, 60.07; H, 4.95; N, 12.24.
Rasta: C, 60,72; H, 5,09; N, 12,16.Found: C, 60.72; H, 5.09; N, 12.16.
7-(2-Furanil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftaleni!karbonil)-1H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys (žalia kieta medžiaga) pagaminamas (11 % išeiga) iš 37 pavyzdžio junginio A ir 2-(tributilstanil)furano pagal 37 pavyzdyje aprašytą junginio B gavimo metodiką.7- (2-Furanyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (green solid) was prepared (11% yield) from Example 37 Compound A and 2- (tributylstanyl) furan according to the procedure described in Example 37 for the preparation of Compound B.
MS: (M + H)+449+.MS: (M + H) < + > 449 + .
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-7-(2tienil)-1 H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys (žalia kieta medžiaga) pagaminamas (10 % išeiga) iš 37 pavyzdžio junginio A ir 2-(tributilstanil)tiofeno pagal 37 pavyzdyje aprašytą junginio B gavimo metodiką.2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7- (2-thienyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound ( green solid) prepared (10% yield) from Example 37 Compound A and 2- (tributylstanyl) thiophene according to the procedure described in Example 37 for the preparation of Compound B.
MS: (M + H)+465.MS: (M + H) + 465.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-7-(4pi ridi n i I)-1 H-1,4-benzodiazepinas (trihidrochloridas) j 2,3,4,5-tetrahidro-4-(1 -naftalenilkarbonil)-7-brom-1 H-1,4benzodiazepino (pagaminto pagal 11 pavyzdyje aprašytą metodiką, 0,26 mmol, 100 mg) ir NEt3 (1,04 mmol, 150 μΙ) tirpalą CH2CI2 (5 ml) pridedama trifluoracto rūgšties anhidrido (0,4 mmol, 60 μΙ), ir homogeninis bespalvis tirpalas palaikomas kambario temperatūroje 1 vai. Reakcijos mišinys koncentruojamas, ir liekana perleidžiama per trumpą silikagelio kolonėlę (gradientinis eliuavimas: 30 % etilacetatas/heksanuose iki gryno etilacetato). Išskiriama pūkų pavidalo balta kieta medžiaga, kuri tolimesnėje stadijoje naudojama be papildomo gryninimo. Ši medžiaga ištirpinama toluene (2,0 ml) kartu su 4-(tributilstanil)piridinu (0,52 mmol, 190 mg) ir Pd(PPh3)4 (30 mg, 0,026 mmol), ir 15 min. per tirpalą leidžiamas argonas. Rudas homogeninis tirpalas šildomas 115 °C temperatūroje 20 vai., ir gaunamas juodas heterogeninis tirpalas. Reakcijos mišinys sukoncentruojamas, liekana ištirpinama MeOH/2N NaOH (vand.) (5 ml : 5 ml) ir tirpalas maišomas kambario temperatūroje 30 min. Sumažintame slėgyje nugarinamas MeOH, reakcijos mišinys paskirstomas tarp 10 % izopropanolio/CH2CI2 ir 2N NaOH/sotaus NaCl (1:1, 10 ml) ir ekstrahuojamas 2x 10 % izopropanoliu/CH2CI2 (2x5 ml). Sumaišytos organinės fazės džiovinamos Na2SO4, koncentruojamos, ir polinėms priemaišoms pašalinti liekana perleidžiama per trumpą silikagelio kolonėlę (eliuojama 95:5:1 CHCI3:MeOH:TEA), Negryna medžiaga ištirpinama 1,2-dichloretano:AcOH mišinyje (1:1, viso 2 ml), veikiama 4-formilimidazolu (62 mg, 0,65 mmol) ir NaBH(OAc)3 (0,78 mmol, 165 mg), ir mišinys šildomas 55 °C temperatūroje 2 vai. Reakcijos mišinys koncentruojamas, paskirstomas tarp 10 % izopropanolio/CH2CI2 ir 2N NaOH/soČiame NaCl (1:1, 10 ml) ir ekstrahuojamas 2x10% izopropanoliu/CH2CI2 (2x5 ml). Sumaišyta organinė fazė koncentruojama, liekana ištirpinama MeOH/TFA (5 ml : 0,5 ml) ir gryninama preparatinės HPLC.metodu (YMC S5 ODS 30x250 mm: sulaikymo laikas = 19-21 min; gradientinis eliuavimas nuo 0 iki 100 % buferio B per 30 min; buferis A = MeOH:H2O:TFA (10:90:0,1); buferis B = MeOH:H2O:TFA (90:10:0,1); 25 ml/min). Trifluoracetato druska paverčiama HCI druska liofilizuojant 1M HCI (2x5 ml), ir gaunama 75 mg (50 % išeiga per 4 stadijas) 40 pavyzdžio junginio, kuris yra blizganti, geltona kieta medžiaga. MS: (M + H)+ 460.2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7- (4-pyridine) -1H-1,4-benzodiazepine (trihydrochloride) 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -7-bromo-1H-1,4-benzodiazepine (prepared according to the procedure described in Example 11, 0.26 mmol, 100 mg) and NEt 3 (1). , 04 mmol, 150 μΙ) solution of CH 2 Cl 2 (5 mL) was added trifluoroacetic anhydride (0.4 mmol, 60 μΙ) and the homogeneous colorless solution was kept at room temperature for 1 h. The reaction mixture was concentrated and the residue was passed through a short silica gel column (gradient elution: 30% ethyl acetate / hexanes to pure ethyl acetate). A white solid is obtained in the form of a fluff which is used without further purification in the subsequent step. This material was dissolved in toluene (2.0 mL) along with 4- (tributylstanyl) pyridine (0.52 mmol, 190 mg) and Pd (PPh 3 ) 4 (30 mg, 0.026 mmol), and 15 min. argon is passed through the solution. The brown homogeneous solution is heated at 115 ° C for 20 hours to give a black heterogeneous solution. The reaction mixture was concentrated, the residue was dissolved in MeOH / 2N NaOH (aq) (5 mL: 5 mL) and the solution was stirred at room temperature for 30 min. The MeOH was evaporated under reduced pressure, the reaction mixture was partitioned between 10% isopropanol / CH 2 Cl 2 and 2N NaOH / saturated NaCl (1: 1, 10 mL) and extracted 2x with 10% isopropanol / CH 2 Cl 2 (2x5 mL). The combined organic phases were dried over Na 2 SO 4 , concentrated, and the residue was passed through a short silica gel column (eluted with 95: 5: 1 CHCl 3 : MeOH: TEA) to remove polar impurities, and the crude material was dissolved in 1,2-dichloroethane: AcOH (1: 1, total 2 mL) was treated with 4-formylimidazole (62 mg, 0.65 mmol) and NaBH (OAc) 3 (0.78 mmol, 165 mg) and the mixture was heated at 55 ° C for 2 h. The reaction mixture was concentrated, partitioned between 10% isopropanol / CH 2 Cl 2 and 2N NaOH / saturated NaCl (1: 1, 10 mL) and extracted with 2x10% isopropanol / CH 2 Cl 2 (2x5 mL). The combined organic phase is concentrated, the residue is dissolved in MeOH / TFA (5 mL: 0.5 mL) and purified by preparative HPLC (YMC S5 ODS 30x250 mm: retention time = 19-21 min; gradient elution from 0 to 100% buffer B). 30 min; buffer A = MeOH: H 2 O: TFA (10: 90: 0.1); buffer B = MeOH: H 2 O: TFA (90: 10: 0.1); 25 mL / min). The trifluoroacetate salt is converted to the HCl salt by lyophilization with 1M HCl (2x5 mL) to give 75 mg (50% yield over 4 steps) of Example 40 as a shiny yellow solid. MS: (M + H) + 460.
2,3,4,5-Tetrahidro-1-[3-(1H-imidazol-2-il)propil]-4-(1-naftalenilkarbonil)7-fenil-1H-1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- [3- (1H-imidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) 7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
A. 3-[lmidazol-2-il]propenkarboksirūgštis (etilo esteris) j šaldomą (0 °C) natrio hidrido (1,86 g, 45,8 mmol, 60 % dispersija mineralinėje alyvoje, perplauta THF ir išdžiovinta N2) tirpalą 1,2dimetoksietane (DME, 20 ml) per 15 min. sulašinamas trietilfosfonacetatas (12 g, 54,1 mmol) ištirpintas DME (10 ml). Tirpalas maišomas 1 vai. kambario temperatūroje, po to pridedama 2-imidazolacetaldehido (4 g, 41,6 mmol) 20 ml DME. Tirpalas maišomas ir virinamas su grįžtamu šaldytuvu (85 °C) 15 min., po to atšaldomas iki 60 °C ir laikomas 1 vai. Šaldant, tirpalas sukoncentruojamas iki 1/2 tūrio ir nufiltruojamas. Kieta medžiaga perkristalinama iš metanolio/etilacetato/heksanų mišinio, ir gaunama 5,1 g (74 %) junginio A, kuris yra balta kristalinė medžiaga. MS (M + H)+ 167+.A. 3- [lmidazol-2-yl] propanoic acid (ethyl ester) in a cooled (0 ° C) solution of sodium hydride (1.86 g, 45.8 mmol, 60% dispersion in mineral oil, washed with THF and dried over N 2 ) 1,2-dimethoxyethane (DME, 20 mL) over 15 min. triethylphosphonacetate (12 g, 54.1 mmol) dissolved in DME (10 mL) was added dropwise. The solution is stirred for 1 hour. at room temperature, followed by the addition of 2-imidazoleacetaldehyde (4 g, 41.6 mmol) in 20 mL of DME. The solution was stirred and refluxed (85 ° C) for 15 minutes, then cooled to 60 ° C and held for 1 hour. Upon cooling, the solution is concentrated to 1/2 volume and filtered. The solid was recrystallized from methanol / ethyl acetate / hexanes to give 5.1 g (74%) of compound A as a white crystalline solid. MS (M + H) + 167 + .
B. 3-[lmidazol-2-il]propankarboksirūgštis (etilo esteris)B. 3- [lmidazol-2-yl] propanoic acid (ethyl ester)
Junginio A (4,01 g, 24,2 mmol) tirpalas absoliučiame etanolyje (100 ml, pašildytas, kad medžiaga ištirptų) hidrinamas, naudojant Pd/C (0,5 g), kambario temperatūroje 16 vai. Vakuume pašalinus H2, katalizatorius nufiltruojamas per celito sluoksnj. Vakuume sukoncentravus filtratą, gaunama 4,0 g (100 %) junginio B, kuris yra balta kristalinė medžiaga. MS (M + H)+ 169+.A solution of Compound A (4.01 g, 24.2 mmol) in absolute ethanol (100 mL, heated to dissolve) was hydrogenated using Pd / C (0.5 g) at room temperature for 16 h. After removal of H 2 in vacuo, the catalyst is filtered through a pad of celite. Concentration of the filtrate in vacuo afforded 4.0 g (100%) of Compound B as a white crystalline solid. MS (M + H) < + > 169 + .
C. 3-[N-trifenilmetiI-lmidazol-2-il]propankarboksirūgštis (etilo esteris)C. 3- [N-Triphenylmethyl-1-imidazol-2-yl] -propionic acid (ethyl ester)
Junginys B pagaminamas iš junginio A pagal 6 pavyzdyje aprašytą junginio A sintezės metodiką, tirpikliu naudojant metileno chloridą, o baze trietilaminą. Po vandeninio tirpalo apdorojimo, perkristalinimo iš etilacetato/heksanų mišinio gaunamas junginys B, kuris yra balta mikrokristalinė medžiaga MS (M + H)+ 411+.Compound B is prepared from Compound A according to the procedure described in Example 6 for the synthesis of Compound A using methylene chloride as the solvent and triethylamine as the base. After treatment of the aqueous solution, recrystallization from ethyl acetate / hexanes gives compound B, which is a white microcrystalline material MS (M + H) + 411 + .
D. 3-[N-trifeniImetil-lmidazol-2-il]propan-1-olisD. 3- [N-Triphenylmethyl-imidazol-2-yl] -propan-1-ol
Junginio C (0,80 g, 1,95 mmol) tirpalas THF (15 ml) atšaldomas iki 0 °C argono atmosferoje ir maišant sulašinamas 1M ličio aliuminio hidrido (2 ml, 2 mmol) tirpalas. Reakcijos mišinys maišomas kambario temperatūroje 16 vai. Lėtai pridedama vandens (2 ml), ir tirpalas sukoncentruojamas. Pridedama vandens (40 ml) ir etilo eterio (60 ml), ir atskiriami sluoksniai. Eterinis sluoksnis džiovinamas (MgSO4) ir koncentruojamas. Liekana chromatografuojama (sparčioji chromatografija per silikagelį, 10:1 metileno chloridas:metanolis). Frakcijos, kuriose yra produktas, supilamos kartu ir sukoncentravus gaunama 680 mg (95 %) junginio D, kuris yra balta kristalinė medžiaga. MS (M + H)+.A solution of Compound C (0.80 g, 1.95 mmol) in THF (15 mL) was cooled to 0 ° C under argon and a solution of 1M lithium aluminum hydride (2 mL, 2 mmol) was added dropwise with stirring. The reaction mixture was stirred at room temperature for 16 hours. Water (2 mL) was added slowly and the solution concentrated. Water (40 mL) and ethyl ether (60 mL) were added and the layers separated. The ether layer was dried (MgSO 4 ) and concentrated. The residue is chromatographed (flash chromatography on silica gel, 10: 1 methylene chloride: methanol). The product-containing fractions were combined and concentrated to give 680 mg (95%) of Compound D as a white crystalline solid. MS (M + H) < + >.
E. 3-[N-trifenilmetil-lmidazol-2-iI]propanalisE. 3- [N-Triphenylmethyl-imidazol-2-yl] -propanal
Oksalilo chlorido (0,3 ml, 0,6 mmol) tirpalas 2 ml metileno chlorido argono atmosferoje atšaldomas iki -63 °C, Per 10 min. pridedama DMSO (0,056 ml, 0,8 mmol) metileno chloride (0,5 ml), o po to per 15 min., laikant reakcijos mišinio temperatūrą, žemiau -50 °C, pridedamas junginio D (147 mg, 0,4 mmol) tirpalas metileno chloride (6 ml). Gautas skaidrus tirpalas maišomas 50 min. -63 °C temperatūroje. Per 15 min., laikant tirpalo temperatūrą žemiau -50 °C, pridedamas trietilamino (0,25 ml, 1,8 mmol) tirpalas metileno chloride (1 ml). Mišinys maišomas 15 min., po to pridedama 1M kalio rūgščiojo sulfato (4,5 ml), vandens (20 ml) ir etilo eterio (60 ml). Atskiriami sluoksniai, vandeninis sluoksnis pašarminamas pusiau sočiu vandeniniu natrio rūgščiuoju karbonatu ir plaunamas etilacetatu (3x30 ml).A solution of oxalyl chloride (0.3 mL, 0.6 mmol) in 2 mL of methylene chloride under argon was cooled to -63 ° C over 10 min. DMSO (0.056 mL, 0.8 mmol) in methylene chloride (0.5 mL) was added followed by the addition of Compound D (147 mg, 0.4 mmol) over 15 min, keeping the reaction temperature below -50 ° C. ) solution of methylene chloride (6 mL). The resulting clear solution was stirred for 50 min. At -63 ° C. A solution of triethylamine (0.25 mL, 1.8 mmol) in methylene chloride (1 mL) was added over a period of 15 min, keeping the temperature below -50 ° C. The mixture was stirred for 15 min, then 1M potassium bisulfate (4.5 mL), water (20 mL) and ethyl ether (60 mL) were added. Separate the layers, basify the aqueous layer with half-saturated aqueous sodium bicarbonate and wash with ethyl acetate (3x30 mL).
Sumaišyti organiniai sluoksniai džiovinami (MgSO4), ir sukoncentravus gaunama 146 mg (>99 %) junginio E, kuris yra gelsva derva.The combined organic layers were dried (MgSO 4 ) and concentrated to give 146 mg (> 99%) of Compound E as a yellowish gum.
F. 2,3,4,5-Tetrahidro-4-(1-naftalenilkarbonil)-7-fenil-1H-1,4benzodiazepinasF. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine
J maišomą EDC (3,0 g, 15,63 mmol), HOBt (2,1 g, 15,63 mmol) ir 1naftalenkarboksirūgšties (2,42 g, 14,06 mmol) tirpalą DMF (20 ml) staigiai supilamas 12 pavyzdžio junginio B (3,5 g, 15,63 mmol) ir N,Ndiizopropiletilamino (2,73 ml, 15,63 mmol) tirpalas DMF (10 ml). Mišinys maišomas 4 vai., supilamas j vandenj (200 ml), ir produktas ekstrahuojamas etilacetatu (2x100 ml). Sumaišyti etilacetato sluoksniai plaunami vandeniu (3x200 ml), sočiu NaCl (100 ml), džiovinami (MgSO4), sukoncentruojama ir chromatografuojama (silikagelis, 50 % etilacetatas/heksane). Frakcijos, kuriose yra norimas junginys, surenkamos ir sukoncentravus gaunamas junginys F, kuris yra skaidri alyva (4,4 g, 93 %), (M+H) + 379+.To a stirred solution of EDC (3.0 g, 15.63 mmol), HOBt (2.1 g, 15.63 mmol) and 1-naphthalenecarboxylic acid (2.42 g, 14.06 mmol) in DMF (20 mL) was added v A solution of compound B (3.5 g, 15.63 mmol) and N, N-diisopropylethylamine (2.73 mL, 15.63 mmol) in DMF (10 mL). The mixture was stirred for 4 h, poured into water (200 mL) and the product extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate layers were washed with water (3 x 200 mL), saturated NaCl (100 mL), dried (MgSO 4 ), concentrated and chromatographed (silica gel, 50% ethyl acetate / hexane). The fractions containing the desired compound are collected and concentrated to give compound F, which is a clear oil (4.4 g, 93%), (M + H) + 379 + .
G. 2,3,4,5-Tetrahidro-1 -[3-(1-trifenilmetil-imidazol-2-il)propil]-4-(1 naftalenilkarbonil)-7-fenil-1 H-1,4-benzodiazepinasG. 2,3,4,5-Tetrahydro-1- [3- (1-triphenylmethyl-imidazol-2-yl) -propyl] -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine
Junginys E (109 mg, 0,29 mmol) ir junginys F (100 mg, 0,26 mmol) ištirpinami 1,2-dichloretane (10 ml). Pridedama acto rūgšties (0,1 ml), o po to natrio triacetoksiborhidrido (84 mg, 0,40 mmol). Mišinys maišomas 50 °C temperatūroje 2 vai. Pridedama sotaus NaHCO3 (10 ml), mišinys sukoncentruojamas ir paskirstomas tarp etilacetato (50 ml) ir vandens (20 ml). Organinis sluoksnis atskiriamas, džiovinamas (MgSO4), koncentruojamas ir chromatografuojamas (silikagelis, 40 % etilacetatas/heksane). Frakcijos, kuriose yra norimas junginys, surenkamos ir sukoncentravus gaunamas junginys G, kuris yra skaidri stiklo pavidalo medžiaga (100 mg, 47 %), (M + H)+ 729+.Compound E (109 mg, 0.29 mmol) and compound F (100 mg, 0.26 mmol) were dissolved in 1,2-dichloroethane (10 mL). Acetic acid (0.1 mL) was added followed by sodium triacetoxyborohydride (84 mg, 0.40 mmol). The mixture was stirred at 50 ° C for 2 hours. Saturated NaHCO 3 (10 mL) was added and the mixture was concentrated and partitioned between ethyl acetate (50 mL) and water (20 mL). The organic layer was separated, dried (MgSO 4 ), concentrated and chromatographed (silica gel, 40% ethyl acetate / hexane). The fractions containing the desired compound are collected and concentrated to give compound G, which is a clear glass material (100 mg, 47%), (M + H) + 729 + .
H. 2,3,4,5-Tetrahidro-1-[3-(1H-imidazol-2-il)propil]-4-(1naftalenilkarbonil)-7-fenil-1 H-1,4-benzodiazepinas (dihidrochloridas)H. 2,3,4,5-Tetrahydro-1- [3- (1H-imidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
Junginio G (70 mg, 0,096 mmol) tirpalas metileno chloride (7 ml), TFA (7 ml) ir trietilsilanas (0,36 mg, 0,50 ml, 0,31 mmol) maišomi 30 min. kambario temperatūroje. Mišinys sukoncentruojamas, liekana ištirpinama metileno chloride (60 ml) ir koncentruojama. Ši procedūra pakartojama penkis kartus, ir gaunamas negrynas produktas, kuris yra balta lipni kieta medžiaga (kiekybinė išeiga). Ši negryna medžiaga gryninama preparatinės HPLC metodu (YMC S-5 ODS-A kolonėlė, 30x250 mm; tirpiklis A, 0,1 % TFA 90 % vandens ir 10 % metanolio mišinyje; tirpiklis B, 0,1 % TFA 10 % vandens ir 90 % metanolio mišinyje; 20-100 % B per 60 min; srauto greitis 25 ml/min.). Frakcijos, kuriose yra norimas produktas, sumaišomos, koncentruojamos ir liofilizuojamos. Liofilizatas ištirpinamas metanolyje (0,5 ml) ir 1N HCI (5 ml).A solution of compound G (70 mg, 0.096 mmol) in methylene chloride (7 mL), TFA (7 mL), and triethylsilane (0.36 mg, 0.50 mL, 0.31 mmol) was stirred for 30 min. at room temperature. The mixture was concentrated and the residue was dissolved in methylene chloride (60 mL) and concentrated. This procedure is repeated five times to give the crude product which is a white sticky solid (quantitative yield). This crude material was purified by preparative HPLC (YMC S-5 ODS-A column, 30 x 250 mm; solvent A, 0.1% TFA in 90% water / 10% methanol; solvent B, 0.1% TFA in 10% water and 90%). % methanol in the mixture; 20-100% B in 60 min; flow rate 25 mL / min). The fractions containing the desired product are mixed, concentrated and lyophilized. The lyophilisate was dissolved in methanol (0.5 mL) and 1N HCl (5 mL).
Šis mišinys koncentruojamas ir liofilizuojamas. Pakartojus šią procedūrą, gaunamas 41 pavyzdžio junginys, kuris yra balta kieta medžiaga (15 mg, 28 %).This mixture is concentrated and lyophilized. Repeat this procedure to give Example 41 as a white solid (15 mg, 28%).
MS (M + H)+ 487+.MS (M + H) < + > 487 + .
1H-BMR (CD3OD, 400 MHz) δ 8,05-7,00 (16H, m), 6,20 (1H, m), 4,47-4,26 (2H, dd, J = 15,0), 4,17 (1 H, m), 4,08 (1 H, m), 3,48 (1 H, m), 3,43 (1H, m), 3,33 (1H, m), 3,12 (1 H, t), 3,06 (1H, t), 2,98 (1 H, m), 2,16 (1H. kv.), 2,04 (1H, kv.). 1 H-NMR (CD 3 OD, 400 MHz) δ 8.05-7.00 (16H, m), 6.20 (1H, m), 4.47-4.26 (2H, dd, J = 15 , 0), 4.17 (1H, m), 4.08 (1H, m), 3.48 (1H, m), 3.43 (1H, m), 3.33 (1H, m) ), 3.12 (1H, t), 3.06 (1H, t), 2.98 (1H, m), 2.16 (1H, sq), 2.04 (1H, s) .
pavyzdysexample
BrBr
7-Brom-2,3,4,5-tetrahidro-4-(1H-imidazol-4-ilmetil)-1-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš 7-brom-1,4-benzodiazepino (pagaminto pagal 1 pavyzdyje aprašytą junginio B sintezės metodiką), panaudojant metodiką, aprašytą tokiems junginiams gauti; 4 pavyzdžio junginiui A; 4 pavyzdžio junginiui B; 4 pavyzdžio junginiui C; 1 pavyzdžio junginiui D, tirpikliu naudojant metileno chloridą, gryninant preparatinės HPLC metodu (YMC S-5 ODS 30x250 mm; gradientinis eliuavimas nuo 0 iki 100 % buferio B per 45 min; buferis A = MeOH:H2O:TFA (10:90:0,1); buferis B = MeOH:H2O:TFA (90:10:0,1); 25 ml/min.) ir paverčiant HCI druska, liofilizuojant iš 1M HCI. MS (M + H)+ 462. 1H-BMR (CD3OD): 3,5 (pl.s, 2H), 3,80 (m, 2H), 4,80 (pl.s, 2H), 5,30 (pi. 2H), 6,60 (m, 1H), 7,15-8,15 (m, 11H), 9,10 (s, 1H).7-Bromo-2,3,4,5-tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (off-white solid) ) prepared from 7-bromo-1,4-benzodiazepine (prepared according to the synthesis procedure for compound B described in Example 1) using the procedure described for the preparation of such compounds; Example 4 for compound A; Compound B of Example 4; Example 4 for compound C; For compound D of Example 1, purification using methylene chloride as a solvent by preparative HPLC (YMC S-5 ODS 30x250 mm; gradient elution from 0 to 100% buffer B over 45 min; buffer A = MeOH: H 2 O: TFA (10:90 : 0.1); buffer B = MeOH: H 2 O: TFA (90: 10: 0.1); 25 mL / min) and converted to the HCl salt by lyophilization from 1M HCl. MS (M + H) + 462. 1 H-NMR (CD 3 OD): 3.5 (ppm, 2H), 3.80 (m, 2H), 4.80 (ppm, 2H), 5.30 (m, 2H), 6.60 (m, 1H), 7.15-8.15 (m, 11H), 9.10 (s, 1H).
pavyzdysexample
8-Chlor-2,3,4,5-tetrahidro-4-(1H-imidazol-4-ilmetil)-1-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš 2 pavyzdžio junginio B pagal 42 pavyzdyje aprašytą metodiką, MS (M + H) + 459. 1H-BMR (CD3OD): 3,40-3,80 (pl.s, 4H), 4,4 (pi., 2H), 4,7 (pi., 2H), 5,20 (pi., 2H), 6,65 (d, 1H), 7,00-8,15 (m, 16H), 9,00 (s, 1H).8-Chloro-2,3,4,5-tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (off-white solid) prepared from Example 2 Compound B according to the procedure described in Example 42, MS (M + H) + 459. 1 H-NMR (CD 3 OD): 3.40-3.80 (m.p., 4H), 4.4 ( pi, 2H), 4.7 (pi, 2H), 5.20 (pi, 2H), 6.65 (d, 1H), 7.00-8.15 (m, 16H), 9, 00 (s, 1H).
pavyzdysexample
2,3,4,5-Tetrahidro-4-(1H-imidazol-4-ilmetil)-1-(1naftalenilkarbonil)-7-fenil-1 H-1,4-benzodiazepinas (hidrochloridas) pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš 12 pavyzdžio junginio B pagal 42 pavyzdyje aprašytą metodiką. MS (M+H)+ 459. 1H-BMR (CD3OD): 3,40-3,80 (pl.s, 4H), 4,4 (pi., 2H), 4,7 (pi., 2H), 5,20 (pi., 2H), 6,65 (d, 1H), 7,00-8,15 (m, 16H), 9,00 (s, 1H).2,3,4,5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (hydrochloride) Example compound (off-white solid) ) is prepared from Example 12 Compound B according to the procedure described in Example 42. MS (M + H) + 459. 1 H-NMR (CD 3 OD): 3.40-3.80 (m.p., 4H), 4.4 (pi, 2H), 4.7 (pi). , 2H), 5.20 (pi, 2H), 6.65 (d, 1H), 7.00-8.15 (m, 16H), 9.00 (s, 1H).
2,3,4,5-Tetrahidro-1,4-bis(1 H-imidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas) pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš pavyzdžio junginio B pagal 1 pavyzdyje aprašytą junginio D sintezės metodiką, tirpikliu naudojant metileno chloridą, 4,3 ekvivalentus 4formilimidazolo, 4,3 ekvivalentus natrio triacetoksiborhidrido ir maišant 4 vai.2,3,4,5-Tetrahydro-1,4-bis (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) Example compound (off-white solid) is prepared from the sample. of compound B according to the procedure for the synthesis of compound D described in Example 1 using methylene chloride as a solvent, 4.3 equivalents of 4-formylimidazole, 4.3 equivalents of sodium triacetoxyborohydride and stirring for 4 hours.
MS (M + H) + 385. 1H-BMR (CD3OD): 3,5 (pl.s, 4H), 4,60 (pi., 2H), 4,9 (pi., 4H), 7,2-8,0 (m, 10H), 8,90 (s, 1H), 9,05 (s, 1H).MS (M + H) + 385. 1 H-NMR (CD 3 OD): 3.5 (m.p., 4H), 4.60 (pi, 2H), 4.9 (pi, 4H), 7.2-8.0 (m, 10H), 8.90 (s, 1H), 9.05 (s, 1H).
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftaleniJmetil)-7fenil-1 H-1,4-benzodiazepinas (trifluoracetatas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trifluoroacetate)
Į 12 pavyzdžio junginio (0,25 g, 0,55 mmol) suspensiją THF (10 ml) pridedama ličio aliuminio hidrido (1M THF, 15 ml, 15 mmol). Ši suspensija virinama su grįžtamu šaldytuvu 5 vai., atšaldoma iki 0 °C ir pridedama 20 % vandeninio NaOH (10 ml) ir H2O (10 ml). Mišinys prisotinamas NaCl ir ekstrahuojamas CH2CI2 (2 x 50 ml). Išdžiovinus Na2SO4 ir nugarinus tirpiklį, gaunama kieta medžiaga (0,21 g), kuri ištirpinama MeOH/TFA (10:1) ir gryninama preparatinės HPLC metodu (YMC S5 ODS 30x250 mm; gradientinis eliuavimas 0-100 % buferio B per 45 min; buferis A = MeOH:H2O:TPA (10:90:0,1); buferis B = MeOH:H2O:TFA (90:10:0,1); 25 ml/min.); gaunamas 46 pavyzdžio junginys (50 mg), kuris yra nelabai balta kieta medžiaga.To a suspension of Example 12 (0.25 g, 0.55 mmol) in THF (10 mL) was added lithium aluminum hydride (1M THF, 15 mL, 15 mmol). This suspension was refluxed for 5 hours, cooled to 0 ° C and treated with 20% aqueous NaOH (10 mL) and H 2 O (10 mL). The mixture was saturated with NaCl and extracted with CH 2 Cl 2 (2 x 50 mL). Drying over Na 2 SO 4 and evaporation of the solvent afforded a solid (0.21 g) which was dissolved in MeOH / TFA (10: 1) and purified by preparative HPLC (YMC S5 ODS 30x250 mm; gradient elution 0-100% buffer B). 45 min; buffer A = MeOH: H 2 O: TPA (10: 90: 0.1); buffer B = MeOH: H 2 O: TFA (90: 10: 0.1); 25 mL / min); Example 46 is obtained (50 mg) which is an off-white solid.
MS (M + H)+ 445.MS (M + H) + 445.
Analizė išskaičiuota pagal C3oH28N40 · 2 HCI · 0,3 H2O.Analysis calculated for C 3 H 28 N 4 0 · 2 HCl · 0.3 H 2 O
Išskaičiuota: C, 68,90; H, 5,90; N, 10,71.Found: C, 68.90; H, 5.90; N, 10.71.
Rasta: C, 68,94; H, 5,78; N, 10,43.Found: C, 68.94; H, 5.78; N, 10.43.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-metoksi-4-(1naftalenilkarbonil)-! H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-methoxy-4- (1-naphthalenylcarbonyl) -! The H-1,4-benzodiazepine (dihydrochloride) sample compound (off-white solid) is prepared from
6-hidroksiizatoinės rūgšties anhidrido pagal tokių junginių gavimo metodiką: 1 pavyzdžio junginio A, virinant su grįžtamu šaldytuvu 18 vai., ir nuosėdas perplaunant vandeniu; pagaminamas metilo eteris, maišant su 1,3 ekvivalento metilo jodido DMF, esant K2CO3, kambario temperatūroje 12 vai.; 1 pavyzdžio junginio B, skaldant 20 % NaOH ir vandeniu, o po to ekstrahuojant CH2CI2: 2 pavyzdžio junginio C, produkto nechromatografuojant; 1 pavyzdžio junginio D, naudojant metileno chloridą, maišant 5 vai. ir prieš pagaminant hidrochlorido druską, gryninant sparčiosios chromatografijos metodu (94,5:5:0,5, CH2CI2:MeOH:NH4OH).6-hydroxyisanoic acid anhydride according to the procedure for the preparation of the following compounds: Example A Compound A was refluxed for 18 hours and the residue was washed with water; producing methyl ether by stirring with 1.3 equivalents of methyl iodide in DMF in K2CO3 at room temperature for 12 hours; Example 1 Compound B, 20% NaOH and water followed by extraction with CH 2 Cl 2 : Example 2 Compound C, without product chromatography; Example D Compound D using methylene chloride with stirring for 5 hours. and purification by flash chromatography (94.5: 5: 0.5, CH 2 Cl 2 : MeOH: NH 4 OH) before the hydrochloride salt was prepared.
Analizė išskaičiuota pagal C24H24N4O2 · 2 HCI 0,61 H2O.Analysis calculated for C 24 H 24 N 4 O 2 · 2 HCl 0.61 H 2 O.
Išskaičiuota: C, 60,50; H, 5,53; N, 11,29.Found: C, 60.50; H, 5.53; N, 11.29.
Rasta: C, 60,51; H, 5,59; N, 11,14.Found: C, 60.51; H, 5.59; N, 11.14.
pavyzdysexample
CO2HCO 2 H
100100
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepin-7-karboksirūgštis (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-7-carboxylic acid (dihydrochloride)
J 11 pavyzdžio junginio (0,12 g, 0,26 mmol) tirpalą THF (10 ml) -78 °C temperatūroje pridedama n-BuLi (2,5 M THF, 0,22 ml, 0,55 mmol). Gautas rudas tirpalas maišomas 4 min. -78 °C temperatūroje, 20 min. leidžiamas CO2, ir skaldoma acto rūgšties ir vandens mišiniu (2:1, 2 ml). Tirpiklis nugarinamas, liekana ištirpinama metileno chloride, ir tirpalas plaunamas sočiu NaCl tirpalu, džiovinamas (Na2SO4) ir nugarinamas. Liekana gryninama preparatinės HPLC metodu (YMC S5 ODS 30x250 mm; gradientinis eliuavimas nuo 0 iki 100 % buferio B per 45 min.; buferis A = MeOH:H2O:TFA (10:90:0,1); buferis B = MeOH:H2O:TFA (90:10:0,1); 25 ml/min.), ir produktas paverčiamas HCI druska, liofiiizuojant iš 1M HCI (5 ml). Gaunamas 48 pavyzdžio junginys (50 mg, 45 %), kuris yra nelabai balta kieta medžiaga.A solution of Example 11 (0.12 g, 0.26 mmol) in THF (10 mL) at -78 ° C was added n-BuLi (2.5 M THF, 0.22 mL, 0.55 mmol). The resulting brown solution was stirred for 4 min. At -78 ° C for 20 min. CO 2 is added and the mixture is diluted with a mixture of acetic acid and water (2: 1, 2 ml). The solvent is evaporated off, the residue is dissolved in methylene chloride and the solution is washed with saturated NaCl solution, dried (Na 2 SO 4 ) and evaporated. The residue was purified by preparative HPLC (YMC S5 ODS 30x250 mm; gradient elution 0 to 100% buffer B over 45 min; buffer A = MeOH: H 2 O: TFA (10: 90: 0.1); buffer B = MeOH H 2 O: TFA (90: 10: 0.1); 25 mL / min) and the product was converted to the HCl salt by lyophilization from 1M HCl (5 mL). Example 48 (50 mg, 45%) is obtained which is an off-white solid.
MS (M + H+) 427.MS (M + H + ) 427.
1H-BMR (CD3OD): 3,05 (pl.m, 1H), 3,20 (m, 1H), 4,00 (pl.s, 1H), 4,20 (pl.s, 1H), 4,40 (pi.d, 1H), 4,50 (pl.s, 1H), 4,65 (s, 1H), 5,05 (s, 1H), 6,60 (d, 1H), 7,19-8,20 (m, 11H), 8,85 (s, 1H), 8,95 (s, 1H). 1 H-NMR (CD 3 OD): 3.05 (ppm, 1H), 3.20 (m, 1H), 4.00 (ppm, 1H), 4.20 (ppm, 1H), 4.40 (pi.d, 1H), 4.50 (ss, 1H), 4.65 (s, 1H), 5.05 (s, 1H), 6.60 (d, 1H), 7 , 19-8.20 (m, 11H), 8.85 (s, 1H), 8.95 (s, 1H).
pavyzdysexample
2,3,4,5-Tetrahidro-1-(1H-imidazol-5-ilmetil)-4-(1naftalenilkarbonil)-7-cikloheksil-1 H-1,4-benzodiazepinas (2,5 hidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-5-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-cyclohexyl-1H-1,4-benzodiazepine (2.5 hydrochloride)
101 { 11 pavyzdžio junginio (0,68 g, 1,4 mmol) tirpalą THF (15 ml) -78 °C temperatūroje pridedama n-BuLi (2,5 M THF, 1,4 ml, 3,5 mmol). Gautas rudas tirpalas maišomas 5 min. -78 °C temperatūroje, po to pridedama cikloheksanono (1,5 ml, 14,4 mmol). Pamaišius -78 °C temperatūroje 10 min., reakcija stabdoma sočiu NH4CI (3 ml) ir sočiu NaHCO3 (10 ml). Vandeninis tirpalas ekstrahuojamas CH2CI2. Organinė fazė džiovinama (Na2SO4) ir nugarinama. Liekana gryninama chromatografijos metodu (silikagėlis, 10 % CH3OH, 0,5 % AcOH CH2CI2), ir gaunamas negrynas alkoholis (80 mg), o taip pat ir 50 pavyzdžio junginio 25 % išeiga. J negryno alkoholio (40 mg) tirpalą CH2Ci2 (15 ml) -78 °C temperatūroje pridedama TFA (3 ml). Gautas mėlynas tirpalas veikiamas kietu NaBH4 (0,7 g, 18,5 mmol). Mišinys sušildmas iki kambario temperatūros ir skaldomas NH4OH (10 ml). Tirpalas praskiedžiamas CH2CI2 (20 ml) ir plaunamas vandeniniu NaOH (1N, 10 ml) ir sočiu NaCl (10 ml). Išdžiovinus Na2SO4 ir nugarinus tirpiklį, gaunama kieta medžiaga, kuri paverčiama jos HCI druska, liofilizuojant iš 1M HCI, ir gaunamas 49 pavyzdžio junginys, kuris yra geltona kieta medžiaga (30 mg). MS (M + H+) 465.A solution of 101 {Example 11 (0.68 g, 1.4 mmol) in THF (15 mL) was added at -78 ° C with n-BuLi (2.5 M in THF, 1.4 mL, 3.5 mmol). The resulting brown solution was stirred for 5 min. At -78 ° C, followed by cyclohexanone (1.5 mL, 14.4 mmol). After stirring at -78 ° C for 10 min, quench the reaction with saturated NH 4 Cl (3 mL) and saturated NaHCO 3 (10 mL). The aqueous solution is extracted with CH 2 Cl 2 . The organic phase is dried (Na 2 SO 4 ) and evaporated. The residue was purified by chromatography (silica gel, 10% CH 3 OH, 0.5% AcOH CH 2 Cl 2 ) to give the crude alcohol (80 mg) as well as 25% of Example 50. To a solution of the crude alcohol (40 mg) in CH 2 Cl 2 (15 mL) at -78 ° C was added TFA (3 mL). The resulting blue solution was treated with solid NaBH 4 (0.7 g, 18.5 mmol). The mixture was warmed to room temperature and quenched with NH 4 OH (10 mL). The solution was diluted with CH 2 Cl 2 (20 mL) and washed with aqueous NaOH (1N, 10 mL) and saturated NaCl (10 mL). Drying of Na 2 SO 4 and evaporation of the solvent afforded a solid which was converted to its HCl salt by lyophilization from 1M HCl to give Example 49 as a yellow solid (30 mg). MS (M + H + ) 465.
1H-BMR (CD3OD): 1,50-2,40 (m, 10H), 2,89 (m, 1H), 3,20 (m, 2H), 4,00 (pl.s, 1H), 4,20 (pl.s, 1H), 4,40 (pi.d, 1H), 4,50 (pl.s, 1H), 4,65 (s, 1H), 4,95 (s, 1H), 6,15 (d, 1H), 7,19-8,10 (m, 11H), 8,85 (s, 1H), 8,95 (s, 1H). 1 H-NMR (CD 3 OD): 1.50 - 2.40 (m, 10H), 2.89 (m, 1H), 3.20 (m, 2H), 4.00 (s, 1H ), 4.20 (p.s.s, 1H), 4.40 (p.s.d. 1H), 4.50 (p.s.s, 1H), 4.65 (s, 1H), 4.95 (s) 1H), 6.15 (d, 1H), 7.19-8.10 (m, 11H), 8.85 (s, 1H), 8.95 (s, 1H).
pavyzdys .Meexample .Me
7-Butil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (dihidrochioridas)7-Butyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)
102 pavyzdžio junginio gavimas aprašytas 49 pavyzdyje.Preparation of Example 102 is described in Example 49.
MS (M + H+) 439.MS (M + H + ) 439.
1H-BMR (CD3OD): 0,5-2,40 (m, 9H), 2,9 (m, 2H). 3,20 (m, 2H), 4,00 (pl.s, 1H), 4,20 (pl.s, 1H), 4,40 (pl.d, 1H), 4,50 (pl.s, 1H), 4,65 (s, 1H), 4,95 (s, 1H), 6,00 (pl.s, 1 H), 7,19-8,10 (m, 11H), 8,85 (s, 1H), 8,95 (s, 1H). 1 H-NMR (CD 3 OD): 0.5-2.40 (m, 9H), 2.9 (m, 2H). 3.20 (m, 2H), 4.00 (m.p., 1H), 4.20 (m.s, 1H), 4.40 (m.p., 1H), 4.50 (m.p. 1H), 4.65 (s, 1H), 4.95 (s, 1H), 6.00 (ss, 1H), 7.19-8.10 (m, 11H), 8.85 ( s, 1H), 8.95 (s, 1H).
1-[[2-(2-Aminoetil)-1H-imidazol-4-il]metil]-2,3,4,5-tetrahidro-4-(1naftalenilkarbonil)-7-fenil-1 H-1,4-benzodiazepinas (trihidrochloridas) pavyzdžio junginys pagaminamas pagal tokių dviejų stadijų metodiką. Atliekamas tetrahidro-4-(1 -naftalenilkarbonil)-7-feni 1-1 H-1,4benzodiazepino (pagaminto pagal 12 pavyzdyje aprašytą metodiką) redukcinis alkilinimas su 20 pavyzdžio junginiu B pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką, maišant 18 vai. Neapdorotas mišinys gryninamas sparčiosios chromatografijos metodu (silikagelis, 60 % etiiacetatas heksanuose), ir gaunamas bis-Boc analogas. Deblokavus ir išgryninus pagal 20 pavyzdyje aprašytą junginio C gryninimo metodiką, gaunamas 51 pavyzdžio junginys, kuris yra nelabai balti milteliai.1 - [[2- (2-Aminoethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4- benzodiazepine (trihydrochloride) sample compound is prepared according to the following two-step procedure. Reductive alkylation of tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (prepared according to the procedure described in Example 12) with the compound B of Example 20 according to the procedure for the preparation of the compound D described in Example 1 is carried out. The crude mixture was purified by flash chromatography (silica gel, 60% ethyl acetate in hexanes) to give the bis-Boc analog. Deprotection and purification according to the purification procedure of Compound C described in Example 20 affords Example 51 as an off-white powder.
MS (M + H)+ 502.MS (M + H) + 502.
Analizė išskaičiuota pagal C32H31N5O · 3 HCI 0,5 H2O.Analysis calculated for C 32 H 31 N 5 O · 3 HCl 0.5 H 2 O.
Išskaičiuota: C, 61,99; H, 5,69; N, 11,29.Found: C, 61.99; H, 5.69; N, 11.29.
Rasta: C, 61,68; H, 6,07; N, 11,22.Found: C, 61.68; H, 6.07; N, 11.22.
pavyzdysexample
103103
1-[[2-(2-Aminometil)-1H-imidazol-4-il]metil]-2,3,4,5-tetrahidro-4-(1naftalenilkarbonil)-7-fenil-1 H-1,4-benzodiazepinas (trihidrochloridas) pavyzdžio junginys pagamintas iš tetrahidro-4-(1 -naftalenilkarbonil)7-fenil-1 H-1,4-benzodiazepino ir [2-(2-[[(1,1-dimetil)etoksikarbonil]amino]metil)-1-[(1,1-dimetil)-etoksikarbonil]-imidazol-4-il]karboksaldehido (žr. 21 pavyzdį) pagal 51 pavyzdyje aprašytą metodiką.1 - [[2- (2-Aminomethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4- benzodiazepine (trihydrochloride) Example compound prepared from tetrahydro-4- (1-naphthalenylcarbonyl) 7-phenyl-1H-1,4-benzodiazepine and [2- (2 - [[(1,1-dimethyl) ethoxycarbonyl] amino] methyl] ) -1 - [(1,1-dimethyl) -ethoxycarbonyl] -imidazol-4-yl] carboxaldehyde (see Example 21) according to the procedure described in Example 51.
MS (M + H)+488.MS (M + H) < + > 488.
Analizė išskaičiuota pagal C31H29N5O 3 HCI.Analysis calculated for C31H29N5O3 HCl.
Išskaičiuota: C, 62,37; H, 5,40; N, 11,73.Found: C, 62.37; H, 5.40; N, 11.73.
Rasta: C, 62,13; H, 5,67; N, 11,73.Found: C, 62.13; H, 5.67; N, 11.73.
pavyzdysexample
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-8[N,N-bis(fenil-metil)amino]-1 H-1,4-benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8 [N, N-bis (phenylmethyl) amino] -1H-1, 4-Benzodiazepine (trihydrochloride)
104104
Į 26 pavyzdžio junginio (0,50 g, 0,12 mmol), benzaldehido (0,04 g, 0,37 mmol) ir AcOH (1 ml) tirpalą CH2CI2 (1 ml) pridedama natrio triacetoksiborhidrido (0,079 g, 0,37 mmol). Pamaišius 16 vai., reakcijos mišinys praskiedžiamas CH2CI2 (10 ml), NH4OH (3 ml) ir NaHCO3 (3 ml) ir maišomas 30 min. Atskiriami sluoksniai, ir vandeninis sluoksnis vėl ekstrahuojamas CH2CI2 (2x50 ml). Sumaišyti organiniai sluoksniai džiovinami MgSO4, nufiltruojami ir koncentruojami. Liekana veikiama HCI/eteriu, susidaro geltona kieta medžiaga, kuri trinama keletą kartų su eteriu ir išdžiovinus vakuume, gaunamas 53 pavyzdžio junginys (0,43 g, 60 %).Sodium triacetoxyborohydride (0.079 g, 0.37) was added to a solution of Example 26 (0.50 g, 0.12 mmol), benzaldehyde (0.04 g, 0.37 mmol) and AcOH (1 mL) in CH 2 Cl 2 (1 mL). mmol). After stirring for 16 h, the reaction mixture was diluted with CH 2 Cl 2 (10 mL), NH 4 OH (3 mL) and NaHCO 3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was re-extracted with CH 2 Cl 2 (2 x 50 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was treated with HCl / ether to give a yellow solid which was triturated several times with ether and dried in vacuo to afford Example 53 (0.43 g, 60%).
MS (M + H)+579.MS (M + H) + 579.
’H-BMR (270 MHz, CD3OD): δ 8,8 (d, 1H, J = 20 Hz), 8,04-7,9 (m, 2H), 7,67,2 (m, 18H), 7,0 (s, 0,5H), 5,87 (s, 0,5H), 4,95-4,8 (m, 5H), 4,5-4,1 (m, 3H), 3,85 (m, 1H), 3,4-3,2 (m, 2H), 3,0 (m, 1H).1 H-NMR (270 MHz, CD 3 OD): δ 8.8 (d, 1H, J = 20 Hz), 8.04-7.9 (m, 2H), 7.67.2 (m, 18H) ), 7.0 (s, 0.5H), 5.87 (s, 0.5H), 4.95-4.8 (m, 5H), 4.5-4.1 (m, 3H), 3.85 (m, 1H), 3.4-3.2 (m, 2H), 3.0 (m, 1H).
N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)1 H-1,4-benzodiazepin-8-il]fenilsulfonamidas (dihidrochloridas) j 26 pavyzdžio junginio (0,50 g, 0,12 mmol) ir trietilamino (0,019 ml, 0,13 mmol) tirpalą CH2CI2 (1 ml) pridedama benzensulfonamido (0,024 g, 0,13 mmol). Pamaišius 16 vai., reakcijos mišinys praskiedžiamas CHCI3 (10 ml) ir NaHCO3 (3 ml) ir maišomas 30 min. Atskiriami sluoksniai, ir vandeninis sluoksnis vėl ekstrahuojamas CHCI3 (2x20 ml). Sumaišyti organiniai sluoksniai džiovinami MgSO4, nufiltruojami ir koncentruojami. LiekanaN- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] phenylsulfonamide (dihydrochloride) To a solution of Example 26 (0.50 g, 0.12 mmol) and triethylamine (0.019 mL, 0.13 mmol) in CH 2 Cl 2 (1 mL) was added benzenesulfonamide (0.024 g, 0.13 mmol). After stirring for 16 h, the reaction mixture was diluted with CHCl 3 (10 mL) and NaHCO 3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was re-extracted with CHCl 3 (2 x 20 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated. Remain
105 veikiama HCI/eteriu, susidaro geltona kieta medžiaga, kuri trinama keletą kartų su eteriu ir išdžiovinus vakuume, gaunamas 54 pavyzdžio junginys (0,642 g, 83 %), kuris yra rusva kieta medžiaga.Treatment with HCl / ether gave a yellow solid which was triturated several times with ether and dried in vacuo to afford Example 54 (0.642 g, 83%) as a brownish solid.
MS (M + H)+ 538.MS (M + H) < + > 538.
1H-BMR (270 MHz, CD3OD): δ 8,8 (d, 1H, J = 20 Hz), 8,1-7,23 (m, 13H), 7,1 (d,0,5H, J = 8 Hz), 7,0 (d, 0,5H, J=8 Hz), 6,9 (d, 0,5H, J=8 Hz), 6,62 (d, 0,5H, J =8 Hz), 6,12 (d, 0,5H, J=8 Hz), 5,71 (d, 0,5H, J=8 Hz), 4,55 (m, 1H), 4,553,9 (m, 3H), 3,45-3,25 (m, 2H), 3,0-2,8 (m, 2H). 1 H-NMR (270 MHz, CD 3 OD): δ 8.8 (d, 1H, J = 20 Hz), 8.1-7.23 (m, 13H), 7.1 (d, 0.5H) , J = 8Hz), 7.0 (d, 0.5H, J = 8Hz), 6.9 (d, 0.5H, J = 8Hz), 6.62 (d, 0.5H, J = 8Hz), 6.12 (d, 0.5H, J = 8Hz), 5.71 (d, 0.5H, J = 8Hz), 4.55 (m, 1H), 4.553.9 ( m, 3H), 3.45-3.25 (m, 2H), 3.0-2.8 (m, 2H).
N-Fenil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepin-7-karboksamidas (dihidrochloridas) pavyzdžio junginio (50 mg, 0,11 mmol), PyBROP (0,28 g, 0,6 mmol), DMAP (0,04 g, 0,3 mmol) ir DIEA (0,3 g, 2,3 mmol) mišinys DMF (5 ml) maišomas 5 min., pridedama anilino (1 ml, 11 mmol), ir gautas homogeninis tirpalas maišomas dvi dienas. Nugarinus DMF, liekana gryninama preparatinės HPLC· metodu (YMC S5 ODS 30x250 mm: Rt = 2223 min.; gradientinis eliuavimas nuo 0 iki 100 % buferio B per 45 min.; buferis A = MeOH:H2O:TFA (10:90:0,1); buferis B = MeOH:H2O:TFA (90:10:0,1); 25 ml/min.) ir paverčiama į HCl druską, liofilizuojant iš 1M HCl (5 ml). Gaunamas 55 pavyzdžio junginys (40 mg, 34 %), kuris yra geltona kieta medžiaga.N-Phenyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-7-carboxamide (dihydrochloride) A mixture of 50 mg, 0.11 mmol), PyBROP (0.28 g, 0.6 mmol), DMAP (0.04 g, 0.3 mmol) and DIEA (0.3 g, 2.3 mmol) in DMF ( 5 ml) was stirred for 5 min, aniline (1 ml, 11 mmol) was added and the resulting homogeneous solution was stirred for two days. After evaporation of DMF, the residue was purified by preparative HPLC (YMC S5 ODS 30x250 mm: Rt = 2223 min; gradient elution from 0 to 100% buffer B over 45 min; buffer A = MeOH: H 2 O: TFA (10:90 Buffer B = MeOH: H 2 O: TFA (90: 10: 0.1); 25 mL / min) and converted to the HCl salt by lyophilization from 1M HCl (5 mL). Example 55 (40 mg, 34%) is obtained as a yellow solid.
MS (M + H)+502.MS (M + H) + 502.
106 1H-BMR (CD3OD): 3,10 (pl.m, 1H), 3,25 (m, 1H), 4,10 (pl.s, 1H), 4,25 (pl.s,106 1 H-NMR (CD 3 OD): 3.10 (ppm, 1H), 3.25 (m, 1H), 4.10 (p.s, 1H), 4.25 (p.s.
1H), 4,45 (pl.d, 1H), 4,55 (pl.s, 1H), 4,60 (s, 1H), 5,10 (s, 1H), 6,64 (d, 1H), 7,19-8,20 (m, 16H), 8,85 (s, 1H), 8,95 (s, 1H).1H), 4.45 (dd, 1H), 4.55 (dd, 1H), 4.60 (s, 1H), 5.10 (s, 1H), 6.64 (d, 1H) ), 7.19-8.20 (m, 16H), 8.85 (s, 1H), 8.95 (s, 1H).
pavyzdysexample
N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)1 H-1,4-benzodiazepin-8-il]-3-metilbenzamidas (dihidrochloridas) pavyzdžio junginys pagaminamas iš m-toluilchlorido ir 26 pavyzdžio junginio pagal 27 pavyzdyje aprašytą metodiką, maišant 16 vai. HCl druska pagaminama tiesiogiai iš negryninto produkto, ir gaunamas 56 pavyzdžio junginys (94 % išeiga), kuris yra ruda kieta medžiaga.N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -3-methylbenzamide ( dihydrochloride) is prepared from m-toluoyl chloride and the compound of Example 26 according to the procedure described in Example 27 by stirring for 16 hours. The HCl salt is prepared directly from the crude product to give Example 56 (94% yield) as a brown solid.
MS (M + H)+516.MS (M + H) < + > 516.
1H-BMR (270 MHz, CD3OD): δ 8,8 (d, 1H, J = 20 Hz), 8,15-7,2 (m, 14H), 6,8 (d, 0,5H, J = 7 Hz), 5,95 (d, 0,5H, J = 7 Hz), 4,98 (s, 1H), 4,7-4,19 (m, 3H), 4,19-3,9 (m, 1H), 3,52-3,2 (m, 1,5H), 3,25-3,15 (m, 0,5H), 3,1-2,8 (m, 1H), 2,46-2,33 (m, 3H). 1 H-NMR (270 MHz, CD 3 OD): δ 8.8 (d, 1H, J = 20 Hz), 8.15-7.2 (m, 14H), 6.8 (d, 0.5H) , J = 7Hz), 5.95 (d, 0.5H, J = 7Hz), 4.98 (s, 1H), 4.7-4.19 (m, 3H), 4.19-3 , 9 (m, 1H), 3.52-3.2 (m, 1.5H), 3.25-3.15 (m, 0.5H), 3.1-2.8 (m, 1H) , 2.46-2.33 (m, 3H).
pavyzdysexample
107107
HNHN
N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)1H-1,4-benzodiazepin-8-il]-4-metilbenzamidas (dihidrochloridas) pavyzdžio junginys pagaminamas iš p-toluilchlorido ir 26 pavyzdžio junginio pagal 56 pavyzdyje aprašytą metodiką.N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) 1H-1,4-benzodiazepin-8-yl] -4-methylbenzamide (dihydrochloride) ) Example compound is prepared from p-toluoyl chloride and Example 26 according to the procedure described in Example 56.
MS (M + H)+ 516.MS (M + H) < + > 516.
1H-BMR (270 MHz, CD3OD): δ 8,8 (d, 1H, J = 20 Hz), 8,15-7,72 (m, 5H), 7,77,2 (m, 9H), 6,77 (d, 0,5H, J = 7 Hz), 5,92 (d, 0,5H, J = 7 Hz), 4,98 (s, 1H), 4,7-4,19 (m, 3H), 4,12-3,9 (m, 1H), 3,52-3,2 (m, 1,5H), 3,25-3,15 (m, 0,5H), 3,1-2,8 (m, 1H), 2,46-2,33 (m, 3H). 1 H-NMR (270 MHz, CD 3 OD): δ 8.8 (d, 1H, J = 20 Hz), 8.15-7.72 (m, 5H), 7.77.2 (m, 9H) ), 6.77 (d, 0.5H, J = 7Hz), 5.92 (d, 0.5H, J = 7Hz), 4.98 (s, 1H), 4.7-4.19 (m, 3H), 4.12-3.9 (m, 1H), 3.52-3.2 (m, 1.5H), 3.25-3.15 (m, 0.5H), 3 , 1-2.8 (m, 1H), 2.46-2.33 (m, 3H).
pavyzdysexample
ClCl
HNHN
3-Chlor-N-[2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepin-8-il]benzamidas (dihidrochloridas)3-Chloro-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] benzamide (dihydrochloride) )
108 pavyzdžio junginys pagaminamas iš 3-chlorbenzoilchlorido ir 26 pavyzdžio junginio pagal 56 pavyzdyje aprašytą metodiką.Example 108 is prepared from 3-chlorobenzoyl chloride and Example 26 according to the procedure described in Example 56.
MS (M + H) + 536.MS (M + H) + 536.
1H-BMR (270 MHz, CD3OD): δ 8,87 (d, 1H, J = 20 Hz), 8,05-7,82 (m, 4H), 7,75-7,2 (m, 10H), 6,8 (d, 0,5H, J = 8 Hz), 5,9 (d, 0,5H, J = 8 Hz), 4,96 (s, 1H), 4,65-3,9 (m, 4H), 3,4-3,3 (m, 2H), 3,05-2,9 (m, 1H). 1 H-NMR (270 MHz, CD 3 OD): δ 8.87 (d, 1H, J = 20 Hz), 8.05-7.82 (m, 4H), 7.75-7.2 (m , 10H), 6.8 (d, 0.5H, J = 8Hz), 5.9 (d, 0.5H, J = 8Hz), 4.96 (s, 1H), 4.65-3 , 9 (m, 4H), 3.4-3.3 (m, 2H), 3.05-2.9 (m, 1H).
7-Brom-2,3,4,5-tetrahidro-1-[[2-[(dimetilamino)-metil]-1H-imidazol-4il]metil]-4-(1-naftalenilkarbonil)-1H-1,4-benzodiazepinas (dihidrochloridas)7-Bromo-2,3,4,5-tetrahydro-1 - [[2 - [(dimethylamino) methyl] -1H-imidazol-4-yl] methyl] -4- (1-naphthalenylcarbonyl) -1H-1,4 benzodiazepine (dihydrochloride)
Maišoma 11 pavyzdžio junginio (100 mg, 0,22 mmol), paraformaldehido (10 mg, 0,33 mmol) ir dimetilamino (40 % vandenyje, 0,041 ml) suspensija acto rūgštyje šildoma 90 °C temperatūroje 18 vai. Mišinys paskirstomas tarp etilacetato ir sotaus NaHCC>3 tirpalo. Organinis sluoksnis atskiriamas, džiovinamas ir koncentruojamas vakuume. Liekana gryninama sparčiosios chromatografijos metodu (30 % MeOH, 69 % etilacetato ir 1 % NH4OH), ir gaunama kieta medžiaga, kuri ištirpinama metanolyje. Pridedama 1N HCI eteryje, ir nugarinus tirpiklj, gaunamas 59 pavyzdžio junginys, kuris yra geltona kieta medžiaga (30 mg, 23 %).A suspension of Example 11 (100 mg, 0.22 mmol), paraformaldehyde (10 mg, 0.33 mmol) and dimethylamine (40% in water, 0.041 mL) was stirred in acetic acid at 90 ° C for 18 h. The mixture was partitioned between ethyl acetate and saturated NaHCC> 3. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by flash chromatography (30% MeOH, 69% ethyl acetate and 1% NH4OH) to give a solid which was dissolved in methanol. 1N HCl in ether was added and evaporation of the solvent gave Example 59 as a yellow solid (30 mg, 23%).
MS (M + H)+ 518.MS (M + H) < + > 518.
pavyzdysexample
109109
7-(4-ChIorfenil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmeti)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginio A (0,142 g, 0,2 mmol) tirpalas DMF (5 ml) ir THF (10 ml) degazuojamas, leidžiant argoną 5 min. Pridedama tetrakis(trifenilfosfin)paladžio (0,10 g, 0,08 mmol), ir tirpalas degazuojamas, leidžiant argoną 20 min. Pridedama natrio karbonato (0,11 g, 0,8 mmol) tirpalo degazuotame H2O (2 ml), o po to 4-chlorbenzenboro rūgšties (0,17 g, 1,1 mmol). Gautas tirpalas kaitinamas 110 °C temperatūroje 14 vai. Tirpiklis nugarinamas, liekana ištirpinama CH2CI2 (15 ml), ir tirpalas veikiamas HSiMe3 (3 ekv.) ir TFA (10 ekv.). Tirpiklis nugarinamas, o liekana išgryninama preparatinės HPLC metodu ir paverčiama HCl druska pagal 48 pavyzdyje aprašytą metodiką. Gaunamas 60 pavyzdžio junginys (40 mg, 40 %), kuris yra pilka kieta medžiaga.7- (4-Chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-yl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example A ( A solution of 0.142 g, 0.2 mmol) in DMF (5 mL) and THF (10 mL) was degassed under argon for 5 min. Tetrakis (triphenylphosphine) palladium (0.10 g, 0.08 mmol) is added and the solution is degassed under argon for 20 min. A solution of sodium carbonate (0.11 g, 0.8 mmol) in degassed H 2 O (2 mL) was added followed by 4-chlorobenzeneboronic acid (0.17 g, 1.1 mmol). The resulting solution was heated at 110 ° C for 14 h. The solvent was evaporated, the residue was dissolved in CH 2 Cl 2 (15 mL), and the solution was treated with HSiMe 3 (3 equiv.) And TFA (10 equiv.). The solvent is evaporated and the residue is purified by preparative HPLC and converted to the HCl salt according to the procedure described in Example 48. Example 60 (40 mg, 40%) is obtained as a gray solid.
MS (M + H)+ 493.MS (M + H) < + > 493.
1H-BMR (CD3OD, 300 MHz): δ 2,95 (pl.m, 1H), 3,30 (m, 1H), 4,00 (pl.s, 1H), 1 H-NMR (CD 3 OD, 300 MHz): δ 2.95 (ppm, 1H), 3.30 (m, 1H), 4.00 (ppm, 1H),
4,20 (pl.s, 1H), 4,40 (pl.d, 1H), 4,60 (m, 1H), 4,65 (m, 1H), 5,05 (s, 1H), 6,05 (d, 1H), 7,00 (d, 1H), 7,15-8,10 (m, 13H), 8,85 (s, 1H), 8,95 (s, 1H).4.20 (m.p., 1H), 4.40 (m.p., 1H), 4.60 (m, 1H), 4.65 (m, 1H), 5.05 (s, 1H), δ , 05 (d, 1H), 7.00 (d, 1H), 7.15-8.10 (m, 13H), 8.85 (s, 1H), 8.95 (s, 1H).
pavyzdysexample
110110
7-(3-Aminofenil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (trihidrochloridas) pavyzdžio junginys (pilka kieta medžiaga) 45 % išeiga pagaminamas iš 37 pavyzdžio junginio A ir 3-aminobenzenboro rūgšties (0,17 g, 1,1 mmol) pagal 60 pavyzdyje aprašytą metodiką.7- (3-Aminophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) Example Compound ( gray solid) is prepared in 45% yield from Example 37 Compound A and 3-aminobenzeneboronic acid (0.17 g, 1.1 mmol) according to the procedure described in Example 60.
MS (M + H)+ 474.MS (M + H) < + > 474.
1H-BMR (CD3OD, 300 MHz): δ 2,95 (pl.m, 1H), 3,30 (m, 1H), 4,00 (pl.s, 1H), 1 H-NMR (CD 3 OD, 300 MHz): δ 2.95 (ppm, 1H), 3.30 (m, 1H), 4.00 (ppm, 1H),
4,20 (pl.s, 1H), 4,40 (pl.d, 1H), 4,60 (m, 1H), 4,65 (m, 1H), 5,05 (s, 1H), 6,05 (d, 1 H), 7,00 (d, 1H), 7,15-8,10 (m, 13H), 8,85 (s, 1H), 8,95 (s, 1H).4.20 (m.p., 1H), 4.40 (m.p., 1H), 4.60 (m, 1H), 4.65 (m, 1H), 5.05 (s, 1H), δ , 05 (d, 1H), 7.00 (d, 1H), 7.15-8.10 (m, 13H), 8.85 (s, 1H), 8.95 (s, 1H).
1-Metil-N-[2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepin-8-il]-1H-pirol-2-karboksamidas (trihidrochloridas)1-Methyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -1H- pyrrole-2-carboxamide (trihydrochloride)
111 j EDC (0,071 g, 0,37 mmol), HOAt (0,051 g, 0,37 mmol) ir 1-metil-2pirolkarboksirūgšties (0,046 g, 0,37 mmol) tirpalą DMF (1 ml) pridedama 26 pavyzdžio junginio (0,050 g, 0,12 mmol). Pamaišius 16 vai., mišinys praskiedžiamas CHCI3 (10 ml) ir NaHCO3 (3 ml) ir maišomas 30 min. Atskiriami sluoksniai, ir vandeninis sluoksnis vėl ekstrahuojamas CHCI3 (2 x 20 ml). Sumaišyti organiniai sluoksniai džiovinami MgSCU, nufiltruojami ir koncentruojami. Liekana gryninama, chromatografuojant per silikagelio kolonėlę, kuri eliuuojama CHCI3, o po to CHCI3/MeOH (19/1), Paveikus produktą HCi/eteryje, gaunama geltona kieta medžiaga, kuri trinama su eteriu keletą kartų ir džiovinama vakuume. Gaunamas 62 pavyzdžio junginys (0,007 g, 11 %), kuris yra rusva kieta medžiaga.To a solution of 111 mL of EDC (0.071 g, 0.37 mmol), HOAt (0.051 g, 0.37 mmol) and 1-methyl-2-pyrrole carboxylic acid (0.046 g, 0.37 mmol) in DMF (1 mL) was added compound 26 (0.050). g, 0.12 mmol). After stirring for 16 h, the mixture was diluted with CHCl 3 (10 mL) and NaHCO 3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was re-extracted with CHCl 3 (2 x 20 mL). The combined organic layers were dried over MgSO 4, filtered, and concentrated. The residue was purified by chromatography on a silica gel column eluting with CHCl 3 followed by CHCl 3 / MeOH (19/1) to give a yellow solid which was triturated with ether several times and dried in vacuo. Example 62 (0.007 g, 11%) is obtained as a brownish solid.
MS (M + H)+ 505.MS (M + H) + 505.
1H-BMR (270 MHz, CD3OD): δ 8,88 (d, 1H, J = 21 Hz), 8,07-7,9 (m, 2,5H), 7,72-7,4 (m, 5H), 7,3 (d, 0,5H, J = 8 Hz), 7,23 (d, 0,5H, J = 8 Hz), 7,16 (d, 0,5H, J = 8 Hz), 7,0 (m, 0,5H), 6,95-6,85 (m, 1H), 6,7 (d, 0,5H, J = 8 Hz), 6,15-6,1 (m, 1H), 5,92 (d, 0,5H, J = 8 Hz), 5-4,9 (m, 2H), 4,65-4,15 (m, 4H), 3,98-3,9 (d, 3H, J = 10), 3,43-3,3 (m, 2,5H), 3,05-2,87 (m, 1H). 1 H-NMR (270 MHz, CD 3 OD): δ 8.88 (d, 1H, J = 21 Hz), 8.07-7.9 (m, 2.5H), 7.72-7.4 (m, 5H), 7.3 (d, 0.5H, J = 8Hz), 7.23 (d, 0.5H, J = 8Hz), 7.16 (d, 0.5H, J = 8Hz), 7.0 (m, 0.5H), 6.95-6.85 (m, 1H), 6.7 (d, 0.5H, J = 8Hz), 6.15-6, 1 (m, 1H), 5.92 (d, 0.5H, J = 8Hz), 5-4.9 (m, 2H), 4.65-4.15 (m, 4H), 3.98 -3.9 (d, 3H, J = 10), 3.43-3.3 (m, 2.5H), 3.05-2.87 (m, 1H).
pavyzdysexample
N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-nafta!enilkarbonil)1 H-1,4-benzodiazepin-8-il]-3-furankarboksamidas (dihidrochloridas) pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš 26 pavyzdžio junginio ir 3-furankarboksirūgšties pagal 62 pavyzdyje aprašytą metodiką.N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -3- Furancarboxamide (dihydrochloride) Example compound (yellow solid) is prepared from Example 26 compound and 3-furancarboxylic acid according to the procedure described in Example 62.
112112
MS (M + H) + 492.MS (M + H) < + > 492.
1H-BMR (270 MHz, CD3OD): δ 8,88 (d, 1H, J = 20 Hz), 8,25 (d, 1H, J = 16 Hz), 8,13-7,38 (m, 9H), 7,38 (d, 0,5H, J = 6 Hz), 7,25 (0,5H, J = 6 Hz), 7,19 (d, 0,5H, J = 8 Hz), 6,95 (d, 0,5H, J = 17 Hz), 6,72-6,68 (m, 1H), 5,93 (d, 0,5H, J = 8 Hz), 5,0-4,9 (m, 2H), 4,66-3,91 (m, 3,5H), 3,4-3,3 (m, 2H), 3,052,89 (m, 1H). 1 H-NMR (270 MHz, CD 3 OD): δ 8.88 (d, 1H, J = 20 Hz), 8.25 (d, 1H, J = 16 Hz), 8.13-7.38 ( m, 9H), 7.38 (d, 0.5H, J = 6Hz), 7.25 (0.5H, J = 6Hz), 7.19 (d, 0.5H, J = 8Hz) , 6.95 (d, 0.5H, J = 17Hz), 6.72-6.68 (m, 1H), 5.93 (d, 0.5H, J = 8Hz), 5.0- 4.9 (m, 2H), 4.66-3.91 (m, 3.5H), 3.4-3.3 (m, 2H), 3.052.89 (m, 1H).
7-(3-Chlorfenil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys (pilka kieta medžiaga) 55 % išeiga pagaminamas iš 37 pavyzdžio junginio A ir 3-chlorbenzenboro rūgšties (0,17 g, 1,1 mmol) pagal 60 pavyzdyje aprašytą metodiką.7- (3-Chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (Gray) The solid was prepared in 55% yield from Example 37 Compound A and 3-chlorobenzeneboronic acid (0.17 g, 1.1 mmol) according to the procedure described in Example 60.
MS (M-t-H)+493.MS (M + H) + 493.
1H-BMR (CD3OD, 300 MHz): δ 2,95 (pi.m,, 1H), 3,30 (m, 1H), 4,00 (pl.s, 1H), 1 H-NMR (CD 3 OD, 300 MHz): δ 2.95 (ppm, 1H), 3.30 (m, 1H), 4.00 (ss, 1H),
4,20 (pl.s, 1H), 4,40 (pl.d, 1H), 4,60 (m, 1H), 4,65 (m, 1H), 5,05 (s, 1H), 6,05 (d, 1H), 7,00 (d, 1H), 7,15-8,10 (m, Ž13H), 8,85 (s, 1H), 8,95 (s, 1H).4.20 (m.p., 1H), 4.40 (m.p., 1H), 4.60 (m, 1H), 4.65 (m, 1H), 5.05 (s, 1H), δ , 05 (d, 1H), 7.00 (d, 1H), 7.15-8.10 (m, J13H), 8.85 (s, 1H), 8.95 (s, 1H).
pavyzdysexample
113113
MeMe
2-Metil-N-[2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepin-8-il]benzamidas (dihidrochloridas) pavyzdžio junginys (gelsva kieta medžiaga) 23 % išeiga pagaminamas iš o-toluilchlorido ir 26 pavyzdžio junginio pagal 56 pavyzdyje aprašytą metodiką.2-Methyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] benzamide ( dihydrochloride) Example 23 (yellow solid) 23% yield of o-toluoyl chloride and Example 26 according to the procedure described in Example 56.
MS (M + H)+ 516.MS (M + H) < + > 516.
1H-BMR (270 MHz, CD3OD): δ 8,8 (d, 1H, J = 20 Hz), 8,05-7,2 (m, 13,5H), 7,1 (d, 0,5H, J = 6 Hz), 6,7 (d, 0,5H, J = 8 Hz), 5,95 (d, 0,5H, J = 8 Hz), 5,1-4,9 (m, 2H), 4,7-3,9 (m, 3H), 3,45-3,3 (m, 2H), 3,8-2,9 (m, 1H), 2,5-2,4 (d, 3H, J = 1 H-NMR (270 MHz, CD 3 OD): δ 8.8 (d, 1H, J = 20 Hz), 8.05-7.2 (m, 13.5H), 7.1 (d, 0 , 5H, J = 6Hz), 6.7 (d, 0.5H, J = 8Hz), 5.95 (d, 0.5H, J = 8Hz), 5.1-4.9 (m , 2H), 4.7-3.9 (m, 3H), 3.45-3.3 (m, 2H), 3.8-2.9 (m, 1H), 2.5-2.4 (d, 3H, J =
Hz).Hz).
pavyzdysexample
HNHN
114114
N-Fenil-N’-[2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepin-8-il]karbamidas (dihidrochloridas) ) 26 pavyzdžio junginio (0,050 g, 0,12 mmol) ir trietilamino (0,020 mi, 0,15 mmol) tirpalą CH2CI2 (1 ml) pridedama fenilizocianato (0,016 ml, 0,15 mmol). Pamaišius 16 vai., reakcijos mišinys praskiedžiamas CHCI3 (10 ml) ir NaHCO3 (3 ml) ir maišomas 30 min. Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCI3 (2 x 20 ml). Sumaišyti organiniai sluoksniai džiovinami MgSO4, nufiltruojami ir koncentruojami. Liekana gryninama, chromatografuojant per silikagelį, eliuuojant CHCI3/CH3OH (19/1). Tinkamos frakcijos koncentruojamos, ir liekana veikiama HCI/eteryje. Kieta medžiaga keletą kartų trinama su eteriu, ir išdžiovinus vakuume, gaunamas 66 pavyzdžio junginys (0,018 g, 25 %), kuris yra gelsva kieta medžiaga.N-Phenyl-N '- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] urea ( dihydrochloride)) To a solution of Example 26 (0.050 g, 0.12 mmol) and triethylamine (0.020 mL, 0.15 mmol) in CH 2 Cl 2 (1 mL) was added phenyl isocyanate (0.016 mL, 0.15 mmol). After stirring for 16 h, the reaction mixture was diluted with CHCl 3 (10 mL) and NaHCO 3 (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl 3 (2 x 20 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with CHCl3 / CH3OH (19/1). The appropriate fractions are concentrated and the residue is treated with HCl / ether. The solid was triturated several times with ether and dried in vacuo to give Example 66 (0.018 g, 25%) as a yellowish solid.
MS (M + H)+ 517.MS (M + H) + 517.
1H-BMR (400 MHz, CD3OD): δ 8,83 (d, 1H, J = 19 Hz), 8,07-7,89 (m, 2H), 7,68-7,2 (m, 11,5H), 7,07-6,98 (m, 1H), 6,85 (d, 0,5H, J = 6 Hz), 6,4 (d, 0,5H, J = 8 Hz), 5,89 (d, 0,5H, J = 8 Hz), 5,1-4,9 (m, 1H), 4,69-3,9 (m, 4H), 3,45-3,3 (m, 2H), 3,05-2,88 (m, 1H). 1 H-NMR (400 MHz, CD 3 OD): δ 8.83 (d, 1H, J = 19 Hz), 8.07-7.89 (m, 2H), 7.68-7.2 (m , 11.5H), 7.07-6.98 (m, 1H), 6.85 (d, 0.5H, J = 6Hz), 6.4 (d, 0.5H, J = 8Hz) , 5.89 (d, 0.5H, J = 8Hz), 5.1-4.9 (m, 1H), 4.69-3.9 (m, 4H), 3.45-3.3 (m, 2H), 3.05-2.88 (m, 1H).
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-7-(3piridinil)-1H-1,4-benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7- (3-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride)
115 pavyzdžio junginys (geltona kieta medžiaga) 8 % išeiga pagaminamas iš 37 pavyzdžio junginio A ir 3-(tributilstanil)piridino pagal 37 pavyzdyje aprašytą junginio B sintezės metodiką.Example 115 Compound (yellow solid) 8% yield is prepared from Example 37 Compound A and 3- (tributylstanyl) pyridine according to the procedure described in Example 37 for the synthesis of Compound B.
MS: (M + H)+ 460.MS: (M + H) + 460.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-iImetil)-9-metoksi-4-(1naftalenilkarbonil)-1H-1,4-diazepinas (dihidrochloridas) pavyzdžio junginys (gelsva kieta medžiaga) pagaminamas iš 8metoksiizatoinės rūgšties anhidrido ir glicino etilo esterio hidrochlorido pagal aprašytą tokių reakcijų seką: 1 pavyzdžio junginys A; redukcija atliekama, virinant su grjžtamu šaldytuvu diono tirpalą su 5 ekv. borano-THF tetrahidrofurane 20 vai; atšaldoma iki 0 °C, parūgštinama 3N HCI, kaitinama 100 °C temperatūroje 30 min., neutralizuojama 5N NaOH, o po to ekstrahuojama metileno chloridu; 2 pavyzdžio junginys C; 1 pavyzdžio junginys D.2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -9-methoxy-4- (1-naphthalenylcarbonyl) -1H-1,4-diazepine (dihydrochloride) Example compound (yellowish solid) of 8-methoxyisatoic acid anhydride and glycine ethyl ester hydrochloride according to the following sequence of reactions: Compound A of Example 1; reduction is carried out by refluxing a solution of dione with 5 eq. borano-THF in tetrahydrofuran or; cooled to 0 ° C, acidified with 3N HCl, heated at 100 ° C for 30 min, neutralized with 5N NaOH, and then extracted with methylene chloride; Compound C of Example 2; Example 1 Compound D.
MS (M + H)+ 413.MS (M + H) < + > 413.
IR: (KBr): 2926, 2837, 1732, 1630, 1580, 1474, 1252, 1078, 804, 781 cm’1.IR: (KBr): 2926, 2837, 1732, 1630, 1580, 1474, 1252, 1078, 804, 781 cm @ -1 .
pavyzdysexample
116116
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-7fenil-1 H-pirido[2,3-e]-1,4-diazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-pyrido [2,3-e] -1,4-diazepine ( trihydrochloride)
A. 2,3,4,5-Tetrahidro-7-brom-1H-pirido[2,3-e]-1,4-diazepin-5-onasA. 2,3,4,5-Tetrahydro-7-bromo-1H-pyrido [2,3-e] -1,4-diazepin-5-one
J 23 pavyzdžio junginio A (100 mg, 0,61 mmol) tirpalą acto rūgštyje (10 ml) pridedama bromo (32 μΙ, 0,61 mmol). Mišinys maišomas 30 min., po to, norint, kad reakcija pilnai įvyktų, pridedamas kitas bromo ekvivalentas (32 μΙ). Pamaišius dar 30 min., reakcijos mišinys praskiedžiamas 30 mi H2O ir 5N NaOH neutralizuojama iki pH 7. Mišinys ekstrahuojamas Et2O (50 ml), po to CH2CI2 (2 x 100 ml). Organiniai sluoksniai sumaišomi, plaunami sočiu NaCl tirpalu ir džiovinami Na2SO4. Sukoncentravus gaunamas junginys A, kuris yra kieta medžiaga (116 mg, 79 %). MS (M + CH3CN)+ 283.To a solution of Example 23 Compound A (100 mg, 0.61 mmol) in acetic acid (10 mL) was added bromine (32 μΙ, 0.61 mmol). The mixture was stirred for 30 min, then another bromine equivalent (32 μΙ) was added to allow the reaction to complete. After stirring for a further 30 min, the reaction mixture was diluted with 30 mL of H 2 O and neutralized to pH 7 with 5N NaOH. The mixture was extracted with Et 2 O (50 mL) followed by CH 2 Cl 2 (2 x 100 mL). The organic layers were combined, washed with brine and dried over Na 2 SO 4 . Concentration gave compound A, which was a solid (116 mg, 79%). MS (M + CH 3 CN) + 283.
B. 2,3,4,5-Tetrahidro-7-fenil-1H-pirido[2r3-e]-1,4-diazepin-5-onasB. 2,3,4,5-Tetrahydro-7-phenyl-1H-pyrido [2, 3 d-e] -1,4-diazepin-5-one
Junginio A (27 mg, 0,11 mmol), PhB(OH)2 (34 mg, 0,28 mmol) ir K5PO4 (59 mg, 0,28 mmol) tirpalas bevandeniame DMF (0,6 ml) ir bevandeniame THF (0,6 ml) degazuojamas, burbuliukais leidžiant N2 srovę 1 vai. į šį tirpalą pridedama perkristalinto Pd(PPh3)4, ir tirpalas šildomas 65 °C temperatūroje 30 vai. Mišinys atvėsinamas iki kambario temperatūros ir praskiedžiamas CH2CI2 (6 ml). Šis mišinys ekstrahuojamas 10 % LiCI, ir vandeninis sluoksnis vėl ekstrahuojamas vieną kartą CH2CI2 (6 mi). Organiniai sluoksniai sumaišomi ir plaunami 1N HCI. Organinis sluoksnis nupilamas, o vandeninis sluoksnis pašarminamas 5N NaOH ir ekstrahuojamas CH2CI2 (3 x 10 ml). Šie organiniai sluoksniai plaunami darCompound A (27 mg, 0.11 mmol) PHB (OH) 2 (34 mg, 0.28 mmol) and K5PO 4 (59 mg, 0.28 mmol) in anhydrous DMF (0.6 mL) and anhydrous THF (0.6 ml) is degassed by bubbling N 2 for 1 hour. recrystallized Pd (PPh 3 ) 4 is added to this solution and the solution is heated at 65 ° C for 30 hours. The mixture was cooled to room temperature and diluted with CH 2 Cl 2 (6 mL). This mixture was extracted with 10% LiCl, and the aqueous layer was extracted once with CH 2 Cl 2 (6 mL). The organic layers were mixed and washed with 1N HCl. The organic layer was removed and the aqueous layer was basified with 5N NaOH and extracted with CH 2 Cl 2 (3 x 10 mL). These organic layers are washed further
117 kartą 10 % LiCI, džiovinami Na2SO4, ir sukoncentravus gaunamas junginys B, kuris yra balta kieta medžiaga (18 mg, 70 %). MS (M+H+CH3CN)+ 281.117 times with 10% LiCl, dried over Na 2 SO 4 , and concentrated to give Compound B as a white solid (18 mg, 70%). MS (M + H + CH 3 CN) + 281.
C. 2,3,4,5-Tetrahidro-7-fenil-1H-pirido[2,3-e]-1,4-diazepinasC. 2,3,4,5-Tetrahydro-7-phenyl-1H-pyrido [2,3-e] -1,4-diazepine
Junginys C pagaminamas pagal 23 pavyzdyje aprašytą junginio B gavimo metodiką, virinant su grįžtamu šaldytuvu 60 vai. Negryna medžiaga chromatografuojama (sparčioji chromatografija, 230-400 mešų, 5-10 % MeOH/CHCI3), ir gaunamas junginys C, kuris yra balta kieta medžiaga (34 %). MS (M + H + CH3CN) + 267.Compound C is prepared according to the procedure described in Example 23 for the preparation of compound B by refluxing for 60 hours. The crude material was chromatographed (flash chromatography, 230-400 mesh, 5-10% MeOH / CHCl 3 ) to give Compound C as a white solid (34%). MS (M + H + CH 3 CN) + 267.
D. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-7-fenil-1H-pirido[2,3-e]-1,4-diazepinas (trihidrochloridas) pavyzdžio junginys (pūkų pavidalo balta kieta medžiaga) bendra 36 % išeiga pagaminamas iš junginio C pagal 23 pavyzdžio junginio C ir 23 pavyzdžio junginio D sintezės metodikas, panaudojant iš viso 6 alikvotines dalis aldehido ir hidrido, kad reakcija pilnai įvyktų.D. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-pyrido [2,3-e] -1,4-diazepine (trihydrochloride) Example Compound (fluffy white solid) is prepared in a total 36% yield from Compound C according to the synthesis procedures of Compound 23 of Example 23 and Compound D of Example 23 using a total of 6 aliquots of aldehyde and hydride for complete reaction.
MS (M + H)+ 460.MS (M + H) + 460.
Analizė išskaičiuota pagal Ο29Η25Ν5Ο · 3 HCI.Analysis calculated with Ο 29 Η 25 Ν 5 Ο · 3 HCl.
Išskaičiuota: C, 61,22; H, 4,96; N, 12,31.Found: C, 61.22; H, 4.96; N, 12.31.
Rasta: C, 61,50; H, 5,21; N, 12,29.Found: C, 61.50; H, 5.21; N, 12.29.
(R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-3-[2-(metiltio)etil]-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (hidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4- benzodiazepine (hydrochloride)
118 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš izatoinės rūgšties anhidrido ir L-metionino O-metilo esterio hidrochlorido pagal aprašytą šių junginių sintezės seką: 1 pavyzdžio junginio A, virinant 18 vai., nugarinant tirpiklį ir paskirstant tarp 1N vandenilio chlorido rūgšties ir dichlormetano; 17 pavyzdžio junginio, išskyrus tai, kad naudojama laisva bazė; 2 pavyzdžio junginys C, panaudojant sparčiąją chromatografiją per silikagelj, eliuuojant etilacetatu:heksanu (1:2); 1 pavyzdžio junginio D. Lyd. temp.: 145-150 °C.Example 118 (yellow solid) is prepared from isatoic anhydride and L-methionine O-methyl ester hydrochloride according to the described synthesis sequence of Example 1 Compound A by boiling for 18 hours, evaporating the solvent and partitioning between 1N hydrochloric acid and dichloromethane ; Example 17 except that the free base is used; Example 2 Compound C using flash chromatography on silica gel eluting with ethyl acetate: hexane (1: 2); The compound of Example 1, D. Lyd. mp: 145-150 ° C.
MS (M + H)+ 456.MS (M + H) + 456.
Analizė išskaičiuota pagal C27H28N4OS 1,6 H2O · 1,3 HCI.Analysis calculated for C 27 H 28 N 4 OS 1.6 H 2 O · 1.3 HCl.
Išskaičiuota: C, 60,86; H, 6,15; N, 10,51; S, 8,65; Cl, 6,02.Found: C, 60.86; H, 6.15; N, 10.51; S, 8.65; Cl, 6.02.
Rasta: C, 60,96; H, 5,67; N, 10,14; S, 8,39; Cl, 5,68.Found: C, 60.96; H, 5.67; N, 10.14; S, 8.39; Cl, 5.68.
pavyzdysexample
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-3(fenilmetil)-lH-1,4-benzodiazepinas (hidrochloridas) pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš izatoinės rūgšties anhidrido ir D,L-fenilalanino O-metilo esterio hidrochlorido pagal 70 pavyzdyje aprašytą metodiką. Lyd. temp.: 78-80 °C.2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride) Example Compound (yellow solid) material) is prepared from isatoic anhydride and D, L-phenylalanine O-methyl ester hydrochloride according to the procedure described in Example 70. Lyd. m.p. 78-80 ° C.
MS (M + H)+ 473.MS (M + H) + 473.
Analizė išskaičiuota pagal C3iH28N4O 1,6 H2O · 1,8 HCI.Analysis calculated for C 3 i H 28 N 4 O 1.6 H 2 O · 1.8 HCl.
Išskaičiuota: C, 65,66; H, 5,87; N, 9,88; Cl, 11,25.Found: C, 65.66; H, 5.87; N, 9.88; Cl, 11.25.
Rasta: C, 65,85; H, 5,68; N, 9,64; Cl, 11,55.Found: C, 65.85; H, 5.68; N, 9.64; Cl, 11.55.
119 pavyzdys <z Example 119 < z
NN
NN
HH
OHOH
2,3,4,5-Tetrahidro-3-(2-hidroksietil)-1-(1H-imidazol-4-ilmetil)-4-(1naftaleniikarbonil)-1 H-1,4-benzodiazepinas (trifluoracetatas) pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš izatoinės rūgšties anhidrido ir D,L-aspartato O-dimetilo esterio hidrochlorido pagal 70 pavyzdyje aprašytą metodiką, išskyrus tai, kad redukcijos stadijoje naudojami 5 ekv. ličio aliuminio hidrido, ir galutinis produktas gryninamas preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Lyd. temp.: 155-160 °C.2,3,4,5-Tetrahydro-3- (2-hydroxyethyl) -1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (trifluoroacetate) Example Compound ( white solid) is prepared from isatoic anhydride and D, L-aspartate O-dimethyl ester hydrochloride according to the procedure described in Example 70, except that 5 eq. lithium aluminum hydride, and the final product is purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 155-160 ° C.
MS (M + H)+ 427.MS (M + H) < + >
Analizė išskaičiuota pagal C26H26N4O2 1,0 H2O 1,3 TFA.Analysis calculated for C26H26N4O2 1.0 H2O 1.3 TFA.
Išskaičiuota: C, 57,95; H, 4,98; N, 9,45; Cl, 11,25.Found: C, 57.95; H, 4.98; N, 9.45; Cl, 11.25.
Rasta: C, 58,09; H, 4,71; N, 9,32; Cl, 11,55.Found: C, 58.09; H, 4.71; N, 9.32; Cl, 11.55.
pavyzdysexample
MeSMeS
2,3,4,5-Tetrahidro-4-(1H-imidazoi-4-ilmetil)-3-[2-(metiltio)etil]-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (trifluoracetatas)2,3,4,5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trifluoroacetate)
120 pavyzdžio junginys pagaminamas iš 2,3,4,5-tetrahidro-3-[2(metiltio)etil]-1H-1,4-benzodiazepino (pagaminto iš D.L-metionino O-metilo esterio hidrochlorido pagal 70 pavyzdyje aprašytą metodiką) pagal tokių junginių suntezės metodiką: 4 pavyzdžio junginio A; 2 pavyzdžio junginio C, reakcija atliekama negryninant junginio; 4 pavyzdžio junginio C; 1 pavyzdžio junginio D, gryninant preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Lyd. temp.: 130-135 °C.Example 120 is prepared from 2,3,4,5-tetrahydro-3- [2 (methylthio) ethyl] -1H-1,4-benzodiazepine (prepared from DL-methionine O-methyl ester hydrochloride according to the procedure described in Example 70) according to the procedure described in Example 70. synthesis of the following compounds: Example 4 Compound A; For the compound C of Example 2, the reaction is carried out without purification of the compound; The compound C of Example 4; Compound D of Example 1 by purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 130-135 ° C.
MS (M + H)+ 456.MS (M + H) + 456.
Analizė išskaičiuota pagal C27H28N4OS · 1,5 H2O · 1,3 TFA.Analysis calculated for C27H28N4OS · 1.5 H 2 O · 1.3 TFA.
Išskaičiuota: C, 56,27; H, 5,15; N, 8,87; S, 5,07; F, 11,73.Found: C, 56.27; H, 5.15; N, 8.87; S, 5.07; F, 11.73.
Rasta: C, 56,24; H, 4,84; N, 8,74; S, 5,10; F, 12,05.Found: C, 56.24; H, 4.84; N, 8.74; S, 5.10; F, 12.05.
pavyzdysexample
(S)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-3(fenilmetil)-l H-1,4-benzodiazepinas (trifluoracetatas) pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš izatoinės rūgšties anhidrido ir L-ienilalanino O-metilo esterio hidrochlorido pagal 70 pavyzdyje aprašytą metodiką; galutinis produktas gryninamas preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Lyd. temp.: 152-154 °C.(S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate) Example compound (white solid) is prepared from isatoic anhydride and L-enylalanine O-methyl ester hydrochloride according to the procedure described in Example 70; the final product is purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 152-154 ° C.
MS (M + H)+ 473.MS (M + H) + 473.
Analizė išskaičiuota pagal C3iH23N4O · 1,0 H2O · 1,2 TFA.Analysis calculated for C 31 H 23 N 4 O · 1.0 H 2 O · 1.2 TFA.
Išskaičiuota: C, 63,94; H, 5,01; N, 8,93; Cl, 10,90.Found: C, 63.94; H, 5.01; N, 8.93; Cl, 10.90.
Rasta: C, 64,12; H, 4,87; N, 8,73; Cl, 11,01.Found: C, 64.12; H, 4.87; N, 8.73; Cl, 11.01.
121 pavyzdysExample 121
Br eBr e
NN
HH
NN
NN
YY
OO
MeMe
4-Acetil-7-brom-2,3,4,5-tetrahidro-1-(1H-imidazo;-4-ilmetil)-3-(fenilmetil)1 H-1,4-benzodiazepinas (hidrochloridas)4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazo-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)
A. 7-Brom-2,3,4,5-tetrahidro-3-(fenilmetil)-1H-1,4-benzodiazepin-2,5dionasA. 7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5dione
Bromizatoinės rūgšties anhidrido (2,93 g, 12,1 mmol), D,L-fenilalanino O-metilo esterio hidrochlorido (2,62 g, 12,1 mmol), dimetilaminopiridino (100 mg, katalitinis kiekis) ir piridino (50 ml) mišinys virinamas su grįžtamu šaldytuvu (vonios temperatūra -140 °C) argono atmosferoje 48 vai. Tirpalas sukoncentruojamas vakuume iki pusiau kietos medžiagos, ir liekana suspenduojama 1N HCI (200 ml) ir dichlormetane (200 ml). Gautos nuosėdos nufiltruojamos, perplaunamos dichlormetanu (50 ml) ir džiovinamos vakuume 50 °C temperatūroje 18 vai. Gaunamas junginys A (1,1 g, 26 %), kuris yra pilka kieta medžiaga.Bromizatoic acid anhydride (2.93 g, 12.1 mmol), D, L-phenylalanine O-methyl ester hydrochloride (2.62 g, 12.1 mmol), dimethylaminopyridine (100 mg, catalytic amount) and pyridine (50 mL) ) was heated to reflux (bath temperature -140 ° C) under argon for 48 hours. The solution is concentrated in vacuo to a semi-solid and the residue is suspended in 1N HCl (200 mL) and dichloromethane (200 mL). The resulting precipitate was filtered off, washed with dichloromethane (50 mL) and dried in vacuo at 50 ° C for 18 h. Compound A (1.1 g, 26%) is obtained as a gray solid.
B. 7-Brom-2,3,4,5-tetrahidro-3-(fenilmetil)-1 H-1,4-benzodiazepinasB. 7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine
J junginio A (500 mg, 1,45 mmol) tirpalą etilenglikolio dimetileteryje (bevandenis, 50 ml) 0 °C temperatūroje ir argono atmosferoje lėtai supilamas BH3:THF tirpalas (20 ml, 1M tirpalas THF). Tirpalui leidžiama sušilti iki kambario temperatūros, po to virinama su grįžtamu šaldytuvu 18 vai., atšaldoma iki 0 °C, skaldoma metanoliu (5 ml) ir sukoncentruojama vakuume iki alyvos pavidalo liekanos. Ši alyva veikiama 6M HCI (100 ml) vandens garųA solution of Compound A (500 mg, 1.45 mmol) in ethylene glycol dimethyl ether (anhydrous, 50 mL) at 0 ° C under argon was added slowly to a solution of BH 3 : THF (20 mL, 1M in THF). The solution was allowed to warm to room temperature, then refluxed for 18 h, cooled to 0 ° C, quenched with methanol (5 mL) and concentrated in vacuo to an oil residue. This oil is exposed to 6M HCl (100 mL) water vapor
122 vonioje 2 vai. (pastebimas dalinis medžiagos ištirpimas). Mišinys atšaldomas iki 0 °C ir kietu NaOH pašarminama iki pH 10. Gautas mišinys paskirstomas etilacetate (200 ml), ekstrahuojamas etilacetatu (2 x 100 ml), džiovinamas (Na2SO4), ir sukoncentravus vakuume, gaunamas junginys B, kuris yra ruda kieta medžiaga (300 mg, 0,94 mmol, 65 %).122 baths for 2 hours. (noticeable partial dissolution of the substance). The mixture was cooled to 0 ° C and basified with solid NaOH to pH 10. The resulting mixture was partitioned between ethyl acetate (200 mL), extracted with ethyl acetate (2 x 100 mL), dried (Na 2 SO 4 ) and concentrated in vacuo to give Compound B brown solid (300 mg, 0.94 mmol, 65%).
C. 4-Acetil-7-brom-2,3,4,5-tetrahidro-3-(fenilmetil)-1 H-1,4benzodiazepinasC. 4-Acetyl-7-bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine
Sumaišomas junginys B (200 mg, 0,63 mmol), dichlormetanas (5 ml) ir vandeninis natrio hidroksidas (1 ml, 1N), ir mišinys atšaldomas iki 0 °C. J mišinį pridedama acetilchlorido (66 ml, 0,94 mmol), ir pamaišius 2 vai. 0 °C temperatūroje, pridedama vandeninio natrio hidroksido (20 ml, 1N) ir dichlormetano (50 ml), o po to ekstrahuojama dichlormetanu (50 ml). Organinės frakcijos sumaišomos, džiovinamos (Na2SO4) ir sukoncentruojamos iki negrynos alyvos (230 mg, 100 %).Compound B (200 mg, 0.63 mmol), dichloromethane (5 mL) and aqueous sodium hydroxide (1 mL, 1N) were added and the mixture was cooled to 0 ° C. Acetyl chloride (66 mL, 0.94 mmol) was added to the mixture and stirred for 2 h. At 0 ° C, aqueous sodium hydroxide (20 mL, 1N) and dichloromethane (50 mL) were added, followed by extraction with dichloromethane (50 mL). The organic fractions were combined, dried (Na 2 SO 4 ) and concentrated to a crude oil (230 mg, 100%).
D. 4-Acetil-7-brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(f eni I m eti I)-1 H-1,4-benzodiazepinas pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš junginio C pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką; galutinis produktas gryninamas preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Lyd. temp.: 112 °C.D. 4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine Exemplary compound (white solid) is prepared from Compound C according to the procedure for the preparation of Compound D described in Example 1; the final product is purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 112 ° C.
MS (M + H)+ 440.MS (M + H) + 440.
Analizė išskaičiuota pagal C22H23N4OBr · 0,5 H2O · 1,3 TFA.Analysis calculated for C 22 H 23 N 4 OBr · 0.5 H 2 O · 1.3 TFA.
Išskaičiuota: C, 49,53; H, 4,27; N, 9,39; F, 12,42.Found: C, 49.53; H, 4.27; N, 9.39; F, 12.42.
Rasta: C, 49,44; H, 4,07; N, 9,34; F, 12,32.Found: C, 49.44; H, 4.07; N, 9.34; F, 12.32.
pavyzdysexample
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2,3,4,5-Tetrahidro-4-(1H-imidazol-4-ilmetil)-1-(1-naftalenilkarbonil)-3(fenilmetil)-1H-1,4-benzodiazepinas (1,5 hidrochloridas) pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš 2,3,4,5tetrahidro-3-(fenilmetil)-1H-1,4-benzodiazepino (pagaminto pagal 71 pavyzdyje aprašytą metodiką), panaudojant metodikas tokiems junginiaims gauti:4 pavyzdžio junginiui A; 2 pavyzdžio junginiui C, pridedant katalitinį kiekį piridino ir gryninant per silikagelį, kuris eliuuojamas heksanu:etilacetatu (4:1); 4 pavyzdžio junginiui C; 1 pavyzdžio junginiui D, gryninant preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Lyd. temp.: 117-120 °C.2,3,4,5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (1.5 hydrochloride) Example compound (a white solid) is prepared from 2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine (prepared according to the procedure described in Example 71) using the following procedures to obtain the following compounds: Compound A of Example 4; To compound C of Example 2 by adding a catalytic amount of pyridine and purifying over silica gel eluting with hexane: ethyl acetate (4: 1); Example 4 for compound C; Compound D of Example 1 by purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp 117-120 ° C.
MS (M + H)+ 473.MS (M + H) + 473.
Analizė išskaičiuota pagal C31H28N4OBr · 0,8 H2O - 1,52 TFA.Analysis calculated for C 31 H 28 N 4 OBr · 0.8 H 2 O - 1.52 TFA.
išskaičiuota: C, 61,92; H, 4,75; N, 8,48; F, 13,12.Found: C, 61.92; H, 4.75; N, 8.48; F, 13.12.
Rasta: C, 62,31; H, 4,40; N, 8,09; F, 12,76.Found: C, 62.31; H, 4.40; N, 8.09; F, 12.76.
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7-Brom-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4H-1,4benzodiazepin-4-karboksamidas (trifluoracetatas)7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxamide (trifluoroacetate)
A. 7-Brom-1,2,3,5-tetrahidro-3-(fenilmetil)-4H-1,4-benzodiazepin-4karboksamidas pavyzdžio junginio B (200 mg, 0,63 mmol), THF (20 ml) ir trimetilsililizocianato (0,13 ml, 0,95 mmol) mišinys maišomas argono atmosferoje, kambario temperatūroje 18 vai. j tirpalą jpilama vandens (5 ml), po to vandeninės vandenilio chlorido rūgšties (20 ml, 1N). Mišinys ekstrahuojamas etilacetatu (2 x 100 ml), organiniai ekstraktai sumaišomi, džiovinami (MgSO4) ir sukoncentravus vakuume, gaunamas junginys A, kuris yra geltona kieta medžiaga (200 mg, 88 %).A. 7-Bromo-1,2,3,5-tetrahydro-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxamide Example B (200 mg, 0.63 mmol), THF (20 mL) and trimethylsilyl isocyanate (0.13 mL, 0.95 mmol) was stirred under argon at room temperature for 18 h. To the solution was added water (5 mL) followed by aqueous hydrochloric acid (20 mL, 1N). The mixture was extracted with ethyl acetate (2 x 100 mL), the organic extracts were combined, dried (MgSO 4 ) and concentrated in vacuo to give Compound A as a yellow solid (200 mg, 88%).
B. 7-Brom-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)4H-1,4-benzodiazepin-4-karboksamidas (trifluoracetatas) pavyzdžio junginys (balta kieta medžiaga) pagaminamas pagal 1 pavyzdyje aprašytą D junginio gavimo metodiką, gryninant preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Lyd. temp.: 162-165 °C.B. 7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxamide (trifluoroacetate) Example compound ( white solid) was prepared according to the procedure described in Example 1 for the preparation of compound D by purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 162-165 ° C.
MS (M + H)+ 440.MS (M + H) + 440.
Analizė išskaičiuota pagal C2iH22N5OBr 0,3 H2O · 1,2 TFA.Analysis calculated for C 2 i H 2 2 N 5 OBr 0.3 H 2 O · 1.2 TFA.
Išskaičiuota: C, 48,24; H, 4,12; N, 12,02; Br, 13,72; F, 11,74.Found: C, 48.24; H, 4.12; N, 12.02; Br, 13.72; F, 11.74.
Rasta: C, 48,23; H, 3,91; N, 11,95; Br, 13,63; F, 11,39.Found: C, 48.23; H, 3.91; N, 11.95; Br, 13.63; F, 11.39.
pavyzdysexample
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7-Brom-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-4(metilsulfonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (hidrochloridas)7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)
A. 7-Brom-2,3,4,5-tetrahidro-4-(metilsulfonil)-3-(fenilmetil)-1 H-1,4benzodiazepinas pavyzdžio junginio B (1,0 g, 3,15 mmol), THF (20 mi), DIEA (0,6 ml, 6,3 mmol) ir metansulfonilchlorido (0,5 ml, 6,3 mmol) mišinys maišomas argono atmosferoje, kambario temperatūroje 2 vai, Mišinys paskirstomas vandeninėje vandenilio chlorido rūgštyje (100 ml, 1N) ir etilacetate (100 ml). Vandeninė fazė ekstrahuojama etilacetatu (2 x 100 ml), organiniai sluoksniai sumaišomi, džiovinami (MgSCū) ir sukoncentravus vakuume, gaunama alyva. Ši alyva chromatografuojama sparčiosios chromatografijos metodu (50 g silikagelio eliuuojama heksanu:etilacetatu (3:1)), ir gaunamas junginys A, kuris yra skaidri alyva (330 mg, 27 %).A. 7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine, Example B, (1.0 g, 3.15 mmol), THF (20 mL), DIEA (0.6 mL, 6.3 mmol) and methanesulfonyl chloride (0.5 mL, 6.3 mmol) were stirred under argon at room temperature for 2 h. The mixture was partitioned between aqueous hydrochloric acid (100 mL, 1N) and ethyl acetate (100 mL). The aqueous phase is extracted with ethyl acetate (2 x 100 mL), the organic layers are combined, dried (MgSO 4) and concentrated in vacuo to give an oil. This oil was subjected to flash chromatography (50 g silica gel eluting with hexane: ethyl acetate (3: 1)) to give Compound A as a clear oil (330 mg, 27%).
B. 7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4(metilsulfonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (hidrochloridas)B. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)
J maišomą junginio A (330 mg, 0,84 mmol), formilimidazolo (120 mg, 1,26 mmol), dichloretano (10 ml) ir acto rūgšties (2 ml) tirpalą kambario temperatūroje pridedama natrio triacetoksiborhidrido (267 mg, 1,26 mmol). Tirpalas maišomas 1 vai., praskiedžiamas etilacetatu (20 ml) ir amonio hidroksidu (2 ml, kone.) ir maišomas dar 18 vai. Mišinys ekstrahuojamas etilacetatu (2 x 25 ml), sumaišyti organiniai ekstraktai plaunami vandeniniu natrio rūgščiuoju karbonatu (25 ml, sotus tirpalas) ir amonio chloridu (25 ml,To a stirred solution of compound A (330 mg, 0.84 mmol), formylimidazole (120 mg, 1.26 mmol), dichloroethane (10 mL) and acetic acid (2 mL) was added sodium triacetoxyborohydride (267 mg, 1.26 mmol) at room temperature. mmol). The solution was stirred for 1 h, diluted with ethyl acetate (20 mL) and ammonium hydroxide (2 mL, almost) and stirred for a further 18 h. The mixture was extracted with ethyl acetate (2 x 25 mL), and the combined organic extracts were washed with aqueous sodium bicarbonate (25 mL, saturated solution) and ammonium chloride (25 mL,
126 sotus vandeninis tirpalas), džiovinami (N2SO4) ir sukoncentruojami vakuume iki pusiau kietos medžiagos. Ši negryna medžiaga gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas) ir liofilizuojama. Gaunama 78 pavyzdžio junginio TFA druska, kuri yra balta kieta medžiaga (330 mg, 83 %); lyd. temp.: 118-120 QC. Ši medžiaga ištirpinama metanolyje (3 ml) ir pridedama 1M HCI (3 ml). Tirpalas nugarinamas, o liekana trinama su metileno chloridu, ir gaunamas 78 pavyzdžio junginys, kuris yra balta kieta medžiaga. Lyd. Temp.: 178-180 °C. MS (M + H)+ 476.126 saturated aqueous solution), dried (N 2 SO 4 ) and concentrated in vacuo to a semi-solid. This crude material was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and lyophilized. The TFA salt of Example 78 was obtained as a white solid (330 mg, 83%); melt M.p .: 118-120 Q C. This material was dissolved in methanol (3 mL) and 1M HCl (3 mL). The solution was evaporated and the residue triturated with methylene chloride to give Example 78 as a white solid. Lyd. 178-180 ° C. MS (M + H) + 476.
Analizė išskaičiuota pagal C2iH23N4O2SBr · 0,25 H2O · 1,2 HCI.Analysis calculated for C 2 i H 23 N 4 O 2 SBr · 0.25 H 2 O · 1.2 HCl.
Išskaičiuota: C, 48,17; H, 4,75; N, 10,70; S, 6,12; Cl, 8,12; Br, 15,26.Found: C, 48.17; H, 4.75; N, 10.70; S, 6.12; Cl, 8.12; Br, 15.26.
Rasta: C, 48,53; H, 4,60; N, 10,25; S, 6,95; Cl, 8,27; Br, 14,93.Found: C, 48.53; H, 4.60; N, 10.25; S, 6.95. Cl, 8.27; Br, 14.93.
4-Acetil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-3(feniImeti!)-1 H-1,4-benžodiazepinas (trifluoracetatas)4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3 (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate)
A. 4-Acetil-2,3,4,5-tetrahidro-7-fenil-3-(fenilmetil)-1H-1,4benzodiazepinasA. 4-Acetyl-2,3,4,5-tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine
J 75 pavyzdžio junginio C (500 mg, 1,39 mmol) tirpalą toluene (20 ml) irA solution of Example 75 (C, 500 mg, 1.39 mmol) in toluene (20 mL) was added
NaHCO3 (5 ml, sotus tirpalas) argono atmosferoje pridedama fenilboro rūgšties tirpalo (340 mg, 2,8 mmol 2 ml etanolio), j šj mišinį pridedama tetrakistrifenilfosfino paladžio(O) (42 mg, 0,07 mmol), ir mišinys virinamas suPhenylboronic acid solution (340 mg, 2.8 mmol in 2 mL ethanol) was added to NaHCO 3 (5 mL, saturated solution) under argon, tetrakistriphenylphosphine palladium (O) (42 mg, 0.07 mmol) was added and the mixture was heated to reflux. with
127 grįžtamu šaldytuvu argono atmosferoje 3 vai. Po to mišinys supilamas j sotų NaCl tirpalą, ekstrahuojamas etilacetatu (2 x 100 ml), organiniai ekstraktai sumaišomi, džiovinami (MgSO4), ir sukoncentravus vakuume, gaunama negryna raudona alyva, kuri gryninama sparčiosios chromatografijos metodu (50 g silikagelio eliuuojama heksanu:etilacetatu (1:1)). Gaunamas junginys A, kuris yra balta kieta medžiaga (200 mg, 59 %).127 reflux under argon for 3 hours. The mixture is then poured into a saturated NaCl solution, extracted with ethyl acetate (2 x 100 mL), the organic extracts are combined, dried (MgSO 4 ) and concentrated in vacuo to give a crude red oil which is purified by flash chromatography (50 g silica gel eluting with hexane (1: 1)). Compound A was obtained as a white solid (200 mg, 59%).
B. 4-Acetil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetiI)-7-fenil-3(fenilmetil)-l H-1,4-benzodiazepinas (trifluoracetatas) pavyzdžio junginys (balta kieta medžiaga) pagaminamas 79 % išeiga iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką, išgryninant preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Lyd. temp.: 120-123 °C.B. Example compound of 4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazole-4-methyl) -7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate) (white solid) is prepared in 79% yield from Compound A according to the procedure for Preparation of Compound D described in Example 1 by purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 120-123 ° C.
MS (M + H)+ 437.MS (M + H) + 437.
Analizė išskaičiuota pagal C28H28N4O · 1,3 H2O · 1,05 TFA.Analysis calculated for C 2 8H 2 O 8N 4 · 1.3 H 2 O · 1.05 TFA.
Išskaičiuota: C, 62,36; H, 5,50; N, 9,66; F, 10,32.Found: C, 62.36; H, 5.50; N, 9.66; F, 10.32.
Rasta: C, 62,42; H, 5,17; N, 9,61; F, 10,24.Found: C, 62.42; H, 5.17; N, 9.61; F, 10.24.
4-Acetil-7-brom-3-[(4-chlorfenil)metil]-2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)4-Acetyl-7-bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
A. D,L-N-(2-Amino-5-brombenzoil)-4-chlorfenilalaninasA. D, L-N- (2-Amino-5-bromobenzoyl) -4-chlorophenylalanine
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J piridiną (50 ml) sudedamas D,L-4-chlorfenilalaninas (pagamintas iš N-Boc-D,L-4-chlorfenilalanino ir 4N HCI dioksane su dimetilsulfidu) ir 6bromizotoinės rūgšties anhidridas (1,0 g, 4,15 mmol), ir mišinys virinamas su grįžtamu šaldytuvu 4 vai. Mišinys atšaldomas, koncentruojamas, ir liekana paskirstoma tarp vandens (200 ml) ir etilacetato (200 ml). Organinis sluoksnis plaunamas vandeniu (3 x 100 ml), sočiu NaCl (50 ml), džiovinamas (MgSO4), ir sukoncentravus gaunamas junginys A, kuris yra gelsvo stiklo pavidalo medžiaga (450 mg, 27 %), MS (M + H)+ 398.Pyridine (50 mL) was added with D, L-4-chlorophenylalanine (made from N-Boc-D, L-4-chlorophenylalanine and 4N HCl in dioxane with dimethylsulfide) and 6-Bromoisotonic acid anhydride (1.0 g, 4.15 mmol). , and the mixture is refluxed for 4 hours. The mixture was cooled, concentrated, and the residue partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (3 x 100 mL), saturated NaCl (50 mL), dried (MgSO 4 ), and concentrated to give Compound A as a yellow glass (450 mg, 27%), MS (M + H). + 398.
B. 7-Brom-3-[(4-chlorfenil)metil]-2,3,4,5-tetrahidro-1 H-1,4benzodiazepin-2,5-dionasB. 7-Bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,5-dione
Junginys A (450 mg, 1,13 mmol), EDO (737 mg, 3,85 mmol) ir HOBt (519 mg, 3,85 mmol) ištirpinami DMF (10 ml) ir iš karto pridedama DIEA (0,52 ml, 2,96 mmol). Mišinys maišomas 16 vai., supilamas į vandenį (100 ml), ir produktas ekstrahuojamas etilacetatu (2 x 50 ml). Sumaišyti etilacetato sluoksniai plaunami vandeniu (3 x 100 ml), sočiu NaCl (100 ml), džiovinami (MgSO4), ir sukoncentravus gaunamas junginys B, kuris yra rudo stiklo pavidalo medžiaga (200 mg, 46 %), MS (M + H)+ 380.Compound A (450 mg, 1.13 mmol), EDO (737 mg, 3.85 mmol) and HOBt (519 mg, 3.85 mmol) were dissolved in DMF (10 mL) and DIEA (0.52 mL, immediately added). 2.96 mmol). The mixture was stirred for 16 h, poured into water (100 mL) and the product extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate layers were washed with water (3 x 100 mL), saturated NaCl (100 mL), dried (MgSO 4 ), and concentrated to give Compound B as a brown glass (200 mg, 46%), MS (M + H). ) + 380.
C. 7-Brom-3-[(4-chlorfenil)metil]-2,3,4,5-tetrahidro-1H-1,4benzodiazepinasC. 7-Bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine
Junginys B (200 mg, 0,53 mmol) ištirpinamas THF (10 ml) ir pridedama borano (1M THF, 4 ml, 4 mmol). Tirpalas virinamas su grįžtamu šaldytuvu 3 vai., po to atšaldomas iki kambario temperatūros. Pridedama metanolio (5 ml), ir tirpalas koncentruojamas, j koncentratą pridedama 5N HCI (10 ml), ir mišinys virinamas su grįžtamu šaldytuvu 4 vai. Mišinys atšaldomas iki kambario temperatūros, 50 % NaOH neutralizuojamas iki pH 6 ir ekstrahuojamas metileno chloridu (3 x 50 ml). Organiniai sluoksniai sumaišomi, plaunami sočiu NaCl (30 ml), džiovinami (MgSO4), ir sukoncentravus gaunamas junginys C, kuris yra šiek tiek gelsva stiklo pavidalo medžiaga (60 mg, 32 %), MS (M + H)+ 352.Compound B (200 mg, 0.53 mmol) was dissolved in THF (10 mL) and borane (1M in THF, 4 mL, 4 mmol) was added. The solution is refluxed for 3 hours, then cooled to room temperature. Methanol (5 mL) was added and the solution concentrated, 5N HCl (10 mL) was added to the concentrate and the mixture was refluxed for 4 h. The mixture was cooled to room temperature, 50% NaOH was neutralized to pH 6 and extracted with methylene chloride (3 x 50 mL). The organic layers were combined, washed with saturated NaCl (30 mL), dried (MgSO 4 ), and concentrated to give Compound C as a slightly yellow glass (60 mg, 32%), MS (M + H) + 352.
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D. 4-Acetil-7-brom-3-[(4-chlorfenil)metil]-2,3,4,5-tetrahidro-1 H-1,4benzodiazepinasD. 4-Acetyl-7-bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine
Junginys C (60 mg, 0,17 mmol) ištirpinamas THF (5 ml), pridedama DIEA (30 μϊ, 0,17 mmol), o po to acetilchlorido (12 μϊ, 0,17 mmol). Tirpalas maišomas 30 min., koncentruojamas, liekana ištirpinama etilacetate (50 ml) ir tirpalas plaunamas vandeniu (3 x 20 ml). Organinis sluoksnis džiovinamas (MgSO4), ir sukoncentravus gaunamas junginys D, kuris yra šiek tiek rusva stiklo pavidalo medžiaga.Compound C (60 mg, 0.17 mmol) was dissolved in THF (5 mL), DIEA (30 μϊ, 0.17 mmol) was added followed by acetyl chloride (12 μϊ, 0.17 mmol). The solution was stirred for 30 min, concentrated, and the residue was dissolved in ethyl acetate (50 mL) and washed with water (3 x 20 mL). The organic layer is dried (MgSO 4 ) and concentrated to give compound D, which is a slightly brownish glass.
E. 4-Acetil-7-brom-3-[(4-chlorfenil)metil]-2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)E. 4-Acetyl-7-bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) )
Junginys E (balta kieta medžiaga) 13 % išeiga pagaminamas iš junginio D pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką; gryninamas preparatinės HPLC metodu (YMC S-5 ODS-A kolonėlė, 30 x 250 mm; tirpiklis A: 0,1 % TFA 90 % vandens ir 10 % metanolio mišinyje; tirpiklis B: 0,1 % TFA 10 % vandens ir 90 % metanolio mišinyje; 20-100 % B per 60 min, srauto greitis 25 ml/min) ir paverčiamas HCI druska, pridedant 1N HCI į jo TFA druskos tirpalą metanolyje ir liofilizuojant.Compound E (white solid) is prepared in 13% yield from Compound D according to the procedure for Compound D described in Example 1; Purification by preparative HPLC (YMC S-5 ODS-A column, 30 x 250 mm; solvent A: 0.1% TFA in 90% water and 10% methanol; solvent B: 0.1% TFA in 10% water and 90% methanol mixture; 20-100% B over 60 min, flow rate 25 mL / min) and converted to the HCl salt by adding 1N HCl to its TFA salt solution in methanol and lyophilizing.
MS (M + H)+475.MS (M + H) + 475.
Ή-BMR (CDaOD, 400 MHz) δ 8,85 (1H, s), 7,49-7,15 (7H, m), 6,81 (1H, m),4,60 (2H, m), 4,49-4,35 (2H, m), 3,63 (1H, m), 2,84-2,63 (2H, m), 2,07 (2H, m), 1,94 (3H, s).1 H-NMR (CD a OD, 400 MHz) δ 8.85 (1H, s), 7.49-7.15 (7H, m), 6.81 (1H, m), 4.60 (2H, m), 4.49-4.35 (2H, m), 3.63 (1H, m), 2.84-2.63 (2H, m), 2.07 (2H, m), 1.94 (3H, s).
pavyzdys <z example < z
NN
HH
NN
MeMe
130130
4-Acetil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)1 H-nafto[2,3-e]-1,4-diazepinas (monohidrochloridas)4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine (monohydrochloride) )
A. 2,3,4,5-tetrahidro-3-(fenilmetil)-1H-nafto[2,3-e]-1,4-diazepin-2,5dionasA. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine-2,5dione
Izatoinės rūgšties anhidrido 2,3-naftil-analogo (pagaminto iš 3-amino2-naftalenkarboksirūgšties, 2,3 ekv. trifosgeno ir trietilamino acetonitrile), D,Lfenilalanino (0,77 g, 4,7 mmol) ir piridino hidrochlorido (540 mg, 4,7 mmol) tirpalas piridine (60 ml) virinamas su gržtamu šaldytuvu 20 vai. azoto atmosferoje, o po to sukoncentruojamas iki alyvos pavidalo liekanos. Įpilama vandens (100 ml), ir trinant tirpalą, gaunama ruda kieta medžiaga. Ši medžiaga nufiltruojama, džiovinama giliame vakuume ir gaunama 1,3 g (87 %) junginio A, kuris yra ruda kieta medžiaga. MS (M + H)+ 317.Isatoic acid anhydride 2,3-naphthyl analogue (made from 3-amino2-naphthalenecarboxylic acid, 2.3 equiv. Of triphosgene and triethylamine in acetonitrile), D, L-phenylalanine (0.77 g, 4.7 mmol) and pyridine hydrochloride (540 mg) (4.7 mmol) in pyridine (60 mL) was refluxed for 20 h. under nitrogen and then concentrated to an oil residue. Water (100 mL) was added and the solution was triturated to give a brown solid. This material was filtered off, dried in a deep vacuum to give 1.3 g (87%) of Compound A as a brown solid. MS (M + H) + 317.
B. 4-Acetii-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)1 H-nafto[2,3-e]-1,4-diazepinas (monohidrochloridas) pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš junginio A pagal metodikas, naudojamas šiems junginiams gauti: 80 pavyzdžio junginiui C: 80 pavyzdžio junginiui D, maišant 1 vai. ir gryninant sparčiosios chromatografijos metodu per silikagelį, kuris eliuuojamas etilacetatu:heksanais (1:5 -1:1); 80 pavyzdžio junginiui E.B. 4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine (monohydrochloride) Example compound (off-white solid) is prepared from Compound A according to the procedures used to prepare the following compounds: Example 80 Compound C: Example 80 Compound D, with stirring for 1 hour. and purification by flash chromatography on silica gel eluting with ethyl acetate: hexanes (1: 5 to 1: 1); Example 80 for compound E.
MS(M + H)+411.MS (M + H) + 411.
Analizė išskaičiuota pagal C26H26N4O 1,19 H2O · 1,5 HCl.Analysis calculated for C 26 H 26 N 4 O 1.19 H 2 O · 1.5 HCl.
Išskaičiuota: C, 64,44; H, 6,17, N, 11,02; Cl, 10,71.Found: C, 64.44; H, 6.17; N, 11.02; Cl, 10.71.
Rasta: C, 64,04; H, 6,38; N,-11,40; Cl, 10,90.Found: C, 64.04; H, 6.38; N, -11.40; Cl, 10.90.
pavyzdysexample
131131
N-Cikloheksil-N’-[2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepin-8-il]karbamidas (dihidrochloridas) pavyzdžio junginys pagaminamas iš cikloheksilizocianato pagal 66 pavyzdyje aprašytą metodiką; kolonėlių chromatografijoje eliuuojama CHCI3/CH3OH (19/1, po to 9/1).N-Cyclohexyl-N '- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] urea (dihydrochloride) Example compound is prepared from cyclohexyl isocyanate according to the procedure described in Example 66; column chromatography eluted with CHCl 3 / CH 3 OH (19/1 then 9/1).
MS (M + H)+ 523.MS (M + H) < + > 523.
1H-BMR (270 MHz, CD3OD) δ 8,83 (d, 1H, J = 19 Hz), 8,0-7,89 (m, 2,5H), 7,63-7,3 (m, 6,5H), 7,23 (d, 0,5H, J = 7 Hz), 6,8 (d, 0,5H, J = 8 Hz), 6,31 (d, 0,5H, J = 7 Hz), 5,83 (d, 0,5H, J = 8 Hz), 4,8 (s, 1H), 4,6-3,8 (m, 4H), 3,6-3,5 (m, 1H), 3,45-3,3 (m, 2H), 3,0-2,8 (m, 1H), 1,9-1,58 (m, 5H), 1,48-1,13 (m, 5H). 1 H-NMR (270 MHz, CD 3 OD) δ 8.83 (d, 1H, J = 19 Hz), 8.0-7.89 (m, 2.5H), 7.63-7.3 ( m, 6.5H), 7.23 (d, 0.5H, J = 7Hz), 6.8 (d, 0.5H, J = 8Hz), 6.31 (d, 0.5H, J = 7Hz), 5.83 (d, 0.5H, J = 8Hz), 4.8 (s, 1H), 4.6-3.8 (m, 4H), 3.6-3.5 (m, 1H), 3.45-3.3 (m, 2H), 3.0-2.8 (m, 1H), 1.9-1.58 (m, 5H), 1.48-1. 13 (m, 5H).
NN
HH
132132
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(fenilmetil)-l H-nafto[2,3-e]-1,4-diazepinas (monohidrochloridas) pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine (monohydrochloride) Example compound (off-white solid) is prepared from
2,3,4,5-tetrahidro-3-(fenilmetil)-1H-nafto[2,3-e]-1,4-diazepino (pagaminto taip, kaip aprašyta 81 pavyzdyje) pagal 78 pavyzdyje aprašytą metodiką.2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine (prepared as described in Example 81) according to the procedure described in Example 78.
MS (M + H)+ 447.MS (M + H) + 447.
1H-BMR (CDCb, 400 MHz) δ 8,72 (1H, m), 7,7-7,1 (12H, m), 5,01 (1H, m), 4,43 (1H, s), 4,41 (1H, s), 3,62 (1H, m), 3,15 (1H, m), 2,95 (1H, m), 2,72 (1H, m), 2,3 (3H, s). 1 H-NMR (CDCl 3, 400 MHz) δ 8.72 (1H, m), 7.7-7.1 (12H, m), 5.01 (1H, m), 4.43 (1H, s) , 4.41 (1H, s), 3.62 (1H, m), 3.15 (1H, m), 2.95 (1H, m), 2.72 (1H, m), 2.3 ( 3H, s).
2,2-DimetiI-N-[2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftaleniikarbonil)-1H-1,4-benzodiazepin-8-il]propanamidas (dihidrochloridas) pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš 26 pavyzdžio junginio ir pivaloilo .chlorido pagal 27 pavyzdyje aprašytą metodiką.2,2-Dimethyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepin-8-yl] propanamide (dihydrochloride) Example compound (white solid) is prepared from Example 26 compound and pivaloyl chloride according to the procedure described in Example 27.
MS (M + H)+ 482.MS (M + H) < + > 482.
1H-BMR (270 MHz, CD3OD) δ 8,88 (d, 1H, J = 20 Hz), 8,05-7,89 (m, 2H), 7,87,4 (m, 6,5H), 7,35 (d, 0,5H, J = 7 Hz), 7,22 (d, 0,5H, J = 7 Hz), 7,1 (d, 0,5H, 1 H-NMR (270 MHz, CD 3 OD) δ 8.88 (d, 1H, J = 20 Hz), 8.05-7.89 (m, 2H), 7.87.4 (m, 6, 5H), 7.35 (d, 0.5H, J = 7Hz), 7.22 (d, 0.5H, J = 7Hz), 7.1 (d, 0.5H,
J = 8 Hz), 6,6 (d, 0,5H, J = 8 Hz), 5,9 (d, 0,5H, J = 8 Hz), 4,6 (s, 1H), 4,5 (m,J = 8Hz), 6.6 (d, 0.5H, J = 8Hz), 5.9 (d, 0.5H, J = 8Hz), 4.6 (s, 1H), 4.5 (m,
2H), 4,22-3,9 (m, 2H), 3,4-3,3 (m, 2H), 3,05-2,85 (kv, 1H), 1,3 (d, 9H, J = 162H), 4.22-3.9 (m, 2H), 3.4-3.3 (m, 2H), 3.05-2.85 (s, 1H), 1.3 (d, 9H, J = 16
Hz).Hz).
133133
2,3,4,5-Tetrahidro-1-(1H-imidazoi-4-ilmetil)-4-(1-naftalenilsulfonil)-7-fenil1 H-1,4-benzodiazepinas (monohidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylsulfonyl) -7-phenyl-1H-1,4-benzodiazepine (monohydrochloride)
A. 2,3,4,5-Tetrahidro-4-(1-naftalenilsulfonil)-7-fenil-1H-1,4benzodiazepinasA. 2,3,4,5-Tetrahydro-4- (1-naphthalenylsulfonyl) -7-phenyl-1H-1,4-benzodiazepine
J 12 pavyzdžio junginio B (500 mg, 2,2 mmol) tirpalą dichlormetane (20 ml) pridedama 1 -naftilsulfonilchlorido (500 mg, 2,2 mmol) ir trietilamino (0,31 ml, 2,2 mmol). Tirpalas maišomas 1 vai., po to koncentruojamas, Liekana paskirstoma tarp sotaus vandeninio natrio rūgščiojo karbonato (30 ml) ir etilacetato (40 ml). Organinis sluoksnis plaunamas sočiu vandeniniu natrio rūgščiuoju karbonatu (2 x 30 ml), vandeniu (1 x 30 ml), 1M kalio rūgščiuoju sulfatu (3 x 30 ml), džiovinamas (Na2SO4), ir sukoncentravus gaunama 800 mg (88 %) junginio A, kuris yra balta kieta medžiaga. MS (M + H)+ 415,2.To a solution of Example 12 Compound B (500 mg, 2.2 mmol) in dichloromethane (20 mL) was added 1-naphthylsulfonyl chloride (500 mg, 2.2 mmol) and triethylamine (0.31 mL, 2.2 mmol). The solution is stirred for 1 h, then concentrated, and the residue is partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (40 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (2 x 30 mL), water (1 x 30 mL), 1M potassium bisulfate (3 x 30 mL), dried (Na 2 SO 4 ), and concentrated to give 800 mg (88%). ) of compound A which is a white solid. MS (M + H) + 415.2.
B. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilsuIfonil)-7fenil-1 H-1,4-benzodiazepinas (monohidrochloridas) pavyzdžio junginys (nelabai balta kieta medžiaga) 83 % išeiga pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D sintezės metodiką.B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylsulfonyl) -7-phenyl-1H-1,4-benzodiazepine (monohydrochloride) Example compound (off-white) solid) in 83% yield from Compound A according to the synthesis procedure for Compound D described in Example 1.
MS (M + H)+ 415.MS (M + H) < + > 415.
Ή-BMR (CD3OD, 270 MHz) δ 8,83 (1H, s), 8,5 (1H, m), 8,24 (1H, d, J = 81 H-NMR (CD 3 OD, 270 MHz) δ 8.83 (1H, s), 8.5 (1H, m), 8.24 (1H, d, J = 8
Hz), 8,11 (1H, J = 8 Hz), 7,94 (1H, m), 7,61-7,25 (9H, m), 7,02 (1H, d, J = 8Hz), 8.11 (1H, J = 8 Hz), 7.94 (1H, m), 7.61-7.25 (9H, m), 7.02 (1H, d, J = 8
Hz), 4,61 (2H, s), 4,41 (2H, s), 3,52 (2H, m), 3,09 (2H, m).Hz), 4.61 (2H, s), 4.41 (2H, s), 3.52 (2H, m), 3.09 (2H, m).
134 pavyzdysExample 134
BrBr
4-Acetil-7-brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(2naftalenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas) pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš D.L-2naftilalanino pagal 80 pavyzdyje aprašytą metodiką.4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (2-naphthalenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (white) solid) prepared from DL-2-naphthylalanine according to the procedure described in Example 80.
MS (M + H)+ 475.MS (M + H) + 475.
1H-BMR (CD3OD, 400 MHz) δ 8,81 (1H, s), 7,84 (4H, m), 7,70 (1H, m), 7,507,25 (5H, m), 6,87 (1H, m), 4,73-4,54 (3H, m), 4,43 (1H, m), 3,73 (1H, m), 3,23 (1H, m), 3,05 (1H, m), 2,93 (1H, m), 2,13 (1H, m), 2,05 (3H, s). 1 H-NMR (CD 3 OD, 400 MHz) δ 8.81 (1H, s), 7.84 (4H, m), 7.70 (1H, m), 7.507.25 (5H, m), δ , 87 (1H, m), 4.73-4.54 (3H, m), 4.43 (1H, m), 3.73 (1H, m), 3.23 (1H, m), 3, 05 (1H, m), 2.93 (1H, m), 2.13 (1H, m), 2.05 (3H, s).
pavyzdysexample
BrBr
4-Acetil-7-brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(1naftalenilmetil)-1 H-1,4-benzodiazepinas (dihidrochloridas)4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (1-naphthalenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
135 pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš D.L-1naftilalanino pagal 80 pavyzdyje aprašytą metodiką.Example 135 (white solid) is prepared from D.L-1-naphthylalanine according to the procedure described in Example 80.
MS (M + H)+ 475.MS (M + H) + 475.
1H-BMR (CD3OD, 400 MHz) δ 8,53 (1H, s), 7,87 (1H, m), 7,74 (1H, m), 7,557,23 (8H, m), 6,74 (1H, m), 4,57-4,43 (2H, m), 4,15 (1H, m), 3,90 (1H, m), 3,83 (1H, m), 3,48 (2H, m), 3,12 (1H, m), 3,00 (1H, m), 2,06 (2H, m), 2,01 (3H, s). 1 H-NMR (CD 3 OD, 400 MHz) δ 8.53 (1H, s), 7.87 (1H, m), 7.74 (1H, m), 7,557.23 (8H, m), δ , 74 (1H, m), 4.57-4.43 (2H, m), 4.15 (1H, m), 3.90 (1H, m), 3.83 (1H, m), 3, 48 (2H, m), 3.12 (1H, m), 3.00 (1H, m), 2.06 (2H, m), 2.01 (3H, s).
7-(2-Chlorfenil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepinas (dihidrochloridas)7- (2-Chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)
A. 2-Chlorbenzenboro rūgštisA. 2-Chlorobenzeneboronic acid
J 2-bromchlorbenzeno (5,4 ml, 46 mmol) ir magnio (drožlės, 1,12 g, 46 mmol) mišinį lėtai pridedama borano-THF (100 ml, 100 mmol). Kolba patalpinama j vandens vonią ir per naktį veikiama ultragarsu. Borano pertekliui suardyti lėtai pilamas vanduo (30 ml). Vandeninis tirpalas virinamas su grįžtamu šaldytuvu 2 vai. Tirpiklis nugarinamas, o liekana neutralizuojama vandeniniu HCI, Vandeninis titpalas ekstrahuojamas eteriu (2 x 50 ml), džiovinamas (Na2SO4), ir nugarinus gaunamas junginys A (6,24 g, 86 %).A mixture of 2-bromo-chlorobenzene (5.4 mL, 46 mmol) and magnesium (chips, 1.12 g, 46 mmol) was added slowly to borane-THF (100 mL, 100 mmol). Place the flask in a water bath and sonicate overnight. Slowly add water (30 ml) to destroy the excess borane. The aqueous solution is refluxed for 2 hours. The solvent was evaporated and the residue was neutralized with aqueous HCl, the aqueous title was extracted with ether (2 x 50 mL), dried (Na 2 SO 4 ), and evaporated to give Compound A (6.24 g, 86%).
B. 7-(2-Chlorfenil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (dihidrochloridas)B. 7- (2-Chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)
136 pavyzdžio junginys (pilka kieta medžiaga) 55 % išeiga pagaminamas iš junginio A ir 37 pavyzdžio junginio A pagal 60 pavyzdyje aprašytą metodiką.Example 136 Compound (gray solid) is prepared in 55% yield from Compound A and Example 37 Compound A according to the procedure described in Example 60.
MS (M + H)+ 493.MS (M + H) < + > 493.
’H-BMR (CDsOD, 300 MHz) δ 2,95 (pi.m, 1H), 3,30 (m, 1 H), 4,00 (pl.s, 1H), 4,20 (pl.s, 1H), 4,40 (pi.d, 1H), 4,60 (m, 1H), 4,65 (m, 1H), 5,05 (s, 1H), 6,05 (d, 1H), 7,00 (d, 1H), 7,15-8,10 (m, 13H), 8,85 (s, 1H), 8,95 (s, 1H).1 H-NMR (CDsOD, 300 MHz) δ 2.95 (ppm, 1H), 3.30 (m, 1H), 4.00 (ppm, 1H), 4.20 (ppm) , 1H), 4.40 (pi.d, 1H), 4.60 (m, 1H), 4.65 (m, 1H), 5.05 (s, 1H), 6.05 (d, 1H) , 7.00 (d, 1H), 7.15-8.10 (m, 13H), 8.85 (s, 1H), 8.95 (s, 1H).
2,3,4,5-Tetrahidro-1-(1 H-imidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepinas (monohidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (monohydrochloride)
2,3,4,5-T etrahi dro-4- [(1,1 -di metiletoksi)-karbonil ]-7-feni I-1 H-1,4benzodiazepino (pagaminto iš 12 pavyzdžio junginio B pagal 4 pavyzdyje aprašytą junginio A sintezės metodiką, 0,20 g) ir 4-formilimidazolo (0,52 g, 5,6 mmol) tirpalas CH2CI2 (10 ml) ir acto rūgštis (2 ml) maišomas 40 min. Pridedama natrio triacetoksiborhidrido (0,9 g, 6 mmol) ir vėl maišoma 4 vai. Pridedama natrio rūgščiojo karbonato (sotus, 5 ml) ir amonio hidroksido (kone. 5 ml), ir mišinys maišomas dar 3 vai. Vandeninis sluoksnis ekstrahuojamas CH2CI2 (3 x 50 ml). Sumaišyti organiniai sluoksniai plaunami 1N NaOH (2 x 10 ml) ir kone. NH4OH (10 ml), džiovinami (Na2SO4) ir nugarinami. Likusi kieta medžiaga maišoma MeOH (5 ml) ir vandeniniame HCI dioksane (4M, 10 ml) per naktį. Tirpiklis nugarinamas, o liekana trinama su CHCI3 ir gaunama kieta medžiaga (0,35 g), kuri gryninama preparatinės HPLC metodu (metanolio/vandens su 0,1 % TFA gradientas) ir paverčiama j2,3,4,5-Tetrahydro-4 - [(1,1-dimethylethoxy) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (prepared from Example 12, Compound B according to Example 4). For synthesis A, a solution of 0.20 g) and 4-formylimidazole (0.52 g, 5.6 mmol) in CH 2 Cl 2 (10 mL) and acetic acid (2 mL) was stirred for 40 min. Sodium triacetoxyborohydride (0.9 g, 6 mmol) was added and stirred again for 4 h. Sodium bicarbonate (saturated, 5 ml) and ammonium hydroxide (almost 5 ml) are added and the mixture is stirred for a further 3 hours. The aqueous layer was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic layers were washed with 1N NaOH (2 x 10 mL) and nearly. NH 4 OH (10 mL), dried (Na 2 SO 4 ) and evaporated. The remaining solid was stirred in MeOH (5 mL) and aqueous HCl in dioxane (4M, 10 mL) overnight. The solvent was evaporated and the residue triturated with CHCl 3 to give a solid (0.35 g) which was purified by preparative HPLC (gradient of methanol / water with 0.1% TFA) to
137137
HCI druską, liofilizuojant iš 1M HCI (5 ml). Gaunamas 89 pavyzdžio junginys (0,12 g, 57 %), kuris yra nelabai balta kieta medžiaga.HCl salt by lyophilization from 1M HCl (5 mL). Example 89 is obtained (0.12 g, 57%) which is an off-white solid.
MS (M + H)+305.MS (M + H) + 305.
1H-BMR (CD3OD): 3,26 (m, 4H), 4,45 (s, 2H), 4,62 (s, 2H), 7,2-7,8 (m, 10H), 1 H-NMR (CD 3 OD): 3.26 (m, 4H), 4.45 (s, 2H), 4.62 (s, 2H), 7.2-7.8 (m, 10H),
8,95 (s, 1H).8.95 (s, 1H).
pavyzdysexample
1-Metil-N-[2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepin-8-il]-2-piperidinkarboksamidas (trihidrochloridas) pavyzdžio junginys (gelsva kieta medžiaga) pagaminamas iš 26 pavyzdžio junginio ir N-metiipipekolino rūgšties pagal 62 pavyzdyje aprašytą metodiką.1-Methyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -2- piperidine carboxamide (trihydrochloride) Example compound (yellowish solid) is prepared from Example 26 compound and N-methylpipecolic acid according to the procedure described in Example 62.
MS (M + H)+ 523.MS (M + H) < + > 523.
1H-BMR (270 MHz, CD3OD): δ 8,9 (d, 1H, J = 22 Hz), 8,08-7,88 (m, 2,5H), 7,7-7,2 (m, 6H), 6,8 (d, 0.5H), 5,9 (m, 0,5H), 5,0 (m, 1,5H), 4,6 (s, 1H), 4,5 (m,2H), 4,3-4,1 (m, 1H), 4,05-3,9 (m, 1H), 3,6-2,7 (m, 8H), 2,3 (t, 1H), 2,051,56 (m, 3H), 1,5-0,8 (m, 3H). 1 H-NMR (270 MHz, CD 3 OD): δ 8.9 (d, 1H, J = 22 Hz), 8.08-7.88 (m, 2.5H), 7.7-7.2 (m, 6H), 6.8 (d, 0.5H), 5.9 (m, 0.5H), 5.0 (m, 1.5H), 4.6 (s, 1H), 4.5 (m, 2H), 4.3-4.1 (m, 1H), 4.05-3.9 (m, 1H), 3.6-2.7 (m, 8H), 2.3 (t , 1H), 2,051.56 (m, 3H), 1.5-0.8 (m, 3H).
pavyzdysexample
138138
N-[2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftaIenilkarbonil)-1H-1,4-benzodiazepin-8-il]-4-morfolinkarboksamidas (dihidrochloridas) pavyzdžio junginys (gelsva kieta medžiaga) pagaminamas iš 26 pavyzdžio junginio ir morfolin-N-karbonilchlorido pagal 27 pavyzdyje aprašytą metodiką.N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -4-morpholinecarboxamide (dihydrochloride) Example 24 (yellowish solid) is prepared from Example 26 and morpholine-N-carbonyl chloride according to the procedure described in Example 27.
MS (M + H)+ 511.MS (M + H) <+> 511.
1H-BMR (270 MHz, CD3OD): δ 8,88 (kv, 1H), 8,1-7,88 (m, 2,5H), 7,7-7,3 (m, 6,5H), 7,2 (t, 0,5H), 6,9 (d, 0,5H), 6,5 (d, 0,5H), 5,85 (d, 0,5H), 5,08-4,9 (m, 2H), 4,6-4,15 (m, 4H), 3,7-3,65 (m, 3H), 3,6-3,4 (m, 4H), 3,4-3,28 (m, 2H), 3,15-2,8 (m, 1H). 1 H-NMR (270 MHz, CD 3 OD): δ 8.88 (kv, 1H), 8.1-7.88 (m, 2.5H), 7.7-7.3 (m, 6, 5H), 7.2 (t, 0.5H), 6.9 (d, 0.5H), 6.5 (d, 0.5H), 5.85 (d, 0.5H), 5.08 -4.9 (m, 2H), 4.6-4.15 (m, 4H), 3.7-3.65 (m, 3H), 3.6-3.4 (m, 4H), 3 , 4-3.28 (m, 2H), 3.15-2.8 (m, 1H).
pavyzdysexample
N-[2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepin-8-il]-3-metilbutanamidas (dihidrochloridas)N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -3-methylbutanamide (dihydrochloride)
139 pavyzdžio junginys (gelsva kieta medžiaga) 67 % išeiga pagaminamas iš 26 pavyzdžio junginio ir izobutirilchlorido pagal 27 pavyzdyje aprašytą metodiką, išskyrus tai, kad reakcijos mišinys koncentruojamas tada, kai nebesimato pradinės medžiagos; liekana veikiama MeOH ir 1N NaOH 30 min., ir po apdorojimo, produktas veikiamas HCI/eteryje.Example 139 Compound (yellowish solid) 67% yield is prepared from Example 26 and isobutyryl chloride according to the procedure described in Example 27 except that the reaction mixture is concentrated when the starting material is no longer visible; the residue was treated with MeOH and 1N NaOH for 30 min and after treatment the product was treated with HCl / ether.
MS (M+H)+ 482.MS (M + H) < + > 482.
1H-BMR (270 MHz, CD3OD): δ 8,88 (d, 1H, J = 21 Hz), 8,08-7,9 (m, 2,5H), 7,7-7,19 (m, 6,5H), 6,81 (d, 0,5H), 5,9 (d, 0,5H), 4,9 (m, 1H), 4,6-3,9 (m, 4H), 1 H-NMR (270 MHz, CD 3 OD): δ 8.88 (d, 1H, J = 21 Hz), 8.08-7.9 (m, 2.5H), 7.7-7.19 (m, 6.5H), 6.81 (d, 0.5H), 5.9 (d, 0.5H), 4.9 (m, 1H), 4.6-3.9 (m, 4H) ),
3,6-3,08 (m, 2H), 3,0-2,76 (m, 4H), 2,3 (m, 1H), 2,05-1,5 (m, 3H), 1,45-0,8 (m, 3H).3.6-3.08 (m, 2H), 3.0-2.76 (m, 4H), 2.3 (m, 1H), 2.05-1.5 (m, 3H), 1, 45-0.8 (m, 3H).
1,2,3,4-Tetrahidro-4-[(1H-imidazol-4-il)metil]-1-(naftalen-1ilsulfonil)chinoksalinas (dihidrochloridas)1,2,3,4-Tetrahydro-4 - [(1H-imidazol-4-yl) methyl] -1- (naphthalen-1-ylsulfonyl) quinoxaline (dihydrochloride)
A. 1,2,3,4-Tetrahidro-1-(naftalen-1-ilsulfonil)chinoksalinas j 3 pavyzdžio junginio A (270 mg, 2 mmol) tirpalą dichlormetane (8 mi) kambario temperatūroje, argono atmosferoje pridedama trietilamino (0,42 ml, 3 mmol) ir naftalensulfonilchlorido (500 mg, 2,2 mmol). Po 18 vai. mišinys plaunamas sočiu NaHCO3, po to sočiu NaCl (kiekvieno po 10 ml), džiovinamas (MgSO4) ir koncentruojamas, j likusią geltoną kietą medžiagą pridedama dichlormetano (1 ml), ir junginys A iškristalinamas. Tirpalas gryninamas chromatografuojant per silikgelio kolonėlę, kuri eliuuojama 30 %A. 1,2,3,4-Tetrahydro-1- (naphthalen-1-ylsulfonyl) quinoxaline To a solution of Example 3 Compound A (270 mg, 2 mmol) in dichloromethane (8 mL) at room temperature under argon was added triethylamine (0, 42 mL, 3 mmol) and naphthalenesulfonyl chloride (500 mg, 2.2 mmol). After 18 or. the mixture was washed with saturated NaHCO 3 followed by saturated NaCl (10 mL each), dried (MgSO 4 ), and concentrated to a yellow solid, dichloromethane (1 mL) was added and compound A crystallized. The solution is purified by column chromatography over silica eluting with 30%
140 etilacetatu heksanuose, ir dar gaunama junginio A. Bendra išeiga 560 mg, 87 %. MS: (M + H)+ = 325+.140 ethyl acetate in hexanes to give compound A. Total yield 560 mg, 87%. MS: (M + H) < + > = 325 + .
B. 1,2,3,4-Tetrahidro-4-[(1H-imidazol-4-il)metil]-1-(naftalen-1ilsulfonil)chinoksalinas (dihidrochloridas) pavyzdžio junginys (šiek tiek gelsva kieta medžiaga) pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką. Išgryninus sparčiosios chromatografijos per silikagelio kolonėlę metodu, eliuuojant 9:1 CHCI3:MeOH, gaunama kieta medžiaga, kuri paverčiama HCI druska, veikiant 1M HCI eteryje (95 mg, 80 %).B. 1,2,3,4-Tetrahydro-4 - [(1H-imidazol-4-yl) methyl] -1- (naphthalen-1-ylsulfonyl) quinoxaline (dihydrochloride) Example compound (slightly yellow solid) is prepared from the compound A according to the procedure for the preparation of compound D described in Example 1. Purification by flash column chromatography on silica gel eluting with 9: 1 CHCl 3 : MeOH afforded a solid which was converted to the HCl salt by treatment with 1M HCl in ether (95 mg, 80%).
MS (M+Hf 405.MS (M + H + = 405).
1H-BMR (laisva bazė) (CDCI3): δ 8,22 (1H, d, J = 7,3 Hz), 8,15 (1H, d, J = 8 Hz), 8,02 (1H, d, J = 8Hz), 7,87 (1H, d, J = 7,3 Hz), 7,49 (2H, t, J d 8Hz), 7,39 (1H, s), 7,37 (1H, s), 7,31 (1H, t, J = 7,3 Hz), 7,26 (1H, s), 7,02 (1H, t, J = 7,3 Hz), 6,65 (1H, t, J = 7,3 Hz), 6,54 (1H, d, J = 8,0 Hz), 6,0 (1H, s), 4,0 (2H, s), 3,83 (2H, t, J = 5,3 Hz), 2,85 (2H, t, J = 5,3 Hz). 1 H-NMR (free base) (CDCl 3 ): δ 8.22 (1H, d, J = 7.3 Hz), 8.15 (1H, d, J = 8 Hz), 8.02 (1H, d, J = 8Hz), 7.87 (1H, d, J = 7.3Hz), 7.49 (2H, t, Jd 8Hz), 7.39 (1H, s), 7.37 (1H , s), 7.31 (1H, t, J = 7.3 Hz), 7.26 (1H, s), 7.02 (1H, t, J = 7.3 Hz), 6.65 (1H , t, J = 7.3 Hz), 6.54 (1H, d, J = 8.0 Hz), 6.0 (1H, s), 4.0 (2H, s), 3.83 (2H) , t, J = 5.3 Hz), 2.85 (2H, t, J = 5.3 Hz).
pavyzdysexample
NN
HH
1,2,3,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-N,N,7-trifenil-4H-1,4benzodiazepin-4-karboksamidas (dihidrochloridas) pavyzdžio junginys (silpnai rožinės spalvos milteliai) pagaminamas iš N,N-difenilkarbamilchlorido pagal 35 pavyzdyje aprašytą metodiką. Lyd.1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N, 7-triphenyl-4H-1,4-benzodiazepine-4-carboxamide (dihydrochloride) Example compound (slightly pink powder) prepared from N, N-diphenylcarbamyl chloride according to the procedure described in Example 35. Lyd.
temp.: >200 °C.mp:> 200 ° C.
MS (M+H) + 500.MS (M + H) < + > 500.
141141
Analizė išskaičiuota pagal C32H29N5O · 0,4 H2O · 1,0 HCI. Išskaičiuota: C, 70,75; H, 5,71; N, 12,89; Cl, 6,53.Analysis calculated for C 32 H 29 N 5 O · 0.4 H 2 O · 1.0 HCl. Found: C, 70.75; H, 5.71; N, 12.89; Cl, 6.53.
Rasta: C, 70,89; H, 5,53; N, 12,77; Cl, 6,65.Found: C, 70.89; H, 5.53; N, 12.77; Cl, 6.65.
1,2,3,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4Hnafto[2,3-e]-1,4-diazepin-4-karboksirūgšties metilo esteris (monohidrochloridas) pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš metilchlorformiato pagal 83 pavyzdyje aprašytą metodiką.1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-naphtho [2,3-e] -1,4-diazepine-4-carboxylic acid methyl ester (monohydrochloride) ) The compound of Example 1 (off-white solid) is prepared from methyl chloroformate according to the procedure described in Example 83.
MS (M + H)+427.MS (M + H) < + >
1H-BMR (CD3OD, 400 MHz): δ 8,72 (1 H, m), 7,7-7,1 (12H, m), 5,01 (1H, m), 4,43 (1H, s), 4,41 (1 H, s), 3,62 (1H, m), 3,15 (1H, m), 2,95 (1H, m), 2,72 (1H, m), 2,6 (3H, s). 1 H-NMR (CD 3 OD, 400 MHz): δ 8.72 (1H, m), 7.7-7.1 (12H, m), 5.01 (1H, m), 4.43 (1H, s), 4.41 (1H, s), 3.62 (1H, m), 3.15 (1H, m), 2.95 (1H, m), 2.72 (1H, m), 2 , 6 (3H, s).
pavyzdysexample
142142
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-4-[(4-feniI-1,2,3tiadiazol-5-il)karbonil]-1 H-1,4-benzodiazepinas (trifluoracetatas) pavyzdžio junginys (baltas liofilizatas) 50 % išeiga pagaminamas iš 4-fenil-5-karboksi-1,2,3-tiadiazolo pagal 34 pavyzdyje aprašytą metodiką, išgryninant junginj preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas).2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(4-phenyl-1,2,3-thiadiazol-5-yl) carbonyl] -1H- 1,4-Benzodiazepine (trifluoroacetate) Example compound (white lyophilisate) 50% yield is prepared from 4-phenyl-5-carboxy-1,2,3-thiadiazole according to the procedure described in Example 34 by purification of the compound by preparative HPLC (0 , 1% TFA gradient).
MS (M + H)+ 493.MS (M + H) < + > 493.
Analizė išskaičiuota pagal C28H24N6OS · 0,11 H2O · 1,6 TFA.Analysis calculated for C 28 H 24 N 6 OS · 0.11 H 2 O · 1.6 TFA.
Išskaičiuota; C, 55,35; H, 3,84; N, 12,41.Excluded; C, 55.35; H, 3.84; N, 12.41.
Rasta: C, 55,28; H, 3,71; N, 12,37.Found: C, 55.28; H, 3.71; N, 12.37.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-4-[(4-fenil-1,2,3tiadiazol-5-iI)karbonil]-1 H-1,4-benzodiazepinas (trifluoracetatas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(4-phenyl-1,2,3-thiadiazol-5-yl) carbonyl] -1H- 1,4-benzodiazepine (trifluoroacetate)
143 pavyzdžio junginys (baltas liofilizatas) 6 % išeiga pagaminamas iš 2,3-metilendioksibenzenkarboksirūgšties pagal 34 pavyzdyje aprašytą metodiką, išgryninant junginį preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas).Example 143 (white lyophilisate) was prepared in 6% yield from 2,3-methylenedioxybenzoic acid according to the procedure described in Example 34 by purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA).
MS (M + H)+ 453.MS (M + H) + 453.
1H-BMR (CD3OD): 3,11 (m, 1H), 3,61 (m, 1H), 3,87 (pl.m, 2H), 4,61-4,64 (m, 2H), 5,81, 6,06 (s, 2H), 5,96 (s, 2H), 6,68-7,69 (m, 12H), 8,42 (m, 1H), 8,89 (m, 1H). 1 H-NMR (CD 3 OD): 3.11 (m, 1H), 3.61 (m, 1H), 3.87 (ppm, 2H), 4.61-4.64 (m, 2H). ), 5.81, 6.06 (s, 2H), 5.96 (s, 2H), 6.68-7.69 (m, 12H), 8.42 (m, 1H), 8.89 ( m, 1H).
pavyzdysexample
8-[[(CikIoheksilamino)karbonil]amino]-2,3,4,5-tetrahidro-1-(1H-imidazol4-ilmetil)-3-(fenilmetil)-1H-1,4-benzodiazepin-4-karboksirūgšties8 - [[(Cyclohexylamino) carbonyl] amino] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid
1,1 -dimetiletilo esteris1,1-Dimethylethyl ester
A. 2,3,4,5-Tetrahidro-3-(fenilmetil)-8-nitro-1H-1,4-benzodiazepin-2,5dionasA. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -8-nitro-1H-1,4-benzodiazepine-2,5-dione
Junginys A pagaminamas iš 7-nitroizatoinės rūgšties anhidrido ir fenilalanino pagal 1 pavyzdyje aprašytą junginio A gavimo metodiką, išskyrus tai, kad pavirinus su grįžtamu šaldytuvu 1 dieną, mišinys buvo koncentruojamas. Pridedama dimetilacetamido, ir mišinys kaitinamas 150 °C temperatūroje 4 vai., sukoncentruojamas ir pridedama vandens. Gelsvai žaliaCompound A was prepared from 7-nitroisatoic acid anhydride and phenylalanine according to the procedure described in Example 1 for the preparation of Compound A, except that after refluxing for 1 day, the mixture was concentrated. Dimethylacetamide is added and the mixture is heated at 150 ° C for 4 hours, concentrated and water is added. Yellowish-green
144 kieta medžiaga nufiltruojama, ir išdžiovinus ore, gaunamas junginys A (80 % išeiga). MS (M + H)+ 312.The 144 solid was filtered off and air-dried to give Compound A (80% yield). MS (M + H) + 312.
B. 2,3,4,5-Tetrahidro-3-(fenilmetil)-8-nitro-1H-1,4-benzodiazepinas j junginį A (7,5 g, 24,01 mmol) pridedama borano tirpalo THF (1M, 86 ml), mišinys virinamas su grįžtamu šaldytuvu 2 dienas, atšaldomas iki kambario temperatūros, parūgštinamas 3N HCI ir kaitinamas garais 30 min. Kieta medžiaga nufiltruojama, ir išdžiovinus gaunamas junginys B (3,75 g, 95 %), kuris yra gelsvai žalia kieta medžiaga. MS (M + H)+ 254. Filtratas pašarminamas 5N NaOH (pH 8-9), ekstrahuojamas CHCI3, džiovinamas MgSO4, nufiltruojamas, ir sukoncentravus gaunamas 2,3,4,5-tetrahidro-3(feni!metil)-8-amino-1 H-1,4-benzodiazepinas (1,1 g, 21 %).B. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -8-nitro-1H-1,4-benzodiazepine to compound A (7.5 g, 24.01 mmol) in borane solution THF (1M, 86 ml), the mixture was refluxed for 2 days, cooled to room temperature, acidified with 3N HCl and heated for 30 min. The solid was filtered off and dried to give Compound B (3.75 g, 95%) as a yellow-green solid. MS (M + H) + 254. The filtrate was basified with 5N NaOH (pH 8-9), extracted with CHCl 3 , dried over MgSO 4 , filtered, and concentrated to give 2,3,4,5-tetrahydro-3 (phenyl) - 8-amino-1H-1,4-benzodiazepine (1.1 g, 21%).
C. 8-Nitro-2,3,4,5-tetrahidro-3-(fenilmetil)-1H-1,4-benzodiazepin-4karboksirūgšties 1,1-dimetiletilo esteris j junginio B (2,0 g, 7 mmol) ir trietilamino (0,71 g, 7 mmol) tirpalą THF (30 ml) argono atmosferoje pridedama Boc anhidrido (1,5 g, 7 mmol). Pamaišius 6 vai., mišinys ekstrahuojamas CHCI3 (3 x 70 ml). Sumaišyti ekstraktai plaunami vandeniu (2 x 50 ml) ir sočiu NaCl (1 x 50 ml), džiovinami MgSO4, nufiltruojami ir koncentruojami. Liekana trinama su heksanu/CHCI3, ir gaunamas junginys C, kuris yra gelsvai žalia kieta medžiaga (0,89 g, 34 %). MS (M-H)'382.C. 8-Nitro-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid 1,1-dimethylethyl ester into compound B (2.0 g, 7 mmol) and of a solution of triethylamine (0.71 g, 7 mmol) in THF (30 mL) under argon was added Boc anhydride (1.5 g, 7 mmol). After stirring for 6 h, the mixture was extracted with CHCl 3 (3 x 70 mL). The combined extracts were washed with water (2 x 50 mL) and saturated NaCl (1 x 50 mL), dried over MgSO 4 , filtered, and concentrated. The residue was triturated with hexane / CHCl 3 to give Compound C as a yellow-green solid (0.89 g, 34%). MS (MH +) 382.
D. 8-Nitro-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)1H-1,4-benzodiazepin-4-karbokširūgšties 1,1-dimetiletilo esterisD. 1,1-Dimethylethyl ester of 8-nitro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid
Junginys D pagaminamas iš junginio C pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką, maišant 15 vai. MS (M + H)+ 464.Compound D is prepared from Compound C according to the procedure described in Example 1 for the preparation of Compound D with stirring for 15 hours. MS (M + H) + 464.
E. 8-Amino-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-1H1,4-benzodiazepin-4-karboksirūgšties 1,1-dimetiletilo esteris j junginio D (1,0 g, 2,15 mmol) tirpalą AcOH/H2O (16 ml, 1:1) pridedama 16 % vandeninio TiCI3 (2,66 g 15 ml H2O, 17,2 mmol). PamaišiusE. 1,1-Dimethylethyl ester of 8-amino-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine-4-carboxylic acid To a solution of compound D (1.0 g, 2.15 mmol) in AcOH / H 2 O (16 mL, 1: 1) was added 16% aqueous TiCl 3 (2.66 g in 15 mL H 2 O, 17.2 mmol). After mixing
145 min., mišinys pašarminamas 5N NaOH, pamaišomas 30 min. ir ekstrahuojamas 10 % izopropanoliu/CH2CI2. Atskiriami sluoksniai, vandeninis sluoksnis ekstrahuojamas 10 % izopropanoliu/CH2Cl2, sumaišyti organiniai sluoksniai džiovinami MgSO4, nufiltruojami ir sukoncentravus gaunamas junginys E (0,70 g, 75 %). MS (M + H)+ 434.145 min, the mixture was basified with 5N NaOH, stirred for 30 min. and extracted with 10% isopropanol / CH 2 Cl 2 . The layers were separated, the aqueous layer was extracted with 10% isopropanol / CH 2 Cl 2 , the combined organic layers were dried over MgSO 4 , filtered and concentrated to give Compound E (0.70 g, 75%). MS (M + H) + 434.
F. 8-[[(Cikloheksilamino)karbonil]amino]-2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-3-(fenilmetil)-1H-1,4-benzodiazepin-4karboksirūgštiesF. 8 - [[(Cyclohexylamino) carbonyl] amino] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid
1,1-dimetiletilo esteris1,1-Dimethylethyl ester
Junginys F pagaminamas iš junginio E pagal 27 pavyzdyje aprašytą metodiką, naudojant cikloheksilizocianatą. Reakcijos mišinys koncentruojamas, ir liekana veikiama 1N NaOH ir MeOH. Pamaišius 30 min., mišinys praskiedžiamas CHCI3 ir NaHCO3. Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas du kartus CHCI3. Sumaišyti organiniai sluoksniai plaunami vandeniu, sočiu NaCl, džiovinami MgSO4, nufiltruojami ir sukoncentravus gaunamas 98 pavyzdžio junginys, kuris yra gelsva kieta medžiaga. MS: [M + H]+ = 559+.Compound F is prepared from compound E according to the procedure described in Example 27 using cyclohexyl isocyanate. The reaction mixture was concentrated and the residue was treated with 1N NaOH and MeOH. After stirring for 30 min, the mixture was diluted with CHCl 3 and NaHCO 3 . The layers were separated and the aqueous layer was extracted twice with CHCl 3 . The combined organic layers were washed with water, saturated with NaCl, dried over MgSO 4 , filtered, and concentrated to give Example 98 as a yellowish solid. MS: [M + H] + = 559 + .
MS (M + H)+ 559.MS (M + H) + 559.
146146
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-8-[[(4metilfenil)sulfonil]amino]-3-(fenilmetil)-1H-1,4-benzodiazepin-4karboksirūgšties 1,1 -dimetiletilo esteris2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -8 - [[(4-methylphenyl) sulfonyl] amino] -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid 1 , 1-dimethylethyl ester
J 8-amino-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(fenilmetil)-1 H1,4-benzodiazepin-4-karboksirūgšties 1,1-dimetiletilo esterio (pagaminto pagal 98 pavyzdyje aprašytą junginio E sintezės metodiką, 0,125 g, 0,28 mmol) ir trietilamino (0,048 ml, 0,34 mmol) tirpalą CH2CI2 (1 ml) 0 °C temperatūroje argono atmosferoje pridedama p-toluensulfonilchlorido (0,054 g, 0,34 mmol). Pamaišius 16 vai., mišinys koncentruojamas, ir liekana veikiama 1N NaOH (0,6 ml) ir MeOH (1 ml). Pamaišius 30 min., reakcijos mišinys praskiedžiamas CHCI3 (5 ml) ir NaHCO3 (3 ml). Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCI3 (2 x 20 ml). Sumaišyti organiniai sluoksniai plaunami vandeniu (1x5 ml), sočiu NaCl (1x5 ml), džiovinami MgSO4, nufiltruojami, ir sukoncentravus gaunamas 99 pavyzdžio junginys (0,15 g, 89 %), kuris yra gelsva kieta medžiaga.J 8-Amino-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine-4-carboxylic acid 1,1-dimethylethyl ester (prepared according to the procedure described in Example 98 for the synthesis of compound E, 0.125 g, 0.28 mmol) and triethylamine (0.048 mL, 0.34 mmol) in CH 2 Cl 2 (1 mL) at 0 ° C under argon was added p-toluenesulfonyl chloride ( 0.054 g, 0.34 mmol). After stirring for 16 h, the mixture was concentrated and the residue was treated with 1N NaOH (0.6 mL) and MeOH (1 mL). After stirring for 30 min, the reaction mixture was diluted with CHCl 3 (5 mL) and NaHCO 3 (3 mL). The layers were separated and the aqueous layer was extracted with CHCl3 (2 x 20 mL). The combined organic layers were washed with water (1x5 mL), saturated NaCl (1x5 mL), dried over MgSO 4 , filtered, and concentrated to give Example 99 (0.15 g, 89%) as a yellowish solid.
MS (M + H) + 588.MS (M + H) < + > 588.
100 pavyzdysExample 100
BrBr
7-Brom-1,2,3,4-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-5H-1,4benzodiazepin-5-onas (dihidrochloridas)7-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -5H-1,4-benzodiazepin-5-one (dihydrochloride)
A. 7-Brom-2,3,4,5-tetrahidro-3-(fenilmetil)-1 H-1,4-benzodiazepin-5onasA. 7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepin-5-one
147147
J 0,5 g (1,45 mmol) 75 pavyzdžio junginio A suspensiją 5 ml THF kambario temperatūroje ir argono atmosferoje pridedama 3 mi (3 mmol) 1M borano tirpalo THF. Susidaro skaidrus, ryškiai geltonas tirpalas. Maišoma per naktj, po to vėl pridedama 2 ml (2 mmol) 1M borano tirpalo THF, ir maišoma dar 8 vai. Suhidrolizavus borano perteklių lašinant metanolį, reakcijos mišinys nugarinamas iki sausos liekanos, ir liekana tirpinama 0,5 ml metanolio ir 0,5 ml kone. HCI mišinyje. Gautas tirpalas virinamas su grįžtamu šaldytuvu 2 vai., atšaldomas iki kambario temperatūros ir nugarinamas iki sausos liekanos. Liekana išskiriama iš metanolio, pridedant ir nugarinant dar tris kartus, ištirpinama etilacetate, ir tirpalas plaunamas sočiu NaCl, džiovinamas, ir nugarinus tirpiklį, gaunama klampi geltona alyva. Išgryninus sparčiosios chromatografijos per silikageij metodu, eliuavimui panaudojant 50 % etilacetatą heksane, gaunama 205 mg (0,62 mmol, 43 %) junginio A, kuris yra balta kieta medžiaga.To a suspension of 0.5 g (1.45 mmol) of Example 75 Compound A in 5 mL of THF at room temperature and under argon is added 3 mL (3 mmol) of a 1M borane solution in THF. A clear, yellow solution is obtained. Stir overnight, then add 2 mL (2 mmol) of 1M borane in THF again and stir for a further 8 h. After hydrolysis of the excess borane by dropwise addition of methanol, the reaction mixture is evaporated to dryness and the residue is dissolved in 0.5 ml methanol and 0.5 ml almost. HCl in the mixture. The resulting solution was refluxed for 2 hours, cooled to room temperature and evaporated to dryness. The residue is isolated from methanol by addition and evaporation three times, dissolved in ethyl acetate, and the solution is washed with saturated NaCl, dried and the solvent is evaporated to give a viscous yellow oil. Purification by flash chromatography on silica gel eluting with 50% ethyl acetate in hexane afforded 205 mg (0.62 mmol, 43%) of Compound A as a white solid.
B. 7-Brom-1,2,3,4-tetrahidro-1-(1 H-imidazol-4-ilmetil)-3-(fenilmetil)-5H1,4-benzodiazepin-5-onas (dihidrochloridas)B. 7-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -5H1,4-benzodiazepin-5-one (dihydrochloride)
100 pavyzdžio junginys (beveik balta kieta medžiaga) 60 % išeiga pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D sintezės metodiką, išgryninant preparatinės HPLC metodu (vandeninio metanolio su 0,1 %TFA gradientas) ir paverčiant HCI druska, veikiant HCI-MeOH.Example 100 Compound (off-white solid) is prepared in 60% yield from Compound A according to the procedure described in Example 1 for the synthesis of Compound D by purification by preparative HPLC (aqueous methanol with 0.1% TFA gradient) and conversion to the HCl salt in HCl-MeOH.
MS (M + H)+ 411.MS (M + H) + 411.
Analizė išskaičiuota pagal C2oHi9N40Br · 0,5 C2HwO · 1,5 HCI.Analysis calculated for C 2 H 9 N 4 Br · 0.5 C 2 HwO · 1.5 HCl.
Išskaičiuota: C, 52,53; H, 5,11; N, 11,14.Found: C, 52.53; H, 5.11; N, 11.14.
Rasta: C, 52,82; H, 4,7i; N, 11,52.Found: C, 52.82; H, 4.7i; N, 11.52.
101-201 pavyzdžiai101-201 Examples
Kiekvienos karboksirūgšties kopuliavimas su 33 pavyzdžio junginiu B buvo atliekamas, naudojant standartinį HOAt/DIC tarpininkaujamą kopuliavimą. Procesas buvo automatizuotas, panaudojant Hamilton 2200 skysčių manipuliatorių. Tiriamųjų mėgintuvėlių svėrimams ir gautų amidųCopulation of each carboxylic acid with Example 33 Compound B was performed using standard HOAt / DIC-mediated copulation. The process was automated using a Hamilton 2200 fluid manipulator. Test tubes for weighing and the resulting amides
148 gryninimui panaudota Zymark Benchmate® robotinis įrenginys. Zymark Benchmate® įrenginio operacinei programai valdyti ir Benchmate® metodikoms sukurti buvo naudojamas IBM PC. Standartinę amidų gavimo metodiką iliustruoja tokie pavyzdžiai:148 were cleaned using a Zymark Benchmate® robotic device. An IBM PC was used to manage the Zymark Benchmate® device operating system and to develop Benchmate® methodologies. The following examples illustrate the standard procedure for the preparation of amides:
j 16x100 mm mėgintuvėlį įdedama atitinkama karboksirūgštis (0,10 mmol, 1 ekv.) ir skysčių manipuliatoriumi su šiuo mėgintuvėliu atliekamos tokios operacijos:j Place the appropriate carboxylic acid (0.10 mmol, 1 equiv.) in a 16x100 mm tube and perform the following operations on the liquid handler:
1) pridedama 0,5 ml 0,2M 1-hidroksi-7-aza-benzotriazolo (HOAt) tirpalo DMF;1) 0.5 ml of a 0.2M solution of 1-hydroxy-7-aza-benzotriazole (HOAt) in DMF is added;
2) pridedama 0,5 ml 33 pavyzdžio junginio B (0,2 M, 0,10 mmol, 1,0 ekv.) tirpalo DMF;2) 0.5 ml of a solution of Example 33 Compound B (0.2 M, 0.10 mmol, 1.0 equiv) in DMF is added;
3) pridedama 1,0 ml diizopropilkarbodiimido (0,016 ml, 0,10 mmol, 1,0 ekv.) tirpalo metileno chloride;3) 1.0 mL of a solution of diisopropylcarbodiimide (0.016 mL, 0.10 mmol, 1.0 equiv) in methylene chloride was added;
4) mėgintuvėlio turinys sumaišomas, sukant 30 sek. 3 greičiu.4) Mix the contents of the tube by turning for 30 seconds. 3 speeds.
Po 24 vai. mišinys koncentruojamas Savant Speed Vac įtaisu (apie 2 mm Hg stulpelio 72 vai.). Liekana gryninama jonų mainų chromatografijos per kietos fazės ekstrakcijos patroną, valdomą Benchmate® robotiniu įrenginiu, metodu, naudojant tokią metodiką:After 24 or. the mixture is concentrated using a Savant Speed Vac device (about 2 mm Hg column for 72 h). The residue is purified by ion-exchange chromatography over a solid phase extraction cartridge controlled by a Benchmate® robotic apparatus using the following procedure:
1) j reakcijos mišinį pridedama 5,0 ml metanolio/metileno chlorido (1.Ί):1) Add 5.0 ml of methanol / methylene chloride (1.Ί) to the reaction mixture:
2) mėgintuvėlio turinys sumaišomas, sukant 60 sek. 3 greičiu;2) mix the contents of the tube for 60 seconds. 3 speeds;
3) Varian kietos fazės ekstrakcijos kolonėlė (1,5 g, SCX katijonitas) kondicionuojama 10 ml metanolio/metileno chlorido, leidžiant 0,15 ml/sek. greičiu;3) A Varian solid phase extraction column (1.5 g, SCX cation exchanger) is conditioned with 10 mL of methanol / methylene chloride at 0.15 mL / sec. Speed
4) reakcijos mišinys supilamas j kolonėlę, leidžiant 0,02 ml/sek. greičiu;4) Pour the reaction mixture onto the column at 0.02 mL / sec. Speed
5) kolonėlė plaunama 2 x 7,5 ml metanolio/metileno chlorido (1:1), leidžiant 0,1 ml/sek. greičiu;5) Wash the column with 2 x 7.5 mL methanol / methylene chloride (1: 1) at 0.1 mL / sec. Speed
6) kolonėlė plaunama 1 x 7,5 ml metanolio, leidžiant 0,1 ml/sek. greičiu;6) Wash the column with 1 x 7.5 mL methanol at 0.1 mL / sec. Speed
7) kolonėlė plaunama 0,01 M amoniaku metanolyje;7) washing the column with 0.01 M ammonia in methanol;
149149
8) kolonėlė eliuuojama 7,5 ml 1M amoniako metanolyje, ir eliuatas renkamas į taruotą rinktuvą 0,05 ml/sek. greičiu.8) The column is eluted with 7.5 ml of 1M ammonia in methanol and the eluate is collected in a tared trap at 0.05 ml / sec. speed.
Po bet kokio tirpalo/tirpiklio padavimo įleidžiama 1,0 ml oro, ir įleidus reakcijos mišinį į jonų mainų kolonėlę, prieš kolonėlės paleidimą naudojamas 5 sek. sulaikymas. Produkto tirpalas koncentruojamas Savant Speed Vac įtaisu (apie 2 mm Hg stulpelio 20 vai.), ir gaunamas norimas junginys.After adding any solution / solvent, 1.0 ml of air is added and the reaction mixture is introduced into the ion exchange column for 5 seconds before starting the column. detention. The product solution is concentrated using a Savant Speed Vac device (about 2 mm Hg column for 20 hours) to give the desired compound.
Sintezių, kuriose reikalingas papildomas gryninimas, atveju naudojama preparatine HPLC (YMC S5 ODS 50 x 100 mm, 30 ml/min., 10 min.trunkantis 10-90 % vandeninio metanolio su 0,1 % TFA gradientas, kontroliavimo bangos ilgis - 220 nm). Tinkamos frakcijos sumaišomos ir koncentruojamos vakuume. Liekanos ištirpinamos metanolyje (5 ml) ir 1N HCI (1 ml), ir sukoncentravus Savant Speed Vac Įtaisu (apie 2 mm Hg stulpelio 20 vai.), gaunamas norimas junginys. Šie junginiai apibūdinti analitinės HPLC ir masių spektrometrijos duomenimis.For syntheses requiring further purification, use preparative HPLC (YMC S5 ODS 50 x 100 mm, 30 ml / min, 10 min. 10-90% aqueous methanol with 0.1% TFA gradient, 220 nm control) ). Appropriate fractions were mixed and concentrated in vacuo. The residue was dissolved in methanol (5 mL) and 1N HCl (1 mL) and concentrated by Savant Speed Vac (about 2 mm Hg column for 20 h) to give the title compound. These compounds were characterized by analytical HPLC and mass spectrometry.
Pvz. Struktūra MasiųFor example, Structure of the masses
101101
102102
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil) -4-[1 -okso-3(1 -piperidinil)propil]-7-fenil-1 H2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [1-oxo-3- (1-piperidinyl) propyl] -7-phenyl-1H
1,4-benzodiazepinas (trihidrochloridas)1,4-benzodiazepine (trihydrochloride)
2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-7-fenil-4-(4chi noli ni I karbonil) -1 H-1,4benzodiazepinas (trihidrochloridas) spektras m/z 444 (M + H) m/z 460 (M + H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (4-quinolinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) m / z 444 (M + + H) m / z 460 (M + H)
150150
4-[(5-brom-3-piridinil)karbonil]4 - [(5-bromo-3-pyridinyl) carbonyl]
2.3.4.5- tetrahidro-1-(1Himidazol-4-iletil)-7-fenil-1 H-1,4benzodiazepinas (trihidrochloridas) (S)-4-[2-(dimetilamino)-1 -okso3-feniipropil]-2,3,4,5-tetrahidro1 -(1 H-imidazol-4-ilmetil)-7-fenil· 1 H-1,4-benzodiazepinas (trihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-yl-ethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) (S) -4- [2- (dimethylamino) -1-oxo-3-phenylpropyl] -2 , 3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl · 1H-1,4-benzodiazepine (trihydrochloride)
2.3.4.5- tetrahidro-4-[4-hidroksi3-(4-morfolinilmetil)benzoil]-1(1 H-i midazol-4-ilmetii)-7-fenil1 H-1,4-benzodiazepinas (trihidrochloridas) (S) -2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-4-[(1-metil-2pirolidinil)karbonil]-7-fenil-1H1,4-benzodiazepinas (trihidrochloridas)2.3.4.5-Tetrahydro-4- [4-hydroxy-3- (4-morpholinylmethyl) benzoyl] -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) (S) -2 , 3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-2-pyrrolidinyl) carbonyl] -7-phenyl-1 H -1,4-benzodiazepine (trihydrochloride)
2.3.4.5- tetrahidro-1-(1Himidazol-4-ilmetil)-7-fenil-4-[[2(propiltio)-3-piridinil]karbonil]1 H-1,4-benzodiazepinas (trihidrochloridas) m/z 489 (M+H) m/z 480 (M + H) m/z 524 (M + H) m/z 416 (M+H) m/z 484 (M + H)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [[2 (propylthio) -3-pyridinyl] carbonyl] 1H-1,4-benzodiazepine (trihydrochloride) m / z 489 (M + H) m / z 480 (M + H) m / z 524 (M + H) m / z 416 (M + H) m / z 484 (M + H)
151151
111111
112112
108108
109109
110110
4-[(2-chlor-6-metil-4piridinil)karbonil]-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (trihidrochloridas)4 - [(2-Chloro-6-methyl-4-pyridinyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-4-[[2(feniltio)-3-piridinil]karbonil]-1H1,4-benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [[2 (phenylthio) -3-pyridinyl] carbonyl] -1 H -1,4-benzodiazepine (trihydrochloride)
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-4-[[2-(4metilfenoksi)-3piri di ni I ] karboni I]-7-fenil-1 H-1,4benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-methylphenoxy) -3-pyridinyl] carbonyl] -7-phenyl-1H-1,4-benzodiazepine ( trihydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-4-[(2-metoksi3-piridinil)karbonil]-7-fenil-1H1,4-benzodiazepinas (trihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxy-3-pyridinyl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)
2.3.4.5- tetrahi dro-1 -(1Himidazol-4-ilmetil)-7-fenil-4-[(5fenil-4-oksazoli I) karbonil]-1H1,4-benzodiazepinas (dihidrochloridas) m/z 458 (M+H) m/z 518 (M + H) m/z 516 (M + H) m/z 440 (M + H) m/z 476 (M + H)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(5-phenyl-4-oxazole I) carbonyl] -1 H -1,4-benzodiazepine (dihydrochloride) m / z 458 (M +) H) m / z 518 (M + H) m / z 516 (M + H) m / z 440 (M + H) m / z 476 (M + H)
152152
115 \115 \
J°J °
4-acetil-2,3,4,5-tetrahidro-1 -(1Him i dazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-4[(tetrahidro-3-furanil)karbonil]1 H-1,4-benzodiazepinas (dihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(tetrahydro-3-furanyl) carbonyl] -1H-1,4-benzodiazepine (dihydrochloride)
2.3.4.5- tetrahidro-1-(1Himidazol-4-ilmetil)-4-[(2metoksietoksi)acetil]-7-fenil-1H1,4-benzodiazepinas (dihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxyethoxy) acetyl] -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-4-[4-(4morfolinilmetil)benzoil]-7-fenil1 H-1,4-benzodiazepinas (trihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [4- (4-morpholinylmethyl) benzoyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)
2.3.4.5- tetrahidro-1-(1Himidazol-4-iImetil)-4-[4(metilsulfonil)benzoil]-7-fenil-1H1,4-benzodiazepinas (dihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [4- (methylsulfonyl) benzoyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-4- [1 -okso-3(fenilsulfonil)propil]-7-fenil-1H1,4-benzodiazepinas (dihidrochloridas) m/z 347 (M+H) m/z 403 (M + H) m/z 421 (M + H) m/z 508 (M+H) m/z 487 (M+H) m/z 501 (M + H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [1-oxo-3- (phenylsulfonyl) propyl] -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride) m / z 347 (M + H) m / z 403 (M + H) m / z 421 (M + H) m / z 508 (M + H) m / z 487 (M + H) m / z 501 (M + H)
153153
119119
2.3.4.5- tetrahidro-l -(1Himidazol-4-ilmetil)-7-fenil-4-(3piridinilacetil)-1 H-1,4benzodiazepinas (trihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (3-pyridinylacetyl) -1H-1,4-benzodiazepine (trihydrochloride)
2.3.4.5- tetrahidro-1-(1Himidazol-4-ilmetil)-7-fenil-4-(2chinoksalinilkarbonil)-1 H-1,4benzodiazepinas (tetrahidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-quinoxalinylcarbonyl) -1H-1,4-benzodiazepine (tetrahydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-4-(4izochinolinilkarbonil)-7-fenil-1H1,4-benzodiazepinas (trihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-isoquinolinylcarbonyl) -7-phenyl-1 H -1,4-benzodiazepine (trihydrochloride)
4-[(2-chlor-3-piridinil)karbonil]2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepinas (trihidrochloridas)4 - [(2-Chloro-3-pyridinyl) carbonyl] 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)
2,3,4,5-tetrahidro-1 -(1Himidazol’4-ilmetil)-7-fenil-4-(3piridinilkarbonil)-1 H-1,4benzodiazepinas (trihidrochloridas) m/z 424 (M + H) m/z 461 (M + H) m/z 460 (M + H) m/z 444 (M + H) m/z 410 (M + H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (3-pyridinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) m / z 424 (M + H) m / z z 461 (M + H) m / z 460 (M + H) m / z 444 (M + H) m / z 410 (M + H)
154154
4-[(2,6-dimetoksi-3piridinil)karbonil]-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (trihidrochloridas)4 - [(2,6-Dimethoxy-3-pyridinyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-4-(2pi razinilkarbonil) -1 H-1,4benzodiazepinas (tetrahidrochloridas) 4-(2-etoksibenzoil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-pyrazinylcarbonyl) -1H-1,4-benzodiazepine (tetrahydrochloride) 4- (2-ethoxybenzoyl) -2, 3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-[3-(dimetilamino)benzoil]2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepinas (trihidrochloridas)4- [3- (dimethylamino) benzoyl] 2.3.4.5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)
2.3.4.5- tetrahidro-1-(1Himidazol-4-ilmetil)-7-fenil-4-[(1feni Ici klopropil) karboni I ]-1 H-1,4benzodiazepinas (dihidrochloridas) m/z 470 (M+H) m/z 411 (M+H) m/z 453 (M + H) m/z 452 (M + H) m/z 449 (M + H)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(1-phenylcyclopropyl) carbonyl] -1H-1,4-benzodiazepine (dihydrochloride) m / z 470 (M + H) m / z 411 (M + H) m / z 453 (M + H) m / z 452 (M + H) m / z 449 (M + H)
155155
131131
132132
133133
129129
130130
4-[(biciklo[4.2.0]okta-1,3,5-trien7-ii)karbonil]-2,3,4,5-tetrahidro1 -(1 H-imidazol-4-ilmetil)-7-fenil1 H-1,4-benzodiazepinas (dihidrochloridas)4 - [(Bicyclo [4.2.0] octa-1,3,5-trien-7-yl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl1 H -1,4-benzodiazepine (dihydrochloride)
4-benzoil-2,3,4,5-tetrahidro-1(1 H-imidazol-4-ilmetil)-7-fenil1 H-1,4-benzodiazepinas (dihidrochloridas)4-Benzoyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(2-chlorbenzoil)-2,3,4,5tetrahidro-1-(1H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (2-Chlorobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(2,3-dichlorbenzoil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (2,3-Dichlorobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
N-[2-[[2,3,4,5-tetrahidro-1 -(1Himidazoi-4-ilmetii)-7-fenil-1 H-1,4benzodiazepin-4il]karbonil]fenil]acetamidas (dihidrochloridas) m/z 435 (M+H) m/z 409 (M + H) m/z 443 (M + H) m/z 478 (M + H) m/z 466 (M + H)N- [2 - [[2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4yl] carbonyl] phenyl] acetamide (dihydrochloride) m / z 435 (M + H) m / z 409 (M + H) m / z 443 (M + H) m / z 478 (M + H) m / z 466 (M + H)
156156
134134
135135
136136
137137
2,3,4,5-tetrahidro-l -(1Himidazol-4-ilmetil)-4-(2fenoksibenzoil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-phenoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-4-(2metoksibenzoil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(2,3-dimetoksibenzoil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (2,3-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(2,4-dimetoksibenzoil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (2,4-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-.(2,5-dimetoksibenzoil)-2,3,4,5tetrahidro-1-(1H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas) m/z 501 (M + H) m/z 439 (M+H) m/z 469 (M + H) m/z 469 (M + H) m/z 469 (M + H)4- (2,5-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 501 (M + H) ) m / z 439 (M + H) m / z 469 (M + H) m / z 469 (M + H) m / z 469 (M + H)
138138
157157
141141
142142
139139
140140
4-(2,6-dimetoksibenzoil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (2,6-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(2,3-dihidroksibenzoil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (2,3-Dihydroxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-([1,1’-bifenil]-2-ilkarbonil)2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4 - ([1,1'-Biphenyl] -2-ylcarbonyl) 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2,3,4,5-tetrahi dro-1 -(1Himidazol-4-ilmetil)-4-(2metilbenzoil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas) m/z 469 (M + H) m/z 439 (M + H) m/z 485 (M + H) m/z 423 (M+H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methylbenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 469 (M + H) m / z 439 (M + H) m / z 485 (M + H) m / z 423 (M + H)
158158
145145
146146
143143
144144
4-(2,3-dimetilbenzoil)-2,3,4,5tetrahidro-1 - (1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (2,3-Dimethylbenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(3-cianobenzoil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (3-Cyanobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(3-chlorbenzoil)-2,3,4,5tetrahidro-1-(1H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (3-Chlorobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2.3.4.5- tetrahidro-1-(1Himidazol-4-ilmetil)-4-(3fenoksibenzoil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-phenoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-4-(3metoksibenzoil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas) m/z 437 (M+H) m/z 434 (M + H) m/z 443 (M + H) m/z 501 (M+H) m/z 439 (M + H)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-methoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 437 (M + H) m / z 434 (M + H) m / z 443 (M + H) m / z 501 (M + H) m / z 439 (M + H)
147147
159159
4-(3,4-dimetoksibenzoil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (3,4-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(3,5-dimetoksibenzoil)-2,3,4,5tetrahidro-1-(1H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (3,5-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-4-(3metilbenzoil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-methylbenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(1,2-diokso-2-feniletil)-2,3,4,5tetrah i d ro -1 - (1H-i m i d azo I-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (1,2-Dioxo-2-phenylethyl) -2,3,4,5-tetrahydro-1- (1H-imidazo-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-[(2-etoksi-1naftalenil)karbonil]-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas) m/z 469 (M + H) m/z 469 (M + H) m/z 423 (M+H) m/z 437 (M + H) m/z 503 (M+H)4 - [(2-Ethoxy-1-naphthalenyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 469 ( M + H m / z 469 (M + H) m / z 423 (M + H) m / z 437 (M + H) m / z 503 (M + H)
160160
155155
156156
153153
154154
2,3,4,5-tetrahidro-l -(1Himidazol-4-ilmetil)-4-(2naftalenilkarbonil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(fluorfenilacetil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (Fluorophenylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(difenilacetil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (Diphenylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2,3,4,5-tetrahidro-4-(2-hidroksi1 -okso-2-feniipropil)-1 -(1Himidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-4- (2-hydroxy-1-oxo-2-phenylpropyl) -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-4-(1H-indol-2ilkarbonil)-7-f enil-1 H-1,4benzodiazepinas (dihidrochloridas) m/z 459 (M + H) m/z 441 (M + H) m/z 499 (M + H) m/z 453 (M + H) m/z 448 (M + H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-2-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 459 (M + H) m / z 441 (M + H) m / z 499 (M + H) m / z 453 (M + H) m / z 448 (M + H)
157157
161161
m/z 448 (M+H)m / z 448 (M + H)
2,3,4,5-tetrahidro-l -(1 Himidazol-4-ilmetil)-4-(1H-indol-3 i I karboni I)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-3-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2,3,4,5-tetrahidro-l -(1Himidazol-4-ilmetil)-4-(1H-indol-5ilkarbonil) -7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-5-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2,3,4,5-tetrahidro-l -(1Himidazol-4-ilmetil)-4-[(1 -metil1H-indol-2-il)karbonil]-7-fenil1 H-1,4-benzodiazepinas (dihidrochloridas) benzofuranilkarbonil-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas) 2,3,4,5-tetrahidro-l -(1Himidazol-4-ilmetil)-7-fenil-4-(3pi ridi ni I karbonil) -1 H-1,4benzodiazepinas (N-oksidas, dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-1H-indol-2-yl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) Benzofuranylcarbonyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) 2,3,4,5-tetrahydro-1- (1H-imidazol-4) -ylmethyl) -7-phenyl-4- (3-pyridinylcarbonyl) -1H-1,4-benzodiazepine (N-oxide, dihydrochloride)
2,3,4,5-tetrahidro-l -(1Himidazol-4-ilmetil)-7-fenil-4-(2piridini lkarbonil)-1 H-1,4benzodiazepinas (trihidrochloridas) m/z 448 (M+H) m/z 462 (M + H) m/z 449 (M + H) m/z 426 (M+H) m/z 410 (M + H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-pyridinecarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) m / z 448 (M + H) m / z 462 (M + H) m / z 449 (M + H) m / z 426 (M + H) m / z 410 (M + H)
162162
164164
165165
2.3.4.5- tetrahidro-l -(1Himidazol-4-ilmetil)-7-fenil-4-(2chinoli nilkarbonil)-1 H-1,4benzodiazepinas (trihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-quinolylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-4-(1izochi nolinilkarbonil)-1 H-1,4benzodiazepinas (trihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (1-isoquinolinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)
166 m/z 460 (M+H) m/z 460 (M+H)166 m / z 460 (M + H) m / z 460 (M + H)
4-(3-chlor-2-nitrobenzoil)2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (3-Chloro-2-nitrobenzoyl) 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
167 m/z 488 (M + H)167 m / z 488 (M + H)
2,3,4,5-tetrahidro-1-(1 Himidazol-4-ilmetil)-4-(2nitrobenzoil)-.7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas) m/z 454 (M + H)2,3,4,5-Tetrahydro-1- (1-imidazol-4-ylmethyl) -4- (2-nitrobenzoyl) -. 7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 454 (M + H).
2,3,4,5-tetrahidro-l -(1Himidazol-4-ilmetii)-4-(3-metoksi2-nitrobenzoil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas) m/z 484 (M + H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-methoxy-2-nitrobenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 484 (M +) H)
168168
163163
m/z 448 (M + H)m / z 448 (M + H)
2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-4-(1H-indol-4 ilkarbonil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-4-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-[(2,6-dihidroksi-3naftalenil)karbonil]-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4 - [(2,6-Dihydroxy-3-naphthalenyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4-(1 H-benzimidazol-5ilkarbonil)-2,3,4,5-tetrahidro-1 (1 H-imidazol-4-ilmetil)-7-fenil1 H-1,4-benzodiazepinas (trihidrochloridas)4- (1H-Benzimidazol-5-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)
4-(1H-benzotriazol-5-ilkarbonil)2.3.4.5- tetrahidro-1-(1Hi midazol-4-i I metil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (1H-benzotriazol-5-ylcarbonyl) 2.3.4.5-tetrahydro-1- (1H-midazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-4-[(4-metoksi2-chinolinil)karbonil]-7-fenil-1H1,4-benzodiazepinas (trihidrochloridas) m/z 491 (M + H) m/z 449 (M + H) m/z 450 (M + H) m/z 490 (M + H)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4-methoxy-2-quinolinyl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) m / z 491 (M + H) m / z 449 (M + H) m / z 450 (M + H) m / z 490 (M + H)
164164
174174
175175
176176
177177
178 \178 \
N-[3-[[2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepin-4il]karbonil]fenil]-acetamidas (dihidrochloridas)N - [3 - [[2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4-yl] carbonyl] phenyl] -acetamide (dihydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-4-(2-metil-1okso-2-feni Ipropil) -7-feni 1-1H1,4-benzodiazepinas (dihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methyl-1-oxo-2-phenylpropyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride)
4-[2-(dimetilamino)benzoil]2.3.4.5- tetrahidro-1-(1 Hi midazol-4-ilmetil)-7-feni 1-1 H-1,4benzodiazepinas (trihidrochloridas)4- [2- (dimethylamino) benzoyl] 2.3.4.5-tetrahydro-1- (1H-midazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)
4-(3-etoksibenzoil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (3-Ethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2.3.4.5- tetrahidro-4-(2hidroksi[1,1 ’-bifenil]-3i Ikarbonil) -1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas) m/z 466 (M+H) m/z 451 (M+H) m/z 452 (M+H) m/z 453 (M + H) m/z 501 (M+H)2.3.4.5-Tetrahydro-4- (2-hydroxy [1,1'-biphenyl] -3i-carbonyl) -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 466 (M + H) m / z 451 (M + H) m / z 452 (M + H) m / z 453 (M + H) m / z 501 (M + H)
165165
179179
180180
2.3.4.5- tetrahidro-4-[2[(2hidroksietil)tio]benzoil]-1(1 H-imidazol-4-ilmetil)-7-fenil1 H-1,4-benzodiazepinas (dihidrochloridas)2.3.4.5-Tetrahydro-4- [2 [(2-hydroxyethyl) thio] benzoyl] -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-4-[(2-metoksi1 -naftalenil)karbonil]-7-fenil-1 H1,4-benzodiazepinas (dihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxy-1-naphthalenyl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
181 m/z 485 (M + H) m/z 489 (M+H)181 m / z 485 (M + H) m / z 489 (M + H)
2,3,4,5-tetrahidro-4-[(2-hidroksi4-chinolinil)karbonil]-1-(1Himidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-4 - [(2-hydroxy-4-quinolinyl) carbonyl] -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
182 m/z 476 (M + H)182 m / z 476 (M + H)
2-[[2,3,4,5-tetrahidro-1-(1 Himidazol-4-ilmetil) -7-fenil-1 H-1,4benzodiazepin-4il]karbonil]benzamidas (dihidrochloridas)2 - [[2,3,4,5-Tetrahydro-1- (1-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4-yl] carbonyl] benzamide (dihydrochloride)
183 m/z 452 (M + H)183 m / z 452 (M + H)
N-(1,1-dimetiletil)-2-[[2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1H-1,4benzodiazepin-4iljkarboniljbenzamidas (dihidrochloridas) m/z 508 (M + H)N - (1,1-Dimethylethyl) -2 - [[2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine-4-ylcarbonyl] -benzamide (dihydrochloride) m / z 508 (M + H)
166166
N-(4-fluorfenil)-N’-[3-[[2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinil]karbonil]feni]karbamidas (dihidrochioridas)N- (4-fluorophenyl) -N '- [3 - [[2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepinyl] carbonyl] phenyl] urea (dihydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-4-[(3-metil-4okso-2-fenil-4H-benzopiran-8il)karbonil]-7-fenil-1 H-1,4benzodiazepinas (dihidrochioridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(3-methyl-4-oxo-2-phenyl-4H-benzopyran-8yl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine ( dihydrochloride)
2.3.4.5- tetrahidro-1-(1Himidazol-4-ilmetil)-7-fenil-4-[3(trifluormetoksi)benzoil]-1 H-1,4benzodiazepinas (dihidrochioridas) 4-(2-cianobenzoil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochioridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- [3- (trifluoromethoxy) benzoyl] -1H-1,4-benzodiazepine (dihydrochloride) 4- (2-cyanobenzoyl) -2,3 , 4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2,3,4,5-tetrahidro-1-(1Himidazo!-4-ilmetil)-4-[2-[[(4metilfenil)sulfonil]amino]benzoil]-7-fenil-1 H-1,4benzodiazepinas (dihidrochioridas) m/z 561 (M+H) m/z 567 (M + H) m/z 493 (M + H) m/z 434 (M + H) m/z 578 (M + H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2 - [[(4-methylphenyl) sulfonyl] amino] benzoyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) ) m / z 561 (M + H) m / z 567 (M + H) m / z 493 (M + H) m / z 434 (M + H) m / z 578 (M + H)
167167
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-4-(6chi nol inil karbonil)-1 H-1,4benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (6-quinolinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-4-(8chinolinilkarbonii) -1 H-1,4benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (8-quinolinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)
4(benzo[b]tiofen-2-ilkarbonil)2,3,4,5-tetrahidro-1 -(1Himi dazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepinas (dihidrochloridas)4- (Benzo [b] thiophen-2-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
4[[4(dimetilamino)-1naftaIenil]karbonil]-2,3,4,5tetrahidro-1-(1H-imidazol-4ilmetil)-7-fenil-1 H-1,4benzodiazepinas (trihidrochloridas)4 - [[4- (Dimethylamino) -1-naphthalenyl] carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-4-(1Hpurin-6-iIkarbonil) -1 H-1,4benzodiazepinas (trihidrochloridas) m/z 460 (M+H) m/z 460 (M+H) m/z 465 (M + H) m/z 502 (M + H) m/z 449 (M + H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (1H-pururin-6-ylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) m / z 460 (M +). H) m / z 460 (M + H) m / z 465 (M + H) m / z 502 (M + H) m / z 449 (M + H)
168168
2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-4(metoksifenilacetil)-7-fenil-1H1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methoxyphenylacetyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride)
2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-4-[(5-metil-1fenil-1 H-pirazol-4-il)karbonil]-7fenil-1 H-1,4-benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(5-methyl-1-phenyl-1H-pyrazol-4-yl) carbonyl] -7-phenyl-1H-1,4 benzodiazepine (trihydrochloride)
2.3.4.5- tetrahidro-1-(1Himidazol-4-ilmetil)-4-[2-(2metilfenil)-1 -oksopropil]-7-fenil1 H-1,4-benzodiazepinas (dihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (2-methylphenyl) -1-oxopropyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-4[(tetrahidro-4-fenil-2H-piran-4il)karbonil]-1 H-1,4benzodiazepinas (dihidrochloridas)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(tetrahydro-4-phenyl-2H-pyran-4yl) carbonyl] -1H-1,4-benzodiazepine (dihydrochloride)
2.3.4.5- tetrahidro-1-(1Himidazol-4-ilmetil)-4-[2(metilfenilamino)benzoil]-7-fenil1 H-1,4-benzodiazepinas (trihidrochloridas) m/z 453 (M+H) m/z 489 (M+H) m/z 451 (M + H) m/z 493 (M + H) m/z 531 (M + H)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (methylphenylamino) benzoyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) m / z 453 (M + H) m / z z 489 (M + H) m / z 451 (M + H) m / z 493 (M + H) m / z 531 (M + H)
169169
201201
199199
200200
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-7-fenil-4-(4chinolinilkarbonil) -1 H-1,4benzodiazepinas (N-oksidas dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (4-quinolinylcarbonyl) -1H-1,4-benzodiazepine (N-oxide dihydrochloride)
N-metil-N-(2-piridinilmetil)-2[[2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-7-fenil-1 H-1,4benzodiazepin-4il]karbonil]benzamidas (trihidrochloridas) m/z 476 (M + H) m/z 557 (M + H)N-Methyl-N- (2-pyridinylmethyl) -2 [[2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4-yl] carbonyl] benzamide (trihydrochloride) m / z 476 (M + H) m / z 557 (M + H)
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-4-(3izochinolinilkarbonil)-7-fenil-1 H1,4-benzodiazepinas (trihidrochloridas) m/z 460 (M + H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-isoquinolinylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) m / z 460 (M + H)
202-219 pavyzdžiai j 4 pavyzdžio junginio A (3,83 g, 15,4 mmol) ir 4imidazolkarboksaldehido (2,22 g, 23,1 mmol) mišinį 120 ml CH2CI2 ir 3 ml AcOH kambario temperatūroje pridedama NaBH(OAc)3 (4,89 g, 23,1 mmol). Mišinys maišomas 1,5 vai., praskiedžiamas 200 ml CH2CI2 ir plaunamas 5 % NaHCO3. Organinė fazė džiovinama Na2SO4, nufiltruojama ir koncentruojama vakuume. Liekana gryninama sparčiosios chromatografijos metodu (eliuuojama 5 % MeOH/CH2CI2 su NH4OH pėdsakais), ir gaunama 2,01 g (40 %) 2,3,4,5-tetrahidro-4-[(1,1-dimetiletoksi)karbonii]-1-(1H-imidazol-4-ilmetil)1 H-1,4-benzodiazepino. Dar 0,42 g (8 %) produkto gaunama, maišant 1,5 g didelį Rf turinčios medžiagos 1:1:1 THF/MeOH/NH4OH, po to ekstrahuojant EtOAc ir išgryninant sparčiosios chromatografijos metodu.Examples 202-219 To a mixture of Example 4 Compound A (3.83 g, 15.4 mmol) and 4imidazolecarboxaldehyde (2.22 g, 23.1 mmol) in 120 mL of CH 2 Cl 2 and 3 mL of AcOH was added NaBH (OAc) at room temperature. ) 3 (4.89 g, 23.1 mmol). The mixture was stirred for 1.5 h, diluted with 200 mL CH 2 Cl 2 and washed with 5% NaHCO 3 . The organic phase is dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 5% MeOH / CH 2 Cl 2 with traces of NH 4 OH) to give 2.01 g (40%) of 2,3,4,5-tetrahydro-4 - [(1,1- dimethylethoxy) carbonyl] -1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine. A further 0.42 g (8%) of product is obtained by stirring 1.5 g of high R f material in 1: 1: 1 THF / MeOH / NH 4 OH followed by extraction with EtOAc and purification by flash chromatography.
170170
Hidroksimetilo derva (3,5 g, 6,58 mmol, 1,88 mmol/g) brinkinama 50 ml 1,2-dichloretano 45 min. kambario temperatūroje purtomoje 125 ml talpos kolboje, j šj mišinj pridedama paraformaldehido (0,15 g, 5,0 mmol). Per mišinj 15 min. leidžiamas HCI (dujinis). Po to į reakcijos mišinj vėl pridedama paraformaldehido (0,15 g, 5,0 mmol), ir purtant, vėl leidžiamas HCI (dujinis) 4 vai. 1,2-dichloretanas nupilamas, ir derva plaunama 1,2-dichloretanu (4 x 20 ml).The hydroxymethyl resin (3.5 g, 6.58 mmol, 1.88 mmol / g) was swollen in 50 mL of 1,2-dichloroethane for 45 min. paraformaldehyde (0.15 g, 5.0 mmol) was added to the mixture in a 125 mL shaking flask at room temperature. Stir for 15 min. HCI (gaseous) is allowed. Paraformaldehyde (0.15 g, 5.0 mmol) was then added again to the reaction mixture and HCl (gaseous) was allowed to shake again for 4 hours. The 1,2-dichloroethane is decanted off and the resin is washed with 1,2-dichloroethane (4 x 20 mL).
Ši derva suspenduojama 20 ml 1,2-dichloretano ir veikiama 2,3,4,5tetrahidro-4-[(1,1-dimetiletoksi)karbonil]-1-(1H-imidazol-4-ilmetil)-1 H-1,4benzodiazepino (2,23 g, 6,78 mmol) tirpalu 25 ml 1,2-dichloretano ir 6 ml DIEA. Mišinys purtomas kambario temperatūroje 12 vai. Pridedama MeOH (2 ml), ir mišinys purtomas dar 1,5 vai. Nupilamas tirpiklis, o derva plaunama iš eilės 1,2-dichloretanu (2 x 20 ml), DMF (2 x 20 ml) ir MeOH (2 x 20 ml). Išdžiovinus šią medžiagą vakuume, gaunama 4,58 g (67 %) dervos, turinčios prijungto per imidazolą 2,3,4,5-tetrahidro-4-[(1,1 -dimetiletoksi)karbonil]-1 (1H-imidazol-4-ilmetil)-1 H-1,4-benzodiazepino (%N = 4,39). J 150 mg (0,135 mmol, 0,90 mmol/g) šios dervos 5 ml talpos polipropileninio švirkšto vamzdelyje pridedama 1,5 ml 3 % Et3SiH CH2CI2 ir 0,5 ml TFA. Vamzdelis patalpinamas j vakuminę eliuavimo kamerą (24 vamzdelių talpos), ir visas aparatas purtomas orbitine purtykle 3 vai. Tirpiklis nupilamas, o derva plaunama iš eilės po 2 ml CH2CI2, 25 % Et3N/CH2CI2, MeOH, DMF ir CH2CI2. Derva brinkinama 0,5 ml DMF tirpalo, turinčio 1M DIEA ir 0,5M HOBT. j šj mišinj pridedama 50 mg karboksirūgšties, po to 1,5 ml CH2CI2 tirpalo, turinčio 0,2M EDC. Mišinys purtomas 18 vai. Nupilamas tirpiklis, o derva plaunama iš eilės po 2 ml CH2CI2, 25 % Et3N/CH2CI2, MeOH, DMF ir CH2CI2. Kopuliavimo procedūra pakartojama. Produktai atskeliami nuo dervos, purtant 18 vai su HBr/TFA/tioanizolo tirpalu (pagamintu sumaišant 45 ml TFA, 1,25 ml tioanizolo ir 5 ml 30 % HBr/HOAc). Tirpiklis nupilamas, ir derva plaunama MeOH (3x3 ml). Tirpiklis nugarinamas vakuume, o liekana gryninama HPLC metodu (C18, 50 x 100 mm, 10%-90% MeOH su 0,1 % TFA, 10 min. gradientas, 20 ml/min.). Tiksliniai junginiai charakterizuoti analitinės HPLC ir masių spektrometrijos duomenimis.This resin is suspended in 20 ml of 1,2-dichloroethane and treated with 2,3,4,5-tetrahydro-4 - [(1,1-dimethylethoxy) carbonyl] -1- (1H-imidazol-4-ylmethyl) -1H-1, 4-Benzodiazepine (2.23 g, 6.78 mmol) in 25 mL of 1,2-dichloroethane and 6 mL of DIEA. The mixture is shaken at room temperature for 12 hours. MeOH (2 mL) was added and the mixture was shaken for another 1.5 h. The solvent was removed and the resin was washed successively with 1,2-dichloroethane (2 x 20 mL), DMF (2 x 20 mL), and MeOH (2 x 20 mL). Drying in vacuo gives 4.58 g (67%) of a resin bound via imidazole 2,3,4,5-tetrahydro-4 - [(1,1-dimethylethoxy) carbonyl] -1 (1H-imidazole-4). -ylmethyl) -1H-1,4-benzodiazepine (% N = 4.39). J 150 mg (0.135 mmol, 0.90 mmol / g) of this resin are added to a 5 mL polypropylene syringe tube with 1.5 mL of 3% Et 3 SiH CH 2 Cl 2 and 0.5 mL of TFA. The tube is placed in a vacuum elution chamber (24 tube capacity) and the whole apparatus is shaken in an orbital shaker for 3 hours. The solvent is removed and the resin is washed successively with 2 mL of CH 2 Cl 2 , 25% Et 3 N / CH 2 Cl 2 , MeOH, DMF, and CH 2 Cl 2 . The resin is swollen with 0.5 ml of DMF solution containing 1M DIEA and 0.5M HOBT. To this mixture was added 50 mg of carboxylic acid followed by 1.5 ml of CH 2 Cl 2 containing 0.2M EDC. The mixture is shaken for 18 hours. The solvent was removed and the resin was washed successively with 2 mL of CH 2 Cl 2 , 25% Et 3 N / CH 2 Cl 2 , MeOH, DMF, and CH 2 Cl 2 . The copying procedure is repeated. The products are separated from the resin by shaking for 18 hours with HBr / TFA / Thioanisole solution (prepared by mixing 45 mL of TFA, 1.25 mL of thioanisole and 5 mL of 30% HBr / HOAc). The solvent was removed and the resin was washed with MeOH (3x3 mL). The solvent was evaporated in vacuo and the residue was purified by HPLC (C18, 50 x 100 mm, 10% -90% MeOH with 0.1% TFA, 10 min gradient, 20 mL / min). The target compounds were characterized by analytical HPLC and mass spectrometry.
171171
Pvz.For example,
202202
StruktūraStructure
2,3,4,5-tetrahidro-l -(1Himidazol-4-ilmetil)-4-[(2naftaleniltio) acetil]-1 H-1,4benzodiazepinas (trifluoracetatas, 1:2)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-naphthalenylthio) acetyl] -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)
Masių spektras m/z 429 (M+H)Mass spectrum m / z 429 (M + H)
203203
4-(3-(3,4-dimetoksifenil)-1 oksopropil]-2,3,4,5-tetrahidro-1· (1 H-imidazol-4-ilmetil)-1 H-1,4benzodiazepinas (trifluoracetatas, 1:2) m/z 421 (M + H)4- (3- (3,4-dimethoxyphenyl) -1-oxopropyl] -2,3,4,5-tetrahydro-1 · (1 H -imidazol-4-ylmethyl) -1 H -1,4-benzodiazepine (trifluoroacetate, 1 : 2) m / z 421 (M + H)
204204
205205
4([1,1 '-bifenil]-4-ilacetil)-2,3,4,5tetrahidro-1-(1 H-imidazol-4ilmetil)-1 H-1,4-benzodiazepinas (trifluoracetatas, 1:2)4 ([1,1'-Biphenyl] -4-ylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)
2,3,4,5-tetrahidro-l -(1Himidazol-4-ilmetil)-4-(2naftalenilacetil)-1 H-1,4benzodiazepinas (trifluoracetatas, 1:2) m/z 423 (M + H) m/z 397 (M + H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-naphthalenylacetyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2) m / z 423 (M + H) m / z z 397 (M + H)
172172
206206
4-([1,1’-bifenil]-2-ilkarbonil)2,3,4,5-tetrahidro-1 -(1Himi dazoI-4-il m eti I)-1 H-1,4benzodiazepinas (trifluoracetatas, 1:2)4 - ([1,1'-Biphenyl] -2-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1) : 2)
207207
208208
209209
2,3,4,5-tetrahi dro-1 -(1Himidazol-4-ilmetil)-4-[(2-fenil-4chi noli nil) karbonil ]-1 H-1,4benzodiazepinas (trifluoracetatas, 1:3)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-phenyl-4-quinolinyl) carbonyl] -1H-1,4-benzodiazepine (trifluoroacetate, 1: 3).
2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-4-(3piridinilacetii)-1 H-1,4benzodiazepinas (trifluoracetatas, 1:3)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-pyridinylacetyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 3)
4-(9H-fluoren-9-ilacetil)-2,3,4,5tetrahidro-1-(1H-imidazol-4ilmetil)-1 H-1,4-benzodiazepinas (trifluoracetatas, 1:2)4- (9H-fluoren-9-ylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)
Ghiralinis (S)-4-[2-(dimetilamino)-1-okso3-fenilpropil]-2,3,4,5-tetrahidro1 -(1 H-imi dazol-4-ilmetil)-1 H-1,4benzodiazepinas (trifluoracetatas, 1:3) m/z 409 (M+H) m/z 460 (M + H) m/z 384 (M + H) m/z 435 (M + H) m/z 404 (M + H)Ghiral (S) -4- [2- (Dimethylamino) -1-oxo-3-phenylpropyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine ( trifluoroacetate, 1: 3) m / z 409 (M + H) m / z 460 (M + H) m / z 384 (M + H) m / z 435 (M + H) m / z 404 (M + H) )
210210
173173
211211
212212
213213
(S)-2,3,4,5-tetrahidro-1 -(1Himidazoi-4-ilmetil)-4-[(2-okso-4fenil-3-oksazolidinil)acetil]-1H1,4-benzodiazepinas (trifluoracetatas, 1:2) 4-(9-akridinilkarbonil)-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil)-1 H-1,4-benzodiazepinas (trifluoracetatas, 1:3) m/z 432 (M + H) m/z 434 (M+H)(S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-oxo-4-phenyl-3-oxazolidinyl) acetyl] -1H1,4-benzodiazepine (trifluoroacetate, 1) : 2) 4- (9-acridinylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 3) m / z 432 ( M + H m / z 434 (M + H)
MM
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-4-(3fenoksibenzoil)-1 H-1,4benzodiazepinas (trifluoracetatas, 1:2) m/z 425 (M+H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-phenoxybenzoyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2) m / z 425 (M + H)
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-4-[[4’(trifluormetil) [1,1 ’-bifeni l]-2 il]karbonil]-1 H-1,4benzodiazepinas (trifluoracetatas, 1:2) m/z 477 (M+H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[4 '(trifluoromethyl) [1,1'-biphenyl] -2-yl] carbonyl] -1H-1, 4-benzodiazepine (trifluoroacetate, 1: 2) m / z 477 (M + H)
174174
215215
216216
217217
218218
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-4-(4fenoksibenzoil)-1 H-1,4benzodiazepinas (trifluoracetatas, 1:2) m/z 425 (M+H)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-phenoxybenzoyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2) m / z 425 (M + H)
2.3.4.5- tetrahidro-1-(1 Himidazol-4-ilmetil)-4-(2naftalenilkarbonil)-1 H-1,4benzodiazepinas (trifluoracetatas, 1:2)2.3.4.5- Tetrahydro-1- (1-imidazol-4-ylmethyl) -4- (2-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilmetil)-4-(1-okso-4 fenilbutil)-1 H-1,4benzodiazepinas (trifluoracetatas, 1:2)2.3.4.5- Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-oxo-4-phenylbutyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)
2.3.4.5- tetrahidro-1 -(1Himidazol-4-ilirietil)-4-[(2fenoksifenil) acetil]-1 H-1,4benzodiazepinas (trifluoracetatas, 1:2)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylethylethyl) -4 - [(2-phenoxyphenyl) acetyl] -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)
2.3.4.5- tetrahidro-1-(1Himidazol-4-ilmetil)-4-[2-[(4metilfenil)sulfinil]benzoil]-1 H1,4-benzodiazepinas (trifluoracetatas, 1:2) m/z 383 (M + H) m/z 375 (M + H) m/z 439 (M+H) m/z 471 (M + H)2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2 - [(4-methylphenyl) sulfinyl] benzoyl] -1 H -1,4-benzodiazepine (trifluoroacetate, 1: 2) m / z 383 (M +) H) m / z 375 (M + H) m / z 439 (M + H) m / z 471 (M + H)
219219
175175
220220
2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-4-[2[(fenilmetil)amino]benzoil]-1 H2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2 [(phenylmethyl) amino] benzoyl] -1H
1,4-benzodiazepinas (trifluoracetatas, 1:3) m/z 438 (M + H)1,4-benzodiazepine (trifluoroacetate, 1: 3) m / z 438 (M + H)
1,2,3,5-Tetrahidro-1(1H-imidazol-4-il-metil)-N,N-difenil-4H-1,4benzodiazepin-4-karboksamidas (hidrochloridas)1,2,3,5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -N, N-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (hydrochloride)
221 pavyzdžio junginys (gelsva kieta medžiaga) pagaminamas iš N,Ndifenilkarbamilchlorido pagal 9 pavyzdyje aprašytą metodiką.Example 221 (yellowish solid) is prepared from N, N-diphenylcarbamyl chloride according to the procedure described in Example 9.
MS (M + H)+ 424MS (M + H) < + >
Analizė išskaičiuota pagal C26H25N5O · 2,2 H2O · 2,2 HCIAnalysis calculated for C 26 H 25 N 5 O · 2.2 H 2 O · 2.2 HCl
Išskaičiuota: C, 57,47; H, 5,87; N, 12,89; Cl, 14,35Found: C, 57.47; H, 5.87; N, 12.89; Cl, 14.35
Rasta: C, 57,25; H, 5,78; N, 13,25; Cl, 14,73.Found: C, 57.25; H, 5.78; N, 13.25; Cl, 14.73.
176176
1,2,3,5-Tetrahidro-1 (1 H-imidazol-4-il-metil)-a,7-difenil-4H-1,4benzodiazepin-4-acto rūgšties metilo esteris (hidrochloridas) j maišomą 12 pavyzdžio junginio B (220 mg, 1,0 mmol) suspensiją MeOH, esant kietam K2CO3, kambario temperatūroje argono atmosferoje pridedama metilbromfenilacetato (0,18 ml, 1,1 mmol). Mišinys maišomas 18 vai., nugarinamas tirpiklis, ir liekana gryninama sparčiosios kolonėlių chromatografijos metodu (3:2, heksanai ir etilacetatas). Gaunamaa 1,2,3,5tetrahidro-a,7-difenil-4H-1,4-benzodiazepin-4-acto rūgšties metilo esteris, kuris yra alyva (220 mg, 63 %). Ši medžiaga veikiama pagal 1 pavyzdžio junginio D gavimo metodiką, ir gaunamas 222 pavyzdžio junginys, kuris yra geltona kieta medžiaga.1,2,3,5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -α, 7-diphenyl-4H-1,4-benzodiazepine-4-acetic acid methyl ester (hydrochloride) in a stirred mixture of Example 12 To a suspension of B (220 mg, 1.0 mmol) in MeOH in solid K2CO3 was added methyl bromophenyl acetate (0.18 mL, 1.1 mmol) at room temperature under argon. The mixture was stirred for 18 hours, the solvent was evaporated, and the residue was purified by flash column chromatography (3: 2, hexanes and ethyl acetate). 1,2,3,5-Tetrahydro-a, 7-diphenyl-4H-1,4-benzodiazepine-4-acetic acid methyl ester is obtained which is an oil (220 mg, 63%). This material was subjected to the procedure for the preparation of Example D Compound D to afford Example 222 as a yellow solid.
MS (M+H) + 453MS (M + H) + 453
Analizė išskaičiuota pagal C28H28N4O2 · 0,2 H2O · 2,5 HCIAnalysis calculated for C 28 H 2 8 N 4 O 2 · 0.2 H 2 O · 2.5 HCl
Išskaičiuota: C, 61,44; H, 5,69; N, 10,24; Cl, 16,19.Found: C, 61.44; H, 5.69; N, 10.24; Cl, 16.19.
Rasta; C, 61,33; H, 5,88; N, 9,94; Cl, 16,00.Found; C, 61.33; H, 5.88; N, 9.94; Cl, 16.00.
4-Acetil-2,3,4,5-tetrahidro-1(1H-imidazol-4-ilmetil)-3-(fenilmetil)-1H-1,4benzodiazepinas (hidrochloridas)4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)
223 pavyzdžio junginys (gelsvai ruda kieta medžiaga) pagaminamas iš izatoinės rūgšties anhidrido ir D,L-fenilalanino O-metilo esterio hidrochlorido pagal 71 pavyzdyje aprašytą metodiką, išskyrus tai, kad vietoj naftoilchlorido vartojamas acetilchloridas (0,25 ekv.).Example 223 (tan solid) is prepared from isatoic acid anhydride and D, L-phenylalanine O-methyl ester hydrochloride according to the procedure described in Example 71, except that acetyl chloride (0.25 eq) is used instead of naphthoyl chloride.
177177
MS (M + H)+453MS (M + H) + 453
Analizė išskaičiuota pagal C22H24N4O · 1,5 H2O · 1,2 HCI Išskaičiuota: C, 61,74; H, 6,26; N, 13,26; Cl, 9,49.Analysis calculated for C 22 H 24 N 4 O · 1.5 H 2 O · 1.2 HCl Calculated: C, 61.74; H, 6.26; N, 13.26; Cl, 9.49.
Rasta: C, 61,80; H, 6,62; N, 13,10; Cl, 9,12.Found: C, 61.80; H, 6.62; N, 13.10; Cl, 9.12.
224 pavyzdysExample 224
(R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetiI)-4-(metilsulfonil)-3(fenilmetil)-l H-1,4-benzodiazepinas (hidrochloridas)(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine ( hydrochloride)
A. (R)-7-Brom-2,3,4,5-tetrahidro-3-(feniImetil)-1 H-1,4-benzodiazepin2,5-dionasA. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione
Maišomas bromizatoinės rūgšties anhidrido (150 g, 0,62 mol) ir Dfenilalanino metilo esterio hidrochlorido (127,3 g, 0,59 mol) tirpalas, kuriame yra 4-dimetilaminopiridino (2 g), piridine '(1500 ml) virinamas su grįžtamu šaldytuvu argono atmosferoje 3 dienas. Piridinas nugarinamas vakuume, o liekana ištirpinama metileno chloride (3 I). Šis tirpalas plaunamas 10 % HCI tirpalu ir sočiu NaCl tirpalu. Organinis tirpalas džiovinamas ir sukoncentruojamas vakuume iki mažo tūrio. Atskyrus ir išdžiovinus susidariusią kietą medžiagą, gaunama 152 g (71 %) junginio A. Lyd. temp.: 242-243 °C.A stirred solution of bromoacetic anhydride (150 g, 0.62 mol) and diphenylalanine methyl ester hydrochloride (127.3 g, 0.59 mol) in 4-dimethylaminopyridine (2 g) was heated to reflux with pyridine (1500 ml). refrigerated under argon for 3 days. The pyridine is evaporated in vacuo and the residue is dissolved in methylene chloride (3 L). The solution was washed with 10% HCl and saturated NaCl. The organic solution was dried and concentrated in vacuo to a small volume. Separation and drying of the resulting solid afforded 152 g (71%) of A. Lyd. mp: 242-243 ° C.
B. (R)-7-Brom-2,3,4,5-tetrahidro-3-(fenilmetil)-1 H-1,4benzodiazepinasB. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine
178178
Maišomas junginio A (30 g, 87 mmol) tirpalas bevandeniame THF (870 ml) kambario temperatūroje ir argono atmosferoje veikiamas boranotetrahidrofurano kompleksu (440 ml 1M tirpalo, 440 mmol). Tirpalas lėtai sušildomas iki virimo ir virinamas su grįžtamu šaldytuvu 18 vai. Mišinys atšaldomas iki 0 °C ir BH3 pertekliui suardyti pridedama metanolio (150 ml). Gautas tirpalas koncentruojamas vakuume, liekana ištirpinama metanolyje (250 ml) ir pridedama 7N HCl tirpalo (50 m!). Šis mišinys šildomas garų vonioje 2 vai. Susidariusi kieta medžiaga atskiriama, suspenduojama vandenyje (400 ml), vandeninė suspensija pašarminama iki pH 11 5N NaOH tirpalu ir ekstrahuojama etilacetatu (2 x 300 ml). Organiniai ekstraktai sumaišomi, džiovinami, koncentruojami vakuume, ir perkristalinus liekaną iš metanolio ir vandens mišinio (9:1), gaunama 25 g junginio B, kuris yra balta kieta medžiaga (91 %). Lyd. temp.: 135-138 °C.A stirred solution of Compound A (30 g, 87 mmol) in anhydrous THF (870 mL) was treated with boranotetrahydrofuran complex (440 mL of 1M solution, 440 mmol) under argon. The solution is slowly brought to the boil and refluxed for 18 hours. The mixture was cooled to 0 ° C and methanol (150 mL) was added to destroy the excess BH 3 . The resulting solution was concentrated in vacuo, the residue was dissolved in methanol (250 mL) and 7N HCl solution (50 mL) was added. This mixture is heated in a steam bath for 2 hours. The resulting solid is separated, suspended in water (400 mL), the aqueous suspension is basified to pH 11 with 5N NaOH solution and extracted with ethyl acetate (2 x 300 mL). The organic extracts were combined, dried, concentrated in vacuo and recrystallized from methanol / water (9: 1) to give 25 g of compound B as a white solid (91%). Lyd. m.p. 135-138 ° C.
C. (R)-7-Brom-2,3,4,5-tetrahidro-4-(metilsulfonil)-3-(fenilmetil)-1 H-1,4benzodiazepinasC. (R) -7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine
J maišomą junginio B (1,5 g, 4,73 mmol), piridino (3 ml) ir DIEA (1,6 ml, 9,46 mmol) tirpalą 0 °C temperatūroje argono atmosferoje pridedama metansulfonilchlorido (0,55 ml, 7,11 mmol). Gautas mišinys pamaišomas 0 °C temperatūroje 2 vai. ir pridedama 1N NaOH tirpalo (30 ml). Šis mišinys pamaišomas 2 vai., atskiriamas organinis sluoksnis, plaunamas 1N HCl tirpalu (2 x 100 ml), džiovinamas ir sukoncentravus vakuume, gaunama 1,7 g junginio C, kuris yra geltona kieta medžiaga (91 %).To a stirred solution of compound B (1.5 g, 4.73 mmol), pyridine (3 mL) and DIEA (1.6 mL, 9.46 mmol) at 0 ° C under argon was added methanesulfonyl chloride (0.55 mL, 7 mL). , 11 mmol). The resulting mixture was stirred at 0 ° C for 2 h. and 1N NaOH solution (30 mL) was added. This mixture was stirred for 2 h, the organic layer was separated, washed with 1N HCl (2 x 100 mL), dried and concentrated in vacuo to give 1.7 g of compound C as a yellow solid (91%).
D. (R)-7-Brom-2,3,4,5-tetrahidro-1 (1 H-imidazol-4-ilmetil)-4(metilsulfonil)-3-(feniImetil)-1 H-1,4-benzodiazepinas (hidrochloridas) į maišomą junginio C (18 g, 45,6 mmol) tirpalą acto rūgštyje (50 ml) ir dichloretane (200 mi) kambario temperatūroje pridedama 4-formilimidazolo (6,6 g, 68,5 mmol). Mišinys maišomas kambario temperatūroje 30 min. j gautą tirpalą pridedama natrio triacetoksiborhidrido (14,5 g, 68,5 mmol). Mišinys maišomas kambario temperatūroje 18 vai., praskiedžiamas etilacetatu (500 ml), atšaldomas iki 0 °C ir pašarminamas iki pH 9D. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4- Benzodiazepine (hydrochloride) was added 4-formylimidazole (6.6 g, 68.5 mmol) to a stirred solution of Compound C (18 g, 45.6 mmol) in acetic acid (50 mL) and dichloroethane (200 mL) at room temperature. The mixture was stirred at room temperature for 30 min. To the resulting solution was added sodium triacetoxyborohydride (14.5 g, 68.5 mmol). The mixture was stirred at room temperature for 18 h, diluted with ethyl acetate (500 mL), cooled to 0 ° C and basified to pH 9
179 koncentruotu NH4OH tirpalu. Šis mišinys maišomas 2 vai. ir paskirstomas tarp etilacetato ir sotaus NaHCO3 tirpalo. Organinis sluoksnis atskiriamas, plaunamas sočiu NH4CI tirpalu, džiovinamas Na2SO4 ir koncentruojamas vakuume. Liekana perkristalinama iš metanolio, ir gaunama balta kieta medžiaga (14 g, 65 %). Ši kieta medžiaga ištirpinama etilacetate ir pridedama 1N HCl tirpalo eteryje (60 ml). Tirpiklis nugarinamas vakuume, ir kietą medžiagą išdžiovinus šildomoje krosnyje vakuume, gaunamas 224 pavyzdžio junginys, kuris yra balta kieta medžiaga. Lyd. temp.: 180-185 °C.179 in concentrated NH 4 OH solution. This mixture is stirred for 2 hours. and partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic layer was separated, washed with saturated NH 4 Cl solution, dried over Na 2 SO 4 and concentrated in vacuo. The residue was recrystallized from methanol to give a white solid (14 g, 65%). This solid was dissolved in ethyl acetate and added with 1N HCl in ether (60 mL). The solvent was evaporated in vacuo and the solid dried in a heated oven in vacuo to afford Example 224 as a white solid. Lyd. mp: 180-185 ° C.
MS (M + H)+476.MS (M + H) + 476.
[ajo20: +58° (c = 0,4, MeOH).[?] 20 : + 58 ° (c = 0.4, MeOH).
(R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(feniImetil)-1 H-1,4-benzodiazepin-7-karbonitrilas (monohidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile ( monohydrochloride)
A. (R)-2,3,4,5’Tetrahidro-4-(metilsulfonil)-3-(fenilmetil)-1H-1,4benzodiazepin-7-karbonitrilasA. (R) -2,3,4,5'Tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile
Maišomas 224 pavyzdžio junginio C (6,9 g, 17,5 mmol) ir vario cianido (4,0 g, 44 mmol) tirpalas N-metilpirolidinone (90 ml) kaitinamas 200 °C temperatūroje 5 vai. Mišinys atvėsinamas iki kambario temperatūros ir supilamas j 10 % vandeninį etilendiamino tirpalą (800 ml). Gauta suspensija maišoma kambario temperatūroje 2 vai. ir ekstrahuojama etilacetatu (3 x 150 ml). Sumaišyti organiniai ekstraktai plaunami 5 % NH4OH tirpalu (2 x 100 ml), sočiu NaCl tirpalu, džiovinami MgSO4 ir koncentruojami. Liekana gryninamaA stirred solution of Example 224 Compound C (6.9 g, 17.5 mmol) and copper cyanide (4.0 g, 44 mmol) in N-methylpyrrolidinone (90 mL) was heated at 200 ° C for 5 h. Cool the mixture to room temperature and add 10% aqueous ethylenediamine (800 mL). The resulting suspension was stirred at room temperature for 2 hours. and extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were washed with 5% NH 4 OH (2 x 100 mL), brine, dried over MgSO 4, and concentrated. The residue is purified
180 sparčiosios chromatografijos metodu (etilacetatas, heksanai; 1:1), ir gaunamas putų pavidalo junginys A (4,5 g, 75 %).180 by flash chromatography (ethyl acetate, hexanes; 1: 1) to give Foam Compound A (4.5 g, 75%).
B. (R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(fenilmetil)-l H-1,4-benzodiazepin-7-karbonitrilas (monohidrochloridas)B. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7- carbonitrile (monohydrochloride)
J maišomą junginio A (4,7 g, 13,8 mmol) tirpalą acto rūgštyje (30 ml) ir dichloretane (120 ml) kambario temperatūroje pridedama 4-formilimidazolo (2,1 g, 22 mmol). Mišinys maišomas kambario temperatūroje 30 min. J gautą tirpalą pridedama natrio triacetoksiborhidrido (4,4 g, 22 mmol). Mišinys maišomas kambario temperatūroje 2 vai., pridedama 4-formilimidazolo (1,3 g, 13,5 mmol), mišinys pamaišomas 30 min. ir pridedama natrio triacetoksiborhidrido (3,0 g, 14 mmol). Šis ciklas pakartojamas du kartus, kol sureaguoja visa pradinė medžiaga. Apdorojimą ir produktas išskiriamas pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką. Gaunamas 225 pavyzdžio junginys, kuris yra balta kieta medžiaga (4,1 g, 65 %). Lyd. temp.: 165 °C.To a stirred solution of compound A (4.7 g, 13.8 mmol) in acetic acid (30 mL) and dichloroethane (120 mL) was added 4-formylimidazole (2.1 g, 22 mmol) at room temperature. The mixture was stirred at room temperature for 30 min. To the resulting solution was added sodium triacetoxyborohydride (4.4 g, 22 mmol). The mixture was stirred at room temperature for 2 hours, 4-formylimidazole (1.3 g, 13.5 mmol) was added and the mixture was stirred for 30 min. and sodium triacetoxyborohydride (3.0 g, 14 mmol) was added. This cycle is repeated twice until all starting material has reacted. The workup and product are isolated according to the procedure for the preparation of compound D described in Example 224. Example 225 is obtained as a white solid (4.1 g, 65%). Lyd. mp: 165 ° C.
MS (M + H)+ 422.MS (M + H) < + > 422.
[a]D 20: +218° (c = 0,23, MeOH).[α] D 20 : + 218 ° (c = 0.23, MeOH).
Analizė išskaičiuota pagal C22H23N5O2S · 1,7 H2O · 1 HCI.Analysis calculated for C 22 H 23 N 5 O 2 S · 1.7H 2 O · 1 HCl.
Išskaičiuota: C, 54,08; H, 5,65; N, 14,33; Cl, 7,26.Found: C, 54.08; H, 5.65; N, 14.33; Cl, 7.26.
Rasta: C, 54,04; H, 5,38; N, 14,33; Cl, 7,27.Found: C, 54.04; H, 5.38; N, 14.33; Cl, 7.27.
226 pavyzdysExample 226
181181
VV
Me (R)-4-Acetil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-3(fenilmetil)-l H-1,4-benzodiazepinas (monohidrochloridas)Me (R) -4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )
A. 2-Amino-5-fenilbenzenkarboksirūgštis j vandens (300 ml) ir THF (300 ml) mišinį pridedama 2-amino-5brombenzenkarboksirūgšties (30,0 g, 139 mmol), benzenboro rūgšties (18,6 g, 153 mmol) ir K2CO3 (48,0 g, 348 mmol). Tirpalo degazavimui per mišinį 1 vai. smarkia srove leidžiamas argonas, ir per 1 vai. sulašinamas paladžio(ll) acetato (2,52 g, 11,2 mmol) tirpalas degazuotame THF (50 ml). Šis mišinys maišomas kambario temperatūroje 16 vai., leidžiant Ar. Mišinys koncentruojamas, filtruojamas per celito sluoksnį ir liofilizuojamas, kad būtų pašalintas vanduo. Liofilizatas trinamas su 90 % dichlormetano ir 10 % metanolio mišiniu (500 ml). Filtratas koncentruojamas, ir perkristalinus iš etilacetato/heksano, gaunamas junginys A, kuris yra ruda kieta medžiaga (25 g, 84%). MS (M + H)+214.A. 2-Amino-5-phenylbenzoic acid To a mixture of water (300 mL) and THF (300 mL) was added 2-amino-5-bromobenzoic acid (30.0 g, 139 mmol), benzeneboronic acid (18.6 g, 153 mmol), and K2CO3 (48.0 g, 348 mmol). For degassing the solution through the mixture for 1 hour. heavy current is allowed to flow through argon, and within 1 hour. a solution of palladium (II) acetate (2.52 g, 11.2 mmol) in degassed THF (50 mL) was added dropwise. This mixture was stirred at room temperature for 16 h with Ar. The mixture is concentrated, filtered through a pad of celite and lyophilized to remove water. The lyophilisate was triturated with a mixture of 90% dichloromethane and 10% methanol (500 mL). The filtrate was concentrated and recrystallized from ethyl acetate / hexane to give compound A as a brown solid (25 g, 84%). MS (M + H) < + > 214.
B. 6-FeniI-3,1-oksazin-2,4(1H)-dionasB. 6-Phenyl-3,1-oxazine-2,4 (1H) -dione
Į junginio A (25,0 g, 0,177 mol) ir trifosgeno (25,0 g, 0,084 mol) tirpalą acetonitrile (250 ml) 0 °C temperatūroje N2 atmosferoje per 1 vai. sulašinamas trietilamino (3,0 g, 4,1 ml, 0,029 mol) tirpalas acetonitrile (50 ml). Mišinys maišomas kambario temperatūroje 16 vai., ir nufiltruojama kieta medžiaga.To a solution of Compound A (25.0 g, 0.177 mol) and triphosgene (25.0 g, 0.084 mol) in acetonitrile (250 mL) at 0 ° C under N 2 for 1 h. A solution of triethylamine (3.0 g, 4.1 mL, 0.029 mol) in acetonitrile (50 mL) was added dropwise. The mixture is stirred at room temperature for 16 hours and the solid is filtered off.
Ant filtro esanti medžiaga plaunama dichlormetanu, ir išdžiovinus vakuume,The material on the filter is washed with dichloromethane and dried in vacuo,
182 gaunamas junginys B, kuris yra rusva kieta medžiaga (17,8 g, 63 %). MS (M + H)+ 241.182 gives compound B, which is an off-white solid (17.8 g, 63%). MS (M + H) + 241.
C. (R)-2,3,4,5-tetrahidro-7-fenil-3-(fenilmetil)-1 H-1,4-benzodiazepin2,5-dionasC. (R) -2,3,4,5-Tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione
Junginys B (9,40 g, 0,0392 mol), D-Phe (6,5 g, 0,0392 mol) ir piridino-HCI (22,6 g, 0,196 mol) ištirpinami piridine (100 ml). Tirpalas virinamas su grjžtamu šaldytuvu 4 vai., atšaldomas ir koncentruojamas. Liekana paskirstoma tarp vandens (200 ml) ir etilacetato (200 ml). Organinis sluoksnis plaunamas vandeniu (3 x 100 ml), sočiu NaCl tirpalu (50 ml), džiovinamas (MgSO4), ir sukoncentravus gaunamas junginys C, kuris yra gelsva stiklo pavidalo medžiaga (6,0 g, 45 %). MS (M + H)+ 343.Compound B (9.40 g, 0.0392 mol), D-Phe (6.5 g, 0.0392 mol) and pyridine-HCl (22.6 g, 0.196 mol) were dissolved in pyridine (100 mL). The solution was heated to reflux for 4 hours, cooled and concentrated. The residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (3 x 100 mL), brine (50 mL), dried (MgSO 4 ), and concentrated to give Compound C as a yellowish glass (6.0 g, 45%). MS (M + H) < + > 343.
D. (R)-2,3,4,5-tetrahidro-7-fenil-3-(fenilmetil)-1H-1,4-benzodiazepinasD. (R) -2,3,4,5-Tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine
Junginys C (6,0 g, 0,017 mol) ištirpinamas THF (100 ml) ir pridedama borano (1M THF, 50 ml, 50 mmol). Tirpalas virinamas su grjžtamu šaldytuvu 4 vai. ir atšaldomas iki kambario temperatūros. Likusio borano suskaldymui pridedama metanolio (50 ml), ir tirpalas koncentruojamas, j liekaną pridedama 1N HCI (100 ml), ir mišinys virinamas su grjžtamu šaldytuvu 4 vai. Šis mišinys atšaldomas iki kambario temperatūros, parūgštinamas iki pH 2 1N HCI (110 ml) ir ekstrahuojamas dichlormetanu (3 x 200 ml). Organiniai sluoksniai sumaišomi, plaunami sočiu NaCl tirpalu (300 ml), džiovinami (N2SO4), ir sukoncentravus gaunamas junginys D, kuris yra gelsva stiklo pavidalo medžiaga (5,5 g, 99 %). MS (M + H)+ 315.Compound C (6.0 g, 0.017 mol) was dissolved in THF (100 mL) and borane (1M in THF, 50 mL, 50 mmol) was added. The solution is heated to reflux for 4 hours. and cooled to room temperature. Methanol (50 mL) was added to decompose the remaining borane, and the solution was concentrated and 1N HCl (100 mL) was added to the residue, and the mixture was refluxed for 4 hours. The mixture was cooled to room temperature, acidified to pH 2 with 1N HCl (110 mL) and extracted with dichloromethane (3 x 200 mL). The organic layers were combined, washed with brine (300 mL), dried (N 2 SO 4 ) and concentrated to give Compound D as a yellowish glass (5.5 g, 99%). MS (M + H) + 315.
E. (R)-4-Acetil-2,3,4,5-tetrahidro-7-fenil-3-(fenilmetil)-1H-1,4benzodiazepinasE. (R) -4-Acetyl-2,3,4,5-tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine
Junginys D (5,0 g, 0,016 mol) ištirpinamas dichlormetane (300 ml) ir iš karto pridedama DIEA (2,06 g, 2,8 ml, 0,016 mol). Per 30 min, sulašinamas acto rūgšties anhidrido (1,46 g, 1,35 ml, 0,0143 mol) tirpalas dichlormetane (20 ml). Tirpalas maišomas 30 min., plaunamas sočiu natrio rūgščiuoju karbonatu (3 x 100 ml), vandeniu (3 x 100 ml), sočiu NaCl tirpalu (100 ml),Compound D (5.0 g, 0.016 mol) was dissolved in dichloromethane (300 mL) and DIEA (2.06 g, 2.8 mL, 0.016 mol) was added immediately. A solution of acetic anhydride (1.46 g, 1.35 mL, 0.0143 mol) in dichloromethane (20 mL) was added dropwise over 30 min. The solution is stirred for 30 min, washed with saturated sodium bicarbonate (3 x 100 mL), water (3 x 100 mL), saturated NaCl solution (100 mL),
183 džiovinamas (Na2SO4), ir sukoncentravus gaunamas junginys E, kuris yra rusva stiklo pavidalo medžiaga (5,0 g, 88 %).183 was dried (Na 2 SO 4 ) to give compound E, which is a brownish glassy material (5.0 g, 88%).
F. (R)-4-Acetil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-3(fenilmetil)-l H-1,4-benzodiazepinas (monohidrochloridas)F. (R) -4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine ( monohydrochloride)
Junginys E (5,0 g, 14,0 mmol) ir 4-formilimidazolas (4,45 g, 46,3 mmol) ištirpinami 1,2-DCE (100 ml) ir acto rūgštyje (50 ml). Iš karto pridedama natrio triacetoksiborhidrido (4,45 g, 21,0 mmol), ir mišinys maišomas kambario temperatūroje 1 vai. Pridedama sotaus NaHCO3 (50 ml), o po to amonio hidroksido (50 ml). Mišinys maišomas 2 vai., koncentruojamas, ir liekana paskirstoma tarp vandens (100 ml) ir etilacetato (200 ml). Organinis sluoksnis plaunamas vandeniu (100 ml), sočiu NaCl tirpalu (100 ml), džiovinamas (Na2SO4), koncentruojamas ir po chromatografijos (silikagelis, 5,1 x 15 cm, 95 % dichlormetano, 5 % metanolio) gaunama 226 pavyzdžio junginio laisva bazė, kuri yra ruda kieta medžiaga (4,9 g). Ši ruda medžiaga dar kartą gryninama preparatinės HPLC metodu (YMC S-15 ODS kolonėlė, 50 x 500 mm; tirpiklis A: 0,1 % TFA 90 % vandens ir 10 % metanolio mišinyje; tirpiklis B: 0,1 % TFA 10 % vandens ir 90 % metanolio mišinyje; 20-100 % B per 60 min; srauto greitis 25 ml/min.). Frakcijos, kuriose yra norimo produkto, sumaišomos, koncentruojamos ir liofilizuojamos. Liofilizatas ištirpinamas acetonitrile (50 ml) ir 1N HCI (50 ml). Šis mišinys koncentruojamas ir liofilizuojamas. Pakartojus šią procedūrą, gaunamas 226 pavyzdžio junginys, kuris yra geltona kieta medžiaga (2,3 g, 35 %).Compound E (5.0 g, 14.0 mmol) and 4-formylimidazole (4.45 g, 46.3 mmol) were dissolved in 1,2-DCE (100 mL) and acetic acid (50 mL). Sodium triacetoxyborohydride (4.45 g, 21.0 mmol) was added immediately and the mixture was stirred at room temperature for 1 h. Saturated NaHCO 3 (50 mL) was added followed by ammonium hydroxide (50 mL). The mixture was stirred for 2 h, concentrated and the residue partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (Na 2 SO 4 ), concentrated, and chromatographed (silica gel, 5.1 x 15 cm, 95% dichloromethane, 5% methanol) to give 226 samples. the free base of the compound which is a brown solid (4.9 g). This brown material was further purified by preparative HPLC (YMC S-15 ODS column, 50 x 500 mm; solvent A: 0.1% TFA in 90% water / 10% methanol; solvent B: 0.1% TFA in 10% water and 90% methanol in the mixture; 20-100% B in 60 min; flow rate 25 mL / min). The fractions containing the desired product are mixed, concentrated and lyophilized. The lyophilisate was dissolved in acetonitrile (50 mL) and 1N HCl (50 mL). This mixture is concentrated and lyophilized. Repeat this procedure to afford Example 226 as a yellow solid (2.3 g, 35%).
MS (M + H)+ 437.MS (M + H) + 437.
1H-BMR (CD3OD, 400 MHz) S'(m.d.) 8,95 (1H, m), 7,68-7,30 (13H, m), 7,04 (1H, m), 5,21-5,10 (1H, m), 4,78-4,63 (2H, m), 4,63-4,48 (1H, m), 4,38 (1H, m), 3,81-3,76 (1H, m), 3,28-3,15 (1H, m), 2,98-2,93 (1H, m), 2,88-2,80 (1H, m), 2,09 (2H, s), 1,62 (1H,s). 1 H-NMR (CD 3 OD, 400 MHz) δ (md) 8.95 (1H, m), 7.68-7.30 (13H, m), 7.04 (1H, m), δ 21-5.10 (1H, m), 4.78-4.63 (2H, m), 4.63-4.48 (1H, m), 4.38 (1H, m), 3.81-. 3.76 (1H, m), 3.28-3.15 (1H, m), 2.98-2.93 (1H, m), 2.88-2.80 (1H, m), 2, 09 (2H, s), 1.62 (1H, s).
227 pavyzdysExample 227
184184
7-Brom-4-[[2-(dimetilamino)etil]sulfonil]-2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-3-(fenilmetil)-4H-1,4-benzodiazepinas (trifluoracetatas, 1:2)7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4- benzodiazepine (trifluoroacetate, 1: 2)
A. 7-Brom-4-[etenilsulfonil]-2,3,4,5-tetrahidro-3-(fenilmetiI)-4H-1,4benzodiazepinasA. 7-Bromo-4- [ethenylsulfonyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -4H-1,4-benzodiazepine
J 224 pavyzdžio junginio B (250 mg, 0,79 mmol) ir THF (20 ml) mišinį pridedama iš eilės 2-chloretansulfonilchlorido (0,1 ml, 0,95 mmol) ir DIEA (0,18 ml, 1,98 mmol). Tirpalas maišomas argono atmosferoje kambario temperatūroje 18 vai., paskirstomas tarp vandeninės vandenilio chlorido rūgšties (100 ml, 1N) ir etilacetato (100 ml) ir ekstrahuojamas etilacetatu (2 x 100 ml). Organiniai sluoksniai sumaišomi, džiovinami (MgSO4), ir sukoncentravus vakuume, gaunama negryna alyva, kuri gryninama sparčiosios chromatografijos metodu (silikagėlis, heksanas.etilacetatas 3:1). Gaunamas junginys A, kuris yra skaidri alyva (85 mg, 26 %).A mixture of compound J from Example J 224 (250 mg, 0.79 mmol) and THF (20 mL) was successively added with 2-chloro-ethanesulfonyl chloride (0.1 mL, 0.95 mmol) and DIEA (0.18 mL, 1.98 mmol). ). The solution was stirred under argon at room temperature for 18 h, partitioned between aqueous hydrochloric acid (100 mL, 1N) and ethyl acetate (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried (MgSO 4 ), and concentrated in vacuo to give a crude oil which was purified by flash chromatography (silica gel, hexane: ethyl acetate 3: 1). Compound A is obtained which is a clear oil (85 mg, 26%).
B. 7-Brom-4-[[2-(dimetilamino)etil]sulfonil]-2,3,4,5-tetrahidro-3(fenilmetil)-4H-1,4-benzodiazepinas j junginio A (85 mg, 0,21 mmol) tirpalą THF (5 ml) pridedama dimetilamino (2 ml, 2M THF) tirpalo. Tirpalas kaitinamas hermetiškai uždarytame slėgį išlaikančiame butelyje 60 °C temperatūroje 48 vai., atšaldomas iki kambario temperatūros, ir sukoncentravus vakuume, gaunamas negrynas alyvos pavidalo junginys B.B. 7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -4 H -1,4-benzodiazepine, Compound A (85 mg, 0 , 21 mmol) in THF (5 mL) was added dimethylamine (2 mL, 2M in THF) solution. The solution is heated in a hermetically sealed pressure bottle at 60 ° C for 48 hours, cooled to room temperature and concentrated in vacuo to give crude oil compound B.
185185
C. 7-Brom-4-[[2-(dimetilamino)etil]sulfonil]-2,3,4,5-tetrahidro-1-(1Himidązol-4-ilmetil)-3-(fenilmetil)-4H-1,4-benzodiazepinas (trifluoracetatas, 1:2)C. 7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1, 4-benzodiazepine (trifluoroacetate, 1: 2)
J maišomą junginio B (90 mg, negrynintas, priimama, kad jame yra 0,21 mmol medžiagos), 4-formilimidazolo (30 mg, 0,32 mmol), dichloretano (4 ml) ir acto rūgšties (2 ml) tirpalą kambario temperatūroje pridedama natrio triacetoksiborhidrido (67 mg, 0,32 mmol). Tirpalas maišomas 48 vai., praskiedžiamas etilacetatu (20 ml) ir amonio hidroksidu (5 ml, kone.) ir maišomas dar 18 vai. Mišinys ekstrahuojamas etilacetatu (2 x 25 ml), sumaišyti organiniai ekstraktai plaunami vandeniniu natrio rūgščiuoju karbonatu (25 ml, sotus tirpalas), po to amonio chloridu (25 ml, sotus vandeninis tirpalas), džiovinami (Na2SO4) ir sukoncentruojama vakuume iki pusiau kietos medžiagos. Ši negryna medžiaga gryninama preparatinės HPLC metodu (vandeninio metanolio, turinčio 0,1 % trifluoracto rūgšties, gradientas, C-18 kolonėlė), ir po liofilizacijos gaunamas 227 pavyzdžio junginys, kuris yra balta kieta medžiaga (50 mg, 44 % išeiga, skaičiuojant pagal junginį A). Lyd. temp.: 118-120 °C.A stirred solution of Compound B (90 mg, crude, assumed to contain 0.21 mmol), 4-formylimidazole (30 mg, 0.32 mmol), dichloroethane (4 mL), and acetic acid (2 mL) was added at room temperature. sodium triacetoxyborohydride (67 mg, 0.32 mmol) was added. The solution was stirred for 48 h, diluted with ethyl acetate (20 mL) and ammonium hydroxide (5 mL, almost) and stirred for a further 18 h. The mixture was extracted with ethyl acetate (2 x 25 mL), the combined organic extracts washed with aqueous sodium bicarbonate (25 mL, saturated solution) followed by ammonium chloride (25 mL, saturated aqueous solution), dried (Na 2 SO 4 ) and concentrated in vacuo to semi-solids. This crude material was purified by preparative HPLC (gradient from water to methanol containing 0.1% trifluoroacetic acid, C-18 column) to give, after lyophilization, the title compound 227 as a white solid (50 mg, 44% yield). compound A). Lyd. mp: 118-120 ° C.
Analizė išskaičiuota pagal C24H3oN5OSBr · 1,0 H2O · 2,0 TFA.Analysis calculated for C 24 H 3 O 5 OSBr · 1.0 H 2 O · 2.0 TFA.
Išskaičiuota: C, 43,20; H, 4,40; N, 9,00; S, 4,12; Br, 10,26.Found: C, 43.20; H, 4.40; N, 9.00; S, 4.12; Br, 10.26.
Rasta: C, 43,85; H, 4,00; N, 8,35; S, 4,39; Br, 9,43.Found: C, 43.85; H, 4.00; N, 8.35; S, 4.39; Br, 9.43.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-4-[(1,2,3,4-tetrahidro1-chinolinil)karbonil]-1 H-1,4-benzodiazepinas (monohidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(1,2,3,4-tetrahydro-1-quinolinyl) carbonyl] -1H-1, 4-Benzodiazepine (monohydrochloride)
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228 pavyzdžio junginys pagaminamas iš N-chlorkarbonil-1,2,3,4tetrahidrochinolino pagal 35 pavyzdyje aprašytą metodiką, išskyrus tai, kad acilinimo produktas chromatografuojamas (silikagelis, 8:2 chloroformas: etilacetatas).Example 228 is prepared from N-chlorocarbonyl-1,2,3,4-tetrahydroquinoline according to the procedure described in Example 35 except that the acylation product is chromatographed (silica gel, 8: 2 chloroform: ethyl acetate).
MS (M + H)+ 464.MS (M + H) + 464.
Analizė išskaičiuota pagal C29H29N5O · 1,0 H2O 1,1 HCl · 0,25 eterio. Išskaičiuota: C, 66,70; H, 6,46; N, 12,96; Cl, 7,22.Analysis calculated for C 29 H 29 N 5 O · 1.0 H 2 O 1.1 HCl · 0.25 ether. Found: C, 66.70; H, 6.46; N, 12.96; Cl, 7.22.
Rasta: C, 66,88; H, 6,36; N, 12,62; Cl, 7,30.Found: C, 66.88; H, 6.36; N, 12.62; Cl, 7.30.
229 pavyzdysExample 229
HH
MeMe
N-Etil-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-N,7-difenil-4H-1,4benzodiazepin-4-karboksamidas (monohidrochloridas)N-Ethyl-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, 7-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (monohydrochloride)
229 pavyzdžio junginys pagaminamas iš N-chlorkarbonil-N-etilanilino pagal 35 pavyzdyje aprašytą metodiką. HCl druska pagaminama, ištirpinant produktą metanolyje, pridedant 4N HCl dioksane, nugarinant, vėl ištirpinamt metanolyje ir nusodinant eteriu.Example 229 is prepared from N-chlorocarbonyl-N-ethylaniline in accordance with the procedure described in Example 35. The HCl salt is prepared by dissolving the product in methanol, adding 4N HCl in dioxane, evaporating, redissolving in methanol and precipitating with ether.
MS (M + H)+ 452.MS (M + H) < + > 452.
Analizė išskaičiuota pagal C28H29N5O · 0,4 H2O · 1,2 HCl 0,25 eterio. Išskaičiuota; C, 66,85; H, 6,48; N, 13,44; Cl, 8,16.Analysis calculated for C 28 H 2 9 N 5 O · 0.4 H 2 O · 1.2 HCl 0.25 ether. Excluded; C, 66.85; H, 6.48; N, 13.44; Cl, 8.16.
Rasta: C, 66,78; H, 6,38; N, 13,49; Cl, 8,05.Found: C, 66.78; H, 6.38; N, 13.49; Cl, 8.05.
230 pavyzdysExample 230
187187
4-[(2,3-Dihidro-1H-indol-1-il)karbonil]-2,3,4,5--tetrahidro-1-(1H-imidazol4-iImetil)-7-fenil-1H-1,4-benzodiazepinas (monohidrochloridas)4 - [(2,3-Dihydro-1H-indol-1-yl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1, 4-Benzodiazepine (monohydrochloride)
230 pavyzdžio junginys pagaminamas iš N-chlorkarbonil-indolino pagal 229 pavyzdyje aprašytą metodiką. Lyd. temp.: 156-166 °C.Example 230 is prepared from N-chlorocarbonylindoline according to the procedure described in Example 229. Lyd. mp 156-166 ° C.
MS (M + H)+450.MS (M + H) < + > 450.
Analizė išskaičiuota pagal C28H27N5O · 0,5 H2O 1,5 HCI.Analysis calculated for C 28 H 27 N 5 O · 0.5 H 2 O 1.5 HCl.
Išskaičiuota: C, 65,52; H, 5,79; N, 13,65; Cl, 10,36.Found: C, 65.52; H, 5.79; N, 13.65; Cl, 10.36.
Rasta: C, 65,40; H, 5,74; N, 13,47; Cl, 10,49.Found: C, 65.40; H, 5.74; N, 13.47; Cl, 10.49.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(f eni I meti l)-7-(4-piri d i nil)-1 H-1,4-benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H- 1,4-benzodiazepine (trihydrochloride)
188188
A. 2,3,4,5-Tetrahidro-1-(trifluoracetil)-4-(metilsulfonil)-3-(fenilmetil)-7brom-1 H-1,4-benzodiazepinas { 78 pavyzdžio junginio A (0,3 mmol) ir trietilamino (2,75 mmol, 384 μΙ) tirpalą CH2CI2 (4 ml) pridedama trifluoracto rūgšties anhidrido (1,2 mmol, 165 μΙ), ir homogeninis tirpalas išlaikomas kambario temperatūroje 5 vai. Reakcijos mišinys koncentruojamas ir gryninamas sparčiosios chromatografijos metodu (40 % EtOAc/heksanas). Išskiriamas junginys A, kuris yra pūkų pavidalo balta kieta medžiaga (100 mg, 68 %). MS (M + NH4) 508.A. 2,3,4,5-Tetrahydro-1- (trifluoroacetyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7bromo-1H-1,4-benzodiazepine {Example 78 Compound A (0.3 mmol) ) and triethylamine (2.75 mmol, 384 μΙ) in CH 2 Cl 2 (4 mL) was added trifluoroacetic anhydride (1.2 mmol, 165 μΙ), and the homogeneous solution was kept at room temperature for 5 hours. The reaction mixture was concentrated and purified by flash chromatography (40% EtOAc / hexane). Compound A was isolated as a fluffy white solid (100 mg, 68%). MS (M + NH 4 ) 508.
B. 2,3,4,5-Tetrahidro-1-(trifluoracetil)-4-(metilsulfonil)-3-(fenilmetil)-7-(4piridinil)-1H-1,4-benzodiazepinasB. 2,3,4,5-Tetrahydro-1- (trifluoroacetyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine
Junginio A (0,15 mmol), 4-stanilpiridino (0,3 mmol, 110 mg) ir 15 mol% Pd(PPh3)4 (26 mg) tirpalas 3 ml THF degazuojamas ir virinamas su grįžtamu šaldytuvu argono atmosferoje. Po 48 vai. pridedama dar 20 mol% katalizatoriaus, kad pilnai sureaguotų pradinė medžiaga. Reakcijos mišinys koncentruojamas ir gryninamas sparčiosios chromatografijos metodu (EtOAc). Išskiriamas geltonos alyvos pavidalo junginys B (46 mg, 63 %). MS (M + H)+ 490.A solution of Compound A (0.15 mmol), 4-stanylpyridine (0.3 mmol, 110 mg) and 15 mol% Pd (PPh 3 ) 4 (26 mg) was degassed in 3 mL of THF and refluxed under argon. After 48 or. an additional 20 mol% of catalyst is added to fully react the starting material. The reaction mixture was concentrated and purified by flash chromatography (EtOAc). Compound B (46 mg, 63%) was isolated as a yellow oil. MS (M + H) < + > 490.
C. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(fenilmetil)-7-(4-piridiniI)-1H-1,4-benzodiazepinas (trihidrochloridas)C. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride)
J junginio B (40 mg, 0,082 mmol) tirpalą 3 ml MeOH pridedama NaOH (5 lašai 2N NaOH tirpalo), mišinys palaikomas kambario temperatūroje 20 min. ir koncentruojamas. Liekana paskirstoma tarp 2N NaOH (5 ml) ir 10 % izopropanolio CH2CI2 (5 ml), ekstrahuojama 10 % izopropanoliu CH2CI2 (3x5 ml), džiovinama Na2SO4 ir koncentruojama. Ši medžiaga ištirpinama 1 ml 1:1 AcOH:dichloretane, veikiama 4-formilimidazolu (0,66 mmol, 63 mg) ir NaBH(OAc)3 (0,66 mmol, 140 mg); mišinys pašildomas 50 °C temperatūroje 2 vai. ir koncentruojamas. Liekana paskirstoma tarp 2N NaOH-sotaus NaCIsotaus NH4OH (10:10:0,3, viso 23 ml) ir 10 % izopropanolio-CH2CI2 (5 ml), ir vandeninė fazė ekstrahuojama 10 % izopropanoliu-CH2CI2 (2x5 ml).To a solution of Compound B (40 mg, 0.082 mmol) in 3 mL of MeOH was added NaOH (5 drops of 2N NaOH solution), and the mixture was kept at room temperature for 20 min. and concentrated. The residue was partitioned between 2N NaOH (5 mL) and 10% isopropanol in CH 2 Cl 2 (5 mL), extracted with 10% isopropanol in CH 2 Cl 2 (3x5 mL), dried over Na 2 SO 4 and concentrated. This material was dissolved in 1 mL of 1: 1 AcOH: dichloroethane, treated with 4-formylimidazole (0.66 mmol, 63 mg) and NaBH (OAc) 3 (0.66 mmol, 140 mg); the mixture is heated at 50 ° C for 2 hours. and concentrated. The residue was partitioned between 2N NaOH-saturated NaCl-saturated NH 4 OH (10:10: 0.3, 23 mL total) and 10% isopropanol-CH 2 Cl 2 (5 mL), and the aqueous phase was extracted with 10% isopropanol-CH 2 Cl 2. (2x5 mL).
189189
Sumaišytos organinės fazės koncentruojamos, ir liekana gryninama preparatine HPLC (YMC S5 ODS 20 x 100 mm, gradientinis eliuavimas nuo 15 iki 75 % buferio B per 60 min. Buferis A = MeOH:H2O:TFA (10:90:0,1); buferis B = MeOH:H2O:TFA (90:10:0,1); srauto greitis 25 ml/min). TFA druska paverčiama HCl druska, panaudojant 1N HCl, ir gaunamas 231 pavyzdžio junginys, kuris yra geltona kieta medžiaga (6,0 mg, 13 %).The combined organic phases are concentrated and the residue is purified by preparative HPLC (YMC S5 ODS 20 x 100 mm, gradient elution 15 to 75% buffer B over 60 min. Buffer A = MeOH: H 2 O: TFA (10: 90: 0.1) buffer B = MeOH: H 2 O: TFA (90: 10: 0.1); flow rate 25 mL / min). The TFA salt was converted to the HCl salt using 1N HCl to give Example 231 as a yellow solid (6.0 mg, 13%).
MS (M + H)+474.MS (M + H) < + > 474.
1H-BMR (CD3OD) δ 8,9 (s, 1H), 8,7 (m, 2H), 8,3 (m, 2H), 7,8 (m, 2H), 7,5 (s, 1H), 7,3 (m, 4H), 7,0 (d, J = 9 Hz, 1H), 4,8 (d, J = 8 Hz, 2H), 4,65 (t, J = 14 Hz, 2H), 4,45 (pl.s, 1H), 3,7 (dd, J = 7, 14 Hz, 1H), 3,4 (dd, J = 7,5 Hz, 1H), 1 H-NMR (CD 3 OD) δ 8.9 (s, 1H), 8.7 (m, 2H), 8.3 (m, 2H), 7.8 (m, 2H), 7.5 ( s, 1H), 7.3 (m, 4H), 7.0 (d, J = 9Hz, 1H), 4.8 (d, J = 8Hz, 2H), 4.65 (t, J = 14 Hz, 2H), 4.45 (ss, 1H), 3.7 (dd, J = 7, 14 Hz, 1H), 3.4 (dd, J = 7.5 Hz, 1H),
2,96 (dd, J = 14, 7 Hz, 1H), 2,8 (dd, J = 14, 7 Hz, 1H), 2,3 (s, 3H).2.96 (dd, J = 14, 7Hz, 1H), 2.8 (dd, J = 14, 7Hz, 1H), 2.3 (s, 3H).
(R)-4-[[2-(Dimetilamino)etil]sulfonil]-2,3,4,5-tetrahidro-1-(1H-imidazol-4i Im eti l)-7-f eni I-3-(f enilmeti I) -1 H-1,4-benzodiazepinas (trifluoracetatas, 1:1)(R) -4 - [[2- (Dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-yl-ethyl) -7-phenyl-3- ( phenylmethyl I) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 1)
A. (R)-7-Brom-2,3,4,5-tetrahidro-3-(fenilmetil)-1 H-1,4benzodiazepinasA. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine
Junginys A pagaminamas iš 224 pavyzdžio junginio A pagal 75 pavyzdyje aprašytą junginio B sintezės metodiką.Compound A is prepared from Example 224 Compound A according to the procedure for the synthesis of Compound B described in Example 75.
190190
B. (R)-7-Fenil-2,3,4,5-tetrahidro-3-(fenilmetil)-1H-1,4benzodiazepinas l junginio A (500 mg, 1,58 mmol) toluene (20 m!) ir vandeninio natrio rūgščiojo karbonato (10 ml, sotus tirpalas) mišinj argono atmosferoje pridedama fenilboro rūgšties tirpalo (385 mg 5 ml absoliutaus etanolio). Pridedama tetrakis(trifenilfosfino) paladžio(O) (91 mg), ir tirpalas virinamas su grįžtamu šaldytuvu (~80 °C). Po 18 vai. mišinys atšaldomas iki kambario temperatūros ir paskirstomas tarp vandeninio natrio hidroksido (100 ml, 3N) ir etilacetato (100 ml). Mišinys ekstrahuojamas etilacetatu (2 x 200 ml), organiniai sluoksniai sumaišomi, džiovinami (MgSO4) ir sukoncentruojama vakuume iki alyvos, kuri gryninama sparčiosios chromatografijos metodu (60 g silikagelio, 10 : 0,5 : 0,05 etilacetatas : metanolis : amonio hidroksidas). Gaunamas junginys B (350 mg, 70 %), kuris yra vaško pavidalo kieta medžiaga.B. (R) -7-Phenyl-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine Compound A (500 mg, 1.58 mmol) in toluene (20 mL) and aqueous sodium bicarbonate (10 mL, saturated solution) was added a solution of phenylboronic acid (385 mg in 5 mL of absolute ethanol) under argon. Tetrakis (triphenylphosphine) palladium (O) (91 mg) is added and the solution is refluxed (~ 80 ° C). After 18 or. the mixture was cooled to room temperature and partitioned between aqueous sodium hydroxide (100 mL, 3N) and ethyl acetate (100 mL). The mixture was extracted with ethyl acetate (2 x 200 mL), the organic layers were combined, dried (MgSO 4 ) and concentrated in vacuo to an oil which was purified by flash chromatography (60 g silica gel, 10: 0.5: 0.05 ethyl acetate: methanol: ammonium hydroxide). ). Compound B (350 mg, 70%) is obtained which is a waxy solid.
C. (R)-4-Etenilsulfonil-2,3,4,5-tetrahidro-7-fenil-3-(fenilmetil)-1 H-1,4benzodiazepinas j junginio B (45 mg, 0,14 mmol) metileno chloride (5 mf) ir vandeninio natrio hidroksido (1 ml, 1M tirpalas) mišinj pridedama 2chloretansulfonilchlorido (0,8 ml, 0,07 mmol). Kas 6 vai. pridedamos papildomos 2-chloretansulfonilchlorido porcijos (0,1 ml, 0,2 ml, 0,2 ml), mišinys maišomas 18 vai., supilamas j sotų NaCl tirpalą ir ekstrahuojamas etilacetatu (3 x 100 ml). Organiniai sluoksniai sumaišomi, džiovinami (MgSO4) ir vakuume sukoncentruojama iki alyvos, kuri gryninama preparatinės HPLC metodu (ODS kolonėlė, vandeninio metanolio, kuriame yra trifluoracto rūgšties, gradientas). Atitinkami mėginiai, kuriuose yra produkto, supilami kartu, ir sukoncentravus vakuume, gaunamas junginys C (10 mg, 17 %), kuris yra skaidri alyva.C. (R) -4-Ethenylsulfonyl-2,3,4,5-tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine in Compound B (45 mg, 0.14 mmol) in methylene chloride (5 mL) and aqueous sodium hydroxide (1 mL, 1M solution) were added 2-chloroethanesulfonyl chloride (0.8 mL, 0.07 mmol). What 6 or. additional portions of 2-chloro-ethanesulfonyl chloride (0.1 mL, 0.2 mL, 0.2 mL) were added, the mixture was stirred for 18 h, poured into saturated NaCl solution and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried (MgSO 4 ), and concentrated in vacuo to an oil which was purified by preparative HPLC (ODS column, gradient of aqueous methanol containing trifluoroacetic acid). The appropriate samples containing the product were combined and concentrated in vacuo to give Compound C (10 mg, 17%) as a clear oil.
D. (R)-4-[[2-(Dimetilamino)etil]sulfoniI]-2,3,4,5-tetrahidro-7-fenil-3(fenilmetil)-1H-1,4-benzodiazepinasD. (R) -4 - [[2- (Dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-7-phenyl-3 (phenylmethyl) -1H-1,4-benzodiazepine
191191
Į junginio C (20 mg, 0,025 mmol) tirpalą tetrahidrofurane (2 ml) pridedamas dimetilamino tirpalas (1 ml, 2M THF). Šis tirpalas šildomas sandariai uždarytame slėgį išlaikančiame butelyje 60 °C temperatūroje 18 vai., atšaldomas iki kambario temperatūros ir vakuume sukoncentruojamas iki alyvos.To a solution of Compound C (20 mg, 0.025 mmol) in tetrahydrofuran (2 mL) was added dimethylamine solution (1 mL, 2M THF). This solution is heated in a sealed pressure bottle at 60 ° C for 18 hours, cooled to room temperature and concentrated in vacuo to an oil.
E. (R)-4-[[2-(Dimetilamino)etil]sulfonil]-2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-7-fenil-3-(fenilmetil)-1H-1,4-benzodiazepinas (trifluoracetatas, 1:1)E. (R) -4 - [[2- (Dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) - 1H-1,4-benzodiazepine (trifluoroacetate, 1: 1)
Junginio D (20 mg, negrynintas, priimama, kad jame yra 0,05 mmol medžiagos) ir 4-formilimidazolo (10 mg, 0,1 mmol) tirpalas dichloretane (4 ml) ir acto rūgštyje (2 ml) maišomas kambario temperatūroje 30 min. Pridedama natrio triacetoksiborhidrido (22 mg, 0,1 mmol) ir tirpalas maišomas 48 vai., praskiedžiamas etilacetatu (20 ml) ir amonio hidroksidu (5 ml, kone.) ir maišomas dar 30 min. Mišinys ekstrahuojamas etilacetatu (2 x 25 ml), sumaišyti organiniai ekstraktai plaunami vandeniniu natrio rūgščiuoju karbonatu (25 ml, sotus tirpalas), po to amonio chloridu (25 ml, sotus vandeninis tirpalas), džiovinami (Na2SO4) ir sukoncentruojama vakuume iki pusiau kietos medžiagos. Ši negryna medžiaga gryninama preparatinės HPLC metodu (vandeninio metanolio, turinčio 0,1 % trifluoracto rūgšties, gradientas, C-18 kolonėlė), ir po liofilizącijos gaunamas 232 pavyzdžio junginys, kuris yra balta kieta medžiaga (10 mg, 37 % išeiga, skaičiuojant pagal junginį C). Lyd. temp.: 115-120 °C.A solution of compound D (20 mg, crude, assumed to contain 0.05 mmol) and 4-formylimidazole (10 mg, 0.1 mmol) in dichloroethane (4 mL) and acetic acid (2 mL) was stirred at room temperature for 30 min. . Sodium triacetoxyborohydride (22 mg, 0.1 mmol) was added and the solution was stirred for 48 h, diluted with ethyl acetate (20 mL) and ammonium hydroxide (5 mL, almost) and stirred for a further 30 min. The mixture was extracted with ethyl acetate (2 x 25 mL), the combined organic extracts washed with aqueous sodium bicarbonate (25 mL, saturated solution) followed by ammonium chloride (25 mL, saturated aqueous solution), dried (Na 2 SO 4 ) and concentrated in vacuo to semi-solids. This crude material was purified by preparative HPLC (gradient of aqueous methanol containing 0.1% trifluoroacetic acid, C-18 column) to give, after lyophilization, the compound of Example 232 as a white solid (10 mg, 37% yield). compound C). Lyd. mp: 115-120 ° C.
MS (M + H)+ 530.MS (M + H) < + > 530.
Ή-BMR (200 MHz, CD3OD) δ 8,8 (d, 1H), 7,7-7,4 (m, 12H), 7,1 (d, 1H), 4,9 (s, 6H), 3,4-3,1 (m, 8H), 3,8-3,2 (m, 8H), 2,7 (s, 6H).1 H-NMR (200 MHz, CD 3 OD) δ 8.8 (d, 1H), 7.7-7.4 (m, 12H), 7.1 (d, 1H), 4.9 (s, 6H) ), 3.4-3.1 (m, 8H), 3.8-3.2 (m, 8H), 2.7 (s, 6H).
233 pavyzdysExample 233
192 °γθ192 ° γθ
[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-1H1,4-benzodiazepin-8-il]karbamo rūgšties cikloheksilo esteris (dihidrochloridas)[2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepin-8-yl] carbamic acid cyclohexyl ester (dihydrochloride)
Cikloheksanolio (0,14 ml, 0,137 g, 1,38 mmol) ir fosgeno (0,14 ml, 2M tirpalas THF) maišomas 4 °C temperatūroje 2 vai. j šį šaltą tirpalą pridedama trietilamino (0,19 ml, 0,14 g, 1,38 mmol) ir 26 pavyzdžio junginio (0,050 g, 0,12 mmol), Pamaišius 16 vai. 4 °C temperatūroje, mišinys praskiedžiamas chloroformu ir NaHCO3 tirpalu ir atskiriami sluoksniai. Vandeninis sluoksnis ekstrahuojamas CHCI3 (2 x 30 ml), sumaišyti organiniai sluoksniai plaunami sočiu NaCl tirpalu (1 x 30 ml), džiovinami MgSO4, nufiltruojami ir koncentruojami. Liekana veikiama MeOH ir ,1N NaOH 30 min. Negrynas produktas gryninamas preparatinę HPLC (vandeninio metanolio, kuriame yra 0,1 % trifluoracto rūgšties, gradientas, C-18 kolonėlė) ir liofilizuojamas. Liekana veikiama HCI/eteryje, ir gaunamas 233 pavyzdžio junginys (0,030 g, 46 %), kuris yra gelsva kieta medžiaga.Cyclohexanol (0.14 mL, 0.137 g, 1.38 mmol) and phosgene (0.14 mL, 2M in THF) were stirred at 4 ° C for 2 h. To this cold solution was added triethylamine (0.19 mL, 0.14 g, 1.38 mmol) and Example 26 (0.050 g, 0.12 mmol), after stirring for 16 h. At 4 ° C, the mixture was diluted with chloroform and NaHCO 3 solution and the layers separated. The aqueous layer was extracted with CHCl 3 (2 x 30 mL), the combined organic layers were washed with brine (1 x 30 mL), dried over MgSO 4 , filtered, and concentrated. The residue was treated with MeOH and 1N NaOH for 30 min. The crude product was purified by preparative HPLC (gradient of aqueous methanol containing 0.1% trifluoroacetic acid, C-18 column) and lyophilized. The residue was treated with HCl / ether to give Example 233 (0.030 g, 46%) as a yellowish solid.
MS (M + H)+ 524.MS (M + H) < + > 524.
1H-BMR (270 MHz, CD3OD) δ 8,0-6,9 (m, 11H), 6,81 (d, 0,5H, J = 8 Hz), 5,85 (d, 0,5H, J = 9 Hz), 5,85 (m, 1H), 4,4-4,0 (m, 3H), 3,9-3,7 (m, 0,5H), 3,4-3,1 (m, 1,5H), 2,88 (m, 1H), 2,0-1,2 (m, 12H). 1 H-NMR (270 MHz, CD 3 OD) δ 8.0-6.9 (m, 11H), 6.81 (d, 0.5H, J = 8 Hz), 5.85 (d, 0, 5H, J = 9Hz), 5.85 (m, 1H), 4.4-4.0 (m, 3H), 3.9-3.7 (m, 0.5H), 3.4-3 , 1 (m, 1.5H), 2.88 (m, 1H), 2.0-1.2 (m, 12H).
234 pavyzdysExample 234
193193
(R)-7-Brom-2,3,4,5-tetrahidro-1-(1-metil-1H-imidazol-5-il)metil)-4(metilsulfonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (hidrochloridas)(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-yl) methyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H- 1,4-Benzodiazepine (hydrochloride)
A. (R)-7-Brom-2,3,4,5-tetrahidro-1-[(((1,1-dimetiietoksi)karbonil)-1Himidazol-4-il)metil]-4-(metilsulfonil)-3-(fenilmetil)-1 H-1,4benzodiazepinasA. (R) -7-Bromo-2,3,4,5-tetrahydro-1 - [(((1,1-dimethoxyethoxy) carbonyl) -1Himidazol-4-yl) methyl] -4- (methylsulfonyl) - 3- (phenylmethyl) -1H-1,4-benzodiazepine
J 260 mg (0,55 mmol) 224 pavyzdžio junginio tirpalą 10 ml metileno chlorido pridedama 131 mg (0,60 mmol) BOC anhidrido ir 3 mg (0,025 mmol) DMAP. Skaidrus bespalvis tirpalas maišomas kambario temperatūroje argono atmosferoje 3 vai. Pridedama dar 40 mg BOC anhidrido ir maišoma per naktį. Neapdorotas mišinys supilamas į 30 cm3 silikagelio kolonėlę ir eliuuojama 25 % etilacetato tirpalu heksane; gaunama 290 mg (0,55 mmol, 100 %) junginio A, kuris yra balta putų pavidalo medžiaga.To a solution of 260 mg (0.55 mmol) of Example 224 in 10 mL of methylene chloride was added 131 mg (0.60 mmol) of BOC anhydride and 3 mg (0.025 mmol) of DMAP. The clear colorless solution was stirred at room temperature under argon for 3 hours. Another 40 mg of BOC anhydride was added and stirred overnight. The crude mixture was applied to a 30 cm 3 silica gel column and eluted with 25% ethyl acetate in hexane; 290 mg (0.55 mmol, 100%) of compound A is obtained which is a white foam.
B. (R)-7-Brom-2,3,4,5-tetrahidro-1-(1-metil-1H-imidazol-5-il)metil)-4(metilsulfonil)-3-(fenilmetil)-1H-1,4-benzodiazepinas (hidrochloridas)B. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-yl) methyl) -4 (methylsulfonyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine (hydrochloride)
J 275 mg (0,48 mmol) junginio A ir 0,091 ml (0,52 mmol) DIEA tirpalą 5 ml metileno chlorido -78 °C temperatūroje argono atmosferoje sulašinama 0,059 ml (0,52 mmol) metiltriflato. Mišiniui leidžiama sušilti iki kambario temperatūros per 3 vai. Dar pridedama 0,091 ml (0,52 mmol) DIEA ir 0,059 ml (0,52 mmol) metiltriflato. Maišoma kambario temperatūroje per naktį. Kas 1 vai. dar tris kartus pridedama po 0,091 ml (0,52 mmol) diizopropiletilamino ir po 0,059 ml (0,52 mmol) metiltriflato. Neapdorotas reakcijos mišinys supilamas į 50 cm3 silikagelio kolonėlę. Eliuuojama CHCKMeOH (98:2) irA solution of 275 mg (0.48 mmol) of Compound A and 0.091 mL (0.52 mmol) of DIEA in 5 mL of methylene chloride is added dropwise to 0.059 mL (0.52 mmol) of methyl triflate at -78 ° C under argon. The mixture was allowed to warm to room temperature over 3 hours. A further 0.091 mL (0.52 mmol) of DIEA and 0.059 mL (0.52 mmol) of methyl triflate are added. Stir at room temperature overnight. What 1 or. three additional portions of 0.091 mL (0.52 mmol) of diisopropylethylamine and 0.059 mL (0.52 mmol) of methyl triflate were added. The crude reaction mixture was applied to a 50 cm 3 silica gel column. Elute with CHCKMeOH (98: 2) and
194 gaunama 134 mg 234 pavyzdžio junginio laisvos bazės, kuri yra balta putų pavidalo medžiaga. J šios medžiagos tirpalą 2 ml etilacetato sulašinama 0,26 ml 1N HCI/eteryje. Nufiltravus susidariusią kietą medžiagą, gaunamas 234 pavyzdžio junginys (102 mg, 38 %), kuris yra balta kieta medžiaga.194 gives 134 mg of the free base of compound 234 as a white foam. To a solution of this material in 2 ml of ethyl acetate is added 0.26 ml of 1N HCl / ether. Filtration of the resulting solid gave Example 234 (102 mg, 38%) as a white solid.
MS (M + H)+ 489, 491.MS (M + H) + 489, 491.
Analizė išskaičiuota pagal C22H24N4O2CI 0,25 EtOAc · 1,25 HCI.Analysis calculated for C22H24N4O2Cl 0.25 EtOAc · 1.25 HCl.
Išskaičiuota: C, 49,59; H, 5,11; N, 10,06.Found: C, 49.59; H, 5.11; N, 10.06.
Rasta: C, 49,97; H, 5,15; N, 9,90.Found: C, 49.97; H, 5.15; N, 9.90.
(R)-7-Ciano-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazol-5-il)metil]-4(metilsulfonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (monohidrochloridas) j 200 mg (0,38 mmol) (R)-7-ciano-2,3,4,5-tetrahidro-1-[(((1,1dimetiletoksi)karbonil)-1 H-imidazol-4-il)metil]-4-(metilsulfonil)-3-(fenilmetil)1H-1,4-benzodiazepino (pagaminto iš 224 pavyzdžio junginio pagal 225 pavyzdyje aprašytą junginio A sintezės metodiką) tirpalą 2 ml metileno chlorido -78 °C temperatūroje argono atmosferoje sulašinama 59 μΙ (0,48 mmol) metiltriflato. Reakcijos mišiniui leidžiama sušilti iki kambario temperatūros (per šj laiką susidaro baltos nuosėdos). Kambario temperatūroje maišoma 3 vai., po to pridedama 140 μΙ (0,8 mmol) DIEA ir kambario temperatūroje maišoma per naktį. Neapdorotas mišinys gryninamas sparčiąja chromatografija per 30 cm3 silikagelio kolonėlę.(R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 (methylsulfonyl) -3- (phenylmethyl) -1H -1,4-Benzodiazepine (monohydrochloride) 200 mg (0.38 mmol) of (R) -7-cyano-2,3,4,5-tetrahydro-1 - [(((1,1-dimethylethoxy) carbonyl) -1 H-Imidazol-4-yl) methyl] -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (prepared from the compound of Example 224 according to the procedure for the synthesis of Compound A described in Example 225) in 2 mL of methylene chloride - At 78 ° C, 59 μΙ (0.48 mmol) of methyl triflate was added dropwise under argon. The reaction mixture was allowed to warm to room temperature (a white precipitate formed during this time). After stirring at room temperature for 3 hours, 140 μΙ (0.8 mmol) of DIEA was added and stirred at room temperature overnight. The crude mixture was purified by flash chromatography over a 30 cm 3 silica gel column.
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Eliuuojama 2 % MeOH-CHCI3 ir gaunama 122 mg (0,28 mmol, 74 %) skaidrios bespalvės alyvos, kuri stovėdama išsikristalina. Ši medžiaga paverčiama hidrochlorido druska, pridedant 0,28 ml 1M HCI eteryje j laisvos bazės tirpalą metileno chloride (2 ml). Susidaro baltos nuosėdos, kurias nufiltravus, gaunama 90 mg baltų miltelių pavidalo 235 pavyzdžio junginio.Elution with 2% MeOH-CHCl 3 gave 122 mg (0.28 mmol, 74%) of a clear colorless oil which crystallized on standing. This material was converted to the hydrochloride salt by adding 0.28 mL of 1M HCl in ether to a solution of the free base in methylene chloride (2 mL). A white precipitate is formed which, after filtration, gives 90 mg of the compound of Example 235 as a white powder.
MS (M + H)+ 436.MS (M + H) + 436.
236 pavyzdys (R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-iImetil)-4-(metilsuifonil)-7-fenil-3(fenilmetil)-1H-pirido[3,2-e]-1,4-diazepinas (monohidrochloridas). BMS-214693Example 236 (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3 (phenylmethyl) -1H-pyrido [3.2 -e] -1,4-diazepine (monohydrochloride). BMS-214693
A. 2-Hidroksi-5-nitro-6-metilpiridinas j 2-aminO'5-nitro-6-metilpiridino ir 2-amino-3-nitro-6-metilpiridino 2:1 mišinj (2,5 g, 16,3 mmol) 15 ml vandens 0 °C temperatūroje pridedama koncentruotos sulfato rūgšties (5 ml), o po to per 90 min. sulašinamas NaNO2 (2,25 g, 32,6 mmol) tirpalas 5 ml vandens. Kai tirpalas sušyla iki kambario temperatūros, maišoma 5 vai., atšaldoma iki 0 °C ir nufiltruojama. Kieta medžiaga plaunama vandeniu (2x) ir išdžiovinus vakuume, gaunama 1,84 g junginio A ir 2-hidroksi-3-nitro-6-metilpiridino (73 %) >4:1 mišinio (pagal HPLC), kuris yra gelsvai ruda kieta medžiaga.A. 2-Hydroxy-5-nitro-6-methylpyridine in 2: 1 mixture of 2-amino-5'-nitro-6-methylpyridine and 2-amino-3-nitro-6-methylpyridine (2.5 g, 16.3) mmol) in 15 mL of water at 0 ° C was added concentrated sulfuric acid (5 mL) followed by 90 min. a solution of NaNO 2 (2.25 g, 32.6 mmol) in 5 mL of water was added dropwise. After the solution has reached room temperature, it is stirred for 5 hours, cooled to 0 ° C and filtered. The solid was washed with water (2x) and dried in vacuo to give 1.84 g of a> 4: 1 mixture of Compound A and 2-hydroxy-3-nitro-6-methylpyridine (73%) as a tan solid. .
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B. 2-Chlor-5-nitro-6-metilpiridinasB. 2-Chloro-5-nitro-6-methylpyridine
Junginio A, 2-hidroksi-3-nitro-6-metilpiridino (0,93 g, 6,05 mmol) ir fosforo pentachlorido (48,9 g, 235 mmol) mišinys toluene (10 ml) kaitinamas 92 °C temperatūroje 16 vai. ir atšaldomas iki 0 °C. Pridedama ledo, ir mišinys maišomas ir paskirstomas. Vandeninis sluoksnis plaunamas toluenu, sumaišytos organinės fazės džiovinamos (magnio sulfatu), nufiltruojama ir nugarinus gaunama 1,03 g junginio B ir 2-chlor-3-nitro-6-metilpiridino 6:1 mišinio (100 %), kuris yra rausvai ruda pusiau kristalinė medžiaga.A mixture of compound A, 2-hydroxy-3-nitro-6-methylpyridine (0.93 g, 6.05 mmol) and phosphorus pentachloride (48.9 g, 235 mmol) in toluene (10 mL) was heated at 92 ° C for 16 h. . and cooled to 0 ° C. Ice is added and the mixture is stirred and distributed. The aqueous layer is washed with toluene, the combined organic phases are dried (magnesium sulfate), filtered and evaporated to give 1.03 g of a 6: 1 mixture (100%) of Compound B and 2-chloro-3-nitro-6-methylpyridine (100%). crystalline material.
C. 2-Fenil-5-nitro-6-metilpiridinasC. 2-Phenyl-5-nitro-6-methylpyridine
Junginio B ir 2-chlor-3-nitro-6-metilpiridino (0,42 g, 2,40 mmol) mišinys THF (10 ml) degazuojamas azotu. Pridedama tetrakistrifenilfosfino paladžio (28 mg, 0,024 mmol), ir mišinys maišomas 30 min. Pridedama fenilboro rūgšties (0,44 g, 3,6 mmol) ir 2M Na2CO3 (1,8 ml), ir mišinys kaitinamas 75 °C temperatūroje 17 vai. ir maišomas kambario temperatūroje 48 vai. Pridedama metileno chlorido, mišinys nufiltruojamas per celitą ir paskirstomas. Mišinys plaunamas sočiu vandeniniu NaHCO3, džiovinamas (magnio sulfatu), nufiltruojamas ir nugarinus gaunama 0,77 g rudos kietos medžiagos. Po sparčiosios chromatografijos (silikagelis, 10 % etilacetatas/heksanuose) gaunama 0,37 g junginio C (72 %), kuris yra balta kieta medžiaga, ir 0,05 g 2fenil-3-nitro-6-metilpiridino (10 %), kuris yra alyva.A mixture of compound B and 2-chloro-3-nitro-6-methylpyridine (0.42 g, 2.40 mmol) in THF (10 mL) was degassed with nitrogen. Tetrakistriphenylphosphine palladium (28 mg, 0.024 mmol) is added and the mixture is stirred for 30 min. Phenylboronic acid (0.44 g, 3.6 mmol) and 2M Na 2 CO 3 (1.8 mL) were added and the mixture heated at 75 ° C for 17 h. and stirred at room temperature for 48 hours. Methylene chloride is added and the mixture is filtered through celite and partitioned. The mixture was washed with saturated aqueous NaHCO 3 , dried (magnesium sulfate), filtered and evaporated to give 0.77 g of a brown solid. Flash chromatography (silica gel, 10% ethyl acetate / hexanes) affords 0.37 g of compound C (72%) as a white solid and 0.05 g of 2-phenyl-3-nitro-6-methylpyridine (10%) is oil.
D. 2-Fenil-5-amino-6-metilpiridinas j junginio C (3,0 g, 14 mmol) suspensiją koncentruotoje HCI (30 ml) dalimis per 45 min. pridedama alavo chlorido dihidrato (9,91 g, 44 mmol). Per 2 vai. tirpalui leidžiama sušilti iki kambario temperatūros, pašildoma 78 °C temperatūroje 15 min., atšaldoma iki 0 °C, neutralizuojama 4M NaOH ir ekstrahuojama metileno chloridu (3x). Sumaišytos organinės fazės džiovinamos (magnio sulfatu), nufiltruojama ir nugarinus gaunama 2,62 g junginio D (100 %), kuris yra geltona alyva, išsikristalinanti stovint.D. 2-Phenyl-5-amino-6-methylpyridine into a suspension of Compound C (3.0 g, 14 mmol) in concentrated HCl (30 mL) over 45 min. tin chloride dihydrate (9.91 g, 44 mmol) was added. Within 2 or. the solution was allowed to warm to room temperature, warmed to 78 ° C for 15 min, cooled to 0 ° C, neutralized with 4M NaOH and extracted with methylene chloride (3x). The combined organic phases were dried (magnesium sulfate), filtered and evaporated to give 2.62 g of compound D (100%) as a yellow oil which crystallized on standing.
E. 2-Fenil-5-(fenilsulfonilamino)-6-metilpiridinasE. 2-Phenyl-5- (phenylsulfonylamino) -6-methylpyridine
197197
2-Fenil-5-amino-6-metilpiridino (2,29 g, 12,4 mmol) ir benzensulfonilchlorido (1,65 ml, 12,9 mmol) mišinys kaitinamas 88 °C temperatūroje 15 vai. Mišinys atšaldomas, ir gauta stiklo pavidalo medžiaga ištirpinama metileno chlorido ir 10 % NaOH mišinyje. Mišinys paskirstomas, organinė fazė plaunama 10 % NaOH, sumaišytos vandeninės fazės parūgštinamos koncentruota HCl ir ekstrahuojamos metileno chloridu (2x). Sumaišytos organinės fazės džiovinamos (magnio sulfatu), nufiltruojama ir nugarinus gaunama 3,40 g junginio D (85 %), kuris yra gelsva kristalinė kieta medžiaga.A mixture of 2-phenyl-5-amino-6-methylpyridine (2.29 g, 12.4 mmol) and benzenesulfonyl chloride (1.65 mL, 12.9 mmol) was heated at 88 ° C for 15 h. The mixture was cooled and the resulting glass material was dissolved in a mixture of methylene chloride and 10% NaOH. The mixture is partitioned, the organic phase is washed with 10% NaOH, the combined aqueous phases are acidified with concentrated HCl and extracted with methylene chloride (2x). The combined organic phases were dried (magnesium sulfate), filtered and evaporated to give 3.40 g of compound D (85%) as a yellowish crystalline solid.
F. 2-Fenil-5-(feniisuIfonilamino)-6-metilpiridin-N-oksidas { junginio E (3,0 g, 9,24 mmol) suspensiją acto rūgštyje (28 ml) pridedama 30 % vandeninio vandenilio peroksido (9,25 ml). Mišinys šildomas 72 °C tempertatūroje 4 vai. ir 62 °C temperatūroje - 22 vai.Pridedama dar 3 ml H2O2, mišinys šildomas 54 °C temperatūroje 20 vai. ir supilamas j ledą. Šis mišinys paliekamas per naktį, pridedama 200 ml vandens, gauta kieta medžiaga nufiltruojama, plaunama vandeniu ir eteriu, ir išdžiovinus vakuume, gaunama 1,43 g (46 %) junginio F, kuris yra geltona kieta medžiaga, turinčio junginio E priemaišų. Plovimui naudotas vanduo ir eteris ekstrahuojami metileno chloridu, ir gaunama 1,0 g junginio E ir junginio F mišinio (maždaug 4:1).F. 2-Phenyl-5- (phenylsulfonylamino) -6-methylpyridine-N-oxide {A suspension of E (3.0 g, 9.24 mmol) in acetic acid (28 mL) was added with 30% aqueous hydrogen peroxide (9.25) ml). The mixture was heated at 72 ° C for 4 h. and at 62 ° C for 22 hours. An additional 3 ml of H 2 O 2 was added and the mixture heated at 54 ° C for 20 hours. and pouring on ice. The mixture is left overnight, 200 ml of water are added, the resulting solid is filtered off, washed with water and ether and dried in vacuo to give 1.43 g (46%) of the compound F, which is a yellow solid, containing impurity E. The washing water and ether were extracted with methylene chloride to give 1.0 g of a mixture of compound E and compound F (approximately 4: 1).
MS (M + H)+341,1.MS (M + H) + 341.1.
G. 2-Fenil-5-(fenilsulfonilamino)-6-acetoksimetilpiridinasG. 2-Phenyl-5- (phenylsulfonylamino) -6-acetoxymethylpyridine
Negryninto junginio F (0,50 g, <1,47 mmol) ir acto rūgšties anhidrido (2,5 ml) tirpalas acto rūgštyje (5 ml) šildomas 90 °C temperatūroje 4 vai., atšaldomas ir supilamas į ledą. Pastovėjęs per naktį, mišinys ekstrahuojamas du kartus metileno chloridu, sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojami ir nugarinus gaunamas junginys G (0,60 g, >100 %), kuris yra geltona putų pavidalo derva.A solution of crude compound F (0.50 g, <1.47 mmol) and acetic anhydride (2.5 mL) in acetic acid (5 mL) was heated at 90 ° C for 4 h, cooled and poured into ice. After standing overnight, the mixture was extracted twice with methylene chloride, the combined organic extracts dried (MgSO 4 ), filtered and evaporated to give compound G (0.60 g,> 100%) as a yellow foam.
H. 2-Fenil-5-(fenilsulfonilamino)-6-hidroksimetilpiridinasH. 2-Phenyl-5- (phenylsulfonylamino) -6-hydroxymethylpyridine
198198
Junginio G (0,60 g, <1,47 mmol) ir 2M NaOH (2 ml) mišinys šildomas 50 °C temperatūroje 2,25 vai. ir atšaldomas iki 0 °C. Pridedama metileno chlorido, o po to koncentruotos vandeninės HCI tol, kol ištirpsta kieta medžiaga. Dedamas kietas Na2HPO4 tol, kol pasiekiamas vandeninės fazės pH 7, ir mišinys išskirstomas. Vandeninė fazė ekstrahuojama metileno chloridu, sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojami ir nugarinami. Liekana gryninama sparčiosios chromatografijos per silikagėlį metodu, eliuuojant 50 % etilacetatu/heksanuose ir gaunama 0,09 g junginio F ir 0,24 g dervos pavidalo junginio H (48 % skaičiuojant pagal negrynintą jungini F).A mixture of Compound G (0.60 g, <1.47 mmol) and 2M NaOH (2 mL) was heated at 50 ° C for 2.25 h. and cooled to 0 ° C. Methylene chloride is added followed by concentrated aqueous HCl until the solid is dissolved. Solid Na 2 HPO 4 is added until the aqueous phase reaches pH 7 and the mixture is partitioned. The aqueous phase is extracted with methylene chloride, the combined organic extracts are dried (MgSO 4 ), filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with 50% ethyl acetate / hexanes to give 0.09 g of compound F and 0.24 g of resin compound H (48% based on crude compound F).
I. 2-Fenil-5-(fenilsulfonilamino)-piridin-6-karboksaldehidasI. 2-Phenyl-5- (phenylsulfonylamino) -pyridine-6-carboxaldehyde
J negryninto junginio H (0,70 g, 2,06 mmol) tirpalą THF (10 ml) pridedama MnO2 (0,36 g, 4,11 mmol). Mišinys maišomas kambario temperatūroje ir vėl pridedama MnO2 po: 1 vai., 0,36 g; 2 vai., 0,36 g; 3 vai., 0,36 g; 7,5 vai., 0,72 g; 22,5 vai., 0,72 g; 32 vai., 0,72 g. Pamaišius 32,5 vai., mišinys nufiltruojamas per celitą, ant filtro esanti medžiaga plaunama tris kartus kartu su celitu, ir nugarinus gaunama 0,55 g junginio I (79 %), kuris yra oranžinė kieta medžiaga. MS (M+H)+ 339,0.To a solution of crude compound H (0.70 g, 2.06 mmol) in THF (10 mL) was added MnO 2 (0.36 g, 4.11 mmol). The mixture was stirred at room temperature and MnO 2 was added again after 1 h, 0.36 g; 2 or 0.36 g; 3 or 0.36 g; 7.5 or 0.72 g; 22.5 or 0.72 g; 32 or 0.72 g. After stirring for 32.5 hours, the mixture is filtered through celite, the filter cake is washed three times with celite to give 0.55 g of compound I (79%) as an orange solid. MS (M + H) + 339.0.
J. D-[N-(2-fenil-5-(fenilsulfonilamino)-6-(piridinilmetil)-fenilalanino] metilo esterisJ. D- [N- (2-Phenyl-5- (phenylsulfonylamino) -6- (pyridinylmethyl) -phenylalanine] methyl ester
Junginio I (0,55 g, 1,62 mmol), D-fenilalanino metilo esterio hidrochlorido (1,05 g, 4,88 mmol), NaOAc (0,40 g, 4,88 mmol) ir 10 % Pd/C (50mg) suspensija 4 ml metanolio ir 2 ml acto rūgšties mišinyje hidrinama, leidžiant vandenilj iš baliono 18 vai., ir nufiltruojama per celitą. Ant filtro esanti medžiaga perplaunama du kartus metanoliu, ir filtratas nugarinamas. Liekana paskirstoma tarp pH 7 fosfatinio buferio ir metileno chlorido. Vandeninė fazė ekstrahuojama metileno chloridu, sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojama ir nugarinus gaunamas junginys J (1,21 g, >100 %).Compound I (0.55 g, 1.62 mmol), D-phenylalanine methyl ester hydrochloride (1.05 g, 4.88 mmol), NaOAc (0.40 g, 4.88 mmol) and 10% Pd / C The suspension (50 mg) in a mixture of 4 ml of methanol and 2 ml of acetic acid was hydrogenated by bubbling hydrogen from the cylinder for 18 hours and filtered through celite. The filter cake is washed twice with methanol and the filtrate is evaporated. The residue is partitioned between pH 7 phosphate buffer and methylene chloride. The aqueous phase was extracted with methylene chloride, the combined organic extracts dried (MgSO 4 ), filtered and evaporated to give compound J (1.21 g,> 100%).
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K. (R)-2,3,4,5-Tetrahidro-7-fenil-3-(fenilmetil)-1H-pirido[3,2-e]-1,4diazepin-2-onasK. (R) -2,3,4,5-Tetrahydro-7-phenyl-3- (phenylmethyl) -1H-pyrido [3,2-e] -1,4-diazepin-2-one
Junginio J (1,21 g, <1,62 mmol) ir polifosforo rūgšties (16 g) mišinys kaitinamas 100 °C temperatūroje 5 vai. Pridedama ledo ir metileno chlorido, ir mišinys atvėsinamas, pašarminamas 4N NaOH ir atskiriami sluoksniai. Vandeninė fazė plaunama du kartus metileno chloridu, sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojami ir nugarinami. Liekana gryninama sparčiosios chromatografijos metodu per silikagelį, eliuuojant 75 % etilacetatu/heksanuose ir gaunama 0,31 g (58 % skaičiuojant pagal junginjA mixture of compound J (1.21 g, <1.62 mmol) and polyphosphoric acid (16 g) was heated at 100 ° C for 5 h. Ice and methylene chloride are added and the mixture is cooled, basified with 4N NaOH and the layers separated. The aqueous phase is washed twice with methylene chloride, and the combined organic extracts are dried (MgSO 4 ), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 75% ethyl acetate / hexanes to give 0.31 g (58% based on compound).
I) junginio K, kuris yra nelabai balta kieta medžiaga. MS (M + H)+ 330,0.I) Compound K which is an off-white solid. MS (M + H) + 330.0.
L. (R)-2,3,4,5-Tetrahidro-4-(metilsulfonil)-7-fenil-3-(fenilmetil)-1Hpirido[3,2-e]-1,4-diazepin-2-onasL. (R) -2,3,4,5-Tetrahydro-4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H-pyrido [3,2-e] -1,4-diazepin-2-one
J junginio K (117 mg, 0,36 mmol) ir TEA (0,06 ml, 0,43 mmol) tirpalą metileno chloride (3 ml) 0 °C temperatūroje pridedama metansulfonilchlorido (0,033 ml, 0,43 mmol). Tirpalas maišomas 0 °C temperatūroje 30 min. ir kambario temperatūroje - 90 min. Vėl pridedama TEA (0,06 ml) ir metansulfonilchlorido (0,032 ml), tirpalas pamaišomas 1 vai. ir paskirstomas tarp vandeninio NaHCO3 ir metileno chlorido, kuriame yra šiek tiek izopropanolio (<10 %). Vandeninis sluoksnis plaunamas metileno chloridu, sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojami ir nugarinus gaunama 145 mg junginio L, kuris yra kieta medžiaga (100 %).To a solution of compound J (117 mg, 0.36 mmol) and TEA (0.06 mL, 0.43 mmol) in methylene chloride (3 mL) at 0 ° C was added methanesulfonyl chloride (0.033 mL, 0.43 mmol). The solution was stirred at 0 ° C for 30 min. and at room temperature for 90 min. TEA (0.06 mL) and methanesulfonyl chloride (0.032 mL) were added again and the solution was stirred for 1 h. and partitioned between aqueous NaHCO 3 and methylene chloride containing a small amount of isopropanol (<10%). The aqueous layer was washed with methylene chloride, the combined organic extracts dried (MgSO 4 ), filtered and evaporated to give 145 mg of compound L as a solid (100%).
MS (M + H)+ 408,1.MS (M + H) + 408.1.
M. (R)-2,3,4,5-Tetrahidro-4-(metilsulfonil)-7-fenil-3-(fenilmetil)-1Hpi rido [3,2-e]-1,4-diazepinasM. (R) -2,3,4,5-Tetrahydro-4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H-pyrido [3,2-e] -1,4-diazepine
J junginio L (53 mg, 0,13 mmol) tirpalą THF (2 ml) 0 °C temperatūroje pridedama 1M borano THF (0,39 ml). Tirpalui per naktį leidžiama sušilti iki kambario temperatūros, pridedama metanolio, ir mišinys nugarinamas. Liekana ištirpinama mažame kiekyje 10 % HCI ir metanolio, pašildoma, kol tirpalas tampa skaidrus, ir nugarinamas metanolis. Pridedama metileno chlorido, o po to kieto K2CO3, iki vandeninio sluoksnio pH pasidaro lygus 11.To a solution of compound L (53 mg, 0.13 mmol) in THF (2 mL) at 0 ° C was added 1M borane in THF (0.39 mL). The solution was allowed to warm to room temperature overnight, methanol was added and the mixture was evaporated. Dissolve the residue in a small amount of 10% HCl and methanol, heat until the solution becomes clear, and evaporate the methanol. Methylene chloride is added followed by solid K2CO3 until the aqueous layer reaches pH 11.
200200
Mišinys padalinamas, vandeninis sluoksnis plaunamas metileno chloridu, sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojama ir nugarinama. Liekana gryninama preparatinės plonasluoksnės chromatografijos per silikagelį metodu, eliuuojant 50 % etilacetatu/heksanuose. Pagrindinė vidurinio Rf juosta išpjaunama ir ekstrahuojama metileno chloridu, kuriame yra keletas lašų metanolio; gaunama gelsvų putų pavidalo 25 mg junginio M (49 %).The mixture is partitioned, the aqueous layer is washed with methylene chloride, the combined organic extracts are dried (MgSO 4 ), filtered and evaporated. The residue was purified by preparative thin layer chromatography on silica gel eluting with 50% ethyl acetate / hexanes. The principal R f band is cut and extracted with methylene chloride containing a few drops of methanol; Yield: 25 mg of compound M (49%).
N. (R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-7fenil-3-(fenilmetil)-1H-pirido[3,2-e]-1,4-diazepinas (monohidrochloridas).N. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H-pyrido [3,2- e] -1,4-diazepine (monohydrochloride).
j junginio M (24 mg, 0,06 mmol) ir imidazol-4-karboksaldehido (17 mg,of compound M (24 mg, 0.06 mmol) and imidazole-4-carboxaldehyde (17 mg,
O, 18 mmol) tirpalą dichloretano (1 ml) ir acto rūgšties (0,5 ml) mišinyje pridedama natrio triacetoksiborhidrido (32 mg, 0,15 mmol). Tirpalas maišomas 1 vai., ir vėl pridedama aldehido (16 mg) ir hidrido (16 mg). Tirpalas maišomas 45 min., ir vėl pridedama hidrido (16 mg). Pridedama NH4OH (0,5 ml), po to etilacetato ir vandeninio NaHCO3. Mišinys išskirstomas, vandeninis sluoksnis plaunamas etilacetatu, sumaišyti organiniai ekstraktai plaunami sočiu NaHCO3 ir sočiu NaCl, džiovinami (MgSO4), nufiltruojama ir nugarinus gaunama junginio N laisva bazė (25 mg, 89 %), kuri yra balta putų pavidalo derva. Ši medžiaga ištirpinama metileno chloride, tirpalas nufiltruojamas per stiklo vatą ir nugarinamas. Liekana ištirpinama metanolyje, pridedama 0,5 ml 1M HCI eteryje, ir mišinys nugarinamas. Liekana nugarinama iš metanolio, ištirpinama 2 ml metanolio, ir tirpalas nufiltruojamas per stiklo vatą. Filtratas nugarinamas, o liekana ištirpinama 0,5 ml metanolio. Pridedama eterio (10 ml), ir gautos nuosėdos nufiltruojamos, perplaunamos eteriu, ir išdžiovinus gaunama 236 pavyzdžio junginys (24 mg), kuris yra geltona kieta medžiaga.A solution of 18 mmol) in dichloroethane (1 mL) and acetic acid (0.5 mL) was added sodium triacetoxyborohydride (32 mg, 0.15 mmol). The solution is stirred for 1 hour and aldehyde (16 mg) and hydride (16 mg) are added again. The solution was stirred for 45 min and hydride (16 mg) was added again. NH 4 OH (0.5 mL) was added followed by ethyl acetate and aqueous NaHCO 3 . The mixture is partitioned, the aqueous layer is washed with ethyl acetate, the combined organic extracts are washed with saturated NaHCO 3 and saturated NaCl, dried (MgSO 4 ), filtered and evaporated to give the free base of compound N (25 mg, 89%) as a white foam. This material is dissolved in methylene chloride, the solution is filtered through glass wool and evaporated. The residue was dissolved in methanol, added with 0.5 mL of 1M HCl in ether, and the mixture was evaporated. Evaporate the residue from methanol, dissolve in 2 ml of methanol and filter through a glass of cotton wool. The filtrate was evaporated and the residue was dissolved in 0.5 ml of methanol. Ether (10 mL) was added and the resulting precipitate was filtered off, washed with ether and dried to give Example 236 (24 mg) as a yellow solid.
MS (M + H)+ 474,3.MS (M + H) + 474.3.
Ή-BMR (CD3OD) δ 2,18 (3H, s); 2,76-2,92 (2H, m); 3,65 (1H, dd, J = 4,4,1 H-NMR (CD 3 OD) δ 2.18 (3H, s); 2.76-2.92 (2 H, m); 3.65 (1H, dd, J = 4.4,
15,2 Hz); 3,98 (1H, dd, J = 10,6, 15,2 Hz); 4,75 (1H, m); 5,18 (1H, d, J = 18,815.2 Hz); 3.98 (1H, dd, J = 10.6, 15.2 Hz); 4.75 (1H, m); 5.18 (1H, d, J = 18.8
Hz); 7,26-7,40 (5H, m); 7,58-7,61 (4H, m); 7,76-7,90 (4H, m).Hz); 7.26-7.40 (5 H, m); 7.58-7.61 (4 H, m); 7.76-7.90 (4 H, m).
201201
4-[2-(4-Chlorfenil)-1,2-dioksoetil]-2,3,4,5-tetrahidro-1-(1H-imidazol-4ilmetil)-7-fenil-1H-1,4-benzodiazepinas (hidrochloridas).4- [2- (4-Chlorophenyl) -1,2-dioxoethyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine ( hydrochloride).
j 2-(4-chlorfenil)-2-oksoacto rūgštį (0,017 g, 0,092 mmol) pridedama HOAt (0,013 g, 0,092 mmol) tirpalo DMF (0,5 ml). į mišinį pridedama 33 pavyzdžio junginio B tirpalo DMF (0,2M, 0,46 ml, 0,092 mmol) ir DIC tirpalo DMF (0,2M, 0,014 ml, 0,092 mmol), ir mišinys maišomas kambario temperatūroje 16 vai. Mišinys gryninamas jonų mainų chromatografijos per kietos fazės ekstrakcijos patroną metodu, naudojant tokią metodiką:To a solution of 2- (4-chlorophenyl) -2-oxoacetic acid (0.017 g, 0.092 mmol) in HOAt (0.013 g, 0.092 mmol) in DMF (0.5 mL) was added. DMF (0.2M, 0.46 mL, 0.092 mmol) and DIC (0.2M, 0.014 mL, 0.092 mmol) in Example 33 were added to the mixture, and the mixture was stirred at room temperature for 16 h. The mixture is purified by ion-exchange chromatography over a solid phase extraction cartridge using the following procedure:
1) Varian’o kieta fazė ekstrakcijos kolonėlė (1,5 g, SCX katijonitas) kondicionuojama 10 ml MeOH/CH2CI2;1) Varian solid phase extraction column (1.5 g, SCX cation exchanger) is conditioned with 10 mL MeOH / CH 2 Cl 2 ;
2) mišinys suleidžiamas j kolonėlę, panaudojant 10 ml švirkštą vienodam sistemos slėgiui palaikyti;2) the mixture is injected onto the column using a 10 ml syringe to maintain a constant system pressure;
3) kolonėlė plaunama 3 x 7,5 ml MeOH/CH2CI2 (1:1);3) washing the column with 3 x 7.5 mL MeOH / CH 2 Cl 2 (1: 1);
4) kolonėlė plaunama 1 x 7,5 ml 0,01 N amoniako MeOH;4) washing the column with 1 x 7.5 mL of 0.01 N ammonia in MeOH;
5) kolonėlė eliuuojama 7,5 ml 1,0 N amoniako MeOH, ir eliuatas renkamas j taruotą rinktuvą.5) Elute the column with 7.5 mL of 1.0 N ammonia in MeOH and collect the eluate in a tared trap.
Produkto tirpalas koncentruojamas Savant Speed Vac įtaisu (apie 2 mm Hg stulpelio 20 vai.). Liekana ištirpinama CH3CN (2 mt), 1N Hci (0,10 mi) ir vandenyje (1 ml), ir po liofilizacijos gaunamas 237 pavyzdžio junginys (0,042 g, 86 %), kuris yra baitas liofilizatas.The product solution is concentrated using a Savant Speed Vac device (about 2 mm Hg column for 20 hours). The residue was dissolved in CH 3 CN (2 mt), 1N Hci (0.10 mL), and water (1 mL), and lyophilized to give Example 237 (0.042 g, 86%) as a byte lyophilisate.
202202
MS: (M + H)+ 471.MS: (M + H) + 471.
Analizė išskaičiuota pagal C27H23N4O2CI · 0,15 CH3CN · 1,0 HCI 0,84 H2O. Išskaičiuota: C, 61,40; H, 4,93; N, 10,88.Analysis calculated for C 27 H 23 N 4 O 2 Cl · 0.15 CH 3 CN · 1.0 HCl 0.84 H 2 O. Calculated: C, 61.40; H, 4.93; N, 10.88.
Rasta: C, 61,41; H, 5,02; N, 11,28.Found: C, 61.41; H, 5.02; N, 11.28.
4-(1,2-Dioksopropil)-1,2-dioksopropil]-2,3,4,5-tetrahidro-1-(1H-imidazol4-iImetil)-7-feniI-1 H-1,4-benzodiazepinas (hidrochloridas).4- (1,2-Dioxopropyl) -1,2-dioxopropyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine ( hydrochloride).
238 pavyzdžio junginys pagaminamas iš piruvo rūgšties pagal 237 pavyzdyje aprašytą metodiką.Example 238 is prepared from pyruvic acid according to the procedure described in Example 237.
MS: (M + H)+ 375.MS: (M + H) < + > 375.
Analizė išskaičiuota pagal C22H22N4O2 · 1,0 HCI · 0,67 H2O.Analysis calculated for C22H22N4O2 · 1.0 HCl · 0.67 H 2 O.
Išskaičiuota: C, 62,47; H, 5,80; N, 13,25.Found: C, 62.47; H, 5.80; N, 13.25.
Rasta: C, 62,46; H, 5,59; N, 13,28.Found: C, 62.46; H, 5.59; N, 13.28.
239 pavyzdysExample 239
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2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-[2-(4-nitrofeniI)-1,2dioksoetilj-7-fenil-1H-1,4-benzodiazepinas (hidrochloridas).2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (4-nitrophenyl) -1,2-dioxoethyl] -7-phenyl-1H-1,4-benzodiazepine (hydrochloride) ).
239 pavyzdžio junginys pagaminamas iš 4-nitrofenilpiruvo rūgšties pagal 237 pavyzdyje aprašytą metodiką.Example 239 is prepared from 4-nitrophenylpyruvic acid according to the procedure described in Example 237.
MS: (M + H)+482.MS: (M + H) < + > 482.
Analizė išskaičiuota pagal C27H23N5O4 1,0 HCI · 0,38 H2O.Analysis calculated for C27H23N5O4 1.0 HCl · 0.38 H 2 O.
Išskaičiuota: C, 61,79; H, 4,76; N, 13,34.Found: C, 61.79; H, 4.76; N, 13.34.
Rasta: C, 61,80; H, 4,72; N, 13,54.Found: C, 61.80; H, 4.72; N, 13.54.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-[2-(4-metoksifenil)-1,2dioksoetil]-7-fenil-1H-1,4-benzodiazepinas (hidrochloridas).2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (4-methoxyphenyl) -1,2-dioxoethyl] -7-phenyl-1H-1,4-benzodiazepine ( hydrochloride).
204204
240 pavyzdžio junginys pagaminamas iš 4-metoksifenilpiruvo rūgšties pagal 237 pavyzdyje aprašytą metodiką.Example 240 is prepared from 4-methoxyphenylpyruvic acid according to the procedure described in Example 237.
MS: (M + H)+ 467.MS: (M + H) + 467.
Analizė išskaičiuota pagal C28H26N4O3 · 1,0 HCI · 0,79 H2O.Analysis calculated for C28H26N4O3 · 1.0 HCl · 0.79 H 2 O.
Išskaičiuota: C, 65,02; H, 5,57; N, 10,83.Found: C, 65.02; H, 5.57; N, 10.83.
Rasta; C, 65,01; H, 5,66; N, 10,75.Found; C, 65.01; H, 5.66; N, 10.75.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-4-(3,3,3-trifluor-1,2dioksopropil)-1H-1,4-benzodiazepinas (trifluoracetatas, 1:2)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (3,3,3-trifluoro-1,2-dioxopropyl) -1H-1,4-benzodiazepine ( trifluoroacetate, 1: 2)
241 pavyzdžio junginys pagaminamas iš trifluorpiruvo rūgšties pagal 237 pavyzdyje aprašytą metodiką, panaudojant metileno chloridą kaip kotirpiklj. Gryninama atvirkštinių fazių preparatinės HPLC metodu (vandeninis metanolis, 0,1 % TFA).Example 241 is prepared from trifluoropyruvic acid according to the procedure described in Example 237 using methylene chloride as a cosolvent. Purification by reverse phase preparative HPLC (aqueous methanol, 0.1% TFA).
MS: (M + H)+429.MS: (M + H) < + > 429.
Analizė išskaičiuota pagal C22Hi9N4O2F3 1,5 TFA · 0,81 H2O.Analysis calculated for C 22 Hi 9 N 4 O 2 F 3 1.5 TFA · 0.81 H 2 O.
Išskaičiuota: C, 48,90; H, 3,63; N, 9,12.Found: C, 48.90; H, 3.63; N, 9.12.
Rasta: C, 48,90; H, 3,58; N, 9,13.Found: C, 48.90; H, 3.58; N, 9.13.
242 pavyzdysExample 242
205205
(R)-7-Chlor-2,3,4,5-tetrahidro-1-[(1H-imidazol-4-ii)metil]-4-(metilsulfonil)3-(f eni I m eti I)-1 H-pi r id o [3,2-e] -1,4-diazepinas (hidrochloridas)(R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-yl) methyl] -4- (methylsulfonyl) -3- (phenylmethyl) -1 H -pyrido [3,2-e] -1,4-diazepine (hydrochloride)
A. 2-Chlor-5-(fenilsulfonilamino)-6-metilpiridinasA. 2-Chloro-5- (phenylsulfonylamino) -6-methylpyridine
Junginys A pagaminamas iš 236 pavyzdžio junginio B pagal 236 pavyzdyje aprašytą junginio D ir 236 pavyzdyje aprašytą junginio E gavimo metodikas.Compound A is prepared from Compound B of Example 236 according to the procedures for preparation of Compound D and Example 236 described in Example 236.
B. 2-Chlor-5-(fenilsulfonilamino)-6-metilpiridin-N-oksidas j junginio A (3,0 g, 10,6 mmol) suspensiją TFA (12,5 ml) pridedama 30% vandeninio vandenilio peroksido (2,2 ml). Mišinys virinamas su grįžtamu šaldytuvu 80 min. Pridedama dar 2,5 ml H2O2, ir mišinys virinamas su grįžtamu šaldytuvu 95 min. Pridedama dar 2,5 ml H2O2, mišinys pavirinamas su grįžtamu šaldytuvu 1 vai. ir supilamas ’j ledą. Šis mišinys paliekamas per naktį, po to nufiltruojamas. Kieta medžiaga plaunama vandeniu, ištirpinama 10 % izopropanolio tirpale metileno chloride, ir išdžiovinus tirpalą gaunama 2,44 g junginio B, kuriame yra junginio A priemaišų. Dar 0,33 g negryno junginio B nusodinama iš vandeninio filtrato. Bendra išeiga 2,77 g (88 %).B. 2-Chloro-5- (phenylsulfonylamino) -6-methylpyridine-N-oxide To a suspension of compound A (3.0 g, 10.6 mmol) in TFA (12.5 mL) was added 30% aqueous hydrogen peroxide (2, 2 ml). The mixture was refluxed for 80 min. Another 2.5 mL of H2O2 was added and the mixture was refluxed for 95 min. An additional 2.5 ml of H 2 O 2 is added and the mixture is refluxed for 1 hour. and pouring 'j ice cream. The mixture was left overnight, then filtered. The solid is washed with water, dissolved in 10% isopropanol in methylene chloride, and dried to give 2.44 g of compound B, which contains impurities of compound A. A further 0.33 g of crude compound B is precipitated from the aqueous filtrate. Total yield 2.77 g (88%).
(M + H)+ 298,9.(M + H) + 298.9.
C. 2-ChIor-5-(fenilsulfonilamino)-6-hidroksimetilpiridinasC. 2-Chloro-5- (phenylsulfonylamino) -6-hydroxymethylpyridine
Junginys C (dervos pavidalo) pagaminamas iš junginio B pagal 236 pavyzdyje aprašytas junginių G ir H gavimo metodikas. (M + H)+ 299,0.Compound C (in the form of a resin) is prepared from compound B according to the procedures for the preparation of compounds G and H described in Example 236. (M + H) + 299.0.
206206
D. 2-Chlor-5-(fenilsulfonilamino)-piridin-6-karboksaldehidas j negryninto junginio C (2,45 g, 8,20 mmol) tirpalą THF (20 ml) pridedama MnO2 (1,43 g, 16,4 mmol). Mišinys maišomas kambario temperatūroje ir vėl pridedama MnO2 po: 1 vai. - 2,86 g: 28 vai. - 2,86 g. Pamaišius 21 vai., mišinys tiesiogiai gryniamas sparčiosios chromatografijos metodu (25 % etilacetato/heksanuose), ir gaunama 0,82 g negryno junginioD. 2-Chloro-5- (phenylsulfonylamino) -pyridine-6-carboxaldehyde To a solution of crude C (2.45 g, 8.20 mmol) in THF (20 mL) was added MnO 2 (1.43 g, 16.4). mmol). The mixture was stirred at room temperature and MnO 2 was added again after 1 h. - 2.86 g: 28 or. - 2.86 g. After stirring for 21 h, the mixture was directly purified by flash chromatography (25% ethyl acetate / hexanes) to give 0.82 g of crude compound.
D.D.
E. D-[N-(2-chlor-5-(fenilsulfonilamino)-6-piridinilmetil)-fenilalanino] metilo esteris j nergyninto junginio D (0,81 g, 2,73 mmol), D-fenilalanino metilo esterio hidrochlorido (0,88 g, 4,10 mmol) ir NaOAc (0,67 g, 8,20 mmol) tirpalą 15 ml metileno chlorido ir 3 ml acto rūgšties mišinio alikvotinėmis dalimis per 90 min. pridedama natrio triacetoksiborhidrido (0,87 g, 4,10 mmol). Mišinys maišomas 90 min. ir paskirstomas tarp pH 7 fosfatinio buferio ir metileno chlorido. Vandeninė fazė ekstrahuojama metileno chloridu, sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojama, ir nugarinus gaunamas oranžinės dervos pavidalo junginys E (1,62 g, >100 %).E. D- [N- (2-Chloro-5- (phenylsulfonylamino) -6-pyridinylmethyl) -phenylalanine] methyl ester and the dehydrogenated compound D (0.81 g, 2.73 mmol), D-phenylalanine methyl ester hydrochloride ( 0.88 g, 4.10 mmol) and NaOAc (0.67 g, 8.20 mmol) in aliquots of a mixture of 15 mL of methylene chloride and 3 mL of acetic acid over 90 min. sodium triacetoxyborohydride (0.87 g, 4.10 mmol) was added. The mixture was stirred for 90 min. and is distributed between pH 7 phosphate buffer and methylene chloride. The aqueous phase is extracted with methylene chloride, the combined organic extracts are dried (MgSO 4 ), filtered and evaporated to give E (1.62 g,> 100%) as an orange gum.
F. (R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-7chlor-3-(fenilmetil)-1H-pirido[3,2-e]-1,4-diazepinas (monohidrochloridas)F. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-chloro-3- (phenylmethyl) -1H-pyrido [3,2- e] -1,4-diazepine (monohydrochloride)
242 pavyzdžio junginys pagaminamas iš junginio E pagal aprašytas metodikas metodikas šiems junginiams gauti: 236 pavyzdžio junginiui K, 236 pavyzdžio junginiui L, 236 pavyzdžio junginiui M, 236 pavyzdžio junginiui N. HCI druska nusodinama iš izopropanolio eteriu, ir gaunamas labai higroskopinių putų pavidalo 242 pavyzdžio junginys.Example 242 is prepared from Compound E according to the procedures described for the following compounds: Example 236 Compound K, Example 236 Compound L, Example 236 Compound M, Example 236 Compound N. The HCl salt is precipitated from isopropanol in ether to give Example 242 in the form of highly hygroscopic foam. compound.
MS (M + H)+ 432,1.MS (M + H) + 432.1.
13C-BMR (CDCb, laisva bazė) δ 7,96, 39,60, 47,97, 48,34, 55,73, 59,27, 118,66, 122,59, 124,89, 126,91, 128,64, 129,16, 135,59, 137,15, 138,88, 139,63, 144,10, 144,54, 182,64 m.d. 13 C-NMR (CDCl 3, free base) δ 7.96, 39.60, 47.97, 48.34, 55.73, 59.27, 118.66, 122.59, 124.89, 126.91 , 128.64, 129.16, 135.59, 137.15, 138.88, 139.63, 144.10, 144.54, 182.64 md
243 pavyzdysExample 243
207207
6,7,8,9-Tetrahidro-5-(1H-imidazol-4-ilmetil)-8-(1-naftalenilkarbonil)-2fenil-5H-piNmido-[5,4-e][1,4]diazepinas (monohidrochloridas)6,7,8,9-Tetrahydro-5- (1H-imidazol-4-ylmethyl) -8- (1-naphthalenylcarbonyl) -2-phenyl-5H-pyrimido [5,4-e] [1,4] diazepine ( monohydrochloride)
A. 2-Fenil-5-brom-4-pirimidinkarboksirūgštisA. 2-Phenyl-5-bromo-4-pyrimidine carboxylic acid
J mukobromo rūgšties (16 g, 62 mmol) tirpalą 800 ml vandens pridedama benzamidino hidrochlorido hidrato (26 g, 166 mmol) ir tritono B (100 ml, 40 % tirpalas vandenyje). Tirpalas maišomas 23 vai., nufiltruojamas nuo nedidelio kiekio tamsios kietos medžiagos ir parūgštinamas koncentruota HCl. Dervingos nuosėdos nufiltruojamos ir, perkristalinus iš 4:1 etanolio ir vandens mišinio, gaunama 5,87 g (34 %) junginio A, kuris yra ruda kristalinė kieta medžiaga. Sukoncentravus pokristalizacinj tirpalą, gaunama dar 1,72 g (bendra išeiga 44%).To a solution of mucobromic acid (16 g, 62 mmol) in 800 mL of water was added benzamidine hydrochloride hydrate (26 g, 166 mmol) and triton B (100 mL, 40% in water). The solution is stirred for 23 hours, filtered off with a small amount of dark solid and acidified with concentrated HCl. The resinous precipitate was filtered off and recrystallized from 4: 1 ethanol / water to give 5.87 g (34%) of Compound A as a brown crystalline solid. Concentration of the subcrystallization solution yields another 1.72 g (44% overall yield).
B. 2-Fenil-5-(2-aminoetilamino)-4-pirimidinkarboksirūgštisB. 2-Phenyl-5- (2-aminoethylamino) -4-pyrimidinecarboxylic acid
3,0 g (10,8 mmol) junginio A ir 300 mg vario sulfato mišinys 15 ml vandens ir 15 ml etilendiamino kaitinamas 100 °C temperatūroje 3 vai. Tamsus tirpalas sausai nugarinamas, ir pusiau kietą liekaną praskiedus vandeniu, gaunamos labai gausios nuosėdos, kurios nufiltruojamos, gerai išplaunamos vandeniu, ir išdžiovinus per naktį ore, gaunama 2,45 g junginio B, kuris yra gelsvai ruda kieta medžiaga. Filtratas sausai nugarinamas, o liekana praskiedžiama vandeniu. Palaikius kambario temperatūroje, gaunama dar 0,6 g junginio B. Šios medžiagos sumaišomos, ir išdžiovinus per naktį 60A mixture of 3.0 g (10.8 mmol) of Compound A and 300 mg of copper sulphate in 15 ml of water and 15 ml of ethylenediamine was heated at 100 ° C for 3 hours. The dark solution is evaporated to dryness and the semi-solid residue is diluted with water to give a very rich precipitate which is filtered off, rinsed well with water and dried overnight in air to give 2.45 g of Compound B which is a tan solid. The filtrate is evaporated to dryness and the residue is diluted with water. A further 0.6 g of compound B is obtained at room temperature. These materials are mixed and dried overnight 60
208 °C temperatūroje vakuume, gaunama 2,85 g (maždaug 100 %) junginio B, kuris yra gelsva kieta medžiaga.At 208 ° C in vacuo, 2.85 g (about 100%) of Compound B is obtained as a yellowish solid.
C. 6,7,8,9-Tetrahidro-2-fenil-5H-pirimido[5,4-e] [1,4]-diazepin-9-onasC. 6,7,8,9-Tetrahydro-2-phenyl-5H-pyrimido [5,4-e] [1,4] -diazepin-9-one
Į 2,8 g (10,8 mmol) junginio B suspensiją 100 ml piridino pridedamaTo a suspension of 2.8 g (10.8 mmol) of Compound B in 100 ml of pyridine is added
3,1 g (16,3 mmol) EDC ir 2,2 g (16,3 mmol) HOBT, ir suspensija maišoma kambario temperatūroje argono atmosferoje 36 vai. Gautas drumstas tirpalas sausai nugarinamas, pusiau kieta liekana praskiedžiama 10 % izopropanolio tirpalu vandenyje ir plaunama sočiu NaCl tirpalu (2x). Plovimo metu vandeniniame sluoksnyje susidaro ryškiai geltonos nuosėdos. Nufiltravus šią medžiagą, gaunama 1,9 g negryno junginio C. Ši medžiaga suspenduojama metanolyje ir kaitinama garų vonioje. Likusios netirpios medžiagos nufiltruojamos, o medžiaga ant filtro vėl ekstrahuojama karštu metanoliu. Sumaišyti filtratai sausai nugarinami, ir gaunama 1,53 g (59 %) junginio C, kuris yra gelsvi milteliai.3.1 g (16.3 mmol) of EDC and 2.2 g (16.3 mmol) of HOBT were added and the suspension was stirred at room temperature under argon for 36 h. The resulting cloudy solution is evaporated to dryness, the semisolid residue is diluted with 10% isopropanol in water and washed with brine (2x). A clear yellow precipitate is formed in the aqueous layer during washing. Filtration of this material gives 1.9 g of crude compound C. This material is suspended in methanol and heated in a steam bath. The remaining insoluble matter is filtered off and the material is again extracted with hot methanol on the filter. The combined filtrates were evaporated to dryness to give 1.53 g (59%) of Compound C as a yellowish powder.
D. 6,7,8,9-Tetrahidro-2-fenil-5H-pirimido[5,4-e] [1,4]-diazepinasD. 6,7,8,9-Tetrahydro-2-phenyl-5H-pyrimido [5,4-e] [1,4] -diazepine
J maišomą 100 mg (0,42 mmol) junginio C tirpalą 2 ml glimo pridedama 85 mg (2,1 mmol) ličio aliuminio hidrido, ir reakcijos mišinys virinamas su grįžtamu šaldytuvu 18 vai. į reakcijos mišinj pridedama 0,5 mi piridino, dar 80 mg LAH, ir 85 °C temperatūroje šildymas tęsiamas dar 18 vai. Mišinys skaldomas pridedant 5 ml etilacetato, o po to 0,5 ml kone. NH4OH. Gauta suspensija nufiltruojama, ir ant filtro esanti medžiaga gerai perplaunama etilacetatu. Filtratas sausai nugarinamas, ir gautas produktas tolesnėje stadijoje naudojamas nęgrynintas. Ši medžiaga taip pat gali būti gryninama sparčiosios chromatografijos per silikagelj metodu, eliuuojant 10 % metanoliu etilacetate, ir gaunamas grynas junginys D, kuris yra oranžinė kieta kristalinė medžiaga.To a stirred solution of 100 mg (0.42 mmol) of Compound C in 2 mL of gluten was added 85 mg (2.1 mmol) of lithium aluminum hydride, and the reaction mixture was refluxed for 18 hours. 0.5 mL of pyridine, 80 mg of LAH was added to the reaction mixture, and heating was continued for 85 hours at 85 ° C. The mixture was quenched by addition of 5 mL of ethyl acetate followed by 0.5 mL of almost. NH 4 OH. The resulting suspension is filtered and the filter cake is rinsed well with ethyl acetate. The filtrate is evaporated to dryness and the product obtained is used without further purification. This material can also be purified by flash chromatography on silica gel eluting with 10% methanol in ethyl acetate to give pure compound D, which is an orange solid crystalline.
E. 6,7,8,9-Tetrahidro-8-(1-naftalenilkarbonil)-2-fenil-5H-pirimido[5,4e][1,4]-diazepinasE. 6,7,8,9-Tetrahydro-8- (1-naphthalenylcarbonyl) -2-phenyl-5H-pyrimido [5,4e] [1,4] -diazepine
209209
J 80 mg (laikoma, kad yra 0,35 mmol medžiagos) negryninto junginio D tirpalą 3 ml metileno chlorido ir 3 ml 1N natrio hidroksido pridedama 60 μΙ (0,4 mmol) 1-naftoilchlorido. Reakcijos mišinys maišomas 0 °C temperatūroje 1 vai. Organinis sluoksnis atskiriamas, plaunamas sočiu amonio chloridu, džiovinamas (MgSO4) ir nugarinamas. Liekana gryninama sparčiosios chromatografijos per silikagelį metodu. Eliuuojama etilacetatu-heksanu (3:1) ir gaunama 40 mg (25 % skaičiuojant pagal junginį C) putų pavidalo junginioTo a solution of 80 mg of crude compound D (0.35 mmol) in 3 mL of methylene chloride and 3 mL of 1N sodium hydroxide is added 60 μΙ (0.4 mmol) of 1-naphthoyl chloride. The reaction mixture was stirred at 0 ° C for 1 h. The organic layer was separated, washed with saturated ammonium chloride, dried (MgSO 4 ) and evaporated. The residue was purified by silica gel flash chromatography. Elute with ethyl acetate-hexane (3: 1) to give 40 mg (25% based on Compound C) of the foam compound
E,E,
F. 6,7,8,9-Tetrahidro-5-(1H-imidazol-4-ilmetil)-8-(1naftalenilkarbonil)-2-fenil-5H-pirimido-[5,4-e][1,4]diazepinas (monohidrochloridas)F. 6,7,8,9-Tetrahydro-5- (1H-imidazol-4-ylmethyl) -8- (1-naphthalenylcarbonyl) -2-phenyl-5H-pyrimido- [5,4-e] [1,4] diazepine (monohydrochloride)
J 23 mg (0,062 mmol) junginio E tirpalą 1 ml metileno chlorido ir 0,2 ml acto rūgšties pridedama 10 mg (1 mmol) 4-formilimidazolo. Reakcijos mišinys pamaišomas 15 min., ir pridedama 21 mg (1 mmol) natrio triacetoksiborhidrido. Po 1, 2, 3 ir 4 vai. maišymo pridedama po 10 mg imidazolo ir po 21 mg hidrido. Maišymas tęsiamas per naktį. Reakcijos mišinys praskiedžiamas metanoliu, ir neapdorotas mišinys gryninamas preparatinės HPLC metodu per YMC ODS-A S 10 kolonėlę, panaudojant gradientinį eliuavimą 0-100 % tirpiklio B (A: 10 % MeOH-H2O + 0,1 % TFA, B: 10 % H2O-MeOH + 0,1 % TFA). Atitinkamos frakcijos sumaišomos ir nugarinamos. Liekana paverčiama hidrochlorido druska, praskiedžiant metanoliniu HCI tirpalu ir nugarinant tirpiklj. Gaunama 31 mg geltonos kietos medžiagos. Ši medžiaga ištirpinama minimaliame metanolio kiekyje ir nusodinama lašinant eterį. Gaunama 12 mg (39 %) gryno 243 pavyzdžio junginio, kuris yra geltoni milteliai.To a solution of 23 mg (0.062 mmol) of compound E in 1 mL of methylene chloride and 0.2 mL of acetic acid is added 10 mg (1 mmol) of 4-formylimidazole. The reaction mixture was stirred for 15 min and 21 mg (1 mmol) of sodium triacetoxyborohydride was added. After 1, 2, 3 is 4 or. 10 mg of imidazole and 21 mg of hydride were added under stirring. Stirring continued overnight. The reaction mixture was diluted with methanol and the crude mixture was purified by preparative HPLC over a YMC ODS-A S 10 column using a gradient elution of 0-100% solvent B (A: 10% MeOH-H 2 O + 0.1% TFA, B: 10 % H 2 O-MeOH + 0.1% TFA). The appropriate fractions are mixed and evaporated. The residue is converted to the hydrochloride salt by dilution with methanolic HCl and evaporation of the solvent. 31 mg of a yellow solid are obtained. This material is dissolved in a minimum amount of methanol and precipitated by the dropwise addition of ether. 12 mg (39%) of the pure compound of Example 243 is obtained as a yellow powder.
MS (M + H)+461.MS (M + H) + 461.
1H-BMR (CD3OD): δ 3,69 (2H, pl.s), 3,90 (2H, m), 4,20 (1H, m), 4,45 (1H, m), 1 H-NMR (CD 3 OD): δ 3.69 (2H, pl.s), 3.90 (2H, m), 4.20 (1H, m), 4.45 (1H, m),
4,70 (1H, m), 4,82 (1H, m), 5,49 (1H, m), 7,32-8,30 (11H, m), 8,43 (1H, s),4.70 (1H, m), 4.82 (1H, m), 5.49 (1H, m), 7.32-8.30 (11H, m), 8.43 (1H, s),
8,60 (1H, s), 8,95 (1H, m), 9,11 (1H, s).8.60 (1H, s), 8.95 (1H, m), 9.11 (1H, s).
244 pavyzdysExample 244
210210
(R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilacetil)-4-(metilsulfonil)3-(fenilmetil)-1H-1,4-benzodiazepinas (monohidrocloridas)(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylacetyl) -4- (methylsulfonyl) 3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )
A. (R)-7-Brom-2,3,4,5-tetrahidro-4-(1,1-dimetiletoksikarbonil)-3(fenilmetil)-l H-1,4-benzodiazepinas j 250 mg (0,79 mmol) 244 pavyzdžio junginio B tirpalą 5 ml metileno chlorido kambario temperatūroje argono atmosferoje pridedama 192 mg (0,88 mmol) BOC anhidrido, ištirpinto 1 ml metileno chlorido. Po 1 vai. pridedama dar 100 mg BOC anhidrido ir maišoma dar 0,5 vai. Neapdorotas reakcijos mišinys gryninamas sparčiosios chromatografijos metodu per 50 cm3 silikagelio kolonėlę. Eliuuojama 20 % EtOAc-heksane ir gaunama 319 mg (96 %) junginio A, kuris yra balta kieta medžiaga.A. (R) -7-Bromo-2,3,4,5-tetrahydro-4- (1,1-dimethylethoxycarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine, 250 mg (0.79) A solution of compound B of Example 244 in 5 mL of methylene chloride at room temperature under argon was added 192 mg (0.88 mmol) of BOC anhydride dissolved in 1 mL of methylene chloride. After 1 or. another 100 mg of BOC anhydride was added and stirred for another 0.5 h. The crude reaction mixture was purified by flash chromatography over a 50 cm 3 silica gel column. Elution with 20% EtOAc in hexane afforded 319 mg (96%) of Compound A as a white solid.
B. (R)-7-Brom-2,3,4,5-tetrahidro-1-(1-trifenilmetil-imidazoI-4-ilacetil)4-(1,1-dimetiletoksikarbonil)-3-(fenilmetil)-1H-1,4-benzodiazepinas j 2,2 g (6 mmol) 1-trifenimetil-4-imidazolilacto rūgšties suspensiją 50 ml THF kambario temperatūroje ir-argono atmosferoje pridedama 836 μΙ (6 mmol) trietilamino. Gautas drumstas tirpalas atšaldomas iki -30 °C ir sulašinama 839 μΙ (6,6 mmol) i-butilchlorformiato. Pamaišius dar 0,5 vai. -30 °C temperatūroje, sulašinamas 500 mg (1,2 mmol) junginio A tirpalas 10 ml THF. Reakcijos mišiniui leidžiama sušilti iki kambario temperatūros per tris valandas, ir maišoma per naktj. Gautas juodas reakcijos mišinys praskiedžiamas etilacetatu ir plaunamas sočiu NaCl tirpalu (2x), džiovinamas (MgSO4) ir nugarinus tirpiklį, gaunama juoda putų pavidalo liekana, kuriB. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-triphenylmethylimidazol-4-ylacetyl) 4- (1,1-dimethylethoxycarbonyl) -3- (phenylmethyl) -1H -1,4-Benzodiazepine To a suspension of 2.2 g (6 mmol) of 1-triphenymethyl-4-imidazolylacetic acid in 50 mL of THF at room temperature and under argon was added 836 μΙ (6 mmol) of triethylamine. The resulting cloudy solution was cooled to -30 ° C and 839 μΙ (6.6 mmol) of i-butyl chloroformate was added dropwise. After stirring for another 0.5 hours. At -30 ° C, a solution of 500 mg (1.2 mmol) of Compound A in 10 ml of THF is added dropwise. The reaction mixture was allowed to warm to room temperature over three hours and stirred overnight. The resulting black reaction mixture was diluted with ethyl acetate and washed with saturated NaCl solution (2x), dried (MgSO 4 ) and evaporated to give a black foam which
211 gryninama sparčiosios chromatografijos per silikagelj metodu. Eliuuojama 25 % etilacetatu heksane ir gaunama 376 mg (40 %) junginio B, kuris yra pilka putų pavidalo kieta medžiaga, o taip pat ir 294 mg junginio A.211 was purified by flash chromatography on silica gel. Elution with 25% ethyl acetate in hexane afforded 376 mg (40%) of Compound B as a gray foamy solid, as well as 294 mg of Compound A.
C. (R)-7-Brom-2,3,4,5-tetrahidro-1-(1-trifenilmetil-imidazol-4-ilacetil)3- (fenilmetiI)-1H-1,4-benzodiazepinas (hidrochloridas)C. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-triphenylmethyl-imidazol-4-yl-acetyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)
370 mg (0,48 mmol) junginio B tirpalas 2 ml 1M HCl acto rūgštyje maišomas kambario temperatūroje 0,5 vai. Reakcijos mišinys nugarinamas iki sausos liekanos žemoje temperatūroje, ir liekana praskiedžiama etilacetatu. Nufiltravus susidariusią kietą medžiagą, gaunama 280 mg (83 %) junginio C.A solution of 370 mg (0.48 mmol) of Compound B in 2 mL of 1M HCl in acetic acid was stirred at room temperature for 0.5 h. The reaction mixture was evaporated to dryness at low temperature and diluted with ethyl acetate. Filtration of the resulting solid afforded 280 mg (83%) of Compound C.
D. (R)-7-Brom-2,3,4,5-tetrahidro-1-(1-trifenilmetil-imidazol-4-ilacetil)4- (metiIsulfonil)-3-(feni!metil)-1H-1,4-benzodiazepinas j 280 mg (0,4 mmol) junginio C tirpalą 3 ml metileno chlorido kambario temperatūroje argono atmosferoje pridedama 167 μΙ (1,2 mmol) trietilamino, o po to 46 μΙ (0,6 mmol) metansulfonilchlorido. Pamaišius 0,5 vai., pridedama dar 167 μΙ trietilamino ir 46 μΙ metansulfonilchlorido ir maišoma dar 0,5 vai. Neapdorotas tirpalas chromatografuojamas sparčiosios chromatografijos metodu per 50 cm3 silikagelio kolonėlę. Eliuuojama 50 % etilacetatu heksane ir gaunama 165 mg (55 %) junginio D, kuris yra balta putų pavidalo kieta medžiaga.D. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-triphenylmethylimidazol-4-ylacetyl) 4- (methylsulfonyl) -3- (phenylmethyl) -1H-1 , 4-Benzodiazepine To a solution of 280 mg (0.4 mmol) of Compound C in 3 mL of methylene chloride was added 167 μΙ (1.2 mmol) of triethylamine at room temperature under argon followed by 46 μΙ (0.6 mmol) of methanesulfonyl chloride. After stirring for 0.5 h, another 167 μΙ of triethylamine and 46 μΙ of methanesulfonyl chloride were added and stirred for another 0.5 h. The crude solution is chromatographed on a 50 cm 3 silica gel flash column. Elution with 50% ethyl acetate in hexane afforded 165 mg (55%) of Compound D as a white foamy solid.
E. (R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazoI-4-ilacetil)-4(metilsu!fonil)-3-(fenilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas) j 80 mg (0,11 mmol) junginio D tirpalą 2 ml metileno chlorido pridedama 0,5 ml trietilsilano ir 1 ml TFA, ir mišinys maišomas kambario temperatūroje argono atmosferoje 3 vai. Reakcijos mišinys sausai nugarinamas, ir gaunama balta kieta liekana, kuri praskiedžiama eteriu ir maišoma 0,5 vai. Tirpiklis nupilamas, o likusios netirpios medžiagos plaunamos eteriu dar du kartus. Likusi kieta medžiaga ištirpinama etilacetateE. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylacetyl) -4 (methylsulfonyl) -3- (phenylmethyl) -1H-1,4 Benzodiazepine (monohydrochloride) To a solution of 80 mg (0.11 mmol) of Compound D in 2 mL of methylene chloride was added 0.5 mL of triethylsilane and 1 mL of TFA, and the mixture was stirred at room temperature under argon for 3 h. The reaction mixture is evaporated to dryness to give a white solid which is diluted with ether and stirred for 0.5 h. The solvent is removed and the remaining insoluble materials are washed twice with ether. The remaining solid was dissolved in ethyl acetate
212 ir plaunama sočiu NaHCO3, sočiu NaCl, džiovinama (MgSO4) ir nugarinus tirpiklį gaunama 45 mg baltos putų pavidalo kietos medžiagos. Ši medžiaga ištirpinama minimaliame kiekyje metileno chlorido ir sulašinama 90 μΙ 1M HCI eteryje. Reakcijos mišinys praskiedžiamas eteriu, ir gauta suspensija paliekama per naktį šaldytuve, Kieta medžiaga nufiltruojama azoto atmosferoje, ir gaunama 36 mg (62 %) 244 pavyzdžio junginio, kuris yra balti milteliai.212 and washed with saturated NaHCO 3, saturated NaCl, dried (MgSO 4) and evaporation of the solvent yields 45 mg of a white foam solid. This material is dissolved in a minimal amount of methylene chloride and added dropwise to 90 μΙ of 1M HCl in ether. The reaction mixture was diluted with ether and the resulting suspension was left overnight in the refrigerator, the solid was filtered off under a nitrogen atmosphere to give 36 mg (62%) of Example 244 as a white powder.
MS: (M+H)+ 503.MS: (M + H) + 503.
Analizė išskaičiuota pagal C22H23N4O3S· 1,5 HCI.Analysis calculated for C 2 2 H 2 3 N 4 O 3 S · 1.5 HCl.
Išskaičiuota: C, 47,35; H, 4,42; N, 10,04.Found: C, 47.35; H, 4.42; N, 10.04.
Rasta: C, 47,55; H, 4,41; N, 9,92.Found: C, 47.55; H, 4.41; N, 9.92.
O OO O
Me (R)-7-Brom-2,3,4,5-tetrahidro-1-(2-1H-imidazoI-4-iletil)-4-(metilsulfonil)-3(f en i I meti I)-1 H-1,4-benzodiazepinas (monohidrochloridas) j 80 mg (0,107 mmol) 244'pavyzdžio laisvos bazės tirpalą 0,5 ml THF kambario temperatūroje argono atmosferoje pridedama 1 ml 1M borano tirpalo THF. Skaidrus bespalvis tirpalas virinamas su grįžtamu šaldytuvu 2 vai., pridedama 0,5 ml kone. HCI ir kaitinama dar 2 vai. 65 °C temperatūroje. Reakcijos mišinys praskiedžiamas vandeniu ir plaunamas du kartus etilacetatu. Sumaišyti organiniai sluoksniai vėl plaunami vieną kartą sočiu NaCl, džiovinami ir nugarinus tirpiklį gaunama skaidri alyvos pavidalo liekana, kuri gryninama sparčiosios chromatografijos metodu per 30 cm3 silikagelioMe (R) -7-Bromo-2,3,4,5-tetrahydro-1- (2-1H-imidazol-4-yl-ethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1 H-1,4-Benzodiazepine (Monohydrochloride) To a solution of 804 mg (0.107 mmol) of the free base 244 'in 0.5 mL of THF at room temperature under argon was added 1 mL of 1M borane solution in THF. The clear, colorless solution is refluxed for 2 hours, added with 0.5 ml. HCl is heated for 2 more hours. At 65 ° C. The reaction mixture was diluted with water and washed twice with ethyl acetate. The combined organic layers are washed once with saturated NaCl, dried and evaporated to give a clear oil which is purified by flash chromatography over 30 cm 3 of silica gel.
213 kolonėlę. Eliuuojama CHCI3:MeOH:NH4OH (95:5:0,5), ir gaunama 112 mg alyvos. Ši medžiaga praskiedžiama 0,5 ml kone. HCI ir vėl šildoma 80 °C temperatūroje 2 vai. Atšaldžius iki kambario temperatūros, reakcijos mišinys praskiedžiamas vandeniu ir ekstrahuojamas du kartus etilacetatu. Sumaišyti organiniai sluoksniai džiovinami (MgSO4), ir nugarinus tirpiklį gaunama 30 mg liekanos. Trinant šią medžiagą su eteriu, gaunama balta kieta medžiaga, kuri ištirpinama 0,2 ml metanolio ir nusodinama lašinant eterį. Nufiltravus susidariusią kietą medžiagą, gaunama 12 mg (21 %) 245 pavyzdžio medžiagos, kuri yra balti milteliai.213 column. Eluted with CHCl 3: MeOH: NH 4 OH (95: 5: 0.5) to give 112 mg of oil. This material is diluted in 0.5 ml almost. HCl was again heated at 80 ° C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried (MgSO 4) and solvent evaporated to afford 30 mg of residue. Trituration with ether gives a white solid which is dissolved in 0.2 ml of methanol and precipitated with ether. Filtration of the resulting solid gave 12 mg (21%) of the 245 sample, which was a white powder.
MS (M + H)+ (didelė skiriamoji geba): išskaičiuota: 489,0957; rasta: 489,096. 13C BMR (67,8 MHz, CD3OD): 24,7, 39,2, 40,3, 47,3, 53,3, 58,1, 60,8, 113,3, 118,1, 118,8, 128,3, 130,1, 130,8, 131,0, 132,4, 134,0, 135,3, 139,8, 149,9MS (M + H) + (high resolution): calculated: 489.0957; found: 489,096. 13 C NMR (67.8 MHz, CD 3 OD): 24.7, 39.2, 40.3, 47.3, 53.3, 58.1, 60.8, 113.3, 118.1, 118.8, 128.3, 130.1, 130.8, 131.0, 132.4, 134.0, 135.3, 139.8, 149.9
m.d.m.d.
246 pavyzdysExample 246
8-[(Cikloheksilkarbonil)amino]-1,2,3,5-tetrahidro-1-(1H-imidazol-4ilmetil)-3-(fenilmetil)-4H-1,4-benzodiazepin-4-karboksirūgšties metilo esteris (dihidrochloridas)8 - [(Cyclohexylcarbonyl) amino] -1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxylic acid methyl ester (dihydrochloride) )
A. 8-Amino-2,3,4,5-tetrahidro-1-(1H-imidazoI-4-ilmetil)-3-(fenilmetil)1H-1,4-benzodiazepin-4-karboksirūgšties 1,1 -dimetiletilo esterisA. 8-Amino-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid 1,1-dimethylethyl ester
Junginys A (balta kieta medžiaga) pagaminamas iš 98 pavyzdžio junginio D pagal 26 pavyzdyje aprašytą metodiką. Naudojama negryninta laisva bazė. MS (M + H)+ = 434.Compound A (white solid) is prepared from Example 98 Compound D according to the procedure described in Example 26. The crude free base is used. MS (M + H) <+> = 434.
214214
B. 8-(Cikloheksilkarbonilamino)-2,3,4,5-tetrahidro-1-(1H-imidazol-4ilmetil)-3-(fenilmetil)-1H-1,4-benzodiazepin-4-karboksirūgštiesB. 8- (Cyclohexylcarbonylamino) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid
1,1-dimetiletilo esteris1,1-Dimethylethyl ester
Junginys B (balta putų pavidalo kieta medžiaga) pagaminamas iš junginio A pagal 27 pavyzdyje aprašytą metodiką. Naudojama negryninta laisva bazė. MS (M + H)+ = 544.Compound B (a white foamy solid) is prepared from Compound A according to the procedure described in Example 27. The crude free base is used. MS (M + H) <+> = 544.
C. N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-1H1,4-benzodiazepin-8-il]cikloheksanamidasC. N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepin-8-yl] cyclohexanamide
Junginys C (rusva kieta medžiaga) pagaminamas iš junginio B veikiant Hcl/dioksanu metanolyje kambario temperatūroje. MS (M+H)+ = 444.Compound C (brownish solid) is prepared from compound B by treatment with Hcl / dioxane in methanol at room temperature. MS (M + H) <+> = 444.
D. 8-[(Cikloheksilkarbonii)amino]-1,2,3,5-tetrahidro-1-(1H-imidazol-4ilmetil)-3-(fenilmetil)-4H-1,4-benzodiazepin-4-karboksirūgšties metilo esteris (dihidrochloridas)D. 8 - [(Cyclohexylcarbonyl) amino] -1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxylic acid methyl ester (dihydrochloride)
J maišomą junginio C (0,05 g, 0,09 mmoi) tirpalą CH2CI2 kambario temperatūroje argono atmosferoje pridedama metilchlorformiato (0,05 g, 0,09 mmol). Pamaišius 3 dienas, mišinys paskirstomas tarp CHCI3 (5 ml) ir NaHCO3 (2 ml). Vandeninis sluoksnis ekstrahuojamas CHCI3 (2 x 10 ml). Sumaišyti organiniai sluoksniai plaunami NaHCO3 ir sočiu NaCl, džiovinami MgSCU, nufiltruojami ir koncentruojami. Liekana gryninama preparatinės HPLC metodu, naudojant 50-100 % vandeninio metanolio su 0,1 % TFA gradientą, o HCI druska pagaminama veikiant 1M HCI/eteryje.To a stirred solution of Compound C (0.05 g, 0.09 mmol) in CH 2 Cl 2 at room temperature under argon was added methyl chloroformate (0.05 g, 0.09 mmol). After stirring for 3 days, the mixture was partitioned between CHCl 3 (5 mL) and NaHCO 3 (2 mL). The aqueous layer was extracted with CHCl 3 (2 x 10 mL). The combined organic layers were washed with NaHCO 3 and saturated NaCl, dried over MgSO 4, filtered, and concentrated. The residue was purified by preparative HPLC using a gradient of 50-100% aqueous methanol in 0.1% TFA, and the HCl salt was made in 1M HCl / ether.
MS (M + H)+ = 502.MS (M + H) <+> = 502.
1H BMR (CD3OD): δ 8,8 (s, 1 H),'7,45-7,1 (m, 7,5H), 7,05 (m, 1H), 6,8 (m, 0,5H), 4,67-4,35 (m, 4H), 4,58 (s, 3H), 3,4-3,0 (m, 3H), 2,9 (m, 1H), 2,7 (m, 1H), 2,3 (m, 1H), 1,9-1,2 (m, 10H). 1 H NMR (CD 3 OD): δ 8.8 (s, 1H), 7.45-7.1 (m, 7.5H), 7.05 (m, 1H), 6.8 (m , 0.5H), 4.67-4.35 (m, 4H), 4.58 (s, 3H), 3.4-3.0 (m, 3H), 2.9 (m, 1H), 2.7 (m, 1H), 2.3 (m, 1H), 1.9-1.2 (m, 10H).
247 pavyzdysExample 247
215 v215 yrs
HH
NN
HNHN
N-[2,3,4,5-Tetrahidro-1-(1H-imidazoI-4-ilmetil)-4-(1-naftalenilkarbonil)1 H-1,4-benzodiazepin-8-il]-1 -piperidinkarboksamidas (dihidrochloridas) l 26 pavyzdžio junginio (0,050 g, 0,125 mmol) ir trietilamino (0,038 ml, 0,275 mmol) tirpalą sausame metileno chloride (1 ml) kambario temperatūroje argono atmosferoje pridedama karbonildiimidazolo (0,045 g, 0,137 mmol). Pamaišius 2 vai., pridedama piperidino (0,013 ml, 0,13 mmol). Pamaišius 15 vai., reakcijos mišinys praskiedžiamas NaHCO3 ir CHCI3. Organinis sluoksnis plaunamas NaHCO3, vandeniu ir sočiu NaCl (1 x po 3 ml), džiovinamas MgSO4l nufiltruojama ir koncentruojama. Produktas gryninamas atvirkštinių fazių HPLC metodu, naudojant 40-90 % vandeninio metanolio su 0,1 % TFA gradientą, o HCI druska pagaminama veikiant 1M HCI/eteryje; gaunamas 247 pavyzdžio junginys (0,006 g, 10 %).N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -1-piperidinecarboxamide ( dihydrochloride) To a solution of Example 26 (0.050 g, 0.125 mmol) and triethylamine (0.038 mL, 0.275 mmol) in dry methylene chloride (1 mL) was added carbonyldiimidazole (0.045 g, 0.137 mmol) at room temperature. After stirring for 2 hours, piperidine (0.013 mL, 0.13 mmol) was added. After stirring for 15 h, the reaction mixture was diluted with NaHCO 3 and CHCl 3 . The organic layer was washed with NaHCO 3, water and saturated aqueous NaCl (1 x 3 ml), dried over MgSO filtered and concentrated 4l. The product was purified by reverse phase HPLC using a gradient of 40-90% aqueous methanol in 0.1% TFA and the HCl salt was made in 1M HCl / ether; Example 247 (0.006 g, 10%) is obtained.
MS (M+H)+509.MS (M + H) + 509.
1H-BMR (CD3OD): δ 8,5 (d, 1H, J=19Hz), 8,06-7,9 (m, 2H), 7,69-7,3 (m, 7H), 1 H-NMR (CD 3 OD): δ 8.5 (d, 1H, J = 19Hz), 8.06-7.9 (m, 2H), 7.69-7.3 (m, 7H),
7,2 (d, 0,5H, J=7Hz), 6,9 (d, 0,5H, J=7Hz), 6,5 (d, 0,5H, J=7Hz), 5,89 (t, 0,5H),7.2 (d, 0.5H, J = 7Hz), 6.9 (d, 0.5H, J = 7Hz), 6.5 (d, 0.5H, J = 7Hz), 5.89 (t , 0.5H),
4,6-3,88 (m, 4,5H), 3,6-3,3 (m, 6H), 3,18-2,85 (m, 1,5H), 1,65-1,55 (m, 6H).4.6-3.88 (m, 4.5H), 3.6-3.3 (m, 6H), 3.18-2.85 (m, 1.5H), 1.65-1.55 (m, 6H).
248 pavyzdysExample 248
216216
(R)-7-Ciano-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4H1,4-benzodiazepin-4-karboksirūgšties etilo esteris (hidrochloridas)(R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H1,4-benzodiazepine-4-carboxylic acid ethyl ester (hydrochloride)
A. (R)-7-Brom-2,3,4,5-tetrahidro-3-(fenilmetil)-1 H-1,4-benzodiazepin2,5-dionas į maišomą 5-bromizatoinės rūgšties anhidrido (150 g, 563 mmol) tirpalą bevandeniame piridine (1,5 I) argono atmosferoje pridedama Dfenilalanino metilo esterio hidrochlorido (127 g, 590 mmol) ir 4dimetilaminopiridino (2 g). Gautas tirpalas virinamas su grįžtamu šaldytuvu 3 dienas ir atšaldomas iki kambario temperatūros. Tirpiklis nugarinamas. Liekana ištirpinama CH2CI2 (3 I), ir tirpalas plaunamas 10 % HCI ir sočiu NaCl, džiovinamas bevandeniu Na2SO4, ir nugarinus gaunama putų pavidalo medžiaga, kuri suspenduojama Et2O (1,0 I). Mišinys maišomas, ir emulsijai suskaldyti pridedama CH2CI2 (100 ml). Pasaldžius ledo vonioje 3 vai., kieta medžiaga nufiltruojama, plaunama Et2O ir nedideliu kiekiu CH2CI2l ir išdžiovinus giliame vakuume, gaunama 152 g (78,4 %) junginio A.A. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione to a stirred 5-bromoisatoic acid anhydride (150 g, 563). of anhydrous pyridine (1.5 L) under argon was added Dphenylalanine methyl ester hydrochloride (127 g, 590 mmol) and 4-dimethylaminopyridine (2 g). The resulting solution was refluxed for 3 days and cooled to room temperature. The solvent is evaporated. The residue is dissolved in CH 2 Cl 2 (3 L) and the solution is washed with 10% HCl and saturated NaCl, dried over anhydrous Na 2 SO 4 , and evaporated to give a foam which is suspended in Et 2 O (1.0 L). The mixture was stirred and CH 2 Cl 2 (100 mL) was added to cleave the emulsion. After freezing in an ice bath for 3 hours, the solid is filtered off, washed with Et 2 O and a small amount of CH 2 Cl 2 and dried under deep vacuum to give 152 g (78.4%) of Compound A.
13C-BMR (DMSO-d6): 33,31, 53,69, 115,94, 123,31, 126,43, 128,22, 129,39, 132,63, 134,97, 136,19, 137,76, 166,45, 171,11 m.d. 13 C-NMR (DMSO-d 6 ): 33.31, 53.69, 115.94, 123.31, 126.43, 128.22, 129.39, 132.63, 134.97, 136.19 , 137.76, 166.45, 171.11 md
B. (R)-7-Brom-2,3,4,5-tetrahidro-3-(feniImetil)-1 H-1,4benzodiazepinasB. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine
J maišomą ir šaldomą (0 °, ledo vonia) junginio A (100 g, 290 mmol) tirpalą bevandeniame THF (1,5 I) argono atmosferoje pridedama boranoA solution of Compound A (100 g, 290 mmol) in anhydrous THF (1.5 L) under argon was stirred and cooled (0 °, ice bath).
217 tetrahidrofurano komplekso (1,0 M tiroalas, 1450 ml, 1450 mmol). Gautas tirpalas atsargiai virinamas su grjžtamu šaldytuvu per naktj. Šis tirpalas atšaldomas iki 0° ir lėtai pilamas MeOH, kol nustoja putoti. Tirpiklis sausai nugarinamas. Liekana praskiedžiama MeOH (900 ml), pridedama 25 % vandeninio HCI tirpalo (180 ml), ir mišinys atsargiai virinamas su grjžtamu šaldytuvu argono atmosferoje 2 vai. Gautas tirpalas atšaldomas iki 0° ledo vonioje, lėtai pilamas Et2O (300 ml), ir mišinys maišomas 1 vai. Kieta medžiaga nufiltruojama. Filtratas nugarinamas, liekana sumaišoma su kieta medžiaga, perplaunama Et2O (500 ml) ir acetonu (500 ml) ir suspenduojama CH2CI2 (2 I) ir vandens (1 I) mišinyje. 3N NaOH suspensijos pH padaromas lygiu 11. Atskiriamas CH2CI2 sluoksnis. Vandeninis sluoksnis prisotinamas NaCl ir ekstrahuojamas CH2CI2. Sumaišyti CH2CI2 ekstraktai plaunami sočiu NaCl, džiovinami bevandeniu Na2SO4 ir nugarinus gaunama 89 g (97 % išeiga) junginio B, kuris yra gelsvai rudos spalvos kieta medžiaga.217 tetrahydrofuran complex (1.0 M tirol, 1450 mL, 1450 mmol). The resulting solution is gently boiled under reflux overnight. This solution is cooled to 0 ° and slowly added to MeOH until it stops foaming. The solvent is evaporated to dryness. The residue was diluted with MeOH (900 mL), 25% aqueous HCl (180 mL) was added and the mixture was gently refluxed under argon for 2 h. The resulting solution was cooled to 0 ° in an ice bath, slowly added with Et 2 O (300 mL) and stirred for 1 h. The solid is filtered off. The filtrate is evaporated, the residue is mixed with the solid, washed with Et 2 O (500 mL) and acetone (500 mL) and suspended in a mixture of CH 2 Cl 2 (2 L) and water (1 L). The pH of the 3N NaOH suspension is adjusted to 11. The layer is separated from CH 2 Cl 2 . The aqueous layer is saturated with NaCl and extracted with CH 2 Cl 2 . The combined CH 2 Cl 2 extracts were washed with saturated NaCl, dried over anhydrous Na 2 SO 4, and evaporated to give 89 g (97% yield) of Compound B as a tan solid.
13C-BMR (CDCI3): 40,55, 52,19, 54,22, 61,74, 112,52, 120,25, 126,50, 128,60, 129,30, 130,13, 132,09, 133,96, 138,52, 148,13 m.d. 13 C-NMR (CDCl 3 ): 40.55, 52.19, 54.22, 61.74, 112.52, 120.25, 126.50, 128.60, 129.30, 130.13, 132 , 09, 133.96, 138.52, 148.13 md
C. (R)-2,3,4,5-Tetrahidro-3-(fenilmetil)-1H-1,4-benzodiazepin-7karbonitrilas j maišomą junginio B (60 g, 190 mmol) suspensiją bevandeniame 1metil-2-pirolidinone (600 ml) azoto atmosferoje pridedama vario(l) cianido (51 g, 569 mmol). Mišinys kaitinamas iki 200° temperatūros 3,5 vai. Intensyviai maišant, šis mišinys lėtai supilamas j 15 % etilendiamino tirpalą vandenyje (1,5 I). Pamaišius 1,0 vai., suspensija ekstrahuojama EtOAc (3 x 750 ml). EtOAc ekstraktai sumaišomi, plaunami 10 % NH4OH (2 x 750 ml) ir sočiu NaCl, džiovinami bevandeniu Na2SO4, ir nugarinus gaunama juoda dervos pavidalo medžiaga. Ši medžiaga perleidžiama per silikgelio (E. Merck 230400 mešų, 1,2 kg) sluoksnį, eliuuojant EtOAc, ir gaunama 40 g (80 %) junginio C, kuris yra gelsvai ruda kieta medžiaga.C. (R) -2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile in a stirred suspension of compound B (60 g, 190 mmol) in anhydrous 1-methyl-2-pyrrolidinone ( Copper (I) cyanide (51 g, 569 mmol) was added under nitrogen (600 mL). The mixture is heated to 200 ° for 3.5 hours. With vigorous stirring, this mixture was slowly added to a 15% solution of ethylenediamine in water (1.5 L). After stirring for 1.0 h, the suspension was extracted with EtOAc (3 x 750 mL). The EtOAc extracts were combined, washed with 10% NH 4 OH (2 x 750 mL) and saturated NaCl, dried over anhydrous Na 2 SO 4 , and evaporated to give a black gum. This material was passed through a pad of silica (E. Merck 230400 mesh, 1.2 kg) eluting with EtOAc to give 40 g (80%) of Compound C, which is a tan solid.
13C-BMR (CD3OD): 40,84, 49,23, 51,62, 51,71, 62,56, 101,42, 119,14, 120,99, 13 C-NMR (CD 3 OD): 40.84, 49.23, 51.62, 51.71, 62.56, 101.42, 119.14, 120.99,
127,56, 129,66, 130,38, 132,71, 134,86, 139,82, 165,29 m.d.127.56, 129.66, 130.38, 132.71, 134.86, 139.82, 165.29 ppm.
218218
D. (R)-7-Ciano-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(fenilmetil)-4H-1,4-benzodiazepinasD. (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -4H-1,4-benzodiazepine
Junginys D pagaminamas iš junginio C pagal reakcijų seką, naudojamą tokiems junginiams gauti:98 pavyzdžio junginiui C, reakciją vykdant be trietilamino ir gryninant sparčiosios chromatografijos per silikgaelj metodu, eliuuojant 4: heksanais:etilacetatu; 1 pavyzdžio junginiui D; veikiant 4M HCl 1:1 dioksane:etilacetate, MS (M + H)+ 344.Compound D is prepared from Compound C according to the reaction sequence used to obtain the following compounds: Compound C of Example 98 is reacted without triethylamine and purified by flash chromatography on silica eluting with 4: hexanes: ethyl acetate; Example 1 for compound D; in 4M HCl in 1: 1 dioxane: ethyl acetate, MS (M + H) + 344.
E. (R)-7-Ciano-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(fenilmetil)-4H-1,4-benzodiazepin-4-karboksirūgšties etilo esteris (hidrochloridas)E. (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxylic acid ethyl ester. (hydrochloride)
J junginio D (0,10 g, 0,22 mmol) ir DIPEA (0,16 ml, 0,9 mmol) tirpalą sausame metileno chloride (1 ml) 0 °C temperatūroje argono atmosferoje pridedama etilchlorformiato (0,023 ml, 0,24 mmol). Pamaišius 2,5 dienos, reakcijos mišinys paskirstomas tarp NaHCO3 (5 ml) ir CHCI3(20 ml). Vandeninis sluoksnis ekstrahuojamas CHCI3 (2 x 10 ml). Sumaišyti organiniai sluoksniai plaunami NaHCO3, vandeniu ir sočiu NaCl, džiovinami MgSO4, nufiltruojama ir koncentruojama. Produktas gryninamas leidžiant per sparčiosios chromatografijos kolonėlę, eliuuojamą EtOAc (200 ml) ir 19/1 CHCI3/CH3OH (200 ml), veikiamas 1N NaOH imidazolo acilo grupei pašalinti ir veikiamas HCI/eteryje; gaunamas 248 pavyzdžio junginys (0,047 g, 52 %). MS (M + H)+ = 416.To a solution of compound J (0.10 g, 0.22 mmol) and DIPEA (0.16 mL, 0.9 mmol) in dry methylene chloride (1 mL) at 0 ° C was added ethyl chloroformate (0.023 mL, 0.24) under argon. mmol). After stirring for 2.5 days, the reaction mixture was partitioned between NaHCO 3 (5 mL) and CHCl 3 (20 mL). The aqueous layer was extracted with CHCl 3 (2 x 10 mL). The combined organic layers were washed with NaHCO 3 , water and saturated NaCl, dried over MgSO 4 , filtered and concentrated. The product was purified by flash column chromatography eluting with EtOAc (200 mL) and 19/1 CHCl3 / CH3OH (200 mL), treated with 1N NaOH to remove the imidazole acyl group, and treated with HCl / ether; Example 248 is obtained (0.047 g, 52%). MS (M + H) <+> = 416.
1H-BMR (CD3OD): δ 8,9 (d, 1H, J = 16 Hz), 7,48-7,12 (m, 8H), 6,9 (m, 1H), 5,0-4,4 (m, 5H), 4,8-3,7 (m, 3H), 3,4-3,2 (m, 2H), 2,89-2,7 (m, 2H), 1,03 (m, 3H). 1 H-NMR (CD 3 OD): δ 8.9 (d, 1H, J = 16 Hz), 7.48-7.12 (m, 8H), 6.9 (m, 1H), 5.0-4 , 4 (m, 5H), 4.8-3.7 (m, 3H), 3.4-3.2 (m, 2H), 2.89-2.7 (m, 2H), 1.03 (m, 3H).
249 pavyzdysExample 249
219219
N-[2,3,4,5-Tetrahidro-1-(1H-imidazo!-4-iImetil)-4-(meti!sulfonil)-3(fenilmetil)-1H-1,4-benzodiazepin-8-il]cikloheksankarboksamidas (dihidrochloridas) j heterogeninį 246 pavyzdžio junginio C (0,030 g, 0,054 mmol), DMF (0,2 ml) ir trietilamino (0,2 ml) mišinį sausame metileno chloride (0,3 ml) kambario temperatūroje argono atmosferoje pridedama metansulfonilchlorido (0,024 ml, 0,38 mmol). Pamaišius 2,5 dienos, pridedamas kitas ekvivalentas metansulfonilchlorido. Pamaišius 3 vai., mišinys praskiedžiamas NaHCO3 ir CHCI3, atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas chloroformu (2 x 20 ml). Sumaišyti organiniai sluoksniai plaunami vandeniu (5 ml) ir sočiu NaCi (5 ml), džiovinami MgSO4, nufiltruojama ir koncentruojama. Liekana gryninama perleidžiant per sparčiosios chromatografijos silikagelio kolonėlę, eliuuojamą CHCI3 ir 9/1 CHCI3/CH3OH (po 200 ml), ir gaunamas 249 pavyzdžio junginys (5 mg, 17 %)·N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepin-8-yl ] cyclohexanecarboxamide (dihydrochloride): To a heterogeneous mixture of Example 246 Compound C (0.030 g, 0.054 mmol), DMF (0.2 mL) and triethylamine (0.2 mL) in dry methylene chloride (0.3 mL) was added methanesulfonyl chloride at room temperature under argon. (0.024 mL, 0.38 mmol). After stirring for 2.5 days, another equivalent of methanesulfonyl chloride is added. After stirring for 3 h, the mixture was diluted with NaHCO 3 and CHCl 3 , the layers were separated, and the aqueous layer was extracted with chloroform (2 x 20 mL). The combined organic layers were washed with water (5 mL) and saturated NaCl (5 mL), dried over MgSO 4 , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with CHCl 3 and 9/1 CHCl 3 / CH 3 OH (200 mL each) to give Example 249 (5 mg, 17%).
MS (M + H)+= 522.MS (M + H) <+> = 522.
1H-BMR (CD3OD): δ 8,88 (s, 1 H), 7,5(m, 2H), 7,3 (m, 5H), 7,05 (d, 1H, J = 8 Hz), 6,8 (d, 1H, J = 8 Hz), 4,8-4,2 (m, 5H), 3,6 (m, 1H), 3,2 (m, 1H), 3,0 (m, 1H), 2,7 (m, 1H), 2,3 (m, 3H), 1,6-1,9 (m, 5H), 1,1-1,5 (m, 4H), 0,9 (m, 2H). 1 H-NMR (CD 3 OD): δ 8.88 (s, 1H), 7.5 (m, 2H), 7.3 (m, 5H), 7.05 (d, 1H, J = 8 Hz), 6.8 (d, 1H, J = 8Hz), 4.8-4.2 (m, 5H), 3.6 (m, 1H), 3.2 (m, 1H), 3, 0 (m, 1H), 2.7 (m, 1H), 2.3 (m, 3H), 1.6-1.9 (m, 5H), 1.1-1.5 (m, 4H) 0.9 (m, 2H).
250 pavyzdysExample 250
220220
(R)-7-Ciano-4-[[2-(dimetilamino)etil]suIfoniI]-2,3,4,5-tetrahidro-1-(1Himidazol-4-iImetil)-3-(fenilmetil)-4H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Cyano-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H- 1,4-Benzodiazepine (dihydrochloride)
A. (R)-7-Ciano-4-(etenilsulfonil)-2,3,4,5-tetrahidro-1-(1H-imidazoI-4ilmetil)-3-(feniImetil)-4H-1,4-benzodiazepinasA. (R) -7-Cyano-4- (ethenylsulfonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine
J 248 pavyzdžio junginio D (1,0 g, 3,79 mmol) ir DIPEA (2,6 ml, 15,2 mmol) tirpalą dichlormetane (16 ml) 0 °C temperatūroje argono atmosferoje pridedama 2-chloretansulfonilchlorido (1,85 g, 11,4 mmol). Pamaišius 16 vai., reakcijos mišinys praskiedžiamas chloroformu ir vandeniniu NaHCO3. Atskiriami sluoksniai ir vandeninis sluoksnis vėl ekstrahuojamas du kartus chloroformu. Sumaišyti organiniai ekstraktai plaunami du kartus NaHCO3 ir sočiu NaCl, džiovinami MgSO4, nufiltruojama ir koncentruojama. Produktas gryninamas leidžiant per sparčiosios chromatografijos silikagelo kolonėlę, eliuuojamą 75 %, o po to 50 % h eksanais/etil acetate, ir gaunamas junginys A (0,31 g, 23 %). MS: (M + H)+ = 434.To a solution of Example D 248 Compound D (1.0 g, 3.79 mmol) and DIPEA (2.6 mL, 15.2 mmol) in dichloromethane (16 mL) at 0 ° C under argon was added 2-chloro-ethanesulfonyl chloride (1.85 g). , 11.4 mmol). After stirring for 16 h, the reaction mixture was diluted with chloroform and aqueous NaHCO 3 . The layers were separated and the aqueous again extracted twice with chloroform. The combined organic extracts were washed twice with saturated NaHCO 3 and NaCl, dried over MgSO 4, filtered and concentrated. The product was purified by flash column chromatography on silica gel eluting with 75%, followed by 50% h exanes / ethyl acetate to afford Compound A (0.31 g, 23%). MS: (M + H) < + > = 434.
B. (R)-7-Ciano-4-[[2-(dimetilamino)etil]sulfonil]-2,3,4,5-tetrahidro-1(1H-imidazol-4-ilmetil)3-(fenilmetil)-4H-1,4-benzodiazepinas (dihidrochloridas)B. (R) -7-Cyano-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) - 4H-1,4-benzodiazepine (dihydrochloride)
Junginys A (0,59 g, 1,36 mmol) 2M dimetilamino tirpale THF (15 ml, 30 mmol) šildomas užlydytame vamzdelyje 60 °C temperatūroje 16 vai.Compound A (0.59 g, 1.36 mmol) in 2M dimethylamine in THF (15 mL, 30 mmol) was heated in a sealed tube at 60 ° C for 16 h.
Reakcijos mišinys sukoncentruojamas, ir liekana gryninama preparatinėsThe reaction mixture is concentrated and the residue is purified by preparative
HPLC metodu (30-90 % vandeninio metanolio su 0,1 % TFA gradientas).By HPLC (30-90% aqueous methanol with 0.1% TFA gradient).
221221
Išgryninta TFA druska paverčiama HCI druska, panaudojant HCI/eteryje, ir po liofilizavimo gaunamas 250 pavyzdžio junginys (11 mg, 1,7 %).The purified TFA salt was converted to the HCl salt using HCl / ether and lyophilized to afford Example 250 (11 mg, 1.7%).
MS: (M+H)+ = 479.MS: (M + H) < + > = 479.
1H-BMR (CD3OD): δ 8,9 (s, 1H), 7,5-7,2 (m, 8H), 6,9 (m, 1H), 4,8-4,4 (m, 5H), 1 H-NMR (CD 3 OD): δ 8.9 (s, 1H), 7.5-7.2 (m, 8H), 6.9 (m, 1H), 4.8-4.4 (m, 5H),
3,95 (m, 1H), 3,4-3,1 (m, 5H), 3,0-2,7 (m, 8H).3.95 (m, 1H), 3.4-3.1 (m, 5H), 3.0-2.7 (m, 8H).
251 pavyzdysExample 251
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazo!-4-ilmetil)-4-[[2-(4morfolinil)etil]sulfonil]-3-(fenilmetil)-4H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -4H-1,4-benzodiazepine (dihydrochloride)
251 pavyzdžio junginys pagaminamas iš 250 pavyzdžio junginio A ir morfolino pagal 250 pavyzdyje aprašytą metodiką (61 %).Example 251 is prepared from Example 250 Compound A and morpholine according to the procedure described in Example 250 (61%).
MS: (M + H)+ = 521.MS: (M + H) < + > = 521.
1H-BMR (CD3OD): δ 8,9 (s, 1H), 7,75-7,2 (m, 8H), 6,95 (m, 1H), 5,0-4,4 (m, 3H), 4,1-3,7 (m, 7H), 3,5-3,1 (m, 6H), 3,0 (m, 3H), 2,85 (m, 1H), 2,55 (m, 1H). 1 H-NMR (CD 3 OD): δ 8.9 (s, 1H), 7.75-7.2 (m, 8H), 6.95 (m, 1H), 5.0-4.4 (m, 3H), 4.1-3.7 (m, 7H), 3.5-3.1 (m, 6H), 3.0 (m, 3H), 2.85 (m, 1H), 2.55 (m, 1H).
222222
N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-iImetil)-4-(2-metoksi-3metilbenzoil)-1H-1,4-benzodiazepin-8-il]cikloheksankarboksamidas (dihidrochloridas) i 246 pavyzdžio junginio C (46 mg, 0,1 mmol) tirpalą DMF (1 ml) kambario temperatūroje argono atmosferoje pridedama iš eilės 2-metoksi-3metilbenzenkarboksirūgšties (20 mg, 0,12 mmol), DIPEA (0,09 ml, 0,5 mmol), HOAt (16 mg, 0,12 mmol) ir EDC (23 mg, 0,12 mmol). Po 18 vai. pridedama NaOH (1N, 1 ml) ir MeOH (2 ml). Po 25 min. lakios medžiagos nugarinamos vakuume, o liekana paskirstoma tarp chloroformo (15 ml) ir NaHCO3 (10 ml). Organinis sluoksnis atskiriamas, džiovinamas ir koncentruojamas vakuume. Liekana gryninama chromatografuojant per silikagelj, kuris eliuuojamas 5 % MeOH chloroforme, ir gaunama balta kieta medžiaga (42 mg, 83 %), kuri ištirpinama MeOH (1 ml) ir pridedama HCI eteryje (1N, 2 ml). Sukoncentravus mišinį vakuume, gaunamas 252 pavyzdžio junginys, kuris yra geltona kieta medžiaga (50 mg).N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methoxy-3-methylbenzoyl) -1H-1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride) ) To a solution of Example 246 Compound C (46 mg, 0.1 mmol) in DMF (1 mL) at room temperature under argon was added successively 2-methoxy-3-methylbenzoic acid (20 mg, 0.12 mmol), DIPEA (0.09 mL, 0.5 mmol), HOAt (16 mg, 0.12 mmol) and EDC (23 mg, 0.12 mmol). After 18 or. NaOH (1N, 1 mL) and MeOH (2 mL) were added. After 25 minutes the volatiles were evaporated in vacuo and the residue partitioned between chloroform (15 mL) and NaHCO 3 (10 mL). The organic layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 5% MeOH in chloroform to give a white solid (42 mg, 83%) which was dissolved in MeOH (1 mL) and added to HCl in ether (1N, 2 mL). Concentration in vacuo gave Example 252 as a yellow solid (50 mg).
MS (M + H)+ = 502,3.MS (M + H) <+> = 502.3.
8-[(Cikloheksilkarbonil)amino]-2,3,4,5-tetrahidro-1-(1H-imidazol-4ilmetil)-N-fenil-1H-1,4-benzodiazepin-4-karboksamidas (dihidrochloridas)8 - [(Cyclohexylcarbonyl) amino] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-phenyl-1H-1,4-benzodiazepine-4-carboxamide (dihydrochloride)
J 246 pavyzdžio junginio C (46 mg, 0,1 mmol) tirpalą DMF (1 ml) kambario temperatūroje argono atmosferoje pridedama iš eilėsA solution of compound C (46 mg, 0.1 mmol) in Example J 246 in DMF (1 mL) at room temperature under argon was added sequentially.
223 fenilizocianato (13 μΙ, 0,12 mmol) ir DIPEA (0,09 ml, 0,5 mmol). Po 18 vai. pridedama NaOH (1N, 1 ml) ir MeOH (2 ml). Po 25 min. lakios medžiagos nugarinamos vakuume, o liekana paskirstoma tarp chloroformo (15 ml) ir vandens (10 ml). Tam tikra norimo produkto iškritusi j nuosėdas dalis nufiltruojama. Organinis sluoksnis atskiriamas ir koncentruojamas vakuume. Liekana sumaišoma su nufiltruota kieta medžiaga, ištirpinama MeOHTTHF mišinyje ir gryninama atvirkštinių fazių HPLC, eliuuojant 50 % - 90 % vandeniniu MeOH, kuriame yra 0,1 % TFA. Tinkamos frakcijos surenkamos ir koncentruojamos. Liekana apdorojama 1N HCl ir sukoncentruojama. Po trijų tokių apdorojimų liekana ištirpinama vandenyje, ir po liofilizavimo gaunamas 253 pavyzdžio junginys, kuris yra geltona kieta medžiaga (30 mg, 55 %).223 Phenylisocyanate (13 μΙ, 0.12 mmol) and DIPEA (0.09 mL, 0.5 mmol). After 18 or. NaOH (1N, 1 mL) and MeOH (2 mL) were added. After 25 minutes the volatiles were removed in vacuo and the residue partitioned between chloroform (15 mL) and water (10 mL). A precipitate of the desired product is filtered off. The organic layer was separated and concentrated in vacuo. The residue is mixed with the filtered solid, dissolved in MeOHTTHF and purified by reverse phase HPLC eluting with 50% to 90% aqueous MeOH containing 0.1% TFA. The appropriate fractions are collected and concentrated. The residue is taken up in 1N HCl and concentrated. After three such treatments, the residue is dissolved in water and lyophilized to give Example 253 as a yellow solid (30 mg, 55%).
MS (M + H)+ = 473,3.MS (M + H) <+> = 473.3.
N-[2,3.4,5Tetrahidro-1-(1 H-imidazol-4-ilmetil)-4-[(2-metilfenil)suIfonil]1H-1,4-benzodiazepin-8-il]cikIoheksanamidas (dihidrochloridas)N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methylphenyl) sulfonyl] 1H-1,4-benzodiazepin-8-yl] cyclohexanamide (dihydrochloride)
254 pavyzdžio junginys'(geltona kieta medžiaga) pagaminamas iš 246 pavyzdžio junginio C ir 2-metilbenzensuIfonilchlorido pagal 253 pavyzdyje aprašytą metodiką, išskyrus tai, kad suskaldytas ir nugarintas reakcijos mišinys tiesiogiai gryninamas preparatinės HPLC metodu (29 %).Example 254 (yellow solid) was prepared from Example 246, C and 2-methylbenzenesulfonyl chloride according to the procedure described in Example 253, except that the cleaved and evaporated reaction mixture was directly purified by preparative HPLC (29%).
MS (M + H)+ = 508,2.MS (M + H) < + > = 508.2.
255 pavyzdysExample 255
224224
N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-[(2metoksifenil)karbonil]-1H-1,4-benzodiazepin-8-il]cikloheksanamidas (dihidrochloridas)N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxyphenyl) carbonyl] -1H-1,4-benzodiazepin-8-yl] cyclohexanamide (dihydrochloride)
255 pavyzdžio junginys (gelsva kieta medžiaga) pagaminamas iš 246 pavyzdžio junginio C ir 2-metoksibenzenkarboksirūgšties pagal 252 pavyzdyje aprašytą metodiką.Example 255 Compound (yellowish solid) is prepared from Example 246 Compound C and 2-methoxybenzoic acid according to the procedure described in Example 252.
MS (M + H)4 = 488,3.MS (M + H) + = 488.3 4.
256 pavyzdysExample 256
(R)-7-Ciano-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4H1,4-benzodiazepin-4-sulfonrūgšties etilo esteris (hidrochloridas)(R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H1,4-benzodiazepine-4-sulfonic acid ethyl ester (hydrochloride)
A. (R)-7-Ciano-1,2,3,5-tetrahidro-3-(fenilmetil)-4H-1,4-benzodiazepin-4sulfonrūgšties etilo esteris j 248 pavyzdžio junginio C (0,3 g, 1,13 mmol) ir DIPEA (0,78 ml, 4,55 mmol) tirpalą dichlormetane (8 ml) 0 °C temperatūroje argono atmosferojeA. (R) -7-Cyano-1,2,3,5-tetrahydro-3- (phenylmethyl) -4H-1,4-benzodiazepine-4sulfonic acid ethyl ester in Example 248 Compound C (0.3 g, 1, 13 mmol) and DIPEA (0.78 mL, 4.55 mmol) in dichloromethane (8 mL) at 0 ° C under argon
225 pridedama etilchlorsulfonato (0,49 g, 3,41 mmol). Pamaišius 16 vai. kai sušyla iki kambario temperatūros, mišinys praskiedžiamas chloroformu ir NaHCO3. Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas chloroformu. Sumaišyti organiniai ekstraktai plaunami NaHCO3, vandeniu, 1N HCI ir du kartus sočiu NaCl, džiovinami MgSO4, nufiltruojama ir sukoncentravus gaunamas junginys A (0,54 g, 13 %). MS (M-H)' = 370.Ethyl chlorosulfonate (0.49 g, 3.41 mmol) was added in 225. After stirring for 16 hours. when returned to room temperature, the mixture was diluted with chloroform and NaHCO third The layers are separated and the aqueous layer is extracted with chloroform. The combined organic extracts were washed with NaHCO 3 , water, 1N HCl and twice saturated NaCl, dried over MgSO 4 , filtered and concentrated to give Compound A (0.54 g, 13%). MS (MH +) = 370.
B. (R)-7-Ciano-1,2,3,5-tetrahidro-1-(1H-imidazoI-4-ilmetil)-3(fenilmetil)-4H-1,4-benzodiazepin-4-sulfonrūgšties etilo esteris (hidrochloridas)B. (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonic acid ethyl ester. (hydrochloride)
256 pavyzdžio junginys pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką, naudojant dichloretaną ir 3A molekulinius tinklelius. Išgryninus preparatinės HPLC metodu, po to pavertus HCI druska ir liofilizavus, gaunamas 256 pavyzdžio junginys.Example 256 is prepared from Compound A according to the procedure described in Example 1 for the preparation of Compound D using dichloroethane and 3A molecular mesh. Purification by preparative HPLC followed by conversion to HCl salt and lyophilization afforded Example 256.
MS (M + H)+ = 535.MS (M + H) <+> = 535.
1H-BMR (400 MHz, CD3OD): δ 8,9 (s, 1H), 7,5-7,2 (m, 8H), 6,9 (d, 1H, J = 8 Hz), 5-4,4 (m, 4H), 4,3 (m, 1H), 4-3,2 (m, 4H), 3,0 (m, 1H), 2,8 (m, 1H), 1,05 (t, 3H). 1 H-NMR (400 MHz, CD 3 OD): δ 8.9 (s, 1H), 7.5-7.2 (m, 8H), 6.9 (d, 1H, J = 8 Hz), 5-4.4 (m, 4H), 4.3 (m, 1H), 4-3.2 (m, 4H), 3.0 (m, 1H), 2.8 (m, 1H), 1 , 05 (t, 3H).
257 pavyzdysExample 257
BrBr
(3R)-7-Brom-1-[ciano(1H-imidazol-4-il)metil]-2,3,4,5-tetrahidro-4(metilsuIfonil)-3-(fenilmetii)-1 H-1,4-benzodiazepinas (monohidrochloridas)(3R) -7-Bromo-1- [cyano (1H-imidazol-4-yl) methyl] -2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1, 4-Benzodiazepine (monohydrochloride)
226 | maišomą 224 pavyzdžio junginio C (390 mg, 1,0 mmol) tirpalą acetonitrilo, metanolio ir acto rūgšties mišinyje (3 ml, 1:1:1) pridedama 4formilimidazolo (100 mg, 1,04 mmol), o po to natrio cianido (55 mg, 1,12 mmol). Mišinys maišomas kambario temperatūroje 2 dienas, skaldomas sočiu kalio karbonatu (2 ml) ir paskirstomas tarp etilacetato ir 1N NH4OH tirpalo. Organinis sluoksnis atskiriamas, plaunamas sočiu NaCl, džiovinamas, ir sukoncentravus gaunama kieta medžiaga (400 mg, 80 %). Dalis šios medžiagos paverčiama jos HCI druska, ištirpinant metanolyje, pridedant 1N HCI eteryje, ir nugarinus tirpiklį gaunamas 257 pavyzdžio junginys. Plonasluoksnė chromatografija: Rf = 0,50 (etilacetatas, dvi dėmės).226 | To a stirred solution of Example 224 Compound C (390 mg, 1.0 mmol) in acetonitrile: methanol: acetic acid (3 mL, 1: 1: 1) was added 4-formylimidazole (100 mg, 1.04 mmol) followed by sodium cyanide ( 55 mg, 1.12 mmol). The mixture was stirred at room temperature for 2 days, partitioned between saturated potassium carbonate (2 mL) and partitioned between ethyl acetate and 1N NH 4 OH. The organic layer was separated, washed with brine, dried, and concentrated to give a solid (400 mg, 80%). A portion of this material is converted to its HCl salt by dissolving in methanol with 1N HCl in ether and evaporating the solvent to give Example 257. TLC: R f = 0.50 (ethyl acetate, two spots).
MS (M + H)+ 500.MS (M + H) < + > 500.
(3R)-1-[2-Amino-1-(1H-imidazol-4-il)etil]-2,3,4,5-tetrahidro-4(metilsulfonil)-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas) j maišomą ličio aliuminio hidrido (95 mg, 2,5 mmol) suspensiją eteryje argono atmosferoje kambario temperatūroje supilamas 257 pavyzdžio laisvos bazės (250 mg, 0,5 mmol) tirpalas bevandeniame THF. Mišinys maišomas kambario temperatūroje 8 vai., praskiedžiamas THF, po to etilacetatu ir amonio hidroksidų. Suspensija maišoma kambario temperatūroje 18 vai. ir nufiltruojama. Filtratas sukoncentruojamas vakuume, ir liekana gryninama chromatografuojant per silikagelį (etilacetatas/metanolis/NH4OH, 10:1:0,1); gaunama pusiau kieta medžiaga (80 mg, 38 %). Dalis šios medžiagos paverčiama jos HCI druska taip, kaip aprašyta 257 pavyzdyje.(3R) -1- [2-Amino-1- (1H-imidazol-4-yl) ethyl] -2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1, 4-Benzodiazepine (dihydrochloride) To a stirred suspension of lithium aluminum hydride (95 mg, 2.5 mmol) in ether under argon at room temperature was added a solution of Example 257 free base (250 mg, 0.5 mmol) in anhydrous THF. The mixture was stirred at room temperature for 8 hours, diluted with THF, followed by ethyl acetate and ammonium hydroxide. The suspension is stirred at room temperature for 18 hours. and filtered off. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (ethyl acetate / methanol / NH 4 OH, 10: 1: 0.1); yielding a semi-solid (80 mg, 38%). Part of this material is converted to its HCl salt as described in Example 257.
227227
MS (M + H) + 426.MS (M + H) < + >
259 pavyzdysExample 259
Me2NMe 2 N
(3R)-1-[2-(Dimetilamino)-1-(1 H-imidazol-4-il)etil]-2,3,4,5-tetrahidro-4(metilsulfonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (dihidrochloridas) j maišomą 258 pavyzdžio laisvos bazės 20 mg) tirpalą metanolyje (1 ml) ir acto rūgštyje (0,5 ml) su natrio acetatu (100 mg) pridedama 30 μΙ formaldehido (37 % vandeninis tirpalas), o po to NaCNBH3 (15 mg). Mišinys pamaišomas 15 min., vėl pridedama formaldehido (30 μΙ) ir NaCNBH3, mišinys pamaišomas 30 min., praskiedžiamas etilacetatu, ir skaldoma 3 ml NH4OH. Organinis sluoksnis atskiriamas, plaunamas 1N NH4OH tirpalu ir sočiu NaCl, džiovinamas ir koncentruojamas. Liekana paverčiama jos HCI druska taip, kaip aprašyta 257 pavyzdyje (23 mg).(3R) -1- [2- (Dimethylamino) -1- (1H-imidazol-4-yl) ethyl] -2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1 H-1,4-Benzodiazepine (dihydrochloride) was added to a stirred solution of 258 free base 20 mg) in methanol (1 mL) and acetic acid (0.5 mL) with sodium acetate (100 mg) and 30 μΙ formaldehyde (37% aqueous solution) was added. ) followed by NaCNBH 3 (15 mg). The mixture is stirred for 15 min, formaldehyde (30 μΙ) and NaCNBH 3 are added again, the mixture is stirred for 30 min, diluted with ethyl acetate and quenched with 3 mL of NH 4 OH. The organic layer was separated, washed with 1N NH 4 OH solution and saturated NaCl, dried and concentrated. The residue is converted to its HCl salt as described in Example 257 (23 mg).
MS (M + H)+ 454.MS (M + H) + 454.
260 pavyzdysExample 260
BrBr
H2NH 2 N
228 (3R)-1-[2-Amino-1-(1H-imidazol-4-il)etil]-7-brom-2,3,4,5-tetrahidro-4(metilsulfonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (dihidrochloridas) į maišomą 258 pavyzdžio laisvos bazės (20 mg) tirpalą chloroforme (1,5 ml) pridedama tetrabutilamonio perbromido. Mišinys maišomas kambario temperatūroje 10 min. ir skaldomas vandeniniu NaS2O3 tirpalu. Organinis sluoksnis atskiriamas ir plaunamas chloroformu. Sumaišyti organiniai sluoksniai džiovinami MgSO4 ir koncentruojami vakuume. Liekana gryninama kolonėlių chromatografijos metodu (etilacetatas/metanolis/NH4OH; 10:1:0 1), ir gaunama balta kieta medžiaga (17 mg), kuri paverčiama jos hidrochlorido druska taip, kaip aprašyta 257 pavyzdyje.228 (3R) -1- [2-Amino-1- (1H-imidazol-4-yl) ethyl] -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1 H -1,4-Benzodiazepine (dihydrochloride) To a stirred solution of the free base (20 mg) of Example 258 in chloroform (1.5 mL) was added tetrabutylammonium perbromide. The mixture was stirred at room temperature for 10 min. and quenched with aqueous NaS 2 O 3 . The organic layer was separated and washed with chloroform. The combined organic layers were dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate / methanol / NH 4 OH; 10: 1: 0 1) to give a white solid (17 mg) which was converted to its hydrochloride salt as described in Example 257.
MS (M + H)+ 504.MS (M + H) + 504.
261 pavyzdysExample 261
(3R)-1-[2-(Dimetilamino)-1-(1H-imidazol-4-il)etil]-7-brom-2,3,4,5tetrahidro-4-(metilsulfonil)-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)(3R) -1- [2- (Dimethylamino) -1- (1H-imidazol-4-yl) ethyl] -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
261 pavyzdžio junginys pagaminamas iš 260 pavyzdžio junginio pagalExample 261 is prepared from Example 260 according to
259 pavyzdyje aprašytą metodiką.259.
MS (M + H)+ 532.MS (M + H) <+> 532.
262 pavyzdysExample 262
229229
7-Ciano-1,3,4,5-tetrahidro-1-(1-metil-1H-imidazol-5-ilmetil)-3-(fenilmetil)4-(fenilsuIfonil)-2H-1,4-benzodiazepin-2-onas (monohidrochloridas)7-Cyano-1,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -3- (phenylmethyl) 4- (phenylsulfonyl) -2H-1,4-benzodiazepine-2 -one (monohydrochloride)
A. (R)-N-(2-amino-5-brom-fenilmetil)-N-(metansulfonil)fenilalanino metilo esterisA. (R) -N- (2-Amino-5-bromo-phenylmethyl) -N- (methanesulfonyl) phenylalanine methyl ester
J maišomą (R)-N-(2-aminofenilmetil)-N-(metansulfonil)-fenilalanino metilo esterio, pagaminto iš D-fenilalanino metilo esterio hidrochlorido, panaudojant redukcinį amininimą su 2-nitrobenzilaldehidu, o po to veikiant metansulfonilchloridu piridine ir redukuojant alavo chloridu etilacetate, (7,0 g, 16,5 mmol) tirpalą chloroforme (75 ml) kambario temperatūroje dalimis pridedama tetrabutilamonio perbromido (7,1 g, 14,8 mmol). Mišinys maišomas kambario temperatūroje 30 min. {pilama sotaus NaHCO3 tirpalo, o po to pridedama kieto Na2S2O3. Mišinys pamaišomas 1 vai., koncentruojamas vakuume, ir liekana paskirstoma tarp vandens ir 50 % etilacetato/heksanuose. Organinis sluoksnis atskiriamas, plaunamas vandeniu, sočiu NaCl, džiovinamas ir koncentruojamas vakuume. Liekana gryninama sparčiosios kolonėlių' chromatografijos metodu, ir gaunamas alyvos pavidalo junginys A (4)5 g, 54 %). MS (M+H)+ 503. [ajū20: + 29,6° (CHCIs), c = 0,25).A stirred R (-N) -N- (2-aminophenylmethyl) -N- (methanesulfonyl) -phenylalanine methyl ester prepared from D-phenylalanine methyl ester hydrochloride by reductive amination with 2-nitrobenzyl aldehyde followed by reaction with methanesulfonyl chloride in pyridine chloride in ethyl acetate (7.0 g, 16.5 mmol) in chloroform (75 mL) at room temperature was added portionwise tetrabutylammonium perbromide (7.1 g, 14.8 mmol). The mixture was stirred at room temperature for 30 min. {Saturated NaHCO 3 solution is added followed by addition of solid Na 2 S 2 O 3 . The mixture was stirred for 1 h, concentrated in vacuo and the residue partitioned between water and 50% ethyl acetate / hexanes. The organic layer was separated, washed with water, saturated NaCl, dried and concentrated in vacuo. The residue was purified by flash column chromatography to give compound A (4) as an oil (5 g, 54%). MS (M + H) + 503. [α] 20 : + 29.6 ° (CHCl3), c = 0.25).
B. 7-Ciano-1,3,4,5-tetrahidro-3-(fenilmetil)-4-(fenilsulfonil)-2H-1,4benzodiazepin-2-onasB. 7-Cyano-1,3,4,5-tetrahydro-3- (phenylmethyl) -4- (phenylsulfonyl) -2H-1,4-benzodiazepin-2-one
Junginio A (2,05 g, 4,07 mmol) tirpalas N-metilpirolidinone (10 ml), pridėjus CuCN (1,1 g, 12,3 mmol), kaitinamas 195 °C temperatūroje 4 vai. Mišinys atšaldomas iki kambario temperatūros ir paskirstomas tarp NH4OHA solution of Compound A (2.05 g, 4.07 mmol) in N-methylpyrrolidinone (10 mL) was added at 195 ° C for 4 h with the addition of CuCN (1.1 g, 12.3 mmol). The mixture was cooled to room temperature and partitioned between NH 4 OH
230 tirpalo ir metileno chlorido. Organinis sluoksnis atskiriamas, o vandeninis sluoksnis ekstrahuojamas metileno chloridu. Sumaišyti organiniai sluoksniai plaunami sočiu NaCl, džiovinami ir koncenrtuojami. Perkristalinus liekaną iš metanolio, gaunamas juunginys B, kuris yra ruda kieta medžiaga (1,1 g, 65 %). MS (M+H) + 416. Lyd. temp.: 222-223 °C.230 solution and methylene chloride. The organic layer is separated and the aqueous layer is extracted with methylene chloride. The combined organic layers were washed with saturated NaCl, dried and concentrated. Recrystallization of the residue from methanol gives compound B, which is a brown solid (1.1 g, 65%). MS (M + H) < + > mp: 222-223 ° C.
C. 7-Ciano-1,3,4,5-tetrahidro-1-(1-trifenilmetil-1H-imidazol-4-ilmetil)3-(fenilmetil)-4-(fenilsulfonil)-2H-1,4-benzodiazepin-2-onas j maišomą junginio B (310 mg, 0,74 mmol), N-tritilimidazol-4-metanolio (510 mg, 1,5 mmol) ir trifenilfosfino (450 mg, 1,72 mmol) tirpalą toluene ir dichloretane (20 ml/3 ml) 60 °C temperatūroje argono atmosferoje pridedama dietilazodikarboksilato (300 μΙ, 1,9 mmol). Mišinys pamaišomas 60 °C temperatūroje 1 vai. ir paskirstomas tarp etilacetato ir vandens. Organinis sluoksnis plaunamas vandeniu ir sočiu NaCl, džiovinamas, koncentruojamas vakuume, ir išgryninus sparčiosios kolonėlių chromatografijos metodu (etilacetatas/heksanai, 2:3), gaunamas alyvos pavidalo junginys C (450 mg, 82 %). MS (M + H)+ 740.C. 7-Cyano-1,3,4,5-tetrahydro-1- (1-triphenylmethyl-1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -2H-1,4-benzodiazepine -2-one to a stirred solution of compound B (310 mg, 0.74 mmol), N-tritylimidazole-4-methanol (510 mg, 1.5 mmol) and triphenylphosphine (450 mg, 1.72 mmol) in toluene and dichloroethane ( 20 mL / 3 mL) was added diethyl azodicarboxylate (300 μΙ, 1.9 mmol) at 60 ° C under argon. The mixture is stirred at 60 ° C for 1 hour. and partitioned between ethyl acetate and water. The organic layer was washed with water and saturated NaCl, dried, concentrated in vacuo and purified by flash column chromatography (ethyl acetate / hexanes, 2: 3) to give O-compound (450 mg, 82%) as an oil. MS (M + H) + 740.
D. 7-Ciano-1,3,4,5-tetrahidro-1-(1-metil-1H-imidazol-5-ilmetil)-3(fenilmetil)-4-(fenilsulfonil)-2H-1,4-benzodiazepin-2-onas (monohidrochloridas)D. 7-Cyano-1,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -2H-1,4-benzodiazepine -2-one (monohydrochloride)
J maišomą junginio C (210 mg, 0,28 mmol) tirpalą THF kambario temperatūroje argono atmosferoje pridedama trifluormetilsuifonato (35 μΐ, 0,31 mmol). Mišinys maišomas kambario temperatūroje 10 min. Pridedama acto rūgšties (0,5 mi) ir trietilsilano (0,25 ml). Mišinys pašildomas 60 °C temperatūroje 30 min. ir paskirstomas tarp 1N NaOH ir etilacetato. Organinis sluoksnis atskiriamas ir plaunamas sočiu NaCl, džiovinamas ir koncentruojamas vakuume. Liekana gryninama sparčiosios kolonėlių chromatografijos metodu, ir gaunama junginio D alyvos pavidalo laisva bazė (100 mg, 71 %). Ši bazė ištirpinama metanolyje ir pridedama 1N HCI tirpalo eteryje. Nugarinus tirpiklį, gaunamas 262 pavyzdžio junginys, kuris yra kieta medžiaga.To a stirred solution of Compound C (210 mg, 0.28 mmol) in THF at room temperature under argon was added trifluoromethylsulfonate (35 μΐ, 0.31 mmol). The mixture was stirred at room temperature for 10 min. Acetic acid (0.5 mL) and triethylsilane (0.25 mL) were added. The mixture was heated at 60 ° C for 30 min. and partitioned between 1N NaOH and ethyl acetate. The organic layer was separated and washed with saturated NaCl, dried and concentrated in vacuo. The residue was purified by flash column chromatography to give the free base of Compound D as an oil (100 mg, 71%). This base is dissolved in methanol and added with 1N HCl in ether. Evaporation of the solvent afforded Example 262 as a solid.
231231
MS (M + H)+ 512. Lyd. temp.: 160 °C.MS (M + H) < + > 512. m.p. mp: 160 ° C.
263 pavyzdysExample 263
7-Ciano-1,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4(fenilsulfonil)-2H-1,4-benzodiazepin-2-onas (monohidrochloridas)7-Cyano-1,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -2H-1,4-benzodiazepin-2-one (monohydrochloride) )
J maišomą 262 pavyzdžio junginio C (200 mg, 0,27 mmol) tirpalą CHCI3 kambario temperatūroje argono atmosferoje pridedama trifluoracto rūgšties (1 ml), o po to trietilsilano (0,5 ml). Mišinys maišomas kambario temperatūroje 2 vai. ir paskirstomas tarp 1N NH4OH ir etilacetato. Organinis sluoksnis atskiriamas, plaunamas sočiu NaCl, džiovinamas ir koncentruojamas vakuume. Liekana gryninama sparčiosios kolonėlių chromatografijos metodu (etilacetatas, metanolis: 95:5), ir gaunama alyvos pavidalo 263 pavyzdžio junginio laisva bazė (110 mg, 82 %). Ši bazė ištirpinama metanolyje ir pridedama 1N HCI tirpalo eteryje. Nugarinus tirpikli, gaunamas 263 pavyzdžio junginys, kuris yra kieta medžiaga.To a stirred solution of Example 262 Compound C (200 mg, 0.27 mmol) in CHCl 3 at room temperature under argon was added trifluoroacetic acid (1 mL) followed by triethylsilane (0.5 mL). The mixture was stirred at room temperature for 2 hours. and partitioned between 1N NH 4 OH and ethyl acetate. The organic layer was separated, washed with saturated NaCl, dried and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate, methanol: 95: 5) to give the free base of Example 263 as an oil (110 mg, 82%). This base is dissolved in methanol and added with 1N HCl in ether. Evaporation of the solvent afforded Example 263 as a solid.
MS (M + H)+ 498.MS (M + H) < + > 498.
Lyd. temp.: 195 °C.Lyd. mp: 195 ° C.
264 pavyzdysExample 264
232232
7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsuifonil)-3-(2feniletil)-1H-1,4-benzodiazepinas (dihidrochloridas)7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (2-phenylethyl) -1H-1,4-benzodiazepine (dihydrochloride)
A. 7-Brom-2,3,4,5-tetrahidro-3-(2-feniletil)-1H-1,4-benzodiazepinasA. 7-Bromo-2,3,4,5-tetrahydro-3- (2-phenylethyl) -1H-1,4-benzodiazepine
Junginys A pagaminamas iš D.L-homoPhe ir 6-bromizatoinės rūgšties anhidrido pagal aprašytą reakcijų seką šiems junginiams gauti: 80 pavyzdžio junginiui A, išskyrus tai, kad vietoj piridino vartojamas DMF ir šildoma 50 °C temperatūroje 24 vai.; 80 pavyzdžio junginiui B; 80 pavyzdžio junginiui C.Compound A is prepared from D.L-homoPhe and 6-bromoacetic acid anhydride according to the reaction sequence described to give the following compounds of Example 80, except that DMF is substituted for pyridine and heated at 50 ° C for 24 hours; Example 80 for compound B; Example 80 for compound C.
B. 7-Brom-2,3,4,5-tetrahidro-4-(metilsulfonil)-3-(2-feniletil)-1 H-1,4benzodiazepinasB. 7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (2-phenylethyl) -1H-1,4-benzodiazepine
Junginys A (100 mg, 0,30 mmol) ištirpinamas THF (5 ml), pridedama DIEA (211 μΙ, 1,21 mmol), o po to metansulfonilchlorido (94 μΙ, 1,21 mmol). Tirpalas maišomas 30 min., koncentruojamas, ištirpinamas etilacetate (50 ml) ir tirpalas plaunamas vandeniu (3x20 ml). Organinis sluoksnis džiovinamas (Na2SO4), ir sukoncentravus gaunamas rusvo stiklo pavidalo junginys B.Compound A (100 mg, 0.30 mmol) was dissolved in THF (5 mL), DIEA (211 μΙ, 1.21 mmol) was added followed by methanesulfonyl chloride (94 μΙ, 1.21 mmol). The solution was stirred for 30 min, concentrated, dissolved in ethyl acetate (50 mL) and washed with water (3 x 20 mL). The organic layer is dried (Na 2 SO 4 ) to give compound B as a brown glass upon concentration.
C. 7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4(metilsulfonil)-3-(2-feniletil)-1 H-1,4-benzodiazepinas (dihidrochloridas)C. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (2-phenylethyl) -1H-1,4-benzodiazepine ( dihydrochloride)
Junginys C ir 4-formilimidazolas ištirpinami 1,2-DCE (5 ml) ir acto rūgštyje (0,5 ml), ir pridedama natrio triacetoksiborhidrido. Mišinys maišomas °C temperatūroje 2 vai. ir pridedama sotaus NaHCO3 (5 ml). Šis mišinys sukoncentruojamas, ir liekana paskirstoma tarp vandens (20 ml) ir etilacetatoCompound C and 4-formylimidazole were dissolved in 1,2-DCE (5 mL) and acetic acid (0.5 mL) and sodium triacetoxyborohydride was added. The mixture was stirred at ° C for 2 h. and saturated NaHCO 3 (5 mL) was added. The mixture was concentrated and the residue partitioned between water (20 mL) and ethyl acetate
233 (20 ml). Organinis sluoksnis plaunamas vandeniu (10 ml), sočiu NaCl (10 ml), džiovinamas (MgSO4), koncentruojamas ir liekana gryninama preparatinės HPLC metodu (vandeninio metanolio gradientas, 0,1 % TFA). Tinkamos frakcijos sumaišomos, koncentruojamos ir liofilizuojamos. Liofilizatas ištirpinamas metanolyje (0,5 ml) ir 1N HCI (5 ml). Mišinys koncentruojamas ir liofilizuojamas. Pakartojus šią procedūrą, gaunamas 264 pavyzdžio junginys, kuris yra balta kieta medžiaga (15 mg, 19%).233 (20 mL). The organic layer was washed with water (10 mL), saturated NaCl (10 mL), dried (MgSO 4 ), concentrated, and purified by preparative HPLC (aqueous methanol gradient, 0.1% TFA). Appropriate fractions are mixed, concentrated, and lyophilized. The lyophilisate was dissolved in methanol (0.5 mL) and 1N HCl (5 mL). The mixture is concentrated and lyophilized. Repeat this procedure to give Example 264 as a white solid (15 mg, 19%).
MS (M + H)+ 490.MS (M + H) < + > 490.
265 pavyzdysExample 265
7-Brom-3-[(3-chlorfenil)metil]-2,3,4,5-tetrahidro-1-(1 H-imidazol-4-ilmetil)4-(meti!sulfonil)-1H-1,4-benzodiazepinas (dihidrochloridas)7-Bromo-3 - [(3-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) 4- (methylsulfonyl) -1H-1,4 benzodiazepine (dihydrochloride)
A. 2-(2-(1,1-Dimetil-etoksikarbonilamino)-3-(3chlorfenil)propilamino]-5-brombenzenkarboksirūgštisA. 2- (2- (1,1-Dimethyl-ethoxycarbonylamino) -3- (3-chlorophenyl) propylamino] -5-bromobenzoic acid
N-Boc-3-chlorfenilalaninalis (800 mg, 2,8 mmol) ir 2-amino-5brombenzenkarboksirūgštis (660 mg, 3,06 mmol) ištirpinami MeOH (10 ml). Pridedama molekulinių tinklelių (3A, 7,0 g) ir ledinės acto rūgšties (0,2 ml), ir mišinys maišomas 30 min. Per 30 min. dalimis pridedama natrio cianborhidrido (200 mg, 2,99 mmol). Mišinys maišomas 16 vai., atšaldomas iki 0 °C ir lėtai įpilama sotaus NaHCO3 (30 ml). Mišinys maišomas 30 min., koncentruojamas ir ekstrahuojamas etilacetatu (100 ml). Etilacetato sluoksnis plaunamas vandeniu (100 ml), sočiu NaCl (100 ml), džiovinamas (MgSO4) irN-Boc-3-chlorophenylalaninal (800 mg, 2.8 mmol) and 2-amino-5-bromobenzoic acid (660 mg, 3.06 mmol) were dissolved in MeOH (10 mL). Molecular grids (3A, 7.0 g) and glacial acetic acid (0.2 mL) were added and the mixture was stirred for 30 min. Within 30 minutes sodium cyanoborohydride (200 mg, 2.99 mmol) was added portionwise. The mixture was stirred for 16 h, cooled to 0 ° C, and saturated NaHCO 3 (30 mL) was added slowly. The mixture was stirred for 30 min, concentrated and extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (100 mL), saturated NaCl (100 mL), dried (MgSO 4 ) and
234 koncentruojamas. Po preparatinės HPLC (vandeninio metanolio gradientas, 0,1 % TFA) gaunamas skaidrios alyvos pavidalo junginys A (100 mg, 7 %).234 concentrated. Preparative HPLC (aqueous methanol gradient, 0.1% TFA) afforded Compound A as a clear oil (100 mg, 7%).
MS (M + H)+ 481.MS (M + H) + 481.
B. 2-[2-Amino-3-(3-chlorfenil)propilamino]-5-brombenzenkarboksirūgštisB. 2- [2-Amino-3- (3-chlorophenyl) propylamino] -5-bromobenzoic acid
Junginys A (100 mg, 0,21 mmol) maišomas dimetilsulfide (0,1 ml) ir 4N HCl dioksane (10 ml) 40 min. Mišinys sukoncentruojamas, ištirpinamas metileno chloride (20 ml) ir koncentruojamas. Pastaroji procedūra pakartojama tris kartus, ir gaunamas skaidraus stiklo pavidalo junginys B.Compound A (100 mg, 0.21 mmol) was stirred in dimethyl sulfide (0.1 mL) and 4N HCl in dioxane (10 mL) for 40 min. The mixture was concentrated, dissolved in methylene chloride (20 mL) and concentrated. The latter procedure is repeated three times to give compound B in the form of a clear glass.
C. 7-Brom-3-[(3-chlorfenil)metil]-2,3,4,5-tetrahidro-1-(1H-imidazol-4ilmetil)-4-(metilsulfonil)-1H-1,4-benzodiazepinas (dihidrochloridas)C. 7-Bromo-3 - [(3-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride)
Junginys C (balta kieta medžiaga) pagaminamas iš junginio B pagal reakcijų seką, naudojamą šiems junginiams gauti: 80 pavyzdžio junginiui B; 80 pavyzdžio junginiui C; 264 pavyzdžio junginiui B; 264 pavyzdžio junginiuiCompound C (white solid) is prepared from Compound B according to the reaction sequence used to prepare the following compounds: Example 80, Compound B; Example 80 for compound C; 264 for compound B; 264 for the compound of Example
C. MS (M + H)+ 510.C. MS (M + H) + 510.
266 pavyzdysExample 266
(R)-7-Brom-(3-cikloheksilmetil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4ilmetil)-4-(metilsulfonil)-1H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Bromo- (3-cyclohexylmethyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride)
266 pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš D-NBoc-cikloheksilalaninalio pagal 265 pavyzdyje aprašytą metodiką.Example 266 (white solid) is prepared from D-NBoc-cyclohexylalaninal according to the procedure described in Example 265.
235235
MS (M + H)+ 510.MS (M + H) + 510.
267 pavyzdysExample 267
7-Brom-3-[(2-chlorfenil)metil]-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)4-(metilsulfonil)-1 H-1,4-benzodiazepinas (dihidrochloridas)7-Bromo-3 - [(2-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) 4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride)
267 pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš D.L-NBoc-2-chlorfenilalaninalio pagal 265 pavyzdyje aprašytą metodiką.Example 267 (white solid) is prepared from D.L-NBoc-2-chlorophenylalaninal according to the procedure described in Example 265.
MS (M + H)+ 510.MS (M + H) + 510.
268 pavyzdysExample 268
(S)-7-Brom-(3-cikloheksilmetil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4iImetil)-4-(metiIsulfoniI)-1 H-1,4-benzodiazepinas (dihidrochloridas)(S) -7-Bromo- (3-cyclohexylmethyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride) )
268 pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš L-NBoc-cikloheksilalaninalio pagal 265 pavyzdyje aprašytą metodiką.Example 268 (white solid) is prepared from L-NBoc-cyclohexylalaninal according to the procedure described in Example 265.
236236
269 pavyzdysExample 269
MS (M + H)+482.MS (M + H) < + > 482.
7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-[(4metoksifenil)metil]-4-(metilsulfonil)-1H-1,4-benzodiazepinas (dihidrochloridas)7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - [(4-methoxyphenyl) methyl] -4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride) )
269 pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš D,L-NBoc-4-metoksifenilalaninalio pagal 265 pavyzdyje aprašytą metodiką.Example 269 (white solid) is prepared from D, L-NBoc-4-methoxyphenylalaninal according to the procedure described in Example 265.
MS (M + H)+ 506.MS (M + H) + 506.
270 pavyzdys270 Example
4-Acetil-7-brom-3-[(2-chlorfenil)metil]-2,3,4,5-tetrahidro-1-(1H-imidazol4-ilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)4-Acetyl-7-bromo-3 - [(2-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
237237
270 pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš 7brom-3-[(2-chlorfenil)metil]-2,3,4,5-tetrahidro-1 H-1,4-benzodiazepino pagal pavyzdyje aprašytas junginių D ir E gavimo metodikas.Example 270 (white solid) is prepared from 7brom-3 - [(2-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine according to the procedures for the preparation of compounds D and E described in the example. .
MS (M + H)+475.MS (M + H) + 475.
271 pavyzdysExample 271
BrBr
4-Acetil-7-brom-3-[(3-chlorfenil)metil]-2,3,4,5-tetrahidro-1-(1H-imidazol4-iImetiI)-1 H-1,4-benzodiazepinas (dihidrochloridas)4-Acetyl-7-bromo-3 - [(3-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
271 pavyzdžio junginys (balta kieta medžiaga) pagaminamas iš 7brom-3-[(3-chiorfenil)metil]-2,3,4,5-tetrahidro-1 H-1,4-benzodiazepino pagal 270 pavyzdyje aprašytą metodiką.Example 271 (white solid) is prepared from 7bromo-3 - [(3-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepine according to the procedure described in Example 270.
MS (M + H)+ 475.MS (M + H) + 475.
272 pavyzdysExample 272
BrBr
HOHO
238238
7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-[(4hidroksifenil)metil]-4-(metilsuIfonil)-1 H-1,4-benzodiazepinas (dihidrochloridas)7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - [(4-hydroxyphenyl) methyl] -4- (methylsulfonyl) -1H-1,4-benzodiazepine ( dihydrochloride)
J 269 pavyzdžio (30 mg, 0,059 mmol) tirpalą dichlormetano (5 ml) irA solution of Example 269 (30 mg, 0.059 mmol) in dichloromethane (5 mL) was added
1,2-dichloretano (5 mf) mišinyje supilamas BBr3 tirpalas (1M dichlormetane, 0,5 ml). Mišinys maišomas 16 vai., ir pridedama 5 % amonio hidroksido (10 ml). Šis mišinys maišomas dar 1 vai., koncentruojamas, ir liekana gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Tinkamos frakcijos sumaišomos, koncentruojamos ir liofilizuojamos. Šis liofilizatas ištirpinamas metanolyje (0,5 ml) ir 1N HCI (5 ml). Šis mišinys koncentruojamas ir liofilizuojamas. Pakartojus šią procedūrą, gaunamas 272 pavyzdžio junginys, kuris yra balta kieta medžiaga (20 mg, 60 %).To the mixture of 1,2-dichloroethane (5 mL) was added a solution of BBr 3 (1M in dichloromethane, 0.5 mL). The mixture was stirred for 16 h and 5% ammonium hydroxide (10 mL) was added. The mixture was stirred for an additional 1 h, concentrated, and the residue was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Appropriate fractions are mixed, concentrated, and lyophilized. This lyophilisate was dissolved in methanol (0.5 mL) and 1N HCl (5 mL). This mixture is concentrated and lyophilized. Repeat this procedure to give Example 272 as a white solid (20 mg, 60%).
MS(M + H)+490.MS (M + H) < + > 490.
(R)-2,3,4,5-Tetrahidro-1-(1H-imidazoi-4-ilmetil)-4-(metilsulfonil)-7-fenil-3(3-piridinilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
273 pavyzdžio junginys (gelsva kieta medžiaga) pagaminamas iš Dpiridilalanino ir 226 pavyzdžio junginio B pagal reakcijų seką, naudojamąExample 273 (yellowish solid) is prepared from Dpyridylalanine and Example 226 by Compound B according to the reaction sequence used
239 šiems junginiams gauti: 226 pavyzdžio junginiui C; 226 pavyzdžio junginiui D;239 for the following compounds: 226 for compound C; Example 226 for compound D;
264 pavyzdžio junginiui B; 264 pavyzdžio junginiui C.264 for compound B; 264 for compound C.
MS (M + H) + 474.MS (M + H) < + > 474.
274 pavyzdysExample 274
2,3,4,5-Tetrahidro-8-(hidroksimetil)-1-(1H-imidazol-4-ilmetil)-4-(1naftalenifkarbonil)-1H-1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-8- (hydroxymethyl) -1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)
A. 8-[2,3,4,5-Tetrahidro-1H-1,4-benzodiazepin-2,5-dionil]karboksirūgštisA. 8- [2,3,4,5-Tetrahydro-1H-1,4-benzodiazepine-2,5-dionyl] carboxylic acid
7-Karboksiizatoinės rūgšties anhidrido (pagaminto iš trifosgeno ir 4karboksi-2-aminobenzenkarboksirūgšties, 20 g, 0,09 mol) ir etilglicino hidrochlorido (13,5 g, 0,097 mol) mišinys bevandeniame piridine (200 ml) virinama su grįžtamu šaldytuvu 30 vai., po to atšaldoma iki kambario temperatūros. Piridinas nugarinamas, o liekana plaunama vandeniu, po to EtOAc. Kieta medžiaga išdžiovinama sumažintame slėgyje, ir gaunamas junginys A (17,5 g, 88 %), kuris yra balta kieta medžiaga.A mixture of 7-carboxysatoic anhydride (made from triphosgene and 4-carboxy-2-aminobenzoic acid, 20 g, 0.09 mol) and ethylglycine hydrochloride (13.5 g, 0.097 mol) in anhydrous pyridine (200 ml) was heated under reflux for 30 hours. , then cooled to room temperature. The pyridine was evaporated and the residue was washed with water followed by EtOAc. The solid was dried under reduced pressure to give Compound A (17.5 g, 88%) as a white solid.
B. 2,3,4,5-Tetrahidro-8-(hidroksimetil)-1 H-1,4-benzodiazepinas j junginio A (10 g, 45 mmol) suspensiją etilenglikolio dimetilo eteryje (10 ml) pridedama borano (1,0 M THF, 1 I). Suspensija maišoma kambario temperatūroje 1 vai., virinama su grįžtamu šaldytuvu 8 vai., atšaldoma iki 0°, ir reakcija stabdoma 6N Hcl (20 ml). Tirpiklis nugarinamas, liekana ištirpinama vandenyje (30 ml), mišinys neutralizuojamas sočiu Na2CO3 ir nugarinamas. Liekana nugarinama iš metanolio ir išgryninus sparčiosios kolonėliųB. 2,3,4,5-Tetrahydro-8- (hydroxymethyl) -1H-1,4-benzodiazepine To a suspension of compound A (10 g, 45 mmol) in ethylene glycol dimethyl ether (10 mL) was added borane (1.0). M THF, 1 L). The suspension was stirred at room temperature for 1 h, refluxed for 8 h, cooled to 0 °, and quenched with 6N HCl (20 mL). Evaporate the solvent, dissolve the residue in water (30 ml), neutralize with saturated Na 2 CO 3 and evaporate. The residue was evaporated from methanol and purified by flash columns
240 chromatografijos metodu (10 % MeOH, 1 % NH4OH CH2CI2), gaunamas junginys B, kuris yra balta kieta medžiaga. MS (M + H)+ 179.240 chromatography (10% MeOH, 1% NH 4 OH CH 2 Cl 2) afforded Compound B as a white solid. MS (M + H) < + > 179.
C. 2,3,4,5-Tetrahidro-8-(hidroksimetil)-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepinas (dihidrochloridas)C. 2,3,4,5-Tetrahydro-8- (hydroxymethyl) -1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)
274 pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš junginio B pagal 41 pavyzdyje aprašytą junginio F gavimo metodiką, chromatografijai naudojant 5 % MeOH/0,5 % NH4OH/metileno chloridą, ir pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką, prieš gaminant HCl druską, išgryninant preparatinės HPLC metodu.Example 274 (off-white solid) is prepared from Compound B according to the procedure described in Example 41 for the preparation of Compound F using chromatography in 5% MeOH / 0.5% NH 4 OH / methylene chloride and following the procedure for the preparation of Compound D in Example 1. HCl salt purification by preparative HPLC.
MS (M + H) 413.MS (M + H) 413.
275 pavyzdysExample 275
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-8(fenoksimetil)-lH-1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8 (phenoxymethyl) -1H-1,4-benzodiazepine (dihydrochloride)
274 pavyzdžio junginio (0,38 g, 0,9 mmol) ir Boc2O (1,2 g, 5,4 mmol) tirpalas CH2CI2 (10 ml) maišomas 48 vai., po to nugarinamas. Liekana gryninama sparčiosios chromatografijos metodu (4 % MeOH CH2CI2), ir gaunamas blokuotas imidazolo analogas, kuris yra balta kieta medžiaga (0,190 g, 40 %). Dalies šios medžiagos (42 mg, 0,08 mmol), Ph3P (28 mg, 0,1 mmol), fenolio (30 mg, 0,3 mmol) ir dietilazodikarboksilato (0,05 ml, 0,3 mmol) mišinys THF (7 ml) maišomas N2 atmosferoje 48 vai. Pridedama 1N HCl (5 ml). Mišinys maišomas 1 vai. ir nugarinamas. Liekana veikiama 6MA solution of Example 274 (0.38 g, 0.9 mmol) and Boc 2 O (1.2 g, 5.4 mmol) in CH 2 Cl 2 (10 mL) was stirred for 48 h then evaporated. The residue was purified by flash chromatography (4% MeOH in CH 2 Cl 2 ) to give the blocked imidazole analog as a white solid (0.190 g, 40%). A mixture of part of this material (42 mg, 0.08 mmol), Ph 3 P (28 mg, 0.1 mmol), phenol (30 mg, 0.3 mmol) and diethyl azodicarboxylate (0.05 mL, 0.3 mmol) THF (7 mL) was stirred under N 2 for 48 h. 1N HCl (5 mL) was added. The mixture is stirred for 1 hour. and is suppressed. The residue is exposed to 6M
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HCI, ekstrahuojama CH2CI2 (2x10 ml), ir nugarinus vandeninį sluoksnį, gaunama kieta medžiaga, kuri gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas); ji paverčiama HCI druska, liofilizuojant iš 1M HCI (5 ml), ir gaunamas 275 pavyzdžio junginys, kuris yra balta kieta medžiaga (10 mg, 24 %).HCl extracted with CH 2 Cl 2 ( 2 x 10 mL) and evaporation of the aqueous layer to give a solid which was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA); it is converted to the HCl salt by lyophilization from 1M HCl (5 mL) to give Example 275 as a white solid (10 mg, 24%).
MS (M + H)+ 489.MS (M + H) < + > 489.
276 pavyzdysExample 276
NHNH
N-Cikloheksil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepin-8-karboksamidas (dihidrochloridas)N-Cyclohexyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride)
A. 2,3,4,5-Tetrahidro-8-(hidroksimetii)-1H-1,4-bis(l-naftalenilkarbonil)-benzodiazepinasA. 2,3,4,5-Tetrahydro-8- (hydroxymethyl) -1H-1,4-bis (1-naphthalenylcarbonyl) -benzodiazepine
J 274 pavyzdžio junginio B (24 g, 29 mmol) tirpalą piridine (150 mi) pridedama naftalenkarboksirūgšties chloranhidrido (18 g, 110 mmol), gautas tirpalas maišomas 10 vai., ir supilamas į ledinį vandenį. Susidariusios nuosėdos nufiltruojamos, kieta medžiaga plaunama vandeniu ir chromatografuojama sparčiosios chromatografijos metodu (3 % MeOH CH2CI2); gaunamas trinaftoatas, kuris yra geltona kieta medžiaga (8,4 g, 45 %). Dalis šios medžiagos (5,63 g, 87 mmol) MeOH (60 ml) maišoma su 1M NaOMe MeOH tirpale (40 ml) 10 vai., ir nugarinamas tirpiklis. Liekana ištirpinama CH2CI2 (150 ml), tirpalas plaunamas H2O (50 ml) ir 1N HCI (50 ml), džiovinamas Na2SO4 ir nugarinamas. Išgryninus sparčiosiosA solution of Example 274 Compound B (24 g, 29 mmol) in pyridine (150 mL) was added naphthalenecarboxylic acid anhydride (18 g, 110 mmol), and the resulting solution was stirred for 10 h and poured into ice water. The precipitate formed is filtered off, the solid is washed with water and chromatographed on flash chromatography (3% MeOH in CH 2 Cl 2 ); trinaaptoate is obtained as a yellow solid (8.4 g, 45%). A portion of this material (5.63 g, 87 mmol) in MeOH (60 mL) was stirred with 1M NaOMe in MeOH (40 mL) for 10 h and the solvent was evaporated. The residue was dissolved in CH 2 Cl 2 (150 mL), washed with H 2 O (50 mL) and 1N HCl (50 mL), dried over Na 2 SO 4 and evaporated. After purifying the shortcut
242 chromatografijos metodu (5 % MeOH CH2C12), gaunamas junginys A, kuris yra balta kieta medžiaga (3,8 g, 89 %). MS (M + H)+ 486.Chromatography (242) (5% MeOH CH 2 Cl 2 ) afforded Compound A as a white solid (3.8 g, 89%). MS (M + H) < + > 486.
B. 2,3,4,5-Tetrahidro-1-(1naftalenilkarbonil)-4-(1-naftalenilkarbonil)1 H-1,4-benzodiazepin-8-karboksirūgštisB. 2,3,4,5-Tetrahydro-1- (1-naphthalenylcarbonyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxylic acid
Į junginio A (2,7 g, 5,6 mmol) tirpalą acetone (50 ml) 0 °C temperatūroje lėtai pridedama Jones'o reagento (5 % CrO3 10 % H2SO4 vandenyje, 15 ml). Tirpalas maišomas 1 vai. kambario temperatūroje. CrO3 perteklius suardomas pridedant iPrOH. Vandeninis tirpalas ekstrahuojamas CH2CI2 (3x100 ml). Sumaišytos organinės fazės džiovinamos Na2SO4, ir nugarinus gaunama kieta medžiaga, kuri gryninama sparčiosios chromatografijos metodu (5 % MeOH CH2CI2); gaunamas junginys B, kuris yra kieta medžiaga (2,30 g, 82,7 %). MS (M + H)+ 499.To a solution of compound A (2.7 g, 5.6 mmol) in acetone (50 mL) at 0 ° C was slowly added Jones reagent (5% CrO 3 in 10% H 2 SO 4 water, 15 mL). The solution is stirred for 1 hour. at room temperature. Excess CrO 3 is destroyed by the addition of iPrOH. The aqueous solution was extracted with CH 2 Cl 2 (3 x 100 mL). The combined organic phases are dried over Na 2 SO 4 and evaporated to give a solid which is purified by flash chromatography (5% MeOH in CH 2 Cl 2 ); to give Compound B as a solid (2.30 g, 82.7%). MS (M + H) + 499.
C. 2,3,4,5-Tetrahidro-4-(1-naftaIenilkarbonil)-1H-1,4-benzodiazepin-8karboksirūgštisC. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxylic acid
Junginio B (1,02 g, 2 mmol) MeOH (40 ml) ir KOH (7,75 g, 138 mmol) H2O (10 ml) mišinys virinamas su grįžtamu šaldytuvu 40 vai. MeOH nugarinamas, o vandeninis sluoksnis neutralizuojamas kone. HCI. Susidariusios nuosėdos nufiltruojamos ir perplaunamos H2O. Išdžiovinus kietą medžiagą, gaunamas junginys C, kuris yra balta kieta medžiaga (0,635 g, 90 %). MS (M + H)+347.A mixture of Compound B (1.02 g, 2 mmol) in MeOH (40 mL) and KOH (7.75 g, 138 mmol) in H 2 O (10 mL) was heated at reflux for 40 h. The MeOH is evaporated and the aqueous layer is almost neutralized. HCl. The resulting precipitate is filtered off and washed with H 2 O. Drying of the solid gives compound C, which is a white solid (0.635 g, 90%). MS (M + H) < + > 347.
D. N-Cikloheksil-2,3,4,5-tetrahidro-4-(1-naftalenilkarbonil)-1H-1,4benzodiazepin-8-karboksamidas į EDC (0,12 g, 0,62 mmol), HOBT (0,13 g, 0,9 mmol) ir junginio C (20 mg, 0,06 mmol) tirpalą DMF (5 ml) supilamas cikloheksilamino (0,32 g, 3,2 mmol) ir diizopropiletilamino (1 ml, 5,7 mmol) tirpalas DMF (1 ml). Šis tirpalas maišomas 24 vai. ir nugarinamas. Liekana ištirpinama EtOAc (20 ml), ir tirpalas plaunamas sočiu NaHCO3, 1N HCI (5 ml), džiovinamas, Na2SO4 ir nugarinus gaunamas junginys D, kuris yra gelsva kieta medžiaga (40 mg).D. N-Cyclohexyl-2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxamide to EDC (0.12 g, 0.62 mmol), HOBT (0 , A solution of 13 g, 0.9 mmol) and compound C (20 mg, 0.06 mmol) in DMF (5 mL) was added to cyclohexylamine (0.32 g, 3.2 mmol) and diisopropylethylamine (1 mL, 5.7 mmol) ) solution in DMF (1 mL). This solution is stirred for 24 hours. and is suppressed. The residue was dissolved in EtOAc (20 mL) and the solution was washed with saturated NaHCO 3 , 1N HCl (5 mL), dried, Na 2 SO 4 and evaporated to give Compound D as a yellowish solid (40 mg).
243243
E. N-Cikloheksil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1naftalenilkarbonil)-1H-1,4-benzodiazepin-8-karboksamidas (dihidrochloridas)E. N-Cyclohexyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride)
Junginys E pagaminamas iš junginio D pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką: prieš pagaminant jo HCI druską, junginys išgryninamas preparatinės HPLC metodu.Compound E is prepared from Compound D according to the procedure described in Example 1 for the preparation of Compound D: The compound is purified by preparative HPLC prior to its HCl salt.
MS (M + H)+ 508.MS (M + H) + 508.
277 pavyzdysExample 277
N-(Cikloheksilmetil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4-iImetil)-4-(1naftalenilkarbonil)-1 H-1,4-benzodiazepin-8-karboksamidas (dihidrochloridas)N- (Cyclohexylmethyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride)
2JT pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš 276 pavyzdžio junginio C ir cikloheksilamino pagal 276 pavyzdyje aprašytas junginių D ir E gavimo metodikas.Example 2JT (off-white solid) is prepared from Example 276 Compound C and cyclohexylamine according to the procedures described in Example 276 for preparing compounds D and E.
MS (M + H)+ 522.MS (M + H) < + > 522.
278 pavyzdysExample 278
244244
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-naftalenilkarbonil)-N(fenilmetil)-l H-1,4-benzodiazepin-8-karboksamidas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -N- (phenylmethyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride)
278 pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš 276 pavyzdžio junginio C ir benzilamino pagal 276 pavyzdyje aprašytas junginių D ir E gavimo metodikas.Example 278 (off-white solid) is prepared from Example 276 Compound C and benzylamine according to the procedures for preparation of compounds D and E described in Example 276.
MS (M + H)+ 517.MS (M + H) + 517.
279 pavyzdysExample 279
MeMe
NN
HH
MeMe
(R)-4-Acetil-7-[2-[(dimetilamino)metil]fenil]-2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (dihidrochloridas)(R) -4-Acetyl-7- [2 - [(dimethylamino) methyl] phenyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine (dihydrochloride)
245245
A. 2-[(R)-2,3,4,5-tetrahidro-3-(fenilmetil)-1H-1,4-benzodiazepin-2,5dion-7-il]-benzaldehidasA. 2 - [(R) -2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione-7-yl] -benzaldehyde
Junginys A (geltona kieta medžiaga) pagaminamas iš 224 pavyzdžio junginio A ir 4-formilbenzenboro rūgšties pagal 12 pavyzdyje aprašytą junginio A sintezės metodiką, tirpikliu naudojant THF, virinant su grįžtamu šaldytuvu 10 vai., ir apdorojant ekstrakcijos būdu. MS (M + H)+ 371.Compound A (a yellow solid) is prepared from the compound A of Example 224 and 4-formylbenzene boronic acid according to the procedure for the synthesis of Compound A described in Example 12 using THF as solvent, boiling under reflux for 10 hours, and extraction. MS (M + H) + 371.
B. (R)-7-[2-(Dimetilaminometil)-fenil]-2,3,4,5-tetrahidro-3-(feniImetil)1 H-1,4-benzodiazepin-2,5-dionasB. (R) -7- [2- (Dimethylaminomethyl) -phenyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione
Junginio A ir dimetilamino (1,0 M THF, 10 ml) tirpalas 1:10 AcOH:CH2CI2 (20 ml) maišomas 1 vai. Pridedama NaBH(OAc)3 (2,0 g). Maišoma dar 14 vai. Nugarinamas tirpiklis, ir liekana veikiama 1N NaOH (10 ml). Vandeninis sluoksnis ekstrahuojamas 10 % iPrOH CH2CI2. Organinė fazė išdžiovinama, ir nugarinus gaunama gelsva kieta medžiaga, kuri gryninama sparčiosios chromatografijos metodu (10 % MeOH, 1 % Et3N CH2CI2). Gaunamas junginys B, kuris yra balta kieta medžiaga (1,13 g, 98 %). MS (M + H)+ 400.A solution of compound A and dimethylamine (1.0 M in THF, 10 mL) in 1:10 AcOH: CH 2 Cl 2 (20 mL) was stirred for 1 h. NaBH (OAc) 3 (2.0 g) was added. Stir for another 14 or. The solvent was evaporated and the residue was treated with 1N NaOH (10 mL). The aqueous layer was extracted with 10% iPrOH CH 2 Cl 2 . The organic phase is dried and evaporated to give a yellow solid which is purified by flash chromatography (10% MeOH, 1% Et 3 N CH 2 Cl 2 ). Compound B was obtained as a white solid (1.13 g, 98%). MS (M + H) < + > 400.
C. (R)-7-[2-(Dimetilaminometil)-fenil]-2,3,4,5-tetrahidro-3-(fenilmetil)1 H-1,4-benzodiazepinasC. (R) -7- [2- (Dimethylaminomethyl) -phenyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine
Junginio B (1,13 g) tirpalas sausame THF 0 °C temperatūroje veikiamas LAH (1,0 M THF, 15 ml). Tirpalas virinamas sugrįžtamu šaldytuvu 10 vai., atšaldomas iki 0 °C, pridedama H2O (5 ml), o po to THF (10 ml) ir 20 % NaOH (5 ml). THF tirpalas nupilamas, o kieta medžiaga plaunama THF. Sumaišyti THF tirpalai nugarinami, o liekana ištirpinama CH2CI2 (20 ml). Nugarinus tirpalą, gaunamas junginys C, kuris yra gelsva kieta medžiaga (0,7 g, 67%). MS (M + H)+ 372.A solution of Compound B (1.13 g) in dry THF at 0 ° C was treated with LAH (1.0 M in THF, 15 mL). The solution was refluxed for 10 h, cooled to 0 ° C, H 2 O (5 mL) was added followed by THF (10 mL) and 20% NaOH (5 mL). The THF solution is drained off and the solid is washed with THF. The combined THF solutions were evaporated and the residue was dissolved in CH 2 Cl 2 (20 mL). Evaporation of the solution gave Compound C as a yellowish solid (0.7 g, 67%). MS (M + H) + 372.
D. (R)-4-Acetil-7-[2-[(dimetilamino)metil]fenil]-2,3,4,5-tetrahidro-3(fenilmetil)-l H-1,4-benzodiazepinasD. (R) -4-Acetyl-7- [2 - [(dimethylamino) methyl] phenyl] -2,3,4,5-tetrahydro-3 (phenylmethyl) -1H-1,4-benzodiazepine
246 j junginio C (0,155 g, 0,41 mmol) ir DIEA (0,4 ml, 2,7 mmol) tirpalą CH2CI2 (10 ml) pridedama acetilchlorido (0,03 ml, 1,1 ekv.) tirpalo CH2CI2 (0,3 ml). Mišinys maišomas 20 min. ir nugarinamas. Liekana ištirpinama EtOAc, ir tirpalas plaunamas sočiu NaHCO3, džiovinamas Na2SO4, ir nugarinus gaunamas alyvos pavidalo junginys D (0,14 g, 84 %).To a solution of 246 compounds of Compound C (0.155 g, 0.41 mmol) and DIEA (0.4 mL, 2.7 mmol) in CH 2 Cl 2 (10 mL) was added acetyl chloride (0.03 mL, 1.1 equiv) in CH 2 Cl 2 (0 , 3 ml). The mixture was stirred for 20 min. and is suppressed. The residue was dissolved in EtOAc and the solution was washed with saturated NaHCO 3 , dried over Na 2 SO 4 , and evaporated to give the oil as a compound D (0.14 g, 84%).
E. (R)-4-Acetil-7-[2-[(dimetilamino)metil]fenil]-2,3,4,5-tetrahidro-1(1H-imidazol-4-ilmetil)-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)E. (R) -4-Acetyl-7- [2 - [(dimethylamino) methyl] phenyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
Junginys E pagaminamas iš junginio D pagal 276 pavyzdyje aprašytą junginio E gavimo metodiką.Compound E is prepared from compound D according to the procedure for preparing compound E described in Example 276.
MS (M + H)+ 492.MS (M + H) < + > 492.
(R)-4-Acetil-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(fenilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas)(R) -4-Acetyl-7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)
A. (R)-7-Ciano-2,3,4,5-tetrahidro-3-(fenilmetil)-4-[(1,1dimetiletoksi)karbonil]-1H-1,4-benzodiazepinasA. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (phenylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] -1H-1,4-benzodiazepine
Junginys A (balta kieta medžiaga) pagaminamas iš 248 pavyzdžio junginio C pagal 4 pavyzdyje aprašytą junginio A gavimo metodiką, maišant THF 10 vai.Compound A (white solid) is prepared from Example C of Example 248 according to the procedure described in Example 4 for the preparation of Compound A by stirring in THF for 10 hours.
247247
B. (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(fenilmetil)-4-[(1,1-dimetiletoksi)karbonil]-1H-1,4-benzodiazepinasB. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] - 1H-1,4-benzodiazepine
Junginys B pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką.Compound B is prepared from Compound A according to the procedure for the preparation of Compound D described in Example 1.
C. (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(fenilmetii)-l H-1,4-benzodiazepinasC. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine
Junginys C pagaminamas iš junginio B, veikiant 4M HCI 4:1 etilacetate:dioksane. MS (M + H)+ 244.Compound C is prepared from Compound B in 4M HCl in 4: 1 ethyl acetate: dioxane. MS (M + H) + 244.
D. (R)-4-Acetil-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(fenilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas)D. (R) -4-Acetyl-7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )
Junginys D pagaminamas iš junginio C, veikiant DIEA, EDC, HOBT ir acto rūgštimi DMF 14 vai. Išgryninus preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas) ir pavertus jo HCI druska liofilizuojant iš 1M HCI, gaunamas 280 pavyzdžio junginys, kuris yra kieta medžiaga.Compound D is prepared from compound C by treatment with DIEA, EDC, HOBT and acetic acid in DMF for 14 hours. Purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and its HCl salt by lyophilization from 1M HCl afforded Example 280 as a solid.
MS (M-H)+ 386.MS (MH) + 386.
281 pavyzdysExample 281
CNCN
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(1-oksobutil)-3(fenilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-oxobutyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride
248248
281 pavyzdžio junginys (kieta medžiaga) pagaminamas iš 280 pavyzdžio junginio C ir sviesto rūgšties pagal 280 pavyzdyje aprašytą junginio D gavimo metodiką.Example 281 (solid) is prepared from Example C compound C and butyric acid according to the procedure described in Example 280 for the preparation of compound D.
MS (M-H)+ 414.MS (MH) + 414.
282 pavyzdysExample 282
CNCN
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(2-metil-1oksopropil)-3-(fenilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methyl-1-oxopropyl) -3- (phenylmethyl) -1H-1, 4-Benzodiazepine (monohydrochloride)
282 pavyzdžio junginys (kieta medžiaga) pagaminamas iš 280 pavyzdžio junginio C ir izosviesto rūgšties pagal 280 pavyzdyje aprašytą junginio D gavimo metodiką.Example 282 (solid) is prepared from Example C compound C and isobutyric acid according to the procedure described in Example 280 for the preparation of compound D.
MS (M-H)+ 414.MS (MH) + 414.
283 pavyzdysExample 283
.0.0
N=\N = \
OO
249 (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-(2piridinilacetil)-1H-1,4-benzodiazepinas (dihidrochloridas)249 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-pyridinylacetyl) -1H-1,4-benzodiazepine (dihydrochloride)
283 pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš 280 pavyzdžio junginio C ir 2-piridilacto rūgšties pagal 280 pavyzdyje aprašytą junginio D gavimo metodiką.Example 283 (off-white solid) is prepared from Example C compound C and 2-pyridylacetic acid according to the procedure described in Example 280 for the preparation of compound D.
MS (M-H)+ 464.MS (MH) + 464.
284 pavyzdysExample 284
CNCN
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-(2tieniisulfonil)-1H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-thienesulfonyl) -1H-1,4-benzodiazepine ( monohydrochloride)
A. (R)-7-Ciano-2,3,4,5-tetrahidro-3-(fenilmetil)-4-(2-tienilsulfonil)-1H1,4-benzodiazepinas j 248 pavyzdžio junginio C (37,4 g, 0,142 mol) ir DIEA (38 ml, 0,23 mol) tirpalą CH2CI2 (500 ml) kambario temperatūroje pridedama 2tiofensulfonilchlorido (34,56 g, 0,19 mol) CH2CI2 (200 ml). Tirpalas maišomas 48 vai. ir nugarinamas. Liekana paskirstoma tarp CH2CI2 (500 ml) ir sotaus NaHCO3 (2 x 500 ml). Organinis sluoksnis išdžiovinamas (Na2SO4) ir nugarinamas. Likusi geltona alyva gryninama sparčiosios chromatografijos metodu (20 %, o po to 50 % etilacetatas/heksanuose), ir gaunamas junginys A, kuris yra geltona kieta medžiaga (55 g, 95 %).A. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (phenylmethyl) -4- (2-thienylsulfonyl) -1H1,4-benzodiazepine, m.p. 0.142 mol) and DIEA (38 mL, 0.23 mol) in CH 2 Cl 2 (500 mL) at room temperature were added 2-thiophenesulfonyl chloride (34.56 g, 0.19 mol) in CH 2 Cl 2 (200 mL). The solution was stirred for 48 h. and is suppressed. The residue was partitioned between CH 2 Cl 2 (500 mL) and saturated NaHCO 3 (2 x 500 mL). The organic layer is dried (Na 2 SO 4 ) and evaporated. The remaining yellow oil was purified by flash chromatography (20% followed by 50% ethyl acetate / hexanes) to give Compound A as a yellow solid (55 g, 95%).
250250
B. (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(fenilmetil)-4-(2-tienilsulfonil)-1H-1,4-benzodiazepinas (monohidrochloridas)B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-thienylsulfonyl) -1H-1,4 benzodiazepine (monohydrochloride)
Junginio A (55 g, »0,134 mol) ir 4-formilimidazolo (51 g, 0,53 mol) mišinys AcOH/CH2CICH2CI (140 ml/600 ml) maišomas 50 min. 55 °C temperatūroje N2 atmosferoje. Per 15 vai. pridedama NaBH(OAc)3 (viso: 72 g, 0,34 mol) (kas 1,5-2 vai. maždaug po 6 g), kol HPLC analizė rodo, kad nebėra junginio A. Pridedama MeOH (250 ml), ir nugarinamas tirpiklis Liekana maišoma su H2O (100 ml), po to su 4 % NaOH (800 ml) 30 min. Vandeninis tirpalas ekstrahuojamas etilacetatu (2 x 800 ml). Sumaišyti organiniai sluoksniai plaunami 5 % NaOH (800 ml) ir džiovinami Na2SO4. Nugarinus tirpiklj, gaunama alyva (85 g), kuri gryninama sparčiosios chromatografijos metodu (silikagelis, 5 % MeOH EtOAc), ir gaunama 70 g drėgnos kietos medžiagos, j šios kietos tirpalą EtOAc (600 ml) pridedama HCI (1,0 M eteryje, 400 ml, 0,4 mol). Gauta suspensija maišoma 20 min. ir nugarinama. Liekana plaunama EtOAc (2 x 500 ml) ir eteriu (2 x 100 ml), ir išdžiovinus giliame vakuume gaunamas junginys B (63 g, 83 %), kuris yra nelabai balta kieta medžiaga.A mixture of Compound A (55 g,> 0.134 mol) and 4-formylimidazole (51 g, 0.53 mol) in AcOH / CH 2 Cl 2 (140 mL / 600 mL) was stirred for 50 min. At 55 ° C under an atmosphere of N 2 . Within 15 or. NaBH (OAc) 3 (total: 72 g, 0.34 mol) (1.5-2 hours approximately 6 g each) was added until HPLC analysis showed no compound A was added. MeOH (250 mL) was added, and evaporated solvent The residue was stirred with H 2 O (100 mL) followed by 4% NaOH (800 mL) for 30 min. The aqueous solution was extracted with ethyl acetate (2 x 800 mL). The combined organic layers were washed with 5% NaOH (800 mL) and dried over Na 2 SO 4 . Evaporation of the solvent afforded an oil (85 g) which was purified by flash chromatography (silica gel, 5% MeOH in EtOAc) to give 70 g of a wet solid, which was added to a solution of this solid in EtOAc (600 mL), 1.0 M in ether, 400 mL, 0.4 mol). The resulting suspension was stirred for 20 min. and is stripped. The residue was washed with EtOAc (2 x 500 mL) and ether (2 x 100 mL) and dried under deep vacuum to give Compound B (63 g, 83%) as an off-white solid.
MS (M + H)+ 490.MS (M + H) < + > 490.
1H-BMR (CD3OD, 300 MHz) δ 2,90 (m, 2H), 3,15 (m, 2H), 3,90 (m, 1H), 4,35,1 (m, 4H), 6,40 (d, 7 Hz, 1H), 7,0-7,6 (m, 11H), 8,90 (s, 1H). 1 H-NMR (CD 3 OD, 300 MHz) δ 2.90 (m, 2H), 3.15 (m, 2H), 3.90 (m, 1H), 4.35.1 (m, 4H) , 6.40 (d, 7Hz, 1H), 7.0-7.6 (m, 11H), 8.90 (s, 1H).
285-295 pavyzdžiai285-295 Examples
285-295 pavyzdžių junginiai pagaminami iš 248 pavyzdžio junginio C (285, 286, 291, 292, 293, 294, 295 pavyzdžių junginiai), 224 pavyzdžio junginio B (287, 288 pavyzdžių junginiai) arba 232 pavyzdžio junginio B (289, 290 pavyzdžių junginiai) ir atitinkamo sulfonilchlorido pagal 284 pavyzdyje aprašytą metodiką.Examples 285-295 are prepared from Example 248 Compound C (Examples 285, 286, 291, 292, 293, 294, 295), Example 224 Compound B (Examples 287, 288) or Example 232 Compound B (Examples 289, 290) compounds) and the corresponding sulfonyl chloride according to the procedure described in Example 284.
Pavyzdys Masių spektrasExample Mass spectrum
251251
285 (R)-7-Ciano-2,3,4,5tetrahidro-1 -(1 H-imidazol4-ilmetil)-4-[(1 - N.285 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1- N .
metiletil)sulfonil]-3(fenilmetil)-l H-1,4- n benzodiazepinas (monohidrochloridas) BMS-214665methylethyl) sulfonyl] -3 (phenylmethyl) -1H-1,4-n benzodiazepine (monohydrochloride) BMS-214665
CNCN
450 (M+H) m/z450 (M + H) m / z
286 (R)-7-Ciano-2,3,4,5tetrahidro-1-(1H-imidazol4-ilmetil)-3-(fenilmetil)-4- N [(trifluormetil)sulfonil]-1 H- A 1,4-benzodiazepinas \ (monohidrochloridas) H 286 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- N - [(trifluoromethyl) sulfonyl] -1H-A 1,4 benzodiazepine \ (monohydrochloride) H
BMS-214666BMS-214666
m/z 476 (M + H)m / z 476 (M + H)
287 (R)-7-Brom-2,3,4,5tetrahidro-1 -(1 H-imidazol4-ilmetil)-3-(fenilmetil)-4(propilsulfonil)-l H-1,4benzodiazepinas (monohidrochloridas)287 (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (propylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride)
BMS-215354BMS-215354
BrBr
m/zm / z
501 (M+H)501 (M + H)
288 (R)-7-Brom-2,3,4,5tetrahidro-1 -(1 H-imidazol4-ilmetil)-3-(fenilmetil)-4(fenilsulfonil)-l H-1,4benzodiazepinas (monohidrochloridas)288 (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride)
BMS-215355BMS-215355
m/z 539 (M + H) (R)-2,3,4,5-T etrahidro-1 (1 H-imidazol-4-ilmetil)-7fenil-3-(fenilmetil)-4- n(fenilsulfonil)-l H-1,4benzodiazepinas n (monohidrochloridas) BMS-215356 m/z 535 (M + H)m / z 539 (M + H) (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -4- (phenylsulfonyl) -1 H-1,4-benzodiazepine n (monohydrochloride) BMS-215356 m / z 535 (M + H)
289289
252252
PhPh
290 (R)-2,3,4,5-Tetrahidro-1(1 H-imidazol-4-ilmetil)-7fenil-3-(fenilmetil)-4(propilsulfonil)-l H-1,4benzodiazepinas (monohidrochloridas)290 (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -4 (propylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride)
BMS-215357BMS-215357
N'N N ' N
HH
291 (R)-7-Ciano-4-[(4fluorfenil)sulfonil]-2,3,4,5tetrahidro-1-(1H-imidazol- n 4-ilmetil)-3-(fenilmetil)-1 H1,4-benzodiazepinas (monohidrochloridas) BMS-218319291 (R) -7-Cyano-4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazolen-4-ylmethyl) -3- (phenylmethyl) -1H1,4- benzodiazepine (monohydrochloride) BMS-218319
CNCN
m/zm / z
501 (M + H) m/z 502 (M + H)501 (M + H) m / z 502 (M + H)
292 (R)-7-Ciano-4-[(3cianofenil)sulfonil]2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-3(fenilmetil)-l H-1,4benzodiazepinas (monohidrochloridas)292 (R) -7-Cyano-4 - [(3-cyanophenyl) sulfonyl] 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )
BMS-218320BMS-218320
m/z 509 (M + H)m / z 509 (M + H)
293 (R)-7-Ciano-2,3,4,5tetrahidro-1-(1 H-imidazoi4-ilmetil)-4-[(1-metil-1Himidazol-4-il)sulfonil]-3(fenilmetil)-l H-1,4benzodiazepinas (dihidrochloridas) BMS-218322293 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-1H-imidazol-4-yl) sulfonyl] -3 (phenylmethyl) - l H-1,4-benzodiazepine (dihydrochloride) BMS-218322
CN m/z 488 (M + H)CN m / z 488 (M + H)
294 (R)-4-[(3Bromfenil)sulfonil]-7ciano-2,3,4,5-tetrahidro1 -(1 H-imidazol-4-ilmetil)3-(fenilmetil)-1 H-1,4benzodiazepinas (monohidrochloridas)294 (R) -4 - [(3-Bromophenyl) sulfonyl] -7 cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )
BMS-218735BMS-218735
m/z 563 (M + H)m / z 563 (M + H)
253253
295 (R)-N-[5-[[7-ciano2,3,4,5-tetrahidro-1 -(1H imidazol-4-iImetil)-3(fenilmetil)-l H-1,4benzodiazepin-4il]sulfonil]-4-metil-2tiazoliljacetamidas (dihidrochioridas)295 (R) -N- [5 - [[7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepin-4-yl] sulfonyl ] -4-Methyl-2-thiazolyl] -acetamide (dihydrochloride)
BMS-218736BMS-218736
m/z 562 (M + H)m / z 562 (M + H)
4-Acetil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-7-(4piridi n ii)-1 H-1,4-benzodiazepinas (trihidrochloridas)4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride) )
A. 4-Acetil-2,3,4,5-tetrahidro-1 -trifluoracetil-3-(fenilmetil)-7-brom-1 H1,4-benzodiazepinasA. 4-Acetyl-2,3,4,5-tetrahydro-1-trifluoroacetyl-3- (phenylmethyl) -7-bromo-1H-1,4-benzodiazepine
J 75 pavyzdžio junginio B (0,32 mmol, 100 mg) ir NEt3 (220 μΙ, 1,58 mmol) tirpalą 5 ml CH2CI2 0 °G temperatūroje pridedama acetilchlorido (35 μΙ, 0,47 mmol). Po 5 min. pridedama trifluoracto rūgšties anhidrido (0,63 mmol, 90 μΙ), reakcijos mišinys maišomas dar 10 min., koncentruojamas, ir išgryninus liekaną sparčiosios chromatografijos metodu (50 %To a solution of Example 75 compound B (0.32 mmol, 100 mg) and NEt 3 (220 μΙ, 1.58 mmol) in 5 mL of CH 2 Cl 2 at 0 ° G was added acetyl chloride (35 μΙ, 0.47 mmol). After 5 minutes trifluoroacetic anhydride (0.63 mmol, 90 μΙ) was added, the reaction mixture was stirred for a further 10 min, concentrated, and purified by flash chromatography (50%).
EtOAc/heksanuose), gaunamas junginys A, kuris yra balta kieta medžiaga (140 mg, 98 % dviems stadijoms). MS (M + H) 455.EtOAc / hexanes) to give Compound A as a white solid (140 mg, 98% for two steps). MS (M + H) 455.
254254
B. 4-Acetil-2,3,4,5-tetrahidro-1-trifluoracetil-3-(tenilmetil)-7-(4pi r i d i ni I)-1 H-1,4-benzodiazepinasB. 4-Acetyl-2,3,4,5-tetrahydro-1-trifluoroacetyl-3- (thienylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine
Junginio A (0,27 mmol, 124 mg), 4-tributilstanilpiridino (0,54 mmol, 200 mg) ir 15 mol% Pd(PPh3)4 (47 mg) mišinys 3 ml tolueno degazuojamas ir virinamas su grįžtamu šaldytuvu argono atmosferoje. Po 16 vai. reakcijos mišinys koncentruojamas ir gryninamas sparčiosios chromatografijos metodu (10 % EtOAc/heksanuose); išskiriamas geltonos alyvos pavidalo junginys B (60 mg, 49 %). MS (M + H) 454.A mixture of compound A (0.27 mmol, 124 mg), 4-tributyltanylpyridine (0.54 mmol, 200 mg) and 15 mol% Pd (PPh 3 ) 4 (47 mg) was degassed in 3 mL of toluene and refluxed under argon. . After 16 or. concentrate the reaction mixture and purify by flash chromatography (10% EtOAc / hexanes); yielding Compound B as a yellow oil (60 mg, 49%). MS (M + H) 454.
C. 4-Acetil-2,3,4,5-tetrahidro-3-(fenilmetil)-7-(4-piridinil)-1H-1,4benzodiazepinas j junginio B (60 mg, 0,13 mmol) tirpalą 3 ml MeOH pridedama NaOH (5 lašai 2N NaOH vandeninio tirpalo), mišinys palaikomas kambario temperatūroje 30 min., koncentruojamas ir paskirstomas tarp 2N NaOH (5 ml) ir 10 % izopropanolio-CH2CI2 (5 ml). Vandeninis sluoksnis ekstrahuojamas 3 kartus 10 % izopropanoliu-CH2CI2, sumaišyti organiniai sluoksniai džiovinami Na2SO4, ir sukoncentravus gaunamas junginys C.C. A solution of 4-Acetyl-2,3,4,5-tetrahydro-3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine in Compound B (60 mg, 0.13 mmol) in 3 mL MeOH was added NaOH (5 drops of 2N aqueous NaOH), the mixture was kept at room temperature for 30 min, concentrated and partitioned between 2N NaOH (5 mL) and 10% isopropanol-CH 2 Cl 2 (5 mL). The aqueous layer was extracted 3 times with 10% isopropanol-CH 2 Cl 2 , the combined organic layers were dried over Na 2 SO 4 and concentrated to give compound C.
D. 4-Acetil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-7(4-piridiniI)-1 H-1,4-benzodiazepinas (trihidrochloridas)D. 4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7 (4-pyridinyl) -1H-1,4-benzodiazepine ( trihydrochloride)
J junginio D ir 2 ml 1:1 AcOH:CICH2CH2CI mišinį pridedama 4formilimidazolo (0,39 mmol, 38 ml) ir NaBH(OAc)3 (0,39 mmol, 83 mg). Mišinys pašildomas 50 °C temperatūroje 4 vai., koncentruojamas ir paskirstomas tarp 2N NaOH ir 10 % izopropanolio-CH2CI2 (5 ml). Vandeninis sluoksnis ekstrahuojamas 3 kartus 10 % izopropanoliu-CH2CI2, sumaišyti organiniai sluoksniai džiovinami Na2SO4, koncentruojama ir gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). TFA druska paverčiama HCI druska panaudojant 1N HCI, ir gaunamas 296 pavyzdžio junginys, kuris yra gelsva kieta medžiaga (32 mg, 49 % skaičiuojant pagal junginį B).To a mixture of compound J and 2 mL of 1: 1 AcOH: CICH 2 CH 2 Cl was added 4formylimidazole (0.39 mmol, 38 mL) and NaBH (OAc) 3 (0.39 mmol, 83 mg). The mixture was heated at 50 ° C for 4 h, concentrated and partitioned between 2N NaOH and 10% isopropanol-CH 2 Cl 2 (5 mL). The aqueous layer was extracted 3 times with 10% isopropanol-CH 2 Cl 2 , the combined organic layers were dried over Na 2 SO 4 , concentrated and purified by preparative HPLC (gradient of aqueous methanol to 0.1% TFA). The TFA salt was converted to the HCl salt using 1N HCl to give Example 296 as a yellowish solid (32 mg, 49% based on Compound B).
MS (M + H) 438.MS (M + H) 438.
255255
2,3,4,5-Tetrahidro-1-(lH-imidazol-4-ilmetil)-4-(2-fenil-1,2-dioksoetil)-7-(4pi ri din i I)-1 H-1,4-benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-phenyl-1,2-dioxoethyl) -7- (4-pyridinyl) -1H-1 , 4-benzodiazepine (trihydrochloride)
297 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš 7brom-1,4-benzodiazepino (žr. 11 pavyzdį) ir benzoilskruzdžių rūgšties pagal reakcijų seką, naudojamą šiems junginiams gauti: 252 pavyzdžio junginiui, 10:1 metileno chlorido ir DMF mišinyje, ir chromatografijoje naudojant 50 % EtOAc/heksanuose; veikiama trifluoracto rūgšties anhidridų ir apdorojama taip, kaip aprašytą 296 pavyzdžio junginio A gavimo metodikoje: 296 pavyzdžio junginiams B, C ir D.Example 297 (yellow solid) is prepared from 7bromo-1,4-benzodiazepine (see Example 11) and benzoyl-formic acid according to the reaction sequence used to obtain the following compounds: Example 252, 10: 1 mixture of methylene chloride and DMF, and chromatography. using 50% EtOAc / hexanes; treated with trifluoroacetic anhydride and treated as described in Preparation Example 296 for Compound A: Example 296 for Compounds B, C, and D.
MS (M + H) 438.MS (M + H) 438.
298 pavyzdysExample 298
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-(4-piridinil)-4-[2(trifluormetoksi)benzoil]-1 H-1,4-benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7- (4-pyridinyl) -4- [2- (trifluoromethoxy) benzoyl] -1H-1,4-benzodiazepine (trihydrochloride) )
256256
298 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš 2(trifluormetoksi)benzenkarboksirūgšties pagal 297 pavyzdyje aprašytą metodiką.Example 298 (yellow solid) is prepared from 2- (trifluoromethoxy) benzoic acid according to the procedure described in Example 297.
MS (M + H) 494.MS (M + H) 494.
299 pavyzdysExample 299
(R)-2,3,4,5-Tetrahidro-1-[(1-metil-1H-imidazol-5-il)metil]-4-(metilsulfonil)7-fenil-3-(fenilmetiI)-1 H-1,4-benzodiazepinas(R) -2,3,4,5-Tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4- (methylsulfonyl) 7-phenyl-3- (phenylmethyl) -1H -1,4-benzodiazepine
A. (R)-2,3,4,5-Tetrahidro-4-(metilsulfonil)-7-fenil-3-(fenilmetil)-1 H-1,4benzodiazepinasA. (R) -2,3,4,5-Tetrahydro-4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine
J 226 pavyzdžio junginio D (0,50 g, 1,3 mmol) ir DIEA (0,78 ml, 4,5 mmol) tirpalą metileno chloride (20 ml) -78 °C temperatūroje įlašinama metansulfonilchlorido (0,12 ml, 1,6 mmol). Mišiniui leidžiama sušilti iki kambario temperatūros ir maišoma 16 vai., reakcija stabdoma 10 % NaHCO3 (100 ml) ir ekstrahuojama etilacetatu (3 x 150 ml). Sumaišyti organiniai sluoksniai džiovinami (Na2SO4), nufiltruojama ir koncentruojama vakuume. Liekan gryninama sparčiosios chromatografijos metodu (5/2 heksanas/etilacetatas), ir gaunamas junginys A (0,52 g, 100 %), kuris yra geltona kieta medžiaga.A solution of compound D (0.50 g, 1.3 mmol) and DIEA (0.78 mL, 4.5 mmol) in Example J 226 in methylene chloride (20 mL) was added dropwise at -78 ° C to methanesulfonyl chloride (0.12 mL, 1 mL). , 6 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h, quenched with 10% NaHCO 3 (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by flash chromatography (5/2 hexane / ethyl acetate) to give Compound A (0.52 g, 100%) as a yellow solid.
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B. 1-[1,1-Dimetiletoksikarbonil]-4-imidazolkarboksaldehidasB. 1- [1,1-Dimethylethoxycarbonyl] -4-imidazolecarboxaldehyde
J 4-formilimidazolo (20,0 g, 208 mmol) ir DIEA (36,2 ml, 208 mmol) suspensiją 400 ml metileno chlorido kambario temperatūroje pridedama ditret-butildikarbonato (55,4 g, 254 mmol). Mišinys šildomas 40 °C temperatūroje (šildant pasidaro skaidrus tirpalas) ir maišomas 16 vai., atšaldomas iki kambario temperatūros, skaldomas sočiu NaHCO3 (200 ml) ir ekstrahuojamas CH2CI2 (3 x 400 ml). Sumaišyti organiniai ekstraktai džiovinami (Na2SO4), nufiltruojami ir koncentruojami vakuume. Liekana gryninama sparčiosios chromatografijos metodu (5-50 % etilacetatas/heksane), ir gaunamas junginys B (35,2 g, 87 %), kuris yra balta kieta medžiaga. MS: (M + NH4+CH3CN)+ 256.To a suspension of 4-formylimidazole (20.0 g, 208 mmol) and DIEA (36.2 mL, 208 mmol) in 400 mL of methylene chloride was added ditretbutyl dicarbonate (55.4 g, 254 mmol) at room temperature. The mixture was heated at 40 ° C (clear solution upon heating) and stirred for 16 h, cooled to room temperature, quenched with sat. NaHCO 3 (200 mL) and extracted with CH 2 Cl 2 (3 x 400 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by flash chromatography (5-50% ethyl acetate / hexane) to give Compound B (35.2 g, 87%) as a white solid. MS: (M + NH 4 + CH 3 CN) + 256.
C. 1-Metil-5-imidazolkarboksaIdehidas į junginio B (35,1 g, 179 mmol) tirpalą CH2CI2 (740 ml) -78 °C temperatūroje lėtai pridedama metiltriflato (22,3 ml, 197 mmol). Mišiniui leidžiama lėtai sušilti iki kambario temperatūros ir maišoma 16 vai. Gautos baltos nuosėdos dalimis skaldomos sočiu kalio karbonato tirpalu (112 g/100 ml H2O) kambario temperatūroje. Šis bifazinis tirpalas maišomas kambario temperatūroje 30 min. Atskiriamos fazės, ir vandeninis sluoksnis ekstrahuojamas 9/1 CH^Ia'iPrOH (4 x 300 ml). Sumaišyti organiniai ekstraktai džiovinami (Na2SO4), nufiltruojama ir koncentruojama vakuume. Liekaną išgryninus sparčiosios chromatografijos metodu (19/1 CHCI3/MeOH), gaunamas junginys C (17,4 g, 88 %), kuris yra balta kieta medžiaga. MS (M + H) + 111.C. 1-Methyl-5-imidazolecarboxyldehyde To a solution of Compound B (35.1 g, 179 mmol) in CH 2 Cl 2 (740 mL) at -78 ° C was slowly added methyl triflate (22.3 mL, 197 mmol). The mixture was allowed to warm slowly to room temperature and stirred for 16 h. The resulting white precipitate was partitioned between saturated potassium carbonate solution (112 g / 100 ml H 2 O) at room temperature. This biphasic solution was stirred at room temperature for 30 min. The phases were separated, and the aqueous layer was extracted with 9/1 CH2Cl2 (4 x 300 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (19/1 CHCl 3 / MeOH) gave Compound C (17.4 g, 88%) as a white solid. MS (M + H) < + >
D. (R)-2,3,4,5-Tetrahidro-1-[(1-metil-1 H-imidazol-5-il)metil]-4(m eti Is u If on i l)-7-f enil-3-(f eni I m eti I)-1 H-1,4-benzodiazepinas j junginio A (0,23 g, 0,59 mmol) su 3A molekuliniais tinkleliais tirpaląD. (R) -2,3,4,5-Tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 (methylethyl) -7-f Enil-3- (Phenylmethyl) -1H-1,4-benzodiazepine in a solution of compound A (0.23 g, 0.59 mmol) with 3A molecular mesh
1/1 DCE:acto rūgštyje (4 ml) pridedama junginio C (0,065 g, 0,59 mmol), ir mišinys maišomas 70 °C temperatūroje 1 vai. Pridedama natrio triacetoksiborhidrido (0,13 g, 0,59 mmol), ir mišinys maišomas 70 °C temperatūroje 30 min. Pastaroji procedūra pakartojama dar du kartus.1/1 DCE: Compound C (0.065 g, 0.59 mmol) was added in acetic acid (4 mL) and the mixture was stirred at 70 ° C for 1 h. Sodium triacetoxyborohydride (0.13 g, 0.59 mmol) was added and the mixture was stirred at 70 ° C for 30 min. The latter procedure is repeated two more times.
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Mišinys atšaldomas iki kambario temperatūros, praskiedžiamas metileno chloridu (10 ml), nufiltruojamas ir filtratas sukoncentruojamas vakuume. Liekana praskiedžiama 25 % NH4OH (100 ml) ir maišoma kambario temperatūroje 10 min. Tirpalas ekstrahuojamas CH2CI2 (3 x 100 ml), sumaišyti organiniai ekstraktai džiovinami (Na2SO4), nufiltruojama ir koncentruojama vakuume. Liekana gryninama preparatinės HPLC metodu (10-90 % vandeninis MeOH su 0,1 % TFA), tinkamos frakcijos sumaišomos ir koncentruojamos vakuume. Liekana tirpinama ir nugarinama keturis kartus iš CH3OH (5 ml) ir 1N HCI (3 ml). Ši liekana ištirpinama CH3CN (3 ml) ir vandenyje (3 ml), ir po liofilizavimo gaunamas 299 pavyzdžio junginys (0,26 g, 80 %), kuris yra balta kieta medžiaga. Lyd. temp.: 106-114 °C.The mixture was cooled to room temperature, diluted with methylene chloride (10 mL), filtered and the filtrate concentrated in vacuo. The residue was diluted with 25% NH 4 OH (100 mL) and stirred at room temperature for 10 min. The solution was extracted with CH 2 Cl 2 (3 x 100 mL), the combined organic extracts dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (10-90% aqueous MeOH with 0.1% TFA), the appropriate fractions were mixed and concentrated in vacuo. The residue was dissolved and evaporated four times from CH 3 OH (5 mL) and 1N HCl (3 mL). This residue was dissolved in CH 3 CN (3 mL) and water (3 mL) and lyophilized to give Example 299 (0.26 g, 80%) as a white solid. Lyd. mp: 106-114 ° C.
MS (M + H)+ 487.MS (M + H) + 487.
[a]D = +91° (c = 0,35, CH3OH).[α] D = + 91 ° (c = 0.35, CH 3 OH).
Elementinė analizė išskaičiuota pagal C28H30N4O2S · HCI · 0,9 H2O Išskaičiuota: C, 57,88; H, 5,17; N, 9,06; Cl, 4,59; S, 5,18.Elemental analysis calculated for C 28 H 30 N 4 O 2 S · HCl · 0.9 H 2 O Calculated: C, 57.88; H, 5.17; N, 9.06; Cl, 4.59; S, 5.18.
Rasta: C, 57,88; H, 5,49; N, 9,14; Cl, 4,64; S, 5,31.Found: C, 57.88; H, 5.49; N, 9.14; Cl, 4.64; S, 5.31.
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(fenilacetil)-3(fenilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas) j virinamą su grįžtamu šaldytuvu (R)-7-ciano-2,3,4,5-tetrahidro-4(fenilacetil)-3-(fenilmetil)-1 H-1,4-benzodiazepino (pagamintą iš 248 pavyzdžio junginio C, panaudojant EDC/HOAt kopuliavimą su fenilacto rūgštimi, 0,100(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylacetyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) refluxing (R) -7-cyano-2,3,4,5-tetrahydro-4- (phenylacetyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (prepared from Compound 248 of Example 248). , using EDC / HOAt copolymer with phenylacetic acid, 0.100
259 g, 0,26 mmol) ir 4-formilimidazolo (0,025 g, 0,26 mmol) tirpalą AcOH (0,3 ml) ir dichioretane (0,5 ml) su 3A molekuliniais tinkleliais pridedama batrio triacetoksiborhidrido (0,055 g, 0,26 mmol). Mišinys maišomas 16 vai., po to, kasdien pridedant aldehido ir natrio triacetoksiborhidrido (3 x po 1 ekv.), maišomas 3 dienas. Mišinys praskiedžiamas CHCI3 (10 ml), NH4OH (5 ml) ir NaHCO3 (5 ml) ir maišomas 30 min. Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCI3 (2 x 20 ml). Sumaišyti organiniai ekstraktai plaunami NaHCO3, vandeniu ir sočiu NaCl, džiovinami MgSO4, nufiltruojama ir koncentruojama. Produktas gryninamas preparatinės HPLC metodu (20-90 % vandeninio metanolio su 0,1 % TFA gradientas), ir pagaminus jo HCI druską, gaunamas 300 pavyzdžio junginys, kuris yra gelsva kieta medžiaga (4 mg, 3 %).A solution of 259 g, 0.26 mmol) and 4-formylimidazole (0.025 g, 0.26 mmol) in AcOH (0.3 mL) and dichloroethane (0.5 mL) with 3A molecular mesh was added barium triacetoxyborohydride (0.055 g, 0, 26 mmol). The mixture was stirred for 16 hours, followed by daily addition of aldehyde and sodium triacetoxyborohydride (3 x 1 eq.) For 3 days. The mixture was diluted with CHCl 3 (10 mL), NH 4 OH (5 mL) and NaHCO 3 (5 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl 3 (2 x 20 mL). The combined organic extracts were washed with NaHCO 3 , water and saturated NaCl, dried over MgSO 4 , filtered and concentrated. The product was purified by preparative HPLC (20-90% aqueous methanol with 0.1% TFA gradient) to give the HCl salt of Example 300 as a yellowish solid (4 mg, 3%).
MS (M + H)+ = 462+.MS (M + H) < + > = 462 + .
301 pavyzdysExample 301
4-(2-Benzotiazolil)-2,3,4,5-tetrahidro-1-(1 H-imidazol-4-ilmetiI)-7-fenil-1H1,4-benzodiazepinas (trihidrochloridas)4- (2-Benzothiazolyl) -2,3,4,5-tetrahydro-1- (1H-imidazole-4-methyl) -7-phenyl-1 H -1,4-benzodiazepine (trihydrochloride)
A. 4-(2-Benzotiazolil)-2,3,4,5-tetrahidro-7-fenil-1 H-1,4benzodiazepinas j 12 pavyzdžio junginio B (0,34 mmol, 100 mg) ir trietilamino (1,36 mmol, 190 μΙ) tirpalą DMF (1,0 ml) pridedama chlorbenzotiazolo (0,41 mmol, μΙ), ir reakcijos mišinys laikomas 60 °C temperatūroje. Po 1 vai. vėl pridedama 2-chlorbenzotiazolo (60 μΙ). Po 2 vai. reakcija stabdoma 2NA. 4- (2-Benzothiazolyl) -2,3,4,5-tetrahydro-7-phenyl-1H-1,4-benzodiazepine, Example B 12 (0.34 mmol, 100 mg) and triethylamine (1.36) of a solution of mmol, 190 μΙ) in DMF (1.0 mL) was added chlorobenzothiazole (0.41 mmol, μΙ) and the reaction mixture was stored at 60 ° C. After 1 or. again 2-chlorobenzothiazole (60 μΙ) was added. After 2 or. the reaction is stopped at 2N
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NaOH (10 ml), ekstrahuojama CH2CI2 (2 x 10 ml), džiovinama Na2SO4, ir sukoncentravus gaunamas junginys A.NaOH (10 mL), extracted with CH 2 Cl 2 (2 x 10 mL), dried over Na 2 SO 4 , and concentrated to give Compound A.
B. 4-(2-Benzotiazolil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-7fenil-1 H-1,4-benzodiazepinas (trihidrochloridas)B. 4- (2-Benzothiazolyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)
J junginio A tirpalą 1:1 AcOH/(CH2CI)2 (2 ml) pridedama 4formilimidazolo (0,68 mmol, 65 mg). Mišinys maišomas 1 vai., reakcija stabdoma 5 ml sotaus NaHCO3, mišinys praskiedžiamas 2N NaOH (50 ml) ir ekstrahuojamas 10 % IPA/CH2CI2 (2 x 25 ml). Sumaišyti organiniai ekstraktai džiovinami Na2SO4, nugarinama, ir liekana gryninama sparčiosios chromatografijos metodu (94 mg, 50 % dviejose stadijose). Po liofilizavimo iš 1N HCI gaunamas 301 pavyzdžio junginys, kuris yra pilka kieta medžiaga.To a solution of Compound A in 1: 1 AcOH / (CH 2 Cl 2 ) 2 (2 mL) was added 4-formylimidazole (0.68 mmol, 65 mg). The mixture was stirred for 1 h, quenched with 5 mL of saturated NaHCO 3 , diluted with 2N NaOH (50 mL) and extracted with 10% IPA / CH 2 Cl 2 (2 x 25 mL). The combined organic extracts were dried over Na 2 SO 4 , evaporated, and the residue purified by flash chromatography (94 mg, 50% over two steps). After lyophilization from 1N HCl, Example 301 is obtained which is a gray solid.
MS (M + H)+ 438.MS (M + H) + 438.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-7-(3-piridinil)-4(tr if I u orą ceti l)-1 H-1,4-benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (3-pyridinyl) -4 (trifluoromethyl) -1H- 1,4-benzodiazepine (trihydrochloride)
A. 2,3,4,5-Tetrahidro-3-(fenilmetil)-7-brom-1,4-bis(trifluoracetil)-1H1,4-benzodiazepinasA. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -7-bromo-1,4-bis (trifluoroacetyl) -1H1,4-benzodiazepine
J 75 pavyzdžio junginio B (1,61 mmol, 510 mg) ir trietilamino (9,66 mmol, 1,35 ml) tirpalą CH2CI2 (10 ml) kambario temperatūroje pridedamaA solution of Example 75 compound B (1.61 mmol, 510 mg) and triethylamine (9.66 mmol, 1.35 mL) in CH 2 Cl 2 (10 mL) was added at room temperature.
261 (CF3CO)2O (7,25 mmol, 1,0 ml). Po 30 min. reakcijos mišinys koncentruojamas, ir išgryninus sparčiosios chromatografijos metodu, gaunamas junginys A, kuris yra balta kieta medžiaga (770 mg, 94 %).261 (CF 3 CO) 2 O (7.25 mmol, 1.0 mL). After 30 minutes the reaction mixture was concentrated and purified by flash chromatography to give Compound A as a white solid (770 mg, 94%).
MS (M-H)+ 507.MS (MH) + 507.
B. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-7-(3piri di n i l)-4- (trif I uoraceti l)-1 H-1,4-benzodiazepinas (trihidrochloridas)B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (3-pyridinyl) -4- (trifluoroacetyl) -1H- 1,4-benzodiazepine (trihydrochloride)
302 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš junginio A, pagal reakcijų seką, naudojamą šiems junginiams gauti: 296 pavyzdžio junginiui B, naudojant 3-tributilstanilpiridiną; 296 pavyzdžio junginiui C; 296 pavyzdžio junginiui D.Example 302 (yellow solid) is prepared from Compound A according to the reaction sequence used to prepare the following compounds: Example 296 Compound B using 3-tributylstanylpyridine; Example 296 for compound C; 296 for compound D.
MS (M + H)+ 492.MS (M + H) < + > 492.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsuIfonil)-3(f eni I meti l)-7-(3-pi rid in i I)-1 H-1,4-benzodiazepinas (trihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (3-pyridine) -1 H-1,4-benzodiazepine (trihydrochloride)
A. 2,3,4,5-Tetrahidro-3-(fenilmetil)-7-(3-piridinil)-1 H-1,4benzodiazepinasA. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -7- (3-pyridinyl) -1H-1,4-benzodiazepine
J 2,3,4,5-tetrahi dro-3-(feni lmetil)-7-(3-piridinil)-1,4-bis(trifluoracetil)-1 H1,4-benzodiazepino (pagaminto pagal 302 pavyzdyje aprašytą junginio B sintezės metodiką: 100 mg, 0,2 mmol) tirpalą MeOH (4 ml) pridedama kietoJ 2,3,4,5-Tetrahydro-3- (phenylmethyl) -7- (3-pyridinyl) -1,4-bis (trifluoroacetyl) -1H1,4-benzodiazepine (prepared according to compound B described in Example 302). Synthesis procedure: 100 mg, 0.2 mmol) of MeOH (4 mL) was added as a solid
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KOH (150 mg). Tirpalas maišomas 50 °C temperatūroje 3 vai., koncentruojamas, praskiedžiamas 2N NaOH (15 ml) ir išekstrahavus 10 % IPA/CH2CI2 (3x5 ml) gaunama 60 mg junginio A.KOH (150 mg). The solution was stirred at 50 ° C for 3 h, concentrated, diluted with 2N NaOH (15 mL) and extracted with 10% IPA / CH 2 Cl 2 (3 x 5 mL) to give 60 mg of Compound A.
B. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(fenilmetil)-7-(3-piridinil)-1H-1,4-benzodiazepinas (trihidrochloridas) j junginio A (0,086 mmol, 27 mg) ir DIEA (0,86 mmol, 150 μΙ) mišinj CH2CI2 (1,0 ml) pridedama metansulfonilchlorido (0,39 mmol, 30 μΙ). Mišinys maišomas 1 vai., koncentruojamas, praskiedžiamas 2N NaOH (10 ml) ir ekstrahuojamas 10 % IPA/CH2CI2 (2x5 ml). Tirpalas džiovinamas Na2SO4 ir koncentruojamas. Liekana ištirpinama 1:1 AcOH:(CH2CI)2 (2 ml). Pridedama 4-formilimidazolo (0,69 mmol, 66,3 mg) ir NaBH(OAc)3 (0,69 mmol, 146 mg), mišinys šildomas 50 °C temperatūroje 16 vai., koncentruojamas, praskiedžiamas 2N NaOH (20 ml)/sočiu NH4OH (5 ml) ir ekstrahuojamas 10 % IPA/CH2CI2 (2x5 ml). Sumaišyti organiniai ekstraktai koncentruojami, ir liekana gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Reikiamos frakcijos sumaišomos, nugarinamos, ir TFA druska paverčiama HCl druska, panaudojant 1N HCl. Gaunamas 303 pavyzdžio junginys (5 mg, išeiga per 3 stadijas: 9 %).B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (3-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride) To a mixture of Compound A (0.086 mmol, 27 mg) and DIEA (0.86 mmol, 150 μΙ) in CH 2 Cl 2 (1.0 mL) was added methanesulfonyl chloride (0.39 mmol, 30 μΙ). The mixture was stirred for 1 h, concentrated, diluted with 2N NaOH (10 mL) and extracted with 10% IPA / CH 2 Cl 2 (2x5 mL). The solution was dried over Na 2 SO 4 and concentrated. The residue was dissolved in 1: 1 AcOH: (CH 2 Cl) 2 (2 mL). 4-Formylimidazole (0.69 mmol, 66.3 mg) and NaBH (OAc) 3 (0.69 mmol, 146 mg) were added and the mixture was heated at 50 ° C for 16 h, concentrated and diluted with 2N NaOH (20 mL). / saturated NH 4 OH (5 mL) and extracted with 10% IPA / CH 2 Cl 2 (2x5 mL). The combined organic extracts are concentrated and the residue is purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The required fractions are mixed, evaporated and the TFA salt is converted to the HCl salt using 1N HCl. Example 303 is obtained (5 mg, yield 3 steps: 9%).
MS (M+H)+474.MS (M + H) < + > 474.
304 pavyzdysExample 304
BrBr
NHNH
MeMe
7-Brom-3-[(1,1-dimetiletoksi)metil]-1,2,3,4-tetrahidro-1-(1H-imidazol-4ilmetil)-5H-1,4-benzodiazepin-5-onas7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -5H-1,4-benzodiazepin-5-one
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A. 2-[(2-(Fluorenilmetoksikarbonilamino)-3-(1,1dimetiletoksi)propil)amino]-5-brombenzenkarboksirūgštisA. 2 - [(2- (Fluorenylmethoxycarbonylamino) -3- (1,1-dimethylethoxy) propyl) amino] -5-bromobenzoic acid
D,L-Fmoc-(O-tBu)-serinalio (pagaminto redukuojant D,L-FmocSer(tBu)-N(Me)OMe LAH; 18 g, 49 mmol), bromantranilo rūgšties (19 g, 88 mmol) ir ledinės acto rūgšties (2 ml) tirpalas sausame metanolyje (5 ml) ir THF (40 ml) pamaišomas 10 min., o po to per 1 vai. pridedama NaBH3CN (5,5 g, 88 mmol). Maišoma dar 1 vai. Iškritęs j nuosėdas produktas nufiltruojamas, plaunamas vandeniu, ir išdžiovinus giliame vakuume gaunama 25 g (89,4 %) junginio A, kuris yra balta kieta medžiaga. (M + H) + 569.D, L-Fmoc- (O-tBu) -serinal (prepared by reduction of D, L-FmocSer (tBu) -N (Me) OMe in LAH; 18 g, 49 mmol), bromoanthranilic acid (19 g, 88 mmol) and glacial a solution of acetic acid (2 mL) in dry methanol (5 mL) and THF (40 mL) was stirred for 10 min and then over 1 h. NaBH 3 CN (5.5 g, 88 mmol) was added. Stir for another 1 or. The precipitate is filtered off, washed with water and dried under deep vacuum to give 25 g (89.4%) of Compound A as a white solid. (M + H) + 569.
B. 7-Brom-3-[(1,1-dimetiletoksi)metiI]-1,2,3,4-tetrahidro-5H-1,4benzodiazepin-5-onasB. 7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one
Į junginio A (17 g, 29 mmol) tirpalą THF (150 ml) pridedama dietilamino (30 ml, 290 mmol). Tirpalas maišomas 2 vai. ir koncentruojamas. Gauta liekana ištirpinama etilo eteryje (100 ml) ir 1N vandeniniame vandenilio chloride (400 ml). Susidariusios sunkios baltos nuosėdos nufiltruojamos, plaunamos heksanais/etilo eteriu ir džiovinamos giliame vakuume. Dalis gautos baltos kietos medžiagos (8,2 g, 24 mmol) su EDC (4,5 g, 24 mmol), HOBt (3,2 g, 24 mmol) ir DIEA (12,4 ml, 71 mmol) DMF (80 ml) maišoma 16 vai., ir mišinys supilamas j 10 % vandeninio LiCI tirpalo (200 ml) ir etilacetato (90 ml) mišinj. Atskiriami sluoksniai. Organinis sluoksnis plaunamas 4 x 40 ml 10 % vandeninio LiCI, 4 χ 1N vandenini vandenilio chloridu, 2 x 50 ml sotaus NaCl ir 1 x 50 ml vandens. Tirpalas išdžiovinamas (Na2SO4), nufiltruojamas, ir sukoncentravus gaunama 7,2 g (83 % per abi stadijas) junginio B, kuris yra balta kieta medžiaga. (M + H)+ 329.To a solution of compound A (17 g, 29 mmol) in THF (150 mL) was added diethylamine (30 mL, 290 mmol). The solution is stirred for 2 hours. and concentrated. The resulting residue was dissolved in ethyl ether (100 mL) and 1N aqueous hydrochloric acid (400 mL). The resulting heavy white precipitate was filtered off, washed with hexanes / ethyl ether and dried in a deep vacuum. Part of the resulting white solid (8.2 g, 24 mmol) with EDC (4.5 g, 24 mmol), HOBt (3.2 g, 24 mmol) and DIEA (12.4 mL, 71 mmol) in DMF (80 ml) was stirred for 16 hours and the mixture was poured into a mixture of 10% aqueous LiCl solution (200 ml) and ethyl acetate (90 ml). The layers are separated. The organic layer was washed with 4 x 40 mL 10% aqueous LiCl, 4 χ 1N aqueous hydrochloric acid, 2 x 50 mL saturated NaCl, and 1 x 50 mL water. The solution is dried (Na 2 SO 4 ), filtered, and concentrated to give 7.2 g (83% over both steps) of Compound B as a white solid. (M + H) + 329.
C. 7-Brom-3-[(1,1-dimetiletoksi)metil]-1,2,3,4-tetrahidro-1-(1Himidazol-4-ilmetil)-5H-1,4-benzodiazepin-5-onasC. 7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -5H-1,4-benzodiazepin-5-one
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304 pavyzdžio junginys (balta kieta medžiaga) 40 % išeiga pagaminamas iš junginio B pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką. (M + H)+ 409.Example 304 Compound (white solid) is prepared in 40% yield from Compound B according to the procedure for Compound D described in Example 224. (M + H) + 409.
305 pavyzdysExample 305
7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(fenoksimetil)-1H-1,4-benzodiazepinas (dihidrochloridas)7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenoxymethyl) -1H-1,4-benzodiazepine (dihydrochloride)
A. 7-Brom-3-[(1,1-dimetiletoksi)metil]-1,2,3,4-tetrahidro-5H-1,4benzodiazepinasA. 7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -1,2,3,4-tetrahydro-5H-1,4-benzodiazepine
304 pavyzdžio junginys B (0,5 g, 1,5 mmol) sumaišomas su 10 ml THF ir 1M LAH THF (4 ml, 4 mmol). Tirpalas virinamas su grįžtamu šaldytuvu 16 vai. Pridedama dietilo eterio (40 ml) ir 1N NaOH (40 ml), o po to sotaus NaCl, ir atskiriami sluoksniai. Organinis sluoksnis plaunamas 1N vandeniniu NaOH, džiovinamas (Na2SO4), nufiltruojamas ir sukoncentravus gaunama 413 mg (88 %) junginio A, kuris yra stiklo pavidalo kieta medžiaga.MS (M + H)+ 314.Example 304 Compound B (0.5 g, 1.5 mmol) was mixed with 10 mL of THF and 1M LAH in THF (4 mL, 4 mmol). The solution is refluxed for 16 hours. Diethyl ether (40 mL) and 1N NaOH (40 mL) were added followed by saturated NaCl and the layers separated. The organic layer was washed with 1N aqueous NaOH, dried (Na 2 SO 4 ), filtered and concentrated to afford 413 mg (88%) of Compound A as a glass solid. MS (M + H) + 314.
B. 7-Brom-3-[(1,1-dimetiletoksi)metil]-4-metansulfonil-1,2,3,4tetrahidro-5H-1,4-benzodiazepinasB. 7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -4-methanesulfonyl-1,2,3,4-tetrahydro-5 H -1,4-benzodiazepine
Junginys B (balta kieta medžiaga) 71 % išeiga pagaminamas iš junginio A pagal 224 pavyzdyje aprašytą junginio C gavimo metodiką. MS (M + H-tBu)+ 337.Compound B (white solid) is prepared in 71% yield from Compound A according to the procedure for Compound C described in Example 224. MS (M + H-tBu) + 337.
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C. 7-Brom-3-(hidroksimetil)-4-metansulfonil-1,2,3,4-tetrahidro-5H-1,4benzodiazepinasC. 7-Bromo-3- (hydroxymethyl) -4-methanesulfonyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine
Junginio B (1,1 g, 2,8 mmol) tirpalas THF (8 ml) ir metileno chloride (8 ml) maišomas 3 vai. ir koncentruojamas. Liekaną ištrynus su etilo eteriu ir išdžiovinus vakuume, gaunama 700 mg (74 %) junginio C, kuris yra balta kieta medžiaga. MS (M+H)+ 337.A solution of Compound B (1.1 g, 2.8 mmol) in THF (8 mL) and methylene chloride (8 mL) was stirred for 3 h. and concentrated. Trituration of the residue with ethyl ether and drying in vacuo afforded 700 mg (74%) of Compound C as a white solid. MS (M + H) + 337.
D. 7-Brom-2,3,4,5-tetrahidro-4-(metilsulfonil)-3-(fenoksimetil)-1H-1,4benzodiazepinasD. 7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenoxymethyl) -1H-1,4-benzodiazepine
Į junginio C (50 mg, 0,15 mmol) tirpalą metileno chloride (10 ml) pridedama 2,6-di-tret-butil-4-metilpiridino (62 mg, 0,30 mmol). Tirpalas N2 atmosferoje atšaldomas iki -40 °C. Pridedama triflo rūgšties anhidrido (0,85 ml, 0,30 mmol), ir tirpalas maišomas N2 atmosferoje -40 °C temperatūroje 1 vai. Atskiroje kolboje j natrio hidrido (44 mg, 1,1 mmol, 60 % dispersija mineralinėje alyvoje, prieš naudojant perplauta heksanais) tirpalą THF (2,5 ml) pridedama fenolio (100 mg, 1,1 mmol). Šis tirpalas pamaišomas 20 min kambario temperatūroje N2 atmosferoje ir greitai supilamas j j triflato tirpalą. Pamaišius 20 min., tirpalas praskiedžiamas metileno chloridu (40 ml) ir plaunamas sočiu vandeniniu natrio rūgščiojo karbonato tirpalu. Organinis sluoksnis džiovinamas (Na2SO4), nufiltruojamas, ir sukoncentravus gaunama kieta medžiaga. Ši medžiaga chromatografuojama per sparčiosios chromatografijos silikagelio kolonėlę, eliuuojant 1:1 etilacetatu:heksanais, ir gaunama 30 mg (49 %) junginio D, kuris yra nelabai balta kieta medžiaga. MS(M + H)+411.To a solution of compound C (50 mg, 0.15 mmol) in methylene chloride (10 mL) was added 2,6-di-tert-butyl-4-methylpyridine (62 mg, 0.30 mmol). The solution is cooled to -40 ° C under N 2 . Triflic acid anhydride (0.85 mL, 0.30 mmol) was added and the solution was stirred under N 2 at -40 ° C for 1 h. In a separate flask, phenol (100 mg, 1.1 mmol) was added to a solution of sodium hydride (44 mg, 1.1 mmol, 60% dispersion in mineral oil, before washing with hexanes) in THF (2.5 mL). This solution is stirred for 20 min at room temperature under N 2 and rapidly added to the triflate solution. After stirring for 20 min, the solution was diluted with methylene chloride (40 mL) and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated to give a solid. This material was purified by flash column chromatography on silica gel eluting with 1: 1 ethyl acetate: hexanes to give 30 mg (49%) of Compound D as an off-white solid. MS (M + H) + 411.
E. 7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4(metilsulfonil)-3-(fenoksimetii)-1H-1,4-benzodiazepinas (dihidrochloridas)E. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenoxymethyl) -1H-1,4-benzodiazepine (dihydrochloride)
305 pavyzdžio junginys (balta kieta medžiaga) 27 % išeiga pagaminamas iš junginio D pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką.Example 305 Compound (white solid) is prepared in 27% yield from Compound D according to the procedure for Compound D described in Example 224.
MS (M + H)+491.MS (M + H) < + > 491.
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306 pavyzdysExample 306
7-Brom-2,3,4,5-tetrahidro-3-(hidroksimetil)-1-(1H-imidazol-4-ilmetil)-4(metilsulfonil)-l H-1,4-benzodiazepinas (monohidrochloridas)7-Bromo-2,3,4,5-tetrahydro-3- (hydroxymethyl) -1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride)
306 pavyzdžio junginys (nelabai balta kieta medžiaga) 12 % išeiga pagaminamas iš 305 pavyzdžio junginio C pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką.Example 306 (off-white solid) is prepared in 12% yield from Example 305 Compound C according to the procedure described in Example 224 for the preparation of Compound D.
MS (M + H)+ 417.MS (M + H) < + > 417.
307 pavyzdysExample 307
7-Brom-3-[(1,1-dimetiletoksi)metil]-2,3,4,5-tetrahidro-1-(1H-imidazol-4ilmetil)-4-(metilsulfonil)-1 H-1,4-benzodiazepinas7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4- benzodiazepine
307 pavyzdžio junginys (nelabai balta kieta medžiaga) 23 % išeiga pagaminamas iš 305 pavyzdžio junginio B pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką.Example 307 Compound (off-white solid) is prepared in 23% yield from Example 305 Compound B according to the procedure for Compound D described in Example 224.
MS (M+H)+ 472.MS (M + H) + 472.
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308 pavyzdysExample 308
[7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-1H-1,4benzodiazepin-8-il]karbamo rūgšties 2-metilpropilo esteris (trihidrochloridas)[7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-8-yl] carbamic acid 2-methylpropyl ester ( trihydrochloride)
A. 2,3,4,5-Tetrahidro-3-(fenilmetil)-4-[(1,1-dimetiletoksi)karbonil]-8amino-1 H-1,4-benzodiazepinasA. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] -8-amino-1H-1,4-benzodiazepine
2,3,4,5-Tetrahidro-3-(fenilmetil)-8-amino-1H-1,4-benzodiazepino (aprašytas 98 pavyzdžio junginys B, 1,0 g, 3,5 mmol) ir Boc anhidrido (0,77 g, 3,5 mmol) tirpalas THF (15 ml) maišomas kambario temperatūroje argono atmosferoje. Po 16 vai. mišinys sukoncentruojamas. Liekana trinama su heksanu ir CHCI3l ir gaunama gelsvai žalsvai pilka kieta medžiaga. Sukoncentravus filtratą, ir liekaną ištrynus su heksanu ir CHCI3, dar gaunama gelsvai žalsvai pilkos kietos medžiagos. Šios kietos medžiagos sumaišomos ir gryninamos sparčiosios chromatografijos per silikagelį metodu (20 % po to 30 % EtOAc heksane): gaunamas junginys A (0,542 g, 40 %). MS (M+H)+ 345.2,3,4,5-Tetrahydro-3- (phenylmethyl) -8-amino-1H-1,4-benzodiazepine (described in Example 98, compound B, 1.0 g, 3.5 mmol) and Boc anhydride (O, A solution of 77 g, 3.5 mmol) in THF (15 mL) was stirred at room temperature under argon. After 16 or. the mixture is concentrated. The residue was triturated with hexane and CHCl 3l to give yellow greenish gray solid. The filtrate was concentrated and the residue was erased with hexane and CHCl 3, also obtained a yellow-green-gray solid. The following solids were combined and purified by silica gel flash chromatography (20% followed by 30% EtOAc in hexane) to give Compound A (0.542 g, 40%). MS (M + H) < + > 345.
B. [2,3,4,5-Tetrahidro-3-(fenilmetil)-4-[(1,1-dimetiletoksi)karbonil]-1H1,4-benzodiazepin-8-il]karbamo rūgšties 2-metilpropilo esterisB. [2,3,4,5-Tetrahydro-3- (phenylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] -1H1,4-benzodiazepin-8-yl] carbamic acid 2-methylpropyl ester
268 j junginio A (115 mg, 0,3 mol) tirpalą dichlormetane (2 ml) argono atmosferoje sulašinama DIPEA (0,1 ml, 0,6 mmol) ir izobutilchlorformiato, Po 20 min. pjpilama vandens (2 ml) ir sotaus NaHCO3, ir mišinys ekstrahuojamas chloroformu (15 ml). Organinis sluoksnis džiovinamas (MgSO4), ir sukoncentravus vakuume gaunama kieta medžiaga, kuri gryninama sparčiosios chromatografijos per silikagelį metodu, eliuuojant 20 % EtOAc heksanuose, ir gaunamas junginys B (125 mg, 92 %), kuris yra kieta medžiaga. MS (M + H)+ = 454+.A solution of 268 compound A (115 mg, 0.3 mol) in dichloromethane (2 mL) under argon was added dropwise to DIPEA (0.1 mL, 0.6 mmol) and isobutyl chloroformate, After 20 min. water (2 mL) and saturated NaHCO3 are added and the mixture is extracted with chloroform (15 mL). The organic layer was dried (MgSO 4 ) and concentrated in vacuo to give a solid which was purified by flash chromatography on silica gel eluting with 20% EtOAc in hexanes to give Compound B (125 mg, 92%) as a solid. MS (M + H) < + > = 454 + .
C. [7-Brom-2,3,4,5-tetrahidro-3-(fenilmetil)-4-[(1,1-dimetiletoksi)karbonil]-1H-1,4-benzodiazepin-8-il]karbamo rūgšties 2-metilpropilo esterisC. [7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] -1H-1,4-benzodiazepin-8-yl] carbamic acid 2-Methylpropyl ester
Į junginio B (100 mg, 0,22 mmol) tirpalą chloroforme (2 ml) per 5 min. sulašinamas tetrabutilamonio tribromido (106 mg, 0,22 mmol) tirpalas chloroforme (1 ml). Po 10 min. mišinys plaunamas natrio rūgščiojo sulfato tirpalu (5 ml), džiovinamas (MgSO4) ir koncentruojamas. Išgryninus kolonėlių chromatografijos per silikagelį metodu, eliuuojant 20 % EtOAc heksanuose, gaunamas junginys C (110 mg, 94 %), kuris yra kieta medžiaga. MS (M + H) + = 532+.To a solution of Compound B (100 mg, 0.22 mmol) in chloroform (2 mL) was added over 5 min. a solution of tetrabutylammonium tribromide (106 mg, 0.22 mmol) in chloroform (1 mL) was added dropwise. After 10 minutes. the mixture was washed with sodium bisulfate solution (5 mL), dried (MgSO 4 ), and concentrated. Purification by silica gel column chromatography eluting with 20% EtOAc in hexanes afforded compound C (110 mg, 94%) as a solid. MS (M + H) <+> = 532 + .
D. [7-Brom-2,3,4,5-tetrahidro-1-(1H-imidązol-4-ilmetli)-3-(fenilmetil)4-[(1,1-dimetiletoksi)-karbonil]-1H-1,4-benzodiazepin-8-il]karbamo rūgšties 2-metilpropilo esteris į junginio C (100 mg, 0,19 mmol) ir 4-formilimidazolo (36 mg, 0,3 mmol) tirpalą dichlormetano (2' ml) ir acto rūgšties (0,6 ml) mišinyje pridedama 3A molekulinių tinklelių, ir mišinys maišomas 15 min. Pridedama natrio triacetoksiborhidrido (105 mg, 0,5 mmol), ir mišinys maišomas per naktį (18 vai.). Pridedama kita aldehido ir borhidridinio reagento porcija (atitinkamai 36 mg ir 105 mg). Po 4 vai. mišinys nufiltruojamas per celitą ir plaunama chloroformu. Filtratas sukoncentruojamas ir veikiamas chloroformu ir NH4OH (po 10 ml). Intensyviai pamaišius 30 min., organinis sluoksnisD. [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) 4 - [(1,1-dimethylethoxy) carbonyl] -1H- 1,4-Benzodiazepin-8-yl] -carbamic acid 2-methylpropyl ester into a solution of compound C (100 mg, 0.19 mmol) and 4-formylimidazole (36 mg, 0.3 mmol) in dichloromethane (2 'mL) and acetic acid acid (0.6 mL) was added to the mixture with 3A molecular grids and the mixture was stirred for 15 min. Sodium triacetoxyborohydride (105 mg, 0.5 mmol) was added and the mixture was stirred overnight (18 h). Another portion of the aldehyde and borohydride reagent (36 mg and 105 mg, respectively) is added. After 4 or. the mixture is filtered through celite and washed with chloroform. The filtrate was concentrated and treated with chloroform and NH 4 OH (10 mL each). After stirring vigorously for 30 minutes, the organic layer is covered
269 atskiriamas, džiovinamas (MgSO4), ir sukoncentravus vakuume gaunamas junginys D (110 mg, 86 %). MS (M + H)+ = 612+.269 was separated, dried (MgSO 4 ), and concentrated in vacuo to give Compound D (110 mg, 86%). MS (M + H) < + > = 612 + .
E. [7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)1H-1,4-benzodiazepin-8-il]karbamo rūgšties 2-metilpropilo esteris (trihidrochloridas)E. [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-8-yl] carbamic acid 2-. methylpropyl ester (trihydrochloride)
Į junginio D (105 mg, 0,17 mmol) tirpalą chloroforme (1 ml) pridedama HCI dioksane (3 ml, 4M tirpalas). Po 4 vai. mišinys koncentruojamas. Pridedama chloroformo (5 ml), ir sukoncentravus mišinj vakuume, gaunamas 308 pavyzdžio junginys, kuris yra nelabai balti milteliai (110 mg, 100 %).To a solution of compound D (105 mg, 0.17 mmol) in chloroform (1 mL) was added HCl in dioxane (3 mL, 4M solution). After 4 or. the mixture is concentrated. Chloroform (5 mL) was added and concentration of the mixture in vacuo gave Example 308 as an off-white powder (110 mg, 100%).
MS (M + H)+ = 512.MS (M + H) <+> = 512.
[4-Acetil-7-brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(fenilmetil)-lH-1,4-benzodiazepin-8-il]karbamo rūgšties 2-metilpropilo esteris j 308 pavyzdžio (18 mg, 0,03 mmol) tirpalą DMF (0,2 ml) pridedama piridino (0,3 ml), acto rūgšties anhidrido (0,2 ml) ir DMAP (10 mg), ir mišinys maišomas 20 vai. Pridedama acto rūgšties anhidrido (0,1 ml), ir mišinys maišomas 4 vai. Šis mišinys paskirstomas tarp chloroformo ir vandens (po 10 ml). Organinis sluoksnis atskiriamas ir plaunamas sočiu CuSO4 (2 x 10 ml),[4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-8-yl] carbamic acid 2-Methylpropyl ester To a solution of Example 308 (18 mg, 0.03 mmol) in DMF (0.2 mL) was added pyridine (0.3 mL), acetic anhydride (0.2 mL), and DMAP (10 mg), and the mixture is stirred for 20 hours. Acetic anhydride (0.1 ml) was added and the mixture was stirred for 4 hours. This mixture is partitioned between chloroform and water (10 mL each). The organic layer is separated and washed with CuSO 4 (2 x 10 mL),
270 džiovinamas (K2CO3) ir koncentruojamas. Išgryninus RP HPLC metodu, chromatografuojant per C-18 kolonėlę, eliuuojamą 40-90 % vandeniniu metanoliu, turinčiu 0,1 % TFA, gaunama kieta medžiaga, kuri veikiama 1N vandeniniu HCI (2 x 10 ml), o po to koncentruojama. Kieta medžiaga ištirpinama vandenyje, ir po liofilizavimo gaunamas 309 pavyzdžio junginys, kuris yra gelsva kieta medžiaga (13 mg, 70 %).270 dried (K2CO3) and concentrated. Purification by RP HPLC chromatography on a C-18 column eluting with 40-90% aqueous methanol containing 0.1% TFA afforded a solid which was treated with 1N aqueous HCl (2 x 10 mL) and then concentrated. The solid was dissolved in water to give, after lyophilization, Example 309 as a yellowish solid (13 mg, 70%).
MS (M + H)+ = 554.MS (M + H) < + > = 554.
N-[4-Acetil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(feniimetil)-1H1,4-benzodiazepin-8-il]cikloheksankarboksamidas (dihidrochloridas)N- [4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride)
310 pavyzdžio junginys (gelsva kieta medžiaga) 50 % išeiga pagaminamas iš 246 pavyzdžio junginio C pagal 309 pavyzdyje aprašytą metodiką.Example 310 Compound (yellowish solid) is prepared in 50% yield from Example 246 Compound C according to the procedure described in Example 309.
MS (M + H)+ = 486.MS (M + H) < + > = 486.
311 pavyzdysExample 311
271271
[7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(fenilmetil)-1H-1,4-benzodiazepin-8-il]karbamo rūgšties 2-metilpropilo esteris j 308 pavyzdžio junginio (31 mg, 0,05 mmol) tirpalą DMF (0,2 ml) kambario temperatūroje pridedama TEA (0,2 ml), dichlormetano (0,2 ml) ir metansulfonilchlorido (0,024 ml, 0,3 mmol), mišinys maišomas 18 vai. ir paskirstomas tarp chloroformo ir sotaus NaHCO3 (po 10 ml.). Organinis sluoksnis atskiriamas, džiovinamas (K2CO3) ir koncentruojamas. Išgryninus RP HPLC metodu, chromatografuojant per C-18 kolonėlę, eliuuojamą 40-90 % vandeniniu metanoliu, turinčiu 0,1 % TFA, gaunama kieta medžiaga, kuri veikiama 1N vandeniniu HCI (2 x 10 ml), o po to koncentruojama. Kieta medžiaga ištirpinama vandenyje, ir po liofilizavimo gaunamas 311 pavyzdžio junginys, kuris yra gelsva kieta medžiaga (13 mg, 70 %).[7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepin-8-yl] 2-Methylpropyl ester of carbamic acid To a solution of the compound of Example 308 (31 mg, 0.05 mmol) in DMF (0.2 mL) at room temperature was added TEA (0.2 mL), dichloromethane (0.2 mL) and methanesulfonyl chloride (0.024 mL) (0.3 mmol), the mixture was stirred for 18 h. and partitioned between chloroform and saturated NaHCO 3 (10 mL each). The organic layer was separated, dried (K 2 CO 3 ) and concentrated. Purification by RP HPLC chromatography on a C-18 column eluting with 40-90% aqueous methanol containing 0.1% TFA afforded a solid which was treated with 1N aqueous HCl (2 x 10 mL) and then concentrated. The solid was dissolved in water to give, after lyophilization, the compound of Example 311 as a yellowish solid (13 mg, 70%).
MS (M + H)+= 590.MS (M + H) <+> = 590.
312 pavyzdysExample 312
272272
CNCN
(R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(fenilsulfonil)-3(fenilmetil)-1H-1,4-benzodiazepin-7-karbonitrilas (monohidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile (monohydrochloride) )
A. (R)-2,3,4,5-Tetrahidro-4-(fenilsulfonil)-3-(fenilmetil)-1H-1,4benzodiazepin-7-karbonitrilasA. (R) -2,3,4,5-Tetrahydro-4- (phenylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile
J maišomą atšaldytą (0°, ledo vonia) 248 pavyzdžio junginio C (45 g, 171,54 mmol) tirpalą, turintį DIEA (50 ml, 287 mmol), bevandeniame CH2CI2 (1 I) argono atmosferoje sulašinamas benzensulfonilchlorido (30 ml, 235 ml) tirpalas bevandeniame CH2CI2 (50 ml). Pabaigus lašinti, mišinys sušildomas iki kambario temperatūros ir maišomas 4 va,. Tirpalas praskiedžiamas CH2CI2 (500 ml), plaunamas vandeniu (2 x 250 ml), 10 % KHSO4 (750 ml), sočiu NaHCO3 ir sočiu NaCl, džiovinamas ir nugarinamas. Liekana perkristalinama iš EtOAc-heksano, ir gaunama 65 g (94 %) junginio A, kuris yra kieta medžiaga. MS (M-H)' 402.A stirred solution of Example 248 Compound C (45 g, 171.54 mmol) in DIEA (50 mL, 287 mmol) in anhydrous CH 2 Cl 2 (1 L) under argon was added dropwise to a solution of benzenesulfonyl chloride (30 mL). ml, 235 ml) solution in anhydrous CH 2 Cl 2 (50 ml). After the addition is complete, the mixture is warmed to room temperature and stirred for 4 h. The solution was diluted with CH 2 Cl 2 (500 mL), washed with water (2 x 250 mL), 10% KHSO 4 (750 mL), saturated NaHCO 3 and saturated NaCl, dried and evaporated. The residue was recrystallized from EtOAc-hexane to give 65 g (94%) of Compound A as a solid. MS (MH) < 402 >.
13C-BMR (CDCI3) 40,22, 46,00, 47,23, 61,36, 116,34, 119,55, 120,99, 126,99, 127,11, 128,10, 129,76, 129,40,.131,97, 132,09, 134,03, 136,77, 139,53, 150,77 m.d. 13 C-NMR (CDCl 3 ) 40.22, 46.00, 47.23, 61.36, 116.34, 119.55, 120.99, 126.99, 127.11, 128.10, 129, 76, 129.40, .131.97, 132.09, 134.03, 136.77, 139.53, 150.77 md
B. (R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(fenilsulfonil)-3(fenilmetil)-lH-1,4-benzodiazepin-7-karbonitrilas (monohidrochloridas)B. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile (monohydrochloride)
Į maišomą junginio A (64,3 g, 159 mmol) ir 4-formilimidazolo (15,3 g,To a stirred mixture of compound A (64.3 g, 159 mmol) and 4-formylimidazole (15.3 g,
159 mmol) HOAC (ledinė, 150 ml) ir 1,2-dichloretano (720 ml) mišinyje argono atmosferoje pridedama natrio triacetoksiborhidrido (33,8 g, 159 mmol). Mišinys šildomas 60 °C temperatūroje 6 vai. Vėl pridedama 4273 formilimidazolo (15,3 g) ir natrio triacetoksiborhidrido (33,8 g). Taip pridedama tris kartus, kol HPLC rodo, kad nesureagavusio junginio A liko 7 %. Gautas tirpalas atšaldomas iki kambario temperatūros. Lėtai įpilama MeOH (250 ml), mišinys pamaišomas 30 min. ir nugarinamas. Liekana aceotropiškai distiliuojama su toluenu (2 x 500 ml). Dervos pavidalo liekana praskiedžiama sočiu NaHCO3 tirpalu ir maišoma. Dedamas kietas NaHCO3, kol nustoja putoti. Suspensija ekstrahuojama EtOAc (3 x 1 I), Sumaišyti EtOAc ekstraktai plaunami sočiu NaHCO3 tirpalu ir sočiu NaCl tirpalu, džiovinami bevandeniu MgSO4, ir nugarinus gaunama putų pavidalo liekana. Ši liekana chromatografuojama sparčiosios chromatografijos metodu per silikagelio kolonėlę (E. Merck 230-400 mešų, 1,6 kg), eliuuojant EtOAc-MeOH (95:5), ir gaunama 312 pavyzdžio junginio laisva bazė. Ši bazė tirpinama EtOAc (1,0 I), veikiama 1,0 N HCI tirpalu Et2O (250 ml), mišinys pamaišomas 30 min. ir nufiltruojamas. Kieta medžiaga plaunama EtOAc (500 ml) ir Et2O (500 ml), ir išdžiovinus giliame vakuume 50° temperatūroje per naktį, gaunama 58 g (70 %) 312 pavyzdžio junginio, kuris yra kieta medžiaga.159 mmol) HOAC (glacial, 150 mL) and 1,2-dichloroethane (720 mL) were added sodium triacetoxyborohydride (33.8 g, 159 mmol) under argon. The mixture is heated at 60 ° C for 6 hours. Again, 4273 formylimidazole (15.3 g) and sodium triacetoxyborohydride (33.8 g) were added. This was added three times until HPLC indicated that 7% of unreacted compound A remained. The resulting solution was cooled to room temperature. MeOH (250 mL) was added slowly, and the mixture was stirred for 30 min. and is suppressed. The residue is aceotropically distilled with toluene (2 x 500 ml). The resinous residue was diluted with saturated NaHCO 3 solution and stirred. Solid NaHCO 3 is added until foaming ceases. The suspension is extracted with EtOAc (3 x 1 L), the combined EtOAc extracts are washed with saturated NaHCO 3 solution and saturated NaCl solution, dried over anhydrous MgSO 4 , and evaporated to give a foamy residue. This residue was flash chromatographed on a silica gel column (E. Merck 230-400 mesh, 1.6 kg) eluting with EtOAc-MeOH (95: 5) to give the free base of Example 312. This base was dissolved in EtOAc (1.0 L), treated with 1.0 N HCl in Et 2 O (250 mL), and stirred for 30 min. and filtered off. The solid was washed with EtOAc (500 mL) and Et 2 O (500 mL) and dried under deep vacuum at 50 ° C overnight to give 58 g (70%) of Example 312 as a solid.
MS (M + H)+ = 484.MS (M + H) <+> = 484.
Analizė išskaičiuota pagal C27H25N5O2S· 0,7H2O· 1 HCI· 0,05 EtOAc-0,03 eterioAnalysis calculated for C 27 H 25 N 5 O 2 S · 0.7H 2 O · 1 HCl · 0.05 EtOAc-0.03 ether
Išskaičiuota: C, 60,85; H, 5,25: N, 12,99; Cl, 6,57: S, 5,94.Found: C, 60.85; H, 5.25: N, 12.99; Cl, 6.57: S, 5.94.
Rasta: C, 60,85; H, 5,19; N, 13,05; Cl, 6,60; S, 5,95.Found: C, 60.85; H, 5.19; N, 13.05; Cl, 6.60; S, 5.95.
313 pavyzdysExample 313
274274
7-Brom-1,2,3,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(fenilmetil)-4H-1,4benzodiazepin-4-acetamidas7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-acetamide
A. 7-Brom-1,2,3,5-tetrahidro-3-(fenilmetil)-4H-1,4-benzodiazepin-4acetamidas pavyzdžio junginio B (250 mg, 0,74 mmol), DIEA (0,067 ml, 0,74 mmol) ir 2-chloracetamido (69 mg, 0,74 mmol) mišinys THF (10 ml) maišomas argono atmosferoje kambario temperatūroje 8 vai. Mišinys paskirstomas tarp sotaus NaCl tirpalo (50 ml) ir etilacetato (50 ml), vandeninis sluoksnis ekstrahuojamas etilacetatu (2 x 50 ml), sumaišyti organiniai sluoksniai džiovinami (MgSO4), ir sukoncentravus gaunamas junginys A, kuris yra skaidri alyva (260 mg, 94 %).A. 7-Bromo-1,2,3,5-tetrahydro-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-acetamide Example B (250 mg, 0.74 mmol), DIEA (0.067 mL, 0 , 74 mmol) and 2-chloroacetamide (69 mg, 0.74 mmol) in THF (10 mL) were stirred under argon at room temperature for 8 h. The mixture was partitioned between saturated NaCl solution (50 mL) and ethyl acetate (50 mL), the aqueous layer was extracted with ethyl acetate (2 x 50 mL), the combined organic layers dried (MgSO 4 ) and concentrated to give Compound A as a clear oil (260 mg). , 94%).
B. 7-Brom-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)4H-1,4-benzodiazepin-4-acetamidasB. 7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-acetamide
313 pavyzdžio junginys (balta kieta medžiaga) 38 % išeiga gaunamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką, maišant 18 vai. ir gryninant preparatinės HPLC metodu.Example 313 (white solid) is obtained in 38% yield from Compound A according to the procedure described in Example 1 for the preparation of Compound D with stirring for 18 hours. and purification by preparative HPLC.
MS (M + H) + = 454.MS (M + H) <+> = 454.
Analizė išskaičiuota pagal C22H24N5OBr· 0,3 H2O· 1,5 TFAAnalysis calculated for C 22 H 24 N 5 OBr · 0.3 H 2 O · 1.5 TFA
Išskaičiuota: C, 45,81; H, 3,95; N, 10,35; Br, 11,81; F, 16,01,Found: C, 45.81; H, 3.95; N, 10.35; Br, 11.81; F, 16.01,
Rasta: C, 45,43; H, 3,80; N, 9,96; Br, 11,50; F, 15,74.Found: C, 45.43; H, 3.80; N, 9.96; Br, 11.50; F, 15.74.
314 pavyzdys • BrExample 314 • Br
MeMe
275275
7-Brom-4-[(dimetilamino)acetil]-2,3,4,5-tetrahidro-1-(1H-imidazol-4i I meti l)-3-(f enil meti l)-1 H-1,4-benzodiazepinas7-Bromo-4 - [(dimethylamino) acetyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1, 4-Benzodiazepine
A. 7-Brom-4-(bromacetil)-2,3,4,5-tetrahidro-3-(fenilmetil)-1H-1,4benzodiazepinasA. 7-Bromo-4- (bromoacetyl) -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine
Junginys A (skaidri alyva) pagaminamas iš 75 pavyzdžio junginio B ir bromacetilbromido pagal 313 pavyzdyje aprašytą junginio A gavimo metodiką, gryninimui naudojant sparčiąją chromatografiją (silikagelis, 3:1 heksanai: etilacetatas).Compound A (clear oil) is prepared from Example B Compound B and bromoacetyl bromide according to the procedure described in Example 313 for the preparation of Compound A by flash chromatography (silica gel, 3: 1 hexanes: ethyl acetate).
B. 7-Brom-4-[(dimetilamino)acetil]-2,3,4,5-tetrahidro-3-(fenilmetil)1 H-1,4-benzodiazepinas j junginio A (126 mg, 0,29 mmol) tirpalą THF (2 ml) pridedama dimetilamino (2 ml, 1M THF). Tirpalas maišomas kambario temperatūroje užlydytame slėgi išlaikančiame vamzdelyje 7 vai., supilamas į vandeni ir ekstrahuojamas etilacetatu. Tirpalas džiovinamas (MgSO4), ir sukoncentravus gaunamas junginys B, kuris yra alyva (110 mg, 94 %).B. 7-Bromo-4 - [(dimethylamino) acetyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine, Compound A (126 mg, 0.29 mmol) to a solution of THF (2 mL) was added dimethylamine (2 mL, 1M THF). The solution is stirred at room temperature in a sealed pressure-maintaining tube for 7 hours, poured into water and extracted with ethyl acetate. The solution was dried (MgSO 4 ) and concentrated to give Compound B as an oil (110 mg, 94%).
C. 7-Brom-4-[(dimetilamino)acetil]-2,3,4,5-tetrahidro-1-(1H-imidazol4-ilmetil)-3-(fenilmetil)-1H-1,4-benzodiazepinasC. 7-Bromo-4 - [(dimethylamino) acetyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine
Junginys C (balta kieta medžiaga) 65 % išeiga gaunamas iš junginio B pagal 313 pavyzdyje aprašytą junginio B gavimo metodiką.Compound C (white solid) is obtained in 65% yield from compound B according to the procedure for preparation of compound B described in Example 313.
MS (M + H)+ = 483.MS (M + H) < + > = 483.
Analizė išskaičiuota pagal C24H28N5OBr· 1,2 H2O· 2,1 TFA.Analysis calculated for C 24 H 28 N 5 OBr · 1.2 H 2 O · 2.1 TFA.
Išskaičiuota: C, 45,56; H, 4,41; N, 9,42; Br, 10,75; F, 16,10.Found: C, 45.56; H, 4.41; N, 9.42; Br, 10.75; F, 16.10.
Rasta: C, 45,75; H, 4,02;'N, 9,19; Br, 11,14; F, 16,08.Found: C, 45.75; H, 4.02; N, 9.19; Br, 11.14; F, 16.08.
315 pavyzdysExample 315
276276
(R)-7-Brom-4-(1,2-dioksopropil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4ϊ I m eti l)-3-(f enil metil)-1 H-1,4-benzodiazepinas (trifluoracetatas)(R) -7-Bromo-4- (1,2-dioxopropyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) - 1H-1,4-benzodiazepine (trifluoroacetate)
315 pavyzdžio junginys (balta kieta medžiaga) bendra 25 % išeiga gaunamas iš 224 pavyzdžio junginio B, kopuliuojant piruvo rūgštį DMF, reakcijos tarpininku esant EDC/HOBt, gryninimui naudojant sparčiąją chromatografiją (silikagelis, 4:1 heksanai:etilacetatas), o po to panaudojant 313 pavyzdyje aprašytą junginio B sintezės metodiką.Example 315 (white solid) is obtained in a total 25% yield from Example 224, compound B, by coupling pyruvic acid in DMF with EDC / HOBt as a reaction medium by flash chromatography (silica gel, 4: 1 hexanes: ethyl acetate) followed by Example 313 describes the synthesis of compound B.
MS (M + H)+ = 468.MS (M + H) < + > = 468.
Analizė išskaičiuota pagal C23H23N4O2Br· 0,8 H2O· 0,95 TFA.Analysis calculated for C 2 3 H 2 3 N 4 O 2 Br · 0.8 H 2 O · 0.95 TFA.
Išskaičiuota: C, 50,68; H, 4,36; N, 9,49; Br, 13,54; F, 9,18.Found: C, 50.68; H, 4.36; N, 9.49; Br, 13.54; F, 9.18.
Rasta: C, 50,37; H, 4,04; N, 9,23; Br, 14,07; F, 9,55.Found: C, 50.37; H, 4.04; N, 9.23; Br, 14.07; F, 9.55.
(R)-7-Brom-4-(ciklopropilkarbonil)-2,3,4,5-tetrahidro-1-(1H-imidazol-411metil)-3-(feniįmetil)-1 H-1,4-benzodiazepinas (trifluoracetatas)(R) -7-Bromo-4- (cyclopropylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazole-411-methyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate) )
277277
316 pavyzdžio junginys (balta kieta medžiaga) bendra 6 % išeiga pagaminamas iš 224 pavyzdžio junginio B ir ciklopropankarboksirūgšties, panaudojant dviejų stadijų metodiką, aprašytą 315 pavyzdyje, negryninant tarpinio junginio.Example 316 (white solid) is prepared in a total 6% yield from Example 224B and cyclopropanecarboxylic acid using the two-step procedure described in Example 315 without purifying the intermediate.
MS (M + H)+ = 466.MS (M + H) < + > = 466.
Analizė išskaičiuota pagal Ο24Η25Ν4ΟΒγ· 1,0 Η2Ο· 0,8 TFA.Analysis was subtracted from Ο 24 Η 25Η 4 ΟΒγ · 1.0 Η 2 Ο · 0.8 TFA.
Išskaičiuota: C, 52,59; H, 4,68; N, 9,43; Br, 13,46; F, 9,60.Found: C, 52.59; H, 4.68; N, 9.43; Br, 13.46; F, 9.60.
Rasta: C, 52,62; H, 4,37; N, 9,46; Br, 12,23; F, 9,46.Found: C, 52.62; H, 4.37; N, 9.46; Br, 12.23; F, 9.46.
317 pavyzdys CNExample 317 CN
Me (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4(propilsulfonil)-1H-1,4-benzodiazepinas (monohidrochloridas)Me (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 (propylsulfonyl) -1H-1,4-benzodiazepine ( monohydrochloride)
A. (R)-7-Ciano-2,3,4,5-tetrahidro-3-(fenilmetil)-4-(propilsulfonil)-1H1,4-benzodiazepinasA. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (phenylmethyl) -4- (propylsulfonyl) -1H1,4-benzodiazepine
J 248 pavyzdžio junginio C (6,0 g, 23 mmol) ir DIEA (12 ml, 68 mmol) tirpalą metileno chloride (120 ml) -78 °C temperatūroje sulašinamas npropilsulfonilchloridas (3,4 ml, 34 mmol). Mišiniui leidžiama sušilti iki kambario temperatūros ir maišoma 16 vai., skaldoma 10 % NaHCO3 (50 ml) ir ekstrahuojama metileno chloridu (3 x 75 ml). Sumaišyti organiniai sluoksniai džiovinami (Na2SO4), nufiltruojama ir koncentruojama vakuume. LiekanaA solution of compound C (6.0 g, 23 mmol) in Example 248 and DIEA (12 mL, 68 mmol) in methylene chloride (120 mL) was added dropwise at -78 ° C to n-propylsulfonyl chloride (3.4 mL, 34 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h, quenched with 10% NaHCO 3 (50 mL) and extracted with methylene chloride (3 x 75 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Remain
278 gryninama sparčiosios chromatografijos metodu (2/1 heksanas/etilacetatas), ir gaunamas junginys A (7,1 g, 85 %), kuris yra geltona kieta medžiaga.278 was purified by flash chromatography (2/1 hexane / ethyl acetate) to give Compound A (7.1 g, 85%) as a yellow solid.
MS (M + H)+ 370.MS (M + H) + 370.
Analizė išskaičiuota pagal C20H23N3O2S -0,19 H2O.Analysis calculated for C20H23N3O2S -0.19 H 2 O.
Išskaičiuota: C, 64,42; H, 6,32; N, 11,27.Found: C, 64.42; H, 6.32; N, 11.27.
Rasta: C, 64,43; H, 6,25; N, 11,09.Found: C, 64.43; H, 6.25; N, 11.09.
B. (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(fenilmetil)-4-(propilsulfonil)-1H-1,4-benzodiazepinas (monohidrochloridas) j junginio A (6,0 g, 16 mmol) su 3A molekuliniais tinkleliais tirpalą 1/1 CH2CI2:acto rūgšties mišinyje (80 ml) pridedama 4-formilimidazolo (3,1 g, 33 mmol), ir mišinys maišomas 70 °C temperatūroje 1 vai. Pridedama natrio triacetoksiborhidrido (6,9 g, 33 mmol), ir mišinys maišomas 70 °C temperatūroje 30 min. j mišinį vėl pridedama 4-formilimidazolo (3,1 g, 33 mmol, 2,0 ekv.) ir maišoma 70 °C temperatūroje dar 1 vai. Pridedama natrio triacetoksiborhidrido (6,9 g, 33 mmol, 2,0 ekv.), ir mišinys maišomas 70 °C temperatūroje 30 min. Formilimidazolo ir hidrido papildomas pridėjimas pakartojamas aštuonis kartus. Mišinys atšaldomas iki kambario temperatūros, praskiedžiamas metileno chloridu (200 ml), nufiltruojamas, ir filtratas koncentruojamas vakuume. Liekana praskiedžiama 25 % NH4OH (200 ml). Tirpalas maišomas kambario temperatūroje 10 min., ekstrahuojamas CH2CI2 (2 x 200 ml), sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojami ir koncentruojami. Liekana gryninama preparatinės HPLC metodu (vandeninio MeOH su 0,1 % TFA gradientas), atrenkamos reikiamos frakcijos ir sukoncentruojamos vakuume. Liekana ištirpinama CH3OH (20 ml) ir 1N HCI (40 ml) ir koncentuojamos vakuume. Ši procedūra pakartojama 3 kartus. Liekana ištirpinama CH3CN (20 ml) ir 1N HCI (20 ml) ir po liofilizavimo gaunamas 317 pavyzdžio junginys (6,8 g, 74 %), kuris yra balta kieta medžiaga. Lyd. temp.: 140-151 °C.B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (propylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride) 4-formylimidazole (3.1 g, 33 mmol) was added to a solution of compound A (6.0 g, 16 mmol) in 3A molecular weight mesh in 1/1 CH 2 Cl 2 : acetic acid (80 mL), and the mixture was stirred at 70 ° C for 1 h. Sodium triacetoxyborohydride (6.9 g, 33 mmol) was added and the mixture was stirred at 70 ° C for 30 min. 4-Formylimidazole (3.1 g, 33 mmol, 2.0 equiv.) was added again and stirred at 70 ° C for a further 1 h. Sodium triacetoxyborohydride (6.9 g, 33 mmol, 2.0 equiv.) Was added and the mixture was stirred at 70 ° C for 30 min. The addition of formylimidazole and hydride is repeated eight times. The mixture was cooled to room temperature, diluted with methylene chloride (200 mL), filtered, and the filtrate concentrated in vacuo. The residue was diluted with 25% NH 4 OH (200 mL). The solution was stirred at room temperature for 10 min, extracted with CH 2 Cl 2 (2 x 200 mL), the combined organic extracts dried (MgSO 4 ), filtered and concentrated. The residue was purified by preparative HPLC (gradient of aqueous MeOH with 0.1% TFA), the desired fractions selected and concentrated in vacuo. The residue was dissolved in CH 3 OH (20 mL) and 1N HCl (40 mL) and concentrated in vacuo. This procedure is repeated 3 times. The residue was dissolved in CH 3 CN (20 mL) and 1N HCl (20 mL) and lyophilized to give Example 317 (6.8 g, 74%) as a white solid. Lyd. 140-151 ° C.
MS (M + H)+ 450.MS (M + H) < + > 450.
Analizė išskaičiuota pagal C24H27N5O2S -1,1 HCI- 0,59 H2O.Analysis calculated for C 2 4 H 27 N 5 O 2 S -1.1 HCl-0.59 H 2 O.
279279
Išskaičiuota: C, 57,62; H, 5,90; N, 14,00; Cl, 7,79: S, 6,41. Rasta: C, 57,61; H, 5,70; N, 13,97; Cl, 7,62; S, 6,44.Found: C, 57.62; H, 5.90; N, 14.00; Cl, 7.79: S, 6.41. Found: C, 57.61; H, 5.70; N, 13.97; Cl, 7.62; S, 6.44.
[ct]D = +201° (c = 1,41, CH3OH).[α] D = + 201 ° (c = 1.41, CH 3 OH).
7-Brom-2,3,4,5-tetrahidro-1,4-bis (1 H-imidazol-4-ilmetil)-3-(fenilmetil)-1 H1,4-benzodiazepinas (dihidrochloridas)7-Bromo-2,3,4,5-tetrahydro-1,4-bis (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine (dihydrochloride)
318 pavyzdžio junginys (balta kieta medžiaga) 55 % išeiga pagaminamas iš 75 pavyzdžio junginio B pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką, naudojant 3 ekvivalentus formilimidazolo ir maišant 2 vai. MS (M + H)+ = 477.Example 318 (white solid) 55% yield of Example 75 Compound B according to the procedure described in Example 1 for the preparation of Compound D using 3 equivalents of formylimidazole and stirring for 2 hours. MS (M + H) <+> = 477.
319 pavyzdysExample 319
BrBr
^Me^ Me
MeMe
280280
7-Brom-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-N,N-dimetil-3(fenilmetil)-4H-1,4-benzodiazepin-4-sulfonamidas (monohidrochloridas)7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonamide (monohydrochloride) )
A. 7-Brom-1,2,3,5-tetrahidro-N,N-dimetil-3-(fenilmetil)-4H-1,4benzodiazepin-4-sulfonamidasA. 7-Bromo-1,2,3,5-tetrahydro-N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonamide
Maišomas 75 pavyzdžio junginio B (100 mg, 0,32 mmol), N,Ndimetilsulfamoilchlorido (50 mg, 0,35 mmol) ir DIPEA (61 μΙ, 0,35 mmol) tirpalas acetonitrile, esant katalitiniam kiekiui DMAP, virinamas su grįžtamu šaldytuvu 18 vai. Mišinys paskirstomas tarp etilacetato ir 1N HCI tirpalo. Organinis sluoksnis atskiriamas, džiovinamas (MgSO4) ir koncentruojamas. Liekana gryninama sparčiosios chromatografijos metodu (1:2, ,heksanai:etilacetatas), ir gaunamas junginys A, kuris yra alyva.A stirred solution of Example 75 Compound B (100 mg, 0.32 mmol), N, N-dimethylsulfamoyl chloride (50 mg, 0.35 mmol), and DIPEA (61 μΙ, 0.35 mmol) in acetonitrile under catalytic amount of DMAP was heated to reflux. 18 or. The mixture was partitioned between ethyl acetate and 1N HCl solution. The organic layer was separated, dried (MgSO 4 ), and concentrated. The residue was purified by flash chromatography (1: 2, hexanes: ethyl acetate) to give Compound A as an oil.
B. 7-Brom-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-N,N-dimetil-3(fenilmetil)-4H-1,4-benzodiazepin-4-sulfonamidas (monohidrochloridas)B. 7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonamide (monohydrochloride)
319 pavyzdžio junginys (kieta medžiaga) 92 % išeiga pagaminamas iš junginio A pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką.Example 319 Compound (Solid) 92% yield is prepared from Compound A according to the procedure for Compound D described in Example 224.
MS (M + H)+ 504.MS (M + H) + 504.
Analizė išskaičiuota pagal C22H26N5O2SBr · 1,0 HCI· 0,5 eterio.Analysis calculated for C 2 2 H 26 N 5 O 2 SBr · 1.0 HCl · 0.5 ether.
Išskaičiuota: C, 49,88; H, 5,58; N, 12,12; Br, 13,82; S, 5,55.Found: C, 49.88; H, 5.58; N, 12.12; Br, 13.82; S, 5.55.
Rasta: C, 49,90; H, 5,42; N, 12,13; Br, 13,22; S, 6,44.Found: C, 49.90; H, 5.42; N, 12.13; Br, 13.22; S, 6.44.
320 pavyzdys320 Example
281281
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(feniImetil)-1 H-1,4-benzodiazepin-7-karbonitrilas (monohidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile (monohydrochloride)
320 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš 75 pavyzdžio junginio B pagal reakcijų seką, aprašytą šiems junginiams gauti: 224 pavyzdžio junginiui C, 225 pavyzdžio junginiui A ir 225 pavyzdžio junginiui B.Example 320 Compound (yellow solid) is prepared from Example 75 Compound B according to the reaction sequence described for the following compounds: Example 224 Compound C, Example 225 Compound A, and Example 225 Compound B.
MS (M + H) + 422.MS (M + H) < + > 422.
Analizė išskaičiuota pagal C22H23N5O2S · 1,0 HCI· 0,2 CH3OH.Analysis calculated for C 22 H 23 N 5 O 2 S · 1.0 HCl · 0.2 CH 3 OH.
Išskaičiuota: C, 57,42; H, 5,38; N, 15,08; Cl, 7,63; S, 6,90.Found: C, 57.42; H, 5.38; N, 15.08; Cl, 7.63; S, 6.90.
Rasta: C, 57,12; H, 5,58; N, 11,94; Cl, 7,77; S, 4,95.Found: C, 57.12; H, 5.58; N, 11.94; Cl, 7.77; S, 4.95.
321 pavyzdysExample 321
CNCN
Me (R)-7-Ciano-1,2,3,5-tetrahidro-1 -(1 H-imidazol-4-ilmetiI)-N,N-dimetil-3(fenilmetil)-4H-1,4-benzodiazepin-4-karboksamidas (monohidrochloridas)Me (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3 (phenylmethyl) -4H-1,4-benzodiazepine -4-Carboxamide (monohydrochloride)
321 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš 248 pavyzdžio junginio C pagal reakcijų seką, naudojamą šiems junginiams gauti: 319 pavyzdžio junginiui A, naudojant dimetilkarbamoilchloridą ir maišant 60 °C temperatūroje 2 vai. ir chromatografijoje naudojant 1:1 heksanų ir etilacetato mišinį; 225 pavyzdžio junginiui B. Lyd. temp.: 147-150 °C.Example 321 (yellow solid) was prepared from Example 248 by Compound C according to the reaction sequence used to prepare Example 319, Compound A using dimethylcarbamoyl chloride and stirring at 60 ° C for 2 hours. and chromatography using a 1: 1 mixture of hexanes and ethyl acetate; For the compound of Example 225, B. Lyd. mp 147-150 ° C.
MS (M + H)+ = 415.MS (M + H) <+> = 415.
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Analizė išskaičiuota pagal C24H26N6O · 0,74 H2O · 1,0 HCI. Išskaičiuota: C, 62,09; H, 6,18; N, 18,10; Cl, 7,61.Analysis calculated for C 24 H 26 N 6 O · 0.74 H 2 O · 1.0 HCl. Found: C, 62.09; H, 6.18; N, 18.10; Cl, 7.61.
Rasta: C, 62,09; H, 6,04; N, 17,86; Cl, 7,91.Found: C, 62.09; H, 6.04; N, 17.86; Cl, 7.91.
[a]D 20: +244° (c = 0,24, MeOH).[α] D 20 : + 244 ° (c = 0.24, MeOH).
N,N-Dietil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonii)-3(fenilmetil)-1H-1,4-benzodiazepin-7-karboksamidas (monohidrochloridas)N, N-Diethyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carboxamide (monohydrochloride)
A. 2,3,4,5-Tetrahidro-4-(metilsulfonil)-3-(fenilmetil)-1H-1,4benzodiazepin-7-karboksirūgštisA. 2,3,4,5-Tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carboxylic acid
225 pavyzdžio junginio A (200 mg, 0,59 mmol) tirpalas etanolyje, pridėjus 10N NaOH tirpalo (4 ml, 40 mmol) virinamas su grįžtamu šaldytuvu 5 vai. Mišinys atšaldomas iki kambario temperatūros, koncentruojamas ir pilamas vandeninis HCI iki pH 3. Šis mišinys sukoncentruojamas. Liekana paskirstoma tarp 1N HCI ir etilacetato. Organinis sluoksnis atskiriamas, džiovinamas MgSO4 ir koncentruojamas. Liekana trinama su metanoliu, ir gaunamas junginys A, kuris yra kieta medžiaga (156 mg, 73 %).A solution of Example 225 Compound A (200 mg, 0.59 mmol) in ethanol was added to reflux for 5 hours with the addition of 10N NaOH (4 mL, 40 mmol). The mixture was cooled to room temperature, concentrated and poured aqueous HCl to pH 3. This mixture was concentrated. The residue was partitioned between 1N HCl and ethyl acetate. The organic layer was separated, dried over MgSO 4, and concentrated. The residue was triturated with methanol to give Compound A as a solid (156 mg, 73%).
B. N,N-Dietil-2,3,4,5-tetrahidro-4-(metilsulfonil)-3-(fenilmetil)-1H-1,4benzodiazepin-7-karboksamidasB. N, N-Diethyl-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carboxamide
J junginio A (50 mg, 0,14 mmol) tirpalą DMF pridedama dietilamino (50 μΙ), po to katalitiniai kiekiai HOBT ir DMAP, ir po to EDC (30 mg). MišinysTo a solution of compound A (50 mg, 0.14 mmol) in DMF was added diethylamine (50 μΙ) followed by catalytic amounts of HOBT and DMAP, followed by EDC (30 mg). Mixture
283 maišomas kambario temperatūroje 2 dienas ir paskirstomas tarp etilacetato ir283 was stirred at room temperature for 2 days and partitioned between ethyl acetate and
1N HCI tirpalo. Organinis sluoksnis atskiriamas, plaunamas sočiu NaHCO3 tirpalu, džiovinamas MgSO4 ir sukoncentravus gaunamas alyvos pavidalo junginys B.1N HCl solution. The organic layer was separated, washed with saturated NaHCO 3 solution, dried over MgSO 4, and concentrated to an oil compound B.
C. N,N-Dietil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4(metilsulfonil)-3-(fenilmetil)-1H-1,4-benzodiazepin-7-karboksamidas (monohidrochloridas)C. N, N-Diethyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7 -carboxamide (monohydrochloride)
Junginys C pagaminamas iš junginio B pagal 225 pavyzdyje aprašytą junginio B gavimo metodiką.Compound C is prepared from Compound B according to the procedure for the preparation of Compound B described in Example 225.
MS (M + H)+ = 496.MS (M + H) <+> = 496.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-4-(1-fenil-1H-tetrazol5-ii)-1H-1,4-benzodiazepinas (monohidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (1-phenyl-1H-tetrazol-5-yl) -1H-1,4-benzodiazepine (monohydrochloride)
A. 2,3,4,5-Tetrahidro-7-fenil-4-(1-fenil-1H-tetrazoI-5-il)-1H-1,4benzodiazepinas pavyzdžio junginio B (100 mg, 0,45 mmol) tirpalas DMF (2 ml) veikiamas 5-chlor-1 -feniltetrazolu (100 mg, 0,55 mmol), pridėjus kalio karbonato (60 mg). Mišinys maišomas 60 °C temperatūroje 18 vai. ir paskirstomas tarp etilacetato ir sotaus NH4CI tirpalo. Organinis sluoksnis plaunamas sočiu NaHCO3 tirpalu, džiovinamas (MgSO4) ir koncentruojamas.A. Solution of 2,3,4,5-Tetrahydro-7-phenyl-4- (1-phenyl-1H-tetrazol-5-yl) -1H-1,4-benzodiazepine, Compound B (100 mg, 0.45 mmol) DMF (2 mL) was treated with 5-chloro-1-phenyltetrazole (100 mg, 0.55 mmol) with potassium carbonate (60 mg). The mixture was stirred at 60 ° C for 18 hours. and partitioned between ethyl acetate and saturated NH 4 Cl solution. The organic layer was washed with saturated NaHCO 3 solution, dried (MgSO 4 ), and concentrated.
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Išgryninus liekaną kolonėlių chromatografijos metodu, gaunamas junginys A, kuris yra balta kieta medžiaga (75 mg, 45 %). Lyd. temp.: 150-151 °C.Purification of the residue by column chromatography afforded Compound A as a white solid (75 mg, 45%). Lyd. mp: 150-151 ° C.
B. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-4-(1-fenil-1Htetrazol-5-il)-1H-1,4-benzodiazepinas (monohidrochloridas)B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (1-phenyl-1H-tetrazol-5-yl) -1H-1,4-benzodiazepine ( monohydrochloride)
Junginys B (geltona kieta medžiaga) pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką. Lyd. temp.: 158 °C.Compound B (yellow solid) is prepared from Compound A according to the procedure described in Example 1 for the preparation of Compound D. Lyd. mp: 158 ° C.
Analizė išskaičiuota pagal C26H24N8 · 0,5 CH3OH · 2,5 HCI.Analysis calculated for C 26 H 24 N 8 · 0.5 CH 3 OH · 2.5 HCl.
Išskaičiuota: C, 57,28; H, 5,17; N, 20,16.Found: C, 57.28; H, 5.17; N, 20.16.
Rasta: C, 57,62: H, 5,12; N, 19,93.Found: C, 57.62: H, 5.12; N, 19.93.
324 pavyzdysExample 324
CN (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-(2pirazinilkarbonil)-4H-1,4-benzodiazepinas (monohidrochloridas)CN (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-pyrazinylcarbonyl) -4H-1,4-benzodiazepine (monohydrochloride)
324 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš 248 pavyzdžio junginio C ir pirazinkarboksirūgšties pagal reakcijų seką, naudojamą tokiems junginiams gauti: 322 pavyzdžio junginiui B, maišant 18 vai ir gryninant sparčiosios chromatografijos metodu (3:2, etilacetatas:heksanai); 225 pavyzdžio junginiui B,Example 324 (yellow solid) is prepared from Example 248, Compound C, and pyrazinecarboxylic acid according to the reaction sequence used to prepare Example 322, Compound B, after stirring for 18 hours and purifying by flash chromatography (3: 2, ethyl acetate: hexanes); 225 for compound B,
MS (M + H)+ = 450.MS (M + H) <+> = 450.
Analizė išskaičiuota pagal C26H23N7O · 1,2 H2O · 1,0 HCI · 1,2 tolueno. Išskaičiuota: C, 66,09; H, 5,78; N, 16,35; Cl, 5,91.Analysis calculated for C 26 H 23 N 7 O · 1.2 H 2 O · 1.0 HCl · 1.2 toluene. Found: C, 66.09; H, 5.78; N, 16.35; Cl, 5.91.
Rasta: C, 65,83 ; H, 5,45; N, 16,11; Cl, 5,96.Found: C, 65.83; H, 5.45; N, 16.11; Cl, 5.96.
285285
325 pavyzdysExample 325
(R)-4-[7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)4H-1,4-benzodiazepin-4-il]-4-oksobutano rūgšties metilo esteris (monohidrochloridas)(R) -4- [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepin-4-yl] -4-Oxobutanoic acid methyl ester (monohydrochloride)
A. (R)-4-[7-Brom-2,3,4,5-tetrahidro-3-(fenilmetil)-4H-1,4benzodiazepin-4-il]-4-oksobutano rūgšties metilo esterisA. (R) -4- [7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -4H-1,4-benzodiazepin-4-yl] -4-oxobutanoic acid methyl ester
Maišomas 224 pavyzdžio junginio B (100 mg, 0,31 mmol) tirpalas veikiamas gintaro rūgšties anhidridu (40 mg, 0,40 mmol) etilacetate. Mišinys maišomas kambario temperatūroje 18 vai. ir paskirstomas 1N HCI tirpale. Organinis sluoksnis džiovinamas (MgSO4), ir sukoncentravus gaunamas junginys A.A stirred solution of Compound B (100 mg, 0.31 mmol) in Example 224 was treated with succinic anhydride (40 mg, 0.40 mmol) in ethyl acetate. The mixture was stirred at room temperature for 18 hours. and distributed in 1N HCl solution. The organic layer was dried (MgSO 4 ) and concentrated to give compound A.
B. (R)-4-[7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(fenilmetil)-4H-1,4-benzodiazepin-4-il]-4-oksobutano rūgšties metilo esteris (monohidrochloridas)B. (R) -4- [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -4H-1,4-benzodiazepine-4- il] -4-Oxobutanoic acid methyl ester (monohydrochloride)
Junginys B (geltona kieta medžiaga) pagaminamas iš junginio A pagal 225 pavyzdyje aprašytą junginio B gavimo metodiką.Compound B (a yellow solid) is prepared from Compound A according to the procedure for the preparation of Compound B described in Example 225.
MS (M + H)+ = 511.MS (M + H) <+> = 511.
326 pavyzdysExample 326
286286
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(4morfolinilkarbonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-morpholinylcarbonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)
326 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš 248 pavyzdžio junginio C ir morfolinokarbamoilchlorido pagal 321 pavyzdyje aprašytą metodiką.Example 326 (yellow solid) is prepared from Example 248, compound C, and morpholinocarbamoyl chloride according to the procedure described in Example 321.
MS (M + H)+ = 457.MS (M + H) <+> = 457.
Analizė išskaičiuota pagal C26H28N6O2 · 0,8 H2O · 1,2 HCI · 0,2 eterio. Išskaičiuota: C, 60,79: H, 6,24; N, 15,87; Cl, 8,03.Analysis calculated for C26H28N6O2 · 0.8 H 2 O · 1.2 HCl · 0.2 ether. Found: C, 60.79: H, 6.24; N, 15.87; Cl, 8.03.
Rasta: C, 60,85; H, 6,02; N, 15,56; Cl, 8,06.Found: C, 60.85; H, 6.02; N, 15.56; Cl, 8.06.
327 pavyzdysExample 327
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)- 3-(fenilmetil)-4£ [2-(1 pi r oi i di ni l) etil] sulf oni I]-1 H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- [2- (1-pyrrolidinone) ) ethyl] sulfonyl] -1H-1,4-benzodiazepine (dihydrochloride)
287287
327 pavyzdžio junginys (gelsva kieta medžiaga) 46 % išeiga pagaminamas iš 250 pavyzdžio junginio A ir pirolidino pagal 250 pavyzdyje aprašytą junginio B gavimo metodiką.Example 327 Compound (yellowish solid) is prepared in 46% yield from Example 250 Compound A and pyrrolidine according to the procedure for Preparation Compound B described in Example 250.
MS (M + H)+ = 505.MS (M + H) <+> = 505.
(S)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-7-fenil-3(3-piridinilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)(S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
328 pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš L-(3-piridil)alanino ir 226 pavyzdžio junginio B pagal seką, naudojamą šiems junginiams gauti: 226 pavyzdžio junginiui C; 226 pavyzdžio junginiui D; 264 pavyzdžio junginiui B; 264 pavyzdžio junginiui C.Example 328 (off-white solid) is prepared from L- (3-pyridyl) alanine and Example 226 Compound B according to the sequence used to prepare the following compounds: Example 226 Compound C; Example 226 for compound D; 264 for compound B; 264 for compound C.
MS (M + H)+ 474.MS (M + H) < + > 474.
329 pavyzdysExample 329
288288
(R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-3-(3-piridinilmetil)4-(2-tienilsulfonil)-1 H-1,4-benzodiazepinas (dihidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (3-pyridinylmethyl) 4- (2-thienylsulfonyl) -1H-1, 4-Benzodiazepine (dihydrochloride)
329 pavyzdžio junginys (nelabai balta kieta medžiaga) pagaminamas iš (R)-2,3,4,5-tetrahidro-7-fenil-3-(3-piri dinilmetil)-1 H-1,4-benzodiazepino (pagaminto pagal 273 pavyzdyje aprašytą metodiką) ir 2-tiofensulfonilchlorido pagal reakcijų seką, naudojamą šiems junginiams gauti: 224 pavyzdžio junginiui C; 224 pavyzdžio junginiui D.Example 329 (off-white solid) is prepared from (R) -2,3,4,5-tetrahydro-7-phenyl-3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (273). and the 2-thiophensulfonyl chloride according to the reaction sequence used to prepare the following compounds: Example 224, Compound C; Example 224 for compound D.
MS (M + H)+ 542.MS (M + H) < + > 542.
330 pavyzdysExample 330
(R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-4-(propilsulfonil)3-(3-piridinilmetiI)-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (propylsulfonyl) -3- (3-pyridinylmethyl) -1H-1,4- benzodiazepine (monohydrochloride)
289289
A. (R)-2,3,4,5-Tetrahidro-7-fenil-4-(propilsulfonil)-3-(3-piridinilmetil)1 H-1,4-benzodiazepinasA. (R) -2,3,4,5-Tetrahydro-7-phenyl-4- (propylsulfonyl) -3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine
Į maišomą (R)-2,3,4,5-tetrahidro-7-feni l-3-(3-piridinil metil)-1 H-1,4benzodiazepino (pagaminto taip, kaip aprašyta 273 pavyzdyje; 200 mg, 0,63 mmol) ir DIEA (0,33 ml, 1,9 mmol) tirpalą -60 °C temperatūroje argono atmosferoje pridedama propansulfonilchlorido (0,11 ml, 0,94 mmol). Mišinys laikomas 4 °C temperatūroje dvi dienas, skaldomas vandeniniu sočiu NaHCO3 tirpalu (10 ml) ir ekstrahuojamas CH2CI2 (3 x 10 ml). Sumaišyti ekstraktai džiovinami (Na2SO4), ir nugarinus sumažintame slėgyje gaunamas junginys A, kuris yra geltona kieta medžiaga. MS (M + H)+ 422.To a stirred (R) -2,3,4,5-tetrahydro-7-phenyl-3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (prepared as described in Example 273; 200 mg, 0, A solution of 63 mmol) and DIEA (0.33 mL, 1.9 mmol) at -60 ° C under argon was added propanesulfonyl chloride (0.11 mL, 0.94 mmol). The mixture was kept at 4 ° C for two days, quenched with aqueous saturated NaHCO 3 solution (10 mL) and extracted with CH 2 Cl 2 (3 x 10 mL). The combined extracts were dried (Na2S 4) and evaporated under reduced pressure to obtain a compound A as a yellow solid. MS (M + H) < + > 422.
B. (R)-2,3,4,5-Tetrahidro-1-(1H-imidazoi-4-ilmetil)-7-fenil-4(propi Isulf oni l)-3-(3-pi ri di nilm eti I)-1 H-1,4-benzodiazepinas (monohidrochloridas)B. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (propylsulfonyl) -3- (3-pyridinyl) ethyl I) -1H-1,4-benzodiazepine (monohydrochloride)
Junginys B (geltona kieta medžiaga) 45 % išeiga pagaminamas iš junginio A pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką, gryninant preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). HCI druska pagaminama j TFA druskos tirpalą etilacetate pridedant 1N HCI eteryje ir nugarinant. MS: (M + H)+ 502.Compound B (yellow solid) is prepared in 45% yield from Compound A according to the procedure for the preparation of Compound D described in Example 224 by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The HCl salt is prepared by adding 1N HCl in ether to a solution of the TFA salt in ethyl acetate and evaporating. MS: (M + H) < + > 502.
331 pavyzdysExample 331
(R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsuIfonil)-3(2-piridinilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (2-pyridinylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)
290290
331 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš D(2-piridil)alanino ir 226 pavyzdžio junginio B pagal reakcijų seką, naudojamą šiems junginiams gauti: 226 pavyzdžio junginiui C; 226 pavyzdžio junginiui D, virinant su grįžtamu šaldytuvu 48 vai.; 264 pavyzdžio junginiui B, gryninant preparatinės HPLC metodu, naudojant vandeninio metanolio su 0,1 % TFA; 264 pavyzdžio junginiui C.Example 331 (yellow solid) is prepared from D (2-pyridyl) alanine and Example 226 Compound B according to the reaction sequence used to prepare the following compounds: Example 226 Compound C; Example 226, Compound D, refluxed for 48 hours; Example 264, Compound B, purified by preparative HPLC using aqueous methanol with 0.1% TFA; 264 for compound C.
MS (M + H)+ 478.MS (M + H) < + > 478.
332 pavyzdysExample 332
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(fenilmetil)-7-(2-pirimidinil)-1H-1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (2-pyrimidinyl) -1H-1,4-benzodiazepine (dihydrochloride) )
332 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš 231 pavyzdžio junginio A ir 2-stanilpirimidino pagal 231 pavyzdyje aprašytas junginių B ir C gavimo metodikas.Example 332 (yellow solid) is prepared from Example 231, Compound A and 2-stanylpyrimidine according to the procedures for preparation of Compounds B and C described in Example 231.
MS (M + H)+ 475.MS (M + H) + 475.
333 pavyzdysExample 333
292292
334 pavyzdžio junginys (balta kieta medžiaga) 26 % išeiga pagaminamas iš 226 pavyzdžio junginio D veikiant trifluoracto rūgšties anhidridu ir DIEA metileno chloridu, o po to pagal 264 pavyzdyje aprašytą junginio C gavimo metodiką, gryninant preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). HCI druska gaunama liofilizuojant du kartus iš 1N HCI.Example 334 (white solid) is prepared in 26% yield from Example 226 Compound D by treatment with trifluoroacetic anhydride and DIEA in methylene chloride followed by the procedure described in Example 264 for the preparation of Compound C by preparative HPLC (aqueous methanol 0.1%). TFA gradient). The HCl salt is obtained by lyophilization twice from 1N HCl.
MS (M + H)+ 491.MS (M + H) < + > 491.
(R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(fenilmetil)-7-(4-piridinil)-1H-1,4-benzodiazepinas (dihidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -7- (4-pyridinyl) -1H-1,4 benzodiazepine (dihydrochloride)
A. (R)-2,3,4,5-Tetrahidro-3-(fenilmetil)-7-(4-piridinil)-1H-1,4benzodiazepin-2,5-dionasA. (R) -2,3,4,5-Tetrahydro-3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine-2,5-dione
224 pavyzdžio junginio A (55,6 mmol, 19,2 g), 4-stanilpiridino (111 mmol, 40,9 g) ir Pd(PPh3)4 (8,24 mmol, 9,6 g) mišinys toluene (2000 ml) degazuojamas ir kaitinamas 110 °C temperatūroje 16 vai. Reakcijos mišinys sukoncentruojamas, praskiedžiamas 1:1 eterio ir heksanu mišiniu ir nufiltruojamas. Kieta medžiaga plaunama 500 ml 1:1 eterio ir heksanu mišiniu ir gaunama 16,7 g junginio A. Sumaišytas filtratas sukoncentruojamas, ir nufiltravus gaunama 5,8 g junginio A (bendra išeiga 80 %). MS (M+H)+ 344.Example 224 A mixture of compound A (55.6 mmol, 19.2 g), 4-stanylpyridine (111 mmol, 40.9 g) and Pd (PPh 3 ) 4 (8.24 mmol, 9.6 g) in toluene (2000) ml) degassed and heated at 110 ° C for 16 hours. The reaction mixture was concentrated, diluted 1: 1 with ether and hexanes and filtered. The solid is washed with 500 mL of a 1: 1 mixture of ether and hexanes to give 16.7 g of compound A. The combined filtrate is concentrated to give 5.8 g of compound A (80% overall yield). MS (M + H) + 344.
291291
BrBr
ΛΛ
NN
(R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4[(t rif I uor meti I) sulf oni I]-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(trifluoromethyl) sulfone] -1 H -1,4-benzodiazepine (monohydrochloride)
333 pavyzdžio junginys (nelabai balta kieta medžiaga) 44 % išeiga pagaminamas iš 224 pavyzdžio junginio B pagal 224 pavyzdyje aprašytą junginio C gavimo metodiką (vietoj metansulfonilchlorido naudojant trifluormetansulfonilchloridą) ir 224 pavyzdyje aprašytą junginio D gavimo metodiką.Example 333 (off-white solid) is prepared in 44% yield from Example 224 Compound B according to the procedure described in Example 224 for the preparation of Compound C (using trifluoromethanesulfonyl chloride in place of methanesulfonyl chloride) and Example 224.
MS (M+H)+ 528.MS (M + H) < + > 528.
334 pavyzdysExample 334
CFCF.
(R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-3-(fenilmetil)-4(trifIuoracetiI)-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -4 (trifluoroacetyl) -1H-1,4-benzodiazepine ( monohydrochloride)
293293
B. (R)-2,3,4,5-Tetrahidro-3-(fenilmetil)-7-(4-piridinil)-1H-1,4benzodiazepinasB. (R) -2,3,4,5-Tetrahydro-3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine
Junginio A (16,7 g, 32 mmol) suspensija THF (250 ml) veikiama BH3THF (1,0 M THF). Mišinys virinamas su grįžtamu šaldytuvu 12 vai., ir skaldomas lėtai pridedant 6N HCI (500 ml). THF nugarinamas sumažintame slėgyje, o likęs tirpalas pašarminamas lėtai pilant koncentruotą NaOH. Vandeninė fazė ekstrahuojama 10 % IPA-CH2CI2 (3 x 300 ml), džiovinamas Na2SO4 ir sukoncentravus išskiriama 9,0 g (90 % išeiga) junginio B. MS (M + H)+ 316.A suspension of Compound A (16.7 g, 32 mmol) in THF (250 mL) was treated with BH 3 in THF (1.0 M THF). The mixture was refluxed for 12 h and quenched by slow addition of 6N HCl (500 mL). The THF was evaporated under reduced pressure and the remaining solution was basified by slow addition of concentrated NaOH. The aqueous phase was extracted with 10% IPA-CH 2 Cl 2 (3 x 300 mL), dried over Na 2 SO 4, and concentrated to give 9.0 g (90% yield) of Compound B. MS (M + H) + 316.
C. (R)-2,3,4,5-Tetrahidro-4-(metilsulfonil)-3-(fenilmetil)-7-(4-piridinil)1 H-1,4-benzodiazepinas j junginio B (28,5 mmol, 9,0 g) tirpalą CH2CI2 (200 ml) pridedama TEA (142,5 mmol, 20 ml) ir metansulfonilchlorido (37,5 mmol, 2,9 ml). Mišinys maišomas kambario temperatūroje 1 vai., supilamas j 2N NaOH (500 ml) ir ekstrahuojamas 10 % IPA-CH2CI2 (3 x 250 ml). Sumaišyti organiniai sluoksniai džiovinami Na2SO4, koncentruojami, ir aceotropiškai nudistiliavus su toluenu gaunamas junginys C.C. (R) -2,3,4,5-Tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine, Compound B (28.5) mmol, 9.0 g) in CH 2 Cl 2 (200 mL) was added TEA (142.5 mmol, 20 mL) and methanesulfonyl chloride (37.5 mmol, 2.9 mL). The mixture was stirred at room temperature for 1 h, poured into 2N NaOH (500 mL) and extracted with 10% IPA-CH 2 Cl 2 (3 x 250 mL). The combined organic layers were dried over Na 2 SO 4 , concentrated, and aceotropically distilled off with toluene to give Compound C.
D. (R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(fenilmetil)-7-(4-piridinil)-1H-1,4-benzodiazepinas (dihidrochloridas)D. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -7- (4-pyridinyl) -1H-1 , 4-benzodiazepine (dihydrochloride)
Negrynintas junginys C ištirpinamas 300 ml 1:1 AcOH:CH2CI2 kartu su NaBH(OAc)3 (123 mmol, 26 g) ir 4-formilimidazolu (123 mmol, 11,8 g), ir mišinys šildomas 55 °C temperatūroje 3 vai. Reakcijos mišinys koncentruojamas, praskiedžiamas 2N NaOH (500 ml) ir ekstrahuojamas 10 % IPA-CH2CI2 (3 x 250 ml). Sumaišyti organiniai sluoksniai nugarinami, o liekana gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). TFA druska paverčiama HCI druska, panaudojant 1N HCI (2 x 150 ml), ir gaunamas junginys D, kuris yra geltona kieta medžiaga (2,9 g, 18 %, skaičiuojant pagal junginj B). MS (M + H)+ 491.The crude compound C was dissolved in 300 mL of 1: 1 AcOH: CH 2 Cl 2 with NaBH (OAc) 3 (123 mmol, 26 g) and 4-formylimidazole (123 mmol, 11.8 g) and the mixture was heated at 55 ° C. 3 or. The reaction mixture was concentrated, diluted with 2N NaOH (500 mL) and extracted with 10% IPA-CH 2 Cl 2 (3 x 250 mL). The combined organic layers were evaporated and the residue purified by preparative HPLC (gradient of aqueous methanol to 0.1% TFA). The TFA salt was converted to the HCl salt using 1N HCl (2 x 150 mL) to give Compound D as a yellow solid (2.9 g, 18% based on Compound B). MS (M + H) < + > 491.
336-343 pavyzdžiai336-343 examples
294294
336-343 pavyzdžių junginiai pagaminami iš atitinkamo sulfonilchlorido ir 335 pavyzdžio junginio B pagal 335 pavyzdyje aprašytą junginių C ir D sintezės metodiką (336-338 pavyzdžiai) arba iš 248 pavyzdžio junginio C pagal 317 pavyzdyje aprašytą junginio A sintezės metodiką (nuo 0 °C iki kambario temperatūros) ir 335 pavyzdyje aprašytą junginio D sintezės metodiką (339-343 pavyzdžiai).Examples 336-343 are prepared from the corresponding sulfonyl chloride and Example 335 Compound B according to Example 335 Synthesis of Compounds C and D (Examples 336-338) or Example 248 Compound C according to Example 317 Synthesis Method (0 ° C to 0 ° C). room temperature) and the procedure for the synthesis of compound D described in Example 335 (Examples 339-343).
Pvz.For example,
336 (R)-2,3,4,5-Tetrahidro-1(1 H-imi dazol-4-ilmetil)-3(fenilmetil)-7-(4-piridinil)-4(2-ti eni Isulfonil)-1 H-1,4benzodiazepinas (dihidrochloridas) BMS-218962336 (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (4-pyridinyl) -4- (2-thienesulfonyl) - 1H-1,4-benzodiazepine (dihydrochloride) BMS-218962
337 (R)-2,3,4,5-Tetrahidro-1(1 H-imidazol-4-ilmetil)-3(fenilmetil)-4-(feniisulfonil)7-(4-piridinil)-1 H-1,4benzodiazepinas (dihidrochloridas) BMS-218963337 (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) 7- (4-pyridinyl) -1H-1, 4-Benzodiazepine (dihydrochloride) BMS-218963
Masių spektras m/z 542 (M + H) m/z 536 (M + H)Mass spectrum m / z 542 (M + H) m / z 536 (M + H)
295295
338 (R)-2,3,4,5-Tetrahidro-1’ (1 H-imidazol-4-ilmetil)-3(fenilmetil)-4(propilsulfonil)-7-(4piridinil)-1 H-1,4benzodiazepinas (dihidrochloridas) BMS-219395338 (R) -2,3,4,5-Tetrahydro-1 '(1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -4 (propylsulfonyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine (dihydrochloride) BMS-219395
339 (R)-7-Ciano-2,3,4,5tetrahi dro-1 -(1 H-imidazol4-ilmetil)-3-(fenilmetil)~4[(3,5-dimetilizoksazol-4il)suifonil]-1 H-1,4benzodiazepinas (dihidrochloridas) BMS-220904339 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(3,5-dimethylisoxazol-4-yl) sulfonyl] -1 H-1,4-benzodiazepine (dihydrochloride) BMS-220904
340 (R)-7-Ciano-4-[(4cianofenil)sulfonii]-2,3,4,5tetrahidro-1 -(1 H-imidazol4-ilmetil)-3-(fenilmetil)-1H1,4-benzodiazepinas (dihidrochloridas) BMS-221604340 (R) -7-Cyano-4 - [(4-cyanophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine (dihydrochloride) ) BMS-221604
341 (R)-7-Ciano-2,3,4,5tetrahidro-1 -(1 H-imidazol4-ilmetil)-3-(fenilmetil)-4[2,2,2-trifluoretil)sulfonil]1 H-1,4-benzodiazepinas (dihidrochloridas)341 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- [2,2,2-trifluoroethyl) sulfonyl] 1H-1 , 4-benzodiazepine (dihydrochloride)
BMS-221764BMS-221764
m/z 539 (M + H) m/z 509 (M + H) m/z 502 (M + H)m / z 539 (M + H) m / z 509 (M + H) m / z 502 (M + H)
296296
342 (R)-[(5-Brom-2tienil)sulfonil j-7-ciano2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-3(fenilmetil)-l H-1,4benzodiazepinas (dihidrochloridas) BMS-221766342 (R) - [(5-Bromo-2-thienyl) sulfonyl] -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine ( dihydrochloride) BMS-221766
343 (R)-7-Ciano-2,3,4,5tetrahidro-1 -(1 H-imidazol 4-ilmetil)-4-[(4metoksifenil)sulfonil]-3(fenilmetil)-1H-1,4benzodiazepinas (dihidrochloridas) BMS-221970343 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4-methoxyphenyl) sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) ) BMS-221970
344 pavyzdys344 Example
m/zm / z
569 (M+H) m/z 514 (M + H)569 (M + H) m / z 514 (M + H)
N-[[7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)1H-1,4-benzodiazepin-3-il]metil]benzamidas (dihidrochloridas)N - [[7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) 1H-1,4-benzodiazepin-3-yl] methyl] benzamide (dihydrochloride)
A. N-[[7-Brom-2,3,4,5-tetrahidro-4-(metilsulfonil)-1 H-1,4benzodiazepin-3-il]metil]benzamidasA. N - [[7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1H-1,4-benzodiazepin-3-yl] methyl] benzamide
297297
J 305 pavyzdžio junginio C (50 mg, 0,15 mmol) tirpalą metileno chloride (10 ml) pridedama 2,6-di-irei-butil-4-metilpiridino (62 mg, 0,30 mmol). Tirpalas N2 atmosferoje atšaldomas iki -40 °C. Pridedama triflo rūgšties anhidrido (0,85 ml, 0,30 mmol), ir tirpalas maišomas 1 vai. N2 atmosferoje -40 °C temperatūroje. Per vamzdelį prileidžiama dujinio NH3, ir 10 min. -40 °C temperatūroje burbuliukais leidžiamas NH3. Tirpalas lėtai sušildomas iki kambario temperatūros visą laiką leidžiant NH3. Įpilama etilo eterio (30 ml) ir sotaus vandeninio natrio rūgščiojo karbonato tirpalo (30 ml), ir atskiriami sluoksniai. Organinis sluoksnis plaunamas 1N vandeniniu HCI. Vandeninis sluoksnis pašarminamas 5N vandeniniu NaOH, ir produktas ekstrahuojamas metileno chloridu (30 ml). Organinis sluoksnis džiovinamas (Na2SO4) ir sukoncentruojamas iki 5 ml. Pridedama benzenkarboksirūgšties (26 mg, 0,21 mmol) ir EDC (40 mg, 0,21 mmol), tirpalas maišomas 16 vai. ir koncentruojamas. Liekana chromatografuojama (sparčioji chromatografija per silikagelį, 1:5-1:1 etilacetatas:heksanas) ir gaunama 15 mg (16 % dviems stadijoms) junginio A, kuris yra balta kieta medžiaga. MS (M + H)+ 439.To a solution of Example 305 Compound C (50 mg, 0.15 mmol) in methylene chloride (10 mL) was added 2,6-di-butyl-butyl-4-methylpyridine (62 mg, 0.30 mmol). The solution is cooled to -40 ° C under N 2 . Triflic acid anhydride (0.85 mL, 0.30 mmol) was added and the solution was stirred for 1 h. In N 2 atmosphere at -40 ° C. Gaseous NH 3 is bubbled through the tube for 10 minutes. Bubbles are bubbled with NH 3 at -40 ° C. The solution is slowly warmed to room temperature with continuous NH 3 . Add ethyl ether (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) and separate the layers. The organic layer was washed with 1N aqueous HCl. The aqueous layer was basified with 5N aqueous NaOH and the product was extracted with methylene chloride (30 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated to 5 mL. Benzoic acid (26 mg, 0.21 mmol) and EDC (40 mg, 0.21 mmol) were added and the solution was stirred for 16 h. and concentrated. The residue was chromatographed (flash chromatography on silica gel, 1: 5-1: 1 ethyl acetate: hexane) to give 15 mg (16% for two steps) of Compound A as a white solid. MS (M + H) + 439.
B. N-[[7-Brom-2,3,4,5-tetrahidro-1-(1 H-imidazol-4-ilmetil)-4(metilsuIfonil)-1H-1,4benzodiazepin-3-il]metil]benzamidas (dihidrochloridas)B. N - [[7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 (methylsulfonyl) -1H-1,4-benzodiazepin-3-yl] methyl] benzamide (dihydrochloride)
Junginys B (balta kieta medžiaga) 16 % išeiga pagaminamas pagaminamas pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką.Compound B (white solid) is prepared in 16% yield using the procedure described in Example 224 for the preparation of compound D.
MS (M + H)+ 518.MS (M + H) < + > 518.
.·· 345 pavyzdys. ·· Example 345
298298
(R)-7”Ciano-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-N,N-dimetil-3(fenilmetil)-4H-1,4-benzodiazepin-4-sulfonamidas (hidrochloridas)(R) -7 "Cyano-1,2,3,5-tetrahydro-1- (1 H -imidazol-4-ylmethyl) -N, N-dimethyl-3 (phenylmethyl) -4 H -1,4-benzodiazepine-4 -sulfonamide (hydrochloride)
A. (R)-7-Ciano-1,2,3,5-tetrahidro-N,N-dimetil-3-(fenilmetil)-4H-1,4benzodiazepin-4-sulfonamidas j 248 pavyzdžio junginio C (0,2 g, 0,75 mmol) ir DIEA (0,19 ml, 1,13 mmol) tirpalą acetonitrile (3 ml) 0 °C temperatūroje argono atmosferoje pridedama dimetilsulfamoilchlorido (0,12 ml, 0,16 g, 1,13 mmol). Pamaišius 16 vai. kambario temperatūroje, reakcijos mišinys praskiedžiamas chloroformu (20 ml) ir NaHCO3 (5 ml). Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas chloroformu (2 x 20 ml). Sumaišyti organiniai ekstraktai plaunami NaHCO3 (2x5 ml), vandeniu (1x10 ml) ir sočiu NaCl (2 x 10 ml), džiovinami MgSO4, nufiltruojami ir koncentruojami. Liekana gryninama sparčiosios chromatografijos metodu per silikagelio kolonėlę, eliuuojamą 30 % EtOAc heksane, ir gaunamas junginys A, kuris yra geltona alyva (0,14 g, 51 %). MS (M + H)+ = 371+.A. (R) -7-Cyano-1,2,3,5-tetrahydro-N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonamide, m.p. dimethylsulfamoyl chloride (0.12 mL, 0.16 g, 1.13 mmol) was added to a solution of gIE, 0.75 mmol) and DIEA (0.19 mL, 1.13 mmol) in acetonitrile (3 mL) at 0 ° C under argon. . After stirring for 16 hours. at room temperature, the reaction mixture was diluted with chloroform (20 mL) and NaHCO 3 (5 mL). The layers were separated and the aqueous layer was extracted with chloroform (2 x 20 mL). The combined organic extracts were washed with NaHCO 3 (2 x 5 mL), water (1 x 10 mL) and saturated NaCl (2 x 10 mL), dried over MgSO 4 , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 30% EtOAc in hexane to give Compound A as a yellow oil (0.14 g, 51%). MS (M + H) < + > = 371 + .
B. (R)-7-Ciano-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-N,Ndimetil-3-(fenilmetil)-4H-1,4-benzodiazepin-4-sulfonamidas (hidrochloridas)B. (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine 4-sulfonamide (hydrochloride)
Junginio A (0,068 g, 0,18 mmol), 4-formilimidazolo (0,017 g, 0,18 mmol) ir AcOH (0,5 ml) tirpalas dichloretane (0,5 ml) ir 3A molekuliai tinkleliai virinami su grįžtamu šaldytuvu 1 vai. Pridedama natrio triacetoksiborhidrido (0,038 g, 0,18 mmol). Kasdien (viso 6 dienas) vėl pridedama aldehido irA solution of Compound A (0.068 g, 0.18 mmol), 4-formylimidazole (0.017 g, 0.18 mmol) and AcOH (0.5 mL) in dichloroethane (0.5 mL) and 3A molecules was heated under reflux for 1 hour. . Sodium triacetoxyborohydride (0.038 g, 0.18 mmol) was added. Daily (for a total of 6 days) aldehyde and
299 natrio triacetoksiborhidrido (po 1 ekv.). Pamaišius 6 dienas, mišinys praskiedžiamas CHCb (10 ml), NH4OH (5 ml) ir NaHCO3 (5 ml) ir maišomas 30 min. Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCb (3 x 30 ml). Sumaišyti organiniai ekstraktai džiovinami MgSO4, nufiltruojami ir koncentruojami. Produktas gryninamas preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas), ir gaunamas junginys B, kuris yra geltona kieta medžiaga (40 mg, 50 %).299 sodium triacetoxyborohydride (1 eq each). After stirring for 6 days, the mixture was diluted with CHCl 3 (10 mL), NH 4 OH (5 mL) and NaHCO 3 (5 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl 3 (3 x 30 mL). The combined organic extracts were dried over MgSO 4 , filtered, and concentrated. The product was purified by preparative HPLC (gradient from aqueous methanol to 0.1% TFA) to give Compound B as a yellow solid (40 mg, 50%).
MS (M + H)+ = 451.MS (M + H) <+> = 451.
346 pavyzdys346 Example
(R)-7-Ciano-1,2,3,5-tetrahidro-N,N-dimetil-1-[(1-metil-1H-imidazol-5il)metil]-3-(fenilmetil)-4H-1,4-benzodiazepin-4-sulfonamidas (hidrochloridas)(R) -7-Cyano-1,2,3,5-tetrahydro-N, N-dimethyl-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- (phenylmethyl) -4H-1 , 4-benzodiazepine-4-sulfonamide (hydrochloride)
345 pavyzdžio junginio A (0,068 g, 0,18 mmol), 1-metil-5formilimidazolo (0,041 g, 0,36 mmol), AcOH (0,2 ml) tirpalas dichloretane (0,5 ml) su 3A molekuliniais tinkleliais šildomas 2 vai. Pridedama natrio triacetoksiborhidrido (0,076 g, 0,36 mmol). Po 1,5, 3 ir 4,5 vai. vėl pridedama aldehido ir natrio triacetoksiborhidrido (po 2 ekv.). Pamaišius 2 dienas, mišinys praskiedžiamas CHCb (10 ml), NH4OH (5 ml) ir NaHCCb (5 ml) ir maišomas 30 min. Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCb (3 x 30 ml). Sumaišyti organiniai ekstraktai plaunami NaHCCb ir sočiu NaCl tirpalu (po 2 x 5 ml), džiovinami MgSO4, nufiltruojama ir koncentruojama. Produktas gryninamas atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas), ir pavertusA solution of Example 345 Compound A (0.068 g, 0.18 mmol), 1-methyl-5-formylimidazole (0.041 g, 0.36 mmol), AcOH (0.2 mL) in dichloroethane (0.5 mL) was heated to 2 with molecular mesh. or. Sodium triacetoxyborohydride (0.076 g, 0.36 mmol) was added. After 1.5, 3 is 4.5 or. aldehyde and sodium triacetoxyborohydride (2 eq. each) are added again. After stirring for 2 days, the mixture was diluted with CHCl 3 (10 mL), NH 4 OH (5 mL) and NaHCO 3 (5 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl 3 (3 x 30 mL). The combined organic extracts were washed with NaHCCb and saturated aqueous NaCl (2 x 5 mL), dried over MgSO 4, filtered and concentrated. The product was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and
300300
HCI druska gaunamas 246 pavyzdžio junginys, kuris yra gelsva kieta medžiaga (32 mg, 38 %).The HCl salt gives Example 246 as a yellowish solid (32 mg, 38%).
MS (M + H)+ 465.MS (M + H) + 465.
347 pavyzdys347 Example
(R)-7-Chlor-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazol-5-il)metil]-4(metilsulfonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 (methylsulfonyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine (monohydrochloride)
A. (R)-7-Chlor-2,3,4,5-tetrahidro-3-(fenilmetil)-1 H-1,4-benzodiazepin2,5-dionasA. (R) -7-Chloro-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione
Chlorizatoinės rūgšties anhidrido (25 g, 0,126 mol), D-Phe metilo esterio (27,2 g, 0,126 mol) ir DMAP (0,4 g) mišinys piridine (275 ml) virinamas su grįžtamu šaldytuvu 5 dienas. Mišinys sukoncentruojamas ir ištirpinamas CH2CI2. Šis tirpalas plaunamas 10 % HCI (3 x 100 ml), džiovinamas MgSO4, nufiltruojama ir sukoncentravus gaunama rožinė kieta medžiaga (39 g), kurią perkristalinus 3 kartus iš eterio/CH2Cl2, gaunamas junginys A (15,0 g, 40 %). MS (M + H)+= 301+.A mixture of chloro-anhydride anhydride (25 g, 0.126 mol), D-Phe methyl ester (27.2 g, 0.126 mol) and DMAP (0.4 g) in pyridine (275 ml) was refluxed for 5 days. The mixture was concentrated and dissolved in CH2Cl2. This solution was washed with 10% HCl (3 x 100 mL), dried over MgSO 4 , filtered and concentrated to a pink solid (39 g) which was recrystallized 3 times from ether / CH 2 Cl 2 to give compound A (15.0 g, 40 mL). %). MS (M + H) < + > = 301 + .
B. (R)-7-Chlor-2,3,4,5-tetrahidro-3-(fenilmetil)-1H-1,4benzodiazepinas j junginį A (20 g, 66,5 mmol) THF (200 ml) pridedama borano THF (1M, 300 ml). Mišinys virinamas su grįžtamu šaldytuvu 1 dieną, atšaldomas ledo vonioje, lėtai jplama meOH (115 ml) ir mišinys sukoncentruojamas.B. (R) -7-Chloro-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine: Compound A (20 g, 66.5 mmol) in THF (200 mL) was added with borane. THF (1M, 300 mL). The mixture was refluxed for 1 day, cooled in an ice bath, slowly stirred with MeOH (115 mL) and concentrated.
301301
Liekana praskiedžiama MeOH (200 ml), pridedama 40 ml 25 % HCI, mišinys virinamas su grįžtamu šaldytuvu 2 vai., ir sukoncentravus iki sausos liekanos gaunama nelabai balta kieta medžiaga, kuri trinama kelis kartus su eteriu ir suspenduojama vandenyje. J suspensiją pridedama NaOH (1N iki pH 11), susidariusi kieta medžiaga nufiltruojama, plaunama eteriu, ir išdžiovinus vakuume gaunama 7,9 g junginio B, kuris yra gelsva kieta medžiaga. Sukoncentravus filtratą, gaunama dar 10,5 g junginio B, kuris yra gelsva kieta medžiaga (100 %). MS (M + H)+ = 273.The residue was diluted with MeOH (200 mL), added with 40 mL of 25% HCl, refluxed for 2 hours, and concentrated to dryness to give an off-white solid which was triturated several times with ether and suspended in water. NaOH (1N to pH 11) is added to the suspension, the resulting solid is filtered off, washed with ether and dried in vacuo to give 7.9 g of compound B, which is a yellowish solid. Concentration of the filtrate yields another 10.5 g of compound B, which is a yellowish solid (100%). MS (M + H) <+> = 273.
C. (R)-7-Chlor-2,3,4,5-tetrahidro-4-(metilsulfonil)-3-(fenilmetil)-1H1,4-benzodiazepinas j junginio B (10 g, 36,6 mmol) tirpalą CH2CI2 (130 ml) 0 °C temperatūroje argono atmosferoje sulašinamas metansulfonilchlorido (3,68 ml, 47,6 mmol) tirpalas CH2CI2 (20 ml). Pamaišius kambario temperatūroje 16 vai., reakcijos mišinys praskiedžiamas vandeniu (20 ml). Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CH2CI2 (2 x 40 ml). Sumaišyti organiniai sluoksniai plaunami vandeniu (1 x 30 ml), KHSO4 (2 x 30 ml), vandeniu (1 x 30 ml), NaHCO3 (2 x 30 ml), sočiu NaCl tirpalu (1 x 30 ml), džiovinami MgSO4, nufiltruojama ir sukoncentravus gaunama geltonai ruda alyva. Ši alyva kristalinama iš EtOAc/heksanų, geltona kieta medžiaga trinama su heksanu, ir išdžiovinus gaunamas junginys C (10,6 g, 82 %). MS: (M + H)+ = 351.C. (R) -7-Chloro-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H1,4-benzodiazepine in a solution of compound B (10 g, 36.6 mmol) CH 2 Cl 2 (130 mL) at 0 ° C was added dropwise a solution of methanesulfonyl chloride (3.68 mL, 47.6 mmol) in CH 2 Cl 2 (20 mL) under argon. After stirring at room temperature for 16 h, the reaction mixture was diluted with water (20 mL). The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (2 x 40 mL). The combined organic layers were washed with water (1 x 30 mL), KHSO 4 (2 x 30 mL), water (1 x 30 mL), NaHCO 3 (2 x 30 mL), brine (1 x 30 mL), dried over MgSO 4 4 , the oil is filtered off and concentrated to a yellow-brown oil. This oil was crystallized from EtOAc / hexanes, triturated with hexane to give a yellow solid, compound C (10.6 g, 82%). MS: (M + H) < + > = 351.
D. (R)-7-Chlor-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazol-5-il)metil]-4(metilsulfonil)-3-(fenilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas) j junginio C (4,0 g, 11,4 mmol), 1-metil-5-formilimidazolo (2,6 g, 22,8 mmol) ir AcOH (22 ml) tirpalą CH2CI2 (22 ml) pridedama natrio triacetoksiborhidrido (4,83 g, 22,8 mmol). Pamaišius 2 dienas, mišinys praskiedžiamas CH2CI2 (30 ml), NH4OH (30 ml) ir NaHCO3 (30 ml) ir maišomas 30 min. Atskiriami sluoksniai, vandeninis sluoksnis ekstrahuojamas CH2CI2 (3 x 50 ml). Sumaišyti organiniai ekstraktai plaunamiD. (R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 (methylsulfonyl) -3- (phenylmethyl) - 1H-1,4-benzodiazepine (monohydrochloride) in a solution of compound C (4.0 g, 11.4 mmol), 1-methyl-5-formylimidazole (2.6 g, 22.8 mmol) and AcOH (22 mL) CH 2 Cl 2 (22 mL) was added sodium triacetoxyborohydride (4.83 g, 22.8 mmol). After stirring for 2 days, the mixture was diluted with CH 2 Cl 2 (30 mL), NH 4 OH (30 mL) and NaHCO 3 (30 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic extracts are washed
302302
NaHCO3, vandeniu, sočiu NaCl tirpalu (3 x 30 ml), džiovinami MgSO4, nufiltruojama ir sukoncentravus gaunama 6,0 g putų pavidalo kietos medžiagos. Šis produktas gryninamas perleidžiant per sparčiosios chromatografijos kolonėlę, eliuuojamą 7/3 EtOAc/heksanu (1 I) ir 19/1 CHCI3/MeOH (2 I); gaunama balta putų pavidalo medžiaga, kuri veikiama 1N HCI eteryje (2 x 25 ml). Kieta medžiaga trinama su eteriu, ir išdžiovinus gaunamas junginys D, kuris yra gelsva kieta medžiaga (3,44 g, 63 %).NaHCO 3 , water, saturated NaCl solution (3 x 30 mL), dried over MgSO 4 , filtered and concentrated to give 6.0 g of a foamy solid. This product was purified by flash column chromatography eluting with 7/3 EtOAc / hexane (1 L) and 19/1 CHCl 3 / MeOH (2 L); a white foam is obtained which is treated with 1N HCl in ether (2 x 25 mL). The solid is triturated with ether to give compound D, which is a yellowish solid (3.44 g, 63%).
MS (M + H)+ 445.MS (M + H) + 445.
348 pavyzdys348 Example
(R)-7-Chlor-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(f eni I m eti I)-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1 , 4-benzodiazepine (monohydrochloride)
348 pavyzdžio junginys (gelsva kieta medžiaga) 70 % išeiga pagaminamas iš 247 pavyzdžio junginio C pagal 247 pavyzdyje aprašytą junginio D gavimo metodiką, naudojant 4-formilimidazolą ir virinant su grįžtamu šaldytuvu 1 vai. bei maišant kambario temperatūroje 16 vai.Example 348 (yellowish solid) Prepared in 70% yield from Example 247 Compound C according to the procedure described in Example 247 for the preparation of Compound D using 4-formylimidazole and refluxing for 1 hour. and stirring at room temperature for 16 hours.
MS (M + H)+= 431.MS (M + H) < + > = 431.
349 pavyzdys349 Example
303303
(R)-7-Chlor-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazol-5-ii)metil]-4(f eni Is ulf oni l)-3-(f eni I meti I)-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4- (phenylsulfonyl) -3- ( Phenylmethyl I) -1H-1,4-benzodiazepine (monohydrochloride)
249 pavyzdžio junginys (gelsva kieta medžiaga) pagaminamas iš 247 pavyzdžio junginio B pagal reakcijų seką, naudojamą tokiems junginiams gauti: 247 pavyzdžio junginiui C, naudojant benzensulfonilchloridą, maišant kambario temperatūroje 3 vai. ir chromatografuojant per silikagelj, eliuuojamą 7/3 heksanais/EtOAc (57 %); 247 pavyzdžio junginiui D, maišant kambario temperatūroje 12 vai ir maišant 2 dienas, pridėjus kitą hidrido ir aldehido ekvivalentą, ir gryninant atvirkštinių fazių HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas; 52 %).Example 249 (yellowish solid) is prepared from Example 247 by Compound B according to the reaction sequence used to prepare Example 247, Compound C using benzenesulfonyl chloride, with stirring at room temperature for 3 hours. and chromatography over silica gel eluting with 7/3 hexanes / EtOAc (57%); Example 247 Compound D was stirred at room temperature for 12 hours and stirred for 2 days with the addition of another equivalent of hydride and aldehyde and purified by reverse phase HPLC (gradient of aqueous methanol to 0.1% TFA; 52%).
MS (M + H)+ = 507.MS (M + H) <+> = 507.
350 pavyzdysExample 350
304 (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(piridin-3i l m eti I )-4- (m etilsulf oni I)-1 H-1,4-benzodiazepinas (tetrahidrochloridas)304 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4- (methylsulfone I) -1 H -1,4-benzodiazepine (tetrahydrochloride)
A. (R)-7-Brom-2,3,4,5-tetrahidro-3-(piridin-3-ilmetil)-1 H-1,4benzodiazepinasA. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (pyridin-3-ylmethyl) -1H-1,4-benzodiazepine
J (R)-7-b rom-2,3,-4,5-tetrahi dro-3-(piri din-3-ilmeti I) -1H -1,4-benzodiazepin2,5-diono (pagaminto iš 5-bromizatoinės rūgšties anhidrido ir D-3piridilananino metilo esterio hidrochlorido pagal 226 pavyzdžio junginio C sintezės metodiką: 11,2 g, 32,4 mmol) tirpalą THF (50 ml) 0 °C temperatūroje sulašinamas boranas-THF (1M, 168 ml, 0,168 mmol). Kai nustoja virti, mišinys virinamas su grįžtamu šaldytuvu 4 vai., atšaldomas iki 0 °C ir pridedamas papildomas 1M borano-TFH ekvivalentas (32,4 ml, 32,4 mmol). Mišinys virinamas su grįžtamu šaldytuvu 2 vai., atšaldomas iki 0 °C, reakcija stabdoma lašinant 6N HCI (125 ml), o po to mišinys virinamas su grįžtamu šaldytuvu 1 vai. Reakcijos mišinys atšaldomas iki kambario temperatūros ir koncentruojamas vakuume. Kieta medžiaga ištirpinama vandenyje (100 ml), ir tirpalas ekstrahuojamas Et2O (3 x 100 ml). Vandeninis sluoksnis atšaldomas iki 0 °C, ir pilamas natrio hidroksidas (50 %) tol, kol tirpalas pasidaro šarminis. Šis šarminis tirpalas ekstrahuojamas 9/1 CH2CI2/iPrOH (3 x 200 ml). Sumaišyti organiniai ekstraktai džiovinami (MgSO4), nufiltruojami, ir sukoncentravus vakuume gaunamas junginys A (8,0 g, 80 %). MS (M + H) + 318,320.J (R) -7-Bromo-2,3,4,5-tetrahydro-3- (pyridine-3-methyl) -1H-1,4-benzodiazepine-2,5-dione (prepared from 5 bromoacetic anhydride and D-3-pyridylalanine methyl ester hydrochloride according to the procedure for the synthesis of Example 226 Compound C: 11.2 g, 32.4 mmol) in THF (50 mL) at 0 ° C dropwise borane-THF (1M, 168 mL, 0.168 mmol ). When it ceases, the mixture is refluxed for 4 hours, cooled to 0 ° C and an additional 1M borane-TFH equivalent (32.4 mL, 32.4 mmol) is added. The mixture was refluxed for 2 h, cooled to 0 ° C, quenched with 6N HCl (125 mL), and then refluxed for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The solid is dissolved in water (100 mL) and the solution is extracted with Et 2 O (3 x 100 mL). The aqueous layer is cooled to 0 ° C and sodium hydroxide (50%) is added until the solution becomes alkaline. This alkaline solution is extracted with 9/1 CH 2 Cl 2 / iPrOH (3 x 200 mL). The combined organic extracts were dried (MgSO 4 ), filtered, and concentrated in vacuo to give Compound A (8.0 g, 80%). MS (M + H) + 318.320.
B. (R)-7-Ciano-2,3,4,5-tetrahidro-3-(piridin-3-ilmetil)-1 H-1,4benzodiazepinasB. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (pyridin-3-ylmethyl) -1H-1,4-benzodiazepine
J junginio A (8,3 g, 26 mmol) tirpalą NMP (41,5 ml), kuris buvo išvalytas leidžiant azotą, kambario temperatūroje pridedama vario cianido (2,6 g, 29 mmol). Mišinys kaitinamas iki 195 °C 3 vai., atšaldomas iki kambario temperatūros ir skaldomas kone. NH4OH (100 ml). įpilama vandens, ir mišinys ekstrahuojamas 9/1 CH^IViPrOH (3 x200 ml). Sumaišyti organiniai ekstraktai koncentruojami vakuume. Liekana ištirpinama 6N HCI (200 ml), ir tirpalas ekstrahuojamas etilacetatu (4 x 200 ml). VandeninisTo a solution of Compound A (8.3 g, 26 mmol) in NMP (41.5 mL) which was purged with nitrogen was added copper cyanide (2.6 g, 29 mmol) at room temperature. The mixture is heated to 195 ° C for 3 hours, cooled to room temperature and quenched. NH 4 OH (100 mL). water is added and the mixture is extracted with 9/1 CH2Cl2 (3 x 200 mL). The combined organic extracts are concentrated in vacuo. The residue was dissolved in 6N HCl (200 mL) and the solution was extracted with ethyl acetate (4 x 200 mL). Aqueous
305 tirpalas atšaldomas iki 0 °C, pašarminamas koncentruotu amonio hidroksidu ir ekstrahuojamas 9/1 C^CI^iPrOH (3 x 200 ml). Sumaišyti organiniai ekstraktai džiovinami (Na2SO4), nufiltruojama ir koncentruojama vakuume. Liekana gryninama sparčiosios chromatografijos metodu (laipsniškas gradientas, etilacetatas, 19/1 CFkCI^iPrOH, 4/1/0,2 CH^I^MeOH/trietilaminas). Sukoncentravus tinkamas frakcijas vakuume, gaunamas junginys B (4,1 g, 60 %), kuris yra ruda kieta medžiaga. MS (M + H)+ 265.The solution of 305 was cooled to 0 ° C, basified with concentrated ammonium hydroxide and extracted with 9/1 C 1 Cl 2 / iPrOH (3 x 200 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient gradient, ethyl acetate, 19/1 CFKCl2 / iPrOH, 4/1/1 0.2 CH2Cl2 / MeOH / triethylamine). Concentration of the appropriate fractions in vacuo afforded compound B (4.1 g, 60%) as a brown solid. MS (M + H) + 265.
C. (R)-7-Ciano-2,3,4,5-tetrahidro-3-(piridin-3-ilmetil)-4-(metilsulfonil)1 H-1,4-benzodiazepinas j junginio B (0,070 g, 0,27 mmol) ir DIEA (0,14 ml, 0,80 mmol) tirpalą metileno chloride (2 ml) -78 °C temperatūroje sulašinamas metilsulfonilchloridas (0,031 ml, 0,39 mmol). Mišiniui leidžiama lėtai sušilti iki kambario temperatūros ir maišoma kambario temperatūroje 16 vai. Mišinys skaldomas 10 % NaHCO3 (10 ml), ir tirpalas ekstrahuojamas metileno chloridu (3 x 10 ml). Sumaišyti organiniai sluoksniai džiovinami (Na2SO4), nufiltruojama ir koncentruojama vakuume. Išgryninus liekaną sparčiosios chromatografijos metodu (19/1 metileno chloridas/iPrOH), gaunamas junginys C (0,064 g, 85 %), kuris yra kieta medžiaga. MS (M + H)+ 343.C. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (pyridin-3-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine, Compound B (0.070 g). A solution of 0.27 mmol) and DIEA (0.14 mL, 0.80 mmol) in methylene chloride (2 mL) was added dropwise at -78 ° C to methyl sulfonyl chloride (0.031 mL, 0.39 mmol). The mixture was allowed to warm slowly to room temperature and stirred at room temperature for 16 hours. The mixture was quenched with 10% NaHCO 3 (10 mL) and the solution was extracted with methylene chloride (3 x 10 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (19/1 methylene chloride / iPrOH) gave Compound C (0.064 g, 85%) as a solid. MS (M + H) < + > 343.
D. (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(piridin-3ilmetil)-4-(metilsulfonil)-1H-1,4-benzodiazepinas (tetrahidrochloridas)D. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4- (methylsulfonyl) -1H-1, 4-Benzodiazepine (tetrahydrochloride)
Į junginio C (0,055 g, 0,16 mmol) tirpalą 1/1 DCE ir acto rūgšties mišinyje (2 ml) su 3A molekuliniais tinkleliais pridedama 4-formilimidazolo (0,062 g, 0,64 mmol), ir mišinys maišomas 70 °C temperatūroje 1 vai. Pridedama natrio triacetoksiborhidrido (0,034 g, 0,32 mmol), ir mišinys maišomas 70 °C temperatūroje 30 min. Pridedama 4-formilimidazolo (0,032 g, 0,32 mmol), ir mišinys maišomas 70 °C temperatūroje 1 vai. Pridedama natrio triacetoksiborhidrido (0,34 g, 0,32 mmol), ir mišinys maišomas 70 °C temperatūroje 30 min. Pastarosios dvi stadijos pakartojamos šešis kartus. Mišinys atšaldomas iki kambario temperatūros, praskiedžiamas metilenoTo a solution of Compound C (0.055 g, 0.16 mmol) in 1/1 DCE / acetic acid (2 mL) with 3A molecular mesh was added 4-formylimidazole (0.062 g, 0.64 mmol) and the mixture was stirred at 70 ° C. 1 or. Sodium triacetoxyborohydride (0.034 g, 0.32 mmol) was added and the mixture was stirred at 70 ° C for 30 min. 4-Formylimidazole (0.032 g, 0.32 mmol) was added and the mixture was stirred at 70 ° C for 1 h. Sodium triacetoxyborohydride (0.34 g, 0.32 mmol) was added and the mixture was stirred at 70 ° C for 30 min. The latter two stages are repeated six times. The mixture was cooled to room temperature and diluted with methylene
306 chloridu (30 ml), nufiltruojamas ir filtratas koncentruojamas vakuume. Liekana praskiedžiama 25 % NH4OH (50 ml), ir tirpalas ekstrahuojamas CH2CI2 (2 x 200 ml). Sumaišyti organiniai ekstraktai džiovinami (Na2SO4), nufiltruojama ir koncentruojama vakuume. Liekana gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas), ir tinkamos frakcijos koncentruojamos vakuume. Liekana nugarinama iš CH3OH (1 ml) ir 1N HCI (1 ml) 4 kartus. Ši liekana ištirpinama CH3CN (1 ml) ir 1N HCI (1 ml), ir po liofilizavimo gaunamas junginys D (0,040 g, 50 %), kuris yra kieta medžiaga. Lyd. temp.: skyla virš 180 °C.306 chloride (30 mL) was filtered off and the filtrate was concentrated in vacuo. The residue was diluted with 25% NH 4 OH (50 mL) and the solution was extracted with CH 2 Cl 2 (2 x 200 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and the appropriate fractions concentrated in vacuo. The residue was evaporated from CH 3 OH (1 mL) and 1N HCl (1 mL) 4 times. This residue was dissolved in CH 3 CN (1 mL) and 1N HCl (1 mL) and lyophilized to give Compound D (0.040 g, 50%) as a solid. Lyd. temp .: decomposes above 180 ° C.
MS: (M + H)+ 423.MS: (M + H) < + >
[a]D = +89° (c = 0,39, CH3OH).[α] D = + 89 ° (c = 0.39, CH 3 OH).
Analizė išskaičiuota pagal C2iH22N6O2S · 1,4 H2O · 4 HCI.Analysis calculated for C 2 i H 22 N 6 O 2 S · 1.4 H 2 O · 4 HCl.
Išskaičiuota: C, 42,44; H, 4,90; N, 14,14.Found: C, 42.44; H, 4.90; N, 14.14.
Rasta: C, 42,44; H, 4,66; N, 14,01.Found: C, 42.44; H, 4.66; N, 14.01.
351 pavyzdysExample 351
(R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-2-ilmetil)-4-(metilsulfonil)-3(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-2-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) )
Produktas (nevisai balta kieta medžiaga) 54 % išeiga pagaminamas išThe product (off-white solid) is obtained in 54% yield
224 pavyzdžio junginio C ir 2-formilimidazolo pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką.Example 224 Compound C and 2-formylimidazole according to the procedure described in Example 1 for the preparation of compound D.
MS (M+H)+ = 476.MS (M + H) <+> = 476.
307307
352 pavyzdysExample 352
BrBr
N Me (R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-[(1 -metil-1 Himidazol-4-il)sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (trihidrochloridas)N, Me (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-1 Himidazol-4-yl) sulfonyl] - 3- (Phenylmethyl) -1H-1,4-benzodiazepine (trihydrochloride)
352 pavyzdžio junginys (nelabai balta kieta medžiaga) 54 % išeiga pagaminamas iš 224 pavyzdžio junginio B ir 1-metilimidazol-4-sulfonilchlorido pagal 224 pavyzdžio junginių C ir D gavimo metodikas.Example 352 (off-white solid) is prepared in 54% yield from Example 224 Compound B and 1-methylimidazole-4-sulfonyl chloride according to the procedure for Preparation 224 Compounds C and D.
MS (M + H)+ = 542.MS (M + H) <+> = 542.
353 pavyzdysExample 353
Cl <z Cl < z
NN
C hC h
O (R)-7-Chlor-2,3,4,5-tetrahidro-1-(1-metil-imidazol-5-ilmetil)-4-[(2morfolin-4-il-etil)-sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)O (R) -7-Chloro-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(2-morpholin-4-yl-ethyl) sulfonyl] -3 - (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
308308
A. (R)-7-Chlor-2,3,4,5-tetrahidro-4-(etenilsulfonil)-3-(fenilmetil)-1H1,4-benzodiazepinas j 4,4 g (16,1 mmol) 347 pavyzdžio junginio B tirpalą 75 ml metileno chlorido -78 °C temperatūroje argono atmosferoje sulašinama apie pusė 2,5 ml (24,2 mmol) 2-chlorsulfonilchlorido tirpalo 15 ml metileno chlorido. Tada greitai sulašinama 5 mi DIPEA, o po to likęs sulfonilohlorido tirpalas ir dar 2,4 ml DIPEA (viso 7,4 ml, 40,3 mmol). Gautas gelsvas tirpalas maišomas -78 °C temperatūroje 0,5 vai., tirpalui leidžiama sušilti iki kambario temperatūros ir nugarinamas iki pusės jo tūrio. Šis negryninto junginio A tirpalas vartojamas tolimesnėje stadijoje.A. (R) -7-Chloro-2,3,4,5-tetrahydro-4- (ethenylsulfonyl) -3- (phenylmethyl) -1H1,4-benzodiazepine, 4.4 g (16.1 mmol) of Example 347 To a solution of compound B in 75 mL of methylene chloride is added dropwise about -1.5 mL of a 2-chlorosulfonyl chloride solution in 15 mL of methylene chloride at -78 ° C under argon. Then 5 mL of DIPEA was added rapidly followed by the remaining sulfonyl chloride solution and another 2.4 mL of DIPEA (7.4 mL total, 40.3 mmol). The resulting yellowish solution was stirred at -78 ° C for 0.5 h, allowed to warm to room temperature and evaporated to half volume. This solution of crude compound A is used in the next step.
B. (R)-7-Chlor-2,3,4,5-tetrahidro-4-[(2-morfolin-4-il-etil)sulfonil]-3(fenilmetil)-l H-1,4-benzodiazepinas j junginio A tirpalą greitai sulašinamas morfolinas (15 mi), ir maišoma kambario temperatūroje per naktį. Reakcijos mišinys plaunamas vandeniu ir sočiu NaCl tirpalu, džiovinamas (MgSO4), ir nugarinus tirpiklį gaunama oranžinė alyvos pavidalo liekana, kuri gryninama sparčiosios chromatografijos metodu per silikagelį (5 % etilacetatas heksane); gaunama 3,9 g (54 %) junginio B, kuris yra balta putų pavidalo kieta medžiaga.B. (R) -7-Chloro-2,3,4,5-tetrahydro-4 - [(2-morpholin-4-yl-ethyl) sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine Morpholine (15 mL) was added dropwise to Compound A solution and stirred at room temperature overnight. The reaction mixture was washed with water and saturated NaCl solution, dried (MgSO 4 ), and evaporated to give an orange oil which was purified by flash chromatography on silica gel (5% ethyl acetate in hexane); 3.9 g (54%) of compound B is obtained which is a white foamy solid.
C. (R)-7-Chlor-2,3,4,5-tetrahidro-1-(1-metil-imidazol-5-ilmetil)-4-[(2morfolin-4-il-etil)sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas) j 3,9 g (8,7 mmol) junginio B tirpalą 40 ml metileno chlorido ir 4 ml acto rūgšties kambario temperatūroje; argono atmosferoje pridedama 3,8 g (34 mmol) 1-metil-5-imidazolkarboksaldehido. Pamaišius 0,5 vai., pridedama 1,9 g (9 mmoi) natrio triacetoksiborhidrido, ir tirpalas šildomas 40 °C temperatūroje. Papildomos 1,9 g hidrido porcijos pridedamos po 1 ir 2,5 vai. Po 4 vai. dar pridedama 1,0 g aldehido ir 1,9 g hidrido ir maišoma per naktį kambario temperatūroje. Reakcijos mišinys sausai nugarinamas, ir liekana praskiedžiama etilacetatu ir sočiu NaHCO3. Dalimis vėl pridedama kieto NaHCO3, kol vandeninis sluoksnis pasidaro šarminis. Organinis sluoksnisC. (R) -7-Chloro-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(2-morpholin-4-yl-ethyl) sulfonyl] -3 - (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) in a solution of 3.9 g (8.7 mmol) of compound B in 40 ml of methylene chloride and 4 ml of acetic acid at room temperature; 3.8 g (34 mmol) of 1-methyl-5-imidazolecarboxaldehyde are added under argon. After stirring for 0.5 h, 1.9 g (9 mmol) of sodium triacetoxyborohydride are added and the solution is heated to 40 ° C. Additional portions of 1.9 g of hydride are added after 1 and 2.5 hours. After 4 or. another 1.0 g of aldehyde and 1.9 g of hydride were added and stirred overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is diluted with ethyl acetate and saturated NaHCO 3 . Solid NaHCO 3 is added again in portions until the aqueous layer becomes alkaline. The organic layer
309 atskiriamas, o vandenins sluoksnis ekstrahuojamas etilacetatu dar du kartus. Sumaišytos organinės frakcijos plaunamos sočiu NaCl, džiovinamos (MgSO4), ir nugarinus tirpiklį gaunama klampi alyvos pavidalo liekana, kuri gryninama sparčiosios chromatografijos per silikageiį metodu (10 % metanolis chloroforme), o po to preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas), ir gaunama3,2 g laisvos bazės, kuri yra balta putų pavidalo kieta medžiaga. Į laisvo amino tirpalą etilacetate pridedamas perteklius 1M HCI eteryje, ir nufiltravus gautas baltas nuosėdas gaunama 3,2 g (63 %) junginio C, kuris yra balti milteliai.309 is separated and the aqueous layer is extracted twice more with ethyl acetate. The combined organic fractions were washed with saturated NaCl, dried (MgSO 4 ), and evaporated to give a viscous oil which was purified by flash chromatography on silica gel (10% methanol in chloroform) followed by preparative HPLC (0.1% aqueous methanol). TFA gradient) to give 3.2 g of free base as a white foamy solid. An excess of 1M HCl in ether was added to a solution of the free amine in ethyl acetate, and the resulting white precipitate was filtered off to give 3.2 g (63%) of Compound C as a white powder.
MS: (M + H)+ 544.MS: (M + H) < + > 544.
Analizė išskaičiuota pagal C27H34N5O3SCI · 2 HCI · H2O.Analysis calculated for C 27 H 34 N 5 O 3 SCI · 2 HCl · H 2 O.
Išskaičiuota: C, 51,07; H, 6,03; N, 11,03.Found: C, 51.07; H, 6.03; N, 11.03.
Rasta: C, 50,76; H, 5,94; N, 11,13.Found: C, 50.76; H, 5.94; N, 11.13.
354 pavyzdysExample 354
ClCl
HNHN
(R)-7-Chlor-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-[(2-morfolin-4-iletil)sulfonil]-3-(feniImetil)-lH-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-morpholin-4-yl-ethyl) sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
353 pavyzdžio junginys B (0,10 g, 0,22 mmol), 4-formilimidazolas (0,042 g, 0,32 mmol), 3A molekuliniai tinkleliai ir AcOH (0,3 ml) virinami su grįžtamu šaldytuvu dichloretane (0,3 ml) argono atmosferoje 2 vai. Pridedama natrio triacetoksiborhidrido (0,07 g, 0,32 mmol), ir mišinys virinamas su grjžtamu šaldytuvu 1 vai., maišomas kambario temperatūroje 16 vai. ir praskiedžiamas CHCI3, NH4OH ir NaHCO3 (po 5 ml). AtskiriamiExample 353 Compound B (0.10 g, 0.22 mmol), 4-formylimidazole (0.042 g, 0.32 mmol), molecular mesh 3A, and AcOH (0.3 mL) were refluxed in dichloroethane (0.3 mL). ) under argon atmosphere for 2 hours. Sodium triacetoxyborohydride (0.07 g, 0.32 mmol) was added and the mixture was refluxed for 1 h, stirred at room temperature for 16 h. and diluted with CHCl 3 , NH 4 OH and NaHCO 3 (5 mL each). Separated
310 luoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCb (2 x 20 ml). Sumaišyti organiniai ekstraktai plaunami vandeniu ir sočiu NaCl tirpalu (po 2 x 5 ml), džiovinami MgSO4l nufiltruojami ir koncentruojami. Liekana gryninama preparatinės HPLC metodu (vandeninio MeOH su 0,1 % TFA gradientas). Tinkamos frakcijos sukoncentruojamos, ir liekana nugarinama iš MeOH (1 ml) ir 1N HCI (1 ml) 3 kartus. Ši liekana ištirpinama vandenyje, ir po liofilizavimo gaunamas 354 pavyzdžio junginys (0,034 g, 29 %), kuris yra kieta medžiaga.310 layers, and the aqueous layer was extracted with CHCl3 (2 x 20 mL). The combined organic extracts were washed with water and saturated aqueous NaCl (2 x 5 mL), dried over MgSO filtered and concentrated to 4l. The residue was purified by preparative HPLC (gradient of aqueous MeOH with 0.1% TFA). The appropriate fractions were concentrated and the residue was evaporated from MeOH (1 mL) and 1N HCl (1 mL) 3 times. This residue was dissolved in water to give, after lyophilization, the compound of Example 354 (0.034 g, 29%) as a solid.
MS (M-H)' = 529.MS (M-H) - = 529.
355 pavyzdysExample 355
(R)-7-Chlor-2,3,4,5-tetrahidro-4-[(dimetilamino)sulfonil]-1-[(1-metil-1Himidazol-5-il)metil]- 3-(fenilmetil)-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Chloro-2,3,4,5-tetrahydro-4 - [(dimethylamino) sulfonyl] -1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- (phenylmethyl) - 1H-1,4-benzodiazepine (monohydrochloride)
A. (R)-7-Chlor-2,3,4,5-tetrahidro-4-[(dimetilamino)sulfonil]-3(fenilmetii)-1H-1,4-benzodiazepinas j 347 pavyzdžio junginio B (0,1 g, 0,36 mmol) ir DIEA (0,095 ml, 0,54 mmol) tirpalą CH3CN (2 ml) 0 °C temperatūroje argono atmosferoje sulašinamas dimetilsulfamoilchloridas (0,058 ml, 0,54 mmol). Mišinys per 16 vai. lėtai sušildomas iki kambario temperatūros ir praskiedžiamas NaHCCb (3 ml) ir CHCb (10 ml). Atskirami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCb (2 x 30 ml). Sumaišyti organiniai sluoksniai plaunami NaHCCb (1 x 10 ml), vandeniu (1 x 10 ml) ir sočiu NaCl tirpalu (1 x 10 ml), džiovinami MgSO4, nufiltruojama ir sukoncentravus gaunama oranžinė alyva,A. (R) -7-Chloro-2,3,4,5-tetrahydro-4 - [(dimethylamino) sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine, Example 347, B (0.1) g, 0.36 mmol) and DIEA (0.095 mL, 0.54 mmol) in CH 3 CN (2 mL) at 0 ° C under argon was added dropwise dimethylsulfamoyl chloride (0.058 mL, 0.54 mmol). 16 hours. warm slowly to room temperature and dilute with NaHCCb (3 mL) and CHCl3 (10 mL). The layers were separated and the aqueous layer was extracted with CHCl 3 (2 x 30 mL). The combined organic layers were washed with NaHCCb (1 x 10 mL), water (1 x 10 mL) and saturated aqueous NaCl (1 x 10 mL), dried over MgSO 4, filtered and concentrated to give an orange oil,
311 kuri gryninama perleidžiant per sparčiosios chromatografijos silikagelio kolonėlę (30 % EtOAc/heksane); gaunamas junginys A, kuris yra skaidri alyva (0,44 g, 32 %). MS (M + H)+ 380.311 which was purified by flash column chromatography over silica gel (30% EtOAc / hexane); Compound A is obtained which is a clear oil (0.44 g, 32%). MS (M + H) + 380.
B. (R)-7-Chlor-2,3,4,5-tetrahidro-4-[(dimetilamino)sulfonil]-1-[(1metil-1 H-imidazol-5-il)metil]-3-(fenilmetil)-1 H-1,4-benzodiazepinas (monohidrochloridas)B. (R) -7-Chloro-2,3,4,5-tetrahydro-4 - [(dimethylamino) sulfonyl] -1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- ( phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)
Junginys B (balta kieta medžiaga) 52 % išeiga pagaminamas iš junginio A pagal 353 pavyzdyje aprašytą junginio C gavimo metodiką, virinant su grjžtamu šaldytuvu 4 vai. ir gryninant tik preparatinės HPLC metodu.Compound B (white solid) is prepared in 52% yield from Compound A according to the procedure described in Example 353 for the preparation of Compound C by boiling under reflux for 4 hours. and purification by preparative HPLC only.
MS (M + H)+ 474.MS (M + H) < + > 474.
356 pavyzdysExample 356
CH3 (R)-7-Chlor-2,3,4,5-tetrahidro-1-(1-metil-imidazol-5-ilmetil)-4-[(4-metilpiperidin-4-il-etii)sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)CH 3 (R) -7-Chloro-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(4-methylpiperidin-4-yl-ethyl) sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
356 pavyzdžio junginys (gelsva kieta medžiaga) 28 % išeiga pagaminamas iš 353 pavyzdžio junginio A ir 1-metilpiperazino pagal 353 pavyzdyje aprašytą junginio B gavimo metodiką, chromatografijoje naudojant 20 % acetoną heksane, o po to 10 % metanolj CHCI3, ir pagal 353 pavyzdžio junginio C gavimo metodiką, gryninant tik preparatinės HPLC metodu.Example 356 Compound (yellowish solid) was prepared in 28% yield from Example 353 Compound A and 1-methylpiperazine according to the procedure for Example 353 in Compound B using 20% acetone in hexane followed by 10% methanol in CHCl 3 and Example 353. the procedure for the preparation of compound C by purification only by preparative HPLC.
MS: (M + H)+ = 557.MS: (M + H) < + > = 557.
357 pavyzdysExample 357
312312
(R)-7-Brom-2,3,4,5-tetrahidro-1-(1-metil-imidazol-5-ilmetil)-4-[(4-metilpiperidin-4-il-etil)sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(4-methylpiperidin-4-yl-ethyl) sulfonyl] -3 - (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
357 pavyzdžio junginys (balta kieta medžiaga) 23 % išeiga pagaminamas iš 224 pavyzdžio junginio B ir 1-metilpiperazino pagal reakcijų seką, naudojamą šiems junginiams gauti: 353 pavyzdžio junginiui A; 353 pavyzdžio junginiui B, chromatografijoje naudojant 9/1 CHCI3/MeOH; 353 pavyzdžio junginiui C, gryninant tik preparatinės HPLC metodu.Example 357 Compound (white solid) is prepared in 23% yield from Example 224 Compound B and 1-methylpiperazine according to the reaction sequence used to prepare the following compounds: Example 353 Compound A; Example 353, Compound B, chromatography using 9/1 CHCl 3 / MeOH; Example 353 for compound C purification by preparative HPLC only.
MS: (M + H)+ = 601.MS: (M + H) <+> = 601.
358 pavyzdysExample 358
(R)-7-Ciano-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4H1,4-benzodiazepin-4-karboksirūgšties izopropilo esteris (hidrochloridas)(R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H1,4-benzodiazepine-4-carboxylic acid isopropyl ester (hydrochloride)
358 pavyzdžio junginys (gelsva kieta medžiaga) 42 % išeiga pagaminamas iš 248 pavyzdžio junginio C pagal reakcijų seką, naudojamąExample 358 Compound (yellowish solid) is prepared in 42% yield from Example 248 Compound C according to the reaction sequence used
313 šiems junginiams gauti: 248 pavyzdžio junginiui E, naudojant izopropilchlorformiato tirpalą toluene ir chromatografijoje naudojant 40 % heksaną EtOAc, ir gaunant laisvą bazę: 354 pavyzdžio junginiui.313 to afford the following compounds: Example 248 Compound E using isopropyl chloroformate in toluene and 40% hexane in EtOAc to give the free base: Example 354.
MS: (M + H) + = 430.MS: (M + H) < + > = 430.
359 pavyzdysExample 359
(R)-7-Brom-2,3,4,5-tetrahidro-4-[[2-(1H-imidazol-1-il)etil]sulfonil]-1-(1Himidazol-4-ilmetil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Bromo-2,3,4,5-tetrahydro-4 - [[2- (1H-imidazol-1-yl) ethyl] sulfonyl] -1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
359 pavyzdžio junginys (gelsva kieta medžiaga) 21 % išeiga pagaminamas iš 224 pavyzdžio junginio B pagal reakcijų seką, naudojamą šiems junginiams gauti: 353 pavyzdžio junginiui A: 353 pavyzdžio junginiui B, naudojant natrio imidazolatą, 2:1 THF.IPA tirpikliu ir chromatografijoje naudojant 10 % EtOAc CHCI3, o po to EtOAc; 353 pavyzdžio junginiui C, 8 dienų laikotarpyje kasdien pridedant aldehido ir hidrido, ir negryninant.Example 359 Compound (yellowish solid) is prepared in 21% yield from Example 224 Compound B according to the reaction sequence used to prepare Example 353 Compound A: Example 353 Compound B using sodium imidazolate in 2: 1 THF.IPA solvent and chromatography using 10% EtOAc in CHCl 3 followed by EtOAc; Example 353 Compound C with daily addition of aldehyde and hydride for 8 days without purification.
MS: (M + H)+ = 557.MS: (M + H) < + > = 557.
360 pavyzdys360 example
314314
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(propilsulfonil)3-(3-piridinilmetil)-1H-1,4-benzodiazepinas (hidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (propylsulfonyl) 3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (hydrochloride)
360 pavyzdžio junginys (balta kieta medžiaga) 15 % išeiga pagaminamas iš propansulfonilchiorido ir 350 pavyzdžio junginio B pagal 350 pavyzdyje aprašytą junginių C ir D gavimo metodiką.Example 360 Compound (white solid) is prepared in 15% yield from propanesulfonyl chloride and Example 350 Compound B according to the procedure for Preparation C and D described in Example 350.
MS: (M + H)+451.MS: (M + H) + 451.
Analizė išskaičiuota pagal C23H26N6O2S · 2,6 HCI 2,02 H2O.Analysis calculated for C23H26N6O2S · 2.6 HCl 2.02 H 2 O.
Išskaičiuota: C, 47,50; H, 5,65; N, 14,45.Found: C, 47.50; H, 5.65; N, 14.45.
Rasta: C, 47,50; H, 5,51; N, 14,10.Found: C, 47.50; H, 5.51; N, 14.10.
361 pavyzdysExample 361
7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-1H-1,4benzodiazepin-5-onas (hidrochloridas)7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-5-one (hydrochloride)
A. 7-Brom-2,3,4,5-tetrahidro-3-(fenilmetil)-1 H-1,4-benzodiazepin-5onasA. 7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepin-5-one
J 0,5 g (1,45 mmol) 75 pavyzdžio junginio A suspensiją 75 ml THF kambario temperatūroje argono atmosferoje pridedama 3 ml (3 mmol) 1MTo a suspension of 0.5 g (1.45 mmol) of Example 75 Compound A in 75 mL of THF at room temperature under argon is added 3 mL (3 mmol) of 1M
315 borano THF. Maišoma per naktį, po to pridedama dar 2 ml (2 mmol) 1M borano THF ir maišoma dar 8 vai. Suhidrolizavus borano perteklių lašinant metanolį, reakcijos mišinys sausai nugarinamas, ir liekana ištirpinama 0,5 ml metanolio ir 0,5 ml kone. HCI. Gautas tirpalas virinamas su grįžtamu šaldytuvu 2 vai., atšaldomas iki kambario temperatūros ir sausai nugarinamas. Liekana nugarinama iš metanolio dar tris kartus. Negrynas produktas ištirpinamas etilacetate, ir tirpalas plaunamas sočiu NaCl tirpalu, džiovinamas, ir nugarinus tirpiklį gaunama klampi geltona alyva, kuri gryninama sparčiosios chromatografijos per silikagelį metodu (50 % etilacetatas heksane): gaunama 205 mg (43 %) junginio A, kuris yra balta kieta medžiaga.315 borane THF. Stir overnight, then add another 2 mL (2 mmol) of 1M borane in THF and stir for a further 8 h. After hydrolysis of the excess borane by dropwise addition of methanol, the reaction mixture is evaporated to dryness and the residue is dissolved in 0.5 ml methanol and 0.5 ml almost. HCl. The resulting solution was refluxed for 2 hours, cooled to room temperature and evaporated to dryness. The residue is evaporated from methanol three more times. The crude product is dissolved in ethyl acetate and the solution is washed with saturated NaCl solution, dried, and evaporated to give a viscous yellow oil which is purified by flash chromatography on silica gel (50% ethyl acetate in hexane) to give 205 mg (43%) of white solid. material.
B. 7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)1 H-1,4-benzodiazepin-5-onas (hidrochloridas) j 205 mg (0,62 mmoi) junginio A suspensiją 10 mi metileno chlorido ir 1 ml acto rūgšties pridedama 120 mg (1,25 mmol) 4-formiiimidazolo. Tirpalas maišomas 1 vai,, pridedama 197 mg (0,93 mmol) natrio triacetoksiborhidrido ir maišoma per naktį. Vėl pridedama 60 mg 4-formilimidazolo ir 100 mg natrio triacetoksiborhidrido ir maišoma dar 4 vai. Reakcijos mišinys sausai nugarinamas. Liekana praskiedžiama metileno chloridu, ir tirpalas plaunamas sočiu NaHCO3 ir sočiu NaCl tirpalu, džiovinamas (MgSO4), ir nugarinus tirpiklį gaunama gelsva putų pavidalo kieta liekana, kuri gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 %TFA gradientas). Sukoncentravus tinkamas frakcijas, gaunama skaidri alyvos pavidalo liekana, kuri paverčiama HCI druska, paveikus HCI-MeOH; gaunama 187 mg (60 %) junginio B, kuris yra beveik balta kieta medžiaga.B. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-5-one (hydrochloride); To a suspension of mg (0.62 mmol) of Compound A in 10 mL of methylene chloride and 1 mL of acetic acid was added 120 mg (1.25 mmol) of 4-formylimidazole. The solution is stirred for 1 hour, 197 mg (0.93 mmol) of sodium triacetoxyborohydride are added and stirred overnight. Again 60 mg of 4-formylimidazole and 100 mg of sodium triacetoxyborohydride are added and stirring is continued for 4 hours. The reaction mixture is evaporated to dryness. The residue is diluted with methylene chloride and the solution is washed with a saturated solution of NaHCO 3 and a saturated NaCl solution, dried (MgSO 4 ), and evaporated to give a yellow foamy solid residue which is purified by preparative HPLC (aqueous methanol with 0.1% TFA gradient). Concentration of the appropriate fractions affords a clear oil residue which is converted to the HCl salt by treatment with HCl-MeOH; 187 mg (60%) of compound B is obtained which is an off-white solid.
MS: (M + H)+ 411.MS: (M + H) + 411.
Analizė išskaičiuota pagal C20Hi9N4OBr· 1,5 HCI · 0,5 C2HwO.Analysis calculated for C 20 Hi 9 N 4 OBr · 1.5 HCl · 0.5 C 2 HwO.
Išskaičiuota: C, 52,53; H, 5,11; N, 11,14.Found: C, 52.53; H, 5.11; N, 11.14.
Rasta: C, 52,82; H, 4,71; N, 11,52.Found: C, 52.82; H, 4.71; N, 11.52.
362 pavyzdysExample 362
316316
(R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-1-ilacetil)-4-(metilsulfonil)3-(fenilmetil)-1H-1,4-benzodiazepinas (trifluoracetatas)(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-1-ylacetyl) -4- (methylsulfonyl) 3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate) )
A. (R)-7-Brom-2,3,4,5-tetrahidro-1-(chloracetil)-4-(metilsulfonil)-3(feniimetil)-l H-1,4-benzodiazepinasA. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (chloroacetyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine
J 224 pavyzdžio junginio C (2,0 g, 5,06 mmol) ir DIEA (4,4 ml, 25 mmol) mišinį dichlormetane (100 ml) ledo vonioje argono atmosferoje pridedama chloracetilchlorido (2,0 ml, 25,3 mmol). Mišinys maišomas 30 min., supilamas į vandeninį natrio hidroksidą (200 ml, 1N) ir ekstrahuojamas dichlormetanu (2 x 100 ml). Organiniai sluoksniai sumaišomi, plaunami sočiu NaCl tirpalu (200 ml) ir vandeniu (200 ml), džiovinami (MgSO4) ir sukoncentruojama iki alyvos, kuri gryninama sparčiosios chromatografijos metodu (60 g silikagelio, 3:1 heksanas:etilacetatas), ir gaunamas junginys A (760 mg, 1,62 mmol, 33 %), kuris yra bespalvė alyva.To a mixture of Example J 224 Compound C (2.0 g, 5.06 mmol) and DIEA (4.4 mL, 25 mmol) in dichloromethane (100 mL) was added chloroacetyl chloride (2.0 mL, 25.3 mmol) in an ice bath. . The mixture was stirred for 30 min, poured into aqueous sodium hydroxide (200 mL, 1N) and extracted with dichloromethane (2 x 100 mL). The organic layers were combined, washed with brine (200 mL) and water (200 mL), dried (MgSO 4 ) and concentrated to an oil which was purified by flash chromatography (60 g silica gel, 3: 1 hexane: ethyl acetate) to give the title compound. A (760 mg, 1.62 mmol, 33%) which is a colorless oil.
B. (R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-1-iiacetil)-4(metilsulfonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (trifluoracetatas)B. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-1-ylacetyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4- benzodiazepine (trifluoroacetate)
Junginio A (300 mg, 0,64 mmol), kalio karbonato (177 mg, 1,28 mmol) ir imidazolo (87 mg, 1,28 mmol) mišinys maišomas 48 vai. Mišinys supilamas j vandeninę vandenilio chlorido rūgštį (200 ml, 1N) ir etilacetatą (200 ml), atskiriami sluoksniai, ir vandeninis sluoksnis pašarminamas iki pH 11 kietu natrio hidroksidu. Šarminis vandeninis tirpalas ekstrahuojamas etilacetatu (200 ml), organiniai ekstraktai sumaišomi, džiovinami (Na2SO4) ir sukoncentruojama iki pusiau kietos medžiagos, kuri gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % trifluoracto rūgštiesA mixture of Compound A (300 mg, 0.64 mmol), potassium carbonate (177 mg, 1.28 mmol) and imidazole (87 mg, 1.28 mmol) was stirred for 48 h. The mixture was poured into aqueous hydrochloric acid (200 mL, 1N) and ethyl acetate (200 mL), the layers were separated, and the aqueous layer was basified to pH 11 with solid sodium hydroxide. The alkaline aqueous solution was extracted with ethyl acetate (200 ml) and the organic extracts were combined, dried (Na2S 4), and concentrated to a semi-solid which was purified by preparative HPLC (aqueous methanol with 0.1% trifluoroacetic acid
317 gradientas, C-18 kolonėlė). Po liofilizavimo gaunamas junginys B, kuris yra balta kieta medžiaga (100 mg, 32 %).317 gradient, C-18 column). After lyophilization, compound B is obtained which is a white solid (100 mg, 32%).
MS: (M + H) + 504.MS: (M + H) + 504.
363 pavyzdysExample 363
1,2,4,5-Tetrahidro-1-(1 H-imidazol-4-ilmetil)-2-(2-feniletil)-3H-1,4benzodiazepin-3-onas1,2,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -2- (2-phenylethyl) -3H-1,4-benzodiazepin-3-one
A. 1,2,4,5-Tetrahidro-2-(2-feniletil)-3H-1,4-benzodiazepin-3-onasA. 1,2,4,5-Tetrahydro-2- (2-phenylethyl) -3H-1,4-benzodiazepin-3-one
J maišomą N-Boc-(2-amino)benzilamino (1,0 g, 4,5 mmol) ir etil-2okso-4-fenilbutirato (1,0 ml, 5,3 mmol) tirpalą dichloretano (20 ml) ir acto rūgšties (1,0 ml) mišinyje kambario temperatūroje argono atmosferoje iš karto pridedama NaBH(OAc)3. Mišinys maišomas 18 vai., pridedama TFA (4 ml), ir šis mišinys šildomas 60 °C temperatūroje argono atmosferoje 2 vai. Nugarinamas tirpiklis, o liekana ištirpinama metanolyje (15 ml). Tirpalas atšaldomas iki 0 °C, ir pilama 10N NaOH iki pH 11. Tirpalas maišomas kambario temperatūroje 18 vai. Tirpiklis nugarinamas, o liekana paskirstoma tarp etilacetato ir sotaus NaHCO3 tirpalo. Organinis sluoksnis atskiriamas, džiovinamas MgSO4 ir koncentruojamas vakuume. Perkristalinus liekaną iš MeOH, gaunamas junginys A (480 mg, 40 %), kuris yra balta kieta medžiaga. Lyd. temp.: 147-148 °C.A stirred solution of N-Boc- (2-amino) benzylamine (1.0 g, 4.5 mmol) and ethyl 2-oxo-4-phenylbutyrate (1.0 mL, 5.3 mmol) in dichloroethane (20 mL) and acetic acid was added. of NaOH (OAc) 3 was added immediately at room temperature under argon. The mixture was stirred for 18 h, TFA (4 mL) was added and the mixture was heated at 60 ° C under argon for 2 h. The solvent was evaporated and the residue was dissolved in methanol (15 ml). The solution is cooled to 0 ° C and 10N NaOH is added to pH 11. The solution is stirred at room temperature for 18 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic layer was separated, dried over MgSO 4, and concentrated in vacuo. Recrystallization of the residue from MeOH gives compound A (480 mg, 40%) as a white solid. Lyd. mp 147-148 ° C.
B. 1,2,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-2-(2-feniletil)-3H-1,4benzodiazepin-3-onasB. 1,2,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -2- (2-phenylethyl) -3H-1,4-benzodiazepin-3-one
318318
Junginys B (balta kieta medžiaga) pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką.Compound B (white solid) is prepared from Compound A according to the procedure described in Example 1 for the preparation of Compound D.
MS: (M + H)+ 347.MS: (M + H) < + > 347.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-2-(2f e nil eti I)-1 H-1,4-benzodiazepinas (monohidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine (monohydrochloride)
A. 2,3,4,5-T etrahidro-1 -(1 H-imidazol-4-ilmetil)-2-(2-feniletil)-1 H-1,4benzodiazepinasA. 2,3,4,5-T tetrahydro-1- (1H-imidazol-4-ylmethyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine
J maišomą ličio aliuminio hidrido (160 mg) suspensiją glime kambario temperatūroje argono atmosferoje supilamas 363 pavyzdžio junginio laisvos bazės (150 mg) tirpalas glime. Mišinys maišomas kambario temperatūroje 18 vai., skaldomas pridedant etilacetato (20 ml), o po to amonio hidroksido (0,5 mi), maišomas 2 vai. ir nufiltruojamas. Sukoncentravus filtratą vakuume, gaunamas alyvos pavidalo junginys A.To a stirred suspension of lithium aluminum hydride (160 mg) at room temperature under argon was added a solution of the free base (150 mg) of the compound of Example 363 in glime. The mixture was stirred at room temperature for 18 h, quenched with ethyl acetate (20 mL), followed by ammonium hydroxide (0.5 mL), stirred for 2 h. and filtered off. Concentration of the filtrate in vacuo afforded compound A as an oil.
B. 2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-2-(2feniletil)-1H-1,4-benzodiazepinas (monohidrochloridas) j maišomą junginio A (50 mg) tirpalą metileno chloride (5 ml), kuriame yra kieto K2CO3, kambario temperatūroje pridedama 100 μΙ metansulfonilchlorido. Tirpalas maišomas 10 min., praskiedžiamas 10 ml metanolio, o po to 1 ml 10N NaOH tirpalo, maišomas 2 vai. ir koncentruojamas. Liekana paskirstoma tarp etilacetato ir sotaus NH4CIB. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine (monohydrochloride), mixed with compound A (50 mg) in methylene chloride (5 mL) containing solid K 2 CO 3 was added 100 μΙ of methanesulfonyl chloride at room temperature. The solution was stirred for 10 min, diluted with 10 mL of methanol followed by 1 mL of 10N NaOH solution, stirred for 2 h. and concentrated. The residue is partitioned between ethyl acetate and saturated NH 4 Cl
319 tirpalo. Organinis sluoksnis atskiriamas, džiovinamas MgSO4 ir koncentruojamas vakuume. Liekana gryninama kolonėlių chromatografijos metodu (etilacetatas/metanolis/NH4OH; 10:1:0,1), ir gaunama alyva, kuri paverčiama jos HCI druska taip kaip aprašyta 1 pavyzdyje junginio D gavimo atveju.319 of the solution. The organic layer was separated, dried over MgSO 4, and concentrated in vacuo. The residue is purified by column chromatography (ethyl acetate / methanol / NH 4 OH; 10: 1: 0.1) to give an oil which is converted to its HCl salt as described in Example 1 for the preparation of compound D.
MS: (M + H) 411.MS: (M + H) 411.
T \T \
Me (R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-7-fenil-3(4-pi ri dinil meti I)-1 H-1,4-benzodiazepinas (dihidrochloridas)Me (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3 (4-pyridinylmethyl) -1H -1,4-benzodiazepine (dihydrochloride)
365 pavyzdžio junginys (gelsva kieta medžiaga) 99 % išeiga pagaminamas iš 226 pavyzdžio junginio B ir D-(4-piridii)alanino pagal reakcijų seką. naudojamą šiems junginiams gauti: 226 pavyzdžio junginiui C; 226 pavyzdžio junginiui D; 264 pavyzdžio junginiui B; 264 pavyzdžio junginiuiExample 365 Compound (yellowish solid) is prepared in 99% yield from Example 226 Compound B and D- (4-pyridyl) alanine according to the reaction sequence. used to prepare the following compounds: Compound C of Example 226; Example 226 for compound D; 264 for compound B; 264 for the compound of Example
D.D.
MS (M + H)+ 474.MS (M + H) < + > 474.
366 pavyzdysExample 366
320320
(R)-2,3,4,5-Tetrahidro-1-(1H-imidazol-2-ilmetil)-4-(fenilsulfonil)-3(fenilmetil)-lH-1,4-benzodiazepin-7-karbonitrilas (hidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-2-ylmethyl) -4- (phenylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile (hydrochloride) )
366 pavyzdžio junginys (geltona kieta medžiaga) 95 % išeiga pagaminamas iš 312 pavyzdžio junginio A ir 2-formilimidazolo pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką.Example 366 (yellow solid) is prepared in 95% yield from Example 312, Compound A and 2-formylimidazole according to the procedure described in Example 1 for the preparation of Compound D.
MS (M + H)+ = 484,1.MS (M + H) < + > = 484.1.
Analizė išskaičiuota pagal C27H25N5O2S · 0,6 H2O · 1,1 HCI.Analysis calculated for C 27 H 25 N 5 O 2 S · 0.6 H 2 O · 1.1 HCl.
Išskaičiuota: C, 60,67; H, 5,15; N, 13,10; S, 5,99; Cl, 7,29.Found: C, 60.67; H, 5.15; N, 13.10; S, 5.99; Cl, 7.29.
Rasta: C, 60,34; H, 5,16: N, 12,81; S, 5,74; Cl, 7,46.Found: C, 60.34; H, 5.16: N, 12.81; S, 5.74. Cl, 7.46.
367 pavyzdysExample 367
(R)-7-Ciano-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-N,N-dimetil-3-(3piridinilmetil)-4H-1,4-benzodiazepin-4-karboksamidas (dihidrochloridas)(R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (3-pyridinylmethyl) -4H-1,4-benzodiazepine; 4-Carboxamide (dihydrochloride)
367 pavyzdžio junginys (kieta medžiaga) 2 % išeiga pagaminamas iš Ν,Ν-dimetilkarbamoilchlorido ir 350 pavyzdžio junginio B pagal aprašytąExample 367 Compound (solid) is prepared in 2% yield from Ν, Ν-dimethylcarbamoyl chloride and Example 350 Compound B as described
321 reakcijų seką, naudojamą šiems junginiams gauti; 350 pavyzdžio junginiui C, ekstrahavimui naudojant 10 % izopropanolj metileno chloride; 350 pavyzdžio junginiui D, ekstrahavimui naudojant 10 % izopropanolj metileno chloride, ir liofilizavimą iš 1N HCI/metanolyje.321 reaction sequences used to obtain these compounds; Example 350 for compound C, extracted with 10% isopropanol in methylene chloride; Example 350 for compound D, extracted with 10% isopropanol in methylene chloride, and lyophilized from 1N HCl / methanol.
HRMS: (M + H)+ Išskaičiuota: 416,2198; rasta: 416,2211.HRMS: (M + H) + Calcd: 416.2198; found: 416.2211.
368 pavyzdys CNExample 368 CN
(R)-7-Ciano-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-N,N-dimetil-3-(3piridinilmetil)-4H-1,4-benzodiazepin-4-sulfonamidas (dihidrochloridas)(R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (3-pyridinylmethyl) -4H-1,4-benzodiazepine; 4-sulfonamide (dihydrochloride)
368 pavyzdžio junginys (kieta medžiaga) 1 % išeiga pagaminamas iš Ν,Ν-dimetilsulfamoilchlorido ir 350 pavyzdžio junginio B pagal 367 pavyzdyje aprašytą metodiką.Example 368 (solid) is prepared in 1% yield from Ν, Ν-dimethylsulfamoyl chloride and Example 350 Compound B according to the procedure described in Example 367.
HRMS: (M + H)+ Išskaičiuota: 452,1868; rasta: 452,1860.HRMS: (M + H) + Calcd .: 452.1868; found: 452.1860.
369 pavyzdysExample 369
4-[(4-Huorfenil)sulfonil]-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazol-5-il)-3(f eni įmeti I)-1 H-tieno[2,3-e]-1,4-diazepinas (monohidrochloridas)4 - [(4-Horophenyl) sulfonyl] -2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) -3 (phenylmethyl) -1H-thieno [2,3-e] -1,4-diazepine (monohydrochloride)
322322
A. 2,3,4,5-Tetrahidro-3-(fenilmetil)-1H-tieno[2,3-e]-1,4-diazepin-2,5dionasA. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-thieno [2,3-e] -1,4-diazepine-2,5dione
Maišomas D,L-N-(2-ciano-1-oksoetil)fenilalanino metilo esterio (5,0 g, 20 mmol), ditiandiolio (1,6 g, 10,5 mmol), piperidino (2,0 ml, 20,2 mmol) ir TEA (2,8 ml, 20,2 mmol) tirpalas etanolyje (30 ml) pavirinamas su grįžtamu šaldytuvu 3 vai. ir nugarinamas. Liekana nugarinama iš tolueno tris kartus. Sausa liekana ištirpinama piridine ir pridedama piridinio chlorido (2,0 g). Šis tirpalas pakaitinamas 130 °C temperatūroje argono atmosferoje 3 dienas ir nugarinamas. Liekana ištirpinama metileno chloride, ir tirpalas plaunamas 1N HCI tirpalu (2 x 100 ml). Organinis sluoksnis džiovinamas ir koncentruojamas vakuume. Liekana trinama su eteriu, ir gaunamas junginys A, kuris yra ruda kieta medžiaga (2,0 g, 40 %). Lyd. temp.: 268-270 °C.D, LN- (2-Cyano-1-oxoethyl) phenylalanine methyl ester (5.0 g, 20 mmol), dithiandiol (1.6 g, 10.5 mmol), piperidine (2.0 mL, 20.2) and a solution of TEA (2.8 mL, 20.2 mmol) in ethanol (30 mL) was refluxed for 3 h. and is suppressed. The residue is evaporated from toluene three times. The dry residue is dissolved in pyridine and pyridine chloride (2.0 g) is added. This solution was heated at 130 ° C under argon for 3 days and evaporated. The residue was dissolved in methylene chloride and the solution was washed with 1N HCl (2 x 100 mL). The organic layer was dried and concentrated in vacuo. The residue was triturated with ether to give Compound A as a brown solid (2.0 g, 40%). Lyd. mp: 268-270 ° C.
B. 2,3,4,5-Tetrahidro-3-(fenilmetil)-1H-tieno[2,3-e]-1,4-diazepinas j maišomą ličio aliuminio hidrido (400 mg) suspensiją glime kambario temperatūroje argono atmosferoje mažomis porcijomis pridedama junginio A (500 mg, 2,05 mmol). Gauta suspensija virinama su grįžtamu šaldytuvu 3 dienas, atšaldoma iki 0 °C, ir LAH perteklius suardomas lėtai pilant etilacetatą. Pridedama NH4OH tirpalo (1 ml), susidariusi suspensija nufiltruojama ir ant filtro esanti medžiaga plaunama etilacetatu. Filtratas koncentruojamas vakuume. Liekana trinama su eteriu, ir gaunamas junginysB. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-thieno [2,3-e] -1,4-diazepine in a stirred suspension of lithium aluminum hydride (400 mg) at room temperature under argon of Compound A (500 mg, 2.05 mmol) was added portionwise. The resulting suspension was refluxed for 3 days, cooled to 0 ° C, and the excess LAH was decomposed by slow addition of ethyl acetate. NH 4 OH solution (1 mL) was added, the resulting suspension was filtered and the filter cake washed with ethyl acetate. The filtrate is concentrated in vacuo. The residue is triturated with ether to give the compound
B, kuris yra ruda kieta medžiaga (220 mg). Lyd. temp.: 139-141 °C.B, which is a brown solid (220 mg). Lyd. m.p. 139-141 ° C.
MS: (M + H)+ 245.MS: (M + H) < + > 245.
C. 4-[(4-Fluorfenil)sulfonil]-2,3,4,5-tetrahidro-3-(fenilmetil)-1Htieno[2,3-e]-1,4-diazepinasC. 4 - [(4-Fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-thieno [2,3-e] -1,4-diazepine
J maišomą junginio B (150 mg, 0,6 mmol) tirpalą metileno chloride su sočiu NaHCC>3 tirpalu pridedama 4-fluorbenzensulfonilchlorido (300 mg, 1,55 mmol). Mišinys maišomas kambario temperatūroje 18 vai. ir praskiedžiamas metanoliu. Pridedama 10N NaOH, ir mišinys maišomas 2 vai. Pridedama koncentruoto NH4OH, mišinys pamaišomas 18 vai. ir koncentruojamasTo a stirred solution of Compound B (150 mg, 0.6 mmol) in methylene chloride with saturated NaHCO 3 solution was added 4-fluorobenzenesulfonyl chloride (300 mg, 1.55 mmol). The mixture was stirred at room temperature for 18 hours. and diluted with methanol. 10N NaOH is added and the mixture is stirred for 2 hours. Concentrated NH 4 OH is added and the mixture is stirred for 18 hours. and concentrated
323 vakuume. Liekana paskirstoma tarp etilacetato ir sotaus NaHCCb. Organinis sluoksnis atskiriamas, džiovinamas MgSO4 ir koncentruojamas vakuume.323 in a vacuum. The residue is partitioned between ethyl acetate and saturated NaHCCb. The organic layer was separated, dried over MgSO 4, and concentrated in vacuo.
Chromatografiškai išgryninus liekaną (1:4, etilacetatas ir heksanai), gaunamas junginys C, kuris yra alyva (120 mg, 50 %).Chromatographic purification of the residue (1: 4, ethyl acetate and hexanes) affords compound C which is an oil (120 mg, 50%).
D. 4-[(4-Fluorfenil)sulfonil]-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazol5-il)-3-(fenilmetil)-1H-tieno[2,3-e]-1,4-diazepinas (monohidrochloridas)D. 4 - [(4-Fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) -3- (phenylmethyl) -1H-thieno [2, 3-e] -1,4-diazepine (monohydrochloride)
Junginys D (kieta medžiaga) 48 % išeiga pagaminamas iš junginio C ir 1-metil-5-formilimidazolo pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką.Compound D (solid) is prepared in 48% yield from Compound C and 1-methyl-5-formylimidazole according to the procedure for Compound D described in Example 224.
MS (M+H)+ 497.MS (M + H) < + > 497.
370 pavyzdysExample 370
(R)-2,3,4,5-Tetrahidro-1-(1-(4-cianofenilmetil)-imidazol-5-ilmetil)-4(metilsulfonil)-3-(feniimetil)-1H-1,4-benzodiazepin-7-karbonitrilas (hidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1- (4-cyanophenylmethyl) -imidazol-5-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine -7-carbonitrile (hydrochloride)
A. (R)-2,3,4,5-Tetrahidro-1-(1-(trifenilmetil)-imidazol-4-ilmetil)*4(metilsulfonil)-3-(fenilmetil)-1H-1,4-benzodiazepin-7-karbonitrilas j 1,2 g (2,85 mmol) 225 pavyzdžio junginio laisvos bazės tirpalą 20 ml acetonitrilo kambario temperatūroje argono atmosferoje pridedama 1,2 mi (8,55 mmol) TEA, o po to 1,2 g (4,3 mmol) trifenilmetilchlorido. Maišoma per naktį. Gautas drumstas tirpalas sausai nugarinamas, ir liekana gryninama sparčiosios chromatografijos metodu, perleidžiant per 100 cm3 silikagelioA. (R) -2,3,4,5-Tetrahydro-1- (1- (triphenylmethyl) -imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine -7-Carbonitrile To a solution of 1.2 g (2.85 mmol) of the free base of Example 225 in 20 mL of acetonitrile at room temperature under argon was added 1.2 mL (8.55 mmol) of TEA followed by 1.2 g (4 , 3 mmol) triphenylmethyl chloride. Stir overnight. The resulting cloudy solution is evaporated to dryness and the residue is purified by flash chromatography over 100 cm 3 of silica gel.
324 kolonėlę (50 % etilacetatas heksane). Gaunama 1,2 g (64 %) klampių baltų putų pavidalo junginio A.324 column (50% ethyl acetate in hexane). 1.2 g (64%) of viscous white foam A are obtained.
B. (R)-2,3,4,5-Tetrahidro-1-(1-(4-cianofenilmetil)-imidazol-5-ilmetil)-4(metilsulfonil)-3-(fenilmetil)-1H-1,4-benzodiazepin-7-karbonitrilas (hidrochloridas)B. (R) -2,3,4,5-Tetrahydro-1- (1- (4-cyanophenylmethyl) -imidazol-5-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4 benzodiazepine-7-carbonitrile (hydrochloride)
200 mg (0,3 mmol) junginio A ir 59 mg (0,3 mmol) 4cianobenzilbromido tirpalas 0,5 ml DMF kaitinamas 100 °C temperatūroje argono atmosferoje 10 vai. Reakcijos mišinys praskiedžiamas metileno chloridu ir pridedama 0,1 ml trietilsilano, o po to 0,5 ml TFA. Mišinys maišomas 1 vai., ir nugarinus gaunama geltona klampi alyvos pavidalo liekana, kuri sumaišoma su medžiaga, gauta panašioje reakcijoje; po sparčiosios chromatografijos per silikagelj (2 % metanolis chloroforme) gaunama 76 mg klampios gelsvai rudų putų pavidalo medžiagos. Po antros sparčiosios chromatografijos (1 % metanolis chloroforme, po to 3 % metanolis chloroforme) gaunama 53 mg kietų baltų putų pavidalo junginio B laisvos bazės. J 50 mg laisvos bazės tirpalą etilacetate pridedama 90 μΙ 1M HCI eteryje. Gautos baltos nuosėdos nufiltruojamos, ir išdžiovinus gaunama 43 mg (0,07 mmol) junginio B, kuris yra balta kieta medžiaga.A solution of 200 mg (0.3 mmol) of Compound A and 59 mg (0.3 mmol) of 4-cyanobenzyl bromide in 0.5 mL of DMF was heated at 100 ° C under argon for 10 h. The reaction mixture was diluted with methylene chloride and 0.1 mL of triethylsilane was added followed by 0.5 mL of TFA. The mixture is stirred for 1 hour and evaporation gives a yellow viscous oil which is mixed with a material obtained in a similar reaction; Flash chromatography on silica gel (2% methanol in chloroform) gives 76 mg of a viscous yellow-brown foam. A second flash chromatography (1% methanol in chloroform followed by 3% methanol in chloroform) yields 53 mg of free base of Compound B as a white solid foam. To a solution of 50 mg of the free base in ethyl acetate is added 90 μΙ of 1M HCl in ether. The resulting white precipitate was filtered off and dried to give 43 mg (0.07 mmol) of Compound B as a white solid.
Analizė išskaičiuota pagal C2oH28Ns02S · HCI · H2O.Analysis calculated for C 2 H 2 8 N 5 O 2 S · HCl · H 2 O.
Išskaičiuota: C, 60,96; H, 5,29; N, 14,22.Found: C, 60.96; H, 5.29; N, 14.22.
Rasta: C, 61,11; H, 5,10; N, 14,07.Found: C, 61.11; H, 5.10; N, 14.07.
MS (M + H)+ = 537.MS (M + H) <+> = 537.
371 pavyzdysExample 371
325325
(R)-2,3,4,5-Tetrahidro-1-(1-(4-cianofenilmeti!)-imidazol-4-ilmetil)-4(metilsulfonil)-3-(fenilmetil)-1H-1,4-benzodiazepin-7-karbonitrilas (hidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1- (4-cyanophenylmethyl) imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4- benzodiazepine-7-carbonitrile (hydrochloride)
A. (R)-2,3,4,5-Tetrahidro-1-(1-((1,1-dimetil)etoksikarbonil)-imidazol-4ilmetil)-4-(metilsulfonil)-3-(fenilmetil)-1H-1,4-benzodiazepin-7karbonitrilasA. (R) -2,3,4,5-Tetrahydro-1- (1 - ((1,1-dimethyl) ethoxycarbonyl) imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine-7-carbonitrile
J 250 mg (0,53 mmol) 225 pavyzdžio junginio laisvos bazės ir 0,6 mg (0,005 mmol) DMAP tirpalą 2 ml metileno chlorido kambario temperatūroje argono atmosferoje supilamas 144 mg (0,66 mmol) BOC anhidrido tirpalas 2 ml metileno chlorido. Maišoma 1 vai. Neapdorotas reakcijos mišinys gryninamas sparčiosios chromatografijos metodu, perleidžiant per 50 cm3 silikagelio kolonėlę (45 % etilacetatas heksane), ir gaunama 307 mg (apie 100 %) kietų baltų putų pavidalo junginio A.To a solution of 250 mg (0.53 mmol) of the free base of Example 225 and 0.6 mg (0.005 mmol) of DMAP in 2 mL of methylene chloride was added a solution of 144 mg (0.66 mmol) of BOC anhydride in 2 mL of methylene chloride at room temperature. Stir in 1 or. The crude reaction mixture was purified by flash chromatography on a 50 cm 3 silica gel column (45% ethyl acetate in hexane) to afford 307 mg (about 100%) of solid A as a white foam.
B. (R)-2,3,4,5-Tetrahidro-1-(1-(4-cianofenilmetil)-imidazol-4-ilmetil)-4(metilsulfonil)-3-(fenilmetil)-1H-1,4'benzodiazepin-7-karbonitrilas (hidrochloridas) mg (0,115 mmol) junginio A ir 23 mg (0,115 mmol) 4cianobenzilbromido tirpalas 1 ml DMF kaitinamas 100 °C temperatūroje argono atmosferoje 10 vai. ir po to nugarinamas. Liekana praskiedžiama metileno chloridu ir sočiu NaHCO3 ir maišoma 0,5 vai. Organinis sluoksnis atskiriamas, džiovinamas (MgSO4), ir nugarinus tirpiklj gaunama skaidri bespalvė stiklo pavidalo liekana. Šis negrynas produktas gryninamasB. (R) -2,3,4,5-Tetrahydro-1- (1- (4-cyanophenylmethyl) -imidazol-4-ylmethyl) -4 (methylsulfonyl) -3- (phenylmethyl) -1H-1,4 Benzodiazepine-7-carbonitrile (hydrochloride) A solution of mg (0.115 mmol) of compound A and 23 mg (0.115 mmol) of 4-cyanobenzyl bromide in 1 mL of DMF was heated at 100 ° C under argon for 10 h. and then evaporated. The residue was diluted with methylene chloride and saturated NaHCO 3 and stirred for 0.5 h. The organic layer was separated, dried (MgSO 4 ) and evaporated to give a clear colorless glassy residue. This impure product is purified
326 perleidžiant per sparčiosios chromatografijos 25 cm3 silikagelio kolonėlę (1 % metanolis chloroforme, po to 3 % metanolis chloroforme), ir gaunama 6 mg kietų baltų putų pavidalo junginio B laisvos bazės, j šios mediagos tirpalą minimaliame etilacetato kiekyje pridedama 100 μΙ 1M HCI eteryje. Gautos baltos nuosėdos nufiltruojamos, ir išdžiovinus gaunama 4,5 mg (7 %) junginio B, kuris yra balta kieta medžiaga.326 was subjected to flash chromatography on a 25 cm 3 silica gel column (1% methanol in chloroform followed by 3% methanol in chloroform) to give 6 mg of a free base of solid white foam Compound B in 100 µl of 1M HCl in a minimum amount of ethyl acetate. . The resulting white precipitate was filtered off and dried to give 4.5 mg (7%) of Compound B as a white solid.
MS: (M + H)+ 537.MS: (M + H) < + > 537.
372 pavyzdysExample 372
NCNC
HN (R)-4-Benzoil-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetiI)-3(feniImetiI)-1 H-1,4-benzodiazepinas (monohidrochloridas)HN (R) -4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )
A. (R)-4-Benzoil-7-ciano-2,3,4,5-tetrahidro-3-(fenilmetil)-1H-1,4benzodiazepinas j 248 pavyzdžio junginio C ir DIEA (0,32 ml, 1,99 mmol) tirpalą dichlormetane (3 ml) 0 °C temperatūroje argono atmosferoje pridedama benzoilchlorido (2,2 ml, 1,9 mmol). Tirpalas lėtai sušildomas iki kambario temperatūros. Po 15 ir 30 vai. pridedama 0,5 ekvivalento benzoilchlorido ir DIEA. Pamaišius 2 dienas, mišinys praskiedžiamas chloroformu (20 ml) ir NaHCO3 (5 ml). Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas chloroformu (2 x 15 ml). Sumaišyti organiniai ekstraktai plaunami NaHCO3 (2 x 5 ml), vandeniu (1 x 10 ml) ir sočiu NaCl tirpalu (2 x 10 ml), džiovinami MgSO4, nufiltruojama ir koncentruojama. Liekana gryninama sparčiosios chromatografijos per kolonėlę metodu, eliuuojant 20 % ir 30 % EtOAc heksane, ir gaunamas junginys A, kuris yra geltona alyva (0,21 g, 77 %).A. (R) -4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine, Example 248, Compound C and DIEA (0.32 mL, 1, A solution of 99 mmol) in dichloromethane (3 mL) at 0 ° C under argon was added benzoyl chloride (2.2 mL, 1.9 mmol). The solution is slowly warmed to room temperature. After 15 is 30 or. 0.5 equivalents of benzoyl chloride and DIEA are added. After stirring for 2 days, the mixture was diluted with chloroform (20 mL) and NaHCO 3 (5 mL). The layers were separated and the aqueous layer was extracted with chloroform (2 x 15 mL). The combined organic extracts were washed with NaHCO 3 (2 x 5 mL), water (1 x 10 mL), and saturated NaCl solution (2 x 10 mL), dried over MgSO 4 , filtered and concentrated. The residue was purified by flash column chromatography eluting with 20% and 30% EtOAc in hexane to give Compound A as a yellow oil (0.21 g, 77%).
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MS (M + H)+ 368.MS (M + H) + 368.
B. (R)-4-Benzoil-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3(f enil meti l)-1 H-1,4-benzodiazepinas (monohidrochloridas)B. (R) -4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4 benzodiazepine (monohydrochloride)
Junginio A (0,1 g, 0,27 mmol), 4-formilimidazolo (0,039 g, 0,40 mmol) ir AcOH (0,3 ml) mišinys toluene (1,0 ml) bei 3 A molekuliniai tinkleliai virinami su grįžtamu šaldytuvu 15 vai. Pridedama natrio triacetoksiborhidrido (0,086 g, 0,4 mmol), mišinys virinamas su grįžtamu šaldytuvu 8 vai., atšaldomas iki kambario temperatūros ir maišomas 15 vai. Pridedamas dar vienas ekvivalentas aldehido, tirpalas pamaišomas 30 min., pridedamas dar vienas ekvivalentas hidrido, ir tirpalas maišomas 16 vai. Vėl pridedama po vieną ekvivalentą aldehido ir hidrido taip kaip aprašyta aukščiau, mišinys maišomas 4 vai., praskiedžiamas CHCI3 (10 ml), NH4OH (5 ml) ir NaHCO3 (5 ml) ir maišomas 10 min. Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCI3 (3 x 30 ml). Sumaišyti organiniai ekstraktai plaunami NaHCO3, vandeniu ir sočiu NaCl tirpalu (po 2x10 ml), džiovinami MgSO4, nufiltruojama ir koncentruojama. Produktas gryninamas preparatinės HPLC metodu (vandeninio MeOH su 0,1 % TFA gradientas). Tinkamos frakcijos koncentruojamos vakuume. Liekana nugarinama iš metanolio (1 ml) ir 1N HCI (1 ml) tris kartus. Ši liekana ištirpinama vandenyje, ir po liofilizavimo gaunamas junginys B, kuris yra gelsva kieta medžiaga (36 mg, 30 %).A mixture of compound A (0.1 g, 0.27 mmol), 4-formylimidazole (0.039 g, 0.40 mmol) and AcOH (0.3 mL) in toluene (1.0 mL) and 3 A molecular mesh was refluxed refrigerator for 15 hours. Sodium triacetoxyborohydride (0.086 g, 0.4 mmol) is added and the mixture is refluxed for 8 hours, cooled to room temperature and stirred for 15 hours. Another equivalent of aldehyde is added, the solution is stirred for 30 min, another equivalent of hydride is added and the solution is stirred for 16 hours. Again, one equivalent of aldehyde and hydride was added as above, the mixture was stirred for 4 h, diluted with CHCl 3 (10 mL), NH 4 OH (5 mL) and NaHCO 3 (5 mL) and stirred for 10 min. The layers were separated and the aqueous layer was extracted with CHCl 3 (3 x 30 mL). The combined organic extracts were washed with NaHCO 3 , water, and brine ( 2 x 10 mL), dried over MgSO 4 , filtered, and concentrated. The product was purified by preparative HPLC (gradient of aqueous MeOH with 0.1% TFA). The appropriate fractions are concentrated in vacuo. The residue was evaporated from methanol (1 mL) and 1N HCl (1 mL) three times. This residue was dissolved in water to give, after lyophilization, Compound B as a yellowish solid (36 mg, 30%).
MS (M + H)+ = 448.MS (M + H) <+> = 448.
373 pavyzdysExample 373
CNCN
OO
IIII
328 (R)-7-Ciano-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazoI-5-il)metil]-3(pi rid i π-3-il met ii )-4- (meti Isulf onil)-1 H-1,4-benzodiazepinas (dihidrochloridas)328 (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- (pyridyl) -3-methyl ) -4- (Methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride)
373 pavyzdžio junginys (kieta medžiaga) 13 % išeiga pagaminamas iš 350 pavyzdžio junginio B pagal 350 pavyzdyje aprašytą junginio C ir 350 pavyzdyje aprašytą junginio D gavimo metodikas, naudojant 1-metil-5formilimidazolą.Example 373 Compound (solid) is prepared in 13% yield from Example 350 Compound B according to the procedures described in Example 350 for the preparation of Compound C and Example 350 using 1-methyl-5-formylimidazole.
MS: (M + H)+ 437. |MS: (M + H) + 437
Analizė išskaičiuota pagal C22H24NsO2S · 2 HCl · 2,1 H2O.Analysis calculated for C 22 H 24 N s O 2 S · 2 HCl · 2.1 H 2 O.
Išskaičiuota: C, 48,28; H, 5,56; N, 15,36.Found: C, 48.28; H, 5.56; N, 15.36.
Rasta: C, 48,28; H, 5,42; N, 15,45.Found: C, 48.28; H, 5.42; N, 15.45.
374 pavyzdys CNExample 374 CN
Me (R)-7-Ciano-2,3,4,5-tetrahidro-1-[(1-metii-1H-imidazol-5-il)metil]-3(piridin-3-ilmetil)-4-(propilsulfonil)-1 H-1,4-benzodiazepinas (trihidrochloridas)Me (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- (pyridin-3-ylmethyl) -4- ( propylsulfonyl) -1H-1,4-benzodiazepine (trihydrochloride)
374 pavyzdžio junginys (kieta medžiaga) 11 % išeiga pagaminamas iš propansulfonilchlorido pagal 373 pavyzdyje aprašytą metodiką.Example 374 (solid) is prepared in 11% yield from propanesulfonyl chloride according to the procedure described in Example 373.
MS: (M + H)+ 465.MS: (M + H) + 465.
Analizė išskaičiuota pagal C24H28N6O2S · 3 HCl - 0,26 H2O.Analysis calculated for C24H28N6O2S · HCl 3 - 0.26 H 2 O.
Išskaičiuota: C, 49,82; H, 5,49; N, 14,52.Found: C, 49.82; H, 5.49; N, 14.52.
Rasta: C, 49,81; H, 5,37; N, 14,58.Found: C, 49.81; H, 5.37; N, 14.58.
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375 pavyzdysExample 375
(R)-7-Ciano-2,3,4,5-tetrahidro-1-[(1H-imidazol-4-il)metil]-3-(piridin-3ilmetil)-4-(fenilsulfonil)-1H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-yl) methyl] -3- (pyridin-3-ylmethyl) -4- (phenylsulfonyl) -1H-1 , 4-benzodiazepine (dihydrochloride)
375 pavyzdžio junginys (kieta medžiaga) 2 % išeiga pagaminamas iš 350 pavyzdžio junginio B pagal 350 pavyzdyje aprašytą junginio C gavimo metodiką, naudojant benzensulfonilchloridą, ir 350 pavyzdyje aprašytą junginio D gavimo metodiką.Example 375 Compound (solid) is prepared in 2% yield from Example 350 Compound B according to the procedure described in Example 350 for the preparation of Compound C using benzenesulfonyl chloride and Example 350 for the preparation of Compound D.
MS: (M+H)+ 485.MS: (M + H) < + > 485.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-7-fenil-3(f enilmeti I)-1 H-1,4-benzodiazepinas2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3 (phenylmethyl) -1H-1,4-benzodiazepine
A. 2,3,4,5-Tetrahidro-7-fenil-3-(fenilmetil)-1H-1,4-benzodiazepinasA. 2,3,4,5-Tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine
330 j 75 pavyzdžio junginio B (200 mg, 0,63 mmol) toluene (20 ml) ir vandeninio natrio rūgščiojo karbonato (10 ml, sotus tirpalas) mišinj argono atmosferoje supilamas fenilboro rūgšties (153 mg 5 ml absoliutaus etanolio) tirpalas. Pridedama tetrakis(trifeniifosfino) paladžio(O) (36 mg), tirpalas virinamas su grįžtamu šaldytuvu (~ 80 °C) 18 valandų, atšaldomas iki kambario temperatūros ir paskirstomas tarp vandeninio natrio hidroksido (100 ml, 3N) ir etilacetato (100 ml). Mišinys ekstrahuojamas etilacetatu (2 x 200 ml), organiniai sluoksniai sumaišomi, džiovinami (MgSO4) ir sukoncentruojama vakuume iki negrynos alyvos, kuri gryninama panaudojant sparčiąją cgromatografiją (silikagelis, 10:0,5:0,05 etilacetatas : metanolis : amonio hidroksidas). Gaunamas junginys A (90 mg, 45 %), kuris yra vaško pavidalo kieta medžiaga,A solution of phenylbutyric acid (153 mg in 5 ml absolute ethanol) was added to a mixture of 330 to 75 compound B (200 mg, 0.63 mmol) in toluene (20 ml) and aqueous sodium bicarbonate (10 ml, saturated solution) under argon. Tetrakis (triphenyphosphine) palladium (O) (36 mg) is added, the solution is refluxed (~ 80 ° C) for 18 hours, cooled to room temperature and partitioned between aqueous sodium hydroxide (100 mL, 3N) and ethyl acetate (100 mL). . The mixture is extracted with ethyl acetate (2 x 200 mL), the organic layers are combined, dried (MgSO 4 ) and concentrated in vacuo to a crude oil which is purified by flash chromatography (silica gel, 10: 0.5: 0.05 ethyl acetate: methanol: ammonium hydroxide). . Compound A (90 mg, 45%) is obtained, which is a waxy solid.
B. 2,3,4.5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-7-fenil3'(fenilmetil)-1H-1,4-benzodiazepinasB. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3 '(phenylmethyl) -1H-1,4-benzodiazepine
Junginys B (balta kieta medžiaga) 40 % išeiga pagaminamas iš junginio A pagal aprašytą reakcijų seką, naudojamą šiems junginiams gauti: 78 pavyzdžio junginiui A, maišant 18 vai. ir nechromatografuojant; 78 pavyzdžio junginiui B.Compound B (white solid) is prepared in 40% yield from Compound A according to the reaction sequence described for the following compounds: Example 78 Compound A with stirring for 18 hours. and by non-chromatography; Example 78 for compound B.
MS: (M + H)+ 473.MS: (M + H) + 473.
Analizė išskaičiuota pagal Ο27Η28Ν4Ο2 · 0,5 H2O · 0,8 TFA.The analysis was based on Ο 27 Η 28 Ν 4 Ο 2 · 0.5 H 2 O · 0.8 TFA.
Išskaičiuota: C, 59,97; H, 5,24; N, 9,78; S, 5,60; F, 7,96.Found: C, 59.97; H, 5.24; N, 9.78; S, 5.60; F, 7.96.
Rasta: C, 59,94; H, 4,87; N, 8,21; S, 4,48; F, 7,86.Found: C, 59.94; H, 4.87; N, 8.21; S, 4.48. F, 7.86.
377 pavyzdysExample 377
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1,2,3,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-N-(1-naftalenil)-7-fenil-4H-1,4benzodiazepin-4-karboksamidas (monohidrochloridas)1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N- (1-naphthalenyl) -7-phenyl-4H-1,4-benzodiazepine-4-carboxamide (monohydrochloride)
A. 1,2,3,5-Tetrahidro-N-(1-naftalenil)-7-fenil-4H-1,4-benzodiazepin-4karboksamidasA. 1,2,3,5-Tetrahydro-N- (1-naphthalenyl) -7-phenyl-4H-1,4-benzodiazepine-4-carboxamide
J 1-naftilizocianato (116 mg, 0,66 mmol) tirpalą 3 ml sauso CH2CI2 argono atmosferoje pridedama 12 pavyzdžio junginio B (148 mg, 0,66 mmol), mišinys maišomas 16 vai. ir sukoncentravus gaunamas negrynas junginys A (267 mg).To a solution of 1-naphthylisocyanate (116 mg, 0.66 mmol) in 3 mL of dry CH 2 Cl 2 under argon was added Example 12 Compound B (148 mg, 0.66 mmol) and stir for 16 h. and concentrating to give crude compound A (267 mg).
B. 1,2,3,5-Tetrahidro-1-(1H-imidazol-4-ilmetii)-N-(1-naftalenil)-7-fenil4H-1,4-benzodiazepin-4-karboksamidas (monohidrochloridas)B. 1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N- (1-naphthalenyl) -7-phenyl-4H-1,4-benzodiazepine-4-carboxamide (monohydrochloride)
Junginys B (švelniai rožinė kieta medžiaga) 46 % išeiga pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką. Lyd. temp.: 170-177 °C (skyla).Compound B (mild pink solid) is prepared in 46% yield from Compound A according to the procedure described in Example 1 for the preparation of Compound D. Lyd. mp 170-177 ° C (dec.).
MS: (M + H) 474.MS: (M + H) 474.
Analizė išskaičiuota pagal C30H27N5O · 1,2 HCI · 0,6 H2O · 0,25 Et2O. Išskaičiuota: C, 68,11; H, 5,88; N, 12,81; Cl, 7,78.Analysis calculated for C 30 H 27 N 5 O · 1.2 HCl · 0.6 H 2 O · 0.25 Et 2 O Calculated: C, 68.11; H, 5.88; N, 12.81; Cl, 7.78.
Rasta: C, 68,02; H, 5,92; N, 12,61; Cl, 7,75.Found: C, 68.02; H, 5.92; N, 12.61; Cl, 7.75.
378 pavyzdysExample 378
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(S)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(fenilmetil)-l H-1,4-benzodiazepinas (hidrochloridas) pavyzdžio junginio laisvos bazės (100 mg, 0,31 mmol) tirpalas izopropanolyje (5 ml) gryninamas, naudojant chiralinės fazės preparatinę HPLC (chiralpak AD kolonėlė, pagaminta Chiral Technologies Ine. (50 mm x 500 mm), 25:75:0,1 izopropanolis:heksanas:trietilaminas, srauto greitis 55 ml/min.), ir gaunamas izomeras A, esant 36 min. sulaikymo laikui(18 mg, 13 %, 378 pavyzdžio junginio laisva bazė), ir izomeras B, esant 54 min. sulaikymo laikui. Hidrochloridas pagaminamas pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką.(S) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine ( hydrochloride) of the free base (100 mg, 0.31 mmol) of the sample compound in isopropanol (5 mL) was purified using chiral phase preparative HPLC (chiralpak AD column, Chiral Technologies Ine. (50mm x 500mm), 25:75): 0.1 isopropanol: hexane: triethylamine, flow rate 55 ml / min) to give isomer A at 36 min. retention time (18 mg, 13%, free base of Example 378), and isomer B at 54 min. for detention time. The hydrochloride is prepared according to the procedure for the preparation of compound D as described in Example 224.
MS: (M + H)+ 476.MS: (M + H) + 476.
Analizė išskaičiuota pagal C2iH23N4O2SBr · 1,2 H2O · 0,7 HCI.Analysis calculated for C 2 i H 2 3 N 4 O 2 SBr · 1.2 H 2 O · 0.7 HCl.
Išskaičiuota: C, 47,43; H, 4,85; N, 10,54; S, 6,03; Br, 15,03; Cl, 8,00.Found: C, 47.43; H, 4.85; N, 10.54; S, 6.03; Br, 15.03; Cl, 8.00.
Rasta: C, 47,71; H, 4,66; N, 9,71; S, 5,59; Br, 12,54; Cl, 8,14.Found: C, 47.71; H, 4.66; N, 9.71; S, 5.59; Br, 12.54; Cl, 8.14.
379 pavyzdysExample 379
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N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(2,3-dimetilbenzoil)-1H1,4-benzodiazepin-8-il]cikloheksankarboksamidas (dihidrochloridas)N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2,3-dimethylbenzoyl) -1H1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride)
A. 8-Nitro-2,3,4,5-tetrahidro-4-Fmoc-1 H-1,4-benzodiazepinasA. 8-Nitro-2,3,4,5-tetrahydro-4-Fmoc-1H-1,4-benzodiazepine
Į -10 °C temperatūros 22 pavyzdžio junginio D dihidrochlorido (15,0 g, 56,4 mmol) ir DIEA (19,6 ml, 113 mmol) tirpalą dichiormetane (100 ml) pridedama FmocOSu (19,0 g, 56,4 mmol). Mišinys maišomas 0 °C temperatūroje 2 vai., skaldomas 10 % NaHCCb (100 ml) ir ekstrahuojamas CH2CI2 (2 x 100 ml). Sumaišyti organiniai ekstraktai plaunami 1N HCI (2 x 100 ml). Organinė frakcija plaunama 10 % NaHCO3 (2 x 100 ml), džiovinama (MgSO4), nufiltruojama ir koncentruojama vakuume. Liekana trinama su eteriu, ir išdžiovinus vakuume gaunamas junginys A, kuris yra balta kieta medžiaga (15,6 g, 67 %). MS: (M + H)+ 416.To a solution of compound D dihydrochloride (15.0 g, 56.4 mmol) and DIEA (19.6 mL, 113 mmol) in dichloromethane (100 mL) at -10 ° C was added FmocOSu (19.0 g, 56.4) mmol). The mixture was stirred at 0 ° C for 2 h, digested with 10% NaHCO 3 (100 mL) and extracted with CH 2 Cl 2 (2 x 100 mL). The combined organic extracts were washed with 1N HCl (2 x 100 mL). The organic fraction was washed with 10% NaHCO 3 (2 x 100 mL), dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was triturated with ether and dried in vacuo to give Compound A as a white solid (15.6 g, 67%). MS: (M + H) < + > 416.
B. 8-Nitro-2,3,4,5-tetrahidro-1-(1 H-imidazol-4-ilmetil)-4-Fmoc-1 H-1,4benzodiazepinasB. 8-Nitro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4-Fmoc-1H-1,4-benzodiazepine
Į junginio A (15,5 g, 37,3 mmol) tirpalą 1/1 CH2Cl2/AcOH (200 ml) su 4A molekuliniais tinkleliais (6 gm) pridedama 4-formilimidazolo (7,16 g, 74,6 mmol). Mišinys maišomas kambario temperatūroje 2 vai. Dalimis per 15 min. pridedama natrio triacetoksiborhidrido (11,9 g, 56 mmoi), ir gautas tirpalas maišomas 3 vai. Pridedama 4-formilimidazolo (1,10 g, 11,5 mmol), ir mišinys maišomas 1 vai. Dalimis per 15 min. pridedama natrio triacetoksiborhidrido (2,39 g, 11,3 mmol), ir gautas tirpalas maišomas 16 vai. Mišinys nufiltruojamas, ir filtratas sukoncentruojamas vakuume. Liekana ištirpinamaTo a solution of compound A (15.5 g, 37.3 mmol) in 1/1 CH 2 Cl 2 / AcOH (200 mL) with 4A molecular mesh (6 gm) was added 4-formylimidazole (7.16 g, 74.6 mmol). . The mixture was stirred at room temperature for 2 hours. Installed in 15 minutes sodium triacetoxyborohydride (11.9 g, 56 mmol) was added and the resulting solution was stirred for 3 h. 4-Formylimidazole (1.10 g, 11.5 mmol) was added and the mixture was stirred for 1 h. Installed in 15 minutes sodium triacetoxyborohydride (2.39 g, 11.3 mmol) was added and the resulting solution was stirred for 16 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue is dissolved
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CH2CI2 (100 ml) ir skaldoma 10 % NaHCO3 (200 ml). Organinė frakcija atskiriama, o vandeninis sluoksnis ekstrahuojamas CH2CI2 (2 x 100 ml). Sumaišytos organinės frakcijos džiovinamos (MgSO4), nufiltruojamos ir koncentruojamos vakuume. Liekana gryninama chromatografuojant per silikagelj (eliuuojant CH2CI2, atmetamos visos frakcijos, ir produktas išstumiamas iš kolonėlės 9/1 CHCI3/MeOH). Gaunamas junginys B (17,6 g, 95 %), kuris yra kieta stiklo pavidalo medžiaga. (M + H)+ 496.CH 2 Cl 2 (100 mL) and decomposed with 10% NaHCO 3 (200 mL). The organic fraction was separated and the aqueous layer was extracted with CH 2 Cl 2 (2 x 100 mL). The combined organic fractions were dried (MgSO 4 ), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (eluting with CH 2 Cl 2 , discarding all fractions, and expelling the product from the column 9/1 CHCl 3 / MeOH). Compound B (17.6 g, 95%) is obtained as a glassy solid. (M + H) + 496.
C. N-[2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(2,3dimetilbenzoil)-1H-1,4-benzodiazepin-8-il]cikloheksankarboksamidas (dihidrochloridas)C. N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2,3-dimethylbenzoyl) -1H-1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride) )
Junginio B (12,0 g, 24,2 mmol) tirpalas DCE (70 ml) supilamas j stiklinėje purtyklės kolboje esančią 2-chlortritilchiorido polistireno dervą (13,9 g, 24,2 mmol, 1,74 mmol/g apkrova, Advanced Chem Tech), kuri buvo išbrinkinta DCE (50 ml) kambario temperatūroje. Pridedama DIEA (4,19 ml,A solution of Compound B (12.0 g, 24.2 mmol) in DCE (70 mL) was charged into a 2-chlorotriethylchloride polystyrene resin (13.9 g, 24.2 mmol, 1.74 mmol / g) in a glass shaker flask, Advanced Chem Tech) which was swelled with DCE (50 mL) at room temperature. DIEA (4.19 ml,
24,2 mmol), ir mišinys purtomas kambario temperatūroje 72 vai. Derva nufiltruojama ir perplaunama DCE (4 x 50 ml). Derva plaunama MeOH (4 x 50 ml), nufiltruojama, ir išdžiovinus vakuume gaunamas oranžinių granulių pavidalo junginys B, prijungtas prie dervos per imidazolo grupę (23,1 g, 89 %; apkrovimas 0,90 mmol/g pagal azoto analizės duomenis). Ši deva (23,1 g, 23,1 mmol) brinkinama DMF (50 ml) 15 min. Įpilama piperidino (50 ml), mišinys putomas 5 vai., nufiltruojama, perplaunama DMF (50 ml) ir nufiltruojama. Įpilama DMF (50 ml), ir mišinys purtomas 15 min. Įpilama piperidino (50 ml), ir mišinys purtomas 5 vai. Derva nufiltruojama, plaunama ir nufiltruojama, paveikus iš eilės DMF (3 x 50 ml), CH2CI2 (3 x 50 ml) ir MeOH (3 x 80 ml), įpylus kiekvieno tirpiklio, dervą palaikant 15 min., kad nusistovėtų pusiausvyra. Išdžiovinus dervą vakuume, gaunama oranžinių granulių pavidalo deblokuota prijungta prie dervos medžiaga (18,2 g 80 %, apkrovimas 1,17 mmol/g, pagal azoto analizės duomenis). Derva sudedama j 25 ml Varian Bont Elut Reservoir vamzdi, sujungtą su 20 mM Varian fritu ir uždaromuoju čiaupu su polipropileniniu galiuku. Vamzdis prijungiamas prie Vac Elut SPS24 ant Innova 2000 Platform Shaker. Derva brinkinama CH2CI2 24.2 mmol) and the mixture is shaken at room temperature for 72 hours. The resin was filtered off and washed with DCE (4 x 50 mL). The resin was washed with MeOH (4 x 50 mL), filtered, and dried in vacuo to give Compound B as an orange granule, bound to the resin via the imidazole group (23.1 g, 89%; load 0.90 mmol / g by nitrogen assay). This dose (23.1 g, 23.1 mmol) was swelled in DMF (50 mL) for 15 min. Piperidine (50 mL) is added, the mixture is foamed for 5 h, filtered, rinsed with DMF (50 mL) and filtered. DMF (50 mL) was added and the mixture was shaken for 15 min. Add piperidine (50 mL) and shake for 5 h. The resin was filtered off, washed and filtered through successive DMF (3 x 50 mL), CH 2 Cl 2 (3 x 50 mL), and MeOH (3 x 80 mL) solutions for 15 minutes to equilibrate the resin. . Drying of the resin in vacuo afforded an orange granular deblocked bond to the resin (18.2 g 80%, load 1.17 mmol / g, according to nitrogen analysis). The resin is packed into 25 ml Varian Bont Elut Reservoir tubes connected to a 20 mM Varian frit and a stopcock with a polypropylene tip. The tube is connected to Vac Elut SPS24 on the Innova 2000 Platform Shaker. The resin is swollen with CH 2 CI 2
335 (2 mi) 15 min. J dervą įpilama 2,3-dimetilbenzenkarboksirūgšties 0,77 M tirpalo DMF (1,25 ml). į šį dervos mišinį įpilama 0,92 M HOAT tirpalo DMF (1,04 ml) ir 0,46 M DIC tirpalo CH2CI2 (2,08 ml). Platformine purtykle kietafazė reakcija maišoma @285 RPM 16 vai. Vamzdyje esantis mišinys nufiltruojamas, ir derva plaunama ir nufiltruojama, paveikus iš eilės DMF (3x5 ml), CH2CI2 (3 x 5 ml) ir MeOH (3x5 ml), įpylus kiekvieno tirpiklio, dervą palaikant 15 min., kad nusistovėtų pusiausvyra. Derva vėl brinkinama CH2CI2 (2 ml) 15 min. į dervą įpilama 0,77 M 2,3-dimetilbenzenkarboksirūgšties tirpalo DMF (1,25 ml). į šį dervos mišinį įpilama 0,92 M HOAT tirpalo DMF (1,04 ml) ir 0,46 M DIC tirpalo CH2CI2 (2,08 ml). Platformine purtykle kietafazė reakcija maišoma @285 RPM 16 vai. Vamzdyje esantis mišinys nufiltruojamas, ir derva plaunama ir nufiltruojama, paveikus iš eilės DMF (3x5 ml), CH2CI2 (3x5 ml) ir MeOH (4x5 ml), įpylus kiekvieno tirpiklio, dervą palaikant 15 min., kad nusistovėtų pusiausvyra. Ši operacijų seka duoda N4-acilintą prie dervos prijungtą medžiagą, kuri naudojama tolimesnėje stadijoje. Ši derva brinkinama 1/1 DMF/CH2CI2 (2 ml) 15 min. Į dervos mišinį pridedama 0,23 M SnCI2-2H2O (0,222g, 0,97 mmol) tirpalo ir TEA (0,672 ml, 4,83 mmol) tirpalo CH2CI2 (4ml). Dervos mišinys purtomas 16 vai. Vamzdyje esantis mišinys nufiltruojamas, ir derva plaunama ir nufiltruojama, paveikus iš eilės DMF (3 x 5 ml), CH2CI2 (3x5 ml) ir MeOH (3x5 ml), įpylus kiekvieno tirpiklio, dervą palaikant 15 min., kad nusistovėtų pusiausvyra. Ši derva brinkinama 1/1 DMF/CH2CI2 (2 ml) 15 min., ir visa šios stadijos procedūra pakartojama du kartus. Ši operacijų seka duoda 8-aminogrupę turinčią prie dervos prijungtą medžiagą, kuri naudojama tolimesnėje stadijoje. Ši derva brinkinama CH2CI2 (2 ml) 15 min. j dervą pridedama 0,77 M cikloheksilkarboksirūgšties tirpalo DMF (1,25 ml). Pridedama 0,92 M HOAT tirpalo DMF (1,04 ml) ir 0,46 M DIC tirpalo CH2CI2 (2,08 ml). Platformine purtykle kietafazė reakcija maišoma @285 RPM 16 vai. Vamzdyje esantis mišinys nufiltruojamas, ir derva plaunama ir nufiltruojama, paveikus iš eilės DMF (3x5 ml), CH2CI2 (3x5 ml) ir MeOH (3x5 ml), įpylus kiekvieno tirpiklio, dervą palaikant 15 min., kad nusistovėtų pusiausvyra. Ši derva vėl brinkinama CH2CI2 (2 ml) 15 min. J dervą pridedama 0,77 M cikloheksilkarboksirūgšties tirpalo DMF (1,25 ml).335 (2 mi) 15 min. To the resin was added a solution of 2,3-dimethylbenzoic acid in 0.77 M DMF (1.25 mL). to this resin mixture was added 0.92 M HOAT solution in DMF (1.04 mL) and 0.46 M DIC in CH 2 Cl 2 (2.08 mL). The platform shaker solid-state reaction is stirred at @ 285 RPM for 16 h. The mixture in the tube is filtered and the resin is washed and filtered by successive addition of DMF (3 x 5 mL), CH 2 Cl 2 (3 x 5 mL) and MeOH (3 x 5 mL) with the resin maintained for 15 min to equilibrate. . The resin was swelled again with CH 2 Cl 2 (2 mL) for 15 min. 0.77 M solution of 2,3-dimethylbenzoic acid in DMF (1.25 ml) was added to the resin. to this resin mixture was added 0.92 M HOAT solution in DMF (1.04 mL) and 0.46 M DIC in CH 2 Cl 2 (2.08 mL). The platform shaker solid-state reaction is stirred at @ 285 RPM for 16 h. The mixture in the tube was filtered and the resin was washed and filtered by successive addition of DMF (3x5 mL), CH 2 Cl 2 (3x5 mL), and MeOH (4x5 mL), with the resin held for 15 min to equilibrate. This sequence of operations yields N4-acylated resin-bound material for use in the subsequent step. This resin was swelled with 1/1 DMF / CH 2 Cl 2 (2 mL) for 15 min. To the resin mixture was added a solution of 0.23 M SnCl 2 - 2H 2 O (0.222 g, 0.97 mmol) and a solution of TEA (0.672 mL, 4.83 mmol) in CH 2 Cl 2 (4 mL). The resin mixture is shaken for 16 hours. The mixture in the tube is filtered off, and the resin is washed and filtered by successive addition of DMF (3 x 5 mL), CH 2 Cl 2 (3 x 5 mL) and MeOH (3 x 5 mL), maintaining the resin for 15 min to equilibrate. . This resin is swelled with 1/1 DMF / CH 2 Cl 2 (2 mL) for 15 min and the entire procedure of this step is repeated twice. This sequence of operations yields an 8-amino-containing resin-bound material for use in the subsequent step. This resin was swelled in CH 2 Cl 2 (2 mL) for 15 min. To the resin was added 0.77 M solution of cyclohexylcarboxylic acid in DMF (1.25 mL). 0.92 M HOAT solution in DMF (1.04 mL) and 0.46 M DIC in CH 2 Cl 2 (2.08 mL) are added. The platform shaker solid-state reaction is stirred at @ 285 RPM for 16 h. The mixture in the tube is filtered off and the resin is washed and filtered by successive addition of DMF (3x5 mL), CH 2 Cl 2 (3x5 mL) and MeOH (3x5 mL), each resin being maintained for 15 min to equilibrate. This resin was swelled again with CH 2 Cl 2 (2 mL) for 15 min. To the resin was added 0.77 M solution of cyclohexylcarboxylic acid in DMF (1.25 mL).
336336
Pridedama 0,92 M HOAT tirpalo DMF (1,04 ml) ir 0,46 M DIC tirpalo CH2CI2 (2,08 ml). Platformine purtykle kietafazė reakcija maišoma @285 RPM 16 vai. Vamzdyje esantis mišinys nufiltruojamas, ir derva plaunama ir nufiltruojama, paveikus iš eilės DMF (3x5 ml), CH2CI2 (3x5 ml) ir MeOH (3x5 ml), įpylus kiekvieno tirpiklio, dervą palaikant 15 min., kad nusistovėtų pusiausvyra. Ši operacijų seka duoda 8-acilintą turinčią prie dervos prijungtą medžiagą, kuri naudojama tolimesnėje stadijoje. Derva brinkinama CH2CI2 (4 ml) 15 min. Pridedama trietilsilano (0,51 ml, 3,2 mmol, 10 ekv.). Dervos mišinys veikiamas TFA (4 ml), ir reakcijos mišinys purtomas 1 vai. Filtratas surenkamas vakuuminės filtracijos būdu. Derva vėl brinkinama CH2CI2 (4 ml) 15 min. Pridedama trietilsilano (0,51 ml, 3,2 mmol, 10 ekv.). Dervos mišinys veikiamas TFA (4 ml), ir reakcijos mišinys purtomas 1 vai. Filtratas surenkamas vakuuminės filtracijos būdu. Liekana gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas), reikiamos frakcijos surenkamos ir koncentruojamos vakuume. Liekana ištirpinama CH3CN (2 ml), veikiama 1N HCl (1 mi) ir sukoncentruojama vakuume keturis kartus. Ši liekana ištirpinama CH3CN (2 ml), veikiama 1N HCl (1 ml), ir po tirpalo liofilizavimo gaunamas 379 pavyzdžio junginys (0,0075 g, 4 % bendra išeiga), kuris yra stiklo pavidalo kieta medžiaga.0.92 M HOAT solution in DMF (1.04 mL) and 0.46 M DIC in CH 2 Cl 2 (2.08 mL) are added. The platform shaker solid-state reaction is stirred at @ 285 RPM for 16 h. The mixture in the tube is filtered off and the resin is washed and filtered by successive addition of DMF (3x5 mL), CH 2 Cl 2 (3x5 mL) and MeOH (3x5 mL), each resin being maintained for 15 min to equilibrate. This sequence of operations yields an 8-acylated resin-bound material for use in the subsequent step. The resin was swelled with CH 2 Cl 2 (4 mL) for 15 min. Triethylsilane (0.51 mL, 3.2 mmol, 10 equiv) is added. The resin mixture is treated with TFA (4 mL) and the reaction mixture is shaken for 1 h. The filtrate is collected by vacuum filtration. The resin was swelled again with CH 2 Cl 2 (4 mL) for 15 min. Triethylsilane (0.51 mL, 3.2 mmol, 10 equiv) is added. The resin mixture is treated with TFA (4 mL) and the reaction mixture is shaken for 1 h. The filtrate is collected by vacuum filtration. The residue was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA), the required fractions were collected and concentrated in vacuo. The residue was dissolved in CH 3 CN (2 mL), treated with 1N HCl (1 mL), and concentrated in vacuo four times. This residue was dissolved in CH 3 CN (2 mL), treated with 1N HCl (1 mL), and lyophilized to give Example 379 (0.0075 g, 4% overall yield) as a glassy solid.
MS (M + H)+ 486.MS (M + H) < + > 486.
MeMe
380 pavyzdys NCExample 380 NC
337 (R)-7-Ciano-N-[2-(dimetilamino)etil]-2,3,4,5-tetrahidro-1-(1H-imidazol-4ilmetil)-N-metil-3-(fenilmetil)-1H-1,4-benzodiazepin-4-karboksamidas (trifluoracetatas, 1:2)337 (R) -7-Cyano-N- [2- (dimethylamino) ethyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-3- (phenylmethyl) - 1H-1,4-Benzodiazepine-4-carboxamide (Trifluoroacetate, 1: 2)
A. (R)-7-Ciano-2,3,4,5-tetrahidro-4-(4-nitrofeniloksikarbonil)-3(fenilmetil)-1H-1,4-benzodiazepinasA. (R) -7-Cyano-2,3,4,5-tetrahydro-4- (4-nitrophenyloxycarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine
J 248 pavyzdžio junginio C (200 mg, 0,76 mmol) tirpalą THF (20 m!) argono atmosferoje pridedama 4-nitrofenilchlorformiato (0,88 ml, 0,76 mmol). Tirpalas maišomas 8 vai., supilamas j vandeninę vandenilio chlorido rūgštį (150 ml, 1N), ekstrahuojamas etilacetatu (2 x 150 ml), džiovinamas (MgSO4) ir sukoncentruojama iki alyvos, kuri gryninama sparčiosios chromatografijos metodu (50 g silikagelio, 2:1 heksanas:etilacetatas), ir gaunamas junginys A (230 mg, 70 %), kuris yra skaidri alyva.To a solution of compound C (200 mg, 0.76 mmol) in Example 248 in THF (20 mL) under argon was added 4-nitrophenyl chloroformate (0.88 mL, 0.76 mmol). The solution was stirred for 8 h, poured into aqueous hydrochloric acid (150 mL, 1N), extracted with ethyl acetate (2 x 150 mL), dried (MgSO 4 ), and concentrated to an oil which was purified by flash chromatography (50 g silica gel, 2: 1 hexane: ethyl acetate) to give Compound A (230 mg, 70%) as a clear oil.
B. (R)-7-Ciano-N-[2-(dimetilamino)etil]-2,3,4,5-tetrahidro-N-metil-3(f enil meti I)-1 H-1,4-benzodiazepin-4-karboksamidasB. (R) -7-Cyano-N- [2- (dimethylamino) ethyl] -2,3,4,5-tetrahydro-N-methyl-3 (phenylmethyl) -1H-1,4- benzodiazepine-4-carboxamide
Junginio A (110 mg, 0,26 mmol) tirpalas Ν,Ν,Ν’-trimetiletilendiamine (2 ml) kaitinamas hermetiniame slėgį išlaikančiame vamzdyje 110 °C temperatūroje 18 vai. Atšaldžius iki kambario temperatūros, tirpalas supilamas j vandeninį natrio hidroksidą (100 ml, 1N), ekstrahuojama etilacetatu (2 x 150 ml), džiovinama (MgSO4), ir sukoncentravus vakuume gaunamas rudos pastos pavidalo negrynas junginys B (išeiga >100 %).A solution of Compound A (110 mg, 0.26 mmol) in Ν, Ν, Ν'-trimethylethylenediamine (2 mL) was heated in an airtight pressure tube at 110 ° C for 18 h. After cooling to room temperature, the solution was poured into aqueous sodium hydroxide (100 mL, 1N), extracted with ethyl acetate (2 x 150 mL), dried (MgSO 4 ), and concentrated in vacuo to give crude paste compound B (> 100% yield).
C. (R)-7-Ciano-N-[2-(dimetilamino)etil]-2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-N-metil-3-(fenilmetil)-1H-1,4-benzodiazepin-4karboksamidas (trifluoracetatas, 1:2)C. (R) -7-Cyano-N- [2- (dimethylamino) ethyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxamide (trifluoroacetate, 1: 2)
Junginio B (140 mg, 0,35 mmol) ir 4-formilimidazolo (68 mg, 0,7 mmol) tirpalas dichloretane (2 ml) ir acto rūgštyje (2 ml) maišomas kambario temperatūroje 30 min., ir pridedama natrio triacetoksiborhidrido (150 mg, 0,7 mmol). Tirpalas pašildomas iki 60 °C, maišoma 18 vai., ir pridedamos papildomos porcijos 4-formilimidazolo ir natrio triacetoksiborhidrido (po 0,2 mmol, 4 porcijos per 8 vai.); mišinys praskiedžiamas etilacetatu (20 ml) irA solution of compound B (140 mg, 0.35 mmol) and 4-formylimidazole (68 mg, 0.7 mmol) in dichloroethane (2 mL) and acetic acid (2 mL) was stirred at room temperature for 30 min and sodium triacetoxyborohydride (150 mL) was added. mg, 0.7 mmol). The solution is heated to 60 ° C, stirred for 18 hours, and additional portions of 4-formylimidazole and sodium triacetoxyborohydride (0.2 mmol, 4 portions over 8 hours) are added; the mixture was diluted with ethyl acetate (20 mL) and
338 amonio hidroksidų (5 ml, kone.), ir maišoma dar 30 min. Šis mišinys ekstrahuojamas etilacetatu (2 x 25 ml), sumaišyti organiniai ekstraktai plaunami vandeniniu natrio rūgščiuoju karbonatu (25 ml, sotus tirpalas), po to amonio chloridu (25 mi, sotus vandeninis tirpalas), džiovinami (Na2SO4) ir sukoncentruojami vakuume iki pusiau kietos medžiagos. Ši negryna medžiaga gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas, C-18 kolonėlė), ir po iiofilizavimo gaunamas junginys C, kuris yra balta kieta medžiaga (80 mg, 48 %).338 ammonium hydroxide (5 mL, almost) and stirred for a further 30 min. This mixture was extracted with ethyl acetate (2 x 25 mL), the combined organic extracts washed with aqueous sodium bicarbonate (25 mL, saturated solution), followed by ammonium chloride (25 mL, saturated aqueous solution), dried (Na 2 SO 4 ) and concentrated in vacuo. to semi-solids. This crude material was purified by preparative HPLC (gradient from aqueous methanol to 0.1% TFA, C-18 column) to give, after lyophilization, Compound C as a white solid (80 mg, 48%).
MS: (M + H) + 471.MS: (M + H) + 471.
Analizė išskaičiuota pagal C27H33N7O · 1,1 H2O · 2,1 TFA.Analysis calculated for C 27 H 33 N 7 O · 1.1 H 2 O · 2.1 TFA.
Išskaičiuota: C, 51,27: H, 5,14; N, 13,42; F, 16,38.Found: C, 51.27: H, 5.14; N, 13.42; F, 16.38.
Rasta: C, 51,60; H, 4,93; N, 13,47; F, 16,28.Found: C, 51.60; H, 4.93; N, 13.47; F, 16.28.
381 pavyzdysExample 381
7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-2okso-3-(fenilmetil)-1H-1,4-benzodiazepinas (trifluoracetatas)7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2-oxo-3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate)
A. N-((2-Nitrofenil)metil)fenilalanino metilo esteris j 2-nitrobenzaldehido (5 g, 33 mmoi) tirpalą acto rūgštyje (150 ml) pridedama D,L-fenilalanino O-metilo esterio (8,54 g, 40 mmol), o po to natrio acetato (3,5 g, 43 mmol). Lėtai pridedama natrio triacetoksiborhidrido (9,09 g, 43 mmol), ir mišinys šildomas 80 °C temperatūroje 4 vai., atšaldomas iki kambario temperatūros, sukoncentruojamas vakuume iki pastos («20 ml) ir ištirpinamas etilacetate (100 ml). Tirpalas neutralizuojamas sočiu natrioA. N - ((2-Nitrophenyl) methyl) phenylalanine methyl ester To a solution of 2-nitrobenzaldehyde (5 g, 33 mmol) in acetic acid (150 mL) was added D, L-phenylalanine O-methyl ester (8.54 g, 40 mL). mmol) followed by sodium acetate (3.5 g, 43 mmol). Sodium triacetoxyborohydride (9.09 g, 43 mmol) was added slowly, and the mixture was heated at 80 ° C for 4 h, cooled to room temperature, concentrated in vacuo to a paste (<20 mL) and dissolved in ethyl acetate (100 mL). The solution is neutralized with saturated sodium
339 karbonatu ir ekstrahuojamas etilacetatu (3 x 200 ml). Sumaišyti organiniai sluoksniai džiovinami (MgSO4), ir sukoncentravus gaunamas junginys A, kuris yra ruda alyva (11,25 g, > 100 %).339 carbonate and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried (MgSO 4 ) and concentrated to give Compound A as a brown oil (11.25 g,> 100%).
B. N-((2-Nitrofenil)metil)-N-(metansiilfonil)-fenilalanino metilo esteris j junginio A (1,12 g, 3,5 mmol) tirpalą piridine (10 ml), esantį ledo vonioje, argono atmosferoje lėtai įpilama metansulfonilchlorido (1,08 ml, 14,0 mmol). Tirpalas sušildomas iki kambario temperatūros, supilamas j vandeninę vandenilio chlorido rūgštį (250 ml, 1N), ekstrahuojamas etilacetatu (2 x 200 ml), ir sumaišyti organiniai sluoksniai džiovinami (MgSO4) ir koncentruojami. Išgryninus gautą alyvą sparčiosios chromatografijos metodu (4:1 heksanas:etilacetatas), gaunamas junginys B (660 mg, 48 %), kuris yra skaidri alyva.B. N - ((2-Nitrophenyl) methyl) -N- (methanesilophonyl) -phenylalanine methyl ester into a solution of compound A (1.12 g, 3.5 mmol) in pyridine (10 mL) in an ice bath under argon slowly methanesulfonyl chloride (1.08 mL, 14.0 mmol) was added. The solution was warmed to room temperature, poured into aqueous hydrochloric acid (250 mL, 1N), extracted with ethyl acetate (2 x 200 mL), and the combined organic layers were dried (MgSO 4 ) and concentrated. Purification of the resulting oil by flash chromatography (4: 1 hexane: ethyl acetate) gave compound B (660 mg, 48%) as a clear oil.
C. N-((2-Aminofenil)metil)-N-(metansulfonil)-fenilalanino metilo esterisC. N - ((2-Aminophenyl) methyl) -N- (methanesulfonyl) -phenylalanine methyl ester
Junginio B (660 mg, 1,68 mmol), alavo(ll) chlorido (1,52 g, 6,7 mmol) ir etilacetato (75 ml) mišinys maišomas kambario temperatūroje 18 vai., po to skaldomas vandeniniu, o po to kietu kalio karbonatu (5 ml, po to 5 g). Mišinys nufiltruojamas, filtratas ekstrahuojamas, organinė fazė džiovinama (MgSO4), koncentruojama vakuume ir gryninama naudojant sparčiąją chromatografiją (3:1 heksanas:etilacetatas). Gaunamas junginys C (315 mg, 52 %), kuris yra skaidri alyva.A mixture of Compound B (660 mg, 1.68 mmol), tin (II) chloride (1.52 g, 6.7 mmol), and ethyl acetate (75 mL) was stirred at room temperature for 18 h, then quenched with aqueous and then solid potassium carbonate (5 mL, followed by 5 g). The mixture was filtered, the filtrate extracted, the organic phase dried (MgSO 4 ), concentrated in vacuo and purified by flash chromatography (3: 1 hexane: ethyl acetate). The compound C (315 mg, 52%) is obtained which is a clear oil.
D. N-((2-Amino-5-bromfenil)metil)-N-(metansulfonil)-fenilalanino metilo esterisD. N - ((2-Amino-5-bromophenyl) methyl) -N- (methanesulfonyl) -phenylalanine methyl ester
Junginys D (balta kieta medžiaga) 60 % išeiga pagaminamas iš junginio C pagal 262 pavyzdyje aprašytą junginio A gavimo metodiką, išskyrus tai, kad junginys gryninamas perkristalinant iš metanolio.Compound D (white solid) is prepared in 60% yield from Compound C according to the procedure for Compound A described in Example 262, except that the compound is purified by recrystallization from methanol.
E. N-[[2-(lmidazol-4-il)metil)-amino)-fenil]-metil]-N-(metansulfonil)fenilalanino metilo esterisE. N - [[2- (Imidazol-4-yl) methyl) -amino) -phenyl] -methyl] -N- (methanesulfonyl) phenylalanine methyl ester
340340
Junginys E (pusiau kieta medžiaga) 100 % išeiga pagaminamas iš junginio D pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką, maišant 4 vai., ir toliau naudojama negryninta laisva bazė.Compound E (semi-solid) is prepared in 100% yield from Compound D according to the procedure described in Example 1 for the preparation of Compound D, with stirring for 4 hours, and the crude free base is further used.
F. N-[[2-(lmidazol-4-il)metil)-amino)-fenil]-metil]-N-(metansulfonil)fenilalaninasF. N - [[2- (Imidazol-4-yl) methyl) -amino) -phenyl] -methyl] -N- (methanesulfonyl) phenylalanine
Junginio E (200 mg, 0,38 mmol) ir LiOH (80 mg, 2 mmol) tirpalas THF (6 ml), metanolyje (1 ml) ir vandenyje (1 ml) maišomas kambario temperatūroje 1 vai., sukoncentruojamas vakuume iki 2 ml ir supilamas j vandeninę vandenilio chlorido rūgštį (20 ml). Mišinys ekstrahuojamas etilacetatu (2 x 50 ml), sumaišyti organiniai sluoksniai džiovinami (MgSO4), ir sukoncentravus gaunamas junginys F (150 mg, 78 %), kuris yra skaidri alyva.A solution of E (200 mg, 0.38 mmol) and LiOH (80 mg, 2 mmol) in THF (6 mL), methanol (1 mL), and water (1 mL) was stirred at room temperature for 1 h and concentrated in vacuo to 2 mL. and poured into aqueous hydrochloric acid (20 mL). The mixture was extracted with ethyl acetate (2 x 50 mL), the combined organic layers dried (MgSO 4 ) and concentrated to give compound F (150 mg, 78%) as a clear oil.
G. 7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4(metilsulfonil)-2-okso-3-(fenilmetil)-1 H-1,4-benzodiazepinas (trifluoracetatas)G. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2-oxo-3- (phenylmethyl) -1H-1,4- benzodiazepine (trifluoroacetate)
Junginio F (150 mg, 0,29 mmol), DMF (3 ml), DIEA (0,66 ml, 0,725 mmol) ir BOP (193 mg, 0,43 mmol) mišinys maišomas kambario temperatūroje 3 vai. Mišinys paskirstomas tarp natrio karbonato (100 ml, sotus tirpalas) ir etilacetato (100 ml), vandeninė fazė ekstrahuojama etilacetatu (2 x 50 ml), sumaišyti organiniai sluoksniai džiovinami (MgSO4) ir koncentrojami. Liekana gryninama preparatinės HPLC metodu (vandeninio metanolio su 0,1 % trifluoracto rūgšties gradientas, C-18 kolonėlė), ir po liofilizavimo gaunamas junginys G, kuris yra balta kieta medžiaga (65 mg, 46 %).A mixture of compound F (150 mg, 0.29 mmol), DMF (3 mL), DIEA (0.66 mL, 0.725 mmol) and BOP (193 mg, 0.43 mmol) was stirred at room temperature for 3 h. The mixture was partitioned between sodium carbonate (100 mL, saturated solution) and ethyl acetate (100 mL), the aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were dried (MgSO 4 ) and concentrated. The residue was purified by preparative HPLC (gradient of aqueous methanol with 0.1% trifluoroacetic acid, C-18 column) to give, after lyophilization, Compound G as a white solid (65 mg, 46%).
MS: (M + H)+ 490.MS: (M + H) < + > 490.
Analizė išskaičiuota pagal C2iH2iN4O3SBr -1,1 H2O · 1,0 TFA.Analysis calculated for C2iH 2 IN 4 O 3 -1.1 SBR H 2 O · 1.0 TFA.
Išskaičiuota: C, 44,33; H, 3,91; N, 8,99; S, 5,14; Br, 12,82.Found: C, 44.33; H, 3.91; N, 8.99; S, 5.14; Br, 12.82.
Rasta: C, 44,29; H, 3,59; N, 8,74; S, 5,05; Br, 12,78.Found: C, 44.29; H, 3.59; N, 8.74; S, 5.05; Br, 12.78.
382 pavyzdysExample 382
341341
(R)-7-Ciano-4-(2-furaniikarbonil)-2,3,4,5-tetrahidro-1-(1H-imidazol-4ilmetil)-3-(fenilmetil)-1H-1,4-benzodiazepinas (trifluoracetatas, 1:1)(R) -7-Cyano-4- (2-furanylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine ( trifluoroacetate, 1: 1)
A. (R)-7-Ciano-4-(2-furanilkarbonil)-2,3,4,5-tetrahidro-3-(fenilmetil)1 H-1,4-benzodiazepinasA. (R) -7-Cyano-4- (2-furanylcarbonyl) -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine
Junginys A (alyva) 100 % išeiga pagaminamas iš 248 pavyzdžio junginio C ir furan-2-karboksirūgšties pagal 381 pavyzdyje aprašytą junginio G gavimo metodiką, maišant 18 vai., apdorojant citrinos rūgštimi ir negryninant.Compound A (oil) is prepared in 100% yield from Compound C of Example 248 and furan-2-carboxylic acid according to the procedure described in Example 381 for the preparation of Compound G, with stirring for 18 hours, without treatment with citric acid.
B. (R)-7-Ciano-4-(2-furanilkarbonil)-2,3,4,5-tetrahidro-1-(1H-imidazol4-ilmetil)-3-(fenilmetil)-1H-1,4-benzodiazepinas (trifluoracetatas, 1:1)B. (R) -7-Cyano-4- (2-furanylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4- benzodiazepine (trifluoroacetate, 1: 1)
Junginys B (balta kieta medžiaga) 7 % išeiga pagaminamas iš junginio A pagal 380 pavyzdyje aprašytą junginio C gavimo metodiką.Compound B (white solid) is prepared in 7% yield from Compound A according to the procedure described in Example 380 for the preparation of Compound C.
MS: (M + H)+ 438.MS: (M + H) < + > 438.
Analizė išskaičiuota pagal C26H23N5O2 · 2,0 H2O · 1,0 TFA.Analysis calculated for C26H23N5O2 · 2.0 H 2 O · 1.0 TFA.
Išskaičiuota: C, 57,24; H, 4,80; N, 11,92.Found: C, 57.24; H, 4.80; N, 11.92.
Rasta: C, 57,22; H, 4,26; N, 11,74.Found: C, 57.22; H, 4.26; N, 11.74.
383 pavyzdysExample 383
342342
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-[(4nitrof eni l)su If on i l]-3-(f en i I meti I)-1 H-1,4-benzodiazepinas (trifluoracetatas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4-nitrophenyl) with If on] -3- (Phenyl) I Methyl) -1H-1,4-benzodiazepine (trifluoroacetate)
383 pavyzdžio junginys (balta kieta medžiaga) 3 % išeiga pagaminamas iš 4-nitrobenzensulfonilchlorido ir 248 pavyzdžio junginio C pagal reakcijų seką, naudojamą šiems junginiams gauti: 350 pavyzdžio junginiui C, išskyrus tai, kad reakcija vykdoma kambario temperatūroje ir produktas negryninamas; 380 pavyzdžio junginiui C.Example 383 (white solid) is prepared in 3% yield from 4-nitrobenzenesulfonyl chloride and Example 248 Compound C according to the reaction sequence used to prepare the following compounds: Example 350 Compound C except that the reaction is carried out at room temperature and is not purified; 380 for compound C.
MS: (M + H)+ 529.MS: (M + H) < + > 529.
384 pavyzdysExample 384
343 (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1 H-imidazol-4-ilmetil)-4-[[4-(4-metil-1piperazinil)fenil]sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (trifluoracetatas)343 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[4- (4-methyl-1-piperazinyl) phenyl] sulfonyl] - 3- (Phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate)
A. (R)-7-Ciano-2,3,4,5-tetrahidro-4-[[(4-metil-1piperazinil)fenil]sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas ) (R)-7-ciano-2,3,4,5-tetrahidro-4-[(4-fluorfenil)sulfonil]-3-(fenilmetil)-1H1,4-benzodiazepino (200 mg, 0,48 mmol, pagaminto taip, kaip aprašyta 291 pavyzdyje) ir DMF (2 ml) mišinj pridedama N-metiipiperazino (2 ml). Tirpalas kaitinamas 110 °C temperatūroje ir maišomas 6 vai., supilamas į vandeninę vandenilio chlorido rūgštį (150 ml, 1M) ir ekstrahuojamas etilacetatu (2 x 100 ml). Organiniai sluoksniai sumaišomi, džiovinami (MgSO4), koncentruojami, ir perkristalinus liekaną iš dichlormetano, gaunamas junginys A (50 mg, 21 %), kuris yra pilka kieta medžiaga.A. (R) -7-Cyano-2,3,4,5-tetrahydro-4 - [[(4-methyl-1-piperazinyl) phenyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine) (R) -7-Cyano-2,3,4,5-tetrahydro-4 - [(4-fluorophenyl) sulfonyl] -3- (phenylmethyl) -1H1,4-benzodiazepine (200 mg, 0.48 mmol, as described in Example 291) and DMF (2 mL) was added to the mixture with N-methylpiperazine (2 mL). The solution was heated at 110 ° C and stirred for 6 h, poured into aqueous hydrochloric acid (150 mL, 1M) and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried (MgSO 4 ), concentrated, and recrystallized from dichloromethane to give Compound A (50 mg, 21%) as a gray solid.
B. (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-[[(4metil-1-piperazinil)fenil]sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (trifluoracetatas)B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[(4-methyl-1-piperazinyl) phenyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate)
Junginys B (balta kieta medžiaga) 65 % išeiga pagaminamas iš junginio A pagal 380 pavyzdyje aprašytą junginio C gavimo metodiką, maišant kambario temperatūroje.Compound B (white solid) is prepared in 65% yield from Compound A according to the procedure described in Example 380 for the preparation of Compound C with stirring at room temperature.
MS: (M + H)+581.MS: (M + H) + 581.
Analizė išskaičiuota pagal C32H35N7O3S · 2,0 H2O · 2,0 TFA.Analysis calculated for C32H35N7O3S · 2.0 H 2 O · 2.0 TFA.
Išskaičiuota: C, 51,12; H, 4,89; N, 11,59; S, 3,79.Found: C, 51.12; H, 4.89; N, 11.59; S, 3.79.
Rasta: C, 50,83; H, 4,68; N, 11,43; S, 4,47.Found: C, 50.83; H, 4.68; N, 11.43; S, 4.47.
385 pavyzdysExample 385
344344
CNCN
MeMe
A k,A k,
MeMe
N ^1 vN ^ 1 v
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1 H-imidazol-4-ilmetil)-4-[[(4dimetilamino)fenil]sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (trifluoracetatas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[(4-dimethylamino) phenyl] sulfonyl] -3- (phenylmethyl) -1H -1,4-benzodiazepine (trifluoroacetate)
A. (R)-7-Ciano-2,3,4,5-tetrahidro-4-[[(4-dimetilamino)fenil]suIfonil]-3(fenilmetil)-1H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-4-[(4-fluorfenil)sulfonil]-3(fenilmetil)-1H-1,4-benzodiazepino (200 mg, 0,48 mmol, pagaminto taip, kaip aprašyta 291 pavyzdyje) tirpalas dimetiiamine (2 ml, 2M THF) maišomas 60 oC temperatūroje užlydytame slėgi išlaikančiame vamzdelyje 24 vai. Vėl pridedama dimetilamino (4 ml, 2M THF), ir tirpalas maišomas dar 6 vai. Reakcijos mišinys koncentruojamas vakuume iki pastos pavidalo liekanos, ir perkristalinus ją iš metanolio, gaunamas junginys A (50 mg, 25 %), kuris yra pilka kieta medžiaga.A. (R) -7-Cyano-2,3,4,5-tetrahydro-4 - [[(4-dimethylamino) phenyl] sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine (R) - 7-Cyano-2,3,4,5-tetrahydro-4 - [(4-fluorophenyl) sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine (200 mg, 0.48 mmol, prepared as (Example 291)) The solution was stirred in dimethylamine (2 mL, 2M THF) in a sealed pressure tube at 60 ° C for 24 h. Dimethylamine (4 mL, 2M THF) was added again and the solution stirred for a further 6 h. The reaction mixture was concentrated in vacuo to a paste residue and recrystallized from methanol to give Compound A (50 mg, 25%) as a gray solid.
B. (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-[[4-(4dimetilamino)fenil]sulfonil]-3-(fenllmetil)-1H-1,4-benzodiazepinas (trifluoracetatas)B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[4- (4-dimethylamino) phenyl] sulfonyl] -3- (phenylmethyl) ) -1H-1,4-benzodiazepine (trifluoroacetate)
Junginys B (baita kieta medžiaga) 43 % išeiga pagaminamas iš junginio A pagal 380 pavyzdyje aprašytą junginio C gavimo metodiką.Compound B (byte solid) is prepared in 43% yield from Compound A according to the procedure for Compound C described in Example 380.
Analizė išskaičiuota pagal C29H30N6O2S · 1,3 H2O · 0,9 TFA.Analysis calculated for C 29 H 30 N 6 O 2 S · 1.3 H 2 O · 0.9 TFA.
Išskaičiuota: C, 56,68; H, 5,17; N, 12,88; S, 4,91; F, 7,80.Found: C, 56.68; H, 5.17; N, 12.88; S, 4.91; F, 7.80.
Rasta: C, 56,36; H, 5,07; N, 12,51; S, 5,39; F, 7,78.Found: C, 56.36; H, 5.07; N, 12.51; S, 5.39; F, 7.78.
345345
386 pavyzdysExample 386
(R)-7-Brom-4-[[2-(dimetilamino)etil]sulfonil]-2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-3-(fenilmetil)-4H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H- 1,4-Benzodiazepine (dihydrochloride)
A. (R)-7-Brom-4-[etenilsulfonil]-2,3,4,5-tetrahidro-3-(fenilmetil)-4H1,4-benzodiazepinas | 224 pavyzdžio junginio B (10 g, 31,5 mmol) tirpalą dichlormetane (120 ml) 0 °C temperatūroje sulašinamas 2-chloretansulfonilchlorido (3,2 ml, 30 mmol) tirpalas dichlormetane (10 ml). Sulašinamas DIEA (5,2 ml, 30 mmol). Po 15 min. pridedama 2-chloretansulfonilchlorido (1,5 ml, 15 mmol), o po to DIEA (10,4 ml, 60 mmol). Mišiniui leidžiama sušilti iki kambario temperatūros, po to jis supilamas į vandenį (80 ml). Organinis sluoksnis atskiriamas, plaunamas 1N HCI ir sočiu vandeniniu NaHCO3 (po 80 mi), džiovinamas (MgSO4), ir sukoncentravus vakuume gaunamas gelsvų kietų putų pavidalo junginys A (15,2 g). MS: (M + H)+ = 406+.A. (R) -7-Bromo-4- [ethenylsulfonyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -4H1,4-benzodiazepine | A solution of Example 224 Compound B (10 g, 31.5 mmol) in dichloromethane (120 mL) at 0 ° C was added dropwise to a solution of 2-chloro-ethanesulfonyl chloride (3.2 mL, 30 mmol) in dichloromethane (10 mL). DIEA (5.2 mL, 30 mmol) was added dropwise. After 15 minutes 2-chloro-ethanesulfonyl chloride (1.5 mL, 15 mmol) was added followed by DIEA (10.4 mL, 60 mmol). The mixture was allowed to warm to room temperature and then poured into water (80 ml). The organic layer was separated, washed with 1N HCl and saturated aqueous NaHCO 3 (80 mL each), dried (MgSO 4 ), and concentrated in vacuo to give yellowish foam compound A (15.2 g). MS: (M + H) < + > = 406 + .
B. (R)-7-Brom-4-[[2-(dimetilamino)etil]sulfonil]-2,3,4,5-tetrahidro-3(fenilmetil)-4H-1,4-benzodiazepinas j kolbą sudedamas junginys A (7 g) ir supilamas dimetilamino tirpalasB. Compound (R) -7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-3 (phenylmethyl) -4H-1,4-benzodiazepine A (7 g) and add a solution of dimethylamine
THF (2M, 20 ml). Kolba užkemšama, mišinys maišomas 18 vai., sukoncentruojama, ir išgryninus chromatografuojant per silikagelio kolonėlę,THF (2M, 20 mL). Stopper the flask, stir for 18 hours, concentrate and purify by silica gel column chromatography,
346 eliuuojamą 20 % acetonu chloroforme, gaunamas junginys B (48 %, skaičiuojant pagal 224 pavyzdžio junginį B).346 eluted with 20% acetone in chloroform afforded Compound B (48% based on Example 224 Compound B).
C. (R)-7-Brom-4-[[2-(dimetilamino)etil]sulfonil]-2,3,4,5-tetrahidro-1(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4H-1,4'benzodiazepinas (dihidrochloridas)C. (R) -7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4'-benzodiazepine (dihydrochloride)
J junginio B (5,3 g, 11,7 mmol) tirpalą dichlormetane (100 ml) pridedama acto rūgšties (15 ml) ir 4-formilimidazolo (1,15 g, 12 mmol). Po 10 min. pridedama natrio triacetoksiborhidrido (2,54 g, 12 mmol). Po 3 vai. pridedama 4-formilimidazolo (0,5 g, 5,8 mmoi) ir borhidrido (1,2 g, 5,5 mmol). Po 5 vai. mišinys koncentruojamas. J liekaną įpilama vandeninio amoniako (100 ml) ir chloroformo (100 ml), ir mišinys intensyviai maišomas 0,5 vai. Atskiriami abu sluoksniai, ir organinis sluoksnis vėl plaunamas vandeniniu amoniaku (100 ml). Sumaišyti vandeniniai sluoksniai ekstrahuojami chloroformu (100 ml), abu organiniai ekstraktai sumaišomi, džiovinami (K2CO3) ir koncentruojami. Jšgryninus liekaną sparčiosios chromatografijos per silikagelio kolonėlę metodu (5 % ir 10 % MeOH chloroforme gradientas), gaunama kieta medžiaga, kuri ištirpinama dichlormetane (50 ml), ir per tirpalą burbuliukais leidžiamas dujinis HCl. Sukoncentravus mišinį vakuume, gaunama kieta medžiaga, kuri ištirpinama vandenyje, ir po liofilizavimo gaunamas junginys C (5,2 g, 73 %).To a solution of Compound B (5.3 g, 11.7 mmol) in dichloromethane (100 mL) was added acetic acid (15 mL) and 4-formylimidazole (1.15 g, 12 mmol). After 10 minutes. sodium triacetoxyborohydride (2.54 g, 12 mmol) was added. After 3 or. 4-formylimidazole (0.5 g, 5.8 mmol) and borohydride (1.2 g, 5.5 mmol) were added. After 5 or. the mixture is concentrated. To the residue was added aqueous ammonia (100 mL) and chloroform (100 mL) and the mixture was stirred vigorously for 0.5 h. The two layers were separated and the organic layer was washed again with aqueous ammonia (100 mL). The combined aqueous layers were extracted with chloroform (100 mL), the two organic extracts were combined, dried (K 2 CO 3 ) and concentrated. Purification of the residue by flash column chromatography on silica gel (5% and 10% MeOH in chloroform gradient) gave a solid which was dissolved in dichloromethane (50 mL) and bubbled with HCl gas. Concentration in vacuo gave a solid which was dissolved in water to give compound C (5.2 g, 73%) after lyophilization.
MS: (M + H)+ 532.MS: (M + H) < + > 532.
Analizė išskaičiuota pagal C24H3oBrN502S · 2 HCl.Analysis calculated for C 24 H 30 BrN 5 O 2 S · 2 HCl.
Išskaičiuota: C, 47,61; H, 5,33; N, 11,57.Found: C, 47.61; H, 5.33; N, 11.57.
Rasta: C, 47,36; H, 5,45; N, 11,34,Found: C, 47.36; H, 5.45; N, 11.34.
387 pavyzdysExample 387
347347
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-(3pi r i d i ni Is ulf oni l)-1 H-1,4-benzodiazepinas (trihidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (3-pyridinyl) -1H -1,4-benzodiazepine (trihydrochloride)
387 pavyzdžio junginys (geltona kieta medžiaga) 15 % išeiga pagaminamas iš 248 pavyzdžio junginio C ir 3-piridinsulfonilchlorido pagal 284 pavyzdyje aprašytą metodiką.Example 387 (yellow solid) is prepared in 15% yield from Example 248, C and 3-pyridinesulfonyl chloride according to the procedure described in Example 284.
MS: (M + H)+ 485.MS: (M + H) < + > 485.
2,3,4,5-Tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(feni!metil)-1H-1,4-benzodiazepinas (dihidrochioridas) j 224 pavyzdžio junginio laisvos bazės (0,104 g, 0,19 mmol) tirpalą2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) and the free compound of Example 224. base (0.104 g, 0.19 mmol)
THF (10 ml) -78 °C temperatūroje pridedama BuLi (1,0 M THF, 5 mmol). Po 5 min. pridedama H2O/THF (1:1, 10 ml). Tirpalas prisotinamas NaCl.BuLi (1.0 M in THF, 5 mmol) was added in THF (10 mL) at -78 ° C. After 5 minutes H 2 O / THF (1: 1, 10 mL) was added. The solution is saturated with NaCl.
Vandeninis sluoksnis ekstrahuojamas CH2CI2. Sumaišytos organinės fazėsThe aqueous layer was extracted with CH2Cl2. Mixed organic phases
348 džiovinamos Na2SO4. Nugarinus tirpiklį, gaunama kieta medžiaga, kuri gryninama atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas), ir pavertus ją HCI druska, gaunama 25 mg (30 %) 388 pavyzdžio junginio, kuris yra geltona kieta medžiaga.348 dried Na 2 SO 4 . Evaporation of the solvent affords a solid which is purified by reverse phase preparative HPLC (gradient from aqueous methanol with 0.1% TFA) to the HCl salt to give 25 mg (30%) of Example 388 as a yellow solid.
MS: (M + H)+ 397.MS: (M + H) < + > 397.
389 pavyzdysExample 389
(R)-7-Brom-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazol-4-il)metil]-4(metilsulfonil)-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas) j 224 pavyzdžio junginio laisvos bazės (0,23 g, 0,19 mmol) tirpalą DMF/THF (1:1,10 ml) -10 °C temperatūroje pridedama NaH (60 % mineralinėje alyvoje, 1 g). Po 20 min. pridedama Mel (0,7 ml). Mišinys maišomas -5 °C temperatūroje 1 vai., skaldomas MeOH (5 ml) ir praskiedžiamas CH2CI2 (20 ml). Organinė fazė plaunama 2,5 % NaOH. Organinė fazė džiovinama Na2SO4. Nugarinus tirpiklį, gaunama kieta medžiaga, kuri gryninama atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas), o po to preparatinės TLC metodu (8 % MeOH, 2 % iPr2NH CH2CI2), ir gaunama 10 mg 389 pavyzdžio junginio (10 %), kuris yra balta kieta medžiaga.(R) -7-Bromo-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-4-yl) methyl] -4- (methylsulfonyl) -3- (phenylmethyl) -1H- 1,4-Benzodiazepine (dihydrochloride) To a solution of the free base of the compound of Example 224 (0.23 g, 0.19 mmol) in DMF / THF (1: 1.10 mL) at -10 ° C was added NaH (60% in mineral oil, 1 g). After 20 minutes Mel (0.7 mL) was added. The mixture was stirred at -5 ° C for 1 h, quenched with MeOH (5 mL) and diluted with CH 2 Cl 2 (20 mL). The organic phase was washed with 2.5% NaOH. The organic phase is dried over Na 2 SO 4 . Evaporation of the solvent gives a solid which is purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) followed by preparative TLC (8% MeOH, 2% iPr 2 NH CH 2 Cl 2 ) to give a solid. 10 mg (10%) of the compound of Example 389 which is a white solid.
MS: (M + H)+ 491.MS: (M + H) < + > 491.
390 pavyzdysExample 390
349349
PhPh
AA
N \N \
zMe z Me
Me (R)-4-[(3-(Dimetilamino)propil]suifonil]-2,3,4,5-tetrahidro-1-(1H-imidazol4-iImetil)-7-feniI-3-(feniImetiI)-1 H-1,4-benzodiazepinas (dihidrochloridas)Me (R) -4 - [(3- (Dimethylamino) propyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1 H-1,4-benzodiazepine (dihydrochloride)
A. (R)-4-[I3-Chlorpropil]sulfonil]-2,3,4,5-tetrahidro-7-fenil-3(f en i I m eti l)-1 H-1,4-benzodiazepinasA. (R) -4- [13-Chloropropyl] sulfonyl] -2,3,4,5-tetrahydro-7-phenyl-3 (phenylmethyl) -1H-1,4-benzodiazepine
J 226 pavyzdžio junginio D (4,7 g, 15 mmol) ir DIEA (7 ml, 40 mmol) tirpalą CK2CI2 (40 ml) 0 °C temperatūroje lėtai supilamas 3chlorpropansulfonilchlorido (2 ml, 16 mmol) tirpalas CH2CI2 (5 ml). Po 2 vai. tirpiklis nugarinamas. Liekana ištirpinama CH2CI2 (20 ml), tirpalas plaunamas 1N NaOH (2 x 50 ml), džiovinamas, ir nugarinus gaunamas alyvos pavidalo junginys A (5,5 g).A solution of compound D (4.7 g, 15 mmol) and DIEA (7 mL, 40 mmol) in Example J 226 in CK 2 Cl 2 (40 mL) at 0 ° C was slowly added a solution of 3-chloropropanesulfonyl chloride (2 mL, 16 mmol) in CH 2 Cl 2. 2 (5 mL). After 2 or. the solvent is evaporated. The residue was dissolved in CH 2 Cl 2 (20 mL), washed with 1N NaOH (2 x 50 mL), dried, and evaporated to give the title compound as an oil (5.5 g).
B. (R)-4-[[3-Chlorpropil]sulfonil]-2,3,4,5-tetrahidro-1-(1H-imidazol-4ilmetil)-7-fenil-3-(fenilmetil)-1H-1,4-benzodiazepinasB. (R) -4 - [[3-Chloropropyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1H-1 , 4-Benzodiazepine
Junginio A (5,5 g) ir 4-formilimidazolo (3 g, 30 mmol) tirpalas AcOH/CH2CI2 (1:5, 300 ml) maišomas 1 vai. Pridedama NaBH(OAc)3 (iš viso 9 g, 42 mmol) (3 g kas 4' vai.), ir tirpalas maišomas 12 vai. Tirpiklis nugarinamas, o liekana veikiama 3 % NaOH (50 ml). Kieta medžiaga nufiltruojama, plaunama vandeniu (5 x 100 ml), ir išdžiovinus gaunamas junginys B (7,5 g).A solution of compound A (5.5 g) and 4-formylimidazole (3 g, 30 mmol) in AcOH / CH 2 Cl 2 (1: 5, 300 mL) was stirred for 1 h. NaBH (OAc) 3 (9 g, 42 mmol) (3 g every 4 ') was added and the solution was stirred for 12 h. The solvent was evaporated and the residue was treated with 3% NaOH (50 mL). The solid was filtered off, washed with water (5 x 100 mL) and dried to give Compound B (7.5 g).
C. (R)-4-[[3-(Dimetilamino)propil]sulfonil]-2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-7-fenil-3-(feni!metil)-1H-1,4-benzodiazepinas (dihidrochloridas)C. (R) -4 - [[3- (Dimethylamino) propyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) ) -1H-1,4-benzodiazepine (dihydrochloride)
350350
Junginio B (7 g) ir dimetilamino (2,0 M THF, 75 ml, 150 mmol) tirpalas DMF (150 ml) šildomas (užlydytame vamzdelyje) 80 °C temperatūroje 30 vai. DMF nugarinamas. Liekana perleidžiama per trumpą silikagelio kolonėlę (5 % MeOH, 0,5 % NH4OH CH2CI2). Eliuentas nugarinamas, o liekana grynama atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas), ir pavertus ją HCI druska, gaunamas junginys C, kuris yra nelabai balta kieta medžiaga (5,0 g, 60 % skaičiuojant pagal 226 pavyzdžio junginį D).A solution of compound B (7 g) and dimethylamine (2.0 M in THF, 75 mL, 150 mmol) in DMF (150 mL) was heated (in a sealed tube) at 80 ° C for 30 h. DMF is evaporated. The residue was passed through a short silica gel column (5% MeOH, 0.5% NH 4 OH CH 2 Cl 2). Evaporation of the eluent and purification of the residue by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) to the HCl salt afforded Compound C, which was an off-white solid (5.0 g, 60% based on 226). Example D).
MS: (M + H)+ 544.MS: (M + H) < + > 544.
1H-BMR (CD3OD, 300 MHz) δ: 1,80 (m, 2H), 2,8 (m, 2H), 3,0 (m, 4H), 3,20 (m, 2H), 3,60 (m, 2H), 4,30 (m, 1H), 4,6 (m, 2H), 6,8 (d, 7 Hz, 1H), 7,1-7,6 (m, 13H, 8,92 (s, 1H). 1 H-NMR (CD 3 OD, 300 MHz) δ: 1.80 (m, 2H), 2.8 (m, 2H), 3.0 (m, 4H), 3.20 (m, 2H), 3, 60 (m, 2H), 4.30 (m, 1H), 4.6 (m, 2H), 6.8 (d, 7Hz, 1H), 7.1-7.6 (m, 13H, 8 , 92 (s, 1H).
391 pavyzdysExample 391
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1 H-imidazol-4-ilmetiI)-3-(fenilmetil)-1H1,4-benzodiazepinas (trihidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine (trihydrochloride)
391 pavyzdžio junginys yra 280 pavyzdžio junginys C.The compound of Example 391 is the compound of Example 280.
MS (M+Hf 244.MS (M + H + 244).
392 pavyzdysExample 392
351351
CNCN
MeMe
4-Butil-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-1H-1,4benzodiazepinas (trihidrochloridas)4-Butyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (trihydrochloride)
391 pavyzdžio junginio (0,23 g, 0,7 mmol) ir sviesto aldehido (1 g, 14 mmol) tirpalas 1:4 AcOH/CH2CI2 (25 ml) maišomas kambario temperatūroje 1 vai. Pridedama NaBH(OAc)3 (3,0 g, 14 mmol) ir maišoma 14 vai. Reakcija stabdoma kone. NH4OH, ir mišinys praskiedžiamas 10 % iPrOH CH2CI2 (50 ml). Organinė fazė plaunama 1N NaOH (2 x 20 ml), džiovinama Na2SO4, ir nugarinus gaunama geltona kieta medžiaga (0,4 g), kuri gryninama atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Pavertus HCI druska, liofilizuojant su 1N HCI, gaunamas 392 pavyzdžio junginys, kuris yra geltona kieta medžiaga (45 mg, 12 %).A solution of Example 391 (0.23 g, 0.7 mmol) and butter aldehyde (1 g, 14 mmol) in 1: 4 AcOH / CH 2 Cl 2 (25 mL) was stirred at room temperature for 1 h. NaBH (OAc) 3 (3.0 g, 14 mmol) was added and stirred for 14 h. The reaction is stopped almost. NH 4 OH, and the mixture was diluted with 10% iPrOH in CH 2 Cl 2 (50 mL). The organic phase is washed with 1N NaOH (2 x 20 mL), dried over Na 2 SO 4 and evaporated to give a yellow solid (0.4 g) which is purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Conversion of the HCl salt to lyophilization with 1N HCl gave Example 392 as a yellow solid (45 mg, 12%).
MS (M + H)+ 400.MS (M + H) < + > 400.
393 pavyzdysExample 393
352 (R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-[[2-(4morfolinil)etil]sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)352 (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
A. (R)-7-Brom-2,3,4,5-tetrahidro-4-[[2-(4-morfolinil)etil]sulfonil]-3(fenilmetil)-1H-1,4-benzodiazepinasA. (R) -7-Bromo-2,3,4,5-tetrahydro-4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine
J 386 pavyzdžio junginio A (0,23 g, 0,34 mmol, 61 % grynumo) tirpalą THF (1,5 ml) kambario temperatūroje pridedama morfolino (0,2 ml). Mišinys maišomas 16 vai., praskiedžiamas etilacetatu (15 ml), plaunamas vandeniu ir sočiu NaCl tirpalu (po 15 ml), džiovinamas ir koncentruojamas vakuume. Liekana gryninama sparčiosios chromatografijos per silikagelio kolonėlę metodu, eliuuojant 20 % acetonu chloroforme, ir gaunamas junginys A, kuris yra balta kieta medžiaga (130 mg, 77 %).A solution of compound A of Example J 386 (0.23 g, 0.34 mmol, 61% purity) in THF (1.5 mL) was added at room temperature with morpholine (0.2 mL). The mixture was stirred for 16 h, diluted with ethyl acetate (15 mL), washed with water and brine (15 mL each), dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 20% acetone in chloroform to give Compound A as a white solid (130 mg, 77%).
B. (R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazoi-4-ilmetil)-4-[[2-(4morfoiinil)etil]sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)B. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) ) -1H-1,4-benzodiazepine (dihydrochloride)
Junginio A (0,060 g, 0,12 mmol), 4-formilimidazolo (0,011 g, 0,12 mmol), 3A molekulinių tinklelių ir AcOH (0,2 ml) mišinys dichloretane (0,3 ml) maišomas kambario temperatūroje argono atmosferoje. Po 2 vai. pridedama natrio triacetoksiborhidrido (0,025 g, 0,12 mmol). Pamaišius 16 vai., mišinys praskiedžiamas CHCI3 (10 ml), NH4OH (5 ml) ir NaHCO3 (5 ml) ir maišomas 30 min. Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas CHCb (2 x 20 ml). Sumaišyti organiniai ekstraktai plaunami NaHCCb, vandeniu ir sočiu NaCl tirpalu (po 3 x 10 ml), džiovinami MgSO4, nufiltruojama ir koncentruojama. Liekana gryninama atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Tinkamos frakcijos koncentruojamos vakuume. Liekana nugarinama iš MeOH (1 ml) ir 1N HCI (1 ml) 3 kartus. Ši liekana ištirpinama vandenyje ir po liofilizavimo gaunamas junginys B, kuris yra geltona kieta medžiaga (0,019 g, 28 %).A mixture of compound A (0.060 g, 0.12 mmol), 4-formylimidazole (0.011 g, 0.12 mmol), 3A molecular weight grids, and AcOH (0.2 mL) in dichloroethane (0.3 mL) was stirred at room temperature under argon. After 2 or. sodium triacetoxyborohydride (0.025 g, 0.12 mmol) was added. After stirring for 16 h, the mixture was diluted with CHCl 3 (10 mL), NH 4 OH (5 mL) and NaHCO 3 (5 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl 3 (2 x 20 mL). The combined organic extracts were washed with NaHCCb, water, and saturated aqueous NaCl (3 x 10 mL), dried over MgSO 4, filtered and concentrated. The residue was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The appropriate fractions are concentrated in vacuo. The residue was evaporated from MeOH (1 mL) and 1N HCl (1 mL) 3 times. This residue was dissolved in water and lyophilized to give Compound B as a yellow solid (0.019 g, 28%).
MS (M + H)+ 574.MS (M + H) + 574.
353353
394 pavyzdysExample 394
(R)-7-Brom-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazol-5-il)metil]-4-[[2-(4morfolinil)etil]sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Bromo-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
394 pavyzdžio junginys (gelsva kieta medžiaga) 23 % išeiga pagaminamas iš 393 pavyzdžio junginio A ir N-metil-5-formilimidazolo pagal 393 pavyzdyje aprašytą junginio B gavimo metodiką, maišant ir virinant su grįžtamu šaldytuvu 7 vai. prieš pridedant hidrido, atšaldant iki kambario temperatūros, pridedant hidrido ir, pridėjus hidrido, maišant 16 vai.Example 394 Compound (yellowish solid) was prepared in 23% yield from Example 393 Compound A and N-methyl-5-formylimidazole according to the procedure described in Example 393 for the preparation of Compound B by stirring and refluxing for 7 hours. before adding the hydride, cooling to room temperature, adding the hydride and stirring for 16 hours with the addition of the hydride.
MS (M + H)+ 588,MS (M + H) + 588,
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(4morfolinilsuifonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-morpholinylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)
354354
A. (R)-7-Ciano-2,3,4,5-tetrahidro-4-(4-morfolinilsulfonil)-3-(fenilmetil)1 H-1,4-benzodiazepinasA. (R) -7-Cyano-2,3,4,5-tetrahydro-4- (4-morpholinylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine
J 248 pavyzdžio junginio C (263 mg, 1 mmol) tirpalą acetonitrile (2 ml) kambario temperatūroje argono atmosferoje pridedama morfolinsulfamoilo chlorido (371 mg, 2 mmol) ir DIEA (0,35 ml, 2 mmol). Gautas rudas mišinys maišomas 65 vai., sukoncentruojamas, ir liekana paskirstoma tarp 1N HCI ir chloroformo (po 10 ml). Organinis sluoksnis atskiriamas, plaunamas sočiu NaHCO3, džiovinamas (MgSO4) ir koncentruojamas. Liekana gryninama sparčiosios chromatografijos per silikagelio kolonėlę metodu, eliuuojant 40 % ir 50 % EtOAc heksanuose laipsnišku gradientu, ir gaunamas junginys A (95 mg, 71 %), kuris yra gelsva kieta medžiaga.A solution of Compound C (263 mg, 1 mmol) in Example 248 in acetonitrile (2 mL) at room temperature under argon was added morpholine sulfamoyl chloride (371 mg, 2 mmol) and DIEA (0.35 mL, 2 mmol). The resulting brown mixture was stirred for 65 h, concentrated, and the residue partitioned between 1N HCl and chloroform (10 mL each). The organic layer was separated, washed with saturated NaHCO 3 , dried (MgSO 4 ), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with a gradient gradient of 40% and 50% EtOAc in hexanes to afford Compound A (95 mg, 71%) as a yellowish solid.
MS (M + H)+ = 413.MS (M + H) <+> = 413.
B. (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(4moriolinilsulfonil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (monohidrochloridas)B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-morolinylsulfonyl) -3- (phenylmethyl) -1H-1,4 benzodiazepine (monohydrochloride)
J junginio A (206 mg, 0,5 mmol) tirpalą 1,2-dichloretane (2 ml) kambario temperatūroje argono atmosferoje pridedama 4-formilimidazolo (380 mg, 4 mmol), HOAc (0,5 ml) ir 3A mloekulinių tinklelių. Mišinys sušildomas iki 50 °C ir pridedama natrio triacetoksiborhidrido (330 mg, 1,5 mmol). Po 18 vai. dar pridedama hidrido (212 mg, 1 mmol). Dar po 5 vai. mišinys atšaldomas iki kambario temperatūros, nufiltruojamas per celitą ir atsargiai paveikiamas 30 % NH4OH (10 ml) ir chloroformu (10 ml). Mišinys intensyviai maišomas 1 vai., organinis sluoksnis atskiriamas ir plaunamas 15 % amoniako tirpalu (15 ml), džiovinamas (K2CO3) ir koncentruojamas. Gauta ruda alyva gryninama chromatografuojant per silikagelio kolonėlę, eliuuojamą 5 % MeOH chloroforme, ir gaunama junginio B laisva bazė (150 mg, 61 %), kuri yra balta kieta medžiaga. 26 mg šios medžiagos veikiami 1N HCI eteryje, ir sukoncentravus vakuume gaunamas junginys B (28 mg).To a solution of Compound A (206 mg, 0.5 mmol) in 1,2-dichloroethane (2 mL) at room temperature under argon was added 4-formylimidazole (380 mg, 4 mmol), HOAc (0.5 mL), and 3A molar mesh. The mixture was warmed to 50 ° C and sodium triacetoxyborohydride (330 mg, 1.5 mmol) was added. After 18 or. additional hydride (212 mg, 1 mmol) was added. 5 more hours. the mixture was cooled to room temperature, filtered through celite and carefully treated with 30% NH 4 OH (10 mL) and chloroform (10 mL). The mixture was stirred vigorously for 1 h., The organic layer was separated and washed with 15% ammonia solution (15 ml), dried (K2CO 3), and concentrated. The resulting brown oil was purified by chromatography on a silica gel column eluting with 5% MeOH in chloroform to give Compound B free base (150 mg, 61%) as a white solid. 26 mg of this material is treated with 1N HCl in ether and concentrated under vacuum to give Compound B (28 mg).
MS (M + H)+ = 493; (M-H)' = 491.MS (M + H) <+> = 493; (MH) '= 491.
355355
396 pavyzdysExample 396
(R)-7-Ciano-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazol-5-il)metil]-4-[(4morfolinil)sulfonil]-3-(fenilmetil)-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 - [(4-morpholinyl) sulfonyl] -3- (phenylmethyl) ) -1H-1,4-benzodiazepine (monohydrochloride)
A. (R)-7-Ciano-2,3,4,5-tetrahidro-1-[(1-trifenilmetil-1H-imidazol-4il)metil]-4-[(4-morfolinil)sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas j 395 pavyzdžio junginio laisvos bazės (120 mg, 0,24 mmol) tirpalą acetonitrile (2 ml) kambario temperatūroje argono atmosferoje pridedama trifenilmetilchlorido (83 mg, 0,3 mmol) ir DIEA (0,053 ml, 0,3 mmol). Mišinys virinamas su grįžtamu šaldytuvu 4 vai., atšaldomas iki kambario temperatūros ir koncentruojamas. Liekana ištirpinama chloroforme (15 ml), ir tirpalas plaunamas vandeniu ir sočiu NaHCO3 (po 15 ml). Organinis sluoksnis džiovinamas (MgSO4) ir koncentruojamas. Liekana plaunama šiltais heksanais (2x5 ml), ir gaunamas junginys A (178 mg, 100 %), kuris yra gelsva kieta medžiaga.A. (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-triphenylmethyl-1H-imidazol-4-yl) methyl] -4 - [(4-morpholinyl) sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine To a solution of the free base of Example 395 (120 mg, 0.24 mmol) in acetonitrile (2 mL) at room temperature under argon was added triphenylmethyl chloride (83 mg, 0.3 mmol) and DIEA ( 0.053 mL, 0.3 mmol). The mixture was refluxed for 4 hours, cooled to room temperature, and concentrated. The residue was dissolved in chloroform (15 mL) and the solution was washed with water and saturated NaHCO 3 (15 mL each). The organic layer was dried (MgSO 4 ) and concentrated. The residue was washed with warm hexanes (2 x 5 mL) to give Compound A (178 mg, 100%) as a yellowish solid.
B. (R)-7-Ciano-2,3,4,5-tetrahidro-1-[(1-metil-1H-imidazol-5-il)metil]-4[(4-morfolinil)sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas)B. (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 - [(4-morpholinyl) sulfonyl] -3 - (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)
J junginio A (170 mg, 0,23 mmol) tirpalą dichlormetane (2 ml) -78 °C temperatūroje argono atmosferoje pridedama metiltriflato (0,027 ml, 0,24 mmol). Po 1 vai. šaldymo vonia pakeičiama ledo vonia (0 °C). Po 2 vai. įpilama 50 % vandeninės acto rūgšties (2 ml), ir mišinys virinamas suTo a solution of Compound A (170 mg, 0.23 mmol) in dichloromethane (2 mL) at -78 ° C under argon was added methyl triflate (0.027 mL, 0.24 mmol). After 1 or. replace the cooling bath with an ice bath (0 ° C). After 2 or. 50% aqueous acetic acid (2 ml) is added and the mixture is refluxed
356 grįžtamu šaldytuvu 40 min. Pridedama chloroformo ir sotaus NaHCO3 (po 10 ml), ir mišinys atsargiai maišomas tol, kol sumašėja dujų skyrimasis. Atsargiai dedamas kietas K2CO3, kol vandeninio sluoksnio pH pasidaro lygus 11. Organinis sluoksnis atskiriamas, džiovinamas (K2CO3) ir koncentruojamas vakuume. Kieta liekana plaunama šiltais heksanais ir eteriu (po 2 x 10 ml). Kieta medžiaga ištirpinama EtOAc (5 ml) ir pridedama 1N HCI eteryje (2 ml). Nuosėdos nufiltruojamos ir plaunamos EtOAc (3x5 ml). Išdžiovinus šią kietą medžiagą vakuume 40 °C temperatūroje, gaunamas junginys B, kuris yra gelsva kieta medžiaga (110 mg, 84 %).356 under reflux for 40 min. Chloroform and saturated NaHCO3 (10 mL each) are added and the mixture is stirred gently until gas evolution is reduced. Carefully add solid K 2 CO 3 until the aqueous layer has a pH of 11. The organic layer is separated, dried (K 2 CO 3 ) and concentrated in vacuo. The solid residue was washed with warm hexanes and ether (2 x 10 mL each). The solid was dissolved in EtOAc (5 mL) and added with 1N HCl in ether (2 mL). The precipitate was filtered off and washed with EtOAc (3x5 mL). Drying this solid in vacuo at 40 ° C gave compound B as a yellowish solid (110 mg, 84%).
MS: (M + H)+ = 507.MS: (M + H) < + > = 507.
Analizė išskaičiuota pagal C26H3oN603S · 1,7 HCI.Analysis calculated for C 26 H 30 N 6 O 3 S · 1.7 HCl.
Išskaičiuota: C, 54,75; H, 5,61; N, 14,73.Found: C, 54.75; H, 5.61; N, 14.73.
Rasta: C, 55,15; H, 5,68; N, 14,29.Found: C, 55.15; H, 5.68; N, 14.29.
397 pavyzdysExample 397
CN (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H'imidazol-4-iimetil)-4-[(4aminofenil)sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (hidrochloridas)CN (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4aminophenyl) sulfonyl] -3- (phenylmethyl) -1H-1, 4-Benzodiazepine (hydrochloride)
J maišomą 383 pavyzdžio junginio laisvos bazės (5 mg) tirpalą etilacetate pridedama SnCI2. Tirpalas maišomas kambario temperatūroje 18 vai. Pridedama ΝΗ4ΟΗ, o po to MgSO4. Suspensija nufiltruojama, o filtratas sukoncentruojamas vakuume. Liekana ištirpinama metanolyje, pridedama 1NTo a stirred solution of the free base (5 mg) of the compound of Example 383 in ethyl acetate was added SnCl 2 . The solution was stirred at room temperature for 18 hours. Adds ΝΗ 4 ΟΗ followed by MgSO 4 . The suspension is filtered off and the filtrate is concentrated in vacuo. The residue was dissolved in methanol and 1N was added
357357
HCI eteryje. Nugarinus tirpiklį, gaunama 2,0 mg (40 %) 397 pavyzdžio junginio, kuris yra geltona kieta medžiaga.HCl in ether. Evaporation of the solvent afforded 2.0 mg (40%) of Example 397 as a yellow solid.
398 pavyzdysExample 398
2,3,4,5-Tetrahidro-1-(1 H-imidazof-4-flmetil)-4-[(4-piridiltio)acetil]-7-feniI1 H-1,4-benzodiazepinas (dihidrochloridas)2,3,4,5-Tetrahydro-1- (1H-imidazo-4-methylmethyl) -4 - [(4-pyridylthio) acetyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)
398 pavyzdžio junginys pagaminamas iš 33 pavyzdžio junginio B pagal 101-201 pavyzdžiuose aprašytas metodikas.Example 398 is prepared from Example 33 by Compound B according to the procedures described in Examples 101-201.
MS (M + H)+ 456.MS (M + H) + 456.
NN
N-(4-Chlorfenil)-N’-ciano-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-7fenil-4H-1,4-benzodiazepin-4-imidaminas (monohidrochloridas)N- (4-Chlorophenyl) -N'-cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4H-1,4-benzodiazepine-4-imidamine (monohydrochloride) )
358358
A. N’(4-Chlorfenil)-N’-ciano-1,2,3,5-tetrahidro-7-fenil-4H-1,4benzodiazepin-4-imidaminas j maišomą 12 pavyzdžio junginio B (110 mg, 0,5 mmol) tirpalą DMF pridedama N-(4-chlorfenil)-N’-cianokarbamido (130 mg, 0,62 mmol), o po to EDC (120 mg, 0,61 mmol). Tirpalas maišomas kambario temperatūroje 18 vai. ir paskirstomas tarp etilacetato ir sotaus NH4CI tirpalo. Organinis sluoksnis atskiriamas, plaunamas sočiu NaHCO3 tirpalu ir sočiu NaCl tirpalu, džiovinamas ir koncentruojamas. Perkristalinus liekaną iš MeOH, gaunamas junginys A, kuris yra kieta medžiaga (150 mg, 75 %). MS: 402 (M+H).A. N '(4-Chlorophenyl) -N'-cyano-1,2,3,5-tetrahydro-7-phenyl-4H-1,4-benzodiazepine-4-imidamine in Example 12 Compound B (110 mg, 0, To a solution of 5 mmol) in DMF was added N- (4-chlorophenyl) -N'-cyanocarbamide (130 mg, 0.62 mmol) followed by EDC (120 mg, 0.61 mmol). The solution was stirred at room temperature for 18 hours. and partitioned between ethyl acetate and saturated NH 4 Cl solution. The organic layer was separated, washed with saturated NaHCO 3 solution and saturated NaCl solution, dried and concentrated. Recrystallization of the residue from MeOH gives Compound A as a solid (150 mg, 75%). MS: 402 (M + H) @ +.
B. N-(4-Chlorfenil)-N’-ciano-1,2,3,5-tetrahidro-1-(1H-imidazoI-4ilmetil)-7-fenil-4H-1,4-benzodiazepin-4-imidaminas (monohidrochloridas)B. N- (4-Chlorophenyl) -N'-cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4H-1,4-benzodiazepine-4-imidamine (monohydrochloride)
Junginys B (kieta medžiaga) 78 % išeiga pagaminamas iš junginio A pagal 1 pavyzdyje aprašytą junginio D gavimo metodiką.Compound B (solid) is prepared in 78% yield from Compound A according to the procedure for Compound D described in Example 1.
MS: 482 (M + H).MS: 482 (M + H) @ +.
Analizė išskaičiuota pagal C27H23N7CI · 2,2 HCI · 2H2O.Analysis calculated for C 27 H 23 N 7 Cl · 2.2 HCl · 2 H 2 O
Išskaičiuota: C, 54,30; H, 4,93; N, 16,42; Cl, 18,99.Found: C, 54.30; H, 4.93; N, 16.42; Cl, 18.99.
Rasta: C, 54,57; H, 4,90; N, 16,76; Cl, 18,90.Found: C, 54.57; H, 4.90; N, 16.76; Cl, 18.90.
400 pavyzdysExample 400
4-Acetil-7-brom-1,2,4,5,r,3’-heksahidro-1-(1H-imidazol-4ilmetil)spiro[3H-1,4-benzodiazepin-3,2’-[2H]indenas] (dihidrochioridas)4-Acetyl-7-bromo-1,2,4,5,1'-hexahydro-1- (1H-imidazol-4-ylmethyl) spiro [3H-1,4-benzodiazepine-3,2 '- [2H] indene] (dihydrochloride)
359359
A. N-[(2-Amino-5-bromfenil)karbonil]-2-amino-2indankarboksirūgštisA. N - [(2-Amino-5-bromophenyl) carbonyl] -2-amino-2-indanoic acid
2-Amino-2-indankarboksirūgšties (680 mg, 4,15 mmol), bromizatoinės rūgšties anhidrido (1,0 g, 4,15 mmol) ir piridino-HCI (2,0 g, 1,72 mmol) tirpalas piridine (30 ml) virinamas su grįžtamu šaldytuvu 4 vai., atšaldomas ir koncentruojamas. Liekana paskirstoma tarp vandens (200 ml) ir etilacetato (200 ml). Organinis sluoksnis plaunamas vandeniu (3 x 100 ml), sočiu NaCl tirpalu (50 ml), džiovinamas (MgSO4), ir sukoncentravus gaunamas gelsvas stiklo pavidalo junginys A (350 mg, 22 %). MS (M+H)+ 375.A solution of 2-amino-2-indanecarboxylic acid (680 mg, 4.15 mmol), bromoacetic anhydride (1.0 g, 4.15 mmol) and pyridine-HCl (2.0 g, 1.72 mmol) in pyridine (30 ml) is refluxed for 4 hours, cooled and concentrated. The residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (3 x 100 mL), brine (50 mL), dried (MgSO 4 ), and concentrated to give a yellowish glassy compound A (350 mg, 22%). MS (M + H) < + > 375.
B. 7-Brom-1,2,4,5,1 ’,3’-heksahidro-spiro[3H-1,4-benzodiazepin-2,5dion-3,2’-[2H]indenas]B. 7-Bromo-1,2,4,5,1 ', 3'-hexahydro-spiro [3H-1,4-benzodiazepine-2,5dione-3,2' - [2H] indene]
Junginio A (350 mg, 0,93 mmol), EDC (203 mg, 1,02 mmol), DIEA (0,35 ml, 2,00 mmol) ir HOBt (135 mg, 1,00 mmol) tirpalas DMF (10 ml) maišomas 16 vai., po to supilamas j vandeni (100 ml). Mišinys ekstrahuojamas etilacetatu (2 x 50 ml). Sumaišyti etil acetatini ai sluoksniai plaunami vandeniu (3 x 100 ml), sočiu NaCl tirpalu (100 ml), džiovinami (MgSO4), ir sukoncentravus gaunamas rudas stiklo pavidalo junginys B (150 mg, 45 %). MS (M + H)+ 358.A solution of compound A (350 mg, 0.93 mmol), EDC (203 mg, 1.02 mmol), DIEA (0.35 mL, 2.00 mmol) and HOBt (135 mg, 1.00 mmol) in DMF (10 ml) is stirred for 16 hours, then added to water (100 ml). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate layers were washed with water (3 x 100 mL), brine (100 mL), dried (MgSO 4 ), and concentrated to give a brown glass compound B (150 mg, 45%). MS (M + H) < + > 358.
C. 7-Brom-1,2,4,5,1’,3’-heksahidro-spiro[3H-1,4-benzodiazepin-3,2’[2H]indenas]C. 7-Bromo-1,2,4,5,1 ', 3'-hexahydro-spiro [3H-1,4-benzodiazepine-3,2' [2H] indene]
Į junginio B (150 mg, 0,42 mmol) tirpalą THF (10 ml) pridedama borano (1M THF, 3 ml, 3 mmol). Tirpalas pavirinamas su grįžtamu šaldytuvu 3 vai. ir atšaldomas iki kambario temperatūros. Pridedama metanolio (5 ml), ir tirpalas sukoncentruojamas. Pridedama 5N HCI (10 ml), mišinys pavirinamas su grįžtamu šaldytuvu 4 vai., atšaldomas iki kambario temperatūros, neutralizuojamas iki pH 6 50 % NaOH ir ekstrahuojamas metileno chloridu (3 x 50 ml). Sumaišyti organiniai sluoksniai plaunami sočiu NaCl tirpalu (30 ml), džiovinami (MgSO4), ir sukoncentravus gaunamas gelsvo stiklo pavidalo junginys C (70 mg, 50 %). MS (M + H)+ 330.To a solution of compound B (150 mg, 0.42 mmol) in THF (10 mL) was added borane (1M THF, 3 mL, 3 mmol). The solution is refluxed for 3 hours. and cooled to room temperature. Methanol (5 mL) was added and the solution concentrated. 5N HCl (10 mL) was added, the mixture was refluxed for 4 h, cooled to room temperature, neutralized to pH 6 with 50% NaOH and extracted with methylene chloride (3 x 50 mL). The combined organic layers were washed with saturated NaCl solution (30 mL), dried (MgSO 4 ), and concentrated to give yellowish glass compound C (70 mg, 50%). MS (M + H) + 330.
360360
D. 4-Acetil-7-brom-1,2,4,5,1 ’,3’-heksahidro-spiro[3H-1,4benzodiazepin-3,2’-[2H]indenas]D. 4-Acetyl-7-bromo-1,2,4,5,1 ', 3'-hexahydro-spiro [3H-1,4-benzodiazepine-3,2' - [2H] indene]
Junginys C (70 mg, 0,21 mmol) ištirpinamas THF (5 ml) ir pridedama DIEA (37 μΙ, 0,21 mmol), o po to acetilchlorido (15 μΙ, 0,21 mmol). Tirpalas maišomas 30 min., koncentruojamas, liekana ištirpinama etilacetate (50 ml) ir plaunama vandeniu (3 x 20 ml). Organinis sluoksnis džiovinamas (MgSO4), ir sukoncentravus gaunamas rusvo stiklo pavidalo junginys D.Compound C (70 mg, 0.21 mmol) was dissolved in THF (5 mL) and DIEA (37 μΙ, 0.21 mmol) was added followed by acetyl chloride (15 μΙ, 0.21 mmol). The solution was stirred for 30 min, concentrated, and the residue was dissolved in ethyl acetate (50 mL) and washed with water (3 x 20 mL). The organic layer was dried (MgSO 4 ) and concentrated to give brownish compound D.
E. 4-Acetil-7-brom-1,2,4,5,r,3’-heksahidro-1-(1H-imidazol-4ilmetil)spiro[3H-1,4-benzodiazepin-3,2’-[2H]indenas] (dihidrochloridas)E. 4-Acetyl-7-bromo-1,2,4,5,1'-hexahydro-1- (1H-imidazol-4-ylmethyl) spiro [3H-1,4-benzodiazepine-3,2 '- [ 2H] indene] (dihydrochloride)
Junginys D ir 4-formilimidazolas ištirpinami 1,2-DCE (5 ml) ir pridedama acto rūgšties (0,5 ml), o po to natrio triacetoksiborhidrido. Mišinys maišomas 50 °C temperatūroje 2 vai., ir pridedama sotaus NaHCO3 (5 ml). Mišinys sukoncentruojamas, ir liekana paskirstoma tarp vandens (20 ml) ir etilacetato (20 ml). Organinis sluoksnis plaunamas vandeniu (10 ml), sočiu NaCl tirpalu (10 ml), džiovinamas (MgSO4), koncentruojamas, ir liekana gryninama atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Frakcijos, kuriose yra norimas produktas, sumaišomos koncentruojamos ir liofilizuojamos. Liofilizatas ištirpinamas metanolyje (0,5 ml) ir 1N HCI (5 ml). Šis mišinys koncentruojamas ir liofilizuojamas. Pakartojus šią procedūrą, gaunamas junginys E, kuris yra balta kieta medžiaga (12 mg, 13 %).Compound D and 4-formylimidazole were dissolved in 1,2-DCE (5 mL) and acetic acid (0.5 mL) was added followed by sodium triacetoxyborohydride. The mixture was stirred at 50 ° C for 2 h and saturated NaHCO 3 (5 mL) was added. The mixture was concentrated and the residue partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried (MgSO 4 ), concentrated, and the residue was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The fractions containing the desired product are mixed by concentration and lyophilized. The lyophilisate was dissolved in methanol (0.5 mL) and 1N HCl (5 mL). This mixture is concentrated and lyophilized. Repeating this procedure gives compound E, which is a white solid (12 mg, 13%).
MS: (M + H)+ 451.MS: (M + H) + 451.
401 pavyzdysExample 401
361361
7-Brom-4-[3-(dimetilamino)-1-oksopropil]-2,3,4,5-tetrahidro-1-(1Himidazol-4-ilmetil)-3-(fenilmetil)-1 H-1,4-benzodiazepinas (trifluoracetatas, 1:1)7-Bromo-4- [3- (dimethylamino) -1-oxopropyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4 benzodiazepine (trifluoroacetate, 1: 1)
401 pavyzdžio junginys (balta kieta medžiaga) bendra 6 % išeiga pagaminamas iš 224 pavyzdžio junginio B pagal tokių reakcijų seką: EDC/HOBt tarpininkaujamas akrilo rūgšties kopuliavimas DMF, gryninant produktą sparčiosios chromatografijos metodu; reakcija, naudojama 232 pavyzdžio junginiu D gauti; reakcija, naudojama 224 pavyzdžio junginiui D gauti.Example 401 (white solid) is prepared in a total 6% yield from Example 224 by Compound B according to the following reaction sequence: EDC / HOBt-mediated copolymerization of acrylic acid in DMF by flash chromatography; the reaction used to yield Example 232, Compound D; reaction used to obtain Example 224, Compound D.
MS: (M + H)+ 466.MS: (M + H) + 466.
402 pavyzdysExample 402
(R)-2,3,4,5-Tetrahidro-1-(1-metil-1H-imidazol-5-ilmetil)-4-(fenilsulfonil)-3(feniImetil)-1 H-1,4-benzodiazepin-7-karbonitrilas (monohidrochloridas)(R) -2,3,4,5-Tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -4- (phenylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine 7-carbonitrile (monohydrochloride)
362 (R)-7-Ciano-2,3,4,5-tetrahidro-1-[(((1,1-dimetiletoksi)-karbonil)-1Himidazol-4-il)metil]-4-(fenilsulfonil)-3-(fenilmetil)-1 H-1,4-benzodiazepino (0,23 g, 0,4 mmol, pagaminto iš 312 pavyzdžio junginio pagal 234 pavyzdyje aprašytą junginio A gavimo metodiką) tirpalas CH2CI2 (3 ml) -78 °C temperatūroje per 30 min. supilamas j atšaldytą metiltriflato (2 ml, 17,6 mmol) tirpalą CH2CI2 (10 ml). Tirpalas per 4 vai. lėtai sušildomas iki 0 °C temperatūros.Pridedama PBS buferio (10 ml) ir maišoma 20 min. Organinė fazė atskiriama. Vandeninis sluoksnis ekstrahuojamas CH2CI2 (2 x 10 ml). Sumaišyti organiniai sluoksniai džiovinami Na2SO4, ir nugarinus gaunama alyva, kurią išgryninus atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas) ir pavertus HCl druska, gaunamas 402 pavyzdžio junginys, kuris yra geltona kieta medžiaga (60 mg, 28%).362 (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(((1,1-dimethylethoxy) carbonyl) -1Himidazol-4-yl) methyl] -4- (phenylsulfonyl) - Solution of 3- (phenylmethyl) -1H-1,4-benzodiazepine (0.23 g, 0.4 mmol, prepared from Example 312 according to the procedure for the preparation of Compound A in Example 234) CH 2 Cl 2 (3 mL) -78 At 30 ° C for 30 min. Pour into a cooled solution of methyl triflate (2 mL, 17.6 mmol) in CH 2 Cl 2 (10 mL). Solutions within 4 or. slowly warm to 0 ° C. PBS buffer (10 mL) was added and stirred for 20 min. The organic phase is separated. The aqueous layer was extracted with CH 2 Cl 2 (2 x 10 mL). The combined organic layers were dried over Na 2 SO 4 and evaporated to an oil, which was purified by reverse phase preparative HPLC (gradient from aqueous methanol to 0.1% TFA) and converted to the HCl salt to give Example 402 as a yellow solid (60 mg). , 28%).
MS (M + H)+ 498.MS (M + H) < + > 498.
2,3,4,5-Tetrahidro-1-[(1-metil-1H-imidazol-5-il)metil]-4-(metilsulfonil)-7fenil-3-(piridin-3-il-metil)-1H-1,4-benzodiazepinas (hidrochlorido, 1:1,5, ir trifluoracetato, 1:0,75, druska) j 2,3,4,5-Tetrahi dro-4-(metil sulfoni I)-7-fenil -3-(pi ri din-3-ilmetil)-1 H-1,4benzodiazepino (0,11 g, 0,27 mmol, pagaminto taip, akip aprašyta 3282,3,4,5-Tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4- (methylsulfonyl) -7-phenyl-3- (pyridin-3-ylmethyl) -1H -1,4-benzodiazepine (hydrochloride, 1: 1.5, and trifluoroacetate, 1: 0.75, salt) to 2,3,4,5-tetrahydro-4- (methylsulfonyl) -7-phenyl - 3- (Pyridin-3-ylmethyl) -1H-1,4-benzodiazepine (0.11 g, 0.27 mmol, prepared as described in 328).
363 pavyzdyje) su 3 A molekuliniais tinkleliais (50 mg) tirpalą 1/1 DCE ir acto rūgšties mišinyje (1,8 ml) pridedama 1-metil-5-formilimidazolo (0,060 g, 0,54 mmol), ir mišinys maišomas 70 °C temperatūroje 1 vai, Pridedama natrio triacetoksiborhidrido (0,057 g, 0,27 mmol), ir mišinys maišomas 70 °C temperatūroje 30 min. J mišinį pridedama 1-metil-5-formilimidazolo (0,060 g, 0,54 mmol), ir mišinys maišomas 70 °C temperatūroje 1 vai. Pridedama natrio triacetoksiborhidrido (0,057 g, 0,27 mmol), ir mišinys maišomas 70 °C temperatūroje 30 min. Pastaroji procedūra pakartojama. Mišinys atšaldomas iki kambario temperatūros, praskiedžiamas metileno chloridu (10 ml), nufiltruojamas, ir filtratas koncentruojamas vakuume. Liekana praskiedžiama 1N NaOH (10 ml) ir maišoma kambario temperatūroje 10 min. Tirpalas ekstrahuojamas CH2CI2 (3 x 50 ml), sumaišyti organiniai ekstraktai džiovinami (Na2SO4), nufiltruojami ir koncentruojami vakuume. Liekana gryninama preparatinės HPLC metodu (vandeninio MeOH su 0,1 % TFA gradientas), atrenkamos tinkamos frakcijos ir koncentruojamos vakuume. Liekana nugarinama iš CH3CN (5 ml) ir 1N HCI (1 ml) 3 kartus. Ši liekana ištirpinama CH3CN (1 ml) irΊN HCI (2 ml), ir po liofilizavimo gaunamas 403 pavyzdžio junginys (0,025 g, 19 %), kuris yra balta kieta medžiaga.In Example 363) with 3 A molecular mesh (50 mg), a solution of 1/1 DCE in acetic acid (1.8 mL) was added 1-methyl-5-formylimidazole (0.060 g, 0.54 mmol) and the mixture was stirred at 70 ° C. At C for 1 h, sodium triacetoxyborohydride (0.057 g, 0.27 mmol) was added and the mixture was stirred at 70 for 30 min. To the mixture was added 1-methyl-5-formylimidazole (0.060 g, 0.54 mmol), and the mixture was stirred at 70 ° C for 1 h. Sodium triacetoxyborohydride (0.057 g, 0.27 mmol) was added and the mixture was stirred at 70 ° C for 30 min. The latter procedure is repeated. The mixture was cooled to room temperature, diluted with methylene chloride (10 mL), filtered, and the filtrate concentrated in vacuo. The residue was diluted with 1N NaOH (10 mL) and stirred at room temperature for 10 min. The solution was extracted with CH 2 Cl 2 (3 x 50 mL), the combined organic extracts dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue is purified by preparative HPLC (gradient of aqueous MeOH with 0.1% TFA), the appropriate fractions selected and concentrated in vacuo. The residue was evaporated from CH 3 CN (5 mL) and 1N HCl (1 mL) 3 times. This residue was dissolved in CH 3 CN (1 mL) and ΊN HCl (2 mL) and lyophilized to give Example 403 (0.025 g, 19%) as a white solid.
MS: (M + H)+ 488.MS: (M + H) < + > 488.
Analizė išskaičiuota pagal C27H29N5O2S 1,5 HCI · 2,02 H2O · 0,75 TFA. Išskaičiuota: C, 51,54; H, 5,36; N, 10,54.Analysis calculated for C 27 H 29 N 5 O 2 S 1.5 HCl · 2.02 H 2 O · 0.75 TFA. Found: C, 51.54; H, 5.36; N, 10.54.
Rasta: C, 51,27; H, 5,72; N, 10,95.Found: C, 51.27; H, 5.72; N, 10.95.
404 pavyzdysExample 404
364364
4-[4-(Fluorfenil)sulfonil]-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-2-(2feniIetil)-1 H-1,4-benzodiazepinas (monohidrochloridas)4- [4- (Fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine (monohydrochloride)
404 pavyzdžio junginys (kieta medžiaga) 41 % išeiga pagaminamas iš 364 pavyzdžio junginio A ir 4-fluorbenzensulfonilchlorido pagal 364 pavyzdyje aprašytą junginio B gavimo metodiką.Example 404 Compound (Solid) 41% yield is prepared from Example 364 Compound A and 4-Fluorobenzenesulfonyl chloride according to the procedure described in Example 364 for the preparation of Compound B.
MS: (M + H)+ 491.MS: (M + H) < + > 491.
405 pavyzdysExample 405
BrBr
7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-2-(2feniletil)-1H-1,4-benzodiazepinas (monohidrochloridas)7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine (monohydrochloride)
A. 2,3,4,5-Tetrahidro-2-(2-feniletil)-1H-1,4-benzodiazepinas j maišomą 363 pavyzdžio junginio A (140 mg, 0,52 mmol) tirpalą bevandeniame.THF kambario temperatūroje pridedama l_AH (110 mg). Gauta suspensija maišoma kambario temperatūroje 18 vai., skaldoma pridedant etilacetato, o po to 0,5 ml kone. NH4OH tirpalo ir nufiltruojama. Sukoncentravus filtratą vakuume, gaunamas alyvos pavidalo junginys A (110 mg, 84 %).A. 2,3,4,5-Tetrahydro-2- (2-phenylethyl) -1H-1,4-benzodiazepine is added to a stirred solution of Example 363 Compound A (140 mg, 0.52 mmol) in anhydrous THF at room temperature. (110 mg). The resulting suspension was stirred at room temperature for 18 hours, quenched by addition of ethyl acetate, followed by 0.5 ml. NH 4 OH solution and filter. Concentration of the filtrate in vacuo afforded Compound A as an oil (110 mg, 84%).
B. 2,3,4,5-Tetrahidro-4-(metilsulfonil)-2-(2-feniletil)-1H-1,4benzodiazepinasB. 2,3,4,5-Tetrahydro-4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine
365365
Junginys B (alyva) 61 % išeiga pagaminamas iš junginio A pagal 224 pavyzdyje aprašytą junginio C gavimo metodiką.Compound B (oil) is prepared in 61% yield from Compound A according to the procedure for Compound C described in Example 224.
C. 7-Brom-2,3,4,5-tetrahidro-4-(metilsulfonil)-2-(2-feniletil)-1 H-1,4benzodiazepinas j maišomą junginio C (80 mg, 0,24 mmol) tirpalą CHCI3 iš karto pridedama tetrabutilamonio perbromido (120 mg, 0,24 mmol). Mišinys maišomas kambario temperatūroje 30 min. ir nugarinamas tirpiklis. Liekana paskirstoma tarp vandens ir 50 % etilacetato tirpalo heksanuose. Organinis sluoksnis atskiriamas, plaunamas vandeniu, sočiu NH4CI tirpalu, džiovinamas, ir sukoncentravus gaunamas alyvos pavidalo junginys C (100 mg, 100 %).C. 7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine in a stirred solution of Compound C (80 mg, 0.24 mmol) CHCl 3 was immediately added with tetrabutylammonium perbromide (120 mg, 0.24 mmol). The mixture was stirred at room temperature for 30 min. and evaporating the solvent. The residue is partitioned between water and 50% ethyl acetate in hexanes. The organic layer was separated, washed with water, saturated NH 4 Cl solution, dried, and concentrated to give O-compound (100 mg, 100%) as an oil.
D. 7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4(meti įsu If oni l)-2-(2-f eni lėti l)-1 H-1,4-benzodiazepinas (monohidrochloridas)D. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylphenyl) -2- (2-phenyl) -1H -1,4-benzodiazepine (monohydrochloride)
Junginys D (kieta medžiaga) 92 % išeiga pagaminamas iš junginio C pagal 224 pavyzdyje aprašytą junginio D gavimo metodiką.Compound D (solid) is prepared in 92% yield from Compound C according to the procedure for the preparation of Compound D described in Example 224.
MS: (M + H)+ 489.MS: (M + H) < + > 489.
406 pavyzdysExample 406
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1-metil-1H-imidazol-5-ilmetil)-4-[[2-(1morfolinil)etil]sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -4 - [[2- (1-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
366366
A. (R)-7-Ciano-2,3,4,5-tetrahidro-4-[etenilsulfonil]-3-(fenilmetil)-1H1,4-benzodiazepinas j 248 pavyzdžio junginio C (1,0 g, 3,79 mmol) ir DIEA (2,6 ml, 15,16 mmol) tirpalą dichlormetane (16 ml) 0 °C temperatūroje argono atmosferoje pridedama 2-chloretansulfonilchlorido. Pamaišius 16 vai., reakcijos mišinys praskiedžiamas chloroformu (20 ml) ir NaHCO3 (5 ml). Atskiriami sluoksniai, ir vandeninis sluoksnis ekstrahuojamas chloroformu (2 x 50 ml). Sumaišyti organiniai ekstraktai plaunami NaHCO3 (2 x 20 ml) ir sočiu NaCl tirpalu (2 x 50 ml), džiovinami MgSO4, nufiltruojami, ir sukoncentravus gaunamas junginys A (1,55 g, 116,5%).A. (R) -7-Cyano-2,3,4,5-tetrahydro-4- [ethenylsulfonyl] -3- (phenylmethyl) -1H1,4-benzodiazepine, Example 248 Example C (1.0 g, 3, 79 mmol) and DIEA (2.6 mL, 15.16 mmol) in dichloromethane (16 mL) at 0 ° C under argon are added 2-chloro-ethanesulfonyl chloride. After stirring for 16 h, the reaction mixture was diluted with chloroform (20 mL) and NaHCO 3 (5 mL). The layers were separated and the aqueous layer was extracted with chloroform (2 x 50 mL). The combined organic extracts were washed with NaHCO 3 (2 x 20 mL) and brine (2 x 50 mL), dried over MgSO 4 , filtered, and concentrated to give Compound A (1.55 g, 116.5%).
B. (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1-metil-1H-imidazol-5-ilmetil)-4[[2-(1-morfolinil)etil]sulfonil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (dihidrochloridas)B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -4 - [[2- (1-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)
Junginys B (gelsva kieta medžiaga) bendra 12 % išeiga pagaminamas pagal reakcijų seką, naudojamą šiems junginiams gauti: 353 pavyzdžio junginiui B, chromatografijoje naudojant 1:1 etilacetatą.'heksanus; 353 pavyzdžio junginiui C, reakciją vykdant kambario temperatūroje, maišant 2 dienas ir gryninant atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas).Compound B (yellowish solid) is prepared in a total 12% yield from the reaction sequence used to prepare Example 353 Compound B using 1: 1 ethyl acetate in chromatography; hexanes; Example 353 Compound C was reacted at room temperature with stirring for 2 days and purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA).
MS: (M + H)+ 535.MS: (M + H) < + > 535.
407 pavyzdysExample 407
(R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(4-bromfenilmetil)-1H-1,4-benzodiazepinas (hidrochloridas)(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (4-bromophenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)
367367
407 pavyzdžio junginys pagaminamas iš D-4-bromfenilalanino pagal 224 pavyzdyje aprašytą metodiką; negrynas produktas gryninamas atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Frakcijos, kuriose yra reikiamas produktas, sumaišomos, neutralizuojamos sočiu vandeniniu Na2CO3 tirpalu ir ekstrahuojamos CH2CI2. Sumaišyti ekstraktai džiovinami (Na2SO4) ir nugarinami sumažintame slėgyje. Liekana ištirpinama etilacetate (10 ml) ir pridedama 1N HCI tirpalo eteryje (10 ml). Vakuume nugarinus tirpiklį, gaunamas 407 pavyzdžio junginys, kuris yra geltona kieta medžiaga.Example 407 is prepared from D-4-bromophenylalanine according to the procedure described in Example 224; the crude product was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The fractions containing the desired product are mixed, neutralized with a saturated aqueous solution of Na 2 CO 3 and extracted with CH 2 Cl 2 . The combined extracts are dried (Na 2 SO 4 ) and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and added with 1N HCl in ether (10 mL). Evaporation of the solvent in vacuo gave Example 407 as a yellow solid.
MS (M + H)+ 555.MS (M + H) + 555.
408 pavyzdysExample 408
Br '3 (R)-7-Brom-2,3,4,5-tetrahidro-1-(1 H-imidazol-4-ilmetil)-4-(metilsulfonil)-3(tiazol-4-ilmetiI)-1 H-1,4-benzodiazepinas (hidrochloridas)Br '3 (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (thiazol-4-ylmethyl) -1 H-1,4-benzodiazepine (hydrochloride)
408 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš D(tiazol-4-il)alanino metilo esterio pagal 407 pavyzdyje aprašytą metodiką.Example 408 (yellow solid) is prepared from D (thiazol-4-yl) alanine methyl ester according to the procedure described in Example 407.
MS (M + H)+484.MS (M + H) < + > 484.
409 pavyzdysExample 409
368368
BrBr
AA
Me (R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(propilsulfonil)3-(tiazol-4-ilmetil)-1H-1,4-benzodiazepinas (hidrochloridas)Me (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (propylsulfonyl) -3- (thiazol-4-ylmethyl) -1H-1, 4-Benzodiazepine (hydrochloride)
409 pavyzdžio junginys pagaminamas pagal 408 pavyzdyje aprašytą metodiką, išskyrus tai, kad vietoj metansulfonilchlorido vartojamas propansulfonilchloridas.The compound of Example 409 is prepared according to the procedure described in Example 408, except that propanesulfonyl chloride is used in place of methanesulfonyl chloride.
MS (M + H)+ 510.MS (M + H) + 510.
410 pavyzdysExample 410
BrBr
MeMe
Br (R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(propilsulfonii)3-(4-bromfenilmetil)-1 H-1,4-benzodiazepinas (hidrochloridas)Br (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (propylsulfonyl) 3- (4-bromophenylmethyl) -1H-1,4 benzodiazepine (hydrochloride)
410 pavyzdžio junginys pagaminamas pagal 407 pavyzdyje aprašytą metodiką, išskyrus tai, kad vietoj metansulfonilchlorido vartojamas propansulfonilchloridas.The compound of Example 410 is prepared according to the procedure described in Example 407, except that propanesulfonyl chloride is used in place of methanesulfonyl chloride.
MS (M + H)+ 583.MS (M + H) + 583.
411 pavyzdysExample 411
369369
BrBr
AA
NN
N—SO2Me (R)-7-Brom-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(piridin-3ilmetil)-4-(metilsulfonil)-1 H-1,4-benzodiazepinas (trihidrochloridas)N-SO 2 Me (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4- (methylsulfonyl) -1 H-1,4-benzodiazepine (trihydrochloride)
411 pavyzdžio junginys (gelsva kieta medžiaga) 16 % išeiga pagaminamas iš 350 pavyzdžio junginio A pagal reakcijų seką, naudojamą šiems junginiams gauti: 350 pavyzdžio junginiui C, prijungimą vykdant 0 °C temperatūroje, ir chromatografijoje naudojant etilacetatą; 350 pavyzdžio junginiui D, šildant 60 °C temperatūroje.Example 411 (yellowish solid) was prepared in 16% yield from Example 350 Compound A according to the reaction sequence used to prepare Example 350 Compound C, coupled at 0 ° C, and chromatography using ethyl acetate; 350 for compound D, heated at 60 ° C.
MS: (M + H)+476.MS: (M + H) + 476.
Analizė išskaičiuota pagal C2oH22N5Br02S · 3,00 HCl · 0,17 H2O.Analysis calculated for C 20 H 22 N 5 BrO 2 S · 3.00 HCl · 0.17 H 2 O.
Išskaičiuota: C, 40,80; H, 4,34; N, 11,89.Found: C, 40.80; H, 4.34; N, 11.89.
Rasta: C, 40,79; H, 4,36; N, 11,79.Found: C, 40.79; H, 4.36; N, 11.79.
412 pavyzdysExample 412
BrBr
N—S0oMeN — S0 o Me
370 (R)-7-Brom-2,3,4,5-tetrahidro-1-(1 H-1-metil-imidazol-5-ilmetil)-3-(piridin3-il metil)-4- (meti Isulf oni I)-1 H-1,4-benzodiazepinas (dihidrochloridas)370 (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-1-methylimidazol-5-ylmethyl) -3- (pyridin3-ylmethyl) -4- (methyl isulf oni I) -1H-1,4-benzodiazepine (dihydrochloride)
412 pavyzdžio junginys (gelsva kieta medžiaga) 31 % išeiga pagaminamas iš (R)-7-brom-2,3,4,5-tetrahidro-3-(piridin-3-ilmetil)-4(metilsulfonil)-l H-1,4-benzodiazepino (pagaminto taip, kaip aprašyta 411 pavyzdyje) ir 1-metil-5-formilimidazolo pagal 350 pavyzdyje aprašytą junginio D gavimo metodiką, šildant 60 °C temperatūroje.Example 412 (yellowish solid) is prepared in a 31% yield from (R) -7-bromo-2,3,4,5-tetrahydro-3- (pyridin-3-ylmethyl) -4 (methylsulfonyl) -1H-1 , 4-benzodiazepine (prepared as described in Example 411) and 1-methyl-5-formylimidazole according to the procedure described in Example 350 for the preparation of compound D by heating at 60 ° C.
MS; (M + H)+ 490.MS; (M + H) + 490.
Analizė išskaičiuota pagal C2iH24N5BrO2S · 2,25 HCI 1,38 H2O.Analysis calculated for C 2 i H 24 N 5 BrO 2 S · 2.25 HCl 1.38 H 2 O.
Išskaičiuota; C, 42,23; H, 4,90; N, 11,72.Excluded; C, 42.23; H, 4.90; N, 11.72.
Rasta: C, 42,23; H, 4,90; N, 11,66.Found: C, 42.23; H, 4.90; N, 11.66.
413 pavyzdysExample 413
1,2,3,4-Tetrahidro-7-brom-4-[(1H-imidazol-4-il)metil]-2-fenil-metil-1(fenilmetiloksikarbonil)chinoksalinas (hidrochloridas)1,2,3,4-Tetrahydro-7-bromo-4 - [(1H-imidazol-4-yl) methyl] -2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline (hydrochloride)
A. N-(2-Nitrofenil)-fenilalaninas j DL-fenilalanino (490 mg, 3 mmol) suspensiją vandenyje kambario temperatūroje pridedama natrio rūgščiojo karbonato (0,84 g, 10 mmol) ir 2fluornitrobenzeno (0,63 ml, 6 mmol). Mišinys šildomas 80 °C temperatūroje. Po 16 vai. pridedama etanolio (95 %, 3 ml). Po 6 vai. mišinys dalinai koncentruojamas, kad būtų pašalintas etanolis, ir gautas tirpalas plaunamas etilacetatu ir chloroformu (po 10 ml). Vandeninis sluoksnis parūgštinamas ikiA. N- (2-Nitrophenyl) -phenylalanine To a suspension of DL-phenylalanine (490 mg, 3 mmol) in water at room temperature was added sodium bicarbonate (0.84 g, 10 mmol) and 2-fluoronitrobenzene (0.63 mL, 6 mmol). . The mixture is heated to 80 ° C. After 16 or. ethanol (95%, 3 mL) was added. After 6 or. the mixture was partially concentrated to remove ethanol and the resulting solution was washed with ethyl acetate and chloroform (10 mL each). The aqueous layer is acidified to
371 pH 1 ir ekstrahuojamas chloroformu (2 x 10 ml). Chloroforminiai ekstraktai sumaišomi, džiovinami (MgSO4), ir sukoncentravus vakuume gaunamas junginys A, kuris yra kieta medžiaga (0,81 g, 94 %). MS (M+)+ 287.371 pH 1 and extracted with chloroform (2 x 10 mL). The chloroform extracts were combined, dried (MgSO 4 ), and concentrated in vacuo to give Compound A as a solid (0.81 g, 94%). MS (M +) + 287.
B. N-(2-Nitrofenil)fenilalanino metilo esterisB. N- (2-Nitrophenyl) phenylalanine methyl ester
Į junginio A (780 mg, 2,7 mmol) tirpalą MeOH (15 ml) kambario temperatūroje pridedama HCI dioksane (3 ml, 4M). Po 18 vai. mišinys sukoncentruojamas. Liekana ištirpinama chloroforme (15 ml), ir tirpalas palunamas sočiu NaHCO3 (10 ml) ir sočiu NaCl tirpalu (15 ml). Organinis sluoksnis džiovinamas (MgSO4) ir koncentruojamas vakuume. Geltona alyva chromatografuojama (silikagelis, sparčioji chromatografija, 20 %To a solution of Compound A (780 mg, 2.7 mmol) in MeOH (15 mL) was added HCl in dioxane (3 mL, 4M) at room temperature. After 18 or. the mixture is concentrated. The residue is dissolved in chloroform (15 ml) and the solution is taken up in saturated NaHCO 3 (10 ml) and saturated NaCl solution (15 ml). The organic layer was dried (MgSO 4 ) and concentrated in vacuo. Yellow oil chromatography (silica gel, flash chromatography, 20%
EtOAc/heksanuose), Gaunamas junginys B (740 mg, 91 %), kuris yra geltona kieta medžiaga. MS (M + H)+ 301.EtOAc / hexanes) to give Compound B (740 mg, 91%) as a yellow solid. MS (M + H) + 301.
C. 1,2,3,4-Tetrahidro-3-okso-2-fenilmetil-chinoksalinas i junginio B (720 mg, 2,34 mmol) tirpalą etilacetate (5 ml) kambario temperatūroje pridedama 20 % Pd(OH)2/C (40 mg). Kolba užpildoma vandenilio dujomis, leidžiant jas iš baliono. Po 5 vai. mišinys nufiltruojamas per celitą, ir filtratas sukoncentruojamas vakuume. Bespalvė kieta medžiaga chromatografuojama (silikagelis, sparčioji chromatografija, 30 %C. 1,2,3,4-Tetrahydro-3-oxo-2-phenylmethyl-quinoxaline To a solution of compound B (720 mg, 2.34 mmol) in ethyl acetate (5 mL) at room temperature was added 20% Pd (OH) 2 /. C (40 mg). The flask is filled with hydrogen gas from the cylinder. After 5 or. the mixture was filtered through celite and the filtrate concentrated in vacuo. Colorless solid chromatography (silica gel, flash chromatography, 30%
EtOAc/heksanuose), ir gaunamas junginys C (550 mg, 98 %), kuris yra kieta medžiaga. MS (M + H)+ 239.EtOAc / hexanes) to give Compound C (550 mg, 98%) as a solid. MS (M + H) < + > 239.
D. 1,2,3,4-Tetrahidro-3-okso-2-fenilmetil-1-(feniImetiloksikarbonil)chinoksalinas j junginio C (525 mg, 2,2 mmoi) tirpalą dichlormetane (6 ml) 0 °C temperatūroje pridedama DIEA (0,52 ml, 3 mmol) ir benzilchiorformiato. Mišiniui leidžiama sušilti iki kambario temperatūros per 3 vai. Pridedama DMAP (10 mg) ir piridino (1 ml), ir mišinys maišomas per naktį (16 vai.). Šis mišinys sukoncentruojamas vakuume, ir liekana paskirstoma tarp etilacetato (20 ml) ir 1N HCI (15 ml). Organinis sluoksnis atskiriamas, plaunamas 1N HCI (15 ml), džiovinamas (MgSO4) ir koncentruojamas vakuume. LiekanaD. 1,2,3,4-Tetrahydro-3-oxo-2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline To a solution of compound C (525 mg, 2.2 mmol) in dichloromethane (6 mL) at 0 ° C was added DIEA (0.52 mL, 3 mmol) and benzyl chloroformate. The mixture was allowed to warm to room temperature over 3 hours. DMAP (10 mg) and pyridine (1 mL) were added and the mixture was stirred overnight (16 h). The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (20 mL) and 1N HCl (15 mL). The organic layer was separated, washed with 1N HCl (15 mL), dried (MgSO 4 ) and concentrated in vacuo. Remain
372 chromatografuojama (silikagelis, sparčioji chromatografija, 10 %372 Chromatography (silica gel, flash chromatography, 10%
EtOAc/chloroforme), ir gaunamas junginys D, kuris yra kieta medžiaga (440 mg, 54%). MS (M + H)+ 373,1.EtOAc / chloroform) to give Compound D as a solid (440 mg, 54%). MS (M + H) + 373.1.
E. 1,2,3,4-Tetrahidro-2-fenilmetil-1-(fenilmetiloksikarbonil)chinoksalinasE. 1,2,3,4-Tetrahydro-2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline
Junginio D (380 mg, 1,02 mmol) ir borano THF (1M, 3 ml) mišinys maišomas kambario temperatūroje argono atmosferoje. Po 24 vai. atsargiai įpilama MeOH (10 ml), o po to 1N HCI (1M eteryje, 5 ml). Po 1 vai. mišinys koncentruojamas vakuume. Dar kartą pakartojus aukščiau aprašytą procedūrą, gaunama balta kieta medžiaga, kuri po to veikiama chloroformu ir 10 % amonio hidroksidų (po 20 ml) ir intensyviai maišoma. Po 1 vai. organinis sluoksnis atskiriamas, džiovinamas (MgSO4), ir sukoncentravus vakuume gaunamas junginys E, kuris yra kieta medžiaga (366 mg, 100 %).A mixture of Compound D (380 mg, 1.02 mmol) and borane in THF (1M, 3 mL) was stirred at room temperature under argon. After 24 or. MeOH (10 mL) was added carefully followed by 1N HCl (1M in ether, 5 mL). After 1 or. the mixture is concentrated in vacuo. Repeating the above procedure again gives a white solid which is then treated with chloroform and 10% ammonium hydroxide (20 mL each) and stirred vigorously. After 1 or. the organic layer was separated, dried (MgSO 4 ), and concentrated in vacuo to give Compound E as a solid (366 mg, 100%).
MS (M + H)+ 359,1.MS (M + H) + 359.1.
F. 1,2,3,4-Te1rahidro-7-brom-2-fenilmetil-1-(fenilmetiloksikarbonil)chinoksalinas j maišomą junginio E (340 mg, 0,95 mmol) tirpalą chloroforme (3 ml) kambario temperatūroje per 2 min. supilamas tetrabutilamonio tribromido (457 mg, 0,95 mmol) tirpalas chloroforme (2 ml). Po 10 min. įpilama vandeninio natrio rūgščiojo sulfito tirpalo (10 ml), ir mišinys ekstrahuojamas chloroformu (10 ml). Organinis sluoksnis atskiriamas, džiovinamas (MgSO4) ir koncentruojamas vakuume. Liekana chromatografuojama (silikagelis, sparčioji chromatografija, 15 % :EtOAc/heksanuose), ir gaunamas tirštos alyvos pavidalo junginys F (355 mg, 86 %). MS (M + H)+ 437, 439.F. 1,2,3,4-Tetrahydro-7-bromo-2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline to a stirred solution of Compound E (340 mg, 0.95 mmol) in chloroform (3 mL) at room temperature over 2 min. . a solution of tetrabutylammonium tribromide (457 mg, 0.95 mmol) in chloroform (2 mL) was added. After 10 minutes. aqueous sodium bisulfite solution (10 ml) is added and the mixture is extracted with chloroform (10 ml). The organic layer was separated, dried (MgSO 4 ), and concentrated in vacuo. The residue was chromatographed (silica gel, flash chromatography, 15%: EtOAc / hexanes) to give compound F (355 mg, 86%) as a thick oil. MS (M + H) + 437, 439.
G. 1,2,3,4-Tetrahidro-7-brom-4-[(1H-imidazol-4-il)metil]-2-fenilmetil-1(fenilmetiloksikarbonil)chinoksalinas (hidrochloridas)G. 1,2,3,4-Tetrahydro-7-bromo-4 - [(1H-imidazol-4-yl) methyl] -2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline (hydrochloride)
Į junginio F (345 mg, 0,79 mmol) tirpalą dichlormetane (3 ml) kambario temperatūroje pridedama 4-formilimidazolo (0,3 g, 3,1 mmol), acto rūgšties (1 ml), 3A molekulinių tinklelių ir natrio triacetoksiborhidrido (212 mg, 1To a solution of compound F (345 mg, 0.79 mmol) in dichloromethane (3 mL) at room temperature was added 4-formylimidazole (0.3 g, 3.1 mmol), acetic acid (1 mL), 3A molecular weight grids, and sodium triacetoxyborohydride ( 212 mg, 1
373 mmol). Po 5 vai. pridedama natrio borhidrido (212 mg, 1 mmol). Po 15 vai. mišinys nufiltruojamas, ir filtratas sukoncentruojamas vakuume. Liekana ištirpinama chloroforme (15 ml), pridedama vandeninio amoniako (15 ml) ir intensyviai maišoma. Po 1 vai. organinis sluoksnis atskiriamas, džiovinamas (MgSO4) ir koncentruojamas vakuume. Po chromatogafijos ( silikagelis, sparčioji chromatografija, 10 % i-PrOH chloroforme) gaunama laisva bazė (280 mg, 69 %). j šią kietą medžiagą pridedama 1N HCI eteryje (2 ml), mišinys išdžiovinamas vakuume, ir gaunamas junginys G (28 mg).373 mmol). After 5 or. sodium borohydride (212 mg, 1 mmol) was added. After 15 or. the mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in chloroform (15 ml), aqueous ammonia (15 ml) was added and vigorously stirred. After 1 or. the organic layer was separated, dried (MgSO 4 ) and concentrated in vacuo. Chromatography (silica gel, flash chromatography, 10% i-PrOH in chloroform) gives the free base (280 mg, 69%). To this solid was added 1N HCl in ether (2 mL), the mixture was dried in vacuo to give compound G (28 mg).
MS (M + H)+ = 517, 519.MS (M + H) <+> = 517, 519.
414 pavyzdysExample 414
CNCN
CN (R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(fenilsulfonil)-3(4-cianofenilmetil)-1H-1,4-benzodiazepinas (hidrochloridas)CN (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3 (4-cyanophenylmethyl) -1H-1,4- benzodiazepine (hydrochloride)
414 pavyzdžio junginys (kieta medžiaga) 12 % išeiga pagaminamas iš (R)-7-brom-2,3,4,5-tetrahidro-3-(4-bromfenilmetil)-1 H-1,4-benzodiazepino (pagaminto taip, kaip aprašyta 407 pavyzdyje) pagal reakcijų seką, naudojamą šiems junginiams gauti: 248 pavyzdžio junginiui C; 224 pavyzdžio junginiui C, naudojant benzensulfonilchloridą; 224 pavyzdžio junginiui D, gryninant atvirkštinių fazių HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas).Example 414 (solid) is prepared in 12% yield from (R) -7-bromo-2,3,4,5-tetrahydro-3- (4-bromophenylmethyl) -1H-1,4-benzodiazepine (prepared as as described in Example 407) according to the reaction sequence used to prepare the following compounds: Compound C of Example 248; Example 224 for compound C using benzenesulfonyl chloride; Example 224 for compound D by reverse phase HPLC purification (gradient of aqueous methanol with 0.1% TFA).
MS (M + H)+ 509.MS (M + H) + 509.
374 13C-BMR (CD3OD, 100 MHz) 39,60, 47,69, 50,29, 55,65, 60,46, 102,42, 111,55, 116,13, 118,47, 119,87, 125,00, 128,22, 129,73, 132,14, 133,34, 133,48, 133,62, 135,32, 136,22, 141,24, 144,60, 152,53 m.d.374 13 C-NMR (CD 3 OD, 100 MHz) 39.60, 47.69, 50.29, 55.65, 60.46, 102.42, 111.55, 116.13, 118.47, 119 , 87, 125.00, 128.22, 129.73, 132.14, 133.34, 133.48, 133.62, 135.32, 136.22, 141.24, 144.60, 152.53 md
(R)-7-Ciano-4-[(N-metil-N-fenilmetil)aminosulfonil]-2,3,4,5-tetrahidro-1[(1 H-imidazol-4-il)metil]-3-(fenilmetil)-1 H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Cyano-4 - [(N-methyl-N-phenylmethyl) aminosulfonyl] -2,3,4,5-tetrahydro-1 [(1H-imidazol-4-yl) methyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)
415 pavyzdžio junginys (pūkų pavidalo kieta medžiaga) 8 % išeiga pagaminamas iš N-metil-N-fenilmetil-sulfamoilchlorido ir 248 pavyzdžio junginio C pagal reakcijų seką, naudojamą šiems junginiams gauti: 355 pavyzdžio junginiui A, reakciją vykdant nuo 0 °C iki kambario temperatūros ir chromatografijoje naudojant 20 % etilacetatą heksanuose; 353 pavyzdžio junginiui C, virinant su grįžtamu šaldytuvu ir pridėjus 3A molekulinių tinklelių. MS: (M + H)+ = 527.Example 415 (fluffy solid) was prepared in 8% yield from N-methyl-N-phenylmethylsulfamoyl chloride and Example 248 Compound C according to the reaction sequence used for the preparation of Example 355 Compound A at 0 ° C to room temperature. temperature and chromatography using 20% ethyl acetate in hexanes; 353 of Example 353 under reflux and addition of 3A molecular mesh. MS: (M + H) < + > = 527.
416 pavyzdysExample 416
375375
(R)-7-Ciano-4-[N-(tetrahidroizochinolinil)sulfonil]-2,3,4,5-tetrahidro-1[(1H-imidazol-4-il)metil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Cyano-4- [N- (tetrahydroisoquinolinyl) sulfonyl] -2,3,4,5-tetrahydro-1 [(1H-imidazol-4-yl) methyl] -3- (phenylmethyl) -1H -1,4-benzodiazepine (monohydrochloride)
416 pavyzdžio junginys (balta kieta medžiaga) 11 % išeiga pagaminamas iš tetrahidroizochinolinilsulfamoilchlorido ir 248 pavyzdžio junginio C pagal 415 pavyzdyje aprašytą metodiką,Example 416 (white solid) is prepared in 11% yield from tetrahydroisoquinolinylsulfamoyl chloride and Example 248 Compound C according to the procedure described in Example 415,
MS: (M + H)+ = 539.MS: (M + H) < + > = 539.
417 pavyzdysExample 417
(R)*7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-4-(fenilsulfonil)-3(2-ti en i I meti I)-1 H-1,4-benzodiazepinas (hidrochloridas)(R) * 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3 (2-thienylmethyl) -1H -1,4-benzodiazepine (hydrochloride)
417 pavyzdžio junginys (geltona kieta medžiaga) pagaminamas iš 2(tienil)alanino ir bromizatoinės rūgšties anhidrido pagal 407 pavyzdyje aprašytą metodiką, vietoj metansulfonilchlorido naudojant benzensulfonilchloridą.Example 417 (yellow solid) is prepared from 2 (thienyl) alanine and bromoacetic anhydride according to the procedure described in Example 407 using benzenesulfonyl chloride in place of methanesulfonyl chloride.
376376
MS: (M + H)+ 490.MS: (M + H) < + > 490.
cis-2,3,4,5-Tetrahidro-1,5-bis(1H-imidazol-4-ilmetil)-3-(fenilmetil)-1H-1,5benzodiazepin-2-karboksirūgšties etilo esteris (trifluoracetatas, 1:2)cis-2,3,4,5-Tetrahydro-1,5-bis (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,5-benzodiazepine-2-carboxylic acid ethyl ester (trifluoroacetate, 1: 2) )
A. 2-Okso-3-fenilmetil·but-3-enkarboksirūgšties etilo esterisA. 2-Oxo-3-phenylmethyl · but-3-enecarboxylic acid ethyl ester
Etil-2-okso-4-fenilbutirato (31,8 mmol, 6,0 ml), Ν,Ν,Ν’,Ν’tetrametildiaminometano (6,6 ml, 54 mmol) ir acto rūgšties anhidrido (10 ml, 106 mmol) tirpalas DMF (100 ml) maišomas kambario temperatūroje 16 vai. ir nugarinamas. Liekana chromatografuojama (sparčioji chromatografija, silikagelis, 20 % EtOAc heksanuose), ir gaunamas skaidrios alyvos pavidalo junginys A (6,46 g, 93 %). MS (M + NH4) + 236.Ethyl 2-oxo-4-phenylbutyrate (31.8 mmol, 6.0 mL), Ν, Ν, Ν ', Ν-tetramethyldiaminomethane (6.6 mL, 54 mmol) and acetic anhydride (10 mL, 106 mmol) DMF (100 mL) was stirred at room temperature for 16 h. and is suppressed. The residue was chromatographed (flash chromatography, silica gel, 20% EtOAc in hexanes) to give Compound A as a clear oil (6.46 g, 93%). MS (M + NH 4 ) + 236.
B. 2,3-Dihidro-3-(fenilmetil)-1 H-1,5-benzodiazepin-2-karboksirūgšties etilo esterisB. 2,3-Dihydro-3- (phenylmethyl) -1H-1,5-benzodiazepine-2-carboxylic acid ethyl ester
Junginio A (6,46 g, 29,6 mmol), fenilendiamino (3,5 g, 32,6 mmol) ir hidrochinono (300 mg, 2,72 mmol) mišinys toluene (250 ml) virinamas su grjžtamu šaldytuvu Dean-Stark'o sąlygomis 6 vai. Mišinys sukoncentruojamas, ir išgryninus liekaną sparčiosios chromatografijos metodu (20 % EtOAc heksanuose) gaunamas junginys B, kuris yra klampi geltona alyva (3,3 g, 36 %). MS (M + H)+ 309.A mixture of compound A (6.46 g, 29.6 mmol), phenylenediamine (3.5 g, 32.6 mmol) and hydroquinone (300 mg, 2.72 mmol) in toluene (250 mL) was refluxed in a Dean-Stark reflux condenser. 's conditions 6 hours. Concentrate the mixture and purify the residue by flash chromatography (20% EtOAc in hexanes) to give Compound B as a viscous yellow oil (3.3 g, 36%). MS (M + H) + 309.
377377
C, cis-2,3,4,5-Tetrahidro-1,5-bis(1H-imidazol-4-ilmetil)-3-(fenilmetil)1H-1,5-benzodiazepin-2-karboksirūgšties etilo esteris (trifluoracetatas,C, cis-2,3,4,5-Tetrahydro-1,5-bis (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,5-benzodiazepine-2-carboxylic acid ethyl ester (trifluoroacetate,
1:2)1: 2)
Junginys B (165 mg, 0,76 mmol) ištirpinamas 2 ml AcOH ir 2 ml CH2CI2 ir veikiamas 4-formilimidazolu (183 mg, 1,9 mmol) ir NaBH(OAc)3 (645 mg, 3,0 mmol). Mišinys maišomas kambario temperatūroje 16 vai., koncentruojamas, ir liekana paskirstoma tarp sotaus NaHCO3 (50 ml) ir 10 % izopropanolio CH2CI2. Organinė fazė plaunama sočiu NaHCO3 (50 ml), džiovinama Na2SO4, ištirpinama MeOH (2 ml), ir išgryninus atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas) gaunama geltona alyva (120 mg, 23 %), kurią liofiiizuojant iš vandens, gaunamas junginys C, kuris yra nevisai balta pūkų pavidalo kieta medžiaga. MS (M + H)+471.Compound B (165 mg, 0.76 mmol) was dissolved in 2 mL AcOH and 2 mL CH 2 Cl 2 and treated with 4-formylimidazole (183 mg, 1.9 mmol) and NaBH (OAc) 3 (645 mg, 3.0 mmol) ). The mixture was stirred at room temperature for 16 h, concentrated and the residue partitioned between saturated NaHCO 3 (50 mL) and 10% isopropanol in CH 2 Cl 2 . The organic phase is washed with saturated NaHCO 3 (50 mL), dried over Na 2 SO 4 , dissolved in MeOH (2 mL), and purified by reverse phase preparative HPLC (a gradient of aqueous methanol with 0.1% TFA) to give a yellow oil (120 mg, 23%). %) which, when lyophilized from water, yields compound C, which is an off-white, fluffy solid. MS (M + H) + 471.
(R)-7-Ciano-4-[(N-piperidinil)sulfonil]-2,3,4,5-tetrahidro-1-[(1H-imidazol4-il)metil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (monohidrochloridas)(R) -7-Cyano-4 - [(N-piperidinyl) sulfonyl] -2,3,4,5-tetrahydro-1 - [(1H-imidazol4-yl) methyl] -3- (phenylmethyl) -1H- 1,4-benzodiazepine (monohydrochloride)
419 pavyzdžio junginys (pūkų pavidalo balta kieta medžiaga) 26 % išeiga pagaminamas iš N-piperidinilsulfamoilchlorido ir 248 pavyzdžio junginio C pagal 415 pavyzdyje aprašytą metodiką, galutinio produkto chromatografavimui naudojant 5 % metanoli chloroforme.Example 419 (fluffy white solid) is prepared in 26% yield from N-piperidinylsulfamoyl chloride and Example 248 Compound C according to the procedure described in Example 415 using 5% methanol in chloroform for chromatography on the final product.
MS (M + H)+ = 491.MS (M + H) <+> = 491.
420 pavyzdysExample 420
378378
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-1-metil-imidazol-5-ilmetil)-3(fenilmetil)-4-(2-tienilsulfonil)-1 H-1,4-benzodiazepinas (hidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-1-methylimidazol-5-ylmethyl) -3- (phenylmethyl) -4- (2-thienylsulfonyl) -1H- 1,4-Benzodiazepine (hydrochloride)
284 pavyzdžio junginio A (150 mg, 0,366 mmol), 1-metil-5formilimidazolo (121 mg, 1,10 mmol) ir 200 mg 3A molekulinių tinklelių mišinys 2 ml 3:1 DCE/AcOH šildomas 60 °C temperatūroje. Po 1 vai., 4 vai., 7 vai. ir 10 vai. pridedamos alikvotinės dalys natrio triacetoksiborhidrido (116 mg, 0,549 mmol). Po 3 vai., 6 vai. ir 9 vai. pridedamos alikvotinės dalys aldehido (91 mg, 0,946 mmol). Po 9 vai. taip pat pridedama acto rūgšties (1 mi). Sudėjus paskutinę hidrido porciją, mišinys pamaišomas 60 °C temperatūroje 2 vai., praskiedžiamas 5 mi metanolio, nufiltruojamas ir sukoncentruojamas vakuume. Liekana praskiedžiama 100 ml EtOAc ir plaunama 1N NaOH (3 x 50 ml) ir sočiu NaCl tirpalu, Organinis sluoksnis džiovinamas Na2SO4, nufiltruojamas ir sukoncentruojamas vakuume. Liekana gryninama atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas), ir tinkamos frakcijos sukoncentruojamos. Liekana ištirpinama 1M HCI (3x5 mi) ir koncentruojama vakuume. Ši liekana ištirpinama minimaliame acetonitrilo kiekyje, praskiedžiama vandeniu, ir išdžiovinus šaltyje gaunama 60 mg (29 %) 420 pavyzdžio junginio, kuris yra balta kieta medžiaga.A mixture of Example 284 Compound A (150 mg, 0.366 mmol), 1-methyl-5-formylimidazole (121 mg, 1.10 mmol) and 200 mg of 3A molecular mesh was heated in 2 mL of 3: 1 DCE / AcOH at 60 ° C. After 1 or., 4 or., 7 or. is 10 or. aliquots of sodium triacetoxyborohydride (116 mg, 0.549 mmol) were added. After 3 or., 6 or. is 9 or. aliquots of aldehyde (91 mg, 0.946 mmol) were added. After 9am. acetic acid (1 mi) was also added. After the final hydride portion was added, the mixture was stirred at 60 ° C for 2 h, diluted with 5 mL of methanol, filtered and concentrated in vacuo. The residue was diluted with 100 ml EtOAc and washed with 1N NaOH (3 x 50 mL) and saturated aqueous NaCl, dried over Na2S organic layer 4, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and the appropriate fractions were concentrated. The residue was dissolved in 1M HCl (3x5 mL) and concentrated in vacuo. This residue was dissolved in a minimum amount of acetonitrile, diluted with water, and freeze-dried to give 60 mg (29%) of Example 420 as a white solid.
(M + H)+ 504.(M + H) + 504.
Analizė išskaičiuota pagal C26H25N5O2S2 · 1,50 HCI · 0,66 H2O.Analysis calculated for C26H25N5O2S2 · 1.50 HCl · 0.66 H 2 O.
Išskaičiuota: C, 54,77; H, 4,92; N, 12,28.Found: C, 54.77; H, 4.92; N, 12.28.
Rasta: C, 54,77; H, 4,92; N, 12,25.Found: C, 54.77; H, 4.92; N, 12.25.
379379
421 pavyzdysExample 421
CNCN
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(piridin-3ilmetil)-4-[[2-(dimetilamino)etil]sulfonil]-1H-1,4-benzodiazepinas (trihidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4 - [[2- (dimethylamino) ethyl] sulfonyl ] -1H-1,4-benzodiazepine (trihydrochloride)
A. (R)-7-Ciano-2,3,4,5-tetrahidro-3-(piridin-3-ilmetil)-4-[[2(dimetilamino)etil]sulfonil]-1H-1,4-benzodiazepinas į 350 pavyzdžio junginio B (1,0 g, 3,8 mmol) ir DIE (0,66 ml, 3,8 mmol) tirpalą CH2CI2 -78 °C temperatūroje pridedama 2-chloretansulfonilchlorido (0,79 ml, 7,6 mmol). Mišinys maišomas -78 °C temperatūroje 15 min. Pridedama DIEA (0,66 ml, 3,8 mmol), ir mišinys maišomas -78 °C temperatūroje 1 vai. j reakcijos mišinj -78 °C temperatūroje vėl pridedama DIEA (2,6 ml, 15,2 mmol). Mišiniui leidžiama sušilti iki kambario temperatūros ir maišoma 16 vai. Tirpalas sukoncentruojamas vakuume. Liekana ištirpinama 3/1 THF/CH2CI2 (4 ml). Mišinys prisotinamas dimetilaminu, sukonderisuotu naudojant sausu ledu šaldomą gaudykfę kambario temperatūroje. Mišinys maišomas kambario temperatūroje 2 vai. Gautas tirpalas praskiedžiamas 10 % NaHCO3 (100 ml) ir tirpalas ekstrahuojamas 9/1 CH2Cl2/iPrOH (3 x 150 ml). Sumaišyti organiniai ekstraktai džiovinami (Na2SO4), nufiltruojama ir sukoncentravus vakuume gaunamas junginys A (1,5 g, 100 %).A. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (pyridin-3-ylmethyl) -4 - [[2- (dimethylamino) ethyl] sulfonyl] -1H-1,4-benzodiazepine To a solution of 350 in Example 350 Compound B (1.0 g, 3.8 mmol) and DIE (0.66 mL, 3.8 mmol) at -78 ° C was added 2-chloro-ethanesulfonyl chloride (0.79 mL, 7.6 mmol) ). The mixture was stirred at -78 ° C for 15 min. DIEA (0.66 mL, 3.8 mmol) was added and the mixture was stirred at -78 ° C for 1 h. DIEA (2.6 mL, 15.2 mmol) was again added to the reaction mixture at -78 ° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. The solution is concentrated in vacuo. The residue was dissolved in 3/1 THF / CH 2 Cl 2 (4 mL). The mixture is saturated with dimethylamine, configured using a dry ice-cooled trap at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with 10% NaHCO 3 (100 mL) and the solution was extracted with 9/1 CH 2 Cl 2 / iPrOH (3 x 150 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to give Compound A (1.5 g, 100%).
MS: (M + H)+ 400.MS: (M + H) < + > 400.
380380
B. (R)-7-Ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(piridin-3ilmetil)-4-[[2-(dimetilamino)etil]sulfonil]-1H-1,4-benzodiazepinas (trihidrochloridas)B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4 - [[2- (dimethylamino) ethyl] sulfonyl] -1H-1,4-benzodiazepine (trihydrochloride)
J junginio A (0,30 g, 0,75 mmol) tirpalą 1/1 DCE ir acto rūgšties mišinyje (5 ml) su 3A molekuliniais tinkleliais pridedama 4-formilimidazolo (0,14 g, 1,5 mmol), ir mišinys maišomas 70 °C temperatūroje 0,5 vai. Pridedama natrio triacetoksiborhidrido (0,32 g, 1,5 mmol), ir mišinys maišomas 70 °C temperatūroje 15 min. Pridedama 4-formilimidazolo (0,14 g, 1,5 mmol), ir mišinys maišomas 70 °C temperatūroje 0,5 vai. Pridedama natrio triacetoksiborhidrido (0,32 g, 1,5 mmol), ir mišinys maišomas 70 °C temperatūroje 15 min. Pastarosios dvi operacijos pakartojamos keturis kartus. Mišinys atšaldomas iki kambario temperatūros, praskiedžiamas metileno chloridu (30 ml), nufiltruojama ir filtratas koncentruojamas vakuume. Liekana praskiedžiama 25 % NH4OH (50 ml), ir tirpalas ekstrahuojamas 9/1 CH2Cl2/iPrOH (4 x 50 ml). Sumaišyti organiniai ekstraktai džiovinami (Na2SO4), nufiltruojama ir koncentruojama vakuume. Liekana gryninama atvirkštinių fazių preparatinės HPLC metodu (vandeninio MeOH su 0,1 % TFA gradientas), atrenkamos reikiamos frakcijos ir koncentruojamos vakuume. Liekana nugarinama iš 1/1 CH3OH/1N HCI (2 ml) 5 kartus. Ši liekana ištirpinama CH3CN (2 ml) ir 1N HCI (4 ml) ir po liofilizavimo gaunamas junginys B (0,071 g, 16 %), kuris yra kieta medžiaga.A solution of Compound J (0.30 g, 0.75 mmol) in 1/1 DCE / acetic acid (5 mL) with 3A molecular mesh was added with 4-formylimidazole (0.14 g, 1.5 mmol) and the mixture was stirred At 70 ° C for 0.5 h. Sodium triacetoxyborohydride (0.32 g, 1.5 mmol) was added and the mixture was stirred at 70 ° C for 15 min. 4-Formylimidazole (0.14 g, 1.5 mmol) was added and the mixture was stirred at 70 ° C for 0.5 h. Sodium triacetoxyborohydride (0.32 g, 1.5 mmol) was added and the mixture was stirred at 70 ° C for 15 min. The latter two operations are repeated four times. The mixture was cooled to room temperature, diluted with methylene chloride (30 mL), filtered and the filtrate concentrated in vacuo. The residue is diluted with 25% NH 4 OH (50 mL) and the solution is extracted with 9/1 CH 2 Cl 2 / iPrOH (4 x 50 mL). The combined organic extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (gradient of aqueous MeOH with 0.1% TFA), the desired fractions were collected and concentrated in vacuo. The residue was evaporated from 1/1 CH 3 OH / 1N HCl (2 mL) 5 times. This residue was dissolved in CH 3 CN (2 mL) and 1N HCl (4 mL) and lyophilized to give Compound B (0.071 g, 16%) as a solid.
MS: (M + H)+ 480.MS: (M + H) + 480.
Analizė išskaičiuota pagal C24H29N7O2S · 3,3 HCI 0,74 H2O.Analysis calculated for C 24 H 29 N 7 O 2 S · 3.3 HCl 0.74 H 2 O.
Išskaičiuota: C, 47.01; H, 5,55; N. 15,99; S, 5,23; Cl, 19,08.Calculated: C, 47.01; H, 5.55; N. 15.99; S, 5.23; Cl, 19.08.
Rasta: C, 47,00; H, 5,43; N, 15,53; S, 5,00; Cl, 18,98.Found: C, 47.00; H, 5.43; N, 15.53; S, 5.00; Cl, 18.98.
422 pavyzdysExample 422
381381
CNCN
(R)-7-Ciano-2,3,4,5-tetrahidro-1-(1H-1-metil-imidazol-5-ilmetil)-3(feniImetil)-4-(propilsulfoniI)-1 H-1,4-benzodiazepinas (hidrochloridas)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-1-methylimidazol-5-ylmethyl) -3- (phenylmethyl) -4- (propylsulfonyl) -1H-1, 4-Benzodiazepine (hydrochloride)
320 mg (0,87 mmol) 317 pavyzdžio junginio A tirpalas 5 ml dichloretano ir 500 ml ledinės acto rūgšties veikiamas 478 mg (4,34 mmol) 1metilimidazol-5-karboksaldehido ir 3 A molekuliniais tinkleliais. Mišinys šildomas 60 °C temperatūroje, maišomas 5 vai. ir veikiamas 763 mg (3,60 mmol) natrio triacetoksiborhidrido. Mišiniui leidžiama atvėsti iki kambario temperatūros, maišoma 18 vai. ir nufiltruojama. Filtratas sukoncentruojamas vakuume. Liekana paskirstoma tarp 150 ml 1N natrio hidroksido ir 150 ml etilacetato. Organinis sluoksnis plaunamas sočiu NaCl tirpalu, džiovinamas (Na2SO4), nufiltruojamas ir sukoncentruojamas vakuume. Ruda alyva gryninama atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Gauta balta putų pavidalo medžiaga nugarinama 3 kartus iš vandeninio chlorido tirpalo metanolyje. Balta putų pavidalo medžiaga ištirpinama vandenyje, ir po liofilizavimo gaunamas 422 pavyzdžio junginys (59 mg, 15 %), kuris yra baltas liofilizatas.A solution of 320 mg (0.87 mmol) of Example 317 Compound A in 5 mL of dichloroethane and 500 mL of glacial acetic acid was treated with 478 mg (4.34 mmol) of 1-methylimidazole-5-carboxaldehyde and 3 A molecular mesh. The mixture is heated to 60 ° C and stirred for 5 hours. and treated with 763 mg (3.60 mmol) of sodium triacetoxyborohydride. The mixture was allowed to cool to room temperature and stirred for 18 hours. and filtered off. The filtrate is concentrated in vacuo. The residue is partitioned between 150 ml of 1N sodium hydroxide and 150 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The brown oil was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The resulting white foam was evaporated 3 times from a solution of aqueous chloride in methanol. The white foam is dissolved in water to give, after lyophilization, the compound 422 (59 mg, 15%) as a white lyophilisate.
MS: (M + H)+ = 464+.MS: (M + H) < + > = 464 + .
423 pavyzdysExample 423
382382
N-(Ciano)-N’-metil-1,2,3,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-7-fenil-4H1,4-benzodiazepin-4-imidatas (hidrochloridas)N- (Cyano) -N'-methyl-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 H -1,4-benzodiazepine-4-imidate (hydrochloride)
A. N-(Ciano)-O-fenil-1,2,3,5-tetrahidro-7-fenil-4H-1,4-benzodiazepin4-imidatasA. N- (Cyano) -O-phenyl-1,2,3,5-tetrahydro-7-phenyl-4H-1,4-benzodiazepin-4-imidate
500 mg (1,58 mmol) 224 pavyzdžio junginio B tirpalas 20 ml DMF argono atmosferoje veikiamas 390 mg (1,64 mmol) difenilcianokarbonimido, o po to 275 μΙ (1,58 mmol) DIEA ir 97 mg (0,79 mmol) DMAP. Mišinys maišomas kambario temperatūroje 15 min., 80 °C temperatūroje - 3,5 vai. ir vėl kambario temperatūroje - 80 vai. Po to mišinys paskirstomas tarp 250 ml etilacetato ir 250 ml 1N natrio hidroksido. Vandeninis sluoksnis ekstrahuojamas 3 kartus po 100 ml etilacetato. Sumaišyti organiniai sluoksniai plaunami sočiu NaCl tirpalu, džiovinami (Na2SO4), nufiltruojami ir koncentruojami vakuume. Alyvos pavidalo liekana gryninama sparčiosios chromatografijos metodu (silikagelis, 40 % etilacetatas heksane), ir gaunama 456 mg (63 %) junginio A, kuris yra balta kieta medžiaga.A solution of 500 mg (1.58 mmol) of Compound B of Example 224 in 20 mL of DMF under argon was treated with 390 mg (1.64 mmol) of diphenylcyanocarbonimide followed by 275 μΙ (1.58 mmol) of DIEA and 97 mg (0.79 mmol). DMAP. The mixture was stirred at room temperature for 15 minutes and at 80 ° C for 3.5 hours. and again at room temperature for 80 hours. The mixture was then partitioned between 250 mL of ethyl acetate and 250 mL of 1N sodium hydroxide. The aqueous layer was extracted 3 times with 100 mL of ethyl acetate. The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The oily residue is purified by flash chromatography (silica gel, 40% ethyl acetate in hexane) to give 456 mg (63%) of Compound A as a white solid.
B. N-(Ciano)-N’-metil-1,2,3,5-tetrahidro-7-fenil-4H-1,4-benzodiazepin4-imidatasB. N- (Cyano) -N'-methyl-1,2,3,5-tetrahydro-7-phenyl-4H-1,4-benzodiazepine-4-imidate
180 mg (0,39 mmol) junginio A tirpalas 1 ml DMF veikiamas 242 μΙ (1,94 mmol) 33 % metilamino tirpalo etanolyje. Mišinys maišomas kambario temperatūroje 1 vai. ir koncentruojamas. Liekana ištirpinama 100 ml etilacetato, plaunama sočiu NaCl tirpalu, džiovinama (Na2SO4), irA solution of 180 mg (0.39 mmol) of Compound A in 1 mL of DMF was treated with 242 μΙ (1.94 mmol) of a 33% solution of methylamine in ethanol. The mixture was stirred at room temperature for 1 hour. and concentrated. The residue is dissolved in 100 ml of ethyl acetate, washed with saturated NaCl solution, dried (Na 2 SO 4 ), and
383 sukoncentravus vakuume gaunama 125 mg (87 %) junginio B, kuris yra balta kieta medžiaga. MS (M + H)+ = 400.Concentration in vacuo yielded 125 mg (87%) of Compound B as a white solid. MS (M + H) <+> = 400.
C. N-(Ciano)-N’-metil-1,2,3,5-tetrahidro-1-(1 H-imidazol-4-ilmetil)-7fenil-4H-1,4-benzodiazepin-4-imidatas (hidrochloridas)C. N- (Cyano) -N'-Methyl-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4H-1,4-benzodiazepine-4-imidate ( hydrochloride)
115 mg (0,29 mmol) junginio B tirpalas 2,5 mi dichloretano ir 2,5 ml ledinės acto rūgšties veikiamas 69 mg (0,71 mmol) 4-imidazolkarboksaldehido, pridėjus 3A molekulinių tinklelių, ir maišoma kambario temperatūroje 18 vai. Šis mišinys veikiamas 122 mg (0,58 mmol) natrio triacetoksiborhidrido, kuris sudedamas iŠ karto, pamaišoma kambario temperatūroje 30 min. ir nufiltruojama. Filtratas paskirstomas tarp 100 ml etilacetato ir 100 ml 1N natrio hidroksido. Organinis sluoksnis plaunamas sočiu NaCl tirpalu, džiovinamas (Na2SO4) ir koncentruojamas vakuume. Alyvos pavidalo liekana gryninama atvirkštinių fazių preparatinės HPLC metodu (vandeninio metanolio su 0,1 % TFA gradientas). Geltona putų pavidalo liekana nugarinama 3 kartus iš vandenilio chlorido tirpalo metanolyje. Putų pavidalo liekana ištirpinama vandenyje, ir po liofilizavimo gaunama 30 mg (22 %) junginio C, kuris yra geltonas liofilizatas.A solution of 115 mg (0.29 mmol) of Compound B in 2.5 mL of dichloroethane and 2.5 mL of glacial acetic acid was treated with 69 mg (0.71 mmol) of 4-imidazolecarboxaldehyde with 3A molecular mesh and stirred at room temperature for 18 h. This mixture was treated with 122 mg (0.58 mmol) of sodium triacetoxyborohydride which was added immediately and stirred at room temperature for 30 min. and filtered off. The filtrate is partitioned between 100 ml of ethyl acetate and 100 ml of 1N sodium hydroxide. The organic layer was washed with saturated NaCl solution, dried (Na 2 SO 4 ) and concentrated in vacuo. The oily residue is purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The yellow foamy residue is evaporated 3 times from a solution of hydrogen chloride in methanol. The foamy residue is dissolved in water and lyophilized to give 30 mg (22%) of Compound C, which is a yellow lyophilisate.
MS: (M + H)+ = 430.MS: (M + H) < + > = 430.
424-430 pavyzdžiai424-430 examples
424-430 pavyzdžių junginiai pagaminami iš 248 pavyzdžio junginio C ir atitinkamo sulfonilchlorido pagal reakcijų seką, naudojamą šiems junginiams gauti: 299 pavyzdžio junginiui A, 317 pavyzdžio junginiui B. Gauti patenkinami 424-430 pavyzdžių junginių C, H ir N analizės duomenys.Examples 424-430 are prepared from Example 248 Compound C and the corresponding sulfonyl chloride according to the reaction sequence used to prepare Example 299 Compound A, Example 317 Compound B. Satisfactory data are obtained for Examples 424-430 Compounds C, H, and N.
Pav.Fig.
Masių spektrasMass spectrum
384384
CNCN
424 (R)-7-Ciano-4-[(2-nitrofenil)sulfonil]-2,3,4,5-tetrahidro-1 (1 H-imidazol-4-ilmetil)-3(fenilmetil)-l H-1,4benzodiazepinas (hidrochloridas)424 (R) -7-Cyano-4 - [(2-nitrophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride)
425 (R)-7-Ciano-4-[(4-metilfenil)sulfonil]-2,3,4,5-tetrahidro-1 (1 H-imidazol-4-ilmetil)-3(fenilmetil)-l H-1,4benzodiazepinas (hidrochloridas)425 (R) -7-Cyano-4 - [(4-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride)
426 (R)-7-Ciano-4-(butilsulfonil)2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-3(fenilmetil)-l H-1,4benzodiazepinas (hidrochloridas)426 (R) -7-Cyano-4- (butylsulfonyl) 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)
427 (R)-7-Ciano-4-[(2trifluometilfenil)-sulfonil]2,3,4,5-tetrahidro-1 -(1Himidazol-4-ilmetil)-3(fenilmetil)-l H-1,4benzodiazepinas (hidrochloridas)427 (R) -7-Cyano-4 - [(2-trifluoromethylphenyl) sulfonyl] 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine ( hydrochloride)
428 (R)-7-Ciano-4-[(2-trifluormetoksifenil)-sulfonil]-2,3,4,5tetrahidro-1 -(1 H-imidazol-4i lmetil)-3-(fenilmetil)-l H-1,4benzodiazepinas (hidrochloridas)428 (R) -7-Cyano-4 - [(2-trifluoromethoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride)
m/zm / z
498 (M+H) m/z498 (M + H) m / z
464 (M+H) m/z 552 (M + H) m/z 529 (M + H) m/z464 (M + H) m / z 552 (M + H) m / z 529 (M + H) m / z
568 (M + H)568 (M + H)
385385
429 (R)-7-Ciano-4-[(2-metoksikarbonilfenil)su!fonil]-2,3,4,5tetrahidro-1 -(1 H-imidazol-4ilmetil) -3-(fenilmetil)-1 H-1,4benzodiazepinas (hidrochloridas)429 (R) -7-Cyano-4 - [(2-methoxycarbonylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride)
430 (R)-7-Ciano-4-[(2-metilsulfonilfenil)su!fonil]-2,3,4,5tetrahidro-1 -(1 H-imidazol-4il metil)-3-(feniImetil)-1 H-1,4benzodiazepinas (hidrochloridas)430 (R) -7-Cyano-4 - [(2-methylsulfonylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine (hydrochloride)
431 pavyzdysExample 431
Panaudojant čia aprašytus metodus, bei kitus specialistams žinomus metodus, buvo pagaminti tokie junginiai:Using the methods described herein and other methods known to those skilled in the art, the following compounds were prepared:
(R)-7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3- m/z 562 (fenilmetil) -4-(((4-metilsuIfonil)fenil)sulfonil)-1 H-1,4- (M + H) benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3- m/z 552 (fenilmetil)-4-(((4-trifluormetil)fenil)sulfonil)-iH-1,4- (M + H) benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3- m/z 480 (fenilmetil)-4-((3-metoksipropil)sulfonil)-1H-1,4-benzodiazepinas (M + H) (R)-7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3- m/z 544 (fenilmetil)-4-((3,4-dimetoksifenil)sulfonil)-1 H-1,4- (M + H) benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3- m/z 502 ((4-fluorfenil)metil)-4-(fenilsulfonil)-1 H-1,4-benzodiazepinas (M + H) (R)-7-ciano-4-[(N-ciklopropilmetil-N-propil)-aminosulfonil]-1-[(1H- m/z 519 imidazol-4-il)metil]-3-(fenilmetil)-1H-1,4-benzodiazepinas (M + H)(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- m / z 562 (phenylmethyl) -4 - (((4-methylsulfonyl) phenyl) sulfonyl) -1H-1,4- (M + H) benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - m / z 552 (phenylmethyl) -4 - (((4-trifluoromethyl) phenyl) sulfonyl) -1H-1,4- (M + H) benzodiazepine (R) -7-cyano-2,3,4,5 -tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- m / z 480 (phenylmethyl) -4 - ((3-methoxypropyl) sulfonyl) -1H-1,4-benzodiazepine (M + H) ( R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-m / z 544 (phenylmethyl) -4 - ((3,4-dimethoxyphenyl) sulfonyl) -1H-1,4- (M + H) benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-m / z 502 ((4-fluorophenyl) methyl) -4- (phenylsulfonyl) -1H-1,4-benzodiazepine (M + H) (R) -7-cyano-4 - [(N-cyclopropylmethyl-N-propyl) -aminosulfonyl] -1 - [(1H-m / z 519 imidazol-4-yl) methyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (M + H)
386 (R)-7-ciano-4-[(N,N-(dibutilamino))sulfonil]-1-[(1 H-imidazol-4- m/z 535 il)metil]-3-(fenilmetil)-1 H-1,4-benzodiazepinas (M + H) (R)-7-chlor-4-(metansulfonil)-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4- m/z 432 ilmetil)-3-(fenilmetil)-1H-pirido[3,4-e]-1,4-diazepinas (M + H)386 (R) -7-Cyano-4 - [(N, N- (dibutylamino)) sulfonyl] -1 - [(1H-imidazole-4-m / z 535 yl) methyl] -3- (phenylmethyl) - 1H-1,4-Benzodiazepine (M + H) (R) -7-Chloro-4- (methanesulfonyl) -2,3,4,5-tetrahydro-1- (1H-imidazole-4-m / z) 432 ylmethyl) -3- (phenylmethyl) -1H-pyrido [3,4-e] -1,4-diazepine (M + H)
1,2,3,4-tetrahidro-7-brom-4-[(1 H-imidazol-4-il)metil]-2-fenilmetil-1 - m/z 460 (metilsulfonil)chinoksalinas (M + H) (R)-7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3- m/z 424 (fenilmetil)-4-((imidazol-4-il)metilsulfonil)-1 H-1,4-benzodiazepinas (M + H)1,2,3,4-Tetrahydro-7-bromo-4 - [(1H-imidazol-4-yl) methyl] -2-phenylmethyl-1- m / z 460 (methylsulfonyl) quinoxaline (M + H) ( R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-m / z 424 (phenylmethyl) -4 - ((imidazol-4-yl) methylsulfonyl) -1H-1,4-benzodiazepine (M + H)
Pagal aukščiau aprašytas metodikas gali būti pagaminami tokie junginiai:The following compounds may be prepared according to the procedures described above:
(R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-((2-tienil)metil)-4(propi Isulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-((2-tienil)metil)-4-((2tienil)sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-((3metil propil) sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-(((3metiltiokso)propil)sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-(((3metilsulfonil) propil)sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-((2metilpropil)sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4(ciklopenti įsu Ifoni I) -1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-((4,4,4trifl uorbutil) sulfonil) -1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4((fenilmetil) sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-[[2-(5(N-benzoil)aminometil)tienil]sulfonil)-1 H-1,4-benzodiazepinas(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - ((2-thienyl) methyl) -4 (propylsulfonyl) -1H- 1,4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - ((2-thienyl) methyl) -4 - (( 2-thienyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((3-methylpropyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- ( phenylmethyl) -4 - (((3-methylthioxo) propyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazole-4- ylmethyl) -3- (phenylmethyl) -4 - (((3-methylsulfonyl) propyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- ( 1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((2-methylpropyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro- 1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (cyclopentylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5- tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((4,4,4-trifluorobutyl) sulfonyl) -1H-1,4-benz odiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 ((phenylmethyl) sulfonyl) -1H-1, 4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [[2- (5 (N- benzoyl) aminomethyl) thienyl] sulfonyl) -1H-1,4-benzodiazepine
387 (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-[[2-(1(3-chlor-5-metil-piridin-2-il))pirolil]sulfonil]-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-((4karboksifeni I) sulfoni I) -1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-[((3metil-1,2,4-oksadiazol-5-il)fenil)sulfonil]-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-((2,5d im etoksifeni I) sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-4-[(N-tetrahidrochinolinil) sulfonil]-1 -[(1 H-imidazol-4-i!)metil]-3(fenilmetil)-l H-1,4-benzodiazepinas (R)-7-ciano-4-[(N,N-bis-[1-(2-metilpropil)amino]sulfonil]-1-[(1H-imidazol-4il)metil]-3-(fenilmetil)-1 H-1,4-benzodiazepinas (R)-7-ciano-4-[(N-metil-N-fenil)aminosulfonil]-1-[(1H-imidazol-4-il)metil]-3(fenilmetil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(2-(2,6-dimetilfenil)etil)-4-(metilsulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1-(N-ftalimidoetil)-imidazol-5-ilmetil)-3(fenilmetil) -4-(metilsuIfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-[(2-(N,N-dimetilamino)etil)-imidazol-5-ilmetil]3-(fenilmetil)-4-(metilsulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-[(2-(N,N-aminoetil)-imidazol-5-ilmetil]-3(fenilr netil)-4-(metilsulfonil)-1 H-1,4-benzodiazepinas (R)-7-brom-4-(metansulfonil)-2,3,4,5-tetrahidro-1-[(1H-imidazol-4-ilmetil)-3(fenilmetil)-1 H-tieno[2,3-e]-1,4-diazepinas (R)-7-brom-4-(metansulfonil)-2,3,4,5-tetrahidro-1-[(1H-imidazol-4-ilmetil)-3(fenilmetil)-l H-tieno[3,2-e]-1,4-diazepinas (R)-4-(metansulfonil)-2,3,4,5-tetrahidro-1-[(1H-imidazol-4-ilmetil)-3-(fenilmetil)1 H-8-okso-pirimidino[4,5-e]-1,4-diazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-((4-(2-metoksietoksi)fenil)metil)-4-(fenilsulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-((4-(2-(dimetilamino)etoksi)fenil) metil)-4-(fenilsulfonil)-1 H-1,4-benzodiazepinas387 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [[2- (1 (3-chloro) 5-methyl-pyridin-2-yl) pyrrolyl] sulfonyl] -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazole-4 -ylmethyl) -3- (phenylmethyl) -4 - ((4-carboxyphenyl) sulfone) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- ( 1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [((3-methyl-1,2,4-oxadiazol-5-yl) phenyl) sulfonyl] -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((2,5d imethoxyphenyl) sulfonyl) -1H- 1,4-Benzodiazepine (R) -7-cyano-4 - [(N-tetrahydroquinolinyl) sulfonyl] -1 - [(1H-imidazol-4-yl) methyl] -3 (phenylmethyl) -1H-1 , 4-Benzodiazepine (R) -7-cyano-4 - [(N, N-bis- [1- (2-methylpropyl) amino] sulfonyl] -1 - [(1H-imidazol-4yl) methyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (R) -7-cyano-4 - [(N-methyl-N-phenyl) aminosulfonyl] -1 - [(1H-imidazol-4-yl) methyl] - 3- (phenylmethyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (2- (2) , 6-dimethylphenyl) e ethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1- (N-phthalimidoethyl) imidazole-5- ylmethyl) -3- (phenylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1 - [(2- (N, N -dimethylamino) ethyl) -imidazol-5-ylmethyl] 3- (phenylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro- 1 - [(2- (N, N-aminoethyl) imidazol-5-ylmethyl] -3- (phenylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (R) -7-bromo-4 - (methanesulfonyl) -2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-thieno [2,3-e] -1,4-diazepine (R) -7-Bromo-4- (methanesulfonyl) -2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-thieno [3.2 -e] -1,4-diazepine (R) -4- (methanesulfonyl) -2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-ylmethyl) -3- (phenylmethyl) 1H- 8-Oxo-pyrimidino [4,5-e] -1,4-diazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (((4- (2-methoxyethoxy) phenyl) methyl) -4- (phenylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H) -imidazol-4-yl ethyl) -3 - ((4- (2- (dimethylamino) ethoxy) phenyl) methyl) -4- (phenylsulfonyl) -1H-1,4-benzodiazepine
388 (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilsulfonil)-3-(fenilmetil)-4(meti lsulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilsulfonil)-3-(fenilmetil)-4(p ropi Isulfonil) -1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilsulfonil)-3-(fenilmetil)-4(fenil sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-innidazol-4-ilsulfonil)-3-(fenilmetil)-4-(2tienilsulfonil)-1 H-1,4-benzodiazepinas388 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylsulfonyl) -3- (phenylmethyl) -4 (methylsulfonyl) -1H-1,4- benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylsulfonyl) -3- (phenylmethyl) -4- (pyropisulfonyl) -1H-1, 4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylsulfonyl) -3- (phenylmethyl) -4 (phenylsulfonyl) -1H-1, 4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-innidazol-4-ylsulfonyl) -3- (phenylmethyl) -4- (2-thienylsulfonyl) -1H-1, 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(R)-[(R)-1 -feniletil]-4(m etilsulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenylethyl] -4 (methylsulfonyl) -1 H-1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(R)-[(R)-1 -feniletil]-4(propi Isulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenylethyl] -4 (propylsulfonyl) -1 H-1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(R)-[(R)-1 -f enil eti l]-4(fenilsulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenyl ethyl] -4 (phenylsulfonyl) -1 H -1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(R)-[(R)-1-fenileti!]-4-((2tienil) sulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenylethyl] -4 - ((2-thienyl) sulfonyl) -1H-1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(S)-[(R)-1 -feniletil]-4(metilsulfonil)-l H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenylethyl] -4 (methylsulfonyl) -1H -1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(S)-[(R)-1-feniletil]-4(propilsulfonil)-l H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenylethyl] -4 (propylsulfonyl) -1H- 1,4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imi dazol-4-il metil) -3- (S) - [(R)-1 -fenil etil ] -4(fenilsulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenyl ethyl] -4 (phenylsulfonyl) -1 H -1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(S)-[(R)-1 -f enil etil]-4-((2tienil) sulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenyl ethyl] -4 - ((2-thienyl) ) sulfonyl) -1H-1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(R)-[(S)-1-feniletil]-4(meti Isulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenylethyl] -4 (methylsulfonyl) -1H -1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(R)-[(S)-1 -fenileti I ]-4(propi Isulfonil) -1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenylethyl] -4 (propylsulfonyl) - 1H-1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(R)-[(S)-1 -f enil eti I]-4(fenilsulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenyl ethyl] -4 (phenylsulfonyl) -1 H -1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(R)-[(S)-1 -f enileti I ] -4- ((2tienil) sulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenylethyl] -4 - ((2-thienyl) ) sulfonyl) -1H-1,4-benzodiazepine
389389
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(S)-[(S)-1-feniletil]-4(metilsulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenylethyl] -4 (methylsulfonyl) -1H- 1,4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(S)-[(S)-1 -f eni lėti I]-4(propilsulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenyl] -4- (propylsulfonyl) -1 H -1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(S)-[(S)-1-feniletil]-4(fenilsulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenylethyl] -4 (phenylsulfonyl) -1H- 1,4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(S)-[(S)-1 -fenil eti I] -4- ((2tienil) sulfonil) -1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenyl ethyl] -4 - ((2-thienyl) ) sulfonyl) -1H-1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(R)-[(R)-fenilciklopropil)4- (meti I sulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4- (methylsulfonyl) -1H- 1,4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(R)-[(R)-fenilciklopropil)4-(propil sulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1 , 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(R)-[(R)-fenilciklopropil)4-(fenilsulfonil)-1 H-1,4-benzodiazepinas7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4- (phenylsulfonyl) -1H-1, 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(R)-[(R)-fenilciklopropil)4- ((2-tienil) sulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4 - ((2-thienyl) sulfonyl) - 1H-1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(R)-[(S)-fenilciklopropil)4-(metilsulfonil)-1 H-1,4-benzodiazepinas7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4- (methylsulfonyl) -1H-1, 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(R)-[(S)-fenilciklopropil)4- (propilsulfonil)-1 H-1,4-benzodiazepinas7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1, 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(R)-[(S)-fenilciklopropil)4-(fenilsulfonil)-1 H-1,4-benzodiazepinas7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4- (phenylsulfonyl) -1H-1, 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidiO-1-(1H-imidazol-4-ilmetll)-3-(R)-[(S)-fenilciklopropil)4-((2-tienil) sulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4 - ((2-thienyl) sulfonyl) - 1H-1,4-benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(S)-[(R)-fenilciklopropil)4- (metilsulfonil)-1 H-1,4-benzodiazepinas7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl) 4- (methylsulfonyl) -1H-1, 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(S)-[(R)-fenilciklopropil)4-(propilsulfonil)-1 H-1,4-benzodiazepinas7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1, 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1 -(1 H-imidazol-4-ilmetil)-3-(S)-[(R)-fenilciklopropil)4- (fenilsulfonil)-l H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl] 4- (phenylsulfonyl) -1H-1 , 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(S)-[(R)-fenilciklopropil)4-((2-tienil)sulfonil)-1 H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl) 4 - ((2-thienyl) sulfonyl) - 1H-1,4-benzodiazepine
390390
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(S)-[(S)-fenilciklopropil)4-(metilsulfonil) -1 H-1,4-benzodiazepinas7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4- (methylsulfonyl) -1H-1, 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(S)-[(S)-fenilciklopropil)4-(propilsulfonil)-1 H-1,4-benzodiazepinas7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1, 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(S)-[(S)-fenilciklopropil)4- (fenilsulfonil)-1 H-1,4-benzodiazepinas7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4- (phenylsulfonyl) -1H-1, 4-Benzodiazepine
7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(S)-[(S)-fenilciklopropil)4-((2-tienil) sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-[(2-(5piridin-2-il))tienil) sulfonil j)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-[(2-(5(1,2-izoksazol-3-il))tienil)sulfonil])-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(3-(1H-imidazol-2-il)-propil)-3-(fenilmetil)-4fenilsulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(3-(1H-imidazol-2-ll)-propil)-3-(fenilmetil)-4metilsulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(3-(1 H-imidazol-2-il)-propil)-3-(fenilmetil)-4p roplį sulfoni I) -1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(3-(1 H-imidazol-2-il)-propil)-3-(fenilmetil)-4-((2tienil)sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(2-(1H-imidazol-2-il)-etilsulfonil)-3-(fenilmetil)4-f enilsulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(2-(1 H-imidazol-2-il)-etilsulfonil)-3-(fenilmetil)4-metilsulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(2-(;1H-imidazol-2-il)-etilsulfonil)-3-(fenilmetil)4-propilsulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(2-(1H-imidazol-2-il)-etilsulfonil)-3-(fenilmetil)4-((2-tienil) sulfonil)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4-((1oksoetil)amino)-1 H-1,4-benzodiazepinas (R)-7-ciano-2,3,4,5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4(metansulfonilamino)-l H-1,4-benzodiazepinas7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4 - ((2-thienyl) sulfonyl) - 1H-1,4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(2- (5-pyridin-2-yl) thienyl) sulfonyl j) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) ) -3- (phenylmethyl) -4 - [(2- (5 (1,2-isoxazol-3-yl)) thienyl) sulfonyl]) - 1H-1,4-benzodiazepine (R) -7-cyano 2,3,4,5-Tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4-phenylsulfonyl) -1H-1,4-benzodiazepine (R) -7 -cyano-2,3,4,5-tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4-methylsulfonyl) -1H-1,4-benzodiazepine (R ) -7-Cyano-2,3,4,5-tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4β-sulfonyl) -1H- 1,4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4- ((2-thienyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (2- (1H-imidazol-2-yl) ethylsulfonyl) -3- (phenylmethyl) 4-phenylsulfonyl) -1H -1,4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (2- (1H-imidazol-2-yl) ethylsulfonyl) -3- (phenylmethyl) 4- methylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (2 - (; 1H-imidazol-2-yl) ethylsulfonyl) -3- (phenylmethyl) 4-propylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (2- (1H-imidazol-2-yl) ethylsulfonyl) ) -3- (Phenylmethyl) 4 - ((2-thienyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazole) -4-ylmethyl) -3- (phenylmethyl) -4 - ((1-oxoethyl) amino) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- ( 1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (methanesulfonylamino) -1H-1,4-benzodiazepine
391 (R)-7-ciano-2,3A5-tetrahidro-1-(1H-imidazol-4-ilmetil)-3-(fenilmetil)-4(fenilsulfonilamino)-l H-1,4-benzodiazepinas.391 (R) -7-Cyano-2,3A-5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonylamino) -1H-1,4-benzodiazepine.
Claims (17)
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US1226596P | 1996-02-26 | 1996-02-26 |
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LT4552B true LT4552B (en) | 1999-10-25 |
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ZA (1) | ZA971621B (en) |
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1997
- 1997-02-25 ZA ZA971621A patent/ZA971621B/en unknown
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- 1998-08-25 LT LT98-120A patent/LT4552B/en not_active IP Right Cessation
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ZA971621B (en) | 1998-08-25 |
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