SK83897A3 - Low molecular weight bicyclic thrombin inhibitors - Google Patents
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Abstract
Description
(54) Názov prihlášky vynálezu: Bicyklické inhibitory trombínu s nízkou molekulovou hmotnosťou(54) Title of the invention: Low molecular weight bicyclic thrombin inhibitors
(57) Anotácia:(57) Annotation:
Opísané sú heterocyklické kompetetívne inhibitory enzýmu trombínu, ktoré majú vzorec (I), v ktorom A môže byť (CH-Rs)o-i, S, SO, SO2, O a NR8, v ktorom R8 je vodík, C|.6alkyl voliteľne prerušený s 1 alebo 2 heteroatómami; C|.e aryl, C3.7 cykloalkyl alebo heterocyklický kruh alebo hydrofóbna skupina; B môže byť S, SO2, O, -N=, NH-, -CH= a CR6R7, v ktorom R« a R7 môžu byť nezávisle vodík alebo C|.6 alkyl s podmienkou keď A je S, SO, SO2, O alebo NRS, potom B je CR6R7; D môže byť (CH-R9)o_2, kde R9 je vodík, Cb6 alkyl alebo -C(O)R|; a CH s dvojitou väzbou k B, keď B je -N= alebo -CH=; E môže byť CH2 alebo CH substituované s -C(O)Rb s podmienkou, že len jedno D a E je substituované s C(O)Rb X môže byť O, N-R5, alebo CH-RS; Y môže byť O, S, SO, SO2, N-R5 alebo CH-R8, s podminenkou, že keď X je N-Rs, potom Y je CH-RS alebo O, a keď X je O, potom Y je CH-R8; Z môže byť O, S a H2; R] je polárny aminokyselinový zvyšok arginylu alebo analóg, alebo derivát, alebo jeho derivát voliteľne substituovaný aminokyselinou, peptidom alebo heterocyklom; R2 môže byť H alebo Cb6 alkyl voliteľne substituovaný s C6 arylom, 6-členný heterocykel alebo C3. .7, cykloalkylový kruh; R3 môže byť H, NR6R7, alebo Cb6 alkyl a R4 a R5 môžu byť nezávisle H; NR6R7> C6.16 aryl alebo C3.7 cykloalkyl voliteľne substituovaný s Cb6 alkylom; Cbl6 alkyl voliteľne prerušený s jedným alebo viac heteroatómami, alebo karbonylovou skupinou a voliteľne substituovaný s OH, SH, NR6R7, alebo Cb|6 arylom, heterocyklom alebo C3.7 cykloalkylovou skupinou vo liteľne substituovanou s halogénom, hydroxylom, Cb6 alkylom; bočný reťazec aminokyseliny; a hydrofóbna skupina. Tieto zlúčeniny možno in vitro použiť ako antikoagulanty a in vivo na liečenie a profílaxiu trombotických ochorení, akými sú cievne trombózy, pľúcne embólie a arteriálne trombózy vyvolávajúce akútne ischemické javy, ako sú myokardiálne infarkty alebo cerebrálne infarkty.Described are heterocyclic competitive inhibitors of the thrombin enzyme having the formula (I) in which A can be (CH-R 5) 0, S, SO, SO 2 , O and NR 8 , wherein R 8 is hydrogen, C 1. C 6 alkyl optionally interrupted with 1 or 2 heteroatoms; C 1-6 aryl, C 3-7 cycloalkyl or a heterocyclic ring or a hydrophobic group; B may be S, SO 2 , O, -N =, NH-, -CH =, and CR 6 R 7, wherein R 7 and R 7 may independently be hydrogen or C 1. 6 alkyl with the proviso that when A is S, SO, SO 2, O, S or NR, then B is CR 6 R 7; D can be (CH-R 9) o_ 2, wherein R 9 is hydrogen, alkyl or d6-C (O) R |; and CH with a double bond to B when B is -N = or -CH =; E may be CH 2 or CH substituted with -C (O) R b with the proviso that only one D and E is substituted with C (O) R b X may be O, NR 5 , or CH-R 5 ; Y may be O, S, SO, SO 2, NR 5 or CH-R 8, p podminenkou that when X is NR, Y is CH-R or O, and when X is O, Y is CH -R 8 ; Z may be O, S and H 2 ; R 1 is a polar amino acid residue of arginyl or an analogue, or a derivative, or a derivative thereof, optionally substituted with an amino acid, a peptide or a heterocycle; R 2 can be H or alkyl optionally substituted d6 with C 6 aryl, 6-membered hetero ring, or C 3. 7, cycloalkyl ring; R 3 may be H, NR 6 R 7, or C b6 alkyl and R 4 and R 5 can be independently H; NR 6 R 7> C 6 . 16 aryl or C 3. 7 cycloalkyl optionally substituted with C alkyl b6; BL6 C alkyl optionally interrupted by one or more heteroatom or carbonyl group and optionally substituted with OH, SH, NR 6 R 7, or C b | 6 aryl, heterocycle or C 3. 7 cycloalkyl of LITEL substituted with halogen, hydroxyl, C alkyl b6; an amino acid side chain; and a hydrophobic group. These compounds can be used in vitro as anticoagulants and in vivo for the treatment and prophylaxis of thrombotic diseases such as vascular thrombosis, pulmonary embolism and arterial thrombosis inducing acute ischemic events, such as myocardial infarctions or cerebral infarctions.
-iBicyklické inhibítory trombínu s nízkou molekulovou hmotnosťouLow molecular weight thrombin inhibitors
Oblasť technikyTechnical field
Tento vynález sa týka zlúčenín vhodných na liečenie trombotických ochorení, presnejšie nových heterocyklických inhibítorov trombínu.The present invention relates to compounds useful in the treatment of thrombotic diseases, more particularly novel heterocyclic thrombin inhibitors.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Nepravidelné trombusové formácie po stenách krvných ciev urýchľujú akútne kardiovaskulárne chorobné stavy, ktoré sú hlavnou príčinou úmrtia v ekonomicky vyvinutých spoločnostiach. Bielkoviny plazmy ako je fibrinogén, proteázy a bunkové receptory, ktoré sa zúčastňujú hemostázy, sa zdajú byť dôležitými faktormi, ktoré hrajú úlohu pri akútnom a pri chronickom koronárnom ochorení, a tak isto aj pri cerebrálnom ochorení artérii tým, že napomáhajú tvorbe trombusu alebo krvných zrazenín, ktoré účinné znižujú normálny krvný prietok a prívod. Vaskuláme aberácie, ktoré pramenia z primárnych patologických stavov, aké sú hypertenzia, prasknutie arterosklerotických plakov alebo obnaženého endotélia, aktivujú biochemické kaskády, ktoré slúžia ako odpoveď a na opravu poškodeného miesta. Trombín je kľúčový regulačný enzým v koagulačnej kaskáde; vykonáva početné úlohy, ako pozitívny aj negatívny spätno-väzobný regulátor. Avšak, za patologických podmienok táto regulačná úloha je znásobená cez katalytickú aktiváciu kofaktormi, ktoré sú potrebné tak na tvorbu trombínu ako aj na aktiváciu faktoru ΧΙΠ vyžadovaného na sieťovanie a stabilizáciu fibrínu.Irregular thrombus formation along the walls of blood vessels accelerates acute cardiovascular disease states, which are the leading cause of death in economically developed societies. Plasma proteins such as fibrinogen, proteases and cellular receptors involved in hemostasis seem to be important factors that play a role in acute and chronic coronary disease, as well as cerebral artery disease, by assisting in the formation of thrombus or blood clots which effectively reduce normal blood flow and intake. Vascular aberrations that stem from primary pathological conditions, such as hypertension, rupture of arterosclerotic plaques or exposed endothelium, activate biochemical cascades that serve as a response and repair of the damaged site. Thrombin is a key regulatory enzyme in the coagulation cascade; performs numerous tasks, both positive and negative feedback regulator. However, under pathological conditions, this regulatory role is multiplied through catalytic activation by the cofactors required for both thrombin formation and activation of the ΧΙΠ factor required for crosslinking and stabilization of fibrin.
Okrem priameho účinku na hemostázu, trombín vykazuje priame účinky na rôzne typy buniek, ktoré podporujú a zvyšujú patogenézu arteriálnej trombózy. Enzým je najsilnejším aktivátorom doštičiek spôsobujúci ich agregáciu a uvoľnenie látok ( ako napr. ADP TXA, NE), ktoré ďalej propagujú trombotický cyklus. Krvné doštičky vo fibrínovej sieti predstavujú zásadný rámec bielej trombózy. Trombín tiež vykazuje priame účinky na endoteliálne bunky, kde spôsobuje uvoľnenie vazokonstrikčných látok a translokáciu adhéznych molekúl, ktoré sa stávajú miestami na pripojenie imúnnych buniek. Naviac, enzým spôsobuje mitogenézu buniek hladkého svalstva a proliferáciu fibroblastov. Z tejto analýzy je jasné, že inhibícia trombínovej aktivity predstavuje životaschopný terapeutický prístup za účelom spomalenia proliferatívnych javov sprevádzajúcich trombózy.In addition to a direct effect on hemostasis, thrombin has direct effects on various cell types that promote and enhance the pathogenesis of arterial thrombosis. The enzyme is the most potent platelet activator causing their aggregation and release of substances (such as ADP TXA, NE) that further promote a thrombotic cycle. Platelets in the fibrin network represent an essential framework for white thrombosis. Thrombin also has direct effects on endothelial cells, where it causes the release of vasoconstrictors and translocation of adhesion molecules, which become sites of attachment of immune cells. In addition, the enzyme causes mitogenesis of smooth muscle cells and fibroblast proliferation. From this analysis, it is clear that inhibition of thrombin activity is a viable therapeutic approach to slow down the proliferative phenomena accompanying thrombosis.
-2• Základný endogénny neutralizačný faktor trombínovej aktivity u cicavcov je antitrombín III (ΑΊΊΠ), ktorý je cirkulujúci plazmatický makroglobulín s nízkou afinitou pre enzým. Heparín vykazuje klinickú účinnosť pri cievnych trombózach tým, že zvyšuje behom katalýzy ATIH/trombínovu väzbu. Avšak, heparín tiež katalyzuje v koagulačnej kaskáde inhibíciu iných proteáz, a jeho efektívnosť v trombózach, ktoré sú závislé na krvných doštičkách, je značne redukovaná alebo rušená v dôsledku neprístupnosti trombus-viažúceho enzýmu. Po dlhšej aplikácii heparínu boli pozorované nežiadúce vedľajšie účinky akými sú napríklad trombocytopénia, osteoporóza, a triglyceridémia.The basic endogenous neutralizing factor of thrombin activity in mammals is antithrombin III (ΑΊΊΠ), which is circulating plasma macroglobulin with a low affinity for the enzyme. Heparin exhibits clinical efficacy in vascular thrombosis by increasing ATIH / thrombin binding during catalysis. However, heparin also catalyzes the inhibition of other proteases in the coagulation cascade, and its efficacy in platelet-dependent thromboses is greatly reduced or abolished due to the inaccessibility of the thrombus-binding enzyme. After prolonged administration of heparin, adverse side effects such as thrombocytopenia, osteoporosis, and triglyceridemia have been observed.
Hirudín, získavaný zo žľazových sekrécii pijavíc hiridio medicinalis, je jedným z prírodných antikoagulačnych proteínových inhibítorov trombínovej aktivity s vysokou molekulovou hmotnosťou (Markwardt F. Cardiovascular Drug Reviews, 10, 211, 1922). Je to biofarmakum, ktoré preukazuje účinnosť pri experimentálnych a klinických trombózach. Potenciálnym nedostatkom využitia hirudínu ako terapeutickej látky je pravdepodobná antigenicita a nedostatok účinných metód neutralizácie, obzvlášť z hľadiska jeho extrémne silných väzbových charakteristík voči trombínu. Nadmerne vysoká afinita voči trombínu je unikátna a je pripisovaná ako súčasnej interakcii s katalytickým miestom, tak aj prítomnosťou vzdialeného “exo-miesta pre väzbu aniónov“ v samotnom enzýme.Hirudin, obtained from the glandular secretions of the leech hiridio medicinalis, is one of the natural anticoagulant protein inhibitors of high molecular weight thrombin activity (Markwardt F. Cardiovascular Drug Reviews, 10, 211, 1922). It is a biopharmaceutical that demonstrates efficacy in experimental and clinical thromboses. The potential drawback of the use of hirudin as a therapeutic agent is the probable antigenicity and lack of effective methods of neutralization, especially in view of its extremely strong thrombin binding characteristics. The excessively high affinity for thrombin is unique and is attributed to both the simultaneous interaction with the catalytic site and the presence of a remote "anion-binding exo-site" in the enzyme itself.
Aktivita trombínu môže byť tiež zrušená hirudínu-podobnými molekulami ako hirulogové (Maraganore, J.M. et al., Biochemistry, 29, 7095, 1990) alebo hirutonínové peptidy (DiMaio, J. et al., J. Med. Chem., 35, 3331, 1992).Thrombin activity can also be abolished by hirudin-like molecules such as hirulog (Maraganore, JM et al., Biochemistry, 29, 7095, 1990) or hirutonin peptides (DiMaio, J. et al., J. Med. Chem., 35, 3331 (1992).
Aktivita trombínu môže byť tiež inhibovaná zlúčeninami s nízkou molekulovou hmotnosťou, ktoré súťažia s fibrinogénom o katalytické miesto trombínu a takto inhibujú proteolýzu tohoto proteínu alebo iných proteínových substrátov ako napríklad trombínového receptora. Spoločná stratégia pri navrhovaní inhibujúcich zlúčenín spolieha na napodobňovanie špecifických vlastnosti v primárnej a sekundárnej štruktúre prirodzených substrátov enzýmu. Takto, Blomback a spol. ako prvý navrhli inhibítor trombínu, ktorý bol modelovaný podľa čiastočnej sekvencie fibrinogénového A(LBl)a reťazca obsahujúceho segment, ktorý podlieha proteolýze (Blomback, et al., J. Clin. Lab. Invest., 24, 59, 1969). Tento segment fibrinogénu obsahuje minimálne zvyšky začínajúce od fenylalanínu:Thrombin activity can also be inhibited by low molecular weight compounds that compete with fibrinogen for the catalytic site of thrombin and thereby inhibit proteolysis of this protein or other protein substrates such as the thrombin receptor. A common strategy in designing inhibitory compounds relies on mimicking specific properties in the primary and secondary structure of natural enzyme substrates. Thus, Blomback et al. they first proposed a thrombin inhibitor that was modeled according to a partial sequence of fibrinogen A (LB1) and a chain containing a segment that undergoes proteolysis (Blomback, et al., J. Clin. Lab. Invest., 24, 59, 1969). This segment of fibrinogen contains minimal residues starting from phenylalanine:
-3Ala-Asp-Ser-Gly-Glu-Gly-Asp-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg-Gly-Pro-Arg-3Ala-Asp-Ser-Gly-Glu-Gly-Asp-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg-Gly-Pro-Arg
T štiepaná väzbaT cleaved bond
Systematická substitúcia aminokyselín vo vnútri tohto segmentu viedla k optimalizácii tripeptidových inhibičných sekvencií, ako v prípade peptidu (D)-Phe-Pro-Arg, ktorý je analogický ku interakciám vo vnútri P-P-P lokálneho väzobného miesta vtrombíne. (Bajusz S. et al., in Peptides: Chemistry Structure and Biology: Proceedings of the Fourth Američan Peptide Symposium, Walter R., Meienhofer J. Eds. Ann Arbor Science Publishers Inc., Ann Arbor MI, 1975, pp. 603).The systematic substitution of amino acids within this segment led to the optimization of tripeptide inhibitory sequences, as in the case of the (D) -Phe-Pro-Arg peptide, which is analogous to the interactions within the P-P-P local binding site of the thrombin. (Bajusz S. et al., In Peptides: Chemistry Structure and Biology: Proceedings of the Fourth American Peptide Symposium, Walter R., Meienhofer J. Eds. Ann Arbor Science Publishers Inc., Ann Arbor MI, 1975, pp. 603) .
Bajusz a spol. tiež opísali podobné zlúčeniny ako je (D)Phe-Pro-Arg-(CO)H (GYKJ14166) a (D)MePhe-Pro-Arg-(CO)H (GYKI 14766) (Peptides-Synthesis, Structure and Function: Proceedings of the Seventh Američan Peptide Symposium, Rich, D.H. & Gross, E. eds., Pierce Chemical Company, 1981, pp. 417). Tieto tripeptidylové aldehydy sú účinnými inhibítormi trombínu ako in vitro tak aj in vivo. V prípade oboch GYKI-14166 a GYKI-14766 sa predpokladá, že aldehydická skupina silne prispieva k inhibičnej aktivite z hľadiska jej chemickej reaktivity voči katalytickému Ser zvyšku trombínu tým, že vytvára hemiacetátový intermediát.Bajusz et al. also disclosed similar compounds such as (D) Phe-Pro-Arg- (CO) H (GYKJ14166) and (D) MePhe-Pro-Arg- (CO) H (GYKI 14766) (Peptides-Synthesis, Structure and Function: Proceedings of the Seventh American Peptide Symposium, Rich, DH & Gross, E. eds., Pierce Chemical Company, 1981, pp. 417). These tripeptidyl aldehydes are potent inhibitors of thrombin both in vitro and in vivo. For both GYKI-14166 and GYKI-14766, the aldehyde group is believed to contribute strongly to the inhibitory activity in terms of its chemical reactivity to the catalytic Ser thrombin residue by forming a hemiacetate intermediate.
Podobné práce v oblasti trombínových inhibičných aktivít využili základný rozpoznávací väzobný motív poskytovaný tripeptidom (D)Phe-Pro-Arg tým, že sa inkorporovali rôzne funkčné a reaktívne skupiny do lokusu, ktorý zodpovedá predpokladanej štiepnej väzbe (Pi-Pi).Similar work in the field of thrombin inhibitory activities utilized the basic recognition binding motif provided by the tripeptide (D) Phe-Pro-Arg by incorporating various functional and reactive groups into the locus that corresponds to the putative cleavage (Pi-Pi).
V patente Spojených štátov 4 318 904, Shaw opisuje chlormetylketóny (PPACK), ktoré sú reaktívne voči Ser a His. Tieto dva zvyšky predstavujú časť ztrombínovej katalytickej triády (Bode, W a spol.., EMBO Joumal 8, 3467, 1989).In U.S. Pat. No. 4,318,904, Shaw discloses chloromethyl ketones (PPACKs) that are reactive against Ser and His. These two residues represent part of the thrombin catalytic triad (Bode, W et al., EMBO Joumal 8, 3467, 1989).
Iné príklady trombínových inhibítorov, v ktorých sa nachádza základný motív (D)PhePro-Arg, sú také, do ktorých sú inkorporované COOH-terminálne boroarginínové varianty akými sú kyselina boritá, alebo boritany (Kettner, C. a spol., J. Biol. Chem., 268, 4734. 1993).Other examples of thrombin inhibitors in which the underlying motif (D) of PhePro-Arg is found are those in which COOH-terminal boroarginine variants such as boric acid or borates are incorporated (Kettner, C. et al., J. Biol. Chem., 268, 4734 (1993).
Ďalšie príbuzné zlúčeniny tohoto motívu sú také, ktoré obsahujú fosfonáty (Wang, C-L.J., Tetrahedron Letters, 33, 7667, 1982) a α-keto estery (Iwanovicy, E.J. a spol., Bioorganic and Medicinal Chemistry Letters, 12, 1607, 1992).Other related compounds of this motif are those containing phosphonates (Wang, CL.J., Tetrahedron Letters, 33, 7667, 1982) and α-keto esters (Iwanovicy, EJ et al., Bioorganic and Medicinal Chemistry Letters, 12, 1607). (1992).
-4Neises, B. a spol. opísali trichlórmetyl ketónový inhibítor trombínu (MDL-73756) a Attenburger, J.M. a spol. objavili príbuzný difluóralkyl amidoketón (Tetrahedron Letters, 32, 7255,1991).-4 Neises, B. et al. have described a trichloromethyl ketone thrombin inhibitor (MDL-73756) and Attenburger, J.M. and company. have discovered a related difluoroalkyl amidoketone (Tetrahedron Letters, 32, 7255, 1991).
Maraganore a spol. (European 0 333 356: WO 91/02750: USA 5 196 404) odhaľujú sériu trombínových inhibítorov, ktoré obsahujú D-Phe-Pro- zvyšok a predpokladajú, že tato navrhnutá štruktúra dobre zapadá do brázdy (ryhy) v blízkosti aktívneho miesta trombínu. Obmeny týchto inhibítorov sú v podstate lineárne alebo cyklické peptidy budované na základe zvyšku D-Phe-ProDalšia séria patentov a patentových prihlášok opisuje pokusy vyvinúť účinné inhibítori trombózy využívajúc alfa-ketoamidové a peptid aldehydové analógy. (EP 0333356: WO 93/15756: WO 93/22344: WO 94/08941: WO 94/17817).Maraganore et al. (European 0 333 356: WO 91/02750: USA 5 196 404) disclose a series of thrombin inhibitors that contain a D-Phe-Pro- residue and suggest that this proposed structure fits well in the furrow near the active site of thrombin. Variants of these inhibitors are essentially linear or cyclic peptides built on the remainder of D-Phe-Pro. Another series of patents and patent applications discloses attempts to develop effective thrombosis inhibitors using alpha-ketoamide and peptide aldehyde analogs. (EP 0333356: WO 93/15756: WO 93/22344: WO 94/08941: WO 94/17817).
Aj ďalší sústredili svoju pozornosť na peptidy, peptidové deriváty, peptidické alkoholy, alebo cyklické peptidy ako anti-trombotické činidlá (WO93/22344, EP 0276014: EP 0341607 : EP 0291982). Ďalší skúšali pre tento istý účel použiť zvyšky amidín-sulfónovej kyseliny (USA 4 781 866), zatiaľ čo iný skúšali para- alebo metá- substituované fenylalanínové deriváty (WO 92/08709: WO 92/6549).Others have also focused their attention on peptides, peptide derivatives, peptide alcohols, or cyclic peptides as anti-thrombotic agents (WO93 / 22344, EP 0276014: EP 0341607: EP 0291982). Others have tried to use amidine sulfonic acid residues (US 4,781,866) for this purpose, while others have tried para- or meta-substituted phenylalanine derivatives (WO 92/08709: WO 92/6549).
Séria patentov Mitsubishi a patentových prihlášok poskytli zrejme účinné arginínamidové zlúčeniny pre použitie ako antitrombotické látky. Chemické štruktúry, ktoré sú opísané v týchto dokumentoch reprezentujú obmeny postranných skupín na arginínamidovej zlúčenine (USA 4173 630 : USA 4 097 591 : CA 1 131 621 : USA 4 096 255 : USA 4 046 876 : USA 4 097 472 : CA 2 114 153).A series of Mitsubishi patents and patent applications have apparently provided potent arginine amide compounds for use as antithrombotic agents. The chemical structures described in these documents represent side group variations on the arginine amide compound (US 4173 630: US 4 097 591: CA 1 131 621: US 4 096 255: US 4 046 876: US 4 097 472: CA 2 114 153 ).
Kanadské prihlášky patentov 2 076 311 a 2 055 850 poskytujú cyklické imino deriváty, ktoré vykazujú inhibičný účinok na bunkové agregácie.Canadian patent applications 2,076,311 and 2,055,850 provide cyclic imino derivatives that have an inhibitory effect on cell aggregation.
Mnohé z príkladov uvedených vyššie konvergujú na udržanie aspoň lineárneho acyklického tripeptidového motívu obsahujúceho arginylovu jednotku, ktorej vedľajší reťazec je potrebný pre interakcie s karboxylovou skupinou lokalizovanou na základe Pi špecifického štepu vtrombíne. Dve susedné hydrofóbne skupiny poskytujú dodatočnú väzbu cez výhodné Van der Waalsove interakcie vo vnútri vedľajšej hydrofóbnej štrbiny na povrchu enzýmu predpokladaného P-P miesta.Many of the examples above converge to maintain at least a linear acyclic tripeptide motif containing an arginyl unit, the side chain of which is required for interactions with a carboxyl group located based on the Pi specific thrombin graft. The two adjacent hydrophobic groups provide additional bonding through preferred Van der Waals interactions within the minor hydrophobic slit on the enzyme surface of the putative P-P site.
Jeden z predmetov predkladaného vynálezu je poskytnúť trombínové inhibítory, ktoré vykazujú inhibičnú aktivitu voči cieľovému enzýmu, trombínu.It is one object of the present invention to provide thrombin inhibitors that exhibit target enzyme inhibitory activity, thrombin.
-5Ďalším predmetom predkladaného vynálezu je poskytnúť trombínové inhibítory, ktoré vykazujú inhibičnú aktivitu voči cieľovému enzýmu trombínu a sú poskytované vo farmakologicky akceptovateľnej forme.It is another object of the present invention to provide thrombin inhibitors that exhibit inhibitory activity against the target thrombin enzyme and are provided in a pharmacologically acceptable form.
Ešte ďalším predmetom predkladaného vynálezu je poskytnúť na použitie heterocyklické trombínové inhibítory, a ich formulácie ako antikoagulantov a trombín inhibičných látok.Yet another object of the present invention is to provide for the use of heterocyclic thrombin inhibitors, and their formulations as anticoagulants and thrombin inhibitors.
Ešte ďalším predmetom predkladaného vynálezu je poskytnúť na použitie heterocyklické trombínové inhibítory a ich formulácie za účelom terapeutických aplikácii pre rôzne trombotické ochorenia.Yet another object of the present invention is to provide for the use of heterocyclic thrombin inhibitors and their formulations for therapeutic applications for various thrombotic diseases.
Ďalším predmetom predkladaného vynálezu je proces syntézy týchto inhibítorov trombínu s nízkou molekulovou hmotnosťou. Enzýmové inhibítory predkladaného vynálezu sú obklopené štruktúrou všeobecného vzorca I.Another object of the present invention is a process for the synthesis of these low molecular weight thrombin inhibitors. The enzyme inhibitors of the present invention are surrounded by the structure of Formula I.
Podstata vynálezuSUMMARY OF THE INVENTION
Predložený vynález poskytuje štyri nové zlúčeniny, ktoré vykazujú trombín inhibičnú aktivitu, ako sú vyjadrené vo vzorci I:The present invention provides four novel compounds that exhibit thrombin inhibitory activity as expressed in Formula I:
kde:where:
A môže byť (CH-Rs)o-i, S, SO, SO2, O, a NRs, v ktorom Rs je vodík, Ci-e alkyl voliteľne prerušený s 1 alebo 2 heteroatómami; Có-16 aryl, C3.7 cykloalkyl alebo heterocyklický kruh alebo hydrofóbna skupina;A can be (CH-R 5) 0-1, S, SO, SO 2, O, and NR 5, wherein R 5 is hydrogen, C 1-6 alkyl optionally interrupted with 1 or 2 heteroatoms; A C 6-16 aryl, C 3-7 cycloalkyl or heterocyclic ring or a hydrophobic group;
B môže byť S, SO2, O., -N=, NH, -CH= a CR6 R7 v ktorom R$ a R7 môžu byť nezávisle vodík alebo Ci.g alkyl s podmienkou keď A je S, SO, SO2, O alebo NRs, potom B je CR^ R7 B is selected from S, SO2, O, -N =, NH, -CH = and CR 6 R 7 wherein R $ and R 7 may each independently H or Ci.g alkyl with the proviso that when A is S, SO, SO 2 , O or NR 5, then B is CR 1 R 7
D môže byť (CH-R9 )0-2 kde R9 je vodík, Ci-6 alkyl alebo -C(O)Ri; a CH s dvojitou väzbou k B, keď B je -N= alebo -CH=;D can be (CH-R 9) 0-2 wherein R 9 is hydrogen, C 1-6 alkyl or -C (O) R 1; and CH with a double bond to B when B is -N = or -CH =;
E môže byť CH2 alebo CH substituované s -C(O)Ri, s podmienkou že len jedno D a E je substituované s -C(O)Ri;E may be CH 2 or CH substituted with -C (O) R 1, provided that only one D and E is substituted with -C (O) R 1;
X môže byť O, N-R5, alebo CH-R5;X may be O, N-R 5, or CH-R 5;
-6Y môže byť O, S, SO, SO?, N-R5 alebo CH-Rg, s podmienkou, že keď X je N-R5, potom Y je CH-Rg alebo O, a keď X je O potom Y je CH-R8;-6Y may be O, S, SO, SO 2, N-R 5 or CH-R 8, with the proviso that when X is N-R 5, then Y is CH-R 8 or O, and when X is O then Y is CH -R 8 ;
Z môže byť O, S a H2;Z may be O, S and H2;
Rj je polárny aminokyselinový zbytok arginylu alebo analóg alebo derivát alebo jeho derivát voliteľne substituovaný aminokyselinou, peptidom alebo heterocyklom;R 1 is a polar amino acid residue of arginyl or an analogue or derivative or derivative thereof optionally substituted with an amino acid, peptide or heterocycle;
R2 môže byť H alebo Ci-6 alkyl voliteľne substituovaný s Có arylom, 6 - členný heterocykel alebo C3.7, cykloalkylový kruh;R 2 can be H or C 1-6 alkyl optionally substituted with C 6 aryl, 6-membered heterocycle or C 3-7, cycloalkyl ring;
R^ môže byť H, NR6R7, alebo Ci-6 alkyl a R4 2 R5 môžu byť nezávisle H; NR^R?; Có-ió aryl alebo C3.7 cykloalkyl voliteľne substituovaný s Ci-6 alkylom;R 6 can be H, NR 6 R 7, or C 1-6 alkyl, and R 4 R 5 can be independently H; NR R ?; C 6-10 aryl or C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl;
C i-i6 alkyl voliteľne prerušený s jedným alebo viac heteroatómami alebo karbonylovou skupinou a voliteľne substituovaný s OH, SH, NR5R7, alebo Có-ió arylom, heterocyklom alebo C3.7 cykloalkylovou skupinou voliteľne substituovanou s halogénom, hydroxylom, C1-6 alkylom; bočný reťazec aminokyseliny; a hydrofóbna skupina.C 1-6 alkyl optionally interrupted with one or more heteroatoms or carbonyl and optionally substituted with OH, SH, NR 5 R 7, or C 6-10 aryl, heterocycle or C 3-7 cycloalkyl optionally substituted with halogen, hydroxyl, C 1-6 alkyl; an amino acid side chain; and a hydrophobic group.
Ako bude jasné z nasledujúcich zistení, molekuly, zmesi a spôsoby podľa tohto vynálezu sú užitočné ako antikoagulanty, alebo pri liečbe a prevencii rôznych chorôb pripisovaným nežiaducim účinkom trombínu, ako aj na diagnostické účely.As will be clear from the following findings, the molecules, compositions and methods of the invention are useful as anticoagulants, or in the treatment and prevention of various diseases attributed to thrombin as an adverse effect, as well as for diagnostic purposes.
Detailnejší opis vynálezuDETAILED DESCRIPTION OF THE INVENTION
Predkladaný vynález sa vzťahuje na molekuly ktoré inhibujú enzým trombín.Tieto molekuly sa vyznačujú heterocyklickými zvyškami, ako je to zobrazené vo Vzorci I:The present invention relates to molecules that inhibit the enzyme thrombin. These molecules are characterized by heterocyclic residues as shown in Formula I:
kde X, Y, Z, A, B, D, E a R, až R4 sú ako boli predtým definované.wherein X, Y, Z, A, B, D, E, and R 1 to R 4 are as previously defined.
Termín hydrofóbna skupina (HG) ako bude ďalej používané, zodpovedá hociktorej skupine, ktorá nemá afinitu ku, alebo vytesňuje vodu. Hydrofóbne skupiny zahrňujú, ale nie sú obmedzené na C 1.20 alkyl, C2.20 alkenyl (napr. vinyl, alyl), alebo C2.20 alkinyl (napr. propargyl C—C-CH-OH) voliteľne prerušený karbonylovou skupinou (napr. tvoriaca acyl skupina); Cô-ió aryl, C3.7 cykloalkyl, Cô-20 aralkyl, C^o cykloalkyl substituovaný C1.20 alkyl, kde alifatická časťThe term hydrophobic group (HG) as used hereinafter refers to any group that has no affinity for or displaces water. Hydrophobic groups include, but are not limited to, C 1-10 alkyl, C 2-20 alkenyl (e.g. vinyl, allyl), or C 2-20 alkynyl (e.g. propargyl C-C-CH-OH) optionally interrupted by a carbonyl group (e.g. acyl group); C 6-10 aryl, C 3-7 cycloalkyl, C 6-20 aralkyl, C 6-10 cycloalkyl substituted with C 1-20 alkyl, wherein the aliphatic moiety
-7je voliteľne prerušená karbonylovou skupinou (napr. tvoriaca acyl skupiny) a kruhová Časť je voliteľne substituovaná C|_6 alkylom, ako je metyl, etyl alebo terc.-butyl; alebo hydrofóbny bočný aminokyselinový reťazec. Výhodné hydrofóbne skupiny sú cyklohexyl, benzyl, fenylmetyl,2-fenyletyl, a para-terc.-butyl-fenylmetyl.-7 is optionally interrupted by a carbonyl group (e.g., forming an acyl group) and the ring moiety is optionally substituted with C 1-6 alkyl such as methyl, ethyl or tert-butyl; or a hydrophobic side amino acid chain. Preferred hydrophobic groups are cyclohexyl, benzyl, phenylmethyl, 2-phenylethyl, and para-tert-butylphenylmethyl.
Termín arginylový zvyšok predstavuje aminokyselinový zvyšok arginínu alebo analógu, alebo jeho derivátu. Napríklad , analóg alebo derivát prírodného zvyšku môže inkorporovať dlhší alebo kratší reťazec z alfa uhlíka (napr. etylénový alebo butylénový reťazec); nahradením guanidínovej skupiny vodíkovou väzbou donorovej alebo akceptorovej skupiny (napr. amino, amidino alebo metoxylom); nahradenie metylénového reťazca so skupinou so stérickym napätím (napr. arylom, cykloalkylom, alebo heterocyklickým kruhom); elimináciou koncového karboxylu (napr. dekarboxy) alebo hydroxylu (napr. aldehydom), alebo ich kombináciou.The term "arginyl" represents an amino acid residue of arginine or an analogue, or a derivative thereof. For example, an analog or derivative of a natural residue may incorporate a longer or shorter alpha carbon chain (e.g., an ethylene or butylene chain); replacing the guanidine group with a hydrogen bond of a donor or acceptor group (e.g., amino, amidino or methoxy); replacing a methylene chain with a steric tension group (e.g., aryl, cycloalkyl, or heterocyclic ring); by eliminating the terminal carboxyl (e.g. decarboxy) or hydroxyl (e.g. aldehyde), or a combination thereof.
Termín alkyl reprezentuje lineárny alebo rozvetvený, nasýtený alebo nenasýtený reťazec, majúci špecifikovaný celkový počet uhlíkových atómov.The term alkyl represents a linear or branched, saturated or unsaturated chain having a specified total number of carbon atoms.
Termín aromatický alebo aryl reprezentuje nenasýtený karbocyklický kruh, pozostávajúci zo 6 až 16 uhlíkových atómov, ktoré sú voliteľne mono- alebo di-substituované s OH, SH, amino (napr. NR.6R7) halogénom alebo C|.c alkylom. Aromatické kruhy zahrňujú benzén, naftalén, penantrén a antracén. Výhodné aromatické kruhy sú benzén a naftalén.The term aromatic or aryl represents an unsaturated carbocyclic ring consisting of 6 to 16 carbon atoms, which are optionally mono- or di-substituted with OH, SH, amino (e.g. NR 6 R 7) halogen or C 1-6 alkyl. Aromatic rings include benzene, naphthalene, penantrene, and anthracene. Preferred aromatic rings are benzene and naphthalene.
Termín cykloalkyl reprezentuje nasýtený karbocyklický kníh pozostávajúci z 3 až 7 uhlíkových atómov, ktoré sú voliteľne mono alebo di-substituované s OH, SH, amino (napr. NRóR?) halogénom alebo Ci-6 alkylom. Cykloalkylové skupiny zahrnujú cyklo - propyl, -butyl, -pentyl, -hexyl a -heptyl. Výhodná cykloalkylová skupina je cyklohexyl.The term cycloalkyl represents a saturated carbocyclic book consisting of 3 to 7 carbon atoms, which are optionally mono or di-substituted with OH, SH, amino (e.g. NR 6 R 6) halogen or C 1-6 alkyl. Cycloalkyl groups include cyclopropyl, -butyl, -pentyl, -hexyl and -heptyl. A preferred cycloalkyl group is cyclohexyl.
Termín aralkyl reprezentuje substituenta obsahujúceho arylový zvyšok naviazaný cez alkylový reťazec (napr. benzyl. fenetyl) kde celkový počet uhlíkových atómov arylových zvyškov a alkylového reťazca je špecifikovaný. Aryl alebo reťazcová časť skupiny je voliteľne mono- alebo di-substituovaná s OH, SH, aminom (napr. NR^Ry), halogénom alebo Ci-6 alkylom..The term aralkyl represents a substituent containing an aryl moiety linked through an alkyl chain (e.g., benzyl, phenethyl) wherein the total number of carbon atoms of the aryl moieties and the alkyl chain is specified. The aryl or chain portion of the group is optionally mono- or di-substituted with OH, SH, an amine (e.g., NR 4 R 7), halogen or C 1-6 alkyl.
Termín heteroatóm, ako je tu používaný, reprezentuje kyslík, dusík alebo síru (O, N alebo S), sulfoxyl alebo sulfonyl (SO alebo SO2) ak nie je ináč ukázané. Je pochopiteľné, že alkylové reťazce prerušované jedným alebo viacerými heteroatómami znamenajú že uhlíkový atóm reťazca je nahradený heteroatómom s rovnakým mocenstvom. Preferenčne, alkylovýThe term heteroatom, as used herein, represents oxygen, nitrogen or sulfur (O, N or S), sulfoxyl or sulfonyl (SO or SO2) unless otherwise indicated. It is understood that alkyl chains interrupted by one or more heteroatoms mean that the carbon atom of the chain is replaced by a heteroatom of the same valence. Preferably, alkyl
-8reťazec je prerušovaný s 0 až 4 heteroatómami a že dva susedné uhlíkové atómy nie sú súčasne nahradené.The -8 chain is interrupted with 0 to 4 heteroatoms and that two adjacent carbon atoms are not simultaneously replaced.
Termín heterocyklický reprezentuje nasýtený alebo nenasýtený mono- alebo polycyklický (napr. bicyklický) kruh v ktorom je inkorporovaný 1 alebo viac (napr. 1-4) heteroatómov, ktorými môžu byť N, O a S. Je jasné, že heterocyklus je voliteľne mono- alebo disubstituovaný s OH, SH, amino (napr. (NR^Rj), halogénom , CF3 , oxo alebo C1-6 alkylom. Príkladmi vhodných monocyklických heterocyklov môžu byť pyridin, piperidín, pyrazín, imidazol, tiazol, oxazol, furán, pyrán a tiofén. Príkladmi vhodných bicyklických heterocyklov môžu byť indol, chinolín, izochinolín, purín a karbazol.The term heterocyclic represents a saturated or unsaturated mono- or polycyclic (e.g. bicyclic) ring in which 1 or more (e.g. 1-4) heteroatoms, which may be N, O and S, are incorporated. It is understood that the heterocycle is optionally mono- or disubstituted with OH, SH, amino (e.g. (NR 1 R 3), halogen, CF 3, oxo or C 1-6 alkyl. Examples of suitable monocyclic heterocycles are pyridine, piperidine, pyrazine, imidazole, thiazole, oxazole, furan, pyran and Examples of suitable bicyclic heterocycles are indole, quinoline, isoquinoline, purine and carbazole.
Termín hydrofóbna aminokyselina reprezentuje aminokyselinový zvyšok ktorý nesie alkylovú alebo arylovú skupinu naviazanú na α-uhlíkovom atóme. Tak glycín, ktorý nemá takúto skupinu naviazanú na α-uhlíkovom atóme nie je hydrofóbna aminokyselina. Alkylová alebo arylová skupina môže byť substituovaná s podmienkou že substituent, alebo substituenty, neuberajú z celkového hydrofóbneho charakteru aminokyseliny. Príklady hydrofóbnych prírodných aminokyselín sú alanín, izoleucín, leucín, fenylalanín, a v prírode sa nenachádzajúcich aminokyselín , ako sú opísané v The Peptides vol.5, 1983, Academic Press, Chapter 6, by D.C. Roberts a F. Vallaccio. Vhodnými, v prírode sa nenachádzajúcimi aminokyselinami, sú cyklohexylalanín a 1-aminocyklohexánkarboxylová kyselina.The term hydrophobic amino acid represents an amino acid residue that carries an alkyl or aryl group attached to an α-carbon atom. Thus, a glycine that does not have such a group attached to the α-carbon atom is not a hydrophobic amino acid. The alkyl or aryl group may be substituted provided that the substituent or substituents do not decrease from the overall hydrophobic nature of the amino acid. Examples of hydrophobic natural amino acids are alanine, isoleucine, leucine, phenylalanine, and non-naturally occurring amino acids as described in The Peptides vol.5, 1983, Academic Press, Chapter 6, by D.C. Roberts and F. Vallaccio. Suitable non-naturally occurring amino acids are cyclohexylalanine and 1-aminocyclohexanecarboxylic acid.
Pod aminokyselinovým bočným reťazcom sa mieni substituent naviazaný na a-uhlík vzhľadom ku amino skupine. Napríklad, bočný reťazec aminokyseliny alanínu je metylova skupina, zatiaľ čo benzyl je bočný reťazec fenylalanínu.By amino acid side chain is meant a substituent attached to the α-carbon relative to the amino group. For example, the amino acid side chain of alanine is a methyl group, while benzyl is the side chain of phenylalanine.
je výhodne H alebo Ci-6 alkyl. Výhodnejšie je H, metyl alebo etyl, a najvýhodnejšie R2 je H.is preferably H or C 1-6 alkyl. More preferably, H is methyl or ethyl, and most preferably R2 is H.
R- je výhodne H alebo Ci-6 alkyl. Výhodnejšie Rj je H, metyl alebo etyl, a najvýhodnejšie R3 je H.Preferably R 1 is H or C 1-6 alkyl. More preferably, R 1 is H, methyl or ethyl, and most preferably R 3 is H.
Je výhodné, ak jeden z R4 alebo Rsje hydrofóbna skupina, tak ako nasýtený alebo nenasýtený 5 alebo 6 uhlíkatý kruh voliteľne spojený s inou skupinou uhlíkatého kruhu, zatiaľ čo druhý je H, Ci-i6 alkyl voliteľne substituovaný s NR6R7 alebo karboxylom. Hydrofóbna časť môže byť naviazaná cez spojítko akým je Cmó alkylový reťazec voliteľne prerušovaný s 1 alebo viac (1-It is preferred that one of R 4 or R 5 is a hydrophobic group, such as a saturated or unsaturated 5 or 6 carbon ring optionally linked to another carbon ring group, while the other is H, C 1-6 alkyl optionally substituted with NR 6 R 7 or carboxyl. The hydrophobic moiety may be attached via a linker such as a C 1-8 alkyl chain optionally interrupted with 1 or more (1-
4) heteroatómami, karbonylovou alebo sulfonylovou skupinou. Výhodnejšie je, ak jeden z R4 alebo R5 je fenyl, cyklohexyl, indol, tienyl, chinolín, tetrahydroizochinolín, naftyl, alebo benzodioxalan viazaný cez Cmô alkyl voliteľne prerušený s heteroatómom alebo karbonyiom, zatiaľ čo druhý je H, karboxymetyl alebo karboxyetyl.4) heteroatoms, carbonyl or sulfonyl. More preferably, one of R 4 or R 5 is phenyl, cyclohexyl, indole, thienyl, quinoline, tetrahydroisoquinoline, naphthyl, or benzodioxalan bonded via C 1-10 alkyl optionally interrupted with a heteroatom or carbonyl, while the other is H, carboxymethyl or carboxyethyl.
Je výhodné, ak A nie je prítomná, alebo je CH2.It is preferred that A is absent or is CH2.
Je výhodné, ak B je S, alebo CH2.It is preferred that B is S or CH2.
Je výhodné, ak D je CH2.It is preferred that D is CH2.
Je výhodné, ak E je CH substituované s -C(O)R|, kde Ri je ako bolo predtým definované.It is preferred that E is CH substituted with -C (O) R 1, wherein R 1 is as previously defined.
Je výhodné, ak X je CH-R5 alebo N- R5.It is preferred that X is CH-R5 or N- R5.
Je výhodné, ak Y je CH-Rg alebo S.It is preferred that Y is CH-R 8 or S.
Je výhodné, ak Z je O.It is preferred that Z is O.
Vo výhodnejšom uskutočnení Rj je reprezentované jedným zo vzorcov Vla až VId:In a more preferred embodiment, R1 is represented by one of formulas VIa to VId:
kde :where :
Rn je vodík alebo Ci-6 alkyl;R 11 is hydrogen or C 1-6 alkyl;
K je väzba alebo -NH-;K is a bond or -NH-;
G je Ci-6 alkoxy; kyano; -NH2; -CH2 -NH2; -C(NH)-NH2; -NH-C(NH)-NH2; -CH2-NHC(NH) -NH2;G is C 1-6 alkoxy; cyano; -NH 2; -CH 2 -NH 2; -C (NH) -NH 2 ; -NH-C (NH) -NH 2 ; -CH 2 -NHC (NH) -NH 2 ;
Cô cykloalkyl alebo aryl substituovaný s kyano, -NH2, -CH2-NH2, -C(NH)-NH2, -ΝΉC(NH)-NH2 alebo -CH2-NH-C(NH) -NH2; alebo 5 alebo 6 členný, nasýtený alebo nenasýtený heterocyklus voliteľne substituovaný s kyano, -NH2, -CH2 -NH2, -C(NH) -NH2, -NH-C(NH) -NH2 alebo -CH -NH-C(NH) -NH2;C 6 cycloalkyl or aryl substituted with cyano, -NH 2, -CH 2 -NH 2, -C (NH) -NH 2 , -ΝΉC (NH) -NH 2 or -CH 2 -NH-C (NH) -NH 2 ; or a 5 or 6 membered, saturated or unsaturated heterocycle optionally substituted with cyano, -NH 2, -CH 2 -NH 2, -C (NH) -NH 2, -NH-C (NH) -NH 2, or -CH -NH-C (NH -NH 2 ;
U je kyano, -NH2, -C(NH) -NH2 alebo -NH-C(NH) -NH2.U is cyano, -NH 2 , -C (NH) -NH 2, or -NH-C (NH) -NH 2 .
P je väzba, -C(O)- alebo dvojmocná skupina:P is a bond, -C (O) - or a divalent group:
x CHx CH
OKOK
' CH'CH
- 10J je Ci-6 alkylén voliteľne substituovaný s OH, NH2 aC|.6 alkylom a voliteľne prerušený heteroatómom, ktorým môže byť O, S a N.-10J is C 1-6 alkylene optionally substituted with OH, NH 2 and C 1-6 alkyl and optionally interrupted by a heteroatom, which may be O, S and N.
n je 0 alebo 1; an is 0 or 1; and
T je H, OH, amino, peptidový reťazec, C m 6 alkyl, C m 6 alkoxy, C6-20 aralkyl, alebo heterocyklus voliteľne substituovaný.T is H, OH, amino, a peptide chain, C 1-6 alkyl, C 1-6 alkoxy, C 6-20 aralkyl, or a heterocycle optionally substituted.
R11 je výhodne H alebo metyl, najvýhodnejšie je H.R 11 is preferably H or methyl, most preferably H.
K je výhodne väzba.K is preferably a bond.
G je výhodne -NH-C(NH) -NH2 naviazaná cez metylénový reťazec z 3-7 uhlíkov, alebo fenyl substituovaný s -C(NH)-NH2 naviazaný cez metylénový reťazec z 0 až 3 uhlíkov. Najvýhodnejšie G je -NH-C(NH)-NH2 naviazané cez metylénový reťazec z 3 atómov.G is preferably -NH-C (NH) -NH 2 attached through a methylene chain of 3-7 carbons, or phenyl substituted with -C (NH) -NH 2 attached through a methylene chain of 0 to 3 carbons. Most preferably G is -NH-C (NH) -NH 2 linked through a methylene chain of 3 atoms.
P je výhodne -C(O)-.P is preferably -C (O) -.
J je výhodne vyberané z: -CH2-S-CH2-CH2; -CH2-O-CH2-CH2; -CH2-NH-CH2-CH2; a väzba, ak n je 0. Najvýhodnejšie J, keď n je 0, a J je väzba,J is preferably selected from: -CH 2 -S-CH 2 -CH 2; -CH2-O-CH2-CH2; -CH2-NH-CH2-CH2; and a bond when n is 0. Most preferably, when n is 0, and J is a bond,
V ďalšom uskutočnení podľa vynálezu R môže byť jedným z nasledujúcich amonikyselinových derivátov pripravených podľa postupu opísaného v Bioorg. Med. Chem. 1995, 3 : 1145 :In another embodiment of the invention, R may be one of the following ammonium acid derivatives prepared according to the procedure described in Bioorg. Med. Chem. 1995, 3: 1145
NH kde n = 1-6, n 1 = 1-2, n2 = 0-7 a T je ako bolo predtým definované.NH where n = 1-6, n 1 = 1-2, n 2 = 0-7 and T is as previously defined.
Vo výhodnom uskutočnení podľa vynálezu, T je peptid s dĺžkou 1 až 4 aminokyselín a A alebo B je výhodne reťazec fibrinogénu alebo fragment jeho derivátu.In a preferred embodiment of the invention, T is a peptide of 1 to 4 amino acids in length and A or B is preferably a fibrinogen chain or fragment thereof.
Podľa ďalšieho uskutočnenia vynálezu T je heterocyklus vybratý zo skupiny pozostávajúcej z :According to another embodiment of the invention, T is a heterocycle selected from the group consisting of:
kde X5, Xio a Xu X12 sú nezávisle vybraté zo skupiny pozostávajúcej z N alebo C-X7, kde X7 je vodík, C1-6 alkyl, alebo Ce-16 aryl;wherein X 5 , X 10 and X 11 X 12 are independently selected from the group consisting of N or C-X 7, wherein X 7 is hydrogen, C 1-6 alkyl, or C 6-16 aryl;
Xó a X13 sú každý nezávisle vybratý zo skupiny pozostávajúcej z C, O, N, S, N-X alebo CH-X7;X 6 and X 13 are each independently selected from the group consisting of C, O, N, S, N-X or CH-X 7;
R' je vodík, Cmô alkyl voliteľne substituovaný karboxylom, -C0-16 alkyl-CO2 - C1-16 alkylom,R 'is hydrogen, C 1-10 alkyl optionally substituted with carboxyl, -C 0-16 alkyl-CO 2 - C 1-16 alkyl,
C6-20 aralkylom, C3.7 cykloalkylom, arylom alebo aromatickým heterocyklom.C6-20 aralkyl, C3-7 cycloalkyl, aryl or aromatic heterocycle.
- 15Výhodne T je vybraté zo skupiny pozostávajúcej z:- 15 Preferably T is selected from the group consisting of:
Výhodnejšie T je vybraté zo skupiny zo skupiny pozostávajúcej z:More preferably, T is selected from the group consisting of:
R*R
R’R '
Kde R' je ako bolo definované predtým.Where R 'is as previously defined.
Výhodnejšie T je vybraté zo skupiny pozostávajúcej z:More preferably, T is selected from the group consisting of:
Kde R' je definované predtým.Where R 'is as previously defined.
- 16Najvýhodnejšie T je orMost preferably T is or
R'R '
kde R' je H alebo Cm alkyl, taký ako metyl, etyl, propyl alebo butyl, a najvýhodnejšie je ak R' je vodík. Iná podstata vynálezu je, že T je 1,2 tiazol voliteľne substituovaný s R' a, alebo je naviazaný na J v 2, 3,4 alebo 5 pozícii kruhu.wherein R 'is H or C 1-4 alkyl, such as methyl, ethyl, propyl or butyl, and most preferably R 1 is hydrogen. Another aspect of the invention is that T is 1,2 thiazole optionally substituted with R 'a, or is attached to J at the 2, 3, 4, or 5 position of the ring.
Podľa ďalšieho uskutočnenia vynálezu sú zlúčeniny vynálezu reprezentované vzorcami Π, ΠΙ, IV, a V, kde X, Y, B, R až R» a Rs sú predtým definované.According to another embodiment of the invention, the compounds of the invention are represented by the formulas Π, ΠΙ, IV, and V, wherein X, Y, B, R to R 6 and R 8 are as previously defined.
Predovšetkým výhodné uskutočnenie podľa vynálezu sú zlúčeniny reprezentované vzorcami VII,A particularly preferred embodiment of the invention are compounds represented by formulas VII,
Vín, IX a X:Wines, IX and X:
(VII) (IX)(IX) (IX)
kdewhere
B je O, S, -CH2-, alebo -NH-;B is O, S, -CH 2 -, or -NH-;
Y môže byť O, S, SO, SO2, N-R5, a CH-Rs;Y may be O, S, SO, SO 2, N-R 5, and CH-R 5;
-17Rj je arginylový zvyšok alebo analóg alebo jeho derivát voliteľne substituovaný s aminokyselinou, peptidom alebo heterocyklom;-17R1 is an arginyl residue or analogue or derivative thereof optionally substituted with an amino acid, peptide or heterocycle;
R2 je H alebo Ci-6 alkyl;R 2 is H or C 1-6 alkyl;
R3 môže byť H, NR6R7 a C m alkyl; aR 3 can be H, NR 6 R 7 and C 1-4 alkyl; and
Rj a R5 sú nezávisle vybraté z H; NR^; Cg-ie arylu alebo C3.7 cykloalkylu voliteľne substituovaného s C1-6 alkylom; C 1.6 alkylu voliteľne prerušeného s jedným alebo viac heteroatómami alebo karbonylovou skupinou a voliteľne substituovaného s OH, SH, NR$R7 alebo Có-iô arylom, heterocyklom alebo C3.7 cykloalkylovou skupinou voliteľne substituovanou s halogénom, hydroxylom, C 1.6 alkylom; z aminokyselinového reťazca; a hydrofóbnou skupinou,R 1 and R 5 are independently selected from H; NR; C 3-7 aryl or C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; A C 1-6 alkyl optionally interrupted with one or more heteroatoms or a carbonyl group and optionally substituted with OH, SH, NR 6 R 7 or C 6-10 aryl, heterocycle or C 3-7 cycloalkyl optionally substituted with halogen, hydroxyl, C 1-6 alkyl; an amino acid chain; and a hydrophobic group,
Rs je vodík, Ci-6 alkyl výhodne prerušený s 1 alebo 2 heteroatómami, Có-ió aryl, C3.7 cykloalkyl alebo heterocyklický kruh a hydrofóbna skupina, a n je 1 alebo 2.R 5 is hydrogen, C 1-6 alkyl preferably interrupted with 1 or 2 heteroatoms, C 6-10 aryl, C 3-7 cycloalkyl or a heterocyclic ring and a hydrophobic group, and n is 1 or 2.
Výhodné zlúčeniny podľa vzorca VII sú:Preferred compounds of formula VII are:
0005 6S-benzylhexahydro-5-oxo-5H tiazolo -[3,2-a] pyridín-3Rkarboxamido (propyl arginín)0005 6S-Benzylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxamido (propyl arginine)
0010 6S-benzylhexahydro-5-oxo-5H tiazolo [3,2-a] pyridín-3Rkarboxamido (butyl arginín)0010 6S-Benzylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxamido (butyl arginine)
0015 6S-benzylhexahydro-5-oxo-5H tiazolo [3,2-a] pyridín-3Rkarboxamido (propylkarbometoxy arginín)0015 6S-Benzylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxamido (propylcarbomethoxy arginine)
0020 6S-cyklohexylmetyl hexahydro-5-oxo-5H tiazolo [3,2-a] pyridín-3Rkarboxamido (benzyl arginín)0020 6S-Cyclohexylmethyl-hexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxamido (benzyl arginine)
- 180025 6S-cyklohexylmetyl hexahydro-5-oxo-5H tiazolo [3,2-a] pyridín-3Rkarboxamido (karbometoxy propylcykloditioketalarginín)- 180025 6S-Cyclohexylmethyl hexahydro-5-oxo-5H thiazolo [3,2-a] pyridine-3R-carboxamido (carbomethoxy propylcyclodithioketalarginine)
0030 6S-cyklohexylmetyl hexaliydro-5-oxo-5H tiazolo [3,2-a] pyridín-3Rkarboxamido ((S)- Arg-(R)kyselina pipekolínová0030 6S-Cyclohexylmethyl hexaliydro-5-oxo-5H thiazolo [3,2-a] pyridine-3R-carboxamido ((S) -Arg- (R) Pipecolinic Acid
0035 6S-benzylhexahydro-5-oxo-5Htiazol [3,2-a] pyridín-3Rkarboxyamido (karboxyamidopropyl cykloditioketal arginín)0035 6S-Benzylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxyamido (carboxyamidopropyl cyclodithioketal arginine)
0040 6S-cyklohexylmetylhexahydro-0040 6S-cyclohexylmethylhexahydro-
5-oxo-5H-tiazol [3,2-a] pyridin-3R- karboxyamido ((S)-Arg amid kys. hexahydropyridín-5-oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxyamido ((S) -Arg hexahydropyridine-
4- karboxylovej4-carboxylic acid
0045 6S-cyklohexylmetylhexahydro-0045 6S-cyclohexylmethylhexahydro-
5- oxo-5H-tiazol [3,2-a] pyridín-3Rkarboxyamido ((S)-Arg amid kys. izohexahydropyridín-5-Oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxyamido ((S) -Arg isohexahydropyridine-
4-karboxylovej4-carboxylic acid
0050 6S-benzylhexahydro-5-oxo-5Htiazol [3,2-a] pyridín-3-Rkarboxyamido (karboxyamidopentyl cykloditioketal arginín)0050 6S-Benzylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3-R-carboxyamido (carboxyamidopentyl cyclodithioketal arginine)
II
H NH N
- 196S-benzylhexahydro-5-oxo-5Htiazol [3,2-a] pyridín-3-Rkarboxyamido (karbometoxypropyl cykloditioketal arginín)- 196S-Benzylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3-R-carboxyamido (carbomethoxypropyl cyclodithioketal arginine)
S -cyklohexylmety lhexahydro-S -cyclohexylmethylhexahydro-
5-oxo-5H-tiazol [3,2-a]pyridín-3-R-karboxyamido (1karboxy-3-tiobutyl ketoarginín)5-Oxo-5H-thiazolo [3,2-a] pyridine-3-R-carboxyamido (1-carboxy-3-thiobutyl ketoarginine)
S -cyklohexylmety lhexahydro-S -cyclohexylmethylhexahydro-
5-oxo-5H-tiazol [3,2-a]pyridín-3-R-karboxyamido (1karboxy-3-tiobutyl ketoarginín)5-Oxo-5H-thiazolo [3,2-a] pyridine-3-R-carboxyamido (1-carboxy-3-thiobutyl ketoarginine)
6S-cyklohexylmetylhexahydro-6S-cyklohexylmetylhexahydro-
5-oxo-5H-tiazol [3,2-a] pyridín-3-R-karboxyamido (1karboxy-2-metyl-3-tiobutyl ketoarginín)5-Oxo-5H-thiazolo [3,2-a] pyridine-3-R-carboxyamido (1-carboxy-2-methyl-3-thiobutyl ketoarginine)
6S-cyklohexylmetylhexahydro-6S-cyklohexylmetylhexahydro-
5-oxo-5H-tiazol [3,2-a]pyridín-3-R-karboxyamido ((3-tiobutyl kyselina sulfonová) ketoarginín)5-Oxo-5H-thiazolo [3,2-a] pyridine-3-R-carboxyamido ((3-thiobutyl sulfonic acid) ketoarginine)
S -cyklohexylmetylhexahydro-S -cyclohexylmethylhexahydro-
5-oxo-5H-tiazol [3,2-a]pyridín-3-R- karboxyamido (izochinolínmetylketoarginín)5-Oxo-5H-thiazolo [3,2-a] pyridine-3-R-carboxyamido (isoquinoline methyl ketoarginine)
swith
-200085 6 S-cyklohexylmety Ihexahydro--200085 6 S-cyclohexylmeths
5-oxo-5H-tiazol [3,2-aJpyridín-3-R- karboxyamido (propylkarbometoxy ketoarginín)5-oxo-5H-thiazolo [3,2-a] pyridine-3-R-carboxyamido (propylcarbomethoxy ketoarginine)
0090 6S-cyklohexylmetylhexahydro5-oxo-5H-tiazol [3,2-aJpyridín-3-Rkarboxyamido (propylketo) ArgPhe-Arg-NHz)0090 6S-Cyclohexylmethylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3-R-carboxyamido (propyl keto) ArgPhe-Arg-NH2)
0095 6S-benzylhexahydro-5-oxo-5H tiazolo [3,2-a] pyridín-3Rkarboxamido ((kyselina propánová) ketoarginín)0095 6S-Benzylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxamido ((propanoic acid) ketoarginine)
0100 6S-benzylhexahydro-5-oxo-5H tiazolo [3,2-a] pyridín-3Rkarboxamido (propyl karbometoxyketoarginín)0100 6S-Benzylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxamido (propyl carbomethoxy keto-arginine)
0105 6S-cyklohexylpropylhexahydro 5-ΟΧΟ-5Η- tiazolo [3,2-a]pyridín-3R-karboxamido (abenzotiazolo ketoarginín) a0105 6S-Cyclohexylpropylhexahydro 5-ΟΧΟ-5Η-thiazolo [3,2-a] pyridine-3R-carboxamido (abenzothiazolo ketoarginine) and
OHO 6S-cyklohexylpropylhexahydro 5-OXO-5H- tiazolo [3,2-a]pyridín-3Rkarboxamido (propylkarbometoxy ketoarginín)OHO 6S-cyclohexylpropylhexahydro 5-OXO-5H-thiazolo [3,2-a] pyridine-3R-carboxamido (propylcarbomethoxy ketoarginine)
NH.NH.
-21 0205 6-Benzyl-5-oxo-hexahydrotiazolo [3,2-a] pyridín-3karboxylová kyselina [1(benzotiazol-2-karbonyl)-4-guanidinobutyl]-amid-21 0205 6-Benzyl-5-oxo-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [1 (benzothiazole-2-carbonyl) -4-guanidinobutyl] -amide
0210 6-Benzyl-5-oxo-hexahydrotiazolo[3,2-a] pyridín-3karboxylová kyselina [1(benzotiazol-2karbonyl)-4-guanidinobutyl]-amid0210 6-Benzyl-5-oxo-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [1 (benzothiazole-2-carbonyl) -4-guanidinobutyl] -amide
0215 6-Benzyl-5-oxo-hexahydrotiazolo [3,2-a] pyridín-3karboxylová kyselina [ 1 (benzotiazol-2karbonyl)-4-guanidinobutyl]-amid0215 6-Benzyl-5-oxo-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [1 (benzothiazole-2-carbonyl) -4-guanidinobutyl] -amide
0220 6-Benzyl-8a-metyl-5-oxohexahydro-tiazolo [3,2-a] pyridín-3 -karboxylová kyselina [l-(benzotiazol-2karbonyl)-4-guanidinobutyl]-amid0220 6-Benzyl-8α-methyl-5-oxohexahydro-thiazolo [3,2-a] pyridine-3-carboxylic acid [1- (benzothiazole-2-carbonyl) -4-guanidinobutyl] -amide
0225 8a-Metyl-5-oxo-6fenyletyl-hexahydrotiazolo [3,2-a] pyridín-3karboxylová kyselinafl(benzotiazol-2karbonyl) -4-guanidinobutyl]-amid0225 8α-Methyl-5-oxo-6-phenylethyl-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [1- (benzothiazole-2-carbonyl) -4-guanidinobutyl] -amide
HH
HH
-22230 8a-Metyl-5-oxo-6fenyletyl-hexahydrotiazolo[3,2-a] pyridín-3karboxylová kyselina [1(benzotiazol-2karbonyl)-4-guanidinobutylj-amid-22230 8α-Methyl-5-oxo-6-phenylethyl-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [1 (benzothiazole-2-carbonyl) -4-guanidinobutyl] -amide
0240 8a-Metyl-5-oxo-6-(2trifluorometyl chinolín6-ylmetyl)-hexahydrotiazolo [3,2-a] pyridín-3karboxylová kyselina[l(benzotiazol-2karbonyl)-4-guanidinobutyl]-amid0240 8α-Methyl-5-oxo-6- (2-trifluoromethyl-quinolin-6-ylmethyl) -hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [1 (benzothiazole-2-carbonyl) -4-guanidinobutyl] -amide
0245 6-Benzyl-5-oxo-hexahydrotiazolo [3,2-a] pyridín-3karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid0245 6-Benzyl-5-oxo-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0250 6-Benzyl-5-oxo-hexahydrotiazolo [3,2-a] pyridín-3karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl] -amid0250 6-Benzyl-5-oxo-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0255 6-Benzyl-5-oxo-hexahydrotiazolo[3,2-a] pyridín-3karboxylová kyselina [4guanidino-1 -(1 -metyl-1H imidazol-2karbony l)buty 1] -amid0255 6-Benzyl-5-oxo-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [4guanidino-1- (1-methyl-1H-imidazole-2-carbonyl) -butyl] -amide
HH
-23 0260-23 0260
02650265
02750275
02800280
6-Benzyl-8a-metyl-5-oxohexahydro-tiazolo[3,2-a]pyridín-3-karboxylová kyselina [4-guanidino-l(tiazol-2-karbonyl)butyl]-amid6-Benzyl-8α-methyl-5-oxohexahydro-thiazolo [3,2-a] pyridine-3-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) butyl] -amide
5- Oxo-6-(3-cyklohexylpropyl)-hexahydrotiazolo [3,2-a] pyridín-3karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid5-Oxo-6- (3-cyclohexylpropyl) -hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
8a-Metyl-5-oxo-6-(3fenyl-propyl-hexahydrotiazolo[3,2-a] pyridín-3karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid8α-Methyl-5-oxo-6- (3-phenyl-propyl-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
8a-Metyl-5-oxo-6-(3fenyl-propyl-hexahydrotiazolo[3,2-a] pyridín-3karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid8α-Methyl-5-oxo-6- (3-phenyl-propyl-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
8a-Metyl-5-oxo-6-(2trifluórmetylchinolin-8-methyl-5-oxo-6- (2trifluórmetylchinolin-
6- yImetyl)-hexahydrotiazolo[3,2-a] pyridín-3karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-buty 1]-amid6-Methyl-hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
02850285
0295 6-(l,3-Dioxo-l,3-dihydroizoindoI-2-yl)-5-oxohexahydro-tiazolo[3,20295 6- (1,3-Dioxo-1,3-dihydroisoindol-2-yl) -5-oxohexahydro-thiazolo [3,2-a]
-a] pyridín-3-karboxyiová kyselina [4-guanidino-l(tiazol-2-karbonyl) -butyl]-amid-a] pyridine-3-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0305 5-Oxo-6-(3-fenylpropionyl amino)-hexahydrotiazolo[3,2-a] pyridín-3karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid0305 5-Oxo-6- (3-phenylpropionyl amino) -hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0315 5-Oxo-6-(3-fenylpropionyl amino)-hexahydrotiazolo [3,2-a] pyridín-3karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid0315 5-Oxo-6- (3-phenylpropionyl amino) -hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
Výhodnejšie zlúčeniny podľa vzorca (VII) sú:More preferred compounds of formula (VII) are:
0085 6S- cyklohexylmetylhexahydro-5-oxo-5H-tiazolo[3,2a]pyridín-3R-karboxamido(propylkarbometoxyarginín);6S-cyclohexylmethylhexahydro-5-oxo-5H-thiazolo [3,2a] pyridine-3R-carboxamido (propylcarbomethoxyarginine);
0090 6S- cyklohexylmetylhexahydro-5-oxo-5H-tiazolo[3,2a]pyridín-3R-karboxamido(propylketo)Arg-Phe-ArgNH2);6S-cyclohexylmethylhexahydro-5-oxo-5H-thiazolo [3,2a] pyridine-3R-carboxamido (propyl keto) Arg-Phe-ArgNH 2 );
0095 6S-benzylhexahydro-5-oxo-5H-tiazolo[3,2-a] pyridín3R-karboxamido ((propanová kyselina) arginín);6S-benzylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxamido ((propanoic acid) arginine);
0105 6S- cyklohexylmetylhexahydro-5-oxo-5H-tiazolo[3,2a]pyridín-3 R-karboxamido (a-benztiazolo-ketoarginín);6S-cyclohexylmethylhexahydro-5-oxo-5H-thiazolo [3,2a] pyridine-3R-carboxamido (α-benzothiazolo-ketoarginine);
-250210 6-Benzyl-5-oxo-hexahydro-tiazolo[3,2-a]pyridín-3karboxylová kyselina [l-(benzotiazol-2-karbonyi)-4guanidino-butyl]-amid;-250210 6-Benzyl-5-oxo-hexahydro-thiazolo [3,2-a] pyridine-3-carboxylic acid [1- (benzothiazole-2-carbonyl) -4-guanidino-butyl] -amide;
0220 6-Benzyl-8a-metyl-5-oxo-hexahydro-tiazoIo[3,2 -a]pyridín-3-karboxylová kyselina [l-(benzotiazol-2karbonyl)-4-guanidino-butyl]-amid;620-Benzyl-8α-methyl-5-oxo-hexahydro-thiazolo [3,2-a] pyridine-3-carboxylic acid [1- (benzothiazole-2-carbonyl) -4-guanidino-butyl] -amide;
0240 8a-Metyl-5-oxo-6-(2-trifluorometyl- chinolin-6-ylmetyl)hexahydro-tiazolo[3,2-a]pyridín-3-karboxylová kyselina [1(benzoti azol-2-karbonyl-4-guanidino-butyl] -amid;0240 8α-Methyl-5-oxo-6- (2-trifluoromethyl-quinolin-6-ylmethyl) -hexahydro-thiazolo [3,2-a] pyridine-3-carboxylic acid [1 (benzothiazole-2-carbonyl-4- guanidino-butyl] -amide;
0245 6-Benzyl-5-oxo-hexahydro-tiazolo[3,2-a]pyridín-3karboxylová kyselina [4-guanidino-l-(tiazol-2karbonyl)-butyl]-amid;0245 6-Benzyl-5-oxo-hexahydro-thiazolo [3,2-a] pyridine-3-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide;
0260 6-Benzyl-8a-metyl-5-oxo-hexahydro-tiazolo[3,2 -a]pyridín-3-karboxylová kyselina [4-guanidino-l-(tiazol-0260 6-Benzyl-8α-methyl-5-oxo-hexahydro-thiazolo [3,2-a] pyridine-3-carboxylic acid [4-guanidino-1- (thiazole-
2-karbonyl)-butyl]-amid;2-carbonyl) -butyl] -amide;
0265 5-Oxo-6-(3-cyklohexyl-propyl)-hexahydro-tiazolo[3,2 -a]pyridín-3-karboxylová kyselina [4-guanidino-l-(tiazoI-0265 5-Oxo-6- (3-cyclohexyl-propyl) -hexahydro-thiazolo [3,2-a] pyridine-3-carboxylic acid [4-guanidino-1- (thiazole-
2-karbonyl)-butyl]-amid;2-carbonyl) -butyl] -amide;
0285 8a-Metyl-5-oxo-6-(2-trifluórmetyl-chinolin-6ylmetyl)-hexahydro-tiazolo[3,2-a]pyridín-3karboxylová kyselina (4-guanidino-l-(tiazol-2-karbonyl) -butyl]-amid; a0285 8α-Methyl-5-oxo-6- (2-trifluoromethyl-quinolin-6-ylmethyl) -hexahydro-thiazolo [3,2-a] pyridine-3-carboxylic acid (4-guanidino-1- (thiazole-2-carbonyl) - butyl] -amide;
0315 5-Oxo-6-(3-fenyl-propionyl amino)-hexahydrotiazolo [3,2-a]pyridín-3-karboxylová kyselina [4-guanidinol-(tiazol-2-karbonyl)-butyl]-amid;5-Oxo-6- (3-phenyl-propionyl amino) -hexahydrothiazolo [3,2-a] pyridine-3-carboxylic acid [4-guanidinol- (thiazole-2-carbonyl) -butyl] -amide;
Najvýhodnejšie zlúčeniny podľa vzorca VII sú:The most preferred compounds of formula VII are:
0085 6S- cyklohexylmetylhexahydro-5-oxo-5H-tiazolo[3,2a] pyridín-3R-karboxamido(propylkarbometoxyketoarginín); a6S-cyclohexylmethylhexahydro-5-oxo-5H-thiazolo [3,2a] pyridine-3R-carboxamido (propylcarbomethoxy ketoarginine); and
0105 6S- cyklohexylmetylhexahydro-5-oxo-5H-tiazolo[3,2a]pyridín-3R-karboxamido (a-benztiazoloketoarginín);6S-cyclohexylmethylhexahydro-5-oxo-5H-thiazolo [3,2a] pyridine-3R-carboxamido (α-benzothiazoloketoarginine);
-26Výhodné zlúčeniny podľa vzorca VIH sú:Preferred compounds of Formula VIH are:
0325 3-Aminometyl-2-benzoyl-4oxooktahydro-pyrolo[ 1,2a] pyridín-6-karboxylová kyselina [ 1 -(benzotiazol-2-karbonyl)-0325 3-Aminomethyl-2-benzoyl-4-oxo-octahydro-pyrrolo [1,2a] pyridine-6-carboxylic acid [1- (benzothiazole-2-carbonyl) -
4-guanidino-butyl]-amid4-guanidino-butyl] -amide
0330 3-Aminometyl-4-oxo-2fenylacetyl-oktahydropyrolo[l,2-a] pyrazín-6karboxylová kyselinafl(benzotiazol-2-karbonyl)-4guanidino-butyl]-amid0330 3-Aminomethyl-4-oxo-2-phenylacetyl-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid f (benzothiazole-2-carbonyl) -4guanidino-butyl] -amide
0335 2-Benzoyl-4-oxo-oktahydropyrolo[l,2-a] pyrazín-6karboxy lová kyse 1 ina [4-guani d ino1 -(tiazol-2-karbonyl)butyl]-amid0335 2-Benzoyl-4-oxo-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanedino-1- (thiazole-2-carbonyl) butyl] -amide
0340 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolof 1,2a] pyrazín-6-karboxylová kyselina [4-guanidino-1 -(tiazol-0340 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolof 1,2a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-
2-karbonyl)-butyl]-amid2-carbonyl) -butyl] -amide
0345 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [4-guanidino-1 -(5-metyltiazol-2-karbonyl)-butyl]-amid0345 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-guanidino-1- (5-methylthiazole-2-carbonyl) -butyl] -amide
oabout
2-(3 -Cyklohexyl-propiony 1)-4oxo-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [4-guanidino-1 -(2-tiazolkarbonyl)-butyl]-amid2- (3-Cyclohexyl-propionyl) -4-oxo-octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-guanidino-1- (2-thiazolecarbonyl) -butyl] -amide
5-Oxo- 7-(3-fenyl-propionyl )oktahydro-2-tia-4a,7-diazanaftalén-4-karboxylová kyselina [4-guanidino-1 -(tiazol-2karbonyl)-butyl]-amid5-Oxo-7- (3-phenyl-propionyl) octahydro-2-thia-4α, 7-diazanaphthalene-4-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
4-Oxo-2-(4-fenyl-butyryl)oktahydro-pyrolofl ,2-4-Oxo-2- (4-phenyl-butyryl) octahydro-pyrrolofl, 2-
a] pyrazín-6-karboxylová kyselina [4-guanidino-1 -(tiazol-2karbonyl)-butyl]-amida] Pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
4-Oxo-2-fenylacetyloktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [4-guanidino-1 -(tiazol-2karbonyl)-butyl]-amid4-Oxo-2-phenylacetylooctahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
2-(2-Amino-3-fenylpropionyl)-4-oxo-oktahydropyrolo[l,2-a] pyrazín-6karboxylová kyselina [4--guanidino-2- (2-Amino-3-phenylpropionyl) -4-oxo-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-
1- (tiazol-2-karbonyl)-butyl]-amid1- (Thiazole-2-carbonyl) -butyl] -amide
2- [2-Amino-3-(4-hydroxy2- [2-Amino-3- (4-hydroxy);
-fenyl] -propionyl)-4-oxooktahydro-pyrolo[ 1,2-a] pyrazín-6-karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid-phenyl] -propionyl) -4-oxooctahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
NMNM
-282-[2-Amino-3-(4-fluorofenyl)-propionyi]-4-oxooktahydro-pyrolof 1,2-a] pyrazín-6-karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid-282- [2-Amino-3- (4-fluorophenyl) -propionyl] -4-oxo-octahydro-pyrrolof 1,2-a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] - amide
4-Oxo-2-(3-fenyl-propyl)oktahydro-pyrolo[ 1,2-a] pyrazín-6-karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid4-Oxo-2- (3-phenyl-propyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
2-(2-Amino-3-( 1 H-indol-3-yl)propionyl)-4-oxo-oktahydropyrolo[l,2-a] pyrazín-6karboxylová kyselina [4-guanidino1 -(tiazol-2-karbonyl)butyl]-amid2- (2-Amino-3- (1H-indol-3-yl) propionyl) -4-oxo-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl)] butyl] -amide
4-Oxo-2-(3-tiofén-3-yl propionyl)-oktahydropyrolo[l,2-a] pyrazín-6karboxylová kyselina [4-guanidino1 -(tiazol-2-karbonyl)butyl]-amid4-Oxo-2- (3-thiophen-3-yl-propionyl) -octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) butyl] -amide
NHNH
NHNH
NHNH
4-Oxo-2-(3-tiofén-2-yl propionyl)-oktahydropyrolo[l,2-a] pyrazín-6karboxylová kyselina [4-guanidino1 -(tiazol-2-karbonyl)butyl]-amid4-Oxo-2- (3-thiophen-2-yl-propionyl) -octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) butyl] -amide
-290410-290410
2-(3-1 H-Imidazol-4-ylpropionyl)-4-oxo-oktahydropyrolo[ 1,2-a]pyrazín-6karboxylová kyselina [4-guanidino1 -(tiazol-2-karbonyl)butyl]-amid2- (3-1H-Imidazol-4-ylpropionyl) -4-oxo-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) butyl] -amide
OABOUT
NMNM
0415 2-(2-Amino-3-tiofén-3-yl propionyl)-4-oxo-oktahydropyrolo[l,2-a] pyrazín-6karboxylová kyselina [4-guanidino1 -(tiazol-2-karbonyl)butyl]-amid0415 2- (2-Amino-3-thiophen-3-yl propionyl) -4-oxo-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) butyl] -amide
OABOUT
NMNM
0420 4-Oxo-2-( 1,2,3,4-tetrahydroizochinolín-3-karbonyl)oktahydro-pyrolo[ 1,2-a] pyrazín-6-karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid0420 4-Oxo-2- (1,2,3,4-tetrahydroisoquinoline-3-carbonyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] ] amide
0425 2-(hydroxy-fenyl 1 -acetyl)-4oxo-oktahydro-pyrolo[ 1,2-a] pyrazín-6-karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid0425 2- (Hydroxy-phenyl-1-acetyl) -4-oxo-octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0430 2-(2-Hydroxy-3-fenylpropionyl)-4-oxo-oktahydropyrolof 1,2-a]pyrazín-6karboxylová kyselina [4-guanidino1 -(tiazol-2-karbonyl)butyl]-amid0430 2- (2-Hydroxy-3-phenylpropionyl) -4-oxo-octahydropyrolof 1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) butyl] -amide
-300435 4-Oxo-2-fenoxyacetyloktahydro-pyrolof 1,2-a] pyrazín-6-karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl] -amid-300435 4-Oxo-2-phenoxyacetylooctahydro-pyrrolof 1,2-a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0440 4-Oxo-2-(3-fenoxy-propionyl)oktahydro-pyrolof 1,2a] pyrazín-6-karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid0440 4-Oxo-2- (3-phenoxy-propionyl) octahydro-pyrrolof 1,2a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0445 4-Oxo-2-(2-fenyletánsulfonyl)-oktahydropyrolo[l,2-a]pyrazín-6karboxylová kyselina [4-guanidino-l(tiazol-2-karbonyl)-butyl]amid0445 4-Oxo-2- (2-phenylethanesulfonyl) -octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1 (thiazole-2-carbonyl) -butyl] amide
NHNH
°.í?° .i?
NHNH
0450 2-(Naftalén-2-sulfonyl)-4oxo-oktahydro-pyrolo[ 1,2-a] pyrazín-6-karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid0450 2- (Naphthalene-2-sulfonyl) -4-oxo-octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0455 4-(6-[4-Guanidino-1 (tiazol-2karbonyl)-butylkarbamoyl]-4-oxohexahydro-pyrolofl ,2-a]pyrazín-2yl)-4-oxo-3-(2propylpentanoylamino)-metylester kyseliny maslovej0455 4- (6- [4-Guanidino-1- (thiazole-2-carbonyl) -butylcarbamoyl] -4-oxohexahydro-pyrrolof1,2-a] pyrazin-2-yl) -4-oxo-3- (2-propylpentanoylamino) methyl butyrate
0460 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolofl ,2-a] pyrazin-6-karboxylová kyselina [4guanidino-1 )-butyl]-amid0460 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolof1,2-a] pyrazine-6-carboxylic acid [4guanidino-1-butyl] -amide
NHNH
-31 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2-a] pyrazín-6-karboxylová kyselina [3guanidino-propyl]-amid-31 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [3-guanidinopropyl] -amide
4-(6-[4-Guanidino-1 (tiazol-2karbonyl)-butylkarbamoyl]-4-oxohexahydro-pyrolo [ 1,2-a] pyrazín -2yl)-4-oxo-kyselina maslová4- (6- [4-Guanidino-1- (thiazole-2-carbonyl) -butylcarbamoyl] -4-oxohexahydro-pyrrolo [1,2-a] pyrazin-2-yl) -4-oxo-butyric acid
4-Oxo-2-(3 -fenyl-propionyl)oktahydro-pyrolo[ 1,2a]pyrazín-6-karboxylová kyselina [1(5-etyl-tiazol-2-karbonyl)4-guanidino-butyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1 (5-ethyl-thiazole-2-carbonyl) 4-guanidino-butyl] -amide
4-Oxo-2-(3 -fenyl-propiony 1)oktahydro-pyrolof 1,2a]pyrazín-6-karboxylová kyselina [4guanidino-1 -(5-metyl-tiazol2-karbonyl)-butyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolof 1,2a] pyrazine-6-carboxylic acid [4guanidino-1- (5-methyl-thiazole-2-carbonyl) -butyl] -amide
4-Oxo-2-(3 -fenyl-propionyl)oktahydro-pyrolo[ 1,2a]pyrazín-6-karboxylová kyselina [4guanidino-1 -(4-metyl-tiazol2-karbonyl)-butyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4guanidino-1- (4-methyl-thiazole-2-carbonyl) -butyl] -amide
4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo [1,2a]pyrazín-6-karboxylová kyselina [1(4-etyl-tiazol-2-karbonyl)4-guanidino-butyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1 (4-ethyl-thiazole-2-carbonyl) 4-guanidino-butyl] -amide
-320495 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2a]pyrazín-6-karboxyiová kyselina (4karbamimidoyl - fenyl) ämid-320495 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid (4-carbamimidoyl-phenyl) -amide
0500 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2a]pyrazín-6-karboxylová kyselina (4guanidino-1 -(5-fenyI-tiazol2-karbonyl)-butyl]-amid0500 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid (4guanidino-1- (5-phenyl-thiazole-2-carbonyl) -butyl] -amide
0505 4-Oxo-2-(3-fenyI-propionyl)oktahydro-pyrolo[ 1,2a]pyrazín-6-karboxylová kyselina ( 1(5-benzyl-tiazol-2-karbonyl 4-guanidino-butyl]-amid0505 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid (1 (5-benzyl-thiazole-2-carbonyl 4-guanidino-butyl) -amide
NHNH
0510 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolof 1,2a]pyrazín-6-karboxylová kyselina [ 1(4-karbamimidoyl-benzyl)-2oxo-2-tiazol-2-yl-etyl]-amid0510 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolof 1,2a] pyrazine-6-carboxylic acid [1 (4-carbamimidoyl-benzyl) -2-oxo-2-thiazol-2-yl-ethyl] - amide
0515 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2a]pyrazín-6-karboxylová kyselina [ 1(3 -karbamimidoyl-benzyl)-2-oxo2-tiazol-2-yI-etyl]-amid0515 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1 (3-carbamimidoyl-benzyl) -2-oxo-2-thiazol-2-yl] -ethyl] amide
0520 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2a]pyrazín-6-karboxylová kyselina [ 1(1 -karbamimidoyl-piperidin-4ylmetyl)-2-oxo-2-tiazol-2-yletyl]-amid0520 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1 (1-carbamimidoyl-piperidin-4-ylmethyl) -2-oxo-2-thiazole-2- ethyl] amide
-330525 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2a]pyrazín-6-karboxylová kyselina [ 1(l-karbamimidoyl-piperidín-3ylmetyl)-2-oxo-2-tiazol-2-yl--330525 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1 (1-carbamimidoyl-piperidin-3-ylmethyl) -2-oxo-2-thiazol-2 yl-
etyl]-amidethyl] -amide
0530 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo [ 1,2a] pyrazín-6-karboxylová kyselina [ 1 (1 -karbamimidoyl-piperidin-2ylmetyl)-2-oxo-2-tiazol-2-yletyl]-amid0530 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1 (1-carbamimidoyl-piperidin-2-ylmethyl) -2-oxo-2-thiazole-2- ethyl] amide
0535 [6-[4-Guanidino-1 -(tiazol-2k.arbonyl)-butylkarbamoyl]-4-oxo2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2a]pyrazin-3-yl]-kyselina octová0535 [6- [4-Guanidino-1- (thiazol-2-carbonyl) -butylcarbamoyl] -4-oxo2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazin-3-yl] -acetic acid
0540 3-[6-[4-Guanidino-l-(tiazol-2karbonyl)-butylkarbamoyl]-4-oxo-0540 3- [6- [4-Guanidino-1- (thiazole-2-carbonyl) -butylcarbamoyl] -4-oxo-
2- (3-fenyl-propionyl)oktahydro-pyrolo[ 1,2-a]pyrazin-2- (3-Phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-
3- yl]-kyselina propionová3-yl] -propionic acid
0545 [6-[ 1 -(1 -Karbamimidoyl-piperin-4-ylmetyl)-2-oxo-2-tiazol-2 -yl-etylkarbamoyl)-4-oxo-2-(3 fenyl-prop ionyl)-oktahydropyrol [ 1,2-a]pyrazin-3-yl] kyselina octová0545 [6- [1- (1-Carbamimidoyl-piperin-4-ylmethyl) -2-oxo-2-thiazol-2-yl-ethylcarbamoyl] -4-oxo-2- (3-phenyl-propionyl) -octahydropyrrole [ 1,2-a] pyrazin-3-yl] acetic acid
-340550 3-[6-[l-(l-Karbamimidoylpiperidin-4-ylmetyl)-2-oxo-2tiazol-2-yl-etylkarbamoyl)-4oxo-2-(3-fenyl-propionyl)oktahydro-pyrolf 1,2-a]pyrazin--340550 3- [6- [1- (1-Carbamimidoylpiperidin-4-ylmethyl) -2-oxo-2-thiazol-2-yl-ethylcarbamoyl] -4-oxo-2- (3-phenyl-propionyl) -octahydro-pyrrole 1,2 a] pyrazin
3-yl]-kyselina octová3-yl] -acetic acid
0555 [6-[l-(l-Karbamimidoylpiperidin-3 -ylmetyl)-2-oxo-2tiazol-2-yl-etylkarbamoyl)-4oxo-2-(3-fenyl-propionyl)oktahydro-pyrol[ 1,2-a]pyrazin-0555 [6- [1- (1-Carbamimidoylpiperidin-3-ylmethyl) -2-oxo-2-thiazol-2-yl-ethylcarbamoyl] -4-oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2-a] ] pyrazin
3-yl]-kyselina octová3-yl] -acetic acid
0560 [6-(3Guanidinopropylkarbamoyl]-4-oxo-2-(3fenyl-propionyl)-oktahydropyrolo[l,2-a]pyrazin-3-yl]kyselina octová0560 [6- (3Guanidinopropylcarbamoyl) -4-oxo-2- (3-phenyl-propionyl) -octahydropyrrolo [1,2-a] pyrazin-3-yl] acetic acid
hTHHTH
0565 3-[6-(3-Guanidinopropylkarbamoyl]-4-oxo-2-(3fenyl-propionyl)-oktahydropyrolo[l ,2-a]pyrazin-3-yl]kyselina propionová0565 3- [6- (3-Guanidinopropylcarbamoyl) -4-oxo-2- (3-phenyl-propionyl) -octahydropyrrolo [1,2-a] pyrazin-3-yl] propionic acid
0570 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolof 1,2a] pyrazín-6-karboxylová kyselina [ 4guanidino-1 -(tiazoI-2karbonyl)-butyl]-metyl amid0570 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolof 1,2a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -methyl-amide
-350575 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [ 1 (1 -karbamimidoyl-piperidin-4ylmetyl)-2-oxo-2-tiazol-2-yletylj-metybamid-350575 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1 (1-carbamimidoyl-piperidin-4-ylmethyl) -2-oxo-2-thiazol-2 -yletylj-metybamid
0580 [6-[ 1 -(1 -Karbamimidoyl-piperidin -4-ylmetyl)-2-oxo-2-tiazol-2 -yl-etyl]-metylkarbamoyl)-4oxo-2-(3-fenyl-propionyl)oktahydro-pyrolf 1,2-a]pyrazin-0580 [6- [1- (1-Carbamimidoyl-piperidin-4-ylmethyl) -2-oxo-2-thiazol-2-yl-ethyl] -methylcarbamoyl) -4-oxo-2- (3-phenyl-propionyl) -octahydro- 1,2-a] pyrazine-
3-yl]-kyselina octová3-yl] -acetic acid
0585 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolof 1,2a]pyrazín-6-karboxylová kyselina [ 1(1 -karbamimidoyl-piperidin-3ylmetyl)-2-oxo-2-tiazol-2-yletylj-metyl amid0585 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolof 1,2a] pyrazine-6-carboxylic acid [1 (1-carbamimidoyl-piperidin-3-ylmethyl) -2-oxo-2-thiazol-2-ylethyl] -methyl amide
0590 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l ,2a]pyrazín-6-karboxylová kyselina (3guanidino-propyl)-metyl-amid0590 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid (3-guanidino-propyl) -methyl-amide
0595 2-(Naftalén-2-karbonyl)-4oxo-oktahydro-pyrolo[l ,2a] pyrazín-6-karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid0595 2- (Naphthalene-2-carbonyl) -4-oxo-octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0600 2-(Naftalén-l-karbonyl)-4oxo-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [4guanidino-l-(tiazol-2karbonyl)-butyl]-amid0600 2- (Naphthalene-1-carbonyl) -4-oxo-octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
-360605 2-(3-Naftalén-l-ylpropionyl)-4-oxo-oktahydropyrolo[l,2-a] pyrazín-6karboxylová kyselina [4-guanidino-l(tiazol-2-karbonyl)-butyl]-amid-360605 2- (3-Naphthalen-1-ylpropionyl) -4-oxo-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0610 2-(4-terc-Butyl-benzoyl)-4-oxooktahydro-pyrolof 1,2a] pyrazín-6-karboxylová kyselina [4guanidino-1-(tiazol-2karbonyl)-butyl]-amid0610 2- (4-tert-Butyl-benzoyl) -4-oxo-octahydro-pyrrolof 1,2a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0615 2-(Benzo[l,3] dioxol-5karbonyl)-4-oxo-oktahydropyrolo[l,2-a] pyrazín-6karboxylová kyselina [4-guanidino-l(tiazol-2-karbonyl)-butyl]-amid0615 2- (Benzo [1,3] dioxole-5carbonyl) -4-oxo-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0620 2-(3-Benzo[l,3] dioxol-5-yl propionyl)-4-oxo-oktahydropyrolo[l,2-a] pyrazín-6karboxylová kyselina [4-guanidino-l(tiazol-2-karbonyl)-butyl]amid0620 2- (3-Benzo [1,3] dioxol-5-yl propionyl) -4-oxo-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1 (thiazole-2-carbonyl) - butyl] -amide
0625 2-[2-(2-Metyl-benzylidén)-but-0625 2- [2- (2-Methyl-benzylidene) -but-
3-enoyl]- 4-oxo-oktahydropyrolof 1,2-a]pyrazín-6karboxylová kyselina [ 1-(1karbamimidoyl-piperidin-3ylmetyl)-2-oxo-2-tiazol-2-yletyl] amid3-enoyl] -4-oxo-octahydropyrrolo 1,2-a] pyrazine-6-carboxylic acid [1- (1-carbamimidoyl-piperidin-3-ylmethyl) -2-oxo-2-thiazol-2-ylethyl] amide
0630 2-[2-(2-Metyl-benzylidén)-but-0630 2- [2- (2-Methyl-benzylidene) -but-
3-enoyl]- 4-oxo-oktahydropyrolo[ 1,2-a]pyrazín-6karboxylová kyselina [ 1-(1karbamimidoyl-piperidin-4ylmetyl)-2-oxo-2-tiazol-2-yletyl] amid3-enoyl] -4-oxo-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [1- (1-carbamimidoyl-piperidin-4-ylmethyl) -2-oxo-2-thiazol-2-ylethyl] amide
NKNK
OABOUT
NH.NH.
-372-(2-Benzyiidén-pent-3-enoyl)-oxo-oktahydro-pyrolo[ 1,2a]pyrazín-6-karboxylová kyselina (3guanidino-propyl)-amid. . r . : -372- (2-Benzylidene-pent-3-enoyl) -oxo-octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid (3-guanidinopropyl) -amide. . r. :
4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín-4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-
6-karboxylová kyselina 4karbamimidoyl-benzyl amid6-Carboxylic acid 4-carbamimidoyl-benzyl amide
4-Oxo-2-(3 -fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín-4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-
6-karboxylová kyselina [4-imidazol-lyl-1 -(tiazol-2-karbonyl)butyl]-amid6-Carboxylic acid [4-imidazol-1-yl-1- (thiazole-2-carbonyl) butyl] -amide
)SNH) SNH
H. NH. N
4-Oxo-2-(3 -fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín-4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-
6-karboxylová kyselina [4-(2-aminoimidazol-1 yl)-1 -(tiazol-2karbonyl)-butyl]-amid o6-Carboxylic acid [4- (2-aminoimidazol-1-yl) -1- (thiazole-2-carbonyl) -butyl] -amide o
4-Oxo-2-(3 -fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín-4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-
6-karboxylová kyselina [3-(2-amino-6metyl-pyrimidin-4-yl)-1 (tiazol-2-karbonyl)-propyl]-amid6-Carboxylic acid [3- (2-amino-6-methyl-pyrimidin-4-yl) -1 (thiazole-2-carbonyl) -propyl] -amide
4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín-4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-
6-karboxylová kyselina [3-(2-amino-6chlór-pyrimidin-4-yl)-1 - (tiazol-2-karbonyl)-propyl]amid6-Carboxylic acid [3- (2-amino-6-chloro-pyrimidin-4-yl) -1- (thiazole-2-carbonyl) -propyl] -amide
OABOUT
mime
-380675 4-Oxo-2-(3-fenyl-propionyl)- oktahydro-pyrolo[l,2-a] pyrazín--380675 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2-a] pyrazine-
6-karboxylová kyselina [3-(6-amino pyridin-2-yl)-l-(tiazoi-2- - ' karbonyl)-propyl]-amid6-Carboxylic acid [3- (6-amino-pyridin-2-yl) -1- (thiazole-2-carbonyl) -propyl] -amide
0680 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín-0680 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-
6-karboxylová kyselina [3-(2-amino pyridin-4-yl)-1 -(tiazol-2karbonyl)-propyl]-amid6-Carboxylic acid [3- (2-amino-pyridin-4-yl) -1- (thiazole-2-carbonyl) -propyl] -amide
0685 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2-a] pyrazín-0685 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-
6-karboxylová kyselina [2-(2-amino pyridin-4-yl)-1 -(tiazol-2karbonyl)-etyl]-amid6-Carboxylic acid [2- (2-amino-pyridin-4-yl) -1- (thiazole-2-carbonyl) -ethyl] -amide
0690 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2-a] pyrazín-0690 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-
6-karboxylová kyselina [2-(6-aminopyr idin-2-y 1)-1 -(t iazol-2karbonyl)-etyl]-amid6-Carboxylic acid [2- (6-aminopyridin-2-yl) -1- (thiazole-2-carbonyl) -ethyl] -amide
0695 2-[4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karbonyl] -3-(tiazol-2karbonyl)-1,2,3,4-tetrahydroizochinolín-6-karboxamidín0695 2- [4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carbonyl] -3- (thiazole-2-carbonyl) -1,2,3,4-tetrahydroisoquinoline- 6-carboxamidine
0700 2-[4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karbonyl]-3- (tiazol-2karbonyl)-1,2,3,4-tetrahydroizochinolín-7-karboxamidín0700 2- [4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carbonyl] -3- (thiazole-2-carbonyl) -1,2,3,4-tetrahydroisoquinoline- 7-carboxamidine
-39N-[l-(4-Oxo-2-(3-fenylpropionyl)-oktahydropyrolo[l,2-a] pyrazín-6karbonyl]-5- (tiazol-2karbonyl)-pyrolidin-3-yl]guanidín-39N- [1- (4-Oxo-2- (3-phenylpropionyl) -octahydropyrrolo [1,2-a] pyrazine-6-carbonyl] -5- (thiazole-2-carbonyl) -pyrrolidin-3-yl] guanidine
4-Oxo-2-(3 -fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [l-(4-amino cyklohexyl)-2-oxo-2-tiazol-2yl-etyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1- (4-amino-cyclohexyl) -2-oxo-2-thiazol-2-yl-ethyl] - amide
4-Oxo-2-(3 -fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [l-(4-amino cyklohexylmetyl)-2-oxo-2tiazol-2-yl-etyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1- (4-amino-cyclohexylmethyl) -2-oxo-2-thiazol-2-yl-ethyl] - amide
4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [l-(4-amino benzyl)-2-oxo-2-tiazol-2-yletyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1- (4-amino-benzyl) -2-oxo-2-thiazol-2-ylethyl] - amide
4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [ 1 -(4aminometyl-benzyl)-2-oxo-2tiazo 1-2-yl-etyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1- (4-aminomethyl-benzyl) -2-oxo-2-thiazol-2-yl-ethyl] - amide
4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [l-(3aminometyl-benzyl)-2-oxo-2tiazol-2-yl-etyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1- (3-aminomethyl-benzyl) -2-oxo-2-thiazol-2-yl-ethyl] -amide
OABOUT
-400735 4-Oxo-2-(3 -fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina-(2-oxo-lpiperidin-4-ylmetyl-2-tiazol2-yl-etyl)-amid-400735 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid- (2-oxo-1-piperidin-4-ylmethyl-2-thiazol-2-yl-ethyl) - amide
0740 4-Oxo-2-(3 -fenyl-prop ionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina-(2-oxo-lpiperidin-3-yl-2-tiazol2-yletyl)-amid0740 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid- (2-oxo-1-piperidin-3-yl-2-thiazol-2-ylethyl) -amide
0745 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [l-(3guanidino-cyklohexylmetyl)-2oxo-2-tiazol-2-yl-etyl]-amid0745 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1- (3-guanidino-cyclohexylmethyl) -2-oxo-2-thiazol-2-yl-ethyl] - amide
0750 4-Oxo-2-(3 -fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [ 1 -(4guanidino-cyklohexylmetyl)-2oxo-2-tiazol-2-yl-etyl]-amid0750 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1- (4-guanidinocyclohexylmethyl) -2-oxo-2-thiazol-2-yl-ethyl] - amide
0755 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [l-(2guanidino-cyklohexylmetyl)-2oxo-2-tiazol-2-yl-etyl]-amid0755 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1- (2-guanidinocyclohexylmethyl) -2-oxo-2-thiazol-2-yl-ethyl] - amide
0760 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [l-(5-benzyl tiazol-2-karbonyl)-4guanidino-butyl]-amid0760 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1- (5-benzyl-thiazole-2-carbonyl) -4guanidino-butyl] -amide
MN.MN.
NM.NM.
-41 0765 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [4-guanidinol-(5-fenyl-tiazol-2karbonyl)-butyl]-amid-41 0765 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidinol- (5-phenyl-thiazole-2-carbonyl) -butyl] -amide
0770 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [4-guanidinol-(tiazoI-2-karbonyl)-butyl]-amid0770 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidinol- (thiazole-2-carbonyl) -butyl] -amide
0775 5-Oxo-7-(3-fenyl-propionyl)oktahydro-2-tia-4a, 7-diazanaftalén-4-karboxylová kyselina [4-guanidino-1 -(tiazol-2karbonyl)-butyl]-amid0775 5-Oxo-7- (3-phenyl-propionyl) octahydro-2-thia-4α, 7-diazanaphthalene-4-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0780 5-Oxo-7-(3-fenyl-propionyl)oktahydro-2-tia-4a,7-diazanaftalén-4-karboxylová kyselina [ 1 -(4-karbamimidoyl-benzyl)-2oxo-2-tiazol-2-yl-etyl]-amid0780 5-Oxo-7- (3-phenyl-propionyl) octahydro-2-thia-4α, 7-diazanaphthalene-4-carboxylic acid [1- (4-carbamimidoyl-benzyl) -2oxo-2-thiazol-2-yl] ethyl] -amide
0785 5-Oxo-7-(3 -fenyl-propionyl)oktahydro-2-tia-4a,7-diazanaftalén-4-karboxylová kyselina [ 1 -(3 -karbamimidoyl-benzy l)-2oxo-2-tiazol-2-yl-etyl]-amid0785 5-Oxo-7- (3-phenyl-propionyl) octahydro-2-thia-4α, 7-diazanaphthalene-4-carboxylic acid [1- (3-carbamimidoyl-benzyl) -2-oxo-2-thiazole-2- yl-ethyl] -amide
0790 5-Oxo-7-(3-fenyl-propionyl)oktahydro-2-tia-4a,7-diazanaftalén-4-karboxylová kyselina [ 1 -(1 -karbamimidoyl-piperidin-3yletyl))-2-oxo-2-tiazol-2-yletyl]-amid0790 5-Oxo-7- (3-phenyl-propionyl) octahydro-2-thia-4α, 7-diazanaphthalene-4-carboxylic acid [1- (1-carbamimidoyl-piperidin-3-yl-ethyl)] - 2-oxo-2- thiazol-2-yl-ethyl] -amide
5-Oxo-7-(3-fenyl-propionyl)oktahydro-2-tia-4a,7-diazanaftalén-4-karboxylová kyselina [ 1 -(1 -karbamimidoyl-piperidin-4ylmetyl-2-oxo-2-tiazol-2-yletyl]-amid [4(4-Guanidino-1 -(tiazol-2karbony l)-butylkarbamoy 1] -5 -oxo-5-Oxo-7- (3-phenyl-propionyl) octahydro-2-thia-4α, 7-diazanaphthalene-4-carboxylic acid [1- (1-carbamimidoyl-piperidin-4-ylmethyl-2-oxo-2-thiazol-2)] [4 (4-Guanidino-1- (thiazole-2-carbonyl) -butylcarbamoyl] -5-oxo-ylethyl] -amide
7-(3 -fenyl-prop ióny 1)oktahydro-2-tia-4a, 7diazanaftalén-6-yl]-kyselina octová7- (3-Phenyl-propions 1) octahydro-2-thia-4α, 7-thiazanaphthalen-6-yl] -acetic acid
5-Oxo-7-(3-fenyl-propionyl)oktahydro-2-tia-4a,7-diazanaftalén-4-karboxylová kyselina [4-guanidino-1 -(tiazol-5-Oxo-7- (3-phenyl-propionyl) octahydro-2-thia-4α, 7-diazanaphthalene-4-carboxylic acid [4-guanidino-1- (thiazole-
2- karbonyl)-butyl]-amid2-carbonyl) butyl] -amide
3- [4(4-Guanidino-1 -(tiazol-2karbonyl)-butylkarbamoyl]-5-oxo-3- [4- (4-Guanidino-1- (thiazole-2-carbonyl) -butylcarbamoyl] -5-oxo-
7-(3-fenyl-propÍonyl)oktahydro-2-tia-4a, 7diazanaftalén-6-yl]-kyselina octová7- (3-Phenyl-propenyl) octahydro-2-thia-4α, 7-thiazanaphthalen-6-yl] -acetic acid
5-Oxo-7-(3-fenyl-propionyl)oktahydro-2-tia-4a,7-diazanaftalén-4-karboxylová kyselina [3-guanidino-propyl]-amid5-Oxo-7- (3-phenyl-propionyl) octahydro-2-thia-4α, 7-diazanaphthalene-4-carboxylic acid [3-guanidinopropyl] -amide
-Oxo-7-(3 -fenyl-propionyl)oktahydro-2-tia-4a,7-diazanaftalén-4-karboxylová kyselina [ 1 -(1 -karbamimidoyl-piperidin-3ylmetyl))-2-oxo-2-tiazol-2-yletyl]-amid-Oxo-7- (3-phenyl-propionyl) octahydro-2-thia-4α, 7-diazanaphthalene-4-carboxylic acid [1- (1-carbamimidoyl-piperidin-3-ylmethyl)] - 2-oxo-2-thiazole- 2-yl-ethyl] -amide
4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [4-guanidino1 -(hydroxy-tiazol-2-yl-metyl)butyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (hydroxy-thiazol-2-ylmethyl) butyl] -amide
4-Oxo-2-(3-fenyl-propionyI)oktahydro-pyrolo[l,2-a] pyrazín-6karboxylová kyselina [4-guanidino-ltiazol-2-yl-metyl-butyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-thiazol-2-yl-methyl-butyl] -amide
4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolof 1,2-a] pyrazín-6karboxylová kyselina [4-guanidino-ltiazol-2-yl-butyl]-amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolof 1,2-a] pyrazine-6-carboxylic acid [4-guanidino-thiazol-2-yl-butyl] -amide
NM.NM.
4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [4-metoxy-l(tiazol-2-karbonyl)-butyl]amid4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-methoxy-1- (thiazole-2-carbonyl) -butyl] -amide
[6-[4-Metoxy-1 -(tiazol-2karbonyl)-butylkarbamoyl]-4-oxo-[6- [4-Methoxy-1- (thiazole-2-carbonyl) -butylcarbamoyl] -4-oxo-
2- (3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazin-2- (3-Phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-
3- yl] -kyselina octová [2-[5-Metoxy-2-([4-oxo-2-(3fenyl-propionyl)-oktahydropyrolo[l,2-a] pyrazín-6karbonyl] -amino)-pentanoyl)tiazol-5-yl] -kyselina octová3-yl] -acetic acid [2- [5-Methoxy-2 - ([4-oxo-2- (3-phenyl-propionyl) -octahydropyrrolo [1,2-a] pyrazine-6-carbonyl] -amino) -pentanoyl) -thiazole -5-yl] acetic acid
-440855 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [4-amino-l(tiazol-2-karbonyl)-butyljamid-440855 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-amino-1- (thiazole-2-carbonyl) -butyl] -amide
0860 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [5-amino-l(tiazol-2-karbonyl)-pentylJamid0860 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [5-amino-1- (thiazole-2-carbonyl) -pentyl] -amide
0865 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [5-guanidino1 -(tiazol-2-karbonyl)-pentyl]amid0865 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [5-guanidino-1- (thiazole-2-carbonyl) -pentyl] -amide
0870 2-(3-Naftalen-2-yl-propionyl)4-oxo-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxyIová kyselina [4guanidino -1 -(tiazol-2karbonyl)-butyl]-amid0870 2- (3-Naphthalen-2-yl-propionyl) 4-oxo-octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0875 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [4-guanidino1 -(1 -metyl-1 H-imidazol-2karbonyl)-butyl]-amid0875 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (1-methyl-1H-imidazole-2-carbonyl) -butyl] -amide
0880 4-Oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[l,2-a] pyrazín6-karboxylová kyselina [4-guanidino1 -(1 -tiazol-2-karbonyl)-butyl]amid0880 4-Oxo-2- (3-phenyl-propionyl) octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (1-thiazole-2-carbonyl) -butyl] amide
-45 0885 8,8-Dimetyl-4-oxo-(3-fenylpropionyl)-oktahydropyrolo[l,2-a] pyrazín-6karboxylová kyselina [4-guanidino-1(1 -tiazol-2-karbonyl)-butyl]-amid-45,085 8,8-Dimethyl-4-oxo- (3-phenylpropionyl) -octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1 (1-thiazole-2-carbonyl) -butyl] - amide
Výhodné zlúčeniny podľa vzorca (VĽH) sú:Preferred compounds of formula (IIH) are:
0325 3-Aminometyl-2-benzoyl-4oxo-oktahydro-pyrolo[ 1,2a] pyridín-6-karboxylová kyselina [l-(benzotiazol-2karbonyl)-4-guanidino-butyl]-amid0325 3-Aminomethyl-2-benzoyl-4-oxo-octahydro-pyrrolo [1,2a] pyridine-6-carboxylic acid [1- (benzothiazole-2-carbonyl) -4-guanidino-butyl] -amide
0330 3 -Aminometyl-4-oxo-2-fenylacetyl-oktahydropyrolof 1,2-a] pyrazín-6-karboxylová kyselina[l(benzotiazol-2-karbonyl)-4-guanidino-butyl]-amid0330 3-Aminomethyl-4-oxo-2-phenylacetyl-octahydropyrrole 1,2-a] pyrazine-6-carboxylic acid [1 (benzothiazole-2-carbonyl) -4-guanidino-butyl] -amide
0515 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a]pyrazín-6-karboxylová kyselina [ l-(3-karbamimidoylbenzyl)-2-oxo-2-tiazol-2-yl-etyl]-amid0515 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1- (3-carbamimidoyl-benzyl) -2-oxo-2-thiazol-2-yl- ethyl] -amide
0530 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [ l-(l-karbamimidoylpiperidin-2-ylmetyl)-2-oxo-2-tiazol-2-yl-etyl]amid0530 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1- (1-carbamimidoylpiperidin-2-ylmethyl) -2-oxo-2-thiazole- 2-yl-ethyl] -amide
0545 [6-[ 1 -(1 -Karbamimidoyl-piperin-4-ylmetyl)-2-oxo-2tiazol-2-yl-etylkarbamoyl)-4-oxo-2-(3-fenylpropionyl)-oktahydro-pyrol[l ,2-a]pyrazin-3-yl]kyselina octová0545 [6- [1- (1-Carbamimidoyl-piperin-4-ylmethyl) -2-oxo-2-thiazol-2-yl-ethylcarbamoyl] -4-oxo-2- (3-phenyl-propionyl) -octahydro-pyrrole [1,1, 2-a] pyrazin-3-yl] acetic acid
0550 3-[6-[ 1 -(1 -Karbamimidoyl-piperidin-4-ylmetyl)-2-oxo2-tiazoI-2-yl-etylkarbamoyl)-4-oxo-2-(3-fenylpropionyl)-oktahydro-pyrol[ 1,2-a]pyrazin-3-yl]kyselina octová0550 3- [6- [1- (1-Carbamimidoyl-piperidin-4-ylmethyl) -2-oxo-2-thiazol-2-yl-ethylcarbamoyl) -4-oxo-2- (3-phenyl-propionyl) -octahydro-pyrrole [ 1,2-a] pyrazin-3-yl] acetic acid
-460555 [6-(1-(1 -Karbamimidoyl-piperidin-3-ylmetyl)-2-oxo-2tiazol-2-yl-etylkarbamoyl)-4-oxo-2-(3-fenylpropionyl)-oktahydro-pyrol[ 1,2-a]pyrazin-3-yl]kyselina octová-460555 [6- (1- (1-Carbamimidoyl-piperidin-3-ylmethyl) -2-oxo-2-thiazol-2-yl-ethylcarbamoyl) -4-oxo-2- (3-phenyl-propionyl) -octahydro-pyrrole [1 2-a] pyrazin-3-yl] acetic acid
0560 (6-(3Guanidino-propylkarbamoyl]-4-oxo-2-(3-fenylpropionyl)-oktahydro-pyroio[ 1,2-a]pyrazin-3-yl]kyselina octová0560 (6- (3Guanidino-propylcarbamoyl) -4-oxo-2- (3-phenylpropionyl) -octahydro-pyrrolo [1,2-a] pyrazin-3-yl] -acetic acid
0565 3-[6-(3-Guanidino-propylkarbamoyl]-4-oxo-2-(3-fenylpropionyl)-oktahydro-pyrolo[l,2-a]pyrazin-3-yl]kyselina propiónová0565 3- [6- (3-Guanidinopropyl-carbamoyl) -4-oxo-2- (3-phenylpropionyl) -octahydro-pyrrolo [1,2-a] pyrazin-3-yl] propionic acid
0575 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [ l-(l-karbamimidoylpiperidin-4-ylmetyl)-2-oxo-2-tiazol-2-yl-etyl]metyl-amid0575 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1- (1-carbamimidoyl-piperidin-4-ylmethyl) -2-oxo-2-thiazole- 2-yl-ethyl] -methyl-amide
0580 [6-(1-(1 -Karbamimidoyl-piperidin-4-yImetyl)-2-oxo-2tiazol-2-yl-etyl]-metylkarbamoyl)-4-oxo-2-(3fenyl-propionyl)-oktahydro-pyrol[ 1,2-a]pyrazin-3-yl]kyselina octová0580 [6- (1- (1-Carbamimidoyl-piperidin-4-ylmethyl) -2-oxo-2-thiazol-2-yl-ethyl] -methylcarbamoyl) -4-oxo-2- (3-phenyl-propionyl) -octahydro-pyrrole [1,2-a] pyrazin-3-yl] acetic acid
0585 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina ( l-(l-karbamimidoylpiperidin-3-ylmetyl)-2-oxo-2-tiazol-2-yl-etyl]metyl-amid0585 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid (1- (1-carbamimidoylpiperidin-3-ylmethyl) -2-oxo-2-thiazole- 2-yl-ethyl] -methyl-amide
0590 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo(l ,2a]pyrazín-6-karboxylová kyselina (3-guanidino-propyl)metyl-amid0590 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo (1,2a) pyrazine-6-carboxylic acid (3-guanidinopropyl) methyl amide
0595 2-(Naftalén-2-karbonyl)-4-oxo-oktahydropyrolo[l,2-a] pyrazín-6-karboxylová kyselina [4guanidino-1 -(tiazol-2-karbonyl)-butyl]-amid0595 2- (Naphthalene-2-carbonyl) -4-oxo-octahydropyrrolo [1,2-a] pyrazine-6-carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
-470625 2-[2-(2-Metyl-benzylidén)-but-3-enoyl]- 4-oxooktahydro-pyrolo[l,2-a]pyrazín-6-karboxylová kyselina [ 1(1 -karbamimidoyl-piperidin-3-ylmetyl)-2-oxo2-tiazol-2-yl-etyl] amid-470625 2- [2- (2-Methyl-benzylidene) -but-3-enoyl] -4-oxo-octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1 (1-carbamimidoyl-piperidine-3) -ylmethyl) -2-oxo-2-thiazol-2-yl-ethyl] -amide
0630 2-[2-(2-Metyl-benzylidén)-but-3-enoyl]- 4-oxooktahydro-pyrolo[l,2-a]pyrazín-6-karboxyIová kyselina [ 1(1 -karbamimidoyl-piperidin-4-ylmetyl)-2-oxo-2-tiazol2-yl-etyl] amid0630 2- [2- (2-Methyl-benzylidene) -but-3-enoyl] -4-oxo-octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [1 (1-carbamimidoyl-piperidine-4-) ylmethyl) -2-oxo-2-thiazol-2-yl-ethyl] amide
635 2-(2-Benzylidén-pent-3-enoyl)-4-oxo-oktahydro-pyrolo[l,2-a]pyrazín-6-karboxylová kyselina (3-guanidino-propyl)-amid635 2- (2-Benzylidene-pent-3-enoyl) -4-oxo-octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid (3-guanidinopropyl) -amide
0645 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [4-imidazol-l-yl-l(tiazol-2-karbonyl)-butyl]-amid0645 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-imidazol-1-yl-1- (thiazole-2-carbonyl) -butyl] - amide
0670 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [3-(2-amino-6-chIórpyrimidin-4-yl)-1 -(tiazol-2-karbonyl)-propyl]-amid0670 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [3- (2-amino-6-chloropyrimidin-4-yl) -1- (thiazole) 2-carbonyl) -propyl] -amide
0675 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [3-(6-aminopyridin-2yl)-1 -(tiazol-2-karbonyl)-propyl]-amid0675 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [3- (6-aminopyridin-2-yl) -1- (thiazole-2-carbonyl) - propyl] -amide
0680 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [3-(2-aminopyridin-4yl)-1 -(tiazol-2-karbonyl)-propyl]-amid0680 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [3- (2-aminopyridin-4-yl) -1- (thiazole-2-carbonyl) - propyl] -amide
0685 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [2-(2-aminopyridin-4yl)-1 -(tiazol-2-karbonyl)-etyl]-amid0685 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [2- (2-aminopyridin-4-yl) -1- (thiazole-2-carbonyl) - ethyl] -amide
0690 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [2-(6-aminopyridin-2yl)-1 -(tiazol-2-karbonyl)-etyl]-amid0690 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [2- (6-aminopyridin-2-yl) -1- (thiazole-2-carbonyl) - ethyl] -amide
-490800 [4(4-Guanidino-1 -(tiazol-2-karbonyl)butylkarbamoyl]-5-oxo-7-(3-fenyl-propionyl)oktahydro-2-tia-4a, 7diaza-naftalen-6-yl]-kyselina octová-490800 [4 (4-Guanidino-1- (thiazole-2-carbonyl) butylcarbamoyl] -5-oxo-7- (3-phenylpropionyl) octahydro-2-thia-4a, 7-diazaphthalen-6-yl] -acetic acid
0810 3-[4(4-Guanidino-1 -(tiazol-2-karbonyl)butylkarbamoyl]-5 -oxo-7-(3 -fenyl-propionyl)oktahydro-2-tia-4a,7diaza-naftalen-6-yl]-kyselina octová0810 3- [4- (4-Guanidino-1- (thiazole-2-carbonyl) butylcarbamoyl] -5-oxo-7- (3-phenylpropionyl) octahydro-2-thia-4a, 7-diazaphthalen-6-yl acetic acid
0815 5-Oxo-7-(3-fenyl-propionyl)-oktahydro-2-tia-4a>7diaza-naftalén-4-karboxyIová kyselina [3-guanidino-propyl]-amid0815 5-Oxo-7- (3-phenyl-propionyl) -octahydro-2-thia-4α-diaza-naphthalene-4-carboxylic acid [3-guanidinopropyl] -amide
0820 5-Oxo-7-(3-fenyl-propionyl)-oktahydro-2-tia-4a, 7-diazanaftalén-4-karboxylo vá kyselina [ 1 -(1 -karbamimidoylpiperidin-3ylmetyl-)-2-oxo-2-tiazol-2-yl-etyl]-amid0820 5-Oxo-7- (3-phenyl-propionyl) -octahydro-2-thia-4α, 7-diazanaphthalene-4-carboxylic acid [1- (1-carbamimidoylpiperidin-3-ylmethyl) -2-oxo-2- thiazol-2-yl-ethyl] -amide
0830 4-Oxo-2-(3 -fenyl-propionyl)-oktahydro-pyrolo[ 1,2-0830 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2-
a] pyrazín-6-karboxylová kyselina [4-guanidino-l-tiazol-2yl-metyl-butyl]-amida] Pyrazine-6-carboxylic acid [4-guanidino-1-thiazol-2-ylmethyl-butyl] -amide
083 5 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2-083 5 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2-
a] pyrazín-6-karboxylová kyselina [4-guanidino-l-tiazol-2yl-butyl]-amida] Pyrazine-6-carboxylic acid [4-guanidino-1-thiazol-2-yl-butyl] -amide
Výhodnejšie zlúčeniny podľa vzorca VRI sú:More preferred compounds of formula VRI are:
0335 2-Benzoyl-4-oxo-oktahydro-pyrolo[l,2-a] pyrazín-6karboxylová kyselina[4-guanidino-1 -(tiazol-2-karbonyl)butyl]-amid0335 2-Benzoyl-4-oxo-octahydro-pyrrolo [1,2-a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) butyl] -amide
0650 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [4-(2-amino-imidazol-l yl)-1 -(tiazol-2-karbonyl)-butyl]-amid0650 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4- (2-amino-imidazol-1-yl) -1- (thiazole-2- carbonyl) -butyl] -amide
0655 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [3-(2-amino-6-metylpyrimidin-4-yl)-1 -(tiazol-2-karbonyl)-propyl]-amid0655 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [3- (2-amino-6-methyl-pyrimidin-4-yl) -1- (thiazole) 2-carbonyl) -propyl] -amide
-500715 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [l-(4-aminocyklohexylmetyl)-2-oxo-2-tiazol-2-yl-etyl]-amid-500715 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1- (4-aminocyclohexylmethyl) -2-oxo-2-thiazol-2-yl] ethyl] -amide
0720 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [l-(4-aminobenzyl)-2oxo-2-tiazol-2-yl-etyl]-amid0720 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1- (4-aminobenzyl) -2-oxo-2-thiazol-2-yl-ethyl] amide
0725 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [l-(4-aminometylbenzyl)-2-oxo-2-tiazol-2-yl-etyl]-amid0725 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1- (4-aminomethyl-benzyl) -2-oxo-2-thiazol-2-yl- ethyl] -amide
073 5 4-Oxo-2-(3 -fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina-(2-oxo-l-piperidin-4ylmetyl-2-tiazol2-yl-etyl)-amid i073 5 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid- (2-oxo-1-piperidin-4-ylmethyl-2-thiazol-2-yl-ethyl) -amide i
iand
0740 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2-a] pyrazín-0740 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2-a] pyrazine-
6-karboxylová kyselina-(2-oxo-1 -piperidin-3 -yl-6-Carboxylic acid- (2-oxo-1-piperidin-3-yl-
2-tiazol2-yl-etyl)-amid2-thiazol-2-yl-ethyl) -amide
0750 4-Oxo-2-(3 -fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [l-(4-guanidinocyklohexylmetyl)-2-oxo-2-tiazol-2-yl-etyl]-amid0750 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1- (4-guanidinocyclohexylmethyl) -2-oxo-2-thiazol-2-yl- ethyl] -amide
0760 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [l-(5-benzyltiazol-2karbonyl)-4-guanidino-butyl]-amid0760 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [1- (5-benzylthiazole-2-carbonyl) -4-guanidino-butyl] -amide
0765 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [4-guanidinotiazol-2-karbonyl)-butyl]-amid0765 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-guanidinothiazole-2-carbonyl] -butyl] -amide
0770 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [4-guanidino-l-(tiazol2-karbonyl)-butyl]-amid0770 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
-51 0775 5-Oxo-7-(3-fenyl-propionyl)-oktahydro-2-tia-4a,7diaza-naftalén-4-karboxylová kyselina [4-guanidino-l(tiazol-2-karbonyl)-butyl]-amid-51 0775 5-Oxo-7- (3-phenyl-propionyl) -octahydro-2-thia-4α, 7-diaza-naphthalene-4-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] - amide
0780 5-Oxo-7-(3-fenyl-propionyl)-oktahydro-2-tia-4a,7diaza-naftalén-4-karboxylová kyselina [l-(4karbamimidoyl-benzyl)-2-oxo-2-tiazol-2-yl-etyl]amid0780 5-Oxo-7- (3-phenyl-propionyl) -octahydro-2-thia-4α, 7-diaza-naphthalene-4-carboxylic acid [1- (4-carbamimidoyl-benzyl) -2-oxo-2-thiazole-2- yl-ethyl] -amide
0785 5-Oxo-7-(3-fenyl-propionyl)-oktahydro-2-tia-4a,7diaza-naftalén-4-karboxylová kyselina [l-(3karbamimidoyl-benzyl)-2-oxo-2-tiazol-2-yl-etyl]-amid0785 5-Oxo-7- (3-phenyl-propionyl) -octahydro-2-thia-4α, 7-diaza-naphthalene-4-carboxylic acid [1- (3-carbamimidoyl-benzyl) -2-oxo-2-thiazole-2- yl-ethyl] -amide
0790 5-Oxo-7-(3-fenyl-propionyl)-oktahydro-2-tia-4a,7diaza-naftalén-4-karboxylová kyselina[ 1-(1karbamimidoyl-piperidin-3-yletyl))-2-oxo-2-tiazol2-yl-etyl]-amid0790 5-Oxo-7- (3-phenyl-propionyl) -octahydro-2-thia-4α, 7-diaza-naphthalene-4-carboxylic acid [1- (1-carbamimidoyl-piperidin-3-ylethyl)] - 2-oxo-2 -tiazol2-yl-ethyl] -amide
0805 5-Oxo-7-(3-fenyl-propionyl)-oktahydro-2-tia-4a,7diaza-naftalén-4-karboxylová kyselina[4-guanidino-1 (tiazol-2-karbonyl)-butyl]-amid0805 5-Oxo-7- (3-phenyl-propionyl) -octahydro-2-thia-4α, 7-diaza-naphthalene-4-carboxylic acid [4-guanidino-1 (thiazole-2-carbonyl) -butyl] -amide
0825 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l ,2a] pyrazín-6-karboxylová kyselina [4-guanidino-l-(hydroxytiazol-2-yl-metyl)-butyl]-amid0825 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-guanidino-1- (hydroxytiazol-2-ylmethyl) -butyl] -amide
0840 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l ,2a] pyrazín-6-karboxylová kyselina [4-metoxy-l-(tiazol-2karbonyl)-butyl]-amid0840 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-methoxy-1- (thiazole-2-carbonyl) -butyl] -amide
0845 [6-[4-Metoxy-1 -(tiazol-2-karbonyl)-butylkarbamoyl]-0845 [6- [4-Methoxy-1- (thiazole-2-carbonyl) -butylcarbamoyl] -
4-oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-3-yl]-kyselina octová4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazin-3-yl] -acetic acid
0850 [2-[5-Metoxy-2-([4-oxo-2-(3-fenyl-propionyl)oktahydro-pyrolo[ 1,2-a] pyrazín-6-karbonyl]-amino)pentanoyl)-tiazol-5-yl] -kyselina octová0850 [2- [5-Methoxy-2 - ([4-oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2-a] pyrazine-6-carbonyl] -amino) -pentanoyl) -thiazole- 5-yl] -acetic acid
0855 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [4-amino-l-(tiazol-2karbonyl)-butyl]-amid0855 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-amino-1- (thiazole-2-carbonyl) -butyl] -amide
0860 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [5-amino-l-(tiazol-2karbonyl)-pentyl]-amid0860 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [5-amino-1- (thiazole-2-carbonyl) -pentyl] -amide
0865 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[ 1,2a] pyrazín-6-karboxylová kyselina [5-guanidino-l-(tiazol2-karbonyl)-pentyl]-amid0865 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [5-guanidino-1- (thiazole-2-carbonyl) -pentyl] -amide
Najvýhodnejšie zlúčeniny podľa vzorca VIII sú:The most preferred compounds of formula VIII are:
0345 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina [4-guanidino-l-(5-metyltiazol-2-karbonyl)-butyl]-amid a0345 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-guanidino-1- (5-methylthiazole-2-carbonyl) -butyl] -amide and
0340 4-Oxo-2-(3-fenyl-propionyl)-oktahydro-pyrolo[l,2a] pyrazín-6-karboxylová kyselina[4-guanidino-l-(tiazol-2karbony l)-buty 1] -amid0340 4-Oxo-2- (3-phenyl-propionyl) -octahydro-pyrrolo [1,2a] pyrazine-6-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
Výhodné zúčeniny podľa vzorca IX sú:Preferred compounds of formula IX are:
0890 3-Amino-l-4-oxo-2-fenyl hexahydro-pyrolo [2,1b [1,3] tiazín-6-karboxylová kyselina [l-(benzotiazol-2karbonyl)-4guanidino-butyl]amid0890 3-Amino-1-4-oxo-2-phenyl hexahydro-pyrrolo [2,1b [1,3] thiazine-6-carboxylic acid [1- (benzothiazole-2-carbonyl) -4guanidinobutyl] amide
-530895 3-Amino-2-benzyl-4-oxohexahydro-pyrolo[2,1 --530895 3-Amino-2-benzyl-4-oxohexahydro-pyrrolo [2,1-
b] [1,3] tiazín-6-karboxylová kyselina [l-(benzotiazol-2karbonyl)-4guanidino-butyl]amidb] [1,3] thiazine-6-carboxylic acid [1- (benzothiazole-2-carbonyl) -4guanidinobutyl] amide
0900 3-Amino-2-cyklohexyl-4-oxohexahydro-pyrolo[2,l-0900 3-Amino-2-cyclohexyl-4-oxohexahydro-pyrrolo [2,1-
b] [1,3] tiazín-6-karboxylová kyselina [l-(benzotiazol-2karbonyl)-4-guanidino-butyl]amidb] [1,3] thiazine-6-carboxylic acid [1- (benzothiazole-2-carbonyl) -4-guanidino-butyl] amide
Výhodné zlúčeniny podľa vzorca X sú:Preferred compounds of formula X are:
0905 7-Benzyl-6-oxo-oktahydropyrolo[2,l-c] [l,4]tiazín-4karboxylová kyselina [1(benzotiazol-2-karbonyl)-4guanidino-butyl]-amid0905 7-Benzyl-6-oxo-octahydropyrrolo [2,1-c] [1,4] thiazine-4-carboxylic acid [1 (benzothiazole-2-carbonyl) -4guanidino-butyl] -amide
0910 7(4-terc.Butyl-benzyl)—Benzyl-6-οχοoktahydro-pyrolo[2,1 -0910 7 (4-tert-Butyl-benzyl) -Benzyl-6-ω-octahydro-pyrrolo [2,1-
c] [l,4]tiazin-4-karboxylová kyselina [1- (benzotiazol-2karbonyl)-4-guanidino-butyl]amidc] [1,4] thiazine-4-carboxylic acid [1- (benzothiazole-2-carbonyl) -4-guanidino-butyl] amide
0915 6-Oxo-oktahydro-pyrido[2,1-0915 6-Oxo-octahydro-pyrido [2,1-
c] [ 1,4]tiazín-4-karboxylová kyselina [4-guanidino-1 -(tiazol2-karbonyl) butyl]-amidc] [1,4] thiazine-4-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) butyl] -amide
HH
'‘Nh'' Nh
CNMCNM
H.NH.N
S ’IOYOU ARE ABOUT
M NM N
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-540925 7-Benzyl-6-oxo-oktahydropyrido[2,l-c] [1,4]tiazín-4karboxylová kyselina [4-guanidinol-(tiazol-2-karbonyl) butyl]amid-540925 7-Benzyl-6-oxo-octahydropyrido [2,1-c] [1,4] thiazine-4-carboxylic acid [4-guanidinol- (thiazole-2-carbonyl) butyl] amide
0935 7-Benzyl-6-oxo-oktahydropyrido[2,l-c] [I,4]tiazín-4karboxylová kyselina [4-guanidinol-(tiazol-2-karbonyl) butyl]amid0935 7-Benzyl-6-oxo-octahydropyrido [2,1-c] [1,4] thiazine-4-carboxylic acid [4-guanidinol- (thiazole-2-carbonyl) butyl] amide
0940 6-Oxo-7-fenetyl-oktahydropyrido[2,l-c] [ 1,4]tiazín-4karboxylová kyselina [4-guanidino1 -(tiazol-2-karbonyl)butyl]-amid0940 6-Oxo-7-phenethyl-octahydropyrido [2,1-c] [1,4] thiazine-4-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) butyl] -amide
0950 7-Benzyl-2,2,6-trioxooktahydro-21) 6 pyrido[2,l-cj[ 1,4]tiazín-4-karboxylová kyselina [4-guanidino-l-(tiazol2-karbonyl) butyl]-amid0950 7-Benzyl-2,2,6-trioxooctahydro-21,66-pyrido [2,1-cj [1,4] thiazine-4-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) butyl] -amide
uat
HH
Výhodnejšie zlúčeniny podľa vzorca X súMore preferred compounds of formula X are
0925 7-Benzyl-6-oxo-oktahydro-pyrido[2,l-c] [ 1,4]tiazín-4karboxylová kyselina [4-guanidino-l-(tiazol-2karbonyl) butylj-amid a0925 7-Benzyl-6-oxo-octahydro-pyrido [2,1-c] [1,4] thiazine-4-carboxylic acid [4-guanidino-1- (thiazole-2-carbonyl) -butyl] -amide and
0940 6-Oxo-7-fenetyl-oktahydro-pyrido[2,l-c] [1,4]tiazín-4karboxylová kyselina (4-guanidino-l-(tiazol-2-karbonyl) butylj-amid0940 6-Oxo-7-phenethyl-octahydro-pyrido [2,1-c] [1,4] thiazine-4-carboxylic acid (4-guanidino-1- (thiazole-2-carbonyl) butyl) -amide
Výhodné zlúčeniny podľa vzorca ΠΙ sú:Preferred compounds of formula ΠΙ are:
-550960 4-Oxo-(3-fenyl-propionyl)oktahydro pyrolo[l,2] pyrimidín--550960 4-Oxo- (3-phenyl-propionyl) octahydro pyrrolo [1,2] pyrimidine-
6-karboxylová kyselina [4guanidino-1 -(tiazol-2karbonyl)-butyl]-amid6-Carboxylic acid [4guanidino-1- (thiazole-2-carbonyl) -butyl] -amide
0965 ' 4-Oxo-l-(fenetyIsulfonyl)oktahydropyrolo[l,2] pyrimidín* 6-karboxylová kyselina [4guanidino-1 -(tiazol-21 karbonyl)-butyl]-amid0965 "4-Oxo-l- (fenetyIsulfonyl) octahydropyrrolo [l, 2] pyrimidine * 6-carboxylic acid [4-guanidino-1 - (thiazol-2 1-carbonyl) -butyl] -amide
Na prípravu zlúčenín vzorca (VII) môžu byť použité rôzne postupy individuálne podľa východiskového materiálu, a/alebo vzniknutých intermediátov. Nasledujúca schéma je jedna z nich.Various procedures can be used to prepare the compounds of formula (VII) individually, depending on the starting material and / or intermediates formed. The following diagram is one of them.
-56SCHÉMA 1-56SCHEMIST 1
Krok 1Step 1
-----►► -----
Krok 3'Step 3 '
Krok 4Step 4
4..........4 ..........
oabout
-57Krok 1: Alkylácia a, sa vykoná s vhodnou bázou podľa postupu opísaného v Evans et al. (J. Chem. Soc., 1981, 103, 2127, resp. 1982, 104, 1737; Aldrichimica Acta 1982, 15, 23), aby sa získalo b.Step 1: Alkylation of α, is performed with a suitable base according to the procedure described by Evans et al. (J. Chem. Soc., 1981, 103, 2127 and 1982, 104, 1737; Aldrichimica Acta 1982, 15, 23) to obtain b.
Krok 2: Zlúčenina b sa podrobí hydroborácii a oxiduje podľa podmienok prístupných v literatúre (Synthesis, 1980, 151), výsledkom čoho je aldehyde.Step 2: Compound b is subjected to hydroboration and oxidized according to conditions available in the literature (Synthesis, 1980, 151), resulting in an aldehyde.
Krok 3: Tvorba produktu adície e z aldehydu c s d sa uskutoční miešaním reaktantov v aromatickom rozpúšťadle napr. benzéne alebo toluéne, v prítomnosti katalytického množstva vhodnej kyseliny, napr. p-toluénsulfónovej kyseliny.Step 3: The formation of the product of addition e from aldehyde c with d is carried out by stirring the reactants in an aromatic solvent e.g. benzene or toluene, in the presence of a catalytic amount of a suitable acid, e.g. p-toluenesulfonic acid.
Krok 3': Zabránenie konverzie aldehydu c na aldehyd a sa ľahko dosiahne ochranou a odstránením ochrany podľa protokolu nachádzajúceho sa v T.Green: Protective Groups In Organic Synthesis. (John Wiley & Sons, 1981).Step 3 ': Preventing the conversion of aldehyde c to aldehyde a is readily accomplished by protecting and removing protection according to the protocol found in T.Green: Protective Groups In Organic Synthesis. (John Wiley & Sons, 1981).
Krok 4: Cyklizácia produktu adície e na f sa môže ľahko dosiahnuť s vhodnou Lewisovou kyselinou napr. trimetylalbumínom vo vhodnom rozpúšťadle napr. dichlórmetáne, metóda sa nachádza v T.Green , (viď krok 3')·Step 4: Cyclization of the product of addition of e to f can be readily accomplished with a suitable Lewis acid e.g. trimethylalbumin in a suitable solvent e.g. dichloromethane, method found in T.Green, (see step 3 ') ·
Krok 4': Alternatívne, zlúčenina f môže vzniknúť pôsobením d na aldehyd a v prítomnosti vhodného aromatického rozpúšťadla napr. benzénu.Step 4 ': Alternatively, compound f can be formed by treatment of d with aldehyde and in the presence of a suitable aromatic solvent e.g. benzene.
Krok 5: Esterová funkčná skupina (-C(O)O-R) bicyklického intermediátu vzorca f je potom podrobená hydrolýze, za použitia vhodného činidla ako je HCL, vhodného rozpúšťadla, ako je etyléter, za vzniku voľnej karboxylovej kyseliny. Vzniknutá zlúčenina je potom naviazaná na RjH s peptidom pomocou spojovacieho činidla, akým je BOP, vo vhodnom rozpúšťadle, ako je DMF, za vzniku bicyklickej zloženej zlúčeniny vzorca (VHI). Podmienky vhodné pre vznik peptidovej väzby sú dobre známe v chémii peptidov. Napr. viď Principál of Peptide Synthesis, Bodanszky M., Springer-Verlag, Berlin, Heidelberg, New York, Tokyo 1984; and The Peptides Analysis, Synthesis, Biology, Vol. 1. edited by Gross E., and Meienhofer J., Academiec Press, New York, San Francisko, London, 1979.Step 5: The ester function of the (-C (O) O-R) bicyclic intermediate of formula f is then subjected to hydrolysis, using a suitable reagent such as HCl, a suitable solvent such as ethyl ether to give the free carboxylic acid. The resulting compound is then coupled to R 1 H with the peptide using a coupling agent such as BOP in a suitable solvent such as DMF to form a bicyclic compound of formula (VHI). Conditions suitable for peptide bond formation are well known in peptide chemistry. E.g. see Principal of Peptide Synthesis, M. Bodanszky, Springer-Verlag, Berlin, Heidelberg, New York, Tokyo 1984; and The Peptides Analysis, Synthesis, Biology, Vol. 1. edited by Gross E., and Meienhofer J., Academiec Press, New York, San Francisco, London, 1979.
Na prípravu zlúčenín vzorca (VHI) môžu sa použiť rôzne postupy v závislosti na použitom východiskovom materiáli a/alebo vznikajúcich intermediátoch. Nasledovná schéma je jedna z možných spôsobov prípravy.Various procedures may be used to prepare the compounds of formula (VHI) depending on the starting material used and / or the intermediates formed. The following scheme is one possible preparation.
-58SCHÉMA2-58SCHÉMA2
Krok 1 ozonolýzaStep 1 ozonolysis
gg
VIIIVIII
-59kde :-59where:
Pgje dusíková ochranná skupina;Pg is a nitrogen protecting group;
každá Rjq a Rj j je nezávisle C alkyl; a X, Rj , R R^ , a R^ sú definované ako predtým.each R jq and R j j is independently C alkyl; and X, R 1, R R 1, and R 1 are as defined above.
V krátkosti je opis procesu v schéme 2 nasledovný:In brief, the description of the process in Scheme 2 is as follows:
Krok 1: Amino a karboxylové funkčné skupiny nenasýtených zlúčeniny vzorca (a) sú chránené s vhodnými ochrannými skupinami. Rozmanité ochranné skupiny, pre rôzne reakčné funkčné skupiny a protokoly vhodnej ochrany a ich odstránenie sa nachádzajú v T.Green, Protective Groups In Organic Synthesis. (John Wiley & Sons, 1981). Použitie vhodných ochranných skupín v danej syntetickej schéme bude závisieť na mnohých faktoroch, zahrňujúcich prítomnosť iných reakčných skupín a reakčné podmienky ich odstránenia. Nenasýtené zlúčeniny vzorca sú ľahko získateľné metódami a protokolmi známymi v chemickom odbore. Ochrana nenasýtených zlúčenín vzorca (a) sa uskutoční za vhodných podmienok dovoľujúcich cyklizáciu použitím vhodného činidla, ako je acetát ortuťnatý v inertnom rozpúšťadle, akým je tetrahydrofúrán (THF) výsledkom čoho je chránený aminoalkohol vzorca (b).Step 1: The amino and carboxyl functional groups of the unsaturated compounds of formula (a) are protected with suitable protecting groups. A variety of protecting groups, for various reaction functional groups and suitable protection protocols and their removal are found in T.Green, Protective Groups In Organic Synthesis. (John Wiley & Sons, 1981). The use of suitable protecting groups in a given synthetic scheme will depend on many factors, including the presence of other reactants and the reaction conditions for their removal. The unsaturated compounds of the formula are readily obtainable by methods and protocols known in the chemical art. The protection of the unsaturated compounds of formula (a) is carried out under suitable conditions allowing cyclization using a suitable reagent such as mercuric acetate in an inert solvent such as tetrahydrofuran (THF) resulting in the protected aminoalcohol of formula (b).
Krok 2: Chránený aminoalkohol vzorca (b) sa oxiduje za použitia vhodného oxidujúceho činidla, tak ako je komplex pyridín - kysličník sírový vo vhodnom rozpúšťadle, takom ako je dichlórmetán alebo dimetylformamid, výsledkom čoho je chránený aminoaldehyd vzorca (c). Alternatívne, intermediát (C) môže byť vyrobený ozonolýzou zlúčeniny vzorca (a') pripravenej podľa Colladó et al., J.Org.Chem. 1995, 60:5011.Step 2: The protected aminoalcohol of formula (b) is oxidized using a suitable oxidizing agent such as pyridine-sulfur trioxide complex in a suitable solvent, such as dichloromethane or dimethylformamide, resulting in the protected aminoaldehyde of formula (c). Alternatively, intermediate (C) can be produced by ozonolysis of a compound of formula (a ') prepared according to Collado et al., J. Org. 1995, 60: 5011.
Krok 3: Aminoaldehyd vzorca (c) je chránený spojením s alkylesterom aminokyseliny vzorca (d), za najprv vytvorenia imínu, následne získaný imín sa dá do vhodného Činidla, ako je triacetoxy tetrahydroboritan sodný NABH(OAc) čím sa získa cyklický intermediát vzorca (e)Step 3: The amino aldehyde of formula (c) is protected by coupling with an alkyl ester of the amino acid of formula (d), first forming the imine, then the imine obtained is added to a suitable reagent such as sodium triacetoxy borohydride NABH (OAc) to give the cyclic intermediate of formula )
Krok 4: Cyklický intermediát vzorca (e) je funkcionalizovaný v amino pozícii, výťažkom čoho je amino substituovaný cyklický intermediát vzorca (f). Vhodné podmienky pre takéto reakcie sú dobre známe a budú závisieť od povahy substituenta R*.Step 4: The cyclic intermediate of formula (e) is functionalized at the amino position, yielding an amino substituted cyclic intermediate of formula (f). Suitable conditions for such reactions are well known and will depend on the nature of the substituent R *.
Krok 5: Ochranná aminoskupina cyklického intermediátu vzorca (f) je odstránená za vhodných podmienok, a výsledná zlúčenina je potom za vhodných podmienok podrobená vnútornému uzavretiu kruhu, tak ako zahriatím pri nízkej teplote v inertnom rozpúšťadle, alebo ako surová zlúčenina, výsledkom čoho je bicyklický intermediát vzorca (g). Bicyklický intermediát vzorca (g) môže byť tiež získaný hydrolýzou esterovej funkčnej skupiny (-QOjO-R?,,) cyklickéhoStep 5: The amino protecting group of the cyclic intermediate of formula (f) is removed under suitable conditions, and the resulting compound is then subjected to internal ring closure under appropriate conditions, such as by heating at low temperature in an inert solvent or as a crude compound, resulting in a bicyclic intermediate of formula (g). The bicyclic intermediate of formula (g) may also be obtained by hydrolysis of the ester function (-QO 10 -R 7) of the cyclic ring.
-60intermediátu vzorca (g) za uvoľnenie karboxylovej skupiny, po čom nasleduje spojenie so štandartným peptidom pri použití vhodného zlučovacieho činidla, akým je benzotriazol-l-yloxytris-(dimetylamino) fosfónium hexafluórfosfát (BOP), v inertnom rozpúšťadle tak ako je dimetyl formamid (DMF).An intermediate of formula (g) to release the carboxyl group, followed by coupling with the standard peptide using a suitable coupling agent such as benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), in an inert solvent such as dimethyl formamide ( DMF).
Krok 6: Esterová funkčná skupina (-CfOjO-R^j ) bicyklického intermediátu vzorca (g) je potom podrobená hydrolýze sa použitia vhodného činidla, ako je HCI, vo vhodnom rozpúšťadle, ako je etyléter výsledkom čoho je voľná karboxylová kyselina. Výsledná zlúčenina je potom pripojená na RiH pomocou peptidového spojovacieho činidla ako BOP vo vhodnom rozpúšťadle, tak ako je DMF výsledkom čoho je, bicyklická zložená zlúčenina vzorca (VHI). Vhodné podmienky pre vznik peptidickej väzby sú dobre známe v peptidovej chémii. Napr. viď Principál of Peptide Šynthesis, Bodanszky M., Springer-Verlag, Berlin, Heidelberg, New York, Tokyo 1984; and The Peptides Analvsis. Synthesis. Biology, Vol. 1. edited by Gross E., and Meienhofer J., Academiec Press, New York, San Francisko, London, 1979.Step 6: The ester function of the (-CfO 3 O-R 6) bicyclic intermediate of formula (g) is then subjected to hydrolysis using a suitable reagent such as HCl in a suitable solvent such as ethyl ether resulting in the free carboxylic acid. The resulting compound is then coupled to R 1 H using a peptide coupling reagent such as BOP in a suitable solvent such as DMF resulting in a bicyclic compound of formula (VHI). Suitable conditions for peptide bond formation are well known in peptide chemistry. E.g. see Principal of Peptide Synthesis, M. Bodanszky, Springer-Verlag, Berlin, Heidelberg, New York, Tokyo 1984; and The Peptides Analvsis. Synthesis. Biology, Vol. 1. edited by Gross E., and Meienhofer J., Academiec Press, New York, San Francisco, London, 1979.
Na prípravu zlúčenín vzorca (D<) môžu byť použité rôzne metódy v závislosti na použitom východiskovom materiáli a/alebo vznikajúcich intermediátoch. Nasledovná schéma je jedna z možných spôsobov prípravy.Various methods may be used to prepare the compounds of formula (D <) depending on the starting material used and / or the intermediates formed. The following scheme is one possible preparation.
Schéma 3Scheme 3
bb
KROK 1STEP 1
----------►---------- ►
MeOMeO
Y= S-Pg NH-PgY = S-Pg NH-Pg
II
oabout
KROK 3STEP 3
cC
-61 kde:-61 where:
Pg je sírová, alebo amínová ochranná skupina;Pg is a sulfur or amine protecting group;
L je odchádzajúca skupina každá R20 a ^21 nezav*s^e C alkyl; a Rj > R y Rj, a R- sú definované predtým.L is a leaving group, each R 20 and R 21 nezav ^ * ^ p and C alkyl; and R j> R y R j, and R 8 are as previously defined.
Postup zobrazený v schéme 2 je v krátkosti opísaný nasledovne:The procedure shown in Scheme 2 is briefly described as follows:
KROK 1:STEP 1:
Karboxylová zlúčenina (a) sa pripojí na cyklickú amínovú zlúčeninu (b) pomocou peptidového spojovacieho činidla tak ako je benzotriazol-l-yloxy-tris-(dimetylamino)fosfónium hexafluórfosfát (BOP činidlo) v prítomnosti bázy, takej ako je n-metylmorfolín vo vhodnom rozpúšťadle, takom ako je dimetylformamid (DMF) alebo dichlorometán (DCM) výsledkom čoho je zlúčenina amidu vzorca (c). Vhodné podmienky na tvorbu peptidickej väzby sú v chémii peptidov dobre známe. Napr. viď Principál of Peptide Synthesis, Bodanszkv M., Springer-Verlag, Berlín, Heidelberg, New York, Tokyo 1984; and The Peptides Analysis, Synthesis, Biology, Vol. 1. edited by Gross E., and Meienhofer J., Academiec Press, New York, San Francisko, London, 1979.The carboxylic compound (a) is coupled to the cyclic amine compound (b) by a peptide coupling reagent such as benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) in the presence of a base such as n-methylmorpholine in a suitable a solvent such as dimethylformamide (DMF) or dichloromethane (DCM) to give the amide compound of formula (c). Suitable conditions for peptide bond formation are well known in peptide chemistry. E.g. see Principal of Peptide Synthesis, M. Bodanszkv, Springer-Verlag, Berlin, Heidelberg, New York, Tokyo 1984; and The Peptides Analysis, Synthesis, Biology, Vol. 1. edited by Gross E., and Meienhofer J., Academiec Press, New York, San Francisco, London, 1979.
KROK 2:STEP 2:
Zlúčenina vzorca (c) je podrobená vhodným podmienkam dovoľujúcim vnútornú cyklizáciu výsledkom čoho je bicyklický intermediát vzorca (d). Napr. cyklizácia sprostredkovaná kyselinou, za použitia p-toluénsulfónovej kyseliny, alebo TFA vo vhodnom rozpúšťadle, takom ako je dichlóretán.The compound of formula (c) is subjected to suitable conditions allowing internal cyclization resulting in a bicyclic intermediate of formula (d). E.g. acid mediated cyclization using p-toluenesulfonic acid, or TFA in a suitable solvent such as dichloroethane.
KROK 3:STEP 3:
Esterovaná funkčná skupina (-C(O)O-R) bicyklického intermediátu vzorca (d) sa podrobí hydrolýze za použitia vhodného činidla, tak ako je hydroxid lítny (LiOH) vo vhodnom rozpúšťadle, takým ako tetrahydrofurán (THF) výsledkom čoho je voľná karboxylová kyselina. Výsledná zlúčenina je potom pripojená na P.H. pomocou peptid spájajúceho činidla, tak ako je BOP vo vhodnom rozpúšťadle, takom ako je DMF, za vzniku zlúčeniny (e). Vhodné podmienky pre tvorbu peptidickej väzby sú v chémii peptidov dobre známe. Napr. viď Principál of Peptide Synthesis, Bodanszkv M., Springer-Verlag, Berlin, Heidelberg, New York, Tokyo 1984; and The Peptides Analysis, Synthesis. Biology. Vol, 1, edited by Gross E., and Meienhofer J., Academiec Press, New York, San Francisko, London, 1979.The esterified functional group (-C (O) O-R) of the bicyclic intermediate of formula (d) is subjected to hydrolysis using a suitable reagent such as lithium hydroxide (LiOH) in a suitable solvent such as tetrahydrofuran (THF) resulting in the free carboxylic acid. The resulting compound is then coupled to P.H. using a peptide coupling agent such as BOP in a suitable solvent such as DMF to give compound (e). Suitable conditions for peptide bond formation are well known in peptide chemistry. E.g. see Principal of Peptide Synthesis, M. Bodanszkv, Springer-Verlag, Berlin, Heidelberg, New York, Tokyo 1984; and The Peptides Analysis, Synthesis. Biology. Vol. 1, edited by Gross E., and Meienhofer J., Academiec Press, New York, San Francisco, London, 1979.
Na izoláciu zlúčenín vzorca (IX) sa môžu použiť rôzne postupy v závislosti na danom štartovacom materiály a/alebo na vznikajúcich intermediátoch.Various procedures can be used to isolate the compounds of formula (IX) depending on the starting material and / or the intermediates formed.
-62 Nasledovná schéma 4 je jedna z možných spôsobov prípravy.-62 The following scheme 4 is one of the possible preparation methods.
SCHÉMA 4SCHEME 4
KROK 1STEP 1
KROK 4 ’STEP 4 ’
TT
-63Kde:-63Kde:
každá z a je nezávisle alkyl; a B, R* , R j, R*, a sú definované ako predtým. Postup načrtnutý v schéme 4 je v krátkosti opísaný nasledovne:Zaj much each independently alkyl; and B, R *, Rj, R *, and are defined as before. The procedure outlined in Scheme 4 is briefly described as follows:
KR0K1:KR0K1:
Halogénovaná zlúčenina vzorca (a) je premenená na halogénmetyl ketón vzorca (b) za použitia vhodného činidla, takého ako je diazometán, v inertnom rozpúšťadle, takom ako je dietyléter pri teplote okolo -25 °C až 0 °C. Výsledná zmes sa potom podrobí kyslým podmienkam za vzniku halogénmetyl ketónu vzorca (b).The halogenated compound of formula (a) is converted to a halomethyl ketone of formula (b) using a suitable reagent such as diazomethane in an inert solvent such as diethyl ether at a temperature of about -25 ° C to 0 ° C. The resulting mixture is then subjected to acidic conditions to form a halomethyl ketone of formula (b).
KROK 2:STEP 2:
Halogénmetyl ketón vzorca (b) je spojený s alkylesterom aminokyseliny vzorca (c) s vhodnou bázou, takou ako je kyanotetrahydroboritan sodný v organickom rozpúšťadle, takom ako je metanol (MeOH) za vzniku cyklického intermediátu vzorca (d).The halomethyl ketone of formula (b) is coupled with an alkyl ester of the amino acid of formula (c) with a suitable base such as sodium cyanotetraborohydride in an organic solvent such as methanol (MeOH) to form the cyclic intermediate of formula (d).
KROK 3:STEP 3:
Cyklický intermediát vzorca (d) sa spracuje za kyslých podmienok použitím vhodnej kyseliny, takej ako je gáforsulfónová kyselina vo vhodnom rozpúšťadle takom ako je toluén, za vzniku intermediátu vzorca (e)The cyclic intermediate of formula (d) is treated under acidic conditions using a suitable acid such as camphorsulfonic acid in a suitable solvent such as toluene to give the intermediate of formula (e)
KROK 4:STEP 4:
Esterová funkčná skupina (-C(O)O-R2q ) bicyklického intermediátu vzorca (e) sa potom podrobí hydrolýze za použitia vhodného činidla, ako je LiOH, výsledkom čoho je voľná karboxylová kyselina. Výsledná zlúčenina sa potom pripojí na R^g pomocou peptidového spojovacieho činidla ako BOP vo vhodnom rozpúšťadle tak ako je dimetylformamid výsledkom čoho je, bicyklická spojená zlúčenina vzorca (X). Vhodné podmienky pre vznik peptidickej väzby sú dobre známe v peptidovej chémii. Napr. viď Principál of Peptide Svnthesis. Bodanszky M., Springer-Verlag, Berlín, Heidelberg, New York, Tokyo 1984; and The Peptides Analysis, Svnthesis, Biology, Vol.The ester function of the (-C (O) O-R 2q) bicyclic intermediate of formula (e) is then subjected to hydrolysis using a suitable reagent such as LiOH to give the free carboxylic acid. The resulting compound is then coupled to R 1g using a peptide coupling reagent such as BOP in a suitable solvent such as dimethylformamide resulting in a bicyclic coupled compound of formula (X). Suitable conditions for peptide bond formation are well known in peptide chemistry. E.g. see Principal of Peptide Svnthesis. Bodanszky M., Springer-Verlag, Berlin, Heidelberg, New York, Tokyo 1984; and The Peptides Analysis, Svnthesis, Biology, Vol.
1. edited by Gross E., and Meienhofer J., Academiec Press, New York, San Francisko, London, 1979.1. edited by Gross E., and Meienhofer J., Academiec Press, New York, San Francisco, London, 1979.
Zlúčeniny predkladaného vynálezu sa ďalej vyznačujú podľa ich schopností inhibovať katalytickú aktivitu trombínu, ktorá je vysvetlená v nasledovnom stanovení. Zlúčeniny predkladaného vynálezu môžu sa pripraviť na stanovenie ich rozpustením v tlmivom roztoku s výslednou koncentráciou od 1 do ΙΟΟμΜ. Na stanovenie inhibičnej disociačnej konštanty K-64daných zlúčenín, sa do roztoku obsahujúceho skúšané zlúčeniny a trombín, pridá chromogénny alebo fluorogénny substrát trombínu; Výsledná katalytická aktivita enzýmu sa stanoví spektrofotometricky. Tento typ stanovenia je u kvalifikovaných ľudí v tomto odbore dobre známy.The compounds of the present invention are further characterized by their ability to inhibit the catalytic activity of thrombin as explained in the following assay. The compounds of the present invention may be prepared for their determination by dissolving in a buffer with a final concentration of 1 to ΙΟΟμΜ. To determine the inhibitory dissociation constant of K-64 given compounds, a chromogenic or fluorogenic thrombin substrate is added to a solution containing the test compounds and thrombin; The resulting catalytic activity of the enzyme is determined spectrophotometrically. This type of assay is well known in the art for those skilled in the art.
Zlúčeniny predkladaného vynálezu môžu byť použité ako antikoagulanty in vivo alebo ex vitro pre prípad kontaktnej aktivácie s cudzím trombogénnym povrchom, ktorý by sa nachádzal v hadici použitej na mimotelový obeh. Zlúčeniny predkladaného vynálezu sa môžu tiež použiť ako povrchový obal takýchto trombogénnych hadíc. Nakoniec, zlúčeniny predkladaného vynálezu sa získajú ako lyofilizovaný prášok, znovu rozpustia v izotonickej fyziologickom roztoku a pridajú v dostatočnom množstve do krvi udržiavanej v antikoagulačnom stave.The compounds of the present invention may be used as anticoagulants in vivo or ex vitro in the event of contact activation with a foreign thrombogenic surface that would be contained in a hose used for extracorporeal circulation. The compounds of the present invention may also be used as surface coatings for such thrombogenic hoses. Finally, the compounds of the present invention are obtained as a lyophilized powder, redissolved in isotonic saline and added in a sufficient amount to the blood maintained in the anticoagulant state.
Liečebné látky predkladaného vynálezu sa môžu podávať samotné, alebo s vhodným farmaceutický akceptovateľným nosičom. Podiel každého nosiča je určený rozpustnosťou a chemickou povahou zlúčeniny, akou cestou je podávaný a štandardnou farmaceutickou praxou. Napr. zlúčeniny môžu byť parenterálne vstrekované, a to môže byť vnútrosvalovo, vnútrožilovo alebo podkožné. Pre parenterálne podávanie, zlúčeniny môžu byť použité vo forme sterilných roztokov obsahujúcich iné roztoky, napr. vhodný fyziologický roztok alebo glukózu, aby bol roztok izotonický. Zlúčeniny môžu byť podávané orálne vo forme tabletiek, kapsúl, alebo granúl obsahujúcich vhodné vehikulum tak ako je škrob, laktóza, biely cukor a podobne. Zlúčeniny môžu byť tiež podávané pod jazyk vo forme tabliet, piluliek alebo pastiliek v ktorých každá aktívna zložka je zmiešaná s cukrom alebo žitnými sirupmi, príchuťovými činidlami a farbivami, a potom sa urobí dostatočne dehydratovaná zmes vhodná na lisovanie do pevnej formy. Zlúčeniny môžu byť podané orálne vo forme roztoku, ktorý môže obsahovať farbiace a/alebo príchuťové látky.The therapeutic agents of the present invention may be administered alone or with a suitable pharmaceutically acceptable carrier. The proportion of each carrier is determined by the solubility and chemical nature of the compound by which it is administered and standard pharmaceutical practice. E.g. the compounds may be parenterally injected, and it may be intramuscular, intravenous or subcutaneous. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutions, e.g. appropriate saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing a suitable vehicle such as starch, lactose, white sugar and the like. The compounds may also be administered sublingually in the form of tablets, pills or lozenges in which each active ingredient is mixed with sugar or rye syrups, flavoring agents and coloring agents, and then a sufficiently dehydrated mixture suitable for compression into solid form is made. The compounds may be administered orally in the form of a solution, which may contain coloring and / or flavoring agents.
Lekári určia dávku danej liečebnej látky, ktorá bude najvhodnejšia. Dávky môžu byť rôzne podľa spôsobu podania a konkrétnej vybranej zlúčeniny. Okrem toho, dávka môže byť rôzna podľa daných podmienok u konkrétneho pacienta.Physicians will determine the dose of the active substance that is most appropriate. Dosages may vary depending on the route of administration and the particular compound selected. In addition, the dosage may vary according to the conditions of the particular patient.
Ak zmes je podaná orálne, tak sa je potrebné väčšie množstvo aktívnej látky, aby mala taký istý účinok, ako keď sa podá parenterálne.If the composition is administered orally, more active substance is required to have the same effect as when administered parenterally.
Pre ďalšie vysvetlenie predloženého vynálezu nasleduje poskytnutie neobmedzeného množstva príkladov takýchto zlúčenín inhibujúcich trombín. Nasledujúce príklady, samozrejme,To further explain the present invention, it follows to provide an unlimited number of examples of such thrombin inhibiting compounds. The following examples, of course,
-65nemôžu obmedzovať rozsah predloženého vynálezu, obmeny v súčasnosti známe alebo neskoršie vyvinuté budú vzhľadom na dosah odborníka z danej oblasti považované, že spadajú do rozsahu uvedeného vynálezu opísaného predtým. Výhodné zlúčeniny podľa vynálezu sú syntetizované za použitia bežných preparatívnych krokov a postupov známym odborníkom z oblasti organickej a bioorganickej syntézy, súčasne poskytujúc nové a unikátne kombinácie pre celkovú syntézu každej zlúčeniny. Výhodné syntetické cesty pre medziprodukty zahrňujú v syntézach okrem toho výsledné antitrombotické zlúčeniny podľa predloženého vynálezu.They will not limit the scope of the present invention, variations currently known or later developed will be considered to be within the scope of the present invention described previously, given the skill of the art. Preferred compounds of the invention are synthesized using conventional preparative steps and procedures known to those skilled in the art of organic and bioorganic synthesis, while providing novel and unique combinations for the overall synthesis of each compound. Preferred synthetic routes for intermediates include, in addition, the resulting antithrombotic compounds of the present invention in the syntheses.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
Roztok terc.butyloxokarbonyl-jodo-alanín-N,O-dimetylamidu (2,65 g, 7.5 mmól) (J.Org.Chem. 1992, 57, 3397-3404) v bezvodom benzéne (30 ml), a bezvodý N,Ndimetylacetamid (2,0 ml) sa dali na spodok okrúhlej, dusíkom premytej banky naplnenej s dvojicou zinok/meď (0,9 g). Výsledná zmes je sonifikovaná pod dusíkom, pokial nezostane žiadny štartovací matéria! (zisťované pomocou tenko-vrstvovej chromatografie). Potom sa pridá bis-(tri-o-tolylfosfin) chlorid paladnatý (0,35 g, 0,40 mmól), a za ním 4-jódbenzonitril (1,72 g, 7,5 mmol). Výsledná zmes sa miešala v dusíkovej atmosfére za zahrievania, následného ochladenia, a potom sa pridá acetát etylnatý (100 ml) a zmes sa filtruje cez deliaci lievik. Jalej je premývaná s HCI (50 ml, 0,lN), destilovanou vodou (3 x 50 ml, a vysušená nad Na2SO^, filtrovaná, koncentrovaná za zníženého tlaku, výsledkom čoho je surový produkt. Rýchla chromatografia cez silikagél (petroéter - etylacetátový gradient) poskytuje purifikovanú zlúčeninu.A solution of tert-butyloxycarbonyl-iodo-alanine-N, O-dimethylamide (2.65 g, 7.5 mmol) (J. Org. Chem. 1992, 57, 3397-3404) in anhydrous benzene (30 mL), and anhydrous N, The dimethylacetamide (2.0 mL) was placed on the bottom of a round, nitrogen-purged flask filled with a zinc / copper pair (0.9 g). The resulting mixture is sonicated under nitrogen until no starting material remains! (as determined by thin-layer chromatography). Palladium (II) bis- (tri-o-tolylphosphine) (0.35 g, 0.40 mmol) was then added followed by 4-iodobenzonitrile (1.72 g, 7.5 mmol). The resulting mixture was stirred under nitrogen with heating followed by cooling, and then ethyl acetate (100 mL) was added and the mixture was filtered through a separatory funnel. It is further washed with HCl (50 mL, 0.1 N), distilled water (3 x 50 mL, and dried over Na 2 SO 4, filtered, concentrated under reduced pressure to give a crude product.) Flash chromatography over silica gel (petroether-ethyl acetate gradient) ) provides the purified compound.
-66Roztok terc. butyloxykarbonyl-jodo-alanín-N,O-dimetylamidu (2,65 g, 7,5 mmól) (J.Org.Chem. 1992, 57, 3397-3404) v bezvodom benzéne (30 ml), a bezvodý N,N-dimetylacetamid (2,0 ml) boli dané na spodok okrúhlej, dusíkom premytej banky naplnenej s dvojicou zinok/meď (0,9 g).Výsledná zmes sa sonifíkovala pod dusíkom, pokial nezostane žiadny štartovací materiál (zisťované pomocou tenko-vrstvovej chromatografíe). Potom sa pridá bis-(tri-o-tolylfosfín) chlorid paládnatý (0,35 g, 0,40 mmól), a za ním 3-jódbenzonitril (1,72 g, 7,5 mmôl). Výsledná zmes sa miešala v dusíkovej atmosfére za zahrievania, následného ochladenia, a potom sa pridá acetát etylnatý (100 ml) a zmes sa filtruje cez deliaci lievik. Ďalej sa premývala s HCI (50 ml, 0,lN), destilovanou vodou (3 x 50 ml, a vysušila nad IS^SO^ filtrovala, koncentrovala za zníženého tlaku, výsledkom čoho je surový produkt. Rýchla chromatografia cez silikagél (petroléter - etylacetátový gradient) poskytuje purifikovanú zlúčeninu.-66Tert solution. butyloxycarbonyl-iodo-alanine-N, O-dimethylamide (2.65 g, 7.5 mmol) (J.Org.Chem. 1992, 57, 3397-3404) in anhydrous benzene (30 mL), and anhydrous N, N -dimethylacetamide (2.0 mL) was placed on the bottom of a round, nitrogen purged flask filled with zinc / copper (0.9 g). The resulting mixture was sonicated under nitrogen until no starting material remained (detected by thin layer chromatography). . Palladium (II) bis (tri-o-tolylphosphine) chloride (0.35 g, 0.40 mmol) was then added followed by 3-iodobenzonitrile (1.72 g, 7.5 mmol). The resulting mixture was stirred under nitrogen with heating followed by cooling, and then ethyl acetate (100 mL) was added and the mixture was filtered through a separatory funnel. It was further washed with HCl (50 mL, 0.1 N), distilled water (3 x 50 mL), and dried over IS 2 SO 4, filtered, concentrated under reduced pressure to give a crude product. Flash chromatography over silica gel (petroleum ether-ethyl acetate) gradient) provides the purified compound.
Roztok terc.butyloxokarbonyl-jodo-alanín-N,0-dimetylamidu (2,65 g, 7,5 mmól) (J.Org.Chem. 1992, 57, 3397-3404) v bezvodom benzéne (30 ml), a bezvodý N,N-dimetylacetamid (2,0 ml) sa dali na spodok okrúhlej, dusíkom premytej banky naplnenej s dvojicou zinok/meď (0,9 g).Výsledná zmes sa sonifíkovala pod dusíkom, pokial nezostane žiadny štartovací materiál (zisťované pomocou tenko-vrstvovej chromatografíe). Potom je pridaný bis-(tri-o-tolylfosfín) chlorid paladnatý (0,35 g, 0,40 mmól), a za ním 2-jódbenzonitril (1,72 g, 7,5 mmôl). Výsledná zmes sa miešala v dusíkovej atmosfére za zahrievania, následného ochladenia, a potom sa pridá acetát etylnatý (100 ml) a zmes sa filtruje cez deliaci lievik. Ďalej sa zmes premývala s HCI (50 ml, 0,lN), destilovanou vodou (3 x 50 ml, a vysušila nad l^SC^, filtrovala, koncentrovala za zníženého tlaku, výsledkom čoho bol surový produkt. Rýchla chromatografia cez silikagél (petroéter - etylacetátový gradient) poskytuje purifikovanú zlúčeninu.A solution of tert-butyloxycarbonyl-iodo-alanine-N, O-dimethylamide (2.65 g, 7.5 mmol) (J. Org. Chem. 1992, 57, 3397-3404) in anhydrous benzene (30 mL), and anhydrous N, N-dimethylacetamide (2.0 mL) was placed on the bottom of a round, nitrogen-purged flask filled with a zinc / copper pair (0.9 g). The resulting mixture was sonicated under nitrogen until no starting material remained (detected by thin-layer chromatography). layer chromatography). Then, bis- (tri-o-tolylphosphine) palladium (II) chloride (0.35 g, 0.40 mmol) is added, followed by 2-iodobenzonitrile (1.72 g, 7.5 mmol). The resulting mixture was stirred under nitrogen with heating followed by cooling, and then ethyl acetate (100 mL) was added and the mixture was filtered through a separatory funnel. Next, the mixture was washed with HCl (50 mL, 0.1 N), distilled water (3 x 50 mL, and dried over 1 SO 4, filtered, concentrated under reduced pressure to give a crude product. Flash chromatography over silica gel (petroether) (ethyl acetate gradient) provides the purified compound.
-67K roztoku terc-butyloxykarbonyl-p<7r<7-kyanofenylalanín-N,O-dimetylamidu (1,33 g, 4,0 mmólu) v bezvodom etanole (20 ml) sa pridal hydroxylamín hydrochlorid (0,416 g, 6,0 mmól), a diizopropyletylamín (1,02 ml, 6,0 mmól). Zmes sa refluxovala a potom ochladila. Zrazenina bola filtrovaná, premývaná so chladeným etanolom, diizopropyl éterom, vysušená s MgSO^, zahustená za zníženého tlaku a použitá priamo k ďalšiemu kroku. Polotuhá bola suspendovaná do zmesi kyselina octová (20 ml) a bezvodý etanol (40 ml) za zahrievania. . Následne bol pridaný katalyzátor Pd/C (0,30 g, 10% Pd) a cez zmes sa za zahrievania prebublával vodík. Hydrogenácia pokračovala, až pokiaľ nebol žiadny štartovací materiál detekovateľný pomocou tenkovrstvovej chromatografie. Katalyzátor bol odstránený filtráciou, roztok bol koncentrovaný za zníženého tlaku (50 ml) a bola pridaná HCI (50 ml), a zmes zas bola skoncentrovaná na 50 ml. Roztok sa zmrazil cez noc za vzniku titulnej zlúčeniny.-67K To a solution of tert-butyloxycarbonyl-β 7 R -7-cyanophenylalanine-N, O-dimethylamide (1.33 g, 4.0 mmol) in anhydrous ethanol (20 mL) was added hydroxylamine hydrochloride (0.416 g, 6.0 mmol). and diisopropylethylamine (1.02 mL, 6.0 mmol). The mixture was refluxed and then cooled. The precipitate was filtered, washed with cold ethanol, diisopropyl ether, dried with MgSO 4, concentrated under reduced pressure and used directly for the next step. The semi-solid was suspended in a mixture of acetic acid (20 mL) and anhydrous ethanol (40 mL) with heating. . Subsequently, Pd / C catalyst (0.30 g, 10% Pd) was added and hydrogen was bubbled through the mixture while heating. Hydrogenation was continued until no starting material was detectable by thin layer chromatography. The catalyst was removed by filtration, the solution was concentrated under reduced pressure (50 mL) and HCl (50 mL) was added, and the mixture was again concentrated to 50 mL. The solution was frozen overnight to give the title compound.
K roztoku terc-butyloxykarbonyl-mern-kyanofenylalanín-N,O-dimetylamidu (1,33 g, 4,0 mmólu) v bezvodom etanole (20 ml) sa pridal hydroxylamín hydrochlorid (0,416 g, 6,0 mmól), a diizopropyletylamín (1,02 ml, 6,0 mmól). Zmes sa refluxovala a potom ochladila. Zrazenina bola filtrovaná, premytaná s chladeným etanolom, diizopropyl éterom, vysušená s MgSO^, zahustená za zníženého tlaku a použitá priamo k ďalšiemu kroku. Polotuhá sa suspendovala do zmesi kyselina octová (20 ml) a bezvodý etanol (40 ml) za zahrievania. Následne sa pridal katalyzátor Pd/C (0,30 g, 10% Pd) a cez zmes sa za zahrievania prebublával vodík. Hydrogenácia pokračovala, až pokiaľ nebol žiadny štartovací materiál detekovateľný pomocou tenkovrstvovej chromatografie. Katalyzátor sa odstránil filtráciou, roztok sa koncentroval za zníženého tlaku (50 ml) a bola pridaná HCI (50 ml), a zmes zas bola skoncentrovaná na 50 ml. Roztok sa zmrazil cez noc za vzniku titulnej zlúčeniny.To a solution of tert-butyloxycarbonyl-m -cyanophenylalanine-N, O-dimethylamide (1.33 g, 4.0 mmol) in anhydrous ethanol (20 mL) was added hydroxylamine hydrochloride (0.416 g, 6.0 mmol), and diisopropylethylamine ( 1.02 ml, 6.0 mmol). The mixture was refluxed and then cooled. The precipitate was filtered, washed with cold ethanol, diisopropyl ether, dried with MgSO 4, concentrated under reduced pressure and used directly for the next step. The semi-solid was suspended in a mixture of acetic acid (20 mL) and anhydrous ethanol (40 mL) with heating. Subsequently, Pd / C catalyst (0.30 g, 10% Pd) was added and hydrogen was bubbled through the mixture while heating. Hydrogenation was continued until no starting material was detectable by thin layer chromatography. The catalyst was removed by filtration, the solution was concentrated under reduced pressure (50 mL) and HCl (50 mL) was added, and the mixture was again concentrated to 50 mL. The solution was frozen overnight to give the title compound.
-68K. roztoku terc.-butyloxykarbonyl-o/7o-kyanofenylalanín-N,O-dimetylamidu (1,33 g, 4,0 mmólu) v bezvodom etanole (20 ml) bol pridaný hydroxylamín hydrochlorid (0,416 g, 6,0 mmól), a diizopropyletylamín (1,02 ml, 6,0 mmól). Zmes bola refluxovaná a potom ochladená. Zrazenina bola filtrovaná, premývaná s chladeným etanolom, diizopropyl éterom, vysušená s MgSO^, zahustená za zníženého tlaku a použitá priamo k ďalšiemu kroku. Polotuhá bola suspendovaná do zmesi kyselina octová (20 ml) a bezvodý etanol (40 ml) za zahrievania. Následne sa pridal katalyzátor Pd/C (0,30 g, 10% Pd) a cez zmes sa za zahrievania prebublával vodík. Hydrogenácia pokračovala, až pokiaľ nebol žiadny východiskový materiál detekovateľný pomocou tenkovrstvovej chromatografie. Katalyzátor bol odstránený filtráciou, roztok bol koncentrovaný za zníženého tlaku (50 ml) a bola pridaná HCI (50 ml), a zmes sa zas skoncentrovala na 50 ml. Roztok sa zmrazil cez noc za vzniku titulnej zlúčeniny.-68K. A solution of tert-butyloxycarbonyl-η 7 -cyanophenylalanine-N, O-dimethylamide (1.33 g, 4.0 mmol) in anhydrous ethanol (20 mL) was added hydroxylamine hydrochloride (0.416 g, 6.0 mmol), and diisopropylethylamine (1.02 mL, 6.0 mmol). The mixture was refluxed and then cooled. The precipitate was filtered, washed with cold ethanol, diisopropyl ether, dried with MgSO 4, concentrated under reduced pressure and used directly for the next step. The semi-solid was suspended in a mixture of acetic acid (20 mL) and anhydrous ethanol (40 mL) with heating. Subsequently, Pd / C catalyst (0.30 g, 10% Pd) was added and hydrogen was bubbled through the mixture while heating. Hydrogenation was continued until no starting material was detectable by thin layer chromatography. The catalyst was removed by filtration, the solution was concentrated under reduced pressure (50 mL) and HCl (50 mL) was added, and the mixture was again concentrated to 50 mL. The solution was frozen overnight to give the title compound.
K roztoku tiazolu (1,28 g, 15,0 mmólu) v bezvodom tetrahydrofuráne (30 ml) sa pridal po kvapkách n - BuLi (1,6 M / hexán, 8,9 ml, 13,9 mmól) pri -78 °C, a roztok sa miešal. Potom sa pridal po kvapkách terc.-butylkarbonyl-/?(7/-íz-amidino-fenylalanín-N,O-dimetylamid (1,15 g, 3,3 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Zmes bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes sa zriedila s etylacetátom (150 ml), a organická vrstva sa premyla s nasýteným vodným roztokom chloridu amonného ( 2 x 50 ml), soľankou (50 ml), vysušila s MgSO^, filtrovala a zahustila za zníženého tlaku. Surový materiál sa purifíkoval na silikagéli (etylacetát /hexán) a koncentroval za zníženého tlaku.To a solution of the thiazole (1.28 g, 15.0 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise n-BuLi (1.6 M / hexane, 8.9 mL, 13.9 mmol) at -78 ° C, and the solution was stirred. Then tert-butylcarbonyl-N- (7H-amidino-phenylalanine-N, O-dimethylamide (1.15 g, 3.3 mmol) in tetrahydrofuran (15 mL) was added dropwise and the resulting mixture was stirred. The mixture was quenched with a saturated aqueous ammonium chloride solution, diluted with ethyl acetate (150 mL), and the organic layer was washed with a saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
-69K roztoku tiazolu (1,28 g, 15,0 mmólu) v bezvodom tetrahydrofuráne (30 ml) sa pridal po kvapkách n - BuLi (1,6 M / hexán, 8,9 ml, 13,9 mmól) pri -78 °C, a roztok sa miešal. Potom bol pridaný po kvapkách terc.-butylkarbonyl-/neta-amidino-fenylalanín-N,O-dimetylamid (1,15 g, 3,3 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Zmes bola rýchlo ochladené s nasýteným vodným roztokom chloridu amonného. Zmes bola nariedená s etylacetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál sa purifikoval na silikagéli (etylacetát /hexán) a koncentroval za zníženého tlaku.A -69K solution of thiazole (1.28 g, 15.0 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise to n-BuLi (1.6 M / hexane, 8.9 mL, 13.9 mmol) at -78 ° C, and the solution was stirred. Then tert-butylcarbonyl- / -eta-amidino-phenylalanine-N, O-dimethylamide (1.15 g, 3.3 mmol) in tetrahydrofuran (15 mL) was added dropwise and the resulting mixture was stirred. The mixture was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
K roztoku tiazolu (1,28 g, 15,0 mmólu) v bezvodom tetrahydrofuráne (30 ml) sa pridal po kvapkách n - BuLi (1,6 M / hexán, 8,9 ml, 13,9 mmól) pri -78 °C, a roztok sa miešal. Potom bol pridaný po kvapkách terc.- butylkarbonyl-orro-amidino-fenylalanín-N,O-dimetylamid (1,15 g, 3,3 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Zmes bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etyl acetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifikovaný na silikagéli (etylacetát /hexán) a koncentrovaný za zníženého tlaku.To a solution of the thiazole (1.28 g, 15.0 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise n-BuLi (1.6 M / hexane, 8.9 mL, 13.9 mmol) at -78 ° C, and the solution was stirred. Then tert-butylcarbonyl-orro-amidino-phenylalanine-N, O-dimethylamide (1.15 g, 3.3 mmol) in tetrahydrofuran (15 mL) was added dropwise and the resulting mixture was stirred. The mixture was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
- 70Terc. - Butyloxykarbonyl-para-kyano-fenylalanín-N,O-dimetylamidu (1,33 g, 4,0 mmólu ) bol rozpustený v etanole nasýtenom amoniakom (30 ml), a bol pridaný pórovitý Raneyov nikel (100 mg). Roztok bol miešaný na trepačke pod pri izbovej teplote (40 psi). Roztok bol filtrovaný cez celit a koncentrovaný za zníženého tlaku čím sa získal číry zvyšok. Zvyšok sa rozpustil v etylacetáte (250 ml), a premyl s 1 N NaOH (2 x 50 ml) a soľankou (2 x 50 ml). Roztok sa vysušil s MgSO^, filtroval a zahustil za zníženého tlaku.- 70Terc. Butyloxycarbonyl-para-cyano-phenylalanine-N, O-dimethylamide (1.33 g, 4.0 mmol) was dissolved in ethanol saturated with ammonia (30 mL), and porous Raney nickel (100 mg) was added. The solution was stirred on a shaker under room temperature (40 psi). The solution was filtered through celite and concentrated under reduced pressure to give a clear residue. The residue was dissolved in ethyl acetate (250 mL), and washed with 1 N NaOH (2 x 50 mL) and brine (2 x 50 mL). The solution was dried with MgSO 4, filtered, and concentrated under reduced pressure.
Terc. - butyloxykarbonyl-meta-kyano-fenylalanín-N,O-dimetylamidu (1,33 g, 4,0 mmólu ) sa rozpustil v etanole nasýtenom amoniakom (30 ml), a pridal sa pórovitý Raneyov nikel (100 mg). Roztok bol miešaný na trepačke pod pri izbovej teplote (40 psi). Roztok sa filtroval cez celit a koncentroval za zníženého tlaku čím sa získal číry zvyšok. Zvyšok sa rozpustil v etylacetáte (250 ml), a premyl s 1 N NaOH (2 x 50 ml) a soľankou (2 x 50 ml). Roztok sa vysušil s MgSO^, filtroval a zahustil za zníženého tlaku.T. butyloxycarbonyl-meta-cyano-phenylalanine-N, O-dimethylamide (1.33 g, 4.0 mmol) was dissolved in ethanol saturated with ammonia (30 mL), and porous Raney nickel (100 mg) was added. The solution was stirred on a shaker under room temperature (40 psi). The solution was filtered through celite and concentrated under reduced pressure to give a clear residue. The residue was dissolved in ethyl acetate (250 mL), and washed with 1 N NaOH (2 x 50 mL) and brine (2 x 50 mL). The solution was dried with MgSO 4, filtered, and concentrated under reduced pressure.
Terc. - butyloxykarbonyl-orto-kyano-fenylalanín-N,O-dimetylamidu (1,33 g, 4,0 mmólu ) sa rozpustil v etanole nasýtenom amoniakom (30 ml), a pridal sa pórovitý Raneyov nikel (100 mg). Roztok bol miešaný na trepačke pod H2 pri izbovej teplote (40 psi). Roztok sa filtroval cez celit a koncentroval za zníženého tlaku čím sa získal číry zvyšok. Zvyšok sa rozpustil v etylacetáte (250 ml), a premyl s 1 N NaOH (2 x 50 ml) a soľankou (2 x 50 ml). Roztok sa vysušil s MgSO^, filtroval a zahustil za zníženého tlaku.T. butyloxycarbonyl-ortho-cyano-phenylalanine-N, O-dimethylamide (1.33 g, 4.0 mmol) was dissolved in ethanol saturated with ammonia (30 mL), and porous Raney nickel (100 mg) was added. The solution was stirred on a shaker under H 2 at room temperature (40 psi). The solution was filtered through celite and concentrated under reduced pressure to give a clear residue. The residue was dissolved in ethyl acetate (250 mL), and washed with 1 N NaOH (2 x 50 mL) and brine (2 x 50 mL). The solution was dried with MgSO 4, filtered, and concentrated under reduced pressure.
terc - Butyloxykarbonyl-pŕ7rň-aminometyl-fenylalanm-N,O-dimetylamidu (1,00 g, 3,1 mmólu ) bol rozpustený v bezvodom tetrahydroftiráne (10 ml) za miešania pod dusíkom. Roztok bol chladený. Pridal sa Ν,Ν'-bis- (benzyloxykarbonyl)-S-metyl-izotiomočovina (1,14 g, 3,2 mmól) a HgC^ (0,95 g, 3,5 mmól). Roztok sa koncentroval za zníženého tlaku, zvyšok sa suspendoval v etylacetáte (200 ml) a sfiltroval cez celit. Filtrát sa zahustil za zníženého tlaku. Rýchla chromatografía cez silikagél (hexán / etylacetát) poskytla čistú zlúčeninu.tert-Butyloxycarbonyl-N-O-aminomethyl-phenylalanine-N, O-dimethylamide (1.00 g, 3.1 mmol) was dissolved in anhydrous tetrahydrophirane (10 mL) with stirring under nitrogen. The solution was cooled. N, N'-Bis- (benzyloxycarbonyl) -S-methyl-isothiourea (1.14 g, 3.2 mmol) and HgCl 2 (0.95 g, 3.5 mmol) were added. The solution was concentrated under reduced pressure, the residue was suspended in ethyl acetate (200 mL) and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane / ethyl acetate) gave the pure compound.
terc - Biityloxykarbonyl-w?eta-aminometyl-fenylalanin-N,O-dimetylamidu (1,00 g, 3,1 mmólu ) bol rozpustený v bezvodom tetrahydrofuráne (10 ml) za miešania pod dusíkom. Roztok bol chladený. Pridala sa Ν,Ν'-bis- (benzyloxykarbonyl)-S-metyl-izotiomočovina (1,14 g, 3,2 mmól) a HgC^ (0,95 g, 3,5 mmól). Roztok sa koncentroval za zníženého tlaku, získaný zvyšok bol suspendovaný do etylacetátu (200 ml), a filtrovaný cez celit. Filtrát bol zahustený za zníženého tlaku Rýchla chromatografía cez silikagél (hexán / etylacetát) poskytla čistú zlúčeninu.tert-Biityloxycarbonyl-ethanaminomethyl-phenylalanine-N, O-dimethylamide (1.00 g, 3.1 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) with stirring under nitrogen. The solution was cooled. N, N'-Bis- (benzyloxycarbonyl) -S-methyl-isothiourea (1.14 g, 3.2 mmol) and HgCl 2 (0.95 g, 3.5 mmol) were added. The solution was concentrated under reduced pressure, the obtained residue was suspended in ethyl acetate (200 mL), and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane / ethyl acetate) gave the pure compound.
OCHjOCH
HgCK/THFHgCK / THF
-72terc - Butyloxykarbonyl-o/7o-aminometyl-fenylalanín-N,O-dimetylamidu (1,00 g, 3,1 mmólu ) sa rozpustil v bezvodom tetrahydrofuráne (10 ml) za miešania pod dusíkom. Roztok bol chladený. Pridal sa Ν,Ν'-bis- (benzyloxykarbonyl)-S-metyl-izotiomočovina (1,14 g, 3,2 mmól) a HgC^ (0,95 g, 3,5 mmól). Roztok bol koncentrovaný za zníženého tlaku, získaný zvyšok bol suspendovaný do etylacetátu (200 ml), a filtrovaný cez celit. Filtrát bol zahustený za zníženého tlaku Rýchla chromatografia cez silikagél (hexán / etylacetát) poskytla čistú zlúčeninu.-72 tert-Butyloxycarbonyl-η 7o-aminomethyl-phenylalanine-N, O-dimethylamide (1.00 g, 3.1 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) with stirring under nitrogen. The solution was cooled. N, N'-Bis- (benzyloxycarbonyl) -S-methyl-isothiourea (1.14 g, 3.2 mmol) and HgCl 2 (0.95 g, 3.5 mmol) were added. The solution was concentrated under reduced pressure, the obtained residue was suspended in ethyl acetate (200 mL), and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane / ethyl acetate) gave the pure compound.
K roztoku tiazolu (1,28 g, 15 mmól) v bezvodom tetrahydrofuráne (30 ml) bol pridaný n BuLi (1,6 M / hexán, 8,9 ml, 13,9 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách chránená aminokyselina (1,36 g, 3,3 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amonného. Zmes bola nariedená s etylacetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amonného ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifikovaný na silikagéli (etylacetát / hexán) a koncentrovaný za zníženého tlaku.To a solution of thiazole (1.28 g, 15 mmol) in anhydrous tetrahydrofuran (30 mL) was added n BuLi (1.6 M / hexane, 8.9 mL, 13.9 mmol) at -78 ° C, and the solution was mixed. The protected amino acid (1.36 g, 3.3 mmol) in tetrahydrofuran (15 mL) was then added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
K roztoku tiazolu (1.28 g, 15 mmól) v bezvodom tetrahydrofuráne (30 ml) bol pridaný n BuLi (1,6 M / hexán, 8,9 ml, 13,9 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách chránená aminokyselina (1,36 g, 3,3 mmól) v tetrahydrofuráne (15 ml) a výslednáTo a solution of the thiazole (1.28 g, 15 mmol) in anhydrous tetrahydrofuran (30 mL) was added n BuLi (1.6 M / hexane, 8.9 mL, 13.9 mmol) at -78 ° C, and the solution was stirred. The protected amino acid (1.36 g, 3.3 mmol) in tetrahydrofuran (15 mL) was then added dropwise and the resulting
-73zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etyl acetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO4, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifíkovaný na silikagéli (etylacetát / hexán) a koncentrovaný za zníženého tlaku.The mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4 , filtered and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
1. Lítium tiazol/THF1. Lithium thiazole / THF
K roztoku tiazolu (1.28 g, 15 mmól) v bezvodom tetrahydrofuráne (30 ml) bol pridaný po kvapkách n - BuLi (1,6 M / hexan, 8,9 ml, 13,9 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách chránená aminokyselina (1,36 g, 3,3 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etylacetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amonného ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO4, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifíkovaný na silikagéli (etylacetát / hexán) a koncentrovaný za zníženého tlaku.To a solution of the thiazole (1.28 g, 15 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise n-BuLi (1.6 M / hexane, 8.9 mL, 13.9 mmol) at -78 ° C, and the solution was stirred. The protected amino acid (1.36 g, 3.3 mmol) in tetrahydrofuran (15 mL) was then added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4 , filtered and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
OCH,OCH
II
CH,CH,
Roztok terc - butyloxykarbonyI-jodo-alanín-N,O-dimetylamidu (2,65 g, 7,5 mmól) (J.Org.Chem. 1992, 57, 3397-3404) v bezvodom benzéne (30 ml), a bezvodý N,N dimetylacetamid (2,0 ml) boli dané na spodok okrúhlej, dusíkom premytej banky naplnenej s dvojicou zinok/meď (0,9 g).Výsledná zmes je sonifikovaná pod dusíkom, pokial nezostane žiadny štartovací materiál (zisťované pomocou tenko-vrstvovej chromatografie). Potom sa pridal bis-(tri -o-tolylfosfín) chlorid paladnatý (0,35 g, 0,40 mmól) a za ním 2-jódbenzonitril (1,72 g, 7,5 mmól). Výsledná zmes je miešaná v dusíkovej atmosfére za zahrievania, následného ochladenia, a potom sa pridá acetát etylnatý (100 ml) a zmes sa filtruje cez deliaci lievik. Ďalej je premývanáA solution of tert-butyloxycarbonyl-iodo-alanine-N, O-dimethylamide (2.65 g, 7.5 mmol) (J.Org.Chem. 1992, 57, 3397-3404) in anhydrous benzene (30 mL), and anhydrous N, N dimethylacetamide (2.0 mL) was placed on the bottom of a round, nitrogen purged flask filled with zinc / copper pair (0.9 g). The resulting mixture was sonicated under nitrogen until no starting material remained (detected by thin-layer analysis). chromatography). Then, bis- (tri-o-tolylphosphine) palladium (II) chloride (0.35 g, 0.40 mmol) was added followed by 2-iodobenzonitrile (1.72 g, 7.5 mmol). The resulting mixture is stirred under a nitrogen atmosphere with heating followed by cooling, and then ethyl acetate (100 mL) is added and the mixture is filtered through a separatory funnel. It is further washed
-74s HCI (50 ml, O,1N), destilovanou vodou (3 x 50 ml, a vysušená nad Na2SO4, filtrovaná, koncentrovaná za zníženého tlaku, výsledkom čoho je surový produkt. Rýchla chromatografia cez silikagél (petroléter - etylacetátový gradient) poskytuje purifikovanú zlúčeninu.HCl (50 mL, 0.1N), distilled water (3 x 50 mL, and dried over Na 2 SO 4 , filtered, concentrated under reduced pressure to give a crude product. Flash chromatography over silica gel (petroleum ether - ethyl acetate gradient) ) provides the purified compound.
K roztoku tiazolu (1.28 g, 15 mmôl) v bezvodom tetrahydrofuráne (30 ml) bol pridaný po kvapkách n - BuLi (1,6 M / hexan, 8,9 ml, 13,9 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách Ν,Ο-dimetylamid aminokyseliny (1,36 g, 3,3 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etyl acetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifikovaný na siiikagéli (etylacetát / hexán) a koncentrovaný za zníženého tlaku.To a solution of thiazole (1.28 g, 15 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise n-BuLi (1.6 M / hexane, 8.9 mL, 13.9 mmol) at -78 ° C, and the solution was stirred. Amino acid Ν, Ο-dimethylamide (1.36 g, 3.3 mmol) in tetrahydrofuran (15 mL) was then added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
1. Zn/Cu dvojica; ultrazvuk1. Zn / Cu pair; ultrasound
2. ío-CH.,C6H4)3PliPdCl2 2. IO CH., C 6 H 4) 2 3PliPdCl
2-kyano-S-bromopyridin2-cyano-S-bromopyridine
OABOUT
Roztok terc - butyloxykarbonyl-jodo-alanin-N,O-dimetylamidu (2,65 g, 7,5 mmól) (J.Org.Chem. 1992, 57, 3397-3404) v bezvodom benzéne (30 ml), a bezvodý N,N-dimetylacetamid (2,0 ml) boli dané na spodok okrúhlej, dusíkom premytej banky naplnenej s dvojicou zinok/meď (0,9 g). Výsledná zmes je sonifikovaná pod dusíkom, pokiaľ nezostane žiadny východiskový materiál (zisťované pomocou tenko-vrstvovej chromatografie). Potom je pridaný bis-(tri-o-tolylfosfm) chlorid paladnatý (0,35 g, 0,40 mmól), a za ním 2-jódobenzonitril (1,72 g, 7,5 mmól). Výsledná zmes je miešaná v dusíkovej atmosfére za zahrievania, následného ochladenia, a potom sa pridá acetát etylnatý (100 ml) a zmes sa filtruje cez deliaci lievik. Ďalej je premývaná s HCI (50 ml, 0,lN), destilovanou vodou (3 x 50 ml, a vysušená nad Na2SO^, filtrovaná, koncentrovaná za zníženého tlaku, výsledkom čoho je surový produkt. Rýchla chromatografia cez silikagél (petroléter - etylacetátový gradient) poskytuje purifikovanú zlúčeninu.A solution of tert-butyloxycarbonyl-iodo-alanine-N, O-dimethylamide (2.65 g, 7.5 mmol) (J. Org. Chem. 1992, 57, 3397-3404) in anhydrous benzene (30 mL), and anhydrous N, N-dimethylacetamide (2.0 mL) was placed on the bottom of a round, nitrogen-purged flask filled with a zinc / copper pair (0.9 g). The resulting mixture is sonicated under nitrogen until no starting material remains (as determined by thin layer chromatography). Palladium (II) bis (tri-o-tolylphosphine) chloride (0.35 g, 0.40 mmol) is then added, followed by 2-iodobenzonitrile (1.72 g, 7.5 mmol). The resulting mixture is stirred under a nitrogen atmosphere with heating followed by cooling, and then ethyl acetate (100 mL) is added and the mixture is filtered through a separatory funnel. It is further washed with HCl (50 mL, 0.1 N), distilled water (3 x 50 mL, and dried over Na 2 SO 4, filtered, concentrated under reduced pressure to give a crude product. Flash chromatography over silica gel (petroleum ether - ethyl acetate gradient) provides the purified compound.
K roztoku terc-butyloxykarbonyl-(4-kyano)-3-pyridylalanín-N,O-dimetylamid (1,34 g, 4,0 mmól) v bezvodom etanole bol pridaný Ν,Ο-hydroxylamín hydrochlorid (0,416 g, 6.0 mmól), a diizopropyletylamín (1,02 ml, 6,0 mmól). Zmes bola refluxovaná a potom ochladená. Zrazenina bola filtrovaná a premytá so studeným etanolom, diizopropyléterom, vysušená s MgSO^, zahustená za zníženého tlaku, a použitá priamo na ďalší krok. Polotuhá bola suspendovaná do zmesi kyselina octová (20 ml) a bezvodý etanol (40 ml) za zahrievania. . Následne sa pridal katalyzátor Pd/C (0,30 g, 10% Pd) a cez zmes sa za zahrievania prebublával vodík. Hydrogenácia pokračovala, až pokiaľ nebol žiadny štartovací materiál detekovateľný pomocou tenkovrstvovej chromatografie. Katalyzátor bol odstránený filtráciou, roztok bol koncentrovaný za zníženého tlaku (50 ml) a bola pridaná HCI (50 ml), a zmes zas bola zkoncentrovaná na 50 ml. Roztok bol zmrazený cez noc za vzniku titulnej zlúčeniny.To a solution of tert-butyloxycarbonyl- (4-cyano) -3-pyridylalanine-N, O-dimethylamide (1.34 g, 4.0 mmol) in anhydrous ethanol was added Ν, Ο-hydroxylamine hydrochloride (0.416 g, 6.0 mmol) , and diisopropylethylamine (1.02 mL, 6.0 mmol). The mixture was refluxed and then cooled. The precipitate was filtered and washed with cold ethanol, diisopropyl ether, dried with MgSO 4, concentrated under reduced pressure, and used directly for the next step. The semi-solid was suspended in a mixture of acetic acid (20 mL) and anhydrous ethanol (40 mL) with heating. . Subsequently, Pd / C catalyst (0.30 g, 10% Pd) was added and hydrogen was bubbled through the mixture while heating. Hydrogenation was continued until no starting material was detectable by thin layer chromatography. The catalyst was removed by filtration, the solution was concentrated under reduced pressure (50 mL) and HCl (50 mL) was added, and the mixture was again concentrated to 50 mL. The solution was frozen overnight to give the title compound.
K roztoku tiazolu (1.28 g, 15 mmól) v bezvodom tetrahydrofuráne (30 ml) sa pridal po kvapkách n - BuLi (1,6 M / hexán, 8,9 ml, 13,9 mmól) pri -78 °C, a roztok sa miešal. Potom bola pridaná po kvapkách Ν,Ο-dimetylamid aminokyseliny (1,16 g, 3,3 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etyl acetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifikovaný na silikagéli (etylacetát /hexán) a koncentrovaný za zníženého tlaku.To a solution of the thiazole (1.28 g, 15 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise n-BuLi (1.6 M / hexane, 8.9 mL, 13.9 mmol) at -78 ° C, and the solution was stirred. Amino acid Ν, Ο-dimethylamide (1.16 g, 3.3 mmol) in tetrahydrofuran (15 mL) was then added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
l.Hj.ľtOj/AcOHl.Hj.ľtOj / AcOH
terc-Butyloxykarbonyl-3-(4-pyridyl)alanín-N,O-dinietylamid (4,5 g, 14,4 mmól) bol rozpustený v kyseline octovej (100 ml), a bol pridaný PtO (100 mg). Roztok bol trepaný pod H? do jeho rt nasýtenia plynom. Roztok bol filtrovaný cez celit, a koncentrovaný za zníženého tlaku, za vzniku terc.-butyloxykarbonyl-3-(4-piperidyl)alanín-N,O-dimetylamid. Zvyšok bol rozpustený v etylacetáte (250 ml), premytý s 1 N NaOH (2 x 50 ml), soľankou (2x50 ml), vysušený s MgSO^ filtrovaný a zahustený za zníženého tlaku za vzniku titulnej zlúčeniny.tert-Butyloxycarbonyl-3- (4-pyridyl) alanine-N, O-diethylamide (4.5 g, 14.4 mmol) was dissolved in acetic acid (100 mL), and PtO (100 mg) was added. The solution was shaken under H ? to his rt gas saturation. The solution was filtered through celite, and concentrated under reduced pressure to give tert-butyloxycarbonyl-3- (4-piperidyl) alanine-N, O-dimethylamide. The residue was dissolved in ethyl acetate (250 mL), washed with 1 N NaOH (2 x 50 mL), brine (2 x 50 mL), dried over MgSO 4, filtered and concentrated under reduced pressure to give the title compound.
1. H;. PtO./AcOH1. H ; . PtO./AcOH
terc-Butyloxykarbonyl-3-(3-pyridyl)alanin-N,O-dimetylamid (4,5 g, 14,4 mmól) bol rozpustený v kyseline octovej (100 ml), a bol pridaný PtO (100 mg). Roztok bol trepaný pod H^, do jeho nasýtenia plynom. Roztok bol filtrovaný cez celit, a koncentrovaný za zníženého tlaku, za vzniku terc.-butyloxykarbonyl-3-(3-piperidyl)alanín-N,O-dimetylamid. Zvyšok bol rozpustený v etylacetáte (250 ml) premytý s 1 N NaOH (2 x 50 ml), soľankou (2 x 50 ml), vysušený s MgSO. filtrovaný a zahustený za zníženého tlaku za vzniku titulnej zlúčeniny.tert-Butyloxycarbonyl-3- (3-pyridyl) alanine-N, O-dimethylamide (4.5 g, 14.4 mmol) was dissolved in acetic acid (100 mL), and PtO (100 mg) was added. The solution was shaken under H 2 until saturated with gas. The solution was filtered through celite, and concentrated under reduced pressure to give tert-butyloxycarbonyl-3- (3-piperidyl) alanine-N, O-dimethylamide. The residue was dissolved in ethyl acetate (250 mL) washed with 1 N NaOH (2 x 50 mL), brine (2 x 50 mL), dried with MgSO 4. filtered and concentrated under reduced pressure to give the title compound.
1. H;. PtO./AcOH1. H ; . PtO./AcOH
--
Terc-Butyloxykarbonyl-3-(2-pyridyl)alanín-N,O-dimetylamid (4,5 g, 14,4 mmól) bol rozpustený v kyseline octovej (100 ml), a bol pridaný PtO (100 mg). Roztok bol trepaný pod do jeho nasýtenia plynom. Roztok bol filtrovaný cez celit, a koncentrovaný za zníženého tlaku, za vzniku tert-butyloxykarbonyl-3-(2-piperidyl) alanin-N,O-dimetylamid. Zvyšok bol rozpustený vTert-Butyloxycarbonyl-3- (2-pyridyl) alanine-N, O-dimethylamide (4.5 g, 14.4 mmol) was dissolved in acetic acid (100 mL), and PtO (100 mg) was added. The solution was shaken under to gas saturation. The solution was filtered through celite, and concentrated under reduced pressure to give tert-butyloxycarbonyl-3- (2-piperidyl) alanine-N, O-dimethylamide. The residue was dissolved in
-ΊΊetylacetáte (250 ml) premytý s 1 N NaOH (2 x 50 ml), soľankou (2 x 50 ml), vysušený s MgSO^ filtrovaný a zahustený za zníženého tlaku za vzniku titulnej zlúčeniny.Ethyl acetate (250 mL) washed with 1 N NaOH (2 x 50 mL), brine (2 x 50 mL), dried over MgSO 4, filtered and concentrated under reduced pressure to give the title compound.
terc-Butyloxykarbonyl-3-(4-piperidyl)alanín-N,O-dimetylamid (1,00 g, 3,2 mmól), bol rozpustený v bezvodom tetrahydrofuráne (10 ml), za miešania pod dusíkom. Roztok bol chladený. Bol pridaný N,N'-bis-(benzyloxykarbonyl)-S-metyl-tiomočovina (1,14 g, 3,2 mmól), a HgC^ (0,95 g, 3,5 mmól). Roztok bol zahustený za zníženého tlaku, obdržaný zvyšok bol suspendovaný do etylacetátu (200 ml), a filtrovaný cez celit. Filtrát bol koncentrovaný za zníženého tlaku. Rýchla chromatografia cez silikagél (hexán / etylacetátový gradient) poskytla titulnú zlúčeninu.tert-Butyloxycarbonyl-3- (4-piperidyl) alanine-N, O-dimethylamide (1.00 g, 3.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), with stirring under nitrogen. The solution was cooled. N, N'-bis- (benzyloxycarbonyl) -S-methylthiourea (1.14 g, 3.2 mmol), and HgCl 2 (0.95 g, 3.5 mmol) were added. The solution was concentrated under reduced pressure, the residue obtained was suspended in ethyl acetate (200 mL), and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane / ethyl acetate gradient) gave the title compound.
terc-Butyloxykarbonyl-3-(3-piperidyl)alamn-N,O-dimetylamid (1,00 g, 3,2 mmól), bol rozpustený v bezvodom tetrahydrofuráne (10 ml), za miešania pod dusíkom. Roztok bol chladený. Bol pridaný N,N'-bis-(benzyloxykarbonyl)-S-metyl-tiomočovina (1,14 g, 3,2 mmól), a HgC^ (0,95 g, 3,5 mmól). Roztok bol zahustený za zníženého tlaku, získaný zvyšok bol suspendovaný do etylacetátu (200 ml), a filtrovaný cez celit. Filtrát bol koncentrovaný za zníženého tlaku. Rýchla chromatografia cez silikagél (hexán / etylacetátový gradient) poskytla titulnú zlúčeninu.tert-Butyloxycarbonyl-3- (3-piperidyl) amino-N, O-dimethylamide (1.00 g, 3.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), with stirring under nitrogen. The solution was cooled. N, N'-bis- (benzyloxycarbonyl) -S-methylthiourea (1.14 g, 3.2 mmol), and HgCl 2 (0.95 g, 3.5 mmol) were added. The solution was concentrated under reduced pressure, the obtained residue was suspended in ethyl acetate (200 mL), and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane / ethyl acetate gradient) gave the title compound.
ΝΖΝΖ
HgCl/THFHgCl / THF
terc-Butyloxykarbonyl-3-(2-piperidyl)alanin-N,O-dimetylamid (1,00 g, 3,2 mmól), bol rozpustený v bezvodom tetrahydrofuráne (10 ml), za miešania pod dusíkom. Roztok bol chladený. Bol pridaný N,N'-bis-(benzyloxykarbonyl)-S-metyl-tiomočovina (1,14 g, 3,2 mmól), a HgCl? (0,95 g, 3,5 mmól). Roztok bol zahustený za zníženého tlaku, obdržaný zvyšok bol suspendovaný do etylacetátu (200 ml), a filtrovaný cez celit. Filtrát bol koncentrovaný za zníženého tlaku. Rýchla chromatografia cez silikagél (hexán / etylacetátový gradient) poskytla titulnú zlúčeninu.tert-Butyloxycarbonyl-3- (2-piperidyl) alanine-N, O-dimethylamide (1.00 g, 3.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), with stirring under nitrogen. The solution was cooled. N, N'-bis- (benzyloxycarbonyl) -S-methylthiourea (1.14 g, 3.2 mmol), and HgCl ? (0.95 g, 3.5 mmol). The solution was concentrated under reduced pressure, the residue obtained was suspended in ethyl acetate (200 mL), and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane / ethyl acetate gradient) gave the title compound.
K roztoku tiazolu v bezvodom tetrahydrofuráne (1.23 g, 14,4 mmól) bol pridaný po kvapkách n - BuLi (1,6 M / hexán, 8,4 ml, 13,4 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách guanidilovaný 4-piperidylalanínový derivát (2,0 g, 3,2 mmól) v bezvodom tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladená s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etyl acetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku.To a solution of the thiazole in anhydrous tetrahydrofuran (1.23 g, 14.4 mmol) was added dropwise n-BuLi (1.6 M / hexane, 8.4 mL, 13.4 mmol) at -78 ° C, and the solution was stirred . The guanidized 4-piperidylalanine derivative (2.0 g, 3.2 mmol) in anhydrous tetrahydrofuran (15 mL) was then added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered and concentrated under reduced pressure.
1. Lítium tiazol/lHl1. Lithium thiazole / 1H1
- 79K roztoku tiazolu v bezvodom tetrahydrofuráne (1.23 g, 14,4 mmól) bol pridaný po kvapkách n - BuLi (1,6 M / hexán, 8,4 ml, 13,4 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách guanidilovaný 3-piperidyIalanínový derivát (2,0 g, 3,2 mmól) v bezvodom tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etyl acetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku.A 79K solution of thiazole in anhydrous tetrahydrofuran (1.23 g, 14.4 mmol) was added dropwise to n-BuLi (1.6 M / hexane, 8.4 mL, 13.4 mmol) at -78 ° C, and the solution was mixed. The guanidized 3-piperidyl-alanine derivative (2.0 g, 3.2 mmol) in anhydrous tetrahydrofuran (15 mL) was then added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered and concentrated under reduced pressure.
oabout
1. Lítium tiazol/THF1. Lithium thiazole / THF
K roztoku tiazolu v bezvodom tetrahydrofuráne (1.23 g, 14,4 mmól) bol pridaný po kvapkách n - BuLi (1,6 M / hexán, 8,4 ml, 13,4 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách guanidilovaný 2-piperidylalanínový derivát (2,0 g, 3,2 mmól) v bezvodom tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etyl acetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku.To a solution of the thiazole in anhydrous tetrahydrofuran (1.23 g, 14.4 mmol) was added dropwise n-BuLi (1.6 M / hexane, 8.4 mL, 13.4 mmol) at -78 ° C, and the solution was stirred . The guanidized 2-piperidylalanine derivative (2.0 g, 3.2 mmol) in anhydrous tetrahydrofuran (15 mL) was then added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered and concentrated under reduced pressure.
terc-Butyloxykarbonyl-/x7ra-nitro-fenylalanín-N,O-dimetylarnid (13,88 g, 39,3 mmól) bol rozpustený v kyseline octovej (100 ml), a bol pridaný PtO (100 mg). Roztok bol trepaný pod do jeho nasýtenia plynom. Roztok bol filtrovaný cez celit, a koncentrovaný za zníženého tlaku, prenesený do H^O (150 ml) a lyofilizovaný. za vzniku terc-butyloxykarbonyl-3-(4-piperidyl)alanín-N,O-dimetylamid. Polotuhý bol rozpustený v etylacetáte (250 ml), premytý s 1 N NaOHtert-Butyloxycarbonyl- N -ra-nitro-phenylalanine-N, O-dimethylarnide (13.88 g, 39.3 mmol) was dissolved in acetic acid (100 mL), and PtO (100 mg) was added. The solution was shaken under to gas saturation. The solution was filtered through celite, and concentrated under reduced pressure, taken up in H 2 O (150 mL) and lyophilized. to give tert-butyloxycarbonyl-3- (4-piperidyl) alanine-N, O-dimethylamide. The semi-solid was dissolved in ethyl acetate (250 mL), washed with 1 N NaOH
-80(3 x 50 ml), soľankou (3 x 50 ml), vysušený s MgSO4 filtrovaný a zahustený za zníženého tlaku za vzniku titulnej zlúčeniny.-80 (3 x 50 mL), brine (3 x 50 mL), dried over MgSO 4, filtered and concentrated under reduced pressure to give the title compound.
/CH,/ CH
N I OCH,N I OCH,
1. H:. 1ΊΟ:/Α<.ΌΗ1 H. 1ΊΟ : /Α<.ΌΗ
/CH, N/ CH, N
II
OCH, terc-Butyloxykarbonyl-/neta-nitro-fenylalanín-N,O-dirnetylamid (13,88 g, 39,3 mmól) bol rozpustený v kyseline octovej (100 ml), a bol pridaný PtO (100 mg). Roztok bol trepaný pod do jeho nasýtenia plynom. Roztok bol filtrovaný cez celit, a koncentrovaný za zníženého tlaku, prenesený o ΡΕ,Ο (150 ml) a lyofilizovaný. za vzniku terc.-butyloxykarbonyl-3-(4-piperidyl) alanín-N,O-dimetylamid. Polotuhý bol rozpustený v etylacetáte (250 ml), premytý s 1 N NaOH (3 x 50 ml), soľankou (3 x 50 ml), vysušený s MgSO^ filtrovaný a zahustený za zníženého tlaku za vzniku titulnej zlúčeniny.OCH, tert-Butyloxycarbonyl-neta-nitro-phenylalanine-N, O-dirylamine (13.88 g, 39.3 mmol) was dissolved in acetic acid (100 mL), and PtO (100 mg) was added. The solution was shaken under to gas saturation. The solution was filtered through celite, and concentrated under reduced pressure, transferred with ΡΕ, Ο (150 mL) and lyophilized. to give tert-butyloxycarbonyl-3- (4-piperidyl) alanine-N, O-dimethylamide. The semi-solid was dissolved in ethyl acetate (250 mL), washed with 1 N NaOH (3 x 50 mL), brine (3 x 50 mL), dried with MgSO 4, filtered and concentrated under reduced pressure to give the title compound.
1. H,. PtOi/AcOH1. H ,. PtOi / AcOH
---------------------->.---------------------->.
terc-Butyloxykarbonyl-o/7o-nitro-fenylalanín-N,O-dimetylamid (13,88 g, 39,3 mmól) bol rozpustený v kyseline octovej (100 ml), a bol pridaný PtO (100 mg). Roztok bol trepaný pod EL do jeho nasýtenia plynom. Roztok bol filtrovaný cez celit, a koncentrovaný za zníženého tlaku, prenesený o ΕΕ,Ο (150 ml) a lyofilizovaný. za vzniku tert-butyloxykarbonyl-3-(4-piperidyl) alanin-N,O-dimetylamid. Polotuhý bol rozpustený v etylacetáte (250 ml), premytý s 1 N NaOH (3 x 50 ml), soľankou (3 x 50 ml), vysušený s MgSO^ filtrovaný a zahustený za zníženého tlaku za vzniku titulnej zlúčeniny.tert-Butyloxycarbonyl-η 7o-nitro-phenylalanine-N, O-dimethylamide (13.88 g, 39.3 mmol) was dissolved in acetic acid (100 mL), and PtO (100 mg) was added. The solution was shaken under EL until saturated with gas. The solution was filtered through celite, and concentrated under reduced pressure, transferred to ΕΕ, Ο (150 mL) and lyophilized. to give tert-butyloxycarbonyl-3- (4-piperidyl) alanine-N, O-dimethylamide. The semi-solid was dissolved in ethyl acetate (250 mL), washed with 1 N NaOH (3 x 50 mL), brine (3 x 50 mL), dried with MgSO 4, filtered and concentrated under reduced pressure to give the title compound.
1. terc.-Butyloxykarbonyl-3-<czV//YW-4-aminocyklohexyl)alanín-N,O-dimetylamid (1,00 g, 3,0 mmól) bol rozpustený v nasýtenom vodnom roztoku hydrouhličitanu sodného a tetrahydrofuránu (THF) [60 ml (1:1)] za miešania. Roztok bol ochladený, a po kvapkách bol pridávaný roztok benzyl chlórmravčanu (0,43 ml, 3,0mmól) v THF (10 ml). Bol pridaný nadbytok hydrouhličitanu sodného. THF bol odstránený za zníženého tlaku a získaná vodná fáza bola naliata do etyl acetátu (250 ml), a dokonale premiešaná. Vodná fáza bola odstránená a získaný roztok bol premytý s nasýteným vodným roztokom hydrouhličitanu sodného (2 x 50 ml), 4 N vodným roztokom hydrosíranu sodného (2 x 50 ml). Roztok bol vysušený s MgSO^ filtrovaný a zahustený za zníženého tlaku. Polotuhý bol chromatografovaný cez silikagél (etylacetát/hexán).1. tert-Butyloxycarbonyl-3- (N, N- (4-aminocyclohexyl) alanine-N, O-dimethylamide (1.00 g, 3.0 mmol) was dissolved in a saturated aqueous solution of sodium bicarbonate and tetrahydrofuran (THF) [60 mL (1: 1)] with stirring. The solution was cooled, and a solution of benzyl chloroformate (0.43 mL, 3.0 mmol) in THF (10 mL) was added dropwise. Excess sodium bicarbonate was added. THF was removed under reduced pressure and the resulting aqueous phase was poured into ethyl acetate (250 mL), and thoroughly stirred. The aqueous phase was removed and the resulting solution was washed with saturated aqueous sodium bicarbonate solution (2 x 50 mL), 4 N aqueous sodium hydrogen sulfate (2 x 50 mL). The solution was dried with MgSO 4, filtered and concentrated under reduced pressure. The semi-solid was chromatographed over silica gel (ethyl acetate / hexane).
2. K roztoku tiazolu (1,16 g, 13,7 mmól) v bezvodom tetrahydrofuráne bol pridaný po kvapkách n - BuLi (1,6 M / hexán, 8,0 ml, 12,8 mmól) pri -78 °C, a roztok bol miešaný. Potom bol pridaný po kvapkách hore uvedený chránený amid aminokyseliny (1,41 g, 3,0 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etyl acetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifikovaný na silikagéli (etylacetát / hexán) a koncentrovaný za zníženého tlaku.2. To a solution of thiazole (1.16 g, 13.7 mmol) in anhydrous tetrahydrofuran was added dropwise n-BuLi (1.6 M / hexane, 8.0 mL, 12.8 mmol) at -78 ° C, and the solution was stirred. The above protected amino acid amide (1.41 g, 3.0 mmol) in tetrahydrofuran (15 mL) was added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
1. Z-Cl. NuHCO/THF:H:O -------------:------------>1. Z-Cl. NuHCO / THF: H : O -------------: ------------>
- Lítium tiazol/THF- Lithium thiazole / THF
1. terc.-Butyloxykarbonyl-3-CcL/tra/?5- 3 -aminocyklohexyl)alanín-N,O-dimetylamid (1,00 g, 3,0 mmól) bol rozpustený v nasýtenom vodnom roztoku hydrouhličitanu sodného a tetrahydrofuránu (THF) [60 ml (1:1)] za miešania. Roztok bol ochladený, a po kvapkách bol pridávaný roztok benzyl chlórmravčanu (0,43 ml, 3,0mmól) v THF (10 ml). Bol pridaný nadbytok hydrouhličitanu sodného. THF bol odstránený za zníženého tlaku a získaná vodná fáza bola naliata do etyl acetátu (250 ml), a dokonale premiešaná. Vodná fáza bola odstránená a získaný roztok bol premytý s nasýteným vodným roztokom hydrouhličitanu sodného (2 x 50 ml), 4 N vodným roztokom hydrosíranu sodného (2 x 50 ml). Roztok bol vysušený s MgSO^ filtrovaný a zahustený za zníženého tlaku. Polotuhý bol chromatografovaný cez silikagél (etylacetát/hexán).1. tert-Butyloxycarbonyl-3-Cc (trans-5- (3-aminocyclohexyl) alanine-N, O-dimethylamide (1.00 g, 3.0 mmol) was dissolved in a saturated aqueous solution of sodium bicarbonate and tetrahydrofuran (THF) ) [60 ml (1: 1)] with stirring. The solution was cooled, and a solution of benzyl chloroformate (0.43 mL, 3.0 mmol) in THF (10 mL) was added dropwise. Excess sodium bicarbonate was added. THF was removed under reduced pressure and the resulting aqueous phase was poured into ethyl acetate (250 mL), and thoroughly stirred. The aqueous phase was removed and the resulting solution was washed with saturated aqueous sodium bicarbonate solution (2 x 50 mL), 4 N aqueous sodium hydrogen sulfate (2 x 50 mL). The solution was dried with MgSO 4, filtered and concentrated under reduced pressure. The semi-solid was chromatographed over silica gel (ethyl acetate / hexane).
2. K roztoku tiazolu (1,16 g, 13.7 mmól) v bezvodom tetrahydrofuráne sa pridal po kvapkách n BuLi (1,6 M / hexán, 8,0 ml, 12,8 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách hore uvedený chránený amid aminokyseliny (1,41 g, 3,0 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etylacetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifikovaný na silikagéli (etyl acetát / hexán) a koncentrovaný za zníženého tlaku.2. To a solution of thiazole (1.16 g, 13.7 mmol) in anhydrous tetrahydrofuran was added dropwise n BuLi (1.6 M / hexane, 8.0 mL, 12.8 mmol) at -78 ° C, and the solution was mixed. The above protected amino acid amide (1.41 g, 3.0 mmol) in tetrahydrofuran (15 mL) was then added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
1. Z-C1. NuHCO/THF:H.O1. Z-C1. NuHCO / THF: H. O.
2. Lítium tiazol/THF2. Lithium thiazole / THF
1. terc.-Butyloxykarbonyl-3-(cz5/t/-m75- 2 -aminocyklohexyl)alanin-N,O-dimetylamid (1,00 g, 3,0 mmól) bol rozpustený v nasýtenom vodnom roztoku hydrouhličitanu sodného a tetrahydrofuránu (THF) [60 ml (1:1)] za miešania. Roztok bol ochladený, a po kvapkách bol pridávaný roztok benzyl chlórmravčanu (0,43 ml, 3,0 mmól) v THF (10 ml). Bol pridaný nadbytok hydrouhličitanu sodného. THF bol odstránený za zníženého tlaku a získaná vodná fáza bola naliata do etyl acetátu (250 ml), a dokonale premiešaná. Vodná fáza bola odstránená a získaný roztok bol premytý s nasýteným vodným roztokom hydrouhličitanu sodného (2 x 50 ml), 4 N vodným roztokom hydrosíranu sodného (2 x 50 ml). Roztok bol vysušený s MgSO^ filtrovaný a zahustený za zníženého tlaku . Polotuhý bol chromatografovaný cez silikagél (etylacetát/hexán).1. tert-Butyloxycarbonyl-3- (η 5 -N-75-2-aminocyclohexyl) alanine-N, O-dimethylamide (1.00 g, 3.0 mmol) was dissolved in a saturated aqueous solution of sodium bicarbonate and tetrahydrofuran ( THF) [60 mL (1: 1)] with stirring. The solution was cooled, and a solution of benzyl chloroformate (0.43 mL, 3.0 mmol) in THF (10 mL) was added dropwise. Excess sodium bicarbonate was added. THF was removed under reduced pressure and the resulting aqueous phase was poured into ethyl acetate (250 mL), and thoroughly stirred. The aqueous phase was removed and the resulting solution was washed with saturated aqueous sodium bicarbonate solution (2 x 50 mL), 4 N aqueous sodium hydrogen sulfate (2 x 50 mL). The solution was dried with MgSO 4, filtered and concentrated under reduced pressure. The semi-solid was chromatographed over silica gel (ethyl acetate / hexane).
2. K roztoku tiazolu (1,16 g, 13,7 mmól) v bezvodom tetrahydrofuráne bol pridaný po kvapkách n - BuLi (1,6 M / hexan, 8,0 ml, 12,8 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách hore uvedený chránený amid aminokyseliny (1,41 g, 3,0 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etylacetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifikovaný na silikagéli (etylacetát / hexán) a koncentrovaný za zníženého tlaku.2. To a solution of thiazole (1.16 g, 13.7 mmol) in anhydrous tetrahydrofuran was added dropwise n-BuLi (1.6 M / hexane, 8.0 mL, 12.8 mmol) at -78 ° C, and the solution was stirred. The above protected amino acid amide (1.41 g, 3.0 mmol) in tetrahydrofuran (15 mL) was then added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
1. terc. - Butyloxykarbonyl-3-fczs/rrans-4-aminocyklohexyl)alanín-N,0-dimetylamid (2,0 g, 6,1 mmól) bol rozpustený v bezvodom tetrahydrofuráne (THF) (20 ml) pod dusíkom, za miešania. Roztok bol ochladený na 0 °C, a bol pridanýN,Nj-bis-(benzyloxykarbonyl)-S-metyl-izomočoviiia (2,18 g, 6,1 mmól). Roztok bol koncentrovaný za zníženého tlaku a získaný zvyšok bol suspendovaný do etylacetátu (300 ml), a filtrovaný cez celit. Filtrát bol zahustený za zníženého tlaku .Rýchla chromatografia cez silikagél (hexan/etylacetátový gradient) poskytla purifíkovaný produkt1. terc. Butyloxycarbonyl-3-trans-4-aminocyclohexyl) alanine-N, O-dimethylamide (2.0 g, 6.1 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (20 mL) under nitrogen, with stirring. The solution was cooled to 0 ° C, and N, N'-bis- (benzyloxycarbonyl) -S-methyl-isomeric (2.18 g, 6.1 mmol) was added. The solution was concentrated under reduced pressure, and the obtained residue was suspended in ethyl acetate (300 mL), and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane / ethyl acetate gradient) gave the purified product
2. K roztoku tiazolu (2,32 g, 27,3 mmól) v bezvodom tetrahydrofuráne bol pridaný po kvapkách n - BuLi (1,6 M / hexán, 15,9 ml, 25,4 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách hore uvedená guanidylovaná aminokyselina (3,88 g, 6,1 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etyl acetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml),2. To a solution of thiazole (2.32 g, 27.3 mmol) in anhydrous tetrahydrofuran was added dropwise n-BuLi (1.6 M / hexane, 15.9 mL, 25.4 mmol) at -78 ° C, and the solution was stirred. The above guanidylated amino acid (3.88 g, 6.1 mmol) in tetrahydrofuran (15 mL) was added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with a saturated aqueous ammonium chloride solution (2 x 50 mL),
NZ soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifíkovaný na silikagéli (etyl acetát / hexán) a koncentrovaný za zníženého tlaku.NZ brine (50 mL), dried over MgSO 4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
och3 och 3
HgCL/THFHgCl / THF
2. Lítium tiazol/THF2. Lithium thiazole / THF
1. terc - Butyloxykarbonyl-3-(cz5/trara-3-aminocyklohexyl)alanín-N,O-dimerylamid (2,0 g, 6,1 mmól) bol rozpustený v bezvodom tetrahydrofuráne (THF) (20 ml) pod dusíkom, za miešania. Roztok bol ochladený na 0 °C, a bol pridaný N,Ni-bis-(benzyloxykarbonyl)-S-metyl-izomočovina produkt (2,18 g, 6,1 mmól). Roztok bol koncentrovaný za zníženého tlaku a získaný zbytok bol suspendovaný do etylacetátu (300 ml), a filtrovaný cez celit. Filtrát bol zahustený za zníženého tlaku .Rýchla chromatografia cez silikagél (hexán/etylacetátový gradient) poskytla purifíkovaný1. tert-Butyloxycarbonyl-3- (η 5 / trara-3-aminocyclohexyl) alanine-N, O-dimerylamide (2.0 g, 6.1 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (20 mL) under nitrogen, with stirring. The solution was cooled to 0 ° C, and N, Ni-bis- (benzyloxycarbonyl) -S-methyl-isourea product (2.18 g, 6.1 mmol) was added. The solution was concentrated under reduced pressure, and the obtained residue was suspended in ethyl acetate (300 mL), and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane / ethyl acetate gradient) yielded purified
2. K roztoku tiazolu (2,32 g, 27,3 mmôl) v bezvodom tetrahydrofuráne bol pridaný po kvapkách n - BuLi (1,6 M / hexan, 15,9 ml, 25,4 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách hore uvedená guanidylovaná aminokyselina (3,88 g, 6,1 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etylacetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifikovaný na silikagéli (etylacetát / hexán) a koncentrovaný za zníženého tlaku.2. To a solution of thiazole (2.32 g, 27.3 mmol) in anhydrous tetrahydrofuran was added dropwise n-BuLi (1.6 M / hexane, 15.9 mL, 25.4 mmol) at -78 ° C, and the solution was stirred. The above guanidylated amino acid (3.88 g, 6.1 mmol) in tetrahydrofuran (15 mL) was added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
HgCl/THFHgCl / THF
2. Lítium tiazol/THF2. Lithium thiazole / THF
1. terc.- Butyloxykarbonyl-3-7cz5/tra/?5-2-aminocyklohexyl)alanín-N,O-dimetylamid (2,0 g,1. tert-Butyloxycarbonyl-3-7 (5-tert-2-aminocyclohexyl) alanine-N, O-dimethylamide (2.0 g,
6,1 mmól) bol rozpustený v bezvodom tetrahydrofuráne (THF) (20 ml) pod dusíkom, za miešania. Roztok bol ochladený na 0 °C, a bol pridaný N,Nj-bis-(benzyloxykarbonyl)-S-metylizomočovina (2,18 g, 6,1 mmól). Roztok bol koncentrovaný za zníženého tlaku a získaný zvyšok bol suspendovaný do etylacetátu (300 ml), a filtrovaný cez celit. Filtrát bol zahustený za zníženého tlaku. Rýchla chromatografia cez silikagél (hexán/'etylacetátový gradient ) poskytla purifikovaný produkt6.1 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (20 mL) under nitrogen, with stirring. The solution was cooled to 0 ° C, and N, N 1 -bis- (benzyloxycarbonyl) -S-methylisourea (2.18 g, 6.1 mmol) was added. The solution was concentrated under reduced pressure, and the obtained residue was suspended in ethyl acetate (300 mL), and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane / ethyl acetate gradient) gave the purified product
2. K roztoku tiazolu (2,32 g, 27,3 mmól) v bezvodom tetrahydrofuráne bol pridaný po kvapkách n - BuLi (1,6 M / hexán, 15,9 ml, 25,'4 mmól) pri -78 °C, a roztok bol miešaný. Potom bola pridaná po kvapkách hore uvedená guanidylovaná aminokyselina (3,88 g, 6,1 mmól) v tetrahydrofuráne (15 ml) a výsledná zmes bola miešaná. Reakcia bola rýchlo ochladené s nasýteným vodným roztokom chloridu amónneho. Zmes bola nariedená s etylacetátom (150 ml), a organická vrstva premytá s nasýteným vodným roztokom chloridu amónneho ( 2 x 50 ml), soľankou (50 ml), vysušená s MgSO^, filtrovaná a zahustená za zníženého tlaku. Surový materiál bol purifikovaný na silikagéli (etylacetát / hexán) a koncentrovaný za zníženého tlaku.2. To a solution of thiazole (2.32 g, 27.3 mmol) in anhydrous tetrahydrofuran was added dropwise n-BuLi (1.6 M / hexane, 15.9 mL, 25.4 mmol) at -78 ° C. , and the solution was stirred. The above guanidylated amino acid (3.88 g, 6.1 mmol) in tetrahydrofuran (15 mL) was added dropwise and the resulting mixture was stirred. The reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous ammonium chloride solution (2 x 50 mL), brine (50 mL), dried with MgSO 4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate / hexane) and concentrated under reduced pressure.
Príklad 2Example 2
Syntéza intermediátov.Synthesis of intermediates.
THF/-7g9c (4S, 5 R)-3-( 1 -oxo-3-fenylpropyl)-4-(fenyl)-5-(metyl)-2-oxazolidón (2).THF / -7g9c (4S, 5R) -3- (1-oxo-3-phenylpropyl) -4- (phenyl) -5- (methyl) -2-oxazolidone (2).
K roztoku 10,0 g (1,0 ekv., 56,4 mmól) (4S, 5R)-4-fenyl-5-metyl-2-oxazolidónu (1) v 250 ml bezvodého THF, miešanom pri -78 °C pod argónom sa pridával po kvapkách n-BuLi (1,6 M v hexáne, 1,1 ekv., 38,8 ml). Po 30 min. miešaní, bol po kvapkách pridávaný hydrocinamoyl chloride v 10 minútových intervaloch. Výsledná zmes bola zohriata na 00C, miešaná ďalšiu hodinu a rýchlo ochladená nasýteným chloridom amónnym. Rozpúšťadlo bolo odstránené vákuovo, a výsledná biela tuhá látka bola rozpustená v etylacetáte a v dd^O. Vodná fáza bola odstránené s dvoma ďalšími prídavkami etylacetátu. Extrakty boli skombinované, premyté s nasýteným chloridom sodný, sušené nad síranom sodným a rozpúšťadlo bolo odstránené vo vákuu, za vzniku bielej tuhej kryštalickej látky (2) (91% výťažok).To a solution of (4S, 5R) -4-phenyl-5-methyl-2-oxazolidone (10.0 g, 1.0 eq., 56.4 mmol) in 250 mL of anhydrous THF, stirred at -78 ° C. n-BuLi (1.6 M in hexane, 1.1 eq., 38.8 mL) was added dropwise under argon. After 30 min. with stirring, hydrocinamoyl chloride was added dropwise at 10 minute intervals. The resulting mixture was warmed to 0 ° C, stirred for an additional hour and quenched with saturated ammonium chloride. The solvent was removed in vacuo, and the resulting white solid was dissolved in ethyl acetate and in dd? O. The aqueous phase was removed with two additional additions of ethyl acetate. The extracts were combined, washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed in vacuo to give a white crystalline solid (2) (91% yield).
b.t. 95-96,5 0C; [a]D =-35,8 (c=l CH?C12); [α]β =-26,6 (c=l,018 CH2C1? );bt 95-96.5 0C; [a] D = -35.8 (c = CH 2 C 1); [α] β = -26.6 (c = 2 C 1 018 CH?);
1HNMR(CDC13) δ 0,89 (d, 3H, CH3 J=6,6Hz), 3,00-3,05 (m, 2H), 3,26-3,341 HNMR (CDCl 3 ) δ 0.89 (d, 3H, CH 3 J = 6.6 Hz), 3.00-3.05 (m, 2H), 3.26-3.34
Roztok 5,0 g (1 ekv., 16,2 mmól) látky (2) v 100ml bezvodého THF, bol ochladený na 78 °C. Enolizácia bola dosiahnutá s bis-trimetylamidom lítnym, ktorý bol počas miešania prikvapkávaný. Roztok sa miešal 30 min. predtým ako bol pridaný 4,45 ml (3 ekv., 48,5 mmól) alyljodidu, a reakcia sa zohriala na -15 °C. Po 1 hod. reakcia bola rýchlo ochladená nasýteným chloridom amónnym a extrahovaná (3x) s etylacetátom. Organická fáza bola premytá s metabisulfitom sodným, vysušená nad síranom sodným a rozpúšťadlo bolo odstránené vákuovo za poskytnutia bezfarebného oleja. Purifíkácia bola dosiahnutá rýchlou chromatografiou naA solution of 5.0 g (1 eq., 16.2 mmol) of (2) in 100 mL of anhydrous THF was cooled to 78 ° C. Enolization was achieved with lithium bis-trimethylamide, which was added dropwise with stirring. The solution was stirred for 30 min. before 4.45 mL (3 eq., 48.5 mmol) of allyl iodide was added, and the reaction was warmed to -15 ° C. After 1 hour the reaction was quenched with saturated ammonium chloride and extracted (3x) with ethyl acetate. The organic phase was washed with sodium metabisulfite, dried over sodium sulfate, and the solvent was removed in vacuo to give a colorless oil. Purification was achieved by flash chromatography on
-86silikagéli použitím postupného gradientu (15:1, 12:1. 10:1) za vzniku (3), bezfarebného oleja (95%).-86 silica gel using a stepwise gradient (15: 1, 12: 1, 10: 1) to give (3), a colorless oil (95%).
[a]D =47,5 (c = 3,12 CH2C12);[α] D = 47.5 (c = 3.12 CH 2 Cl 2 );
1HNMR(CDC13) δ 0,82 (d, 3H, CH3 J=6,6Hz), 2,31-2,40 (m, 1H1 HNMR (CDCl 3 ) δ 0.82 (d, 3H, CH 3 J = 6.6 Hz), 2.31-2.40 (m, 1H
RCH=CHCH2), 2,49-2,57(m, 1HRCH=CHCH2 ), 2,84-3,00 (m, 2H, Ph-CH2 ) 4,32-4 ,37 (m, 1H CH-(N)CO), 4,53-4,56 (m, 1HCH3-CH-), 5,03-5,13 (m, ΤΗ,ΑΒΧ,RCH = CHCH 2 ), 2.49-2.57 (m, 1H RCH = CHCH 2 ), 2.84-3.00 (m, 2H, Ph-CH 2 ) 4.32-4.37 (m, 1H CH (N) CO), 4.53 to 4.56 (m, 1HCH 3 -CH), 5.03-5.13 (m, ΤΗ, ΑΒΧ,
CH=CH2), 5,21, (d.,lH, Ph-CH, J= 7, 1 Hz), 5,81-5,89 (m, 1H„ CH=CH2 ), 7,20-7,42 (m, 10H, ArH);CH = CH 2 ), 5.21 (d, 1H, Ph-CH, J = 7.1 Hz), 5.81-5.89 (m, 1H, CH = CH 2 ), 7.20- 7.42 (m, 10H, ArH);
13C(CDC13) δ 14,4, 36,2, 38,2, 43,9, 54,7, 78,4,13 C (CDC1 3) δ 14.4, 36.2, 38.2, 43.9, 54.7, 78.4,
133,1, 134,8, 138,9, 152,4, 174,9.133.1, 134.8, 138.9, 152.4, 174.9.
117,1, 125,4, 126,3, 128,2, 129,0,117.1, 125.4, 126.3, 128.2, 129.0,
Na alylovú zlúčeninu (3), (4,75g, 13,6 mmól) v THF (100 ml), sa pôsobilo s 13,6 ml (1 ekv. 13,6 mmól) 0,1 M roztokom tetrahydrofurán boranovým komplexom pri 0 °C a miešalo 2h. Rozpúšťadlo bolo odparené a za miešania sa pridal chloroform (100 ml). Oxidácia organobóranu bola prevedená pridaním 4,7 g (2 ekv., 27,2 mmól) 3-chlóroperoxybenzoovej kyseliny pri 0 0C, so zahriatím na teplotu okolia a miešaním ďalšiu hodinu. Organická fáza bola premytá s 5% Na2CO3, ddH2O a sušená nad síranom sodným. Vzhľadom na veľkú nestabilitu alkoholu, bola prevedená rýchlo kolóna na odstránenie nepolámeho materiálu, ktorý pochádzal z 3chlórperoxybenzoovej kyseliny. Alkohol (4) bol získaný v 65% výťažku.Allyl compound (3), (4.75g, 13.6 mmol) in THF (100 mL), was treated with 13.6 mL (1 eq. 13.6 mmol) of 0.1 M tetrahydrofuran borane complex at 0 ° C and stirred for 2h. The solvent was evaporated and chloroform (100 mL) was added with stirring. Oxidation of the organoborane was accomplished by the addition of 4.7 g (2 eq., 27.2 mmol) of 3-chloroperoxybenzoic acid at 0 ° C, warming to ambient temperature and stirring for an additional hour. The organic phase was washed with 5% Na 2 CO 3 , ddH 2 O and dried over sodium sulfate. Due to the great instability of the alcohol, a column was removed quickly to remove the non-polar material that was derived from 3-chloroperoxybenzoic acid. The alcohol (4) was obtained in 65% yield.
[a]D39,3 (c= 1,936 CH2C12);[α] D 39.3 (c = 1.936 CH 2 Cl 2 );
1NMR(CDC13) δ l,07(d, 3H, CH3-CH J= 6,5 Hz), 1,81-1,92 (m, 3H CH2-CHH), 2,10-2,19 (m, 1HR, ΟΗ?-CH-H), 3J0-3,17(m, 2H, Ph-CH2 ) 3,87-3,90 (m, 2H1 NMR (CDC1 3) δ l, 07 (d, 3H, CH 3 CH J = 6.5 Hz), 1.81-1.92 (m, 3 H CH 2 -CHH), 2.10-2.19 (m, 1HR, ΟΗ? CH-H), 3J0-3,17 (m, 2H, Ph-CH 2) 3.87 to 3.90 (m, 2H
CH2 OH), 4,43-4 ,49 (m, 1H CH- CO), 4,70-4,75 (m, fH,CH3-CH), 5,36, (d.,lH, Ph-CH, J=7, 1 Hz), 7,41-7,63 (m, 10H, ArH);CH 2 OH), 4.43-4.49 (m, 1H CH-CO), 4.70-4.75 (m, fH, CH 3 -CH), 5.36 (d, 1H, Ph) -CH, J = 7.1 Hz), 7.41-7.63 (m, 10H, ArH);
K roztoku alkoholu (4) (1,0 g, 2,7 mmól), rozpusteného v dichlórometane (27 ml), bolo pridané 876 mg (1,5 ekv., 4,1 mmól) pyridín chlórmetánu a 1,0 g 4 angstromového molekulového sita a zmes sa menila z oranžovej na čiernu farbu. Reakcia bola sledovaná s tenkovrstvovou chromatografiou a po 30 min., keď už nebol žiadny štartovací materiál, bolo pridané ďalšie množstvo molekulového sita. Roztok bol filtrovaný cez celit a rozpúšťadlo bolo odparené. Zvyšok bol rozpustený v etylacetáte a premytý s nasýteným roztokom chloridu sodného. Ak oranžová farba pretrvávala v organickej fáze, bola prevedená ďalšia filtrácia cez celit. Aldehyd bol získaný v kvantitatívnom výťažku ako priesvitný bezfarebný olej (5).To a solution of alcohol (4) (1.0 g, 2.7 mmol) dissolved in dichloromethane (27 mL) was added 876 mg (1.5 eq, 4.1 mmol) pyridine chloromethane and 1.0 g 4. angstrom molecular sieve and the mixture changed from orange to black. The reaction was monitored by thin layer chromatography and after 30 min, when there was no more starting material, an additional amount of molecular sieve was added. The solution was filtered through celite and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with saturated sodium chloride solution. If the orange color persisted in the organic phase, further filtration through celite was performed. The aldehyde was obtained in quantitative yield as a transparent colorless oil (5).
1H NMR (CDCip δ 0,84 (d, 3H, CHyCH- J= 6,6 Hz), 1,87-1,94 (m, 1H CH2 CH(H)-CHO), 2,04-2,12 (m, 1H CH2~CH(Hr-CHO), 2,45-2,50 (m, 2H, Ph-CHj ), 2,79-2,85 (dd, 1HCH2-CHO J=13,3 a J= 6,6), 2,92-2,99 (dd, 1HCH2-CHO J=Í3?2 a J= 8,8),4,19-4,22 (m, 1H CH-CO), 4,46-4,51 (m, 1H, CH3-CH-), 5,13-5,25, (m.,1H, PhCH), 7,20-7,39 (m, 10H, ArH), 9,69 (s, 1H, CHO);1 H NMR (CDCl 3 δ 0.84 (d, 3H, CH 3 CH- J = 6.6 Hz), 1.87-1.94 (m, 1H CH 2 CH (H) -CHO), 2.04-2, 12 (m, 1H CH 2 -CH (H 2 -CHO), 2.45-2.50 (m, 2H, Ph-CH 3), 2.79-2.85 (dd, 1HCH 2 -CHO J = 13, 3 and J = 6.6), 2.92-2.99 (dd, 1HCH 2 -CHO J = 13.2 and J = 8.8), 4.19-4.22 (m, 1H CH-CO ), 4.46 to 4.51 (m, 1 H, CH 3 -CH-), 5.13 to 5.25 (m., 1 H, Ph), 7.20-7.39 (m, 10 H, ArH), 9.69 (s, 1H, CHO);
13C(CDC13) δ 14,2,23,8, 39,0, 41,2, 43,8, 54,9, 78,6, 125,2, 126,4, 128,2, 128,4, 128,5,13 C (CDC1 3) δ 14,2,23,8, 39.0, 41.2, 43.8, 54.9, 78.6, 125.2, 126.4, 128.2, 128.4, 128.5.
::
Aldehyd (5) (2,6 g, 7,0 mmól) bol rozpustený v benzéne (70 ml) a bolo pridané katalytické množstvo p-toluénsulfónovej kyseliny, a potom bolo pridané l,58g (1,2 ekv. , 8,52 mmól) etylesteru L-cysteínu a 4 A molekulové sito. Reakcia prebiehala za miešania cez noc pri izbovej teplote, potom nasledovalo odstránenie rozpúšťadla vo vákuu. Zvyšok bol rozpustený v chloroforme, premytý s nasýteným roztokom chloridu sodného, ddH2O a vysušený nad síranom sodným. Rozpúšťadlo bolo odstránené vo vákuu pri vzniku gumovitej tuhej látky (6).Aldehyde (5) (2.6 g, 7.0 mmol) was dissolved in benzene (70 mL) and a catalytic amount of p-toluenesulfonic acid was added, followed by 1.58 g (1.2 eq, 8.52). mmole) of L-cysteine ethyl ester and a 4 A molecular sieve. The reaction was allowed to stir overnight at room temperature, followed by removal of the solvent in vacuo. The residue was dissolved in chloroform, washed with saturated sodium chloride solution, ddH 2 O, and dried over sodium sulfate. The solvent was removed in vacuo to give a gummy solid (6).
2,0 M trimetylalumínium v hexáne (2,4 ml, 4,8 mm'pl, 3 ekv.), bol pomaly pridaný k štartovaciemu materiálu (6) (800 mg, 1,61 mmól) za miešania v dichlórmetáne pod argónom, pri použití sušiarne. Po celonočnom miešaní, HPLC ukázala, že reakcia prebehla kompletne.2.0 M trimethylaluminium in hexane (2.4 mL, 4.8 mm -1, 3 eq) was added slowly to the starting material (6) (800 mg, 1.61 mmol) with stirring in dichloromethane under argon, when using a dryer. After stirring overnight, HPLC showed that the reaction was complete.
Zmes bola rýchlo ochladená s nadbytkom metanolu, potom filtrovaná na krátkej silikagélovej kolóne (premývaná nadbytkom 10% metanolu v etylacetáte). Po odparení sa získalo 784 mg surového materiálu, ktorý bol purifikovaný použitím silikagélovej kolóny vymývanej s hexán : etylacetát 2 : 1, čo poskytlo 258 mg (0,81 mmól, 50%výťažok) čistej látky (7), 6Sbenzylhexahydro-5-oxo-5H-tiazol [3,2-a] pyridín-3R-etylester, ako žlto-bielu tuhú látku.The mixture was quenched with excess methanol, then filtered on a short silica gel column (washed with excess 10% methanol in ethyl acetate). Evaporation gave 784 mg of crude material, which was purified using a silica gel column eluted with 2: 1 hexane: ethyl acetate to afford 258 mg (0.81 mmol, 50% yield) of pure (7), 6S-benzylhexahydro-5-oxo. 5H-thiazolo [3,2-a] pyridine-3R-ethyl ester as a yellow-white solid.
1HNMR(CDC13) δ 1,28-1,31 (M, 3H), 1,72-1,81 (m, 3H), 2,10-2,13 (m, 1H), 2,66 (dd, 1H, J= 11,5 a 6,0 Hz), 3,29-3,34 (m, 2H), 4,19-4,29 (M, 2H), 4,88 (dd, 1H, J=9,0 a 5,0 Hz), 5,22 (dd, 1H J= 8,0 a 6,é Hz), 7,18-7,23 (M, 3H), 7,28-7,31 (m, 2H).1 HNMR (CDCl 3 ) δ 1.28-1.31 (M, 3H), 1.72-1.81 (m, 3H), 2.10-2.13 (m, 1H), 2.66 (dd) 1 H, J = 11.5 and 6.0 Hz), 3.29-3.34 (m, 2H), 4.19-4.29 (M, 2H), 4.88 (dd, 1H, J = 9.0 and 5.0 Hz), 5.22 (dd, 1H J = 8.0 and 6 Hz), 7.18-7.23 (M, 3H), 7.28-7.31 (m, 2H).
88
LiOH.^O (48 mg, 1,12 mmól) v 10 ml vody bol pridaný do východiskového materiálu (7) (240 mg, 0,76 mmól) rozpusteného v 10 ml dioxánu. Po 1 hodine, tenkovrstvová chromatografia v hexán : etylacetáte 1:1, neukázala žiadny štartovací materiál. Reakčná zmes bola rýchlo ochladená s 10% kyselinou citrónovou, potom extrahovaná 2 x s dichlórmetánom. Sušením a odparovaním, spojené organické vrstvy dali 354 mg surového produktu. Tento bol rozpustený v dichlórmetáne, a potom vyzrážaný nadbytkom hexánu. Product bol filtrovaný a dal 200 mg (0,68 mmól, 90% výťažok) nie celkom bielej tuhej látky (8), tiež známej ako 6S-benzylhexahydro-5oxo-5H-tiazol [3,2-a] pyridín-3R-karboxylová kyselina.LiOH .40 (48 mg, 1.12 mmol) in 10 mL water was added to the starting material (7) (240 mg, 0.76 mmol) dissolved in 10 mL dioxane. After 1 hour, thin layer chromatography in hexane: ethyl acetate 1: 1 showed no starting material. The reaction mixture was quenched with 10% citric acid, then extracted twice with dichloromethane. By drying and evaporation, the combined organic layers gave 354 mg of crude product. This was dissolved in dichloromethane and then precipitated with excess hexane. The product was filtered to give 200 mg (0.68 mmol, 90% yield) of an off-white solid (8), also known as 6S-benzylhexahydro-5-oxo-5H-thiazolo [3,2-a] pyridine-3R-carboxylic acid acid.
-89H NMR (CD30D) d 1,71-1,82 (m, 3H), 2,12-2,17 (m, IH), 2,67 (dd, IH, J= 14 a 11 Hz), 2,77-2,81 (m, IH), 3,30-3,40 (m, 3H), 4,81 (dd, IH J= 8,5 a 4,9 Hz), 5,16 (t, IH J-7,5 Hz), 7,18-7,31 (m, 5H).-89H NMR (CD3OD) d 1.71-1.82 (m, 3H), 2.12-2.17 (m, 1H), 2.67 (dd, 1H, J = 14 and 11 Hz), 2 77-2.81 (m, 1H), 3.30-3.40 (m, 3H), 4.81 (dd, 1H J = 8.5 and 4.9 Hz), 5.16 (t, 1H (J = 7.5 Hz), 7.18-7.31 (m, 5H).
OH (COCI)2 OH (COCI) 2
----------►---------- ►
CiC
Oxalyl chlorid (9) (25 g, propiónová kyselina (20 ml, 0,14 mól). Toto sa cez noc miešalo. Výsledná zmes bola destilovaná za 84% výťažku bezfarebnej kvapaliny (10), chloridu kyseliny cyklohexán propiónovej.Oxalyl chloride (9) (25 g, propionic acid (20 mL, 0.14 mol)) was stirred overnight The resulting mixture was distilled in 84% yield of a colorless liquid (10), cyclohexane propionic acid chloride.
OABOUT
0,197 mól) bol ochladený na 0 °C a bola pridaná cyklohexán0.197 mol) was cooled to 0 ° C and cyclohexane was added
1. n-BuLi / THF / -78oC1. n-BuLi (THF) -78 ° C
HN OHN O
CH3 PhCH 3 Ph
2.Second
CH3 PhCH 3 Ph
ClCl
Pomocný chirálny (11) (13,6 g 76,7 mmól, 1 ekv.) bol rozpustený v THF a ochladený na -78 °C. Potom bol pridaný n-BuLi (52,8 ml, 84,4 mmól, 1,2 ekv.) a nechaný 30 min (tmavo oranžový roztok). Potom bol pridaný chlorid kyseliny (10) (13,4 g, 76,6 mmól, 1 ekv.) a nechal sa miešať cez noc. Ďalej sa spracoval rýchlym ochladením s etylacetátom nasýteným chloridom amónnym., extrakty boli premyté s vodou a soľankou, vysušené nad síranom sodným a skoncentrované.Z pevnej kolóny so suchou náplňou, (hexán : etylacetát 6:1) vytiekol čistý produkt. Toto poskytlo bielu tuhú látku (12), ktorá bola rekryštalizovaná z éteru a hexánu, za vzniku menovanej zlúčeniny, v 78% výťažku.Auxiliary chiral (11) (13.6 g 76.7 mmol, 1 eq) was dissolved in THF and cooled to -78 ° C. Then n-BuLi (52.8 mL, 84.4 mmol, 1.2 eq.) Was added and left for 30 min (dark orange solution). Acid chloride (10) (13.4 g, 76.6 mmol, 1 eq) was then added and allowed to stir overnight. It was further worked up by rapid cooling with ethyl acetate saturated with ammonium chloride. The extracts were washed with water and brine, dried over sodium sulfate and concentrated. A solid product (hexane: ethyl acetate 6: 1) eluted the pure product. This gave a white solid (12) which was recrystallized from ether and hexane to give the title compound in 78% yield.
[a]D = -20,1 (c=l, EtOH), MP/BP, mp = 90,5 - 91,5 °C[α] D = -20.1 (c = 1, EtOH), MP / BP, mp = 90.5-91.5 ° C
1HNMR(CDC13) δ 0,86-1,10 (M, 5H), 1,18-1,30 (m 4H), 1,54-1,75 (m, 7H), 2,862,97 (m, 2H), 4,70-4,76 (m, IH), 5,65 (d, IH, J= 7,2 Hz), 7,28-7,42 (m, 5H).1 HNMR (CDCl 3 ) δ 0.86-1.10 (M, 5H), 1.18-1.30 (m 4H), 1.54-1.75 (m, 7H), 2,862.97 (m, 2H), 4.70-4.76 (m, 1H), 5.65 (d, 1H, J = 7.2 Hz), 7.28-7.42 (m, 5H).
-9QVýchodiskový materiál (12) (9,13 g, 29 mmól, 1 ekv.) bol rozpustený v THF a ochladený na 78 °C, potom bol počas 40 min po kvapkách pridávaný LiHMDS (31,9 ml, 31,9 mmól, 1,1 ekv.). Potom o 30 min neskoršie bol pomaly počas 10 min. pridávaný alylbromid (7,5 ml, 86,9 mmól, 3 ekv.). Zmes bola nechaná cez noc aby sa zahriala. Spracovanie bolo zakončené ochladením s nasýteným chloridom amónnym, extrakciou s etylacetátom, premytím s 10% tiosíranom sodným, a odfarbením s aktívnym uhlím, sušením nad síranom sodným a skoncentrované vo vákuu. Produkt bol získaný ako žltý olej (13), v 96% výťažku.The starting material (12) (9.13 g, 29 mmol, 1 eq.) Was dissolved in THF and cooled to 78 ° C, then LiHMDS (31.9 mL, 31.9 mmol) was added dropwise over 40 min. 1.1 eq). Then 30 min later was slowly over 10 min. allyl bromide (7.5 mL, 86.9 mmol, 3 eq.) was added. The mixture was allowed to warm overnight. The work up was quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with 10% sodium thiosulfate, and decolourised with charcoal, dried over sodium sulfate and concentrated in vacuo. The product was obtained as a yellow oil (13) in 96% yield.
[a]D = +9,5 (c=l,EtOH),[α] D = +9.5 (c = 1, EtOH),
1HNMR(CDC13) δ 0,92-1,10 (M, 5H), 1,10-1-35 (m, 5H), 1,63-1,75 (m, 6H), 2,272,42 (m, 2H), 4,01-4,14 (m, 1H), 4,76-4,85 (m, 1H), 5,00-5,07 (m, 2HO, 5,65 (d, 1H, J= 7 hz), 5,64-5,88 (m, 1HO, 7,27-7,46 (M, 5H).1 HNMR (CDCl 3 ) δ 0.92-1.10 (M, 5H), 1.10-1-35 (m, 5H), 1.63-1.75 (m, 6H), 2.272.42 (m 2H, 4.01-4.14 (m, 1 H), 4.76-4.85 (m, 1 H), 5.00-5.07 (m, 2 H, 5.65 (d, 1 H, J = 7 Hz, 5.64-5.88 (m, 1H, 7.27-7.46 (M, 5H)).
K bóran dimetylsulfidovému komplexu bol pridaný pri -12 °C 2-metyl-2-butén. Reakcia bola pri tejto teplote udržovaná 15 min. a potom bola ohriata na 0 °C, a potom sa nechala miešať 2 hod. Potom bol pridaný k zmesi štartovacej látky (13) v THF za použitia obojstrannej ihly pri 0 °C disilamyl bóran.Zmes sa nechala miešať 2 hod., po ktorých bolo rozpúšťadlo odstránené a zvyšok bol rozpustený v dichóorometane. Toto bolo opatrne pridané k suspenzii pyridínium chlórchromanu v dichlórmetáne, ktorá bola v banke opatrenej refluxom. Po poklese počiatočnej exotermickej reakcii, zmes bola refluxovaná 1 hod. pri 50 °C. Tmavo hnedá tekutina bola rozpustená v etylacetáte a prefiltrovaná cez Florisil. Čierny zvyšok PCC bol extrahovaný s etylacetátom a prefiltrovaný cez ten istý florisil. Po skoncentrovaní fíltrátu sa získal 78% výťažok žltého gumovitého produktu (14).To the borane dimethylsulfide complex was added 2-methyl-2-butene at -12 ° C. The reaction was maintained at this temperature for 15 min. and then warmed to 0 ° C, and then allowed to stir for 2 hours. The disilamyl borane was then added to the mixture of the starting material (13) in THF using a double sided needle at 0 ° C. The mixture was allowed to stir for 2 hours, after which the solvent was removed and the residue was dissolved in dichloromethane. This was carefully added to a suspension of pyridinium chlorochromate in dichloromethane which was in a reflux flask. After the initial exothermic reaction decreased, the mixture was refluxed for 1 hour. at 50 ° C. The dark brown liquid was dissolved in ethyl acetate and filtered through Florisil. The black PCC residue was extracted with ethyl acetate and filtered through the same florisil. Concentration of the filtrate gave a 78% yield of a yellow gum (14).
[a]D=-17,8 (¢=1,245, EtOH)[α] D = -17.8 (¢ = 1.245, EtOH)
-91 1HNMR(CDC13) δ 0,89-1,18 (m, 5H), 1,20-1,47 (m, 8H), 1,60-1,74 (m, 6H) 1,832,00 (m, 1H) 2,48-2,53 (m, 2H), 3,90-4,10 (m, 1HO, 4,12-4,16 (m, 1H), 4,76-4,80 (m, 1HO, 5,67 (d, 1H, J=7Hz), 7,27-7,46 (m, 5H), 9,77 (s, 1H).-91 1 HNMR (CDCl 3 ) δ 0.89-1.18 (m, 5H), 1.20-1.47 (m, 8H), 1.60-1.74 (m, 6H) m, 1H) 2.48-2.53 (m, 2H), 3.90-4.10 (m, 1H, 4.12-4.16 (m, 1H), 4.76-4.80 (m, 1H) m, 1H, 5.67 (d, 1H, J = 7 Hz), 7.27-7.46 (m, 5H), 9.77 (s, 1H).
CO2EtCO 2 Et
Získaný aldehyd (14) (7,7 g surový, 20,8 mmól, 1 ekv.), bol rozpustený v 75 ml toluénu. K roztoku bolo pridané katalytické množstvo p- toluénsulfónovej kyseliny (50 mg), 10 g 4 A molekulového sita a etylester L-cysteínu (3,87 g, 20,8 mmól, 1 ekv.) Zmes sa cez noc nechala miešať, prefiltrovala sa a skoncentrovala. Zvyšok bol purifikovaný pomocou sikagélovej chromatografie (hexán : etylacetát 6 : 1), pričom sa získalo 6,36 g produktu (15) v 61% výťažku.The obtained aldehyde (14) (7.7 g crude, 20.8 mmol, 1 eq) was dissolved in 75 mL toluene. To the solution was added a catalytic amount of p-toluenesulfonic acid (50 mg), 10 g of 4 A molecular sieve and L-cysteine ethyl ester (3.87 g, 20.8 mmol, 1 eq.) The mixture was allowed to stir overnight, filtered and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 6: 1) to give 6.36 g of the product (15) in 61% yield.
[a]D=-48,3 (c=l,095, EtOH)[α] D = -48.3 (c = 1.095, EtOH)
1HNMR(CDC13) δ 0,84-0,98 (m, 4H), 1,11-1,38 (m, 7H), l,50-l,90(m, 1OH), 2,802,99 (m, 1H), 3,24-3,34 (m, 1H), 3,77-4,29 (m, 4H), 4,46-4,81 (m, 2H), 5,66 (d, lh, J= 7 Hz), 7,27-7,46 (m, 5H).1 HNMR (CDCl 3 ) δ 0.84-0.98 (m, 4H), 1.11-1.38 (m, 7H), 1.50-1.90 (m, 1OH), 2.802.99 (m 1H, 3.24-3.34 (m, 1H), 3.77-4.29 (m, 4H), 4.46-4.81 (m, 2H), 5.66 (d, 1h) J = 7 Hz), 7.27-7.46 (m, 5H).
OABOUT
i.i.
SWITH
NHNH
CHjCH
Phph
Me3AI / DCMMe 3 Al / DCM
P*P *
0°C RT2 ° C RT
'CO2EtCO 2 Et
Východiskový materiál (15) (1,97 g, 3,9 mmól, 1 ekv.) bol rozpustený v 20 ml suchého dichlórmetánu a ochladený na 0 °C. Po kvapkách bol pridaný trimetylalumínium (5,9 ml, 11,8 mmól, 3 ekv.), a zmes sa nechala miešať cez noc. Po kompletnej reakcii, dokázanej pomocouThe starting material (15) (1.97 g, 3.9 mmol, 1 eq) was dissolved in 20 mL dry dichloromethane and cooled to 0 ° C. Trimethylaluminum (5.9 mL, 11.8 mmol, 3 eq) was added dropwise, and the mixture was allowed to stir overnight. After complete reaction, proved by
-92HPLC, sa pridával metanol, pokiaľ sa nevytvorila žltá tuhá hmota. Na jej rozpustenie bol pridaný dichlórmetán a celá zmes bola miešaná cez 15-30 min. a potom prefiltrovaná. Zvyšok po zkoncentrovaní vo vákuu bol preliaty cez rýchlu kolónu (hexán : etylacetát 6 : 1), aby sa odstránili vedľajšie a čo najviac možných polárnych rozkladových produktov, za 50% výťažku žltého oleja (16).-92HPLC, methanol was added until a yellow solid formed. Dichloromethane was added to dissolve and the whole was stirred for 15-30 min. and then filtered. The residue after concentration in vacuo was passed through a flash column (hexane: ethyl acetate 6: 1) to remove by-products and as many polar decomposition products as possible in 50% yield of a yellow oil (16).
1HNMR(CDC13) δ 0,83-0,98 (m, 2H), 1,09-1,38 (m, 1OH), 1,57-2,00 (m, 11H), 2,122,18 (m, IH), 2,49-2,54 (m, IH), 3,10 (dd, IH, >11 a 6 Hz), 3,27 (dd, IH, >11,5 a 8,0 Hz), 4,11-4,25 (m, 2H), 4,88 (dd, IH, >11,0 a 5,0 Hz), 5,14 (dd, IH >10 a 6 Hz).1 HNMR (CDCl 3 ) δ 0.83-0.98 (m, 2H), 1.09-1.38 (m, 1OH), 1.57-2.00 (m, 11H), 2.122.18 (m (IH), 2.49-2.54 (m, IH), 3.10 (dd, IH,> 11 and 6 Hz), 3.27 (dd, IH,> 11.5 and 8.0 Hz) 4.11-4.25 (m, 2H), 4.88 (dd, 1H, > 11.0 and 5.0 Hz), 5.14 (dd, 1H > 10 and 6 Hz).
Východiskový materiál (16) (0,95 g, 2,9 mmól, 1 ekv.) bol rozpustený v 10 ml dioxánu. Roztok bol ochladený na 10 °C a bol k nemu pridaný LiOH . F^O (0,123 g, 2,9 mmól, 1 ekv.) rozpustený v 10 ml vody. Kúpeľ bola odstránená a zmes sa miešala pri izbovej teplote 1 hod. Tenkovrstvová chromatografia ukázala kompletne prebehnutú reakciu a rozpúšťadlo bolo odparené pod vákuom. Získaná vodná vrstva bola (2 x) premytá éterom, okyslená s 10% kyselinou citrónovou a extrahovaná (3 x) s dichlórmetánom. Kombinované extrakty boli vysušené nad síranom sodným a koncentrované za vzniku bielej tuhej látky, ktorá bola rekryštalizovaná z éteru. Koncentráciou filtrátu a purifíkáciou silikagélovou kolónovou chromatografiou (hexán : etylacetát 2 : 1) sa získalo viac produktu (17) s b.t. 198,2 - 199 °C.The starting material (16) (0.95 g, 2.9 mmol, 1 eq) was dissolved in 10 mL dioxane. The solution was cooled to 10 ° C and LiOH was added. F 2 O (0.123 g, 2.9 mmol, 1 eq) dissolved in 10 mL water. The bath was removed and the mixture was stirred at room temperature for 1 hour. Thin layer chromatography showed the reaction was complete and the solvent was evaporated under vacuum. The resulting aqueous layer was washed (2X) with ether, acidified with 10% citric acid, and extracted (3X) with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated to give a white solid, which was recrystallized from ether. Concentration of the filtrate and purification by silica gel column chromatography (hexane: ethyl acetate 2: 1) gave more product (17) with m.p. 198.2-199 ° C.
1HNMR (DMSO-d6) d 0,78-0,93 (m, 2H), 1,11-1,27 (m, 5H), 1,34-1,36 (M, IH), 1,511,56 (m, IH), 1,60-1,75 (m, IH), 1,82-1,87 (m, IH), 2,15-2,18 (m, IH), 2,37-2,41 (m, IH), 3,03 (dd, IH, > 11,5 a 5,5 Hz), 3,35-3,38 (m, 2H), 4,83 (dd, IH, >9a4Hz),1 HNMR (DMSO-d 6) d 0.78-0.93 (m, 2H), 1.11-1.27 (m, 5H), 1.34-1.36 (M, 1H), 1.511.56 ( m, 1H), 1.60-1.75 (m, 1H), 1.82-1.87 (m, 1H), 2.15-2.18 (m, 1H), 2.37-2, 41 (m, 1H), 3.03 (dd, IH,> 11.5 and 5.5 Hz), 3.35-3.38 (m, 2H), 4.83 (dd, IH,> 9 and 4 Hz) .
4,95 (dd, IH, >8a5,5 Hz).4.95 (dd, 1H,> 8 and 5.5 Hz).
C3Z /C3Z /
NN
HN N i-.HN N i-.
Čozwhich
HN NHHN NH
-93BOC-DiCBz Arg (18) (17,6 g, 14,0 mmól) bol rozpustený bezvodom THF (40 ml) a ochladený na 0 °C. Potom bol pridaný trietylamín (2,2 ml) a za ním 14,5 mmólu IM toluénového roztoku izopropyl chlórmravčanu, cez injekčnú striekačku. Reakcia sa miešala 30 min pri 0 °C a potom sa rýchlo prefiltrovala. Biela tuhá látka bola odstránená. Cez filtrát bol bol prebubiávaný čerstvo pripravený diazometán, až pokiaľ nevznikla žltá farba roztoku. Reakčná zmes sa nechala stáť cez noc v dobre vetranom odparovacom kryte ktorého zariadenie odoberie nadbytočný diazometán. Na vyzrážanie diazoketónu bol pridaný suchý éter. Produkt bol filtrovaný a vysušený vo vákuu za vzniku svetložltej páperovitej tuhej látky (4,6 g, 58%).-93BOC-DiCBz Arg (18) (17.6 g, 14.0 mmol) was dissolved in anhydrous THF (40 mL) and cooled to 0 ° C. Then triethylamine (2.2 ml) was added followed by 14.5 mmol of IM toluene solution of isopropyl chloroformate via syringe. The reaction was stirred at 0 ° C for 30 min and then quickly filtered. The white solid was removed. Freshly prepared diazomethane was bubbled through the filtrate until a yellow color appeared. The reaction mixture was allowed to stand overnight in a well ventilated evaporator enclosure, which was taken up by excess diazomethane. Dry ether was added to precipitate the diazoketone. The product was filtered and dried under vacuum to give a pale yellow fluffy solid (4.6 g, 58%).
Diazoketón (19) (lg, 1,77 mmól) bol rozpustený v THF (20 ml) a k tomuto roztoku bola pridaná pri 0 °C, IM HCI v éteri (20 ml).Reakcia sa nechala miešať cez noc pri izbovej teplote, a počas tohoto času sa vytvorila biela zrazenina. Precipitácia bola dosiahnutá pridaním éteru. Filtráciou a sušením látky sa získal produkt (20) (1,02 g, 100%).Diazoketone (19) (1g, 1.77 mmol) was dissolved in THF (20 mL) and this solution was added at 0 ° C, 1M HCl in ether (20 mL). The reaction was allowed to stir overnight at room temperature, and during this time a white precipitate formed. Precipitation was achieved by addition of ether. Filtration and drying of the product gave 20 (1.02 g, 100%).
1HNMR (DMSO-d6) δ 1,65-1,77 (m, 3H), 2706-2,50 (m, 1H), 3,86-3,90 (m, 2H),1 HNMR (DMSO-d 6) δ 1.65-1.77 (m, 3H), 2706-2.50 (m, 1H), 3.86-3.90 (m, 2H),
4,76 (d, 1H, J= 18,7 Hz), 4,95 (d, 1H, J=18Hz), 7,35 (s, 2H), 7,35-7,41 (m, 10H), 8,71 (br s, 3H), 10,1 (br s, 2H).4.76 (d, 1H, J = 18.7Hz), 4.95 (d, 1H, J = 18Hz), 7.35 (s, 2H), 7.35-7.41 (m, 10H) 8.71 (br s, 3H), 10.1 (br s, 2H).
C NMR (DMSO-d6) δ 23,7, 26,4, 47,2, 47,9, 56,2, 68,0, 69,3, 128,6, 126,7, 128,8, 128,9, 135,2, 135,9, 153,4, 157,4, 198,9.C NMR (DMSO-d 6) δ 23.7, 26.4, 47.2, 47.9, 56.2, 68.0, 69.3, 128.6, 126.7, 128.8, 128, 9, 135.2, 135.9, 153.4, 157.4, 198.9.
HN NC5Z .~*NHN NC5Z
NN
NHNH
1,42 mmól) v THF (50 ml) pri 0 °C, a v prítomnosti N-metyl1.42 mmol) in THF (50 mL) at 0 ° C, and in the presence of N-methyl
S?WITH?
K zlúčenine (17) (0,422 morfolínu bol pomaly pridaný IM toluénový roztok izopropylchlórmravčanu (1,71 ml). Reakcia bežala za miešania pri 0 °C, 30 min., a potom bola v malých častiach spracovaná s aminochlórmetylketónu (20). Kompletne reakcia prebehla ďalším 15 min. miešaním a pridaním N-metylmorfolínu (0,19ml). Reakcia sa nechala miešať pri izbovej teplote 3 hod., potom sa etrahovala etylacetátom, po ktorom nasledovalo premývanie so soľankou a 10% kyselinou citrónovou. Po odstránení organického rozpúšťadla sa získala biela penovitá látka (21) (1,03 g, 96%), ktorá bola použitá bez ďalšej purifikácie.To compound (17) (0.422 morpholine) was slowly added 1M toluene solution of isopropyl chloroformate (1.71 mL) The reaction was stirred with stirring at 0 ° C, 30 min, and then treated in small portions with aminochloromethylketone (20). The reaction was allowed to stir at room temperature for 3 hours, then extracted with ethyl acetate, followed by washing with brine and 10% citric acid. gave a white foam (21) (1.03 g, 96%) which was used without further purification.
1HNMR(CDC13) δ 0,07-0,97 (m, 1H), 1,15-1,41 (m, 7H), 1,62-1,91 (m, 1OH), 2,102,16 (m, 1H), 2,43-2,48 (m, 1H), 2,74-2,80 (m, 1H), 3,01-3,07 (m, 1H), 3,87-3,94 (m,1 HNMR (CDCl 3 ) δ 0.07-0.97 (m, 1H), 1.15-1.41 (m, 7H), 1.62-1.91 (m, 1OH), 2,102.16 (m 1 H, 2.43-2.48 (m, 1 H), 2.74-2.80 (m, 1 H), 3.01-3.07 (m, 1 H), 3.87-3.94 (m,
-941Η), 4,11-4,19 (m, 2H), 4,60-4,66 (m, 1H), 4,74-4,86 (m, 2H), 5,09-5,24 (m, 4H),-941Η), 4.11-4.19 (m, 2H), 4.60-4.66 (m, 1H), 4.74-4.86 (m, 2H), 5.09-5.24 (m, 4H)
47,30-7,39 (m, 1OH), 7,95 (d, 1H, J= 8 Hz), 9,4 (br s. 1H), 9,56 (br s. 1H).47.30-7.39 (m, 1H), 7.95 (d, 1H, J = 8 Hz), 9.4 (br s, 1H), 9.56 (br s, 1H).
PRÍKLAD 3EXAMPLE 3
Z (N-t-BOC-N-tosyl) butyrylketoarginínu (240 mg, 0,525 mmól), bola odstránená chrániacej skupina použitím 30% trifluóroctovej kyseliny v dichlórmetáne. Po odstránení chrániacej skupiny bol derivát arginínu, spojený smimetickou (8) (100 mg, 0,343 mmól) v DMF za alkalických podmienok (EtN, pH=8-9), ako dehydratačné činidlo bol použitý BOP (228 mg, 0,52 mmól). Kompletná reakcia prebehla za 3-4 hod. Po extrakcii s etylacetátom nasledovalo za sebou idúce premývanie so soľankou a 10% vodným roztokom kyseliny citrónovej za vzniku surového produktu. Surový produkt bol purifikovaný kolónovou chromatografiou, čím sa získalo 181 mg (76%) čistého produktu. Na odstránenie tosylovej skupiny z tohto produktu sa použil HF. Purifikáciou izolovaného produktu bez ochrannej skupiny, pomocou HPLC sa získal BCH-2737.From (N-t-BOC-N-tosyl) butyryl ketoarginine (240 mg, 0.525 mmol), the protecting group was removed using 30% trifluoroacetic acid in dichloromethane. After deprotection, the arginine derivative, coupled with the smimetic (8) (100 mg, 0.343 mmol) in DMF under alkaline conditions (EtN, pH = 8-9), was used BOP (228 mg, 0.52 mmol) as dehydrating agent. . The reaction was complete in 3-4 hours. Extraction with ethyl acetate was followed by successive washing with brine and 10% aqueous citric acid solution to give the crude product. The crude product was purified by column chromatography to give 181 mg (76%) of pure product. HF was used to remove the tosyl group from this product. Purification of the isolated, deprotected product by HPLC gave BCH-2737.
PRÍKLAD 4EXAMPLE 4
1. HS-CH2-CO2H1. HS-CH2-CO2H
NHCOÍ ( NMM/THF/RT ncs:NHCO 3 (NMM / THF / RT ncs:
2. BBR3/DCM2. BBR 3 / DCM
OABOUT
Chlórmetylketón (21) (0,188 g, 0,254 mmól) bol rozpustený v THF (10 ml), upravený s NMM (0,036ml), a následne s merkaptooctovou kyselinou (0,02 ml, 0,299 mmól). Reakčná zmes bola miešaná pri izbovej teplote cez noc. Po etrakcii reakčnej zmesi s etylacetátom, následnom po sebe idúcom premývaní so soľankou a 10% kyselinou citrónovou, a po odparení organickéhoChloromethylketone (21) (0.188 g, 0.254 mmol) was dissolved in THF (10 mL), treated with NMM (0.036 mL) followed by mercaptoacetic acid (0.02 mL, 0.299 mmol). The reaction mixture was stirred at room temperature overnight. After reaction of the reaction mixture with ethyl acetate, followed by successive washing with brine and 10% citric acid, and evaporation of the organic
-95rozpúšťadla sa získal surový produkt ktorý bol purifikovaný kolónovou chromatografiou za vzniku penovitého tuhého produktu (0,125 g, 62%).A -95 solvent gave the crude product which was purified by column chromatography to give a foamy solid (0.125 g, 62%).
Tento prekurzor s ochrannou skupinou (0,125 g, 0,154 mmólov) bol rozpustený v DCM (5 ml) a ochladený na -78 °C. Pomaly bol pridávaný IM roztok BBr v DCM (1,54 ml, 1,54 mmól). Reakčná zmes bola miešaná pri izbovej teplote 5 hod., potom ochladená na -78 °C a zas spracovaná s bezvodým metanolom (2 ml). Reakcia bola prenesená na izbovú teplotu a nechala sa miešať ďalšie 2 hod. Rozpúšťadlo bolo odstránené za zníženého tlaku a zvyšok bol rozdelený medzi éter a vodu. Vodná vrstva bola zbieraná, lyofilizovaná a po HPLC a lyofilizácii bol získaný konečný produkt (23) vo forme prášku.This protecting group precursor (0.125 g, 0.154 mmol) was dissolved in DCM (5 mL) and cooled to -78 ° C. A 1M solution of BBr in DCM (1.54 mL, 1.54 mmol) was added slowly. The reaction mixture was stirred at room temperature for 5 hours, then cooled to -78 ° C and treated again with anhydrous methanol (2 mL). The reaction was brought to room temperature and allowed to stir for an additional 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ether and water. The aqueous layer was collected, lyophilized, and after HPLC and lyophilization the final product (23) was obtained as a powder.
Produkty hore opísaných reakcii môžu byť získané vo voľnej forme, alebo vo forme ich solí. Okrem toho môžu byť produkty získané vo farmaceutický akceptovateľnej kyseliny prídavkom solí reagujúcej jednou z voľných báz s kyselinou. Podobne, produkt môže byť získaný ako farmaceutický akceptovateľná soľ, reagovaním jednej z voľných karboxylových kyselín s bázou. Podobne, pôsobením bázy alebo kyseliny na soľ, sa regeneruje voľný amid.The products of the reactions described above can be obtained in free form or in the form of their salts. In addition, the products obtained in a pharmaceutically acceptable acid may be added by the addition of salts reacting one of the free bases with an acid. Similarly, the product can be obtained as a pharmaceutically acceptable salt by reacting one of the free carboxylic acids with a base. Similarly, by treating the salt with a base or acid, the free amide is regenerated.
-96PRÍKLAD 5EXAMPLE 5
Všeobecná metóda syntézy zlúčenín vzorca Π alebo ΙΠ.General method for the synthesis of compounds of formula Π or ΙΠ.
ch3cnch 3 cn
NaCN8H3 NaCN8H 3
RT 16 hiRT 16 hi
KHMDS/THFKHMDS / THF
Tosyl NgTosyl Ng
ako v príklade 3as in Example 3
-97Príklad 6-97Example 6
Syntéza zlúčeniny:Synthesis of compound:
(16 >(16>
KROK 1:STEP 1:
Syntéza terc, butylesteru 2-benzyloxykarbonylamino-4-hydroxybutánovej kyseliny oSynthesis of tert-butyl 2-benzyloxycarbonylamino-4-hydroxybutanoate
1) \ A )—o Cl1) \ A) —o Cl
N MM. THFN MM. THF
2) NaBH4. MeOH2) NaBH 4 . MeOH
NHZ (Cvl'lohexvi).NH.HOOCXzZJxco NHZ (Cv-hexvi). NH.HOOC XzZ Jx co
HOHO
NHZNHZ
CO.t-BuCO.t-Bu
K roztoku kyseliny asparágovej s chránenou skupinou (1) (Bachem) 2,5 g, 4,95 mmólov) v 50 ml bezvodého tetrahydrofiiránu (THF), pri -100C, pod dusíkom, bol pridaný N-metylmorfolín (109 μΐ, 0,2 ekv.) a izopropyl chlórmravčan (1,0M/ toluén : 384 μΐ, 1,1 ekv.Roztok sa miešal 60 min. pri -10 °C. V inej banke bol suspendovaný NaBH^ (375 mg, 2 ekv.) v bezvodej zmesi (THF/MeOH (50ml), pri -78 °C, pod dusíkom. Táto suspenzia sa miešala pri -78 °C, 30 min. Zmiešaný anhydridový roztok bol potom po kvapkách pridávaný k NaBH^ cez kanylu, a výsledný roztok bol miešaný 3 hod. pri -78 °C. Potom bola pridaná kyselina octová (2,8 ml, lOekv.) a roztok bol zohriaty na izbovú teplotu (30 min). Rozpúšťadlá boli potom odparené a zvyšok bol daný do etylacetátu a premytý s nasýteným roztokom NaHCO^ (2x) a so soľankou. Organická vrstva bola vysušená nad MgSO^, tuhá látka bola prefiltrovaná a rozpúšťadlo odparené za vzniku 1,53 g (4,95 mmólov, 100%) alkoholu (2), ako priezračného oleja. 1HNMR(CDC13 400MHz):Ô 7,40-7,31 (m, 5H, ArH), 5,63 (d, 1H, J=7,3, NH), 5,13 (AB systém, 2H, J= 12,2, C^Ph), 4,43 (m, 1H, H-2), 3,69 (m, 2H, H-4), 2,17 (m, 1H, H-3), 1,63 (m, 1H, H-3), 1,48 (s, 9H, t-Bu).To a solution of protected group aspartic acid (1) (Bachem) (2.5 g, 4.95 mmol) in 50 mL of anhydrous tetrahydrofuran (THF), at -100C, under nitrogen, was added N-methylmorpholine (109 μΐ, 0, 2 equiv.) And isopropyl chloroformate (1.0M / toluene: 384 μΐ, 1.1 equiv.) The solution was stirred at -10 ° C for 60 min. In another flask was suspended NaBH 4 (375 mg, 2 equiv.) In Anhydrous mixture (THF / MeOH (50ml), at -78 ° C, under nitrogen. This suspension was stirred at -78 ° C, 30 min. The mixed anhydride solution was then added dropwise to NaBH 4 via cannula, and the resulting solution was After stirring at -78 ° C for 3 h, acetic acid (2.8 mL, 10 eq.) was added and the solution warmed to room temperature (30 min), then the solvents were evaporated and the residue was taken up in ethyl acetate and washed with sat. NaHCO 3 solution (2x) and brine The organic layer was dried over MgSO 4, the solid was filtered and the solvent evaporated to give 1.53 g (4.95 mmol, 100%) a1 methoxybenzyl alcohol (2), as a clear oil. 1 H NMR (CDC1 3 400 MHz): delta 7.40-7.31 (m, 5H, Ar-H), 5.63 (d, 1 H, J = 7.3, NH), 5 13 (AB system, 2H, J = 12.2, C-Ph), 4.43 (m, 1H, H-2), 3.69 (m, 2H, H-4), 2.17 (m 1H, H-3), 1.63 (m, 1H, H-3), 1.48 (s, 9H, t-Bu).
KROK 2STEP 2
Terc.-Butylesteru 2-benzyloxykarbonylamino-4-jódbutánovej kyseliny2-Benzyloxycarbonylamino-4-iodobutanoic acid tert-butyl ester
-98K roztoku alkoholu (2) (1,53 g, 4,95 mmólov) v zmesi CH^CN/Et 2O (50ml), pri -10 °C, pod dusíkom boli následne za sebou pridaní imidazol (607 mg, 1,8 ekv.) a fenolfosfát (2,21 g, 1,7 ekv.). Potom bol pridaný jód (2,14g, 17 ekv) v malých častiach v priebehu 15 min. Po úplnom pridaní sa vytvorila biela zrazenina a roztok bol hnedý. Toto bolo miešané 45 min. pri - 10 °C. Potom to bolo naliate do etanolu, a organická fáza bola premytá s nasýteným roztokom siričitanu sodného, nasýteným roztokom síranu meďnatého, vodou a vysušená nad síranom horečnatým. Tuhé látky boli prefiltrované a rozpúšťadlo odparené, pričom sa získal žltý olej, ktorý bol purifíkovaný rýchlou chromatografíou (silikagél, 5 až 20% octan etylnatý / hexán). Jodid (3) bol obdržaný v 83% výťažku (1,71 g), ako priezračný olejA -98K solution of alcohol (2) (1.53 g, 4.95 mmol) in CH 2 CN / Et 2 O (50 mL) at -10 ° C, under nitrogen, was subsequently added imidazole (607 mg, 1 mL). , 8 eq) and phenol phosphate (2.21 g, 1.7 eq). Then iodine (2.14g, 17 eq) was added in small portions over 15 min. Upon complete addition, a white precipitate formed and the solution was brown. This was stirred for 45 min. at - 10 ° C. Then it was poured into ethanol, and the organic phase was washed with saturated sodium sulfite solution, saturated copper sulfate solution, water and dried over magnesium sulfate. The solids were filtered and the solvent was evaporated to give a yellow oil which was purified by flash chromatography (silica gel, 5 to 20% ethyl acetate / hexane). Iodide (3) was obtained in 83% yield (1.71 g) as a clear oil
1HNMR(CDC13 400 MHz) :δ 7,41-7,31 (m, 5H, ArH), 5,35 (bd, 1H, J= 7,3, NH), 5,13 (s, 2H, CH2Ph), 4,30 (m, 1H, H-2), 3,22-3,12 (m, 2H, H-4), 2,42 (m, 1H, H-3), 2,20 (m, 1H, H-3), 1,48 (s, 9H, t-Bu).1 H NMR (CDCl 3, 400 MHz): δ 7.41-7.31 (m, 5H, ArH), 5.35 (bd, 1H, J = 7.3, NH), 5.13 (s, 2H, CH) 2 Ph), 4.30 (m, 1H, H-2), 3.22-3.12 (m, 2H, H-4), 2.42 (m, 1H, H-3), 2.20 (m, 1H, H-3), 1.48 (s, 9H, t-Bu).
KROK 3STEP 3
Syntéza terc.-butylesteru 2-benzyloxykarbonylamino-4-hexénovej kyselinySynthesis of 2-benzyloxycarbonylamino-4-hexenoic acid tert-butyl ester
K suspenzii CuJ (2,27 g, 5 ekv.), v bezvodom THF (20ml), pri -78 °C, pod dusíkom bol pomaly pridávaný 1,0 M vinylbromid horečnatý v THF (23,4 ml, 9,8 ekv.). Roztok bol potom zahriaty na10 °C (sčemal) a ochladený späť na -78 °C. Potom bol pomaly k meďnatému roztoku pridávaný roztok jodidu (3) (1,0 g, 2,39 mmólov) v bezvodom THF (3,5 ml). Reakčná zmes sa nechala miešať pri -78 °C, 2,5 hod. K zmesi bol pridávaný nasýtený roztok chloridu amónneho (50 ml), a zmes bola prenesená späť na izbovú teplotu za silného miešania. Potom bola naliata do etanolu a miešala sa 5 min. Tmavá suspenzia bola prefiltrovaná cez deliaci lievik a boli oddelené fázy. Vodná fáza bola (2 x) extrahovaná s etanolom a spojené organické extrakty boli vysušené nad síranom horečnatým. Tuhá látka bola odfiltrovaná, rozpúšťadlo odparené a surový olej bol purifíkovaný rýchlou chromatografíou (silikagél, 5 % octan etylnatý/hexán) za vzniku 0,51 g (67%) čistého alkénu (4).To a suspension of CuJ (2.27 g, 5 eq) in anhydrous THF (20 mL) at -78 ° C, under nitrogen, was slowly added 1.0 M magnesium vinyl bromide in THF (23.4 mL, 9.8 eq). .). The solution was then warmed to 10 ° C (mixed) and cooled back to -78 ° C. A solution of iodide (3) (1.0 g, 2.39 mmol) in anhydrous THF (3.5 mL) was then slowly added to the cupric solution. The reaction mixture was allowed to stir at -78 ° C, 2.5 h. To the mixture was added saturated ammonium chloride solution (50 mL), and the mixture was brought back to room temperature with vigorous stirring. It was then poured into ethanol and stirred for 5 min. The dark suspension was filtered through a separatory funnel and the phases were separated. The aqueous phase was extracted twice with ethanol, and the combined organic extracts were dried over magnesium sulfate. The solid was filtered off, the solvent was evaporated and the crude oil was purified by flash chromatography (silica gel, 5% ethyl acetate / hexane) to give 0.51 g (67%) of pure alkene (4).
1HNMR(CDC13 400 MHz) :δ 7,37-7,31 (m, 5H, ArH), 5,80 (m, 1H H_5), 5,33 (d, 1H,1 H NMR (CDCl 3, 400 MHz): δ 7.37-7.31 (m, 5H, ArH), 5.80 (m, 1H H-5), 5.33 (d, 1H,
J=7,8, NH), 5,12 (s, 2H, CH2Ph), 5,05 (d, 1H, J= 17,2, H-6), 5,01 (d, 1H, J= 10,4, H-6),J = 7.8, NH), 5.12 (s, 2H, CH2 Ph), 5.05 (d, 1 H, J = 17.2, H-6), 5.01 (d, 1 H, J = 10.4, H-6),
-994,30 (q, 1H,J=17,2, H-2), 2,16-2,08 (m, 2H, H-4), 1,92 (m, 1H, H-3), 1,74 (m, 1H,-994.30 (q, 1H, J = 17.2, H-2), 2.16-2.08 (m, 2H, H-4), 1.92 (m, 1H, H-3), 1.74 (m, 1 H,
H-3), 1,48 (s, 9H, t-Bu).H-3), 1.48 (s, 9H, t-Bu).
KROK 4STEP 4
Syntéza terc.-butylesterul-benzyloxykarbonyl-5-hydroxymetyl-2-pyrolidínkarboxylovej kyseliny.Synthesis of tert-butyl ester-benzyloxycarbonyl-5-hydroxymethyl-2-pyrrolidinecarboxylic acid.
(4) (5)(4)
K roztoku alkénu (4) (50 mg, 0,157 mmólov) v bezvodom THF (3,1 ml), pri izbovej teplote, pod dusíkom, bol pridaný octan ortutnatý (75 mg, 1,5 ekv.). Roztok sa miešal pri izbovej teplote 18 hod., potom sa ochladil na 0 °C. Potom bol pridaný nasýtený roztok NaHCO^ (2 ml), a zmes sa miešala pri 0 °C, 30 min. Potom bol pridaný KBr (0,11 g, 6 ekv.) a zmes sa miešala pri izbovej teplote 2 hod. Potom bola naliata do ^O/l^O a boli oddelené fázy. Vodná fáza bola extrahovaná s Et20 (2x) a spojené organické fázy boli vysušené nad MgSO^ Tuhá fáza bola odfiltrovaná a rozpúšťadlá odparené. Kyslík (C^) bol prebublávaný cez suspenziu NaBH^ (3,3 mg, 0,55 ekv.) v suchom DMF (0,4 ml) 1 hod., a k tomuto bol po kvapkách pridaný (injekčnou striekačkou, 3ml/hod) a roztok bromidu organoortutnatého v DMF (1,1 ml) za neustálej prítomnosti kyslíka. Prebublávanie pokračovalo 1 hod. a bol pridaný Et^C) (5 ml). Šedá suspenzia bola prefiltrovaná cez celit a filtrát bol odparený. Zvyšok bol chromatografovaný (silikagél, octan etylnatý : hexán, 4 : 6) za vzniku pyrolidinolu (5) (30 mg, 57%) ako čistý olej.To a solution of alkene (4) (50 mg, 0.157 mmol) in anhydrous THF (3.1 mL), at room temperature, under nitrogen, was added mercuric acetate (75 mg, 1.5 eq). The solution was stirred at room temperature for 18 hours, then cooled to 0 ° C. Saturated NaHCO 3 solution (2 mL) was then added, and the mixture was stirred at 0 ° C, 30 min. KBr (0.11 g, 6 eq.) Was then added and the mixture was stirred at room temperature for 2 h. It was then poured into O0 / 10 ^0 and the phases were separated. The aqueous phase was extracted with Et 2 O (2x) and the combined organic phases were dried over MgSO 4. The solid phase was filtered off and the solvents were evaporated. Oxygen (C 1) was bubbled through a suspension of NaBH 4 (3.3 mg, 0.55 eq) in dry DMF (0.4 mL) for 1 hour when added dropwise (syringe, 3ml / hour) and a solution of organo-mercuric bromide in DMF (1.1 mL) in the presence of oxygen. Bubbling continued for 1 hour. and Et 2 O (5 mL) was added. The gray suspension was filtered through celite and the filtrate was evaporated. The residue was chromatographed (silica gel, ethyl acetate: hexane, 4: 6) to give pyrrolidinol (5) (30 mg, 57%) as a clear oil.
1HNMR(CDC13 400 MHz) :δ 7,37-7,28 (m, 5H, ArH), 5,22-5,09 (m, 2H, C^Ph), 4,30 (dd, 1H, J= 1,4, 8,3,,2-H), 4,24 (m, 1H, H-5), 3,70-3,57 (m, 3H, CH2_OH), 2,25 (m, 1H), 2,13 (m, 1H), 1,92 (m, 1H), 1,34 (s, 9H t-Bu).1 HNMR (CDCl 3 400 MHz): δ 7.37-7.28 (m, 5H, ArH), 5.22-5.09 (m, 2H, C 1 H 3 O), 4.30 (dd, 1H, J = 1.4, 8.3, 2-H), 4.24 (m, 1H, H-5), 3.70-3.57 (m, 3H, CH 2 OH), 2.25 (m 1H, 2.13 (m, 1H), 1.92 (m, 1H), 1.34 (s, 9H t-Bu).
KROK5STEP 5
Syntéza terc-butylesteru l-benzyloxykarbonyl-5-karboxy-2-pyrolidínkarboxylovej kyseliny.Synthesis of 1-benzyloxycarbonyl-5-carboxy-2-pyrrolidinecarboxylic acid tert-butyl ester.
SO,-Pyr. Et,NSO, Pyr. Et, N
DMSO/CHjClj. 0°CDMSO / CHjClj. 0 ° C
Ot-Bu (5)Ot-Bu
(6)(6)
- iooK roztoku alkoholu (5) (50 mg, 0,149 mmólov) a Et2N (62 μΐ, 3ekv.) v suchom CH^C^ (0,8 ml) bol pomaly pridaný pod dusíkom, pri 0 °C, roztok komplexu SOypyridín (71 mg, 3ekv.) v suchom DMSO. Roztok bol miešaný pri 0 °C 30 min., a potom bola pridaná 10% kys. citrónová. pH bolo upravené na 4 s IM NaOH, a vodná fáza bola extrahovaná s Et2O (3x). Spojené organické extrakty boli sušené nad MgSO^. Tuhá fáza bola odfiltrovaná a roztok odparený za vzniku surového oleja, ktorý bol purifikovaný rýchlou chromatografiou (silikagél, octan etylnatý : hexán, 3 : 7). Čistý aldehyd (6) bol získaný ako čistý olej (45 mg, 90%).- a 10 ° C solution of alcohol (5) (50 mg, 0.149 mmol) and Et 2 N (62 μΐ, 3 eq.) in dry CH 2 Cl 2 (0.8 mL) was slowly added under nitrogen at 0 ° C, a solution of SOypyridine ( 71 mg, 3 eq) in dry DMSO. The solution was stirred at 0 ° C for 30 min, and then 10% aq. citric acid. The pH was adjusted to 4 with 1M NaOH, and the aqueous phase was extracted with Et 2 O (3x). The combined organic extracts were dried over MgSO 4. The solid phase was filtered off and the solution evaporated to give a crude oil which was purified by flash chromatography (silica gel, ethyl acetate: hexane, 3: 7). Pure aldehyde (6) was obtained as a clear oil (45 mg, 90%).
1HNMR(CDC13 400 MHz) :δ 9,63-9,56 (ds, 2H, CHO), 7,36-7,29 (m, 5H, ArH), 5,23-1 H NMR (CDCl 3, 400 MHz): δ 9.63-9.56 (ds, 2H, CHO), 7.36-7.29 (m, 5H, ArH), 5.23-
5,11 (m, 2H, CH2Ph), 4-57-4,19 (M, 2H, H-2, H-5), 2,30-1,97 (m, 4H, H-3, H-4), 1,47 (2s, 9H t-Bu).5.11 (m, 2H, CH 2 Ph), 4-57-4,19 (m, 2H, H-2, H-5), 2.30 to 1.97 (m, 4 H, H-3, H-4), 1.47 (2s, 9H t-Bu).
KROK 6 (7)STEP 6 (7)
MgSO4, CH2c:2MgSO 4 , CH 2 c: 2
2) Na3H(0AC); 2) Na 3 H (OAC) ;
AcOH, TH?AcOH, TH?
(ó)(about)
Pirolidín-aldehyd (6) bol naviazaný na chránenú diamino-propánovú kyselinu (7), vytvorením najprv imínu (8) (MgSO^ CH2C12). Izolácia imínu (8) sa uskutočnila filtráciou MgSO^ a odparením roztoku. Surový imín spracovaný s NaBH (OAc) a kyselinou octovou v THF, 15 hod., po extrakcii za vzniku amínu (8).The pyrrolidine-aldehyde (6) was coupled to the protected diamino-propanoic acid (7) by first forming the imine (8) (MgSO 4 CH 2 Cl 2 ). Isolation of the imine (8) was accomplished by filtration of MgSO 4 and evaporation of the solution. The crude imine treated with NaBH (OAc) and acetic acid in THF, 15 h, after extraction to give the amine (8).
KROK 7STEP 7
U* ·>U * ·>
Hi!Hi!
U -M-/ÍH (?íU -M- / IH (?
CB7 ochranná skupina amínu (8) bola odstránená hydrogenáciou s paládiom na 10% aktívnom uhlí v metanole, použitom ako katalyzátor. Katalyzátor bol odfiltrovaný a metanol bol odparený, za získania surového diamínu (9) ktorý sa môže použiť bez ďalšej purifikácie.The CB7 amine protecting group (8) was removed by hydrogenation with palladium on 10% activated carbon in methanol used as catalyst. The catalyst was filtered off and the methanol was evaporated, yielding the crude diamine (9) which can be used without further purification.
- 101 KROK 8- 101 STEP 8
OBucOBUCA
TeploHeat
--------->--------->
Cyklizácia sa uskutočnila zahriatím surového oleja (9), z kroku 7, trochu nad bod varu metanolu. Bicyklický laktám (10), bol purifíkovaný rýchlou chromatografiou.The cyclization was carried out by heating the crude oil (9), from step 7, slightly above the boiling point of methanol. The bicyclic lactam (10) was purified by flash chromatography.
KROK 9STEP 9
8CC . (10;8CC. (10;
G HG H
8CC (11)8CC (12)
Sekundárny amín bicyklického laktámu (10) bol chránený ako amid, za použitia chloridu v pyridíne. Odparenie pyridínu a spracovanie extrakciou dalo byciklický laktám-amid (11).The bicyclic lactam secondary amine (10) was protected as an amide using chloride in pyridine. Evaporation of pyridine and treatment with extraction afforded the bycyclic lactam-amide (11).
KROK 10STEP 10
9OC (i:· <í-2! 9OC (i: · < 1 - 2!
Ochranné skupiny bicyklického laktám amidu (11), BOC a terc-butylester, boli odstránené za kyslých podmienok (HCI v etylétere (Et20). Z roztoku vyprecipitovala amínová soľ (12) sa získala filtráciou.The protecting groups of the bicyclic lactam amide (11), BOC and tert-butyl ester, were removed under acidic conditions (HCl in ethyl ether (Et 2 O). The amine salt (12) precipitated from the solution by filtration.
KROK 11STEP 11
(12) (13)(12)
- 102 Zlúčenina primárneho amínu (12) bola chránená s CBZ skupinou vzniknutou reakciou benzylchlórmravčanu v acetonitrile s K^CO^ ako bázou. Extrakčné spracovanie dalo plne chránenú karboxylovú kyselinu (13), ktorá môže byť bez ďalšej purifikácie použitá pre krok 12 .The primary amine compound (12) was protected with a CBZ group formed by the reaction of benzyl chloroformate in acetonitrile with K 2 CO 2 as the base. The extraction work-up gave the fully protected carboxylic acid (13), which can be used for step 12 without further purification.
KROK 12STEP 12
Karboxylová kyselina (13) je spojená s benzotiazol ketoarginínom (14) v DMF, za použitia spojovacieho činidla BOP v prítomnosti diizopropyletylenamínu (EtNiPr). S ektrakciou s etylacetátom (EtOAc) sa získala zlúčenina 15, vo forme tuhej látky, ktorá bola chromatograficky purifikovaná .The carboxylic acid (13) is coupled with benzothiazole ketoarginine (14) in DMF, using the BOP coupling agent in the presence of diisopropylethyleneamine (EtNiPr). Elution with ethyl acetate (EtOAc) gave compound 15 as a solid which was chromatographically purified.
KROK 13STEP 13
Na odstránenie dvoch ochranných skupín CBZ (Z) zo zlúčeniny (15) sa použila katalytická hydrogenácia, s použitím 10% Pd/C ako katalyzátora. Katalyzátor sa odfiltroval a rozpúšťadlo odstránilo odparovaním, za vzniku amino-guanidínu (16).Catalytic hydrogenation was used to remove the two CBZ (Z) protecting groups from compound (15) using 10% Pd / C as a catalyst. The catalyst was filtered off and the solvent removed by evaporation to give amino-guanidine (16).
-103 Príklad 7Example 7
Syntéza zlúčeniny (10)Compound synthesis (10)
KROK 1STEP 1
(2)(2)
4-Metylmorfolín (NMM) sa pridal k roztoku karboxylovej kyseliny (2) (l,7g, 4,9 mmól, 1,0 ekv.), 4-hydroxyprolínu (3) (5,39 mmól, 1,1 ekv), a BOP činidla (2,17g, 4,9 mmól, 1,0 ekv.) v bezvodom DMF (10ml) pri teplote miestnosti. Reakčná zmes sa miešala pri teplote miestnosti cez noc, ochladila soľankou (50 ml) a etylacetátom (100 ml). Organické vrstvy sa premyli s vodnou kyselinou citrónovou (10%, 2 x 50 ml), hydrogénuhličitanom sodným (10%, 2 x 50 ml) a soľankou (50 ml). Výsledná organická vrstva sa sušila nad bezvodým síranom horečnatým, prefiltrovala a rozpúšťadlo sa odparilo. Surový zvyšok sa čistil rýchlou chromatografiou (5:4:1, etylacetát-hexán-metanol). Získalo sa 1,1 g čistého produktu v 48% výťažku.4-Methylmorpholine (NMM) was added to a solution of the carboxylic acid (2) (1.7g, 4.9 mmol, 1.0 eq), 4-hydroxyproline (3) (5.39 mmol, 1.1 eq), and BOP reagents (2.17g, 4.9mmol, 1.0eq) in anhydrous DMF (10ml) at room temperature. The reaction mixture was stirred at room temperature overnight, cooled with brine (50 mL) and ethyl acetate (100 mL). The organic layers were washed with aqueous citric acid (10%, 2 x 50 mL), sodium bicarbonate (10%, 2 x 50 mL), and brine (50 mL). The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The crude residue was purified by flash chromatography (5: 4: 1, ethyl acetate-hexane-methanol). 1.1 g of pure product were obtained in 48% yield.
1) triaylamín1) triaylamine
2) MsO2) MsO
CPCCPC
- 104 K roztoku 4-hydroxyprolínového derivátu (4) (115 mg, 240 pmól, 1,0 ekv.) v dichlórmetáne (10 ml, bezvodý) pri 0 °C sa pridal trietylamín (72 mg, 720 pmól, 3 ekv.) a metánsulfonyl chlorid (28 mg, 240 pmól, 1 ekv.) a reakčná zmes sa miešala pri teplote miestnosti. Zmes sa potom ochladila s vodným roztokom chloridu amónneho a extrahovala etylacetátom. Organická vrstva sa premyla s 10% kyselinou citrónovou a soľankou, vysušila, sfíltrovala a rozpúšťadlo sa odparilo za vzniku zlúčeniny (5).- 104 To a solution of the 4-hydroxyproline derivative (4) (115 mg, 240 pmol, 1.0 eq.) In dichloromethane (10 mL, anhydrous) at 0 ° C was added triethylamine (72 mg, 720 pmol, 3 eq.) and methanesulfonyl chloride (28 mg, 240 pmol, 1 eq) and the reaction mixture was stirred at room temperature. The mixture was then cooled with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with 10% citric acid and brine, dried, filtered and the solvent was evaporated to give compound (5).
KROK 3STEP 3
l)Hg(CAc)2 (l) Hg (CAc) 2
CF3CCCH/CPCCF3CCCH / CPC
2)Nc3H4 2) Nc 3 H 4
Na enamín (5) (1 ekv.) sa pôsobí octanom ortuťnatým (1,1 ekv.) v THF. Rozpúšťadlo sa odparilo sušením a zvyšok sa rozpustil v metanole. Výsledná organoortuťnatá zlúčenina sa redukčné štiepi s tetrahydroboritanom sodným (1,3 ekv.). Výsledný surový laktám tioéter sa čistí rýchlou chromatografiou na silikagéli za poskytnutia zlúčeniny (6).The enamine (5) (1 eq) was treated with mercuric acetate (1.1 eq) in THF. The solvent was evaporated by drying and the residue was dissolved in methanol. The resulting organo-mercuric compound was reductively cleaved with sodium borohydride (1.3 eq). The resulting crude lactam thioether was purified by flash chromatography on silica gel to afford compound (6).
KROK 4STEP 4
K roztoku laktám tioéteru (6) (1,0 ekv.) v suchom dichlórmetáne sa pridá Nchlórsukcínimid (1,0 ekv.) pri teplote 0 °C. Reakčná zmes sa zohreje na teplotu miestnosti. Ak saTo a solution of thioether lactam (6) (1.0 eq) in dry dichloromethane was added N-chlorosuccinimide (1.0 eq) at 0 ° C. The reaction mixture was warmed to room temperature. if
-105 už pri reakcii nezistí východiskový materiál, tak sa tuhá látka sfiltruje a rozpúšťadlo odparí sušením. Surový produkt (7) sa použije bez ďalšieho čistenia na krok 5.The starting material is no longer detected in the reaction, so the solid is filtered and the solvent is evaporated by drying. The crude product (7) was used without further purification for step 5.
KROK 5STEP 5
(7)(7)
PhjClliPhjClli
THFTHF
(8)(8)
K roztoku alfa-chlórtioéteru (7) (1,0 ekv.) v THF (bezvodom) sa pridá roztok fenyl meďnatanu (1,0 ekv.) (pripraveného podľa návodu známeho z literatúry) pri nízkej teplote. Keď reakčná zmes nevykazuje východiskový chlórtioéter, pridá sa etylacetát a soľanka. Organická vrstva sa suší, sfiltruje a odparí sušením za získania požadovaného produktu (8).To a solution of alpha-chlorothioether (7) (1.0 eq) in THF (anhydrous) was added a solution of phenyl copper (1.0 eq) (prepared according to literature) at low temperature. When the reaction mixture does not show the starting chlorothioether, ethyl acetate and brine are added. The organic layer is dried, filtered and evaporated by drying to give the desired product (8).
Izolovaný bicyklický laktám (8) sa hydrolyzuje s jedným ekvivalentom hydroxidu lítneho v zmesi THF a voda (1:1). Zmes sa mieša pri teplote miestnosti počas 1 hodiny. Surová zmes sa extrahuje s éterom a výsledný roztok sa naleje do 10% vodného roztoku kyseliny citrónovej a extrahuje s dichlórmetánom za vzniku odpovedajúcej karboxylovej kyseliny (9).The isolated bicyclic lactam (8) is hydrolyzed with one equivalent of lithium hydroxide in THF / water (1: 1). The mixture was stirred at room temperature for 1 hour. The crude mixture was extracted with ether and the resulting solution was poured into a 10% aqueous citric acid solution and extracted with dichloromethane to give the corresponding carboxylic acid (9).
KROK 7STEP 7
O)ABOUT)
(10)(10)
- ί 06 Neupravená karboxylová kyselina (9) sa spojí s benzyltiazol ketoarginínom v DMF za použitia BOP ako spájacieho činidla za prítomnosti diizopropyletylamínu. Extrakciou s etylacetátom sa získa tuhá látka, ktorá sa čistí na siiikagéli za vzniku chráneného amidu. CBZ ochranná skupina sa odstráni s BBr v dichlórmetáne pri teplote miestnosti, čí sa nakoniec získajú bicyklické benzotiazol ketoarginínové inhibítory (10).The untreated carboxylic acid (9) is coupled with benzylthiazole ketoarginine in DMF using BOP as coupling agent in the presence of diisopropylethylamine. Extraction with ethyl acetate gave a solid which was purified on silica to give the protected amide. The CBZ protecting group is removed with BBr in dichloromethane at room temperature to finally give the bicyclic benzothiazole ketoarginine inhibitors (10).
Nasledujúce zlúčeniny sa pripravili okrem toho tak, že sa uskutočnili vhodné substitúcie produktov, aby sa získali konečné zlúčeniny.In addition, the following compounds were prepared by making appropriate product substitutions to obtain the final compounds.
Zlúčenina #11Compound # 11
(11) Lnh ' ' H N(11) Lnh 'H N
Zlúčenina #12Compound # 12
(12)(12)
-107 --107 -
Príklad 8Example 8
Komerčne vhodný monoetylester chlorid kyseliny glutarovej (1) (20 ml, 0,144 mól) sa rozpustil v 40 ml suchého tetrahydrofuránu (THF) a ochladil sa na -15 °C. Prebytok čerstvo pripraveného diazometánu v 300 ml éteru sa vložil kanylou pri teplote -15 °C do roztoku. Zmes sa nechala zohriať na teplotu miestnosti počas noci. Prebytok diazometánu sa evakuoval z nádoby prúdom argónu. Aby sa reakcia ukončila pridalo sa 75 ml 1 N HCI v éteri pri teplote 0 °C a zmes sa nechala zohrievať na teplotu miestnosti počas 5 hodín. Objem rozpúšťadla sa zredukoval a potom premyl 2 x 5% NaHCOj. vysušil Na2CO3 a odparil za získania surového chlórmetylketónu (20,46 g, 79%), ktorý sa použil v ďalšom kroku bez ďalšieho čistenia.The commercially acceptable monoethyl ester of glutaric acid chloride (1) (20 mL, 0.144 mol) was dissolved in 40 mL of dry tetrahydrofuran (THF) and cooled to -15 ° C. An excess of freshly prepared diazomethane in 300 mL of ether was cannulated at -15 ° C into the solution. The mixture was allowed to warm to room temperature overnight. Excess diazomethane was evacuated from the vessel with a stream of argon. To quench the reaction, add 75 mL of 1 N HCl in ether at 0 ° C and allow the mixture to warm to room temperature for 5 hours. The solvent volume was reduced and then washed with 2 x 5% NaHCO 3. dried over Na 2 CO 3 and evaporated to give the crude chloromethyl ketone (20.46 g, 79%), which was used in the next step without further purification.
'HNMR(CDC13, 400 MHz, d 1,16-1,2 (t, 1H), 1,83-1,9 (m, 2H), 2,27-2,35 (m, 2H), 2,6-2,64 (t, 1H), 3,6 (s, 3H), 4,04 (s, 2H).1 HNMR (CDCl 3 , 400 MHz, d 1.16-1.2 (t, 1H), 1.83-1.9 (m, 2H), 2.27-2.35 (m, 2H), 2 6-2.64 (t, 1H); 3.6 (s, 3H); 4.04 (s, 2H).
KROK 2STEP 2
1 HC.H-Cvs-CtT / CH.COCNa/NcCNBH. 1 HC.H-Cs-CtT / CH.COCNa / NcCNBH.
/ ---------------3------------, MeCH.R.T o^och3 / --------------- ------------ 3, the MeCH.RT ^ OCH3
Neupravený chlórmetylketón (2) (10,04 g, 56,15 mmól) sa rozpustil v 300 ml suchého metanolu. Pridal sa octan sodný (2 ekv., 9,21 g, 112,3 mmól), nasledovne L-cysteín etylester hydrochlorid (1,3 ekv., 13,55 g, 72,98 mmól) a kyántetrahydroboritan sodný (1,4 ekv., 4,9 g, 78,59 mmól). Heterogénna zmes sa miešala pri teplote miestnosti počas 2,5 hodiny. Potom sa pridalo 200 ml metanolu, aby sa rozpustili všetky tuhé látky a pH sa udržiavalo s IN HCI. Zmes sa potom zalkalizovala nasýteným hydrogénuhličitanom sodným až do pH 8. Metano, sa odparilUntreated chloromethyl ketone (2) (10.04 g, 56.15 mmol) was dissolved in 300 mL dry methanol. Sodium acetate (2 eq., 9.21 g, 112.3 mmol) was added, followed by L-cysteine ethyl ester hydrochloride (1.3 eq, 13.55 g, 72.98 mmol) and sodium cyanoborohydride (1.4 eq.). eq., 4.9 g, 78.59 mmol). The heterogeneous mixture was stirred at room temperature for 2.5 hours. Then 200 mL of methanol was added to dissolve all solids and the pH was maintained with 1N HCl. The mixture was then basified with saturated sodium bicarbonate until pH 8. Metano, evaporated
-108 a zostávajúci vodný roztok sa premyl s etylacetátom a dichlórmetánom. Roztoky sa spojili, vysušili nad síranom sodným a odparili. Surový zvyšok sa čistil rýchlou kolónovou chromatografiou na silikagéli za použitia gradientových eluentov etylacetát/hexán v nasledujúcich pomeroch: (3:7, 5:5, 7:3) za získania cyklickej zlúčeniny (3).-108 and the remaining aqueous solution was washed with ethyl acetate and dichloromethane. The solutions were combined, dried over sodium sulfate and evaporated. The crude residue was purified by flash column chromatography on silica gel using ethyl acetate / hexane gradient eluents in the following ratios: (3: 7, 5: 5, 7: 3) to give cyclic compound (3).
'H NMR (CDC13, 400 MHz) zlúčeniny (3) d 1,21-1,27 (t, 3H), J=7,06 Hz), 1,41-1,48 (m, 2H), 1,65-1,73 (m, 2H), 2,28-2,39 (m, 4H), 2,57-2,63 (t, IH, J=10,9), 2,72-2,76 (dd, IH, J=10,7 Hz!, 2,8-2,86 (m, IH), 3,6-3,64 (d, 4H, J=2,55 Hz), 3,63 (s, 3H), 4,13-4,2 (m, 2H) ,3C NMR (CDC13,400 MHz), 13,078,19,888, 28,326, 31,133, 32,741, 35,277, 50,462, 56,394, 59,149, 60,188, 69,713, 170,182,172,52.1 H NMR (CDCl 3 , 400 MHz) of compound (3) d 1.21-1.27 (t, 3H), J = 7.06 Hz), 1.41-1.48 (m, 2H), 1 65-1.73 (m, 2H), 2.28-2.39 (m, 4H), 2.57-2.63 (t, 1H, J = 10.9), 2.72-2, 76 (dd, 1H, J = 10.7 Hz), 2.8-2.86 (m, 1H), 3.6-3.64 (d, 4H, J = 2.55 Hz), 3.63 (s, 3H), 4.13-4.2 (m, 2H) , 3 C NMR (CDCl 3 , 400 MHz), 13,078,19,888, 28,326, 31,133, 32,741, 35,277, 50,462, 56,394, 59,149, 60,188, 69.713, 170.182.172.52.
KROK 4STEP 4
O. .OCH.CH, <5^ r 3O.CHCH
Toluén / H+ Toluene / H +
RefliKRefliK
Cyklická zlúčenina (3) (913 mg, 3,32 mmól) sa rozpustila v 50 ml suchého toluénu. Pridala sa (lS)-(+)-10-gáforsulfónová kyselina (92 mg, 0,39 mmól) a zmes sa nechala refluxovať počas 4 dní. Keď sa spotreboval všetok východiskový materiál (TLC), zmes sa upravila odparením rozpúšťadla, zvyšok sa rozustil v etylacetáte a premyl 2 x 5% hydrogénuhličitanom sodným. Vrstva etylacetátu sa vysušila síranom sodným a odparila. Surový zvyšok sa čistil rýchlou kolónovou chromatografiou na silikagéli za použitia 60% etylacetátu/40% hexánu, následne 70%etylacetátu/30% hexánu za vzniku 62,5 % bicyklickej zlúčeniny (4).Cyclic compound (3) (913 mg, 3.32 mmol) was dissolved in 50 mL dry toluene. (1S) - (+) - 10-Camphorsulfonic acid (92 mg, 0.39 mmol) was added and the mixture was refluxed for 4 days. When all of the starting material (TLC) was consumed, the mixture was treated by evaporation of the solvent, the residue was dissolved in ethyl acetate and washed with 2 x 5% sodium bicarbonate. The ethyl acetate layer was dried over sodium sulfate and evaporated. The crude residue was purified by flash column chromatography on silica gel using 60% ethyl acetate / 40% hexane followed by 70% ethyl acetate / 30% hexane to give 62.5% bicyclic compound (4).
’HNMR (CDCls, 400 MHz) zlúčeniny (4) d 1,27-1,31 (t, 3H, J=7Hz), 1,5-1,6 (m, IH), 1,72-1,87 (m, 2H), 2,02-2,1 (m, IH), 2,33-2,46 (m, 2H), 2,52-2,59 (m, 2H), 2,83-2,88 (dd, IH, J=14,4 Hz), 3,14-3,18 (d, IH), 3,78-3,85 (m, IH), 4,2-4,27 (Q, 2H, J=3,9 Hz), 5,9-5,92 (t, lh, J=3,4 Hz).1 H NMR (CDCl 3, 400MHz) Compound (4) d 1.27-1.31 (t, 3H, J = 7Hz), 1.5-1.6 (m, 1H), 1.72-1.87 (m, 2H), 2.02-2.1 (m, 1H), 2.33-2.46 (m, 2H), 2.52-2.59 (m, 2H), 2.83-2 .88 (dd, 1H, J = 14.4 Hz), 3.14-3.18 (d, 1H), 3.78-3.85 (m, 1H), 4.2-4.27 (Q) (2H, J = 3.9 Hz), 5.9-5.92 (t, 1H, J = 3.4 Hz).
-109 KROK 5-109 STEP 5
ΐίΟΗ.Η2Ο.ΤΗΡ/Η2ΟΗίΟΗ.Η 2 Ο.ΤΗΡ / Η 2 Ο
O°C +G.T0 ° C + G.T
55
Bicyklická zlúčenina (4) (3,66 mg, 1,5 mmól) sa rozpustila v 25 ml THF a 5 ml vody. Pridal sa monohydrát hydroxidu lítneho (1,1 ekv., 7,05 mg, 1,68 mmól) v 2,3 ml vody pri 0 °Ca zmes sa nechala miešať pri tejto teplote 1 hodinu a pri teplote miestnosti ešte 3 hodiny. THF sa potom odparil a zvyšná vodná zmes sa okyslila pridaním kyseliny citrónovej do pH 2. Extrakciou 2 x CH2CI2 a 2 x etylacetátom, sušením kombinovanej organickej vrstvy so síranom sodným a odparením sa získal surový zvyšok, ktorý sa čistil rýchlou chromatografiou na kolóne na silikagéli za použitia 70 % etylacetátu/30 % hexánu a následne 4,7 % HOAC/etylacetát za získania čistej kyseliny (5) s 5 % výťažkom, 16 % východiskovej látky sa regenerovalo.The bicyclic compound (4) (3.66 mg, 1.5 mmol) was dissolved in 25 mL THF and 5 mL water. Lithium hydroxide monohydrate (1.1 eq., 7.05 mg, 1.68 mmol) in 2.3 mL of water at 0 ° C was added and the mixture was allowed to stir at this temperature for 1 hour and at room temperature for 3 hours. The THF was then evaporated and the remaining aqueous mixture was acidified by addition of citric acid to pH 2. Extraction with 2 x CH 2 Cl 2 and 2 x ethyl acetate, drying the combined organic layer with sodium sulfate and evaporation gave a crude residue which was purified by flash column chromatography on silica gel using 70% ethyl acetate / 30% hexane followed by 4.7% HOAC / ethyl acetate to give pure acid (5) in 5% yield, 16% starting material recovered.
'HNMR(MeOD, 400 MHz) zlúčeniny (5) d 1,57-1,69 (m, 1H), 1,70-1,80 (m, 1H), 1,81-1,89 (m, 1H), 2,05-2,12 (m, 1H), 2,35-2,5 (m, 2H), 2,51-2,66 (m, 2H), 2,86-2,91 (dd, 1H, J=13,8 4 Hz), 3,12-3,17 (d, 1H), 3,3-3,32 (m, 1H), 3,78-3,84 (m, 1H), 5,76-5,78 (t, 1H, J=3,53 Hz).1 HNMR (MeOD, 400 MHz) of compound (5) d 1.57-1.69 (m, 1H), 1.70-1.80 (m, 1H), 1.81-1.89 (m, 1H) 2.05-2.12 (m, 1H), 2.35-2.5 (m, 2H), 2.51-2.66 (m, 2H), 2.86-2.91 (dd) 1H, J = 13.8 (4 Hz), 3.12-3.17 (d, 1H), 3.3-3.32 (m, 1H), 3.78-3.84 (m, 1H) , 5.76-5.78 (t, 1H, J = 3.53 Hz).
,3C NMR (MeOD, 400 MHz) d 17,052, 27,7,28,928, 31,382, 32,096, 51,016, 55,138, 170,088, 171,24. 13 C NMR (MeOD, 400 MHz) d 17.052, 27.7, 28.928, 31.382, 32.096, 51.016, 55.138, 170.088, 171.24.
KROK 6STEP 6
ήή
K roztoku lítium bis (trimetylsilyl) amidu (5 ml 1 M THF roztok, 5 mmól) v THF (10 ml sa pridal pri teplote -78 °C roztok karboxylovej kyseliny (5) (500 mg, 2,32 mmól). VýslednýTo a solution of lithium bis (trimethylsilyl) amide (5 mL of 1 M THF solution, 5 mmol) in THF (10 mL was added at -78 ° C a solution of carboxylic acid (5) (500 mg, 2.32 mmol).
- 110 roztok sa miešal pri teplote -78 °C počas 1 hodiny. Potom sa pridal benzylbromid (0,26 ml, 2,22 mmól) a zmes sa nechala pri teplote miestnosti a miešala počas 15 hodín. Zmes sa potom vliala do 10% HCI (50 ml) a extrahovala s dichlórmetánom (4x 60 ml). Kombinovaná organická fáza sa vysušila síranom horečnatým a rozpúšťadlo sa odstránilo odparením, čím sa získal surový alkylovaný amid (6).The 110 solution was stirred at -78 ° C for 1 hour. Benzyl bromide (0.26 mL, 2.22 mmol) was then added and the mixture was left at room temperature and stirred for 15 hours. The mixture was then poured into 10% HCl (50 mL) and extracted with dichloromethane (4 x 60 mL). The combined organic phase was dried with magnesium sulfate and the solvent was evaporated to give the crude alkylated amide (6).
Surový alkylovaný amid (6) sa spojil s benzyltiazol ketoarginínom v DKíF za použitia BOP ako spájacieho činidla za prítomnosti diizopropyletylamínu. Extrakciou s etylacetátom sa získala tuhá látka, ktorá sa čistila na silikagéli za získania chráneného amidu. CBZ ochranná skupina sa odstránila s BBr v dichlórmetáne pri teplote miestnosti, čím sa nakoniec získali bicyklické benztiatol ketoarginínové inhibítory.The crude alkylated amide (6) was coupled with benzylthiazole ketoarginine in DKF using BOP as coupling agent in the presence of diisopropylethylamine. Extraction with ethyl acetate gave a solid which was purified on silica gel to afford the protected amide. The CBZ protecting group was removed with BBr in dichloromethane at room temperature to finally obtain the bicyclic benzthiol keto-arginine inhibitors.
Nasledujúce zlúčeniny sa pripravili rovnako, s tým, že sa uskutočnili vhodné substitúcie, aby sa získali konečné zlúčeniny.The following compounds were prepared in the same way, with suitable substitutions being made to obtain the final compounds.
Zlúčenina #8Compound # 8
XNH ^NH H N X NH 4 NH HN
Príklad 9Example 9
Stanovenie K hodnoty heterocyklických zlúčenínDetermination of K value of heterocyclic compounds
Afinita inhibitorov trombínu sa merala podľa metód opísaných v (DiMaio a iní J.Bio.The affinity of thrombin inhibitors was measured according to the methods described in (DiMaio et al. J.Bio.
Chem., 1990, 265:21698). Inhobícia amidolytickej aktivity ľudského trombínu sa meralaChem., 1990, 265: 21698). The inhibition of amidolytic activity of human thrombin was measured
-111 fluorometricky za použitia Tos-Gly-Pro-Arg-AMC ako fluorogenického substrátu v 50 mM TrisHCI pufri (pH 7,52 pri 37 °C) obsahujúcom 0,1 M NaCl a 0,1 % polyetylénglykol 8000 pri teplote miestnosti (Szewczuk a iní, Biochémia, 1992 31:9132).-111 fluorometrically using Tos-Gly-Pro-Arg-AMC as a fluorogenic substrate in 50 mM TrisHCl buffer (pH 7.52 at 37 ° C) containing 0.1 M NaCl and 0.1% polyethylene glycol 8000 at room temperature (Szewczuk et al., Biochemistry, 1992 31: 9132).
Hydrolýza substrátu trombínom sa monitorovala na spektrometri Varian-Cary 2000 fluorescenčnom režime (λεΧ=383 nm, Xem= 455 nm) alebo na fluorescenčnom spektrometri Hitachi F2000Tí^ (λ=383 nm, λ=455 nm), a fluorescenčná intenzita sa kalibrovala použitím AMC. Reakcia získala ustálený stav do 3 minút po zmiešaní trombínu so substrátom a inhibítorom. Ustálený stav rýchlosti sa potom meral počas niekoľkých minút. Zlúčeniny podľa vynálezu boli tiež predinkubované trombínom počas 20 minút pri teplote miestnosti pred pridaním substrátu. Ustálený stav sa dosiahol do 3 minút a meralo sa niekoľko minút. Kinetické údaje (ustálený stav rýchlosti pri rôznej koncentrácii substrátu a inhibítorov) konkurenčných inhibítorov sa analyzoval s použitím metód opísaných Segelom (1975). Nelineárny regresný program PNLIN vIMSL knižnici (IMSL, 1987), LMDER vMINPACK knižnici (More a iní, 1980) alebo Microsoft™ Excell™, sa použili na výpočet kinetických parametrov (K, V a K).Substrate hydrolysis by thrombin was monitored on a Varian-Cary 2000 spectrometer with fluorescence mode (λεΧ = 383 nm, λem = 455 nm) or Hitachi F2000 Ti ^ fluorescence spectrometer (λ = 383 nm, λ = 455 nm), and the fluorescence intensity was calibrated using AMC. The reaction became steady state within 3 minutes after mixing of thrombin with the substrate and inhibitor. The steady state speed was then measured for a few minutes. The compounds of the invention were also preincubated with thrombin for 20 minutes at room temperature before adding the substrate. Steady state was reached within 3 minutes and measured for several minutes. Kinetic data (steady state velocity at different substrate concentrations and inhibitors) of competing inhibitors were analyzed using the methods described by Segel (1975). The nonlinear PNLIN regression program in the IMSL library (IMSL, 1987), the LMDER in the MINPACK library (More et al., 1980) or Microsoft ™ Excell ™ were used to calculate kinetic parameters (K, V and K).
dTT testdTT test
Fibrínový zrážací test sa vykonal v 50 mM Tris HCI pufri (pH 7,52 pri 37 °C) obsahujúcom 0,1 M NaCl a 0,1% polyetylénglykol 8000 s 9,0 x 10-10 M (0,1 NIH jednotiek /ml) a 0,03 % (hmotnosť/objem) konečnej koncentrácie ľudského trombínu a dobytčieho fibrinogénu, jednotlivo, ako je opísané inde (Szewczuk a iní., supra). Doba zrážania sa vyniesla oproti koncentrácii inhibítora a ICó, vypočítala sa ako koncentrácia inhibítora potrebná k dvom dobám zrážania vzhľadom na kontrolu. Výsledky sú zhrnuté v Tabuľke 1 a 2 ďalej.The fibrin clotting assay was performed in 50 mM Tris HCl buffer (pH 7.52 at 37 ° C) containing 0.1 M NaCl and 0.1% polyethylene glycol 8000 with 9.0 x 10-10 M (0.1 NIH units / ml) and 0.03% (w / v) final concentrations of human thrombin and cattle fibrinogen, respectively as described elsewhere (Szewczuk et al., supra). Clotting time was plotted against inhibitor concentration and IC 50, calculated as inhibitor concentration required for two clotting times relative to control. The results are summarized in Tables 1 and 2 below.
Fibrínový zrážací testFibrin clotting test
Fibrínový zrážací test sa vykonal v podstate tak ako je opísané Krtenanskym a inými., FEBS, 1987, 211:10. Zriedený roztok inhibítora sa pripravil v 50 mM Tris HCI pufra (pH 7,8 pri 23 °C) obsahujúcom 0,1 M NaCl a 0,1% (hmotnosť/objem) polyetylénglykolu 8000. Ľudská plazma (60 μΐ, zhromaždená v citrane sodnom, krv/antikoagulant 9:1) sa pridala do mikrotitračnej nádoby (mikrotitračná platňa, Falcon) obsahujúcej 100 μΐ rôznych zriedení inhibítora. Roztok sa miešal po pridaní 50 μΐ ľudského trombínu (lnM, konečná kone.) a miešal sa počas 15 sekúnd. Zákal zrážania sa ihneď monitoroval mikroplatňovým autočítačom (Dynateck MR 5000) pri 405The fibrin clotting assay was performed essentially as described by Krtenansky et al., FEBS, 1987, 211: 10. Dilute inhibitor solution was prepared in 50 mM Tris HCl buffer (pH 7.8 at 23 ° C) containing 0.1 M NaCl and 0.1% (w / v) polyethylene glycol 8000. Human plasma (60 μΐ, collected in sodium citrate) , blood / anticoagulant 9: 1) was added to a microtitre vessel (Falcon plate) containing 100 μΐ of various inhibitor dilutions. The solution was stirred after adding 50 μΐ of human thrombin (1 nM, final horse) and stirred for 15 seconds. The turbidity of clotting was immediately monitored by a microplate reader (Dynateck MR 5000) at 405
-112 nm a zapísal každé 3 minúty. Maximálny zákal v neprítomnosti inhibítorov sa dosiahol do 60 minút. IC hodnoty sa vypočítali pri 30 minútach ako koncentrácia inhibítora, ktorá dáva polovičnú optickú hustotu kontrolnej vzorky.-112 nm and recorded every 3 minutes. Maximum turbidity in the absence of inhibitors was achieved within 60 minutes. IC values were calculated at 30 minutes as the concentration of inhibitor that gave half the optical density of the control.
Trombocytové zhlukovanie a sekréciaPlatelet aggregation and secretion
Krv z potkana sa nazbierala do ACD (6/1 v/v) kardiálnou punkciou. Suspenzia premytých trombocytov sa pripravila podľa postupu opísaného Ardlie a iní (Br. J. Haematol. 1970, 19:7 and Proc. Soc. Exp. Biol. Med., 1971, 136:1021). Konečné suspendujúce médium sa modifikovalo roztokom Tyrode ((NaCl 138 mM, KC1 2,9 mM, HEPES 20 mM, Na2HPO4 0,42 mM, NaHCCh 12 mM, CaCh , MgCl 2,0,1% glukóza, 0,35% albumín, apyráza 1 μΙ/ml pH 7,4). Výsledná suma trombocytov sa upravila na 5 000 000/μ1.Rat blood was collected by ACD (6/1 v / v) cardiac puncture. The washed platelet suspension was prepared according to the procedure described by Ardlie et al. (Br. J. Haematol. 1970, 19: 7 and Proc. Soc. Exp. Biol. Med., 1971, 136: 1021). The final suspending medium was modified with Tyrode solution ((NaCl 138 mM, KCl 2.9 mM, HEPES 20 mM, Na2HPO4 0.42 mM, NaHCCh 12 mM, CaCh, MgCl 2.0.1% glucose, 0.35% albumin, apyrase 1 μΙ / ml pH 7.4) The resulting platelet count was adjusted to 5,000,000 / μ1.
Na umožnenie merania rozsahu uvoľnenia obsahu hustých okrúhlych teliesok, trombocyty sa označili pri prvom premytí roztoku s 14C-serotonínom (5-HT) (1 pCi/10 ml premývacej kvapaliny) a uvoľnený l4C-serotonín sa stanovil postupom uvedeným v Holmsen a iní (Enzymology, 1989, 169:206). Inipramín (5 μΜ koneč. kone.) sa pridal na zistenie reabsorbcie uvoľneného serotonínu.To allow measurement of the extent of release of the dense round bodies, platelets were labeled when first washed with a solution of 14 C-serotonin (5-HT) (1 pCi / 10 ml wash liquid) and the released 14 C-serotonin was determined according to Holmsen et al. (Enzymology, 1989, 169: 206). Inipramine (5 μΜ final horse) was added to detect the reabsorption of serotonin released.
Trombocytové zhluky sa zaznamenaváli pri 37 °C v agregometri (BioData PAP-4) pri rýchlosti miešania 1 100 rpm meraním zmien svetelnej priepustnosti. Percentá zhlukovania sa stanovili 3 minúty po pridaní stimulátora (ľudský trombín 0,1 IU/ml koneč. kone.) Inhibitory sa predinkubovali 1 minútu pri 37 °C pred pridaním stimulátora. IC hodnoty reprezentujú koncentráciu potrebnú na potlačenie trombocytových zhlukov alebo sekrécií vzhľadom k 50 % kontrolných vzoriek.Platelet aggregates were recorded at 37 ° C in an aggregometer (BioData PAP-4) at a stirring speed of 1,100 rpm by measuring changes in light transmittance. Aggregation percentages were determined 3 minutes after addition of stimulator (human thrombin 0.1 IU / ml final horse.) Inhibitors were preincubated for 1 minute at 37 ° C before addition of stimulator. IC values represent the concentration required to suppress platelets or secretions relative to 50% of the control samples.
Model arteriálnej trombózyModel of arterial thrombosis
FeCE Model vyvolaného karotického arteriálneho poškodeniaFeCE Model of induced carotid arterial injury
S FeCE vyvolané poškodenie karotickej artérie (tepny) u potkanov sa vyvolalo podľa postupu opísaného Kurz, K.D., Main, R.W., Sandusky G.E., Trombosis Research 60. 269-280, 1990 and Schumacher W.A. a iní J. Pharmacology and Experimental Therapeutics 267. 12371242, 1993. Samci, Sprague-Dawley potkaní (375-410 g) sa anestetizovali uretánom (1500 mg/kg ip). Zvieratá sa uložili na podložku zohriatu na 37 °C. Karotická artéria sa vystavilaFeCE-induced carotid artery (artery) damage in rats was induced according to the procedure described by Kurz, K.D., Main, R.W., Sandusky, G.E., Trombosis Research 60, 269-280, 1990 and Schumacher W.A. and others J. Pharmacology and Experimental Therapeutics 267. 12371242, 1993. Male, Sprague-Dawley rats (375-410 g) were anesthetized with urethane (1500 mg / kg ip). The animals were placed on a plate heated to 37 ° C. The carotid artery was exposed
-113účinku cez stredovú čiaru cervikálnej incízii. Opatrná tupá disekcia sa použila na izoláciu cievy z karotickej pošvy. S použitím pinzety sa zdvihla artéria, a pod ňu sa vložili dva malé kúsky polyetylénových rúrok (PE-205), aby sa uskutočnilo účinné odstránenie. Teplotná sonda (Physitemp MT23/3) sa umiestnila medzi jedným kúskom rúrky a artériou. Ochorenie sa vyvolalo lokálnou aplikáciou na karotickú artériu hore uvedenej teplotnej sonde malého disku (3 mm dia). Whatman č. 1 pričom filtračný papier bol najskôr ponorený do 36% roztoku FeC13. Incízna oblasť sa pokryla hliníkovou fóliou, aby chránila FeCh pred degradáciou svetlom. Teplota cievy sa monitorovala počas 60 minút po aplikácii FeCh ako indikácia krvného prúdu. Zmeny teploty cievy sa zaznamenali na termistore (Cole-Palmer Model 08533-41).-113 effect across the midline of the cervical incision. Careful blunt dissection was used to isolate the vessel from the carotid vagina. Using the tweezers, the artery was lifted, and two small pieces of polyethylene tubes (PE-205) were inserted under it to effect removal. A temperature probe (Physitemp MT23 / 3) was placed between one piece of tube and the artery. The disease was induced by topical application to the carotid artery of the above small disk temperature probe (3 mm dia). Whatman č. 1 wherein the filter paper was first immersed in a 36% FeCl3 solution. The incision region was covered with aluminum foil to protect FeCh from light degradation. The vessel temperature was monitored for 60 minutes after FeCl2 administration as an indication of blood flow. Changes in vessel temperature were recorded on a thermistor (Cole-Palmer Model 08533-41).
Čas medzi aplikáciou FeCh a časom pri ktorom teplota cievy prudko klesá (>2,4 °C) sa zaznamenávala ako čas do oklúzie cievy. Zlúčeniny inhibítorov sa dávali iv ako bolus (pilulka) (mg/kg) po čom nasledovala ihneď iv infúzia (pg/kg/min. cez stehnovú žilu). Stanovilo sa, že dávka inhibitora potrebovala dvojnásobok času na oklúziu v porovnaní s kontrolnou vzorkou zvierat v ktorých poškodenie bolo vyvolané v neprítomnosti inhibitora.The time between application of FeCl 3 and the time at which the vessel temperature drops sharply (> 2.4 ° C) was recorded as the time to vessel occlusion. The inhibitor compounds were administered iv as a bolus (pill) (mg / kg) followed immediately by iv infusion (pg / kg / min via the thigh vein). It was determined that the dose of inhibitor required twice the time for occlusion compared to a control animal in which injury was induced in the absence of inhibitor.
114 Tabuľka 1114 Table 1
Antitrombocytová aktivita' μΜAntithrombocyte activity 'μΜ
’ Suspenzia premytých trombocytov z potkanov Inhibičná disociačná konštanta ľudského a-trombínu´ Suspension of washed platelets from rats Inhibitory dissociation constant of human α-thrombin
-115Tabuľka 2-115Table 2
-116Tabuľka 2 (pokračovanie)-116Table 2 (continued)
a = skoršiá elúcia jednotlivého izoméru na RP HPLC b = neskoršia elúcia jednotlivého izoméru na RP HPLC a + b - zmesa = early elution of single isomer on RP HPLC b = later elution of single isomer on RP HPLC a + b - mixture
7/7 /
- 117PATENTOVÉ NÁROKY- 117PATENT CLAIMS
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