US 7,442,802 B2Granted

Cyclooxygenase-2 selective inhibitors, compositions and methods of use

AssigneeNitroMed, Inc.

InventorsUpul K. Bandarage, Richard A. Earl, Maiko Ezawa, Xinqin Fang, David S. Garvey, Subhash P. Khanapure, Ramani R. Ranatunge, Stewart K. Richardson, Joseph D. Schroeder, Cheri A. Stevenson, Shiow-Jyi Wey

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Abstract

The invention describes novel cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, optionally nitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal and/or respiratory toxicity; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

Claims25

Dependent claims

A compound of Formula (I), (II) or a pharmaceutically acceptable salt thereof;

wherein the compound of Formula (I) is:
wherein:
R1 is —S(O)2—CH3;
R1′ at each occurrence is independently a hydrogen, a halogen, a methyl or CH2OH;
R2 is a substituted lower alkyl group, a cycloalkyl group, an aryl group or a heteroaryl;
R3 is:
(a) —(C(R4)(R′4))k—Y—(C(R4)(R′4))n—O—V;
(b) —C(Z)-(C(R4)(R′4))k—O—V;
(c) —C(Z)-(C(R4)(R′4))k—Y—(C(R4)(R′4))n—O—V;
(d) —(C(R4)(R′4))k—Y—(C(R4)(R′4))n—C(Z)—(C(R4)(R′4))n—O—V;
(e) —(C(R4)(R′4))k—CH═CH—(C(R4)(R′4))p—O—V;
(g) —(C(R4)(R′4))n—W-Q-(C(R4)(R′4))k—O—V;
(h) —(C(Z)-W-Q-(C(R4)(R′4)k—O—V;
(i) —C(O)—N(Ri)—O—(C(R4)(R′4)n—O—V;
(j) —(C(R4)(R′4))k—C≡C—(C(R4)(R′4))p—O—V;
(k) —(C(R4)(R′4))k—Y—(C(R4)(R′4))k—Y—(C(R4)(R′4))k—O—V;
(l) —(C(R4)(R′4))p-E-N(Ri)—O—W-Q-(C(R4)(R′4)k—O—V;
(m) —(C(R4)(R′4))p-E-N(Ri)—O—(C(R4)(R′4)k—O—V;
(n) —(C(R4)(R′4))p—N(Ri)—O—(C(R4)(R′4)k—O—V;
(o) —(C(R4)(R′4))p—O—N(Ri)—(C(R4)(R′4)k—O—V;
(p) —(C(R4)(R′4))p—O—N(Ri)-E-(C(R4)(R′4)k—O—V;
or
(q) —(C(R4)(R′4))p—O—N(Ri)-E-W-Q-(C(R4)(R′4)k—O—V;
R4 and R′4 at each occurrence are independently a hydrogen, a halogen, a lower alkyl group, or an alkoxy group;
V is —NO, —NO2, or a hydrogen;
Y at each occurrence is independently an oxygen,—S(O)o— or —N(Ra)Ri—;
Z is an oxo, a thial, an oxime or a hydrazone;
Q is Y or a covalent bond;
W at each occurrence is independently an aryl group, an alkylaryl group, a heterocyclic ring or an alkylheterocyclic ring;
E is —C(O) or —S(O)o;
Ra is a lone pair of electron, a hydrogen or a lower alkyl group;
Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —(C(R4)(R′4))n—O—V, or —(N2O2—)−•M+, wherein M+is an organic or inorganic cation;
o is an integer from 0 to 2;
k is an integer from 1 to 6;
p at each occurrence is independently an integer from 0 to 10;
n at each occurrence is independently an integer from 2 to 10;
wherein the compound of Formula (II) is:
wherein R1, R1′, R2 and R3 are as defined herein.

35 more elements

A compound selected from the group consisting of

1-(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one;
1-(3-((1Z)-4-(hydroxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl-4-methylsulfonyl)benzene;
4-(3-((3-hydroxypropoxy)methyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene;
1-(3-(difluoro(3-hydroxypropoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(1-(4-chlorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl) benzene;
1-(3-((3-hydroxypropoxy)methyl)-1-(4-methylphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(3-((3-hydroxypropoxy)methyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(3-((3-hydroxypropoxy)methyl)-1-(4-methoxyphenyl)pyrazol-5-yl)-4-(methylsulfonyl) benzene;
1-(3-((1Z)-4-(hydroxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-methylsulfonyl)benzene;
4-hydroxy- 1-(1-(4-methylphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)butan-1-one;
1-(1-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one;
1-(1-(4-bromophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one;
1-(1-cyclohexyl-3-((2-hydroxyethoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(1-cyclohexyl-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(1-(4-fluorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(3-((3-hydroxybutoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(3-((1E)-4-(hydroxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-methylsulfonyl)benzene;
1-(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)-pyrazol-3-yl)-6-hydroxyhexan-1-one;
4-hydroxy-1-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)-phenyl)pyrazol-3-yl) butan-1-one;
4-hydroxy-1-(1-(4-methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)-pyrazol-3-yl) butan-1-one;
4(3-((1E)-3-hydroxyprop-1-enyl)-1-cyclohexylpyrazol-5-yl)-l (methylsulfonyl) benzene;
1-(1-cyclohexyl-3-(((2-hydroxyethyl)amino)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;
4-(3-(4-hydroxybutanoyl)-5-(4-(methylsulfonyl)phenyl)pyrazolyl) benzenecarbonitrile;
1-(1-(4-chloroophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one;
(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(2-hydroxyethyl)carboxamide;
(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(3-hydroxypropyl) carboxamide;
1-(3-((1Z)-4-(nitrooxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl) benzene;
4-(3-((3-(nitrooxy)propoxy)methyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene;
1-(3-(difluoro-(3-(nitrooxy)propoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl) benzene;
1-(1-(4-chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl) benzene;
1-(1-(4-methylphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl) benzene;
4-(methylsulfonyl)-1-(3-((3-(nitrooxy)propoxy)methyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-5-yl)benzene;
1-(1-(4-methoxy-3-nitrophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl) benzene;
1-(3-((1Z)-4-(nitrooxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(3-((1E)-4-(nitrooxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(1-(4-methylphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy) butan-1-one;
1-(1-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy) butan-1-one
1-(1-(4-bromophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy) butan-1-one;
1-(1-cyclohexyl-3-((2-(nitrooxy)ethoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(1-cyclohexyl-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(1-(4-fluorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl) benzene;
4-(methylsulfonyl)-1-(3-((3-(nitrooxy)butoxy)methyl)-1-phenylpyrazol-5-yl)benzene;
1-(3-((1E)-4-(nitrooxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene;
1-(1-cyclohexyl-5-(4-(methylsulfonyl)pyrazol-3-yl)-6-(nitrooxy)hexan-1-one;
1-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one;
1-(1-(4-methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl-4-(nitrooxy) butan-1-one;
1-(5-(4-(methysulfonyl)phenyl)-1-(2-pyridyl)pyrazol-3-yl)-2-(nitrooxy)ethan-1-one;
4-(1-(4-methoxyphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl) benzene;
4-(1-(4-methyl-3-nitrophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;
1-(3-((1E)-3-(nitrooxy)prop-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl) benzene;
4-(5-(4-(methylsulfonyl)phenyl)-3-(4-(nitrooxy)butanoyl)pyrazolyl) benzenecarbonitrile;
1-(1-(4-chlorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy) butan-1-one;
(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(2-(nitrooxy)ethyl)carboxamide;
(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(3-(nitrooxy)propyl)carboxamide;
3-(nitrooxy)propyl, 4-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)-phenyl)pyrazol-3-yl)butanoate;
1-(3-((1Z)-4-hydroxybut-1-enyl)-5-(3-pyridyl)pyrazolyl)-4-(methylsulfonyl)benzene;
and
1-(3-((1Z)-4-(nitrooxy)but-1-enyl)-5-(3-pyridyl)pyrazolyl)-4-(methylsulfonyl)benzene;
or a pharmaceutically acceptable salt thereof.

56 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/418,187Filed 5 May 2006 · division
Priority: 27 Jun 2002
Published: US 2006/0194861 A131 Aug 2006
Granted: 28 Oct 2008
Term ends: Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/14
Drugs for disorders of the alimentary tract or the digestive system: prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics,…

Family

Application60/391,769Us provisional application · filed 27 Jun 2002
Application60/454,307Us provisional application · filed 14 Mar 2003
Application10/603,098Parent of this division · filed 25 Jun 2003
US 2006/0194861 A1Pre-grant publication · published 31 Aug 2006
US 7,087,630 B2Parent of this division
US 2004/0053985 A1Published application
US 7,442,802 B2This patent

From the US filing history. Foreign family members aren’t listed.