CS225817B2 - The production of the 9-/3-/3,5-cis/dimenhylpiperazine/propyl/carbazole - Google Patents

Description

The present invention provides a process for the manufacture of substances having valuable anti-aggressive and antipsychotic properties. These substances can be used in the form of pharmaceutical compositions in the human and veterinary medicine.

Australian Patent Specification No. 201630 discloses carbazoles of Formula I and French Patent Specification No. 5,960,144.

1167510

(I) in which

A represents a divalent saturated aliphatic hydrocarbon radical having a straight or branched chain of 2 to 6 carbon atoms, representing a hydrogen atom, a lower alkyl group, an aryl group or an araiphatic group,

J and * 1 independently of one another are in each case hydrogen or halogen, lower alkyl, alkoxy, aryl or aryloxy, the ring bearing the radical Ϊ and Yj may contain further substituents and one or more carbon atoms of the piperazine ring may be substituted by a methyl group.

These carbazoles are reported to have antiepileptic properties.

2258 * 7

It has now been found that a particular compound which is 9- [3- (3,5-cis-dimethylpiperRzino) prepyl] carbazole (sometimes also referred to as cis-9- [3- (3,5-dimethyl-1-pipsraziryrl) ) poopylJkarbaial or 9- [3- (cis-3,5-dimmSlhy "1P) -P ^erezin yl) P ^r o? pl] karbazzD, odpooídajjci formula A

and furthermore, for simplicity, called carbazole A, its pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these pharmaceutically acceptable salts unexpectedly exhibit valuable aggressive and entipsychotic properties which can be used in the treatment of aggression and psychoses in human melamine. Surprisingly, these substances do not exhibit toxic side effects, such as dyslexia or sedative. an efficacy which the psyche, such as chlorpromazine, etc., has.

As used herein, the term "treatment" refers to the prophylaxis of carbazole A to patients (in human meedcin). who have previously experienced aggressive or psychotic symptoms as well as therapeutic application of carbazole A to patients (human meelcinё) _ё who develop acute aggressive or psychotic symptoms. A pharmacoklogical test used to demonstrate the anti-»aggressive and anti-psychotic properties of carbazole A was described by GM McKennie in Brain Reeearch, 34-323 (1971). In this test, carbazole A antagonized apomorphine-induced aggressive symptoms in rats. Further evidence of the antipsychotic and anti-aggressive properties of this agent has been found to suppress instinctive muricidal behavior in rats (i.e., killing mm²tf) (see Leaf et al., Aggressive Behavior, eds. S. Ger. Attini and EB Sigg, pp. 120-131, John Wiley and Sons, Inc., New York, 1969.

It has been found that the morphological and anti-psychotic properties of carbazole A depend on the specific position of its methylsubstitutes. For example, carbazole A has been found to be more effective than the deprotecting unmethylated derivative and than the analogous 4-methyl or 3,5-trimethyl-derivative.

A valuable feature of carbazole A is that its antipsychotic and anti-aggressive effects are substantially free of undesirable side effects such as sedation, recurrence and extrapyramidal dysfunction, which have commonly used psychotic drugs, such as recollection. The fact that carbazole A is an extrapyramidal function is not indicated by the fact that it does not antagonize apomorphine-induced stereotyped rat behavior (see NE Andien, J. Psychiat. Kee., 11, 97, 1974). Also, significantly lower anticoagulants and anti-hissanin effects are associated with the efficacy of carbazole A than they exhibit in flotation.

The useful biological properties of carbazole A are based on the basic moiocula. This base may form salts (i.e., acid addition salts), which are generally within the scope of the invention. For therapeutic purposes, the acid residue of these salts is preferably pharmaceutically acceptable for the present invention. Examples of the above-mentioned pharmaceutically acceptable salts are mentioned.

(a) salts. with inorganic acids such as sulfuric acid and with halogenated acids such as hydrochloric acid; and

(b) salts with organic acids such as acetic acid, heptanoic acid, fumaric acid, lactic acid (e.g. DL-lactic acid), malic acid (e.g. L-malic acid), malic acid, succinic acid and acid. tartaric acid (e.g., L-tartaric acid) as well as salts with iancansulonic acids, such as methanesulfonic acid, and arylsulfonic acids, such as p-toluenesulfonic acid.

Carbazole A in the free base form can be converted into salts, and these salts can be converted into the free base or into salts with other acids in a manner known per se. Thus, salts that are not themselves pharmaceutically acceptable may be valuable for the preparation of pharmaceutically acceptable salts. In addition to salts, the basic carbazole A may form well-defined solvates, such as hydrates and solvates derived from alcohols (e.g., methanol or ethanol), all of which are also within the scope of the invention.

Carbazole A can be prepared by any of the methods known in the art for preparing compounds of analogous structure.

The present invention provides a process for the preparation of 9- (3- (3,5-dimethhlpiperazino) propyl] carbazole of formula A

(A) its or its salts and

IIA solvates of these salts, characterized in that the compound of the formula II

(IA) a displaceable atom or group in which

Z is reacted with carbazole or a reactive derivative thereof in the case of a compound of formula II or 35-cis-dimethylpiperazine, in the case of a compound of formula IIA and the resulting product of formula A is isolated as the free base or as a pharmaceutically acceptable acid salt, preferably hydrochloric acid or as a pharmaceutically acceptable solvate of the pharmaceutically acceptable salt.

Any cleavable atom or group which allows the substitution to take place at the appropriate amino group, such as, for example, halogen atoms (preferably chlorine), arylsulphonyloxy groups (preferably p-toluenesulphonyloxy) or alkylsulphonyloxy groups (preferably), can be used as a leaving group Z.

While the compound of formula (II) may react directly with carbazole, it is preferred to use a carbazole derivative, with particular preference. the derivatives are alkali metal or alkaline earth metal derivatives, in particular alcohol, sodium, potassium, zinc, cadmium and calcium. For this purpose, it is also possible to use a carbamazonium magnesium halide, for example iodide.

The alkali metal carbazole derivatives are conveniently prepared by reacting carbazole with an alkali metal hydride or amide in an inert, preferably polar, aprotic solvent such as liquid ammonium, dimethylformamide or dimethyl sulfoxide. Other suitable solvents include hydrocarbons such as alkanes, cycloalkanes and aromatic hydrocarbons. The same reaction medium can then be used to effect the substitution on the nitrogen of the invention. This substitution is preferably carried out under heating and expedient in solution in an inert atmosphere such as a nitrogen atmosphere.

Alternatively, the compound of formula (II) above may be reacted with a carbazole in the presence of a compound of formula (II). an alkali metal hydroxide or an alkali metal alkoxide in a polar solvent such as dimethylformamide, dimethylecetamide, water or the corresponding bullying, for example in the presence of potassium tert-butoxide in tert-butanol.

The reaction of 3,5-cis-dimethylpiperazine with a compound of formula HA can be carried out in a polar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or acetonitrile, or in a solvent such as water or an aliphatic alcohol.

The starting materials of formula (IIe) are readily prepared from the corresponding alcohol in a conventional manner. For example, the alcohol in use can be converted into a chloride by reaction with thionyl chloride. The alcohol itself can be obtained by reacting a substituted alcohol of the formula z- (CH ₂ ) ₃ -oh, wherein:

Z has the same meaning as in formula II, with the 3,5,5-cis-dirtthllpiperaziner.

The starting materials of formula (IIA) may be prepared by N-substitution analogous to the reaction of a compound of formula (II) with carbazole to form carbazole A.

The starting materials of formulas (II) and (IIA) can also be obtained by a coupling reaction consisting of condensation (in the Michael reaction) of piperazine or carbazole with an acrylic acid or a derivative thereof, such as the corresponding halide, ester, amide or nitrile. The acid derivative can be hydrolyzed to an acid that is reduced to the alcohol in use. This alcohol can then be converted into the starting material of formula II or IIA as described above.

Carbazole A, its pharmaceutically acceptable salts, and solvates of these pharmaceutically acceptable salts are useful for controlling the psychotic and aggressive conditions of a human. For example, they can be used for the prophylaxis and / or treatment of schizophrenia, manna or semitum, involuntary or organic psychoses, and depressive psychoses.

Carbazole A can also be used for the prophylaxis and treatment of aggressive cattle. This behavior may be associated with other disorders such as psychotic and personal disorders, as well as in children with autism and hyperkinetics.

Carbazole A, its pharmaceutically acceptable salts and solvates potentiate the locomotor activity of the d-amphetamine, similar to most of the antidepressant agents. This potentiation of the effects of d-amphet amine suggests that carbazole A may have antidepressant activity in humans.

Kwbazole A, its pharmaceutically acceptable salts, and solvates of these salts can further be used to control aggressive symptoms that may occur in a minority of delayed patients and / or in patients with disorders of the brain, or to control aggression associated with with epilepsy, acute or chronic organic brain syndromes, alcohol and narcotic addiction, and other forms of aggression of already known or unknown origin.

Preferably, krbazole A, pharmaceutically acceptable salts thereof, and solvates of these pharmaceutically acceptable salts are administered to a mammal, e.g., a human, preferably orally at a dosage of from 1 mg to 30 mg (calculated on a free basis) per kilogram of body mammal being treated for aggression; psychosis, wherein the most preferred oral dose is 2 to 5 mgg / kg. For the treatment of the above-mentioned conditions, carbazole A, its pharmaceutically acceptable salts and salts are preferably administered at the above-mentioned doses three times a day. For intremuscular injections, generally half the dose used for oral administration is generally used. For example, in the treatment of schizophrenia, a suitable dose is from 1 m < 3 > / kg to 15 mg / kg, preferably from 2 mg / kg to 5 mg / kg, for example in unit dosage form containing 60 to 900 mg of active ingredient. . The unit dose is conveniently administered once or several times a day, for example in the form of one or more tablets each containing 10 to 300, suitably 60 mg of carbazole A, a pharmaceutically acceptable salt or solvate thereof, preferably three times a day.

While carbazole A or a salt thereof can be used as such for therapeutic application, it is nevertheless preferred to administer it in the form of a pharmaceutical composition in which it is included with a suitable carrier. This carrier must be understandably acceptable in that it will be compatible with the other ingredients of the composition and not deleterious to the recipient to whom the composition will be administered. The carrier can be a solid or liquid, or a mixture of solids and liquids, and is preferably formulated with carbazole A or a salt thereof into unit dosage forms such as tablets, capsules or caches for oral administration or suppositories for rectal administration. The compositions of the invention, which may also contain other pharmaceutically active agents, may be prepared by any of the well-known pharmaceutical techniques based largely on mixing the individual ingredients. For example, tablets may be made by granulation, crushing, grinding, coating, grinding, compression or compression.

Suitably, unit dosage forms for rectal or intravenous administration comprise from 5 mg to 75 mg of carbazole A or a pharmaceutically acceptable salt or solvate thereof, calculated on the free base.

The fine powder or granular formulations of the present invention for oral administration may contain diluents, dispersants and surfactants and may be administered as a beverage in water or syrup, in capsules or cachets in a dry state or in an aqueous or non-aqueous suspension in which a suspending agent may also be present in tablets, which are preferably prepared from the granulate of the active ingredient together with the diluent, by compression together with binders and glidants, or in suspension in water, syrup or oil, or in an emulsion of water and oil, which preparations may also contain flavoring agents, preservatives, suspending agents, thickeners and emulators. The granules or tablets may be coated, and the tablets may be provided with a breaking line.

For intranasal administration (iotraoullkillar, iotogal, iotraigitloeal, or subcutaneous injection), carbazole A, preferably in the form of a pharmaceutically acceptable salt or hydrate, may be present in containers containing a single or multiple dose in aqueous or non-aqueous, injectable they may contain antioxidants, buffers, bacteriostatic additives and soluble substances for isotonic treatment of preparations, or in aqueous or non-aqueous suspensions, which may also contain suspending agents and thickeners. Occasionally, injection solutions and suspensions may be prepared from sterile powders, granules or tablets which may contain diluents, dispersants and surfactants, binders and glidants.

Carbazole A, its pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of these salts may also be included in known depot preparations, from which, once introduced into the body of the recipient, the active ingredient (drug) is gradually released over a prolonged period. Such formulations, such as long-acting injections, are beneficial in the human medicine for the treatment of, for example, psychotic conditions such as schizophrenia, when unacceptably frequent opomina occurs! regular use of the drug by the patient if the drug is prescribed, for example, in the form of tablets. _

In the veterinary field, carbazole A, its pharmaceutically acceptable salts and the pharmaceutically acceptable solvates of these salts are of particular importance in the treatment of aggressive behavior in mammals such as dogs, pigs, horses and cattle. For this purpose, the active compounds can be administered as described above. Particularly preferred compositions for veterinary use are depot preparations as described above. above, which are used in situations where it is desirable or practical to apply carbazo! A, a salt or solvate thereof only at longer intervals.

Carbazole A, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates of these salts at the above dosages also exhibit antidepressant activity. ·

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way. Vacuum distillations are carried out on a steam bath at a pressure of 2 atm.

He did

Preparation of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate

A. 3- (3,5,5-cis-dimethylpiperazio) -propanol dihydrochloride

11-4.2 g (1.0 mol) of 2,6-disdimethylpiperazine, 94.5 g (1.0 mol) of 3-chloropropanol,

Sodium carbonate (10%) and ethylene glycol mono-ether (400 ml) were stirred and refluxed for four hours. The reaction mixture is filtered while hot and the filtrate is freed from the solvent by vacuum distillation.

The resulting solid was dissolved in 500 mL of ethanol and this solution was saturated with dry hydrogen chloride. The white precipitate was collected, dried in vacuo and used. without further purification in the next step. The hydrochloride obtained melts at 240-241 ° C.

B. 3- (3,5-cis-dimethylpiperazio) propyl chloride dihydrochloride

300 g of thionyl chloride are slowly added to 200 g of 3- (3,5-cis-dimethylpiperosyl) -propanol dihydrochloride. The reaction mixture was gently refluxed for 1 hour, then excess chloride was removed by vacuum distillation. The lime solid was washed with several portions of benzene and then several portions of ether. The product melts at 291-292 ° C.

C. 9- (3- (3,5-cis-dimethylpiperazio) propyl) carbazole dihydrochloride

A solution of 83.5 g (0.5 mol) of carbazole in 150 ml of dimethylformamide was added to a suspension of sodium hydride (1.6 mol) made from a mixture of 70 g of a 57% sodium hydride dispersion in mineral oil and 200 ml of dimethylformamide. After the hydrogen evolution had ceased, a suspension of 131 g (0.5 mol) of 3- (3,5-cis-diretylpiperazo) propyl chloride dihydrochloride in 200 µl of dimethylformamide was slowly added to the network. The reaction is carried out under nitrogen. When. the addition of the suspension causes foaming and the rate of addition is adjusted so that the foaming is rationalized. After the addition was complete, the reaction mixture was heated to 90-120 ° C for 16-18 hours, then cooled, filtered and the solvent was distilled off under vacuum.

The viscous residue is heated with 2 liters of 1N hydrochloric acid,. Cool and wash with 500 mL of ether. The ether layer containing unreacted carbazole was removed, the aqueous layer was clarified with activated carbon and filtered through diatomaceous earth. The filtrate was basified with sodium hydroxide and then extracted four times with ether. Both the ether and aqueous layers are clear at the end of the extraction. The ether layer was dried with anhydrous magnesium sulfate or sieve and 9- [3- (3,5-cis-4-dihydro-piperazino) -propyl] -carbazole-di-chlorochloride precipitated from the solution by introducing dry hydrogen chloride.

The precipitate was collected and recrystallized from ethyl acetate or ethanol-ether to give 50 g of 9- [3- (3,5-cis-sulfinylpiperazino) propyl] carbazole-SL-hydrocycloid hemihydrate, m.p. 288-290 ° C.

Example 2

9- (3- (3,5-cis-dimethylpiperazino-) propyl) carbazole dihydrochloride hemihydrate

A. 9- (3-Chloropropyl) carbazole

134 g (0.8 mol) of carbazole in 1.5 liters of dimethylformamide are slowly added to a suspension of 0.8 mol of sodium hydride prepared from a 39 g · 50% dispersion of sodium hydride in mineral oil and 500 ml of dimethylformamide. After the evolution of hydrogen ceased, the reaction temperature was cooled to about 5 ° C by cooling in ice, and 500 g (4.4 mol) of 1,3-dichloropropane was added at a rate of not more than 10 ml per minute. After all 1,3-dichloropropene was added, the reaction mixture was stirred until the temperature dropped to room temperature (about 1.5 hours).

The reaction mixture is filtered to remove the sodium chloride formed, freed from the solvent by distillation in a water-jet vacuum and the thick syrup residue is distilled in a high Valu.

The first fraction boiling at 70 [deg.] C. at a pressure of 0.039 Pa is formed by excess -1,3-dichloropropane, which is regenerated for the new product. The second fraction at 120 ° C // 0.013 Pa consists of unreacted carbazole containing a certain molarity of the final product (38 g). The third fraction boiling at 145 ° C / 0.00698 Pa consists of 9- (3 (chloropropyl) carbazole. The product melting at 34-35 ° C resulted in a yield of 107 g (55%).

Pro C ₁₅ H _U W1 calculated: 73.91% C, 5.79% H, 5.75% N; Found:% C, 73.35;% H, 5.81;% N, 5.22.

B. 9- (3- (3,5-Cddimethylpiperazino) propyl) carbazole dihydrochloride hemihydrate

12.2 g (0.05 mol) of 9- (3-chloropropyl) carbazole, 5.7 g (0.05 mol) of 2,6-cis-diretidipiperazine, 10 g of potassium carbonate and 50 ml of methylene chloride amide · The mixture was heated at reflux for 1 hour, cooled and filtered. The filtrate was freed from the solvent by distillation in a water pump vacuum. 250 ml of 1N hydrochloric acid are added to the residue, and the resulting solution is shaken with ether. The ether phase is discarded, quartz is added to the acidic aqueous phase, the mixture is filtered and the filtrate is distilled to dryness in vacuo. The residue was recrystallized from a mixture of ethanol and ether to give 9- (3- (3,5-dimethyl-piperidino-propyl) -carbazole-dihydrochloride hemihydrate), m.p. 288 DEG-290 DEG, yield 18 g (90%).

Example 3

9- (3- (3,5-Chloro-ethylpiperazino) -propyl] -ambaasone monohydro chloride

A suspension of 3- (3,5-di-ethylpiperazino) propyl chloride (Example 1, step B) in toluene was poured into ice and 10N sodium hydroxide and the pH of the network was adjusted to 13.5. The toluene phase was separated and the residue was extracted four more times with toluene. After drying, the solvent was evaporated from the toluene solution to give crude 3- (3,5-cit-dimethylpiperazino) propyl chloride as an oil.

In diethyl ether, the reaction is treated with sodium methoxide and carbazole, and the methanol is then evaporated off under vacuum. The residue was mixed with the crude oil product from the previous reaction step and heated to 100 ° C for 15 hours. The reaction mixture was cooled and diluted with water, whereby crude 9- (3- (3,5-cit-direthylpiperazios) propyl) carbazole was catalysed, which was filtered off and heated with 1 N cy225617 hydrochloric acid, cooled, extracted with ether. The ether extract was discarded and the remaining aqueous layer was neutralized to pH 7 with 5N sodium hydroxide. The precipitate was filtered off and dried under reduced pressure to give 9- (3- (3,5-cis-dimethylpiperazioo)). m.p. 309-111 ° C.

Example 4

Preparation of 9- [3- (3,5-cis-fimetlylpiperbenzil) propylcarbazole

150 g of 9- (3- (3,5-cis-dimethyloioerazino-4-naphthyl) carbazole dihydrochloride hemihydrate, 680 ml of anhydrous ethanol containing about 5% methanol, 275 ml of water and 76 ml of 1N sodium hydroxide are mixed, heated to dissolve. 500 ml of water is slowly added to the solution, and the solution is then slowly cooled to a temperature The mixture is cooled to 0 ° C for one hour and then filtered.

110 g (92 theory) of 9- (3- (3,3-C8-dimethylyl-benzyl) propylcarbonyl), m.p. 107-109 ° C.

For C21H27N2 calculated: 78.48% C, found: 78.4330,

H, 8.47; N, 13.07

8.46% H, 13.05 3 N.

Example · 5

9- (3- (3,5- (3,5-Methyllyloioeabzino) oropropyl) carbazole monochloride g 9- (3- (3,5-cis-methylmethylpiperazio) prooylkabazolylphosphoric chloride hemihydrate) was dissolved in 250 ml of water and the solution was not treated with 5 N The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 3.7 g of 9- (3- (3,5-cis-dimethyloioerβzino) propynylbabbizole monohydrone), m.p. 311 DEG C. (decomposition) The product has the following elementary analysis.

For C ₂ H ₂ 8N3C1 calcd: 70.4730, 7.89% H, 11.74 · 3N ,. 9.913C1;

Found: 70.5330, 7.93 3 H, 11.69 3 N, 9.83% Cl.

Example · 6

9- (3- (3,3-cis-fimetlylpioeaazio) propyllbbrbololeate) dissolve in 71 ml warm acetone and slowly add 3.7 g maleic acid to form The resulting thick slurry was heated to reflux for 10 minutes with stirring, then allowed to warm to room temperature and filtered, washed with acetone and then recrystallized from water to give 10.5 g of 9- (3- (3). 162-163 [deg.] C. (decomposition), which was followed by elemnary analysis, m.p. 162-163 [deg.] C. (decomposition).

^{For C} 25 ^H 3 ^N 3 ^O4: calculated: 68.63% C, 7.14% H, 9.60% N; found: 6в, И% C · 7.25 «H · 9.74% N.

, 9

Example7.

9- [3- (3,5-cis-dimethylpiperazin) propyl] carbazoo-3/4-succinate g of 9-3- (3,5-cis-dimethylpiperazino) propyl] carbazole was dissolved in 50 ml of hot ethanol containing about 5% methanol and 3.8 g of succinic acid are slowly added to the solution. The mixture was stirred at reflux for 10 minutes and then cooled to 5 ° C. The product is isolated by filtration and crystallized from a mixture of ethanol and 5% methanol and. water (95: 5 v / v) to give 9- (3- (3,5-cis-dimethylpiperazino) propyl] carbazole-3/4-succinate (10.4 g), m.p. 175.5-176.5. ° C (stechiomeerie confirmed №), which has the following elemental analysis.

^{For C} 24 ^H -1 ⁽ 5 ^NO 3 calculated; 70.30% C, 7.74% H, 10.24%; Found: C 70.21, 7.71 XH, 10.20% N.

EXAMPLE B cis-9- [3- (3,5-dinehehlpptraint) popoyl] cabbazzO- (a: ceta-1/4-hydrogenate g 9- (3- (3,5-di-dimethylpiptrazino) propyl) carbazole was dissolved in 70 ml of hot toluene and 2 ml of acetic acid was added, the mixture was cooled to 20 ° with stirring, the resulting product was collected by filtration, washed with 35 ml of cyclohexane and dried under reduced pressure to give 10.4 g of cis-9. -33-33,5-Dilylpiperazazinyl) carbonyl] carbazoaacetate-1/4-hydrate of m.p. 144-146 ° C, which is followed by an elemnary analysis.

^{For C} 23 ^H 31.5 ^N 3 ° 2.25 calculated: 71.56% C, 8.22 & H, 10.88% N;

Found: C, 71.57; H 8.08%, N 10.84%.

Example 9

Cis-9 Moonoyydate (33-33, - Dimethylpiperazino) proppl] carbazzO-sulphate

To 10 g of cis-9- [3- (33'-dimethylpiptrazino) p-propyl] knrbazole, soluble in 100 m of warm acetone, slowly add a solution of 3.05 sulfuric acid in 5 ml of water with stirring, immediately precipitating. The suspension was stirred under reflux with a reflux condenser for 10 minutes and then cooled to 20 ° C. The product is collected by filtration, washed with 20 ml of acetone, stirred in 70 ml of water, filtered, washed with 40 ml of acetone and dried under reduced pressure. 12.9 g of cis-9- [3- (-33,5-dilylpiperazino) propyl] -carbazo-sulphate monohydrate is obtained, m.p.

For C2 H31 N-O2 S.

H, 7.14; N, 9.60.

Found: C, 75.77; C, 75.77; H, 9.77;

Example 10

By analogy to the preceding examples, 9- [3- (3,5-cis-dimethyl-piperrazino) -propyl] -carbazole-DIL is obtained by reacting 9 - [- (3,5-dimethyl-piperazino) -propyl] -carbazole with an equimolar amount of L-lactic acid. mp 194.5-197 ° C.

In the following, the results of the pharmacological activity tests of the substances according to the invention are presented.

Test 1

The inhibition of muricidal activity and apomorphine-induced aggression after intraperitoneal administration of 9- (3- (3,5-cis-diethylpiperazino) propyl) carbazsl-dihydrochloride hemihydrate was increased.

ED50 values of 15 mg / kg (antimuricidal activity) and 12.5 mg / kg (anti-aggressive activity) were found for the test substance.

Test 2 Male Feets were orally and intravenously administered 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole dihydrosulfide hemilh / wire for toxicity. The following LD ₅₀ values were found:

oral administration: 977 mg / kg intravenous administration: 31 m ^ kg.

The following table ί compares the efficacy and toxicity of 9- (3- (3,5-c8-diethylpiperazino) propyl) carbazole-dihydischloidide hemihydrate (Compound A) and 9- [3- (4-methylpiperazino) propyl] carbazole dihydrochloride ( The data given in Table I clearly show the significant advantage of Compound A according to the invention over the known substance B.

Table 'I

Substance LD ₅₀ (mg / kg) rat (per os) ED50 (mg / kg) anti-aggressive activity rat (per os) Therapeutic index in- .. AND 957 48 20 May (B) 830 75 1 i

The following Table II shows, among other things, the other significant advantages of carbazole A over Compound B. The minimum dose of carbazole A (for mma) at which the equilibrium reflex loss (ED min) is about three times higher than that of B. a decrease in muscle tone was observed in rats at a much lower dose than with carbazole A.

Table II also compares the anticonvulsant effects of the above two substances and the commercial anticonvulsant effect of phenytoin (Diiannin). Phenytoin is almost 2.5 times more potent than substance A. The degree of anticonynusive activity of Compound B is at the limit of its idle use, while the anticonymic activity of Compound A, which is less than half that of Compound B, does not interfere with the predicted Compound A.

1

Table II

Substance Loss of equilibrium reflex ED min (mg / kg) to mouse (intraperitoneal) Decrease muscle tone ED min (mg / kg) rat (intraperitoneal) Anticonvulsive efficacy (MES) ⁿ⁾ EDr ₀ (mg / kg) cape (intraperitoneal) AND 160 125 43 В 50 50 20 May phenytoin > 100 - 8.5

Legend:

^a ) Maximal Electroskock Test [Woodbury and Davenport, Arch. Int., Pharmecodyn. Ther., 22, 9Ί-107 (1952)].

The prior art 9- [3- (4-methylpiperazino) propyl] carbazole, listed in Tables I and II as substance B, is described in Example 7 of the aforementioned Australian patent application. of the French patent.

Claims (6)

SUBJECT OF THE INVENTION A process for the preparation of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole of the formula A (A), its salts and solvates thereof, characterized in that the compound of the general formula II or IIA (II) (IIA) ) in which Z has a cleavable atom or group, such as a halogen atom, preferably chlorine, an arylsulfonyloxy or alkylsulfonyloxy group, reacts with cresbazole or a reactive derivative thereof for the compound of formula II, or with 3,5-cis-dimethylpiperazine for the compound of formula IIA and the resulting product of Formula A is isolated as the free base or as a pharmaceutically acceptable acid salt, preferably hydrochloric acid, or as a pharmaceutically acceptable solvate of the pharmaceutically acceptable salt. 2. The process of claim 1, wherein the compound of formula (II) wherein Z is as in point 1 is reacted with carbazole or a reactive derivative thereof. 22> 816 3. A process according to claim 1, wherein the compound of formula (IIA) is:. wherein Z is as in 1, reacted with 3,5-cis-dimethylpiperazine. 4. A process according to any one of claims 1 to 2, wherein the compound of formula (II) in which Z has a significant value in (1) or (2) is reacted with an alkali metal or alkaline earth metal carbazole derivative. sodium. 5. A process according to claim 1, wherein the 3- (3,5-cis-dimethylpiperazino) propyl chloride is reacted with n-triacarbazole. 6. The process of claim 1 wherein the 9-3- (chloropropyl) carbazole is reacted with 3,5-Dis-dimethylpiperazine. Severography, n. P., MOST