Fused heterocyclic compounds

Abstract

There is provided a CRF receptor antagonist comprising a compound of the formula (I) : wherein R1 is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano or an acyl; R2 is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group; X is oxygen, sulfur or -NR3- (wherein R3 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; Y1, Y2 and Y3 are each an optionally substituted carbon or a nitrogen, provided that one or less of Y1, Y2 and Y3 is nitrogen; and Z is a bond, -CO-, oxygen, sulfur, -SO-, -SO2-, -NR4-, -NR4-alk-, -CONR4- or -NR4CO- (wherein alk is an optionally substituted C3.-4 alkylene and R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; or a salt thereof or a prodrug thereof .

Description

technical field

[0001] The present invention relates to novel nitrogen-containing fused heterocyclic compounds having CRF (corticotropin releasing factor) antagonistic activity and pharmaceutical compositions containing them. Background technique

[0002] Corticotropin-releasing factor (hereinafter referred to as "CRF") is a neuropeptide having 41 amino acids, which is isolated and purified from the pituitary gland as a peptide that promotes the release of adrenocorticotropic hormone (ACTH). Its structure was first determined from sheep hypothalamus, and its existence was also confirmed in rats and humans and its structure was determined [Science, 213, 1394 (1981); Proc.Natl.Acad.Sci USA, 80, 4851 (1983); EMBO J. 5, 775(1983)]. The amino acid sequence is identical in human and rat, but differs by 7 amino acids in sheep. CRF is synthesized, cleaved and secreted as a carboxy-terminal prepro-CRF. CRF peptides and their mRNA are most abundant in the hypothalamus and pituitary...

Examples

Embodiment 1

[0308] N-(4-bromo-2-methoxy-6-methylphenyl)-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine hydrochloride

[0309]

[0310] Methyl 2-chloro-3-nitrobenzoate

[0311] A suspension of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 mL of dichloromethane was cooled in an ice bath. Dimethylformamide (0.40 mL) was added to the reaction, followed by dropwise addition of 13.85 g (109 mmol) of oxalic acid. The reaction was allowed to warm to room temperature and stirred for 6h. Methanol (200 mL) was added dropwise and the reaction was stirred overnight. The reaction was concentrated to give a residue which was dissolved in dichloromethane and passed through a plug of silica gel eluting with a 50% ethyl acetate / hexane mixture. The filtrate was concentrated in vacuo to afford 21.5 g (100%) of the title compound.

[0312] 1 H NMR (CDCl 3 )δ3.98(s, 3H), 7.48(t, J=7.8Hz, 1H), 7.84(d, J=8.2Hz, 1H), 7.95(d, J=7.8Hz, 1H).

[0313] Methyl 2-methylamino-3-nitrobenzoate

[031...

Embodiment 8

[0341] {2-[(4-bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl}(4-methoxyphenyl)methyl ketone.

[0342]

[0343] 7-(4-Methoxybenzoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

[0344] 12 mL (6.00 mmol) of 4-methoxymagnesium bromide solution (0.5 M in THF) was diluted with 15 mL THF and cooled in an ice bath. To this solution was slowly added 309 mg (1.50 mmol) of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-7-carboxylic acid methyl ester and the reaction was stirred at 60°C 24h. The reaction was quenched with water. The aqueous mixture was extracted with ethyl acetate. The extract was washed with 1N aqueous hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography, eluting with 20-70% ethyl acetate / n-hexane, to give the title compound (148 mg, 35%).

[0345] 1 H NMR (DMSO-d 6 )δ3.00(s, 3H), 3.87(s, 3H), 6.98(d, J=8.1Hz, 1H), 7.00-7.15(m, 3H), 7.19(d, J=8.1Hz, 1H), 7.81 ...

Embodiment 9

[0354] N-(4-bromo-2-methoxy-6-methylphenyl)-4-(1-ethylbutyl)-3-methyl-3H-imidazo[4,5-c]pyridine- 2-amine

[0355]

[0356] 4-Bromo-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one

[0357] Heat 20.0 g (103 mmol) of 3-methyl-4-nitro-1H-imidazo[4,5-c]pyridin-2(3H)-one in 168 mL of 48% hydrobromic acid at 135 °C Solution 6h. An additional 33 mL of 48% hydrobromic acid was added and the reaction was stirred overnight at 135°C. The reaction was cooled to room temperature and quenched into 1675 mL of ice water. The resulting suspension was adjusted to pH 9 by adding 125 mL of saturated aqueous ammonia solution. The precipitate was filtered and washed with 200 mL of water and dried in a 50° C. oven under vacuum overnight to give 17.58 g (75%) of the title product as a pale yellow solid.

[0358] 1 H NMR (DMSO-d 6 ) δ 3.54 (3H, s), 7.08 (1H, d, J=4.9Hz), 7.94 (1H, d, J=4.9Hz), 11.71 (1H, s).

[0359] MS calcd: 227; found: 228 (M+H).

[0360] (E)-4-(Hex-3-en-3-yl)-3-methyl-1H-im...

technical field

[0001] The present invention relates to novel nitrogen-containing fused heterocyclic compounds having CRF (corticotropin releasing factor) antagonistic activity and pharmaceutical compositions containing them. Background technique

[0002] Corticotropin-releasing factor (hereinafter referred to as "CRF") is a neuropeptide having 41 amino acids, which is isolated and purified from the pituitary gland as a peptide that promotes the release of adrenocorticotropic hormone (ACTH). Its structure was first determined from sheep hypothalamus, and its existence was also confirmed in rats and humans and its structure was determined [Science, 213, 1394 (1981); Proc.Natl.Acad.Sci USA, 80, 4851 (1983); EMBO J. 5, 775(1983)]. The amino acid sequence is identical in human and rat, but differs by 7 amino acids in sheep. CRF is synthesized, cleaved and secreted as a carboxy-terminal prepro-CRF. CRF peptides and their mRNA are most abundant in the hypothalamus and pituitary...

Examples

Embodiment 1

[0308] N-(4-bromo-2-methoxy-6-methylphenyl)-1-methyl-7-(1-propylbutyl)-1H-benzimidazol-2-amine hydrochloride

[0309]

[0310] Methyl 2-chloro-3-nitrobenzoate

[0311] A suspension of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 mL of dichloromethane was cooled in an ice bath. Dimethylformamide (0.40 mL) was added to the reaction, followed by dropwise addition of 13.85 g (109 mmol) of oxalic acid. The reaction was allowed to warm to room temperature and stirred for 6h. Methanol (200 mL) was added dropwise and the reaction was stirred overnight. The reaction was concentrated to give a residue which was dissolved in dichloromethane and passed through a plug of silica gel eluting with a 50% ethyl acetate / hexane mixture. The filtrate was concentrated in vacuo to afford 21.5 g (100%) of the title compound.

[0312] 1 H NMR (CDCl 3 )δ3.98(s, 3H), 7.48(t, J=7.8Hz, 1H), 7.84(d, J=8.2Hz, 1H), 7.95(d, J=7.8Hz, 1H).

[0313] Methyl 2-methylamino-3-nitrobenzoate

[031...

Embodiment 8

[0341] {2-[(4-bromo-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl}(4-methoxyphenyl)methyl ketone.

[0342]

[0343] 7-(4-Methoxybenzoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

[0344] 12 mL (6.00 mmol) of 4-methoxymagnesium bromide solution (0.5 M in THF) was diluted with 15 mL THF and cooled in an ice bath. To this solution was slowly added 309 mg (1.50 mmol) of 1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-7-carboxylic acid methyl ester and the reaction was stirred at 60°C 24h. The reaction was quenched with water. The aqueous mixture was extracted with ethyl acetate. The extract was washed with 1N aqueous hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography, eluting with 20-70% ethyl acetate / n-hexane, to give the title compound (148 mg, 35%).

[0345] 1 H NMR (DMSO-d 6 )δ3.00(s, 3H), 3.87(s, 3H), 6.98(d, J=8.1Hz, 1H), 7.00-7.15(m, 3H), 7.19(d, J=8.1Hz, 1H), 7.81 ...

Embodiment 9

[0354] N-(4-bromo-2-methoxy-6-methylphenyl)-4-(1-ethylbutyl)-3-methyl-3H-imidazo[4,5-c]pyridine- 2-amine

[0355]

[0356] 4-Bromo-3-methyl-1H-imidazo[4,5-c]pyridin-2(3H)-one

[0357] Heat 20.0 g (103 mmol) of 3-methyl-4-nitro-1H-imidazo[4,5-c]pyridin-2(3H)-one in 168 mL of 48% hydrobromic acid at 135 °C Solution 6h. An additional 33 mL of 48% hydrobromic acid was added and the reaction was stirred overnight at 135°C. The reaction was cooled to room temperature and quenched into 1675 mL of ice water. The resulting suspension was adjusted to pH 9 by adding 125 mL of saturated aqueous ammonia solution. The precipitate was filtered and washed with 200 mL of water and dried in a 50° C. oven under vacuum overnight to give 17.58 g (75%) of the title product as a pale yellow solid.

[0358] 1 H NMR (DMSO-d 6 ) δ 3.54 (3H, s), 7.08 (1H, d, J=4.9Hz), 7.94 (1H, d, J=4.9Hz), 11.71 (1H, s).

[0359] MS calcd: 227; found: 228 (M+H).

[0360] (E)-4-(Hex-3-en-3-yl)-3-methyl-1H-im...

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