Derivatives pyrimidinylpiperazine and antitumor agent

 

(57) Abstract:

The present invention relates to a new compound represented by the General formula I

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where the preferred examples of R1- R6the following:

R1and R3each represents alkyl group which may be substituted with halogen atom, amino group, hydroxyl group, CNS group or thiol group, a hydrogen atom, halogen atom or CNS group;

R3is a hydrogen atom; R4is a methyl group;

R5is hydrogen or an alkyl group;

R6group of the formula

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where Z is a phenyl group having antitumor activity, and antitumor agent based on it. 2 C. and 8 C.p. f-crystals, 2 tab.

The technical field

The present invention relates to new compounds having antitumor activity and antitumor means containing these compounds as active ingredient.

Background of the invention

It was known that derivatives of pyrimidinylpiperazine possess antihypertensive and psychotropic actions (see, for example, JP-B-47-14233 and JP-B-48-42072; the term "JP-B" as used here, on the antitumor activity of these compounds.

The aim of the present invention is to develop a highly effective anticancer agents with novel chemical structures, which are still not known.

The invention

As a result of intensive studies, the authors of the present invention have found that the new derived pyrimidinylpiperazine, represented by the following formula (I) has a strong antitumor effect, which is the present invention.

The present invention relates to a compound represented by the General formula (I):

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where R1and R2can be either the same or different and selected from the group comprising a hydrogen atom, a C1-C4alkyl group, a hydroxyl group or a C1-C4alkoxygroup;

R3represents a hydrogen atom;

R4represents C1-C4is an alkyl group;

R5represents a hydrogen atom; and

R6is tetrahydroisoquinoline group; piperidino group or a group of the formula

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where Z represents a phenyl group,

and R6possibly substituted by one or more substituents selected from the group including: ATO is -C4is an alkyl group which may be substituted by a halogen atom, or Z represents pyridyloxy, pyramidalnou, benzyl, benzhydryl, hydroxyl, C1-C4is an alkyl group, or its salt.

Preferred are compounds where R4is a methyl group.

Also preferred are compounds where R1and R2selected from the group comprising: hydrogen, C1-C4is an alkyl group or a C1-C4-CNS group.

More preferred compounds are compounds where R6represents a group of the formula:

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where Z is specified previously.

Even among the preferred compounds are the compounds where R6represents a group of the formula:

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where Z indicated previously, each of which is optionally substituted by one or more substituents selected from the group comprising: halogen atom, cyano, hydroxyl group and karbamoilnuyu group.

Preferred are compounds where R6represents a group of the formula:

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where Z indicated previously, each of which is optionally substituted by one or more substituents, SEL is iny connection where R6represents a group of the formula:

< / BR>
where Z is specified previously.

Preferred are compounds where Z represents a phenyl group.

And even more preferred are compounds where R6represents a group of the formula:

< / BR>
where Z represents a phenyl group.

The invention relates also to an antitumor agent containing an effective amount of the compounds of General formula (I) or its salt as an active ingredient.

The compound of formula (I) according to the present invention can be obtained in various ways. Typical examples of ways to obtain are the following.

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where R1, R2, R3, R4and R6every one above.

Namely, the compound of formula (II) is subjected to reaction manniche with base H-R6. Thus obtained compound (III) is then converted into the compound (IV) by restoring and subsequent degidrirovaniya. Thus can be obtained target compound (I).

Further, each reaction is described in detail.

The reaction manniche

In the presence of a condensing agent, the compound (II) and a principal with indoesia to use the H-R6in the form of a salt, such as hydrochloride or hydrobromide.

The examples used here solvents include alcohol solvents such as methanol, ethanol and propanol, amide solvents such as N, N-dimethylformamide, ndimethylacetamide and dimethylacetamide, halogenated hydrocarbon solvents, such as chloroform, dichloromethane and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, and aromatic solvents such as benzene, toluene and xylene. You can also use a mixture of these solvents.

Examples of condensing agents include paraformaldehyde and formaldehyde.

The reaction temperature usually ranges from -20 to 150oC, preferably from 0 to 100oC.

The reaction time usually ranges from 5 minutes to 120 minutes, preferably from 30 minutes to 72 hours.

Recovery

The compound (II) recover in a solvent to obtain thus the compound (IV).

The examples used here solvents include alcohol solvents such as methanol, ethanol and propanol, amide solvents such as N, N-dimethylformamide, ndimethylacetamide and dimethyl what kind ether solvents such as diethyl ether, tetrahydrofuran and dioxane, and aromatic solvents such as benzene, toluene and xylene. You can also use a mixture of these solvents.

Recovery can be accomplished by a method usually used in this field. For example, the compound (III) can be processed in the presence of a reducing agent or a hydrogenating agent in the presence of a catalyst.

Examples of the reducing agent include borhydride compounds and derivatives of aluminum hydride, such as sodium borohydride, Lamborghini sodium and sociallyengaged. Examples of the catalyst include palladium, Raney Nickel and platinum oxide.

The reaction temperature usually ranges from -20 to 150oC, preferably from 0 to 100oC.

The reaction time usually ranges from 5 minutes to 72 minutes, preferably from 10 minutes to 24 hours.

The de-hydration

The compound (IV) dehydration in a solvent to obtain thus the compound (I).

The examples used here solvents include alcohol solvents such as methanol, ethanol and propanol, amide solvents such as N, N-dime the dichloromethane and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, and aromatic solvents such as benzene, toluene and xylene. You can also use a mixture of these solvents.

The de-hydration can be accomplished by a method usually used in this field. For example, the compound (IV) can be heated in the presence of acid.

As the acid, you can use either organic acid or inorganic acid. Examples of inorganic acids include chloroethanol acid, sulfuric acid, Hydrobromic acid and potassium hydrosulfate, while examples of the inorganic acid include p-toluensulfonate acid, methanesulfonate acid and oxalic acid. Inorganic acid is the preferred acid. Alternatively, you can use aluminum oxide.

The reaction temperature usually ranges from -20 to 150oC, preferably from 0 to 100oC.

The reaction time usually ranges from 5 minutes to 72 minutes, preferably from 10 minutes to 24 hours.

The above method of synthesis can be obtained compound, where R5is a hydrogen atom and Alchemilla part nach the art is in the CIS-form, can be synthesized by the following method.

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where X is represented by a chlorine atom, a bromine atom or an iodine atom; and R1, R2, R3, R4and R6everyone listed above.

Namely, the compound (Ia) is subjected to Wittig reaction with compound (V) obtaining thus the compounds represented by formula I.

Further, this method of obtaining explained in detail.

The compound (V) is subjected to interaction with the tertiary phosphine in a solvent. Thus obtained salt is treated with a base in a solvent and then subjected to interaction with compound (IIa) and obtain thus the compound (I).

The examples used here solvents include ethereal solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic solvents such as benzene, toluene and xylene, alcohol solvents such as methanol, ethanol and propanol, amide solvents such as N,N-dimethylformamide, ndimethylacetamide and dimethylacetamide, halogenated hydrocarbon solvents, such as chloroform, dichloromethane and carbon tetrachloride. You can also use a mixture of these solvents.

The examples used disutility, finality, sodium hydride, tert-piperonyl potassium, ethoxide sodium and 1,8-diazabicyclo [5,4,0]undec-7-ene (TLD).

The reaction temperature usually ranges from 30 to 150oC, preferably from 50 to 100oC.

The reaction time usually ranges from 5 minutes to 72 hours, preferably from 10 minutes to 24 hours.

The initial compounds, namely, compounds (II) and (IIa) and the base of the H-R6and X-CH2CH2R6each are either widely known compound or compound that can be easily obtained well-known methods.

The compound of the present invention, if desired, can be converted to its physiologically acceptable salt with an inorganic acid, such as chloromethane acid, sulfuric acid or phosphoric acid, an organic acid, such as formic acid, acetic acid or methansulfonate acid.

The best way of carrying out the invention

The following experimental examples demonstrate the antitumor activity of compounds of the present invention obtained by the above described methods.

Experimental example 1 (table 1)

Two lines oodi calf, 2 mm L-glutamine and 100 μg/ml of kanamycin sulfate, respectively, inoculant on 96-well-microplate at a density of cells 5,0102cells/150 μl/well (P388) and 5,0103cells/150 μl/well (PC-6). After 2 hours (P388) and 24 hours (PC-6) 50 ál/ml MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] was added thereto at a ratio of 20 µl/well. Four hours later the culture medium is removed and added dimethylsulfoxide at a ratio of 150 μl/well. Then determine the absorbance at 540 nm. The antitumor effect is expressed as concentration (µg/ml) of the medicinal product, in which the growth of cells of the selected group suppressives by 50% relative to the control group (p50).

Experimental example 2 (table 2)

Cells P388 murine leukemia transplanted intraperitoneally to male mice CDF-1 7-10 weeks of age (body weight 21-34 g), each group has 6 animals) with a ratio of 1106cells in the animal. The test substance is administered intraperitoneally to the animals after 1 day and 5 days after transplantation and see extending the life of the action.

The matter under investigation before the introduction of dissolved or suspended in solution BTC (solution of 0.9% benzyl alcohol, 0.4%of protivoopujolevoe action expressed in [T/C, 100], where T denotes the average lifespan (days) treatment group and C denotes the average life expectancy of the control group, which does not give investigated the connection.

As is clear from tables 1 and 2, compounds synthesized by the present invention possess anti-tumor activity and therefore can be used as anticancer agents in the treatment of various tumors.

Antitumor agents of the present invention can be introduced by various methods, for example, in the form of injections such as intravenous injection, intramuscular injection or hypodermic injection, or oral medication. Of these routes of administration are particularly preferred are the intravenous injection of aqueous drug and oral administration.

Water preparation can be prepared by converting compounds of the present invention in an acid additive salt by adding pharmacologically acceptable salt or salts of alkaline metal such as sodium salt.

In oral administration the compound of the present invention can be either in free form or in the form of a salt of introducing and using different methods, usually used in this field.

Examples of oral preparations suitable for use as anticancer agents include tablets, powders, granules, capsules, solutions, syrups, elixirs and oil or water suspension.

Injections can optionally contain stabilizers, preservatives and promotes dissolution agents. In addition, the solution, which optionally contains these additives may be placed in a container and transferred to the solid state, for example, freeze drying, to obtain thereby the product that needs to be prepared before use. Each tank can contain a single dose of the drug. Alternatively, the drug may be placed in a container in an amount corresponding to two or more doses.

Examples of the liquid preparation include solutions, suspensions and emulsions. For the preparation of these drugs may be optionally used additives such as suspendresume agents and emulsifiers.

Antitumor agent containing the compound of the present invention, is administered to an adult in the appropriate dose (depending on connection) once a day. Preferably, protivoopujoleve 50 mg to 2 g

Examples

The following examples are given to further describe the present invention in more detail.

Example 1

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-chlorophenyl)-1-piperazinil]-1-TRANS-propene

10 g of the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3-chlorophenyl)-1-piperazinil] -1-propanone was dissolved in a mixture of solvents containing 600 ml of tetrahydrofuran and 600 ml of ethanol. After cooling to 0oC to the mixture was added 2.5 g of sodium borohydride and the mixture was stirred at the same temperature for 45 minutes. To the mixture was added 500 mg of sodium borohydride, followed by stirring for 1 hour. After adding to the reaction mixture 30 ml of 4 N. hydrochloric acid, the solvent is distilled off. To the thus obtained residue was added 1200 ml of tetrahydrofuran and 5.9 g of the monohydrate of p-toluensulfonate acid. Then the reaction mixture is heated under reflux for 2 hours. After evaporation of the solvent it is neutralized with an aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is camping products collected by filtration and recrystallized from ethanol. Thereby obtaining 4.0 g specified in the connection header.

So pl. 186-191oC (decomp.).

NMR (in DMSO-d6) : 2,62 (s, 3H), 3,0-3,3 (m, 4H), 3,5-3,6 (m, 2H), 3,8-4,0 (m, 4H), 6,23 (dt, 1H, J = 16, 7 Hz), PC 6.82 (d, 1H, J = 16 Hz), 6.87 in (DD, 1H, J = 8, 2 Hz), of 6.96 (DD, 1H, J = 8, 2 Hz), 7,05 (t, 1H, J = 2 Hz), 7,27 (t, 1H, J = 8 Hz), 7,53 (t, 1H, J = 5 Hz), 8,10 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 2

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-phenyl-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 1, using 1.35 g of the hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-phenyl-1-piperazinil] -1-propanone. After you complete the selection, get 265 mg specified in the connection header.

So pl. 197-201oC (decomp.).

NMR (in DMSO-d6) : 2,62 (s, 3H), 3,0-3,2 (m, 4H), of 3.5-3.7 (m, 2H), of 3.7-3.9 (m, 4H), 3,9-4,0 (m, 2H), 6,24 (dt, 1H, J = 15, 7 Hz), 6,83 (d, 1H, J = 15 Hz), 7,01 (d, 2H, J = 8 Hz), 7,27 (t, 2H, J = 8 Hz), 7,54 (t, 1H, J = 4 Hz), 7,87 (t, 1H, J = 8 Hz), 8,08 (s, 1H), 8,92 (d, 2H, J = 4 Hz).

Example 3

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2-were)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 1, using 3,61 g of the hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2-were)-1-piperazinil] -1-propanone. After you complete the selection, receive 998 mg specified in the header C3,3 (m, 4H), 3,5-3,6 (m, 2H), 3,9-4,0 (m, 2H), 6,23 (dt, 1H, J = 16, 7 Hz), at 6.84 (d, 1H, J = 16 Hz), 7,02 (t, 1H, J = 8 Hz), 7,06 (d, 1H, J = 8 Hz), 7,19 (t, 1H, J = 8 Hz), 7,20 (d, 1H, J = 8 Hz), 7,54 (t, 1H, J = 5 Hz), 8,10 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 4

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(4-forfinal)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 1 using 1.0 g of the hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(4-forfinal)-1-piperazinil]-1-propanone. After you complete the selection, get 230 mg specified in the connection header.

So pl. 205-215oC (decomp.).

NMR (in DMSO-d6) : 2,62 (s, 3H), 3,0-3,3 (m, 4H), 3,5-4,1 (m, 6H), 6,23 (dt, 1H, J = 15, 7 Hz), 6,83 (d, 1H, J = 15 Hz), 7,0-to 7.3 (m, 6H), 7,54 (t, 1H, J = 5 Hz), of 8.09 (s, 1H), 8,93 (d, 2H, J = 5 Hz).

Example 5

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2-chlorophenyl)-1-piperazinil]-1-TRANS-propene

3.7 g of the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-chlorophenyl)-1-piperazinil)-1-propanone was dissolved in 300 ml of methanol. After addition of 1.25 g of sodium borohydride resulting mixture was stirred at the same temperature for 2 hours. To the reaction mixture add another 0.5 g of sodium borohydride, followed by stirring for 2 hours. Under ice cooling to the reaction mixture are added water and meom of sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is subjected to column chromatography on silica gel and treated with a mixture of solvents (chloroform/methanol, 30:1) to obtain thus 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-chlorophenyl)-1-piperazinil] -1-propanol. Then the product is added 16 ml of 1 N. hydrochloric acid/ethanol solution. After dissolution by heating to it then add the ether. Dropped when the crystals are collected by filtration to obtain thus obtain 1.26 g specified in the connection header.

So pl. 245-250oC (decomp.).

NMR (in DMSO-d6) : 2,62 (s, 3H), 3,0-3,3 (m, 4H), 3,4-3,7 (m, 4H), 3,9-4,1 (m, 2H), and 6.25 (dt, 1H, J = 16, 7 Hz), 6,85 (d, 1H, J = 16 Hz), 7,1-7,2 (m, 1H), 7,2-7,3 (m, 1H), and 7.3-7.5 (m, 2H), 7.5 to about 7.6 (m, 1H), 8,08 (s, 1H), 8,92 (d, 2H, J = 5 Hz), 11,09 (s, 1H).

Example 6

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-(1,2,3,4-tetrahydroisoquinoline-2-yl)-1-TRANS-propene

(1) Hydrochloride 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-(1,2,3,4-tetrahydroisoquinoline-2-yl)-1-propanone

1.01 g of 1-(2-Pyrimidinyl)-4-acetyl-5-methylpyrazole was dissolved in 100 ml of ethanol. After addition of 450 mg of paraformaldehyde and 848 mg hydrochloride 1,2,3,4-tetrahydroisoquinoline the mixture is heated under reflux during the night. Then to reactionarism during the night. To the obtained reaction mixture was added chloroform. Then it was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is subjected to column chromatography on silica gel and treated with a mixture of solvents (chloroform/methanol, 30:1). The fraction containing the target compound concentrate. To the thus obtained precipitate was added 1 N. hydrochloric acid/ethanol solution. After concentrating obtain 550 mg specified in the connection header.

So pl. 165-168oC (decomp.).

NMR (in DMSO-d6) : of 2.81 (s, 3H), of 3.0 to-3.9 (m, 8H), 4,3-4,8 (m, 2H), and 7.1 to 7.4 (m, 4H), to 7.67 (t, 3H, J = 5 Hz), 8,43 (s, 1H), 9,01 (d, 2H, J = 5 Hz), 11,09 (s, 1H).

(2) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-(1,2,3,4-tetrahydroisoquinoline-2-yl)-1-TRANS-propane

500 mg of the Compound obtained above (1), dissolved in a mixture solvent containing 20 ml of methanol and 40 ml of ethanol. After addition of 500 mg of sodium borohydride, the mixture is stirred at room temperature for 3 hours. Then the reaction mixture was concentrated. After addition of chloroform, washed with saturated aqueous sodium chloride and dried on the dioxane and 500 mg of the monohydrate of p-toluensulfonate acid and the mixture heated under reflux for 5 hours. After evaporation of the solvent to the residue was added chloroform. Then it was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is subjected to column chromatography on silica gel and treated with a mixture of solvents (chloroform/methanol, 20:1). The fraction containing the target compound concentrate. To the thus obtained precipitate was added 1 N. hydrochloric acid/ethanol solution. After concentrating obtain 185 mg specified in the connection header.

So pl. 200-220oC (decomp.).

NMR (in DMSO-d6) : 2,63 (s, 3H), 3,0-4,2 (m, 6H), 4,2-4,7 (m, 2H), of 6.29 (dt, 1H, J = 15, 7 Hz), 6.87 in (d, 1H, J = 15 Hz), 7,2-7,4 (m, 4H), 7,54 (t, 1H, J = 5 Hz), 8,07 (s, 1H), 8,07 (s, 1H), 8,93 (d, 2H, J = 5 Hz).

Example 7

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2-forfinal)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 6 (1) and (2), but replacing hydrochloride 1,2,3,4-tetrahydroisoquinoline used in example 6 (1), the hydrochloride of 1-(2-forfinal)piperazine. After you complete the selection, receive specified in the header of the connection.

So pl. 210-215oC (decomp.).

NMR (in DMSO-d6) : 2,62 J = 5 Hz).

Example 8

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-methyl-1,2,3,4-tetrahydro-1-pyridyl]-1-TRANS-propene

Repeat the procedure of example 6 (1) and (2), but replacing hydrochloride 1,2,3,4-tetrahydroisoquinoline used in example 6 (1) of the hydrochloride of 4-methyl-1,2,5,6-tetrahydropyridine. After you complete the selection, receive specified in the header of the connection.

So pl. 225-230oC (decomp.).

NMR (in DMSO-d6) : of 1.73 (s, 3H), of 2.1 to 2.6 (m, 2H), 2,61 (s, 3H), 3,0-4,0 (m, 8H), 5,43 (s, 1H), of 6.20 (dt, 1H, J = 15, 7 Hz), for 6.81 (d, 1H, J = 15 Hz), 7,54 (t, 1H, J = 5 Hz), with 8.05 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 9

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-TRANS-propene

Repeat the procedure of example 1, using 500 mg of the hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(4-chlorophenyl)-1-piperidyl]-1-propanone. After you complete the selection, get 185 mg specified in the connection header.

So pl. 230-235oC (decomp.).

NMR (in DMSO-d6) : 1,8-2,0 (m, 2H), 2,3-2,5 (m, 2H), 2,62 (s, 3H), 3,2-3,6 (m, 4H), 3,8-4,0 (m, 2H), ceiling of 5.60 (s, 1H), and 6.25 (dt, 1H, J = 15, 7 Hz), 6,85 (d, 1H, J = 15 Hz), 7,44 (t, 1H, J = 8 Hz), 7,49 (d, 2H, J = 8 Hz), 7,54 (t, 1H, J = 5 Hz), 8,09 (c, 1H), 8,93 (d, 2H, J = 5 Hz).

Example 10

Hydrochloride of 1-[5-methyl-1-(4-methyl-6-methoxy-2-pyrimidinyl)-4-a feast is-pyrimidinyl)-4-acetyl-5-methylpyrazole] and 1,2,3,4-tetrahydroisoquinoline, used in example 6 (1), respectively, at 1-(4-methyl-6-methoxy-2-pyrimidinyl)-4-acetyl-5-methylpyrazole hydrochloride and 1-(2-were)piperazine. After you complete the selection, receive specified in the header of the connection.

So pl. 206-212oC (decomp.).

NMR (in DMSO-d6) : of 2.27 (s, 3H), of 2.45 (s, 3H), of 2.66 (s, 3H), 3,0-3,3 (m, 6H), 3,5-3,6 (m, 2H), 3,98 (s, 3H), 3,9-4,0 (m, 2H), 6,24 (dt, 1H, J = 16, 8 Hz), for 6.81 (s, 1H), at 6.84 (d, 1H, J = 16 Hz), 7,02 (t, 1H, J = 7 Hz), 7,05 (d, 1H, J = 7 Hz), 7,19 (d, 1H, J = 7 Hz), 7,19 (t, 1H, J = 7 Hz), with 8.05 (s, 1H).

Example 11

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-chloro-2-were)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 6 (1) and (2), but replacing hydrochloride 1,2,3,4-tetrahydroisoquinoline used in example 6 (1), 680 mg of the hydrochloride of 1-(2-chloro-3-were)piperazine. After you complete the selection, receive 93 mg specified in the connection header.

So pl. 210-218oC (decomp.).

NMR (in DMSO-d6) : 2,32 (s, 3H), 2,65 (s, 2H), 3,0-3,2 (m, 4H), 3,5-3,6 (m, 2H), 3,9-4,0 (m, 2H), 6,24 (dt, 1H, J = 16, 8 Hz), at 6.84 (d, 1H, J = 16 Hz), 7,07 (DD, 1H, J = 7, 2 Hz), 7,19 (DD, 1H, J = 7, 2 Hz), 7,21 (t, 1H, J = 7 Hz), 7,52 (t, 1H, J = 5 Hz), 8,07 (s, 1H), 8,91 (d, 2H, J = 5 Hz).

Example 12

Hydrochloride of 1-[5-methyl-1-(4-methyl-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-chlorophenyl)-1-piperazinil]-1-TRANS-propene
tetrahydroisoquinoline, used in example 6 (1), respectively, at 1-(4-methyl-2-pyrimidinyl)-4-acetyl-5-methylpyrazole hydrochloride and 1-(2-chlorophenyl)piperazine. After you complete the selection, receive specified in the header of the connection.

So pl. 200-205oC (decomp.).

NMR (in DMSO-d6) : to 2.55 (s, 3H), 2,61 (s, 3H), 3,1-3,3 (m, 3H), 3,3-3,7 (m, 4H), 3,8-4,0 (m, 2H), of 6.26 (dt, 1H, J = 16, 8 Hz), at 6.84 (d, 1H, J = 16 Hz), 7,12 (t, 1H, J = 8 Hz), 7.23 percent (d, 1H, J = 8 Hz), and 7.3 and 7.6 (m, 3H), of 8.04 (s, 1H), up 8.75 (d, 2H, J = 5 Hz).

Example 13

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-triptoreline)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 6 (1) and (2), but replacing hydrochloride 1,2,3,4-tetrahydroisoquinoline used in example 6 (1), 730 mg of the hydrochloride of 1-(3-triptoreline)piperazine. After you complete the selection, receive 75 mg specified in the connection header.

So pl. 196-201oC (decomp.).

NMR (in DMSO-d6) : to 2.65 (s, 3H), 3,1-3,3 (m, 4H), of 3.5-3.7 (m, 2H), 3,9-4,1 (m, 4H), 6,24 (dt, 1H, J = 16, 8 Hz), 6,83 (d, 1H, J = 16 Hz), to 7.15 (d, 1H, J = 8 Hz), 7,26 (s, 1H), 7,28 (d, 1H, J = 8 Hz), 7,47 (t, 1H, J = 8 Hz), 7,52 (t, 1H, J = 5 Hz), 8,07 (c, 1H), 8,91 (d, 2H, J = 5 Hz).

Example 14

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-were)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 6 (1) and (2), but replacing perazine. After you complete the selection, receiving 88 mg specified in the connection header.

So pl. 200-202oC (decomp.).

NMR (in DMSO-d6) : of 2.27 (s, 3H), 2.63 in (s, 3H), 3,0-3,3 (m, 4H), of 3.5-3.7 (m, 2H), of 3.7-3.9 (m, 2H), 3,9-4,0 (m, 2H), 6,23 (dt, 1H, J = 16, 7 Hz), 6,69 (d, 1H, J = 8 Hz), to 6.80 (d, 1H, J = 16 Hz), PC 6.82 (s, 1H), 6,83 (d, 1H, J = 8 Hz), 7,14 (t, 1H, J = 8 Hz), 7,53 (t, 1H, J = 5 Hz), 8,08 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 15

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-bromophenyl)-1-piperazinil]-1-TRANS-propene

(1) 1-(3-Bromophenyl)piperazine

100 ml of a solution of 10 g of 3-bromoaniline and 10.4 g of the hydrochloride of bis(2-chloroethyl) amine in 1-butanol is heated under reflux for 48 hours. After adding 6,16 g of sodium carbonate the mixture is still heated under reflux for 72 hours. After cooling, insoluble products collected by filtration, suspended in aqueous sodium hydroxide solution and extracted with chloroform. The extract is washed successively with water and saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent receive of 10.05 g specified in the title compound as an orange oily product.

1H-NMR (CDCl
2,42 g of 4-Acetyl-1-(2-pyrimidinyl)-5-methylpyrazole, 2,89 g of compound obtained above (1), and 12 ml of a solution of 1 N. hydrochloric acid/ethanol was dissolved in 150 ml of ethanol and heated under reflux for 32 hours. During this period portions to the mixture was added 10 g of paraformaldehyde. The reaction mixture is evaporated and the residue is neutralized by adding an aqueous solution of sodium hydroxide. After extraction with chloroform, the extract washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is subjected to column chromatography on silica gel (chloroform/methanol, 100:1), thus obtaining 2.17 g specified in the connection header in the form of a solid product.

1H-NMR (CDCl3) : to 2.67 (t, 4H, J = 5 Hz), is 2.88 (t, 2H, J = 7 Hz), 3.00 and (s, 3H), to 3.09 (t, 2H, J = 7 Hz), 3,21 (t, 4H, J = 5 Hz), 6,83 (DD, 1H, J = 8, 2 Hz), to 6.95 (DDD, 1H, J = 8, 2, 1 Hz), 7,03 (t, 1H, J = 2 Hz), 7,10 (t, 1H, J = 8 Hz), 7,35 (t, 1H, J = 5 Hz), 8,15 (s, 1H), 8,86 (d, 2H, J = 5 Hz).

(3) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3-bromophenyl)-1-piperazinil]-1-TRANS-propene

2 g of the Compound obtained above (2), dissolved in a mixture solvent containing 50 ml of ethanol and 50 ml of tetrahydrofuran. Under ice cooling to implement the TS. the hydrochloric acid. After evaporation of the solvent the residue is dissolved in 150 ml of tetrahydrofuran and to it was added 1.7 g of monohydrate p-toluensulfonate acid followed by heating under reflux for 60 minutes. After evaporation of the solvent to the residue was added aqueous sodium hydroxide solution and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is subjected to column chromatography on silica gel (chloroform : methanol = 100 : 1). The product is then converted into the hydrochloride using a 2.8 ml of 1 n hydrochloric acid/ethanol and recrystallization from ethanol to obtain thus 876 mg specified in the title compounds as a colorless solid product.

1H-NMR (CDCl3) : 2,62 (s, 3H), 3,0-3,2 (m, 4H), 3,5-3,6 (m, 2H), 3,8-4,0 (m, 4H), 6,23 (dt, 1H, J = 16, 8 Hz), PC 6.82 (d, 1H, J = 16 Hz), 7,01 (DD, 2H, J = 8, 2 Hz), 7,19 (d, 1H, J = 8 Hz), 7,20 (t, 1H, J = 8 Hz), 7,53 (t, 1H, J = 5 Hz), 8,08 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 16

Hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3,4-dichlorophenyl)-1-piperazinil]-1-TRANS-propene

1.0 g of the Hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-anola and 50 ml of tetrahydrofuran. After cooling with ice to 0oC to the mixture was added 500 mg of sodium borohydride and the mixture was stirred at the same temperature for 45 minutes. Then add another 50 mg of sodium borohydride and the mixture is stirred for another 2 hours. Further, it is neutralized by addition of a solution of 1 N. hydrochloric acid/ethanol. After evaporation of the ethanol to the concentrated residue was added chloroform. Then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent to the resulting residue are added 50 ml of dioxane, 50 ml of tetrahydrofuran and 220 mg of the monohydrate of p-toluensulfonate acid. Then the resulting mixture was heated under reflux for 5 hours. After evaporation of the solvent to the residue was added chloroform. Then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is subjected to column chromatography on silica gel (chloroform : methanol = 30 : 1), is converted into hydrochloride by adding 1 n hydrochloric acid/ethanol and recrystallized (decomp.)

1H-NMR (DMSO-d6) : of 2.51 (s, 6H), 2,60 (s, 3H), 3,1-of 3.25 (m, 4H), 3,5-3,6 (m, 2H), 3,9-of 4.05 (m, 4H), to 6.22 (dt, 1H, J = 15,6, 7,3 Hz), to 6.80 (d, 1H, J = 15.6 Hz), 7,01 (DD, 1H, J = 8,8, 3.0 Hz), 7,25 (s, 1H), 7,29 (s, 1H), 7,46 (t, 1H, J = 8,8 Hz), 8,03 (s, 1H).

Example 17

Hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3,5-dichlorophenyl)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 16, using 1.0 g of the hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3,5-dichlorophenyl)-1-piperazinil] -1-propanone. After you complete the selection, receive 654 mg specified in the connection header.

So pl. 212-218oC (decomp.)

1H-NMR (DMSO-d6) : of 2.51 (s, 6H), 2,60 (s, 3H), 3,05-3,3 (m, 4H), 3,45-3,55 (m, 2H), 3,9-of 4.05 (m, 4H), 6,21 (dt, 1H, J = 15,6, 7,3 Hz), to 6.80 (d, 1H, J = 15.6 Hz), of 6.96 (s, 1H), 7,06 (s, 2H), 7,29 (s, 1H), 8,03 (s, 1H).

Example 18

Hydrochloride of 1-[5-methyl-1-(4-hydroxy-6-methyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2-were)-1-piperazinil]-1-TRANS-propene

(1) Hydrochloride 1-[5-methyl-1-(4-hydroxy-6-methyl-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-were)-1-piperazinil]-1-propanone

300 mg Tribromide boron is added to 3 ml of methylene chloride and the resulting solution is cooled. To the solution is added dropwise a solution of 470 mg of the hydrochloride of 1-[5-methyl-1-(4-methoxy-6-methyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2-mechanie 72 hours added water and the mixture is extracted twice with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (800 g silica gel, chloroform : methanol = 10 : 1-5 : 1). Then the resulting product is converted into hydrochloride by adding 1 n hydrochloric acid/ethanol and recrystallized from ethanol to obtain thus 150 mg specified in the connection header.

So pl. 208-211oC (decomp.)

1H-NMR (DMSO-d6) : of 2.28 (s, 3H), of 2.38 (s, 3H), and 2.83 (s, 3H), 3,05-to 3.35 (m, 6H), 3.45 points-of 3.65 (m, 6H), 6,56 (user., 1H),? 7.04 baby mortality (m, 2H), 7,19 (m, 2H), 8,39 (s, 1H).

(2) the Hydrochloride of 1-[5-methyl-1-(4-hydroxy-6-methyl-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-were)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 16, using 130 mg of the compound obtained above (1). After you complete the selection, receive 27 mg specified in the connection header.

So pl. 220-225oC (decomp.)

1H-NMR (DMSO-d6) : of 2.27 (s, 3H), 2,31 (s, 3H), of 2.64 (s, 3H), 3.0 to 3.15 in (m, 2H), 3,15 to 3.3 (m, 4H), 3,5-3,6 (m, 2H), 3.95 to of 4.05 (m, 2H), and 6.25 (dt, 1H, J = the 15.6, 6.8 Hz), 6,33 (user., 1H), 6,83 (d, 1H, J = 15.6 Hz), 7,03 (m, 2H), 7,19 (m, 2H), 8,12 (s, 1H).

Example 19

Hydrochloride of 1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-pyridyl)-1-piperazinil]-1-propanone

606 mg of 4-Acetyl-1-(2-pyrimidinyl)-5-methylpyrazole was dissolved in 60 ml of ethanol and add 490 mg of the hydrochloride of 2-pyridinediamine and 270 mg of paraformaldehyde. The resulting mixture was heated under reflux for 24 hours. Then add 100 mg of paraformaldehyde and the mixture was heated under reflux for 60 hours. The ethanol is then half evaporated and the residue filtered. To the precipitate was added chloroform. Next, it is washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation. The residue is subjected to column chromatography on silica gel (silica gel 50 g, chloroform : methanol= 50 : 1 - 40 : 1). Then the resulting product is converted into the hydrochloride by addition of 1 N. hydrochloric acid and recrystallized from ethanol to obtain thus 300 mg specified in the connection header.

So pl. 218-224oC (decomp.)

1H-NMR (DMSO-d6) : and 2.83 (s, 3H), 3,1-of 3.25 (m, 2H), 3,3-3,8 (m, 8H), 4.4 to 4.5 (m, 2H), 6,86 (t, 1H, J = 5 Hz), to 7.15 (d, 1H, J = 8,8 Hz), 7,66 (t, 1H, J = 4.9 Hz), 7,78 (m, 1H), 8,16 (d, 1H, J = 5 Hz), to 8.41 (s, 1H), of 9.00 (d, 2H, J = 4,9 Hz).

(2) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-pyridyl)-1-piperazinil]-1 is Rhenia selection get 51 mg specified in the connection header.

So pl. 218-224oC (decomp.)

1H-NMR (DMSO-d6) : 2,62 (s, 3H), 3,05 is 3.15 (m, 2H), of 3.25 to 3.35 (m, 2H), 3,5-3,6 (m, 2H), 3,9-4,0 (m, 2H), 4,35 is 4.45 (m, 2H), 6,21 (dt, 1H, J = 16 Hz), for 6.81 (t, 1H, J = 5 Hz), PC 6.82 (d, 1H, J = 16 Hz), 7,07 (d, 1H, J = 8,8 Hz), 7,53 (t, 1H, J = 4.9 Hz), 8,08 (s, 1H), 8,16 (d, 1H, J = 5 Hz), 8,91 (d, 2H, J = 4,9 Hz).

Example 20

Hydrochloride of 1-[5-methyl-1-(4-methoxy-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-chlorophenyl)-1-piperazinil]-1-TRANS-propene

(1) Hydrochloride 1-[5-methyl-1-(4-methoxy-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3-chlorophenyl)-1-piperazinil]-1-propanone

Repeat the procedure of example 19 (1), using 2,32 g of the hydrochloride of 4-acetyl-1-(4-methoxy-2-pyrimidinyl)-5-methylpyrazole and of 2.33 g of the hydrochloride of 3-chlorophenylpiperazine. After you complete the selection, receive 1.50 g specified in the connection header.

So pl. 194-197oC (decomp.)

1H-NMR (DMSO-d6) : 2,84 (s, 3H), 3,05-of 3.25 (m, 4H), 3,45-3,55 (m, 2H), 3,55-the 3.65 (m, 2H), 3,85-3,95 (m, 2H), 4.00 points (s, 3H), to 6.88 (d, 1H, J = 8 Hz), of 6.99 (d, 1H, J = 8 Hz), 7,07 (d, 1H, J = 6 Hz), to 7.09 (s, 1H), 7,27 (t, 1H, J = 8 Hz), to 8.41 (s, 1H), 8,67 (d, 1H, J = 6 Hz).

(2) the Hydrochloride of 1-[5-methyl-1-(4-methoxy-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3-chlorophenyl)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 16, using of 0.47 g of the compound obtained above (1). After you complete the selection, obtain 256 mg specified in the header is, ,85-3,95 (m, 4H), of 4.00 (s, 3H), 6,23 (dt, 1H, J = 16, 7 Hz), 6,83 (dt, 1H, J = 16 Hz), 6.87 in (d, 1H, J = 8 Hz), 6,92 (d, 1H, J = 5 Hz), 6,97 (DD, 1H, J = 8, 2 Hz), 7,05 (s, 1H), 7,26 (t, 1H, J = 8 Hz), 8,07 (d, 1H, J = 5 Hz), 8,58 (s, 1H).

Example 21

Hydrochloride of 1-[5-methyl-1-(4-hydroxy-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3-chlorophenyl)-1-piperazinil]-1-TRANS-propene

(1) Hydrochloride 1-[5-methyl-1-(4-hydroxy-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3-chlorophenyl)-1-piperazinil]-1-propanone

Repeat the procedure of example 19 (1) using 950 mg of the hydrochloride of 1-[5-methyl-1-(4-methoxy-2-pyrimidinyl)-4-pyrazolyl] - 3-[4-(3-chlorophenyl)-1-piperazinil] -1-propanone. After you complete the selection, receive 167 mg specified in the connection header.

So pl.: 177-181oC (decomp.)

1H-NMR (DMSO-d6) : 2,84 (s, 3H), 3,85-3,95 (m, 2H), 3,9-4,0 (m, 2H), to 6.88 (d, 1H, J = 7.8 Hz), only 6.64 (d, 1H, J = 6 Hz), 6.87 in (d, 1H, J = 8 Hz), 6,98 (d, 1H, J = 8 Hz), was 7.08 (s, 1H), 7,26 (t, 1H, J = 8 Hz), 8,31 (d, 1H, J = 6 Hz), 8,42 (s, 1H).

(2) the Hydrochloride of 1-[5-methyl-1-(4-hydroxy-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3-chlorophenyl)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 16, using 147 g of the compound obtained above (1). After you complete the selection, receive 86 mg specified in the connection header.

So pl. 197-201oC (decomp.)

1H-NMR (DMSO-d6) : of 2.64 (s, 3H), 3,05-of 3.25 (m, 4H), 3,5-3,6 (m, 2 Hz), of 8.09 (d, 1H, J = 5 Hz), 8,15 (s, 1H).

Example 22

Hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2,3-dichlorophenyl)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 16, using 710 mg of the hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2,3-dichlorophenyl)-1-piperazinil] -1-TRANS-propanone. After you complete the selection, receive 515 mg specified in the connection header.

So pl. 205-208oC (decomp.).

1H-NMR (DMSO-d6) : of 2.51 (s, 6H), 2,62 (s, 3H), 3,1-3,3 (m, 4H), 3,4-3,5 (m, 2H), 3,5-of 3.65 (m, 2H), 3.95 to of 4.05 (m, 2H), from 6.22 (dt, 1H, J = 16,1, 7,3 Hz), 6,83 (d, 1H, J = 16.1 Hz), 7,18 (d, 1H, J = 8 Hz), 7,28 (s, 1H), to 7.35 (t, 1H, J = 8 Hz), 7,37 (d, 1H, J = 8 Hz), 8,03 (s, 1H).

Example 23

Hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2-chlorophenyl)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 16, using 1.48 g of the hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2,3-dichlorophenyl)-1-piperazinil] -1-TRANS-propanone. After you complete the selection, receive 1.29 g specified in the connection header.

So pl. 201-206oC (decomp.)

1H-NMR (DMSO-d6) : of 2.51 (s, 6H), 2,61 (s, 3H), 3,1-of 3.25 (m, 4H), 3,4-3,5 (m, 2H), 3,55-the 3.65 (m, 2H), 3.95 to of 4.05 (m, 2H), from 6.22 (dt, 1H, J = 15,6, 7,3 Hz), 6,83 (d, 1H, J = 15.6 Hz), 7,12 (d, 1H, J = 7 Hz), 7,22 (d, 1H, J = 7 Hz), 7,29 4-pyrazolyl] -3-[4-(2-pyrimidinyl)-1-piperazinil]-1-TRANS-propene

(1) the Dihydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-pyrimidinyl)-1-piperazinil]-1-propanone

404 mg of 4-Acetyl-1-(2-pyrimidinyl)-5-methylpyrazole and 474 mg of the dihydrochloride of 1-(2-pyrimidinyl)piperazine are dissolved in 15 ml of ethanol, heated under reflux for 23 hours. During this period portions added 900 mg of paraformaldehyde. The reaction mixture is cooled and formed thus precipitate is subjected to filtration and washed with methanol. Thus 327 mg specified in the title compound obtained as a colorless solid product.

1H-NMR (DMSO-d6) : of 2.81 (s, 3H), 3,0-3,2 (m, 2H), 3,3-3,4 (m, 2H), 3,4-3,5 (m, 2H), 3,5-3,6 (m, 2H), up 3.6-3.7 (m, 2H), 4,6-4,8 (m, 2H), 6,78 (t, 1H, J = 5 Hz), 7,66 (t, 1H, J = 5 Hz), 8,40 (s, 1H), 8,46 (d, 2H, J = 5 Hz), 9,00 (d, 2H, J = 5 Hz).

(2) the Dihydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-pyrimidinyl)-1-piperazinil]-1-TRANS-propene

200 mg of the Compound obtained above (1), dissolved in a mixture of solvents containing 8 ml of ethanol and 8 ml of tetrahydrofuran. After cooling with ice to 0oC portions to the mixture was added 160 mg of sodium borohydride in a period of 130 minutes. Then the reaction mixture was quenched with conc. of hydrochloric acid. After evaporation of the ethanol, the residue is dissolved in 10 ml tetrahydrofurane 30 minutes. After evaporation of the solvent to the residue was added aqueous sodium hydroxide solution followed by extraction with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (chloroform : methanol = 100 : 2), then the product is converted into the hydrochloride using 1 n hydrochloric acid/ethanol and recrystallized from methanol/ethyl acetate to obtain thus 29 mg specified in the title compounds as a colorless solid product.

So pl. 130 - 140oC.

1H-NMR (DMSO-d6) : 2,61 (s, 6H), to 3.0-3.2 (m, 4H), 3,3-3,6 (m, 2H), 3,5-3,6 (m, 2H), 3,9-of 4.05 (m, 2H), 4,7-4,8 (m, 2H), 6,21 (dt, 1H, J = 17, 8 Hz), 6,77 (t, 1H, J = 5 Hz), to 6.80 (d, 1H, J = 17 Hz), 7,54 (t, 1H, J = 5 Hz), 8,07 (s, 1H), 8,45 (d, 2H, J = 5 Hz), of 8.92 (d, 2H, J = 5 Hz).

Example 25

Hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2,5-dichlorophenyl)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 16, using 1,53 g of the hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2,5-dichlorophenyl)-1-piperazinil] -1-TRANS-propanone. After you complete the selection, receive 840 mg specified in the header joint is 3,95-of 4.05 (m, 2H), from 6.22 (dt, 1H, J = 15,6, 7,3 Hz), 6,83 (d, 1H, J = 15.6 Hz), 7,18 (DD, 1H, J = 8,3, 2.0 Hz), 7,26 (s, 1H), 7,29 (s, 1H), 7,49 (d, 1H, J = 8,3 Hz), of 8.04 (s, 1H).

Example 26

Hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2,5-dichlorophenyl)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 16, using 408 mg of the hydrochloride of 1-[5-methyl-1-(4,6-dimethyl-2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2,4-dichlorophenyl)-1-piperazinil] -1-propanone. After you complete the selection, receive 131 mg specified in the connection header.

So pl. 212-216oC (decomp.)

1H-NMR (DMSO-d6) : of 2.51 (s, 6H), 2,61 (s, 3H), 3,1-of 3.25 (m, 4H), 3,4-3,5 (m, 4H), 3,55-the 3.65 (m, 2H), 3,9-4,0 (m, 4H), to 6.22 (dt, 1H, J = 15,6, 7,3 Hz), PC 6.82 (d, 1H, J = 15.6 Hz), 7,24 (d, 1H, J = 8,8 Hz), 7,29 (s, 1H), 7,41 (DD, 1H, J = 8,8, 1.5 Hz), to 7.61 (s, 1H), 8,03 (s, 1H).

Example 27

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3,5-dichlorophenyl)-1-piperazinil]-1-TRANS-propene

(1) Hydrochloride 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3,5-dichlorophenyl)-1-piperazinil]-1-propanone

of 1.75 g of 4-Acetyl-1-(2-pyrimidinyl)-5-methylpyrazole and dissolved in 150 ml of ethanol and gain of 2.21 g of the hydrochloride 3,5-dichloronitrobenzene and 740 mg of paraformaldehyde. The resulting mixture was heated under reflux for 24 hours. Then add 300 mg of paraformaldehyde and the and the precipitate is filtered, followed by addition of chloroform. Next, it is washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (90 g silica gel, chloroform : methanol = 50 : 1). Then the resulting product is converted into the hydrochloride by addition of 1 N. hydrochloric acid and recrystallized from ethanol to obtain thus 1,82 g specified in the connection header.

So pl. 208-211oC (decomp.)

1H-NMR (DMSO-d6) : 2,82 (s, 3H), 3,1-of 3.25 (m, 4H), 3.45 points and 3.6 (m, 4H), up 3.6-3.7 (m, 2H), 3.95 to of 4.05 (m, 2H), of 6.96 (s, 1H), was 7.08 (s, 2H), to 7.67 (t, 1H, J = 4.9 Hz), 8,42 (s, 1H), 9,00 (d, 2H, J = 4,9 Hz).

(2) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3,5-dichlorophenyl)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 16, using 1.45 g of the hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3,5-dichlorophenyl)-1-piperazinil] -1-propanone. After you complete the selection, receive 358 mg specified in the connection header.

So pl. 209-212oC (decomp.)

1H-NMR (DMSO-d6) : 2,62 (s, 3H), 3,05-of 3.25 (m, 4H), 3,5-3,6 (m, 2H), 3,9-of 4.05 (m, 4H), 6,21 (dt, 1H, J = the 15.6, and 7.8 Hz), for 6.81 (d, 1H, J = 15.6 Hz), to 6.95 (s, 1H), 7,05 (s, 2H), 7,53 (t, 1H, J = 4.9 Hz), 8,08 (s, 1H), 8,92 (d, 2H, J = 4,9 Hz).

So pl. 234-238oC (decomp.)

1H-NMR (DMSO-d6) : 3,1-3,2 (m, 4H), 3,4-3,5 (m, 4H), 6,56 (p, 2H, J = 9,3 Hz), 6,70 (d, 1H, J = 9,3 Hz).

(2) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3,5-differenl)-1-piperazinil]-1-propanone

1.01 g of 4-Acetyl-1-(2-pyrimidinyl)-5-methylpyrazole was dissolved in 85 ml of anhydrous ethanol and added 1.10 g of the compound obtained above (1) and 0.45 g of paraformaldehyde. In the mixture heated under reflux for a further 60 hours. The ethanol is then evaporated and to the residue was added chloroform. Next, it is washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (silica gel 50 g, chloroform : methanol= 50 : 1 - 40 : 1). The product is then converted into hydrochloride by adding a solution of 1 N. hydrochloric acid/ethanol and recrystallized from ethanol. Thus obtain 129 mg specified in the connection header.

So pl. 195-200oC (decomp.)

1H-NMR (DMSO-d6) : 2,82 (s, 3H), 3,1-of 3.25 (m, 4H), 3,45-3,55 (m, 4H), up 3.6-3.7 (m, 2H), 3.95 to of 4.05 (m, 2H), return of 6.58 (t, 1H, J = 8,8 Hz), 6,77 (d, 2H, J = 10.3 Hz), to 7.67 (t, 1H, J = 4.9 Hz), 8,42 (s, 1H), 9,01 (d, 2H, J = 4,9 Hz).

(3) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3,5-differenl)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 16, using 103 mg of the compound obtained above (2). After you complete the selection, receive 39 mg specified in the connection header.

So pl. 189-193oC (decomp.)

1H-NMR (DMSO-d6) : 2,62 (s, 3H), 3,05-of 3.25 (m, 4H), 3,5-3,6 (m, 2H), 3,9-of 4.05 (m, 4H), 6,21 (dt, 1H, J = 15,1, 7,3 Hz), to 6.58 (t, 1H, J = 9.3 Hz), 6,76 (d, 2H, J = 9,3 Hz), for 6.81 (d, 1H, J = 15.6 Hz), 7,54 (t, 1H, J = 4.9 Hz), 8,10 (s, 1H), 8,92 (d, 2H, J = 4,9 Hz).

Example 29
oC portions to the mixture was added 319 mg sodium borohydride for 7 hours. After decomposition of sodium borohydride by adding conc. hydrochloric acid, the solvent is removed by evaporation. Then the residue is neutralized by adding an aqueous solution of sodium hydroxide and extraction with chloroform. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is dissolved in 7 ml of tetrahydrofuran. Then add 250 mg of the monohydrate of p-toluensulfonate acid and the mixture heated under reflux for 60 minutes. After evaporation of the solvent the residue is neutralized by adding an aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (chloroform : methanol = 100 : 2 to 3), then the product is converted into hydrochloride by adding 0.3 ml of a solution of 1 N. hydrochloric acid/ethanol and recrystallized from methanol/ethyl acetate. Thus A14oC.

1H-NMR (DMSO-d6) : 2,63 (s, 6H), 2,7-2,9 (m, 4H), 2.8 to 3.0 (m, 1H), 3,2-3,2 (m, 1H), up 3.6-3.7 (m, 1H), of 3.7-3.9 (m, 1H), 3,9-4,1 (m, 2H), 6.22 per (user. s, 1H), of 6.26 (dt, 1H, J = 16, 8 Hz), 6,86 (d, 1H, J = 16 Hz), 7,33 (t, 1H, J = 7 Hz), 7,40 (t, 2H, J = 7 Hz), 7,50 (d, 2H, J = 7 Hz), 7,53 (t, 1H, J = 5 Hz), 8,07 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 30

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-nitrophenyl)-1-piperazinil]-1-TRANS-propene

(1) 1-(3-Nitrophenyl)piperazine

50 ml of a solution of 5 g of 3-nitroaniline and 6,46 g of the hydrochloride of bis(2-chloroethyl)amine in 1-butanol is heated under reflux for 25 hours. After addition of 3.84 g of sodium carbonate the mixture is still heated under reflux for 60 hours. After cooling, insoluble products collected by filtration, suspended in aqueous sodium hydroxide solution and extracted with chloroform. The extract is washed successively with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (chloroform : methanol = 100 : 3). So get a 4.03 g specified in the title compound as a red oily product.

1H-NMR (CDCl3) : 3,05 (t, 2H, J = 5 Hz), 3,24 (t, 2H, J = 5 Hz), 7,19 the Il] -3-[4-(3-nitrophenyl)-1-piperazinil]-1-propanone

487 mg of 4-Acetyl-1-(2-pyrimidinyl)-5-methylpyrazole, 524 mg of the compound obtained above (1), and 3.6 ml of a solution of 1 N. hydrochloric acid/ethanol was dissolved in 40 ml of ethanol and heated under reflux for 54 hours. During this period portions to the mixture was added 4.3 g of paraformaldehyde. After cooling, insoluble products collected by filtration. Thus obtain 630 mg specified in the title compound as a yellow solid product.

1H-NMR (CDCl3) : 2,82 (s, 3H), 3,2-3,3 (m, 4H), 3,5-3,6 (m, 4H), 3,6-3,8 (m, 2H), 4,0-4,1 (m, 2H), 7,51 (dt, 1H, J = 8, 2 Hz), 7,54 (t, 1H, J = 8 Hz), 7,66 (t, 1H, J = 5 Hz), 7,68 (dt, 1H, J = 8, 2 Hz), 7,79 (t, 1H, J = 2 Hz), 9,01 (d, 2H, J = 5 Hz), 9,01 (d, 2H, J = 5 Hz).

(3) the Hydrochloride Of 1-[5-Methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3-nitrophenyl)-1-piperazinil]-1-TRANS-propene

200 mg of the Compound obtained above (2), dissolved in a mixture solvent containing 10 ml ethanol and 10 ml of tetrahydrofuran and stirred under ice cooling for 2 hours. During this time the reaction mixture portions added 90 mg of sodium borohydride. Then added to 1.4 ml of 20% hydrochloric acid. After removal of the solvent to the residue was added 20 ml of tetrahydrofuran and 210 mg of the monohydrate of p-toluensulfonate acid. The mixture is heated OBR is a sodium hydroxide solution and then extracted with chloroform. The extract was sequentially washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is subjected to column chromatography on silica gel (chloroform : methanol = 100 : 1). The product is then converted into the hydrochloride using a solution of 1 N. hydrochloric acid/ethanol and recrystallization from ethanol. So get 64 mg specified in the title compound as a yellow solid product.

So pl. 189oC (decomp.).

1H-NMR (DMSO-d6) : 2,63 (s, 3H), 3,1-3,3 (m, 4H), 3,2-3,4 (m, 4H), 3,9-4,1 (m, 4H), 6,23 (dt, 1H, J = 16, 8 Hz), PC 6.82 (d, 1H, J = 16 Hz), of 7.48 (d, 1H, J = 8 Hz), 7,54 (t, 1H, J = 5 Hz), 7,54 (t, 1H, J = 8 Hz), to 7.67 (d, 1H, J = 8 Hz), 7,76 (user. s, 1H), of 8.09 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 31

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-acetylaminophenol)-1-piperazinil]-1-TRANS-propene

(1) 1-(5-Methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-acetylaminophenol)-1-piperazinil]-1-propanone

404 mg of the Compound obtained in example (2), 113 ml of acetic anhydride, 347 ml of triethylamine and 110 mg of 10% Pd/C is suspended in 22 ml of acetic acid and stirred in a stream of hydrogen gas. Then the insoluble products are removed by filtration. After evaporation rastvorjajut 277 mg specified in the connection header.

1H-NMR (CDCl3) : of 2.16 (s, 3H), 2,6-2,7 (m, 4H), 2,89 (t, 2H, J = 7 Hz), 3.00 and (s, 3H), 3,10 (t, 2H, J = 7 Hz), 3,1-3,3 (m, 4H), of 6.6 to 7.3 (m, 4H), 7,35 (t, 1H, J = 5 Hz), 8,14 (s, 1H), 8,86 (d, 2H, J = 5 Hz).

(2) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]- 3-[4-(3-acetylaminophenol)-1-piperazinil]-1-TRANS-propene

Repeat the procedure of example 30 (3), using 150 mg of the compound specified above. After you complete the selection, receive 16 mg specified in the title compound as a yellow solid product.

So pl. 200-220oC (decomp.).

1H-NMR (DMSO-d6) : 2,12 (s, 3H), was 2.76 (s, 3H), of 3.13 (t, 2H, J = 12 Hz), or 3.28 (t, 2H, J = 12 Hz), of 3.69 (d, 2H, J = 12 Hz), 3,85 (d, 2H, J = 12 Hz), 4,01 (d, 2H, J = 7 Hz), to 6.22 (dt, 1H, J = 16, 8 Hz), 6,77 (DD, 1H, J = 8, 2 Hz), 6,92 (d, 1H, J = 16 Hz), 6,98 (d, 1H, J = 8 Hz), 7,22 (t, 1H, J = 8 Hz), the 7.43 (t, 1H, J = 5 Hz), 7,44 (d, 1H, J = 2 Hz), 8,07 (s, 1H), 8,86 (d, 2H, J = 5 Hz).

Example 32

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-cyanophenyl)-1-piperazinil]-1-TRANS-propene

(1) 1-(3-Cyanophenyl)piperazine

Repeated interaction and the subsequent treatment according to example 30 (1), using to 4.41 g of 3-cyanoaniline and get the result 2,62 g specified in the title compound as a yellow product.

1H-NMR (CDCl3) : 3,03 (t, 2H, J = 5 Hz), 3,18 (t, 2H, J = 5 Hz), 7,00 to 7.2 (m, 3H), 7,32 (DD, 1H, J = 7, 9 Hz).

1H-NMR (DMSO-d6) : 2,82 (s, 3H), 3,1-3,3 (m, 4H), 3,4-3,6 (m, 4H), up 3.6-3.7 (m, 2H), 3,9-4,0 (m, 2H), 7,26 (d, 1H, J = 8 Hz), 7,37 (DD, 1H, J = 8, 2 Hz), was 7.45 (t, 1H, J = 8 Hz), 7,47 (d, 1H, J = 2 Hz), 7,66 (t, 1H, J = 5 Hz), 8,43 (s, 1H), 9,01 (d, 2H, J = 5 Hz).

(3) the Hydrochloride Of 1-[5-Methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(3-cyanophenyl)-1-piperazinil]-1-TRANS-propene

Repeated interaction and the subsequent treatment according to example 30 (3), using 350 mg of the compound obtained above (2), and get the result 165 mg specified in the title compounds as colorless crystals.

So pl. 215-225oC (decomp.).

1H-NMR (DMSO-d6) : 2,62 (s, 3H), 3,0-3,3 (m, 4H), 3,5-3,6 (m, 4H), 3,9-4,1 (m, 4H), 6,23 (dt, 1H, J = 16, 8 Hz), PC 6.82 (d, 1H, J = 16 Hz), 7,25 (d, 1H, J = 7 Hz), 7,39 (d, 1H, J = 8 Hz), of 7.4-7.5 (m, 2H), 7,54 (t, 1H, J = 5 Hz), 8,08 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 33

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(3-carbamoylphenoxy)-1-piperazinil]-1-TRANS-propene

88 mg of the Compound obtained in example 32 (3) dissolved in 0.5 ml conc. hydrochloric acid and stirred at room temperature for 62 hours. Then the reaction mixture natakamani aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is subjected to column chromatography on silica gel (chloroform : methanol = 100 : 3). The product is then converted into the hydrochloride using a solution of 1 N. hydrochloric acid/ethanol and recrystallization from ethanol. Thus receive 50 mg specified in the title compounds as colorless crystals.

So pl. 140-146oC (decomp.).

1H-NMR (DMSO-d6) : 2,63 (s, 3H), 3,1-3,3 (m, 4H), of 3.5-3.7 (m, 2H), 3,8-4,0 (m, 4H), 6,24 (dt, 1H, J = 16, 8 Hz), at 6.84 (d, 1H, J = 16 Hz), 7,16 (d, 1H, J = 8 Hz), 7,33 (t, 1H, J = 8 Hz), of 7.48 (user. s, 1H), 7,53 (t, 1H, J = 5 Hz), 8,08 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 34

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(5-chloro-2-hydroxyphenyl)-1-piperazinil]-1-TRANS-propene

(1) 1-(5-Chloro-2-hydroxyphenyl)piperazine

A solution of 3.0 g of 2-amino-4-chlorophenol and of 3.73 g of the hydrochloride of bis(2-chloroethyl)amine in 1-butanol (35 ml) is heated under reflux for 25 hours. After addition of 2.21 g of sodium carbonate the mixture is heated under reflux for 12 hours. After cooling, insoluble products collected by filtration and suspended in an aqueous solution of sodium hydroxide. After washing with chloroform, neutralized with an aqueous solution of ammonium chloride and extracted hatria. After evaporation of the solvent receive 1,90 g specified in the title compound as a brown solid product.

1H-NMR (CDCl3) : 2,82 (t, 4H, J = 5 Hz), 3.04 from (t, 4H, J = 5 Hz), to 6.88 (d, 1H, J = 9 Hz),? 7.04 baby mortality (DD, 1H, J = 9, 2 Hz), 7,11 (d, 1H, J = 2 Hz).

(2) 1-[5-Methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(5-chloro-2-hydroxyphenyl)-1-piperazinil]-1-propanone

Repeated interaction and the subsequent treatment according to example 30 (2), using 400 mg of the compound obtained above (1), and receive as a result of this 294 mg specified in the connection header.

1H-NMR (DMSO-d6) : 2,82 (s, 3H), 2,9-3,1 (m, 2H), 3,2-3,4 (m, 2H), 3,4-3,7 (m, 8H), at 6.84 (d, 1H, J = 8 Hz), 6,88 (user. s, 1H), 6.89 in (d, 1H, J = 8 Hz), 7,66 (t, 1H, J = 5 Hz), 8,42 (s, 1H), 9,01 (d, 2H, J = 5 Hz).

(3) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(5-chloro-2-hydroxyphenyl)-1-piperazinil]-1-TRANS-propene

250 mg of the Compound obtained above (2), dissolved in a mixture solvent containing 10 ml ethanol and 10 ml of tetrahydrofuran and stirred under ice cooling for 1.5 hours. During this time the reaction mixture portions added 90 mg of sodium borohydride. Then add 1.5 ml of 10% hydrochloric acid and the solvent is removed by evaporation. To the residue was added 20 ml of tetrahydrofuran and 167 mg manage the donkey evaporation of the solvent the residue is neutralized with an aqueous solution of sodium bicarbonate and extracted with chloroform. The extract is successively washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (chloroform : methanol = 100 : 1). The product is then converted into the hydrochloride using a solution of 1 N. hydrochloric acid/ethanol and recrystallization from ethanol. Thus obtain 131 mg specified in the title compounds as colorless crystals.

So pl. 210-220oC (decomp.).

1H-NMR (DMSO-d6) : 2,63 (s, 3H), 2,0-3,1 (m, 2H), 3,1-3,3 (m, 4H), of 3.5-3.7 (m, 4H), 3,9-4,0 (m, 2H), 6,23 (dt, 1H, J = 16, 8 Hz), 6,8-7,0 (m, 4H), 7,54 (t, 1H, J = 5 Hz), of 8.09 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 35

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2-hydroxyphenyl)-1-piperazinil]-1-TRANS-propene

(1) Hydrochloride 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-hydroxyphenyl)-1-piperazinil]-1-propanone

To 700 mg dihydrobromide 1-(2-hydroxyphenyl)piperazine was added a saturated aqueous solution of sodium bicarbonate. After extraction with chloroform, the extract washed with saturated aqueous sodium chloride and dried over sodium sulfate. After evaporation of the solvent to the residue was added 397 mg of 4-acetyl-1-(2-PI is adalnikam for 58 hours. During this period portions to the mixture was added 3.0 g of paraformaldehyde. After cooling, insoluble products collected by filtration to obtain thus 176 mg specified in the connection header.

1H-NMR (DMSO-d6) : 2,82 (s, 3H), 2,9-3,1 (m, 2H), 3,2-3,3 (m, 2H), 3,4-3,6 (m, 6H), up 3.6-3.7 (m, 2H), 6,77 (t, 1H, J = 7 Hz), at 6.84 (d, 1H, J = 7 Hz), 6.87 in (t, 1H, J = 7 Hz), 6,91 (d, 1H, J = 7 Hz), to 7.67 (t, 1H, J = 7 Hz), 8,43 (s, 1H), 9,01 (d, 1H, J = 5 Hz).

(2) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-hydroxyphenyl)-1-piperazinil]-1-TRANS-propene

Repeated interaction and the subsequent treatment according to example 34 (3), using 158 mg of the compound obtained above (1), and receive as a result of this 72 mg specified in the title compounds as colorless crystals.

So pl. 216-228oC (decomp.).

1H-NMR (DMSO-d6) : of 2.64 (s, 3H), 2,9-3,1 (m, 2H), 3,1-3,3 (m, 2H), 3,4-3,6 (m, 4H), 3,9-4,0 (m, 2H), 6,24 (dt, 1H, J = 16, 8 Hz), 6,76 (t, 1H, J = 8 Hz), at 6.84 (d, 1H, J = 16 Hz), 6,85 (d, 1H, J = 8 Hz), to 6.88 (t, 1H, J = 8 Hz), 6.90 to (d, 1H, J = 8 Hz), 7,53 (t, 1H, J = 5 Hz), of 8.09 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 36

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(4-methoxyphenyl)-1-piperazinil]-1-TRANS-propene

(1) Hydrochloride 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(4-methoxyphenyl)-1-piperazinil]-1-propanone is orida 1-(4-methoxyphenyl)piperazine and 0.8 g of paraformaldehyde, the mixture is heated under reflux for 24 hours. Then add 0.8 g of paraformaldehyde and the mixture was heated under reflux for 48 hours. Then the reaction mixture was concentrated and neutralized by adding saturated aqueous solution of sodium bicarbonate. After extraction with chloroform, the extract washed with saturated aqueous sodium chloride and dried over sodium sulfate. After evaporation of the solvent thus obtained residue is purified column chromatography on silica gel (chloroform : methanol = 50 : 1), is converted into hydrochloride by adding a solution of 1 N. hydrochloric acid/ethanol and then recrystallized from ethanol. Thus obtained 1.1 g specified in the title compounds as pale yellow powder.

So pl. 150-152,8oC.

1H-NMR (DMSO-d6) : of 2.81 (s, 3H), 3,0-3,1 (m, 2H), 3,2-3,3 (m, 2H), 3,4-3,6 (m, 4H), of 3.5-3.7 (m, 4H), 3,70 (s, 3H), 6.87 in (d, 2H, J = 9,3 Hz), 6,97 (d, 2H, J = 9,3 Hz), to 7.67 (t, 1H, J = 4.9 Hz), 8,43 (s, 1H), 9,10 (d, 2H, J = 4,9 Hz).

(2) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(4-methoxyphenyl)-1-piperazinil]-1-TRANS-propene

80 mg of the Compound obtained above (1), dissolved in a mixture solvent containing 5 ml of ethanol and 5 ml of tetrahydrofuran. Then to the reaction mixture at -10oSenia solution of 1 N. hydrochloric acid/ethanol and the solvent is removed by evaporation. Thus obtained residue is dissolved in a solvent mixture containing 5 ml of 1,4-dioxane and 5 ml of tetrahydrofuran. After addition of 38 mg of the monohydrate of p-toluensulfonate acid the mixture is heated under reflux for 1 hour. Then the reaction mixture was concentrated, neutralized by adding an aqueous solution of sodium bicarbonate and then extracted with chloroform. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (chloroform : methanol = 50 : 1), is converted into hydrochloride by adding a solution of 1 N. hydrochloric acid/ethanol and then recrystallized from ethanol. Thus obtain 31 mg specified in the title compound as a white powder.

So pl. 154,3-155,5oC (decomp.).

1H-NMR (DMSO-d6) : 2,62 (s, 3H), 3,0-3,1 (m, 2H), 3,1-3,2 (m, 2H), of 3.5-3.7 (m, 4H), 3,70 (s, 3H), 3,9-4,0 (m, 2H), from 6.22 (dt, 1H, J = 16,1, 7,3 Hz), PC 6.82 (d, 1H, J = 16.1 Hz), 6,86 (d, 1H, J = 9.0 Hz), of 6.96 (d, 2H, J = 9.0 Hz), 7,54 (t, 1H, J = 4.9 Hz), 8,10 (s, 1H), 8,93 (d, 2H, J = 4,9 Hz).

Example 37

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(4-�roxiprin)-1-piperazinil]-1-propanone

2.0 g of 1-(2-Pyrimidinyl)-4-acetyl-5-methylpyrazole was dissolved in 50 ml of ethanol. After addition of 2.6 g of the dihydrochloride of 1-(4-hydroxyphenyl)piperazine, 10 ml solution of 1 N. hydrochloric acid/ethanol and 1.6 g of paraformaldehyde, the mixture is heated under reflux for 24 hours. Then add 3.2 g of paraformaldehyde and the mixture was heated under reflux for 48 hours. Then the reaction mixture was concentrated and neutralized by adding saturated aqueous solution of sodium bicarbonate. After extraction with chloroform, the extract washed with saturated aqueous sodium chloride and dried over sodium sulfate. After evaporation of the solvent thus obtained residue is purified column chromatography on silica gel (chloroform : methanol = 20 : 1), is converted into hydrochloride by adding a solution of 1 N. hydrochloric acid/ethanol and then recrystallized from ethanol. Thus receive 946 mg specified in the title compound as pale brown powder.

So pl. 141,8-142,9oC (decomp.).

1H-NMR (DMSO-d6) : 2,90 (s, 3H), is 3.08 (t, 2H, J = 4, 2 Hz), 3,1-3,2 (m, 2H), 3,4-3,5 (m, 2H), 3.5 to 3.8 (m, 4H), of 6.68 (d, 2H, J = 9,2 Hz), 6.8 or 6.9 (m, 2H), 7,55 (t, 1H, J = 4.9 Hz), of 8.04 (s, 1H), 8,93 (d, 2H, J = 4,9 Hz).


Repeated interaction and the subsequent treatment according to example 36 (2), using 437 mg of the compound obtained above (1), and receive the result, 337 mg specified in the title compound as pale brown powder.

So pl. 136,2-137,5oC (decomp.).

1H-NMR (DMSO-d6) : 2,62 (s, 3H), 3,0-3,1 (m, 2H), 3,1-3,2 (m, 2H), of 3.5-3.7 (m, 4H), 3,9-4,0 (m, 2H), 6,23 (dt, 1H, J = 16,3, 6.5 Hz), 6,74 (d, 2H, J = 8,3 Hz), 6.87 in (d, 1H, J = 16,3 Hz) 6,91 (d, 2H, J = 8,3 Hz), 7,58 (t, 1H, J = 4,8 Hz), 7,58 (t, 1H, J = 4,8 Hz), 8,13 (c, 1H), 8,93 (d, 2H, J = 4,8 Hz).

Example 38

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(4-diphenylmethyl)-1-piperazinil]-1-TRANS-propene

(1) Hydrochloride 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(4-diphenylmethyl)-1-piperazinil]-1-propanone

Repeated interaction and the subsequent treatment according to example 36 (1), using 1.26 g of 1-(diphenylmethyl)piperazine and get the result 867 mg specified in the connection header.

So pl. 220-223oC (decomp.).

1H-NMR (DMSO-d6) : 2,80 (s, 3H), 3,1-3,6 (m, 12H), 4,49 (s, 1H), 7,2-7,5 (m, 10H), 7,66 (t, 1H, J = 5 Hz), scored 8.38 (s, 1H), 9,00 (d, 2H, J = 5 Hz).

(2) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(4-methoxyphenyl)-1-piperazinil]-1-TRANS-propene

806 mg of the Compound obtained above (1), dissolved in ice to 0oC add 250 mg of sodium borohydride and the mixture is stirred at the same temperature for 1 hour. Add another 50 mg of sodium borohydride and the mixture is stirred for further 1 hour. Then the reaction mixture is neutralized by addition of a solution of 1 N. hydrochloric acid/ethanol. After evaporation of the solvent concentrated thus the residue is extracted with chloroform and saturated aqueous sodium bicarbonate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent to the residue was added 25 ml of anhydrous dioxane, 25 ml of anhydrous tetrahydrofuran and 432 mg of the monohydrate of p-toluensulfonate acid and the resulting mixture heated under reflux for 5 hours. After evaporation of the solvent the residue is extracted with chloroform and saturated aqueous sodium bicarbonate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent, the obtained residue is purified column chromatography on silica gel (40 g, chloroform : methanol = 50 : 1), is converted into hydrochloride by adding a solution of 1 N. hydrochloric acid/ethanol and then Perl. 202-205 areoC.

1H-NMR (DMSO-d6) : 2,60 (s, 3H), of 3.4 to 3.8 (m, 10H), to 4.38 (s, 1H), x 6.15 (dt, 1H, J = 16, 8 Hz), PC 6.82 (d, 1H, J = 16 Hz), and 7.1 to 7.4 (m, 10H), 7,53 (t, 1H, J = 5 Hz), of 8.04 (s, 1H), 8,91 (d, 2H, J = 5 Hz).

Example 39

The dihydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-benzyl-1-piperazinil]-1-TRANS-propene

(1) Hydrochloride 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4 - benzyl-1-piperazinil]-1-propanone

1.01 g of 4-Acetyl-1-(2-pyrimidinyl)-5-methylpyrazole was dissolved in 80 ml of anhydrous ethanol. After addition of 1.25 g of the hydrochloride of 1-benzylpiperazine and 0.45 g of paraformaldehyde, the mixture is heated under reflux for 18 hours. Then add to 0.60 g of the hydrochloride of 1-benzylpiperazine and 0.20 g of paraformaldehyde and the mixture was heated under reflux for 8 hours. After cooling, the crystals are collected by filtration and extracted with chloroform and saturated aqueous sodium bicarbonate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent thus obtained residue is purified column chromatography on silica gel (50 g, chloroform : methanol = 50 : 1), is converted into hydrochloride by adding a solution of 1 N. selenocosmiinae.

So pl. 166-169oC (decomp.).

1H-NMR (DMSO-d6) : 2,80 (s, 3H), of 3.2 to 3.8 (m, 14H), of 7.4 to 7.7 (m, 5H), 7,66 (t, 1H, J = 5 Hz), at 8.36 (s, 1H), 9,00 (d, 2H, J = 5 Hz).

(2) the Dihydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-benzyl-1-piperazinil]-1-TRANS-propene

Repeated interaction and the subsequent treatment according to example 38 (2), using 430 mg of the compound obtained above (1), and receive as a result of this 132 mg specified in the connection header.

So pl. 197-201oC (decomp.).

1H-NMR (DMSO-d6) : 2,62 (s, 3H), 3,2-4,0 (m, 12H), x 6.15 (dt, 1H, J = 16, 8 Hz), 6,85 (d, 1H, J = 16 Hz), of 7.4 to 7.4 (m, 5H), 7,53 (t, 1H, J = 5 Hz), 8,03 (s, 1H), 8,91 (d, 2H, J = 5 Hz).

Example 40

The dihydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-piperidino-1-piperidyl]-1-TRANS-propene

(1) the Dihydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-piperidino-1-piperidyl]-1-propanone

Repeated interaction and the subsequent treatment according to example 39 (1) using of 1.23 g of 4-piperidinylidene, and receive as a result of this 900 mg specified in the connection header.

So pl. 274-278oC (decomp.).

1H-NMR (CD3OD) : 1,8-2,1 (m, 4H), 2,15-2,3 (m, 2H), 2,4-2,5 (m, 2H), 2,98 (s, 3H), 3,0-3,1 (m, 1H), 3,15-to 3.35 (m, 4H), 3.45 points-of 3.65 (m, 6H), 3,8-3,9 (m, 2H), 7,55 (t, 1H, J = 5 Hz), 8,35 (s, 1H), 8,93 (d, 2H, J = 5 Hz).

So pl. 267-273oC (decomp.).

1H-NMR (CD3OD) : 1,8-2,0 (m, 4H), 2.05 is-2,1 (m, 2H), 2,4-2,5 (m, 2H), 2,74 (s, 3H), 3,0-3,2 (m, 2H), 3.25 to 3,4 (m, 6H), 3,5-3,6 (m, 2H), of 3.7-3.8 (m, 1H), 3,9-4,0 (m, 2H), 6,21 (dt, 1H, J = 16, 8 Hz), 6.90 to (d, 1H, J = 16 Hz), was 7.45 (t, 1H, J = 5 Hz), 8,07 (s, 1H), 8,86 (d, 2H, J = 5 Hz).

Example 41

Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2,5-differenl)-1-piperazinil]-1-TRANS-propene

(1) Hydrochloride 1-(2,5-differenl)piperazine

7.0 g of the Hydrochloride of bis-(2-chloroethyl)amine are suspended in 60 ml of butanol and at room temperature was added 5 g of 2,5-diferencia. After heating under reflux for 72 hours, the reaction mixture is cooled and added 4.1 g of sodium carbonate. After heating under reflux for an additional 24 hours the precipitate is collected by filtration, dissolved in water and extracted with chloroform. Then the extract was successively washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is dissolved in a small amount of chloroform, converted into hydrochloride by adding RA is to be placed.

So pl. 234-238oC (decomp.)

1H-NMR (CD3OD) : of 3.25 to 3.45 (m, 8H), 6,76 (DDD, 1H, J = 12, 8, 3 Hz), 6,86 (DDD, 1H, J = 10, 7, 3 Hz), to 7.09 (DDD, 1H, J = 12, 9, 5 Hz).

(2) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2,5-differenl)-1-piperazinil]-1-propanone

Repeated interaction and the subsequent treatment according to example 36 (1), using a 1.00 g of the hydrochloride of 1-(2,5-differenl)piperazine, and get the result 190 mg specified in the connection header.

So pl. 174-176oC (decomp.)

1H-NMR (DMSO-d6) : 2,82 (s, 3H), 3,1-of 3.25 (m, 2H), 3,2-3,4 (m, 4H), of 3.5-3.7 (m, 6H), 6.8 or 6.9 (m, 2H), 6,95-7,05 (m, 4H), 7,2-7,3 (m, 1H), to 7.67 (t, 1H, J = 5 Hz), 8,42 (s, 1H), 9,00 (d, 2H, J = 5 Hz).

(3) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl] -3-[4-(2,5-differenl)-1-piperazinil]-1-TRANS-propene

Repeated interaction and the subsequent treatment according to example 38 (2), using 165 mg of the compound obtained above (2), and receive as a result of this 54 mg specified in the connection header.

So pl. 209-212oC (decomp.)

1H-NMR (DMSO-d6) : 2,63 (s, 3H), 3,1-3,3 (m, 4H), 3,5-of 3.65 (m, 4H), 3,9-4,0 (m, 2H), from 6.22 (dt, 1H, J = 16, 8 Hz), PC 6.82 (d, 1H, J = 16 Hz), 6.8 or 6.9 (m, 1H), 7,00 (DDD, 1H, J = 10, 7, 3 Hz), 7,22 (DDD, 1H, J = 12, 9, 5 Hz), 7,54 (t, 1H, J = 5 Hz), of 8.09 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Example 42

Hydrochloride of 1-[5-methyl-1-(2-Piri is erazine

7,14 g of the Hydrochloride of bis-(2-chloroethyl)amine are suspended in 70 ml of butanol and at room temperature was added 6,48 g 2,5-dichloraniline. After heating under reflux for 48 hours the reaction mixture is cooled and added 5,52 g of sodium carbonate. After heating under reflux for an additional 24 hours, the insoluble products is filtered off and the filtrate concentrated. Then the obtained residue is extracted with chloroform and saturated aqueous sodium bicarbonate. The extract is washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel (100 g, chloroform : methanol= 50 : 1 - 30 : 1). The product is converted into the hydrochloride by adding a solution of 1 N. hydrochloric acid/ethanol to obtain thus 1,41 g specified in the connection header.

So pl. 200-205oC (decomp.)

1H-NMR (CD3OD) : of 3.25 to 3.45 (m, 8H), 7,13 (d, 1H, J = 8 Hz), 7,20 (s, 1H), 7,40 (d, 1H, J = 8 Hz).

(2) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2,5-dichlorophenyl)-1-piperazinil]-1-propanone

Repeated interaction and the subsequent treatment according to example 36 (1), use the connection.

So pl. 200-203oC (decomp.)

1H-NMR (DMSO-d6) : 2,82 (s, 3H), 3,1-3,3 (m, 4H), 3.45 points and 3.6 (m, 6H), 3,65 of 3.75 (m, 4H), 7,18 (d, 1H, J = 8 Hz), 7,27 (s, 1H), 7,49 (d, 1H, J = 8 Hz), 7,66 (t, 1H, J = 5 Hz), 8,42 (s, 1H), 9,00 (d, 2H, J = 5 Hz).

(3) the Hydrochloride of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2,5-dichlorophenyl)-1-piperazinil]-1-TRANS-propene

Repeated interaction and the subsequent treatment according to example 38 (2), using 564 mg of the compound obtained above (2), and get the result 378 mg specified in the connection header.

So pl. 210-215oC (decomp.)

1H-NMR (DMSO-d6) : 2,63 (s, 3H), 3,1-3,3 (m, 4H), 3,4-3,7 (m, 4H), 3.95 to of 4.05 (m, 2H), from 6.22 (dt, 1H, J = 16, 8 Hz), 6,83 (d, 1H, J = 16 Hz), 7,18 (d, 2H, J = 8 Hz), 7,27 (s, 1H), 7,49 (d, 1H, J = 8 Hz), 7,54 (t, 1H, J = 5 Hz), 8,10 (s, 1H), 8,92 (d, 2H, J = 5 Hz).

Industrial applicability

Since the compounds of the present invention, represented by formula (I) and salts thereof, possess antitumor effect, they are used as anticancer agents.

1. Derivatives pyrimidinylpiperazine General formula I

< / BR>
where R1and R2can be either the same or different and selected from the group comprising a hydrogen atom, a C1-C4is an alkyl group, a hydroxyl group or a C1-C4-alkoxylated;

R6- tetrahydroisoquinoline group, piperideine group, or a group of the formula

< / BR>
< / BR>
where Z represents a phenyl group, possibly substituted by one or more substituents selected from the group comprising halogen atom, acetylamino, the nitro-group, hydroxyl group, cyano, karbamoilnuyu group, C1-C4is an alkyl group which may be substituted by a halogen atom, or Z represents pyridyloxy, pyrimidinyl, benzyl, benzhydryl, group,

or their salts.

2. Connection on p. 1 and its salt, where R4is a methyl group.

3. Connection on p. 1 and its salt, where R1and R2selected from the group comprising a hydrogen atom, a C1-C4is an alkyl group or a C1-C4-CNS group.

4. Connection on p. 1 and its salt, where R6represents a group of the formula

< / BR>
< / BR>
where Z is specified in paragraph 1.

5. Connection on p. 1 and its salt, where R6represents a group of the formula

< / BR>
< / BR>
where Z is specified in paragraph 1,

each of which is optionally substituted by one or more substituents selected from the group comprising halogen atom, a cyano, a hydroxyl group and/BR>< / BR>
< / BR>
where Z is specified in paragraph 1,

each of which is optionally substituted by one or more substituents selected from the group comprising a halogen atom and a hydroxyl group.

7. Connection on p. 1 and its salt, where R6represents a group of the formula

< / BR>
where Z is specified in paragraph 1.

8. The compound according to any one of paragraphs.4-7 and its salt, where Z represents a phenyl group.

9. Connection on p. 1 and its salt, where R6represents a group of the formula

< / BR>
where Z represents a phenyl group.

10. Antitumor agent containing an effective amount of a compound according to any one of paragraphs.1-9, or its salt as an active ingredient.

 

Same patents:

The invention relates to new substituted pyrrole General formula I

< / BR>
where R is hydrogen, hydroxyl;

R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;

R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,

R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;

R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;

R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);

Z - group-CH - or N-atom;

m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to a new derived tetrazole having effect in reducing blood sugar and lipid in the blood, and it contains the tool for use in the treatment of diabetes and hyperlipemia

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts

The invention relates to a new derivative of naphthalene, having Antiasthmatic activity, and the method of its production
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