Method of using soluble epoxide hydrolase inhibitors

• US 6,831,082 B2
• Filed: 06/14/2002
• Issued: 12/14/2004
• 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: Proudfoot, John R., Ingraham, Richard H.
• Primary Examiner(s): Ramsuer, Robert W.
• Application Number:
  US10/172,457
• Publication Number:
  US 20030022929A1
• Time in Patent Office: 914 Days
• Field of Search: 544/131, 546/256, 514/237.2
• US Class Current: 514/237.2
• 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 novel compounds of the formula Ia and methods of using soluble epoxide hydrolase (sEH) inhibitors of the formulas I and Ia for diseases related to cardiovascular disease.

Claims

1. A compound of the formula (Ia)

wherein:

R₁ is pyridyl and R₃ 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 is heterocyclyl 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) alkyl,

R₄ is pyridyl substituted with one or more —

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 alkylsulfinylalkyl 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 NH₂ or mono-or-diC1-5alkylamino;

or the pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 wherein:

R₂ is H;

R₃ is halogen, methyl, ethyl, CF₃, CN, cyclopropyl, vinyl, SCH₃, methoxy, heterocyclyl selected from tetrahydrofuranyl, pyridyl, furanyl or thiazolyl or aryl optionally substituted with halogen, C_1-4 alkyl, CN, methoxy or (CH₃)₂N;

R₄ is —

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; and

R₈ is NH₂.

3. The compound according to claim 2 wherein:

R₁ is 2-, 3-, or 4-pyridyl;

R₃ is CN, CF₃, Cl, methyl, ethyl, SCH₃, cyclopropyl, vinyl or 2-furanyl;

and

R₄ is pyridyl substituted with one to three —

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 compound according to claim 3 wherein:

R₁ is 3-pyridyl or 4-pyridyl;

R₂ is H;

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

and

R₄ is a pyridyl substituted with one to three —

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. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1.

6. A method of treating a cardiovascular disease, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of according to claim 1.

7. The method according to claim 6 wherein the cardiovascular disease is involves endothelial dysfunction.

8. The method according to claims 6 wherein the cardiovascular disease is chosen from type 1 and type 2 diabetes, insulin resistance syndrome, hypertension, atherosclerosis, coronary artery disease, angina, ischemia, ischemic stroke, Raynaud'"'"'s disease and renal disease.