NO162615B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1,3,4,5-TETRAHYDROBENZ (C, D) INDOLES. - Google Patents

Abstract

1. Tetrahydrobenzindoles of the general formula see diagramm : EP0148440,P9,F1 in which R1 and R2 denote hydrogen or C1 -C6 -alkyl or, together with the nitrogen atom, form a heterocyclic 5-membered or 6-membered ring which is optionally substituted by 1 or 2 C1 -C6 -alkyl groups, and X represents OR3 or SR3 , wherein R3 denotes hydrogen or C1 -C4 -alkyl, and salts thereof.

Description

The invention relates to the production of new 1,3,4,5-tetrahydro-benz[c,d]indoles and their salts with physiologically harmless acids. The 1,3,4,5-tetrahydrobenz[c,d]indoles are used to treat cardiovascular diseases and diseases of the central nervous system with an effect on the serotoninergic system.

The invention relates to the preparation of tetrahydrobenzindoles with the general formula I

in which

Ri and R£ mean hydrogen, C₁-C₁-alkyl or C₂-C₅-alkenyl,

X means 0R3 or SR3, in that

R3 means H or C1-C4-alkyl,

and physiologically acceptable salts thereof.

The compounds of formula I are produced according to the invention

by that

a) compounds of the general formula II

nltered in para position to the substituent X, the formed

the nitro compound III i

acylated with oxalic acid esters of the formula R4-O-CO-CO-OR4, Where R4 means CH3 or C2H5 to compounds of the general formula IV

in these, the ester groups are saponified, the nitro groups are reduced and then ring-closed and decarboxylated in one or more steps, or

b) compounds of general formula III

are reduced to anilines of formula VII these are transferred to isonitriles of formula VIII and these are finally cyclized with a strong base to compounds of formula I, and the thereby obtained compounds are optionally converted into physiologically acceptable salts thereof. The final cyclization and decarboxylation in method variant a) proceeds over intermediate products with the formulas V and VI

to compounds of formula I, where R 1 , R 2 and X in the formulas have the meanings indicated above.

The active substances of formula I clearly differ from known active substances of similar structure (e.g. US patent 4 110 339) by the substituent X in the 6-position of the tricyclic ring system. While they knew connections where

X = H has a strong effect on the dopaminergic system occurs in the compounds of formula I, in which X has the above meaning, the effect on the dopaminergic system in the background against a strong effect on the serotoninergic system. It has been shown that the compounds produced according to the invention have a high affinity to the brain's serotonin receptors, especially to those of the 5-HT 2 type (see table 1). The compounds of formula I are thus selective 5-HT 1 receptor ligands.

The active substances produced according to the invention have a strong effect on the central nervous system in animal experiments. In particular, they show efficacy in experimental devices, in which anxiolytic and antidepressant effects are found. Moreover, they lead to a strong stimulation of sexual relations in rats.

Because of these properties, the compound produced according to the invention means an enrichment of the medicines. They are suitable for combating diseases of the central nervous system, especially for the treatment of anxiety and tension states, sleep disorders and depression, preferably for the treatment of problems with sexual potency.

Preparation of compounds of formula I is preferred, in which

R 1 and R 2 mean a straight or branched C 1 -C 6 alkyl or C 2 -C 6 alkenyl residue, and

X means 0CH3 or SCH3.

Particularly preferred is the preparation of compounds of formula I, in which

R 1 and R 2 mean a straight or branched C 1 -C 4 alkyl residue, and

X means the 0CH3~ residue.

The production of the compounds of formula I is explained, for example, by the following formula:

The nitration of 2-aminotetralin II to the nitro compounds III takes place in mineral acid or organic carboxylic acids with conc. or fuming nitric acid or NaNC>3 as nitration reagent. Sulfuric acid, nitric acid or trifluoroacetic acid are preferably used as solvent. The reaction is carried out at temperatures between -60°C and +40°C. The preferred temperature ranges are between -20°C and room temperature.

The acylation of compounds III to compounds IV with oxalic acid dimethyl ester or diethyl ester is carried out in the presence of a strong base in an inert protic or aprotic solvent. As bases for deprotonation of the activated methylene group, metal-organic bases, such as lithium diisopropylamide, n-butyllithium, NaH or alkali alcoholates, such as Na- or K-methylate or

-ethylate.

As solvents, aprotic solvents are used, especially ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme or aprotic solvents such as dimethylformamide or dimethylsulfoxide or protic solvents, especially alcohols, such as methanol or ethanol or mixtures of these solvents.

The reaction is carried out at temperatures between -80°C and room temperature. A preferred embodiment of the acylation reaction is the use of oxalic acid diethyl ester as acylation reagent, potassium ethanolate as base, a mixture of diethyl ether/ethanol as solvent and carrying out the reaction at room temperature.

The saponification of the ester function in the compounds of formula IV is preferably carried out in an aqueous alkaline environment. Alkali or alkaline earth hydroxides or carbonates are preferably used as bases. The reaction is carried out in water or preferably in a solvent mixture of water and a water-miscible solvent, such as MeOH or EtOH. The reaction temperature is between 0°C and room temperature.

The reduction of the nitro group in the compound of formula V and the cyclization to the compounds of formula VI take place under conditions which are usual for the reduction of an aromatic nitro group to an NH 2 ~ group. As a reducing agent, it can be used, for example: with noble metal catalysts such as Pt or Pd activated hydrogen, iron II salts in alkaline resp. ammoniacal medium, zinc in glacial acetic acid or sodium dithionite. Water or an alcohol/water mixture or glacial acetic acid are preferably used as solvents. The reaction temperature is between room temperature and the boiling temperature of the solvent. Preferably, the reduction is carried out with iron II sulfate in an aqueous ammoniacal solution at reflux temperature.

The decarboxylation of the compounds VI to the compounds according to the invention with formula I is carried out in an inert solvent at temperatures between 150 and 300°C, optionally in the presence of a catalyst such as Cu powder. Preferably, basic organic solvents are used, such as quinoline, quinaldine or 8-methyl-quinoline.

The starting substances with formula II are known from the literature or can be prepared analogously to known compounds (D.E. Ames et al., J. Chem. Soc. 1965, 2636).

The therapeutically active compounds are used in common pharmaceutical preparations, preferably in a concentration of 0.1 to 99.5, preferably of 0.5 to 95% by weight of the total mixture.

The pharmaceutical preparations listed above may, in addition to compounds of formula (I) and/or their salts, also contain other pharmaceutically active substances.

The production of the above-mentioned pharmaceutical preparations takes place in the usual way according to known methods, e.g. by mixing the active substance(s) with the carrier oil or carriers.

The compounds of formula (I) and/or their salts as well as pharmaceutical preparations containing one or more of the compounds of formula (I) and/or their salts are also used in human medicine to prevent, improve and/or cure the diseases listed above.

The active substances or the pharmaceutical preparations can preferably be administered orally, parenterally and/or rectally, preferably orally or parenterally, especially orally and intravenously.

In general, it has proven advantageous to administer the active substance(s) by parenteral (i.v. or i.m.) application in amounts of 0.005 to 5, preferably of 0.01 to 1 mg/kg body weight per 24 hours and when used orally in amounts of 0.01 to 10, preferably 0.05 to 5 mg/kg body weight per 24 hours, possibly in the form of several individual submissions to achieve the desired results.

The following table 1 explains, for example, the high affinity of the compounds produced according to the invention to the brain's serotonin receptors. The compounds were examined with a view to antidepressant and sexual relationship-influencing effects. The amphetamine potentiation and anti-tetrabenazine test served as a test for the antidepressant effect. Antidepressant substances potentiate amphetamine-induced stereotypy in rats and antagonize tetrabenazine-induced ptosis in mice. The indicated EDsQ value is the dose at which the ratio after administration of 2 mg/kg DL-amphetamine sulfate i.v. reinforced around $50 resp. it using 20 mg/kg i.p. tetrabenazine induced ptosis is reduced to 50$.

Literature: J.L. Howard et al. in: "Antidepressants: Neurochemical, behavioral and clinical perspectives Eds.: S.J. Enna et al., Raven Press, New York, pp. 107-120, 1981.

Measurement of the ejaculation latency and the number of copulation attempts served as a test of the sexual relationship-influencing effect. The values indicate the time that elapses between the mating of male and female animals and the male's first ejaculation and the number of copulation attempts.

Literature: Larsson K., Fuxe K.; Everitt B.J., Holmgren M.

and Sodersten P. (1978). Sexual behavior in male rats after intercerebral injection of 5-7-dihydrotryptamine, Brain Research, 151, 293-303.

Example 1

6-methoxy-4-dipropylamino-1,3,4,5-tetrahydrobenz[c,d]-indole

A solution of 0.35 g (0.00106 mol) of 6-methoxy-4-dipropyl-amino-1,3,4,5-tetrahydrobenz[c,d]-indole-2-carboxylic acid in

10 ml of 8-methylquinoline was mixed with 0.2 g of Cu powder and then heated under nitrogen purging in a custllator for 1 1/2 hours at 250°C. The dark red colored reaction solution was applied to a column filled with Kleselgel (Kleselgel 60 from

E. Merck, Darmstadt). To separate 8-methylquinoline, the reaction product was eluted with CH 2 Cl 2 and then with CH 2 Cl 2 : MeOH / 20:4. The raw material was again chromatographed on silica gel (Kleselgel 60 from the company E. Merck, Darmstadt) with ethyl acetate/MeOH/20:2. The reaction product was dissolved in ether and, by addition of ethereal hydrochloric acid, transferred to the hydrochloride. The hydrochloride was dried in a desiccator over NaOH.

Yield: 0.226 g. Temp. 134-136°C.

Preparation of the starting compound: 6-methyl-4-dipropylamino-1,3,4,5-tetrahydrobenz[c,d]-indole-2-carboxylic acid

A solution of 2 g (0.005285 mol) of 4-(5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene)-2-oxo-acetic acid in 7.5 ml of 25#- 1 g aqueous ammonia was mixed with stirring with a hot solution of 9.69 g (0.03485 mol) FeSO 4 . 7 H 2 O in 10.6 ml H 2 O and then heated for 1 hour under reflux. After cooling to room temperature, the insoluble black residue was filtered off and washed with a mixture of MeOH:CH2Cl2/50:50. After removal of the solvent b] the residue chromatographed on silica gel (Kleselgel 60 from firn E. Merck, Darmstadt) with CH 2 Cl 2 : MeOH/20 : 6. The filtered product was crystallized by expulsion with CH 2 Cl 2 and dried in a desiccator over P 2 O 5 .

Yield: 0.35 g

4-(5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene)-2-oxoacetic acid

11.5 g (0.0283 mol) of ethyl 2-(5-nitro-8-methoxy-2-dipropyl-amino-1,2,3,4-tetrahydronaphthalene)-2-oxaacetate was dissolved in 300 ml of MeOH and mixed under a nitrogen purge at 18°C with 100 mL (0.1 mol) 1 N NaOH. The red colored reaction solution was then allowed to stand for 14 hours at 4°C. The reaction solution was neutralized with 100 mL (0.1 mol) 1 N HCl and freed from MeOH on a rotary evaporator. The remaining aqueous phase was extracted with CH 2 Cl 2 . After removal of the solvent, the residue was dried in the desiccator over P2O5.

Yield: 10.2 g of yellow crystalline product.

Temp. (Mettler FP 61 ) = 200.9°C.

Ethyl 2-(5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene)-2-oxoacetate

0.94 g (0.024 mol) of potassium was covered under nitrogen and moisture exclusion with 22 ml of absolute diethyl ether and then mixed with stirring at room temperature in 5 portions with each time 1.11 ml (0.0191 mol) abs. ethanol. After the potassium had dissolved, 3.26 ml (0.024 mol) of diethyl oxalic acid and a solution of 7.4 g (0.02415 mol) of 5-nitro-8-methoxy-2-dipropylamino-1,2 ,3,4-tetrahydronaphthalene in 7.5 ml abs. diethyl ether, allowed to stir for 1 1/2 hours, then added another portion of 3.26 mL (0.024 mol) oxalic acid diethyl ester and completed the reaction by stirring for 18 hours at 18"C. The reaction solution was mixed with 150 mL of CH 2 Cl 2 and filtered over diatomaceous earth. The filtrate was freed from

solvent and chromatographed the oily residue on silica gel (Kleselgel 60 from the company E. Merck, Darmstadt, 0.04-0.063 mm grain size) with eluent mixture CH 2 Cl 2 : MeOH/20 : 0.5.

Yield: 4.3 g; 1.4 g of starting product was recovered.

5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene

A solution of 5.5 g (0.02106 mol) of 8-methoxy-2-dipropyl-amino-1,2,3,4-tetrahydronaphthalene in 152 ml (1.976 mol) of trifluoroacetic acid was stirred, moisture excluded and nitrogen purged at a temperature of 5°C mixed with 2.9 g (0.0341 mol) of sodium nitrate and then stirred for 1 hour at 5°C.

The reaction solution was poured onto ice and adjusted to pH 10 with a 30% aqueous NaOH solution. Extraction was then carried out with methylene chloride. The residue from the Cl^C^ phase was chromatographed on AI2O3 (AI2O3 90 from Merck, Darmstadt, grain size 0.063 - 0.200 mm) with toluene as eluent.

Yield: 3.3 g of yellow oil (50.8& of the theoretical).

Claims (2)

1. Analogous process for the preparation of therapeutically active tetrahydrobenzindoles of the general formula I in which R 1 and R 2 mean hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkenyl, and X means 0R 3 or SR 3 , wherein R3 means H or C1-C4-alkyl, and physiologically acceptable salts thereof, characterized in that a) compounds with the general formula II is nitrated in paraposition to the substituent X, the formed nitro compound III are acylated with oxalic acid esters of the formula R4-O-CO-CO-OR4, Where R4 means CH3 or C2H5 to compounds of the general formula IV 1 these ester groups are saponified, the nitro groups are reduced and then cyclized and decarboxylated in one or more steps, or b) compounds with general formula III are reduced to anilines of formula VII these are transferred to isonitriles of formula VIII and these are finally ring-closed with a strong base to compounds of formula I, and the compounds thus obtained are optionally converted into physiologically acceptable salts thereof. 2. Analogous method according to claim 1 for the production of 6-methoxy-4-dipropylamino-1,3,4,5-tetrahydrobenz[c,d]-indole, characterized in that corresponding starting materials are used.