WO2007016095A2 - Cyclooxygenase-2 selective inhibitor compounds comprising nitric oxide enhancing groups, compositions and methods of use - Google Patents

Cyclooxygenase-2 selective inhibitor compounds comprising nitric oxide enhancing groups, compositions and methods of use Download PDF

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Publication number
WO2007016095A2
WO2007016095A2 PCT/US2006/028856 US2006028856W WO2007016095A2 WO 2007016095 A2 WO2007016095 A2 WO 2007016095A2 US 2006028856 W US2006028856 W US 2006028856W WO 2007016095 A2 WO2007016095 A2 WO 2007016095A2
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nitric oxide
group
compound
ester
inhibitors
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PCT/US2006/028856
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French (fr)
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WO2007016095A3 (en
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David S. Garvey
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Nitromed, Inc.
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Publication of WO2007016095A2 publication Critical patent/WO2007016095A2/en
Publication of WO2007016095A3 publication Critical patent/WO2007016095A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • compositions and kits comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor compound comprising at least one nitric oxide enhancing group, or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent.
  • COX-2 cyclooxygenase 2
  • 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 cyclooxygenase 2 selective inhibitors of the invention are 2(2-((2-chloro-6- fluorophenyl) amino)5-methylphenyl)acetic acid derivatives comprising at least one nitric oxide enhancing group.
  • the nitric oxide enhancing groups are nitroxides and/or heterocyclic nitric oxide donors.
  • 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 NSADDs 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.
  • 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)).
  • the invention provides novel COX-2 selective inhibitors comprising at least one nitric oxide enhancing group, and pharmaceutically acceptable salts thereof.
  • the cyclooxygenase 2 selective inhibitors of the invention are 2(2-((2-chloro-6-fluorophenyl) amino)5-methyl ⁇ henyl)acetic acid derivatives.
  • the nitric oxide enhancing groups are nitroxides and/or heterocyclic nitric oxide donor groups that are linked to the COX-2 selective inhibitor compounds through one or more sites such as oxygen (hydroxy! 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 -koines.
  • 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 COX-2 selective inhibitor 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 COX-2 selective inhibitor compound.
  • 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 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 COX-2 selective inhibitor, comprising 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 (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
  • compositions comprising at least one COX-2 selective inhibitor comprising 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 pylori inhibitor, a phosphodiesterase inhibitor
  • 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 COX-2 selective inhibitor, comprising 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 resulting from the use of drugs; (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 in a patient in need thereof comprising administering to the patient an effective amount of at least one COX-2 selective inhibitor comprising 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
  • the methods can optionally further comprise the administration of at least one nitric oxide enhancing compound.
  • the methods can involve (i) administering the selective inhibitors comprising at least one nitric oxide enhancing group, (ii) administering the selective cyclooxygenase-2 COX-2 inhibitors comprising at least one nitric oxide enhancing group and nitric oxide enhancing compound, (iii) administering the selective COX-2 inhibitors comprising at least one nitric oxide enhancing group and therapeutic agents, or (iv) administering the selective COX-2 inhibitors comprising at least one nitric oxide enhancing group, nitric oxide enhancing compounds, and therapeutic agents.
  • the selective COX-2 inhibitors comprising 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 selective cyclooxygenase-2 (COX-2) inhibitor comprising at least one nitric oxide enhancing group, and, optionally, at least one nitric oxide enhancing 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glau
  • the selective cyclooxygenase-2 (COX-2) inhibitor comprising at least one nitric oxide enhancing group, the nitric oxide enhancing compound 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 earners.
  • 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-EUison 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.
  • NSAID refers to a nonsteroidal anti-inflammatory compound or a nonsteroidal antiinflammatory drug. NSAIDs inhibit cyelooxygenase, 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 IC 50 of less than about 2 ⁇ M and a cyclooxygenase- 1 IC 5O 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 IC 50 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.
  • 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, wound
  • Heart failure includes, but is not limited to congestive heart failure, compensated heart failure, decompensated heart failure, 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”.
  • 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.
  • Optid disorders include, but are not limited to, glaucoma, elevated intraocular pressure, ocular pain (e.g., following corneal surgery), cataracts, ophthalmic infections, 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
  • Opti infections include, but are not limited, to an inflammation of the conjunctiva (conjunctivitis), inflammation of the cornea (keratitis), corneal ulcers, and the like, caused by an organisms such as, for example, Staphylococci, Streptococci, Enterococci, Bacillus, Corynebacterium, Chlamydia, Neisseria, and the like, including important species of these genus such as, for example, Staphloccus aureus, Streptococcus viridans, Staphloccus epidermidis, Streptococcus pneumoniae, staphylococci, streptococci, enterococci, and the like.
  • an organisms such as, for example, Staphylococci, Streptococci, Enterococci, Bacillus, Corynebacterium, Chlamydia, Neisseria, and the like, including important species of these genus such as, for example, Staphloccu
  • 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, brachial
  • 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.
  • 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 (NSADD), 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, is
  • 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 and/or nitroxide derivatives.
  • nitric oxide donors have therapeutic activity
  • therapeutic agent dose not include the nitric oxide enhancing compounds described herein, since nitric oxide enhancing compounds are separately defined.
  • 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 + -ATP ase enzyme system at the secretory surface of the gastric parietal cell.
  • 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.
  • 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.
  • Thiboxane synthase inhibitor refers to any compound that reversibly or irreversibly inhibits the enzyme thromboxane synthesis thereby reducing the formation of thromboxane Az. 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 VlH 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.
  • Plate 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.
  • Effective amount refers to the amount of the compound and/or composition that is effective to achieve its intended purpose.
  • 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.
  • the radical scavenging compound contains a nitroxide group.
  • Neroxide 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.
  • N-oxide a stable aminoxyl radical
  • 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, oxatxiazol-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 gi'oup, 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 -Ci 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 -Ci 0 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 groups, wherein each R 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 -C 8 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.
  • 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.
  • 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
  • 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 Ca-Ci 0 hydrocarbon (preferably a C 2 - Cg 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, phenylethyl, 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-fluoro ⁇ henylethyl, 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.
  • Ary Heterocyclic 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 R5 0 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 R 55 O-, wherein R 55 is an aryl group, as defined herein.
  • exemplary arylkoxy groups include napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like.
  • Alkylthio refers to R 50 S-, wherein R 5 0 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 benzyl thiomethyl, 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 R 54 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 5 4 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.
  • 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.
  • “Hydroxyalkyl” 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 .
  • Thionitrite and “nitrosothiol” refer to -S-NO.
  • Niro refers to the group -NO 2 and “nitrosated” refers to compounds that have been substituted therewith.
  • Niroso refers to the group -NO and “nitrosylated” refers to compounds that have been substituted therewith.
  • Halogen or “halo” refers to iodine (I), bromine (Br), chlorine (Cl), and/or fluorine
  • 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 R 50 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 R 52 R 53 N-, wherein R 52 and R 53 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 RO O N-, wherein R 55 and R 60 are each independently an aryl group, as defined herein.
  • Alkylarylamino or “arylalkylamino” refers to R 52 Rs S N-, wherein R 52 is an alkyl group, as defined herein, and R 55 is an aryl group, as defined herein.
  • Alkylarylalkylamino refers to R 52 RTON-, wherein R 52 is an alkyl group, as defined herein, and R 79 is an arylalkyl group, as defined herein.
  • Alkylcycloalkylamino refers to R 52 R 8 oN-, wherein R 52 is an alkyl group, as defined herein, and Rso 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.
  • Sulfinyl refers to -S(O)-.
  • Method refers to -C(S)-.
  • Sulfonic acid refers to -S(O) 2 OR 7O , 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 R 5 8 is an alkyl group, an aryl group, or an aryl heterocyclic ring, as defined herein.
  • “Sulfonamido” refers to -S(O) 2 -N(R 5 i)(R 5 7), wherein Rs 1 and R57 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.
  • 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 R 50 S-, wherein R 50 is an alkyl group, as defined herein
  • Arylthio refers to R 55 S-, wherein R 55 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 Rs 0 -S(O)-, wherein R 50 is an alkyl group, as defined herein.
  • Alkylsulfonyl refers to Rs O -S(O) 2 -, wherein R 50 is an alkyl group, as defined herein.
  • Alkylsulfonyloxy refers to Rs O -S(O) 2 -O-, wherein R 50 is an alkyl group, as defined herein.
  • Arylsulfinyl refers to Rs 5 -S(O)-, wherein R 55 is an aryl group, as defined herein.
  • Arylsulfonyl refers to R 5S -S(O) 2 -, wherein R 55 is an aryl group, as defined herein.
  • Arylsulfonyloxy refers to R 55 -S(O) 2 -O-, wherein R 55 is an aryl group, as defined herein.
  • “Amidyl” refers to R 51 C(O)N(R 57 )- wherein R 51 and Rs 7 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
  • Ester refers to R 51 C(O)Rs 2 - wherein R5 1 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein and Rg 2 is oxygen or sulfur.
  • Carbamoyl refers to -0-C(O)N(RsO(Rs?), wherein R51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R 5 i 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 Rs 5 -R 52 -C(O)-, wherein R 55 is an aryl group, as defined herein, and Rs 2 is an alkyl group, as defined herein.
  • Alkylarylcarbonyl refers to Rs 2 -R 5S -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.
  • 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 5I )(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, 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 5 ⁇ -C(O)N(R 5J )(R 57 ) wherein R 5i , R 57 , 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 70 )(R 71 )(R 72 ), wherein R 70 is a lone pair of electrons, thial 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)(OR 5 OOH 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)(R 5 i)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 invention described COX-2 selective inhibitor compounds of Formula (I), and pharmaceutically acceptable salts thereof;
  • R 4 is methyl or ethyl
  • R 5 is chloro or fluoro
  • Re is hydrogen or fluoro
  • R 7 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxyl;
  • R 8 is hydrogen or fluoro
  • R 9 is chloro, fluoro, trifluoromethyl or methyl;
  • K is:
  • V 4 is V 3 , R 6 , -U 3 -V 5 or V 6 ;
  • V 3 is:
  • R 24 is -C 6 H 4 R 37 , -CN, -S(O) 2 -C 6 H 4 R 37 , -C(O)-N(R 8 )(Ri), -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 8 )(RO, -NO 2 Or -C(O)-OR 25 ;
  • T' is oxygen, sulfur or NR 16 ;
  • Ri 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 )(R f )) h -, -N(R a )Ri, an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, -(CH 2 CH 2 O) q i- or a heterocyclic nitric oxide donor;
  • E at each occurrence is independently -T 3 -, an alkyl group, an aryl group, -(C(Re)(R f ) )ir, a heterocyclic ring, an arylheterocyclic ring, -(CH 2 CH 2 O) q i- 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;
  • R j 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, -S(O) 0 - or -N(R 8 )R 1 ; h is an integer from 1 to 10; qi is an integer from 1 to 5;
  • 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 alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkyl
  • U 3 is an oxygen, sulfur or -N(R 3 )Ri;
  • V 5 is -NO or -NO 2 (i.e. an oxidized nitrogen); ki 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 alkylcarboxarnido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, an arylsulphonyloxy, a sulfonamide, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, -CHa-C-(Ua-V 5 )(Re)(R f ), a bond to an adjacent atom creating a double bond to that atom or
  • the COX-2 selective inhibitor is 2(2-((2-chloro-6 ⁇ fluorophenyl)amino)5-methylphenyl) acetic acid (COX 189, registration number 220991-20- 8), and its derivatives, as disclosed in, for example, WO 99/11605, WO 01/23346 and WO 02/20090, the disclosures of each of which are incorporated by reference herein in their entirety.
  • the structure of the COX-2 selective inhibitor, 2(2-((2-chloro-6- fluorophenyl)amino)5- methylphenyl)acetic acid (COX 189), is shown below:
  • the COX-2 selective inhibitors of Formula (I) is a nitric oxide enhancing COX 189 of Formula (II), wherein the compound of Formula (II) is:
  • T' is oxygen, sulfur or NRi 6 ;
  • Ri 6 is a hydrogen, a lower alkyl group, or an aryl group;
  • R n is: a hydrogen or:
  • R 24 is -C 6 H 4 R 37 , -CN, -S(O) 2 -C 6 H 4 R 37 , -C(O)-N(Ra)(R;), -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 8 )(Ri), -NO 2 or -C(O)-OR 25 ;
  • T' is oxygen, sulfur or NRi 6 ;
  • Ri 6 is a hydrogen, a lower alkyl group, or an aryl group
  • R a , Rj, R j , Rt, R e and R f are as defined herein; and with the proviso that the compound of Formula (II) must contain at least one nitric oxide enhancing group linked to the compound of Formula (II) through an oxygen atom, a nitrogen atom or a sulfur atom via a bond or moiety that can be hydrolyzed.
  • the invention describes COX-2 selective inhibitor compounds of the invention comprising a nitric oxide enhancing group and pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts do not include the nitrate salt.
  • 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. It is to be understood that the invention anticipates and includes within its scope all such isomers and mixtures thereof.
  • Another embodiment of the invention describes the metabolites of the COX-2 selective inhibitor comprising a nitric oxide enhancing group and pharmaceutically acceptable salts thereof.
  • These metabolites include but are not limited to, the non-nitric oxide enhancing derivatives, degradation products, hydrolysis products, and the like, of the COX-2 selective inhibitor comprising a nitric oxide enhancing group and pharmaceutically acceptable salts thereof.
  • Another embodiment of the invention provides processes for making the novel compounds of the invention and to the intermediates useful in such processes.
  • 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 compounds of the invention can be synthesized in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or 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.
  • all starting materials are known or readily prepared from known starting materials. Methods for the preparation of the compounds, include, but are not limited to, those described below. All references cited herein are hereby incorporated herein by reference in their entirety.
  • the compounds of Formulas (I) and (II) can be synthesized by one skilled in the art using conventional methods.
  • the synthesis of the parent COX-2 inhibitors i.e. the COX-2 selective inhibitors that do not contain a nitric oxide enhancing group
  • the COX-2 selective inhibitor compounds that are substituted to contain at least one nitric oxide enhancing group linked to the COX-2 selective inhibitor compound through one or more sites such as oxygen, sulfur and/or nitrogen can be synthesized using conventional methods known to one skilled in the art.
  • the methods of linking the nitric oxide enhancing group to compounds described in these references can be applied by one skilled in the art to produce any of the COX-2 selective inhibitor compounds comprising a nitric oxide enhancing group described herein.
  • the COX-2 selective inhibitor compounds comprising a nitric oxide enhancing group of the invention donate or transfer a biologically active form of nitrogen monoxide (i.e., nitric oxide).
  • COX-2 selective inhibitor compounds that contain a nitric oxide enhancing group, linked through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen, are, optionally, used in combination with nitric oxide enhancing compounds that release nitric oxide, increase endogenous 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- ammoniopro ⁇ yl)-N-(n-propyl)amino)diazen-l-ium-l,2-diolate (“PAPA/NO”), (Z)-l-(N-(3- aminopropyl)-N-(4-(3-aminopropylammonio)butyl)-amino) diazen-l-ium-l,2-diolate (spermine NONOate or "SPER/NO”) and sodium(Z)-l ⁇ (N,N- diemylamino)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,
  • Suitable sydnonimines include, but are not limited to, molsidomine (N- ethoxycarbonyl-3-morpholinosydnonimine), SIN-I (3-morpholinosydnonimine) CAS 936 (3- (cis-2,6-dimethylpiperidmo)-N-(4-methoxybenzoyl)-sydnonimine, pirsidomine), C87-3754 (3-(cis-2,6-dimethylpiperidino)sydnonimine, 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-rritrosothiols, 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.
  • 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-nitros
  • 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 alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkyl
  • U 3 is an oxygen, sulfur- or -N(R a )Rf,
  • V 5 is -NO or -NO 2 (i.e. an oxidized nitrogen);
  • R a is a lone pair of electrons, a hydrogen or an alkyl group
  • R 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 -Vs)(R 6 )(R f ), a bond to an adjacent atom creating a double bond to that atom or -(N 2 Or) ⁇ M 1 + , wherein Mi + is an organic or in
  • R e and R f are independently a heterocyclic ring or taken together R e and R f are a heterocyclic ring, then Rj can be a substituent on any disubstituted nitrogen contained within the radical wherein Ri 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, thiazole-2-nitrosimines, oligonitroso sydnonimines, 3-alkyl-N-nitroso-
  • 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.
  • N-oxo-N-nitrosoamines that donate, transfer or release nitric oxide and are represented by the formula: R 1 R 2 N-N(0-M + )-N0, where R 1 and R 2 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 Mi + 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, immo(((4-methylphenyl)methyl) amino)methylhydroxylamine, imino(((4-methoxyphenyl)methyl)amino) methylhydroxylamine, imino(((4-(trifluoromethyl)phenyl)methyl) amino) methylhydroxylamine, imino((4-nitiOphenyl) methyl)amino)methylhydroxylamine, (butylamino) iminomethylhydroxylamine, imino (propylamino) methylhydroxylamine, imino(pentylamino)methylhydroxylamine, imino (propylamino)methylhydroxylamine, imino ((methylethyl)amino)methylhydroxylamine, (cyclopropylamino) iminomethylhydroxylamine, imino-2-l,2,3,4-
  • 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)).
  • 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-pyi ⁇ oline-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 therapeutic agents, 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, sedating or non-sedating anti-hiscami ⁇ es, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors
  • Suitable steroids include, but are not limited to, budesonide, dexamethasone, corticosterone, prednisolone, and the like. Suitable steroids are described more fully in the literature, such as in the Merck Index on CD-ROM, 13 th Edition.
  • Suitable COX-2 inhibitors include, but are not limited to, nimesulide, celecoxib
  • 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 does or as multiple doses per day;
  • the lumiracoxib is administered in an amount of about 40 milligrams to about 1200 milligrams as a single does or as multiple doses per day;
  • the paracoxib is administered in an amount of about 20 milligrams to about 100 milligrams as a single does 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 does or as multiple doses per day;
  • Suitable NSAIDs 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 does or as multiple doses per day;
  • the flurbiprofen is administered in an amount of about 100 milligrams to about 300 milligrams as a single does 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 does or as multiple doses per day;
  • the indomethacin is administered in an amount of about 25 milligrams to about 200 milligrams as a single does 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 leukotriene A 4 hydrolase with an IC 50 of less than about lO ⁇ M, and preferably with an IC5 0 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-(hydroxycarbamoyI)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] agonists, 5-HT IB agonists and 5-HT ID 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 (PRAVACHOL®), 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 acid
  • 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 does 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 H 2 receptor anatgonists include, but are not limited to, cimetidine, roxatidine, rantidine 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 hydralazine compounds include, but are not limited to, compounds having the formula: wherein a, b and c are independently a single or double bond; Ri and 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, R 2 , R 3 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 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 ⁇ b/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- (aminoiminomethyl)-4-piperidinyl)methyl)-N-(3,3-diphenylpropinyl)-L-proline amide),3-(2- phenylethylamino)-6-methyl- 1 - (2-amino-6-methyl-5 -methylene- carboxamidomethylpyridinyl)-2-pyrazinone, 3-(2-phenethylamino)-6-methyl-l-(2-amino-6- methyl-5- methylenecarboxamidomethylpyridinyl)-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, 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, chlor
  • 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 antitussives include, but are not limited to, codeine, hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like.
  • Suitable inducible nitric oxide synthase (iNOS) inhibitors are disclosed in U. S. Patent
  • Suitable opioids 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, piroximon
  • Suitable proton pump inhibitors include, but are not limited to, disulprazole, esomeprazole, lansoprazole, leminoprazole, omeprazole, pantoprazole, rabeprazole, timoprazole, tenatoprazole, 2-(2-benzimidazolyI)-pyridine, 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)
  • 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.
  • Suitable compounds used for the treatment of glaucoma include, but are not limited to, acetylcholinesterase inhibitors (such as, for example, citicoline, donepezil, heptatigmine, galantamine, metafonate, physostignine, rivastignine, tarcine, velnacrine, and the like) carbachol, pilocarpine and the like.
  • acetylcholinesterase inhibitors such as, for example, citicoline, donepezil, heptatigmine, galantamine, metafonate, physostignine, rivastignine, tarcine, velnacrine, and the like
  • carbachol such as in Goodman and Gilman
  • compositions comprising (i) selective COX-2 inhibitors comprising at least one nitric oxide enhancing group or pharmaceutically acceptable salt thereof, (ii) a nitric oxide enhancing compound, such as, isosorbide dinitrate and/or isosorbide mononitrate (such as, isosorbide dinitrate), and (iii) a hydralazine compound (such as, hydralazine hydrochloride).
  • a nitric oxide enhancing compound such as, isosorbide dinitrate and/or isosorbide mononitrate (such as, isosorbide dinitrate)
  • a hydralazine compound such as, hydralazine hydrochloride
  • the hydralazine hydrochloride can be administered in an amount of about 30 milligrams per day to about 400 milligrams per day; the isosorbide dinitrate can be administered in an amount of about 10 milligrams per day to about 200 milligrams per day; or the isosorbide mononitrate can be administered in an amount of about 5 milligrams per day to about 120 milligrams per day.
  • the hydralazine hydrochloride can be administered in an amount of about 50 milligrams per day to about 300 milligrams per day, the isosorbide dinitrate can be administered in an amount of about 20 milligrams per day to about 160 milligrams per day; or the isosorbide mononitrate can be administered in an amount of about 15 milligrams per day to about 100 milligrams per day.
  • the hydralazine hydrochloride can be administered in an amount of about 37.5 milligrams to about 75 milligrams one to four times per day; the isosorbide dinitrate can be administered in an amount of about 20 milligrams to about 40 milligrams one to four times per day; or the isosorbide mononitrate can be administered in an amount of about 10 milligrams to about 20 milligrams one to four times per day.
  • the patient can be administered a composition comprising about 225 mg hydralazine hydrochloride and about 120 mg isosorbide dinitrate once per day (i.e., q.d.).
  • the patient can be administered a composition comprising about 112.5 mg hydralazine hydrochloride and about 60 mg isosorbide dinitrate twice per day (i.e., b.i.d.). In another embodiment of the methods of the invention, the patient can be administered a composition comprising about 56.25 mg hydralazine hydrochloride and about 30 mg isosorbide dinitrate twice per day (i.e., b.i.d.). In another embodiment of the methods of the invention, the patient can be administered a composition comprising about 75 mg hydralazine hydrochloride and about 40 mg isosorbide dinitrate three times per day (i.e., t.i.d.).
  • the patient can be administered a composition comprising about 37.5 mg hydralazine hydrochloride and about 20 mg isosorbide dinitrate three times per day (i.e., ti.d.).
  • the particular amounts of hydralazine and isosorbide dinitrate or isosorbide mononitrate can be administered as a single dose once a day; or in multiple doses several times throughout the day; or as a sustained-release oral formulation, or as an injectable formulation.
  • the invention provides methods for treating inflammation, pain (both chronic and acute), and 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, menstrual cramps; 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,
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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 COX-2 selective inhibitor compound comprising 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound.
  • the COX-2 selective inhibitor compounds comprising 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.
  • 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-EUison 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
  • bacterial infections including, for example, a Helicobacter Pylori associated disease
  • short-bowel (anastomosis) syndrome hypersecretory states associated with systemic mastocytosis
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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 COX-2 selective inhibitor compound comprising 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound.
  • the COX-2 selective inhibitor compounds comprising 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 COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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 COX-2 selective inhibitor compound comprising 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter py
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound.
  • the COX-2 selective inhibitor compounds comprising 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, respiratory and other toxicity (such as, for example, kidney toxicity) resulting from the use of drugs, such as, nonsteroidal anti-inflammatory drugs and/or COX-2 inhibitors 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 COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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 COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, including but not limited to, such as, for example, steroids, selective 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, sedating or non-sedating antihistamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiestea, a
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound.
  • the COX-2 selective inhibitor compounds comprising 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 COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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 COX-2 selective inhibitor compound comprising 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- hypeiiipidemic compounds, H 2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound.
  • the COX-2 selective inhibitor compounds comprising 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
  • 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.
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group.
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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 COX-2 selective inhibitor compound comprising 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, decongestant
  • the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound.
  • the COX-2 selective inhibitor compounds comprising 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 COX-2 selective inhibitor comprising at least 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 COX-2 selective inhibitor comprising 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 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 COX-2 selective inhibitor optionally substituted with at least 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 earners, adjuvants, and vehicles, as desired.
  • Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • the organic nitric oxide enhancing salt of the NSAID 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 II (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 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.
  • 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 earner such as lactose, saccharose, sorbitol, mannitol, potato starch, com 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 deletei ⁇ ously 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 deletei ⁇ ously 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 deletei ⁇ ously 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.
  • 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, preferably crystalline, solid form.
  • microparticle dosage forms comprising pure, preferably crystalline, therapeutic agents are preferred.
  • 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.
  • Preferred 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 antiproliferative 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.
  • 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 COX-2 inhibitor comprising at least one nitric oxide enhancing group or a pharmaceutically acceptable salt thereof, and, optionally at least one nitric oxide enhancing compound, or the sustained release formulations can comprise an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group or a pharmaceutically acceptable salt thereof, and at least one therapeutic agent , and, optionally, at least one nitric oxide enhancing compound.
  • compositions of the invention can be formulated as pharmaceutically acceptable salt forms.
  • Pharmaceutically acceptable salts include, for example, alkali metal salts and addition salts of free acids or free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically- acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid and the like.
  • organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, algenic, ⁇ -hydroxybutyric, cyclohexylaminosulfonic, galactaric and gal
  • Suitable pharmaceutically-acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from primary, secondary and tertiary amines, cyclic amines, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine and the like.
  • AU of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • the pharmaceutically acceptable salts of the compounds of the invention do not include the nitrate salt.
  • 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 COX-2 selective compound comprising 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 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 novel COX-2 selective inhibitor compounds comprising 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 (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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of gla
  • steroids

Abstract

The invention describes compositions and kits comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor comprising at least one nitric oxide enhancing group, or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor comprising at least one nitric oxide enhancing group, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. 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 cyclooxygenase 2 selective inhibitors of the invention are 2(2-((2-chloro-6-fluorophenyl) amino)5-methylphenyl)acetic acid derivatives comprising at least one nitric oxide enhancing group. The nitric oxide enhancing groups are nitroxides and/or heterocyclic nitric oxide donors.

Description

CYCLOOXYGENASE-2 SELECTIVE INHIBITOR COMPOUNDS COMPRISING NITRIC OXIDE ENHANCING GROUPS, COMPOSITIONS AND METHODS OF
USE
RELATED APPLICATIONS
This application claims priority under 35 USC § 119 to U.S. Application No. 60/702,639 filed July 27, 2005; the disclosures of which is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION The invention describes compositions and kits comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor compound comprising at least one nitric oxide enhancing group, or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. 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 cyclooxygenase 2 selective inhibitors of the invention are 2(2-((2-chloro-6- fluorophenyl) amino)5-methylphenyl)acetic acid derivatives comprising at least one nitric oxide enhancing group. The nitric oxide enhancing groups are nitroxides and/or heterocyclic nitric oxide donors.
BACKGROUND OF THE INVENTION
Nonsteroidal anti-inflammatory compounds (NSAIDs) 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 NSADDs 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.
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 NSAEDs 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 and/or respiratory 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 COX-2 selective inhibitors comprising at least one nitric oxide enhancing group, and pharmaceutically acceptable salts thereof. The cyclooxygenase 2 selective inhibitors of the invention are 2(2-((2-chloro-6-fluorophenyl) amino)5-methylρhenyl)acetic acid derivatives. The nitric oxide enhancing groups are nitroxides and/or heterocyclic nitric oxide donor groups that are linked to the COX-2 selective inhibitor compounds through one or more sites such as oxygen (hydroxy! 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 -koines. 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 COX-2 selective inhibitor 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 COX-2 selective inhibitor compound. 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 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 COX-2 selective inhibitor, comprising 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 compounds used for the treatment of glaucoma, 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 COX-2 selective inhibitor comprising 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. 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 COX-2 selective inhibitor, comprising 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 resulting from the use of drugs; (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 in a patient in need thereof comprising administering to the patient an effective amount of at least one COX-2 selective inhibitor comprising 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, 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 selective inhibitors comprising at least one nitric oxide enhancing group, (ii) administering the selective cyclooxygenase-2 COX-2 inhibitors comprising at least one nitric oxide enhancing group and nitric oxide enhancing compound, (iii) administering the selective COX-2 inhibitors comprising at least one nitric oxide enhancing group and therapeutic agents, or (iv) administering the selective COX-2 inhibitors comprising at least one nitric oxide enhancing group, nitric oxide enhancing compounds, and therapeutic agents. The selective COX-2 inhibitors comprising 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 selective cyclooxygenase-2 (COX-2) inhibitor comprising at least one nitric oxide enhancing group, and, optionally, at least one nitric oxide enhancing 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, and combinations of two or more thereof. The selective cyclooxygenase-2 (COX-2) inhibitor comprising at least one nitric oxide enhancing group, the nitric oxide enhancing compound 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 earners. 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-EUison 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 cyelooxygenase, 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 IC5O 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. "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. "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.
"Heart failure" includes, but is not limited to congestive heart failure, compensated heart failure, decompensated heart failure, 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".
"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.
"Ophthalmic disorders" include, but are not limited to, glaucoma, elevated intraocular pressure, ocular pain (e.g., following corneal surgery), cataracts, ophthalmic infections, 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. "Ophthalmic infections" include, but are not limited, to an inflammation of the conjunctiva (conjunctivitis), inflammation of the cornea (keratitis), corneal ulcers, and the like, caused by an organisms such as, for example, Staphylococci, Streptococci, Enterococci, Bacillus, Corynebacterium, Chlamydia, Neisseria, and the like, including important species of these genus such as, for example, Staphloccus aureus, Streptococcus viridans, Staphloccus epidermidis, Streptococcus pneumoniae, staphylococci, streptococci, enterococci, and the like.
"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.
"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 (NSADD), 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, 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 and/or nitroxide derivatives. Although nitric oxide donors have therapeutic activity, the term "therapeutic agent" dose not include the nitric oxide enhancing compounds described herein, since nitric oxide enhancing compounds are separately defined.
"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+-ATP ase enzyme system at the secretory surface of the gastric parietal cell.
"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 Az. 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 each of which are incorporated by reference herein in their 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 VlH 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.
"Effective amount" refers to the amount of the compound and/or composition that is effective to achieve its intended purpose.
"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, oxatxiazol-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 gi'oup, 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-CiO 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-Ci0 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 R groups, wherein each R 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-C8 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-ρyranyl, 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 Ca-Ci0 hydrocarbon (preferably a C2- Cg 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, phenylethyl, 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-fluoroρhenylethyl, 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.
"Ary Heterocyclic 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 benzyl thiomethyl, 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 R54O-, 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 =0.
"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-0R81 wherein R8i 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(R8i)(R'si) wherein R'si is independently selected from R8I, and R8] 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 "nitrosylated" 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 -C(=N-R5])- 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 R52R53N-, wherein R52 and R53 are each independently an alkyl group, as defined herein. Exemplary dialkylamino groups include dimethylamino, diethylamino, methyl propargylamino, and the like.
"Diarylamino" refers to R55ROON-, wherein R55 and R60 are each independently an aryl group, as defined herein. "Alkylarylamino" or "arylalkylamino" refers to R52RsSN-, wherein R52 is an alkyl group, as defined herein, and R55 is an aryl group, as defined herein.
"Alkylarylalkylamino " refers to R52RTON-, wherein R52 is an alkyl group, as defined herein, and R79 is an arylalkyl group, as defined herein.
"Alkylcycloalkylamino" refers to R52R8oN-, wherein R52 is an alkyl group, as defined herein, and Rso 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. "Sulfinyl" 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)2OR7O, 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 R58 is an alkyl group, an aryl group, or an aryl heterocyclic ring, as defined herein.
"Sulfonamido" refers to -S(O)2-N(R5i)(R57), wherein Rs1 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.
"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 Rs0-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 Rs5-S(O)-, wherein R55 is an aryl group, as defined herein. "Arylsulfonyl" refers to R5S-S(O)2-, wherein R55 is an aryl group, as defined herein.
"Arylsulfonyloxy" refers to R55-S(O)2-O-, wherein R55 is an aryl group, as defined herein.
"Amidyl" refers to R51C(O)N(R57)- wherein R51 and Rs7 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
"Ester" refers to R51C(O)Rs2- wherein R51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein and Rg2 is oxygen or sulfur.
"Carbamoyl" refers to -0-C(O)N(RsO(Rs?), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R5i 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 Rs5-R52-C(O)-, wherein R55 is an aryl group, as defined herein, and Rs2 is an alkyl group, as defined herein.
"Alkylarylcarbonyl" refers to Rs2-R5S-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(R5I)(Rs7), 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(R5^-C(O)N(R5J)(R57) wherein R5i, 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(R70)(R71)(R72), wherein R70 is a lone pair of electrons, thial 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)(OR5OOH 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)(R5i)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, the invention described COX-2 selective inhibitor compounds of Formula (I), and pharmaceutically acceptable salts thereof;
Figure imgf000022_0001
(D wherein:
R4 is methyl or ethyl; R5 is chloro or fluoro;
Re is hydrogen or fluoro;
R7 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxyl;
R8 is hydrogen or fluoro;
R9 is chloro, fluoro, trifluoromethyl or methyl; K is:
Ca) -^)3-Eb-(C(Re)(Rf))P1-Ee-(C(Re)(Rf))K-(W3)C-(C(Re)(Rf)V(W3)J-Ej-(W3)S- (C(Re)(Rf))z-V4; or
Cb) -(Ws)3-Eb-(C(Re)(Rf))P1-Ec-(C(Re)(Rf))X-(W3)C-(C(Re)(Rf))^(W3)J-Ej-(W3)S-
Figure imgf000023_0001
with the proviso that at least one Re is selected as -U3-V5, or -C(R0)(Rp)id -U3-Vs, when K is (b);
Figure imgf000023_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, 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)(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 NR16;
Ri6 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(Ra)Ri, an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, -(CH2CH2O) qi- or a heterocyclic nitric oxide donor;
E at each occurrence is independently -T3-, an alkyl group, an aryl group, -(C(Re)(Rf) )ir, a heterocyclic ring, an arylheterocyclic ring, -(CH2CH2O)qi- 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, -S(O)0- or -N(R8)R1; h is an integer from 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-V5, V6, - (C(R0)(Rp)X1-U3-V5, -(C(Ro)(Rp))M-U3-V3, -(C(Ro)(Rp))ICi-U3-V6, -(C(R0)(Rp)^i-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 alkylarylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an aiylalkoxy, 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, V^ 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(R3)Ri;
V5 is -NO or -NO2 (i.e. an oxidized nitrogen); ki 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 alkylcarboxarnido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, an arylsulphonyloxy, a sulfonamide, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, -CHa-C-(Ua-V5)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom or -(N2θ2-)»Mi+, wherein Mi+ is an organic or inorganic cation; and with the proviso that the compound of Formula (I) must contain at least one nitric oxide enhancing group linked to the compound of Formula (I) through an oxygen atom, a nitrogen atom or a sulfur atom via a bond or moiety that can be hydrolyzed.
In cases where multiple designations of variables which 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, E0 would denote a covalent bond, while E2 denotes (E-E) and (C(R4)(R4O)2 denotes -C(R4)(R4J-C(R4)(R4)-.
In one embodiment the COX-2 selective inhibitor is 2(2-((2-chloro-6~ fluorophenyl)amino)5-methylphenyl) acetic acid (COX 189, registration number 220991-20- 8), and its derivatives, as disclosed in, for example, WO 99/11605, WO 01/23346 and WO 02/20090, the disclosures of each of which are incorporated by reference herein in their entirety. The structure of the COX-2 selective inhibitor, 2(2-((2-chloro-6- fluorophenyl)amino)5- methylphenyl)acetic acid (COX 189), is shown below:
Figure imgf000029_0001
In other embodiments of the invention, the COX-2 selective inhibitors of Formula (I) is a nitric oxide enhancing COX 189 of Formula (II), wherein the compound of Formula (II) is:
Figure imgf000030_0001
(H) wherein:
T' is oxygen, sulfur or NRi6;
Ri6 is a hydrogen, a lower alkyl group, or an aryl group; Rn is: a hydrogen or:
Figure imgf000030_0002
Figure imgf000031_0001
Figure imgf000032_0001
R24 is -C6H4R37, -CN, -S(O)2-C6H4R37, -C(O)-N(Ra)(R;), -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)(Ri), -NO2 or -C(O)-OR25;
T' is oxygen, sulfur or NRi6;
Ri6 is a hydrogen, a lower alkyl group, or an aryl group;
Ra, Rj, Rj, Rt, Re and Rf are as defined herein; and with the proviso that the compound of Formula (II) must contain at least one nitric oxide enhancing group linked to the compound of Formula (II) through an oxygen atom, a nitrogen atom or a sulfur atom via a bond or moiety that can be hydrolyzed.
In another embodiment, the invention describes COX-2 selective inhibitor compounds of the invention comprising a nitric oxide enhancing group and pharmaceutically acceptable salts thereof. In one embodiment, the pharmaceutically acceptable salts do not include the nitrate salt.
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. It is to be understood that the invention anticipates and includes within its scope all such isomers and mixtures thereof.
Another embodiment of the invention describes the metabolites of the COX-2 selective inhibitor comprising a nitric oxide enhancing group and pharmaceutically acceptable salts thereof. These metabolites, include but are not limited to, the non-nitric oxide enhancing derivatives, degradation products, hydrolysis products, and the like, of the COX-2 selective inhibitor comprising a nitric oxide enhancing group and pharmaceutically acceptable salts thereof.
Another embodiment of the invention provides processes for making the novel compounds of the invention and to the intermediates useful in such processes. 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 for the preparation of the compounds of this invention. The chemical reactions are described by, for example, Smith and March, March's Advanced Organic Chemistry, Reactions, Mechanisms and Structure, Fifth Edition, John Wiley & Sons, New York (2001) and by Larock, Comprehensive Organic Transformations, VCH Publishers, Inc. (1989). The compounds of the invention can be synthesized in a number of ways well known to one skilled in the art of organic synthesis. The compounds can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or 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. Methods for the preparation of the compounds, include, but are not limited to, those described below. All references cited herein are hereby incorporated herein by reference in their entirety.
The compounds of Formulas (I) and (II) can be synthesized by one skilled in the art using conventional methods. The synthesis of the parent COX-2 inhibitors (i.e. the COX-2 selective inhibitors that do not contain a nitric oxide enhancing group) are disclosed in, for example, WO 99/11605, WO 01/23346 and WO 02/20090, the disclosures of each of which are incorporated by reference herein in their entirety. The COX-2 selective inhibitor compounds that are substituted to contain at least one nitric oxide enhancing group linked to the COX-2 selective inhibitor compound through one or more sites such as oxygen, sulfur and/or nitrogen can be synthesized using conventional methods known to one skilled in the art. Known methods for linking the nitric oxide enhancing group to compounds are described in WO 99/64417, WO 94/01422; EP 0 574 726 Al, EP 0 683 159 Al; and in J. Med. Chem., 47: 2688-2693 (2004); J. Med. Chem., 47: 1840-1846 (2004); /. Med. Chem ., 46: 3762-3765 (2003); /. Med. Chem., 46: 747-754 (2003); Chem Rev., 102: 1091-1134 (2002); /. Med. Chem., 42: 1941-1950 (1999); /. Med. Chem., 41: 5393-5401 (1998); /. 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 nitric oxide enhancing group to compounds described in these references can be applied by one skilled in the art to produce any of the COX-2 selective inhibitor compounds comprising a nitric oxide enhancing group described herein. The COX-2 selective inhibitor compounds comprising a nitric oxide enhancing group of the invention donate or transfer a biologically active form of nitrogen monoxide (i.e., nitric oxide).
Compounds contemplated for use in the invention, e.g., COX-2 selective inhibitor compounds that contain a nitric oxide enhancing group, linked through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen, are, optionally, used in combination with nitric oxide enhancing compounds that release nitric oxide, increase endogenous 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- ammonioproρyl)-N-(n-propyl)amino)diazen-l-ium-l,2-diolate ("PAPA/NO"), (Z)-l-(N-(3- aminopropyl)-N-(4-(3-aminopropylammonio)butyl)-amino) diazen-l-ium-l,2-diolate (spermine NONOate or "SPER/NO") and sodium(Z)-l~(N,N- diemylamino)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-dimethylpiperidmo)-N-(4-methoxybenzoyl)-sydnonimine, pirsidomine), C87-3754 (3-(cis-2,6-dimethylpiperidino)sydnonimine, 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-rritrosothiols, 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)ra-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 sulfonarnido, 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, - (C(R0)(Rp))H-U3-V5, -(C(R0)(Rp)X1-U3-V6, -(C(R0)(Rp))M-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 imgf000037_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 imgf000038_0001
ki is an integer form 1 to 3; U3 is an oxygen, sulfur- or -N(Ra)Rf,
V5 is -NO or -NO2 (i.e. an oxidized nitrogen);
Ra is a lone pair of electrons, a hydrogen or an alkyl group;
R; 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-Vs)(R6)(Rf), a bond to an adjacent atom creating a double bond to that atom or -(N2Or)^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 Rj can be a substituent on any disubstituted nitrogen contained within the radical wherein Ri 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, thiazole-2-nitrosimines, 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(0-M+)-N0, where R1 and R2 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 Mi+ 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, immo(((4-methylphenyl)methyl) amino)methylhydroxylamine, imino(((4-methoxyphenyl)methyl)amino) methylhydroxylamine, imino(((4-(trifluoromethyl)phenyl)methyl) amino) methylhydroxylamine, imino(((4-nitiOphenyl) methyl)amino)methylhydroxylamine, (butylamino) iminomethylhydroxylamine, imino (propylamino) methylhydroxylamine, imino(pentylamino)methylhydroxylamine, imino (propylamino)methylhydroxylamine, imino ((methylethyl)amino)methylhydroxylamine, (cyclopropylamino) iminomethylhydroxylamine, 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-tetrahydroisoquinolyl)) iminomethylhydroxylamine, (((4-chlorophenyl)methyl) amino)iminomethylhydroxylamine, ((4-chlorophenyl)amino) iminomethylhydroxylamine, (4-chlorophenyl) (hydroxy imino) methylamine, and l-(4-chlorophenyI)-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-pyiτoline-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 therapeutic agents, 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, sedating or non-sedating anti-hiscamiπes, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, and combinations of two or more thereof. The therapeutic agent may optionally be nitrosated and/or nitrosylated and/or contain at least one heterocyclic nitric oxide donor group and/or at least one nitroxide group.
Suitable steroids, include, but are not limited to, budesonide, dexamethasone, corticosterone, prednisolone, and the like. Suitable steroids are described more fully in the literature, such as in the Merck Index on CD-ROM, 13th Edition. 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 does or as multiple doses per day; the lumiracoxib is administered in an amount of about 40 milligrams to about 1200 milligrams as a single does or as multiple doses per day; the paracoxib is administered in an amount of about 20 milligrams to about 100 milligrams as a single does 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 does or as multiple doses per day; the valdecoxib is administered in an amount of about 10 milligrams to about 40 milligrams as a single does or as multiple doses per day.
Suitable NSAIDs 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 does or as multiple doses per day; the flurbiprofen is administered in an amount of about 100 milligrams to about 300 milligrams as a single does 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 does or as multiple doses per day; the indomethacin is administered in an amount of about 25 milligrams to about 200 milligrams as a single does or as multiple doses per day; the ketoprofen is administered in an amount of about 50 milligrams to about 300 milligrams as a single does 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 does or as multiple doses per day; the aspirin is administered in an amount of about 10 milligrams to about 2 grams as a single does 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 leukotriene 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-(hydroxycarbamoyI)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] agonists, 5-HTIB agonists and 5-HTID 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 (PRAVACHOL®), 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 does 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 H2 receptor anatgonists, include, but are not limited to, cimetidine, roxatidine, rantidine 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 hydralazine compounds include, but are not limited to, compounds having the formula:
Figure imgf000046_0001
wherein a, b and c are independently a single or double bond; Ri and 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 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 ϋb/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-diphenylpropinyl)-L-proline amide),3-(2- phenylethylamino)-6-methyl- 1 - (2-amino-6-methyl-5 -methylene- carboxamidomethylpyridinyl)-2-pyrazinone, 3-(2-phenethylamino)-6-methyl-l-(2-amino-6- methyl-5- methylenecarboxamidomethylpyridinyl)-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 2921, 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 antitussives include, but are not limited to, codeine, hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like. 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 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 combinations 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)-pyridine, 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-hydroxyethoxy)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, pyiϊdylsulfinyl 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.
Suitable compounds used for the treatment of glaucoma, include, but are not limited to, acetylcholinesterase inhibitors (such as, for example, citicoline, donepezil, heptatigmine, galantamine, metafonate, physostignine, rivastignine, tarcine, velnacrine, and the like) carbachol, pilocarpine and the like. Suitable compounds used for the treatment of glaucoma 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.
The invention provides compositions comprising (i) selective COX-2 inhibitors comprising at least one nitric oxide enhancing group or pharmaceutically acceptable salt thereof, (ii) a nitric oxide enhancing compound, such as, isosorbide dinitrate and/or isosorbide mononitrate (such as, isosorbide dinitrate), and (iii) a hydralazine compound (such as, hydralazine hydrochloride). In one embodiment, the hydralazine hydrochloride can be administered in an amount of about 30 milligrams per day to about 400 milligrams per day; the isosorbide dinitrate can be administered in an amount of about 10 milligrams per day to about 200 milligrams per day; or the isosorbide mononitrate can be administered in an amount of about 5 milligrams per day to about 120 milligrams per day. In another embodiment, the hydralazine hydrochloride can be administered in an amount of about 50 milligrams per day to about 300 milligrams per day, the isosorbide dinitrate can be administered in an amount of about 20 milligrams per day to about 160 milligrams per day; or the isosorbide mononitrate can be administered in an amount of about 15 milligrams per day to about 100 milligrams per day. In yet another embodiment, the hydralazine hydrochloride can be administered in an amount of about 37.5 milligrams to about 75 milligrams one to four times per day; the isosorbide dinitrate can be administered in an amount of about 20 milligrams to about 40 milligrams one to four times per day; or the isosorbide mononitrate can be administered in an amount of about 10 milligrams to about 20 milligrams one to four times per day. In another embodiment of the methods of the invention, the patient can be administered a composition comprising about 225 mg hydralazine hydrochloride and about 120 mg isosorbide dinitrate once per day (i.e., q.d.). In another embodiment of the methods of the invention, the patient can be administered a composition comprising about 112.5 mg hydralazine hydrochloride and about 60 mg isosorbide dinitrate twice per day (i.e., b.i.d.). In another embodiment of the methods of the invention, the patient can be administered a composition comprising about 56.25 mg hydralazine hydrochloride and about 30 mg isosorbide dinitrate twice per day (i.e., b.i.d.). In another embodiment of the methods of the invention, the patient can be administered a composition comprising about 75 mg hydralazine hydrochloride and about 40 mg isosorbide dinitrate three times per day (i.e., t.i.d.). In another embodiment of the methods of the invention, the patient can be administered a composition comprising about 37.5 mg hydralazine hydrochloride and about 20 mg isosorbide dinitrate three times per day (i.e., ti.d.). The particular amounts of hydralazine and isosorbide dinitrate or isosorbide mononitrate can be administered as a single dose once a day; or in multiple doses several times throughout the day; or as a sustained-release oral formulation, or as an injectable formulation.
The invention provides methods for treating inflammation, pain (both chronic and acute), and 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, menstrual cramps; 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 COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound. In yet another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, and combinations of two or more thereof. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound. The COX-2 selective inhibitor compounds comprising 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 COX-2 selective inhibitors 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-EUison 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 COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound. In yet another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, and combinations of two or more thereof. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound. The COX-2 selective inhibitor compounds comprising 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 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 COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound. In yet another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, and combinations of two or more thereof. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound. The COX-2 selective inhibitor compounds comprising 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, respiratory and other toxicity (such as, for example, kidney toxicity) resulting from the use of drugs, such as, nonsteroidal anti-inflammatory drugs and/or COX-2 inhibitors 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 COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound. In yet another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, including but not limited to, such as, for example, steroids, selective 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, sedating or non-sedating antihistamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, and combinations of two or more thereof. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound. The COX-2 selective inhibitor compounds comprising 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 COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound. In yet another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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- hypeiiipidemic compounds, H2 antagonists, hydralazine compounds, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, carbonic anhydrase inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, and combinations of two or more thereof. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound. The COX-2 selective inhibitor compounds comprising 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 infaraction, 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, endotlielium-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 COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and at least one nitric oxide enhancing compound. In yet another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising 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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, and combinations of two or more thereof. In another embodiment, the patient can be administered an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound. The COX-2 selective inhibitor compounds comprising 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 COX-2 selective inhibitor comprising at least 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 COX-2 selective inhibitor comprising 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 COX-2 selective inhibitor comprising 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 COX-2 selective inhibitor optionally substituted with at least 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 earners, adjuvants, and vehicles, as desired. Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. In one embodiment of the invention the organic nitric oxide enhancing salt of the NSAID 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 II (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. 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 earner such as lactose, saccharose, sorbitol, mannitol, potato starch, com 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.
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 deleteiϊously 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.
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, preferably crystalline, solid form. For sustained release administration, microparticle dosage forms comprising pure, preferably crystalline, therapeutic agents are preferred. 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. Preferred 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 antiproliferative 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 one 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 COX-2 inhibitor comprising at least one nitric oxide enhancing group or a pharmaceutically acceptable salt thereof, and, optionally at least one nitric oxide enhancing compound, or the sustained release formulations can comprise an effective amount of at least one COX-2 selective inhibitor compound comprising at least one nitric oxide enhancing group or a pharmaceutically acceptable salt thereof, and at least one therapeutic agent , and, optionally, at least one nitric oxide enhancing compound.
The compounds and compositions of the invention can be formulated as pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include, for example, alkali metal salts and addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically- acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid and the like.
Appropriate organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, algenic, β-hydroxybutyric, cyclohexylaminosulfonic, galactaric and galacturonic acid and the like. Suitable pharmaceutically-acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from primary, secondary and tertiary amines, cyclic amines, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine and the like. AU of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. In one embodiment, the pharmaceutically acceptable salts of the compounds of the invention do not include the nitrate salt.
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 COX-2 selective compound comprising 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 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 novel COX-2 selective inhibitor compounds comprising 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 (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, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, isoprostane inhibitors, and compounds used for the treatment of glaucoma, and the like, 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. 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 imgf000065_0001
(D wherein:
R4 is methyl or ethyl; R5 is chloro or fluoro; R6 is hydrogen or fluoro;
R7 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxyl; R8 is hydrogen or fluoro; R9 is chloro, fluoro, trifluoromethyl or methyl; K is: (a) -(W3)a-Eb-(C(Re)(Rf))pl-Ec-(C(Re)(Rf))χ-(W3)d-(C(Re)(Rf))y-(W3)i-Ej-(W3)g-
Figure imgf000065_0002
(b) -(W3)a-Eb-(C(Re)(Rf))pl-Ec-(C(Re)(Rf))x-(W3)d-(C(Re)(Rf))y-(W3)i-Ej-(W3)g- (C(Re)(Rf))z-R3; and with the proviso that at least one Re is selected as -U3-V5, or -C(R0)(Rp)ki -U3-V5, when K is (b); R3 is:
Figure imgf000066_0001
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 imgf000066_0002
Figure imgf000067_0001
Figure imgf000068_0001
R24 is -C6H4R37, -CN, -S(O)2-C6H4R37, -C(O)-N(R3)(R1), -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(0)-N(Ra)(R;), -NO2 or -C(O)-OR25;
T' is oxygen, sulfur or NR16;
Ri6 is a hydrogen, a lower alkyl group, or an aryl group;
V6 is:
Figure imgf000068_0002
Z5 is -CH2 or oxygen;
Z6 is -CH or nitrogen;
W3 at each occurrence is independently -C(O)-, -C(S)-, -T3-, -(C(Re)(Rf)) ir, -N(R3)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))ir, a heterocyclic ring, an arylheterocyclic ring, -(CH2CH2O)qi- or Y4-,
Y4 is:
Figure imgf000069_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 R^ 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, -S(O)0- or -N(Ra)R1; h is an integer from 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 aiyl, 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 arylsulfoπyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-V5, V6, - (C(R0)(Rp))W-U3-V5, -(C(R0)(Rp))W-U3-V3, -(C(R0)(Rp))kl -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 imine, a hydrazone, a bridged cycloalkyl group,
Figure imgf000070_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 inline, a hydrazone a bridged cycloalkyl group,
Figure imgf000071_0001
U3 is an oxygen, sulfur or -N(Ra)Rf,
V5 is -NO or -NO2 (i.e. an oxidized nitrogen); ki is an integer from 1 to 3;
Ra is a lone pair of electrons, a hydrogen or an alkyl group;
R; 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-V5)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom or -(N2O2-OrIVIi+, wherein M1 + is an organic or inorganic cation; and with the proviso that the compound of Formula (I) must contain at least one nitric oxide enhancing group linked to the compound of Formula (I) through an oxygen atom, a nitrogen atom or a sulfur atom via a bond or moiety that can be hydrolyzed.
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 the compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) is:
Figure imgf000072_0001
(H) wherein:
T' is oxygen, sulfur or NR16;
Ri6 is a hydrogen, a lower alkyl group, or an aryl group; Rn is: a hydrogen or:
Figure imgf000072_0002
Figure imgf000073_0001
Figure imgf000074_0001
R24 is -C6H4R37, -CN, -S(O)2-C6H4R37, -C(O)-N(Ra)(R1), -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)(Ri), -NO2 Or -C(O)-OR25;
T' is oxygen, sulfur or NR16;
R16 is a hydrogen, a lower alkyl group, or an aryl group;
Ra, Rj, Rj, Rk, Re and Rf are as defined herein; and with the proviso that the compound of Formula (II) must contain at least one nitric oxide enhancing group linked to the compound of Formula (II) through an oxygen atom, a nitrogen atom or a sulfur atom via a bond or moiety that can be hydrolyzed.
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 H2 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, an isoprostane inhibitor, and combinations of two or more thereof.
6. The composition of claim 5, wherein the therapeutic agent is at least one compound selected from the group consisting of a nonsteroidal antiinflammatory compound, 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 4, 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 a gastrointestinal property 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 renal and/or respiratory toxicity; inhibiting platelet aggregation; 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 9, 10, 12, 14 or 18, 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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