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Spiro-containing dihydropyrazole compounds

A compound and cycloalkyl technology, applied in the field of dihydropyrazole compounds containing a spiro ring, can solve the problems of easy to cause hyperkalemia, poor selectivity, affecting clinical wide application, etc.

Active Publication Date: 2015-11-25
KBP医药科技新加坡公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Both are steroidal compounds, which have poor selectivity to other steroid hormone receptors, are likely to cause hyperkalemia, and have relatively large side effects; and their complex structures are difficult to synthesize, and their physical and chemical properties are poor, which affects their wide clinical application.
[0009] However, the activity test at the cell level in vitro shows that its activity is not good, and its physical and chemical properties are poor. In order to improve the clinical treatment effect and facilitate clinical and safe drug use, it is necessary to develop new non-steroidal compounds with good activity, easy synthesis, and good physical and chemical properties.

Method used

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  • Spiro-containing dihydropyrazole compounds
  • Spiro-containing dihydropyrazole compounds
  • Spiro-containing dihydropyrazole compounds

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0175] The preparation of formula (I) compound

[0176] Dissolve raw material 1 (1.3-2 equivalents) in a polar aprotic solvent (such as N,N-dimethylacetamide), add raw material 2 (1 equivalent), and finally add 3 equivalents of tertiary amine (including but not limited to diiso Propylethylamine), terminate the reaction after reacting at 90°C-120°C for 3-6 hours, pour into water after cooling, extract, dry the organic phase, spin dry, and purify with preparative liquid chromatography to obtain the compound of formula (I).

[0177] In the reaction equation, Cy 1 , L, X, Y 1 , Y 2 , n 1 , n 2 , n 3 , n 4 , R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , and m are as defined above.

[0178] The pharmaceutical composition of the present invention containing the compound of general formula (I), its pharmaceutically acceptable salt, ester or solvate, or their prodrug or isomer may contain one or more pharmaceutically acceptable carriers.

[0179] The term "pharm...

specific Embodiment approach

[0211] The above-mentioned content of the present invention will be further described in detail through specific implementation in the form of examples below, but it should not be understood that the scope of the above-mentioned theme of the present invention is limited to the following examples.

[0212] In the examples, the raw material compounds used are commercially available, obtained from Shanghai Jingyan Chemical, Shanghai Titan Chemical, Shanghai Darui, Beijing Coup Technology Co., Ltd., Zhengzhou Taiji Hongnuo Pharmaceutical Technology Co., Ltd., Sichuan Guanghan Biology, Shaoyuan (Shanghai) Chemical Technology, Alfa Aisha (China), Shanghai TCI, Beijing Bailingwei, Shanghai Biide Pharmaceutical and other companies.

Embodiment 1

[0213] Example 12-Chloro-4-(5-cyclopentyl-3-(2-(4-hydroxypiperidine-1-carbonyl)-7-azaspiro [3.5] Preparation of nonan-7-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzonitrile (compound 2)

[0214]

[0215] (1) Preparation of tert-butyl 2-(4-hydroxypiperidine-1-carbonyl)-7-azaspiro[3.5]nonane-7-carboxylate

[0216]

[0217] In a dry round bottom flask, add 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid (1.2g, 4.46mmol), 4-hydroxypiperidine (0.50g , 4.94mmol), DMF30mL, N,N-diisopropylethylamine (DIEA) (0.6g, 4.64mmol), and finally added 2-(7-azobenzotriazole)-N,N,N' , N'-tetramethyluronium hexafluorophosphate (HATU) (1.86g, 4.89mmol), react overnight at room temperature. The reaction solution was poured into 150 mL of ice water, extracted with dichloromethane (100 mL × 3), the organic phase was washed with a saturated solution of sodium bicarbonate, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain Light yellow visc...

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Abstract

The present invention provides compounds represented by general formula (I), their pharmaceutically acceptable salts, esters or solvates, or their prodrugs or their isomers. Wherein, Cy1, L, X, Y1, Y2, n1, n2, n3, n4, R1a, R1b, R3a, R3b, R4, R5, and m are as described in the specification.

Description

[0001] This application claims the priority of the Chinese patent application with the filing date of March 18, 2011 and the application number of 201110065760.7, and the content of the priority text is fully cited as a reference in this application. The content of all documents cited in this application is also taken as a part of this application in its entirety. technical field [0002] The present invention belongs to the technical field of medicine, and specifically relates to dihydropyrazole compounds containing spiro rings, their pharmaceutically acceptable salts, esters, solvates or their prodrugs or isomers, and the preparation methods of these compounds include these Pharmaceutical preparations of compounds, their pharmaceutically acceptable salts, esters, solvates or their prodrugs or isomers, and these compounds, their pharmaceutically acceptable salts, esters, solvates or their prodrugs or isomers The application of the construct in the preparation of medicines for...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04C07D417/14C07D471/10C07D405/14C07D487/10C07D401/14A61K31/541A61K31/496A61K31/4545A61K31/454A61K31/438A61P9/12A61P13/12
CPCC07D401/04C07D401/14C07D403/14C07D405/14C07D471/10C07D487/10A61P9/12A61P13/12C07D417/14
Inventor 张蕙张艳其他发明人请求不公开姓名
Owner KBP医药科技新加坡公司
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