CS225848B2 - The production of the 9-/3-/3,5-cis-dimethylpiperazine/ 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 human and veterinary medicine.

Australian patent S. 201630 and French patent 2. describe carbazoles of formula I

1167511 ^Y 1

(I) in which

A represents a divalent saturated straight or branched chain aliphatic hydrocarbon radical having 2 to 6 carbon atoms,

R 6 represents a hydrogen atom, a lower alkyl group, an aryl group or an araliphatic group,

Y and Y each independently represent a hydrogen or halogen atom, a lower alkyl, alkoxy, aryl or aryloxy group, wherein the ring bearing the residue Y or Y 'may contain further substituents and one or more carbon atoms of the piprazine ring may be substituted by a methyl group .

These carbazoles are said to have antiepileptic properties.

It has now been found that a particular compound which is 9- [3- (3,5-cis-dimethylpiperazino) 225848 propyl] carbazole / sometimes referred to as cis-9- [3- (3,5-dimethyl-1-piperezinyl) propyl] carbazole or as 9- [3- (cis-3,5-dimethyl-1-piperazinyl) propyl] carbazole], corresponding to formula A

and, for simplicity, called carbazole A, its pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these pharmaceutically acceptable salts unexpectedly exhibit valuable anti-aggressive and antipsychotic properties that can be used in the treatment of aggression and psychoses in human medicine. Surprisingly, these substances do not exhibit toxic side effects, such as dyslexia or sedative efficacy, that antipsychotics such as chlorpromezine and the like have.

The term treatment as used herein includes both prophylactic administration of carbazole A to patients (in human medicine) who have previously experienced aggressive or psychotic symptoms, and therapeutic application of carbazole A to patients (in human medicine) who develop acute aggressive or psychotic symptoms. symptoms. A pharmacological test used to demonstrate the anti-aggressive and antipsychotic properties of carbazole A has been described by G. M. McKenzie in Brain Research, Ji, 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 was found to suppress the instinctive muricidal behavior of rats (i.e., killing mice) (see Leafa et al., Agressive Behavior, ed. S. Garettini and E. B. Sigg, pp. 120-131). John Wiley and Sons, Inc., New York, 1969).

It has been found that the degree of anti-aggressive and aptipsychotic properties of carbazole A depends on the particular position of its methyl substituents. For example, carbazole A has been found to be more potent than the corresponding unmethylated derivative and than the analogous 4-methyl- or 3,4,5-trimethyl derivative,

Especially a valuable property of carbazole A is that its antipsychotic and anti-aggressive effects are essentially free of undesirable side effects such as sedation, catalepsy and extrapyramidal dysfunction, which have commonly used antipsychotics, such as phenothesins. The fact that carbazole A does not interfere with extrapyramidal function is evidenced by the fact that it does not antagonize the apomorphine-induced stereotypical behavior of rats (see N.E. Andien, J. Psychiat. Res., 11, 97, 1974). Also significantly lower anticholinergic and antihistaminic effects are associated with the efficacy of carbazole A than with phenothiazines.

The useful biological properties of carbazole A are based on the basic part of the molecule. 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 to the recipient. Examples of the above-mentioned pharmaceutically acceptable salts include

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

b) salts with organic acids such as acetic acid, citric acid, fumaric acid, lactic acid (e.g. DL-lactic acid), malic acid (e.g. L-malic acid), maleic acid, succinic acid and tartaric acid (for example with L-tartaric acid) and salts with alkanesulfonic 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 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-cis-dimethylpiperazino) propyl] carbazole of formula A

salts thereof, and solvates thereof, characterized in that the aldehyde of formula II

O

N-CH ₂ -CH ₂ -CHO

O is reacted with 3,5-cis-dimethylpiperazine followed by selective reduction, 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 this pharmaceutically acceptable salt.

The reaction of the compound of formula XI with eis-3,5-dimethylpiperazine can be carried out in an inert, preferably polar, aprotic solvent such as dimethylformamide or dimethylsulfoxide, followed by selective reduction in the same medium in the same reaction vessel using hydride, borohydride or borane. , for example, sodium borohydride or lithium aluminum hydride, or a functionally equivalent reducing agent.

The starting aldehyde of formula II can be prepared from the corresponding acetal, for example, from the corresponding 3,3-diethoxypropyl derivative using, for example, pyridine p-toluenesulfonate in aqueous acetone at reflux. The above acetal can be prepared in a conventional manner from carbazole by reaction with chloropropionaldehyde diethyl acetal, for example under the conditions described in the description of the invention to U.S. Pat. No. 225,817.

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

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

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

Carbazole A, its pharmaceutically acceptable salts and solvates thereof may further be used to control aggressive symptoms that may be present in mentally delayed patients and / or in patients with behavioral disorders, or to control aggression associated with epilepsy, acute or chronic organic brain syndromes, alcoholism and addiction to narcotics, and other forms of aggression al of already known or unknown origin.

Carbazole A, its pharmaceutically acceptable salts, and solvates of these pharmaceutically acceptable salts are preferably administered orally to a mammal, for example a human, at a dosage of from 1 mg to 30 mg (calculated on a free basis) per kilogram body weight of the mammal being treated for aggression or psychosis. wherein the most preferred dose for oral administration is 2 to 5 mg / kg.

For the treatment of the above-mentioned conditions, carbazole A, its pharmaceutically acceptable salts and solvates are preferably administered at the above-mentioned doses three times a day. For intramuscular injections, generally half the dose used for oral administration is used. For example, in the treatment of schizophrenia, a suitable dose is administered from 1 mg / kg to 15 mg / kg, preferably from 2 mg / kg to 5 mg / kg, for example in the form of a unit dose 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, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient to whom the composition will be administered. The carrier may 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 cachets for oral administration or suppositories for rectal administration.

The compositions of the invention, which may also contain 1 additional pharmaceutically active agents, may be prepared by any of the known pharmaceutical techniques based primarily on mixing the individual components. For example, tablets may be made by granulation, crushing, mixing, coating, grinding, compression or compression.

Suitably, unit dosage forms for rectal or parenteral 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, dispersers 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 is also present in the 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, the preparations may also contain flavoring agents, preservatives, suspending agents, thickeners and emulsifiers. The granules or tablets may be coated, and the tablets may be provided with a breaking line.

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

Carbazole A, pharmaceutically acceptable salts thereof, 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 released gradually over a prolonged period. Such formulations, such as long-acting injections, are useful in human medicine for the treatment of, for example, psychotic conditions such as schizophrenia, in which unacceptably partial omission of the regular use of the drug by the patient when prescribed, for example in the form of tablets, occurs.

In the field of veterinary medicine, carbazole A, its pharmaceutically acceptable salts and 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, which are used in situations where it is desirable or practical to apply carbazole 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 non-limiting examples. Vacuum distillations are carried out on a steam bath at a pressure of 2 atm.

Example 1

Preparation of 9- [3- (3,5-cis-dimethyl-1-piperazinyl) propyl] carbazole monohydrochloride

A. 9- (3,3-Diethoxypropyl) carbazole

To a suspension of 17.28 g (0.36 mol) of 50% sodium hydride in 225 ml of dimethylformamide was slowly added a solution of 50.1 g (0.3 mol) of carbezole in 300 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 1 hour. To this was first added 2 g (0.04 mol) of sodium iodide and then dropwise 60 ml (0.36 mol) of 3-chloropropanal diethyl acetal over 15 minutes. The reaction mixture was heated at 70 ° C for 3 hours, then allowed to cool and poured into 1.8 L of water. The aqueous mixture is extracted four times with 600 ml of hexane each and then discarded. The extracts were combined and dried over magnesium sulfate.

After concentration of the solution by evaporation of the solvent, 54.1 g (61%) of 9- (3,3-diethoxypropyl) carbazole precipitated, which after filtration and drying in vacuo melted at 57-58 ° C.

B. 3- (9-Carbazolyl) propanal

A solution of 30 g (0.1 mol) of 9,3,3-diethoxypropyl) carbazole and 5 g (0.02 mol) of pyridinium tosylate in 500 ml of acetone is refluxed for 4 hours, then allowed to cool and volatiles are removed. evaporate at a temperature below 40 ° C at 2 kPa. 500 ml of fresh acetone was added to the residue, the solution was heated under reflux for 18 hours, then evaporated again, 500 ml of fresh acetone was added again and the mixture was refluxed for 4 hours. The volatiles were evaporated, 500 ml of ether was added to the residue, the crystalline pyridinium tolysate was filtered off and the filtrate was evaporated to a viscous oily residue which solidified after trituration with 150 ml of hexene. The off-white solid was filtered off and dried under reduced pressure. There was obtained 17.4 g (77%) of 3- (9-carbezolyl) propanol, m.p. 78.5-79.5 ° C.

C. 9- [3- (3,5-cis-dimethyl-1-piperazinyl) propyl3-carbezole monohydrochloride

The pH of a solution of 2.25 g (20 mmol) of 2,6-cis-dimethylpiperazine in 75 ml of methanol is adjusted to 5.1 with methanolic hydrogen chloride and 4.0 g (18 mmol) of the amine salt solution are added in rapid succession. of solid 3- (9-carbazolyl) propanol and 1.15 g (18 mmol) of sodium cyanoborohydride. After 2 hours, the precipitate formed is filtered off, washed with 10 ml of cold methanol and 25 ml of ether, and dried under reduced pressure. 2.5 g (39%) of 9- [3- (3,5-cis-dimethyl-1-piperezinyl) propyl] carbobenzole monohydrochloride are obtained, m.p.

For C ₂₎ H ₂₈ N ₃ C1 calculated: 70.47% C, 7.89% H, 11.74% N;

Found:% C, 70.21;% H, 7.92;% N, 11.70.

Example 2

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

150 g of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate, 680 ml of anhydrous ethanol containing about 5% methanol, 275 ml of water and 76 ml of 10N sodium hydroxide are mixed, dissolved by heating, 500 ml of water are slowly added to the hot solution and the solution is then slowly cooled to room temperature. The mixture was further cooled to 0 ° C for one hour and then filtered. 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 ° C.

For C ₂₁ H _2; N ₃ calculated: 78.46% C, 8.47% H, 13.07% N;

Found:% C, 78.43;% H, 8.46;% N, 13.05.

Example 3

9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole monohydrochloride g of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate is dissolved in 250 ml of water and the solution is neutralized The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure. There were obtained 3.7 β 9- [3- (3,5-cis-dimethylpiperazinolopropyl) carbazole monohydrochloride, m.p. 309 DEG-311 DEG C. (decomposition).

For C ₂₁ ^H 28 ^N 3 ^Cl calculated: 70.47% C, 7.89% Η, 11.74% N, 9.91% Cl;

Found: C, 70.53; H, 7.93; N, 11.69; Cl, 9.83.

Example 4

9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole maleate Dissolve 9- [3- (3,5-ois-dimethylpiperazino) propyl] carbazole in 71 ml of warm acetone and slowly add 3, 7 g of maleic acid to form a precipitate. The suspension was heated to reflux with stirring for 10 minutes, then cooled to room temperature and filtered. The precipitate was washed with acetone and then recrystallized from water. There were obtained 10.5 g of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole maleate, m.p. 162-163 ° C (dec.), Which had the following elemental analysis.

For C ₂₅ H ₃ N ₃ O ₄ calculated: 68.63% C, found: 68.91% C,

Example 5

H, 7.14; N, 9.60. H, 7.25; N, 9.74.

9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole-3/4-succinate g Dissolve 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole in 50 ml of hot ethanol containing ca. 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 with 5Ϊ 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 (NMR confirmed stoichiometry) having the following elemental analysis.

^C 24 ^H 31.5 ^N 3 ^O 3 requires C, 70.30; H, 7.74; N, 10.24.

Found:% C, 70.21;% H, 7.71;% N, 20.20.

Example 6 cis-9- [3- (3,5-dimethylpiperazino) propyl] carbazole acetate-1,4-hydrate 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole is dissolved in 70 ml. of hot toluene and 2 ml of acetic acid are added. The mixture is cooled to 2 ° C with stirring, the resulting product is collected by filtration, washed with 35 ml of cyclohexane, and dried under reduced pressure. 10.4 g of cis-9- [3- (3,5-dimethylpiperazino) propyl] carbazolacetet-1/4-hydrate of melting point 144 DEG-146 DEG C. were obtained, which had the following elemental analysis.

For ^C 23 ^H 31.5 ^N 3 ° 2.25 calculated:

71.56% C,

71.57% G,

H 8.22, H 8.08,

N, 10.88; 10.84% N.

Example

Cis-9- [3- (3,5-dimethylpiperazino) propyl] carbazole sulfate monohydrate

To 10 g of cis-9- [3- (3,5-dimethylpiperazino) propyl] carbazole dissolved in 100 ml of warm acetone was slowly added, with stirring, a solution of 3.05 g of sulfuric acid in 5 ml of water, immediately precipitating a precipitate. . The suspension was stirred at reflux 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- (3,5-dimethylpiperazino) propyl] carbazole sulfate monohydrate are obtained, m.p. 243 DEG-246 DEG C. (decomposition), which has the following elemental analysis.

For C ₂₁ H ₃₁ N ₃ O ₈ S requires C, 57.46; H, 7.14; N, 9.60.

Found:% C, 57.75;% H, 7.10;

Example 8

By analogy to the previous examples, 9- [3- (3,5-cis-dimethylpiperazino) propyl] is obtained by reacting 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole with an equimolar amount of DL-lactic acid. ] carbezol-DL-lactate, m.p. 194.5-197 ° C.

The results of the tests of the pharmacological activity of the compounds according to the invention are shown in the following.

-Test 1

Inhibition of muricidal activity and apomorphine-induced aggression after intraperitoneal administration of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate was observed.

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

Test 2

Male mice were treated orally and intravenously with 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate to determine toxicity. The following LD ^^ values were found:

oral administration: 977 mg / kg intrevenous administration: 31 mg / kg

The following Table I compares the efficacy and toxicity of 9- [3- (3,5-cis-dimethylpiperazino) propyl] carbazole dihydrochloride hemihydrate (Compound A) and 9- [3- (4-methylpiperazino) propyl] carbazole dihydrochloride ( compound B) known from the prior art. The data in Table I clearly show the significant advantage of Compound A according to the invention over the known substance B.

Table 1

Substance LD ₅ q (jBg / kg) rat (per os) . EDjq (mg / kg) anti-aggressive activity rat (per os) Therapeutic index LD ₅₀ / ED ₅₀ X AND 957 48 20 May (B) 830 75 11

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

Table II also compares the enticonvulsive effects of the above two substances and the commercial anticonvulsively active phenytoin (Dilantin). Penytoin is almost 2.5 times more potent than substance B and five times more potent than substance A. The degree of anticonvulsive activity of Compound B is at the limit for its intended use, while the anticonvulsive activity of Compound A, which is less than half that of Compound B, use of substance A.

Table II

Substance Loss of equilibrium reflex ED min (mg / kg) mouse (intraperitoneal) Decrease muscle tone ED min (mg / kg) rat (intraperitoneally) Anticonvulsive efficacy (MES) ^and >EDt> ₀ (mg / kg) cape (intraperitoneal) AND 160 125 43 (B) 50 50 20 May phenytoin > 100 - 8.5

Legend:

^a ) Maximal Electroshock Test [Woodbury and Davenport, Arch. Int., Pharmacodyn. Ther., 92, 97-107 (1952)].

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

Claims (2)

SUBJECT OF THE INVENTION 1 ,. A process for the preparation of 9-? 3- (3,5-eis-dimethylpiperazino) propyl] carbazole of the formula A, its salts and solvates thereof, characterized in that the aldehyde of the formula II -CH 2 -CH ₂ - CHO (II) is reacted with 3,5-cis-dimethylpiperazine followed by selective reduction, 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 salt. an acceptable solvate of this pharmaceutically acceptable salt. 2. The process according to claim 1, wherein the selective reduction is carried out in the same medium as the reaction of the compound of formula II with 3,5-cis-dimethylpiperazine.