Methods of using soluble epoxide hydrolase inhibitors

• US 6,890,925 B2
• Filed: 09/25/2003
• Issued: 05/10/2005
• Est. Priority Date: 06/29/2001
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Ingraham, Richard H., Proudfoot, John R.
• Primary Examiner(s): SHAMEEM, GOLAM M
• Application Number:
  US10/670,668
• Publication Number:
  US 20040092567A1
• Time in Patent Office: 593 Days
• Field of Search: 544/124, 548/356.1, 548/364.1, 514/235.8, 514/231.2, 514/406, 546/268.1, 546/275.7
• US Class Current: 514/235.8
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

Disclosed are methods of using soluble epoxide hydrolase (sEH) inhibitors of the formulas I and Ia for diseases related to cardiovascular disease.

Claims

1. A method of treating a condition caused by endothelial dysfunction, chosen from insulin resistance syndrome, hypertension, angina, ischemia, ischemic stroke, renal disease and Raynaud'"'"'s disease, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I:

wherein;

R₁ and R₃ are the same or different and each is CF₃, halogen, CN, C_1-8 alkyl or branched alkyl, C_2-8 alkenyl or C_3-8 branched alkenyl, C_2-8 alkynyl or C_3-8 branched alkynyl, C_3-8 cycloalkyl optionally substituted with OH, CN or methoxy, C_1-8 alkyloxy, C_1-4 alkyloxyC_1-4 alkyl, C_1-8 alkylthio, C_1-4 alkylthioC_1-4alkyl, C_1-8 dialkylamino, C_1-4 dialkylaminoalkyl, CO₂R₅ where R₅ is C_1-4 alkyl or C_2-4 alkenyl optionally substituted with carbocyclyl or heterocyclyl, aryl or R₁, is heterocyclyl connected to the pyrazole in any position that makes a stable bond optionally substituted with halogen, C_1-4 alkyl, C_2-4 alkenyl, CN, (CH₃)₂N, CO₂CH₃, alkyloxy, aryl, heterocyclyl or R₅;

R₂ is H, halogen or methyl;

L is —

NHC(O)—

, —

NHC(O)O—

or —

NHC(O)C(O)—

,

R₄ is C_1-8 alkyl, C_1-8 alkyloxy, C_1-8 alkylthio, C_1-8 alkylamino, C_1-4 alkyloxyalkyl, C_1-4 alkylthioalkyl, C_1-4alkylaminoalkyl, C_1-4dialkylaminoalkyl, carbocyclyl or heterocyclyl each optionally substituted with one or more halogen, —

CN, —

NO₂, SO₂NH₂ alkylthio, alkylsulfinyl, alkylsulfonyl or R₇ where R₇ is phenyl, heterocyclyl, C_3-6 cycloalkyl, C_1-6 alkyl, C_2-6 alkenyl, C_1-6 alkyloxyalkyl, C_1-4 alkyloxy, C_1-5 alkylamino, C_1-6 alkylthioalkyl, C_1-6 alkylsulfmylalkyl or C_1-6 alkylsulfonylalkyl, each R₇ in turn is optionally substituted with halogen, OH, alkyloxy, CN, COO-lower alkyl, —

CONH-lower alkyl, —

CON(lower alkyl)₂, dialkylamino, phenyl or heterocylcyl;

R₈ is H;

or the pharmaceutically acceptable salts thereof;

with the proviso that when R₃ is alkyl or CF₃ and R₄ is pyridyl, then the pyridyl is substituted except that the substituents on the pyridyl cannot be halogen; and

with the proviso that the following compounds are excluded;

N-[4-(5-ethyl-3-pyridin-3-yl-pyrazol-1-yl)-phenly]nicotinamide;

N-[4-(5-Ethyl-3-pyridin-3-yl-pyrazol- 1yl)phenyl]-1-methylindole-2-carboxamide;

4-(3-Cyanopropoxy)-N-[4-(5-cyano-3-pyridin-3-yl-pyrazol-1-yl)phenyl]benzamide; and

N-[4-(5-cyano-3-pyridin-3-yl-pyrazol-1yl)phenyl]-4-(3-[1,3]dioxolan-2-yl-propoxy)benzamide.

2. The method according to claim 1 and wherein:

in formula (I);

R₁ is C_1-8 alkyl or branched alkyl, C_3-8 alkenyl or branched alkenyl, C_3-8 alkynyl or branched alkynyl, C_3-8 cycloalkyl, C_1-3 alkyloxyC_1-3 alkyl, C_1-5 alkyloxy, C_1-3 alkylthioC_1-3 alkyl, C_1-5 alkylthio, CF₃, heterocyclyl selected from tetrahydrofuranyl, pyridyl, furanyl or thiazolyl or aryl optionally substituted with halogen, C_1-4 alkyl, CN, alkyloxy or (CH₃)₂N;

R₂ is H;

R₃ is halogen, methyl, ethyl, CF₃, CN, cyclopropyl, vinyl, SCH₃, methoxy, or aryl optionally substituted with halogen, C_1-4 alkyl, CN, methoxy or (CH₃)₂N;

L is —

NHC(O)—

,

R₄ is C_1-6 alkyl, carbocyclyl or heterocyclyl selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl and indazolyl, each optionally substituted with one or more halogen, —

CN, alkylthio, alkylsulfinyl, alkylsulfonyl , —

NO₂, SO₂NH₂ or R₇ where R₇ is C_1-6 alkyl, C_2-6 alkenyl, C_1-6 alkyloxyalkyl, C_1-4 alkyloxy, C_1-5 alkylamino, or C_1-6 alkylthioalkyl each optionally substituted with OH, CN, —

COO-lower alkyl, —

CONH-lower alkyl, —

CON(lower alkyl)₂, dialkylamino, phenyl or heterocyclyl as hereinabove described in this paragraph.

3. The method according to claim 2 and wherein:

in the formula (I)

R₁ is ethyl, isopropyl, n-propyl, t-butyl, cyclopentyl, CF₃, ethoxy, CH₃OCH₂—

, 2- or 3-tetrahydrofuranyl, 2-, 3-, or 4-pyridyl, 2-furanyl, or 2-thiazolyl;

R₃ is CN, CF₃, Cl, methyl, ethyl, SCH₃, cyclopropyl, or vinyl; and

R₄ is a phenyl or pyridyl each optionally substituted with one to three halogen, —

CN, alkylthio, alkylsulfinyl, alkylsulfonyl or R₇ where R₇ is C_1-6 alkyl, C_2-6 alkenyl, C_1-6 alkyloxyC_1-6 alkyl, C_1-4 alkyloxy, C_1-5 alkylamino each optionally substituted with halogen, OH, CN, COO-lower alkyl, —

CONH-lower alkyl, —

CON(lower alkyl)₂, dialkylamino, phenyl, morpholinyl or pyridyl.

4. The method according to claim 3 and wherein:

in the formula (I)

R₁ is isopropyl, CF₃, 3-pyridyl or 4-pyridyl;

R₂ is H;

R₃ is CN, CF₃, Cl, methyl, SCH₃ or ethyl; and

R₄ is a phenyl or pyridyl each optionally substituted with one to three groups selected from halogen, —

CN, alkylthio, alkylsulfinyl, alkylsulfonyl or R₇ where R₇ is C_1-6 alkyl, C_1-4 alkyloxy, C_1-5 alkylamino each optionally substituted with OH, CN, COO-lower alkyl, —

CONH-lower alkyl, —

CON(lower alkyl)₂, dialkylamino, phenyl, morpholinyl or pyridyl.

5. The method according to claim 1 wherein the condition is hypertension.

6. The method according to claim 1 wherein the compound is chosen from:

or the pharmaceutically acceptable salts thereof.

7. The method according to claim 1 or 5 wherein the compound is chosen from:

or the pharmaceutically acceptable salts thereof.