SU1014469A3 - Process for preparing 9-(3-(3,5-cis-dimethylpiperazine)-propyl)carbazole or its salt or solvate of its salt - Google Patents

Abstract

1. The method of obtaining

Description

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The invention relates to the field of obtaining new derivatives of the carbazole series, which have biological activity and can be used in medicine.

Known to obtain amines by the interaction of amines with aldehydes in the presence of a corresponding reducing agent C1,

The aim of the invention is to develop on the basis of a known method, a method for producing new compounds with valuable pharmacological properties.

This goal is achieved by the fact that according to the method of obtaining. (3 5 5 cis-dimethyl piperazino) propyl carbazole or its salt, or a solvate of its salt 5 comprising the fact that the 3- (9 carbazolyl) propanal is reacted with 3: 5 cis-dimethyl piperazine while reducing sodium cyanoborohydride and the desired product is isolated in free form or as a salt, or as a solvate of its salt. In addition, the target product is isolated as a salt with hydrochloric acid,

PRI m e R; 1, Preparation of (qi 3 5 dimethyl-1-piperazinyl) propyl carbazole monohydrochloride.

a) 9 (W (3 Diethoxypropyl) carbazole,

A solution of carbazole 50 51 g OGmol in 300 ml of dimethylformamide is slowly added to a suspension of 17.28 g (0.3b mol) (50%) of sodium hydride in 225 ml of dimethylformamide and the resulting mixture is stirred at room temperature for 1 h. To this mixture 2 g (0 mol) of sodium iodide are added, followed by 60 ml (O, 36 mol) of 3-chloropropanal diethyl acetal, which is added dropwise over 15 minutes. The mixture is heated for 3 hours, allowed to cool and poured into 1.80 l of water. The aqueous mixture is extracted with hexane (BOO ml) and discarded. The extracts are combined and dried over sodium sulfate. After concentration of the solvent J, g (61%) of 9- (3,3-diethoxypropyl) carbazole, the precipitated is filtered and dried under vacuum. Melting point 57 ° C.

c) 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 pyridinol sulphonyl

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500 ml of acetone is heated under reflux for k hours, allowed to cool, and volatile products are removed under reduced pressure of 5 (15 mm Hg). Fresh acetone (500 ml) was charged and the solution was refluxed for 18 hours. The evaporation and re-loading process was repeated. After

10 additional reflux for k h, volatile products are removed and 500 ml of ether is added to the precipitate. Crystallized pyridinol sulphonyl is filtered off and the filtrate is evaporated to form a viscous oil, which is hard when rubbed with 150 ml of hexanas. The white solid was filtered and dried under reduced pressure to obtain 17 g

(77%) 3 (9 carbazolyl) propanal with

melting point 7B

c) (cis-3,5 Dimethyl-1-piperazinyl) propyl carbazole monohydro25 chloride o

A solution of 2,6-cis-dimethylpiperazine (2.25 g, 20 mmol) in 75 ml of methanol was adjusted to pH 5.1 with a methanolic solution of hydrogen chloride. Solid

30 3 (9 carbazolyl) propanal (, 0 g, 18 mmol) and sodium cyanoborohydride (1.15 g, 18 mmol) are added in rapid succession to the stirred solution of the amine salt. After 2 h, the precipitate obtained is filtered off, washed with 10 ml of cold methanol and 25 ml of ether and dried under reduced pressure to obtain 2.5 g (39%) (cis-3.5 dimethyl-1-piperazinyl

0 Propyl carbazole monohydrochloride with a melting point of 307 AP3C. Elemental analysis: Calculated,%: C 70.7; H 7.8 O; N 11.75.

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

P and measure 2 Obtaining (3,5 CIS-dimethylpiperazino) propyl

0 carbazole.

(3.5 Dimethyl piperazino) propyl dicarbazole dihydrochloride hemihydrate (150 g), anhydrous ethanol, containing about 5% methanol (680 ml),

5 ° DU (275 ml) and 10 N. A solution of sodium hydroxide solution (79 ml) is mixed and heated until a solution is obtained. To a hot solution, water (500 ml) is gradually added and the honey is allowed.

Cool to room temperature. The mixture is additionally cooled to within 1 h, then filtered, the Product is washed thoroughly with water and dried, which gives (3.5 cis-dimethyl piperazino) propyl Dcarbazole (110 g, 32% of theory),, 107-109 ° С,

Calculated,%: C 78.6; H 8.7; N 13.07.

. Found,%: C 78.43; H 8.46;

N 13.05.

Froze 9-13- (3,5-cis-dimethylpiperazino) propyl carbazole monohydrochloride.

(3,5 cis-dimethyl piperazino) propyl 3-carbazole dihydrochloride, the hemihydrate (5 g) of example 1 is dissolved in water (250 ml) and the solution is neutralized to 5 n. sodium hydroxide solution. The resulting precipitate is collected by filtration, washed with water and dried under reduced pressure to give (3.5 cis-dimethyl piperazino) propyl carbazole monohydrochloride (3.7 g), m.p. 309-311 ° C (with decomposition), which has the following elementary analysis data:

Calculated,%: C 70, (7; H 7.89; N 11, C1 9.91.

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Found,%: C 70.53; H 7.93; N 11.69; C1 9.83.

Example lo (3,5-cis-dimethylpiperazino) propyl carbazole maleate.

 (3,5-Cis-dimethylpiperazino) propyl carbazole (10 g) at the perimeter k is dissolved in warm acetone (71 ml), Maleic acid (3.7 g) is added gradually, being careful not to form a precipitate. The resulting suspension is stirred by heating the reflux condenser for 10 minutes. The collected precipitate is washed with acetone, then recrystallized from water, which gives (3.5 cis-dimethylpiperazino) propyl carbazole-maleate (10.5 g) so pl. 162-163 0 (decomposition), which has elementary analysis data.

Calculated,%: C 68.63; H 7, U; N 9.60.

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Found,%: C 68.91; H 7.25; N 9.74.

PRI me R 5. (3,5-CIS-dimethylpiperazino) propyl carbazole 3/4 succinate.

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(3, 5 cis-dimethyl piperazino) propyl carbazole (10 g) in Example 2 is dissolved in the warm product FOR (ethanol containing about 5 methanol — 50 ml) and succinic acid (3.8 g) is gradually added. The mixture is stirred and heated under reflux for 10 minutes, then cooled to 5 ° C, the product is collected by filtration and crystallized from a mixture with water (95: 5 by volume per volume), which gives 9-D- (3.5-Cis- dimethyl piperazino propyl carbazole 3/4 succinate (10.4 g), mp 175.5-176, C

(stoichiometry confirmed by nuclear magnetic resonance data), which has the following elementary analysis data:

Calculated,%: C, 70.30; H 7.74;

N 10.24,

N P ,,

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Ideno, I: C, 70.21; H 7.71; N 10.20. EXAMPLE 6: Cis-9- 3- (3,5-Dimethyl-piperazinyl) propyl carbazole acetate per quarter of the hydrate, K (3,5-Cys-dimethyl piperazino) propyl carbazole (10 g), Example 2 Acetic acid (2.0 ml) is added to the solution dissolved in hot to-toluene (70 ml). The mixture is stirred and cooled to 2 ° C. The resulting product is collected by filtration, washed with cyclohexane (35 ml) and dried under reduced pressure, which gives

cis-9-3 (3.5 dimethyl piperazinyl) propyl carbazole acetate per quarter hydrate (10.4 g), t, mp, 144-146 ° C, which is characterized by elemental analysis data:

Calculated,%: C 71.56; H 8.22; N 10.88.

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Found: C 71.57; H 8.08;

N 10.84,

PRI me R 7. CIS-9- 3- (3,5-Dimethylpiperidine) propyl carbazole sulfate monohydrate,

To cis-9-C3 (3, 5-Dimethyl piperazinyl | propyl carbazole (10 g), as in Example 2, dissolved in warm acetone (100 ml), a solution of sulfuric acid (3.05 g) in water ( 5 ml), which is followed by immediate precipitation. The suspension is stirred under the effect of a reflux condenser for 10 minutes, then cooled to 20 ° C. The product is collected by filtration and washed with acetone (20 ml). Product re vzmu5

It is taken up in water (70 ml), filtered, washed with acetone (kO ml) and dried under reduced pressure. Cis-9- 3 (3 5 dimethyl piperazinyl) propyl-3-carbazole sulfate monohydrate is obtained (12.9 g), m.p. 2k3-2kff C (with folding), which is characterized by the data of elementary analysis.

Calculated,%: C 57.6; H 7, N 9.60.

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Found,% -. C.57.75; H 7.10; N 9.7.

Carbazole, their pharmaceutically acceptable salts, and the solvates of such salts suitable for pharmaceutical use are useful in the treatment of psychosis and aggressive conditions in humans. For example, carbazole is useful for the prevention and treatment of schizophrenia, manic or senile mental illness, involutional or organic psychoses, as well as depressive psychoses.

In addition, carbazole. : can be used for the prevention and treatment of aggressive behavior. Such behavior can be associated with other disorders, such as impaired mental activity, also in children, the occurrence of overcoming of the inner life (autism) and excessive motor activity,

Carbazole, its pharmaceutically acceptable salts and solvates enhance the action of the motor activity of d-amphetamine, which is a feature manifested by the majority of tricyclic exciters. This increased effect of amphetamine suggests that carbazole may have a stimulating effect on humans,

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The additional use of carbazole, its pharmaceutically acceptable salts, and the solvates of such salts is made in the treatment of symptoms of aggressive behavior. Such symptoms may occur in patients with mental retardation and / or in patients with disorders of normal behavior. Examples of other mental diseases in this case are aggressive states associated with epilepsy, acute and chronic complexes of disorders of the brain activity of organic origin, alcoholism, b9.

drug habit, as well as other forms of aggressive behavior of known and unknown origin.

5 The compound carbazole, its pharmaceutically acceptable salts and solvates of such suitable pharmaceutically salts are administered to mammals for therapeutic purposes, for example, humans, preferably by oral administration at a dosage of from 1 to 30 mg / kg (based on) the patient's body weight, being treated for aggressive behavior and / or

5 psychosis. When taken by mouth, it is most preferable to treat at a dosage of 2-5 mg / kg. The compound carbazole, its pharmaceutically acceptable salts and solvates.

0 it is preferable to give three times a day at the above dosage and circumstances.

For intramuscular administration, the size of the dose is usually half the amount to be taken by mouth. For example, in the treatment of schizophrenia, the appropriate dosage should be in the range of from 1 to 15 mg / kg, most preferably from 2 to 5 mg / kg. Example

g of the whole unit dosage is a weight amount from 60 to 900 mg. It is convenient to give a single dose as a medicine one or more times a day, for example, in the form of one or several tablets, each containing from 10 to 300, more conveniently 60 mg of carbazole, its pharmaceutical salts or their solvates. Tablets taken 3 times a day.

Although for medical use, carbazole or its salt can be given directly as a chemical compound, it is preferable to use them together with an acceptable carrier as part of a pharmaceutical formulation. Of course, the carrier must be acceptable for reasons of compatibility with other parts of the formulation, without adversely affecting the patient taking the medicine. The carrier may be a solid, or liquid, or a mixture of solid and liquid substances. Preferably, the carbazole or its salt is introduced into the mixture intended for single use, for example, j in the form of a tablet, capsule or cachets for the medication, in the case of 7 ingestion, or in the form of supporitant, introduced into the rectum. Other pharmaceutical active substances could also be contained in the formulations of the invention. C tava can be prepared in the form of medicinal formulations using any of the technical methods well known in the pharmaceutical industry and consisting mainly in the mixing of ingredients. For example, tablets can be prepared by grinding, grinding, mixing, applying coating milling, pouring over. , pressing, molding. Formulations for single use, administered through the rectum or the gastrointestinal tract, usually contain from 5 to 75 mg of carbazole as a base or a pharmaceutically acceptable salt or solvate thereof, calculated on the basis of. For ingestion, the compound is in the form of fine powder or granules. may also contain diluents, dispersants, and surfactants, and may be given to a patient for ingestion with water or syrup. For administration in capsules or wafers, the compounds are taken in a dry form, or in the form of an aqueous or non-aqueous suspension, if it is possible to include a suspending agent; In the manufacture of tablets, it is advisable to base the granules of the active component with a diluent and then compress them, crawling with binders and lubricants, which facilitate the removal of the tablets from the mold. In the case of a suspension in water, syrup or oil, or in an emulsion consisting of water and oil, it is also possible to add flavoring and aromatic substances, also preserving, thickening and emulsifying medium c. Granules or tablets may have a coating, and tablets, in addition, have grooves that facilitate the separation of the tablet into parts. For subcutaneous administration (by intramuscular, intravenous, intraperitoneal or subcutaneous injection), -carbazole, preferably i, as a pharmaceutically acceptable salt / hydrate can be contained in an ampoule for single use, or in a vial of 3.8 for multiple use. Solutions for injection in an aqueous or non-aqueous medium may contain antioxidants, buffering agents, microbial growth retardants, and solutes that give the compounds isotonic properties in relation to blood, then carbazole, preferably in the form of a pharmaceutically suitable salt or hydrate, can be added to the composition of the aqueous or non-aqueous suspensions together with suspending agents and thickeners. Injectable solutions for immediate use, as well as suspensions, may be prepared from sterile powders, granules or tablets, which may contain diluents, dispersants and surfactants, binders and lubricants. Carbazole, its pharmaceutically acceptable salts, and the acceptable pharmaceutically solvates of such salts may also be present as depot formulations and for gradual pickling. Of the compounds of this kind, known in the pharmaceutical technology, the active part (drug) is released for a prolonged period of time while the medicinal composition continues to be in the body of the patient who took the medicine. Such formulations in the form of, for example, long-term injections are beneficial when people are healed. For example, mental diseases such as schizophrenia, with prescribed drug treatment of which, for example tablets, their frequency becomes unacceptably high. In the field of veterinary medicine, carbazole, its suitable pharmaceutical salts and pharmaceutically acceptable solvates of such salts are of particular use and value for the treatment of aggressive conditions in mammals recognized by on the appearance of aggressive symptoms, in particular in dogs, pigs, horses and cattle. In these cases, it is practical to administer the drug in the manner indicated above. Particularly advantageous for veterinary use are compositions that form a depot, as described above, in cases where carbazole, its salt or solvate is desired, for practical reasons, to be administered at long intervals. Carbazole, its pharmaceutically acceptable salts and pharmaceutically acceptable solvates have also been found to have anti-depressive effects at the same dosages as above, Table. 1 shows a significant therapeutic advantage of carbazole given as dihydrochloride hemihydrate of example 1 (compound A) in comparison with the carbazole derivatives of the prior art; (methylpyperazino) propyl carbazole, given as dihydrochloride (compound B Table 1 shows a comparison of the activity and toxicity of carbazole (compound A) with the same characteristics (-methyl piperazino) propyl 7 carbazole (compound B) Table 2 summarizes various other These are the significant advantages of carbazole as compared with Compound 1-1.I -.- ch1- Compound Effective LD. mg D A957 B830 Introduction to rats h Properties

Loss of the reflex of the correct behavior of ED (mg / kg) in the mouse by intraperitoneal injection

More than 100

50 910 I eat B. The minimum dose (in mice) of carbazole, at which the reflex is properly understood, is lost, and (ED min) is about three times the value of compound B. Similarly, the decrease in muscle tone (in a rat ) was observed in the case of compound B at a significantly lower dose than that of carbazole. Table 2 also shows a comparison of the anti-convulsant effects of the two compounds and the commercially available anticonvulsant drug phenytoin (dilantin R). Phenytoin was found to be almost 2.5 times more active than compound B and 5 times more active than carbazole (compound A). The level of the anticonvulsant effect shown by Compound B is close to the marginal value in compensation and this final application. Carbazole exhibits less than half the anticonvulsant effect than Compound B PoetsGmu should be considered to be a further consideration of the anti-state carbazole hardly any the children are justified. Table 1 . - aggravating agent, mg / kg. Therapeutic ratio / ED: 20 y / o HO 7510 from. Table2 Connection 1 Phenytoin

The weakening of the muscular tone ED min V (mg / kg) in rats with intraperitoneal administration

Anticonvulsant action of SMET) (mg / kg) in mice after intraperitoneal administration

Maximum Electroshock Test (Woodbury and Davenport, Arch int pharindcodyn Thar. 92, 97-107 (19B2).

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Claims (2)

1. The method of obtaining 9 ^- [3- (3,5 ~ -cis-dimethylpiperazine) -propyl} carbazole or its salt, or its solvate: salt, characterized in that 3 ~ (9 ~ carbazolyl) propanal is reacted with 3, 5-cis-dimethylpiperazine with simultaneous reduction with sodium cyanoborohydride and the target product are isolated in free form either as a salt or as a solvate of its salt. 2. The method of pop. 1, characterized in that the target product is isolated in the form of its salt with hydrochloric acid.