DK172221B1

DK172221B1 - Use of ACE Inhibitors or their Physiologically Acceptable Salts for the Preparation of Nootropic Drugs

Info

Publication number: DK172221B1
Application number: DK153587A
Authority: DK
Inventors: Franz Hock; Josef Scholtholt; Hansjoerg Urbach; Rainer Henning; Ulrich Lerch; Wolf-Ulrich Nickel; Wolfgang Rueger
Original assignee: Hoechst Ag
Priority date: 1986-03-27
Filing date: 1987-03-26
Publication date: 1998-01-12
Also published as: CS276179B6; NO871282L; OA08506A; FI871304A0; DE3610391A1; JPS62240698A; PH27210A; EP0243645A3; IE870784L; CN1031267C; ATE102954T1; NO871282D0; NO178546B; CS212687A3; DK153587D0; EP0243645A2; PT84564A; MA20919A1; CN87102304A; ZA872230B

Abstract

The invention relates to novel compounds having a nootropic activity, the use of ACE inhibitors as medicaments having nootropic activity, agents containing them, and their use in the treatment and prophylaxis of cognitive malfunctions.

Description

DK 172221 B1DK 172221 B1

Den foreliggende opfindelse angår anvendelsen af ACE-inhibitorer (inhibitorer af angiotensin-omdannende enzym) eller deres fysiologisk acceptable salte til fremstilling af lægemidler med nootrop virkning (dvs. som forbedrer den 5 cognitive funktion).The present invention relates to the use of ACE inhibitors (inhibitors of angiotensin-converting enzyme) or their physiologically acceptable salts for the preparation of drugs with nootropic action (i.e., which improves cognitive function).

Fra EP-A 050 800 og EP-A 116 276 kendes ACE-inhibitorer indeholdende heterocycliske grupper, og som udviser blodtrykssænkende virkning.From EP-A 050 800 and EP-A 116 276 ACE inhibitors containing heterocyclic groups are known and which exhibit blood pressure lowering effect.

Det har nu - hvilket på baggrund af den kendte teknik 10 må betragtes som uventet og overraskende - vist sig, at den nedenfor definerede gruppe af ACE-inhibitorer også udviser en nootrop virkning.It has now - which in light of the prior art 10 must be regarded as unexpected and surprising - has shown that the group of ACE inhibitors defined below also exhibits a nootropic effect.

Opfindelsen angår således anvendelsen af ACE-inhibitorer med formlen II 15Thus, the invention relates to the use of ACE inhibitors of formula II 15

Jr Jr Jr R300C - CH - N - C - CH - NH - CH - (CH2)n-R (II) I. L [| I, I , R4 R5 O R1 COOR2 20 eller deres fysiologisk acceptable salte til fremstilling af lægemidler med nootrop virkning, i hvilken formel n betyder 1 eller 2, 25 R betyder en aromatisk gruppe med 6-12 carbonatomer, R1 betyder hydrogen, en aliphatisk gruppe med 1-21 carbonatomer eller den om fornødent beskyttede sidekæde af en naturligt forekommende α-aminosyre, R2 og R3 er ens eller forskellige og betyder hydrogen, en 30 aliphatisk gruppe med 1-21 carbonatomer, en alicyclisk gruppe med 3-20 carbonatomer, en aromatisk gruppe med 6-12 carbonatomer eller en araliphatisk gruppe med 7-32 carbonatomer, og R4 og R5 sammen med atomerne, der bærer dem, danner et mono-, 35 bi- eller tricyclisk heterocyclisk ringsystem valgt blandt pyrrolidin, decahydroisoquinolin, octahydroindol, octahydro-cyclopenta[b]pyrrol, 2-azaspiro[4.5]decan, 2-azaspiro [4.4] -nonan, spiro[(bicyclo[2.2.1]heptan)-2,3'-pyrrolidin], spi- 2 DK 172221 B1 ro[(bicyclo[2.2.2]octan)-2,3'-pyrrolidin], 2-azatricyclo-[4.3.0.1®'9]decan, decahydrocyclohepta[b]pyrrol, octahydro-isoindol, octahydrocyclopenta[c]pyrrol og 2,3,3a, 4,5,7a-hexa-hydroindol.Jr. Jr. Jr. R300C - CH - N - C - CH - NH - CH - (CH2) n-R (II) I. L [| I, I, R4 R5 O R1 COOR2 20 or their physiologically acceptable salts for the preparation of drugs of nootropic effect, in which formula n means 1 or 2, 25 R represents an aromatic group of 6-12 carbon atoms, R1 represents hydrogen, an aliphatic a group of 1-21 carbon atoms or the if appropriate protected side chain of a naturally occurring α-amino acid, R 2 and R 3 are the same or different and represent hydrogen, an aliphatic group of 1-21 carbon atoms, an alicyclic group of 3-20 carbon atoms, an aromatic group of 6-12 carbon atoms or an araliphatic group of 7-32 carbon atoms and R 4 and R 5 together with the atoms carrying them form a mono-, 35- or tricyclic heterocyclic ring system selected from pyrrolidine, decahydroisoquinoline, octahydroindole, octahydro-cyclopenta [b] pyrrole, 2-azaspiro [4.5] decane, 2-azaspiro [4.4] -nonane, spiro [(bicyclo [2.2.1] heptane) -2,3'-pyrrolidine], spi- 2 DK 172221 B1 ro [(bicyclo [2.2.2] octane) -2,3'-pyrrolidine], 2-azatricyclo- [4.3.0.1®'9 ] decane, decahydrocyclohepta [b] pyrrole, octahydroisoindole, octahydrocyclopenta [c] pyrrole and 2,3,3a, 4,5,7a-hexa-hydroindole.

5 Ved en aliphatisk gruppe forstås en aliphatisk acyc- lisk gruppe, dvs. en gruppe med en åben, lige eller forgrenet carbonkæde, f.eks. alkyl, alkenyl, alkynyl og tilsvarende flerumættede grupper. Den er fortrinsvis usubstitueret eller, som beskrevet eksempelvis nedenfor ved carboxy, carbamoyl, 10 aminoalkyl, alkanoylaminoalkyl, alkoxycarbonylaminoalkyl, arylalkoxycarbonylaminoalkyl, arylalkylaminoalkyl, alkyl-aminoalkyl, dialkylaminoalkyl, alkylthioalkyl, arylthioalkyl, carboxyalkyl, carbamoylalkyl, alkoxycarbonylalkyl, alkanoyl-oxyalkyl, alkoxycarbonyloxyalkyl, aroyloxyalkyl eller aryl-15 oxycarbonyloxyalkyl, monosubstitueret.By an aliphatic group is meant an aliphatic acyclic group, i.e. a group having an open, straight or branched carbon chain, e.g. alkyl, alkenyl, alkynyl and corresponding polyunsaturated groups. Preferably, it is unsubstituted or, as described for example below by carboxy, carbamoyl, 10 aminoalkyl, alkanoylaminoalkyl, alkoxycarbonylaminoalkyl, arylalkoxycarbonylaminoalkyl, arylalkylaminoalkyl, alkyl, aminoalkyl, dialkylaminoalkyl, alkylthioalkyl, arylthioalkyl, carboxyalkyl, carbamoylalkyl, alkoxycarbonylalkyl, alkanoyl oxyalkyl, alkoxycarbonyloxyalkyl, aroyloxyalkyl or aryl-oxycarbonyloxyalkyl, monosubstituted.

En alicyclisk gruppe og en via en åben carbonkæde bundet, tilsvarende eventuelt substitueret alicyclisk-ali-phatisk gruppe er en fortrinsvis mono- til pentacyclisk isocyclisk, ikke-aromatisk gruppe med enkelte dobbeltbin-20 dinger eller usymmetrisk fordelte dobbeltbindinger, der også kan være forgrenet (dvs. bærer åbenkædede aliphatiske sidekæder), og som er forbundet via et ring-carbonatom eller et sidekæde-carbonatom. Den er fortrinsvis usubstitueret.An alicyclic group and an open carbon chain linked, corresponding to optionally substituted alicyclic aliphatic group, is a preferably mono- to pentacyclic isocyclic, non-aromatic single double bond or unsymmetrically spaced double bond which may also be branched ( i.e., carrying open-chain aliphatic side chains) and which are connected via a ring carbon or a side chain carbon atom. It is preferably unsubstituted.

Flere ringe som komponenter af en sådan gruppe er kondense-25 rede, spiro-forbundne eller isolerede. Eksempler på sådanne grupper er cycloalkyl, cycloalkenyl, cycloalkylalkyl, bicyc-loalkyl, tricycloalkyl og grupper afledt af mono-, bi- eller oligocycliske terpener, såsom menthyl, isomenthyl, bornanyl, bornyl, caranyl, epibornyl, epiisobornyl, isobornyl, menth-30 anyl, neomenthyl, neoisomenthyl, pinanyl, thujanyl; de er fortrinsvis usubstituerede (aliphatiske sidekæder er ifølge den foreliggende definition ikke substituenter).Several rings as components of such a group are condensed, spiro-linked or isolated. Examples of such groups are cycloalkyl, cycloalkenyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl and groups derived from mono-, bi- or oligocyclic terpenes such as menthyl, isomenthyl, bornanyl, bornyl, caranyl, epibornyl, epiisobornyl, isobornyl, isobornyl, , neomenthyl, neoisomenthyl, pinanyl, thujanyl; they are preferably unsubstituted (aliphatic side chains, by the present definition, are not substituents).

En aromatisk gruppe er fortrinsvis aryl, såsom phenyl, biphenylyl eller naphthyl, som eventuelt er mono-, di- eller 35 trisubstitueret som angivet nedenfor ved aryl. Grupper afledt af aryl, såsom aralkyl, aryloxy, arylthio eller aroyl, for- 3 DK 172221 B1 trinsvis benzoyl, kan være substitueret som aryl.An aromatic group is preferably aryl such as phenyl, biphenylyl or naphthyl which is optionally mono-, di- or trisubstituted as indicated below by aryl. Groups derived from aryl such as aralkyl, aryloxy, arylthio or aroyl, preferably benzoyl, may be substituted as aryl.

Ved en araliphatisk gruppe forstås især arylalkylgrup-per, såsom arylalkyl, diarylalkyl, indanyl eller fluorenyl, hvori aryl er som ovenfor defineret og kan være substitueret 5 på den dér angivne måde.In particular, an araliphatic group is understood to mean arylalkyl groups such as arylalkyl, diarylalkyl, indanyl or fluorenyl, wherein aryl is as defined above and may be substituted in the manner indicated therein.

R4 og r5 kan sammen med atomerne, der bærer dem, danne et mono-, bi- eller tricyclisk heterocyclisk ringsystem valgt blandt følgende ringsystemer:R4 and r5, together with the atoms carrying them, can form a mono-, bi- or tricyclic heterocyclic ring system selected from the following ring systems:

Pyrrolidin (0); decahydroisoquinolin (B) ; octahydro-10 indol (C); octa-hydrocyclopenta-[b]pyrrol (D); 2-azaspiro-[4.5]decan (E) ; 2-azaspiro[4.4]nonan (F) ; spiro[(bicyclo-[2.2.1]heptan)-2,3'-pyrrolidin] (G); spiro[(bicyclo[2.2.2J-octan)-2,3'-pyrrolidin] (H); 2-azatricyclo[4.3.0.1®'^]decan (I); decahydrocyclohepta-[b]pyrrol (J); octahydroisoindol 15 (K); octahydrocyclopenta-[c]pyrrol (L); 2,3,3a, 4,5,7a-hexa- hydroindol (M).Pyrrolidine (0); decahydroisoquinoline (B); octahydro-indole (C); octa-hydrocyclopenta- [b] pyrrole (D); 2-azaspiro- [4.5] decane (E); 2-azaspiro [4.4] nonane (F); spiro [(bicyclo- [2.2.1] heptane) -2,3'-pyrrolidine] (G); spiro [(bicyclo [2.2.2J-octane) -2,3'-pyrrolidine] (H); 2-azatricyclo [4.3.0.1®] decane (I); decahydrocyclohepta- [b] pyrrole (J); octahydroisoindole (K); octahydrocyclopenta- [c] pyrrole (L); 2,3,3a, 4,5,7a-hexa-hydroindole (M).

Ved forbindelser med formlen II, som har flere chirale atomer, kommer alle mulige diastereomere som racemater eller enantiomere eller blandinger af forskellige diastereomere i 20 betragning.For compounds of formula II having multiple chiral atoms, all possible diastereomers such as racemates or enantiomers or mixtures of different diastereomers come into consideration.

De heterocycliske ringsystemer, der kommer i betragtning, udviser de følgende strukturformler.The considered heterocyclic ring systems exhibit the following structural formulas.

44

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DK 172221 B1 GCX‘“'’ ck .DK 172221 B1 GCX '' '' ck.

J- COORJ- COOR

5 I C^C5 in C ^ C

10 d k r Nm/~coor10 d k r Nm / ~ coor

Qo-^f C Η I 1 20 Ci^WOR3 ^-COOR3Qo- ^ f C Η I 1 20 Ci ^ WOR3 ^ -COOR3

J KJ K

25 Ο-COOR325 Ο-COOR3

L ML M

30 _ O00*’ O^/coor3 i \30 O00 / coor3

O PUP

35 5 DK 172221 B135 5 DK 172221 B1

En foretrukken udførelsesform er ejendommelig ved, at der anvendes forbindelser med formlen II, hvori n betyder 1 eller 2, R betyder aryl med 6-12 carbonatomer, 5 R1 betyder hydrogen, alkyl med 1-6 carbonatomer, alkenyl med 2-6 carbonatomer, alkynyl med 2-6 carbonatomer, en eventuelt beskyttet sidekæde af en naturligt fore-10 kommende or-aminosyre med formlen R^-CH (NH2) -COOH, R2 og R3 er ens eller forskellige og betyder hydrogen, alkyl med 1-6 carbonatomer, alkenyl med 2-6 carbonatomer, 15 aryl med 6-12 carbonatomer, (c6“c12) -aryl- (C^-C^ -alkyl, (C3-C9)-cycloalkyl, og R4 og r5 har den ovenfor angivne betydning, især sådanne forbindelser, hvori 20 n betyder 1 eller 2, R betyder (Cg-C12)-aryl# især phenyl, R1 betyder hydrogen eller alkyl med 1-6 carbonatomer, alkenyl med 2-6 carbonatomer eller en sidekæde af en naturligt forekommende, eventuelt beskyttet ot-aminosyre, 25 dog især hydrogen, alkyl med 1-3 carbonatomer, alkenyl med 2 eller 3 carbonatomer, den eventuelt beskyttede sidekæde af lysin, benzyl, 4-methoxybenzyl, 4-ethoxy-benzyl, phenethyl, 4-aminobutyl eller benzoylmethyl, R2 og R3 er ens eller forskellige og betyder hydrogen, 30 alkyl med 1-6 carbonatomer, alkenyl med 2-6 carbon atomer eller (Cg-C^)-aryl-(C1-C4)-alkyl, dog især hydrogen, alkyl med 1-4 carbonatomer eller benzyl, og R4 og R3 har den ovenfor angivne betydning.A preferred embodiment is characterized in that compounds of formula II are used wherein n is 1 or 2, R is aryl of 6-12 carbon atoms, R 1 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, an optionally protected side chain of a naturally occurring or amino acid of the formula R 1 -CH (NH 2) -COOH, R 2 and R 3 are the same or different and means hydrogen, alkyl of 1-6 carbon atoms , alkenyl of 2-6 carbon atoms, aryl of 6-12 carbon atoms, (c6 "c12) -aryl- (C1-C4-alkyl, (C3-C9) -cycloalkyl, and R4 and R5 have the meaning given above. , especially those compounds wherein 20 n is 1 or 2, R is (C 6 -C 12) -aryl # especially phenyl, R 1 is hydrogen or alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms or a side chain of a naturally occurring , optionally protected o-amino acid, but in particular hydrogen, alkyl of 1-3 carbon atoms, alkenyl of 2 or 3 carbon atoms, optionally protecting it the side chain of lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-aminobutyl or benzoylmethyl, R 2 and R 3 are the same or different and represent hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms or (Cg-C ^) - aryl (C1-C4) alkyl, but especially hydrogen, alkyl of 1-4 carbon atoms or benzyl, and R R and R R have the meaning given above.

Hvis R1 betyder en sidekæde af en beskyttet, naturligt 35 forekommende a-aminosyre, f.eks. beskyttet Ser, Thr, Asp,If R 1 represents a side chain of a protected, naturally occurring α-amino acid, e.g. protected Ser, Thr, Asp,

Asn, Glu, Gin, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp eller 6 DK 172221 B1Asn, Glu, Gin, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp or 6 DK 172221 B1

His, foretrækkes som beskyttelsesgrupper de inden for peptidkemien gængse grupper (jf. Houben-Weyl, bind XV/1 og XV/2). Hvis R1 betyder en beskyttet lysin-sidekæde, foretrækkes de kendte aminobeskyttelsesgrupper, dog især Z, Boc 5 eller alkanoyl med 1-6 carbonatomer. På tale som O-beskyttelsesgrupper for tyrosin kommer fortrinsvis alkyl med 1-6 carbonatomer, især methyl eller ethyl.His, as protecting groups, are preferred to the groups common in peptide chemistry (cf. Houben-Weyl, Vol. XV / 1 and XV / 2). If R 1 represents a protected lysine side chain, then the known amino protecting groups are preferred, however, in particular Z, Boc 5 or alkanoyl of 1-6 carbon atoms. Speaking as O-protecting groups for tyrosine preferably come alkyl of 1-6 carbon atoms, especially methyl or ethyl.

Ifølge opfindelsen kan der særlig fordelagtigt anvendes følgende forbindelser: 10 2-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-(3S)-deca- hydroisoquinolin-3-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-(2S,3aS, 7aS)-octahydroindol-2-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-lysyl]-(2S,3aS,7aS)-15 octahydroindol-2-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-0-methyl-S-tyrosyl]-(2S,3aS,7aS)-octahydroindol-2-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl]-(2S,3aS,7aS)-octahydroindol-2-carboxylsyre 20 1-[N-(l-S-carbethoxy-3-(3,4-dimethylphenyl-propyl)-S-ala nyl] - (2S,3aS,7aS)-octahydroindol-2-carboxylsyre 1-[N-[l-S-carbethoxy-3-(4-fluorphenyl)-propyl]-S-alanyl]-( 2S , 3aS , 7aS).-octahydroindol-2-carboxylsyre 1-[N-[l-S-carbethoxy-3-{4-methoxyphenyl)-propyl] -S-alanyl]-25 (2S,3aS,7aS)-octahydroindol-2-carboxylsyre 1-[N-[l-S-carbethoxy-3-(3,4-dimethoxyphenyl)-propyl]-S-alanyl]-(2S,3aS,7aS)-octahydroindo1-2-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]- (2S,3aR, 7 aS)-octahydroindol-2-carboxylsyre 30 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-lysyl]-(2 S,3aR,7aS)- octahydroindol-2-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl]- (2S,3aS, 7aR)-octahydroindol-2-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]- (2S,3aR, 35 7aR)-octahydroindol-2-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-lysyl]-(2S,3aR,7aS)-octahydroindol-2-carboxylsyreAccording to the invention, the following compounds can be particularly advantageously used: 2- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] - (3S) -deca-hydroisoquinoline-3-carboxylic acid 1- [N- ( 1S-carbethoxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -S-lysyl] - (2S, 3aS, 7aS) -15-octahydroindole-2-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -O-methyl-5-tyrosyl] - (2S, 3aS, 7aS) -octahydroindole -2-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -O-ethyl-5-tyrosyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- [N- ( 1S-carbethoxy-3- (3,4-dimethylphenyl-propyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- [N- [1S-carbethoxy-3- (4- fluorophenyl) propyl] -S-alanyl] - (2S, 3aS, 7aS) octahydroindole-2-carboxylic acid 1- [N- [1S-carbethoxy-3- (4-methoxyphenyl) -propyl] -S-alanyl] -25 (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- [N- [1S-carbethoxy-3- (3,4-dimethoxyphenyl) propyl] -S-alanyl] - (2S, 3aS, 7aS) -octahydroindo-2-carboxylic acid 1- [N- (1S- carbethoxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -S-lysyl] - (2S, 3aR, 7aS) - Octahydroindole-2-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -O-ethyl-S-tyrosyl] - (2S, 3aS, 7aR) -octahydroindole -2-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aR, 7aR) -octahydroindole-2-carboxylic acid 1- [N- (1S-carbethoxy) 3-phenyl-propyl) -S-lysyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid

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7 DK 172221 B1 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-(2S,3aS, 7aR)-octahydroindol-2-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl]-(2S, 3aS,7aS)-octahydroindol-2-carboxylsyre 5 1-[N-(l-S-carbethoxy-3,4-dimethylphenyl-propyl) -S-alanyl]- (2S,3aS,7aS)-octahydroindol-2-carboxylsyre 1-[N-[l-S-carbethoxy-3-(4-fluorphenyl)-propyl]-S-alanyl]-(2S,3aS,7aS)-octahydroindol-2-carboxylsyre 1-[N-[l-S-carbethoxy-3-(4-methoxyphenyl)-propyl]-S-alanyl]-10 (2S,3aS,7aS)-octahydroindol-2-carboxylsyre 1-[N-[l-S-carbethoxy-3-(3,4-diraethoxyphenyl)-propyl]-S-alanyl]- (2S,3aS ,7aS)-octahydroindol-2-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-lysyl] - (2S,3aR,6aS)-octahydrocyclopenta[b]pyrrol-2-carboxylsyre 15 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl]- (2S, 3aR,6aS)-octahydrocyclopenta[b]pyrrol-2-carboxylsyre 1- [N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-2-(2S,3aR, 6aS)-octahydrocyclopenta[b]pyrrol-2-carboxylsyre 2- [N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl] -2-azaspiro- 20 [4.5]decan-3-S-carboxylsyre 2- [N- (l-S-c'arbethoxy-3-phenyl-propyl) -O-ethyl-2-tyrosyl] -2-azaspiro-[4,5]decan-3-S-carboxylsyre 2-[N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl]-2-azaspiro-[4,5]decan-3-S-carboxylsyre 25 2-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-2-azaspiro- [4.4]nonan-3-S-carboxylsyre 2-[N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl]-2-azaspiro[4.4]nonan-3-S-carboxylsyre 2-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-lysyl] -2-azaspiro-30 [4.4]nonan-3-S-carboxylsyre 1'-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-spiro[bi-cyclo[2.2.1]heptan-2,3’-pyrrolidin]-5'-S-carboxylsyre 1'-[N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl]-spiro[bicyclo[2.2.1]heptan-2,31-pyrrolidin]-5'-S-carb-35 oxylsyre 1'-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-lysyl]-spiro[bicyclo [2 . 2.1] heptan-2,3'-pyrrolidin]-5'-S-carboxylsyre1- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aS, 7aR) -octahydroindole-2-carboxylic acid 1- [N- (1S-carbethoxy-3 -phenyl-propyl) -O-ethyl-5-tyrosyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- [N- (1S-carbethoxy-3,4-dimethylphenyl-propyl) -S- alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- [N- [1S-carbethoxy-3- (4-fluorophenyl) propyl] -S-alanyl] - (2S, 3aS, 7aS) - octahydroindole-2-carboxylic acid 1- [N- [1S-carbethoxy-3- (4-methoxyphenyl) propyl] -S-alanyl] -10 (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- [N- [1S-carbethoxy-3- (3,4-diraethoxyphenyl) propyl] -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl) propyl) -S-lysyl] - (2S, 3aR, 6aS) -octahydrocyclopenta [b] pyrrole-2-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -O-ethyl-S-tyrosyl ] - (2S, 3aR, 6aS) -octahydrocyclopenta [b] pyrrole-2-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] -2- (2S, 3aR, 6aS) -octahydrocyclopenta [b] pyrrole-2-carboxylic acid 2- [N- (1S-carbethoxy-3-phenyl-propyl) - S-alanyl] -2-azaspiro [4.5] decane-3-S-carboxylic acid 2- [N- (1S-c'arbethoxy-3-phenyl-propyl) -O-ethyl-2-tyrosyl] -2- azaspiro- [4,5] decane-3-S-carboxylic acid 2- [N- (1-S-carbethoxy-3-phenyl-propyl) -S-lysyl] -2-azaspiro- [4,5] decane-3 -S-carboxylic acid 2- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] -2-azaspiro [4.4] nonane-3-S-carboxylic acid 2- [N- (1S-carbethoxy) -3-phenyl-propyl) -O-ethyl-S-tyrosyl] -2-azaspiro [4.4] nonane-3-S-carboxylic acid 2- [N- (1S-carbethoxy-3-phenyl-propyl) -S-lysyl ] -2-azaspiro-30 [4.4] nonan-3-S-carboxylic acid 1 '- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] -spiro [bi-cyclo [2.2.1] heptane-2,3'-pyrrolidine] -5'-S-carboxylic acid 1 '- [N- (1S-carbethoxy-3-phenyl-propyl) -O-ethyl-S-tyrosyl] -spiro [bicyclo [2.2.1 ] heptane-2,31-pyrrolidine] -5'-S-carboxylic acid 1 '- [N- (1S-carbethoxy-3-phenyl-propyl) -S-lysyl] -spiro [bicyclo [2. 2.1] heptane-2,3'-pyrrolidine] -5'-S-carboxylic acid

OISLAND

8 DK 172221 B1 1[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-spiro- tbicyclo[2.2.2] octan-2,3'-pyrrolidin]-5'-S-carboxylsyre 1[N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-tyrosyl]- spiro- [bicy'clo [2.2.2] octan-2,3 '-pyrrolidin] -5 ' -S-carboxylsyre 5 1'-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-lysyl]-spiro[bi- cyclo[2.2.2]octan-2,3'-pyrrolidin]-51-S-carboxylsyre 2-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-2-azatri-6 9 cyclo[4.3.0.1 ' ]decan-3-S-carboxylsyre 2-[N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl]-2-8 DK 172221 B1 1 [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] -spirbicyclo [2.2.2] octane-2,3'-pyrrolidine] -5'-S-carboxylic acid 1 [N- (1S-carbethoxy-3-phenyl-propyl) -O-ethyl-tyrosyl] -spiro [bicylic] [2.2.2] octane-2,3 '-pyrrolidine] -5'-S-carboxylic acid 1 '- [N- (1S-carbethoxy-3-phenyl-propyl) -S-lysyl] -spiro [bicyclo [2.2.2] octane-2,3'-pyrrolidine] -51-S-carboxylic acid 2- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] -2-azatri-6,9-cyclo [4.3.0.1 '] decane-3-S-carboxylic acid 2- [N- (1S-carbethoxy) 3-phenyl-propyl) -O-ethyl-S-tyrosyl] -2-

g Qg Q

10 azatricyclo[4.3.0.1 ' ]decan-3-S-carboxylsyre 2-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-lysyl] -2-azatri-cyclo[4.3.0.l6'^]decan-3-S-carboxylsyre 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl)-decahydro-cyclohepta[b]pyrrol-2-S-carboxylsyre 15 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl]- decahydrocyclohepta[b]pyrrol-2-S-carboxylsyre 1- [N-(l-S-carbethoxy-3-phenyl-propyl)-S-lysyl]-decahydrocyclohepta [b]pyrrol-2-S-carboxylsyre 2- [N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-trans-octa- 20 hydroisoindo1-1-S-carboxylsyre 2-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-cis-octa-hydroisoindol-1-S-carboxylsyre 2-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-cis-octa-hydrocyclopenta[c]pyrrol-l-S-carboxylsyre 25 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-2,3,3a,4, 5,7a-hexahydroindol-cis-endo~2-S-carboxylsyre I- [N-(l-S-carbethoxy-3-phenyl-propyl)-S-lysyl]-2,3,3a,4, 5,7 a-hexahydroindol-cis-endo-2-S-carboxylsyre II- [N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-(3'S,5'S)- 30 spiro-bicyclo[2.2.2]-octan-2,31-pyrrolidin-5'-carboxylsyre 1'-[N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-(3'R,5'S ,)-spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre 1'-[N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]- (3 ' S , 5 ' R) -spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre 35 1'-[N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-(3'R,5'R)- spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre 1'-[N-(l-R-carbethoxy-3-phenylpropyl)-S-alanyl]-(3'S,5'R)-spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyreAzatricyclo [4.3.0.1 '] decane-3-S-carboxylic acid 2- [N- (1S-carbethoxy-3-phenyl-propyl) -S-lysyl] -2-azatricyclo [4.3.0.16' ' ] decane-3-S-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl) -decahydro-cyclohepta [b] pyrrole-2-S-carboxylic acid 1- [N- ( 1S-carbethoxy-3-phenyl-propyl) -O-ethyl-5-tyrosyl] decahydrocyclohepta [b] pyrrole-2-5-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -S- lysyl] -decahydrocyclohepta [b] pyrrole-2-S-carboxylic acid 2- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] -trans-octa-hydroisoindo-1-S-carboxylic acid 2- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] -cis-octa-hydroisoindole-1-S-carboxylic acid 2- [N- (1S-carbethoxy-3-phenyl-propyl) -S- alanyl] -cis-octa-hydrocyclopenta [c] pyrrole-1S-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] -2,3,3a, 4, 5,7a -hexahydroindole-cis-endo-2-S-carboxylic acid 1- [N- (1S-carbethoxy-3-phenyl-propyl) -S-lysyl] -2,3,3a, 4,5,7,7-hexahydroindole-cis -endo-2-5-carboxylic acid II- [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S, 5'S) - spiro-bicyclo [2.2.2] -octane-2,31-pyrrolidine-5'-carboxylic acid 1 '- [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'R, 5'S,) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid 1 '- [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3' S, 5 ' R) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid 1 '- [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'R 5'R) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid 1 '- [N- (1R-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S , 5 'R) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid

OISLAND

9 DK 172221 B1 1[N-(l-R-carbethoxy-3-phenylpropyl)-S-alanyl]-(3'S,5 'S)-spiro-bicyclo[2.2.2]octan,2,3'-pyrrolidin-5'-carboxylsyre 11-[N-(l-R-carbethoxy-3-phenylpropyl)-S-alanyl]-(3'R,51 S)-spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre 5 1'-[N-(l-R-carbethoxy-3-phenylpropyl)-S-alanyl]- (3'R,5 'R) - spiro-bicyclo[2.2.2]octan-2,31-pyrrolidin-5'-carboxylsyre 1'-[N-(l-S-carbethoxy-3-phenylpropyl)-R-alanyl]-(3'S,5’S)-spiro-bicyclo[2.2.2]octan-2,31-pyrrolidin-51-carboxylsyre 1'-[N-(l-S-carbethoxy-3-phenylpropyl)-R-alanyl]-(3'R,5 1 S) -10 spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre 11 -[N-(l-S-carbethoxy-3-phenylpropyl)-R-alanyl]-(3'S,51R)-spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre 11 -[N-(l-S-carbethoxy-3-phenylpropyl)-R-alanyl]-(3'R,51R) -spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre 15 1'—[N—(l-R-carbethoxy-3-phenylpropyl)-R-alanyl]-(3'S,51 S)- spiro-bicyclo[2.2.2]octan-2,31-pyrrolidin-5'-carboxylsyre 11 -[N-(l-R-carbethoxy-3-phenylpropyl)-R-alanyl]-(3'R,5'S)-spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre 11-[N-(l-R-carbethoxy-3-phenylpropyl)-R-alanyl]-(3'S,5’R)-20 spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre 1'-[N-(l-R-carbethoxy-3-phenylpropyl)-R-alanyl]-(3'R,5'R)-spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre.[N- (1R-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S, 5 'S) -spiro-bicyclo [2.2.2] octane, 2,3'-pyrrolidine-5' -carboxylic acid 11- [N- (1R-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'R, 51S) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5 ' -carboxylic acid 5 1 '- [N- (1R-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'R, 5' R) -spiro-bicyclo [2.2.2] octane-2,31-pyrrolidine 5'-carboxylic acid 1 '- [N- (1S-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'S, 5'S) -spiro-bicyclo [2.2.2] octane-2,31-pyrrolidine-51-carboxylic acid 1 '- [N- (1S-Carbethoxy-3-phenylpropyl) -R-alanyl] - (3'R, 5L S) -10 Spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidin-5 '-carboxylic acid 11 - [N- (1S-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'S, 51R) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid 11 - [N- (1S-Carbethoxy-3-phenylpropyl) -R-alanyl] - (3'R, 51R) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid 1 '- [N - (1R-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'S, 51S) -spiro-bicyclo [2.2.2] octane-2,31-pyrrolidine-5'-carboxylic acid 11 - [N- (LR-carbethoxy-3-phenyl propyl) -R-alanyl] - (3'R, 5'S) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid 11- [N- (1R-carbethoxy-3-phenylpropyl) ) -R-alanyl] - (3'S, 5'R) -20-spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid 1 '- [N- (1R-carbethoxy-3- phenylpropyl) -R-L-alanyl] - (3'R, 5'R) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid.

Disse forbindelser kan f.eks. fremstilles ifølge den i DE patentansøgning nr. 3.333.455 beskrevne fremgangs-25 måde ved, at de i denne ansøgning beskrevne tert.butyl- eller benzylderivater på kendt måde omdannes til monocarb-oxylsyrederivaterne ved sur eller alkalisk hydrolyse eller ved ædelmetalkatalyseret hydrogenolyse. —benzyloxycar- bonylbeskyttelsesgruppen af lysinderivaterne fjernes ved 30 ædelmetalkatalyseret hydrogenolyse. De ovenfor anførte for bindelser kan med fysiologisk acceptable syrer eller baser (når der er tale om mono- eller dicarboxylsyrer) let omdannes til de tilsvarende salte (f.eks. hydrochlorider, maleinater, fumarater) og anvendes som salte til den her 35 omhandlede anvendelse.These compounds may e.g. is prepared according to the process described in DE patent application 3,333,455 by converting the tert-butyl or benzyl derivatives described in this application into known monocarboxylic acid derivatives by acid or alkaline hydrolysis or by noble metal catalyzed hydrogenolysis. The benzyloxycarbonyl protecting group of the lysine derivatives is removed by 30 precious metal catalyzed hydrogenolysis. The above listed compounds can be readily converted to the corresponding salts (e.g. hydrochlorides, maleinates, fumarates) with physiologically acceptable acids or bases (in the case of mono- or dicarboxylic acids) and used as salts for the purposes of the present invention. .

10 DK 172221 B110 DK 172221 B1

Forbindelserne med formlen II er inhibitorer af angiotensin-omdannende enzym (ACE), henholdsvis mellemprodukter ved fremstilling af sådanne inhibitorer og kan også anvendes til behandling af forhøjet blodtryk af for-5 skellig genese. Forbindelserne med formlen II og fremgangsmåder til deres fremstilling er delvis kendte, f.eks. fra US-patentskrift nr. 4.129.571 og 4.374.829, EP-offent-liggørelsesskrift nr. 79522, 79022, 49658 og 51301, US-patentskrift nr. 4.454.292 og 4.374*847, EP-offent-10 liggørelsesskrift nr. 72352, US-patentskrift nr. 4.350.704, EP-offentliggørelsesskrift nr. 50800 og 46953, US-patent-skrift nr. 4.344.949, EP-offentliggørelsesskrift nr.The compounds of formula II are inhibitors of angiotensin-converting enzyme (ACE) or intermediates, respectively, in the preparation of such inhibitors and can also be used to treat elevated blood pressure of various genesis. The compounds of formula II and processes for their preparation are partially known, e.g. from U.S. Patent Nos. 4,129,571 and 4,374,829, European Patent Publication Nos. 79522, 79022, 49658 and 51301, U.S. Patent Nos. 4,454,292 and 4,374 * 847, European Patent Publication No. No. 72352, U.S. Patent No. 4,350,704, European Patent Publication No. 50800 and 46953, U.S. Patent No. 4,344,949, European Patent Publication No.

84164, US-patentskrift nr. 4.470.972 og EP-offentliggø-relsesskrift nr. 65301 og 52991. Hidtil ukendte forbindel-15 ser med formlen II fremstilles på analog måde.No. 84164, U.S. Patent No. 4,470,972 and EP Publication No. 65301 and 52991. New compounds of formula II are prepared in an analogous manner.

Fordelagtige er også oralt virksomme ACE-inhibitorer (virksomme stoffer er til dels allerede nævnte ovenfor), f.eks. enalapril (f), lisinopril (g) og indolapril (h).Also advantageous are orally active ACE inhibitors (active substances are in part already mentioned above), e.g. enalapril (f), lisinopril (g) and indolapril (h).

Oralt virksomme ACE-inhibitorer er f.eks. beskrevet af Brun- 2 0 ner et al., J. Cardiovasc. Pharmacol. 7. (suppl. I) 1985 S2-S11.Orally active ACE inhibitors are e.g. described by Brunner et al., J. Cardiovasc. Pharmacol. 7. (Suppl. I) 1985 S2-S11.

I “2H ^-6 ^C-CH-NH-CH * z ^==7 25 ° «3 «2C2H5 (i’ ΓΊ ^In "2H ^ -6 ^ C-CH-NH-CH * z ^ == 7 25 ° 3" 2C2H5 (i 'ΓΊ ^

3 0 i æ2H CtP'-CO.H30 in æ2H CtP'-CO.H

X-CH-NH-ΟΓ 2 2N=/ W2n -O^OL-OX-CH-NH-ΟΓ 2 2N = / W2n -O ^ OL-O

(L 3 NH Lu (g) H1-CH-NH-CH' W(L 3 NH Lu (g) H1-CH-NH-CH 'W

(CH2)4-NH2 C02H <3. 0^ ^ ,y 35 11 DK 172221 B1 o(CH 2) 4-NH 2 CO 2 H <3. 0 ^ ^, y 35 11 DK 172221 B1 o

Foretrukne er de fra EP-offentliggørelsesskrift nr. 79022 kendte ACE-inhibitorer med formlen IIIPreferred are the ACE inhibitors of formula III known from EP Publication No. 79022

5 COOHCOOH

\ I«/ (δϊ lS> jT~\ >C - CH - HH - CH - CH2 - CH2~y) (ΠΙ)\ I «/ (δϊ lS> jT ~ \> C - CH - HH - CH - CH2 - CH2 ~ y) (ΠΙ)

CHj C00RCH2 C00R

10 hvori R betyder hydrogen, methyl, ethyl eller benzyl, især forbindelsen med formlen III, hvori R betyder ethyl 15 (ramipril).Wherein R is hydrogen, methyl, ethyl or benzyl, especially the compound of formula III, wherein R is ethyl 15 (ramipril).

Foretrukne er endvidere de fra EP-offentliggørelses-skrift nr. 84164 kendte ACE-inhibitorer med formlen IVAlso preferred are the ACE inhibitors of formula IV known from EP Publication No. 84164

20 Ce6H <IV) ^4·»/ ,s> ,s' jT\ <T CHj ioOR" 2 25 hvori R^ betyder hydrogen, alkyl med 1-4 carbonatomer eller benzyl,, især forbindelsen med formlen IV, hvori R^ betyder ethyl.Wherein R ^ means hydrogen, alkyl of 1-4 carbon atoms or benzyl, in particular the compound of formula IV wherein R ^ is hydrogen, alkyl of 1-4 carbon atoms or benzyl; means ethyl.

Foretrukket'er derudover 1[N-(l-S-carboethoxy-3-30 -phenyl-propyl)-S-alanyl]-exo- og -endo-spirobicyclo- -[2.2.2]octan-2,3'-pyrrolidin-5'-yl-carboxylsyre og isomere.In addition, 1 [N- (1S-carboethoxy-3-30-phenyl-propyl) -S-alanyl] -exo- and -endo-spirobicyclo- [2.2.2] octane-2,3'-pyrrolidine 5'-yl-carboxylic acid and isomers.

35 12 DK 172221 B1 På tale som salte af forbindelserne med formlen II kommer, alt efter den sure eller basiske natur af disse forbindelser, alkalimetal- eller jordalkalimetalsalte eller salte med fysiologisk acceptable aminer eller salte med 5 uorganiske eller organiske syrer, f.eks. saltsyre, hydrogen-bromidsyre, svovlsyre, maleinsyre, fumarsyre, vinsyre og citronsyre.In the case of salts of the compounds of formula II, depending on the acidic or basic nature of these compounds, alkali metal or alkaline earth metal salts or salts with physiologically acceptable amines or salts with inorganic or organic acids, e.g. hydrochloric, hydrobromic, sulfuric, maleic, fumaric, tartaric and citric.

Kapillærstrukturerne af blodkarrene i hjernen adskiller sig fra kapillærstrukturerne af blodkarrene i andre 10 områder af legemet. Hjernekapillærerne er omgivet af et lag af endothelceller, der er knyttet særligt tæt til hinanden (via såkaldte "tight junctions"). Hjernekapillærer har desuden betydeligt færre af de porer, gennem hvilke lavmolekylære stoffer i andre blodkapillærer kan komme ind i det 15 omgivende væv eller komme ud af dette. På denne måde får lipidopløseligheden ved hjernekapillærer en meget større betydning for fordelingen mellem blod og omgivende væv end, hvad der er tilfældet for resten af kroppen.The capillary structures of the blood vessels in the brain differ from the capillary structures of the blood vessels in other 10 regions of the body. The brain capillaries are surrounded by a layer of endothelial cells that are particularly closely related (via so-called "tight junctions"). In addition, brain capillaries have significantly fewer pores through which low molecular weight substances in other blood capillaries can enter or exit the surrounding tissue. In this way, the lipid solubility of brain capillaries becomes much more important for the distribution between blood and surrounding tissue than is the case for the rest of the body.

Der foretrækkes derfor forbindelser med formlen II, 20 hvori mindst to af symbolerne R, R1, R2 og R3 betyder en lipofil gruppe, såsom en langkædet aliphatisk, alicyclisk-aliphatisk eller araliphatisk gruppe, en tilstrækkelig stor alicyclisk gruppe eller en tilsvarende substitueret alicyc-lisk eller aromatisk gruppe eller indeholder en sådan som 25 delstruktur.Therefore, compounds of formula II, 20 in which at least two of the symbols R, R 1, R 2 and R 3 are a lipophilic group such as a long chain aliphatic, alicyclic-aliphatic or araliphatic group, a sufficiently large alicyclic group or a corresponding substituted alicyclic, are preferred. or aromatic group or containing such as sub-structure.

Forbindelserne med formlen II kan fremstilles ved, at fragmenterne deraf omsættes med hinanden i et egnet opløsningsmiddel, eventuelt i nærværelse af en base og/eller et koblingshjælpemiddel, eventuelt intermediært dannede, 30 umættede forbindelser, såsom Schiff-baser, reduceres, beskyttelsesgrupper, som midlertidigt er indført til beskyttelse af reaktionsdygtige grupper, fraspaltes, forbindelser med formlen II med én eller flere frie carboxylgrupper eventuelt forestres, og de fremkomne forbindelser eventuelt omdannes 35 til deres fysiologisk acceptable salte.The compounds of formula II can be prepared by reacting the fragments thereof with each other in a suitable solvent, optionally in the presence of a base and / or a coupling aid, optionally intermediate unsaturated compounds such as Schiff bases are reduced, protecting groups which temporarily are introduced to protect reactive groups, are cleaved, compounds of formula II having one or more free carboxyl groups optionally esterified, and the resulting compounds optionally converted to their physiologically acceptable salts.

OISLAND

13 DK 172221 B1 På den nævnte måde kan man f.eks. omsætte forbindelser med formlen V med forbindelser med formlen VI.13 DK 172221 B1 In the said manner, e.g. reacting compounds of formula V with compounds of formula VI.

R3OOC-CH-N-H HOOC-CH-NH-CH-(ch9) -RR3OOC-CH-N-H HOOC-CH-NH-CH- (ch9) -R

'4 '5 '1 1 2 Δ n'4' 5 '1 1 2 Δ n

5 R RT Rx COOR5 R RT Rx COOR

(V) (VI)(V) (VI)

Omsætningen af disse forbindelser kan f.eks. gennem-10 føres analogt med kendte peptidkoblingsmetoder i et or ganisk opløsningsmiddel, såsom DMF, CH2C12, DMA, i nærværelse af koblingshjælpemidler, såsom carbodiimider (f.eks. dicyclohexylcarbodiimid), diphenylphosphoryl-azid, alkanphosphorsyreanhydrider, dialkylphosphinsyre-15 anhydrider eller Ν,Ν-succinimidylcarbonater i et opløs ningsmiddel, såsom CH^CN. Aminogrupper i forbindelser med formlen V kan aktiveres med tetraethyldiphosphit. Forbindelserne med formlen VI kan omdannes til aktive estere (f.eks. med 1-hydroxybenzotriazol), blandede anhydrider 20 (f.eks. med chlormyresyreestere), azider eller carbodi- imidderivater og dermed aktiveres (jf. Schroder, Lubke,The reaction of these compounds may e.g. by analogy to known peptide coupling methods in an organic solvent such as DMF, CH 2 Cl -succinimidyl carbonates in a solvent such as CH Amino groups in compounds of formula V can be activated with tetraethyl diphosphite. The compounds of formula VI can be converted into active esters (e.g., with 1-hydroxybenzotriazole), mixed anhydrides 20 (e.g., with chloromyric acid esters), azides or carbodiimide derivatives and thus activated (cf. Schroder, Lubke,

The Peptides, bind 1, New York 1965, side 76-136). Omsætningen gennemføres fortrinsvis mellem -20°C og .'reaktionsblandingens kogepunkt.The Peptides, Volume 1, New York 1965, pages 76-136). The reaction is preferably carried out between -20 ° C and the boiling point of the reaction mixture.

25 Ligeledes kan også forbindelser med formlen VII om sættes med forbindelser med formlen VIII under dannelse af forbindelser med formlen II:Likewise, compounds of formula VII can also be reacted with compounds of formula VIII to form compounds of formula II:

R300C-CH-N—C-CH-Y1 Y2-CH-(CH?) -RR300C-CH-N-C-CH-Y1 Y2-CH- (CH?) -R

i 4 c 1' I ) I 2 ά “i 4 c 1 'I) I 2 ά “

30 R R 0 R COOR30 R R 0 R COOR

(VII) (VIII) 1 2 hvori Y betyder amino, og Y betyder en afgangsgruppe, 2 35 eller Y betyder en afgangsgruppe, og Y betyder amino.(VII) (VIII) 1 2 wherein Y means amino and Y means a leaving group, or 35 or Y means a leaving group and Y means amino.

Egnede afgangsgrupper er f.eks. chlor, brom, iod, alkyl- 2 sulfonyloxy eller arylsulfonyloxy.Suitable leaving groups are e.g. chlorine, bromine, iodine, alkylsulfonyloxy or arylsulfonyloxy.

OISLAND

14 DK 172221 B114 DK 172221 B1

Alkyleringer af denne art gennemføres hensigtsmæssigt i vand eller et organisk opløsningsmiddel, såsom en lavere aliphatisk alkohol (såsom ethanol), benzylalkohol, aceto-nitril, nitromethan eller glycolether, ved en temperatur 5 mellem -20°C og reaktionsblandingens kogepunkt i nærværelse af en base, såsom et alkalimetalhydroxid eller en organisk amin.Suitably, alkylations of this kind are carried out in water or an organic solvent such as a lower aliphatic alcohol (such as ethanol), benzyl alcohol, acetonitrile, nitromethane or glycol ether, at a temperature between -20 ° C and the boiling point of the reaction mixture in the presence of a base. , such as an alkali metal hydroxide or an organic amine.

Endvidere kan forbindelser med formlen IX kondenseres med forbindelser med formlen X: 10 R3OOC-CH-N—0-0-=01 q2=c-(CH-) -r i 4 i c II i 1 i nFurthermore, compounds of formula IX can be condensed with compounds of formula X: R3OOC-CH-N-0-0- = 01 q2 = c- (CH-) -r i 4 i c II i 1 i n

R R 0 R C00RR R 0 R C00R

(IX) (X) 15 1 2 hvori Q betyder amino + hydrogen, og Q betyder oxo, 1 2 eller Q betyder oxo, og Q betyder amino + hydrogen. Kondensationen gennemføres hensigtsmæssigt i vand eller et organisk opløsningsmiddel, såsom en lavere aliphatisk alkohol, 20 ved en temperatur mellem -20°C og reaktionsblandingens kogepunkt i nærværelse af et reduktionsmiddel, såsom NaBH^CN, hvorved der direkte fås forbindelser med formlen I. Man kan imidlertid også reduceres de som mellemprodukter dannede Schiff-baser eller enaminer, eventuelt efter forud-25 gående isolering, under dannelse af forbindelser med form len II, f.eks. ved hydrogenering i nærværelse af en overgangsmetalkatalysator.(IX) (X) 15 1 2 wherein Q is amino + hydrogen and Q is oxo, 1 2 or Q is oxo and Q is amino + hydrogen. The condensation is conveniently carried out in water or an organic solvent, such as a lower aliphatic alcohol, at a temperature between -20 ° C and the boiling point of the reaction mixture in the presence of a reducing agent such as NaBH ^CN to give direct compounds of formula I. however, the Schiff bases or enamines formed as intermediates are also reduced, optionally after prior isolation, to form compounds of formula II, e.g. by hydrogenation in the presence of a transition metal catalyst.

Endelig fører også omsætningen af forbindelser med formlen IX (Q1 = Η + Ni^) med forbindelser med formlen XI 30 eller omsætning af disse med forbindelser med formlerne XII og XIII, hensigtsmæssigt i nærværelse af en base, såsom et natriumalkoholat, i et organisk opløsningsmiddel, såsom en lavere alkohol, ved en temperatur mellem -10°C og reaktionsblandingens kogepunkt til forbindelser med 35 formlen II (n = 2): 15 DK 172221 B1 R2OOC-CH=CH-COR (XI) OCH-COOR2 (XII) 5 R-CO-CH3 (XIII) idet intermediært dannede Schiff-baser reduceres som ovenfor beskrevet, og en carbonylgruppe reduktivt omdannes til methylen (f.eks. med et komplekst hydrid).Finally, the reaction of compounds of formula IX (Q1 = Η + Ni +) with compounds of formula XI 30 or their reaction with compounds of formulas XII and XIII, conveniently in the presence of a base such as a sodium alcoholate, also results in an organic solvent. , such as a lower alcohol, at a temperature between -10 ° C and the boiling point of the reaction mixture for compounds of formula II (n = 2): 15 CHOOC-CH = CH-COR (XI) OCH-COOR2 (XII) 5 R-CO-CH 3 (XIII), intermediate Schiff bases are reduced as described above and a carbonyl group is reductively converted to methylene (e.g. with a complex hydride).

10 I de ovennævnte formler V-XIII er R-R^ og n de fineret som i formlen II. Beskyttelsesgrupper, som er indført midlertidigt til beskyttelse af reaktionsdygtige grupper, som ikke deltager i omsætningen, fraspaltes efter endt omsætning på i og for sig kendt måde (jf. Schroder, 15 Liibke, loc cit. , side 1-75 og 246-270; Greene, "Protective Groups in Organic Synthesis”, New York 1981).In the above formulas V-XIII, R-R 2 and n are veneered as in formula II. Protective groups introduced temporarily to protect reactive groups that do not participate in the turnover are split off after the turnover in a manner known per se (cf. Schroder, 15 Liibke, loc cit., Pages 1-75 and 246-270; Greene, "Protective Groups in Organic Synthesis", New York 1981).

Fremstillingen af forbindelserne med den almene formel II kan f.eks. også ske under anvendelse af forestringsmeto-der, der er velkendte af fagmanden (se f.eks. Buchler, Pear-20 son, Survey of Organic Syntheses, bind 1, New York 1970, s. 802-825; Houben-Weyl, Methoden der Organischen Chemie, bind E5, 1985, s. 656-773) a) Omsætning af en mono- eller dicarboxylsyre med den almene formel II, hvori mindst ét af symbolerne R2 og 25 R3 betyder hydrogen, med en tilsvarende alkohol under sur katalyse (uorganisk syre eller sur ionbytter).The preparation of the compounds of general formula II can e.g. also occur using esterification methods well known to those skilled in the art (see, e.g., Buchler, Pearson, Survey of Organic Syntheses, Vol. 1, New York 1970, pp. 802-825; Houben-Weyl, The Method der Organischen Chemie, Vol. E5, 1985, pp. 656-773) a) Reaction of a mono- or dicarboxylic acid of the general formula II, wherein at least one of the symbols R2 and R3 is hydrogen, with a corresponding alcohol under acid catalysis ( inorganic acid or acid ion exchange).

b) Alkylering af en mono- eller dicarboxylsyre med den almene formel II, hvori mindst ét af symbolerne R2 og R3 betyder hydrogen, med en forbindelse R2Z eller R3Z, hvori 30 Z betyder en afgangsgruppe, der fortrænges nucleofilt (såsom halogen, tosylat), i et polært protisk eller dipolært apro-tisk opløsningsmiddel i nærværelse af en base, såsom et alkalimetalhydroxid eller -alkoholat.b) Alkylation of a mono- or dicarboxylic acid of the general formula II, wherein at least one of the symbols R2 and R3 is hydrogen, with a compound R2Z or R3Z, wherein 30Z represents a leaving group displaced nucleophilic (such as halogen, tosylate), in a polar protic or dipolar aprotic solvent in the presence of a base such as an alkali metal hydroxide or alcoholate.

c) Omsætning af en mono- eller dicarboxylsyre med 35 den almene formel II, hvori mindst ét af symbolerne R2 og R3 betyder hydrogen, med en diazoalken i et indifferent or- 16 DK 172221 B1 ganisk opløsningsmiddel, såsom methylenchlorid.c) Reaction of a mono- or dicarboxylic acid of general formula II, wherein at least one of the symbols R 2 and R 3 is hydrogen, with a diazo alkene in an inert organic solvent such as methylene chloride.

Den nootrope virkning af de her omhandlede forbindelser er undersøgt på mus, der har en vægt på 20-25 g, ved en såkaldt inhibitory (passive) avoidance test 5 (step-through-model). En modificeret form af testmetoden beskrevet af J. Kopp, Z. Bodanecky og M.E. Jarvik er beskrevet åf J. Bures, O. Buresova og J. Huston i "Techniques and Basic Experiments for the Study of Brain and Behavior", Elsevier Scientific Publishers, Amsterdam 10 (1983).The nootropic effect of the compounds of this invention has been investigated in mice weighing 20-25 g by a so-called inhibitory (passive) avoidance test 5 (step-through model). A modified form of the test method described by J. Kopp, Z. Bodanecky and M.E. Jarvik is described in J. Bures, O. Buresova and J. Huston in "Techniques and Basic Experiments for the Study of Brain and Behavior", Elsevier Scientific Publishers, Amsterdam 10 (1983).

Svarende til disse litteraturangivelser betegnes en substans som nootropt virksom, når den kan ophæve den amnesi, der er fremkaldt ved hjælp af et elektrokonvulsivt chok eller ved hjælp af scopolamin.According to these literature, a substance is termed nootropically active when it can abolish the amnesia induced by an electroconvulsive shock or by scopolamine.

15 Forsøgene gennemføres ifølge modificerede testme toder. Som sammenligningsforbindelse anvendes det kendte nootropikum 2-oxo-l-pyrrolidinyleddikesyreamid (piracetam).The tests are conducted according to modified test methods. As a comparison compound, the known nootropic 2-oxo-1-pyrrolidinylacetic acid amide (piracetam) is used.

Den tydelige overlegenhed af de her omhandlede forbindelser i forhold til sammenligningsforbindelsen viser sig ved, 20 at den scopolaminfremkaldte amnesi ved den såkaldte inhibitory avoidance-test kan ophæves med en minimal effektiv dosis (MED) på 1,0-30 mg/kg p.o. Sammenligningsforbindelsen har en MED på ca. 500-1000 mg/kg p.o.The apparent superiority of the compounds of this invention with respect to the comparative compound is demonstrated by the fact that the scopolamine-induced amnesia can be abolished by the so-called inhibitory avoidance test with a minimal effective dose (MED) of 1.0-30 mg / kg p.o. The comparison compound has a MED of approx. 500-1000 mg / kg p.o.

De her omhandlede forbindelser har for det meste 25 kun en ringe toksicitet.The compounds of this invention generally have only a slight toxicity.

De her omhandlede forbindelser er på grund af deres farmakologiske egenskaber foruden til behandling af forhøjet blodtryk også egnet til behandling af cognitive dysfunktioner af forskellig genese, der f.eks. optræder 30 ved Alzheimer's sygdom eller ved senil demens.Due to their pharmacological properties, the compounds of this invention are also suitable for the treatment of high blood pressure, for the treatment of cognitive dysfunctions of various genesis, e.g. 30 occur in Alzheimer's disease or in senile dementia.

De her omhandlede forbindelser er derfor anvendelige ved behandling og forebyggelse af cognitive dysfunktioner hos patienter med højt blodtryk.The compounds of the present invention are therefore useful in the treatment and prevention of cognitive dysfunction in patients with high blood pressure.

De ovenfor beskrevne inhibitorer af angiotensin-omdan-35 nende enzym kan anvendes på pattedyr, såsom aber, hunde, katte, rotter, mennesker osv.The above described inhibitors of angiotensin converting enzyme can be used on mammals such as monkeys, dogs, cats, rats, humans, etc.

DK 172221 B1 17 Lægemidlerne fremstilles ved i og for sig kendte metoder, der er gængse for fagmanden. Som lægemidler anvendes de her omhandlede, farmakologisk virksomme forbindelser (virksomt stof) enten som sådanne eller fortrinsvis i kom-5 bination med egnede farmaceutiske hjælpestoffer i form af tabletter, drageer, kapsler, suppositorier, emulsioner, suspensioner eller opløsninger, hvorved indholdet af virksomt stof udgør indtil ca. 95%, mere fordelagtigt mellem 10 og 75%.The drugs are prepared by methods known per se to those skilled in the art. As pharmaceuticals, the presently employed pharmacologically active compounds (active substance) are used either as such or preferably in combination with suitable pharmaceutical excipients in the form of tablets, dragons, capsules, suppositories, emulsions, suspensions or solutions whereby the active substance content amounts to approx. 95%, more advantageously between 10 and 75%.

10 Hvilke hjælpestoffer, der er egnede til den ønskede lægemiddelformulering, kan let bestemmes af en fagmand på grund af dennes fagviden. Foruden opløsningsmidler, geldannere, suppositoriegrundlag, tablethjælpestoffer og andre bærere af virksomt stof kan der f.eks. anvendes 15 antioxidanter, dispergeringsmidler, emulgatorer, skumdæmpende midler, smagskorrigerende midler, konserveringsmidler, opløsningsformidlende midler eller farvestoffer.10 Which adjuvants suitable for the desired drug formulation can be readily determined by one of ordinary skill in the art because of their skill in the art. In addition to solvents, gels, suppository bases, tablet adjuvants and other carriers of active substance, e.g. 15 antioxidants, dispersants, emulsifiers, antifoam agents, flavor correction agents, preservatives, solvents or colorants are used.

De virksomme stoffer kan f.eks. indgives oralt, rek-talt eller parenteralt (f.eks. intravenøst eller subcutant) , 20 idet oral indgivelse er foretrukket.The active substances can e.g. orally, orally or parenterally (eg, intravenously or subcutaneously), with oral administration being preferred.

Til en oral anvendelsesform blandes de aktive forbindelser med de dertil egnede tilsætningsstoffer, såsom bærestoffer, stabilisatorer og indifferente fortyndingsmidler, og bringes ved gængse metoder på egnede indgivelsesformer, 25 såsom tabletter, drageer, stikkapsler, vandige, alkoholiske eller olieholdige suspensioner eller vandige, alkoholiske eller olieholdige opløsninger. Som indifferente bærestoffer kan der f.eks. anvendes gummiarabicum, magnesiumoxid, magnesiumcarbonat, lactose, glucose eller stivelse, især 30 majsstivelse. Derved kan tilberedningen ske ved både tør granulering og fugtig granulering. Som olieformige bærestoffer eller opløsningsmidler kan der f.eks. anvendes vegetabilske eller animalske olier, såsom solsikkeolie eller levertran.For an oral use, the active compounds are mixed with the appropriate additives, such as carriers, stabilizers and inert diluents, and are brought by conventional methods to suitable administration forms, such as tablets, dragees, sachets, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As inert carriers, e.g. gum arabic, magnesium oxide, magnesium carbonate, lactose, glucose or starch, especially maize starch, are used. Thereby, the preparation can be done by both dry granulation and moist granulation. As oily carriers or solvents, e.g. vegetable or animal oils such as sunflower oil or liver oil are used.

35 18 DK 172221 B135 18 DK 172221 B1

Til subcutan eller intravenøs indgivelse bringes de aktive forbindelser eller deres fysiologisk acceptable salte i opløsning, suspension eller emulsion, om ønsket med de dertil gængse stoffer, såsom opløsningsformidlende 5 stoffer, emulgatorer eller yderligere hjælpestoffer. På tale som opløsningsmidler kommer f .eks. vand, fysiologisk natriumchloridopløsning eller alkoholer, f.eks. ethanol, propanol, glycerol, desuden også sukkeropløsninger, såsom glucose- eller mannitolopløsninger, eller også en blan-10 ding af de forskellige nævnte opløsningsmidler.For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts are brought into solution, suspension or emulsion, if desired, with the usual substances, such as solvents, emulsifiers or additional excipients. Speaking as solvents, e.g. water, physiological sodium chloride solution or alcohols, e.g. ethanol, propanol, glycerol, in addition, also sugar solutions, such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned.

I de følgende eksempler 1-6 angives anvendelsesformer til forebyggelse og behandling af cognitive funktioner ifølge den her omhandlede metode. De her omhandlede forbindelser kan analogt med eksemplerne bringes på de til-15 svarende anvendelsesformer.In the following Examples 1-6, uses are provided for the prevention and treatment of cognitive functions according to the method of the present invention. The compounds of this invention can be brought, by analogy with the examples, to the corresponding uses.

Eksempel 1Example 1

Fremstilling af et ifølge opfindelsen anvendt middel 20 til oral anvendelse ved behandling og forebyggelse af cognitive dysfunktioner.Preparation of an agent 20 according to the invention used for oral use in the treatment and prevention of cognitive dysfunctions.

1000 tabletter, der hver indeholder 10 mg l'-[N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-(3'S,5'S)spirobicyc-lo[2.2.2]octan-2,31-pyrrolidin-5'-carboxylsyre, fremstilles 25 med følgende hjælpemidler: 1'-[N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl] -(31 S,51 S)spirobicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-carboxylsyre 10 g 30 majsstivelse 140 g gelatine 7,5 g mikrokrystallinsk cellulose 2,5 g magnesiumstearat 2,5 g 35 1'-[N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl] -(3'S,5'S)- spirobicyclo[2.2.2]octan-2,31-pyrrolidin-5'-carboxylsyre og DK 172221 Bl 19 majsstivelse blandes med en vandig gelatineopløsning. Blandingen tørres og formales til et granulat. Mikrokrystallinsk cellulose og magnesiumstearat blandes med granulatet. Det fremkomne granulat presses til 1000 tabletter, hvorved hver 5 tablet indeholder 10 mg af ACE-inhibitoren.1000 tablets each containing 10 mg of 1 '- [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S, 5'S) spirobicyclo [2.2.2] octane-2,31-pyrrolidine- 5'-carboxylic acid is prepared with the following aids: 1 '- [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] - (31S, 51S) spirobicyclo [2.2.2] octane-2.3 '-pyrrolidine-5'-carboxylic acid 10 g maize starch 140 g gelatin 7.5 g microcrystalline cellulose 2.5 g magnesium stearate 2.5 g 35' 1 - [N- (1-S-carbethoxy-3-phenylpropyl) -S -alanyl] - (3'S, 5'S) - spirobicyclo [2.2.2] octane-2,31-pyrrolidine-5'-carboxylic acid and cornstarch mixed with an aqueous gelatin solution. The mixture is dried and ground into a granulate. Microcrystalline cellulose and magnesium stearate are mixed with the granulate. The resulting granules are pressed into 1000 tablets, each containing 5 mg of the ACE inhibitor.

Disse tabletter kan anvendes til behandling og forebyggelse af cognitive dysfunktioner.These tablets can be used to treat and prevent cognitive dysfunction.

Eksempel 2 (udgået) 10Example 2 (deleted) 10

Eksempel 3Example 3

Gelatinekapsler, der hver indeholder 10 mg 11 -[N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-15 -(3'R,5'S)-spirobicyclo[2.2.2]octan-2,31-pyrrolidin-5'- -carboxylsyre, fyldes med følgende blanding: 11 -[N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]- 10 mg (3'R,5'S)-spirobicyclo[2.2.2]octan-2,3'-pyrroli-20 din-5'-carboxylsyre magnesiumstearat 1 mg lactose 214 mgGelatin capsules each containing 10 mg of 11 - [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] -15 - (3'R, 5'S) -spirobicyclo [2.2.2] octane-2,31-pyrrolidine -5'-carboxylic acid, is filled with the following mixture: 11 - [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] - 10 mg (3'R, 5'S) -spirobicyclo [2.2.2] octane 2,3'-pyrrolidine-5'-carboxylic acid magnesium stearate 1 mg lactose 214 mg

Disse kapsler kan anvendes til behandling og forebyg-25 gelse af cognitive dysfunktioner.These capsules can be used to treat and prevent cognitive dysfunctions.

Eksempel 4Example 4

En injektionsopløsning fremstilles som beskrevet i 30 det følgende: 35 DK 172221 B1 20 1-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-(2S,3aR,7aS)-octahydroindol-2-carboxylsyre-hydro-chlorid 250 mg methylparaben 5 g 5 propylparaben 1 g natriumchlorid 25 g vand til injektion 5 liter 1-[N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl] -(2S,3aR,7aS)-10 octahydroindol-3-carboxylsyre-hydrochlorid, konserveringsmidler og natriumchlorid opløses i 3 liter vand til injektion, og der fyldes op til 5 liter med vand til injektion. Opløsningen sterilfiltreres og fyldes aseptisk i forsteriliserede flasker, der lukkes med steriliserede gummihætter. Hver 15 flaske indeholder 5 ml opløsning.An injection solution is prepared as described below: 1- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid hydrochloride 250 mg methylparaben 5 g 5 propylparaben 1 g sodium chloride 25 g water for injection 5 liters of 1- [N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aR, Dissolve 7aS) -10 octahydroindole-3-carboxylic acid hydrochloride, preservatives and sodium chloride in 3 liters of water for injection and make up to 5 liters with water for injection. The solution is sterile filtered and aseptically filled into pre-sterilized bottles which are closed with sterilized rubber caps. Each 15 bottle contains 5 ml of solution.

Eksempel 5Example 5

Tabletter, der kan anvendes til behandling eller 20 forebyggelse af cognitive dysfunktioner, fremstilles som beskrevet i eksempel 1, idet der anvendes 1-[N-(l-S-carboxy-3-phenyl-propyl)-S-alanyl]-(2S,3aR, 7aS)-octahydroindol-2-carboxylsyre eller 1-[N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-cis-2,3,3a,-25 4,5,7a-hexahydro[IH]indol-2-S-endo-carboxylsyre eller 1-[N-(l-S-carboxy-3-phenyl-propyl)-S-alanyl]-cis-2,3,3a,4,-5,7a-hexahydro[IH]indol-2S-endo-carboxylsyre eller 1'-[N-(l-S-carbethoxy-3-phenyl-propyl)-S-alanyl]-exo-spiro-bicyclo[2.2.2]octan-2,3'-pyrrolidin-5'-S-yl-carboxylsyre eller 30 i[N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-endo-spiro-bicyclo[2.2.2]octan-2,31-pyrrolidinyl-5'-S-carboxylsyre.Tablets that can be used to treat or prevent cognitive dysfunction are prepared as described in Example 1 using 1- [N- (1S-carboxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aR 7aS) -octahydroindole-2-carboxylic acid or 1- [N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl] -cis-2,3,3a, -25 4,5,7a- hexahydro [1H] indole-2-5-endo-carboxylic acid or 1- [N- (1S-carboxy-3-phenyl-propyl) -S-alanyl] -cis-2,3,3a, 4, 5,7a -hexahydro [1H] indole-2S-endo-carboxylic acid or 1 '- [N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl] -exo-spiro-bicyclo [2.2.2] octane-2, 3'-pyrrolidin-5'-5-yl-carboxylic acid or in [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] -endo-spiro-bicyclo [2.2.2] octane-2,31 pyrrolidinyl-5'-S-carboxylic acid.

35 2135 21

Eksempel 6 DK 172221 B1Example 6 DK 172221 B1

En injektionsopløsning fremstilles analogt med den i eksempel 4 angivne forskrift, idet der anvendes 5 1-[N-(l-S-carboxy-3-phenyl-propyl)-S-alanyl]-(2S,3aR,7aS)- octahydroindol-2-carboxylsyre eller 1-[N-(l-S-carboxy-3-phenyl-propyl)-S-alanyl]-cis-2,3,3a,4, 5,7a-hexahydro[IH]indol-2-S-endo-carboxylsyre eller 1'[N-(l-S-carboxy-3-phenylpropyl)-S-alanyl]-endo-spirobi-10 cyclo[2.2.2]octan-2,3'-pyrrolidin-51-S-carboxylsyre eller 1'[N-(l-S-carboxy-3-phenylpropyl)-S-alanyl]-exo-spirobi-cyclo[2.2.2]octan-2,3'-pyrrolidin-5'-S-carboxylsyre.An injection solution is prepared analogously to the specification set forth in Example 4 using 5 1- [N- (1S-carboxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aR, 7aS) - octahydroindole-2 carboxylic acid or 1- [N- (1S-carboxy-3-phenyl-propyl) -S-alanyl] -cis-2,3,3a, 4, 5,7a-hexahydro [1 H] indole-2-S-endo carboxylic acid or 1 '[N- (1S-carboxy-3-phenylpropyl) -S-alanyl] -endo-spirobicyclo [2.2.2] octane-2,3'-pyrrolidine-51-5-carboxylic acid or 1' [N- (S-carboxy-3-phenylpropyl) -S-alanyl] -exo-spirobi-cyclo [2.2.2] octane-2,3'-pyrrolidine-5'-S-carboxylic acid.

Fremstillingen af forbindelserne med formlen II illustreres i de følgende eksempler 7-95.The preparation of the compounds of formula II is illustrated in the following Examples 7-95.

1515

Eksempel 7 2-[N-(IS)-Ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-cis-endo-2-azabicyclo[3.3.0]octan-3-S-carboxylsyreoctade-20 cylester (ikke omfattet af opfindelsen) 23 g af den analogt med EP-offentliggørelsesskrift nr. 79022 fremstillede cis,endo-2-azabicyclo[3.3.0]octan--3-carboxylsyreoctadecylester omsættes med 6,7 g 25 HOBt, 13,8 g N-(IS)-carbethoxy-3-phenylpropyl)-S-alanin og 10,2 g dicyclohexylcarbodiimid i 200 ml dimethylform-amid. Efter 3 timers omrøring ved stuetemperatur fraskilles det udfældede dicyclohexylurinstof ved sugning, der inddampes, optages i 1 liter eddikesyreethylester og 30 udrystes med 3 x 500 ml 5%'s natriumhydrogencarbonatop-løsning. Den organiske fase inddampes, chromatograferes med ethylacetat/petroleumsether i forholdet 2:1 på en søjle af 1 kg silicagel og adskilles på denne måde i titelforbindelsen og den diastereomere (S,S,R)-forbindel-35 se.Example 7 2- [N- (IS) -Ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid octadecyl ester (not included in the invention) ) 23 g of the cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid octadecyl ester, prepared analogously to 6.7 g of 25 HOBt, 13.8 g of N- (IS) -carbethoxy-3-phenylpropyl) -S-alanine and 10.2 g of dicyclohexylcarbodiimide in 200 ml of dimethylformamide. After 3 hours of stirring at room temperature, the precipitated dicyclohexylurea is separated by suction which is evaporated, taken up in 1 liter of acetic acid ethyl ester and shaken with 3 x 500 ml of 5% sodium hydrogen carbonate solution. The organic phase is evaporated, chromatographed with ethyl acetate / petroleum ether in a 2: 1 ratio on a column of 1 kg of silica gel, and is thus separated into the title compound and the diastereomeric (S, S, R) compound.

Eksempel 8Example 8

OISLAND

22 DK 172221 B1 1-[N-(IS)-Dodecyloxycarbonyl-3-phenylpropyl)-S-alanyl]--2S,3aR,7aR-octahydroindol-2-carboxylsyre 5 a) 1-[N-(IS)-Dodecyloxycarbonyl-3-phenylpropyl)-S-alanyl]--2S,3aR,7aR-octahydroindol-2-carboxylsyre-benzylester 10 mmol S-alanyl-2S,3aR,7aR-octahydroindol-2-carboxyl-10 syre-benzylester (fremstillet ifølge EP-offentliggørel- sesskrift nr. 84164) opløses i 30 ml vandfri ethanol. Opløsningen indstilles til en pH-værdi på 7,0 ved hjælp af ethanolisk kaliumhydroxid, og der tilsættes 1 g pulveriseret molekylsigte (4A) og derefter 10 mmol 2-keto-4-15 -phenylsmørsyredodecylester. Der tilsættes langsomt dråbe vis en opløsning af 1 g natriumcyanoborhydrid i 10 ml vandfri ethanol. Efter en reaktionstid på 20 timer ved 20-25°C filtreres reaktionsopløsningen, og opløsningsmidlet afdestilleres. Remanensen optages i ethylacetat/vand.B1 1- [N- (IS) -Dodecyloxycarbonyl-3-phenylpropyl) -S-alanyl] -2S, 3aR, 7aR-octahydroindole-2-carboxylic acid a) 1- [N- (IS) -Dodecyloxycarbonyl -3-phenylpropyl) -S-alanyl] -2S, 3aR, 7aR-octahydroindole-2-carboxylic acid benzyl ester 10 mmol S-alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid benzyl ester (prepared according to EP Publication No. 84164) is dissolved in 30 ml of anhydrous ethanol. The solution is adjusted to a pH of 7.0 using ethanolic potassium hydroxide, and 1 g of powdered molecular sieve (4A) is added and then 10 mmol of 2-keto-4-15-phenylbutyric acid dodecyl ester. Slowly add a solution of 1 g of sodium cyanoborohydride in 10 ml of anhydrous ethanol. After a reaction time of 20 hours at 20-25 ° C, the reaction solution is filtered and the solvent is distilled off. The residue is taken up in ethyl acetate / water.

20 Efter inddampning af ethylacetatfasen chromatograferes remanensen på silicagel med ethylacetat/cyclohexan i forholdet 1:4.After evaporation of the ethyl acetate phase, the residue is chromatographed on silica gel with ethyl acetate / cyclohexane in a ratio of 1: 4.

b) Den ifølge a) fremstillede forbindelse hydrogeneres 25 i ethanol i nærværelse af palladium på carbon (10%’s) ved 20-25°C under normalt tryk. Efter fraskillelse af katalysatoren sættes der 0,5N ethanolisk hydrogenchlorid til opløsningen indtil sur reaktion. Opløsningen inddampes i vakuum, og remanensen udrives med isopropylether til 30 krystallisation.b) The compound prepared according to (a) is hydrogenated in ethanol in the presence of palladium on carbon (10% s) at 20-25 ° C under normal pressure. After separating the catalyst, 0.5N ethanolic hydrogen chloride is added to the solution until acidic reaction. The solution is evaporated in vacuo and the residue is triturated with isopropyl ether for crystallization.

3535

Eksempel 9Example 9

OISLAND

23 DK 172221 B1 2- [N-[(2S)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(IS, 3S,5S)-2-azabicyclo[3.3.0]octan-3-carboxylsyreisobutylester 5 (ikke omfattet af opfindelsen) 2,00 g (4,80 mmol) 2-[N-[(IS)-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl]-(IS,3S,5S)-2-azabicyclo[3.3.0]octan- 3- carboxylsyre opløses i 100 ml isobutanol, der tilsættes 0,1 ml koncentreret svovlsyre, og blandingen koges i 10 15 timer under tilbagesvaling. Efter afkøling fjernes op løsningsmidlet i en rotationsfordamper, og remanensen optages i methylenchlorid. Denne opløsning vaskes en gang med vand, en gang med mættet vandig natriumhydrogencar-bonatopløsning og igen en gang med vand, tørres over mag-15 nesiumsulfat, inddampes og skilles ved chromatografi på 200 g silicagel (elueringsmiddel: methylenchlorid/ethyl-acetat i forholdet 8:2) fra urenheder. Der fås et olie-formigt produkt i et udbytte på 51% af det teoretiske.2- [N - [(2S) -Ethoxycarbonyl-3-phenylpropyl] -L-alanyl] - (IS, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid isobutyl ester 5 (not 2.00 g (4.80 mmol) of 2- [N - [(IS) -ethoxycarbonyl-3-phenyl-propyl] -L-alanyl] - (IS, 3S, 5S) -2-azabicyclo [ 3.3.0] Octane-3-carboxylic acid is dissolved in 100 ml of isobutanol, 0.1 ml of concentrated sulfuric acid is added and the mixture is refluxed for 10 hours. After cooling, the solvent is removed in a rotary evaporator and the residue is taken up in methylene chloride. This solution is washed once with water, once with saturated aqueous sodium hydrogen carbonate solution and again with water, dried over magnesium sulfate, evaporated and separated by chromatography on 200 g of silica gel (eluent: methylene chloride / ethyl acetate 8 : 2) from impurities. An oily product is obtained in a yield of 51% of theory.

20 [a]£°= “28'2° (c = 1' methanol).[.Alpha.] D @ 20 = + 28 DEG C. (c = 1 'methanol).

Dette produkt opløses i ether og indstilles med mættet etherisk saltsyre til en pH-værdi på 2, opløsningsmidlet afdampes, og remanensen krystalliseres fra diiso-25 propylether.This product is dissolved in ether and adjusted with saturated ethereal hydrochloric acid to a pH of 2, the solvent is evaporated and the residue is crystallized from diisopropyl ether.

Data for hydrochloridet:Hydrochloride data:

Smeltepunkt: 123 - 124°C, [a]^°= +17,7° (c = 1, methanol).Melting point: 123 - 124 ° C, [α] D = + 17.7 ° (c = 1, methanol).

Eksempel 10 30 - 2-[N-[(IS)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]--(IS,3S,5S)-2-azabicyclo[3.3.0]octan-3-carboxylsyre-benzhydrylester (ikke omfattet af opfindelsen) 2,07 g (4,97 mmol) 2-[N-[(IS)-ethoxycarbonyl-3--phenylpropyl]-L-alanyl]-(IS,3S,5S)-2-azabicyclo[3.3.0]— -octan-3-carboxylsyre opløses i 50 ml acetone, og under 35Example 10 - 2- [N - [(IS) -Ethoxycarbonyl-3-phenylpropyl] -L-alanyl] - (IS, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzhydryl ester (not included in the invention) 2.07 g (4.97 mmol) of 2- [N - [(IS) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] - (IS, 3S, 5S) -2-azabicyclo [3.3.0] -octane-3-carboxylic acid is dissolved in 50 ml of acetone and below 35

OISLAND

DK 172221 Bl 24 isafkøling tilsættes der dråbevis en opløsning af 1,16 g (5,98 mmol) diphenyldiazomethan i 50 ml acetone. Derefter omrøres opløsningen i 26 timer ved stuetemperatur, opløsningsmidlet afdampes i en rotationsfordamper, 5 og remanensen renses ved flashchromatografi på 150 g silicagel (elueringsmiddel: toluen/ethanol i forholdet 98:2). Der fås et olieformigt produkt i et udbytte på 2,55 g (88%) .To ice-cooling, a solution of diphenyl diazomethane (1.16 g, 5.98 mmol) in acetone (50 ml) is added dropwise. Then, the solution is stirred for 26 hours at room temperature, the solvent is evaporated in a rotary evaporator, and the residue is purified by flash chromatography on 150 g of silica gel (eluent: toluene / ethanol 98: 2). An oily product is obtained in a yield of 2.55 g (88%).

10 [ a. ] = -33,8° (c = 1, methanol).[Α.] = -33.8 ° (c = 1, methanol).

Eksempel 11 2-[N-[(IS)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-15 (IS,3S,5S)-2-azabicyclo[3.3.0]octan-3-carboxylsyreocta- decylester (ikke omfattet af opfindelsen) 2,08 g (5,00 mmol) 2-[N-[(IS)-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl]-(IS ,3S,5S)-2-azabicylco[3.3.0]octan-3-2o -carboxylsyre opløses i 25 ml absolut dimethylformamid, der tilsættes 1,00 g (10,0 mmol) kaliumhydrogencarbonat, og der omrøres i 90 minutter ved 40°C. Efter afkøling til stuetemperatur tilsættes der dråbevis en opløsning af 4,00 g (12,0 mmol) 1-bromoctadecan i 20 ml absolut di-25 methylformamid og omrøres i 4 timer ved 40°C. Opløsnings midlet fjernes på en rotationsfordamper ved et tryk på ca. 1 mm Hg, og remanensen fordeles mellem vand og me-thylenchlorid. Den organiske fase fraskilles, tørres over magnesiumsulfat og inddampes. Fra råproduktet (5,40 g) iso-30 leres der ved søjlechromatografi på 200 g silicagel (elueringsmiddel: toluen/ethanol i forholdet 99:1) 3,05 g (92%) af produktet.Example 11 2- [N - [(IS) -Ethoxycarbonyl-3-phenylpropyl] -L-alanyl] -15 (IS, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid octacetyl ester (not included in the invention) 2.08 g (5.00 mmol) of 2- [N - [(IS) -ethoxycarbonyl-3-phenyl-propyl] -L-alanyl] - (IS, 3S, 5S) -2-azabicyl [ 3.3.0] octane-3-carboxylic acid is dissolved in 25 ml of absolute dimethylformamide, added 1.00 g (10.0 mmol) of potassium hydrogen carbonate and stirred for 90 minutes at 40 ° C. After cooling to room temperature, a solution of 4.00 g (12.0 mmol) of 1-bromoctadecane in 20 ml of absolute dimethylformamide is added dropwise and stirred for 4 hours at 40 ° C. The solvent is removed on a rotary evaporator at a pressure of approx. 1 mm Hg and the residue is partitioned between water and methylene chloride. The organic phase is separated, dried over magnesium sulfate and evaporated. From the crude product (5.40 g), column chromatography of 200 g of silica gel (eluent: toluene / ethanol 99: 1) isolates 3.05 g (92%) of the product.

[a]p^ = -19,6° (c = 1, methanol).[.alpha.] D @ 20 = -19.6 DEG (c = 1, methanol).

3535

Eksempel 12Example 12

OISLAND

25 DK 172221 B1 2-[N-[(ls)-Benzhydryloxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]octan-3-carboxylsyrebenzyl-5 ester (ikke omfattet af opfindelsen) a) (2R)-Hydroxy-4-phenylsmørsyrebenzhydrylester2- [N - [(1s) -Benzhydryloxycarbonyl-3-phenylpropyl] -L-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester (not included in the invention) a) (2R) -Hydroxy-4-phenylbutyric acid benzhydryl ester

Til en opløsning af 7,40 g (41,1 mmol) (2R)-hydroxy--4-phenylsmørsyre i 200 ml absolut acetone sættes der dråbevis 10 under isafkøling i løbet af 20 minutter en opløsning af 10,1 g (52,1 mmol) diphenyldiazomethan i 400 ml absolut acetone, og reaktionsblandingen omrøres i 20 timer ved stuetemperatur. Opløsningsmidlet afdampes, og remanensen udrives med 100 ml petroleumsether. Der fås 6,4 g krystallinsk produkt. Moderluden 15 inddampes, og ved søjlechromatografi på 700 g silicagel (elue-ringsmiddel: toluen/ethanol i forholdet 99:1) isoleres yderligere 6,0 g produkt.To a solution of 7.40 g (41.1 mmol) of (2R) -hydroxy-4-phenylbutyric acid in 200 ml of absolute acetone, a solution of 10.1 g (52, 1 mmol) diphenyldiazomethane in 400 ml of absolute acetone and the reaction mixture is stirred for 20 hours at room temperature. The solvent is evaporated and the residue is triturated with 100 ml of petroleum ether. 6.4 g of crystalline product are obtained. The mother liquor 15 is evaporated and by column chromatography of 700 g of silica gel (eluent: toluene / ethanol 99: 1 ratio) an additional 6.0 g of product is isolated.

Samlet udbytte: 12,4 g (87%).Total yield: 12.4 g (87%).

Smp.: 88-89°C.Mp: 88-89 ° C.

20 [a]j^ = (c ~ methanol).[A] j 2 = (c ~ methanol).

b) 2-[N-[(IS)-Benzhydryloxycarbonyl-3-phenylpropyl]-L-alanyl]-(IS ,3S,5S)-2-azabicyclo[3.3. 0]octan-3-carboxyl-syrebenzylester 25 b-^) 1,80 g (4,33 mmol) 2-(N-tert.butoxycarbonyl-L-alanyl)- -(IS,3S,5S)-2-azabicyclo[3.3.0]octan-3-carboxylsyrebenzyl-ester opløses i 4,5 ml trifluoreddikesyre og omrøres i 90 minutter ved stuetemperatur. Reaktionsopløsningen inddam-30 pes, og til fjernelse af trifluoreddikesyreestere afdrives der tre gange med toluen på en rotationsfordamper. Remanensen, der består af 1,90 g 2-(L-alanyl)-(IS,3S,5S)-2-azabicyclo-[3.3.0]octan-3-carboxylsyrebenzylester-trifluoracetat, opløses i 10 ml absolut methylenchlorid (opløsning A).b) 2- [N - [(IS) -Benzhydryloxycarbonyl-3-phenylpropyl] -L-alanyl] - (IS, 3S, 5S) -2-azabicyclo [3.3. 0] octane-3-carboxylic acid benzyl ester (b) 1.80 g (4.33 mmol) 2- (N-tert-butoxycarbonyl-L-alanyl) - - (IS, 3S, 5S) -2-azabicyclo [3.3.0] Octane-3-carboxylic acid benzyl ester is dissolved in 4.5 ml of trifluoroacetic acid and stirred for 90 minutes at room temperature. The reaction solution is evaporated and to remove trifluoroacetic acid esters three times with toluene is evaporated on a rotary evaporator. The residue, consisting of 1.90 g of 2- (L-alanyl) - (IS, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester trifluoroacetate, is dissolved in 10 ml of absolute methylene chloride (solution A).

3535

OISLAND

DK 172221 Bl 26 k>2) 1,63 g (4,71 mmol) (2R) -hydroxy-4-phenyl-smørsyre- -benzhydrylester fra eksempel 12 a) opløses sammen med 0,4 ml absolut pyridin i 25 ml absolut ethylenchlorid, og ved -10°C tilsættes der dråbevis i løbet af 20 minutter 1,41 g 5 (5,00 mmol) trifluormethansulfonsyreanhydrid. Derefter fjernes kølebadet, og efter at stuetemperatur er nået, afdampes opløsningsmidlet. Remanensen filtreres over 50 g silicagel med me-thylenchlorid og inddampes. Der fås 1,70 g 4-phenyl-(2R)--trifluormethylsulfonyloxy-smørsyrebenzhydrylester, som opløses 10 i 10 ml absolut methylenchlorid (opløsning B).DK 172221 B1 26 k> 2) 1.63 g (4.71 mmol) (2R) -hydroxy-4-phenylbutyric acid-benzhydryl ester of Example 12 a) are dissolved together with 0.4 ml of absolute pyridine in 25 ml of absolute ethylene chloride and at -10 ° C 1.41 g of 5 (5.00 mmol) of trifluoromethanesulfonic anhydride are added dropwise over 20 minutes. Then the cooling bath is removed and after the room temperature is reached, the solvent is evaporated. The residue is filtered over 50 g of silica gel with methylene chloride and evaporated. 1.70 g of 4-phenyl (2R) -trifluoromethylsulfonyloxy-butyric acid benzhydryl ester is obtained, which is dissolved in 10 ml of absolute methylene chloride (solution B).

b^) Til opløsning A sættes 1,0 ml (7,40 mmol) triethylamin og derefter langsomt dråbevis ved 0°C opløsning B. Kølebadet fjernes, og reaktionsopløsningen omrøres i 19 timer ved stue-15 temperatur, hvorefter den vaskes tre gange med vand, tørres over magnesiumsulfat og inddampes. Remanensen renses chromato-grafisk på 80 g silicagel (elueringsmiddel: cyclohexan/ethyl-acetat i forholdet 8:2 og 7:3) og der fås 0,95 g (30%) af det ønskede produkt.b ^) To solution A is added 1.0 ml (7.40 mmol) of triethylamine and then slowly dropwise at 0 ° C solution B. The cooling bath is removed and the reaction solution is stirred for 19 hours at room temperature, then washed three times with water, dried over magnesium sulfate and evaporated. The residue is purified chromatographically on 80 g of silica gel (eluent: cyclohexane / ethyl acetate in the ratio of 8: 2 and 7: 3) to give 0.95 g (30%) of the desired product.

20 Smp.: 81-85°C.Mp: 81-85 ° C.

[ct]^ = -55,2° (c = 1, methanol).[α] D = -55.2 ° (c = 1, methanol).

Ved passende kombinationer af de i de foregående eksempler beskrevne metoder fremstilles følgende yderligere forbin-25 delser (ringsystemernes betegnelser svarer til betegnelserne for forbindelserne med den almene formel II) .By suitable combinations of the methods described in the preceding examples, the following additional compounds are prepared (the ring system names correspond to the names of the compounds of the general formula II).

30 35 27 DK 172221 B1 * * # * A-y R^OOC - JH - N - C -CH - NH - CH - CH2 - CHg-fM R4 fc5 O CH5 C00R2 r5ooc-ch-n-30 35 27 DK 172221 B1 * * # * A-y R ^ OOC - JH - N - C -CH - NH - CH - CH2 - CHg-fM R4 fc5 O CH5 C00R2 r5ooc-ch-n-

Eks. R4 R5 R2 R3 13 (udgået) 14 Ringsystem B “C2H5 -CH2-CH(CHj)2 15 Ringsystem C -CH^ -CH2~~^Q^ 16 Ringsystem C ”^2^5 -CH(CgH,-)2 17 Ringsystem D -C2^5 "0^ 18 Ringsystem D “^2^5 ”CZ^ 19 Ringsystem I) “C2H5 ~^P) 20 Ringsystem D "C2H5 21 Ringsystem I) "C2H5Ex. R4 R5 R2 R3 13 (discontinued) 14 Ring system B “C2H5 -CH2-CH (CHj) 2 15 Ring system C -CH ^ -CH2 ~~ ^ Q ^ 16 Ring system C” ^ 2 ^ 5 -CH (CgH, -) 2 17 Ring System D -C2 ^ 5 "0 ^ 18 Ring System D" ^ 2 ^ 5 "CZ ^ 19 Ring System I)" C2H5 ~ ^ P) 20 Ring System D "C2H5 21 Ring System I)" C2H5

’ ' ” r ^ 20 _ _91 j-O'' "R ^ 20 _ _91 j-O

22 Ringsystem D -C-Hj. -(CH5),.-oO) la d ' _W (c = 1, CH3OH) 23 Ringsystem B “^2^5 -(CH2)^-CHj 24 Ringsystem F -CH^ -CH(CgH^)2 25 Ringsystem G ~^2H5 -CH(CHj)2 26 Ringsystem G “^2^5 -CH(CgH^)2 28 DK 172221 B1 * * * * π OOC - CH - N - C -CH - NH - CH - CH0 - CH0 U 15 Π T I 2 2 2 FT ΊΤ o ch3 cooir R300C-CH-N-22 Ring system D-C-Hj. - (CH5), .- oO) la d '_W (c = 1, CH3OH) 23 Ring System B "^ 2 ^ 5 - (CH2) ^ - CHj 24 Ring System F -CH ^ -CH (CgH ^) 2 Ring System G ~ 2H5 -CH (CHj) 2 26 Ring system G "^ 2 ^ 5 -CH (CgH ^) 2 28 DK 172221 B1 * * * * π OOC - CH - N - C -CH - NH - CH - CH0 - CH0 U 15 Π TI 2 2 2 FT ΊΤ o ch3 cooir R300C-CH-N-

Eks. R4 R5 R2 R3 27 Ringsystem G ”C2H5 “(CH2^2“© 28 Ringsystem H CJHc -CH(CH_)0 2 P 3 2 29 Ringsy stem H -CH2-CH(CH5)2 30 Ringsystem H ^2^5 -(CH2)^-CH^ 31 Ringsystem H C2H5 “C3 32 Ringsystem H ^2^5 33 Ringsystem H CgH^ 34 Ringsystem H TqIQ) 35 Ringsystem Η H -CH2-^5) 36 Ringsystem H ^2^5 -CH(CgH^)2 37 Ringsystem H -(CH2)q-^^ 38 Ringsystem I CH^ 39 Ringsystem J C2^5 -CH(CgH^g 40 Ringsystem K C2H5 -(CH2)^-CHj 41 Ringsystem L C2B5 -C(CHj)j 29 DK 172221 B1 •X * # *Ex. R4 R5 R2 R3 27 Ring system G "C2H5" (CH2 ^ 2 "© 28 Ring system H CJHc -CH (CH_) 0 2 P 3 2 29 Ring system H -CH2-CH (CH5) 2 30 Ring system H ^ 2 ^ 5 - (CH2) ^ - CH ^ 31 Ring system H C2H5 “C3 32 Ring system H ^ 2 ^ 5 33 Ring system H CgH ^ 34 Ring system H TqIQ) 35 Ring system Η H -CH2- ^ 5) 36 Ring system H ^ 2 ^ 5 -CH ( CgH2) 2 37 Ring system H - (CH2) q - ^^ 38 Ring system I CH ^ 39 Ring system J C2 ^ 5 -CH (CgH ^ g 40 Ring system K C2H5 - (CH2) ^ - CHj 41 Ring system L C2B5 -C ( CHj) j 29 DK 172221 B1 • X * # *

Fr OOC - CH _ N - C -CH - NH - CH - CH0 - CH~ li |5 II I ' 2 2 2 R4 Fr 0 CH5 COOR* r5ooc-ch-n- *4. I ς pFr OOC - CH _ N - C -CH - NH - CH - CH0 - CH ~ li | 5 II I '2 2 2 R4 Fr 0 CH5 COOR * r5ooc-ch-n- * 4. I ς p

Eks. R^ R° ΊΓ 42 Ringsystem M -(CH2)2-CH(CH3)5 43 (udgået) ^ (lidgåét) ' 45 Ringsystem O C2H^ ”(CH2^2"^) 46 (udgået) 47 (udgået) 48 (udgået) 49 Ringsystem B CH(CH^)2 -C(CH^)^Ex. R ^ R ° ΊΓ 42 Ring system M - (CH2) 2-CH (CH3) 5 43 (discontinued) ^ (membered) '45 Ring system O C2H ^' (CH2 ^ 2 "^) 46 (discontinued) 47 (discontinued) 48 (discontinued) 49 Ring system B CH (CH ^) 2 -C (CH ^) ^

50 Ringsystem C CH(CgH^)2 -HRing system C CH (CgH ^) 2 -H

51 Ringsystem D CHg- -CH2-^5) 52 Ringsystem D CH2-CH(CH3)2 -CHg-© (c = 1, CH3OH) —.......... ..... 1 ------------------1 "|-aj 20_ +2 2o 55 Ringsystem I CH2-CH(CHj)2 -H (c ° i, ch^OH).51 Ring system D CH 2 - CH 2 - 5) 52 Ring system D CH 2 - CH (CH 3) 2 - CH 2 - ((c = 1, CH 3 OH) --.......... ..... 1 - ----------------- 1 "| -aj 20_ +2 2o 55 Ring System I CH2-CH (CHj) 2 -H (c ° i, ch ^ OH).

--smp. 162-163° 54 Ringsystem D CH2-CH(CH3)2 -CH(CgHjj)2 55 Ringsystem D CH(CgH3)2 -C(CHj)3--smp. 162-163 ° 54 Ring system D CH2-CH (CH3) 2 -CH (CgHjj) 2 Ring system D CH (CgH3) 2 -C (CHj) 3

56 Ringsystem D CH(CgH3)2 -H56 Ring system D CH (CgH3) 2 -H

30 DK 172221 B1 ·* * * * nOOC - Cfl - N - C -CH - NH - CH - CH0 - CH0 I a i ς (i * t 7 ά d R^ R? O CHj COOR* r3ooc-ch-n-30 DK 172221 B1 · * * * * nOOC - Cfl - N - C -CH - NH - CH - CH0 - CH0 I a i ς (i * t 7 ά d R ^ R? O CHj COOR * r3ooc-ch-n-

Eks. R4 R5 R2 R5 57 Ringsystem E —CH^ -(CH2)5-CH3 58 Ringsystem E -CH2-CH(CH3)2 -CH(4-E-CgH4)2 59 Ringsystem G -CH(CgH5)2 60 Ringsystem G -CH(CgH5)2 -C(CH3>3 61 Ringsystem H -CHgCHiCH^ ”CH2-^Ex. R4 R5 R2 R5 57 Ring system E -CH2 - (CH2) 5-CH3 58 Ring system E -CH2-CH (CH3) 2 -CH (4-E-CgH4) 2 59 Ring system G -CH (CgH5) 2 60 Ring system G -CH (CgH5) 2 -C (CH3> 3 61 Ring system H -CHgCHiCH

62 Ringsystem H -CH2CH(CH3)2 -H62 Ring system H -CH2CH (CH3) 2 -H

63 Ringsystem H -CH2CH(CH3)2 -CH(C6H5)2 64 Ringsystem H -CH2-@> -CH2*® 65 Ringsystem H -C(CH3)3 66 Ringsystem H -CH(CgH3)2 -CH2-^)^63 Ring system H -CH2CH (CH3) 2 -CH (C6H5) 2 64 Ring system H -CH2 - @> -CH2 * ® 65 Ring system H -C (CH3) 3 66 Ring system H -CH (CgH3) 2 -CH2- ^) ^

67 Ringsystem H -CH(CgH3)2 -H67 Ring system H -CH (CgH3) 2 -H

68 Ringsystem H -CH(CgH3)2 -C(CH3)3 69 Ringsystem H -CH(CgH3)2 -CH(CgH3)268 Ring system H -CH (CgH3) 2 -C (CH3) 3 69 Ring system H -CH (CgH3) 2 -CH (CgH3) 2

70 Ringsystem I -O70 Ring System I -O

71 Ringsystem J -(CHgJ^-CHj -CH(CgH3)2 31 DK 172221 B1 , * * * R-’OOC - CH - N - C -CH - NH - CH - CH9 - CH~ IA I c i> I I 2 2 271 Ring system J - (CHgJ2 -CH2 -CH (CgH3) 2 31) 17 * 21 R-OOC - CH - N - C -CH - NH - CH - CH9 - CH ~ IA I ci> II 2 2 2

IT R5 O CHj COORIT R5 O CHj COOR

R5OOC-CH-N-R5OOC-CH-N-

Eks. h4 R5 R2 R5 72 Ringsystem K -^] 73 Ringsystem L ”CH2^2”^) -(CH^g-CH^ 74 Ringsystem M -(CH2)2-CH(CH5)2 -CH(C6H5)2 75 (udgået) 76 Ringsystem O -CH(CHj)2 -CH(CgH^)2 77 (udgået) 78 (udgået) -[ot] D = +27,0 78a Ringsystem D C2Hc MenthyKc = 1, CH30H) ,Ex. h4 R5 R2 R5 72 Ring system K - ^] 73 Ring system L "CH2 ^ 2" ^) - (CH ^ g-CH ^ 74 Ring system M - (CH2) 2-CH (CH5) 2 -CH (C6H5) 2 75 ( discontinued) 76 Ring system O -CH (CH2) 2 -CH (CgH2) 2 77 (discontinued) 78 (discontinued) - [ot] D = +27.0 78a Ring system D C2Hc MenthyKc = 1, CH30H),

smp.(maleat) 118-120 Cmp (maleate) 118-120 ° C

78b Ringsystem 6 Menthyl ^2^6^5 32 DK 172221 B1 c R3OOC-C*H-N-C- {CH} -X278b Ring system 6 Menthyl ^ 2 ^ 6 ^ 5 32 DK 172221 B1 c R3OOC-C * H-N-C- {CH} -X2

I, LI II, LI I

k Rs O CH3 3 -3 3 pk Rs O CH3 3 -3 3 p

Eks. R OOC-CH-N- R X m • 4 IsEx. R OOC-CH-N- R X m • 4 Is

R RR R

79 Ringsystem O -OHCgH^ -CH2SH 1 1Q --—:-- 80 Ringsystem O -(CH^-CH^ -CH2SH 1 81 (udgået) 15 (udgået) 83 CH3°\^g^^ -NH-CH-(CH2) 2-^^> 179 Ring system O -OHCgH ^ -CH2SH1 1Q - -: - 80 Ring system O - (CH2 -CH2 -CH2SH1 81 (discontinued) 15 (discontinued) 83 CH3 ° \ ^ g ^^ -NH-CH- (CH2) 2 - ^^> 1

Eksempel 92 25 4- (N-(IS)-Carboethoxy-3-phenylpropyl)-S-benzyl)-exo- spiro(bicyclo[2.2.2]octan-2,3-pyrrolidin)-5-carboxylsyre a) N-(lS-Carbethoxy-3-phenylpropyl)-S-laurylbenzylester 3,4 g (10 mmol) 2-(D)-trifluormethylsulfonyloxy-4-30 phenylsmørsyreethylester og 5,9 g (15 mmol) L-leucinbenzyl- estertosylat blandes i 50 ml absolut methylenchlorid, og efter tilsætning af 4,2 ml triethylamin omrøres der i 6,5 timer ved stuetemperatur. Efter inddampning af opløsningen isoleres produktet ved søjlechromatografi (silicagel, cyclohexan/ethyl-35 acetat i forholdet 9:1). Der fås 3,2 g farveløs olie.Example 92 4- (N- (1S) -Carboethoxy-3-phenylpropyl) -S-benzyl) -exopiro (bicyclo [2.2.2] octane-2,3-pyrrolidine) -5-carboxylic acid a) N- (1S-Carbethoxy-3-phenylpropyl) -S-laurylbenzyl ester 3.4 g (10 mmol) of 2- (D) -trifluoromethylsulfonyloxy-4-30 phenylbutyric acid ethyl ester and 5.9 g (15 mmol) of L-leucine benzyl ester tosylate are mixed. of absolute methylene chloride, and after the addition of 4.2 ml of triethylamine, stir for 6.5 hours at room temperature. After evaporation of the solution, the product is isolated by column chromatography (silica gel, cyclohexane / ethyl acetate 9: 1 ratio). 3.2 g of colorless oil is obtained.

1H-NMR S = 0,95 (d, CH3), 1,2 (t, CH3) 1,8 (m, CH2) 2,6 (m, CH2) 3,3 (m, CH) 4,1 (q, CH2) 5,1 (s, CH2) 7,3 (s, CH) ppm.1 H-NMR S = 0.95 (d, CH 3), 1.2 (t, CH 3) 1.8 (m, CH 2) 2.6 (m, CH 2) 3.3 (m, CH) 4.1 ( q, CH 2) 5.1 (s, CH 2) 7.3 (s, CH) ppm.

33 DK 172221 B133 DK 172221 B1

OISLAND

b) N-(l-S-Carboethoxy-3-phenylpropyl)-S-leucin 3,1 g af den under a) fremstillede benzylester spaltes hydrogenolytisk med 500 mg platin på carbon (10%'s) i 200 ml 5 ethanol. Efter frafiltrering af katalysatoren og inddampning af opløsningen fås 2,3 g farveløst krystallisat af carboxylsyren med et smeltepunkt på 120-121°C.b) N- (1- S-Carboethoxy-3-phenylpropyl) -S-leucine 3.1 g of the benzyl ester prepared under (a) is decomposed hydrogenolytically with 500 mg of platinum on carbon (10%) in 200 ml of ethanol. After filtration of the catalyst and evaporation of the solution, 2.3 g of colorless crystallate of the carboxylic acid were obtained with a melting point of 120-121 ° C.

1H-NMR 8 = 0,9 (d, CH3), 1,25 (t, CH3) , 1,8-2,1 (m, CH2) , 2,7 (m, CH2), 3,3 (q, CH), 4,25 (q, CHj), 10 7,2 (s, CH) ppm.1 H-NMR δ = 0.9 (d, CH 3), 1.25 (t, CH 3), 1.8-2.1 (m, CH 2), 2.7 (m, CH 2), 3.3 (q , CH), 4.25 (q, CH 2), 7.2 (s, CH) ppm.

c) 4-[N-(IS)-Carbethoxy-3-phenylpropyl)-S-leucyl]-exo-spirobicyclo[2.2,2]octan-2,3-pyrrolidin-5-carboxylsyre 2 g (6,2 mmol) N-(l-S-carboethoxy-3-phenylpropyl)-S-15 leucin og 1,9 g (3,9 mmol) exo-spiro(bicyclo[2.2.2]-octan--2,3-pyrrolidin)-5-carboxylsyrebenzylester omrøres i 100 ml dimethylformamid med 4,3 ml triethylamin og 6,5 ml n-propyl-phosphonsyreanhydrid natten over ved stuetemperatur. Reaktionsopløsningen optages i ethylacetat og omrystes to gange med van-20 dig 10%'s natriumhydrogencarbonatopløsning og en gang med vandig 10%'s citronsyre, vandig mættet natriumhydrogencarbonatopløs-ning og mættet vandig natriumchloridopløsning. Derefter fraskilles, tørres og inddampes den organiske fase. Råproduktet med et udbytte på 2,8 g adskilles ved søjlechromatografi 25 (silicagel, toluen/ethylacetat i forholdet 95:5) i de to diastereomere. Af hver benzylester fås 1 g rent produkt.c) 4- [N- (1S) -Carbethoxy-3-phenylpropyl) -S-leucyl] -exo-spirobicyclo [2.2,2] octane-2,3-pyrrolidine-5-carboxylic acid 2 g (6.2 mmol) N- (1S-carboethoxy-3-phenylpropyl) -S-leucine and 1.9 g (3.9 mmol) of exospiro (bicyclo [2.2.2] octane-2,3-pyrrolidine) -5- carboxylic acid benzyl ester is stirred in 100 ml of dimethylformamide with 4.3 ml of triethylamine and 6.5 ml of n-propylphosphonic anhydride overnight at room temperature. The reaction solution is taken up in ethyl acetate and shaken twice with aqueous 10% sodium bicarbonate solution and once with aqueous 10% citric acid, aqueous saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase is then separated, dried and evaporated. The crude product, with a yield of 2.8 g, is separated by column chromatography (silica gel, toluene / ethyl acetate 95: 5 ratio) in the two diastereomers. Of each benzyl ester, 1 g of pure product is obtained.

1 g af den første diastereomer hydrogeneres med palladium på carbon i 40 ml ethanol. Der fås 780 mg krystallinsk carboxylsyre med et smeltepunkt på 131-132°C.1 g of the first diastereomer is hydrogenated with palladium on carbon in 40 ml of ethanol. 780 mg of crystalline carboxylic acid are obtained, mp 131-132 ° C.

30 [a]^ = “2,8° (c = 1, methanol).[.Alpha.] D @ 20 = 2.8 DEG (c = 1, methanol).

860 mg af den anden diastereomer hydrogeneres med palladium på carbon i 35 ml ethanol, og udbyttet efter frafiltrering af katalysator og inddampning af opløsningen er 720 mg.860 mg of the second diastereomer is hydrogenated with palladium on carbon in 35 ml of ethanol and the yield after filtration of catalyst and evaporation of the solution is 720 mg.

Smp.: Forbindelsen sintrer fra 65°C.Mp: The compound sinters from 65 ° C.

35 [a]^ = “22/2° (c = 1, methanol).[.Alpha.] D @ 22 = 22 DEG (c = 1, methanol).

OISLAND

34 DK 172221 B134 DK 172221 B1

Eksempel 93 4-[N-(IS)-Carboxyl-3-phenylpropy1)-S-leucyl]-exo-spiro-(bicyclo[2.2.2]octan-2,3-pyrrolidin)-5-carboxylsyre 5 102 mg (0,2 mmol) af carboxylsyren fra eksempel 92c) omrøres i vandig 4N kaliumhydroxidopløsning, indtil alt er opløst. Opløsningen anbringes på en ionbytter ("Amberlite R 120") og elueres med vandig 2%'s pyridinopløsning. Udbyttet er 70 mg.Example 93 4- [N- (IS) -Carboxyl-3-phenylpropyl) -S-leucyl] -exo-spiro- (bicyclo [2.2.2] octane-2,3-pyrrolidine) -5-carboxylic acid 102 mg ( 0.2 mmol) of the carboxylic acid of Example 92c) is stirred in aqueous 4N potassium hydroxide solution until all is dissolved. The solution is placed on an ion exchanger ("Amberlite R 120") and eluted with aqueous 2% pyridine solution. The yield is 70 mg.

10 [a]^ = +3'9° (c = 1/ methanol).[Α] D = + 3'9 ° (c = 1 / methanol).

Følgende forbindelser med formlen II fremstilles på analog måde (betegnelserne for ringsystemerne svarer til betegnelserne for forbindelserne med den almene formel II) : 15 H00C - CH - N - C - CH - CH - CH, - CH0The following compounds of formula II are prepared in an analogous manner (the terms for the ring systems are similar to those for the compounds of general formula II): H00C - CH - N - C - CH - CH - CH, - CH0

r5 6 V cooc2h5 Wr5 6 V cooc2h5 W

R1 HOOC - CH - HHR1 HOOC - CH - HH

20 R« R520 R «R5

CH2“C6H11 (CH2-Cyclohexyl) CCH2 “C6H11 (CH2-Cyclohexyl) C

ch2-c6h4 och3 Gch2-c6h4 and3 G

25 ch2-c6h4 oc2h5 CCh2-c6h4 and c2h5 C

ch2-c6h4-oc3h7 Cch2-c6h4-oc3h7 C

ch2-c6h4-oc4h9 a (CH2)4~NH2 D [a]£°= -23,7° (c = 0,152, CH3OH) (CH2)3-NH2 a 30 ch2-ch^-s ch3 ach2-c6h4-oc4h9 a (CH2) 4 ~ NH2 D [a] £ ° = -23.7 ° (c = 0.152, CH3OH) (CH2) 3-NH2 and ch2-ch ^ -s ch3 a

CH— CHCH— CH

II I·II I ·

CH, - C CH ACH, - C CH A

''S' 35 HOOC - CH - N - C - CH - CH - CH5 - CHp -/y 1/ ic h li · ^ ^ \e/ R4 R5 O R1 C00C2H5 35 DK 172221 B1'' S '35 HOOC - CH - N - C - CH - CH - CH5 - CHp - / y 1 / ic h li · ^^ \ e / R4 R5 O R1 C00C2H5 35 DK 172221 B1

R1 HOOC - CH - NHR1 HOOC - CH - NH

R* R5 CH(CH3)2 b CH(CH3)CH2CH5 b CH2c6H5 bR * R5 CH (CH3) 2 b CH (CH3) CH2CH5 b CH2c6H5 b

CH2-C6Hn DCH2-C6Hn D

CH2-C6H4-OCH5 ηCH2-C6H4-OCH5 η

CH2~C6H4~0C2H5 GCH2 ~ C6H4 ~ 0C2H5 G

ΟΗ^ϋβΗ^-Οη-ϋ^Ηγ GΟΗ ^ ϋβΗ ^ -Οη-ϋ ^ Ηγ G

CH2~C6H4“ 0n_C4H9 cCH2 ~ C6H4 “0n_C4H9 c

(ch2)4-nh2 C(ch2) 4-nh2 C

(ch2)5-nh2 G(ch2) 5-nh2 G

ch2-ch2-s-ch5 Dch2-ch2-s-ch5 D

CH— CHCH— CH

CH5 - C CH BCH5 - C CH B

HOOC - CH - N - C - CH - CH - CH0 - CH0 1Δ 'S · M · ^ * \—/ R4 R5 O R1 C00C2H5 36 DK 172221 B1HOOC - CH - N - C - CH - CH - CH0 - CH0 1Δ 'S · M · ^ * \ - / R4 R5 O R1 C00C2H5 36 DK 172221 B1

R1 HOOC - CH - NHR1 HOOC - CH - NH

k4 R5 ch(ch3)2 c CH(CH3)CH2CH3 ck4 R5 ch (ch3) 2 c CH (CH3) CH2CH3 c

CH2CgH3 CCH2CgH3 C

CH2-CgHj^ ECH2-CgH2 ^ E

ch2-c6h4-och3 Ich2-c6h4-och3 I

ch2-c6h4-oo2h5 H al CH2-C5H4-On-C3H7 H b)ch2-c6h4-oo2h5 H al CH2-C5H4-On-C3H7 H b)

CH2-C6H4-0n-C4H9 GCH2-C6H4-0n-C4H9 G

(ch2)4-nh2 G c>(ch2) 4-nh2 G c>

(ch2)3-nh2 H(ch2) 3-nh2 H

CH2-€H2-S-CH3 HCH2- € H2-S-CH3 H

CH— CHCH— CH

CHp - C CH CCHp - C CH C

""s' a^mindre polær diastereomer [a]^= -28,6° (c = 1, CH^OH) mere polær diastereomer [ot] 20— +20,7° (c = 1, CH-OH) D + 3 MS (FAB): 591 (M +1)less polar diastereomer [α] = -28.6 ° (c = 1, CH 2 OH) more polar diastereomer [ot] 20 + 20.7 ° (c = 1, CH-OH) D + 3 MS (FAB): 591 (M + 1)

b) smp. = 53-57°Cb) m.p. = 53-57 ° C

MS (FAB): 605 (M+ + 1)MS (FAB): 605 (M + + 1)

c) smp. = 142°Cc) m.p. = 142 ° C

HOOC - CH - N - C - CH - CH - CH0 - CH«HOOC - CH - N - C - CH - CH - CH0 - CH «

• Λ t c « 11 I « * W• Λ t c «11 I« * W

R4 R5 O R1 C00C2H5 37 DK 172221 B1R4 R5 O R1 C00C2H5 37 DK 172221 B1

R1 HOOC - CH - NHR1 HOOC - CH - NH

R4 R5R4 R5

ch(ch5)2 Dch (ch5) 2 D

ch(ch5)ch2ch5 Dch (ch5) ch2ch5 D

ch2c6h5 Dch2c6h5 D

CH2-C6Hn FCH2-C6Hn F

CH2~^6H4~ 0C2H5 ICH2 ~ ^ 6H4 ~ 0C2H5 I

CH2_€6H4~0n”C3H7 1CH2_ € 6H4 ~ 0n ”C3H7 1

CH2'C6H4'0n”C4H9 HCH2'C6H4'0n ”C4H9 H

(ch2)4-nh2 H(ch2) 4-nh2 H

(ch2)3-nh2 O(ch2) 3-nh2 O

CH2-CHr S-CH3 ICH2-CHr S-CH3 I

CH-CHCH-CH

CH? - C CH DCH? - C CH D

HOOC - CH - N - C - CH - CH - CH0 - CH~HOOC - CH - N - C - CH - CH - CH0 - CH ~

* A IC· «4 i 2 2 W* A IC · «4 i 2 2 W

R4 R? O R1 C00C2H5 38 DK 172221 B1R4 R? O R1 C00C2H5 38 DK 172221 B1

R1 HOOC - CH - NHR1 HOOC - CH - NH

R« R5 ch(ch5)2 g ch(ch5)ch2ch5 e ch2c6h5 h a) ch2-c6h11 g CH2"C6H4“0CH3 0R «R5 ch (ch5) 2 g ch (ch5) ch2ch5 e ch2c6h5 h a) ch2-c6h11 g CH2" C6H4 "0CH3 0

CH2-CgH^- On—C^H^ ICH2-CgH2 - On-C2H2I

CH—CHCH-CH

CH5 - C CH KCH5 - C CH K

^s' 1. diastereomer [a]^= +16,4° (c = 1, CH^OH) 2. diastereomer [a]^= +29,9° (c = 1, CH^OH) (tert.butyl-NI^-salt) HOOC - CH - N - C - CH - CH - CH9 - CH9 i a I c i* · i · * c w R4 R5 O R1 C00C2H5 39 DK 172221 B1^ s' 1. diastereomer [a] ^ = + 16.4 ° (c = 1, CH ^ OH) 2. diastereomer [a] ^ = + 29.9 ° (c = 1, CH ^ OH) (tert. butyl-N 1 - salt) HOOC - CH - N - C - CH - CH - CH9 - CH9 ia I ci * · i · * cw R4 R5 O R1 C00C2H5 39 DK 172221 B1

R1 HOOC - CH - NHR1 HOOC - CH - NH

R< *5 CH(CH3)2 h CH(CH5)CH2CH3 f ch2c6h5 i CH2-C6H11 h ch2-c6h4-oc2h5 oR <* 5 CH (CH3) 2 h CH (CH5) CH2CH3 f ch2c6h5 in CH2-C6H11 h ch2-c6h4-oc2h5 o

CH2'‘CgH^- 0n-C3H^ OCH2'CgH2 - 0n-C3H2O

CH— CHCH— CH

Il IIIl II

CH0 - C CH GCH0 - C CH G

HOOC - CH - N - C - CH - CH - CH5 - CHd • / 15 * '1 1 * * \*s/ R4 R5 O R1 C00C2H5 40 DK 172221 B1HOOC - CH - N - C - CH - CH - CH5 - CHd • / 15 * '1 1 * * \ * s / R4 R5 O R1 C00C2H5 40 DK 172221 B1

R1 HOOC - CH - NHR1 HOOC - CH - NH

R4 R5R4 R5

ch(ch5)2 Ich (ch5) 2 I

ch(ch3)ch2ch5 Gch (ch3) ch2ch5 G

CHa-CgH^ ICH₂-CgH ^I

CH2"CgH^“ On—O CH— CHCH2 "CgH2" On — O CH— CH

CHo - C CH HCHo - C CH H

HOOC - CH - N - C - CH - CH - CH0 - CH0 I i te < μ I * * Vbs/ R4 R5 O R1 COOC2H5 41 DK 172221 B1HOOC - CH - N - C - CH - CH - CH0 - CH0 I i te <µ I * * Vbs / R4 R5 O R1 COOC2H5 41 DK 172221 B1

R1 HOOC - CH - NHR1 HOOC - CH - NH

R4 R5 CH(CH3)2 o CH(CH3)CH2CH3 η a) CH2c6H5 oR4 R5 CH (CH3) 2 o CH (CH3) CH2CH3 η a) CH2c6H5 o

CH^CgH,, LCH ^CgH ,,, L

CH2-CH2-S-CH3 gCH2-CH2-S-CH3 g

CH— CHCH— CH

II III I

CHo - C CH ICHo - C CH I

\ ^\ ^

SS

a) [<x]p°= -7,3° (c = 1, CH3OH) smp. = 117°Ca) [<x] p ° = -7.3 ° (c = 1, CH 3 OH) m.p. = 117 ° C

HOOC - CH - N - C - CH - CH - CH0 - CH0 i a t ς ·· m ' ^ * V—/ R4 R5 O R1 COOC2H5 42 DK 172221 B1HOOC - CH - N - C - CH - CH - CH0 - CH0 i a t ς ·· m '^ * V— / R4 R5 O R1 COOC2H5 42 DK 172221 B1

R1 HOOC - CH - NHR1 HOOC - CH - NH

R* R5R * R5

CH2‘C6Hn MCH2'C6Hn M

CH2-C6H4-0CH3 dCH2-C6H4-0CH3 d

ch2'C6H4"0C2H5 Dch2'C6H4 "0C2H5 D

CH2-C6H4-0n-C3H7 DCH2-C6H4-0n-C3H7 D

HOOC - CH - N - C - CH - CH - CH,, - CH, • Λ i c « i \ i ^ * \—/ R4 R** O R1 C00C2H5 43 DK 172221 B1HOOC - CH - N - C - CH - CH - CH ,, - CH, • Λ i c «i \ i ^ * \ - / R4 R ** O R1 C00C2H5 43 DK 172221 B1

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55

R1 HOOC - CH - HHR1 HOOC - CH - HH

i4 έ5i4 έ5

10 CH2-C6H4~0n-C4Hg DCH2-C6H4 ~ 0n-C4Hg D

CH(CH^)CH^CHj XCH (CH 2) CH 2 CH 2 X

CH2-C6Hn OCH2-C6Hn O

1515

Eksempel 94 1-[N-(IS)-Carboethoxybutyl)-S-alanyl]-octahydrocyclopenta-20 [b]pyrrol)-2-carboxylsyre a) PL-2-Trlfluormethylsulfonyloxy-pentansyreethylester 5 g (34 mmol) 2-hydroxyvalerianesyreethylester og 2,85 g (35,9 mmol) absolut pyridin opløses i 100 ml absolut 25 methylenchlorid under beskyttelsesgas og afkøles til 0°C, og der tilsættes 9,66 g (34 mmol) trifluormethansulfonsyre-anhydrid. Efter opvarmning til stuetemperatur omrøres der i 6 timer. Efter inddampning af opløsningen renses det fremkomne 30 35Example 94 1- [N- (IS) -Carboethoxybutyl) -S-alanyl] -octahydrocyclopenta-20 [b] pyrrole) -2-carboxylic acid a) PL-2-Trifluoromethylsulfonyloxy-pentanoic acid ethyl ester 5 g (34 mmol) of 2-hydroxyvaleric acid 2.85 g (35.9 mmol) of absolute pyridine is dissolved in 100 ml of absolute 25 methylene chloride under protective gas and cooled to 0 ° C and 9.66 g (34 mmol) of trifluoromethanesulfonic anhydride is added. After warming to room temperature, stir for 6 hours. After evaporation of the solution, the resulting 30 is purified

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DK 172221 B1 44 råprodukt søjlechromatografisk (silicagel, petroleumsether/-methylenchlorid i forholdet 6:1). Udbyttet er 9,3 g af en farveløs, let viskos væske.DK 172221 B1 44 crude product column chromatography (silica gel, petroleum ether / methylene chloride 6: 1 ratio). The yield is 9.3 g of a colorless, slightly viscous liquid.

IR: 2880 - 3000 1770, 1420, 5 1200 - 1220 1150, 620 cm"1 b) N-(1-S-Carboethoxybutyl)-S-alaninbenzylester 4,9 g (17,6 mmol) af den således fremstillede trifluor-methansulfonsyreester opløses under nitrogen i 70 ml absolut 10 methylenchlorid med 4,08 g L-alaninbenzylester-hydrochlorid (19 mmol) under tilsætning af 5,4 ml triethylamin og omrøres 3 timer ved stuetemperatur. Opløsningen inddampes, og råproduktet optages i ethylacetat, vaskes 3 gange med vand, tørres og inddampes. Diastereomerene adskilles ved søjlechromatografi 15 (silicagel, cyclohexan/ethylacetat i forholdet 5:1). Udbyttet af hver isomer er 500 mg. Den ved den første filtrering isolerede diastereomer har S,S-konfiguration.IR: 2880-3000 1770, 1420, 5 1200-1220 1150, 620 cm 6 1 (b) N- (1-S-Carboethoxybutyl) -S-alanine benzyl ester 4.9 g (17.6 mmol) Methanesulfonic acid ester is dissolved under nitrogen in 70 ml of absolute 10 methylene chloride with 4.08 g of L-alanine benzyl ester hydrochloride (19 mmol) with the addition of 5.4 ml of triethylamine and stirred for 3 hours at room temperature. The solution is evaporated and the crude product is taken up in ethyl acetate, washed 3 The diastereomers are separated by column chromatography (silica gel, cyclohexane / ethyl acetate 5: 1 ratio) The yield of each isomer is 500 mg. The diastereomer isolated by the first filtration has S, S configuration.

1H-NMR1 H-NMR

S = 0,9 (t,CH3), 1,3 (t,CH3), 1,35 (d,CH3), 1,4 (m,CH2), 20 1,6 (m,CH2), 1,9 (s,NH), 3,3 (t,CH), 3,4 (q,CH), 4,2 (πι,Οί^) , 5,15 (q,CH2 Ph) , 7,4 (s, CH aromat.) ppm.S = 0.9 (t, CH 3), 1.3 (t, CH 3), 1.35 (d, CH 3), 1.4 (m, CH 2), 1.6 (m, CH 2), 1, 9 (s, NH), 3.3 (t, CH), 3.4 (q, CH), 4.2 (πι, Οί ^), 5.15 (q, CH 2 Ph), 7.4 (s , CH aromat.) Ppm.

c) N-(1-S-Carboethoxybuty1)-S-alanin 25 600 mg (1,95 mmol) benzylester (diastereomer A) hydro generes med palladium på carbon i 34 ml ethanol. Derefter frafiltreres katalysatoren, og opløsningen inddampes i vakuum. Produktet fremkommer derved som et hvidt fast stof med et smeltepunkt på 137°C i et udbytte på 430 mg.c) N- (1-S-Carboethoxybutyl) -S-alanine 600 mg (1.95 mmol) of benzyl ester (diastereomer A) hydro is generated with palladium on carbon in 34 ml of ethanol. The catalyst is then filtered off and the solution is evaporated in vacuo. The product thus appears as a white solid with a melting point of 137 ° C in a yield of 430 mg.

30 d) 430 mg (1,98 mmol) N-(1-S-carboethoxybutyl)-S-alanin og 486 mg (1,98 mmol) L- (-)-octahydrocyclopenta-[b]-pyrrol--2-carboxylsyrebenzylester opløses under nitrogen i 20 ml dimethylformamid og afkøles til -10°C, og der tilsættes 35 1,5 ml triethylamin og 2 ml n-propylphosphonsyreanhydrid.D) 430 mg (1.98 mmol) of N- (1-S-carboethoxybutyl) -S-alanine and 486 mg (1.98 mmol) of L- (-) - octahydrocyclopenta- [b] -pyrrole-2- Carboxylic acid benzyl ester is dissolved under nitrogen in 20 ml of dimethylformamide and cooled to -10 ° C and 35 ml of triethylamine and 2 ml of n-propylphosphonic anhydride are added.

Der omrøres i 1 time ved -10°C og derefter natten over ved stuetemperatur. Opløsnincpn optages i 200 ml ethylacetat og va-Stir for 1 hour at -10 ° C and then overnight at room temperature. The solution is taken up in 200 ml of ethyl acetate and

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45 DK 172221 B1 skes med mættet vandig natriumhydrogencarbonatopløsning, 10%'s vandig citronsyre og mættet vandig natriumchloridopløsning. Efter tørring og inddampning af opløsningen adskilles de diastereomere forbindelser ved søjlechromatografi (silica-5 gel, cyclohexan/ethylacetat i forholdet 9:1). Udbyttet er 360 mg. De to diastereomere hydrogeneres med palladium på carbon i ethanol som beskrevet i eksempel 94 c) og fremkommer efter inddampning af opløsningen som et hvidt fast stof.B1 is made with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid and saturated aqueous sodium chloride solution. After drying and evaporating the solution, the diastereomeric compounds are separated by column chromatography (silica gel, cyclohexane / ethyl acetate 9: 1 ratio). The yield is 360 mg. The two diastereomers are hydrogenated with palladium on carbon in ethanol as described in Example 94 (c) and appear after evaporation of the solution as a white solid.

10 Eksempel 95 1-[N-(IS)-Carboxybutyl)-S-alanyl]-(octahydrocyclopenta[b]pyr-rol)-2-carboxylsyre 60 mg (0,17 mmol) carboxylsyre (eksempel 94 d) omrø-15 res i 2 ml 4 N vandig kaliumhydroxidopløsning indtil fuldstændig opløsning. Derefter anbringes opløsningen på en stærkt sur ionbytter og elueres med vandig 2%'s pyridinopløsning. Udbyttet er efter inddampning af opløsningen 39 mg.Example 95 1- [N- (1S) -Carboxybutyl) -S-alanyl] - (octahydrocyclopenta [b] pyrrole) -2-carboxylic acid 60 mg (0.17 mmol) of carboxylic acid (Example 94 d) residue in 2 ml of 4 N aqueous potassium hydroxide solution until complete dissolution. Then, the solution is placed on a highly acidic ion exchanger and eluted with aqueous 2% pyridine solution. The yield after evaporation of the solution is 39 mg.

Analogt med eksempel 94 og 95 kan der fremstilles 20 følgende yderligere forbindelser med formlen IIAnalogously to Examples 94 and 95, the following additional compounds of formula II can be prepared

, H R^OOC -CH-N-C-CH-N-CH (CH~) -R, H R ^ OOC -CH-N-C-CH-N-CH (CH ~) -R

*4 * c 1 I i I a ^ ^ R* B? 0 R1 C00R2 25 1 2 hvori, idet n betyder 2, R betyder methyl, R betyder ethyl, 3 og R betyder hydrogen, og R og molekyldelen* 4 * c 1 I i I a ^ ^ R * B? Wherein R1 is 2, R is methyl, R is ethyl, 3 and R is hydrogen, and R is the molecular moiety.

3 H3 H

30 R OOC-CH-N30 R OOC-CH-N

'4 '3'4' 3

R4 RJR4 RJ

har den i tabellen nedenfor angivne betydning: 35has the meaning given in the table below:

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46 DK 172221 B146 DK 172221 B1

R HOOC-CH-NHR HOOC-CH-NH

R4 R5 5 -(CH2)9-CH5 cR4 R5 5 - (CH2) 9-CH5 c

2-Naphthyl D2-Naphthyl D

R HOOC-CH-NHR HOOC-CH-NH

10 *4 *510 * 4 * 5

CHj BCH 2 B

-ch2ch2ch3 B-ch2ch2ch3 B

15 -(ch2)9-ch3 D15 - (ch2) 9-ch3 D

2-Naphthyl F2-Naphthyl F

4-Biphenylyl C4-Biphenylyl C

—(ch2)^3—ch3 b 20- (ch2) ^ 3-ch3 b 20

R HOOC-CH-NHR HOOC-CH-NH

1 & 16 _R4 Rp_1 & 16 _R4 Rp_

ch3 Cch3 C

25 -CH2CH2CH3 c -(ch2)9-ch3 g-CH2CH2CH3 c - (ch2) 9-ch3 g

2-Naphthyl G2-Naphthyl G

4-Biphenylyl D4-Biphenylyl D

-(ch2)13-ch, C- (ch 2) 13-ch, C

30 ' J30 'J

35 4735 47

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DK 172221 B1DK 172221 B1

R HOOC-CH-NHR HOOC-CH-NH

_Bti?_ CH3 d 5 -CH2CH2CH3 d -(ch2)9-ch3 h_Bti? _ CH3 d 5 -CH2CH2CH3 d - (ch2) 9-ch3 h

2-Naphthyl H2-Naphthyl H

4-Biphenylyl H4-Biphenylyl H

10 -(ch2)13-ch3 D10 - (ch2) 13-ch3 D

R HOOC-CH-NHR HOOC-CH-NH

R4 R5 15 --- CH3 g -ch2ch2ch3 g -(ch2)9-ch3 kR4 R5 15 --- CH3 g -ch2ch2ch3 g - (ch2) 9-ch3 k

2-Naphthyl I2-Naphthyl I

2020

4-Biphenylyl L4-Biphenylyl L

—(ch2)^3—ch3 g- (ch2) ^ 3-ch3 g

„ R HOOC-CH-NHR ROC-CH-NH

25 U '5 __ΊΓ R7 _ ch3 Η25 U '5 __ΊΓ R7 _ ch3 Η

-ch2ch2ch3 H-ch2ch2ch3 H

ao -(ch2)9-ch3 Nao - (ch2) 9-ch3 N

2-Naphthyl M2-Naphthyl M

35 DK 172221 B1DK 172221 B1

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4848

R HOOC-CH-NHR HOOC-CH-NH

_åii!_ -(CH2)9-CH3 o- (CH2) 9-CH3 o

— (CH2) O- (CH 2) O

R HOOC-CH-NHR HOOC-CH-NH

'4 '«5 _ΊΓ Rp_ 10'4' «5 _ΊΓ Rp_ 10

4-Biphenylyl G4-Biphenylyl G

4-Biphenylyl H4-Biphenylyl H

15 20 25 30 3515 20 25 30 35

Claims

49 DK 172221 B1 Patent claims:

Use of ACE Inhibitors of Formula II * * *

R3OOC - CH - N - C - CH - NH - CH - (CHo) nR (II) II II II R4 R5 O R1 COOR2 or their physiologically acceptable salts for the manufacture of drugs of nootropic effect, in which formula 10 n means 1 or 2, R is an aromatic group having 6-12 carbon atoms, R 1 is hydrogen, an aliphatic group having 1-21 carbon atoms, or the if appropriate protected side chain of a naturally occurring α-amino acid,

R 2 and R 3 are the same or different and represent hydrogen, an aliphatic group of 1-21 carbon atoms, an alicyclic group of 3-20 carbon atoms, an aromatic group of 6-12 carbon atoms or an araliphatic group of 7-32 carbon atoms, and

20 R4 and R5 together with the atoms bearing them form a mono-, bi- or tricyclic heterocyclic ring system selected from pyrrolidine, decahydroisoquinoline, octahydroindole, octahydro-cyclopenta [b] pyrrole, 2-azaspiro [4.5] decane, 2-azaspiro [4.4] -nonane, spiro [(bicyclo [2.2.1] heptane) -2,3'-pyrrolidine], spiro [(bicyclo [2.2.2] octane) -2,3'-pyrrolidine], 2 -azatricyclo- [4.3.0.16'®] decane, decahydrocyclohepta [b] pyrrole, octahydroisoindole, octahydrocyclopenta [c] pyrrole, and 2,3,3a, 4,5,7a-hexa-hydroindole.

Use according to claim 1, characterized in that (S, S, S, S, S) -1- [N- (1-carbethoxy-3-phenyl-propyl) -alanyl] -octahydroindole-2 is used. carboxylic acid, 1- [N- (1-S - carbethoxy-3-phenylpropyl) -S-alanyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid, (S, S, S, S, S) -2- [N- (1-carbethoxy-3-phenylpropyl) -alanyl] -decahydroisoquinoline-3-carboxylic acid, or 1- [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] -cis, a -do-1H, 2,3,3a, 4,5,7a-hexahydroindole-2-S- or -2-R-carboxylic acid. DK 172221 B1 O 50

Use according to claim 1, characterized in that 1 '- [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] -exo / endo-spirobicyclo [2.2.2] octane-2 is used. 3'-pyrrolidine-51-carboxylic acid, 1 '- [N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl] - (3'S, 51S) -spiro-bicyclo-O [2.2. 2] -octane-2,3'-pyrrolidine-5'-carboxylic acid, 11 - [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S, 5'R) -spiro-bicyclo [ 2.2.2] Octane-2,3'-pyrrolidine-51-carboxylic acid, 1 '- [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] -10 - (3'R, 5'S) -spiro bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid, 1 '- [N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3' R, 5 'R ) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid, 1 '- [N- (1R-carbethoxy-3-phenyl-propyl) -S-alanyl] - ( 31 s, 5'S) -spiro-bicyclo [2.2.2] -octane-2,3,3-pyrrolidine-5'-carboxylic acid, 1 '- [N- (1-R-carbethoxy-3-phenylpropyl) - S-alanyl] - (3'S, 5'R) -spiro-bicyclo [2.2.2] -octane-2,3'-pyrrolidine-5'-carboxylic acid, 1 '- [N- (1-R-carb-ethoxy) -3-phenylpropyl) -S-alanyl] - (3'R, 5'S) -spiro-bicyclo [2.2. 2] octane-2,3'-pyrrolidine-5'-carboxylic acid, 1 '- [N-20 (1R-carbethoxy-3-phenylpropyl) -S-alanyl] - (3' R, 5 'R) -spiro -bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid, 1 '- [N- (1S-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'S, - 5'S) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5 '- carboxylic acid, 1' - [N- (1S-carbethoxy-3-phenylpropyl) -R-25-alanyl] - (3 'R, 5'S) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5' -carboxylic acid, 1 '- [N- (1S-carbethoxy-3-phenyl-propyl) -R-alanyl] - (3'S, 5'R) -spiro-bicyclo [2.2.2] octane - 2,3'-pyrrolidine-5'-carboxylic acid, 1 '- [N- (1-S-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'R, 5'R) -spiro-bicyclo [2.2.2] -30-octane-2,3'-pyrrolidine-5'-carboxylic acid, 1 '- [N- (1- R-carb-ethoxy-3-phenylpropyl) -R-alanyl] - (3'S, 5'S) -spiro-bicyclo- [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid, 1 '- [N - (1-R-carbethoxy-3-phenylpropyl) -R-L-alanyl] - (3'R, 5'S) -spiro - bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid, 1 '- [N- (1R-carbethoxy-3-phenylpropyl) -R-alanyl] - (31S, -5'R) -spiro-bicy clo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid or 1 '- [N- (1-R-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'R, 5' R) -spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid. 10 15 20 25 30 35