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Nipecotic acid derivative and use thereof for medical purposes

A technology of piperidinecarboxylic acid and its derivatives, which can be applied in the direction of drug combination, pharmaceutical formula, and active ingredients of heterocyclic compounds, etc. It can solve the problems that there is no 3-piperidinecarboxylic acid diamide structure, and the relationship of inhibitory activity is not disclosed or implied. , to achieve excellent therapeutic effect and reduce side effects

Inactive Publication Date: 2014-12-03
TORAY IND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It should be noted that among the compounds having sEH inhibitory activity reported so far, there is no compound having the structure of 3-piperidinecarboxylic acid diamide
[0009] On the other hand, as compounds having a 3-piperidinecarboxylic acid diamide structure, heteroarylamide derivatives in which heteroarylamines are condensed on 3-piperidinecarboxylic acid (Patent Document 3), amidine derivatives (Patent Document 4) and hydroxamic acid derivatives (Patent Document 5), but there is no disclosure or hint about the relationship with sEH inhibitory activity

Method used

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  • Nipecotic acid derivative and use thereof for medical purposes
  • Nipecotic acid derivative and use thereof for medical purposes
  • Nipecotic acid derivative and use thereof for medical purposes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0177] (Example 1) (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-propionamidecyclobutanecarbonyl)piperidine-3-carboxamide synthesis:

[0178] 〔step 1〕

[0179] Synthesis of 4-bromo-2-(trifluoromethoxy)benzaldehyde:

[0180] At -78°C, a solution of n-butyllithium hexane was added dropwise over 1.5 hours to a solution of 4-bromo-1-iodo-2-(trifluoromethoxy)benzene (25 g, 68 mmol) in THF (0.40 L) (1.6N, 86mL, 0.14mol). After stirring at -78° C. for 1 hour, DMF (11 mL, 0.14 mmol) was added dropwise to the reaction solution over 10 minutes. After stirring at -78°C for 2 hours, an aqueous citric acid solution (0.25M, 0.25L, 63mmol) was added to the reaction solution, followed by extraction with ether. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 16 g (87%) of 4-bromo-2-(trifluoromethoxy)benzaldehyde (hereinafter referred to as Reference Example Compound 1).

[0181] [Step 2]

[0182] Synthesis of (4-bromo-2-(...

Embodiment 2）

[0211] (Example 2) (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(2-methyl-2-(methylsulfonamide)propionyl)piper Synthesis of pyridine-3-carboxamide:

[0212] 〔step 1〕

[0213] (R)-tert-butyl(1-(3-((4-cyano-2-(trifluoromethoxy)benzyl)carbamoyl)piperidin-1-yl)-2-methyl-1 -Oxopropan-2-yl) carbamate synthesis:

[0214] Under ice-cooling, in reference example compound 8 (3.5g, 11mmol), 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (2.6g, 13mmol), DIPEA (4.1mL, 24mmol) HATU (4.9 g, 13 mmol) was added to DMF (40 mL) solution. After stirring at room temperature for 1 hour, water and 1N hydrochloric acid were added to the reaction solution, followed by extraction with ether. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (Amine silica gel DM1020 manufactured by Fuji Shirishia Chemical Co.,...

Embodiment 3）

[0221] (Example 3) (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(methylsulfonamide)cyclopropanecarbonyl)piperidine-3- Synthesis of formamide:

[0222] 〔step 1〕

[0223] (R)-tert-Butyl(1-(3-((4-cyano-2-(trifluoromethoxy)benzyl)carbamoyl)piperidine-1-carbonyl)cyclopropyl)carbamate Synthesis of esters:

[0224] Under ice-cooling, DMF of reference compound 8 (0.67g, 2.0mmol), 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (0.49g, 2.4mmol), DIPEA (1.1mL, 6.1mmol) (5.0 mL) solution was added HATU (1.1 g, 2.5 mmol). After stirring at room temperature for 1 hour, water and 1N hydrochloric acid were added to the reaction solution, followed by extraction with ether. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (Amine silica gel DM1020 manufactured by Fuji Shirishia Chemical Co., Lt...

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Abstract

The purpose of the present invention is to provide: a compound having an sEH-inhibiting activity; and a medicinal agent capable of exhibiting a therapeutic or prophylactic effect on chronic kidney diseases and pulmonary hypertension which relies on a sEH-inhibiting activity. The present invention provides a nipecotic acid derivative represented by chemical formula (1) or a pharmacologically acceptable salt thereof.

Description

technical field [0001] The present invention relates to 3-piperidinecarboxylic acid derivatives and their medicinal use. Background technique [0002] With the increase of kidney disease patients, artificial dialysis patients continue to increase in the world, and the number has reached more than 10 times in the past 30 years. Under such circumstances, the concept of a new disease such as chronic kidney disease was proposed in 2002, and a wide range of kidney diseases ranging from the state of renal function decline that did not reach renal failure to the end stage of renal failure were called chronic kidney disease (non-patented kidney disease). Literature 1). This is because it has gradually become clear that even symptoms at the level of decreased renal function progress to serum creatinine (serum creatinine; hereinafter referred to as sCre) values, serum cystatin C (Cystatin C; hereinafter referred to as Cys-C) value shows a high risk of renal failure. [0003] If pat...

Claims

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Application Information

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IPC IPC(8): C07D211/60A61K31/445A61K31/453A61K31/454A61P9/12A61P11/00A61P13/12A61P43/00C07D401/06C07D405/06
CPCC07D405/06A61K31/445A61K31/454C07D211/60C07D401/06A61K31/453A61P11/00A61P13/12A61P43/00A61P9/12
Inventor 西村裕加藤祐子林新之助山崎亚衣子山本将史浅冈由次山田将辉山田尚弘
Owner TORAY IND INC
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