Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• This invention relates to a sodium-hydrogen exchanger type 1 (NHE-1) inhibitor.
• NHE-1 sodium-hydrogen exchanger type 1
• Myocardial ischemic injury can occur in out-patient as well as in perioperative settings and can lead to the development of sudden death, myocardial infarction or congestive heart failure.
• Such a therapy is anticipated to be life-saving and can reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
• Pharmacological cardioprotection would reduce the incidence and progression of myocardial infarction and dysfunction occurring in these surgical settings (perioperatively). In addition to reducing myocardial damage and improving post-ischemic myocardial function in patients with ischemic heart disease, cardioprotection would also decrease the incidence of cardiac morbidity and mortality due to myocardial infarction and dysfunction in patients "at risk” (such as greater than 65 years, exercise intolerant, coronary artery disease, diabetes mellitus, hypertension) that require non-cardiac surgery. The mechanism(s) responsible for the myocardial injury observed after ischemia and reperfusion is not fully understood.
• N- [(substituted five-membered heteroaryl)]guanidine compounds to be useful as inhibitors of Na + /H + exchange and consequently effective for the treatment of various diseases such as hypertension, arrhythmia, angina pectoris, myocardial infarct, arteriosclerosis, and complications of diabetes.
• This invention is directed to a compound of Formula I
• a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug includes the proviso that [5- cyclopropyl-1-(quinolin-5-yl)-1 H-pyrazole-4-carbonyl]guanidine is not included.
• This invention is also directed to substantially pure [5-cyclopropyl-1-(2- quinolon-5-yl)-1H-pyrazole-4-carbonyl]guanidine, or a pharmaceutically acceptable salt of said compound.
• the above compound is named [5-cyclopropyl-1-(2-quinolon-5- yl)-1H-pyrazole-4-carbonyl]guanidine.
• a preferred salt is the hydrochloride salt, and most preferably, the monohydrochloride salt.
• Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition mediated by NHE-1 by administering a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug to the mammal.
• a mammal e.g., human
• administering a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug to the mammal.
• Another aspect of this invention is directed to a method of reducing tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) resulting from ischemia comprising administering to a mammal (e.g., a female or male human) in need of such treatment a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• ischemic tissues taken individually or as a group are cardiac, brain, liver, kidney, lung, gut, skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue, the vasculature, or intestinal tissue.
• An especially preferred ischemic tissue is cardiac tissue.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug is administered to prevent perioperative myocardial ischemic injury.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug is administered prophylactically.
• the ischemic damage may occur during organ transplantation either to the organ or the patient.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug is administered prior to, during and/or shortly after cardiac surgery or non-cardiac surgery.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug is administered locally.
• a preferred dosage is about 0.01 to 100 mg/kg/day of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• An especially preferred dosage is about 0.01 to 50 mg/kg/day of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• Another aspect of this invention is directed to a method of reducing myocardial tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) during surgery (e.g., coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), organ transplantation, or other non-cardiac surgeries) comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method of reducing myocardial tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) in patients presenting with ongoing cardiac (acute coronary syndromes, e.g. myocardial infarction or unstable angina) or cerebral ischemic events (e.g., stroke) comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a chronic method of reducing myocardial tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) in a patient with diagnosed coronary heart disease (e.g., previous myocardial infarction or unstable angina) or patients who are at high risk for myocardial infarction (e.g., age > 65 and two or more risk factors for coronary heart disease) comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method of preventing ischemic damage comprising the chronic oral administration to a mammal in need of such treatment a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• Another aspect of this invention is directed to a method for treating cardiovascular diseases comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• Another aspect of this invention is directed to a method for treating arteriosclerosis comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug e.g., a female or male human
• Another aspect of this invention is directed to a method for treating arrhythmia comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method for treating angina pectoris comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method for treating cardiac hypertrophy comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method for treating renal diseases comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug e.g., a female or male human
• Another aspect of this invention is directed to a method for treating restenosis comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug e.g., a female or male human
• Another aspect of this invention is directed to a method for treating cancerous diseases comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method for treating fibrotic diseases comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method for treating glomerular nephrosclerosis comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method for treating pulmonary fibrosis comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method for treating cerebro ischemic disorders comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• a therapeutically effective amount of a the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug e.g., a female or male human
• Another aspect of this invention is directed to a method for treating myocardial dysfunction comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method for treating cerebrovascular diseases comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• Another aspect of this invention is directed to a method for treating organ hypertrophies or hyperplasias comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• a mammal e.g., a female or male human
• This invention is also directed to pharmaceutical compositions which comprise an amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent.
• This invention is also directed to pharmaceutical compositions for the reduction of tissue damage resulting from ischemia which comprise a therapeutically effective amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent.
• the term "reduction” is intended to include partial prevention or prevention which, although greater than that which would result from taking no compound or from taking a placebo, is less than 100%, in addition to substantially total prevention.
• 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.
• treating includes preventative (e.g., prophylactic) and palliative treatment.
• 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 (mesylate) and 4-toluene-sulfonate. Since more than one basic moiety exists the expression may include 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).
• a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form.
• pharmaceutically acceptable it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
• reaction-inert solvent and “inert solvent” refers 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.
• the compound of this invention can exist in radiolabelled form, i.e., the compound may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number ordinarily found in nature. Radioisotopes of hydrogen and carbon include 2 H, 3 H, and 14 C respectively.
• a compound of this invention, which contains those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e., 3 H, and carbon-14, i.e., 1 C, radioisotopes are particularly preferred for their ease of preparation and detectability.
• a radiolabelled Formula I compound can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabelled compounds can be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below by substituting a readily available radiolabelled reagent for a non-radiolabelled reagent.
• the compound of Formula I is a human metabolite of 5-cyclopropyl-1-
• [5-cyclopropyl-1 -(2-quinolon-5-yl)-1 H-pyrazole-4- carbonyljguanidine may be prepared by administering [5-cyclopropyl-1-(quinolin-5- yl)-1 H-pyrazole-4-carbonyl]guanidine to a human and isolating the desired metabolite from the plasma.
• the metabolite need not be isolated from the human since it is produced in vivo.
• the compound of this invention can be made by processes which include processes analogous to those known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compound of this invention are provided as further features of the invention and are illustrated by the following reaction scheme. Other processes are described in the experimental section.
• the formula IA compound (prepared as described in Capps, J. D.; Hamilton, C. S. J. Am. Chem. Soc. 1938, 60, 2104) is dissolved in a protic solvent such as ethanol and treated with an appropriate reducing agent such as stannous chloride dihydrate. The resulting mixture is stirred at a temperature of about 0 °C to about 115 °C for about 30 minutes to about 24 hours. The resulting mixture is cooled to about 23 °C and filtered.
• a protic solvent such as ethanol
• an appropriate reducing agent such as stannous chloride dihydrate
• the resulting solid material is purified in a suitable way, such as by triturating with hydrochloric acid (for example, 1 M aqueous) at about 100 °C for about 1 hour, cooling to about 23 °C and filtering to provide the formula II compound as its hydrochlohde salt.
• hydrochloric acid for example, 1 M aqueous
• the formula II compound can be isolated from the reaction mixture as the free base by basifying with an inorganic base, and extracting with an appropriate organic solvent.
• the formula II compound can also be isolated as other salts. Other reduction methods that will perform this reduction are known to those skilled in the art, such as for example catalytic hydrogenation.
• the formula II compound is diazotized in hydrochloric acid and water using sodium nitrite at about 0 °C for about 15 minutes to about 2 hours.
• the resulting diazonium salt solution is reduced with an appropriate reducing agent, such as stannous chloride dihydrate in hydrochloric acid and water at about 0 °C to about 23 °C for about 30 minutes to about 6 hours.
• the resulting solid is collected by filtration and purified in a suitable manner, such as by trituration with hydrochloric acid (for example, 1 M aqueous) at about 23 °C for about 30 minutes.
• the compound of formula III is collected by filtration as its hydrochlohde salt.
• the formula III compound can be isolated from the reaction mixture as the free base by basifying, with an inorganic base, and extracting with an appropriate organic solvent.
• the formula III compound can also be isolated as other salts.
• the formula IV compound is prepared by methods known to those skilled in the art, such as by the reaction of an N,N-dialkylformamide dialkylacetal, for example, N,N-dimethylformamide dimethylacetal with an ester of 3-cyclopropyl-3- oxopropanoic acid at a temperature of about 23 °C to about 115 °C for about 1 hour to about 4 hours with or without an acid catalyst.
• the group R 1 and R 2 are conveniently any alkyl, cycloalkyl, cycloalkylalkyl, or arylalkyl group. Furthermore, the two R 2 groups may be tethered together to form a cyclic entity.
• the formula IV compound is reacted with the formula III compound in an alcoholic solvent such as ethanol at a temperature of about 23 °C to about 115 °C for about 15 minutes to about 12 hours.
• an alcoholic solvent such as ethanol
• the formula V compound is collected by filtration.
• the formula V compound may be isolated by other methods such as concentration followed by addition of water and extraction with a suitable organic solvent.
• the formula V compound may be prepared using the formula III compound and other compounds in place of the formula IV compound, such as a compound in which the (R 2 ) 2 N group is replaced by a R 2 O group.
• the formula V compound is hydrolyzed with a base such as sodium or lithium hydroxide in a solvent such as water, and/or methanol, and/or THF conveniently at about 23 °C or at an elevated temperature such as at reflux temperature for about 30 minutes to about 12 hours.
• a base such as sodium or lithium hydroxide
• a solvent such as water, and/or methanol, and/or THF conveniently at about 23 °C or at an elevated temperature such as at reflux temperature for about 30 minutes to about 12 hours.
• the formula VI acid is then isolated by, for example, removing the organic solvents, acidifying and filtering.
• the formula VI compound can be isolated from the reaction mixture by removing the organic solvents, acidifying and extracting with an appropriate organic solvent.
• the Formula VI acid is coupled with guanidine in the presence of a suitable coupling agent.
• a suitable coupling agent is one which transforms a carboxylic acid into a reactive species which forms an amide linkage on reaction with an amine.
• the coupling agent may be a reagent which effects this condensation in a one pot process when mixed together with the carboxylic acid and guanidine.
• Exemplary coupling reagents are 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-hydroxybenzotriazole (EDC/HBT), dicyclohexylcarbodiimide (DCC)/hydroxybenzotriazole(HBT), 2-ethoxy-1 -ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ), and diethylphosphorylcyanide.
• the coupling is performed in an inert solvent, preferably an aprotic solvent at a temperature of about -20°C to about 50°C for about 1 to about 48 hours, in the presence of excess guanidine as base.
• Exemplary solvents include acetonit le, dichloromethane, dimethylsulfoxide, dimethylformamide, chloroform and mixtures thereof.
• the coupling agent may also be that agent which converts the carboxylic acid to an activated intermediate which is isolated and/or formed in a first step and allowed to react with guanidine in a second step.
• Examples of such coupling agents and activated intermediates are thionyl chloride or oxalyl chloride to form the acid chloride, cyanuric fluoride to form an acid fluoride or an alkyl chloroformate such as isobutyl or isopropenyl chloroformate or propanephosphonic anhydride (propanephosphonic acid anhydride, PPA) with a tertiary amine base to form a mixed anhydride of the carboxylic acid, or carbonyldiimidazole to form an acylimidazole.
• the coupling agent is oxalyl chloride
• This activated acid derivative may be coupled by mixing with the intermediate in an appropriate solvent together with an appropriate base.
• Appropriate solvent/base combinations are for example, dichloromethane, dimethylformamide or acetonitrile or mixtures thereof in the presence of excess guanidine as base.
• solvent/base combinations include water or a ((C-*-C 5 )alcohol) or a mixture thereof together with a cosolvent such as dichloromethane, tetrahydrofuran or dioxane and a base such as sodium, potassium or lithium hydroxide in sufficient quantity to consume the acid liberated in the reaction.
• a cosolvent such as dichloromethane, tetrahydrofuran or dioxane
• a base such as sodium, potassium or lithium hydroxide
• the formula VI acid is activated with excess thionyl chloride at a temperature of about reflux temperature for about 15 minutes to about 3 hours and the excess thionyl chloride is removed by concentration.
• the resulting acid chloride is combined with excess guanidine hydrochloride and an inorganic base, such as sodium hydroxide in tetrahydrofuran and water.
• the reaction is stirred conveniently at 23 °C or at an elevated temperature, such as reflux temperature, for about 30 minutes to about 6 hours.
• the formula I compound is isolated form this reaction mixture in a variety of ways.
• the reaction mixture is concentrated to remove the THF; the aqueous layer is acidified to pH 9, and the solid is collected by filtration.
• the formula I compound may be isolated by extraction with an organic solvent.
• the formula I compound may be transformed to the corresponding hydrochloride salt by treating a solution of it in methanol with hydrogen chloride in ether, and collection of the resulting solid by filtration or concentration.
• Other salts may be prepared by analogous methods.
• Some of the compounds (e.g., prodrugs) of this invention are acidic and they form a salt with a pharmaceutically acceptable cation. Most of the 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 solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug inhibits the sodium/proton (Na+/H+) exchange transport system and hence is useful as a therapeutic or prophylactic agent for diseases caused by the acceleration of the sodium/proton (Na+/H+) exchange transport system, for example, cardiovascular diseases [e.g., arteriosclerosis, hypertension, arrhythmia (e.g., ischemic arrhythmia, arrhythmia due to myocardial infarction, 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, shock (e.g.
• arteriosclerosis hypertension
• arrhythmia e.g., ischemic arrhythmia, arrhythmia due to myocardial infarction
• 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 induced by surgical treatment such as coronary artery bypass grafting (CABG) surgeries, vascular surgeries, organ transplantation, non-cardiac surgeries or percutaneous transluminal coronary angioplasty (PTCA)], cerebrovascular diseases (e.g., ischemic stroke, hemorrhagic stroke, etc.), cerebro ischemic disorders (e.g., disorders associated with cerebral infarction, disorders caused after cerebral apoplexy as sequelae, or cerebral edema).
• CABG coronary artery bypass grafting
• PTCA percutaneous transluminal coronary angioplasty
• cerebrovascular diseases e.g., ischemic stroke, hemorr
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug can also be used as an agent for myocardial protection during coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), organ transplantation, or non-cardiac surgeries.
• CABG coronary artery bypass grafting
• PTCA percutaneous transluminal coronary angioplasty
• organ transplantation or non-cardiac surgeries.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug can be used as agents for myocardial protection before, during, or after coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), organ transplantation, or non-cardiac surgeries.
• CABG coronary artery bypass grafting
• PTCA percutaneous transluminal coronary angioplasty
• organ transplantation or non-cardiac surgeries.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug can be used as agents for myocardial protection in patients presenting with ongoing cardiac (acute coronary syndromes, e.g., myocardial infarction or unstable angina) or cerebral ischemic events (e.g., stroke).
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug can be used as agents for chronic myocardial protection in patients with diagnosed coronary heart disease (e.g., previous myocardial infarction or unstable angina) or patients who are at high risk for myocardial infarction (e.g., age greater than 65 and two or more risk factors for coronary heart disease).
• diagnosed coronary heart disease e.g., previous myocardial infarction or unstable angina
• patients who are at high risk for myocardial infarction e.g., age greater than 65 and two or more risk factors for coronary heart disease.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug 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 Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug are valuable 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
• Such assays also provide a means whereby the activities of the Formula I compound, or a pharmaceutically acceptable salt of said compound or of said prodrug can be compared with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
• BCECF loaded cells are incubated for 30 min at 37°C in acid loading media (70 mM choline chloride, 50 mM NHCI 4 , 5 mM KCI, 1 mM MgCI 2> 1.8 M CaCI 2 , 5 mM glucose, 10 mM HEPES, pH 7.5), and then placed in a Fluorescent Imaging Plate Reader (Molecular Devices, CA). BCECF fluorescence is monitored using excitation and emission wavelengths of 485 nM and 525 nM, respectively.
• acid loading media 70 mM choline chloride, 50 mM NHCI 4 , 5 mM KCI, 1 mM MgCI 2> 1.8 M CaCI 2 , 5 mM glucose, 10 mM HEPES, pH 7.5
• BCECF fluorescence is monitored using excitation and emission wavelengths of 485 nM and 525 nM, respectively.
• Intracellular acidification is initiated via rapid replacement of acid loading media with recovery media (120 mM NaCI, 5 mM KCI, 1 mM MgCI 2 , 1.8 mM CaCI 2 , 5 mM glucose, 10 mM HEPES, pH 7.5) ⁇ test compound, and NHE-mediated recovery of intracellular pH is monitored as the subsequent time- dependent increase BCECF fluorescence.
• the potency of human NHE-1 inhibitors is calculated as the concentration that reduces recovery of intracellular pH by 50% (IC 50 ). Under these conditions reference NHE inhibitors amiloride and HOE-642 had IC 50 values for human NHE-1 of 50 ⁇ M and 0.5 ⁇ M, respectively.
• the compound of Formula I demonstrated an IC 50 value of 200nM in the above assay.
• the therapeutic effects of the compounds of this invention in preventing heart tissue damage resulting from an ischemic insult can be demonstrated in vitro along lines presented in Liu et al. (Cardiovasc. Res., 28:1057-1061 , 1994), as described specifically herein. Cardioprotection, as indicated by a reduction in infarcted myocardium, can be induced pharmacologically using adenosine receptor agonists in isolated, retrogradely perfused rabbit hearts as an in vitro model of myocardial ischemic preconditioning (Liu et al., Cardiovasc. Res., 28:1057-1061 , 1994).
• the in vitro test described below demonstrates that an active test compound can also pharmacologically induce cardioprotection, i.e., reduce myocardial infarct size, when administered to a rabbit isolated heart.
• the effects of the test compound are compared to ischemic preconditioning and the A1/A3 adenosine agonist, APNEA (N 6 - [2-(4-aminophenyl)ethyl]adenosine), that has been shown to pharmacologically induce cardioprotection in the rabbit isolated heart (Liu et al., Cardiovasc. Res., 28:1057-1061 , 1994).
• APNEA A1/A3 adenosine agonist
• the heart is removed from the chest and rapidly ( ⁇ 30 sec) mounted on a Langendorff apparatus.
• the heart is retrogradely perfused in a non-recirculating manner with a modified Krebs solution (NaC1 118.5 mM, KCI 4.7 mM, Mg SO 4 1.2 mM, KH 2 PO 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 is maintained at 7.4-7.5 by bubbling with 95% O 2 /5% CO 2 .
• Heart temperature is tightly controlled by using heated reservoirs for the physiological solution and water jacketing around both the perfusion tubing and the isolated heart.
• Heart rate and left ventricular pressures are determined via a latex balloon which is inserted in the left ventricle and connected by stainless steel tubing to a pressure transducer.
• the intraventricular balloon is inflated to provide a systolic pressure of 80-100 mmHg, and a diastolic pressure ⁇ 10 mmHg.
• Total coronary flow is also continuously monitored using an in-line flow probe and normalized for heart weight.
• the heart is allowed to equilibrate for 30 min, over which time the heart must show stable left ventricular pressures within the parameters outlined above. If the heart rate falls below 180 bpm at any time prior to the 30 min period of regional ischemia, the heart is paced at about 200 bpm for the remainder of the experiment.
• Ischemic preconditioning is induced by total cessation of cardiac perfusion (global ischemia) for 5 min, followed by reperfusion for 10 min.
• the regional ischemia is provided by tightening the snare around the coronary artery branch. Following the 30 min regional ischemia, the snare is released and the heart reperfused for an additional 120 min.
• Pharmacological cardioprotection is induced by infusing the test compound at predetermined concentrations, starting 30 min prior to the 30 min regional ischemia, and continuing until the end of the 120 min reperfusion period. Hearts which receive test compound do not undergo the period of ischemic preconditioning.
• the reference compound, APNEA 500 nM is perfused through hearts (which do not receive the test compound) for a 5 min period which ends 10 min before the 30 min regional ischemia.
• the coronary artery snare is tightened, and a 0.5% suspension of fluorescent zinc cadmium sulfate particles (1-10 ⁇ M) Duke Scientific Corp.(Palo Alto, CA) is perfused through the heart; this stains all of the myocardium, except that area-at-risk for infarct development (area-at-risk).
• the heart is removed from the Langendorff apparatus, blotted dry, wrapped in aluminum foil and stored overnight at -20°C. The next day, the heart is sliced into 2 mm transverse sections from the apex to the top of the ventricles.
• the slices are stained with 1 % triphenyl tetrazolium chloride (TTC) in phosphate-buffered saline for 20 min at 37°C. Since TTC reacts with living tissue (containing NAD-dependent dehydrogenases), this stain differentiates between living (red stained) tissue, and dead tissue (unstained infarcted tissue).
• the infarcted area (no stain) and the area- at-risk (no fluorescent particles) are calculated for each slice of left ventricle using a precalibrated image analyzer.
• the data is expressed as the ratio of infarct area vs. area-at-risk (%IA/AAR). All data are expressed as mean ⁇ SE and compared statistically using a Mann-Whitney non-parametric test with a Bonferroni correction for multiple comparisons. Significance is considered as p ⁇ 0.05.
• Administration of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug can be via any method which delivers the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug preferentially to the desired tissue (e.g., liver and/or cardiac tissues). These methods include oral routes, parenteral, intraduodenal routes, etc.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug is administered in single (e.g., once daily) or multiple doses or via constant infusion in, for example, an isotonic saline solution.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug is useful, for example, in reducing or minimizing damage effected directly to any tissue that may be susceptible to ischemia/reperfusion injury (e.g., heart, brain, lung, kidney, liver, gut, skeletal muscle, retina), through for example mediation by NHE-1 , as the result of an ischemic event (e.g., myocardial infarction).
• the active compound is therefore usefully employed prophylactically to prevent, (i.e., prospectively or prophylactically) to blunt or stem, tissue damage (e.g., myocardial tissue) in patients who are at risk for ischemia (e.g., myocardial ischemia).
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug of this invention is administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). 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.
• the amount and timing of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug 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 judgement of the prescribing physician.
• the dosages given below 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., cardiovascular disease).
• an amount of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug is used that is effective for ischemic protection.
• a preferred dosage is about 0.01 to 100 mg/kg/day of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug of this invention.
• An especially preferred dosage is about 0.01 to 50 mg/kg/day of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug of this invention.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug may be administered just prior to cardiac surgery (e.g., within twenty-four hours before surgery), during or subsequent to cardiac surgery (e.g., within twenty-four hours after surgery) where there is risk of myocardial ischemia.
• an infusion is administered with a loading dose of about 1 mg to about 300 mg for about one minute to about one hour prior to surgery followed by a constant infusion of about 1 mg/kg/day to about 100 mg/kg/day for the remaining presurgery, surgery and post surgery periods, including for example about 2 to about 7 days post surgical treatment.
• the compound of this invention may also be administered in a chronic daily mode.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug is generally administered in the form of a pharmaceutical composition comprising the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug together with a pharmaceutically acceptable vehicle, carrier or diluent.
• a pharmaceutically acceptable vehicle, carrier or diluent e.g., a pharmaceutically acceptable salt of said compound or of said prodrug.
• 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.
• dilute sterile, aqueous or partially aqueous solutions are prepared.
• compositions according to the invention may contain for example 0.0001 %-95% of the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• the composition or formulation to be administered will contain an amount effective to treat the disease/condition of the subject being treated.
• the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug 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 ingredient means the Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
• Formulation 1 Gelatin Capsules
• Hard gelatin capsules are prepared using the following: Ingredient Quantity (mg/capsule)
• a tablet formulation is prepared using the ingredients below: Formulation 2: Tablets
• Aerosol solution is prepared containing the following ingredients: Formulation 5: Aerosol
• Suppositories are prepared as follows: Formulation 6: Suppositories
• the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimal necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
• An intravenous formulation is prepared as follows: Formulation 7: Intravenous Solution
• the solution of the above ingredients is intravenously administered to a patient.
• GENERAL EXPERIMENTAL PROCEDURES 300 and 400 MHz 1 H NMR spectra were recorded on a Varian Unity ⁇ 300 or 400 spectrometer (Varian Co., Palo Alto, CA) equipped with two RF channels, indirect detection, and pulsed-field gradients (Z-axis only). Spectra were generally acquired near room temperature (21 °C) , and standard auto-lock and auto-shim routines were employed for shimming samples. Chemical shifts are expressed in parts per million downfield from trimethylsilane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet, q, quartet; m, multiplet; bs, broad singlet.
• Atmospheric pressure chemical ionization mass spectra were obtained on a Fisons Platform II or a Micromass ZMD spectrometer (Microsmass, Manchester, U.K.). Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for 35 CI/ 37 CI-containing ions and 1 :1 for 79 Br/ 81 Br-containing ions) and M is based on 35 CI and 79 Br. In some cases only representative 1 H NMR and APCIMS peaks are given.
• Human subjects were dosed intravenously with 5-cyclopropyl-1-(quinolin-5- yl)-1H-pyrazole-4-carbonyl]guanidine monohydrochloride monohydrate.
• Human plasma samples were pooled together and proteins were precipitated by twice volume of acetonitrile. After centrifugation, the supernatant was concentrated in a water bath with N 2 at 40°C.
• the 16 mass units difference between 5-cyclopropyl-1-(quinolin-5- yl)-1 - -pyrazole-4-carbonyl]guanidine (m/z 321) and metabolite (m/z 337) in human plasma suggested that it is formed through oxidation.
• LC/MS/MS product ion spectrum of protonated metabolite at m/z 337 [M+H] + ) showed fragment ions at m/z 278, 260, 250, 236, 223 and 208.
• the salts were removed from the above concentrated sample by solid phase extraction.
• the sample was concentrated to contain approximately 5-10 ⁇ g of the metabolite.
• 50 ⁇ L of this sample was injected onto an LC/NMR instrument equipped with a Zorbax Rx-C8 4.6 x 150 mm column, analyzed on a Bruker 500 MHz NMR spectrometer and monitored by UV detector at 235 nm.
• the analyses were performed using a mobile phase flow rate of 1 ml/minute, where the mobile phase consisted of 15 mM deuterated aqueous formic acid adjusted to pH 3.3 with deuterated ammonium hydroxide in D 2 O as solvent C and acetonitrile-d 3 as solvent D.
• the absence of the downfield peak at 8.92 ppm that is present in [5-cyclopropyl-1-(quinolin-5-yl)- 1f/-pyrazole-4-carbonyl]guanidine suggested that the 2-position on the quinoline ring was the site of oxidation.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Veterinary Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Epidemiology (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Treatment Of Water By Ion Exchange (AREA)
• Preventing Corrosion Or Incrustation Of Metals (AREA)
• Plural Heterocyclic Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=22741697

Family Applications (1)

Country Status (40)

Families Citing this family (7)

Family Cites Families (1)

• 2001
  • 2001-02-28 DZ DZ013310A patent/DZ3310A1/fr active
  • 2001-02-28 EP EP01908037A patent/EP1276737A1/en not_active Withdrawn
  • 2001-02-28 UA UA2002108497A patent/UA73348C2/uk unknown
  • 2001-02-28 TR TR2002/02439T patent/TR200202439T2/xx unknown
  • 2001-02-28 NZ NZ521348A patent/NZ521348A/en unknown
  • 2001-02-28 YU YUP-796/02A patent/YU79602A/sh unknown
  • 2001-02-28 BR BR0110268-0A patent/BR0110268A/pt not_active IP Right Cessation
  • 2001-02-28 WO PCT/IB2001/000277 patent/WO2001083470A1/en not_active Application Discontinuation
  • 2001-02-28 PL PL01357765A patent/PL357765A1/xx not_active Application Discontinuation
  • 2001-02-28 EA EA200201023A patent/EA004882B1/ru not_active IP Right Cessation
  • 2001-02-28 HU HU0300651A patent/HUP0300651A2/hu unknown
  • 2001-02-28 KR KR1020027014355A patent/KR20020093079A/ko active IP Right Grant
  • 2001-02-28 OA OA1200200331A patent/OA12256A/en unknown
  • 2001-02-28 CZ CZ20023408A patent/CZ20023408A3/cs unknown
  • 2001-02-28 MX MXPA02010600A patent/MXPA02010600A/es active IP Right Grant
  • 2001-02-28 EE EEP200200615A patent/EE200200615A/xx unknown
  • 2001-02-28 SK SK1487-2002A patent/SK14872002A3/sk unknown
  • 2001-02-28 JP JP2001580898A patent/JP2003531900A/ja active Pending
  • 2001-02-28 IL IL15207501A patent/IL152075A0/xx unknown
  • 2001-02-28 AU AU2001235896A patent/AU2001235896A1/en not_active Abandoned
  • 2001-02-28 CN CNB018087256A patent/CN1225466C/zh not_active Expired - Fee Related
  • 2001-02-28 AP APAP/P/2002/002651A patent/AP2002002651A0/en unknown
  • 2001-02-28 CA CA002407535A patent/CA2407535A1/en not_active Abandoned
  • 2001-03-06 HN HN2001000042A patent/HN2001000042A/es unknown
  • 2001-03-12 PA PA20018513301A patent/PA8513301A1/es unknown
  • 2001-04-20 GT GT200100064A patent/GT200100064A/es unknown
  • 2001-04-24 UY UY26680A patent/UY26680A1/es not_active Application Discontinuation
  • 2001-04-26 AR ARP010101970A patent/AR028375A1/es unknown
  • 2001-04-26 MY MYPI20011977A patent/MY133842A/en unknown
  • 2001-04-26 PE PE2001000376A patent/PE20011270A1/es not_active Application Discontinuation
  • 2001-04-27 SV SV2001000418A patent/SV2002000418A/es not_active Application Discontinuation
  • 2001-04-27 CO CO01032977A patent/CO5221125A1/es not_active Application Discontinuation
  • 2001-04-27 TN TNTNSN01065A patent/TNSN01065A1/fr unknown
• 2002
  • 2002-09-23 BG BG107139A patent/BG107139A/bg unknown
  • 2002-09-24 IS IS6567A patent/IS6567A/is unknown
  • 2002-10-18 MA MA26875A patent/MA26897A1/fr unknown
  • 2002-10-18 CR CR6797A patent/CR6797A/es not_active Application Discontinuation
  • 2002-10-21 IS IS6588A patent/IS6588A/is unknown
  • 2002-10-24 ZA ZA200208605A patent/ZA200208605B/en unknown
  • 2002-10-25 HR HR20020851A patent/HRP20020851A2/hr not_active Application Discontinuation
  • 2002-10-25 NO NO20025132A patent/NO20025132L/no not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events