EP0343911A2
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Cycloalkyl-substituted glutaramide diuretic agents
Assignee: Pfizer Ltd
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Filing: 1989-05-23
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Granted: —
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Expires: 2009-05-23
Abstract
Abstract Compounds having the formula: wherein A completes a 4 to 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further carbocyclic ring; B is (CH 2 ) m wherein m is 1 to 3; R and R 4 are H, C 1 -C 6 alkyl, benzyl or biolabile ester-forming groups; R 1 is H or C 1 -C 4 alkyl; R 2 and R 3 are each H, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, or are linked together and are (CH 2 ) r wherein r is 1 to 4; Y is an optional alkylene group of from 1 to 6 carbon atoms which may be straight or branched-chain; and R 5 is R 6 CONR 9- , R 6 SO 2 NR 9 -, R 6 CO 2 -, R 6 CO-, R 6 SOq-, R 7 NR 9 CO-, R 7 NR 9 S0 2 - or R 7 0CO-; wherein R 6 is a group of the formula R 8 (R 1O R 11 C-CONR 9 ) n R 1O R 11 C-; R 7 is a group of the formula R 10 R 11 R 12 C- and R 9 is H, C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heterocyclyl, aryl(C 1 -C 6 alkyl) or heterocyclyl(C 1 -C 6 alkyl); wherein R 8 is R 9 CONR 9 -, R 9 SO 2 NR 9 -, R 13 R 14 -N-(CH 2 ) p -, or R 9 0-, R 10 and R 11 are H or C 1 -C 6 alkyl; or R 10 is H and R 11 is C 1 -C 6 alkyl which is substituted by OH, SH, SCH 3 , NH 2 , aryl(C 1 -C 6 alkyl)OCONH-, NH 2 CO-, C0 2 H, guanidino, aryl, or heterocyclyl; or the two groups R 10 and R 11 are joined to form a five or 6 membered carbocyclic ring which may be saturated, mono-unsaturated, optionally substituted by C 1 -C 4 alkyl or fused to a further carbocylic ring; or R 8 and R 11 are linked to form a 2-(N-COR 9- 4-aminopyrrolidinyl) group; R 12 is R 13 R 14 NCO-, R 9 0CO-, R 9 0CH 2 - or heterocyclyl, R 13 and R 14 are H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, aryl(C 1 -C 6 alkyl), C 2 -C s alkoxyalkyl, amino (C 1 -C 6 alkyl), heterocyclyl or heterocyclyl(C 1 -C 6 alkyl); or the two groups R 13 and R 14 form a pyrrolidinyl, piperidino, morpholino, piperazinyl, N-(C 1 -C 4 alkyl) piperazinyl, pyrrolyl, imidazolyl, pyrazolyl or triazolyl group; n is 0 or 1; p is 0 or 1 to 6; and q is 0, 1 or 2; and pharmaceutically acceptable salts thereof and bioprecursors therefor, are diuretic agents of value in the treatment of hypertension, heart failure and renal insufficiency.
Inventors
- 👤 Keith Dr. James
- 👤 John Christopher Dr. Danilewicz
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-06 08:31
CPC Classifications
C; C07; C07D; C07D213/00; C07D213/02; C07D213/04; C07D213/60; C07D213/78; C07D213/81; C07D213/82; A; A61; A61P; A61P13/00; A61P13/02; A61P15/00; A61P7/00; A61P7/10; A61P9/00; A61P9/12; C07C; C07C233/00; C07C233/57; C07C233/63; C07C235/00; C07C235/40; C07C237/00; C07C237/24; C07C271/00; C07C271/06; C07C271/08; C07C271/10; C07C271/22; C07C311/00; C07C311/01; C07C311/02; C07C311/03; C07C311/06; C07D277/00; C07D277/02; C07D277/04; C07D277/06; C07D295/00; C07D295/16; C07D295/18; C07D295/182; C07D295/185; C07K; C07K5/00; C07K5/02; C07K5/0207; C07K5/04; C07K5/06; C07K5/06086; A61K; A61K38/00; C07C2601/00; C07C2601/04; C07C2601/06; C07C2601/08; C07C2601/12; C07C2601/14
Claims Analysis
Total Claims: 13
Claim 1
Independent Claim
552 words
A compound having the formula: wherein A completes a 4 to 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring; B is (CH 2 ) m wherein m is an integer of from 1 to 3; each of R and R4 is independently H, C 1 -C 6 alkyl, benzyl or an alternative biolabile ester-forming group; R 1 is H or C 1 -C 4 alkyl; R 2 and R 3 are each independently H, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; or R 2 and R 3 are linked together and are (CH 2 ), wherein r is an integer of from 1 to 4; Y is an optional alkylene group of from 1 to 6 carbon atoms which may be straight or branched-chain; and R 5 is R 6 CONR 9- , R 6 S0 2NR 9- , R 6 C0 2 -, R 6 CO-, R 6 SOq-, R 7 NR 9 CO-, R 7 NR 9 SO 2 - or R 7 0CO-; wherein R 6 is a group of the formula: R 7 is a group of the formula: and R 9 is H, C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heterocyclyl, aryl(C 1 -C 6 alkyl) or heterocyclyl(C 1 -C 6 alkyl); wherein R S is R 9 CONR 9 -, R 9 SO 2 NR 9 -, R 13 R 14 N-(CH 2 ) p -, or R 9 0-, wherein each R 9 is as previously defined above; R 10 and R 11 are each independently H or C 1 -C 6 alkyl; or R 10 is H and R 11 is C 1 -C 6 alkyl which is substituted by OH, SH, SCH 3 , NH 2 , aryl(C 1 -C 6 alkyl)OCONH-, NH 2 CO-, C0 2 H, guanidino, aryl, or heterocyclyl; or the two groups R 10 and R 11 are joined together to form, with the carbon atom to which they are attached, a 5 or 6 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be substituted by C 1 -C 4 alkyl or fused to a further 5 or 6 membered saturated or unsaturated carbocyclic ring; or R 10 is H, n is 0 and R 8 and R 11 are linked to form a 2-(N-COR 9- 4-aminopyrrolidinyl) group; R 12 is R 13 R 14 NCO-, R 9 0CO-, R 9 0CH 2 - or heterocyclyl, wherein R 9 is as previously defined above; R 13 and R 14 are each independently H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, aryl(C 1 -C 6 alkyl), C 2 -C 6 alkoxyalkyl, amino(C 1 -C 6 alkyl), heterocyclyl or heterocyclyl(C 1 -C 6 alkyl); or the two groups R 13 and R 14 are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino, morpholino, piperazinyl, N-(C 1 -C 4 alkyl)piperazinyl, pyrrolyl, imidazolyl, pyrazolyl or triazolyl group; n is 0 or 1; p is 0 or an integer of from 1 to 6; and q is 0, 1 or 2; and pharmaceutically acceptable salts thereof and bioprecursors therefor.
Claim 2
Dependent Claim
552 words
A compound having the formula: wherein A completes a 4 to 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring; B is (CH 2 ) m wherein m is an integer of from 1 to 3; each of R and R4 is independently H, C 1 -C 6 alkyl, benzyl or an alternative biolabile ester-forming group; R 1 is H or C 1 -C 4 alkyl; R 2 and R 3 are each independently H, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; or R 2 and R 3 are linked together and are (CH 2 ), wherein r is an integer of from 1 to 4; Y is an optional alkylene group of from 1 to 6 carbon atoms which may be straight or branched-chain; and R 5 is R 6 CONR 9- , R 6 S0 2NR 9- , R 6 C0 2 -, R 6 CO-, R 6 SOq-, R 7 NR 9 CO-, R 7 NR 9 SO 2 - or R 7 0CO-; wherein R 6 is a group of the formula: R 7 is a group of the formula: and R 9 is H, C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heterocyclyl, aryl(C 1 -C 6 alkyl) or heterocyclyl(C 1 -C 6 alkyl); wherein R S is R 9 CONR 9 -, R 9 SO 2 NR 9 -, R 13 R 14 N-(CH 2 ) p -, or R 9 0-, wherein each R 9 is as previously defined above; R 10 and R 11 are each independently H or C 1 -C 6 alkyl; or R 10 is H and R 11 is C 1 -C 6 alkyl which is substituted by OH, SH, SCH 3 , NH 2 , aryl(C 1 -C 6 alkyl)OCONH-, NH 2 CO-, C0 2 H, guanidino, aryl, or heterocyclyl; or the two groups R 10 and R 11 are joined together to form, with the carbon atom to which they are attached, a 5 or 6 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be substituted by C 1 -C 4 alkyl or fused to a further 5 or 6 membered saturated or unsaturated carbocyclic ring; or R 10 is H, n is 0 and R 8 and R 11 are linked to form a 2-(N-COR 9- 4-aminopyrrolidinyl) group; R 12 is R 13 R 14 NCO-, R 9 0CO-, R 9 0CH 2 - or heterocyclyl, wherein R 9 is as previously defined above; R 13 and R 14 are each independently H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, aryl(C 1 -C 6 alkyl), C 2 -C 6 alkoxyalkyl, amino(C 1 -C 6 alkyl), heterocyclyl or heterocyclyl(C 1 -C 6 alkyl); or the two groups R 13 and R 14 are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino, morpholino, piperazinyl, N-(C 1 -C 4 alkyl)piperazinyl, pyrrolyl, imidazolyl, pyrazolyl or triazolyl group; n is 0 or 1; p is 0 or an integer of from 1 to 6; and q is 0, 1 or 2; and pharmaceutically acceptable salts thereof and bioprecursors therefor.
Claim 3
Dependent Claim
29 words
A compound as claimed in claim 1 wherein A is (CH 2 ) 4 , R 1 is H and B is (CH 2 ) 2 having the formula:
Claim 4
Dependent Claim
18 words
A compound as claimed in claim 1 or claim 2 wherein R and R 4 are both H.
Claim 5
Dependent Claim
35 words
A compound as claimed in claim 1 or claim 2 wherein one of R and R 4 is H and the other is C 1 -C 6 alkyl, benzyl or an alternative biolabile ester-forming group.
Claim 6
Dependent Claim
35 words
A compound as claimed in claim 4 wherein said alternative biolabile ester forming group is 1-(2,2-diethylbutyryloxy)ethyl, 2-ethylpropionyloxymethyl, 1-(2-ethylpropionyloxy)ethyl, 1-(2,4-dimethylbenzoyloxy)-ethyl,a-benzoyloxybenzyl, 1-(benzoyloxy)ethyl, 2-methyl-1-propionyloxy-propyl, 2,4,6-trimethylbenzoylox- ymethyl, 1-(2,4,6-trimethylbenzoyloxy)ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1-or 2-napthyl, 2,4-dimethylphenyl, 4-t-butylphenyl, 5-(4-methyl-1,3-dioxalynyl-2-onyl)methyl or 5-indanyl.
Claim 7
Dependent Claim
35 words
A compound as claimed in any previous claim wherein R 5 is R 6 CONR 9 -, R 7 NR 9 CO-, wherein R 6 , R 7 and R 9 are as previously defined.
Claim 8
Dependent Claim
68 words
A compound as claimed in claim 6 wherein R 5 is R 6 CONR 9 -, R 9 is H and R 6 is a group of the formula: wherein R 9 is (C 1 -C 6 alkyl)CONH-, arylCONH or C 1 -C 6 alkyl)S0 2 NH-, R 10 is H and R 11 is C 1 -C 4 alkyl, benzyl or amino (C 1 -C 6 alkyl).
Claim 9
Dependent Claim
66 words
A compound as claimed in claim 6 wherein R 5 is R 7 NR 9 CO-wherein R 8 is H and R 7 is a group of the formula wherein R 12 is H0 2 C, (C 1 -C 6 alkyl)NHCO-, (C 1 -C 6 alkyl) 2 NCO-, aryINHCO- or 1-pyrrolidinoyl, R 10 is H and R 11 is benzyl or amino(C 1 -C 6 alkyl).
Claim 10
Dependent Claim
24 words
A compound is claimed as claim 7 wherein R 5 is N 2- acetyl-L-lysyl-amino, N 2- benzoyl-L-lysyl-amino, N 2- naphthoyl-L-lysyl-amino, or N 2- methanesulphonamido-L-lysyl-amino.
Claim 11
Dependent Claim
41 words
A compound as claimed in claim 7 wherein said compound is-: 2-(N 2 -acetyl-L-lysyfaminomethyl)-3-{1-[(cis-4-carboxy-cyclohexyl)carbamoyl]cyclopentyl}propanoic acid, 2-(N 2 -benzoyl-L-lysylaminomethyl)-3-{1-[(cis-4-carboxy-cyclohexyl)carbamoyl]cyclopentyl}propanoic acid, 2-(N 2 -naphthoyl-L-lysylaminomethyl)-3-(1-[(cis-4-carboxy-cyclohexyl)carbamoyl]cyclopentyl}propanoic acid, 2-(N 2 -acetyl-L-lysylaminomethyl)-3-{1-[cis-4-carboxy-cis-3-butyl-cyclohexyl)carbamoyl]-cyclopentyl}propanoic acid. 2-(N 2 -acetyl-L-lysylaminomethyl)-3{1-[cis-4-carboxy-trans-3-butyl-cyclohexyl)carbamoyi]-cyclopentyl}propanoic acid, 2-(N 2 -methanesulphonyl-L-lysylaminomethyl)-3{1-(cis-4-carboxy-cis-3-(methylbutyl)-cyclohexyl)carbamoyl]-cyclopentyl} propanoic acid, or 2-(N 2 -methanesulphonyl-L-lysylaminomethyl)-3{1-[cis-4-carboxy-cis-3-butyl-cyclohexyl)carbamoyl]-cyclopentyl}propanoic acid.
Claim 12
Dependent Claim
39 words
A pharmaceutical composition comprising a compound of the formula (I) or (II) as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or bioprecursor therefor, together with a pharmaceutically acceptable diluent or carrier.
Claim 13
Dependent Claim
41 words
A compound of the formula (I) or (II) as claimed in any of claims 1 to 10 or a pharmaceutically acceptable salt thereof or bioprecursor therefor, for use in medicine, particularly for the treatment of hypertension, heart failure or renal insufficiency.
References Cited (Backward Citations)
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