Soluble Epoxide Hydrolase Inhibitors and Methods of Using Same

• US 20060276515A1
• Filed: 05/01/2006
• Published: 12/07/2006
• Est. Priority Date: 05/06/2005
• Status: Abandoned Application

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Eldrup, Anne Bettina, Soleymanzadeh, Fariba, Taylor, Steven John, De Lombaert, Stephane, Ingraham, Richard Harold, Cardozo, Mario G., Cywin, Charles Lawrence
• Application Number:
  US11/381,015
• Publication Number:
  US 20060276515A1
• Time in Patent Office: Days
• US Class Current: 514/343
• 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 9/08 Vasodilators for multiple indications
• 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 213/56 Amides
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 215/50 attached in position 4
• CPC Class Codes: C07D 217/26 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• 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 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 241/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond

Abstract

Disclosed are compounds active against soluble epoxide hydrolase (sEH), compositions thereof and methods of using and making same.

Claims

1. A method of treating hypertension comprising administering to a patient an effective amount of a compound of the formula (I):

wherein;

n is 0 or 1;

X₁ is bond or a heteroatom chosen from O, S or a bond;

X₂ is —

C(O)—

;

L is an ethylene linking group optionally substituted by hydoxy, amino, lower alkoxy, lower alkylamino, lower alkylthio or 1-3 fluorine atoms;

Ar₁ is carbocycle, heteroaryl or heterocyclyl optionally substituted by Y;

Ar₂ and Ar₃ are carbocycle, heteroaryl or heterocyclyl each optionally substituted by one or more halogen, lower alkylS(O)_m, NR₂R₃—

C(O)—

, lower alkoxy or carboxamide;

R₁ is hydrogen or lower alkyl;

wherein the group —

(CH₂)_n—

in the formula (I) is optionally substituted by lower alkyl;

Y is chosen from

lower alkyl, lower alkoxy, lower alkenyl, lower acyl, lower alkyl(OH), —

NR₂R₃;

or Y is a cyclic group chosen from heterocycle, heteroaryl and carbocycle;

each Y where possible is optionally substituted by one to three oxo, lower acyl, halogen, nitrile, lower alkylS(O)_m—

, lower alkoxycarbonyl, NR₂R₃—

C(O)—

, —

NR₂R₃, lower alkyl, C_3-6 cycloalkylC_0-2alkyl, hydroxy, lower alkoxy, aryloxy, arylC_0-4 alkyl, heteroaryl C_0-4 alkyl and heterocycle C_0-4alkyl, each above-listed heterocycle, heteroaryl and aryl group is optionally substituted by one to three hydroxy, oxo, lower alkyl, lower alkoxy, lower alkoxycarbonyl, NR₂R₃—

C(O)—

or lower acyl;

each R₂ and R₃ are independently hydrogen, arylC_0-4 alkyl, heteroaryl C_0-4 alkyl, heterocycle C_0-4alkyl, C_1-2 acyl, aroyl and lower alkyl optionally substituted by lower alkylS(O)_m—

, lower alkoxy, hydroxy or mono or diC_1-3 alkyl amino;

or R₂ and R₃ optionally combine with the nitrogen atom to which they are attached to form a heterocyclic ring;

m is 0, 1 or 2;

or the pharmaceutically acceptable salts thereof.

2. The method according to claim 1 and wherein:

Ar₁ is cyclohexyl, phenyl;

ademantyl, norbonyl,

or

heteroaryl chosen from pyridinyl, pyridinyl N-oxide, isoquinolinyl, quinolinyl, pyridazinyl and pyrimidinyl,

or

heterocyclyl chosen from piperidinyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrrolidinonyl and benztriazolyl;

each Ar₁ is optionally substituted by Y;

Ar₂ and Ar₃ are each phenyl or pyridinyl optionally substituted by one or more lower alkoxy, F, Cl, lower alkylS(O)₂, lower alkyl-NH—

C(O)—

or carboxamide;

L is an ethylene linking group.

3. The method according to claim 2 and wherein

Ar₂ and Ar₃ are each phenyl or pyridinyl substituted by one or more lower alkoxy, F, Cl, CH₃—

S(O)₂—

, CH₃—

NH—

C(O)—

or carboxamide.

4. A method of treating hypertension comprising administering to a patient an effective amount of a compound of the formula (II):

wherein;

Ar₁ is carbocycle, heteroaryl or heterocyclyl optionally substituted by Y;

Ar₂ and Ar₃ are each carbocycle optionally substituted by halogen, lower alkoxy, lower alkylS(O)_m, NR₂R₃—

C(O)—

or carboxamide;

L is an ethylene linking group optionally substituted by hydoxy, amino, lower alkoxy, lower alkylamino, lower alkylthio or 1-3 fluorine atoms;

Y is chosen from

lower alkyl, lower alkoxy, lower alkenyl, lower acyl, lower alkyl(OH), —

NR₂R₃;

or Y is a cyclic group chosen from heterocycle, heteroaryl and carbocycle;

each Y where possible is optionally substituted by one to three oxo, lower acyl, halogen, nitrile, lower alkylS(O)_m—

, lower alkoxycarbonyl, NR₂R₃—

C(O)—

, —

NR₂R₃, lower alkyl, C_3-6 cycloalkylC_0-2alkyl, hydroxy, lower alkoxy, aryloxy, arylC_0-4 alkyl, heteroaryl C_0-4 alkyl and heterocycle C_0-4alkyl, each above-listed heterocycle, heteroaryl and aryl group is optionally substituted by one to three hydroxy, oxo, lower alkyl, lower alkoxy, lower alkoxycarbonyl, NR₂R₃—

C(O)—

or lower acyl;

each R₂ and R₃ are independently hydrogen, arylC_0-4 alkyl, heteroaryl C_0-4 alkyl, heterocycle C_0-4alkyl, C_1-2 acyl, aroyl and lower alkyl optionally substituted by lower alkylS(O)_m—

, lower alkoxy, hydroxy or mono or diC_1-3 alkyl amino;

or R₂ and R₃ optionally combine with the nitrogen atom to which they are attached to form a heterocyclic ring;

m is 0, 1 or 2;

or the pharmaceutically acceptable salts thereof.

5. The method according to claim 4 and wherein:

Ar₁ is cyclohexyl, phenyl, adamantyl, norbornyl,

or

heteroaryl chosen from pyridinyl, pyridinyl N-oxide, isoquinolinyl, quinolinyl, pyridazinyl and pyrimidinyl,

or

heterocyclyl chosen from piperidinyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrrolidinonyl and benztriazolyl;

each optionally substituted by Y;

Ar₂ and Ar₃ are each phenyl or pyridinyl optionally substituted by one or more lower alkoxy, F, Cl, lower alkylS(O)₂, lower alkyl-NH—

C(O)—

or carboxamide;

L is an ethylene linking group.

6. The method according to claim 5 and wherein:

Ar₂ and Ar₃ are each phenyl or pyridinyl substituted by one or more lower alkoxy, F, Cl, CH₃—

S(O)₂—

, CH₃—

NH—

C(O)—

or carboxamide.

7. A compound of the formula (III):

wherein;

each A is independently nitrogen or C—

H such that each of the ring of which A is a member may be pyridinyl or phenyl, said pyridinyl or phenyl are optionally substituted by Y or Z;

Y and Z on their respective rings are in the meta or para position, and are independently F, Cl, Br, CN, OR, R, —

S(O)₂R, —

C(O)NRR or —

S(O)₂NRR, wherein R is independently hydrogen or lower alkyl unsubstituted or substituted with hydroxy, amino, C_1-4 alkoxy, C_1-4 alkylamino, C_1-4 alkylthio, or one to three fluorine atoms;

L is an ethylene linker optionally substituted with hydroxy, amino, C_1-4 alkoxy C_1-4 alkylamino, C_1-4 alkylthio, or one to three fluorine atoms;

X is O or S;

W is chosen from phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, naphthyl, quinolinyl and isoquinolinyl each optionally with one to three substituents independently chosen from;

halogen, hydroxy, amino, cyano, carboxy, carboxamido, C_1-4 alkyl unsubstitued or substituted with one to three halogen atoms, C_3-6 cycloalkyl unsubstitued or substituted with one to three halogen atoms, C_2-4 alkynyl, C_1-4 alkyloxycarbonyl, C_1-4 alkylamidocarbonyl, C_1-4 dialkylamidocarbonyl, C_1-4 alkylamino, C_1-4 dialkylamino, C_3-6 cycloalkylamino, di(C_3-6 cycloalkyl)amino, C_1-4 alkylsulfonyl, C_1-4 alkylheterocylyl, phenyl, or heterocylyl;

with the proviso that if the phenyl or pyridinyl rings possessing the aforementioned A are either unsubstituted or both substituted by halogen, then W must be substituted by any of the above-listed substituents for W;

or the pharmaceutically acceptable salts thereof.

10. A method of treating a disease or condition 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, said method comprising administering to a patient a pharmaceutically effective amount of a compound according to claim 7, 8 or 9.

11. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 7, 8 or 9 and one or more pharmaceutically acceptable carriers.

8. A compound of the formula (IV):

wherein for the Formula (IV), the component

is chosen from A1-A8 in the table I below;

in combination with any component

chosen from B1-B10 in the table I below;

A1 A2 A3 A4 A5 A6 A7 A8 A9  

A10 B1 B2 B3 B4 B5 B6 B7 B8 B9  

B10

or the pharmaceutically acceptable salts thereof, with the proviso that if

then

cannot be

9. A compound chosen from

or the pharmaceutically acceptable salts thereof.