IE62456B1 - Compounds having a cognition adjuvant action, agents containing them, and the use thereof for the treatment and prophylaxis of cognitive dysfunctions - Google Patents
Compounds having a cognition adjuvant action, agents containing them, and the use thereof for the treatment and prophylaxis of cognitive dysfunctionsInfo
- Publication number
- IE62456B1 IE62456B1 IE78487A IE78487A IE62456B1 IE 62456 B1 IE62456 B1 IE 62456B1 IE 78487 A IE78487 A IE 78487A IE 78487 A IE78487 A IE 78487A IE 62456 B1 IE62456 B1 IE 62456B1
- Authority
- IE
- Ireland
- Prior art keywords
- carboxylic acid
- alanyl
- carbethoxy
- phenylpropyl
- octane
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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
The invention relates to the use of angiotensin converting enzyme inhibitors (ACE inhibitors) or their physiologically tolerated salts as medicaments having a nootropic action (improving cognitive function) and to the use thereof in the preparation of corresponding pharmaceutical formulations. ACE inhibitors with various heterocyclic structures which can be used to reduce blood pressure are known from EP-A-050800 and EP-A-116276.
Examples of suitable compounds for this novel use are those of the formula II R OOC - CH - Nf C - CH - NH - ?H (II) COOR in which n is 1 or 2, R denotes hydrogen, an aliphatic radical having 1-21 carbon atoms, an aromatic radical having 6-12 carbon atoms, R1 denotes hydrogen, an aliphatic radical having 1-21 carbon atoms, or if not already covered by the above definitions, the side-chain, protected where necessary, of a naturally occurring α-amino acid, R3 and R3 are identical or different and denote hydrogen, an aliphatic radical having 1-21 carbon atoms, an alicyclic radical having 3-20 carbon atoms, an aromatic radical having 6-12 carbon atoms, an araliphatic radical having 7-32 carbon atoms, and R* and R5 form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring carbon atoms.
An aliphatic radical is understood to be an aliphatic 30 acyclic radical, i.e. a radical with an open, straight or branched carbon chain such as, for example, alkyl, alkenyl, alkynyl and corresponding multiply unsaturated radicals. It is preferably unsubstituted or, as described below, for example, for carboxyl, carbamoyl, aminoalkyl, alkanoylaminoalky1, alkoxycarbonylaminoalkyl, ary lalkoxy carbonyl aminoalkyl, ary lalky laminoalky 1, alkylaminoalkyl, dialkylaminoalkyl, alkylthioalkyl, arylthioalkyl, carboxyalkyl, carbamoylalkyl, alkoxycarbonylalky1, alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, aroyloxyalkyl or aryloxycarbonyloxyalkyl, monosubstituted.
An alicyclic radical, and the corresponding optionally substituted alicyclic-aliphatic radical which is linked via an open carbon chain, is a preferably mono- to pentacyclic, isocyclic, nonaromatic radical which has single bonds or asymmetrically distributed double bonds and can also be branched (i.e. carry open-chain aliphatic side-chains) and is linked via a ring carbon atom or a side-chain carbon atom. It is preferably unsubstituted. When several rings are components of a radical of this type, they are fused, spiro-linked or isolated. Examples of radicals of this type are cycloalkyl, cycloalkenyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl and radicals derived from mono-, bi- or oligocyclic terpenes such as menthyl, isomenthyl, boranyl, bornyl, caranyl, epibornyl, epiisobornyl, isoborayl, menthanyl, neomenthyl, neoisomenthyl, pinanyl and thujanyl; they are preferably unsubstituted (according to the present definition, aliphatic side-chains are not substituents).
An aromatic radical is preferably aryl such as phenyl, biphenylyl or naphthyl, which is optionally mono-, di- or trisubstituted as indicated below for aryl. Radicals derived from aryl, such as aralkyl, aryloxy, arylthio or aroyl, preferably benzoyl, can be substituted as for aryl.
An araliphatic radical is understood to be, in particular, aralkyl radicals such as arylalkyl, diarylalkyl, indanyl or fluorenyl, in which aryl is as defined above and which can be substituted in the manner indicated there.
R4 and R5 can form, with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system which has 3 to 15 ring carbon atoms and preferably has up to 2 sulfur atoms and up to 2 nitrogen atoms in the ring, in particular up to 1 sulfur atom.
Particularly suitable ring systems of these types are those of the following group: Pyrrolidine (0); tetrahydroisoquinoline (A) ; decahydroisoquinoline (B) ; octahydroindole (C); indoline (2) ; octahydrocyclopenta[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[2.2.2] octane)-2,3'-pyrrolidine] (H); 2-azatricyclo [4.3.0.li,s] decane (I); decahydrocyclohepta[b]pyrrole (J); octahydroisoindole (K); octahydrocyclopenta[c]pyrrole (L); 2,3,3a,4,5,7a-hexahydroindole (M) ; 2-azabicyclo[3.1.0] hexane (N) ; 1,2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole (P), all of which can optionally be substituted. Pyrrolidine (0) and thiazolidine (R); can be monosubstituted by, for example, (Cj-C12)-aryl, (phenyl, 2-hydroxyphenyl etc.), (C6-C12) -arylmercapto (such as phenylmercapto) or (C3-C7)-cycloalkyl (such as cyclohexyl). Tetrahydroisoquinoline (A) can carry, for example, in the aryl moiety, up to 2 (Cx-C£)-alkoxy radicals, preferably methoxy radicals. A corresponding statement applies to the other ring systems. However, the unsubstituted systems are preferred.
With compounds of the formula ZI which have several chiral atoms all possible diastereomers, as racemates or enantiomers, or mixtures of various diastereomers are suitable.
The suitable heterocyclic ring systems have the following structural formulae.
I χ £ A preferred embodiment comprises use of compounds of the formula I, preferably those of the formula II, in which n is 1 or 2, R denotes hydrogen, alkyl having 1-8 carbon atoms, alkenyl having 2-6 carbon atoms, aryl which has 6-12 carbon atoms, R1 denotes hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, or the optionally protected side-chain of a naturally occurring α-amino acid, R1-CH(NHa) -COOH, R2 and R3 are identical or different and denote hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, aryl having 6-12 carbon atoms, (Cj-Cu) -aryl- (Cx-C4) -alkyl, (Cj-Cj) -cycloalkyl or and R4 and R5 have the abovementioned meaning, particularly such compounds in which n is 1 or 2, R denotes (Cj-Cj) -alkyl, (C2-C6)-alkenyl, (Cg-C12)-aryl, in particular methyl, ethyl or phenyl R1 denotes hydrogen or (Cx-Cj)-alkyl, (C2-C6)-alkenyl, or a side-chain of a naturally occurring, optionally protected α-amino acid, but in particular hydrogen, (Cx-Cj)-alkyl, (C2 or C3)-alkenyl, the optionally protected side-chain of lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-aminobutyl or benzoyImethyl, R2 and R3 denote identical or different radicals hydrogen, (Cx-Cs)-alkyl, (C2-Ce)-alkenyl or (C6-Cl2)-aryl(Cx-C4)-alkyl, but in particular hydrogen, (Cj-C4)alkyl or benzyl, and R4 and R5 have the abovementioned meaning.
If R1 represents a side-chain of a protected naturally occurring α-amino acid, such as, for example, protected Ser, Thr, Asp, Asn, Glu, Gin, Arg, Lys, Hyl, Cys, Om, Cit, Tyr, Trp or His, preferred protective groups are the groups customary in peptide chemistry (cf. Houben-Weyl, vol. XV/1 and XV/2) . In the case where R1 denotes the protected side-chain of lysine, the known amino protective groups are preferred, but in particular Z, Boc or (Οχ-Cg)-alkanoyl. Suitable and preferred O-protective groups for tyrosine are (Cj-Cg) -alkyl, in particular methyl or ethyl.
It is possible and particularly advantageous to use the following compounds according to the invention: 2- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] -S-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid 2- [N- (l-S-carbethoxy-3-cyclohexylpropyl) -S-alanyl] -S1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl)-S-lysyl]-S-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl)-O-ethyl-S-tyrosyl]S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-[N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-(3S)decahydroisoguinoline-3-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] - (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl](2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N-(l-S-carbethoxy-3-phenylpropyl)-S-lysyl]-(2S,3aS, 7aS)-octahydroindole-2-carboxylic acid 1-[N-(l-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl]-(2S, 3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N-(l-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl]-(2S, 3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl) -O-methyl-S-tyrosyl] (2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl)-O-ethyl-S-tyrosyl](2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1-[N-(1-S-carbethoxy-3-(3,4-dimethylphenylpropyl)-Salanyl]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N-[l-S-carbethoxy-3-(4-fluorophenyl)-propyl]-Salanyl]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N- [l-S-carbethoxy-3-(4-methoxyphenyl)-propyl]-Salanyl]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N- [l-S-carbethoxy-3- (3,4-dimethoxyphenyl) -propyl] -Salanyl]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1-[N-(l-S-carbethoxy-3-cyclopentylpropyl)-S-alanyl](2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] - (2S,3aR, 7aS)-octahydroindole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-cyclohexylpropyl) -S-alanyl] - (2S, 3aR,7aS)-octahydroindole-carboxylic acid 1-[N-(l-S-carbethoxy-3-phenylpropyl)-S-lyeyl]-(2S,3aR, 7aS)-octahydroindole-2-carboxylic acid 1-[N-(l-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl]-(2S, 3aR,7aS)-octahydroindole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl)-O-ethyl-S-tyrosyl](2S,3aS,7aR)-octahydroindole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] - (2S,3aR, 7aR)-octahydroindole-2-carboxylic acid 1-[N-(l-S-carbethoxy-3-phenylpropyl)-S-lysyl]-(2S,3aR, 7aS)-octahydroindole-2-carboxylic acid 1- [N-(l-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl](2S,3aR,7aR)-octahydroindole-2-Carboxylic acid 1- [N- (l-S-carbethoxy-3-cyclohexylpropyl)-O-ethyl-Styrosyl]-(2S,3aR,7aR)-octahydroindole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] - (2S,3aS, 7aR)-octahydroindole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl)-O-ethyl-S-tyrosyl](2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3,4-dime thy lpheny lpropyl) -S-alanyl] (2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N- [l-S-carbethoxy-3- (4-fluorophenyl)-propyl] -Salanyl]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N- [l-S-carbethoxy-3-(4-methoxyphenyl)-propyl]-Salanyl]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N- [l-S-carbethoxy-3- (3,4-dimethoxyphenyl) -propyl] -Salanyl]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1- [N-(l-S-carbethoxy-3-cyclopentylpropyl)-S-alanyl](2S,3aS,7aS)-octahydroindole-2-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-cis-endo2-azabicyclo[3.3.0]octane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl) -S-lysyl] -cis-endo-2azabicyclo[3.3.0]octane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-cyclohexylpropyl) -S-alanyl] -cisendo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid 2- [N- (l-S-carboxy-3-cyclohexylpropyl) -S-alanyl] -cis-endo2-azabicyclo[3.3.0]octane-3-S-carboxylic acid 2- [N- (1-S-carbethoxy-butyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3- (3,4-dimethoxyphenylpropyl) -Salanyl] -cis-endo-2-azabicyclo[3.3.0] octane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-cyclopentylpropyl) -S-alanyl] -cisendo-azabicyclo-[3.3.0]octane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl) -0-methyl-S-tyrosyl] cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl] cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3 - (4-f luoropheny lpropyl) -S-alanyl] cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3- (4-methoxyphenylpropyl) -S-alanyl] cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid 1- [N- (1-S-carbethoxy-3-phenylpropyl) - S-lysyl] - (2S, 3aR 6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid 1-[N-(l-S-carbethoxy-3-cyclohexylpropyl)-lysyl]-(2S, 3aR,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl]-O-ethyl-S-tyrosyl](2S, 3aR, 6aS) -octahydrocyclopenta[b]pyrrole-2-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] -2- (2S,3aR, 6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid 2- [N- (1-S-carbethoxy-3-phenylpropyl) -S-alanyl] -2-azaspiro- [4.5]decane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl)-O-ethyl-2-tyrosyl]2-azaspiro-[4.5]decane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl) -S-lysyl] -2-azaspiro[4.5]decane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-cyclohexylpropyl) -S-alanyl] -2-azaspiro[4.5]decane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-eye1ohexyIpropyl)-S-lysyl]-2-azaspiro[4.5]decane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] -2-azaspiro[4.4]nonane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenyIpropyl)-O-ethyl-S-tyrosyl]2-azaspiro[4.4]nonane-3-S-carboxylic acid 2 -[N-(l-S-carbethoxy-3-phenyIpropyl)-S-lysyl]-2-azaspiro [4.4]nonane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-cyclohexyIpropyl) -S-alanyl] -2-azaspiro[4.4]nonane-3-S-carboxylic acid 2-[N-(1-S-carbethoxy-3-cyclopentyIpropyl)-S-alanyl]-2azaspiro[4.4]nonane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-cyclopentylpropyl) -S-lysyl] -2-azaspiro[4.4]nonane-3-S-carboxylic acid 1' - [N- (l-S-carbethoxy-3-phenyIpropyl) -S-alanyl] -spiro [bicyclo [2.2.1] heptane-2,3' -pyrrolidine] - 5' - S-carboxylic acid 1' - [N- (l-S-carbethoxy-3-phenyIpropyl) -O-ethyl-S-tyrosyl] spiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine]- 5'-Scarboxylic acid 1' - [N- (l-S-carbethoxy-3-phenyIpropyl)-S-lysyl]-spiro[bicyclo [2.2.1] heptane-2,3' -pyrrolidine] - 5' - S-carboxylic acid 1' - [N-(l-S-carbethoxy-3-cyclohexyIpropyl)-S-alanyl]spiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine] 5' - Scarboxylic acid 1' - [N- (l-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl]spiro[bicyclo[2.2.1]heptane-2,3’-pyrrolidine]-5'-Scarboxylic acid 1*-[N-(l-S-carbethoxy-3-phenyIpropyl)-S-alanyl]-spiro[bicyclo [2.2.2] octane-2,3' -pyrrolidine] -5' -S-carboxylic acid 1'-[N-(1-S-carbethoxy-3-phenylpropyl)-O-ethyltyrosyl]spiro-[bicyclo[2.2.2]octane-2,3'-pyrrolidine]- 5'-Scarboxylic acid 1' - [N- (1-S-carbethoxy-3-phenylpropyl)-S-lysyl]-spiro [bicyclo [2.2.2] octane-2,3'-pyrrolidine] -5'-S-carboxylic acid 1' -[N-(l-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl]spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine] - 5' -Scarboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] -2-azatricyclo [4.3.0. l6,s] decane-3 -S-carboxylie acid 2- [N- (l-S-carbethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl] 2-azatricyclo[4.3.0.ls,s]decane-3-S-carboxylic acid 2- [N-(l-S-carbethoxy-3-phenylpropyl)-S-lysyl] -2-azatricyclo [4.3.0. I*'9] decane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-cyclohexylpropyl) -S-alanyl] -2azatricyclo[4.3.0.l*'9]decane-3-S-carboxylic acid 2-[N-(l-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl]-2azatricyclo [4.3.0. le,s] decane-3-S-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] -decahydrocyclohepta[b]pyrrole-2-S-carboxylic acid 1- [N- (1-S-carbethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl] decahydrocyclohepta[b]pyrrole-2-S-carboxylic acid 1- [N- (1-S-carbethoxy-3-phenylpropyl) -S-lysyl] -decahydrocyclohepta [b]pyrrole-2-S-carboxylic acid 1- [N- (l-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl]decahydrocyclohepta[b]pyrrole-2-S-carboxylic acid 1- [N- (l-S-carbethoxy-3-cyclohexylpropyl) -S-lysyl) -decahydrocyclohepta [b]pyrrole-2-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] -transoctahydroisoindole-1-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-cisoctahydroisoindole-1-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-cyclohexylpropyl) -S-alanyl] -transoctahydroisoindole-1-S-carboxylic acid 2- [N- (1-S-carbethoxy-3-cyclohexylpropyl) -S-alanyl] -cisoctahydroisoindole-1-S-carboxylic acid 2- [N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-cisoctahydrocyclopenta[c]pyrrole-l-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-cyclohexylpropyl) -S-alanyl] -cisoctahydrocyclopenta[c]pyrrole-1-S-earboxylic acid benzyl ester 2-[N-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl]-cis11 octahydrocyclopenta[c]pyrrole-1-S-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-2,3,3a,4, ,7a-hexahydroindole-cis-endo-2-S-carboxylic acid 1- [N- (l-S-carbethoxy-3-phenylpropyl) - S-lysyl] -2,3,3a,4, 5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid 2- [N-(l-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl]-2azabicyclo [3.1.0] hexane-3- S-carboxylic acid 2- [N- (1-S-carboxy-3-phenylpropyl) -S-lysyl] -2-azabicyclo[3.1.0]hexane-cis-endo-3-S-carboxylic acid 2-[N-(l-S-carbethoxy-3-cyclopentylpropyl)-S-alanyl]-2azabicyclo [3.1.0] hexane-3-carboxylic acid 2- [N- (1-S-carbethoxy-3-phenylpropyl) -S-alanyl] -cis-endo2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid 2- [N- (l-S-carbethoxy-3-cyclohexylpropyl) -S-alanyl] -cisendo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid 1'- [N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl](3' S, 5' S) -spiro-bicyclo [2.2.2] octane-2,3' -pyrrolidine-5' carboxylic acid 1'- [N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl](3' R, 5' S) - spiro-bicyclo [2.2.2] octane-2,3' -pyrrolidine-5' carboxylic acid 1'-[N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl](3' S, 5'R) - spiro-bicyclo [2.2.2] octane-2,3' -pyrrolidine-5' carboxylic acid 1'-[N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl](3'R, 5'R) - spiro-bicyclo [2.2.2] octane-2,3' -pyrrolidine-5' carboxylic acid 1'- [N-(l-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-carbethoxy- 3-phenylpropyl, -S-alanyl](3' S, 5' S) - spiro-bicyclo [2.2.2] octane,2,3' -pyrrolidine-5' carboxylic acid 1'- [N- (l-R-carbethoxy-3-phenylpropyl)-S-alanyl](3'R,5'S) -spiro-bicyclo [2.2.2] octane-2,3' -pyrrolidine-5' carboxylic acid 1'-[N-(l-R-carbethoxy-3-phenylpropyl)-S-alanyl](3'R,5'R)-spiro-bicyclo[2.2.2]octane-2,3'-pyrrolidine12 '-carboxylic acid 1*- [N-(1-S-carbethoxy-3-phenylpropyl)-R-alanyl](3' S, 5' S) - spiro-bicyclo [2.2.2] octane-2,3· -pyrrolidine- 5 ’ carboxylic acid 1'-[N-(1-S-carbethoxy-3-phenylpropyl)-R-alanyl](3 ' R, 5' S) - spiro-bicyclo [2.2.2] octane-2,3 · -pyrrolidine-5' carboxylic acid 1'- [N-(1-S-carbethoxy-3-phenylpropyl)-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]octane-2,3' -pyrrolidine-5' carboxylic acid 1'-[N-(l-R-carbethoxy-3-phenylpropyl)-R-alanyl](3'S,5'S) -spiro-bicyclo[2.2.2]octane-2,3' -pyrrolidine-5' carboxylic acid 1'- [N-(l-R-carbethoxy-3-phenylpropyl)-R-alanyl](3' R, 5' S) - spiro-bicyclo [2.2.2] octane-2,3' -pyrrolidine- 5' carboxylic acid 1'- [N-(l-R-carbethoxy-3-phenylpropyl)-R-alanyl](3' S, 5'R) - spiro-bicyclo [2.2.2] octane-2,3' -pyrrolidine-5' carboxylic acid 1'-[N-(l-R-carbethoxy-3-phenylpropyl)-R-alanyl](3'R, 5'R) -spiro-bicyclo[2.2.2] octane-2,3' -pyrrolidine-5' carboxylic acid These compounds can be prepared by, for example, the process described in German Patent Application P 33 33 455.2, in which the tert.-butyl or benzyl derivatives described in the application are converted in a known manner, by acid or alkaline hydrolysis or by hydrogenolysis catalyzed with noble metals, into the monocarboxylic acid derivatives. The M* -benzyloxycarbonyl protective group of the lysine derivatives is removed by hydrogenolysis catalyzed with noble metals. The compounds listed above can readily be converted with physiologically tolerated acids or bases (in the case of mono- or dicarboxylic acids) into the corresponding salts (for example hydrochlorides, maleates, fumarates etc.), and be used as salts according to the invention.
The compounds of the formula II are inhibitors of angiotensin converting enzyme (ACE) or are intermediates in the preparation of such inhibitors, and they can also be used for controlling high blood pressure of a variety of etiologies. Some of the compounds of the formula II and processes for their preparation are disclosed in, for example, US Patent 4,129,571, US Patent 4,374,829, European Patent A-79522, European Patent A-79022, European Patent A-49658, European Patent A-51301, US Patent 4,454,292, US Patent 4,374,847, European Patent A-72352, US Patent 4,350,704, European Patent A-50800, European Patent A-46953, US Patent 4,344,949, European Patent A-84164, US Patent 4,470,972, European Patent A-65301 and European Patent A-52991. New compounds of the formula II are prepared in an analogous manner.
Orally effective ACE inhibitors (some of the active compounds already mentioned above) are also advantageous, such as, for example, ramipril, enalapril(f), pentopril(a), lisinopril(g), cilazapril(ο), RHC 3659, C6S 13945, CGS 13928C(1), CGS 14824A(h), CI-906(j), alacepril, CI-925(k), CV 3317(m), indolapril(h), perindopril(i), and others. Orally effective ACE inhibitors are described in, for example, Brunner et al., J. Cardiovasc. Pharmacol. 7 (Suppl. I) [1985] S2-S11.
CX, co2h ΐ C-CH-NH θ' ,1 χ (ch2)4-nh2 C02H is) ΜίΑο2η «J CH-NH-CH I x»2«2·© Cf? Hi Z«2W2«3 ;-W-NH-OC °*3 CO^Hj Xi A ΟζΧςο, riiW2-Q -C-CH-NH-CH ‘ 1 co2c2hs (1) 0^ A «3 C-OWM-ffl II 1 00¾ OjCjHj Γ-H (j) X*. 3,4 00¾½) — CH-NH-CH Wj^OjH «, OJjCjHj Χ«Ζ°<2-© (ml «, ®Λη5 (q) The ACE inhibitors which are disclosed in European Patent A-79022 and are of the formula XII CSJ CH - CH2 ioon (in) in which R denotes hydrogen, methyl, ethyl or benzyl, are 5 preferred, in particular the compound of the formula III in which R denotes ethyl (ramipril).
Also preferred are the ACE inhibitors which are disclosed in European Patent A-84164 and are of the formula IV (IV) in which R4 denotes hydrogen, lar the compound of ethyl.
(Cx-C4) -alkyl or benzyl, in particuthe formula IV in which R4 denotes Furthermore, preference is given to 1*-[N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl]-exo- or 15 endo-spirobicyclo[2.2.2]octane-2,3'-pyrrolidin-5'-ylcarboxylic acid and isomers, and (S,S,S)-l-methyl-2-(1carbethoxy-3-phenylpropyl) -2H-undecahydrocydopenta[4.5] pyrrolo[1,2-a]pyrazine-3,8-dione.
The invention also relates to new compounds of the 20 formula II * . * * RJOOC - CH-H-O-CH-HH-Ca - (CHj)n-B (II) R4 R5 0 R1 COOR2 The capillary structure of the blood vessels in the brain differs from that in other regions of the body. The brain capillaries are surrounded by a layer of endothelial cells which are particularly closely linked together (by tight junctions). In addition, brain capillaries have very many fewer of the pores through which, in other blood capillaries, low molecular weight substances can penetrate into or emerge from the surrounding tissue. In this way, in the brain capillaries the property of lipid solubility has a very much greater importance for partition between blood and surrounding tissue than is the case for the remainder of the body.
Hence the preferred compounds of the formula II are those in which at least one of the radicals R, R1, R3 and R3 represents a lipophilic radical, such as a long-chain aliphatic, alicyclic-aliphatic, araliphatic or heteroaraliphatic radical, a sufficiently large alicyclic radical, or an appropriately substituted alicyclic, aromatic or heteroaromatic radical, or contains a radical of this type as a part-structure.
The invention also relates to a process for the preparation of a compound of the formula II, which comprises reacting together its fragments in a suitable solvent, where appropriate in the presence of a base and/or of a coupling aid, reducing, where appropriate, unsaturated compounds which have formed as intermediates, such as Schiff's bases, eliminating protective groups which have been introduced temporarily to protect reactive groups, esterifying, where appropriate, compounds of the formula II having one or more free carboxyl groups, and converting, where appropriate, the resulting compounds into their physiologically tolerated salts.
It is possible, for example, in the said manner to react compounds of the formula V with compounds of the formula VI.
(V) (VI) The reaction of these compounds can be carried out, for example, in analogy to known peptide coupling methods in an organic solvent such as DMF, CH2C12 or DMA in the presence of coupling aids such as carbodiimides (for example dicyclohexylcarbodiimide), diphenylphosphoryl azide, alkanephosphoric anhydrides, dialkylphosphinic anhydrides or Ν,Ν-succinimidyl carbonates, in a solvent such as CH3CN. Amino groups in compounds of the formula V can be activated with tetraethyl diphosphite. The compounds of the formula VI can be converted into active esters (for example with 1-hydroxybenzotriazole), mixed anhydrides (for example with chloroformic esters), azides or carbodiimide derivatives and thus activated (cf. Schroder, Lubke, 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.
It is likewise possible to react compounds of the formula VII with compounds of the formula VIII with the formation of compounds of the formula II X2 CB-(CB.) -R doOH2 2 ’ (vxi) (vixD in which either Y1 represents amino and Y3 represents a leaving group, or Y1 represents a leaving group and Y3 represents amino. Examples of suitable leaving groups are Cl, Br, I, alkylsulfonyloxy or arylsulfonyloxy.
Alkylations of this type are expediently carried out in water or an organic solvent such as a lower aliphatic alcohol (such as ethanol), benzyl alcohol, acetonitrile, nitromethane or glycol ethers, 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.
Furthermore, it is possible to condense compounds of the formula IX with compounds of the formula X COOR (XX) (X) in which either Q1 represents amino + hydrogen and Q3 represents oxo, or Q1 represents oxo and Q3 represents amino * hydrogen. The condensation is expediently 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, compounds of the formula I being obtained directly. However, it is also possible to reduce Schiff's bases or enamines which are produced as intermediates, where appropriate after previous isolation, with the formation of compounds of the formula II, for example by hydrogenation in the presence of a transition metal catalyst.
Finally, reaction of compounds of the formula IX (Qx H + NH2) with compounds of the formula XI, or their reaction with compounds of the formula XII and XIII, expediently in the presence of a base such as sodium alcoholate, in an organic solvent such as a lower alcohol, at a temperature between -10°C and the boiling point of the reaction mixture, also results in compounds of the formula II (n 2), R2OOC-CH=CH-COR (XI) OCH-COOR2 (XII) R-CO-CHj (XIII) with Schiff's bases which have been produced as intermediates being reduced as described above, and a carbonyl group being converted by reduction (for example with a complex hydride) into methylene.
In the abovementioned formulae V - XIII, R-R5 and n are as defined in formula II. Protective groups temporarily introduced to protect reactive groups not involved in the reaction are eliminated in a manner known per se after the reaction is complete (cf. Schroder, Lubke, loc. cit., pages 1-75 and 246 - 270; Greene, Protective Groups in Organic Synthesis, New York 1981).
The new compounds of the formula I or II can also be prepared, for example, using methods of esterification familiar to the expert (see, for example, Buehler, Pearson, Survey of Organic Syntheses, vol. 1, New York 1970, pages 802 - 825; Houben-Weyl, Methoden der Organischen Chemie, (Methods of Organic Chemistry), volume E5, 1985, pages 656 - 773) . a) Reaction of a mono- or dicarboxylic acid of the formula I or II in which at least one of the radicals R2 and R3 denotes hydrogen with an appropriate alcohol with acid catalysis (mineral acid or acid ion exchanger). b) Alkylation of a mono- or dicarboxylic acid of the formula I or II in which at least one of the radicals R2 and R3 denotes hydrogen with a compound R2Z or RJZ, in which Z denotes a leaving group which can be displaced nucleophilically (such as halogen. tosylate), in a polar protic or dipolar aprotic solvent, in the presence o£ a base such as an alkali metal hydroxide or alcoholate. c) Reaction of a mono- or dicarboxylic acid of the formula I or II in which at least one of the radicals R3 and R3 denotes hydrogen with a diazoalkene in an inert organic solvent such as ¢2,01,.
The nootropic action of the compounds according to the invention has been tested in the inhibitory (passive) avoidance test (step-through model) in mice having a body weight of 20-25 g. A modified form of the test method described by J. KOPP, Z. BODANECKY and M.E. JARVIK has been described by J. BURES, 0. BURESOVA and J. HUSTON in Techniques and Basic Experiments for the Study of Brain and Behavior, Elsevier Scientific Publishers, Amsterdam (1983) .
According to the statements in this literature, a substance is said to have nootropic activity when it is able to abolish the amnesia induced in the experimental animals by an electroconvulsive shock or the amnesia induced by scopolamine.
The experiments were carried out by modified test methods. The comparison compound used was the known nootropic agent 2-oxo-l-pyrrolidinylacetamide (piracetam) . The marked superiority of the compounds according to the invention over the comparison substance was evident from the fact that the scopolamine-induced amnesia in the inhibitory avoidance test can be abolished with an oral MED (minimal effective dose) of 1.0-30 mg/kg. The comparison substance has an oral MED of about 500-1,000 mg/kg.
Most of the compounds according to the invention have only low toxicity.
By reason of their pharmacological properties, the compounds according to the invention are suitable not only for the treatment of high blood pressure but also for the treatment of cognitive dysfunctions of various etiologies, as occur with, for example, Alzheimer's disease or senile dementia.
Bence the invention also relates to the use of the compounds according to the invention for the treatment and prophylaxis of cognitive dysfunctions in patients with high blood pressure.
The invention furthermore embraces medicaments containing the said compounds, processes for their preparation and the use of the compounds according to the invention for the preparation of medicaments which can be used for the treatment and prophylaxis of the abovementioned diseases.
It is possible, in practicing the method according to the invention, to use the angiotensin converting enzyme inhibitors which are described above in mammals such as monkeys, dogs, cats, rats, humans etc.
The medicaments are prepared by processes which are known per se and familiar to those skilled in the art. The pharmacologically active compounds (a active compound) according to the invention are used as medicaments either as such or, preferably, combined with suitable pharmaceutical auxiliaries, in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the content of active compound being up to about 95%, preferably between 10 and 75%.
The auxiliaries suitable for the desired medicament formulation are familiar to those skilled in the art by reason of their expert knowledge. Apart from solvents, gel-forming agents, suppository bases, tabletting auxiliaries and other active compound vehicles, it is possible to use, for example, antioxidants, dispersing agents. emulsifiers, antifoam agents, masking flavors, preservatives, solubilizers or colorants.
The active compounds can, for example, be administered orally, rectally or parenterally (for example intravenously or subcutaneously), oral administration being preferred.
For a form for oral use, the active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents, and converted by the customary methods into suitable presentations such as tablets, coated tablets, hard gelatin capsules, agueous, alcoholic or oily suspensions, or agueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, lactose, glucose or starch, in particular corn starch. This formulation can take the form of dry and of moist granules. Examples of suitable oily excipients or solvents are vegetable or animal oils such as sunflower oil or fish-liver oil.
For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted into solutions, suspensions or emulsions, if appropriate with the substances customary for this purpose such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents are water, physiological saline solution or alcohols such as ethanol, propanol, glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, as well as a mixture of the various solvents mentioned.
The following examples 1-6 indicate the forms used for the prophylaxis and treatment of cognitive dysfunctions by the method according to the invention. The compounds according to the invention can be converted into the appropriate use forms in analogy to the examples.
Example 1 Preparation of the agent used according to the invention for oral use in the treatment and prophylaxis of cognitive dysfunctions. 1000 tablets each containing 10 mg of 2-[N- (l-Scarbethoxy-3 -phenylpropyl)-S-alanyl]-IS,3S,5S-2azabicyclo[3.3.0]octane-3-carboxylic acid are prepared using the following auxiliaries: 2- [N-(l-S-carbethoxy-3-phenylpropyl)- 10 g S-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]octane3- carboxylic acid com starch 140 g gelatin 7.5 g microcrystalline cellulose 2.5 g magnesium stearate 2.5 g 2- [N- (l-S-Carbethoxy-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)2-azabicyclo[3.3.0]octane-3-carboxylic acid and com starch are mixed with an aqueous gelatin solution. The mixture is dried and milled to from granules. Microcrystalline cellulose and magnesium stearate are mixed with the granules.
The resulting granules are compressed to form 1000 tablets, each tablet containing 10 mg of the ACE inhibitor. These tablets can be used for the treatment and prophylaxis of cognitive dysfunctions.
Example 2 In analogy to Example 1, 1000 tablets each containing 10 mg of 1* - [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] (3'S,5'S)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'carboxylic acid are prepared. - 24 Example 3 Gelatin capsules each containing 10 ag of 1*-[N-(1-Scarbethoxy- 3-phenylpropyl) -S-alanyl] - (3'R,5'S) -spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid are filled with the following mixture: 1'-[N-(1-S-Carbethoxy-3-phenylpropyl)-S-alanyl](3'R,5'S) -spirobicyclo[2.2.2] octane-2,3' -pyrrolidine-5' carboxylic acid 10 mg Magnesium stearate 1 mg Lactose 214 mg These capsules can be used for the treatment and prophylaxis of cognitive dysfunctions.
Example 4 The preparation of an injection solution is described below: 2- [N- (1-S-Carboxy-3-phenylpropyl) -S-alanyl] - (1S,3S,5S) 2-azabicyclo[3.3.0]octane-2-carboxylic acid 250 mg Methylparahen 5 g Propylparaben 1 g Sodium chloride 25 g Water for injections 5 1 2- [N- (l-S-Carboxy-3-phenylpropyl) - S-alanyl] -(1S,3S,5S)2-azabicyclo[3.3.0]octane-3-carboxylic acid, the preservatives and sodium chloride are dissolved in 3 1 of water for injections, and the solution is made up to 5 1 with water for injections. The solution is filtered sterile and dispensed aseptically into presterilized vials, which are closed with sterilized rubber caps. Each vial contains 5 ml of solution.
Example 5 Tablets which can be used for the treatment or prophylaxis of cognitive dysfunctions are prepared as described in Example 1 with the exception that in place of 2- [N- (1-S-carbethoxy-3-phenylpropyl)-S-alanyl](15.35.55) -2-azabicyclo[3.3.0]octane-3S-carboxylic acid use is made of 2-[N- (l-S-carboxy-3-phenylpropyl) -Salanyl] - (1S,3S,5S) -2-azabicyclo[3.3.0] octane-3-carboxylic acid or 1-[N-(l-S-carboxy-3-phenylpropyl)-S-alanyl](2S,3aR,7aS)-octahydroindole-2-carboxylic acid or 1-[N(1 - S-carbethoxy-3-phenylpropyl)-S-alanyl]-cis2,3,3a, 4,5,7a-hexahydro [IH] indole-2-S-endo-carboxylic acid or 1- [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] cis-2,3,3a,4,5,7a-hexahydro[IH]indole-2S-endo-carboxylic acid or 2-[N-(l-S-carboxy-3-phenylpropyl)-S-lysyl](15.35.55) -2-azabicyclo[3.3.0]octane-3-carboxylic acid or 2- [N- (l-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl]IS,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid or N- (l-S-carboxy-3-cyclohexylpropyl)-S-lysyl-(1S,3S,5S)-2azabicyclo[3.3.0]octane-3-carboxylic acid or l'-[N-(1-Scarbethoxy-3-phenylpropyl) -S-alanyl]-exo-spirobicyclo[2.2.2]octane-2,3'-pyrrolidin-5'-S-ylcarboxylic acid or (S, S, S)-1-methyl-2-(1-carbethoxy-3-phenylpropyl)-2Hundecahydrocyclopenta [4.5]pyrrolo [1,2-a]pyrazine-3,8dione ori' - [N- (l-S-carbethoxy-3-phenylpropyl) -S-alanyl] endo-spirobicyclo[2.2.2]octane-2,3'-pyrrolidin-5'-Sylcarboxylic acid.
Example 6 An injection solution is prepared in analogy to the procedure described in Example 4 with the exception that in place of 2-[N-(l-S-carbethoxy-3-phenylpropyl)-Salanyl] - (1S,3S,5S) -2-azabicyclo[3.3.0]octane-3-carboxylic acid use is made of 2-[N-(l-S-carboxy-3-phenylpropyl)-Salanyl] - (1S,3S,5S) -2-azabicyclo[3.3.0]octane-3-carboxylic acid or 1-[N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl](2S,3aR,7aS)-octahydroindole-2-carboxylic acid hydroloride or l-[N-(l-S-carboxy-3-phenylpropyl)-S-alanyl](2S, 3aR, 7aS) octahydroindole-2-carboxylic acid or 1- [N- (1S-carbethoxy-3-cyclohexylpropyl)-S-alanyl]-cis26 2,3,3a,4,5,7a-hexahydro[1H] indole-2-S-endo-carboxylic acid or 1-[N-(l-S-carboxy-3-phenylpropyl)-S-alanyl]-cis2,3,3a,4,5,7a-hexahydro [1H] indole-2-S-endo-carboxylic acid or 2-[N-(l-carboxy-3-phenylpropyl)-S-lysyl](15.35.55) -2-azabicyclo[3.3.0.]octane-3-carboxylic acid or 2-[N-(l-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl](15.35.55) -2-azabicyclo[3.3.0]octane-3-carboxylic acid or 2- [N- (l-S-carboxy-3-cyclohexylpropyl)-S-lyeyl](15.35.55) -2-azabicyclo[3.3.0]octane-3-carboxylic acid or 1* - [N- (l-S-carboxy-3-phenylpropyl) -S-alanyl] -endospirobicyclo [2.2.2] octane-2,3' -pyrrolidine-5' -S-carboxylic acid or l'-[N-(l-S-carboxy-3-phenylpropyl)-S-alanyl]exospirobicyclo[2.2.2]octane-2,3·-pyrrolidine-5'-Scarboxylic acid.
The Examples 7-95 which now follow are intended to illustrate the process according to the invention for the preparation of the new compounds of the formula I and III, without confining the invention to them.
Example 7: Octadecvl 2-[N-(IS) -ethoxycarbonyl-3-phenvlpropvl) -S-alanyl]-cis,endo-2-azabicvclo[3.3.01 octane-3-S-carboxylate g of octadecyl cis,endo-2-azabicyclo[3.3.0]octane-3carboxylate prepared in analogy to European Patent A-79022 are reacted with 6.7 g of HOBt, 13.8 g of N-(IS)carbethoxy-3-phenylpropyl)-S-alanine and 10.2 g of dicyclohexylcarbodiimide in 200 ml of dimethylformamide. After stirring at room temperature for 3 hours, the precipitated dicyclohexylurea is filtered off with suction, the filtrate is concentrated, the residue is taken up in 1 1 of ethyl acetate, and the solution is extracted by shaking with 3 x 500 ml of 5% strength NaHCO, solution. The organic phase is concentrated and chromatographed on a column of 1 kg of silica gel with ethyl acetate/petroleum ether in the ratio 2:1, and in this way is separated into the title compound and the diastereomeric (S,S,R) compound.
Example 8: 1- [N- (IS) -Dodecvloxvcarbonvl-3-phenvlpropyl) -S-alanyl] 2S,3aR,7aR-octahvdroindole-2-carboxvlic acid a) Benzyl 1 - [N- (IS) -dodecvloxvcarbonvl-3-phenylpropyl) S-alanyl]-2S,3aR,7aR-octahvdrolndole-2-carboxylate mmol of benzyl S-alanyl-2S,3aR,7aR-octahydroindole-2-carboxylate (prepared as in European Patent A-84164) are dissolved in 30 ml of anhydrous ethanol. Ethanolic potassium hydroxide is used to adjust the pH of the solution to 7.0, and 1 g of powdered molecular sieve (4A), and then 10 mmol of dodecyl 2-keto-4-phenylbutyrate, are added. A solution of 1 g of sodium cyanoborohydride in 10 ml of anhydrous ethanol is slowly added dropwise. After a reaction time of 20 hours at 20 to 25°C, the reaction solution is filtered, and the solvent is removed by distillation. The residue is taken up in ethyl acetate/water. After the ethyl acetate phase has been evaporated, the residue is chromatographed on silica gel with ethyl acetate/cyclohexane (1:4). b) The compound obtained as in a) is hydrogenated in ethanol in the presence of palladium/animal charcoal (10%) at 20-25°C under atmospheric pressure. After the catalyst has been removed, 0.5 H ethanolic hydrogen chloride is added to the solution until it gives an acid reaction. The solution is concentrated in vacuo, and the residue is crystallized by trituration with diisopropyl ether.
Example 9: Isobutvl 2-[N-[(2S)-ethoxycarbonyl-3-phenylpropyl]-L-alanvll-(IS.3S,5S)-2-azabicvclo(3.3.01 octane-3-carboxylate 2.00 g (4.80 mmol) of 2-[N-[ (IS)-ethoxycarbonyl-3-phenylpropyl] -L-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3carboxylic acid were dissolved in 100 ml of isobutanol. 0.1 ml of concentrated sulfuric acid was added, and the mixture was boiled under reflux for 15 hours. After cooling, the solvent was removed in a rotary evaporator, and the residue was taken up in methylene chloride. This solution was washed once with water, once with saturated aqueous NaHCO, solution and again with water, dried over MgSO4, and concentrated, and impurities were removed by chromatography on 200 g of silica gel (mobile phase methylene chloride/ethyl acetate 8:2).
Yield 0:51% of theory of oily product. [a]" -28.2° (c 1, methanol) This product was dissolved in ether, the pH was adjusted to 2 with saturated ethereal hydrochloric acid, the solvent was evaporated off, and the residue was crystallized from diisopropyl ether.
Data on the hydrochloride: Melting point 123 - 124°C [a]™ a 4-17.7° (c a l, methanol) Example 10: Benzhydryl 2- [N- [ (IS)-ethoxvcarbonyl-3-phenvlpropvll-Lalanvil - (IS, 3S. 5S) -2-azabicyclo [3.3.01 octane-3-carboxylate 2.07 g (4.97 mmol) of 2-[N-[(IS)-ethoxyearbonyl-3-phenylpropyl] -L-alanyl]- (1S,3S,5S)-2-azabicyclo [3.3.0]octane-3carboxylic acid were dissolved in 50 ml of acetone and, while cooling in ice, a solution of 1.16 g (5.98 mmol) of diphenyldiazomethane in 50 ml of acetone was added dropwise. The solution was then stirred at room temperature for 26 hours, the solvent was evaporated off in a rotary evaporator, and the residue was purified by flash chromatography on 150 g of silica gel (mobile phase toluene/ethanol 98:2).
Yield: 2.55 g (88 %) of oily product [a]£° -33.8° (c - 1, methanol).
Example 11: Octadecyl 2-ΓΝ-(IS)-ethoxvcarbonvl-3-phenylpropyl!-L-alanvll-(1S.3S.5S)-2-azabicvclo[3.3.Q]octane-3-carboxvlate 2.08 g (5.00 mmol) of 2-[N- [ (IS) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl]-(1S.3S.5S)-2-azabicyclo [3.3.0] octane-3 carboxylic acid were dissolved in 25 ml of absolute dimethylformamide, 1.00 g (10.0 mmol) of potassium bicarbonate was added, and the mixture was stirred at 40°C for 90 minutes. After cooling to room temperature, a solution of 4.00 g (12.0 mmol) of 1-bromooctadecane in 20 mil of absolute dimethylf ormamide was added dropwise, and the mixture was stirred at 40°C for 4 hours. The solvent was removed in a rotary evaporator at about 1 torr, and the residue was partitioned between water and methylene chloride. The organic phase was separated off, dried over MgSO4 and concentrated. 3.05 g (92 %) of the product were isolated from the crude product (5.40 g) after column chromatography on 200 g of silica gel (mobile phase toluene/ethanol 99:1). [a]p° = -19.6° (c = l, methanol) Example 12: Benzyl 2- [N- [ (IS)-benzvhvdroloxvcarbonvl-3-phenylpropyl1L-alanvl] - (1S.3S.5S) -2-azabicyclo[3.3.0]octane-3-carboxylate a) Benzhvdrvl (2R)-hydroxy-4-phenvlbutvrate A solution of 10.1 g (52.1 mmol) of diphenyldiazomethane in 400 ml of absolute acetone was added dropwise over 20 minutes to a solution of 7.40 g (41.1 mmol) of (2R) -hydroxy-4-phenylbutyric acid in 200 mil of absolute acetone while cooling in ice, and the reaction mixture was etirred at room temperature for 20 hours. The solvent was evaporated off, and the residue was tirturated with 100 ml of petroleum ether. 6.4 g of crystalline product were obtained. The mother liquor was concentrated, and a further 6.0 g of the product were isolated by column chromatography on 700 g of eilica gel (mobile phase toluene/ethanol 99:1).
Total yield: 12.4 g (87 %).
Melting point 88 - 89°C. [α]’° e -1-8° (c « 5, methanol). b) Benzyl 2-ΓΝ-[(IS)-benzhvdrvloxvcarbonvl-3-phenvlpropyll-L-alanvll-(1S.3S.5S)-2-azabicvclo(3.3.0] octane-3-carboxylate bj 1.80 g (4.33 mmol) of benzyl 2-(N-tert, bu toxyca rbony 1 -L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate were dissolved in 4.5 ml of trifluoroacetic acid, and the reaction solution was stirred at room temperature for 90 minutes. It was then concentrated and, to remove trifluoroacetic esters, toluene was evaporated off three times in a rotary evaporator. The residue, which comprised 1.90 g of benzyl 2-(Lalanyl] - (1S,3S,5S) -2-azabicyclo[3.3.0] octane-3carboxylate trifluoroacetate, was dissolved in 10 ml of absolute methylene chloride (solution A). b2) 1.63 g (4.71 mmol) of benzhydryl (2R) -hydroxy-4phenylbutyrate from Example 12 a) were dissolved together with 0.4 ml of absolute pyridine in 25 ml of absolute methylene chloride and, at -10’C, 1.41 g (5.00 mmol) of trifluoromethanesulfonic anhydride were added dropwise within 20 minutes. The cooling bath was then removed and, after room temperature had been reached, the solvent was evaporated off. The residue was filtered through 50 g of silica gel using methylene chloride, and the filtrate was concentrated. 1.70 g of benzhydryl 4-phenyl-(2R)-trifluoromethylsulfonyloxy butyrate were obtained and were dissolved in 10 ml of absolute methylene chloride (solution B). b3) 1.0 ml (7.40 nmol) of triethylamine was added to solution A and then, at 0®C, solution B was slowly added dropwise. The cooling bath was removed and the reaction solution was stirred at room temperature for 19 hours, then washed three times with water, dried over MgSO4 and concentrated. The residue was purified by chromatography on 80 g of silica gel (mobile phase cyclohexane/ ethyl acetate 8:2 and 7:3), and 0.95 g (30%) of the desired product was obtained.
Melting point 81-85°C. [o]n° -55.2® (c 1, methanol) By suitable combinations of the methods described in the foregoing examples, the following additional compounds are prepared (the designation of the ring systems corresponds to that for the compounds of the formulae I and II): R OOC - CN - N - C I Λ I β II CH^ Example r3ooc-ch-nR4 R5 R2 R’ 13 Ring system λ -C,HS -CH(CH,), 14 Ring system B -CjH, -CH,-CH(CH,)a 15 Ring system C -CH, -ra2"© 16 Ring system C -C,H, -CH(C(H,), 17 Ring system D -C,HS Ό 18 Ring system D -C,HS Ό 19 Ring system D -C,HS 20 Ring system D -C,H, ·©© 21 Ring system D -C,HS w 22 Ring system D -C,H, -(ra2 ),.<§> 23 Ring system B -C,H, -{CH,),-CH, 24 Ring system F -CH, -CH(C,H5), 25 Ring system G -C,H, -CH(CH,), R^OOC « CN i4 N - J -(fH - NH R5 0 CH3 CE - CH2 COOR2 CE Example R5OOC-fH-NR4 R5 R2 R1 26 Ring system 0 -C,8, -ch(c,h,)2 27 Ring system G -C,8, -(CH2)2-@ 28 Ring system H C,H, -CHiCH,), 29 Ring system H C,H, -CH,-CHiCH,), 30 Ring system H C,H5 -{CH,)5-CH, 31 Ring system H C,H, Ό 32 Ring system H C,H, -©CH, 33 Ring system H CaH, ·©© 34 Ring system H C,H, w 35 Ring system H H -CH2-© 36 Ring system H C,H, -CH(C,H,)2 37 Ring system H C,H, -8-@ 38 Ring system I CH, 39 Ring system J CaH, -CH(C,H5)j 40 Ring system K CaH, -(CH,)4-CH, * * * Σν OOC - ρ - Ν - C -^Η - ΗΗ - CH - CH2 - CH2 R4 t5 0 CHj COOR2 ΒΧΒΒφΙβ R3OOC-fH-KR4 R5 Rs RJ 41 Ring system L C,HS -C(CHj), 42 Ring system M C,HS - (CHa) 3-CH (CHj) j 44 Ring system N CsH5 -CH(CH2)2 45 Ring system 0 c,h5 -(CH2)2-@ 46 Ring system P c,h5 -o 48 Ring system λ CH2CH(CHj)2 -ch2-© 49 Ring system B CH(CHj) j -C(CHj)j 50 Ring system C CH(C«H5)2 -H 51 Ring system D CH,- -ra2-© 52 Ring system D CHj-CHtCHj), -ra2-®> 53 Ring system D CH2-CH(CH,) 2 -H 54 Ring system D CH2-CH(CHj)2 -CH(C,H5)2 55 Ring system D CH(C,Hs)2 -C(CHj), 56 Ring system D CH(C,Hs)2 -H * * ♦ 1T00C - CN - N - C -CH - HH - CH - CH, - CH, 14, 15 II T 1 2 2 2 R4 R3 0 CHj COOR2 Example R3OOC-fH-RR4 R5 R2 R1 57 Ring system B -(CH3)5-CHj 59 Ring system G -CHiCeH,), -ch2-@ 60 Ring system β -CH(C,Hs)a -C(CHj)j 61 Ring system H -CHjCHtCHj), -CE2-© 62 Ring eye tern H -CHaCH(CH,)a -H 63 Ring system H -CHjCHiCH,), -CH(C,H5)j 64 Ring system H -ch2-@ -ra2-© 65 Ring system H - -C(CHj)j 66 Ring system H -CH(C,H5)j -ch2-© 67 Ring system H -CH(C,H,)a -H 68 Ring system H -CH(C,H5), -C(CHj)j 69 Ring system H -CH(CjH5)2 -CH(C,Hs)a 70 Ring system X -o -CM5> 71 Ring system J -(CHJs-CH, -CH(C,H,)a , * * * R-’OOC - yN - Κ - C -^Η - KH - CB - CS2 - CH2 R4 fc5 0 CHj COOR2 Example R300C-CH-Kb 1 ζ R4 R5 Ra R* 72 Ring system R -o -ra2-@ 73 Ring system L -cb2-® -(CH3)s-CH3 74 Ring system M -(CHa)a-CH- (CH,)S -CH(C,Hs)a 75 Ring system N -CH(C,H,)a -C(CHj) ,-CHjCH, 76 Ring system 0 -CH(CH3)3 -CH(C,H,)3 77 Ring system P -CH(CH3)a -C(CHj)j 78 Ring system Q -C(CHj)j -=H2- 78a Ring system D C2H5 menthyl 7 8b Ring system G menthyl CHaC,H5 83 COOR3 -CH(C,H5)j -NH-CH-(CH2)2-@ 85 r’OOC-CHj-N- -ch2-@ -NH-CH- (CHa)a 1 1 COO-GH (C3HS) 2 Y>HH n-40 ch2-coor3 - Ih - CH2 - CH2 COOR2 Bxample Y2 R2 R2 87 CH, -c,h5 -CH(C,HS), 89 CH, -CH,-CH(CH,), -ch2-@ Example R2 R2 90 -CH(C,H5), -C(CH,), 91 -ακσ,Η,), -CH(C,HS), Example 92 4- [N- (IS) -Carboethoxy-3-phenylpropyl) -S-bezizyl] exospiro(bicyclo[2.2.2]octane-2,3-pyrrolidine)- 5 carboxylic acid a) N- (IS-Carbethoxy-3-phenylpropyl)-S-laurvlbenzvl ester 3.4 g (10 mmol) of ethyl 2-(D)-trifluoromethylsulfonyloxy-4-phenylbutyrate and 5.9 g (15 mmol) of the benzyl ester of L-leucine tosylate were mixed in 50 ml of abs. CH2C1, and, after addition of 4.2 ml of triethylamine, the mixture was stirred at room temperature for 6.5 hours. After concentration of the solution, the product was isolated by column chromatography (silica gel, cyclohexane/ethyl acetate 9:1). 3.2 g of colorless oil were obtained. JH-NMR 6 = 0.95 (d, CHj), 1.2 (t, CH3) 1.8 (m, CHa) 2.6 (m, CHa) 3.3 (m, CH) 4.1 (q, CHj) 5.1 (s, CH,) 7.3 (s, CH) ppm. b) N-(l-S-Carboethoxv-3-phenylpropyl)-S-leucine 3.1 g of the benzyl ester obtained in a) were cleaved by hydrogenolysis with 500 mg of Pt/C (10%) in 200 ml of ethanol. After removal of the catalyst by filtration and concentration of the solution, 2.3 g of colorless crystals of the carboxylic acid of melting point 120-121°C were obtained.
XH-NMR δ = 0.9 (d, CH3) , 1.25 (t, CH3) , 1.8-2.1 (m, CHj) , 2.7 (m, CHj), 3.3 (q, CH) , 4.25 (q, CHa) , 7.2 (s, CH) ppm. c) 4- [N- (IS) -Carbethoxy-3-phenylpropyl) -S-leucvl] -exospirobicyclo[2.2.2] octane- 2,3-pyrrolidine- 5 carboxylic acid g (6.2 mmol) of N- (1-S-carboethoxy-3phenylpropyl)-S-leucine and 1.9 g (3.9 mmol) of benzyl exo-spiro(bicyclo[2.2.2]-octane-2,3 pyrrolidine)-5-carboxylate were stirred in 100 ml of dimethylformamide with 4.3 ml of triethylamine and 6.5 ml of n-propylphosphonic anhydride at room temperature overnight. The reaction solution was taken up in ethyl acetate and shaken twice with aqueous NaHCO3 solution and once each with 10 % aqueous citric acid, saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution. The organic phase was then separated off, dried and concentrated. The crude product, with a yield of 2.8 g, was separated into the two diastereomers by column chromatography (eilica gel, toluene/ethyl acetate 95:5) . 1 g of pure product was obtained for each benzyl ester. 1 g of the first diastereomer was hydrogenated with Pd/C in 40 ml of ethanol. 780 mg of crystalline carboxylic acid of melting point 131132°C were obtained.
Rotation [α]™ = -2.8° (c = 1, methanol) 860 mg of the second diastereomer were hydrogenated with Pd/C in 35 ml of ethanol and, after removal of the catalyst by filtration and concentration of the solution, the yield was 720 mg.
Melting point: the substance sinters above 65°C Rotation [a]£° = -22.2° (c = 1, methanol) Example 93 4-[N-(IS)-Carboxyl-3-phenylpropyl)-S-leucyl]-exo10 spiro (bicyclo [2.2.2] octane-2,3-pyrrolidine) -5-carboxylic acid 102 mg (0.2 mmol) of the carboxylic acid from Example 92c) were stirred in agueous 4N KOH solution until all the substances had dissolved. The solution was applied to an ion exchanger ( Amberlite R 120) and eluted with a 2% strength solution of pyridine in water. The yield was 70 mg.
Rotation [a]£° = +3.9° (c = 1, methanol) The following compounds of the formula II are prepared in analogous manner (the designations of the ring systems correspond to those for the compounds of the formulae I and II): HOOC - CH - Ν - C I. I, ll R4 R5 0 CH - NH - CH - CHa R1 COOCjHj R1 HOOC - CH - NH R4 R5 CB(CH5)2 a CK(CH5)CH2CH5 a ch2c6h5 a CE2-C6Hn (CE2-Cyclohexyl) C CE2-Cgc^ OCEj G CE2~CgS4 oc2E5 c ce2-c6e4-oc3e7 c ce2-c6b4-oc4h9 a (ce2)4-.ne2 d (ch2)5-hh2 a CH2-CK2- 5 CHj a HOOC - CH - Ν - C CH - NH - CH - CH2 R* R5 0 R1 COOCjH5 R1 HOOC - CH - NH R* R5 CH(CEj)2 b CH(CHj)CE2CEj b CE2CgBj B CH2-C6En D CE2~CgE^-OCEj E CE2—CgE^~0C2H j G CE2~C6H^-On-CjH7 G CE2"CgE£-On-C^Eg C (CH2)^—NH2 C (CE2)j-EE2 g CE2-CE2-S-CKj d * HOOC - CH - Ν - C CH - NH - CH - CH, R4 R5 0 Rx COOCjHj R1 HOOC - CH - NH R4 R5 CH(CEj)2 c CE(CE3)CE2CH3 c CE2CgE3 C CE2"CgE^Έ CB2-C6E4-OCH5 I ce2-c6e4- oc2e5 h CS2-C6E4-On-C3E7 H CH2-C6E4'0n-C4H9 G (ce2)4-ne2 g (ce2)3-ke2 e ce2-ce2-s-ce5 h * HOOC - CH - Ν - C -CH· 1. 1. " 1. R4 R5 0 R1 NH - CH - CH2 - CH2 I COOCjH5 5 R1 HOOC - CH - NH A· ch(ce5)2 CH(CH3)CE2CE3 CE2CgH3CH2"C6E11 ch2-c6e4-oce3 ce2-c6e4-oc2e5 CE2-€gE4-0n-c3E7 CH2-CgE4«- 0n-C4Hg (ce2)4-ke2 (ce2)3-ne2 CE2-CH^ S-CH3 Γ D D P E I I E E 0 I * HOOC -CH-N-C - CH- L 1. ι 1, R‘ Rs 0 R1 NH - CH - CHj - CHj I COOC,HS 5 Rl HOOC - CH - NH A- A. ch(ck5)2 CE(CH3)CE2CH3 ch2c6h5 ce2~c6e1 1 CE2-C6E4-0CE3 ce2-c6e4-oc2h5 CH2-C6E4-Οη-Ο^Ηγ CH^ On-C^Eg (ch2)4-kr2 (CE2)j-HE2 S-CEj G Σ Ε G 0 N N I N P ? HOOC - CH - N - C I. I, I R* R5 O CH - NH - CH - CHj R1 R1 COOCjHs HOOC - CH - NH R4 R5 ce(ch3)2 CH(CE5)CE2CE5 CE2C6B5CK2C6H11 CE2~c6E4- oce3 CE2-C6E4-0C2E5 CE2—CgE^-Οη-Ο^Εγ CE2-C6E4-On-C4E9 ( ce2 ) 4~ ne2 (<*^2) 3~ CE2*CE2-S CEj H y I H ? N Q Q Q HOOC -CH-N-C - CH · ι ι II ι • NH - CH - CH2 - CHj I 1. 1, ll I, R* R5 0 R1 1 COOCjH5 5 Rl HOOC - CH - NH l4 l5 R* R5 CH(CHj)2 CE(CHj)CE2CHj CH5C2- 1 CE2-C6E4-0CHj CE2~C6H4'0C2H5 CH2CgE4-On-C^Εγ CE2-C6E4-On-C4E9 (ck2)4- nh2 CE2-CH2-S-CEj I G N I Q J P 0 ? N - 47 HOOC - CH - Ν - C CH - NH - CH - CHj R4 R5 0 Rl COOCjH5 R1 HOOC - CH - NH R4 R5 CK(CHj)2 0 CH(CHj)CH2CBj h CH2C6E5 0 CH-rCgE,, I CH2-C£B4-0C2Ej q CH2~On-CjH^ Q CH2-On-C^H^ ? CB^CH2-S-CBj g * HOOC - CH - Ν - C CH - NH - CH - CHa R4 R5 0 R1 COOCjH5 R1 HOOC - CH - NH R4 Rs ch(ch3)2 ? ch2- c6H5 ρ Clbj-CgH^ M CH2-CgE4-OCH3 p CE2—CgH4«0C2E5 P CH2~CgE4-On—C^Ey P CE2-C6E4-0n-C4Eg Q * HOOC - CH - N - C CH - NH CH - CHa - CHj R4 R5 0 R1 COOCjHj R1 HOOC - CH - NH R4 R5 CH(CHj)2 » CH(CHj)CH2CHj ? CH2"C6E5 Q CE2-C6B4' 0n-C4Hg I cb(ce.)ch2cHj o CE(CE,)CE,CEj I ck2-c6e,, 0 CE^CgE,, Q Example 94: 1- [N- (IS) -Carboethoxybutyl) -S-alanyl] -octahydrocyclo10 penta[b]pyrrole)-2-carboxylic acid a) Ethyl DL-2-trifluoromethylsulfonvloxypentanoate g (34 mmol) of ethyl 2-hydroxyvalerate and 2.85 g (35.9 mmol) of absolute pyridine were dissolved in 100 ml of absolute CH2C12 under protective gas, the solution was cooled to 0°C and 9.66 g (34 mmol) of trifluoromethanesulfonic anhydride were added. The mixture was warmed to room temperature and stirred for 6 hours. The solution was concentrated and the resulting crude product was purified by column chromatography (silica gel, petroleum ether/CHjCl, 6:1). The yield was 9.3 g of a colorless, slightly viscous liguid.
IR: 2880 - 3000 1770, 1420, 1200 - 1220 1150, 620 cm*1 b) Benzyl ester of N-(1-S-carboethoxybutyl)-S-alanine 4.9 g (17.5 mmol) of the trif luoromethanesulfonic ester thus obtained were dissolved, under nitrogen, in 70 ml of absolute CH2C13 with 4.08 g of the benzyl ester of L-alanine hydrochloride (19 mmol) with the addition of 5.4 ml of triethylamine, and the solution was stirred at room temperature for 3 hours. It was then concentrated, the crude product was taken up in ethyl acetate, and the solution was washed three times with water, dried and concentrated. The diastereomers were separated by column chromatography (silica gel, cyclohexane/ethyl acetate (5:1). The yield of each isomer was 500 mg.
The diastereomer isolated in the first filtration had the S,S configuration. lH NMR 6« 0.9 (t.CHj), 1.3 (t,CH3), 1.35 (d.CBj), 1.4 (m,CE2), 1.6 (b,CB2), 1.9 (b,EK), 3.3 (t.CH), 3.4 (q.CE), 4.2 (b,CH2), 5.15 (q,CE2 ?h), 7.4 (s, CB aroaat.) PPffl. c) N-(1-S-Carboethoxybutvl)-S-alanine 600 mg (1.95 mmol) of benzyl eeter (diastereomer A) were hydrogenated with Pd on charcoal in 34 ml of ethanol. The catalyst was then filtered off, and the solution was concentrated in vacuo. The product was then obtained as a white solid with a melting point of 137° and a yield of 430 mg. d) 430 mg (1.98 mmol) of N-(1-S-carboethoxybutyl)-Salanine and 486 mg (1.98 mmol) of benzyl L(-)-octahydrocyclopenta [b] pyrrole- 2 -carboxylate were dissolved, under nitrogen, in 20 ml of dimethylformamide, the solution was cooled to -10°C, and 1.5 ml of triethylamine and 2 ml of n-propylphosphonic anhydride were added. The solution was stirred at -10°C for 1 hour and then at room temperature overnight. It was then taken up in 200 ml of ethyl acetate and washed with saturated aqueous NaHCO3 solution 10% agueous citric acid and saturated agueou NaCl solution. After the solution had been dried and concentrated, the diastereomeric compounds were separated by column chromatography (silica gel, cyclohexane/ethyl acetate 9:1). The yield was 360 mg. Both diastereomers were hydrogenated with Pd/C in ethanol as described in Example 94 c) and, after concentration of the solution, they were obtained as white solids.
Example 95: 1- [N- (IS) -Carboxybutyl) -S-alanyl] - (octahydrocyclopenta[b]pyrrole)-2-carboxylic acid mg (0.17 mmol) of carboxylic acid (Example 94 d) were stirred into 2 ml of 4 N agueous KOH solution until the substance had completely dissolved. The solution was then applied to a strongly acid ion exchanger and eluted with a 2% strength solution of pyridine in water. The yield after concentration of the solution was 39 mg.
In analogy to the compounds prepared in Examples 94 and 95, it is possible to synthesize the following additional compounds of the formula II H R^OOC -CH-N-C-CH-N-CH (CH2) -R ι λ ι β ι 1 4 I 9 R4 R5 0 R1 COOR2 which, withnn = 2, R1 is CH3, Ra is C3H5, R3 is H, and R and the part of the molecule R OOC-CH-N · A R4 R3 are substituted as indicated in the table detailed below.
HOOC-CH-HH R4 R5 CHj -CE2CE2CHj -(CH2)g-CHj 2-Haphthyl 4-Biphenylyl -(CS^ j-CEj A A C D A A R HOOC-CH-HH R4 R5 CHj B -CE2CE2CHj B — (CE2)g —CHj D 2-Naphthyl y 4-Biphenylyl c — (CE2)|j-CEj B R HOOC-CH-HH R4 R5 CHj C -CE2CH2CHj C • -(CE2)9-CEj G 2-Naphthyl G 4-Biphenylyl D -(CE^j-CHj C r HOOC-CH-NH R4 R5 CHj D -CH2CH2CEj D —(CH2)g-CHj E 2-Naphthyl E 4-Biphenylyl H -(CE2)1 j-Cxij D R hooc-ch-bb R4 R5 CHj G -CE2CE2CHj G — (CE2)g—CEj K 2-Naphthyl I 4-Biphenylyl I -(CH2)1j-CEj G R HOOC-CH-NH R4 P? CHj • H -ce?ce2ce, E -(CE?)p-CS, N 2-Naphthyl M 4-Biphenylyl N — (CE2)j—CEj N HOOC-CH-NH Β4 R5 CHj N —CH^CE^CRj N " (CH2) g—Ciij 0 2-Naphthyl N 4-Biphenylyl P -(CB2)13-CB3 0 R HOOC-CH-NH R4 R5 CHj Q —CE2CH2CHj Q -(CH^-CHj P 4-Biphenylyl Q — (CH2) j—CHj P R HOOC-CE-KH R4 R5 CHj p —CH~CH,CH, £ 2 5 p -(CH2)5-CHj Q 4-Biphenylyl C- -(CH2),j-CHj Q 4-Biphenylyl H
Claims (3)
1. The use of ACE inhibitors of the formula (II) or their physiologically tolerated salt for the preparation of a medicament having a nootropic action, where in formula (II) * ♦ * R J OOC - CH - N - C - CH - NH - CH - (CrL) n -R (11) ι ι II ' ) R 4 R 3 O R' COOR 3 n is 1 or 2; R denotes hydrogen, an aliphatic radical having 1-21 carbon atoms, an aromatic radical having 6-12 carbon atoms, R 1 denotes hydrogen, an aliphatic radical having 1-21 carbon atoms, or if not already covered by the above definitions, the side-chain, protected where necessary, of a naturally occurring α-amino acid, R 3 and R 3 are identical or different and denote hydrogen, an aliphatic radical having 1-21 carbon atoms, an alicyclic radical having 3-20 carbon atoms, an aromatic radical having 6-12 carbon atoms, an araliphatic radical having 7-32 carbon atoms, and R 4 and R 5 form, together with the atoms carrying them, a mono-, bi- or tricyclic ring system from the series comprising pyrrolidine, tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, indoline, octahydrocyclopenta[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 [4.3.0.1 6,9 ] decane, decahydrocyclohepta[b]pyrrole, octahydroisoindole, octahydrocyclopenta [c]pyrrole, 2,3,3a,4,5,6a-hexahydro56 indole, 1,2,3,3a,4,5a-hexahydrocyclopenta [b]pyrrole and 2-azabicyclo[3.1.0]hexane.
2. The use as claimed in claim 1, wherein use is made of (S,S,S,S,S)-1-[N-(1-carbethoxy-3-phenylpropyl)alanyl]-octahydroindole-2-carboxylic acid, 1-[N-(1S-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, (S,S,S)-2-[N-(1carbethoxy-3-phenylpropyl)-alanyl]-tetrahydroisoquinoline-3 -carboxylic acid, (S,S,S,S,S)-2-[N-(1carbethoxy-3-phenylpropyl) -alanyl] -2-azabicyclo[3.3.0]octane-3-carboxylic acid, 2-N-(1-S-car-bethoxy-3-phenylpropyl) -S-alanyl] -cis,endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid or 1-[N-(l-Scarbethoxy-3 -phenylpropyl)-S-alanyl]-cis,endo-lH2,3,3a,4,5,7a-hexahydroindole-2-S- or -2-R-carboxylic acid.
3. The use as claimed in claim 1, wherein use is made of 1' - [N- (l-S-carbethoxy-3-phenylpropyl)-S-alanyl]exo/endo-spirobicyclo [2.2.2] octane-2,3' -pyrrolidines'-carboxylic acid, 1'[N-(l-S-carbethoxy-3-phenylpropyl) -S-alanyl]-(3'S,5'S)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, l'-[N(l-S-carbethoxy-3-pheny lpropyl) -S-alanyl] - (3'S,5'R) spirobicyclo [2.2.2]-octane-2,3'-pyrrolidine-5' carboxylic acid, 1'-[N-(l-S-carbethoxy-3-phenylpropyl) -S-alanyl]-(3'R,5'S)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, l'-[N(l-S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'R,5'R) spirobicyclo [2.2.2]octane-2,3'-pyrrolidine-5'carboxylic acid, 1*-[N-(l-R-carbethoxy-3-phenylpropyl)-S-alanyl] -(3' S,5'S)-spirobicyclo [2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, 1' - [N- (l-R-carbethoxy-3-phenylpropyl)-S-alanyl](3'S,5'R)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5' -carboxylic acid, 1'-[N-(l-R-carbethoxy-357 phenylpropyl)-S-alanyl]-(3 ' R, 5' S)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, 1' - [N- (l-R-carbethoxy-3-phenylpropyl) -S-alanyl] (3'R,5'R)- epirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5' -carboxylic acid, 1'-[N-(1-S-carbethoxy3-phenylpropyl)-R-alanyl]-(3'S,5'S)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, 1' - [N- (l-S-carbethoxy-3-phenylpropyl) -R-alanyl] (3'R,5'S)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine- 5' -carboxylic acid, 1'-[N-(1-S-carbethoxy-3phenylpropyl)-R-alanyl]-(3'S,5'R)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, 1' - [N- (l-S-carbethoxy-3-phenylpropyl) -R-alanyl] (3'R,5'R)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine- 5' -carboxylic acid, 1'-[N-(l-R-carbethoxy-3phenylpropyl)-R-alanyl]-(3'S,5'S)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, 1' - [N- (l-R-carbethoxy-3-phenylpropyl)-R-alanyl](3'R,5'S)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5' -carboxylic acid, 1'-[N-(l-R-carbethoxy-3phenylpropyl) -R-alanyl] - (3'S, 5'R) -spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid or 1' - [N- (l-R-carbethoxy-3-phenylpropyl)-R-alanyl](3'R,5'R)-spirobicyclo[2.2.2]octane-2,3'-pyrrolidine- 5' -carboxylic acid.
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| DE19863610391 DE3610391A1 (en) | 1986-03-27 | 1986-03-27 | COMPOUNDS WITH NOOTROPPER ACTION, THESE CONTAINERS AND THEIR USE IN THE TREATMENT AND PROPHYLAXIS OF COGNITIVE DYSFUNCTIONS |
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| JP (1) | JPS62240698A (en) |
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| AT (1) | ATE102954T1 (en) |
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| HU (2) | HU203117B (en) |
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| NZ (1) | NZ219764A (en) |
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| US5231084A (en) * | 1986-03-27 | 1993-07-27 | Hoechst Aktiengesellschaft | Compounds having a cognition adjuvant action, agents containing them, and the use thereof for the treatment and prophylaxis of cognitive dysfuncitons |
| US4743450A (en) * | 1987-02-24 | 1988-05-10 | Warner-Lambert Company | Stabilized compositions |
| CA1321753C (en) * | 1987-04-27 | 1993-08-31 | Abraham Sudilovsky | Method for inhibiting loss of cognitive functions employing an ace inhibitor |
| DE3731085A1 (en) * | 1987-09-16 | 1989-04-06 | Hoechst Ag | NEW AMINO ACID ESTERS, METHOD FOR THE PRODUCTION THEREOF, MEDICINAL PRODUCTS CONTAINING THEM AND THE USE THEREOF |
| DE3739690A1 (en) * | 1987-11-24 | 1989-06-08 | Hoechst Ag | STABILIZED MEDICINAL PRODUCTS, METHOD FOR THEIR PRODUCTION AND STABLE MEDICAL PREPARATIONS |
| DE3801587A1 (en) * | 1988-01-21 | 1989-08-03 | Hoechst Ag | NEW AMINO ACID GLYCERIDES, METHOD FOR THE PRODUCTION THEREOF, MEDICINAL PRODUCTS CONTAINING THEM AND THE USE THEREOF |
| EP0331609A3 (en) * | 1988-01-27 | 1992-07-01 | Hoechst Aktiengesellschaft | Angiotensin converting enzyme inhibitors having psychotropic effects |
| DE3803225A1 (en) * | 1988-02-04 | 1989-08-17 | Hoechst Ag | AMINO ACID AMIDE WITH PSYCHOTROPIC EFFECT, METHOD FOR THE PRODUCTION THEREOF, AGENTS CONTAINING THE SAME AND THEIR USE |
| JPH01275529A (en) * | 1988-03-21 | 1989-11-06 | E R Squibb & Sons Inc | Suppressing treatment agent of delayed motion effect |
| US5037821A (en) * | 1988-06-01 | 1991-08-06 | E. R. Squibb & Sons, Inc. | Method for inhibiting loss of cognitive functions employing a calcium channel blocker alone or in combination with an ACE inhibitor |
| US5093129A (en) * | 1989-01-30 | 1992-03-03 | E. R. Squibb & Sons, Inc. | Method for treating addiction to a drug of abuse employing an ace inhibitor |
| US5032578A (en) * | 1990-09-17 | 1991-07-16 | E. R. Squibb & Sons, Inc. | Method for preventing or treating depression employing a combination of an ace inhibitor and a drug that acts at serotonin receptors |
| WO2002074293A2 (en) * | 2001-03-15 | 2002-09-26 | Saegis Pharmaceuticals Inc | Methods for restoring cognitive function following systemic stress |
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| DE19575012I2 (en) * | 1980-10-23 | 2002-01-24 | Schering Corp | Carboxyalkyl dipeptides Process for their preparation and medicaments containing them |
| DE3300774A1 (en) * | 1983-01-12 | 1984-07-12 | Hoechst Ag, 6230 Frankfurt | NEW SPIROCYCLIC AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE USE THEREOF AND NEW SPIROCYCLIC AMINO ACIDS AS INTERMEDIATE PRODUCTS AND METHOD FOR THE PRODUCTION THEREOF |
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