SU1153826A3 - Method of obtaining 9-/3-(3,5-cis-dimethylpiperazine)-propyl/-carbazole or its salts,or solvates of its salts (versions) - Google Patents

Abstract

1. The method of obtaining

Description

The invention relates to the HOBbrk derived carbazole derivatives having the properties of preventing aggressive states and psychosis. The literature describes the exchange of halogen to nitrogen by the interaction of halogen-free with amines fij. 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 preparing 9-p- (3,5-cis-dimethylpiperizino) -pril-D-carbazole, a compound of the general formula. (Hg) h-2, where Z is a halogen, is reacted with carbazole in the presence of sodium hydride or methylate. The compound can also be obtained by reacting 9- (3-halopropyl) -carbazole with 2,6-cis-dimethylpiperazine (in both cases, the target product is isolated in free water or in the form of salts, mainly in the form of its salt with hydrochloric acid, or in the form of solvates of its salts). In the examples given, the distillation under vacuum is derived from a steam bath at a residual pressure of about 20 mm Hg, unless otherwise specified. Example t, Preparation of (3,5-cis-dimethyl piperazino) -propyl-carbazole hemihydrate dihydrochloride. A, 3- (3,5-cis-Limethyl piperazino)

-propanol dihydrochloride.

2, 6-cis-dimethyl piperazine (114.2 g, 1.0 mol), 3-chloropropanol (94.5 g, 1.0 mol), sodium carbonate (105 g), and these are ionomethyl ether. LENGLYCOL (400 ml) is stirred under the action of the opposite, with a refrigerator for 4 hours. The reaction mixture is filtered while still warm and the solvent is evaporated off by distillation in vacuo.

The resulting pacT-j solid is stolen in ethanol (500 ml), and

The viscous residue is heated with 2 liters 1 and. The solution of hydrochloric acid is cooled and washed with ether (500 ml). The ether layer, which contains some unreacted caroaeol, is discarded. The aqueous layer is treated with activated carbon and filtered through Celite preparation, the filtrate is brought to an alkaline medium with sodium hydroxide, then extracted 4 times with ether. The ether and water layers become transparent by the time the solution is saturated with dry hydrogen chloride. The white precipitate is collected, evaporated in vacuo and used as the hydrochloride salt in the next step without further purification, so pl. 240-241 0. B. 3- (3,5-cis-Dimetipiperazino) -propyl chloride dihydrochloride .. Thionyl chloride (300 g) is gradually added to 3 (3,5-cis-dimethylpiporino) propanol dihydrochloride (200 g). The reaction is carried out with a weak effect of a reflux condenser for 1 hour, after which the excess thionyl chloride is removed by distillation in vacuo. The remaining substance is washed with several portions of benzene, then with several portions of ether, m.p. 291-292 ° C. B. (3,5-cis-Dimethylpiperazino) -propyl-carbazole dihydrochloride hemihydrate. A solution of carbazole (83.5 g, 0.5 mol) in DMF (150 ml) is added to a suspension of sodium hydride (1.6 mol) prepared from 70 g of a 57% dispersion in mineral oil and 200 ml of dimethylformamide (DMF). ml) After the evolution of hydrogen ceased, a suspension of 3- (3,5-cie-dimethyl-piperazine) propyl chloride-dihydrochloride (131 g, 0.5 mol) in DMF (200 ml) was slowly added to the reaction mixture. The reaction is continued under a nitrogen atmosphere using a flow system with an oil pressure tank. Some foaming occurs as the suspension is added. The rate of addition is selected so that the foaming is kept to a minimum. After the addition is complete, the reaction mixture is heated at 90-120 ° C for 16-18 h, cooled, filtered and the solvent is evaporated by distillation in a vacuum. termination of extraction. The ether layer is dried over anhydrous magnesium sulphate or under molecular sieves, and 9-C- (3,5-cis-dimethyl-piperazino) hydrochloride salt saws carbazole is precipitated by passing that dry chlorine hydrogen into the solution. The precipitate is collected and recrystallized from ethyl acetate or from a mixture of ethanol and ether, which gives (3,5-cis-dimethylpiperazino) -propyl-carc bases ol dihydrochloride hemihydrate (50 g), m.p. 2888-290 C. p 2, Preparation of 9-1 (3,3-cis-dimethyl piperazino) propyl 2-car bazole. (3,5-cis-Dimesh1piperazino) -propyl {-carbazole dihydrochloride hemihydrate (150 g), anhydrous ethanol containing about 5% methanol (680 m water (.275 ml) and Yun. Sodium hydroxide solution (79 mp) are mixed and heated until a solution is obtained, water (500 ml) is gradually added to the hot solution and left to cool slowly to room temperature.The mixture is further cooled to 0 for 1 h, then filtered. The product is washed thoroughly with water and dried, which gives (3,5-cis-dimethylpiperazino) -p -ylcarbazole (110 g, 92% of theory, mp. 107-109 ° C. Calculated: C 78.46; H 8.47; N1 Gj, H, Found: G, 48; H 8.46; N 13.0 Kromez / 9- 3- (3, 5-cis-Dime. Tilpiperazino) -propyl-carbazole mono-hydrochloride, 9-ГЗ- ( 3,5-cis-Dimethylpiperazino-propyl-carbazole dihydrochloride hydrate (5 g) of Example 1 is a solution in water (250 ml), and the solution is neutralized to a pH of -7 with 5N sodium hydroxide solution. The resulting precipitate is collected by filtration , washed with water and dried under reduced pressure to give 9-.3- (3,5-cis-dimesh1 piperazino) -propyl | -carbazole monohydrochloride (3.7 g), so pl. 309-311 ° C (with decomposition), c 70.47; and 7.89; Calculated: 11,745 C1 9. 91-. C2, VfjCl C 70.53; Found; H 7.93; 9.83. 11.69; C1 PRI mme R 4. (3,5-cis-Dietilpiperazino) -propyl carbazole aleate. 9- 3- (3,5-cis-Dimetsh1nneprazino) -propyl-carbazole (10 g) in Example 4 is dissolved in warm acetone (71 ml). Aleic acid (3.7 g) is added gradually to prevent formation of 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 9-C3- (3,5-W C-dimethylpiperaeno) -propyl-carbazole maleate (10.5 g), so pl. 162-163 ° C (decomposition). Calculated: C 68.63. H 7.14; N 9.60. C ,,, N, 0 Found: C 68.91; H 7.25; N 9.74. And p and me R 5. (3,5-CIS-Dimethyl piperazino) -propyl-carbazole 3/4 succinate. 9-W- (3, 5-cis-Dimethyl piperazino) -propyl-carbazole (10 g) in Example 4 was dissolved in warm product SD3A (ethanol containing about 5% methanol — 50 ml) and succinic acid (3 , 8 g) The mixture is stirred and heated under reflux for 10 minutes, then cooled to 5. The product is collected by filtration and crystallized from a mixture with water (95: 5 by volume per volume), which gives 9-T3- (3 , 5-cis-dimethylpiperazino) -propyl-carbazole 3/4 succinate (10.4 g), mp 175.5-176.5 (stoichiometry is confirmed by nuclear magnetic resonance data). Calculated: C70.30; H, 74; N 10.24. C, 4 ".. Found: C 70.21; H 7.7r, N 10.20 .. Example 6 cis - (- (3,5-Dimethylpiperazinyl) -propyl-carbazole acetate per one a fourth part hydrate. To (3,5-cis-dimethyl piperazno) -propyl-β-carbazole (10 g) by example, 4 dissolved in hot toluene (70 ml), acetic acid (2.0 ml) is added The mixture is stirred and cooled to 2. The resulting product is collected by filtration, washed with cyclohexane (35 ml) and dried under reduced pressure, which gives cis-9-f3- (3,5-dimethylpxIepazinyl) -sprofil-caparbase ace5 tat per one-fourth hydrate (10.4 g, mp. 144-146 C, which is characterized by data elemental analysis Calculated: C 71.56, H 8.22; N 10.8, K5, 5N, 0, V Found: C 71.57; H 8.08; N 10.8 IT p im 7. cis-9- 3- (3,5-Di methylpiperazinyl) -propyl} -carbazole sulfate monohydrate. To cis-9-Gz- (3,5-dimethylpiperazinyl) -propyl-carbazole CU d) in example 4, dissolved in warm acetone (100 ml), a solution of sulfuric acid (3: 05 g) in water (5 ml) was gradually added with stirring, followed by immediate precipitation. The suspension is stirred under the action of the reverse chill for 10 minutes, then cooled to. The product is collected by filtration and washed with acetone (20 ml). The product was re-stirred up in water (70 ml), filtered, washed with acetone (40 ml) and dried under reduced pressure. Cis-9- 3- (3,5-dimesh1piperazinyl) -propyl -carbazrl sulfate monohydrate (12.9 g), m.p. 1.243 246 ° С (with decomposition) is obtained. Calculated: C 57, 7.14, N 9.6 C ,, H ,, N, 05 Found: C 57.75, H 7.10, N 9.47 For m-e r. 8. Following the procedure specified in Example 7, (3,5-cis-dimethylpiperidine) -productJ-ka basol is reacted with equimolecules with a pnm amount of a suitable acid to obtain the following salts: 9-E- (3,3-cis-d methyl piperazino ) -propyl1 carbazole fumarate} 9- {3- (3,5-cis-dimethylpiperazino) -propyl-carbazole citrate; 9-Gz- (3,5-cis-dimethylpiperazino) -propyl-carbazole L-malate; 9-, 3-cis-dimethyl-piperazine) - -propyl, -carbazole L-tartrate, 9-D (3, 5-cis-dimethyl 1 -spered o) -propyl-carbazole methanesulfonate; 9-D (3,5-cis-dimethylpiperazine) -propyl-carbazole DL-lactate, melting point 194.5-197s. Example 9 p. 9-p- (3,5-cis-dimethyl piperazino) -propyl -carbaz dihydrochloride hemihydrate. A. 9- (3-Chloropropyl) -carbazole. Carbazole (134 g, 0.8 mol) in dimethylformamide (1.5 d) is gradually added 6 to a suspension of sodium hydride (0.8 mol) prepared from 39 g of a 50% suspension in mineral oil and 500 ml dimethylformamide, and the temperature is maintained at a lower level. After the termination of hydrogen separation, the reaction mixture is cooled to a temperature of about 5 ° C in an ice bath and 1,3-dichloropropane (500 g, 4.4 mol) is added at a rate not exceeding 10 ml per minute. After adding the total amount of 1,3-dichloropropane, the reaction mixture is stirred a little. Allow to cool to room temperature (about 1.5 hours). The reaction mixture is filtered to remove the generated sodium chloride, then the solvent is stripped off under vacuum (water pump). The residue in the form of a thick syrup is then distilled under high vacuum. The first fraction, removed at 70 ° C and 300 microns, represents an excess amount of 7, 3-dichloropropane, which is used for subsequent use. The second fraction, distilled at 120 ° C and 100 µm, is unreacted carbazole mixed with a quantity of product, with a total weight of 38 g. The third fraction (bp 145 C at 60 µm) represents 9- (3-chloropro-1) - carbazole, 107 g, 55% yield, mp.34-35 ° C. Calculated: C, 73.9 G, H 5.79; N, 5.75. C ,, I ,, NC1 Found: C, 73.85; H, 5.81; N5.72. B. 9-GZ- (3,5-cis-Lx etylpiperazino) -propyl-carbazole dihydrochloride hemihydrate. 9- (3-Chloropropyl) -carbazole (12.2 g, 0.05 mol); 2,6-cis-dimetryppiperazine (5.7 g, 0.05 mol), potassium carbonate (10 g) and dimethylformamnd (50 ml) are heated under the action of a reflux condenser for 1 h, cooled and filtered. The filtrate is stripped from the solvent in a vacuum (water jet pump) and the residue is treated with 250 MP 1 n. hydrochloric acid solution. The resulting solution is embedded in ether. The ether phase is discarded, and the phase formed by hydrochloric acid is treated with the Celite @ material, filtered and peregnoguyu in vacuum to form an ear residue. The residue was recrystallized from a mixture of ethanol and sir, 7 which gave (3, 5-cis dimethyl piperazino) -propyl-carbazole dihydrochloro hemihydrate. (18 g, 90% yield), so pl. 288-290 ° C. Try on. 9-Gz- (3,5-cis-Limethyl piperazino) -propyl-carbazole monohydrochloride. A suspension of 3- (3,5-cis-dimethyl piperazino) -propyl chloride of hydrochloride in toluene (Example 1, Step B) is cooled in a mixture of ice with Yun, sodium hydroxide solution and the mixture is adjusted to pH 13.5. The toluene phase is separated and additional extraction is carried out 4 times with toluene. After drying, the solvent is removed from the toluene solution, resulting in a crude purity of 3- (3,5-cis-dimethylpiperazino) propyl chloride in the form of an oil. Equimolecular amounts of sodium methoxide and carbazole are reacted together in dimethylformamide, followed by distillation in vacuo to release the methanol. This mixture is combined with the appropriate amount of crude oil from the preceding stage and the resulting mixture is heated at a SOO C for 15 hours. Dilution with water thus obtained gives (3.5-cis-dimethyl-piperazino) -propyl-carc basol. The latter is filtered off, heated with 1 n. a solution of hydrochloric acid and the resulting solution after cooling, extracted with ether. The ether layer is discarded and the remaining aqueous layer is neutralized to pH 7.5 with 5N. a solution of hydroxide of 1 atri. The resulting precipitate is filtered off, washed with water and dried under reduced pressure, which gives (3,5-cis-dimethylpiperazino) -propyl-carc basol monohydrochloride, m.p. 309311 with (with decomposition). The resulting compound, its pharmaceutically acceptable salts, and solvates of such salts suitable for pharmaceutical use can be used in the treatment of psychosis and aggressive conditions. For example, carbazole is useful for the prevention and treatment of schizophrenia, manic or senile mental illness, involutional or organic psysoses, as well as depressive psychosis. In addition, they are used to prevent and treat aggressive behavior. Such behavior may be associated with other disorders, such as impaired mental activity, the phenomenon of dominance of the inner life (autism) and excessive motor activity. They also enhance the action of motor activity — amphetamine is a property exhibited by the majority of tricyclic excitants. In tab. Figure 1 shows the significant therapeutic advantage of the resulting compound, given as hemihydrate dihydrochloride in Example 1 (compound A) in comparison with carbazole derivatives, namely (4-methylpiperazino) propyl carbazole, which is used as a dihydrochloride (compound B). Table 1 Comparison of the activity and toxicity of compound A with the same characteristics of compound B. Action preventing aggressive behavior Introduction to the rat by mouth. . In tab. Table 2 summarizes the other significant advantages of compound A as compared with compound B. The minimum dose (in mice) of compound A, at which the reflex of correct understanding (E, n) is lost, is about three times the value of compound B. Similarly, a decrease in muscle tone (in a rat) is observed in the case of compound B with a significantly lower dose than in compound A. Table. 2 also compares the anticonvulsant effects of the two compounds and the commercially available anticonvulsant drug phenytoin. Phenytoin is almost 2.5 times 5 more active than Biv compound 5 times more active than compound A. Comparison of some B-compounds and feni The level of anticonvulsant effects shown by compound B is close to the marginal value when compensating for final use. Compound A exhibits less than half the degree of anticonvulsant action, rather than compound B. Tablice 2 properties of the compound. Oh, oina.

Loss of reflex of proper behavior of EPD, (mg / kg) in a mouse after intraperitoneal administration. Muscle tone weakening (µ / kg) in a rat when administered intraperitoneally.

Anti-roadway action (MET) EP 50 (mg / kg) in mice with intraperitoneal administration

Maximum electric shock test

50

More than 100

50

20

8.5

Claims (2)

‘SALTS (ITS OPTIONS). 1. The method of obtaining 9- [3- (3,5-cis-dimethylpiperazino) propyl]] -carbazole or its salts, or solvates of its salts, with the exception of the fact that the compound of General formula sc ₅ where Z is halogen, is reacted with carbazole in the presence of sodium hydride or methylate, followed by isolation of the target product in free form or in the form of its salts, or in the form of solvates of its salts. 2 · The method according to p. 1, characterized in that the target product is isolated in the form of its salt with hydrochloric acid.