NO310914B1 - Tiolderivater med metallopeptidasehemmende aktivitet, fremgangsmate for fremstilling derav, farmasoytiske preparater sominneholder en slik forbindelse, samt anvendelse av forbindelsenefor fremstilling av medikamenter - Google Patents
Tiolderivater med metallopeptidasehemmende aktivitet, fremgangsmate for fremstilling derav, farmasoytiske preparater sominneholder en slik forbindelse, samt anvendelse av forbindelsenefor fremstilling av medikamenter Download PDFInfo
- Publication number
- NO310914B1 NO310914B1 NO19982977A NO982977A NO310914B1 NO 310914 B1 NO310914 B1 NO 310914B1 NO 19982977 A NO19982977 A NO 19982977A NO 982977 A NO982977 A NO 982977A NO 310914 B1 NO310914 B1 NO 310914B1
- Authority
- NO
- Norway
- Prior art keywords
- phenylalanine
- phenylmethylpropionyl
- mercapto
- thiazolyl
- phenylcarbonylthio
- Prior art date
Links
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- ZRIMQZXATCDHTO-BBMPLOMVSA-N methyl (2s)-2-[[2-(benzoylsulfanylmethyl)-3-pyridin-3-ylpropanoyl]amino]-3-[4-(1,3-thiazol-2-yl)phenyl]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)C(CSC(=O)C=1C=CC=CC=1)CC=1C=NC=CC=1)C(C=C1)=CC=C1C1=NC=CS1 ZRIMQZXATCDHTO-BBMPLOMVSA-N 0.000 description 1
- DZJQJKVARYLEPT-GITCGBDTSA-N methyl (2s)-2-[[2-(benzoylsulfanylmethyl)-3-thiophen-2-ylpropanoyl]amino]-3-[4-(1,3-thiazol-2-yl)phenyl]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)C(CSC(=O)C=1C=CC=CC=1)CC=1SC=CC=1)C(C=C1)=CC=C1C1=NC=CS1 DZJQJKVARYLEPT-GITCGBDTSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Description
Foreliggende oppfinnelse omfatter tiolderivater med metallopeptidasehemmende aktivitet, oppfinnelsen omfatter særlig N-merkaptoacylfenylalaninderivater som er anvendbare ved behandling av kardiovaskulære sykdommer.
Den farmakologiske interesse med hensyn til studiene av metallopeptidasehemmende molekyler stammer fra betydningen som disse enzymer har for nivået i det kardiosirkulatoriske system.
Det er godt kjent at forbindelser med angiotensinomdannelsesenzym (ACE)-hemmende aktivitet i det vesentlige er anvendbare ved behandlingen av høyt blodtrykk, hjertesvikt og post-infarkt ved at de hemmer dannelsen av angiotensin II, en forbindelse som har flere virkninger, deriblant økning av blodtrykket.
Forbindelser med endotelinomdannelsesenzym(ECE)-hemmende aktivitet er anvendbare som anti-vasokonstriktorer ettersom de hemmer dannelsen av endotelin, et peptid på 21 aminosyrer med vasokonstriktoraktivitet.
Isteden er forbindelser med hemmende aktivitet på nøytralt endopeptidase (NEP)-enzym, også kalt enkefalinase, anvendbare som vasodilatorer ved at NEP-enzymet er ansvarlig for inaktiveringen ikke kun av endogent enkefalin, men også av enkelte natriuretiske faktorer, for eksempel arteriefaktoren (ANF), et hormon sekretert fra hjerte som øker vasodilasjonen, og som på nyrenivå øker diurese og natriurese.
Selv om de utøver sin virkning på det kardiovaskulære system med ulike virkningsmekanismer, benyttes derfor forbindelsene med metallopeptidasehemmende aktivitet generelt, alene eller i kombinasjon, ved behandling av høyt blodtrykk, nyresvikt, kongestiv hjertesvikt og iskemiske
kardiopatologier.
Blant tiolderivathemmerne av metallopeptidaser er henholdsvis Thiorphan [(DL-(3-merkapto-2-benzylpropanoyl)glysin], beskrevet for første gang av Roques et al. i Nature, vol. 288, s. 286-288, (1980), og Captopril (The Merck, Index, XI red. nr. 1773, s. 267) ansett for å være opphavsforbindelser for NEP-hemmere og ACE-hemmere.
Andre molekyler med tiolstruktur som er utrustet med metallopeptidasehemmende aktivitet er beskrevet i litteraturen.
US patenter nr. 4401677 og nr. 4199512 (begge i navn av E.R. Squibb & Sons, Inc.) beskriver merkaptoalkanoylamino-syrer med henholdsvis enkefalinasehemmende aktivitet og ACE-hemmende aktivitet.
Europeisk patentsøknad nr. 0419327 (Société Civile Bioproject) beskriver aminosyrederivater utrustet med henholdsvis enkefalinase- og ACE-hemmende aktivitet.
Europeisk patentsøknad nr. 044 9523 (E.R. Squibb & Sons, Inc.) beskriver merkapto eller acyltiotrifluormetyl-amider med NEP-hemmende aktivitet.
Internasjonal patentsøknad nr. WO 93/08162 [Rhone-Poulenc Rorer S.A. - Institut National de la Santé et de la Recherche Médicale (INSERM) ] beskriver p,P-disubstituerte a-merkaptometylpropionylamider utrustet med blandet ACE/NEP-hemmende aktivitet.
Europeisk patentsøknad nr. 0524553 [Institut National de la Santé et de la Recherche Médicale (INSERM)] beskriver acylmerkaptoalkanoyldipeptider utrustet med nøytral endopeptidase og peptidyldipeptidase A-hemmende aktivitet.
Europeisk patentsøknad nr. 0566157 (Schering Corporation) beskriver tiolderivater, for eksempel slike som N-merkaptoacylaminosyrer, utrustet med NEP-hemmende aktivitet.
a-Merkaptoacyldipeptider utrustet med ACE-hemmende og NEP-hemmende aktivitet er også beskrevet av S.S. Bhagwat et al. i Bioorganic & Medicinal Chemistry Letters, 7, 735-738," 1995.
I dette siste arbeid konkluderte forfatterne med at mens tilstedeværelsen av en bifenylmetylgruppe overfører en interessant blandet ACE/NEP-hemmende aktivitet til molekylene med en a-merkaptoacyldipeptidstruktur forårsaker substitueringen av bifenylgruppen med grupper slik som a-eller P-naftyl et betydelig aktivitetstap.
Søkeren har nå funnet N-merkaptoacylfenylalaninderivater som er utrustet med en betydelig inhibitorisk aktivitet på det angiotensinomdannende enzym, så vel som det nøytrale endopeptidaseenzym (blandet eller dobbel ACE/NEP-hemmende aktivitet) noe som gjør disse særlig anvendbare ved behandling av kardiovaskulære patologier.
Målsetningen med oppfinnelsen er derfor forbindelser med formel
hvori
R er en merkaptogruppe eller en R4COS-gruppe som i organismen kan omdannes til
merkaptogruppe;
Rx er en rettkjedet eller forgrenet C2-C4
alkylgruppe eller en arylalkylgruppe med fra 1 til 6 karbonatomer i alkylresten, hvor aryl er en fenyl- eller en 5-6-leddet aromatisk heterosyklisk gruppe valgt blant furyl, tienyl, pyridyl eller isoksazolyl, eventuelt substituert med én eller flere substituenter, som er like eller
forskjellige, utvalgt fra gruppen bestående av halogenatomer, Cj-^-alkoksy- eller
Cx - C„ - alky lgrupper ; R2 er et hydrogenatom eller en rettkjedet
eller forgrenet Cx-C4-alkylgruppe ;
R3 er en fenylgruppe substituert med en 5-eller 6-leddet aromatisk heterosyklisk gruppe valgt blant tiazolyl, furyl,
pyrimidinyl, pyrazinyl, pyridyl og tienyl; R4 er en rettkjedet eller forgrenet C1- Ci-alkylgruppe eller en fenylgruppe;
karbonatomene merket med en stjerne er stereogene sentre; og farmasøytisk akseptable salter derav.
Forbindelsene med formel I inneholder to stereogene sentere og kan således være til stede i form av stereoisomerer.
En målsetning med oppfinnelsen er derfor forbindelsene med formel I i form av stereoisomer blanding, så vel som i form av enkle stereoisomerer.
Forbindelsene med formel I, ifølge oppfinnelsen er utstyrt med en dobbelt ACE/NEP-hemmende aktivitet og er anvendbare ved behandling av kardiovaskulære sykdommer.
Selv om begrepene blandet og dobbel brukes om hverandre er begrepet dobbel mer akseptert i litteraturen for forbindelser utrustet med både ACE- og NEP-hemmende aktivitet.
I denne sammenheng er begrepene blandet og dobbel ansett for å være like.
I den foreliggende beskrivelse, med mindre annet er spesifisert, er det med begrepet rettkjedet eller forgrenet alkylgruppe med en alkylgruppe, som metyl-, etyl-, n-propyl-, isopropyl-, n-butyl-, sek-butyl-, tert-butyl-, isobutyl-, n-pentyl-, 2-pentyl-, 3-pentyl-, isopentyl-, tert-pentyl-, n-heksyl- og isoheksylgruppe; med begrepet rettkjedet eller forgrenet alkoksygruppe ment en alkoksygruppe, slik som metoksy-, etoksy-, n-propoksy- og isopropoksygruppe; med begrepet halogenatom er det ment et fluor-, klor-, brom- eller jodatom; med begrepet acyl er det ment en acylgruppe avledet fra en alifatisk eller aromatisk karboksylsyre, slik som eddiksyre, propionsyre, smørsyre og benzosyre; med begrepet 5-eller 6-leddet aromatisk heterosyklisk gruppe inneholdende 1 eller 2 heteroatomer utvalgt fra nitrogen, oksygen og svovel menes en gruppe, slik som tiazol, isoksazol, oksazol, isotiazol, pyrazol, imidazol, tiofen, pyrrol, pyridin, pyrimidin, pyrazin, pyridazin og furan eventuelt benzokondensert.
Eksempler på farmasøytisk akseptable salter til forbindelsene med formel I er salter med alkali- eller jordalkalimetaller og saltene med farmasøytisk akseptable organiske baser.
Foretrukne forbindelser med formel I er forbindelsene hvori Rx betegner en arylalkylgruppe eventuelt substituert med én eller flere substituenter som er like eller forskjellige, utvalgt fra gruppen bestående av halogenatomer, C^-C^-alkyl eller ^-C^-alkoksy.
Ytterligere andre foretrukne forbindelser i denne klasse er forbindelsen med formel I hvori Rx betegner en fenylalkylgruppe som eventuelt er substituert med én eller flere substituenter som er like eller forskjellige, utvalgt fra gruppen bestående av halogenatomer, C^-C^-alkyl eller C^-C^-alkoksy.
Foretrukne eksempler på farmasøytisk akseptable salter til forbindelsene med formel I er saltene med alkalimetaller, slik som natrium, litium og kalium.
Det er åpenbart for en fagmann på området at forbindelsene med formel I, hvori R er en R4COS-gruppe som i organismen kan omdannes til merkaptogruppe, i tillegg til forbindelser med formel I, hvori R2 er en alkylgruppe, er biologiske forløpere (pro-medikamenter) for de tilsvarende forbindelser med formel I, hvori henholdsvis R er en merkaptogruppe (R=SH) eller R2 er et hydrogenatom (R2=H) .
Spesifikke eksempler på foretrukne forbindelser med formel I ifølge oppfinnelsen er: N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(2-tiazolyl)-fenylalaninmetylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(2-pyridyl)-fenylalaninmetylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(3-pyridyl)-fenylalaninbenzylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(2-furyl)-fenylalaninmetylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl) -4-(5-pyrimidinyl)-fenylalaninetylester;
N-(3-fenylkarbonyltio)-2-fenylmetylproionyl)-4-(2-pyrazinyl)-fenylalaninmetylester;
N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(2-tienyl)-fenylalaninmetylester: N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(3-tienyl)-fenylalaninmetylester; N- (3-fenylkarbonyltio-2-fenylmetylpropionyl) -4- (3-furyl) - fenylalaninmetylester: N- [3-fenylkarbonyltio-2- (3-pyridylmetyl)propionyl] -4- (2-tiazolyl)-fenylalaninmetylester; N-[3-acetyltio-2-(3-metoksyfenyl)metyl-propionyl]-4-(2-t iazolyl)-fenylalaninmetylester; N- [3-acetyltio-2- (2-fluorfenyl)metyl-propionyl] -4- (2-tiazolyl)-fenylalaninmetylester; N-[3-fenylkarbonyltio-2-(2-tienyl) metyl-propionyl]-4-(2-tiazolyl)-fenylalaninmetylester; N-[2-(2-furyl)metyl-3-fenylkarbonyltio-propionyl]-4-(2-tiazolyl)-fenylalaninmetylester; N- [2- (3-metyl-5-isoksazolyl)metyl-3-fenylkarbonyltio-propionyl] -4- (2-tiazolyl) -fenylalaninmetylester; N- (3-merkapto-2-f enylmetylpropionyl) -4- (2-tiazolyl) - fenylalanin; N- (3-merkapto-2-fenylmetylpropionyl) -4- (2-pyridyl) - fenylalanin; N- (3-merkapto-2-fenylmetylpropionyl) -4- (3-pyridyl) - fenylalanin; N- (3-merkapto-2-fenylmetylpropionyl) -4- (2-furyl) -fenylalanin; N- (3-merkapto-2-fenylmetylpropionyl) -4- (5-pyrimidinyl) - fenylalanin; N- (3-merkapto-2-fenylmetylpropionyl) -4- (2-pyrazinyl) - fenylalanin; N- (3-merkapto-2-fenylmetylpropionyl) -4- (2-tienyl) -fenylalanin; N- (3-merkapto-2-fenylmetylpropionyl) -4- (3-tienyl) -fenylalanin; N- (3-merkapto-2-fenylmetylpropionyl) -4- (3-furyl) -fenylalanin; N- [3-merkapto-2- (3-pyridylmetyl) propionyl] -4- (2-tiazolyl) - fenylalanin;
N- [3-merkapto-2- (3-metoksyfenyl) metyl-propionyl] -4- (2-tiazolyl)-fenylalanin;
N- [3-merkapto-2- (2-tienyl)metyl-propionyl] -4- (2-tiazolyl) - fenylalanin;
N- [3-merkapto-2- (3-metyl-5-isoksazolyl) metyl-propionyl] -4- (2-tiazolyl)-fenylalanin;
N- [2- (2-f luorfenyl) metyl-3-merkapto-propionyl] -4- (2-tiazolyl) - fenylalanin; N- [2- (2-furyl) metyl - 3-merkapto-propionyl] -4- (2-tiazolyl) - fenylalanin.
Fremstillingen av forbindelsene med formel I ifølge oppfinnelsen, er utført ifølge en syntetisk prosess omfattende reaksjonen mellom en forbindelse med formel
hvori
R og Rx har samme betydning som ovenfor;
og et fenylalaninderivat med formel
hvori
R2 °9 R3 nar samme betydning som ovenfor.
Kondenseringsreaksjonen utføres ifølge vanlige peptidkj emiteknikker.
Før utførelse av reaksjonen kan det være nyttig å beskytte de eventuelle funksjonelle grupper som kan interferere reaksjonen.
Den eventuelle beskyttelse utføres ifølge vanlige - teknikker.
I denne sammenheng er fortrinnsvis forbindelsene med formel II, hvor R er en R4COS-gruppe, anvendt som mellomprodukter, for således å erholde de tilsvarende forbindelser med formel I, hvori R=R4COS hvorfra forbindelsene med formel I, hvori R=SH, kan erholdes ved hydrolyse.
Evalueringen av nytten av den eventuelle beskyttelse så vel som utvelgelse av type tilpasset beskyttelse ifølge reaksjonen som utføres og de funksjonelle grupper som skal beskyttes, er innen den normale kunnskap til en fagmann på
området.
Fjerningen av eventuelt beskyttede grupper utføres ifølge vanlige teknikker.
For en generell referanse med hensyn til anvendelse av beskyttede grupper i organisk kjemi se Theodora W. Greene og Peter G.M. Wuts "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., II red., 1991.
Forbindelsene med formel II er kjente, eller kan lett fremstilles ifølge vanlige fremgangsmåter som for eksempel beskrevet i britisk patent nr. 1576161 i navn av E.R. Squibb & Sons Inc.
Alternativt kan forbindelsene med formel II fremstilles ifølge de syntetiske fremgangsmåter beskrevet i M.C. Fournié-Zalusky et al. i J. Med. Chem. 1994, 37., 1070-1083 .
Også mellomproduktene med formel III er kjente, eller kan lett fremstilles ifølge kjente fremgangsmåter.
For eksempel kan forbindelsene med formel III fremstilles ifølge de syntetiske fremgangsmåter beskrevet av W.C. Shieh et al. i J. Org. Chem. 1992, 57, 379-381.
Alternativt kan forbindelsene med formel III fremstilles ved hjelp av koblingsmetoder (krysskobling) som går ut fra halogenerte heterosykliske forbindelser og stannylfenylalaninderivater, som beskrevet av D.S. Wilbur et al. i Bioconjugate Chem., 1993, 4, 574-580.
Forbindelsene med formel I i form av enkle steroisomerer fremstilles ved hjelp av stereoselektive synteser eller ved separering av den stereoisomere blanding_ ifølge vanlige teknikker.
Også fremstillingen av salter av forbindelsene med formel I, ifølge foreliggende oppfinnelse, utføres ifølge vanlige teknikker.
Forbindelsene med formel I ifølge oppfinnelsen er utrustet med en blandet ACE/NEP-hemmende aktivitet og er anvendbare ved behandling av kardiovaskulære sykdommer.
Den hemmende aktivitet til forbindelsene med formel I ble evaluert ved hjelp av in vi tro-tester (eksempel 8).
Særlig ble den hemmende aktivitet til forbindelsene med formel I evaluert ved sammenligning med Thiorphan og Captopril nevnt ovenfor.
Den in vitro-hemmende aktivitet til forbindelsene med formel I, uttrykt som IC50-verdi, var i konsentrasjoner på nM-nivå.
Denne aktivitet var sammenlignbar med den til Captopril, når det gjelder ACE-hemmende aktivitet, og høyere enn den til Thiorphan med hensyn til NEP-hemmende aktivitet.
Den hemmende aktivitet til forbindelsene med formel I ble dessuten evaluert ved hjelp av ex vivo-tester sammenlignet med kjente forbindelser (eksempel 9).
Særlig ble N[3-merkapto-2-(3 , 4-metylendioksyfenyl)-metyl-propionyl]-(S)-fenylalanin og N-[3-merkapto-2-[3,4 - metylendioksyf enyl)metyl-propionyl] -(S)-tyrosin, beskrevet som enkefalinase og ACE-hemmere i ovennevnte europeiske patentsøknad nr. 0419327 og heretter referert til som henholdsvis forbindelsene R-l og R-2, så vel som N-(3-merkapto-2-metylpropanoyl)-L-tyrosin og N-(3-merkapto-2-metylpropanoyl)-L-triptofan, beskrevet som ACE-hemmere i U.S. 4199512 og som enkefalinasehemmere i US 4401677, og heretter referert til som henholdsvis forbindelsene R-3 og R-4, anvendt som sammenligningsforbindelser.
Den ACE/NEP-hemmende aktivitet ex vivo, ble særlig bestemt ved evaluering av enzymaktiviteten i vevshomogenatene (lunge og nyre henholdsvis med hensyn til ACE og NEP-aktivitet) fra rotter med spontan hypertensjon (SHR) behandlet med de testede forbindelser ad intravenøs eller oral vei.
Det betyr ingenting at aktiviteten som er vist til-ved forbindelsene med formel I i ex vivo-testene bekrefter den blandede aktivitet (dobbel aktivitet) vist i in vitro-testene, også etter oral administrering.
Nevnte aktivitet viste seg dessuten å være signifikant høyere enn den til sammenligningsforbindelsene.
For en praktisk anvendelse ved terapi kan forbindelsene med formel I formuleres i faste eller flytende farmasøytiske preparater, som er egnet for oral eller parenteral administrering.
Derfor er de farmasøytiske preparater inneholdende en terapeutisk effektiv mengde av en forbindelse med formel I blandet med en bærer for farmasøytisk anvendelse, en ytterligere målsetning med oppfinnelsen.
Spesifikke eksempler på farmasøytiske preparater ifølge oppfinnelsen er tabletter, belagte tabletter, kapsler, granuler, oppløsninger og suspensjoner egnet for oral administrering, oppløsninger og suspensjoner egnet for parenteral administrering.
De farmasøytiske forbindelser ifølge oppfinnelsen fremstilles ifølge vanlige teknikker.
Den daglige dose av forbindelsen med formel I eller tilsvarende promedikament vil avhenge av flere faktorer, slik som sykdommens alvorlighetsgrad, pasientens individuelle respons eller type formulering, men den består vanligvis av mellom 0,1 mg og 10 mg pr. kg kroppsvekt fordelt i en enkelt dose eller i flere daglige doser.
For å illustrere oppfinnelsen er følgende eksempler gitt.
Dersom ikke annet er spesifisert ble hurtigkromatografiene utført ved anvendelse av hurtigkromatografisilikagel fra Baker company (kode 7024-00).
Eksempel 1
Fremstilling av N-tert-butoksykarbonyl-4-(5-pyrimidinyl)-L-fenylalaninetylester
En blanding av 5-pyrimidinylborsyre (850 mg; 2 mmol) , N-1ert-butoksykarbonyl-4 -1rifluormetylsulfonyl-L-fenylalaninetylester (450 mg; 2,2 mmol), en oppløsning av natriumkarbonat (530 mg) i vann (2,59 ml) og en blanding av toluen;etanol=10:4, 5 (20 ml) ble degasset med nitrogen i 30 minutter.
Etter dette ble palladium(O)tetrakis(trifenylfosfin)
(120 mg; 0,06 mmol) tilført blandingen og reaksjonsblandingen ble oppvarmet til 90 °C og holdt under omrøring i 3 timer. Blandingen ble så holdt ved romtemperatur og N-tert-butoksykarbonyl-4 -trif luormetylsulf onyl -L- f enylalaninetylester (112 mg) og palladium(0)tetrakis(trifenylfosfin)(30 mg) ble tilsatt på ny.
Blandingen ble ytterligere oppvarmet til en temperatur på 90 °C og holdt under omrøring i ytterligere 18
timer.
Etter avkjøling av reaksjonsblandingen ved romtemperatur ble etylacetat (100 ml) og vann (40 ml) tilsatt.
Fasene ble separert og den organiske fase ble tørket på natriumsulfat og fordampet under vakuum. Den erholdte rest ble renset ved hjelp av hurtigkromatografi (silikagel, elueringsmiddel heksan:etylacetat=7:3, nitrogentrykk 0,1 atm) for således å gi N-tert-butoksykarbonyl-4-(5-pyrimidinyl)-L-fenylalaninetylester (13 0 mg; 14 % utbytte) i form av en fargeløs olje.
<l>H-NMR (200 MHz, CDC13): 6 (ppm): 1.24 (t, 3H, CH2-CH3); 1.40 [s, 9H, CCCHtø];
3.01-3.25 (m, 2H, CH2-CH); 4.19 (q, 2H, CH2-CH3); 4.52-4.65 (m, 1H, CH-COO); 5.06 (d, 1H, NH); 7.25-7.52 (m, 4H, fénylen) ; 8.91 (s, 2H, N-CH-C-CH-N); 9.19 (s, 1H, N-CH-N).
Eksempel 2
Fremstilling av N-tert-butoksykarbonyl-4-(2-tiazolyl)-L-fenylalaninmetylester
N-tert-butoksykarbonyl-4-(trifluormetylsulfonyl) -L-fenylalaninmetylester (8 g; 32,3 mmol) og palladium-bis(trifenylfosfin)klorid (2,3 g) ble tilsatt en oppløsning av 2-trimetylstannyl-tiazol (13,8 g; 32,3 mmol) i en blanding av tetrahydrofuran:toluen=10:1 (50 ml) som tidligere var degasset med nitrogen.
Blandingen ble kokt med tilbakestrøm i 24 timer og-deretter ble 2-trimetylstannyl-tiazol (2 g) tilsatt på ny.
Etter 6 timer med koking med tilbakestrøm ble N-tert-butoksykarbonyl-4- (trifluormetylsulfonyl)-L-fenylalaninmetylester (2 g) og palladium-bis(trifenylfosfin)klorid (700 mg) tilsatt.
Den resulterende reaksjonsblanding ble holdt under omrøring ved 70 °C i 16 timer og deretter avkjølt ved romtemperatur.
Vann (200 ml) ble så tilsatt blandingen, som ble ekstrahert med metylenklorid (4x299 ml).
De oppsamlede organiske faser ble tørket på natriumsulfat og fordampet under vakuum.
Den erholdte rest ble renset ved hjelp av hurtigkromatografi (silikagel, elueringsmiddel metylenklorid:etylacetat = 9:1, nitrogentrykk = 0,1 atm) for så å gi N-tert-butoksykarbonyl-4-(2-tiazolyl)-L-fenylalaninmetylester (2,3 g; 20 % utbytte).
^-NMR (200 MHz, CDCI3)<:> 5 (ppm): 1.40 [s, 9H, C(CH3)3]<;> 3.00-3.21 (m, 2H, CH2);
3.70 (s, 3H, COOCH3); 4.42-4.65 (m, 1H, CH-COO); 5.02 (bd, 1H, NH); 7.30 (d, 1H, S-CH-CH-N); 7.81 (d, 1H, S-CH-CH-N); 7.15-7.90 (m, 4H, fenylen)
Eksempel 3
Fremstilling av N-tert-butoksykarbonyl-4-(3-pyridyl)-L-fen<y>lalaninmet<y>lester
3-brompyridin (1,67 g; 10 mmol) og
palladium(0)tetrakis(trifenylfosfin) (370 mg; 0,219 mmol) ble tilført en oppløsning av N-tert-butoksykarbonyl-4-(tributylstannyl)-L-fenylalaninmetylester (4 g; 7,03 mmol), fremstilt som beskrevet av D.S. Wilbur et al. i Bioconjugate Chem., 1973, 4, 574-580, i vannfritt dimetylformamid (30 ml), som på forhånd var degasset med nitrogen.
Reaksjonsblandingen ble holdt under omrøring i 10 minutter ved romtemperatur og deretter oppvarmet til 105 °C i 6 timer.
Palladium(0)tetrakis(trifenylfosfin) (0,0035 mmol) ble på ny tilført og blandingen ble holdt under omrøring ved 105 °C i 8 timer for så å avkjøles ved romtemperatur.
Vann (100 ml) ble tilsatt og reaksjonsblandingen ble ekstrahert med heksan (3x150 ml).
De oppsamlede organiske faser ble vasket med en mettet vandig oppløsning av kaliumfluorid, tørket på natriumsulfat og fordampet under vakuum.
Den erholdte rest ble oppsamlet med etylacetat og filtrert.
Den resulterende rest ble fordampet under vakuum og resten ble renset ved hjelp av hurtigkromatografi (silikagel, eluent heksan:etylacetat = 8:2, nitrogentrykk 0,1 atm) noe som ga N-tert-butoksykarbonyl-4-(3-pyridyl)-L-fenylalaninmetylester (1,5 g; 60 % utbytte) i form av en fargeløs olje.
Masse (C.I.): (M+H)<+>=357
*H-NMR (200 MHz, CDC13): 8 (ppm): 1.40 [s, 9H, C(CH3)3]; <3.00-3.20> (m, <2>H, CH2);
3.71 (s, 3H, C00CH3); 4.55 (m, 1H, CH-COO); 5.05 (bd, 1H, NH); 7.19-7.51 (m, 4H,
fenylen);7,30-8,82(bm, 4H,pyridyl)
Ved å arbeide på en analog måte ble de følgende forbindelser fremstilt: N- tert- butoksvkarbonvl- 4- ( 2- pvridyl) - L- f enylalaninmetylester Masse (CI.) : (M+H) +=357
<!>H-NMR (200 MHz, CDCI3): 5 (ppm): 1.40 [s, 9H, C(CH3)3]; 3.03-3.21 (m, 2H, CHy CH); 3.70 (s, 3H, C00CH3); 4.54-4.65 (m, 1H, CH-COO); 4.98 (d, 1H, CONH); 7.16-7.21
(m, 1H, N-C-CH-CH); 7.65-7.77 (m, 2H, N-CH-CH-CH); 7.19-7.93 (m, 4H, fenylen);
8.63-8.68 (m, 1H, N-CH);
N- tert - butoksykarbonvl - 4 - ( 2 - pyrazinyl) - L- f enylalaninmetylester <1>H-NMR(200 MHz, CDC13): 8 (ppm): 1.40 [s, 9H, C(CH3)3]; 3.02 (m, 2H, CH2); 3.70 (s,
3H, COOCH3); 4.53-4.70 (m, 1H, CH-COO); 5.03 (bd, 1H, NH); 7.21-7.98 (m, 4H,
f enylen) ;8.49 og 8.62 [2(bs, 2H, N-CH-CH-N)]; 9.00 (s, 1H, CH-N-CH-CH);
N- tert- butoksvkarbonvl- 4- ( 2- tienyl) - L- f enylalaninmetylester <l>H-NMR (200 MHz, CDC13): 8 (ppm): 1.41 [m, 9H, C(CH3)3]; 2.98-3.18 (m, 2H, CH2);
3.71 (s, 3H, COOCH3); 4.53-4.64 (m, 1H, CH-COO); 4.98 (bd, 1H, NH); 7.02-7.28 (m, 3H,
tienyl); 7,10-7,54 (m,4H,fenylen).
Eksempel 4
Fremstilling av 4-(3-pyridyl)-L-fenylalaninmetylesterdihydroklorid
Tionylklorid (0,85 ml; 4,78 mmol) ble tilført dråpevis til en oppløsning av N-tert-butoksykarbonyl-4-(3-pyridyl)-L-fenylalaninmetylester (1,4 g; 3,93 mmol) i metanol (30 ml) fremstilt som beskrevet i eksempel 3, der temperaturen ble holdt ved 0 °C.
Mot slutten av tilføringen ble reaksjonsblandingen bragt til romtemperatur og holdt under omrøring i 8 timer.
Oppløsningsmidlet ble fordampet under vakuum for å gi 4-(3-pyridyl)-L-fenylalaninmetylesterdihydroklorid (820 mg;
71 % utbytte) anvendt i denne form i de følgende reaksjoner. Masse (C.I.) : (M+H) +=257 (fri base)
^-NMR (200 MHz, D20): 8 (ppm): 3.11-3.32 (m, 2H, CH2); 3.67 (s, 3H, CH3); 4.31-4.37 (m, 1H, CH); 7:30-7.63 (m, 4H,fenylen); 7.97 (dd, 1H, CH-N-CH-CH-CH); 8.59 (d, 1H,
CH-N-CH-CH-CH); 8.65-8.71 (m, 1H, CH-N-CH-CH); 8.89 (d, 1H, CH-N-CH-CH-CH).
Ved å arbeidet på en tilsvarende måte ble følgende forbindelser fremstilt: 4-( 2- pyridyl)- L- fenylalaninmetylesterdihydroklorid Masse (C. I.) : (M+H)<+> = 257 (fri base)
<1>H-NMR(200 MHz, D20): 8 (ppm): 3.12-3.33 (m, 2H, CH2); 3.64 (s, 3H, CH3); 4.30-4.37
(m, 1H, CH); 7.36-7.73 (m, 4H, f enylen) ;7.78-8.58 (m, 4H, pyridyl);
4-( 5- pvrimidinvl)- L- fenvlalaninetylesterdihvdroklorid <1>H-NMR(200 MHz, OMSO-d^): 8 (ppm): 1.11 (t, 3H, CH2-CH3); 3.10-3.35 (m, 2H, CH2-CH); 4.04-4.20 (m, 2H, CH2-CH3); 4.22-4.35 (m, 1H, CH); 7.40-7.84 (m, 4H, tenylen);
9.15 (s, 2H, N-CH-C-CH-N); 9.19 (s, 1H, N-CH-N);
4-( 2- pyrazinyl)- L- fenvlalaninmetvlesterdihydroklorid Masse (C.I.): (M+H)<+> = 258 (fri base)
^H-NMR (200 MHz, DC1 IN): 8 (ppm): 3.45-3.67 (m, 2H, CH2); 3.98 (s, 3H, CH3); 4.65-4.72 (m, 1H, CH);7.68-8.26 (m, 4H, f enylen) ;9.02 (d, 1H, CH-N-CH-QD; 9.44 (dd, 1H,
CH-N-CH-CH); 9.54 (d, 1H, CH-N-CH-CH);
4-( 2- tienyl)- L- fenylalaninmetylesterhvdroklorid Masse (C.I.): (M+H)<+> = 262 (fri base)
^-NMR (200 MHz, D20): 8 (ppm): 2.98-3.19 (m, 2H, CH2); 3.65 (s, 3H, CH3); 4.21-4.28 (m, 1H, CH); 6.96-7.28 (m, 3H, tienyl); 7.08-7.52 (m, 4H, lenyleu);
4-( 2- tiazolvl)- L- fenylalaninmetylesterdihvdroklorid
<l>H-NMR (200 MHz, D20): 5 (ppm): 3.10-3.32 (m, 2H, CH2-CH); 3 68 <s« 3H» CH3* 4 30*
4.38 (m, 1H CH); 7.30-7.80 (m, 4H, fenylen) ; 7.70-7.91 (m, 2H, tiazolyl.
Eksempel 5
Fremstilling av 2- isobutvl- 3- fenylkarbonvltio- propionsyre
En blanding av 2-isobutylakrylsyre (6,34 g; 49 mmol) og tiobenzosyre (5,96 ml; 51 mmol) ble oppvarmet til 100 °C under omrøring i 2 timer.
Reaksjonsblandingen ble så behandlet med petroleumseter 40-60 °C (100 ml) og avkjølt ved -70 °C i et tørris/acetonbad.
Ved filtrering og vasking med petroleumseter ved -70 °C ble en rest oppsamlet og tørket ved redusert trykk, dette ga 2-isobutyl-3-fenylkarbonyltio-propionsyre (11,12 g; 85 % utbytte) i form av et hvitt faststoff.
^H-NMR (200 MHz, CDC13): 8 (ppm): 0.90-1.00 (m, 6H); 1.40-1.90 (m, 3H); 2.70-2.90 (m,
1H); 3.10-3.40 (m, 2H); 7.35-7.62 (m, 3H); 7.90-8.00 (d, 2H).
Ved å arbeide på samme måte ble de følgende forbindelser fremstilt: 2 -( 3- metoksyfenyl) metyl- 3 - fenylkarbonyltio- propionsyre <!>H-NMR (200 MHz, CDCI3): 8 (ppm): 2.32 (s, 3H); 2.80-3.15 (m, 5H); 3.77 (s, 3H); 6.70-6.80 (m, 3H); 7.14-7.25 (m, 1H).
3- acetyltio- 2-( 2- fluorfenyl) metyl- propionsyre !H-NMR (200 MHz, CDCI3): 8 (ppm): 2.31 (s, 3H); 2.90-3.20 (m, 5H); 6.95-7.30 (m, 4H).
3 -fenylkarbonyltio-2-(2-tienyl)metyl-propionsyre benzvlaminsalt
^-NMR (200 MHz, DMSO-dg): 5 (ppm): 2.45-3.25 (m, 5H, S-CH2-CH-CH2); 3.90 (s, 2H, CH2-fenyl) 6.85-7.91 (m, 13H, aryl). •
Eksempel 6
Fremstilling av N-[(2S)-3-fenylkarbonyltio-2-fenylmetylpropionyl]- 4-( 2- tiazolyl)- L- fenylalaninmetylester
(forbindelse 1)
En oppløsning av hydroksybenzotriazol (0,54 g; 4 mmol) i tetrahydrofuran (30 ml) og deretter en oppløsning av disykloheksylkarbodiimid (0,825 g; 4 mmol) i metylenklorid (15 ml) ble tilsatt ved 0 °C under omrøring til en blanding av (2S)-3-fenylkarbonyltio-2-fenylmetylpropionsyre (1,2 g; 4 mmol) , 4-(2-tiazolyl)-L-fenylalaninmetylesterdihydroklorid (1,34 g; 4 mmol) fremstilt som beskrevet i eksempel 4, trietylamin (1,11 ml; 8 mmol) i tetrahydrofuran (20 ml) og metylenklorid (30 ml).
Reaksjonsblandingen ble holdt under omrøring i 20 timer, disykloheksylurea ble så filtrert fra og oppløsningsmidlet ble fordampet ved redusert trykk.
Resten ble oppsamlet med etylacetat og oppløsningen ble vasket med en vandig oppløsning av 20 % natriumklorid, 5 % bikarbonat og igjen 20 % natriumklorid.
Etter separering av fasene og fordampning av den organiske fase ble det resulterende hvite faste stoff renset ved hjelp av hurtigkromatografi (silikagel, elueringsmiddel etylacetat:heksan = 40:60, nitrogentrykk 0,1 atm) for så å gi N-[(2S)-3-fenylkarbonyltio-2-fenylmetylpropionyl]-4-(2-tiazolyl)-L-fenylalaninmetylester (1,5 g).
Smeltepunkt 98-100 °C
Masse (C.I.): (M+H)<+>=545
<*>H-NMR (200 MHz, CDC13): 6 (ppm): 2.63-3.35 (m, 7H, CH2-CH-CH2, CH2-C6H4-*ia<->
zolyi); 3.68 (s, 3H, COOCH3); 4.75-4.85 (m, 1H, CH-COO); 5.78 (d, 1H, NH); 7.10-8.00
(m, 16H, aryi).
Ved å arbeide på samme måte, med utgangspunkt i forbindelsene kjent eller fremstilt som beskrevet i eksemplene 4 og 5 ble følgende forbindelser erholdt: N- [(2S)-3-fenylkarbonyltio-2-fenylmetylpropionyl]-4-(2-furyl)-L- fenylalaninmetylester (forbindelse 2)
Smeltepunkt 132-134 °C
Masse (CI.) (M+H)<+> = 528
^-NMR (200 MHz, CDC13): 8 (ppm): 2.60-3.35 (m, 7H, CH2-CH-CH2, CH^-C^-furyi); 3.58 (s, 3H, COOCH3); 4.71-4.81 (m, 1H, CH-COO); 5.73 (d, 1H, NH); 6.40-8.00
(m, 17H, aryi);
N- [2S)-3-fenylkarbonyltio-2-fenylmetylpropionyl]-4- (5-pyrimidinyl)- L- fenylalaninetylester (forbindelse 3) Smeltepunkt 117-119 °C
Masse (C.I.)(M+H)<+> = 554
<l>H-NMR (200 MHz, CDCI3): 8 (ppm):-1.18 (t, 3H, CH3-CH2); 2.65-3.35 (m, 7H, CH2-CH-CH2, CH2-C6H4-pyirmiainyl); 3.95-4.20 (m, 2H, COOCH2); 4.70-4.80 (m, 1H, CH-COO); 5.78 (d, 1H, NH); 7.05-8.00 (m, 14H,f enyl', fenylen); ; 8.68 (s, 2H, CH-N-CH-N-QD; 9.11 (s, 1H,N-CH-N);
N- [ (2S)-3-fenylkarbonyltio-2-fenylmetylpropionyl]-4- (2-pyrazinyl)- L- fenylalaninmetylester (forbindelse 4) Smeltepunkt 145-147 °C
Masse (CI.) (M+H)<+> = 540
<!>H-NMR (200 MHz, CDCI3): 8 (ppm): 2.65-3.35 (m, 7H, CH2-CH-CH2, CH^C^-pyrazinyl); 3.61 (s, 3H, COOCH3); 4.75-4.85 (m, 1H, CH-COO); 5.78 (d, 1H, NH); 7.10-8.00 (m, 14H, f enyl, fenylen);, 8.48-8.75 (m, 3H, CH-N-CH-CH-N);
N- [ (2S)-3-fenylkarbonyltio-2-fenylmetylpropionyl]-4- (3-pyridvl)- L- fenylalaninmetylester (forbindelse 5) Smeltepunkt 132-134 °C
Masse (CI.) (M+H)<+> = 539
<l>H-NMR (200 MHz, CDCI3): 8 (ppm): 2.66-2.79 (m, 1H, CH2-CH-CH2); 2.88-3.35 (ro,
6H, CH2-CH-CH2, ^-CgHt-pyridyl); 3.61 (s, 3H, COOCH3); 4.75-4.85 (m, 1H, CH-COO); 5.77 (d, 1H, NH); 7.07-7.99 (m, 16H, CH-CH-CH-N, Eayl,fenylen); 8.51-8.64
(m, 2H, CH-N-CH);
N- [ (2S)-3-fenylkarbonyltio-2-fenylmetylpropionyl]-4- (2-pyridvl)- L- fenylalaninmetylester (forbindelse 6) Smeltepunkt 123-125 °C
Masse (C.I.)(M+H)<+> = 539
^-NMR (200 MHz, CDC13): 8 (ppm): 2.63-2.77 (m, 1H, CH2-CH-CH2); 2.85-3.35 (m,
6H, CH2-CH-CH2, CH2-C6H4-pyridyi); 3.56 (s, 3H, COOCH3); 4.75-4.85 (m, 1H, CH-COO); 5.75 (d, 1H, NH); 7.09-7.99 (m, 16H, CH-CH-CH-N, f enyl, fenylen); 8.61-8.65
(m, 1H, N-CH-CH);
N-[(2S)-3-fenylkarbonyltio-2-fenylmetylpropionyl]-4-(2-tienvl)- L- fenylalaninmetylester (forbindelse 7)
Masse (C. I. ) (M+H)<+> = 544
^H-NMR (200 MHz, CDCI3): 5 (ppm): 2.64-3.36 (m, TH, CH2-CH-CH2, CONH-CH-CH2);
3.58 (s, 3H, COOCH3); 4.74-4.83 (m, 1H, CH-COO); 5.74 (d, 1H, NH); 6.97-7.99 (m, 17H,
aryl);
N-[(2S)-3-fenylkarbonyltio-2-fenylmetylpropionyl]-4-(3-tienyl)- L- fenylalaninmetylester (forbindelse 8)
Masse (C. I. ) (M+H) + = 544
<l>H-NMR (200 MHz, CDCI3). 5 (ppm): 2.63-3.35 (m, TH, CH2-CH-CH2, NH-CH-CH2);
3.58 (s, 3H, COOCH3); 4.T3-4.85 (m, IH, CH-COO); 5.70-5.76 (bd, 1H, NH); 7.00-7.62
(m, 15H, f enyl, fenylen); CH-CH-S); 7.93-8.00 (m, 2H, CH-S-CH);
N-[(2S) -3-fenylkarbonyltio-2-fenylmetylpropionyl]-4-(3- furyl) - L- fenylalaninmetylester (forbindelse 9)
Smeltepunkt 115-117 °C
Masse (C. I. ) (M+H)<+> = 528
*H-NMR (200 MHz, CDCy: 8 (ppm): 2.62-3.36 (m, 7H, CH2-CH-CH2, NH-CH-CH2);
3.58 (s, 3H, COOCH3); 4.71-4.82 (m, 1H, CH-COO); 5.72 (bd, 1H, NH); 6.50-8.00 (m,
17H,aryi);
N-[3-fenylkarbonyltio-2-(3-pyridylmetyl)propionyl]-4- (2-tiazolyl)- L- fenylalaninmetylester -
stereoisomer A (forbindelse 10)
Masse (C.I.)(M+H)<+> = 546
TLC (etvlacetatpetroleumseter = 95:5), Rf = 0,33
^H-NMR (200 MHz, CDC13): 5 (ppm): 2.60-3.38 (m, 7H, CH2-CH-CH2, NH-CH-CH2);
3.60 (s, 3H, CQOCH3); 4.79-4.90 (m, 1H, CH-COO); 6.21 (bd, 1H, NH); 7.29-7.81 (m, 2H, tiazolyl); 6,75-8,48 (m, 13H, fenyl, fenylen, pyridyl);
N-[3-fenylkarbonyltio-2-(3-pyridylmetyl)propionyl]-4-(2-tiazolyl)- L- fenylalaninmetylester -
stereoisomer (forbindelse 11)
Masse (C.I.)(M+H)<+> = 546
TLC (etylacetat:petroleumseter = 95:5), RF = 0,24
<l>H-NMR (200 MHz, CDCI3): 5 (ppm): 2.61-3.25 (m, 7H, CH2-CH-CH2, NH-CH-CH2);
3.60 (s, 3H, COOCH3); 4.80-4.91 (m, 1H, CH-COO); 6.09 (bd, 1H, NH); 7.27-7.80 (m, 2H, tiazolyl); 7,10-8,40 (m, 13H, fenyl, fenylen, pyridyl);
N-[2-isobutyl-3-fenylkarbonyltio-propionyl]-4-(2-tiazolyl)-L-fenylalaninmetylester (forbindelse 12)
<I>H-NMR(200 MHz, CDCI3): 5 (ppm): 0.80-0.95 (m, 6H); 1.30-1.80 (m, 3H); 2.40-2.60 (m,
1H); 3.00-3.30 (m, 4H); 3.70 (d, 3H); 4.90-5.05 (m, 1H); 6.00-6.15 (bt, 1H); 7.10-8.00 (m,
UH);
N-[3-acetyltio-2-(3-metoksyfenyl)metyl-propionyl] -4-(2-tiazolyl)- L- fenylalaninmetylester (forbindelse 13)
<*>H-NMR (200 MHz, CDCI3): 5 (ppm): 2.30 (d, 3H); 2.45-3.20 (m, 7H); 3.63 (d, 3H); 3.75 (d, 3H); 4.70-4.93 (m, 1H); 5.70-5.90 (dd, 1H); 6.60-6.85 (m, 4H); 7.17-7.32 (m, 3H); 7.68-7.90 (m, 3H);
N-[3-acetyltio-2-(3-fluorfenyl)metyl-propionyl]-4-(2-tiazolyl)- L- fenylalaninmetylester (forbindelse 14)
<1>H-NMR(200 MHz, CDCI3): 5 (ppm): 2.29 (s, 3H); 2.55-3.20 (m, 7H); 3.65 (2s, 3H); 4.70-4.90 (m, 1H); 5.80-6.00 (2d, 1H); 6.70-7.32 (m, 3H);
N-[3-fenylkarbonyltio-2-(2-tienyl)metyl-propionyl]-4-(2-tiazolyl)- L- fenylalaninmetylester (forbindelse 15)
<*>H-NMR (200 MHz, CDCI3): 5 (ppm): 2.68-3.37 (m, 7H); 3.60-3.61 (2s, 3H, COOCH3);
4.31-4.45 (m, 1H, CH-COOCH3); 6.01-6.10 (2d, 1H, NH); 6.80-8.00 (m, 14H);
Eksempel 7
Fremstilling av N- [ (2S)-3-merkapto-2-fenylmetylpropionyl] -4-( 2- tiazolyl)- L- fenylalanin (forbindelse 16)
N-[(2S)-3-fenylkarbonyltio-2-fenylmetylpropionyl]-4-(2-tiazolyl)-L-fenylalaninmetylester (1,4 g; 2,57 mmol), fremstilt som beskrevet i eksempel 6 ble suspendert i etanol (3 0 ml) og degasset ved hjelp av nitrogenbobling for å eliminere oksygenet.
En vandig degasset oppløsning av natriumhydroksid IN (7,7 ml) ble tilsatt dråpevis ved 5 °C, og mot slutten av tilsetningen ble ytterligere degasset etanol (20 ml tilsatt dråpevis ved 5 °C til suspensjonen.
Reaksjonsblandingen ble holdt under omrøring i 4 timer ved romtemperatur, for så å avkjøles til 0 °C og gjort sur med 5 % saltsyre (10 ml).
Reaksjonsblandingen ble fordampet til tørrhet og resten ble oppsamlet med acetonitril og vann og ble deretter filtrert for å gi N-[(2S)-3-merkapto-2-fenylmetylpropionyl]-4-(2-tiazolyl)-L-fenylalanin (1 g).
Smeltepunkt 180-182 °C
Masse (C.I.)(M+H)<+> = 427
^H-NMR (200 MHz, DMSO-dg): 6 (ppm): 1.80-1.88 (m, 1H, SH); 2.22-2.84 (m, 5H, CH2-CH-CH2); 2.86-3.18 (m, 2H, CH2-CH-COO); 4.46-4.57 (m, 1H, CH-COO); 7.10-7.25 (m,
5H, fenyl, 7.32-7.84 (m, 4H, fenylen); 7.74 (d, 1H, N-CH=CH-S); 7.89 (d, 1H, N-CH-CH-S), 8.35 (d, 1H, NH); 12.76 (s, 1H, COOH): Ved å arbeide på en tilsvarende måte ble følgende forbindelser fremstilt: N-[(2R)-3-merkapto-2-fenylmetylpropionyl]-4-(2-tiazolyl)-L-fen<y>lalanin (forbindelse 17)
H-1MMR (200 MHz, DMSO-d6): 6 (ppm): 2.15-2.23 (m, 1H SH); 2.31-2.74 (m, 5H, CH2-CF-CH2); 2.78-3.07 (m, 2H, CH2-CH-COO); 4.42-4.53 (m, IK, CH-COO); 7.02-7.80 (m.
<9>H, f enyl og fenyien)';" 7 75 (d, 1H, N-CH=CH-S); 7.90 (d, iH, N-CH=CH-S); 8.36 (d, 1H, NH);
N-[(2S)-3-merkapto-2-fenylmetylpropionyl]-4-(2-furyl) -L-fen<y>lalanin (forbindelse 18)
Smeltepunkt 153-155 °C
Masse (C.I.)(M+H)<+> = 410
<*>H-NMR (200 MHz, CDC13): 8 (ppm): 1.40 (t, 1H, SH); 2.45-3.25 (m, 7H, CH2-CH-CH2,
CH2-CH-COO); 4.80-4.90 (m, 1H, CH-COO); 5.86 (d, 1H, NH); 6.42-7.42 (m, 3H, furyl);
7,07-7,57 (m, 9H, fenyl, fenylen);
N- [ (2S) -3-merkapto-2-fenylmetylpropionyl] -4- (5-pyrimidinyl) -L-fenylalanin (forbindelse 19)
Smeltepunkt 193-195 °C
Masse (CI.) (M+H)<+> = 422
<l>H-NMR (200 MHz, OMSO-dg): 8 (ppm): 1.81 (bm, 1H, SH); 2.21-3.20 (m, 7H, CH2-CH-CH2, CHj-Céat-pyirmidinyl); 4.46-4.57 (m, 1H, CH-COO); 7.06-7.29 (m, 5H, fenyl);
7.36-7.72(m, 4H, f enylen) ;8.33 (d, 1H, NHCO); 9.08 (s, 2H, N-CH-C-CH-N); 9.15 (s,
1H, N-CH-N);
N- [ (2S) -3-merkapto-2-fenylmetylpropionyl] -4- (2-pyrazinyl) -L-fen<y>lalanin (forbindelse 20)
Smeltepunkt 176-178 °C
Masse (CI.) (M+H=<+> = 422
<l>H-NMR (200 MHz, DMSO-de): 5 (ppm): 1.84 (bt, 1H, SH); 2.21-3.21 (m, 7H, CH2-CH-CH2, CH2-CH-COO); 4.48-4.59 (m, 1H, CH-COO); 7.10-7.26 (m, 5H, fenyl) ;7.37-8.05 (m, 4H, fenylen);. 8.37 (d, 1H, NHCO); 8.58 (d, 1H, CH-N-CH-CH-N); 8.68-8.70 (m, 1H,
CH-N-CH-CH-N); 9.21 (d, 1H, C-CH-N); 12.78 (b, 1H, COOH);
N- [ (2S) -3-merkapto-2-fenylmetylpropionyl] -4- (3-pyridyl) -L-fen<y>lalanin (forbindelse 21)
Smeltepunkt 14 6-148 °C
Masse (CI.) (M+H)<+> = 421
'h-NMR (200 MHz, DMSO-d6): 5 (ppm): 1.69-1.89 (b, 1H, SH); 2.22-3.18 (m, 7H, CH2-CH-CH2, CHr fenylen);; 4.45-4.56 (m, 1H, CH-COO); 7.09-7.26 (m, 5H, fenyl); 7.42-7.48 (m, 1H, CH-N-CH-CH-CH); 7.62-7.33 (m, 4H, fenylen); 7.98-8.04 (m, 1H, CH-N-CH-CH-CiD; 8.30 (d, IH, CONH); 8.53 (dd, 1H, CH-N-CH-CH-CH); 8.83 (d, 1H, CH-N-CH-CH-CH);
N-[(2S)-3-merkapto-2-fenylmetylpropionyl]-4-(2-pyridyl)-L-fen<y>lalanin (forbindelse 22)
Smeltepunkt 157-159 °C
Masse (C.I.)(M+H)<+> = 421
lH-NMR (200 MHz, DMSO-d6): 5 (ppm): 1.87 (b, 1H, SH); 2.23-3.19 (m, 7H, S-CHj-CH-CH2, CONH-CH-CH2); 4.44-4.45 (m, 1H, CH-COO); 7.09-7.93 (m, 8H, N-CH-CH-CH-CH, fenyl) ;7.30-7.99 (m, 4H, f enylen); 8.29 (d, 1H, CONH); 8.61-8.65 (m, 1H, C-N-CH);
N- [ (2S) - 3-merkapto-2-fenylmetylpropionyl] -4- (2-tienyl) -L-fen<y>lalanin (forbindelse 23)
Smeltepunkt 152-154 °C
^H-NMR (200 MHz, CDC13): 5 (ppm): 1.34-1.43 (m, 1H, SH); 2.44-3.26 (m, TH, S-CH2-CH-CH2, CONH-CH-CH2); 4.80-4.89 (m, 1H, NH-CH-COO); 5.81 (d, 1H, NH); T.02-T.52
(m, 12H, aryl);
N- [ (2S) -3-merkapto-2-fenylmetylpropionyl] -4- (3-tienyl) -L-fen<y>lalanin (forbindelse 24)
Smeltepunkt 169-171 °C
Masse (C.I.)(M+H)<+> = 426
TLC (etylacetat:heksan:eddiksyre = 50:50:5), Rf = 0,44
<l>H-NMR (200 MHz, CDCI3): 6 (ppm): 1.84 (bs, 1H, SH); 2.23-3.13 (m, TH, S-CH2-CH-CH2, NH-CH-CH2); 4.42-4.53 (m, 1H, NH-CH-COO); T.12-T.80 (m, 12H, aryl); 8.30 (d,
1H, JHH=8.2 Hz, NH);
N-[(2S)-3-merkapto-2-fenylmetylpropionyl]-4-(3-furyl)-L-fenylalanin (forbindelse 25)
Smeltepunkt 140-142 °C
Masse (C.I.)(M+H)<+> = 410
TLC (etylacetat:heksan:eddiksyre=50:50:5), Rf = 0,42 LH-NMR (200 MHz, CDCI3): 5 (ppm): 1.T9-1.90 (m, 1H, SH); 2.22-3.11 (m, 7H, S-CH2-CH-CH2, NH-CH-CH2); 4.41-4.53 (m, 1H, NH-CH-COO); 7.11-7.50 (m, 9H, fenyl);
fenylen) ; 6.91-8.12 (m, 3H, furyl); 8.30 (d, 1H, JHH=8.2 Hz, NH);
N-[3-merkapto-2-(3-pyridylmetyl)propionyl]-4-(2-tiazolyl)-L-fenylalanin - stereoisomer A (forbindelse 26)
Smeltepunkt 193-196 °C
Masse (C.I.)(M+H)<+> = 428
TLC (metylenklorid:metanol:eddiksyre=85:15:1, 5) , Rf = 0,53
*H-NMR (200 MHz, DMSO-d6): 5 (ppm): 2.37-3.05 (m, 7H, S-CH2-CH-CH2, NH-CH-C<H>2); 4.36-4.47 (m, 1H, NH-CH-COO); 7.76-7.90 (m, 2H, tiazol); 7.10-8.33 (m, 9H, NH, pyridyl, fenylen);
N-[3-merkapto-2-(3-pyridylmetyl)propionyl]-4-(2-tiazolyl) -L-fenylalanin - stereoisomer B (forbindelse 27)
Masse (C.I.)(M+H)<+> = 428
TLC (metylenklorid:metanol:eddiksyre = 85:15:1,5), Rf = 0,47 <l>H-NMR (200 MHz, DMSO-dg): 5 (ppm): 2.28-3.20 (m, 7H, S-CH2-CH-CH2, NH-CH-CH2); 4.20-4.35 (m, 1H, NH-CH-COO); 7.70-7.90 (m, 2H, tiazolyl)^. 17.8.40 (m, 9H, NH, pyridyl, fenylen);
N-[2-isobutyl-3-merkapto-propionyl)-4-(2-tiazolyl)-L-fenylalanin - (forbindelse 28)
Masse (C.I.)(M+H)<+> = 393
<l>H-NMR (200 MHz, DMSO-de): 5 (ppm): 0.50-1.44 (m, 9H); 1.68-2.25 (m, 4H); 2.79-3.22
(m, 2H); 4.50-4.63 (m, 1H); 7.34-7.85 (m, 4H); 7.73-7.90 (m, 2H); 8.27,8.39 (2d\ 1H); N-[3-merkapto-2-(3-metoksyfenyl)metyl-propionyl]-4-(2-tiazolyl)- L- fenylalanin (forbindelse 29)
Masse (C.I.)(M+H)<+> = 457
<l>H-NMR (200 MHz, DMSO-d^O): 5 (ppm): 2.20-3.21 (m, TH); 3.70 (d, 3H); 4.48 (m,
1H); 6.55-6.86 (m, 3H); T.00-T.40 (m, 3H); T.65-T.95 (m, 4H); 8.2T-8.45 (bt, CONH);
N- [3-merkapto-2-(2-fluorfenyl)metyl-propionyl]-4-(2-tiazolyl) - L- fenylalanin (forbindelse 30)
Masse (C.I.)(M+H)<+> = 445
<l>H-NMR (200 MHz, DMSO-dg): 6 (ppm): 2.20-3.18 (m, 8H); 4.35-4.55 (m, 1H); 6.85-7.35
(m, 6H); 7.65-7.90 (m, 4H); 8.35 (d, 1H);
N- [3-merkapto-2-(2-tienyl)metyl-propionyl]-4-(2-tiazolyl)-L-fen<y>lalanin (forbindelse 31) lH-NMR (200 MHz, DMSO-ds): 5 (ppm): 1.82-3.19 (m, 8H, CH2-CH2-CH2; NH-CH-CH2); 4.44-4.59 (m, 1H, CH-COO); 6.62-7.91 (m, 9H, aryl); 8.42 (d, 1H NH); N-[3-merkapto-2-(2-furyl)metyl-propionyl]-4-(2-tiazolyl) -L-fen<y>lalanin (forbindelse 32)
<l>H-NMR (200 MHz, DMSO-de): 5 (ppm). 1.79-3.18 (m, 8H, S-CH2-CH2-CH2; NH-CH-CS2); 4.43-4.58 (m, 4H, CH-NH); 5.79-7.47 (m, 3H, furyi); 7.30-7.85 (m, 4H, fenylen);
7.73-7.91 (m, 2H, tiaa>lyl),;8.40-8.46 (2d, 1H, NH);
N-(3-merkapto-2-(3-metyl-5-isoksazolyl)metyl-propionyl] -4-(2-tiazolyl)- L- fenylalanin forbindelse 33
<l>H-NMR (200 MHz, DMSO-dg): 5 (ppm): 2.00-2.12 (2S, 3H, CH3-isoksazolyli;2.28-3.19
(m, 8H, S-CH2-CH2-CH2; CH2-tenylen); 4.43-4.59 (m, 1H, CH-NH); 5.75-6.03 (2s, 1H, isoksazolyl); 7,29-7,86 (m, 4H, fenylen); 7,74-7,90 (m, 2H, tiazolyl); 8,46-8,53 (2d, 1H, NH);
Eksempel 8
Jn vitro- evaluering av den farmakologiske aktivitet
a) NEP- hemmende aktivitet
Den NEP-hemmende aktivitet ble evaluert i
rottenyrekorteksmembraner fremstilt ifølge fremgangsmåten beskrevet av T. Maeda et al. i Biochim. Biophys. Acta 1983, 731(1), 115-120.
Nyrer ble fjernet fra Sprague-Dawley hannrotter som veide omtrent 3 00 g og holdt ved 4 °C.
Nyrekorteks ble forsiktig dissekert, fint hakket og suspendert i homogeniseringsbuffer (10 mm natriumfosfat pH 7,4 inneholdende 1 mM MgCl2, 30 mM NaCl, 0,02 % NaN3) 1:15 vekt/volum.
Vevet ble så kald-homogenisert i 3 0 sekunder ved anvendelse av en Ultra-Turrax homogenisator.
Omtrent 10 ml av homogenat ble lagt i et lag over 10 ml sukrose (41 % vekt/volum) og sentrifugert ved 31200 rpm i 3 0 minutter ved 4 °C i en rotor med fiksert vinkel.
Membranene ble samlet fra buffer/sukrosemellomfasen, vasket to ganger med 50 mM TRIS/HCl-buffer (pH 7,4) og resuspendert i den samme buffer for lagring i små delmengder ved -80 °C inntil anvendelse.
Den NEP-hemmende aktivitet ble evaluert ved anvendelse av fremgangsmåten beskrevet av C. Llorens et al. , i Eur. J. Pharmacol., 69., (1981), 113-116, som angitt heretter.
Delmengder av membransuspensjonen fremstilt som beskrevet ovenfor (konsentrasjon 5 ug/ml proteiner) ble forinkubert i nærvær av en aminopeptidasehemmer (Bestatin -
1 mM) i 10 minutter ved 3 0 °C.
[<3>H] [Leu<5>]-enkefalin (15 nM) og buffer TRIS/HC1 pH 7,4 (50 mM) ble tilsatt for å erholde et endelig volum på 100 ul.
Inkubering (20 minutter ved 3 0 °C) ble stoppet ved tilsetning av HC1 0,1M (100 [ il). Dannelsen av metabolitten [3H] Tyr-Gly-Gly ble kvantifisert ved hjelp av kromatografi på polystyrenkolonner (Porapak Q).
Den prosentvise hemming av metabolittdannelsen i membranpreparatene behandlet med forbindelsene med formel I og med de sammenlignbare forbindelser med hensyn til ubehandlede membranpreparater, ble uttrykt i form av IC50 (nM)-verdi.
b) ACE- hemmende aktivitet
Den ACE-hemmende aktivitet ble evaluert ifølge
fremgangsmåten beskrevet i litteraturen av B. Holmquist et al., i Analytical Biochemistry 95, 540-548 (1979). 50 uM ACE (250 mU/ml renset fra kaninlunge, EC 3.4.15.1 SIGMA) ble forinkubert med 50 ul av forbindelsen med formel I eller med sammenligningsforbindelsen eller en relatert vehikkel i termostatiske kyvetter ved 37 °C.
Reaksjonen ble startet ved tilsetning av furylakryloylf enylalanylglycylglysin 0 , 8 mM (FAPGG-SIGMA)
Samtidig ble absorbansen ved 34 0 nm registrert kontinuerlig i 5 minutter ved anvendelse av et Beckman DU-50 spektrofotometer tilveiebragt med et program for beregning av delta A/minutter og regresjonskoeffisienter til enzymkinetikkurver.
Den prosentvise enzymhemming i preparatene behandlet med forbindelsene med formel I eller med sammenligningsforbindeIsene med hensyn til ubehandlede preparater ble uttrykt i form av IC50 (nM)-verdi.
IC50 (nM)-verdier med hensyn til ACE-hemmende aktivitet og NEP-hemmende aktivitet til forbindelsene 16, 18-25, 27-33 og sammenligningsforbindelsene Thiorphan og Captopril er vist i Tabell 1 nedenfor.
Dataene vist i tabell 1 viser at forbindelsene med formel I, som er gjenstand for oppfinnelsen, er utrustet med en betydelig blandet ACE-NEP-hemmende aktivitet.
Aktiviteten var sammenlignbar med den til Captopril med hensyn til ACE-hemmende aktivitet og større enn den til Thiorphan med hensyn til NEP-hemmende aktivitet.
Eksempel 9
" Ex vivo "- evaluering av den farmakologiske aktivitet
a) NEP- hemmende aktivitet
Ex vivo-NEP-hemmende aktivitet ble evaluert ifølge
prosedyren beskrevet av M. Orlowsky et al., i Biochemistry 1981, 20, 4942-4950.
Den hemmende aktivitet til forbindelsene med formel I ble evaluert i nyrer hos rotter med spontant høyt blodtrykk (SHR), 5 minutter etter i.v.-injeksjon (0,6 og 21 umol/kg) og 3 0 minutter, 60 minutter og 4 timer etter oral administrering (30 umol/kg) av de testede forbindelser.
Etter fjerningen av nyrene fra SHR ble nyrevevet homogenisert og inkubert i 15 minutter ved 37 °C i nærvær av Glutaryl-Ala-Ala-Phe-2-naftylamid (GAAP), som substrat og aminopeptidase M ved pH 7,6.
Reaksjonen ble stoppet ved tilsetning av en vandig oppløsning med 10 % trikloreddiksyre. Det frigjorte 2-naftylamin ble påvist ved tilsetning av lysekte dyprød farge (2 ml).
Enzymreaksjonshastigheter ble bestemt ved måling av økningen i optisk tetthet ved 524 nm (OD524 ) med hensyn til en standard erholdt med 2-naftylamin i kompleks med lysekte dyprød farge.
NEP-hemmende aktivitet til de testede forbindelser ble uttrykt i form av prosent av NEP-hemming i SHR-nyrer.
b) ACE- hemmende aktivitet
Ex vivo-ACE-hemmende aktivitet ble evaluert ved
anvendelse av en radiometrisk analysemetode, som beskrevet av J. W. Ryan et al. i Biochem. J. (1977), 167, 501-504.
Den hemmende aktivitet til forbindelsene med formel I ble evaluert i lunger hos rotter med spontant høyt blodtrykk (SHR), 5 minutter etter i .v.-injeksjon (0,6 og 21 umol/kg) og 3 0 minutter, 60 minutter og 4 timer etter oral administrering (3 0 umol/kg) av de testede forbindelser.
Etter fjerning av lungene fra SHR ble lungevevet homogenisert og inkubert i 2 timer ved 37 °C i nærvær av [3H] Hyp-Gly-Gly, som et substrat.
Reaksjonen ble stoppet ved tilføring av saltsyre.
Den frigjorte radiomerkede hippursyre ble ekstrahert med etylacetat og beregnet ved hjelp av flytende skintillasjonsspektrometri, ifølge vanlige fremgangsmåter.
Den ACE-hemmende aktivitet til forbindelsene ble uttrykt som prosent ACE-hemming i SHR-lunger.
For eksempel er prosentverdiene av basal enzymaktivitet erholdt ved ex vivo-testene etter intravenøs eller oral administrering av forbindelse 16 og for sammenligningsforbindeIsene R-l, R-2, R-3 og R-4 vist i tabell 2 nedenfor.
Dataene vist i Tabell 2 bekrefter at forbindelsene med formel I, ifølge oppfinnelsen, er utstyrt med en betydelig ACE/NEP-hemmende aktivitet etter intravenøs administrasjon såvel som etter oral administrasjon.
Den ex vivo-ACE/NEP-hemmende aktivitet til forbindelsene I ser dessuten ut til å være signifikant høyere enn dem til sammenligningsforbindelsene.
Claims (10)
1. Forbindelse med formel
karakterisert ved at R er en merkaptogruppe eller en R4COS-gruppe
som i organismen kan omdannes til merkaptogruppe;
Rx er en rettkjedet eller forgrenet C2-C4
alkylgruppe eller en arylalkylgruppe med fra 1 til 6 karbonatomer i alkylresten, hvor aryl er en fenyl- eller en 5-6-leddet aromatisk heterosyklisk gruppe valgt blant furyl, tienyl, pyridyl eller isoksazolyl, eventuelt substituert med én eller flere substituenter, som er like eller forskjellige, utvalgt fra gruppen bestående av halogenatomer, C1-C4-alkoksy- eller Cx - C4 - alky lgrupper ;
R2 er et hydrogenatom eller en rettkjedet
eller forgrenet Cx-C4-alkylgruppe;
R3 er en fenylgruppe substituert med en 5-
eller 6-leddet aromatisk heterosyklisk gruppe valgt blant tiazolyl, furyl, pyrimidinyl, pyrazinyl, pyridyl og tienyl;
R4 er en rettkjedet eller forgrenet C1-C4-
alkylgruppe eller en fenylgruppe;
karbonatomene merket med en stjerne er stereogene sentre; og farmasøytisk akseptable salter derav.
2. Forbindelse med formel I ifølge krav 1, karakterisert ved at^ betegner en arylalkylgruppe, eventuelt substituert med én eller flere substituenter, som er like eller forskjellige, utvalgt fra gruppen bestående av halogenatomer, C^-C-alkyl- eller C2 - C4 - alkoksygrupper.
3. Forbindelse med formel I ifølge krav 1, karakterisert ved at Rj betegner en fenylalkylgruppe, eventuelt substituert med én eller flere substituenter, som er like eller forskjellige, utvalgt blant halogenatomer, C^-C^-alkyl- eller C^-C-alkoksygrupper.
4. Forbindelse med formel I ifølge krav 1, karakterisert ved at den er i form av et salt med et alkalimetall utvalgt fra gruppen bestående av natrium, litium og kalium.
5. Forbindelse,
karakterisert ved at den er utvalgt fra gruppen bestående av N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(2-tiazolyl) -L-fenylalaninmetylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(2-pyridyl)-L-fenylalaninmetylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(3-pyridyl) -L-fenylalaninbenzylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(2-furyl)-L-fenylalaninmetylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(5-pyrimidinyl)-L-fenylalaninetylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(2-pyrazinyl) - L-fenylalaninmetylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(2-tienyl)-L-fenylalaninmetylester; N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(3-tienyl)-L-f enylalaninmetylester ,-N-(3-fenylkarbonyltio-2-fenylmetylpropionyl)-4-(3-furyl)-L-fenylalaninmetylester; N-[3-fenylkarbonyltio-2-(3-pyridylmetyl)propionyl]-4-(2-tiazolyl)-L-fenylalaninmetylester; N-(3-merkapto-2-fenylmetylpropionyl)-4-(2-tiazolyl)-L-fenylalanin; N-(3-merkapto-2-fenylmetylpropionyl)-4-(2-pyridyl)-L-fenylalanin; N-(3-merkapto-2-fenylmetylpropionyl)-4-(3-pyridyl)-L-fenylalanin; N-(3-merkapto-2-fenylmetylpropionyl)-4-(2-furyl)-L-fenylalanin; N-(3-merkapto-2-fenylmetylpropionyl)-4-(5-pyrimidinyl)-L-fenylalanin; N-(3-merkapto-2-fenylmetylpropionyl)-4-(2-pyrazinyl)-L-fenylalanin; N-(3-merkapto-2-fenylmetylpropionyl)-4-(2-tienyl)-L-fenylalanin; N-(3-merkapto-2-fenylmetylpropionyl)-4-(3-tienyl)-L-fenylalanin; N-(3-merkapto-2-fenylmetylpropionyl)-4-(3-furyl)-L-fenylalanin; N-[3-merkapto-2-(3-pyridylmetyl)propionyl]-4-(2-tiazolyl)-L-fenylalanin; N-[3-acetyltio-2-(3-metoksyfenyl)metyl-propionyl]-4-(2-tiazolyl)-L-fenylalaninmetylester; N-[3-acetyltio-2-(2-fluorfenyl)metyl-propionyl]-4-(2-tiazolyl)-L-fenylalaninmetylester; N-[3-fenylkarbonyltio-2-(2-tienyl)metyl-propionyl]-4-(2-tiazolyl)-L-fenylalaninmetylester; N-[ 2-(2-furyl)metyl-3-fenylkarbonyltio-propionyl]-4-(2-tiazolyl)-L-fenylalaninmetylester;
N-[2-(3-metyl-5-isoksazolyl)metyl-3-fenylkarbonyltio-propionyl]-4-(2-tiazolyl)-L-fenylalaninmetylester; N-[3-merkapto-2-(3-metoksyfenyl)metyl-propionyl]-4-(2-tiazolyl)-L-fenylalanin; N-[3-merkapto-2-(2-tienyl)metyl-propionyl]-4-(2-tiazolyl)-L-fenylalanin; N-[3-merkapto-2-(3-metyl-5-isoksazolyl)metyl-propionyl] -4-(2-tiazolyl)-L-fenylalanin; N-[2-(2-fluorfenyl)metyl-3-merkapto-propionyl]-4-(2-tiazolyl)-L-fenylalanin; N-[2-(2-furyl)metyl-3-merkapto-propionyl]-4-(2-tiazolyl) -L-fenylalanin;
og stereoisomerene (2S) eller (2R) derav.
6. Forbindelse ifølge krav 5, karakterisert ved at den omfatter N-[(2S)-3-merkapto-2-fenylmetylpropionyl]-4-(2-tiazolyl)-L-fenylalanin.
7. Fremgangsmåte for fremstilling av en forbindelse med formel I ifølge krav 1,
karakterisert ved at den omfatter reaksjonen mellom en forbindelse med formel
hvor
R og Rx har samme betydninger som ovenfor; og et fenylalaninderivat med formel
hvori
R2 og R3 har samme betydning som ovenfor.
8. Farmasøytisk preparat, karakterisert ved at det inneholder en terapeutisk effektiv mengde av en forbindelse med formel I ifølge krav 1, i blanding med en bærer for farmasøytisk anvendelse.
9. Farmasøytisk preparat ifølge krav 8, karakterisert ved at det anvendes for behandling av kardiovaskulære sykdommer.
10. Anvendelse av en forbindelse med formel (I) for fremstilling av et medikament for behandling av kardiovaskulære sykdommer.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT95MI002773A IT1277737B1 (it) | 1995-12-28 | 1995-12-28 | Derivati tiolici ad attivita' inibitrice delle metallopeptidasi |
PCT/EP1996/005663 WO1997024342A1 (en) | 1995-12-28 | 1996-12-17 | Thiol derivatives with metallopeptidase inhibitory activity |
Publications (3)
Publication Number | Publication Date |
---|---|
NO982977D0 NO982977D0 (no) | 1998-06-26 |
NO982977L NO982977L (no) | 1998-08-27 |
NO310914B1 true NO310914B1 (no) | 2001-09-17 |
Family
ID=11372827
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO19982977A NO310914B1 (no) | 1995-12-28 | 1998-06-26 | Tiolderivater med metallopeptidasehemmende aktivitet, fremgangsmate for fremstilling derav, farmasoytiske preparater sominneholder en slik forbindelse, samt anvendelse av forbindelsenefor fremstilling av medikamenter |
Country Status (31)
Country | Link |
---|---|
EP (1) | EP0877740B1 (no) |
JP (1) | JP2000502687A (no) |
KR (1) | KR19990076809A (no) |
CN (1) | CN1071325C (no) |
AP (1) | AP1186A (no) |
AR (1) | AR004413A1 (no) |
AT (1) | ATE292123T1 (no) |
AU (1) | AU713156B2 (no) |
BG (1) | BG63942B1 (no) |
BR (1) | BR9612373A (no) |
CA (1) | CA2241414A1 (no) |
CZ (1) | CZ204698A3 (no) |
DE (1) | DE69634543D1 (no) |
EA (1) | EA000991B1 (no) |
EE (1) | EE03766B1 (no) |
GE (1) | GEP19991871B (no) |
HK (1) | HK1018008A1 (no) |
IL (1) | IL124915A (no) |
IS (1) | IS1885B (no) |
IT (1) | IT1277737B1 (no) |
NO (1) | NO310914B1 (no) |
NZ (1) | NZ325785A (no) |
OA (1) | OA10704A (no) |
PL (1) | PL188151B1 (no) |
RO (1) | RO119882B1 (no) |
SK (1) | SK282977B6 (no) |
TR (1) | TR199801229T2 (no) |
UA (1) | UA62923C2 (no) |
UY (1) | UY24425A1 (no) |
WO (1) | WO1997024342A1 (no) |
ZA (1) | ZA9610891B (no) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9004163B2 (en) | 2009-04-03 | 2015-04-14 | Statoil Petroleum As | Equipment and method for reinforcing a borehole of a well while drilling |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
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IT1289522B1 (it) * | 1996-12-24 | 1998-10-15 | Zambon Spa | Processo per la preparazione di eteroaril-fenilalanine |
MY153569A (en) | 1998-01-20 | 2015-02-27 | Mitsubishi Tanabe Pharma Corp | Inhibitors of ?4 mediated cell adhesion |
US8168616B1 (en) | 2000-11-17 | 2012-05-01 | Novartis Ag | Combination comprising a renin inhibitor and an angiotensin receptor inhibitor for hypertension |
GB0203665D0 (en) * | 2002-02-15 | 2002-04-03 | Glaxo Group Ltd | Process |
MY140707A (en) | 2002-02-28 | 2010-01-15 | Mitsubishi Tanabe Pharma Corp | Process for preparing a phenylalanine derivative and intermediates thereof |
EP1481967B1 (en) | 2002-03-05 | 2011-05-04 | Sumitomo Chemical Company, Limited | Process for the preparation of biaryl compounds |
TW200407310A (en) * | 2002-06-07 | 2004-05-16 | Glaxo Group Ltd | Compounds |
GB0213122D0 (en) * | 2002-06-07 | 2002-07-17 | Glaxo Group Ltd | Compounds |
US7045653B2 (en) | 2002-12-23 | 2006-05-16 | Pfizer, Inc. | Pharmaceuticals |
GB0327839D0 (en) | 2003-12-01 | 2003-12-31 | Novartis Ag | Organic compounds |
US20080161321A1 (en) | 2004-03-17 | 2008-07-03 | David Louis Feldman | Use of Renin Inhibitors in Therapy |
CN102811989A (zh) | 2010-02-03 | 2012-12-05 | Meh联合公司 | 作为具有选择性和生物活性的等排物的多取代氟甲烷 |
TW201136582A (en) | 2010-03-16 | 2011-11-01 | Novartis Ag | Improved pharmaceutical compositions of aliskiren and methods of delivery |
Family Cites Families (4)
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US4401677A (en) * | 1981-10-09 | 1983-08-30 | E. R. Squibb & Sons, Inc. | Enkephalinase inhibitors |
FR2652087B1 (fr) * | 1989-09-15 | 1993-10-15 | Bioprojet Ste Civile | Derives d'amino-acides, leur procede de preparation et leurs applications therapeutiques. |
FR2682952B1 (fr) * | 1991-10-25 | 1993-12-03 | Institut Nal Sante Recherc Medic | Nouveaux n-(mercaptoacyl) amino-acides, leur preparation et les compositions pharmaceutiques qui les contiennent. |
IT1273455B (it) * | 1995-01-27 | 1997-07-08 | Zambon Spa | Derivati tiolici ad attivita' inibitrice delle metallopeptidasi |
-
1995
- 1995-12-28 IT IT95MI002773A patent/IT1277737B1/it active IP Right Grant
-
1996
- 1996-12-17 TR TR1998/01229T patent/TR199801229T2/xx unknown
- 1996-12-17 RO RO98-01109A patent/RO119882B1/ro unknown
- 1996-12-17 EA EA199800544A patent/EA000991B1/ru not_active IP Right Cessation
- 1996-12-17 CZ CZ982046A patent/CZ204698A3/cs unknown
- 1996-12-17 EE EE9800192A patent/EE03766B1/xx not_active IP Right Cessation
- 1996-12-17 BR BR9612373A patent/BR9612373A/pt not_active Application Discontinuation
- 1996-12-17 UA UA98074090A patent/UA62923C2/uk unknown
- 1996-12-17 AU AU13018/97A patent/AU713156B2/en not_active Ceased
- 1996-12-17 SK SK889-98A patent/SK282977B6/sk unknown
- 1996-12-17 CA CA002241414A patent/CA2241414A1/en not_active Abandoned
- 1996-12-17 CN CN96199354A patent/CN1071325C/zh not_active Expired - Fee Related
- 1996-12-17 GE GEAP19964406A patent/GEP19991871B/en unknown
- 1996-12-17 NZ NZ325785A patent/NZ325785A/en unknown
- 1996-12-17 DE DE69634543T patent/DE69634543D1/de not_active Expired - Lifetime
- 1996-12-17 KR KR1019980704934A patent/KR19990076809A/ko not_active Application Discontinuation
- 1996-12-17 JP JP09524001A patent/JP2000502687A/ja not_active Ceased
- 1996-12-17 AP APAP/P/1998/001264A patent/AP1186A/en active
- 1996-12-17 PL PL96327580A patent/PL188151B1/pl not_active IP Right Cessation
- 1996-12-17 WO PCT/EP1996/005663 patent/WO1997024342A1/en not_active Application Discontinuation
- 1996-12-17 AT AT96944583T patent/ATE292123T1/de not_active IP Right Cessation
- 1996-12-17 IL IL12491596A patent/IL124915A/en not_active IP Right Cessation
- 1996-12-17 EP EP96944583A patent/EP0877740B1/en not_active Expired - Lifetime
- 1996-12-23 ZA ZA9610891A patent/ZA9610891B/xx unknown
- 1996-12-27 UY UY24425A patent/UY24425A1/es not_active IP Right Cessation
- 1996-12-27 AR ARP960105957A patent/AR004413A1/es not_active Application Discontinuation
-
1998
- 1998-06-18 BG BG102553A patent/BG63942B1/bg unknown
- 1998-06-22 IS IS4780A patent/IS1885B/is unknown
- 1998-06-26 OA OA9800094A patent/OA10704A/en unknown
- 1998-06-26 NO NO19982977A patent/NO310914B1/no unknown
-
1999
- 1999-07-20 HK HK99103110A patent/HK1018008A1/xx not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9004163B2 (en) | 2009-04-03 | 2015-04-14 | Statoil Petroleum As | Equipment and method for reinforcing a borehole of a well while drilling |
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