EP1828155A2 - Diuretic compounds comprising heterocyclic nitric oxide donor groups,compositions and methods of use - Google Patents

Diuretic compounds comprising heterocyclic nitric oxide donor groups,compositions and methods of use

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Publication number
EP1828155A2
EP1828155A2 EP05851657A EP05851657A EP1828155A2 EP 1828155 A2 EP1828155 A2 EP 1828155A2 EP 05851657 A EP05851657 A EP 05851657A EP 05851657 A EP05851657 A EP 05851657A EP 1828155 A2 EP1828155 A2 EP 1828155A2
Authority
EP
European Patent Office
Prior art keywords
nitric oxide
compound
oxide donor
group
heterocyclic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05851657A
Other languages
German (de)
French (fr)
Other versions
EP1828155A4 (en
Inventor
designation of the inventor has not yet been filed The
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nicox SA
Original Assignee
Nitromed Inc
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Filing date
Publication date
Application filed by Nitromed Inc filed Critical Nitromed Inc
Priority claimed from PCT/US2005/041321 external-priority patent/WO2006055542A2/en
Publication of EP1828155A2 publication Critical patent/EP1828155A2/en
Publication of EP1828155A4 publication Critical patent/EP1828155A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • novel diuretic compounds comprising at least one heterocyclic nitric oxide donor group, or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one diuretic compound comprising at least one heterocyclic nitric oxide donor group, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent.
  • novel compositions and kits comprising at least one diuretic compound of the invention comprising at least one heterocyclic nitric oxide donor 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 conditions resulting from excessive water and/or electrolyte retention; (b) treating cardiovascular diseases; (c) treating renovascular diseases; (d) treating diabetes; (e) treating diseases resulting from oxidative stress; (f) treating endothelial dysfunctions; (g) treating diseases caused by endothelial dysfunctions; (h) treating cirrhosis; (j) treating pre-eclampsia; (k) treating osteoporosis; (1) treating nephropathy; (m) treating peripheral vascular diseases; (n) treating portal hypertension; (o) treating central nervous system disorders; and (p) treating sexual dysfunctions.
  • the heterocyclic nitric oxide donors are preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.
  • Cardiovascular compounds such as ACE inhibitors, beta-adrenergic blockers, antithrombotic and vasodilator compounds or anti- hyperlipidemic compounds, show, for example, respiratory toxicity resulting in asthma and/or bronchitis.
  • ACE inhibitors beta-adrenergic blockers
  • antithrombotic and vasodilator compounds anti- hyperlipidemic compounds
  • the invention provides novel diuretic compounds comprising at least one heterocyclic nitric oxide donor group, and pharmaceutically acceptable salts thereof.
  • the heterocyclic nitric oxide donors that are preferably furoxans, sydnonimines, oxatriazole-5- ones and/or oxatriazole-5-imines are linked to the diuretic compounds through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen.
  • 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 diuretic compound comprising a heterocyclic nitric oxide donor group, or a pharmaceutically acceptable salt thereof, and, optionally, at least one nitric oxide enhancing compound improves the properties of the diuretic 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.
  • compositions comprising at least one diuretic compound comprising at least one heterocyclic nitric oxide donor group and at least one nitric oxide enhancing compound.
  • the invention also provides for such compositions in a pharmaceutically acceptable carrier.
  • the heterocyclic nitric oxide donors groups are preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.
  • compositions comprising at least diuretic compound comprising a heterocyclic nitric oxide donor group, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent, including; but not limited to, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin ⁇ antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, ⁇ -adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H 2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two
  • the at least one therapeutic agent is selected from the group consisting of an aldosterone antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme (ACE) inhibitors, a ⁇ -adrenergic antagonist, a digitalis, a diuretic, and a hydralazine compound.
  • an aldosterone antagonist an angiotensin II antagonist
  • an angiotensin-converting enzyme (ACE) inhibitors a ⁇ -adrenergic antagonist
  • ACE angiotensin-converting enzyme
  • compositions comprising an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group of the invention, and at least one therapeutic agent selected from the group consisting of an aldosterone antagonist, an angiotensin II antagonist, an angiotensin- converting enzyme (ACE) inhibitor, a ⁇ -adrenergic antagonist, a diuretic and a hydralazine compound.
  • ACE angiotensin- converting enzyme
  • ACE angiotensin- converting enzyme
  • the invention provides methods for (a) treating conditions resulting from excessive water and/or electrolyte retention; (b) treating cardiovascular diseases; (c) treating renovascular diseases; (d) treating diabetes; (e) treating diseases resulting from oxidative stress; (f) treating endothelial dysfunctions; (g) treating diseases caused by endothelial dysfunctions; (h) treating cirrhosis; (j) treating pre-eclampsia; (k) treating osteoporosis; (1) treating nephropathy; (m) treating peripheral vascular diseases; (n) treating portal hypertension; (o) treating central nervous system disorders; and (p) treating sexual dysfunctions in a patient in need thereof comprising administering to the patient an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, optionally, at least one therapeutic agent, such as, for example, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin ⁇ antagonists, angiotensin
  • the methods can optionally further comprise the administration of at least one nitric oxide enhancing compound.
  • the methods can involve (i) administering the diuretic compounds comprising a heterocyclic nitric oxide donor group, (ii) administering the diuretic compounds comprising a heterocyclic nitric oxide donor group, and nitric oxide enhancing compounds, (iii) administering the diuretic compounds comprising a heterocyclic nitric oxide donor group and therapeutic agents, or (iv) administering the diuretic compounds comprising a heterocyclic nitric oxide donor group, nitric oxide enhancing compounds, and therapeutic agents.
  • the at least one therapeutic agent is selected from the group consisting of an aldosterone antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme (ACE) inhibitor, a ⁇ -adrenergic antagonist, a diuretic, and a hydralazine compound.
  • the diuretic compounds comprising a heterocyclic nitric oxide donor 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 diuretic compound comprising a heterocyclic nitric oxide donor group, and, optionally, at least one nitric oxide enhancing compound.
  • the kit can further comprise at least one therapeutic agent, such as, for example, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, ⁇ -adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H 2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof.
  • the diuretic compound comprising a heterocyclic nitric oxide donor group, the nitric oxide enhancing compound and/or therapeutic agent, can be
  • Constants resulting from excessive water and/or electrolyte retention include but are not limited to lower extremity swelling, fatigue, body fluid retention, cardiac enlargement, shortness of breath, pulmonary edema, cerebral edema, edema associated at least in part with a cause selected from the group consisting of congestive heart failure, cirrhosis of the liver, poor blood circulation, lymphatic system failure, chronic nephritis, malnutrition, use of birth control pills, premenstrual syndrome, sunburn, hypertension, Meniere's disease, glaucoma, cystic fibrosis and/or an imbalance of sodium and potassium, and the like.
  • Cardiovascular disease or disorder refers to any cardiovascular disease or disorder known in the art, including, but not limited to, congestive heart failure, restenosis, hypertension (e.g. pulmonary 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, atherosclerosis, atherogenesis, cerebrovascular disease, angina,
  • hypertension e.g. pulmonary hypertension, labile hypertension, idiopathic hypertension, low-renin hypertension, salt-sensitive hypertension, low-renin, salt-sensitive hypertension, thromboembolic pulmonary hypertension; pregnancy
  • ischemic heart disease including chronic, stable, unstable and variant (Prinzmetal) angina pectoris
  • cerebral ischemia including chronic, stable, unstable and variant (Prinzmetal) angina pectoris
  • thrombosis including chronic, stable, unstable and variant (Prinzmetal) angina pectoris
  • 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
  • Thromboembolic events include, but are not limited to, ischemic stroke, transient ischemic stroke, myocardial infarction, angina pectoris, thrombosis (for example, restenosis, arterial thrombosis, coronary thrombosis, heart valve thrombosis, coronary stenosis, stent thrombosis, graft thrombosis, and first and subsequent thrombotic stroke, and the like), thromboembolism (for example, pulmonary thromboembolism, cerebral thromboembolism, and the like), thrombophlebitis, thrombocytopenia, bleeding disorders, thrombotic occlusion and reocclusion and acute vascular events.
  • thrombosis for example, restenosis, arterial thrombosis, coronary thrombosis, heart valve thrombosis, coronary stenosis, stent thrombosis, graft thrombosis, and first and
  • Patients who are at risk of developing thromboembolic events may include those with a familial history of, or genetically predisposed to, thromboembolic disorders, who have had ischemic stroke, transient ischemic stroke, myocardial infarction, and those with unstable angina pectoris or chronic stable angina pectoris and patients with altered prostacyclin/thromboxane A 2 homeostasis or higher than normal thromboxane A 2 levels leading to increase risk for thromboembolism, including patients with diabetes and rheumatoid arthritis.
  • Diseases resulting from oxidative stress refers to any disease that involves the generation of free radicals or radical compounds, such as, for example, atherogenesis, atheromatosis, arteriosclerosis, atherosclerosis, vascular hypertrophy associated with hypertension, hyperlipoproteinaemia, normal vascular degeneration through aging, parathyroidal reactive hyperplasia, renal disease (e.g., acute or chronic), neoplastic diseases, inflammatory diseases, neurological and acute bronchopulmonary disease, tumorigenesis, ischemia-reperfusion syndrome, arthritis, sepsis, cognitive dysfunction, endotoxic shock, endotoxin-induced organ failure, and the like.
  • free radicals or radical compounds such as, for example, atherogenesis, atheromatosis, arteriosclerosis, atherosclerosis, vascular hypertrophy associated with hypertension, hyperlipoproteinaemia, normal vascular degeneration through aging, parathyroidal reactive hyperplasia, renal disease (e.g., acute or chronic), neoplastic diseases,
  • Renivascular diseases refers to any disease or dysfunction of the renal system including, but not limited to, renal failure (e.g., acute or chronic), renal insufficiency, nephrotic edema, acute glomerulonephritis, oliguric renal failure, renal deterioration associated with severe hypertension, unilateral perechymal renal disease, polycystic kidney disease, chronic pyelonephritis, renal diseases associated with renal insufficiency, complications associated with dialysis or renal transplantation, renovascular hypertension, nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, 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.
  • 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 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.
  • ADMA asymmetric dimethylarginine
  • 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, congestive 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, congestive 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.
  • “Sexual dysfunction” refers to any sexual dysfunction in a patient, including, but not limited to, sexual desire disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders, and the like.
  • Female sexual dysfunction refers to any female sexual dysfunction including, but not limited to, sexual desire disorders, sexual arousal dysfunctions, orgasmic dysfunctions, sexual pain disorders, dyspareunia, vaginismus, and the like.
  • the female can be pre-menopausal or menopausal.
  • Sexual dysfunction can be caused, for example, by pregnancy, menopause, cancer, pelvic surgery, chronic medical illness or medications.
  • Male sexual dysfunction refers to any male sexual dysfunctions including, but not limited to, male erectile dysfunction, impotence, 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, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti- hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, ⁇ - adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H 2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and the like.
  • NSAIDs nonsteroidal antiinflammatory compounds
  • Therapeutic agent includes the pharmaceutically acceptable salts thereof, pro-drugs, and pharmaceutical derivatives thereof including, but not limited to, the corresponding nitrosated and/or nitrosylated and/or heterocyclic nitric oxide donor derivatives.
  • nitric oxide enhancing compounds have therapeutic activity, the term "therapeutic agent" does not include the nitric oxide enhancing compounds described herein, since nitric oxide enhancing compounds are separately defined.
  • Prodrug refers to a compound that is made more active in vivo.
  • Antioxidant refers to and includes any compound that can react and/or quench a free radical.
  • Angiotensin converting enzyme (ACE) inhibitor refers to compounds that inhibit an enzyme which catalyzes the conversion of angiotensin I to angiotensin ⁇ .
  • ACE inhibitors include, but are not limited to, amino acids and derivatives thereof, peptides, including di- and tri-peptides, and antibodies to ACE which intervene in the renin- angiotensin system by inhibiting the activity of ACE thereby reducing or eliminating the formation of the pressor substance angiotensin H.
  • Angiotensin ⁇ antagonists refers to compounds which interfere with the function, synthesis or catabolism of angiotensin II.
  • Angiotensin ⁇ antagonists include peptide compounds and non-peptide compounds, including, but not limited to, angiotensin II antagonists, angiotensin II receptor antagonists, agents that activate the catabolism of angiotensin ⁇ , and agents that prevent the synthesis of angiotensin I from angiotensin H
  • the renin-angiotensin system is involved in the regulation of hemodynamics and water and electrolyte balance. Factors that lower blood volume, renal perfusion pressure, or the concentration of sodium in plasma tend to activate the system, while factors that increase these parameters tend to suppress its function.
  • 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.
  • Diauretic compound refers to and includes any compound or agent that increases the amount of urine excreted by a patient.
  • Neuronal endopeptidase inhibitors refers to and includes compounds that are antagonists of the renin angiotensin aldosterone system including compounds that are dual inhibitors of neutral endopeptidases and angiotensin converting (ACE) enzymes.
  • ACE angiotensin converting
  • Rhin inhibitors refers to compounds which interfere with the activity of renin.
  • Phosphodiesterase inhibitor or PDE inhibitor refers to any compound that inhibits the enzyme phosphodiesterase. The term refers to selective or non-selective inhibitors of cyclic guanosine 3 ',5 '-monophosphate phosphodiesterases (cGMP-PDE) and cyclic adenosine 3 ',5 '-monophosphate phosphodiesterases (c AMP-PDE).
  • Platelet reducing 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 + /K + -ATPase enzyme system at the secretory surface of the gastric parietal cell.
  • NSAK refers to a nonsteroidal anti-inflammatory compound or a nonsteroidal anti-inflammatory drug.
  • NSAIDs inhibit cyclooxygenase, the enzyme responsible for the biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of the various isozymes of cyclooxygenase (including but not limited to cyclooxygenase- 1 and -T), 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 50 of greater than about 5 ⁇ M, in the human whole blood COX-2 assay (as described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) and also has a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase- 1 inhibition of at least 10, and preferably of at least 40.
  • the compound has a cyclooxygenase- 1 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.
  • “Patient” refers to animals, preferably mammals, most preferably humans, and includes males and females, and children and adults. "Therapeutically 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 a compound and/or composition such that the blood levels of the compound are maintained within a desirable 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.
  • “Nitroxide group” refers to compounds that have the ability to mimic superoxide dimutase and catalase and act as radical scavengers via a stableaminoxyl radical i.e. N- oxide.
  • Nitric oxide adduct or “NO adduct” refers to compounds and functional groups which, under physiological conditions, can donate, release and/or directly or indirectly transfer any of the three redox forms of nitrogen monoxide (NO + , NO " , NO«), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
  • Nitric oxide releasing or “nitric oxide donating” refers to methods of donating, releasing and/or directly or indirectly transferring any of the three redox forms of nitrogen monoxide (NO + , NO-, NO»), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
  • Nitric oxide donor or “NO donor” refers to compounds that donate, release and/or directly or indirectly transfer a nitrogen monoxide species, and/or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo and/or are oxidized to produce nitric oxide and/or are substrates for nitric oxide synthase and/or cytochrome P450.
  • NO donor also includes compounds that are precursors of L-arginine, inhibitors of the enzyme arginase and nitric oxide mediators.
  • Heterocyclic nitric oxide donor refers to a trisubstituted 5-membered ring comprising two or three nitrogen atoms and at least one oxygen atom.
  • the heterocyclic nitric oxide donor is capable of donating and/or releasing a nitrogen monoxide species upon decomposition of the heterocyclic ring.
  • Exemplary heterocyclic nitric oxide donors include oxatriazol-5-ones, oxatriazol-5-imines, sydnonimines, furoxans, and the like.
  • Alkyl refers to a lower alkyl group, a substituted lower alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein.
  • An alkyl group may also comprise one or more radical species, such as, for example a cycloalkylalkyl group or a heterocyclicalkyl group.
  • Lower alkyl refers to branched or straight chain acyclic alkyl group comprising one to about ten carbon atoms (preferably one to about eight carbon atoms, more preferably one to about six carbon atoms).
  • Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the like.
  • Substituted lower alkyl refers to a lower alkyl group, as defined herein, wherein one or more of the hydrogen atoms have been replaced with one or more R 100 groups, wherein each R 100 is independently a hydroxy, an ester, an amidyl, an oxo, a carboxyl, a carboxamido, a halo, a cyano, a nitrate, a nitrite, a thionitrate, a thionitrite or an amino group, as defined herein.
  • Haloalkyl refers to a lower alkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein, to which is appended one or more halogens, as defined herein.
  • exemplary haloalkyl groups include trifluoromethyl, chloromethyl, 2-bromobutyl, l-bromo-2-chloro-pentyl, and the like.
  • alkenyl refers to a branched or straight chain C 2 -C 1O hydrocarbon (preferably a C 2 -C 8 hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) that can comprise one or more carbon-carbon double bonds.
  • alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbuten-l-yl, 3-methylbuten-l-yl, hexan-1-yl, hepten-1- yl, octen-1-yl, and the like.
  • “Lower alkenyl” refers to a branched or straight chain C 2 -C 4 hydrocarbon that can comprise one or two carbon-carbon double bonds.
  • Substituted alkenyl refers to a branched or straight chain C 2 -C 1O hydrocarbon (preferably a C 2 -C 8 hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) which can comprise one or more carbon-carbon double bonds, wherein one or more of the hydrogen atoms have been replaced with one or more R 100 groups, wherein each R 100 is independently a hydroxy, an oxo, a carboxyl, a carboxamido, a halo, a cyano or an amino group, as defined herein.
  • Alkynyl refers to an unsaturated acyclic C 2 -C 10 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-l-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 maybe in the thio, sulfinyl or sulfonyl oxidation state.
  • the heterocyclic ring or group can be fused to an aromatic hydrocarbon group.
  • Heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester, alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido, alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester, sulfonamide nitrate and nitro.
  • heterocyclic groups include pyrrolyl, furyl, thienyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4- dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrahydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, imidazolinyl, imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4- thiadiazolyl,
  • Heterocyclic compounds refer to mono- and polycyclic compounds comprising at least one aryl or heterocyclic ring.
  • Aryl refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or two aromatic rings.
  • exemplary aryl groups include phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamido and nitro.
  • aryl groups include tetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfonyl, and the like.
  • Cycloalkenyl refers to an unsaturated cyclic C 2 -C 10 hydrocarbon (preferably a
  • C 2 -C 8 hydrocarbon more preferably a C 2 -C 6 hydrocarbon which can comprise one or more carbon-carbon triple 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-fluorophenylethyl, and the like.
  • Arylalkenyl refers to an aryl radical, as defined herein, attached to an alkenyl radical, as defined herein.
  • exemplary arylalkenyl groups include styryl, propenylphenyl, and the like.
  • Cycloalkylalkyl refers to a cycloalkyl radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Cycloalkylalkoxy refers to a cycloalkyl radical, as defined herein, attached to an alkoxy radical, as defined herein.
  • Cycloalkylalkylthio refers to a cycloalkyl radical, as defined herein, attached to an alkylthio radical, as defined herein.
  • Heterocyclicalkyl refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Arylheterocyclic ring refers to a bi- or tricyclic ring comprised of an aryl ring, as defined herein, appended via two adjacent carbon atoms of the aryl ring to a heterocyclic ring, as defined herein.
  • Exemplary arylheterocyclic rings include dihydroindole, 1,2,3,4- tetra-hydroquinoline, and the like.
  • Alkylheterocyclic ring refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Exemplary alkylheterocyclic rings include 2-pyridylmethyl, l-methylpiperidin-2-one-3 -methyl, and the like.
  • Alkoxy refers to R 50 O-, wherein R 50 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 50 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.
  • Arylalldythioalkyl refers to an arylalkylthio group, as defined herein, to which is appended an alkyl group, as defined herein.
  • exemplary arylalklythioalkyl groups include benzylthiomethyl, phenylethylthiomethyl, chlorophenylethylthioethyl, and the like.
  • Alkylthioalkyl refers to an alkylthio group, as defined herein, to which is appended an alkyl group, as defined herein.
  • exemplary alkylthioalkyl groups include allylthiomethyl, ethylthiomethyl, trifluoroethylthiomethyl, and the like.
  • Alkoxyalkyl refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined herein.
  • exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.
  • Alkoxyhaloalkyl refers to an alkoxy group, as defined herein, appended to a haloalkyl group, as defined herein.
  • Exemplary alkoxyhaloalkyl groups include 4- methoxy-2-chlorobutyl and the like.
  • Cycloalkoxy refers to 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 Rs 4 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.
  • Oxy refers to -O-
  • Oxylate refers to -O " R 77 + wherein R 77 is an organic or inorganic cation.
  • Hydrazino refers to H 2 N-N(H)-.
  • Organic cation refers to a positively charged organic ion. Exemplary organic cations include alkyl substituted ammonium cations, and the like.
  • Inorganic cation refers to a positively charged metal ion.
  • Exemplary inorganic cations include Group I metal cations such as for example, sodium, potassium, magnesium, calcium, and the like.
  • Hydroalkyl refers to a hydroxy group, as defined herein, appended to an alkyl group, as defined herein.
  • Nirate refers to -0-NO 2 i.e. oxidized nitrogen.
  • Nirite refers to -O-NO i.e. oxidized nitrogen.
  • Thionitrate refers to -S-NO 2 .
  • Niro refers to the group -NO 2 and “nitrosated” refers to compounds that have been substituted therewith.
  • Niroso refers to the group -NO and “nitrosylated” refers to compounds that have been substituted therewith.
  • Halogen or “halo” refers to iodine (T), bromine (Br), chlorine (Cl), and/or fluorine
  • 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 Rs 0 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 Rs 5 R 6O N-, wherein R 55 and R 60 are each independently an aryl group, as defined herein.
  • Alkylarylamino or arylalkylamino refers to Rs 2 R 5S 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 R 79 N-, 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 80 N-, wherein R 52 is an alkyl group, as defined herein, and R 8 o is a cycloalkyl group, as defined herein.
  • Aminoalkyl refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an alkyl group, as defined herein.
  • exemplary aminoalkyl groups include dimethylaminopropyl, diphenylaminocyclopentyl, methylaminomethyl, and the like.
  • aminoaryl refers to an aryl group to which is appended an alkylamino group, a arylamino group or an arylalkylamino group.
  • exemplary aminoaryl groups include anilino, N-methylanilino, N-benzylanilino, and the like.
  • Method refers to -C(S)-.
  • Sulfonic acid refers to -S(O) 2 OR 76 , wherein R 76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
  • Alkylsulfonic acid refers to a sulfonic acid group, as defined herein, appended to an alkyl group, as defined herein.
  • Arylsulfonic acid refers to a sulfonic acid group, as defined herein, appended to an aryl group, as defined herein
  • Sulfonic ester refers to -S(O) 2 OR 58 , wherein R 58 is an alkyl group, an aryl group, or an aryl heterocyclic ring, as defined herein.
  • “Sulfonamido” refers to -S(O ⁇ -N(R 51 )(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.
  • 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 5 oS-, wherein R 50 is an alkyl group, as defined herein (preferably a lower 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 R 5O -S(O)-, wherein R 50 is an alkyl group, as defined herein.
  • Alkylsulfonyl refers to R 5O -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 R 55 -S(O)-, wherein R 55 is an aryl group, as defined herein.
  • Arylsulfonyl refers to Rs S -S(O) 2 -, wherein R 55 is an aryl group, as defined herein.
  • Arylsulfonyloxy refers to Rs 5 -S(O) 2 -O-, wherein R 55 is an aryl group, as defined herein.
  • “Amidyl” refers to Rs 1 C(O)N(R 57 )- wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
  • “Ester” refers to R 51 C(O)R 76 - wherein R 51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein and R 76 is oxygen or sulfur.
  • Carbamoyl refers to -0-C(O)N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R 51 and R 57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Carboxyl refers to -C(O)OR 76 , wherein R 76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
  • Carbonyl refers to -C(O)-.
  • Alkylcarbonyl refers to R 52 -C(O)-, wherein R 52 is an alkyl group, as defined herein.
  • Arylcarbonyl refers to R 5S -C(O)-, wherein R 55 is an aryl group, as defined herein.
  • Arylalkylcarbonyl refers to R 5 s-R 52 -C(O) ⁇ , wherein R 55 is an aryl group, as defined herein, and R 52 is an alkyl group, as defined herein.
  • Alkylarylcarbonyl refers to R 52 -R 55 -C(O)-, wherein R 55 is an aryl group, as defined herein, and R 52 is an alkyl group, as defined herein.
  • Heterocyclicalkylcarbonyl refers to R 78 C(O)- wherein R 78 is a heterocyclicalkyl group, as defined herein.
  • Carboxylic ester refers to -C(O)ORs 8 , 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 gi'oup, 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(Rs 1 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R 51 and R 57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Alkylcarboxamido refers to an alkyl group, as defined herein, appended to a carboxamido group, as defined herein.
  • Arylcarboxamido refers to an aryl group, as defined herein, appended to a carboxamido group, as defined herein.
  • Rea refers to -N(R 59 )-C(O)N(R 51 XR 57 ) wherein R 51 , 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 7 o)(R 71 )(R7 2 ), 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.
  • “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.
  • Organic acid refers to compound having at least one carbon atom and one or more functional groups capable of releasing a proton to a basic group.
  • the organic acid preferably contains a carboxyl, a sulfonic acid or a phosphoric acid moeity.
  • Exemplary organic acids include acetic acid, benzoic acid, citric acid, camphorsulfonic acid, methanesulfonic acid, taurocholic acid, chlordronic acid, glyphosphate, medronic acid, and the like.
  • Inorganic acid refers to a compound that does not contain at least one carbon atom and is capable of releasing a proton to a basic group.
  • Exemplary inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic base refers to a carbon containing compound having one or more functional groups capable of accepting a proton from an acid group.
  • the organic base preferably contains an amine group.
  • Exemplary organic bases include triethylamine, benzyldiethylamine, dimethylethyl amine, imidazole, pyridine, pipyridine, and the like.
  • the compounds and compositions of the invention are diuretics, including, 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
  • the diuretic compounds of the invention are substituted with at least one heterocyclic nitric oxide donor group that is linked to the diuretic compound through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen.
  • the diuretic compounds comprising a heterocyclic nitric oxide donor group are in accordance with the invention and/or are included in the compositions of the invention, including those exemplified below.
  • the heterocyclic nitric oxide donors are preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.
  • the invention described diuretic compounds comprising a heterocyclic nitric oxide donor group of Formula (I) and pharmaceutically acceptable salts thereof:
  • X 2 is -C(O)- or -S(O) 2 ;
  • Y 2 is chlorine or CF 3 ;
  • D 1 is a hydrogen, V 3 or K
  • V 3 is:
  • R 24 is -C 6 H 4 R 27 , -CN, -S(O) 2 -C 6 H 4 R 27 , -C(O)-N(R a )(R 1 ), -NO 2 or -C(O)-OR 25 ;
  • R 25 is an alkyl group or an aryl group
  • R 26 is -C(O)- or -S(O) 2 - ;
  • R 27 is a hydrogen, -CN, -S(O) 2 -R 25 , -C(O)-N(R a )(Rj), -NO 2 or -C(O)-OR 25 ;
  • T' is oxygen, sulfur or NR 6 ;
  • R 6 is a hydrogen, a lower alkyl group, an aryl group
  • W at each occurrence is independently -C(O)-, -C(S)-, -T 3 -, -(C(R 6 )(Rf)) h ⁇ , -N(Ra)Ri, an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, -(CH 2 CH 2 O) ql - or a heterocyclic nitric oxide donor;
  • E at each occurrence is independently -T 3 -, an alkyl group, an aryl group, -(C(R e )(R f )X-, a heterocyclic ring, an arylheterocyclic ring, -(CH 2 CH 2 O) Q1 - or Y 3;
  • Y 3 is:
  • T is a -S(O) 0 -; a carbonyl or a covalent bond; o is an integer from O 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 a )Ri; h is an integer form 1 to 10; q t 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 alkyl
  • 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
  • R a is a lone pair of electrons, a hydrogen or an alkyl group
  • Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, -CH 2 -C-(U 3 -Vs)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom,
  • diuretic compounds comprising a heterocyclic nitric oxide donor group of Formula (IT) and pharmaceutically acceptable salts thereof:
  • X 4 is:
  • Y 4 is:
  • D is V 3 or K
  • V 4 is a thio group or an oxygen atom
  • D 1 , Y 2 , V 3 and K are as defined herein; and with the proviso that the diuretic compounds of Formula (II) must contain at least one heterocyclic nitric oxide donor group linked to the diuretic compound through an oxygen atom, a nitrogen atom or a sulfur atom.
  • diuretic compounds comprising a heterocyclic nitric oxide donor group of Formula (JE) and pharmaceutically acceptable salts thereof:
  • X 3 is: - K is as defined herein; and with the proviso that the heterocyclic diuretic compounds of Formula (HI) must contain at least one heterocyclic nitric oxide donor group linked to the diuretic compound through an oxygen atom, a nitrogen atom or a sulfur atom.
  • the compound of Formula (I) is a heterocyclic nitric oxide donor althiazide, a heterocyclic nitric oxide donor bendroflumethiazide, a heterocyclic nitric oxide donor benzthiazide, a heterocyclic nitric oxide donor buthiazide, a heterocyclic nitric oxide donor chlorothiazide, a heterocyclic nitric oxide donor cyclothiazide, a heterocyclic nitric oxide donor ethiazide, a heterocyclic nitric oxide donor fenquizone, a heterocyclic nitric oxide donor hydrochlorothiazide, a heterocyclic nitric oxide donor hydroflumethiazide, a heterocyclic nitric oxide donor methyclothiazide, a heterocyclic nitric oxide donor metolazone, a heterocyclic nitric oxide donor paraflutizide, a heterocyclic nitric
  • the diuretic compounds of Formula (I) is a chlorothiazide comprising a heterocyclic nitric oxide donor group or a hydrochlorothiazide comprising a heterocyclic nitric oxide donor group of Formula (W) and the diuretic compound of Formula (H) is a chlorthalidone comprising a heterocyclic nitric oxide donor group of Formula (V), a furosemide comprising a heterocyclic nitric oxide donor group of Formula (VI) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IV) is:
  • bond a-b can be a single bond (hydrochlorothiazide) or a double bond
  • R n is: a hydrogen or:
  • T', R 24 , R 25 , R 26 , Rj, Rk, Re and R f are as defined herein; and with the proviso that the compounds of Formula (PV), (V) and (Vl) must contain at least one heterocyclic nitric oxide donor group.
  • the furosemide compound or derivative comprising a heterocyclic nitric oxide donor group of Formula (VI) is: benzoic acid, 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]-, (4 ⁇ methyl-5-oxido- l,2,5-oxadiazol-3-yl)methyl ester; , benzoic acid, 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]-, 2-[(4-methyl-5- oxido- 1 ,2,5-oxadiazol-3-yl)methoxy]-2-oxoethyl ester benzoic acid, 2-amino-5-(aminosulfonyl)-4-chloro-, (4-methyl-5-oxido-l,2,5-oxadiazol-3- yl)methyl ester; or a pharmaceutically acceptable salt thereof.
  • Compounds of the invention that have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates. 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 diuretic compounds comprising a heterocyclic nitric oxide donor group and pharmaceutically acceptable salts thereof.
  • These metabolites include but are not limited to, the non- heterocyclic nitric oxide donor derivatives, degradation products, hydrolysis products, and the like, of the diuretic compounds comprising a heterocyclic nitric oxide donor 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.
  • sulfur and oxygen protecting groups are well known for protecting thiol and alcohol groups against undesirable reactions during a synthetic procedure and many such protecting groups are known and described by, for example, Greene and Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).
  • the compounds of 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 (T), (U), (JJT), (IV), (V) and (VI) can be synthesized by one skilled in the art following the methods and examples described herein.
  • Some of the parent diuretic compounds i.e. diuretic compounds that do not contain a heterocyclic nitric oxide donor group
  • the synthesis of the parent diuretic compounds are also disclosed in, for example, U.S. Patent Nos.
  • the parent diuretic compounds are substituted to contain a heterocyclic nitric oxide donor group linked to the diuretic compound through one or more sites such as oxygen, sulfur and/or nitrogen using conventional methods known to one skilled in the art.
  • the methods of linking the heterocyclic nitric oxide donor group to compounds described in these references can be applied by one skilled in the art to produce any of the diuretic compounds comprising a heterocyclic nitric oxide donor group described herein.
  • the diuretic compounds comprising a heterocyclic nitric oxide donor 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., diuretic compounds that contain a heterocyclic nitric oxide donor 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 and compounds that release 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- ammonio ⁇ ropyl)-N-(n- ⁇ ro ⁇ yl)amino)diazen- 1 -ium- 1 ,2-diolate (“PAPA/NO”), (Z)- 1 -(N-(3- aminopropyl)-N-(4-(3-arninopropylammonio)butyl)-amino) diazen- 1 -ium- 1 ,2-diolate (spermine NONOate or "SPER/NO”) and sodium(Z)-l -(N 5 N- diethylamino)diazenium- 1,2-diolate (diethylamine NONOate or "
  • NONOates are also described in U.S. Patent Nos. 6,232,336, 5,910,316 and 5,650,447, the disclosures of which are incorporated herein by reference in their entirety.
  • the "NO adducts" can be mono-nitrosylated, poly-nitrosylated, mono-nitrosated and/or poly-nitrosated at a variety of naturally susceptible or artificially provided binding sites for biologically active forms of nitrogen monoxide.
  • Suitable furoxanes include, but are not limited to, CAS 1609, C93-4759, C92- 4678, S35b, CHF 2206, CHF 2363, and the like.
  • Suitable sydnonimines include, but are not limited to, molsidomine (N- ethoxycarbonyl-3-morpholinosydnonimine), SIN-I (3-morpholinosydnonimine) CAS 936 (3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydnonimine, pirsidomine), C87- 3754 (3-(cis-2,6-dimethylpiperidino)sydnonimine, linsidomine, C4144 (3-(3,3-dimethyl- l,4-thiazane-4-yl)sydnonimine hydrochloride), C89-4095 (3-(3,3-d
  • Suitable oximes include, but are not limited to, NOR-I, NOR-3, NOR-4, and the like.
  • S-nitrosothiols are compounds that include at least one -S-NO group.
  • S-nitroso-polypeptides include proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated sugars; S-nitrosylated, modified and unmodified, oligonucleotides (preferably of at least 5, and more preferably 5-200 nucleotides); straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.
  • S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof.
  • Such compounds include, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril, S- nitroso-N-acetylpenicillainine, 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.
  • 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 aiylalklythio, 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 al
  • 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
  • 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;
  • Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, arylsulphonyloxy, a sulfonamide a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, -CH 2 -C(U 3 -V 5 )(R
  • 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 R; 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 hydrocarbon
  • Preferred 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, l,3,4-thiadiazole-2-nitrosimines, benzothiazole- 2(3H)-nitrosimines, thiazole-2-nitrosimines, oligonitroso sydnonimines, 3-alkyl-N-nitro
  • 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.
  • Preferred among 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
  • Preferred examples of compounds comprising at least one O 2 N-O-, O 2 N-N- or O 2 N-S- group include isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol, propatylnitrate and organic nitrates with a sulfhydryl-containing amino acid such as, for example SPM 3672, SPM 4757, SPM 5185, SPM 5186 and those disclosed in U. S. Patent Nos.
  • R 1 R 2 N-N(0-M + )-N0 Another group of NO adducts are 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 M 1 + is an organic or inorganic cation, such, as for example, an alkyl substituted ammonium cation or a Group I metal cation.
  • the invention is also directed to compounds that stimulate endogenous NO or elevate levels of endogenous endothelium-derived relaxing factor (EDRF) in vivo or are oxidized to produce nitric oxide and/or are substrates for nitric oxide synthase and/or cytochrome P450.
  • EDRF endogenous endothelium-derived relaxing factor
  • Such compounds include, for example, L-arginine, L-homoarginine, and N-hydroxy-L-arginine, N-hydroxy-L-homoarginine, N-hydroxydebrisoquine, N- hydroxypentamidine including their nitrosated and/or nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N- hydroxy-L-arginine, nitrosated and nitrosylated L-homoarginine), N-hydroxyguanidine compounds, amidoxime, ketoximes, aldoxime compounds, that can be oxidized in vivo to produce nitric oxide.
  • Compounds that may be substrates for a cytochrome P450 include, for example, imino(benzylamino)methylhydroxyl amine, imino(((4-methylphenyl)methyl) amino)methylhydroxylamine, imino(((4-methoxyphenyl)methyl)amino) methylhydroxylamine, imino(((4-(trifluoromethyl)phenyl)methyl) amino) methylhydroxylamine, imino(((4-nitrophenyl) methyl)amino)methylhydroxylamine, (butylamino) iminomethylhydroxylamine, imino (propylamino) methylhydroxylamine, imino(pentylamino)methylhydroxylamine, imino (propylamino)methylhydroxylamine, imino ((methylethyl)amino)methylhydroxylamine, (cyclopropylamino) iminomethylhydroxylamine, imino-2-1 ,2,3,4-tetra
  • 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)).
  • NO nitric oxide
  • the invention is also directed to nitric oxide enhancing compounds that can increase endogenous nitric oxide.
  • Such compounds include for example, nitroxide containing compounds, include, but are not limited to, substituted 2,2,6,6-tetramethyl-l- piperidinyloxy compounds, substituted 2,2,5, 5-tetramethyl-3-pyrroline-l-oxyl compounds, substituted 2,2,5,5-tetramethyl-l-pyrrolidinyloxyl compounds, substituted 1,1,3,3- tetramethylisoindolin-2-yloxyl compounds, substituted 2,2,4,4-tetramethyl-l-oxazolidinyl- 3-oxyl compounds, substituted 3-imidazolin-l-yloxy, 2,2,5,5 ⁇ tetramethyl-3 ⁇ imidazolin ⁇ l- yloxyl compounds, OT-551, 4-hydroxy-2,2,6,6-tetramethyl-l-piperidinyloxy (tempol), and the like.
  • Suitable substituents include, but are not limited to, aminomethyl, benzoyl, 2- bromoacetamido, 2-(2-(2-bromoacetamido)ethoxy)ethylcarbamoyl, carbamoyl, carboxy, cyano, 5-(dimethylamino)-l-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, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti- hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, ⁇ - adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H 2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NS AIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof.
  • the therapeutic agent may
  • Suitable aldosterone antagonists include, but are not limited to, canrenone, potassium canrenoate, drospirenone, spironolactone, eplerenone (INSPRA®), epoxymexrenone, fadrozole, pregn-4-ene-7,21-dicarboxylic acid, 9,ll-epoxy-17-hydroxy- 3-oxo, ⁇ -lactone, methyl ester, (7 ⁇ ,ll ⁇ ,17 ⁇ .)-; pregn-4-ene-7,21-dicarboxylic acid, 9,11- epoxy-17-hydroxy-3-oxo-dimethyl ester, (7 ⁇ ,ll ⁇ ,17 ⁇ .)-; 3 ⁇ -cyclopropa(6,7)pregna-4,6- diene-21-carboxylic acid, 9,ll-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, ⁇ -lactone, (6 ⁇ ,7 ⁇ ,ll ⁇ ,17 ⁇ )-; pregn-4-ene-7,21-
  • aldosterone antagonists can be administered in the form of their pharmaceutically acceptable salts and/or stereoisomers. Suitable aldosterone antagonists 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 aldosterone antagonist is eplerenone or spironolactone (a potassium sparing diuretic that acts like an aldosterone antagonist).
  • eplerenone is administered in an amount of about 25 milligrams to about 300 milligrams as a single dose or as multiple doses per day;
  • spironolactone is administered in an amount of about 25 milligrams to about 150 milligrams as a single dose or as multiple doses per day.
  • Suitable alpha-adrenergic receptor antagonists include but are not limited to, phentolamine, tolazoline, idazoxan, deriglidole, RX 821002, BRL 44408, BRL 44409, BAM 1303, labetelol, ifenprodil, rauwolscine, corynathine, raubascine, tetrahydroalstonine, apoyohimbine, akuammigine, ⁇ -yohimbine, yohimbol, yohimbine, pseudoyohimbine, epi-3 ⁇ -yohimbine, 10-hydroxy-yohimbine, 11 -hydroxy-yohimbine, tamsulosin, benoxathian, atipamezole, BE 2254, WB 4101, HU-723, tedisamil, mirtazipine, setiptiline, reboxitine, delequamine, naftopil, saterinone, SL
  • Suitable alpha-adrenergic 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; and the Merck Index on CD-ROM, Thirteenth Edition; and on STN Express, file phar and file registry.
  • Suitable angiotensin II antagonists include, but are not limited to, angiotensin, abitesartan, candesartan, candesartan cilexetil, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan, forasartan, glycyllosartan, irbesartan, losartan, olmesartan, milfasartan, medoxomil, ripisartan, pratosartan, saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan, 3-(2' (tetrazole-5-yl)- 1 , 1 '-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl- 3H-imidazo(4,5-b)pyridine, antibodies
  • angiotensin H antagonists can be administered in the form of pharmaceutically acceptable salts and/or stereoisomers.
  • Suitable angiotensin ⁇ antagonists 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 angiotensin ⁇ antagonists are candesartan, eprosartan, irbesartan, losartan, omlesartan, telmisartan or valsartan.
  • the candesartan is administered as candesartan cilexetil in an amount of about 15 milligrams to about 100 milligrams as a single dose or as multiple doses per day;
  • the eprosartan is administered as eprosartan mesylate in an amount of about 400 milligrams to about 1600 milligrams as a single dose or as multiple doses per day;
  • the irbesartan is administered in an amount of about 75 milligrams to about 1200 milligrams as a single dose or as multiple doses per day;
  • the losartan is administered as losartan potassium in an amount of about 25 milligrams to about 100 milligrams as a single dose or as multiple doses per day;
  • the omlesartan is administered
  • Suitable angiotensin-converting enzyme inhibitors include, but are not limited to, alacepril, benazepril (LOTENSIN®, CEBACEN®), benazeprilat, captopril, ceronapril, cilazapril, delapril, duinapril, enalapril, enalaprilat, fasidotril, fosinopril, fosinoprilat, gemopatrilat, glycopril, idrapril, imidapril, lisinopril, moexipril, moveltipril, naphthopidil, omapatrilat, pentopril, perindopril, perindoprilat, quinapril, quinaprilat, ramipril, ramiprilat, rentipril, saralasin acetate, spirapril, temocapril
  • angiotensin-converting enzyme inhibitors may be administered in the form of pharmaceutically acceptable salts, hydrates, acids and/or stereoisomers thereof.
  • Suitable angiotensin-converting enzyme 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, Twelfth Edition, Version 12:1, 1996; and on STN Express, file phar and file registry.
  • angiotensin-converting enzyme inhibitors are benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril, trandolapril or trandolaprilat.
  • the benazepril is administered as benazepril hydrochloride in an amount of about 5 milligrams to about 80 milligrams as a single dose or as multiple doses per day;
  • the captopril is administered in an amount of about 12.5 milligrams to about 450 milligrams as a single dose or as multiple doses per day;
  • the enalapril is administered as enalapril maleate in an amount of about 2.5 milligrams to about 40 milligrams as a single dose or as multiple doses per day;
  • the fosinopril is administered as fosinopril sodium in an amount of about 5 milligrams to about 60 milligrams as a single dose or as multiple doses per day;
  • the lisinopril is administered in an amount of about 2.5 milligrams to about 75 milligrams as a single dose or as multiple doses per day;
  • the moexipril is administered as moexipril hydrochloride in an
  • Suitable antidiabetic compounds include but are not limited to, acarbose, acetohexamide, buformin, carbutamide, chlorpropamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepid, glyburide, glybuthiazol(e), glybuzole, glyhexamide, glymidine, glypinamide, insulin, metformin, miglitol, nateglinide, phenbutamide, phenformin, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, tolcyclamide, troglitazone, voglibose, and the like.
  • Suitable antidiabetic 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.
  • 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 antioxidants include, but are not limited to, small-molecule antioxidants and antioxidant enzymes.
  • Suitable small-molecule antioxidants include, but are not limited to, hydralazine compounds, glutathione, vitamin C, vitamin E, cysteine, N-acetyl- cysteine, ⁇ -carotene, ubiquinone, ubiquinol-10, tocopherols, coenzyme Q, superoxide dismutase mimetics, such as, for example, 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO), DOXYL, PROXYL, nitroxide compounds; 4-hydroxy-2,2,6,6-tetramethyl-l- piperidinyloxy (Tempol), M-40401, M-40403, M-40407, M-40419,M-40484, M-40587, M-40588, and the like.
  • TEMPO 2,2,6,6-tetramethyl-l-piperidinyloxy
  • M-40401 M-
  • Suitable antioxidant enzymes include, but are not limited to, superoxide dismutase, catalase, glutathione peroxidase, NADPH oxidase inhibitors, such as, for example, apocynin, aminoguanidine, ONO 1714, S 17834 (benzo(b)pyran-4-one derivative), and the like; xanthine oxidase inhibitors, such as, for example, allopurinol, oxypurinol, amflutizole, diethyldithiocarbamate, 2-styrylchromones, chrysin, luteolin, kaempferol, quercetin, myricetin, isorhamnetin, benzophenones such as 2,2' ,4,4'- tetrahydroxybenzophenone, 3,4,5,2',3',4'-hexahydroxybenzophenone and 4,4'- dihydroxybenzophenone; benzothiazinone analogues such
  • the antioxidant enzymes can be delivered by gene therapy as a viral vertor and/or a non- viral vector. Suitable antioxidants are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thirteenth Edition; and on STN Express, file phar and file registry. In some embodiments the antioxidants are apocynin, hydralazine compounds and superoxide dimutase mimetics.
  • Suitable antithrombotic and vasodilator compounds include, but are not limited to, abciximab, acetorphan, acetylsalicylic acid, argatroban, bamethan, benfurodil, benziodarone, betahistine, bisaramil, brovincamine, bufeniode, citicoline, clobenfurol, clopidogrel, cyclandelate, dalteparin, dipyridamol, droprenilamine, enoxaparin, fendiline, ifenprodil, iloprost, indobufen, isobogrel, isoxsuprine, heparin, lamifiban, midrodine, nadroparin, nicotinoyl alcohol, nylidrin, ozagrel, perhexiline, phenylpropanolamine, prenylamine, papaveroline, reviparin
  • Suitable antithrombotic and vasodilator 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.
  • Suitable antithrombotic and vasodilator compounds include, but are not limited to, abciximab, acetorphan, acetylsalicylic acid, argatroban, bamethan, benfurodil, benziodarone, betahistine, bisaramil, brovincamine, bufeniode, citicoline, clobenfurol, clopidogrel, cyclandelate, dalteparin, dipyridamol, droprenilamine, enoxaparin, fendiline, ifenprodil, iloprost, indobufen, isobogrel, isoxsuprine, heparin, lamifiban, midrodine, nadroparin, nicotinoyl alcohol, nylidrin, ozagrel, perhexiline, phenylpropanolamine, prenylamine, papaveroline, reviparin
  • Suitable antithrombotic and vasodilator 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.
  • Suitable ⁇ -adrenergic antagonists include, but are not limited to, acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butofilolol, carazolol, capsinolol, carteolol, carvedilol (COREG®), celiprolol, cetamolol, cindolol, cloranolol, dilevalol, diprafenone, epanolol, ersentilide, esmolol, esprolol, hedroxalol, inden
  • the ⁇ -adrenergic antagonists are atenolol, bisoprolol, carvedilol, metoprolol, nebivolol, propranolol or timolol.
  • the atenolol is administered in an amount of about 50 milligrams to about 200 milligrams as a single dose or as multiple doses per day;
  • the bisoprolol is administered as bisoprolol fumarate in an amount of about 2.5 milligrams to about 30 milligrams as a single dose or as multiple doses per day;
  • the carvedilol is administered in an amount of about 3.125 milligrams to about 200 milligrams as a single dose or as multiple doses per day;
  • the metoprolol is administered as metoprolol tartarate or metoprolol succinate in an amount of about 25 milligrams to about 300 milligrams as a single dose or as multiple doses per day;
  • the nebivolol is administered as nebivolol hydrochloride in an amount of about 2.5 milligrams to about 20 milligrams as a single dose or as multiple doses per day;
  • the propranolol is
  • Suitable calcium channel blockers include, but are not limited to, amlodipine (NORVASC®), anipamil, aranidipine, amrinone, azelnidipine, barnidipine, bencyclane, benidipine, bepridil, cilnidipine, cinnarizine, clentiazem, diltiazem, dotarizine, efonidipine, elgodipine, fantofarone, felodipine, fendiline, flunarizine, fluspirilene, furnidipine, gallopamil, ipenoxazone, isradipine, lacidipine, lemildipine, lercanidipine, lomerizine, manidipine, mibefradil, monatepil, nicardipine, nifedipine, niguldipine, niludipine, nilvadipine, nimodip
  • Suitable calcium channel blockers 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 calcium channel blockers are amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil.
  • Suitable digitals include but are not limited to digoxin and digoxitin.
  • the digoxin is administered to achieve a steady state blood serum concentration of at least about 0.7 nanograms per ml to about 2.0 nanograms per ml.
  • 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 endothelin antagonists include, but are not limited to, atrasentan, bosentan, darusentan, endothelin, enrasentan, sitaxsentan, sulfonamide endothelin antagonists, tezosentan, BMS 193884, BQ-123, SQ 28608, and the like.
  • Suitable endothelin antagonists 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.
  • Suitable hydralazine compounds include, but are not limited to, compounds having the formula:
  • R 1 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 R 1 , 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 H 2 receptor antagonists include, but are not limited to, burimamide, cimetidine, ebrotidin, famotidine, nizatidine, roxatidine, rantidine, tiotidine, and the like. Suitable H 2 receptor antagonists are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901-915; the Merck Index on CD-ROM, 13 th Edition; and in WO 00/28988 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety.
  • Suitable neutral endopeptidase inhibitors include, but are not limited to, atrial natriuretic peptides, diazapins, azepinones, ecadotril, fasidotril, fasidotrilat, omapatrilat, sampatrilat, BMS 189,921, Z 13752 A, and the like.
  • Neutral endopeptidase inhibitors are described more fully in the literature, such as in Goodman and Gilman, The
  • 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 dose or as multiple doses per day;
  • the flurbiprofen is administered in an amount of about 100 milligrams to about 300 milligrams as a single dose or as multiple doses per day;
  • the ibuprofen is administered in an amount of about 400 milligrams to about 3.2 grams as a single dose or as multiple doses per day;
  • the indomethacin is administered in an amount of about 25 milligrams to about 200 milligrams as a single dose or as multiple doses
  • Suitable 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 potassium channel blockers include but are not limited to, nicorandil, pinacidil, cromakalim (BRL 34915), aprikalim, bimakalim, emakalim, lemakalim, minoxidil, diazoxide, 9-chloro-7-(2-chlorophenyl)-5H-pyrimido(5,4,-d)(2)-benzazepine, Ribi, CPG-11952, CGS-9896, ZD 6169, diazixide, Bay X 9227, P1075, Bay X 9228, SDZ PCO 400, WAY-120,491, WAY-120,129, Ro 31-6930, SR 44869, BRL 38226, S 0121, SR 46142A, CGP 42500, SR 44994, artilide fumarate, lorazepam, temazepam, rilmazafone, nimetazepam, midazolam, lormetaze
  • Suitable potassium channel blockers 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.
  • Suitable platelet reducing agents include but are not limited to, fibrinolytic agents such as for example, ancrod, anistreplase, bisobrin lactate, brinolase, Hageman factor (i.e. factor XH) fragments, plasminogen activators such as, for example, streptokinase, tissue plasminogen activators (TPA), urokinase, pro-Urokinase, recombinant TPA, plasmin, plasminogen, and the like; anti-coagulant agents including but are not limited to, inhibitors of factor Xa, factor TFPI, factor VHa, factor IXc, factor Va, factor VIHa, inhibitors of other coagulation factors, and the like; vitamin K antagonists, such as, for example, coumarin, coumarin derivatives (e.g., warfarin sodium); glycosoaminoglycans such as, for example, heparins both in unfractionated form and in low molecular weight
  • Suitable proton pump inhibitors include, but are not limited to, disulprazole, esomeprazole, lansoprazole, leminoprazole, omeprazole, pantoprazole, rabeprazole, timoprazole, tenatoprazole, 2-(2-benzimidazolyl)-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)p
  • 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 renin inhibitors include, but are not limited to, aldosterone, aliskiren
  • Suitable renin inhibitors are described more fully in U.S. Patent Nos. 5,116,835, 5,114,937, 5,106,835, 5,104,869, 5,095,119, 5,098,924), 5,095,006, 5,089,471; 5,075,451, 5,066,643, 5,063,208, 4,845,079, 5,055,466, 4,980,283, 4,885,292), 4,780,401, 5,071,837, 5,064,965, 5,063,207, 5,036,054, 5,036,053, 5,034,512, and 4,894,437, 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.
  • Suitable COX-2 inhibitors include, but are not limited to, nimesulide, celec
  • COX-2 inhibitors are in U.S. Patent Nos. 5,344,991, 5,380,738, 5,393,790, 5,409,944,
  • the COX-2 inhibitors are celecoxib, etoracoxib, lumiracoxib, paracoxib, rofecoxib or valdecoxib.
  • the celecoxib is administered in an amount of about 100 milligrams to about 800 milligrams as a single dose or as multiple doses per day;
  • the etoricoxib is administered in an amount of about 50 milligrams to about 200 milligrams as a single dose or as multiple doses per day;
  • the lumiracoxib is administered in an amount of about 40 milligrams to about 1200 milligrams as a single dose or as multiple doses per day;
  • the paracoxib is administered in an amount of about 20 milligrams to about 100 milligrams as a single dose or as multiple doses per day;
  • the rofecoxib is administered in an amount of about 12.5 milligrams to about 50 milligrams as a single dose or as multiple doses per day;
  • compositions comprising (i) a diuretic compound comprising a heterocyclic nitric oxide donor group of the invention or pharmaceutically acceptable salt thereof, and (ii) at least one compound selected from the group consisting of aldosterone antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, ⁇ -adrenergic antagonists, diuretics, and hydralazine compounds in one or more pharmaceutically acceptable carriers.
  • ACE angiotensin-converting enzyme
  • the aldosterone antagonist is eplerenone or spironolactone
  • the angiotensin II antagonist is candesartan cilexetil, eprosartan mesylate, irbesartan, losartan potassium, medoxomil, telmisartan, trandolapril, trandolaprilat or valsartan
  • the angiotensin-converting enzyme inhibitor is benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril hydrochloride, quinapril hydrochloride, ramipril
  • the ⁇ -adrenergic antagonist is bisoprolol fumarate, carvedilol, metoprolol tartrate, propranolol hydrochloride or timolol maleate
  • the diuretic is amiloride hydrochloride
  • the invention provides methods for treating conditions resulting from excess water and/or electrolyte retention by administering to the 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 diuretic compound comprising a heterocyclic nitric oxide donor group.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and at least one nitric oxide enhancing compound.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, including but not limited to, such as, for example, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin- converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, ⁇ -adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H 2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound.
  • condition resulting from excess water and/or electrolyte retention is lower extremity swelling, fatigue, body fluid retention, cardiac enlargement, shortness of breath, and/or edema.
  • the diuretic compounds comprising a heterocyclic nitric oxide donor 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 cardiovascular disorders by administering to the 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 diuretic compound comprising a heterocyclic nitric oxide donor group.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and at least one nitric oxide enhancing compound.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, including but not limited to, such as, for example, aldosterone antagonists, alpha- adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, ⁇ -adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H 2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound.
  • the cardiovascular disorder is hypertension, congestive heart failure and/or diastolic dysfunction.
  • the diuretic compounds comprising diuretic compounds comprising a heterocyclic nitric oxide donor 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 renovascular diseases by administering to the 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 diuretic compound comprising a heterocyclic nitric oxide donor group.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and at least one nitric oxide enhancing compound.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, including but not limited to, such as, for example, aldosterone antagonists, alpha- adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, ⁇ -adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H 2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound.
  • the renovascular disease is renal failure or renal insufficiency.
  • the diuretic compounds comprising a heterocyclic nitric oxide donor 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 diabetes; treating diseases resulting from oxidative stress; treating endothelial dysfunctions; treating diseases caused by endothelial dysfunctions; treating cirrhosis; treating pre-eclampsia; treating osteoporosis; treating nephropathy; treating peripheral vascular diseases; treating portal hypertension; treating central nervous system disorders; and treating sexual dysfunctions by administering to the 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 diuretic compound comprising a heterocyclic nitric oxide donor group.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and at least one nitric oxide enhancing compound.
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, including but not limited to, such as, for example, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, ⁇ -adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H 2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors,
  • NSAIDs nonster
  • the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound.
  • the diuretic compounds comprising a heterocyclic nitric oxide donor group, nitric oxide enhancing compounds, and/or therapeutic agents can be administered separately or asi components of the same composition in one or more pharmaceutically acceptable carriers.
  • the diuretic compound comprising comprising a heterocyclic nitric oxide donor group, nitric oxide enhancing compound and/or therapeutic agent 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 diuretic compound comprising a heterocyclic nitric oxide donor 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 diuretic compound comprising a heterocyclic nitric oxide donor group.
  • the compounds and compositions of the invention can be administered by any available and effective delivery system including, but not limited to, orally, bucally, parenterally, by inhalation, by topical application, by injection, transdermally, or rectally (e.g., by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles, as desired.
  • Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • the diuretic compound comprising a heterocyclic nitric oxide donor group is administered orally, parentally or by inhalation.
  • Transdermal compound administration involves the delivery of pharmaceutical compounds via percutaneous passage of the compound into the systemic circulation of the patient.
  • Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • Other components can be incorporated into the transdermal patches as well.
  • compositions and/or transdermal patches can be formulated with one or more preservatives or bacteriostatic agents including, but not limited to, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.
  • Dosage forms for topical administration of the compounds and compositions can include creams, sprays, lotions, gels, ointments, eye drops, nose drops, ear drops, and the like.
  • the compositions of the invention can be mixed to form white, smooth, homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1% or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution.
  • the compositions can contain polyethylene glycol 400.
  • compositions can be mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt) as preservative, white petrolatum, emulsifying wax, and tenox ⁇ (butylated hydroxyanisole, propyl gallate, citric acid, propylene glycol).
  • Woven pads or rolls of bandaging material e.g., gauze, can be impregnated with the compositions in solution, lotion, cream, ointment or other such form can also be used for topical application.
  • the compositions can also be applied topically using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
  • compositions can also be applied topically using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
  • a transdermal patch such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
  • the compositions of the invention are administered as a transdermal patch, more particularly as a sustained-release transdermal patch.
  • the transdermal patches of the invention can include any conventional form such as, for example, adhesive matrix, polymeric matrix, reservoir patch, matrix or monolithic-type laminated structure, and are generally comprised of one or more backing layers, adhesives, penetration enhancers, an optional rate controlling membrane and a release liner which is removed to expose the adhesives prior to application.
  • Polymeric matrix patches also comprise a polymeric-matrix forming material. Suitable transdermal patches are described in more detail in, for example, U.
  • Solid dosage forms for oral administration can include capsules, sustained-release capsules, tablets, sustained release tablets, chewable tablets, sublingual tablets, effervescent tablets, pills, powders, granules and gels.
  • the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms can also comprise buffering agents.
  • Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the invention and vegetable oil.
  • Hard gelatin capsules can contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin.
  • Tablets and pills can be prepared with enteric coatings.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • Suppositories for vaginal or rectal administration of the compounds and compositions of the invention can be prepared by mixing the compounds or compositions with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at rectal temperature, such that they will melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at rectal temperature, such that they will melt in the rectum and release the drug.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • Sterile fixed oils are also conventionally used as a solvent or suspending medium.
  • compositions of this invention can further include conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds.
  • suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like.
  • the pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • particularly suitable vehicles consist of solutions
  • the composition can also contain minor amounts of wetting agents, emulsifying agents and/or pH buffering agents.
  • the composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like.
  • 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 anti-proliferative therapeutic agents.
  • biodegradable microparticles or nanoparticles comprise biodegradable microparticles or nanoparticles. More particularly, biodegradable microparticles or nanoparticles are formed of a polymer containing matrix that biodegrades by random, nonenzymatic, hydrolytic scissioning to release therapeutic agent, thereby forming pores within the particulate structure.
  • the compositions of the invention are orally administered as a sustained release tablet or a sustained release capsule.
  • the sustained release formulations can comprise an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor 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 diuretic compound comprising a heterocyclic nitric oxide donor group or a pharmaceutically acceptable salt thereof, and at least ,one nitric oxide donor, and, optionally at least one therapeutic agent
  • 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 pharmaceuticaHy-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), mefhanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, algenic, ⁇ -hydroxybutyric, cyclohexylaminosulfonic, galactaric and
  • 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. All 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 drag combination.
  • the amount of a given diuretic compound comprising a heterocyclic nitric oxide donor group of the invention 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 diuretic compounds comprising a heterocyclic nitric oxide donor group, and one or more of the nitric oxide enhancing compounds described herein.
  • kits can be additional therapeutic agents or compositions (e.g., aldosterone antagonists, alpha- adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, ⁇ -adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H 2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, 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
  • Example 3a A mixture of the product of Example 3a (0.1 g, 1.9 mmol), 1,2,5-oxadiazole, A- (bromomethyl)-3-methyl-, 2-oxide (76 mg, 0.39 mmol, prepared as described in WO 2005/060603 A2, Example 6c) and K 2 CO 3 (0.11 g, 0.80 mmol) in DMF (1 mL) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo. The residue was taken up in CH 2 Cl 2 ZMeOH (10:1), washed with water, brine and dried over Na 2 SO 4 .

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Abstract

The invention describes novel diuretic compounds comprising at least one heterocyclic nitric oxide donor group, or pharmaceutically acceptable salts thereof, and novel composition comprising at least one diuretic compound comprising at least one heterocyclic nitric oxide donor group, and optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. The invention also provides novel compositions and kits comprising at least one diuretic compound of the invention comprising at least one heterocyclic nitric oxide donor 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 conditions resulting from excessive water and/or electrolyte retention; (b) treating cardiovascular diseases; (c) treating renovascular diseases; (d) treating diabetes; (e) treating diseases resulting from oxidatives stress; (f) treating endothelial dysfunctions; (g) treating diseases caused by endothelial dysfunctions; (h) treating cirrhosis; (j) treating pre-eclampsia; (k) treating osteoporosis; (1) treating nephropathy; (m) treating peripheral vascular diseases; (n) treating portal hypertension; (o) treating central nervous system disorders; and (p) treating sexual dysfunctions. The heterocyclic nitric oxide donors are preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.

Description

DIURETIC COMPOUNDS COMPRISING HETEROCYCLIC NITRIC OXIDE DONOR GROUPS, COMPOSITIONS AND METHODS OF USE
RELATED APPLICATIONS This application claims priority under 35 USC § 119 to US Application No.
60/627, 177 filed November 15, 2004; to US Application No. 60/656,546 filed February 28, 2005; and to US Application No. 60/692,231 filed June 21, 2005.
FIELD OF THE INVENTION The invention describes novel diuretic compounds comprising at least one heterocyclic nitric oxide donor group, or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one diuretic compound comprising at least one heterocyclic nitric oxide donor group, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. The invention also provides novel compositions and kits comprising at least one diuretic compound of the invention comprising at least one heterocyclic nitric oxide donor 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 conditions resulting from excessive water and/or electrolyte retention; (b) treating cardiovascular diseases; (c) treating renovascular diseases; (d) treating diabetes; (e) treating diseases resulting from oxidative stress; (f) treating endothelial dysfunctions; (g) treating diseases caused by endothelial dysfunctions; (h) treating cirrhosis; (j) treating pre-eclampsia; (k) treating osteoporosis; (1) treating nephropathy; (m) treating peripheral vascular diseases; (n) treating portal hypertension; (o) treating central nervous system disorders; and (p) treating sexual dysfunctions. The heterocyclic nitric oxide donors are preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.
BACKGROUND OF THE INVENTION
The decline in cardiovascular morbidity and mortality in the United States over the past three decades has been the result of significant advances in research on cardiovascular disease mechanisms and therapeutic strategies. The incidence and prevalence of myocardial infarction and death from myocardial infarction, as well as that from cerebrovascular accident, have decreased significantly over this period largely owing to advances in prevention, early diagnosis, and treatment of these very common diseases.
The compounds administered for the treatment of diuresis, cardiovascular diseases, and diseases resulting from oxidative and/or endothelial dysfunctions often result in toxic, chronic and/or debilitating side effects. Cardiovascular compounds such as ACE inhibitors, beta-adrenergic blockers, antithrombotic and vasodilator compounds or anti- hyperlipidemic compounds, show, for example, respiratory toxicity resulting in asthma and/or bronchitis. Hence there is a need in the art for compounds that have improved efficacy, lower toxicity 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 diuretic compounds comprising at least one heterocyclic nitric oxide donor group, and pharmaceutically acceptable salts thereof. The heterocyclic nitric oxide donors that are preferably furoxans, sydnonimines, oxatriazole-5- ones and/or oxatriazole-5-imines are linked to the diuretic compounds through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen. 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 diuretic compound comprising a heterocyclic nitric oxide donor group, or a pharmaceutically acceptable salt thereof, and, optionally, at least one nitric oxide enhancing compound improves the properties of the diuretic 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 diuretic compound comprising at least one heterocyclic nitric oxide donor group and at least one nitric oxide enhancing compound. The invention also provides for such compositions in a pharmaceutically acceptable carrier. The heterocyclic nitric oxide donors groups are preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines. The invention provides compositions comprising at least diuretic compound comprising a heterocyclic nitric oxide donor group, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent, including; but not limited to, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin π antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof. In a preferred embodiment the at least one therapeutic agent is selected from the group consisting of an aldosterone antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme (ACE) inhibitors, a β-adrenergic antagonist, a digitalis, a diuretic, and a hydralazine compound. The invention also provides for such compositions in a pharmaceutically acceptable carrier.
Another embodiment of the invention provides compositions comprising an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group of the invention, and at least one therapeutic agent selected from the group consisting of an aldosterone antagonist, an angiotensin II antagonist, an angiotensin- converting enzyme (ACE) inhibitor, a β-adrenergic antagonist, a diuretic and a hydralazine compound. The invention also provides for such compositions in a pharmaceutically acceptable carrier.
The invention provides methods for (a) treating conditions resulting from excessive water and/or electrolyte retention; (b) treating cardiovascular diseases; (c) treating renovascular diseases; (d) treating diabetes; (e) treating diseases resulting from oxidative stress; (f) treating endothelial dysfunctions; (g) treating diseases caused by endothelial dysfunctions; (h) treating cirrhosis; (j) treating pre-eclampsia; (k) treating osteoporosis; (1) treating nephropathy; (m) treating peripheral vascular diseases; (n) treating portal hypertension; (o) treating central nervous system disorders; and (p) treating sexual dysfunctions in a patient in need thereof comprising administering to the patient an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, optionally, at least one therapeutic agent, such as, for example, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin π antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti- hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β- adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAlDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof. The methods can optionally further comprise the administration of at least one nitric oxide enhancing compound. In this embodiment of the invention, the methods can involve (i) administering the diuretic compounds comprising a heterocyclic nitric oxide donor group, (ii) administering the diuretic compounds comprising a heterocyclic nitric oxide donor group, and nitric oxide enhancing compounds, (iii) administering the diuretic compounds comprising a heterocyclic nitric oxide donor group and therapeutic agents, or (iv) administering the diuretic compounds comprising a heterocyclic nitric oxide donor group, nitric oxide enhancing compounds, and therapeutic agents. In a preferred embodiment the at least one therapeutic agent is selected from the group consisting of an aldosterone antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme (ACE) inhibitor, a β-adrenergic antagonist, a diuretic, and a hydralazine compound. The diuretic compounds comprising a heterocyclic nitric oxide donor 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 diuretic compound comprising a heterocyclic nitric oxide donor group, and, optionally, at least one nitric oxide enhancing compound. The kit can further comprise at least one therapeutic agent, such as, for example, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof. The diuretic compound comprising a heterocyclic nitric oxide donor 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 carriers.
These and other aspects of the invention are described in detail herein. DETAILED DESCRIPTION OF THE INVENTION
As used throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
"Conditions resulting from excessive water and/or electrolyte retention" include but are not limited to lower extremity swelling, fatigue, body fluid retention, cardiac enlargement, shortness of breath, pulmonary edema, cerebral edema, edema associated at least in part with a cause selected from the group consisting of congestive heart failure, cirrhosis of the liver, poor blood circulation, lymphatic system failure, chronic nephritis, malnutrition, use of birth control pills, premenstrual syndrome, sunburn, hypertension, Meniere's disease, glaucoma, cystic fibrosis and/or an imbalance of sodium and potassium, and the like.
"Cardiovascular disease or disorder" refers to any cardiovascular disease or disorder known in the art, including, but not limited to, congestive heart failure, restenosis, hypertension (e.g. pulmonary 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, 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.
"Thromboembolic events" include, but are not limited to, ischemic stroke, transient ischemic stroke, myocardial infarction, angina pectoris, thrombosis (for example, restenosis, arterial thrombosis, coronary thrombosis, heart valve thrombosis, coronary stenosis, stent thrombosis, graft thrombosis, and first and subsequent thrombotic stroke, and the like), thromboembolism (for example, pulmonary thromboembolism, cerebral thromboembolism, and the like), thrombophlebitis, thrombocytopenia, bleeding disorders, thrombotic occlusion and reocclusion and acute vascular events. Patients who are at risk of developing thromboembolic events, may include those with a familial history of, or genetically predisposed to, thromboembolic disorders, who have had ischemic stroke, transient ischemic stroke, myocardial infarction, and those with unstable angina pectoris or chronic stable angina pectoris and patients with altered prostacyclin/thromboxane A2 homeostasis or higher than normal thromboxane A2 levels leading to increase risk for thromboembolism, including patients with diabetes and rheumatoid arthritis. "Diseases resulting from oxidative stress" refers to any disease that involves the generation of free radicals or radical compounds, such as, for example, atherogenesis, atheromatosis, arteriosclerosis, atherosclerosis, vascular hypertrophy associated with hypertension, hyperlipoproteinaemia, normal vascular degeneration through aging, parathyroidal reactive hyperplasia, renal disease (e.g., acute or chronic), neoplastic diseases, inflammatory diseases, neurological and acute bronchopulmonary disease, tumorigenesis, ischemia-reperfusion syndrome, arthritis, sepsis, cognitive dysfunction, endotoxic shock, endotoxin-induced organ failure, and the like.
"Renovascular diseases" refers to any disease or dysfunction of the renal system including, but not limited to, renal failure (e.g., acute or chronic), renal insufficiency, nephrotic edema, acute glomerulonephritis, oliguric renal failure, renal deterioration associated with severe hypertension, unilateral perechymal renal disease, polycystic kidney disease, chronic pyelonephritis, renal diseases associated with renal insufficiency, complications associated with dialysis or renal transplantation, renovascular hypertension, nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, 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, congestive 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, congestive 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.
"Sexual dysfunction" refers to any sexual dysfunction in a patient, including, but not limited to, sexual desire disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders, and the like. Female sexual dysfunction refers to any female sexual dysfunction including, but not limited to, sexual desire disorders, sexual arousal dysfunctions, orgasmic dysfunctions, sexual pain disorders, dyspareunia, vaginismus, and the like. The female can be pre-menopausal or menopausal. Sexual dysfunction can be caused, for example, by pregnancy, menopause, cancer, pelvic surgery, chronic medical illness or medications. Male sexual dysfunction refers to any male sexual dysfunctions including, but not limited to, male erectile dysfunction, impotence, 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, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti- hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β- adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and the like. Therapeutic agent includes the pharmaceutically acceptable salts thereof, pro-drugs, and pharmaceutical derivatives thereof including, but not limited to, the corresponding nitrosated and/or nitrosylated and/or heterocyclic nitric oxide donor derivatives. Although nitric oxide enhancing compounds have therapeutic activity, the term "therapeutic agent" does not include the nitric oxide enhancing compounds described herein, since nitric oxide enhancing compounds are separately defined.
"Prodrug" refers to a compound that is made more active in vivo. "Antioxidant" refers to and includes any compound that can react and/or quench a free radical.
"Angiotensin converting enzyme (ACE) inhibitor" refers to compounds that inhibit an enzyme which catalyzes the conversion of angiotensin I to angiotensin π. ACE inhibitors include, but are not limited to, amino acids and derivatives thereof, peptides, including di- and tri-peptides, and antibodies to ACE which intervene in the renin- angiotensin system by inhibiting the activity of ACE thereby reducing or eliminating the formation of the pressor substance angiotensin H.
"Angiotensin π antagonists" refers to compounds which interfere with the function, synthesis or catabolism of angiotensin II. Angiotensin π antagonists include peptide compounds and non-peptide compounds, including, but not limited to, angiotensin II antagonists, angiotensin II receptor antagonists, agents that activate the catabolism of angiotensin π, and agents that prevent the synthesis of angiotensin I from angiotensin H The renin-angiotensin system is involved in the regulation of hemodynamics and water and electrolyte balance. Factors that lower blood volume, renal perfusion pressure, or the concentration of sodium in plasma tend to activate the system, while factors that increase these parameters tend to suppress its function. "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.
"Diuretic compound" refers to and includes any compound or agent that increases the amount of urine excreted by a patient.
"Neutral endopeptidase inhibitors" refers to and includes compounds that are antagonists of the renin angiotensin aldosterone system including compounds that are dual inhibitors of neutral endopeptidases and angiotensin converting (ACE) enzymes.
"Renin inhibitors" refers to compounds which interfere with the activity of renin. "Phosphodiesterase inhibitor" or "PDE inhibitor" refers to any compound that inhibits the enzyme phosphodiesterase. The term refers to selective or non-selective inhibitors of cyclic guanosine 3 ',5 '-monophosphate phosphodiesterases (cGMP-PDE) and cyclic adenosine 3 ',5 '-monophosphate phosphodiesterases (c AMP-PDE).
"Platelet reducing 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+/K+-ATPase enzyme system at the secretory surface of the gastric parietal cell.
"NSAK)" refers to a nonsteroidal anti-inflammatory compound or a nonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, the enzyme responsible for the biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of the various isozymes of cyclooxygenase (including but not limited to cyclooxygenase- 1 and -T), and as inhibitors of both cyclooxygenase and lipoxygenase.
"Cyclooxygenase-2 (COX-2) selective inhibitor" refers to a compound that selectively inhibits the cyclooxygenase-2 enzyme over the cyclooxygenase- 1 enzyme. In one embodiment, the compound has a cyclooxygenase-2 IC50 of less than about 2 μM and a cyclooxygenase- 1 IC50 of greater than about 5 μM, in the human whole blood COX-2 assay (as described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) and also has a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase- 1 inhibition of at least 10, and preferably of at least 40. In another embodiment, the compound has a cyclooxygenase- 1 IC50 of greater than about 1 μM, and preferably of greater than 20 μM. The compound can also inhibit the enzyme, lipoxygenase. Such selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
"Patient" refers to animals, preferably mammals, most preferably humans, and includes males and females, and children and adults. "Therapeutically 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 a compound and/or composition such that the blood levels of the compound are maintained within a desirable 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 via a stableaminoxyl radical i.e. N- oxide.
"Nitric oxide adduct" or "NO adduct" refers to compounds and functional groups which, under physiological conditions, can donate, release and/or directly or indirectly transfer any of the three redox forms of nitrogen monoxide (NO+, NO", NO«), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
"Nitric oxide releasing" or "nitric oxide donating" refers to methods of donating, releasing and/or directly or indirectly transferring any of the three redox forms of nitrogen monoxide (NO+, NO-, NO»), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
"Nitric oxide donor" or "NO donor" refers to compounds that donate, release and/or directly or indirectly transfer a nitrogen monoxide species, and/or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo and/or are oxidized to produce nitric oxide and/or are substrates for nitric oxide synthase and/or cytochrome P450. "NO donor" also includes compounds that are precursors of L-arginine, inhibitors of the enzyme arginase and nitric oxide mediators. "Heterocyclic nitric oxide donor" refers to a trisubstituted 5-membered ring comprising two or three nitrogen atoms and at least one oxygen atom. The heterocyclic nitric oxide donor is capable of donating and/or releasing a nitrogen monoxide species upon decomposition of the heterocyclic ring. Exemplary heterocyclic nitric oxide donors include oxatriazol-5-ones, oxatriazol-5-imines, sydnonimines, furoxans, and the like.
"Alkyl" refers to a lower alkyl group, a substituted lower alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein. An alkyl group may also comprise one or more radical species, such as, for example a cycloalkylalkyl group or a heterocyclicalkyl group.
"Lower alkyl" refers to branched or straight chain acyclic alkyl group comprising one to about ten carbon atoms (preferably one to about eight carbon atoms, more preferably one to about six carbon atoms). Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the like.
"Substituted lower alkyl" refers to a lower alkyl group, as defined herein, wherein one or more of the hydrogen atoms have been replaced with one or more R100 groups, wherein each R100 is independently a hydroxy, an ester, an amidyl, an oxo, a carboxyl, a carboxamido, a halo, a cyano, a nitrate, a nitrite, a thionitrate, a thionitrite or an amino group, as defined herein.
"Haloalkyl" refers to a lower alkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein, to which is appended one or more halogens, as defined herein. Exemplary haloalkyl groups include trifluoromethyl, chloromethyl, 2-bromobutyl, l-bromo-2-chloro-pentyl, and the like.
"Alkenyl" refers to a branched or straight chain C2-C1O hydrocarbon (preferably a C2-C8 hydrocarbon, more preferably a C2-C6 hydrocarbon) that can comprise one or more carbon-carbon double bonds. Exemplary alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbuten-l-yl, 3-methylbuten-l-yl, hexan-1-yl, hepten-1- yl, octen-1-yl, and the like.
"Lower alkenyl" refers to a branched or straight chain C2-C4 hydrocarbon that can comprise one or two carbon-carbon double bonds.
"Substituted alkenyl" refers to a branched or straight chain C2-C1O hydrocarbon (preferably a C2-C8 hydrocarbon, more preferably a C2-C6 hydrocarbon) which can comprise one or more carbon-carbon double bonds, wherein one or more of the hydrogen atoms have been replaced with one or more R100 groups, wherein each R100 is independently a hydroxy, an oxo, a carboxyl, a carboxamido, a halo, a cyano or an amino group, as defined herein. "Alkynyl" refers to an unsaturated acyclic C2-C10 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-l-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 maybe in the thio, sulfinyl or sulfonyl oxidation state. The heterocyclic ring or group can be fused to an aromatic hydrocarbon group. Heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester, alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido, alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester, sulfonamide nitrate and nitro. Exemplary heterocyclic groups include pyrrolyl, furyl, thienyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4- dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrahydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, imidazolinyl, imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4- thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4- dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, benzothiazolinyl, quinolinyl, 2,6- dioxabicyclo(3.3.0)octane, and the like.
"Heterocyclic compounds" refer to mono- and polycyclic compounds comprising at least one aryl or heterocyclic ring.
"Aryl" refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or two aromatic rings. Exemplary aryl groups include phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamido and nitro. Exemplary substituted aryl groups include tetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfonyl, and the like. "Cycloalkenyl" refers to an unsaturated cyclic C2-C10 hydrocarbon (preferably a
C2-C8 hydrocarbon, more preferably a C2-C6 hydrocarbon) which can comprise one or more carbon-carbon triple 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-fluorophenylethyl, and the like.
"Arylalkenyl" refers to an aryl radical, as defined herein, attached to an alkenyl radical, as defined herein. Exemplary arylalkenyl groups include styryl, propenylphenyl, and the like.
"Cycloalkylalkyl" refers to a cycloalkyl radical, as defined herein, attached to an alkyl radical, as defined herein. "Cycloalkylalkoxy" refers to a cycloalkyl radical, as defined herein, attached to an alkoxy radical, as defined herein.
"Cycloalkylalkylthio" refers to a cycloalkyl radical, as defined herein, attached to an alkylthio radical, as defined herein.
"Heterocyclicalkyl" refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein.
"Arylheterocyclic ring" refers to a bi- or tricyclic ring comprised of an aryl ring, as defined herein, appended via two adjacent carbon atoms of the aryl ring to a heterocyclic ring, as defined herein. Exemplary arylheterocyclic rings include dihydroindole, 1,2,3,4- tetra-hydroquinoline, and the like. "Alkylheterocyclic ring" refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein. Exemplary alkylheterocyclic rings include 2-pyridylmethyl, l-methylpiperidin-2-one-3 -methyl, and the like.
"Alkoxy" refers to R50O-, wherein R50 is an alkyl group, as defined herein (preferably a lower alkyl group or a haloalkyl group, as defined herein). Exemplary alkoxy groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, trifluoromethoxy, and the like.
"Aryloxy" refers to R55O-, wherein R55 is an aryl group, as defined herein. Exemplary arylkoxy groups include napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like.
"Alkylthio" refers to R50S-, wherein R50 is an alkyl group, as defined herein. "Lower alkylthio" refers to a lower alkyl group, as defined herein, appended to a thio group, as defined herein.
"Arylalkoxy" or "alkoxyaryl" refers to an alkoxy group, as defined herein, to which is appended an aryl group, as defined herein. Exemplary arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy, and the like. "Arylalklythio" refers to an alkylthio group, as defined herein, to which is appended an aryl group, as defined herein. Exemplary arylalklythio groups include benzylthio, phenylethylthio, chlorophenylethylthio, and the like. " Arylalldythioalkyl" refers to an arylalkylthio group, as defined herein, to which is appended an alkyl group, as defined herein. Exemplary arylalklythioalkyl groups include benzylthiomethyl, phenylethylthiomethyl, chlorophenylethylthioethyl, and the like.
" Alkylthioalkyl" refers to an alkylthio group, as defined herein, to which is appended an alkyl group, as defined herein. Exemplary alkylthioalkyl groups include allylthiomethyl, ethylthiomethyl, trifluoroethylthiomethyl, and the like.
"Alkoxyalkyl" refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined herein. Exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, isopropoxymethyl, and the like. "Alkoxyhaloalkyl" refers to an alkoxy group, as defined herein, appended to a haloalkyl group, as defined herein. Exemplary alkoxyhaloalkyl groups include 4- methoxy-2-chlorobutyl and the like.
"Cycloalkoxy" refers to 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 Rs4S-, 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-ORsi wherein R81is 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(R81)(RI 81) wherein R'81 is independently selected from R81, and Rg1 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 -0-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 (T), bromine (Br), chlorine (Cl), and/or fluorine
(F).
"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 Rs0NH-, 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 Rs5R6ON-, wherein R55 and R60 are each independently an aryl group, as defined herein.
"Alkylarylamino or arylalkylamino" refers to Rs2R5SN-, wherein R52 is an alkyl group, as defined herein, and R55 is an aryl group, as defined herein.
"Alkylarylalkylamino" refers to R52R79N-, wherein R52 is an alkyl group, as defined herein, and R79 is an arylalkyl group, as defined herein. "Alkylcycloalkylamino" refers to R52R80N-, wherein R52 is an alkyl group, as defined herein, and R8o is a cycloalkyl group, as defined herein.
"Aminoalkyl" refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an alkyl group, as defined herein. Exemplary aminoalkyl groups include dimethylaminopropyl, diphenylaminocyclopentyl, methylaminomethyl, and the like.
"Aminoaryl" refers to an aryl group to which is appended an alkylamino group, a arylamino group or an arylalkylamino group. Exemplary aminoaryl groups include anilino, N-methylanilino, N-benzylanilino, and the like.
"Thio" refers to -S-.
"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)2OR76, wherein R76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
"Alkylsulfonic acid" refers to a sulfonic acid group, as defined herein, appended to an alkyl group, as defined herein. "Arylsulfonic acid" refers to a sulfonic acid group, as defined herein, appended to an aryl group, as defined herein
"Sulfonic ester" refers to -S(O)2OR58, wherein R58 is an alkyl group, an aryl group, or an aryl heterocyclic ring, as defined herein.
"Sulfonamido" refers to -S(O^-N(R51)(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.
"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 R5oS-, 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 R5O-S(O)-, wherein R50 is an alkyl group, as defined herein. "Alkylsulfonyl" refers to R5O-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 R55-S(O)-, wherein R55 is an aryl group, as defined herein. "Arylsulfonyl" refers to RsS-S(O)2-, wherein R55 is an aryl group, as defined herein.
"Arylsulfonyloxy" refers to Rs5-S(O)2-O-, wherein R55 is an aryl group, as defined herein.
"Amidyl" refers to Rs1C(O)N(R57)- wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein. "Ester" refers to R51C(O)R76- wherein R51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein and R76 is oxygen or sulfur.
"Carbamoyl" refers to -0-C(O)N(R51)(R57), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
"Carboxyl" refers to -C(O)OR76, wherein R76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
"Carbonyl" refers to -C(O)-.
"Alkylcarbonyl" refers to R52-C(O)-, wherein R52 is an alkyl group, as defined herein.
"Arylcarbonyl" refers to R5S-C(O)-, wherein R55 is an aryl group, as defined herein.
"Arylalkylcarbonyl" refers to R5s-R52-C(O)~, wherein R55 is an aryl group, as defined herein, and R52 is an alkyl group, as defined herein.
"Alkylarylcarbonyl" refers to R52-R55-C(O)-, wherein R55 is an aryl group, as defined herein, and R52 is an alkyl group, as defined herein.
"Heterocyclicalkylcarbonyl" refers to R78C(O)- wherein R78 is a heterocyclicalkyl group, as defined herein.
"Carboxylic ester" refers to -C(O)ORs8, 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 gi'oup, 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(Rs1)(R57), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
"Alkylcarboxamido" refers to an alkyl group, as defined herein, appended to a carboxamido group, as defined herein.
"Arylcarboxamido" refers to an aryl group, as defined herein, appended to a carboxamido group, as defined herein.
"Urea" refers to -N(R59)-C(O)N(R51 XR57) wherein R51, R57, and R59 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein. "Phosphoryl" refers to -P(R7o)(R71)(R72), wherein 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.
"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.
"Organic acid" refers to compound having at least one carbon atom and one or more functional groups capable of releasing a proton to a basic group. The organic acid preferably contains a carboxyl, a sulfonic acid or a phosphoric acid moeity. Exemplary organic acids include acetic acid, benzoic acid, citric acid, camphorsulfonic acid, methanesulfonic acid, taurocholic acid, chlordronic acid, glyphosphate, medronic acid, and the like.
"Inorganic acid" refers to a compound that does not contain at least one carbon atom and is capable of releasing a proton to a basic group. Exemplary inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
"Organic base" refers to a carbon containing compound having one or more functional groups capable of accepting a proton from an acid group. The organic base preferably contains an amine group. Exemplary organic bases include triethylamine, benzyldiethylamine, dimethylethyl amine, imidazole, pyridine, pipyridine, and the like. The compounds and compositions of the invention are diuretics, including, 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, 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. The contemplated diuretic compounds are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, (1996); Merck Index on CD-ROM, 13th Edition; STN Express, file phar and file registry, the disclosures of each of which are incorporated by reference herein in their entirety.
The diuretic compounds of the invention are substituted with at least one heterocyclic nitric oxide donor group that is linked to the diuretic compound through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen. The diuretic compounds comprising a heterocyclic nitric oxide donor group are in accordance with the invention and/or are included in the compositions of the invention, including those exemplified below. The heterocyclic nitric oxide donors are preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.
In another embodiment, the invention described diuretic compounds comprising a heterocyclic nitric oxide donor group of Formula (I) and pharmaceutically acceptable salts thereof:
(D wherein:
X2 is -C(O)- or -S(O)2;
Y2 is chlorine or CF3;
-V2-U2-W2- is:
(i) -N(Di)-(C(Rq)(Rr))-N(Di)-;
(ii) -N=C(Rq))-N(D1)-; or
(iii) -N(D1)-(C(Rq)(Rr))-N(Rq)-;
Rq and Rr at each occurrence are independently a hydrogen, a lower alkyl group, a substituted alkyl group, a benzyl group, an aryl group, an alkylaryl group, -CH2-S-CH- CH=CH2; -CH2-S-CF3 or -CH2-S-CH2-C6H5;
D1 is a hydrogen, V3 or K;
K is -(W)a-Eb-(C(Re)(Rf))p1-Ec-(C(Re)(Rf))x-(W)d-(C(Re)(Rf))r(W)i-Ej-(W)g- 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;
V3 is:
R24 is -C6H4R27, -CN, -S(O)2-C6H4R27, -C(O)-N(Ra)(R1), -NO2 or -C(O)-OR25;
R25 is an alkyl group or an aryl group;
R26 is -C(O)- or -S(O)2- ;
R27 is a hydrogen, -CN, -S(O)2-R25, -C(O)-N(Ra)(Rj), -NO2 or -C(O)-OR25;
T' is oxygen, sulfur or NR6;
R6 is a hydrogen, a lower alkyl group, an aryl group;
W 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) ql- or a heterocyclic nitric oxide donor;
E at each occurrence is independently -T3-, an alkyl group, an aryl group, -(C(Re)(Rf)X-, a heterocyclic ring, an arylheterocyclic ring, -(CH2CH2O)Q1- or Y3; Y3 is:
• T is a -S(O)0-; a carbonyl or a covalent bond; o is an integer from O 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(Ra)Ri; h is an integer form 1 to 10; qt 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, a 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, -C(R0)(Rp)ki-U3-V5, 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 or a bridged cycloalkyl group;
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, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-Vs, 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 or a bridged cycloalkyl group; U3 is an oxygen, sulfur or -N(Ra)Ri; V5 is -NO or -NO2; 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 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)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom, -(N2O2-^M1 +, wherein M1 + is an organic or inorganic cation; and with the proviso that the diuretic compounds of Formula (T) must contain at least one heterocyclic nitric oxide donor group linked to the diuretic compound through an oxygen atom, a nitrogen atom or a sulfur atom.
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, Eo would denote a covalent bond, while E2 denotes (E-E) and (C(R4)(RO)2 denotes -C(R4)(R4VC(R4)(R4)-.
Another embodiment of the invention describes diuretic compounds comprising a heterocyclic nitric oxide donor group of Formula (IT) and pharmaceutically acceptable salts thereof:
(π) wherein:
X4 is:
(ϋ)
(V) -S(O)2-N(D)(D i);
(g) -C(O)-O-D; or
(h)
Z4 is:
(i)al lydrogen;
(ϋ)
(iii) - =C(H)-C(H)=C(OD)(CH3); (iv) -S(O)2-N(Dj)-CH2-CH=CH2; (V) -NH(D1);
(vi) -CH3; or
(vii) -OD1
Y4 is:
(i) Y2; or
W4 is:
(i) a hydrogen;
D is V3 or K;
V4 is a thio group or an oxygen atom; and
D1, Y2, V3 and K are as defined herein; and with the proviso that the diuretic compounds of Formula (II) must contain at least one heterocyclic nitric oxide donor group linked to the diuretic compound through an oxygen atom, a nitrogen atom or a sulfur atom.
Another embodiment of the invention describes diuretic compounds comprising a heterocyclic nitric oxide donor group of Formula (JE) and pharmaceutically acceptable salts thereof:
wherein:
X3 is: - K is as defined herein; and with the proviso that the heterocyclic diuretic compounds of Formula (HI) must contain at least one heterocyclic nitric oxide donor group linked to the diuretic compound through an oxygen atom, a nitrogen atom or a sulfur atom.
In other embodiments of the invention the compound of Formula (I) is a heterocyclic nitric oxide donor althiazide, a heterocyclic nitric oxide donor bendroflumethiazide, a heterocyclic nitric oxide donor benzthiazide, a heterocyclic nitric oxide donor buthiazide, a heterocyclic nitric oxide donor chlorothiazide, a heterocyclic nitric oxide donor cyclothiazide, a heterocyclic nitric oxide donor ethiazide, a heterocyclic nitric oxide donor fenquizone, a heterocyclic nitric oxide donor hydrochlorothiazide, a heterocyclic nitric oxide donor hydroflumethiazide, a heterocyclic nitric oxide donor methyclothiazide, a heterocyclic nitric oxide donor metolazone, a heterocyclic nitric oxide donor paraflutizide, a heterocyclic nitric oxide donor polythiazide, a heterocyclic nitric oxide donor quinethazone, a heterocyclic nitric oxide donor teclothiazide, a heterocyclic nitric oxide donor trichlormethiazide; the compound of Formula (II) is a heterocyclic nitric oxide donor ambuside, a heterocyclic nitric oxide donor azosemide, a heterocyclic nitric oxide donor bumetanide, a heterocyclic nitric oxide donor chloraminophenamide, a heterocyclic nitric oxide donor chlorthalidone, a heterocyclic nitric oxide donor clofenamide, a heterocyclic nitric oxide donor clopamide, a heterocyclic nitric oxide donor disulfamide, a heterocyclic nitric oxide donor furosemide, a heterocyclic nitric oxide donor mefruside, a heterocyclic nitric oxide donor piretanide, a heterocyclic nitric oxide donor xipamide; the compound of Formula (DI) is a heterocyclic nitric oxide donor ethacrynic acid, a heterocyclic nitric oxide donor ticrynafen, and pharmaceutically acceptable salts thereof.
In other embodiments of the invention, the diuretic compounds of Formula (I) is a chlorothiazide comprising a heterocyclic nitric oxide donor group or a hydrochlorothiazide comprising a heterocyclic nitric oxide donor group of Formula (W) and the diuretic compound of Formula (H) is a chlorthalidone comprising a heterocyclic nitric oxide donor group of Formula (V), a furosemide comprising a heterocyclic nitric oxide donor group of Formula (VI) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IV) is:
(IV) wherein the bond a-b can be a single bond (hydrochlorothiazide) or a double bond
(chlorothiazide); and the compound of Formula (V) is:
(V) and the compound of Formula (VI) is:
(VD wherein Rm-Rn taken together are a hydrogen atom; or Rm is:
(i) -C-(O)-;
(ii) -C-(O)-NR6;
(Ui) -C(O)-O-;
(Iv) -C(O)-S;
(v) -CH2-O-;
(vi) -CH(CH3)-0-;
(vii) -N-C(O)-S-;
(viii) -N-C(O)-CH2-; or
(ix) -N-C(O)-O-; Rn is: a hydrogen or:
wherein:
T', R24, R25, R26, Rj, Rk, Re and Rf are as defined herein; and with the proviso that the compounds of Formula (PV), (V) and (Vl) must contain at least one heterocyclic nitric oxide donor group.
In another embodiment, the furosemide compound or derivative comprising a heterocyclic nitric oxide donor group of Formula (VI) is: benzoic acid, 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]-, (4~methyl-5-oxido- l,2,5-oxadiazol-3-yl)methyl ester; , benzoic acid, 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]-, 2-[(4-methyl-5- oxido- 1 ,2,5-oxadiazol-3-yl)methoxy]-2-oxoethyl ester benzoic acid, 2-amino-5-(aminosulfonyl)-4-chloro-, (4-methyl-5-oxido-l,2,5-oxadiazol-3- yl)methyl ester; or a pharmaceutically acceptable salt thereof.
Compounds of the invention that have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates. 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 diuretic compounds comprising a heterocyclic nitric oxide donor group and pharmaceutically acceptable salts thereof. These metabolites, include but are not limited to, the non- heterocyclic nitric oxide donor derivatives, degradation products, hydrolysis products, and the like, of the diuretic compounds comprising a heterocyclic nitric oxide donor 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 (T), (U), (JJT), (IV), (V) and (VI) can be synthesized by one skilled in the art following the methods and examples described herein. Some of the parent diuretic compounds (i.e. diuretic compounds that do not contain a heterocyclic nitric oxide donor group) are commercially available. The synthesis of the parent diuretic compounds are also disclosed in, for example, U.S. Patent Nos. 2,809,194, 2,976,289, 3,055,904, 3,058,882, 3,255,241, 3,360,518, 3,392,168, 3,565,911, 3,665,002, 3,758,506, 3,806,534, 4,010,273, 4,018,020, 6,767,917 and in JP 7305,585 and in DE 1,163,332, and in J. Am. Chem. Soc. 82: 1132 (1960), the disclosures of each of which are incorporated by reference herein in their entirety. The parent diuretic compounds are substituted to contain a heterocyclic nitric oxide donor group linked to the diuretic compound through one or more sites such as oxygen, sulfur and/or nitrogen using conventional methods known to one skilled in the art. Known methods for linking the heterocyclic nitric oxide donor group to compounds are described in WO 99/64417, WO 94/01422; EP 0 574726 Al, EP 0 683 159 Al; and in J. Med. Chem., Al: 2688-2693 (2004); /. Med. Chem., 47: 1840-1846 (2004); J. Med. Chem ., 46: 3762-3765 (2003); /. Med. Chem., 46: 747-754 (2003); Chem Rev., 102: 1091-1134 (2002); /. Med. Chem., 42: 1941-1950 (1999); J. 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 heterocyclic nitric oxide donor group to compounds described in these references can be applied by one skilled in the art to produce any of the diuretic compounds comprising a heterocyclic nitric oxide donor group described herein. The diuretic compounds comprising a heterocyclic nitric oxide donor 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., diuretic compounds that contain a heterocyclic nitric oxide donor 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 and compounds that release 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- ammonioρropyl)-N-(n-ρroρyl)amino)diazen- 1 -ium- 1 ,2-diolate ("PAPA/NO"), (Z)- 1 -(N-(3- aminopropyl)-N-(4-(3-arninopropylammonio)butyl)-amino) diazen- 1 -ium- 1 ,2-diolate (spermine NONOate or "SPER/NO") and sodium(Z)-l -(N5N- diethylamino)diazenium- 1,2-diolate (diethylamine NONOate or "DEA/NO") and derivatives thereof. NONOates are also described in U.S. Patent Nos. 6,232,336, 5,910,316 and 5,650,447, the disclosures of which are incorporated herein by reference in their entirety. The "NO adducts" can be mono-nitrosylated, poly-nitrosylated, mono-nitrosated and/or poly-nitrosated at a variety of naturally susceptible or artificially provided binding sites for biologically active forms of nitrogen monoxide.
Suitable furoxanes include, but are not limited to, CAS 1609, C93-4759, C92- 4678, S35b, CHF 2206, CHF 2363, and the like. Suitable sydnonimines include, but are not limited to, molsidomine (N- ethoxycarbonyl-3-morpholinosydnonimine), SIN-I (3-morpholinosydnonimine) CAS 936 (3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydnonimine, pirsidomine), C87- 3754 (3-(cis-2,6-dimethylpiperidino)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-nitrosothiols, which are compounds that include at least one -S-NO group. These compounds include S-nitroso-polypeptides (the term "polypeptide" includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated sugars; S-nitrosylated, modified and unmodified, oligonucleotides (preferably of at least 5, and more preferably 5-200 nucleotides); straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds. S-nitrosothiols and methods for preparing them are described in U.S. Patent Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae et al, Org. Prep. Proc. Int., 15(3): 165-198 (1983), the disclosures of each of which are incorporated by reference herein in their entirety.
Another embodiment of the invention is S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof. Such compounds include, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril, S- nitroso-N-acetylpenicillainine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso- glutathione, S-nitroso-cysteinyl-glycine, and the like.
Suitable S-nitrosylated proteins include thiol-containing proteins (where the NO group is attached to one or more sulfur groups on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator (TPA) and cathepsin B; transport proteins, such as lipoproteins; heme proteins, such as hemoglobin and serum albumin; and biologically protective proteins, such as immunoglobulins, antibodies and cytokines. Such nitrosylated proteins are described in WO 93/09806, the disclosure of which is incorporated by reference herein in its entirety. Examples include polynitrosylated albumin where one or more thiol or other nucleophilic centers in the protein are modified. Other examples of suitable S-nitrosothiols include: (i) HS(C(Re)(Rf))mSNO; (ii) ONS(C(Re)(Rf))mRe; or
(iii) H2N-CH(CO2H)-(CH2)m-C(O)NH-CH(CH2SNO)-C(O)NH-CH2-CO2H; wherein m is an integer from 2 to 20;
Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an aiylalklythio, 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, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamide an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-Vs, -C(R0)(Rp)ki-U3-V5, 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, a hydrazone or a bridged cycloalkyl group;
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, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-Vs, 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 or a bridged cycloalkyl group; ki is an integer form 1 to 3; U3 is an oxygen, sulfur- or -N(Ra)Ri;
V5 is -NO or -NO2 (i.e. an oxidized nitrogen); Ra is a lone pair of electrons, a hydrogen or an alkyl group; Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, arylsulphonyloxy, a sulfonamide 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, -(N2O2-)"»M! +, wherein M1 + 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 R; 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. Preferred 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, l,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. Preferred 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. Preferred 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 M1 + is an organic or inorganic cation, such, as for example, an alkyl substituted ammonium cation or a Group I metal cation. The invention is also directed to compounds that stimulate endogenous NO or elevate levels of endogenous endothelium-derived relaxing factor (EDRF) in vivo or are oxidized to produce nitric oxide and/or are substrates for nitric oxide synthase and/or cytochrome P450. Such compounds include, for example, L-arginine, L-homoarginine, and N-hydroxy-L-arginine, N-hydroxy-L-homoarginine, N-hydroxydebrisoquine, N- hydroxypentamidine including their nitrosated and/or nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N- hydroxy-L-arginine, nitrosated and nitrosylated L-homoarginine), N-hydroxyguanidine compounds, amidoxime, ketoximes, aldoxime compounds, that can be oxidized in vivo to produce nitric oxide. Compounds that may be substrates for a cytochrome P450, include, for example, imino(benzylamino)methylhydroxyl amine, imino(((4-methylphenyl)methyl) amino)methylhydroxylamine, imino(((4-methoxyphenyl)methyl)amino) methylhydroxylamine, imino(((4-(trifluoromethyl)phenyl)methyl) amino) methylhydroxylamine, imino(((4-nitrophenyl) methyl)amino)methylhydroxylamine, (butylamino) iminomethylhydroxylamine, imino (propylamino) methylhydroxylamine, imino(pentylamino)methylhydroxylamine, imino (propylamino)methylhydroxylamine, imino ((methylethyl)amino)methylhydroxylamine, (cyclopropylamino) iminomethylhydroxylamine, imino-2-1 ,2,3,4-tetrahydroisoquinolyl methylhydroxylamine, imino( 1 -methyl(2- 1 ,2,3 ,4-tetrahydroisoquinolyl))methylhydroxylamine, (1,3 -dimethyl(2- 1,2,3,4-tetrahydroisoquinolyl)) iminomethylhydroxylamine, (((4-chlorophenyl)methyl) amino)iminomethylhydroxylamine, ((4-chlorophenyl)amino) iminomethylhydroxylamine, (4-chlorophenyl)(hydroxyimino)methylamine, and 1 -(4-chlorophenyl)- 1 -(hydroxyimino) ethane, and the like, precursors of L-arginine and/or physiologically acceptable salts thereof, including, for example, citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids, inhibitors of the enzyme arginase (e.g., N- hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid), nitric oxide mediators and/or physiologically acceptable salts thereof, including, for example, pyruvate, pyruvate precursors, α-keto acids having four or more carbon atoms, precursors of α-keto acids having four or more carbon atoms (as disclosed in WO 03/017996, the disclosure of which is incorporated herein in its entirety), and the substrates for nitric oxide synthase, cytokines, adenosin, bradykinin, calreticulin, bisacodyl, and phenolphthalein. EDRF is a vascular relaxing factor secreted by the endothelium, and has been identified as nitric oxide (NO) or a closely related derivative thereof (Palmer et al, Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. ScL USA, 84:9265-9269 (1987)). The invention is also directed to nitric oxide enhancing compounds that can increase endogenous nitric oxide. Such compounds, include for example, nitroxide containing compounds, include, but are not limited to, substituted 2,2,6,6-tetramethyl-l- piperidinyloxy compounds, substituted 2,2,5, 5-tetramethyl-3-pyrroline-l-oxyl compounds, substituted 2,2,5,5-tetramethyl-l-pyrrolidinyloxyl compounds, substituted 1,1,3,3- tetramethylisoindolin-2-yloxyl compounds, substituted 2,2,4,4-tetramethyl-l-oxazolidinyl- 3-oxyl compounds, substituted 3-imidazolin-l-yloxy, 2,2,5,5~tetramethyl-3~imidazolin~l- yloxyl compounds, OT-551, 4-hydroxy-2,2,6,6-tetramethyl-l-piperidinyloxy (tempol), and the like. Suitable substituents, include, but are not limited to, aminomethyl, benzoyl, 2- bromoacetamido, 2-(2-(2-bromoacetamido)ethoxy)ethylcarbamoyl, carbamoyl, carboxy, cyano, 5-(dimethylamino)-l-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, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti- hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β- adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NS AIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, 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.
Suitable aldosterone antagonists include, but are not limited to, canrenone, potassium canrenoate, drospirenone, spironolactone, eplerenone (INSPRA®), epoxymexrenone, fadrozole, pregn-4-ene-7,21-dicarboxylic acid, 9,ll-epoxy-17-hydroxy- 3-oxo, γ-lactone, methyl ester, (7α,llα,17β.)-; pregn-4-ene-7,21-dicarboxylic acid, 9,11- epoxy-17-hydroxy-3-oxo-dimethyl ester, (7α,llα,17β.)-; 3Η-cyclopropa(6,7)pregna-4,6- diene-21-carboxylic acid, 9,ll-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone, (6β,7β,llα,17β)-; pregn-4-ene-7,21-dicarboxylic acid, 9,ll-epoxy-17-hydroxy-3-oxo-, 7- (1-methylethyl) ester, monopotassium salt, (7α, 1 lα, 17β.)-; pregn-4-ene-7,21-dicarboxylic acid, 9,ll,-epoxy-17-hydroxy-3-oxo-, 7-methyl ester, monopotassium salt, (7α,llα,17β.)-; 3Η-cyclopropa(6,7) pregna-l,4,6-triene-21-carboxylic acid, 9,ll-epoxy-6,7-dihydro-17- hydroxy-3-oxo-, γ-lactone, (6β,7β,llα)-; 3'H-cyclopropa(6,7)pregna-4,6-diene-21- carboxylic acid, 9,ll-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, methyl ester, (6β,7β,llα,17β)-; 3'H-cyclopropa (6,7)pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy- 6,7-dihydro-17-hydroxy-3-oxo-, monopotassium salt, (6β,7β,llα,17β)-; 3Η- cyclopropa(6,7)pregna-l,4,6-triene-21-carboxylic acid, 9,1 l-epoxy-6,7-dihydro-17~ hydroxy-3-oxo-, γ-lactone, (6β,7β,l lα,17β)-; ρregn-4-ene-7,21-dicarboxylic acid, 9,11- epoxy-17-hydroxy-3-oxo-, γ-lactone, ethyl ester, (7α,llα,17β)-; pregn-4-ene-7,21- dicarboxylic acid, 9,1 l-epoxy-17-hydroxy-3-oxo-, γ-lactone, 1-methylethyl ester, (7α,l lα,17β)-; RU-28318, and the like. One skilled in the art will appreciate that the aldosterone antagonists can be administered in the form of their pharmaceutically acceptable salts and/or stereoisomers. Suitable aldosterone antagonists 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 aldosterone antagonist is eplerenone or spironolactone (a potassium sparing diuretic that acts like an aldosterone antagonist). In one embodiment eplerenone is administered in an amount of about 25 milligrams to about 300 milligrams as a single dose or as multiple doses per day; the spironolactone is administered in an amount of about 25 milligrams to about 150 milligrams as a single dose or as multiple doses per day. Suitable alpha-adrenergic receptor antagonists include but are not limited to, phentolamine, tolazoline, idazoxan, deriglidole, RX 821002, BRL 44408, BRL 44409, BAM 1303, labetelol, ifenprodil, rauwolscine, corynathine, raubascine, tetrahydroalstonine, apoyohimbine, akuammigine, β-yohimbine, yohimbol, yohimbine, pseudoyohimbine, epi-3α-yohimbine, 10-hydroxy-yohimbine, 11 -hydroxy-yohimbine, tamsulosin, benoxathian, atipamezole, BE 2254, WB 4101, HU-723, tedisamil, mirtazipine, setiptiline, reboxitine, delequamine, naftopil, saterinone, SL 89.0591, ARC 239, urapidil, 5-methylurapidil, monatepi, haloperidol, indoramin, SB 216469, moxisylyte, trazodone, dapiprozole, efaroxan, Recordati 15/2739, SNAP 1069, SNAP 5089, SNAP 5272, RS 17053, SL 89.0591, KMD 3213, spiperone, AH 11110A, chloroethylclonidine, BMY 7378, niguldipine, and the like. Suitable alpha-adrenergic 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; and the Merck Index on CD-ROM, Thirteenth Edition; and on STN Express, file phar and file registry. Suitable angiotensin II antagonists include, but are not limited to, angiotensin, abitesartan, candesartan, candesartan cilexetil, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan, forasartan, glycyllosartan, irbesartan, losartan, olmesartan, milfasartan, medoxomil, ripisartan, pratosartan, saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan, 3-(2' (tetrazole-5-yl)- 1 , 1 '-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl- 3H-imidazo(4,5-b)pyridine, antibodies to angiotensin π, A-81282, A-81988, BAY 106734, BIBR-363, BIBS-39, BIBS-222, BMS-180560, BMS-184698, BMS-346567, CGP- 38560A, CGP-42112A, CGP-48369, CGP-49870, CGP-63170, CI-996, CP-148130, CL- 329167, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, DuP-753, E- 1477, E-4177, E-4188, EMD-66397, EMD-666R4, EMD-73495, EMD-66684, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, EXP-9954, FK-739, FRI 153332, GA-0050, GA-0056, HN-65021, HOE-720, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, KRI-1177, KT3-671, KT-3579, KW-3433, L-158809, L-158978, , L-159282, L-159689, L-159874, L-161177, L-162154, L-162234, L-162441, L-163007, L-163017, LF-70156, LRB-057, LRB-081, LRB-087, LY-235656, LY-266099, LY-285434, LY- 301875, LY-302289, LY-315995, ME-3221, MK-954, PD-123177, PD-123319, PD-
126055, PD-150304, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, SC-51757, SC-54629, SC-52458, SC-52459, SK 1080, SL-910102, SR-47436, TAK-536, UP-2696, U-96849, U-97018, UK-77778, UP-275-22, WAY-126227, WK-1260, WK-1360, WK- 1492, WY 126227, YH-1498, YM-358, YM-31472, X-6803, XH-148, XR-510, ZD-6888, ZD-7155, ZD-8731, ZD 8131, the compounds of ACS registry numbers 124750-92-1, 133240-46-7, 135070-05-2, 139958-16-0, 145160-84-5, 147403-03-0, 153806-29-2, 439904-54-8P, 439904-55-9P, 439904-56-0P, 439904-57-1P, 439904-58-2P, 155918-60- 8P, 155918-61-9P, 272438-16-1P, 272446-75-0P, 223926-77-0P, 169281-89-4, 439904- 65-1P, 165113-01-9P, 165113-02-OP, 165113-03-1P, 165113-03-2P, 165113-05-3P, 165113-06-4P, 165113-07-5P, 165113-08-6P, 165113-09-7P, 165113-10-OP, 165113-11- IP, 165113-12-2P, 165113-17-7P, 165113-18-8P, 165113-19-9P, 165113-20-2P, 165113- 13-3P, 165113-14-4P, 165113-15-5P, 165113-16-6P, 165113-21-3P, 165113-22-4P, 165113-23-5P, 165113-24-6P, 165113-25-7P, 165113-26-8P, 165113-27-9P, 165113-28- OP, 165113-29-1P, 165113-30-4P, 165113-31-5P, 165113-32-6P, 165113-33-7P, 165113- 34-8P, 165113-35-9P, 165113-36-0P, 165113-37-1P, 165113-38-2P, 165113-39-3P, 165113-40-6P, 165113-41-7P, 165113-42-8P, 165113-43-9P, 165113-44-0P, 165113-45- IP, 165113-46-2P, 165113-47-3P, 165113-48-4P, 165113-49-5P, 165113-50-8P, 165113- 51-9P, 165113-52-OP, 165113-53-1P, 165113-54-2P, 165113-55-3P,165113-56-4P, 165113-57-5P, 165113-58-6P, 165113-59-7P, 165113-60-0P, 165113-61-1P, 165113-62- 2P, 165113-63-3P, 165113-64-4P, 165113-65-5P, 165113-66-6P, 165113-67-7P, 165113- 68-8P, 165113-69-9P, 165113-70-2P,165113-71-3P, 165113-72-4P, 165113-73-5P, 165113-74-6P, 114798-27-5, 114798-28-6, 114798-29-7, 124749-82-2, 114798-28-6, 124749-84-4, 124750-88-5, 124750-91-0,124750-93-2, 161946-65-2P, 161947-47-3P, 161947-48-4P, 161947-51-9P, 161947-52-0P, 161947-55-3P, 161947-56-4P, 161947-60- OP, 161947-61-1P, 161947-68-8P, 161947-69-9P, 161947-70-2P, 161947-71-3P, 161947- 72-4P, 161947-74-6P, 161947-75-7P, 161947-81-5P,161947-82-6P,161947-83-7P, 161947-84-8P, 161947-85-9P, 161947-86-0P, 161947-87-1P, 161947-88-2P, 161947-89- 3P, 161947-90-6P, 161947-91-7P, 161947-92-8P, 161947-93-9P, 161947-94-0P, 161947- 95-1P, 161947-96-2P, 161947-97-3P, 161947-98-4P, 161947-99-5P, 161948-00-lP,
161948-01-2P, 161948-02-3P, 168686-32-6P, 167301-42-OP, 166813-82-7P, 166961-56- 4P, 166961-58-6P, 158872-96-9P, 158872-97-0P, 158807-14-8P, 158807-15-9P, 158807- 16-OP, 158807-17-1P, 158807-18-2P, 158807-19-3P, 158807-20-6P, 155884-08-5P, 154749-99-2, 167371-59-7P, 244126-99-6P, 177848-35-0P and 141309-82-2P, and the like. One skilled in the art will appreciate that the angiotensin H antagonists can be administered in the form of pharmaceutically acceptable salts and/or stereoisomers. Suitable angiotensin π antagonists 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 one embodiment the angiotensin π antagonists are candesartan, eprosartan, irbesartan, losartan, omlesartan, telmisartan or valsartan. In other embodiments the candesartan is administered as candesartan cilexetil in an amount of about 15 milligrams to about 100 milligrams as a single dose or as multiple doses per day; the eprosartan is administered as eprosartan mesylate in an amount of about 400 milligrams to about 1600 milligrams as a single dose or as multiple doses per day; the irbesartan is administered in an amount of about 75 milligrams to about 1200 milligrams as a single dose or as multiple doses per day; the losartan is administered as losartan potassium in an amount of about 25 milligrams to about 100 milligrams as a single dose or as multiple doses per day; the omlesartan is administered as omlesartan medoxomil in an amount of about 5 milligrams to about 40 milligrams as a single dose or as multiple doses per day; the telmisartan is administered in an amount of about 20 milligrams to about 80 milligrams as a single dose or as multiple doses per day; the valsartan is administered in an amount of about 80 milligrams to about 320 milligrams as a single dose or as multiple doses per day.
Suitable angiotensin-converting enzyme inhibitors (ACE inhibitors) include, but are not limited to, alacepril, benazepril (LOTENSIN®, CEBACEN®), benazeprilat, captopril, ceronapril, cilazapril, delapril, duinapril, enalapril, enalaprilat, fasidotril, fosinopril, fosinoprilat, gemopatrilat, glycopril, idrapril, imidapril, lisinopril, moexipril, moveltipril, naphthopidil, omapatrilat, pentopril, perindopril, perindoprilat, quinapril, quinaprilat, ramipril, ramiprilat, rentipril, saralasin acetate, spirapril, temocapril, trandolapril, trandolaprilat, urapidil, zofenopril, acylmercapto and mercaptoalkanoyl pralines, carboxyalkyl dipeptides, carboxyalkyl dipeptide, phosphinylalkanoyl pralines, registry no.796406, AVE 7688, BPl.137, CHF 1514, E 4030, ER 3295, FPL-66564, MDL 100240, RL 6134, RL 6207, RL 6893, SA 760, S-5590, Z 13752A, and the like. One skilled in the art will appreciate that the angiotensin-converting enzyme inhibitors may be administered in the form of pharmaceutically acceptable salts, hydrates, acids and/or stereoisomers thereof. Suitable angiotensin-converting enzyme 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, Twelfth Edition, Version 12:1, 1996; and on STN Express, file phar and file registry.
In some embodiments the angiotensin-converting enzyme inhibitors are benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril, trandolapril or trandolaprilat. In other embodiments the benazepril is administered as benazepril hydrochloride in an amount of about 5 milligrams to about 80 milligrams as a single dose or as multiple doses per day; the captopril is administered in an amount of about 12.5 milligrams to about 450 milligrams as a single dose or as multiple doses per day; the enalapril is administered as enalapril maleate in an amount of about 2.5 milligrams to about 40 milligrams as a single dose or as multiple doses per day; the fosinopril is administered as fosinopril sodium in an amount of about 5 milligrams to about 60 milligrams as a single dose or as multiple doses per day; the lisinopril is administered in an amount of about 2.5 milligrams to about 75 milligrams as a single dose or as multiple doses per day; the moexipril is administered as moexipril hydrochloride in an amount of about 7.5 milligrams to about 45 milligrams as a single dose or as multiple doses per day; the quinapril is administered as quinapril hydrochloride in an amount of about 5 milligrams to about 40 milligrams as single or multiple doses per day; the ramapril hydrochloride is administered in an amount of about 1.25 milligrams to about 40 milligrams as single or multiple doses per day; the trandolapril is administered in an amount of about 0.5 milligrams to about 4 milligrams as single or multiple doses per day; the trandolaprilat is administered in an amount of about 0.5 milligrams to about 4 milligrams as single or multiple doses per day.
Suitable antidiabetic compounds include but are not limited to, acarbose, acetohexamide, buformin, carbutamide, chlorpropamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepid, glyburide, glybuthiazol(e), glybuzole, glyhexamide, glymidine, glypinamide, insulin, metformin, miglitol, nateglinide, phenbutamide, phenformin, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, tolcyclamide, troglitazone, voglibose, and the like. Suitable antidiabetic 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.
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-l,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 antioxidants include, but are not limited to, small-molecule antioxidants and antioxidant enzymes. Suitable small-molecule antioxidants include, but are not limited to, hydralazine compounds, glutathione, vitamin C, vitamin E, cysteine, N-acetyl- cysteine, β-carotene, ubiquinone, ubiquinol-10, tocopherols, coenzyme Q, superoxide dismutase mimetics, such as, for example, 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO), DOXYL, PROXYL, nitroxide compounds; 4-hydroxy-2,2,6,6-tetramethyl-l- piperidinyloxy (Tempol), M-40401, M-40403, M-40407, M-40419,M-40484, M-40587, M-40588, and the like. Suitable antioxidant enzymes include, but are not limited to, superoxide dismutase, catalase, glutathione peroxidase, NADPH oxidase inhibitors, such as, for example, apocynin, aminoguanidine, ONO 1714, S 17834 (benzo(b)pyran-4-one derivative), and the like; xanthine oxidase inhibitors, such as, for example, allopurinol, oxypurinol, amflutizole, diethyldithiocarbamate, 2-styrylchromones, chrysin, luteolin, kaempferol, quercetin, myricetin, isorhamnetin, benzophenones such as 2,2' ,4,4'- tetrahydroxybenzophenone, 3,4,5,2',3',4'-hexahydroxybenzophenone and 4,4'- dihydroxybenzophenone; benzothiazinone analogues such as 2-amino-4H-l,3- benzothiazine-4-one, 2-guanidino-4H-l,3-benzothiazin-4-one and rhodanine; N- hydroxyguanidine derivative such as, PR5 (l-(3, 4-dimethoxy-2-chlorobenzylideneamino)- 3-hydroxyguanidine); 6-formylρterin, and the like. The antioxidant enzymes can be delivered by gene therapy as a viral vertor and/or a non- viral vector. Suitable antioxidants are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thirteenth Edition; and on STN Express, file phar and file registry. In some embodiments the antioxidants are apocynin, hydralazine compounds and superoxide dimutase mimetics.
Suitable antithrombotic and vasodilator compounds include, but are not limited to, abciximab, acetorphan, acetylsalicylic acid, argatroban, bamethan, benfurodil, benziodarone, betahistine, bisaramil, brovincamine, bufeniode, citicoline, clobenfurol, clopidogrel, cyclandelate, dalteparin, dipyridamol, droprenilamine, enoxaparin, fendiline, ifenprodil, iloprost, indobufen, isobogrel, isoxsuprine, heparin, lamifiban, midrodine, nadroparin, nicotinoyl alcohol, nylidrin, ozagrel, perhexiline, phenylpropanolamine, prenylamine, papaveroline, reviparin sodium salt, ridogrel, suloctidil, tinofedrine, tinzaparin, trifusal, vintoperol, xanthinal niacinate, and the like. Suitable antithrombotic and vasodilator 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. Suitable antithrombotic and vasodilator compounds include, but are not limited to, abciximab, acetorphan, acetylsalicylic acid, argatroban, bamethan, benfurodil, benziodarone, betahistine, bisaramil, brovincamine, bufeniode, citicoline, clobenfurol, clopidogrel, cyclandelate, dalteparin, dipyridamol, droprenilamine, enoxaparin, fendiline, ifenprodil, iloprost, indobufen, isobogrel, isoxsuprine, heparin, lamifiban, midrodine, nadroparin, nicotinoyl alcohol, nylidrin, ozagrel, perhexiline, phenylpropanolamine, prenylamine, papaveroline, reviparin sodium salt, ridogrel, suloctidil, tinofedrine, tinzaparin, trifusal, vintoperol, xanthinal niacinate, and the like. Suitable antithrombotic and vasodilator 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.
Suitable β-adrenergic antagonists include, but are not limited to, acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butofilolol, carazolol, capsinolol, carteolol, carvedilol (COREG®), celiprolol, cetamolol, cindolol, cloranolol, dilevalol, diprafenone, epanolol, ersentilide, esmolol, esprolol, hedroxalol, indenolol, labetalol, landiolol, laniolol, levobunolol, mepindolol, methylpranol, metindol, metipranolol, metrizoranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivolol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sotalolnadolol, sulfinalol, taliprolol, talinolol, tertatolol, tilisolol, timolol, toliprolol, tomalolol, trimepranol, xamoterol, xibenolol, 2-(3-(l,l- dimethylethyl)-amino-2-hydroxypropoxy)-3-pyridenecarbonitrilHCl, l-butylamino~3-(2,5- dichlorophenoxy)-2-propanol, l-isopropylamino-3-(4-(2-cyclopropylmeth.oxyethyl) phenoxy)-2-propanol, 3-isoproρylamino-l-(7-methylindan-4-yloxy)-2-butanol, 2-(3~t- butylamino-2-hydroxy-propylthio)-4-(5-carbamoyl-2-thienyl)thiazol, 7-(2-hydroxy-3-t- butylaminρropoxy)phthalide, Ace 9369, AMO-140, BIB-16S, CP-331684, Fr-172516, ISV-208, L-653328, LM-2616, SB-226552, SR-58894A, SR-59230A, TZC-5665, UK- 1745, YM-430, and the like. Suitable β-adrenergic antagonists 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 β-adrenergic antagonists are atenolol, bisoprolol, carvedilol, metoprolol, nebivolol, propranolol or timolol. In more particular embodiments the atenolol is administered in an amount of about 50 milligrams to about 200 milligrams as a single dose or as multiple doses per day; the bisoprolol is administered as bisoprolol fumarate in an amount of about 2.5 milligrams to about 30 milligrams as a single dose or as multiple doses per day; the carvedilol is administered in an amount of about 3.125 milligrams to about 200 milligrams as a single dose or as multiple doses per day; the metoprolol is administered as metoprolol tartarate or metoprolol succinate in an amount of about 25 milligrams to about 300 milligrams as a single dose or as multiple doses per day; the nebivolol is administered as nebivolol hydrochloride in an amount of about 2.5 milligrams to about 20 milligrams as a single dose or as multiple doses per day; the propranolol is administered as propranolol hydrochloride in an amount of about 40 milligrams to about 240 milligrams as a single dose or as multiple doses per day; the timolol is administered as timolol maleate in an amount of about 10 milligrams to about 30 milligrams as a single dose or as multiple doses per day.
Suitable calcium channel blockers include, but are not limited to, amlodipine (NORVASC®), anipamil, aranidipine, amrinone, azelnidipine, barnidipine, bencyclane, benidipine, bepridil, cilnidipine, cinnarizine, clentiazem, diltiazem, dotarizine, efonidipine, elgodipine, fantofarone, felodipine, fendiline, flunarizine, fluspirilene, furnidipine, gallopamil, ipenoxazone, isradipine, lacidipine, lemildipine, lercanidipine, lomerizine, manidipine, mibefradil, monatepil, nicardipine, nifedipine, niguldipine, niludipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, oxodipine, perhexilene, phenytoin, phenytprenylamine, pranidipine, ranolazine, ryosidine, semotiadil, tamolarizine, temiverine hydrochloride, terodiline, tiapamil, vatanidipine hydrochloride, verapamil, ziconotide, AE-0047, CAI, JTV-519, CHF- 1521, L-651582, NS-7, NW-1015, RO-2933, SB-237376, SL-34.0829-0S, S-312d, SD-3212, TA-993, YM-430, and the like. Suitable calcium channel blockers 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 calcium channel blockers are amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil. Suitable digitals include but are not limited to digoxin and digoxitin. In some embodiments the digoxin is administered to achieve a steady state blood serum concentration of at least about 0.7 nanograms per ml to about 2.0 nanograms per ml.
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 endothelin antagonists include, but are not limited to, atrasentan, bosentan, darusentan, endothelin, enrasentan, sitaxsentan, sulfonamide endothelin antagonists, tezosentan, BMS 193884, BQ-123, SQ 28608, and the like. Suitable endothelin antagonists 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. 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; R1 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 R1, 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. Ih some embodiments the hydralazine compound is hydralazine or a pharmaceutically acceptable salt thereof such as hydralazine hydrochloride. In more particular embodiments the hydralazine is administered as hydralazine hydrochloride in an amount of about 10 milligrams to about 300 milligrams as a single dose or as multiple doses per day. Suitable H2 receptor antagonists include, but are not limited to, burimamide, cimetidine, ebrotidin, famotidine, nizatidine, roxatidine, rantidine, tiotidine, and the like. Suitable H2 receptor antagonists are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901-915; the Merck Index on CD-ROM, 13th Edition; and in WO 00/28988 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety.
Suitable neutral endopeptidase inhibitors include, but are not limited to, atrial natriuretic peptides, diazapins, azepinones, ecadotril, fasidotril, fasidotrilat, omapatrilat, sampatrilat, BMS 189,921, Z 13752 A, and the like. Neutral endopeptidase 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, Thirteenth Edition; and on STN Express, file phar and file registry.
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 dose or as multiple doses per day; the flurbiprofen is administered in an amount of about 100 milligrams to about 300 milligrams as a single dose or as multiple doses per day; the ibuprofen is administered in an amount of about 400 milligrams to about 3.2 grams as a single dose or as multiple doses per day; the indomethacin is administered in an amount of about 25 milligrams to about 200 milligrams as a single dose or as multiple doses per day; the ketoprofen is administered in an amount of about 50 milligrams to about 300 milligrams as a single dose or as multiple doses per day; the naproxen is administered in an amount of about 250 milligrams to about 1.5 grams as a single dose or as multiple doses per day; the aspirin is administered in an amount of about 10 milligrams to about 2 grams as a single dose or as multiple doses per day.
Suitable 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 potassium channel blockers include but are not limited to, nicorandil, pinacidil, cromakalim (BRL 34915), aprikalim, bimakalim, emakalim, lemakalim, minoxidil, diazoxide, 9-chloro-7-(2-chlorophenyl)-5H-pyrimido(5,4,-d)(2)-benzazepine, Ribi, CPG-11952, CGS-9896, ZD 6169, diazixide, Bay X 9227, P1075, Bay X 9228, SDZ PCO 400, WAY-120,491, WAY-120,129, Ro 31-6930, SR 44869, BRL 38226, S 0121, SR 46142A, CGP 42500, SR 44994, artilide fumarate, lorazepam, temazepam, rilmazafone, nimetazepam, midazolam, lormetazepam, loprazolam, ibutilide fumarate, haloxazolam, flunitrazepam, estazolam, doxefazepam, clonazepam, cinolazepam, brotizolam, and the like. Suitable potassium channel blockers 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.
Suitable platelet reducing agents include but are not limited to, fibrinolytic agents such as for example, ancrod, anistreplase, bisobrin lactate, brinolase, Hageman factor (i.e. factor XH) fragments, plasminogen activators such as, for example, streptokinase, tissue plasminogen activators (TPA), urokinase, pro-Urokinase, recombinant TPA, plasmin, plasminogen, and the like; anti-coagulant agents including but are not limited to, inhibitors of factor Xa, factor TFPI, factor VHa, factor IXc, factor Va, factor VIHa, inhibitors of other coagulation factors, and the like; vitamin K antagonists, such as, for example, coumarin, coumarin derivatives (e.g., warfarin sodium); glycosoaminoglycans such as, for example, heparins both in unfractionated form and in low molecular weight form; ardeparin sodium, bivalirudin, bromindione, coumarin, dalteparin sodium, danaparoid sodium; dazoxiben hydrochloride, desirudin, dicumarol, efegatran sulfate, enoxaparin sodium, ifetroban, ifetroban sodium, lyapolate sodium, nafamostat mesylate, phenprocoumon, sulfatide, tinzaparin sodium, retaplase; trifenagrel, warfarin, dextrans and the like; abciximab, acadesine, anipamil, argatroban, aspirin, clopidogrel, diadenosine 5',5'"-Pl, P4- tetraphosphate (Ap4A) analogs, difibrotide, dilazep dihydrochloride, dipyridamole, dopamine, 3-methoxytyramine, glucagon, glycoprotein πb/IHa antagonists, such as, for example, Ro-43-8857, L-700,462, iloprost, isocarbacyclin methyl ester, itazigrel, ketanserin, BM-13.177, lamifiban, lifarizine, molsidomine, nifedipine, oxagrelate, prostaglandins, platelet activating factor antagonists such as, for example, lexipafant, prostacyclins, pyrazines, pyridinol carbamate, ReoPro (i.e., abciximab), sulfinpyrazone, synthetic compounds BN-50727, BN-52021, CV-4151, E-5510, FK-409, GU-7, KB-2796, KBT-3022, KC-404, KF-4939, OP-41483, TRK-100, TA-3090, TFC-612, ZK-36374, 2,4,5,7-tetrathiaoctane, 2,4,5,7-tetrathiaoctane 2,2-dioxide, 2,4,5-trithiahexane, theophyllin pentoxifyllin, thromboxane and thromboxane synthetase inhibitors such as, for example, picotamide, sulotroban, ticlopidine, tirofiban, trapidil, ticlopidine, trifenagrel, trilinolein, 3-substituted 5,6-bis(4-methoxyphenyl)-l,2,4-triazines; antibodies to glycoprotein Db/IIIa; anti-serotonin drugs, such as, for example, clopridogrel; sulfinpyrazone and the like; aspirin; dipyridamole; clofibrate; pyridinol carbamate; glucagon, caffeine; theophyllin pentoxifyllin; ticlopidine, and the like.
Suitable proton pump inhibitors include, but are not limited to, disulprazole, esomeprazole, lansoprazole, leminoprazole, omeprazole, pantoprazole, rabeprazole, timoprazole, tenatoprazole, 2-(2-benzimidazolyl)-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, A- aminoquinoline, 4-amino-3-acylquinoline, 3-butyryl-4-(2-methylphenylamino)-8-(2- hydroxyethoxy)quinoline, quinazoline, tetrahydroisoquinolin-2-yl pyrimidine, YH 1885, 3- substituted l,2,4-thiadiazolo(4,5-a) benzimidazole, 3-substituted imidazo(l,2-d)- thiadiazole, 2-sulfinylnicotinamide, pyridylsulfinylbenz imidazole, pyridylsulfinyl thieno imidazole, theinoimidazole-toluidine, 4,5-dihydrooxazole, thienoimidazole-toluidine, Hoe- 731, imidazo(l,2-a)pyridine, pyrrolo(2,3-b)pyridine,.and the like. Suitable proton pump inhibitors are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; the Merck Index on CD-ROM, 13th Edition; and in WO 00/50037 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety. Suitable renin inhibitors include, but are not limited to, aldosterone, aliskiren
(SPP-100), ditekiren, enalkrein (A-64662), medullipin, terlkiren, tonin, zankiren, RO 42-5892 (remikiren), A 62198, A 64662, A 65317, A 69729, A 72517 (zankiren), A 74273, CP 80794, CGP 29287, CGP-38560A, EMD 47942, ES 305, ES 1005, ES 8891, FK 906, FK 744, H 113, H-142, KRI 1314, pepstatin A, RO 44-9375 (ciprokiren), RO 42-5892, RO 66-1132, RO 66-1168, SP 500, SP 800, SR-43845, SQ 34017, U 71038, YM-21095, YM-26365, urea derivatives of peptides, amino acids connected by nonpeptide bonds, di- and tri-peptide derivatives (e.g., Act-A, Act-B, Act-C, ACT-D, and the like), amino acids and derivatives thereof, diol sulfonamides and sulfinyls, modified peptides, peptidyl beta-aminoacyl aminodiol carbamates, monoclonal antibodies to renin. Suitable renin inhibitors are described more fully in U.S. Patent Nos. 5,116,835, 5,114,937, 5,106,835, 5,104,869, 5,095,119, 5,098,924), 5,095,006, 5,089,471; 5,075,451, 5,066,643, 5,063,208, 4,845,079, 5,055,466, 4,980,283, 4,885,292), 4,780,401, 5,071,837, 5,064,965, 5,063,207, 5,036,054, 5,036,053, 5,034,512, and 4,894,437, 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. Suitable COX-2 inhibitors include, but are not limited to, nimesulide, celecoxib
(CELEBREX®), etoricoxib (ARCOXIA®), flosulide, lumiracoxib (PREXIG®, COX- 189), parecoxib (DYNSTAT®), rofecoxib (VIOXX®), tiracoxib (JTE-522), valdecoxib (BEXTRA®), ABT 963, BMS 347070, CS 502, DuP 697, GW-406381, NS-386, SC- 57666, SC-58125, SC-58635, and the like, and mixtures of two or more thereof. Suitable COX-2 inhibitors are in U.S. Patent Nos. 5,344,991, 5,380,738, 5,393,790, 5,409,944,
5,434,178, 5,436,265, 5,466,823, 5,474,995, 5,510,368, 5,536,752, 5,550,142, 5,552,422, 5,604,253, 5,604,260, 5,639,780, 5,932,598 and 6,633,272, and in WO 94/03387, WO 94/15723, WO 94/20480, WO 94/26731, WO 94/27980, WO 95/00501, WO 95/15316, WO 96/03387, WO 96/03388, WO 96/06840, WO 96/21667, WO 96/31509, WO 96/36623, WO 97/14691, WO 97/16435, WO 01/45703 and WO 01/87343, the disclosures of each of which are incorporated herein by reference in their entirety; and in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thirteenth Edition; and on STN Express, file phar and file registry. In some embodiments the COX-2 inhibitors are celecoxib, etoracoxib, lumiracoxib, paracoxib, rofecoxib or valdecoxib. In more particular embodiments the celecoxib is administered in an amount of about 100 milligrams to about 800 milligrams as a single dose or as multiple doses per day; the etoricoxib is administered in an amount of about 50 milligrams to about 200 milligrams as a single dose or as multiple doses per day; the lumiracoxib is administered in an amount of about 40 milligrams to about 1200 milligrams as a single dose or as multiple doses per day; the paracoxib is administered in an amount of about 20 milligrams to about 100 milligrams as a single dose or as multiple doses per day; the rofecoxib is administered in an amount of about 12.5 milligrams to about 50 milligrams as a single dose or as multiple doses per day; the valdecoxib is administered in an amount of about 10 milligrams to about 40 milligrams as a single dose or as multiple doses per day.
The invention provides compositions comprising (i) a diuretic compound comprising a heterocyclic nitric oxide donor group of the invention or pharmaceutically acceptable salt thereof, and (ii) at least one compound selected from the group consisting of aldosterone antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, β-adrenergic antagonists, diuretics, and hydralazine compounds in one or more pharmaceutically acceptable carriers. In other embodiments of the invention the aldosterone antagonist is eplerenone or spironolactone; the angiotensin II antagonist is candesartan cilexetil, eprosartan mesylate, irbesartan, losartan potassium, medoxomil, telmisartan, trandolapril, trandolaprilat or valsartan; the angiotensin-converting enzyme inhibitor is benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril hydrochloride, quinapril hydrochloride, ramipril; the β-adrenergic antagonist is bisoprolol fumarate, carvedilol, metoprolol tartrate, propranolol hydrochloride or timolol maleate; the diuretic is amiloride hydrochloride, chlorthalidone, hydrochlorothiazide or triamterene; and the hydralazine compound is hydralazine hydrochloride.
The invention provides methods for treating conditions resulting from excess water and/or electrolyte retention 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 diuretic compound comprising a heterocyclic nitric oxide donor group. In another embodiment, the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor 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 diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, including but not limited to, such as, for example, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin- converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof. In another embodiment, the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound. In one embodiment the condition resulting from excess water and/or electrolyte retention is lower extremity swelling, fatigue, body fluid retention, cardiac enlargement, shortness of breath, and/or edema. The diuretic compounds comprising a heterocyclic nitric oxide donor 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 cardiovascular disorders 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 diuretic compound comprising a heterocyclic nitric oxide donor group. In another embodiment, the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor 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 diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, including but not limited to, such as, for example, aldosterone antagonists, alpha- adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof. In another embodiment, the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound. In one embodiment the cardiovascular disorder is hypertension, congestive heart failure and/or diastolic dysfunction. The diuretic compounds comprising diuretic compounds comprising a heterocyclic nitric oxide donor 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 renovascular diseases 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 diuretic compound comprising a heterocyclic nitric oxide donor group. In another embodiment, the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor 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 diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, including but not limited to, such as, for example, aldosterone antagonists, alpha- adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof. In another embodiment, the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound. In one embodiment the renovascular disease is renal failure or renal insufficiency. The diuretic compounds comprising a heterocyclic nitric oxide donor 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 diabetes; treating diseases resulting from oxidative stress; treating endothelial dysfunctions; treating diseases caused by endothelial dysfunctions; treating cirrhosis; treating pre-eclampsia; treating osteoporosis; treating nephropathy; treating peripheral vascular diseases; treating portal hypertension; treating central nervous system disorders; and treating sexual dysfunctions 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 diuretic compound comprising a heterocyclic nitric oxide donor group. In anottier embodiment, the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor 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 diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, including but not limited to, such as, for example, aldosterone antagonists, alpha-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more thereof. In another embodiment, the patient can be administered an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor group, and, at least one therapeutic agent, and, at least one nitric oxide enhancing compound. The diuretic compounds comprising a heterocyclic nitric oxide donor group, nitric oxide enhancing compounds, and/or therapeutic agents can be administered separately or asi components of the same composition in one or more pharmaceutically acceptable carriers.
When administered separately, the diuretic compound comprising comprising a heterocyclic nitric oxide donor group, nitric oxide enhancing compound and/or therapeutic agent 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 diuretic compound comprising a heterocyclic nitric oxide donor 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 diuretic compound comprising a heterocyclic nitric oxide donor group and/or at least one nitric oxide enhancing compound and/or at least one 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 diuretic compound comprising a heterocyclic nitric oxide donor group.
The compounds and compositions of the invention can be administered by any available and effective delivery system including, but not limited to, orally, bucally, parenterally, by inhalation, by topical application, by injection, transdermally, or rectally (e.g., by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles, as desired. Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. In one embodiment of the invention the diuretic compound comprising a heterocyclic nitric oxide donor group is administered orally, parentally or by inhalation.
Transdermal compound administration, which is known to one skilled in the art, involves the delivery of pharmaceutical compounds via percutaneous passage of the compound into the systemic circulation of the patient. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. Other components can be incorporated into the transdermal patches as well. For example, compositions and/or transdermal patches can be formulated with one or more preservatives or bacteriostatic agents including, but not limited to, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and the like. Dosage forms for topical administration of the compounds and compositions can include creams, sprays, lotions, gels, ointments, eye drops, nose drops, ear drops, and the like. In such dosage forms, the compositions of the invention can be mixed to form white, smooth, homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1% or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution. In addition, the compositions can contain polyethylene glycol 400. They can be mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt) as preservative, white petrolatum, emulsifying wax, and tenox π (butylated hydroxyanisole, propyl gallate, citric acid, propylene glycol). Woven pads or rolls of bandaging material, e.g., gauze, can be impregnated with the compositions in solution, lotion, cream, ointment or other such form can also be used for topical application. The compositions can also be applied topically using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
The compositions can also be applied topically using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing. In a particular embodiment, the compositions of the invention are administered as a transdermal patch, more particularly as a sustained-release transdermal patch. The transdermal patches of the invention can include any conventional form such as, for example, adhesive matrix, polymeric matrix, reservoir patch, matrix or monolithic-type laminated structure, and are generally comprised of one or more backing layers, adhesives, penetration enhancers, an optional rate controlling membrane and a release liner which is removed to expose the adhesives prior to application. Polymeric matrix patches also comprise a polymeric-matrix forming material. Suitable transdermal patches are described in more detail in, for example, U. S. Patent Nos. 5,262,165, 5,948,433, 6,010,715 and 6,071,531, the disclosures of each of which are incorporated herein in their entirety.
Solid dosage forms for oral administration can include capsules, sustained-release capsules, tablets, sustained release tablets, chewable tablets, sublingual tablets, effervescent tablets, pills, powders, granules and gels. In such solid dosage forms, the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, effervescent tablets, and pills, the dosage forms can also comprise buffering agents. Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the invention and vegetable oil. Hard gelatin capsules can contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin. Tablets and pills can be prepared with enteric coatings.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Suppositories for vaginal or rectal administration of the compounds and compositions of the invention, can be prepared by mixing the compounds or compositions with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at rectal temperature, such that they will melt in the rectum and release the drug.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils are also conventionally used as a solvent or suspending medium. The compositions of this invention can further include conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds. Suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like. The pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds. For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Aqueous suspensions may contain substances which increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol and/or dextran. Optionally, the suspension may also contain stabilizers.
The composition, if desired, can also contain minor amounts of wetting agents, emulsifying agents and/or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like.
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 anti-proliferative therapeutic agents.
Particular sustained release dosage forms of the invention comprise biodegradable microparticles or nanoparticles. More particularly, biodegradable microparticles or nanoparticles are formed of a polymer containing matrix that biodegrades by random, nonenzymatic, hydrolytic scissioning to release therapeutic agent, thereby forming pores within the particulate structure.
In a particular embodiment, the compositions of the invention are orally administered as a sustained release tablet or a sustained release capsule. For example, the sustained release formulations can comprise an effective amount of at least one diuretic compound comprising a heterocyclic nitric oxide donor 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 diuretic compound comprising a heterocyclic nitric oxide donor group or a pharmaceutically acceptable salt thereof, and at least ,one nitric oxide donor, and, optionally at least one therapeutic agent
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 pharmaceuticaHy-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), mefhanesulfonic, 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. All 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 drag combination.
The amount of a given diuretic compound comprising a heterocyclic nitric oxide donor group of the invention 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 diuretic compounds comprising a heterocyclic nitric oxide donor 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., aldosterone antagonists, alpha- adrenergic receptor antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic compounds, anti-hyperlipidemic compounds, antioxidants, antithrombotic and vasodilator compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H2 receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, 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.
EXAMPLES Example 1: Benzoic acid, 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]-,
(4-methyI-5-oxido-l,2,5-oxadiazol-3-yI)methyI ester
A mixture of furosemide (0.75 g, 2.3 mmol), l,2,5-oxadiazole-3-methanol, 4- methyl-, 5-oxide (0.3 g, 2.3 mmol, prepared as described in WO 2005/060603 A, Example 6b) and N,N-dimethylaminopyridine (DMAP, 0.27 g, 2.2 mmol) in CH2Cl2 (7 mL) and DMF (1 mL) at 0 0C was treated with l-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.5 g, 2.6 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with CH2Cl2, washed with water, brine and dried over Na2SO4. The residue after filtration and evaporation was chromatographed on silica gel eluting with CH2Cl2:EtOAc (7: 1) to give the title compound (0.3 g, 30% yield) as a white solid. Mp 182-183 0C. 1H NMR (300 MHz, d6-DMSO) δ 8.42 (s, IH), 8.36 (br t, J = 5.6 Hz, IH), 7.62 (s, IH), 7.41 (br s, 2H), 7.14 (s, IH), 6.36-6.43 (m, 2H), 5.48 (s, 2H), 4.62 (d, J = 5.8 Hz, 2H), 2.19 (s, 3H). 13C NMR (75 MHz, dό-DMSO) δ 165.4, 155.0, 152.2, 151.1, 142.8, 137.1, 132.9, 127.2, 114.1, 113.0, 110.5, 107.8, 106.2, 56.9, 7.5. Mass spectrum (API- TIS) m/z 441 (M-H), 443 (MH+), 460 (MNH4 +). Anal, calcd for C16H15ClN4O7S: C, 43.40; H, 3.41; N, 12.65. Found: C, 43.21; H, 3.15; N, 12.48. Example 2: Benzoic acid, 5-(aminosulfonyl)-4-chloro-2-[(2-furanyImethyl)amino]-,
2-[(4-methyl-5-oxido-l,2,5-oxadiazol-3-yl)methoxy]-2-oxoethyl ester
A mixture of benzoic acid, 5-(aminosurfonyi)-4~chloro-2-[(2- furanylmethyl)amino]-, carboxymethyl ester (0.75 g, 1.9 mmol, prepared as described in US 2005/0059655, Example Ib) , l,2,5-oxadiazole-3-methanol, 4-methyl-, 5-oxide (0.25 g, 1.9 mmol, prepared as described in WO 2005/060603 A, Example 6b) and NJN- dimethylaminopyridine (DMAP, 0.24 g, 2.0 mmol) in (7:1) CH2Cl2 :DMF (8 mL) at 0 °C was treated with l-(3-(dimethylamino)propyl)-3-ethylcai-bodiimide hydrochloride (0.46 g, 2.4 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with CH2Cl2, washed with water, brine and dried over Na2SO4. The residue after filtration and evaporation was chromatographed on silica gel eluting with CH2Cl2:Et0Ac (7:1) to give the title compound (0.1 g, 10% yield) as a white solid. Mp 112-115 0C. 1H NMR (300 MHz, CDCl3/d4-Me0H) δ 8.67 (s, IH), 8.40 (br t, J= 5.6 Hz, IH), 7.44 (s, IH), 6.96 (s, IH), 6.31-6.40 (m, 2H), 5.32 (s, 2H), 4.91 (s, 2H), 4.49 (d, / = 5.6 Hz, 2H), 2.21 (s, 3H). 13C NMR (75 MHz, d6-DMSO) δ 167.0, 166.3, 153.1, 152.3, 149.9, 140.0, 137.1, 132.9, 126.2, 112.6, 106.5, 60.5, 56.8, 55.1, 39.9, 7.2. Mass spectrum (API-TIS) m/z 499 (M-H), 501 (MH+), 518 (MNH4 +). Anal, calcd for C18HnClN4O9S-LImOl H2O: C, 41.52; H, 3.69; N, 10.76. Found: C, 41.08; H, 3.39; N, 10.66. Example 3: Benzoic acid, 2-amino-5-(aminosulfonyl)-4-chloro-, (4-methyl-5-oxido- l,2,5-oxadiazol-3-yl)methyI ester 3a. Benzoic acid, 2-amino-5-(aminosulfonyl)-4-chloro-
Trifluoroacetic acid (3 mL) was added dropwise to a solution of furosemide (1 g, 3.0 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 3 days. The residue after evaporation of the solvent was chromatographed on silica gel eluting with CH2Cl2:Et0Ac:Me0H (1:1:0.1) to give the title compound (0.5 g, 53% yield) as a white solid. Mp >2500 0C (with decomposition). 1H NMR (300 MHz, d6-DMSO) δ 8.38 (s, IH), 7.22-7.45 (m, 3H), 7.00 (s, IH). 13C NMR (75 MHz, d6-DMSO) δ 168.2, 153.9, 135.1, 133.4, 126.8, 117.4, 107.1. Mass spectrum (API-TIS) m/z 250 (MH+), 268 (MNH4 +).
3b. Benzoic acid, 2-amino-5-(aminosulfonyl)-4-chloro-, (4-methyl-5-oxido-l,2,5- oxadiazol-3-yl)methyl ester
A mixture of the product of Example 3a (0.1 g, 1.9 mmol), 1,2,5-oxadiazole, A- (bromomethyl)-3-methyl-, 2-oxide (76 mg, 0.39 mmol, prepared as described in WO 2005/060603 A2, Example 6c) and K2CO3 (0.11 g, 0.80 mmol) in DMF (1 mL) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo. The residue was taken up in CH2Cl2ZMeOH (10:1), washed with water, brine and dried over Na2SO4. The residue after filtration and evaporation was chromatographed on silica gel eluting with CH2Cl2:EtOAc:MeOH (1:1:0.1) to give the title compound (50 mg, 34% yield) as a white solid. Mp 169-172 0C. 1H NMR (300 MHz, d6-DMSO) δ 8.34 (s, IH), 7.38 (br s, 2H), 7.35 (s, IH), 7.01 (s, IH), 5.47 (s, 2H), 2.19 (s, 3H). Mass spectrum (API-TIS) m/z 380 (MNH4 +).
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 diuretic compound or a pharmaceutically acceptable salt thereof, that must contain at least one heterocyclic nitric oxide donor group; wherein the at least one heterocyclic nitric oxide donor group is linked to the diuretic compound through an oxygen atom, a nitrogen atom or a sulfur atom.
2. The diuretic compound of claim 1 wherein the diuretic compound containing at least one heterocyclic nitric oxide donor group is a compound of Formula (T), (TT) or (M), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (T) is:
(D wherein:
X2 is -C(O)- or -S(O)2;
Y2 is chlorine or CF3;
-V2-U2-W2- is:
(i) -N(D1)-(C(Rq)(Rr))-N(D1)-;
(ii) -N=C(Rq^-N(D1)-; or
Rq and Rr at each occurrence are independently a hydrogen, a lower alkyl group, a substituted alkyl group, a benzyl group, an aryl group, an alkylaryl group, -CH2-S-CH- CH=CH2; -CH2-S-CF3 or -CH2-S-CH2-C6H5;
D1 is a hydrogen,V3 or K;
K is -(W)a-Eb-(C(Re)(Rf))p1-Ec-(C(Re)(Rf))χ-(W)d-(C(Re)(Rf))y-(W)i-Ej-(W)g- a, b, c, d, g, i and j are each independently an integer from 0 to 3;
P1, x, y and z are each independently an integer from 0 to 10;
V4 is V3, Re or -U3-V5;
V3 is:
R24 is -C6H4R27, -CN, -S(O)2-C6H4R27, -C(O)-N(Ra)(Ri), -NO2 Or -C(O)-OR25;
R25 is an alkyl group or an aryl group;
R26 is -C(O)- or -S(O)2- ;
R27 is a hydrogen, -CN, -S(O)2-R25, -C(O)-N(R3)(Ri), -NO2 or -C(O)-OR25;
T' is oxygen, sulfur or NR6;
R6 is a hydrogen, a lower alkyl group, an aryl group;
Wat each occurrence is independently -C(O)-, -C(S)-, -T3-, -(C(Re)(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))h-, a heterocyclic ring, an arylheterocyclic ring, -(CH2CH2O)ql- or Y3;
Y3 is:
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(Ra)Ri; h is an integer form 1 to 10; qi is an integer from 1 to 5;
Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a 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, -C(R0)(Rp)ki-U3-V5, 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 or a bridged cycloalkyl group;
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, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, -U3-Vs, 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 or a bridged cycloalkyl group; U3 is an oxygen, sulfur or -N(R3)Ri; V5 is -NO or -NO2; 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 alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, -CH2-C-(U3-V5)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom, -(N2O2-^M1 +, wherein M1 + is an organic or inorganic cation; and with the proviso that the diuretic compounds of Formula (I) must contain at least one heterocyclic nitric oxide donor group linked to the diuretic compound through an oxygen atom, a nitrogen atom or a sulfur atom; wherein the compound of Formula (II) is:
(H) wherein:
X4 Is:
(iii) (iv)
(V) -S(O)2-N(D)(D1);
(g) -C(O)-O-D; or (h)
Z^ is:
(i) a hydrogen; (ϋ)
)CH2
(iii) -N=C(H)-C(H)=C(OD)(CH3);
(iv) -S(O)2-N(DO-CH2-CH=CH2;
(V) -NH(D1);
(vi) -CH3; or
(vii) -OD1
Y4 is:
(i) Y2; or
(ϋ)
W4 is:
(i) a hydrogen;
(iϋ) -N(Di)-(CHa)3-CH3;
D is V3 or K;
V4 is a thio group or an oxygen atom; and
D1, Y2, V3 and K are as defined herein; and with the proviso that the diuretic compounds of Formula (IT) must contain at least one heterocyclic nitric oxide donor group linked to the diuretic compound through an oxygen atom, a nitrogen atom or a sulfur atom; wherein the compound of Formula (DI) is:
(IE) wherein:
X3 is:
K is as defined herein; and with the proviso that the heterocyclic diuretic compounds of Formula (DT) must contain at least one heterocyclic nitric oxide donor group linked to the diuretic compound through an oxygen atom, a nitrogen atom or a sulfur atom.
3. A composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.
4. The compound of claim 2, wherein the compound of Formula (I) is a heterocyclic nitric oxide donor althiazide, a heterocyclic nitric oxide donor bendroflumethiazide, a heterocyclic nitric oxide donor benzthiazide, a heterocyclic nitric oxide donor buthiazide, a heterocyclic nitric oxide donor chlorothiazide, a heterocyclic nitric oxide donor cyclothiazide, a heterocyclic nitric oxide donor ethiazide, a heterocyclic nitric oxide donor fenquizone, a heterocyclic nitric oxide donor hydrochlorothiazide, a heterocyclic nitric oxide donor hydroflumethiazide, a heterocyclic nitric oxide donor methyclothiazide, a heterocyclic nitric oxide donor metolazone, a heterocyclic nitric oxide donor paraflutizide, a heterocyclic nitric oxide donor polythiazide, a heterocyclic nitric oxide donor quinethazone, a heterocyclic nitric oxide donor teclothiazide, a heterocyclic nitric oxide donor trichlormethiazide; the compound of Formula (TT) is a heterocyclic nitric oxide donor ambuside, a heterocyclic nitric oxide donor azosemide, a heterocyclic nitric oxide donor bumetanide, a heterocyclic nitric oxide donor chloraminophenamide, a ! heterocyclic nitric oxide donor chlorthalidone, a heterocyclic nitric oxide donor clofenamide, a heterocyclic nitric oxide donor clopamide, a heterocyclic nitric oxide donor disulfamide, a heterocyclic nitric oxide donor furosemide, a heterocyclic nitric oxide donor mefruside, a heterocyclic nitric oxide donor piretanide, a heterocyclic nitric oxide donor xipamide; the compound of Formula (TTT) is a heterocyclic nitric oxide donor ethacrynic acid, a heterocyclic nitric oxide donor ticrynafen, or a pharmaceutically acceptable salt thereof.
5. The compound of claim 2, the compound of Formula (T) is a chlorothiazide comprising a heterocyclic nitric oxide donor group or a hydrochlorothiazide comprising a heterocyclic nitric oxide donor group of Formula (TV) and the diuretic compound of Formula (TT) is a chlorthalidone comprising a heterocyclic nitric oxide donor group of
Formula (V), a furosemide comprising a heterocyclic nitric oxide donor group of Formula (VI) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (TV) is:
(IV) wherein the bond a-b can be a single bond (hydrochlorothiazide) or a double bond (chlorothiazide); and the compound of Formula (V) is:
(V) and the compound of Formula (VT) is:
(VI) wherein
R1n-Rn taken together are a hydrogen atom; or
Rm is:
(i) -C-(O)-;
(U) -C-(O)-NR6;
(Ui) -C(O)-O-;
(iv) -C(O)-S; (V) -CH2-O-;
(vi) -CH(CH3)-O-;
(vii) -N-C(O)-S-;
(viii) -N-C(O)-CH2-; or
(ix) -N-C(O)-O-; Rn is: a hydrogen or:
wherein:
T', R24, R25, R26, Rj, Rk, Re and Rf are as defined herein; and with the proviso that the compound of Formula (IV), (V) and (VI) must contain at least one heterocyclic nitric oxide donor group.
6. A method for treating conditions resulting from excessive water and/or electrolyte retention in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 3.
7. The method of claim 6, wherein conditions resulting from excessive water and/or electrolyte retention are lower extremity swelling, fatigue, body fluid retention, a cardiac enlargement, shortness of breath, a pulmonary edema, a cerebral edema, an edema associated at least in part with a cause selected from the group consisting of congestive heart failure, cirrhosis of the liver, poor blood circulation, a lymphatic system failure, chronic nephritis, malnutrition, use of birth control pills, premenstrual syndrome, sunburn, hypertension, Meniere's disease, glaucoma, cystic fibrosis and/or an imbalance of sodium and potassium.
8. A method for treating a cardiovascular disease in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 3.
9. The method of claim 8, wherein the cardiovascular disease is congestive heart failure, restenosis, hypertension, diastolic dysfunction, a coronary artery disease, myocardial infarction, cerebral infarction, atherosclerosis, atherogenesis, cerebrovascular disease, angina, aneurysm, ischemic heart disease, cerebral ischemia, myocardial ischemia, thrombosis, platelet aggregation, platelet adhesion, smooth muscle cell proliferation,' a vascular or non- vascular complication associated with the use of a medical device, a wound associated with the use of a medical device, vascular or non- vascular wall damage, peripheral vascular disease, neointimal hyperplasia following percutaneous transluminal coronary angiograph, vascular grafting, coronary artery bypass surgery, a thromboembolic event, post-angioplasty restenosis, coronary plaque inflammation, hypercholesterolemia, embolism, stroke, shock, arrhythmia, atrial fibrillation or atrial flutter, or thrombotic occlusion and reclusion cerebrovascular incident.
10. The method of claim 9, wherein the cardiovascular disease is congestive heart failure, hypertension or diastolic dysfunction.
11. A method for treating a renovascular disease in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 3.
12. The method of claim 11, wherein the renovascular disease is renal failure or renal insufficiency.
13. A method for treating diabetes; treating a disease resulting from oxidative stress; treating an endothelial dysfunction; treating a disease caused by endothelial dysfunction; treating cirrhosis; treating pre-eclampsia; treating osteoporosis; treating nephropathy; treating a peripheral vascular disease; treating portal hypertension; treating a central nervous system disorder; or treating a sexual dysfunction in a patient in need thereof comprising administering to the patient an effective amount of the composition of claim 3.
14. The composition of claim 3, 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.
15. The composition of claim 14, wherein the therapeutic agent is an aldosterone antagonist, an alpha-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme inhibitor, an antidiabetic compound, an anti- hyperlipidemic compound, an antioxidant, an antithrombotic and vasodilator compound, a β-adrenergic antagonist, a calcium channel blocker, a digitalis, a diuretic, an endothelin antagonist, a hydralazine compound, a H2 receptor antagonist, a neutral endopeptidase inhibitor, a nonsteroidal antiinflammatory compound, a phosphodiesterase inhibitor, a potassium channel blocker, a platelet reducing agent, a proton pump inhibitor, a renin inhibitor, a selective cyclooxygenase-2 inhibitor, or a combination of two or more thereof.
16. The composition of claim 15, wherein the therapeutic agent is at least one compound selected from the group consisting of an aldosterone antagonist, an angiotensin π antagonist, an angiotensin-converting enzyme inhibitor, a β-adrenergic antagonist, a diuretic and a hydralazine compound.
17. The composition of claim 16, wherein the aldosterone antagonist is eplerenone or spironolactone; the angiotensin II antagonist is candesartan cilexetil, eprosartan mesylate, irbesartan, losartan potassium, medoxomil, telmisartan, trandolapril, trandolaprilat or valsartan; the angiotensin-converting enzyme inhibitor is benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril hydrochloride, quinapril hydrochloride, ramipril; the β-adrenergic antagonist is bisoprolol fumarate, carvedilol, metoprolol tartrate, propranolol hydrochloride or timolol maleate; the diuretic is amiloride hydrochloride, chlorthalidone, hydrochlorothiazide or triamterene; and the hydralazine compound is hydralazine hydrochloride.
18. The composition of claim 15, 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.
19. The method of claims 6, 8, 11 or 13, further comprising administering (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound.
20 The method of claim 19, wherein the therapeutic agent is an aldosterone antagonist, an alpha-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin-converting enzyme inhibitor, an antidiabetic compound, an anti- hyperlipidemic compound, an antioxidant, an antithrombotic and vasodilator compound, a β-adrenergic antagonist, a calcium channel blocker, a digitalis, a diuretic, an endothelin antagonist, a hydralazine compound, a H2 receptor antagonist, a neutral endopeptidase inhibitor, a nonsteroidal antiinflammatory compound, a phosphodiesterase inhibitor, a potassium channel blocker, a platelet reducing agent, a proton pump inhibitor, a renin inhibitor, a selective cyclooxygenase-2 inhibitor, or a combination of two or more thereof.
21. The method of claim 19, wherein the nitric oxide donor 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.
22. A kit comprising at least one compound of claim 2.
23. The kit of claim 22, 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 enhyancing compound.
24. The kit of claim 23, 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.
25. A compound selected from the group consisting of: benzoic acid, 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]-, (4-methyl-5-oxido- l,2,5-oxadiazol-3-yl)methyl ester; benzoic acid, 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]-, 2~[(4-methyl-5- oxido- 1 ,2,5-oxadiazol-3-yl)methoxy]-2-oxoethyl ester; benzoic acid, 2-amino-5-(aminosulfonyl)-4-chloro-, (4-methyl-5-oxido-l,2,5-oxadiazol-3- yl)methyl ester; or a pharmaceutically acceptable salt thereof.
EP05851657A 2004-11-15 2005-11-15 Diuretic compounds comprising heterocyclic nitric oxide donor groups,compositions and methods of use Withdrawn EP1828155A4 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041803A1 (en) * 2002-11-05 2004-05-21 Merck Frosst Canada & Co. Nitric oxide releasing prodrugs of diaryl-2-(5h)-furanones as cyclooxygenase-2 inhibitors
WO2005023183A2 (en) * 2003-08-28 2005-03-17 Nitromed, Inc. Nitrosated ad nitrosylated diuretic compouds, compositions and methods of use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041803A1 (en) * 2002-11-05 2004-05-21 Merck Frosst Canada & Co. Nitric oxide releasing prodrugs of diaryl-2-(5h)-furanones as cyclooxygenase-2 inhibitors
WO2005023183A2 (en) * 2003-08-28 2005-03-17 Nitromed, Inc. Nitrosated ad nitrosylated diuretic compouds, compositions and methods of use

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BURGAUD J L ET AL: "NITRIC-OXIDE RELEASING MOLECULES: A NEW CLASS OF DRUGS WITH SEVERAL MAJOR INDICATIONS", CURRENT PHARMACEUTICAL DESIGN, BENTHAM SCIENCE PUBLISHERS, NL, vol. 8, no. 3, 1 January 2002 (2002-01-01) , pages 201-213, XP001122072, ISSN: 1381-6128, DOI: DOI:10.2174/1381612023396357 *
PRANDI C ET AL: "Development of Absorption Furosemide Prodrugs: Synthesis, In Vitro and in Vivo Evaluation", FARMACO, SOCIETA CHIMICA ITALIANA, PAVIA, IT, vol. 47, no. 2, 1 January 1992 (1992-01-01), pages 249-263, XP007917297, ISSN: 0014-827X *
See also references of WO2006055542A2 *

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