Derivatives of indole, the method of production thereof and pharmaceutical composition for treatment of mental disorders based on them

 

(57) Abstract:

Usage: as biologically active compounds in pharmaceutical compositions suitable for the treatment of mental disorders. The inventive product: indole derivatives of General formula (I) described in the text of the description, where R1- (C1- C4)alkyl, R2- (C1- C7)alkyl, in free form or in salt form. Reagent 1: 7 - (C1- C4)-alkoxy-1H-indol-3-yl carboxylic acid. Reagent 2: propane alkaloid General formula II, where R2- (C1- C7) alkyl. Reaction conditions: inert solvent at 20 - 70oC. Pharmaceutical composition comprises a pharmaceutically acceptable carrier and an active substance 1 in the amount of 2.5 μg to 2.5 mg 3 S. and 1 C. p. F. - ly.

The invention relates to new 3,7-disubstituted indole derivatives, method for their production and pharmaceutical compositions based on them.

The following derivative indole:

(1H, 5H-8-methyl-8-Aza-bicyclo(3.2.1) Oct-3-ilen ether 7-hydroxy-1H-indole-3-carboxylic acid, which is described as a possible additional product conversion;

(1H, 5H)-8-methyl-8-Aza-bicyclo (3,2,1) Oct-ilen epitomy (in vitro (Mol.Foxicol, 1,341-350, 1987);

1,2,3,9-tetrahydro-8-hydroxy-9-methyl-3-/ (2-methyl-1H-imidazol-1-yl)methyl/-4H-CT - basal-4-it, which is described as the product of the transformation 1,2,3,9-tetrahydro-9-methyl-3/(2-methyl-1H-imidazol-1-yl)methyl/-4H - carbazole-4-it (Eur.J. Cancer Clin.Oncol. 25, suppl.a 1.75-77, 1989).

The invention relates to compounds of the formula

(I) where R1(C1-C4) alkyl;

R2(C1-C7) alkyl.

These compounds can exist in free form or in salt form. These compounds possess valuable pharmacological properties.

Indole compounds of General formula I is obtained by condensation of compounds of formula

OH(II) where R1have the above significance, with a compound of General formula

HON-R2(III) where R2have the above meaning.

The process is carried out at a temperature from room temperature up to 70aboutIn the presence of an inert solvent, for example, ethyl acetate. You can also use alcohol, in particular, in the form of a salt of an alkali metal, preferably lithium salts. Such salts receive by known methods, for example, in the reaction of n-utility with alcohol in tetrahydrofuran. If desired, the reaction is carried out in the presence of heterocycling or tertiary is aboutC. In an inert organic solvents Pets also use ether or dimethoxyethane.

Isolation and purification of the compounds of formula (I) also carry out the conventional methods.

The compounds of formula (I) in free base form may be converted into a salt with one or another acid, in particular hydrochloric acid, malonic acid, hydrobromide, maleic, malic, fumaric, Sheveleva or tartaric acids. Partial ammonium salt compounds of formula (I) are obtained by conventional means, for example, in the reaction with methylated iodine.

P R I m e R 1. (1 N, 5 N)-8-methyl-8-Aza-bicyclo (3.2.1)Oct-3 - silt ester of 7-methoxy-1H-indole-3-carboxylic acid.

to 19.1 g of 7-methoxy 1H-indol-3-yl carboxylic acid suspension in 300 ml of ethyl acetate. 10 ml oxalyl-chloride added to the mixture for 30 min at room temperature. The resulting solution of red-mud color is stirred for 3 h at room temperature and then concentrated to 2/3 of the original volume. Then, the condensate is added dropwise 14 g of tropine in 50 ml of ethyl acetate at a temperature of about 50aboutC. the Resulting mixture is stirred for another 2 h at 50aboutAfter what lacerata (three times) and then washed 2NHCl. Acid phase is then alkalinized potassium carbonate, extracted three times CH2CL2and evaporated to obtain the desired compound with a melting point 298-299aboutWith in which it occurs decomposition.

18,8 g of the thus obtained base is dissolved in 200 ml of ethanol and add 1 equivalent 4NHCl (15 ml). The solution is concentrated to 2/3 of the original volume.

After crystallization from ethanol the product is filtered and washed. Obtain 19 g of the desired product as hydrochloride. So pl. 298-299aboutC (decomposition).

In the literature it is not known use as pharmaceutical compounds of the formula (I) in free form or in the form suitable for pharmaceutical purposes of salts and complexes, which are referred to as the "compounds according to the invention". These compounds possess valuable pharmaceutical properties and can be recommended for clinical use.

In particular, the compounds according to the invention have azeotropes activity (A. K. Dixon etal.Adv. Study Behav, 1990, 19, 171-204), as shown when tested on mice by a known method (A. K. Dixon et al. Triangle, 1982, 21, 95-105). This study found that these compounds e manifested in dosages from 0.01 to 100 µg/kg after oral or parenteral administration and impact on socio-search behavior of mice, encourage and ambivalent protective reaction, which was oppressed.

The action of the compounds according to the invention on social behavior is also shown in the study (K. A. Dixon et al. Adv. Study Behav. 19, 171, 1990), in which pairs contained in the individual cells of the males were transferred into one big, shared cage, unfamiliar animals, then registered their behavioral reactions and poses. One member of each pair received either the test compound or the solvent in the form of intraperitoneal injection for 45 min prior to transplantation in a common cell. Set the action of the test compounds on the social behavior of mice (increased search activity) after intraperitoneal administration at doses of 0.01-100 μg/kg

Compounds according to the invention inhibit the increase in the concentration of corticosterone in the blood plasma of mice in the form of aggressive, but isolated male. When administered orally in doses of 0.1-10 mg/kg / day for 14 days they restore the concentration of corticosterone in the blood to normal size.

In addition, the compounds according to the invention are antagonists NT3. This is confirmed by the following.

They are characterized by active jt (Mol.Pharm. 33, 303-309). Figure RKaboutfor described in example connection is 8,870,01.

They have a stimulating effect on gastric emptying in rats, as shown in the standard tests in vivo after intraperitoneal injection in doses of from 0.01 to about 1 mg/kg of the Tested compounds injected 15 min prior to the introduction of animals 25 glass beads, and removing the last of the gastrointestinal tract recorded after 5, 10, 15 and 30 minutes Index ED50for described in the above example, the compound is 0.2 mg/kg in the case intraperitoneal injection.

They cause the blockade of reflex Benzalde-Arish, as shown, for example, in the study by the method of I. R. Fojard (Naunyn-Schmiedeberg Arch. Fharm. 326, 36-44, 1984). When the test compounds described in the above example, the value of U50is 70 ág/kg

In connection with the foregoing, the compounds according to the invention can be recommended for the treatment of mental disorders, in particular anxiety of various origins and disorders caused by stress exposure. They can also be used in the treatment of disorders such as depressive and manic-depressive States, antisocialist, E. panic, fear of space, compulsive phenomena.

Recommended daily doses ranging from 0.01 to 5 mg, you can enter fractional, for example, 4 times a day.

Preferably used for therapeutic purposes, the compounds described in the above example.

Compounds according to the invention can be entered in free form or in a form suitable for pharmaceutical use salts or compositions. Of activity similar to the activity of free connections.

These indole derivatives can be used in pharmaceutical compositions, which include the connection according to the invention and suitable for pharmaceutical purposes solvents or carriers. These compounds can be entered in the usual ways, for example, parenterally, in the form of injectable solutions or suspensions), and oral (for example, in the form of tablets or capsules), or intranasal or use for their introduction of the candle. A single dosage of the free compounds or their suitable for pharmaceutical applications salts may be 2.5 mg to 2.5 mg

Sample preparation of pharmaceutical compositions.

Ingredient Weight (mg)

The active ingredient of 0.5 Stearate Mg 2,0

Total: 200,0

Ingredient connect easily and fill 80 mg capsules.

1. Derivatives of indole of General formula I

< / BR>
where R1WITH1WITH4-alkyl;

R2C1C7-alkyl,

in free form or in salt form.

2. Derivatives under item 1, wherein R1R2- CH3.

3. The method of obtaining derivatives of indole of General formula I

< / BR>
where R1WITH1WITH4-alkyl;

R2WITH1WITH7-alkyl,

in free form or in salt form, wherein conducting the condensation of compounds of General formula II

< / BR>
where R1has the specified value,

with a compound of General formula III

< / BR>
where R2has the specified value,

with the release of the product in free form or in salt form.

4. Pharmaceutical composition for treatment of mental disorders, comprising an active substance and a pharmaceutically acceptable carrier, characterized in that the active substance composition comprises the compounds of General formula I on PP. 1 and 2 in the amount of 2.5 μg to 2.5 mg

 

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33 cl, 8 tbl, 32 ex

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