HRP20000786A2 - New heterocyclically substituted amides, their production and their use - Google Patents
New heterocyclically substituted amides, their production and their use Download PDFInfo
- Publication number
- HRP20000786A2 HRP20000786A2 HR20000786A HRP20000786A HRP20000786A2 HR P20000786 A2 HRP20000786 A2 HR P20000786A2 HR 20000786 A HR20000786 A HR 20000786A HR P20000786 A HRP20000786 A HR P20000786A HR P20000786 A2 HRP20000786 A2 HR P20000786A2
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- Croatia
- Prior art keywords
- alkyl
- hydrogen
- phenyl
- formula
- mmol
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 26
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
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Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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Description
Predloženi izum odnosi se na nove amide koji su inhibitori enzima, posebno cistein proteaza, kao što su kalpain (= o kalciju ovisne cistein proteaze) i njegovi izoenzimi, katepsini, na primjer В i L.
Kalpaini su intracelularni, proteolitički enzimi iz takozvane skupine cistein proteaza i nađeni su u mnogim stanicama. Kalpaini se aktiviraju s povišenom koncentracijom kalcija, pri čemu postoji razlika između kalpaina I ili μ-kalpaina, koji se aktivira s μ-molarnim koncentracijama kalcijevih iona, i kalpaina II ili m-kalpaina, koji se aktivira s m-molarnim koncentracijama kalcijevih iona (P. Johnson, Int. J. Biochem. 1990, 22(8), 811-22). Danas se pretpostavlja da postoje i daljnji kalpainski izoenzimi (K. Suzuki et al., Biol. Chem. Hoppe-Seyler, 1995, 376(9), 523-9).
Pretpostavlja se da kalpaini imaju važnu ulogu u raznim fiziološkim procesima. Tu spada cijepanje regulacijskih proteina, kao što je protein kinaza C, cito-skeletni proteini, kao MAP 2 i spektrin, mišićni proteini, razgradnja proteina kod reumatoidnog artritisa, proteini u aktivaciji trombocita, metabolizam neuropeptida, proteini u mitozi i drugi koji su navedeni u M. J. Barrett et al., Life Sci. 1991, 48, 1659-69 i К. К. Wang et al., Trends u Pharmacol. Sci., 1994, 15, 412-9.
Povišene razine kalpaina izmjerene su u raznim patofiziološkim procesima, na primjer: ishemija srca (npr. kardijalni infarkt), bubrega ili središnjeg nervnog sistema (npr. udar kapi), upale, distrofije mišića, katarakti očiju, ozljede središnjeg nervnog sistema (npr. trauma), Alzheimerova bolest itd. (vidi K. K. Wang, gore). Pretpostavlja se da postoji određena povezanost tih bolesti s povišenim i trajnim unutarstaničnim razinama kalcija. Posljedica toga je da se procesi ovisni o kalciju prekomjerno aktiviraju i više se ne podvrgavaju fiziološkoj regulacji. S tim u skladu, prekomjerno aktiviranje kalpaina također može uzrokovati patofiziološke procese.
Zbog toga se je pretpostavilo da bi se inhibitori enzima kalpaina mogli upotrijebiti za liječenje tih bolesti. To su potvrdila razna istraživanja. Tako su Seung-Chyul Hong et al., Stroke 1994, 25(3), 663-9 i R. Т. Bartus et al., Neurological Res. 1995, 17, 249-58, pokazali neuroprotektivno djelovanje inhibitora kalpaina kod akutnih neurodegenerativnih poremećaja ili ishemija, kao što su oni koji se javljuju nakon moždanog udara. Također, nakon eksperimentalne traume mozga inhibitiri kalpaina poboljšavaju oporavak od gubitka sposobnosti pamćenja i neuromotornih poremećaja koji se pri tome pojavljuju (К. Е. Saatman et al. Proc. Natl. Acad. Sci. USA, 1996, 93, 3428-3433). С. L. Edelstein et al., Proc. Natl. Acad. Sci. USA, 1995, 92, 7662-6, pronašli su zaštitno djelovanje inhibitora kalpaina na bubrege oštećene hipoksijom. Yoshida, Ken Ischi et al., Jap. Circ. J. 1995, 59(1) 40-8, uspjeli su pokazati korisne učinke inhibitora kalpaina nakon kardijalnih oštećenja nastalih ishemijom ili reperfuzijom. Budući da inhibitori kalpaina inhibiraju oslobađanje β-AP4 proteina, preporučena je njegova moguća upotreba kao terapeutika za Alzheimerovu bolest (J. Higaki et al., Neuron, 1995, 14, 651-59). Oslobađanje interleukina 1α također je bilo spriječeno pomoću inhibitora kalpaina (N. Watanabe et al., Cytokine 1994, 6(6), 597-601). Osim toga, pronađeno je da inhibitori kaplaina pokazuju citotoksične učinke na tumorske stanice (Е. Shiba et al., 20th Meeting Int. Ass. Breast Cancer Res., Sendai Jp, 1994, 25-28 Sept., Int. J. Oncol. 5(Suppl.), 1994, 381).
Daljnje moguće upotrebe inhibitora kalpaina navedene su u К. К. Wang, Trends u Pharmacol. Sci., 1994, 15, 412-8.
Inhibitori kalpaina već su bili opisani u literaturi. Međutim, oni su uglavnom peptidni inhibitori. U pravilu, ireverzibilni inhibitori su alklirane tvari i imaju nedostatak da reagiraju neselektivno u tijelu ili su netopivi. Stoga ti inhibitori često pokazuju neželjene sporedne učinke, kao što je toksičnost, i s tim u skladu oni su ograničeni u pogledu upotrebe ili su beskorisni. Među ireverzibilne inhibitore mogu se uključiti, na primjer, epoksidi E 64 (E.B. McGowan et al., Biochem. Buiphys. Res. Commun. 1989, 158, 432-5), α-haloketoni (H. Angliker et al., J. Med. Chem. 1992, 35, 216-20) ili disulfidi (R. Matsueda et al., Chem. Lett. 1990, 191.194).
Mnogi poznati reverzibilni inhibitori cistein proteaza, kao što je kalpain, su peptidni aldehidi, posebno dipeptidni i tripeptidni aldehidi, kao na primjer, Z-Val-Phe-H (MDL 28170) (S. Mehdi, Trends u Biol. Sci. 1991, 16, 150-3). Pod fiziološkim uvjetima, peptidni aldehidi imaju nedostatak da su često nepostojani zbog velike reaktivnosti, mogu se brzo metabolizirati i skloni su nespecifičnim reakcijama koje mogu biti uzrokom toksičnih učinaka (J. A. Ferentz i B. Castro, Synthesis 1983, 676-78).
U JP 08183771 (CA 1996, 605307) i EP 520336 kao inhibitori kalpaina su opisani aldehidi koji su derivirani od 4-piperidinoilamida i 1-karbonilpiperidino-4-ilamida. U WO 97/21690 opisani su aldehidi derivirani od N-sulfonilprolinamida. WO 96/06211 opisuje aldehidni derivat analogan općoj strukturi I, ali tamo je Y derivat ksantina koji ne nosi nikakve daljnje radikale kao R1-X. Međutim, ovdje zahtjevani aldehidi, koji su derivirani od heteroaromatski supstituiranih amida opće strukture I, nisu nikada ranije bili opisani.
Peptidni ketonski derivativi su također bili opisani kao inhibitori cistein proteaza, a posebno kalpaina. Tako, na primjer, u slučaju serinskih proteaza derivati ketona su poznati kao inhibitori, pri čemu se keto skupinu aktivira sa skupinom koja privlači elektrone kao što je CF3. U slučaju cistein proteaza, derivati s keto skupinama aktiviranim pomoću CF3 ili sličnim skupinama, nisu vrlo aktivni ili su inaktivni (M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13). Iznenađujuće, u slučaju kalpaina, do sada je pronađeno da su samo keto derivati, u kojima, s jedne strane, otpusne skupine u α položaju uzrokuju ireverzibilnu inhibiciju, a s druge strane, derivat karboksilne kiseline aktivira keto skupinu, učinkoviti inhibitori (vidi M. R. Angelastro et al., vidi gore; WO 92/11850; WO 92/12140; WO 94/00095 i WO 95/00535). Međutim, od tih keto amida i keto estera, dosad su bili opisani samo peptidni derivati kao učinkoviti (Zhaozhao Li et al., J. Med. Chem. 1993, 36, 3472-80; S. L. Harbenson et al., J. Med. Chem. 1994, 37, 2918-29 i vidi gore M. R. Angelastro et al.).
Ketobenzamidi su već poznati u literaturi. Tako je ketoester PhCO-Abu-COOCH2CH2 opisan u WO 91/09801, WO 94/00095 i 92/11850. Za analogoni fenilni derivat Ph-CONH-CH(CH2Ph)-CO-COCOOCH3, koji je opisan u M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13 , pronađeno je, međutim, da je samo slabi kalpain inhibitor. Ovaj derivat je također opisan u J. P. Burkhardt, Tetrahedron Lett., 1988, 3433-36. Međutim, značaj heterociklički supstituiranih amida dosad nikada nije bio ispitan.
U predloženom izumu opisani su supstituirani nepeptidni aldehidi, esteri ketokarboksilnih kiselina i ketoamidni derivati. Ovi spojevi su novi i imaju iznenađujuću mogućnost da se ugradnjom krutih strukturnih fragmenata dobiju jaki nepeptidni inhibitori cistein proteaza, kao što je na primjer, kalpain.
Predloženi izum odnosi se na heterociklički supstituirane amide opće formule I
[image]
i njihove tautomerne i izomerne oblike, moguće enantiomerne i diastereomerne oblike, kao i moguće fiziološki podnošljive soli, u kojima varijable imaju slijedeća značenja:
R1 može biti fenil, naftil, kinolil, piridil, pirimidil, pirazil, piridazil, imidazolil, tiazol, kinazil, izokinolil, kinazil, kinoksalil, tienil, benzotienil, benzofuranil, furanil, i indolil, gdje prstenovi mogu biti dodatno supstituirani sa do 3 radikala R5,
R2 je klor, brom, fluor, C1-C6-alkil, C1-C6-alkenil, C1-C6-alkinil, C1-C6-alkilfenil, C1-C6-alkenilfenil,
C1-C6-alkinilfenil, fenil, NHCO-C1-C4-alkil, NHSO2-C1-C4-alkil, -NHCO-fenil, -NHCO-naftil, NO2, -O-C1-C4-alkil i NH2, gdje aromatksi prstenovi mogu dodatno nositi jedan ili radikala R5 i dva radikala R2 zajedno mogu biti lanac –CH=CH-CH=CH- i tako oblikovati fuzionirani benzo prsten, koji sa svoje strane može biti supstituiran s jednim R5 i
R3 je -C1-C6-alkil, koji je razgranat ili nerazgranat, i koji može dodatno nositi radikal S-СН3 ili fenil, cikloheksilni, cikloheptilni, ciklopentilni, indolilni, piridilni ili naftilni prsten koji je sa svoje strane supstituiran s najviše dva radikala R5, gdje R5 predstavlja vodik, C1-C4-alkil, koji je razgranat ili nerazgranat, -O- C1-C4-alkil, OH, Cl, F, Br, J, CF3, NO2, NH2, CN, COOH, COO- C1-C4-alkil, -NHCO-C1-C4-alkil, -NHCO-fenil, -NHSO2-C1-C4-alkil, -NHSO2-fenil, -SO2-C1-C4-alkil, -(CH2)n-NR12R13 i -SO2-fenil,
X je veza, -(CH2)m-, -(CH2)m-O-(CHm)o-, -(CH2)o-S-(CH2)m-, -(CH2)o-SO-(CH2)m-, -(CH2)o-SO2-(CH2)m-, -CH=CH-, -C≡C-, -CO-CH=CH-, -(CH2)o-CO-(CH2)m-, -(CH2)m-NHCO-(CH2)o-, -(CH2)m-CONH-(CH2)o-, -(CH2)m-NHSO2-(CH2)o-, -NH-CO-CH=CH-, -(CH2)m-SO2NH-(CH2)o-, -CH=CH-CONH- i
[image]
i u slučaju skupine CH=CH dvostruke veze mogu imati E ili Z oblik i
R1-X zajedno također mogu biti
[image] i
Y je nezasićen heterociklički prsten kao piridin, pirimidin, pirazin, imidazol i tiazole i
R4 je vodik, COOR6 i CO-Z, gdje Z predstavlja NR7R8, i
[image]
R6 je vodik, C1-C6-alkil, koji je linearan ili razgranat, i koji može biti supstituiran s fenilnim prstenom koji sam može dodatno biti supstituiran s jednim ili dva radikala R9, i
R7 je vodik, C1-C6-alkil, koji je razgranat i nerazgranat, i
R8 je vodik, C1-C6-alkil, koji je razgranat ili nerazgranat koji može dodatno biti supstituiran s fenilnim prstenom koji može dodatno nositi a radikal R9, i s
[image]
i
R9 može biti vodik, C1-C4-alkil, koji je razgranat ili nerazgranat, -O-C1-C4-alkil, OH, Cl, F, Br, J, CF3, NO2, NH2, CN, COOH, COO-C1-C4-alkil, -NHCO-C1-C4-alkil, -NHCO-fenil, -NHSO2-C1-C4-alkil, -NHSO2-fenil, -SO2-C1-C4-alkil i
-SO2-fenil,
R10 je vodik, C1-C6-alkil, koji je linearan ili razgranat, i koji može biti supstituted s fenilnim prstenom koji sam može dodatno biti supstituiran s jednim ili dva radikala R9, i
R11 je vodik, C1-C6-alkil, koji je linearan ili razgranat, i koji može biti supstituted s fenilnim prstenom koji sam može dodatno biti supstituiran s jednim ili dva radikala R9, i
n je broj 0, 1 ili 2, i
m i o međusobno neovisno predstavljaju brojeve 0, 1, 2, 3 ili 4.
Spojevi formule 1 mogu se upotrijebiti kao racemati ili kao enantiomerno čisti spojevi, ili kao diastereomeri. Ako se žele enantiomerno čisti spojevi, oni se mogu dobiti, na primjer, klasičnim rastavljanjem racemata spojeva formule I ili njihovih intermedijata upotrebom prikladne optički aktivne baze ili kiseline. S druge strane, enantiomerni spojevi mogu se također proizvesti upotrebom komercijalno dostupnih spojeva, na primjer optički aktivnih amino kiselina kao što su fenilalanin, triptofan i tirozin.
Predloženi izum odnosi se također na spojeve koji su mezomerni ili tautomerni sa spojevima formule I, na primjer s onima u kojima je keto skupina formula I prisutna kao enolni tautomer.
Predloženi izum odnosi se nadalje na fiziološki podnošljive soli spojeva I, koji se mogu dobiti reakcijom spoja I s prikladnom kiselinom ili bazom. Prikladne kiseline i baze opisane su, na primjer, u “Fortschritte der Arzneimittelforschung, Svezak 10, str. 224-285, Birkhäuser Verlag, Basel i Stuttgart, 1966. One uključuju, na primjer, klorovodičnu kiselinu, limunsku kiselinu, vinsku kiselinu, mliječnu kiselinu, fosfornu kiselinu, metansulfonsku kiselinu, octenu kiselinu, mravlju kiselinu, maleinsku kiselinu, fumarnu kiselinu itd, ili natrijev hidroksid, litijev hidroksid, kalijev hidroksid i α,α,α-tris-(hidroksimetil)metilamin, trietilamin itd.
Amidi I prema izumu, koji nose aldehidnu skupinu, mogu se proizvesti na razne načine, koji su prikazani u shemi sinteze.
Shema sinteze
[image]
Heterociklička karboksilna kiselina II povezuje se na odgovarajući aminoalkohol III, čime se dobije odgovarajući amid IV. Ovdje su primijenjene uobičajene metode povezivanja peptida, koje su opisane u C.R. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, str. 972 i dalje, ili u Houben-Weyl, Methoden der organischen Chemie, 4. izdanje, E5, Pogl. V. Reakcija se provodi upotrebom “aktiviranih” derivata kiseline II, pri čemu je skupina COOH prevedena u skupinu COL. L je otpusna skupina, kao na primjer Cl, imidazol ili N-hidroksi-benzotriazol. Zatim se tu aktiviranu kiselinu prevede u amid IV upotrebom amina. Reakcija se odvija u bezvodnim, inertnim otapalima, kao što su metilen klorid, tetrahidro-furan i dimetilformamid, pri temperaturama od –20 do +25oC.
Ovi alkoholni derivati IV mogu se oksidirati u nove aldehidne derivate I. U tu svrhu mogu se primijeniti razne uobičajene reakcije oksidacije (vidi C. R, Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, str. 604 i dalje) kao što je, na primjer, Swernova i oksidacije analogne Swernovoj (Т. Т. Tidwell, Synthesis 1990, 857-70), natrijev hipoklorid/TEMPO (S. L. Harbenson et al., vidi gore) ili Dess-Martin (J. Org. Chem. 1983, 48, 4155). Povoljno, ova reakcija se provodi u inertnim aprotonskim otapalima, kao što su dimetilformamid, tetrahidrofuran ili metilen klorid, upotrebom oksidanata kao što su DMSO/piridin x SO3 ili DMSO/oksalil klorid pri temperaturama od -50 do +25°C, ovisno o metodi (vidi gornju literaturu).
Alternativno, karboksilna kiselina II može reagirati s derivatom aminohidroksamske kiseline VI, čime se dobiju benzamidi VII. U tom slučaju primjenjuje se isti reakcijski postupak kao za pripravljanje spoja IV. Derivati hidroksamske kiseline VI mogu se također dobiti i iz zaštićenih amino kiselina V reakcijom s hidroksilaminom. U tom postupku, također se može primijeniti već opisani postupak za pripravljanje amida. Odstranjivanje zaštitne skupine X, na primjer Boc, provodi se na uobičajen način, na primjer upotrebom trifluoroctene kiseline. Tako dobivena amidohidroksamska kiselina VII može se redukcijom prevesti u aldehide I prema izumu. U tom postupku, kao redukcijsko sredstvo može se upotrijebiti, na primjer, litij aluminijev hidrid pri temperaturi od -60 do 0°C u inertnim otapalima kao što su tetrahidrofuran ili eter.
Analogno posljednjem postupku, također se mogu proizvesti karboksilne kiseline ili kiselinski derivati, kao što su esteri IX (Y = COOR’, COSR’), koji se također mogu prevesti redukcijom u aldehid I prema izumu. Ovi postupci popisani su u R. C. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, str. 619-26.
Pripravljanje heterocikličkih supstituiranih amida I prema izumu, koji nose ketoamidnu ili ketoestersku skupinu, može se provesti na razne načine, koji su prikazani u shemama sinteze 2 i 3.
Ako je to prikladno, esteri IIa karboksilne kiseline se pretvore u kiseline II upotrebom kiseline ili baze kao što je litijev hidroksid, natrijev hidroksid ili kalijev hidroksid u vodenoj sredini ili u mješavini vode i organskih otapala kao što su alkoholi ili tetrahidrofuran pri sobnoj temperaturi ili pri povišenoj temperaturi, kao 25-100°C.
Kiseline II povezuju se s derivatima α-amino kiselina, pri čemu se primjenjuju uobičajeni uvjeti koji su navedeni, na primjer, u houben-Weyle, Methoden der organischen Chemie, 4. izd., E5, Pogl. V, i C.R. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, Pogl. 9.
Na primjer, karboksilnu kiselinu II se prevede u “aktivirani” derivat kiseline IIb = Y-COL, gdje L predstavlja otpusnu skupinu, i on se zatim prevede u derivat XI dodatkom derivata amino kiseline H2N-CH(R3)-COOR. Ovu reakciju se provodi u bezvodnim, inertnim otapalima kao što je metilen klorid, tetrahidrofuran i dimetilformamid pri temperaturama od –20 do +25oC.
Shema 1
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Derivati XI, koji su u pravilu esteri, prevode se u ketokarboksilne kiseline XII analogno gore opisanoj hidrolizi. Ketoesteri I’ se proizvode u reakciji koja je analogna Dakin-Westovoj reakciji, pri čemu se reakcija provodi u skladu s metodom ZhaoZhao Li et al., J. Med. Chem. 1993, 36, 3472-80. U ovom postupku, karboksilna kiselina kao XII reagira s monoester kloridom oksalne kiseline pri povišenoj temperaturi (50-100oC) u otapalima, kao što je npr. tetrahidrofuran i tako dobiveni proizvod zatim reagira s bazom kao što je natrijev hidroksid u etanolu i pri povišenoj temperaturi od 25-80oC, čime se dobije ketoester I’ u skladu s izumom. Ketoesteri I’ se mogu hidrolizirati kako je gore opisano, na primjer u ketokarboksilne kiseline prema izumu.
Reakciju za dobivanje ketobenzamida I’ provodi se također analogno metodi koju su opisali ZhaoZhao Li et al. (vidi gore). Keto skupinu u I’ se zaštiti dodatkom 1,2-etanditiola uz katalizator Lewisovu kiselinu, kao što je na primjer borov trifluorid eterat, u inertnom otapalu, kao što je metilen kloird, pri sobnoj temperaturi, pri čemu se dobije ditian. Ovi derivati reagiraju s aminima R3-H u polarnim otapalima, kao što su alkoholi, pri temperaturama od 0-80oC, pri čemu se dobiju ketoamidi I (R4 je Z ili NR7R8).
Shema 2
[image]
Alternativna metoda je prikazana u shemi 2. Ketokarboksilne kiseline II reagiraju s derivatima amino-hidroksikarboksilnih kiselina XIII (za pripravljanje spojeva XIII vidi S. L. Harbenson et al., J. Med. Chem. 1994, 37, 2918-29, ili J. P. Burkhardt et al. Tetrahedron Lett. 1988, 29, 3433-3436) metodom uobičajenom za povezivanje peptida (vidi gore Houben-Weyl), čime se dobije amid XIV.
Ovi alkoholni derivati XIV mogu se oksidirati u derivate I ketokarboksilne kiseline prema izumu. U tu svrhu mogu se primijeniti razne uobičajene reakcije oksidacije (vidi C. R, Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, str. 604 i dalje) kao što je, na primjer, Swernova i oksidacije analogne Swernovoj, povoljno dimetil sulfoksid/piridin-sumporni trioksidni kompleks u otapalima kao što je metilen klorid ili tetrahidrofuran, ako je prikladno s dodatkom dimetil sulfoksida, pri sobnoj temperaturi ili temperaturama od -50 do 25°C (Т. Т. Tidwell, Synthesis 1990, 857-70) ili natrijev hipoklorid/ TEMPO (S. L. Harbenson et al., vidi gore).
Ako su XIV α-hidroksi esteri (X = O-alkil), oni se mogu hidrolizirati u karboksilne kiseline XII, pri čemu se reakcija provodi analogno gornjim metodama, ali ponajprije upotrebom litijevog hidroksida u mješavini vode i tetrahidrofurana pri sobnoj temperaturi. Proizvodnja drugih estera ili amida XIV provodi se reakcijom s aminima pod uvjetima povezivanja koji su već opisani. Derivat alkohola XVI može se oksidirati, čime se ponovno dobiju derivati ketokarboksilne kiseline I prema izumu.
Pripravljanje estera karboksilne kiseline II već je bilo opisano u nekim slučajevima ili se provodi u skladu s uobičajenim kemijskim metodama.
Spojevi u kojima je X veza proizvode se uobičajenim aromatskim povezivanjem, na primjer Suzukijevim povezivanjem s derivatima borne kiseline i halogenida uz paladijev katalizator ili povezivanjem aromatskih halogenida s bakrenim katalizatorom. Radikali alkilnog mosta (X = -(CH2)m-) mogu se proizvesti redukcijom analognih ketona ili alkiliranjem organskog spoja litija, npr. orto-fenil-oksazolidina, ili drugih organometalnih spojeva (vidi I. M. Dordor et al., J. Chem. Soc. Perkin Trans. I, 1984, 1247-52).
Derivati s eterskim mostom proizvedeni su alkiliranjem odgovarajućih alkohola ili fenola s halogenidima.
Sulfoksidi i sulfoni se mogu dobiti oksidacijom odgovarajućih tioetera.
Spojevi s alkenskim i alkinskim mostom proizvedeni su, na primjer, Heckovom reakcijom iz aromatskih halogenida i odgovarajućih alkena i alkina (vidi I. Sakamoto et al., Chem. Pharm. Bull., 1986, 34, 2754-59).
Kalkoni nastaju kondenzacijom acetofenona s aldehidima i mogu se prema potrebi hidrogenacijom prevesti u analogne alkilne derivate.
Amidi i sulfonamidi su proizvedeni iz amina i kiselinskih derivata analogno gore opisanim metodama.
Heterociklički supstituirani amidi I obuhvaćeni predloženim izumom su inhibitori cistein proteaza, posebno cistein proteaza kao što su kalpaini I i II i katepsini B i L.
Inhibicijsko djelovanje heterocikličkih supstituiranih amida I utvrđeno je primjenom uobičajenih enzimskih pokusa poznatih iz literature, pri čemu je kao mjerilo djelovanja utvrđena koncentracija inhibitora pri kojoj je inhibirano 50% djelovanja enzima (= IC50). Na taj način su izmjereni benzamidi I u pogledu inhibicije djelovanja kalpaina I, kalpaina II i katepsina B.
Ispitivanje katepsina B
Inhibicija katepsina B utvrđena je analogno metodi koju su opisali S. Hasnain et al., J. Biol. Chem. 1993, 268, 235-40.
2 μl otopine inhibitora, pripravljene od inhibitora i DMSO (krajnje koncentracije 100 μM do 0,01 μM) doda se k 88 μl katepsina B (katepsin B iz ljudske jetre, Calbiochem), razrijeđenog na 5 jedinica u 500 μM pufera). Ovu mješavinu se najprije inkubira 60 minuta pri sobnoj temperaturi (25oC) i zatim se inicira reakciju dodatkom 10 μl 10 mM Z-Arg-Arg-pNA (u puferu s 10% DMSO). Reakciju se promatra 30 minuta pri 450 nM u čitaču mikrotiraske ploče. Zatim se iz maksimalnih gradijenata odrede vrijednosti IC50.
Ispitivanje kalpaina I i II
Ispitivanje inhibicijskih svojstava kalpain inhibitora provedeno je u puferu upotrebom 50 mM tris HCl, pH 7,5; 0,1 M NaCl; 1 mM ditiotreitola; 0,11 mM CaCl2; fluorogenskog kalpain supstrata Suc-Leu-Tyr-AMC (25 mM otopljenog u DMSO, Bachem/Švicarska). Humani μ-kalpain je izoliran iz eritrocita i, nakon nekoliko stupnjeva kromatografije (DEAE-Sepharose, fenil-Sepharose, Superdex 200 i Blue Sepharose), enzim čistoće >95%, ispitan je prema SDS-PAGE, Western blot analizi i N-terminalnim sekvenciranjem. Fluorescencija odcijepljenog proizvoda 7-amino-4-metil-kumarina (AMC) promatrana je u Spex-Fluorolog fluorimetru pri λ = 380 nm i λ = 460 nm. U mjernom području od 60 min, cijepanje supstrata je linearno i autokatalitičko djelovanje kalpain je nisko ako se pokusi vrše pri temperaturama od 12°C. Inhibitori i kalpainski supstrat se dodaju u pokusnu šaržu kao DMSO otopine, pri čemu DMSO ne smije prijeći krajnju koncentraciju od 2%.
U pokusnoj mješavini, 10 μl supstrata (250 μM krajnje) i zatim 10 μl μ-kalpacina (2 μg/ml krajnje, tj. 18 nM) doda se u kivetu od 1 ml koja sadrži pufer. Cijepanje supstrata posredovano kalpainom mjeri se 15 – 20 minuta. Zatim se doda 10 μl inhibitora (50 – 100 μM otopina u DMSO) i inhibiciju cijepanja mjeri se tijekom 40 minuta.
Ki vrijednsoti su određene prema slijedećoj jednadžbi za reverzibilnu inhibiciju:
Ki = I/(v0/vi) - 1; gdje I = koncentracija inhibitora,
v0 je početna brzina prije dodatka inhibitora; vi je brzina reakcije u ravnoteži.
Brzina je izračunata iz v = oslobađanje AMC/vrijeme, tj. visina/vrijeme.
Kalpain je intracelularna cistein proteaza. Kalpain inhibitori moraju proći kroz staničnu membranu da bi spriječili razgradnju intracelularnih proteina s kalpainom. Neki poznati kalpain inhibitori, kao na primjer, E 64 i leupeptin, teško prevladavaju stanične membrane, i iako su dobri kalpain inhibitori, u stanicama pokazuju skromno djelovanje. Cilj je pronaći spojeve koji bolje prolaze kroz membrane. Kao dokaz da inhibitori kalpaina prolaze kroz membranu, upotrijebljeni su humani trombociti.
Razgradnja tirozin kinaze pp60src u trombocitima posredstvom kalpaina
Nakon aktiviranja trombocita, tirozin kinaza pp60src je odcijepljena s kalpainom. Ovo ispitivanje opisali su u pojedinostima Oda et al. u J. Biol. Chem., 1993, Vol 268, 12603-12608. Time je pokazano da se cijepanje pp60src može učinkovito spriječiti s kalpeptinom, inhibitorom kalpaina. Učinkovitost naših tvari u stanici ispitana je prema ovoj publikaciji. Svježa krv pomiješana sa citratom centrifugira se 15 min pri 200 g. Plazma bogata s trombocitima se skupi i razrijedi 1:1 s puferom za trombocite (pufer za trombocite: 68 mM NaCl, 2,7 mM KCl, 0,5 mM MgCl2 x 6 H2O, 0,24 mM NaH2PO4 x Н2О, 12 mM НаНСО3, 5,6 mM glukoze, 1 mM EDTA, pH 7,4). Nakon centrifugiranja i ispiranja s puferom za trombocite, trombociti se namjeste na 107 stanica/ml. Izolacija humanih trombocita izvršena je pri sobnoj temperaturi.
U ispitnoj mješavini, izolirani trombociti (2 x 106) su prethodno inkubirani 5 minuta pri 37°C s različitim koncentracijama inhibitora (otopljenog u DMSO). Zatim su trombociti aktivirani s 1 μM ionoforom A23187 i 5 mM CaCl2. Nakon 5 min inkubacije, trombociti su kratko centrifugirani pri 13000 okr./min i talog je preuzet u SDS pufer za uzorke (SDS pufer za uzorke: 20 mM tris-HCl, 5mM EDTA, 5 mM EGTA, 1 mM DTT, 0,5 mM PMSF, 5 μg/ml leupeptina, 10 μg/ml pepstatina, 10% glicerola i 1% SDS). Proteini su odvojeni u 12%-tni gel i pp60src i njegovi proivodi cijepanja 52 kDa i 47 kDa su identificirani pomoću Western blot-a. Upotrijebljeno poliklonsko zečje antitijelo anti-Cis-src (рр600-src) bilo je od tvrtke Biomol Feinchemikalien (Hamburg). To primarno antitijelo detektirano je upotrebom HRP-povezanog drugog antitijela iz koze (Boehringer Mannheim, FRG). Western blot ispitivanje je provedeno na poznati način.
Brojčano utvrđivanje cijepanja pp60src provedeno je denzitometrijom, a za kontrolu su upotrijebljeni neaktivirani trombociti (kontrola 1: nema odcjepljenja) i trombociti su pomiješani s ionoforom i kalcijem (kontrola 2: odgovora 100%-tnom odcjepljenju). Vrijednosti ED50 odgovaraju koncentraciji inhibitora pri kojoj je intenzitet obojene reakcija smanjen za 50%.
Smrt stanica u kortikalnim neuronima inducirana glutamatom
Ovo ispitivanje provedeno je kako su opisali Choi D. W., Maulucci-Gedde M. A, i Kriegstein A. R., "Glutamate neurotoksicity in cortical cell culture". J. Neurosci. 1989, 7, 357-368.
Polovice korteksa izvađene su iz 15 dana starih mišjih embrija i pojedinačne stanice su dobivene enzimatski (tripsin). Te stanice (glia i kortikalni neuroni) su inokulirane u pločicama s 24 jamice. Nakon tri dana (pločice premazane s lamininom) ili sedam dana (pločice premazane s ornitinom), izvršena je obrada s mitozom upotrebom FDU (5-fluor-2-deoksiuridin). 15 dana nakon pripravljanja stanica, smrt stanica inducirana je dodatkom glutamata (15 minuta). Nakon odstranjivanja glutamata, dodaju se inhibitori kalpaina. 24 sata kasnije, oštećenje stanica utvrđeno je određivanjem laktat dehidrogenaze (LDH) u supernatantu stanične kulture.
Polazi se od toga da kalpain također ima ulogu u apoptičkoj smrti stanice (M. K. T. Squier et al. J. Cell. Physiol. 1994, 159, 229-237; T. Patel et al. Faseb Journal 1996, 590, 587-597). Zbog toga je u slijedećem modelu smrt stanice inducirana s kalcijem u prisutnosti kalcijevog ionofora u humanoj staničnoj liniji. Kalpain inhibitori moraju ući u stanicu i tamo inhibirati kalpain kako bi spriječili induciranu smrt stanice.
Smrt stanice u NT2 stanicama posredovana s kalcijem
Smrt stanice može se inducirati u humanoj staničnoj liniji NT2 (Stratagene GmbH) pomoću kalcija u prisutnosti ionofora A 23187. 105 stanica/jamici stavi se u mikrotitarske pločice 20 sati prije pokusa. Po isteku tog perioda, stanice se inkubiraju s raznim koncentracijama inhibitora u prisutnosti 2,5 uM ionofora i 5 mM kalcija. Nakon 5 sati u reakcijsku šaržu doda se 0,05 ml XTT (garnitura II za proliferaciju stanica, Boehringer Mannheim). Optičku gustoću utvrdi se približno 17 sati kasnije u skladu s uputama proizvođača, u Easy Reader-u EAR 400 tvrtke SLT. Optička gustoća pri kojoj je umrlo pola stanica izračuna se iz dviju kontrola sa stanicama bez inhibitora, koje su bile incubirane u odsutnosti i u prisutnosti ionofora.
U brojnim neurološkim bolestima ili psihološkim poremećajima dolazi do povišenog djelovanje glutamata, koje dovodi do stanja prekomjerne stimulacije ili toksičkih učinaka u središnjem nervnom sistemu (CNS). Glutamat posreduje svoje učinke pomoću raznih receptora. Dva od ovih receptora klasificirani su prema specifičnim agonistima kao MMDA receptor i AMPA receptor. Antagonisti protiv tih glutamatom posredovanih učinaka mogu se stoga upotrijebiti za liječenje tih bolesti, posebno za terapeutsku aplikaciju protiv neurodegenerativnih bolesti kao što su Huntingtonova bolest i Parkinsonova bolest, neurotoksički poremećaji nakon hipoksije, anoksije, ishemije i nakon lezija, kao što su one koje nastaju nakon udara i trauma, ili alternativno kao antiepileptici (vidi Arzneim. Forschung 1990, 40, 511-514; TIPS, 1990, 11, 334-338; Drugs of Future 1989, 14. 1059-1071).
Zaštita protiv cerebralne prekomjerne stimulacije s ekscitatorskim amino kiselinama (NMDA ili AMPA antagonizam u miševima)
Intracerebralnom aplikacijom ekscitatorskih amino kiselina (EAA) iducirana je masivna prekomjerna stimulacija tako da u kratkom vremenu dovodi do spazmi i smrti životinja (miševa). Ti simptomi se mogu inhibirati sistemskim, npr. intraperitonealnim, davanjem središnje aktivnih spojeva (EAA antagonista). Budući da prekomjerno aktiviranje EAA receptora središnjeg nervnog sistema ima važnu ulogu u patogenezi raznih neuroloških poremećaja, iz pokazanog EAA antagonizma in vivo može se zaključiti o mogućoj terapeutskoj upotrebi tvari protiv CNS poremećaja toga tipa. Kao mjera učinkovitosti tvari, određena je vrijednost ED50 pri kojoj je 50% životinja bilo bez simptoma kao rezultat fiksne doze NMDA ili AMPA prije i.p. aplikacije standardne tvari.
Već je bilo pokazano da inhibitori kalpaina imaju zaštitno djelovanje u staničnim kulturama protiv smrti stanice uzrokovane s EAA (H. Cauter et al., Brain Research 1993, 607, 354-356; Yu Cheng i A.Y. Sun, Neurochem. Res. 1994, 19, 1557-1564). Iznenađujuće, inhibitori kalpaina uključeni u ovu patentnu prijavu djeluju čak protiv spazmi uzrokovanih in vivo (miševi) pomoću EAA (na primjer NMDA ili AMPA), čime se dakle naglašava moguća terapeutska upotreba za gore spomenute CNS poremećaje.
Heterociklički supstituirani amidi I su inhibitori cisteinskih derivativa kao što su kalpain I ili II i katepsin B ili L i stoga se mogu upotrijebiti za suzbijanje bolesti koje su povezane s povišenim enzimskim djelovanjem kalpain enzima ili katepsin enzima. Predloženi amidi I mogu se, s tim u skladu, upotrijebiti za liječenje neurodegenerativnih procesa koji se javljaju nakon ishemije, traume, subarahnoidnih krvarenja i udara, i neurodegenerativnih boelsti kao što je multipla infarktna demencija, Alzheimerova bolest, Huntingtonova bolest i epilepsije, te osim toga za liječenje ozljede srca nakon kardijalne ishemije, ozljeda i reperfuzija nakon vaskularne okluzije, ozljede bubrega nakon bubrežne ishemije, distrofije mišića, ozljede koja se javlja zbog proliferacije glatkih mišićnih stanica, koronarnih vazospazmi, cerebralnih vaospazmi, katarakta očiju, restenoza krvnih struja nakon angioplastije. Osim toga, amidi I mogu se upotrijebiti u kemoterapiji tumora i njihovih metastaza i za liječenje bolesti u kojima dolazi do povišene razine interleukina 1, kao što su upale i reumatski poremećaji.
Dodatno uz uobičajene farmaceutske pomoćne tvari, farmaceutski pripravci prema izumu sadrže terapeutski učinkovitu količinu spojeva I.
Za lokalnu vanjsku aplikaciju, na primjer u puderima, pomastima, aktivni spojevi mogu biti sadržani u uobičajenim koncentracijama. U pravilu, aktivni spojevi su sadržani količinom od 0,001 do 1 mas. %, ponajprije 0,001 do 0,1 mas. %.
U slučaju unutarnje aplikacije, pripravci se daju u pojedinačnim dozama. U pojedinačnoj dozi previđeno je 0,1 do 100 mg po kg tjelesne težine. Pripravak se može dati u jednoj ili više dnevnih doza, ovisno o naravi i ozbiljnosti poremećaja.
Prema željenom načinu aplikacije, farmaceutski pripravci prema izumu osim aktivnog spoja sadrže uobičajene pomoćne tvari i sredstva za razređenje. Za lokalnu vanjsku aplikation, mogu se upotrijebiti farmaceutska pomoćna sredstva kao etanol, izopropanol, etoksilirano ricinusovo ulje, etoksilirano hidrogenirano ricinusovo ulje, poliakrilna kiselina, polietilen glikol, polietilen glikol stearat, etoksilirani masni alkoholi, parafinsko ulje, vazelin i vunena mast. Za unutarnju aplikaciju prikladna je, na primjer, laktoza, propilen glikol, etanol, škrob, talk i polivinilpirolidon.
Mogu se dodati antioksidanti kao tokoferol i butilirani hidroksianizol kao i butilatirani hidroksi-toluen, dodaci za poboljšanje okusa, stabilizatori, emulgatori i lubrikanti.
Tvari sadržane u pripravku, dodatno uz aktivan spoj i tvari koje se upotrebljavaju za proizvodnju farmaceutskih pripravaka, su toksikološki prihvatljive i kompatibilne su s dotičnim aktivnim spojem. Farmaceutski pripravci se proizvode na uobičajen način, na primjer miješanjem aktivnog spoja s uobičajenim pomoćnim dodacima i sredstvima za razrjeđivanje.
Farmaceutski pripravci mogu se dati na razne načine, na primjer, oralno, parenteralno kao intravenski ili infuzijom, subkutano, intraperitonealno, i površinski. Tako su mogući pripravci u obliku tableta, emulzija, infuzijskih i injekcijskih otopina, paste, pomasti, gelovi, kreme, losioni, puderi i sprejevi.
PRIMJERI
Primjer 1
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(S)-4(N-(1-naftilmetil)karbamoil)-N-(3-fenilpropan-1-al-2-il)piridin-2-karboksamid
a) Etil 4-(N-(l-naftilmetil)karbamoil)piridin-2-karboksilat
4,9 g (25 mmolova) 2-etoksikarbonilpiridin-3-karboksilne kiseline (K. Finch et al., J. Med. Chem. 1980, 23, 1405) otopi se in 110 ml tetrahidrofuran/ dimetil-formamida (10/1) i pomiješa se sa 4,5 g (27,5 mmolova) 1,1’-karbonildiimidazola. Nakon miješanja smjese 30 min pri sobnoj temperature, doda se još 3,9 g (25 mmolova) 1-amino-metilnaftalena i smjesu se miješa još 72 h pri sobnoj temperaturi. Zatim se tetrahidrofuran odstrani u vakuumu i ostatak se podijeli između 200 ml etil acetata i 200 ml vodene otopine natrijevog hidrogenkarbonata. Organsku fazu se dodatno ispere s vodom, osuši i koncentrira u vakuumu. Dobiveno je 7,9 g (95%) proizvoda.
1H-NMR:
b) 4-(N-(1-naftilmetil)karbamoil)piridin-2-karboksilna kiselina
6,9 g (20 mmolova) intermedijata 1a otopi se u 100 ml etanola i pomiješa se s 3,3 g (82 mmol) natrijevog hidroksida, otopi se u 50 ml vode. Cijelu smjesu se miješa 16 h pri sobnoj temperaturi. Reakcijsku otopinu se zatim neutralizira s 1M solnom kiselinom i etanol se odstrani u vakuumu. Dobiveni talog se odsisa i osuši. Dobiveno je 5,6 g (89%) proizvoda.
c) (S)-4-(N-(1-naftilmetil)karbamoil)-N-(3-fenilpropan-1-ol-2-il)piridin-2-karboksamid
2,7 g (9 mmolova) intermedijata 1b i 1,4 g (9 mmolova) (S)-fenilalaninola doda se u 60 ml metilen klorida i pomiješa se s 2,3 g (22,5 mmola) trietilamina, 50 ml dimetilformamida i 0,4 g (3 mmola) 1-hidroksibenzotriazola. zatim se doda 1,7 g (9 mmolova) l-etil-3-(dimetilamino-propil)karbodiimid hidroklorida pri 0°C i ukupnu smjesu se najprije miješa 16 h pri 0°C, a zatim pri sobnoj temperaturi. Reakcijsku smjesu se ispere uzastopno sa 100 ml 5%-tne limunske kiseline i 100 ml otopine natrijevog hidrogenkarbonata, i nakon sušenja, i koncentriranja u vakuumu dobiveno je 2,4 g (62%) proizvoda.
d) (S)-4-(N-(1-naftilmetil)karbamoil)-N-(3-fenilpropan-1-al-2-il)piridin-2-karboksamid
1,9 g (4,4 mmol) intermedijarnog spoja 1c otopi se u 50 ml suhog dimetil sulfoksida i pomiješa se s otopinom 1,8 g (17,4 mmolova) trietilamina i 2,8 g (17,4 mmol) kompleksa piridin-sumpornog trioksida u 50 ml suhog dimetil sulfoksida. Ukupnu smjesu se miješa 16 h pri sobnoj temperaturi. Reakcijsku smjesu se zatim doda k vodi i talog se odsisa. Dobiveno je 1,5 g (80%} proizvoda.
1H-NHR (D6-DMSO): δ = 3,1 (1H), 3,5(1H), 4,7(1H), 5,1 (1H), 7,1-7,3(6H), 7,4-7,7(5H), 7,9(1H), 7,95(1H), 8,15 (1H), 8,2(1H), 8,4(1H), 9,1(1H), 9,2(1H), 9,4(1H) i 9,8(1H) ppm.
Primjer 2
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(S)-2-(2-naftalensulfonamido)-N-(3-fenilpropan-1-al-2-il)-piridin-3-karboksamid
a) Metil 2-(2-naftalensulfonamido)piridin-3-karboksilat
5,9 g (26 mmol) naftalen-2-sulfonil klorida doda se u obrocima pri sobnoj temperaturi k 4,7 g (25 mmolova) metil 6-aminonikotinat hidroklorida u 100 ml suhog piridina. Ukupnu smjesu se zatim miješa 16 h pri sobnoj temperaturi. Reakcijsku otopinu se zatim prelije na 500 ml vode i dobiveni talog se odsisa. Dobiveno je 6,4 g (75%) proizvoda.
b) 2-(2-naftalensulfonamido)piridin-3-karboksilna kiselina
6 g (17 mmolova) intermedijarnog spoja 2a, otopi se u 100 ml metanola, miješa se 16 h pri sobnoj temperaturi sa 4,2 g (104 mmolova) natrijevog hidroksida, otopljenog u 100 ml vode. Zatim se organsko otapalo odstrani u vakuumu i dobivenu vodenu otopinu se neutralizira s 1M solnom kiselinom. Dobiveni talog se odsisa. Dobiveno je 5,1 g (90%) proizvoda.
c) (S)-2-(2-naftalensulfonamido)-N-(3-fenilpropan-1-ol-2-il)-piridin-3-karboksamid
2,5 g (7,5 mmolova) intermedijarnog spoja 2b reagira sa (S)-fenilalaninolom analogno postupku 1c. Dobiveno je 0,7 g (21%) proizvoda.
d) (S)-2-(2-naftalensulfonamido)-N-(3-fenilpropan-1-al-2-il)-piridin-3-karboksamid
0,5 g (1,2 mmola) intermedijarnog spoja 2c se oksidira analogno postupku 1d, čime se dobije 0,4 g (78%) proizvoda.
1H-NHR (D6-DMSO): δ = 2,8(1H), 3,3(1H), 4,5(1H), 7,0-7,4 (5H), 7,7(2H), 7,9(1H), 8,1(3H), 8,25(1H), 8,5(1H), 8,7 (1H), 8,9(lH), 9,6(1H) i približno 12,5 (široki, 1H) ppm.
Primjer 3
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(S)-2-(2-naftalnamido)-N-(3-fenilpropan-1-al-2-il)-piridin- 5-karboksamid
a) 6-aminonikotinska kiselina hidroklorid
20 g (0,145 mol) 6-aminonikotinska kiselina se refluktira otprilike 5 h u mješavini od 200 ml metanola i 250 ml 2,5 M solne kiseline. Cijelu smjesu se zatim koncentrira u vakuumu i dobije se 26,6 g (97%) proizvoda.
b) Metil 6-(2-naftalenamido)nikotinat
4,7 g (25 mmola) intermedijarnog spoja 3а se otopi u 100 ml piridina i pomiješa u obrocima pri sobnoj temperaturi s 5 g (25 mmolova) 2-naftoil klorida. Ukupnu smjesu se miješa 16 h pri sobnoj temperaturi. Zatim se reakcijsku smjesu prelije u vodu i dobiveni talog se odisa, Dobiveno je 5,4 g (70%) proizvoda.
c) 6-(2-naftalenamido)nikotinska kiselina
4,7 g (15 mmol) intermedijanog spoja 3b otopi se u 75 ml etanol i pomiješa s 2,5 g natrijevog hidroksida, otopljenog vode. Cijelu smjesu se miješa 16 h pri sobnoj temperaturi. Zatim se etanol odstrani u vakuumu i vodeni ostatak se neutralizira s 1M solnom kiselinom. Dobiveni talog se odsisa. Dobiveno je 3,1 g (69%) proizvoda.
d) (S)-2-(2-naftalenamido)-N-(3-fenilpropan-1-ol-2-il)-S piridin-5-karboksamid
2,7 g (9,2 mmolova} intermedijarnog spoja 3c reagira sa (S)-fenilalaninolom analogno postupku 1c. Dobiveno je 2,1 g (54%) proizvoda.
e) (S)-2-(2-naftalenamido)-N-(3-fenilpropan-1-al-2-il)-piridin-5-karboksamid
1,7 g (4 mmola) intermedijarnog spoja 3d oksidira se analogno postupku 1d. Dobiveno je 1,3 g (79%) proizvoda.
MS: m/e = 423 (М+).
Primjer 4
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(S)-5-klor-2-(2-naftalensulfonamido)-N-(3-fenilpropan-1-al-2-il)piriinidin-6-karboksamid
a) Etil 5-(klor-2-(2-naftalensulfonamido)pirimidin-6-5 karboksilat
6 g (26 mmolova) 2-naftalensulfonil klorida doda se pri sobnoj temperaturi k 5 g (25 mmolova) etil 2-amino-5-klorpirimidin-6-karboksilata u 100 ml suhog piridina. Ukupnu smjesu se dodatno miješa još 16 h. Smjesu se zatim prelije u vodu i dobiveni talog se odsisa. Dobiveno je 9,8 g (59%) proizvoda.
b) 5-klor-2-(2-naftalensulfonamido)pirimidin-6-karboksilna kiselina
5,6 g (14 mmolova) intermedijarnog spoja 4a otopi se u 100 ml metanol/tetrahidrofurana (1/1) i hidrolizira se pri sobnoj temperaturi s 2,8 g natrijevog hidroksida, otopi se u 10 ml vode. Nakon 16 h, organsko otapalo se odstrani u vakuumu i vodenu fazu se mamjesti na pH 6 upotrebom 2M solne kiseline. Nastali talog se odsisa. Dobiveno je 2,8 g
(55%) proizvoda.
c) (S)-5-klor-2-(2-naftalensulfonamido)-N-(3-fenilpropan- l-ol-2-il)pirimidin-6-karboksamid
1,9 g (5,2 mmolova) intermedijarnog spoja 4b reagira sa (S)-fenilalaninolom analogno postupku 1c. Dobiveno je 1,4 g (55%) proizvoda.
d) (S)-5-klor-2-(2-naftalensulfonamido)-N-(3-fenilpropan-1-al-2-il)pirimidin-6-karboksamid
1,73 (2,5 mmola) intermedijarnog spoja 4c oksidira se analogno postupku 1d. Dobiveno je 1.1 g (85%) proizvoda.
1H-NHR (D6-DMSO): δ = 2,95(1H), 3,4(1H), 4,6(lH), 7,2-8,2 (12H), 8,45(1H), 9,2(1H) i 9,7(1H) ppm.
Primjer 5
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(S)-5-klor-2-(2-naftalensulfonamido}-N-(l-karbamoil-1-okso-3-fenilpropan-2-il)pirimidin-6-karboksamid
a) (S)-5-klor-2-(2-naftalensulfonamido)-N-(1-karbamoil-1-hidroksi-3-fenilpropan-2-il)pirimidin-6-karboksamid
0,77 g (2,1 mmola) intermedijarnog spoja 4b i (2S),(3R,S)-3-amino-2-hidroksi-3-fenilbutiramid reagiraju
analogno postupku 1c. Dobiveno je 0,24 g (23%) proizvoda.
b) (S)-5-klor-2-(2-naftalensulfonamido)-N-(1-karbamoil-1-okso-3-fenilpropan-2-il)pirimidin-6-karboksamid
0,19 g (0,35 mmol) intermedijarnog spoja 5a oksidira se analogno postupku 1d. Dobiveno je 0,024 g proizvoda.
1H-NHR (D6-DMSO): δ = 3,0(1H), 3,25(1H), 5,4(1H), 7,2-8,0 (11Н), 8,1(1H), 8,4(1H), 9,0(1Н).
Primjer 6
(S)-2-(2-naftalenamido)-N-(3-fenilpropan-1-al-2-il)-tiazol-4-karboksamid
[image]
a) Etil 2-(2-naftalenamido)tiazol-4-karboksilat
4,7 g (24,9 mmola) 2-naftoil klorida otopi se u 50 ml bezvodnog tetrahidrofurana, kap po kap pri 0oC doda se k 4 g (23,3 mmola) etil 2-aminotiazol-4-karboksilata i 6,4 ml (46,5 mmolova) trietilamina u 150 ml bezvodnog tetrahidro-furana. Ukupnu smjesu se zatim miješa 16 h. Reakcijsku otopinu se zatim prelije u mnogo vode i ekstrahira s etil acetatom. Organsku fazu se zatim ispere s vodenoom otopinom natrijevog hidrogenkarbonata, osuši i koncentrira u vakuumu. Ostatak se očisti kromatografijom (sredstvo za ispiranje: metilen klorid), čime je dobiveno 5,6 g (82%) proizvoda.
b) 2-(2-naftalenamido)tiazol-4-karboksilna kiselina
5,4 g (16,6 mmolova) intermedijarnog spoja 6a otopi se u 50 ml tetrahidrofurana i pomiješa sa 100 ml 2M otopine natrijevog hidroksida. Ukupnu smjesu miješa se 16 h pri sobnoj temperaturi. Smjesu se zatim razrijedi s vodom i neutralizira s koncentriranom ocetnom kiselinom. Nastali talog se odsisa, čime je dobiveno 4,7 g (95%) proizvoda.
c) (S)-2-(2-naftalenamido)-N-(3-fenilpropan-1-ol-2-il)-tiazol-4-karboksamid
1 g (3,4 mmola) intermedijarnog spoja 6b i (2S),(3R,S)-3-amino-2-hidroksi-3-fenilbutiramid reagiraju analogno postupku 1c. Dobiveno je 1,2 g (93%) proizvoda.
d) (S)-2-(2-naftalenamido)-N-(3-fenilpropan-1-al-2-il)-i tiazol-4-karboksamid
1 g (2,3 mmola) intermedijarnog spoja 6c oksidira se analogno postupku 1d. Dobiveno je 0,73 g (74%) proizvoda.
MS: m/e = 429 (M+)
Primjer 7
(S)-2-(2-naftalenamido)-N-(l-karbamoil-1-okso-3-fenil-propan-2-il)tiazol-4-karboksamid
[image]
a) (S)-2-(2-naftalenamido)-N-(l-karbamoil-1-hidroksi-3-fenil-propan-2-il)tiazol-4-karboksamid
1,35 g (4,5 mmola) intermedijarnog spoja 6b i 1,4 g (2S)(3R,S)-3-amino-2-hidroksi-3-fenilbutiramid trifluor-acetata reagira analogno postupku 1c. Dobiveno je 1,4 g (66%) proizvoda.
b) (S)-2-(2-naftalenamido)-N-(l-karbamoil-1-okso-3-fenil-propan-2-il)tiazol-4-karboksamid
1,2 g (2,5 mmola) intermedijarnog spoja 7a oksidira se analogno postupku 1d. Dobiveno je 1,05 g (88%) proizvoda.
MS: m/e = 472 (M+).
Primjer 8
(S)-N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-4-metil-1-(2-naftalenmetil)imidazol-5-karboksamid
[image]
a) Etil 4-metil-1-(2-naftalenmetil)imidazol-5-karboksilat
4,2 g (27,2 mmolova) etil 4-metilimidazol-5-karboksilata, 3,8 g (27,2 mmol) kalijevog karbonata i 6,0 (27,2 mmolova) 2-brom-metilnaftalena grije se 1 h pri 100°C for u 100 ml dimetilformamida. Ukupnu smjesu se zatim prelije u vodu i ekstrahira s etil acetatom. Organsku fazu se osuši i koncentrira u vakuumu. Ostatak se zatim očisti kromatografijom na silika gel (sredstvo za ispiranje: etil acetat). Dobiveno je 4,8 g (60%) proizvoda.
b) 4-metil-1-(2-naftalenmetil)imidazol-5-karboksilna kiselina
4,6 g (15,6 mmolova) intermedijarnog spoja 8a otopi se u 50 ml tetrahidrofurana, pomiješa se sa 100 ml 1M otopine natrijevog hidroksida i ukupnu smjesu se zatim refluktira 6 h. Organsko otapalo se zatim odstrani u vakuumu i vodeni ostatak se neutralizira s octenom kiselinom. Talog se odsisa. Dobiveno je 3,5 g (85%) proizvoda.
c) (S)-N-(l-karbamoil-1-hidroksi-3-fenilpropan-2-il}-4-metil-1-(2-naftalenmetil)imidazol-5-karboksamid
1 g (3,8 mmola) intermedijarnog spoja 8b i 1,2 g (3,8 mmola) (2S),(3R,S)-3-amino-2-hidroksi-3-fenilbutiramid trifluoracetata reagiraju analogno postupku 1c. Dobiveno je 0,7 g (42%) proizvoda.
d) (S)-N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-4-metil-1-(2-naftalenmetil)-imidazol-5-karboksamid
0,6 g (1,4 mmola) intermedijarnog spoja 8c oksidira se analogno postupku 1d. Dobiveno je 0,33 g (56%) proizvoda.
MS: m/e = 440 (M+).
Primjer 9
(S)-N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-2-metil-1-(2-naftilmetil)imidazol-5-karboksamid
[image]
a) Etil 2-metil-1-(2-naftil)metilimidazol-4-karboksilat
4,6 g (29,8 mmola) etil 2-metilimidazol-4-karboksilata i 6,6 g (29,8 mmolova) 2-brommetilnaftalena reagira analogno postupku 8a. Dobiveno je 5,7 g (65%) proizvoda.
b) 2-metil-1-(2-naftil)metilimidazol-4-karboksilna kiselina
5,5 g (18,7 mmolova) intermedijarnog spoja 9a hidrolizira se analogno postupku 8b. Dobiveno je 3,2 g (65%) proizvoda.
c) (S)-N-(l-karbamoil-1-hidroksi-3-fenilpropan-2-il)-2-metil-1-(2-naftilmetil)imidazol-5-karboksamid
1 g (3,8 mmola) intermedijarnog spoja 9b i 1,2 g (3,8 mmola) (2S),(3R,S)-3-amino-2-hidroksi-3-fenilbutiramid trifluoroacetata reagira analogno postupku 1c. Dobiveno je 0,65 g (39%) proizvoda.
d) (S)-N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-2-metil-1-(2-naftilmetil)imidazol-5-karboksamid
0,6 g (1,4 mmola) intermedijarnog proizvoda 9c oksidira se analogno postupku 1d. Dobiveno je 0,42 g (71%) proizvoda.
MS: m/e = 440 (M+).
Primjer 10
(S)-N(l-karbamoil-1-okso-3-fenilpropan-2-il)-1-(2-naftil-metil)imidazol-2-karboksamid
[image]
a) Butil 1-(2-naftil )metilimidazol-2-karboksilat
5,0 g (29,7 mmolova) butil imidazol-2-karboksilata i 6,6 g (29,7 mmolova) 2-brom-metilnaftalena reagira analogno postupku 8a. Dobiveno je 6,4 g (71%) proizvoda.
b) l-(2-naftil)metilimidazol-2-karboksilna kiselina
6,2 g (20,1 mmolova) intermedijarnog spoja lOa hidrolizira se analogno postupku 8b. Dobiveno je 4,2 g (83%) proizvoda.
c) (S}-N-(l-karbamoil-1-hidroksi-3-fenilpropan-2-il)-1-(2-naftilmetil) imidazol-2 -karboksamid
1,1 g (4,4 mmola) intermedijarnog spoja 10b i 1,3 g (4,4 mmola) (2S),(3R,S)-3-amino-2-hidroksi-3-fenilbutiramid trifluoroacetata reagira analogno postupku 1c. Dobiveno je 1,3 g (70%) proizvoda.
d) (S)-N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-1-(2-nafti1-metil)imidazol-2-karboksamid
1,0 g (2,3 mmol) intermedijarnog spoja 10с oksidira se analogno postupku 1d. Dobiveno je 0,73 g (74%) proizvoda.
MS: m/e = 426 (М+).
Primjer 11
(S)-1-benzil-N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-imidazol-2-karboksamid
[image]
a) Butil l-benzilimidazol-2-karboksilat
5,4 g (32,1 mmola) butil imidazol-2-karboksilata reagira sa 4,1 g (32,1 mmola) benzil klorida analogno postupku 8a. Dobiveno je 7,3 g (78%) proizvoda.
b) 1-benzilimidazol-2-karboksilna kiselina
7 g (27,1 mmolova) intermedijarnog spoja 11a hidrolizira se upotrebom otopine natrijevog hidroksida analogno postupku 8b. Dobiveno je 3,7 g (68%) proizvoda.
c) (S)-1-benzil-(l-karbamoil-1-hidroksi-3-fenilpropan-2-il)-imidazol-2-karboksamid
1,0 g (5,1 mmola) intermedijarnog spoja 11b i 1,6 g (5,1 mmola) (2S),(3R,S)-3-amino-2-hidroksi-3-fenilbutiramid trifluoracetata reagira analogno postupku 1c. Dobiveno je 1,1 g (58%) proizvoda.
d) (S)-1-benzil-N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-imidazole-2-karboksamid
1,0 g (2,3 mmola) intermedijarnog spoja l1c oksidira se analogno postupku 1d. Dobiveno je 0,79 g (80%) proizvoda.
MS: m/e = 376 (М+).
Primjer 12
(S)-N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-1-(2-naftil-metil)imidazol-5-karboksamid
[image]
a) Etil 1-(2-naftilmetil)imidazol-5-karboksilat
2,4 g (17,1 mmolova) butil imidazol-5-karboksilata reagira sa 4,1 g (32,1 mmola) benzil klorida analogno postupku 8a. Dobiveno je 7,3 g (78%) proizvoda.
b) 1-(2-naftilmetil)imidazol-5-karboksilna kiselina
3 g (10,7 mmola) intermedijarnog spoja 12a hidrolizira se upotrebom otopine natrijevog hidroksida analogno postupku 8b. Dobiveno je 1,9 g (73%) proizvoda.
c) (S)-N-(l-karbamoil-1-hidroksi-3-fenilpropan-2-il)-1-(2-naftilmetil)imidazol-5-karboksamid
1,0 g (4,0 mmola) intermedijarnog spoja 12b i 1,2 g (4,0 mmola) (2S),(3R,S)-3-amino-2-hidroksi-3-fenilbutiramid trifluoroacetata reagira analogno postupku 1c. Dobiveno je 0,85 g (51%) proizvoda.
d)(S)-N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-1-(2-naftil-metil)imidazol-5-karboksamid
0,8 g (1,9 mmola) intermedijarnog spoja 12c oksidira se analogno postupku 1d. Dobiveno je 0,41 g (52%) proizvoda.
MS: m/e = 426 (М+).
Primjer 13
[image]
(S)-2-(2-naftil)eten-1-il)-N-(3-fenilpropan-1-al-2-il)-piridin-3-karboksamid
a) Etil 2-(2-naftileten-1-il)piridin-3-karboksilat hidroklorid
10 g (43,5 mmola) etil 2-brompiridin-3-karboksilata, 8,7 g (56,5 mmolova) 2-vinilnaftalena, 15 ml (0,11 mola) trietilamina, 0,36 g paladijevog(II) acetata i 0,96 g tri-o-tolilfosfina otopi se u 150 ml dimetilformamida. Zatim se doda još 1 ml vode i cijelu smjesu se refluktira 3 h. Zatim se cijelu smjesu ekstrahira s eterom. Organsku fazu se dodatno ispere s vodom, osuši i koncentrira u vakuumu. Ostatak se otopi u acetonu i obradi sa solnom kiselinom otopljenom u dioksanu. Proizvod se zatim istaloži dodatkom etera. Dobiveno je 8,7 g (67%) proizvoda.
b) 2-(2-naftileten-1-il)piridin-3-karboksilna kiselina
8,5 g (28 mmola) intermedijarnog proizvoda 13a otopi se u 70 ml tetrahidrofurana i pomiješa se sa 140 ml 2M otopine natrijevog hidroksida. Ukupnu smjesu se refluktira 8 h. Smjesu se zatim prelije u ledenu vodu i neutralizira s octenom kiselinom. Proizvod koji polako kristalizira se odsisa i osuši. Dobiveno je 5,6 g (73%) proizvoda.
c) (S)-2-(2-naftil)eten-1-il-N-(3-fenilpropan-1-ol-2-il)piridin-3-karboksamid
2 g (7,3 mmolova) intermedijata 13b i 1,1 g (7,3 mmolova) (2S),(3R,S)-3-amino-2-hidroksi-3-fenilbutiramid trifluoroacetata reagira analogno postupku 1c. Dobiveno je 2,1 g (71%) proizvoda.
d) (S)-2-(2-naftil)eten-1-il)-N-(3-fenilpropan-1-al-2-il)piridin-3-karboksamid
1,9 g (4,7 mmola) intermedijarnog spoja 13c oksidira se analogno postupku 1d. Dobiveno je 0,56 g (30%) proizvoda.
MS: m/e = 406 (M+).
Primjer 14
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(S)-N-(3-fenilpropan-1-al-2-il)-2-(4-piridil)eten-1-il)-piridin-3-karboksamid
a) Etil 2-(4-piridin)eten-1-ilpiridin-3-karboksilat
11,5 g (49,9 mmolova) etil 2-brompiridin-3-karboksilata i 6,8 g (64,9 mmolova) 4-vinilpiridina reagira analogno postupku 13a. Dobiveno je 7,0 g (49%) proizvoda.
b) 2-(4-piridil)eten-1-ilpiridin-3-karboksilna kiselina
7,0 g (27,5 mmolova) intermedijata 14a otopi se u 50 ml tetrahidrofurana i pomiješa sa 100 ml 2M otopine natrijevog hidroksida. Ukupnu smjesu se refluktira 2 h. Organsko otapalo se zatim odstrani u vakuumu i dobivenu vodenu fazu se zakiseli s octenom kiselinom. Vodenu fazu se koncentrira i ostatak se očisti kromatografijom (sredstvo za ispiranje: etil acetat/metanol/octena kiselina = 50/50/l). Dobiveno je 5,5 g (89%) proizvoda.
c) (S)-N-(3-fenilpropan-1-ol-2-il)-2-(4-piridil)eten-1-ilpiridin-3-karboksamid
1,5 g (6,6 mmolova) intermedijata 14b i 1,0 g (6,6 mmolova) (S)-2-amino-3-fenilpropanola reagira analogno postupku 1c. Dobiveno je 1,7 g (72%) proizvoda.
d) (S)-N-(3-fenilpropan-1-al-2-il)-2-(4-piridil)eten-1-ilpiridin-3-karboksamid
1,5 g (4,2 mmola) intermedijarnog spoja 14c oksidira se analogno postupku 1d. Dobiveno je 0,71 g (48%) proizvoda.
MS: m/e = 357 (М+).
Slijedeći primjeri su proizvedeni analogno gornjim primjerima i postupcima:
Primjer 15
(S)-N-(3-fenilpropan-1-al-2-il)-2-(4-piridil)kinolin-4-karboksamid
1H-NMR (d6-DMSO): δ = 3,0(1H), 3,4(1H), 4,8(1H), 7,25 (1Н), 7,7(2H), 7,9(2H), 8,1(1Н), 8,25(1Н), 8,7(1Н), 9,0 (1Н), 9,5(1H) i 9,8(1H) ppm.
Primjer 16
(S)-N-(3-fenilpropan-1-al-2-il)-2-(2-piridil)kinolin-4-
karboksamid
1H-NMR (d6-DMSO): δ = 2,9(1H), 3,3(1H), 4,8(1H), 7,2-8,2 (11H), 8,5(1H), 8,6(1H), 8,8(1H), 9,4(1H) i 9,0(1H) ppm.
Primjer 17
N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-2-(2-piridil)-quinolin-4-karboksamid
MS: m/e = 424 (M+).
Primjer 18
N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-2-(E-2-(4-piridil)-eten-1-il)piridin-3-karboksamid
1H-NMR (CF3-COOD): δ = 3,1 (1Н), 3,7(1H), 6,1(1H), 7,1-7,6 (5H), 8,0(1H), 8,1-8,5(4H), 8,6(1H), 9,0(2H) i 9,1(1H) ppm.
Primjer 19
N-(1-karbamoil-1-okso-3-fenilpropan-2-il)-2-(2-piridil)-kiino1in-4-karboksamid
MS: m/e = 424 (М+).
Primjer 20
N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-2-(1,2,3,4-tetrahidro-izokinolin-2-il)piridin-3-karboksamid
1H-NHR (D6-DMSO): δ = 2,8(2H), 2,9(1H), 3,2(2H), 3,3(1H), 4,3(1H), 5,3(1H), 6,8(1H), 7,0-7,5 (9H), 7,5(1H), 7,9-8,1 (2H) i 9,0(1H) ppm.
Primjer 21
N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-2-(6,7-dimetoksi-1,2,3,4-tetrahidroizokinolin-2-il)piridin-3-karboksamid
1H-NHR (D6-DMSO): δ = 2,7(2H), 2,8(1H), 3,2(2Н), 3,4(1Н), 3,7(6Н), 4,2(1Н), 5,3(1Н), 6,7(1H), 6,95(1Н), 7,1-7,5 (6Н) 7,9(1Н), 8,1(1Н), 8,4(1Н), 9,0(1Н) ppm.
Primjer 22
N-(l-karbamoil-1-okso-3-fenilpropan-2-il)-2-(3-fenil-pirolidin-1-il)piridin-3-karboksamid
1H-NHR (CF3COOD): δ = 2,0-2,7(2Н), 2,95(1Н), 3,3-4,0(6Н), 5,9(1Н), 6,9(1Н), 7,0-7,5(10Н) i 7,9(1H) ppm.
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Primjer 86
2-(4,6-dimetoksipirimidin-1-il)oksi-N-(3-fenilpropan-1-al-2-il)kinolin-4-karboksamid
MS: m/e = 458 (M+).
Primjer 87
N-(3-fenilpropan-1-al-2-il)-2-(2-piridil)oksi-8-trifluormetilkinolin-4-karboksamid
1H-NHR (D6-DMSO): δ = 3,0(1H), 3,4(1Н), 4,9(1Н), 7,3-8,9(13Н), 9,5(1Н) i 9,9(1Н) ppm.
Primjer 88
N-(3-fenilpropan-2-al)-2-il)-2-(nafto[c]pirimidion-3-il)-5-nikotinamid
1H-NHR (CF3COOD): δ = 3,1-3,4(2H), 4,8(1H), 6,7(1H), 7,1-8,3(12Н), 8,7(1H) i 8,9(1Н) ppm.
Primjer 89
N-(3-klorfenil)karbamoil-6-metil-N-(3-fenilpropan-2-al)-2-il)piridin-3-karboksamid
1H-NHR (CF3COOD): δ = 2,0-2,7(2H), 2,95(1H), 3,3-3,4(6Н), 5,9(1Н), 6,9(1H), 7,0-7,5 (10Н) i 7,9(1Н) ppm.
Claims (19)
1. Amidi opće formule I
[image]
i njihovi tautomerni i izomerni oblici, mogući enantiomerni i diastereomerni oblici, kao i moguće fiziološki podnošljive soli, naznačeni time, da u njima varijable imaju slijedeća značenja:
R1 može biti fenil, naftil, kinolil, piridil, pirimidil, pirazil, piridazil, imidazolil, tiazol, kinazil, izokinolil, kinazil, kinoksalil, tienil, benzotienil, benzofuranil, furanil, i indolil, gdje prstenovi mogu biti dodatno supstituirani sa do 3 radikala R5,
R2 je klor, brom, fluor, C1-C6-alkil, C1-C6-alkenil, C1-C6-alkinil, C1-C6-alkilfenil, C1-C6-alkenilfenil,
C1-C6-alkinilfenil, fenil, NHCO-C1-C4-alkil, NHSO2-C1-C4-alkil, -NHCO-fenil, -NHCO-naftil, NO2, -O-C1-C4-alkil i NH2, gdje aromatksi prstenovi mogu dodatno nositi jedan ili dva radikala R5 i dva radikala R2 zajedno mogu biti lanac
–CH=CH-CH=CH- i tako oblikovati fuzionirani benzo prsten, koji sa svoje strane može biti supstituiran s jednim R5 i
R3 je -C1-C6-alkil, koji je razgranat ili nerazgranat, i koji može dodatno nositi radikal S-СН3 ili fenil, cikloheksilni, cikloheptilni, ciklopentilni, indolilni, piridilni ili naftilni prsten koji je sa svoje strane supstituiran s najviše dva radikala R5, gdje R5 predstavlja vodik, C1-C4-alkil, koji je razgranat ili nerazgranat, -O- C1-C4-alkil, OH, Cl, F, Br, J, CF3, NO2, NH2, CN, COOH, COO- C1-C4-alkil, -NHCO-C1-C4-alkil, -NHCO-fenil, -NHSO2-C1-C4-alkil, -NHSO2-fenil, -SO2-C1-C4-alkil, -(CH2)n-NR12R13 i
-SO2-fenil,
X je veza, -(CH2)m-, -(CH2)m-O-(CHm)o-, -(CH2)o-S-(CH2)m-, -(CH2)o-SO-(CH2)m-, -(CH2)o-SO2-(CH2)m-, -CH=CH-, -C≡C-, -CO-CH=CH-, -(CH2)o-CO-(CH2)m-, -(CH2)m-NHCO-(CH2)o-, -(CH2)m-CONH-(CH2)o-, -(CH2)m-NHSO2-(CH2)o-, -NH-CO-CH=CH-, -(CH2)m-SO2NH-(CH2)o-, -CH=CH-CONH- i
[image]
i u slučaju skupine CH=CH dvostruke veze mogu imati E ili Z oblik i
R1-X zajedno također mogu biti
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i
Y je nezasićen heterociklički prsten kao piridin, pirimidin, pirazin, imidazol i tiazole i
R4 je vodik, COOR6 i CO-Z, gdje Z predstavlja NR7R8, i
[image]
R6 je vodik, C1-C6-alkil, koji je linearan ili razgranat, i koji može biti supstituiran s fenilnim prstenom koji sam može dodatno biti supstituiran s jednim ili dva radikala R9, i
R7 je vodik, C1-C6-alkil, koji je razgranat i nerazgranat, i
R8 je vodik, C1-C6-alkil, koji je razgranat ili nerazgranat koji može dodatno biti supstituiran s fenilnim prstenom koji može dodatno nositi radikal R9, i s
[image]
i
R9 može biti vodik, C1-C4-alkil, koji je razgranat ili nerazgranat, -O-C1-C4-alkil, OH, Cl, F, Br, J, CF3, NO2, NH2, CN, COOH, COO-C1-C4-alkil, -NHCO-C1-C4-alkil, -NHCO-fenil, -NHSO2-C1-C4-alkil, -NHSO2-fenil, -SO2-C1-C4-alkil i
-SO2-fenil,
R10 je vodik, C1-C6-alkil, koji je linearan ili razgranat, i koji može biti supstituiran s fenilnim prstenom koji sam može dodatno biti supstituiran s jednim ili dva radikala R9, i
R11 je vodik, C1-C6-alkil, koji je linearan ili razgranat, i koji može biti supstituiran s fenilnim prstenom koji sam može dodatno biti supstituiran s jednim ili dva radikala R9, i
n je broj 0, 1 ili 2, i
m i o međusobno neovisno predstavljaju brojeve 0, 1, 2, 3 ili 4.
2. Amid formule I prema zahtjevu 1, naznačen time, da
R3 predstavlja benzil, СН2СН2СН2СН3, СН2СН2СН2СН2СН3 i
Y je piridin i
R4 je CO-NR7R8 i
R7 je vodik,
R8 je СН2СН2, CН2СН2СН2, CН2СН2СН2СН2 i
R9 je vodik i
n je 0 i 1, a
sve preostale varijable imaju ista značenja kao u zahtjevu 1.
3. Amid formule I prema zahtjevu 1, naznačen time, da
R3 predstavlja benzil, СН2СН2СН2СН3, СН2СН2СН2СН2СН3 i
Y je piridin i
R4 je vodik, i
R9 je vodik i
n je 0 i 1, a
sve preostale varijable imaju ista značenja kao u zahtjevu 1.
4. Amid formule I prema zahtjevu 1, naznačen time, da
R3 predstavlja benzil, СН2СН2СН2СН3, СН2СН2СН2СН2СН3 i
Y je imidazol i tiazol, i
R4 je CO-NR7R8 i
R7 je vodik,
R8 je СН2СН2, CН2СН2СН2, CН2СН2СН2СН2 i
R9 je vodik i
n je 0 i 1, a
sve preostale varijable imaju ista značenja kao u zahtjevu 1.
5. Amid formule I prema zahtjevu 1, naznačen time, da
R3 predstavlja benzil, CH2-piridin, СН2СН2СН2СН3, СН2СН2СН2СН2СН3 i
Y je imidazol i tiazol, i
R4 je vodik i
R9 je vodik, i
n je 0 i 1, a
sve preostale varijable imaju ista značenja kao u zahtjevu 1.
6. Upotreba amida formula I prema zahtjevima 1-5, naznačena time, da se oni koriste za liječenje bolesti.
7. Upotreba amida formule I prema zahtjevima 1-5, naznačena time, da se oni koriste kao inhibitori cistein proteaza.
8. Upotreba prema zahtjevu 6, naznačena time, da se oni koriste kao inhibitori cistein proteaza kao što su kalpaini i katepsini, posebno kalpaini I i II i katepsini B i L.
9. Upotreba amida formule I prema zahtjevima 1-5, naznačena time, da se oni koriste za proizvodnju lijekova za liječenje bolesti u kojima dolazi do povišene aktivnosti kalpaina.
10. Upotreba amida formule I prema zahtjevima 1-5, naznačena time, da se oni koriste za proizvodnju lijekova za liječenje neurodegenerativnih bolesti i neuronskih oštećenja.
11. Upotreba prema zahtjevu 9, naznačena time, da se oni koriste za liječenje onih neurodegenerativnih bolesti i neuronskih oštećenja koja su uzrokovana ishemijom, traumom ili obimnim krvarenjima.
12. Upotreba prema zahtjevu 10, naznačena time, da se oni koriste za liječenje moždanog udara i kraniocerebralne traume.
13. Upotreba prema zahtjevu 10, naznačena time, da se oni koriste za liječenje Alzheimerove bolesti i Huntingtonove boelsti.
14. Upotreba prema zahtjevu 10, naznačena time, da se oni koriste za liječenje epilepsije.
15. Upotreba spojeva formule I prema zahtjevima 1-5, naznačena time, da se oni koriste za proizvodnju lijekova i za liječenje ozljeda srca nakon kardijanih ishemija, ozljede bubrega nakon renalne ishemije, ozljede i reperfuzije nakon vaskularne okluzije, ozljeda kostura i mišića, distrofija mišića, ozljeda koje su posljedica proliferacije glatkih mišićnih stanica, koronarnih vazospazmi, cerebralnih vazospazmi, katarakta očiju i restenoza krvnih struja nakon angioplastije.
16. Upotreba amida formule I prema zahtjevima 1-5, naznačena time, da se oni koriste za proizvodnju lijekova za liječenje tumora i njihovih metastaza.
17. Upotreba amida formule I prema zahtjevima 1-5, naznačena time, da se oni koriste za proizvodnju lijekova za liječenje bolesti u kojima dolazi do povišenih razina interleukina 1.
18. Upotreba amida formule I prema zahtjevima 1-5, naznačena time, da se oni koriste za liječenje upala i reumatskih poremećaja.
19. Farmaceutski pripravak za oralnu, parenteralnu i intraperitonealmu upotrebu, naznačen time, da u pojedinačnoj dozi, osim uobičajenih farmaceutskih pomoćnih tvari, sadrži najmanje jedan amid I prema zahtjevima 1-5.
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DE19817459A DE19817459A1 (de) | 1998-04-20 | 1998-04-20 | Neue heterozyklische substituierte Amide, Herstellung und Anwendung |
PCT/EP1999/002611 WO1999054304A1 (de) | 1998-04-20 | 1999-04-19 | Heterozyklische substituierte amide, deren herstellung und anwendung |
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EP3426674A4 (en) | 2016-03-09 | 2019-08-14 | Blade Therapeutics, Inc. | CYCLIC KETO AMID COMPOUNDS AS CALPAIN MODULATORS AND METHOD FOR THE PRODUCTION AND USE THEREOF |
EP3481835A4 (en) | 2016-07-05 | 2020-02-26 | Blade Therapeutics, Inc. | CALPAIN MODULATORS AND THEIR THERAPEUTIC USES |
EP3523294A4 (en) * | 2016-09-28 | 2021-01-13 | Blade Therapeutics, Inc. | CALPAIN MODULATORS AND THEIR THERAPEUTIC USES |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
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DE4000204A1 (de) | 1990-01-05 | 1991-07-11 | Steag Ag | Vorrichtung zum dosierten austragen von schuettfaehigem feststoff |
JPH06504061A (ja) | 1990-12-28 | 1994-05-12 | コーテックス ファーマシューティカルズ インコーポレイテッド | 神経変性の治療および予防におけるカルパイン阻害剤の使用 |
JPH06504547A (ja) | 1990-12-28 | 1994-05-26 | ジョージア・テック・リサーチ・コーポレーション | ペプチドケトアミド、ケト酸およびケトエステル |
CA2071621C (en) * | 1991-06-19 | 1996-08-06 | Ahihiko Hosoda | Aldehyde derivatives |
AU4544993A (en) | 1992-06-24 | 1994-01-24 | Cortex Pharmaceuticals, Inc. | Use of calpain inhibitors in the inhibition and treatment of medical conditions associated with increased calpain activity |
WO1996006211A1 (en) | 1992-11-16 | 1996-02-29 | E.I. Du Pont De Nemours And Company | Fishing lines and related products |
KR100490807B1 (ko) * | 1995-11-28 | 2005-10-14 | 세파론, 인코포레이티드 | 시스테인및세린프로테아제의d-아미노산함유억제제 |
DE19642591A1 (de) * | 1996-10-15 | 1998-04-16 | Basf Ag | Neue Piperidin-Ketocarbonsäure-Derivate, deren Herstellung und Anwendung |
US6100267A (en) * | 1997-03-14 | 2000-08-08 | Smithkline Beecham Corporation | Quinoline- and naphthalenecarboxamides, pharmaceutical compositions and methods of inhibiting calpain |
US6214856B1 (en) * | 1997-03-14 | 2001-04-10 | Smithkline Beecham Corporation | Indolecarboxamides, pharmaceutical compositions and methods of inhibiting calpain |
SK14512000A3 (sk) * | 1998-04-20 | 2001-04-09 | Basf Aktiengesellschaft | Substituované amidy, ich príprava a použitie |
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1998
- 1998-04-20 DE DE19817459A patent/DE19817459A1/de not_active Withdrawn
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1999
- 1999-04-19 IL IL13870499A patent/IL138704A0/xx unknown
- 1999-04-19 EP EP99922102A patent/EP1073638B1/de not_active Expired - Lifetime
- 1999-04-19 BR BR9909772-9A patent/BR9909772A/pt not_active IP Right Cessation
- 1999-04-19 AU AU39271/99A patent/AU3927199A/en not_active Abandoned
- 1999-04-19 US US09/673,087 patent/US6630493B1/en not_active Expired - Lifetime
- 1999-04-19 CA CA2328438A patent/CA2328438C/en not_active Expired - Fee Related
- 1999-04-19 AT AT99922102T patent/ATE402149T1/de not_active IP Right Cessation
- 1999-04-19 ID IDW20002135A patent/ID26980A/id unknown
- 1999-04-19 HU HU0101688A patent/HUP0101688A3/hu unknown
- 1999-04-19 TR TR2000/03056T patent/TR200003056T2/xx unknown
- 1999-04-19 JP JP2000544645A patent/JP4621350B2/ja not_active Expired - Fee Related
- 1999-04-19 CN CN99806401A patent/CN1301255A/zh active Pending
- 1999-04-19 ES ES99922102T patent/ES2310937T3/es not_active Expired - Lifetime
- 1999-04-19 WO PCT/EP1999/002611 patent/WO1999054304A1/de active IP Right Grant
- 1999-04-19 PL PL99343467A patent/PL343467A1/xx unknown
- 1999-04-19 SK SK1452-2000A patent/SK14522000A3/sk unknown
- 1999-04-19 KR KR1020007011608A patent/KR20010042841A/ko not_active Application Discontinuation
- 1999-04-19 DE DE59914814T patent/DE59914814D1/de not_active Expired - Lifetime
-
2000
- 2000-10-10 BG BG104831A patent/BG104831A/xx unknown
- 2000-10-19 NO NO20005264A patent/NO20005264L/no not_active Application Discontinuation
- 2000-11-17 HR HR20000786A patent/HRP20000786A2/hr not_active Application Discontinuation
- 2000-11-17 ZA ZA200006718A patent/ZA200006718B/en unknown
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2003
- 2003-06-23 US US10/601,356 patent/US20040097508A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
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WO1999054304A1 (de) | 1999-10-28 |
US20040097508A1 (en) | 2004-05-20 |
ID26980A (id) | 2001-02-22 |
CA2328438A1 (en) | 1999-10-28 |
DE59914814D1 (de) | 2008-09-04 |
ZA200006718B (en) | 2001-11-19 |
DE19817459A1 (de) | 1999-10-21 |
KR20010042841A (ko) | 2001-05-25 |
NO20005264D0 (no) | 2000-10-19 |
EP1073638B1 (de) | 2008-07-23 |
AU3927199A (en) | 1999-11-08 |
BR9909772A (pt) | 2000-12-19 |
ES2310937T3 (es) | 2009-01-16 |
IL138704A0 (en) | 2001-10-31 |
CN1301255A (zh) | 2001-06-27 |
HUP0101688A3 (en) | 2002-12-28 |
CA2328438C (en) | 2011-02-22 |
BG104831A (en) | 2001-05-31 |
US6630493B1 (en) | 2003-10-07 |
ATE402149T1 (de) | 2008-08-15 |
JP4621350B2 (ja) | 2011-01-26 |
JP2002512228A (ja) | 2002-04-23 |
HUP0101688A2 (hu) | 2001-11-28 |
PL343467A1 (en) | 2001-08-13 |
SK14522000A3 (sk) | 2001-05-10 |
TR200003056T2 (tr) | 2001-02-21 |
EP1073638A1 (de) | 2001-02-07 |
NO20005264L (no) | 2000-10-19 |
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