Derivatives of 4-(2-pyrimidinyl)-1-piperazinil or their pharmaceutically acceptable salts

 

(57) Abstract:

Usage: in the pharmaceutical industry, because the product has biological activity, in particular anxiolytic. The essence of the invention: new derivatives of 4-(2-pyrimidinyl)-1-piperazinil f-ly 1, where R is a hydrogen atom, n is 1 to 6, Het is selected from imidazole or pyrazole f-crystals 2, where a and b are different and represent a carbon atom or nitrogen. R2and R4- same or different and mean hydrogen, halogen, lower alkyl, nitro, cyano, phenyl or phenyl substituted by halogen, or R2and R3or R3and R4together form alkylenes chain containing four carbon atoms which may be saturated or unsaturated, or a pharmaceutically acceptable salt. The structure of compounds 1 and 2:

, . 5 table.

The invention relates to the field of synthesis of new biologically active compounds.

New compounds belong to the group of derivatives of 4-(2-pyrimidinyl)-1-piperazinil with anxiolytic and tranquilizing activity.

Known compounds of buspirone and ipsapirone (see Megs Index, 11th edition, non 1493, page 229 and 4967, page 803), showing similar activity. However, their activity defects in the joints.

This goal is achieved by using derivatives of 4-(2-pyrimidinyl)-1-piperazinil General formula:

I

in which R1means a hydrogen atom, n is 1 to 6; Het denotes an imidazole or pyrazole of the General formula II:

< / BR>
where a and b are different and represent a carbon atom or nitrogen,

R2-R4identical or different, denote a hydrogen atom, halogen, lower alkyl, nitro, cyano, phenyl or phenyl substituted by halogen, lower alkoxyl, or R2-R3or R3and R4together form alkylenes chain containing 4 carbon atoms which may be saturated or unsaturated,

or their pharmaceutically acceptable salts.

New derivatives of General formula I can be obtained by the following method:

The reaction of compounds of General formula IV

(IV)

in which R1has the above-mentioned values and

X represents a halogen atom or the group that you want, select from tosyloxy or mesilate, with the compound of General formula V:

(V)

in which A, B, R2, R3and R4have the above values.

The reaction is carried out in the presence of an appropriate solvent, for example dimethyl sulfoxide, dimethylformamide, alcohol, uglevodorodnaya. This reaction is mainly carried out in the presence of a base, for example, hydroxide, carbonate or bicarbonate of alkali metals or their salts.

Mostly the reaction temperature is between room temperature and the temperature phlegmy solvent, and the reaction time is between 1 hour and 24 hours.

Compounds of General formula I is transferred to the salt by treatment of a mineral or organic acid in an environment suitable solvent.

The following examples illustrate the invention:

Example 1. Obtaining 1H-pyrazole-1-(4-(4-(2-pyrimidinyl)-1-piperazinil)-butyl).

Heated under the phlegm within 14 hours a mixture of 4 g (13.3 mmol) of 2-pyrimidine-1-(4-bromobutyl)-4-piperazine, of 1.02 g (15 mmol) of pyrazole and 2.76 g (20 mmol) of potassium carbonate in 50 ml of dimethylformamide. Evaporated in vacuo, add chloroform, washed with water, dried on sodium sulfate, evaporated in vacuo and obtain 3.5 g of oil, which represents 1H-pyrazole-1-(4-(4-(2-pyrimidinyl)-1-piperazinil)-butyl).

Identified compound in examples 2-14 receive in the same way. Data identification are in tables I-III.

Example 16. Getting dichlorhydrate 1H-feast who yl)-1-piperazinil)-butyl) in 100 ml of ethanol and heated to 60oC. With ethanol saturated with hydrochloric acid to bring the solution to pH 4.5-5. Concentrate the resulting solution to half volume and left to crystallize at 5oC for 12 hours. Obtain 5.5 g of crystals with a melting point 194-197,5oC, which correspond to diclorhidrato 1H-pyrazole-4-chloro-1-(4-(4-(2-pyrimidinyl)-1-piperazinil)-butyl).

The product of example 15 get in the same way.

Spectroscopic data that identifies these products are shown in table IV.

Biological activity

Several examples illustrate the effect on the Central nervous system, or rather their anxioliticescoy and tranquilizing action, using test driven response evasion, according to the method of J. S. New and others (J. S. New J. P. Jevich, M. S. Eison, D. P. Taylor, A. S. Eison, L. A. Riblet, C. P. Van der Maelen, D. L. Tample, J. Med.Chem. 1986, 29, 1476).

In this test using rats species Wistar, male, weighing 200 grams, trained to jump over a barrier in a cage with a latch and output (shuttle box) (Letica, link L 1 910 L1 and 2700), within 30 seconds after their introduction into the cell.

Products or anxiolytic anxiolytic activity eliminate due to the response of evasion.

The second and third days: 2 experiences of the day, only with selected rats [sum of the first day (except the first experience) over 14]

Day experience: the group formed by selected rats. The product or excipient administered 45 minutes before the start of the study.

In table V summarizes the results obtained with the test products.

Given their high pharmacodynamic properties, derivatives of 1H-pyrazole-(4-(4-(2-pyrimidinyl)-1-piperazinil)-butyl) can be used satisfactorily in the treatment of humans or animals, especially in the treatment of disorders of the Central nervous system, and especially for the treatment of painful fear, or as tranquilizers.

Derivatives of 4-(2-pyrimidinyl)-1-piperazinil General formula I

< / BR>
where R1hydrogen;

n 1 6;

Het is selected from imidazole or pyrazole of the General formula

< / BR>
where A and B are different and represent a carbon atom or nitrogen;

R2R4the same or different, hydrogen, halogen, lower alkyl, nitro, cyano, phenyl or phenyl substituted by halogen, lower alkoxyl, or R2R3or R3R4together form alkylenes chain containing four carbon atoms, to the organisations of the formula I on p. 1, wherein R1, R2and R4the hydrogen.

3. The compounds of formula I on p. 1, wherein R3halogen selected from chlorine, bromine, fluorine.

 

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