Bicyclic dihydropyrazole compounds

A compound and hydrogen atom technology, applied in the field of medicine, can solve problems such as large side effects, poor activity, and difficulty in synthesis

Active Publication Date: 2014-11-12
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.
[0008] 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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  • Bicyclic dihydropyrazole compounds
  • Bicyclic dihydropyrazole compounds
  • Bicyclic dihydropyrazole compounds

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0143] (1) Preparation of intermediate 1 hydrochloride

[0144] In a dry round-bottomed flask, add the derivative of raw material 1 (1 eq), raw material 2 (1.1 eq), DMF, DCM, DIEA (1.1 eq. ), and finally add HATU (1.1 equivalents), react overnight at room temperature. The reaction solution was poured into ice water, extracted with an organic solvent, the organic phase was washed with a saturated sodium bicarbonate solution, dried, and purified by column chromatography to obtain intermediate 1 with a protective group.

[0145] The above-mentioned intermediate 1 with a protective group is removed by a common method, for example, the intermediate 1 with a protective group is dissolved in dichloromethane, and dry HCl gas is introduced into the ice bath system for half an hour. After the reaction is completed, , spin to dry the solvent, and wash with ether to obtain the hydrochloride of Intermediate 1.

[0146] (2) preparation of formula 1 compound

[0147] The hydrochloride sal...

experiment example

[0175] Experimental example In vitro pharmacological activity of the compounds of the present invention

[0176] Test sample: some compounds 1, 3, 4, 6, 8, 9, 10, 11, 14, 15, 16, 17, 18, 19 and 27 of the present invention are self-made, and their chemical names and structural formulas are as described above.

[0177] The compound of formula V is self-made, and its structural formula is as described above.

[0178] Nuclear receptor assay

[0179] experimental method:

[0180] Accurately weigh the test compound 1 and 3, add DMSO to dissolve, mix thoroughly, and make 1000 μM. Then the above mother solution was serially diluted with DMSO to 200 μM, 40 μM, 8 μM, 1.6 μM, 0.3 μM, 0.06 μM, 0.01 μM, 0 μM, 0 μM.

[0181] Dual-luciferase detection: Mix 1 μL pBind-NR (100ng / μL), 1 μL pG5luc (100ng / ul), 2.5 μL DMEM and 0.5 μL Fugene, incubate at room temperature for 15 minutes, and prepare a transfection solution. According to 3×10 5 cells / mL Prepare a cell suspension, add 100 μL to ...

Embodiment 1

[0189] Example 1: 2-chloro-4-{5-cyclopentyl-3-[(1α, 5α, 6α)-6-(4-hydroxypiperidine-1-carbonyl)-3-azabicyclo[3.1. 0] hexane Preparation of -3-yl]-4,5-dihydro-1H-pyrazol-1-yl}benzonitrile (compound 1)

[0190]

[0191] (1) Preparation of (1α, 5α, 6α)-6-(4-hydroxypiperidine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

[0192]

[0193] In a dry round bottom flask, add (1α, 5α, 6α)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (1.50 g, 6.6 mmol) respectively, 4-Hydroxypiperidine (0.73g, 7.2mmol), DMF 30mL, CH 2 Cl 2 30 mL, DIEA (0.90 g, 7.0 mmol), finally added HATU (2.76 g, 7.3 mmol), and reacted at room temperature overnight. The reaction solution was poured into 250 mL of ice water, extracted with dichloromethane (100 mL × 3), the organic phase was washed with saturated sodium bicarbonate solution, dried, and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain Light yellow viscous liq...

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PUM

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Abstract

The invention belongs to the field of pharmaceutical technology, in particular to bicyclic dihydropyrazole compounds shown in a general formula (I), pharmaceutically acceptable salts or isomers of the bicyclic dihydropyrazole compounds, pharmaceutical preparations of the pharmaceutically acceptable salts or isomers, and application of the bicyclic dihydropyrazole compounds and the pharmaceutically acceptable salts or isomers to preparation of drugs used for treating and / or preventing renal injury and / or hypertension. Cy1, L, X, Y1, Y2, n1, n2, n3, n4, R1a, R1b, R2a, R2b, R3a, R3b, R4, R5, R13, R14 and m are defined in the patent specification.

Description

1. Technical field [0001] The present invention belongs to the technical field of medicine, and specifically relates to a dihydropyrazole compound containing a ring, its pharmaceutically acceptable salt or its isomer, and the pharmaceutical preparation of these compounds' pharmaceutically acceptable salt or its isomer. And the application of these compounds, their pharmaceutically acceptable salts or their isomers in the preparation of medicines for treating and / or preventing kidney damage and / or hypertension. 2. Background technology [0002] Primary kidney disease, secondary kidney disease such as diabetic nephropathy, renal insufficiency and other kidney damage diseases, clinically manifested as a large amount of proteinuria, if not treated in time, it will lead to renal failure. There are many causes of kidney damage, such as diabetes, high blood pressure and other common diseases can lead to kidney damage. For example, 15% to 25% of patients with type 1 diabetes and 30...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D487/04C07D403/04C07D403/14C07D405/14A61K31/454A61K31/5377A61K31/496A61K31/4155A61K31/541A61K31/4545A61P13/12A61P9/12
Inventor 张蕙松山皓治张艳
Owner KBP医药科技新加坡公司
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