Loading patent…
AssigneeNitroMed, Inc.
InventorsSubhash P. Khanapure, David S. Garvey, Richard A. Earl, Maiko Ezawa, Xinqin Fang, Ricky D. Gaston
Estimating the term…
The invention describes novel substituted aryl compounds that are 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, optionally, at least one therapeutic agent, such as, steroids, nonsterodal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobaxcter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, 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 toxicity or other toxicities; 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.
A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
A method for improving the cardiovascular profile of a COX-2 selective inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one of a 3-hydroxy-3-methylglutaryl coenzyme A, an antiplatelet agent, a thrombin inhibitor or a thromboxane inhibitor, wherein the compound of Formula (I) comprises at least one “—U—V” moiety, wherein U and V are as defined herein.
A composition comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and, optionally, at least one therapeutic agent.
The composition of claim 26, wherein the compound comprising at least one ON—O—, ON—N— or ON—C— group is an ON—O-polypeptide, an ON—N-polypepetide, an ON—C-polypeptide, an ON—O-amino acid, an ON—N-amino acid, an ON—C-amino acid, an ON—O-sugar, an ON—N-sugar, an ODN—C-sugar, an ON—O-oligonucleotide, an ON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—C-hydrocarbon, an ON—O-heterocyclic compound, an ON—N-heterocyclic compound or a ON—C-heterocyclic compound.
A kit comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof.
A kit comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase.
A kit. comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutic agent.
A compound selected from 1-(6-(cyclohexylidenemethyl) (2-H-benzo(3,4-d)1,3-dioxolen-5-yl))-4-(methylsulfonyl)benzene, 1-(6-(cyclohexylmethyl)(2-H-benzo(3,4-d)1,3-dioxolen-5-yl))-4-(methylsulfonyl)benzene, 1-(6-(cyclohexylhydroxymethyl) (2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, cyclohexyl 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) ketone, 1-(6-(hydroxyphenylmethyl) (2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 4-(methylsulfonyl)-1-(6-benzyl(2H-benzo(3,4-d)1,3-dioxolan-5-yl)) benzene, 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) phenyl ketone, (2-fluorophenyl)(6-(4-methylthiophenyl)(2H-benzo(d) 1,3-dioxolan-5-yl))methan-1-ol, 1-(6-((2-fluorophenyl)methyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 2-fluorophenyl 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) ketone, 1-(6-((3-fluorophenyl)hydroxymethyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 1-(6-((3-fluorophenyl)methyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 3-fluorophenyl 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) ketone, 1-(6-(hydroxy-3-pyridylmlethyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene, 4-(methylsulfonyl)-1-(6-(3-pyridylmethyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))benzene, 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) 3-pyridyl ketone, ethyl (2E)-2-methyl-3-(6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl))prop-2-enoate, 1-(6-((1E)-3-hydroxy-2-methylprop-1-enyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl)benzene 4-(methylsulfonyl)-1-(6-((3-((nitrooxy)methyl)piperidyl)methyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))benzene, 1-(6-((3-(hydroxymethyl)piperidyl)methyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-4-(methylsulfonyl) benzene, 4-(methylsulfonyl)-1-(6-((3-((nitrooxy)methyl)piperidyl)methyl) (2H-benzo(3,4-d) 1,3-dioxolan-5-yl))benzene, 1-((6-(4-methylsulfonyl)phenyl)-2H-benzo(d) 1,3-dioxolan-5-yl)methyl)piperidin-2-one, 4-(6-(cyclopentylidenemethyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-1-(methylsulfonyl), 4-(6-(cyclopenthylmethyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 4-(6-(cycloheptylidenemethyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-1-(methylsulfonyl) benzene, 4-(6-(cycloheptylmethyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 4-(6-(hydroxy(3-methylphenyl)methyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 3-methylphenyl 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d) 1,3-dioxolan-5-yl)ketone, 6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl)3-((nitrooxy)methyl)phenylketone, 1-(6-(hydroxy(3-methoxyphenyl)methyl)(2H-benzo(3,4-d) 1,3-dioxolan-5yl))-4-(methylsulfonyl)benzene, 3-methoxyphenyl-6-(4-(methylsulfonyl) phenyl)(2H-benzo(d)1,3-dioxolan-5-yl) ketone, 4-(6-(3-methoxyphenyl)methyl)(2H-benzo(3,4-d) 1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 4-(6-((2-fluoro-5-methylphenyl) hydroxymethyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene, 2-fluoro-5-methylphenyl6-(4-(methylsulfonyl)phenyl)(2H-benzo(d)1,3-dioxolan-5-yl)ketone, 4-(1-(3′, 5′-difluorophenyl)-1-hydroxymethyl)-1,2-methylenedioxy-5-(4-methylsulfonylphenyl)benzene, 5-(1-(3′,5′-difluorophenyl)methyl)-1,2-methylenedioxy-4-(4-methylsulfonylphenyl)benzene, 4-(1-(3′,5′-difluorophenyl)-1-oxomethyl)-1,2-methylenedioxy-5-(4-methylsulfonylphenyl)benzene, 4-(1-(3′,5′-difluorophenyl)-1-hydroxymethyl)-1,2-dimethoxy-5-(4-methylsulfonylphenyl) benzene, 5-(1-(3′,5′-difluorophenyl)methyl)-1,2-dimethoxy-4-(4-methylsulfonylphenyl)benzene, 5-(1-(3′,5′-difluorophenyl)methyl)-1,2-dihydroxy-4-(4-methylsulfonylphenyl)benzene, 1,2-(bis(ethoxycarbonyl))methylenedioxy-5-(1-(3′,5′-difluorophenyl)methyl)-4-(4-methylsulfonylphenyl)benzene, 4-(1-(3′,5′-difluorophenyl)-1-oxomethyl)-1,2-dimethoxy-5-(4-methylsulfonylphenyl)benzene, 4-(1-(3′,5′-difluorophenyl)-1-oxomethyl)-1,2-hydroxy-5-(4-methylsulfonylphenyl)benzene, ethyl 7-((3,5-difluorophenyl)methyl)-6-(4-(methylsulfonyl) phenyl)-2H, 3H-benzo(e)1,4-dioxin-2-carboxylate, ethyl 6-((3,5-difluorophenyl)methyl)-7-(4-(methylsulfonyl)phenyl)-2H, 3H-benzo(e) 1,4-dioxin-2-carboxylate, (7-((3, 5-difluorophenyl) methyl)-6-(4-(methylsulfonyl)phenyl)(2H, 3H-benzo(e)1,4-dioxin-2-yl))-N-(2-hydroxyethyl)carboxamido, (6-((3,5-difluorophenyl)methyl)-7-(4-(methylsulfonyl)phenyl)(2H, 3H-benzo(e)1,4-dioxin-2-yl))-N-(2-hydroxyethyl)carboxamido, (7-((3,5-difluorophenyl) methyl)-6-(4-(methylsulfonyl)phenyl)(2H, 3H-benzo(e)1,4-dioxin-2-yl))-N-(2-(nitrooxy) ethyl)carboxamido, 1-(7-((3,5-difluorophenyl)methyl)-2-(hydroxymethyl)(2H, 3H-benzo(3,4-e)1,4-dioxin-6-yl))-4-(methylsulfonyl)benzene, 1-(7-((3,5-difluorophenyl)methyl)-3-(hydroxymethyl)(2H, 3H-benzo(e)1,4-dioxin-6-yl))-4-(methylsulfonyl)benzene, 1-(7-((3,5-difluorophenyl)methyl)-2-((nitrooxy)methyl)(2H, 3H-benzo(3,4-e)1,4-dioxin-6-yl))-4-(methylsulfonyl)benzene, 1-(7-((3,5-difluorophenyl)methyl)-3-((nitrooxy)methyl)(2H, 3H-benzo(e)1,4-dioxin -6-yl))-4-(methylsulfonyl)benzene, 1-(7-((3,5-difluorophenyl)methyl)(2H, 3H-benzo(3,4-e)1,4-dioxin-6-yl))-4-(methylsulfonyl)benzene, 7-((3,5-difluorophenyl)methyl)-6-(4-(methylsulfonyl)phenyl)-2H, 3H-benzo(e)1,4-dioxin-2-carboxamide, 3,5-difluorophenyl 7-(4-(methylsulfonyl)phenyl)(2H, 3H-benzo(e)1,4-dioxin-6-yl) ketone, ((4-(6-((3,5-difluorophenyl)methyl)(2H-benzo(3,4-d)1,3-dioxolan-5-yl))phenyl)methyl)nitrooxy, 1-(2-(cyclohexylidenemethyl)phenyl)-4-(methylsulfonyl)benzene, 1-(2-((3-fluorophenyl) hydroxymethyl)phenyl)-4-(methylsulfonyl)benzene, 3-fluorophenyl 2-(4-(methylsulfonyl) phenyl)phenyl ketone, 1-(2-((3-fluorophenyl)methyl)phenyl)-4-(methylsulfonyl)benzene or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.