CA2023089C - Method for the treatment of cardiac and of vascular hypertrophy and hyperplasia - Google Patents
Method for the treatment of cardiac and of vascular hypertrophy and hyperplasia Download PDFInfo
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- CA2023089C CA2023089C CA002023089A CA2023089A CA2023089C CA 2023089 C CA2023089 C CA 2023089C CA 002023089 A CA002023089 A CA 002023089A CA 2023089 A CA2023089 A CA 2023089A CA 2023089 C CA2023089 C CA 2023089C
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Abstract
The invention relates to a method for the treatment of cardiac and of vascular hypertrophy and hyperplasia by administration of angiotensin converting enzyme inhibit-ors. Administration of compounds of the formula I
(see formula I) in which n is 1 or 2, R, R1, R2 and R3 are identical or different and each is hydrogen or an organic radical, and R4 and R5 form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system, is preferred. The invention additionally relates to angio-tensin converting enzyme inhibitors and to agents con-taining these for administration for the treatment of the abovementioned diseases.
(see formula I) in which n is 1 or 2, R, R1, R2 and R3 are identical or different and each is hydrogen or an organic radical, and R4 and R5 form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system, is preferred. The invention additionally relates to angio-tensin converting enzyme inhibitors and to agents con-taining these for administration for the treatment of the abovementioned diseases.
Description
~~ t G' ti 4 q r.r l.,~.~ ., . ..
HOECHST .d~~CTxENGESELLSCHAFT HOE S9/~' 260 Dr. VdS/PP
Description A method for the treatment of cardiac and of vascular hypertrophy and hyperplasia The invention relates to a method for 'the treatment of cardiac and of vascular hypertrophy and/or hyperplasia by oral or parenteral administration of compounds which inhibit angiotensin converting enxyrnea Particularly suitable in this connection are compounds of the formula I
R aac - ~~ - ~5- ~ - R~ ° ~ - ~aaR~c~~~n ~
in which n is 1 or 2, R is hydrogen, an optionally substituted aliphatic radical with 1-8 carbon atoms, an optionally substituted alicyclic radical with 3-9 carbon atoms, an optionally substi-tuted aromatic radical with 6-12 carbon atoms, an optionally substituted araliphatic radical with 7-14 carbon atoms, an optionally substituted alicyclic-.
aliphatic radical with 7-14 carbon atoms or a radical ORe or SRa in which R~ is an optionally substituted aliphatic radical with 1-4 carbon atoms, an optionally substituted aromatic radical with 6-12 carbon atoms or an optionally substituted heteroaromatic radical with 5-12 zing atoms, R1 is hydrogen, an aptionally substitwted aliphatic xadical with 1-6 carbon atoms, an optionally substi toted alicyclic radical with 3-9 carbon atoms, an optionally substituted alicyclic-aliphatic radical with 4-13 carbon atoms, an optionally substituted x ,:~ .~. ,,-,. r~~~ ~, - 2 ... G" '~ b~ ~a ~i ~; ;:~
aromatic radical with 6-a2 carbon atoms, an option-ally substituted araliphatic radical with 7-16 carbon atoms, an optionally substituted heteroaro-matic radical with 5-12 ring atoms or the side-chain, which is protected where necessary, of a naturally occurring «-amino acid, RZ and R3 are identical or different and are hydrogen, an optionally substituted aliphatic :radical with ~.-6 carbon atoms, an optionally substituted alicyclic radical with 3-9 carbon atoms, an optionally subs~ti-tuted aromatic radical with 6-12 carbon atoms, an optionally substituted araliphatic radical with 7-16 carbon atoms and R° and RS form, together with the atoms carrying them, a heterocyclic mono-, bi- or tricyclic ring system with 4 to 15 carbon atoms.
Particularly suitable ring systems of this type are those from the following groups tetrahydroisoquinoline (A); decahydroisoquinoline (B);
octahydroindole (C); octahydrocyclopenta[b]pyrrole (D);
2- -azaspiro[~.5]decane (E); 2-azaspiro[4.4]nonane (F);
spiro[(bicyclo[2.2.i]heptane)-2,3'-pyrrolidine] (G);
spiro[(bicyclo[2.2.2]octane)-2,3'-pyrrol:idine] (FI); 2 azatricyala[4,3,0,188]decane (T); decahydrocyclo hepta[b]pyrrole (J_); octahydroisoindole (.~); octahydro-cyclopentajc]pyrrole (~); 2,3,3a,4,5,7a-hexahydroindole (nZ~) ; 2-azabicyclo [ 3 . ~.. 0 ]hexane ( K ) ; all of which can optionally be substituted. However, the unsubstituted systems are preferred.
In the case of compounds which contain several chiral atoms, all possible diastereomers as racemates or enant-iomcars, or mixtures of various diastereomars, ar~
su3.~table .
The suitable cyclic amino acid esters have the following structural formulae.
HOECHST .d~~CTxENGESELLSCHAFT HOE S9/~' 260 Dr. VdS/PP
Description A method for the treatment of cardiac and of vascular hypertrophy and hyperplasia The invention relates to a method for 'the treatment of cardiac and of vascular hypertrophy and/or hyperplasia by oral or parenteral administration of compounds which inhibit angiotensin converting enxyrnea Particularly suitable in this connection are compounds of the formula I
R aac - ~~ - ~5- ~ - R~ ° ~ - ~aaR~c~~~n ~
in which n is 1 or 2, R is hydrogen, an optionally substituted aliphatic radical with 1-8 carbon atoms, an optionally substituted alicyclic radical with 3-9 carbon atoms, an optionally substi-tuted aromatic radical with 6-12 carbon atoms, an optionally substituted araliphatic radical with 7-14 carbon atoms, an optionally substituted alicyclic-.
aliphatic radical with 7-14 carbon atoms or a radical ORe or SRa in which R~ is an optionally substituted aliphatic radical with 1-4 carbon atoms, an optionally substituted aromatic radical with 6-12 carbon atoms or an optionally substituted heteroaromatic radical with 5-12 zing atoms, R1 is hydrogen, an aptionally substitwted aliphatic xadical with 1-6 carbon atoms, an optionally substi toted alicyclic radical with 3-9 carbon atoms, an optionally substituted alicyclic-aliphatic radical with 4-13 carbon atoms, an optionally substituted x ,:~ .~. ,,-,. r~~~ ~, - 2 ... G" '~ b~ ~a ~i ~; ;:~
aromatic radical with 6-a2 carbon atoms, an option-ally substituted araliphatic radical with 7-16 carbon atoms, an optionally substituted heteroaro-matic radical with 5-12 ring atoms or the side-chain, which is protected where necessary, of a naturally occurring «-amino acid, RZ and R3 are identical or different and are hydrogen, an optionally substituted aliphatic :radical with ~.-6 carbon atoms, an optionally substituted alicyclic radical with 3-9 carbon atoms, an optionally subs~ti-tuted aromatic radical with 6-12 carbon atoms, an optionally substituted araliphatic radical with 7-16 carbon atoms and R° and RS form, together with the atoms carrying them, a heterocyclic mono-, bi- or tricyclic ring system with 4 to 15 carbon atoms.
Particularly suitable ring systems of this type are those from the following groups tetrahydroisoquinoline (A); decahydroisoquinoline (B);
octahydroindole (C); octahydrocyclopenta[b]pyrrole (D);
2- -azaspiro[~.5]decane (E); 2-azaspiro[4.4]nonane (F);
spiro[(bicyclo[2.2.i]heptane)-2,3'-pyrrolidine] (G);
spiro[(bicyclo[2.2.2]octane)-2,3'-pyrrol:idine] (FI); 2 azatricyala[4,3,0,188]decane (T); decahydrocyclo hepta[b]pyrrole (J_); octahydroisoindole (.~); octahydro-cyclopentajc]pyrrole (~); 2,3,3a,4,5,7a-hexahydroindole (nZ~) ; 2-azabicyclo [ 3 . ~.. 0 ]hexane ( K ) ; all of which can optionally be substituted. However, the unsubstituted systems are preferred.
In the case of compounds which contain several chiral atoms, all possible diastereomers as racemates or enant-iomcars, or mixtures of various diastereomars, ar~
su3.~table .
The suitable cyclic amino acid esters have the following structural formulae.
3 ~.i !n z ~ v'~;' ~.
COORS COORS
N' N
~ C N COORS
A
COORS
~,~- COORS
.~''°' COORS
~- COORS OOR ~ COOR'~
N
a C R
a ~°- 3 COORS Ia" COOR . COORS
o ~~ A rte a I
J K L
--COORS \ ~"° COORS
I
M N
~, preferred embodiment comprises wing compounds o~ the ~a~cmula I in which ri is 1 Or 2, R i:~ hydrogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbon atoms, aryl which ., ~ . -.l 4. ~~ .; t".
COORS COORS
N' N
~ C N COORS
A
COORS
~,~- COORS
.~''°' COORS
~- COORS OOR ~ COOR'~
N
a C R
a ~°- 3 COORS Ia" COOR . COORS
o ~~ A rte a I
J K L
--COORS \ ~"° COORS
I
M N
~, preferred embodiment comprises wing compounds o~ the ~a~cmula I in which ri is 1 Or 2, R i:~ hydrogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbon atoms, aryl which ., ~ . -.l 4. ~~ .; t".
has 6-12 carbon atoms and can be mono-, di- or trisubstituted by ( C1-C4 ) -alkyl, ( Cz-C4 ) -alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, ( C1-C~ ) -alkylamino, di- ( C1-C~ ) -alkylamino, ( C~-C4 ) -alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy with 1-4 carbon atoms, aryloxy which has f-12 carbon atoms and can be substituted as described above for aryl, mono- or bicyclic heteroaryloxy which has 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen, and which can be substituted as described above for aryl, amino- ( C1-C4 ) -alkyl , ( C1-C4 ) -alkanoyl amino-( C1-C4 ) -alkyl , ( C7-C13 ) -aroylamino- ( Cs-C4 ) -alkyl , ( Cl-C4 ) -alkoxycarbonylamino-(C1-C4)-alkyl, (Cs-Clz)-aryl-( Cl-C4 ) -alkoxycarbonylamino- ( Cl-C,, ) alkyl , ( Cs-Caz ) -aryl- ( Cl-C4 ) -alkylamino- ( Cl-C4 ) -alkyl, ( C1-C4 ) -alltyl-amino- ( Cl-C,, ) -alkyl, di- ( C1-C4 ) -alkylamino-( Cl-C4 ) -alkyl, guanidino-(Cl-C4)-alkyl, imidazolyl, indolyl, ( C1-C4 ) -alkylthio, C1-C4 ) -alkylthio- ( Cl-C4 ) -alkyl , ( Cs-Clz ) -arylthio- ( C1-CG ) -alkyl which can be substi-tuted in the aryl moiety as described above for aryl, ( Cs-Cxz ) -aryl- ( C1-C4 ) -alkylthio which can be sub-stituted in the aryl moiety a:~ described above for aryl-, carboxy-(C1-C4)-alkyl, carboxyl, carbamoyl, carbamoyl- ( Cl-Cu ) -alkyl, ( C1-C4 ) -alkoxycarbonyl-( Cl-C,, ) -alkyl, ( Ca-Clz ) -aryloxy- ( Cl-C4 ) -alkyl which can be subati~tu-ted in the aryl moiety as described above for aryl, or ( Cs-Clz ) -aryl- ( Cl-Co ) -alkoxy which can be substituted in the aryl moiety as described above for aryl, Rl is hydrogen, alkyl with 1-G carbon atoms, alkenyl with 2-6 carbon atoms, alkyxiyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbon atoms, F_t t1 ~f! ;'° s ° 5 - r. . r,~ ..'r;1~~~r cycloalkenyl with 5-9 carbon atoms, (C~-C9) cycioalkyl- ( C1-Ca ) -alkyl, ( C$-Cy ) -cycloalkenyl- ( Cl-Ca ) alkyl, optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted as described above for R, ( Cs-Crz ) -aryl- ( C1-Ca ) "alkyl or ( Cy°G.'13 ) -aroyl- ( C1 or Cz)-alkyl, both of which can be substituted like the aryl above, mono- or bicyclic, optionally partially hydrogenated heteroaryl which has 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen atoms, and which can be substituted like the aryl above, or the optionally protected side-chain of a naturally occurring a-amino acid R1-CH(NHz)-COON, RZ and R3 are identical or different and are hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, da.-(Cl-Ca)-alkylamino-(C1-Ca)-alkyl, (C1-CS)-alkanayloxy-(Cl-Ca)°alkyl,(C1-Cs)-alkoxycarbonyloxy-( C1-Ca ) -alkyl , ( C~-Cr3 ) -aroyloxy- ( C1-C4 ) -alkyl , ( Cs°Ciz ) -ar'Yloxycarbonyloxy ( Cl-Ca ) -alkyl, aryl with 6-12 carbon atoms, ( Cs-Clz) -aryl- ( Cl-Ca ) °
alkyl, (C3-CB)-cycloalkyl or (C3-C9)-cycloalkyl-( Ci-Ca ) -alkyl, and R'' and RS have the abovementioned meaning.
A particularly preferred embodiment aompri.ses using compounds of the formula I in which n is 1 or 2, R is (C1-Cs)-alkyl, (Cz-C6)-alkenyl, (C3-C9)-cycloalkyl, amino- (Cz-Ca ) -alkyl, ( Cz-CS ) -acylamino- ( Cl-Ca ) -alkyl, ( C~°C13 ) -aroylamino- ( C1-Ca ) -alkyl, ( Cl-Ca ) -alkoxy_ carbonylamino- ( Cl-Ca ) -alkyl, ( Cs-C~2 ) -aryl- ( Cl-Ca ) °' alkaxycarbonylamino-(Cl-Ca)-alkyl,(Cs-Clz)-aryl which can be mono-, di- or trisubstituted by ( C1-Ca ) -allcyl, ,~5 (Cz-Ca)-alkoxy, hydroxyl, halogen, nitro, amino, ( Cl-Ca ) --alkylamino, di- ( C1-Ca ) -alkylam:ino and/or rnethylenedioxy, or 3-indoly.l, in particular methyl, ethyl, cyclohexyl, tart. butoxycarbonylamino-(C1-Ca)-alkyl, benzoylaxycarbonylamino- ( C~-Ca ) -alkyl or ',:. ;,. .,,' 'rn~ f, ,~J
..., ?,i ~:,~ -..; -.
phenyl which can be mono- or disubstituted by phenyl, (C1-CZ)-alkyl, (C~ or CZ)-alkoxy, hydroxyl.
fluorine, chlorine, bromine, amino, (Cl-Ca)-alkyl-amino, di(C~,-Ca)-alkylamino, nitro and/or methyl-enedioxy or, in the case of methoxy, trisubstituted, Rl is hydrogen or (C1-Cs)-alkyl which can optionally be substituted by amino, (C1-C6)-acylamino or benzoyl-amino, or (CZ-Co)-alkenyl, (C3-Co)-cycloalkyl, ( CS-C9 ) -cycloalkenyl , ( C3-C7 ) -cyclnalkyl- ( Ca-Ca ) -alkyl , (C~°C1~)-aryl or partially hydrogenated aryl, each of which can be substituted by ( Cl-Ca ) -alkyl, ( Cl or CZ) -alkoxy or halogen, or ( Cs-C12 ) -aryl- ( C1 to Ca ) -alkyl or ( C~-C13 ) -aroyl- ( Ci-Cz ) -alkyl , both of which can be substituted in the aryl radical as defined above, or a mono- or bicyclic heterocyclic radical with 5 to 7 or 8 to 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen atoms, or a side-chain of a naturally occurring, optionally protected a-amino acid, but in 2 0 particular hydrogen, ( C1-C~ ) -alkyl , ( CZ or C3 ) - .
alkenyl, the optionally protected sills-chain of lysine, benzyl, ~-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-aminobutyl or benzoylmethyl, R2 and R3 are identical or different radicals and are 2 ~ hydrogen, ( Cl-Cg ) -alkyl, ( CZ-Cb ) ialkenyl or ( Cs-Cy2 ) aryl-(C1-Ca)-alkyl, but in particular hydrogen, ( C1-Ca ) -alkyl or benzyl , and R° and RS have the abovementioned meaning.
Particularly preferred is the use of compounds of 30 the formula x in which n is ~, R is Qhenyl, R1 is methyl, RZ and R3 are identical or different (Cl-CB)-alkyl radicals or (C7-Clo)-aralkyl radicals such as benzyl or nitro benzyl, and Ra and R3 together are a radical of the formula n~ l < 'S
_ 7 _ t,' J:
(~~~P
K
- (CFi~~m in which m is 0 or 1, p is 0, 1 or 2 and X is -CHZ-, -CFh-CHZ- or -CH=CH-, it also being possible fax a 6-membered ring formed with X to be a benasene ring.
Aryl preferably means here and hereinafter optionally substituted phenyl, biphenylyl or naphthyl. A
corresponding statement applies to radicals derived from aryl, such as aryloxy and arylthio. Aroyl particularly means benzoyl. Aliphatic radicals can be straight-chain or branched.
Rxamples of the meaning of a mono- or bicyclic heterocyclic radical with 5 to 7 or 8 ~0 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or of which Z to 4 ring atoms are nitrogen atoms, are thienyl, benza[b]thienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naph~thyrad-inyl, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, ~0 oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. these radicals can also be partially or completely hydrogenated, Naturally occurring «-amino acids are described, for example, in I3ouben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry) Vol. XV/1 and XVf2.
If R1 is a sid~-chain of a protected naturally occurring «-amino acid, such as, for example, protected Ser, ~Chr, Asp, Asn, Glu, Oln, Arg, ~ys, ~iyl, Cys, Orn, Cit, ',~yr, '.~rp, His or Hyp, preferred protective groups are the groups customary in peptide chemistry (cf.
Flouben-Weyl, Vol. XV/1 and XV/2). In 'the case where R~ is the protected lysine side-chain, the known amino protec-tive groups, but in particular Z, ftoc or ~Cl-CB)-alkanoyl, are preferred. Suitable and preferred O-protective groups r1 ~,.) p ~..,yy a ', t',7 ~J '..V ~i~ f.~l ._. .'~.,,j , .
- $ -for tyrosine axe (C1-C~)-alkyl, in particular methyl or ethyl.
The follo~ring compounds can be particularly advantageously used in the method according to the invention:
N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acict N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-S-1,2,3,4-tetrahydroisoc~uinoline-3-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-3S-decahydro-isoguinoline-3-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-(2S,3aS,?aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-(2S,3aS,7aS)-octahydroindole-2-carboxyl3.c acid N-(1-S-Carbethoxy-3-(3,4-dimethylphenyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-[1-S-Carbathoxy-3-(4-fluorophenyl)-propyl]-S-alan;yl-(2S,3aS,7aS)-octahydroindole-2-carboxylic said N-[~,-S-Carbethoxy-3-(4-methoxyphenyl)--propyl]-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-[1-S-Carbethoxy-3-(3,4-dimethoxyphenyl)-propyl~-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclopentylpropyl)-S-alanyl-(2S,3aS,7aS)-actahydroindole--2-carboxylic acid ~~ ~ (k \~ t4, ,f~
r ~1 ;1 .., 4~,~ ' J a.~ :,~'r i1i l, d N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-0-ethyl-S-tyrosyl-(2S,3aS,7aR)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aR)-octahydroindale-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-(2S,3aR,7aR)-octahydroindale-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-O-ethyl-S-vyrosyl-(2S,3aR,7aR)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aR)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-0-ethyl-S-tyrosyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3,4-dimethylphenyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-[1-S-Carbethoxy-3-(4-fluorophenyl)-propyl]-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carbo:cylic acid N-[1-S-Carbethoxy-3-(4-methoxyphenyl)-propyl]-S-alan;yl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-[1-S-Carbethaxy-3-(3,~-dimethoxyphenyl)-propyl]-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclopentylpropyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(Z-S-Carboxy-3-ayclohexyl-propyl)-S-alanyl-c3.s-ends-2-,:.. ''.;. ~.~ ;:~~ ~_:; , '..J
- to -azabicyclo[3.3.0]octane-2-S-carboxylic acid N-(1-S-Carbethoxy-bwty~)-S-alanyl-cis-endo-2-azabicyclo-[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-(3,4-dimethoxyphenylpropyl)-S-alanyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclopentyl-propyl)-S-alanyl-cis-endo-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Caxbethoxy-3-phenyl-propyl)-O-anethyl-S-tyrosyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyxosyl-cis-endo-2-azabicyclo[3.3.0]octane--3-S-carboxylic acid N-(1-S-Carbethoxy-3-(4-flaaoxophenyl-propyl)-S-alanyl-cis-endo-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-(4-methoxyphenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic ac:i.d N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,6aS)-octahydrocyclopenta[b]pyrxole-2-carboxylic acid N-(1-S-Caxbethoxy-3-cyclohexylpxopyl)-lysyl-(2S,3aR,6aS)-octahydrocycaopenta[b]pyxrole-2-carboxylic acid N-(1-S-Caxbethoxy-3-phenyl-propyl)-O-ethyl-S-tyxosyl-(2S,3aR,6aS)-octahydxocyclopenta[b]pyrxole-2-carboxylic acid N-(1-S-Caxbethoxy-3-phenyl-pxopyl)-S-alanyl-2-(2S,3aR,6aS)octahydrocyclopenta[b]pyrrole-2-carboxylic acid N-(1-S~Caxbethoxy-3-phenyl-prapyl)-S-alanyl-2-azaspi.ro-[4,5]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-O-ethyl-2-tyrosyl-azaspixo-[4,5]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-2-azaspixo-[4,5]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-ayclohexylpropyl)-S-alanyl-2-aza-sp3ro-[~,5]decane-3-S-carboxylic acid N-(1-S-~Caxbethoxy-3-cyclohexylpxopyl)-S-lysyl-2-azaspiro-[4,5]decane-3-S-carboxylic acid N-(1-S-Caxbethoxy-3-phenyl-pxopyl)-S-alanyl-2-azaspixo-[4,4]nonane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propy:l)-O-ethyl-S-tyrasyl.-2-azaspiro[4,~]nonane-3-S-carboxylic acid ,f, ;i, ,~
,.,. °'°~ s.' G.3 ;i ;
N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-2-azaspiro-[4,4]nonane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-2-a~a-spiro[4,4]nonane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclopentyl-propyl)-S-alanyl-2-azaspiro[4,4]nonane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclopentyl-propyl)-S-lysyl-2-a~a-spiro[4,4]nonane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-spire[bi-cyclo[2.2.1]heptane-2,3'-pyrrolidine]-5'-S-carboxylic ac id N-(1-S-Carbethoxy-3-phenyl-propyl)-0-ethyl-S-tyrosyl-spiro[bicyclo[2.2.1]hegtane-2,3'-pyrrolidine]-5'-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-spiro[bicyclo-[2.2.1]heptane-2,3°-pyrrolidine]-5'-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-spiro-[bicyclo[2.2.1]heptane-2,3°-pyrrolidine]5°-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-spiro-[bicyclo[2.2.1]heptane-2,3'-pyrrolidine]-5'-S-carboxylic ac id N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-spiro~
[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-0-ethyl-tyrosyl-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-spiro[bicyclo-[2.2.2]octane-2,3'-pyrrolidine]-5'-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-spiro-[b:i.cyclo[2.2.2]octane-2,3°-pyrrolidine]-5'-S-carboxylic ac id N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-2-azatri-cyclo[4,3,0,1°'°]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-o-ethyl-S-tyrosyl-2-a~atricyclo[4,3,0,18°]decane-3-S-carboxylic said ~~-(1-S-Carbe~thoxy-3-phenyl-propyl)-S-lysyl-2-azatricyclo-[4,3,0,1°'°]decane-3-S-carboxylic said ,, S.S .;~ .r..s t-: ~t ~;rJ ~~,.A n. ~. -. .... 'L' N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-2-azatri-cyclo[4,3,0,16'9]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-2-azatri-cyclo[4,3,0,16'9]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-decahydxo-cyclohepta[b]pyrrole-2-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-o-ethyl-S-tyrosyl-decahydrocyclahepta[b]pyrrole-2-S-carbo3~ylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-decahydro-cyclohepta[b]pyrrole-2-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-deca-hydrocyclohepta[b]pyxrole-2-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-decahydro-cyclohepta[b]pyrrole-2-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-traps-octa-hydroisoindole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-c.is-octa-hydroisoindole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-trans-octahydroisoindole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-octahydroisoindole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-cis-octa-hydrocyclopenta[c]pyrrole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-octahydrocyclopenta[c]pyrrole-1-S-carboxylic acid-benzyl ester N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-cis-octahydrocyclopenta[c]pyrrole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-2,3,3a,~,5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-2,3,3a,4,5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid N-(1-S-Carbethaxy-3-cyclohexyl-propyl)-S-lysyl-2-azabi-cyclo[3.1.0]hexane-3-S-carboxylic acid N-(1-S-Carboxy-3-phenyl-propyl)-S-lys~yl-2-azabicyclo-[3.1.0]hexane-cis-endo-3-S-carboxylic said N-(1-S-Carbethoxy-3-cyclopentylpropyl)-S-alanyl-2-aza-Cw ~ ''''~1 ~ " ~ ~ Zr:~
a_1 ..
~'~ j f,,.; °..i bicyclo[3.1.0]hexane-3-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid These compounds can be prepared, for example, by the process described in German Patent Application P 3,333,455.2, in which the tart. butyl or benzyl radi-cals described in the application are converted in a known manner by acid or alkaline hydrollrsis or by noble metal-catalyzed hydrogenolysis into the monocarboxylic acid derivatives. The N'-benzyloxycarbonyl protective group of the lysine derivatives is removed by noble metal-catalyzed hydrogenolysis. The compounds listed above can easily be converted with physiologically tolerated acids or bases (in the case of mono- or di-carboxylic acids) into the corresponding salts (for example hydrochlorides, maleates, fumarates etc.) and used according to the invention as salts.
The compounds of the formula T are inhibitors of angiotensin converting enzyme (ACE) or intermediates for the preparation of inhibitors of this type, and can also be employed for controlling high blood pressure of a variety of etiologies. The compounds of the formula I are disclosed, for example, in US Patent 4,129,5?1, US
Patent 4,374,829, EP-A-79,522, EP-A-79,022, EP-A-49,65$, EP-A-51,301, US Patent 4,454,292, US Patent 4,374,847, Ep-A-72,352, US Patent 4,350,704, Ep-A-50,800, EP-A-46,953, US Patent 4,344,949, EP-A-84,164, US patent 4,470,972, EP-A-65,301 arid Ep-A-52,991.
Also advantageous are orally effective ACE inhibitors such as, for example, ramipril, enalapril, captopril, lisl,x~opr~.l, perindopril, cilazapril, RHC 3659, CGS 13945, CGS 1392$0, CGS 14824A, C1-906, SCH 31846, zofenopril, fosenopril, alacepril and others. Orally e:~fective ACE
inhibitors are described, for example, in Brunner et al . , J. Cardiovasc. Pharmacol. 7 (Suppl. I) [1985] 52-511.
!.~ ~'' -Preferred AC1E inhibitors are those of the formula III
disclosed in RP-A-79,022 CooH
(s) 4s) g ~ ~H ~ ~IH - CH - CH2 - CH2 ~ 1~ I I I ) O CHI boor in which R is hydrogen, anethyl, ethyl or benzyl, in particular the compound of the formula III in which R is ethyl (ramipril).
Additionally preferred are the ACS inhibitors of the formula IV disclosed in EP-A-8,164 H
CooH ( I'~) to (s) (s) N
~ ~ c a cH - NH - cH -~cHZ ~ cx~
cH~ cooR
in which R° is hydrogen, (C~-C4)-alkyl or benzyl, in particular the compound of the formula I't7 in which R4 is ethyl.
Applying the method according to the invention, it is possible to adminster the angiotensin converting enzyme inhibitors described above to mammals such as monkeys, dogs, cats, rats, humans etc. The compounds suitable for the use according to the invention are expediently incorporated in a customary manner into pharmaceutical 2o products. They can be converted into the customary administration farms such as capsules, tablets, coated tablets, solutions, ointments, emulsions and into depot form too. The active aampound can also, where appro-priate, be present in microencapsulated form. The pro-dusts can contain tolerated organic or inorr~an~.c ,.r,.t~7 ~ ~~A
ieD '~:i' additives, for example granulating auxiliaries, adhesives and binders, lubricants, suspending agents, solvents, antibacterial agents, wetting agents and preservatives.
Forms for oral and parenteral administration are pre-y ferred. The compounds of the formula I can be admin-istered in doses of 0.001 mg/kg - 20 mg/kg, in particular 0.005 mg/kg - 1 mg/kg, once to three times a day.
Growth factors which lead to proliferation and to swel-ling of cells make a crucial contribution to the develop-meat of cardiac hypertrophy as a consequence of hyper-tension, and in the hypertrophy and hyperplasia of smooth muscles of vessels, as are observed in hypertension and in the development of atherosclerotic plaques.
I-t is known from the literature that angiotensin II is a growth factor of this type. Treatment of muscle cells with angiotensin II leads to stimulation of phospho-lipase C (J. Biol. Chem. 260, 8901 (1986)), to mobiliza-tion of intracellular calcium (Hypertension 7, 447 (1988)), to activation of Naø/H~ exchange (J. Biol.
Chem. 262, 5057 (1987) and to activation of protein synthesis and induction of messenger RNA for the c-fos protooncogene (J. Biol. Chem. 264, 526 (1989)). Further-more, angiotensin II potentiates the proliferative action of other growth factors such as PnGF and EGF (,~lmer. J.
Physiol (1987), F 299). These described orations of angiotensin II are mainly elicited by locally synthesized peptide. Compounds capable of local prevention of ~the formation of angiotensin II ought therefore to have an action on hypertrophy and hyperplas:ia of smooth muscle of vessels, and of the myocardium. P~~ have now found, surprisingly, that inhibitors of angiotensin converting enzyme are able to abolish the described ~trophic effects of arxgiotensin II even at doses at which they do not yet display an antihypertens3:ve action.
The results with IJ-(1-~-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.x.0]octane-3-S-carboxylic ~,,~ f,~; ,~'~. ,;,~~ °w)' ;.~t e3 - is -acid (formula IIj in each case are to serve as examples hereinafter.
H
~C00!3 ~J'~~
H N
i C
o~ ~'cH-uH-cu-cH2-cH~ ~
CH3 C02G~H~
Description of e~pera~nents Cardiac hypertrophy was generated in conscious rats by constriction of the abdominal aorta. Once this had been completely established, groups of the animals received 1 mglkg/d (antihypertensive dosej or 10 ugJkgld (non-antihypertensive dose] of the compound of the formula II
ZO by oral administration fox 3 weeks. Control groups of animals which were not given the substance and which had undergone a sham operation were included. e'~fter the end of the ~ weeks, the animals were sacrificed, and the weight of the heart, the thickness of the left ventricle wall and the myocardial pratein content were determined.
The values obtained in the 'two treated groups were significantly reduced and indistinguishable Exam the controls which had undergone a sham operation.
The examples which follow indicate the forms to be x0 administered for the 'treatment of cardiac and of vascular hypertrophy and hyperplasia by the method according to the invention. The compounds of the formula I can be converted into the forms appropriate fox administration in an~alagy to the examples.
~5 example ~.
)Preparation of the agent used according to the .invention far oral administration in the treatrnewt of cardiac and of vascular hypertrophy and hyperplasia.
- 17 - ~~', ?;1~ s';~;' ,'f ~ ',, 1000 tablets which each contain 10 mg of 1-N-(~.-S-car-bethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo-[3.3.0]octane-3-carboxylic acid are prepared with the following auxiliariess N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl- 10 g 1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid Corn starch 140 g Gelatin ~~5 g Microcrystalline cellulose ~~5 g Magnesium stearate 2.5 g Id-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid and corn starch are mixed with an aqueous gelatin solution. The mixture is dried and ground to granules. Microcrystalline cel lulose and magnesium stearate are mixed with the gran ules. The resulting granules are compressed to 1000 tablets, each tablet containing 10 mg of the 1~CE ins hibitor. These tablets can be used for the treatment of cardiac and of vascular hypertrophy and'Yiy.perplasia.
IExample 2 1000 tablets, each of which contains 1 mg of P1-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabi-cyclo[3.3.0]octane-3-carboxylic acid, are prepared in analogy to Example 1 by using 1 g of this compound in the mixture described in Example 1.
Example 3 100U tablets, each of which contains 10 mg of N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,?aS)-octa-hydroindole-Z-carboxylic acid hydrochloride, are prepared in analogy to Example 1.
,., : - / b If t - 1 ~ - f ~', ,a »~ :~'~ ''a 1..,: ;~!
Example 1000 tablets, each of which contains 1 mg of N-(~.-S
carbethoxy-3-phenyl-propyl)-S-alanyl-(~S,3aR,7aS)-octa_ hydroindole-2-carboxylic acid hydrochloride, are prepared in analogy to Example 2.
Example 5 Gelatin capsules, each of which contains 10 mg of N-(1 S-carbethoxy-3-phenyl-propyl),-S_alanyl-1S,3S,5S-2-azabi cyclo(3>3.0]octane-3-carboxylic acid, are filled with the ZO following mixtures N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl- 10 1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid Magnesium stearate 1 ~
Lactose ~1~ ~!
These capsules can be used for the treatment of athero-cardiac and of vascular hypertrophy and~liyperplasia.
Lxample 6 Gelatin capsules, each of which contains 1 mg of N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabi-cyclo[3.3.0]octane-3-carboxylic acid, are prepared analo-gously using ZO mg of active compound.
Examp~.e 7 The' preparation of a solution for ~.n~eot~ton for the treatment of cardiac and of vascular hypertrophy and hyperplasia is described bolows .,,, f., r~ ~'~
~~. , ~, :'l '. , . ~ ,';J
'~.~.;-')e; .:
dv : ., .
N-(Z-S-carboxy-3-phenyl-propyl)-S-alanyl- 250 rr~
1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid Methylparaben 5 Propylparaben Sodium chloride ~5 water for injections 5 1 N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid, the preserv-atives and sodium chloride are dissolved in 3 1 of water for injections and made up to 5 1 with water for injec-tions. 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 S
Tablets which can be used for the treatment of _,.
cardiac and'-of-vascular hypertrophy and hyperplasia -~ ' are prepared as described in Example 1, with the ?0 exception that, in place of N-(1-S-carbethoxy-3-phenyl propyl)-S-alanyl-~.S,3S,5S-~-azabicyclo[3.3.0]octane-3S
carboxylic acid, H-(1-S-c,srboxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S~-2-azabicyclo[3.3.0]octane-3-carboxylic acid or Z5 N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid or N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-2,3,3a,4,5,?a-hexahydro[1H]indole-2-S-endo-carboxylic acid or 30 PI-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-cis-2,3,4a,4,5,?a-hexahydro[1H]indole-2S-endo-carboxylic acid or ~1-(1-S-carboxy-3-phenyl-propyl)-S-lysyl-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid o~
35 N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid or I.,7 '~. ~l ~~n' N-(1-S-carboxy-3-cyclohexyl-propyl)-S-lysyl-1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid are used.
Example 9 A solution for injection is prepared in analog to the procedure described in Example 7 with the exception that in place of N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid, N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid or N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid hydrochloride or N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-oc~tahydroindole-2-carboxylic acid or N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-c:i.s-2,3,3a,4,5,7a-hexahydro(1H]indole-2-S-endo-carboxylic acid or N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-cis-2,3,3a,4,5,7a-hexahydro(1H]indole-2-S-endo-carboxylic acid or N-(1-carboxy-3-phenyl-propyl)-S-lysyl-1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid or N-(1-S-carbethoxy-3-cyclohexyl)-S-alanyl-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid or N-(1-S-carboxy-3-cyclohexyl-propyl)-S-lysyl-1S,3S,5S--2-azabicyclo[3.3.0]octane-3-carboxylic acid are used.
alkyl, (C3-CB)-cycloalkyl or (C3-C9)-cycloalkyl-( Ci-Ca ) -alkyl, and R'' and RS have the abovementioned meaning.
A particularly preferred embodiment aompri.ses using compounds of the formula I in which n is 1 or 2, R is (C1-Cs)-alkyl, (Cz-C6)-alkenyl, (C3-C9)-cycloalkyl, amino- (Cz-Ca ) -alkyl, ( Cz-CS ) -acylamino- ( Cl-Ca ) -alkyl, ( C~°C13 ) -aroylamino- ( C1-Ca ) -alkyl, ( Cl-Ca ) -alkoxy_ carbonylamino- ( Cl-Ca ) -alkyl, ( Cs-C~2 ) -aryl- ( Cl-Ca ) °' alkaxycarbonylamino-(Cl-Ca)-alkyl,(Cs-Clz)-aryl which can be mono-, di- or trisubstituted by ( C1-Ca ) -allcyl, ,~5 (Cz-Ca)-alkoxy, hydroxyl, halogen, nitro, amino, ( Cl-Ca ) --alkylamino, di- ( C1-Ca ) -alkylam:ino and/or rnethylenedioxy, or 3-indoly.l, in particular methyl, ethyl, cyclohexyl, tart. butoxycarbonylamino-(C1-Ca)-alkyl, benzoylaxycarbonylamino- ( C~-Ca ) -alkyl or ',:. ;,. .,,' 'rn~ f, ,~J
..., ?,i ~:,~ -..; -.
phenyl which can be mono- or disubstituted by phenyl, (C1-CZ)-alkyl, (C~ or CZ)-alkoxy, hydroxyl.
fluorine, chlorine, bromine, amino, (Cl-Ca)-alkyl-amino, di(C~,-Ca)-alkylamino, nitro and/or methyl-enedioxy or, in the case of methoxy, trisubstituted, Rl is hydrogen or (C1-Cs)-alkyl which can optionally be substituted by amino, (C1-C6)-acylamino or benzoyl-amino, or (CZ-Co)-alkenyl, (C3-Co)-cycloalkyl, ( CS-C9 ) -cycloalkenyl , ( C3-C7 ) -cyclnalkyl- ( Ca-Ca ) -alkyl , (C~°C1~)-aryl or partially hydrogenated aryl, each of which can be substituted by ( Cl-Ca ) -alkyl, ( Cl or CZ) -alkoxy or halogen, or ( Cs-C12 ) -aryl- ( C1 to Ca ) -alkyl or ( C~-C13 ) -aroyl- ( Ci-Cz ) -alkyl , both of which can be substituted in the aryl radical as defined above, or a mono- or bicyclic heterocyclic radical with 5 to 7 or 8 to 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen atoms, or a side-chain of a naturally occurring, optionally protected a-amino acid, but in 2 0 particular hydrogen, ( C1-C~ ) -alkyl , ( CZ or C3 ) - .
alkenyl, the optionally protected sills-chain of lysine, benzyl, ~-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-aminobutyl or benzoylmethyl, R2 and R3 are identical or different radicals and are 2 ~ hydrogen, ( Cl-Cg ) -alkyl, ( CZ-Cb ) ialkenyl or ( Cs-Cy2 ) aryl-(C1-Ca)-alkyl, but in particular hydrogen, ( C1-Ca ) -alkyl or benzyl , and R° and RS have the abovementioned meaning.
Particularly preferred is the use of compounds of 30 the formula x in which n is ~, R is Qhenyl, R1 is methyl, RZ and R3 are identical or different (Cl-CB)-alkyl radicals or (C7-Clo)-aralkyl radicals such as benzyl or nitro benzyl, and Ra and R3 together are a radical of the formula n~ l < 'S
_ 7 _ t,' J:
(~~~P
K
- (CFi~~m in which m is 0 or 1, p is 0, 1 or 2 and X is -CHZ-, -CFh-CHZ- or -CH=CH-, it also being possible fax a 6-membered ring formed with X to be a benasene ring.
Aryl preferably means here and hereinafter optionally substituted phenyl, biphenylyl or naphthyl. A
corresponding statement applies to radicals derived from aryl, such as aryloxy and arylthio. Aroyl particularly means benzoyl. Aliphatic radicals can be straight-chain or branched.
Rxamples of the meaning of a mono- or bicyclic heterocyclic radical with 5 to 7 or 8 ~0 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or of which Z to 4 ring atoms are nitrogen atoms, are thienyl, benza[b]thienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naph~thyrad-inyl, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, ~0 oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. these radicals can also be partially or completely hydrogenated, Naturally occurring «-amino acids are described, for example, in I3ouben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry) Vol. XV/1 and XVf2.
If R1 is a sid~-chain of a protected naturally occurring «-amino acid, such as, for example, protected Ser, ~Chr, Asp, Asn, Glu, Oln, Arg, ~ys, ~iyl, Cys, Orn, Cit, ',~yr, '.~rp, His or Hyp, preferred protective groups are the groups customary in peptide chemistry (cf.
Flouben-Weyl, Vol. XV/1 and XV/2). In 'the case where R~ is the protected lysine side-chain, the known amino protec-tive groups, but in particular Z, ftoc or ~Cl-CB)-alkanoyl, are preferred. Suitable and preferred O-protective groups r1 ~,.) p ~..,yy a ', t',7 ~J '..V ~i~ f.~l ._. .'~.,,j , .
- $ -for tyrosine axe (C1-C~)-alkyl, in particular methyl or ethyl.
The follo~ring compounds can be particularly advantageously used in the method according to the invention:
N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acict N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-S-1,2,3,4-tetrahydroisoc~uinoline-3-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-3S-decahydro-isoguinoline-3-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-(2S,3aS,?aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-(2S,3aS,7aS)-octahydroindole-2-carboxyl3.c acid N-(1-S-Carbethoxy-3-(3,4-dimethylphenyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-[1-S-Carbathoxy-3-(4-fluorophenyl)-propyl]-S-alan;yl-(2S,3aS,7aS)-octahydroindole-2-carboxylic said N-[~,-S-Carbethoxy-3-(4-methoxyphenyl)--propyl]-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-[1-S-Carbethoxy-3-(3,4-dimethoxyphenyl)-propyl~-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclopentylpropyl)-S-alanyl-(2S,3aS,7aS)-actahydroindole--2-carboxylic acid ~~ ~ (k \~ t4, ,f~
r ~1 ;1 .., 4~,~ ' J a.~ :,~'r i1i l, d N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-0-ethyl-S-tyrosyl-(2S,3aS,7aR)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aR)-octahydroindale-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-(2S,3aR,7aR)-octahydroindale-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-O-ethyl-S-vyrosyl-(2S,3aR,7aR)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aR)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-0-ethyl-S-tyrosyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3,4-dimethylphenyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-[1-S-Carbethoxy-3-(4-fluorophenyl)-propyl]-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carbo:cylic acid N-[1-S-Carbethoxy-3-(4-methoxyphenyl)-propyl]-S-alan;yl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-[1-S-Carbethaxy-3-(3,~-dimethoxyphenyl)-propyl]-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-cyclopentylpropyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(Z-S-Carboxy-3-ayclohexyl-propyl)-S-alanyl-c3.s-ends-2-,:.. ''.;. ~.~ ;:~~ ~_:; , '..J
- to -azabicyclo[3.3.0]octane-2-S-carboxylic acid N-(1-S-Carbethoxy-bwty~)-S-alanyl-cis-endo-2-azabicyclo-[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-(3,4-dimethoxyphenylpropyl)-S-alanyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclopentyl-propyl)-S-alanyl-cis-endo-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Caxbethoxy-3-phenyl-propyl)-O-anethyl-S-tyrosyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyxosyl-cis-endo-2-azabicyclo[3.3.0]octane--3-S-carboxylic acid N-(1-S-Carbethoxy-3-(4-flaaoxophenyl-propyl)-S-alanyl-cis-endo-azabicyclo[3.3.0]octane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-(4-methoxyphenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic ac:i.d N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,6aS)-octahydrocyclopenta[b]pyrxole-2-carboxylic acid N-(1-S-Caxbethoxy-3-cyclohexylpxopyl)-lysyl-(2S,3aR,6aS)-octahydrocycaopenta[b]pyxrole-2-carboxylic acid N-(1-S-Caxbethoxy-3-phenyl-propyl)-O-ethyl-S-tyxosyl-(2S,3aR,6aS)-octahydxocyclopenta[b]pyrxole-2-carboxylic acid N-(1-S-Caxbethoxy-3-phenyl-pxopyl)-S-alanyl-2-(2S,3aR,6aS)octahydrocyclopenta[b]pyrrole-2-carboxylic acid N-(1-S~Caxbethoxy-3-phenyl-prapyl)-S-alanyl-2-azaspi.ro-[4,5]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-O-ethyl-2-tyrosyl-azaspixo-[4,5]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-2-azaspixo-[4,5]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-ayclohexylpropyl)-S-alanyl-2-aza-sp3ro-[~,5]decane-3-S-carboxylic acid N-(1-S-~Caxbethoxy-3-cyclohexylpxopyl)-S-lysyl-2-azaspiro-[4,5]decane-3-S-carboxylic acid N-(1-S-Caxbethoxy-3-phenyl-pxopyl)-S-alanyl-2-azaspixo-[4,4]nonane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propy:l)-O-ethyl-S-tyrasyl.-2-azaspiro[4,~]nonane-3-S-carboxylic acid ,f, ;i, ,~
,.,. °'°~ s.' G.3 ;i ;
N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-2-azaspiro-[4,4]nonane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-2-a~a-spiro[4,4]nonane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclopentyl-propyl)-S-alanyl-2-azaspiro[4,4]nonane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclopentyl-propyl)-S-lysyl-2-a~a-spiro[4,4]nonane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-spire[bi-cyclo[2.2.1]heptane-2,3'-pyrrolidine]-5'-S-carboxylic ac id N-(1-S-Carbethoxy-3-phenyl-propyl)-0-ethyl-S-tyrosyl-spiro[bicyclo[2.2.1]hegtane-2,3'-pyrrolidine]-5'-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-spiro[bicyclo-[2.2.1]heptane-2,3°-pyrrolidine]-5'-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-spiro-[bicyclo[2.2.1]heptane-2,3°-pyrrolidine]5°-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-spiro-[bicyclo[2.2.1]heptane-2,3'-pyrrolidine]-5'-S-carboxylic ac id N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-spiro~
[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-0-ethyl-tyrosyl-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-spiro[bicyclo-[2.2.2]octane-2,3'-pyrrolidine]-5'-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-spiro-[b:i.cyclo[2.2.2]octane-2,3°-pyrrolidine]-5'-S-carboxylic ac id N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-2-azatri-cyclo[4,3,0,1°'°]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-o-ethyl-S-tyrosyl-2-a~atricyclo[4,3,0,18°]decane-3-S-carboxylic said ~~-(1-S-Carbe~thoxy-3-phenyl-propyl)-S-lysyl-2-azatricyclo-[4,3,0,1°'°]decane-3-S-carboxylic said ,, S.S .;~ .r..s t-: ~t ~;rJ ~~,.A n. ~. -. .... 'L' N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-2-azatri-cyclo[4,3,0,16'9]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-2-azatri-cyclo[4,3,0,16'9]decane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-decahydxo-cyclohepta[b]pyrrole-2-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-o-ethyl-S-tyrosyl-decahydrocyclahepta[b]pyrrole-2-S-carbo3~ylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-decahydro-cyclohepta[b]pyrrole-2-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-deca-hydrocyclohepta[b]pyxrole-2-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-decahydro-cyclohepta[b]pyrrole-2-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-traps-octa-hydroisoindole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-c.is-octa-hydroisoindole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-trans-octahydroisoindole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-octahydroisoindole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-cis-octa-hydrocyclopenta[c]pyrrole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-octahydrocyclopenta[c]pyrrole-1-S-carboxylic acid-benzyl ester N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-lysyl-cis-octahydrocyclopenta[c]pyrrole-1-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-2,3,3a,~,5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-2,3,3a,4,5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid N-(1-S-Carbethaxy-3-cyclohexyl-propyl)-S-lysyl-2-azabi-cyclo[3.1.0]hexane-3-S-carboxylic acid N-(1-S-Carboxy-3-phenyl-propyl)-S-lys~yl-2-azabicyclo-[3.1.0]hexane-cis-endo-3-S-carboxylic said N-(1-S-Carbethoxy-3-cyclopentylpropyl)-S-alanyl-2-aza-Cw ~ ''''~1 ~ " ~ ~ Zr:~
a_1 ..
~'~ j f,,.; °..i bicyclo[3.1.0]hexane-3-carboxylic acid N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid N-(1-S-Carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid These compounds can be prepared, for example, by the process described in German Patent Application P 3,333,455.2, in which the tart. butyl or benzyl radi-cals described in the application are converted in a known manner by acid or alkaline hydrollrsis or by noble metal-catalyzed hydrogenolysis into the monocarboxylic acid derivatives. The N'-benzyloxycarbonyl protective group of the lysine derivatives is removed by noble metal-catalyzed hydrogenolysis. The compounds listed above can easily be converted with physiologically tolerated acids or bases (in the case of mono- or di-carboxylic acids) into the corresponding salts (for example hydrochlorides, maleates, fumarates etc.) and used according to the invention as salts.
The compounds of the formula T are inhibitors of angiotensin converting enzyme (ACE) or intermediates for the preparation of inhibitors of this type, and can also be employed for controlling high blood pressure of a variety of etiologies. The compounds of the formula I are disclosed, for example, in US Patent 4,129,5?1, US
Patent 4,374,829, EP-A-79,522, EP-A-79,022, EP-A-49,65$, EP-A-51,301, US Patent 4,454,292, US Patent 4,374,847, Ep-A-72,352, US Patent 4,350,704, Ep-A-50,800, EP-A-46,953, US Patent 4,344,949, EP-A-84,164, US patent 4,470,972, EP-A-65,301 arid Ep-A-52,991.
Also advantageous are orally effective ACE inhibitors such as, for example, ramipril, enalapril, captopril, lisl,x~opr~.l, perindopril, cilazapril, RHC 3659, CGS 13945, CGS 1392$0, CGS 14824A, C1-906, SCH 31846, zofenopril, fosenopril, alacepril and others. Orally e:~fective ACE
inhibitors are described, for example, in Brunner et al . , J. Cardiovasc. Pharmacol. 7 (Suppl. I) [1985] 52-511.
!.~ ~'' -Preferred AC1E inhibitors are those of the formula III
disclosed in RP-A-79,022 CooH
(s) 4s) g ~ ~H ~ ~IH - CH - CH2 - CH2 ~ 1~ I I I ) O CHI boor in which R is hydrogen, anethyl, ethyl or benzyl, in particular the compound of the formula III in which R is ethyl (ramipril).
Additionally preferred are the ACS inhibitors of the formula IV disclosed in EP-A-8,164 H
CooH ( I'~) to (s) (s) N
~ ~ c a cH - NH - cH -~cHZ ~ cx~
cH~ cooR
in which R° is hydrogen, (C~-C4)-alkyl or benzyl, in particular the compound of the formula I't7 in which R4 is ethyl.
Applying the method according to the invention, it is possible to adminster the angiotensin converting enzyme inhibitors described above to mammals such as monkeys, dogs, cats, rats, humans etc. The compounds suitable for the use according to the invention are expediently incorporated in a customary manner into pharmaceutical 2o products. They can be converted into the customary administration farms such as capsules, tablets, coated tablets, solutions, ointments, emulsions and into depot form too. The active aampound can also, where appro-priate, be present in microencapsulated form. The pro-dusts can contain tolerated organic or inorr~an~.c ,.r,.t~7 ~ ~~A
ieD '~:i' additives, for example granulating auxiliaries, adhesives and binders, lubricants, suspending agents, solvents, antibacterial agents, wetting agents and preservatives.
Forms for oral and parenteral administration are pre-y ferred. The compounds of the formula I can be admin-istered in doses of 0.001 mg/kg - 20 mg/kg, in particular 0.005 mg/kg - 1 mg/kg, once to three times a day.
Growth factors which lead to proliferation and to swel-ling of cells make a crucial contribution to the develop-meat of cardiac hypertrophy as a consequence of hyper-tension, and in the hypertrophy and hyperplasia of smooth muscles of vessels, as are observed in hypertension and in the development of atherosclerotic plaques.
I-t is known from the literature that angiotensin II is a growth factor of this type. Treatment of muscle cells with angiotensin II leads to stimulation of phospho-lipase C (J. Biol. Chem. 260, 8901 (1986)), to mobiliza-tion of intracellular calcium (Hypertension 7, 447 (1988)), to activation of Naø/H~ exchange (J. Biol.
Chem. 262, 5057 (1987) and to activation of protein synthesis and induction of messenger RNA for the c-fos protooncogene (J. Biol. Chem. 264, 526 (1989)). Further-more, angiotensin II potentiates the proliferative action of other growth factors such as PnGF and EGF (,~lmer. J.
Physiol (1987), F 299). These described orations of angiotensin II are mainly elicited by locally synthesized peptide. Compounds capable of local prevention of ~the formation of angiotensin II ought therefore to have an action on hypertrophy and hyperplas:ia of smooth muscle of vessels, and of the myocardium. P~~ have now found, surprisingly, that inhibitors of angiotensin converting enzyme are able to abolish the described ~trophic effects of arxgiotensin II even at doses at which they do not yet display an antihypertens3:ve action.
The results with IJ-(1-~-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.x.0]octane-3-S-carboxylic ~,,~ f,~; ,~'~. ,;,~~ °w)' ;.~t e3 - is -acid (formula IIj in each case are to serve as examples hereinafter.
H
~C00!3 ~J'~~
H N
i C
o~ ~'cH-uH-cu-cH2-cH~ ~
CH3 C02G~H~
Description of e~pera~nents Cardiac hypertrophy was generated in conscious rats by constriction of the abdominal aorta. Once this had been completely established, groups of the animals received 1 mglkg/d (antihypertensive dosej or 10 ugJkgld (non-antihypertensive dose] of the compound of the formula II
ZO by oral administration fox 3 weeks. Control groups of animals which were not given the substance and which had undergone a sham operation were included. e'~fter the end of the ~ weeks, the animals were sacrificed, and the weight of the heart, the thickness of the left ventricle wall and the myocardial pratein content were determined.
The values obtained in the 'two treated groups were significantly reduced and indistinguishable Exam the controls which had undergone a sham operation.
The examples which follow indicate the forms to be x0 administered for the 'treatment of cardiac and of vascular hypertrophy and hyperplasia by the method according to the invention. The compounds of the formula I can be converted into the forms appropriate fox administration in an~alagy to the examples.
~5 example ~.
)Preparation of the agent used according to the .invention far oral administration in the treatrnewt of cardiac and of vascular hypertrophy and hyperplasia.
- 17 - ~~', ?;1~ s';~;' ,'f ~ ',, 1000 tablets which each contain 10 mg of 1-N-(~.-S-car-bethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo-[3.3.0]octane-3-carboxylic acid are prepared with the following auxiliariess N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl- 10 g 1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid Corn starch 140 g Gelatin ~~5 g Microcrystalline cellulose ~~5 g Magnesium stearate 2.5 g Id-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid and corn starch are mixed with an aqueous gelatin solution. The mixture is dried and ground to granules. Microcrystalline cel lulose and magnesium stearate are mixed with the gran ules. The resulting granules are compressed to 1000 tablets, each tablet containing 10 mg of the 1~CE ins hibitor. These tablets can be used for the treatment of cardiac and of vascular hypertrophy and'Yiy.perplasia.
IExample 2 1000 tablets, each of which contains 1 mg of P1-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabi-cyclo[3.3.0]octane-3-carboxylic acid, are prepared in analogy to Example 1 by using 1 g of this compound in the mixture described in Example 1.
Example 3 100U tablets, each of which contains 10 mg of N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,?aS)-octa-hydroindole-Z-carboxylic acid hydrochloride, are prepared in analogy to Example 1.
,., : - / b If t - 1 ~ - f ~', ,a »~ :~'~ ''a 1..,: ;~!
Example 1000 tablets, each of which contains 1 mg of N-(~.-S
carbethoxy-3-phenyl-propyl)-S-alanyl-(~S,3aR,7aS)-octa_ hydroindole-2-carboxylic acid hydrochloride, are prepared in analogy to Example 2.
Example 5 Gelatin capsules, each of which contains 10 mg of N-(1 S-carbethoxy-3-phenyl-propyl),-S_alanyl-1S,3S,5S-2-azabi cyclo(3>3.0]octane-3-carboxylic acid, are filled with the ZO following mixtures N-(1-S-Carbethoxy-3-phenyl-propyl)-S-alanyl- 10 1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid Magnesium stearate 1 ~
Lactose ~1~ ~!
These capsules can be used for the treatment of athero-cardiac and of vascular hypertrophy and~liyperplasia.
Lxample 6 Gelatin capsules, each of which contains 1 mg of N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabi-cyclo[3.3.0]octane-3-carboxylic acid, are prepared analo-gously using ZO mg of active compound.
Examp~.e 7 The' preparation of a solution for ~.n~eot~ton for the treatment of cardiac and of vascular hypertrophy and hyperplasia is described bolows .,,, f., r~ ~'~
~~. , ~, :'l '. , . ~ ,';J
'~.~.;-')e; .:
dv : ., .
N-(Z-S-carboxy-3-phenyl-propyl)-S-alanyl- 250 rr~
1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid Methylparaben 5 Propylparaben Sodium chloride ~5 water for injections 5 1 N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid, the preserv-atives and sodium chloride are dissolved in 3 1 of water for injections and made up to 5 1 with water for injec-tions. 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 S
Tablets which can be used for the treatment of _,.
cardiac and'-of-vascular hypertrophy and hyperplasia -~ ' are prepared as described in Example 1, with the ?0 exception that, in place of N-(1-S-carbethoxy-3-phenyl propyl)-S-alanyl-~.S,3S,5S-~-azabicyclo[3.3.0]octane-3S
carboxylic acid, H-(1-S-c,srboxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S~-2-azabicyclo[3.3.0]octane-3-carboxylic acid or Z5 N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid or N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-2,3,3a,4,5,?a-hexahydro[1H]indole-2-S-endo-carboxylic acid or 30 PI-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-cis-2,3,4a,4,5,?a-hexahydro[1H]indole-2S-endo-carboxylic acid or ~1-(1-S-carboxy-3-phenyl-propyl)-S-lysyl-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid o~
35 N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid or I.,7 '~. ~l ~~n' N-(1-S-carboxy-3-cyclohexyl-propyl)-S-lysyl-1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid are used.
Example 9 A solution for injection is prepared in analog to the procedure described in Example 7 with the exception that in place of N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid, N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid or N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid hydrochloride or N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-oc~tahydroindole-2-carboxylic acid or N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-c:i.s-2,3,3a,4,5,7a-hexahydro(1H]indole-2-S-endo-carboxylic acid or N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-cis-2,3,3a,4,5,7a-hexahydro(1H]indole-2-S-endo-carboxylic acid or N-(1-carboxy-3-phenyl-propyl)-S-lysyl-1S,3S,5S-2-azabicyclo(3.3.0]octane-3-carboxylic acid or N-(1-S-carbethoxy-3-cyclohexyl)-S-alanyl-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid or N-(1-S-carboxy-3-cyclohexyl-propyl)-S-lysyl-1S,3S,5S--2-azabicyclo[3.3.0]octane-3-carboxylic acid are used.
Claims (26)
1. An angiotensin converting enzyme inhibitor of formula I or physiologically tolerated salt thereof for administration as agent for the treatment of cardiac and of vascular hypertrophy and hyperplasia, wherein formula I is of the formula;
in which n is 1 or 2, R is hydrogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbon atoms, aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C1-C4)-alkyl, (C1-C4) alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, (C1-C4)-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy with 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and can be substituted as described above for aryl, mono- or bicyclic heteroaryloxy which has 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen, and which can be substituted as described above for aryl, amino- (C1-C4)-alkyl, (C1-C4)-alkanoylamino- (C1-C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl, (C1-C4)-alkoycarbonylamino-(C1-C4)-alkyl, (C6-C12)-aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)alkyl, (C6-C12)-aryl (C1-C4)-alkylamino-(C1-C4 )-alkyl, (C1-C4)-alkylamino-(C1-C4)-alkyl, di(C1-C4)-alkylamino-(C1-C4)-alkyl, guanidino-(C1-C4)-alkyl, imidazolyl, indolyl, (C1-C4)-alkylthio, (C1-C4)-alkylthio-(C1-C4)-alkyl, (C6-C12)-arylthio-(C1-C4)-alkyl which can be substituted in the aryl moiety as described above for aryl, (C6-C12)-aryl-(C1-C4)-alkylthio which can be substituted in the aryl moiety as described above for aryl, carboxy-(C1-C4)-alkyl, carboxyl, carbamoyl, carbamoyl-(C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl-(C1-C4)-alkyl, (C6-C12)-aryloxy-(C1-C4)-alkyl which can be substituted in the aryl moiety as described above for aryl, or (C6-C12)-aryl-(C1-C4)-alkoxy which can be substituted in the aryl moiety as described above for aryl, R1 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with
in which n is 1 or 2, R is hydrogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbon atoms, aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C1-C4)-alkyl, (C1-C4) alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, (C1-C4)-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy with 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and can be substituted as described above for aryl, mono- or bicyclic heteroaryloxy which has 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen, and which can be substituted as described above for aryl, amino- (C1-C4)-alkyl, (C1-C4)-alkanoylamino- (C1-C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl, (C1-C4)-alkoycarbonylamino-(C1-C4)-alkyl, (C6-C12)-aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)alkyl, (C6-C12)-aryl (C1-C4)-alkylamino-(C1-C4 )-alkyl, (C1-C4)-alkylamino-(C1-C4)-alkyl, di(C1-C4)-alkylamino-(C1-C4)-alkyl, guanidino-(C1-C4)-alkyl, imidazolyl, indolyl, (C1-C4)-alkylthio, (C1-C4)-alkylthio-(C1-C4)-alkyl, (C6-C12)-arylthio-(C1-C4)-alkyl which can be substituted in the aryl moiety as described above for aryl, (C6-C12)-aryl-(C1-C4)-alkylthio which can be substituted in the aryl moiety as described above for aryl, carboxy-(C1-C4)-alkyl, carboxyl, carbamoyl, carbamoyl-(C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl-(C1-C4)-alkyl, (C6-C12)-aryloxy-(C1-C4)-alkyl which can be substituted in the aryl moiety as described above for aryl, or (C6-C12)-aryl-(C1-C4)-alkoxy which can be substituted in the aryl moiety as described above for aryl, R1 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with
2-6 carbon atoms, alkynyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbon atoms, cycloalkenyl with 5-9 carbon atoms, (C3-C9)-cycloalkyl-(C1C4)-alkyl, (C5-C9)-cycloalkenyl-(C1-C4)-alkyl, optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted as described above for R, (C6-C12)-aryl-(C1-C4)-alkyl or (C7-C13)-aroyl-(C1 or C2)-alkyl, both of which can be substituted like the aryl above, mono- or bicyclic, optionally partially hydrogenated heteroaryl which has 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen atoms, and which can be substituted like the aryl above, or the optionally protected side-chain of a naturally occurring .alpha.-amino acid R1-CH(NH2)-COOH, R2 and R3 are identical or different and are hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, di-(C1-C4) -alkylamino-(C1-C4)-alkyl, (C1-C5)-alkanoyloxy-(C1-C4)-alkyl, (C1-C6)-alkoxycarbonyloxy-(C1-C4)-alkyl, (C7-C13)-aroyloxy-(C1-C4)-alkyl, (C6-C12) -aryloxycarbonyloxy (C1-C4)-alkyl, aryl with 6-12 carbon atoms, (C6-C12)-aryl-(C1-C4)-alkyl, (C3-C9)-cycloalkyl or (C3-C9)-cycloalkyl-(C1-C4)-alkyl, and R4 and R5 together with the atoms carrying them, are an optionally substituted system from the series comprising tetra-hydroisoquinoline, 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 [4,3,0,1 6,9]decane, decahydrocyclohepta [b]pyrrole, octahydroisoindole, octahydrocyclopenta [c]pyrrole, 2,3,3a,4,5,7a-hexahydroindole and 2-azabicyclo
[3.1.0]hexane.
2. The angiotensin converting enzyme inhibitor of claim 1, wherein the enzyme inhibitor is [S,S,S,S,S]-N-(1-carbethoxy-3-phenyl-propyl) -alanyl-octahydroindole-2-carboxylic acid or the corresponding dicarboxylic acids thereof.
3. The angiotensin converting enzyme inhibitor of claim 1, wherein the enzyme inhibitor is N-[1-(S)-carbethoxy-3-phenyl-propyl-(S) -alanyl]-2S,3aR, 7aS-octahydroindole-2-carboxylic acid or the corresponding dicarboxylic acids thereof.
2. The angiotensin converting enzyme inhibitor of claim 1, wherein the enzyme inhibitor is [S,S,S,S,S]-N-(1-carbethoxy-3-phenyl-propyl) -alanyl-octahydroindole-2-carboxylic acid or the corresponding dicarboxylic acids thereof.
3. The angiotensin converting enzyme inhibitor of claim 1, wherein the enzyme inhibitor is N-[1-(S)-carbethoxy-3-phenyl-propyl-(S) -alanyl]-2S,3aR, 7aS-octahydroindole-2-carboxylic acid or the corresponding dicarboxylic acids thereof.
4. The angiotensin converting enzyme inhibitor of claim 1, wherein the enzyme inhibitor is [S,S,S,S,S]-N-[(1-carbethoxy-3-phenyl-propyl-alanyl]-decahydroisoquinoline-3-carboxylic acid or the corresponding dicarboxylic acids thereof.
5. The angiotensin converting enzyme inhibitor of claim 1, wherein the enzyme inhibitor is [S,S,S]-N-[(1]carbethoxy-3-phenyl -propyl)-alanyl]-tetra-hydroisoquinoline-3-carboxylic acid or the corresponding dicarboxylic acids thereof.
6. The angiotensin converting enzyme inhibitor of claim 1, wherein the enzyme inhibitor is (S,S,S,S,S)-N-(1-carbethoxy-3-phenyl-propyl) -alanyl-2-azabicyclo[3.3.0]octane-3-carboxylic acid or the corresponding dicarboxylic acids thereof.
7. The angiotensin converting enzyme inhibitor of claim 1, wherein the enzyme inhibitor is N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid or the corresponding dicarboxylic acids thereof.
8. The angiotensin converting enzyme inhibitor of claim 1, wherein the enzyme inhibitor is N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2,3,3a,4,5,7a-hexahydroindole-2-S-carboxylic acid or the corresponding dicarboxylic acids thereof.
9. An angiotensin converting enzyme inhibitor as claimed in any one of claims 1 to 8 in combination with pharmaceutically suitable vehicles and auxiliaries for the forms appropriate for administration.
10. A pharmaceutical agent containing a compound of the formula I as claimed in any one of claims 1 to 8, or the physiologically tolerated salt thereof, and a tolerated organic or inorganic additive, for administration for the treatment of cardiac and of vascular hypertrophy and hyperplasia.
11. A use of a compound of the formula I as claimed in any one of claims 1 to 8 or of an agent as claimed in claim 10 for the treatment of cardiac and of vascular hypertrophy and hyperplasia.
12. An angiotensin converting enzyme inhibitor as claimed in any one of claims 1 to 8 for the treatment of cardiac hypertrophy and hyperplasia.
13. An angiotensin converting enzyme inhibitor as claimed in any one of claims 1 to 8 for the treatment of vascular hypertrophy and hyperplasia.
14. A use of an angiotensin converting enzyme inhibitor or physiologically tolerated salt thereof in the preparation of a medicament, for the treatment of cardiac and of vascular hypertrophy and hyperplasia in mammals, wherein the enzyme inhibitor is of the formula I
in which n is 1 or 2, R is hydrogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbon atoms, aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, (C1-C4)-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy with 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and can be substituted as described above for aryl, mono- or bicyclic heteroaryloxy which has 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen, and which can be substituted as described above for aryl, amino-(C1-C4)-alkyl, (C1-C4)-alkanoylamino-(C1-C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl, (C1-C4)-alkoxcycarbonylamino(C1-C4)-alkyl, (C6-C12)-aryl-(C1-C4) -alkoxycarbonylamino-(C1-C4)alkyl, (C6-C12)-aryl-(C1-C4)-alkyl amino-(C1-C4)-alkyl, (C1-C4)-alkylamino-(C1C4) -alkyl, di-(C1-C4)-alkylamino-(C1-C4)-alkyl, guanidino-(C1-C4)-alkyl, imidazolyl, indolyl, (C1-C4)-alkylthio, (C1-C4)-alkylthio-(C1-C4)-alkyl, (C6-C12)-arylthio-(C1-C4)-alkyl which can be substituted in the aryl moiety as described above for aryl, (C6-C12)-aryl-(C1-C4)-alkylthio which can be substituted in the aryl moiety as described above for aryl, carboxy-(C1-C4)-alkyl, carboxyl, carbamoyl, carbamoyl- (C1-C4) -alkyl, (C1-C4)-alkoxycarbonyl- (C1-C4)alkyl, (C6-C12)-aryloxy-(C1-C4)-alkyl which can be substituted in the aryl moiety as described above for aryl, or (C6-C12)-aryl-(C1-C4)-alkoxy which can be substituted in the aryl moiety as described above for aryl, R1 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbon atoms, cycloalkenyl with 5-9 carbon atoms, (C3-C9)-cycloalkyl-(C1-C4)-alkyl, (C5-C9)-cycloalkenyl-(C1-C4)-alkyl, optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted as described above for R, (C6-C12)-aryl-(C1-C4)-alkyl or (C7-C13)-aroyl-(C1 or C2)-alkyl, both of which can be substituted like the aryl above, mono- or bicyclic, optionally partially hydrogenated heteroaryl which has 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen atoms, and which can be substituted like the aryl above, or the optionally protracted side-chain of a naturally occurring .alpha.-amino acid R1-CH(NH2)-COOH, R2 and R3 are identical or different and are hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, di-(C1-C4)-alkylamino-(C1-C4)-alkyl, (C1-C5)-alkanoyloxy-(C1-C4)-alkyl, (C1-C6)-alkoxycarbonyloxy (C1-C4)-alkyl, (C7-C13)-aroyloxy-(C1-C4)-alkyl, (C6-C12)-aryloxycarbonyloxy (C1-C4)-alkyl, aryl with 6-12 carbon atoms, (C6-C12)-aryl-(C1-C4)-alkyl, (C3-C9)-cycloalkyl or (C3-C9)-cycloalkyl-(C1-C4) -alkyl, and R4 and R5, together with the atoms carrying them, are an optionally substituted system from the series comprising tetra-hydroisoquinoline, 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[4,3,0,169]decane, decahydrocyclohepta[b]pyrrole, octahydroisoindole, octahydrocyclopenta[c]pyrrole, 2,3,3a,4,5,7a-hexahydroindole and 2-azabicyclo [3.1.0]hexane.
in which n is 1 or 2, R is hydrogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbon atoms, aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, (C1-C4)-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy with 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and can be substituted as described above for aryl, mono- or bicyclic heteroaryloxy which has 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen, and which can be substituted as described above for aryl, amino-(C1-C4)-alkyl, (C1-C4)-alkanoylamino-(C1-C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl, (C1-C4)-alkoxcycarbonylamino(C1-C4)-alkyl, (C6-C12)-aryl-(C1-C4) -alkoxycarbonylamino-(C1-C4)alkyl, (C6-C12)-aryl-(C1-C4)-alkyl amino-(C1-C4)-alkyl, (C1-C4)-alkylamino-(C1C4) -alkyl, di-(C1-C4)-alkylamino-(C1-C4)-alkyl, guanidino-(C1-C4)-alkyl, imidazolyl, indolyl, (C1-C4)-alkylthio, (C1-C4)-alkylthio-(C1-C4)-alkyl, (C6-C12)-arylthio-(C1-C4)-alkyl which can be substituted in the aryl moiety as described above for aryl, (C6-C12)-aryl-(C1-C4)-alkylthio which can be substituted in the aryl moiety as described above for aryl, carboxy-(C1-C4)-alkyl, carboxyl, carbamoyl, carbamoyl- (C1-C4) -alkyl, (C1-C4)-alkoxycarbonyl- (C1-C4)alkyl, (C6-C12)-aryloxy-(C1-C4)-alkyl which can be substituted in the aryl moiety as described above for aryl, or (C6-C12)-aryl-(C1-C4)-alkoxy which can be substituted in the aryl moiety as described above for aryl, R1 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbon atoms, cycloalkenyl with 5-9 carbon atoms, (C3-C9)-cycloalkyl-(C1-C4)-alkyl, (C5-C9)-cycloalkenyl-(C1-C4)-alkyl, optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted as described above for R, (C6-C12)-aryl-(C1-C4)-alkyl or (C7-C13)-aroyl-(C1 or C2)-alkyl, both of which can be substituted like the aryl above, mono- or bicyclic, optionally partially hydrogenated heteroaryl which has 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen atoms, and which can be substituted like the aryl above, or the optionally protracted side-chain of a naturally occurring .alpha.-amino acid R1-CH(NH2)-COOH, R2 and R3 are identical or different and are hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, di-(C1-C4)-alkylamino-(C1-C4)-alkyl, (C1-C5)-alkanoyloxy-(C1-C4)-alkyl, (C1-C6)-alkoxycarbonyloxy (C1-C4)-alkyl, (C7-C13)-aroyloxy-(C1-C4)-alkyl, (C6-C12)-aryloxycarbonyloxy (C1-C4)-alkyl, aryl with 6-12 carbon atoms, (C6-C12)-aryl-(C1-C4)-alkyl, (C3-C9)-cycloalkyl or (C3-C9)-cycloalkyl-(C1-C4) -alkyl, and R4 and R5, together with the atoms carrying them, are an optionally substituted system from the series comprising tetra-hydroisoquinoline, 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[4,3,0,169]decane, decahydrocyclohepta[b]pyrrole, octahydroisoindole, octahydrocyclopenta[c]pyrrole, 2,3,3a,4,5,7a-hexahydroindole and 2-azabicyclo [3.1.0]hexane.
15. The use as claimed in claim 14, wherein the enzyme inhibitor is [S,S,S,S,S]-N--(1-carbethoxy-3-phenyl-propyl)-alanyl octahydroindole-2-carboxylic acid.
16. The use as claimed in claim 14, wherein the enzyme inhibitor is N-[1-(S)-carbethoxy-3-phenyl-propyl-(S)-alanyl]-2;S,3aR,7aS-octahydroindole-2-carboxylic acid.
17. The use as claimed in claim 14, wherein the enzyme inhibitor is [S,S,S,S,S]-N-[(1-carbethoxy-3-phenyl-propyl)-alanyl]decahydroisoquinoline-3-carboxylic acid.
18. The use as claimed in claim 14, wherein the enzyme inhibitor is [S,S,S]-N-[11-carbethoxy-3-phenyl-propyl)-alanyl]- tetrahydroisoquinoline-3-carboxylic acid.
19. The use as claimed in claim 14, wherein the enzyme inhibitor is (S,S,S,S,S)-N-(1-carbethoxy-3-phenyl-propyl)-alanyl-2-azabicyclo[3.3.0]octane-3-carboxylic acid.
20. The use as claimed in claim 14, wherein the enzyme inhibitor is N-(1-S-carbetboxy-3-phenyl-propyl)-S-alanyl-cisendo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid.
21. The use as claimed in claim 14, wherein the enzyme inhibitor is N-(1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl-cisendo-2,3,3a,4,5,7a-hexahydroindole-2-S-carboxylic acid.
22. The use as claimed in any one of claims 15 to 21, wherein, in place of the ethyl esters, the corresponding dicarboxylic acids are used.
23. The use as claimed in claim 14, wherein the medicament is an orally administered medicament.
24. The use as claimed in claim 14, wherein the medicament is a parenterally administered medicament.
25. The use according to any one of claims 14 to 22 wherein the angiotensin converting enzyme inhibitor is combined with pharmaceutically suitable vehicles and auxiliaries for the forms appropriate for administration.
26. The use according to any one of claims 14-25 wherein a sub-anti hypertensively effective dose of angiotensin converting enzyme inhibitor is used.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3926606A DE3926606A1 (en) | 1989-08-11 | 1989-08-11 | METHOD FOR THE TREATMENT OF CARDIALS AND VASCULAR HYPERTROPHY AND HYPERPLASIA |
| DEP3926606.0 | 1989-08-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2023089A1 CA2023089A1 (en) | 1991-02-12 |
| CA2023089C true CA2023089C (en) | 2003-01-14 |
Family
ID=6386970
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002023089A Expired - Lifetime CA2023089C (en) | 1989-08-11 | 1990-08-10 | Method for the treatment of cardiac and of vascular hypertrophy and hyperplasia |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5231083A (en) |
| EP (1) | EP0417473B1 (en) |
| JP (1) | JP3452199B2 (en) |
| KR (1) | KR0185969B1 (en) |
| AT (1) | ATE94409T1 (en) |
| AU (1) | AU631914B2 (en) |
| CA (1) | CA2023089C (en) |
| CS (1) | CS277644B6 (en) |
| DD (1) | DD297063A5 (en) |
| DE (2) | DE3926606A1 (en) |
| DK (1) | DK0417473T3 (en) |
| ES (1) | ES2059931T3 (en) |
| FI (1) | FI903936A7 (en) |
| HU (1) | HU205008B (en) |
| IE (1) | IE64604B1 (en) |
| IL (1) | IL95327A (en) |
| NO (1) | NO306979B1 (en) |
| NZ (1) | NZ234836A (en) |
| PH (1) | PH30831A (en) |
| PL (1) | PL286442A1 (en) |
| PT (1) | PT94957B (en) |
| ZA (1) | ZA906327B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE157871T1 (en) | 1994-05-19 | 1997-09-15 | Mitsubishi Chem Corp | MEDICINAL PRODUCTS FOR THE THERAPEUTIC AND PROPHYLACTIC TREATMENT OF DISEASES CAUSED BY HYPERPLASIA OF SMOOTH MUSCLE CELLS |
| SG68529A1 (en) * | 1995-05-25 | 1999-11-16 | Univ Singapore | The use of des-aspartate-angiotensin i (agr-val-tyr-ile-his-pro-phe-his-leu) as an anti-cardiac hypertrophic agent |
| SE9903028D0 (en) * | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
| EE05670B1 (en) * | 1999-08-30 | 2013-08-15 | Aventis Pharma Deutschland Gmbh | Ramipril for the 'financing of cardiovascular events |
| US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
| CA2586760A1 (en) * | 2004-11-05 | 2006-05-18 | Edward S. Wilson | Stabilized ramipril compositions and methods of making |
| WO2012071369A2 (en) | 2010-11-24 | 2012-05-31 | The Trustees Of Columbia University In The City Of New York | A non-retinoid rbp4 antagonist for treatment of age-related macular degeneration and stargardt disease |
| WO2013166037A1 (en) | 2012-05-01 | 2013-11-07 | The Trustees Of Columbia University In The City Of New York | Non-retinoid antagonists for treatment of eye disorders |
| WO2014152013A1 (en) | 2013-03-14 | 2014-09-25 | The Trustees Of Columbia University In The City Of New York | 4-phenylpiperidines, their preparation and use |
| US9938291B2 (en) | 2013-03-14 | 2018-04-10 | The Trustess Of Columbia University In The City Of New York | N-alkyl-2-phenoxyethanamines, their preparation and use |
| US9637450B2 (en) | 2013-03-14 | 2017-05-02 | The Trustees Of Columbia University In The City Of New York | Octahydrocyclopentapyrroles, their preparation and use |
| WO2014151936A1 (en) | 2013-03-14 | 2014-09-25 | The Trustees Of Columbia University In The City Of New York | Octahydropyrrolopyrroles, their preparation and use |
| AU2015253232B2 (en) | 2014-04-30 | 2020-10-01 | The Trustees Of Columbia University In The City Of New York | Substituted 4-phenylpiperidines, their preparation and use |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL58849A (en) * | 1978-12-11 | 1983-03-31 | Merck & Co Inc | Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them |
| US4311705A (en) * | 1980-10-06 | 1982-01-19 | E. R. Squibb & Sons, Inc. | Carboxyalkanoyl and hydroxycarbamoylalkanoyl derivatives of substituted prolines |
| US4337201A (en) * | 1980-12-04 | 1982-06-29 | E. R. Squibb & Sons, Inc. | Phosphinylalkanoyl substituted prolines |
| US4381297A (en) * | 1981-05-04 | 1983-04-26 | E. R. Squibb & Sons, Inc. | Substituted carbonyl phosphinyl-alkanoyl compounds |
| US4602002A (en) * | 1983-02-07 | 1986-07-22 | Merck & Co., Inc. | N-carboxymethyl substituted lysyl and α-(ε-aminoalkyl) glycyl amino acid antihypertensive agents |
| US4587253A (en) * | 1984-07-30 | 1986-05-06 | Merck & Co., Inc. | Bridged pyridine compounds useful as calcium channel blockers and analgesics |
| US4548941A (en) * | 1984-07-30 | 1985-10-22 | Merck & Co., Inc. | 1,5-Methano-1H-4-benzazonine dicarboxylates, process for preparing and use as calcium blockers |
| US4599341A (en) * | 1984-10-01 | 1986-07-08 | Merck & Co., Inc. | Substituted and bridged pyridines useful as calcium channel blockers |
| US4656188A (en) * | 1985-10-09 | 1987-04-07 | Merck & Co., Inc. | Ace inhibitors in macular degeneration |
| DE3705220A1 (en) * | 1987-02-19 | 1988-09-01 | Boehringer Ingelheim Kg | AGENT FOR TREATING CORONARY DISEASES OR ORGANIC BRAIN SYNDROME |
| ZA896851B (en) * | 1988-09-14 | 1990-06-27 | Hoffmann La Roche | Use of ace-inhibitors |
-
1989
- 1989-08-11 DE DE3926606A patent/DE3926606A1/en not_active Withdrawn
-
1990
- 1990-08-08 DK DK90115230.6T patent/DK0417473T3/en active
- 1990-08-08 DE DE90115230T patent/DE59002721D1/en not_active Expired - Lifetime
- 1990-08-08 ES ES90115230T patent/ES2059931T3/en not_active Expired - Lifetime
- 1990-08-08 AT AT90115230T patent/ATE94409T1/en not_active IP Right Cessation
- 1990-08-08 EP EP90115230A patent/EP0417473B1/en not_active Expired - Lifetime
- 1990-08-09 IL IL9532790A patent/IL95327A/en unknown
- 1990-08-09 PH PH41000A patent/PH30831A/en unknown
- 1990-08-09 PT PT94957A patent/PT94957B/en not_active IP Right Cessation
- 1990-08-09 FI FI903936A patent/FI903936A7/en not_active Application Discontinuation
- 1990-08-09 NZ NZ234836A patent/NZ234836A/en unknown
- 1990-08-09 US US07/564,618 patent/US5231083A/en not_active Expired - Lifetime
- 1990-08-09 DD DD90343366A patent/DD297063A5/en unknown
- 1990-08-10 AU AU60920/90A patent/AU631914B2/en not_active Expired
- 1990-08-10 HU HU904966A patent/HU205008B/en unknown
- 1990-08-10 NO NO903532A patent/NO306979B1/en not_active IP Right Cessation
- 1990-08-10 IE IE291090A patent/IE64604B1/en not_active IP Right Cessation
- 1990-08-10 ZA ZA906327A patent/ZA906327B/en unknown
- 1990-08-10 JP JP21056490A patent/JP3452199B2/en not_active Expired - Lifetime
- 1990-08-10 CA CA002023089A patent/CA2023089C/en not_active Expired - Lifetime
- 1990-08-10 CS CS903958A patent/CS277644B6/en not_active IP Right Cessation
- 1990-08-10 KR KR1019900012267A patent/KR0185969B1/en not_active Expired - Lifetime
- 1990-08-10 PL PL28644290A patent/PL286442A1/en unknown
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