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Branched chain alkyl heteroaromatic ring derivative

An alkyl and alkoxy technology, which is applied in drug combination, digestive system, endocrine system diseases, etc., can solve the problem of not disclosing OX receptor antagonistic activity

Inactive Publication Date: 2015-02-18
TAISHO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Meanwhile, Patent Document 2 discloses a compound having a pyrazole-ethylamide skeleton, and Patent Document 3 discloses a compound having a heteroaromatic ring-branched alkylamide skeleton, but Patent Document 2 and Patent Document 3 do not disclose OX receptor antagonism Activity or the compound with heteroaromatic ring-branched chain alkylamide skeleton described in this application

Method used

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  • Branched chain alkyl heteroaromatic ring derivative
  • Branched chain alkyl heteroaromatic ring derivative
  • Branched chain alkyl heteroaromatic ring derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1003] Example 1: N-ethyl-N-{(2S)-1-[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]prop-2-yl}-5 -Methyl-2-(2H-1,2,3-triazol-2-yl)benzamide

[1004] [Formula 134]

[1005]

[1006] To (2S)-N-ethyl-1-[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]propan-2-amine disalt obtained in Reference Example 8 5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.11 g, 0.52 mmol) was added to a DMF (5.0 mL) solution of acid salt (0.14 g, 0.44 mmol) , HATU (0.25 g, 0.65 mmol) and DIPEA (0.68 mL, 3.92 mmol), and the resulting mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was saturated NaHCO 3 aqueous and brine washes and MgSO 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 (KP-OH 25 g, hexane / EtOAc = 80 / 20-20 / 80) and HPLC to give the title compound (0.027 g) (colorless and amorpho...

Embodiment 18

[1014] Example 18: N-ethyl-N-{(2S)-1-[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]propan-2-yl}-2 -(2H-1,2,3-triazol-2-yl)benzamide

[1015] [Formula 135]

[1016]

[1017] To N-{(2S)-1-[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]propan-2-yl}-2-( 2H-1,2,3-triazol-2-yl)benzamide (0.13 g, 0.33 mmol) in DMF (5.0 mL) was added 60% NaH (0.020 g, 0.50 mmol), and the resulting mixture Stir at room temperature for 30 minutes. EtI (0.032 mL, 0.40 mmol) was added to the reaction solution, and the resulting mixture was stirred at room temperature for 24 hrs. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was saturated NaHCO 3 aqueous and brine washes and MgSO 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 (KP-NH 28 g, hexane / EtOAc = 80 / 20-40 / 60) to obtain the title compound (0.058 g) (colorless and amorphous).

[1018] ...

Embodiment 34

[1026] Example 34: N-Ethyl-5-fluoro-N-{(2S)-1-[4-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]propan-2- Base}-2-(pyrimidin-2-yl)benzamide

[1027] [Formula 136]

[1028]

[1029] To 5-fluoro-N-{(2S)-1-[4-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]propan-2-yl obtained in Reference Example 81 }-2-(pyrimidin-2-yl)benzamide (0.028 g, 0.067 mmol) in DMF (1.5 mL) was added 60% NaH (0.0039 g, 0.10 mmol), and the resulting mixture was stirred at room temperature 10 minutes. EtI (0.0064 ml, 0.080 mmol) was added to the reaction solution, and the resulting mixture was stirred at room temperature for 1.5 hr. 60% NaH (0.0039 g, 0.10 mmol) was added to the reaction solution, the mixture was stirred at room temperature for 10 minutes, then EtI (0.0064 ml, 0.080 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 16 Hour. will saturate NH 4 Aqueous Cl solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was c...

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Abstract

A branched chain alkyl heteroaromatic ring derivative represented by formula (Ia) or a pharmaceutically acceptable salt thereof is useful for treatment or prophylaxis of diseases such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, cephalalgia, hemicrania, pain, digestive diseases, epilepsy, inflammation, immune-related diseases, endocrine-related diseases and hypertension, on the basis of an 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 containing such compounds or salts as active ingredients, which are used for diseases such as sleep disorders, Depression, anxiety, panic attacks, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headaches, migraines, pain, gastrointestinal disorders, epilepsy, inflammation , immune disease, endocrine disease or high blood pressure. Background technique [0002] Orexin is a neuropeptide spliced ​​from prepro-orexin, which is specifically expressed in the lateral hypothalamus. So far, OX-A comprising 33 amino acids and OX-B comprising 28 amino acids have been identified, both of which are involved in the regulation of sleep-wake patterns and the regulation of food intake. [0003] Both OX-A and OX-B act on OX r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/06A61K31/4439A61K31/506A61P1/00A61P5/00A61P9/12A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P29/00A61P37/02C07D401/14C07D403/12C07D413/12C07D413/14
CPCC07D401/14C07D413/14A61K31/4439A61K31/506C07D403/12C07D249/06A61K31/4192A61K31/4245A61K31/444C07D413/12A61P1/00A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P29/00A61P37/02A61P5/00A61P9/12C07D403/14
Inventor 荒木裕子野泽大铃木亮太田裕之二村彩阿部正人天田英明小西一豪尾形有也
Owner TAISHO PHARMACEUTICAL CO LTD
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