FI69074C - FOER FARING FOR FRAMING PROCESSING WITH A PSYCHOTROPIC MEDICINE - Google Patents

Description

1 69074

A process for preparing a carbatol derivative useful as a psychotropic agent

The invention relates to a process for the preparation of a carbazole derivative useful as a psychotropic substance and to intermediates used in the process.

AU patent 201 630 and FR patent 1 167 510 describe carbazoles of the formula (I) 10 (I) 15 / \ A - N N - R, N ___ / 1 in which A is a divalent saturated aliphatic, straight-line or a branched chain hydrocarbon radical, R 1 is hydrogen, a lower alkyl, aryl or araliphatic group, Y and are hydrogen or halogen atoms, lower alkyl, alkoxy, aryl or aryloxy groups, wherein in the rings to which Y and Y 1 are attached, there may be other substituents in addition to Y 1 and Y 2, and the piperazine ring 25 may further have a methyl substituent.

FI patent publication 65 244 · (published on May 2, 1980) discloses 9- ^ 3- (3,5-cis-dimethyl-piperazino) propyl / carbazole of the formula (A) (sometimes referred to as cis-9- ^ 3- (3,5-dimethylpiperazinyl) propyl] -30 carbazole or 9- [3- (cis-3,5-dimethyl-1-piperazinyl) propyl] carbazole or cis-9- [3- (3,5-dimethyl- 1-piperazinyl) propyl / carbazole) 2,69074

Ccu (CH2) 3 (A)

5 I

A

H 2 N / VCH

d H

10 and the preparation of pharmaceutically acceptable salts and pharmaceutically acceptable solvates of pharmaceutically acceptable salts thereof. These compounds are valuable anti-aggressive and antipsychotic agents that can be used to treat human aggression and psychosis. Surprisingly, these compounds do not have toxic side effects, such as dyslexia or sedation, which are common side effects of antipsychotics, for example chlorpromazine.

The compound of formula (A) is hereinafter referred to as "carbazole". "Carbazole" can be administered for prophylactic purposes to a patient (human) who has been diagnosed with aggressive or psychotic symptoms, and as a therapy, to a human patient with aggressive and psychotic symptoms. The pharmacological test used to demonstrate the anti-aggressive and antipsychotic properties of "carbazole" has been described by G.M. McKenzie,

Brain Research, 34, 323 (1971). In this experiment, the rat exhibits aggressive behavior with apomorphine, with "carbazole" being shown to be antagonistic to this effect. In addition, the antipsychotic and anti-aggressive effect of "carbazole" is demonstrated by its ability to suppress instinctive murine behavior (e.g., killing mice) in rats (see Leaf 35 et al., Aggressive Behavior, ed. S. Garattini and EB Sigg, pp. 120-131, John Wiley and Sons, Inc., New York, 1969).

It has been found that the anti-aggressive and antipsychotic effect of "carbazole" has been found to be due in particular to the position of its methyl substituents. It has been found to be more potent than the corresponding methyl-free compound or analogous 4-methyl or 3,4,5-trimethyl compound.

"Carbazole" is particularly valuable because, in addition to its antipsychotic and anti-aggressive effect, it has essentially no undesirable side effects, such as sedative, cataleptic and extrapyramidal dysfunctional effects, which are common with currently used antipsychotics such as phenothiazines. Evidence that "carbazol-1α" has no extrapyramidal side effect is its lack of ability to antagonize apomorphine-induced stereotyped behavior in rats (see Andien, N.E., J. Psychiat. Res., 11, 97, 1974). The mode of action of "carbazole" is also associated with substantially less anticholinergic and antihistamine activity than phenothiazines.

Due to the biological properties of the "carbazole" from the base itself, the salts of the base (i.e., acid addition salts) are also effective and are within the scope of the invention. For therapeutic use, the acid moiety of such a salt must be pharmaceutically acceptable to the user of the drug. Examples of pharmaceutically acceptable salts include (a) salts of inorganic acids such as sulfate and hydrohalides, for example hydrochloride, and (b) salts of organic acids such as acetate, citrate, fumarate, lactate (e.g. DL-lactate), malate (e.g. L-malate), maleate, succinate and tartrate (e.g. L-tartrate) and alkane sulfonates such as methanesulfonate and aryl sulfonates such as p-toluenesulfonate. The "carbazole" can be converted to a salt and the salts can be converted to a base or salts of other acids by methods known in the art. Thus, salts that are not pharmaceutically acceptable also play a role in the preparation of pharmaceutically acceptable salts. In addition, salts of the "carbastol" base may form hydrates and alcohol solvates (e.g., with methanol or ethanol), which are also within the scope of the invention.

The "carbazole" is prepared according to the invention by removing the protecting group Z from the protected intermediate (II)

O

The β-N- (CH 2) O-N N-Z (II) 15 ch 3 Z protecting group may be formyl, acetyl or ethoxycarbonyl.

The protecting group Z can be removed from a compound of formula (II) by methods known in the art, e.g. by hydrolysis with aqueous acid or aqueous base or treatment with anhydrous acid (e.g. HBr acetic acid solution) or anhydrous base (e.g.

25 with KOH-methanol solution).

Other suitable reagents include thiol salts, iodometrimethylsilane (see e.g. Groutas, WC and Felker, D., Synthesis 861-868 (1980)), hydrogen and a catalyst (preferably palladium) or a metal such as sodium metal in ammonia or amine. , in which case other proton donors, such as alcohols, may be added.

Such methods have been extensively described in the literature, see, e.g., "Protective Groups in Organic Chemistry", ed. J. F. W. Mcomies, Pleunum Press (1973), 35 ISBN 0-306-30717-0, and Harfenist, M. and Magnien, E., J.Amer. Chem. Soc., 79, 2215-6 (1957).

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Protected intermediates of formula (II) may be prepared by reacting a compound of formula (III) ^ CH 3 5 L- (CH 3) -N NZ (III) N_ / CH 3 wherein Z is as defined in formula 10 (II) and L is leaving group, to react with carbazole or a reactive derivative thereof. Suitable values for L include halogen (preferably chlorine), arylsulfonyloxy (preferably p-toluenesulfonyloxy) and alkylsulfonyloxy (preferably methanesulfonyloxy).

Particularly suitable reactive derivatives of carbastol are alkali or alkaline earth metal derivatives, in particular lithium, sodium, potassium, zinc, cadmium and calcium derivatives, although carbazole magnesium halide, e.g. iodide, can also be used.

Alkali metal carbazoles are conveniently prepared by reacting the carbazole with a suitable alkali metal hydride or amide in an inert, preferably polar, aprotic medium such as liquid ammonia, dimethylformamide or dimethyl sulfoxide; other suitable media include hydrocarbons, e.g., alkanes, cycloalkanes, and aromatic compounds. The same reaction medium can be used for N-substitution, which is preferably carried out by heating. The N-substitution is preferably performed in a solvent and in an inert atmosphere such as nitrogen gas.

Alternatively, a compound of formula (III) may be reacted with a carbazole in the presence of an alkali metal hydroxide or alkoxide in a polar solvent such as dimethylformamide, dimethylacetamide, water or the like alkanol, e.g. in the presence of tert-butoxide in tert-butanol.

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Compounds of formula (III) are readily obtained from the corresponding alcohol (wherein L is hydroxy) in a conventional manner. For example, the alcohol can be converted to p-toluenesulfonate (L is p-toluenesulfonyloxy) by reaction with p-toluenesulfonyl chloride.

The alcohol itself can be prepared by reacting the formula (IV) / - ^ HO- (CHO) O-N N-H (IV) 10 2 3

V

a piperazine derivative according to the reaction with an amine protecting compound such as formic acid, carboxylic anhydride (e.g. acetic anhydride), carboxylic acid chloride (e.g. benzoyl chloride), alkyl halide (e.g. ethyl halide) or alkyl halide (e.g. ethyl chloroformate) or selectively hydroxyl function e.g. by hydrolysis.

The compound of formula (IV) may be prepared from 3-propanol and 3,5-cis-dimethylpiperazine in a suitable solvent such as ethanol or dimethoxyethane.

"Carbazole", its pharmaceutical! acceptable salts and pharmaceutically acceptable solvates thereof are useful in the treatment of human psychotic and aggression states. It can be used, for example, to treat division-30 mental illness, passion, depression due to old age or other causes.

"Carbazole" can also be used to prevent and treat aggressive behavior. Such behavior may be associated with other disorders such as psychotic and personality disorders, as well as childhood isolation and mobility.

7,69074 "Carbazole", its pharmaceutically acceptable salts and solvates enhance d-amphetamine-induced locomotor activity, an effect of most tricyclic antidepressants. This enhancement of the effect of d-amphetamine 5 suggests that "carbazole" may have an antidepressant effect in humans.

Another use of "carbazole", its pharmaceutically acceptable salts and solvates is in the treatment of aggressive symptoms in mentally retarded and / or disordered patients or in the treatment of aggressions associated with epileptic diseases due to acute or chronic brain damage, alcoholism, alcoholism. and addressing aggression from other known and unknown causes.

"Carbazole", pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates thereof may be administered to mammals, e.g., humans, preferably orally at a dose of 1-30 mg / kg (calculated as base) of body weight to treat aggression or psychosis; the preferred dose is 2-5 mg / kg. "Carbazole", a pharmaceutically acceptable salt or solvate thereof, is preferably administered in the treatment of these diseases three times a year at the above-mentioned dose. The intramuscular dose is usually half the oral dose. For example, in the treatment of osteoarthritis, a suitable dose is 1-15 mg / kg, preferably 2-5 mg / kg, given, for example, in a unit dose of 60-900 mg. The unit dose is suitably administered once or more 30 times a day, for example 3 times a day in the form of tablets containing 10 to 300 mg, suitably 60 mg of "carbazole", a pharmaceutically acceptable salt or solvate thereof.

"Carbazole", its pharmaceutically acceptable salts and pharmaceutically acceptable solvates have antidepressant activity at doses equal to those described above.

69074 8

Pharmacological experiments

Table I shows a substantially better result obtained with "carbazole" in the form of the dihydrochloride hemihydrate prepared in Example 1 (a) (Compound A) compared to the result obtained with 5 known carbazole derivatives, 9-1- (4-methylpiperazino) propyl] carbazole (as dihydrochloride) (Compound B).

Table I

Comparison of the activity and toxicity of "carbazole" (Compound A) and 9-Z.3- (4-methylpiper-10-racino) propyl / carbazole (Compound B).

Compound Anti-aggressive effect LD5q (mg / kg) ED5q (mg / kg) Therapeutic ratio

Rat, p.o. Rat, p.o. LD ^ / ED ^ 15 A 957 48 20 B 830 75 11

Table II summarizes e.g. many other advantages of "carbazole" over Compound B. The minimum dose (at hii-20) at which the correction reflex disappears (ED min.) Is about three times the value obtained with compound B.

Similarly, a reduction in muscle tone (in the rat) is obtained with Compound B at a significantly lower dose than "carbazole".

Table II also compares the anticonvulsant activity of the two compounds and commercial anticonvulsant phenytoin (Dilant®). Phenytoin is about 2.5 times as active as Compound B and 5 times as active as "Carbozole" (Compound A).

The level of anticonvulsant activity of Compound B is within the range at which the use of the compound for this purpose can be considered. "Carbazole" having an anticonvulsant activity of less than half the activity of Compound B, respectively, cannot be considered a sufficiently active anti-convulsant to be considered for this purpose.

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Table II

Comparison of some properties of Compound A, Compound B and phenytoin.

Correction Reflex Muscle Muscle Anticonvulsant Loss in Mouse, Decreased Activity 5 ED min. (mg / kg i.p.) rat ED min. (MES) a mouse

Compound (mg / kg i.p.) ED 2 (mg / kg.i.p.) A 160 125 43 B 50 50 20

Phenytoin> 100 - 8.5 10 (a) Maximum electric shock test (Woodbury and Davenport, Arch.

Int. Pharmacodyn. Ther., 92, 97-107 (1952).

A known carbazole derivative, 9- [3- (4-methyl-piperazino) propyl] carbazole, designated Compound B in Tables I and II above, is prepared in Example 7 of the AU and FR patents mentioned in the prior art description. compound.

The following examples are provided to illustrate the invention. In these examples, all temperatures are in degrees Celsius and vacuum distillation was performed on a steam-20 bath at a pressure of about 20 mmHg unless otherwise indicated.

Example 1 Preparation of cis-9- [3- (3,5-dimethyl-1-piperazinyl) propyl] carbazole 25 a) Preparation of cis-3- (3,5-dimethyl-1-piperazinyl) -1-hydroxypropane dihydrochloride cis-2, 6-Dimethylpiperazine (28.5 g, 0.25 mol), 3-chloropropanol (23.6 g, 0.25 mol) and sodium carbonate (30 g, 0.28 mol) are refluxed in 100 ml of dimethoxyethane for 4 hours. . The solid is filtered off and the solvent is removed from the filtrate by distillation in vacuo. The obtained solid residue is dissolved in ethanol, and anhydrous hydrogen chloride is added to the solution. The solid 10 69074 is filtered and dried to give 46 g (75%) of a white solid. The IR spectrum of the free base has a broad OH absorption (3160 cm -1) and a sharp NH absorption (3250 cm -1).

5 b) Preparation of cis-3- (4-acetyl-3,5-dimethyl-1-piperazinyl) -1-acetoxypropane from cis-3- (3,5-dimethyl-1-piperazinyl) -1-hydroxypropane dihydrochloride A solution of (15.5 g, 63 mmol) in water (75 mL) is basified with NaOH solution and extracted with chloroform (3 x 75 mL). The combined chloroform extracts are dried over sodium sulfate and evaporated to dryness. The residue (9.5 g, 87%) is dissolved in pyridine (75 ml) under nitrogen, and the solution is stirred with acetic anhydride (12.5 ml, 0.13 mol) for 12 hours. The pyridine is evaporated to give about 15.7 g of an oil. It is dissolved in chloroform (75 ml), and the solution is extracted with water (50 ml) and then with dilute NaOH solution (50 ml). The chloroform extract is dried over sodium sulfate and evaporated to give 14 g of a crystalline residue. It is recrystallized from ether / petroleum ether to give 9.4 g of crystals, m.p.

65.5 to 66.2 °. Thin layer chromatogram (TLC): one spot Rf 0.27 (Whatman MK6F silica gel, ethyl acetate / acetonitrile / diethylamine 85: 10: 5, visualized with 25 iodoplatinate). IR: 1738, 1620 cm -1 NMR: δ 1.35 (d, 6H), δ 1.5-2.9 (m, 14H), δ S4.2 (b, t, 4H).

c) Preparation of cis-3- (4-acetyl-3,5-dimethyl-1-piperazinyl) -1-hydroxypropane cis-3- (4-acetyl-3,5-dimethyl-1-piperazinyl) -30 L -acetoxypropane (7.4 g, 28.9 mol) is stirred in anhydrous 4.8 M HCl in methanol (100 mL). After 90 minutes, the solution is evaporated and 11.69074 g of aqueous NaOH and chloroform are added to the residue, the phases are separated. The aqueous phase is extracted with chloroform (2 x 30 ml). The combined chloroform extracts are dried over sodium sulfate and evaporated to give 6.55 g of a pale oil. TLC: 5 single spot Rf 0.12 (Whatman MK6F silica gel, ethyl acetate & cetonitrile / diethylamine, 85: 10: 5). IR: 3400, 1625 cm-1. NMR δ 1.2-3.0 (multiplet, 17H), δ 3.80 (t, 2H), <3 * 4.30 (broad multiplet, 2H), (f4.50 (p. 1H, variable).

D) Preparation of cis-3- (4-acetyl-3,5-dimethyl-1-piperazinyl-DCL-tosylpropane cis-3- (4-acetyl-3,5-dimethyl-1-piperazinyl) -1- A solution of hydroxypropane (6.5 g, 30.3 mmol) in ice-cold pyridine (50 mL) is treated with a solution of p-toluene-sulfonyl chloride (6.35 g, 33.3 mmol) in pyridine (50 mL). The overnight solution is dissolved in chloroform (75 ml), extracted with ice-cold cold dilute NaOH solution, dried over sodium sulphate and evaporated to give 10.6 g of a pale yellow solid. oil. IR: 1635, 1360, 1175 cm-1.

e) Preparation of cis-9- [3- (4-acetyl-3,5-dimethyl-1-piperazinyl) propyl] carbazole Sodium hydride (0.25 g, 50% mineral oil suspension, 5.43 mmol) is stirred under nitrogen in Petro ether (10 ml) for several minutes, then the solvent is decanted off. Add dimethylformamide (10 mL) and then carbazole (0.91 g, 5.43 mmol). After gas evolution has ceased, a solution of cis-3- (4-acetyl-3,5-dimethyl-1-piperazinyl) -1-tosylpropane (2.0 g, 5.43 mmol) in dimethylformamide (dropwise) is added dropwise to the dark green solution. 15 ml). The reaction mixture is refluxed for 6 hours, then poured into ice water (400 ml). The insoluble residue is extracted with ether (2 x 150 ml). The ether is extracted with dilute HCl solution. The acidic extract is basified with dilute NaOH solution and the product is isolated by extraction with ether, drying over the extract over sodium sulphate and evaporation.

The resulting pale yellow oil (1.4 g) is crystallized by scraping in petroleum ether to give 0.75 g of white crystals, m.p. 116 to 117.5 °. TLC: single spot RF 0.33 10 (Whatman MK6F silica gel, ethyl acetate / acetonitrile / diethylamine, 85: 10: 5). IR: 1625, 1595 cm f) Preparation of cis-9-Z '3- (3,5-dimethyl-1-piperazinyl) propyl] carbazole cis-9- [3- (4-acetyl-3,5-dimethyl-1 -piperazin-15-yl) propyl-7-carbazole (0.10 g, 0.27 mmol) and concentrated hydrochloric acid (3 mL) are heated on a steam bath.

After 48 hours, the solution is poured into ice-cold NaOH solution. The product is isolated by extraction with ether, drying of the extract over sodium sulphate and evaporation of the extract to dryness. The residue (0.06 g) is crystallized from petroleum ether, m.p. 105-107 °. TLC: largest spot Rf 0.23, small spots Rf 0.44, 0.05.0 (Whatman MK6F silica gel, ethyl acetate / acetonitrile / diethylamine, 85: 10: 5).

Example 1 (a) 25 cis-9-Z3- (3,5-dimethyl-1-piperazinyl) propyl] carbazole dihydrochloride hemihydrate The title compound is prepared from the carbazole base prepared in Example 1 by means of dry HCl gas and crystallizing the product from ethyl acetate or ethanol / -30 ether. , sp. 288-290 °.

Example 2

The compound prepared in Example 1 (a) was administered intraperitoneally to rats to determine their inhibition of muridial activity and inhibition of apomorphine-induced aggressiveness. The compound had an ED 50 value of 15 mg / kg (antimurisidal effect) and 12.5 (anti-aggressive effect).

Example 3

The compound prepared in Example Ka) was administered to male mice to determine the oral and intravenous LDrn of the compound; the following results were obtained: O u

Oral LD ^ q Intravenous DL ^ g 977 mg / kg 31 mg / kg

Example 4 Preparation of 9- [13- (3,5-cis-dimethylpiperazino) propyl] carbazole 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole solid hydrochloride hemihydrate (150 g) containing about 5% methanol a mixture of anhydrous ethanol (680 ml), water (275 ml) and 10N NaOH solution (76 ml) was heated until a solution was obtained. To the hot solution was added 500 ml of water, and the solution was then allowed to slowly cool to room temperature. It was further cooled to 0 ° 20 and filtered after 1 hour. The product was washed thoroughly with water and dried to give 110 g (92%) of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole, m.p. 107-109 °. Calculated from the formula ^ 21 ^ 27 ^ 3 C 78.46 H 8.47 N 13.07 25 Found C 78.43 H 8.46 N 13.05.

Example 5 9- [3- (3,5-cis-dimethylpiperazino) propyl] -7-carbazole monohydrochloride

A solution of 9- [3- (3,5-cis-30-dimethylpiperazino) -propyl] -carbazole dihydrochloride dihydrate (5 g) prepared in Example 1 (a) in water (250 ml) was neutralized to pH 7 with 5N NaOH solution. The precipitate was filtered, washed with water and dried under reduced pressure to give 9- [3- (3,5-cis-dimethylpiperazino) propyl] 7-35 carbazole (3.7 g), m.p. 309-311 ° (dec.).

Calculated from C21H28N3Cl C 70.47 H 7.89 N 11.74 Cl 9.91

Found: C 70.53 H 7.93 N 11.69 Cl 9.83.

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Example 6 9 - (C3-Cis-cis-dimethylpiperazino) propyl E7-carbazole maleate

9- [3- (3,5-cis-dimethyl-5-lipiperazino) propyl] carbazole (10 g) prepared in Example 4 was dissolved in warm acetone (71 ml). Maleic acid (3.7 g) was slowly added to the solution to form a precipitate. The resulting slurry was stirred while heating under reflux for 10 minutes. The mixture was cooled to room temperature and filtered. The precipitate was washed with acetone and recrystallized from water to give 10.5 g of 9 - [. 3- (3,5-cis-dimethylpiperazino) propyl] carbazole maleate, m.p. 162-163 ° (dec.).

Calculated from the formula ^ 25 ^ 31 ^ 3 ^ 41 C 68.63 H 7.14 N 9.60 15 Found: C 68.91 H 7.25 N 9.74.

Example 7 9 - [3- (3,5-Cis-dimethylpiperazino) propyl] -carbazole-3/4-succinate

The 9 - [. 3- (3,5-cis-dimethyl-20-piperazino) propyl] carbazole (10 g) prepared in Example 4 was dissolved in warm SD3A-ethanol (ethanol containing about 5% methanol, 50 ml) and amber was slowly added to the solution. acid (3.8 g). The mixture was stirred and refluxed for 10 minutes, then the mixture was cooled to 5 °. The product was filtered and crystallized from SD3A / water (95: 5, v / v) to give 10.4 g of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole-3/4-succinate, m.p. 175.5-176.5 ° (gross formula determined by NMR spectrum).

30 Calculated from the formula C 70.30 H 7.74 N 10.24

Found: C 70.21 H 7.71 N 10.20.

Example 8 cis-9- [3- (3,5-Dimethylpiperazinyl) propyl] carbazole acetate 1/4 hydrate The 9- [3- (3,5-cis dimethylpiperazino) propyl] carbazole prepared in Example 4 (10 g) was dissolved in hot toluene (70 ml) and acetic acid (2.0 ml) was added to the solution. The mixture was stirred at 2 °.

The product was filtered, washed with cyclohexane (35 ml) and dried under reduced pressure to give 10.4 g of cis-9- [3- (3,5-dimethylpiperazinyl) propyl] carbazole acetate 1/4 hydrate, m.p. 144-146 °.

Calculated from the formula ^ 23 ^ 31 5 ^ 3 ^ 2 5: ^ H 8.22 N 10.88

Found: C 71.57 H 8.08 N 10.84.

Example 9 10 cis-9- [3- (3,5-Dimethylpiperazinyl) propyl] carbazole sulfate monohydrate

The cis-9- [3- (3,5-dimethylpiperazinyl) propyl] carbazole (10 g) prepared in Example 4 was dissolved in warm acetone (100 ml), and sulfuric acid (3.05 g) and water (5 ml) were added slowly with stirring. mixture, which immediately gave a precipitate. The slurry was stirred at reflux for 10 minutes, then cooled to 20 °. The product was filtered and washed with acetone (20 mL). It was reslurried in water (70 ml), filtered, washed with acetone (40 ml) and dried under reduced pressure to give 12.9 g of cis-9- [3- (3,5-dimethylpiperazinyl) propyl] carbazole sulphate monohydrate, m.p. 243-246 ° (dec.).

Calculated from the formula ^ 21 ^ 31 ^ 3 ^ 5 ^ C 57.46 H 7.14 N 9.60 25 Found: C 57.75 H 7.10 N 9.47.

Example 10

As described in Example 6, 9 - [(3- (3,5-dimethylpiperazino) propyl] carbazole was reacted with an equimolar amount of the appropriate acid to give the following salts: 9 - [. 1- (3,5-cis-dimethylpiperazino) ) propyl E 7carbazole fumarate 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole citrate 35 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole L-malate 16 69074 9- / - (3,5-cis-dimethylpiperazino) propyl] carbazole L-tartrate 9- [T- (3,5-cis-dimethylpiperazino) propyl] carbazole methanesulfonate 59- [1- (3,5-cis-dimethylpiperazino) propyl Ε7carbazole DL-lactate, mp 194.5-197 °.

Example 11 Preparation of cis-9- [3- (3,5-dimethyl-1-piperazinyl) propyl] carbazole 10 (a) cis-9- [3- (4-Formyl-3,5-dimethyl-1-piperazole)]. sinyl) propyl-7-carbazole Following the procedure used for the preparation of the corresponding 4-acetyl compound (Example 1 (e), cis-3- (4-formyl-3,5-dimethyl-1-piperazinyl) -15-1-tosyloxypropane and carbazole were reacted with each other to give title compound, mp 100.5-101.5 °.

Calculated from the formula ^ 22 ^ 27 ^ 3 ^ 1 C 75.61 H 7.79 N 12.02 Found: C 75.58 H 8.00 N 11.98.

TLC: one spot Rf 0.47 (Whatman MK6F silica gel, ethyl acetate / acetonitrile / diethylamine, 85: 10: 5).

IR: 1670, 1630, 1595 cm -1.

(b) cis-9- [L3- (3,5-dimethyl-1-piperazinyl) propyl] carbazole A solution of the compound obtained in step (a) (0.20 g, 0.60 mmol) in 0.74 m In KOH-methanol solution (10 mL) was refluxed under nitrogen for 18 hours, the mixture was cooled and concentrated. Water (5 ml) and chloroform (20 ml) were added to the residue, the layers were separated, the chloroform extract was dried (sodium sulfate) and evaporated, and the residual oil crystallized on scraping with a petroleum ether solution. The solid product was recrystallized from ethyl acetate / ether / petroleum ether to give the title compound, m.p. 100-104 °.

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Example 12 Preparation of cis-9- [3- (3,5-dimethyl-1-piperazinyl) propyl] carbazole (a) cis-9- [C3- (4-ethoxycarbonyl-3,5-dimethyl-1-5 piperazinyl) propyylf7karbatsoli

Following the procedure used for the preparation of the corresponding 4-acetyl compound (Example 1 (e)), cis-3- (4-ethoxycarbonyl-3,5-dimethyl-1-piperazinyl) -1-tosyloxypropane and carbazole were reacted with each other to give the title compound was obtained, mp 92-95 ° (dec.) TLC: one spot Rf 0.74 (Whatman MK6F silica gel, ethyl acetate / acetonitrile / diethylamine, 85: 10: 5) IR: 1690, 1625, 1595 cm -1 NMR: 8.1 ppm (d, 2H), 7.4 ppm (m, 6H), 4.3 (m, 6H), 2.8 ppm (m, 8H), δ 1.55 ( d, 6H), 125 (t, 3H).

(b) cis-9- [3- (3,5-dimethyl-1-piperazinyl) propyl] carboxylate

A solution of the compound from step (a) (0.30 g, 0.76 mmol) in 48% hydrobromic acid (13 mL) was heated on a steam bath for 18 hours, then the mixture was poured onto ice (100 mL) and 50% NaOH solution (15 mL) and extracted with chloroform. The chloroform extract was extracted with 1N hydrochloric acid (15 mL) and then water (15 mL), the combined aqueous extracts were basified with dilute NaOH solution and extracted with ether (2 x 30 mL). The ether extracts were combined dried (sodium sulfate) and evaporated. The residue was crystallized from ethyl acetate / ether / petroleum ether to give the title compound, m.p. 105-108 °.

Claims (7)

A process for the preparation of cis-9- [3- (3,5-dimethyl-1-piperazinyl) propyl] carbazole, a salt thereof or a solvate of a salt thereof useful as a psychotropic substance, characterized in that the compound of formula (II) O 10 | The compound according to <* CH3 N- (CH9), -N NZ (II) / K ^ 15 is deprotected and the product is converted, if necessary, into a carbazole base, a salt or a solvate thereof. Process according to Claim 1, characterized in that Z is formyl, acetyl or ethoxycarbonyl. Process according to Claim 1 or 2, characterized in that the compound of formula (II) is hydrolysed with an aqueous acid or an aqueous base. Process according to one of Claims 1 to 3, characterized in that the compound of the formula (II) is treated with an anhydrous acid or an anhydrous base. Process according to one of Claims 1 to 4, characterized in that the carbazole product is isolated in the form of a pharmaceutically acceptable salt or as a pharmaceutically acceptable solvate of such a pharmaceutically acceptable salt. Process according to one of Claims 1 to 4, characterized in that the carbazole product is isolated as the hydrochloride salt or a pharmaceutically acceptable solvate thereof. 19 69074 A compound of formula (II) O 5 fCH 3 N ~ (CH 2) 3 'M-z (II) / K W 1 - CH 3 10 wherein Z is formyl, acetyl or ethoxycarbonyl. 69074