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New piperidine derivative

A technology of piperidine compounds and compounds, applied in the direction of effective components of heterocyclic compounds, digestive system, organic chemistry, etc., can solve problems such as undiscovered

Inactive Publication Date: 2005-08-17
MITSUBISHI TANABE PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, as a therapeutic agent for the above-mentioned various diseases (particularly for vomiting, depression, urinary disorders, etc.), no drug having an excellent tachykinin receptor antagonism (specifically, SP receptor antagonism) and at the same time has not been found. Compounds with sufficiently satisfactory safety profile, sustainability (metabolism, in vivo kinetics, and absorption), etc.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0465](1) 1.43 g of 1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl) was dissolved in 30 ml of methanol )-4-oxopiperidine, to which 114 mg of sodium borohydride was added. The mixture was stirred at room temperature for 3 hours. To the reaction mixture were added an aqueous ammonium chloride solution and ethyl acetate, and after the mixture was stirred, the layers were separated. The organic layer was washed with water and brine, dried, and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=4:1) to give 0.99 g of 1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl -2-(4-Fluoro-2-methylphenyl)-4-hydroxypiperidine, as shown in Table 1 below.

[0466] (2) 200 mg of the compound of (1) above was further purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 18 mg of (a) trans-1-{N-(3,5-bistris Fluorometh...

Embodiment 2

[0468] Dissolve 200 mg of (2R)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-( in 10 ml of tetrahydrofuran 4-Fluoro-2-methylphenyl)-4-oxopiperidine, 60 mg of sodium borohydride was added thereto, and the mixture was refluxed. While the mixture was continuously refluxed, a mixed solvent of 1 ml of methanol and 5 ml of tetrahydrofuran was added dropwise thereto. After 5 hours, the reaction mixture was poured into water and the layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water and saturated brine and dried, and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-1:2) to provide 33 mg of (a)(2R,4R)-1-[N-{1-(S)-(3) , 5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine and 160 mg (b)(2R , 4S)-1-[N-{1-(S)-(3,5-bistrifluorome...

Embodiment 3

[0470] (2R)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxo substituted piperidine, treated in the same manner as Example 2 to provide (a)(2R,4R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl -2-(4-Fluoro-2-methylphenyl)-4-hydroxypiperidine and (b)(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)- N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine, as shown in Table 2 below.

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Abstract

The present invention provides a novel piperidine compound of the formula [I]: wherein Ring A represents an optionally substituted benzene ring, Ring B represents an optionally substituted benzene ring, R>1< represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, etc., or a group of the formula: (a) wherein R>11< AND R>12< are the same or different, and each represents hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group, etc., R>2< represents hydrogen atom, etc., Z represents oxygen atom or a group represented by -N(R>3<)-, R>3< represents hydrogen atom or an alkyl group, etc., R>4< represents hydrogen atom or an alkyl group, etc.,or a pharmaceutically acceptable salt thereof.

Description

technical field [0001] The present invention relates to novel piperidine compounds having excellent tachykinin receptor antagonism. Background technique [0002] Tachykinin is a generic name for a group of neuropeptides, and Substance P (hereinafter referred to as SP), Neurokinin-A, and Neurokinin-B have been known in mammals. These peptides are known to exhibit various types of biological activities by binding to their corresponding receptors (neurokinin-1, neurokinin-2, neurokinin-3) present in the body. Among them, SP is one of those with the longest history among neuropeptides and has been studied in detail. Its presence was confirmed in 1931 in extracts from horse intestines, and it is a peptide containing 11 amino acids, the structure of which was determined in 1971. [0003] SP widely exists in the peripheral nervous system, and it has physiological activities such as vasodilation, vascular permeability promotion, smooth muscle contraction, nerve hyperexcitability (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/445A61K31/451A61K31/454A61K31/4545A61K31/4709A61K31/497A61K31/513A61K38/00C07D211/46C07D211/54C07D211/58C07D211/62C07D211/74C07D401/04C07D401/12C07D401/14C07D405/12C07D409/04C07D409/12C07D417/04C07D417/12C07D473/34C07K5/02C07K5/06C07K5/083C07K5/087C07K5/097C07K5/103
CPCC07K5/0812C07D211/58C07D417/04C07K5/1008C07D405/12C07D409/12C07K5/0808C07D211/62C07D401/14C07D401/12C07K5/0202C07D409/04C07D211/74C07D417/12A61K38/00C07D473/34C07D211/54C07D211/46C07K5/06191C07D401/04C07K5/0821A61P1/00A61P11/14A61P13/00A61P25/00A61P25/06A61P29/00A61P37/00A61P37/02A61P37/08A61P9/00A61P9/12
Inventor 高桥政巳三宅努盛谷恭典浅井秀敏石井健敏河野理夏子
Owner MITSUBISHI TANABE PHARMA CORP
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