Superior way to obtain 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1 methyl-3-n-propyl-1,6-dihydro-7h-pyrazole [4,3-d] pyrimidine-7-it

 

(57) Abstract:

The invention relates to an improved process for the preparation of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-she formulas (I) and its pharmaceutically acceptable salts by the interaction of the compounds of formula (II), where R1and R2means hydrogen or R1means hydrogen and R2means methyl, with a mixture of formic acid and formaldehyde in the presence of tetrabutylammonium bromide, and the ratio of tetrabutylammonium bromide to the original compound is from 1:60 to 1:130, preferably 1:100. Also we propose a way to obtain 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-she formulas (I) and its pharmaceutically acceptable salts by reacting the compounds of formula (II), where R1means methyl, a R2means hydrogen, formic acid and formaldehyde or dimethylsulfate in the presence of tetrabutylammonium bromide, and the ratio of tetrabutylammonium bromide to the original compound is from 1:60 to 1:130, preferably 1:100, if necessary, in the presence of a base such as sodium hydroxide, Hydra is.p. f-crystals.

The present invention relates to an improved and economical process for the preparation of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it and its pharmaceutically acceptable salts.

5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it has been disclosed in U.S. patent US 5250534. Described in this patent, the method includes several stages, and the final product is obtained with a very low yield and low purity.

5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he and related compounds described in European patent application EP 0463756 A1. In this application disclosed the use of these compounds in the treatment of cardiovascular diseases. This activity is attributed to the selective inhibition of cyclic guanosin-3',5'-monophosphate phosphodiesterase (cGMP PDE), and not cyclic adenosine-3',5'-monophosphate phosphodiesterase (camp PDE), which leads to increase of cGMP concentrations. Thus, these compounds are used in the treatment of several disorders, including stable, unstable and variant (Prinzmetala) walls and blood vessels, for example, after percutaneous intraluminal coronary angioplasty (post-CVCA), peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma or diseases characterized by intestinal disorders such as irritable bowel syndrome.

The way to obtain 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-she disclosed in European patent application EP-A-0463756, lies in the interaction of the compounds of formula:

N-methylpiperazine.

In European patent application EP 0463756 A1 describes how to obtain 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it is by O-alkylation of compounds of formula:

In a later European patent application EP 08128454 A2 solved obtain 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it is by cyclization of compounds of formula:

in the presence of a base and a peroxide.

The present invention relates to an improved method floor is a and its predecessor. The method corresponding to the present invention, it is economical and commercially feasible method of obtaining 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it is of high purity and with high yield.

The present invention relates to a method for producing 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it is by catalytic methylation of the compounds of formula:

where R1and R2mean hydrogen or R1means hydrogen and R2means methyl, using a mixture of formic acid and formaldehyde in the presence of a catalyst, such as tetrabutylammonium bromide, to obtain the compound of the formula:

The use of tetrabutylammonium bromide in an appropriate amount provides a high yield with the highest speed. According to the present invention, the ratio of tetrabutylammonium bromide to the original compound is from 1:60 to 1:130.

In a preferred embodiment of the invention, the ratio of catalyst to the original connection is 1:100.

1means methyl, a R2means hydrogen, is converted into a compound of the formula:

by interacting with dimethylsulfate that can be carried out in the presence of a base and a catalytic amount of tetrabutylammonium bromide.

The compound of the formula:

produced by interaction of 4-amino-3-n-propylpyrazole-5-carboxamide with 2-ethoxy-5-(piperazine-1-ylsulphonyl)-benzoyl chloride to obtain the intermediate product 4-[2-ethoxy-5-(piperazine-1-ylsulphonyl)-benzamido]-3-n-propylpyrazole-5-carboxamide, which cyclist using a base selected from the group comprising sodium hydroxide, potassium hydroxide or alkoxides of alkali metals or a mixture of any of the above grounds with hydrogen peroxide.

An alternative can be obtained by interaction of 4-amino-3-n-propylpyrazole-5-carboxamide with 2-ethoxybenzonitrile obtaining 4-(2-ethoxybenzoyl)-3-n-propylpyrazole-5-carboxamide, which cyclist, and then sequentially treated with chlorosulfonic acid, and then anhydrous piperazine.

Therefore, by choosing a suitable pyrazole and piperazine can be obtained compound of the formula:

SUB> means hydrogen and R2means methyl, can be converted into 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he, i.e. the compound of the formula:

interaction with a mixture of formic acid and formaldehyde in the presence of a catalyst, such as tetrabutylammonium bromide.

The compound of the formula:

where R1means methyl, a R2means N, can easily be converted to 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he, i.e. the compound of the following formula:

or with formic acid and formaldehyde, or by methylation using meteorologi reagent, such as dimethylsulfate, in the presence of a catalyst, such as tetrabutylammonium bromide.

Using the present invention can provide a commercially suitable way to obtain 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it and its predecessor with high yield and high purity more cost effective way than in the previous rorisang the following schemes 1 and 2:

where R1and R2mean hydrogen or R1mean N and R2means methyl, and Vice versa.

In accordance with a preferred embodiment of the present invention the compounds of formula:

produced by interaction of 4-amino-3-n-propylpyrazole-5-carboxamide with 2-ethoxy-5-(piperazine-1-ylsulphonyl)-benzoyl chloride to obtain the intermediate product, 4-[2-ethoxy-5-(piperazine-1-ylsulphonyl)-benzamido]-3-n-propylpyrazole-5-carboxamide, which cyclist using a base selected from the group comprising sodium hydroxide, potassium hydroxide or alkoxides of alkali metals or a mixture of any of the above grounds with hydrogen peroxide.

In accordance with a preferred embodiment of the present invention the compounds of formula:

can be obtained by the interaction of the compounds of the formula:

with a mixture of formic acid with formaldehyde in the presence of a catalyst, such as tetrabutylammonium bromide.

The method corresponding to the present invention, without limiting its scope is described using the following examples:

the n-7-she is slowly added to a mixture of 18.4 g of formic acid with 32,4 g of 37% formaldehyde. The solution is stirred for 15 hours at 40 to 45°C. To stop the reaction the reaction mass is then poured into approximately 2000 ml of water and filtered, receiving USD 5.76 g of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it. The purity of 96.5%.

Example 2

Spend interaction, as in example 1, in the presence of tetrabutylammonium bromide as a catalyst, while maintaining all other parameters of the process. The concentration of the catalyst was, however, changed as follows.

1. 9.0 g of 5-[2-Ethoxy-5-(piperazine-1-ylsulphonyl)-phenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-she is slowly added to a mixture of 18.4 g of formic acid with 32,4 g of 37% formaldehyde and 150 mg of tetrabutylammonium bromide. The solution is stirred for 5 hours at 40 to 45°C. To stop the reaction the reaction mass is then poured into approximately 2000 ml of water and filtered, obtaining of 6.96 g of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it. Purity 98,85%.

2. 5-[2-Ethoxy-5-(piperazine-1-ylsulphonyl)-phenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he (9.0 g) is slowly added to a mixture of 18.4 g of formic acid with 32,4 g of 37% formaldehyde. To the resulting reaction mA the reaction the reaction mass is then poured into approximately 2000 ml of water and filtered, receiving of 6.96 g of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it. Purity 99,50%.

3. 9.0 g of starting compound, 5-[2-ethoxy-5-(piperazine-1-ylsulphonyl)-phenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidine-7-she gradually added to a mixture of 18.4 g of formic acid with 32,4 g of 37% formaldehyde in the presence of 90 mg of tetrabutylammonium bromide. The solution is stirred for 5 hours, keeping the temperature between 40 to 45°C. To stop the reaction the reaction mass is then poured into approximately 2000 ml of water and filtered, obtaining 7.2 g of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it. Purity 99,69%.

4. 9.0 g of 5-[2-Ethoxy-5-(piperazine-1-ylsulphonyl)-phenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-she is slowly added to a mixture of 18.4 g of formic acid with 32,4 g of 37% formaldehyde and 75 mg of tetrabutylammonium bromide. The solution is stirred for 5 hours at 40 to 45°C. To stop the reaction the reaction mass is then poured into approximately 2000 ml of water and filtered, obtaining 6,92 g of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it. Purity 99,52%.

5. 9.0 g of 5-[2-Ethoxy-5-(piperazine-1-ylsulphonyl)-f is 32,4 g of 37% formaldehyde in the presence of tetrabutylammonium bromide (64,28 mg). The solution is stirred for 5 hours at 40 to 45°C. To stop the reaction the reaction mass is then poured into approximately 2000 ml of water and filtered, obtaining of 6.90 g of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it. Purity 99,50%.

The obtained yield was maximum when the ratio of catalyst to the original connection was 1:100.

Example 3

5.5 g of 5-[2-Ethoxy-5-(piperazine-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-it while mixing, slowly add to the mixture 11,04 g of formic acid from 19.44 g of 37% formaldehyde. The reaction mass is stirred for 20 hours at 35 to 40°C. After the reaction for stopping the reaction, the reaction mass is then poured into approximately 2000 ml of water and filtered, obtaining 3.94 g of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it. Purity 96,75%.

Example 4

Spend interaction as in example 4, in the presence of tetrabutylammonium bromide as a catalyst, while maintaining all other parameters of the process. The ratio of catalyst to the original connection was varied from 1:90 to 1:150. Found that the reaction gave optimal W, below this ratio (i.e. less than 1:130) catalyst to the initial connection does not occur to any significant increase in output. Purity 99,54%.

Example 5

A suspension of 6.9 g of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-she and 75 ml of acetone was stirred at room temperature. Then slowly added at room temperature 2.25 g of dimethylsulfate. The reaction mass is heated to 35 to 40°C and maintained for 8 hours. After completion of the reaction the solvent is removed by distillation and the residue for stopping the reaction was poured into water and filtered, obtaining 4.68 g of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-it. Purity 96,58%.

Example 6

A suspension of 6.9 g of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-she, 75 ml of acetone and 69 mg of tetrabutylammonium bromide was stirred at room temperature. Then slowly added at room temperature 2.25 g of dimethylsulfate. The reaction mass is heated to 35 to 40°C and maintained for 2 hours. After completion of the reaction the solvent is removed by distillation and the residue to stop reaction Viliv-7H-pyrazole[4,3-d]pyrimidine-7-it. Purity 99,56%.

Example 7

Reaction as in example 6, was carried out at different ratios of catalyst to the original connection, while maintaining all other parameters of the process. Selected ratios were- 1:110, 1:100, 1:80, 1:60 and 1:40. The yield of the final product was of 5.75 respectively; 5,85; 5,79; 5,78 and 5,78. The average purity of the obtained final product 99,58%.

1. The way to obtain 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-she formulas (I)

and its pharmaceutically acceptable salts by reacting the compounds of formula (II)

where R1and R2mean hydrogen or R1means hydrogen and R2means methyl, with a mixture of formic acid and formaldehyde in the presence of tetrabutylammonium bromide, and the ratio of tetrabutylammonium bromide to the original compound is from 1:60 to 1:130.

2. The method according to p. 1, in which the ratio of tetrabutylammonium bromide to the original connection is 1:100.

3. The way to obtain 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-she formulas (I) and its pharmaceutically pickup the/P>

R2means hydrogen,

with formic acid and formaldehyde or dimethylsulfate in the presence of tetrabutylammonium bromide, and the ratio of tetrabutylammonium bromide to the original compound is from 1:60 to 1:130.

4. The method according to p. 3, in which the ratio of tetrabutylammonium bromide to the original connection is 1:100.

5. The method according to p. 4, which use dimethylsulfate, and the reaction is carried out in the presence of a base.

6. The method according to p. 5, in which the specified radix is chosen from the group including sodium hydroxide, potassium hydroxide and potassium carbonate.



 

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FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 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 a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

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SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

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EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

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

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

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