WO2005079803A1 - Composes pour traitement des maladies cardio-vasculaires - Google Patents

Composes pour traitement des maladies cardio-vasculaires Download PDF

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WO2005079803A1
WO2005079803A1 PCT/US2005/004512 US2005004512W WO2005079803A1 WO 2005079803 A1 WO2005079803 A1 WO 2005079803A1 US 2005004512 W US2005004512 W US 2005004512W WO 2005079803 A1 WO2005079803 A1 WO 2005079803A1
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PCT/US2005/004512
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Ross W. Tracey
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Pfizer Products, Inc.
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    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines

Definitions

  • This invention relates to pharmaceutical compositions containing sodium-hydrogen exchanger type 1 (NHE-1) inhibitors in combination with Ca 2+ overload inhibitors, and the use of such combination inhibitors to treat, for example, cardiovascular diseases, such as ischemia, particularly, perioperative myocardial ischemic injury in mammals, including humans.
  • NHE-1 sodium-hydrogen exchanger type 1
  • NHEs sodium-hydrogen exchangers
  • the sodium-hydrogen exchangers are cell membrane transport proteins which exchange extracellular Na + for intracellular H + driven by concentration gradients. NHEs play a key role in intracellular pH regulation, ion-transport and control of cell volume. There are at least eight known isoforms that are designated NHE-1 through NHE-8.
  • NHE-1 is expressed in virtually all cell types; NHE-2 is expressed in the intestine and kidney; NHE-3 is expressed in the kidney (proximal tubule, thick and thin loops of Henle) and intestine; NHE-4 is expressed in the stomach, kidney, intestine, and hippocampus; NHE-5 is expressed in the brain, testis, spleen, and skeletal muscle; NHE-6 is expressed by mitochondria; NHE-7 is expressed in the golgi network; and NHE-8 is expressed in the kidney. Each of the eight isoforms is a distinct gene product.
  • NHE-1 Cardiac cells rely mainly on NHE-1 , which is referred to as the myocardial Na + /H + exchanger to prevent intracellular acidosis that inhibits contractility and mediates myocardial injury during periods of ischemia and reperfusion.
  • NHE-1 which is referred to as the myocardial Na + /H + exchanger to prevent intracellular acidosis that inhibits contractility and mediates myocardial injury during periods of ischemia and reperfusion.
  • Mentzer et al. Intracellular Sodium Hydrogen Exchange Inhibition and Clinical Myocardial Protection, Ann. Thorac. Surg., 2003; 75:S700-8; and Karmazyn ef al., The Myocardial Na + - H + Exchange, Structure, Regulation, and Its Role in Heart Disease, Circulation Research, AHA, Inc., pp. 777-86 (1999).
  • NHE-1 the sole isoform present in the myocardium
  • selective NHE-1 inhibitors are desirable due to the important physiological functions played by the additional NHE isoforms in other tissues.
  • NHE-2 and NHE-3 appear to have significant roles in the gastrointestinal and renal systems.
  • the cardioprotective ability of a selective NHE-1 inhibitor could be extremely beneficial in hospital settings; for example, in patients that are at risk for myocardial ischemic injury during cardiac surgery. For surgical settings, an agent with high aqueous solubility that would allow for intravenous administration would be preferred.
  • NHE-1 Non-ethyl-NHE-1
  • zoniporide which is known by the formula names [5-cyclopropyl-1-(quinolin-5-yl)-1 rY-pyrazole-4-carbonyl]guanidine and, alternatively, [1 -(quinolin-5-yl)-5-cyclopropyl-1 /-/-pyrazole-4-carbonyl]guanidine
  • cariporide, eniporide, and related guanidine based compounds have been described in the literature (e.g., Guzman- Perez et al., Discovery of Zoniporide: A Potent and Selective Sodium - Hydrogen Exchanger Type 1 (NHE-1) Inhibitor with High Aqueous Solubility, Bioorg.
  • sarcoplasmic reticulum an organelle of each muscle cell, plays in excitation-contraction coupling and relaxation in cardiac muscle. See, e.g., Frank et al., Basic Res. Cardiol. 97; Suppl. 1 , 1/72 - 1/78 (2002).
  • the sarcoplasmic reticulum reversibly sequesters Ca 2+ ions at a very high concentration. Muscle contraction stimulates electrical potentials causing a rapid release of these sequestered Ca 2+ ions into the sarcoplasmic fluid. Muscle relaxation is effectuated by ATP mediated calcium pump re-uptake into the reticulum. Numerous proteins, such as calsequestrin, troponin, and trypomyosin, are associated with maintaining appropriate calcium uptake and release.
  • Ca 2+ uptake into the sarcoplasmic reticulum is carried out by the Ca 2+ pump, referred to as Ca 2+ -ATPase, which is present on the membrane of endoplasmic reticulum.
  • Gwathmey Abnormal Sarcoplasmic Reticulum Ca 2+ Activity and Uptake in Le Prigent and D. Feuvray: Altered Ca 2+ handling in ventricular myocytes isolated from diabetic rates. Am. J. Physiol. 270: H1529-H1537, (1996)).
  • Compounds that inhibit Ca 2+ overload include sarcoplasmic reticulum calcium -
  • ATPase activators or "SERCA” activators such as a 2-(1 -piperazinyl)-5-methylbenzene- sulfonic acid (i.e., MCC-135), and related aminobenzenesulfonic acid based compounds have been described in the literature.
  • MCC-135 2-(1 -piperazinyl)-5-methylbenzene- sulfonic acid
  • aminobenzenesulfonic acid based compounds have been described in the literature.
  • Ca 2+ overload inhibitors are Ca 2+ channel inhibitors (e.g., amlodipine), and Na + /Ca 2+ exchanger (NCX) inhibitors (e.g., SEA0400, KB-R7943).
  • Ca 2+ channel inhibitors e.g., amlodipine
  • NCX Na + /Ca 2+ exchanger
  • This combination exhibits this effect when the two drugs are administered at the same time, e.g., in a composition containing both drugs, or when administered in combination separately or sequentially, so that medicaments of the invention facilitate the treatment of cardiovascular diseases.
  • medicaments of the invention can be used on demand in treatment (e.g., rescue treatment) of cardiovascular diseases and can facilitate treatment of such diseases with a single medicament.
  • the terms “treat,” “treats,” “treated,” “treating,” and the like refer to reversing, alleviating (or reducing or ameliorating), inhibiting the progress of, and/or preventing the disease, condition, or syndrome being treated, including reversing, alleviating (or reducing or ameliorating), inhibiting the progress of, and/or preventing one or more symptoms of such disease, condition, or syndrome.
  • the terms “reversing, “alleviating,” “reducing,” “ameliorating,” “inhibiting,” and “preventing” should be understood broadly and refer to partial as well as complete reversal, alleviation, reduction, amelioration, inhibition, and prevention.
  • the terms “treatment” and the like refer to the act of "treating.” Thus, these terms are to be understood broadly and refer to, for example, prophylactic and palliative treatment.
  • cardiovascular disease should be understood broadly to mean a disease, condition, or syndrome in which the heart, pericardium, or blood vessels are directly or indirectly involved.
  • cardiac disease includes, for example, endocarditis, myocarditis, cardiomyopathy, rheumatic heart disease, ischemic cardiac disease, non-cardiac ischemia, cerebrovascular disease (e.g., stroke), peripheral vascular disease, and hypertensive disease (e.g., high blood pressure).
  • diseases, conditions, and syndromes in which the heart, pericardium, or blood vessels are directly involved include coronary artery disease, cardiomyopathy, valvular disease, congenital heart disease, arrhythmias, and conduction disturbances.
  • diseases, conditions, and syndromes in which the heart, pericardium, or blood vessels are indirectly involved include systemic hypertension, pulmonary hypertension, and serum electrolyte abnormalities.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a mixture of an NHE-1 inhibitor and a Ca 2+ overload inhibitor, preferably in therapeutically effective amounts, optionally together with one or more pharmaceutically acceptable additional active ingredients (e.g., therapeutic agents) and/or inactive ingredients (e.g., carriers, vehicles, diluents).
  • additional active ingredients e.g., therapeutic agents
  • inactive ingredients e.g., carriers, vehicles, diluents
  • the present invention provides a medicament which is a combination containing, separately or together, an NHE-1 inhibitor and Ca 2+ overload inhibitor, for simultaneous, sequential, and/or separate administration in the treatment of a disease, condition, or syndrome, e.g., cardiovascular disease, such as ischemia.
  • a disease, condition, or syndrome e.g., cardiovascular disease, such as ischemia.
  • the invention further provides a process for preparing a pharmaceutical composition or medicament that includes an NHE-1 inhibitor and a Ca 2+ overload inhibitor.
  • the combination of this invention may be in the form of a kit that includes at least one NHE-1 inhibitor and at least one Ca 2+ overload inhibitor in one or more dosage forms for simultaneous, sequential, or separate administration, and the kit may further include a container.
  • Another aspect of this invention is a method of treating a mammal (e.g., a human) having a disease, condition, or syndrome responsive to the combination of this invention of an
  • the present invention provides a method of treating a cardiovascular disease, such as ischemia, by combination therapy which comprises simultaneously, sequentially, and/or separately administering to a subject, such as a human, in need of such treatment a pharmaceutically acceptable amount (preferably therapeutically effective amount) of an NHE-1 inhibitor and a pharmaceutically acceptable amount (preferably therapeutically effective amount) of a Ca 2+ overload inhibitor.
  • the NHE-1 inhibitor and the Ca 2+ overload inhibitor may be administered in an NHE-1 inhibitor/Ca 2+ overload inhibitor ratio of from about 20:1 to about 1 :20, such as from about 10:1 to about 1 :10.
  • the NHE-1 inhibitor may be a compound of the following general formula wherein Z is a suitable substituent:
  • Formula I a prodrug thereof, or a pharmaceutically acceptable salt or solvate of said compound or of said prodrug, and the Ca 2+ overload inhibitor may be a compound of the following general formula wherein n is an integer from 1 to 4 and, R 9 and R 10 are suitable independent substituents:
  • one aspect of this invention concerns a method of treating a mammal (e.g., a human) having a disease, condition, or syndrome responsive to the combination of an NHE-1 inhibitor and a Ca 2+ overload inhibitor, such as a disease, condition, or syndrome identified herein, by simultaneously, sequentially, and/or separately administering to the mammal a pharmaceutically acceptable amount (preferably therapeutically effective amount) of an NHE-1 inhibitor, such as a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable amount (preferably therapeutically effective amount) of a Ca 2+ overload inhibitor, such as a compound of Formula II, or a pharmaceutically acceptable salt or solvate of said compound.
  • a pharmaceutically acceptable amount preferably therapeutically effective amount
  • an NHE-1 inhibitor such as a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug
  • a pharmaceutically acceptable amount preferably therapeutically effective amount of
  • the method may further include the step of identifying a patient in need of such treatment.
  • a more specific aspect of this invention concerns a method of treating to prevent or reduce tissue damage resulting from cardiovascular disease (e.g., ischemia) comprising simultaneously, sequentially, and/or separately administering to a mammal (e.g., a female or male human) in need of such treatment a pharmaceutically acceptable amount (preferably therapeutically effective amount) of an NHE-1 inhibitor in combination with a pharmaceutically acceptable amount (preferably therapeutically effective amount) of a Ca 2+ overload inhibitor.
  • the NHE-1 inhibitor may be a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt or solvate of said compound or of said prodrug
  • the Ca 2+ overload inhibitor may be a compound of Formula II, or a pharmaceutically acceptable salt or solvate of said compound.
  • Preferred ischemic tissues taken individually or as a group are ischemic cardiac, brain, liver, kidney, lung, gut, skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue, the vasculature, and/or intestinal tissue. Especially preferred is ischemic cardiac tissue.
  • the combination of this invention may be administered to treat prophylactically, such as prior to an ischemic event, or to treat during an event, whether chronic or acute (e.g., an ischemic event). Alternatively, it may be administered upon reperfusion.
  • the damage e.g., ischemic damage
  • the damage sought to be prevented or ameliorated may also occur during organ transplantation.
  • the combination of this invention is administered prior to, during, or shortly after cardiac surgery or non-cardiac surgery.
  • Myocardial tissue damage may be reduced by administration (e.g., chronic administration) of the combination of this invention to a patient.
  • another specific aspect of this invention is a method of treating to reduce myocardial tissue damage, for example, (a) during surgery (e.g., coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA) or any percutaneous transluminal coronary intervention (PTCI), organ transplantation, or other non-cardiac surgeries), (b) in a patient presenting with ongoing cardiac (acute coronary syndromes, e.g., myocardial infarction or unstable angina) or cerebral ischemic events (e.g., stroke), and (c) in a patient who is at high risk for myocardial infarction (age > 65 and two or more risk factors for coronary heart disease).
  • CABG coronary artery bypass grafting
  • PTCA percutaneous transluminal coronary angioplasty
  • PTCI percutaneous translumina
  • the compounds be administered to prevent perioperative myocardial ischemic injury.
  • perioperative refers to the time period a patient is in the operating suite and its adjoining facilities, in other words, the pre-operative, intra- operative, and post-operative time period.
  • diseases, conditions, and syndromes that may be treated using the combinations (compositions and medicaments) and methods of this invention include: arteriosclerosis, hypertension, arrhythmia, angina pectoris, renal diseases, diabetic complications, restenosis, diseases of cell proliferation, cancerous diseases, fibrotic diseases, glomerular nephrosclerosis, organ hypertrophies or hyperplasias, pulmonary fibrosis, cerebroischemic disorders, myocardial stunning, myocardial dysfunction, cerebrovascular diseases, and organ hypertrophies or hyperplasias.
  • the method of this invention for treating comprises simultaneously, sequentially, and/or separately administering to a mammal (e.g., a female or male human) a pharmaceutically acceptable (preferably therapeutically effective) amount of an NHE-1 inhibitor in combination with a pharmaceutically acceptable (preferably therapeutically effective) amount of a Ca 2+ overload inhibitor.
  • a mammal e.g., a female or male human
  • the NHE-1 inhibitor may be a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt or solvate of said compound or of said prodrug
  • the Ca 2+ overload inhibitor may be a compound of Formula II, or a pharmaceutically acceptable salt or solvate of said compound.
  • the combinations of this invention may be combined with one or more additional therapeutic agents useful in the treatment of cardiovascular disease, e.g., myocardial ischemia-reperfusion injury.
  • additional therapeutic agents useful in the treatment of cardiovascular disease
  • cardiovascular disease e.g., myocardial ischemia-reperfusion injury.
  • the combinations of the invention may be combined with one or more additional therapeutic agents used for those other diseases.
  • the combinations of this invention may further include one or more active ingredients such as one or more of any of those additional therapeutic agents. Examples of additional active ingredients are as follows.
  • PDE5 inhibitors such as sildenafil, vardenafil or tadalafil
  • NSAIDs standard non-steroidal anti-inflammatory agents
  • piroxicam diclofenac
  • propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen
  • fenamates such as mefenamic acid, indomethacin, sulindac, apazone
  • pyrazolones such as phenylbutazone
  • salicylates e.g., aspirin
  • COX-2 inhibitors e.g., celecoxib, valdecoxib, paracoxib, rofecoxib and etoricoxib
  • analgesics and intraarticular therapies e.g., corticosteroids and hyaluronic acids, such as hyalgan and synvisc
  • intraarticular therapies e.g., corticosteroids and hyaluronic acids, such as hyalgan and synvisc
  • calcium channel blockers such as amlodipine diltiazem, verapamil, felodipine, isradipine, lacidipine, lercanidipine, nicardipine nifedipine, nimodipine and nisoldipine;
  • lipid lowering agents such as statins, e.g., atorvastatin, fluvastatin, pravastatin, simvastatin, lovastatin and rosuvastatin;
  • fibrates such as fenofibrate, clofibrate, gemfibrozil; 6. niacin; bile acids or cholestyramine resins (e.g., cholybat, Locholest, prevalite, and questran); colesevelam; colestipol; or IBAT inhibitors;
  • cholesterol absorption inhibitors e.g., ezetimibe
  • beta-blockers e.g., acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, celiprolol, esmolol, labetalol, levobunolol, metoprolol, metipranolol, nadolol, nebivolol, oxprenolol, pindolol, propranolol, sotalolol and timolol);
  • beta-blockers e.g., acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, celiprolol, esmolol, labetalol, levobunolol, metoprolol, metipranolol, nadolol, nebivolol,
  • ACE inhibitors e.g., benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril
  • benazepril e.g., benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril
  • benazepril e.g., benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, qui
  • Angiotensin-2 receptor antagonists e.g., telmisartan, olmesartan, candesartan, eprosartan, irbesartan, losartan and valsartan
  • platelet aggregation inhibitors e.g., clopidogrel, BM-531 , aspirins, NSAIDs, selective COX-2 inhibitors
  • monocyte-endothelial cell adhesion inhibitors e.g., K-7174
  • aldosterone antagonists e.g., eplerenone or spironolactone
  • CETP inhibitors e.g., JTT-705 or CP529414
  • diuretics e.g., hydrocholothiazide, amiloride, furosemide, bumetanide, torasemide, indapamide, metolazone, and triamterene
  • antiarrhythmics e.g., lidocaine
  • alpha blockers e.g., doxazosin, prazosin and terazosin.
  • agents for the treatment of diabetes insulin-like growth factor type I (IGF-1 ) mimetic; alpha-glucosidase inhibitors (e.g., acarbose or miglitol), biguanides (e.g., metformin), insulins, megltinides (e.g., nateglinide and repaglinide), sulfonylureas (e.g., acetohexamide, chlorpropamide, glimepride, glipizide, glyburide, tolazamide, or tolbutamide), or thiazolidinediones (e.g., pioglitazone or rosiglitazone).
  • IGF-1 insulin-like growth factor type I mimetic
  • alpha-glucosidase inhibitors e.g., acarbose or miglitol
  • biguanides e.g., metformin
  • insulins e.g., met
  • TNF- ⁇ inhibitors such as anti-TNF monoclonal antibodies (e.g., Remicade, CDP-870, and D2E7), TNF receptor immunoglobulin molecules (e.g., Enbrel®), and/or dual thromboxane synthase inhibitors/thromboxane receptor antagonists (e.g., BM-573) in the combination.
  • TNF- ⁇ inhibitors such as anti-TNF monoclonal antibodies (e.g., Remicade, CDP-870, and D2E7), TNF receptor immunoglobulin molecules (e.g., Enbrel®), and/or dual thromboxane synthase inhibitors/thromboxane receptor antagonists (e.g., BM-573) in the combination.
  • BM-573 dual thromboxane synthase inhibitors/thromboxane receptor antagonists
  • 6,423,705 for use in combination with NHE-1 inhibitors may also be used in the combination of this invention (as previously indicated, that patent is incorporated herein in its entirety for all purposes).
  • Use in the combination of many other therapeutic agents e.g., CNS agents, anti-Parkinsonian drugs, osteoporosis agents, immunosuppressant agents, receptor antagonists for leukotrienes, anticholinergic agents, anticancer agents, and antiviral agents
  • CNS agents e.g., CNS agents, anti-Parkinsonian drugs, osteoporosis agents, immunosuppressant agents, receptor antagonists for leukotrienes, anticholinergic agents, anticancer agents, and antiviral agents
  • Preferred agents (most preferably cardiovascular agents) for use in the combination include, for example, ⁇ -blockers (e.g., acebutolol, atenolol, bopindolol, labetolol, mepindolol, nadolol, oxprenol, pindolol, propranolol, sotalol), calcium channel blockers (e.g., amlodipine, nifedipine, nisoldipine, nitrendipine, verapamil), potassium channel openers, adenosine, adenosine agonists, ACE inhibitors (e.g., captopril, enalapril), nitrates (e.g., isosorbide dinitrate, isosorbide 5-mononitrate, glyceryl trinitrate), diuretics (e.g., hydrochlorothiazide, indapamide, pir
  • a preferred aldose reductase inhibitor for use in the combination is zopolrestat: 1 -phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-trif luoromethyl)-2-benzothiazolyl]methyl]-.
  • the combination of this invention which can be used in a method of treating to reduce tissue damage resulting from or which could result from ischemia, comprises: a. an NHE-1 inhibitor compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt or solvate of said Formula I compound or of said prodrug; b. a Ca 2+ overload inhibitor compound of Formula II, or a pharmaceutically acceptable salt or solvate of said Formula II compound; and c.
  • kits of this invention may comprise: a. a therapeutically effective amount of a Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt or solvate of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehicle, or diluent in a first unit dosage form; b. a therapeutically effective amount of a Formula II compound, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle, or diluent in a second unit dosage form; c.
  • first, second, and third dosage forms optionally a therapeutically effective amount of a cardiovascular agent and a pharmaceutically acceptable carrier, vehicle, or diluent in a third unit dosage form; and d. means for containing said first and second dosage forms, wherein the amounts of the first and second compounds and optional cardiovascular agent result in a therapeutic effect.
  • Figure 1 illustrates the maximum reduction of infarct size obtainable by a 30 minute/120 minute ischemia/reperfusion standard protocol by the administration of a Ca 2+ overload inhibitor or an NHE-1 inhibitor.
  • Figure 2 illustrates the maximum reduction of infarct size obtainable by a 30 minute/120 minute and 60 minute/120 minute ischemia/reperfusion protocol by the separate administration of a Ca 2+ overload inhibitor or an NHE-1 inhibitor.
  • Figure 3 illustrates the maximum reduction of infarct size obtainable by a 60 minute/120 minute ischemia/reperfusion protocol by the administration of a Ca 2+ overload inhibitor or an NHE-1 inhibitor separately and in combination.
  • the present invention is directed to a combination of at least one NHE-1 inhibitor, which preferably comprises at least one compound of Formula I, and at least one Ca 2+ overload inhibitor, which preferably comprises at least one compound of Formula II, as defined below.
  • the NHE-1 inhibitor of the combination may be a compound of Formula I:
  • Z is a carbon of (a) a five-membered, diaza, diunsaturated ring having two contiguous nitrogens, said ring optionally mono-, di-, or tri-substituted with up to three substituents independently selected from R 1 , R 2 and R 3 , or of (b) a five-membered, triaza, diunsaturated ring, said ring optionally mono- or di-substituted with up to two substituents independently selected from R 4 and R 5 ; wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy(CrC )alkyl, (C ⁇ -C 4 )alkyl, (C C 4 )alkylthio, (C 3 -C 4 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C ⁇ -C 4 )alkyl, (C C 4 )alkoxy, (C C 4
  • NHE-1 inhibitor compounds of the present invention are cariporide 4-isopropyl-3-methylsulfonylbenzoyl-guanidine methanesulfonate, which has the following formula:
  • a most preferred NHE-1 inhibitor is zoniporide methanesulfonate (zoniporide mesylate), which has the formula:
  • NHE-1 inhibitors are anhydrous crystalline zoniporide mesylate, the anhydrous crystalline Form A of zoniporide mesylate, the anhydrous crystalline Form D of zoniporide mesylate, and the hemihydrate crystalline Form C of zoniporide mesylate.
  • Each of these crystalline forms can be prepared in accordance with the procedures set forth in Hamanaka et al., U.S. Patent No. 6,492,401 , and Brostrom et al., International Application Publication No. WO 2001/30759, both of which documents as previously noted are incorporated by reference herein in their entirety for all purposes.
  • Ca 2+ overload inhibitor compounds of the combination of the invention may be aminobenzenesulfonic acid derivates of the formula:
  • R 9 represents hydrogen atom, a C C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a C C 4 halogenated alkyl group, a halogen atom or a C 6 -C 12 aryl group
  • R 10 represents hydrogen atom, a C
  • n represents an integer of 1 to 4, or 2 to 3, or a pharmaceutically acceptable salt or solvate thereof.
  • R 9 there may be included hydrogen atom, a C C 6 straight or branched alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and n-hexyl groups, a C 3 -C 7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, a C C 4 halogenated alkyl group such as trifluoromethyl group, a halogen atom such as fluorine, chlorine and bromine atoms or C 6 -C ⁇ 2 aryl group such as phenyl, tolyl and naphthyl groups; and, as R 10 , there may be included hydrogen atom; a CrC- ⁇ straight or branched alkyl group such as methyl, ethyl, n-propyl, iso
  • Pref erred Ca 2+ overload inhibitor compounds of general Formula II include: aminobenzenesulfonic acid compounds wherein n is 1 to 4, 1 or 4, 2 or 3, or 2; aminobenzenesulfonic acid compounds wherein R 10 is hydrogen atom, C 1 -C 3 alkyl group or C 7 -C 12 aralkyl group which may be substituted by C C 3 alkyl group, C C 3 alkoxy group or a halogen atom; aminobenzenesulfonic acid compounds wherein R 10 is hydrogen atom or C 7 -C 12 aralkyl group which may be substituted by CrC 3 alkyl group; aminobenzenesulfonic acid compounds wherein R 9 is hydrogen atom, C ⁇ -C 6 alkyl group, C 5 -C 6 cycloalkyl group, trifluoromethyl group, a halogen atom or phenyl group; aminobezenesulfonic acid compounds wherein R 9 is C 1 -C 3 alkyl group, cyclo
  • the Ca 2+ overload inhibitor compound is:
  • cardio-protective agents for ischemia- induced damage which include at least one of the aminobenzenesulfonic acid compounds of Formula II as an active ingredient and, more preferably, those subgenera and particular Ca 2+ overload inhibitor compounds identified above.
  • medicament means a combination of an NHE-1 inhibitor and a Ca 2+ overload inhibitor, whether combined in a composition or separate as in individual unit dosage forms, such as in a kit.
  • the medicament may include an NHE-1 inhibitor of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt or solvate of said compound or of said prodrug, and a Ca 2+ overload inhibitor compound of Formula II, or a pharmaceutically acceptable salt or solvate of said compound.
  • damaged resulting from ischemia refers to conditions directly associated with reduced blood flow to tissue, for example due to a clot or obstruction of blood vessels which supply blood to the subject tissue and which result, inter alia, in lowered oxygen transport to such tissue, impaired tissue performance, tissue dysfunction and/or necrosis.
  • the oxygen carrying capacity of the blood or organ perfusion medium may be reduced, e.g., in hypoxic environment, such that oxygen supply to the tissue is lowered, and impaired tissue performance, tissue dysfunction, and/or tissue necrosis ensues.
  • pharmaceutically acceptable it is meant that the carrier, diluent, excipients, salt, etc. in question must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • pharmaceutically acceptable salt refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate. Where more than one basic moiety exists the expression includes multiple salts (e.g., di-salt).
  • nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N- benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1 ,3- propanediol).
  • nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N- benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1 ,3- propaned
  • prodrug refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
  • alkylene saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons.
  • exemplary of such groups are methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene).
  • halo is meant chloro, bromo, iodo, or fluoro.
  • alkyl is meant straight chain saturated hydrocarbon or branched saturated hydrocarbon.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
  • alkoxy is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxygen.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.
  • a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom.
  • pyridyl means 2-, 3-, or 4-pyridyl
  • thienyl means 2-, or 3-thienyl, and so forth.
  • reaction-inert solvent and “inert solvent” refer to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • reaction-inert solvent and “inert solvent” refer to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configu rational isomers. All such isomers and mixtures thereof are included in this invention. Hydrates of the compounds of this invention are also included.
  • DMF means N,N-dimethylformamide.
  • DMSO means dimethyl sulfoxide.
  • THF means tetrahydrofuran.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered as part of this invention. Also, some of the compounds of this invention are atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • the compounds of Formula I can exist in several tautomeric forms. All such tautomeric forms are considered as part of this invention. For example, all of the tautomeric forms of the carbonylguanidine moiety of the compounds of Formula I are included in this invention. Also, for example, all enol-keto forms of the compounds of Formula I are included in this invention.
  • Some of the compounds of this invention are acidic and they form a salt with a pharmaceutically acceptable cation.
  • All of the NHE-1 inhibitor compounds of this invention are basic and they form a salt with a pharmaceutically acceptable anion. All such salts, including di-salts, are within the scope of this invention and they can be prepared by conventional methods. For example, they can be prepared simply by contacting the acidic and basic entities, in either an aqueous, non-aqueous or partially aqueous medium. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate. In addition, when the compounds of this invention form metabolites, hydrates or solvates, they are also within the scope of the invention.
  • a preferred dosage of an NHE-1 inhibitor, such as an NHE-1 inhibitor of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt or solvate of said compound or of said prodrug, for treating a patient (e.g., for ischemic protection) is about 0.001 to 100 mg/kg/day.
  • An especially preferred dosage of an NHE-1 inhibitor, such as compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt or solvate of said compound or of said prodrug is about 0.01 to 50 mg/kg/day.
  • a preferred dosage of an Ca 2+ overload inhibitor such as a Ca 2+ inhibitor of Formula II a prodrug thereof, or a pharmaceutically acceptable salt or solvate of said compound or of said prodrug, for treating a patient (e.g., for ischemic protection) is about 0.001 to 100 mg/kg/day.
  • a preferred dosage of an Ca 2+ inhibitor, such as a compound of Formula II, or a pharmaceutically acceptable salt or solvate of said compound, when the compound is used orally, is within the range from 0.01 mg to 1000 mg (preferably from 0.1 mg to 100 mg) for human adult per day, but more preferably be increased or decreased suitably depending on the age, sex, condition, symptom, and presence of simultaneous treatment.
  • the Ca 2+ overload inhibitor of the present invention is used as an injection agent, whether or not the NHE-1 inhibitor is so used, it should be preferably administered continuously or intermittently to a human adult in an amount of from about 0.01 mg to about 100 mg per dose.
  • the number of administrations may be once per day of either or both essential ingredients of the combination, in several divided doses per day with appropriate intervals of either or both essential ingredients of the combination, or using any other appropriate regimen.
  • Administration of the compounds of this invention can be via any method which delivers a compound of this invention preferentially to the desired tissue (e.g., liver and/or cardiac tissues). These methods include oral routes, parenteral (e.g., intravenous, intramuscular, subcutaneous or intramedullary), intraduodenal routes, etc. Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorders or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Administration may be localized or systemic. The compounds of the present invention are usually administered in single (e.g., once daily) or multiple doses or via constant infusion.
  • the amount and timing of compounds administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician.
  • the dosages set forth herein are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient.
  • the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases (e.g., different cardiovascular diseases).
  • the compounds of this invention may be administered just prior to surgery (e.g., within twenty-four hours before surgery for example cardiac surgery) during or subsequent to surgery (e.g., within twenty-four hours after surgery) where there is risk of myocardial ischemia.
  • the compounds of this invention may also be administered in a chronic daily mode.
  • the compounds of this invention i.e., the NHE-1 inhibitor/Ca 2+ overload inhibitor combination
  • the compounds of this invention are generally administered in the form of a pharmaceutical composition comprising at least one NHE-1 inhibitor and at least one Ca 2+ overload inhibitor together with a pharmaceutically acceptable carrier, vehicle, or diluent.
  • the compounds of this invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form.
  • a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
  • Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions for example, in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
  • aqueous or partially aqueous solutions are prepared.
  • the combination of this invention may be administered with other drug therapies to mammals (e.g., humans, male or female) using, for example, conventional methods.
  • the NHE-1 inhibitor compounds of the present invention inhibit the sodium/proton (Na+/H+) exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused or aggravated by the acceleration of the sodium/proton (Na+/H+) exchange transport system.
  • the Ca 2+ overload inhibitor compounds of the present invention inhibit Ca 2+ overload and hence are useful as a therapeutic or prophylactic agent for diseases caused or aggravated by the increase in Ca 2+ .
  • the medicaments of the present invention that contain these compounds are useful in treating a variety of diseases, conditions, and syndromes, for example, arteriosclerosis, hypertension, arrhythmia (e.g., ischemic arrhythmia, arrhythmia due to myocardial infarction, myocardial stunning, myocardial dysfunction, arrhythmia after PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy, myocardial infarction, heart failure (e.g., congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g., hemorrhagic shock, endotoxin shock, etc.), renal diseases (e.g., diabetes mellitus, diabetic nephropathy, ischemic acute renal failure, etc.), organ disorders associated with ischemia or ischemic reperfusion [(e.g., heart muscle ischemic reperfusion associated disorders, acute renal failure, or disorders
  • the compounds of this invention can also be used as an agent for myocardial protection during coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), PTCI, organ transplantation, or non- cardiac surgeries.
  • CABG coronary artery bypass grafting
  • PTCA percutaneous transluminal coronary angioplasty
  • PTCI percutaneous transluminal coronary angioplasty
  • organ transplantation or non- cardiac surgeries.
  • non- cardiac surgeries are notable for their strong inhibitory effect on the proliferation of cells, for example the proliferation of fibroblast cells and the proliferation of the smooth muscle cells of the blood vessels.
  • the compounds of this invention are valuable treating or treatment (therapeutic) agents for use in diseases in which cell proliferation represents a primary or secondary cause and may, therefore, be used as antiatherosclerotic agents, and as agents against diabetic late complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, glomerular nephrosclerosis, organ hypertrophies or hyperplasias, in particular hyperplasia or hypertrophy of the prostate, pulmonary fibrosis, diabetic complications or recurrent stricture after PTCA, or diseases caused by endothelial cell injury.
  • fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, glomerular nephrosclerosis, organ hypertrophies or hyperplasias, in particular hyperplasia or hypertrophy of the prostate, pulmonary fibrosis, diabetic complications or recurrent stricture after PTCA, or diseases caused by endothelial cell injury.
  • compositions according to the invention may contain for example 0.0001 %-95% of the compound(s) of this invention.
  • the composition or medicament to be administered will contain a quantity of one or more compounds according to the invention in an amount effective to treat the disease, condition, or syndrome of the subject being treated.
  • the kit may comprise two separate pharmaceutical compositions: a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt or solvate of such compound or prodrug, and a second compound of Formula II or a pharmaceutically acceptable salt or solvate thereof.
  • the kit may comprise means for containing the separate compositions such as a container, a divided bottle or a divided foil packet.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, ..., etc. Second Week, Monday, Tuesday, ... etc.”
  • a "daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a combination of a Formula I compound and a Formula II compound can consist of one or more tablets, capsules, or other dosage forms
  • a daily dose of the first compound can consist of one or more tablets, capsules, or other dosage forms
  • a daily dose of the second compound can consist of one or more tablets, capsules, or other dosage forms.
  • the memory aid should reflect this.
  • a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided.
  • the dispenser is equipped with a memory aid, so as to further facilitate compliance with the regimen.
  • a memory aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
  • a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • the compounds of this invention generally will be administered in a convenient formulation.
  • the following formulation examples are illustrative only and are not intended to limit the scope of the present invention.
  • active ingredients means a combination of the compounds of this invention.
  • Hard gelatin capsules are prepared using the following: Formulation 1 : Gelatin Capsules Ingredients Quantity (mg/capsule)
  • a tablet formulation is prepared using the ingredients below: Formulation 2: Tablets
  • tablets each containing 0.25-100 mg of active ingredients are made up as follows:
  • Formulation 3 Tablets Ingredients Quantity (mg/tablet)
  • the active ingredients, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50° - 60°C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
  • Formulation 4 Suspensions Ingredients Quantity (mg/5 ml)
  • Active ingredients 0.25-100 mg .
  • the active ingredients are passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form smooth paste.
  • the benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • Aerosol solution is prepared containing the following ingredients: Formulation 5: Aerosol
  • the active ingredients are mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30°C, and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container.
  • Suppositories are prepared as follows:
  • Formulation 6 Suppositories Ingredients Quantity (mg/suppository)
  • An intravenous formulation is prepared as follows:
  • the solution of the above ingredients is intravenously administered to a patient.
  • the active ingredients above may also be a combination of agents. DETAILED DESCRIPTION OF THE
  • NHE-1 inhibitor compared to the separate efficacies of the NHE-1 inhibitor and the Ca 2+ overload inhibitor.
  • the NHE-1 inhibitor utilized in the comparative example efficacy analysis immediately below is CP-566,827, and it is represented by the formula:
  • the heart was rapidly removed from the chest, mounted on a Langendorff apparatus, and maintained by retrograde perfusion (non-recirculating) with a modified Krebs solution (NaCI 118.5 mM, KCI 4.7 mM, Mg S0 4 1.2 mM, KH 2 P0 4 1.2 mM, NaHCO 3 24.8 mM, CaCI 2 2.5 mM, and glucose 10 mM) at a constant pressure of 80 mmHg and a temperature of 37°C.
  • Perfusate pH was maintained at 7.4 -7.5 by bubbling with 95% O 2 /5% CO 2 .
  • the temperature of the hearts was maintained by suspending them in heated, water jacketed organ baths.
  • a fluid-filled latex balloon was inserted in the left ventricle and connected by stainless steel tubing to a pressure transducer; the balloon was inflated to provide a systolic pressure of 80-120 mmHg, and a diastolic pressure ⁇ 10 mmHg.
  • Heart rate and left ventricular diastolic and systolic pressures were recorded using a PO-NE-MAH Data Acquisition and Archive System; left ventricular developed pressures (LVDP) were calculated by subtracting the left ventricular diastolic pressure from the left ventricular systolic pressure.
  • Total coronary flow rates (CF) were determined using an in-line flow probe; all coronary flows were normalized for heart weight. These parameters were continuously monitored for the duration of the experiment.
  • Hearts were allowed to equilibrate for 30 min.; if stable left ventricular pressures within the parameters outlined above were not observed, the heart was discarded. Hearts were not paced, unless the heart rate fell below 180 bpm prior to the 30 min. period of regional ischemia; in this case, the heart was paced at 200 bpm, which was the average spontaneous rate observed.
  • the coronary artery snare was tightened and a 0.5% suspension of fluorescent zinc cadmium sulfate particles (1 -10 ⁇ m) was perfused through the heart to delineate the left ventricular area-at-risk (no crystals present) for infarct development.
  • the heart was removed from the Langendorff apparatus, blotted dry, weighed, wrapped in aluminum foil and stored overnight at -20°C. Frozen hearts were sliced into 2 mm transverse sections and incubated with 1% triphenyl tetrazolium chloride in phosphate-buffered saline for 20 min.
  • the infarct size was expressed as the ratio of infarct area vs. area-at-risk (% IA/AAR).
  • the area-at-risk as a percent of left ventricular area (% AAR/LV) was not significantly different (P > 0.05) between groups.
  • the maximum reduction in infarct size that could be obtained in the 30 minute/120 minute ischemia/reperfusion protocol by administration of either CP- 566,827 or MCC-135 was a reduction to about 10%.
  • the maximum reduction in infarct size achievable in this model is a % IA/AAR of about 10%, and it would not be expected that infarct size could be reduced any further by the separate administration of the NHE-1 inhibitor or the Ca 2+ overload inhibitor regardless of the amount(s) administered.
  • HR heart rate
  • CF total coronary flow
  • LVDP left ventricular developed pressure
  • the cardiomyocytes are loaded at 37°C with fura 2, sodium-binding benzofuran isophthalate (SBFI), or 2',7'-bis(2-carboxyethyl)-5,6- carboxyfluorescein (BCECF), respectively.
  • the cells are incubated in medium 199 for 15 min with the acetoxymethylesters of fura 2 (5 ⁇ M fura 2-AM), for 30 min with 10 ⁇ M SBFI, or for 30 min with 3 ⁇ M BCECF.
  • the cells are washed twice with medium 199 containing 1% (wt/vol) bovine serum albumin. This washing is followed by a 30-min postincubation period, to allow hydrolysis of the acetoxymethylesters within the cells.
  • These loading protocols are selected from a large number of variations because they provided the highest yield in fluorescence and minimal dye compartmentation.
  • the cells are chemically "skinned" by use of digitonin.
  • the fluorescence retained in skinned cells is ⁇ 15% of previous fluorescence for fura 2, ⁇ 5% for SBFI, and ⁇ 12% for BCECF (after subtraction of background fluorescence of the cell before dye exposure). These percentages indicate only a small extent of dye compartmentation.
  • the coverslip with the loaded cells is then introduced into an airtight, temperature-controlled (37°C), transparent perfusion chamber positioned in the light beam of an inverted microscope (Diaphot TMD, Nikon, D ⁇ sseldorf, Germany).
  • Alternating excitation of the fluorescent dye at wavelengths of 340 and 380 nm for fura 2 and SBFI and 450 to 490 nm for BCECF are performed with the use of the AR-CM Cation Measurement System (Spex Industries, Grasbrunn, Germany) adapted to the microscope.
  • the emitted light (490-520 nm for fura 2 and SBFI and 520-560 nm for BCECF) from a 10 x 10 ⁇ m area within a single fluorescent cell is collected by a photomultiplier of the Spex system.
  • the signal is recorded and analyzed with the use of an IBM PC/AT-based data analyzing system (model DM3000CM, Spex Industries). Autofluorescence intensity is measured before loading a cell with the fluorescent dyes and subtracted from the fluorescence signals.
  • the "diastolic" fura 2 signal defined as the fura 2 signal when not oscillating, the curve of minima when the signal is oscillating, and the frequency of oscillations of the fura 2 signal at given times are determined.
  • Fura 2 signals are calibrated by exposing the cells to 5 ⁇ M ionomycin in modified Tyrode solution containing either 3 mM Ca 2+ or 5 mM ethylene glycol-bis( ⁇ - aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) to obtain the maximum (R max ) and the minimum (Rn,i n ) ratio of fluorescence, respectively.
  • EGTA ethylene glycol-bis( ⁇ - aminoethyl ether)-N,N,N',N'-tetraacetic acid
  • SBFI-ratio signals are calibrated in loaded cells with 6 ⁇ M gramicidin D, a Na + ionophore, and incubation media with various Na + concentrations. Calibration of the BCECF ratio signals is performed, with 10 ⁇ g/ml nigericin, a K + /H + ionophore, and incubation media with various pH values.
  • the cell's microscopic picture is recorded at the time of measurement of the fluorescence signal with the aid of a video camera and is stored on tape.
  • the changes in the cell's length are determined from this recording.
  • the cell diameter is determined along with its previous longitudinal axis.
  • the perfusion chamber on the microscopic stage (1 ml filling volume) is perfused at a rate of 0.5 ml/min with modified, glucose-free Tyrode solution containing (in mM) 140.0 NaCI, 2.6 KCI, 1.2 KH 2 PO 4 , 1.2 MgS0 4 , 1.0 CaCI 2 , and 25.0 N-2- hydroxyethylpiperazine-N'-2-ethanesulfonic acid; pH is 7.4 at 37°C.
  • Media are made anoxic by autoclaving and by equilibrating before and during use with 100% N 2 . Oxygenated media are equilibrated with air.
  • the anoxic cardiomyocyte Incubation protocols. In the standard experiment for Ca 2+ measurements, the anoxic cardiomyocyte is allowed to accumulate Ca 2+ until the saturation of the fura 2 ratio is reached and then is reoxygenated. During the anoxic incubation, the cells undergo rigor shortening. The time to rigor shortening varies among individual cells, but the changes after rigor shortening follow a reproducible time course. The time between rigor shortening and saturation of the fura 2 signal differs between anoxic media of pH 7.4 and 6.4. Different times for reoxygenation are therefore chosen for these different anoxic protocols.
  • isolated, calcium tolerant, adult rabbit cardiomyocytes are prepared by collagenase perfusion. Each isolate provides about 12 million calcium tolerant myocytes.
  • cells are resuspended into fresh KH buffer with glucose, placed in a 1.8 ml microcentrifuge tube, and are centrifuged into a pellet.
  • Each cell pellet occupies a volume of about 0.25 ml, and measures 0.8-1 cm in thickness. Excess supernatant is removed to leave a fluid layer above the pelleted cells of about one third the volume of the pellet. After layering with mineral oil to exclude gaseous exchange, the cell pellets are incubated without agitation at 37°C for up to 4 hours.
  • a 25 ⁇ l sample of the cell pellet is removed through the oil layer at the appropriate time points and is resuspended for 3- 5 min at 30°C, in 200 ⁇ l of hypotonic (85 mOsm) buffer, consisting of KH buffer diluted to the appropriate osmolarity.
  • a 25 ⁇ l sample is mixed on a microscope slide with an equal volume of 85 mOsm counting media (0.5% glutaraldehye in modified Tyrode solution, with reduced NaCI, containing 1% trypan blue and 3mM amytal) for 3-5 min at room temperature. Microscopic examination at 100X magnification determines the morphology (rod, round, or square) and the permeability of the cells to trypan blue.
  • Each isolation provides sufficient cells for four experimental groups and four oxygenated control groups.
  • Each experimental protocol usually contains two internal control groups.
  • a negative (untreated) control group is preincubated for 5 min at 30°C with 11 mM glucose, with oxygenation in 1.5 ml of 1.25 mM calcium containing KH buffer.
  • the positive control is similarly incubated for 5 min but in the absence of glucose.
  • the two experimental groups are suspended in glucose containing or glucose-free media, according to the particular protocol to be followed. Following the preincubation periods, all groups are subjected to a post incubation period in glucose containing medium lasting in most experiments for 30 min prior to ischemic pelleting.
  • Experimental groups are treated during the 30 min post incubation period with either zoniporide, MCC-135, or both compounds in combination; the compound(s) remain present during the 4 hours of ischemic pelleting.
  • Four parallel oxygenated control groups are subjected to the same pre- and postincubation protocols as the experimental groups, but are then resuspended into oxygenated, glucose containing media for 240 min at 37°C, in place of ischemic pelleting. All groups, including oxygenated controls, are swollen prior to determination of viability.
  • NHE-1 inhibitor compounds of the present invention can be prepared in accordance with the teachings of Hamanaka et al., U.S. Patent No. 6,492,401 , and Brostrom et al., International Application Publication No. WO 2001/30759, both of which documents as previously noted are incorporated by reference herein in their entirety for all purposes.
  • the following examples illustrate the preparation of preferred NHE-1 inhibitors.
  • This solid was air-dried for 1 hour and then dried for 24 h under high vacuum at 40 °C to afford 3.5 g of the free base of the title compound.
  • This solid was dissolved in 25 ml of hot methanol and treated with 1.85 ml of cone. HCI. This pale yellow solution was stirred for 15 min at room temperature and concentrated in vacuo to a light amber gum. The residual H 2 0 was removed in vacuo via codistillation with 3x25 ml portions of anhydrous ethanol. The resulting pale yellow solid was recrystallized from hot ethanol to afford 3.58 g of the title compound (62% yield).

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Abstract

Cette invention concerne des compositions pharmaceutiques contenant des inhibiteurs d'échangeur sodium-hydrogène de type 1 (NHE-1) combinés à des inhibiteurs de surcharge en Ca 2+, et l'utilisation de cette combinaison d'inhibiteurs dans le traitement, par exemple, de maladies cardio-vasculaires telles que l'ischémie, en particulier les lésions ischémiques due myocarde périopératoires chez des mammifères, dont l'homme.
PCT/US2005/004512 2004-02-13 2005-02-11 Composes pour traitement des maladies cardio-vasculaires WO2005079803A1 (fr)

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WO2008137408A1 (fr) 2007-04-30 2008-11-13 Genentech, Inc. Inhibiteurs pyrazolés de la signalisation des wnt
US8927559B2 (en) 2010-10-11 2015-01-06 Merck Sharp & Dohme Corp. Quinazolinone-type compounds as CRTH2 antagonists
US10093741B1 (en) 2017-05-05 2018-10-09 Fusion Pharmaceuticals Inc. IGF-1R monoclonal antibodies and uses thereof
US11191854B2 (en) 2017-05-05 2021-12-07 Centre For Probe Development And Commercialization Pharmacokinetic enhancements of bifunctional chelates and uses thereof
US11318134B2 (en) 2018-01-10 2022-05-03 Recurium Ip Holdings, Llc Benzamide compounds
US11433148B2 (en) 2017-05-05 2022-09-06 Centre For Probe Development And Commercialization IGF-1R monoclonal antibodies and uses thereof
US11603396B2 (en) 2019-05-22 2023-03-14 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11679120B2 (en) 2019-12-04 2023-06-20 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11845950B2 (en) 2018-06-06 2023-12-19 Massachusetts Institute Of Technology Circular RNA for translation in eukaryotic cells

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WO1999043663A1 (fr) * 1998-02-27 1999-09-02 Pfizer Products Inc. Derives de la n-[(a cycle di ou triaza diinsature substitue) carbonyle] guanidine utilises pour le traitement de l'ischemie
US20020028822A1 (en) * 1998-02-12 2002-03-07 Hisashi Kawasumi Medicament for treatment of diastolic dysfunction
US20020099075A1 (en) * 2001-01-25 2002-07-25 Tracey Wayne R. Combination therapy

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020028822A1 (en) * 1998-02-12 2002-03-07 Hisashi Kawasumi Medicament for treatment of diastolic dysfunction
WO1999043663A1 (fr) * 1998-02-27 1999-09-02 Pfizer Products Inc. Derives de la n-[(a cycle di ou triaza diinsature substitue) carbonyle] guanidine utilises pour le traitement de l'ischemie
US20020099075A1 (en) * 2001-01-25 2002-07-25 Tracey Wayne R. Combination therapy

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008137408A1 (fr) 2007-04-30 2008-11-13 Genentech, Inc. Inhibiteurs pyrazolés de la signalisation des wnt
US8927559B2 (en) 2010-10-11 2015-01-06 Merck Sharp & Dohme Corp. Quinazolinone-type compounds as CRTH2 antagonists
US10093741B1 (en) 2017-05-05 2018-10-09 Fusion Pharmaceuticals Inc. IGF-1R monoclonal antibodies and uses thereof
US11191854B2 (en) 2017-05-05 2021-12-07 Centre For Probe Development And Commercialization Pharmacokinetic enhancements of bifunctional chelates and uses thereof
US11433148B2 (en) 2017-05-05 2022-09-06 Centre For Probe Development And Commercialization IGF-1R monoclonal antibodies and uses thereof
US11813259B2 (en) 2018-01-10 2023-11-14 Recurium Ip Holdings, Llc Benzamide compounds
US11318134B2 (en) 2018-01-10 2022-05-03 Recurium Ip Holdings, Llc Benzamide compounds
US11344546B2 (en) 2018-01-10 2022-05-31 Recurium IP Holding, LLC Benzamide compounds
US11590126B2 (en) 2018-01-10 2023-02-28 Recurium Ip Holdings, Llc Benzamide compounds
US11813260B1 (en) 2018-01-10 2023-11-14 Recurium Ip Holdings, Llc Benzamide compounds
US11981909B2 (en) 2018-06-06 2024-05-14 Massachusetts Institute Of Technology Circular RNA for translation in eukaryotic cells
US11845950B2 (en) 2018-06-06 2023-12-19 Massachusetts Institute Of Technology Circular RNA for translation in eukaryotic cells
US11603396B2 (en) 2019-05-22 2023-03-14 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11802144B2 (en) 2019-05-22 2023-10-31 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11771715B2 (en) 2019-12-04 2023-10-03 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11766449B2 (en) 2019-12-04 2023-09-26 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11679120B2 (en) 2019-12-04 2023-06-20 Orna Therapeutics, Inc. Circular RNA compositions and methods

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