Means to improve cognitive function

 

(57) Abstract:

The invention relates to medicine, namely to psychiatry and neurology. The tool allows you to improve cognitive function. This is done using 1H-pyrazole-4-chloro-1[4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl] and its physiologically acceptable salts. table 4.

The invention to the use of 1H-azole-/omega/-4-/2-pyrimidinyl/-1-piperazinil/-alkyl/-derivatives, as well as physiologically joint salts, to obtain drugs for the treatment of mental disorders such as senile or predtechenskii dementia, memory dysfunction, disorders of consciousness and in particular Alzheimer's disease.

It is known that all benzodiazepine anxiolytics have always shown themselves unable to treat mental disorders, affecting the ability to learn, however, the applicant unexpectedly found that some 1H-azole-/omega/4-/2-pyrimidinyl/-1-piperazinil/-alkyl/-derivatives are very effective for the treatment of these specific disorders of the Central nervous system.

Proposed connection satisfies the General formula

< / BR>
in which

"n" can have a value of 1 to 6; and

R denotes the atom of odor the seal or N-disubstituted sulfa moiety, the nitro radical, hydroxyl, oxo radical, a lower C1C4CNS radical, cyano radical, /lower alkyl with C1C4/-carboxylate radical, aryl or substituted aryl radical, amino or substituted amino radical of the formula

< / BR>
in which

R1and R2the same or different represent a hydrogen atom; alkyl, aryl, alkylcarboxylic, arylcarboxylic, alkylsulfonyl or arylsulfonyl radical; and alkyl fragments of these radicals contain 1 to 4 C-atoms.

The compounds of formula 1 are not new. They are described in the application for Europatent EP-A-O 382637, published on 16 August 1990, where indicated on their tranquilizing and/or anxiolytic activity.

These derivatives of General formula 1 can be obtained by any of the following methods:

Method a By reacting compounds of General formula II

< / BR>
in which

X denotes a halogen atom or a group to delete, select tosyloxy or mesilate, with the compound of General formula III

< / BR>
in which

R have the above values.

The reaction is carried out in the presence of an adequate solvent, for example dimethyl sulfoxide, digitiform the silt ether, or mixtures of these solvents. This reaction preferably proceeds in the presence of a base, such as hydroxides, carbonate or bicarbonates of alkali metals, or mixtures of these bases. The most adequate temperature change from room temperature up to the boiling temperature under reflux of the solvent and the reaction time is equal to 1 -24 hours

Method B. By restoring the compounds of General formula I, in which R denotes a nitro group.

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

The reaction is carried out in alcohol, such as methanol, ethanol, or any of propanolol or butanol, or mixture of alcohol and water.

The most appropriate temperature range from -10oC to the boiling temperature under reflux of the solvent, and the reaction time is 1 to 24 hours

The way Century. By acylation of compounds of General formula I, in which

R denotes an amino group is risotti adequate solvent, such as a hydrocarbon, ketone or ether, in the presence of a base such as pyridine or trialkylamine.

The most suitable temperatures vary from -10oC to the boiling point of the solvent, and the reaction time is 1 to 24 hours

Way, By alkylating reductant compounds of General formula 1, in which

R denotes a nitro group, and it alkylating recovery is implemented using an alkali metal borohydride in the presence of chloride Nickel (II) and compounds which contain ketone or aldehyde group. This reaction is carried out in alcohol or mixture of alcohol and water.

The most suitable temperatures range from -15oC to the boiling temperature under reflux of the solvent, and the reaction time is the amount of from several minutes to 24 hours.

The way D. By reacting compounds of General formula IV

< / BR>
in which

X and n have the above meanings, with a compound of General formula V

< / BR>
The following examples illustrate the obtaining of some derivatives included in the scope of the invention.

Also describes some of the mold used.

Method AND

Example 1. Getting 1-/4-/4-/2- mmol) 2-pyrimidine-1-/-4-bromobutyl/-4-piperazine, 1,02 g (15 mmol) of pyrazole and 2.76 g (20 mmol) of potassium carbonate, 50 ml of dimethylformamide. Evaporated under vacuum, add chloroform, washed with water, dried over sodium sulfate, evaporated under vacuum and obtain 3.5 g of oil, which is a 1-/4-/4-/2-pyrimidinyl/-1-piperazinil/-butyl/-1H-pyrazole.

Compounds identified by examples 1 to 9, receive the same method and data for their identification are presented in table.1.

Method B

Example 10. Getting 4-amino-1-/4-/4-/2-pyrimidinyl/-1-piperazinil/-butyl/-1H-pyrazole

10.2 g (43.2 mmol) of uranyl chloride Nickel/H/ are added to a solution of 7.2 g (21 mmol) of 4-nitro-1-/4-/4-/2-pyrimidinyl/-1-piperazinil/-butyl/-1H-pyrazole (example # 7) in 60 ml of ethanol under vigorous stirring. Cooled with an ice bath and slowly added 10.2 g (81 mmol) of sodium borohydride. Stirred for 1 h and after 1 h at room temperature, add water, evaporated concentrated hydrochloric acid, filtered off, alkalinized with ammonia and extracted with diethyl ether. Thus obtain 4.4 g of 4-amino-1-/4-/-4/2- pyrimidinyl/-1-piperazinil/-butyl/-1H-pyrazole in the form of liquid.

Spectroscopic data for identification are given in tail/-1H-pyrazole

Slowly add 1.8 g (16 mmol) of methanesulfonamide to a chilled solution of 4.4 g (14.6 mmol) of 4-amino-1-/4-/4-/2- pyrimidinyl/-1-piperazinil/-butyl/-1H-pyrazole (example 16) in 30 ml of pyridine. Leave to stand for 1 h at 0oC, then leave the temperature rises to room for 4 h, poured into ice water, extracted with chloroform and obtain 3.7 g of 4-methylsulfonylamino-1-/4-/4-/2-pyrimidinyl/-1 - piperazinil/-/butyl/-1H-pyrazole, which can be recrystallized from diethyl ether, S. T. pl. 132oC.

Identified in examples 12 and 13 connections get in the same way, and the data for their identification are presented in table.2.

Method D

Example 14. Getting 4-/2-butyl/-amino-1- /4-/-4/2-pyrimidinyl/-1-piperazinil/-butyl/-1H-pyrazole.

0.9 g (24 mmol) of sodium Borohydride is added to a suspension of 2.8 g (12 mmol) of uranyl dichloride Nickel in a solution of 2 g (6 mmol) of 4-nitro-1- /4-/4-/2-pyrimidinyl/-1-pyrazinyl/-butyl/-1H-pyrazole (example 7) and 10 ml of methyl ethyl ketone in 50 ml of ethanol, cooled to 0oC. Maintain this temperature for 30 min, leave it to rise to room, continue stirring for 2 hours, evaporated under vacuum, treated with ethyl acetate and obtain 1.22 g of 4-/2-butyl/AE of this product are presented in table.2.

For compounds of formula I show the presence of activity to improve abilities to cognitive activity as follows.

Radiate an influence of the studied products on the adaptation process Masha in the dough with a light and dark areas of the chamber are described A. M Barues al. (Pharmacol Brochem. Benav, 1990, 35, 955 -962). Study on the one hand, the impact on the ability to irradiation (speed adjusting) and on the other hand the ability of the block opposite esters produced by exopalaemon.

The mouse is placed in the light chamber area, divided into two compartments, one illuminated and the other low-light scenes.

1/ Count the number of times the mouse rises on its hind legs in each compartment for 5 min (see table.3).

2/ Activity in each compartment is determined by counting the number of intersections of the cells that divided each compartment (see tab.3).

3/ Measure the time spent in dark compartment within 5 min of counting (see tab.3).

4/ Define initial latent period, i.e. the time elapsed from the moment the animal is placed in the bright compartment, with the start of the experiment, until the entrance of the darkened compartment (see tab.3).

The control animals make two obamabots a day 0.01 mg/kg administered intraperitoneally. This operation is repeated daily for three days. Animals are trained to remain more time in the dark compartment and faster to go back there.

On the fourth day enter exopolymer (2 0.25 mg/kg, administered intraperitoneally). With this treatment the animals of the control group "forget" about saucenon act, which is to stay a longer time in a darkened compartment.

Processing using a product that improves cognition, shows that

1/ memorized behavior is improving, learning proceeds more quickly, and the time spent in dark compartment increases;

2/ the reversion of learning caused by exopalaemon, completely blocked.

The data obtained are presented in table.3. They show on the basis of the results obtained, for example, with the compound of example 27 activity improve cognition, which suggests that this compound improves the learning process and blocks the effects of scopolamine. Tested under the same conditions piracetam has no activity.

In addition, the antidepressant activity of example 27, using the test radiating depressive behavior in mice, described by R. D. P the CSOs they can't get out. Measure for groups of 10 mice at the tested dose, duration of immobility in the interval between 2 5 min

The studied product is administered intraperitoneally injected for 1 h before the test. In this test, explain the immobility of animals as related to their depressive state ("despair") in connection with the opposition of the hostile situation and insoluble in a hostile environment such as water. Antidepressants reduce this stillness. This experience is used Imipramine (30 mg/kg administered intraperitoneally) in the number of control product.

The results show that the connection 27 has antidepressant activity, as it significantly reduces the immobility time in the control group (see table.4).

Derivatives of General formula I, therefore, suitable as active principles of drugs for treatment of disorders associated with learning such as senile dementia, disorders of memory, disorder of consciousness, and so on, as well as depression.

In human therapy injected dose is undoubtedly dependent on the risk of specific disorders of the Central nervous system.

It is usually 5 to 100 mg/day.

About the l

Below are examples of two private herbal form.

An example of a formula tablets

Connection 27 5 mg

Lactose 60 mg

Microcrystalline cellulose 25 mg

Povidone 5 mg

Pre gelatinising starch 3 mg

Colloidal silicon dioxide 1 mg

Magnesium stearate 1 mg weight tablet: 100 mg

An example of a formula capsules

Connection 27 10 mg

Polyoxyethylenated glycerin 135 mg

Glycerin-beginat 5 mg 150 mg

Excipient: soft gelatin(

The application of 1H-pyrazole-4-chloro-1[4-[4-(2-pyrimidinyl)-1-piperazinil] -butyl] and its physiologically acceptable salts as a means to improve cognitive function.

 

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< / BR>
I R 2-naphthyl; RI=H;

II R C6H5; RIC6H5

-phenylpiperazine)ethyl] benzamide, possessing neuroleptic activity, and 3 - methyl-n-[2-(4-phenylpiperazine)ethyl]benzamide as a starting compound for the synthesis of" target="_blank">

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< / BR>
(I) possessing neuroleptic activity, and 3-methyl-N-[2-(4-phenylpiperazine)ethyl] benzamide as starting compounds in the synthesis of hydrochloride of 3-methyl-N-[2-(4-phenylpiperazine)ethyl]benzo - Mead

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(I) where R is hydrogen, halogen, lower alkyl or lower alkoxygroup;

And group O or S;

In group-CH2-CH2or СНR1where R1means hydrogen, lower alkyl or hydroxyl;

X is oxygen or the group NH

The Y group of the formula)qwhere R2means lower alkyl, q is 2 or 3, and their salts, in particular physiologically tolerable salts, which possess pharmacological activity, in particular activity antimuskarinovoe act occurs, and therefore can be used to treat diseases of the gastrointestinal tract and respiratory tract

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

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18 cl, 18 tbl, 7 ex

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