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Heteroaromatic methyl cyclic amine derivatives

A methyl and alkyl technology, applied in the field of heteroaromatic methyl cyclic amine derivatives, can solve the problems of compounds without disclosed heteroaromatic methyl cyclic amine skeleton, compounds without disclosed methyl cyclic amine skeleton, etc.

Active Publication Date: 2017-03-08
TAISHO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Patent Document 1 discloses a heteroaryl ring derivative as a compound having OX receptor antagonistic activity, but does not disclose a compound having a heteroaromatic (heteroaromatic) methylcycloamine skeleton as described in the present application
In addition, for example, compounds having various structures described in Non-Patent Document 11 are generally called OX receptor antagonists, but compounds having a heteroaromatic methylcyclic amine skeleton described in this application are not disclosed

Method used

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  • Heteroaromatic methyl cyclic amine derivatives
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  • Heteroaromatic methyl cyclic amine derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0454] Example 1: (-)-(2-{[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-3-yl )[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone

[0455] [Formula 44]

[0456]

[0457] Under ice-water cooling, [2-(hydroxymethyl)-1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2, 3-triazol-2-yl)phenyl]methanone (1.7 g, 5.9 mmol) and TEA (1.2 mL, 8.8 mmol) in CHCl 3 To a solution in (30 mL), MsCl (0.55 mL, 7.1 mmol) was added, and the resulting mixture was stirred for 1 hour. Under ice-water cooling, water was added to the reaction mixture, followed by CHCl 3 extraction. The organic layer was washed with saturated aqueous sodium chloride, washed with Na 2 SO 4 After drying, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50g, hexane / EtOAc=88 / 12 to 0 / 100) to obtain {3-[5-methyl-2-(2H-1,2,3- Triazol-2-yl)benzoyl]-1,3-oxazolidin-2-yl}methylsulfonate (pale yellow oil). 5...

Embodiment 5

[0464] Example 5: (-)-[(2S,5S)-2-{[4-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-5-methyl- 1,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone

[0465] [Formula 45]

[0466]

[0467] By using (2RS,5S)-5-methyl-3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl] obtained in Reference Example 5 -1,3-Oxazolidine-2-carboxylic acid ethyl ester (0.11g, 0.33mmol) as starting material, the same procedure as in Reference Example 2 was carried out to obtain [2-(hydroxymethyl)-5-methyl-1 ,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone diastereomeric mixture (without color oil). The diastereomeric mixture obtained was purified by thin layer chromatography (1 mm, hexane / EtOAc=50 / 50) to obtain [(2S,5S)-2-(hydroxymethyl)-5-methyl-1 ,3-oxazolidin-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (colorless oil). Under ice-water cooling, to the obtained [(2S,5S)-2-(hydroxymethyl)-5-methyl-1,3-oxazolidin-3-yl][5-methyl-2-( 2H-1,2,3-triazol...

Embodiment 11

[0474] Example 11: (±)-(2-{[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-3-yl )[2-(2H-1,2,3-triazol-2-yl)phenyl]methanone

[0475] [Formula 46]

[0476]

[0477] To 2-[1-(2,2-diethoxyethyl)-1H-pyrazol-3-yl]-5-fluoropyridine (4.0 g, 14.3 mmol) obtained in Reference Example 12 in CHCl 3 To a solution in (72 mL), TFA (6.4 mL, 85.9 mmol) was added, and the resulting mixture was stirred at 35°C for 6 hours. TFA (6.4 mL, 85.9 mmol) was added thereto, and the mixture was stirred at 35°C for 3 hours. The reaction mixture was cooled to room temperature, then NaHCO 3 Aqueous solution was added to the reaction mixture, followed by CHCl 3 extraction. The organic layer was washed with saturated aqueous sodium chloride, washed over MgSO 4 Dry, then filter off the desiccant. The solvent was distilled off under reduced pressure to obtain [3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]acetaldehyde (colorless oil). To [3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]acetaldehy...

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Abstract

Heteroaromatic methyl cyclic amine derivatives represented by formula (IA) or pharmaceutically acceptable salts thereof are used for the treatment or prevention of diseases, such as sleep disorders, depression, anxiety disorders, panic disorders, schizophrenia, drug dependence , Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune-related disorders, endocrine-related disorders, and hypertension, based on orexin (OX ) receptor antagonist activity.

Description

technical field [0001] The present invention relates to compounds having orexin (OX) receptor antagonistic activity and pharmaceutically acceptable salts thereof, and therapeutic or preventive medicines for diseases, such as sleep disorders, depression, containing such compounds or salts as active ingredients anxiety disorders, panic disorders, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headaches, migraines, pain, gastrointestinal disorders, epilepsy, inflammation, immunity disease, endocrine disease or high blood pressure. Background technique [0002] Orexin is a neuropeptide cleaved from prepro-orexin and specifically expressed in the lateral hypothalamus. So far, OX-A consisting of 33 amino acids and OX-B consisting of 28 amino acids have been identified, both of which are involved in regulating sleep-wake patterns and regulating feeding. [0003] Both OX-A and OX-B act on OX receptors. So far, two...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14A61K31/4439A61K31/5355A61P1/04A61P1/14A61P3/00A61P9/12A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/36A61P29/00A61P37/02
CPCC07D413/14A61P1/00A61P1/04A61P1/14A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/36A61P29/00A61P3/00A61P3/04A61P37/00A61P37/02A61P5/00A61P9/00A61P9/12A61K31/422A61K31/4439A61K31/5355
Inventor 二村彩荒木裕子阿部正人太田裕之铃木亮野泽大
Owner TAISHO PHARMACEUTICAL CO LTD
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