FI114634B - Förfarande för framställning av farmakologiskt effektiva hydrazinderivat - Google Patents

Förfarande för framställning av farmakologiskt effektiva hydrazinderivat Download PDF

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FI114634B
FI114634B FI923017A FI923017A FI114634B FI 114634 B FI114634 B FI 114634B FI 923017 A FI923017 A FI 923017A FI 923017 A FI923017 A FI 923017A FI 114634 B FI114634 B FI 114634B
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substituted
formula
acid
unsubstituted
lower alkyl
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Marc Lang
Peter Schneider
Guido Bold
Alexander Faessler
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Novartis Ag
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Claims (3)

1. Analogiförfarande för framställning av ett farmaceutiskt användbart hydrazinderivat med formeln R, I R7 r, Rfi I <\ I Re samt farmaceutiskt användbara salter av denna förening, om saltbildan.de grupper förekommer, i vilken formel Rx och R9 betecknar oberoende av varandra väte, lägalkanoyl, fenyllä-galkanoyl, fenyllägalkanoyl, i vilken lägalkanoylresten är substituerad med karbamoyl, morfolinolägalkanoyl, tiomorfo-linolägalkanoyl, pyridyllägalkanoyl, kinolyllägalkanoyl, tetrazolyllägalkanoyl, med N-morfolino- eller N-tiomorfo-linokarbonyl i aminokväve substituerad aminolägalkanoyl, halogenlägalkanoyl, som innehäller högst 3 halogenatomer, 2-(N-morfolinolägalkylkarbamoyl)-lägalkanoyl, 2-(N-pyridyl-lägalkyl-karbamoyl)-lägalkanoyl, 2(R,S)-(N-(2-pyridylme-tyl)-karbamoyl)-3-metyl-butyryl, lägalkoxikarbonyl, fenyl-·: lägalkoxikarbonyl, bensyloxikarbonyl, tetrahydrofuranyl- lägalkoxikarbonyl, lägalkylsulfonyl, morfolinosulfonyl, tiomorfolinosulfonyl, N-pyridyllägalkyl-N-lägalkyl-karba-,* moyl, eller en acylrest av aminosyra, vilken aminosyra är glycin, alanin, valin, leucin, isoleucin, glutaminsyra, eller asparagin i (D)-, (L)- eller (D,L)-form, varvid a-ami- nogruppen är osubstituerad eller acylerad med nägon annan ovan nämnd rest Rx eller Rg, förutsatt att högst en av res-.’ , terna Rx och R9 betecknar väte, R2, R4, Rs och R8 betecknar väte, R3 betecknar lägalkyl; cyklohexyllägalkyl; eller fenyllä-,* galkyl, som är osubstituerad eller substituerad med halo- gen, lägalkoxi eller cyano, R5 betecknar hydroxi, och 199 1 1 46 3 4 R7 betecknar lägalkyl; cyklohexyllagalkyl; eller fenyllägalkyl , som är osubstituerad eller substituerad med halogen, lägalkoxi eller cyano, säsom sist definierats för res-ten R3, kännetecknat därav, att a) ett hydrazinderivat med formeln i7 HN __Rs (ΠΙ) Re vari resterna har de ovan nämnda betydelserna, ansluts till en epoxid med formeln R3XXr4 vari resterna har de ovan nämnda betydelserna, varvid de fria funktionella grupperna med undantag av de i reaktionen deltagande grupperna eventuellt förekommer i skyddad form, • och eventuellt förekommande skyddsgrupper avskiljs, eller » ,: b) för framställning av föreningar med formeln I, vari Rx I och R9 betecknar acyl, sulfo, med en osubstituerad eller substituerad alkyl, aryl, heterocyklyl, alkoxi, som är osubstituerad eller substituerad, eller med aryloxi substi-;· tuerad sulfonyl, eller sulfamoyl, vilken i kväve är osub stituerad eller substituerad, och de andra resterna har de . anförda betydelserna, en aminoförening med formeln i · I \A|’ ·: <V) R, R< | R. 2oo 1 1 4634 väri resterna har de ovan anförda betydelserna, kondenseras med en syra med formeln R9-OH (VI) eller dess reaktionsdugliga syraderivat, vari resten Rg har de ovan anförda betydelserna, varvid de fria funktionella grupperna med undantag av de grupper som deltagit i reak-tionen eventuellt förekommer i skyddad form och eventuellt förekommande skyddsgrupper avskiljs, eller c) för framställning av föreningar med formeln I, vari Rx och R9 betecknar acyl, sulfo med en osubstituerad eller substituerad alkyl, aryl, heterocyklyl, alkoxi, vilken är osubstituerad eller substituerad, eller med aryloxi substituerad sulfonyl, eller sulfamoyl, vilken i kväve är osubstituerad eller substituerad, och de andra resterna har de anförda betydelserna, en aminoförening med formeln ;; : R. ,i vari resterna har de ovan anförda betydelserna, kondenseras med en syra med formeln Rjl-OH (VIII) eller dess reaktionsdugliga syraderivat, vari resten Rx har de ovan anförda betydelserna, varvid de fria funktionella grupperna med undantag av de grupper som deltagit i reak-.: tionen eventuellt förekommer i skyddad form och eventuellt • förekommande skyddsgrupper avskiljs, eller 201 114634 d) för framställning av föreningar med formeln I, väri och R9 betecknar tvä likadana rester, vilka är acyl, sulfo, med en osubstituerad eller substituerad alkyl, aryl, hete-rocyklyl, alkoxi, som är osubstituerad eller substituerad, eller med aryloxi substituerad sulfonyl, eller sulfamoyl, vilken i kväve är osubstituerad eller substituerad, och de andra resterna har de anförda betydelserna, en diaminoföre-ning med formeln Ra | R7 | Rs R, I h/"OC'vn/" <K) < X | RB väri resterna har de ovan anförda betydelserna, kondenseras med en för anslutande av identiska rester R7 och R9 lämplig syra eller dess reaktionsdugliga syraderivat, väri resterna R-l och R9 har de ovan anförda betydelserna, varvid de fria funktionella grupperna med undantag av de grupper som del-tagit i reaktionen eventuellt förekommer i skyddad form och eventuellt förekommande skyddsgrupper avskiljs, eller * · e) för framställning av en förening med formeln I, väri i stället av resten R7 förekommer resten R7", som betecknar en osubstituerad eller substituerad alkyl eller cykloalkyl, j i en förening med formeln I' ? \ Λ ?' <\ i R, » väri R7' betecknar väte och de andra resterna har de anför-• da betydelserna, fogas en rest R7" genom att substituera : med en förening med formeln XII R/-X (XII) 114634 väri X är en avlägsnande grupp och R7" betecknar en osub-stituerad eller substituerad alkyl eller cykloalkyl, varvid de fria funktionella grupperna med undantag av de grupper som deltagit i reaktionen eventuellt förekommer i skyddad form, och eventuellt förekommande skyddsgrupper avskiljs, eller f) i en förening med formeln I, väri substituenterna har de ovan anförda betydelserna, förutsatt att i ifrägavarande förening med formeln I ätminstone en funktionell grupp är skyddad med skyddsgrupper, avskiljs de förekommande skydds-grupperna, och, om sä önskas, omvandlas en förening med formeln I er-hällen enligt nägot av de ovan anförda förfarandena a) -f), väri finns ätminstone en saltbildande grupp, omvandlas till dess sait eller ett erhället sait omvandlas tili en fri förening eller tili ett nägot annat sait och/eller se-pareras eventuellt erhällna isomerblandningar separeras och/eller omvandlas en förening enligt uppfinningen med ,, formeln I tili nägon annan förening enligt uppfinningen med • formeln I.
·'; 2. Förfarande enligt patentkravet 1 för framställning av en <· förening med formeln I samt ett farmakologiskt användbart sait av denna förening, väri R3 och R9 betecknar en envär-dig grupp, som är bunden via karboxigruppen hos aminosyran (L)-valin och som är acylerad i aminokväve med bensyloxi-karbonyl, R2 och R8 betecknar väte, R3 betecknar bensyl, R4 betecknar väte, R5 betecknar hydroxi, R6 betecknar väte och R7 betecknar bensyl och de asymmetriska kolatomerna, vid vilka resterna R3 och Rs är fästa, förekommer i S-konfi-: guration, kännetecknat därav, att man använder : pä motsvarande sätt substituerade utgängsämnen. 203 1 1 4634
3. Förfarande enligt patentkravet 1 för framställning av en förening med formeln I samt ett farmakologiskt användbart sait av denna förening, väri R3 och R9 betecknar en envär-dig grupp, som är bunden via karboxigruppen hos aminosyran (L)-valin och som är acylerad i aminokväve med 4-tiomorfo-linokarbonyl, R2 och Rs betecknar väte, R3 betecknar bensyl, R4 betecknar väte, Rs betecknar hydroxi, R6 betecknar väte och R7 betecknar isobutyl och de asymmetriska kolatomerna, vid vilka resterna R3 och R5 är fästa, förekommer i S-kon-figuration, kännetecknat därav, att man använ-der pä motsvarande sätt substituerade utgängsämnen. > t > I » · * » » f * » • · 1 * * i » · » a 1 » ' · t i t
FI923017A 1991-07-03 1992-06-29 Förfarande för framställning av farmakologiskt effektiva hydrazinderivat FI114634B (sv)

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