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WO2006099416A1 - 2-methyl indole cyclooxygenase-2 selective inhibitors, compositions and methods of use - Google Patents

2-methyl indole cyclooxygenase-2 selective inhibitors, compositions and methods of use 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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PCT/US2006/009127
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French (fr)
Inventor
Shiow-Jyi Wey
David S. Garvey
Xinqin Fang
Stewart K. Richardson
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Nitromed, Inc.
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Publication of WO2006099416A1 publication Critical patent/WO2006099416A1/en

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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

The invention describes 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.

Description

2-METHYL INDOLE CYCLOOXYGENASE-^ SELECTIVE INHIBITORS, COMPOSITIONS AND METHODS OF USE
RELATED APPLICATIONS
This application claims priority under 35 USC § 119 to U.S. Application No. 60/660,436 filed March 11, 2005.
FIELD OF THE INVENTION
The invention describes 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.
BACKGROUND OF THE INVENTION
Nonsteroidal anti-inflammatory compounds (NS AIDs) 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. The NSAIDs also inhibit the production of other prostaglandins, especially prostaglandin G2, prostaglandin H2 and prostaglandin E2, 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. The undesirable side effects are also due to the inhibition of prostaglandin in the affected organ. i Recently two isoforms of cyclooxygenase, encoded by two distinct genes (Kujubu et al, /. Biol. Chem., 266, 12866-12872 (1991)), have been identified - a constitutive form, cyclooxygenase- 1 (COX-I), and an inductive form, cyclooxygenase-2 (COX-2). It is thought that the antiinflammatory effects of NSAIDs are mediated by the inhibition of COX-2, whereas the side effects seem to be caused by the inhibition of COX-I. The NSAIDs currently on the market either inhibit both isoforms of COX with little selectivity for either isoform or are COX-I selective. Recently compounds that are COX-2 selective inhibitors have been developed and marketed. These COX-2 selective inhibitors have the desired therapeutic profile of an antiinflammatory drug without the adverse effects commonly associated with the inhibition of COX-I. However, these compounds can result in dyspepsia and can cause gastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)). Additionally the 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)).
There is still a need in the art for novel COX-2 selective inhibitor compounds that have gastroprotective properties, facilitate wound healing, decreased renal toxicity and dyspepsia, improved cardiovascular profile and that can be used at low dosages. The invention is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
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. Thus, 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.
The invention provides 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H2 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. In one embodiment the at least one therapeutic agent is selected from the group consisting of an NSAID, aspirin, a proton pump inhibitor and an H2 antagonist. In another embodiment of the invention 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.
Another embodiment of the invention provides 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 B4 (LTB4) receptor antagonist, a leukotriene A4 (LTA4) hydrolase inhibitor, a 5-HT agonist, an anti-hyperlipidemic compound, a H2 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 pylori inhibitor, a phosphodiesterase inhibitor, a proton pump inhibitor, an isoprostane inhibitor, and combinations of two or more thereof. The invention also provides for such compositions in a pharmaceutically acceptable carrier.
Another embodiment of the invention provides 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, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H2 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. The methods can optionally further comprise the administration of at least one nitric oxide enhancing compound. In this embodiment of the invention, 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. In one embodiment 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 B4 (LTB4) receptor antagonist, a leukotriene A4 (LTA4) hydrolase inhibitor, a 5-HT agonist, an anti-hyperlipidemic compound, a H2 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. In one embodiment the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H2 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.
Another embodiment of the invention provides 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H2 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. 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.
These and other aspects of the invention are described in detail herein. DETAILED DESCRIPTION OF THE INVENTION
As used throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
"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.
"Upper 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. In one embodiment, the compound has a cyclooxygenase-2 IC50 of less than about 2 μM and a cyclooxygenase- 1 IC50 of greater than about 5 μM, 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. In another embodiment, the compound has a cyclooxygenase- 1 IC50 of greater than about 1 μM, and preferably of greater than 20 μM. 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. "Proton 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H2 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. Although 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, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, vascular or non-vascular complications associated with the use of medical devices, wounds associated with the use of medical devices, vascular or non-vascular wall damage, peripheral vascular disease, neointimal hyperplasia following percutaneous transluminal coronary angiograph, vascular grafting, coronary artery bypass surgery, thromboembolic events, post-angioplasty restenosis, coronary plaque inflammation, hypercholesterolemia, embolism, stroke, shock, arrhythmia, atrial fibrillation or atrial flutter, thrombotic occlusion and reclusion cerebrovascular incidents, left ventricular dysfunction and hypertrophy, and the like.
"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. 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 A2 homeostasis or higher than normal thromboxane A2 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.
"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.
"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.
"Ophthalmic 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.
"Thromboxane inhibitor" refers to any compound that reversibly or irreversibly inhibits thromboxane synthesis, and includes compounds which are the so-called thromboxane A2 receptor antagonists, thromboxane A2 antagonists, thromboxane A2/prostaglandin endoperoxide antagonists, thromboxane receptor (TP) antagonists, thromboxane antagonists, thromboxane synthase inhibitors, and dual acting thromboxane synthase inhibitors and thromboxane receptor antagonists. The characteristics of the preferred thromboxane inhibitor should include the suppression of thromboxane A2 formation (thromboxane synthase inhibitors) and/or blockade of thromboxane A2 and prostaglandin H2 platelet and vessel wall (thromboxane receptor antagonists). The effects should block platelet activation and therefore platelet function.
"Thromboxane A2 receptor antagonist" refers to any compound that reversibly or irreversibly blocks the activation of any thromboxane A2 receptor.
"Thromboxane synthase inhibitor" refers to any compound that reversibly or irreversibly inhibits the enzyme thromboxane synthesis thereby reducing the formation of thromboxane A2. Thromboxane synthase inhibitors may also increase the synthesis of antiaggregatory prostaglandins including prostacyclin and prostaglandin D2. Thromboxane A2 receptor antagonists and thromboxane synthase inhibitors and can be identified using the assays described in Tai, Methods of Enzymology, Vol. 86, 110-113 (1982); Hall, Medicinal Research Reviews, 11:503-579 (1991) and Coleman et al., Pharmacol Rev., 46: 205-229 (1994) and references therein, the disclosures of which are incorporated herein by reference in its entirety.
"Dual acting thromboxane receptor antagonist and thromboxane synthase inhibitor" refers to any compound that simultaneously acts as a thromboxane A2 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. Preferably, 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.
"Platelet 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).
"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.
"Penetration enhancement" or "permeation 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.
"Nitroxide 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 R100 groups, wherein each R100 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 C2-C1O hydrocarbon (preferably a C2- C8 hydrocarbon, more preferably a C2-C6 hydrocarbon) that can comprise one or more carbon-carbon double bonds. Exemplary 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 C2-C4 hydrocarbon that can comprise one or two carbon-carbon double bonds.
"Substituted alkenyl" refers to a branched or straight chain C2-C1O hydrocarbon (preferably a C2-C8 hydrocarbon, more preferably a C2-C6 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 R100 groups, wherein each R100 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 C2-CiO hydrocarbon (preferably a C2-Cs hydrocarbon, more preferably a C2-C6 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. Exemplary 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, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4- dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, benzothiazolinyl, quinolinyl, 2,6- dioxabicyclo(3.3.0)octane, and the like.
"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 (including bicyclic 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, sulfonamide, alkylsulfonyl, arylsulfonyl, and the like.
"Cycloalkenyl" refers to an unsaturated cyclic C2-C1O hydrocarbon (preferably a C2- Cs hydrocarbon, more preferably a C2-C6 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 R50O-, wherein R50 is an alkyl group, as defined herein (preferably a lower alkyl group or a haloalkyl group, as defined herein). Exemplary 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 R50S-, 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 Rs4O-, wherein R54 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 R54S-, wherein R54 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.
"Hydroxy" refers to -OH.
"Oxy" refers to -O-
"Oxo" refers to =O.
"Oxylate" refers to -O" R77 + wherein R77 is an organic or inorganic cation.
"Thiol" refers to -SH.
"Thio" refers to -S-.
"Oxime" refers to =N-OR81 wherein R81 is a hydrogen, an alkyl group, an aryl group, an alkylsulfonyl group, an arylsulfonyl group, a carboxylic ester, an alkylcarbonyl group, an arylcarbonyl group, a carboxamido group, an alkoxyalkyl group or an alkoxyaryl group.
"Hydrazone" refers to =N-N(Rs1)(R'81) wherein R1S1 is independently selected from R81, and R81 is as defined herein.
"Hydrazino" refers to H2N-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.
"Hydroxyalkyl" refers to a hydroxy group, as defined herein, appended to an alkyl group, as defined herein.
"Nitrate" refers to -O-NO2 i.e. oxidized nitrogen.
"Nitrite" refers to -O-NO i.e. oxidized nitrogen.
"Thionitrate" refers to -S-NO2.
"Thionitrite" and "nitrosothiol" refer to -S-NO.
"Nitro" refers to the group -NO2 and "nitrosated" refers to compounds that have been substituted therewith.
"Nitroso" refers to the group -NO and "nitro sylated" refers to compounds that have been substituted therewith.
"Nitrile" and "cyano" refer to -CN.
"Halogen" or "halo" refers to iodine (I), bromine (Br), chlorine (Cl), and/or fluorine (F).
"Imine" refers to -CC=N-Rs1)- wherein R51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein
"Amine" refers to any organic compound that contains at least one basic nitrogen atom.
"Amino" refers to -NH2, 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 R50NH-, wherein R50 is an alkyl group, as defined herein. Exemplary alkylamino groups include methylamino, ethylamino, butylamino, cyclohexylamino, and the like.
"Arylamino" refers to R55NH-, wherein R55 is an aryl group, as defined herein.
"Dialkylamino" refers to Rs2Rs3N-, wherein Rs2 and Rs3 are each independently an alkyl group, as defined herein. Exemplary dialkylamino groups include dimethylamino, diethylamino, methyl propargylamino, and the like.
"Diarylamino" refers to R55R60N-, wherein R55 and Rβo are each independently an aryl group, as defined herein.
"Alkylarylamino" or "arylalkylamino" refers to Rs2RsSN-, wherein R52 is an alkyl group, as defined herein, and R55 is an aryl group, as defined herein.
"Alkylarylalkylamino" refers to Rs2R79N-, wherein Rs2 is an alkyl group, as defined herein, and R79 is an arylalkyl group, as defined herein.
"Alkylcycloalkylamino" refers to Rs2R8ON-, wherein R52 is an alkyl group, as defined herein, and R8o 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.
"Sulfmyl" refers to -S(O)-.
"Methanthial" refers to -C(S)-.
"Thial" refers to =S. "Sulfonyl" refers to -S(O)2 " .
"Sulfonic acid" refers to -S(O)2OR76, wherein R76 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)2ORs8, wherein Rs8 is an alkyl group, an aryl group, or an aryl heterocyclic ring, as defined herein.
"Sulfonamido" refers to -S(O)2-N(Rs1)(Rs7), wherein Rs1 and Rs7 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or Rs1 and Rs7 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 R50S-, 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 R50 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 R50 is an alkyl group, as defined herein.
"Arylsulfinyl" refers to Rss-S(O)-, wherein R55 is an aryl group, as defined herein.
"Arylsulfonyl" refers to RsS-S(O)2-, wherein R55 is an aryl group, as defined herein.
"Arylsulfonyloxy" refers to R5S-S(O)2-O-, wherein R55 is an aryl group, as defined herein.
"Amidyl" refers to Rs1C(O)N(Rs7)- wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
"Ester" refers to Rs1C(O)Rg2- wherein R51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein and R82 is oxygen or sulfur. "Carbamoyl" refers to -0-C(O)N(R51)(R57), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
"Carboxyl" refers to -C(O)OR76, wherein R76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
"Carbonyl" refers to -C(O)-.
"Alkylcarbonyl" refers to R52-C(O)-, wherein R52 is an alkyl group, as defined herein.
"Arylcarbonyl" refers to R55-C(O)-, wherein R55 is an aryl group, as defined herein.
"Arylalkylcarbonyl" refers to R55-R52-C(O)-, wherein R55 is an aryl group, as defined herein, and R52 is an alkyl group, as defined herein.
"Alkylarylcarbonyl" refers to R52-R55-C(O)-, wherein R55 is an aryl group, as defined herein, and R52 is an alkyl group, as defined herein.
"Heterocyclicalkylcarbonyl" refer to R78C(O)- wherein R78 is a heterocyclicalkyl group, as defined herein.
"Carboxylic ester" refers to -C(O)OR58, wherein R58 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(R51)(R57), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 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.
"Urea" refers to -N(R59)-C(O)N(R5i)(R57) wherein R51, R57, and R59 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
"Phosphoryl" refers to -P(R7o)(R71)(R72), wherein R7o is a lone pair of electrons, tliial or oxo, and R71 and R72 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)(ORs1)OH wherein R51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
"Phosphinic acid" refers to -P(O)(Rs1)OH wherein R51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
"Silyl" refers to -Si(R73)(R74)(R75), wherein R73, R74 and R75 are each independently a covalent bond, a lower alkyl, an alkoxy, an aryl or an arylalkoxy, as defined herein.
In one embodiment of the invention 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.
In one embodiment, the invention describes 2-methyl indole COX-2 selective inhibitors of Formula (I), and pharmaceutically acceptable salts thereof:
Figure imgf000023_0001
I wherein:
R31 is an atkoxy group, a hydroxyl group or an aminosulfonyloxy group; R33 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;
R34 is a hydrogen or halogen;
R3S and R39 are hydrogen or R38 and R39 when taken together with the carbon atom to which they are attached form a carbonyl group;
R4O is a cylcloalkyl group or an aryl group; X is:
Ca) -CH2-N(R36)-; (b)-C(O)-N(R36)-; (C) -CH2-O-;
(d) -CH2-P(O)(OH)(O)-; or Ce) -C(O)-O-;
R36 is a hydrogen or an alkylcarbonyl group;
K is -(W3)a-Eb-(C(Re)(Rf))pl-Ec-(C(Re)(Rf))x-(W3)d-(C(Re)(Rf))y-CW3)i-Ej-(W3)g-
Figure imgf000023_0002
a, b, c, d, g, i and j are each independently an integer from 0 to 3; P1, x, y and z are each independently an integer from 0 to 10; V4 is V3, R6, -U3-V5 or V6; V3 is:
Figure imgf000024_0001
Figure imgf000025_0001
R24 is -C6H4R37, -CN, -S(O)2-C6H4R37, -C(O)-N(R8)(RO, -NO2, -C(O)-OR25 or -S(O)2-R25;
R25 is an aryl group, a lower alkyl group, a haloalkyl group, a hydroxyalkyl group or an arylalkyl group;
R26 is -C(O)- or -S(O)2- ; R37 is a hydrogen, -CN, -S(O)2-R25, -C(O)-N(R3)(Ri), -NO2 Or-C(O)-OR25;
T' is oxygen, sulfur or NR6;
R6 is a hydrogen, a lower alkyl group, or an aryl group;
V6 is:
Figure imgf000026_0001
Z5 is -CH2 or oxygen;
Z6 is -CH or nitrogen;
W3 at each occurrence is independently -C(O)-, -C(S)-, -T3-, -(C(R6)(Rf)) h-, -N(R8)Ri, an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, -(CH2CH2O) ql- or a heterocyclic nitric oxide donor;
E at each occurrence is independently -T3-, an alkyl group, an aryl group, -(C(Re)(Rf)V, a heterocyclic ring, an arylheterocyclic ring, -(CH2CH2O)ql- or Y4;
Y4 is:
Figure imgf000026_0002
Figure imgf000027_0001
T is a -S(O)0-; a carbonyl or a covalent bond; o is an integer from 0 to 2;
Rj and Rk are independently selected from an alkyl group, an aryl group, or Rj and Rk taken together with the nitrogen atom to which they are attached are a heterocylic ring;
T3 at each occurrence is independently a covalent bond, a carbonyl, an oxygen,
Figure imgf000027_0002
h is an integer form 1 to 10; qi is an integer from 1 to 5;
Re and Rf 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 alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamide, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-V5, Ve, -(C(R0)(Rp))kl-U3-V5, -(C(R0)(Rp))Id-U3-V3, -(C(R0)(Rp))kl-U3-V6, -(C(R0)(Rp))kl-U3-C(O> V6, or Re and Rf taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, an imine, a hydrazone, a bridged cycloalkyl group,
Figure imgf000028_0001
R0 and Rp 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 alkyϊarylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamide, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-V5, V6, or R0 and Rp taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, an imine, a hydrazone a bridged cycloalkyl group,
Figure imgf000028_0002
U3 is an oxygen, sulfur or -N(Ra)Ri;
V5 is -NO or -NO2 (i.e. an oxidized nitrogen);
Ic1 is an integer from 1 to 3;
Ra 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, -CH2-C-(Us-Vs)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom or -(N2O2-^M1 +, wherein M1 + is an organic or inorganic cation; and
In cases where Re and Rf are a heterocyclic ring or Re and Rf 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.
In cases where multiple designations of variables that reside in sequence are chosen as a "covalent bond" or the integer chosen is 0, the intent is to denote a single covalent bond connecting one radical to another. For example, Eo would denote a covalent bond, while E2 denotes (E-E) and (C(Re)(Rf))2 denotes -C(R6)(Rf)-C(R6)(Rf)-.
In other embodiments of the invention, 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-
2-methylindol-3-yl}-N-(3-hydroxypropyl)acetamide:
Figure imgf000029_0001
(H) wherein the compound of Formula (III) is phenylmethyl 2-{6-chloro-l-[(4- chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl } acetate:
Figure imgf000030_0001
(HI) wherein the compound of Formula (IV) is 2~{6-chloro-l-[(4-chlorophenyl)carbonyl]- 5-methoxy-2-methylindol-3-yl } acetic acid:
Figure imgf000030_0002
(IV) wherein the compound of Formula (V) is phenylmethyl 2-{4-chloro-l-[(4- chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}acetate:
Figure imgf000030_0003
(V) wherein the compound of Formula (VI) is 2-{ l-[(4-chlorophenyl)carbonyl]-5- methoxy-2-methylindol-3-yl}-N-(3-hydroxypropyl)acetamide:
Figure imgf000030_0004
(VI)
wherein the compound of Formula (VII) is 2-{ l-[(4-chlorophenyl)carbonyl]-5- methoxy-2-methylindol-3-yl}-N-(4-hydroxybutyl)acetamide:
Figure imgf000031_0001
(VII) wherein the compound of Formula (VIII) is (2-{ l-[(4~chlorophenyi)carbonyi]-5- methoxy-2-methylindol-3-yl}acetylamino)acetate:
Figure imgf000031_0002
(VIII) wherein the compound of Formula (IX) is (N-acetyl-2-{l-[(4-chlorophenyl)carbonyl]- 5-methoxy-2-methylindol-3-yl } acetylamino) acetate:
Figure imgf000031_0003
(IX) wherein the compound of Formula (X) is 2-{ l-[(4-chlorophenyl)carbonyl]-5- methoxy-2-methylindol-3-yl}-N-(2-hydroxyethoxy)acetamide:
Figure imgf000031_0004
(X) wherein the compound of Formula (XI) is 2-{ l-[(4-chlorophenyl)carbonyl]-5- methoxy-2-methylindol-3-yl}-N-(3-hydroxypropoxy)acetamide:
Figure imgf000032_0001
(XI)
wherein the compound of Formula (XII) is 4-chlorophenyl 3-(2-hydroxyethyl)-5- methoxy-2-methylindolyl ketone:
Figure imgf000032_0002
(xπ) wherein the compound of Formula (XIII) is 3-(2-aminoethyl)-5-methoxy-2- methylindolyl 4-chlorophenyl ketone hydrochloride:
Figure imgf000032_0003
(XΠD wherein the compound of Formula (XIV) is 3-[2-({[4-(chloromethyi)phenyl] sulfonyl } amino)ethyl]-5-methoxy-2-methylindolyl 4-chlorophenyl ketone:
Figure imgf000033_0001
(XIV) wherein the compound of Formula (XV) is 4-chlorophenyl 3-(2-{[(3- chloropropyl)sulfonyl]amino}ethyl)-5-methoxy-2-methylindolyl ketone:
Figure imgf000033_0002
(XV) wherein the compound of Formula (XVI) is 4-chlorophenyl 3-(2-{ [(3- hydroxypropyl)sulfonyl] amino } ethyl)-5-methoxy-2-methylindolyl ketone:
Figure imgf000033_0003
(XVI) wherein the compound of Formula (XVII) is (2-{ l-[(4-chlorophenyl)carbonyl]-5- methoxy-2-methylindol-3-yl}ethyl)-dimethoxyphosphino-l-one:
Figure imgf000033_0004
(xvπ) wherein the compound of Formula (XVIII) is 4-chlorophenyl 5-methoxy-2-methyl-3- (2-phosphonoethyl)indolyl ketone:
Figure imgf000034_0001
wherein the compound of Formula (XEX) is ethyl 2-(5-methoxy-2-methyl-l-{ [4-
(methylsulfonyl)phenyl]methyl}indol-3-yl)acetate:
Figure imgf000034_0002
(XIX) wherein the compound of Formula (XX) is 2-(5-methoxy-2-methyl-l-{[4-
(methylsulfonyl)phenyl]methyl}indol-3-yl)acetic acid:
Figure imgf000034_0003
(XX) wherein the compound of Formula (XXI) is ethyl 2-[l-(cyclohexylmethyl)-5- methoxy-2-methylindol-3-yl]acetate:
Figure imgf000034_0004
(XXI)
wherein the compound of Formula (XXII) is 2-[l-(cyclohexylmethyl)-5-methoxy-2- methylindol-3-yl]acetic acid:
Figure imgf000035_0001
(XXQ) wherein the compound of Formula (XXIII) is 2-[l-(cyclohexylmethyl)-5-methoxy-2- methylindol-3-yl] ethan- 1 -ol:
Figure imgf000035_0002
(XXIII)
In other embodiments of the invention, 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:
Figure imgf000035_0003
(xxrv) wherein the compound of Formula (XXI) is l-[(4-chlorophenyl)carbonyl]-2-rnethyl- 3-({N-[3-(nitrooxy)-propyl]carbamoyl} methyl)indol-5-yl aminosulfonate:
Figure imgf000035_0004
(XXV) wherein the compound of Formula (XXVI) is 2-{6-chloro-l-[(4- chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-[3-(nitrooxy)propyl]acetamide:
Figure imgf000036_0001
(XXVI) wherein the compound of Formula (XXVII) is 2-{ l-[(4-chlorophenyi)carbonyl]-5- methoxy-2-methylindol-3-yl}-N-[3-(nitrooxy)propyl]acetamide:
Figure imgf000036_0002
(xvπi) wherein the compound of Formula (XXVIII) is N-[2,2-dimethyl-3-(nitrooxy)propyl]- 2-{ l-[(4-chlorophenyl)-carbonyl]-5-methoxy-2-methylindol-3-yl}acetamide:
Figure imgf000036_0003
(xxvπi) wherein the compound of Formula (XXIX) is N- { l,l~bis[(nitrooxy)methyl]-2- (nitrooxy)ethyl } -2- { 1 -[(4-chlorophenyi)-carbonyl] -5-methoxy-2-methylindol-3- yl}acetamide:
Figure imgf000036_0004
(XXIX) wherein the compound of Formula (XXX) is 4-clorophenyl 5-methoxy-2-methyl-3-[2- (nitrooxy)ethyl]-indolyl ketone:
Figure imgf000037_0001
(XXX) wherein the compound of Formula (XXXI) is (2-{ l-[(4-chlorophenyi)carbonyl]-5- methoxy-2-methylindol-3-yl}ethoxy)-N-[3-(nitrooxy)propyl]carboxamide:
Figure imgf000037_0002
(XXXI) wherein the compound of Formula (XXXII) is (2-{ l-[(4-chlorophenyl)carbonyl]-5- methoxy-2-methylindol-3-yl}ethoxy)-N-({[3-(nitrooxy)propyl]amino}sulfonyl)carboxamide:
Figure imgf000037_0003
(xxxπ) wherein the compound of Formula (XXXIII) is 3-(nitrooxy)propyl [(2-{ l-[(4- chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}ethoxy)carbonylamino]sulfonate:
Figure imgf000037_0004
(XXXIII) wherein the compound of Formula (XXXIV) is N-(2-{ l-[(4-chlorophenyl)carbonyl]- 5-methoxy-2-methylindol-3-yl } ethyl) { 4- [(nitrooxy)methyl]ρhenyl } carboxamide:
(XXXIV) wherein the compound of Formula (XXXV) is N-(2-{ l-[(4-chlorophenyl)carbonyl]-5- methoxy-2-methylindol-3-yl}ethyl){t3-(nitrooxy)propyl]amino}carboxamide:
Figure imgf000038_0002
(XXXV) wherein the compound of Formula (XXXVI) is 4-chlorophenyl 5-methoxy-2~methyl- 3-{2-[({4-[(nitrooxy)methyl]phenyl}-sulfonyl)amino]ethyl}indolyl ketone:
Figure imgf000038_0003
(XXXVI) wherein the compound of Formula (XXXVII) is 4-chlorophenyl 5-methoxy-2-methyl- 3-[2-({ [3-(nitrooxy)-propyl]sulfonyl}-amino)ethyl]indolyl ketone:
Figure imgf000038_0004
(XXXVII) wherein the compound of Formula (XXXVIII) is 2-(5-methoxy-2-methyl-l-{[4- (methylsulfonyl)phenyl]methyl}indol-3-yl)-N-[3-(nitrooxy)propyl]acetamide:
Figure imgf000039_0001
(xxxvπi) wherein the compound of Formula (XXXIX) is 2-[l-(cyclohexylmethyl)-5-methoxy- 2-methylindol-3-yl]-N-[3~(nitrooxy) propyl]acetamide:
Figure imgf000039_0002
(XXXIX) wherein the compound of Formula (XL) is {2-[l-(cyclohexylmethyl)-5-methoxy-2- methylindol-3-yl]ethyl}nitrooxy:
Figure imgf000039_0003
(XL)
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. The use of sulfur and oxygen protecting groups is 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 chemical reactions described herein are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by one skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to one skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily prepared from known starting materials.
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. Known methods for linking a nitric enhancing donor group to compounds, such as, for example, 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. For example, 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. Chem ., 46: 3762-3765 (2003); J. Med. Chem., 46: 747-754 (2003); Chem Rev., 102: 1091-1134 (2002); J. Med. Chem., 42: 1941- 1950 (1999); J. Med. Chem., 41: 5393-5401 (1998); J. Med. Chem., 38: 4944-4949 (1995); Arzneim. Forsch. Drug Res., 47 (II): 847-854 (1997); the disclosures of each of which are incorporated by reference herein in their entirety. 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. 5,380,758, 5,859,053, 5,703,073 and 6,297,260; and in WO 94/03421, WO 94/04484, WO 94/12463, WO 95/09831, WO 95/19952, WO 95/30641, WO 97/27749, WO 98/09948, WO 98/19672, WO 98/21193, WO 00/51988, WO 00/61604, WO 00/72838, WO 01/00563, WO 01/04082, WO 01/10814, WO 01/12584, WO 01/45703, WO 00/61541, WO 00/61537, WO 02/11707, WO 02/30866 and in Oae et al, Org. Prep. Proc. Int., 15(3): 165-198 (1983), the disclosures of each of which are incorporated by reference herein in their entirety. The methods of nitrosating and/or nitrosylating the compounds described in these references can be applied by one skilled in the art to produce any of the nitrosated and/or nitrosylated compounds described herein.
Known methods of linking the nitroxide group to compounds are described in U.S. Patent Nos. 6,448,267, 6,455,542, 6,759,430, and in WO 2004/050084, WO 03/088961, the disclosures of each of which are incorporated by reference herein in their entirety.
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. In contrast to the nitric oxide radical (NO*), nitrosonium (NO+) does not react with O2 or O2- species, and 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.
The term "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.
The term "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, hydroxylamines, N-hydroxyguanidines, hydroxyureas, benzofuroxanes, furoxans as well as substrates for the endogenous enzymes which synthesize nitric oxide.
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-aminoproρylammonio)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.
One group of NO adducts is the S-nitrosothiols, which are compounds that include at least one -S-NO group. These compounds include S-nitroso-polypeptides (the term "polypeptide" includes 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-nitrosothiols and methods for preparing them are described in U.S. Patent Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae et al, Org. Prep. Proc. Int., 15(3): 165-198 (1983), the disclosures of each of which are incorporated by reference herein in their entirety.
Another embodiment of the invention is 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. Such 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.
Other examples of suitable S-nitrosothiols include:
(i) HS(C(Re)(Rf))mSNO;
(ii) ONS(C(Re)(Rf))mRe; or
(iii) H2N-CH(CO2H)-(CH2)m-C(O)NH-CH(CH2SNO)-C(O)NH-CH2-CO2H; wherein m is an integer from 2 to 20;
Re and Rf 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 alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-V5, V6, -(C(R0)(Rp))H-U3-V5, -(C(R0)(Rp))Ic1-U3-V6, -(C(R0)(Rp))U-U3-C(O)-V6, or R6 and Rf taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, a hydrazone, a bridged cycloalkyl group,
Figure imgf000044_0001
R0 and Rp 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 alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-Vs, V6, or R0 and Rp taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, an imine, a hydrazone, a bridged cycloalkyl group,
Figure imgf000045_0001
ki is an integer form 1 to 3;
U3 is an oxygen, sulfur- or -N(R3)Ri;
V5 is -NO or -NO2 (i.e. an oxidized nitrogen);
Ra 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, -CH2-C(U3-V5)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom or -(N2O2-)""M1 +, wherein Mi+ is an organic or inorganic cation. In cases where Re and Rf are independently a heterocyclic ring or taken together Re and Rf 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 NaNO2 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.
Another group of 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 hydrocarbons; and ON-O-, ON-N- or ON-C- heterocyclic compounds. 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-nitroso-sydnonimines, 2H-l,3,4-thiadiazine nitrosimines.
Another group of NO adducts for use in the invention include nitrates that donate, transfer or release nitric oxide, such as compounds comprising at least one O2N-O-, O2N-N- or O2N-S- group. Among these compounds are O2N-O-, O2N-N- or O2N-S- polypeptides (the term "polypeptide" includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); O2N-O-, O2N-N- or O2N-S- amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); O2N-O-, O2N-N- or O2N-S- sugars; O2N-O-, O2N-N- or O2N-S- modified and unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); O2N-O-, O2N-N- or O2N-S- straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbons; and O2N-O-, O2N-N- or O2N-S- heterocyclic compounds. Examples of compounds comprising at least one O2N-O-, O2N-N- or O2N-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. 5,284,872, 5,428,061, 5,661,129, 5,807,847 and 5,883,122 and in WO 97/46521, WO 00/54756 and in WO 03/013432, the disclosures of each of which are incorporated by reference herein in their entirety.
Another group of NO adducts are N-oxo-N-nitrosoamines that donate, transfer or release nitric oxide and are represented by the formula: R1 R2 N-N(O-M+)-NO, where R1 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 M1 + 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. 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) iminomethylhydroxylaπiine, imino-2-l,2,3,4-tetrahydroisoquinolyl methylhydroxylamine, imino(l-methyl(2-l,2,3,4- tetrahydroisoquinolyl))methylhydroxylamine, (l,3-dimethyl(2-l,2,3,4-tetxahydroisoquinolyl)) iminomethylhydroxylamine, (((4-chlorophenyl)methyl) amino)iminomethylhydroxylamine, ((4-chlorophenyl)amino) iminomethylhydroxylamine, (4-chlorophenyl)(hydroxyimino) methylamine, and l-(4-chlorophenyl)-l-(hydroxyimino) ethane, and the like, precursors of L- arginine and/or physiologically acceptable salts thereof, including, for example, citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids, inhibitors of the enzyme arginase (e.g., N-hydroxy-L-arginine and 2(S)-amino-6- boronohexanoic acid), nitric oxide mediators and/or physiologically acceptable salts thereof, including, for example, pyruvate, pyruvate precursors, α-keto acids having four or more carbon atoms, precursors of α-keto acids having four or more carbon atoms (as disclosed in WO 03/017996, the disclosure of which is incorporated herein in its entirety), and the substrates for nitric oxide synthase, cytokines, adenosin, bradykinin, calreticulin, bisacodyl, and phenolphthalein. 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. Such compounds, include for example, 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti- hyperlipidemic compounds, H2 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.
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, fluprednisolone, flurandrenolide, fluticasone propionate, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, haloprednone acetate, hydrocortamate, hydrocortisone and its derivatives (such as phosphate, 21 -sodium succinate and the like), hydrocortisone terbutate, isoflupredone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paremethasone, prednicarbate, prednisolone and its derivatives (such as 21-stearoylglycolate, sodium phosphate and the like), prednisone, prednival, prednylidene and its derivatives (such as 21-diethylaminoactetate and the like), rimexolone, tixocortol, trimcinolone and its derivatives (such as acetonide, benetonide and the like), and the like. 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, 13th 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.
In some embodiments 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. 5,344,991, 5,380,738, 5,393,790, 5,409,944, 5,434,178, 5,436,265, 5,466,823, 5,474,995, 5,510,368, 5,536,752, 5,550,142, 5,552,422, 5,604,253, 5,604,260, 5,639,780, 5,932,598 and 6,633,272, and in WO 94/03387, WO 94/15723, WO 94/20480, WO 94/26731, WO 94/27980, WO 95/00501, WO 95/15316, WO 96/03387, WO 96/03388, WO 96/06840, WO 96/21667, WO 96/31509, WO 96/36623, WO 97/14691, WO 97/16435, WO 01/45703 and WO 01/87343, the disclosures of each of which are incorporated herein by reference in their entirety; and 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.
In some embodiments the COX-2 inhibitors are celecoxib, etoracoxib, lumiracoxib, paracoxib, rofecoxib or valdecoxib. In more particular embodiments 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; the valdecoxib is administered in an amount of about 10 milligrams to about 40 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, pranoprofen, protizinic acid, salicylamide, sulindac, suprofen, suxibuzone, tiaprofenic acid, tolmetin, xenbucin, ximoprofen, zaltoprofen, zomepirac, aspirin, acemetcin, bumadizon, carprofenac, clidanac, diflunisal, enfenamic acid, fendosal, flufenamic acid, flunixin, gentisic acid, ketorolac, meclofenamic acid, mefenamic acid, mesalamine, prodrugs thereof, and the like. 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, 13th 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.
In some embodiments the NSAIDs are acetaminophen, diclofenac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen or aspirin. In more particular embodiments 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 per day; the ketoprofen is administered in an amount of about 50 milligrams to about 300 milligrams as a single dose or as multiple doses per day; the naproxen is administered in an amount of about 250 milligrams to about 1.5 grams as a single dose or as multiple doses per day; the aspirin is administered in an amount of about 10 milligrams to about 2 grams as a single dose or as multiple doses per day.
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 LTB4 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 LTB4 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 A4 (LTA4) hydrolase inhibitors refer to compounds that selectively inhibit leukotiiene A4 hydrolase with an IC50 of less than about lOμM, and preferably with an IC50 of less than about 1 μM. Suitable LTA4 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-HT1 agonists, 5-HT1B agonists and 5-HT1D 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), VYTORIN™ (ezetimibe/simvastatin), GR-95030, SQ 33,600, BMY 22089, BMY 22,566, CI 980, and the like; gemfibrozil, cholystyramine, colestipol, niacin, nicotinic acid, bile acid sequestrants, such as, for example, cholestyramine, colesevelam, colestipol, poly(methyl-(3- trimethylaminopropyl) imino-trimethylene dihalide) and the like; probucol; fibric acid agents or fibrates, such as, for example, bezafibrate (Bezalip™), beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate (Lipidil™, Lipidil Micro™), gemfibrozil (Lopid™.), nicofibrate, pirifibrate, ronifibrate* simfibrate, theofibrate and the like; cholesterol ester transfer protein (CETP) inhibitors, such as for example, CGS 25159, CP-529414 (torcetrapid), JTT-705, substituted N-[3-(l,l,2,2-tetrafluoroethoxy)benzyl]-N-(3- phenoxyphenyl)-trifluoro-3-amino-2-propanols, N,N-disubstituted trifluoro-3-amino-2- propanols, PD 140195 (4-phenyl-5-tridecyl-4H- 1,2,4- triazole-3 -thiol), SC-794, SC-795, SCH 58149, and the like.
In some embodiments the anti-hyperlipidemic compounds are atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin. In more particular embodiments 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 is administered in an amount of about 5 milligrams to about 80 milligrams as a single dose or as multiple doses per day.
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, β- 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. 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 such as 2-amino-4H-l,3-benzothiazine-4-one, 2-guanidmo-4H-l,3-benzothiazin-4- one and rhodanine; N-hydroxyguanidine derivative such as, PR5 (l-(3, 4-dimethoxy-2- chlorobenzylideneamino)-3-hydroxyguanidine); 6-formylpterin, and the like. 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.
In some embodiments the antioxidants are apocynin, hydralazine compounds and superoxide dimutase mimetics.
Suitable hydralazine compounds include, but are not limited to, compounds having the formula:
Figure imgf000054_0001
wherein a, b and c are independently a single or double bond; Riand R2 are each independently a hydrogen, an alkyl, an ester or a heterocyclic ring, wherein alkyl, ester and heterocyclic rind are as defined herein; R3 and R4 are each independently a lone pair of electrons or a hydrogen, with the proviso that at least one of Ri, R2, R3 and R4 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.
In some embodiments the hydralazine compound is hydralazine or a pharmaceutically acceptable salt thereof such as hydralazine hydrochloride. In more particular embodiments 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 H2 receptor antagonists include, but are not limited to, burimamide, cimetidine, ebrotidin, famotidine, nizatidine, roxatidine, rantidine, tiotidine, and the like. Suitable H2 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, 13th 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. In a preferred embodiment of the invention, 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-
(aminoiminomethyl)-4-piperidinyl)methyl)-N-(3,3-diphenylρropinyl)-L-proline amide),3-(2- phenylethylamino)-6-methyl-l-(2-amino-6-methyl-5-methylene- carboxamidomethylpyridinyl)-2-pyrazinone, 3-(2-phenethylamino)-6-methyl- 1 -(2-amino-6- methyl-5- methylenecarboxamidomemylpyridinyl)-2-pyridinone, and the like. Suitable thrombin inhibitors are also described in WO 00/18352, the disclosure of which is incorporated herein by reference in its entirety.
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, 13th Edition; and on STN Express, file phar and file registry.
In some embodiments 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, chlorazanil, chlormerodrin, chlorthalidone, cicletanide, clofenamide, clopamide, clorexolone, conivaptan, daglutril, dichlorophenamide, disulfamide, ethacrynic acid, ethoxzolamide, etozolon, fenoldopam, fenquizone, furosemide, indapamide, mebutizide, mefruside, meralluride, mercaptomerin sodium, mercumallylic acid, mersalyl, methazolamide, meticane, metolazone, mozavaptan, muzolimine, N-(5-l,3,4-thiadiazol-2- yl)acetamide, nesiritide, pamabrom, paraflutizide, piretanide, protheobromine, quinethazone, scoparius, spironolactone, theobromine, ticrynafen, torsemide, torvaptan, triamterene, tripamide, ularitide, xipamide or potassium, AT 189000, AY 31906, BG 9928, BG 9791, C 292I5 DTI 0017, JDL 961, KW 3902, MCC 134, SLV 306, SR 121463, WAY 140288, ZP 120, and the like. 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, 13th Edition; and on STN Express, file phar and file registry.
Depending on the diuretic employed, 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.
In some embodiments the diuretics are amiloride, furosemide, chlorthalidone, hydrochlorothiazide or triamterene. In more particular embodiments 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, 13th Edition; and on STN Express, file phar and file registry.
Suitable inducible nitric oxide synthase (iNOS) inhibitors are disclosed in U. S. Patent Nos. 5,132,453 and 5,273,875, and in WO 97/38977 and WO 99/18960, the disclosures of each of which are incorporated by reference herein in their entirety.
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-204448, CT-3, CP- 99,994, CP-99,994, and mixtures of two or more thereof.
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, piroximone, milrinone, amrinone, tolafentrine, dipyridamole, papaveroline, E4021, thienopyrimidine derivatives, triflusal, ICOS-351, tetrahydropiperazino(l,2-b)beta-carboline-l,4-dione derivatives, carboline derivatives, 2- pyrazolin-5-one derivatives, fused pyridazine derivatives, quinazoline derivatives, anthranilic acid derivatives, imidazoquinazoline derivatives, tadalafil, vardenafil, and in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Ed.), McGraw-Hill, Inc. (1995), The Physician's Desk Reference (49th Ed.), Medical Economics (1995), Drug Facts and Comparisons (1993 Ed), Facts and Comparisons (1993), and the Merck Index on CD-ROM, 13th Edition; and the like. Phosphodiesterase inhibitors and their nitrosated and/or nitrosylated derivatives are also disclosed in U. S. Patent Nos. 5,932,538, 5,994,294, 5,874,437, 5,958,926 reissued as U.S. Patent No. RE 03772346,172,060, 6,197,778, 6,177,428, 6,172,068, 6,221,881, 6,232,321, 6,197,782, 6,133,272, 6,211,179, 6,316,457 and 6,331,542, the disclosures of each of which are incorporated herein by reference in their entirety.
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-b)pydridine, RO 18-5362, IY 81149, 4- amino-3-carbonyl quinoline, 4-amino-3-acylnaphthyride, 4-aminoquinoline, 4-amino-3- acylquinoline, 3-butyryl-4-(2-methylphenylamino)-8-(2-liydroxyethoxy)quinoline, quinazoline, tetrahydroisoquinolin-2-yl pyrimidine, YH 1885, 3-substituted 1,2,4- thiadiazolo(4,5-a) benzimidazole, 3-substituted imidazo(l,2-d)-thiadiazole, 2- sulfinylnicotinamide, pyridylsulfinylbenz imidazole, pyridylsulfinyl thieno imidazole, theinoimidazole-toluidine, 4,5-dihydrooxazole, thienoimidazole-toluidine, Hoe-731, imidazo(l,2-a)pyridine, pyrrolo(2,3-b)pyridine, and the like. 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, 13th 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. For example, 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. In another embodiment, 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. In another embodiment, 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H2 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. In another embodiment, 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. In one embodiment the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H2 antagonist. In another embodiment 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. Such 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, head injury, severe body trauma or burns. For example, 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. In another embodiment, 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. In another embodiment, 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H2 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. In another embodiment, 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. In one embodiment the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H2 antagonist. In another embodiment 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.
Yet another embodiment of the invention provides methods for facilitating wound healing (such as, for example, ulcer healing, bone healing including osteoporosis) by administering to the patient in need thereof an effective amount of the compounds and/or compositions described herein. 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. For example, 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. In another embodiment, 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. In another embodiment, 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H2 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. In another embodiment, 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. In one embodiment the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H2 antagonist. In another embodiment 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. For example, 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. In another embodiment, 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. In another embodiment, 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H2 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. In another embodiment, 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. For example, 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. In another embodiment, 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. In another embodiment, 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H2 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. In another embodiment, 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. In one embodiment the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H2 antagonist. In another embodiment 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 (e.g., COX-2 mediated disorders) 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, lung cancer, breast cancer and skin cancer, such as squamus cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body, benign and cancerous tumors, growths, polyps, adenomatous polyps, including, but not limited to, familial adenomatous polyposis, fibrosis resulting from radiation therapy, and the like; treatment of inflammatory processes in diseases, such as, for example, vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like; treatment of ophthalmic diseases and disorders, such as, for example, retinitis, retinopathies, uveitis, ocular photophobia, acute injury to the eye tissue, glaucoma, inflammation of the eye and elevation of intraocular pressure and the like; treatment of pulmonary inflammation, such as, for example, those associated with viral infections and cystic fibrosis, and the like; treatment of central nervous system disorders, such as, for example, cortical dementia including Alzheimer's disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia, senile dementia, and central nervous system damage resulting from stroke, ischemia and trauma, and the like; treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis; treatment of inflammations and/or microbial infections including, for example, inflammations and/or infections of the eyes, ears, nose, throat, and/or skin; treatment and/or prevention of cardiovascular disorders, such as, for example, coronary artery disease, aneurysm, arteriosclerosis, atherosclerosis, including, but not limited to, cardiac transplant atherosclerosis, myocardial infaractioη, hypertension, ischemia, embolism, stroke, thrombosis, venous thrombosis, thromboembolism, thrombotic occlusion and reclusion, restenosis, angina, unstable angina, shock, heart failure, coronary plaque inflammation, bacterial-induced inflammation, such as, for example, Chlamydia- induced inflammation, viral induced inflammation, inflammation associated with surgical procedures, such as, for example, vascular grafting, coronary artery bypass surgery, revascularization procedures, such as, for example, angioplasty, stent placement, endarterectomy, vascular procedures involving arteries, veins, capillaries, and the like; treatment and/or prevention of urinary and/or urological disorders, such as, for example, incontinence and the like; treatment and/or prevention of endothelial dysfunctions, such as, for example, diseases accompanying these dysfunctions, endothelial damage from hypercholesterolemia, endothelial damage from hypoxia, endothelial damage from mechanical and chemical noxae, especially during and after drug, and mechanical reopening of stenosed vessels, for example, following percutaneous transluminal angiography (PTA) and percuntaneous transluminal coronary angiography (PTCA), endothelial damage in postinfarction phase, endothelium-mediated reocculusion following bypass surgery, blood supply distrubances in peripheral arteries, as well as, cardiovascular diseases, and the like; methods for treating and/or preventing tissue deterioration, such as, for example, for organ transplants, and the like; disorders treated by the inhibition and/or prevention of activation, adhesion and infiltration of neutrophils at the site of inflammation; and disorders treated by the inhibition and/or prevention of platelet aggregation. In one embodiment of the invention, the disorder is platelet aggregation. The compounds and compositions of the invention can also be used as a pre-anesthetic medication in emergency operations to reduce the danger of aspiration of acidic gastric contents.
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. For example, 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. In another embodiment, 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. In another embodiment, 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti- hyperlipidemic compounds, H2 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. In another embodiment, 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. In one embodiment the at least one therapeutic agent is selected from the group consisting of an NSAID, a proton pump inhibitor and an H2 antagonist. In another embodiment 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.
When administered separately, the 2-methyl indole COX-2 selective inhibitor, that is optionally substituted with at lest one nitric oxide enhancing group, 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.
When administered in vivo, the compounds and compositions of the invention can be administered in combination with pharmaceutically acceptable carriers and in dosages described herein. When 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. The 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. In one embodiment of the invention 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, which is known to one skilled in the art, 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. For example, 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. In such dosage forms, 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. In addition, the compositions can contain polyethylene glycol 400. They 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.
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. In a particular embodiment, 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. S. Patent Nos. 5,262,165, 5,948,433, 6,010,715 and 6,071,531, the disclosure of each of which are incorporated herein in their entirety.
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. In such solid dosage forms, 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. In the case of capsules, tablets, effervescent tablets, and pills, 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, such as for treating pediatric fever and the like, 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.
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. Among the 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.
The 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. For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Aqueous suspensions may contain substances which increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol and/or dextran. Optionally, the suspension may also contain stabilizers.
The composition, if desired, 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). 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. Appropriate 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. Alternatively, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. Additionally for sterile ophthalmic ointment formulations, 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.
The bioavailability of the 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. For example, 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.
Particular sustained release dosage forms of the invention 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.
In a particular embodiment, the compositions of the invention are orally administered as a sustained release tablet or a sustained release capsule. For example, 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
While individual needs may vary, determination of optimal ranges for effective amounts of the compounds and/or compositions is within the skill of the art. Generally, the dosage required to provide an effective amount of the compounds and compositions, which can be adjusted by one of ordinary skill in the art, 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. For example, 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. Associated with such 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 B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, anti-hyperlipidemic compounds, H2 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 a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products which reflects approval by the agency of manufacture, use or sale for humans.
EXAMPLES
The following non-limiting examples further describe and enable one of ordinary skill in the art to make and use the invention.
Example 1. l-[(4-ChlorophenyI)carbonyl]-2-methyl-3-({N-[3-(nitrooxy) propyljcarbamoyljmethyOindol-S-yl aminosuIfonate
Ia. 2-{ l-[(4-Chlorophenyl)carbonyl]-5-hydroxy-2-methylindol-3-yl}acetic acid
Figure imgf000073_0001
A solution of BBr3 (54 rnL, IM in CH2Cl2, 54 mmol) was added slowly to an ice-cold solution of indomethacin (9.4 g, 26.3 mmol) in CH2Cl2 (100 mL) and stirred at room temperature overnight. The resulting mixture was poured into crushed ice (250 g) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The resulting solid was washed with Et2O and dried under vacuum to give the title compound as a yellow solid (6.49 g, 72% yield); mp >205 °C (with decomposition); 1H NMR (300 MHz, CD3OD) δ 7.65 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 2.4 Hz, IH), 6.82 (d, J = 8.9 Hz, IH), 6.54 (dd, J = 8.9 and 2.4 Hz, IH), 3.62 (s, 2H), 2.34 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 175.2, 170.0, 154.6, 140.0, 136.6, 135.9, 132.5, 132.3, 131.8, 130.2, 115.9, 114.6, 113.0, 104.5, 30.8, 13.5; Mass Spectrum (API-TIS) mlz 344 (MH+). Anal, calcd for C18H14CINO4: C, 62.89; H, 4.10; N, 4.07; Found: C, 62.59; H, 3.95; N, 3.98.
Ib. 2-{ l-[(4-Chlorophenyl)carbonyl]-5-hydroxy-2-methylindol-3-yl}-N-[3- (nitrooxy)propyl] acetamide
Figure imgf000073_0002
A solution of the product of Example Ia (1.46 g, 4.3 mmol), 3-(nitrooxy)propylamine nitric acid salt (0.87 g, 4.8 mmol, prepared as described in WO 2005/030135 A2, Example 8a), DMAP (100 mg, 0.82 mmol), EDAC (1.07 g, 5.6 mmol) and NEt3 (1.8 mL, 12.9 mmol) in CH2Cl2 (50 mL) were stirred at room temperature for 4 hours. The reaction mixture was partitioned between 3N HCl (30 mL) and CH2Cl2 (50 mL x 2). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in EtOAc (5 mL) and CH2Cl2 (5 mL) and triturated with Et2O (80 mL). The solid was collected and dried under vacuum to give the title compound as a white solid (0.89 g, 47% yield); mp 135-137 °C; 1H NMR (300 MHz, DMSO-d6) δ 9.19 (s, IH), 8.02 (br t, IH), 7.67 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.8 Hz, IH), 6.84 (d, J = 2.1 Hz, IH), 6.54 (dd, J = 8.9, 2.4 Hz, IH), 4.47 (t, / = 6.4 Hz, 2H), 3.43 (s, 2H), 3.13 (br q, 2H), 2.19 (s, 3H), 1.85-1.70 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 169.8, 167.9, 153.4, 137.5, 134.9, 134.5, 131.1, 129.6, 129.1, 114.6, 114.0, 112.0, 103.7, 71.7, 35.3, 31.3, 26.5, 13.4; Mass Spectrum (API-TIS) mlz 446 (MH+). Ic. l-[(4-Chlorophenyl)carbonyl]-2-methyl-3-({N-[3-(nitrooxy)-propyl]carbamoyl} methyl)indol-5-yl aminosulfonate
Figure imgf000074_0001
A solution of sulfamoyl chloride (0.19 g, 1.7 mmol), and the product of Example Ib (0.19 g, 0.42), in N-methyl-2-pyrrolidinone (NMP, 3 mL) were stirred at room temperature for 4 hours. The reaction was quenched with brine and extracted with a mixture of EtOAc (20 mL) and CHCI3 (50 mL). The organic extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in CHCI3 (50 mL) and stirred with water (30 mL) overnight to remove trace amount of NMP. The white solid suspended in CHCI3 layer was collected and dried under vacuum (0.105 g, 48 % yield); mp 146-148 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.11 (br t, IH), 7.90 (br s, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 2.1 Hz, IH), 7.11 (d, J = 8.9 Hz, IH), 7.01 (dd, J = 8.9, 2.1 Hz, IH), 4.47 (t, J= 6.2 Hz, 2H), 3.52 (s, 2H), 3.13 (br q, 2H), 2.22 (s, 3H), 1.85-1.70 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 169.8, 167.9, 153.4, 137.5, 134.9, 134.5, 131.1, 129.6, 129.1, 114.6, 114.0, 112.0, 103.7, 71.7, 35.3, 31.3, 26.5, 13.4; Mass Spectrum (API-TIS) m/z 525 (MH+). Anal, calcd for C21H2 IClN4O8S: C, 48.05; H, 4.03; N,
10.67; Found: C, 48.05; H, 3.94; N, 10.46.
Example 2. 2-{l-[(4-ChIorophenyl)carbonyl]-5-hydroxy-2-methylindol-3-yl}-N-(3- hydroxypropyl)acetamide
Figure imgf000075_0001
A solution of the product of Example Ia (0.84 g, 2.4 mmol), 3-amino-l-propanol (0.2 niL, 2.6 mmol), DMAP (35 mg, 0.29 mmol), EDAC (0.57 g, 2.97 mmol) and NEt3 (0.37 niL, 2.7 mmol) in CH2Cl2 (100 mL) were stirred at room temperature overnight. The reaction mixture was partitioned between 3N HCl (30 mL) and CH2Cl2 (50 mL x 2). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography eluting with MeOHZCHCl3 (gradient from 1:20 to 1:15) to give the title compound (0.56 g, 57% yield); 1H NMR (300 MHz, 10% CD3OD/CDC13) δ 7.65 (d, J= 8.5 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 6.81-6.80 (m, 2H), 6.68 (br t, IH), 6.61 (dd, J = 8.9, 2.4 Hz, IH), 3.57 (s, 2H), 3.54 (t, J = 5.8 Hz, 2H), 3.32 (q, J = 5.8 Hz, 2H), 2.36 (s, 3H), 1.70-1.55 (m, 2H); 13C NMR (75 MHz, 10% CDsOD/CDCls) δ 171.8, 168.6, 153.1, 139.4, 136.0, 133.6, 131.0, 130.4, 130.3, 129.1, 115.0, 112.5, 102.8, 59.5, 36.9, 31.9, 31.4, 13.0; Mass Spectrum (API-TIS) mlz 401 (MH+). Example 3. 2-{6-Chloro-l-[(4-chlorophenyI)carbonyl]-5-methoxy-2-methylindol-3-yl}-
N-[3-(nitrooxy)propyl]acetamide 3a. 3-Chloro-4-methoxyphenylhydrazine Hydrochloride
Figure imgf000075_0002
A solution of NaNO2 (4.77 g, 69.1 mmol) in water (15 mL) was added to an ice-cold mixture of 3-chloro-p-anisidine in 6N HCl (100 mL) and stirred for 20 minutes. The resulting solution was added slowly to a solution of SnCl2»2H2O in concentrated HCl (250 mL) at ~5°C and the mixture stirred at room temperature for 1 hour. The crude material was collected by filtration and dissolved in MeOH (500 mL), dried over Na2SO4, filtered, and concentrated. The resulting yellow solid was washed with Et2O (300 mL) and dried under vacuum to give the title compound (13.62 g, 99% yield); 1H NMR (300 MHz, DMSO-d6) δ 10.40 (br, 4H), 7.24 (d, J = 2.1 Hz, IH), 7.20-7.00 (m, 2H), 3.80 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 149.8, 139.6, 121.2, 117.4, 115.4, 113.5, 56.4. 3b. Phenylmethyl 2-(6-chloro-5-methoxy-2-methylindol-3-yl)acetate 3c. Phenylmethyl 2-(4-chloro-5-methoxy-2-methylindol-3-yl)acetate
Figure imgf000076_0001
Benzyl levulinate (7.23 g, 35.1 mmol) and the product of Example 3a (7.53 g, 36.0 mmol) were heated to reflux in acetic acid (100 mL) for 3 hours. After cooling to room temperature, acetic acid was removed under vacuum. The residue was partitioned between water (100 mL) and EtOAc (100 mL x 2). The combined organic extracts were washed with saturated NaHCO3, 3N HCl, water, brine, dried Na2SO4, filtered and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (gradient form 1:3 to 1:2, R/= 0.2, 0.1). The more polar compound is Example 3c (1.96 g, 16 % yield); mp 124-125 0C; 1H NMR (300 MHz, CDCl3) δ 7.93 (br, IH), 7.4-7.3 (m, 5H), 6.98 (d, J= 8.7 Hz, IH), 6.78 (d, J = 8.7 Hz, IH), 5.17 (s, 2H), 3.99 (s, 2H), 3.88 (s, 3H), 2.21 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.0, 148.9, 136.0, 135.7, 131.7, 128.4, 128.0, 125.9, 112.7, 109.1, 108.7, 103.9, 66.5, 55.9, 30.7, 11.3; Mass Spectrum (API-TIS) m/z 344 (MH+). The less polar compound is Example 3b (4.11 g, 33% yield) and was recrystallized from Et2O and hexane; mp 94-95 0C; 1H NMR (300 MHz, CDCl3) δ 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); 13C NMR (75 MHz, CDCl3) δl71.8, 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 Ci9H18ClNO3: C, 66.38; H, 5.28; N, 4.07; Found: C, 66.14; H, 5.22; N, 4.11.
3d. Phenylmethyl 2- { 6-chloro- 1 - [(4-chlorophenyl)carbonyl] -5-methoxy-2-methylindol-3- yl} acetate
Figure imgf000076_0002
A solution of the product of Example 3b (0.68 g, 2.0 mmol), 4-chlorobenζoyl chloride (0.28 mL, 2.2 mmol), DMAP (0.12 g, 1.0 mmol) and NEt3 (1.5 mL, 10.8 mmol) in CH2Cl2 (20 mL) were stirred at room temperature for 24 hours. The reaction mixture was partitioned between 3N HCl (10 mL) and CH2Cl2 (100 mL). The organic layer was washed with 3N HCl, water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (1:3, R/= 0.3) to give the title compound as a white solid (0.75 g, 79% yield); mp 104-105 °C; 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.34-7.20 (m, 5H), 7.20 (s, IH), 6.94 (s, IH), 5.13 (s, 2H), 3.81 (s, 3H), 3.69 (s, 2H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.2, 167.8, 151.3, 139.2, 135.5, 135.4, 133.3, 130.9, 130.1, 129.0, 128.7, 128.3, 128.2, 128.0, 118.8, 115.6, 112.1, 100.6, 66.6, 56.1, 30.2, 13.3; Mass Spectrum (API-TIS) mlz 482 (MH+). Anal, calcd for C26H21Cl2NCH: C, 64.74; H, 4.39; N, 2.90;
Found: C, 64.61; H, 4.42; N, 2.74.
3e. 2- { 6-Chloro- 1 - [(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3 -yl } acetic acid
Figure imgf000077_0001
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. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with CH2Cl2MeOH (20:1, R/= 0.1) to give the title compound (0.26 g, 87% yield); mp 69-71 0C; 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J= 8.5 Hz, 2H), 7.47 (d, J= 8.5 Hz, 2H), 7.15 (s, IH), 6.97 (s, IH), 3.93 (s, 3H), 3.66 (s, 2H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) 5 176.8, 168.0, 151.6, 139.7, 136.0, 133.2, 131.1, 130.2, 129.2, 128.7, 119.2, 115.8, 111.5, 100.6, 56.5, 30.0, 13.4; Mass Spectrum (API-TIS) m/z 392 (MH+). f . 2- { 6-Chloro- 1 - [(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3 -yl } -N- [3-
(nitrooxy)propyl] acetamide
Figure imgf000077_0002
Figure imgf000078_0001
A solution of the product of Example 3e (1.11 g, 2.8 mmol), 3-(nitrooxy)propylamine nitric acid salt (0.51 g, 3.1 mmol, prepared as described in WO 2005/030135 A2, Example 8a), DMAP (63 mg, 0.5 mmol), EDAC (0.71 g, 3.7 mmol) and NEt3 (1.4 mL, 10.0 mmol) in CH2Cl2 (150 mL) were stirred at room temperature for 5 hours. The reaction mixture was partitioned between 3N HCl (50 mL) and CH2Cl2 (50 mL x 2). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeOH (5 mL) and triturated with Et2O (80 mL). The solid was collected, washed with 5% MeOH/Et2O and dried under vacuum to give the title compound as a yellow solid (0.61 g, 59% yield); mp 154-155 °C; 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.15 (s, IH), 6.92 (s, IH), 5.73 (br, t, IH), 4.42 (t, J = 6.2 Hz, 2H), 3.92 (s, 3H), 3.64 (s, 2H), 3.34 (br q, 2H), 2.33 (s, 3H), 2.00-1.85 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 169.5, 167.8, 151.0, 137.7, 135.5, 133.9, 131.2, 129.7, 129.6, 129.0, 117.2, 115.2, 114.1, 101.6, 71.6, 56.4, 35.2, 31.1, 26.4, 13.5; Mass Spectrum (API-TIS) m/z 494 (MH+). Example 4. Phenylmethyl 2-{4-chloro-l-[(4-chlorophenyI)carbonyl]-5-methoxy-2- ate
Figure imgf000078_0002
A solution of the product of Example 3c (1.25 g, 3.6 mmol), 4-chlorobenzoyl chloride (0.55 mL, 4.3 mmol), DMAP (0.23 g, 1.9 mmol) and NEt3 (2.6 mL, 18.7 mmol) in CH2Cl2 (20 mL) were stirred at room temperature for 24 hours. The reaction was partitioned between 3N HCl (50 mL) and CH2Cl2 (100 mL). The organic layer was washed with 3N HCl, water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The crude material was dissolved in CH2Cl2 (2 mL) and triturated with Et2O (70 mL). The light colored solid was collected, washed with Et2O and dried under vacuum to give the title compound (1.52 g, 87 % yield); mp 147-148 0C; 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 8.5 Hz, 2H), 7.45 (d, J= 8.5 Hz, 2H), 7.33 (m, 5H), 6.99 (d, J = 9.0 Hz, IH), 6.73 (d, J= 9.0 Hz, IH), 5.18 (s, 2H), 4.05 (s, 2H), 3.87 (s, 3H), 2.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.2, 168.1, 151.3, 139.6, 137.3, 135.9, 133.6, 132.1, 131.2, 129.2, 128.5, 128.1, 127.6, 113.3, 112.7, 112.2, 108.9, 66.8, 57.2, 31.0, 13.2; Mass Spectrum (API-TIS) mlz 482 (MH+). Example 5. 2-{l-[(4-ChIorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-(3- hydroxypropyl)acetamide
Figure imgf000079_0001
A solution of indomethacin (1.55 g, 4.3 mmol), 3-aminopropan-l-ol (0.35 mL, 4.6 mmol), DMAP (65 mg, 0.5 mmol), EDAC (1.02 g, 5.3 mmol) and NEt3 (1.2 mL, 8.6 mmol) in CH2Cl2 (70 mL) were stirred at room temperature overnight. The reaction was partitioned between 3N HCl (50 mL) and CH2Cl2 (100 mL). The organic layer was washed with 3N HCl, water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was purified by silica gel column chromatography eluting with MeOH/CHCl3 (1:15, R/= 0.25) to give the title compound as a light colored solid (1.23 g, 68% yield); mp 106-107 °C; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 2.2 Hz, IH), 6.85 (d, J = 9.0 Hz, IH), 6.66 (dd, J = 9.0 and 2.2 Hz, IH), 6.48 (br t, IH), 3.80 (s, 3H), 3.61 (s, 2H), 3.54 (t, J= 5.4 Hz, 2H), 3.45 (br, IH), 3.32 (br q, 2H), 2.35 (s, 3H), 1.30-1.20 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 170.9, 168.2, 156.1, 139.3, 136.2, 133.4, 131.0, 130.7, 130.3, 129.0, 115.0, 112.7, 112.0, 100.8, 59.4, 55.6, 36.6, 31.8, 31.7, 13.1; Mass Spectrum (API-TIS) mlz 415 (MH+). Anal, calcd for C22H23ClN2O4: C, 63.69; H, 5.59;
N, 6.75; Found: C, 63.38; H, 5.56; N, 6.65.
Example 6. 2-{l-[(4-ChIorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-(4- hydroxybutyl)acetamide
Figure imgf000079_0002
A solution of indomethacin (1.6 g, 4.5 mmol), 4-aminobutan-l-ol (1.02 g, 4.7 mmol), DMAP (0.12 g, 1.0 mmol), EDAC (0.97 g, 5.1 mmol) and NEt3 (1.5 mL, 10.8 mmol) in CH2Cl2 (60 mL) were stirred at room temperature for 6 hours. The reaction was partitioned between3N HCl (50 mL) and CH2Cl2 (100 mL). The organic layer was washed with 3N HCl, water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was purified by silica gel column chromatography eluting with MeOHyCHCl3 (1:15, R/= 0.17). The product was further purified by washing with EtOAc and Et2O to give the title compound as a light colored solid (1.02 g, 53% yield); mp 134-136 0C; 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 2.0 Hz, IH), 6.86 (d, J = 9.0 Hz, IH), 6.69 (dd, J = 9.0 and 2.0 Hz, IH), 6.0 (br t, IH), 3.81 (s, 3H), 3.62 (s, 2H), 3.55 (t, J = 5.4 Hz, 2H), 3.23 (br q, 2H), 2.58 (s, 3H), 1.30-1.20 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 170.0, 168.4, 156.2, 139.6, 136.3, 133.5, 131.2, 130.9, 130.3, 129.2, 115.0, 112.9, 112.1, 101.0, 62.1, 55.7, 39.3, 32.2, 29.6, 26.1, 13.2; Mass Spectrum (API-TIS) mlz 429 (MH+). Anal, calcd for C23H25CIN2O4: C, 64.41; H, 5.87; N, 6.53; Found: C, 64.26; H,
5.56; N, 6.39.
Example 7. 2-{l-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-[3- (nitrooxy)propyl]acetamide
Figure imgf000080_0001
A solution of indomethacin (1.55 g, 4.3 mmol), 3-(nitrooxy)propylamine nitric acid salt (0.78 g, 5.0 mmol, prepared as described in WO 2005/030135 A2, Example 8a), DMAP (125 mg, 1.02 mmol), EDAC (1.09 g, 5.7 mmol) and NEt3 (1.6 mL, 11.5 mmol) in CH2Cl2 (60 mL) were stirred at room temperature for 3.5 hours. The reaction mixture was partitioned between 3N HCl (50 mL) and CH2Cl2 (100 mL). The organic extract was washed with 3N HCl, water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The crude material was dissolved in CH2Cl2 (3 mL) and triturated with Et2O (60 mL). The solid was collected and dried under vacuum to give the title compound as a yellow solid (1.17 g, 59% yield); mp 122-124 0C; 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 6.88 (d, / = 2.3 Hz, IH), 6.85 (d, J = 9.0 Hz, IH), 6.69 (dd, J = 9.0 and 2.3 Hz, IH), 5.86 (br t, IH), 4.39 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.65 (s, 2H), 3.31 (br q, 2H), 2.39 (s, 3H), 1.90-1.85 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 170.3, 168.3, 156.3, 139.6, 136.5, 133.5, 131.1, 130.9, 130.2, 129.2, 115.2, 112.5, 112.2, 100.8, 70.9, 55.7, 36.4, 32.2, 28.6, 27.0, 13.2; Mass Spectrum (API-TIS) mlz 460 (MH+). Anal, calcd for C22H22CIN3O6: C, 57.46; H, 4.82; N, 9.14; Found: C, 57.74; H, 4.88; N, 8.78. Example s. N-[2,2-Dimethyl-3-(nitrooxy)propyl]-2-{l-[(4-chlorophenyl)-carbonyl]-5- methoxy-2-methyϊindoI-3-yI}acetamide
Figure imgf000081_0001
A solution of indomethacin (1.15 g, 3.2 mmol), 2,2-dimethyl-3- (nitrooxy)propylamine nitric acid salt (0.70 g, 3.3 mmol, prepared as described in WO 2005/030135 A2, Example 9a), EDAC (0.74 g, 3.9 mmol) and NEt3 (0.95 mL, 6.8 mmol) in CH2Cl2 (40 mL) were stirred at room temperature for 2 hours. The reaction was partitioned between 3N HCl (50 mL) and CH2Cl2 (100 mL). The organic layer was washed with 3N HCl, water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The crude material was dissolved in CH2Cl2 (3 mL) and triturated with Et2O (60 rnL). The solid was collected, washed with MeOH and dried under vacuum to give the title compound as a white solid (0.57g, 37% yield); mp 148 °C (with decomposition); 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 8.5 Hz, 2H), 7.49 (d, / = 8.5 Hz, 2H), 6.90 (d, J = 2.4 Hz, IH), 6.86 (d, J = 9.0 Hz, IH), 6.69 (dd, J = 9.0 and 2.4 Hz, IH), 5.80 (br t, IH), 4.08 (s, 2H), 3.81 (s, 3H), 3.67 (s, 2H), 3.16 (br d, 2H), 2.42 (s, 3H), 0.89 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 170.3, 168.2, 156.3, 139.5, 136.4, 133.5, 131.1, 130.9, 130.1, 129.1, 115.2, 112.5, 112.3, 100.7, 79.1, 55.6, 46.6, 35.7, 32.1, 22.2, 13.1. Mass Spectrum (API-TIS) m/z 488 (MH+). Example 9. N-{l,l-Bis[(nitrooxy)methyl]-2-(nitrooxy)ethyl}-2-{l-[(4-chlorophenyl)- carbonyl]-5-methoxy-2-methylindol-3-yl}acetamide 9a. l,3-Bis(nitrooxy)-2-[(nitrooxy)methyl]prop-2-ylamine hydrochloride
Figure imgf000081_0002
The title compound was synthesized as described in US 2,975,208.
9b. N-{ l,l-Bis[(nitrooxy)methyl]-2-(nitrooxy)ethyl}-2-{ l-[(4-chlorophenyl)-carbonyl]-5- methoxy-2-methylindol-3 -yl } acetamide
Figure imgf000082_0001
Oxalyl chloride (0.19 mL, 2.2 mmol) was added to an ice-cold solution of indomethacin (0.6 g, 1.7 mmol) in CH2Cl2 (50 mL) and DMF (10 μL) 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 CH2Cl2 (50 mL). The product of Example 9a was added to the above solution, followed by the addition of NEt3 (0.5 mL, 3.6 mmol) and stirred at room temperature for 3 hours. The reaction was partitioned between 3N HCl (50 mL) and CH2Cl2 (100 mL x 2). The combined organic extracts were washed with water, saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (1:3, R/= 0.2). The resulting yellow solid, after evaporation of the solvents, was washed with Et2O and dried under vacuum to give the title compound as a white solid (0.16 g, 16 % yield); mp >122 °C (with decomposition); 1H NMR (300 MHz, Acetone-d6) δ 7.75 (d, J = 8.4 Hz, 2H), 7.72 (br, IH), 7.62 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 2.4 Hz, IH), 7.02 (d, J= 9.0 Hz, IH), 6.70 (dd, J = 9.0 and 2.4 Hz, IH), 5.04 (s, 6H), 3.82 (s, 3H), 3.70 (s, 2H), 2.31 (s, 3H); 13C NMR (75 MHz, Acetone-d6) δ 171.9, 168.9, 157.2, 139.2, 136.7, 133.6, 132.1, 131.9, 131.8, 129.9, 115.7, 114.1, 112.6, 102.0, 70.8, 57.2, 55.9, 32.5, 13.6; Mass Spectrum (API-TIS) mlz 596 (MH+). Example 10. (2-{l- [(4-Chϊorophenyl)carbonyl]-5-methoxy-2-methylindol-3- yljacetylamino) acetate 10a. 2- { 1 - [(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3 -yl } ethanehydroxamic
Figure imgf000082_0002
Oxalyl chloride (0.8 mL, 9.2 mmol) was added to an ice-cold solution of indomethacin (2.51 g, 7.0 mmol) in CH2Cl2 (50 mL) and DMF (20 μL) 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 CH2Cl2 (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. To the reaction mixture was added 3N HCl (100 mL) and the solid that precipitated out was collected, washed with CH2Cl2 and Et2O, dried under vacuum to give a white solid (1.04 g, 40 % yield); 1H NMR (300 MHz, DMSO-d6) δ 10.60 (s, IH), 8.70 (br, IH)5 7.68-7.65 (m, 4H), 7.15 (d, J = 2.3 Hz, IH), 6.92 (d, / = 9.0 Hz, IH), 6.71 (dd, J = 9.0 and 2.3 Hz, IH), 3.77 (s, 3H), 3.40 (s, 2H), 2.25 (s, 3H); 13C NMR (75 MHz, DMSO- d6) δ 167.9, 166.4, 155.5, 137.6, 135.3, 134.2, 131.2, 130.8, 130.3, 129.1, 114.5, 113.8, 111.2, 102.1, 55.5, 28.4, 13.3; Mass Spectrum (API-TIS) mlz 373 (MH+). 10b. (2- { 1 -[(4-Chlorophenyl)carbonyl] -5-methoxy-2-methylindol-3-yl } acetylamino) acetate
Figure imgf000083_0001
A solution of the product of Example 10a (0.49 g, 1.3 mmol), DMAP (20 mg) and acetic anhydride (0.16 mL, 1.7 mmol) in DMSO (5 mL) were stirred at room temperature for 3 days. The solvents were evaporated under vacuum. The residue was dissolved in EtOAc (60 mL), washed with 3N HCl, water, brine dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography eluting with MeOHZCHCl3 (1:20, R/= 0.3). The crude purified material was washed with MeOH to give the title compound as a solid (0.24 g, 44% yield); mp 153-156 0C; 1H NMR (300 MHz, CDCl3) δ 9.10 (br, IH), 7.62 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 2.3 Hz, IH), 6.90 (d, J = 9.0 Hz, IH), 6.69 (dd, J = 9.0 and 2.3 Hz, IH), 3.84 (s, 3H), 3.73 (s, 2H), 2.38 (s, 3H), 2.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.4, 168.3, 156.2, 139.4, 136.4, 133.4, 131.1, 130.8, 130.1, 129.1, 115.0, 112.3, 111.1, 100.9, 55.6, 29.4, 18.0, 13.2; Mass Spectrum (API-TIS) mlz 415 (MH+). Anal, calcd for C21H19ClN2O5: C, 60.80; H, 4.62; N, 6.75; Found: C, 66.53; H, 4.62; N, 6.48.
Example 11. (N-AcetyI-2-{l-[(4-chIorophenyI)carbonyI]-5-methoxy-2-methyIindol-3- yl}acetylamino) acetate
Figure imgf000084_0001
A solution of the product of Example 10a (0.42 g, 1.13 mmol) in a mixture of THF (10 mL), DMSO (2 mL) and acetic anhydride (5 mL) were stirred at room temperature overnight. The solvents were evaporated under vacuum. The residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO3, 3N HCl, water, brine, dried over Na2SO4, filtered, and concentrated. The residue was triturated with Et2O and the solid was collected, dried under vacuum to give the title compound (0.32 g, 61 % yield); mp 156-158 °C; 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 8.4 Hz, 2H), 7.46 (d, / = 8.4 Hz, 2H), 6.87 (d, J = 9.0 Hz, IH), 6.84 (d, J = 2.3 Hz, IH), 6.66 (dd, J= 9.0 and 2.3 Hz, IH), 4.06 (br s, 2H), 3.82 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.2, 167.9, 167.4, 155.1, 139.2, 136.4, 133.8, 131.2, 130.8, 130.5, 129.1, 115.0, 111.8, 111.2, 101.0, 55.7, 32.2, 24.3, 17.9, 13.4; Mass Spectrum (API-TIS) mlz 457 (MH+). Anal, calcd for C23H21C1N2O6: C, 60.47; H, 4.63; N, 6.13; Found: C, 66.50; H, 4.73; N, 5.92.
Example 12. 2-{l-[(4-chlorophenyI)carbonyl]-5-methoxy-2-methylindol-3-yl}-N- (phenylmethoxy)acetamide
Figure imgf000084_0002
A solution of indomethacin (4.01 g, 11.2 mmol), O-benzylhydroxyamine (0.70 g, 3.3 mmol), EDAC (2.76 g, 14.4 mmol) and NEt3 (3.6 mL, 25.8 mmol) in CH2Cl2 (100 mL) were stirred at room temperature overnight. The reaction was partitioned between 3N HCl (100 mL) and CH2Cl2 (100 mL). The organic layer was washed with 3N HCl, water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (1:1, R/= 0.2). The resulting yellow solid, after evaporation of solvents, was washed with Et2O, dried under vacuum to give the title compound as a white solid (1.98 g, 38% yield); mp 152-153 °C (with decomposition); 1H NMR (300 MHz, CDCl3) δ 8.30 (br, IH), 7.57 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.40-7.20 (m, 5H), 6.88 (d, J = 2.4 Hz, IH), 6.83 (d, J = 9.0 Hz, IH), 6.69 (dd, J = 9.0 and 2.4 Hz, IH), 4.84 (s, 2H), 3.80 (s, 3H), 3.58 (s, 2H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.2, 167.3, 156.2, 139.5, 136.1, 134.7, 133.5, 131.1, 130.8, 129.3, 129.1, 128.7, 128.5, 115.0, 112.1, 111.5, 100.9, 78.2, 55.7, 29.2, 13.2; Mass Spectrum (API-TIS) ml z 463 (MH+). Example 13. 2-{l-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindoI-3-yl}-N-(2- hydroxyethoxy)acetamide 13a. 2-(2-Hydroxyethoxy)benzo[c]azoline-l,3-dione •
Figure imgf000085_0001
A solution of sodium acetate (33.21 g, 0.4 mol), N-hydroxyphthalimide (22.0 g, 0.135 mol) and 2-bromoethanol (50.6 g, 0.4 mol) in DMSO (400 ml) were heated to 70 °C for 6 hours. After cooling to room temperature, water (400 mL) was added and the mixture was extracted with CH2Cl2 (250 mL x 3). The combined organic extracts were washed with water (250 mL x 2), 3N HCl (150 mL), brine, dried over Na2SO4, filtered and concentrated. The resulting crude material was washed with 50 % ethanol in water (120 mL), filtered, dried under vacuum to give the title compound as a white solid (17.76 g, 64% yield); mp 82-84 0C; 1H NMR (300 MHz, CD3OD) δ 7.90-7.80 (m, 4H), 4.30-4.25 (m, 2H), 3.90-3.82 (m, 2H); 13C NMR (75 MHz, CD3OD) δ 165.2, 135.8, 130.2, 124.3, 80.5, 60.8; Mass Spectrum (API-TIS) mlz 208 (MH)+. 13b. 2-(Aminooxy)ethan-l-ol
H2N. /\ ΛDH
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, CHCl3 (100 mL) was added to the reaction mixture. The resulting slurry was filtered and washed with CHCl3 (100 mL x 2). The filtrate was concentrated and the residue was distilled under vacuum (0.025 mmHg) at 75 to 80 °C to give a colorless oil (4.54 g, 78% yield); 1H NMR (300 MHz, CDCl3) δ 3.78 (s, 4H); 13C NMR (75 MHz, CDCl3) δ 76.3, 60.7. 13c. 2-{ l-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-(2- hydroxyethoxy)acetamide
Figure imgf000086_0001
A solution of indomethacin (6.23 g, 17.4 mmol), the product of Example 13b (1.35 g, 17.5 mmol), EDAC (4.32 g, 22.5 mmol) and NEt3 (5.6 mL, 40.2 mmol) in CH2Cl2 (100 mL) were stirred at room temperature for 2 hours. The reaction was partitioned between 3N HCl (100 mL) and CH2Cl2 (100 mL x 2). The combined organic extracts were washed with 3N HCl, water, brine, dried over Na2SO4, filtered, and concentrated. The resulting crude material was washed with methanol, filtered and dried under vacuum to give the title compound as a yellow solid (5.32 g, 73% yield); mp 146-148 °C; 1H NMR (300 MHz, CDCl3) δ 8.69 (br s, IH), 7.62 (d, J = 8.5 Hz, 2H), 7.46 (d, / = 8.5 Hz, 2H), 6.90 (d, J = 2.4 Hz, IH), 6.84 (d, J = 9.0 Hz, IH), 6.69 (dd, J = 9.0 and 2.4 Hz, IH), 3.90-3.70 (m, 2H), 3.80 (s, 3H), 3.60-3.50 (m, 4H), 2.29 (s, 3H); 13C NMR (75 MHz, 20% CD3OD/CDCI3) δ 169.2, 168.4, 155.8, 139.2, 136.0, 133.4, 130.9, 130.6, 130.2, 128.9, 114.7, 111.8, 111.4, 101.0, 77.6, 59.0, 55.3, 28.6, 12.8; Mass Spectrum (API-TIS) m/z 417 (MH+). Anal, calcd for C2lH21ClN2O5: C, 60.51; H, 5.08; N, 6.72; Found: C, 60.50; H, 4.99; N, 6.69.
Example 14. 2-{l-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methyIindol-3-yl}-N-(3- hydroxypropoxy)acetamide
14a. 2-(3-Hydroxypropoxy)benzo[c]azolidine-l,3-dione
Figure imgf000086_0002
The title compound was prepared as a white solid (70% yield), from 3-bromopropan- l-ol by following the procedure for Example 13a. mp 78-80 0C; 1H NMR (300 MHz, CDCl3) δ 7.9-7.75 (m, 4H), 4.39 (t, J = 6.0 Hz, 2H), 3.93 (t, J= 6.0 Hz, 2H), 3.04 (br s, IH), 2.06- 1.95 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.7, 134.5, 128.6, 123.5, 75.8, 58.8, 30.7; Mass Spectrum (API-TIS) m/z 222 (MH+). 14b. 3-(Aminooxy)propan-l-ol
H2N
The title compound was prepared as colorless oil (87% yield) by following the procedure for Example 13b followed by distillation under vacuum (0.05 mmHg) at 90-95 0C. 1H NMR (300 MHz, CDCl3) δ 6.0-5.0 (br, 3H), 3.79 (t, J = 6.1 Hz, 2H), 3.67 (t, / = 6.1 Hz,
2H), 1.81 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 73.0, 59.2, 31.2.
14c. 2-{ l-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-(3- hydroxypropoxy)acetamide
Figure imgf000087_0001
A solution of indomethacin (2.1 g, 5.9 mmol), the product of Example 14b (0.64 g, 7.1 mmol), EDAC (1.45 g, 22.5 mmol) and NEt3 (1.6 mL, 11.5 mmol) in CH2Cl2 (50 mL) were stirred at room temperature overnight. The reaction mixture was partitioned between 3N HCl (50 mL) and CH2Cl2 (50 mL x 2). The combined organic extracts were washed with 3N HCl, water, brine, dried over Na2SO4, filtered, and concentrated. The resulting crude material was dissolved in ethyl acetate and triturated with hexane. The solid was collected, dried under vacuum to give the title compound as a yellow solid (2.40 g, 95% yield); mp 112- 114 °C; 1H NMR (300 MHz, CDCl3) δ 9.15 (br s, IH), 7.62 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 6.92 (d, / = 2.4 Hz, IH), 6.84 (d, J = 9.0 Hz, IH)5 6.67 (dd, J = 9.0 and 2.4 Hz, IH), 3.99 (t, J = 5.7 Hz, 2H), 3.81 (s, 3H), 3.74 (t, J = 5.7 Hz, 2H), 3.59 (s, 2H), 2.37 (s, 3H), 1.80-1.73 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 168.3, 168.2, 156.0, 139.3, 136.3, 133.4, 131.1, 130.7, 130.2, 129.0, 114.9, 111.7, 101.1, 74.5, 59.4, 55.6, 30.4, 29.2, 13.2; Mass Spectrum (API-TIS) mlz 431 (MH+).
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
Figure imgf000087_0002
A solution of BH3-SMe2 in THF (2M, 15 mL, 30 mmol) was added slowly to an ice- cold solution of indomethacin (10.2 g, 28.6 mmol) in THF (150 mL). The reaction mixture was warmed up slowly and stirred at room temperature overnight. Excess BH3 was destroyed by the slow addition of MeOH (2 mL). The reaction mixture was evaporated to dryness under reduced pressure. The crude product was dissolved in CH2Cl2 (200 mL), washed with saturated NaHCO3, water, 3N HCl, water, brine, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in Et2O (50 mL) and triturated with hexane (200 mL). The yellow solid was collected and dried under vacuum to give the title compound (8.01 g, 81% yield); mp 111-113 °C; 1H NMR (300 MHz, CDCl3) 57.63 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 2.4 Hz, IH), 6.87 (d, J = 9.0 Hz, IH), 6.65 (dd, J = 9.0 and 2.4 Hz, IH), 3.86 (t, J = 6.7 Hz, 2H), 3.83 (s, 3H), 2.94 (t, J = 6.7 Hz, 2H), 2.35 (s, 3H), 1.81 (br, IH); 13C NMR (75 MHz, CDCl3) δ 168.3, 156.0, 139.1, 135.4, 134.0, 131.08, 131.04, 130.97, 129.0, 116.0, 115.0, 111.3, 101.3, 62.1, 55.7, 27.6, 13.3; Mass Spectrum (API-TIS) ml z 344 (MH+). Anal, calcd for C19H18ClNO3: C, 66.38; H, 5.28; N, 4.07;
Found: C, 66.15; H, 5.40; N, 3.94.
15b. 2- { 1 - [(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl } ethyl methylsulfonate
Figure imgf000088_0001
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 CH2Cl2 (15 mL) and then stirred at room temperature for 2 hours. The reaction mixture was partitioned between 3N HCl (10 mL) and CH2Cl2 (30 mL). The organic extract was washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product, >95% purity from NMR analysis, was use in the next step without purification. 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 2.4 Hz, IH), 6.89 (d, J = 9.0 Hz, IH), 6.67 (dd, J = 9.0 and 2.4 Hz, IH), 4.39 (t, J = 7.0 Hz, 2H), 3.83 (s, 3H), 3.13 (t, J = 7.0 Hz, 2H), 2.92 (s, 3H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.1, 155.9, 139.1, 135.6, 133.7, 131.0, 130.7, 130.3, 129.0, 114.9, 113.7, 111.4, 100.8, 68.5, 55.6, 37.2, 24.4, 13.1; Mass Spectrum (API-TIS) mlz 422 (MH+). 15c. 4-Clorophenyl 5-methoxy-2-methyl-3-[2-(nitrooxy)ethyl]-indolyl ketone
Figure imgf000089_0001
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 Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (1:5, R/= 0.25) to give the title compound as a sticky oil (0.12 g, 24% yield); 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 2.5 Hz, IH), 6.88 (d, J = 9.0 Hz, IH), 6.68 (dd, J = 9.0 and 2.5 Hz, IH), 4.62 (t, J= 7.1 Hz, 2H), 3.83 (s, 3H), 3.09 (t, J= 7.1 Hz, 2H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.2, 156.1, 139.3, 135.8, 133.8, 131.1, 130.9, 130.3, 129.1, 115.1, 113.5, 111.6, 100.7, 71.6, 55.7, 22.1, 13.1; Mass Spectrum (API-TIS) m/z 389 (MH+).
Example 16. (2-{l-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}ethoxy)- N-[3-(nitrooxy)propyl]carboxamide
Figure imgf000089_0002
A solution of the product of Example 15a (0.39 g, 1.1 mmol) in THF (5 mL) was added to a mixture of phosgene (20% in toluene, 10 mL) and KaCO3 (0.16 g, 1.2 mmol) and the resulting solution was stirred at room temperature for 1 hour then heated to 50 °C for an additional 0.5 hour. The reaction mixture was cooled to room temperature. The excess phosgene was removed by evaporate the reaction mixture to half its volume under reduced pressure. The resulting crude intermediate was dissolved in THF (20 mL), 3- (nitrooxy)propylamine nitric acid salt (0.20 g, 1.1 mmol, prepared as described in WO 2005/030135 A2, Example 8a), and DMAP (0.44 g, 3.6 mmol) were added and then the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with 3N HCl (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with 3N HCl, water, brine, dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (2:3, R/= 0.25) to give the title compound as a solid (0.47 g, 83% yield). The product was recrystallized from CHCl3 /hexane. mp 51-52 °C; 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 2.1 Hz, IH), 6.87 (d, J = 9.0 Hz, IH), 6.64 (dd, J= 9.0 and 2.1 Hz, IH), 5.15 (br, IH), 4.44 (t, J = 5.9 Hz, 2H), 4.23 (t, J = 6.7 Hz, 2H), 3.81 (s, 3H), 3.24 (br q, 2H), 2.96 (t, J= 6.7 Hz, 2H), 2.32 (s, 3H), 2.00-1.80 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 168.1, 156.4, 155.8, 138.9, 135.1, 133.9, 130.9, 130.7, 128.9, 115.3, 114.8, 111.0, 101.2, 70.6, 55.5, 37.3, 27.2, 23.9, 13.0; Mass Spectrum (API-TIS) mlz 490 (MH+).
Example 17. (2-{l-[(4-ChIorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}ethoxy)- N-({[3-(nitrooxy)propyI]amino}suIfonyI)carboxamide
Figure imgf000090_0001
Chlorosulfonyl isocyanate (115 μL, 1.3 mmol) and NEt3 (180 μL, 1.3 mmol) were added to an ice-cold solution of the product of Example 15a (0.40 g, 1.2 mmol) in CH2Cl2 (15 mL) and then stirred in an ice-bath for 30 min. 3-(Nitrooxy)propylamine nitric acid salt (0.26 g, 1.4 mmol, prepared as described in WO 2005/030135 A2, Example 8a), and NEt3 (250 μL, 1.8 mmol) were added to the reaction mixture and allowed to warm up slowly in an ice-bath to room temperature. After 3 hours, the reaction mixture was diluted with CH2Cl2 (80 mL) and washed with 3N HCl, water, brine, dried over Na2SO4, filtered, and concentrated. The products were separated by silica gel column chromatography eluting with EtOAc/hexane (1:1, R/ = 0.32) to give the title compound (0.15 g, 23% yield). The product was recrystallized from CHCl3 / hexane. mp 127-129 0C; 1H NMR (300 MHz, DMSO-d6) δ 7.66 (d, / = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.09 (d, / = 2.4 Hz, IH), 6.99 (d, J = 9.0 Hz, IH), 6.70 (dd, J = 9.0 and 2.4 Hz, IH), 4.54 (t, J = 6.3 Hz, 2H), 4.31 (t, J = 6.9 Hz, 2H), 3.80 (s, 3H), 3.03-2.97 (m, 4H), 2.23 (s, 3H), 1.90-1.80 (m, 2H); 13C NMR (75 MHz, 5% CDCl3/DMSO-d6) δ 168.0, 155.9, 151.8, 137.8, 135.2, 134.3, 131.3, 130.7, 130.6, 129.2, 115.0, 114.8, 111.5, 101.5, 71.0, 64.4, 55.5, 39.8, 26.2, 23.4, 13.2; Mass Spectrum (API-TIS) mlz 569 (MH+).
Example 18. 3-(Nitrooxy)propyl [(2-{l-[(4-chlorophenyl)carbonyl]-5-methoxy-2- methylindol-3-yl}ethoxy)carbonylamino]sulfonate
Figure imgf000091_0001
Chlorosulfonyl isocyanate (130 μL, 1.5 mmol) and NEt3 (210 μL, 1.5 mmol) were added to an ice-cold solution of the product of Example 15a (0.52 g, 1.5 mmol) in CH2Cl2 (20 mL) and stirred in an ice-bath for 30 min. 3-(Nϊtrooxy)propan-l-ol (0.25 g, 2.1 mmol, prepared as described in US 2004/0024057; WO 2004/004648, Example 40a ) and NEt3 (210 μL, 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. The reaction mixture was partitioned between 3N HCl (20 mL) and CH2Cl2 (50 mL). The organic extract was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The products were separated by silica gel column chromatography eluting with EtOAc/hexane (1:1, R/ = 0.1) to give the title compound as a solid (0.143 g, 17% yield); mp 44-46 °C; 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 2.3 Hz, IH), 6.89 (d, J = 9.0 Hz, IH), 6.65 (dd, J = 9.0 and 2.3 Hz, IH), 4.48 (t, J = 6.0 Hz, 2H), 4.36 (t, J = 6.9 Hz, 2H), 4.31 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.02 (br t, 2H), 2.31 (s, 3H), 2.15-2.00 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 168.5, 156.0, 150.9, 139.2, 135.6, 133.6, 131.1, 130.9, 130.6, 129.0, 115.0, 114.5, 111.3, 101.2, 69.0, 68.5, 66.1, 55.7, 26.3, 23.4, 13.1; Mass Spectrum (API-TIS) ml z 570 (MH+).
Example 19. N-(2-{l-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3- yl}ethyl){4-[(nitrooxy)methyl]phenyl}carboxamide
19a 3-(2-Azidoethyl)-5-methoxy-2-methylindolyl 4-chlorophenyl ketone
Figure imgf000091_0002
To the crude product of Example 15b (1.51 g, 4.4 mmol), was added NaN3 (0.58 g, 8.9 mmol) and then the mixture was heated to 70 °C in DMSO (50 mL) for 2 hours. After cooling to room temperature, DMSO was evaporated under vacuum. The residue was dissolved in CH2Cl2 (150 mL), washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum to give the title compound. The product, >95% purity from NMR analysis, was use in the next step without purification. An analytical sample was purified by silica gel column chromatography eluting with EtOAc/hexane (1:5, R/= 0.45). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 2.5 Hz, IH), 6.89 (d, J = 9.0 Hz, IH), 6.67 (dd, J = 9.0 and 2.5 Hz, IH), 3.83 (s, 3H), 3.49 (t, / = 7.0 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.2, 155.9, 139.1, 135.4, 133.9, 131.1, 130.9, 130.5, 129.0, 115.5, 115.0, 111.2, 101.0, 55.7, 50.7, 24.1, 13.1. 19b. 3-(2-Aminoethyl)-5-methoxy-2-methylindolyl 4-chlorophenyl ketone hydrochloride
Figure imgf000092_0001
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 CH2Cl2 (200 mL) and water (100 mL). The organic layer was washed with saturated Na2CO3, water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was dissolved in Et2O and was treated with HCUEt2O. The brown solid was collected and washed with Et2O then dried under vacuum (1.21 g, 73% yield for 4 steps); mp >200 °C; 1H NMR (300 MHz, DMSO-de) δ 8.30 (br, 3H), 7.71 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 2.1 Hz, IH), 6.96 (d, J= 9.0 Hz, IH), 6.71 (dd, J= 9.0 and 2.1 Hz, IH), 3.80 (s, 3H), 3.00 (br m, 4H), 2.23 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 168.0, 155.7, 137.6, 134.9, 134.2, 131.2, 130.5, 130.3, 129.0, 114.7, 111.5, 101.5, 55.6, 38.5, 21.6, 13.1; Mass Spectrum (API-TIS) ml z 343 (M-Cl)+. 19c. N-(2- { 1 -[(4-Chlorophenyl)carbonyl] -5-methoxy-2-methylindol-3 -yl }ethyl) { 4-
[(nitrooxy)methyl]phenyl } carboxamide
Figure imgf000093_0001
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 NEt3 (1.6 mL, 11.5 mmol) in CH2Cl2 (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). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (2:3, R/= 0.25 in 1:1) to give the title compound (0.28 g, 20% yield). The product was recrystallized from Et2O and hexane. mp 141-144 °C; 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J= 8.2 Hz, 2H), 7.61 (d, J= 8.5 Hz, 2H), 7.43 (d, J= 8.5 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 2.5 Hz, IH), 6.89 (d, J = 9.0 Hz, IH), 6.67 (dd, J = 9.0 and 2.5 Hz, IH), 6.40 (br t, IH), 5.43 (s, 2H), 3.74 (s, 3H), 3.67 (br q, 2H), 3.00 (t, J = 6.6 Hz, 2H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.2, 166.8, 156.0, 139.1, 136.0, 135.3, 135.0, 133.8, 131.0, 130.88, 130.85, 129.0, 128.8, 127.4, 116.6, 115.0, 111.5, 101.0, 55.6, 39.9, 23.9, 13.2; Mass Spectrum (API-TIS) mlz 522 (MH+).
Example 20. N-(2-{l-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3- yl}ethyl){[3-(nitrooxy)propyl]amino}carboxamide
Figure imgf000093_0002
N,N'-Carbonyldiimidazole (79 mg, 0.49 mmol) and the product of Example 19b (0.16 g, 0.46 mmol) in CH2Cl2 (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 NEt3 (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 CH2Cl2 (50 mL). The organic extract was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (gradient from 2:1 to 4:1, R/ = 0.33 in 2: 1) to give the title compound (0.081 g, 40% yield). The product can further purified by washing with Et2O. mp 112-114 °C; 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 2.1 Hz, IH), 6.87 (d, J = 9.0 Hz, IH), 6.66 (dd, J = 9.0 and 2.1 Hz, IH), 4.58 (br s, 2H), 4.46 (t, J= 6.0 Hz, 2H), 3.83 (s, 3H), 3.40 (br q, 2H), 3.23 (br q, 2H), 2.86 (t, / = 6.6 Hz, 2H), 2.30 (s, 3H), 1.92-1.80 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 168.4, 158.0, 156.1, 139.3, 135.1, 133.9, 131.1, 131.0, 129.1, 128.8, 116.8, 115.0, 111.2, 101.4, 71.0, 55.7, 40.1, 36.9, 27.8, 24.8, 13.2; Mass Spectrum (API-TIS) m/z 489 (MH+). 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
4-chlorophenyl ketone
Figure imgf000094_0001
4-(Bromomethyl)benzenesulfonyl chloride (1.15 g, 4.3 mmol) and NEt3 (1.0 mL, 7.2 mmol) were added to the product of Example 19b in CH2Cl2 (50 mL) and then stirred at room temperature overnight. The reaction mixture was partitioned between 3N HCl (30 mL) and CH2Cl2 (50 mL x 3). The combined organic extracts were washed with 3N HCl, saturated NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (1:2, R/= 0.25) to give the title compound (0.83 g, 53% yield); mp 58-60 0C; 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 9.0 Hz, IH), 6.85 (d, J = 2.4 Hz, IH), 6.64 (dd, J = 9.0 and 2.4 Hz, IH), 5.15 (br t, IH), 4.57 (s, 2H), 3.80 (s, 3H), 3.21 (br q, 2H), 2.88 (t, /= 6.9 Hz, 2H), 2.25 (s, " 3H); 13C NMR (75 MHz, CDCl3) δ 168.2, 155.9, 142.0, 139.7, 139.1, 135.3, 133.7, 131.0, 130.8, 130.4, 129.0, 128.95, 127.2, 115.3, 115.0, 111.4, 100.9, 55.6, 44.8, 42.5, 24.8, 13.2; Mass Spectrum (API-TIS) m/z 531 (MH+). 21b. 4-Chlorophenyl 5-methoxy-2-methyl-3- { 2-[( { 4- [(nitrooxy)methyl]phenyl } - sulfonyl)amino]ethyl}indolyl ketone
Figure imgf000095_0001
A solution of the product of Example 21a (0.83 g, 1.6 mmol) and AgNO3 (0.61 g, 3.95 mmol) in acetonitrile (60 mL) were heated to 70 0C for 6 hours. The reaction mixture was cooled to room temperature and the stirred with brine (50 mL) for 1 hour. The silver salts were filtered off through Celite and the filtrate was extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (1:2, R/= 0.15) to give the title compound. The product was washed with 10%EtOAc/hexane to give a light yellow solid (0.50 g, 57% yield); mp 143-146 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.90-7.70 (m, 3H), 7.70-7.60 (m, 6H), 6.99 (d, J = 2.4 Hz, IH), 6.97 (d, J = 9.0 Hz, IH), 6.71 (dd, J = 9.0 and 2.4 Hz, IH), 5.65 (s, 2H), 3.78 (s, 3H), 3.01 (br q, 2H), 2.79 (t, J = 6.6 Hz, 2H), 2.15 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 67.8, 155.6, 141.2, 137.6, 136.9, 134.5, 134.2, 131.2, 130.5, 130.4, 129.5, 129.0, 126.8, 116.1, 114.7, 111.3, 101.2, 73.8, 55.4, 42.4, 24.4, 13.2; Mass Spectrum (API-TIS) mlz 558 (MH+). Anal, calcd for C26H24ClN3O7S: C, 55.97; H, 4.34; N, 7.53; Found: C, 55.99; H, 4.25; N, 7.30. Example 22. 4-ChIorophenyI 3-(2-{[(3-hydroxypropyl)suIfonyI]amino}ethyI)-5- methoxy-2-methylindolyl ketone 22a. 4-Chlorophenyl 3-(2-{ [(3-chloropropyl)sulfonyl]amino }ethyl)-5-methoxy-2- methylindolyl ketone
Figure imgf000095_0002
3-Chloropropanesulfonyl chloride (0.24 mL, 2.0 mmol) and NEt3 (0.5 mL, 3.6 mmol) were added to the product of Example 19b in CHCl3 (20 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between 3N HCl (30 mL) and CH2Cl2 (50 mL x 2). The combined organic extracts were washed with 3N HCl, saturated NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (1:2, R/ = 0.12) to give the title compound (0.55 g, 77% yield); 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 8.4 Hz, 2H), 7.43 (d, J= 8.4 Hz, 2H), 6.98 (d, J = 2.4 Hz, IH), 6.90 (d, J= 9.0 Hz, IH), 6.65 (dd, J = 9.0 and 2.4 Hz, IH), 5.00 (t, J = 6.3 Hz, IH), 3.82 (s, 3H), 3.55 (t, J = 6.0 Hz, 2H), 3.35 (br q, 2H), 3.06 (m, 2H), 2.94 (t, J = 6.9 Hz, 2H), 2.33 (s, 3H), 2.15-2.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 168.2, 155.9, 139.0, 135.2, 133.7, 130.9, 130.5, 128.9, 115.4, 114.9, 111.3, 101.0, 55.6, 49.7, 42.6, 26.6, 25.5, 13.2; Mass Spectrum (API-TIS) mlz 483 (MH+). Anal, calcd for C22H24Cl2N2O4S: C, 54.66; H, 5.00; N, 5.79; Found: C, 54.64; H, 4.84; N, 5.79. 22b. 4-Chlorophenyl 5-methoxy-2-methyl-3-[2-({ [3-(nitrooxy)-propyl]sulfonyl}- amino)ethyl]indolyl ketone
Figure imgf000096_0001
A solution of the product of Example 22a (3.08 g, 6.4 mmol) and AgNO3 (3.14 g, 18.5 mmol) in acetonitrile (100 mL) were heated to reflux for 3 days. The reaction mixture was cooled to room temperature and then stirred with brine (50 mL) for 30 min. The silver salts were filtered off through Celite and the filtrate was extracted with CH2Cl2. The organic extracts were washed with brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (2:3, R/= 0.19) to give the title compound as a yellow solid (1.96 g, 60% yield); 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 2.4 Hz, IH), 6.89 (d, J = 9.0 Hz, IH), 6.67 (dd, J = 9.0 and 2.4 Hz, IH), 4.73 (t, J = 6.3 Hz, IH), 4.47 (t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.36 (br q, 2H), 2.92-3.0 (m, 4H), 2.34 (s, 3H), 2.15-2.05 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 168.3, 156.0, 139.3, 135.5, 133.7, 131.1, 130.9, 130.5, 129.1, 115.3, 115.0, 101.1, 70.5, 55.7, 49.0, 42.8, 25.6, 21.6, 13.3; Mass Spectrum (API-TIS) mlz 510 (MH+). 22c. 4-Chlorophenyl 3-(2-{ [(3-hydroxypropyl)sulfonyl]amino}ethyl)-5-methoxy-2- methylindolyl ketone
Figure imgf000097_0001
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. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting EtOAc/hexane (2:1, R/= 0.1) to give the title compound (0.27 g, 80% yield); mp 116-118 °C; 1H NMR (400 MHz, CDCl3) 57.65 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 2.4 Hz, IH), 6.89 (d, J = 8.8 Hz, IH ), 6.67 (dd, J= 8.8, 2.4 Hz, IH), 4.64 (br t, IH), 3.84 (s, 3H), 3.67 (t, J = 6.0 Hz, 2H), 3.37 (br q, 2H), 3.07 (m, 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.36 (s, 3H), 2.00-1.90 (m, 2H), 1.80-1.70 (br, IH); 13C NMR (100 MHz, CDCl3) δ 168.4, 156.1, 139.4, 135.5, 133.8, 131.2, 131.0, 130.6, 129.1, 115.5, 115.0, 111.5, 101.2, 60.6, 55.8, 49.8, 42.8, 26.8, 25.6, 13.4; Mass Spectrum (API-TIS) mlz 465 (MH)+. Example 23. 4-Chlorophenyl 5-methoxy-2-methyl-3-(2-phosphonoethyl)indolyl ketone methoxy-2-methylindolyl 4-chlorophenyl ketone
Figure imgf000097_0002
To the crude product of Example 15b (1.03 g 3.0 mmol), was added LiBr (0.55 g, 6.4 mmol) and the mixture was heated to 55 0C in acetone (100 mL) for 24 hours. After cooling to room temperature, acetone was evaporated under vacuum. The residue was dissolved in CH2Cl2 (100 mL), washed with water, brine, dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc/hexane (1:10, R/= 0.25) to give the title compound (0.96 g, 79% yield). The product was recrystallized from Et2O and hexane: mp 92-93 °C; 1H NMR (300 MHz, CDCl3) 57.63 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.91 (d, J= 2.5 Hz, IH), 6.90 (d, J= 8.9 Hz, IH), 6.66 (dd, J = 8.9 and 2.5 Hz, IH), 3.82 (s, 3H), 3.56 (t, J = 7.6 Hz, 2H), 3.21 (t, J= 7.6 Hz, 2H), 2.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.1, 155.9, 139.1, 135.4, 133.9, 131.0, 130.9, 130.2, 129.0, 116.6, 115.0, 111.3, 100.9, 55.7, 31.4, 27.9, 13.3; Mass Spectrum (API-TIS) mlz 406 (MH+).
23b. (2-{ l-[(4-Chloroρhenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}ethyl)- dimethoxyphosphino- 1 -one
Figure imgf000098_0001
A solution of the product of Example 23a (0.43 g, 1.1 mmol) in P(OMe)3 (3 niL) was heated to 110 °C for 2 days. The product was purified by silica gel column chromatography eluting with MeOH/ EtOAc (1:10, R/= 0.3) to give the title compound (0.32 g, 70% yield); 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 2.5 Hz, IH), 6.89 (d, J= 9.0 Hz, IH), 6.66 (dd, J = 9.0 and 2.5 Hz, IH), 3.83 (s, 3H), 3.76 (d, JPH= 10.7 Hz, 6H), 3.01-2.90 (m, 2H), 2.35 (s, 3H), 2.15-2.00 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 168.0, 155.8, 138.9, 134.0, 133.9, 130.9, 130.8, 130.1, 128.9, 118.2 (d, JCP = 16.7 Hz), 114.9, 111.1, 100.9, 55.6, 52.2 (d, JCP = 6.5 Hz)), 24.5 (d, JCP = 137.4 Hz), 16.84 (d, JCp = 4.3 Hz), 13.0; Mass Spectrum (API-TIS) mlz 436 (MH+).
23c. 4-Chlorophenyl 5-methoxy-2-methyl-3-(2-phosphonoethyl)indolyl ketone
Figure imgf000098_0002
Bromotrimethylsilane (0.65 mL, 4.9 mmol) was added to an ice-cold solution of the product of Example 23b (0.96 g, 2.2 mmol) in CH2Cl2 (30 mL) and then stirred at room temperature overnight. The reaction mixture was partitioned between IN HCl (80 mL) and CH2Cl2 (100 mL x 2). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The residue was dissolved in CHCl3 (5 mL) and triturated with Et2O (10OmL). The light colored solid was collected and washed with Et2O then dried under vacuum to give the title compound (0.51 g, 57% yield); mp 165-167 °C; 1H NMR (300 MHz, CD3OD) δ 7.62 (d, J = 8.4 Hz, 2H), 7.52 (d, J= 8.4 Hz, 2H), 7.01 (d, J= 2.1 Hz, IH), 6.92 (d, J= 9.0 Hz, IH), 6.64 (dd, J= 9.0 and 2.1 Hz, IH), 3.81 (s, 3H), 3.00-2.90 (m, 2H), 2.27 (s, 3H), 2.05-1.90 (m, 2H); 13C NMR (75 MHz, CD3OD) δ 169.9, 157.7, 140.0, 135.9, 134.9, 132.4, 132.2, 131.8, 130.2, 120.5 (d, JCP = 18 Hz), 116.1, 112.5, 102.1, 55.1, 28.4 (d, JCP = 134.3 Hz), 18.5 (d, JCp = 3.8 Hz), 13.4; Mass Spectrum (API-TIS) rø/z 408 (MH+).
Example 24: 2-(5-Methoxy-2-methyl-l-{[4-(methylsulfonyl)phenyl]methyl}indol-3-yI)-N- [3- (nitrooxy )pr opy 1] acetamide
24a. Ethyl 2-(5-methoxy-2-methylindol-3-yl)acetate
Figure imgf000099_0001
A stirred mixture of 4-methoxyphenylhydraζine hydrochloride (26 g, 0.149 mol), ethyl levulinate (21.5 g, 0.149 mol), and sodium acetate (12.2 g, 0.149 mol) in glacial acetic acid (200 mL) was heated at reflux for 3 hours. The reaction mixture was concentrated to dryness. The residue was dissolved in ethanol (120 mL), treated with 4M HCl in 1,4-dioxane (80 mL), and heated at a gentle reflux for 15 hours. The reaction mixture was concentrated to remove the volatiles, and the residue was taken up with EtOAc, washed with water, aqueous K2CO3, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Chromatography of the residue (1:1 EtOAc:Hexane, silica gel) gave the title compound (28 g, 76% yield) as a viscous oil. 1H NMR (300 MHz, CDCl3) 57.83 (br s, IH), 7.06 (d, J= 8.7 Hz, IH), 7.00 (d, J = 2.4 Hz, IH), 6.77-6.73 (m, IH), 4.12 (q, J= 7.1 Hz, 2H), 3.84 (s, 3H), 3.64 (m, 2H), 2.32 (s, 3H), 1.23 (t, J= 7.1 Hz, 3H); Mass Spectrum (API-TIS) mJz 248 (MH+). 24b. 4-(Bromomethyl)- 1 -(methylsulfonyl)benzene
Figure imgf000099_0002
This title compound was synthesized according to the procedure described by Kelley, et al (J. Med. Chem. 1989, 32 (8), 1757-1763). 24c. Ethyl 2-(5-Methoxy-2-methyl-l~{ [4-(methylsulfonyl)phenyl]methyl}indol-3- yl)acetate
Figure imgf000099_0003
To a stirred solution of the product of Example 24a (1.45 g, 5.87 mmol), and the product of Example 24b (1.46 g, 5.87 mmol) in THF (80 mL) was added t-BuOK (1.0 M in THF, 5.87 mL, 5.87 mmol) via a syringe at room temperature under N2. The reaction mixture was heated at a gentle reflux for 16 hours. After cooling, the mixture was poured into ice, neutralized with IN HCl, and extracted with EtOAc (2x). The organic extract was dried over Na2SO4, filtered, and concentrated. Chromatography of the residue (1:1 EtOAc:Hexane, silica gel) gave the title compound (2.01 g, 82% yield) as a solid: mp 123- 124 °C; 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H), 7.13-6.99 (m, 4H), 6.78 (m, IH), 5.34 (s, 2H), 4.14 (q, J= 7.1 Hz, 2H), 3.86 (s, 3H), 3.71 (s, 2H), 3.00 (s, 3H), 2.31 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); Mass Spectrum (API-TIS) m/z 416 (MH+). l-{ [4-(methylsulfonyl)phenyl]methyl}indol-3-yl)acetic acid
Figure imgf000100_0001
To a stirred solution of the product of Example 24c (2.01 g, 4.84 mmol) in THF (50 mL) was added 2N NaOH (aqueous solution, 50 mL) and the resulting mixture was stirred at room temperature for 4 hours, and then concentrated to remove the volatiles. After acidification to pH 2 with 2N HCl, the mixture was extracted with EtOAc (2x). The organic extract was dried over Na2SO4, filtered, and concentrated to give a solid that was recrystallized from THF.ΕtOAc (1:4) to give the title compound (1.80 g, 95% yield) as a beige solid: mp 168 °C; 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 7.05-7.00 (m, 2H), 6.81-6.76 (m, IH), 5.35 (s, 2H), 3.86 (s, 3H), 3.76 (s, 2H), 3.01 (s, 3H), 2.31 (s, 3H) 1.54 (br, IH); Mass Spectrum (API-TIS) m/z 388 (MH+). 24e. 2-(5-Methoxy-2-methyl-l-{[4-(methylsulfonyl)phenyl]methyl}indol-3-yl)-N-[3-
(nitrooxy)propyl] acetamide
Figure imgf000100_0002
To a stirred mixture of 3-(nitrooxy)propylamine nitric acid salt (0.240 g, 1.31 mmol, prepared as described in WO 2005/030135 A2, Example 8a), the product of Example 24d (0.465 g, 1.20 mmol), and EDAC (0.251 g, 1.31 mmol) in THF (15 mL) was added triethylamine (0.366 mL, 2.62 mmol). After 15 hours, the reaction mixture was diluted with EtOAc, washed with IN HCl, dried over Na2SO4, filtered, and concentrated. Chromatography (1:1 EtOAc:Hexane, neutral Al2O3) gave the title compound (106 mg, 18% yield); mp 106 °C; 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 8.3 Hz, 2H), 7.28 (m, IH), 7.21 (d, J = 8.3 Hz, 2H), 7.02 (m, IH), 6.75-6.70 (m, IH), 5.53 (s, 2H), 4.63 (t, J= 6.1 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 2H), 3.19 (s, 3H), 2.94 (m, 2H), 2.54 (m, IH), 2.31 (m, 3H), 2.01 (m, 2H); Mass Spectrum (API-TIS) m/z 490 (MH+). Anal. Calcd. for C23H27N3O7S: C, 56.43; H, 5.56; N, 8.58. Found: C, 56.66; H, 5.72; N, 8.39.
Example 25: 2-[l-(Cyclohexylmethyl)-5-methoxy-2-methyIindol-3-yl]-N-[3- (nitrooxy)propyl]acetamide
25a. Ethyl 2-[l-(cyclohexylmethyl)-5-methoxy-2-methylindol-3-yl]acetate
Figure imgf000101_0001
To a stirred solution of the product of Example 24a (5.40 g, 21.9 mmol) in THF at room temperature was added potassium tert-butoxide (1.0 M in THF, 21.9 mL) under nitrogen. The reaction mixture was heated at reflux for 15 hours. After cooling, the mixture was poured into ice, acidified to pH 2 with 2N HCl, and extracted with EtOAc (2x). The organic extract was dried over Na2SO4, filtered, and concentrated. Chromatography (2% to 10% EtOAc in hexane gradient, silica gel) gave the title compound (3.88 g, 52% yield) as an oil. 1U NMR (300 MHz, CDCl3) δ 7.15 (d, J = 8.8 Hz, IH), 7.04 (d, J = 2.4 Hz, IH), 6.83- 6.79 (m, IH), 4.14 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.85 (m, 2H), 3.69 (s, 2H), 2.40 (s, 3H), 1.73-1.67 (m, 6H), 1.26 (t, J= 7.1 Hz, 3H), 1.23-1.00 (m, 5H); Mass Spectrum (API-TIS) m/z 344 (MH+).
25b. 2-[l-(Cyclohexylmethyl)-5-methoxy-2-methylindol-3-yl]acetic acid
Figure imgf000101_0002
To a stirred solution of the product of Example 25 a (740 mg, 2.16 mmol) in 1:1 THRMeOH (20 mL) was added 2N aqueous NaOH (5 niL). After being stirred at room temperature overnight, the mixture was acidified to pH 1 with IN HCl and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give a tan solid that was recrystalization from EtOAc (10 mL) to give the title compound (0.56 g, 82% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 11.60-9.50 (br s, IH), 7.13 (d, J = 8.8 Hz, IH), 6.97 (d, J = 2.3 Hz, IH), 6.78 (dd, J = 6.4 and 2.4 Hz, IH), 3.84 (s, 3H), 3.82 (m, 2H), 3.69 (s, 2H), 2.35 (s, 3H), 1.7-1.5 (m, 5H), 1.2-0.9 (m, 6H); Mass Spectrum (API-TIS) m/z 316 (MH+).
25c. 2-[l-(Cyclohexylmethyl)-5-methoxy-2-methylindol-3-yl]-N-[3-(nitrooxy) propyl] acetamide
Figure imgf000102_0001
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 Na2SO4, filtered, and concentrated. The resulting tan solid was recrystallized from EtOAc.Ηexane (1:5) to give the title compound (282 mg, 92% yield) as a white solid: mp 38 °C; 1H NMR (300 MHz, CDCl3) δ 7.17 (d, J = 8.8 Hz, IH), 6.90-6.80 (m, 2H), 5.83 (br t, IH), 4.35 (t, J= 6.3 Hz, 2H), 3.85 (d, J = 7.4 Hz, 2H), 3.82 (s, 3H), 3.65 (m, 2H), 3.25 (m, 2H), 2.33 (m, 3H), 1.84 (t, J= 6.5 Hz, 2H), 1.80-1.50 (m, 5H), 1.2-1.0 (m, 6H); Mass Spectrum (API-TIS) m/z 418 (MH+). Anal. Calcd. for C22H3IN3O5: C, 63.30; H, 7.43; N, 10.07. Found: C, 63.62; H, 7.65; N, 9.83.
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
Figure imgf000103_0001
To a stirred solution of the product of Example 25a (0.52 g, 1.52 mmol) in THF (15 niL) was added IM LiAlH4 in THF (3 mL, 3 mmol), and the resulting mixture was stirred at room temperature for 45 minutes. The mixture was poured onto solid Na2SO4-IOH2O and aged for 10 minutes before filtration. The filter cake was washed throughly several times with EtOAc. The combined filtrates and EtOAc washings were concentrated, and the residue was purified by chromatography (1:2 EtOAc.Ηexane, silica gel) to give the title compound (0.45 g, 98% yield ) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.14 (d, J = 8.8 Hz, IH), 6.99 (d, J = 2.4 Hz, IH), 6.80 (dd, J = 8.8, 2.4 Hz, IH), 3.86 (s, 3H), 3.90-3.81 (m, 4H), 2.97 (t, J = 6.5 Hz, 2H), 2.05 (s, 3H), 1.80-0.99 (m, 12 H). 13C NMR (75 MHz, CDCl3) δ 154.6, 134.7, 131.7, 128.0, 110.1, 110.0, 106.2, 100.1, 62.7, 55.8, 49.7, 38.9, 31.1, 28.0, 26.2, 25.8, 10.5; Mass Spectrum (API-TIS) m/z 302 (MH+).
26b. 3-(2-Bromoethyl)-l-(cyclohexylmethyl)-5-methoxy-2-methylindole
Figure imgf000103_0002
To a stirred solution of the product of Example 26a (0.430 g, 1.43 mmol) in toluene (15 mL) was added 48% aqueous HBr (1.59 mL, 14.3 mmol), and the mixture was heated at reflux for 2 hours. After cooling, the mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and water. The organic extract was dried over Na2SO4, filtered, and concentrated. Chromatography (1:19 EtOAc:Hexane, silica gel) of the residue gave the title compound (0.45 g, 86% yield) as a foam. 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J = 8.8 Hz, IH), 6.95 (d, J = 2.4 Hz, IH), 6.81 (dd, J = 8.8 and 2.4 Hz, IH), 3.87 (s, 3H), 3.86-3.83 (m, 2H), 3.52 (m, 2H), 3.26 (t, J = 8.3 Hz, 2H), 2.36 (s, 3H), 1.80-0.99 (m, HH); Mass Spectrum (API-TIS) m/z 364, 366 (MH+ for 79Br and 81Br respectively). 26c. {2-[l-(Cyclohexylmethyl)-5-methoxy-2-methylindol-3-yl]ethyl}nitrooxy
Figure imgf000104_0001
To a stirred solution of the product of Example 26b (0.450 g, 1.23 mmol) in acetonitrile (10 niL) was added AgNO3 (0.419 g, 2.46 mmol) and the resulting mixture was stirred for 15 hours at which point the bromide had been completely consumed as indicated by TLC. Upon concentration to dryness, the residue was taken up with EtOAc, treated with saturated aqueous NaCl, and agitated for 10 minutes. The resulting mixture was filtered, and the organic layer was separated, dried over Na2SO4, filtered, and concentrated. Chromatography (1:9 EtOAc:Hexane, silica gel) of the residue gave the title compound (0.345 g, 81% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J= 8.8 Hz, IH), 6.97 (d, J = 2.0 Hz, IH), 6.82 (dd, J = 8.8 and 2.0 Hz, IH), 4.58 (t, J = 7.5 Hz5 2H), 3.90 (s, 3H), 3.88-3.84 (m, 2H), 3.12 (t, J = 7.3 Hz, 2H), 2.36 (s, 3H), 1.74-1.57 (m, 6H), 1.19-1.01 (m, 5H); Mass Spectrum (API-TIS) m/z 341 (MH+). Anal. Calcd. for C19H26N2O4: C, 65.90; H, 7.51; N, 8.10. Found: C, 66.13; H, 7.66; N, 7.96.
Example 27: Assay for Human COX-I and COX-2 Enzyme Activity in Human Whole Blood
The assay for COX-I and COX-2 enzyme activity, in the human whole blood was performed as described in Brideau et al., Inflamm Res., 45: 68-74 (1996)). Human blood (-50 mL) from male or female donors who had not received any aspirin or NSAEDs for 14 days was collected at two local area blood donor centers and placed in polypropylene syringes containing sodium heparin (20 units per mL blood, final concentration). The blood was transported to the laboratory on ice packs and used within 1.5 hours of collection. Upon receipt in the laboratory, the blood was allowed to come to room temperature for 15 minutes prior to distribution in 1 mL aliquots per well of 24 well tissue culture plates. The plates were then placed on a gently rotating platform shaker in a 5% CO2 incubator at 37° C for 15 minutes. Test compounds were dissolved in DMSO, at 1000 fold the final desired concentration, and further diluted, as indicated, in DMSO. One μL 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 μL DMSO.
To induce COX-2, lipopolysaccharide (LPS) from E. coli (LPS, serotype 026:B6 or serotype 0127:B8, Sigma Chemical Co., St. Louis, MO, Catalogue No. L3755 or L3129, respectively) was added at 10 μg/mL (2 μL of 5 mg/mL LPS in DMSO) to appropriate wells 15 minutes after the addition of the test compound. (Basal or background wells not incubated with LPS received 2 μL of DMSO.) For the stimulation of COX-I, the calcium ionophore, A23187 (free acid from Sigma Chemical Co., St. Louis, MO, Catalogue No. C7522) was added at 25 μM (1 μL of 25 mM stock in DMSO) to separate wells 4.5 hours after the addition of the test compound. (Again, basal, background or control wells not stimulated with A23187 received 1 μL of DMSO.) At 5 hours after the addition of the test compound, all incubations were terminated by placement on ice and the addition of 2 mM EGTA (100 μL of 20 mM EGTA, tetrasodium, in PBS (phosphate buffered saline) without Ca++ and Mg++, pH 7.2)). The resulting solutions, were transferred by polyethylene transfer pipettes to 15 mL polypropylene centrifuge tubes and centrifuged at 1200 g for 10 minutes at 40C. One hundred μL 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 0C. The next day, the samples were centrifuged at 2000 g for 10 minutes at 40C and the supernatants transferred to glass tubes and evaporated to dryness. The samples were assayed for thromboxane B2 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).
The inhibition for COX-I and COX-2 enzyme activity in human whole blood by the test compounds, at the indicated concentrations, are given in Table 1 (n = 2 to 12).
TABLE l
Figure imgf000105_0001
Figure imgf000106_0001
The results show that the compounds of the invention have COX-2 selectivity. 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. Six days after the initial air injection, 1 mL of a 1% solution of carrageenan (Sigma, lambda fraction) dissolved in pyrogen-free saline was injected directly into the pouch to produce an inflammatory response. The test compound in vehicle (3 mL/rat, 0.5% Methocel) was administered by oral intubation 1 hour prior to carrageenan injection into the inflammatory pouch. After 4 hours the exudate was removed by pipette into a calibrated centrifuge tube and the volume measured. The number of leukocytes in the exudate was determined by cell counting with a Beckman Coulter Particle Counter with the lower threshold set to exclude red blood cells. The exudate samples were assayed without further processing for PGE2 (prostaglandin E2) using PGE2 EIA kit-Monoclonal, from Cayman Chemical Co. (Ann Arbor, MI, Catalogue No. 514010).
The % inhibition for the cell infiltration and the % inhibition for PGE2 by the test compounds, at the indicated concentrations, are given in Table 2.
TABLE 2
Figure imgf000107_0001
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. Food was withheld after the initial dosing. Rats were euthanized by CO2 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.
TABLE 3
Figure imgf000108_0001
The disclosure of each patent, patent application and publication cited or described in the present specification is hereby incorporated by reference herein in its entirety.
Although the invention has been set forth in detail, one skilled in the art will appreciate that numerous changes and modifications can be made to the invention, and that such changes and modifications can be made without departing from the spirit and scope of the invention.

Claims

CLAIMSWhat is claimed is:
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof ; wherein the compound of Formula (I) is:
Figure imgf000109_0001
wherein:
R31 is an alkoxy group, a hydroxyl group or an aminosulfonyloxy group; R33 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;
R34 is a hydrogen or halogen;
R38 and R39 are hydrogen or R38 and R39 when taken together with the carbon atom to which they are attached form a carbonyl group;
R4O is a cylcloalkyl group or an aryl group; X is:
Ca) -CH2-N(R36)-; Cb)-C(O)-N(R36)-; (c) -CH2-O-;
(d) -CH2-P(O)(OH)(O)-; or (e) -C(O)-O-;
R36 is a hydrogen or an alkylcarbonyl group;
K is -(W3)a-Eb-(C(Re)(Rf))pi-Ec-(C(Re)(Rf))x-(W3)d-(C(Re)(Rf))y-(W3)i-Ej-(W3)g-
Figure imgf000109_0002
a, b, c, d, g, i and j are each independently an integer from 0 to 3; pi, x, y and z are each independently an integer from 0 to 10; V4 is V3, Re, -U3-V5 or V6; V3 is:
Figure imgf000110_0001
Figure imgf000111_0001
R24 is -C6H4R37, -CN, -S(O)2-C6H4R37, -C(O)-N(R3)(Ri), -NO2, -C(O)-OR25 or -S(O)2-R25;
R25 is an aryl group, a lower alkyl group, a haloalkyl group, a hydroxyalkyl group or an arylalkyl group;
R26 is -C(O)- or -S(O)2- ; R37 is a hydrogen, -CN, -S(O)2-R25, -C(O)-N(R8)(RO, -NO2 Or -C(O)-OR25;
T' is oxygen, sulfur or NR6;
R6 is a hydrogen, a lower alkyl group, or an aryl group;
V6 is:
Figure imgf000112_0001
Z5 is -CH2 or oxygen;
Z6 is -CH or nitrogen;
W3 at each occurrence is independently -C(O)-, -C(S)-, -T3-, -(C(R6)(Rf)) h-, -N(R8)Ri,. an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, -(CH2CH2O) ql- or a heterocyclic nitric oxide donor;
E at each occurrence is independently -T3-, an alkyl group, an aryl group, -(C(Re)(Rf))h-, a heterocyclic ring, an arylheterocyclic ring, -(CH2CH2O)ql- or Y4;
Y4 is:
Figure imgf000112_0002
Figure imgf000113_0001
T is a -S(O)0-; a carbonyl or a covalent bond; o is an integer from 0 to 2;
Rj and Rk are independently selected from an alkyl group, an aryl group, or Rj and Rk taken together with the nitrogen atom to which they are attached are a heterocylic ring;
T3 at each occurrence is independently a covalent bond, a carbonyl, an oxygen,
Figure imgf000113_0002
h is an integer form 1 to 10; qi is an integer from 1 to 5;
Re and Rf 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 alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-Vs, Vβ, -(C(R0)(Rp))kl-U3-V5, -(C(Ro)(Rp))IcI-U3-V3, -(C(R0)(Rp))M-U3-V6, -(C(R0)(Rp))M-U3-C(O)- V6, or Re and Rf taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, an inline, a hydrazone, a bridged cycloalkyl group,
Figure imgf000114_0001
R0 and Rp 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 alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-V5, V6, or R0 and Rp taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, an imine, a hydrazone a bridged cycloalkyl group,
Figure imgf000114_0002
U3 is an oxygen, sulfur or -N(R2)RJ;
V5 is -NO or -NO2 (i.e. an oxidized nitrogen);
Ic1 is an integer from 1 to 3;
Ra 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, -CH2-C-(U3-Vs)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom or -(N2O2-)#M!+, wherein M1 + is an organic or inorganic cation.
2. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
3. The compound of claim 1, wherein the compound of Formula (I) is 2-{ l-[(4-chlorophenyl)carbonyl]-5-hydroxy-2-methylindol-3-yl}-N-(3- hydroxypropyl)acetamide; phenylmethyl 27{6-chloro-l-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3- yl} acetate;
2- { 6-chloro- 1 - [(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl } acetic acid; phenylmethyl 2- { 4-chloro- 1 - [(4-chlorophenyl)carbonyl] -5-methoxy-2-methylindol-3- yl} acetate;
2-{ l-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-(3- hydroxypropyl)acetamide;
2- { 1 -[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl } -N-(4- hydroxybutyl)acetamide;
(2- { l-[(4-chlorophenyl)carbonyl] -5-methoxy-2-methylindol-3-yl } acetylamino)acetate;
(N-acetyl-2- { 1 -[(4-chlorophenyl)carbonyl] -5-methoxy-2-methylindol-3 -yl } acetylamino) acetate;
2-{ l-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-(2- hydroxyethoxy)acetamide;
2-{l-[(4-chloroρhenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-(3- hydroxypropoxy)acetamide;
4-chlorophenyl 3-(2-hydroxyethyl)-5-methoxy-2-methylindolyl ketone; 3-(2-aminoethyl)-5-methoxy-2-methylindolyl 4-chlorophenyl ketone hydrochloride; 3-[2-({ [4-(chloromethyl)phenyl] sulfonyl}amino)ethyl]-5-methoxy-2-methylindolyl 4- chlorophenyl ketone;
4-chlorophenyl 3-(2-{ [(3-chloropropyl)sulfonyl]amino}ethyl)-5-methoxy-2-methylindolyl ketone;
4-chlorophenyl 3-(2-{[(3-hydroxypropyl)sulfonyl]amino}ethyl)-5-methoxy-2-methylindolyl ketone;
(2- { 1 - [(4-chlorophenyl)carbonyl] -5-methoxy-2-methylindol-3-yl } ethyl)- dimethoxyphosphino-1-one;
4-chlorophenyl 5-methoxy-2-methyl-3-(2-phosphonoethyl)indolyl ketone; ethyl 2-(5-methoxy-2-methyl-l-{[4-(methylsulfonyl)phenyl]methyl}indol-3-yl)acetate;
2-(5-methoxy-2-methyl-l-{ [4-(methylsulfonyl)phenyl]methyl}indol-3-yl)acetic acid; ethyl 2-[l-(cyclohexylmethyl)-5-methoxy-2-methylindol-3-yl]acetate;
2-[l-(cyclohexylmethyl)-5-methoxy-2-methylindol-3-yl]acetic acid;
2- [ 1 -(cyclohexylmethyl)-5 -methoxy-2-methylindol-3 -yl] ethan- 1 -ol;
2- { 1 - [(4-chlorophenyl)carbonyl] -5-hydroxy-2-methylindol-3-yl } -N- [3-
(nitrooxy)propyl] acetamide; l-[(4-chlorophenyl)carbonyl]-2-methyl-3-({N-[3-(nitrooxy)-propyl]carbamoyl} methyl)indol-5-yl aminosulfonate;
2-{6-chloro-l-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}-N-[3-
(nitrooxy)propyl] acetamide ;
2- { 1 - [(4-chlorophenyl)carbonyl] -5-methoxy-2-methylindol-3-yl } -N- [3-
(nitrooxy)propyl] acetamide;
N-[2,2-dimethyl-3-(nitrooxy)propyl]-2-{ l-[(4-chlorophenyl)-carbonyl]-5-methoxy-2- methylindol-3-yl } acetamide;
N- { 1 , 1 -bis [(nitrooxy)methyl]-2-(nitrooxy)ethyl } -2- { 1 - [(4-chlorophenyl)-carbonyl]-5- methoxy-2-methylindol-3-yl } acetamide;
4-clorophenyl 5-methoxy-2-methyl-3-[2-(nitrooxy)ethyl]-indolyl ketone;
(2-{ l-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}ethoxy)-N-[3- (nitrooxy)propyl] carboxamide;
(2-{l-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}ethoxy)-N-({[3- (nitrooxy)propyl]amino } sulfonyl)carboxamide; :
3-(nitrooxy)propyl [(2-{ l-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3- yl } ethoxy)carbonylamino] sulfonate; N-(2- { l-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-yl } ethyl) { A- [(nitrooxy)methyl]phenyl } carboxamide;
N-(2-{l-[(4-chloroρhenyl)carbonyl]-5-methoxy-2-methylindol-3-yl}ethyl){[3-
(nitrooxy)propyl] amino } carboxamide;
4-chlorophenyl 5-methoxy-2-methyl-3- { 2-[({4-[(nitxooxy)methyl]phenyl } - sulfonyl)amino]ethyl } indolyl ketone;
4-chlorophenyl 5-methoxy-2-methyl-3-[2-({[3-(nitrooxy)-propyl]sulfonyl}- amino)ethyl]indolyl ketone;
2-(5-methoxy-2-methyl-l-{[4-(methylsulfonyl)ρhenyl]methyl}indol-3-yl)-N-[3-
(nitrooxy)ρropyl] acetamide;
2-[l-(cyclohexylmethyl)-5-methoxy-2-methylindol-3-yl]-N-[3-(nitrooxy) proρyl]acetamide;
{ 2-[l-(cyclohexylmethyl)-5-methoxy-2-methylindol-3-yl]ethyl }nitrooxy; and pharmaceutically acceptable salts thereof.
4. The composition of claim 2, further comprising (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound; or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound.
5. The composition of claim 4, wherein the therapeutic agent is a steroid, a selective cyclooxygenase-2 inhibitor, a nonsteroidal antiinflammatory compound, a 5- lipoxygenase (5-LO) inhibitor, a leukotriene B4 (LTB4) receptor antagonist, a leukotriene A4 (LTA4) hydrolase inhibitor, a 5-HT agonist, an anti-hyperlipidemic compound, a Ha antagonist, a hydralazine compound, an antineoplastic agent, an antiplatelet agent, a thrombin inhibitor, a thromboxane inhibitor, a carbonic anhydrase inhibitor, a decongestant, a diuretic, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a, Helicobacter pylori inhibitor, a phosphodiesterase inhibitor, a proton pump inhibitor and an isoprostane inhibitor.
6. The composition of claim 5, wherein the therapeutic agent is at least one compound selected from the group consisting of an NSAID, a proton pump inhibitor and an H2 antagonist.
7. The composition of claim 5, wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.
8. The composition of claim 5, wherein the nitric oxide enhancing compound is selected from the group consisting of a S-nitrosothiol, a nitrite, a nitrate, a S-nitrothiol, a sydnonimine, a NONOate, a N-nitrosoamine, a N-hydroxyl nitrosamine, a nitrosimine, a diazetine dioxide, an oxatriazole 5-imine, an oxime, a hydroxylamine, a N-hydroxyguanidine, a hydroxyurea, a furoxan or a nitroxide.
9. A method for treating or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2.
10. A method for treating a gastrointestinal disorder or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2.
11. The method of claim 10, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia
12. A method for facilitating wound healing in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2.
13. The method of claim 12, wherein the wound is an ulcer.
14. A method for treating a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2.
15. The method of claim 14, wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, a skin-related condition, neoplasia, an inflammatory process in a disease, an ophthalmic disorder, pulmonary inflammation, a central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, a microbial infection, a cardiovascular disorder, a urinary disorder, a urological disorder, endothelial dysfunction, organ deterioration, tissue deterioration, or activation, adhesion and infiltration of neutrophils at the site of inflammation.
16. The method of claim 15, wherein the neoplasia is a brain cancer, a bone cancer, an epithelial cell-derived neoplasia (epithelial carcinoma), a basal cell carcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouth cancer, an esophageal cancer, a small bowel cancer, a stomach cancer, a colon cancer, a liver cancer, a bladder cancer, a pancreas cancer, an ovary cancer, a cervical cancer, a lung cancer, a breast cancer, a skin cancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, a polyp, an adenomatous polyp, a familial adenomatous polyposis or a fibrosis resulting from radiation therapy.
17. The method of claim 15, wherein the central nervous system disorder is cortical dementia, Alzheimer's disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia, senile dementia, or central nervous system damage resulting from stroke, ischemia or trauma.
18. A method for treating or reversing renal and/or respiratory toxicity; inhibiting platelet aggregation; 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 in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 2.
19. The method of claims 4, 5, 7, 9 or 13, further comprising administering (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound; or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound.
20. A kit comprising at least one compound of claim 1.
21. The kit of claim 20, further comprising further comprising (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound; or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound.
22. The kit of claim 21, wherein the (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound; or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound are in the form of separate components in the kit.
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