Diazepane derivative, pharmaceutical composition comprising thereof and inhibitor of blood coagulation activated factor x

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

 

The technical field

This invention relates to a new diazepamum derivative or its salt, which is suitable as a pharmaceutical, particularly as an inhibitor of activated factor X in the coagulation of blood and to such pharmaceutical agent.

Background of invention

Due to changes in European and American lifestyle and the rising level of the elderly population in recent years has increased the number of patients with thromboembolic disease, including myocardial infarction, thrombosis, cerebrovascular and peripheral arterial thrombosis, and social significance of their treatment was more and more increased. As fibrinolysin therapy and antithrombotics therapy, anticoagulation therapy is part of drug therapy in the treatment and prevention of thrombosis (Sogo Rinsho, 41: 2141-2145, 1989). In particular, the security, which is opposed to the long-term introduction, and the exact and correct expression antikoaguliruyuschey activity are essential in the prevention of thrombosis. Warfarin-potassium is often used around the world as the only oral anticoagulant, but the in-clinic use of this medicine is fraught with difficulty, since it is extremely difficult to control anticoagulate action blah is odara properties, based on the mechanism of its action (J.Clinical Pharmacology, 32, 196-209, 1992 and N.Eng.J.Med., 324(26), 1865-1875, 1991), making great efforts have focused on developing more appropriate and more easily applicable anticoagulants.

Thrombin regulates the conversion of fibrinogen into fibrin, which is the final stage of coagulation, and also largely associated with the activation and aggregation of platelets ("T-PR and Pro-UK" edited by S.Matsuo, published by Gakusai Kikaku, pp.5-40, "Blood Coagulation", 1986), and its inhibitor was the center of research on anticoagulants, as a target for developing pharmaceutical drugs. However, thrombin inhibitors that can be administered orally, were not put on the market up to the present time because of their low bioavailability when administered orally and concerns regarding security (Biomed.Biochim. Acta, 44, 1201-1210, 1985).

Activated factor X in the coagulation of blood is a key enzyme, which is located at the point of connection of the external and internal reactions of the coagulation cascade and is above (to the left) of thrombin, resulting exists the possibility that the suppression of this factor is more effective than suppression of the activity of thrombin, and a specific inhibitor can suppress the system of coagulation (Thrombosis Research, (19), 339-349, 1980).

Amidinotransferase derivatives or their salts have been known as compounds the Oia, with overwhelming effect on factor X in the coagulation of blood (Japanese Patent Laid-Open No. 208946/1993; Thrombosis Haemostasis, 71(3), 314-319, 1994; Thrombosis Haemostasis, 72(3), 393-396, 1994).

In WO 96/16940 indicates that amidinothiourea derivative or its salt represented by the following formula, is the connection with the action, overwhelming activated factor X in the coagulation of blood (prototype 1).

(The meanings of symbols, see link)

In WO 99/00121, WO 99/00126, WO 99/00127, WO 99/00128, WO 00/39111, WO 00/39117 and WO 00/39118 phenylendiamine connections, etc. represented by the following formula, referred to as inhibitors of factor XA (prototype 2).

(The meanings of symbols, see link)

In addition, in WO 99/32477 a wide range of compounds represented by the following next formula, referred to as anticoagulants (prototype 3).

(The meaning of symbols, see link)

Description of the invention

The present inventors have been received diazepinone derivative represented by the following further by formula (I)or its salt and found that it has excellent overwhelming effect on the activated factor X in the coagulation of blood and, in particular, has excellent activity when administered orally, the consequence of which was the creation of the present invention.

Still the way this invention relates to diazepamum derivative represented by the following further by formula (I), or salts thereof, and pharmaceutical compositions, in particular inhibitor of activated factor X in the coagulation of blood, containing a derivative of diazepan or its salt as an active ingredient.

The symbols in the above formula have the following meanings.

Rings a and b are the same or different, and each represents an aryl or heteroaryl, which may have 1-3 substituent;

X1represents-C(=O)-NR2- or-NR2-C(=O)-;

X2represents-C(=O)-NR3- or-NR3-C(=O)-;

R represents a hydrogen atom, halogen atom, lower alkyl or-O-lower alkyl and

R1, R2and R3are the same or different, and each represents a hydrogen atom or lower alkyl.

The compound of this invention (I) has a different structure from the structure of the compounds mentioned in prototype 1, in that it has diazepambuy component and four cyclic fragment and that the nitrogen atom of diazepan directly connected with the ring C. in Addition, the compound of this invention has a different structure from the prototype 2 in that it has diazepambuy fragment. Moreover, in the prototype are not specifically named compounds, having diazepambuy fragment. Thus, the hallmark of the compound (I) of the present invention in terms of chemical structure is that diazepam.elavil or diazepameliezer linked to the benzene ring via an amide bond that the benzene ring is optionally linked to the aryl or heteroaryl through amide bond and, in addition, that the benzene ring has an Oh group.

Further, the compound of the present invention will be illustrated in detail.

The term "lower" in the definition for the formula in the description means a straight or branched carbon chain having 1-6 carbon atoms, unless otherwise specified. Therefore, examples of "lower alkyl" for R, R1and R3and examples of the substituents, which will be referred to later, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Among them, preferred having 1-3 carbon atoms and most preferred methyl and ethyl.

"Ar is l" means an aromatic hydrocarbon ring, including a condensed ring, and it preferably is an aryl having 6-14 carbon atoms and, more preferably, phenyl, naphthyl, etc.

"Heteroaryl" means heterocyclic aryl having 1-4 identical or different heteroatoms selected from the group consisting of N, S and O, including a condensed ring, and specific examples are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, indazoles, indolizinyl, hinely, ethanolic, hintline, hinolinol, honokalani, cinnoline, benzimidazolyl, imidazopyridine, benzofuranyl, dihydrobenzofuranyl, naphthylidine, 1, 2-benzisoxazole, benzoxazole, benzothiazole, oxazolopyridine isothiazolones and sensational, although the invention is not limited to them.

Examples of the "substituent" for the "aryl or heteroaryl, which may have 1-3 substituent are optionally substituted lower alkyl, lower alkenyl, lower quinil,3-8-cycloalkyl, -O-optionally substituted lower alkyl, halogen atom, NH2, -NH-lower alkyl, -N(lower alkyl)2, -C(=NH)-NH2, -C(=N-OH)-NH2-C(=NH)-NH-C(=O)-O-lower alkyl, COOH, -C(=O)-O-optionally substituted lower alkyl, -C(=O)- O-optionally substituted C6-14-aryl, -C(=O)-O-it is certainly substituted heteroaryl, CN, NO2HE, -O-CO-optionally substituted lower alkyl, -O-CO-NH2, -O-CO-NH-lower alkyl, -O-CO-N-(lower alkyl)2SH, -C(=O)-NH2-C(=O)-NH(lower alkyl) and-C(=O)-N-(lower alkyl)2although this invention is not limited to this.

Examples of the substituent for "optionally substituted lower alkyl" and "optionally substituted heteroaryl" are halogen atom, -COOH, -C(=O)-O-Nishi alkyl, HE, NH2, -NH-lower alkyl and-N(lower alkyl)2although this invention is not limited to this.

Examples of the "halogen atom" include fluorine atom, chlorine atom, iodine atom and a bromine atom. Particularly preferred chlorine atom and a bromine atom.

In this case, X2represents-C(=O)-NR3- or-NR3-C(=O)- and, more preferably, it is-NR3-C(=O)-. R2and R3are the same or different and each represents a hydrogen atom or lower alkyl, and hydrogen atom is more preferred.

The compound of the present invention includes various stereoisomers such as geometrical isomers, tautomers and optical isomers or as mixtures, or in isolated form.

The compound (I) of the present invention can form an additive salt of the acid. In addition, it can form a salt with a base depending on the type of substituent. Specific examples the AMI such salts are additive salt of the acid, educated mineral acid, such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid and phosphoric acid, or organic acid, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid and econsultancy acid, or acidic amino acid such as aspartic acid and glutamic acid, and salts of inorganic bases, such as sodium, potassium, magnesium, calcium and aluminium, or organic bases, such as methylamine, ethylamine, and ethanolamine, basic amino acids such as lysine and ornithine, and ammonium salt.

In addition, this invention also includes hydrates, pharmaceutically acceptable various solvate and polymorphism of this compound (I). Incidentally, it goes without saying that the invention is not limited to the compounds mentioned in the following examples, but includes all diazepinone derivative represented by the formula (I)and their pharmaceutically acceptable salts.

The compound of the present invention includes all so-called prodrugs, i.e. compounds that can be transformed into compounds is s, represented by formula (I)or its salt metabolism in vivo. Examples of groups that form the prodrugs of the compounds of this invention are group named Prog.Med., 5: 2157-2161 (1985) and named "lyakuhin no Kaihatsu" (Development of Pharmaceuticals), published by Hirokawa Shoten in 1990, Vol.7, "Molecular Design", pp.163-198.

Ways to get

Typical methods for obtaining the compounds of this invention will be shown hereafter.

(in formulas a, b, R, X1and X2have the meanings specified above, and W are such that when Q represents-NH2or-NH-lower alkyl, W is-COOH, while, when Q represents-COOH, W is-NH2or-NH-lower alkyl; R1is a hydrogen atom, a lower alkyl or a protecting group for an amine; and R2is a hydrogen atom or a protecting group for a phenol.)

Stage And

This stage represents the fusion reaction (Ia), in which the amine and carboxylic acid comprising a combination of compound (II) and compound (IV), interact, preferably in the presence of a condensing agent. This reaction may be carried out in accordance with conventional acylation reaction.

Examples of the condensing agent primarily used are N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(N,N-dimethylene is about)propyl]carbodiimide, carbonyldiimidazole, diphenylphosphoryl (DFA) and diethylphosphoramidite.

You can also convert the carboxylic acid into an active derivative of the corresponding carboxylic acid and then condensing with an amine.

Examples of the active carboxylic acid derivative are active ester obtained by the reaction with the phenolic compound type, such as p-NITROPHENOL or N-hydroxyamino type, such as 1-hydroxysuccinimide and 1-hydroxybenzotriazole, monoalkyl ester of carboxylic acid, a mixed acid anhydride obtained by the reaction with an organic acid, and a mixed anhydride of the acid-type phosphoric acid obtained by the reaction with phosphorylchloride and N-methylmorpholine; azide acid obtained by the reaction of ester with hydrazine and alkylation; halides such as acid chloride or bromohydrin; and the acid anhydride of the symmetric type. Usually the above reaction is carried out in a solvent in the temperature range of from cooling to room temperature, although, in some cases, it should be carried out in anhydrous conditions, depending on the type of reaction acylation.

Examples of the used solvents are inert solvents which do not participate in the reaction, such as dimethylformamide, dioxane, tetrahydrofuran, ether, dichloromethane, di is Loretan, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile and dimethylsulfoxide, and a mixture thereof, and preferred is an appropriate choice depending on the applied method.

In addition, depending on the method used, in some cases, the reaction smoothly proceeds in the presence of a base, or when using a base as a solvent, where the base is an N-methylmorpholine, triethylamine, trimethylamine, pyridine, sodium hydride, tert-piperonyl potassium, utility, nutrional or the like.

Stage

This stage represents the fusion reaction (Ia), which react with amine and carboxylic acid, including the combination of compounds (III) and compound (V). This reaction is carried out in the same manner as in stage A.

When R1in compound (Ia) of the present invention is a protective group for the amine and the protective group is not cleaved during stages a and b, the removal of the protective group using a method suitable for the removal of the protective group R1that is when it is possible to obtain the compounds of this invention (I)in which R1is a hydrogen atom. In addition, when R2in compound (Ia) of the present invention is a protective group for a phenol and protective grappone cleaved during stages a and b, cleavage using a method that is appropriate for the removal of the protective group R2that is, when possible, to obtain the compounds of this invention (I).

In regard to the protective group for the amine, examples of which are given for R1to date there is no particular limitation, as it is a group that is typically used to protect the amine, and examples of it are the lowest alkoxycarbonyl, Uralelectromed, acyl, lower alkyl, aralkyl and sulfonyl.

In regard to the protective group for a phenol, examples of which are given to R2to date there is no particular limitation, as it is a group that is typically used for protection of the phenol, and the examples of it are optionally substituted lower alkyl, aralkyl, three(lower alkyl)silyl, lower alkylsulphonyl, lower allyloxycarbonyl and sulfonyl. "Aralkyl" means a group where the hydrogen atom of the above the above alkyl substituted by aryl, and its specific examples are benzyl and phenylethyl. Specific examples of the "acyl" are formyl, acetyl, propionyl, butyryl.

It is also possible to carry out conventional N-alkylation using the compounds of this invention (I), where R1represents a hydrogen atom, to obtain the compound of this invention (I), g is e R 1is lower alkyl.

The compound represented by formula (I)can be also obtained an optional combination of steps which usually can be chosen by the person skilled in the art, such as known alkylation, acylation, oxidation, recovery and hydrolysis. Furthermore, the method shown in the following reaction scheme is particularly effective for the synthesis of compounds represented by formula (I).

(in formulas a, b, R1, R2, R, R2and R3have the values specified above. )

This method is a reaction in which the compound (VI) and the amine (IVa) or compound (VII) and amine (Va) interact with the formation of amide linkages with obtaining the compound (Ib) or compound (IC) and which is carried out in the above-mentioned inert solvent at room temperature or when heated. In addition, depending on the applied method, in some cases, the reaction proceeds smoothly in the presence of a base or the use of such a base as a solvent, when the substrate is N-methylmorpholine, triethylamine, grimmelmann, pyridine, sodium hydride, tert-piperonyl potassium, butyllithium, amidon sodium or the like.

The means of obtaining the source connections

There will be further illustrated by obecnie methods of obtaining the starting compounds for the compounds (I) of the present invention.

The method of obtaining 1

(in the formulae, X2, P1, P2, R, Q and W have the meanings indicated above, and U represents-COOH, -COOP3, -NH2-, -NH-lower alkyl, -NH-P4, -N(P4) -lower alkyl or NO2where P3and P4are protective groups for carboxyl and Amin, respectively).

The method of obtaining 1

This method of obtaining represents the reaction of amide bond formation by the condensation of carboxylic acids with amines, including the combination of compounds (VIII) and compound (V). This reaction is carried out in the same manner as in the above stage A.

When U in the compound (IIA) is NO2connection, where U is NH2can be obtained by the reaction of recovery, while, when U is-COOP3, -NH-P4or(P4)-lower alkyl, the compounds where U is-COOH, -NH2or-NH-lower alkyl, can be obtained in a way that is suitable for removal of each of the protective groups.

The method of obtaining 2

(in the formula A, X1, R2, R, Q, W, and U have the same values as above)

The method of obtaining 2

This method is a reaction in which an amide bond is formed by condensation of carboxylic acid and amine, including the combination of compounds (VII) and compound (IV). This reaction is carried out in the same manner as in the above stage A. When U compound (IIIa) is NO2connection, where U is NH2can be obtained by the reaction of recovery, while, when U represents-COOP3, -NH-P4or-N(P4)-lower alkyl, the compounds where U is-COOH, -NH2or-NH-lower alkyl, can be obtained in a way that is suitable for removal of each of the protective groups.

Compounds represented by formulas (II) and (III)can be also obtained by using the optional combination of stages that usually can be chosen by the person skilled in the art, such as known alkylation, acylation, oxidation, recovery and hydrolysis. Furthermore, the method represented by the following reaction scheme is particularly effective for the synthesis of compounds represented by formulas (II) and (III).

(in formulas a, b, R, R2, R3, R1and R2have the values specified above).

This method is a reaction where the amide bond is formed by the reaction of compound (IX) with an amine (Va) or amine (IVa) with a compound (IIb) or compound (IIIb), and it is held in the above-mentioned inert solvent at room temperature or when heated. In addition, depending the spine from the applied method, in some cases, the reaction smoothly proceeds in the presence of a base, or when using a base as a solvent, and the base is N-methylmorpholine, triethylamine, trimethylamine, pyridine, sodium hydride, tert-piperonyl potassium, utility, sodium amide or the like.

The compound of this invention thus obtained can be isolated and purified by the known methods such as extraction, precipitation, separation, chromatography, fractional crystallization, recrystallization. The compound of this invention can also be converted into a desired salt by conventional reactions of formation of salts.

In addition, the compound of this invention can exist in the form of optical isomers, when it has asymmetric carbon atoms. These optical isomers can be separated by conventional fractionated crystallization, in which the isomer precrystallization along with a corresponding salt, or column chromatography.

Industrial application

The compound of this invention exhibits strong anticoagulate action by specific inhibition of activated factor X in the coagulation of blood. Accordingly, the connection applicable as an inhibitor of blood coagulation or medicines for the prevention and Leche is of diseases, caused by thrombosis or embolism.

Examples of such diseases include cerebrovascular diseases such as stroke, cerebral thrombosis, cerebral embolism, transient cerebral blood flow (pnmc, TIA), subarachnoid hemorrhage (vasospasm), and the like, ischemic heart disease, such as acute or chronic myocardial infarction, unstable angina, thrombosis coronary arteries and the like, vascular diseases of the lung, such as lung thrombosis, pulmonary embolism and the like, and various vascular diseases, such as blockage of peripheral artery disease, deep vein thrombosis, disseminated intravascular coagulation, thrombus formation after surgery for replacement of blood the artificial vessel or after artificial valve, re-occlusion and re-stenosis after surgery coronary artery bypass grafting, re-occlusion and re-stenosis after surgery, CVCA (percutaneous intraluminal coronary angioplasty) or CWCR (percutaneous intraluminal coronary recanalization) and thrombus formation during extracorporeal circulation.

In addition, it has been suggested the possibility of using compounds with overwhelming activated factor X coagulate the blood and action, as a medicine to use for the prevention and treatment of infection caused by the influenza virus, based on its activity to suppress the growth of influenza virus (Japanese Patent Laid-Open No. 227971/1994), and therefore, it is believed that the compound of this invention also has the same effect.

The high activity of the compounds of this invention on the inhibition of activated factor X in the coagulation of blood was confirmed by the following tests.

1) Test for the measurement of coagulation time of the blood with the help of activated factor X in the coagulation of blood.

To 90 μl of human blood plasma was added 10 μl of drug or saline solution and 50 μl of factor XA person (Enzyme Research Labs), incubation was carried out at 37°C for 3 minutes, was added 100 μl of 20 mm CaCl2pre-heated to 37°and the time until coagulation was measured using coagulometer (X from Amelung). With regard to the human blood plasma, every 45 ml of blood was collected from the cubital vein of six healthy volunteers, using a syringe containing 5 ml of 3.8% sodium citrate, and centrifuged at 4°C for 15 minutes at 3000 rpm and separated blood plasma were combined and frozen until use. Regarding factor Ha man, was chosen as the concentration at which coagulation time when EXT is vlassa saline (control), approximately 30-40 seconds. The CT value2(the concentration at which coagulation time is increased twofold) was determined by plotting a graph of the concentration of the medicinal product and the relative value (ratio) time of coagulation in relation to the control with subsequent presentation of linear regression. The result is shown forth in the following table 1.

2) Test for the measurement of coagulation time of using bovine thrombin

To 50 μl of human plasma was added 50 μl of drug or saline solution, incubation was carried out at 37°C for 3 minutes, was added 50 μl of a solution of thrombin (500 units thrombin (derived from the bull; Mochida Pharmaceuticals)), preheated to 37°and he measured the time until coagulation using coagulometer (X from Amelung). With regard to the human blood plasma, every 45 ml of blood was collected ie cubital vein of six healthy volunteers, using a syringe containing 5 ml of 3.8% sodium citrate, and centrifuged at 4°C for 15 minutes at 3000 rpm and separated blood plasma were combined and frozen until use. In respect of thrombin, was chosen as the concentration at which coagulation time, when added to the physiological solution (control)was approximately 20 seconds. Is ARTICLE2(the concentration at which time coagu is acii increases twice) were determined, plotting a graph of the concentration of the medicinal product and the relative value (ratio) time of coagulation in relation to the control with subsequent presentation of linear regression. The result is shown forth in the following table 1.

Table 1.
 ConnectionThe test for the measurement of coagulation time of blood through ACTIVIA cell factor X coagulation of human blood (ST2) (μm)The test for the measurement of coagulation time of using bovine thrombin (CL2) (μm)
ConnectionExample 11,71>100
exampleExample 31,33>100
ControlControl 1of 17.0>100
connectionControl 211,3-

3) Test for the measurement of suppression of enzyme activity by the method with a synthetic substrate

In a 96-well plate was added 80 μl of the reaction buffer (pH 8,4), 15 μl of a medicinal product and 30 μl of a 2 mm solution of the synthetic substrate S-2222 (Chromogenix)was then added to the 25 μl of 0.025 U/ml of activated factor X in the coagulation of human blood (factor XA; Enzyme Research Labs), the reaction was carried out at 37°C for 10 minutes, the change in absorption at 405 nm was measured using Bio-Rad, model 3550, and hoped IC50.

Measurements in the above 1), 2) and 3) it was confirmed that the compound of the present invention specifically inhibits activated factor X in the coagulation of blood and manifests strong anticoagulate action on the blood. For example, the compounds shown in examples 1 and 3 of the present invention, as confirmed explicitly extended coagulation at low concentrations, showing excellent activity against blood coagulation compared with example 42 (control 1) and example 198 (control 2) of WO 99/00121, which are believed to have a structure most similar to the compounds of the present invention.

4) Test on the measurement of ex vivo time coagulation in mice (oral administration)

Drug, which are dissolved or suspended in 0.5% methylcellulose, forcibly administered per os (100 mg/kg) via oral probe to male ICR mice (20-30 g; Nippon SLC), starving for 12 hours or more, and after 30 minutes and 2 hours under anesthesia with diethyl ether selected 0.9 ml of blood from the inferior Vena cava syringe containing 100 μl of 3.8% sodium citrate, and blood plasma was separated by centrifugation at 3000 rpm for 10 minutes. Using the obtained plasma is blood, measured time of the external coagulation (PT; RT) and the internal blood clotting (CATV; ART) in accordance with the following methods (a) and (b).

a) the Time of the external coagulation (PT)

Net thromboplastin ortho (54 mg/vial; liofilizovannye drug; Ortho Clinical diagnostics) was dissolved in 2.5 ml of water Milli-Q and pre-warmed up at 37°C. above the separated blood plasma (50 µl) warmed up with 30°C for 1 min, was added the above solution of thromboplastin and measured clotting time. For measuring clotting time used Amelung KC 10A.

b) the internal coagulation (CATV)

To 50 μl of the above-mentioned plasma was added 50 μl Hemoliance Thrombosil I (Dia latron), the mixture warmed up at 37°C for 3 minutes, was added 50 μl of a 20 mm solution of CaCl2pre-heated to 37°and he measured clotting time. For measuring clotting time used the CC 10A manufactured by Amelung.

Also studied the dependence anticoagulative action is dose-dependent and temporal changes when you change the input dose or clotting time of blood.

5) Test ex vivo measurement of coagulation time of the cynomolgus monkeys (oral administration)

Drug (5 mg/ml), which was dissolved (suspended) in 0.5% methylcellulose, forcibly administered per OS at a dose of 2 ml/kg (10 mg/kg) che the ez oral probe after blood collection before the introduction of drugs to the male cynomolgus monkeys (weighing about 4 kg), starving for 12 hours or more, and after 1, 2, 4, 6 and 8 hours, 2 ml of blood was collected from the femoral vein using 1/10 volume of 3.8% solution of sodium citrate and blood plasma was separated by centrifugation at 3000 rpm for 10 minutes. Using the obtained blood plasma was determined by the time of the external coagulation (PT) and the internal blood clotting (CATV) the above methods (a) and (b). By the way, the experiment was performed without anesthesia.

In tests 4 and 5), it was confirmed that the compound of the present invention has an effect to increase clotting time and also by oral administration.

Pharmaceutical composition, which contains as active ingredient one or more compounds of this invention represented by formula (I)or their pharmaceutically acceptable salts, are produced in the form of tablets, diluted powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, plasters and the like using commonly used carriers, fillers and other additives and injected or oral, or parenteral.

The choice of the clinical dosage of the compounds of this invention in humans, if possible, takes account of the symptoms, body weight, age, sex and the like of each patient who needs treatment, and usually the leaves from 0.1 to 500 mg for oral administration or from 0.01 to 100 mg for parenteral administration per day for an adult, moreover, the daily dose is divided into one or more doses per day. As the dose varies under different conditions, in some cases it may be sufficient a smaller dose than the specified interval.

Solid composition for use in oral administration according to this invention is applied in the form of tablets, diluted powders, granules and the like. In such solid compositions one active substance or more is mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid or magnesium aluminate. Usually in addition to the inert diluent, the composition may contain other additives, such as increasing the slip agent (e.g., magnesium stearate), disintegrity agent (for example, Cellulosics calcium), stabilizing agent (e.g., lactose) and solubilizing auxiliary agent (for example, glutamic acid and aspartic acid). If necessary, tablets or pills may be coated with a film of a substance soluble in the stomach or intestines, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose and the like.

Liquid compositions for oral administration include pharmaceutically PR is acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contain commonly used inert diluent, such as pure water or ethanol. In addition to the inert diluent, this composition may also contain auxiliary agents, such as solubilizers agent or solubilizers an adjuvant that increases the wetting agent, suspendisse agent and the like, as well as sweeteners to improve the taste and smell, flavorings and preservatives.

Injectable preparations for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the diluent for use in aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of diluents for use in non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oil (e.g. olive oil), alcohol (e.g. ethyl alcohol), Polysorbate 80 (trade mark) and the like.

Such a composition may further contain additives such as an isotonic agent, an antiseptic agent that increases the wetting agent, emulsifier, dispersing agent, a stabilizer (e.g., lactose) and increases the dissolving agent or auxiliary solubilizers tool. These compo is icii sterilized by filtration through inhibiting bacteria filters, adding to the mixture of antibacterial agents or irradiation. Alternatively, they can be applied first production of sterile solid compositions and then dissolving them in sterile water or a sterile solvent for injection before use.

The best way of carrying out the invention

The following description specifically illustrates a method of obtaining compounds of this invention with reference to examples of the preparation of compounds of the present invention. Due to the fact that the starting materials for compounds of the present invention include new compounds, methods for their preparation are also described as reference examples.

Reference example 1

3-Hydroxy-2-nitrobenzoic acid (1,83 g) was dissolved in 50 ml of N,N-dimethylformamide was then added to 1.23 g of 4-methoxyaniline, 2.50 g of 1-ethyl-3-dimethylaminopropylamine-hydrochloride, 1.35 g of 1-hydroxybenzotriazole and is 1.81 ml of triethylamine and the mixture was stirred at room temperature for 66 hours. The reaction solution was concentrated in vacuo, added water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate and concentrated in vacuum. To the obtained residue was added chloroform and the resulting precipitate was filtered to obtain 2,04 g of 3-hydroxy-4'-methoxy-2-nitrobenzamide the Filtrate was purified column chromatography on silica gel, using a mixture of chloroform-methanol (98:2) as eluting solvent, the obtained crude product was added chloroform and the resulting precipitate was filtered to obtain additional 0.24 g of 3-hydroxy-4'-methoxy-2-nitrobenzamide.

Reference example 2

3-Hydroxy-4'-methoxy-2-nitrobenzamide (1/15 g) suspended in 50 ml of methanol, was added 300 mg of powder of 10% palladium on coal and the mixture was stirred in hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered through celite and washed with methanol and the filtrate was concentrated in vacuum to obtain 966 mg of 2-amino-3-hydroxy-4'-methoxybenzanilide.

Reference example 3

4-(4-Methyl-1,4-diaaepam-1-yl)benzonitrile (18,86 g) was dissolved in 185 ml of 12 N aqueous hydrochloric acid was stirred for 12 hours and concentrated in vacuum. Added water, the mixture was stirred at room temperature and the resulting precipitate was filtered and washed with water. The obtained solid was dried in vacuum to obtain 18,25 g of the hydrochloride of 4-(4-methyl-1,4-diazepan-1-yl)benzoic acid.

Reference example 4

The hydrochloride of 4-(4-methyl-1,4-diazepan-1-yl)benzoic acid (6,09 g) was dissolved in 23 ml of thionyl chloride and stirred at 60°C for 1 hour. The reaction solution was concentrated under vacuum, was added toluene and the mixture is again con who was interaval in vacuum. The resulting residue is suspended in 120 ml of pyridine, was added 3,82 g 2-amino-3-NITROPHENOL at 0°and the mixture was stirred at room temperature for 3 days. Was added ethanol (10 ml) followed by stirring for 1 hour. The reaction solution was concentrated in vacuo, to the residue was added chloroform, and the mixture was podslushivaet 200 ml of 5% aqueous sodium bicarbonate solution and was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The obtained residue was purified column chromatography on silica gel using a mixture of chloroform-methanol-saturated aqueous ammonia (100:10:1) as eluting solvent. The purified product (4,92 g) is 4.93 g, obtained above, was dissolved in 130 ml of ethanol was added 500 mg of powder of 10% palladium on coal and the mixture was stirred in hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through celite and concentrated in vacuum. The obtained residue was dissolved in 130 ml of methanol, was added 1.50 g of powder of 10% palladium on coal and the mixture was stirred in hydrogen atmosphere at room temperature for 12 hours and then was stirred in hydrogen atmosphere at a pressure of 3 atmospheres at room temperature for 20 hours. The reaction solution was filtered through celite and co is centered in vacuum to obtain 3.42 g of 2'-amino-6'-hydroxy-4-(4-methyl-1,4-diazepan-1-yl)benzanilide.

Reference example 5

3-Hydroxy-2-nitrobenzoic acid (10.5 g) was dissolved in 60 ml of N,N-dimethylformamide was then added 15 ml of benzylbromide and 19.0 g of potassium carbonate at 0°and the mixture was stirred for one night at room temperature. The reaction solution was filtered through celite and concentrated in vacuum. To the obtained residue was added water and the mixture was extracted with ether, washed with brine and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum to obtain 20.7 g benzyl 3-benzyloxy-2-nitrobenzoate.

Reference example 6

To 20.7 g benzyl 3-benzyloxy-2-nitrobenzoate was added 100 ml of ethanol and 120 ml of 1 N aqueous sodium hydroxide solution and the mixture was stirred at room temperature for one night at 60°C for 3 hours and at 80°C for 5 hours. After the ethanol evaporated in vacuo, the resulting aqueous solution was washed with ether and was added an aqueous solution of hydrochloric acid. The precipitate was filtered and dried in vacuum to obtain to 15.8 g of 3-benzyloxy-2-nitro-benzoic acid.

Reference example 7

To 5,47 g of 3-benzyloxy-2-nitrobenzoic acid was added 20 ml of thionyl chloride and a few drops of N,N-dimethylformamide and the mixture was stirred at 80°C for 30 minutes. The reaction solution was concentrated in vacuo, to the residue was added 35 ml of n is Regina and 2.55 g of 2-amino-5-chloropyridine at 0° C and the mixture was stirred at room temperature for one night. The reaction solution was concentrated in vacuo, to the residue was added saturated aqueous sodium bicarbonate solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuum and the residue was subjected to eEurope processing toluene with getting 7,44 g of 3-benzyloxy-N-(5-chloro-2-pyridyl)-2-nitrobenzamide.

Reference example 8

To 7,44 g of 3-benzyloxy-N-(5-chloro-2-pyridyl)-2-nitrobenzamide was added 40 ml triperoxonane acid and 3.72 g of pentamethylbenzene and the mixture was stirred at 40°C for one night. The reaction solution was concentrated in vacuo, to the residue was added saturated aqueous sodium bicarbonate solution until such time as the balance does not become alkaline, and the mixture was extracted with chloroform. The organic layer was extracted with 1 N aqueous sodium hydroxide solution and the aqueous layer was acidified by addition of an aqueous solution of hydrochloric acid and was extracted with chloroform. The extract was dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuo and to the residue was added 200 ml of an ethanol suspension of Raney Nickel. The mixture was stirred in hydrogen atmosphere for 6 hours, was added N,N-dimethylformamide and insoluble substances tfilter is provided. The solvent is evaporated in vacuo and to the residue was added water. The obtained residue was filtered and dried in vacuum to obtain 4,58 g 2-amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide.

Reference example 9

2-Amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (a 3.06 g) and of 1.80 g of N-chlorosuccinimide was dissolved in 60 ml of N,N-dimethylformamide, the solution was stirred at 50°C for 8 hours and at room temperature for 4 hours and the insoluble substance was filtered. After the solvent is evaporated in vacuo, to the residue was added 1 N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuum and the obtained residue was purified column chromatography on silica gel. To the obtained crudely purified product was added ethanol and the resulting precipitate was filtered and dried in vacuum to obtain 767 mg of 2-amino-5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide.

The mother liquid was concentrated, was added a mixture of ethyl acetate and isopropylalcohol ether and the resulting precipitate was filtered and dried in vacuum to obtain additional 942 mg of the above compound.

Compounds of reference examples 10 and 11 were obtained in the same manner as in reference example 9.

Reference the use of the 12

Ethyl 2-amino-5-chloro-3-hydroxybenzoate (3,23 g) was dissolved in 160 ml of 3 N aqueous hydrochloric acid and stirred at 85°C for 3 hours and at 80°C for 5 days. The reaction solution was cooled to room temperature, insoluble substances were filtered off, the filtrate was added 320 ml of 1 N aqueous sodium hydroxide solution and the mixture was stirred at room temperature for 1 hour. The obtained residue was filtered off, washed with pure water and dried in vacuum to obtain 1.55 g of 2-amino-5-chloro-3-hydroxybenzoic acid.

Reference example 13

2-Amino-5-chloro-3-hydroxybenzoic acid (1.12 g) was dissolved in 60 ml of N,N-dimethylformamide was then added 7,38 g of 4-methoxyaniline, 1.73 g of 1-ethyl-3-dimethylaminopropionitrile, to 1.21 g of 1-hydroxybenzotriazole and 1.26 ml of triethylamine and the mixture was stirred at room temperature for 13 hours. The reaction solution was concentrated in vacuo, to the residue was added ethyl acetate and the mixture washed with clean water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuum. To the obtained residue was added chloroform, and the mixture was stirred for 30 minutes and the precipitate was filtered off, washed with chloroform and dried in vacuum to obtain 0.96 g of 2-amino-5-chloro-3-hydroxy-4'-methoxy-2-benzanilide.

Example 1

G is drochloric 4-(4-methyl-1,4-diazepan-1-yl)benzoic acid (812 mg) was dissolved in 8 ml of thionyl chloride and stirred at 60° C for 30 minutes. The reaction solution was concentrated and dried in vacuum. Solution, where 774 mg of 2-amino-4’-methoxy-3-hydroxybenzamide dissolved in 15 ml of pyridine was added to the resulting residue at 0°and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo, to the residue was added toluene and the mixture is again concentrated under vacuum. To the obtained residue was added saturated aqueous sodium bicarbonate solution and ethyl acetate and the resulting precipitate was filtered. An ethyl acetate layer the mother liquor was dried over anhydrous sodium sulfate and concentrated in vacuum. The obtained residue was mixed with the filtered residue was purified column chromatography on silica gel using a mixture of chloroform-methanol (98:2) as eluting solvent, to obtain 873 mg of 3-hydroxy-4’-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide. The compound obtained suspended in 10 ml of ethanol, was added 0.7 ml of a solution of 4 N hydrochloric acid in ethyl acetate, and the mixture was stirred and the resulting precipitate was filtered, washed with ethanol and dried in vacuum to obtain 896 mg of the hydrochloride of 3-hydroxy-4'-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide.

The compounds of examples 2-4, 8 and 9 were obtained by the method of example 1.

Example 5

2'-Amino-6'-hydroxy-4-(4-methyl-1,4-diazepan-1-yl)benzanilide (2,03 g) was dissolved in 60 ml of pyridine, added 1.12 g of 4-methoxybenzylamine at 0°and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated in vacuo, to the residue was added 150 ml of chloroform and the mixture was podslushivaet 150 ml of 5% aqueous sodium bicarbonate solution and was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum, was added toluene and the mixture is again concentrated under vacuum. The obtained residue was purified column chromatography on silica gel using a mixture of chloroform-methanol-saturated aqueous ammonia (100:10:1) as buyukdere solvent. The residue was recrystallized from ethanol with the receipt of 1.74 g of 3-hydroxy-Nl-(4-methoxybenzoyl)-N2-[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine. 1.10 g of 3-hydroxy-N1-(4-methoxybenzoyl)-N2-[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine and 269 mg of maleic acid was dissolved in 11 ml of 50% ethanol-water solution by heating, was added 11 ml of water and cooled. The obtained crystals were filtered and dried to obtain 1.18 g of the maleate of 3-hydroxy-N1-(4-methoxybenzoyl)-N2-[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine.

Example 6

The hydrochloride of 4-(4-methyl-1,4-diazepan-1-yl)benzoic acid (755 mg) was dissolved in 2.2 ml of thionyl chloride and paramashiva and at 60° C for 30 minutes. The reaction solution was concentrated and dried in vacuum. To the residue was added a solution of 891 mg of 2-amino-5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide in 10 ml of pyridine and the mixture was stirred at room temperature for 13 hours. The reaction solution was concentrated in vacuo, to the residue was added 20 ml of acetic acid and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated in vacuo, to the residue was added saturated aqueous sodium bicarbonate solution and the mixture was extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of chloroform-methanol-aqueous ammonia (97:3:0.3 to 95:5:0.5 to) as an eluting solvent to obtain roughly purified 5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide. This substance was further purified ODS column chromatography using a mixture of acetonitrile-0,002 N aqueous solution of hydrochloric acid (2:8 to 3:7) as an eluting solvent, suspended in a dilute aqueous solution of hydrochloric acid and liofilizovane with getting 492 mg of the hydrochloride of 5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide.

Connection example was synthesized in the same manner as in example 6.

Structural formulas and physical-chemical properties of the compounds of the above reference examples and examples are presented in tables 2-5. Symbols in the tables have the following meanings.

JV:Reference example No.
PR:Example No.
Structure:The structural formula
Sol:Sol

Free:Free base
Data:Physico-chemical data
NMR:Spectrum of nuclear magnetic resonance (TMS international standard)
FAB-MS:Analytical mass value
Me:Methyl
Et:Ethyl
Table 2
SPStructure (Sol)Data
1NMR (DMSO-d6) δ: 3,74(3H, s), 6,92(2H, d, J=8,8 Hz), 7,19-7,30 (2H, m)to 7.50 (1H, t, J=8.6 Hz), 7,58 (2H, d, J=9.3 Hz), 10,46 (1H, s), 11,25 (1H, Sirs).
2 NMR (DMSO-d6) δ: 3,74 (3H, s), 5,79(2H, s), 6,46 (1H, t, J=7.8 Hz), PC 6.82 (1H, d, J=7.8 Hz), make 6.90 (2H, d, J=8,8 Hz), to 7.15 (1H, d, J=7.8 Hz), to 7.61 (2H, D, J=8,8 Hz), of 9.56 (1H, s), 9,81 (1H, s)
3NMR (DMSO-d6) δ: 2.06 to of 2.24 (1H, m), 2,30 at 2.45 (1H, m), 2,77 (3H, s), 3.00 and-3,24 (2H, m), 3,24-3,55 (4H, m), 3,70-4,00 (2H, m), for 6.81 (2H, d, J=9.1 Hz), 7,78 (2H, d, J=9.1 Hz), 11,06 (1H, s), 12,20 (1H, s).
4NMR (DMSO-d6) δ: 1,99-2,07 (2H, m), 2,39 (3H, s), 2,55 at 2.59 (2H, m), 2.71 to to 2.74 (2H, m), 3,54-to 3.58 (2H, m), 3,62-the 3.65 (2H, m), 6.42 per (1H, DD, J=1.1 Hz, 7.9 Hz), 6,60 (1H, DD, J=1.1 Hz, 8,3 Hz), of 6.71 (2H, d, J=9.0 Hz), 6,95-7,00 (1H, m), 7,81 (2H, d, J=9.0 Hz), to 7.93 (1H, Sirs)
5NMR (DMSO-d6) δ: 5,33 (4H, s), 7,31 was 7.45 (10H, m), to 7.61 (1H, DD, J=1.4 Hz, 7.5 Hz), to 7.68(1H, t, J=7.9 Hz), 7,74(1H, DD, J=1.5 Hz and 8.2 Hz).

6NMR (DMSO-d6) δ: 5,32(2H, s), 7,31-7,44 (5H, m), 7,56 (1H, DD, J=1.7 Hz, 7,3 Hz), to 7.64 (1H, t, J=7.9 Hz), to 7.68 (1H, DD, J=1.7 Hz, 8,3 Hz).
7NMR (DMSO-d6) δ: 5,23 (2H, s), 7,22-7,26 (2H, m), 7,31-7,39 (5H, m), 7,46 (1H, t, J=8,3 Hz), 7,69 (1H, DD, J=2.7 Hz, 9.1 Hz), and 8.0 (1H, d, J=2,9 Hz), compared to 8.26 (1H, d, J=8,8 Hz), 9,01 (1H, Shir. C).
Table 3
SPStructure (Sol)Data
8NMR (DMSO-d6) δ: to 5.93 (2H, s), 6,44 (1H, t, J=7.9 Hz), PC 6.82 (1H, d, J=7,7 Hz), 7,27 (1H, d, J=7,3 Hz), to 7.93 (1H, DD, J=2,6 Hz, 9.0 Hz), 8,14 (1H, d, J=8,8 Hz), to 8.41 (1H, d, J=2.4 Hz), 9,60 (1H, s), 10,46 (1H, ).
9NMR (DMSO-d6) δ: 6,04 (2H, Sirs), to 6.80 (1H, d, J=2.4 Hz), was 7.36 (1H, d, J=2.0 Hz), to 7.93 (1H, DD, J=2,5 Hz and 8.8 Hz), 8,11 (1H, d, J=9.3 Hz), 8,42 (1H, d, J=2.5 HZ), 10,16 (1H, Sirs), 10,67 (1H, s).
10NMR (DMSO-d6) δ: the 6.06 (2H, Sirs), of 6.90 (1H, d, J=2.2 Hz), 7,47 (1H, d, J=2.2 Hz), to 7.93 (1H, DD, J=2,8 Hz, 9.0 Hz), 8,10 (1H, d, J=9.0 Hz), 8,42 (1H, d, J=2.2 Hz), 10,15 (1H, Sirs), 10,69 (1H, s).
11NMR (DMSO-d6) δ: to 1.38 (3H, t, J=7,3 Hz)to 4.33 (2H, q, J=7,3 Hz), 5,00-6,30 (3H, W), for 6.81 (1H, d, J=2.0 Hz), of 7.48 (1H, d, J=2,4 Hz).

12NMR (DMSO-d6) δ: 3,37 (1,5H, Sirs), is 6.78 (1H, d, J=2.4 Hz), 7,17 (1H, d, J=2.5 Hz), 8.34 per (1,5H, Sirs), 10,19 (1H, s).
13NMR(DMSO-d 6) δ: 3,74 (3H, s), to 5.93 (2H, Sirs), is 6.78 (1H, d, J=1.9 Hz), 6,91 (2H, d, J=9.3 Hz), 7.23 percent (1H, d, 3=2.5 Hz), to 7.59 (2H, d, J=9.3 Hz), for 9.90 (1H, s), of 10.09 (1H, Sirs).
Table 4
PRStructure (Sol)Data
1NMR (DMSO-d6) δ: 2,10-to 2.41 (2H, m), 2,78 (3H, s), 3,02-up 3.22 (2H, m), 3,35 is 3.57 (4H, m), 3,67-3,81 (4H, m) a 3.87-to 3.99 (1H, m), 6,80-to 6.95 (4H, m), 7,11 (1H, d, J=7,3 Hz), 7,17-7,28 (2H, m), EUR 7.57 (2H, d, J=8,8 Hz), 7,85 (2H, d, J=8,8 Hz), 10,02 (1H, s), 10,19 (1H, s), 10,41 (1H, s), at 10.64 (1H, Sirs). FAB-MS(m/z): 475(M+N)+
2NMR (HMCO-d6) δ: 2,12-of 2.21 (1H, m), 2, 26-2,39 (1H, m), 2,78 (3H, s), 3,03-3,20 (2H, m), 3,30-of 3.54 (4H, m), 3.72 points-of 3.78 (1H, m), 3,89-of 3.96 (1H, m), at 6.84 (2H, d, J=9.3 Hz), 7,10-7,13 (1H, m), 7,15-to 7.18 (1H, m), 7,22-7,26 (1H, m), of 7.36 (2H, d, J=8,8 Hz), 7,71 (2H, d, J=8.7 Hz), the 7.85 (2H, D, J=8,8 Hz), 9,96 (1H, s), 9,99 (1H, s), the 10.40 (1H, s), of 10.76 (1H, Sirs). ESS-MS(m/z): 479 (M+N)+
3NMR (DMSO-d6) δ: 2,10-2,22 (1H, m), 2,28-to 2.41 (1H, m), 2,77 (3H, d, J=4.9 Hz), 3,02-is 3.21 (2H, m), 3,38 is 3.57 (4H, m in), 3.75 (1H, DD, J=9.7 Hz, 16.1 Hz), 3,93 (1H, DD, J=2,9 Hz, 16.6 Hz), 6,85 (2H, d, J=8,8 Hz), 7,09-7,27 (5H, m), 7,69 (2H, DD, J=5,1 Hz, 9.1 Hz), the 7.85 (2H, D, J=8,8 Hz), 9,75-10,10 (1H, Shir), 10,14 (1H, s), 10,86 (1H, Sirs). FAB-MS(m/z): 463 (M+N)+

4/img> NMR (DMSO-d6) δ: 2,11-to 2.40 (1H, m), and 2.27 (3H, s), 2,78 (3H, s), 3,01-up 3.22 (2H, m), 3,38-3,55 (4H, m), of 3.73 (1H, DD, J=9.7 Hz, 16.1 Hz), 3,93 (1H, d, J=15.1 Hz), 6,83-6,91 (3H, m), 7,11 (1H, DD, J=1.4 Hz, 8,3 Hz), 7,15-then 7.20 (2H, m), 7,24 (1H, t, J=7.8 Hz), 7,44 (1H, d, J=8,3 Hz), 7,49 (1H, s), 7,86 (2H, d, J=8,8 Hz), 9,96 (1H, s), 10,14 (1H, s), 10,17 (1H, s), 10,54 (1H, Sirs). FAB-MS(m/z): 459(M+H)+
5NMR (DMSO-d6) δ: 2,11-of 2.20 (2H, m), and 2.83 (3H, s), 3,20 is-3.45 (4H, m), 3,52 (2H, t, J=6.0 Hz), 3.72 points-3,88 (5H, m), 6,03 (2H, s), to 6.80 (1H, d, J=8.0 Hz), 6,85 (2H, d, J=8,8 Hz),? 7.04 baby mortality (2H, d, J=8,8 Hz), 7,14 (1H, t, J=8.0 Hz), 7,24 (1H, d, J=8.0 Hz), the 7.85 (2H, d, J=8,8 Hz), to $ 7.91 (2H, d, J=8,8 Hz), for 9.47 (1H, s), 9,67 (1H, s), 9,77 (1H, s). FAB-MS(m/z): 475(M+H)+
Table 5
PRStructure (Sol)Data
6NMR (DMSO-d6) δ: 2,10-of 2.21 (1H, m), 2,30-is 2.37 (1H, m), and 2.79 (3H, d, J=4.9 Hz), 3,02-is 3.21 (2H, m), 3,37 of 3.56 (4H, m), 3,66-of 3.95 (2H, m), for 6.81 (2H, d, J=8,8 Hz), 7,15 (2H, s), of 7.82 (2H, D, J=8,8 Hz), 7,89 (1H, DD, J=2,5 Hz and 8.8 Hz), 8,08 (1H, d, J=8,8 Hz), at 8.36 (1H, d, J=2.4 Hz), of 9.51 (1H, s), 10,33-10,63 (2N, W), is 10.68 (1H, s). FAB-MS(m/z): 514(M+H)+
7NMR (DMSO-d6) δ: 2,10 is 2.33 (2H, m), and 2.79 (3H, s), 3,01-up 3.22 (2H, m), 3,35-3,51 (4H, m), 3,65-with 3.79 (1H, m), 3,85-3,98 (1H, m), for 6.81 (2H, d, J=8,8 Hz), 7,27 (2H, s), of 7.82 (2H, d, J=9.3 Hz), 7,89 (1H, DD, J=2.5 Hz, 8,8 Hz), 8,08 (1H, d, J=9,2 Hz), at 8.36 (1H, d, J=2,9 Hz), 9,50 (1H, s)to 1.37 (1H, Sirs), 10,44 (1H, s), 10,69 (1H, s)FAB-MS(m/z): 558, 560(M+H)+
8NMR (DMSO-d6) δ: 2,22 (2H, Sirs), is 2.74 (3H, s), 3.00 and-3,60 (6N, m), 3,81 (2H, Sirs), PC 6.82 (2H, d, J=9.3 Hz), 7,10-of 7.25 (3H, m), 7,83 (2H, d, J=8,8 Hz), of 7.90 (1H, DD, J=2,8 Hz, 9.1 Hz), 8,13 (1H, d, J=8.7 Hz), 8,35 (1H, d, J=2.5 Hz), 9,71 (1H, s), for 9.95 (1H, s), of 10.58 (1H, s), to 10.62-10,88 (1H, Shir). FAB-MS(m/z): 480 (M+H)+

9NMR (DMSO-d6) δ: 2,10-of 2.34 (2H, m), of 2.81 (3H, s), 3,01-of 3.25 (2H, m), 3,35-of 3.60 (4H, m), 3,62-with 3.79 (4H, m), 3,82-4,00 (1H, m), at 6.84 (2H, d, J=9.3 Hz), to 6.88 (2H, d, J=8,8 Hz), 7,12 (1H, d, J=2.5 Hz), 7,18 (1H, d, J=2.4 Hz), 7,54 (2H, d, J=9.3 Hz), to 7.84 (2H, d, J=8,8 Hz), 9,86 (1H, Sirs), 9,96 (1H, s), 10,16 (1H, s), 10,43 (1H, s). FAB-MS(m/z): 509(M+H)+

1. Diazepinone derivative of General formula (I) or its pharmaceutically acceptable salt:

where the ring is a phenyl;

ring a is a pyridyl, optionally substituted with halogen, or phenyl, optionally substituted lower alkyl, lower alkoxy or halogen;

X1represents-C(=O)-NR2- or-NR2-C(=O)-, where R2represents a hydrogen atom;

X2represents-C(=O)-NR3- or-NR3-C(=O)-, where R3represents a hydrogen atom;

R represents a hydrogen atom or a halogen atom;

R1represents lower alkyl.

2. Diazepinone derivative or its salt according to claim 1, in which ring b is a phenyl, ring a is a phenyl substituted lower alkoxy.

3. Diazepinone derivative or its salt according to claim 1 selected from 3-hydroxy-4'-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide, 3-hydroxy-N1-(4-methoxy-benzoyl)-N2-[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine, 5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide and 5-chloro-3-hydroxy-4'-methoxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzanilide, 5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide, or their pharmaceutically acceptable salts.

4. Pharmaceutical composition having activity inhibitor of activated factor X in the coagulation of blood, containing as the active ingredient diazepinone derivative or its pharmaceutically acceptable salt as defined in claim 1.

5. Inhibitor of activated factor X in the coagulation of blood, representing diazepinone derivative or its salt according to claim 1.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, insecticides, chemical technology.

SUBSTANCE: invention describes derivative of 1-aryl-3-cyano-5-heteroarylalkylaminopyrazole of the general formula (1): wherein A means: (A-1) , (A-2) , (A-3) and (A-4) and wherein X represents C-halogen; R1 represents (C1-C4)-alkyl group or halogen-(C1-C4)-alkyl group; A represents any group among (A-1) - (A-4) wherein R4 represents hydrogen atom or (C1-C4)-alkyl group; n = 0, 1 or 2 under condition that R1 represents halogen-(C1-C4)-alkyl group with exception for perhalogenalkyl group when A represents (A-1) and n = 0, and that n doesn't equal 0 when A represents (A-4). Also, invention describes derivative of pyrazole of the formula (2): wherein A means: (A-1) and Y means: (Y-1) , (Y-2) and (Y-3) wherein X, R2, R3 and R4 have values given above; R5 represents hydrogen atom; A represents (A-1); Y means any group among (Y-1) - (Y-3); Z represents halogen atom that are intermediate compounds used for synthesis of the compound (1). Invention describes methods for preparing compounds of the formula (1) and (2) and insecticide comprising compound of the formula (1) as an active component. Insecticide shows high systemic activity, high safety and reduced harmful effect on environment in vicinity areas of its applying.

EFFECT: improved methods for preparing, valuable insecticide properties of compound.

11 cl, 9 tbl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new heterocyclic compounds corresponding to general formulas: (I) , (II) , (Ia) and (Ib) wherein substitutes have values given in the description. Such compounds are reversible inhibitors of cathepsins S, K, F, L and B. Also, invention relates to a method for preparing these compounds, pharmaceutical composition eliciting inhibitory activity with respect to cysteine proteases and to a method for modulation of autoimmune diseases, treatment of Alzheimer's disease and osteoporosis.

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

42 cl, 106 ex

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compound: N-[2-hydroxy-3(1-piperidinyl)-propoxy]-pyridine-1-oxyde-3-carboxyimidoyl chloride, stereoisomers thereof acid additional salts useful in treatment of pathological insulin resistance.

EFFECT: new compound useful in medicine.

5 cl, 10 tbl, 10 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

The invention relates to organic chemistry and can find application in medicine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes applying the known 2-imidazolyl-substituted carbinols as inhibitor of Na+/H+ exchange in treatment or prophylaxis of diseases caused by ischemia (myocardium infarction, stenocardia, heart ischemic state, ischemic state of peripheral and central nervous system, insult, shock state, hypoxic states of donor organs in removing, storage and transplantation in the recipient body). Also, compounds can be used as anti-arrhythmic agents with cardioprotective effect and for prophylaxis of high blood pressure genesis in essential hypertension.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: medicine, surgery.

SUBSTANCE: medicinal mixture consisting of 10 ml 0.25%-novocaine, 1 ml 1%-emoxypin and 64 c.u. lidase should be injected strictly subcutaneously per 1 ml for each point of injection into the center of plantar surface of nail phalanx of every toe, and for the first inter-toe space - subcutaneously in plantar and rear directions, then, after injections, it is necessary to carry out massage in area if injection with stretching and stroking movements in proximal direction for 10-15 sec, moreover curative seances should be performed every other day , the course being of 5-10 procedures, at repeating this course 3-6 mo later. The present innovation enables to activate transcapillary exchange due to pathogenetically proved impact onto surface and deep lymphatic network of inferior limbs.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves inducing angina pectoris attack on no medicament background. Provoking factor action time is measured to the moment the angina pectoris attack takes place. Nitroglycerine is administered in therapeutic dose to reach rapid relief of symptoms. The provoking factor action is repeated to reproduce attack of the same intensity. Provoking factor action time is measured once more. Prediction coefficient K value is calculated as ratio of the repeated provoking factor action time to the provoking factor action time to the moment the angina pectoris attack takes place. Prognosis is considered to be favorable, unfavorable or uncertain during the nearest year depending on K value.

EFFECT: high accuracy in evaluating coronary reserve.

2 tbl

FIELD: medicine, biochemistry.

SUBSTANCE: invention proposes applying CDP-choline (cytidinediphosphocholine) or its salt as a prophylactic agent for treatment of cerebral ischemia and a method for such prophylactic treatment. Invention found new and unknown early mechanism of action of CDP-choline or its salt: inhibition of activation of caspase cascade being the effectiveness of this effect is high in prophylactic intake of drug.

EFFECT: valuable medicinal properties of agent.

6 cl, 5 dwg, 4 ex

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