Soluble epoxide hydrolase inhibitors

A compound, cycloalkyl technology, applied in the field of medicinal chemistry, can solve the problem of low activity

Inactive Publication Date: 2009-08-26
ARETE THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Despite the potent effects of EET in vivo, the epoxy moiety of EET is rapidly hydrolyzed to the less active form of dihydroxyeicosatrienoic acid (DHET) by an enzyme called soluble epoxide hydrolase (sEH)

Method used

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  • Soluble epoxide hydrolase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example

[0327] In the examples below and throughout the application, the following abbreviations have the following meanings. If not defined otherwise, said terms have their commonly accepted meanings.

[0328] aq. = aqueous solution

[0329] brs = broad singlet

[0330] d = doublet

[0331] DCM = dichloromethane

[0332] DMAP = dimethylaminopyridine

[0333] DMF = dimethylformamide

[0334] DMSO = dimethyl sulfoxide

[0335] EtOAc = ethyl acetate

[0336] g = gram

[0337] LCMS = Liquid Chromatography Mass Spectrometry

[0338] m = multiplet

[0339] MHz = megahertz

[0340] mL = milliliter

[0341] m.p. = melting point

[0342] N = equivalent

[0343] RT = room temperature

[0344] s = singlet

[0345] t = triplet

[0346] TEA = Triethylamine

[0347] TLC = thin layer chromatography

example 1

[0349] 4-(3-Adamantan-1-yl-ureido)-benzenesulfonamide (1)

[0350]

[0351] Adamantyl isocyanate (0.07 mL, 0.745 mmol) was added to a stirred solution of 4-aminobenzenesulfonamide (150 mg, 0.850 mmol) in ethanol (15 mL) at room temperature overnight. The precipitated solid was filtered, washed with petroleum ether and pentane and recrystallized in acetone to give the title compound (100 mg, 49%) as a white solid; mp 270-275 °C; LC / MS purity 99.7%; mass: 350[ M+1]; 1 HNMR: (300MHz; DMSO-D 6 )δ: 1.60-2.20 (m, 15H CH 2 ); 7.23-7.65 (4H, ArCH); 9.26 (brs, 2H, NH).

example 2

[0353] 3-(3-Adamantan-1-yl-ureido)-benzenesulfonamide (2)

[0354]

[0355] To a stirred solution of 3-nitrobenzenesulfonamide (300 mg, 0.95 mmol) in methanol (10 mL) was added Pd-C (100 mg) and stirred at room temperature under hydrogen atmosphere overnight. The solution was filtered and the filtrate was concentrated under vacuum to give 3-aminobenzenesulfonamide as a yellow solid (yield 250 mg); mass: 172 [M+1].

[0356] To a stirred solution of 3-aminobenzenesulfonamide (150 mg, 0.872 mmol) in ethanol (15 mL) was added adamantyl isocyanate (0.12 mL, 0.855 mmol) at room temperature overnight. The precipitated solid was filtered, washed with petroleum ether and pentane and recrystallized in acetone to give the title compound (180 mg, 45%) as an off-white solid; mp 158-162 °C; LC / MS purity 99.4%; mass: 360[M+1]; 1 HNMR: (300MHz; DMSO-D 6 )δ: 1.60-2.19 (15H, adamantyl CH 2 ); 7.20-7.45 (4H, ArCH); 9.26 (brs, 2H, NH).

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Abstract

Disclosed are sulfonamide compounds of formula (I), wherein R-R, Y and m are as defined in the claims, and compositions that inhibit soluble epoxide hydrolase (sEH), methods for preparing the compounds and compositions, and methods for treating patients with such compounds and compositions. The compounds, compositions, and methods are useful for treating a variety of sEH-mediated diseases, including hypertensive, cardiovascular, inflammatory, pulmonary, and diabetes-related diseases.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Serial No. 60 / 848,503, filed September 28, 2006, which is hereby incorporated by reference in its entirety. technical field [0003] The invention relates to the field of medicinal chemistry. Provided herein are sulfonamide compounds that inhibit soluble epoxide hydrolase (sEH), pharmaceutical compositions containing the compounds, methods of making the compounds and formulations, and methods of treating patients using the compounds and compositions. The compounds, compositions, and methods are useful in the treatment of a variety of sEH-mediated diseases, including hypertension, cardiovascular disease, inflammatory disease, pulmonary disease, and diabetes-related diseases. Background technique [0004] The arachidonic acid cascade is a ubiquitous lipid signaling cascade in which the plasma membrane releases arachidonic acid from plasma membrane lipid sto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/18C07C311/47C07C311/50C07D295/12C07D295/22A61P9/12
CPCC07C2103/74C07C311/47C07D295/22C07C311/50C07D295/13C07C2603/74A61P11/00A61P29/00A61P43/00A61P9/00A61P9/12A61P3/10
Inventor 理查德·D·小格雷斯
Owner ARETE THERAPEUTICS INC
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