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US 2009/0023731 A1Published application
Soluble epoxide hydrolase inhibitors
AssigneeArete Therapeutics, Inc.
InventorsRichard D. Gless, JR., Sampath Kumar Anandan
Life of this patent
Estimating the term…
Abstract
Disclosed are urea and thiourea compounds 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, and diabetic-related diseases.
Claims43
A compound of Formula (I′) or a pharmaceutically acceptable salt thereof:
- wherein:
- Q is O or S;
- Q′ is O or S;
- R is selected from the group consisting of substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
- each R1 is independently selected from the group consisting of alkyl, cyano, halo, and haloalkyl;
- n is 0, 1, 2, or 3;
- X is selected from the group consisting of a covalent bond, NH, or CR′R″ where R′ and R″ are independently H or alkyl or R′ and R″ together form a C3-C6 cycloalkyl ring;
- and
- Y is selected from the group consisting of heteroaryl, substituted heteroaryl, and
- wherein R4 and R8 are independently hydrogen or halo;
- and
- R5, R6, and R7 are independently selected from the group consisting of hydrogen, halo, alkyl, acyl, acyloxy, alkoxy, heterocycloalkyloxy, carboxyl ester, acylamino, alkylamino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonylamino, (carboxyl ester)amino, aminosulfonyl, (substituted sulfonyl)amino, haloalkyl, haloalkoxy, haloalkylthio, cyano, alkylsulfonyl and haloalkylsulfonyl;
- or R6 and R7 together form a heterocycloalkyl ring;
- provided that
- (1) if X is NH and Q is O, then R is not pyridyl, piperidinyl, or piperidinyl substituted with at least one substituent selected from the group consisting of —C(O)H, —C(O)CH3, —C(O)Oalkyl, —C(O)N(CH3)2, dimethylamino, cyanoimino-morpholin-4-yl-methyl, N1-azetidin-1-yl-N-cyano-amidino, N2-cyano-N1,N1-dimethylamidino, N′-cyano-N,N-dimethyl-carbamimidoyl, propionyl, and methylsulfonyl;
- (2) if X is NH, Q is O, and Y is methoxyphenyl, then R is not hydroxymethylphenyl, pyridylalkyl, fluoropyridyl, and acetylphenyl;
- (3) if Y is pyridyl or substituted pyridyl, then R is alkyl substituted with NR2R3 wherein R2 and R3 together form a morpholino or piperazinyl ring;
- (4) R is not haloalkyl or mono-substituted alkyl where the substituent is cyano, hydroxyl, or —O—C(O)O-alkyl;
- (5) when Y is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl, R is not heteroaryl selected from the group consisting of benzimidazolyl, benzothiazolyl, benzoxazolyl, diazaindolinyl, pyridoimidazolyl, azaindolizinyl, 3,4-diazaindolyl, azaindolyl, 3,4-dihydro-1,4-a,5-triazacarbazolonyl, and 3,4-dihydro-1,4-a-diazacarbazolonyl, wherein the heteroaryl is substituted with at least one substituent selected from the group consisting of amino, (carboxyl ester)amino, acylamino, (substituted sulfonyl)amino, substituted sulfonyl, aminosulfonylamino, and aminocarbonylamino;
- and
- (6) Formula (I′) is not
18 more elements
30-31. (canceled)
A method for treating a soluble expoxide hydrolase mediated disease, said method comprising administering to a patient a compound of Formula (II) or a pharmaceutically acceptable salt thereof:
- wherein:
- Q is O or S;
- Q′ is O or S;
- R is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
- each R1 is independently selected from the group consisting of alkyl, cyano, halo, and haloalkyl;
- n is 0, 1, 2, or 3;
- X is selected from the group consisting of a covalent bond, NH, or CR′R″ where R′ and R″ are independently H or alkyl or R′ and R″ together form a C3-C6 cycloalkyl ring;
- and
- Y is selected from the group consisting of heteroaryl, substituted heteroaryl, and
- wherein R4 and R8 are independently hydrogen or halo;
- and
- R5, R6, and R7 are independently selected from the group consisting of hydrogen, halo, alkyl, acyl, acyloxy, alkoxy, heterocycloalkyloxy, carboxyl ester, acylamino, alkylamino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonylamino, (carboxyl ester)amino, aminosulfonyl, (substituted sulfonyl)amino, haloalkyl, haloalkoxy, haloalkylthio, cyano, alkylsulfonyl and haloalkylsulfonyl;
- or R6 and R7 together form a heterocycloalkyl ring.
10 more elements
A method for inhibiting a soluble epoxide hydrolase, comprising contacting the soluble epoxide hydrolase with an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof:
- wherein:
- Q is O or S;
- Q′ is O or S;
- R is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
- each R1 is independently selected from the group consisting of alkyl, cyano, halo, and haloalkyl;
- n is 0, 1, 2, or 3;
- X is selected from the group consisting of a covalent bond, NH, or CR′R″ where R′ and R″ are independently H or alkyl or R′ and R″ together form a C3-C6 cycloalkyl ring;
- and
- Y is selected from the group consisting of heteroaryl, substituted heteroaryl, and
- wherein R4 and R8 are independently hydrogen or halo;
- and
- R5, R6, and R7 are independently selected from the group consisting of hydrogen, halo, alkyl, acyl, acyloxy, alkoxy, heterocycloalkyloxy, carboxyl ester, acylamino, alkylamino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonylamino, (carboxyl ester)amino, aminosulfonyl, (substituted sulfonyl)amino, haloalkyl, haloalkoxy, haloalkylthio, cyano, alkylsulfonyl and haloalkylsulfonyl;
- or R6 and R7 together form a heterocycloalkyl ring.
10 more elements
A compound or a pharmaceutically acceptable salt thereof selected from:
- Compound
- Structure
- Name
- 41
- 1-Cyclohexyl-3-[3-(3-morpholin-4-yl-propoxy)-phenyl]-urea
- 42
- 1-tert-Butyl-3-[3-(3-morpholin-4-yl-propoxy)-phenyl]-urea
- 43
- 2-Adamantan-1-yl-N-[3-(3-morpholin-4-yl-propoxy)-phenyl]-butyramide
- 44
- 3,3-Dimethyl-N-[3-(3-morpholin-4-yl-propoxy)-phenyl]-butyramide
- 45
- 1-Cyclohexyl-3-[4-(3-morpholin-4-yl-propoxy)-phenyl]-urea
- 46
- 2-Adamantan-1-yl-N-[4-(3-morpholin-4-yl-propoxy)-phenyl]-acetamide
- 47
- 1-Adamantan-1-yl-3-[3-(3-morpholin-4-yl-propoxy)-phenyl]-urea
- 48
- 1-Adamantan-11-yl-3-[3-(3-morpholin-4-yl-propoxy)-cyclohexyl]-urea
- 49
- 2-Adamantan-1-yl-N-[3-(3-morpholin-4-yl-propoxy)-cyclohexyl]-acetamide
- 50
- 2-Adamantan-1-yl-N-[4-(3-morpholin-4-yl-propoxy)-cyclohexyl]-acetamide
- 51
- 2-Cyclohexyl-N-[3-(3-morpholin-4-yl-propoxy)-phenyl]-acetamide
- 52
- 2-Adamantan-1-yl-N-[4-fluoro-3-(3-morpholin-4-yl-propoxy)-phenyl]-acetamide
- 53
- 1-Adamantan-1-yl-3-[4-fluoro-3-(3-morpholin-4-yl-propoxy)-phenyl]-urea
- 54
- 1-Cyclohexyl-3-[4-fluoro-3-(3-morpholin-4-yl-propoxy)-phenyl]-urea
- 55
- Adamantane-1-carboxylicacid [3-(3-morpholin-4-yl-propoxy)-phenyl]-amide
- 56
- Cyclohexanecarboxylicacid [3-(3-morpholin-4-yl-propoxy)-phenyl]-amide
- 57
- 1-Adamantan-1-yl-3-(3-benzyloxy-phenyl)-urea
- 58
- 2-(Adamantan-1-ylamino)-N-[3-(3-morpholin-4-yl-propoxy)-phenyl]-acetamide
- 59
- 3-(4-(3-Adamantan-1-ylureido)phenoxy)benzoicacid
- 61
- 1-adamantan-1-yl-3-[3-(3-morpholin-4-yl-propoxy)cyclohexyl]thiourea
- 62
- 1-[4-(3-morpholin-4-yl-propoxy)cyclohexyl]-3-phenylurea
- 63
- 1-[3-(3-Morpholin-4-yl-propoxy)cyclohexyl]-3-phenylurea
- 65
- 4-(4-(3-(adamantanyl)ureido)phenoxy)benzoic acid
- 68
- 4-(3-(3-(adamantanyl)ureido)phenoxy)benzoicacid
- 70
- 3-(3-(3-(adamantanyl)ureido)phenoxy)benzoicacid
- 72
- 1-(4-(benzyloxy)phenethyl)-3-(adamantanylethyl)urea
- 73
- 1-(4-(benzyloxy)phenethyl)-3-(adamantanylmethyl)urea
54 more elements
A compound or a pharmaceutically acceptable salt thereof, which compound is
- 74
- 4-((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyloxy)benzoic acid
A compound or a pharmaceutically acceptable salt thereof, which compound is
- 75
- 4-((1R,4R)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyloxy)benzoic acid
(canceled)
Dependencies are inferred from the claim text.