Derivatives of 4-(2-pyrimidinyl)piperazine

 

(57) Abstract:

Usage: in medicine, in particular as anxiolytic sedatives. The inventive product is a derivative of 4-(2-pyridinyl)piperazine of the formula where A = -C(O)R ; -S(O)(O)R1The R group of the formula and R1group of the formula Reagent 1 - compound of formula 2 or 3 : R is H; Cl(CH) -S(O) -R. the Reagent 2 - compound of formula 4 or 5. Reaction conditions: in an environment of inert rastvoritelya. The structure of the formulas in table 2.

The invention relates to derivatives of 4-(2-pyrimidinyl)-piperazine, which can be useful as anxiolytic sedatives. The invention relates to compounds in which the acyl Deputy represents geterotsiklicheskikh or heterocyclisation group.

You know the invention [1] - a series of N-(heteroalicyclic)-piperazinylmethyl - azaspirodecanedione formula

(C-A-NN-B, where a represents C2-6alkylen; 2-pyrimidinyl; and n is 4 or 5. These compounds possess anxiolytic and antiemetic ability.

I found that some of 1-acyl-3-[4-(2-pyrimidinyl)-1-piperazinil] propane formula [1] is useful as it eliminates fear, anxiety ilarly 1') or - R1(compound of formula 1) where R represents the group:

N- , N-,

- , NN-,

N- , N-,

N-,

N- , N-,

N- , N-,

N - or N-

R1group of the formula:

- , -,

ClN- , H-NN-,

N , N,

N-

The invention also includes pharmaceutically acceptable acid additive salts of compounds of the formula [1].

The term pharmaceutically acceptable acid additive salts of compounds of the formula [1] mean salts of hydrochloric, Hydrobromic, idiscovered, sulfuric, sulfamic acid, paratoluenesulfonyl, acetic, lactic, citric, ascorbic, acid, methane-sulfonic acids and salts with other organic acids, known to specialists, which are used in obtaining pharmaceutically acceptable salts accession acids. These salts get known methods, for example by reacting the corresponding compounds of formula [1] c equimolar or nearly equimolar amount of the desired acid in a reaction-inert solvent (ethanol, water, halogenated hydrocarbons), followed by separation of the salts by filtration or by evaporation of solvent.

Connection of the proposed invented the corresponding amine of the formula RH in a reaction-inert solvent, i.e., such a solvent which does not react with the reactants or the resulting products. Suitable dehydrating agents are combinations known in the art and include carbodiimide, such as dicyclohexylcarbodiimide in di-para-dimethylaminopyridine, N, N'-carbonite - imidazole, n-ethyl-5-phenyltetrazole-3'-sulfonate and diethylthiophosphate. 1-hydroxybenzotriazole usually added to the reaction mixture to facilitate the reaction combinations. Examples of the reaction-inert solvents include methylene chloride, chloroform, tetrahydrofuran, dioxane and bis-(2-methoxyethoxy) ether.

Although the stoichiometry of the specified reaction required equimolar amount of individual reagents, in practice, amine, acid, agent combination and 1-hydroxybenzotriazole usually used in a molar ratio of 1:1:1, 1:1: 5. Of course in the specialist there are various changes in the proportions of reagents used for optimization of technology for specific compounds of formula [1]. The above reaction is carried out at a temperature from about 0aboutWith up to ambient temperature. The target products are colored using known methods.

The acid component [4-4-(2-use this form in a specified reaction. As a consequence, to neutralize the acid contained in the specified salt in this reaction using a sufficient number of grounds. You can use various grounds. To the preferred bases are tertiary amines such as triethylamine and N-methylmorpholine.

4-[4-(2-pyrimidinyl)-1-piperazinil]butyric acid is obtained by reacting 1-(2-pyrimidinyl)piperazine with ethyl ether tetrabromobisphenol acid in a reaction-inert solvent such as isobutyl ketone, at a temperature of reflux distilled boiling up until reaction is essentially complete. In the reaction using the molar ratio of the reagents along with a 10% excess of sodium bicarbonate as an acid acceptor. To speed up the reaction using about from 1 to 10% iodotope potassium by weight ethyl 4-bromobutyrate. The resulting ester is separated by filtering off the solid by-products and solvent removal. Acid hydrolysis of ester, for example, hydrochloric acid, gives the desired acid.

The compounds of formula (1") is easily obtained by interaction of 1-(2-pyrimidinyl)piperazine with the corresponding 3-chloropropanesulfonyl format in a reaction-inert solvent, as which you can actually use any solvent that does not interact with the reactants or the resulting products. As the solvent used isobutyl ketone. The reaction is carried out at boiling point (reflux distilled) of the reaction mixture to complete or almost complete interaction. In order to facilitate the completion of the reaction using the reaction temperature in the range from 60 to 150aboutC. If the reaction of the selected upper limit value of the temperature of the specified interval, the solvent used bis-2-methoxymethyl ether.

Amin and chloropropanesulfonyl usually introduced into the reaction at a molar ratio of 1:1 in the presence of an acid acceptor, such as anhydrous sodium carbonate or a tertiary amine, such as triethylamine, N-methylmorpholine or pyridine. To accelerate the reaction, add about 1 to 10 wt.% potassium iodide per chlorine reagent. The product distinguish known methods.

The required 3-chloropropanesulfonyl easily obtained by the interaction of the amine R1H (where R1means heterocyclic residue of the formula [1" a-g] above, with 3-chloropropanesulfonyl the equivalent 3-chloropropanesulfonyl added to the solution, containing one equivalent of each of the corresponding amine and triethylamine at a temperature of from about 0 to 10aboutC. After complete addition, the reaction mixture is stirred for additional 10 min, then warmed up to room temperature. Product highlight extraction.

The activity of compounds of the invention as sedatives (relieves anxiety) funds is determined by modifying engaged in anti-conflict test Vogel. This technique is based on the ability of test compounds to increase the number of perceived irritation thirsty rats, which is subjected to irritation of drinking. The methodology is that of male rats weighing 160-170 g, located in vivarium, a week before the experiment was transferred to an experimental laboratory in cell and 6 rats per cage. Animals deprived of water for 48 h before the test on the conflict situation. Before the test animals (8 animals per group) are placed in the experimental chamber for a three-minute period of training. After placing the tray with water to drink, give each animal the opportunity for three minutes to drink without the use of punishment, after which the animal is removed from the camera.

Enter the standard anxiolytic with a simultaneous test of the tested compounds. Then carry out a statistical analysis of the average number of perceived each group of stimuli in comparison with the average number of responses to stimulation of the corresponding control group.

Compounds of the invention exhibit an increase of at least twice the number of animals perceive stimuli (shocks) in comparison with control groups of animals, which did not enter any anxiolytic.

Listed below are the data of pharmacological activity of the compounds of the invention (examples 1-21) and two Suomenlinna group substituted by dimetilan. For each of these compounds contains data of the following three tests activity:

1. Analysis of the binding of serotonin 1A using 3H 8-hydroxy-2(di-N-propylamino)tetralin;

2. Inhibition serotoninergicheskogo neural inflammation in the nuclei of the dorsal trunk;

3. Protivoglistnoe test Vogel.

Below you will find examples and formulations are for illustration only. For NMR spectra absorption capacity is given in parts per million (million share) from tetramethylsilane.

P R I m e R s 1-14. A General method of preparing compounds of the formula [1].

The solution containing the appropriate amine, one molar equivalent of dichlorhydrate 4-[4-(2-pyrimidinyl)-1-Pipa - retinyl]butyric acid, 2 equivalents of triethylamine and 1.5 equivalent of 1-hydroxybenzotriazole in methylene chloride, poured into the three-neck round bottom flask, equipped with a fridge, opening for flow of nitrogen, a magnetic stirrer and a thermometer, and cooled to 0aboutC in a water bath with ice and salt. Then added 1.1 equivalent of dicyclohexylcarbodimide - imide. The resulting mixture was stirred at 0aboutC for 3 h, then slowly warmed to room temperature with subsequent displacement and removal of traces of 1-hydroxybenzotriazole the filtrate washed with water (3 x 100 ml) and twice with saturated sodium bicarbonate solution. The aqueous layers are combined and washed with methylene chloride. The combined organic layers dried, filtered and after evaporation receive semi-solid product. Specified semi-solid product take in a minimum quantity of acetone and stirred for 1 h for crystallization of the residual traces of dicyclohexylamine. The insoluble product is filtered off, the filtrate is condensed to a brown oil.

Refined products are produced either by direct crystallization of the resulting oil from ethyl acetate, or flash chromatography on a column of silica gel. Target products then recrystallized from ethyl acetate. The yields are not optimized.

The following compounds whose properties are presented in table. 2.

P R I m e R s 15-21. A General method of preparing compounds of formula (1").

Hydrochloride of 1-(2-pyrimidyl)piperazine is dissolved in water, after which the resulting solution is alkalinized to pH 12-14 using 10% NaOH. The obtained two-phase mixture of the product as a yellow oil) is extracted three times with isobutyl ketone (MIBK).

In odnogolosy round bottom flask, equipped with magnetic stirrer, sump Dean-stark, fridge and atomidine)piperazine. To the specified base add one equivalent of the corresponding 3-chloropropanesulfonyl [formula Cl(CH2)3-SO2NR1where R1have the above values] , 1.3 equivalent of anhydrous Na2CO3and a catalytic amount TO a1. The reaction mixture was then refluxed over night at a moderate speed.

Inorganic solids contained in the reaction mixture is then filtered, the resulting filtrate is evaporated to obtain oil. In most cases, the crude oil is subjected to chromatography on silica gel using ethyl acetate as eluent. In some cases, the desired product crystallized from the crude oil dissolved in ethyl acetate. In all cases, after crystallization of the purified product from ethyl acetate and isopropyl alcohol have a pure crystalline product.

DERIVATIVES of 4-(2-PYRIMIDINYL)PIPERAZINE of General formula I

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where a group

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The R group

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R1group

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or its pharmaceutically acceptable acid-add the

 

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20 cl, 1 sch, 3 tbl, 31 ex

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FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

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EFFECT: valuable medicinal properties of inhibitors.

3 cl, 11 ex

Casr antagonist // 2315036

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel compound represented by the following formula (1) , its pharmaceutically acceptable salts or optically active isomers wherein each symbol is given in the invention description. Proposed compound possesses antagonistic effect with respect to calcium-sensitive receptor (CASR). Also, invention relates to a therapeutically medicinal agent used in treatment of osteoporosis based on this compound, to a method for treatment of osteoporosis, calcium receptor antagonist and to agent promoting secretion of parathyroid hormone (PTH).

EFFECT: valuable medicinal properties of antagonist.

33 cl, 66 tbl, 5 ex

FIELD: chemistry.

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EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

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