Treatment of neuropathic pain with 6
View Patent ↗6H-pyrrolo[3,4-d]pyridazine compounds and methods of their use of as ligands of voltage gated calcium channels (VGCC), useful in the treatment of neuropathic pain, and psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, panic, and bipolar disorder, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm disorders, drug addiction, drug abuse, drug withdrawal and other.
1. A method of binding the α 2 δ subunit of voltage gated calcium channels comprising a step of administering to a patient in need thereof an effective amount of a compound represented by Formula (I) selected from:
or a pharmaceutically acceptable salt thereof.
2. A compound selected from:
or a pharmaceutically acceptable salt thereof.
3. A compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is —C 0-6 alkyl-aryl, —C 0-6 alkyl-heteroaryl, —C 0-6 alkyl-C 3-6 cycloalkyl, or —C 0-6 alkyl-heteroC 3-7 cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO 2 , —C 1-6 alkyl, —C 0-6 alkyl-C 3-6 cycloalkyl, —C 0-6 alkyl-heteroC 3-7 cycloalkyl, —OR 6 , —NR 6 R 7 , —C(═NR 6 )NR 7 R 8 , —N(—NR 88 R 6 )NR 7 R 8 , —NR 6 COR 7 , —NR 6 CO 2 R 7 , —NR 6 SO 2 R 88 , —NR 6 CONR 7 R 8 , —SR 88 , —SOR 88 , —SO 2 R 88 , —SO 2 NR 6 R 7 , —COR 6 , —CO 2 R 6 , —CONR 6 R 7 , —C(═NR 6 )R 7 , or —C(═NOR 6 )R 7 substituents;
R 2, and R 3, each independently is —C 1-6 alkyl, —C 0-6 alkyl-aryl, —C 0-6 alkyl-heteroaryl, —C 0-6 alkyl-C 3-6 cycloalkyl, or —C 0-6 alkyl-heteroC 3-7 cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO 2 , —C 1-6 alkyl, —OR 6 , —NR 6 R 7 , —C(═NR 6 )NR 7 R 8 , —N(—NR 88 R 6 )NR 7 R 8 , —NR 6 COR 7 , —NR 6 CO 2 R 7 , —NR 6 SO 2 R 88 , —NR 6 CONR 7 R 8 , —SR 88 , —SOR 88 , —SO 2 R 88 , —SO 2 NR 6 R 7 , —COR 6 , —CO 2 R 6 , —CONR 6 R 7 , —C(═NR 6 )R 7 , or —C(═NOR 6 )R 7 substituents;
R 4 , and R 5 each independently is —C 0-6 alkyl, —C 0-6 alkyl-aryl, —C 0-6 alkyl-heteroaryl, —C 0-6 alkyl-C 3-6 cycloalkyl, or —C 0-6 alkyl-hetero C 3-7 cycloalkyl, optionally substituted with 1-6 independent halogen, —CN, NO 2 , —C 1-6 alkyl, —OR 6 , —NR 6 R 7 , —C(═NR 6 )NR 7 R 8 , —N(—NR 88 R 6 )NR 7 R 8 , —NR 6 COR 7 , —NR 6 CO 2 R 7 , —NR 6 SO 2 R 88 , —NR 6 CONR 7 R 8 , —SR 88 , —SOR 88 , —SO 2 R 88 , —SO 2 NR 6 R 7 , —COR 6 , —CO 2 R 6 , —CONR 6 R 7 , —C(═NR 6 )R 7 , or —C(═NOR 6 )R 7 substituents; and
R 6 , R 7 , R 8 , and R 88 each independently is —C 0-6 alkyl, —C 3-7 cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, —CN, —C 1-6 alkyl, —O(C 0-6 alkyl), —O(C 3-7 cycloalkyl), —O(aryl), —N(C 0-6 alkyl)(C 0-6 alkyl), —N(C 0-6 alkyl)(C 3-7 cycloalkyl), or —N(C 0-6 alkyl)(aryl) substituents, wherein when the carbon atom in —C 0-6 alkyl equals “ 0 ” then no alkyl is present; provided that the compound is not
6-methyl-6H-pyrrolo[3,4-d]pyridazine,
1,4,5,7-tetramethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,
1,4,5-trimethyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,
5,7-dimethyl-1,4,6-triphenyl-6H-pyrrolo[3,4-d]pyridazine,
5-methyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine,
1,4-bis-(4-methoxy-phenyl)-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,
1,4-bis-(4-methoxy-phenyl)-5-methyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,
1,4-diethyl-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,
1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine,
N-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzamide,
1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine picrate,
1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine,
5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine,
5,7-dimethyl-2-phenacyl-6H-pyrrolo[3,4-d]pyridazinium bromide,
2-(2-methoxycarbonylvinyl)-5,7-dimethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafloroborate
5,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine,
5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,
1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine,
5-methyl-1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine,
6-benzyl-1,4-diphenyl-5-p-tolyl-6H-pyrrolo[3,4-d]pyridazine,
6-benzyl-5-(2-chloro-phenyl)-1,4-diphenyl-6H-pyrrolo[3,4-d]pyridazine,
1,4,5,6,7-pentaphenyl-6H-pyrrolo[3,4-d]pyridazine,
6,7,10,11-tetraphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline,
11-(4-nitro-phenyl)-6,7,10-triphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline,
6-benzyl-1,4,5-triphenyl-6H-pyrrolo[3,4-d]pyridazine,
9,12-diphenyl-pyridazino[4′, 5′:3,4]pyrrolo[2, 1-a]isoquinoline,
5-methylsulfanyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine,
1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester,
7,10-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoline,
11,14-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-f]phenanthridine,
1-oxo-7-oxy-6b,11b-dihydro(pyridazino[4′,5′-c]-pyrrolo)[2.1-c]benzoxazine-1,4,
10-methyl-1,4-diphenyl-8,9-dihydro-7H-benzo(ef)pyridazino[4,5-a]cycl[3.3.2]azine,
11-methyl-1,4-diphenyl-7,8,9,10-tetrahydrocyclohepta(ef)pyridazino[4,5-a]cycl[3.3.2]azine,
1,4-dichloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,
1-chloro-4-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,
1-chloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium chloride,
1-ethoxy-2,5,6,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate,
1-ethoxy-5,6,7-trimethyl-2H,6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate,
1-ethoxy-3-ethyl-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate,
1-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine,
5-cyano-1,4-dimethylpyridazino[4,5-a]indolizine,
1,4-dimethyl-6-phenyl-2,3,8a-triaza-fluorene-9-carbonitrile,
6-benzolyl-1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile,
6-benzyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,
1,4,6-trimethyl-2,3,8a-triaza-fluorene-9-carbonitrile,
5-cyano-1,4-diphenylpyridazino[4,5-a]indolizine,
6-methyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,
6-benzoyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,
1,4,6-triphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,
5,7-dimethyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile,
9,12-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline-8-carbonitrile,
dimethyl 3,12,13,17-tetramethyl-7 2 ,7 3 -diazabenzo[g]porphyrin-2,18-dipropionate,
5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol,
5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol-hydrochloride,
3-methyl-6,9-diphenylthiazolo[3′,2′:1,2]pyrrolo[3,4d]pyridine, or
1,4-diphenylpyridazino[4′,5′:3,4]pyrrolo[2,1-b]benzothiazole; and
is not selected from the following table: