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WO2006099416A1 - Inhibiteurs selectifs de la 2-methyle-indole cyclooxygenase-2, compositions et procedes d’utilisation - Google Patents

Inhibiteurs selectifs de la 2-methyle-indole cyclooxygenase-2, compositions et procedes d’utilisation Download PDF

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Publication number
WO2006099416A1
WO2006099416A1 PCT/US2006/009127 US2006009127W WO2006099416A1 WO 2006099416 A1 WO2006099416 A1 WO 2006099416A1 US 2006009127 W US2006009127 W US 2006009127W WO 2006099416 A1 WO2006099416 A1 WO 2006099416A1
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Prior art keywords
group
methoxy
chlorophenyl
carbonyl
nitric oxide
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Shiow-Jyi Wey
David S. Garvey
Xinqin Fang
Stewart K. Richardson
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Nitromed Inc
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Nitromed Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • compositions and kits comprising 2-methyl indole cyclooxygenase 2 (COX- 2) selective inhibitors or pharmaceutically acceptable salts thereof, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent.
  • the 2-methyl indole cyclooxygenase 2 selective inhibitors can be optionally substituted with at least one nitric oxide enhancing group.
  • the invention also provides methods for (a) treating inflammation, pain and fever; (b) treating gastrointestinal disorders and/or improving the gastrointestinal properties of COX-2 selective inhibitors; (c) facilitating wound healing; (d) treating renal and/or respiratory toxicities; (e) treating disorders resulting from elevated levels of cyclooxygenase-2; (f) improving the cardiovascular profile of COX-2 selective inhibitors; (g) treating diseases resulting from oxidative stress; (h) treating endothelial dysfunctions; (j) treating diseases caused by endothelial dysfunctions; (k) treating inflammatory disease states and/or disorders; (1) treating ophthalmic disorders; and (m) treating peripheral vascular diseases.
  • the nitric oxide enhancing groups are organic nitrates, organic nitrites, nitrosothiols, thionitrites, thionitrates, NONOates, heterocyclic nitric oxide donors and/or nitroxides.
  • the heterocyclic nitric oxide donors are furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.
  • Nonsteroidal anti-inflammatory compounds are widely used for the treatment of pain, inflammation, and acute and chronic inflammatory disorders such as osteoarthritis and rheumatoid arthritis. These compounds inhibit the activity of the enzyme cyclooxygenase (COX), also known as prostaglandin G/H synthase, which is the enzyme that converts arachidonic acid into prostanoids.
  • COX cyclooxygenase
  • the NSAIDs also inhibit the production of other prostaglandins, especially prostaglandin G 2 , prostaglandin H 2 and prostaglandin E 2 , thereby reducing the prostaglandin-induced pain and swelling associated with the inflammation process.
  • the chronic use of NSAIDs has been associated with adverse effects, such as gastrointestinal ulceration and renal toxicity.
  • these compounds can result in dyspepsia and can cause gastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)).
  • COX-2 selective inhibitors can increase the risk of cardiovascular events in a patient (Mukherjee et al., JAMA 286(8) 954-959 (2001)); Hennan et al., Circulation, 104:820-825 (2001)).
  • the invention provides novel 2-methyl indole COX-2 selective inhibitors comprising at least one nitric oxide enhancing group, and pharmaceutically acceptable salts thereof.
  • the 2-methyl indole COX-2 selective inhibitor can optionally be substituted with at least one nitric oxide enhancing group.
  • the nitric oxide enhancing groups are organic nitrates, organic nitrites, nitrosothiols, thionitrites, thionitrates, NONOates, heterocyclic nitric oxide donors and/or nitroxides that are linked to the 2-methyl indole COX-2 selective inhibitor through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen via a bond or moiety that can be hydrolyzed.
  • the heterocyclic nitric oxide donor groups are furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.
  • the invention also provides compositions comprising the novel compounds described herein in a pharmaceutically acceptable carrier.
  • the invention is also based on the discovery that administering at least one 2-methyl indole COX-2 selective inhibitor optionally comprising at least one nitric oxide enhancing group or a pharmaceutically acceptable salt thereof, and, optionally, at least one nitric oxide enhancing compound improves the properties of the 2-methyl indole COX-2 selective inhibitor.
  • Nitric oxide enhancing compounds include, for example, S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, furoxans, sydnonimines, SPM 3672, SPM 4757, SPM 5185, SPM 5186 and analogues thereof, substrates of the various isozymes of nitric oxide synthase, and nitroxides.
  • another embodiment of the invention provides compositions comprising at least one 2-methyl indole COX-2 selective inhibitor, optionally comprising at least one nitric oxide enhancing group and at least one nitric oxide enhancing compound.
  • the invention also provides for such compositions in a pharmaceutically acceptable carrier.
  • compositions comprising at least one 2-methyl indole COX-2 selective inhibitor, that is optionally substituted with at least one nitric oxide enhancing group, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent, including, but not limited to, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter
  • the at least one therapeutic agent is selected from the group consisting of an NSAID, aspirin, a proton pump inhibitor and an H 2 antagonist.
  • the at least one therapeutic agent is aspirin.
  • the compositions can further comprise at least one nitric oxide enhancing compound. The invention also provides for such compositions in a pharmaceutically acceptable carrier.
  • compositions comprising at least one 2-methyl indole COX-2 selective inhibitor, that is optionally substituted with at least one nitric oxide enhancing group, and at least one therapeutic agent selected from the group consisting of a steroid, a selective cyclooxygenase-2 (COX-2) inhibitor, a nonsteroidal antiinflammatory compound (NSAID), a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B 4 (LTB 4 ) receptor antagonist, a leukotriene A 4 (LTA 4 ) hydrolase inhibitor, a 5-HT agonist, an anti-hyperlipidemic compound, a H 2 antagonist, a hydralazine compound, an antineoplastic agent, an antiplatelet agent, a thrombin inhibitor, a thromboxane inhibitor, a decongestant, a diuretic, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a Helicobacter py
  • compositions comprising at least one 2-methyl indole COX-2 selective inhibitor that is optionally substituted with at least one nitric oxide enhancing group, aspirin and, optionally, at least one nitric oxide enhancing compound.
  • the invention also provides for such compositions in a pharmaceutically acceptable carrier.
  • the invention provides methods for (a) treating inflammation, pain and fever; (b) treating gastrointestinal disorders and/or improving the gastrointestinal properties of COX-2 selective inhibitors; (c) facilitating wound healing; (d) treating renal and/or respiratory toxicities; (e) treating disorders resulting from elevated levels of cyclooxygenase-2; (f) improving the cardiovascular profile of COX-2 selective inhibitors; (g) treating diseases resulting from oxidative stress; (h) treating endothelial dysfunctions; Q) treating diseases caused by endothelial dysfunctions; (k) treating inflammatory disease states and/or disorders; (1) treating ophthalmic disorders; and (m) treating peripheral vascular diseases in a patient in need thereof comprising administering to the patient an effective amount of at least one 2- methyl indole COX-2 selective inhibitor, that is optionally substituted with at least one nitric oxide enhancing group, and, optionally, at least one therapeutic agent, such as, for example, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, non
  • the methods can optionally further comprise the administration of at least one nitric oxide enhancing compound.
  • the methods can involve (i) administering the 2-methyl indole COX-2 selective inhibitors, that are optionally substituted with at least one nitric oxide enhancing group (ii) administering the 2-methyl indole COX-2 selective inhibitors, that are optionally substituted with at least one nitric oxide enhancing group, and nitric oxide enhancing compounds, (iii) administering the 2-methyl indole COX-2 selective inhibitors, that are optionally substituted with at least one nitric oxide enhancing group and therapeutic agents, or (iv) administering the 2-methyl indole COX-2 selective inhibitors, that are optionally substituted with at least one nitric oxide enhancing group, nitric oxide enhancing compounds, and therapeutic agents.
  • the at least one therapeutic agent is selected from the group consisting of a steroid, a nonsteroidal antiinflammatory compound (NSAID), a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B 4 (LTB 4 ) receptor antagonist, a leukotriene A 4 (LTA 4 ) hydrolase inhibitor, a 5-HT agonist, an anti-hyperlipidemic compound, a H 2 antagonist, an antineoplastic agent, an antiplatelet agent, a thrombin inhibitor, a thromboxane inhibitor, a proton pump inhibitor, a selective cyclooxygenase-2 (COX-2) inhibitor, and combinations of two or more thereof.
  • NSAID nonsteroidal antiinflammatory compound
  • 5-LO 5-lipoxygenase
  • LTB 4 leukotriene B 4
  • LTA 4 leukotriene A 4 hydrolase inhibitor
  • a 5-HT agonist an anti-hyperlipidemic compound
  • H 2 antagonist an antineoplastic agent
  • the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H 2 antagonist. In another embodiment the at least one therapeutic agent is aspirin.
  • the 2-methyl indole COX-2 selective inhibitors, that are optionally substituted with at least one nitric oxide enhancing group, nitric oxide enhancing compounds, and/or therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • kits comprising at least one 2-methyl indole COX-2 selective inhibitor, that is optionally substituted with at least one nitric oxide enhancing group, and, optionally, at least one nitric oxide donor compound.
  • the kit can further comprise at least one therapeutic agent, such as, for example, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, inducible nitric oxide synthase inhibitors, opioids, analgesics, Heli
  • the organic nitric oxide donor salt of a selective cyclooxygenase-2 (COX-2) inhibitor, the nitric oxide donor and/or therapeutic agent can be separate components in the kit or can be in the form of a composition in one or more pharmaceutically acceptable carriers.
  • COX-2 selective cyclooxygenase-2
  • Gastrointestinal disorder refers to any disease or disorder of the upper gastrointestinal tract of a patient including, for example, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, constipation, ulcerative colitis, peptic ulcers, stress ulcers, bleeding ulcers, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, bacterial infections (including, for example, a Helicobacter Pylori associated disease), short-bowel (anastomosis) syndrome, hypersecretory states associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia, and bleeding peptic ulcers that result, for example, from neurosurgery, head injury, severe body trauma or burns.
  • inflammatory bowel disease including, for example, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, constipation, ulcerative colitis, peptic ulcers
  • Ultra gastrointestinal tract refers to the esophagus, the stomach, the duodenum and the jejunum.
  • ulcers refers to lesions of the upper gastrointestinal tract lining that are characterized by loss of tissue. Such ulcers include gastric ulcers, duodenal ulcers and gastritis.
  • NSAID refers to a nonsteroidal anti-inflammatory compound or a nonsteroidal antiinflammatory drug. NSAIDs inhibit cyclooxygenase, the enzyme responsible for the biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of the various isozymes of cyclooxygenase (including but not limited to cyclooxygenase- 1 and -2), and as inhibitors of both cyclooxygenase and lipoxygenase.
  • Cyclooxygenase-2 (COX-2) selective inhibitor refers to a compound that selectively inhibits the cyclooxygenase-2 enzyme over the cyclooxygenase- 1 enzyme.
  • the compound has a cyclooxygenase-2 IC50 of less than about 2 ⁇ M and a cyclooxygenase- 1 IC 50 of greater than about 5 ⁇ M, in the human whole blood COX-2 assay (as described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) and also has a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase- 1 inhibition of at least 10, and preferably of at least 40.
  • the compound has a cyclooxygenase- 1 IC5 0 of greater than about 1 ⁇ M, and preferably of greater than 20 ⁇ M.
  • the compound can also inhibit the enzyme, lipoxygenase. Such selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
  • Antiplatelet agents refers to compounds that prevent the formation of a blood thrombus via any number of potential mechanisms.
  • Platelet reducing agents include, but are not limited to, fibrinolytic agents, anti-coagulant agents and any inhibitors of platelet function.
  • Inhibitors of platelet function include agents that impair the ability of mature platelets to perform their normal physiological roles (i.e., their normal function, such as, for example, adhesion to cellular and non-cellular entities, aggregation, release of factors such as growth factors) and the like.
  • Protein pump inhibitor refers to any compound that reversibly or irreversibly blocks gastric acid secretion by inhibiting the H + ZK + -ATPaSe enzyme system at the secretory surface of the gastric parietal cell.
  • Therapeutic agent includes any therapeutic agent that can be used to treat or prevent the diseases described herein.
  • “Therapeutic agents” include, for example, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and the like.
  • Therapeutic agent includes the pharmaceutically acceptable salts thereof, pro-drugs, and pharmaceutical derivatives thereof including, but not limited to, the corresponding nitrosated and/or nitrosylated and/or heterocyclic nitric oxide donor derivatives and/or nitroxide derivative and/or NONOate derivative.
  • nitric oxide enhancing compounds have therapeutic activity, the term "therapeutic agent" does not include the nitric oxide enhancing compounds described herein, since nitric oxide enhancing compounds are separately defined.
  • Cardiovascular disease or disorder refers to any cardiovascular disease or disorder known in the art, including, but not limited to, heart failure, restenosis, hypertension (e.g. pulmonary hypertension, systolic hypertension, labile hypertension, idiopathic hypertension, low-renin hypertension, salt-sensitive hypertension, low-renin, salt-sensitive hypertension, thromboembolic pulmonary hypertension; pregnancy-induced hypertension; renovascular hypertension; hypertension-dependent end-stage renal disease, hypertension associated with cardiovascular surgical procedures, hypertension with left ventricular hypertrophy, and the like), diastolic dysfunction, coronary artery disease, myocardial infarctions, cerebral infarctions, arterial stiffness, atherosclerosis, atherogenesis, cerebrovascular disease, angina, (including chronic, stable, unstable and variant (Prinzmetal) angina pectoris), aneurysm, ischemic heart disease, cerebral ischemia, myocardial ischemia, thrombosis,
  • Restenosis is a cardiovascular disease or disorder that refers to the closure of a peripheral or coronary artery following trauma to the artery caused by an injury such as, for example, angioplasty, balloon dilation, atherectomy, laser ablation treatment or stent insertion. Restenosis can also occur following a number of invasive surgical techniques, such as, for example, transplant surgery, vein grafting, coronary artery bypass surgery, endarterectomy, heart transplantation, balloon angioplasty, atherectomy, laser ablation, endovascular stenting, and the like.
  • Atherosclerosis is a form of chronic vascular injury in which some of the normal vascular smooth muscle cells in the artery wall, which ordinarily control vascular tone regulating blood flow, change their nature and develop “cancer-like” behavior. These vascular smooth muscle cells become abnormally proliferative, secreting substances such as growth factors, tissue-degradation enzymes and other proteins, which enable them to invade and spread into the inner vessel lining, blocking blood flow and making that vessel abnormally susceptible to being completely blocked by local blood clotting, resulting in the death of the tissue served by that artery.
  • Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all common manifestations of atherosclerosis and are therefore encompassed by the terms “atherosclerosis” and "atherosclerotic disease”.
  • “Improving the cardiovascular profile” refers to and includes reducing the risk of thromboembolic events, reducing the risk of developing atherosclerosis and atherosclerotic diseases, and inhibiting platelet aggregation of the parent COX-2 inhibitor.
  • Thromboembolic events include, but are not limited to, ischemic stroke, transient ischemic stroke, myocardial infarction, angina pectoris, thrombosis (for example, restenosis, arterial thrombosis, coronary thrombosis, heart valve thrombosis, coronary stenosis, stent thrombosis, graft thrombosis, and first and subsequent thrombotic stroke, and the like), thromboembolism (for example, pulmonary thromboembolism, cerebral thromboembolism, and the like), thrombophlebitis, thrombocytopenia, bleeding disorders, thrombotic occlusion and reocclusion and acute vascular events.
  • thrombosis for example, restenosis, arterial thrombosis, coronary thrombosis, heart valve thrombosis, coronary stenosis, stent thrombosis, graft thrombosis, and first and
  • Patients who are at risk of developing thromboembolic events may include those with a familial history of, or genetically predisposed to, thromboembolic disorders, who have had ischemic stroke, transient ischemic stroke, myocardial infarction, and those with unstable angina pectoris or chronic stable angina pectoris and patients with altered prostacyclin/thromboxane A 2 homeostasis or higher than normal thromboxane A 2 levels leading to increase risk for thromboembolism, including patients with diabetes and rheumatoid arthritis.
  • Diseases resulting from oxidative stress refers to any disease that involves the generation of free radicals or radical compounds, such as, for example, atherogenesis, atheromatosis, arteriosclerosis, atherosclerosis, vascular hypertrophy associated with hypertension, hyperlipoproteinaemia, normal vascular degeneration through aging, parathyroidal reactive hyperplasia, renal disease (e.g., acute or chronic), neoplastic diseases, inflammatory diseases, neurological and acute bronchopulmonary disease, tumorigenesis, ischemia-reperfusion syndrome, arthritis, sepsis, cognitive dysfunction, endotoxic shock, endotoxin-induced organ failure, and the like.
  • free radicals or radical compounds such as, for example, atherogenesis, atheromatosis, arteriosclerosis, atherosclerosis, vascular hypertrophy associated with hypertension, hyperlipoproteinaemia, normal vascular degeneration through aging, parathyroidal reactive hyperplasia, renal disease (e.g., acute or chronic), neoplastic diseases,
  • Endothelial dysfunction refers to the impaired ability in any physiological processes carried out by the endothelium, in particular, production of nitric oxide regardless of cause. It may be evaluated by, such as, for example, invasive techniques, such as, for example,) coronary artery reactivity to acetylcholine or methacholine, and the like, or by noninvasive techniques, such as, for example, blood flow measurements, brachial artery flow dilation using cuff occlusion of the arm above or below the elbow, brachial artery ultrasonography, imaging techniques, measurement of circulating biomarkers, such as, asymmetric dimethylarginine (ADMA), and the like. For the latter measurement the endothelial- dependent flow-mediated dialation will be lower in patients diagnosed with an endothelial dysfunction.
  • invasive techniques such as, for example,) coronary artery reactivity to acetylcholine or methacholine, and the like
  • noninvasive techniques such as, for example, blood flow measurements, bra
  • Methods for treating endothelial dysfunction include, but are not limited to, treatment prior to the onset/diagnosis of a disease that is caused by or could result from endothelial dysfunction, such as, for example, atherosclerosis, hypertension, diabetes, heart failure, and the like.
  • Methods for treating diseases caused by endothelial dysfunction include, but are not limited to, the treatment of any disease resulting from the dysfunction of the endothelium, such as, for example, arteriosclerosis, heart failure, hypertension, cardiovascular diseases, cerebrovascular diseases, renovascular diseases, mesenteric vascular diseases, pulmonary vascular diseases, ocular vascular diseases, peripheral vascular diseases, peripheral ischemic diseases, and the like.
  • Optid disorders include, but are not limited to, ophthalmic infections, cataracts, glaucoma, elevated intraocular pressure, ocular pain (e.g., following corneal surgery), dry eye disorder, ocular hypertension, ocular bleeding, retinal diseases or disorders, presbyopia, macular degeneration, choroidal neovascularization (CNV), retinopathies, such as for example, diabetic retinopathy, vitreoretinopathy, and the like, retinitis, such as for example, cytomegalovirus (CMV) retinitis, uveitis, macular edema, neuropathies and the like.
  • CNV choroidal neovascularization
  • retinopathies such as for example, diabetic retinopathy, vitreoretinopathy, and the like
  • retinitis such as for example, cytomegalovirus (CMV) retinitis, uveitis, macular edema, neuropath
  • Thromboxane inhibitor refers to any compound that reversibly or irreversibly inhibits thromboxane synthesis, and includes compounds which are the so-called thromboxane A 2 receptor antagonists, thromboxane A 2 antagonists, thromboxane A 2 /prostaglandin endoperoxide antagonists, thromboxane receptor (TP) antagonists, thromboxane antagonists, thromboxane synthase inhibitors, and dual acting thromboxane synthase inhibitors and thromboxane receptor antagonists.
  • thromboxane A 2 receptor antagonists thromboxane A 2 antagonists
  • thromboxane A 2 /prostaglandin endoperoxide antagonists thromboxane receptor (TP) antagonists
  • thromboxane antagonists thromboxane synthase inhibitors
  • dual acting thromboxane synthase inhibitors and thromboxane receptor antagonists
  • the characteristics of the preferred thromboxane inhibitor should include the suppression of thromboxane A 2 formation (thromboxane synthase inhibitors) and/or blockade of thromboxane A 2 and prostaglandin H 2 platelet and vessel wall (thromboxane receptor antagonists). The effects should block platelet activation and therefore platelet function.
  • Thromboxane A 2 receptor antagonist refers to any compound that reversibly or irreversibly blocks the activation of any thromboxane A 2 receptor.
  • Thromboxane synthase inhibitor refers to any compound that reversibly or irreversibly inhibits the enzyme thromboxane synthesis thereby reducing the formation of thromboxane A 2 . Thromboxane synthase inhibitors may also increase the synthesis of antiaggregatory prostaglandins including prostacyclin and prostaglandin D 2 . Thromboxane A 2 receptor antagonists and thromboxane synthase inhibitors and can be identified using the assays described in Tai, Methods of Enzymology, Vol.
  • Double acting thromboxane receptor antagonist and thromboxane synthase inhibitor refers to any compound that simultaneously acts as a thromboxane A 2 receptor antagonist and a thromboxane synthase inhibitor.
  • Thrombin inhibitors refers to and includes compounds that inhibit hydrolytic activity of thrombin, including the catalytic conversion of fibrinogen to fibrin, activation of Factor V to Va, Factor VIII to Villa, Factor XIII to XIIIa and platelet activation. Thrombin inhibitors may be identified using assays described in Lewis et at., Thrombosis Research. 70: 173-190 (1993).
  • Anti-hyperlipidemic compounds refers to any compound or agent that has the effect of beneficially modifying serum cholesterol levels such as, for example, lowering serum low density lipoprotein (LDL) cholesterol levels, or inhibiting oxidation of LDL cholesterol, whereas high density lipoprotein (HDL) serum cholesterol levels may be lowered, remain the same, or be increased.
  • the anti-hyperlipidemic compound brings the serum levels of LDL cholesterol and HDL cholesterol (and, more preferably, triglyceride levels) to normal or nearly normal levels.
  • Platelet aggregation refers to the binding of one or more platelets to each other. Platelet aggregation is commonly referred to in the context of generalized atherosclerosis, not with respect to platelet adhesion on vasculature damaged as a result of physical injury during a medical procedure. Platelet aggregation requires platelet activation which depends on the interaction between the ligand and its specific platelet surface receptor.
  • Plate activation refers either to the change in conformation (shape) of a cell, expression of cell surface proteins (e.g., the Ilb/IIIa receptor complex, loss of GPIb surface protein), and secretion of platelet derived factors (e.g., serotonin, growth factors).
  • cell surface proteins e.g., the Ilb/IIIa receptor complex, loss of GPIb surface protein
  • platelet derived factors e.g., serotonin, growth factors
  • Prodrug refers to a compound that is made more active in vivo.
  • Patient refers to animals, preferably mammals, most preferably humans, and includes males and females, and children and adults.
  • Transdermal refers to the delivery of a compound by passage through the skin and into the blood stream.
  • Transmucosal refers to delivery of a compound by passage of the compound through the mucosal tissue and into the blood stream.
  • Poration enhancement refers to an increase in the permeability of the skin or mucosal tissue to a selected pharmacologically active compound such that the rate at which the compound permeates through the skin or mucosal tissue is increased.
  • Carriers or “vehicles” refers to carrier materials suitable for compound administration and include any such material known in the art such as, for example, any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is non-toxic and which does not interact with any components of the composition in a deleterious manner.
  • sustained release refers to the release of an active compound and/or composition such that the blood levels of the active compound are maintained within a desirable therapeutic range over a period of time.
  • the sustained release formulation can be prepared using any conventional method known to one skilled in the art to obtain the desired release characteristics.
  • Nitric oxide enhancing refers to compounds and functional groups which, under physiological conditions can increase endogenous nitric oxide. Nitric oxide enhancing compounds include, but are not limited to, nitric oxide releasing compounds, nitric oxide donating compounds, nitric oxide donors, radical scavenging compounds and/or reactive oxygen species scavenger compounds. In one embodiment the radical scavenging compound contains a nitroxide group.
  • Neitroxide group refers to compounds that have the ability to mimic superoxide dimutase and catalase and act as radical scavengers, or react with superoxide or other reactive oxygen species via a stable aminoxyl radical i.e. N-oxide.
  • Nitric oxide adduct or “NO adduct” refers to compounds and functional groups which, under physiological conditions, can donate, release and/or directly or indirectly transfer any of the three redox forms of nitrogen monoxide (NO + , NO " , NO»), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
  • Nitric oxide releasing or “nitric oxide donating” refers to methods of donating, releasing and/or directly or indirectly transferring any of the three redox forms of nitrogen monoxide (NO + , NO-, NO»), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
  • Nitric oxide donor or “NO donor” refers to compounds that donate, release and/or directly or indirectly transfer a nitrogen monoxide species, and/or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo and/or are oxidized to produce nitric oxide and/or are substrates for nitric oxide synthase and/or cytochrome P450.
  • NO donor also includes compounds that are precursors of L-arginine, inhibitors of the enzyme arginase and nitric oxide mediators.
  • Heterocyclic nitric oxide donor refers to a trisubstituted 5-membered ring comprising two or three nitrogen atoms and at least one oxygen atom.
  • the heterocyclic nitric oxide donor is capable of donating and/or releasing a nitrogen monoxide species upon decomposition of the heterocyclic ring.
  • Exemplary heterocyclic nitric oxide donors include oxatriazol-5-ones, oxatriazol-5-imines, sydnonimines, furoxans, and the like.
  • Alkyl refers to a lower alkyl group, a substituted lower alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein.
  • An alkyl group may also comprise one or more radical species, such as, for example a cycloalkylalkyl group or a heterocyclicalkyl group.
  • Lower alkyl refers to branched or straight chain acyclic alkyl group comprising one to about ten carbon atoms (preferably one to about eight carbon atoms, more preferably one to about six carbon atoms).
  • Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the like.
  • Substituted lower alkyl refers to a lower alkyl group, as defined herein, wherein one or more of the hydrogen atoms have been replaced with one or more R 100 groups, wherein each R 100 is independently a hydroxy, an ester, an amidyl, an oxo, a carboxyl, a carboxamido, a halo, a cyano, a nitrate, a nitrite, a thionitrate, a thionitrite or an amino group, as defined herein.
  • Haloalkyl refers to a lower alkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein, to which is appended one or more halogens, as defined herein.
  • exemplary haloalkyl groups include trifluoromethyl, chloromethyl, 2-bromobutyl, l-bromo-2-chloro-pentyl, and the like.
  • alkenyl refers to a branched or straight chain C 2 -C 1 O hydrocarbon (preferably a C 2 - C 8 hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) that can comprise one or more carbon-carbon double bonds.
  • alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbuten-l-yl, 3-methylbuten-l-yl, hexan-1-yl, hepten-1-yl, octen-1-yl, and the like.
  • “Lower alkenyl” refers to a branched or straight chain C 2 -C 4 hydrocarbon that can comprise one or two carbon-carbon double bonds.
  • Substituted alkenyl refers to a branched or straight chain C 2 -C 1O hydrocarbon (preferably a C 2 -C 8 hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) which can comprise one or more carbon-carbon double bonds, wherein one or more of the hydrogen atoms have been replaced with one or more R 100 groups, wherein each R 100 is independently a hydroxy, an oxo, a carboxyl, a carboxamido, a halo, a cyano or an amino group, as defined herein.
  • Alkynyl refers to an unsaturated acyclic C 2 -CiO hydrocarbon (preferably a C 2 -Cs hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) that can comprise one or more carbon- carbon triple bonds.
  • exemplary alkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn- 2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-l-yl, hexyl-1-yl, hexyl-2-yl, hexyl-3-yl, 3,3- dimethyl-butyn-1-yl, and the like.
  • Bridged cycloalkyl refers to two or more cycloalkyl groups, heterocyclic groups, or a combination thereof fused via adjacent or non-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro.
  • Exemplary bridged cycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl, 2,6-dioxabicyclo(3.3.0)octane, 7-oxabicyclo(2.2.1)heptyl, 8- azabicyclo(3,2,l)oct-2-enyl and the like.
  • Cycloalkyl refers to a saturated or unsaturated cyclic hydrocarbon comprising from about 3 to about 10 carbon atoms. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo, alkylsulfinyl, and nitro.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta-l,3-dienyl, and the like.
  • Heterocyclic ring or group refers to a saturated or unsaturated cyclic hydrocarbon group having about 2 to about 10 carbon atoms (preferably about 4 to about 6 carbon atoms) where 1 to about 4 carbon atoms are replaced by one or more nitrogen, oxygen and/or sulfur atoms. Sulfur may be in the thio, sulfinyl or sulfonyl oxidation state.
  • the heterocyclic ring or group can be fused to an aromatic hydrocarbon group.
  • Heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester, alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido, alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester, sulfonamide nitrate and nitro.
  • heterocyclic groups include pyrrolyl, furyl, thienyl, 3- pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrahydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, imidazolinyl, imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl
  • Heterocyclic compounds refer to mono- and polycyclic compounds comprising at least one aryl or heterocyclic ring.
  • Aryl refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or two aromatic rings.
  • Exemplary aryl groups include phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamido and nitro.
  • exemplary substituted aryl groups include tetrafluorophenyl, pentafluorophenyl,
  • Cycloalkenyl refers to an unsaturated cyclic C 2 -C 1 O hydrocarbon (preferably a C 2 - Cs hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) which can comprise one or more carbon-carbon double bonds.
  • Alkylaryl refers to an alkyl group, as defined herein, to which is appended an aryl group, as defined herein.
  • exemplary alkylaryl groups include benzyl, phenylefhyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the like.
  • Arylalkyl refers to an aryl radical, as defined herein, attached to an alkyl radical, as defined herein.
  • exemplary arylalkyl groups include benzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl, 2-fluorophenylethyl, and the like.
  • Arylalkenyl refers to an aryl radical, as defined herein, attached to an alkenyl radical, as defined herein.
  • exemplary arylalkenyl groups include styryl, propenylphenyl, and the like.
  • Cycloalkylalkyl refers to a cycloalkyl radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Cycloalkylalkoxy refers to a cycloalkyl radical, as defined herein, attached to an alkoxy radical, as defined herein.
  • Cycloalkylalkylthio refers to a cycloalkyl radical, as defined herein, attached to an alkylthio radical, as defined herein.
  • Heterocyclicalkyl refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Arylheterocyclic ring refers to a bi- or tricyclic ring comprised of an aryl ring, as defined herein, appended via two adjacent carbon atoms of the aryl ring to a heterocyclic ring, as defined herein.
  • exemplary arylheterocyclic rings include dihydroindole, 1,2,3,4- tetra-hydroquinoline, and the like.
  • Alkylheterocyclic ring refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein.
  • exemplary alkylheterocyclic rings include 2- pyridylmethyl, l-methylpiperidin-2-one-3 -methyl, and the like.
  • Alkoxy refers to R 50 O-, wherein R50 is an alkyl group, as defined herein (preferably a lower alkyl group or a haloalkyl group, as defined herein).
  • alkoxy groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, trifluoromethoxy, and the like.
  • Aryloxy refers to R55O-, wherein R55 is an aryl group, as defined herein.
  • exemplary arylkoxy groups include napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like.
  • Alkylthio refers to R5 0 S-, wherein R50 is an alkyl group, as defined herein.
  • Lower alkylthio refers to a lower alkyl group, as defined herein, appended to a thio group, as defined herein.
  • Arylalkoxy or “alkoxyaryl” refers to an alkoxy group, as defined herein, to which is appended an aryl group, as defined herein.
  • exemplary arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy, and the like.
  • Arylalklythio refers to an alkylthio group, as defined herein, to which is appended an aryl group, as defined herein.
  • exemplary arylalklythio groups include benzylthio, phenylethylthio, chlorophenylethylthio, and the like.
  • Arylalklythioalkyl refers to an arylalkylthio group, as defined herein, to which is appended an alkyl group, as defined herein.
  • exemplary arylalklythioalkyl groups include benzylthiomethyl, phenylethylthiomethyl, chlorophenylethylthioethyl, and the like.
  • Alkylthioalkyl refers to an alkylthio group, as defined herein, to which is appended an alkyl group, as defined herein.
  • exemplary alkylthioalkyl groups include allylthiomethyl, ethylthiomethyl, trifluoroethylthiomethyl, and the like.
  • Alkoxyalkyl refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined herein.
  • exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.
  • Alkoxyhaloalkyl refers to an alkoxy group, as defined herein, appended to a haloalkyl group, as defined herein.
  • exemplary alkoxyhaloalkyl groups include 4- methoxy- 2-chlorobutyl and the like.
  • Cycloalkoxy refers to Rs 4 O-, wherein R 54 is a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • exemplary cycloalkoxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Cycloalkylthio refers to R 54 S-, wherein R 54 is a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • exemplary cycloalkylthio groups include cyclopropylthio, cyclopentylthio, cyclohexylthio, and the like.
  • Haloalkoxy refers to an alkoxy group, as defined herein, in which one or more of the hydrogen atoms on the alkoxy group are substituted with halogens, as defined herein.
  • exemplary haloalkoxy groups include 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.
  • Oxy refers to -O-
  • Oxylate refers to -O " R 77 + wherein R 77 is an organic or inorganic cation.
  • Hydrazino refers to H 2 N-N(H)-.
  • Organic cation refers to a positively charged organic ion.
  • exemplary organic cations include alkyl substituted ammonium cations, and the like.
  • Inorganic cation refers to a positively charged metal ion.
  • Exemplary inorganic cations include Group I metal cations such as for example, sodium, potassium, magnesium, calcium, and the like.
  • Hydroalkyl refers to a hydroxy group, as defined herein, appended to an alkyl group, as defined herein.
  • Nirate refers to -O-NO 2 i.e. oxidized nitrogen.
  • Nirite refers to -O-NO i.e. oxidized nitrogen.
  • Thionitrate refers to -S-NO 2 .
  • Niro refers to the group -NO 2 and “nitrosated” refers to compounds that have been substituted therewith.
  • Niroso refers to the group -NO and "nitro sylated” refers to compounds that have been substituted therewith.
  • Halogen or “halo” refers to iodine (I), bromine (Br), chlorine (Cl), and/or fluorine (F).
  • Amine refers to any organic compound that contains at least one basic nitrogen atom.
  • Amino refers to -NH 2 , an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein.
  • Alkylamino refers to R 50 NH-, wherein R50 is an alkyl group, as defined herein.
  • exemplary alkylamino groups include methylamino, ethylamino, butylamino, cyclohexylamino, and the like.
  • Arylamino refers to R 55 NH-, wherein R 55 is an aryl group, as defined herein.
  • Dialkylamino refers to Rs 2 Rs 3 N-, wherein Rs 2 and Rs 3 are each independently an alkyl group, as defined herein.
  • Exemplary dialkylamino groups include dimethylamino, diethylamino, methyl propargylamino, and the like.
  • Diarylamino refers to R 55 R 60 N-, wherein R 55 and R ⁇ o are each independently an aryl group, as defined herein.
  • Alkylarylamino or “arylalkylamino” refers to Rs 2 RsSN-, wherein R 52 is an alkyl group, as defined herein, and R 55 is an aryl group, as defined herein.
  • Alkylarylalkylamino refers to Rs 2 R 79 N-, wherein Rs 2 is an alkyl group, as defined herein, and R 79 is an arylalkyl group, as defined herein.
  • Alkylcycloalkylamino refers to Rs 2 R 8O N-, wherein R 52 is an alkyl group, as defined herein, and R 8 o is a cycloalkyl group, as defined herein.
  • Aminoalkyl refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an alkyl group, as defined herein.
  • exemplary aminoalkyl groups include dimethylaminopropyl, diphenylaminocyclopentyl, methylaminomethyl, and the like.
  • aminoaryl refers to an aryl group to which is appended an alkylamino group, an arylamino group or an arylalkylamino group.
  • exemplary aminoaryl groups include anilino, N-methylanilino, N-benzylanilino, and the like.
  • Method refers to -C(S)-.
  • Sulfonic acid refers to -S(O) 2 OR 76 , wherein R 76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
  • Alkylsulfonic acid refers to a sulfonic acid group, as defined herein, appended to an alkyl group, as defined herein.
  • Arylsulfonic acid refers to a sulfonic acid group, as defined herein, appended to an aryl group, as defined herein
  • Sulfonic ester refers to -S(O) 2 ORs 8 , wherein Rs 8 is an alkyl group, an aryl group, or an aryl heterocyclic ring, as defined herein.
  • “Sulfonamido” refers to -S(O) 2 -N(Rs 1 )(Rs 7 ), wherein Rs 1 and Rs 7 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or Rs 1 and Rs 7 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Alkylsulfonamido refers to a sulfonamido group, as defined herein, appended to an alkyl group, as defined herein.
  • Arylsulfonamido refers to a sulfonamido group, as defined herein, appended to an aryl group, as defined herein.
  • Alkylthio refers to R5 0 S-, wherein R50 is an alkyl group, as defined herein (preferably a lower alkyl group, as defined herein).
  • Arylthio refers to R55S-, wherein R55 is an aryl group, as defined herein.
  • Arylalkylthio refers to an aryl group, as defined herein, appended to an alkylthio group, as defined herein.
  • Alkylsulfinyl refers to Rso-S(O)-, wherein R 50 is an alkyl group, as defined herein.
  • Alkylsulfonyl refers to RsO-S(O) 2 -, wherein R50 is an alkyl group, as defined herein.
  • Alkylsulfonyloxy refers to RsO-S(O) 2 -O-, wherein R 50 is an alkyl group, as defined herein.
  • Arylsulfinyl refers to Rss-S(O)-, wherein R 55 is an aryl group, as defined herein.
  • Arylsulfonyl refers to RsS-S(O) 2 -, wherein R 55 is an aryl group, as defined herein.
  • Arylsulfonyloxy refers to R 5 S-S(O) 2 -O-, wherein R 55 is an aryl group, as defined herein.
  • “Amidyl” refers to Rs 1 C(O)N(Rs 7 )- wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
  • Ester refers to Rs 1 C(O)Rg 2 - wherein R 51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein and R 82 is oxygen or sulfur.
  • Carbamoyl refers to -0-C(O)N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R 51 and R 57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Carboxyl refers to -C(O)OR 76 , wherein R 76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
  • Carbonyl refers to -C(O)-.
  • Alkylcarbonyl refers to R 52 -C(O)-, wherein R 52 is an alkyl group, as defined herein.
  • Arylcarbonyl refers to R 55 -C(O)-, wherein R 55 is an aryl group, as defined herein.
  • Arylalkylcarbonyl refers to R 55 -R 52 -C(O)-, wherein R 55 is an aryl group, as defined herein, and R 52 is an alkyl group, as defined herein.
  • Alkylarylcarbonyl refers to R 52 -R 55 -C(O)-, wherein R 55 is an aryl group, as defined herein, and R 52 is an alkyl group, as defined herein.
  • Heterocyclicalkylcarbonyl refer to R 78 C(O)- wherein R 78 is a heterocyclicalkyl group, as defined herein.
  • Carboxylic ester refers to -C(O)OR 58 , wherein R 58 is an alkyl group, an aryl group or an aryl heterocyclic ring, as defined herein.
  • Alkylcarboxylic acid and “alkylcarboxyl” refer to an alkyl group, as defined herein, appended to a carboxyl group, as defined herein.
  • Alkylcarboxylic ester refers to an alkyl group, as defined herein, appended to a carboxylic ester group, as defined herein.
  • Alkyl ester refers to an alkyl group, as defined herein, appended to an ester group, as defined herein.
  • Arylcarboxylic acid refers to an aryl group, as defined herein, appended to a carboxyl group, as defined herein.
  • Arylcarboxylic ester and “arylcarboxyl” refer to an aryl group, as defined herein, appended to a carboxylic ester group, as defined herein.
  • Aryl ester refers to an aryl group, as defined herein, appended to an ester group, as defined herein.
  • Carboxamido refers to -C(O)N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R 51 and R 57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Alkylcarboxamido refers to an alkyl group, as defined herein, appended to a carboxamido group, as defined herein.
  • Arylcarboxamido refers to an aryl group, as defined herein, appended to a carboxamido group, as defined herein.
  • Rea refers to -N(R 59 )-C(O)N(R 5 i)(R5 7 ) wherein R 51 , R57, and R 59 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R 51 and R 57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Phosphoryl refers to -P(R 7 o)(R 71 )(R 7 2), wherein R 7 o is a lone pair of electrons, tliial or oxo, and R 71 and R 72 are each independently a covalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, a hydroxy, an oxy or an aryl, as defined herein.
  • Phosphoric acid refers to -P(O)(ORs 1 )OH wherein R 51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
  • Phosphinic acid refers to -P(O)(Rs 1 )OH wherein R 51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
  • “Silyl” refers to -Si(R 73 )(R 74 )(R 75 ), wherein R 73 , R 74 and R 75 are each independently a covalent bond, a lower alkyl, an alkoxy, an aryl or an arylalkoxy, as defined herein.
  • the 2-methyl indole COX-2 selective inhibitors are substituted with at least one nitric oxide enhancing group that is linked to the 2-methyl indole COX-2 selective inhibitors through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen via a bond or moiety that can be hydrolyzed.
  • the 2-methyl indole COX-2 selective inhibitors comprising at least one nitric oxide enhancing group are in accordance with the invention and/or are included in the compositions of the invention can be any of those known in the art, including those exemplified below.
  • the nitric oxide enhancing groups are organic nitrates, organic nitrites, nitrosothiols, thionitrites, thionitrates, NONOates, heterocyclic nitric oxide donors and/or nitroxides.
  • the heterocyclic nitric oxide donors are furoxans, sydnonimines, oxatriazole-5- ones and/or oxatriazole-5-imines.
  • the invention describes 2-methyl indole COX-2 selective inhibitors of Formula (I), and pharmaceutically acceptable salts thereof:
  • R 31 is an atkoxy group, a hydroxyl group or an aminosulfonyloxy group
  • R 33 is a hydrogen, an alkylcarbonyl group, a nitro group, a nitroso group, a hydroxyalkyl group, an aryl alkoxy group, an alkylsulfonyl group, an alkoxy group, an alkyl carbonyl group, or K;
  • R 34 is a hydrogen or halogen
  • R 3S and R 39 are hydrogen or R 38 and R 39 when taken together with the carbon atom to which they are attached form a carbonyl group;
  • R 4O is a cylcloalkyl group or an aryl group;
  • X is:
  • R 36 is a hydrogen or an alkylcarbonyl group
  • R 24 is -C 6 H 4 R 37 , -CN, -S(O) 2 -C 6 H 4 R 37 , -C(O)-N(R 8 )(RO, -NO 2 , -C(O)-OR 25 or -S(O) 2 -R 25 ;
  • R 25 is an aryl group, a lower alkyl group, a haloalkyl group, a hydroxyalkyl group or an arylalkyl group;
  • R 26 is -C(O)- or -S(O) 2 - ;
  • R 37 is a hydrogen, -CN, -S(O) 2 -R 25 , -C(O)-N(R 3 )(Ri), -NO 2 Or-C(O)-OR 25 ;
  • T' is oxygen, sulfur or NR 6 ;
  • R 6 is a hydrogen, a lower alkyl group, or an aryl group
  • V 6 is:
  • Z 5 is -CH 2 or oxygen
  • Z 6 is -CH or nitrogen
  • W 3 at each occurrence is independently -C(O)-, -C(S)-, -T 3 -, -(C(R 6 )(Rf)) h -, -N(R 8 )Ri, an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, -(CH 2 CH 2 O) ql - or a heterocyclic nitric oxide donor;
  • E at each occurrence is independently -T 3 -, an alkyl group, an aryl group, -(C(Re)(Rf)V, a heterocyclic ring, an arylheterocyclic ring, -(CH 2 CH 2 O) ql - or Y 4;
  • Y 4 is:
  • T is a -S(O) 0 -; a carbonyl or a covalent bond; o is an integer from 0 to 2;
  • Rj and R k are independently selected from an alkyl group, an aryl group, or R j and R k taken together with the nitrogen atom to which they are attached are a heterocylic ring;
  • T 3 at each occurrence is independently a covalent bond, a carbonyl, an oxygen, h is an integer form 1 to 10; qi is an integer from 1 to 5;
  • Re and R f are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkyls
  • R 0 and R p are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alky ⁇ arylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkyl
  • U 3 is an oxygen, sulfur or -N(R a )Ri;
  • V5 is -NO or -NO 2 (i.e. an oxidized nitrogen);
  • Ic 1 is an integer from 1 to 3;
  • R a is a lone pair of electrons, a hydrogen or an 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 alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, an arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, -CH 2 -C-(Us-Vs)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom or -(N 2 O 2 - ⁇ M 1 + , wherein M 1 + is an organic or in
  • R e and R f are a heterocyclic ring or R e and R f taken together with the carbon atom to which they are attached are a heterocyclic ring, then Rj can be a substituent on any disubstituted nitrogen contained within the radical where Ri is as defined herein.
  • the 2-methyl indole COX-2 selective inhibitor of Formula I are compounds of Formula (II) to (XXIII), and pharmaceutically acceptable salts thereof: wherein the compound of Formula (II) is 2- ⁇ l-[(4-chlorophenyl)carbonyl]-5-hydroxy-
  • the 2-methyl indole COX-2 selective inhibitor substituted with at least one nitric oxide enhancing group of Formula I are compounds of Formula (XXIV) to (XL) and pharmaceutically acceptable salts thereof: wherein the compound of Formula (XXIV) is 2- ⁇ l-[(4-Chlorophenyl)carbonyl]-5- hydroxy-2-methylindol-3-yl ⁇ -N-[3-(nitrooxy)propyl]acetamide:
  • Another embodiment of the invention describes the metabolites of the compounds of Formula (I), and pharmaceutically acceptable salts thereof.
  • These metabolites include but are not limited to, the derivatives that do not contain a nitric oxide enhancing group, degradation products, hydrolysis products, and the like, of the compounds of Formula (I) and pharmaceutically acceptable salts thereof.
  • Compounds of the invention that have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates.
  • the invention includes within its scope all such isomers and mixtures thereof.
  • Another embodiment of the invention provides processes for making the novel compounds of the invention.
  • the reactions are performed in solvents appropriate to the reagents and materials used are suitable for the transformations being effected. It is understood by one skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to one skilled in the art.
  • sulfur and oxygen protecting groups are well known for protecting thiol and alcohol groups against undesirable reactions during a synthetic procedure and many such protecting groups are known and described by, for example, Greene and Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).
  • the compounds of Formula (I) can be synthesized by one skilled in the art following the methods and examples described herein.
  • the synthesis of the some indole COX-2 inhibitors are disclosed in, for example, U. S. Patent Nos. 5,436,265, 5,510,368, 5,604,253 and 5,639,780 and in WO 96/37467, WO 96/37468, WO 96/37469, WO 98/39330 and WO 00/40087; the disclosures of each of which are incorporated by reference herein in their entirety.
  • the indole COX-2 selective inhibitors can be substituted with at least one nitric oxide enhancing group by one skilled in the art using conventional methods.
  • nitric enhancing donor group linking nitrates, thionitrates, nitrites, thionitrites, (i.e. nitrosated and/or nitrosylated compounds), NONOates, heterocyclic nitric oxide donors, and the like are described in the literature.
  • heterocyclic nitric oxide donor compounds are described in WO 99/64417, WO 94/01422; EP 0 574726 Al, EP 0 683 159 Al; and in J. Med. Chem., 47: 2688-2693 (2004); J. Med. Chem., Al: 1840-1846 (2004); J. Med.
  • the methods of linking the heterocyclic nitric oxide donor group to compounds described in these references can be applied by one skilled in the art to produce any of the 2-methyl indole COX-2 selective inhibitors substituted with at least one nitric oxide donor group described herein.
  • Linking a nitrate group, a thionitrate group, a nitrite group and/or a thionitrite group to a compound can be achieved by the nitrosated and/or nitrosylated of a compound through one or more sites such as oxygen, sulfur and/or nitrogen using conventional methods known to one skilled in the art.
  • Known methods for nitrosating and/or nitrosylating compounds are described in U.S. Patent Nos.
  • Compounds contemplated for use in the invention e.g., 2-methyl indole cyclooxygenase 2 selective inhibitors of the invention, optionally substituted with at least one nitric oxide donor group, are optionally used in combination with nitric oxide enhancing compounds that release nitric oxide, increase endogeneous levels of nitric oxide or otherwise directly or indirectly deliver or transfer a biologically active form of nitrogen monoxide to a site of its intended activity, such as on a cell membrane in vivo.
  • Nitrogen monoxide can exist in three forms: NO- (nitroxyl), NO* (nitric oxide) and NO + (nitrosonium).
  • NO* is a highly reactive short-lived species that is potentially toxic to cells. This is critical because the pharmacological efficacy of NO depends upon the form in which it is delivered.
  • NO* nitric oxide radical
  • NO + nitrosonium
  • functionalities capable of transferring and/or releasing NO + and NO- are also resistant to decomposition in the presence of many redox metals. Consequently, administration of charged NO equivalents (positive and/or negative) does not result in the generation of toxic by-products or the elimination of the active NO group.
  • nitric oxide encompasses uncharged nitric oxide (NO*) and charged nitrogen monoxide species, preferably charged nitrogen monoxide species, such as nitrosonium ion (NO + ) and nitroxyl ion (NO-).
  • the reactive form of nitric oxide can be provided by gaseous nitric oxide.
  • the nitrogen monoxide releasing, delivering or transferring compounds have the structure F-NO, wherein F is a nitrogen monoxide releasing, delivering or transferring group, and include any and all such compounds which provide nitrogen monoxide to its intended site of action in a form active for its intended purpose.
  • NO adducts encompasses any nitrogen monoxide releasing, delivering or transferring compounds, including, for example, S-nitrosothiols, nitrites, nitrates, S- nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines, (NONOates), (E)-alkyl-2-((E)- hydroxyimino)-5-nitro-3-hexeneamide (FK-409), (E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3- hexeneamines, N-((2Z, 3E)-4-ethyl-2-(hydroxyimino)-6-methyl-5-nitro-3-heptenyl)-3- pyridinecarboxamide (FR 146801), N-nitrosoamines, N-hydroxyl nitrosamines, nitrosimines, diazetine dioxides, oxatriazole 5-imines, oximes
  • Suitable NONOates include, but are not limited to, (Z)-l-(N-methyl-N-(6-(N-methyl- ammoniohexyl)amino))diazen-l-ium-l,2-diolate ("MAHMA/NO”), (Z)-l-(N-(3- ammoniopropyl)-N-(n-propyl)amino)diazen-l-ium-l,2-diolate (“PAPA/NO”), (Z)-l-(N-(3- aminopropyl)-N-(4-(3-aminopro ⁇ ylammonio)butyl)-amino) diazen-l-ium-l,2-diolate (spermine NONOate or "SPER/NO”) and sodium(Z)-l-(N,N- diethylamino)diazenium-l,2- diolate (diethylamine NONOate or "DEA/NO”) and derivatives thereof.
  • NONOates are also described in U.S. Patent Nos. 6,232,336, 5,910,316 and 5,650,447, the disclosures of which are incorporated herein by reference in their entirety.
  • the "NO adducts" can be mono- nitrosylated, poly-nitrosylated, mono-nitrosated and/or poly-nitrosated at a variety of naturally susceptible or artificially provided binding sites for biologically active forms of nitrogen monoxide.
  • Suitable furoxanes include, but are not limited to, CAS 1609, C93-4759, C92-4678, S35b, CHF 2206, CHF 2363, and the like.
  • Suitable sydnonimines include, but are not limited to, molsidomine (N- ethoxycarbonyl-3-morpholinosydnonimine), SIN-I (3-morpholinosydnonimine) CAS 936 (3- (cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydnonimine, pirsidomine), C87-3754 (3-(cis-2,6-dimethylpiperidino)sydnonirnine, linsidomine, C4144 (3-(3,3-dimethyl-l,4- thiazane-4-yl)sydnonimine hydrochloride), C89-4095 (3-(3,3-dimethyl-l,l-dioxo-l,4- thiazane-4-yl)sydnonimine hydrochloride, and the like.
  • Suitable oximes include, but are not limited to, NOR-I, NOR-3, NOR-4, and the like.
  • S-nitrosothiols are compounds that include at least one -S-NO group.
  • S-nitroso-polypeptides include proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated sugars; S-nitrosylated, modified and unmodified, oligonucleotides (preferably of at least 5, and more preferably 5-200 nucleotides); straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.
  • S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof.
  • Such compounds include, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril, S- nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso- glutathione, S-nitroso-cysteinyl-glycine, and the like.
  • Suitable S-nitrosylated proteins include thiol-containing proteins (where the NO group is attached to one or more sulfur groups on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator (TPA) and cathepsin B; transport proteins, such as lipoproteins; heme proteins, such as hemoglobin and serum albumin; and biologically protective proteins, such as immunoglobulins, antibodies and cytokines.
  • TPA tissue-type plasminogen activator
  • cathepsin B transport proteins, such as lipoproteins; heme proteins, such as hemoglobin and serum albumin; and biologically protective proteins, such as immunoglobulins, antibodies and cytokines.
  • nitrosylated proteins are described in WO 93/09806, the disclosure of which is incorporated by reference herein in its entirety. Examples include polynitrosylated albumin where one or more thiol or other nucleophilic centers in the protein are modified.
  • S-nitrosothiols include:
  • R e and R f are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alky
  • R 0 and R p are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhalo alkyl, a sulfonic acid, a sulfonic ester, an alkyl
  • ki is an integer form 1 to 3;
  • U 3 is an oxygen, sulfur- or -N(R 3 )Ri;
  • V5 is -NO or -NO 2 (i.e. an oxidized nitrogen);
  • R a is a lone pair of electrons, a hydrogen or an 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 alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, -CH 2 -C(U 3 -V 5 )(R e )(R f ), a bond to an adjacent atom creating a double bond to that atom or -(N 2 O 2 -) " "M 1 + , wherein Mi
  • R e and R f are independently a heterocyclic ring or taken together R e and R f are a heterocyclic ring, then R; can be a substituent on any disubstituted nitrogen contained within the radical wherein Rj is as defined herein.
  • Nitrosothiols can be prepared by various methods of synthesis. In general, the thiol precursor is prepared first, then converted to the S-nitrosothiol derivative by nitrosation of the thiol group with NaNO 2 under acidic conditions (pH is about 2.5) which yields the S-nitroso derivative. Acids which can be used for this purpose include aqueous sulfuric, acetic and hydrochloric acids.
  • the thiol precursor can also be nitrosylated by reaction with an organic nitrite such as tert-butyl nitrite, or a nitrosonium salt such as nitrosonium tetrafluoroborate in an inert solvent.
  • NO adducts for use in the invention, where the NO adduct is a compound that donates, transfers or releases nitric oxide, include compounds comprising at least one ON-O- or ON-N- group.
  • the compounds that include at least one ON-O- or ON-N- group are preferably ON-O- or ON-N-polypeptides (the term "polypeptide” includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); ON-O- or ON-N-amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); ON-O- or ON-N-sugars; ON-O- or -ON-N- modified or unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); ON-O- or ON-N- straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted
  • Examples of compounds comprising at least one ON-O- or ON-N- group include butyl nitrite, isobutyl nitrite, tert-butyl nitrite, amyl nitrite, isoamyl nitrite, N- nitrosamines, N-nitrosamides, N-nitrosourea, N-nitrosoguanidines, N-nitrosocarbamates, N- acyl-N-nitroso compounds (such as, N-methyl-N-nitrosourea); N-hydroxy-N-nitrosamines, cupferron, alanosine, dopastin, 1,3-disubstitued nitrosiminobenzimidazoles, 1,3,4-thiadiazole- 2-nitrosimines, benzothiazole-2(3H)-nitrosimines, tMazole-2-mtrosimines, oligonitroso sydnonimines, 3-alkyl-N-nitros
  • NO adducts for use in the invention include nitrates that donate, transfer or release nitric oxide, such as compounds comprising at least one O 2 N-O-, O 2 N-N- or O 2 N-S- group.
  • these compounds are O 2 N-O-, O 2 N-N- or O 2 N-S- polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); O 2 N-O-, O 2 N-N- or O 2 N-S- amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); O 2 N-O-, O 2 N-N- or O 2 N-S- sugars; O 2 N-O-, O 2 N-N- or O 2 N-S- modified and unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); O 2 N-O-, O 2 N-
  • Examples of compounds comprising at least one O 2 N-O-, O 2 N-N- or O 2 N-S- group include isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol, propatylnitrate and organic nitrates with a sulfhydryl-containing amino acid such as, for example SPM 3672, SPM 4757, SPM 5185, SPM 5186 and those disclosed in U. S. Patent Nos.
  • R 1 R 2 N-N(O-M + )-NO N-oxo-N-nitrosoamines that donate, transfer or release nitric oxide and are represented by the formula: R 1 R 2 N-N(O-M + )-NO, where R 1 and R are each independently a polypeptide, an amino acid, a sugar, a modified or unmodified oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and where M 1 + is an organic or inorganic cation, such, as for example, an alkyl substituted ammonium cation or a Group I metal cation.
  • the invention is also directed to compounds that stimulate endogenous NO or elevate levels of endogenous endothelium-derived relaxing factor (EDRF) in vivo or are oxidized to produce nitric oxide and/or are substrates for nitric oxide synthase and/or cytochrome P450.
  • EDRF endogenous endothelium-derived relaxing factor
  • Such compounds include, for example, L-arginine, L-homoarginine, and N-hydroxy-L- arginine, N-hydroxy-L-homoarginine, N-hydroxydebrisoquine, N-hydroxypentamidine including their nitrosated and/or nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated and nitrosylated L-homoarginine), N-hydroxyguanidine compounds, amidoxime, ketoximes, aldoxime compounds, that can be oxidized in vivo to produce nitric oxide.
  • Compounds that may be substrates for a cytochrome P450 include, for example, imino(benzylamino)methylhydroxyl amine, imino(((4-methylphenyl)methyl) amino)methylhydroxylamine, imino(((4-methoxyphenyl)methyl)amino) methylhydroxylamine, imino(((4-(trifluoromethyl)phenyl)methyl) amino) methylhydroxylamine, imino(((4-nitrophenyl) methyl)amino)methylhydroxylamine, (butylamino) iminomethylhydroxylamine, imino (propylamino) methylhydroxylamine, imino(pentylamino)methylhydroxylamine, imino (propylamino)methylhydroxylamine, imino ((methylethyl)amino)methylhydroxylamine, (cyclopropylamino) iminomethylhydroxyla ⁇ iine, imino-2-l,2,3,4-t
  • EDRF is a vascular relaxing factor secreted by the endothelium, and has been identified as nitric oxide (NO) or a closely related derivative thereof (Palmer et al, Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. ScL USA, 84:9265-9269 (1987)).
  • the invention is also directed to nitric oxide enhancing compounds that can increase endogenous nitric oxide.
  • nitroxide containing compounds include, but are not limited to, substituted 2,2,6,6-tetramethyl-l-piperidinyloxy compounds, substituted 2,2,5,5-tetramethyl-3-pyrroline-l-oxyl compounds, substituted 2,2,5,5-tetramethyl-l-pyrrolidinyloxyl compounds, substituted 1,1,3,3-tetramethylisoindolin- 2-yloxyl compounds, substituted 2,2,4,4-tetramethyl-l-oxazolidinyl-3-oxyl compounds, substituted 3-imidazolin-l-yloxy, 2,2,5,5-tetramethyl-3-imidazolin-l-yloxyl compounds, OT- 551, 4-hydroxy-2,2,6,6-tetramethyl-l-piperidinyloxy (tempol), and the like.
  • Suitable substituents include, but are not limited to, aminomethyl, benzoyl, 2-bromoacetamido, 2-(2- (2-bromoacetamido)ethoxy)ethylcarbamoyl, carbamoyl, carboxy, cyano, 5-(dimethylamino)- 1-naphthalenesulfonamido, ethoxyfluorophosphinyloxy, ethyl, 5-fluoro-2, 4-dinitroanilino, hydroxy, 2-iodoacetamido, isothiocyanato, isothiocyanatomethyl, methyl, maleimido, maleimidoethyl, 2-(2-maleimidoethoxy)ethylcarbamoyl, maleimidomethyl, maleimido, oxo, phosphonooxy, and the like.
  • the invention is also based on the discovery that compounds and compositions of the invention may be used in conjunction with other therapeutic agents for co-therapies, partially or completely, in place of other conventional antiinflammatory compounds, such as, for example, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti- hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, is
  • Suitable steroids include, but are not limited to, 21-acetoxypregnenolone, alcolometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chlorprednisone, clobetasol, clobentasone, clocortolone, cloprednol, corticosterone, cortisine, corticazol (cortivatol), deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluzacort, flucloronide, flumethasone, flunisolide, flucinolone acetonide, fluodninide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisol
  • Suitable NSAIDs are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw- Hill, 1995, Pgs. 617-657; the Merck Index on CD-ROM, 13 th Edition; and in U.S. Patent Nos. 6,057,347 and 6,297,260 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety.
  • the steroids are dexamethasone, fluorometholone, hydrocortisone, and prednisolone.
  • Suitable COX-2 inhibitors include, but are not limited to, nimesulide, celecoxib (CELEBREX®), etoricoxib (ARCOXIA®), flosulide, lumiracoxib (PREXIG®, COX-189), parecoxib (DYNSTAT®), rofecoxib (VIOXX®), tiracoxib (JTE-522), valdecoxib (BEXTRA®), ABT 963, BMS 347070, CS 502, DuP 697, GW-406381, NS-386, SC-57666, SC-58125, SC-58635, and the like, and mixtures of two or more thereof.
  • Suitable COX-2 inhibitors are in U.S. Patent Nos.
  • the COX-2 inhibitors are celecoxib, etoracoxib, lumiracoxib, paracoxib, rofecoxib or valdecoxib.
  • the celecoxib is administered in an amount of about 100 milligrams to about 800 milligrams as a single dose or as multiple doses per day;
  • the etoricoxib is administered in an amount of about 50 milligrams to about 200 milligrams as a single dose or as multiple doses per day;
  • the lumiracoxib is administered in an amount of about 40 milligrams to about 1200 milligrams as a single dose or as multiple doses per day;
  • the paracoxib is administered in an amount of about 20 milligrams to about 100 milligrams as a single dose or as multiple doses per day;
  • the rofecoxib is administered in an amount of about 12.5 milligrams to about 50 milligrams as a single dose or as multiple doses per day;
  • Suitable NSAEDs include, but are not limited to, acetaminophen, acemetacin, aceclofenac, alminoprofen, amfenac, bendazac, benoxaprofen, bromfenac, bucloxic acid, butibufen, carprofen, cinmetacin, clopirac, diclofenac, etodolac, felbinac, fenclozic acid, fenbufen, fenoprofen, fentiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen, indomethacin, isofezolac, isoxepac, indoprofen, ketoprofen, lonazolac, loxoprofen, metiazinic acid, mofezolac, miroprofen, naproxen, oxaprozin, pirozolac, pirprofen
  • Suitable NSAIDs are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617-657; the Merck Index on CD-ROM, 13 th Edition; and in U.S. Patent Nos. 6,057,347 and 6,297,260 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety.
  • the NSAIDs are acetaminophen, diclofenac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen or aspirin.
  • the acetaminophen is administered in an amount of about 325 milligrams to about 4 grams as a single dose or as multiple doses per day;
  • the diclofenac is administered in an amount of about 50 milligrams to about 250 milligrams as a single dose or as multiple doses per day;
  • the flurbiprofen is administered in an amount of about 100 milligrams to about 300 milligrams as a single dose or as multiple doses per day;
  • the ibuprofen is administered in an amount of about 400 milligrams to about 3.2 grams as a single dose or as multiple doses per day;
  • the indomethacin is administered in an amount of about 25 milligrams to about 200 milligrams as a single dose or as multiple doses
  • Suitable 5-LO inhibitors include, but are not limited to, A-76745, 78773 and ABT761; Bay-x-1005; CMI-392; E-3040; EF-40; F-1322; ML-3000; PF-5901; R-840; rilopirox, flobufen, linasolast, lonapolene, masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast, and mixtures of two or more thereof.
  • Suitable 5-LO inhibitors are also described more fully in WO 97/29776, the disclosure of which is incorporated herein by reference in its entirety.
  • Suitable LTB 4 receptor antagonists include, but are not limited to, ebselen, linazolast, ontazolast; WAY 121006; Bay-x-1005; BI-RM-270; CGS-25019C; ETH-615; MAFP; TMK- 688; T-0757; LY 213024, LY 210073, LY 223982, LY 233469, LY 255283, LY 264086, LY 292728 and LY 293111; ONO-LB457, ONO-4057, and ONO-LB-448, S-2474, calcitrol; PF 10042; Pfizer 105696; RP 66153; SC-53228, SC-41930, SC-50605, SC-51146 and SC- 53228; SB-201146 and SB-209247; SKF-104493; SM 15178; TMK-688; BPC 15, and mixtures of two or more thereof.
  • the preferred LTB 4 receptor antagonists are calcitrol, ebselen, Bay-x-1005, CGS-25019C, ETH-615, LY-293111, ONO-4057 and TMK-688, and mixtures of two or more thereof.
  • Leukotriene A 4 (LTA 4 ) hydrolase inhibitors refer to compounds that selectively inhibit leukotiiene A 4 hydrolase with an IC5 0 of less than about lO ⁇ M, and preferably with an IC50 of less than about 1 ⁇ M.
  • Suitable LTA 4 hydrolase inhibitors include, but are not limited to, RP-64966, (S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acid benzyl ester, N- (2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine, 7-(4-(4- ureidobenzyl)phenyl) heptanoic acid and 3 (3-(lE,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithium salt, and mixtures of two or more thereof.
  • Suitable 5-HT agonists include, but are not limited to, rizatriptan, sumatriptan, naratriptan, zolmitroptan, eleptriptan, almotriptan, ergot alkaloids, ALX 1323, Merck L 741604 SB 220453 and LAS 31416. Suitable 5-HT agonists are described more fully in WO 0025779, and in WO 00/48583.
  • 5-HT agonists refers to a compound that is an agonist to any 5-HT receptor, including but not limited to, 5-HT 1 agonists, 5-HT 1 B agonists and 5-HT 1 D agonists, and the like.
  • Suitable anti-hyperlipidemic compounds include, but are not limited to, statins or HMG-CoA reductase inhibitors, such as, for example, atorvastatin (LIPITOR®), bervastatin, cerivastatin (BAYCOL®), dalvastatin, fluindostatin (Sandoz XU-62-320), fluvastatin, glenvastatin, lovastatin (MEV ACOR®), mevastatin, pravastatin (PRAV ACHOL®), rosuvastatin (CRESTRO®), simvastatin (ZOCOR®), velostatin (also known as synvinolin), VYTORINTM (ezetimibe/simvastatin), GR-95030, SQ 33,600, BMY 22089, BMY 22,566, CI 980, and the like; gemfibrozil, cholystyramine, colestipol, niacin, nicotinic
  • the anti-hyperlipidemic compounds are atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin.
  • the atorvastatin is administered in an amount of about 10 milligrams to about 80 milligrams as a single dose or as multiple doses per day;
  • the fluvastatin is administered in an amount of about 20 milligrams to about 80 milligrams as a single dose or as multiple doses per day;
  • the lovastatin is administered in an amount of about 10 milligrams to about 80 milligrams as a single dose or as multiple doses per day;
  • the pravastatin is administered in an amount of about 10 milligrams to about 80 milligrams as a single dose or as multiple doses per day;
  • the rosuvastatin is administered in an amount of about 5 milligrams to about 40 milligrams as a single dose or as multiple doses per day;
  • the simvastatin
  • Suitable antioxidants include, but are not limited to, small-molecule antioxidants and antioxidant enzymes.
  • Suitable small-molecule antioxidants include, but are not limited to, hydralazine compounds, glutathione, vitamin C, vitamin E, cysteine, N-acetyl-cysteine, ⁇ - carotene, ubiquinone, ubiquinol-10, tocopherols, coenzyme Q, superoxide dismutase mimetics, such as, for example, 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxide compounds; 4-hydroxy-2,2,6,6-tetramethyl-l-piperidinyloxy (Tempol), M-40401, M-40403, M-40407, M-40419,M-40484, M-40587, M-40588, and the like.
  • TEMPO 2,2,6,6-tetramethyl-l-piperidinyloxy
  • M-40401 M-
  • Suitable antioxidant enzymes include, but are not limited to, superoxide dismutase, catalase, glutathione peroxidase, NADPH oxidase inhibitors, such as, for example, apocynin, arninoguanidine, ONO 1714, S17834 (benzo(b)pyran-4-one derivative), and the like; xanthine oxidase inhibitors, such as, for example, allopurinol, oxypurinol, amflutizole, diethyldithiocarbamate, 2-styrylchromones, chrysin, luteolin, kaempferol, quercetin, myricetin, isorhamnetin, benzophenones such as 2,2',4,4'-tetrahydroxybenzophenone, 3,4,5,2', 3',4'-hexahydroxybenzophenone and 4,4'-dihydroxybenzophenone; benzothiazinone analogues
  • the antioxidant enzymes can be delivered by gene therapy as a viral vertor and/or a non- viral vector. Suitable antioxidants are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thirteenth Edition; and on STN Express, file phar and file registry.
  • the antioxidants are apocynin, hydralazine compounds and superoxide dimutase mimetics.
  • Suitable hydralazine compounds include, but are not limited to, compounds having the formula: wherein a, b and c are independently a single or double bond; Riand R 2 are each independently a hydrogen, an alkyl, an ester or a heterocyclic ring, wherein alkyl, ester and heterocyclic rind are as defined herein; R 3 and R 4 are each independently a lone pair of electrons or a hydrogen, with the proviso that at least one of Ri, R2, R3 and R 4 is not a hydrogen.
  • Exemplary hydralazine compounds include budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pildralazine, todralazine, and the like. Suitable hydralazine compounds are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thirteenth Edition; and on STN Express, file phar and file registry.
  • the hydralazine compound is hydralazine or a pharmaceutically acceptable salt thereof such as hydralazine hydrochloride.
  • the hydralazine is administered as hydralazine hydrochloride in an amount of about 10 milligrams to about 300 milligrams as a single dose or as multiple doses per day.
  • Suitable H 2 receptor antagonists include, but are not limited to, burimamide, cimetidine, ebrotidin, famotidine, nizatidine, roxatidine, rantidine, tiotidine, and the like. Suitable H 2 receptor antagonists are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw- Hill, 1995, Pgs. 901-915; the Merck Index on CD-ROM, 13 th Edition; and in WO 00/28988 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety.
  • Suitable antineoplastic agents include, but are not limited to, 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, altretamine, anaxirone, aclarubicin and the like. Suitable antineoplastic agents are also described in U. S. Patent No. 6,025,353 and WO 00/38730, the disclosures of which are incorporated herein by reference in their entirety.
  • Suitable antiplatelet agents include, but are not limited to, aspirin, ticlopidine, dipyridamole, clopidogrel, glycoprotein Ilb/IIIa receptor antagonists, and the like. Suitable antineoplastic agents are also described in WO 99/45913, the disclosure of which is incorporated herein by reference in its entirety.
  • the antiplatelet agent is aspirin, more preferably, low-dose aspirin (i.e. 75 mg - 100 mg/day).
  • Suitable thrombin inhibitors include, but are not limited to, N'-((l-
  • Suitable thromboxane inhibitors include, but are not limited to thromboxane synthase inhibitors, thromboxane receptor antagonists, and the like. Suitable thromboxane inhibitors, are also described in WO 01/87343, the disclosure of which is incorporated herein by reference in its entirety.
  • Suitable carbonic anhydrase inhibitors include, but are not limited to, acetazolamide, brinzolamide, dorzolamide, ethoxzolamide, 6-hydroxy-2-benzothiazolesulfonamide, methazolamide, thiophene sulfonamide, an aromatic sulfonamide, an ester of 6-hydroxy-2- benzothiazolesulfonamide, an ester of 5-hydroxy-2-benzothiazolesulfonamide, and the like.
  • Suitable carbonic anhydrase inhibitors are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw- Hill, 1995; and the Merck Index on CD-ROM, 13 th Edition; and on STN Express, file phar and file registry.
  • the carbonic anhydrase inhibitors are brinzolamide and dorzolamide.
  • Suitable decongestants include, but are not limited to, phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, levo-desoxyephedrine, and the like.
  • Suitable diuretics include, but are not limited to, thiazides (such as, for example, althiazide, bendroflumethiazide, benzclortriazide, benzhydrochlorothiazide, benzthiazide, buthiazide, chlorothiazide, cyclopenethiazide, cyclothiazide, epithiazide, ethiazide, hydrobenzthiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, methylcyclothiazide, penflutazide, polythiazide, teclothiazide, trichlormethiazide, triflumethazide, and the like); alilusem, ambuside, amiloride, aminometradine, azosemide, bemetizide, bumetanide, butazolamide, butizide, canrenone, carperitide, chloraminophenamide,
  • Suitable diuretics are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw- Hill, 1995; and the Merck Index on CD-ROM, 13 th Edition; and on STN Express, file phar and file registry.
  • potassium may also be administered to the patient in order to optimize the fluid balance while avoiding hypokalemic alkalosis.
  • the administration of potassium can be in the form of potassium chloride or by the daily ingestion of foods with high potassium content such as, for example, bananas or orange juice.
  • the method of administration of these compounds is described in further detail in U.S. Patent No. 4,868,179, the disclosure of which is incorporated by reference herein in its entirety.
  • the diuretics are amiloride, furosemide, chlorthalidone, hydrochlorothiazide or triamterene.
  • the amiloride is administered as amiloride hydrochloride in an amount of about 5 milligrams to about 15 milligrams as a single dose or as multiple doses per day;
  • the furosemide is administered in an amount of about 10 milligrams to about 600 milligrams as a single dose or as multiple doses per day;
  • the chlorthalidone is administered in an amount of about 15 milligrams to about 150 milligrams as a single dose or as multiple doses per day;
  • the hydrochlorothiazide is administered in an amount of about 12.5 milligrams to about 300 milligrams as a single dose or as multiple doses per day;
  • the triamterene is administered in an amount of about 35 milligrams to about 225 milligrams as a single dose or as multiple doses per day.
  • Suitable antitussive compounds include, but are not limited to, dextromethorphan, carbetapentane, caramiphen, diphenylhydramine, hydrocodene, codeine and the like. Suitable antitussive compounds are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and the Merck Index on CD-ROM, 13 th Edition; and on STN Express, file phar and file registry.
  • iNOS inducible nitric oxide synthase
  • Suitable opioids and other analgesics including, but not limited to, narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. non-addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, neurokinin 1 receptor antagonists, Substance P antagonists, neurokinin- 1 receptor antagonists, sodium channel blockers, N-methyl-D-aspartate receptor antagonists, and mixtures of two or more thereof.
  • Preferred combination therapies would be with morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone, Tramadol ((+) enantiomer), DuP 747, Dynorphine A, Enadoline, RP-60180, HN-11608, E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene, nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631, Tramadol ((-) enantiomer), GP-531, acadesine, AKI-I, AKI-2, GP-1683, GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742, SNX-111, ADL2-1294, ICI-2044
  • Suitable phosphodiesterase inhibitors include, but are not limited to, filaminast, piclamilast, rolipram, Org 20241, MCI- 154, roflumilast, toborinone, posicar, lixazinone, zaprinast, sildenafil, pyrazolopyrimidinones, motapizone, pimobendan, zardaverine, siguazodan, CI 930, EMD 53998, imazodan, saterinone, loprinone hydrochloride, 3- pyridinecarbonitrile derivatives, acefylline, albifylline, bamifylline, denbufyllene, diphylline, doxofylline, etofylline, torbafylline, theophylline, nanterinone, pentoxofylline, proxyphylline, cilostazol, cilostamide, MS 857, piroxi
  • Suitable proton pump inhibitors include, but are not limited to, disulprazole, esomeprazole, lansoprazole, leminoprazole, omeprazole, pantoprazole, rabeprazole, timoprazole, tenatoprazole, 2-(2-benzimidazolyi) ⁇ pyridirie, tricyclic imidazole, thienopydidine benzimidazole, fluoroalkoxy substituted benzimidazole, dialkoxy benzimidazole, N-substituted 2-(pyridylalkenesulfinyl) benzimidazole, cycloheptenepyridine, 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole, alkylsulfinyl benzimidazole, fluoro- pyridylmethylsulfinyl benzimidazole, imidazo(4,5
  • Suitable proton pump inhibitors are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; the Merck Index on CD-ROM, 13 th Edition; and in WO 00/50037 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety.
  • the invention provides methods for treating inflammation, pain (both chronic and acute), and/or fever, such as, for example, analgesic in the treatment of pain, including, but not limited to headaches, migraines, postoperative pain, dental pain, muscular pain, and pain resulting from cancer; as an antipyretic for the treatment of fever, including but not limited to, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains, strains, myositis, neuralgia, synovitis; arthritis, including but not limited to rheumatoid arthritis, degenerative joint disease (osteoarthritis), spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, by administering to the patient in need thereof an effective amount of the compounds and/or compositions described herein.
  • analgesic in the treatment of pain including, but not limited to headaches, migraines,
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one 2- methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one therapeutic agent, including but not limited to, such as, for example, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphoridine
  • the patient can be' administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound and at least one therapeutic agent.
  • the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H 2 antagonist.
  • the at least one therapeutic agent is aspirin.
  • the 2-methyl indole COX-2 selective inhibitors, optionally substituted with at least one nitric oxide enhancing group, nitric oxide enhancing compounds, and/or therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • the invention provides methods for treating gastrointestinal disorders and/or improving the gastrointestinal properties of the COX-2 selective inhibitor by administering to the patient in need thereof an effective amount of the compounds and/or compositions described herein.
  • gastrointestinal disorders refer to any disease or disorder of the upper gastrointestinal tract (e.g., esophagus, the stomach, the duodenum, jejunum) including, for example, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, peptic ulcers, stress ulcers, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, bacterial infections (including, for example, a Helicobacter Pylori associated disease), short-bowel (anastomosis) syndrome, hypersecretory states associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia, and bleeding peptic ulcers that result, for example, from neurosurgery
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one therapeutic agent, including but not limited to, such as, for example, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphoridine
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound and at least one therapeutic agent.
  • the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H 2 antagonist.
  • the at least one therapeutic agent is aspirin.
  • the 2-methyl indole COX-2 selective inhibitors, optionally substituted with at least one nitric oxide enhancing group, nitric oxide enhancing compounds, and/or therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • wound healing such as, for example, ulcer healing, bone healing including osteoporosis
  • Wound refers to, and includes, any lesion that is characterized by loss of tissue, and, includes, but is not limited to, ulcers, cuts, burns, bone fractures, orthopedic procedure, wound infliction, and the like.
  • Ulcers refers to lesions of the upper gastrointestinal tract lining that are characterized by loss of tissue, and, include, but are not limited to, gastric ulcers, duodenal ulcers, gastritis, and the like.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one therapeutic agent, including but not limited to, such as, for example, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphoridine
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound and at least one therapeutic agent.
  • the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H 2 antagonist.
  • the at least one therapeutic agent is aspirin.
  • the 2-methyl indole COX-2 selective inhibitors, optionally substituted with at least one nitric oxide enhancing group, nitric oxide enhancing compounds, and/or therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • Another embodiment of the invention provides methods for treating renal toxicity or respiratory toxicities, for example, adverse effects on the structure and/or function of the respiratory system; treating ophthalmic disorders and treating peripheral vascular diseases by administering to a patient in need thereof an effective amount of the compounds and/or compositions described herein.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one therapeutic agent, including but not limited to, such as, for example, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5- LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors,
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound and at least one therapeutic agent.
  • the 2-methyl indole COX-2 selective inhibitors, optionally substituted with at least one nitric oxide enhancing group, nitric oxide enhancing compounds, and/or therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • Another embodiment of the invention provides methods to treat disorders resulting from elevated levels of COX-2 by administering to a patient in need thereof an effective amount of the compounds and/or compositions described herein.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one therapeutic agent, including but not limited to, such as, for example, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphoridine
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound and at least one therapeutic agent.
  • the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H 2 antagonist.
  • the at least one therapeutic agent is aspirin.
  • the 2-methyl indole COX-2 selective inhibitors, optionally substituted with at least one nitric oxide enhancing group, nitric oxide enhancing compounds, and/or therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • disorders resulting from elevated levels of COX-2 include, but are not limited to, for example, angiogenisis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis; skin-related conditions, such as, for example, psoriasis, eczema, surface wounds, burns and dermatitis; post-operative inflammation including from ophthalmic surgery, such as, for example, cataract surgery and refractive surgery, and the like; treatment of neoplasia, such as, for example, brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma), such as, for example, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, such as, for example, lip cancer, mouth cancer, esophageal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer
  • Another embodiment of the invention provides methods for improving the cardiovascular profile of COX-2 selective inhibitors; treating diseases resulting from oxidative stress; treating endothelial dysfunctions; treating diseases caused by endothelial dysfunctions; treating inflammatory disease states and/or disorders; treating ophthalmic disorders; and treating peripheral vascular diseases by administering to a patient in need thereof an effective amount of the compounds and/or compositions described herein.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound.
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one therapeutic agent, including but not limited to, such as, for example, steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti- hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,
  • COX-2
  • the patient can be administered an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound and at least one therapeutic agent.
  • the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H 2 antagonist.
  • the at least one therapeutic agent is aspirin.
  • the 2-methyl indole COX-2 selective inhibitors, optionally substituted with at least one nitric oxide enhancing group, nitric oxide enhancing compounds, and/or therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • the 2-methyl indole COX-2 selective inhibitor when administered separately, can be administered about the same time as part of the overall treatment regimen i.e., as a combination therapy.
  • “About the same time” includes administering the 2-methyl indole COX-2 selective inhibitor, that is optionally substituted with at least one nitric oxide enhancing group, simultaneously, sequentially, at the same time, at different times on the same day, or on different days, as long as they are administered as part of an overall treatment regimen, i.e., combination therapy or a therapeutic cocktail.
  • the compounds and compositions of the invention can be administered in combination with pharmaceutically acceptable carriers and in dosages described herein.
  • the compounds and compositions of the invention are administered as a combination of at least one 2-methyl indole COX-2 selective inhibitor, that is optionally substituted with at least one nitric oxide enhancing group and/or at least one nitric oxide enhancing compound and/or therapeutic agent, they can also be used in combination with one or more additional compounds which are known to be effective against the specific disease state targeted for treatment.
  • nitric oxide enhancing compounds, therapeutic agents and/or other additional compounds can be administered simultaneously with, subsequently to, or prior to administration of the 2-methyl indole COX-2 selective inhibitor, that is optionally substituted with at lest one nitric oxide enhancing group.
  • the compounds and compositions of the invention can be administered by any available and effective delivery system including, but not limited to, orally, bucally, parenterally, by inhalation, by topical application, by injection, transdermally, or rectally (e.g., by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles, as desired.
  • Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • the 2-methyl indole COX-2 selective inhibitor optionally substituted with at least one nitric oxide enhancing group, is administered orally, parentally or by inhalation.
  • Transdermal compound administration involves the delivery of pharmaceutical compounds via percutaneous passage of the compound into the systemic circulation of the patient.
  • Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • Other components can be incorporated into the transdermal patches as well.
  • compositions and/or transdermal patches can be formulated with one or more preservatives or bacteriostatic agents including, but not limited to, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.
  • Dosage forms for topical administration of the compounds and compositions can include creams, sprays, lotions, gels, ointments, eye drops, nose drops, ear drops, and the like.
  • the compositions of the invention can be mixed to form white, smooth, homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1% or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution.
  • the compositions can contain polyethylene glycol 400.
  • compositions can be mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt) as preservative, white petrolatum, emulsifying wax, and tenox H (butylated hydroxyanisole, propyl gallate, citric acid, propylene glycol).
  • Woven pads or rolls of bandaging material e.g., gauze, can be impregnated with the compositions in solution, lotion, cream, ointment or other such form can also be used for topical application.
  • the compositions can also be applied topically using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
  • compositions can also be applied topically using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
  • a transdermal patch such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
  • the compositions of the invention are administered as a transdermal patch, more particularly as a sustained-release transdermal patch.
  • the transdermal patches of the invention can include any conventional form such as, for example, adhesive matrix, polymeric matrix, reservoir patch, matrix or monolithic-type laminated structure, and are generally comprised of one or more backing layers, adhesives, penetration enhancers, an optional rate controlling membrane and a release liner which is removed to expose the adhesives prior to application.
  • Polymeric matrix patches also comprise a polymeric-matrix forming material. Suitable transdermal patches are described in more detail in, for example, U.
  • Solid dosage forms for oral administration can include capsules, sustained-release capsules, tablets, sustained release tablets, chewable tablets, sublingual tablets, effervescent tablets, pills, powders, granules and gels.
  • the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms can also comprise buffering agents.
  • Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the invention and vegetable oil.
  • Hard gelatin capsules can contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin.
  • Tablets and pills can be prepared with enteric coatings.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • Suppositories for vaginal or rectal administration of the compounds and compositions of the invention can be prepared by mixing the compounds or compositions with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at rectal temperature, such that they will melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at rectal temperature, such that they will melt in the rectum and release the drug.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • Sterile fixed oils are also conventionally used as a solvent or suspending medium.
  • compositions of this invention can further include conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds.
  • suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like.
  • the pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • particularly suitable vehicles consist of solutions
  • the composition can also contain minor amounts of wetting agents, emulsifying agents and/or pH buffering agents.
  • the composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like.
  • the compounds of the invention can be incorporated into various types of pharmaceutical compositions, such as, for example, ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
  • ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
  • the compounds are preferably incorporated into topical ophthalmic formulations, such as for example, solutions, suspensions, gels, ointments, implants, and the like.
  • the compounds of the invention may be combined with ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, water to form an aqueous, sterile ophthalmic suspensions or solutions, and the like.
  • Suitable preservatives include, but are not limited to, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, ONAMER ® , and the like.
  • the preservatives are typically employed at a concentration between about 0.001% and about 1.0% by weight.
  • co-solvents include, but are not limited to, Polysorbate 20, 60 and 80; Pluronic F-68, F-84 and P-103; Tyloxapol ® ; Cremophor ® EL; sodium dodecyl sulfate; glycerol; PEG 400; propylene glycol; cyclodextrins, and the like.
  • the co-solvents are typically employed at a concentration between about 0.01% and about 2% by weight.
  • Viscosity enhancers are required as a viscosity greater than that of simple aqueous solutions may be desirable to increase ocular absorption of the active compound, to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation and/or otherwise to improve the ophthalmic formulation.
  • Suitable viscosity enhancers include, but are not limited to, polyvinyl alcohol, methyl cellulose, hydroxy propyl carboxymethyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, and the like.
  • Gelling agents can also be used, including, but not limited to, gellan and xanthan gum, and the like. Viscosity enhancers are typically employed at a concentration between about 0.01% and about 2% by weight.
  • Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer.
  • the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
  • the compounds of the invention may be combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-974, and the like.
  • Various delivery systems are known and can be used to administer the compounds or compositions of the invention, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules and the like.
  • the required dosage can be administered as a single unit or in a sustained release form.
  • compositions can be enhanced by micronization of the formulations using conventional techniques such as grinding, milling, spray drying and the like in the presence of suitable excipients or agents such as phospholipids or surfactants.
  • Sustained release dosage forms of the invention may comprise microparticles and/or nanoparticles having a therapeutic agent dispersed therein or may comprise the therapeutic agent in pure, crystalline, solid form.
  • the therapeutic dosage forms of this aspect of the invention may be of any configuration suitable for sustained release.
  • Nanoparticle sustained release therapeutic dosage forms are preferably biodegradable and, optionally, bind to the vascular smooth muscle cells and enter those cells, primarily by endocytosis.
  • the biodegradation of the nanoparticles occurs over time (e.g., 30 to 120 days; or 10 to 21 days) in prelysosomic vesicles and lysosomes.
  • Larger microparticle therapeutic dosage forms of the invention release the therapeutic agents for subsequent target cell uptake with only a few of the smaller microparticles entering the cell by phagocytosis.
  • a practitioner in the art will appreciate that the precise mechanism by which a target cell assimilates and metabolizes a dosage form of the invention depends on the morphology, physiology and metabolic processes of those cells.
  • the size of the particle sustained release therapeutic dosage forms is also important with respect to the mode of cellular assimilation.
  • the smaller nanoparticles can flow with the interstitial fluid between cells and penetrate the infused tissue.
  • the larger microparticles tend to be more easily trapped interstitially in the infused primary tissue, and thus are useful to deliver anti-proliferative therapeutic agents.
  • biodegradable microparticles or nanoparticles comprise biodegradable microparticles or nanoparticles. More particularly, biodegradable microparticles or nanoparticles are formed of a polymer containing matrix that biodegrades by random, nonenzymatic, hydrolytic scissioning to release therapeutic agent, thereby forming pores within the particulate structure.
  • the compositions of the invention are orally administered as a sustained release tablet or a sustained release capsule.
  • the sustained release formulations can comprise an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and, optionally at least one nitric oxide enhancing compound, or the sustained release formulations can comprise an effective amount of at least one 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound, and, optionally at least one therapeutic agent
  • the dosage required to provide an effective amount of the compounds and compositions will vary depending on the age, health, physical condition, sex, diet, weight, extent of the dysfunction of the recipient, frequency of treatment and the nature and scope of the dysfunction or disease, medical condition of the patient, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound used, whether a drug delivery system is used, and whether the compound is administered as part of a drug combination.
  • the amount of a given 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, that will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques, including reference to Goodman and Gilman, supra; The Physician's Desk Reference, Medical Economics Company, Inc., Oradell, N.J., 1995; and Drug Facts and Comparisons, Inc., St. Louis, MO, 1993. The precise dose to be used in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided by the physician and the patient's circumstances.
  • the amount of a given 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group that will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques, including reference to Goodman and Gilman, supra; The Physician's Desk Reference, Medical Economics Company, Inc., Oradell, NJ., 1995; and Drug Facts and Comparisons, Inc., St. Louis, MO, 1993. The precise dose to be used in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided by the physician and the patient's circumstances.
  • the amount of nitric oxide enhancing compound in a pharmaceutical composition can be in amounts of about 0.1 to about 10 times the molar equivalent of the 2-methyl indole COX-2 selective inhibitor, optionally substituted with at lest one nitric oxide enhancing group.
  • the usual daily doses of the 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group are about 0.001 mg to about 140 mg/kg of body weight per day, preferably 0.005 mg to 30 mg/kg per day, or alternatively about 0.5 mg to about 7 g per patient per day.
  • inflammations may be effectively treated by the administration of from about 0.01 mg to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
  • the compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, and most preferably once per day.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems and are in the same ranges or less than as described for the commercially available compounds in the Physician's Desk Reference, supra.
  • the invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compounds and/or compositions of the invention, including, at least, one or more of the 2-methyl indole COX-2 selective inhibitor, optionally substituted with at least one nitric oxide enhancing group, and one or more of the nitric oxide enhancing compounds described herein.
  • kits can be additional therapeutic agents or compositions (e.g., steroids, selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAED), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and combinations of two or more thereof), devices for administering the compositions, and notices in the form prescribed by
  • Example 3b (4.11 g, 33% yield) and was recrystallized from Et 2 O and hexane; mp 94-95 0 C; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 7.74 (br, IH), 7.30-7.20 (m, 6H), 6.97 (s, IH), 5.11 (s, 2H), 3.81 (s, 3H), 3.68 (s, 2H), 2.33 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) ⁇ l71.8, 149.3, 135.8, 134.0, 129.6, 128.4, 128.2, 128.0, 117.1, 111.7, 104.1, 100.8, 66.5, 56.5, 30.4, 11.6; Mass Spectrum (API-TIS) m/z 344 (MH + ). Anal, calcd for Ci9H 18 ClNO3: C, 66.38; H, 5.28; N, 4.07; Found: C, 66.14; H
  • Example 3d The product of Example 3d (0.37 g, 0.76 mmol) was hydrogenated in EtOAc (30 mL) and methanol (5 mL) in the presence of 10% Pd/C (33 mg) at 30 psi for 2.5 hours. The reaction mixture was filtered through Celite and the filter cake was washed with EtOAc.
  • Oxalyl chloride (0.19 mL, 2.2 mmol) was added to an ice-cold solution of indomethacin (0.6 g, 1.7 mmol) in CH 2 Cl 2 (50 mL) and DMF (10 ⁇ L) and the resulting solution was stirred in an ice-bath for 15 minutes, and then at room temperature for 2 hours.
  • the reaction mixture was evaporated to dryness under reduced pressure and the resulting crude material was dissolved in CH 2 Cl 2 (50 mL).
  • the product of Example 9a was added to the above solution, followed by the addition of NEt 3 (0.5 mL, 3.6 mmol) and stirred at room temperature for 3 hours.
  • Example 10 (2- ⁇ l- [(4-Ch ⁇ orophenyl)carbonyl]-5-methoxy-2-methylindol-3- yljacetylamino) acetate 10a. 2- ⁇ 1 - [(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3 -yl ⁇ ethanehydroxamic
  • Oxalyl chloride (0.8 mL, 9.2 mmol) was added to an ice-cold solution of indomethacin (2.51 g, 7.0 mmol) in CH 2 Cl 2 (50 mL) and DMF (20 ⁇ L) and the resulting solution was stirred in an ice-bath for 30 minutes and then at room temperature for 2 hours.
  • the reaction mixture was evaporated to dryness under reduced pressure and the resulting crude acid chloride was dissolved in CH 2 Cl 2 (50 mL). Hydroxylamine hydrochloride (0.51 g, 7.3 mmol) and DMAP (1.71 g, 14.0 mmol) were added to the above solution and stirred at room temperature overnight.
  • Example 13a A solution of the product of Example 13a (15.57 g, 75.2 mmol) and hydrazine hydrate (5.4 mL, 0.11 mol) in methanol (150 mL) were heated to 70 °C for 1.5 hours. After cooling to room temperature, CHCl 3 (100 mL) was added to the reaction mixture. The resulting slurry was filtered and washed with CHCl 3 (100 mL x 2).
  • Example 15 4-Clorophenyl 5-methoxy-2-methyl-3-[2-(nitrooxy)ethyl]-indolyl ketone 15a. 4-Chlorophenyl 3-(2-hydroxyethyl)-5-methoxy-2-methylindolyl ketone
  • Triethyl amine (0.22 mL, 1.6 mmol) and methanesulfonyl chloride (0.15 mL, 1.9 mmol) were added to a solution of the product of Example 15a in CH 2 Cl 2 (15 mL) and then stirred at room temperature for 2 hours.
  • the reaction mixture was partitioned between 3N HCl (10 mL) and CH 2 Cl 2 (30 mL). The organic extract was washed with water, brine, dried over Na 2 SO 4 , filtered, concentrated and dried under vacuum.
  • the product >95% purity from NMR analysis, was use in the next step without purification.
  • Example 15b The crude product of Example 15b in toluene (15 niL) with tetrabutylammonium nitrate (0.47 g, 1.54 mmol) was heated to 100 °C overnight. After cooling to room temperature, the reaction mixture was dissolved in EtOAc (100 niL), washed with water, brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • Chlorosulfonyl isocyanate (130 ⁇ L, 1.5 mmol) and NEt 3 (210 ⁇ L, 1.5 mmol) were added to an ice-cold solution of the product of Example 15a (0.52 g, 1.5 mmol) in CH 2 Cl 2 (20 mL) and stirred in an ice-bath for 30 min.
  • 3-(N ⁇ trooxy)propan-l-ol (0.25 g, 2.1 mmol, prepared as described in US 2004/0024057; WO 2004/004648, Example 40a ) and NEt 3 (210 ⁇ L, 1.5 mmol) were added to the reaction mixture and allowed to warm up slowly in an ice- bath to room temperature and then stirred overnight.
  • Example 19a The crude product of Example 19a was hydrogenated in EtOAc (30 mL) in the presence of 10% Pd/C (0.14 g) and acetic acid (0.5 mL) at 30 psi for 2 hours.
  • the reaction mixture was filtered through Celite and the filter cake was washed with MeOH (100 mL).
  • the filtrate was concentrated and the residue was partitioned between CH 2 Cl 2 (200 mL) and water (100 mL).
  • the organic layer was washed with saturated Na 2 CO 3 , water, brine, dried over Na 2 SO 4 , filtered, concentrated and dried under vacuum.
  • the product was dissolved in Et 2 O and was treated with HCUEt 2 O.
  • Example 19b A mixture of the product of Example 19b (1.01 g, 2.7 mmol), 4 ⁇ [(nitrooxy)mefhyl] benzoic acid (0.59 g, 3.0 mmol, prepared as described in US 2004/0024057, Example Ha), DMAP (0.4 g, 3.3 mmol), EDAC (0.67 g, 3.5 mmol) and NEt 3 (1.6 mL, 11.5 mmol) in CH 2 Cl 2 (30 mL) and THF (20 mL) were stirred at room temperature for 2 days. The reaction mixture was partitioned between 3N HCl (30 mL) and EtOAc (50 mL x 2).
  • N,N'-Carbonyldiimidazole (79 mg, 0.49 mmol) and the product of Example 19b (0.16 g, 0.46 mmol) in CH 2 Cl 2 (10 mL) were stirred at room temperature for 45 minutes.
  • 3- (Nitrooxy) propylamine nitric acid salt (85 mg, 0.46 mmol, prepared as described in WO 2005/030135 A2, Example 8a), and NEt 3 (0.07 mL,0.5 mmol) in THF (5 mL) were added to the resulting solution and the resulting mixture stirred for an additional 5 hours, then partitioned between 3N HCl (30 mL) and CH 2 Cl 2 (50 mL).
  • the organic extract was washed with water, brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • the product can further purified by washing with Et 2 O.
  • Example 21 4-Chlorophenyl 5-methoxy-2-methyl-3- ⁇ 2-[( ⁇ 4-[(nitrooxy)methyl]phenyl ⁇ - sulfonyl)amino]ethyl ⁇ indolyl ketone 21a. 3- [2-( ⁇ [4-(Chloromethyl)phenyi] sulfonyl ⁇ amino)ethyl] -5-methoxy-2-methylindolyl
  • Example 22b The product of Example 22b (0.36 g, 0.71 mmol) was hydrogenated in EtOAc (20 mL) in the presence of 10% Pd/C (55 mg) at 35 psi for 3.5 hours. The reaction mixture was filtered through Celite and the filter cake was washed with EtOAc.
  • Example 25b To a stirred solution of the product of Example 25b (230 mg, 0.730 mmol), EDAC (280 mg, 1.46 mmol), and 3-(nitrooxy)propylamine nitric acid salt (0.160 g, 0.880 mmol, prepared as described in WO 2005/030135 A2, Example 8a), in dichloromethane was added triethylamine (0.418 mL, 3.00 mmol) and DMAP (10 mg). After being stirred at room temperature for 3 hours, the reaction mixture was concentrated. The solid residue was taken up with EtOAc, washed with 2N hydrochloric acid and water. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated.
  • Example 26 ⁇ 2-[l-(Cyclohexylmethyl)-5-methoxy-2-methylindol-3-yl]ethyl ⁇ nitrooxy 26a. 2-[l-(Cyclohexylmethyl)-5-methoxy-2-methylindol-3 ⁇ yl]ethan-l-ol
  • test compounds were dissolved in DMSO, at 1000 fold the final desired concentration, and further diluted, as indicated, in DMSO. One ⁇ L of each dilution of the test compound was added per well, in duplicate wells; wells not receiving test compound (e.g., basal, background or control wells) received 1 ⁇ L DMSO.
  • LPS lipopolysaccharide
  • E. coli lipopolysaccharide
  • serotype 026:B6 or serotype 0127:B8 Sigma Chemical Co., St. Louis, MO, Catalogue No. L3755 or L3129, respectively
  • the resulting solutions were transferred by polyethylene transfer pipettes to 15 mL polypropylene centrifuge tubes and centrifuged at 1200 g for 10 minutes at 4 0 C.
  • One hundred ⁇ L of plasma was removed from each blood sample and added to 1 mL of methanol in new 15 mL polypropylene centrifuge tubes, vortexed, and stored overnight at -20 0 C.
  • the next day the samples were centrifuged at 2000 g for 10 minutes at 4 0 C and the supernatants transferred to glass tubes and evaporated to dryness.
  • the samples were assayed for thromboxane B 2 using EIA kits supplied by Cayman Chemical Co. (Ann Arbor, MI, Catalogue No. 519031) in duplicate wells after reconstitution with EIA Buffer and appropriate dilution (2000 fold for COX-I and 500 fold for Cox-2 samples).
  • Example 28 Rat Carrageenan Air-Pouch
  • the carrageenan air pouch model was performed as described by Sedgwick et al., Agents Actions 18, 429-438, (1986) and Masferrer et al,. Proc. Natl. Acad. ScL 91, 3228-3232 (1994).
  • Air pouches were produced by subcutaneous injection of 20 ml of sterile air on day (-6) into the intrascapular area of the back of the anesthesia rat (male CD, Charles River, 175- 20Og). An additional 10 mL of sterile air was injected into the pouch 3 days later to keep the space open and to assist in the development of the interior membrane.
  • Example 29 Comparative In Vivo Antiinflammatory and Gastric Lesion Activities
  • the rat gastric lesion test described by Kitagawa et al, J. Pharmacol. Exp. Ther., 253:1133-1137 (1990), and Al-Ghamdi et al, J. Int. Med. Res., 19:2242 (1991), was used to evaluate the activity of compounds to produce gastric lesion.
  • Male Sprague Dawley rats (Charles River Laboratories, Wilmington, MA) weighing 230-250 g were used for the experiments. The rats were housed with laboratory chow and water ad libitum prior to the study. The rats were fasted for 24 hours with free access to water and then dosed by oral gavage with vehicle or with test compounds given at a volume of 0.5 mL/100 g.
  • Rats were euthanized by CO 2 three hours after dosing.
  • the stomachs were dissected along the greater curvature, washed with a directed stream of 0.9% saline and pinned open on a sylgard based petri dish for examination of the hemorrhagic lesion.
  • Gastric lesion score was expressed in mm and calculated by summing the length of each lesion.
  • Table 3 shows the gastric lesion compared to indomethacin. The results show that the compounds of the invention have significantly and unexpectedly decreased gastric lesion activities.

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Abstract

L’invention décrit des compositions et des kits comprenant des inhibiteurs 2-méthyle-indole sélectifs de la cyclooxygénase 2 (COX-2) ou des sels desdits inhibiteurs acceptables sur le plan pharmaceutique et, éventuellement au moins un composé renforçateur monoxyde d’azote et/ou au moins un agent thérapeutique. Les inhibiteurs 2-méthyle-indole sélectifs de la cyclooxygénase 2 peuvent éventuellement être substitués avec au moins un groupe renforçateur ***monoxyde d’azote. L’invention prévoit également des procédés destinés à (a) traiter l’inflammation, la douleur et la fièvre ; (b) traiter les troubles gastro-intestinaux et/ou améliorer les propriétés gastro-intestinales d’inhibiteurs sélectifs de COX-2 ; (c) faciliter la guérison des blessures ; (d) traiter les intoxications rénales et/ou respiratoires ; (e) traiter des troubles résultant de niveaux élevés de cyclooxygénase-2 ; (f) améliorer le profil cardiovasculaire des inhibiteurs sélectifs de COX-2 ; (g) traiter des maladies résultant de stress oxydatif ; (h) traiter les dysfontionnements endothéliaux ; (j) traiter des maladies dues aux dysfonctionnement endothéliaux ; (k) traiter des états et/ou des troubles dus à une maladie inflammatoire ; (l) traiter des troubles ophthalmiques ; et (m) traiter des maladies vasculaires périphériques. Les groupes renforçateurs monoxyde d’azote sont des nitrates organiques, des nitrites organiques, des nitrosothiols, des thionitrites, des thionitrates, des NONOates, des donneurs hétérocycliques d’acide nitrique et/ou des nitroxydes. Les donneurs de monoxyde d’azote hétérocycliques sont des furoxanes, des sydnonimines, des oxatriazole-5-ones et/ou des oxatriazole-5-imines.
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JP2013536876A (ja) * 2010-09-07 2013-09-26 ロッタファルム・ソシエタ・ペル・アチオニ 選択性ｃｏｘ−２阻害剤および一酸化窒素ドナーである１，５−ジアリール−２−アルキルピロール−３−置換ニトロエステル
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