Derivatives piperazinylmethyl or their salts, having the property of braking withdrawal syndrome

 

(57) Abstract:

Usage: in medicine as a treatment for withdrawal symptoms. The inventive products: derivatives piperazinylmethyl formula where n is an integer from 1 to 6; R is hydrogen, halogen, C1-C4- alkyl, heteroaryl, sulfonyl, mono - or disubstituted sulfa group, nitro, hydroxy, oxo, C1-C4- alkoxy, cyano, C1-C4alkylcarboxylic group, unsubstituted or substituted aryl, amino or substituted amino group. Reagent I where X is a halogen. Reagent 2: where R has the above meanings reaction Conditions: in a medium of an organic solvent in the presence of a base. 6 table.

The invention relates to new derivatives of 1H-azole-( -4-1-(2-pyrimidinyl)-piperazinil)-alkyl, and their physiologically acceptable salts, intended for the treatment of disorders associated with withdrawal syndrome induced by the removal of benzodiazepines, particularly diazepam, cocaine, alcohol and/or nicotine.

At that time, known as anxiolytics [1] always be not able to inhibit withdrawal syndrome, was completely unexpected that some derivatives of 1H-azole-( -(4-(2-tx2">

Compounds according to the invention correspond to General formula I

NN(CH2)n-N (l) where n can have values from 1 to 6 and R represents a hydrogen atom, halogen, lower alkyl with C1-C4the radical heteroaryl, sulfonovy radical, substituted N-sulfamerazine or disubstituted N-sulfamerazine, a nitro radical, a hydroxy radical, an oxo radical, lower alkoxy radical with C1-C4, a cyano radical, a lower radical alkylcarboxylic with1-C4the radical aryl or substituted aryl radical, the radical is amino or substituted amino radical of the formula

-N where R1and R2identical or different, represent a hydrogen atom, alkyl radical, aryl radical, the radical of alkylcarboxylic, radical, arylcarbamoyl, alkylsulfonyl radical or a radical arylsulfonyl, fragments of these alkyl radicals containing 1-4 carbon atoms.

These derivatives of General formula I can be obtained by one of the following methods.

Method AND

By the reaction of one of the compounds of General formula II

NN(CH2)n-X (ll) where X represents halogenatom or a group chosen among tosyloxy or mesilate one compound of General formula III

HN (lll) where R is viewpo is insulted, of dimethylformamide, alcohol, aromatic or non-aromatic hydrocarbon, ether such as dioxane or diphenyl ether, or in the presence of a mixture of these solvents. Mainly, this reaction is conducted in the presence of a single base, such as hydroxides, carbonates or bicarbonates of alkali metals, or in the presence of a mixture of these bases. The most appropriate temperature range from ambient temperature to the reflux temperature of the solvent, and the reaction time is from 1 to 24 hours

Method C.

By restoring one of the compounds of General formula I, in which R represents a nitro group.

Among the numerous reducing agents that can be used to restore one nitro group of one amino group include the following reducing agents: catalytic hydrogenation using catalysts of Nickel, palladium or platinum, is an amalgam of zinc with hydrochloric acid, borhydride alkali metals, etc.

The reaction is carried out in such one alcohol, like methanol, ethanol or in one of propanolol or butanol, or mixtures of one of the alcohol with water. Most adeci is from 1 to 24 hours

Method

By acylation of one of the compounds of General formula I, in which R represents an amino group of one acid halide or anhydride.

The reaction is carried out without solvent or in the presence of one adequate solvent, such as hydrocarbon, ketone or ether, in the presence of a single base, such as pyridine or trialkylamine. The most appropriate temperature range from -10aboutC to the boiling point of the solvent, and the reaction time is from 1 to 24 hours

Method D

By alkylated recovery of one of the compounds of General formula I, in which R represents a nitro group, and it alkilirovanie recovery is performed with alkali metal borohydride in the presence of Nickel chloride II and one of the compounds having the group of the ketone or aldehyde. This reaction is carried out in alcohol or in a mixture of alcohol and water. The most suitable temperatures are temperatures from -15aboutC to the reflux temperature of the solvent, and the reaction time is from several minutes to 24 hours

Method E

By the reaction of one of the compounds of General formula IV

X-(CH2)n-N (lV) where X and n incasino getting some derivatives in the framework of the present invention. Also describes some applications.

Method AND

P R I m e R 1. Obtaining 1H-pyrazole-1-(4-(-4(2-pyrimidinyl)-1-piperazinyl)-Boo").

Heated at reflux for 14 h the 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 is 1H-pyrazole-1-(4-(4-(2-pyrimidinyl)-1-piperazinil)-butyl).

Compounds identified by examples 2-9, get in the same way as data for identifying lead in the table.1.

Method IN

P R I m e R 10. Obtaining 1H-pyrazole-4-amino-1-(4-(4-(2-pyrimidinyl)-1-piperazin - nil)-butyl).

Added 10.2 g (43.2 mmol) of hexahydrotriazine Nickel II in a solution of 7.2 g (21 mmol) of 1H-pyrazole-4-nitro-1-(4-(4-(2-pyrimidinyl)-1-piperazinil)-butyl) (example 7) in 60 ml of ethanol with vigorous stirring. Cooled in the ice bath and slowly added 10.2 g (81 mmol) of sodium borohydride. Left under stirring for 1 h, and after 1 h at ambient temperature, water is added, evaporated in vacuo, acidified with concentrated is om. Thus, the gain of 4.4 g of 1H-pyrazole-4-amino-1-(4-(4-(2-pyrimidinyl)- 1-piperazinil)-butyl) in liquid form.

Spectroscopic data for the identification of lead in the table.2.

Method

P R I m e R 11. Obtaining 1H-pyrazole-4-methylsulfonylamino-1-(4-(4-(2-pyrimidinyl)-1-piperazinil)-butyl ).

Slowly add 1.8 g (16 mmol) of methanesulfonamide to the cooled solution of 4.4 g (14.6 mmol) of 1H-pyrazole-4-amino-1-(4-(4-(2-pyrimidinyl)-1-piperazinil)-butyl) (example 16) in 30 ml of pyridine. Leave for 1 h at 0aboutWith leave at ambient temperature for 4 h, poured into ice water, extracted with chloroform and obtain 3.7 g of 1H-pyrazole-4-methyl-sulphonamido-1-(4-(4-(2-pyrimidinyl)-1-piperazinil)-butyl), which can be recrystallizing in ethyl ether with a melting point of 132aboutC.

Compounds identified by examples 12 and 13 receive the same method and data to identify lead in the table.2.

Method D

P R I m e R 14. Obtaining 1H-pyrazole-4-(2-butyl)amino-1-(4-(-4(2-pyrimidinyl)-1 - piperazinil)-butyl).

Add 0.9 g (24 mmol) of sodium borohydride in a suspension of 2.8 g (12 mmol) of hexahydrotriazine Nickel in a solution of 2 g (6 mmol) of 1H-piraso to 0aboutC. Maintain this temperature for 30 min, leave the mixture to rise at room temperature, continue stirring for 2 h, evaporated in vacuo, absorb with ethyl acetate and obtain 1.22 g of 1H-pyrazole-4-(2-butyl)amino-1-(4-(4-(2-pyrimidinyl)-1-Pipera - sinil)-butyl) in liquid form.

Spectroscopic data of this product indicated in the table.2.

The study of anxiolytic or concern activity in mice

Use a test light and dark boxes (J. Phar. Pharmacol, 1988, 40, p. 494-500). The mouse is placed in a light area of a box divided into two compartments: one strongly lit, light box, and other poorly lit, dark box.

Count the number of times the mouse rises on its hind legs in each compartment within 5 minutes (see column 2, table. 3-6).

Activity in each compartment is given by counting the number of re-baptizing cells, which constitute separate each compartment (see column 3, table.3-6).

Measure the time spent in the dark box for 5 minutes countdown (see column 4, table.3-6).

Determine the source of the latency, i.e. the time elapsed from the premises of the animal in the light box, in the start of the test until it povedenie mice during different periods of treatment, always comparing it with the behavior of groups of control animals not subjected to any processing.

Treatment and experimental scheme

The dependence of a particular treatment (diazepam, cocaine, alcohol or nicotine) by daily injection over a period of 7 or 14 days. This processing causes anxiolytic response response (increased activity and are present in a light box).

Dosage:

diazepam: 10 mg/kg i.p. 2 times a day for 7 days;

cocaine: 1 kg/kg i.p. within 14 days;

the alcohol is introduced at a rate of 8% weight/volume in drinking water for 14 days;

nicotine: 0.1 mg/kg i.p. 2 times a day for 14 days.

Stop treatment for 24 h causes a withdrawal syndrome, which manifests as akcionerna response (increases the activity and presence in the black box).

3) various Other groups in addition to get diazepam, cocaine, alcohol or nicotine related processing products, which are the objects of the present invention in comparison with buspirone or ipsapirone. These groups are also exempt from treatment with diazepam, cocaine, alcohol or nicotine, and there is also a return reacts the l-4-chloro-1-(4-(4-(2-pyrimide-nil)-1-piperazinil)-butyl) (example 4): 0.5 mg/kg i.p. 2 times a day;

1H-pyrazole-1-(4-(4-(2-pyrimidinyl)1-piperazinil)-butyl) (example 1): 0.5 mg/kg i. p. 2 times a day; 1H-pyrazole-4-methylsulfonylamino-1-(4-(4-(2-pyrimidinyl)-1-piperazinil)-butyl (example 11): 1 mg/kg i.p. 2 times a day (compared to diazepam, alcohol and nicotine) and 0.5 mg/kg i.p. 2 times a day (in relation to cocaine).

The observed results are shown in table.3-6.

The following reaction products, which are the objects of the invention:

Produced by examples 1 and 4 inhibit withdrawal syndrome, which manifests as entries response, inductively diazepam, cocaine, alcohol and nicotine, and in addition they hold a significant anxiolytic response, when stop the introduction of diazepam, cocaine, alcohol or nicotine.

Derivatives with respect to example 11 inhibit withdrawal syndrome, which manifests as entries response, inductively diazepam, alcohol and nicotine, and, in addition, they hold a significant anxiolytic response, when stop the introduction of diazepam and alcohol.

Buspirone saves withdrawal syndrome, which manifests as entries response, range of complete scientolo syndrome, and anxiogenic. Buspirone hampers only some parameters entries response after stopping treatment with alcohol.

Ipsapirone saves withdrawal syndrome, which manifests as entries response, inductively diazepam, cocaine and nicotine. Ipsapirone inhibits withdrawal syndrome, which manifests itself in the form of entries reaction inductional alcohol.

Therefore, derivatives of General formula I according to the invention are useful as active compounds in medicaments for the treatment of disorders associated with withdrawal syndrome, which is manifested, in particular, in the form of entries of the reaction, inductional abrupt elimination of prolonged treatment with benzodiazepines such as diazepam, cocaine or prolonged absorption of alcohol and/or nicotine.

In human therapy, the dose of the introduction of course depends on serious syndrome.

It usually is about 5-100 mg/day.

Derivatives of the invention are introduced, for example, in the form of tablets, solutions or suspensions, or in the form of gelatin capsules.

As examples BR>
Microcrystalline

cellulose 25

Povidone 5

Pre Gelati-

nirovany starch 3

Colloidal silicon dioxide 1

______________________________________________________

Weight tablets 100

The reception of tablets:

Mix in the mixer connection I, lactose and pre gelatinizing starch to a homogeneous state. The resulting mixture was mixed with an ethanol solution of povidone. Dried in an oven at 50aboutWith over 10 hours Granularit through a sieve with an aperture of 1 mm, Determine the weight of the granules and mixed with microcrystalline cellulose and colloidal silicon dioxide to a homogeneous state. Add magnesium stearate and mix for no more than 5 minutes Take a sample and analyze. After analysis of pressed pellets in a pressing machine and get a tablet with a theoretical weight of 100 mg (boundary settings according to Ph.Eur.). A sample is taken for final inspection.

An example formula for Gelati-

had been forecast capsules mg

Compound IV 10

Polyoxyethylenated

glycerin 135

Beginat glycerin 5

________________________

150

Excipient: soft gelatin in sufficient quantity.

An example of obtaining generalplan mix. In the resulting mixture was heated to 45-55aboutWith injected under stirring compound IV, and continue stirring until a homogeneous state. The mixture is allowed to cool with stirring and then when you reach the desired consistency change anchor stirrer. Continue cooling to 25aboutAnd then the stirring is stopped. Select a sample for analysis. After the establishment of the analysis carried out, the addition of fillers. To this stirred while melting the following softening ingredients: gelatin, glycerin, pigment and purified water. Transfer the mixture into the funnel filler machine, equipped with soft mixing. Batched together the mixture and a soft gelatin shell so that the weight of the capsules were in the following ranges:

Theoretical weight: 150 mg (standard for Ph. Eur.)

Total weight: 200 mg ( 5%).

Washed obtained capsules and dried. Select samples for final inspection.

Derivatives piperazinylmethyl General formula

< / BR>
where n is an integer from 1 to 6;

R is hydrogen, halogen, C1-C4-alkyl, sulfonyl, mono - or disubstituted sulfa group, nitro, hydroxy, oxo, C1-C4-alkoxy, cyano, C1-C4alkylcarboxylic 1 and R2the same or different, hydrogen, alkyl, alkylcarboxylic, alkylsulfonyl containing 1 to 4 carbon atoms in the alkyl, phenyl, phenylcarbene or phenylsulfonyl,

or their salts, having the property of braking withdrawal syndrome.

 

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3 ex

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