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Pyrazole derivatives as cytochrome P450 inhibitors

A compound, R15 technology, applied in antiviral agents, medical preparations containing active ingredients, organic chemistry, etc., can solve problems such as side effects and metabolic side effects

Inactive Publication Date: 2009-08-19
PFIZER PRODS ETAT DE CONNECTICUT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, RTV has clinically significant gastrointestinal and metabolic side effects, including nausea, vomiting, diarrhea, and dyslipidemia

Method used

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  • Pyrazole derivatives as cytochrome P450 inhibitors
  • Pyrazole derivatives as cytochrome P450 inhibitors
  • Pyrazole derivatives as cytochrome P450 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0532] Example 1: 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine

[0533]

[0534] With mechanical stirring, thermocouple and N 2 THF (6.0 L), methyl isonicotinate (259.1 g, 1.89 mol) and 4-fluorophenylacetone (287.5 g, 1.89 mol) were added to a 22-liter three-necked round-bottom flask of the reflux condenser of the inlet adapter. Sodium methoxide (204.3 g, 3.78 mol) was added portionwise. There was a slight exotherm upon addition of sodium methoxide. The reaction mixture turned orange and was heated to reflux for 2 hours. After 2 hours, LC-MS confirmed the absence of methyl isonicotinate and the formation of β-diketone. After the addition of ethanol (6 L) and acetic acid (380 mL), the temperature of the reaction mixture dropped to 45 °C. The reflux condenser was then replaced with a dropping funnel, and hydrazine (387 g, 6.0 mol) was added dropwise. During the dropwise addition, the reaction temperature rose to 60°C. Then, the reaction mixture was stirred slowly ov...

Embodiment 2

[0535] Example 2: Methyl [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetate

[0536]

[0537] In the installation with mechanical stirring, with thermocouple and N 2 Add THF (10L) and 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl] to a 22-liter three-necked round-bottomed flask with a Claisen adapter for the inlet adapter and a 250ml dropping funnel Pyridine (385.5 g, 1.52 mol). The resulting solution was cooled to 5°C in a water / ice / salt bath. Sodium hydride (60% dispersion in mineral oil, 66.9 g, 1.67 mol) was then added in portions so that the internal temperature did not exceed 15°C. The resulting red mixture was stirred at 5°C for 1.5 hours. Then methyl bromoacetate (254 g, 1.67 mol) was added dropwise at a rate such that the temperature would not exceed 15°C. The mixture was then allowed to slowly come to room temperature overnight. The mixture was then filtered through celite, and the celite was washed with ethyl acetate. Most of the THF was removed by rotary...

Embodiment 3

[0538] Example 3: [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid

[0539]

[0540] Add [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]methyl acetate (235g, 0.72mol ), THF (3.5L), methanol (1.2L) and 2M LiOH (1.2L). The resulting solution was stirred at room temperature for 1.5 hours. After LC-MS confirmed the absence of starting material, most of the THF was removed by rotary evaporation. The solution was then acidified with 2M HCl (pH=3), and the white precipitate was filtered and washed with water. After drying under reduced pressure, 210 g (93%) of the title compound were obtained. 1 H NMR (400MHz, DMSO-D6) δ ppm 8.53(d, 2H), 7.68(d, 2H), 7.31(t, 2H), 7.14(t, 2H), 6.57(s, 1H), 5.00(s, 2H), 4.01(s, 2H); C 17 h 14 N 3 o 2 The m / z(APCI+) of F is 312.2(M+H) + .

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PUM

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Abstract

The present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, methods for their preparation, methods for their use, and pharmaceutical formulations comprising them.

Description

[0001] This application claims priority to U.S. Application 60 / 806,596, filed July 5, 2006, U.S. Application 60 / 910,988, filed April 10, 2007, and U.S. Application 60 / 941,808, filed June 4, 2007 , the above-mentioned patent application is hereby incorporated by reference in its entirety. Background technique [0002] The cytochrome P450 (CYP450) enzyme system is responsible for the biotransformation of active drugs into inactive metabolites, and solvent compounds are readily excreted through the body. Moreover, the rapid metabolism of certain drugs by the CYP450 enzyme system can significantly alter their pharmacokinetic (PK) profiles and can lead to prolonged subtherapeutic plasma levels of these drugs. In the field of anti-infective therapy, such as in the field of treatment of viral infections such as human immunodeficiency virus (HIV) infection, such subtherapeutic drug plasma levels may increase viral resistance. [0003] Ritonavir (RTV), a commercially available HIV pro...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D401/14C07D403/04C07D409/14C07D413/14A61K31/4427A61K31/443A61K31/4433A61K31/4155A61P31/18
CPCC07D401/14C07D413/14C07D403/04C07D409/14C07D401/04A61P31/18
Inventor 西蒙·保罗·普兰肯斯科特·常宁·萨顿荣良·陈
Owner PFIZER PRODS ETAT DE CONNECTICUT
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