UA73348C2 - Sodium-hydrogen exchanger inhibitor of the type 1 (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

Description of the invention

This invention relates to sodium-ion exchanger type 1 inhibitor (NSE-1). 2 Ischemic myocardial injury can occur in ambulatory patients as well as in perioperative patients and can lead to sudden death, myocardial infarction, or congestive heart failure. There is an ongoing medical need to prevent or reduce myocardial ischemic injury, particularly perioperative myocardial infarction. It is expected that such therapy will help save many lives and reduce the number of hospitalizations, increase the quality of life and reduce the overall costs of health care for 70 high-risk patients.

Pharmacological cardioprotection is able to reduce the occurrence and development of myocardial infarction and disorders that occur during surgical interventions (perioperative). In addition to reducing myocardial damage and improving post-ischemic myocardial function in patients with coronary heart disease, Cardioprotection will also reduce the incidence of heart disease and death from myocardial infarction and disorders in 12 "at-risk" patients (those aged 65 , unaccustomed to physical exertion, with coronary heart disease, suffering from diabetes, hypertension) requiring non-cardiac surgical intervention.

The mechanism(s) responsible for the myocardial injury observed after ischemia and reperfusion is not yet fully understood.

There are many publications relating to the use of guanidine derivatives for the treatment of, for example, arrhythmias.

A recent patent application, PCT//B99/00206, published under No. U/O 99/43663 on September 2, 1999, the disclosure of which is incorporated herein by reference, relates to various MNE-1 inhibitors including (b-cyclopropyl-1-(quinoline -5-yl)-1H-pyrazole-4-carbonylguanidine. The publication also mentions that "preferred salts of the compound just mentioned are the mono- or dimesylate salts" One group of preferred He) compounds, which are the hydroxyquinoline compounds, is described in paragraph 102 of the published application. Of course, some of these hydroxyquinolines can exist in several tautomeric forms, such as the quinolone form, as described in this patent application. In addition, Commonly Assigned Patent Application Ser. No. 60/162,374, filed October 29, 1999, relates to crystalline forms of the MNE-1 inhibitor described above. co

Application PCT/PO7/04650 published on June 25, 1998 relates to M-I(substituted five-membered "His heteroaryl)|guanidines useful as inhibitors of Ma"/H" exchange and therefore used for the treatment of various diseases, such as hypertension, arrhythmia, angina pectoris , myocardial infarction, arteriosclerosis and complications caused by diabetes. Go)

Thus, there is a need and the search in this field continues for compounds suitable for the treatment of perioperative myocardial ischemia. -

This invention relates to a compound of Formula (d) mne

Zh « / і ki Mne - - vychi. is" Co Formula "My - its prodrug form or a pharmaceutically acceptable salt of the mentioned compound or the mentioned prodrug oo form, provided that it does not contain |(5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazol-4- carbonylguanidine.

As used herein, the phrase "a prodrug form thereof or a pharmaceutically acceptable salt of said compound and or said prodrug form" includes the condition that does not contain 20 β-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazol- 4-carbonylguanidine.

This invention also relates to substantially pure co (b-cyclopropyl-1-(2-quinolon-5-yl)-1-yl-pyrazole-4-carbonyl) uanidine or a pharmaceutically acceptable salt of said compound.

Alternatively, the above mentioned compound is called 25 β-cyclopropyl-1-(2-quinolon-5-yl)-1H-pyrazole-4-carbonyl|guanidine. The preferred salt is hydrogen chloride

F! acid, and most preferably, the monohydrochloride salt.

Another aspect of the present invention is a method of treating a mammal (for example, a human) having a disease or condition mediated by MNE-1 by administering to the mammal a therapeutically effective amount of a compound of Formula

And, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of reducing tissue damage (eg, significantly preventing tissue damage, including tissue protection) due to ischemia, which comprises administering to a mammal (eg, male or female) in need of such treatment a therapeutically effective amount of a compound

Formula I!, its prodrug form or a pharmaceutically acceptable salt of the said compound or said prodrug form.

The predominant ischemic tissues, taken individually or in a group, are tissues of the heart, brain, liver, kidney,

lungs, intestines, skeletal muscle, spleen, pancreas, nerve tissue, spinal cord tissue, retina, blood vessels or intestines. The tissue of the heart is a particularly prevalent ischemic tissue. It is particularly preferred that the compound of Formula I, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form is prescribed for the prevention of perioperative ischemic damage to the myocardium.

Preferably, the compound of Formula I, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form is prescribed for prophylactic purposes.

Ischemic injury can occur during organ-to-organ or patient-to-organ transplantation.

Preferably, a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound 70 or said prodrug is administered prior to, during, and/or shortly after initiation of cardiac or non-cardiac surgery.

In one aspect of the present invention, the compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form is administered locally.

A preferred dose of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said 7/5 bpoluka or said prodrug form is from about 0.01 to 100μ/kg/day. A particularly preferred dose of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form is from about 0.01 to 5 Ω/kg/day.

Another aspect of the present invention relates to a method of reducing myocardial tissue damage (eg, significantly preventing tissue damage, including tissue protection) during surgery (eg, coronary artery bypass grafting (CABG), vascular surgery, percutaneous transluminal coronary angioplasty (PTCA), transplantation organ or other non-cardiac operations), which consists in administering to a mammal (eg, male or female) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug.

Another aspect of the present invention relates to a method of reducing myocardial tissue damage (for example, significant prevention of tissue damage, including tissue protection) in patients suffering from heart disease (acute coronary syndrome, such as myocardial infarction or unstable angina pectoris) or i) cerebral ischemic manifestations (e.g., a shot) comprising administering to a mammal (e.g., male or female) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug. Another aspect of the present invention relates to a method of permanently reducing myocardial tissue damage (e.g., significantly preventing tissue damage, including tissue protection) in patients diagnosed with coronary heart disease (e.g., preceding myocardial infarction or unstable angina) or patients with have a high risk of myocardial infarction (e.g., age 265 and more than two risk factors for coronary heart disease), which consists in administering to a mammal (e.g., male or female) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable i- salts of the mentioned compound or the mentioned prodrug form.

Another aspect of the present invention relates to a method of preventing ischemic damage, which consists in the continuous oral administration by a mammal in need of such treatment of a therapeutically effective amount of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said "prodrug form." Another aspect of the present invention relates to a method of treating cardiovascular diseases, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula |, its;» prodrug form or pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating atherosclerosis, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula I, its prodrug form -I or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating hypertension, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula I, its prodrug form 2) or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating arrhythmia, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula I, its prodrug form c or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating angina, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating cardiac hypertrophy, which consists in the appointment

F) to a mammal (for example, male or female) a therapeutically effective amount of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating kidney diseases, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating complications caused by diabetes, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula |, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form. 65 Another aspect of the present invention relates to a method of treating restenosis, which consists in administering to a mammal (eg, male or female) a therapeutically effective amount of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating diseases caused by cell proliferation, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound

Formula I!, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating cancer, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form. 70 Another aspect of the present invention relates to a method of treating fibrosis, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating glomerular nephrosclerosis, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula |, its /5 prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating pulmonary fibrosis, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating cerebroischemic disorders, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating a heart attack, which consists in administering to a mammal (eg, male or female) a therapeutically effective amount of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form. high school

Another aspect of the present invention relates to a method of treating myocardial dysfunction, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula I, its prodrug i) form, or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating cerebrovascular diseases, which consists in administering to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula |, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form.

Another aspect of the present invention relates to a method of treating hypertrophy or hyperplasia of an organ, which consists in - prescribing to a mammal (for example, a man or a woman) a therapeutically effective amount of a compound of Formula |, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form.

This invention also relates to pharmaceutical compositions containing a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable carrier, solvent, or diluent.

This invention also relates to pharmaceutical compositions for reducing tissue damage as a result of ischemia containing a therapeutically effective amount of a compound of Formula I, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form and a pharmaceutically acceptable carrier, solvent or diluent. By "reduction" is meant partial prevention or prevention that, although greater than no compound or placebo, is less than 10095, in addition to essentially total;" prevention.

The term "damage as a result of ischemia, as used here, refers to conditions directly caused by a decrease in blood flow to a tissue, for example, as a result of a thrombus or blockage of blood vessels through which blood is supplied to the specified tissue and, as a result, ipieg aa, a decrease in transport of oxygen to such tissue, tissue damage, tissue dysfunction, and/or necrosis.Alternatively, when blood flow or organ perfusion is quantitatively adequate, the ability of blood to carry oxygen or the medium to perfuse the organ may be reduced, for example, with environmental hypoxemia, such as that the supply of oxygen to the tissues

Decreased, causing tissue damage, tissue dysfunction, and/or tissue necrosis. The term "treatment" or "therapy" as used herein includes prevention (eg, prophylactic) and palliative 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, di lactate, tartrate, citrate, gluconate , methanesulfonate (mesylate) and 4-toluenesulfonate. Since more than one primary functional group may be present, the term includes complex salts (eg, disalts). The term also (F) refers to non-toxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathines (M,M'-dibenzylethylenediamine), cholines, ethanolamines, diethanolamines, ethylenediamines, meglamines (M -methylglucamines), benetamines (M-benzylphenethylamines), piperazines or tromethamines (2-amino-2-hydroxymethyl-1,3-propanediol).

The expression "prodrug form" refers to compounds that are precursors, which, after administration, release the drug ip mimo due to some chemical and physiological processes, for example, the prodrug under the influence of physiological pH or the action of an enzyme is transformed into a drug. Again, provided that it does not contain (b-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonylguanidine. 65 The term "pharmaceutically acceptable" refers to a carrier, diluent, excipient and/or salt that should be compatible with the other ingredients of the formulation, and which are not harmful to the person using them.

As used herein, the terms "reaction-inert solvent" and "inert solvent" refer to a solvent or solvent mixture that does not interact with starting compounds, reactants, intermediates, or products in a manner that adversely affects the yield of the desired product.

It should be understood that the compounds of the present invention may exist in radiolabeled form, that is, the compounds may contain one or more atoms having an atomic mass or atomic number that differs from the atomic mass or mass number commonly found in nature. The radioisotopes of hydrogen and carbon are 2H, ЗН and "С, respectively. The compounds of the present invention, which contain these radioisotopes and/or other radioisotopes of other atoms, fall within the scope of the present invention. The radioisotopes of tritium, i.e., ЗН, and carbon-14, i.e., 11b , are 70 particularly preferred due to the ease of their preparation and detection. A radiolabeled compound of the Formula can be prepared using techniques well known to those skilled in the art. Accordingly, such radiolabeled compounds can be prepared using the techniques described in the Schemes and/or in the Examples below by substituting a readily available isotopically labeled reagent the reagent is not labeled with the isotope.

Other features and advantages will be clear from the description and claims that disclose the invention.

Compound Formula | is a human metabolite of β-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyliguanidine. it was identified in human plasma samples obtained after intravenous administration of (b-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl|iguanidine to humans. The structure of this compound was independently confirmed by chemical synthesis. in another aspect of the present invention (b-cyclopropyl-1-(2-quinolon-5-yl)-1H-pyrazole-4-carbonyl|iguanidine can be obtained by introducing |b-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole -4-carbonyl|h uanidine into a human and isolating the desired metabolite from the plasma Alternatively, there is no need to isolate the metabolite from the human after it has been produced ip mimo.

Usually, the compound of the present invention can be obtained by methods that include methods similar to those known from the chemical literature, in particular, in light of the description given here. Some methods of obtaining the compound of the present invention are provided by the following invention and are illustrated by the following reaction scheme. Other methods are described in the experimental part. at

The following is a detailed description of the synthetic aspect of the invention: . nn in - 02-h iy o o g o "

And 'I so (ery ov rai o "in i-

And no

H-- " he ov' g g GA « tu nn: goes o, s o - o N o ;" m u

According to the scheme given above, the compound of formula IA (obtained as described in Sarrz, 9U.0.; Natiop, S.5. 3). At. Spent Zos. 1938, 60, 2104) is dissolved in a protic solvent such as ethanol and treated with an acceptable reducing agent such as stannous chloride dihydrate. The resulting mixture is stirred at a temperature of about 02C to about 11523 for about 30 minutes to about 24 hours.

The resulting mixture is cooled to approximately 232C and filtered. The resulting solid is purified by a suitable means, such as treatment with hydrochloric acid (e.g., 1M aqueous solution) at about 20 1002C for about 1 hour, cooled to about 232C, and filtered to give a compound of the formula

IP in the form of its hydrochloride salt. Alternatively, the compound of formula I can be isolated from the reaction mixture in the form of a free base by basing with an inorganic base and extracting with an acceptable organic solvent. The compound of formula II can be isolated in the form of other salts. Other reduction methods that will provide this reduction are known to those skilled in the art, and one example is catalytic hydrogenation. 29 The compound of Formula II is diazotized in hydrochloric acid and water using sodium nitrite at a temperature

HF) at about 02C for about 15 minutes to about 2 hours. The resulting diazonium salt solution is reduced with a suitable reducing agent such as stannous chloride dihydrate in hydrochloric acid and water at a temperature of about 02C to about 232C for about 30 minutes to about 6 hours.

The resulting solid is collected by filtration using an acceptable method such as trituration with 60% hydrochloric acid (e.g., 1M aqueous solution) at about 232 for about

30 minutes. The compound of formula III is collected by filtration in the form of a hydrogen chloride salt. Alternatively, the compound of formula I can be isolated from the reaction mixture in the form of a free base by basing with an inorganic base and extracting with an acceptable organic solvent. The compound of formula IP can also be isolated in the form of other salts. Other reducing agents to be used in this conversion will be known to those skilled in the art.

The compound of formula IM is prepared by methods known to a person skilled in the art, such as the reaction of a dialkyl acetal of M,M-dialkylformamide, for example, of a dimethyl acetal of M,M-dimethylformamide with an ester

C-cyclopropyl-3-oxopropanoic acid at a temperature of about 232 to about 11593 for about 1 hour to about 4 hours in the presence or absence of an acid catalyst. Group B! and 2 is, respectively, any alkyl, cycloalkyl, cycloalkylalkyl or arylalkyl group. In addition, two 2 groups can be linked together to form a cyclic substituent.

A compound of formula IM is reacted with a compound of formula I in an alcoholic solvent such as ethanol at a temperature of from about 232C to about 11523 for about 15 minutes to about 12 hours. 70 When a compound of formula I is used as the hydrochloride salt, it is useful to carry out the reaction in the presence of an excess of a non-nucleophilic base such as triethylamine. The compound of formula M is collected by filtration. Alternatively, the compound of formula M can be isolated by other methods, such as concentration followed by the addition of water and extraction with a suitable organic solvent. Alternatively, a compound of formula M can be prepared using a compound of formula PS and other compounds in place of compound 75 of formula M, such as a compound in which the (BE22M group is replaced by a B2O group.

A compound of formula M is hydrolyzed with a base such as sodium or lithium hydroxide in a solvent such as water and/or methanol and/or THF at a temperature of about 232C or a higher temperature such as reflux for about 30 minutes to about 12 hours. The acid of formula MI is then isolated, for example, by removal of organic solvents, acidification and filtration. Alternatively, the compound of formula MI can be isolated from the reaction mixture by removal of the organic solvent, acidification and extraction with an acceptable organic solvent.

An acid of formula MI is condensed with guanidine in the presence of a suitable condensing agent. A suitable condensing agent transforms the carboxyl group into a reactive one that forms an amide bond in the reaction with an amine. with

A condensing agent can be a reagent that causes this condensation in one reaction flask when Ho) mix together carboxylic acid and guanidine. Examples of condensing agents are 1-"3-dimethylaminopropyl)-3-ethylcarbodiimidu-hydroxybenzotriazole hydrochloride (EOS/HVT), dicyclohexylcarbodiimide (OosSsSuhydroxybenzotriazole (HB), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline (EEBO) and diethylphosphoryl cyanide. The condensation is carried out in an inert solvent, preferably an aprotic solvent, at a temperature of from about -202C to about 502C for about 1 to about 48 hours, in the presence of an excess of guanidine as a base. Examples of solvents are acetonitrile, dichloromethane, dimethylsulfoxide, dimethylformamide, chloroform and their mixtures. Shk

The condensing agent can also be an agent that converts the carboxyl group into an activated group that is released and/or formed in the first step and further interacts with guanidine in the second step. Examples of such condensing agents and activated groups are thionyl chloride or oxalyl chloride, which give an acid chloride, cyanurofluoride, which gives an acid fluoride, or an alkyl chloroformate, such as isobutyl or isopropenyl chloroformate, or propanephosphonic anhydride (propanephosphonic anhydride, ACE) with a tertiary amine gives a mixed carboxylic acid anhydride , or carbonyldiimidazole, giving acylimidazole. "

If the condensing agent is oxalyl chloride, it is useful to use a small amount of dimethylformamide in C 70 as a cosolvent with another solvent (such as dichloromethane) that catalyzes the formation of the acid chloride. This activated acid derivative can be condensed by mixing the intermediate compound in an acceptable solvent together with an acceptable base. Acceptable solvent/base combinations are, for example, dichloromethane, dimethylformamide or acetonitrile or mixtures thereof in the presence of excess guanidine as a base.

Other acceptable solvent/base combinations are water or (C -C )alcohol) or a mixture thereof together with a -I 45 cosolvent such as dichloromethane, tetrahydrofuran or dioxane and a base such as sodium, potassium or lithium hydroxide in a sufficient amount of acid scavenger. which is formed during the reaction. The use of these (4) condensing agents and the appropriate 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 disclosure. These and other examples of conditions are useful for condensation

Mothers of carboxylic acids are described in Noirep-Uueu!Yi, Mo! KhM, ragi II, E. MUspezsp, Ed., b. Tneite Megapad, 1974, BIMyshOat; t» 20 m, VodapezKu, Rgtgipsirieev oi Reriide Bupipeviz, Zrgipdeg-Megiad, Vepip 1984; and Te Reriide5, Apaiuziv, zZupipeviz apa Viiodu (ed. E. Sgovz apa 9. Meieproheg), moYz 1-5 (Asadetis Rgevzv, MU 1979-1983). In one embodiment, the acid of formula MI is activated with an excess of thionyl chloride at about the 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 an excess of 99 guanidine hydrochloride and an inorganic base such as sodium hydroxide in tetrahydrofuran and water. Reactionary

GF) the mixture is stirred at 232C or at a higher temperature, such as reflux, for about 30 minutes to about 6 hours. The compound of formula I! isolated from this reaction mixture in different ways. For example, the reaction mixture is concentrated by removing THF; the aqueous layer is acidified to pHeO, and the solid is collected by filtration. Alternatively, a compound of the formula | can be 60 isolated by extraction with an organic solvent. The compound of the formula | can be transformed into the corresponding hydrochloride salt by treatment with a solution of methanol with hydrogen chloride in ether, and collection of the resulting solid by filtration or concentration. Other salts can be obtained in similar ways.

It should be clear to one skilled in the art that it is also possible to transform a compound of formula M directly into a compound of formula | by treating a compound of formula M with an excess of guanidine in an inert solvent such as an alcoholic solvent such as ethanol, or in the absence of solvent, at a temperature of from about 60°C to about 150°C.

It should be clear to one skilled in the art that the compound of Formula | can exist in several tautomeric forms. All such tautomeric forms are considered as part of the present invention. For example, all tautomeric forms of the carbonylguanidine substituent of the compound of Formula | are included in this invention. All tautomeric forms of the 2-quinolone substituent of the compound of Formula I, such as the 2-hydroxyquinoline form, are also included in this invention.

The starting materials and reagents for the compounds described above are readily available or can be readily synthesized by a person skilled in the art using well-known methods of organic synthesis. 70 In addition, when a compound of the present invention forms metabolites, hydrates, or solvates, they are also within the scope of the present invention.

Some compounds (for example, prodrugs) of the present invention are acids and they form a salt with a different pharmaceutically acceptable cation. Most of the compounds of the present invention are bases and can form a salt with various pharmaceutically acceptable anions. All such salts, including disalts, are within the scope of this 7/5 invention and can be obtained using generally known methods. For example, they can be obtained by a simple interaction of acidic and basic reagents in an aqueous, non-aqueous or partially aqueous environment. Salts are isolated by filtration, by precipitation from the solvent followed by filtration, evaporation of the solvent or, in the case of an aqueous solution, by lyophilization, depending on the circumstances.

A compound of formula I, a prodrug form thereof, or a pharmaceutically acceptable salt of said compound or said prodrug form inhibits the transport system of the sodium/proton (Mat/N) exchange system and is thus useful as a therapeutic or prophylactic agent for the treatment of diseases caused by the acceleration of the sodium transport system /proton (Mazh/Nya) exchange, for example, cardiovascular diseases

For example, atherosclerosis, hypertension, arrhythmia (for example, ischemic arrhythmia, arrhythmia due to myocardial infarction, arrhythmia after RTSA or after thrombosis, etc.), angina pectoris, cardiac hypertrophy, myocardial infarction,

Cardiac arrests (for example, cardiac arrests due to obstruction, acute cardiac arrest, cardiac hypertrophy, etc.), restenosis after RTSA, shock (for example, hemorrhagic shock, endotoxic shock, etc.)), kidney diseases (for example , diabetes mellitus, diabetic nephropathy, acute ischemic kidney injury, etc.), organ disorders caused by ischemia or ischemic reperfusion (for example, ischemic reperfusion of the heart muscle caused by disorders, acute kidney injury or disorders caused by surgery, He ) such as coronary artery bypass grafting (CABG), vascular surgery, organ transplantation, non-cardiac surgery or subcutaneous transluminal coronary angioplasty (PTCA)), cerebrovascular in diseases (for example, ischemic stroke, hemorrhagic stroke, etc.), cerebroischemic disorders (for example, "In disorders caused by cerebral infarction, disorders caused by cerebral palsy, as a complication or cerebral edema). A compound of Formula I, its prodrug form or a pharmaceutically acceptable salt and.

35 of said compound or said prodrug can also be used as an agent to protect the myocardium during coronary artery bypass surgery (CABG), vascular surgery, subcutaneous transluminal coronary angioplasty (PTCA), organ transplantation, or non-cardiac surgery.

Preferably, a compound of Formula I, a prodrug form thereof, or a pharmaceutically acceptable salt of said compound or said prodrug form can be used as an agent to protect the myocardium before, during, or after coronary artery bypass surgery (CABG), vascular surgery, subcutaneous transluminal bypass surgery coronary angioplasty (PTCA), organ transplantation or non-cardiac surgery. Preferably, a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug may be used to protect the myocardium in patients at high risk for cardiac disease (acute coronary syndrome, such as myocardial infarction or unstable angina) or cerebroischemic manifestations (for example, a stroke). Preferably, a compound of Formula I, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form can be used as agents for permanent protection of the myocardium in o patients with a diagnosis of coronary heart disease (for example, sudden myocardial infarction or unstable

He) angina) or patients who have a high risk of myocardial infarction (for example, age over 65 and 50 two or more risk factors for coronary heart disease). In addition, the compound of Formula I, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form is valuable due to its strong inhibitory effect on cell proliferation, for example, fibroblastoma cell proliferation and vascular smooth muscle cell proliferation. For this reason, a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug form is a valuable therapeutic agent in diseases in which cell proliferation is the primary or secondary cause and therefore may be useful as antiatherosclerotic agents, and in iF ) qualities of agents used in the treatment of late diabetic complications, cancers, and fibrosis, such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, glomerular nephrosclerosis, organ hypertrophy or hyperplasia, in particular, prostate hyperplasia or hypertrophy, pulmonary fibrosis, because complications are due diabetes or recurrent vasoconstriction after RTSA, or disease caused by endothelial cell damage.

The ability of a compound of Formula I, a prodrug form thereof, or a pharmaceutically acceptable salt of said compound or said prodrug form, as a medical agent in the treatment of diseases such as those disclosed herein in mammals (e.g., humans), e.g., myocardial protection during surgery or myocardial protection in b5 patients with a high risk of cardiac or cerebroischemic manifestations or permanent cardioprotection in patients with a diagnosis of coronary heart disease, demonstrated by the activity of the compound of Formula I, or a pharmaceutically acceptable salt of the mentioned compound in well-known ip miigo and other preclinical studies of cardioprotection | see ip mimo study described by Kieip, N. ei ai., Sigstiaop 92: 912-917 (1995); research on the isolated heart of Zspoi7, Moscow State University. ei ai., Sagaiomazciag Kezeagsp 29: 260-268 (1995); study of antiarrhythmic effect MazshakKe M. ei aI.,, At. 9. Rpuzioi!., 36: H2430-nH2440 (1994); NMR study of KoikKe ei ai.,

U. Tpogas. Sagaiomavzs. Zygu 112: 765-775 (1996)). Such studies also provide numerical values of the activity of a compound of Formula I, or a pharmaceutically acceptable salt of said compound or said prodrug form, which can be compared with the activity of other known compounds. The results of these comparisons are useful in determining dose levels for mammals, including humans, in the treatment of such diseases. 70 Measurement of human MNE-1 inhibition activity

The methodology for measuring human MNE-1 activity and inhibitory activity is based on the method described

UUaigop ei a!., At. U.RPuzioi., 24: 5229-05238, 1991), where MNE-mediated restoration of intracellular pH was measured by subsequent intracellular acidification. Thus, fibroblasts stably expressing human MNE-1 (Sotspiyop, | ei aiYi., Moi. Rpagtasoi., 44: 1041-1045 (1993) were placed on collagen, /5 which is covered with 96-well tablets (50,000/well) Her grown to confluence in nutrient medium (OMEM (Dulbecco's modified Eagle's medium) enriched with glucose, 1095 bovine embryo serum,

BOmc/ml of penicillin and streptomycin). The merged tablets were incubated for 30 min. at 37 2C with the pH-sensitive fluorescent probe VSESE (5 μM; Moieszczyag Rgobez, Eideppe, OK). ALL labeled cells were incubated for 30 min. at 372C in an acidic medium (70mM choline chloride, 300Mm MNaCl, 5mM KCl, 1mM Masi, 1.8mM 2oSac, 5Mm glucose, 10Mm NEREZ, pH7.5), and then placed in Ripogesepe Itadipud Riaie Keadeg (Moiiesciag

Oemisez, SA). ALL fluorescence was observed using radiation with excitation and emission wavelengths of 485 nm and 525 nm, respectively. Intracellular acidification was initiated by rapidly replacing the acidic medium with a reducing medium (120 mM Masi, 5 mM KS, iM Moasis, 1.8 nM Sasi, 1.8 nM glucose, LONM NEREZB, pH7.5) 4 the compound under study, and MNE-mediated reduction of Ha was monitored intracellular pH, as a result of a time-dependent increase in ALL fluorescence. The strength of inhibition of human MNE-1 activity was calculated as the concentration that reduces the restoration of intracellular pH by 50905 (ICo). Under these conditions, the MNE inhibitors amiloride and NOE-642, which had IC50 values for human MNE-1 of 5µM and 0.5µM, respectively, were studied. Compound Formula | in the above study, the ISvo value is 20 ohms. (se)

It was noted that short-term periods of coronary artery reperfusion after myocardial ischemia protect the heart from subsequent severe myocardial ischemia (Miggu et al., Sigstiaop 74: 1124-1136, 1986). This phenomenon C is known as preliminary preparation for ischemia. co

The therapeutic effect of the compounds of the present invention in preventing damage to heart tissue as a result of an ischemic stroke can be demonstrated by the method described in the article (Sagaiiomavzs. Kev., 28: 1057-1061, 1994), as was specifically described here. Cardioprotection, as indicated, by reducing myocardial infarction, can be induced pharmacologically using adenosine receptor agonists in selected regressively perfused rabbit hearts, which are used as an ip mygo model of previously prepared myocardial ischemia (ish ei aiYi., Sagaiomavzs. Kev., 28: 1057-1061, 1994). A study described below has shown that the active compound under investigation can also pharmacologically induce cardioprotection, 70 that is, reduce myocardial infarct size when injected into the isolated rabbit heart. The effect of the compound under investigation was compared with pre-prepared ischemia and the ATt1/AZ adenosine agonist, ARMEA m (m9-(2-(4-aminophenyl)ethyl|adenosine), which showed pharmacologically induced cardioprotection in the isolated rabbit heart ( Hm ei ai., Sagaiomavs. Kev., 28: 1057-1061, 1994).The exact method is described below.

The protocol used in these experiments is given in its entirety in Iish eyi a!., Sagaiomazs. Kev., 28: 1057-1061, 1994. Male white New Zealand rabbits (3-4 kg) were anesthetized with sodium pentobarbital (ZOmg/kg, - IV). After deep anesthesia (determined by the absence of the eye blink reflex), the animals were incubated and ventilated with 10095 O5 using a positive pressure ventilator. A thoracotomy was performed on the left side, the heart was opened, and a loop (silk 2-0), approximately 2/3 from the apex of the heart, was placed on the projection of the left coronary artery. The heart was removed from the chest and quickly ("ZOsek") placed in the Langendorff apparatus. The heart was retrogradely perfused for 50 minutes in a non-recirculating manner with a modified Krebs solution (mass 118.5 mM, KSI 4.7 mM, Ma5O,X 12 mM, KNORO, 1.2 mM, Mansoz 24.8 mM, CaCl 2.5 mM, and glucose 100 mM), with a constant with a pressure of 8 Ohm Na and a temperature of 372C. The pH of the perfusate was maintained within 7.4-7.5 by bubbling through it 9595 О5/595 СО".

Heart temperature was controlled using heated saline reservoirs and a water jacket around both perfusion tubes and the isolated heart. Heart rate and pressure in the main left ventricle were determined using a latex balloon inserted into the left ventricle and connected by a steel hose to a pressure sensor. The balloon located in the ventricle is pumped to obtain a systolic pressure of 80-100 mm Hg, and a diastolic pressure of less than 100 mm Hg. Also, the total coronary flow is continuously monitored using a linear flow probe and normalized based on the weight of the heart.

The heart is left to equilibrate on the LV, and during this time the heart should show a stable 60 pressure in the left ventricle within the parameters given above. If the heart rate drops below 180 beats/min. at any time ЗОхв. during the period of regional ischemia, the heart is stimulated to approximately 200 beats per minute. for the remainder of the experiment. Preliminary preparation for ischemia is caused by the general cessation of cardiac perfusion (global ischemia) on the right side, followed by reperfusion within 10 minutes. Regional ischemia is ensured by tightening the loop around the process of the coronary artery. Next come ЗОхв. of regional ischemia, the 65 loop is removed and the heart is reperfused for another 120 minutes.

Pharmacological protection of the heart is caused by the infusion of the compound being studied, in a predetermined concentration, starting from ZOkhv. to ЗОхв. regional ischemia, and continuing until the end of 120 min. reperfusion period. Hearts receiving the test compound were not subjected to a preconditioning period for ischemia. A control compound, ARMEA (500 nM) was perfused through hearts (which did not receive the test compound) for 5 min. after which they left for 1 Ohv. before ЗОхв. regional ischemia.

After 120 Ohv. reperfusion, the loop was removed from the coronary artery and a 0.595 suspension of fluorescent particles of zinc cadmium sulfate (1-1OμM) was perfused through the heart. (Rayu Ayu, SA); it stains the entire myocardium, except for areas at risk for the development of a heart attack (area at risk). The heart was removed from the Langendorff apparatus, subjected to dry marking, wrapped in aluminum foil and stored overnight at -202С on 7/0. The next day, the heart was cut into pieces of 2 mm in cross-section from the apex to the upper part of the ventricle. The pieces were labeled with 195 triphenytetrazolium chloride (TTT) in a phosphate-buffered saline solution for 2 hours. at 37 C. Since CTT reacts with living tissue (containing MAJU-dependent dehydrogenase), there is a difference between the color of living (red color) tissue and dead tissue (unstained infarcted tissue). The areas of the infarcted area (unstained) and the area 75 at risk (absent fluorescent particles) were calculated for each slice of the left ventricle using a pre-calibrated analyzer. To normalize ischemic injury for different risk areas of the heart, data were expressed as the ratio of infarct area to risk area (9501/OR). All data were expressed as 45E values and compared with the non-parametric Mann-Whitney test statistically used with correction

Bonferroni for multiple comparisons. Values of p "0.05" were considered.

The results of the above IP study can be used to demonstrate that the compounds of the present invention cause significant cardioprotection compared to the control group.

Administration of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug may be performed by any method that releases the compound

Formulas !, its prodrug form or a pharmaceutically acceptable salt of said compound or said He prodrug form preferably in the desired tissue (for example, liver and/or heart tissue). These methods include oral, parenteral, intraduodenal routes, etc. Typically, a compound of Formula |, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or said prodrug form is administered in single (eg, once daily) or divided doses or by continuous infusion in, for example, an isotonic saline solution. (uh)

A compound of Formula I, a prodrug form thereof, or a pharmaceutically acceptable salt of said compound or said prodrug form is useful, for example, in reducing or minimizing damage to any tissue that may be susceptible to ischemia/reperfusion injury (eg, heart, brain, lung, kidney, liver, Go) intestine, skeletal muscles, retina), for example, due to the mediation of MNE-1, and the consequence is ischemic manifestations (for example, myocardial infarction). Thus, the active compound is useful for prophylactically preventing, (ie, predicting or preventing) blunting or delaying tissue damage (eg, myocardial tissue) in patients at risk of ischemia (eg, myocardial ischemia).

Usually, the compound of Formula I, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form of the present invention is administered orally or parenterally (for example, "intravenously, intramuscularly, subcutaneously or intramedullary). Local administration may also be required, for example, when the patient suffers from gastrointestinal disorders or whenever the treatment is best applied to the surface of a tissue or organ, as determined by the physician. and The amount and mode of administration of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form to be administered will, of course, depend on the condition of the subject being treated, the complexity of the condition, the method of administration, and physician's judgment. Thus, since patients differ from each other, doses below the specified standard may be used, and the physician may determine such doses that achieve treatment that the physician considers to be appropriate for the patient. Taking into account the desired degree of treatment, the physician must take into account factors such as the patient's age, other medical conditions the patient has had, as well as other existing diseases (eg, (95) cardiovascular disease). of a pharmaceutically acceptable salt of said compound or said prodrug form that is effective in protecting against ischemia. an important dose is about 0.01 to 10 µM/kg/day of the compound

IR e) Formula !, its prodrug form or a pharmaceutically acceptable salt of the mentioned compound or the mentioned prodrug form of the present invention.

A particularly preferred dose is approximately 0.01 to 5 Ω/kg/day of the compound of Formula I, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form of the present invention.

In one method of administering a compound of Formula I, a prodrug form thereof, or a pharmaceutically acceptable salt of said compound or said prodrug form, it may be administered prior to cardiac surgery (e.g., within twenty-four hours before surgery), during, or immediately after surgery. on the heart (for example, within twenty-four hours after surgery) when there is a risk of myocardial ischemia. In a particularly preferred method of infusion, the infusion is administered using a dose of from about 1 mg to about 300 mg for about one minute to about one hour before surgery, followed by a continuous infusion of from about 1 µg/kg/day to about 100 µg/kg/day for the remainder of the time. before surgery, during surgery, and after surgery, including, for example, from about 2 to about 7 days after surgery.

The compound of the present invention can also be administered continuously throughout the day. 6E A compound of Formula I, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form is usually administered in the form of a pharmaceutical composition containing a compound of Formula I, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form together with a pharmaceutically acceptable solvent, carrier or diluent. Thus, a compound of Formula |, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form

Can be administered by any known oral, parenteral, rectal or transdermal dosage form.

For oral use, the pharmaceutical composition can be in 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 can be used together with various disintegrants such as 7/0 starch, preferably potato or tapioca starch, and some complex silicates, together with binding agents , such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting purposes. Solid compositions of this type can also be used as a filler in hard and soft gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as 7/5 V high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of the present invention are combined with various sweetening or flavoring agents, coloring agents or dyes, and, if desired, emulsifying and/or suspending agents, as well as diluents such as water , ethanol, propylene glycol, glycerin and various combinations thereof.

For parenteral administration, solutions of the compound in sesame or peanut oil or in an aqueous solution of propylene glycol can be used, 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 is first made isotonic using saline or glucose. Such aqueous solutions are particularly suitable for administration in the form of intravenous, intramuscular, subcutaneous and intraperitoneal injections. In this context, the preparation of all these solutions under sterile conditions is performed according to standard pharmaceutical techniques, which are well known to those skilled in the art.

For purposes of transdermal (e.g., topical) administration, dilute sterile aqueous or semi-aqueous solutions (usual concentration of about 0.195 to 595) or other similar parenteral solutions are obtained.

Known methods of preparing various pharmaceutical compositions with a specific amount of active ingredient or so will be apparent in light of this description to a person skilled in the art. For examples of methods of obtaining pharmaceutical compositions, see Ketipdiop's Rpagtaseciisa! Zsiepsez Mask Rybiizpipd Sotrapu, Eazieg, Ra., 150 Oedipus - (1975). with

Pharmaceutical compositions according to the invention may contain, for example, 0.000195-9596 of a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form. In any event, the composition or formulation to be administered will contain an amount effective to treat the disease/condition in the subject being treated.

Typically, a compound of Formula I, a prodrug form thereof, or a pharmaceutically acceptable salt of said compound or said prodrug form will be administered in a suitable formulation. Examples of formulations are provided below for illustrative purposes only and should not be construed as limiting the scope of the present invention. z c In the following recipes, the term "active ingredient" means a compound of Formula I, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form. ;" Recipe 1: Gelatin capsules

Large gelatin capsules are obtained using the following components: ! niya -I Ingredient Amount (mg/capsule)

Active ingredient 0.25-100 (95) Starch, NO 0o-650 g) Starch in the form of powder 0-50 iz 50 Liquid silicone 350 0-15 so The recipe for tablets is obtained using the following ingredients:

Recipe 2: Tablets

Ingredient Amount (mg/pills) 52 Active ingredient 0.25-100

GF) Cellulose, microcrystalline 200-650 g) Silicon dioxide 10-650

Stearic acid 5-15 bo The components are mixed and formed into tablets.

Alternatively, tablets containing 0.25-100 mg of the active ingredient are obtained as follows:

Recipe 3: Tablets

Ingredient Amount (mg/pills) b5 Active ingredient 0.25-100

Starch 45

Cellulose, microcrystalline 5

Polyvinylpyrrolidone (in the form of 1095 aqueous solution) 4

Sodium cellulose carboxymethyl 4.5

Magnesium stearate 0.5

Talc 1

The active ingredient, starch and cellulose are passed through a Mo45 mesh sieve and mixed. The solution of polyvinylrolidone is mixed with the resulting powder and the resulting mixture is passed through a Mo14 mesh sieve. 70 The granules obtained in this way are dried at 050-609 and passed through a Mo18 mesh sieve. Sodium starch carboxymethyl, magnesium stearate and talc are passed through a MobOo mesh sieve and added to the granules, after which everything is mixed and the resulting mixture is loaded into a tableting machine for obtaining tablets.

Suspensions containing 0.25-100 mg of active ingredient per 5 ml dose are obtained as follows:

Recipe 4: Suspensions and nya

Ingredient Quantity (mg/ml)

Active ingredient 0.25-100 mg

Sodium cellulose carboxymethyl Bomg

Syrup 1.25 mg

Benzoic acid solution O1Oml

Organoleptic corrector Yam.

Yam dye.

Purified water to Bml re The active ingredient is passed through a Mo45 mesh sieve and mixed with cellulose carboxymethyl sodium and syrup until a uniform paste is obtained. The benzoic acid solution, the organoleptic corrigent and the dye are diluted with a small amount of water and added while stirring. Then add a sufficient amount of water to obtain the required volume.

The following aerosol solution containing the following ingredients was obtained: so 20 Recipe 5: Aerosol "

Ingredient Amount (wt. 95)

Active ingredient 0.25 o

Ethanol 25.75 Geo)

Propellant 22 (Chlorodifluoromethane) 74.00 and -

The active ingredient is mixed with ethanol and a portion of propellant 22 cooled to 302 is added to the mixture and placed in a suitable vessel. The desired amount is then placed in a steel container and diluted with a sufficient amount of propellant. The charged container is equipped with a valve. "

Suppositories are obtained as follows: With c t0 Recipe 6: Suppositories

From" Ingredient Quantity (mg/suppositories)

Active ingredient 250

Glycerides of saturated fatty acids 2000 - The active ingredient is passed through a MobO mesh sieve and suspended when heated with glycerides of saturated fatty acids, using a minimum temperature. The mixture is poured into suppository molds with a content of 2g and cooled. o Intravenous formulation is obtained as follows: iz 20 Formulation 7: Solution for intravenous injection (Fe) Ingredient Quantity

Active ingredient 2BmMg

Isotonic salt solution 100 Oml

A solution containing the above ingredients is administered to the patient intravenously.

F, BASIC EXPERIMENTAL METHODS (name) 300 and 400 MHz "H NMR spectra were recorded on Magiap Opiu 300 or 400 spectrometers (Mapap So.,

Rayo AYU, SA) equipped with two RF channels, an indirect detector and pulsating field gradients (only along 60o axis 7). Spectra were usually taken at near room temperature (2122) and a standard autolock and autoshim controller were used to shim the samples. The chemical shift was expressed in parts per million relative to tetramethylsilane. The appearance of the peaks was marked as follows: c, singlet; d, doublet; t, triplet; k, quartet; m, multiplet; shs, wide singlet. Resonance was denoted as the ability to exchange, which is not manifested in separate NMR experiments, when several drops of 020 are added.

Mapspezieg, Sh.K.). When the intensity of chlorine- or bromine-containing ions is described, the expected ratio of intensities is observed (approximately 3:11 for ЗСИ/3/"C|I-containing ions and 1:11 for "Bg/9Bg-containing ions) and

M is based on SI and "Vu. In some cases, only "H NMR and HIATMS data are given.

Column chromatography was carried out either on VacKeg silica gel (40 µm) (9U.T. VacKeg, RPAyirerigo, M.).) or silica gel 60 (EM bZsiepsevs, (Sirrviomup, M.).) in a glass column or on Riazpy 12, 40 or 75 (Vioiade) (SpagiotsevzmuiShe, MA) columns under low nitrogen pressure. Radial chromatography was performed using

Spgothaiioigop (Naitizop Kezeagsi, Raio AMo, SA). Unless otherwise noted, reagents used were obtained from commercial sources. Dimethylformamide, 2-propanol, methanol, dimethylsulfoxide, 1,2-dichloroethane, tetrahydrofuran, toluene, dichloromethane, and other solvents used in the reactions as solvents were dehydrated and obtained from AiYidgis Spetis! Sotrapu (Mim'"aKee, MUUizsopvip).

Microanalysis was carried out using Zspulag2Koriya Misgoapaiumis! And aroghaiogu, MUoodzide, MU. "Vacuum concentration" and "vacuum evaporation" are understood to mean the removal of the solvent on a rotary evaporator with a water pump at a bath temperature of less than 902C. Reactions carried out at "0-202C" or "0-25907" began with cooling the flask with an ice bath, which was then removed, and the flask was heated to 75 room temperature for several hours. Under the abbreviation "min." and "r" mean "minutes" and "hours", respectively.

EXAMPLE 1

5-amino-2-quinolone hydrochloride

A solution of b5-nitro-2-quinolone (12.37g, b5mmol) (obtained as described in Sarrzv, 9U.O0.; Natiyop, S.5.U.At. 20 Spect. bos. 1938, 60, 2104) in EYUN (17 bml) was treated with ZpsSi oeNoO (73.4 g, 325 mmol) in a nitrogen atmosphere.

The heterogeneous reaction mixture was stirred at 232C for 2 hours and heated under reflux for 2 hours. The obtained heterogeneous mixture was cooled to 2329C and filtered. The solid was triturated with HCl (1M aqueous solution, 788ml, 78mmol) at reflux for 1 hour, cooled to 232°C and filtered to give 10.08g of the desired product (7895 yield). high school

TN nMR (400 MHz, DMSO-dv) 5 6.42 (5, 9-10, 1). 6.71 (d, U-7.6, 1H), 6.81 (d, 9-8, 1H), 7.27 (d, 9-8, (8) 1H), 8.04 (d, 9-10, 1H), 11.71 (shs, 1H).

HIATMS 161 |IMA1|"

EXAMPLE 2 5-hydrazino-2-quinolone hydrochloride

A solution of 5-amino-2-quinolone hydrochloride (10.08g, 51.2mmol) in NH (concentrated, 42.7ml) and NOO (18.2ml) was treated dropwise with Mamo solution (3.53g, 51, 2mmol) in HO (26.4ml) keeping the temperature at 9 below 52. The resulting red suspension was left at 02C and stirred for 1 hour.

In a separate three-necked round-bottom flask equipped with a mechanical stirrer, a suspension of 35 ZpSiI»eNioO (25.41g, 112.bmol) in NSII (concentrated, 34.2ml) and NgO (93.9ml) was cooled to 02. The suspension was treated dropwise with the red suspension of the diazonium salt obtained above, keeping the temperature below 5920. The reaction mixture was heated to 232C and stirred for 3 hours. The resulting suspension was filtered. The collected solid was triturated with HCl (1M aqueous solution, 61.4 ml, 61.4 mmol) at 232C for 30 minutes. The solid was collected by filtration to give 7.88 g of the desired product (7390 yield). - 70 TN NMR (400MHz, DMSO-dv) 5 6.43 (5, 9-10, 1H), 6.63 (d, 9-8, 1H), 6.88 (d, 9-8, 1H) , 7.38 (t, 9-8, 1H), s 7.98 (d, 9-10, 1H), 8.97 (shs, 1H), 10.40 (shs, 1H), 11.77 ( shs, 1H). :z" HIATMS 176 (MAG

EXAMPLE Z

Methyl 5-cyclopropyl-1 -(2-quinolon-5-yl)-1H-pyrazole-4-carboxylate -1 Solution of methyl 3-cyclopropyl-2-(dimethylaminomethylene)-33-oxopropanoate (7.85g, 39, 6 mmol) in EUN (257 ml) was treated under a nitrogen atmosphere with triethylamine (7.77 ml, 55.8 mmol), followed by 5-hydrazino-2-quinolone hydrochloride (95) (7.88 g, 37.2 mmol). The resulting heterogeneous reaction mixture was refluxed for 4 hours and cooled to 232. A pale yellow solid precipitate formed which was collected by filtration to give 5.06g of the desired product (4495 yield). o "H NMR (300 MHz, DMSO-iv) 5 0.59-0.73 (w 4H), 1.87 (m, 1H), 3.79 (s, 1H), 6.54 (d, 9- 10, 1H), 7.17 (d, o -10, 1H), 7.34 (d, 9- 7.5, 1H), 7.49 (d, 9-8, 1H), 7.66 ( t, 9-8, 1H), 8.08 (s, 1H), 12.10 (shs, 1H).

HIATMSSOZ19|M 1

EXAMPLE 4 5-Cyclopropyl-1-(2-quinolon-5-yl)-1H-pyrazole-4-carboxylic acid

A suspension of methyl 5-cyclopropyl-1-(2-quinolon-5-yl)-1H-pyrazole-4-carboxylate (5.06bg, 16b.4mmol) in THF (81.vml) and Meon (40.9ml) treated with GION (1 M aqueous solution, 81.8 ml, 81.8 mmol) and heated under reflux for 2.5 hours. The resulting heterogeneous mixture was cooled to 2320. Meon and THF were removed in vacuo. The obtained suspension was cooled to 09Сb and acidified to рНЗ-4 using НС bo (concentrated). The mixture was filtered. 4.94 g of solid of the desired product were obtained (10095 yield).

TN nMR (400 MHz, DMSO-dv) 5 0.58 (5, 9-44, 2H), 0.64 (d, 9-8, 2H), 1.82 (m, 1H), 6.50 (d , 9-10, 1H), 7.12 (d, 9-10.1H), 7.27 (d, 9U-7.6, 1), 7.44 (d, 92-84, 1H), 7 .60 (t, 9-8, 1H), 7.97 (s, 1H), 12.03 (shs, 1H), 12.38 (shs, 1H).

HIATMS 296 |MA1|" 65 EXAMPLE 5

Hydrochloride (|5-cyclopropyl-1-(2-quinolon-5-yl)-1H-pyrazole-4-carbonyl|guanidine

A solution of 5-cyclopropyl-1-(2-quinolin-5-yl)-1H-pyrazole-4-carboxylic acid (13.27g, 45.0mmol) in ZOSI" (bOml) was heated under reflux for 1 hour. The excess of 5OXI 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 Mahon (2M aqueous solution, 162 mL, 324 mmol) under nitrogen. The resulting mixture was stirred at 232 for 2 hours. The reaction mixture was concentrated in vacuo by removing THF. The aqueous layer was cooled to O2 and acidified to pHeO. The pale yellow solid precipitate was collected to give 11.41 g of the free base of the desired compound. A solution of the solid in Meon (700ml) was treated with NCI (1M in ether, 84.9ml, 84.9mmol). The volume of the solvent was reduced under vacuum. The resulting pale brown solid 70 was collected to yield 8.49 g (5195 yield). (Additional amount of free base can be obtained by extracting the aqueous layer using E(Fas-THF(1:1)). -2, 8.4, 2H), 1.92 (m, 1H), 6.53 (dd, 9-1.6, 10, 1H)U, 7.17 (d, 9-10, 1H), 7.32 (d, 9U-7, 1H), 7.48 (d, 9-84, 1H), 7.64 (t, 9U-8.2, 1H), 8.34 (shs, 2H), 8.60 (shs

ZN), 11.64 (s, 1H), 12.10 (s, 1H).

HIATMS 337 |MA1|"

EXAMPLE 6

Identification of |5-cyclopropyl-1-(2-quinolon-5-yl)-1H-pyrazole-4-carbonyl|iguanidine in human plasma samples by liquid chromatography (LC)/mass spectroscopy (MSMS and LC/NMR)

5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl|guanidine monohydrochloride monohydrate was administered intravenously to humans. Human plasma samples were combined and proteins were precipitated with two volumes of acetonitrile. After centrifugation, the supernatant was concentrated in a Mo water bath at 4020.

An aliquot (10 μl or 50 μl) of the concentrated sample was introduced into a LC/MS/MS device equipped with a 7-ogra BEx-S8 column 4.6x 150 mm, analyzed on a RE Zsieh ARI 2000 or Rippidap RHO mass spectrometer and controlled by SM using a UV detector with a wavelength of 254 nm. The eluent from the column was separated so that 595 g of the eluent (He) was fed to the mass spectrometer and the remainder was fed to the UV detector. Analyzes were carried out using a flow rate of the mobile phase Iml/minute, where the mobile phase contained 5 mM ammonium formate (pHZ,O) as solvent A and acetonitrile as solvent B. The gradient was 5/95-40/60 V/A for 20 minutes after the start of administration within 3 minutes. Under these conditions, LC detected a metabolite with a retention time of 11.8 minutes so (B-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl|iguanidine was detected at 13.7 minutes). The difference of 16 g mass units between (|5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl|guanidine (t/2 321) and the metabolite (t/2 337) of human plasma, that it is formed as a result of oxidation. The LC/MS/MS ion spectrum of the protonated me) metabolite with m/2 337 (IM--NI) showed the presence of ions with m/2 278, 260, 250, 236, 223, and 208.

Salts were removed from the above-mentioned concentrated sample using solid-phase extraction. Sample

Zo was concentrated to a metabolite content of approximately 5-1O0μg. 5 µm of this sample was injected into the LC/NMR device - equipped with a 7-ogra column of KhX-S8 4.6 x 150 mm, a VgyKeg analyzer of a 5O00 MHz NMR spectrometer and monitored using a UV detector with a wavelength of 235 nm. Analyzes were carried out using a flow rate of the mobile phase of 1 ml/minute, where the mobile phase contained 15 mM of a deuterated aqueous solution of formic acid with a pH of 3, prepared using deuterated ammonium hydroxide in 050, which was used as solvent B, and acetonitrile-dz, in quality of the solvent G. The gradient was 5/95-20/80 s V/G for 17 minutes after the start of administration for 3 minutes. The desired metabolite was captured by NMR analysis using a stopped-flow technique with a peak at 13.6 minutes. The proton NMR spectrum and CO5U spectrum of the human metabolite contained two doublets (6.64 and 7.41 ppm), which are related to each other, but not to any other peaks. The absence of the peak at 8.92 ppm present in the spectrum of 75 (b-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonylguanidine) confirms that the 2-position of the quinoline ring has undergone oxidation . Based on these data, the structure of the metabolite - (95) I(B-cyclopropyl-1-(2-quinolon-5-yl)-1H-pyrazole-4-carbonyl|iguanidine) was determined. Comparison of the "H LC/NMR spectrum of the metabolite with by the spectrum of its synthetic analogue hydrochloride (b-cyclopropyl-1-(2-quinolon-5-yl)-1H-pyrazole-4-carbonylguanidine, obtained as described in Example 5, thus confirming the structural correspondence.

IR e)

Claims (30)

The formula of the invention 1. Compound of Formula F) ime) 60 b5 o Mne; Formula Ж щ / Х M Mn, o M Схх Сг Мо n its prodrug form or a pharmaceutically acceptable salt of the mentioned compound or the mentioned prodrug form, provided that the specified compound is not (5-cyclopropyl-1-(quinolin-5-yl )-1H-pyrazole-4-carbonyl|guanidine. 2. The compound according to claim 1, which is (|5-cyclopropyl-1-(2-quinolon-5-yl)-1H-pyrazole-4-carbonyliguanidine, or its pharmaceutically acceptable salt. 3. A method of reducing tissue damage due to ischemia or hypoxia, in which a therapeutically effective amount of the compound according to point 1, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form is administered to a mammal in need of such treatment. Ha 4. The method according to point C, in which the tissue is the tissue of the heart, brain, liver, kidney, lung, intestine, skeletal muscle, spleen, pancreas, nerve tissue, tissue of the spinal cord, retina, blood vessels, or intestine. 5. The method according to point C, in which the amount of the compound according to point 1, its prodrug form, or a pharmaceutically acceptable salt of said compound or said prodrug form is from about ee) 0.01 μ/kg/day to about 50 μ/kg/ day. 6. The method according to item 5, wherein the mammal is male or female. M 7. The method of claim 6, wherein said tissue is heart tissue. co 8. The method of claim 6, wherein said tissue is brain tissue. 9. The method of claim 6, wherein said tissue is liver tissue. and. 10. The method of claim 6, wherein said tissue is kidney tissue. - 11. The method of claim 6, wherein said tissue is lung tissue. 12. The method of claim 6, wherein said tissue is intestinal tissue. 13. The method of claim 6, wherein said tissue is skeletal muscle tissue. " 14. The method of claim 6, wherein said tissue is spleen tissue. 15. The method of claim 6, wherein said tissue is pancreatic tissue. 8 p 16. The method of claim 6, wherein said tissue is nerve tissue. c 17. The method according to point 6, in which the compound is prescribed for prophylactic purposes. "» 18. The method according to item 6, in which the compound is administered before surgery. 19. The method of claim 6, wherein the compound is administered prior to cardiac surgery. 20. The method according to item 6, in which the compound is administered during a surgical operation. -AND 21. The method of claim 6, wherein the compound is administered during heart surgery. 22. The method according to point b, in which the compound is administered within twenty-four hours after a surgical operation. lake 23. The method of claim b, wherein the compound is administered within twenty-four hours after cardiac surgery. i.e 24. The method according to item 6, in which the tissue damage due to ischemia is ischemic damage, which is a consequence of organ transplantation. 25. The method according to item 6, in which the compound is prescribed to prevent perioperative ischemic damage to the myocardium. 26. A pharmaceutical composition that contains a compound according to point 1, its prodrug form or a pharmaceutically acceptable salt of the said compound or said prodrug form and a pharmaceutically acceptable F, carrier, solvent or diluent. co 27. A pharmaceutical composition for reducing tissue damage due to ischemia or hypoxia, which contains a therapeutically effective amount of a compound according to item 1, its prodrug form or a pharmaceutically acceptable salt of said compound or said prodrug form and a pharmaceutically acceptable carrier, solvent or diluent. 28. The method of claim 6, wherein the compound is administered before, during, and after surgery. 29. The method of claim 6, wherein the compound is administered before, during and after heart surgery. 30. The method of obtaining (|5-cyclopropyl-1-(2-quinolon-5-yl)-1H-pyrazole-4-carbonyl|Iguanidine, which consists in introducing (5-cyclopropyl-1-(quinolin-5-yl )-1H-pyrazole-4-carbonyliguanidine in humans. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 7, 15.07.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. c o c " so so and - shi s ;" -I (95) (95) iz 50 IR e) F) name) 60 b5