Pyrasolbenzodiazepines as cdk2 inhibitors, synthesis intermediates and pharmaceutical composition containing the same

FIELD: organic chemistry, pharmaceutical compositions.

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

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

 

The present invention relates to new personendaten with the ability to inhibit cyclin-dependent kinase (CDK), especially CDK2. These compounds and their pharmaceutically acceptable salts and prodrugs of these compounds are anti-proliferative agents that may be used to treat or suspension of development of diseases associated with cell proliferation, primarily cancer. The invention relates also to pharmaceutical compositions containing such compounds, and to methods for treating and/or preventing cancer, especially to treat or stop the development of solid tumors. Preferred compounds according to the invention can be used to treat or stop the development of tumors of the breast, colon, lung or prostate cancer. The invention also relates to intermediate products, which can be used to obtain the above antiproliferative agents.

Uncontrolled cell proliferation is a hallmark of cancer. Cancer cells are usually characterized by a particular form of violation of genes that directly or indirectly regulate the cell division cycle.

Cyclin-dependent kinase (CDK) are enzymes that are crucial for the control cells is knogo cycle. These enzymes regulate the transitions between different phases of the cell cycle, for example the transition from phase G1to the S phase (the period of active DNA synthesis), or the transition from phase G2for phase Meters, in which there is active mitosis and cell division.

CDK consist of a catalytic CDK subunit and regulatory cyclenbuy subunit. Cyclonona subunit is the most important regulator of the activity of CDK, each CDK interacts with a specific subset of tsiklonov: for example, cyclin A (CDK1, CDK2). Different pairs kinase/cyclin regulate the passage through certain stages of the cell cycle.

Violation of the system of control of the cell cycle lead to the uncontrolled growth of cancer cells. There is an extensive literature devoted to the use of compounds capable of inhibiting CDK, as antiproliferative therapeutic agent.

The present invention relates to personendaten with the ability to inhibit the activity of one or more CDK, especially CDK2. Such compounds can be used for the treatment of cancer, especially solid tumors. In particular, the compounds of the present invention can preferably be used for the treatment or stop the development of tumors of the breast, colon, lung and prostate as the drive. The invention also relates to intermediate compounds that can be used in obtaining the above personendaten.

Compounds of the present invention have the formula I below

where

R1means hydrogen, -NO2, -CN, halogen, -OR5, -R6OR7, -COOR7, -CONR8R9, -NR10R11, -NHCOR12, -NHSO2R13or linear (ness.)alkyl, which is optionally substituted by a hydroxy-group and/or halogen;

R2and R4each independently of one another denotes hydrogen, halogen, -NO2, -CF3or linear (ness.)alkyl;

R3means hydrogen, cycloalkyl, aryl, heterocyclyl, heteroaryl, -COOR7, -CN, alkenyl, -CONR8R9, quinil or (ness.)alkyl, which is optionally substituted by a hydroxy-group, OR9, F and/or aryl;

R5means (ness.)alkyl, which is optionally substituted by halogen;

R6means (ness.)alkyl;

R7means hydrogen or (ness.)alkyl;

R8and R9each independently of one another denotes hydrogen or (ness.)alkyl, which is optionally substituted by a hydroxy-group and/or-NH2; alternatively, R8and R9may form a five - or six-membered heterocycle, which is optionally substituted by a hydroxy-group, -NH2and/or (ness.)by alkyl;

R10, R11and R12each independently of one another denotes hydrogen or (NISS. )alkyl;

R13means (ness.)alkyl, which is optionally substituted by halogen and/or-NR14R15; and

R14and R15each independently of one another denotes hydrogen or (ness.)alkyl, which is optionally substituted by halogen, or alternative-NR14R15means heterocyclyl.

In addition, the invention relates to prodrugs and pharmaceutically active metabolites of compounds of formula I and pharmaceutically acceptable salts of the aforementioned compounds.

In addition, the present invention relates to the use of compounds of the formula I, or prodrugs, and pharmaceutically active metabolites of compounds of formula I and pharmaceutically acceptable salts of the aforementioned compounds as medicines; and to pharmaceutical compositions comprising pharmaceutically effective amount of one or more of the above compounds or a pharmaceutically acceptable salt of the prodrug, and a pharmaceutically acceptable carrier or excipient.

The present invention is also directed to the use of compounds of formula I, prodrugs or pharmaceutically active metabolites of compounds of formula I or pharmaceutically acceptable salts of the aforementioned compounds in the production of p is eparate for the treatment of solid tumors, in particular tumors of the breast, colon, lung and prostate cancer, more particularly tumors of the breast and colon.

In the context of the present invention, the following terms will have the following values.

The term “aryl” means an aromatic group containing 6 to 10 carbon atoms and comprising 1 or 2 rings. Examples of aryl groups include phenyl and 1 - or 2-naphthyl.

The term “alkenyl” means a linear or branched substituted or unsubstituted aliphatic unsaturated hydrocarbon having 2-6, preferably 2-4, carbon atoms and containing a double bond. Typical alkeneamine groups include ethylene, propylene, isopropylene, butylene and the like. Preferred alkeneamine groups are linear.

The term “quinil” means a linear or branched substituted or unsubstituted aliphatic unsaturated hydrocarbon having 2-6, preferably 2-4 carbon atoms and containing a triple bond. Typical alkyline groups include acetylene group, and the like. Preferred alkyline groups are linear.

The term “cycloalkyl” means non-aromatic, partially or completely saturated cyclic aliphatic hydrocarbon group containing 3 to 8 atoms. Examples cycloalkyl groups included the t cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “effective amount” means an amount of at least one compound of formula I or its pharmaceutically acceptable salt, prodrug or metabolite that significantly inhibits proliferation of tumor cells, including lines of human tumor cells.

The term “halogen” means fluorine, chlorine, bromine or iodine. The preferred Halogens are fluorine and chlorine.

The term “heteroaryl” group means an aromatic group having 5 to 10 atoms, one or 2 of the ring and containing one or more heteroatoms. Examples of heteroaryl groups are 2-, 3 - or 4-pyridyl, tetrazolyl, oxadiazolyl, pyrazinyl, hinely, pyrrolyl and imidazolyl.

The term “heteroatom” means an atom selected from N, O and S.

The term “heterocyclyl” means 3-10-membered non-aromatic, partially or fully saturated hydrocarbon group, such as tetrahydropyranyl, which contains one or two rings and at least one heteroatom.

The term “IC50” refers to the concentration of specific pyrazolopyridazine required to inhibit 50% of specific measured activity. The value of the IC50can be measured, among other things, as described in example 4 below.

The term “(ness.)alkyl” means linear or branched, substituted the first or unsubstituted, saturated aliphatic hydrocarbon containing 1-6, preferably 1-4, carbon atoms. Typical (ness.)alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, 2-butyl, pentyl, hexyl and the like.

The term “pharmaceutically acceptable salt” refers to conventional acid-additive salts or salts of accession grounds that retains the biological effectiveness and properties of the compounds of formula I and derived from acceptable non-toxic organic or inorganic acids or organic or inorganic bases. An example of an acid additive salts include salts derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and salts derived from organic acids, such as n-toluensulfonate, salicylic acid, methanesulfonate, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like. Example salts of joining bases include salts derived from hydroxides of ammonium, potassium, sodium and Quaternary ammonium compounds, such as, for example, a hydroxide of Tetramethylammonium.

The term “pharmaceutically acceptable”such as pharmaceutically receiving the controlled media, filler, prodrug, etc., means pharmacologically acceptable and practically non-toxic to the subject, which introduces a separate connection.

The term “pharmaceutically active metabolite” means a product of the metabolism of the compounds of formula I, which is pharmaceutically acceptable and effective.

The term “prodrug” refers to a connection that under physiological conditions or by solvolysis can turn into any of the compounds of formula I or pharmaceutically acceptable salt of the compounds of formula I. the Prodrug may be inactive when administered to a subject, but in vivo to become active compound of formula I.

The term “substituted”as in substituted alkyl, means that the substitution can be carried on one or more of the provisions and that the substituents in each position substitutions are selected independently from each other from certain options, if not specified otherwise.

Connection

In one variant embodiment of the present invention is directed to compounds having the formula:

and prodrugs and pharmaceutically active metabolites of compounds of formula I and pharmaceutically acceptable salts of the above compounds, where R1and R15have the above values.

In a preferred embodiment, voploscheni the compounds of the formula I R 1means hydrogen, -NO2, -CN, -CONH2, halogen or unsubstituted (ness.)alkyl. Preferred (ness.)alkilani are methyl and ethyl. More preferably R1means-NO2, -CN or-CONH2. Preferably R1is in position 7 or 8.

In another preferred variant of embodiment of the compounds of the formula I R2is in position 2' and means a hydrogen or halogen.

In another preferred variant of embodiment of the compounds of the formula I R3means unsubstituted (ness.)alkyl, hydroxy(ness.)alkyl, cycloalkyl, heterocyclyl or heteroaryl. Preferred (ness.)alkyl groups are methyl, ethyl and hydroxymethyl. Preferred cycloalkyl groups are unsubstituted group3-C5.

In another preferred variant of embodiment of the compounds of the formula I R4is in position 4' and means hydrogen or halogen, most preferably R4means hydrogen.

In another preferred variant of embodiment of the compounds of the formula I R5and R6mean independently from each other methyl, ethyl, each of which optionally may be substituted by halogen. More preferably R5means trifluoromethyl.

In another preferred variant of embodiment of the compounds of the formula I R7means hydrogen, methyl ility.

In another preferred variant of embodiment of the compounds of the formula I R8and R9means each independently from each other hydrogen, methyl, ethyl or hydroxyethyl. When R8and R9form a heterocycle, preferred heterocyclic groups are 6-membered unsubstituted group, most preferably include two heteroatoms. Preferred heteroatoms are selected from O and N.

In another preferred variant of embodiment of the compounds of the formula I R10, R11and R12means each independently from each other hydrogen, methyl or ethyl.

In another preferred variant of embodiment of the compounds of the formula I R13means (ness.)alkyl, which optionally may be substituted with hydrogen, most preferably R13means methyl, ethyl or trifluoromethyl.

In another preferred variant of embodiment of the compounds of the formula I R14and R15means each independently from each other hydrogen, methyl, ethyl or a heterocycle. Preferred heterocycles are 3-7-membered rings, which include at least one nitrogen.

The following intermediate derivatives are also examples of more preferred compounds of the present invention:

where

R1, R2and R4 have the above meanings;

and

where in each of the immediately preceding formulas, each of R1, R2, R3and R4has the meanings given in the description above. These intermediate derivatives applicable to the synthesis of compounds of formula I.

Compounds disclosed in the description and protected in the above formulae, may have tautomerism or structural isomerism. It is assumed that the invention encompasses any tautomeric or isomeric structural form of these compounds or a mixture of these forms and is not limited to any one tautomeric or structural isomeric form, used when writing formulas.

The synthesis of compounds of formula I

Compounds according to the invention can be obtained by methods known in this field. Appropriate methods of synthesis of these compounds are given in the examples. As a rule, these compounds can be obtained according to the following schema.

Scheme 1

R3=H

a) a reagent Losson (known reaction for most substitutions);

b) reaction with Me2N-CH(OEt)2;

C) reaction with hydrazine.

Connection 1 or is commercially available, or synthetic is irout ways, well-known specialists.

Scheme 2

R3does not mean H

a) a reagent Losson (known reaction for most substitutions);

d) reaction with R3-CHO in the presence of a base, preferably piperidine;

C) reaction with hydrazine;

d) oxidation of dihydropyrazolo in pyrazole (in the presence of air in DMSO, from CT to 150° or in the presence of air and substrate (Cs2CO3/DMF).

Scheme 3

An alternative scheme, when R3does not mean N

a) a reagent Losson (known reaction for most substitutions);

e) reaction with R3-CHO in the presence of a base, preferably of diazabicyclo or 2,2,6,6-tetramethylpiperidine;

g) dehydration by treating it with a weak acid (pyridinium salt of n-toluenesulfonic acid, pyridinium salt of acetic acid, etc.);

C) reaction with hydrazine;

d) oxidation of dihydropyrazolo in pyrazole (in the presence of air in DMSO, from CT to 150° or in the presence of air and substrate (Cs2CO3/DMF).

Scheme 4

Transformation of functional groups R1or R3

where R1'can have any of the above values for R1and similarly R3'can be any of the above values is s for R 3.

Some substitutions can be made by chemical modification of existing functional groups using known methods, as described above in scheme 4. For example, if the required R1=NH2such substitution may be carried out by the recovery of the corresponding nitro. Similarly, if the required R1=Other' (where R' means-COR12, -SO2R13or-R10R11), this substitution can be accomplished by interaction of the corresponding compounds in which R1=NH2with acid chloride or acid anhydride. If the required R1=CONRR ' where R means hydrogen or (ness.)alkyl, and R" means (ness.)alkyl), this substitution can be accomplished by interaction of the corresponding compounds in which R1is iodine, with carbon monoxide and a primary or secondary amine in the presence of palladium catalyst.

In addition, if R3in the original substance means-CO2Et can be used standard chemical modification to obtain compounds containing the following relevant groups R3:

-CH2HE (repair); -Cho (partial recovery); -CH2NMe2(reductive amination of aldehyde); -CH2OMe (alkylation of alcohol); -CH=CH2(rafinirovaniyu aldehyde); -CONRR' (where R is H or (ness.)alkyl and R ' denotes H or (ness.)alkyl, aminals with the appropriate amine HNRR', in which R means H or (ness.)alkyl and R ' denotes H or (ness.)alkyl); -CONHNHR (where R is H, (ness.)alkyl or aryl, hydrazines - reaction with hydrazine); -CN (dehydration of amide-CONH2).

In previous schemes compound 1, or is commercially available, for example from the company Sigma, or can be easily synthesized by methods known in the art. Thus, compound 2 is obtained from the corresponding lactam (compound 1) according to the method Sternbach et al., J. Org. Chem., 29:231 (1964) or by the interaction with the reagent Losson.

Composition/formulation

In an alternative embodiment, the present invention relates to pharmaceutical compositions comprising at least one compound of formula I or its prodrug or pharmaceutically acceptable salt of the compounds of formula I or a prodrug of such a compound.

Such pharmaceutical compositions can be administered orally, for example in the form of tablets, filmtabletten, pills, gelatin capsules with hard or soft coating, solutions, emulsions or suspensions. They can be administered rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection.

The pharmaceutical compositions of the present invention, including the compounds of formula I, prodrugs such connection is on or their salts, can be obtained well-known in this field method, for example using conventional mixing processes, calculatoare, dissolving, granulating, emulsifying, inclusion, drazhirovanija or lyophilization. Such pharmaceutical compositions can be prepared with therapeutically inert, inorganic or organic carriers. As such carriers for tablets, filmtabletten, tablets and gelatin capsules with a hard coating can be applied lactose, corn starch or its derivatives, talc, stearic acid or its salts. Acceptable carriers for gelatin capsules, soft coated include vegetable oils, waxes and fats. Depending on the nature of the active substance in the case of gelatin capsules, soft coated usually do not require any medium. Suitable carriers for the manufacture of solutions and syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection solutions are water, alcohols, polyols, glycerine, vegetable oil, phospholipids and surfactants. Suitable carriers for suppositories are natural or hydrogenated oils, waxes, fats and semi-liquid polyols.

Pharmaceutical compositions may also contain preservatives, solubilizing agents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffers, agents for coating or antioxidants. They can also contain other possessing therapeutic activity of substances, including additional active ingredients other than the compounds of formula I.

Doses

As indicated above, the compounds of formula I, their prodrugs and their salts, and compositions containing these compounds, can be used to treat or suspension of development of diseases associated with cell proliferation, first of all oncological diseases. These compounds and compositions containing these compounds, preferably can be used to treat or suspension of the development of solid tumors, such as tumors of the breast and colon.

In the context of the present invention the term “therapeutically effective amount of the compound” refers to the amount of compound that is effective in preventing, alleviating or improving the symptoms of the disease or increases the survival rate of the patient undergoing treatment. Determination of therapeutically effective amount is within the competence of the specialist in this field.

Therapeutically effective amount or dose of the compounds is of formula I can vary within wide limits, and they must be selected in accordance with the individual requirements in each particular case. In General, for oral or parenteral administration to adult humans weighing approximately 70 kg can be used daily dose from about 10 mg to about 10000 mg, preferably from about 200 mg to about 1000 mg, although the upper limit may be exceeded when indicated. The daily dose can be administered as a single dose or in divided doses, or in the case of parenteral administration, it may be given by continuous infusion.

Example 1: pyrazoles obtained in accordance with scheme 1

Step a: reaction of lactam (compound 1) with a reagent of Losona education thiolactam (connection 2)

1.1 Connection A1: R1=H, R2=F, R4=H

To a solution of 5,085 g (20 mmol) of lactam 1 (where R1=H, R2=F and R4=H) in 50 ml of dimethoxyethane at 75° With added 8,9 g (22 mmole) of reagent Losson (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide; B.S. Pedersen, Schheibye S., Nilsson N.H., Lawesson, S.-O., Bull. Soc. Chim. Belg., 1978, 87:223). The mixture was stirred for 30 minutes, cooled and then poured into 10% aqueous sodium bicarbonate solution. The aqueous mixture was extracted with methylene chloride, the extracts washed with water, dried over anhydrous sodium sulfate, filtered and kontsentrirovaniya reduced pressure. The residue was recrystallize from a mixture of methylene chloride-methanol, obtaining 4.0 g of compound A1 (thiolactam 2).

1H-NMR (DMSO-d6, 300 MHz): 12,56 (s, 1H, NH), 7,10-the 7.65 (m, 8H), 4,59 (s, 2H).

1.2 Connection A2: R1=F, R2=R4=H

Compound A2 was obtained in the same way as described above for compound A1.1H-NMR (DMSO-d6, 300 MHz): 12,50 (s, 1H, NH), 7,37-7,56 (m, 7H), 7,06 (dd, J=3,9 Hz, 1H), 4,60 (ush. s, 2H).

Step b: reaction of thiolactam 2 with DMF acetal with education dimethylaminomethylene derived 3

1.3 Connection A3: R1=CL, R2=Cl, R4=H

The solution 0,999 g (3.1 mmole) of thiolactam 2 (R1=Cl, R2=Cl, R4=H), 10 ml of anhydrous tetrahydrofuran and 10 ml of diethylacetal of dimethylformamide was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure, obtaining the remainder of the red-orange color. Crystallization from a mixture of hexane-ethyl acetate gave 0,716 g of compound A3 (derived 3, where R1=Cl, R2=Cl, R4=H) as a red solid, tPL196-198° C.

1H-NMR (DMSO-d6, 400 MHz): of 10.21 (s, 1H), to 7.84 (s, 1H), 7,43-7,56 (m, 4H), 7,32 (dd, J=3,9 Hz, 1H), 7,00 (d, J=9 Hz, 1H), 6,60 (d, J=3 Hz, 1H), 3.27 to (s, 6H).

Stage: the transformation dimethylaminomethylene derivative 3 in the pyrazole 4

1.4 Connection A4: R1=Cl, R2=Cl, R3=R4=H

5-(2-chlorophenyl)-7-chloropyrazole[3,4][1,4]be zodiazepine.

To a solution of 0,265 g (of 0.71 mmole) in 10 ml of anhydrous methylene chloride was added approximately 39,8 ál (1,27 mmole) of anhydrous hydrazine. The mixture was stirred in an argon atmosphere for 85 minutes, then dissolved in methylene chloride and washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, getting 0,219 g of compound A4 (pyrazole 4, where R1=Cl, R2=Cl, R3=R4=H) as a yellowish brown solid. An analytical sample was filtered through a low layer of silica gel, elwira with ethyl acetate, and then recrystallize from ethyl acetate, tPL>300° C.

1H-NMR (DMSO-d6, 400 MHz): 12,07 (s, 1H, NH), 8,03 (s, 1H, NH), 7,58 (s, 1H), between 7.4 to 7.5 (m, 4H), 7,17 (dd, J=2,9 Hz, 1H), 6,79 (d, J=9 Hz, 1H), and 6.25 (s, 1H).

The following pyrazoles (compound 4) was obtained in accordance with scheme 1 and as described above in steps a-C.

1.5 Connection A5: R1=NO2, R2=Cl, R3=H, R4=H

5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

1H-NMR (AMCO-d6, 300 MHz): 9,16 (s, 1H, NH), of 7.90 (dd, J=2,8 Hz, 1H), 7,4-7,6 (m, 5H), was 7.08 (d, J=2 Hz, 1H), 6.75 in (d, J=8 Hz, 1H).

1.6 Connection A6: R1=Cl, R2=H, R3=H, R4=H

5-phenyl-7-chloropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 200 MHz): of 7.97 (s, 1H, NH), a 7.62 (s, 1 H), 7,35-of 7.60 (m, 5H), 7,29 (dd, J=2,9 Hz, 1H), 6,93 (d, J=9 Hz, 1H), 6,60 (d, J=2 Hz, 1H).

1.7 Connection A7: R1 =Cl, R2=F, R3=H, R4=H

5-(2-forfinal)-7-chloropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): 12,10 (s, 1H, NH), 8,01 (s, 1H), 7,60 (s, 1H), 7,5 (m, 2H), 7.18 in-7,33 (m, 3H), 6,83 (d, J=8 Hz, 1H), 6,47 (s, 1H).

1.8 Connection A8: R1=Cl, R2=Cl, R3=H, R4=Cl

5-(2,4-dichlorophenyl)-7-chloropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): 12,09 (s, 1H, NH), with 8.05 (s, 1H, NH), 7,68 (s, 1H), 7,56 (s, 1H), 7,52 (d, J=10 Hz, 1H), of 7.48 (d, J=10 Hz, 1H), 7,19 (dd, J=2, 9 Hz, 1H), 6,78 (d, J=9 Hz, 1H), 6,27 (d, J=2 Hz, 1H).

1.9 Compound A9: R1=H, R2=H, R3=H, R4=H

5-phenylpyrazol[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 12,04 (s, 1H), to 7.77 (s, 1H), 7,58 (s, 1H), 7,32-7,47 (m, 5H), 7,22 (dt, J=2, 8 Hz, 1H), 6,92 (d, J=8 Hz, 1H), 6,76 (d, J=8 Hz, 1H), to 6.67 (dd, J=1, 8 Hz, 1H).

1.10 Connection a10: R1=H, R2=F, R3=H, R4=H

5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 200 MHz): 12.00 (s, 1H, NH), 7,79 (s, 1H), 7,32-7,56 (m, 3H), 7,00-to 7.32 (m, 3H), 6,78 (d, J=6 Hz. 1H), 6.48 in (d, J=6 Hz, 1H).

1.11 Connection A11: R1=F, R2=F, R3=H, R4=H

5-(2-forfinal)-7-ftorurazila[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 200 MHz): 12,10 (s, 1H, NH), a 7.85 (s, 1H), and 7.4 to 7.7 (m, 3H), 7.18 in-7,39 (m, 2H), 7,05 (m, 1H), 6,86 (m, 1H), 6,26 (ush. d, J=8 Hz, 1H).

1.12 Connection A12: R1=CH3Oh, R2=Cl, R3=H, R4=H

5-(2-chlorophenyl)-7-methoxypyrazine[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 200MHz): 12,00 (s, 1H, NH), 7,35-of 7.60 (m, 5H), for 6.81 (d, J=8 Hz, 1H), 6.75 in (d, J=8 Hz, 1H), of 5.89 (s, 1H), 3.46 in (s, 3H).

1.13 Connection A13: R1=NO2, R2=F, R3=H, R4=H

5-(2-forfinal)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 12,14 (s, 1H, NH), 9,06 (s, 1H, NH), 7,89 (dd, J=2,9 Hz, 1H), 7,55 (s, 1H), between 7.4 to 7.5 (m, 2H), 6,76 (d, J=9 Hz, 1H).

1.14 Connection A14: R1=CH3SO2, R2=H, R3=H, R4=H

5-phenyl-7-methansulfonate[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): 12,18 (s, 1H, NH), 8,54 (s, 1 H, NH), 7,72 (dd, J=2,9 Hz, 1H), to 7.64 (s, 1H), 7,43 (m, 5H), 7,14 (d, J=2 Hz, 1H), 7,06 (d, J=9 Hz, 1H), 3,01 (s, 3H).

1.15 Connection A15: R1=CN, R2=F, R3=H, R4=H

5-(2-forfinal)-7-cyanopyridine[3,3][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 12,16 (s, 1H, NH), 8,63 (s, 1H, NH), to 7.59 (s, 1H), 7,4-7,58 (m, 3H), 7,2-7,37 (m, 2H), PC 6.82 (dd, J=2,8 Hz, 1H), 6,78 (s, 1H).

1.16 Connection A16: R1=NO2, R2=H, R3=H, R4=H

5-phenyl-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): 12,19 (s, 1H, NH), 8,96 (s, 1H, NH), 8,03 (dd, J=2, 9 Hz, 1H), 7.62mm (s, 1H), 7,35-7,5 (m, 6N), 6,94 (d, J=9 Hz, 1H).

1.17 Connection A17: R1=NO2, R2=CF3, R3=H, R4=H

5-(2-triptoreline)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 12,12 (s, 1H, NH), 9,18 (s, 1H, NH), 7,45 to 7.9 (m, 6H), 7,00 (s, 1H), of 6.71 (d, J=9 Hz, 1H).

1.18 Connection A18: R1=CO2CH3, R2=H, R3=H, R4=H

5-phenyl-7-carbomethoxybiphenyl[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 12,15 (s, 1H, NH), 8,42 (s, 1H, NH), 7,78 (dd, J=2,9 Hz, 1H), 7.62mm (s, 1H), 7,35-7,45 (m, 5H), 7,29 (d, J=2 Hz, 1H), 6,93 (d, J=9 Hz, 1H), 3,66 (s, 3H).

1.19 Connection A19: R1=I, R2=F, R3=H, R4=H

5-(2-forfinal)-7-Moderato[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 12,09 (s, 1H, NH), to 7.99 (s, 1H, NH), 7,58 (s, 1H), 7,4-of 7.55 (m, 3H), 7,19-7,35 (m, 2H), 6,76 (s, 1H), 6,62 (d, J=8 Hz, 1H).

1.20 Connection A20: R1=CO2Et, R2=F, R3=H, R4=H

5-(2-forfinal)-7-carbomethoxybiphenyl[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 12,08 (s, 1H, NH), and 8.50 (s, 1H, NH), a 7.62 (d, J=8 Hz, 1H), EUR 7.57 (s, 1H), between 7.4 to 7.5 (m, 2H), 7.18 in-7,35 (m, 2H), 7,14 (s, 1H), 6,80 (d, J=8 Hz, 1H), 4,15 (q, J=6 Hz, 2H), 1,17 (t, J=6 Hz, 3H).

1.21 Connection A21: R1=H, R2=Cl, R3=H, R4=H

5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,95 (s, 1H), 8,40 (s, 1H), to 7.84 (s, 1H), 7,53 (s, 1H), 7,38-of 7.48 (m, 4H), to 7.09 (t, J=8 Hz, 1H), 6,78 (t, J=8 Hz, 1H), 6,61 (t, J=8 Hz, 1H), 6,34 (d, J=8 Hz, 1H).

Example 2: transformation of thiolactam 2 substituted pyrazole 7 in accordance with schemes 2 and 3

2.1 Connection B1: R1=NO2, R2=Cl, R3=2-pyrrolyl, R4=H (scheme 2)

3-(2-pyrrolyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

A mixture of 0.995 g (3 mmole) of thiolactam 2 (R1=NO2, R2=Cl, R3=2-pyrrolyl, R4=H), 0,571 g ( mmol) of pyrrole-2-carboxaldehyde, 0,383 g (4.5 mmole) of piperidine (Aldrich) and 10 ml of dimethoxyethane was stirred under argon for 2 hours. The mixture was dissolved in ethyl acetate and washed successively with 0.1 M sulfuric acid, water, then saturated salt solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The corresponding olefin 5 were isolated by chromatography on silica gel (elution with hexane/ethyl acetate (1:1)) as a red solid (0,309 g) and directly used in the next step. Olefin 5 (0,309 g) was dissolved in 6 ml of dimethyl sulfoxide and introduced into a reaction from 72.5 mg (2.2 mmole) of hydrazine in the atmosphere of argon. After 20 min the mixture was dissolved in ethyl acetate and washed successively with water and saturated salt solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, obtaining a mixture of dihydropyrazolo 6 (0,296 g). The mixture of compounds 6 was dissolved in dimethyl sulfoxide and heated in the presence of air at 130°C for 2 hours, cooled, dissolved in ethyl acetate and washed successively with water and then a saturated solution of salt. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Product 7 (compound B1) was purified by chromatography on silica gel (elution by the mixture hexane-ethyl acetate, 25/75).

ÈA; 1H-NMR (DMSO-d6, 300 MHz): 12,12 (s, 1H, NH), accounted for 10.39 (s, 1H, NH), 9,07 (s, 1H, NH), of 7.96 (dd, J=2, 8 Hz, 1H), 7,45-the 7.65 (m, 4H), to 7.15 (d, J=2 Hz, 1H), 6.90 to (s, 1H), 6,79 (d, J=8 Hz, 1H), 6.48 in (s, 1H), 6,12 (d, J=2 Hz, 1H).

2.2 Connection B2: R1=NO2, R2=Cl, R3=CO2Et, R4=H (scheme 3)

3 carboethoxy-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

A mixture of 5.0 g (15,1 mmole) of thiolactam 2 (R1=NO2, R2=Cl), 6 ml of 50% solution of ethyl ether glyoxalase acid in toluene, and 4.5 ml (31 mmol) of diazabicyclo and 100 ml of dimethoxyethane was stirred in an argon atmosphere for 30 minutes at room temperature. The mixture was acidified 0.005 M sulfuric acid was extracted with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Alderny adduct 8 was obtained as a mixture of diastereoisomers (5.6 g) using chromatography on silica gel (elution by the mixture hexane-ethyl acetate 60/40).

A mixture of 4.7 g (10.8 mmole) Algologie adduct 8, obtained above, 100 ml of pyridine and 6.9 ml (54,4 mmole) of trimethylchlorosilane was stirred for 10 minutes at room temperature and then was heated at 120° C for 1.5 hours. The mixture was cooled, dissolved in 1 l of ethyl acetate and washed successively with water and saturated salt solution, the organic layer was dried over anhydrous sodium sulfate. After filtration and is of pariwana volatiles under reduced pressure the crude residue was filtered through a layer of silica gel, elwira a mixture of hexane-ethyl acetate (1:1), was obtained 4.3 g of olefin 5.

A solution of 4.3 g of olefin 5, obtained above, in 210 ml of dichloromethane was mixed with 0.68 ml (21.6 mmole) of anhydrous hydrazine in 30 minutes. The mixture is then distributed between water and dichloromethane, the aqueous phase was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue, which contained a mixture of dihydropyrazolo 6, was dissolved in 50 ml of dimethylsulfoxide and heated at 130° in the presence of air for 3 hours. The reaction mixture was cooled, dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was isolated by chromatography on silica gel, elwira a mixture of hexane-ethyl acetate (40/60), received 0,580 g of compound B2 (R1=NO2, R2=Cl, R3=CO2Et2, R4=H).

1H-NMR (DMSO-d6, 400 MHz): 13,33 (s, 1H), 9.15, with (s, 1H), 8,02 (dd, J=2, 9 Hz, 1H), 7,46-of 7.55 (m, 4H), 7,18 (d, J=2 Hz, 1H), 6.89 in (d, J=9 Hz, 1 H), 4,25 (q, J=7 Hz, 2H), 1.27mm (t, J=7 Hz, 3H).

The following pyrazoles (compound 7) was obtained in accordance with scheme 2, or 3, as described above.

2.3 Connection B3: R1=NO2, R2=Cl, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]be zodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,85 (s, 1H, NH), 9,04 (s, 1H, NH), 7,83 (dd, J=2,9 Hz, 1H), 7,39-7,52 (m, 4H), 7,05 (d, J=2 Hz, 1H), 6,69 (d, J=9 Hz, 1H), up to 1.98 (s, 3H).

2.4 Connection B4: R1=NO2, R2=Cl, R3=CH2CH3, R4=H (scheme 2)

3-ethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,91 (s, 1H, NH), 9,05 (s, 1H, NH), a 7.85 (dd, J=2,8 Hz, 1H), 7,35-7,58 (m, 4H),? 7.04 baby mortality (d, J=2 Hz, 1H), of 6.71 (d, J=8 Hz, 1H), 2,41 (q, J=7 Hz, 2H), 1.06 a (t, J=7 Hz, 3H).

2.5 Connection B5: R1=NO2, R2=Cl, R3=CH2CH2Ph, R4=H (scheme 2)

3-(2-phenylethyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 200 MHz): 11,95 (s, 1H, NH), 9,05 (s, 1H, NH), of 7.82 (dd, J=2,8 Hz, 1H), 7,05-of 7.60 (m, 10H), 6,70 (d, J=8 Hz, 1H), 2,82 (m, 2H), 2,64 (m, 2H).

2.6 Connection B6: R2=NO2, R2=Cl, R3=i-Pr, R4=H (scheme 2)

3-(1-methylethyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,90 (s, 1H, NH), of 9.02 (s, 1H, NH), to 7.84 (dd, J=2, 9 Hz, 1H), 7,35-of 7.55 (m, 4H),? 7.04 baby mortality (d, J=2 Hz, 1H), 6,74 (d, J=9 Hz, 1H), 2,86 (sept, J=9 Hz, 1H), 1,14 (d, J=9 Hz, 6N).

2.7 Connection B7: R1=CN, R2=F, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carbonitrile.

1H-NMR (DMSO-d6, 300 MHz): a 12.05 (s, 1H, NH), 8,55 (s, 1H, NH), was 7.45 (m, 3H), 7,25 (m, 2H), 6,78 (d, J=8 Hz, 1H), of 6.71 (s, 1H), 2,03 (s, 3H).

2.8 Connection G8: R1=NO2, R2=Cl, R3 =CH2Ph, R4=H (scheme 2)

3-(phenylmethyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 12,08 (s, 1H, NH), remaining 9.08 (s, 1H), a 7.85 (d, J=9 Hz, 1H), 7,40-7,56 (m, 4H), 7,16-7,34 (m, 5H), 7,06 (ush. s, 1 H), of 6.71 (d, J=9 Hz, 1H), 3,71 (s, 2H).

2.9 Connection b: R1=CO2Et, R2=F, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-forfinal)-7-carbomethoxybiphenyl[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): Rl=CO2Et, R2=F, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-forfinal)-7-carbomethoxybiphenyl[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,81 (s, 1H), of 8.37 (s, 1H), to 7.59 (dd, J=2,9 Hz, 1H), 7,39-7,51 (m, 2H), 7,16-7,31 (m, 2H), to 7.09 (s, 1H), 6,74 (d, J=9 Hz, 1H), 4,08 (q, J=7 Hz, 2H), 2,04 (s, 3H), of 1.12 (t, J=7 Hz, 3H).

2.10 Connection ± 10: R1=NO2, R2=Cl, R3=5-(4-Me)pyrazolyl, R4=H (scheme 2)

3-(4-methylpyrazole-5-yl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): to 12.58 (s, 1H), 9,26 (s, 1H), 8,75 (ush. s, 1H), 7,95 (d, J=8 Hz, 1H), 7,42-to 7.6 (m, 5H), 7,12 (s, 1H), for 6.81 (d, J=8 Hz, 1H), 2,32 (s, 3H).

2.11 Connection b: R1=NO2, R2=Cl, R3=CH2-iPr, R4=H (scheme 2)

3-(2-methylpropyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): 11,91 (s, 1H), 9,06 (s, 1H), 7,87 (dd, J=2,9 Hz, 1H), 7,4-7,56 (m, 4H), was 7.08 (d, J=2 Hz, 1H), 6,74 (d, J=9 Hz, 1H), 2,28 (d, J=7 Hz, 2H), 1,89 (d, J=7 Hz, 1H), from 0.88 (d, J=7 G is, 6N).

2.12 Connection ± 12: R1=NO2, R2=Cl, R3=CF3, R4=H (scheme 3)

3-trifluoromethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (CDCl3+DMSO-d6, 300 MHz): 7,98 (dd, J=2,9 Hz, 1H), 7,2-7,6 (m, 6H), 7,02 (ush. s, 1H), 6,62 (d, J=9 Hz, 1H).

2.13 Connection B: R1=NO2, R2=Cl, R3=1-thiazolyl, R4=H (scheme 3)

3-(1-triazolyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 13,08 (s, 1H), of 9.21 (s, 1H), 7,88-a 7.92 (m, 2H), to 7.84 (d, J=3 Hz, 1H), 7,42 to 7.62 (m, 4H), 7,12 (d, J=2 Hz, 1H), 6,79 (d, J=8 Hz, 1H).

2.14 Connection B: R1=NO2, R2=Cl, R3=4-imidazolyl, R4=H (scheme 2)

3-(4-imidazolyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): of 12.33 (s, 1H), 12,29 (s, 1H), 9,07 (s, 1H), of 7.90 (dd, J=2, 9 Hz, 1H), 7,76 (s, 1H), 7,44-7,63 (m, 4H), 7,35 (s, 1H), 7,11 (d, J=2 Hz, 1H), 6,78 (d, J=9 Hz, 1H).

2.15 Connection ± 15: R1=NO2, R2=Cl, R3=2-pyrazolyl, R4=H (scheme 2)

3-(2-pyrazolyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 13,11 (s, 1H), 12,48 (s, 1H), 9,12 (s, 1H), to 7.93 (d, J=9 Hz, 1H), 7,76 (s, 1H), 7,39-of 7.60 (m, 4H), 7,11 (s, 1H), 6,78 (d, J=9 Hz, 1H), 6,59 (s, 1H).

2.16 Connection B16: R1=NO2, R2=Cl, R3=3-pyrazolyl, R4=H (scheme 2)

3-(3-pyrazolyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6300 MHz): to 13.09 (s, 1H), 12,31 (s, 1H), 9,13 (s, 1H), 7,80-with 8.05 (m, 4H), 7,40 to 7.62 (m, 3H), 7,13 (s, 1H), 6,78 (d, J=9 Hz, 1H).

2.17 Connection B: R1=NO2, R2=Cl, R3=CH(Me)CH2Me, R4=H (scheme 2)

3-(1-methylpropyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,90 (s, 1H), 9,04 (s, 1H), a 7.85 (dd, J=2,9 Hz, 1H), 7,38-of 7.55 (m, 4H), 7,05 (d, J=2 Hz, 1H), 6,72 (d, J=9 Hz, 1H), 2,65 (m, 1H), of 1.52 (m, 2H), 1,13 (d, J=7 Hz, 3H), of 0.79 (t, J=8 Hz, 3H).

2.18 Connection B18: R1=MeO, R2=Cl, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-chlorophenyl)-7-methoxypyrazine[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): of 11.69 (s, 1H), 7,34-to 7.50 (m, 5H), 6,77 (dd, J=2,9 Hz, 1H), 6,72 (d, J=9 Hz, 1H), 5,86 (d, J=9 Hz, 1H), 5,85 (d, J=2 Hz, 1H), 3,44 (s, 3H), of 2.05 (s, 3H).

2.19 Connection B: R1=Cl, R2=H, R3=CH3, R4=H (scheme 2)

3-methyl-5-phenyl-7-chloropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): 11,85 (s, 1H), of 7.90 (s, 1H), 7,46-7,52 (m, 2H), 7,39-7,44 (m, 3H), 7,29 (dd, J=2, 9 Hz, 1H), 6,92 (d, J=9 Hz, 1H), 6,62 (d, J=2 Hz, 1H), 2,16 (s, 3H).

2.20 Connection b: R1=Cl, R2=Cl, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-chlorophenyl)-7-chloropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,78 (s, 1H), 7,95 (s, 1H), 7,38-of 7.55 (m, 4H), 7,17 (dd, J=2, 9 Hz, 1H), 6.75 in (d, J=9 Hz, 1H), from 6.22 (d, J=2 Hz, 1H), 2,03 (s, 3H).

2.21 Connection B: R1=H, R2=F, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine./p>

1H-NMR (DMSO-d6, 300 MHz): of 11.75 (s, 1H), 7,69 (s, 1H), was 7.36-7,52 (m, 2H),? 7.04 baby mortality-7,30 (m, 3H), 6,77 (d, J=8 Hz, 1H), 6,63 (t, J=8 Hz, 1H), 6,50 (d, J=8 Hz, 1H), 2,07 (s, 3H).

2.22 Connection B: R1=F, R2=H, R3=CH3, R4=H (scheme 2)

3-methyl-5-phenyl-7-ftorurazila[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,85 (s, 1H), of 7.70 (s, 1H), 7,46-of 7.55 (m, 2H), 7,35-the 7.43 (m, 2H), 7,11 (dt, J=3, 9 Hz, 1H), 6,92 (dd, J=5,9 Hz, 1H), 6,41 (dd, J=3, 10 Hz, 1H), and 2.14(s, 3H).

2.23 Connection B: R1=NO2, R2=Cl, R3=phenyl, R4=H (scheme 2)

3-phenyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): 12,65 (s, 1H), 9,18 (s, 1H), 7,95 (dd, J=2,9 Hz, 1H), 7,78 (d, J=8 Hz, 2H), 7,32-7,63 (m, 7H), 7,14 (d, J=2 Hz, 1H), 6,85 (d, J=9 Hz, 1H).

2.24 Connection B: R1=NO2, R2=Cl, R3=n-propyl, R4=H (scheme 2)

3-propyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): 11,91 (s, 1H), 9,06 (s, 1H), 7,86 (d, J=8 Hz, 1H), 7,41-7,53 (m, 4H), was 7.08 (s, 1H), 6,72 (d, J=8 Hz, 1H), of 2.38 (t, J=8 Hz, 2H), and 1.54 (tq, J=8, 7 Hz, 2H), from 0.88 (t, J=7 Hz, 3H).

2.25 Connection B: R1=NO2, R2=Cl, R3-cyclopropyl, R4=H (scheme 2)

3-cyclopropyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 400 MHz): 11,72 (s, 1H), 9,05 (s, 1 H), 7,87 (dd, J=2, 9 Hz, 1H), 7,41-of 7.55 (m, 4H), was 7.08 (d, J=2 Hz, 1H), 6,72 (d, J=9 Hz, 1H), 1,79 (p, J=7 Hz, 1H), from 0.88 (d, J=7 Hz, 4H).

2.26 Connection B: R1=F, R2=F, R3=CH3 , R4=H (scheme 2)

3-methyl-5-(2-forfinal)-7-ftorurazila[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,82 (s, 1H), 7,76 (s, 1H), 7,41-7,58 (m, 2H), 7.18 in-7,35 (m, 2H), 7,05 (dt, J=3, 9 Hz, 1H), at 6.84 (dd, J=6,9 Hz, 1H), and 6.25 (dd, J=3,9 Hz, 1H), 2,08 (s, 3H).

2.27 Connection B: R1=NO2, R2=H, R3=CH3, R4=H (scheme 2)

3-methyl-5-phenyl-7-nitropyrazole[3,4][1,4]benzodiazepine.

Connection B: R1=H, R2=H, R3=CH3, R4=H (scheme 2)

3-methyl-5-phenylpyrazol[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,78 (s, 1H), 7,66 (s, 1H), 7,47 (m, 2H), 7,39 (m, 3H), 7,20 (dt, J=1.8 Hz, 1H), to 6.88 (d, J=8 Hz, 1H), 6.75 in (t, J=8 Hz, 1H), of 6.68 (dt, J=1.8 Hz, 1H), and 2.14 (s, 3H).

2.29 Connection B: R1=I, R2=F, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-forfinal)-7-iteratio[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,81 (s, 1H), of 7.90 (s, 1H), 7,39-EUR 7.57 (m, 3H), 7,18 and 7.36 (m, 2H), 6.75 in (s, 1H), 6,59 (d, J=9 Hz, 1H), 2,07 (s, 3H).

2.30 Connection B: R1=H, R2=Cl, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzodiazepine.

2.31 Connection B: R1=NO2, R2=F, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-forfinal)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,90 (s, 1H), 9,00 (s, 1H), 7,87 (dd, J=3,9 Hz, 1H), 7,47 (m, 2H), 7.18 in-7,32 (m, 3H), 6.73 x (d, J=9 Hz, 1H), 2,02 (s, 3H).

2.32 Connection B: R1=Cl, R2F, R3=CH3, R4=H (scheme 2)

3-methyl-5-(2-forfinal)-7-chloropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,81 (s, 1H), of 7.96 (s, 1H), 7,40-of 7.55 (m, 2H), 7,17-to 7.32 (m, 3H), 6,79 (d, J=9 Hz, 1H), 6.42 per (s, 1H), 2,08 (s, 3H).

Connection BSZ: R1=I, R2=H, R3=CH3, R4=H (scheme 2)

3-methyl-5-phenyl-7-iteratio[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 11,82 (s, 1H), a 7.85 (s, 1H), was 7.36-of 7.55 (m, 6H), 6,91 (d, J=2 Hz, 1H), 6,70 (d, J=9 Hz, 1H), 2,15 (s, 3H).

2.34 Connection B: R1=Br, R2=H, R3=CH3, R4=H (scheme 2)

3-methyl-5-phenyl-7-bromopyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 7,89 (s, 1H), 7,49 (m, 2H), 7,38 (m, 4H), 6,85 (d, J=9 Hz, 1H), 6,74 (d, J=2 Hz, 1H), 2,15 (s, 3H).

2.35 Connection BSZ: R1=CN, R2=F, R3=CH2OH, R4=H (scheme 3)

3-hydroxymethyl-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carbonitrile.

Example 3: modification of functional groups in accordance with scheme 4

As mentioned above with reference to figure 4, some compounds can be easily obtained by the transformation of existing functional groups. Some of these additional transformations are given below as examples.

A. Substitution of iodine carbonyl: R1=I in R1=CONRR'

3.1 Connection B1: R1=CONC(-CH2CH2-O-CH2CH2-), R2=F, R3=H, R4=H

5-(2-forfinal)-7-morpholinylcarbonyl[3,4][1,4]benzodiazepine.

The mixture 0,0712 g (0,17 mmole) of pyrazole 4 (R1=I, R2=F, R3=H, R4=H), 0,0082 g (0,0012 mmole) of catalyst dichloride bis(triphenylphosphine)palladium, 1 ml of the research was stirred and heated (75° (C) in an atmosphere of carbon monoxide for 90 minutes. The mixture was cooled and then purified by chromatography on reversed phase silica gel (gradient elution with a mixture of water-acetonitrile)to give 0.06 g of compound B1 (pyrazole 4, in which R1=CON(-CH2CH2-O-CH2CH2-), R2=F, R3=H, R4=H).

1H-NMR (DMSO-d6, 300 MHz): 12,02 (s, 1H, NH), 8,18 (s, 1H, NH), to 7.59 (s, 1H), between 7.4 to 7.5 (m, 2H), 7.18 in-7,35 (m, 3H), at 6.84 (d, J=9 Hz, 1H), 3,25 (m, 8H).

The following compounds are obtained using the above method A.

3.2 Connecting B2: Rl=CONHCH2CH2OH, R2=F, R3=H, R4=H

N-(2-hydroxyethyl)-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide.

1H-NMR (DMSO-d6, 300 MHz): 12,08 (s, 1H, NH), to 8.20 (s, 1H, NH), 8,16 (m, 1H, NH), to 7.61 (d, J=9 Hz, 1H), EUR 7.57 (s, 1H), between 7.4 to 7.5 (m, 2H), 7,14-to 7.3 (m, 2H), 7,11 (s, 1H), 6.89 in (d, J=9 Hz, 1H), 4,63 (m, 1H, HE), 3,40 (m, 2H), 3,18 (m, 2H).

3.3 Connection B3: R1=CON(CH2CH2OH)2, R2=F, R3=H

N,N-bis(2-hydroxyethyl)-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide.

1H-NMR (DMSO-d6, 300 MHz): 12,10 (s, 1H, NH), 8,11 (s, 1H, NH), to 7.59 (s, 1H), 7,4-7,52 (m, 2H), 7,15-to 7.3 (m, 3H), to 6.80 (d, J=9 Hz, 1H), return of 6.58 (s, 1H)and 4.65 (m, 2H, HE), 3,30 (m, 8H).

B. Restoration of the nitro group to the amino group: R1=NO2in R1=NH2

3.4 Connection B4: R1=NH2, R2=Cl, R3=CH3, R4=H

3-methyl-5-(2-chlorophenyl)-7-aminopyrazole[3,4][1,4]benzodiazepine.

A solution of 0.20 g (0.57 mmole) of pyrazole 7 (R1=NO2, R2=Cl, R3=CH3, R4=H) in 8 ml of ethanol was stirred at room temperature in a hydrogen atmosphere with Ni-Raney (0.5 ml of a 5% suspension in water, rinsed with ethanol immediately before use). After 4 hours the mixture was filtered and concentrated under reduced pressure, getting 0,177 g of compound B4 (amino derivatives 7, in which R1=NH2, R2=Cl, R3=CH3, R4=H), tPL260-263° C.

1H-NMR (DMSO-d6, 300 MHz): are 11.62 (s, 1H), 7,38-7,47 (m, 4H), 7,07 (s, 1H), 6,53 (d, J=8 Hz, 1H), 6,38 (dd, J=2, 9 Hz, 1H), 5,74 (d, J=2 Hz, 1H), 4.52 (s, 2H), 2.06 to (s, 3H).

The following compounds are obtained using the above method B.

3.5 Connection B5: R1=NH2, R2=Cl, R3=H, R4=H

5-(2-chlorophenyl)-7-aminopyrazole[3,4][1,4]benzodiazepine.

1H-NMR (CD3OD, 300 MHz): 7,35-of 7.55 (m, 5H), 6,72 (dd, J=3,7 Hz, 1H), 6,62 (d, J=7 Hz, 1H), 6,13 (d, J=3 Hz, 1H).

3.6 Connection B6: R1=NH2, R2=Cl, R3=i-Pr, R4=H

3-(1-methylethyl)-5-(2-chlorophenyl)-7-aminopyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6that 300 is Hz): 11,65 (s, 1H), 7,38 to 7.4 (m, 4H), was 7.08 (s, 1H), 6.75 in (d, J=8 Hz, 1H), to 6.39 (dd, J=2, 8 Hz, 1H), 5,74 (d, J=2 Hz, 1H), 2,98 (sept, J=7 Hz, 1H), 1,18 (d, J=7 Hz, 6N).

C. the Conversion of amino compounds in derivatives: R1=NH2in R1=Other' (as shown above in scheme 4)

3.7 Connection V7: R1=NHAc, R2=Cl, R3=CH3, R4=H

N-(3-methyl-5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzodiazepine-7-yl)ndimethylacetamide.

Suspension 0,323 g (1 mmol) of pyrazole 7 (R1=NH2, R2=Cl, R3=CH3, R4=H) in 20 ml of dichloromethane were introduced into a reaction with 0,112 g (1.1 mmole) of acetic anhydride in an inert atmosphere at room temperature for 2 hours. Then the mixture was diluted with ethyl acetate and washed successively with water and saturated salt solution. The aqueous layers were extracted with ethyl acetate, the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was isolated by chromatography on silica gel, elwira a mixture of hexane-ethyl acetate (30/70), received 0,175 g of compound B7.

1H-NMR (DMSO-d6, 300 MHz): 11,71 (s, 1H), of 9.56 (s, 1H), 7,56 (s, 1H), 7,38-EUR 7.57 (m, 5H), to 6.67 (d, J=8 Hz, 1H), to 6.57 (d, J=2 Hz, 1H), 2.05 is (s, 3H)and 1.83 (s, 3H).

The following compounds are obtained analogously to the compound of V7 in accordance with the method described above Century

3.8 Connection B8: R1=acryloyl-NN, R2=Cl, R3=CH3, R4=H

N-(3-methyl-5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzo who azepin-7-yl)-2-propenamide.

1H-NMR (DMSO-d6, 300 MHz): 11,71 (s, 1H), 9,78 (s, 1H), 7,63 (s, 1 H), 7,52 (dd, J=2,9 Hz, 1H), 7,35 is 7.50 (m, 4H), of 6.71 (d, J=9 Hz, 1H), 6,69 (d, J=2 Hz, 1H), 6,23 (dd, J=10,18 Hz, 1H), between 6.08 (dd, J=2,18 Hz, 1H), ceiling of 5.60 (dd, J=2.10 Hz, 1H), 2.05 is (s, 3H).

3.9 Connection B9: R1=CH3SO2NN, R2=Cl, R3=CH3, R4=H

N-(3-methyl-5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzodiazepine-7-yl)methanesulfonamide.

The mixture 0,323 g (1 mmol) of pyrazole 7 (R1=NH2, R2=Cl, R3=CH3, R4=H), 0,122 g (1 mmol) of 4-dimethylaminopyridine and 5 ml of tetrahydrofuran was stirred under inert atmosphere at room temperature for 2 hours. The mixture was diluted with ethyl acetate and washed successively with water and saturated salt solution at re-extraction of the aqueous layers with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was isolated by chromatography on silica gel, elwira a mixture of hexane-ethyl acetate (10/90), received 0,244 g of compound B9 (pyrazole 7, in which R1=CH3SO2NN, R2=CL, R3=CH3, R4=H) (recrystallization from ethyl acetate), tPL196-198° C.

1H-NMR (DMSO-d6, 300 MHz): 11,74 (s, 1H), 9,12 (s, 1H), 7,71 (s, 1H), was 7.36-7,46 (m, 4H), 6,94 (dd, J=2, 8 Hz, 1H), 6,72 (d, J=8 Hz, 1H), of 6.31 (d, J=2 Hz, 1H), 2,70 (s, 3H), of 2.05 (s, 3H).

, Aminals R3=CO2Et in R3=CONRR'

Any B10: R 1=NO2, R2=Cl, R3=CONH2, R4=H

5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine-3-carboxamide.

Mixed 0.15 g (of 0.36 mmole) of pyrazole 7 (R1=NO2, R2=Cl, R3=CO2Et, R4=H) with a solution of ammonia (15 ml) in ethanol (50 ml) at room temperature for 48 hours. Volatiles were removed under reduced pressure, the product was purified by chromatography on silica gel. Elution with a mixture of ethyl acetate-isopropanol (95/5) gave 0,074 g of compound 10 (pyrazole 7', in which R1=NO2, R2=Cl, R3=CONH2, R4=H) in the form of solids, tPL&γτ;340° C (recrystallization from ethyl acetate).

1H-NMR (DMSO-d6, 400 MHz): 12,95 (ush. s, 1H), 9,23 (ush. s, 1H), 7,92 (d, J=8 Hz, 1H), 7,81 (s, 1H), 7,45-to 7.61 (m, 4H), 7,21 (s, 1H), was 7.08 (s, 1H), 6.75 in (d, J=8 Hz, 1H).

The following compounds are obtained analogously to compound 10 by using the above method,

3.11 Connection B11: R1=NO2, R2=Cl, R3=CONMe2, R4=H

N,N-dimethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine-3-carboxamide

1H-NMR (DMSO-d6, 300 MHz): 12,65 (s, 1H), 9,18 (s, 1H), to $ 7.91 (d, J=9 Hz, 1H), 7,41-of 7.55 (m, 4H), was 7.08 (s, 1H), 6.75 in (d, s=9 Hz, 1H), 3,01 (s, 3H).

3.12 Connection B12: R1=NO2, R2=Cl, R3=CONHNH2, R4=H

N-amino-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine-3-ka is backslid.

1H-NMR (DMSO-d6, 300 MHz): 13,02 (s, 1H), 9,19 (s, 1H), 8,58 (t, J=5 Hz, 1H), to $ 7.91 (dd, J=2, 9 Hz, 1H), 7,41 to 7.62 (m, 4H), to 7.09 (d, J=2 Hz, 1H), 6.75 in (d, J=9 Hz, 1H), 4,54 (d, J=5 Hz, 2H).

D. Recovery of R1=CO2Et in R3=CHO and R3=CH2HE

3.13 Connection B13: R1=NO2, R2=Cl, R3=CHO, R4=H;

Connection B14: R1=NO2, R2=Cl, R3=CH2OH, R4=H

A mixture of 0.48 g (1,17 mmole) of pyrazole 7 (R1=NO2, R2=Cl, R3=CO2Et, R4=H) and 30 ml of tetrahydrofuran at -15° in an inert atmosphere was treated of 1.52 ml of 1 M solution of lithium aluminum hydride in tetrahydrofuran for 30 minutes. Then the mixture was diluted with ethyl acetate, washed sequentially with an aqueous solution of potassium sulfate and a saturated solution of salt, again extragere washing with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel with elution by the mixture hexane-ethyl acetate gave 0.21 g of compound 13 (pyrazole 7', in which R1=NO2, R2=Cl, R3=SNO, R4=H) as a red solid and 0.11 g of compound 14 (pyrazole 7', in which R1=NO2, R2=Cl, R3=CH2OH, R4=H) as a red solid.

Connection B13:

5-(2-chlorophenyl)-7-nitro is irazola[3,4][1,4]benzodiazepine-3-carboxaldehyde.

1H-NMR (DMSO-d6, 300 MHz): to 13.29 (s, 1H), to 9.66 (s, 1H), 9,27 (s, 1 H), of 7.96 (dd, J=2,9 Hz, 1H), 7,45-to 7.59 (m, 4H), 7,13 (d, s=2 Hz, 1H), 6,79 (d, J=9 Hz, 1H).

Connection B14:

3-hydroxymethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

1H-NMR (DMSO-d6, 300 MHz): 12,11 (s, 1H), remaining 9.08 (s, 1H), a 7.85 (dd, J=2,9 Hz, 1H), 7,41-to 7.50 (m, 4H), 7,06 (d, J=2 Hz, 1H), of 6.71 (d, J=9 Hz, 1H), 5,23 (t, J=5 Hz, 1H), 4,27 (d, J=5 Hz, 1H), 4,27 (d, J=5 Hz, 2H).

That is, Reductive amination of aldehyde: R3=CHO, R3=CH2NR2

3.14 Connection B15: R1=NO2, R2=Cl, R3=CH2NMe2, R4=H

3-(N,N-dimethylaminomethyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

Suspension 0,142 g (of 0.39 mmole) of pyrazole 7 (R1=NO2, R2=Cl, R3=CHO, R4=H), 0,0631 g (0,78 mmole) of dimethylamine hydrochloride, of 0.11 ml (0,78 mmole) of triethylamine, 0, 165 (1 mmol) triacetoxyborohydride sodium, 0.2 g of molecular sievesand 20 ml dichloromethane was stirred under inert atmosphere for 3 hours. The mixture was filtered, diluted with ethyl acetate and washed successively with water and saturated salt solution, re-extragere aqueous layers with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on reversed phase silica gel (gradient suirou is the mixture of water-acetonitrile-triperoxonane acid) gave 0,147 g of compound 15 (pyrazole 7', in which R1=NO2, R2=Cl, R3=CH2NMe2, R4=H) in the form of a salt with triperoxonane acid.

1H-NMR (DMSO-d6, 300 MHz): 12.54 (s, 1H), 9,92 (s, 1H), 9,25 (s, 1H), to $ 7.91 (dd, J=2,8 Hz, 1H), 7,45-of 7.55 (m, 4H), 7,10 (d, J=2 Hz, 1H), 6,76 (d, J=8 Hz, 1H), 4,08 (s, 2H), 2,75 (s, 6H).

J. Alkylation of alcohols: R3=CH2OH in R3=CH2Och3

3.15 Connection B16: R1=NO2, R2=Cl, R3=CH2OCH3, R4=H

3-methoxymethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

A mixture of 0.075 g (0.2 mmole) of pyrazole 7 (R1=NO2, R2=Cl, R3=CH2OH, R4=H), 0.2 g of silica gel and 20 ml of tetrahydrofuran was stirred with a solution of diazomethane in ether (50 ml, approximately 9.2 mmole). After 2 hours the mixture was filtered, concentrated under reduced pressure. The product was purified by chromatography on silica gel, elwira a mixture of hexane-ethyl acetate, obtained In connection 16 (pyrazole 7', in which R1=NO2, R2=Cl, R3=CH2OCH3, R4=H) as a red solid.

1H-NMR (DMSO-d6, 300 MHz): 12,27 (s, 1H), 9,11 (s, 1H), 7,86 (dd, J=2,9 Hz, 1H), 7,43-to 7.50 (m, 4H), 7,06 (d, J=2 Hz, 1H), 6,72 (d, J=9 Hz, 1H), 4,20 (s, 2H), 3,25 (s, 3H).

H. Metroidvania aldehyde: R3=CHO, R3=CHCH2

3.16 Connection B17: R1=NO2, R2=Cl, R3=CHCH2, R4=H

3-ethynyl-5-(2-chlorophenyl)-7-nitropyrazole is[3,4][1,4]benzodiazepine.

To a solution of methyltriphenylphosphonium obtained by the interaction 0,109 g (0,31 mmole) bromide methyltriphenylphosphonium in 5 ml of tetrahydrofuran and to 0.29 ml of 1 M solution of tert.-butoxide potassium in tetrahydrofuran at -78° in an inert atmosphere was added 0,080 g (0.22 mmole) of pyrazole 7 (R1=NO2, R2=Cl, R3=CHO, R4=H). The mixture was heated to boiling and stirred overnight, after which the mixture was cooled to room temperature, diluted with ethyl acetate and washed successively with water and saturated salt solution. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel with elution by the mixture hexane-ethyl acetate (70/30) gave 0,043 g of compound 17 (pyrazole 7', in which R1=NO2, R2=Cl, R3=CHCH2, R4=H) as a red solid.

1H-NMR (DMSO-d6, 300 MHz): of 12.33 (s, 1H), 9,11 (s, 1H), 7,88 (dd, J=2,9 Hz, 1H), 7,40-to 7.50 (m, 4H), was 7.08 (d, J=2 Hz, 1H), 6,74 (d, J=9 Hz, 1H), 6,40 (dd, J=12,18 Hz, 1H), 5,85 (d, J=18 Hz, 1H), are 5.36 (d, J=12 Hz, 1H).

I. the Dehydration of amide: R3=CONH2in R3=CN

3.17 Connection B18: R1=NO2, R2=Cl, R3=CN, R4=H

5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine-3-carbonitrile.

A mixture of 0.47 g (1,23 mmole) of pyrazole 7 (R1=NO2, R2=Cl, R3=CONH2, R4 =H), 0, 34 g (2,46 mmole) of potassium carbonate, 0,94 g (x 6.15 mmole) of phosphorus oxychloride and 20 ml of acetonitrile was heated at boiling for 4 hours in an inert atmosphere. The mixture was cooled to room temperature, diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution, water and saturated salt solution, optionally extragere aqueous layers with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographically on silica gel, elwira a mixture of hexane-ethyl acetate (70/30)was obtained 0.24 g of compound 18 (pyrazole 7', in which R1=NO2, R2=Cl, R3=CN, R4=H) as an orange solid (recrystallization from dichloromethane), tPL193-196° C.

IR-spectrum (KBR): 2240 cm-1.1H-NMR (DMSO-d6, 300 MHz): 9,36 (s, 1H), of 7.96 (dd, J=2, 9 Hz, 1H), of 7.48-7,58 (m, 4H), 7,11 (d, J=2 Hz, 1H), 6,77 (d, J=9 Hz, 1H).

K. Hydrolysis of nitrile: R1=CN in R1=CONH2

3.18 Connection B19: R1=CONH2, R2=F, R3=CH3, R4=H 3-methyl-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide.

To a solution of 0.5 g (1.6 mmole) of pyrazole 7 (R1=CN, R2=F, R3=CH3, R4=H) in 79 ml of dimethyl sulfoxide was added 47 ml ice hydrogen peroxide (30% aqueous solution) is 24 ml of 1 M sodium hydroxide solution. After completion of the reaction the mixture was extracted with ethyl acetate, the extracts washed successively with water, saturated salt solution and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. Purification by chromatography on silica gel (elution with a mixture of ethylacetate (95/5)gave 0.5 g of compound 19 (pyrazole 7, in which R1=CONH2, R2=F, R3=CH3, R4=H) as a yellow solid, tPL323-324° C.

1H-NMR (DMSO-d6, 300 MHz): to 11.79 (s, 1H), 8,08 (s, 1H), to 7.64 (s, 1H), 7,58 (dd, J=2,9 Hz, 1H), 7,38-7,52 (m, 2H), 7,02-7,30 (m, 4H), 6.73 x (d, J=9 Hz, 1H), 2.05 is (s, 3H).

Additional compounds not specifically listed above in examples 1-3, obtained using the methods described above. The data connection is marked with the letter “G”included below in tables I-IV.

Example 4. Antiproliferative activity

The following data characterize the antiproliferative activity of the compounds according to the invention. The presented results indicate that the compounds of the present invention can be used for the treatment of cancer, especially solid tumors such as tumors of the breast and colon.

The determination of the activity of CDK2 using the tablet for rapid analysis

To determine the inhibition of CDK2 activity the purified recombi ntim protein retinoblastoma (Rb) was senzibilizirani wells of 96-well plates for rapid analysis (firm New England, Boston, Massachusetts). Rb is a natural substrate for phosphorylation using CDK2 (see Herwig and Strauss, Eur. J. Biochem., volume 246, str-601 (1997) and are listed in the references). Recombinant complexes of human cyclin E/CDK2 was partially purified from extracts of insect cells. Complexes of active cyclin E/CDK2 was added to sensitized with Rb tablets for rapid analysis in combination with33P-ATP and appropriate dilutions of the test compounds. The plates were incubated with shaking for 25 min at room temperature, then washed and radioactivity was counted using a scintillation counter type Topcount, Packard Instrument Co., Downers grove, Illinois). Dilution of the test compounds was evaluated in each assay with redundancy. The percentage of inhibition of phosphorylation using Rb, which is a measure of inhibition of Rb activity was determined using the following formula:

where “test. connect” denotes the average number of pulses per minute in the experiments with redundancy, “respecof.” indicates the average number of pulses per minute for option, when not added to the complex of cyclin E/CDK2, and "total" denotes the average number of pulses per minute for option, when not added to the connection.

The results of the above experimental the comrade in vitro are presented below in tables IA-IB.

In the remaining tables of the positions of the substituents R1, R2, R3and R4correspond to those indicated above in table IA.

Table IB
Inhibition of CDK2 activity connection where the value of the IC50is in the range 1-9,99 microns
Conn. No.R1R2R3R4
A6ClHHH
A7ClFHH
A9HHHH
A10HFHH
A11FFHH
A14CH3SO2HHH
A18CO2CH3HHH
A19IFHH
B2NO2 ClCO2EtH
B5NO2ClCH2CH2PhH
B8NO2ClCH2PhH
BNO2ClCH2-ISO-PrH
BIHCH3H
B3CON(CH2CH2OH)2FHH
B5NH2ClHH

B11NO2ClCONMe2H
GNO2Cl2-benzofuranylH
GNO2Cl2-indolylH
GNO2Cl2-N-Me-pyrrolylH
GCO2HFHH
GNO2ClMeta-HE-PhH
G NO2ClPair-MePhH
GNO2ClMeta-CNPhH
GNO2Cl2-(5-IU)-thiophenylH
Policy number G27NO2H3-pyridinylH
GNO2ClCouple

Me2NPh
H
GNO2ClOrtho-CNPhH
GNO2ClMeta-MePhH
GNO2ClMeta-tO-PhH
GNO2Cl2-(5-Et)-furanylH
GNO2Cl2-naphthylH
GNO2H2-imidazolylH
GCO2NaHHH
GNO2ClOrtho-MePhH

Analysis of the use of cells

Negative in relation to the estrogen receptor cell line of epithelial breast carcinoma (MDA-MB-435) were obtained from American collections model of cell cultures (ATS, Rockville, MD) and were grown in the medium recommended by ATS. To analyze the effect of test compounds on the growth of these cells, the cells were sown in 96-well plates to tissue culture in quantity of 2000 cells per well and incubated over night at 37° C in an atmosphere containing 5% CO2. The next day, test compounds were dissolved in 100%dimethylsulfoxide (DMSO), receiving 10 mm mother liquor. Each compound was diluted with sterile medium to 1 mm in a quantity sufficient to obtain a final concentration of 120 μm. Then the compounds were serially diluted medium with the addition of 1.2% DMSO. One quarter of the final volume of the diluted compounds was transferred into 96-well plates. The tested compounds were analyzed with redundancy. In a number of wells containing control cells, was added DMSO in an amount such that the final concentration of DMSO in each well was 0.3%. Wells that are not made of cells, served as "net control". The wells, which were not added inhibitor, served as a control without inhibitor. The tablets were again placed in a thermostat and 5 days after adding test the connection has been created out analysis according to the method described below.

To each well was added bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazole (thiazolinones blue; MTT), receiving the final concentration in each well of 1 mg/ml Then the plates were incubated for 3 h at 37° C. the plates were centrifuged at 1000 rpm for 5 min before aspirate containing MTT environment. Then containing MTT medium was removed and to each well was added 100 μl of 100%ethanol to dissolve the formed formosanus metabolite. In order to ensure complete dissolution of the tablets was shaken for 5 min at room temperature. Using the tablet reader for titration microplate (firm Molecular Dynamics) were measured absorbance values at a wavelength of 570 nm using a reference wavelength of 650 nm. The percentage of inhibition was calculated by subtracting the values of absorbance measured for all wells, the values of absorbance measured for the holes of the net control (containing no cells), and subsequent subtraction from 1.00 coefficient obtained by dividing the average absorbance values for each of the two replicates of experience on the mean absorbance value measured for controls. Inhibiting concentration (IC50) was obtained by the method of linear regression using the graph of the dependence of the logarithm of concentration against percent inhibition.

The results described what about the above analysis using the cell line MDA-MB-435 presented below in tables IIA-IIB.

NH2
Table IIA
Analysis of antiproliferative activity using cell line MDA-MB-435 (carcinoma of the breast) connection where the value of the IC50is in the range of 0.01-1 μm
Conn.No.R1R2R3R4
B3NO2ClCH3H
B4NO2ClCH2CH3H
B6NO2ClISO-PrH
B7CNFCH3H
BFHCH3H
BNO2ClCyclopropylH
BNO2HCH3H
BNO2FCH3H
BCNFCH2HEH
B4ClCH3H
V7AcNHClCH3H
B8Acryloyl-NHClCH3H
B9MsNHClCH3H
B13NO2ClSNOH
B14NO2ClCH2HEH
B17NO2ClCH=CH2H
G3Me2NSO2NHClCH3H

Table IIB
Analysis of antiproliferative activity using cell line MDA-MB-435 (carcinoma of the breast) connection where the value of the IC50is in the range of 1.1-9,99 mcm
Conn.No.R1R2R3R4
A15CNFHH
BCo2Et FCH3H
± 10NO2Cl5-(4-Me)pyrazoleH
± 12NO2ClCF3H
BNO2Cl4-imidazolylH
B16NO2Cl3-pyrazolylH
B18MeOClCH3H
BClHCH3H
BClClCH3H
BHFCH3H
BHClCH3H
B6NH2ClISO-PrH
B16NO2ClCH2OmeH
G4ClCH2NHSO4NHClCH3H
G5Morpholinyl-SO2NHClCH3 H
GCON-morphodynamicFCH3H
GCONHCH2CH2HEFCH3H
GCONHCH2CH2-N-morpholinylFCH3H

Table IIB
Analysis of antiproliferative activity using cell line MDA-MB-435 (carcinoma of the breast) connection where the value of the IC50is in the range of 10-30 microns
Conn. No.R1R2R3R4
A5NO2ClHH
A13NO2FHH
B2NO2ClCO2EtH
B5NO2ClCH2CH2PhH
B8NO2ClCH2PhH
BNO2Cl 1-thiazolylH
± 15NO2Cl2-pyrazolylH
BNO2ClCutH
B5NO2ClHH
10NO2ClCONH2H
B15NO2ClCH2NMe2H
B18NO2ClCNH
WNO2Cl1-oxadiazolylH

Line cell adenocarcinoma of the colon SW480 and cell line carcinoma of the colon HCT-116 was also received from ATS and tested according to the same Protocol described above for analysis using the cell line MDA-MB-435, with the following modifications. The cell line SW480 were sown in quantities of 1000 cells per well and analyzed 6 days after addition of test compounds. Cell line HCT-116 were sown in quantities of 1000 cells per well and analyzed 4 days after adding the test compound.

The results of the above analysis using the whether the rd cells SW480 (adenocarcinoma of the colon) and HCT-116 (colon carcinoma colon) are presented below in tables IIIA-IIIB, and IVA-IVB, respectively.

Table IIIA
Analysis of antiproliferative activity using cell line SW480 (adenocarcinoma of the colon) connection where the value of the IC50is in the range of 0.01-1 μm
Conn. No.R1R2R3R4
B3NO2ClCH3N
B4NO2ClCH2CH3N
B6NO2ClISO-PrN
B7CNFCH3N
± 10NO2Cl5-(4-Me)pyrazolylN
BHFCH3N
BFFCH3N
BNO2HCH3N
BNO2FCH3N
BCNFCH2OHN
B1CON-morphodynamicFNN
B4NH2ClCH3N
V7AcNHClCH3N
B8Acryloyl-NHClCH3N
B9MsNHClCH3N
B14NO2ClCH2OHN
B19CONH2FCH3N
G2NO2CFsCH3N
GCON-morphodynamicFCH3N
GCONHCH2CH2OHFCH3N
GCONHCH2CH2-N-morpholinylFCH3N

Table IIIB
Analysis of antiproliferative activity using cell line SW480 (adenocarcinoma of the colon) connection where the value of the IC50is in the range of 1.1-9,99 mcm
Conn.No.R1R2R3R4
A5NO2ClHN
A13NO2FHN
A15CNFHN
B1NO2Cl2-pyrrolylN
BCO2EtFCH3N
B18MeoClCH3N
BClHCH3N
BClClCH3N
B FHCH3N
BNO2ClCyclopropylN
BIFCH3N
BHClCH3N
BClFCH3N
G3Me2NSO2NHClCH3N
G4ClCH2NHSO4NHClCH3N
G5Morpholinyl-SO4-NHClCH3N
GCONH2FNN
Table IIIB
Analysis of antiproliferative activity using cell line SW480 (adenocarcinoma of the colon) connections for which the value of IC 50is in the range of 10-30 microns
Conn. No.R1R2R3R4
A9NNNN
A10NFNN
A11FFNN
A21NClNN
B5NO2ClCH2CH2PhN
B8NO2ClCH2PhN
BNO2ClPhN
BNO2ClCutN
BINCH3N
B5NH2 ClNN
B12NO2ClCONHNH2N
G6NO2Cl2-thiophenylN

G7NO2Cl2-furanylN
GNO2Cl3-pyridinylN
GNO2Cl4-pyridinylN
GNO2Cl2-indolylN
GBrHCH3N
GNO2ClOrtho-MePhN
GNO2ClOrtho-CF3PhN
GNO2 Cl1-naphthylN
Table IVA
Analysis of antiproliferative activity using cell line HCT 116 (colon carcinoma colon) connection where the value of the IC50is in the range of 0.01-1 μm
Conn. No.R1R2R3R4
B3NO2ClCH3N
B4NO2ClCH2CH3N
Table IV
Analysis of antiproliferative activity using cell line HCT 116 (colon carcinoma colon) connection where the value of the IC50is in the range of 1.1-9,99 mcm
Conn. No.R1R2R3R4
A15CNFHN
B1NO2Cl 2-pyrrolylN
B6NO2ClISO-PrN
B7CNFCH3N
BCO2EtFCH3N
± 10NO2Cl5-(4-Me)pyrazolylN
BNO2ClCyclopropylN
B12NO2ClCONHNH2N
GCONH2FNN

Table IVB
Analysis of antiproliferative activity using cell line HCT 116 (colon carcinoma colon) connection where the value of the IC50is in the range of 10-30 microns
Conn. No.R1R2R3 R4
A5NO2ClNN
A9NNNN
A10NFNN
A13NO2FNN
A14CH3SO2NNN
A16NO2NNN
A21NClNN
B5NO2ClCH2CH2PhN
B8NO2ClCH2PhN
BNO2ClPhN
BNO2ClCutN
B1CON-morphodynamicFNN
B2CONHCH2CH2HEFNN
B5NH2ClN N
G6NO2ClNeilN
G7NO2Cl2-furanylN
G8NO2Cl2-(3-IU)thiophenylN
GNO2Cl3-pyridinylN
GNO2Cl4-pyridinylN
GNO2ClPair-MeSPhN
G12NO2ClA pair of CF3PhN
GNO2ClOrtho, meta-methylendioxy-PhN
GNO2ClPair-IT-ortho-MeOPhN
GNO2NCyclopropylN
GNO2Cl2-benzofuranylN
GNO2Cl2-indolylN
GNO2ClOrtho-Meh N
GNO2ClMeta-CF3PhN
GNO2Cl4-N-pyrrolyl-PhN
GNO2Cl1-naphthylN
GNO2Cl4-ethenolysisN

Example 5: Composition of tablets

No.IngredientsMg tablet
1Connection 1*525100250500750
2Anhydrous lactose1038335193857
3Crosscarmelose sodium668163248
4Povidone, KSO556122436
5Magnesium stearate111369
 The total mass120120150300600900
*compound 1 is a compound according to the invention

The procedure of manufacture:

1. Mix the ingredients 1, 2 and 3 in a suitable mixer for 15 minutes

2. Granularit powdery mixture obtained in stage 1 along with 20%solution of povidone, CSO (ingredient 4).

3. The granules obtained in stage 2, dried at 50° C.

4. The granules obtained in stage 3, is passed through suitable device for grinding.

5. To grind the granules obtained in stage 4, add ingredient 5 and mix for 5 minutes

6. Pressing the granulate obtained in stage 5, using a suitable press.

Example 6: Composition capsules

No.IngredientMg/capsule
1Connection 1*525100250500
2Anhydrous lactose159123148--
3Corn starch25354035 70
4Talc1015101224
5Magnesium stearate12236
 The total mass of filler200200300300600
*compound 1 is a compound according to the invention

The procedure of manufacture:

1. Mix the ingredients 1, 2 and 3 in a suitable mixer for 15 minutes

2. Add ingredients 4 and 5 and mix for 3 minutes

3. Received product suitable fill the capsule.

Example 7: the Composition of the solution/emulsion for injection

No.IngredientMg/ml
1Connection 1*1 mg
2PEG 40010-50 mg
3Lecithin20-50 mg
4Soybean oil1-5 mg
5Glycerin8-12 mg
6Waterq.s. 1 ml
* connection 1 represents the connection and the attainment

The procedure of manufacture:

1. Ingredient 1 is dissolved in ingredient 2.

2. Add ingredients 3, 4 and 5 ingredient 6 and mixed to obtain a dispersion, and then homogenized.

3. To the mixture obtained in stage 2, add the solution obtained in stage 1, and homogenized to obtain a translucent dispersion.

4. The product is sterilized by filtering through a filter with pore size 0.2 μm, and the product is filled bubbles.

Example 8: the Composition of the solution/emulsion for injection

No.IngredientMg/ml
1Connection 1*1 mg
2Glucotrol10-50 mg
3Lecithin20-50 mg
4Soybean oil1-5 mg
5Glycerin8-12 mg
6Waterq.s. 1 ml
* compound 1 is a compound according to the invention

The procedure of manufacture:

5. Ingredient 1 is dissolved in ingredient 2.

6. Add ingredients 3, 4 and 5 ingredient 6 and mixed to obtain a dispersion, and then homogenized.

7. To the mixture obtained in stage 2, add auth solution obtained in stage 1, and homogenized to obtain a translucent dispersion.

8. The product is sterilized by filtering through a filter with pore size 0.2 μm, and the product is filled bubbles.

Although the invention has been described with reference to specific and preferred embodiments of specialists in this field should be obvious that using standard experiments and tests can be developed for other options and modifications. Thus, it is understood that the invention is not limited to the above description, but is defined by the following claims and their equivalents.

1. Pyrazolopyridazine formula

where R1means hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, CONR8R9, -NR10R11, -NHCOR12, -NHSO2R13;

R2and R4each independently of one another denotes hydrogen, halogen, -NO2, -CF3;

R3means hydrogen, cycloalkyl containing 3-8 carbon atoms, aryl represents an aromatic group containing 6 to 10 carbon atoms and comprising 1 or 2 rings, heteroaryl having 5-10 atoms, 1 or 2 ring containing 1-3 heteroatoms selected from N, O and S, -COOR7, -CN, alkenyl having 2-6 carbon atoms, -ONR 8R9or alkyl having 1-6 carbon atoms, which is optionally substituted by a group OR9F or the above-mentioned aryl;

R5means alkyl having 1-6 carbon atoms;

R7means hydrogen or alkyl having 1-6 carbon atoms;

R8and R9each independently of one another denotes hydrogen or alkyl having 1-6 carbon atoms, which is optionally substituted by a hydroxy-group or NH2; alternatively, R8and R9can form morpholinopropan;

R10, R11and R12each independently of one another denotes hydrogen or alkyl having 1-6 carbon atoms;

R13means alkyl having 1-6 carbon atoms, which is optionally substituted by halogen or-NR14R15;

R14and R15each independently of one another denotes hydrogen or alkyl having 1-6 carbon atoms, which is optionally substituted by halogen, or alternative-NR14R15means morpholinopropan,

or pharmaceutically acceptable salts of the above compounds.

2. The compound according to claim 1, where R1means hydrogen, -NO2, -CN, -CONH2the halogen.

3. The compound according to claim 1 or 2, where R1means-NO2, -CN or-CONH2.

4. The compound according to any one of claims 1 to 3, where R2is in position 2' and means in Gorod or halogen.

5. The compound according to any one of claims 1 to 4, where R3means alkyl containing 1-6 carbon atoms, hydroxy(C1-C6)alkyl, cycloalkyl containing 3-8 carbon atoms or heteroaryl having 5-10 atoms, 1 or 2 ring containing 1-3 heteroatoms selected from N, O or S.

6. The compound according to any one of claims 1 to 4, where R3means methyl, ethyl or hydroxymethyl.

7. The compound according to claim 1, which represents a 3-methyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

8. The compound according to claim 1, which represents a 3-methyl-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carbonitrile.

9. The compound according to claim 1, which represents a 3-methyl-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide.

10. The compound according to claim 1, which represents a 3-hydroxymethyl-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carbonitrile.

11. The compound of formula I according to claim 1, which means 5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

5-(2-chlorophenyl)-7-aminopyrazole[3,4][1,4]benzodiazepine,

5-phenyl-7-chloropyrazole[3,4][1,4]benzodiazepine,

5-(2-forfinal)-7-chloropyrazole[3,4][1,4]benzodiazepine,

5-(2-chlorophenyl)-7-chloropyrazole[3,4][1,4]benzodiazepine,

5-(2,4-dichlorophenyl)-7-chloropyrazole[3,4][1,4]benzodiazepine,

5-phenylpyrazol[3,4][1,4]benzodiazepine,

5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine,

5-(2-forfinal)-7-fluoro who irazola[3,4][1,4]benzodiazepine,

5-(2-chlorophenyl)-7-methoxypyrazine[3,4][1,4]benzodiazepine,

5-(2-forfinal)-7-nitropyrazole[3,4][1,4]benzodiazepine,

5-(2-forfinal)-7-cyanopyridine[3,4][1,4]benzodiazepine,

5-phenyl-7-nitropyrazole[3,4][1,4]benzodiazepine,

5-(3-nitrophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

5-(2-trifluoromethyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

5-phenyl-7-carbomethoxybiphenyl[3,4][1,4]benzodiazepine,

sodium salt of (5-phenylpyrazol[3,4][1,4]benzodiazepine-7-yl)carboxylic acid,

5-(2-forfinal)-7-iteratio[3,4][1,4]benzodiazepine,

5-(2-forfinal)-7-carbomethoxybiphenyl[3,4][1,4]benzodiazepine,

N-(2-hydroxyethyl)-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide,

5-(2-forfinal)-7-morpholinylcarbonyl[3,4][1,4]benzodiazepine,

N,N-bis(2-hydroxyethyl)-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide,

(5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-yl)carboxylic acid,

5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide or

5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzodiazepine.

12. The compound of formula I according to claim 1, which means

3-ethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-phenylethyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(1-methylethyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,][1,4]benzodiazepine,

3-(1-methylethyl)-5-(2-chlorophenyl)-7-aminopyrazole[3,4][1,4]benzodiazepine,

3-phenylmethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-methyl-5-(2-forfinal)-7-carbomethoxybiphenyl[3,4][1,4]benzodiazepine,

3-(2-methylpropyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-trifluoromethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-hydroxymethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

N-(2-hydroxyethyl)-3-methyl-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine-7-carboxamide,

3-(1-methylpropyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-methoxymethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-ethynyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-methyl-5-(2-chlorophenyl)-7-methoxypyrazine[3,4][1,4]benzodiazepine,

3-methyl-5-(2-chlorophenyl)-7-aminopyrazole[3,4][1,4]benzodiazepine,

3-methyl-5-phenyl-7-chloropyrazole[3,4][1,4]benzodiazepine,

3-methyl-5-(2-chlorophenyl)-7-chloropyrazole[3,4][1,4]benzodiazepine,

3-methyl-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiazepine,

N-(3-methyl-5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzodiazepine-7-yl)acetamide", she

N-(3-methyl-5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzodiazepine-7-yl)methanesulfonamide,

3-methyl-5-phenyl-7-ftorurazila[3,4][1,4]benzodiazepine,

3-methyl-5-(2-chlorp the Nile)pyrazolo[3,4][1,4]benzodiazepine,

3-methyl-5-phenyl-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-methyl-5-(2-forfinal)-7-iteratio[3,4][1,4]benzodiazepine

3-methyl-5-(2-forfinal)-7-morpholinylcarbonyl[3,4][1,4]benzodiazepine,

3-methyl-5-(2-forfinal)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-methyl-5-phenylpyrazol[3,4][1,4]benzodiazepine,

3-methyl-5-(2-forfinal)-7-chloropyrazole[3,4][1,4]benzodiazepine,

3-methyl-5-(2-triptoreline)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-methyl-5-phenyl-7-iteratio[3,4][1,4]benzodiazepine,

3-methyl-5-phenyl-7-bromopyrazole[3,4][1,4]benzodiazepine,

3-methyl-5-(2-forfinal)-7-ftorurazila[3,4][1,4]benzodiazepine,

3-cyclopropyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-cyclopropyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine or

3-propyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

13. The compound of formula I according to claim 1, which means

3 carboethoxy-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine-3-carboxamide,

N,N-dimethyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine-3-carboxamide, or

5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine-3-carbonitrile.

14. Compounds selected from the set:

3-(4-were)-5-(2-chlorophenyl)-7-nitropyrazole is[3,4][1,4]benzodiazepine,

3-(4-dimethylaminophenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-cyanophenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-were)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-nitrophenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-triptoreline)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-triptoreline)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(1-naphthyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-methoxyphenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(4-(methylthio)phenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(4-trifloromethyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(4-hydroxy-2-methoxyphenyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-hydroxyphenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-((1,1'-biphenyl)-yl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-nitrophenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-phenoxyphenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-cyanophenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-ethoxyphenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]growing presence who EPIN,

3-(3-were)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine

or

3-(2-forfinal)-5-phenyl-7-nitropyrazole[3,4][1,4]benzodiazepine.

15. The compound of formula I according to claim 1, which represents the

3-phenyl-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine

or

3-(2-naphthyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

16. The compound of formula I according to claim 1, which means

3-(4-methylpyrazole-5-yl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(1-triazolyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(1,3,4-oxadiazol-2-yl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(4-imidazolyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-pyrazolyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-pyrazolyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-thienyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-furanyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-methyltin-2-yl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(indol-2-yl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(1-methyl-1H-pyrrol-2-yl)5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-pyridinyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(4-pyridinyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(4-(1-pyrrolyl)phenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-pyrrolyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(4-ethenolysis)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-benzofuranyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-thienyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(5-methyltin-2-yl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2-imidazolyl)-5-phenyl-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(3-pyridinyl)-5-phenyl-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(1,3-benzodioxol-5-yl)-5-phenyl-7-nitropyrazole[3,4] [1,4]benzodiazepine,

3-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-phenyl-7-nitropyrazole[3,4][1,4]benzodiazepine,

3-(2,3-methylenedioxyphenyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine or

3-(5-ethylfuran-2-yl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine.

17. Compounds selected from the range

5-phenyl-7-methysulfonylmethane[3,4][1,4]benzodiazepine,

3-(N,N-dimethylaminomethyl)-5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine,

N-(3-methyl-5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzodiazepine-7-yl)-2-propenamide,

N-[2-(4-morpholinyl)ethyl]-3-methyl-5-(2-forfinal)pyrazolo[3,4][1,4]benzodiaz the pin-7-carboxamid,

5-(2-chlorophenyl)-7-nitropyrazole[3,4][1,4]benzodiazepine-3-carboxaldehyde,

N'-(3-methyl-5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzodiazepine-7-yl)-N,N-dimethylbenzenesulfonamide,

N'-(3-methyl-5-(2-chlorophenyl)pyrazolo[3,4][1,4]benzodiazepine-7-yl)-N,N-chloromethanesulfonyl,

N'-(3-methyl-5-(2-chlorophenyl)pyrazolo[3,4][l,4]benzodiazepine-7-yl)-4-morpholinoethyl or

N-amino-5-(2-chlorophenyl)-7-nitropyrazole[3,4][l,4]benzodiazepine-3-carboxamide.

18. Thiolactam formulas

or

where R2and R4have the meanings as defined in claim 1;

R1denotes H, -NO2, -CN, halogen, -OR5or-COOR7;

R5and R7have the meanings indicated in claim 1;

R3matter; as in claim 1, with the exception of group-CONR8R9.

19. The pharmaceutical composition inhibiting cyclin-dependent kinase CDR2 comprising as active ingredient a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier or excipient.

20. Compounds according to any one of claims 1 to 17, intended for the treatment and prevention of breast tumors or rim of the intestine.



 

Same patents:

FIELD: organic chemistry.

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

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

7 cl, 2 ex

FIELD: organic chemistry, pharmacy.

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

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, chemical technology, herbicides.

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

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

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

(IVa)

or (IVb) ,

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

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to imidazole derivative of the formula (I)

or its pharmaceutically acceptable salt

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

The invention relates to heterocyclic compounds with substituted phenyl group of formula Ior its pharmaceutically acceptable salt, in which R1represents a C1-C6alkyl; R2represents a C1-C6alkyl; R3represents H or halogen andrepresents a substituted heterocycle, as defined in paragraph 1 of the claims; and X represents NH or O

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

The invention relates to an improved process for the preparation of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-she formulas (I) and its pharmaceutically acceptable salts by the interaction of the compounds of formula (II), where R1and R2means hydrogen or R1means hydrogen and R2means methyl, with a mixture of formic acid and formaldehyde in the presence of tetrabutylammonium bromide, and the ratio of tetrabutylammonium bromide to the original compound is from 1:60 to 1:130, preferably 1:100

FIELD: organic chemistry, biochemistry, pharmacy.

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

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

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

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

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzene of the formula (I): wherein A represents a group taking among the following groups: -C≡C-, -CH=CH-, -CH2-CH2; n = 1 or 2; X represents hydrogen, chlorine or fluorine atom or methyl or methoxy-group; Y represents hydrogen, chlorine or fluorine atom; R1 represents cyclohexyl group monosubstituted, disubstituted, trisubstituted or tetrasubstituted with methyl group, phenyl group monosubstituted or disubstituted with fluorine or chlorine atom or methoxy-group, cycloheptyl, tert.-butyl, dicyclopropylmethyl, 4-tetrahydropyranyl or 1- or 2-adamantyl, or adamantine-2-ol group; or R1 represents phenyl group and in this case X and Y both represents chlorine atom; R2 represents hydrogen atom or (C1-C4)-alkyl group; R3 represents (C5-C7)-cycloalkyl, and salts of these compounds formed by addition of pharmaceutically acceptable acids, and their solvates and hydrates also. Also, invention relates to methods for preparing compounds of the formula (I) and to pharmaceutical composition able to interact with receptors sigma-2 based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for treatment of autoimmune states, disturbance on heart contraction frequency and control against proliferation of tumor cells.

EFFECT: improved preparing methods, valuable medicinal properties of compositions.

18 cl, 14 tbl, 78 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with systemic chemotherapy in case of different oncological diseases. At first, one should carry out 4 courses of systemic chemotherapy at 2-mo-long interval between each other, then, since 10-11th mo against the onset of chemotherapeutic treatment one should additionally conduct 6 courses more at 4-mo-long interval between them. The innovation enables to considerably prolong the period of remissions and that of patient's life duration due to prolonging the terms of therapy by carrying out chemotherapeutic courses before the highest lethal risk.

EFFECT: higher efficiency of therapy.

4 dwg, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: medicine, oncology, phytotherapy.

SUBSTANCE: invention relates to the development of agents of vegetable origin used for treatment of malignant neoplasms. The vegetable species comprises 11 medicinal plants. Clinical applying the preparation showed its high effectiveness in treatment of surgery oncological patients at I, II and III stage of disease. Indication for applying this phytopreparation is impossibility for carrying out chemical-radiation therapy in oncological patients after surgery operations.

EFFECT: valuable medicinal properties of species.

1 ex

FIELD: medicine.

SUBSTANCE: method involves administering selective modulator of steroid sex hormones being in particular compounds of general formula(I) and some quantity of steroid sex hormones precursor selected from a group composed from dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-en-3β,17β-diol and compounds in vivo transformable into one of cited precursors. Bisphosphonates combined with selective estrogen receptor modulators and/or steroid sex hormones precursor are additionally introduced for medically treating and/or inhibiting osteoporosis progress.

EFFECT: enhanced effectiveness of treatment; excluded adverse side effects.

41 cl, 13 dwg, 4 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds designated for applying in photochemotherapy or diagnosis and indicated compounds represent 5-aminolevulinic acid aryl-substituted esters, their derivatives or pharmaceutically acceptable salts. In particular, invention provides preparing compounds of the general formula (I): R

22
N-CH2COCH2CH2CO-OR1 wherein R1 represents aryl-substituted C1-alkyl group, preferably C1-alkyl group substituted with non-heteroaromatic aryl wherein indicated group aryl is substituted group, and especially preferable this radical is substituted with one or more alkyl groups (for examples, (C1-C2)-alkyl), alkoxy- (for example, methoxy-) groups, fluorine, chlorine atoms, nitro- or trifluoromethyl groups; R2 being each of that can be similar or different represents hydrogen atom or alkoxycarbonyloxy-; indicated alkyl group is broken optionally with one or more groups: -O-, -NR3-, -S- or -PR3- wherein R3 represents hydrogen atom or (C1-C6)-alkyl group, and their salts for applying in diagnosis and photochemotherapy of injures and disorders of internal and external surfaces of body, and products and sets for realization of this invention also.

EFFECT: valuable medicinal properties of compounds.

18 cl, 17 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutical, cosmetic and food industry.

SUBSTANCE: method involves destruction and hydrolysis of alga taken among the group including: laminaria, zooster and focus followed by separating the cytoplasmatic fraction and addition of food acid polyvalent metal salt. Then correction of acidity is carried out to obtain pH = 5-7 followed by drying and conversion of fraction to form useful for storage by sterilization or freezing, or drying, or preserving. The food acid polyvalent metal an aqueous solution is added preferably in the amount 0.75% of preparation mass. Invention provides expanding functional capacity of the preparation with respect to stimulation of processes in healing wounds and burns, regeneration of post-traumatic damages, oncoprotecting and photo-sensitizing activity with respect to cancer cells at maximal absorption of light radiation in the region 630-770 nm.

EFFECT: improved producing method, valuable medicinal properties of preparation.

11 cl, 3 ex

The invention relates to the use of compounds defined above, of formula I, including compounds which can be in racemic form or in the form of enantiomers or diastereoisomers
Up!