HU187332B - Process for preparing 9-/3-/3,5-cys-dimethyil-piperazinyl/-propyl/-carbazole, its salts and the solvates of the salts - Google Patents

Abstract

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Description

FIELD OF THE INVENTION The present invention relates to the preparation of a compound having valuable anti-aggression and antipsychotic properties, and to pharmaceutical compositions containing them.

According to Australian Patent Nos. 201,630 and 1,167,510, the carbazole derivatives of the formula I have anti-epileptic activity. In this formula

A is a divalent saturated straight or branched aliphatic hydrocarbon radical having from 2 to 6 ring members; R ¹ is hydrogen, lower alkyl, aryl or aralkyl; Y and Y ¹ are hydrogen, halogen, lower alkyl, alkoxy, aryl or aryloxy; wherein the ring containing Y and Y 'may have substituents other than Y and Y ¹ ; and one or more carbon atoms of the piperazine ring may be linked to a methyl group.

We have found that a particular compound of formula (A), 9- (3- (3,5-cis-dimethyl-1-piperazinyl) propyl) carbazole, otherwise known as cis-9- [3- (3,5-dimethylpiperazinyl) propyl] carbazole or 9- [3- (cis-3,5-dimethyl-1-piperazino) propyl] carbazole and cis-9- [3- (3,5-dimethyl-1-piperazinyl) propyl] carbazole, hereinafter referred to as the compound of formula (A), and its pharmaceutically acceptable salts and pharmaceutically acceptable solvates of its pharmaceutically acceptable salts have surprisingly valuable anti-aggressive and anti-psychotic properties, and are thus suitable for treating aggressive and psychiatric conditions in human medicine. also that the compounds described below are free of toxic side effects, such as sedative effects or dyslexia (reading disorder), which are characteristic of chlorpromazine or of psychosis similar to chlorpromazine. drugs.

In the context of the present invention, the term "treating", on the one hand, means that the compound of formula (A) is administered prophylactically to a patient (human) who has previously been shown to have aggressive or psychotic symptoms; on the other hand, the compound of formula (A) is administered therapeutically to a patient (man) who is showing signs of aggressive or psychotic symptoms. In a test to detect the anti-aggression and antipsychotic properties of compound (A) (Brain Research 34, 323 (1971)), the compound antagonized the state of apomorphine-induced aggression in the rat. It has also been found that the anti-aggressive and antipsychotic properties of the compound of formula (A) are also found to inhibit murine murine (murine, murine) behavior. (This experiment is described in Leaf et al., Agressive Behavior, published by S. Garattini and B. Sigg, John Wiléy & Sons, Inc., New York 1969, pp. 120-131.)

It has been found that the anti-aggressive and anti-psychotic properties of the compound of formula (A) depend on the particular position of the methyl groups in its molecule. For example, it has been observed that the compound of formula (A) is more effective than the corresponding non-methylated or analog 4-methyl or 3,4,5-trimethyl derivative.

(A) compound is especially valuable drug because aggression antipsychotic effect and is substantially free of undesired, such as sedation, cataleptic side effects and extrapyramidal ⁵ lis that antipsychotic drugs currently in use, such as fentiazinokra characteristics. To the (A) compound does not interfere with extrapyramidal function is a demonstration that does not antagonize apomorphine-induced stereotyped behavior in rats ^10. (This assay is described in And. E. Andién, J. Psychiat. Sl., 11, 97 (1974).) The anticholinergic and antihistamine activity of compound (A) is much lower than that of the phentiazines.

¹⁵ Although beneficial physiological effects of the (A) compound are rooted in the base part of the molecule, this base capable of forming salts (i.e. to form acid addition salts), and the preparation of these salts are within the scope of this invention. For therapeutic purposes, the acid component of these salts is preferably selected to be suitable for the drug user. The acids salts used pharmaceutically include inorganic acids such as sulfuric acid and hydrochloric acid, and organic ²⁵ 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 ( such as L-tartaric acid) and alkanesulfonic acids such as methanesulfonic acid and arylsulfonic acids such as p-toluenesulfonic acid. The compound of formula (A) can be converted into its salts, and the salts can be converted into the base or other acid addition salts by methods known per se. Thus, salts which are suitable ³⁵ may be useful in the production of non-pharmaceutically acceptable salts for medicinal purposes. Moreover, the compound (A) the base salts of a well-defined formula hydrates (e.g. methanol or ethanol) and may form solvates with alcohols, and all such solvates are included within the scope of ⁴⁰ the invention.

The compound of formula (A) may be prepared by any method known per se for the synthesis of compounds of similar structure.

Accordingly, (A) a compound of formula 5 may be ^4, so that a compound of formula (II) removing the Z protecting group. The following Z protecting groups are suitable:

formyl;

acyl, preferably having from 2 to 5 carbon atoms, is ⁵⁰ noils, such as acetyl;

alkoxycarbonyl, preferably ethoxycarbonyl, preferably having 2 to 5 carbon atoms;

aroyl such as benzoyl; and aralkyl such as benzyl.

Z ⁵⁵ preferred protecting groups include formyl;

Alkanoyl containing from 2 to 5 carbon atoms;

Alkoxycarbonyl containing from 2 to 5 carbon atoms; and benzoyl.

θθ Group Z can be removed from compounds of formula (II) by well-established methods such as hydrolysis with aqueous acids or aqueous bases, and with anhydrous acids (e.g., acetic acid hydrobromic acid) or water 65

With bases (e.g., potassium hydroxide in methanol).

Further reagents suitable for group Z removal include salts of thiols, trimethyl iodosilane (Synthesis 1980, 861), and in particular aralkyl (e.g. benzyl), hydrogenation in the presence of a catalyst (preferably palladium) or metal (e.g. sodium) ammonia or amine solution with or without a proton source (such as an alcohol).

These procedures are described in detail in the literature (e.g., J. F. W. McOmie, Protextive Groups in Organic Chemistry, Plenum Press, New York 1973, and J. Am. Chem. Soc. 79, 2215 (1957)).

The protecting compounds of formula II can be prepared by reacting a compound of formula III wherein Z is the same as in formula II and L represents a leaving atom or leaving group with a carbazole or a reactive derivative of carbazole. reacted. Suitable examples of L-quality include halogen (preferably chlorine), arylsulfonyloxy (preferably p-toluenesulfonyloxy) and alkylsulfonyloxy (preferably methanesulfonyloxy) groups.

Particularly suitable reactive derivatives of carbazole are salts of the carbazole with alkali metals or alkaline earth metals, such as, for example, the lithium, sodium, potassium, zinc, cadmium and calcium salts. It is also possible to use a magnesium halide of the carbazole, for example magnesium iodide.

The alkali metal salts of carbazole are conveniently prepared by reacting the carbazole with the appropriate alkali metal hydride or alkali metal amide in an inert, preferably polar, aprotic medium such as liquid ammonia, dimethylformamide or dimethylsulfoxide. Suitable media for this purpose are hydrocarbons such as alkanes, cycloalkanes and aromatic solvents. The same medium can be used in the following for the nitrogen substitution reaction, which is preferably carried out by heating. It is advisable to substitute nitrogen in solution in an inert gas atmosphere, for example under nitrogen.

The compounds of formula (III) may also be reacted with carbazole by reaction in the presence of an alkali hydroxide or alkali alcohol, using a polar solvent such as dimethylformamide, dimethylacetamide, water or an alkanol corresponding to the alcoholate. For example, potassium tert-butylate in tert-butanol solution may be used.

Compounds of formula (III) are readily prepared from the corresponding alcohol derivative (in this case, L is hydroxy in the compound of formula (III)) by conventional procedures. For example, the alcohol derivative can be reacted with p-toluenesulfonic acid chloride to form p-toluenesulfonate (in this case, L in the compound of formula (III) is p-toluenesulfonyloxy).

The alcohol derivative may be prepared by reacting the piperazine compound of formula IV with an amine protecting agent such as formic acid, a carboxylic anhydride (e.g., acetic anhydride), a carboxylic acid chloride (e.g., benzoyl chloride), a halo alkyl halide (e.g. benzyl chloride) and then the protecting group attached to the hydroxyl group is selectively removed, for example by hydrolysis.

The compound of formula (IV) may be prepared by: a

3-Chloropropanol is reacted with 3,5-cis-dimethylpiperazine in a suitable solvent such as ethanol or dimethoxyethane.

The pharmaceutically acceptable salts of the compound of formula (A), as well as the solvates of these pharmaceutically acceptable salts, are useful in the treatment of psychotic and aggressive conditions in humans. These agents may be used, for example, in the prevention and / or treatment of schizophrenia, mania, and psychoses of age, involution, or organic, and depression.

The compound of formula (A) may also be used to prevent and treat an aggressive form of behavior. This type of behavior may be associated with other illnesses, such as psychotic and personality disorder, as well as autistic and hyperkinetic symptoms in children.

The pharmaceutically acceptable salts and solvates of the compound (A) potentiate damfetamine-induced site-shifting activity, which is the effect of most tricyclic anti-depressant agents. The potentiation of this effect of d-amphetamine suggests that the compound of formula (A) may have an anti-depressive effect in humans.

The pharmaceutically acceptable salts of the compound of formula (A) and the solvates of these salts are also useful in the treatment of aggressive symptoms and conditions of patients with mental retardation and / or behavioral disorders, such as epileptic disorders, acute or chronic organic brain syndrome, alcoholism, drug addiction or forms of aggression known or unknown from a pathological point of view.

The compound of formula (A), and pharmaceutically acceptable salts thereof, and solvates of these pharmaceutically acceptable salts are administered to a mammal, such as a human, preferably in an amount of 1-30 mg / kg body weight, most preferably 2-5 mg / kg, to treat either aggressive or psychotic condition. administered (based on base) orally. The compound of formula (A), pharmaceutically acceptable salts and solvates thereof, are preferably administered three times daily at the above dose for the treatment of said condition. In the case of intramuscular injection, the dose is approximately half of the oral dose. For example, to exclude schizophrenia, a dosage of 1-15 mg / kg, most preferably 2 to 5 mg / kg, and a dosage unit of 60-900 mg are preferred. It is advisable to administer the dosage unit once or more times a day, for example one or more tablets three times a day, each containing 10 to 300 mg, preferably 60 mg of formula (A).

-387,332 or a pharmaceutically acceptable salt thereof, or a solvate of these salts.

Although the compound of formula (A), or a salt thereof, may be administered alone as a chemical in medicine, it may conveniently be used in conjunction with a suitable carrier in the form of a pharmaceutical composition. The carrier, of course, must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The carrier may be a solid or liquid, or a mixture of solids and liquids, and may be formulated with the compound of formula (A) or a salt thereof, preferably in unit dosage form such as tablets, capsules or cachets, or rectally in the form of a suppository. for rectal administration). The compositions of the invention may also contain other pharmaceutically active substances and may be formulated by any of the methods well known in the art of pharmacy, and may be prepared by substantially mixing the components. For example, tablets may be made by the following operations: granulation, comminution, blending, coating, grinding, polishing, pressing or molding.

Dosage unit formulations suitable for rectal or parenteral administration conveniently contain from 5 to 75 mg of the compound of formula (A), or a pharmaceutically acceptable salt or solvate of the pharmaceutically acceptable salts thereof (calculated as the base with respect to the salts or solvates).

For oral use, fine dusts or granules of the above compounds may be mixed with diluents, dispersants and surfactants and may take the form of an aqueous beverage or syrup; dry powder in capsules or wafers; an aqueous or non-aqueous suspension, which also contains a suspending agent; a tablet, preferably made by compression of the active ingredient and diluent particles with binders and lubricants; suspension in water or syrup or in oil or in a water / oil emulsion, in which case the preparation may also contain flavoring, preserving, suspending, thickening and emulsifying agents. The granules or tablets may be coated and the tablets scored.

For parenteral administration (i. and soluble substances which render the solutions isotonic with blood; aqueous or non-aqueous suspensions which may also contain suspending agents and thickening agents; topical injection solutions and suspensions, which may be in the form of sterile powders, granules or tablets, and may contain diluents, dispersants and surfactants, as well as binders and lubricants.

The compound of formula (A), pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates of these salts may also be formulated as depot formulations of a known type in which the active ingredient (drug) is released over an extended period of time, once the active ingredient reaches its proper site. Such formulations, for example, in the form of sustained-release injections, are useful in human medicine, for example for the treatment of psychotic conditions such as schizophrenia, especially when the patient is not following the prescribed treatment because she would have to take too many tablets.

The veterinary use of a compound of formula (A), pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates of these salts is particularly advantageous and valuable for the treatment of aggressive symptoms in mammals, such as dogs, pigs, horses and calves. The above materials can be used for this purpose in the same manner as described above. Particularly preferred for veterinary use are the depot formulations described above, particularly under conditions where it is desirable or expedient to administer the compound of formula (A) or a salt or solvate thereof at prolonged intervals.

The compound of formula (A), pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, also have an antidepressant action at the above dosages.

From the foregoing, it will be understood that the present invention provides, but is not limited to, the following new knowledge and uses of the following therapies.

a) 9- (3- (3,5-cis-Dimethylpiperazinyl) -propyl] -carbazole, its salts and solvates of these salts;

b) 9- (3- (3,5-cis-Dimethylpiperazinyl) propyl] carbazole dihydrochloride hemihydrate;

c) the methods described above for the preparation of both compounds a) and b);

d) a pharmaceutical composition comprising 9- (3- (3,5-cis-dimethylpiperazinyl) propyl) carbazole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof, in association with an acceptable carrier;

e) a method of making the composition of d) comprising mixing the components;

f) a method for treating an aggressive condition of a mammal having an aggressive symptom which comprises administering to the mammal 9- (3- (3,5-cis-dimethylpiperazinyl) -propyl] -carbazole, or a pharmaceutically acceptable salt or pharmaceutically acceptable salt thereof; administering an amount of a pharmaceutically acceptable solvate of its usable salt which is effective against aggression and non-toxic;

(g) the method of (f) if the mammal is a human;

h) a method of treating psychosis in a person in which psychotic symptoms have been identified, which comprises:

187,332 (3,5-cis-dimethylpiperazinyl) -propyl] -carbazole, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof, which is effective and non-toxic to psychosis.

The process of the present invention will be described in detail in the following examples, without limiting the invention to the examples.

In the examples, all temperatures are given in degrees Celsius. Vacuum distillation was always carried out in a steam bath at a pressure of 26.6 · 10 ² Pa except where specifically mentioned.

Example I

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

The step:

Preparation of 3- (3,5-cis-Dimethyl-1-piperazinyl) -1-hydroxypropane dihydrochloride

A mixture of 28.5 g (0.25 mol) of cis-2,6-dimethylpiperazine, 23.6 g (0.25 mol) of 3-chloropropanol, 30 g (0.28 mol) of sodium carbonate and 100 ml of dimethoxyethane is refluxed for 4 hours. . The solid precipitate was filtered off and the solvent removed in vacuo. The solid residue was dissolved in ethanol and treated with anhydrous hydrogen chloride gas. The solid thus obtained is filtered off and dried. A white solid was obtained in a yield of 46 g (75). In the IR spectrum of the free base, the hydroxyl group appears in broad band (3160 cm ^-1 ) and the NH group in sharp absorption (3250 cm ^-1 ).

Step B:

Preparation of 3- (4-Acetyl-3,5-cis-dimethyl-1-piperazinyl) -1-acetoxypropane

15.5 g (63 mmol) of 3- (3,5-cis-dimethyl-1-piperazinyl) -1-hydroxypropane dihydrochloride are dissolved in 75 ml of water, basified with sodium hydroxide solution and extracted with 3 x 75 ml of chloroform. The chloroform solutions were combined, dried over sodium sulfate and the solvent removed. so

9.5 g (87%) of a solid residue are dissolved in 75 ml of pyridine and 12.5 ml (0.13 mol) of acetic anhydride are added and the solution is stirred under nitrogen for 12 hours. The pyridine was removed in vacuo by ca. 15.7 g of an oil are obtained. It was dissolved in chloroform (75 ml) and extracted with water (50 ml) and then diluted sodium hydroxide solution (50 ml). The chloroform layer was dried over sodium sulfate and concentrated. 14 g of residue are obtained which crystallize on standing in the flask. This solid residue was recrystallized from ether / petroleum ether to give 9.4 g of crystals, m.p. 65.5-66.2 ° C. The TLC shows a single spot with an R of 0.27 (Whatman MK.6F silica gel, eluent: ethyl acetate-acetonitrile-diethylamine 85: 10: 5, detection with iodine platinum).

IR: 1738 cm ^-1 , 1620 cm ^-1 .

Nuclear Magnetic Resonance Spectrum: δ 1.35 (d, 6H), 1.5-2.9 (m, 14H),

4.2 (b, 1.4H).

Step C:

Preparation of 3- (4-Acetyl-3,5-cis-dimethyl-1-piperazinyl) -1-hydroxypropane

A mixture of 7.4 g (28.9 mmol) of 3- (4-acetyl-3,5-cis-dimethyl-1-piperazinyl) -1-acetoxypropane and 100 ml of 4.8 M dry methanolic hydrochloric acid is stirred for 90 minutes and the solution is stirred for 90 minutes. the residue was partitioned between dilute aqueous sodium hydroxide and chloroform. The aqueous phase was extracted twice more with 30 ml of chloroform. The chloroform solutions were combined and dried over sodium sulfate and then concentrated. 6.55 g of a pale yellow oil are obtained. A single spot appears on the TLC with R _f 0, 1.2 (Whatman MK6F silica gel, eluent: ethyl acetate: acetonitrile / diethylamine 85: 10: 5).

IR spectrum: 3400 cm ^-1 , 1625 cm ^-1 .

Nuclear Magnetic Resonance Spectrum: δ 1.2-3.0 (multiplet, 17H), 3.80 (t, 2H), 4.30 (b, multiplet, 2H), 4.50 (s, 1H, interchangeable).

Step D:

Preparation of 3- (4-Acetyl-3,5-cis-dimethyl-1-piperazinyl) -1-p-toluenesulfonyloxypropane

To a solution of 6.5 g (30.3 mmol) of 3- (4-acetyl-3,5-cis-dimethyl-1-piperazinyl) -1-hydroxypropane in 50 ml of ice-cold pyridine was added 6.35 g (33.3 mmol) of p-toluenesulfonic acid chloride and 50 ml of pyridine solution are added. The mixture was kept at 5 ° C overnight, and the resulting orange solution was concentrated by rotary evaporation at room temperature to a small volume. The residue was dissolved in 75 ml of chloroform, extracted with ice-cold dilute sodium hydroxide solution, dried over sodium sulfate and concentrated to give 10.6 g of a pale yellow oil.

IR: 1635 cm ^-1, 1360 cm ^-1, 1175 cm ^1st

Step E:

Preparation of 9- [3- (4-Acetyl-3,5-cis-dimethyl-1-piperazinyl) -propyl] -carbazole

0.26 g of a 50% sodium hydride suspension in mineral oil (5.43 mmol) was stirred with 10 ml of petroleum ether for a few minutes under nitrogen and the solvent was decanted. To the residue was added 10 ml of dimethylformamide followed by 0.91 g (5.43 mmol) of carbazole. After the gas evolution had ceased, a solution of 2.0 g (5.43 mmol) of 3- (4-acetyl-3,5-cis-dimethyl-1-piperazinyl) -1-p-toluenesulfonyloxypropane and 5 mL of dimethylformamide was added dropwise to the dark green solution. The reaction mixture was refluxed for 4 hours and then poured into 400 ml of ice water. The insoluble residue is extracted twice with 150 ml of ether. The ethereal solution was extracted with dilute hydrochloric acid and the acidic extract was made basic with dilute sodium hydroxide solution. The alkaline solution is extracted with ether, dried over sodium sulfate, and the ethereal solution is concentrated. The resulting 1.4 g pale yellow oily product crystallizes on trituration with petroleum ether. Yield: 0.75 g white solid, m.p. 116-117.5 ° C. The thin layer chromatogram shows a single spot with an R of 0.33 (Whatman MK6F silica gel, eluent: ethyl acetate / acetonitrile / diethylamine 85: 10: 5).

IR: 1625 ^cin-1, 1595 ^cm-first

(F) Step 1:

Preparation of 3- (3,5-cis-Dimethyl-1-piperazinyl) -propyl] -bazole

-5187 332

A mixture of 9- [3- (4-acetyl-3,5-cis-dimethyl-piperazinyl) -propyl] -carbazole (0.10 g, 0.27 mmol) and concentrated hydrochloric acid (3 ml) was heated on a steam bath. After 48 hours, the solution was poured into ice-cold sodium hydroxide solution. The product was isolated by ether extraction, the ethereal solution was dried over sodium sulfate and concentrated. This gives 0.06 g of a residue which crystallizes on petroleum ether, m.p. 105-107 ° C. The thin layer chromatogram shows an f spot with an R _{f of} 0.23 and further traces of a trace amount with an R _{f of} 0.44, 0.05 and 0 (Whatman MK6F silica gel, ethyl acetate-acetonitrile-diethylamine as eluent).

85: 10: 5).

la. example

9- [3- (3,5-cis-Dimethyl-1-piperazinyl) -propyl] -

Preparation of -carbazole dihydrochloride hemihydrate

This material is prepared by the conventional method from the carbazole base prepared in Example 1 with dry hydrochloric acid gas. After recrystallization from ethyl acetate or ethanol-ether, m.p. 288-290 ° C.

Example 2

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

A mixture of 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 ION sodium hydroxide solution is heated to dissolve and heated to boiling. 500 ml of water are added slowly and the solution is allowed to cool slowly to room temperature. After cooling at 0 ° C for 1 hour, the mixture was filtered and the product was washed well with water and dried. 110 g (92%) of the title compound are obtained, m.p. 107-109 ° C. Analysis results for C ₂₁ H ₂₇ N ₃ :

calculated:

C, 78.46%; H = 8.47%; N = 13.07%;

Found:

C, 78.43%; H = 8.46%; N = 13.05%;

Example 3

Preparation of 9- [3- (3,5-cis-Dimethyl-1-piperazinyl) -propyl] -carbazole monohydrochloride The material prepared in Example 1a was dissolved in 250 ml of water and adjusted to pH 7 with 5N sodium hydroxide. The resulting precipitate was filtered off, washed with water and dried in vacuo. 3.7 g of the title compound are obtained, m.p. 309-311 ° C (dec.).

Analysis results for C ₂₁ H _{2 g} N ₃ Cl:

calculated:

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%.

Example 4

Preparation of 9- (3- (3,5-cis-Dimethyl-1-piperazinyl) -propyl] -carbazole maleate The base prepared in Example 2 was dissolved in hot acetone (71 mL) and 3.7 g of maleic acid was added slowly to form a pasty mixture. which is stirred at reflux for 10 minutes, cooled to room temperature and filtered, washed with acetone and recrystallized from water to give 10.5 g of the title compound, m.p. 162-163 ° C (dec.).

Analysis results for C ₂₅ H ₃₁ N ₃ O ₄ :

Calculated: C, 68.63; H, 7.14; N, 9.60. Found: C, 68.91; H = 7.25%; N, 9.74%.

Example 5

Preparation of 9- [3- (3,5-cis-Dimethyl-1-piperazinyl) -propyl] -carbazole 3/4 succinate The base prepared in Example 2 is dissolved in 50 ml of ethanol containing about 5% methanol and added slowly. , 8 g of succinic acid. The mixture was stirred at reflux for 10 minutes and then cooled to 5 ° C. The precipitate was filtered and recrystallized from ethanol / water (95/5 v / v) containing 5% methanol. 10.4 g of the title compound are obtained, m.p. 175.5-176.5 ° C (stoichiometric ratio confirmed by NMR). Analysis results for C ₂₄ H ₃₁₅ N ₃ O ₃ :

calculated:

C, 70.30%; H = 7.74%; N = 10.24%; Found:

C = 0.21%; H = 7.71%; N, 10.20%.

Example 6

Preparation of 9- [3- (3,5-cis-Dimethyl-1-piperazinyl) -propyl} -carbazole steel hydrate containing a quarter of crystalline water The base prepared in Example 2 was dissolved in hot toluene (70 mL) and acetic acid (2.0 mL) was added. After cooling to 2 ° C with stirring, the precipitate was filtered off, washed with cyclohexane (35 ml) and dried in vacuo. 10.4 g of the title compound are obtained, m.p. 144-146 ° C.

Analysis results for C ₂₃ H ₅ N ₃ O _{2 25} :

Calculated: C, 71.56; H = 8.22%;

N = 10.88%;

Found: C, 71.57; H = 8.08%;

N, 10.84%.

187,332

Example 7

Preparation of 9- [3- (3,5-cis-Dimethyl-1-piperazinyl) -propyl] -carbazole sulfate monohydrate The base prepared in Example 2 is dissolved in 100 ml of hot acetone and slowly added to this solution with stirring. 05 g of sulfuric acid and 5 ml of water. A precipitate formed immediately. The pasty mixture was stirred at reflux for 10 minutes and then cooled to 20 ° C. The precipitate was filtered and washed with acetone (20 mL), triturated with water (70 mL), filtered again, washed with acetone (40 mL) and dried in vacuo. 12.9 g of the title compound are obtained, m.p. 243-246 ° C (dec.).

Analysis results for C ₂₁ H ₃₁ N ₃ O ₅ S:

Calculated: C, 57.46; H, 7.14; N, 9.60; Found: C, 57.75%; H = 7.10%, N = 9.47%.

Example 8

According to the procedure of Example 4, 9- [3- (3,5-cis-dimethyl-1-piperazinyl) -propyl] -carbazole is reacted with an equimolecular amount of the corresponding acid to give the following salts:

9- [3- (3,5-cis-dimethylpiperazinyl) propyl] carbazole furamate;

9- [3- (3,5-cis-dimethylpiperazinyl) propyl] carbazole citrate;

L-malic acid of 9- (3- (3,5-cis-dimethylpiperazinyl) -propyl] -carbazole;

9- [3- (3,5-cis-dimetilpiperazinil) propyl] carbazole

L-tartrate;

9- (3- (3,5-cis-dimethylpiperazinyl) propyl] carbazole methanesulfonate;

9- (3- (3,5-cis-dimethylpiperazinyl) propyl] carbazole DL-lactate, m.p. 194.5-197 ° C.

Step B)

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

A mixture of the product from step A (0.20 g, 0.60 mmol) and potassium hydroxide solution (10 mL, 0.75 N in methanol) was refluxed for 18 hours under nitrogen and then cooled and concentrated. The residue was partitioned between water (5 mL) and chloroform (20 mL), and the chloroform layer was dried over sodium sulfate and concentrated. The resulting oily product is solidified by trituration with petroleum ether. The solid product was recrystallized from ethyl acetate / petroleum ether to give the title compound, mp 100-104 ° C.

Example 10

Preparation of 9- (3- (3,5-cis-Dimethyl-1-piperazinyl) -propyl] -carbazole Step A)

Preparation of 9- [3- (4-Ethoxycarbonyl-3,5-cis-dimethyl-1-piperazinyl) -propyl] -carbazole

In the same manner as in Example 1, Step E, for the preparation of the 4-acetyl derivative, 3- (4-ethoxycarbonyl-3,5-cis-dimethyl-1-piperazinyl) -1-p-toluenesulfonyloxypropane is reacted with carbazole to give the title compound. m.p. 92-95 ° C (dec.).

The TLC shows a single spot with an R of 0.74 (Whatman MK6F silica gel, eluent: ethyl acetate-acetonitrile-diethylamine 85: 10: 5).

IR spectrum: 1690 cm ^-1 1625 cm ^-1 , 1595 cm ^-1 .

N \ R spectrum:

8.1 ppm (d, 2H), 7.4 ppm (m, 6H), 4.3 (m, 6H),

2.8 ppm (m, 8H), 1.55 (d, 6H), 1.25 (t, 3H).

Example 9

Preparation of 9f 3- (3,5-cis-Dimethyl-1-piperazinyl) propyl] carbazole Step A:

Preparation of 9- (3- (4-Formyl-3,5-cis-dimethyl-1-piperazinyl) propyl] carbazole

In Step E of Example 1, a suitable method for the preparation of the 4-acetyl derivative is the reaction of 3- (4-formyl-3,5-cis-dimethyl-1-piperazinyl) -1-p-toluenesulfonyloxypropane with carbazole, m.p. 100.5-101.5 "C. Analysis results for C ₂₂ H ₂₇ N ₃ O:

calculated:

C = 75.61%; H = 7.79%; N = 12.02%;

Found:

C = 75.58%; H, 8.00%; N, 11.98%.

The TLC shows a single spot with an R of 0.47 (Wathman MK6F silica gel, eluent: acetic acetate-acetonitrile-diethylamine 85: 10: 5).

IR spectrum: 1670 cm- ¹ , 1630 cm- ¹ , 1595 cm- ¹ .

B) tear

Preparation of 9- (3- (3,5-cis-Dimethyl-1-piperazinyl) propyl] carbazole

0.30 g (0.76 mmol) of) product from Step A and 13 mL of 48 ° "aqueous hydrobromic acid was heated on a steam bath for 18 expense and then poured into 100 ml of ice and 15 ml of a sodium hydroxide solution 50 _u mixture, and then extracted with chloroform. The chloroform phase was extracted with 15 ml of 1 N hydrochloric acid, followed by 15 ml of water, the aqueous extracts were combined, basified with dilute sodium hydroxide solution and extracted twice with 30 ml of ether. The ethereal phases were combined, dried over sodium sulfate, concentrated and the residue was recrystallized from ethyl acetate / petroleum ether to give the title compound, mp 105-108 ° C.

Manufacture of pharmaceutical preparations

In the following examples, which refer to the pharmaceutical compositions of the present invention, unless otherwise stated, the term "active ingredient"

-7ί 87 332 is a compound of the formula A as defined above, or a pharmaceutically acceptable salt or solvate thereof. The established dose refers to the base; if salt is used instead of base, the dose will, of course, need to be increased in appropriate proportions.

Example 77

Tablet

Parts Each tablet! quantity (mg) Active ingredient (compound prepared according to Example 3) 60.0 Lactose 125.0 wheat starch 50.0 polyvinylpyrrolidone 3.0 stearic L0 magnesium stearate L0 Example 12 Capsule Parts Active ingredient (prepared according to Example 4) Each capsule! quantity (mg) 60.0 compound) Lactose 174.0 wheat starch 174.0 stearic 2.0

Example 13

ampoule

Parts Per ampoule!

quantity

Active ingredient (60.0 mg dihydrochloride of the compound prepared according to Example 2)

1.0 ml of water for reconstitution is sufficient to make up a total volume

Example 14

Suppository

Components Suppository quantity

Active ingredient (60.0 mg of the compound as prepared in Example 1a)

Theobroma oil (cocoa butter) needed for a total weight of 2.0 g

Example 75

Tablet

Parts per tablet:

quantity (mg)

Active ingredient (Compound 30.0 prepared according to Example 2)

Lactose 125.0

Wheat starch 50.0

Parts per tablet!

quantity (mg)

Polyvinylpyrrolidone 3.0

Stearic acid 1.0

Magnesium Stearate 1.0

Pharmacological Studies Example 16

The substance prepared according to Example 1a) was administered intraperitoneally to rats to test for inhibition of muricidal activity and apomorphine-induced aggression. It has been found that the ED ₅₀ which elicits an antimuricidal effect is 15 mg / kg and the ED ₅₀ is 12.5 mg / kg.

Example 77

The substance prepared in Example 1a) was administered to male mice for oral and intravenous LD ₅₀ determination. We found the following:

LD _S0 orally: LD ₅₀ intravenously:

977 mg / kg 31 mg / kg

Table I shows the significant therapeutic benefit of the compound (A) (dihydrochloride hemihydrate, prepared according to example (Ia)) with the carbazole derivative known in the art, 9- [3- (4-methyl-1-piperazinyl) propyl] -. carbazole (which was added as the dihydrochloride, designated Compound B in Table I).

Table 7

Comparison of Effect and Toxicity of Compound A and Compound 9- [3- (4-Methyl-1-piperazinyl) propyl] carbazole (Compound B)

Compound Anti-aggression LD < _n (mg / kg) ED _$ n (mg / kg) Therapeutic index rat, p. She. rat, p. She. LDjo / ED ,,, "THE" 957 48 20 "B" 830 75 11

II. Tables 1 to 4 summarize, among other things, other significant advantages of compound (A) over compound (B). The minimum dose (when tested in a mouse) of the compound of formula (A) at which administration is directed; loss of reflex (ED _min ) occurs, about three times greater than for Compound B. Similarly, a decrease in muscle tone (when tested in rat) is observed at a much lower dose for Compound B than for Compound A.

II. Table II further compares the anticonvulsant (anticonvulsant) efficacy of the above two compounds with the anticonvulsant activity of commercially available phenytoin (Dilantin ^R ). Phenytoin is about 2.5 times more potent than Compound B and 5 times more potent than Compound A. The anticonvulsant efficacy of Compound B is marginal in its therapeutic effect on the target. The compound of formula (A) having an anticonvulsant effect of "B"

With less than half the effect of 187,332 compounds, it is considered that it does not have sufficient efficacy for this therapeutic purpose.

Table IL

Comparison of some properties of Compound A and Compound B and aphenytoin

Compound Loss of orientation reflex: ED _m , "(mg / kg) Mouse, ip Decrease in muscle tone: ED _ln (mg / kg) Rat, ip Anticonvulsant Activity (MES ^J ) ED _S0 (mg / kg) Mouse, ip "THE" 160 125 43 "B" 50 50 20 phenytoin > 100 - 8.5

MES ^a stands for Maximum Electroshock Test (Arch, Int. Pharmacodyn. Ther. 92, 9Ί (1952)

9- [3- (4-Methyl-piperazinyl) -propyl] -carbazole is known in the art, i. The compound designated as "B" in Tables 1 and 2 is found in Example 7 of the aforementioned Australian and French patents.

Claims (8)

I. A process for the preparation of 9- [3- (3,5-cis-dimethyl-1-piperazinyl) -propyl] -carbazole of formula (A), a salt thereof or a solvate of one of its salts, wherein a compound of formula (II) wherein Z represents a protecting group - the protecting group is cleaved and the resulting base is optionally converted into a salt or solvate of a salt. Process according to claim 1, characterized in that it is based on compounds of formula (II) wherein Z is acyl or alkoxycarbonyl. means a group. 3. The process of claim 1, wherein the compound is of formula II wherein Z is formyl, C2 -C5 alkonocarbon or C2 -C5 alkoxycarbonyl. 4. The process of claim 1, wherein the compound is of formula II wherein Z is formyl, acetyl or ethoxyl. 5. Process according to any one of claims 1 to 3, characterized in that the deprotection is carried out by hydrolysis of the compounds of formula (II) with an aqueous acidic or aqueous base solution. The process according to any one of claims 1-4, wherein the deprotection is carried out by hydrolysis of the compounds of formula II with a non-aqueous acid or a non-aqueous base. 7. A process according to any one of claims 1 to 6, wherein the compound of formula (A) is isolated in the form of a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate of such a salt. 8. A process according to any one of claims 1 to 3 wherein the compound of formula (A) is isolated in the form of its hydrochloride or a pharmaceutically acceptable solvate thereof. 9. A process for the preparation of a pharmaceutical composition comprising one or more pharmaceutically acceptable salts of 9- [3- (3,5-cis-dimethyl-1-piperazinyl) propyl] carbazole prepared according to claim 1 or a solvate thereof. mixed with a pharmaceutical excipient and optionally other conventional excipients to form a pharmaceutical composition.