Dihydropyrazolopyrimidinone derivatives

FIELD: chemistry.

SUBSTANCE: invention describes a compound of general formula where A1 is selected from the following formula R1c denotes a hydrogen atom, a lower alkenyl group or a -Q3-A3(R1d)R1e group; A3 denotes a methane or lower alkyl group; Q3 denotes a single bond; R1d and R1e independently denote a hydrogen atom, hydroxyl group, lower alkyl group or hydroxyl-containing lower alkyl group, or together form a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1 denotes a lower alkenyl group or a lower alkynyl group; R2 denotes a phenyl, pyridyl or thienyl group, which can contain a -Q4-A4(R1g)R1h group; A4 denotes a nitrogen atom, a lower alkyl group optionally substituted with a hydroxy-lower alkyl group, or a methane group optionally substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Q denotes a single bond or a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1g and R1h independently denote a hydrogen atom, a lower alkyl group or a lower alkylsulphonyl group; R5 and R6 independently denote a hydrogen atom, a lower alkyl group or a hydroxyl-containing lower alkyl group, or a pharmaceutically acceptable salt thereof. The invention also describes a pharmaceutical composition based on compounds of formula I, having anti-cancer activity, an anticancer agent, a codrug, as well as an exposure sensitising agent containing the pharmaceutical composition.

EFFECT: novel compounds are obtained and described, having excellent Well-kinase inhibitory action and can therefore be used in medicine, especially when treating different malignant tumours.

13 cl, 21 ex

 

The technical field

The present invention is applicable in the field of medicine. More precisely, the derivative of dihydropyrimidinase the invention is applicable in the treatment of various malignant tumors as a kinase inhibitor, particularly as an inhibitor of Weel kinase.

The level of technology

Cells have a regulatory mechanism, namely, that when damaged their DNA, cells temporarily stop the cell cycle and eliminate DNA damage (Cell Proliferation, Vol. 33, pp. 261-274). In about half of cases of malignant human tumor suppressor gene in malignant tumors p53 was mutated or lost, and cells thereof have lost their G1 regulatory function. Despite this, these malignant tumors can still retain their remaining G2 controlling function, which is considered as the sole factor in lowering the sensitivity of cells to anticancer agents, active against DNA and exposures.

Weel-kinase represents the tyrosine kinase, which is involved in the G2 control of the cell cycle. Weel phosphorylates Cdc2(Cdk1) tyrosine 15, which is involved in the promotion to the M stage from the G2 stage of the cell cycle, therefore inactivating Cdc2 and temporarily stopping the cell cycle at G2 stage (The EMBO Journal, Vol. 12, p. 75-85). Thus, for malignant tumor cells that have lost p53 function, as such, believe that the G2 control function implemented Weel, important in the elimination of damaged DNA, in order to avoid cell death. To date, it was reported that the decrease in expression of the Weel by effects on RNA or inhibition Weel compounds may increase the sensitivity of malignant tumor cells to adriamycin, x-ray irradiation and gamma irradiation (Cancer Biology &Therapy, Vol. 3, pp. 305-313; Cancer Research, Vol. 61, pp. 8211-8217). Based on the foregoing, I believe that the inhibitor Weel may inhibit G2 regulatory function no longer p53 of malignant tumor cells, therefore increasing the sensitivity of cells to anticancer agents, active against DNA and exposures.

As a low molecular weight inhibitor of Weel kinase known, for example, compounds described in the application U.S. 2005/0250836, WO 2003/091255, Cancer Research, Vol. 61, pp. 8211-8217, or in Bioorg. & Med. Chem. Lett., Vol. 15, pp. 1931-1935. However, the compounds described in these references are quite different from the compounds according to the invention from the point of view of their structures.

On the other hand, WO 2004/056786, WO 2005/021532 or WO 2006/091737 disclose various compounds such as dihydropyrimidine, which is quite similar to the compounds according to the invention from the point of view OS the ESD structures of their structure. However, these references do not disclose specific and do not offer any inhibitory effect on Weel-kinase of these compounds, and also does not disclose the compounds according to the invention.

The invention

The purpose of the invention to provide a new agent against malignant tumors, has inhibitory effects on the kinase, in particular inhibitory effect on Weel-kinase.

As a result of painstaking research, the authors of the present invention have found that compounds of General formula (I) possess excellent inhibitory effect on the kinase, in particular excellent inhibitory effect on Weel-kinase, and completed the present invention:

where

A1choose from the following formula (aa1):

R1crepresents a hydrogen atom, a lower alkenylphenol group or a group-Q3-A3(R1dR1e;

A3represents a nitrogen atom or represents Metin or 1-vinyl-2-ridenow group, optionally substituted hydroxyl group, lower alkyl group or a hydroxyl-containing lower alkyl group;

Q3represents a single bond or lower alkylenes group in which one, or two or more methylene groups, with the bringing of the lower alkylenes group, can be independently replaced by an oxygen atom, a sulfur atom, a carbonyl group, sulfanilic group or sulfonyloxy group and/or substituted by a halogen atom, cyano, hydroxyl group or lower alkyl group;

R1dand R1erepresent independently a hydrogen atom, halogen atom, cyano, hydroxyl group, lower alkyl group or hydroxyl-containing lower alkyl group, or together form a lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom, a sulfur atom, sulfanilic group, sulfonyloxy group, carbonyl group, vanilinovoi group or a group-N(R1f)-, and/or substituted by a hydroxyl group or a lower alkyl group;

R1frepresents a hydrogen atom, a lower alkyl group, halogenated lower alkyl group, lower alkenylphenol group or lower alkanoyloxy group;

R1represents the lowest alkenylphenol group or lower alkylamino group;

R2represents phenyl, pyridyloxy or thienyl group, which may contain the group-Q4-A4(R1gR1h;

A4represents a nitrogen atom or a methine group, not battelino substituted by halogen atom, hydroxyl group, lower alkyl group or a hydroxy-lower alkyl group;

Q4represents a single bond or lower alkylenes group in which one or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom or carbonyl group, and/or substituted lower alkyl group;

R1gand R1hrepresent independently a hydrogen atom, halogen atom, cyano, hydroxyl group, lower alkyl group containing lower alkoxygroup lower alkyl group, lower alkanoyloxy group, lower alkoxycarbonyl group or lower alkylsulfonyl group, or together form a lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom, a sulfur atom, sulfanilic group, sulfonyloxy group, a carbonyl group or a group-N(R1i)-, and/or substituted by a halogen atom or a lower alkyl group;

R1irepresents a hydrogen atom, a lower alkyl group or halogenated lower alkyl group;

R5and R6represent independently a hydrogen atom, a lower alkyl group or hydroxyl-containing lower alkyl gr the foam.

Compounds (I) according to the invention have an inhibitory effect on the kinase, in particular inhibitory effect on Well-kinase, and therefore applicable in the quality of medicines in various malignant tumors, such as brain cancer sanitarily cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, lung cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, horiokartsinoma, uterine cancer, cervical cancer, cancer of the renal pelvis/ureter, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms ' cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic miliitary leukemia, Hodgkin's lymphoma.

In particular, the compounds (I) according to the invention is applicable as medicines, for example, in breast cancer, lung cancer, pancreas cancer, colon cancer, ovarian cancer, acute leukemia, chronic leukemia, chronic malacitana leukemia, Hodgkin's disease.

The invention relates to compounds of formula (I) and their salts, as well as how they are perceived by the Oia and their application.

The meaning of the terms used in the present description, described below, and the invention is described in more detail below.

"Halogen atom" means a fluorine atom, chlorine atom, bromine atom and iodine atom.

"Lower alkyl group" means a straight or branched alkyl group having from 1 to 6 carbon atoms, including, for example, methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow group, isopentyl group, hexoloy group, isohexyl group.

"Halogenated lower alkyl group" means the above lower alkyl group in which any substitutable position is substituted by one, or two, or more, preferably from 1 to 3, identical or different, above-mentioned halogen atoms, including, for example, formeterol group, deformational group, triptorelin group, 2-foretelling group, 1,2-deperately group, chloromethylene group, 2-chloraniline group, 1,2-dichloroethylene group, bromatology group, otmetilo group.

"Hydroxyl-containing lower alkyl group" means the above lower alkyl group in which any substitutable position is substituted by one, or two, or more, preferably 1 or 2, hydroxyl groups, including, for example, hydroxymethylene group, 2-hydroxyethyloxy group, 1-hydroxy-1-methylamino group, 1,2-dihydroxyethyl group, 3-hydroxypropyl group.

"Lower CNS group" means a straight or branched CNS group having from 1 to 6 carbon atoms, including, for example, metaxylene group, ethoxyline group, propoxyphenyl group, isopropoxyphenyl group, butoxyl group, sec-butoxyphenyl group, isobutoxy group, tert-butoxyl group, pentylhexyl group, isobutylamino group, hexylamino group, isohexadecane group.

"Lower alcoolica group" means alkanoyloxy group having the above-mentioned lower alkyl group, or one that is alkanoyloxy group having 2 to 7 carbon atoms, including, for example, acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, valerino group, isovaleryl group, pivaloyl group.

"Lower Allenova group" means a straight or branched alkylenes group having from 1 to 6 carbon atoms, including, for example, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group.

"Lower Alchemilla GRU is PA" denotes a straight or branched alkenylphenol group, having from 2 to 6 carbon atoms, including, for example, vinyl group, 1-propenyloxy group, allyl group, Isopropenyl group, 3-butenyloxy group, 2-butenyloxy group, 1-butenyloxy group, 1-methyl-2 - propenyloxy group, 1-methyl-1-propenyloxy group, 1-ethyl-1-atenolol group, 2-methyl-2-propenyloxy group, 2-methyl-1-propenyloxy group, 3-methyl-2-butenyloxy group, 4-pentanediol group.

"Lower Alchemilla group" means a straight or branched alkylamino group having from 2 to 6 carbon atoms, including, for example, etinilnoy group, 1-propenyloxy group, 2-propenyloxy group, 3-butenyloxy group, 2-butenyloxy group, 1-butenyloxy group, 1-methyl-2-propenyloxy group, 1-ethyl-2-propenyloxy group, 1-methyl-2-butenyloxy group, 4-pantanillo group.

"Contains the lowest CNS lower alkyl group" means the above lower alkylamino group in which any of the substituted provisions substituted one, or two, or more, preferably 1 or 2, identical or different, above-mentioned lower CNS groups, including, for example, methoxymethyl group, ethoxymethyl group, 2-methoxyaniline group, 2-ethoxyethylene group, 1-methoxy-1-methylamino group, 1,2-dimethoxyaniline group, 3-methoxypropyl group.

"Lower alkoxycarbonyl the group" denotes alkoxycarbonyl group, with the above-mentioned lower CNS group, or one that is alkoxycarbonyl group having 2 to 7 carbon atoms, including, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxyethanol group, tert-butoxycarbonyl group, ventilatsioonile group.

"Lower alkylsulfonyl group" means a straight or branched alkylsulfonyl group having from 1 to 6 carbon atoms, including, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylphenyl group, butylsulfonyl group, sec-butylsulfonyl group, isobutylamino group, tert-butylsulfonyl group, pentylaniline group, isopentenyladenine group, hexylaniline group, isohexanol group.

"Salts" of the compounds according to the invention denotes the usual pharmaceutically acceptable salt. For example, when the compounds have a carboxyl group, a hydroxyl group or an acidic heterocyclic group, such as tetrataenia group, they may form a primary additive salt of carboxyl group, hydroxyl group, or an acid, heterocycle eskay group; in either case, when the compounds have an amino group or a basic heterocyclic group, they may form an acid additive salt at the amino group or a basic heterocyclic group.

Basically additive salts include, for example, salts of alkaline metal such as sodium, potassium; salts of alkaline earth metal such as calcium salts, magnesium salts; ammonium salts; and salts of organic amine, such as salts of trimethylamine, salt, triethylamine salt dicyclohexylamine, ethanolamine salt, diethanolamine salt, triethanolamine salt, salts of procaine, salts of N,N'-dibenziletilendiaminom.

Acid additive salts include, for example, salts of inorganic acids, such as hydrochloride, sulfates, nitrates, phosphates, perchlorates; salts of organic acids, such as maleate, fumarate, tartratami, citrates, ascorbates, triptoreline; and sulfonates such as methanesulfonate, isethionate, bansilalpet, p-toluensulfonate.

"Esters" of the compounds according to the invention represent a conventional pharmaceutically acceptable esters for carboxy group, if any, connections. They include, for example, esters with lower alkyl group such as methyl group, ethyl group, through the group, isopropyl group, bucilina group, sec-bucilina group, tert-bucilina group, entellina group, isopentyl group, neopentylene group, cyclopropyl group, cyclobutyl group, cyclopentenone group; esters with aranceles group such as benzyl group, penicilina group; esters with lower alkenylphenol group such as allyl group, 2-bucinellina group; esters with containing lower CNS group, a lower alkyl group, such as methoxymethyl group, 2-ethoxyethylene group, 2-ethoxyethylene group; esters with containing the lower alkanoyloxy lower alkyl group, such as acetoxymethyl group, pivaloyloxymethyl group, 1-pivaloyloxymethyl group; esters with containing lower alkoxycarbonyl group, a lower alkyl group, such as methoxycarbonylmethyl group, isopropoxycarbonyl group; esters with containing carboxypropyl lower alkyl group, such as carboxymethyl group; esters with containing the lower alkoxycarbonyl lower alkyl group such as 1-(ethoxycarbonyl)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group; esters with containing carbamoyloximes lower alkyl group, such as carbamoylmethyl group; esters with italicising group; esters with a (5-substituted-2-oxo-1,3-dioxol-4 and is)methyl group, such as (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group.

To illustrate the compounds according to the invention, more specifically, preferred examples of symbols used in the formula (I), and others described in more detail below.

R1represents the lowest alkenylphenol group or lower alkylamino group.

"Lower Alchemilla group" for R1represents, for example, preferably, allyl group, 2-methyl-2-propenyloxy group, 3-methyl-2-butenyloxy group, particularly preferably allyl group.

"Lower Alchemilla group" for R1represents, for example, preferably, 2-propenyloxy group.

In preferred embodiments of the invention R1represents, for example, lower alkenylphenol group optionally substituted by a halogen atom, more specifically, allyl group, 2-methyl-2-propenyloxy group, 3-methyl-2-butenyloxy group; more preferably, allyl group.

In other preferred embodiments of the invention R1represents, for example, lower alkylamino group optionally substituted by a halogen atom, more specifically, 2-propenyloxy group.

In particular, the lower Alchemilla group such as allyl group, etc. is preferred for R1.

R1 represents, for example, preferably, allyl group, 2-methyl-2-propenyloxy group, 3-methyl-2-butenyloxy group, 2-propenyloxy group, more preferably allyl group.

R2represents phenyl, pyridyloxy or thienyl group which may have a group-Q4-A4(R1gR1h.

"Phenyl, perederina or thienyl group which may have a group-Q4-A4(R1gR1hfor R2denotes the above-mentioned unsubstituted phenyl, pyridyloxy or thienyl group, or the above-mentioned phenyl, pyridyloxy or thienyl group substituted by a group-Q4-A4(R1gR1h. The group may be the same or different, number one, or two, or more, preferably 1 or 2 groups-Q4-A4(R1gR1hin any substitutable position in it.

In the group-Q4-A4(R1gR1hthe Deputy may be such that A4represents a nitrogen atom or a methine group optionally substituted by halogen atom, hydroxyl group, lower alkyl group or a hydroxyl-containing lower alkyl group; Q4represents a single bond or lower alkylenes group in which one, or two or more methylene groups, sost is engaged in the lower alkylenes group, can be independently replaced by an oxygen atom or carbonyl group, and/or substituted lower alkyl group; R1gand R1hrepresent independently a hydrogen atom, halogen atom, cyano, hydroxyl group, lower alkyl group containing lower alkoxygroup lower alkyl group, lower alkanoyloxy group, lower alkoxycarbonyl group or lower alkylsulfonyl group, or together form a lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom, a sulfur atom, sulfanilic group, sulfonyloxy group, a carbonyl group or a group-N(R1i)-, and/or substituted by a halogen atom or a lower alkyl group.

"Methine group optionally substituted by halogen atom, hydroxyl group, lower alkyl group or a hydroxyl-containing lower alkyl group" for A4denotes unsubstituted methine group or a methine group having a Deputy selected from the group consisting of halogen atom, hydroxyl group, lower alkyl groups and hydroxyl-containing lower alkyl groups.

One, or two or more methylene groups constituting the lower alkylenes group for Q4can be independent, what about replaced by oxygen atom or carbonyl group, and/or substituted lower alkyl group.

Lower Allenova group, which R1gand R1htogether form, represents, for example, preferably, ethylene group, trimethylene group, tetramethylene group, pentamethylene group. When A4"with which they are associated, is a nitrogen atom, then they form together with the nitrogen atom 1-aziridinyl group, 1-azetidinol group, 1-pyrrolidinyloxy group, piperidino group; when A4represents a methine group, they form together with retinovoy group cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group. Basically, more preferred are 1-pyrrolidinyl group, piperidino group, cyclobutyl group, tsiklogeksilnogo group.

One, or two or more methylene groups constituting the above-mentioned lower alkylenes group may be independently replaced by an oxygen atom, a sulfur atom, sulfanilic group or sulfonyloxy group, a carbonyl group or a group-N(R1i)-, and/or substituted by a halogen atom or a lower alkyl group. Examples of the substituted or substituted groups are preferably selected from the following formula (bb3'):

R1iin the group-N(R1 is a hydrogen atom, a lower alkyl group or halogenated lower alkyl group.

The lower alkyl group for R1irepresents, for example, preferably, methyl group, ethyl group.

Halogenated lower alkyl group for R1irepresents, for example, preferably, formeterol group, deformational group.

Preferred examples of the invention, the group-Q4-A4(R1gR1hrepresents, for example, as the following:

(i) A4represents a nitrogen atom, Q4represents a single bond or methylene group, optionally substituted lower alkyl group, and R1gand R1hrepresent independently a hydrogen atom, a lower alkyl group, lower alkanoyloxy group, lower alkoxycarbonyl group or lower alkylsulfonyl group;

(ii) A4represents a nitrogen atom or a methine group optionally substituted by halogen atom, hydroxyl group, lower alkyl group or a hydroxyl-containing lower alkyl group, Q4represents a carbonyl group, and R1gand R1hrepresent independently a hydrogen atom or a lower alkyl group;

(iii) A4not only is em a methine group, optionally substituted by halogen atom, hydroxyl group, lower alkyl group or a hydroxyl-containing lower alkyl group, Q4represents a single bond or methylene group, optionally replaced by oxygen atom, and R1gand R1hrepresent independently a hydrogen atom, halogen atom, hydroxyl group, lower alkyl group or lower alkoxycarbonyl group;

(iv) A4represents a methine group optionally substituted by halogen atom, hydroxyl group, lower alkyl group or a hydroxyl-containing lower alkyl group, Q4represents a single bond, and R1gand R1htogether form the lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom or a group-N(R1i)-; or

(v) A4represents a nitrogen atom, Q4represents a single bond, and R1gand R1htogether form the lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by a carbonyl group or a group-N(R1i); more preferred above (iii).

More specifically, the group-Q 4-A4(R1gR1hrepresents, for example, preferably, the amino group, dimethylaminomethyl group, methylsulfonylamino, N-methyl-N - methylsulfonylamino group, karbamoilnuyu group, dimethylcarbamoyl group, methyl group, 1-fluoro-1-methylamino group, hydroxymethylene group, 1-hydroxy-1-methylamino group, 2-hydroxy-1,1-dimethylethylene group, 2-hydroxy-2-methylpropyloxy group, 2-hydroxy-1,1 - dimethylpropylene group, methoxy group, 2-hydroxyethoxy, 1-hydroxyisobutyryl group, 2-oxo-1-pyrrolidinyl group or 3-methyl-2-Oxymetazoline-1-ilen group, even more preferred 1-hydroxy-1-mtilatila group and others

Preferred examples of the invention, for R2represents, for example, phenyl or pyridyl, more preferred Peregrina group having a group-Q4-A4(R1gR1h.

More specifically, therefore, phenyl, perederina or thienyl group which may have a group-Q4-A4(R1gR1hfor R2represents, for example, preferably, phenyl group, 3-dimethylaminomethylphenol group, 3-dimethylcarbamoyl group, 3-(1-hydroxy-1-methylethyl)phenyl group, 3-thienyl group, 2-pyridyloxy group, 6-amino-2-pyridyloxy group, -(N-methyl-N-methylsulfonylamino)-2-pyridyloxy group, 6-methyl-2-pyridyloxy group, 6-(1-hydroxy-1-methylethyl)-2-pyridyloxy group, 6-(2-hydroxy-1,1-dimethylethyl)-2-pyridyloxy group, 6-(2-hydroxy-2-methylpropyl)-2-pyridyloxy group, 6-(2-hydroxy-1,1-dimethylpropyl)-2-pyridyloxy group, 6-(2-hydroxyethoxy)-2-pyridyloxy group, 6-(1-hydroxycyclopent)-2-pyridyloxy group, 6-(2-oxo-1-pyrrolidinyl)-2-pyridyloxy group or 6-(3-methyl-2-Oxymetazoline-1-yl)-2-pyridyloxy group, more preferred 6-(1-hydroxy-1-methylethyl)-2-Peregrina group and others

Preferred examples of the invention, for R1and R2in the formula (I) are, for example, R1represents the lowest alkenylphenol or lower alkylamino, more preferably, lower alkenylphenol group, and R2represents phenyl or pyridyloxy, more preferably, pyridyloxy group with the group-Q4-A4(R1gR1h.

A1in the formula (I) selected from following formula (aa1):

R1Cin the group-N(R1cis a hydrogen atom, a lower alkenylphenol group or a group-Q3-A3(R1dR1e.

Lower Alchemilla group for R1Crepresents, for example, preferably, the vinyl group, allyl group.

In the group-Q3-A3(R1dR1efor R1cA3 represents a nitrogen atom or represents Metin or 1-vinyl-2-ridenow group, optionally substituted hydroxyl group, lower alkyl group or a hydroxyl-containing lower alkyl group; Q3represents a single bond or lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom, a sulfur atom, a carbonyl group, sulfanilic group or sulfonyloxy group and/or substituted by a halogen atom, cyano, hydroxyl group or lower alkyl group; R1dand R1erepresent independently a hydrogen atom a halogen atom, cyano, hydroxyl group, lower alkyl group or hydroxyl-containing lower alkyl group, or together form a lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom, a sulfur atom, sulfanilic group, sulfonyloxy group, carbonyl group, vanilinovoi group or a group-N(R1f)-, and/or substituted by a hydroxyl group or lower alkyl group.

"Methine or 1-vinyl-2-Ledeneva group, optionally substituted hydroxyl group, lower alkyl the Noah group or hydroxyl-containing lower alkyl group" for A 3denotes unsubstituted methine or 1-vinyl-2-ridenow group, or a methine or 1-vinyl-2-ridenow group having a Deputy selected from the group consisting of hydroxyl group, lower alkyl groups and hydroxyl-containing lower alkyl groups.

Deputy represents, preferably, hydroxyl group, lower alkyl group such as methyl group and ethyl group.

Lower Allenova group for Q3represents, for example, preferably methylene group, ethylene group, trimethylene group.

One, or two or more methylene groups constituting the lower alkylenes group for Q3may be independently replaced by an oxygen atom, a sulfur atom, a carbonyl group, sulfanilic group or sulfonyloxy group and/or substituted by a halogen atom, cyano, hydroxyl group or lower alkyl group.

The halogen atom for R1dor R1erepresents, for example, preferably, fluorine atom, chlorine atom.

The lower alkyl for R1dor R1erepresents, for example, preferably, methyl group, ethyl group.

Hydroxyl-containing lower alkyl group for R1dor R1erepresents, for example, preferably, hydroxymethylene group, 2-hydroxide is inuu group.

Lower Allenova group, which R1dand R1etogether form, represents, for example, preferably, ethylene group, trimethylene group, tetramethylene group. When A3"with which they are associated, is a nitrogen atom, then they form together with the nitrogen atom 1-aziridinyl group, 1-azetidinol group, 1-pyrrolidinyl group; when A3represents a methine group, they form together with retinovoy group cyclopropyl group, cyclobutyl group, cyclopentyl group; when A3" is a 1-vinyl-2-ridenow group, then they form together with 1-vinyl-2-alienboy group 1-cyclobutenyl group, 1-cyclopentenyl group, 1-cyclohexenyl group. Mostly preferred are cyclopropyl group, cyclobutyl group, cyclopentenone group.

One, or two or more methylene groups constituting the above-mentioned lower alkylenes group may be independently replaced by an oxygen atom, a sulfur atom, sulfanilic group or sulfonyloxy group, carbonyl group, vanilinovoi group or a group-N(R1f)-, and/or substituted by a hydroxyl group or lower alkyl group.

R1fin the group-N(R1fis a hydrogen atom, a lower alkyl the second group, halogenated lower alkyl group, lower alkenylphenol group or lower alkanoyloxy group.

Preferred examples of the invention, the group-Q3-A3(R1dR1erepresents, for example, such as the following:

(i) A3represents a methine group optionally substituted by a hydroxyl group or a lower alkyl group, Q3represents a single bond, and R1dand R1erepresent independently a hydrogen atom or a lower alkyl group; or

(ii) A3represents a methine group optionally substituted by a hydroxyl group or a lower alkyl group, Q3represents the lowest alkylenes group in which one or two methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom, a carbonyl group or sulfonyloxy group and/or substituted by a hydroxyl group, and R1dand R1erepresent independently a hydrogen atom, halogen atom, cyano or lower alkyl group; more preferably above (i).

More specifically, the group-Q3-A3(R1dR1erepresents a,for example, preferably, methyl group, ethyl group, through the group, isopropyl group, Tr is t-boutelou group, hydroxymethylene group, 1-hydroxy-1-methylamino group, 2-hydroxyethylene group, 2-methoxyaniline group, 2-ethoxyethylene group, 2-hydroxy-2-methylpropyloxy group, 3-fluoro-2-hydroxypropyl group, acetyl group, propionyl group, 2-methoxyacetyl group, tert-butoxycarbonyl group, methylsulfonyl group, 2-(methylsulphonyl)ethyl group; more preferably, methyl group, ethyl group, tert-boutelou group, 2-hydroxyethylene group, 2-methoxyaniline group, acetylcoa group; more preferably, a methyl group.

R1Crepresents preferably a hydrogen atom or a group-Q3-A3(R1dR1emore preferably, the group-Q3-A3(R1dR1e.

Preferred embodiments of the invention for A1represents, for example, 1-piperazinilnom group, 4-methyl-1-piperazinilnom group, 4-ethyl-1-piperazinilnom group, 4-isopropyl-1-piperazinilnom group, 4-tert-butyl-1-piperazinilnom group, 4-cyclopropyl-1-piperazinilnom group, 4-cyclobutyl-1-piperazinilnom group, 4-cyclopropylmethyl-1-piperazinilnom group, 4-(2-hydroxyethyl)-1-piperazinilnom group, 4-(2-methoxyethyl)-1-piperazinilnom group, 4-(2-methoxyacetyl)-1-piperazinilnom group, 4-acetyl-1-piperazinilnom group, 4-matilal who were radioactive-1-piperazinilnom group, 4-methyl-3-oxo-1-piperazinilnom group, 4-piperidino group, 1-methyl-4-piperidino group, 1-(2-hydroxyethyl)-4-piperidino group, 4-hydroxy-1-methyl-4-piperidino group, more preferably, 4-methyl-1-piperazinilnom group, 4-ethyl-1-piperazinilnom group, 4-(2-hydroxyethyl)-1-piperazinilnom group, 4-acetyl-1-piperazinilnom group, 1-methyl-4-piperidino group.

R5and R6represent independently a hydrogen atom, a lower alkyl group or hydroxyl-containing lower alkyl group.

Preferred examples of the invention, for R5and R6represents, for example, such that they both represent hydrogen atoms, or when any of them is a hydrogen atom and the other represents a lower alkyl group such as methyl group and ethyl group, or hydroxyl-containing lower alkyl group, such as hydroxymethylene group and 2-hydroxyethylene group.

In the compound of formula (I) R5, R6and A1may be at any substitutable position adjacent phenyl group.

A group of the formula

represents, preferably, 4-(4-methyl-1-piperazinil)phenyl group, 3-methyl-4-(4-methyl-1 - piperazinil)phenyl group, 3-hydroxymethyl-4-(4-methyl-1-piperazinil)FeNi is inuu group, 4-(4-ethyl-1-piperazinil)phenyl group, 4-(4-(2-hydroxyethyl)-1-piperazinil)phenyl group, 4-(4-acetyl-1-piperazinil)phenyl group, 4-(1-methyl-4-piperidyl)phenyl group.

The term "any substitutable position" means a position having a substitutable hydrogen(s) atom(s) of carbon, nitrogen, oxygen and/or sulphur, where the substitution of hydrogen chemically valid and the results of substitution are stable connection.

In the compounds according to the invention is the replacement of the methylene group (s)forming the lower alkylenes group, various radicals, such as oxygen, sulfur, sulfinil, sulfonyl, carbonyl, vinile and substituted or unsubstituted, Imin valid in the case where the substitution is chemically allowed and the results of substitution are stable connection.

Depending on the type of substituent and its salt forms of the compounds according to the invention can be in the form of stereoisomers and tautomers, such as optical isomers, diastereomers, geometric isomers; and the compounds according to the invention include all of these stereoisomers and tautomers, and mixtures thereof.

The invention includes various crystals, amorphous forms, salt, hydrate and solvate of the compounds according to the invention. In addition, prodrugs of the compounds according to the invention are within the scope of the invention.

Examples of compounds of formula (I) and the salts are, for example, the compounds and their salts, described in the examples; and more preferred are the following compounds:

3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl)-N,N-dimethylbenzamide,

2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,

2-allyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,

2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,

2-allyl-6-{[3-hydroxymethyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,

2-allyl-1-(6-aminopyridine-2-yl)-6-[{4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,

2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,

2-allyl-6-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,

6-{[4-(4-acetylpiperidine-1-yl)phenyl]amino}-2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,

2-allyl-6-({4-[4-(2-hydroxyethyl)piperazine-1-yl]phenyl}amino)-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]Piri is one-3-one,

2-allyl-1-[6-(2-hydroxy-2-methylpropyl " pyridine-2-yl]-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,

2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1-[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,

N-{[6-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridin-2-yl]methyl}-N-methylmethanesulfonamide,

1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-PROPYNYL)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-he and

2-allyl-1-[6-(3-methyl-2-Oxymetazoline-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one.

Methods for producing compounds according to the invention are described below.

Compounds (I) according to the invention can be obtained, for example, in accordance with the methods of obtaining mentioned below, or in accordance with methods set forth in the examples and in the examples of the production of the receipt. However, the means of obtaining for the compounds (I) according to the invention should not be limited to these examples reactions.

The method of obtaining 1

The compound of General formula (II)

where L1represents a leaving group; R1prepresents the lowest alkenylphenol group or lower alkylamino group; R2pis aboutenergy, pyridyloxy or thienyl group, which may contain the group-Q4p-A4p(R1gpR1hp; Q4prepresents a single bond or lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom or optionally protected carbonyl group and/or substituted lower alkyl group; RDrand R1hprepresent independently a hydrogen atom, halogen atom, cyano, optionally protected hydroxyl group, a lower alkyl group containing lower alkoxygroup lower alkyl group, lower alkanoyloxy group, lower alkoxycarbonyl group or lower alkylsulfonyl group, or together form a lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom, a sulfur atom, sulfanilic group, sulfonyloxy group, optionally protected carbonyl group or a group-N(R1ip)-, and/or substituted by a halogen atom or a lower alkyl group,

is reacted with a compound of General formula (III) or its salt

where A1pchoose from the following formula (aap1):

R1srrepresents a hydrogen atom, a lower alkenylphenol group or a group-Q3p-A3p(R1dpR1ep;3prepresents a nitrogen atom or a methine group or 1-vinyl-2-ridenow group which may be substituted by an optionally protected hydroxyl group, lower alkyl group or containing optionally protected hydroxy-group of the lower alkyl group; Q3prepresents a single bond or lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom, a sulfur atom, optionally protected carbonyl group, sulfanilic group or sulfonyloxy group and/or substituted by a halogen atom, cyano, optionally protected hydroxyl group or lower alkyl group; R1dpand R1eprepresent independently a halogen atom, cyano, optionally protected hydroxyl group, lower alkyl group or containing optionally protected hydroxy-group of the lower alkyl group, or together form a lower alkylenes group in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom is and, a sulfur atom, sulfanilic group, sulfonyloxy group, optionally protected carbonyl group, vanilinovoi group or a group-N(R1fp)-, and/or substituted by an optionally protected hydroxyl group or lower alkyl group; R1fprepresents an imino-protective group, a hydrogen atom, a lower alkyl group, halogenated lower alkyl group, lower alkenylphenol group or lower alkanoyloxy group; R5pand Rrepresent independently a hydrogen atom, a lower alkyl group or containing optionally protected hydroxy-group of the lower alkyl group, leading to the formation of compounds of General formula (IV)

where A1p, R1p, R2p, R5pand R6pshall have the same meaning as above, and, optionally, a protective group is removed from it by obtaining compounds of General formula (I)

where A1, R1, R2, R5and R6have the same values as above.

Leaving group L1includes, for example, halogen atom such as chlorine atom, bromine atom, iodine atom; an organic sulfonyloxy group, such as methylsulfinyl group, methylsulfonyl group, ethylsulfonyl group, phenylsulfonyl group; and organic sulfonyloxy is, such as methylsulfonylamino, triftormetilfullerenov, p-coolsolutionsgroup; preferably, a chlorine atom, methylsulfinyl group, methylsulfonyl group.

Way to obtain is a General method for obtaining compounds of formula (I).

In the above reaction, when the reagents have the amino group, aminogroup, hydroxyl group, carboxyl group, carbonyl group or the like, which do not participate in the reaction, then the amino group, aminogroup, hydroxyl group, carboxyl group and carbonyl group may be suitably protected amino - or imino-protecting group, the hydroxyl-protecting group, carboxyl-protecting group or a carbonyl-protecting group, and thereafter, the reagents can react, and after the reaction of the protective group can be deleted.

Not specifically defined "amino - or imino-protective group" may be any group that has its function. For example, it includes aracelio group such as benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, benzydamine group, triticina group; lower alkanoyloxy group such as formyl group, acetyl group, propylaniline group, Butyrina group, pivellina group; benzo is inuu group; arylalkylamine group, such as phenylacetylene group, phenoxyacetyl group; lower alkoxycarbonyl group, such as methoxycarbonyl group, ethoxycarbonyl group, propylenecarbonate group, tert-butoxycarbonyl group; aracelikarsaalyna group, such as benzyloxycarbonyl group, p-nitrobenzisoxazole group, ventilatsiooniga group; lower alkylsilane group, such as trimethylsilyl group, tert-butyldimethylsilyl group; tetrahydropyranyl group; trimethylsilylamodimethicone group; lower alkylsulfonyl group, such as methylsulfonyl group, ethylsulfonyl group; arylsulfonyl group, such as benzolsulfonat group, toluensulfonyl group; and especially preferably, acetyl group, benzoyloxy group, tert-butoxycarbonyl group, trimethylsilylamodimethicone group, methylsulfonyl group.

Not specifically defined "hydroxyl protective group" may be any group that has its function. For example, it includes a lower alkyl group such as methyl group, ethyl group, through the group, isopropyl group, tert-bucilina group; lower alkylsilane group, such as trimethylsilyl group, tert-butyldimethylsilyl group; n is SCHOU alkoxymethyl group, such as methoxymethyl group, 2-methoxyethoxymethyl group; tetrahydropyranyl group; trimethylsilylamodimethicone group; aracelio group such as benzyl group, p-methoxybenzyl group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, triticina group; acyl group such as formyl group, acetyl group; and especially preferably a methyl group, methoxymethyl group, tetrahydropyranyloxy group, trityloxy group, trimethylsilylamodimethicone group, tert-butyldimethylsilyloxy group, acetyl group.

Not specifically defined "carboxyl-protective group" may be any group that has its function. For example, it includes a lower alkyl group such as methyl group, ethyl group, through the group, isopropyl group, tert-bucilina group; halogenated lower alkyl group, such as 2,2,2-trichlorethylene group; lower alkenylphenol group such as allyl group; aracelio group such as benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, benzydamine group, triticina group; and particularly preferably, methyl group, ethyl group, tert-boutelou group, allyl group, benzyl group, p-methoxybenzyloxy group, benziger the function group.

Not specifically defined "carbonyl-protective group" may be any group that has its function. For example, it includes acetals and ketals, such as atlantal, trimethylacetyl, dimethylacetal.

For the reaction of compounds of formula (II) and compounds of formula (III)generally, equimolar or excess molar amount, preferably from an equimolar amount to 1.5 moles of compound (III) used to pray one of compound (II).

The reaction is carried out usually in an inert solvent. The inert solvent is, for example, preferably, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, N-organic, dimethylsulfoxide and mixed of these solvents.

Preferably, the reaction is carried out in the presence of a base. The base includes, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine, 4 - dimethylaminopyridine; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide.

The amount used can be usually equimolar amount to the excess molar amount, preferably from 1 to 3 moles with respect to one pray the compounds of formula (II).

T is mperature reaction may be, usually from 0°C to 200°C, preferably from 20°C to 150°C.

The reaction time may be generally from 5 minutes to 7 days, preferably from 30 minutes to 24 hours.

After the reaction system can be processed in the usual method of obtaining the crude product of the compound of formula (IV). Thus obtained compound of the formula (IV) is treated in the usual method, or not clear, it is not necessarily subjected to removal of protective groups, amino groups, hydroxyl groups, carboxyl groups and carbonyl groups, where they are optional, although conveniently combine for obtaining the compounds of formula (I).

The method of removal of the protective group varies depending on the type of the protective group and the stability of the intended compound (I). For example, the removal of protection can be achieved in accordance with the methods described in references [see Protective Groups in Organic Synthesis, 3rd. Ed., by T. W. Greene, John Wiley & Sons (1999)], or in accordance with methods like these. For example, this document actually apply the method of solvolysis of acid or base, which includes processing secure connections acid in amount of from 0.01 mol to a large excess, preferably, triperoxonane acid, formic acid or hydrochloric acid, or processing base in the amount of equimolar the CSOs to large excess amount, preferably, potassium hydroxide or calcium hydroxide; and the method of chemical reduction with complex metal hydride or by catalytic reduction with a palladium catalyst with coal or with catalyst Raney Nickel.

The compounds of formula (I) can be easily isolated and purified by any conventional method of selection. Examples of the method are, for example, solvent extraction, recrystallization, column chromatography, preparative thin-layer chromatography.

The compounds may be converted into their pharmaceutically acceptable salts or esters conventional method; and, on the contrary, their salts or esters can also be converted into the free compounds by usual method.

"Salts" of the compounds of formula (III) include conventional salts used in the field of organic chemistry. For example, when the compound has an amino group or a basic heterocyclic an amino group, then its salts are acid additive salt at the amino group or a basic heterocyclic group.

Acid additive salts include, for example, salts of inorganic acids, such as hydrochloride, sulfates, nitrates, phosphates, perchlorates, salts of organic acids, such as maleate, fumarate, tartratami, citrates, ascorbates, triptoreline; sulfonates, such as methanesulfonate, isethionate, Ben is alsultany, p-toluensulfonate.

Compounds of formulas (II) and (III) may be commercially available or can be obtained in accordance with methods described in references [see WO 2006/004040, WO 2003/037872; Journal of Medicinal Chemistry, Vol. 48, pp. 2371-2387; Bioorg. & Med. Chem. Lett., Vol. 14, pp. 5793-5797; Journal of the Chemical Society, Perkin Transaction II, Vol. 3, p. 843], or in accordance with methods such as these, or in accordance with the methods described below, or in accordance with the methods described in examples and production examples getting, not necessarily, but may be merged.

The method of obtaining A

where Et represents an ethyl group; L2represents a leaving group; Me represents a methyl group; R1pand R2phave the same values as above.

The method of obtaining A represents a method for obtaining compounds of formula (II), in which the leaving group for L1represents methylsulfinyl group, or a method for obtaining compounds of formula (II-1).

In accordance with this method of obtaining the compound of the formula (II-1) can be obtained by reaction of compounds of formula (1) and hydrazine powered derivative of the formula (2) in the presence of a base, with the formation of the compounds of formula (3), and then the introduction of the group R1pin the compound (3), with the formation of compound (5), and in the end the oxidation metalcorp in connection (5) to methylsulfinyl group.

At the stage of reacting the compounds of formula (1) and hydrazine powered derivative of the formula (2) in the presence of a base to form compounds of formula (3)as a rule, from 0.5 mol to excess molar amount, preferably from an equimolar amount to 3.0 moles of hydrazine powered derivative (2) apply in relation to pray one of the compounds (1).

Usually the reaction is carried out in an inert solvent. The inert solvent is, for example, preferably, methylene chloride, chloroform, tetrahydrofuran, diethyl ether, benzene, toluene, dimethylformamide or a mixed solvent of them.

Preferably, the reaction is carried out in the presence of a base. The base includes, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate.

Generally, the amount used of the base is preferably from an equimolar amount to excessive molar amount relative to one pray connection (1). When the base is a liquid, then the base can also serve as a solvent.

The reaction temperature may be generally from -78°C to 100°C, preferably, the t 20°C to 80°C.

The reaction time may be generally from 5 minutes to 7 days, preferably from 30 minutes to 24 hours.

At the stage of reacting the compound (3) and compound (4) with the formation of compound (5)is usually from 0.5 mol to excess molar amount, preferably from 2.0 to 5.0 moles of moles of the compound (4) apply in relation to pray one connection (3).

Leaving group for L2represents preferably a halogen atom such as chlorine atom, bromine atom, iodine atom.

Usually, the reaction can be carried out in an inert solvent, such as tetrahydrofuran, benzene, toluene, acetonitrile, dimethylformamide, in the presence of a base such as sodium hydride, sodium amide, sodium alkoxide, or in a solvent such as methanol, ethanol, acetonitrile, in the presence of a base such as sodium hydroxide, potassium hydroxide, potassium carbonate.

Usually the reaction temperature is preferably from 0°C to the boiling point of the solvent used in the reaction; and, usually, the reaction time is preferably from 1 hour to 48 hours.

For the stage of oxidation of metalcorp in connection (5) to obtain the compound (II-1), the applicable method is the oxidation of metalcorp in methylsulfinyl group or methylsulfonylamino group, as such are well known in the field of organic chemistry. Ordinary is, for example, in an inert solvent, such as benzene, toluene, methylene chloride, chloroform, tetrahydrofuran, acetonitrile or dimethylformamide, 0.5 mol to excess molar amount, preferably from an equimolar amount to 1.5 moles of oxidizing agent, such as metachlorobenzoic acid or oxen can be used against one pray connection (5) for oxidation.

The reaction temperature is usually preferably from 0°C to the boiling point of the solvent used in the reaction, and, usually, the reaction time is preferably from 30 minutes to 8 hours.

Compounds of formulas (1) and (2) may be commercially available or can be obtained in accordance with known methods, or in accordance with methods described in the examples or according to methods similar to them, not necessarily, but may be merged.

The method of obtaining B

where M is a commonly encountered in organic compounds metal atom; RPrepresents a hydrogen atom or imino-protective group; Et, M, Me, R1pand R2phave the same values as above.

Imino-protective group, RRrepresents, for example, preferably, benzyl group, para-methoxybenzyloxy group, tert-butoxycarbonyl the optimum group, benzyloxycarbonyloxy group.

The method of obtaining B is a method for obtaining compounds of formula (II-1).

In accordance with this method of obtaining the compound of the formula (II-1) can be obtained by reaction of compounds of formula (1) and hydrazine powered derivative of the formula (8) in the presence of base, followed by hydrolysis of the resulting compound and cyclization with formation of the compound of formula (9), and then by the reaction of compound (9) with the ORGANOMETALLIC compound of the formula (10) in the presence of a catalyst for the introduction, thus, the group R2pin him, with the formation of compound (5), and, ultimately, the oxidation of metalcorp in connection (5) to methylsulfonylamino group.

On the reaction of compounds of formula (1) and hydrazine powered derivative of the formula (8) in the presence of a base, typically, the amount of hydrazine powered derivative (8) can be from 0.5 mol to excess molar amount, preferably from an equimolar amount to 1.5 moles with respect to one pray connection (1).

The reaction can usually be carried out in the presence of organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, or inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, is hydrocarbonate sodium, in an inert solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, benzene, toluene, dimethylformamide or a mixed solvent.

Generally, the amount used of the base is preferably from an equimolar amount to excessive molar amount relative to one pray connection (1). When the base is a liquid, then the base can also serve as a solvent.

The reaction temperature may be generally from -78°C to 200°C, preferably from 20°C to 100°C.

The reaction time may be generally from 5 minutes to 7 days, preferably from 8 hours to 24 hours.

For stage hydrolysis of the compound obtained in the preceding reaction, applicable is a method of hydrolysis of carboxylates, in itself known in the field of organic chemistry. Usually in a solvent such as methanol, ethanol, tetrahydrofuran, dioxane, water or a mixed of them, the solvent, the compound may be treated with acid, such as hydrochloric acid or sulfuric acid, or base, such as sodium hydroxide, potassium hydroxide or calcium hydroxide.

Usually the reaction temperature is preferably from 50°C to the boiling point of the solvent used in the reaction; and usually the reaction time is preferred is entrusted, from 1 hour to 48 hours.

After hydrolysis of the resulting compound cyclizes obtaining compound (9). To this reaction liquid medium may be acidified after hydrolysis, in this case, the cyclization can be carried out. In the case where the cyclization does not occur, then gidrolizovannogo connection can be heated under reflux in the presence of acetic anhydride, or gidrolizovannogo the connection can be treated with thionyl chloride to achieve the expected cyclization connection.

When cyclization with acetic anhydride, the amount of acetic anhydride is, preferably, excess molar amount, and the reaction time is usually preferably from 1 hour to 48 hours.

When gidrolizovannogo connection is treated with thionyl chloride, the amount of thionyl chloride is preferably excess molar amount, and the reaction time is usually preferably from 1 hour to 48 hours.

Stage reaction of compound (9) with the ORGANOMETALLIC compound of the formula (10) in the presence of a catalyst for the introduction, thus, the group R2pin him, with the formation of compound (5)may be carried out with the use of halide compounds having the group R2pinstead of metal-organic soy is inane formula (10). When such halide lamp is used, then as the preferred catalyst is a complex of copper iodide(I)-diamine.

Stage oxidation metalcorp in connection (5) to obtain the compound (II-1) can be carried out using the same method as oxidation step of metalcorp in connection (5) to obtain the compound (II-1) in the method of obtaining A.

The compound of formula (8) may be commercially available or can be obtained in accordance with known methods, or in accordance with methods described in the examples or according to methods similar to them, not necessarily, but may be merged.

Examples of pharmaceutical test for compounds according to the invention is shown below.

Pharmaceutical test 1 (inhibitory effect on Weel-kinase)

(1) Purification of Weel kinase:

cDNA Weel kinase with glutathione-S-transferase (GST), attached at its amino end, was introduced into the baculovirus expression vector to construct a recombinant baculovirus, which were infected cells insect cell line Sf9 to achieve a high level of expression in them. Infected cells were removed and were solubilizers, and then protein GST-tagged Weel kinase was adsorbing on a glutathione column and suirable column with glutathione, and the active fraction bessoleva and on the desalting column, receiving the purified enzyme.

(2) Determination of the activity of Weel kinase:

When defining the activity of Weel kinase as a substrate used synthetic peptide Poly(Lys,Tyr)hydrobromide (Lys:Tyr (4:1)), purchased from the company Sigma.

The number of the reaction mixture was 21.1 μl; and the composition of the reaction buffer was as follows: 50 mm Tris-HCl buffer (pH of 7.4)/10 mm of magnesium chloride/1 mm dithiothreitol. Purified Weel-kinase, 2.5 µg of substrate peptide, 10 μm unlabeled adenosine triphosphate (ATP) and 1 mccoury [γ33P]-labeled ATP (2500 Curie/mmol or more) was added thereto and incubated at 30°C for 30 minutes. Next, 10 ál 350 mm phosphate buffer was added to the reaction mixture to stop the reaction. Substrate peptide was adsorbing onto P81 filter paper 96-hole tablet, then washed several times 130 mm phosphate buffer and the radioactivity was counted using a liquid scintillation counter. [γ-33P]-labeled ATP was purchased from the company Amersham Bioscience.

To add a test compound in the reaction system connection was diluted with dimethylsulfoxide (DMSO) to prepare a series of dilutions. 1,1 μl solution of each dilution was added to the reaction system. As control of 1.1 µl of DMSO was added to the reaction system.

As can be seen from table 1, the compounds according to the invention show excellent is one Weel-inhibitory activity.

Table 1
ConnectionWeel-inhibitory effect (IC50, nm)
Example 17
Example 27,6
Example 313
Example 418
Example 520
Example 911
Example 188,8
Example 206,3
Example 2117

Pharmaceutical test 2 (inhibitory effect on tumor growth)

Cancer cells of human colon cancer WiDr (obtained from ATCC) were implanted subcutaneously on the back F344/N Jcl-rnu Nude rats. Eight days after implantation them intravenous gemcitabine was administered (50 mg/kg, Gemzar injection, Eli-Lilly); and after 24 hours, the test compound was dissolved in the solvent (5% glucose) and was introduced to them by continuous intravenous injection for 8 hours. Tumor volume (0, × (longest diameter) × (the smallest diameter) 2) was determined at 0, 3, 6, 10 and 13 days. Day 0 denotes the day on which gemcitabine was administered. Relative tumor volume is a relative value, which is calculated on the basis of the fact that the volume of the tumor is equal to 1 at 0 day. The percentage of tumor growth (%T/C) was determined in accordance with the following formula:

When the change of tumor volume, counting from 0 days in the group that was subjected to introduction of the test compounds was more than 0 (>0):

% T/C = [(change in tumor volume in the case of the test compounds for 3, 6, 10, 13 day)/(change in tumor volume in the control at 3, 6, 10, 13 day)] × 100.

When the change of tumor volume counting from 0 days in the group that was subjected to introduction of the test compounds was less than 0 (<0):

%T/C = [(change in tumor volume in the case of the test compounds for 3, 6, 10, 13 day)/(change in tumor volume in the case of test compounds in day 0)] × 100.

Data on the inhibitory effect on tumor growth are shown in table 2.

Table 2
Connectionn%T/C
day 3day 6day 10 day 13
Control4100100100100
Gemcitabine 50 mg/kg422315465
The compound of example 9, 0.75 mg/kg/hour386748189
Gemcitabine + compound of example 9, 0.5 mg/kg/hour3-132443
Gemcitabine + compound of example 9, 0.75 mg/kg/hour4-20-37214

Introduction gemcitabine reduced the percentage of tumor growth, but when gemcitabine was combined with the connection according to the invention, then the percentage of tumor growth even further decreased. Namely, in the group where chemical dose was high, the animals showed involution of the tumor.

As noted above, the connection according to the invention in combination with another anticancer agent increases the effect of another anticancer agent.

Pharmaceutical test 3 (method of determining the effectiveness of drugs with cells (sensitizing effects of x-ray irradiation)

a) Reagents:

Embryonic bovine serum (FBS) was obtained from Morgate; RPMI 1640 medium and 0.25% trypsin EDTA were from Invitrogen; a set of reagents to cycle test plus DNA was from Becton Dickinson and polyamide mesh filter was from Millipore.

(b) Cells:

Cells non-small cell human lung cancer (NCI-H1299) were obtained from ATCC.

c) Method for determination of effects:

NCI-H1299 cells suspended in RPMI 1640 medium with 10% FBS-containing cell suspension was applied to a 6-hole Nunclondelta-processionary plastic tablet from Nunc in the amount of 100,000 cells/2 ml/well and incubated overnight in an atmosphere of 5% CO2- 95% air at 37°C. Using Softex's M-150WE, cells were subjected to x-ray irradiation 5000 x-ray and then further incubated in an atmosphere of 5% CO2- 95% air at 37°C for 16 hours. Test the connection phases were diluted with DMSO and applied at 2 ml per plate with seeded cells subjected to x-ray irradiation. Incubated in an atmosphere of 5% CO2- 95% air at 37°C for 8 hours and ZAT the m cell culture was partially selected. 0.25% Trypsin was added to the cells remaining in the hole, in the amount of 600 μl, and left in a static condition at room temperature for preparation of the diluted cell suspension. The diluted cell suspension and the preselected cell culture was mixed for each sample then was centrifuged and the supernatant was removed. Sampling was thus completed. The sample suspended in the buffer (1 ml) of a set of reagents to cycle test plus DNA was frozen and kept at -80°C. Maintain the sample was thawed on the day of testing, centrifuged and the supernatant was removed and the precipitate suspended in solution (250 μl) for cyclic test, was left under static conditions at room temperature for 10 minutes, and then there was added a solution of B (150 μl) and left under static conditions at room temperature for 10 minutes. Then, the solution C (150 μl) was added to the analyzed sample was left under static conditions at 4°C for 10 minutes and then filtered through a nylon mesh filter, thus, carrying out the staining of DNA. Using Becton Dickinson's FACS Calibur, quantify the amount of DNA in each cell in accordance with the FACS process and determined the relative number of cells with ongoing fragmentation of DNA.

Table 3
Fragmentation of DNA through indochinoise impact (N) (subG1, %)
X-ray irradiationThe compound of example 9X-ray irradiation + compound of example 9
27,1a 3.9of 54.8

As shown in table 3, the connection according to the invention has excellent inducing effect on DNA fragmentation, cells derived from cancer cells (NCI-H1299).

As noted above, the connection according to the invention in combination with x-irradiation enhances the effects of x-irradiation.

The compounds of formula (I) can be administered orally or parenterally, and after the creation of drugs that are suitable for the introduction of such methods, the compounds can be used as pharmaceutical compositions and anticancer agents.

The term "malignant tumor", as referred to in the present description includes a variety of sarcoma and carcinoma, and includes solid cancer and hematopoietic cancer. Solid cancer, as referred to herein includes, for example, brain tumor, sanitarily cancer, PI is the euodius, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, lung cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, horiokartsinoma, uterine cancer, cervical cancer, cancer of the renal pelvis/ureter, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Williams cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue sarcoma. On the other hand, hematopoietic cancer includes, for example, acute leukemia, chronic lymphocytic leukemia, chronic miliitary leukemia, true polycythemia, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, nahodkinskuju lymphoma.

The term "treatment of malignant tumors", as referred to herein, indicates that the anticancer agent is administered to a patient with a malignant tumour in order to inhibit the growth of cancer cells in the patient. Preferably, when the treatment results in regression of the growth of a malignant tumor or when treatment leads to a decrease in detectable malignant tumors. More preferably, when the treatment results in complete disappearance of a malignant tumor.

With the organisations according to the invention, expected to be effective especially in the case of solid human cancer. Solid cancer person includes, for example, brain cancer, sanitarily cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, lung cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, horiokartsinoma, uterine cancer, cervical cancer, cancer of the renal pelvis/ureter, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Williams cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic miliitary leukemia, Hodgkin's lymphoma.

Pharmaceutical composition and anticancer agent of the invention can contain a pharmaceutically acceptable carrier or diluent. Herein "pharmaceutically acceptable carrier or diluent" refers to excipients [e.g., fats and waxes, semisolid and liquid polyols, natural or hydrogenated oils, and others]; water (such as distilled water, specially distilled water for injection and other), physiological salt solution, alcohol (EmOC is emer, ethanol), glycerol, polyols, aqueous solution of glucose, mannitol, vegetable oils and other); additives [e.g., thinning agent, disintegrity agent, a binding agent, a sliding agent, a moisturizing agent, stabilizer, emulsifier, dispersing agent, a preservative, a sweetener, a coloring matter, flavoring agent or flavor, concentrating agent, a diluent, a buffer substance, a solvent or solubilizers agent, chemical to achieve preservation, salt for modifying the osmotic pressure, the covering agent or antioxidant] and the like.

In respect of each of the pharmaceutical compositions and anti-cancer agent of the invention various forms of a drug can be selected, and examples include oral drugs such as tablets, capsules, powders, granules or liquids; or sterilized liquid parenteral medicines, such as solutions or suspensions; suppositories, ointments and the like.

Solid drugs can be obtained in the form of tablets, capsules, granules and powder without any additional auxiliary substances, or obtained by using appropriate excipients (inactive ingredients). Examples of such fillers (excipients) m which may include sugars, such as lactose or glucose; starch from corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as metasilicates magnesium or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkyleneglycol; alcohols, such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hypromellose; and other commonly used excipients such as gelatin, talc, vegetable oil and Arabian gum.

These solid pharmaceutical preparations such as tablets, capsules, granules and powders may typically contain, for example, from 0.1 to 100 wt. -%, and preferably from 5 to 98% of the mass. compounds of the above formula (I) as an active ingredient, based on the total weight of the medicinal product.

Liquid medications receive in the form of a suspension, syrup, injection and intravenous drip infusion (intravenous solution), using suitable excipients that are commonly used in liquid pharmaceutical preparations, such as water, alcohol or obtained from a plant oil such as soybean oil, peanut oil and sesame oil.

Namely, when drug-ven the rat is injected parenterally in the form of intramuscular injections, intravenous injection or subcutaneous injection, a suitable solvent or diluent may be presented with distilled water for injection, an aqueous solution of hydrochloride lidocaine (for intramuscular injection), physiological saline, aqueous glucose solution, ethanol, polyethylene glycol, propylene glycol, solution for intravenous injection (e.g., an aqueous solution of citric acid, sodium citrate and the like), or an electrolyte solution (for intravenous drip infusion and intravenous injection), or a combination of them with a solution.

Such injection may be in the form of pre-prepared solution, or in the form of powder in pure form, or powder, connected with a suitable filler (auxiliary material), which is dissolved at the time of use. The injection solution may contain, for example, from 0.1 to 10 wt%. the active ingredient, based on the total weight of the medicinal product.

Liquid medications, such as suspension or syrup for oral administration may contain, for example, from 0.1 to 10 wt%. the active ingredient, based on the total weight of the medicinal product.

Drugs can be obtained by the average person skilled in the art in accordance with conventional techniques or conventional equipment. For example,the receipt may be carried out, if the drug is an oral medication, for example, by mixing the appropriate amounts of compounds according to the invention with an appropriate amount of lactose and loading the mixture into hard gelatin capsules, which are suitable for oral administration. On the other hand, may be exercised if a drug containing the compound of the invention is an injectable solution, for example, by mixing the appropriate amounts of compounds according to the invention with an appropriate amount of 0.9% saline solution and loading the mixture in ampoules for injection solution.

Compounds according to the invention can be used optionally as combined with some other substance useful for the treatment of various malignant tumors, or with radiation therapy. Individual ingredients for such a combination can be introduced at different points in time or at the same time as the fractional medicines or as a single drug in the treatment period. In accordance with this invention should be interpreted in such a way that it includes all techniques at one time or at different points in time, and the introduction to this invention, therefore, should be interpreted. Possible combinationcodeine according to the invention and any other substances, applicable in the case of the above-mentioned diseases, should include, in principle, any and every combination of it with any and every pharmaceutical substance suitable for the treatment of the aforementioned diseases.

Radiation therapy by itself implies the usual way in the treatment of malignant tumors. For radiation therapy feasible are various radiations such as x-rays, γ-radiation, neutron radiation, electron beam, proton beam; and radiation sources. In the most common radiation therapy uses a linear accelerator for radiation external radiation, γ-radiation.

Compounds according to the invention can be combined with radiation therapy to enhance therapeutic effects of radiotherapy; and consequently, the compounds may be applicable as a radio sensibilizators in the treatment of malignant tumors.

Another aspect of the compounds according to the invention is that the compounds are also applicable as sensitizers for any other anticancer agents in the treatment of malignant tumors.

Compounds according to the invention can be combined with radiation therapy and/or combination with any other anti-cancer agents, as described below, when used on the I treatment of malignant tumors.

"Sensitizer for radiation therapy or anticancer agent, as mentioned in this document, is intended to refer to a medicinal product which when used as combined with radiation therapy and/or chemotherapy with an anticancer agent, may be additive or synergistic to enhance therapeutic effect of this radiation therapy and/or chemotherapy.

Substances for drugs combined in the invention can be in any form, selected in any way, and they can be obtained in the same manner as for the above-mentioned drugs. Combined agent comprising the compound according to the invention and another anti-cancer agent, can be easily obtained by a person skilled in the art by conventional means or by using conventional equipment.

The above combination include not only compositions according to the invention, which contain some of the only active substance, but also those that contain two or more other active substances. There are many examples of combination compositions according to the invention and one, or two, or more active substances selected from therapeutic agents for the above diseases.

Agents for combining with compositions include, for example, the anti-Christ. Orekhovy agent, selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, anticancer agents of plant origin, anticancer coordination compounds of platinum anticancer derivatives camptothecin, anticancer inhibitors of tyrosine kinases, monoclonal antibodies, interferons, biological modifiers sensitivity and other anticancer agents, as well as their pharmaceutically acceptable(IIR) salt(s) or ester(s).

The term "anticancer alkylating agent"as used in the present description of the invention refers to an alkylating agent with anticancer activity, and the term "alkylating agent" in this document generally refers to the agent, giving the alkyl group in the alkylation reaction in which a hydrogen atom of an organic compound substituted alkyl group. The term "anticancer alkylating agent can be represented, as an example, the N-oxide nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide or carmustine.

The term "antitumor antimetabolite", as used in the present description of the invention, refers to the antimetabolite with protivosokovu the activity, and the term "antimetabolite" in this document includes, in a broad sense, substances that disrupt the normal metabolism, and substances that inhibit electron transport system, preventing the formation of energy-rich intermediates, due to their structural or functional similarities to metabolites that are important for living organisms (such as vitamins, coenzymes, amino acids and sugars). The term "anticancer antimetabolites" can be represented, as an example, methotrexate, 6-mercaptopyrimidine, mercaptopurine, 5-fluorouracil, tecaform, doxifluridine, carmofur, citarabinom, tsitarabina ocfosfate, enocitabine, S-1, gemcitabine, fludarabine or pemetrexed disodium, and preferred are cytarabine, gemcitabine, and the like.

The term "anticancer antibiotic"as used in the present description the invention relates to antibiotic with antitumor activity, and "antibiotic" in this document includes substances which are produced by microorganisms and inhibit cell growth and other functions of microorganisms and other living organisms. The term "anticancer antibiotics" may be represented, as an example, actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, AKL is rouzina, pirarubicin, epirubicin, zinostatin stimulation, idarubitsina, sirolimus or valrubicin, and preferred are doxorubicin, mitomycin C, and the like.

The term "anticancer agent of plant origin", as used in the present description of the invention, includes compounds having anticancer activity, which come from plants or compounds obtained by chemical modification to the above compounds. The term "anticancer agent of plant origin" can be represented, as an example, vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel and vinorelbine, and preferred are the etoposide and the like.

The term "anticancer derived camptothecin as used in the present description of the invention refers to compounds that are structurally related to camptothecin and inhibit the growth of cancer cells, including camptothecin as such. The term "anticancer derived camptothecin" is not particularly limited, but may be represented, as an example, camptothecin, 10-hydroxycamptothecin, topotecan, irinotecan or 9-aminocamptothecin, and camptothecin preferred. In addition, irinotecan exposed metabolismo vivo and shows anticancer effects, as, for example, SN-38. The mechanism of action and activity of derivatives of camptothecin believed to be essentially the same as for camptothecin (for example, Nitta, et al., Gan to Depending Ryoho, 14, 850-857 (1987)).

The term "anticancer coordination compound of platinum", as used in the present description of the invention, refers to the coordination compound of platinum having anticancer activity, and the term "coordination compound of platinum" in this document refers to the coordination compound of platinum, which ensures the existence of platinum in the ionic form. Preferred platinum compounds include cisplatin; ion CIS-diamminedichloroplatinum (II); chloro(Diethylenetriamine)platinum (II) chloride; dichloro(Ethylenediamine)platinum (II); diammin(1,1-cyclobutanedicarboxylate)platinum (II) (carboplatin); spiroplatin; iproplatin; diammin(2-ethylmalonate)platinum (II); etilendiaminmonoatsetat (II); Aqua(1,2-diaminocyclohexane)selfadaptation (II); Aqua(1,2-diaminocyclohexane)melanoplinae (II); (1,2-diaminocyclohexane)melanoplinae (II); (4-carboxylato)(1,2-diaminocyclohexane)platinum (II); (1,2-diaminocyclohexane)(isocitrate)platinum (II); (1,2 - diaminocyclohexane)occultopedia (II); ormaplatin; tetraploid; carboplatin, nedaplatin and oxaliplatin, and it is preferable to cisplatin. In addition, other anticancer coordination is by platinum compounds, mentioned in the description of the invention, are known and commercially available and/or can be obtained by the average person skilled in the art by using conventional equipment.

The term "anticancer inhibitor of the tyrosine kinase"as used in the description of the invention, refers to the inhibitor tyrosine kinase with antitumor activity, and the term "inhibitor of tyrosine kinases" in this document refers to a chemical substance, the inhibitory "tyrosine kinase", which moves the γ-phosphate group of ATP to the hydroxyl group of a specific tyrosine in the protein. The term "anticancer inhibitor of tyrosine kinases can be represented, as an example, gefitinib, imatinib or erlotinib.

The term "monoclonal antibody"as used in the description of the invention, which is also known as one clone antibody refers to an antibody obtained using monoclonal antibody-producing cells, and examples thereof include cetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab.

The term "interferon"as used in the description of the invention refers to interferon having anti-cancer activity, and it is a glycoprotein having a molecular weight of about 20000, which is produced and secreted by most animals CL is current in viral infection. He has not only the effect of inhibiting the development of the virus, but also various immunoelectron mechanisms of action, including inhibition of cell growth (i.e. tumor cells) and the strengthening of the natural activity of the killer cells, consequently referred to as one of the types of cytokines. Examples of "interferon" include interferon α, interferon α-2a, interferon α-2b, interferon β, interferon γ-1a, and interferon γ-n1.

The term "modifier biological sensitivity"as used in the description of the invention, is a so-called modifier biological sensitivity or BRM, and is normally a General term for substances or drugs designed to change the defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of cells of the tissue in order to Orient them to be useful to the individual in opposition to tumor, infection or other diseases. Examples of the modifier biological sensitivity" include baptisms, lentinan, sizofiran, picibanil and ubenimex.

The term "another anti-cancer agent"as it is used in the present description the invention relates to an anticancer agent, which does not belong to any of the above agents with anticancer activity. Examples of "other the Gogo anticancer agent" include mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoietin Alfa, anastrozole, exemestane, bikalutamid, leuprorelin, flutamide, fulvestrant, pegaptanib Octanate, denileukin diftitox, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine, and goserelin.

The above terms "anticancer alkylating agent", "anti-cancer antimetabolite", "antitumor antibiotic", "anti-cancer agent of plant origin", "anticancer coordination compound of platinum", "anti-cancer derived camptothecin", "anticancer inhibitor of tyrosine kinases", "monoclonal antibody, interferon, biological modifier sensitivity" and "the other anticancer agent are known and are either commercially available or received by an average person skilled in the art ways, as such known, through a well-known or conventional methods. The process of obtaining gefitinib described, for example, in USP No. 5770599; the process of receiving cetuximab described, for example, in WO 96/40210; the process of obtaining bevacizumab described, for example, in WO 94/10202; the process of obtaining oxaliplatin described, for example, in USP No. 5420319 and 5959133; the process of receiving gemcitabine described, for example, in USP No. 5434254 and 5223608 and the process of obtaining camptothecin is written in USP No. 5162532, 5247089, 5191082, 5200524, 5243050 and 5321140; the process of receiving irinotecan described, for example, in USP No. 4604463; the process of receiving topotecan described, for example, in USP No. 5734056; the process of obtaining temosolomida described, for example, in JP-B No. 4-5029 and the process of receiving rituximab described, for example, in JP-W No. 2-503143.

The above-mentioned anticancer alkylating agents are commercially available that presents, as an example, the following: N-oxide nitrogen mustard from Mitsubishi Pharma Corp. as Nitromin (trade name); cyclophosphamide from company Shionogi & Co., Ltd. as Endoxan (trade name); ifosfamide from the company Shionogi & Co., Ltd. as Ifomide (trade name); melphalan from GlaxoSmithKline Corp. as Alkeran (trade name); busulfan from the company Takeda Pharmaceutical Co., Ltd. as Mablin (trade name); mitobronitol from Kyorin Pharmaceutical Co., Ltd. as Myebrol (trade name); carboquone from the company Sankyo Co., Ltd. as Esquinon (trade name); thiotepa from the firm Sumitomo Pharmaceutical Co., Ltd. as Tespamin (trade name); ranimustine from Mitsubishi Pharma Corp. as Cymerin (trade name); nimustine from the company Sankyo Co., Ltd. as Nidran (trade name); temozolomide from the firm Schering Corp. as Temodar (trade name), carmustin from the company Guilford Pharmaceuticals Inc. as Gliadel Wafer (trade name).

The above-mentioned anticancer antimetabolites are commercially available that p is estaline, as an example, the following: methotrexate from the company Takeda Pharmaceutical Co., Ltd. as Methotrexate (trade name); 6-mercaptopurine from the firm Aventis Corp. as Thioinosine (trade name); mercaptopurine from the company Takeda Pharmaceutical Co., Ltd. as Leukerin (trade name); 5-fluorouracil from the company Kyowa Hakko Kogyo Co., Ltd. as 5-FU (trade name); tegafur from the company Taiho Pharmaceutical Co., Ltd. as Futraful (trade name); doxifluridine from the company Nippon Roche Co., Ltd. as Furutulon (trade name); carmofur from the company Yamanouchi Pharmaceutical Co., Ltd. as Yamafur (trade name); cytarabine from the company Nippon Shinyaku Co., Ltd. as Cylocide (trade name); cytarabine ocfosfate from the company Nippon Kayaku Co., Ltd. as Strasid (trade name); enocitabine from the company Asahi Kasei Corp. as Sanrabin (trade name); S-1 from the company Taiho Pharmaceutical Co., Ltd. as TS-1 (trade name); gemcitabine from Eli Lilly & Co. as Gemzar (trade name); fludarabine from the company Nippon Schering Co., Ltd. as Fludara (trade name) and pemetrexed disodium from Eli Lilly & Co. as Alimta (trade name).

The above-mentioned anticancer antibiotics are commercially available that presents, as an example, the following: actinomycin D from the company Banyu Pharmaceutical Co., Ltd. as Cosmegen (trade name); doxorubicin from the company Kyowa Hakko Kogyo Co., Ltd. as adriacin (trade name); daunorubicin from the company Meiji Seika Kisha Ltd. as Daunomycin; neocarzinostatin from the company Yamanouchi Pharmaceutical Co., Ltd. as Neocarzinostatin (trade name); bleomycin from the company Nippon Kayaku Co., Ltd. as Bleo (trade name); paromycin from the company Nippon Kayaku Co., Ltd. as Pepro (trade name); mitomycin C from company Kyowa Hakko Kogyo Co., Ltd. as Mitomycin (trade name); aclarubicin from the company Yamanouchi Pharmaceutical Co., Ltd. as Aclacinon (trade name); pirarubicin from the company Nippon Kayaku Co., Ltd. as Pinorubicin (trade name); epirubicin from the firm Pharmacia Corp. as Pharmorubicin (trade name); zinostatin stimulater from the company Yamanouchi Pharmaceutical Co., Ltd. as Smancs (trade name); idarubitsin from the firm Pharmacia Corp. as Idamycin (trade name); sirolimus from the firm Wyeth Corp. as Rapamune (trade name) and valrubicin from the company Anthra Pharmaceuticals Inc. as Valstar (trade name).

The above-mentioned anticancer agents of plant origin are commercially available that presents, as an example, the following: vincristine from the company Shionogi & Co., Ltd. as Oncovin (trade name); vinblastine from the company Kyorin Pharmaceutical Co., Ltd. as Vinblastine (trade name); vindesine from the company Shionogi & Co., Ltd. as Fildesin (trade name); etoposide from company Nippon Kayaku Co., Ltd. as Lastet (trade name); sobuzoxane from the company Zenyaku Kogyo Co., Ltd. as Perazolin (trade name); docetaxel from the firm Aventis Corp. as Taxsotere (that is advice name); paclitaxel from the company Bristol-Myers Squibb Co. as Taxol (trade name) and vinorelbine from the company Kyowa Hakko Kogyo Co., Ltd. as Navelbine (trade name).

The above-mentioned anticancer coordination compounds of platinum are commercially available that presents, as an example, the following: cisplatin from the company Nippon Kayaku Co., Ltd. as Randa (trade name); carboplatin from company Bristol-Myers Squibb Co. as Paraplatin (trade name); nedaplatin from the company Shionogi & Co., Ltd. as Aqupla (trade name) and oxaliplatin from the firm Sanofi - Synthelabo Co. as Eloxatin (trade name).

The above-mentioned anticancer derivatives camptothecin are commercially available that presents, as an example, the following: irinotecan from the company Yakult Honsha Co., Ltd. as Campto (trade name); topotecan from GlaxoSmithKline Corp. as Hycamtin (trade name) and camptothecin from the firm Aldrich Chemical Co., Inc., U.S.A.

The above-mentioned anticancer inhibitors of tyrosine kinases are commercially available that presents, as an example, the following: gefitinib from the firm AstraZeneca Corp. as Iressa (trade name); imatinib from the firm Novartis AG as Gleevec (trade name) and erlotinib from the company OSI Pharmaceuticals Inc. as Tarceva (trade name).

The above-mentioned monoclonal antibodies are commercially available that represent the go, as an example, the following: cetuximab from the company Bristol-Myers Squibb Co. as Erbitux (trade name); bevacizumab from the firm Genentech, Inc. as Avastin (trade name); rituximab from the company Biogen Ide Inc. as Rituxan (trade name); alemtuzumab from the company Berlex Inc. as Campath (trade name) and trastuzumab from the company Chugai Pharmaceutical Co., Ltd. as Herceptin (trade name).

The above interferons are commercially available that presents, as an example, the following: interferon α from the firm Sumitomo Pharmaceutical Co., Ltd. as Sumiferon (trade name); interferon α-2a from the company Takeda Pharmaceutical Co., Ltd. as Canferon-A (trade name); interferon α-2b from the firm Schering-Plough Corp. as Intron A (trade name); interferon β from the company Mochida Pharmaceutical Co., Ltd. as IFNβ (trade name); interferon γ-1a from the company Shionogi & Co., Ltd. as Imunomax-γ (trade name) and interferon γ-n1 from the company Otsuka Pharmaceutical Co., Ltd. as Ogamma (trade name).

The above modifiers biological sensitivity are commercially available that presents, as an example, the following: baptisms from the company Sankyo Co., Ltd. as krestin (trade name); lentinan from the firm Aventis Corp. as Lentinan (trade name); sizofiran from the company Kaken Seiyaku Co., Ltd. as Sonifiran (trade name); picibanil from the company Chugai Pharmaceutical Co., Ltd. as Picibanil (shopping is imenovanje) and ubenimex from the company Nippon Kayaku Co., Ltd. as Bestatin (trade name).

The above-mentioned other anticancer agents are commercially available that presents, as an example, the following: mitoxantrone from the firm Wyeth Lederle Japan, Ltd. as Novantrone (trade name); L-asparaginase from the company Kyowa Hakko Kogyo Co., Ltd. as Leunase (trade name); procarbazine from the company Nippon Roche Co., Ltd. as Natulan (trade name); dacarbazine from the company Kyowa Hakko Kogyo Co., Ltd. as Dacarbazine (trade name); hydroxycarbamide from the company Bristol-Myers Squibb Co. as Hydrea (trade name); pentostatin from a company Called Oyobi Kessei Ryoho Kenkyusho as Coforin (trade name); tretinoin from company Nippon Roche Co., Ltd. as Vesanoid (trade name); alefacept from the company Biogen Idec Inc. as Amevive (trade name); darbepoietin alpha from company Amgen Inc. as Aranesp (trade name); anastrozole from firm AstraZeneca Corp. as Arimidex (trade name); exemestane from Pfizer Inc. as Aromasin (trade name); bikalutamid from the firm AstraZeneca Corp. as Casodex (trade name); leuprorelin from the company Takeda Pharmaceutical Co., Ltd. as Leuplin (trade name); flutamide from firm Schering-Plough Corp. as Eulexin (trade name); fulvestrant from the firm AstraZeneca Corp. as Faslodex (trade name); pegaptanib Octanate from the firm Gilead Sciences, Inc. as Macugen (trade name); denileukin diftitox from the company Ligand Pharmaceuticals Inc. as Ontak (tor the TV name); aldeslakin from Chiron Corp. as Proleukin (trade name); thyrotropin alpha from the firm Genzyme Corp. as Thyrogen (trade name); arsenic trioxide from the company Cell Therapeutics, Inc. as Trisenox (trade name); bortezomib from the company Millennium Pharmaceuticals, Inc. as Velcade (trade name); capecitabine from company Hoffmann-La Roche, Ltd. as Xeloda (trade name) and goserelin from the firm AstraZeneca Corp. as Zoladex (trade name).

The invention also relates to a method of treatment of a malignant tumor, which comprises the administration to a patient in need of treatment a therapeutically effective amount of the compounds according to the invention, or its salt or its ester.

In the course of the process according to the invention, the preferred therapeutic single dose may vary according to, for example, by way of introducing the compounds according to the invention, the type of connection according to the invention and used dosage form of the compounds according to the invention; type, method of administration and dosage form of another anticancer agent used in combination; and the type of cells being treated, the patient's condition, etc. of the Optimal treatment for these conditions can be set by the average person skilled in the art based on the usually accepted therapeutic single dose and/or based on the content of the crust is asego the description.

In the course of the process according to the invention, therapeutic unit dose of a compound according to the invention may vary in accordance with generally type of connection, the type composed of a composition, frequency of application and the specific area of treatment, severity of disease, age of patient, medical diagnosis, type of cancer, etc. However, as illustrative references, the daily dose for an adult may be in the range of, for example, from 1 to 1000 mg in the case of oral administration. In the case of parenteral administration, preferably intravenous administration, and more preferably intravenous drip infusion daily dose may be in the range of, for example, from 1 to 100 mg/m2(the surface area of the body). In this document, in the case of intravenous drip infusion, the administration can continuously be carried out during, for example, from 1 to 48 hours. In addition, the frequency of injection may vary depending on the method of introduction and symptoms, but it is, for example, from one to five times a day. Alternatively, periodically interrupting the introduction, such as the introduction through the day, the introduction of two days and the like can also be used as a way of introduction. The period of termination of the appointment of the drug in the case of parenteral administration is, for example, 1 to 6 weeks.

Despite the fact that a single therapeutic dose of another anti-cancer agent used in combination with the connection according to the invention, is not particularly limited, it can be installed, if necessary, an average person skilled in the art in accordance with known literature data. Examples can be as following.

Therapeutic single dose for 5-fluorouracil (5-FU) is such that in the case of oral administration, for example, 200 to 300 mg per day are entered from one to three times consecutively and in the case of injections, for example, from 5 to 15 mg/kg / day injected once a day for the first five consecutive days by intravenous injection or intravenous drip infusion, and then from 5 to 7.5 mg/kg injected once daily through day by intravenous injection or intravenous drip infusion (dose may be appropriate by the way, raised or lowered).

Therapeutic single dose of S-1 (Tegafur, Ginestet and Mod potassium) such that, for example, the initial dose (single dose) is installed in the following standard, in accordance with the surface area of the body, and she orally injected twice a day, after Breakfast and after lunch, during 28 consecutive days, followed by termination of the appointment of the drug in ECENA 14 days. This is set as one course introduction, which is repeated. The initial standard quantity per unit area of the surface of the body (the equivalent of Tegafur) is 40 mg per one introduction to space less than 1.25 m2; 50 mg per injection for a total area of 1.25 m2to less than 1.5 m2; 60 mg per injection for a total area of 1.5 m2or more. This dose accordingly increases or decreases depending on the patient's condition.

Therapeutic single dose for gemcitabine is, for example, 1 g of gemcitabine/m2for one, the introduction, which is injected intravenously by infusion over a period of time of 30 minutes, and one infusion per week lasts for 3 weeks, followed by termination of the appointment of the medicinal product during the fourth week. This is set as one course introduction, which is repeated. The dose is appropriately reduced according to age, symptom or side effects.

Therapeutic single dose of doxorubicin (e.g., doxorubicin hydrochloride) is such that, for example, in the case of intravenous injection, 10 mg (0.2 mg/kg) (titer) is injected once daily disposable intravenous introduction within 4 to 6 days, followed by termination of the appointment lekarstvennoj the funds within 7 to 10 days. This is set as one course introduction, which is repeated two or three times. In this document, the total dose is preferably 500 mg (titer)/m2(the surface area of the body) or less, and it may be appropriately increased or decreased in the range.

Therapeutic single dose of etoposide is such that, for example, in the case of intravenous injection, from 60 to 100 mg/m2(area of body surface) per day injected for 5 consecutive days, followed by termination of the appointment of a medicinal product within three weeks, the dose may be appropriately increased or decreased). This is set as one course introduction, which is repeated. Meanwhile, in the case of oral administration, for example, from 175 to 200 mg / day injected for 5 consecutive days, followed by termination of the appointment of a medicinal product within three weeks, the dose may be appropriately increased or decreased). This is set as one course introduction, which is repeated.

Therapeutic single dose of docetaxel (docetaxel hydrate) is such that, for example, 60 mg of docetaxel/m2(the surface area of the body) is injected once a day by intravenous drip infusion over a period of time from 1 hour or more every 3 d is 4 weeks (dose may be appropriately increased or decreased).

Therapeutic single dose of paclitaxel is such that, for example, 210 mg/m2(the surface area of the body) is injected once a day by intravenous drip infusion over a period of time of 3 hours, followed by termination of the appointment of a medicinal product for at least 3 weeks. This is set as one course introduction, which is repeated. The dose may be appropriately increased or decreased.

Therapeutic single dose of cisplatin is such that, for example, in the case of intravenous injection, 50 to 70 mg/m2(the surface area of the body) is injected once a day, followed by termination of the appointment of a medicinal product for 3 weeks or longer (the dose may be appropriately increased or decreased). This is set as one course introduction, which is repeated.

Therapeutic single dose for carboplatin such that, for example, from 300 to 400 mg/m2enter once a day by intravenous drip infusion over a period of time of 30 minutes or longer, followed by termination of the appointment of a medicinal product for at least 4 weeks (dose may be appropriately increased or decreased). This is set as one course introduction, which is repeated.

T is rapitinka single dose for oxaliplatin is 85 mg/m2enter once a day by intravenous injection, followed by termination of the appointment of a medicinal product in two weeks. This is set as one course introduction, which is repeated.

Therapeutic single dose for irinotecan (e.g., irinotecan hydrochloride) is such that, for example, 100 mg/m2enter once a day by intravenous drip infusion, 3 or 4 times with an interval of one week, followed by termination of the appointment of a medicinal product for at least two weeks.

Therapeutic single dose of topotecan is such that, for example, 1.5 mg/m2enter once a day by intravenous drip infusion for 5 days, followed by termination of the appointment of a medicinal product for at least 3 weeks.

Therapeutic single dose of cyclophosphamide is such that, for example, in the case of intravenous injection, 100 mg injected once daily by intravenous injection for consecutive days. If the patient can tolerate, the daily dose can be increased to 200 mg Total dose ranges from 3000 to 8000 mg, which may be appropriately increased or decreased. If necessary, it can be introduced by injection or infusion of nutribase is but intraorale or inside the tumor. On the other hand, in the case of oral administration, for example, from 100 to 200 mg entered in the day.

Therapeutic single dose for gefitinib is that 250 mg orally injected once a day.

Therapeutic single dose of cetuximab is such that, for example, 400 mg/m2introduced on the first day by intravenous drip infusion, then 250 mg/m2introduced each week by intravenous drip infusion.

Therapeutic single dose for bevacizumab such that, for example, 3 mg/kg are introduced each week by intravenous drip infusion.

Therapeutic single dose for trastuzumab such that, for example, usually an adult, once a day, 4 mg in the form of trastuzumab/kg (body weight) is given initially, followed by intravenous drip infusion of 2 mg/kg over a period of time of 90 minutes or longer each week from the second injection.

Therapeutic single dose for exemestane such that, for example, usually an adult, 25 mg orally injected once daily after a meal.

Therapeutic single dose for leuprorelin (for example, leuprorelin acetate) is such that, for example, usually an adult, 11,25 mg subcutaneously once every 12 weeks.

Therapeutic single dose of imatinib that the ova, what, for example, usually adults in the chronic phase of chronic myeloid leukemia, 400 mg is administered orally once daily after a meal.

Therapeutic single dose for the combination of 5-FU and leucovorin is such that, for example, 425 mg/m25-FU 200 mg/m2leucovorin is entered from the first to the fifth day by intravenous drip infusion, and the course is repeated with an interval of 4 weeks.

The invention is described more specifically with reference to the following examples and the examples of the preparation, which, however, are not intended to limit the scope of the invention.

For thin-layer chromatography in the examples and the examples of obtaining silica gel Silica gel60F254(Merck) was used for plate and a UV detector was used for detection. WakogelTMC-300 or C-200 (Wako Pure Chemical Industries), or NH (Fuji Silysia Chemical) was used as silica gel for column chromatography. For mass spectrometry used JMS-SX102A (JEOL) or QUATTROII (Micromass). For NMR spectrometry was used sulfoxide as an internal standard in the form of a solution of heavy dimethylsulfoxide; spectrometer Gemini-300 (300 MHz; Varian), VXR-300 (300 MHz; Varian), Mercury 400 (400 MHz; Varian) or Inova 400 (400 MHz; Varian) was used; and all δ values are given in ppm

Designation reductions in NMR are shown below.

s: singlet

d: doublet

DD: doublet of doublet

<> t: triplet

dt: doublet of triplet

kV: Quartet

m: multiplet

user: extended

J: binding constant of

Hz: Hertz

DMSO-d6: heavy dimethyl sulfoxide

Example obtain 1

Getting 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) Tert-butyl 1-arylhydrazines:

250 g of tert-butylhydroperoxide was added to a solution of 280 g ftalievogo anhydride in toluene (3 l). Using the nozzle Dean-stark for the Department of water, the reaction mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, the precipitate was separated by filtration, getting 516 g of crude tert-butyl(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)carbamate.

520 g of potassium carbonate, to 43.3 g of the chloride of benzyltriethylammonium and 250 ml of allylbromide were added in that order to a solution of the above compound in acetonitrile (3.5 l) and stirred at room temperature for 18 hours. 1.5 liters of water was added to the reaction solution and was separated by a layer of acetonitrile and concentrated. One liter of water was added to the residue and the aqueous layer was extracted with ethyl acetate and an ethyl acetate layer was washed with saturated aqueous salt solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and precipitated in sieges is to colourless solid was washed with hexane and dried, getting 460 g of crude tert-butylether(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)carbamate.

While cooling in an ice bath, 100 ml of methylhydrazine was added to a solution of the above compound in tetrahydrofuran (3.0 l), then returned to room temperature and was stirred for 18 hours. Precipitated precipitated insoluble substance was separated by filtration and the filtrate was concentrated. Mixed solvent, representing hexane/ethyl acetate (3/1)was added to the residue and the precipitated precipitated insoluble substance was separated by filtration. This operation was repeated five times, and then the filtrate was concentrated under reduced pressure, the resulting residue was distilled under reduced pressure, getting 211 g specified in the title compounds as a pale yellow oily substance.

ESI-MS (mass spectrum with ionization elektrorazpredelenie). Found: m/z[M+H]+173,4.

2) Getting 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

260 ml of N,N-diisopropylethylamine and 106 g of hydrazine obtained in the above stage 1)was added to a solution of 142 g of ethyl 4-chloro-2-(methylthio)pyridine-5-carboxylate in tetrahydrofuran (1.5 l) and stirred at reflux for 18 hours. After cooling to room temperature the reaction solution was evaporated under reduced pressure and to the residue was added 500 ml of diethyl ether and precipitated precipitated solid substance was separated by filtration. The filtrate was evaporated under reduced pressure, the residue was cooled in an ice bath and to it was slowly added to 400 ml triperoxonane acid and stirred at room temperature for 1 hour and then at 70°C for 1 hour. The reaction solution was evaporated under reduced pressure, and thereto was added 500 ml of ethanol and cooled in an ice bath and to it there was added 1 liter of 6 n sodium hydroxide solution and stirred at room temperature for 15 minutes. Chilled in an ice bath, the reaction solution was acidified with 400 ml of concentrated hydrochloric acid and then evaporated under reduced pressure. The residue was distributed into chloroform and water, the chloroform layer was extracted, washed with saturated salt water solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting yellow solid was separated by filtration, washed with ethanol and diethyl ether and dried, obtaining of 99.1 g specified in the title compound as a yellow solid.

1H-NMR (400 MHz, DMSO-d6) δ: 8,66 (1,0H, users), of 5.83 (1,0H, DDT, J=17.1 to, 9,8, a 5.4 Hz), 5,13 (1,0H, d, J=9.8 Hz), is 5.06 (1,0H, d, J=17,1 Hz), 4,34 (2,0H, d, J=5.4 Hz), of 2.51 (3,0H, C).

ESI-MS. Found: m/z[M+H]+223,3.

Example of getting 2

Getting 6-(methylthio)-1-phenyl-1,2-dihydro-3H-pyrazolo[3,4-d]PI is kidin-3-one

60 ml of triethylamine was added to a solution of 25 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 12.7 ml of phenylhydrazine in tetrahydrofuran (200 ml) and stirred at room temperature for 18 hours. The solvent was concentrated under reduced pressure, to the residue was added water, then washed with ether, and acidified with aqueous 5 n hydrochloric acid, is added there. Precipitated precipitated solid substance was separated by filtration and washed with water and 2-propanol, receiving 10.8 g specified in the title compound as white solid.

1H-NMR (400 MHz, CDCl3) δ: 12,18 (1H, c), of 9.02 (1H, c), 8,13 (2H, DD, J=8,8, 1.0 Hz), 7,52 (2H, TD, J=7,1, 1,6 Hz), 7,26 (1H, TT, J=7,1, 1.0 Hz), 2,61 (3H, s).

ESI-MS. Found: m/z[M+H]+259,1.

Example 1

Obtaining 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl)-N,N-dimethylbenzamide

1) preparation of methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]benzoate:

20 ml of pyridine was added to a solution in chloroform of 7.5 g of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it, 6,1 g of copper acetate(II) and 10 g of [3-(methoxycarbonyl)]phenylboronic acid and stirred at room temperature for 3 days. Aqueous 30%ammonia solution and saturated saline water retardulously in the reaction liquid medium in the specified order and was extracted with chloroform. The organic layer was washed with saturated saline aqueous solution, then dried over anhydrous magnesium sulfate and the solvent was removed by evaporation. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate)to give 6.7 g of methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]benzoate as a yellow oily substance.

1H-NMR (400 MHz, CDCl3) δ: of 8.92 (1H, s), 8,11-of 8.06 (2H, m), 7,65-to 7.59 (2H, m), of 5.68 (1H, DDD, J=17.1 to, 10,2, 5,9 Hz), 5,13 (1H, DD, J=10,2, 1.0 Hz), equal to 4.97 (1H, DD, J=17,1, 1.0 Hz), of 4.45 (2H, d, J=5,9 Hz), of 3.96 (3H, s), of 2.51 (3H, s).

2) Obtain methyl 3-[2-allyl-6-(methylsulfinyl)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]benzoate:

At 0°C was added 6.5 g of m-chloroperbenzoic acid to the solution in chloroform 6.7 g of the compound obtained in the above reaction, and stirred for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the liquid reaction medium and was extracted with chloroform/isopropanol (80/20). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by evaporation, obtaining 5.6 g of crude methyl 3-[2-allyl-6-(methylsulfinyl)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]benzoate.

3) Obtain methyl 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]benzoate:

0.87 g of 4-(4-methyl-1-piperazinil)EN is Lina and 2 ml of N,N - diisopropylethylamine was added to the solution in toluene, 1.7 g of the crude product, obtained in the above reaction, and stirred at 70°C for 12 hours. The solvent was removed by evaporation, the product was purified by column chromatography on silica gel (chloroform/methanol)to give 2.2 g of methyl 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]benzoate as a pale yellow solid.

1H-NMR (400 MHz, CDCl3) δ: 8,81 (1H, s), 8,18-8,13 (1H, m), of 8.04 (1H, d, J=7.8 Hz), 7,66-7,56 (2H, m), 7,45 (2H, d, J=8.5 Hz), to 6.88 (2H, d, J=8.5 Hz), of 5.68 (1H, DDD, J=17.1 to, to 10.2, 6.3 Hz), 5,10 (1H, DD, J=10,2, 1.0 Hz), to 4.98 (1H, DD, J=17,1, 1.0 Hz), and 4.40 (2H, d, J=6.3 Hz), of 3.97 (3H, s), 3,26-is 3.21 (4H, m), 2,72-of 2.64 (4H, m), 2,43 (3H, users).

4) to Obtain 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl)-N,N-dimethylbenzamide:

Aqueous 1 n sodium hydroxide solution was added to the solution in 1,4-dioxane/methanol (50/50) 2.2 g of methyl 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]benzoate and stirred at room temperature for 2.5 hours. This reaction mixture was neutralized 1 N. hydrochloric acid and the solvent was removed by evaporation, getting a free carboxylic acid, the source of ester. To a solution in N,N-dimethylformamide resulting carboxylic acid was added to 1.67 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1.18 g of 1-Hydra is cybersociety and 11 ml of 1,0M solution of dimethylamine in tetrahydrofuran and stirred at room temperature for 6 hours. Aqueous saturated sodium hydrogen carbonate solution and water was added to the reaction liquid, extracted with chloroform/isopropanol (80/20) and was purified by column chromatography on silica gel (chloroform/methanol)to give 560 mg of 3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl)-N,N-dimethylbenzamide in the form of a pale yellow solid.

1H-NMR (400 MHz, CDCl3) δ: 8,81 (1H, s), EUR 7.57-7,51 (2H, m), 7,49-7,38 (4H, m), of 6.90 (2H, d, J=8,8 Hz), 5,69 (1H, DDT, J=17.1 to, to 10.2, 6.3 Hz), 5,10 (1H, DD, J=10,2, 1.0 Hz), 5,00 (1H, DD, J=17,1, 1.0 Hz), and 4.40 (2H, d, J=6.3 Hz), 3,32 (3H, C)3,14 (3H, s), 2,99 of 2.92 (4H, m), 2,84-a 2.71 (4H, m)of 2.50 (3H, s).

ESI-MS. Found: m/z[M+H]+513.

Example 2

Getting 2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

17,5 mg specified in the title compound was obtained as yellow solid in the same manner as in example 1-1 to 1-3, for which, however, 3-thienylboronic acid was used instead of [3-(methoxycarbonyl)]phenylboronic acid used in example 1-1, and [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol was used instead of 4-(4-methylpiperazin-1-yl)aniline used in example 1-3.

1H-NMR (400 MHz, CDCl3) δ: 8,82 (1H, s), 7,17-7,63 (6H, m), 5,65 is 5.77 (1H, m)to 5.13 (1H, d, J=10,2 Hz), 5,04 (1H, d, J=17,1 Hz), was 4.76 (2H, s), 4,42 (2H, d, J=6.3 Hz), 2,98-of 3.06 (4H, m), 2,50 was 2.76 (4H, m, 2,39 (3H, s).

ESI-MS. Found: m/z[M+H]+478.

Example 3

Getting 2-allyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 3-(1-hydroxy-1-methylethyl)phenylboronic acid:

In nitrogen atmosphere under ice cooling, from 5.29 ml of 3'-bromoacetophenone was added to 25 ml of a 2M solution of methylmagnesium in diethyl ether and 100 ml diethyl ether and was stirred for 20 minutes. Water and 2 N. hydrochloric acid was added to the reaction liquid, extracted with ethyl acetate, washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline aqueous solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, obtaining the crude 2-(3-bromophenyl)propan-2-ol.

In nitrogen atmosphere, 33 ml of 1,66M solution of n-utility in hexane was added dropwise to a solution of the obtained substances in tetrahydrofuran (200 ml) at -60°C or lower and stirred 20 minutes. 11,08 ml of triisopropoxide was added to the reaction liquid, and stirred for 30 minutes. Water was added to the reaction liquid, washed with diethyl ether and the resulting aqueous layer was acidified aqueous 10%solution of phosphoric acid. It was extracted with ethyl acetate, washed with aqueous saturated the solution of sodium bicarbonate and saturated saline aqueous solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting crystals were collected, receiving 3.13 g specified in the title compound as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 7.96 (2H, s), 7,88 (1H, users), 7,60 (1H, d, J=7,3 Hz)to 7.50 (1H, d, J=8,3 Hz), 7,24 (1H, t, J=7,6 Hz), is 4.93 (1H, s)of 1.43 (6H, d, J=13,7 Hz).

2) Getting 2-allyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

35.2 mg specified in the title compound was obtained as yellow solid in the same manner as in example 1-1 to 1-3, for which, however, the above baronova acid was used instead of [3-(methoxycarbonyl)]phenylboronic acid used in example 1-1.

1H-NMR (400 MHz, CDCl3) δ: 8,80 (1H, s), EUR 7.57 (1H, s), 7,47 (2H, d, J=4.9 Hz), the 7.43 (2H, d, J=8,8 Hz), 7,31-7,28 (1H, m), to 6.88 (2H, d, J=8,8 Hz), 5,70 (1H, DDT, J=17.1 to, 10,0, 6.3 Hz), 5,10 (1H, DD, J=10,0, 1.2 Hz), to 4.98 (1H, DD, J=of 17.1, 1.5 Hz), to 4.38 (2H, d, J=6.3 Hz), 3,21 (4H, t, J=4,1 Hz)to 2.66 (4H, s)to 2.41 (3H, s)of 1.62 (6H, s).

ESI-MS. Found: m/z[M+H]+500.

Example 4

Getting 2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

2,9 ml methanesulfonanilide and 11 ml of N,N-diisopropylethylamine added to this is the manner by solution in chloroform (50 ml) 3.0 g of 2-allyl-1-[3-(hydroxymethyl)phenyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, which was obtained using [3-(hydroxymethyl)phenyl]Bronevoy acid instead of [3- (methoxycarbonyl)]phenylboronic acid used in example 1-1, and stirred at room temperature for 1 hour. The reaction liquid was washed 0,5N hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, obtaining the crude 2-allyl-1-[3-(methylsulfonylmethyl)phenyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one as a yellow oily substance.

20 ml of a 2M solution of dimethylamine in tetrahydrofuran was added to a solution of 1.5 g of the above compound in tetrahydrofuran (100 ml) and stirred at room temperature for 18 hours. The solvent was removed by evaporation under reduced pressure, and the residue was separated and purified with column chromatography on silica gel (ethyl acetate)to give 2.5 g specified in the title compound as a yellow solid.

1H-NMR (400 MHz, CDCl3) δ: 8,90 (1H, s), 7,53-7,26 (4H, m), 5,73-5,62 (1H, m), 5,11 (1H, DD, J=10,2, 1.0 Hz), of 4.95 (1H, DD, J=17,1, 1.0 Hz), of 4.44 (2H, d, J=3,7 Hz), 3,49 (2H, s), 2,48 (3H, s), and 2.27 (6H, s).

ESI-MS. Found: m/z M+H]+ 356,1.

2) Getting 2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

4 n solution of hydrochloric acid is ethyl acetate was added to 100 mg of the compound, obtained in the above stage 1), was stirred at room temperature and the solvent was removed by evaporation under reduced pressure, obtaining the hydrochloride of 2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one.

70 mg of m-chloroperbenzoic acid was added to a solution of the above compound in N,N-dimethylformamide (2 ml) and stirred at room temperature for 15 minutes. The reaction liquid was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, obtaining the crude 2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-(methylsulfonyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one as a white solid.

50 mg of 4-(4-methylpiperazin-1-yl)aniline and 0.1 ml of N,N - diisopropylethylamine were added in that order to a solution of the above compound in dimethyl sulfoxide/toluene (1/10, 10 ml) and stirred at 120°C for 15 hours. The solvent was removed by evaporation under reduced pressure, was added water and was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was separated and purified using standard column chromatography on silica gel (ethyl acetate)to give 11.4 mg pointed to by the th in the title compound as a yellow solid.

1H-NMR (400 MHz, CDCl3) δ: 8,80 (1H, c), of 7.48-7,33 (6H, m), 6.87 in (2H, d, J=8,8 Hz), 5,80-the ceiling of 5.60 (1H, m), 5,09 (1H, DD, J=10,2, 1.0 Hz), equal to 4.97 (1H, DD, J=17,1, 1.5 Hz), to 4.38 (1H, d, J=5,9 Hz), 3,51 (2H, s)3,18 (4H, t, J=4.9 Hz), 2,60 (4H, t, J=4.9 Hz), is 2.37 (3H, s), of 2.28 (6H, s).

ESI-MS. Found: m/z[M+H]+499.

Example 5

Getting 2-allyl-6-{[3-hydroxymethyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidine-3-it:

2.4 ml of N,N'-dimethylethylenediamine was added to the solution in 1,4-dioxane (50 ml) 4.44 g of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it, 3.80 g of copper iodide(I), 5,33 g of 2-iodopyridine and 3.80 g of potassium carbonate and stirred overnight at 95°C. the Reaction liquid was cooled, and thereto was added an aqueous solution of ammonia and was extracted with ethyl acetate, washed with saturated salt water solution and dried over anhydrous sulfate magnesium. The solvent was removed by evaporation under reduced pressure and was led from ethyl acetate, getting 5,15 g specified in the title compound as a white solid.

1H-NMR (400 MHz, CDCl3) δ: to 8.94 (1H, s), charged 8.52 (1H, d, J=5,1 Hz), of 7.90 (2H, d, J=3.5 Hz), 7,29-of 7.25 (1H, m), of 5.68 (1H, DDT, J=17,0, to 10.2, 6.3 Hz), of 5.05 (1H, d, J=10,2 Hz), 4,91 (1H, d, J=17,0 Hz), is 4.85 (1H, d, J=6.3 Hz), 2,58 (3H, ).

ESI-MS. Found: m/z[M+H]+300.

2) Getting 2-allyl-6-{[3-HYDR shall kemetyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

796 mg of m-chloroperbenzoic acid (>65%) was added to a solution in toluene (20 ml) 898 mg of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidine-3-it was stirred for 30 minutes. 1,60 ml of N,N-diisopropylethylamine, 800 mg of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol and 10 ml of tetrahydrofuran was added to the reaction liquid and stirred over night. Aqueous saturated solution of sodium bicarbonate was added to the reaction liquid medium and was extracted with a mixed solution of chloroform/isopropanol (80/20). The extract was dried over anhydrous magnesium sulfate, the solvent was removed by evaporation, and the residue was purified by standard column chromatography on silica gel (hexane/ethyl acetate = 50/50 to 0/100). The resulting crystalline substance was recrystallized from ethanol, getting 941 mg specified in the title compound as a white crystalline substance.

1H-NMR (400 MHz, CDCl3) δ: 8,84 (1H, c), 8,53 (1H, d, J=4,8 Hz), to $ 7.91 (1H, DD), 7,88 (1H, DD, J=8,8, 7,6 Hz), 7,87 (1H, d, J=7,6 Hz), to 7.64 (1H, s), 7,33 (1H, d, J=8,8 Hz), 7,26 (1H, DD, J=8,8, 4,8 Hz), 7,19 (1H, d, J=8,8 Hz), of 5.68 (1H, DDD, J=17,2, of 10.4, 5.6 Hz), of 5.50 (1H, s), free 5.01 (1H, q, j 10.4 Hz), 4,91 (1H, d, J=and 17.2 Hz), 4,79 (2H, s), 4,79 (2H, d, J=5.6 Hz), 3,01 (4H, m), 2,62 (4H, m), is 2.37 (3H, s).

ESI-MS. Found: m/z[M+H]+472.

Example 6

Getting 2-allyl-1-(6-aminopyridine-2-yl)-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4d]pyrimidine-3-one

1) preparation of di-tert-butyl {6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl]-2-pyridinyl}of medicalsocial:

2,00 g specified in the title compound was obtained as a white solid in the same manner as in example 5-1, for which, however, di-tert-butyl (6-bromopyridin-2-yl)medicalsocial used instead of 2-iodopyridine used in example 5-1.

1H-NMR (400 MHz, CDCl3) δ: of 8.92 (1H, s), 7,92 (1H, t, J=8.0 Hz), 7,80 (1H, d, J=8,8 Hz), 7,35 (1H, d, J=7.8 Hz), 5,63 (1H, DDT, J=17.1 to, to 10.2, 6.3 Hz), to 5.03 (1H, DD, J=10,2, 1.0 Hz), 5,00 (1H, DD, J=17,1, 1.2 Hz), 4,82 (2H, d, J=6.3 Hz), 2,58 (3H, s)and 1.51 (18H, s).

ESI-MS. Found: m/z[M+H]+515.

2) Getting 2-allyl-1-(6-aminopyridine-2-yl)-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

53 mg of m-chloroperbenzoic acid (>65%) was added to a solution in toluene (2 ml) 103 mg of di-tert-butyl {6-[2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine-1-yl]-2-pyridinyl}of medicalsocial and was stirred for 30 minutes. 0,105 ml of N,N-diisopropylethylamine and 49 mg of 3-methyl-4-(4-methylpiperazin-1-yl)aniline was added to the reaction liquid and stirred over night. Aqueous saturated solution of sodium bicarbonate was added to the reaction liquid, there was added ethyl acetate for extraction, the resulting extract was washed with saturated saline water Rast is a PR and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the residue was purified by standard column chromatography on silica gel (hexane/ethyl acetate = 1/1 to 0/1). After concentration was received 93,2 mg of a white solid.

2 ml triperoxonane acid was added to the obtained compound was mixed and there was added a saturated solution of sodium bicarbonate, extracted with ethyl acetate, washed with salt water solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, getting to 51.8 mg specified in the title compound as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 8,81 (1H, s), 7,60 (1H, t, J=7.8 Hz), 7,52 (1H, s), 7,34 (1H, DD, J=8,8, 2.4 Hz), 7,00 (1H, d, J=8,3 Hz), to 6.43 (1H, d, J=7.8 Hz), 5,71 (1H, DDT, J=16,8, 10,2, 5,9 Hz), is 5.06 (1H, DD, J=10,2, 1.0 Hz), 5,00 (1H, DD, J=16,8, 1.2 Hz), 4,71 (2H, d, J=5,9 Hz), 4,58 (2H, s), 2,95 (4H, t, J=4.6 Hz), 2,66 (4H, s), 2,42 (3H, s), 2,31 (3H, s).

ESI-MS. Found: m/z[M+H]+412.

Example 7

Getting 2-allyl-1-(6-aminopyridine-2-yl)-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

966 mg specified in the title compound was obtained as yellow solid in the same manner as in example 6-1 to 6-2, for which, however, 4-(4-methylpiperazin-1-yl)aniline was used instead of 3-methyl-4-(4-methylpiperazin-1-yl)aniline used in example 6-2.

1H-NMR (400 MHz, CDCl 3) δ: 8,80 (1H, s), to 7.59 (1H, t, J=7.8 Hz), 7,39 (1H, users), 6,91 (2H, d, J=8,8 Hz), 6.42 per (1H, d, J=8,3 Hz), 5,71 (1H, DDT, J=17.1 to, 10,2, 5,9 Hz), is 5.06 (1H, DD, J=10,2, 1.0 Hz), 5,00 (1H, DD, J=17,1, 1.0 Hz), 4,70 (2H,, d, J=5,9 Hz), of 4.57 (2H, s), 3,20 (4H, t, J=5,1 Hz), 2,61 (4H, t, J=4.9 Hz), of 2.38 (3H, s).

ESI-MS. Found: m/z[M+H]+458.

Example 8

Getting 2-allyl-1-{6-[(dimethylamino)methyl]pyridine-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 2-allyl-1-[6-(hydroxymethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

3,40 g specified in the title compound was obtained as a white solid in the same manner as in example 5-1, for which, however, (6-bromopyridin-2-yl)methanol was used instead of 2-iodopyridine used in example 5-1.

1H-NMR (400 MHz, CDCl3) δ: to 8.94 (1H, s), to $ 7.91 (1H, t, J=7.8 Hz), 7,78 (1H, DD, J=8,0, 0.7 Hz), 7,27 (1H, d, J=7.8 Hz), 5,76-to 5.66 (1H, m), 5,07 (1H, DD, J=10,2, 1.0 Hz), of 4.95 (1H, DD, J=17,1, 1.0 Hz), 4,84-of 4.77 (4H, m), 2,58 (3H, s).

ESI-MS. Found: m/z[M+H]+330.

2) obtaining the hydrochloride of 2-allyl-1-{6-[(dimethylamino)methyl]-2-pyridinyl}-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

of 1.16 ml of triethylamine and 0,451 ml methanesulfonamide was added to the solution in tetrahydrofuran (20 ml) of 1.37 g of the compound obtained in the above stage 1), and was stirred for 30 minutes, and then 6 ml of 2,0M solution of dimethylamine in tetrahydrofuran was added to react the Onna liquid medium and was stirred for 8 hours. Water was added to the reaction liquid medium and were extracted with ethyl acetate. The extract was washed with saturated saline aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 10 ml of ethyl acetate and 1.5 ml of 4 n solution of hydrochloric acid in dioxane was added to the resulting residue, and then the solvent was concentrated under reduced pressure and the residue was led from methanol/diethyl ether, receiving 1.50 g specified in the title compound as a white solid.

1H-NMR (400 MHz, DMSO-d6) δ: 8,17 (1H, s), of 7.36 (1H, t, J=7.8 Hz), 7,21 (1H, d, J=7.8 Hz), 6,76 (1H, d, J=7,3 Hz)to 4.92 (1H, DDT, J=17.1 to, to 10.2, 6.0 Hz), 4.26 deaths (1H, DD, J=10,2, 1.5 Hz), 4,14 (1H, DD, J=17,1, 1.5 Hz), 4,00 (2H, dt, J=6,0, 1.3 Hz in), 3.75 (2H, s), and 2.14 (6H, s)of 1.78 (3H, s).

ESI-MS. Found: m/z[M+H]+357.

3) Getting 2-allyl-1-{6-[(dimethylamino)methyl]pyridine-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

65 mg of m-chloroperbenzoic acid was added to a solution in N,N-dimethylformamide (2 ml) 100 mg of the compound obtained in the above stage 2), and stirred at room temperature for 15 minutes. The reaction liquid was washed aqueous saturated solution of sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, obtaining the neo is ewenny 2-allyl-1-{6-[(dimethylamino)methyl]pyridine-2-yl}-6- (methylsulfonyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one as a white solid.

40 mg of 4-(4-methylpiperazin-1-yl)aniline and 0.1 ml of N,N - diisopropylethylamine were added in that order to the solution in dimethyl sulfoxide/toluene (1/10, 10 ml) 40 mg of the above compound, and stirred at 120°C for 15 hours. The solvent was removed by evaporation under reduced pressure, there was added ice water, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, the residue was separated and purified using standard column chromatography on silica gel (ethyl acetate), obtaining an 8.4 mg specified in the title compound as a yellow solid.

1H-NMR (400 MHz, CDCl3) δ: 8,82 (1H, s), 7,82 (1H, t, J=7.8 Hz), 7,74 (1H, d, J=7.8 Hz), 7,47 (2H, d, J=8,8 Hz), 7,39 (1H, d, J=7,3 Hz), 6,92 (2H, d, J=6.3 Hz), 5,74-5,63 (1H, m)5,00 (1H, DD, J=10,2, 1.0 Hz), 4,89 (1H, DD, J=17,1, 1.0 Hz), 4,80 (2H, d, J=5,9 Hz), to 3.64 (2H, s), up 3.22 (4H, t, J=4,9 Hz)of 2.64 (4H, d, J=4.4 Hz), 2,39 (3H, s), of 2.34 (6H, s).

ESI-MS. Found: m/z[M+H]+500.

Example 9

Getting 2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 2-(6-bromo-2-pyridinyl)-2-propanol:

In nitrogen atmosphere, 30 ml of 3M methylmagnesium/in diethyl ether was added to 300 ml of diethyl ether 8,72 g of methyl 6-bromopyridin-2-carboxylate. Water and 2 N. hydrochloric keys, the GTC was added to the reaction liquid medium and were extracted with ethyl acetate. The extract washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline aqueous solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, getting 8,51 g of the crude 2-(6-bromo-2-pyridinyl)-2-propanol as a yellow oily substance.

1H-NMR (400 MHz, CDCl3) δ: 7,56 (1H, t, J=7.8 Hz), 7,38 (1H, DD, J=7,8, 1.0 Hz), was 7.36 (1H, DD, J=7,8, 1.0 Hz), of 1.55 (6H, s).

ESI-MS. Found: m/z[M+H]+216, 218.

2) Getting 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

12,89 g specified in the title compound was obtained in the same manner as in example 5-1, for which, however, the compound obtained in the above reaction, was used instead of 2 - iodopyridine used in example 5-1.

1H-NMR (400 MHz, CDCl3) δ: 8,95 (1H, s), to $ 7.91 (1H, t, J=8.0 Hz), 7,76 (1H, d, J=7,3 Hz), 7,40 (1H, DD, J=7,8, 1.0 Hz), 5,70 (1H, DDT, J=17.1 to, to 10.2, 6.3 Hz), is 5.06 (1H, DD, J=10,2, 1.0 Hz), is 4.93 (1H, DD, J=17,1, 1.2 Hz), to 4.81 (2H, d, J=6.3 Hz), 2,59 (4H, s)to 1.59 (6H, s).

ESI-MS. Found: m/z[M+H]+358.

3) Getting 2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

817 mg of m-chloroperbenzoic acid (>65%) was added to a solution in toluene (20 ml) of 1.10 g of the product obtained above and stirred for 20 minutes. 1,61 ml of N,N - diisopropyl the ethylamine and 706 mg of 4-(4-methylpiperazin-1-yl)aniline was added to the reaction liquid and stirred over night. Aqueous saturated solution of sodium bicarbonate was added to the reaction liquid, extracted with ethyl acetate, washed with saturated salt water solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue was purified by standard column chromatography on silica gel (hexane/ethyl acetate = 1/1 to 0/1, ethyl acetate/ethanol = 98/2). After concentration was performed recrystallization from ethyl acetate, receiving 1.20 g specified in the title compound as a yellow solid.

1H-NMR (400 MHz, CDCl3) δ: 8,83 (1H, s), 7,86 (1H, DD, J=8,0, 7,8 Hz), of 7.75 (1H, d, J=7,3 Hz), 7,49 (1H, users), of 7.48 (2H, d, J=9.0 Hz), 7,34 (1H, d, J=7,4 Hz), 6,93 (2H, d, J=9.0 Hz), 5,70 (1H, DDT, J=17.2 in, of 10.0, 6.5 Hz), 5,04 (1H, d, J=10.0 Hz), 4,94 (1H, d, J=and 17.2 Hz), 4,74 (2H, d, J=6.5 Hz), 3,26 (4H, t, J=4,8 Hz), 2,73 (4H, users), is 2.44 (3H, s)to 1.59 (6H, s).

ESI-MS. Found: m/z[M+H]+501.

Example 10

Getting 2-allyl-6-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

50,3 mg specified in the title compound was obtained as yellow solid in the same manner as in example 9-1 to 9-3, for which, however, 4-(4-ethyl-1-piperazinil)aniline was used instead of 4-(4-methylpiperazin-1-yl)aniline used in example 9-3.

1H-NMR (400 MHz, CDCl3) δ: 8,83 (1H, s), a 7.85 (1H, t, J=7.8 Hz), 7,76 (1H, d, J=7.8 Hz), 7,46 (2H, q, j =8,8 Hz), 7,34 (1H, d, J=8,3 Hz), 6,93 (2H, d, J=8,8 Hz), 5,76-5,64 (1H, m), 5,04 (1H, DD, J=10,2, 1.0 Hz), 4,94 (1H,DD, J=17,1, 1.0 Hz), and 4.75 (2H, d, J=6.3 Hz), 4,00 (1H, users), 3,23 (4H, t, J=4.9 Hz), 2,65 (4H, t, J=4.9 Hz), of 2.51 (2H, q, J=7,3 Hz)to 1.59 (6H, s)of 1.16 (3H, t, J=7,3 Hz).

ESI-MS. Found: m/z[M+H]+515.

Example 11

Obtain 6-{[4-(4-acetylpiperidine-1-yl)phenyl]amino}-2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

66,4 mg specified in the title compound was obtained as yellow solid in the same manner as in example 9-1 to 9-3, for which, however, 4-(4-acetyl-1-piperazinil)aniline was used instead of 4-(4-methylpiperazin-1-yl)aniline used in example 9-3.

1H-NMR (400 MHz, CDCl3) δ: 8,84 (1H, s), 7,87 (1H, t, J=7.8 Hz), 7,74 (1H, d, J=8,8 Hz)to 7.50 (2H, d, J=8,8 Hz), was 7.36 (1H, d, J=8,3 Hz)6,94 (2H, d, J=8,8 Hz), 5,76-the 5.65 (1H, m), 5,04 (1H, d, J=10,2 Hz), 4,94 (1H, d, J=17.1 to Hz), 4,74 (2H, d, J=5,9 Hz), a 4.03-of 3.95 (1H, m), 3,80 (2H, t, J=4.9 Hz), the 3.65 (2H, t, J=5,1 Hz), 3,17 (2H, t, J=4.9 Hz), 3,14 (2H, t, J=5,1 Hz)of 2.16 (3H, s)to 1.59 (6H, s).

ESI-MS. Found: m/z[M+H]+529.

Example 12

Getting 2-allyl-6-({4-[4-(2-hydroxyethyl)piperazine-1-yl]phenyl}amino)-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

40 mg indicated in the title compound was obtained as yellow solid in the same manner as in example 9-1 to 9-3, for which, however, 2-[4-(4-AMINOPHENYL)-1-piperazinil]ethanol was used instead of 4-(-methylpiperazin-1-yl)aniline, used in example 9-3.

1H-NMR (400 MHz, CDCl3) δ: 8,83 (1H, s), 7,86 (1H, t, J=7.8 Hz), of 7.75 (1H, d, J=7.8 Hz), 7,47 (2H, d, J=8,8 Hz), 7,34 (1H, d, J=8,3 Hz), 6,93 (2H, d, J=8,8 Hz), 5,76-the 5.65 (1H, m), 5,04 (1H, d, J=10,2 Hz), 4,94 (1H, d, J=17.1 to Hz), 4,74 (2H, d, J=6.3 Hz), a 4.03-of 3.95 (1H, m), of 3.69 (2H, t, J=5,1 Hz), up 3.22 (4H, t, J=4.9 Hz), 2,73 (4H, t, J=4.6 Hz), to 2.65 (2H, t, J=5.4 Hz), to 1.59 (6H, s).

ESI-MS. Found: m/z[M+H]+531.

Example 13

Getting 2-allyl-1-[6-(1-hydroxycyclopent)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 1-(6-bromo-2-pyrimidinyl)cyclobutanol:

In a nitrogen atmosphere at -10°C was added dropwise to 10.8 ml 2,66M solution of n-utility in hexane to 16 ml of 0,9M solution of n-butylacrylamide in tetrahydrofuran there was added a solution in toluene (60 ml) 9,48 g 2,6-dibromopyridine dropwise at 0°C or below. The reaction liquid was stirred for 1.5 hours, then cooled in a bath of dry ice in acetone and 5.0 g of cyclobutanone was added at -50°C or below. After stirring for 10 minutes was added water and 2 N. hydrochloric acid to the reaction liquid and the organic layer was separated, washed with aqueous saturated sodium hydrogen carbonate solution and saturated salt water solution and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure the residue was purified by column using the HRO is ecografia on silica gel (hexane/ethyl acetate = 20/1 to 4/1), getting 5.30 g specified in the title compound as a yellow oily substance.

1H-NMR (400 MHz, CDCl3) δ: 7,60 (1H, t, J=7.8 Hz), 7,52 (1H, DD, J=7,8, 1.0 Hz), 7,40 (1H, DD, J=7,8, 1.0 Hz), 2,53-2,48 (4H, m), 2,12 is 2.01 (1H, m), 1.91 a-1,82 (1H, m).

ESI-MS. Found: m/z[M+H]+228, 230.

2) Getting 2-allyl-1-[6-(1-hydroxycyclopent)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

1.44 g specified in the title compound was obtained in the same manner as in example 9-2, for which, however, the compound obtained in the above reaction, was used instead of 2-(6 - bromo-2-pyridinyl)-2-propanol used in example 9-2.

1H-NMR (400 MHz, CDCl3) δ: to 8.94 (1H, s), 7,95 (1H, t, J=8.0 Hz), to 7.77 (1H, d, J=7.8 Hz), 7,54 (1H, d, J=7.8 Hz), 5,70 (1H, DDT, J=17.1 to, to 10.2, 6.3 Hz), 5,07 (1H, d, J=10,2 Hz), 4,94 (1H, d, J=17,1 Hz), 4,80 (2H, d, J=6.3 Hz), 2,58 (3H, s), 2,56-of 2.50 (4H, m), 2,15-2,03 (1H, m), 1,97-of 1.84 (1H, m).

ESI-MS. Found: m/z[M+H]+370.

3) Getting 2-allyl-1-[6-(1-hydroxycyclopent)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

80,8 mg specified in the title compound was obtained as yellow solid in the same manner as in example 9-3, for which, however, the compound obtained in the above reaction, was used instead of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one used in example 93.

1H-NMR (400 MHz, CDCl3) δ: 8,83 (1H, s), of 7.90 (1H, t, J=7.8 Hz), to 7.77 (1H, d, J=7.8 Hz), of 7.48 (2H, DD, J=12,2, 8,3 Hz), of 7.48 (1H, users), 6,93 (2H, d, J=9.3 Hz), 5,70 (1H, TDD, J=5,9, 17,1, 10,0 Hz), 5,04 (1H, DD, J=10,0, 1.2 Hz), 4,94 (1H, DD, J=17,1, 1.0 Hz), to 4.73 (2H, d, J=5,9 Hz), 4,20 (1H, s), 3,24 (4H, t, J=4.6 Hz), 2,65 (4H, users), of 2.53 (4H, t, J=8.0 Hz), is 2.41 (3H, s), 2,14-to 2.06 (1H, m), 1,96-of 1.84 (1H, m).

ESI-MS. Found: m/z[M+H]+513.

Example 14

Getting 2-allyl-1-[6-(2-hydroxy-2-methylpropyl " pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 1-(6-bromopyridin-2-yl)-2-methylpropan-2-ol:

In the atmosphere of nitrogen, 400 ml of tetrahydrofuran containing 31 ml Diisopropylamine, cooled in a bath of dry ice in acetone and 82.7 ml 2,66M solution of n-utility in hexane was added, and 50 ml of tetrahydrofuran containing 34.4 g of 6-brancolini was added dropwise there at -70°C or below. After addition of 29.4 ml of acetone was added at -60°C or below. After stirring for 35 minutes was added water to the reaction liquid and the organic solvent was concentrated under reduced pressure. This concentrate was extracted with diethyl ether, washed with saturated salt water solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure the residue was purified by means of distillation, getting 27,60 g specified in the connection header in the form of b is izvetnogo oily substance.

1H-NMR (400 MHz, CDCl3) δ: 7,50 (1H, t, J=7,6 Hz), 7,37 (1H, d, J=7.8 Hz), 7,12 (1H, d, J=7.8 Hz), 2.91 in (2H, s)of 1.23 (6H, s).

ESI-MS. Found: m/z[M+H]+: 230, 232.

2) Getting 2-allyl-1-[6-(2-hydroxy-2-methylpropyl " pyridine-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

20,70 g specified in the title compound was obtained in the same manner as in example 9-2, for which, however, the compound obtained in the above reaction, was used instead of 2-(6 - bromo-2-pyridinyl)-2-propanol used in example 9-2.

1H-NMR (400 MHz, CDCl3) δ: 8,93 (1H, s), to 7.84 (1H, t, J=7.8 Hz), 7,71 (1H, d, J=8,3 Hz), to 7.15 (1H, d, J=7,3 Hz), 5,67 (1H, DDT, J=16,8, to 10.2, 6.3 Hz), of 5.05 (1H, DD, J=10,2, 1.0 Hz), is 4.93 (1H, DD, J=16,8, 1.2 Hz), of 4.77 (2H, d, J=6.3 Hz), of 2.97 (2H, s), 2,58 (3H, s), 1,25 (6H, s).

ESI-MS. Found: m/z[M+H]+372.

3) Getting 2-allyl-1-[6-(2-hydroxy-2-methylpropyl " pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1.06 g specified in the title compound was obtained as yellow solid in the same manner as in example 9-3, for which, however, the compound obtained in the above reaction, was used instead of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one used in example 9-3.

1H-NMR (400 MHz, CDCl3) δ: 8,82 (1H, s), 7,79 (1H, t, J=7.8 Hz), 7,66 (1H, users), was 7.45 (2H, d, J=8,8 Hz), was 7.08 (1H, d, J=7.8 Hz), 6,93 (2H, d, J=8,8 Hz), 78-5,62 (1H, m), 5,13-4,94 (2H, m), 4,63 (2H, s), 3,23 (4H, t, J=4.6 Hz), 2,98 (2H, s)of 2.64 (4H, s), is 2.40 (3H, s)of 1.24 (6H, s).

ESI-MS. Found: m/z[M+H]+515.

Example 15

Getting 2-allyl-1-[6-(2-hydroxy-2-methylpropyl " pyridine-2-yl]-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

to 36.8 mg specified in the title compound was obtained as yellow solid in the same manner as in example 14-1 through 14-3, for which, however, 4-(1-methylpiperidin-4-yl)aniline was used instead of 4-(4-methylpiperazin-1-yl)aniline used in example 14-3.

1H-NMR (400 MHz, CDCl3) δ: cent to 8.85 (1H, s), 7,89-7,76 (2H, osirm), 7,80 (1H, t, J=7.8 Hz), 7,52 (2H, d, J=8,3 Hz), 7,22 (2H, d, J=8,3 Hz), 7,10 (1H, d, J=7.8 Hz), 5,77-5,64 (1H, osirm), to 5.08 (1H, d, J=9.8 Hz), free 5.01 (1H, d, J=17.6 Hz), 4,71-4,58 (2H, osirm), 3,05 (2H, d, J=11.2 Hz), 2,99 (2H, s), 2,56 at 2.45 (1H, m), of 2.38 (3H, s), 2.21 are 2,07 (2H, m), 1,95-of 1.81 (4H, m), 1,24 (6H, s).

ESI-MS. Found: m/z[M+H]+514.

Example 16

Getting 2-allyl-1-[6-(2-hydroxy-1,1,2-trimethylpropyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 2-(6-bromopyridin-2-yl)-2-methylpropionate:

In nitrogen atmosphere with 100 ml of tetrahydrofuran containing 14 ml of Diisopropylamine, cooled in a bath of dry ice in acetone, and 38 ml of 2,66M solution of n-utility in hexane was added to obtain diisopropylamide lithium. This resulting solution was added dropwise to 100 ml of t is trageriemen, containing 4,55 ml 6-brancolini and 6.06 ml diethylmalonate, at -60°C or below. After stirring for 20 minutes 6,23 ml under the conditions was added and warmed to room temperature. Water was added to the reaction liquid was extracted with diethyl ether, washed with saturated salt water solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure the residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 100/0 to 8/1), receiving of 10.72 g specified in the title compounds as a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: 7,49 (1H, t, J=7.8 Hz), 7,33 (1H, DD, J=7,8, 1.0 Hz), 7,22 (1H, DD, J=7,8, 1.0 Hz), of 4.16 (2H, q, J=7,0 Hz)to 1.59 (6H, s)of 1.20 (3H, t, J=7,1 Hz)0,00 (1H, d, J=3,4 Hz).

ESI-MS. Found: m/z[M+H]+272, 274.

2) Obtaining 3-(6-bromopyridin-2-yl)-2,3-dimethylbutan-2-ol:

In nitrogen atmosphere 13 ml of a 2M solution of methylmagnesium in diethyl ether was added to the solution in diethyl ether (20 ml) of 2.72 g of ethyl 2-(6-bromopyridin-2-yl)-2-methylpropionate, while using cooling ice bath. The reaction liquid was stirred at room temperature for 3 hours and then there was added water and aqueous 10% solution of phosphoric acid, was extracted with diethyl ether, washed with aqueous saturated sodium hydrogen carbonate solution and saturated SOLEV the m aqueous solution, then was dried over anhydrous magnesium sulfate. After concentration under reduced pressure the residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 9/1 to 8/1)to give 1.47 g specified in the title compounds as a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: 7,53 (1H, t, J=7.8 Hz), 7,35 (1H, d, J=7,3 Hz), 7,31 (1H, d, J=7,8 Hz)to 1.38 (6H, s)of 1.09 (6H, s).

ESI-MS. Found: m/z[M+H]+258, 260.

3) Getting 2-allyl-1-[6-(2-hydroxy-1,1,2-trimethylpropyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

74,5 mg specified in the title compound was obtained as yellow solid in the same manner as in example 9-2 9-3 on, in which, however, the compound obtained in the above reaction, was used instead of 2-(6-bromo-2-pyridyl)-2-propanol used in example 9-2.

1H-NMR (400 MHz, CDCl3) δ: 8,82 (1H, s), 7,81 (1H, t, J=7.9 Hz), 7,81 (1H, users), was 7.45 (2H, d, J=8,4 Hz), 7,30 (1H, s), 6,93 (2H, d, J=9,2 Hz), 5,71 (1H, s), to 5.08 (2H, s), 4,63 (2H, s), 3,24 (4H, s)to 2.66 (4H, s)to 2.41 (3H, ), to 1.47 (6H, s)of 1.09 (6H, s).

ESI-MS. Found: m/z[M+H]+543.

Example 17

Getting 2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1-[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

Under ice cooling 0,012 ml of triethylamine and 12.4 mg of the acid chloride of 4-harpalani acid was added to the Astaro in tetrahydrofuran (1 ml) 20 mg connections, obtained in example 7, 2-allyl-1-(6-aminopyridine-2-yl)-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, and was stirred at room temperature for 1 hour. Water was added to the reaction mixture was extracted with chloroform and the organic layer was washed with saturated salt water solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, the resulting residue was dissolved in 1 ml N,N-dimethylformamide there were added 5 mg of tert-butoxide potassium and stirred at room temperature for 30 minutes. To the reaction mixture were added a saturated solution of ammonium chloride, extracted with ethyl acetate and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified using preparative thin-layer chromatography (chloroform/methanol = 10/1)to give 5 mg indicated in the title compound as a yellow solid.

1H-NMR (400 MHz, CDCl3) δ: 8,82 (1H, s), a 8.34 (1H, d, J=8.0 Hz), the 7.85 (1H, t, J=8.0 Hz), 7,58 (1H, d, J=8.0 Hz), 7,49-7,34 (1H, osirm), 7,46 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz), of 5.68 (1H, DDT, J=17.1 to, 10,2, 5,9 Hz), 5,04 (1H, DD, J=10,2, 1.0 Hz), 4,94 (1H, DD, J=17,1, 1.0 Hz), was 4.76 (2H, d, J=5,9 Hz), 4,13-Android 4.04 (2H, m), 3,30-3,20 (4H, m), was 2.76-2,61 (6H, m), 2,42 (3H, s), 2.21 are 2,09 2H, m).

ESI-MS. Found: m/z[M+H]+526.

Example 18

Obtain N-{[6-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridin-2-yl]methyl}-N-methylmethanesulfonamide

1) preparation of 2-allyl-1-[6-(hydroxymethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

of 1.36 g of imidazole and of 1.81 g of tert-butyl(chloro)dimethylsilane was added to a solution in N,N-dimethylformamide (30 ml) 3,29 g of the compound obtained in example 8-1, and was stirred overnight. Water was added to the reaction liquid medium and was extracted with diethyl ether. The extract was washed with saturated salt water solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure the resulting residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 9/1 to 4/1) and the solvent was removed by evaporation under reduced pressure. 40 ml of toluene and 3,20 g of m-chloroperbenzoic acid (>65%) was added to the residue and stirred for 30 minutes. 5,20 ml of N,N-diisopropylethylamine and to 2.29 g of 4-(4-methylpiperazin-1-yl)aniline was added to the reaction liquid and stirred over night. Aqueous saturated solution of sodium bicarbonate was added to the reaction liquid medium and were extracted with ethyl acetate. The dried extract is over anhydrous magnesium sulfate, the solvent was removed by evaporation, the residue was purified by column chromatography on silica gel (chloroform/ethanol = 100/1 to 100/3) and the solvent was removed by evaporation under reduced pressure. 50 ml of 4 N. hydrochloric acid was added to the residue and stirred, and then the solution was podslushivaet using 4 N. aqueous sodium hydroxide solution. This solution was extracted with a mixed solution of chloroform/isopropanol (80/20), dried over anhydrous magnesium sulfate, the solvent was removed by evaporation and the residue was led from ethyl acetate, receiving of 3.78 g specified in the title compound as a yellow crystalline substance.

1H-NMR (400 MHz, CDCl3) δ: 8,83 (1H, s), 7,86 (1H, t, J=6.0 Hz), of 7.75 (1H, d, J=8,2 Hz), 7,46 (2H, d, J=8.6 Hz), 7,40 (1H, users), 7,22 (1H, d, J=7,6 Hz), 6,92 (2H, d, J=9.0 Hz), 5,71 (1H, DDT, J=16,8, 10,2, 5,9 Hz), is 5.06 (1H, d, J=10,2 Hz), 4,96 (1H, d, J=16,8 Hz), to 4.81 (2H, d, J=5.5 Hz), 4,71 (1H, d, J=5,9 Hz), 3,23 (4H, users), 3,14 (1H, t, J=5,5 Hz)of 2.64 (4H, users), is 2.40 (3H, s).

ESI-MS. Found: m/z[M+H]+473.

2) Getting 2-allyl-1-{6-[(methylamino)methyl]pyridine-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

4,46 ml of triethylamine and 1.0 ml of methanesulfonamide was added to the solution in tetrahydrofuran (120 ml) of 3.78 g of the compound obtained in the above example 1, and stirred. 20 ml of 2,0M solution of methylamine in tetrahydrofuran was added to the reaction LM is coy environment and stirred over night. Water was added to the reaction liquid medium and were extracted with ethyl acetate. The extract was washed with saturated saline aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the resulting residue was purified by standard column chromatography on silica gel (hexane/ethyl acetate = 50/50 to 0/100, then chloroform), getting to 3.38 g specified in the title compound as a yellow solid.

1H-NMR (400 MHz, CDCl3) δ: 8,82 (1H, s), 7,81 (1H, t, J=7.8 Hz), 7,72 (1H, d, J=7.8 Hz), 7,46 (2H, d, J=8,8 Hz), 7,25 (1H, d, J=7,3 Hz), 6,92 (2H, d, J=9.3 Hz), 5,69 (1H, DDT, J=17.1 to, to 10.2, 6.3 Hz), 5,02 (1H, DD, J=10,2, 1.5 Hz), to 4.92 (1H, DD, J=17,1, 1.5 Hz), and 4.75 (2H, d, J=6.3 Hz), 3,91 (2H, s), is 3.21 (4H, t, J=4.9 Hz), 2,62 (4H, t, J=4.9 Hz), of 2.51 (3H, s), of 2.38 (3H, s).

ESI-MS. Found: m/z[M+H]+486.

3) Obtain N-{[6-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridin-2-yl]methyl}-N-methylmethanesulfonamide:

1,50 ml of triethylamine and 0.4 ml of methanesulfonamide was added to the solution in tetrahydrofuran (50 ml) 1.70 g of the compound obtained in the above stage 2), and stirred. Water was added to the reaction liquid medium and were extracted with ethyl acetate. The extract was washed with saturated saline aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the resulting the STATCOM was led from 15 ml of ethyl acetate and 10 ml of ethanol, getting 849 mg specified in the title compound as a yellow solid.

1H-NMR (400 MHz, CDCl3) δ: 8,83 (1H, s), 7,89 (1H, t, J=7.8 Hz), 7,81 (1H, d, J=8,3 Hz), of 7.48 (1H, d, J=9.3 Hz), 7,47 (1H, users), 7,41 (2H, d, J=7,3 Hz), 6,93 (2H, d, J=8,8 Hz), of 5.68 (1H, DDT, J=17.1 to, to 10.2, 6.3 Hz), to 5.03 (1H, d, J=10,2 Hz)to 4.92 (1H, d, J=18,0 Hz), and 4.75 (2H, d, J=6.3 Hz), 4,50 (2H, s)to 3.38 (4H, users), 2,95 (3H, s), of 2.92 (4H, users), only 2.91 (3H, s), 2,58 (3H, s).

ESI-MS. Found: m/z[M+H]+564.

Example 19

Getting 2-allyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 2-(6-bromopyridin-2-yl)-2-methylpropan-1-ol:

In the bath with dry ice/acetone, 100 ml of 1,01M solution diisobutylaluminium in toluene was added to a solution in toluene (50 ml) of 10.72 g of the compound obtained in example 16-1, warmed to room temperature and was stirred for 40 minutes. Under ice cooling to the reaction liquid was added an aqueous saturated solution of ammonium chloride and the organic layer was separated. This layer washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate), obtaining a total of 8.74 g is specified in the header connect the deposits in the form of a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: 7,52 (1H, t, J=7.8 Hz), 7,33 (1H, DD, J=7,8, 1.0 Hz), 7,27 (1H, d, J=7.8 Hz), 3,74 (2H, s)of 1.32 (6H, s).

ESI-MS. Found: m/z[M+H]+230, 232.

2) Getting 2-allyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridine-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

7,45 g specified in the title compound was obtained in the same manner as in example 9-2, for which, however, the compound obtained in the above reaction, was used instead of 2-(6-bromo-2-pyridinyl)-2-propanol used in example 9-2.

1H-NMR (400 MHz, CDCl3) δ: 8,93 (1H, s), 7,86 (1H, t, J=8.0 Hz), 7,60 (1H, d, J=8,8 Hz), 7,31 (1H, d, J=7.8 Hz), 5,67 (1H, DDT, J=17.1 to, to 10.2, 6.3 Hz), of 5.05 (1H, DD, J=10,2, 1.0 Hz), to 4.92 (1H, DD, J=17,1, 1.5 Hz), 4,79 (2H, d, J=6.3 Hz), of 3.78 (2H, s), 2,58 (3H, s)to 1.37 (6H, s).

ESI-MS. Found: m/z[M+H]+372.

3) Getting 2-allyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

1.4 g specified in the title compound was obtained as yellow solid in the same manner as in example 9-3, for which, however, the compound obtained in the above reaction, was used instead of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one used in example 9-3.

1H-NMR (400 MHz, CDCl3) δ: 8,83 (1H, s), 7,81 (1H, t, J=7.8 Hz), 7,52-7,41 (3H, m), 7,25 (1H, d, J=9.3 Hz), 6,92 (2H, DD, J=6,8, and 2.4 Hz), 5,72 (1H, is IRS), 5,14-4,96 (2H, osirm), with 4.64 (2H, users), with 3.79 (2H, d, J=6.3 Hz), 3,24 (4H, t, J=5.0 Hz), 2,65 (4H, users), is 2.41 (3H, s)to 1.38 (6H, s).

ESI-MS. Found: m/z[M+H]+515.

Example 20

Obtaining 1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-PROPYNYL)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-6-(methylthio)-2-(2-PROPYNYL)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

440 mg of ammonium formate and 230 mg dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) was added to the solution in tetrahydrofuran (13,6 ml) of 500 mg of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one obtained in example 9, and was stirred at 90°C for 3 hours. The reaction liquid was cooled to room temperature, thereto was added distilled water and was extracted with a mixed solution of chloroform/isopropanol (80/20). The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure, received 770 mg of black amorphous substance. 61,0 mg of sodium hydride was added to a solution of the resulting compound in N,N-dimethylformamide (14,0 ml) and was stirred for 30 minutes. 0,316 ml propylbromide was added to the reaction solution and stirred for 3.5 hours. Water nassen the th solution of sodium bicarbonate and saturated saline aqueous solution was added to the reaction liquid medium and was extracted with a mixed solution of chloroform/isopropanol (80/20). The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure, getting a black amorphous substance. The resulting amorphous substance was purified by column chromatography on silica gel (hexane/ethyl acetate)to give 254 mg specified in the title compound as a white connection.

1H-NMR (400 MHz, CDCl3) δ: to 8.94 (1H, s), 7,94 (2H, d, J=3.6 Hz), the 7.43 (1H, t, J=3.6 Hz), equal to 4.97 (2H, d, J=2.4 Hz), 2,62 (3H, s)of 2.16 (1H, t, J=2,4 Hz)to 1.59 (6H, s).

ESI-MS. Found: m/z[M+H]+357.

2) Obtaining 1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-PROPYNYL)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

7,3 mg specified in the title compound was obtained as yellow solid in the same manner as in example 9-3, for which, however, the compound obtained in the above reaction, was used instead of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one used in example 9-3.

1H-NMR (400 MHz, CDCl3) δ: 8,83 (1H, s), 7,92 (1H, d, J=8.0 Hz), 7,87 (1H, DD, J=8,0, 8.0 Hz), 7,47 (2H, d, J=7,6 Hz), 7,35 (1H, d, J=8.0 Hz), 6,94 (2H, d, J=7,6 Hz), 4,89 (2H, d, J=2.0 Hz), 3,23 (4H, m), 2.63 in (4H, m), 2,39 (3H, s)to 2.13 (1H, t, J=2.0 Hz), to 1.59 (6H, s).

ESI-MS. Found: m/z[M+H]+499.

Example 21

Getting 2-allyl-1-[6-(3-methyl-2-Oxymetazoline-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1 and is)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one

1) preparation of 2-allyl-1-(6-bromopyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

In the same way as in example 5-1, but using 2,6-dibromopyridin instead of 2-iodopyridine used in example 5-1, 2,94 g specified in the title compound was obtained as a white solid.

1H-NMR (400 MHz, CDCl3) δ: to 8.94 (1H,C)to 7.95 (1H, d, J=7.8 Hz), 7,73 (1H, t, J=8.0 Hz), the 7.43 (1H, d, J=7.8 Hz), 5,69 (1H, DDT, J=17.1 to, to 10.2, 6.3 Hz), is 5.06 (1H, DD, J=10,2, 1.2 Hz), 5,00 (1H, d, J=17,1 Hz), 4,88 (2H, d, J=6.3 Hz), 2,60 (3H, s).

2) Getting 2-allyl-1-[6-(3-methyl-2-Oxymetazoline-1-yl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

1-Methylimidazolidine-2-he (96 mg), copper iodide (76 mg), potassium carbonate (110 mg) and N,N'-dimethylated-1,2-diamine (85 μl) was added to the solution in dioxane (5 ml) of 2-allyl-1-(6-bromopyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (150 mg) and stirred overnight in a sealed vessel at heated to 100°C.

The reaction liquid was cooled, and thereto was added an aqueous solution of ammonia and was extracted three times with chloroform. The organic layer was washed with saturated saline aqueous solution, dried over anhydrous magnesium sulfate, filtered and the solvent was removed by evaporation. The crude product was purified by column chromatography on silica gel, getting to 136.4 mg specified in the connection header in the IDA white solid.

1H-NMR (400 MHz, CDCl3) δ: of 8.92 (1H, s), compared to 8.26 (1H, d, J=8,4 Hz), 7,81 (1H, DD, J=8,4, a 7.6 Hz), 7,41 (1H, d, J=7,6 Hz), to 5.66 (1H, DDD, J=16,8, 10,0, 6.4 Hz), is 5.06 (1H, d, J=10.0 Hz), of 4.95 (1H, d, J=16,8 Hz), 4,80 (2H, d, J=6.4 Hz), to 4.01 (2H, d, J=8.0 Hz), 3,51 (1H, t, J=8.0 Hz), to 2.94 (3H, s), to 2.57 (3H, s).

ESI-MS. Found: m/z[M+H] 398.

3) Getting 2-allyl-1-[6-(3-methyl-2-Oxymetazoline-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-it:

In the same way as in example 5-2, but using 4-(4-methylpiperazin-1-yl)aniline instead of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in example 5-2, and using 2-allyl-1-[6-(3-methyl-2-Oxymetazoline-1-yl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one instead of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidine-3-it, 115,6 mg specified in the title compound was obtained as a yellow solid.

1H-NMR (400 MHz, CDCl3) δ: 8,81 (1H, s), by 8.22 (1H, d, J=8,4 Hz), 7,78 (1H, DD, J=8,4, 8.0 Hz), 7,46 (2H, d, J=8.0 Hz), 7,40 (1H, d, J=8.0 Hz), make 6.90 (2H, d, J=8.0 Hz), of 5.68 (1H, DDD, J=16,8, of 10.4, 6.0 Hz), 5,04 (1H, d, J=10.4 Hz), of 4.95 (1H, d, J=16,8 Hz), 4,74 (2H, d, J=6.0 Hz), was 4.02 (2H, t, J=8,4 Hz), 3,49 (2H, t, J=8,4 Hz), to 3.02 (4H, m)to 2.94 (3H, s), 2,60 (4H, m), is 2.37 (3H, s).

Mass SP. with ionization elektrorazpredelenie, found: m/z[M+H] 541.

Applicability in industrial conditions

Compounds according to the invention have an excellent inhibitory effect on Weel-kinase and therefore applicable in the field of medicine, abeno in the treatment of various malignant tumors.

1. The compound of General formula (I):

where a1choose from the following formula (Aa1):

R1crepresents a hydrogen atom, a lower alkenylphenol group or a group-Q3-A3(R1dR1e;
And3represents Metin or a lower alkyl group;
Q3represents a single bond;
R1dand R1erepresent independently a hydrogen atom, hydroxyl group, lower alkyl group or hydroxyl-containing lower alkyl group, or together form a lower alkylenes group in which one or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom;
R1represents the lowest alkenylphenol group or lower alkylamino group;
R2represents phenyl, pyridyloxy or thienyl group, which may contain the group-Q4-A4(R1gR1h;
And4represents a nitrogen atom, lower alkyl group, optionally substituted hydroxy-lower alkyl group, or a methine group optionally substituted by halogen atom, hydroxyl group, lower alkyl group or a hydroxy-lower alkyl group;
Q4represents a single bond Il is lower alkylenes group, in which one, or two or more methylene groups constituting the lower alkylenes group may be independently replaced by an oxygen atom;
R1gand R1hrepresent independently a hydrogen atom, a lower alkyl group or lower alkylsulfonyl group;
R5and R6represent independently a hydrogen atom, a lower alkyl group or hydroxyl-containing lower alkyl group, or its pharmaceutically acceptable salt.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where R1represents the lowest alkenylphenol group.

3. The compound according to claim 2 or its pharmaceutically acceptable salt, where R1represents an allyl group.

4. The compound according to claim 1 or its pharmaceutically acceptable salt, where R2represents phenyl or pyridyloxy group containing the group-Q4-A4(R1gR1h.

5. The compound according to claim 1 or its pharmaceutically acceptable salt, where R1crepresents a hydrogen atom or a group-Q3-A3(R1dR1eand in the group-Q3-A3(R1dR1e,
And3represents a methine group, Q3represents a single bond, and R1dand R1erepresents independently a hydrogen atom or a lower alkyl group.

6. The compound according to claim 1 and the and its pharmaceutically acceptable salt, representing:
3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl)-N,N-dimethylbenzamide, 2-allyl-1-[3-(1-hydroxy-3-methylethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, 2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, 2-allyl-6-{[3-hydroxymethyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-Il-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, 2-allyl-1-(6-aminopyridine-2-yl)-6-[{4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, 2-allyl-1-[6-(3-hydroxy-1-methylethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,
2-allyl-6-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, 6-{[4-(4-acetylpiperidine-1-yl)phenyl]amino}-2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one, 2-allyl-6-({4-[4-(2-hydroxyethyl)piperazine-1-yl]phenyl}amino)-1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-4]pyrimidine-3-one,
2-allyl-1-[6-(2-hydroxy-2-methylpropyl " pyridine-2-yl]-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one,
2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1-[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-1,2-dihydro-3H-feast of the olo[3,4-d]pyrimidine-3-one,
N-{[6-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-1-yl)pyridin-2-yl]methyl}-N-methylmethanesulfonamide or
1-[6-(1-hydroxy-1-methylethyl)pyridine-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-PROPYNYL)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one.

7. Pharmaceutical composition having anti-cancer activity comprising a therapeutically effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent.

8. Anticancer agent comprising the pharmaceutical composition according to claim 7.

9. Combined medicinal product for simultaneous, separate or sequential injection in the treatment of malignant tumors, including two separate drug (a) and (b):
(a) the medicinal product, including, together with a pharmaceutically acceptable carrier or diluent, the compound of the above formula (I) or its pharmaceutically acceptable salt; and
(b) the medicinal product, including, together with a pharmaceutically acceptable carrier or diluent, one anticancer agent selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, anticancer agents of plant origin is, anticancer coordination of platinum complex compounds, anticancer derivatives camptothecin, anticancer inhibitors of tyrosine kinases, monoclonal antibodies, interferons, biological modifiers sensitivity and other anticancer agents or their pharmaceutically acceptable salts, including anticancer alkylating agents are the N-oxide nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, carmustine;
anticancer antimetabolites are methotrexate, 6-mercaptopurine, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, tsitarabina ocfosfate, enocitabine, S-1, gemcitabine, fludarabine and pemetrexed disodium;
anticancer antibiotics are actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimulater, idarubitsin, sirolimus and valrubicin;
anticancer agents from plant origin are vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel and vinorelbine;
anticancer coordination complex platinum compounds are cisplatin, carboplast is h, nedaplatin and oxaliplatin;
anticancer derivatives camptothecin are irinotecan, topotecan and camptothecin;
anticancer inhibitors of tyrosine kinases are gefitinib, imatinib and erlotinib;
monoclonal antibodies are cetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab;
interferons are interferon α, interferon α-2A, interferon α-2b, interferon β, interferon γ-1A, and interferon γ-n1, modifiers biological sensitivity are christening, lentinan, sizofiran, picibanil or ubenimex, and
other anticancer agents represent mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoietin Alfa, anastrozole, exemestane, bikalutamid, leuprorelin, flutamide, fulvestrant, pegaptanib Octanate, denileukin diftitox, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine, and goserelin.

10. The pharmaceutical composition comprising, together with a pharmaceutically acceptable carrier or diluent, the compound according to claim 1 or its pharmaceutically acceptable salt; and an anti-cancer agent selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, about voracova agents of plant origin, anticancer coordination of platinum complex compounds, anticancer derivatives camptothecin, anticancer inhibitors of tyrosine kinases, monoclonal antibodies, biological modifiers sensitivity and other anticancer agents for which the definition of each antitumor agent is the same as defined in claim 9, or their pharmaceutically acceptable salts.

11. The sensitizer exposure, including pharmaceutical composition according to claim 7.

12. The sensitizer for cancer agent, comprising the pharmaceutical composition according to claim 7, in which the anticancer agent is selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, anticancer agents of plant origin, anticancer coordination of platinum complex compounds, anticancer derivatives camptothecin, anticancer tyrosine kinase inhibitors, monoclonal antibodies, biological modifiers sensitivity and other anticancer agents for which the definition of each antitumor agent is the same as defined in claim 9, or their pharmaceutically acceptable salts.

13. The use of compounds according to claim 1 or its pharmaceutically acceptable salt to obtain anti-cancer agent.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of general formulae (I-c) (I-d), pharmaceutically acceptable salt or stereoisomer thereof, where R1 = -OR11 or -NH-SO2R12; R2 = hydrogen and R3 =C1-6-alkyl; n = 3-6; W is a radical of formula , where R5 = phenyl, possibly substituted with C1-6alkyl or alkoxy; thiazolyl, possibly substituted with C1-6alkyl; or pyridyl; R11 denotes hydrogen; R12 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: said compounds are hepatitis C virus inhibitors and can be used in medicine.

3 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel antiviral active components - substituted indoles of general formula 1 and pharmaceutically acceptable salts thereof, which can be used to treat and/or prevent viral diseases caused by hepatitis C virus (HCV). In general formula , R1 denotes a hydrogen atom, optionally substituted C1-C4alkyl, C6cycloalkyl, phenyl, ethoxycarbonyl, nitro group; R2 denotes a hydrogen atom; R3 denotes N-mono- or N,N-disubstituted 1-methylene-piperidine-3-carboxamide of general formula 1a or N-mono- or N,N-disubstituted 1-methylene-piperdine-4-carboxamide of general formula 1b; R4 denotes a hydrogen atom, optionally substituted C2-C3alkyl, a -CH2-R12 group, where R12 denotes a hydrogen atom or phenyl which is optionally substituted with halogen or C1-C4alkyl; or R2, R3, and R4 together with atoms with which they are bonded form a substituted azaheterocycle of general formula 1.2; or R2 and R3 together with carbon atoms with which they are bonded form a substituted 2,3,4,9-tetrahydro-1H-carbazole of general formula 1.1, in which R1 denotes methyl, ethoxycarbonyl, nitro group; R4 denotes a hydrogen atom, methyl, C2-C3alkyl substituted with N-benzylamine; R7 and R8 denote hydrogen atoms or R7 and R8 together with a carbon atom with which they are bonded form a C=O group; R5 and R6, which are optionally identical, denote a hydrogen atom, optionally substituted C1-C3alkyl or C3-C6cycloalkyl; or R5 and R6 together with a nitrogen atom with which they are bonded form an optionally substituted 5- or 6-member azaheterocyclyl containing one or two nitrogen atoms, etc.

EFFECT: improved properties of compounds.

11 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I): or its pharmaceutically acceptable salt where Q is 2,6-pyrimidyl; where Q is optionally substituted by 1-5 substitutes JQ; Z is a link or NH; R1 is H; R2 is H; R3 is halogen or -(U)m-X where m is equal to 0; X is H or halogen; JQ is halogen, OCF3, -(Vn)-R", -(Vn)-CN or -(Vn)-(C1-4 halogenaliphatic group) where JQ is not H; V is C1-10aliphatic group where up to three methylene groups are substituted by GV where Gv is selected from -NH-, -NR-, -O-, -S-, -CO2-, -C(O)CO-, -C(O), -C(O)NH-, -C(O)NR-, -C(=N-CN)-, -NHCO-, -NRCO-, -NHSO2-, -NRSO2-, -NHC(O)NH-, -NRC(O)NH-, -NHC(O)NR-, -NRC(O)NR or -SO2-; and where V is optionally substituted by 1-6 substitutes JV; R" is H or an optionally substituted group selected from C1-6aliphatic group, C3-10cycloaliphatic group, C6-10aryl, 5-10-member heteroaryl or 5-10-member heterocyclyl; or two R" groups on the same substitute or various substitutes together with atom (s) whereto each group R" is attached, form optionally substituted 3-8-member heterocyclyl; where each optionally substituted R" group is independently and optionally substituted by 1-6 substitutes JR; R is an optionally substituted group selected from C1-6aliphatic group and C6-10aryl where each group R is independently and optionally substituted by 1-4 substitutes JR; each Jv and JR are independently selected from halogen, L, - (Ln)-R', - (Ln)-N(R')2, -(Ln)-OR', C1-4haloalkyl, -(Ln)-CN, - (Ln)-OH, -CO2R', -CO2H or -COR'; or two Jv, JR groups on the same substitute or various substitutes together with atom (s) whereto each group JV and JR is attached, form a 5-7-member saturated, unsaturated or partially saturated ring; R' is H or C1-6aliphatic group; L is C1-6aliphatic group where up to three methylene units are substituted by -C(O)-; each n is independently equal to 0 or 1. Besides, an invention refers to of a pharmaceutical composition for ROCK or JAK kinase inhibition on the basis of the given compounds, to a method of ROCK or JAK kinase activity inhibition, and also to application of the compounds of formula I, for preparing a drug where Q, Z, R1, R2 and R3 are those as described in cl. 1 of the patent claim, effective as protein kinase inhibitors, especially JAK and ROCK families kinase inhibitors.

EFFECT: there are prepared and described new compounds which can find the application in medicine.

42 cl, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidines of general formula (I) or pharmaceutically acceptable salts thereof, having JANUS: JAK2, JAK3 protein kinase, protein kinase A (PKA), serine/threonine protein kinase ROCK inhibiting properties. The compounds can be used to treat such diseases as allergy, asthma, atopic dermatitis and others. In structural formula (I): R1 denotes H; R2 denotes H; Z1 denotes C1-6aliphatic group or C5-7cycloaliphatic group, optionally substituted with 0-1 groups Jz; if the bond between Z1 and C is a double bond, then Z1 can also denote =O or =C(R)2; Z2 denotes H; or C1-10halogenalkyl, -(Vn)-CN, (Vn)-(heterocyclyl), where the heterocyclyl is a 6-member ring containing a nitrogen atom or two oxygen atoms as heteroatoms, -(Vn)-(phenyl) or -(Vn)-(C3-10cycloaliphatic group), optionally substituted with 0-1 groups Jz; or Z1 and Z2 together with the carbon atom with which they are bonded form a ring Q; Z3 denotes H or C1-6alkyl, optionally substituted with 0-1 groups Jz; or Z1, Z2 and Z3 together with the carbon atom with which they are bonded form a 6-8-member saturated bicyclic ring Q; where if the bond between Z1 and C is a triple bond, then Z2 and Z3 are absent; if the bond between Z1 and C is a double or triple bond, then Z3 is absent or Z2 and Z3 are absent; Q denotes a 3-8-member saturated or partially saturated monocyclic ring containing 0-2 heteroatoms selected from nitrogen, oxygen or sulphur, where said Q is optionally and independently condensed with Q1; where said Q is optionally substituted with 0-4 groups JQ, where said Q is optionally substituted with 0-4 groups JQ. Values of other radicals are given in the claim.

EFFECT: high efficiency of using the compositions.

35 cl, 5 dwg, 5 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel conformationally stable compounds of general formula (I), which imitate the secondary structure of reverse-configuration regions of biologically active peptides and proteins which are reverse-configuration mimetics. The compounds can be used to inhibit or treat disorders modulated by Wnt-signalling pathway, such as cancer, especially colorectal cancer. The invention also relates to a library containing the disclosed compound. In general formula (I), A denotes -(C=O)-, B denotes -(CHR4)-, D denotes -(C=O)-, E denotes -(ZR6)-, G denotes -(XR7)-, Z denotes CH, X denotes a nitrogen atom, W denotes -(C=O)NH-, R1 denotes benzyl; R2 denotes a heterocyclylC1-6alkyl group, including a 9-member condensed bicyclic ring having 2-3 heteroatoms selected from nitrogen, oxygen or sulphur atoms; a substituted hetercyclylC1-6alkyl group, including a 9-member condensed bicyclic ring having 2-3 heteroatoms selected from nitrogen, oxygen or sulphur atoms, an the ring has 1-3 substitutes independently selected from a group comprising halogen, piperidinyl, morpholinyl, C2-6alkenyl, phenyl, hydroxyphenyl, C1-6alkoxycarbonyl, dialkylamino, hydroxypiperidinyl, C1-6alkyl, hydroxyC1-6alkylpiperazinyl, amino, piperidinyl carbonyl; heterocyclyl-C1-6alkyl group having a 9-member condensed bicyclic ring which has one or two nitrogen atoms; and other values given in the claim. R4 denotes a substituted benzyl, having a substitute selected from disodium phosphate, monosodium phosphate, phosphate; R6 denotes hydrogen; R7 denotes: C1-6alkyl; C1-6alkynyl; C2-6alkenyl; substituted benzyl, having one or more substitutes independently selected from halogen and C1-6alkyl.

EFFECT: high efficiency of the compounds.

8 cl, 34 dwg, 19 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing novel compounds of general formula , where NR1R2=NH2; NHAlk, where Alk=C1-C6, or cycloalkyl-C3-C6; NAlk2, where Alk=C1-C6, or cycloalkyl-C3-C6; N(CH2)n, where n=2, 3, 4, 5, 6; N(CH2CH2)2O; NHAr, where Ar=C6H5, C6H4R3, where R3=Alk(C1-C6), NO2, halide, which can be used as biologically active substances and intermediate products in synthesis of biologically active substances (anomalous nucleosides, nucleotides etc). Sodium salts of 5-NR1R2-tetrazolo[1,5-a]-1,3,5-triazin-7-ones are obtained via successive substitution of chlorine atoms in 2-NR1R2-4,6-dichloro-1,3,5-triazines with a hydroxy and azido group. The corresponding 2-NR1R2-4,6-dichloro-1,3,5-triazine reacts with aqueous sodium hydroxide solution followed by acidation and the obtained 4-NR1R2-6-chloro-(3H)-1,3,5-triazin-2-one is treated with sodium azide in an organic solvent such as acetone, acetonitrile, dimethylformamide or mixtures thereof.

EFFECT: obtaining sodium salts of 5-NR1R2-tetrazolo[1,5-a]-1,3,5-triazin-7-ones directly from 2-amino-4,6-dichloro-1,3,5-triazines without obtaining and use of bis- and mono-trinitromethyl-1,3,5-triazines.

1 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel derivatives of condensed pyrazole-, imidazole-, oxazole- and triazole pyrimidines, structural formulae of which are disclosed in the claims, as well as pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with cannabinoid receptor 1 (CB1) activity.

EFFECT: improved properties of compounds.

33 cl, 448 ex, 1 tbl

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 5,6-dihydro-4H-benzo[f]pyrrolo[ 1,2-α][1,4]diazepin-6-one 1, involving moulding a pyrrolodiazepine frame as a result of reduction of nitro-groups of N-(2,5-dioxoalkyl)-2-nitrobenzamides 4, in acetic acid in the presence of iron while carrying out the reaction until boiling and holding for 60 minutes at room temperature.

EFFECT: simultaneous formation of a pyrrole and a diazepine ring, and high output of end products owing to change in the sequence and conditions of the reaction.

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formulae Ia, Ic, Ig, Ik and pharmaceutically acceptable salts thereof, having activity towards cannabinoid 1 receptor. In formulae

, ,

, ,

R2 is selected from halogen, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, pyridinyl-N-oxide and phenyl; where the said pyrimidinyl, pyridinyl, pyridinyl-N-oxide, pyrazinyl and phenyl are optionally substituted with an amino group; R3 is selected from hydrogen, methylsulphonyl, methlsulphoxide and dimethylaminocarbonyl; R4 is selected from hydrogen, cyano, nitro, carbamimidoyl, tetrazolyl, aminosulphonyl, aminocarbonyl, methylsulphonylamino and methylsulphonyl; R6 is selected from hydrogen, hydroxyethylaminomethyl and methylsulphonylaminomethyl. The invention also relates to a pharmaceutical composition, methods of treating and preventing diseases mediated by the cannabinoid 1 receptor, and use of said compounds in preparing a medicinal agent used to treat such diseases.

EFFECT: improved properties of the derivatives.

12 cl, 1 tbl, 62 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutic industry, in particular to method of obtaining medication, possessing adaptogenic activity. Method obtaining medication, possessing adaptogenic activity, by extraction of milled natural raw material, which contains seeds of elettaria, rhizome of elecampane, rhizome of Zingiber oficinale, wood of Caragana jubata with 40% ethanol at room temperature with the following filtration, under defined conditions.

EFFECT: medication, obtained by method described above, has expressed adaptogenic activity.

8 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to dentistry, and namely to method of reducing increased vomiting reflex level of patient at dental appointment. Method of reducing increased vomiting reflex level of patient at dentist appointment, consists in the fact, that immediately before carrying out therapeutic manipulations, patient during 2-3 minutes rinses oral cavity with 20% alcohol tincture (1:10), obtained from collection of medicinal plants, taken in the following weight fractions: rhizome with roots of Rhaponticum carthamoides -2, rhizome of erect cinquefoil - 1, leaves of peppermint - 1.

EFFECT: method makes it possible to considerably reduce vomiting reflex level in carrying out dental manipulations.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: application of alpha-1-antitrypsin (AAT) for preparing a drug for treating chronic fatigue syndrome (CFS) is offered. It is shown: AAT inhibited intracellular elastase activity of mononuclear cells of peripheral blood of the CFS patients, prevented degradation RNAase L 83 kDa with formation of the overactive RNAase L 37 kDa form. After treating with the preparation AAT, elastase activity in the specified blood cells decreased from approximately 1459 U/mg to 134 U/mg; the patient showed obvious clinical improvements, decreased cognitive disorders cognitive infringements, has went back to work. Particularly, the invention refers to the application of plasma or other therapeutic forms containing alpha-1-antitrypsin sufficient for produce a dosage of alpha-1-antitrypsin equal to 6 mg or more per one kg of body weight with frequency 1 to 31 days.

EFFECT: higher clinical effectiveness.

4 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to neurology, and can be used for increasing a level of synaptic proteins in a nerve cell or a brain cell in a subject. That is ensured by introduction a combination of agents to the specified subject, namely omega-3 fatty acid and/or omega-6 fatty acid in a combination with uridine or choline salts.

EFFECT: versions of the method provide the increased level of synaptic proteins in the nerve cell, including the brain cell that can be used for correction of age-related memory disorders.

15 cl, 11 dwg, 7 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a preparation for drug hypersensitivity correction in integrated therapy of pulmonary tuberculosis. Application of biologically active substances with antimicrobial activity recovered from Pleurotus 1137 fungus mycelium (Russian National Collection of Industrial Microorganisms, F-819), as a preparation for drug hypersensitivity correction in integrated therapy of pulmonary tuberculosis.

EFFECT: biologically active substances recovered from fungus mycelium effectively reduce development of side reactions of antituberculous preparations.

2 cl, 17 tbl, 12 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and biotechnology and concerns a preparation of 4-hydroxy - 17R - methylincisterol affecting tissue exchange and exhibiting anticancer and hypolipidemic activities and a producer of a biologically active substance of sterol 4-hydroxy - 17R - methylincisterol derivative. Substance of the invention involves submerged Pleurotus ostreatus 1137 (Russian National Collection of Industrial Microorganisms, F-819) fungus cultivation followed by mycelium separation from a culture fluid and recovery from the mycelium by extraction in ethanol at acid value pH of a medium of low-molecular 100 to 500 Da biologically active substances and recovery of sterol 4-hydroxy - 17R - methylincisterol derivative with preset molecular weight, gross formula and structural formula by dichloromethane. The invention also concerns application of Pleurotus ostreatus 1137 (Russian National Collection of Industrial Microorganisms, F-819) strain as a producer of the biologically active substance of sterol 4 - hydroxy - 17R - methylincisterol derivative.

EFFECT: advantage of the invention consists in development of such preparation which is able to modulate manifestations of hypolipidemic activity along with anticancer activity.

3 cl, 7 tbl, 15 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to potentiating preparation for radiation therapy, which as effective component contains uracyl derivative, represented by formula (1) where R1 represents halogen atom or cyanogroup; and R2 represents (4-8)-member heterocyclic group, which has from 1 to 3 nitrogen atoms and optinally has as substituent C1-C4 alkyl group, iminogroup, hydroxyl group, hydroxymethyl group, methansulphonyloxy group or aminogroup; amidinothiogroup, in which hydrogen atom, bound to nitrogen atom, can be substituted by C1-C4 alkyl group; guanidinogroup, in which hydrogen atom, bound to nitrogen atom, can be substituted by C1-C4 alkyl group or cyanogroup; C1-C4 alkylamidinogroup; or 1-pyrrolidinylmethyl group or its pharmaceutically acceptable salt. Invention also relates to method of radiation therapy potentiation, and to method of cancer treatment, which include introduction of described above uracyl derivative of formula (1) to patient who needs it.

EFFECT: invention ensures reduction of negative effect of radiation therapy, reduction of radiotherapy dose and enhancement of therapeutic effect.

18 cl, 3 tbl, 1 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to ophthalmology, ophthalmic surgery, physiotherapy. In case of localization of inflammatory focus in orbit without involvement into the process of paraorbital areas hospitalisation of patient into ophthalmology department of hospital is carried out. Orbitotomy in one or more quadrants is performed. Traditional intensive therapy is carried out. In case of intraorbital complications second stage of treatment is carried out. 1% solution of nicotinic acid is introduced intravenously in dose 2 ml on the first day, with daily 0.5-1.0 ml increase on the following days until maximal therapeutic efficiency is achieved, after that, successively dose is daily reduced by 0.5-1.0 ml to initial dose. Additionally after each injection of nicotinic acid, intravenous drip infusion of 2% pentoxifylline 5 ml on physiological solution in dose 100-200 ml is carried out during 7-15 days. Parabulbarly dexason 0.4% in dose 0.5 ml is introduced. Intramuscularly introduced are lidase in dose 64 U, actovegin in dose 2 ml and proserin 0.05% in dose 1 ml daily during 10 days. Electrophoresis with 0.05% proserin is carried out alternately with 0.5% hydrocortosone emulsion endonasally in case of optic nerve neuritis and bath method - in case of affection of eye-moving muscles with course of 10-15 procedures. If inflammatory process spreads into orbit from anatomically adjacent regions hospitalisation into otolaryngology department or into department of maxillofacial surgery, or neurosurgery or septic department of hospital is carried out. Sanitation of primary focuses of purulent infection is carried out. Traditional intensive therapy, which includes antibacterial, detoxication, desensibilising, immunologic and vitamin therapy, is performed. In case of intraorbital complications second stage of treatment is carried out in ophthalmology department of hospital.

EFFECT: method ensures obtaining early functional and cosmetic effect, prevents spread of inflammatory process into skull cavity.

5 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: claimed is preparation for overcoming multidrug resistance, which presents hexapeptide of structural formula: lisyl-histidyl-glycyl-lisyl-histidyl-glycine. On the basis of claimed substance it is possible to create medications, possessing higher efficiency of overcoming multidrug resistance, enhanced by specificity of action with respect to transport proteins of multidrug resistance (MRP), enhanced harmlessness and not causing toxic reactions.

EFFECT: medications can be used for prevention and therapy of patients with phenomena of multidrug resistance.

4 cl, 7 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where X denotes S; R1 and R2 taken together with atoms to which they are bonded form a 5-member carbocycle, substituted with up to two substitutes selected from alkyl and CF3; R3 is selected from a group consisting of a hydrogen atom and C1-8-alkyl; R3a denotes a hydrogen atom; R4 denotes a hydrogen atom; R4a denotes a hydrogen atom; R5 denotes a hydrogen atom; R5a denotes a hydrogen atom; R6 denotes a hydrogen atom; R6a denotes a hydrogen atom; R7 denotes a hydrogen atom; or pharmaceutically acceptable salts thereof. The invention also relates to compounds of the given formula, compounds selected from the group, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which modulate serotonin receptor activity.

6 cl, 19 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to indole and indazole compounds of formula in which n equals a whole number from 1 to 3, m equals 0 or 1, A denotes phenyl, X denotes C or N, R1 denotes hydrogen, alkyl, -(CH2)rNR7R8, where r equals a whole number from 1 to 5, and R7 and R8 independently denote hydrogen, alkyl or alkylcarbonyl, or can together form an optionally alkyl-substituted alkylene chain, where optionally one methylene is substituted with a N atom, R2 denotes hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, denotes -(CH2)pCO2R7, -(CH2)pOR7, -(CH2)pNR7R8, -NHR10, -N(H)S(O)2R7, -NHC(O)R10, -(CH2)pS(O)2R7 or (CH2)p-heterocycle-R10, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, R10 denotes hydrogen, oxo, alkylsulphonyl, alkylcarbonyl, alkyloxycarbonyl, alkoxy, alkyl or heterocycle, R3 denotes hydrogen, cyano, halogen, alkyl or phenyl, or denoes -(CH2)n-heterocycle or -(CH2)n-aryl, where n equals a whole number from 0 to 3, provided that R3 denotes phenyl when X denotes C and m=0, R4 denotes -YR11, where Y denotes a direct bond or -(CR7R8)pY′-, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, Y′ is selected from a group consisting of -O-, -S-, -NR12-, -NR12C(O)-, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)q- and -S(O)qNR12-, where R12 denotes hydrogen, alkyl, aryl or heteroaryl, q equals a whole number from 0 to 2, R11 is selected from a group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and -(CH2)tB-R13, where t equals a whole number from 0 to 3, B denotes heterocycle, heteroaryl or aryl, R13 denotes hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulphonyl, R5 denotes hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, R6 denotes (CR7R8)p-Z-D-W-R14, where Z denotes a direct bond, or is selected from a group consisting of -C(O)-, -C(O)O, -C(O)NR12- and -S(O)y-, y equals a whole number from 1 or 2, D denotes a direct bond, or denotes cycloalkyl, heteroaryl or heterocycle, W denotes a direct bond, or denotes -NR -, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)y-, -S(O)yNR12- or -NR12S(O)y, wherein R14 denotes hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, R5 and R6 together denote an alkylene chain, provided that R6 denotes cycloalkyl or heterocyclyl when X denotes N, where the heteroaryl is a 5-6-member aromatic ring containing 1-2 heteroatoms selected from N, O and S, the heterocycle is a 3-8-member ring containing 1-3 heteroatoms selected from N, O and S, where the alkyl, alkoxy, aryl, cycloalky, heterocycle and heteroaryl can be optionally substituted, and the substitutes, one or more, are selected from a group consisting of hydroxy, halogen, nitrile, amino, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo, and pharmaceutically acceptable salts or stereoisomers thereof. The invention also relates to a composition, as well as a method of preparing said composition.

EFFECT: obtaining novel biologically active compounds for preventing or treating necrosis and necrosis-associated diseases.

40 cl, 162 ex, 2 tbl

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