FI79299B - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT AKTIVA TETRAHYDROBENSINDOLER. - 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

x 79299

A process for the preparation of therapeutically active tetrahydrobenzindoles

The invention relates to a process for the preparation of 1,3,4,5-tetrahydrobenz-5 [c, d] indoles. These compounds and their salts with physiologically acceptable acids can be used in the control of diseases, in particular in the treatment of cardiovascular diseases and in the treatment of diseases of the central nervous system by acting on the serotonergic system.

According to the invention, tetrahydrobenzene

indoles of general formula I

___R, 15 || xry ^ i

B

Wherein R 1 and R 2 represent hydrogen or C 3 -C 6 alkyl, and X is OR 1, wherein R 3 is hydrogen or C 1 -C 4 alkyl.

These compounds include compounds of formula I in both racemic and individual enantiomeric forms.

Compounds of general formula I are prepared according to the invention so that a compound of general formula II

yCx ^ X R2 is nitrated in the para position with respect to the substituent X to give a compound of formula 2 79299 N ° 2 αχ.

c j ^ R

5 X R2 this nitro compound is acylated with an oxalic acid ester of formula R.-O-C-C-O-R.

VK 4 10 0 0

wherein R 4 is CH 3 or C 2 H 5 to a compound of general formula III

0R4

15 I

X 2 and this is converted to the compound of formula I by saponification of the ester group, reduction of the nitro group, cyclization and decarboxylation in one or more steps. In the latter process step, compounds of the formula are formed as intermediates

C00H

I H \ COOH

N ° 2 c = 0 N-f

X R2 T V

X R2 35 (V) (VI) 3 79299 wherein, R2 and X in formulas II to VI have the same meaning as in formula I.

The compounds of formula I prepared according to the invention differ from known active ingredients which have a similar structure (see, e.g., U.S. Patent No. 4,110,339) with respect to the X substituent at the 6-position of the tricyclic ring system. Known compounds in which X is H have a strong effect on the dopaminergic system, while compounds of formula I according to the invention in which X has the meaning given above have a dopaminergic effect on the serotonergic system. impact. It has been shown that the compounds of the invention have a high affinity for brain serotonin receptors, especially 5-HT 1A type receptors (see Table I). The compounds of the invention are thus selective 5-HT 1A receptor ligands.

The active compounds of the formula I prepared according to the invention have a strong action on the central nervous system. In particular, their effect is evident in experimental arrangements where anxiolytic and antidepressant effects are observed. In addition, they cause a strong stimulation of sexual behavior in rats.

Based on these properties, the compounds of the invention enrich the range of drugs. They are suitable for the treatment of diseases of the central nervous system Tor-30, in particular for the treatment of pain and tension states, sleep disorders and depression, and especially problems related to sexual ability.

The preparation of compounds of formula I is exemplified by the following reaction scheme.

35 4 79299

Reaction scheme Ν02 5 NaN ° 2 r'r ^ i LLa / C3H7 CF COOHV U JL y C3H7

I C3H7! B; 5 ° C ^ C H

OCH-, UCH3 3 '3 0 10 <j-OC2H5 no2 c =: 0 1.) KOC2H5 / EtOH: diethyl ether 2. ^ 15 2.) Ht-C2O-C-C-OC-H,. i ^ C-, H_ 5 2 || || 2 5 OCH., 3 7

0 0 J 18 h; 18 ° C

(Yeah

20 o2n C = o

In NaOH / CH-jOH jj j c H FeSO4 / NH3 / --5-> H „0 15 h; 4 ° C - 2 y H 3 CO C 3 H 7 1 h; reflux H · ^ _ COOH DEGREE I U C, H7 30 3 7 T c3h7 OCH-. Hx J N- - Δ 8-methylquinoline | \ 1 1/2 h; 250 ° C 0CH 3 3 7 5 79299

The nitration of the 2-aminotetralin of the formula II is carried out in mineral acid or organic carboxylic acids with concentrated or fuming nitric acid or using NaNO3 as the nitration reagent. It is preferable to use sulfuric acid, nitric acid or trifluoroacetic acid as the solvent. The reaction is carried out at temperatures between -60 ° C and + 40 ° C. The preferred temperature range is between -20 ° C and room temperature.

The acylation of the resulting nitro compound to the compound of formula III is carried out with oxalic acid dimethyl ester or diethyl ester in the presence of a strong base in an inert, protic or aprotic solvent. Suitable protons for the removal of the proton of the activated methyl group are organometallic bases, such as lithium diisoprop-ylamide, n-butyllithium, sodium hydride or alkali metal alcoholates, such as, for example, sodium or potassium methylate or ethylate.

The solvents used are aprotic solvents, in particular ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme or aprotic solvents, such as dimethylformamide or dimethyl sulfoxide, or protic solvents, in particular alcohols, such as methanol or ethanol, or mixtures of 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 an acylation reagent, the use of potassium methanolate as a base and the use of a diethyl ether / ethanol mixture as a solvent, and the reaction is carried out at room temperature.

The saponification of the ester group present in the compounds of formula III is preferably carried out in an aqueous alkaline environment. Alkali or alkaline earth metal hydroxides or carbonates are mainly 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 methanol or ethanol. The reaction temperature is between 0 ° C and room temperature.

The reduction of the nitro group of the compounds of formula V and the ring closure to the compounds of formula VI takes place under conditions customary for the reduction of the aromatic scavenger group to the NH2 group. As reducing agents, for example, noble metal catalysts such as hydrogen activated with Ptr or Pdr, iron II salts in an alkaline, e.g. ammoniacal medium, zinc in glacial acetic acid or sodium dithionite can be used. The solvent used is mainly an alcohol / water mixture or glacial acetic acid. Reaction temperatures are between room temperature and the boiling point of the solvent. It is preferred to reduce with ferrous sulfate in an aqueous ammonia solution at reflux temperature.

The decarboxylation of the compounds of the formula VI to the desired compounds of the formula I is carried out in an inert solvent at a temperature of from 150 to 300 ° C, optionally in the presence of a catalyst such as Cu powder. It is preferred to use organic solvents such as quinoline, quinaldine or 8-methylquinoline.

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

The compounds of formulas III, V and VI are new. Their preparation and use for the preparation of compounds of formula I is an integral part of the invention.

The compounds of the invention may be formulated as preparations which, in addition to non-toxic, inert, pharmaceutically acceptable carriers, contain one or more compounds of formula I or salts thereof, or which consist of one or more compounds of formula I or salts thereof.

7 79299

The therapeutically active compounds should be present in the above-mentioned pharmaceutical preparations preferably in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight of the total mixture.

The pharmaceutical preparations can contain not only the compounds of the formula I and / or their salts, but also other pharmaceutically active substances.

The preparation of the pharmaceutical preparations is carried out in a conventional manner, e.g. by mixing the active substance or substances with a carrier or substances.

The active compounds or pharmaceutical preparations can be administered primarily orally, parenterally and / or rectal administration, especially oral administration, and decreased to 15 monsisäisesti.

In general, it has been found advantageous to administer the active ingredient or ingredients by parenteral administration (iv or im) of about 0.005 to 5, preferably 0.01 to 1 mg / kg of body weight every 24 hours and by oral administration of about 0.0 to 10, preferably 0.05-5 mg / kg body weight every 24 hours, possibly in the form of several single doses to achieve the desired results.

A single dose contains about 0.005 to 10, preferably 0.01 to 1 mg / kg of active ingredient or active ingredients per body weight. However, it may be necessary to deviate from said dosages depending on the nature and body weight of the subject being treated, the nature and severity of the disease, the use of the drug and the nature of the preparation, and the period and time interval within which the drug is administered. Thus, in some cases it may be sufficient to cope with less than the above-mentioned amount of said active ingredient; while in other cases the amounts of active ingredient 35 given above must be exceeded. The optimum dose and mode of administration of the active ingredient required for each β 79299 can be readily determined by any expert based on his knowledge.

The compounds of the formula I can also be used in pharmaceutical preparations in combination with other active ingredients. Primary mention should be made of β-receptor blockers, parasympatholytics, anxiolytics, neuroleptics, hypnotics and sedatives.

Table I below illustrates by way of example the high affinity of compounds 10 of the invention for brain serotonin receptors.

The compounds were tested for antidepressant and effects on sexual behavior. The antiderpressive effect was tested in an amphetamine-enhancing and antitetrabenazine test. Antidepressants potentiate amphetamine-induced stereotypic behavior in rats and antiagonize tetrabenazine-induced ptosis in rats.

The ED50 value given is the dose at which behavior was enhanced by 50% after intravenous administration of DL-amphetamine sulphate (2 mg / kg) or by a 50% reduction in ptosis induced by intraperitoneal administration of tetrabenazine. mg / kg.

25 Table II

Antidepressant effect Test system Animal ED50 (mg / kg i.v.)

Amphetamine 30 boost in rat 0.1

Tetrabenazine antagonism in mice 2.5 9 79299

Literature: J. L. Howard et al .; Antidepressants: Neurochemical, behavioral and clinical perspectives; Publ.

S. J. Ennä et al., Raven Press, New York (1981), p. 107-120.

5

An experiment on the effect on sexual behavior was the measurement of ejaculation delay and the number of mating attempts. The values give the time taken for the association of male and female animals and the first ejaculation of the male 10, as well as the number of mating attempts.

Table III

Effect on sexual behavior in male rats

Dose Ejaculation Mating attempts mg / kg Number of animals delayed (seconds) i.v. Num. Check Example 1 Check Example 1 20 - 0.032 6 141 104 4.5 4 0.125 6 143 70 ** 7.0 1 * 0.50 12 163 56 ** 7.5 0 *** 25 * P - 0, 05 ** P - 0.025 *** P - 0.01

According to the Mann-Whitney test

Literature: Larsson L., Fuxe K., Everitt B. J., Holmgren M., and Södersten P. (1978); Sexual behavior in male rats after intercelebral injection of 5 - 7 dihydro-30 tryptamine Brain Research, 141, p. 293 - 303.

10 79299 0 -

H M

P Ή I

H X H CO HO

H 0 * 0-0

Xl O H OOOOOO

• Η H O H O H

Λ X Σ (N (S

G <0 G

H> w

G

O

(1) Ή · Η

μ G H H G H

jC h h G -h

3 G -H H H -H H

M 0) -H M X H μ X

G -H dl * G O) A! G -H G 0) μ O 01 μ

O (O O G O P G O

O O P <0 E O <0 S

h o o p h μ p h

0) X H 0) CO <D <U CO

μ ai s * ω co * ω

0 CO

p

01 -H

HO H G

01 G H

O O Ή -H Ή x μ ό -h μ

Λ -H G G O

3 G (O O 01

H -H 01 P G

3 -H -H O (O

10 G H μ P

HOI O O

p a mx

O m II

μ aa O mm m

1 -H

H · Η H

P CO I

P (O (O E I G

O (OH (O (O G O l o μμ o o c x p χιό o a: μ h o <o

• H SP ai-HHHPP

g oio a οι οι o o μ p • H Σ E · Η3 (θμ (000 h a a> a p o μ p <

B

μ o

P H

aa <-i in

0 a H H

01 tn k a

0> i I I

a p m m 11 79299

Example 1 6-Methoxy-4-dipropylamino-1,3,4,5-tetrahydrobenz- [c, d] indole 5 ° -ch3. CH2-CH2-CH3 I w ch2-ch2-ch3 10 Yr 1. HCl HN-1 A solution of 0.35 g (0.00106 moles) of 6-methoxy-4-dipropylamino-1,3,4,5-tetrahydrobenz [c, d] indole-2-carboxylic acid in 10 ml in 8-methylquinoline, was mixed with 0.2 g of Cu powder, and then heated under a stream of nitrogen in a "custillator" at 250 ° C for 20 1 1/2 hours. The red-brown solution was applied to a column packed with silica gel (Kieselgel 60, E. Merck, Darmstadt). To separate 8-methylquinoline, CH 2 Cl 2 was eluted, and then the reaction product was eluted with CH 2 Cl 2 -MeOH (20: 4). The crude material was rechromatographed on silica gel (Kieselgel 60) using ethyl acetate / methanol (20: 2). The reaction product was dissolved in ether, and converted to the hydrochloride by adding ethereal hydrochloric acid. Hydrochloric acid was dried in a desiccator over sodium hydroxide.

Yield 0.226 g; mp. 134-136 ° C.

12,79299 Preparation of starting materials 6-methoxy-4-dipropylamino-1,3,4,5-tetrahydrobenzo- [c, d] indole-2-carboxylic acid 5 O-CH-] ch2-ch2-ch3 CHO-CH ~ -CHO 10 2 2 3 HN-

COOH

To a solution of 2 g (0.0005285 moles) of 4- (5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene) -2-oxoacetic acid in 7.5 ml A 25% aqueous ammonia solution was added with stirring to a warm solution of 9.69 g (0.03485 moles) of FeSO 4 .7H 2 O in 10.6 mL of water and then heated to reflux.

The mixture was cooled to room temperature, after which the insoluble black residue was removed by filtration and washed with MeOH / CH 2 Cl 2 (50:50). After removal of the solvent, the residue was chromatographed on silica gel 25 (Kieselgel 60, E. Merck, Darmstadt) using CH 2 Cl 2 / MeOH (20: 6). The product thus obtained was crystallized by trituration with CH 2 Cl 2 and dried in a desiccator over P 2 O 5. Yield 0.35 g.

i3 79299 4- (5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene) -2-oxoacetic acid 5 CH3? ^ CH2 ~ CH2 ~ CH3 Γ Ϊ J ch2-ch2-ch3 o9n c = o

10 C-OH

11.5 g (0.0283 mol) of ethyl 2- (5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene) -2-oxoacetate were dissolved in 300 ml. to methanol, and 100 ml (0.1 mol) of 1N sodium hydroxide was added under a stream of nitrogen at 18 ° C. The reddish reaction solution was then allowed to stand for 14 hours at -4 ° C. The reaction solution was neutralized with 100 ml (0.1 mol) of 1N hydrochloric acid, and the methanol was removed 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 a desiccator over P 2 O 5.

Yield 10.2 g of a yellow crystalline product.

Sp. (Mettler FP 61): 200.9 ° C.

i4 79299

Ethyl 2- (5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene) -2-oxoacetate 5 CH3 ° ^ CH2-CH2-CH3 ^ CH2-CH2'CH3 0.0 c = 0

2 I

10

II

O-ch2-ch3 0.095 g (0.024 moles) of potassium was layered under nitrogen and 22 ml of anhydrous diethyl ether under a moisture barrier, and five 1.11 ml (0.0191 moles) of anhydrous portions were then added with stirring at room temperature. ethanol. After the potassium was dissolved, 3.26 ml (0.024 mol) of oxalic acid diethyl ester and a solution of 7.4 g (0.02415 mol) of 5-nitro-8-methoxy-2-dipropylamino-1 were added to the reaction mixture. 2,3,4-Tetrahydronaphthalene in 7.5 ml of anhydrous diethyl ether. After stirring for 1 1/2 hours, another 3.26 ml portion of oxalic acid diethyl ester was added and the reaction was completed by stirring for 18 hours at 18 ° C. To the reaction solution was added 150 mL of CH 2 Cl 2 and filtered through diatomaceous earth. The solvent was removed from the filtrate and the oily residue was chromatographed on silica gel (Kieselgel 60, E. Merck, Darmstadt; grain size 0.063 mm) using a solvent mixture of CH 2 Cl 2-30 MeOH (20: 0.5).

Yield 4.3 g; 1.4 g of starting material were recovered.

is 79299 5-Nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene 5 CH3 ° .ch2-ch2-ch3

IS

10 2

To a solution of 5.5 g (0.02106 moles) of 8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene 152 in 15 ml (1.976 moles) of trifluoroacetic acid was added with stirring a moisture barrier and a stream of nitrogen. below 5 ° C, 2.9 g (0.0341 mol) of sodium nitrate, and was then stirred for 1 hour at 5 ° C.

The reaction solution was added over ice, and the pH was adjusted to 10 with 30% aqueous sodium hydroxide solution. It was then extracted with methylene chloride. The residue of the CH 2 Cl 2 phase was chromatographed on Al 2 O 3 (Al 2 O 3, 90 E. Merck, Darmstadt; grain size 0.063-0.200 mm) using toluene as eluent.

Yield 3.3 g of a yellow oil (50.8% of theory).

Claims (4)

A process for the preparation of therapeutically active tetrahydrobenzindoles of the general formula I 5 R, IXr2 x 1 10 T li y NT V I H in which R 1 and R 2 represent hydrogen or C 1 -C 6 alkyl and X is OR 3, where R 3 is hydrogen or C 3 -C 4 alkyl, characterized in that the compound of general formula II X 2 wherein R x . 4. ii 4 4 30 0 0 wherein R 4 is CH 3 or C 2 H 5, to a compound of general formula III i 7 79299 γ4 ΝΗ 2 c = o <Ϊ1 <; X 2 wherein, R 1, R 4 and X are as defined above, the ester group is saponified, the nitro group is reduced and then cyclized and decarboxylated in one or more steps. 18 79299 Fertilizers for the production of therapeutically active tetrahydrobenzindoles with all of the formulas I 5 Rt N '1 1 \ R2 10. Il / ks JJ—- N v I H color 15 Rx and R1 are optionally substituted with C3-C6-alkyl and X is ORj, color R3 is used with C1-C4-alkyl, the same being selected from the group consisting of the compounds of formula II: "X R2 25 color R3, R 2 and X are selected from the group consisting of substituents X and the same as those of the substituents X, which are acyl-rich nitroforming with oxalyl esters of the formula R.-O-CO-CO-R. 4. ii II 4 30 0 0 color R4 is CH3 or C2 H5, as described in formula III