Ethanolate n-(5-cyclopropyl-1-quinoline-5-yl-1h-pyrazole-4-carbonyl)guanidine, the method of production thereof, pharmaceutical composition based on these compounds and the method for mesilate salt of n-(5-cyclopropyl-1-quinoline-5-yl-1h-pyrazole-4-carbonyl)guanidine

 

The invention relates to new monoethanol and hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, to crystalline forms of these Atanasov, methods for producing Atanasov, methods of treatment using Atanassov and mutilates salts obtained using Atanassov. The invention relates also to a pharmaceutical composition having inhibitory activity against sodium-hydrogen exchange type 1(NHE-1), on the basis of these compounds. The technical result is to provide new compounds and pharmaceutical compositions based on them in order to prevent and reduce tissue damage resulting from ischemia or hypoxia. 10 N. and 5 C.p. f-crystals, 2 ill., 8 table.

The technical field to which the invention relates.

The present invention relates to new ethanolate inhibitor of sodium-hydrogen exchange type 1 (NHE-1), namely N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, to new crystalline forms of these Atanasov, methods of producing such Atanasov, methods of treatment using these Atanasov and mesilate salt inhibitor of NHE-1, obtained with the use of these Atanasov.

Preil-1H-pyrazole-4-carbonyl)guanidine useful for the prevention and treatment of ischemic myocardial damage. Myocardial ischemia may occur as outpatients, and in case surgical procedures, and can lead to sudden death, myocardial infarction or congestive heart failure. It is expected that therapy with N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine able to save lives and reduce hospitalization rates, improve quality of life and reduce the total cost of maintaining the health of patients of high risk.

In the patent application PCT published as W099/43663A1 described by reference, discusses the many inhibitors of NHE-1, including N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

Thus, there is a need, which supports in the art constant search for connections and forms of such compounds that would be useful in the treatment of surgical myocardial ischemia.

A brief description of the invention

One aspect of the present invention relates to N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidino as ethanolate.

As an additional aspect of the present invention it is monoethanol is referring to monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, which is x-ray powder that includes peaks with values approximately 7,07; 8,60; 14,18; 18,93; 21,34 and 28,54 29-scale and preferably also includes peaks with values approximately 16,49; 16,92; 20,70; 23,49; 26.00 and 29,04 29-scale.

An additional aspect of the present invention relates to hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

Another aspect of the present invention relates to hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, which is characterized by x-ray powder comprising peaks with values approximately 7,02; 16,44; 18,87; each holding 21.25 and 26,32 26-scale, and preferably also includes peaks with values approximately 8,55; 12,31; 14,11; 16,91; 23,44; 24,88 and to 25.22 2-scale.

Another aspect of the present invention relates to a method of obtaining monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine, including:

education solution containing N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine in ethanol at a concentration, which is approximately the saturation point of the compounds in ethanol, and

crystallization of monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-to the receiving hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, including:

education solution containing N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine in ethanol at a concentration, which is approximately the saturation point of the compounds in ethanol;

crystallization of monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine from the specified solution; and

the location of monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine in drying conditions with the formation of hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

Another aspect of the present invention relates to methods of preventing or reducing tissue damage resulting from ischemia or hypoxia, which include the introduction of a mammal in need of such treatment, preferably human, a therapeutically effective amount of monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine or a pharmaceutical composition comprising the specified connection.

An additional aspect of the present invention includes methods of preventing or reducing tissue damage resulting from ischemia or hypoxia, which include the introduction to a mammal in need taminophen-5-yl-1H-pyrazole-4-carbonyl)guanidine, characterized by x-ray powder comprising peaks with values approximately 7,07; 8,60; 14,18; 18,93; 21,34 and 28,54 2-scale, or pharmaceutical compositions comprising the specified connection.

Another aspect of the present invention includes methods of preventing or reducing damage to tissue, resulting in ischemia or hypoxia, which include the introduction in need of such treatment to a mammal, preferably a human, a therapeutically effective amount of hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine or a pharmaceutical composition comprising the specified connection.

Another aspect of the present invention includes methods of preventing or reducing damage to tissue, resulting in ischemia or hypoxia, which include the introduction in need of such treatment to a mammal, preferably a human, a therapeutically effective amount of hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, which is characterized by x-ray powder comprising peaks with values approximately 7,02; 16,44; 18,87; each holding 21.25 and 26,32 2-scale, or pharmaceutical composition, vklyuchayushchii, containing monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine and the pharmaceutically acceptable excipient, diluent or carrier.

Another aspect of the present invention includes pharmaceutical compositions containing monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, which is characterized by x-ray powder comprising peaks with values approximately 7,07; 8,60; 14,18; 18,93; 21,34 and 28,54 2-the scale, and a pharmaceutically acceptable excipient, diluent or carrier.

Another aspect of the present invention includes pharmaceutical compositions containing hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine and the pharmaceutically acceptable excipient, diluent or carrier.

An additional aspect of the present invention includes pharmaceutical compositions containing hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, which is characterized by x-ray powder x-ray that includes peaks with values approximately 7,02; 16,44; 18,87; each holding 21.25 and 26,32 2-the scale, and a pharmaceutically acceptable excipient, diluent or carrier.

-pyrazole-4-carbonyl)guanidine, comprising combining in an aprotic solvent, preferably tetrahydrofuran, compounds selected from monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine and hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, methanesulfonic acid at a temperature from about 40°to about 80°C., preferably from about 50°to about 60°C.

Another aspect of the present invention relates to methods of producing a pharmaceutical composition, comprising receiving nelfinavir N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine according to the method of the present invention and the Union of the specified nelfinavir N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine with a pharmaceutically acceptable excipient, diluent or carrier. An additional aspect of the present invention relates to methods of preventing or reducing tissue damage resulting from ischemia or hypoxia, including the introduction in need of such treatment to a mammal, preferably a human, a therapeutically effective amount of nelfinavir N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine obtained by the method of the present isopropylene relates to pharmaceutical compositions, including mesilate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine obtained by the method of the present invention, and a pharmaceutically acceptable excipient, diluent or carrier.

In a preferred embodiment, methods of the present invention, for obtaining monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine specified crystallization was carried out under specified cooling the solution to a temperature sufficient to implement such crystallization, more preferably specified cooling is carried out gradually, over a period of time equal to at least two hours. In another preferred embodiment, methods of obtaining monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine this crystallization was carried out by removal of ethanol from this solution by evaporation of the quantity of solvent which is enough for making such crystallization.

In a preferred embodiment, methods of obtaining hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine, according to the present invention, these conditions include drying spouliot heating, preferably from a temperature of about 40°to about 45°C. In another preferred embodiment, the above drying conditions include heating and vacuum, preferably when the specified heating is conducted at a temperature from about 40°to about 45°C and the specified vacuum of approximately 15 mm Hg or less. In an additional preferred embodiment, monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine is subjected to the drying process for at least five hours. In another preferred variant of realization of the specified crystallization was carried out by cooling the specified solution to a temperature sufficient to implement such crystallization. In another preferred variant of realization of the specified crystallization was carried out by removing ethanol from the specified solution in a quantity sufficient to implement such crystallization.

The term "hemiethanolate" in the context of the present description refers to a crystalline N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine containing from about 0.4 to about 0.6 of ethanol molecules, each molecule of N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-Carabanchel crystalline N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine, containing from about 0.9 to about 1.1 of ethanol molecules, each molecule of N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine in its crystal structure.

The term "saturation point" in the context of the present description denotes the concentration at which the solution contains such quantity of the dissolved substance, over which the substance will not dissolve under the existing characteristics of the solution (such as, for example, temperature, pH, pressure).

Specialists in the art it is clear that some compounds according to the present invention will contain one or more atoms that have a special stereochemical or geometric configuration, giving them the opportunity to form stereoisomers and spatial isomers. All such isomers and mixtures thereof are included in the present description. Specialists in this field it is obvious that monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine and mesilate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine can exist in several tautomeric forms. All such tautomeric forms restera x-ray powder for crystalline forms of monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine according to the present invention, obtained by the method of example 5.

In Fig.2 presents a characteristic x-ray powder x-ray for crystal form hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine according to the present invention obtained by the method of example 6.

Detailed description of the invention

Scheme 1 illustrates a method of obtaining ethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine. This method and other methods is illustrated by the examples in the experimental section of the present description.

As shown in scheme 1, the compound of formula II together with a compound of formula III to obtain the compounds of formula IV. The compound of formula IV cyclist with the compound of the formula V with the formation of ester of formula VI. An ester of formula VI hydrolyzing to obtain the acid of formula VII. The acid of formula VII is treated with thionyl chloride to obtain an activated acid chloride of formula VIII. The compound of formula VIII is associated then with guanidine with obtaining an inhibitor of NHE-1 formula IX, i.e., N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

Monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-keisala the specified connection from the solution. The compound, which crystallized from ethanol solution, is monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine.

Crystallization can be carried out are well known in the art methods. For example, monoethanol can be crystallized with sufficient cooling, the ethanol solution, leading to crystallization of the compounds from the solution.

Monoethanol can also be crystallized from ethanol solution by evaporation to a sufficient amount of ethanol in order to make the specified connection to crystallize from solution. Evaporation of the ethanol can be carried out by heating ethanol solution, preferably to a temperature sufficient to boil the solution. Alternatively, for such evaporation can be used in vacuum or a combination of vacuum with heating.

Preferably, the concentration of N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine solution was close to the saturation point. For specialists in the art it is obvious that the saturation point will depend on the temperature of the solution and can tacheometric pressure.

Specialists in this field it is also clear that regardless of the initial concentration of N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine in ethanol solution, the method used for crystallization of the specified monoetanolamin of ethanol solution, will lead to the formation of a mixture having such a concentration of N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, which corresponds to or is close to the saturation point of this compound in ethanol. For example, if used for crystallization method, associated with the cooling solution, the saturation point will be reached as soon as the solution is cooled. If used for crystallization method of evaporation of ethanol from the solution, the saturation point will be reached once the ethanol is removed from the solution.

In a preferred embodiment, the implementation of N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine dissolved in boiling ethanol to form a solution and crystallized from this solution monoethanol. Specialists in the art it is obvious that the temperature at which boiling solution of ethanol and N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, may depend on such factors as the barometer of the/p>

In another preferred embodiment, the implementation of monoethanol crystallized from ethanol solution with a gradual cooling of the specified solution, preferably to room temperature, and preferably within a time equal to at least about half hour, more preferably for a time period equal to at least about one hour, more preferably for a time period equal to at least about two hours, and, finally, more preferably in a period of time equal to at least about four hours.

Large crystals of ethanolate can be obtained by dissolving N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine in boiling ethanol, followed by a gradual cooling of the specified solution, as described above, with the formation of large white crystals monoetanolamin. X-ray analysis of single crystals obtained by the method, confirms the presence of monoetanolamin, showing the ratio of one to one between the molecules of ethanol and N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine. However, the position of the ethanol in the structure, as shown, is disordered.

In another is-pyrazole-4-carbonyl)guanidine is obtained by combining guanidine with a suspension or solution of 5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonylchloride in relative reaction inert solvent, such as tetrahydrofuran, to form a solution of N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine in the reaction solvent, monoethanol can be obtained upon evaporation of the reaction solvent, as for example by removal of the solvent from the solution, followed by adding ethanol and subsequent evaporation of the solution that results in monoetanolamin. Multiple cycles of ethanol addition and evaporation can be used to ensure essentially complete removal of tetrahydrofuran prior to final crystallization in monoethanol.

Monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine, prepared according to the above method, is formed in crystalline form characterized by x-ray powder corresponding, essentially, is shown in Fig. 1. The main peaks are observed at points with values approximately 7,07; 8,60; 14,18; 18,93; 21,34 and 28,54 2-scale. Additional major peaks are observed at points with values approximately 16,49; 16,92; 20,70; 23,49; 26.00 and 29,04 2-scale.

Hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine can be obtained by the building of the Cabinet of monoetanolamin at room temperature in a stream of nitrogen is insufficient for appreciable conversion of monoetanolamin in hemiethanolate. In this regard, the drying conditions should be sufficiently stringent to implement the specified transformation.

In a preferred embodiment, receiving hemiethanolate monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine placed in a vacuum drying oven with a temperature of from about 40°to about 45°C With a barometric pressure of approximately 15 mm Hg, preferably at least two hours, more preferably at least five hours and even more preferably at least about 10 hours, obtaining hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

In another preferred embodiment, receiving hemiethanolate monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine get through Association with guanidine 5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonylchloride, which is suspended in tetrahydrofuran to form a solution of N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine in tetrahydrofuran. This solution is evaporated to remove tetrahydrofuran with the formation of residue. The resulting residue is dissolved in ethanol and the ethanol is distilled off. Multiple cycles add etano the crystallization in monoethanol. The resulting monoethanol then placed in a vacuum drying oven with a temperature of from about 40°to about 45°C at a barometric pressure of approximately 15 mm Hg, preferably at least two hours, more preferably at least five hours and even more preferably at least about 10 hours, to obtain hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

Hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine, prepared according to the just described method has a crystalline form characterized by x-ray powder corresponding essentially shown in Fig. 2. The main peaks are observed at points with values approximately 7,02; 16,44; 18,87; each holding 21.25 and 26,32 2-scale. Additional major peaks are observed at points with values approximately 8,55; 12,31; 14,11; 16,91; 23,44; 24,88 and to 25.22 2-scale.

Mesilate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine can be obtained by the reaction of monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine with methanesulfonic acid. Specified mutilata salt can be the Olin-5-yl-1H-pyrazole-4-carbonyl)-guanidine. Preferably, monoethanol or hemiethanolate, depending on what is acceptable, is subjected to the interaction with methanesulfonic acid in an aprotic solvent such as tetrahydrofuran or a mixture of from about 60% to about 90% acetone and the residual amount of 1-methyl-2-pyrrolidinone, at a temperature from about 40°to about 80°C.

Source material and reagents for producing the above compounds are easily available or can be easily synthesized by specialists in the art using conventional methods of organic synthesis.

Introduction compounds obtained by the method of the present invention, can be carried out by any method that enables delivery of the compounds of the present invention is preferably in the desired tissue (e.g., in the tissue of the liver and/or heart). Such methods include oral route, parenteral route, intraduodenal path, etc. In General, the compounds of the present invention are introduced in the form of one-time (e.g., once daily) or multiple doses or by continuous infusion.

Ethanolate and mutilata salt of N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine obtained by the method in which I at any fabric, which may be more sensitive to ischemia/reperfusion (e.g., tissue of the heart, brain, lung, kidney, liver, intestine, skeletal muscle, retina), resulting in ischemic attack (e.g., myocardial infarction). In this connection, this connection can be used prophylactically to prevent, blunting or suspension of tissue damage (e.g., myocardial tissue) from patients where there is a risk of ischemia (e.g., myocardial ischemia).

Basically, the compounds obtained by the method of the present invention, are administered orally or parenterally (e.g. intravenously, intramuscularly, subcutaneously or intramedullary). Can be shown also local injection, for example, in the case where the patient suffers from gastro-intestinal disorders or in the case when the tool is best applied to the surface of the tissue or organ, as it considers the treating physician.

The number and time of the connection is, of course, depend on the patient to be treated, the severity of the lesion, the method of administration and from the opinions of a treating physician. Therefore, due to the variability of these factors from patient to patient, the following dosages are only General ruary he considers most appropriate for this patient. When considering the desired impact, the physician must consider many factors, such as the patient's age, presence of previous disease, and the presence of other diseases (such as diseases of the cardiovascular system).

For example, in one of the modes of introduction of the compound of the present invention may be administered immediately prior to surgery (e.g., within twenty-four hours before surgery, such as heart surgery), during surgery or immediately after it (e.g., within twenty-four hours after the operation), when there is a risk of myocardial ischemia. The specified connection may also be entered in the daily mode.

Use this amount of the compounds of the present invention, which is effective for protection from ischemia. The preferred dosage of the compounds is from about 0.001 to 100 mg/kg/day. Especially preferred dosage of the compounds is from about 0.01 to 50 mg/kg/day.

Compounds of the present invention mainly introduced in the form of pharmaceutical compositions containing at least one of capitalim. Thus, the compounds of the present invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form.

For oral administration the pharmaceutical composition may be in the form of solution, suspension, tablets, pills, capsules, powders, etc., Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate, used in conjunction with various leavening agents that contribute to decomposition, such as starch and preferably potato starch or starch from tapioca, and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum. Additionally, in the process of obtaining tablets used lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type are also used as fillers in soft and hard gelatin capsules, the preferred materials for such purposes also include lactose or milk sugar and high molecular weight glycols. In the case when oral administration is desirable aqueous suspension and/or Eli is involved, dyes, emulsifiers and/or suspendresume agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various combinations.

For purposes of parenteral administration can be used solutions, for example, in sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions can be, if necessary, suitably buffered, you can use liquid diluent, which previously made isotonic due to sufficient saline or glucose. These aqueous solutions are especially acceptable for the purposes of intravenous, intramuscular, subcutaneous and intraperitoneal injection. For this purpose use sterile water environment, and all of them can be easily obtained by any expert in the art by known standard methods.

For the purposes of percutaneous (e.g., local) introduction get diluted sterile aqueous or partially aqueous solutions (usually with a concentration of from about 0.1% to 5%), but otherwise similar to those described above parenteral solutions.

Methods of cooking , is whether they will become obvious to specialists in this field in light of the above description. So, for example, methods of obtaining pharmaceutical compositions are given in the manual Remington (see Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 19th Edition, 1995).

The pharmaceutical compositions according to the present invention may contain, for example, from 0.0001% to 95% of the compound of the present invention. In any case, the input composition or formulation to contain the specified compound in a quantity effective to treat the disease/condition of the subject to be treated.

Compounds of the present invention mainly introduced in the form of traditional songs. The following examples of compositions are given for the purpose of illustration and in no way limit the scope of the present invention.

The following compositions, the term "active ingredient" means any monoethanol or hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine according to the present invention, or mesilate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine according to the present invention. The above active ingredient may also be a combination of two of these with the crystals prepared using the following ingredients:

IngredientQuantity (mg/capsule)
The active ingredientof 0.25-100
Starch, national formulary0-650
Starch flowable powder0-50
Silicone fluid, 350 Centistokes0-15

The composition of the tablets obtained using the following ingredients:

Composition 2: Tablets

IngredientAmount mg/tablet)
The active ingredientof 0.25-100
Cellulose, microcrystalline200-650
Silicon dioxide, steaming10-650
Stearic acid5-15

The components are mixed and pressed to form tablets.

Alternative tablets, each containing 0.25 to 100 mg of active ingredient was prepared as follows:

Composition 3: Tablets

IngredientQuantity (mg/tablet)
The active ingredientof 0.25-100
Starch45
Cellulose, microcrystalline35
Polyvinylpyrrolidone (as 10% solution in water)4
Sodium carboxymethylcellulose4,5
Magnesium stearate0,5
Tularemia. The solution of polyvinylpyrrolidone is mixed with the obtained powder, which is then passed through sieve No. 14 mesh US. The obtained granules were dried at 50°-60°C and passed through sieve No. 18 mesh US. Sodium carboxymethyl-starch, magnesium stearate and talc, previously passed through sieve No. 60 U.S. and then added to the granules which, after mixing compressed on a tablet machine to obtain tablets.

Suspensions, each containing 0.25 to 100 mg of active ingredient per dose 5 ml, was prepared as follows:

Track 4: Suspension

IngredientQuantity (mg/5 ml
The active ingredient0.25 to 100 mg
Sodium carboxymethylcellulose50 mg
Syrup1.25 mg
A solution of benzoic acid0.10 ml
Flavouring substanceq.v.
Dyeq.v.
Purified water to5 ml

The active ingredient is passed through sieve No. 45 mesh U.S. and mixed with the sodium carboxymethyl cellulose and syrup with the formation of a homogeneous paste. A solution of benzoic acid, flavoring substance and the dye is diluted with a small amount of water and added with stirring. Then add enough to the s:

Composition 5: Aerosol

IngredientQuantity (weight. %)
The active ingredient0,25
Ethanol25,75
The propellant 22 (Chlorodifluoromethane)74,00

The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30°C, and transferred to the device for bottling. The required amount of this mixture is placed in a stainless steel container and diluted with the remaining amount of propellant. Then attached to the container valve device.

Suppositories prepared as follows:

Track 6: Suppositories

IngredientQuantity (mg/suppository)
The active ingredient250
Glycerides of saturated fatty acids2000

The active ingredient is passed through sieve No. 60 mesh U.S. and suspended in pre-molten glycerides of saturated fatty acids using the minimum required heating. The mixture is then poured into the form of a suppository with a nominal capacity of 2 g and allowed to cool.

Intravenous composition was prepared as follows:

Track 7: NR the ingredient

25 mg
Isotonic saline1000 ml

The solution of the above ingredients is administered to the patient intravenously.

Experimental methods

NMR spectra recorded on the instrument Varian XL-300 (Varian Co., Palo Alto, CA) spectrometer Bruker AM-300 (Bruker Co., Billerica, mA) or on the instrument Varian Unity 400 at a temperature of about 23°C at 300 or 400 MHz for proton. As the solvent used DMSO. Forms peaks denoted as follows: s (C.) = singlet, d (DV) = doublet, t (t) = triplet, q (K.) = Quartet, m (m) = multiplet, bs (W.with.) = broad singlet.

X-ray diffraction analysis performed on powder x-ray diffractometer for the analysis of powder Siemens D5000 (Bruker AXS, Inc., Madison, WI, formerly Siemens), equipped with a copper radiator, using the geometry of theta/2-theta and detector solid state Kevex (Thermo Noran, Middleton, WI).

X-ray analysis of single crystals was performed at room temperature using a diffractometer Siemens P4. The atomic scattering factors calculated using the international tables (International Tables for X-Ray Crystallography, Vol. IV, pp. 55, 99, 149; Birmingham: Kynoch Press, 1974). A diagram of the crystal structure is built using the SHELXTL softwareN,N-dimethylformamide (14.7 ml) is heated at 75°C for 1.5 hours in a nitrogen atmosphere. Then, the resulting orange oil is cooled to room temperature to obtain crude methyl-3-cyclopropyl-2-dimethylamino-3-oxopropanoic.

Analysis by thin layer chromatography (TLC) (EtOAc/hexane, 1:1) shows the disappearance of the starting material and the appearance of spots a small amount of the less polar product and the main spots are more polar product (methyl-3-cyclopropyl-2-dimethylamino-3-oxopropanoic).

Example 2

Methyl ester 5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carboxylic acid

The crude methyl-3-cyclopropyl-2-dimethylamino-3-oxopropanoic (20,9 g) obtained by the method of example 1, diluted with ethanol (250 ml). Add triethylamine (34,4 ml) and then the quinoline-5-ilkerin (22.9 grams). After adding the quinoline-5-Algeria there is a slight evolution of gas. The obtained heterogeneous mixture is heated at the boiling point under reflux (78°C) in nitrogen atmosphere for 2 hours. Then the mixture is cooled to room temperature. Analysis by TLC (ethyl acetate/hexane, 1:1) indicates the appearance of a spot a few of the less polar product (complex intronaut by evaporation of excess solvent. To the obtained residue is added ethyl acetate (300 ml) and 0.1 N. hydrochloric acid (400 ml). Formed emulsion is stirred for 10 minutes at room temperature and filtered through a pillow celite (Celite®; Celite Corporation, Lompoc, CA) to remove solid material. The obtained two-phase mixture is separated. The aqueous layer was extracted with ethyl acetate (CH ml). The combined organic layers washed with 0.1 N. hydrochloric acid (g ml), then dried over sodium sulfate and concentrated by evaporation of the solvent. To the obtained residue, add hot isopropyl ether (80 ml). The obtained turbid solution is stirred for two minutes. Then add hexane (125 ml) and the resulting solid is left overnight for granulation. The obtained solid material is collected by filtration, giving specified in the title compound as a yellow-orange powder (20,8 g).

Example 3

5-Cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carboxylic acid

To a solution of complex methyl ester 5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carboxylic acid (20 g) in methanol (120 ml) is added 2N. sodium hydroxide (54,5 ml). The resulting solution was heated at boiling temperature under reflux (65°C.) for 1.5 hours shows the disappearance of the starting material. The methanol is removed under vacuum with gentle heating (35°C) on a rotary evaporator. The alkaline aqueous layer was then washed with ethyl acetate (CH ml). Received the alkaline aqueous layer is carefully acidified to pH about 1 to 2 using concentrated hydrochloric acid. The product precipitates in the process of acidification. The obtained suspension was stirred at room temperature for 0.5 hours, after which the resulting solid material is collected by filtration. Specified the solid material is washed with 1N. hydrochloric acid (g ml) and dried to obtain specified in the title compounds as a pale brown solid (18,8 g).

Example 4

5-Cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonylchloride

In nitrogen atmosphere in the reactor to 100 liters with glass inner cover is placed 63 liters of toluene and 5.2 kg 5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carboxylic acid. The reactor is heated to boiling and collecting 11 liters of distillate for azeotropic drying system. The tank is cooled to a temperature of about 40°C and add 2.4 kg of thionyl chloride. The reactor is heated to a temperature of about 75°C and maintain the specified temperature for about 13 hours. Then the reactor glmaterial washed with toluene to obtain a "wet cake" specified in the connection header.

Example 5

Monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine

In nitrogen atmosphere in the tank is 100 liters with glass inner coating containing 64 liters of tetrahydrofuran (THF), tolerate wet cake 5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonylchloride of example 4. For suspension of solid mass in a specified vessel use shaking.

In a separate reactor at 200 liters with glass inner coating in an atmosphere of nitrogen was placed 31 liter of water, 5,1 kg of pellets of potassium hydroxide and of 3.60 kg of guanidine hydrochloride to achieve a pH of 14. You can use an additional amount of potassium hydroxide until then, until the pH value reaches 14. The potassium hydroxide may be replaced by sodium hydroxide.

The resulting solution is cooled to a temperature of 0-5°C. for 30 minutes in the reactor at 200 liters add a suspension of 5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonylchloride/THF while maintaining the reactor temperature in the range from about 0°to about 5°C. the Tank is heated to a temperature of about 20°C. and stirred the contents for 90 minutes. Then the stirring reactor cease and defending it formed two liquid 38 liters). Three of the obtained fractions THF are combined and stirred with activated charcoal and auxiliary filter substrate for 1 hour at a temperature of about 50°C. a Suspension of activated charcoal/auxiliary filter substrate is filtered while hot and washed with THF.

The obtained filtrate is transferred into a tank of 200 liters, fitted for distillation in a nitrogen atmosphere at atmospheric pressure. The tank is heated to boiling and collecting about 100 liters of distillate. In specified tank for distillation contribute ninety-four liters of ethanol (100%) and conduct the distillation, collecting an additional 94 liters of distillate. Contribute in the tank for distillation, the second portion of ethanol (94 liters) and repeat the distillation, collecting an additional 94 liters of distillate. The third portion of ethanol (94 liters) contribute in the tank for distillation and carry out the distillation, collecting 82 liters of distillate. By the end of the distillation is the crystallization of monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine. After that, the tank is cooled to a temperature of about 20°C and the solid material is separated by filtration and washed with ethanol to obtain specified in the connection header.

Monoethanol N-(5-cyclopropyl-1-hin the ka, corresponding essentially to the illustration in Fig.1.

Example 6

Hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine

Monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine of example 5 is dried in a vacuum drying Cabinet at a temperature of from about 40°to about 45°C and at a pressure of approximately 15 mm Hg with getting 5,10 kg hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

The ethanol content in hemiethanolate confirmed by analysis of the NMR method.

1H NMR

CartoonsJ-HzComes from...Integration
9,0dd4,1; 1,9Ar-H1H
by 8.22d8,4Ar-H1H
8,01sAr-H (pyrazole)1H
a 7.92dd8,4; 7,5Ar-H1H
7,79dd7,5; 1,1Ar-H1H
a 7.62mAr-H2H
4,39t5,1OH (EtOH)0.5 H
3,45mCH2(EtOH)1H
1,97mCH (cyclopropyl)1H
1,07t6,9CH3(EtOH)1,5 H
0,58mCH2-CH2(tucany according to the method of this example, shows the radiograph of the powder, equivalent, essentially, is shown in Fig.2.

Example 7

Mesilate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine

In the reactor at 50 liters with glass inner cover 44 is placed liter of THF, 4.4 liters of dimethyl sulfoxide and to 4.81 kg of hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine. The reactor is heated to a temperature of about 35°C. in a nitrogen atmosphere, getting a solution. This solution is filtered in the second tank to remove traces of insoluble material. In a separate flask above the vessel containing the specified filtrate, prepare a solution 1246 g methanesulfonic acid in THF (about 8 liters). The tank containing the filtrate is heated to a temperature of about 53°C, and slowly, within 1 hour, add to it a solution of the acid. Mesilate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine crystallized towards the end of the process of adding acid. The obtained solid material is separated by filtration, washed with THF and dried in vacuum, obtaining 5,13 kg nelfinavir N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

Example 8

Monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)Guan is Aut in 36 ml of boiling ethanol (100%). Then the obtained solution is allowed to slowly cool overnight to room temperature, which leads to the formation of large white crystals monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine. The output is 0.95 grams.

The presence of monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine confirmed by x-ray diffraction analysis of single crystals. Before conducting x-ray diffraction analysis of crystals extracted directly from the mother ethanol mixture and cover with epoxy-resin. X-ray analysis of single crystals shows that the crystal monoetanolamin really is characterized by the ratio of one to one between the molecule N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine and a molecule of ethanol. However, the position of the ethanol inside the structure, as shown, is disordered.

The ethanol content in monoethanolamine was also confirmed by the results of the analysis by NMR using the specified in the title compound, obtained by the method of example 8. However, after the formation of crystals of the ethanol is removed by decantation and the solid residue is dried at room temperature in a stream of gaseous nitrogen is Vashego of the invention, for specialists in this area, obviously, can be introduced certain variations and modifications of the described variations without departure from the essence and scope of the present invention.

Claims

1. N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)-guanidine in the form of ethanolate.

2. Monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

3. Monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine under item 2, which is characterized by x-ray powder that includes peaks with values approximately 7,07; 8,60; 14,18; 18,93; 21,34 and 28,54 2-scale.

4. Monoethanol N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine under item 3, which is characterized by x-ray powder that includes peaks with values approximately 16,49; 16,92; 20,70; 23,49; 26/00 and 29,04 2-scale.

5. Hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

6. Hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine under item 5, which is characterized by x-ray powder that includes peaks with values approximately 7,02; 16,44; 18,87; each holding 21.25 and 26,32 2-scale.

8. Pharmaceutical composition for inhibiting the sodium-hydrogen exchange type 1, including a connection for PP.1-7 and a pharmaceutically acceptable excipient, diluent or carrier.

9. The method of producing monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine comprising the formation of a solution containing N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine in ethanol at a concentration, which is approximately the saturation point of the compounds in ethanol and crystallization of monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-lH-pyrazole-4-carbonyl)guanidine from the specified solution.

10. The method of producing hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl) guanidine comprising the formation of a solution containing N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine in ethanol at a concentration, which is approximately the saturation point of the compounds in ethanol; crystallization of monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine from the specified solution; and the location of monoetanolamin N-(5-cycle of the saw-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine.

11. A method of treatment comprising the administration to a mammal, for which the necessary prevention or reduction of tissue damage resulting from ischemia or hypoxia, a therapeutically effective amount of compound on the PP.1-7.

12. A method of treatment comprising the administration to a mammal, for which the necessary prevention or reduction of tissue damage resulting from ischemia or hypoxia, a therapeutically effective amount of the pharmaceutical composition under item 8.

13. The method according to p. 11 or 12, characterized in that the mammal is a human.

14. The method of receiving nelfinavir N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine comprising combining in an aprotic solvent, compounds selected from monoetanolamin N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine and hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, with methanesulfonic acid at a temperature of from about 40°C to about 80°C.

15. A method of obtaining a pharmaceutical composition, comprising preparing nelfinavir N-(5-cyclopropyl-1-quinoline-5-yl-lH-pyrazole-4-carbonyl)guanidine by method p. 14 and then the Union of the specified nelfinavir N-(5-elem or the media.



 

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