MXPA02010600A - Sodium hydrogen exchanger type 1 inhibitor (nhe 1). - Google Patents

Abstract

NHE 1 inhibitor, methods of using the NHE 1 inhibitor and pharmaceutical compositions containing the NHE 1 inhibitor. The NHE 1 inhibitor is useful for the reduction of tissue damage resulting from tissue ischemia.

Description

INHIBITOR OF EXCHANGE- * PE SODIUM-HYDROGEN TYPE 1 BACKGROUND OF THE INVENTION This invention relates to an inhibitor of the sodium-hydrogen exchanger type 1 (NHE-1). Myocardial ischemic lesions can occur in outpatient clinics, as well as in perioperative settings, and can lead to the development of sudden death, myocardial infarction or congestive coronary insufficiency. There is a medical need not covered to prevent or minimize myocardial ischemic injuries, particularly perioperative myocardial infarction. It is hoped that this therapy can save lives and reduce hospitalizations, improve the quality of life and reduce the costs of global health care for high-risk patients. The pharmacological cardioprotection would reduce the appearance and progression of myocardial infarction and the dysfunctions that occur in these surgical scenarios (perioperatively). In addition to reducing myocardial lesions and improving postischemic myocardial function in patients with ischemic heart disease, cardioprotection would also reduce the incidence of cardiac morbidity and mortality due to myocardial infarction and myocardial dysfunction in "at-risk" patients (such as the elderly). 65 years old, people intolerant to exercise, those who they suffer from coronary artery disease, diabetes mellitus, hypertension) that require non-cardiac surgery. The mechanism (s) responsible for the myocardial lesions observed after ischemia and reperfusion are not fully understood. A variety of publications have described the use of guanidine derivatives as useful for the treatment, for example, of arrhythmias. The recently published patent application PCT / IB99 / 00206, published as WO 99/43663 on September 2, 1999, the disclosure of which is incorporated herein by reference, discloses a variety of NHE-1 inhibitors, including [ 5-Cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carbonyl] guanidine. The publication further indicates that "the preferred salts of the immediately preceding compound are the mono- or dimesylate salts". A group of preferred compounds, including the hydroxyquinoline compounds, is described in claim 102 of the published application. Of course, some of these hydroxyquinoline compounds may exist in various tautomeric forms, such as the quinolone form described in this patent application. In addition, the provisional US application assigned together with the present serial number 60 / 162,374, filed on October 29, 1999, is directed to crystalline forms of the NHE-1 inhibitor described above.

Application PCT / JP97 / 04650, published on June 25, 1998, discloses N - [(substituted five-membered heteroaryl)] guanidine compounds, which are useful as inhibitors of NaH exchange and are therefore effective for the treatment of various diseases, such as hypertension, angina pectoris, myocardial infarction, arterioscelerosis and complications of diabetes. Therefore, there is clearly a need and in this field of the art a search is currently underway for compounds for the treatment of perioperative myocardial ischemia.

BRIEF DESCRIPTION OF THE INVENTION This invention is directed to a compound of formula Formula I its prodrug, or a pharmaceutically acceptable salt of said compound or said prodrug, with the proviso that [5-cyclopropyI-1- (quinoiin-5-yl) -1H-pyrazole-4-carbonyl] -guanidine it is not included.

As used herein, the term "its prodrug, or a pharmaceutically acceptable salt of said compound or said prodrug" includes the condition that [5-cyclopropyl-1- (quinolin-5-yl) -1 H -pyrazol-4-carbonyl] -guanidine is not included. This invention is also directed to [5-cyclopropyl-1- (2-quinolone-5-yl) -1H-pyrazole-4-carbonyl] -guanidine substantially pure, or a pharmaceutically acceptable salt of said compound. Alternatively, the above compound is referred to as [5-cyclopropyl-1- (2-quinolone-5-yl) -1H-pyrazole-4-carbonyl] -guanidine. A preferred salt is the hydrochloride salt, and more preferably the monohydrochloride salt. Another aspect of the invention is a method for treating a mammal (e.g., a human) suffering from a disease or disorder mediated by NHE-1, by administering a therapeutically effective amount of the compound of formula I, its prodrug, 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 injury by inducing tissue protection) resulting from ischemia, which comprises administering to a mammal (e.g., a woman or a man). ) in need of such treatment, a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or said prodrug.

The preferred ischemic tissues, taken individually or as a group, are the cardiac, cerebral, hepatic, renal, pulmonary, intestine, skeletal muscle, spleen, pancreatic, nervous, spinal cord, retinane tissues of the vasculature or intestinal. A particularly preferred ischemic tissue is cardiac tissue. It is especially preferred that the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug be administered to prevent perioperative myocardial ischemic injuries. Preferably, the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug is administered prophylactically. Ischemic lesions may occur during organ transplantation, in the organ or in the patient. Preferably, the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug is administered before, during and / or shortly after cardiac surgery or non-cardiac surgery. In one aspect of this invention, the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug is administered locally.

A preferred dosage is from about 0.01 to 100 mg / kg / day of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug. An especially preferred dosage is from about 0.01 to 50 mg / kg / day of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention is directed to a method for reducing myocardial tissue injury (e.g. substantially preventing tissue injury by inducing tissue protection) during surgery (e.g., coronary artery bypass graft surgery (CABG). ), vascular surgery, percutaneous transluminal coronary angioplasty (PTCA), organ transplantation, or other non-cardiac surgeries), which comprises administering to a mammal (e.g., a woman or a man) a therapeutically effective amount of the compound of Formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention is directed to a method for reducing myocardial tissue damage (e.g. substantially preventing tissue damage by inducing tissue protection) in patients with developing cardiac events (acute coronary syndromes, e.g., myocardial infarction or angina) unstable) or brain ischemic (eg, cerebrovascular accidents), which comprises administering to a mammal (eg, a woman or a man) an amount Therapeutically effective of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention is directed to a chronic method for reducing myocardial tissue damage (e.g. substantially preventing tissue damage by inducing tissue protection) in a patient with a diagnosed coronary heart disease (e.g., myocardial infarction or angina) unstable) or in patients who are at high risk of myocardial infarction (eg, those over 65 and two or more risk factors for coronary heart disease), which comprises administering to a mammal (eg, a a woman or a man) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said pro-drug. Another aspect of this invention is directed to a method for preventing ischemic injury, comprising chronic oral administration to a mammal in need of such treatment, of a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. compound or of said pro drug. Another aspect of this invention is directed to a method for treating cardiovascular diseases, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. said compound or said prodrug.

Another aspect of this invention is directed to a method of treating arteriosclerosis, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. compound or said prodrug. Another aspect of this invention is directed to a method of treating hypertension, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. compound or said prodrug. Another aspect of this invention is directed to a method for treating arrhythmia, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. compound or said prodrug. Another aspect of this invention is directed to a method of treating angina pectoris, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt. of said compound or said prodrug. Another aspect of this invention is directed to a method of treating cardiac hypertrophy, which comprises administering to a mammal (e.g., a woman or a man) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention is directed to a method of treating kidney diseases, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. said compound or said prodrug. Another aspect of this invention is directed to a method of treating diabetic complications, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug, or a pharmaceutically acceptable salt thereof. said compound or said prodrug. Another aspect of this invention is directed to a method of treating restenosis, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. compound or said prodrug. Another aspect of this invention is directed to a method for treating cell proliferation diseases, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically salt acceptable of said compound or said pro drug.

Another aspect of this invention is directed to a method of treating cancerous diseases, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. said compound or said prodrug. Another aspect of this invention is directed to a method for treating fibrotic diseases, which comprises administering to a mammal (for example, a woman or a man) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention is directed to a method for treating glomerular nephrosclerosis, which comprises administering to a mammal (for example, a woman or a man) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention is directed to a method for treating pulmonary fibrosis, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of this invention is directed to a method for treating cerebroischemic disorders, which comprises administering to a mammal (e.g., a woman or a man) an amount Therapeutically effective of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug. Another aspect of this invention is directed to a method for treating myocardial stunning, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. said compound or said prodrug. Another aspect of this invention is directed to a method for treating myocardial dysfunction, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. said compound or said prodrug. Another aspect of this invention is directed to a method for treating cerebrovascular diseases, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt thereof. said compound or said prodrug. Another aspect of this invention is directed to a method for treating organ hyperplasia or hypertrophy, which comprises administering to a mammal (e.g., a female or a male) a therapeutically effective amount of the compound of formula I, its prodrug or a salt pharmaceutically acceptable of said compound or said prodrug.

This invention is also directed to pharmaceutical compositions comprising an amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable carrier, carrier or diluent. This invention is also directed to pharmaceutical compositions for the reduction of tissue lesions resulting from ischemia, comprising a therapeutically effective amount of the compound of formula I, its prodrug or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable carrier, carrier or diluent. The term "reduction" is intended to include prevention or partial prevention, which, although altogether, is greater than that which would occur if the compound is not taken or a placebo is taken, is less than 100%, in addition to substantially total prevention . The term "lesions resulting from ischemia", as used herein, refers to disorders directly associated with decreased blood flow to tissues, for example due to a clot or blockage of blood vessels that they supply the blood to the concrete tissue, and that results, among others, in a lower transport of oxygen to said tissue, a diminished tissue action, and a tissue dysfunction and / or necrosis. Alternatively, when the blood flow or perfusion of the organ is quantitatively adequate, the Oxygen carrying capacity of the blood or perfusion medium of the organ can be reduced, for example, in a hypoxic medium, such that the supply of oxygen to the tissue is diminished, and decreased tissue performance occurs, tissue dysfunction and / or tissue necrosis. The terms "treat", "treat" or "treatment", as used herein, include palliative and preventive (eg, prophylactic) treatment. The term "pharmaceutically acceptable salt" refers to non-toxic 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-toluenesulfonate. Since there is more than one basic moiety, the expression may include multiple salts (e.g., disalts). The term also refers to non-toxic cationic salts, such as (but are not limited to) sodium salts, potassium, calcium, magnesium, ammonium or protonated benzathine (N, N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methylglucamine), benetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino- 2-hydroxymethylene-1,3-propanediol). The term "prodrug" refers to compounds that are precursors of the drug which, after administration, release the drug in vivo through a chemical or physiological process (e.g., a prodrug, after changing to a physiological pH or by an action enzymatic, it becomes the desired drug form). Again, there is a condition that [5-cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carbonylj-guanidine is not included. The term "pharmaceutically acceptable" means that the carrier, carrier, excipients and / or salts must be compatible with the other ingredients of the formulation, and not be deleterious to the recipient thereof. As used herein, the terms "solvent inert to the reaction" and "inert solvent" refer to a solvent or mixture of solvents that do not interact with the starting materials, reactants, intermediates or products, a way that adversely affects the performance of the desired product. It will be understood that the compound of the invention can exist in radioactively labeled form, ie, the compound can contain one or more atoms containing an atomic mass or a mass number different from the atomic mass or the mass number that is normally found In nature. The radioisotopes of hydrogen and carbon include 2H, 3H and 14C, respectively. A compound of this invention, which contains these radioisotopes and / or other radioisotopes of other atoms, is within the scope of this invention. Tritiated, ie, 3H, and carbon 14, i.e., i4C, radioisotopes are particularly preferred for their ease of preparation and detectability. A radiolabelled compound of formula I can be prepared in general by very known to those skilled in the art. Conveniently, these radiolabelled compounds can be prepared by carrying out the procedures described in the schemes and / or the examples below, by replacing a radiolabelled reagent with a radioactively labeled reagent that can be easily purchased. . Other features and advantages will be apparent from the specification and the claims describing the invention.

DETAILED DESCRIPTION OF THE INVENTION The compound of formula I is a human metabolite of [5-cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carbonyl] -guanidine. It was identified from human plasma samples obtained after intravenous administration of [5-cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carbonyl] -guanidine to human subjects. The structure of this compound was verified independently by chemical synthesis. In another aspect of this invention, [5-cyclopropyl-1- (2-quinolone-5-yl) -1H-pyrazole-4-carbonyl] guanidine can be prepared by the administration of [5-cyclopropyl-1- (quinolin -5-yl) -1H-pyrazole-4-carbonyl] guanidine to a human being, and the isolation of the desired metabolite from the plasma. As an alternative, it is not necessary to isolate the metabolite of the human being, since it is produced in vivo. In general, the compound of this invention can be prepared by processes that include processes analogous to those known in the art. chemical technique, in particular in light of the description contained herein. Certain processes for the preparation of the compound of this invention are provided as other characteristics of the invention, and are illustrated by the following reaction scheme. Other processes are described in the experimental section. A detailed description of the synthetic aspect of the invention is as follows: According to the above scheme, the compound of formula IA (prepared as described in Capps, JD, Hamilton, CS, J. Am. Chem. Soc.i 1938, 60, 2104) is dissolved in a protic solvent such as ethanol, and treat with an appropriate reducing agent, such as stannous chloride dihydrate. The resulting mixture is stirred at a temperature from about 0 ° C to about 115 ° C, for about 30 minutes at approximately 24 hours. The resulting mixture is cooled to about 23 ° C and filtered. The resulting solid material is purified in a suitable way, such as by trituration with hydrochloric acid (eg, 1 M aqueous) at about 100 ° C for about 1 hour, cooling to about 23 ° C and filtering to give the compound of formula II as its hydrochloride salt. Alternatively, the compound of formula II can be isolated from the reaction mixture in the form of the free base by basification with an inorganic base, and extraction with an appropriate organic solvent. The compound of formula II can also be isolated in the form of other salts. Other reduction methods that can carry out this reduction are known to those skilled in the art, such as for example catalytic hydrogenation. The compound of formula II is diazotized in hydrochloric acid and water, using sodium nitrate 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 from 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 (eg, aqueous 1M) at about 23 ° C for about 30 minutes. The compound of formula III is collected by filtration as its hydrochloride salt. As an alternative, the compound of formula III can be isolated from the reaction mixture in the form of the free base by basification with an inorganic base, and extraction with an appropriate organic solvent. The compound of formula III can also be isolated in the form of other salts. Other reducing agents that can carry out this transformation are known to those skilled in the art. The compound of formula IV is prepared by methods known to those skilled in the art, such as by the reaction of a N, N-dialkylformamide acetal, for example, N, N-dimethylformamide dimethylacetal, with an ester of 3-cyclopropyl- 3-oxopropanoic acid at a temperature from about 23 ° C to about 115 ° C, for about 1 hour to about 4 hours with or without an acid catalyst. The groups R1 and 2 are conveniently any alkyl, cycloalkyl, cycloalkylalkyl or arylalkyl group. In addition, the two R2 groups can be joined to form a cyclic entity. The compound of formula IV is reacted with the compound of formula III in an alcoholic solvent such as ethanol at a temperature from about 23 ° C to about 115 ° C, for about 15 minutes to about 12 hours. When the compound of formula III is used in the form of its hydrochloride salt, it is advantageous to carry out the reaction in the presence of an excess of a non-nucleophilic base, such as triethylamine. The compound of formula V is collected by filtration. Alternatively, the compound of formula V can Isolate by other methods, such as concentration followed by addition of water and extraction with a suitable organic solvent. Alternatively, the compound of formula V can be prepared using the compound of formula III and other compounds in place of the compound of formula IV, as a compound in which the (R2) 2N group is replaced by a group R2O. The compound of formula V 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 reflux temperature / approximately 30 minutes to approximately 12 hours. The acid of formula VI is then isolated, for example, by removal of the organic solvents, acidification and filtration. Alternatively, the compound of formula VI can be isolated from the reaction mixture by removal of the organic solvents, acidification and extraction with an appropriate organic solvent. The acid of formula VI is coupled with guanidine in the presence of a suitable coupling agent. A suitable coupling agent is one that transforms a carboxylic acid into a reactive species that forms an amide bond upon reaction with an amine. The coupling agent can be a reagent that carries out this condensation in a one-step process, when mixed with the carboxylic acid and the guanidine. Examples of coupling agents are 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydroxychloride / hydroxybenzotriazole (EDC / HBT), dicyclohexylcarbodiimide (DCCyhydroxybenzotriazole (HBT), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) and diethylphosphorylnide. it is carried out in an inert solvent, preferably an aprotic solvent at a temperature from about -20 ° C to about 50 ° C, for about 1 to about 48 hours, in the presence of an excess of guanidine as the base. include acetonitrile, dichloromethane, dimethylsulfoxide, dimethylformamide, chloroform and mixtures thereof The coupling agent can also be one which converts the carboxylic acid into an activated intermediate which is isolated and / or formed in a first step, and is allowed to react with the guanidine in a second step Examples of these activated coupling agents and intermediates are thionon chloride or oxalyl chloride to form the acid, the cyanuric fluoride to form an acid fluoride or an alkyl chloroformate such as isobutyl chloroformate or isopropenyl, or propanephosphonic anhydride (propanephosphonic anhydride, PPA) with a tertiary amine base to form a mixed anhydride of the carboxylic acid, or a carbonyldiimidazole to form an acylimidazole. If the coupling agent is oxalyl chloride, it is advantageous to use a small amount of dimethylformamide as a co-solvent with another solvent (such as dichloromethane), to catalyze the formation of the acid chloride. This activated acid derivative can be coupled by mixing with the intermediate in an appropriate solvent, together with an appropriate base. Suitable solvent / base combinations are, for example, dichloromethane, dimethylformamide, acetonitrile or mixtures thereof, in the presence of an excess of guanidine as a base. Other suitable solvent / base combinations include water, (C1-C5) alcohol or mixtures thereof, together with a cosolvent such as dichloromethane, tetrahydrofuran or dioxane, and a base such as sodium, potassium or lithium hydroxide in an amount sufficient to consume the acid released in the reaction. The use of these coupling agents and the proper selection of solvents and temperatures are known to those skilled in the art, or can be readily determined from the literature in light of this description. These conditions and other examples of conditions useful for coupling carboxylic acids are described in Houben-Weyl, volume XV, part II, E. Wunsch ed., G. Theime Verlag, 1974, Stuttgart; M. Bodansky, Principies of Peptide Synthesis, Springer-Verlag, Berlin, 1984; and The Peptides, Analysis, Synthesis and Biology (E. Gross and J. Meienhofer, ed.), volumes 1-5 (Academia Press, New York, 1979-1983). In one embodiment, the acid of formula VI is activated with an excess of thionyl chloride at a temperature of about the reflux temperature, for about 15 minutes to about 3 hours, and the excess of thionyl chloride is removed by concentration. The resulting acid chloride is combined with the excess guanidine hydrochloride and an inorganic base, such as sodium hydroxide in tetrahydrofuran and water. The reaction is agitated conveniently to 23 ° C or at an elevated temperature, such as the reflux temperature, from about 30 minutes to about 6 hours. The compound of formula I is isolated from this reaction mixture in several ways. For example, the reaction mixture is concentrated to remove THF; The aqueous layer is acidified to pH 9, and the solid is collected by filtration. Alternatively, the compound of formula I can be isolated by extraction with an organic solvent. The compound of formula I can be transformed into the corresponding hydrochloride salt by treating a solution thereof in methanol with hydrogen chloride in ether, and collecting the resulting solid by filtration or concentration. Other salts can be prepared by analogous methods. Those skilled in the art will understand that it is also possible to transform the compound of formula V directly into the compound of formula I by treating the compound of formula V with an excess of guanidine in an inert solvent, such as an alcohol solvent, for example ethanol, or absence of a solvent from about 60 ° C to about 150 ° C. Those skilled in the art will understand that the compound of formula I can exist in various tautomeric forms. All these tautomeric forms are considered part of this invention. For example, all tautomeric forms of the carbonylguanidine moiety of the compound of formula I are included in this invention. All tautomeric forms of the 2-quinolone moiety The compound of formula I, like the 2-hydroxyquinoline form, are also included in this invention. The starting materials and reagents for the compounds described above can also be purchased without problems, or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. In addition, when the compound of the invention forms metabolites, hydrates or solvates, these are also within the scope of the invention. Some of the compounds (e.g., pro-drugs) of this invention are acids, and form a salt with a pharmaceutically acceptable cation. The majority of the compounds of this invention are basic, and form a salt with a pharmaceutically acceptable anion. All these salts, including the disalts, are within the scope of this invention and can be prepared by conventional methods. For example, can be prepared simply by contacting the acidic and basic entities, in an aqueous, non-aqueous or partially aqueous medium. The salts are recovered 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 compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug, inhibit the sodium / proton exchange transport system (Na + / H +), and thus they are useful as therapeutic or prophylactic agents for diseases caused by the acceleration of the sodium / proton exchange transport system (Na + / H +), for example cardiovascular diseases [eg, arteriosclerosis, hypertension, arrhythmia (eg, ischemic arrhythmia) , arrhythmia due to myocardial infarction, arrhythmia after PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy, myocardial infarction, heart failure (eg, congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), restenosis after PTCA, shock (eg, hemorrhagic shock, endotoxin shock, etc.)], kidney diseases (eg, diabetes mellitus, diabetic neuropathy, acute ischemic renal failure, etc.), organ disorders associated with ischemia or ischemic reperfusion [(eg, disorders associated with ischemic muscle reperfusion heart failure, acute renal failure, or disorders induced by surgical treatments such as coronary artery bypass surgeries (CABG), vascular surgeries, organ transplantation, non-cardiac surgeries or percutaneous coronary transluminal angioplasty (PTCA)], cerebrovascular diseases (for example, ischemic strokes, hemorrhagic shock, etc.), brain ischemic disorders (for example, disorders associated with cerebral infarction, disorders caused after a cerebral stroke as sequelae, or cerebral edema). The compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug, may also be used as agents for myocardial protection during coronary artery bypass graft surgeries (CABG), vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), organ transplantation or non-cardiac surgeries. Preferably, the compound of formula I, its prodrug, 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 graft surgeries (CABG ), vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), organ transplantation or non-cardiac surgeries. Preferably, the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug, can be used as agents for myocardial protection in patients presenting with developing cardiac events (acute coronary syndromes, eg myocardial infarction). or unstable angina) or cerebral ischemic (eg, cerebrovascular accidents). Preferably, the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug, can be used as agents for myocardial protection in patients with a diagnosed coronary heart disease (e.g., myocardial infarction or unstable angina). previous) or in patients who have a high risk of myocardial infarction (for example, those over 65 and two or more risk factors for coronary heart disease). In addition to this, the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug is remarkable for its strong inhibitory effect on cell proliferation, for example the proliferation of fibroblast cells and the proliferation of smooth muscle cells of blood vessels. For this reason, the compound of formula I, its prodrug, 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 therefore can be used as antiatherosclerotic agents, and as agents against late complications of diabetes, cancer diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, glomerular nephrosclerosis, hypertrophies or hyperplasias of organs, in particular hypertrophy or hyperplasia of the prostate, pulmonary fibrosis, diabetic complications or recurrent stenosis after PTCA, or diseases caused by endothelial cell lesions. The utility of the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug as medical agents in the treatment of diseases, such as those detailed herein in mammals (eg, humans), by example, myocardial protection during surgery or myocardial protection in patients presenting with developing cardiac events or cerebral ischemic events, or chronic cardioprotection in patients with a diagnosed coronary heart disease, is demonstrated by the activity of the compound of formula I, or a pharmaceutically acceptable salt of said compound, in a conventional in vitro assay and other preclinical cardioprotective assays [see the in vivo assay in Klein, H. et al., Circulation, 92: 912-917 (1995); the isolated heart assay in Scholz, W. et al., Cardiovascular Research, 29: 260-268 (1995); the antiarrhythmic assay in Yasutake M. et al., Am. J. Physiol., 36: H2430-H2440 (1994); the NMR assay in Kolke et al., J. Thorac. Cardiovasc. Surg., 112: 765-775 (1996)]. These assays also provide a means by which the activities of the compound of formula I, or a pharmaceutically acceptable salt of said compound or of said prodrug can be compared to 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 these diseases.

Measurement of the inhibitory activity of human NHE-1 The methodologies for the measurement of human NHE-1 activity and inhibitory potency are based on those published by Watson et al., Am. J. Physiol., 24: G229-G238, 1991), in which recovery mediated by NHE of intracellular pH is measured after intracellular acidification. Therefore, fibroblasts stably expressing human NHE-1 (Counillon, L. et al., Mol.Pharmacol., 44: 1041-1045 (1993)) are placed in 96 well plates coated with collagen (50,000 / well) and are grown to confluence in growth medium (DMEM with high glucose content, 10% fetal bovine serum, 50 μ / ml penicillin and streptomycin). The confluent plates are incubated for 30 minutes at 37 ° C with the pH-sensitive fluorescent probe BCECF (5 μM, Molecular Probos, Eugene, OR). The BCECF loaded cells are incubated for 30 minutes at 37 ° C in acid loading medium (70 mM choline chloride, 50 mM NHCU, 5 mM KCl, 1 mM MgCl 2, 1.8 mM CaCl 2, 5 mM glucose, 10 mM HEPES) , pH 7.5), and then placed in a fluorescent imaging plate reader (Molecular Devices, CA). The fluorescence of BCECF is controlled using excitation and emission wavelengths of 485 mM and 525 nM, respectively. Intracellular acification is initiated by rapid substitution of the acid loading medium with recovery medium (120 mM NaCl, 5 mM KCl, 1 mM MgCl 2, 1.8 mM CaCl 2, 5 mM glucose, 10 mM HEPES, pH 7.5) ± the compound assay, and the NHE-mediated recovery of intracellular pH is monitored as the fluorescence increase of subsequent time-dependent BCECF. The potency of the human NHE-1 inhibitors is calculated as the concentration that reduces the intracellular pH recovery by 50% (IC 50). Under these conditions, the NHE-642 standard NHE inhibitors and HOE-642 have Cl50 values for NHE-1. 50 μM and 0.5 μM, respectively. The compound of formula I shows a Cl50 value of 200 nM in the above test. It has been suggested that brief periods of myocardial ischemia followed by reperfusion of the coronary artery protect the heart from subsequent severe myocardial ischaemia (Murry et al., Circulation, 74: 1124-1136, 1986). This phenomenon is known as ischemic preconditioning. The therapeutic effects of the compounds of this invention to prevent lesions of cardiac tissue that appear as a result of an ischemic attack can be demonstrated in. vitro following the lines presented in Liu et al. (Cardiovasc. Res., 28: 1057-1061, 1994), as specifically described herein. Cardioprotection, indicated as a reduction in the infarcted myocardium, can be induced pharmacologically using adenosine receptor agonists in isolated retro-perfused rabbit hearts, as an in vitro model of myocardial ischemic preconditioning (Liu et al., Cardiovasc. Res., 28: 1057-1061, 1994). The In vitro assay described below demonstrates that an active test compound can also induce cardioprotection pharmacologically, i.e., reduces the size of myocardial infarction, when administered to an isolated rabbit heart. The effects of the test compound are compared to ischemic preconditioning and the A1 / A3 adenosine agonist, APNEA (N6- [2- (4-aminophenyl) ethyl] adenosine), which has been shown to induce cardioprotection pharmacologically in the isolated rabbit heart (Liu et al., Cardiovasc. Res., 28: 1057-1061, 1994). The exact methodology is described below. The protocol used for these experiments largely follows that described by Liu et al., Cardiovasc. Res., 28: 1057-1061, 1994. Male New Zealand white rabbits (3-4 kg) are anesthetized with sodium pentobarbital (30 mg / kg, intravenously). After achieving deep anesthesia (determined by the absence of the ocular flicker reflex), the animal is intubated and ventilated with 100% O2 using a positive pressure ventilator. A left thoracotomy is performed, the heart is exposed, and a loop (silk 2-0) is loosely placed around a prominent branch of the left coronary artery, at a distance of 2/3 to the apex of the left coronary artery. heart. The heart is removed from the chest and mounted quickly (<30 sec) on a Langendorff device. The heart is reperfused retrogradely in a non-circulating manner with a modified Krebs solution (118.5 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO4, 1.2 mM KH2P04, 24.8 mM NaHCO3, 2.5 mM CaCl2 and 10 mM glucose), at a constant pressure 80 mm of Hg and a temperature of 37 ° C. The pH of the perfusate is maintained at 7.4-7.5 by bubbling with 95% O2 / 5% C02. The temperature of the heart is controlled very well by using heated deposits for the physiological solution and a water jacket around the perfusion tubes and the isolated heart. The heart rate and left ventricular pressures are determined by a latex balloon that is inserted into the left ventricle and connected by a tube of stainless steel to a pressure transducer. The intraventricular balloon is inflated to provide a systolic pressure of 80-100 mm Hg, and a diastolic pressure of < 10 mm Hg. Total coronary flow is also continuously monitored using an in-line and normalized flow probe for the weight of the heart. The heart is allowed to equilibrate for 30 minutes, after which the heart must show left ventricular pressures within the parameters indicated above. If the heart rate drops more than 180 Ipm at any time before the 30-minute period of regional ischemia, the heart is marked at a rate of 200 Ipm for the remainder of the experiment. Ischemic preconditioning is induced by total cessation of cardiac perfusion (global ischemia) for 5 minutes, followed by reperfusion for 10 minutes. Regional ischemia is achieved by tightening the loop around the branch of the coronary artery. After 30 minutes of regional ischemia, the loop is loosened and the heart is reperfused for 120 more minutes. Pharmacological cardioprotection is induced by infusion of the test compound at predetermined concentrations, beginning 30 minutes before the regional ischemia of 30 minutes, and continuing until the end of the reperfusion period of 120 minutes. The hearts that receive the test compound do not undergo the period of ischemic preconditioning. The standard compound, APNEA (500 nM), is perfused through the hearts (which do not receive the compound of trial) for a period of 5 minutes, ending 10 minutes before regional ischemia of 30 minutes. At the end of the 120 minute reperfusion period, the coronary artery loop is tightened, and a 0.5% suspension of fluorescent cadmium and zinc sulfate particles (1-10 (μM) Duke Scientific Corp. (Palo Alto, CA ) is prefused through the heart, this stains the entire myocardium, except the area of risk of developing a heart attack (risk area) .The heart is removed from the Langendorff device, dried with blotting paper, wrapped in a foil of aluminum and stored overnight at -20 ° C. The next day, the heart is cut in 2 mm cross sections from the apex to the top of the ventricles.The cuts are stained with 1% triphenyltetrazolium chloride (TTC) in phosphate buffered saline for 20 minutes at 37 ° C. Since TTC reacts with living tissue (containing NAD-dependent dehydrogenases), this staining differentiates between living tissue (dyed red) and dead tissue (infarcted non-stained tissue). The infarcted area (without dye) and the risk area (without fluorescent particles) are calculated in each left ventricle section, using a precalibrated image analyzer. To normalize ischemic lesions to detect differences in the area of risk between the hearts, the data are expressed as the proportion of infarcted area versus the area of risk (AI% / ADR). All data are expressed as the mean ± SE, and are compared statistically using a nonparametric Mann-Whitney test with a Bonferroni correction for multiple comparisons. It is considered a significance of p < 0.05. The results of the above in vitro assay can be used to demonstrate that the compounds of this invention induce significant cardioprotection relative to the control group. The administration of the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug can be carried out by any method which administers the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said preferably a prodrug to the desired tissue (for example hepatic and / or cardiac tissues). These methods include oral, parenteral, intraduodenal, etc. In general, the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said pro-drug are administered in a single dose (eg, once daily) or in multiple doses, or by constant infusion, by example, in an isotonic saline solution. The compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug are useful, for example, to reduce or minimize lesions produced directly to any tissue that may be susceptible to reperfusion / ischemia lesions ( for example, heart, brain, lung, kidney, liver, intestine, skeletal muscle, retina), for example by means of NHE-1, as a result of an ischemic event (e.g. myocardium). The active compound can therefore be used with prophylactic utility to prevent (ie, prospectively or prophylactically) stopping or stopping tissue lesions (eg, of myocardial tissue) in patients who are at risk of ischemia (e.g. myocardial ischemia). In general, the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug is administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously or intramédularly). Topical administration may also be indicated, for example, when a patient suffers from gastrointestinal disorders or when the medication is best applied to the surface of a tissue or organ, as determined by the attending physician. The schedule and amount administered of the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug will, of course, depend on the subject being treated, the severity of the disease, the route of administration. and the criteria of the doctor in charge. Thus, due to the variability between patients, the dosages indicated below with a guide, and the doctor can assess other doses of the drug to achieve the treatment it considers appropriate for the patient. Depending on the degree of treatment desired, the doctor must consider a variety of factors, such as the age of the patient, the presence of a pre-existing disease, as well as the presence of other diseases (for example, cardiovascular disease).

Typically, an amount of the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug that is effective for ischemic protection is used. A preferred dosage is from about 0.01 to 100 mg / kg / day of the compound of formula I, its pro-drug, or a pharmaceutically acceptable salt of said compound or of said prodrug of this invention. An especially preferred dosage is from about 0.01 to 50 mg / kg / day of the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug of this invention. In a mode of administration, the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug may be administered just prior to cardiac surgery (e.g., in the twenty-four hours prior to surgery), during or after cardiac surgery (for example, within twenty-four hours after surgery), when there is a risk of myocardial ischemia. In an especially preferred mode of administration, an infusion is administered at a loading dose of about 1 mg to about 300 mg for about one minute to about one hour before surgery, followed by a constant infusion of about 1 mg / kg / day at approximately 100 mg / kg / day for the rest of the periods - pre-surgical, surgical and postsurgical, including for example post-surgical treatment from approximately 2 to approximately 7 days. The compound of the invention can also be administered in a chronic daily fashion. The compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug is generally administered in the form of a pharmaceutical composition comprising the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug, together with a pharmaceutically acceptable carrier, vehicle or diluent. Thus, the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug can be administered in any conventional oral, parenteral, rectal or transdermal dosage form. For oral administration, 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 used, together with various disintegrants such as starch and preferably potato starch or tapioca, and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for the preparation of tablets. Solid compositions of similar type are also used as fillers in hard and soft fill gelatin capsules; the preferred materials to this respect also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of the invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as diluents such as water, ethanol , propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions may be employed, for example in sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts. These aqueous solutions can be suitably buffered, if necessary, and the liquid diluent first made isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this regard, the sterile aqueous media used can be obtained easily by conventional techniques well known to those skilled in the art. For transdermal (e.g. topical) administration, aqueous or partially aqueous solutions (usually at a concentration of about 0.1% to 5%) are prepared which are sterile diluted, which are otherwise similar to the above parenteral solutions.

The methods for preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this description for those skilled in the art. For examples of methods of preparing pharmaceutical compositions, see Reminaton's Pharmaceutical Sciences. Mack Publishing Company, Easter, PA, 15th edition (1975). The pharmaceutical compositions according to the invention may contain, for example. 0.0001% -95% of the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug. In any case, the composition or formulation to be administered will contain an amount effective to treat the disease / disorder of the subject being treated. The compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug in general are administered in a convenient formulation. The following formulation examples are illustrative only, and are not intended to limit the scope of the present invention. In the formulations which follow, "active ingredient" means the compound of formula I, its prodrug, or a pharmaceutically acceptable salt of said compound or said prodrug.

Formulation 1: Gelatin capsules Hard gelatin capsules are prepared using the following: A capsule formulation is prepared using the following ingredients: Formulation 2: tablets The components are mixed and compressed to form tablets. Alternatively, tablets each containing 0.25-100 mg of the active ingredient are prepared as follows: Formulation 3: tablets The active principle, starch and cellulose are passed through a US sieve of No. 54 mesh and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are then passed through a US sieve of No. 14 mesh. The produced granules are dried at 50 ° C-60 ° C and passed through a No. 18 mesh US sieve. Sodium carboxymethylcellulose, magnesium stearate and talc, which have previously been passed through a No. 60 mesh US sieve, are then added to the granules, which then of mixing are compressed in a tabletting machine to produce the tablets. Suspensions are prepared each containing 0.25-100 mg of the active ingredient per 5 ml dose as follows: Formulation 4: suspensions The active ingredient is passed through a US sieve of No. 45 mesh, and mixed with sodium carboxymethylcellulose and syrup to form a fine paste. The benzoic acid solution, the flavor and the dye are diluted with a little water and added with stirring.

Then enough water is added to produce the required volume. An aerosol solution is prepared which contains the following ingredients: Formulation 5: spray The active ingredient is mixed with the ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ° C and transferred to a filling device. The desired amount is then introduced into a stainless steel container and diluted with the rest of the propellant. Then the valve units are adjusted to the container.

Suppositories are prepared as follows: Formulation 6: suppositories The active principle is passed through a US sieve of No. 60 mesh, and is suspended in the saturated fatty acid glycerides which are previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold with a nominal capacity of 2 g and allowed to cool. An intravenous formulation is prepared as follows: Formulation 7: intravenous solution The dissolution of the above ingredients is administered intravenously to the patient.

GENERAL EXPERIMENTAL PROCEDURES The 1 H NMR spectra of 300 and 400 MHz were recorded using a Varian Unity + 300 or 400 spectrometer (Varian Co., Palo Alto, CA), equipped with two RF channels, indirect detection, and gradients of Pulsed field (only the Z axis). The spectra were generally achieved close to the ambient temperature (21 ° C), and the conventional auto-blocking and autofocus routines were used for the out-of-focus samples. Chemical shifts are expressed in parts per million downstream of trimethylsilane. The shapes of the peaks are indicated as follows: s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; sa, wide singlet. The so-called interchangeable resonances do not appear in a separate NMR experiment, in which the sample was stirred with several drops of D2O in the same solvent. The chemical ionization mass spectra at atmospheric pressure (APCIMS) were obtained on a Fisons Platform II or Micromass ZMD spectrometer (Microsmass, Manchester, United Kingdom). When the intensity of the ions containing chlorine or bromine is described, the expected intensity ratio (approximately 3: 1 for the ion containing 13CI / 37CI, and 1; 1 for the ion containing 79Br / 81Br) was observed, and M is based on 35CI and 79Br. In some cases, only the 1H NMR and representative APCIMS peaks appear. Column chromatography was carried out on Baker silica gel (40 μm) (J.T. Baker, Phillipsburg, NJ) or on silica gel 60 (EM Sciences, Gibbstown, NJ), on glass columns or on Flash 12, 40 or 75 columns (Biotage) (Charlottesville, VA) at low nitrogen pressure. Radial chromatography was carried out using a Chromatotron (Harrison Research, Palo Alto, CA). Unless otherwise specified, the reagents were used as obtained from commercial sources. The dimethylformamide, 2-propanol, methanol, dimethyl sulfoxide, 1,2-dichloroethane, tetrahydrofuran, toluene, dichloromethane and other reaction solvents were of anhydrous quality, supplied by Aldrich Chemical Company (Milwaukee, Wisconsin). The microanalyses were carried out at Schwarzkopf Microanalytical Laboratory, Woodside, New York. The terms "vacuum concentrate" and "vacuum removed" refer to the removal of the solvent under reduced pressure in a rotary evaporator with a bath at a temperature of less than 90 ° C. Reactions that were carried out at "0-20 ° C" or "0-25 ° C" were performed with an initial cooling of the vessel in an isolated ice bath, which was allowed to warm to room temperature for several hours. The abbreviations "min" and "h" mean "minutes" and "hours", respectively.

EXAMPLE 1 5-Amino-2-quinolone hydrochloride A solution of 5-nitro-2-quinolone (12.37 g, 65 mmol) (prepared as described in Capps, JD, Hamilton, CS, J. Am. Chem. Soc, 1938, 60, 2104) in EtOH (176 ml. ) under a nitrogen atmosphere, was treated with SnCl2-2H2O (73.4 g, 325 mmol). The heterogeneous reaction mixture was allowed to stir at 23 ° C for 2 hours, and was heated to reflux for 2 hours. The resulting heterogeneous mixture was cooled to 23 ° C and filtered. The solid material was triturated in HCl (1 M aqueous, 78 mL, 78 mmol) at reflux for 1 hour, it was cooled to 23 ° C and filtered to yield 10.08 g of the desired product (78% yield). 1 H NMR (400 MHz, DMSO-d 6) • 6.42 (d, J = 10, 1 H), 6.71 (d, J = 7.6, 1 H), 6.81 (d, J = 8, 1 H), 7.27 ( d, J = 8, 1 H), 8.04 (d, J = 10, 1 H), 11.71 (ss, 1 H). APCIMS 161 [M + 1] + EXAMPLE 2 5-Hydrazino-2-quinolone hydrochloride A solution of 5-amino-2-quinolone hydrochloride (10.08 g, 51.2 mmol) in HCl (concentrate, 42.7 ml) and H2O (18.2 ml) at 0 ° C was treated dropwise with a solution of NaNO2 (3.53 g). , 51.2 mmol) in H2O (26.4 ml), while maintaining the temperature below 5 ° C. The resulting red suspension was allowed to stir at 0 ° C for 1 hour. In another three-necked round bottom flask equipped with a mechanical stirrer, a suspension of SnCl2.2H2O (25.41 g, 112.6 mmol) in HCl (concentrate, 34.2 ml) and H2O (93.9 ml) was cooled to 0 ° C. The suspension was treated dropwise with the red diazonium salt suspension prepared above, while maintaining the temperature below 5 ° C. The reaction mixture was heated to 23 ° C and allowed to stir for 3 hours. The resulting suspension was filtered. The collected solid was triturated with HCl (1 M aqueous, 61.4 ml, 61.4 mmol) at 23 ° C for 30 minutes. The solid is collected by filtration, to yield 7.88 g of the desired product (73% yield). 1 H NMR (400 MHz, DMSO-d 6) • 6.43 (d, J = 10, 1 H), 6.63 (d, J = 8, 1 H), 6.88 (d, J = 8, 1 H), 7.38 ( t, J = 8, 1 H), 7.98 (d, J = 10, 1 H), 8.97 (sa, 1 H), 10.40 (sa, 1 H), 11.77 (sa, 1 H). APCIMS 176 [M + 1] + EXAMPLE 3 Methyl 5-cyclopropyl-1- (2-quinolone-5-H) -1 H -prazole-4-carboxylate A solution of methyl 3-cyclopropyl-2- (dimethylaminomethylene) -3-oxopropanoate (7.85 g, 39.8 mmol) in EtOH (257 ml) was treated under a nitrogen atmosphere with triethylamine (7.77 ml, 55.8 mmol), followed by 5-hydrazino-2-quinolone hydrochloride (7.88 g, 37.2 mmol). The resulting heterogeneous reaction mixture was refluxed for 4 hours and cooled to 23 ° C. A pale yellow solid precipitated and was collected by filtration to yield 5.06 g of the desired product (44% yield). 1 H NMR (300 MHz, DMSO-d 6) • 0.59-0.73 (m, 4 H), 1.87 (m, 1 H), 3.79 (s, 1 H), 6.54 (d, J = 10, 1 H), 7.17 (d , J = 10, 1H), 7.34 (d, J = 7.5, 1 H), 7.49 (d, J = 8, 1 H), 7.66 (t, J = 8, 1H), 8.08 (s, 1H), 12.10 (sa, 1H). APCIMS 310 [M + 1] + EXAMPLE 4 5-Cyclopropyl-1- (2-quinolone-5-ll) -1H-pyrazole-4-carboxylic acid A suspension of methyl 5-cyclopropyl-1- (2-quinolone-5-yl) -1H-pyrazole-4-carboxylate (5.06 g, 16.4 mmol) in THF (81.8 mL) and MeOH (40.9 mL) was treated with LiOH (1 M aqueous, 81.8 mL, 81.8 mmol) and heated to reflux for 2.5 hours. The resulting heterogeneous mixture was cooled to 23 ° C. The MeOH and THF were removed in vacuo. The resulting suspension was cooled to 0 ° C and acidified to pH 3-4 using HCl (concentrate). The mixture was filtered. The solid was dried to yield 4.94 g of the desired product (100% yield). 1 H NMR (400 MHz, DMSO-d 6) • 0.58 (d, J = 4.4, 2H), 0.64 (d, J = 8, 2H), 1.82 (m, 1H), 6.50 (d, J = 10, 1H ), 7.12 (d, J = 10, 1H), 7.27 (d, J = 7.6, 1H), 7.44 (d, J = 8.4, 1 H), 7.60 (t, J = 8, 1H), 7.97 (s) , 1H), 12.03 (sa, 1 H), 12.38 (sa, 1H). APCIMS 296 [M + 1] + EXAMPLE 5 Hydrochloride of r5-cyclopropyl-1- (2-quinolone-5-yl) -1 H -pyrrazole-4-carbonylauanidine A solution of 5-cyclopropyl-1- (2-quinoIon-5-yl) -1H-pyrazole-4-carboxylic acid (13.27 g, 45.0 mmol) in SOCI2 (60 mL) was refluxed for one hour. The SOCfe excess was removed under vacuum. The residue was treated with dry toluene and concentrated in vacuo. A solution of the solid residue in THF (50 ml) was treated with a solution of guanidine hydrochloride (15.47 g, 162 mmol) in NaOH (2 M aqueous, 162 ml, 324 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 23 ° C for 2 hours. The reaction mixture was then concentrated in vacuo to remove THF. The aqueous layer was cooled to 0 ° C and acidified to pH 9. A pale yellow solid precipitated and was collected to yield 11.41 g of the free base of the desired compound. A solution of the solid in MeOH (700 ml) was treated with HCl (1 M in ether, 84.9 ml, 84.9 mmol). The volume of the solvent was reduced in vacuo. The resulting pale brown precipitate was collected to yield 8.49 g (51% yield) (more product can be obtained as the free base by extraction of the aqueous layer using EtOAc-THF (1: 1). MHz, DMSO-d6) • 0.51 (m, 2H), 0.70 (dd, J = 2, 8.4, 2H), 1.92 (m, 1 H), 6.53 (dd, J-1.6, 10, 1H), 7.17 ( d, J = 10, 1 H), 7.32 (d, J = 7, 1 H), 7.48 (d, J = 8.4, 1 H), 7.64 (t, J = 8.2, 1 H), 8.34 (sa, 2H), 8.60 (sa, 3H), 11.64 (s, 1H), 12.10 (s, 1H). APCIMS 337 [M + 1] + EXAMPLE 6 Identification of [5-cyclopropyl-1- (2-quinolon-5-yl) -1H-pyrazole-4-carbonipquanidine in human plasma samples by liquid chromatography (LCV mass spectroscopy (MS) / MS v LC / NMR Human subjects were dosed intravenously with [5-cyclopropyl-1- (quinolin-5-yl) -1H-pyrazoyl-4-carbonyljguanidine monohydrate monohydrochloride. The human plasma samples were pooled and the proteins were precipitated by a double volume of acetonitrile. After centrifugation, the supernatant was collected in a water bath with N2 at 40 ° C. An aliquot (100 μl or 50 μl) of the concentrated sample was injected onto an LC / MS / MS instrument equipped with a 4.6 x 150 mm Zorbax Rx-C8 column, analyzed on a PE Sciex API 2000 or Finnigan mass spectrometer LCQ, and was controlled by a UV detector at 254 nm. The eluent of the column was divided, so that 5% of the eluent was diverted to the mass spectrometer and the rest was passed to the UV detector. The analyzes were carried out using a flow rate of the mobile phase of 1 ml / minute, and the mobile phase consisted of 5 mM ammonium formate (pH 3.0) as solvent A and acetonitrile as solvent B. One gradient included 5/95 to 40/60 B / A for a period of 20 minutes after an initial 3 minute stop. Under these LC conditions a metabolite was detected with a retention time of 11.8 minutes ([5-cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carbonyl] guanidine was detected at 13.7 minutes) . The 16 mass units of difference between [5-cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carbonyl] guanidine (m / z 321) and the metabolite (m / z 337) in human plasma suggest that it is formed by oxidation. The LC / MS / MS ion spectrum of the protonated metabolite at m / z 337 ([M + H] +) shows ion fragments at m / z 278, 260, 250, 236, 223 and 208. The salts were removed from the Previous concentrated sample by solid phase extraction. The sample was concentrated to contain approximately 5-10 μg of the metabolite. 50 μl of this sample was injected on 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 controlled by a UV detector at 235 nm. The analyzes were carried out using a flow rate of the mobile phase of 1 ml / minute, and the mobile phase consisted of 15 mM deuterated aqueous formic acid adjusted to pH 3.3 with deuterated ammonium hydroxide in D2O as solvent C, and acetonitrile-d3 as solvent D. A gradient included 5/95 to 20/80 D / C for a period of 17 minutes after an initial 3 minute stop. The desired metabolite was captured on the NMR probe using the peak flow arrest technique at 13.6 minutes. The proton NMR spectra and the COZY spectra of the human metabolite contained two doublets (6.64 and 7.41 ppm) were coupled to each other, but not to other peaks. The absence of the downfield peak at 8.92 ppm, which is present in [5-cyclopropyl-1- (quinolin-5-yl) -1H-pyrazole-4-carbonyl] guanidine, suggests that the position 2 of the ring of the Quinolein is the site of oxidation. Based on these data, the metabolite structure was determined as [5-cyclopropyl-1- (2-quinolone-5-y!) - 1 H -pyrazole-4-carbonyl] guanidine. Comparison of the 1H LC / NMR spectrum of the metabolite with that of a synthetic hydrochloride standard of [5-cyclopropyl-1- (2-quinolone-5-yl) -1H-pyrazole-4-carbonyl] guanidine, prepared as described in example 5, confirmed the structural determination.

Claims (30)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula its prodrug, or a pharmaceutically acceptable salt of said compound or said prodrug, with the proviso that [5-cyclopropyI-1- (quinolin-5-yl) -1H-pyrazole-4-carbonyl] guanidine is not included .

2. The [5-cyclopropyl-1- (2-quinolon-5-yl) -1H-pyrazole-4-carbonyljguanidine, or its pharmaceutically acceptable salt.

3. The use of a compound of claim 1, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug for the manufacture of a medicament for reducing the incidental lesions resulting from ischemia or hypoxia in a mammal.

4. The use as claimed in claim 3, wherein the tissue is cardiac, cerebral, hepatic, renal, pulmonary tissue of the intestine, Skeletal, splenic, pancreatic, nervous, spinal, retinal, vasculature or intestinal muscle.

5. The use as claimed in claim 3, wherein the compound of claim 1, its prodrug, or a pharmaceutically salt Acceptable of said compound or of said prodrug is administrable in an amount from about 0.01 mg / kg / day to about 50 mg / kg / day.

6. The use as claimed in claim 5, wherein the mammal is a woman or a man.

7. The use as claimed in claim 6, wherein said tissue is cardiac tissue.

8. The use as claimed in claim 6, wherein said tissue is brain tissue.

9. The use as claimed in claim 6, wherein said tissue is liver tissue.

10. The use as claimed in claim 6, wherein said tissue is renal tissue.

11. The use as claimed in claim 6, wherein said tissue is lung tissue.

12. The use as claimed in claim 6, wherein said tissue is intestinal tissue.

13. The use as claimed in claim 6, wherein said tissue is skeletal muscle tissue.

14. - The use as claimed in claim 6, wherein said tissue is tissue of the spleen.

15. The use as claimed in claim 6, wherein said tissue is pancreatic tissue.

16. The use as claimed in claim 6, wherein said tissue is retinal tissue.

17. The use as claimed in claim 6, wherein the compound is administrable prophylactically.

18. The use as claimed in claim 6, wherein the compound is administrable before surgery.

19. The use as claimed in claim 6, wherein the compound is administrable before cardiac surgery.

20. The use as claimed in claim 6, wherein the compound is administrable during surgery.

21. The use as claimed in claim 6, wherein the compound is administrable during cardiac surgery.

22. The use as claimed in claim 6, wherein the compound is administrable in the twenty-four hours following surgery.

23. The use as claimed in claim 6, wherein the compound is administrable in the twenty-four hours following cardiac surgery.

24. The use as claimed in claim 6, wherein the tissue lesions resulting from ischemia are ischemic lesions and occur during organ transplantation.

25. The use as claimed in claim 6, wherein the compound is administrable to prevent perioperative myocardial ischemic injuries.

26. A pharmaceutical composition comprising an amount of the compound of claim 1, its prodrug, or a pharmaceutically acceptable salt of said compound or of said prodrug, and a pharmaceutically acceptable carrier, vehicle or diluent.

27. A pharmaceutical composition for the reduction of the tissue lesions resulting from the squemia or hypoxia, comprising a therapeutically effective amount of the compound of claim 1, its prodrug, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier, vehicle or diluent.

28. The use as claimed in claim 6, wherein the compound is administrable before, during and after surgery.

29. The use as claimed in claim 6, wherein the compound is administrable before, during and after cardiac surgery.

30. The substantially pure [5-cyclopropyl-1- (2-quinolon-5-yl) -1H-pyrazole-4-carbonyl] guanidine, or a pharmaceutically acceptable salt of said compound.