PL168230B1 - Method of obtaining 3,7-disubstituted indole derivatives - Google Patents

Abstract

1. Production method of 3,7-disubstituted indole derivatives of the formula I, v wherein R1 is [beta] 1-4EZ-alkyl, and R2 is (1-7E) -alkyl, in the form free or in the form of a salt, characterized by that the compound of Formula 2, wherein R 1 has as defined above or reactive thereof derivative, is condensed with a compound of formula 3, wherein R3 has as defined above and the compound obtained Formula 1 is isolated as free or in the form of a salt.

Description

The present invention relates to a process for the preparation of 3,7-disubstituted indole derivatives having pharmaceutical properties, in particular serotonin antagonistic properties.

The present invention provides compounds of general formula I wherein R1 is (1-4C) -alkyl and R2 is (1-7C) -alkyl, in free form or in the form of pharmaceutically acceptable salts. The above compounds are for pharmaceutical use.

Preferably R1 is a methyl radical.

In R2, the (1-7C) -alkyl group is preferably a (1-4C) -alkyl group, especially methyl.

The compounds of formula 1 may be in free or salt form. Suitable salts include acid addition and quaternary ammonium salts.

The process according to the invention for the preparation of compounds of formula 1 is condensed with a compound of formula 3 in which R 2 is as defined above, in which Rima is indicated above, or compounds of formula I are isolated as such, either as acid addition salts or as quaternary ammonium salts.

The process can be carried out in a manner conventional for analogous compounds.

For example, a carboxylic acid group can be activated as a reactive acid derivative.

Suitable reactive acid derivatives can be prepared by reaction with N, N'-carbonyldiimidazole to give the carboxylic acid intermediate or by reaction with N-hydroxy-succinyl. An acid halide, for example an acid chloride, for example obtained by reaction with oxalyl chloride, can also be used.

The alcohol of formula III is reacted with the compound of formula II or a reactive derivative thereof. The reaction can be carried out at room temperature to 7 ° C. Preferably an inert solvent is used, for example ethyl acetate. The alcohol can also be used, for example, in the form of an alkali metal salt, especially a lithium salt. Such salts may be prepared in a conventional manner, e.g. by reacting n-butyllithium with an alcohol in tetrahydrofuran. If desired, the reaction can be carried out in the presence of a heterocyclic or tertiary amine, e.g. pyridine or methylamine.

The reaction temperature is preferably from about -10 ° C to about 10 ° C. Suitable organic solvents are, for example, ether or dimethoxretase.

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The compounds of formula I can be isolated and purified in a known manner.

While the preparation of the starting materials is not described in detail here, the compounds are known or can be prepared analogously to the known methods or to the methods described herein, e.g. in the example.

Compounds of formula I as free base can be converted into salts. For example, acid addition salts may be prepared in a conventional manner by reaction with a suitable acid, e.g., hydrochloric acid, malonic acid, hydrobromic acid, maleic acid, malic acid, fumaric acid, oxalic acid, and tartaric acid. The quaternary ammonium salts of compounds of the formula I can be prepared in a known manner, e.g. by reaction with methyl iodide.

Compounds of formula I in free form or in the form of pharmaceutically acceptable salts and complex compounds have not yet been described in the literature as pharmaceuticals. They exhibit valuable pharmacological properties, as shown in animal tests, and can therefore be used in medicine.

In particular, these compounds exhibit a sociotropic activity (A.K. Dixon et al., Adv. Study Behav., 1990, 19, 171-204) as shown e.g. in the mouse intruder test described by A.K. Dixon, Triangle, 1982, 21, 95-105. In this test, the compounds of the invention show a dose-related increase in approaching social effects when administered at doses of about 0.01-100 gg / kg. These effects are seen after oral or parenteral administration and influence social inquiry (growth) and defensive contradiction of feelings (strain).

Compounds of formula I also exert an influence on social behavior, as demonstrated by the K.A. Dixon et al., Adv. Study Behav., 19, 171 (1990), where pairs of individually bred males are brought together into a large cage unknown to both and their behavior and attitudes are recorded. In this test, one of the couple's partners receives the test compound or vehicle intraperitoneally 45 minutes before the social meeting. When administered intraperitoneally at doses of about 0.01-100 µg / kg, the compounds show an effect on the social behavior of mice, e.g. an increase in social study is observed.

The compounds of formula I also reduce the increase in plasma corticosterone levels induced in mice by the presence of an aggressive but inaccessible male mouse. These compounds, administered orally for 14 days at doses of about 0.1-10 mg / kg, bring the plasma corticosterone levels to a normal level.

In addition, the compounds of formula 1 exhibit HT3 antagonist properties as shown as follows:

1. These compounds show potent and selective binding properties for 5-HT3 binding sites, e.g. N1E-115 cells, measured according to the method described by D. Hoyer and H.C. Neijt, Mol. Pharm., 33, 303-309. The compound of the example exhibits a pKd value of 8.87 ± 0.01.

2. These compounds have an effect on gastric emptying in rats as shown in in vivo tests after intraperitoneal administration at doses of about 0.01-1 mg / kg. Test compounds are administered 15 minutes prior to the administration of the glass beads and gastric emptying is measured at 5, 10, 15 and 30 minutes after the administration of the beads. The compound of the example shows an ED50 value of 0.2 mg / kg intraperitoneally.

3. These compounds induce the blockade of Benzold Jarisch Reflex, as demonstrated e.g. by the test according to J.R. Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol. 326, 36-44 (1984). The compound of the example exhibits an ID50 of 70 gg / kg.

The compounds of the formula I are therefore indicated for the treatment of psychiatric disorders, in particular for the treatment of anxiety of various origins and stress-related disorders. The compounds are also indicated for the treatment of diseases such as social withdrawal, cyclophrenia mental disorders, psychoses, depression, cognitive disorders, wakefulness disorders, e.g. geriatric diseases, panic disorders, agoraphobia, obsessive compulsive disorders.

A recommended daily dose is about 0.01-5 mg of the compound, usually administered, for example, in divided doses up to 4 times a day.

The compound of the example is preferable.

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The compounds of the invention can be administered in free form or in the form of pharmaceutically acceptable salts or complex compounds. Such salts can be prepared in a known manner and exhibit the same level of activity as the free compounds.

The compounds of formula 1 can be converted into pharmaceutical compositions containing the active compound together with a pharmaceutically acceptable diluent or carrier. Such compositions can be prepared in known manner.

The compounds of formula I in free or salt form have not yet been specifically described in the literature. Similar compounds are known from the literature, such as:

- 7-hydroxy-1H-indole-3-carboxylic acid (1H, 5H) -8-methyl-8-aza-bicyclo [3,2,1] -oct-3-yl ester, mentioned in Mol. Toxicol. 1, 341-350, 1987 as possible minor metabolite produced in vitro in the metabolism of (1H, 5H) -8-methyl-8-aza-bicyclo [3.2.1] -oct-3-yl ester 1H-indole -3-carboxylic acid by differentiated rat and human hepatoma cells:

- 1,2,3,9-tetrahydro-8-hydroxy-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) -methyl] -4H-carbazol-4-one, mentioned in Eur. J. Cancer Clin. Oncol. 25 (Suppl. 1) 75-77, 1989, as metabolite 1,2,3,9-tetrahydro-9-methyl] o-3 - [(2-methyl-1H-imida-7-ol-1-yl) -methyl ] -4H-carbazol-4-one.

Example. 7-Methoxy-1H-indole-3-carboxylic acid (Ia H, 5 aH) -8-methyl-8-aza-bicyclo [3.2.1] oct-3a-yl ester.

19.1 g of 7-methoxy-1H-indol-3-yl-carboxylic acid are suspended in 300 ml of ethyl acetate. Then 10 ml of oxalyl chloride are added during 30 minutes at room temperature. The resulting red-brown solution was stirred for 3 hours at room temperature and then concentrated to 2/3 of the original volume. Then a solution of 14 g of tropine in 50 ml of ethyl acetate is added dropwise at about 50 ° C. The resulting mixture is stirred for a further 2 hours at about 50 ° C and then overnight at room temperature. The resulting suspension was dissolved by adding water, and the mixture was extracted three times with ethyl acetate and then washed with 2N hydrochloric acid. The acid phase is basified with potassium carbonate, extracted three times with methylene chloride and evaporated to give the title compound, mp 298-299 ° C (decomposition).

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Claims (2)

Patent claims A process for the preparation of 3,7-disubstituted indole derivatives of formula I, wherein R 1 is a (1-4C) -alkyl group and R2 is a (1-7C) -alkyl group, in free or salt form, characterized by that the compound of formula 2, in which R 1 is as defined above, or a reactive derivative thereof, is condensed with a compound of formula 3, wherein R 3 is as defined above, and the resulting compound of formula 1 is isolated in the free form or in the form of salt. 2. The method according to p. A process as claimed in claim 1, characterized in that in the preparation of 7-methoxy-1H-indole-3-carboxylic acid (1aH, 5aH) -8-methyl-8-aza-bicyclo [3.2.1] oct-3a-yl ester, in free form or in the form of a salt, 7-methoxy-1H-indol-3-ylcarboxylic acid is condensed with tropine, and the obtained compound is then isolated in free or salt form