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US 6,589,954 B1Granted
Compounds and methods to treat cardiac failure and other disorders
AssigneeScios, Inc.
InventorsBabu J. Mavunkel, David Y. Liu, George F. Schreiner, John A. Lewicki, John J. Perumattam
Life of this patent
Estimating the term…
Abstract
Indoles, benzimidazoles and benztriazoles which are substituted at the 5 or 6 position with a substituent comprising an aromatic moiety linked through a piperazine ring to said indole, benzimidazole or benztriazole are useful in treating cardiac conditions associated with heart failure and in treating conditions characterized by proinflammation.
Claims67
A compound of the formula:
- and the pharmaceutically acceptable salts thereof,
- wherein each of Z1 and Z2 is independently CR4 or N;
- where each R4 is independently selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms selected from O, S, and N and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);
- or
- R1 is
- wherein
- X1 is CO, SO, SO2 or CHOH;
- m is 1;
- Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;
- n is 0, 1 or 2;
- Z3 is N;
- X2 is CH, CH2 or an isostere thereof;
- and
- Ar consists of one or two phenyl moieties directly coupled to X2, said one or two phenyl moieties being optionally substituted by one or more substituents selected from the group consisting of halo, nitro, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, CF3, RCO, COOR, CONR2, NR2, OR, SR, OOCR, NROCR;
- and phenyl, itself optionally substituted by one or more of the foregoing substituents, wherein R in the foregoing optional substituents is H or alkyl (1-6C);
- R2 is selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl or aryl optionally including one or more heteroatoms which are selected from O, S and N, and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) with the proviso that when both Z1 and Z2 are CH, R2 is other than H;
- R3 is selected from the group consisting of H, halo, NO2, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR2, RCO, COOR, CONR2, OOCR, and NROCR where R is H or alkyl (1-6C).
14 more elements
A compound which is selected from the group consisting of:
- 4-(2,6-difluorobenzyl)-piperazinyl-benzymidazole-5-carboxamide;
- 4-(2,3-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(3,5-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(3-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-carboxymethyl benzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-methoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-trifluoxomethoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-methylbenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(2,4-dichlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(3,4-dichlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-[trans-3-(trifluoromethyl)-cinnamoyl]-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-chlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-benzoylpiperazine-benzimidazole-5-carboxamide;
- 4-(2-trifluoromethylbenzoyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-methoxybenzoyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(3,4-dichlorophenyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-chlorobenzhydryl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-trans-1-cinnamyl piperazinyl-benzimidazole-5-carboxamide;
- 4-[bis(4-fluorophenyl)-methyl]-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(2-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-benzylpiperazinyl-benzimidazole-5-carboxamide;
- 4-(4-methylthiobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(3,4,5-trimethoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-diethylaminobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(biphenylmethyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-Phenoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;
- 4-(4-chlorobenzyl)-piperazinyl-1-(2-propyl)-indole-5-carboxamide;
- 4-(3-chlorobenzyl)-piperazinyl-N-benzyl-benzimidazole-5-carboxamide;
- 4-(3-chlorobenzyl)-piperazinyl-N-benzyl-benzimidazole-6-carboxamide;
- 4-(3-chlorobenzyl)-piperazinyl-N-(2-propyl)-benzimidazole-5-carboxamide;
- 4-(3-chlorobenzyl)-piperazinyl-N-(2-propyl)-benzimidazole-6-carboxamide;
- 4-(3-chlorobenzyl)-piperazinyl-N-ethyl-benzimidazole-5-carboxamide;
- 4-(3-chlorobenzyl)-piperazinyl-N-ethyl-benzimidazole-6-carboxamide;
- 4-(3-chlorobenzyl)-piperazinyl-N-methyl-benzimidazole-5-carboxamide;
- and
- 4-(3-chlorobenzyl)-piperazinyl-N-methyl-benzimidazole-6-carboxamide.
34 more elements
A compound of the formula:
- and the pharmaceutically acceptable salts thereof,
- wherein each of Z1 and Z2 is independently CR4 or N;
- where each R4 is independently selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms selected from O, S, and N and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);
- or
- R1 is
- wherein
- X1 is CO or an isostere thereof,
- m is 1;
- Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;
- n is 0, 1 or 2;
- Z3 is N;
- X2 is CH, CH2 or an isostere thereof;
- and
- Ar is a phenyl moiety optionally substituted by a substituent selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, CF3, RCO, COOR, CONR2, NR2, OR, SR, OOCR, NROCR, and phenyl, itself optionally substituted by the foregoing substituents, wherein R in the foregoing optional substituents is H or alkyl (1-6C);
- R2 is selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms which are selected from O, S and N, and each of said alkyl being optionally substituted by one or more substituents selected from halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) with the proviso that if both Z1 and Z2 are CH, R2 is other than H;
- R3 is selected from the group consisting of H, halo, NO2, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR2, RCO, COOR, CONR2, OOCR, and NROCR where R is H or alkyl (1-6C).
13 more elements
A compound of the formula:
- and the pharmaceutically acceptable salts thereof,
- wherein Z1 is CR4′ and Z2 is CH;
- where R4′ is selected from the group consisting of alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms selected from O, S, and N and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);
- or
- R1 is
- wherein
- X1 is CO or an isostere thereof;
- m is 1;
- Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;
- n is 0, 1 or 2;
- Z3 is N;
- X2 is CH, CH2 or an isostere thereof;
- and
- Ar is one or two phenyl moieties, optionally substituted by one or more substituents selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, CF3, RCO, COOR, CONR2, NR2, OR, SR, OOCR, NROCR, and phenyl itself optionally substituted by the foregoing substituents, wherein R in the foregoing optional substituents is H or alkyl (1-6C);
- R2 is selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl or aryl optionally including one or more heteroatoms which are selected from O, S and N, and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);
- R3 is selected from the group consisting of H, halo, NO2, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR2, RCO, COOR, CONR2, OOCR, and NROCR where R is H or alkyl (1-6C).
13 more elements
A compound of the formula:
- and the pharmaceutically acceptable salts thereof,
- wherein Z1 and Z2 are each independently N or CR4;
- where R4 is selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms selected from O, S, and N and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);
- or
- R1 is
- wherein
- X1 is CO or an isostere thereof;
- m is 1;
- Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;
- n is 1 or 2;
- Z3 is N;
- X2 is CH, CH2 or an isostere thereof;
- and
- Ar is one or two phenyl moieties, optionally substituted by one or more substituents selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, CF3, RCO, COOR, CONR2, NR2, OR, SR, OOCR, NROCR, and phenyl, itself optionally substituted by the foregoing substituents, wherein R in the foregoing optional substituents is H or alkyl (1-6C);
- R2 is selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl or aryl optionally including one or more heteroatoms which are selected from O, S and N, and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, ═O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);
- R3 is selected from the group consisting of H, halo, NO2, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR2, RCO, COOR, CONR2, OOCR, and NROCR where R is H or alkyl (1-6C).
13 more elements
Dependencies are inferred from the claim text.