DK157295B - TETRAHYDROBENZE INDOLES AND THEIR USE AS MEDICINES - 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

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The present invention relates to novel 1,3,4,5-tetrahydrobenz [c, d] indoles and their salts with physiologically acceptable acids and their use in pharmaceuticals. In particular, they can be used to treat cardiovascular disease and central nervous system disease by affecting the serotoninergic system.

The invention relates to tetrahydrobenzindoles of the general formula 10 * R? γΊ 1

H

wherein 1 2 R and R are hydrogen or C 1-6 alkyl, and 3 X is OR or SR where 20 R 1 is H or C 1-6 alkyl and salts thereof.

The present invention relates to active substances of formula I in both racemic form and in the form of the individual enantiomers.

The stated compounds of general formula I 25 are prepared by converting compounds of general formula 30 JL JL

X

35 0 2

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by nitration in para position to the substituent X of formula S is of the formula no2 ^ 111

V

X

4 - 4 '4 thereon by acylation with oxalic acid esters (R OC-COR

10 II II J

0 0 or C "H, -J converts these into compounds of formula 2 5 ~ OR 4 J ° 2 Ç = 0 15

I j IV

T Nv * 20 and finally, by reacting the ester group, reducing the nitro group, cyclization and decarboxylation in one or more steps via intermediate steps of the forms It and ¥ 1

C00H C .C00H

p_o N-f> OCX'1 OCX .- ** "I I NvR2

X X

30 for compounds of formula I wherein in 2R, R and X in formulas II to VI have the meaning given above. Further, compounds of general formula I are obtained when reducing compounds of formula III to 35 anilines of formula VII, 0 3

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5 VI1 [[1 j. Il I J VIII

For example, in A2 10, they transfer in a two-phase system of C ^ ^C ^ / NAOH to isonitriles of Formula VIII, and finally, they cylindrical with a strong base, e.g. lithum diisopropylamide, for compounds of formula I.

The active substances of formula I according to the invention unequivocally differ from known active substances of similar structure (cf., for example, U.S. Patent No. 4,110,339) 20 at the substituent X in the 6-position of the tricyclic ring system. While the known compounds, where X = H, have a powerful effect on the dopaminergic system, the compounds of formula I according to the invention, where X has the above-mentioned meaning, affect the effect on the dopaminergic system in the background relative to a dopaminergic system. powerful effect on the serotoninergic system. It can be shown that the compounds of the invention have a high affinity for the brain's serotonin receptors, especially for the 5-HT - β type receptors (see Table I). Accordingly, the compounds of the invention are selective 5-HT 1 receptor ligands.

The active substances according to the invention have a powerful effect on the central nervous system by animal testing. In particular, they show the activity of test devices in which anxiolytic and antidepressant effects have been produced. Furthermore, they lead to Vigorous stimulation of the sexual 0 4

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behavior of rats.

On the basis of these properties, the compounds of the invention are an advancement in the pharmaceutical field. They are suitable for combating diseases. i.central-5 nervous system, especially for the treatment of anxiety and tension states, sleep disorders and depression experiences, preferably for the treatment of problems with the sexual potency.

Compounds of formula I are preferred wherein R and R are a straight or branched C1-6 alkyl group and X is OCH3 or SCH3.

Particularly preferred are compounds of formula I / 1 wherein R 2 and R 2 are a straight or branched C 1-4 alkyl group and X is the OCH 3 group.

Preparation of Compounds of Formula I

is illustrated, for example, by the following reaction scheme: 20 NaNO 3 * C 3 H 7 CF COOH 3 AND 3

3 1 t; 5 ° C

25 ° 3 H? Îch3 X = 3H7 30 35

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5

1. KOC2H5 / Ethanoic Diethyl Ether H

2. H-C-0-C-C-0C-Hc ^ C- ° C2H5; 2 Π 5 »2

18 t; 18 ° C

LX ^ / ^ 3H7 OCH3. , C3H7

"'V' ..... COOH

0 C C = 0

1n NaOH / CH3OH 2 »I

i5t * 40 c ni .CH- Ι ^ Ι ^ / ν ^^ Γ3Η7 i [Ν: 3η? H3C0 | FeS04 / NH3 / H2 O ** ----—! 11 reflux HN, n ^ cooh

CXJv ^ 7 A

In Nc3H7 8-Methyl quinoline jj

0CH3 1 1/2 t; 250 ° C

H

and 3 '? 3H7 TP 69 0 6

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The nitration of the 2-aminotetralines II to the nitro compounds III takes place in mineral or organic carboxylic acids with concentrated or fuming nitric acid or NaNO3 healthy nitrating reagent. The solvent is preferably used as sulfuric acid, nitric acid or trifluoroacetic acid. The reaction is carried out at temperatures between -60 and 40 ° C.

The preferred temperature range is 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 indifferent.

protic or aprotic solvent. As bases: for deprotonation of the activated methylene group, metal organic bases such as lithium diisopropylamide, n-butyl-lithium, NaH or alkali metal alcoholates, such as alkyl or K-methylate or ethylate, are considered.

As solvents, aprotic: solvents, especially ethers, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diethylene glycol ether, or aprotic solvents such as dimethylformamide or dimethyl sulfoxide, or protic solvents, or protic solvents, or protic solvents, are used. or ethanol, éiler. mixtures of these solvents.

................ The reaction is carried out at temperatures between 25 ~ 80 ° C and room temperature. A preferred embodiment of the acylation reaction is the use of oxalic acid diethyl ester as an acylation reagent, potassium ethanolate as a base, a mixture of diethyl ether and ethanol as a solvent, and the reaction at room temperature.

Preferably, the saponification of the ester function of the compounds of formula IV is carried out in an aqueous alkaline environment. As bases, alkali metal or alkaline earth metal hydroxides or carbonates are preferably used. The reaction is carried out in water or preferably in a solvent-water mixture and a water-miscible solvent.

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such as methanol or ethanol. The reaction temperature is between 0 ° C and room temperature.

The reduction of the nitro group in compounds 5 of formula V and the cyclization of the compounds of formula VI occur under conditions common to the reduction of an aromatic nitro group to an NE 2 group.

As reactants, hydrogen, activated with noble metal catalysts, such as Pt or Pd, iron 10 (II) salts in alkaline, for example, ammonia medium, zinc in glacial acetic acid or sodium dithionite can be used, for example. As solvent, water or an alcohol / water mixture or glacial acetic acid is preferably used. The reaction temperatures are between room temperature and the boiling point of the solvent. Preferably, the reduction with iron (II) sulfate is carried out in an aqueous ammonia solution at reflux temperature.

The decarboxylation of compounds VI to the compounds of the invention of formula I is carried out in an inert solvent at temperatures between 20 150 and 300 ° C, optionally in the presence of a catalyst such as Cu powder. Preferably, basic organic solvents such as quinoline, quinaldine or 8-methyl-quinoline are used.

The starting materials of formula II are known from the literature or can be prepared by analogy with the known compounds, cf. THE. Ames et al., J. Chem. Soc. 1965, 2636.

The compounds of formulas III, IV, V and VI are novel.

The present invention includes compositions which, in addition to inert pharmaceutically suitable carriers, contain one or more compounds of the invention or their salts.

Pharmaceutical compositions may be present in dosage units. This means that the compositions are in the form of individual parts, e.g. tablets, dragees, capsules, 0

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8 capsules, pills, suppositories and ampoules whose content of active substance corresponds to a fraction or multiple of a single dose. The dosage units may e.g. contain 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a 5 single dose. Preferably, a single dose contains the amount of active ingredient that is ingested upon administration, which usually corresponds to one whole, half or one third or one quarter of the daily dose.

By non-toxic, inert, pharmaceutically acceptable carriers are understood solid, semi-solid or liquid diluents, fillers and preparations of any kind.

As preferred pharmaceutical preparations: may be mentioned tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions.

Tablets, dragees, capsules, pills and granules may contain the active substance (s) in addition to the usual carriers, such as (a) fillers and extenders, such as starch, milk sugar, cane sugar, glucose, mannitol 20 and silicic acid, (b) binders, such as carboxymethyl cellulose, alginates, gelatin and polyvinylpyrrolidone, (c) moisturizing agents such as glycerol, (o) disintegrants such as agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolving retardants, such as paraffin, and (f) (g) wetting agents, such as cetyl alcohol and glycerol monostearate, (h) adsorbents, such as kaolin and bentonite, and (i) lubricants, such as talc, calcium and magnesium stearates, and solid polyethylene glycols. , or mixtures of the substances specified in (a) to (i).

The tablets, dragees, capsules, pills and granules may be provided with the usual coatings and inlay materials, which may contain opalizing agents, and may also be so composed as to produce, or possibly delay, the active substance (s) alone. or, preferably, in a particular part of the intestinal region, which can be used, for example, as an inert mass, for example polymère ςί-nffpr ησ vokRarter.

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The active substance (s). may also optionally be in microencapsulated form with one or more of the carriers listed above.

Suppositories may contain, in addition to the active substance (s) (5), the usual water-soluble or water-insoluble carriers, such as polyethylene glycols, fats, such as cocoa fat, and higher esters (e.g., C or mixtures of these substances.

Solutions and emulsions may contain, in addition to the active substance (s), the usual carriers such as solvent, solvent dissolving agent and emulsifier, e.g., water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, dimethylformamide, oils, in particular cotton seed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions may also be in sterile and blood isotonic form.

Suspensions may contain, in addition to the active substance (s), the usual carriers, such as liquid diluents, e.g., water, ethyl alcohol and propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methahydroxide, bentonite, agar - agar and tragacanth or mixtures of these substances.

Said preparation forms may also contain coloring agents, preservatives, and flavoring and flavoring additives, such as peppermint oil and eucalyptus oil and sweeteners, such as saccharin.

Preferably, the therapeutically active compounds should be present in the above-mentioned pharmaceutical compositions at a concentration of ca. 0.1% to 99.5% by weight, especially preferably from ca. 0.5 to 95% by weight of the entire mixture.

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The above-mentioned pharmaceutical compositions may contain, in addition to compounds of formula I and / or their salts, other pharmaceutically active substances.

The release of the above-mentioned pharmaceutical compositions is customary by known methods, for example, by mixing the active substance (s) with the carrier substance (s).

The active substances or pharmaceutical compositions may be administered preferably orally, parenterally and / or rectally, preferably orally and parenterally, especially orally and intravenously.

In general, it has been found to be advantageous to administer the active substance (s) by parenteral (i.v. or i.m.) administration in amounts ranging from ca. 0.005 to approx. 15 mg / kg, preferably 0.01 to 1 mg / kg body weight every 24 hours and by oral administration in amounts of about 0.01 to approx. 10 mg / kg preferably 0.05 to 5 mg / kg body weight every 24 hours, optionally in the form of multiple single doses to achieve the desired results. A single dose contains the active ingredient (s), preferably in amounts from 0.005 to approx. 10 mg / kg body weight, in particular from 0.1 to 1 mg / kg body weight.

However, it may be necessary to deviate from the aforementioned dosages, namely, depending on the nature and body weight of the patient to be treated, the nature and severity of the disease, the nature of the preparation and the drug administration, and the period or interval within which the administration occurs. . Thus, in some cases it is possible to cope with less than the amount of active substance indicated above, while in other cases 30 the amount of active substance stated above must be exceeded. The determination of the optimum dosage and mode of administration of the active substance each time required can easily be accomplished by any skilled person in the light of his professional knowledge.

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The following Table I illustrates with the compound of the invention of Example 1 as an example the high affinity of the compounds of this invention to the brain's serotonin receptors.

The selective 5-HT 1 receptor antagonist activity of the compounds of Formula I is shown by the displacement 3 of [H] 5-HT from the cerebral cortex of rats, preferably relative to the displacement of [H] spiroperidol, which preferably binds to 5 ~ HT 2 receptors. In Peroutka et al., Molecular Pharmacology 16: 687-699 (1979), this test procedure is described and the serotonin 3,3 receptors labeled with [H] 5-HT and [H] spiroperidol are designated respectively. 5-HT 2 and 5-HT 2 · Icgo (Concentration required to displace 50% of the [3 H] 5-HT-15 bond from the cerebral cortex in rats) for the compounds 6-methoxy-1,3,4, 5-tetrahydrobenz [c, d] indole-4-amine hemioxalate, 6-hydroxy-1,3,4,5-tetrahydrobenz [c, d] -4-amine oxalate and N, N-dimethyl 6-methoxy-1,3,4,5-tetrahydrobenz [c, d] indole-4-amine oxalate is from ca. 40 to approx. 70 nM.

Selective 5-HT 1 receptor antagonist activity of the compounds of Formula I may also be demonstrated by the ability to antagonize the action of serotonin in an in vitro basilar artery preparation by dogs, Peroutka et al., Brain Research 259: 327 330 (1983). 6-Methoxy-1,3,4,5-25 -tetrahydrobenz [c, d] indole-4-amine hemioxalate shows selective 5-HT, activity at ΚΏ = 4.63 x 10 ^M.

The central serotoninergic effect of drugs with compounds of formula I as active substance is demonstrated in two ways. The first method shows inhibition of tritiated serotonin uptake according to the following specification (weak inhibition of tritiated spiperone uptake is also determined). (-) - 4-di-n-propylamino-6-substituted-1,3,4,5-tetrahydroindoles plus the corresponding drug from U.S. Patent No. 4,110,339, which lacks a C-6, are tested. substituent.

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Inner tissue is obtained from male-Wistar rats weighing 150-200 g. The cerebral cortex is dissected and homogenized and then centrifuged by the procedure described by Nelson and colleagues, Mol. Pharmacol., 14, 983-995 (1978), using pre-incubation in buffer without added monoamine oxidase inhibitor to remove endogenous serotonin. For receptor binding, each sample contains 300-400 micrograms of membrane protein and 10 μΜ pargyline 3 in addition to the H ligand in 1 ml of 0.05 M Tris buffer: pH = 10 7.4. The analysis for serotonin binding is done by: the method of Bennett and Snyder, Mol. Pharmacol., 12, 373-389 (1976), and the assay for tritiated spiperone according to Peroutka and Snyder, Mol. Pharmacol., 16, 687-699 (1979). The samples are incubated for 15 minutes at 37 ° C and then filtered through GF / C glass fiber filter layers using a Brandel M-24 cell harvesting device modified for receptor binding. After two 5 ml flushes, the filter discs are placed in scintillation haze glasses and counted in 10 ml Amersham PCS scintillation fluid. Non-specific binding of JH-serotonin (H-5HT) is determined at -5. 3 presence of 10 M serotonin and of H-spiperone in near- 6 room of 10 M LSD. Specific binding is calculated as the difference between total binding without added non-radioactive compound and the non-specific binding.

25 IC 50 values are determined, where IC 50 is the amount of substance that causes 50% inhibition of the specific binding, using 10-12 concentrations in a range of -9-4 3 from 10 to 10 M. The concentrations of H- the ligands are: serotonin (Amersham, 11 Ci / mmol), 2-3 nM; LSD (Amersham, 1.8 Ci / mmol) ^ 1.8-2.6 nM); spiperone (Amersham, 20 Ci / mmol), 0.6-0.7 nM.

The results obtained are given below.

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Receptor binding H-ligand IC ™ * 3 3

Compound Name_H-5HT_H-SPIP_ (+) -4-di-n-propylamino-6-methoxy-73,4,5-tetrahydrobenz [c, d] indole (+) - 4-dimethylamino-1,3, 4,5-tetrahydrobenz [c, d] indole 120 730 *) The values are in nanomole inhibitor.

Next, the decrease of brain serotonin metabolites is measured as a measure of central serotonin antagonist activity. A measure of dopamine agonist activity is also shown by changes in dopamine metabolites.

The following regulations are applied:

Wistar rats weighing 150-200 g receive 0.3 mg / kg (+) - 4-di-n-propylamino-6- substituted-1,3,4,5-tetrahydrobenz [c] at 15 subcutaneous administration. , d] indole. Each rat is decapitated after 60 minutes, and the hypothalamus and striatum are dissected and extracted. The amounts of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum and of 5-hydroxyindole acetic acid (5HIAA) in the hypothalamus are measured by high performance liquid chromatography using electrochemical detection. We also measure corticosteroids. The following table lists the results of this experiment. In the table, columns 1 and 2 indicate the substitution pattern of the compounds of this invention, columns 3 to 5 5HT or dopamine metabolite concentrations and column 6 contains the corticosteroids.

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g O H U g Q) 4-) O * * CQ O Oî 1—1

S OH

S ü \ +1 +1 +1 U -H tn 0) -P 3. 00 H Γ "ω M ^

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U

• tn 0) Λ P «flj * ü 4J tn oo H t" · ό + J \ H 04 C4

H i-I (P.

H O <1 + 1 + 1 + 1 Ü 0 S>% o iz trj ro oo ^ <ü (C w N + i 4_) g * * · »4->

Q) g 04 'si * O

Ë 3 H

l4-i * *

β (0 O M 00 P

rl -Ht) H <N fO · ©.

g M C PH

G 4-1 CP + i +1 +1 Λ ω O <u OP rH 10) CO g

H Q -H υο H 10) -H

H * - - * 4J

^ in

H H

(U 1

Λ Oh

tti cp tn o

Eh l-N 2 4î -K * Λ g tn 5> f. H “

ro O O H

H H H tn. 2 Ο ο ο o ^ -P G g1

H + 1 + 1 + 1 S

K

LT) H <01 Cl 0Π LO) 140 ΙΟ -

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H H CM

Ό <ü

S

•

tn -P

and

P rô

0) M

ü -H

04 -H PH

pi · η · Η

GG

tri P -H Cn

O P (U -H

G g (U ω

H I I G

· Η vH P

Ό rH <U tn

O tn -H

P H 4-1 .µ Φ tn

G Ό -H

O G -P

X · -H <tS

^ -Q -P

Où) P tn g S o X Ο Ο (XI 4t 0 15

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The two compounds tested appear to have some dopamine agonist activity. They also have significant serotonin agonist activity at the sanitary dose level.

Finally, the test rats receive (+) - 4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrobenz [c, d] indole to obtain a template for central serotonin agonist activity.

The decrease in brain serotonin turnover is measured as a function of 5-hydroxytryptophan (5-HTP) accumulation when the decarboxylation of 5-HTP is blocked by m-hydroxybenzylhydrazine using the above rule except that m- hydroxybenzylhydrazine is injected at a dose of 100 mg / kg ip 30 minutes after injection of the drug. 40 minutes later, each 15 rat is decapitated, the hypothalamus is dissected and extracted. The amount of 5-HTP in each extract is measured by high performance liquid chromatography using electrochemical detection. In normal rats, the 5-HTP content of the brain is so low that it cannot in fact be detected. The control group 20 received the same dose of m-hydroxybenzylhydrazine as the test rats, but no drug. The results of this experiment are given in the following table.

Table IV

25 Inhibition of uptake Drug dose 5HTP content in nanomoles of mg / kg hypothalamus + mean deviation 30 0 1.81 + 0.11 0.01 1.85 + 0.06 0.03 1.72 + 0.07 0.10 1 , 16 + 0.051 0.30 0.97 + 0.031 35

Significant difference from the 0-dose group (P <0.05).

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The above results show that certain dose levels of (+) - 4-di-n-propylamino-6-methoxy-1,3,4,5-tetrahydrofuran [c, d] indole significantly decrease 5HTP accumulation, and thus suggest central serotonin-5 agonist activity at these dose levels or at higher dose levels.

The compounds are also tested for antidepressant and effect affecting sexual behavior. The compound of the invention of Example 1 is used in Example.

To test the antidepressant effect, the amphetamine potentiation test and the antithetrabenazine test serve.

Antidepressant drugs potentiate the amphetamine-induced steroid behavior in rats and antagonize the tetrabenazine-induced ptosis in mice. The indicated EDç-Q value is the dose at which the behavior after administration of 2 mg / kg DL amphetamine sulfate i.v. 50%, respectively, the dose at which it is increased by 20 mg / kg i.p. tetrabenazine induced ptosis is reduced 50%.

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Table V

Antidepressant effect 5 Test system Animal species ED_n (mg / kg i.p.) _______ J U _ ^ _

Amphetamine potency. Rat 0.1 ring

Tetrabenazine Mice 2.5 Antagonism 10:

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.

15

As a test of the effect that influences sexual behavior, the measurement of ejaculation latency and the number of copulation attempts serves. The values indicate the time elapsed from the male and female animals being put 20 together to the first ejaculation of the male, and the number of copulation attempts.

Table VI 25

Impact on male rats' sexual ward

Dose Number of animals Ejaculation latency Number of copulation mg / kg i.p. (seconds) try

Control Example 1 Control Example 1 30 0.032 6 141 104 4.5 4 0.125 6 143 70 7.0 1 0.50 12 163 56 ** 7.5 0 *** 35 J »w Jejltil 'P -0.05 P -0.025 P - 0.01 according to Mann-Whitney test

Literature: Larsson K., Fuxe K., Everitt B. J., Holmgren M., and Sôdersten P. (1978). Sexual behavior in male rats after

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18

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Pi H 1

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O -H 00 H

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• H H ^ <N CN H

d R d (d

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m o ta d ® m d ocu

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Example 1 6-Methoxy-4-dipropylamino-1,3,4,5-tetrahydrobenz [c, d] -indole 5Γ ™ 3 m 2 CH 2 -C82-CH 3 -CHO-CH, II II N_Il * HCl 10

To a solution of 0.35 g (0.00106 mol) of 6-methoxy- - -s-4-dipropylamino-1,3,4,5-tetrahydrobenz [c] dj indole-2-carboxylic acid in 10 ml To 8-methylquinoline 0.2 g of Cu powder is added,

and then heated under nitrogen rinsing in a custila-15 °

Dry for 1.5 hours at 250 ° C. The dark red-colored reaction solution is added to a column filled with silica gel (Kieselgel 60 from E. Merck, Darmstadt). To separate 8-methylquinoline, the reaction product is eluted with CH 2 Cl 2 and then with a 20: 4 CH 2 Cl 2 / methanol mixture.

20 ^.

The crude material is chromatographed on silica gel (Keiselgel 60 from E. Merck, Darmstadt) with a mixture of ethyl acetate and methanol in the ratio 20; 2. The reaction product is dissolved in ether and converted by adding ethereal hydrochloric acid to the hydrochloride. The hydrochloride is dried in a desiccator over NaOH.

Yield yield: 0.226 g, m.p. 134-136 ° C.

Preparation of the starting compounds: 6-Methyl-4-dipropylamino-1,3,4,5-tetrahydrobenz [c, d] -indole-2-_-carboxylic acid _________ O-CH, J 3 £ δ ô oc il r CH.-CH.-CH, 35 I Jl I 2 2 3

^ COOH

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To a solution of 2 g (0.005285 mol) of 4- (5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene) -2-oxoacetic acid in 7.5 To a 25% aqueous ammonia solution, a hot solution of 6.69 g of 5 (0.03485 mole) of FeSO4 is added with stirring. 7H2 O in 10.6 ml of water and then heated at reflux for 1 hour.

After cooling to room temperature, the insoluble black residue is filtered off and washed with a mixture of methanol and CE 50 C in a ratio of 50:50. After removal of the solvent, the residue is chromatographed on silica gel (silica gel 60 from E. Merck, Darmstadt) with a 20: 6 mixture of methanol and methanol. The product thus obtained is crystallized by grating with C CïC ^ and dried in a desiccator over ^ 2 ^5 * 15 Yield: 0.35 g.

4- (5-Nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene) -2-oxo-acetic acid CH3-CH2-CH2-CH3 [VcH2'CH2_CH3 ° 2 NC = 0

25 f0H

ISLAND

11.5 g (0.0283 Mole) of ethyl 2- (5-nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene) -2-oxoacetate are dissolved in 300 ml of methanol, and 100 ml (0.1 mol) of 1 N NaOH solution are added under nitrogen rinsing at 18 ° C. The red-colored reaction solution is then left for 14 hours at 4 ° C. The reaction oxone solution is neutralized with 100 ml (0.1 mol / 1N hydrochloric acid and freed from methanol by means of a rotary evaporator. The aqueous 35 residue is extracted with CH2 Cl2

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Yield: 10.2 g of yellow-colored crystalline product.

Mp. (Mettler FP 61) = 200.9 ° C.

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

CH -'- O ^ CH.-CH ^ -CH

c i i 1 \ f T ch2 “CH2“ CH3 0o N C = 0 2 I C = 0! o-ch2-ch3 0.94g (0.124mol) of potassium is covered under nitrogen and the exclusion of humidity with 22ml of absolute diethyl ether, and then 5 portions of 1.11ml (0.0191mol) of absolute, are added under stirring at room temperature. ethanol. After the potassium metal is dissolved, the first part (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 are added to the reaction solution. -dipropylamino-1,2,3,4-tetrahydronaphthalene in 7.5 ml of absolute diethyl ether, stirring for 1.5 hours, then adding the second part (3.26 ml (0.024 mol)) of oxalic acid diethyl ester and completing the reaction with 18 hours stirring at 18 ° C.

To the reaction solution is added 150 ml of CH 2 Cl 2 and filtered over diatomaceous earth. The filtrate is freed from the solvent and the oily residue is chromatographed on silica gel (Kieselgel 60 from E. Merck, Darmstadt? 0.04-0.063 mm 30 grain size) with the eluent mixture CH2 Cl2 / methanol in a ratio of 20: 0.5.

Yield: 4.3 g. 1.4 g of starting product are recovered.

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DK 157295 B

5-Nitro-8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene C83-8 CH -CH -CH, N ^ 23 5YY ch2-ch2-ch3

02 N

10

To a solution of 5.5 g (0.02106 mole) of 8-methoxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene in 152 ml (1,976 mole) of trifluoroacetic acid is added under stirring, to exclude moisture. and rinsing with nitrogen at a temperature of 5 ° 2.9 g (0.0341 mole) of sodium nitrate and then stirring for 1 hour at 5 ° C.

The reaction mixture is added to ice and adjusted to a pH of 10 with a 30% aqueous NaOH solution. Extract with methylene chloride. The C ^ C ^ phase residue is chromatographed on (A ^ O ^ 90 from company

Merck, Darmstadt? grain size 0.063-0.200 mm) with toluene as eluent.

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

25 30 35

Claims (8)

1. Tetrahydrobenzindoles of the general formula r 2 10 H in which r! and R 2 is hydrogen or C 1-6 alkyl, X is OR 3 or SR 3, while R 3 is hydrogen or C 1-4 alkyl / 15 and salts thereof. 2. Tetrahydrobenzindoles according to claim 1, characterized in that r! and R2 is a straight or branched C1-4 alkyl group, and 20. is OCH3 or SCH3, and salts thereof. Tetrahydrobenzindoles according to claims 1 or 2, characterized in that R 3 and R 2 are a straight or branched C 1-4 alkyl group, 25 and X are OCH 3, and salts thereof. 4. Use of Compounds of General Formula N-R R1 Wherein R 1 and R 2 are hydrogen or C 1-6 alkyl, X is OR 3 or SR 3, wherein R 3 is hydrogen or C 1-4 alkyl / 5 for the manufacture of drugs. 5. A composition containing one or more compounds of the general formula H wherein R 1 and R 2 are hydrogen or C 1-6 alkyl, X is OR 3 or SR 3, R 3 being hydrogen or C 1-4 alkyl, and inert pharmaceutically suitable carriers.