IE60767B1 - Use of angiotensin converting enzyme inhibitors for the treatment of atherosclerosis, thrombosis and peripheral vessel disease - Google Patents

Use of angiotensin converting enzyme inhibitors for the treatment of atherosclerosis, thrombosis and peripheral vessel disease

Info

Publication number
IE60767B1
IE60767B1 IE271186A IE271186A IE60767B1 IE 60767 B1 IE60767 B1 IE 60767B1 IE 271186 A IE271186 A IE 271186A IE 271186 A IE271186 A IE 271186A IE 60767 B1 IE60767 B1 IE 60767B1
Authority
IE
Ireland
Prior art keywords
carboethoxy
carboxylic acid
alkyl
phenylpropyl
alanyl
Prior art date
Application number
IE271186A
Other versions
IE862711L (en
Original Assignee
Hoechst Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoechst Ag filed Critical Hoechst Ag
Publication of IE862711L publication Critical patent/IE862711L/en
Publication of IE60767B1 publication Critical patent/IE60767B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/14—Angiotensins: Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The preferred angiotensin converting enzyme inhibitors have the formula I <IMAGE> in which n is 1 or 2, R, R<1>, R<2> and R<3> are identical or different and each is hydrogen or an organic radical, and R<4> and R<5> form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system. Agents containing these compounds for treating the specified diseases are also described.

Description

The invention relates to a method for the treatment of atherosclerosis, of thrombosis and/or of peripheral vessel disease by oral or parenteral administration of compounds which inhibit angiotensin converting enzyme. Particularly suitable for this purpose are compound of the formula I (I) in which n is 1 or 2, R denotes aryl which has 6-12 carbon atoms and can be mono-, di- or trisubs ti tuted by (Cx-C4) -alkyl, (C1-C4) -alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (Cx-C4)-alkylamino, di-(Cx-C4)-alkylamino, (Cx-C4) -alkanoylamino, methyienedioxy, carboxyl, cyano and/or sulfamoyl, R1 denotes hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-'6 carbon atoms, alkynyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, cycloalkenyl having 5-9 carbon atoms, (Cj-C,)-cycloalkyl- (Cx-C4) -alkyl, (C5-C,) -cycloalkenyl- (Cx-C4) alkyl, optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted ae described above for R, (C4-Cia) -aryl- (Cx-C4) -alkyl or (C7-C„)-aroyl-(Cx or Ca)-alkyl, both of which car. be substituted as the abovementioned aryl, mono- or bicyclic, optionally partially hydrogenated heteroaryl which has 5-7 or 8-10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, or the optionally protected side chain of a naturally- occurring a-amino acid R^CH (NHa)-COOH, R3 and R3 are identical or different and denote hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, di-(Cx-C4)-alkylamino2 (C1-C4) -alkyl, (C1-Cs) -alkanoyloxy- (C1-C4) -alkyl, (Cj-Cj) -alkoxycarbonyloxy- (C1-C4) -alkyl, (C,-C13) aroyloxy- (Cl-C4) -alkyl , (C6-Cn) -aryloxycarbonyloxy(C1-C4)-alkyl, aryl having 6-12 carbon atoms, (Cj-Cjj) - aryl-(Cx-C4)-alkyl, (C3-C,)-cycioalkyl or (Cj-C,) -cycioalkyl- (Cx-C4) -alkyl, and in which R* and R5 together with the atoms carrying them represent a system from the series comprising tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 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, li,s] decane, decahydrocyclopenta [b] pyrrole, octahydroisoindole, octahydrocyclopenta [c] pyrrole, 2,3,3a,4,5,7a-hexahydroindole and 2-azabicyclo[3.1.0]hexane.
In the case of compounds which have several chiral atoms, all possible diastereomers are suitable, as racemates or enantiomers or mixtures of various diastereomers.
The cyclic amino acid esters which are suitable have the following structural formulae.
COOR COOR It is particularly preferred to use compounds of the formula I in which n is 2, R denotes phenyl, R1 denotes methyl, RJ and R3 denote identical or different (C1-Cg)-alkyl radicals or (C,-Cl0) -aralkyl radicals such as benzyl or nitrobenzyl, and R4 and R5 together represent -a radical of the formula in which m denotes 0 or 1, p denotes 0, 1 or 2, and X denotes -CHa-, -CHj-CHj- or -CH=CH-, it also being possible for a 6-ring formed with X to be a benzene ring.
In this context and in the following, aryl is to be understood preferably to be substituted phenyl, biphenylyl or naphthyl. A corresponding statement applies to radicals derived from aryl, such as aryloxy and arylthio. Aroyl is particularly understood to be benzoyl. Aliphatic radicals can be straight-chain or branched.
A mono- or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, is to be understood to be, for example, thienyl, benzo[b]thienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxyzolyl, isoxazolyl, thiazolyl or isothiazolyl. These radicals can also be partially or completely hydrogenated.
Naturally occurring a-amino acids are described in, for example, Houben-Weyl, Methoden der Organisehen Cbemie (Methods of Organic Chemistry), Vols. XV/1 and XV/2.
Where R1 represents a side chain of a protected naturally occurring a-amino acid such as, for example, protected Ser, Thr, Asp, Asn, Glu, Gin, -Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp, His or Hyp, the preferred protective groups are the groups customary in peptide chemistry (cf. Houben-Weyl, Vols. XV/1 and XV/2) . In the case where R1 denotes the protected side chain of lysine, the known amino protective groups, but in particular Z, Boc or (Cj-Cj)-alkanoyl, are preferred. Suitable and preferred as O-protective groups for tyrosine are (C1-C<)-alkyl, in particular methyl or ethyl.
ACE inhibitors of the formula I can be prepared by reacting together their fragments in a suitable solvent, where appropriate in the presence of a base and/or of a coupling auxiliary, where appropriate reduction of unsaturated compounds which have resulted as intermediates, such as Schiff's bases, and elimination of protective groups which have been introduced temporarily to protect reactive groups and, where appropriate, conversion of the resulting compounds into their physiologically tolerated salts.
It is possible in the said manner to react compounds of the formula V with compounds of the formula VI R3OOC-Cir-N-H HOOC-CH-NH-CH-(CH^) -R 14 5 I I 2 nR R R1 COOR2 (V) (VI) The reaction of these compounds can, for example, [lacuna] in analogy to known peptide coupling processes in the presence of coupling auxiliaries such as carbodiimides (for example dicyclohexylcarbodiimide) , diphenylphospharyl azide, alkanephosphoric anhydrides, dialkylphosphinic anhydrides or Ν,Ν-succinylimidyl carbonates in 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 be activated (cf. Schroder, Lubke, The Peptides, Vol. 1, New York, 1965, pages 76-136) .
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 I R3OOC-CH-N-C-CH-Y1 Y2-CH-(CB2)n-R (VII) (VIII) in which either Y1 represents amino and Y2 represents a leaving group, or Y1 represents a leaving group and Y2 represents amino. Examples of suitable leaving groups are Cl, Br, I, alkylsulfonyloxy or arylsulfonyloxy.
Alkylations of this type are advantageously carried out in water or an organic solvent, in the presence of a base.
Furthermore, compounds of the formula IX can be condensed with compounds of the formula X (IX) COOR (X) in which either Q1 represents amino + hydrogen and Q2 represents oxo, or Q1 represents oxo and Q2 represents amino + hydrogen.
The condensation is advantageously carried out in water or an organic solvent such as a. lower alcohol, and in the presence of a reducing agent such as NaBH3CN, whereupon compounds of the formula I are obtained directly. However, it is also possible to reduce the Schiff's bases or enamines which result as intermediates, where appropriate after previous isolation, with the formation of compounds of the formula I, for example by hydrogenation in the presence of a transition metal catalyst.
Finally, reaction of compounds of the formula IX (Q1 = Ξ + NHa) with compounds of the formula XI, or their reaction with compounds of the formulae XII or XIII, also results in compounds of the formula I (n=2), r2ooc-ch«ch-co-r (XI) OCH—COOR2 R-CO-CH3 (XII) (XIII) there being reduction of Schiff's bases produced as intermediates, and conversion of a carbonyl group into methylene by reduction.
In the abovementloned formulae V-XIII, R-Rs and n are as defined in formula I. Protective groups introduced temporarily to protect reactive groups not involved in the reaction are «1 -ίτη-ϊ nated after reaction is complete in a manner known per se (cf. Schroder, Lxibke, loc. cit., pages 1-75 and 246-270).
It is possible and particularly advantageous to use the following compounds in the method according to the invention: N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-S-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid N-(l-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-S1.2.3.4- tetrahydroisoquinoline-3-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) - S-lysyl-S-l, 2,3,4tetrahydroisoquinoline-3-carboxylic acid N- (1-S-carboethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl-S1.2.3.4- tetrahydroisoquinoline-3 -carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-3S-decahydroisoquinoline-3-carboxylic acid N- (1-S-carboethoxy-3-phenylpropyl) -S-alanyl- (2S,3aS,7aS) octahydroindole-2-carboxylic acid N- (1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N- (1-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aS,7aS)octahydroindole-2-carboxylic acid N- (1 -S-carboethoxy-3-cyclohexylpropyl)-S-lysyl(2S,3aS,7aS)-octahydroindole-2-carboxylic acid Ν- (1-S-carboethoxy-3 - cyc1ohexyIpropy1) -S-lysyl (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -O-methyl-S-tyrosyl (2S,3aS,7aS)-octahydroindole-2 - carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl • (2S,3aS,7aS)-octahydroindole-2-carboxylic acid N- (l-S-carboethoxy-3 - (3,4-dimethylphenylpropyl) -S-alanyl i (2S, 3aS,7aS) -octahydroindole-2-carboxylic acid N- (l-S-carboethoxy-3- (4-fluorophenyl) -propyl] -S-alanyl 10 (2S,3aS,7aS)-octahydroindole-2-carboxylic acid N- (l-S-carboethoxy-3- (4-methoxyphenyl) -propyl] -S-alanyl (2S,3aS,7aS)-octahydroindole-2-carboxylic acid N- (l-S-carboethoxy-3- (3,4-dimethoxyphenyl) -propyl] -S alanyl- (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid N- (1 -S-carboethoxy-3-cyclopentylpropyl) -S-alanyl (2S,3aS,7aS)-octahydroindole-2-carboxylic acid N- (1-S-carboethoxy-3-pheny lpropyl) -S-alanyl- (2S,3aR,7aS) octahydroindole-2-carboxylic acid N-(1 - S-carboethoxy-3-cyclohexylpropyl)-S-alanyl 20 (2S, 3aR, la.S) -octahydroindole-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-lysyl- (2S,3aR,7aS) octahydroindole-2-carboxylic acid N- (1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyl (2S,3aR,7aS)-octahydroindole-2-carboxylic acid N- (1-S-carboethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl (2S,3aS,7aR) -octahydroindole-2-carboxylic acid N- (1-S-carboethoxy-3-phenylpropyl) -S-alanyl- (2S,3aR,7aR) octahydroindole-2-carboxylic acid N- (1-S-carboethoxy-3-phenylpropyl) - S-lysyl - (2S,3aR,7aS) 30 octahydroindole-2-carboxylic acid N- (l-S-carboethoxy-3-cyclohexylpropyl) -S-alanyl (2S,3aR,7aR)-octahydroindole-2-carboxylic acid N- (l-S-carboethoxy-3-cyclohexylpropyl) -O-ethyl-S-tyrosyl . (2S,3aR,7aR)-octahydroindole-2-carboxylic acid N- (1-S-carboethoxy-3-pheny lpropyl) -S-alanyl- (2S,3aR,7aR) . octahydroindole-2-carboxylic acid N- (1-S-carboethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl (2S,3aS,7aS)-octahydroindole-2-carboxylic acid N- (l-S-carboethoxy-3,4-dimethy lpheny lpropyl) -S-alanyl (2S,3aS,7aS)-octahydroindole-2-carboxylic acid N- [1-S-carboethoxy-3- (4-fluorophenyl) -propyl] -S-alanyl(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N- [l-S-carboethoxy-3-(4-methoxyphenyl)-propyl]-S-alanyl(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N- [l-S-carboethoxy-3-(3,4-dimethoxyphenyl)-propyl]-Salanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclopentylpropyl] -S-alanyl- ( (2S,3aS,7aS)-octahydroindole-2-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-cis-endo-2azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(l-S-carboethoxy-3-phenylpropyl)-S-lysyl-cis-endo-2azabicyclo[3.3.0]octane-3-S-carboxylic acid N- (l-S-carboethoxy-3-cyclohexylpropyl) -S-alanyl-cis-endo2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N- (1 - S - carboxy-3-cyclohexy lpropyl) -S-alanyl-cis-endo-2azabicyclo[3.3.0]octane-3-S-carboxylic acid N- (1-S-carboethoxybutyl)-S-alanyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N- (l-S-carboethoxy-3-(3,4-dimethoxyphenylpropyl) -Salanyl-cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid N- (l-S-carboethoxy-3-cyclopentylpropyl) -S-alanyl-cisendo-2-azabicyclo- [3.3.0]octane-3-S-carboxylic acid N-(l-S-earboethoxy-3-phenylpropyl)-0-methyl-S-tyrosylcis -endo- 2 -azabicyclo [3.3.0]octane-3-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl-cisendo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N- (l-S-carboethoxy-3- (4-fluorophenylpropyl) -S-alanyl-cisendo-azabicyclo [3.3.0] octane-3-S-carboxylic acid N- (l-S-carboethoxy-3- (4-methoxyphenylpropyl) -S-alanylcis-endo-2-azabicyclo [3.3.0]octane-3-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aR,6aS)octahydrocyclopenta[b]pyrrole-2-carboxylic acid * N- (1 - S-carboethoxy-3 - eye1ohexylpropy1) -lysyl(2S, 3aR, 6aS) -octahydrocyclopenta [b]pyrrole-2-carboxylic , acid N- (l-S-carboethoxy-3-phenylpropyl)-O-ethyl-S-tyrosyl(2S, 3aR, 6aS) -octahydrocyclopenta [b] pyrrole-2-carboxylic acid N- (1-S-carboethoxy-3-phenylpropy 1) -S-alanyl-2(2S,3aR, 6aS) -octahydrocyclopenta [b]pyrrole-2-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-2-azaspiro[4,5]decane-3-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -O-ethyl-2-tyrosylazaspiro- [4,5] decane-3-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-2-azaspiro[4,5]decane-3-S-carboxylic acid N- (l-S-carboethoxy-3-cyclohexylpropyl) -S-alanyl-2-azaspiro [4,5] decane-3-S-carboxylic acid N- (1-S-carboethoxy-3-cyclohexylpropyl) - S-lysyl-2-azaspiro[4,5]decane-3-S-carboxylic acid N- (1-S-carboethoxy-3-phenylpropyl) -S-alanyl-2-azaspiro[4,4]nonane-3-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl-2azaspiro [4,4]nonane-3-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-lysyl-2-azaspiro[4,4]nonane-3-S-carboxylic acid N- (1-S-carboethoxy-3-cyclohexylpropyl) -S-alanyl-2-azaspiro[4,4]nonane-3-S-carboxylic acid N-(l-S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-2azaspiro[4,4]nonane-3-S-carboxylic acid N- (l-S-carboethoxy-3-cyclopentylpropyl) -S-lysyl-2-azaspiro[4,4]nonane-3-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-spiro[bicyclo [2.2.1]heptane-2,3* -pyrrolidine] - 5' - S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl)-O-ethyl-S-tyrosylspiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine]-5'-Scarhoxylic acid U_ (i-s-carboethoxy-3-phenylpropyl) -S-lysyl-spiro- [bicyclo [2.2.1] heptane-2,3 * -pyrrolidine] -5' -S-carboxylic acid N- (l-S-carboethoxy-3-cyclohexylpropyl) -S-alanyl-spiro[bicyclo [2,2.1]heptane-2,3' -pyrrolidine] - 5' -S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-lysyl-spiro[bicyclo[2.2.1]heptane-2,3' -pyrrolidine] - 5' - S-carboxylic acid Ν- (1-S-carboethoxy-3-phenylpropyl) -S-alanyl-spiro[bicyclo [2.2.2] octane-2,3' -pyrrolidine] - 5' -S-carboxylic acid N-(l-S-carboethoxy-3-phenylpropyl)-O-ethyl-tyrosylspiro [bicyclo [2.2.2] octane-2,3 ' -pyrrolidine] - 5' -S carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl)-S-lysyl-spiro[bicyclo [2.2.2] octane-2,3' -pyrrolidine] -5' -S-carboxylic acid N-(l-S-carboethoxy-3-eyclohexyIpropyl)-S-alanyl-spiro[bicyclo [2.2.2] octane-2,3' -pyrrolidine] -5' -S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-2-azatricyclo [4,3,0,l®'9] decane-3-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl-2azatricyclo [4,3, 0, l*'9] decane-3-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-lysyl-2-azatricyclo [4,3,0,1*’»] decane-3-S-carboxylic acid N-(1-S- carboethoxy- 3 - cydohexylpropyl).-S-alanyl-2 - aza tri cyclo [4,3,0,I®'9] decane-3-S-carboxylic acid N- (l-S-carboethoxy-3-cydohexylpropyl) - S-lysyl-2-aza tricyclo [4,3,0,1®'9] decane-3-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-decahydrocyclohepta [b] pyrrole-2-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -O-ethyl-S- tyrosyldecahydrocyclohepta [b]pyrrole-.2-S-carboxylic acid N-(l-S-carboethoxy-3-phenylpropyl) - S-lysyl-decahydrocyclohepta [b]pyrrole-2-S-carboxylic acid N- (l-S-carboethoxy-3-cydohexylpropyl) - S-alanyl-decahydrocyclohepta [b]pyrrole-2-S-carboxylic acid N- (l-S-carboethoxy-3-cydohexylpropyl) -S-lysyl-decahydrocyclohepta [b]pyrrole-2-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-trans-octahydroisoindole-l-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-cis-octahydroisoindole-1-S-carboxylic acid N- (l-S-carboethoxy-3-cydohexylpropyl) -S-alanyl-transoc tahydroisoindole-1 - S - carboxylic acid N- (l-S-carboethoxy-3-cyclohexy Ipropyl) -S-alanyl-cis-octahydroisoindole- 1-S-carboxylic acid N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-cis-octahydrocyclopenta[c]pyrrole-l-S-carboxylic acid N- (1-S-carboethoxy-3-cyclohexy Ipropyl) -S-alanyl-cis-octahydrocyclopenta [c]pyrrole-1-S-carboxylic acid benzyl ester N-(1-S-carboethoxy-3-cyclohexyIpropyl)-S-lysyl-cis-octahydrocyclopenta[c]pyrrole-l-S-carboxylic acid N - (1-S-carboe thoxy - 3 - pheny Ipropy 1) - S - alanyl - 2,3,3a,4,5, 7 a-hexahydroindo1e-cis-endo-2 -S-carboxy1ic acid N-(1-S-carboethoxy-3-phenyIpropyl)-S-lysyl-2,3,3a,4,5, 7a-hexahydroindole-cis-endo-2 -S-carboxylic acid N- (l-S-carboethoxy-3-cyclohexylpropyl) -S-lysyl-2-azabicyclo [3.1.0]hexane-3-S-carboxylic acid N-(l-S-carboethoxy-3-phenylpropyl)-S-lysyl-2-azabicyclo[3.1.0] hexane-cis-endo-3-S-carboxylic acid N- (1-S-carboethoxy-3-cyelopentyIpropyl) -S-alanyl-2-azabicyclo [3.1.0] hexane-3-carboxylic acid N- (1-S-carboethoxy-3-phenyIpropyl) -S-alanyl-cis-endo-2azabicyclo [3.1.0] hexane-3-S-carboxylie acid N- (l-S-carboethoxy-3-cyclohexylpropyl) -S-alanyl-cis-endo2-azabicyclo [3.1.0] hexane-3-S-carboxylic acid.
These compounds can be prepared by, for example, the process described in German Patent Application P 3,333,455.2, in which process the tert.-butyl or benzyl radicals described in the application are converted into the monocarboxylic acid derivatives in known manner by acid or alkaline hydrolysis or by hydrogenolysis catalyzed by noble metals. The Ne -benzyloxycarbonyl protective group of the lysine derivatives is removed by hydrogenolysis catalyzed by noble metals. The compounds listed above can be readily 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 I are inhibitors of angiotensin converting enzyme (ACE) or intermediates in the preparation of such inhibitors, and they can also be used to control high blood pressure of various etiologies. The compounds of the formula I are disclosed in, for example, US Patent 4,129,571, US Patent 4,374,829, European Patent A-79,522, European Patent A-79,022, European Patent ( A-49,658, European Patent A-51,301, US Patent 4,454,292, US Patent 4,374,847, European Patent A-72,352, US Patent 4,350,704, European Patent A-50,800, European Patent A-46,953, US Patent 4,344,949, European Patent A-84,164, US Patent 4,470,972, European Patent A-65,301 and European Patent A-52,991.
Also advantageous are orally effective ACE inhibitors such as, for example, ramipril, enalapril, captopril, lisinopril, perindopril, cilazapril, RHC 3559, CGS 13945, CGS 13928C, CGS 14824A, CI-906, SCH 31846, zofenopril, fosenopril, alacepril and others. Orally effective ACE inhibitors are described in, for example, Brunner et al., J. Cardiovasc. Pharmacol. 7 (Suppl. I) (1985) S2-S11.
Preferred ACE inhibitors are those disclosed in European Patent A-79022, of the formula III \-COOH N' (S) in which R denotes hydrogen, methyl, ethyl or benzyl, in particular the compound of the formula III in which R denotes ethyl (ramipril).
Other preferred ACE inhibitors are those disclosed in European Patent A-84,164, of the formula IV ct> H COOH (S) TC - CH - HH ·? ι CH. in. which R4 denotes hydrogen, (Cj-CJ -alkyl or benzyl, in particular the compound of the formula IV, in which R4 denotes ethyl.
In carrying out the method according to the invention, the angiotensin converting enzyme inhibitors described above can be administered to mammals such as monkeys, dogs, cats, rats, humans etc. The compounds which are suitable for the use according to the invention are advantageously incorporated in pharmaceutical products in customary manner. They can be converted into the customary administration forms, such as capsules, tablets, coated tablets, solutions, ointments and emulsions, as well as into a depot form. The active compound can, where appropriate, also be in microencapsulated form. The products can contain additional, tolerated organic or inorganic substances, for example granulating substances, adhesives and binders, lubricants, suspending agents, solvents, antibacterial agents, wetting agents and preservatives. Forms for oral and parenteral administration are preferred, The compounds of the formula I can be administered in dosages of 0.1-50 mg per dose once to three times a day.
It is also possible according to the invention to use the ACE inhibitors in combination with substances which influence prostaglandin metabolism. Examples of such substances are stable prostacyclin analogs, inhibitors of thromboxane synthetase, and thromboxane antagonists.
Hence the invention also relates to pharmaceutical compositions containing a) an ACE inhibitor or its physiologically tolerated salt and b) a substance which influences prostaglandin metabolism or its physiologically tolerated salt, and to their use for the treatment of atherosclerosis, of thrombosis and/or of peripheral vessel disease.
The invention furthermore relates quite generally to products containing the substances mentioned above under a) and b), as combination product for concurrent, separate or sequential administration for the treatment of atherosclerosis, of thrombosis and/or of peripheral vessel disease.
An increased aggregability of the blood platelets plays a particularly important part in the development of atherosclerosis. Sxamples of sequelae are thromboses and peripheral vessel disease; these diseases are the main cause of the increased morbidity and mortality associated with high blood pressure. Blood platelets contain an angiotensin-I-processing system, and their membrane has binding sites with high affinity for angiotensin II. The fact that angiotensin converting enzyme (ACE) is preponderantly located on the luminal cytoplasmic membrane of the endothelial cells points to platelet/ endothelium interactions being associated with local angiotensin II production; ACE inhibitors can interfere with this. Furthermore, inhibition of ACE potentiates the action of bradykinin by preventing its breakdown. It is known that bradykinin is a potent stimulator of the release of prostacyclin from endothelial cells; bradykinin is in turn a potent inhibitor of platelet aggregation.
The activity of ' the compounds of the formula I on platelet aggregation and thus on atherosclerosis, thrombosis and peripheral vessel disease, as well as other disease states associated with increased aggregability of the blood platelets, can be deduced from a variety of test models.
In each of the examples which follow use is made of the results with N- (1-S-carboethoxy-3-phenylpropyl) - S-alanylcis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid (Formula II) .
A In vitro results Platelet-rich rabbit plasma is obtained as stated by Bom (Arzneimittel-Forsch. 31, 2012 (1981)). Platelet aggregation is measured by the increase in light passing through a cell which contains this plasma. The platelet count is adjusted to 450,000/mm3 by dilution with autologous, platelet-poor plasma. The compound of the formula II has, in concentrations of 0.1-10 /ig/ml of plasma, no effect on the aggregation induced by 0.24 mmol/1 arachidonic acid, 5 mmol/1 ADP or 4 ^g/ml collagen. In contrast, the inhibition, brought about by 4 gg/ml PGIj, of aggregation caused by arachidonic acid is increased to 100% by the compound of the formula II in the said dose range.
B In vivo results 1. Acute study Conscious rabbits received a single oral dose of 1.0-10.0 mg/kg of the compound of the formula II. After 1 hour, the animals are sacrificed, and platelet-rich plasma is obtained. Platelet aggregation is determined as described under A) .
There is found to be a reduction in aggregation in response to the three stimulators described there, in particular in response to arachidonic acid. A potentiation of the PGI2 effect is also observed. 2. Chronic study Conscious rabbits received 1 mg/kg/d of the compound of the formula II for 14 days, and then the procedure was continued as described under 1). Pronounced inhibition of the platelet aggregation induced by arachidonic acid and ADP is found in all animals.
The examples which follow indicate the forms for administration to treat atherosclerosis, thrombosis and peripheral vessel disease by the method according to the invention. The compounds of the formula I can be converted into the corresponding forms for administration in analogy to the examples.
Example 1 Preparation of the agent used according to the invention for oral administration in the treatment of atherosclerosis, of thrombosis and of peripheral vessel disease. 1000 tablets each containing 10 mg of 1-N-(1-S-carboe thoxy - 3 - pheny lpr opy 1) - S - a 1 anyl - lS,3S,5S-2-azabicyclo[3.3.0] octane-3-carboxylic acid are prepared with the following auxiliaries: N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl1S,3S,5S-2-azabicyclo[3.3.0]octane-3carboxylic acid Corn starch , 5 Gelatine Microcrystalline cellulose J Magnesium stearate g 140 g 7.5 g 2.5 g 2.5 g N-(l-S-carboethoxy-3-phenylpropyl)-S-alanyl-lS,3S-5S,-2azabicyclo [3.3.0] octane-3-carboxylic acid and corn starch are mixed with an aqueous gelatine solution. The mixture is dried and milled to 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 of atherosclerosis, of thrombosis and/or of peripheral vessel disease.
Example 2 1000 tablets each containing 10 mg of N- (1-S-carboethoxy3-phenylpropyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2carboxylic acid hydrochloride are prepared in analogy to Example 1.
Example 3 Gelatine capsules each containing 10 mg of N- (1-S-carboethoxy-3-phenylpropyl)-S-alanyl-IS,3S,5S-2-azabicyclo[3.3.0] octane-3-carboxylic acid are filled with the following mixture: N- (1-S-carboethoxy-3-phenylpropyl)-S-alanyl1S,3S,5S-2-azabicyclo[3.3.0]octane-3carboxylic acid Magnesium stearate Lactose mg 1 mg 214 mg - 19 These capsules can be used for the treatment of atherosclerosis, of thrombosis and/or of peripheral vessel disease.
Example 4 The preparation of an injection solution for the treat- ( ment of atherosclerosis, of thrombosis and/or of peripheral vessel disease is described below: N- (1-S-carboethoxy-3-phenyIpropyl) -S-alanyl1S, 3S, 5S-2-azabicyclo [3.3.0] octane-3carboxylic acid 250 mg Methylparahen 5 g Propylparaben 1 g Sodium chloride 25 g Water for injections 5 1 N- (1-S-carboxy-3-phenylpropyl)-S-alanyl-lS, 3S, 5S-2azabicyclo[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 bottles, which are closed with sterilized rubber caps. Each bottle contains 5 ml of solution.
Example 5 Tablets which can he used for the treatment of atherosclerosis, of thrombosis and/or peripheral vessel disease are prepared as described in Example 1, with the exception that in place of N-(l-S-carboethoxy-3phenyIpropyl) -S-alanyl-IS, 3S, 5S-2-azabicyclo [3.3.0] octane-3S-carboxylic acid N- (l-S-carboxy-3-phenylpropyl) -S-alanyl-lS, 3S, 5S-2azabicyclo[3.3.0]octane-3-carboxylic acid or N~ (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-2S,3aR, 7aSoctahydroindole-2-carboxylic acid or I.
N- (1-S-carboethoxy-3phenyIpropy1) -S-alanyl-cis2,3,3a,4,5,7a-hexahydro[IH] indole-2-S-endo-carboxylic acid or N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-cis-2,3,4a,4, ,7a-hexahydro[IH]indole-2S-endo-carboxylic acid or N-(1-S-carboxy-3-phenyIpropyl)-S-lysyl-lS,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid or N- (l-S-carboethoxy-3-cyclohexylpropyl) -S-alanyl-lS,3S,5S2-azabicyclo[3.3.0]octane-3-carboxylic acid or N-(1-S-carboxy-3-cyclohexylpropyl)-S-lysyl-lS-3S,5S-2azabicylco[3.3.0]octane-3-carboxylic acid are used.
Example 6 An injection solution is prepared in analogy to the procedure described in Example 4, with the exception that in place of N-(l-S-carboethoxy-3-phenylpropyl)-S-alanyl1S, 3S, 5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid N- (1-S-carboxy-3-phenylpropyl)-S-alanyl-lS,3S,5S-2azabicyclo [3.3.0] octane-3-carboxylic acid or N- (l-S-carboethoxy-3-phenylpropyl) -S-alanyl-2S,3aR,7aS20 octahydroindole-2-carboxylic acid hydrochloride or N- (1-S-carboxy-3-phenylpropyl)-S-alanyl-2S,3aR, 7aSoctahydroindole-2-carboxylic acid or N- (1-S-carboethoxy-3-cyclohexylpropyl) -S-alanyl-cis2,3,3a,4,5,7a-hexahydro[IH] indole-2-S-endo-carboxylic acid or N- (1-S-carboxy-3-phenylpropyl) - S-alanyl-cis-2,3,3a,4,5, 7a-hexabydro [IH] indole-2-S-endo-carboxylic acid or N- (1-carboxy-3-phenylpropyl) -S-lysyl-lS, 3S, 5S-2-azabicyclo [3.3.0] octane-3-carboxylic acid or N- (1-S-carboethoxy-3-cyclohexyl)-S-alanyl-lS,3S,5S-2azabicyclo [3.3.0] octane-3-carboxylic acid or N-(1-S-carboxy-3-cyclohexylpropyl)-S-lysyl-lS,3S,5S-2azabicyclo[3.3.0]octane-3-carboxylic acid are used.

Claims (4)

1. Patent Claims:
1. The use of an angiotensin converting enzyme inhibitor or its physiologically tolerated salts in the preparation of a pharmaceutical composition for the treatment of atherosclerosis, of thrombosis and/or of peripheral vessel disease in mammals, which comprises employing an angiotensin converting enzyme inhibitor of the formula I * * * R’OOC - CH - N - C - CH - NH - CH - (CHj) n - R R 4 R 5 0 R’ COOR 2 in which n is 1 or 2, R denotes aryl which has 6-12 carbon atoms and can be mono-, di- or trisubs ti tuted by (C x -C 4 )-alkyl, (C x -C 4 )-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C x -C 4 )-alkylamino, di-(C x -C 4 )-alkylamino, (C x -C 4 )-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, R 1 denotes hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, cycloalkenyl having 5-9 carbon atoms, (C3-C,)-cycloalkyl- (Cx-C4) -alkyl, (C5-Cs) -cycloalkenyl- (Cx-C4) alkyl, optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted as described above for R, (Ct-Cx2)-aryl-(Cx-C4)-alkyl or (C7-CX3)-aroyl-(Cx or C2)-alkyl, both of which can be substituted as the abovementioned aryl, mono- or bicyclic, optionally partially hydrogenated heteroaryl which has 5-7 or 8-10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these, ring atoms representing nitrogen atoms, or the optionally protected side chain of a naturally occurring α-amino acid R 1 -CH (NHa)-COOH, R a and R 3 are identical or different and denote hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, di-(C x -C 4 )-alkylamino(C x -C 4 ) -alkyl, (C 1 -C 5 ) -alkanoyloxy- (C x -C 4 ) -alkyl, (Ci-Cj) -alkoxycarbonyloxy- (C^-CJ - alkyl, (C 7 -C n ) aroyloxy- (C 1 -C 4 ) -alkyl, (Ο 4 -Ο 12 ) -aryloxycarbonyloxy(C x -C 4 )-alkyl, aryl having 6-12 carbon atoms, (C s -C n )-aryl-(Cx-Cj-alkyl, (C 3 -C,)-cycioalkyl or (Cj-C,) -cycioalkyl- (C 3 -C 4 ) -alkyl, and in which R 4 and R 5 together with the atoms carrying them represent a system from the series comprising tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 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, l i,J ] decane, decahydrocyclopenta [b] pyrrole, octahydroisoindole, octahydrocyclopenta [c] pyrrole, 2,3,3a,4,5,7a-hexahydroindole and 2-azabicyclo[3.1.0]hexane.
2. The use as claimed in claim 1, wherein there is administration of [S,S,S,S,S]-N-(l-carboethoxy-3-phenylpropyl)-alanyl-octahydroindole-2-carboxylic acid, N- [1-(S)- carboethoxy-3-phenylpropyl) -(S)-alanyl]2S,3aR,7aS-octahydroindole- 2 - carboxylic acid, [S,S,S,S,S]-N-[(l-carboethoxy-3-phenylpropyl)-alanyl]decahydroisoquinoline-3-carboxylic acid, [S,S,S]-N-[(1carboethoxy-3-phenylpropyl) -alanyl] -tetrahydroisoquinoline-3-carboxylic acid, N- (1-S-carboethoxy-3-phenylpropyl) -S-alanyl-cis-endo-2-azabicyclo[3.1.0]hexane-3-Scarboxylic acid or N-(l-S-carboethoxy-3-phenylpropyl)-Salanyl - cis - endo - 2,3,3a, 4,5,7a-hexahydroindole-2 - Scarboxylic acid.
3. The use as claimed in claim 1, wherein there is administration of (S,S,S,S,S)-N-(l-carboethoxy-3-phenylpropyl) -alanyl-2-azabicyclo[3.3.0]octane-3-carboxylic acid.
4. The use as claimed in claim 3, wherein in place of the ethyl esters there is administration of the corresponding dicarboxylic acids.
IE271186A 1985-10-15 1986-10-14 Use of angiotensin converting enzyme inhibitors for the treatment of atherosclerosis, thrombosis and peripheral vessel disease IE60767B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19853536687 DE3536687A1 (en) 1985-10-15 1985-10-15 METHOD FOR TREATING ATHEROSCLEROSIS, THROMBOSIS AND PERIPHERAL VESSEL DISEASE

Publications (2)

Publication Number Publication Date
IE862711L IE862711L (en) 1987-04-15
IE60767B1 true IE60767B1 (en) 1994-08-10

Family

ID=6283587

Family Applications (1)

Application Number Title Priority Date Filing Date
IE271186A IE60767B1 (en) 1985-10-15 1986-10-14 Use of angiotensin converting enzyme inhibitors for the treatment of atherosclerosis, thrombosis and peripheral vessel disease

Country Status (12)

Country Link
EP (1) EP0219782B1 (en)
JP (1) JPS6287524A (en)
KR (1) KR930008094B1 (en)
AT (1) ATE95064T1 (en)
AU (1) AU594711B2 (en)
CA (1) CA1320904C (en)
DE (2) DE3536687A1 (en)
DK (1) DK490486A (en)
ES (1) ES2059301T3 (en)
IE (1) IE60767B1 (en)
PT (1) PT83535B (en)
ZA (1) ZA867771B (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4962105A (en) * 1987-10-19 1990-10-09 Ciba-Geigy Corporation Potentiation of antihypertensive effect of ace inhibitors
DE3818245A1 (en) * 1988-05-28 1989-12-07 Hoechst Ag COMBINATION OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS WITH COLD CHANNEL MODULATORS AND THEIR USE IN MEDICINAL PRODUCTS
US4931464A (en) * 1989-02-15 1990-06-05 E. R. Squibb & Sons, Inc. Method of reducing pre- and post-ischemic myocardial arrhythmias and fibrillation
CA2016467A1 (en) 1989-06-05 1990-12-05 Martin Eisman Method for treating peripheral atherosclerotic disease employing an hmg coa reductase inhibitor and/or a squalene synthetase inhibitor
DE3923402A1 (en) * 1989-07-14 1991-01-17 Thera Patent Verwaltungs Gmbh USE OF ACE INHIBITORS FOR THE PROPHYLAXIS AND THERAPY OF THE CHRONIC-VENOESE INSUFFICIENCY
DE3925759A1 (en) * 1989-08-03 1991-02-07 Thera Patent Verwaltungs Gmbh USE OF ACE INHIBITORS FOR ATHEROSKLEROSEPROPHYLAXE
US5212165A (en) * 1989-10-23 1993-05-18 E. R. Squibb & Sons, Inc. Method for rehabilitating the vasorelaxant action of the coronary arteries impaired through atherosclerosis or hypercholesterolemia employing an ace inhibitor
US5061694A (en) * 1989-10-23 1991-10-29 E. R. Squibb & Sons, Inc. Method for stabilizing or causing regression of atherosclerosis in coronary arteries employing an ace inhibitor
US5298497A (en) * 1990-05-15 1994-03-29 E. R. Squibb & Sons, Inc. Method for preventing onset of hypertension employing a cholesterol lowering drug
CA2040865C (en) * 1990-05-15 2002-07-23 James L. Bergey Method for preventing, stabilizing or causing regression of atherosclerosis employing a combination of a cholesterol lowering drug and an ace inhibitor
US5140012A (en) * 1990-05-31 1992-08-18 E. R. Squibb & Sons, Inc. Method for preventing onset of restenosis after angioplasty employing pravastatin
US5622985A (en) * 1990-06-11 1997-04-22 Bristol-Myers Squibb Company Method for preventing a second heart attack employing an HMG CoA reductase inhibitor
US5130333A (en) * 1990-10-19 1992-07-14 E. R. Squibb & Sons, Inc. Method for treating type II diabetes employing a cholesterol lowering drug
US5190970A (en) * 1990-10-19 1993-03-02 E. R. Squibb & Sons, Inc. Method for preventing onset of or treating Type II diabetes employing a cholesterol lowering drug alone or in combination with an ace inhibitor
US5157025A (en) * 1991-04-01 1992-10-20 E. R. Squibb & Sons, Inc. Method for lowering serum cholesterol employing a phosphorus containing ace inhibitor alone or in combination with a cholesterol lowering drug
US6369103B1 (en) 1994-01-18 2002-04-09 Bristol-Myers Squibb Company Method for preventing or reducing risk of onset of cardiovascular events employing an HMG CoA reductase inhibitor
CA2261040C (en) * 1996-07-15 2009-01-20 Sankyo Company, Limited Pharmaceutical composition comprising combination useful for treatment or prevention of arteriosclerosis or xanthoma
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4470972A (en) * 1981-04-28 1984-09-11 Schering Corporation 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids
US4374847A (en) * 1980-10-27 1983-02-22 Ciba-Geigy Corporation 1-Carboxyalkanoylindoline-2-carboxylic acids
SU1327787A3 (en) * 1981-11-05 1987-07-30 Хехст Аг (Фирма) Method of producing cis,endo-2-azabicyclo-(3,3,0)-octane-3-carboxylic acids or acid-additive salts thereof
DE3438545A1 (en) * 1984-10-20 1986-04-24 Merck Patent Gmbh, 6100 Darmstadt PEPTIDE

Also Published As

Publication number Publication date
DK490486D0 (en) 1986-10-14
KR870004054A (en) 1987-05-07
AU6389086A (en) 1987-04-16
ATE95064T1 (en) 1993-10-15
DE3536687A1 (en) 1987-04-16
ES2059301T3 (en) 1994-11-16
DE3689099D1 (en) 1993-11-04
KR930008094B1 (en) 1993-08-25
JPS6287524A (en) 1987-04-22
IE862711L (en) 1987-04-15
AU594711B2 (en) 1990-03-15
DK490486A (en) 1987-04-16
EP0219782A2 (en) 1987-04-29
PT83535A (en) 1986-11-01
ZA867771B (en) 1987-05-27
PT83535B (en) 1989-05-31
EP0219782A3 (en) 1990-05-30
EP0219782B1 (en) 1993-09-29
CA1320904C (en) 1993-08-03

Similar Documents

Publication Publication Date Title
IE60767B1 (en) Use of angiotensin converting enzyme inhibitors for the treatment of atherosclerosis, thrombosis and peripheral vessel disease
US5256687A (en) Pharmaceutical composition for the treatment of high blood pressure
IE59975B1 (en) Combination of angiotensin-converting enzyme inhibitors with calcium antagonists as well as their use in drugs
US5231080A (en) Method for the treatment of atherosclerosis, thrombosis, and peripheral vessel disease
KR0185969B1 (en) Pharmaceutical composition for treating of cardiac and vascular hypertrophy and hyperplasia
US5403856A (en) Method of treating cardiac insufficiency using angiotensin-converting enzyme inhibitors
DK172221B1 (en) Use of ACE Inhibitors or their Physiologically Acceptable Salts for the Preparation of Nootropic Drugs
US5231084A (en) Compounds having a cognition adjuvant action, agents containing them, and the use thereof for the treatment and prophylaxis of cognitive dysfuncitons
US5684016A (en) Method of treating cardiac insufficiency
EP0488059B1 (en) Use of a combination of an ace inhibitor with a calcium antagonist in the treatment of proteinuria
JPH029896A (en) Novel amino acid glyceride and production thereof
JPH01246222A (en) Compound having psychotropic action and suppository containing the same
CA1340722C (en) Pharmaceutical composition for the treatment of high blood pressure
KR900003321B1 (en) Compounds having a cognition adjuvant acton agents containing them,and the use there of the treatment and prophylaxis of cognitives dysfunctions

Legal Events

Date Code Title Description
MM4A Patent lapsed