Derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines, method for their preparing (variants), pharmaceutical composition and applying

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

 

The technical field to which the invention relates.

The present invention relates to new cyanoacryl (or cyanovalerianic)-carbonylmethyl-pyrimidines of General formula (I)and their physiologically acceptable salts, to processes for their preparation, their use as a drug for human therapy and/or for therapeutic use in veterinary medicine and to the containing pharmaceutical compositions

New compounds which are the object of the present invention can be used in the pharmaceutical industry as intermediates for the manufacture of medicines.

The level of technology

In the publication WO 99/05121 described some derivatives of acyl-piperazinil-pyrimidines, among which are the compounds of General formula (I) as agents with sedative, anticonvulsive, hypnotic and General anaesthetic activity. In the specified publication describes derivatives of General formula (I), where R2represents, in particular, the aryl radical and a heteroaryl radical. The term "aryl" represents a phenyl radical, unsubstituted or substituted 1, 2 or 3 identical or different substituents, such as fluorine, chlorine, bromine, Amin, ndimethylacetamide, nitro, methyl, trifluoromethyl or methoxy. The term g is tetraaryl" represents a substituted or unsubstituted 5 - or 6-membered heteroaromatic ring or a substituted or unsubstituted, condensed 9 - or 10-membered heteroaromatic system containing 1 or 2 heteroatoms such as nitrogen, oxygen or sulfur, where the substituents can be groups such as fluorine, chlorine, bromine, Amin, ndimethylacetamide, nitro, methyl, trifluoromethyl or methoxy.

It was found that the introduction of ceanography (-C=N) aryl or heteroaryl radicals leads to the production of new compounds of General formula (I), which are more effective compared to previously described compounds with interesting biological properties that make them particularly useful for human therapy and/or therapeutic use in veterinary medicine. Connection, which is the object of the present invention are useful as agents acting on the Central nervous system of mammals, including humans. In particular, the new compounds are useful as a sedative, anticonvulsive, hypnotic and General anaesthetics.

Detailed description of the invention

The present invention relates to new compounds having the following properties: sedative, anticonvulsive, analgesic, miorelaksantnoe, antitussive, anxiolytic, antipsychotic, antidepressant, against cerebral ischemia, ANTIMIGRAINE, sleep disorders, near the degenerative diseases, disorders of perception and Alzheimer's disease, hypnotic or General anesthetic for mammals, including humans. In particular, the new compounds according to the invention is able to induce conscious sedation, to act as hypnotic tools and products that may cause or maintain General anesthesia, depending on the dose and method of administration.

Connection, which is the object of the present invention have the General structural formula (I)

where R1represents an alkoxy radical and R2represents cyanoaniline or cyanovalerianic radical.

In the present invention, the term "alkoxy" represents a radical OR3where R3represents alkyl, C1-C4(i.e. the alkyl radical of a saturated hydrocarbon with a linear or branched chain with 1 to 4 carbon atoms)such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy.

The term "cyanoacryl" denotes a phenyl radical substituted by at least one cyano radical (-C=N).

The term "cyanovalerianic" denotes the radical of a 5 - or 6-membered heteroaromatic ring or a radical of substituted or unsubstituted condensed 9 or 10-membered heteroaromatic systems containing 1 or 2 heteroatom is a, such as nitrogen, oxygen or sulfur and which is substituted by at least cyano radical (-C=N), such as, for example, 3-cyano-2-furyl, 3-cyano-2-thienyl, 5-cyano-2-thienyl, 3-cyano-2-pyrrolyl, 3-cyano-2-pyridyl, 2-cyano-3-pyridyl, 2-cyano-4-pyridyl, 3-cyano-2-indolyl, 2-cyano-3-indolyl, 3-cyano-2-benzo[b]thienyl or 2-cyano-3-benzo[b]thienyl.

The present invention also relates to physiologically acceptable salts of the compounds of General formula (I), particularly to additive salts of mineral acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, and organic acids, such as n-toluensulfonate or methansulfonate acid.

New derivatives of General formula (I) can be obtained by methods A-G below:

METHOD:

Compounds of General formula (I) can be obtained by reaction of the amine of General formula (II)in which R1is the same as defined above, with a carboxylic acid of General formula R2COOH (III)in which R2has the above meaning, or a salt of this acid or reactive derivative of R2COX (IV) (Scheme 1 ).

Examples of such salts include salts of alkali metals such as sodium and potassium salts, alkaline earth metals such as calcium salts and magnesium, ammonium salt and organic salt on the ground, such as triethylamine, trimethylamine, pyridine and picoline.

Examples of reactive derivatives of the General formula R2SOKH (IV) include derivatives in which X represents a halogen atom, preferably a chlorine atom or bromine, azide group (-N3), 1-imidazolidinyl group, O-CO-R4group, where R4can be alkyl radical with 1-6 carbon atoms or aryl radical, optionally substituted by one or more halogen atoms, or or5group, where R5represents an aromatic group with one or two rings, substituted by one or more halogen atoms or nitroreductase, preferably groups 4-nitrophenyl, 2,4-dinitrophenyl, pentachlorophenyl, pentafluorophenyl, 1-benzotriazolyl or N-succinimide. Similarly, instead of using the above reaktionstechnik derivatives, compounds of General formula (I) can be obtained by the direct interaction of the amine (II) with a carboxylic acid of General formula R2COOH (III), in this case, it is preferable that the reaction proceeded in the presence of activating reagents to carbonyl group, such as N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide or 3-(3-dimethylamino)propyl-1-ethylcarbodiimide. This reaction can also be carried out using the above carbodiimide in presets the following 1-benzotriazole or N-hydroxysuccinimide. Acids of General formula (III) and the amine of General formula (II) also react directly in the presence of N,N'-carbonyldiimidazole or anhydride propriospinal acid.

The reaction proceeds in an organic solvent, for example in organic chlorinated hydrocarbon, such as dichloromethane or chloroform, linear or cyclic ether, such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, polar aprotic solvent, such as pyridine, dimethyl sulfoxide, acetonitrile or dimethylformamide, or any other suitable solvent. The reaction may proceed in the presence of mineral or organic bases, such as aliphatic amine, preferably triethylamine or N-methylmorpholine, under stirring and the temperature being in the range between room temperature and the boiling temperature of the solvent during the period of from ten minutes to twenty-four hours, preferably from thirty minutes to five hours.

METHOD:

New derivatives of General formula (I), where R1is the same as defined above, and R2represents cyanoaniline radical, can be obtained in accordance with the method shown in Scheme 2.

The reaction of the amine of General formula (II), where R1is the same as defined above, with 3-bromophthalide (V) leads to recip is the aldehyde of General formula (VI), where R1is as defined above (Alonso, R., Castedo, L., Dominguez, D., J. Org. Chem. 1989, 54 (2), 424).

The reaction is carried out in an organic solvent, for example in organic chlorinated hydrocarbon, such as dichloromethane or chloroform, linear or cyclic ether, such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, polar aprotic solvent, such as pyridine, dimethyl sulfoxide, acetonitrile or dimethylformamide, or any other suitable solvent. The reaction may proceed in the presence of mineral or organic bases, such as aliphatic amine, preferably triethylamine or N-methylmorpholine, under stirring and the temperature being in the range between room temperature and the boiling temperature of the solvent during the period of from ten minutes to twenty-four hours, preferably from thirty minutes to five hours.

The oxime of General formula (VII), where R1is the same as defined above, is obtained by reaction of an aldehyde of General formula (VI) with hydroxylamine or a hydroxylamine salt. The reaction is carried out in an organic solvent, such as ethanol, or a mixture of ethanol with water or any other suitable solvent. The reaction proceeds in the presence of a base such as sodium hydroxide, carbonatite or sodium acetate, or aliphatic amine, preferably pyridine, triethylamine or N-methylmorpholine, under stirring and the temperature being in the range between room temperature and the boiling temperature of the solvent, during the period from one hour to twenty-four hours.

The conversion of the oxime of General formula (VII), where R1is the same as defined above, in the cyanide derivative of General formula (I), where R1is the same as defined above, is carried out by reaction of the oxime (VII) with some dehydrating reagents such as (PhO)2RNO, n-ClC6NOS(=S)Cl, N,N'-carbonyldiimidazole, and in the presence of ions Cu(II), such as Cu(ASO)2or acylation aldoxime acetic anhydride or triperoxonane anhydride, and subsequent formation of cyanide radical using a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, pyridine or triethylamine. The reaction is carried out at a temperature between room temperature and the boiling temperature of the solvent during the period from one hour to 4 days.

The METHOD:

New derivatives of General formula (I), where R1is the same as defined above, and R2represents cyanoaniline or cyanopyridine radical, can be obtained in accordance what about the way presented in figure 3:

The reaction of the amine of General formula (II), where R1is the same as defined above, with an anhydride of General formula (VIII), where Y represents a nitrogen atom (N) or aromatic carbon atom linked to a hydrogen atom (SN), or the reaction of the amine of General formula (II)in which R1is the same as defined above, with an acid of General formula (IX), where Y represents a nitrogen atom (N) or aromatic carbon atom linked to a hydrogen atom (SN), lead to the acid of General formula (X), where R1and Y are as described above.

The reaction with the anhydride (VIII) is carried out in an organic solvent, for example in organic chlorinated hydrocarbon, such as dichloromethane or chloroform, linear or cyclic ether, such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, polar aprotic solvent, such as pyridine, dimethylsulfoxide, dimethylformamide or acetonitrile, or any other suitable solvent. The reaction may proceed in the presence of mineral or organic bases, such as aliphatic amine, preferably triethylamine or N-methylmorpholine, under stirring and the temperature being in the range between room temperature and the boiling temperature of the solvent for a period of time and, amounting from ten minutes to twenty-four hours, preferably from thirty minutes to five hours.

The reaction of the acid of General formula (IX) is carried out in the presence of activating reagents to carbonyl group, such as N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide or 3-(3-dimethylamino)propyl-1-ethylcarbodiimide. This reaction can also take place by using these carbodiimides in the presence of 1-benzotriazole or N-hydroxysuccinimide or by reacting the acid of General formula (IX) with reagents such as thionyl chloride, oxalicacid, ethylchloride, pianorchestra or methansulfonate. The acid of General formula (IX) and the amine of General formula (II) also react directly in the presence of N,N'-carbonyldiimidazole or anhydride propriospinal acid. The reaction proceeds in an organic solvent such as methylene chloride, chloroform, pyridine or any other suitable solvent. The reaction proceeds in the presence of a base such as sodium hydroxide, sodium carbonate or sodium acetate, or an aliphatic amine, preferably pyridine, triethylamine or N-methylmorpholine, under stirring and the temperature being in the range between room temperature and the boiling temperature of the solvent, during the period from one hour before LW is dcate four hours.

Amide of General formula (XI)in which R1and Y are as stated above, get in the reaction of the acid of General formula (X) with an activating reagent to the carbonyl group and subsequent treatment with ammonia. Activation of the carbonyl group of the acid of General formula (X) is conducted by the reaction of (X) with reagents such as thionyl chloride, oxalicacid, ethylchloride, pianorchestra or methansulfonate. The reaction of the acid (X) with ammonia can also take place in the presence of activating reagents to carbonyl group, such as N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide or 3-(3-dimethylamino)propyl-1-ethylcarbodiimide. This reaction can also take place by using the above carbodiimide in the presence of 1-benzotriazole or N-hydroxysuccinimide. The acid of General formula (X) and ammonia also reacts directly in the presence of N,N'-carbonyldiimidazole. The reaction is carried out in an organic solvent, such as methylene chloride, chloroform, pyridine or any other suitable solvent. The reaction proceeds in the presence of a base such as sodium hydroxide, sodium carbonate or sodium acetate, aliphatic amine, preferably pyridine, triethylamine or N-methylmorpholine, under stirring and the temperature being in the range between room temperature and tempera is uroi the boiling point of the solvent, during the period of time of one to twenty-four hours.

The transformation of the amide of General formula (XI), where R1and Y are as described above, in the cyanide derivative of General formula (I), where R1and Y are as described above, is achieved by dehydration of amide (XI) certain reagents, such as thionyl chloride, oxalicacid, triperoxonane anhydride, catalytic Bu2SnO or, preferably, methansulfonate (A.D. Dunn, M.J. Mills, and Henry W., Org. Prep. Proced. Int., 1982 Vol. 14(6) 396-399) or other dehydrating reagents. The reaction proceeds in an organic solvent, such as dimethylformamide, methylene chloride, toluene, in the presence of a base such as triethylamine or pyridine, at a temperature in the range between 0°and the boiling point of the solvent, during the period from one hour to twenty-four hours.

The WAY D:

New derivatives of General formula (I), where R1is the same as defined above, and R2represents cyanoaniline or cyanopyridine radical, can be obtained in accordance with the method presented in Scheme 4.

The reaction of the amine of General formula (II), where R1is the same as defined above, with a carboxylic acid of General formula (XII), where R6represents an alkyl for the al, such as methyl or ethyl, and Y represents a nitrogen atom (N) or aromatic carbon atom linked to a hydrogen atom (SN), get amide of General formula (XIII)where R1, R6and Y are as described above.

The reaction is carried out by treatment of the acid of General formula (XII) an activating reagent to the carbonyl group followed by treatment of the amine of General formula (II). Activation of the carbonyl group of the acid of General formula (XII) is achieved by treatment with reagents such as thionyl chloride, oxalicacid, ethylchloride, pianorchestra or methansulfonate. The reaction of the acid (XII) and an amine of General formula (II) may also take place in the presence of activating reagents to carbonyl group, such as N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide or 3-(3-dimethylamino)propyl-1-ethylcarbodiimide. This reaction can also be carried out with the above carbodiimide in the presence of 1-benzotriazole or N-hydroxysuccinimide. The acid of General formula (XII) and amine (II) also react directly in the presence of N,N'-carbonyldiimidazole or anhydride propriospinal acid. The reaction is carried out in an organic solvent such as methylene chloride, chloroform, pyrimidine or any other suitable solvent. The reaction proceeds in the presence of a base, such as hydroxide intothree is, sodium carbonate, sodium acetate or aliphatic amine, preferably a pyrimidine, triethylamine or N-methylmorpholine, under stirring and the temperature being in the range between room temperature and the boiling temperature of the solvent, during the period from one hour to twenty-four hours.

Hydrolysis of the ether group, amide of General formula (XIII), in which R1, R6and Y are as described above, leads to the production of acids of General formula (XIV), where R1and Y are as defined above. The hydrolysis is carried out by conventional means, such as saponification with sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate or hydrolysis in acidic medium such as hydrochloric acid. The reaction proceeds in a solvent such as methanol, ethanol, water, tetrahydrofuran or mixtures thereof at a temperature in the range between room temperature and the boiling point of the solution, during the period from one hour to twenty-four hours.

Amide of General formula (XV), where R1and Y are such as defined above, is obtained by reaction of the acid of General formula (XIV) with an activating reagent to the carbonyl group and subsequent treatment with ammonia. Activation of the carbonyl group of the acid of General form is s (XIV) is carried out using reagents such as thionyl chloride, oxalicacid, ethylchloride, pianorchestra or methansulfonate. The reaction of the acid (XIV) with ammonia can also take place in the presence of activating reagents to carbonyl group, such as N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide or 3-(3-dimethylamino)propyl-1-ethylcarbodiimide. This reaction may also proceed with the above carbodiimide in the presence of 1-benzotriazole or N-hydroxysuccinimide. The acid of General formula (XIV) and ammonia also reacts directly in the presence of N,N'-carbonyldiimidazole. The reaction proceeds in an organic solvent such as methylene chloride, chloroform or pyridine, or any other suitable solvent. The reaction proceeds in the presence of a base such as sodium hydroxide, sodium carbonate, sodium acetate or aliphatic amine, preferably pyridine, triethylamine or N-methylmorpholine, under stirring and the temperature being in the range between room temperature and the boiling temperature of the solvent, during the period from one hour to twenty-four hours.

The transformation of the amide of General formula (XV), where R1and Y are as described above, in the cyanide derivative of General formula (I), where R1and Y are as defined, is Elena above, is achieved by dehydration of amide (XV) some reagents, such as thionyl chloride, oxalicacid, triperoxonane anhydride, catalytic Bu2SnO or, preferably, methansulfonate (A.D. Dunn, M.J. Mills, and Henry W., Org. Prep. Proced. Int., 1982 Vol. 14(6) 396-399) or other dehydrating reagents. The reaction is carried out in an organic solvent, such as DMF, methylene chloride or toluene, in the presence of a base such as triethylamine or pyridine, at a temperature in the range between 0°and the boiling temperature of the solvent during the period from one hour to twenty-four hours.

METHOD E:

New derivatives of General formula (I), where R1so, as stated above, and R2represents cyanoaniline or cyanopyridine radical, can be obtained by the method presented in Scheme 5:

The reaction of the amine of General formula (II), where R1is the same as above, with N,N'-carbonyl diimidazol leads to the production of compounds of General formula (XVI). The reaction is carried out in an anhydrous organic solvent, such as tetrahydrofuran or dimethylformamide, at a temperature in the range of 0°to room during the time period of one to twenty-four hours.

The introduction of the atom m is the metal in the compound of General formula (XVII), where Z represents a sulfur atom (S) or oxygen atom (O) with n-BuLi, sec-BuLi or tert-BuLi in anhydrous solvent such as tetrahydrofuran, at a temperature of -78°and then adding the compound (XVI) results in cyanide derivative of General formula (I), where R1and Z are as described above.

The WAY F:

New derivatives of General formula (I), where R1and R3are such as described above can be obtained by the reaction of chloropyrimidine derivative of General formula (XVIII), where R1is the same as defined above, with piperazinone derivative of General formula (XIX), where R2so, as stated above, in accordance with the method presented in Scheme 6:

The reaction is carried out in an organic solvent, such as chlorinated organic hydrocarbons, such as dichloromethane or chloroform, linear or cyclic ether, such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aprotic polar solvent, such as pyridine, dimethylsulfoxide, dimethylformamide or acetonitrile, proton polar solvent, such as methanol, ethanol, isopropanol or n-butanol or any other suitable solvent for the implementation of the reaction of aromatic nucleophilic substitution. The reaction may proceed in Pris is accordance mineral Foundation such as sodium carbonate or potassium carbonate, or organic bases such as aliphatic amine, preferably triethylamine or N-methylmorpholine, under stirring and the temperature being in the range between room temperature and the boiling temperature of the solvent during the period of from ten minutes to twenty-four hours, preferably for a period of from thirty minutes to five hours.

The WAY G:

Salts of compounds of General formula (I) obtained by reaction with a mineral acid, such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid or organic acid, such as n-toluensulfonate acid or methansulfonate acid, in a suitable solvent, such as methanol, ethanol, ethyl ether, ethyl acetate or acetone, to obtain the corresponding salt normal precipitation or crystallization.

Carboxylic acid used to obtain the cyanide derivative of General formula (I), where R1and R2are as described above, in accordance with the methods described in this invention are commercially available or they get the usual methods described in the scientific literature (Kenneth A. Hold and Phillip Shadbolt, Br. Polym. J., 1983, 15 (4), No.201-207; Carol K. Sauers and Robert J. Cotter, J. Org. Chem., 1961, 26, 6-10; Louis A. Carpino, J. Am. Che. Soc., 1962, 84, 2196-2201; A.D. Dunn, M.J. Mills, and Henry W., Org. Prep. Proced. Int., 1982, 14(6), 396-399; Pierre Dubus, Bernard Decroix, Jean Morel et Paul Pastour, Bull. Soc. Chim. Fr., 1976. (3-4. Pt. 2), 628-634; William M. Murray and J. Edward Semple, Synthesis, 1996, 1180-1182; Luc I. M. Spiessens and Marc J. OR. Anteunis, Bull. Soc. Chim. Belg., 1980, 89 (3), 205-231; I. Thunus et M. Dejardin-Duchene, J. Pharm. Belg., 1969, 51, 3-21; S. Fallab und H. Erlenmeyer, Helv. Chim. Acta, 1951, 34, 488-496).

The following examples describe the acquisition of new compounds in accordance with the invention. Also describes some of the common ways used in various applications, as well as herbal formulations suitable for compounds which are the object of the invention.

The following methods are given only for illustration and should not be construed as limiting the scope of the invention.

METHOD:

Example 1. Getting 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-methoxypyridazine.

To a suspension of 2.0 g (14 mmol) 2-cyanobenzoic acid in 100 ml of CH2CI2add 1.5 ml (17.5 mmol) of oxalicacid and a catalytic amount of pyridine. The slurry is mixed at room temperature for 3 hours. The solvent is evaporated under reduced pressure to give crude product, which was suspended in 100 ml of CH2Cl2and slowly added to a solution of 2.45 g (12.6 mmol) of 4-methoxy-2-(1-piperazinil)pyrimidine and 4 ml (28 mmol) of triethylamine in 50 ml of CH2Cl2cooled to 0°in an ice bath. The solution from the side at 0° With in an hour, and then give him the opportunity to come to room temperature. The reaction mixture was washed with H2Oh, dried over Na2SO4after which the solvent is removed under reduced pressure. The resulting crude product was then purified using chromatography on silica gel using ethyl acetate as eluent, getting 2.06 g (6.4 mmol) of 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-methoxypyridine with melting point =166-168°C

METHOD:

Example 3. Getting 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine.

To a solution of 2.08 g (10 mmol) 4-ethoxy-2-(1-piperazinil)pyrimidine and 5 ml of triethylamine in 60 ml of dry THF added 2.15 g (10 mmol) 3-bromophthalide and allowed to mix at room temperature for 4 hours. The triethylamine hydrobromide is filtered off, then washed with THF and the solvent is removed under reduced pressure to give crude product, which was purified using chromatography on silica gel using ethyl acetate as eluent. Polycut 2.45 g (7.20 mmol) of 4-ethoxy-2-[4-(2-formylmethyl)-1-piperazinil]pyrimidine with a melting point=134-136°C.

To a solution of 2.45 g (7.2 mmol) of 4-ethoxy-2-[4-(2-formylmethyl)-1-piperazinil]pyrimidine in ethanol - N2O (80:20) add 2.5 g (18.4 mmol) and AcONa·3H2Oh and 0.75 g (8.6 mmol) of hydroxylamine hydrochloride. The reaction mixture is heated when it is singing with a reflux condenser, controlling the process by TLC. The solvent is removed under reduced pressure, the residue is dissolved in CH2Cl2and washed with N2O. the Organic solvent is evaporated under reduced pressure, obtaining the oil, which is crystallized in ethyl ether, receiving 0.5 g (1.40 mmol) of 4-ethoxy-2-{4-[2-(gidroksilaminami)benzoyl]-1-piperazinil) pyrimidine with a melting point =136-140 C.

To a solution of 0.5 g (1.40 mmol) of 4-ethoxy-2-(4-[2-(gidroksilaminami)benzoyl]-1-piperazinil} pyrimidine in 30 ml of ethyl acetate added 0.15 ml of acetic anhydride and heated at the boil under reflux for 2 hours. The solvent is evaporated at low pressure, getting acetylated oxime.

Acetylated oxime was dissolved in 20 ml of acetonitrile and add the excess To2CO3then leave to mix at room temperature for 78 hours. The solid is filtered, the solvent is removed under reduced pressure, dissolved in CH2Cl2and washed with N2O. the Solvent is evaporated under reduced pressure to give crude product which is crystallized from ethyl ether, receiving 0.2 g (0.60 mmol) 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine with melting point =151-154 C.

The METHOD:

Example 15. Getting 2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]-4-toxiferine the ina.

To a suspension of 0.75 g (5.04 mmol) quinolinic anhydride in 25 ml of acetonitrile is added 1.05 g (5.04 mmol) of 4-ethoxy-2-(1-piperazinil)pyrimidine and 0.8 ml (5.07 mmol) of triethylamine and heated at the boil under reflux for 18 hours. The solvent is evaporated under reduced pressure and the resulting crude product was then purified using chromatography on silica gel, using as eluents CHCl3:Meon 3:2, receiving 0.6 g (1.68 mmol) of 2-[4-(3-carboxy-2-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine with melting point=186-189°C.

To a suspension of 0.3 g (0.8 mmol) of 2-[4-(3-carboxy-2-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine in 20 ml of methylene chloride add 0.5 ml (3.6 mmol) of triethylamine, cooled to 0°and add 0.1 g (0,92 mmol) ethylchloride, leaving the solution at this temperature for 30 minutes. Through the resulting mixture is passed MN3(gas) for 1 minute and the temperature is maintained at 0°C for 2 hours. The solution is allowed to warm to room temperature, then washed with N2Oh, methylene chloride is removed under reduced pressure, obtaining a paste, which after solidification give 184 mg (0.51 mmol) 2-[4-(3-carbarnoyl-2-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine with melting point =161-163°C.

To a solution of 84 mg (0.23 mmol) of 2-[4-(3-carbarnoyl-2-pyridylcarbonyl)-1-piperazinil]-4-is oxypyridine in 15 ml of methylene chloride add 0.2 ml of triethylamine and 0.1 ml of methanesulfonanilide. The resulting mixture was left to mix for 18 hours at room temperature. The organic solution is washed with a solution of Na2CO3the solvent is removed under reduced pressure to give crude product, which was purified using chromatography on silica gel using ethyl acetate as eluent, receiving 42 mg (0.12 mmol) of 2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine with melting point =137-140°C.

The WAY D:

Example 19. Getting 2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine.

To a solution of 1.33 g (7.45 mmol) of 2-methoxycarbonylamino acid in 15 ml of DMF, cooled in an ice bath, added 1.20 g (7.45 mmol) of N,N'-carbonyldiimidazole and stirred for 40 minutes. To the reaction mixture are added 1.53 g (7.45 mmol) of 4-ethoxy-2-(1-piperazinil)pyrimidine and leave at room temperature for two hours. Then the solution is diluted with ethyl acetate and washed with N2Oh, dried over Na2SO4and the solvent is removed under reduced pressure, obtaining oil, which crystallized in ethyl ether, receiving 1.5 g (4.04 mmol) of 4-ethoxy-2-[4-(2-methoxycarbonyl-3-pyridylcarbonyl)-1-piperazinil]pyrimidine with a melting point =126-128°C.

To a solution of 1.4 g (3.77 mmol) of 4-ethoxy-2-[4-(2-methoxycarbonyl-3-pyridylcarbonyl)-1-piperazinil]pyrimidine in 25 ml of THF and 10 ml Meon add 0.158 g (3.77 mmol) LiOH× H2Oh and leave mixed at room temperature for two hours. After the solution is passed SO2and the solvent is removed under reduced pressure. The resulting crude product is suspended in 30 ml of methylene chloride and added 0.45 ml (3.3 mmol) of triethylamine, and then cooled to 0°and then added 0.3 g (2.76 mmol) of ethylchloride, leaving the solution at this temperature for 30 minutes. Through the resulting mixture miss NH3(gas) for 1 minute and the temperature is maintained at 0°C for 2 hours. The solution is allowed the opportunity to reach room temperature, then washed with N3O. methylene Chloride is removed under reduced pressure and get a paste that hardens with the formation of crude product which crystallized in ethyl acetate. Obtain 0.12 g (0.34 mmol) 2-[4-(2-carbarnoyl-3-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine with melting point =152-156°C.

To a solution of 100 mg (0.28 mmol) of 2-[4-(2-carbarnoyl-3-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine in 5 ml of pyridine, add 1.0 ml of methanesulfonanilide. The resulting mixture is stirred for 24 hours at room temperature. The solvent is evaporated to dryness and the product partitioned between methylene chloride and water, then washed with NaHCO3and the solvent is removed under reduced pressure, the AI, give crude product, which was purified using chromatography on silica gel, using as eluent ethyl acetate. Receive 60 mg (0.18 mmol) 2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine with melting point =177-178 C.

METHOD E:

Example 9. Getting 2-[4-(3-cyano-2-thienylboronic)-1-piperazinil]-4-methoxypyridazine.

To a solution of 1.5 g (7.7 mmol) of 4-methoxy-2-(1-piperazinil)pyrimidine in 20 ml of THF, cooled to 0°add 1.25 g (7.7 mmol) of N,N'-carbonyldiimidazole. The mixture is allowed to mix at room temperature for 3 hours. The solvent is removed under reduced pressure and add H2Oh, forming a precipitate, filtered and obtain 1.8 g (6.24 mmol) of 2-[4-(1-imidazolidinyl)-1-piperazinil]-4-methoxypyridine with melting point =125-126°C.

To a solution of 0.62 ml (6.8 mmol) of 3-cyanothiophene in 25 ml anhydrous THF, cooled to -78°C. in the argon atmosphere is added slowly 4.26 ml (6.8 mmol) of n-BuLi 1.6M in hexane. The mixture is left at -78°C for 30 minutes and then slowly add a solution of 1.8 g (6.2 mmol) of 2-[4-(1-imidazolidinyl)-1-piperazinil]-4-methoxypyridine in 25 ml anhydrous THF. The mixture should be allowed the opportunity to slowly warm to room temperature, after which it leaves at the same temperature for 2 hours. The solution was poured into water and extracted with ethyl acetate, the floor is tea crude product, which is purified using chromatography on silica gel, using as eluent a mixture of ethyl acetate:hexane 7:3. Obtain 1.0 g (3.0 mmol) of 2-[4-(3-cyano-2-thienylboronic)-1-piperazinil]-4-methoxypyridine with melting point =140-142°C.

The WAY F:

Example 1. Getting 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-methoxypyridazine.

To a solution of 1.0 g (6.8 mmol) of 2-cyanobenzoic acid in 20 ml of anhydrous DMF, cooled to 0°add 1.1 g (6.8 mmol) of N,N'-carbonyldiimidazole and left to mix for 40 minutes. Then added 1.26 g (6.8 mmol) of 1-(tert-butoxycarbonyl)piperazine and leave at room temperature for 2 hours. Then poured into water and extracted with ethyl ether. The organic phase is dried and evaporated under reduced pressure to give crude product, which solidifies in petroleum ether. Obtain 1.24 g (3.94 mmol) of 4-(tert-butoxycarbonyl)-1-(2-cyanobenzoyl)piperazine melting temperature =126-128°C.

To a solution of 1.2 g (3.81 mmol) of 4-(tert-butoxycarbonyl)-1-(2-cyanobenzoyl)piperazine in 10 ml of methylene chloride, cooled to 0°add 10 ml triperoxonane acid and allowed to mix at room temperature for 2 hours. The reaction mixture is evaporated to dryness and the resulting crude product is crystallized from methylene chloride:ethyl ether with the formation of 1.04 g (3.16 mmol) 1-2-cyanobenzoyl)piperazinecarboxamide with melting point =136-141° C.

A mixture of 1.0 g (3.04 mmol) of 1-(2-cyanobenzoyl)piperazinecarboxamide, 0.5 g (3.35 mmol) of 2-chloro-4-methoxypyridine and 1.0 g (6.68 mmol) of potassium carbonate in 20 ml of DMF is heated to 100°within hours. The solvent is removed under reduced pressure and water is added. The obtained solid is filtered, washed with water and purified using chromatography on silica gel, using as eluent ethyl acetate. Obtain 0.51 g (1.58 mmol) of 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-methoxypyridazine.

The WAY G:

Example 4. Getting 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine hydrochloride.

4.76 g (14.12 mmol) 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine dissolved in acetone and add a few drops of ethyl ether/HCl and ethyl ether, the resulting precipitate filtered and dried, obtaining 3.85 g (10.31 mmol) 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine hydrochloride with melting point=147-151 C.

Table 1 shows the number of compounds, indicating the method of obtaining the melting point and spectral characteristics, which are the illustration of the present invention

Overall an anaesthetic activity

Studies were performed on three kinds of animals: the mouse, the rat and the dog, following the techniques described below.

a) an anaesthetic activity in mice.

Anesthetic activity determined after intravenous (IV) administration of the investigational product in three different doses (15, 10 and 5 mg/kg) into the tail vein of the mouse. Record the percentage of shot animals and calculate the average time of anesthesia. Mice are shot with the loss of three reflexes: positional reflex, reflex response to painful stimulus (compression of the tail) and palpebral reflex.

Obtained in this test, the results show that the products of the present invention are strong anesthetic substances compared with one of the most widely used for the clinical application of human anesthetic substance propofol (table 2).

TABLE 2

An anaesthetic activity in mice
Example% anestesiology (anestesiologia) Dose (mg/kg/in)
15105
4100(5.8')100(2.6')0
6100(9.6')100(7.6') 90(1.2')
8100(13.3')100(6.8')60(0.9')
12100(5.4')100(1.6')0
14100(8.9')100(2.2')0
18100(4.6')100(3.9')0
Propofol80(1.3')80(1')0

b) an anaesthetic activity in dogs.

Salt and a solution of the product poured using a perfusion pump at a concentration and at a speed of 5 mg/ml/minute through a catheter inserted into a vein of the front paw. Intravenous infusion cease when the animal is fully anesteziruta (loss of motor coordination, sedation, loss of response to painful stimulus - prick the fingers of the front paw and loss palpebral reflex), and determine the anesthetic dose (table 3).

* Animals treated with propofol only after falling asleep, because they retain palpebralis and painful reflexes.
TABLE 3

An anaesthetic activity in dogs (IV infusion)
ExampleAn anaesthetic dose (mg/kg)
410.1
617.4
821.2
1814
Propofol21.6*

Received on dogs results show that the products according to the invention are far superior to Propofol, causing complete anesthesia.

(C) an anaesthetic activity in rats.

In this test through the catheter in the tail Vienna rats pour in a solution of the product at a concentration of 10 mg/kg infusion Speed range to maintain anesthesia in rats for 1 hour. Determine the total injected dose, indicating that the products according to the invention are more active compared with Propofol (table 4).

TABLE 4.- An anaesthetic activity in the rat: IV infusion required to maintain full anesthesia within 1 hour
ExampleTotal dose (mg/kg)
456.8
642.1
833.1
1866.2
Propofol67

Anticonvulsive activity

This test shows the ability of the products to counteract the appearance of convulsions with intravenous pentamethylenetetrazol (cardiazol) at a dose of 45 mg/kg in Mostovoy vein of mice. The results show that the analyzed foods have more of anticonvulsive activity compared with propofol (table 5).

TABLE 5. - Anticonvulsive activity in mice (Convulsions called cardiazol)
Example% Activity (mg/kg, intraperitoneally)
80402010ED-50
2100733626.1
4876940-25.1
6936369024.1
810070562525.0
Propofol1004633-32.5

Sedative activity

Sedative activity are examined through the study of animal behavior after intraperitoneal administration at a dose of 80 mg/kg, This study conducted at different times, studying sedative effect and its duration. The results show that the products have sedative the m action in some cases, comparable to the action of zolpidem, and in other cases they have greater duration of action (table 6).

TABLE 6. - Sedative activity in mice (80 mg/kg, intraperitoneally)
Example30'1 h2 hours3 hours4 h5 h24 hours
490757535000
898100982727220
143033383520100
16100100200000
Zolpidem10090300000

Miorelaksantnoe activity

Miorelaksantnoe activity of the products according to the invention is examined by determining the effect on the tone of the body and abdominal tone rats by the method described in S. IRWIN (Gordon Res. Conf. on Medicinal Chem., 1959, p. 133). Examine the tone of the body and br is used tone rats receiving investigational products intraperitoneally at a dose of 80 mg/kg and after a few times of introduction (1/2, 1, 2, 3, 4 and 5 hours), comparing muscles with tension control animals. The results in Table 7 show that most of the products have significant miorelaksantnoe activity with a duration of action longer than the effects of propofol, which is used as a product comparison

The results from table 7 show that many products have remarkable activity as muscle relaxants, with the effect that is more prolonged than in the case of propofol, which is used as product comparison

TABLE 7

Muscular activity in the IRWIN test in rats (80 mg/kg, intravenously)
Example% muscle relaxation after:
1/2 hour1 hour2 hours3 hours4 hours5 hours
410010010070330
8100100100000
1610010066440
propofol10010070000

Pharmaceutical compositions

1. Injected intramuscular/ intravenous (VM/C):

Example 4 5 mg

Sodium chloride H. D.

HCl 0.1 N or NaOH 0.1 N BH

Water for injection, reagent grade. 3 ml

2. Capsules

Example 4 from 0.5 to 4.0 mg

Colloidal silicon dioxide 0.5 mg

Magnesium stearate 1.0 mg

Lactose reagent grade. 100 mg

3. Tablets

Formula A (direct pressure).

Example 4 from 0.5 to 4.0 mg

Colloidal silicon dioxide 0.5 mg

Magnesium stearate 1.0 mg

Crosscarmellose sodium 3.0 mg

Microcrystalline

cellulose 60 mg

Lactose reagent grade. 100 mg

The formula In (wet granulation)

Example 4 from 0.5 to 4.0 mg

Colloidal silicon dioxide 0.5 mg

Magnesium stearate 1.0 mg

Povidone K-30 5.0 mg

Sodium carboximetilkrahmal 5.0 mg

Microcrystalline cellulose 20 mg

Lactose reagent grade. 100 mg

Example 1

Comparative examples

The following compounds were tested for their anesthetic activity in mice

Connection of D1

Compound A: 2-[4-(2-triethylborane)-1-piperazinyl-4-ethoxypyridine;

Connection: 2-[4-(2-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine;

Connection: 2-[4-(3-chloro-5-triptime the Il-2-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine;

Connection D:2-[4-(benzoyl)-1-piperazinil]-4-methoxypyridazine (example 57, HCl salt);

Compound E: 2-[4-(benzoyl)-1-piperazinil]-4-ethoxypyridine:

Compound F: 2-[4-(3-chloro-2-thienylboronic)-1-piperazinil]-4-ethoxypyridine (HCl salt);

Compound G: 2-[4-(2-perbenzoic)-1-piperazinil]-4-methoxypyridazine (example 50B HCl salt);

Compound H: 2-[4-(2-chlorobenzoyl)-1-piperazinil]-4-methoxypyridazine (example 52, HCl salt);

Compound I: 4-methoxy-2-{4-[2-(trifluoromethyl)benzoyl]-1-piperazinil} pyrimidine (example 63, HCl salt);

Connection J:4 ethoxy-2-{4-[2-trifluoromethyl)benzoyl]-1-piperazinil}pyrimidine (example 79, HCl salt);

Connection: 2-[4-(2-chlorobenzoyl)-1-piperazinil]-4-ethoxypyridine (HCl salt was not directly disclosed in the DI, but it falls under the General formula).

Compounds of the present invention

Example 12: 2-[4-(3-cyano-2-triethylborane)-1-piperazinil]-4-ethoxypyridine (HCl salt);

Example 18: 2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]-4-propoxyphene (HCl salt);

Example 28: 2-[4-(2-cyano-2-pyridylcarbonyl)-1-piperazinil]-4-propoxyphene (HCl salt);

Example 2:2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-methoxypyridazine (HCl salt);

Example 4:2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine (HCl salt);

Table: Analiticheskaya activity in mice.
Examples% activity time (anesthesia)ED-50
15 mg/kg10 mg/kg5 mg/kg
And100(2')75(1,1')j8,3
F80(1,6')20(0,8')0the 11.6
12100(5,4')100(1,6')07,0
InToxic1Toxic207,0
inactive
18100(4,6')100(3,9')07,0
28100(4,5')100(4,2')20(1,5')6,4
D000more than 15
G00 0more than 15
H000more than 15
I000more than 15
1000more than 15
21000012,5
E10050010
J500015
To100012,5
410010007,5
1- Mortality 8/8

2- Mortality 7/10

The following conclusions should be drawn from the above data:

- substitution of hydrogen atoms or halogen atoms on the cyano group in the thienyl ring increases the activity of the compounds (see compound A, F, and 12);

- the presence of ceanography in pyridinium ring transforms inactive, even toxic compounds in the active connections (see connections, and 18, 28);

- substitution of hydrogen atoms or halogen or ha is agenulcenna of cyano radicals on the phenyl ring increases the activity of the compounds (see compounds D, G, H, I, E, J, K and 2, 4).

Given the above data show that the introduction of cyano in different groups (phenyl, pyridyl, thienyl) leads to unexpected and unpredictable technical result. The applicant believes that the objections to the invention in this part should be removed.

Example 2

Example retrieve

The way A

Getting 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine (example 3);

To a solution 3,68 g (25 mmol) 2-cyanobenzoic acid in 60 ml of anhydride-DMF, cooled to 0°With add of 4.05 g (25 mmol)of carbonyldiimidazole. This solution is stirred for 45 minutes. Then add 5.20 g (25 mmol) 4 ethoxy-2-(1-piperazinil)pyridine and leave for 2 hours at room temperature. This solution is evaporated under reduced pressure and water is added. The formed precipitate is filtered and dried, obtaining 6,45 g crude product. This solid product is then dissolved in warm ethanol (50 ml) and add water (25 ml). This solution was stored until use in the cold. The precipitate thus obtained is filtered, dried, that provides 5.6 g (of 16.6 mmol) 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine (yield 66%).

Similarly, the following compounds (i.e. under the scheme And, according to paragraph 3 of the formula and is gaining).

Example 5: 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-propoxyphene (Yield 53%);

Example 19: 2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine (Yield 43%);

Example 25: 2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]-4-methoxypyridazine (Yield 69%);

Example 29: 4-butoxy-2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]pyrimidine (Yield 56%);

Example 35: 4-butoxy-2-[4-(3-cyano-3-thienylboronic)-1-piperazinil]pyrimidine (Yield 59%).

1. Cyanoacryl (or cyanovalerianic)-carbonylmethyl-pyrimidine derivative of the General formula (I)

where R1is a OR3radical, in which R3represents a saturated hydrocarbon radical with a linear or branched chain, having from 1 to 4 carbon atoms, and R2represents a phenyl radical substituted by cineradiogram (- ≡N), or a radical of 5 or 6 membered heteroaromatic ring in which the heteroatom is selected from O, N or S, and substituted by cineradiogram (-C≡N);

and their physiologically acceptable salts.

2. The compound of General formula (I) according to claim 1, selected from among the following:

[1] 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-methoxypyridine,

[2] 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-methoxypyridine hydrochloride

[3] 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine,/p>

[4] 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine hydrochloride

[5] 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-propoxyimino,

[6] 2-[4-(2-cyanobenzoyl)-1-piperazinil]-4-propoxyphene hydrochloride

[7] 4 butoxy-2-[4-(2-cyanobenzoyl)-1-piperazinil]pyrimidine,

[8] 4 butoxy-2-[4-(2-cyanobenzoyl)-1-piperazinil]pyrimidine hydrochloride

[9] 2-[4-(3-cyano-2-thienylboronic)-1-piperazinil]-4-methoxypyridine,

[10] 2-[4-(3-cyano-2-thienylboronic)-1-piperazinil]-4-methoxypyridine hydrochloride

[11] 2-[4-(3-cyano-2-thienylboronic)-1-piperazinil]-4-ethoxypyridine,

[12] 2-[4-(3-cyano-2-thienylboronic)-1-piperazinil]-4-ethoxypyridine hydrochloride

[13] 2-[4-(3-cyano-2-thienylboronic)-1-piperazinil]-4-propoxyimino,

[14] 2-[4-(3-cyano-2-thienylboronic)-1-piperazinil]-4-propoxyphene hydrochloride

[15] 2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine,

[16] 2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine monohydrochloride,

[17] 2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]-4-propoxyimino,

[18] 2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]-4-propoxyphene monohydrochloride,

[19] 2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]-4-ethoxypyridine,

[20] 2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]-4-this is xipamide monohydrochloride,

[21] 2-[4-(4-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine,

[22] 2-[4-(4-cyanobenzoyl)-1-piperazinil]-4-ethoxypyridine hydrochloride

[23] 2-[4-(3-cyano-2-fullcarbon)-1-piperazinil]-4-methoxypyridine,

[24] 2-[4-(3-cyano-2-fullcarbon)-1-piperazinil]-4-methoxypyridine hydrochloride

[25] 2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]-4-methoxypyridine,

[26] 2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]-4-methoxypyridazine monohydrochloride,

[27] 2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]-4-propoxyimino,

[28] 2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]-4-propoxyphene monohydrochloride,

[29] 4 butoxy-2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]pyrimidine,

[30] 4-butoxy-2-[4-(2-cyano-3-pyridylcarbonyl)-1-piperazinil]pyrimidine monohydrochloride,

[31] 2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]-4-methoxypyridine,

[32] 2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]-4-methoxypyridazine monohydrochloride,

[33] 4 butoxy-2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]pyrimidine,

[34] 4 butoxy-2-[4-(3-cyano-2-pyridylcarbonyl)-1-piperazinil]pyrimidine monohydrochloride,

[35] 4 butoxy-2-[4-(3-cyano-2-thienylboronic)-1-piperazinil]pyrimidine,

[36] 4 butoxy-2-[4-(4-cyano-3-pyridylcarbonyl)-1-piperazinil]pyrimidine,

[37] 4 butoxy-2-4-(3-cyano-4-pyridylcarbonyl)-1-piperazinil]pyrimidine,

[38] 4-butoxy-2-[4-(3-cyano-4-pyridylcarbonyl)-1-piperazinil]pyrimidine monohydrochloride,

3. The method of obtaining compounds of General formula (I) according to claim 1, including the interaction of the amine of General formula (II)

where R1is a OR3radical, in which R3represents a saturated hydrocarbon radical with a linear or branched chain, having from 1 to 4 carbon atoms, with a carboxylic acid of General formula (III) or a salt of this acid

R2CO2H (III)

where R2represents a phenyl radical substituted by cineradiogram (-C≡N), or the radical of a 5 - or 6-membered heteroaromatic ring in which the heteroatom is selected from O, N or S, and substituted by cineradiogram (-C≡N).

4. The method of obtaining compounds of General formula (I) according to claim 1, including the interaction of the amine of General formula (II)

where R1is a OR3radical, in which R3represents a saturated hydrocarbon radical with a linear or branched chain, having from 1 to 4 carbon atoms, with a carboxylic acid derivative of General formula (IV)

R2COX (IV)

where R2represents a phenyl radical substituted by cineradiogram (-C≡N), or the radical of a 5 - what if 6-membered heteroaromatic ring, in which the heteroatom is selected from O, N or S, and substituted by cineradiogram (-C≡N); and

X represents a halogen atom, asiagraph (-N3), 1-imidazolidinyl group, -O-CO-R4group, where R4represents an alkyl radical having from 1 to 6 carbon atoms or aryl radical, optionally substituted by one or more halogen atoms or or5group, where R5represents an aromatic group with one or two rings, substituted by one or more halogen atoms or nitroreductase or N-succinimido.

5. The method of obtaining compounds of General formula (I) according to claim 1, in which R2represents a phenyl radical substituted by cineradiogram (-C≡N), including the interaction of the amine of General formula (II)

where R1is a OR3radical, in which R3represents a saturated hydrocarbon radical, linear or branched chain, having from 1 to 4 carbon atoms, with 3-bromophthalide, with the formation of aldehyde, which reacts with hydroxylamine or its salt, to obtain the corresponding oxime, which (i) is subjected to processing dehydrating agent in the presence of ions Cu(II) or (ii) acelerou acetic anhydride or triperoxonane anhydride and process organizes the m or inorganic base.

6. The method of obtaining compounds of General formula (I) according to claim 1, in which R2represents a phenyl radical substituted by cineradiogram (-C≡N) or peredelnyj radical, substituted by cineradiogram (-C≡N), including the interaction of the amine of General formula (II)

where R1is a OR3radical, in which R3represents a saturated hydrocarbon radical with a linear or branched chain, having from 1 to 4 carbon atoms, phthalic anhydride, phthalic acid, 2,3-pyridylcarbonyl anhydride or 2,3-pyridinedicarboxylic acid, with the formation of acid, which is subjected to the interaction with the carbonyl group activating reagent and then with ammonia to obtain the amide, which is subjected to interaction with the dehydrating agent.

7. The method of obtaining compounds of General formula (I) according to claim 1, in which R2represents a phenyl radical substituted by cineradiogram (-C≡N), or peredelnyj radical, substituted by cineradiogram (-C≡N), including the interaction of the amine of General formula (II)

where R1is a OR3radical, in which R3represents a saturated hydrocarbon radical with a linear or branched chain, having from 1 d is 4 carbon atoms, with monomethylfumarate or 2-methoxycarbonylamino acid, followed by hydrolysis of the pre-formed ester with the formation of acid, which is subjected to the interaction with the carbonyl group activating reagent and then with ammonia, amide formation, which is subjected to interaction with the dehydrating agent.

8. The method of obtaining compounds of General formula (I) according to claim 1, in which R2represents cyanoaniline or cyanopyridine radical, including the interaction of the amine of General formula (II)

where R1is a OR3radical, in which R3represents a saturated hydrocarbon radical with a linear or branched chain, having from 1 to 4 carbon atoms, with 1,1'-carbonyl diimidazol and the product obtained by the reaction of 3-cyanothiophene or 3-cianfuran with alkyllithium derived.

9. The method of obtaining compounds of General formula (I) according to claim 1, including interaction derived chloropyrimidine General formula (XVIII) with piperazine derivatives of General formula (XIX)

where R1is a OR3radical, in which R3represents a saturated hydrocarbon radical with a linear or branched chain, having from 1 to 4 and the Ohm carbon, and R2represents a phenyl radical substituted by cineradiogram (-C≡N), or a radical of 5 or 6-membered heteroaromatic ring in which the heteroatom is selected from O, N or S, and substituted by cineradiogram (-C≡N).

10. The method of obtaining physiologically acceptable salts of the compounds of General formula (I) according to claim 1, including the interaction of the compounds of General formula (I) with a mineral or organic acid in a suitable solvent.

11. Pharmaceutical composition having sedative, anticonvulsive, analgesic, miorelaksantnoe, antitussive, antibiotically, antipsychotic, antidepressant activity, activity against cerebral ischemia, ANTIMIGRAINE activity, activity against sleep disorders, against neurodegenerative diseases disorders of perception and Alzheimer's disease, activity hypnotic or General anesthetic agent for mammals, including humans, characterized in that it contains at least one compound of General formula (I) or one of its physiologically acceptable salts according to any one of claim 1 or 2, and pharmaceutically acceptable filler.

12. The use of compounds of General formula (I) or its pharmaceutically acceptable salt according to any one of claim 1 or 2 to obtain drugs, active in Rel is the solution of disorders of the Central nervous system of mammals, including humans.

13. The use of compounds of General formula (I) or its pharmaceutically acceptable salt according to any of claim 1 or 2 for obtaining a medicinal product which is active as a sedative, anticonvulsive, analgesic, miorelaksantnoe, antitussive, antitsiklonicheskogo, antipsychotic, antidepressant, against cerebral ischemia, ANTIMIGRAINE, sleep disorders, neurodegenerative diseases, disorders of perception and Alzheimer's disease, hypnotic or General anesthetic agent for mammals, including humans.



 

Same patents:

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thienyl(amino)sulfonylureas of formula I ,

wherein A represents nitrogen or methane; Q represents direct bond or imino; R1 represents fluorine, chlorine, bromine, unsubstituted C1-C4-alkyl, C1-C4-alkoxyl optionally substituted with halogen, unsubstituted C1-C4-alkylthio, or di(C1-C4-alkyl)amino; R2 represents hydrogen or C1-C4-alkyl. Compounds of present invention are useful as herbicide agents.

EFFECT: new compounds with herbicide activity.

5 cl, 11 tbl, 5 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thien-3-yl-sulfonylamino(thio)carbonyl-triazolin(thi)ons of general formula I

(wherein Q represents oxygen or sulfur; R1 represents unsubstituted alkyl; R2 represents hydrogen, halogen, unsubstituted alkyl; R3 represents hydrogen, halogen, alkyl optionally substituted with alkoxy, alkoxy or arylthio, optionally substituted with alkoxy or halogen, unsubstituted cycloalkyl or cycloalkyloxy, or unsubstituted arylalkoxy or aryloxy; R4 represents unsubstituted alkyl, alkoxy, dialkylamino, cycloalkyl) and their salts. Compounds of present invention are useful as herbicide agents. Also disclosed is herbicide composition and new synthetic intermediates for compounds of formula I.

EFFECT: new compounds and intermediates thereof with herbicide activity.

16 cl, 13 tbl, 67 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

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

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

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: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: bioactive compounds.

SUBSTANCE: invention relates to new 3-phenyl-1,2,4-benzotriazines and their derivatives of general formula 1

wherein R1 and R2 are independently fluorine or C1-C4-alkoxy, optionally substituted with halogen or tetrahydrofuryl. Compounds of present invention are useful in treatment and prophylaxis of diseases, induced by pathogenic for human and animals viruses including pathogenic for human orthopoxviruses, as well as postvaccinal sequelae.

EFFECT: compounds with improved antiviral activity.

1 cl, 12 ex, 7 tbl

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, pharmacy.

SUBSTANCE: invention relates to new derivatives of borrelidin of the general formula (I)

wherein R represents the group of the general formulae -COOR1, -CONR2R3, -CONR4CONR2R5 or -CH2OR6 wherein R1 represents (C2-C6)-alkyl group, (C1-C6)-alkyl group substituted with hydroxyl group or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprise oxygen atom in addition to nitrogen atom) or 5-6-membered nitrogen-containing aromatic heterocyclic group or (C3-C6)-cycloalkyl group; R2 and R3 are similar or different and represent independently hydrogen atom or (C1-C6)-alkyl group that can be substituted optionally with hydroxyl, (C2-C5)-alkoxycarbonyl or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprises oxygen atom in addition to nitrogen atom) or 5-6-membered aromatic homocyclic group or aromatic heterocyclic group comprising oxygen and/or nitrogen atom, 5-6-membered cycloalkyl or heteroaryl group; R4 and R5 are similar or different and represent independently hydrogen atom or (C3-C6)-cycloalkyl group; R6 represents hydrogen atom; also, invention relates to tautomers, solvates of these compounds, their mixtures and acid-additive salts. Also, invention relates to pharmaceutical compositions comprising compounds of the general formula (I) as an active component. Angiogenesis inhibitors of the present invention inhibit formation of new vessels in tissues of live organisms and can be used for prophylaxis and inhibition of the angiogenesis process arising in the tumor proliferation, and for prophylaxis of formation of tumor metastasis. Invention provides preparing new derivatives of borrelidin eliciting the value physiological effect.

EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

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

13 cl, 3 tbl, 35 ex

The invention relates to a method for paroxetine, comprising the following stages: a) hydrogenation of compounds of formula (II) in which R stands for a group selected from (C1-C5) alkyl, (C1-C5)carboxyethyl, optionally substituted phenyl and optionally substituted benzyl, and the hydrogenation reaction is catalyzed by a complex compound of a transition metal with chiral diphosphine ligands, where the transition metal is selected from the group consisting of ruthenium, iridium and rhodium, and the process of hydrogenation is carried out at a pressure from 1 to 150 ATM, alcohol or halogenosilanes solvent, or a mixture thereof at a temperature of from 60 to 150°C, which leads to the formation of enriched 4R-enantiomer of compounds of formula (III):

b) reaction of the compound of formula (III) with a reagent capable of converting IT group to a leaving group, selected from a number of Teilhard, methanesulfonanilide, benzosulfimide, which is added to the compound (III) at a temperature between -20 and +25°C in the presence of an inert solvent and basic compound, with subsequent nucleophilic substitution of its sesamol(3,4-methylendioxy MES heated for 2-4 hours with obtaining enriched 4R-enantiomer derivative of the formula (IV):

in) N-dealkylation of the compound (IV) with the formation of paroxetine

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

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

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