SU793404A3 - Method of preparing vincinic acid derivatives or their salts or their quaternary salts - Google Patents

Abstract

Vincinic acid derivatives of the general formula (I): <IMAGE> wherein R represents hydrogen or an alkyl group containing from 2 to 6 carbon atoms, optionally substituted with hydroxyl, R1 represents hydroxyl, R2 represents hydrogen, or if R does not represent hydrogen, R1 and R2 together may form a valence bond between two adjacent carbon atoms, and acid addition salts and quaternary salts thereof, especially the esters thereof, show valuable vasodilating activity and may be used as active ingredients of pharmaceutical compositions. The compounds are prepared by hydrolysis of vincine to vincinic acid, optionally followed by esterification and/or dehydration and/or salt formation.

Description

(54) METHOD FOR OBTAINING VINCINIC ACID DERIVATIVES OR SALTS OR QUARTERTIES OF THE INVENTION The invention relates to a method for producing new synthetic derivatives of the vinca alkaloids class, vincinic acid derivatives of the general formula 1: a hydroxyl group and R2 are hydrogen, if R. - y-hydroxyethyl RJ and Rj BMecTe form a carbon-carbon bond, or their salts, or their quaternary salts, which have valuable pharmacological properties. The use of the known method for the esterification of carboxylic acids with alkyl halides or aliphatic alcohols in the presence of dehydrating agents (I) makes it possible to obtain new vincic acid derivatives possessing the pharmacological activity of HH. The purpose of the invention is to expand the range of synthetic derivatives of vincamine alkaloids with

(CH. SALTS with valuable pharmacological properties. The goal is achieved by the described method of obtaining vincine acid derivatives of formula 1 or their salts or quaternary salts, which consist in reacting vincic acid with ethylene halohydrin or ethyl alcohol in the presence of water-removing agents, preferably sulfuric acid or acetic acid. acid or acetic anhydride, after which the target products are isolated in free form, in the form of salts or quaternary salts by known methods. Example 1. Vincinova Slots of 1 g (0.0026 mol of vincine are dissolved in 50 ml of anhydrous methanol and the solution is stirred with 0.56 g of CO, 01 mol) of potassium hydroxide. The mixture is heated under reflux for 5 hours, then cooled to 2025 ° C and Glacial acetic acid is adjusted to pH 6-7, after which Vincine acid immediately begins to precipitate as crystals. The mixture is kept for 8-10 hours at 0-2 ° C to achieve full crystallization of the product, then the crystalline product filtered off, washed with 10 ml of methanol and dried. Thus, 0.95 g of chromatographically homogeneous vincinic acid (98% is obtained); m.p. 214 ° C.

Calculated,%: from 68.09, H 7.07, 7.56.5

Ci5% 604. Found: C 68, Exhaust gas, H 7.49, 7.58.

d About (0.1 n) - NaOH, C 1).

Rf (on silica gel, solvent: S: 6: 20: 11 a mixture of ethyl acetate, glacial xrous acid, pyridine, and water). 0.31.

IR spectrum: 3700-3200 cm (VOH), 3100-2880 cm- (СН2.СНЗ), 1630 cm 15 V С-С), 781, 738 cm- (at СЕ).

Example 2. Vincine acid - hydroxyethyl ether. 4 g (0.01 mol) of VINCINOIC acid are mixed with. .0.48 g (o, 012 mol) of solid sodium hydroxide and 20 ml of ethylene chlorohydrin and 40 ml of boil under reflux for 5 hours. The course of the reaction is monitored by thin layer chromatography (adsorbent: silica gel, solvent mixture: ethyl acetate: ice on acetic acid: pyridine: water 60: 6: 20: 11. After completion of the reaction, the reaction mixture is cooled to 20-25 ° C, stirred with 100 ml of an aqueous solution of sulfuric acid, then to achieve a pH of 8-9 20% aqueous solution of sodium hydroxide. From the solution containing the precipitate, the product is extracted with chlorine. form 3 X 50 ml, the extraction paths of chloroform are combined, dried over anhydrous potassium carbonate, filtered and the filtrate is evaporated under reduced pressure. The residue after evaporation is dissolved in 15 ml of a mixture of 40 benzene: ethanol 95: 5 and the chromatographic solution on the column, containing 30 times the amount of silica gel relative to the weight of the evaporation product (silica gel size is 0.05-0.2 mm). Each 200 ml fraction of the eluate is collected. For fraction 1 through 7, a 95: 5 mixture of benzene and ethanol was used as the eluate, and a mixture of benzene and ethanol 90:10 was used for fraction 8 through 15. Individual 5U fractions are identified by thin layer chromatography; Fractions 7 to 15 containing the desired V-hydroxylethylether of vincine acid are combined and evaporated at -55 lower pressure. The residue after evaporation is crystallized from 15 ml of ether. In this way, 2.2 g of oxacyl ester of vincinic acid (49%) is obtained; 1b6-168 p.40

Ri 0.5 (on silica gel, solvent: 60: 6: 20: 11 a mixture of ethyl acetate, glacial acetic acid, pyriAin and water

Cw 63.9 (c 1, c, pyridine).

IR: 3700-3000 cm (V OH, V CH aromatic, 3000-2800 (V CHiCHj), 1725 cm (V), 1220 cm- (} soy), 1180 cm (V SOS) 810 (In CH)

Calculated,%: C 66.7; H 7.2 IN 6.7.

C HjoOsNi.

Found,%: C 66.8, H 7.1, N 6.6.

Example 3. Vincine acid-β-hydroxyethyl methyl iodide 0.2 g (0.00048 mol), b-hydroxyethyl vindeate is dissolved in 5 ml of methanol and stirred with 0.1 g (0.0007 mol) of methyl iodide. The mixture is maintained at 20–25 ° C for 5 h, and the reaction is monitored by thin layer chromatography (adsorbent – silica gel, solvent – chloroform: ethyl acetate: methanol 8: 1: 1). After the formation of the quaternary salt is completed, the reaction mixture is kept at 0-2 ° C for 9 hours in order to crystallize the product. Then the crystals are filtered off, washed with 4-5 ml of cooled acetone and dried. Thus, 0.23 g of vincine hydroxyethyl ether (85.7%;; 239-243 ° C. RE G) + 27.6 ° (from 0.08 in methanol

Example 4. Apovincine acid ethyl ester.

1 g (0.0027 mol) of vincinic acid is stirred with 50 ml of anhydrous ethanol, 3 ml of concentrated sulfuric acid is added and the mixture is boiled for 8 hours under reflux. The course of the reaction is monitored by thin layer chromatography. After completion of the reaction, the reaction mixture is cooled to 2O-25 ° C and concentrated under reduced pressure to a volume of 6-8 ml. The concentrate is diluted with water to 150 ml and the pH is adjusted to 8-9 by adding 20% sodium hydroxide solution. From the solution containing the precipitate, the product is extracted with 6x50 ml of dichloromethane. The organic extracts are combined, dried over anhydrous potassium carbonate, filtered and evaporated under reduced pressure. The evaporation residue is dissolved in 5 ml of benzene and chromatographed on a column containing ten times the amount of alumina (111) with respect to the weight of the evaporation residue. The column was eluted with benzene and 10 ml fractions were collected each. Fractions 1–3 containing the product are combined and evaporated with reduced dissolution. In the residue, 0.63 g of apovincine acid ethyl ester is obtained, Sb1% of the theoretical. . DKI5 +56.40 Cs 0.7, in pyridine)

Claims (2)

Rf 0.77 adsorbent, silica gel, solvent: 8: 2: 1 mixture of lorofrma, ethyl acetate and methanol. JC spectrum: 3100-3000 cm (CH aromatic., 3000-2800 cm (VCHjC 1728 (, 1635 cm (), 1265 (VCOC), 1168), 817 (VCH). Example 5. Ethyl ester tartrate of apovincinic acid. K 0 , 63 g (0.0016 mol of ethyl ester of apovincine acid is added with tartaric acid ethyl ester to pH 4-5. The reaction mixture is kept for 8-10 hours during the crystallization of the product, then the crystals are filtered, washed with chilled ethyl ether and dried Thus, 0.45 g of apovincine acid ethyl ester tartrate (C51%) is obtained, mp 98-104 s. - rh +52.7 (with 1, in pyridine). RX adsorbent, silica gel, An 8: 2: 1 solvent mixture of chloroform, ethyl acetate, and methanol: 0.77 Example 6. Apovincine acid-ethyl ester-sodium hydrogen sulfate 0.23 g (0.006 mol) of apovincinic acid ethyl ester is dissolved in 5 ml of benzene. From 11.5 sodium hydrosulfate and 15-20 ml of benzene, a chromatographic column is prepared and filled with benzene solution of ethyl ester of apovincine acid. The salt thus formed is eluted with chloroform, and fractions of 10 ml each are collected. Fractions 1-7 containing the desired product are combined and evaporated under reduced pressure. The residue after evaporation is stirred with 6 ml of ether and held for 8 hours at 0-2 ° C in order to crystallize. Thus, 0.24 g of sodium hydrosulfate of ethyl ester of apovincine-acid (79% of the theoretical) are obtained, m.p. 123-127 ° C. f (adsorbent: silica gel, solvent: an 8: 2: 1 mixture of chloroform, ethyl acetate and methanol) 0.72. W 40.3 ° IR spectrum: 3000-2800 cm (V 2700-2300 cM -. (Vlc (OH)). 1740 cm C0 1230, 1075 cm (vJjO,) 848 cm (s-0) It was found That the new compounds of general formula 1 possess selective brain, vasodilatory actions in terms of their effectiveness surpass the majority of the compounds described. A pharmacological study of these compounds is carried out on narcotized with chlorazourethan (Ch1og1ose-Urethan) dogs. femoral artery, cerebral blood supply - on the internal carotid and vertebral arteries, blood resistance Vessel circulation is calculated from the blood pressure and from the corresponding blood supply values. The active substances during these studies are administered intravenously at doses of 1 mg / kg. Changes compared to the values measured before the active substances were injected The values obtained for six animals are listed in Table 1. For comparison, the table also contains the results of experimental studies obtained with the use of viicamine, which is currently successfully used in therapy but. Average values obtained with po; With the help of intravenous doses of 1 mg / kg of the active substance, you are “1% modified in%. The active substance A Vincinov acid-2 + 2 + 5 + 5 and - Vincine hydroxyethyl ester -8 +2 + 6 +41 acids -19 -17 + 19 + 1 Vincamin Indicators in separate columns of the table: A - blood pressure (mm Hg Art.); B - pulse rate; C — blood supply to the extremities (ml / min); D - cerebral blood supply (ml / min). . From the results shown in the table it can be seen that the effect of cerebral blood circulation has a particularly noticeable th-hydroxyethyl ether, which in its effectiveness is several times higher than that of vincamine. Stimulation of blood supply in the extremities is less noticeable, first of all the blood supply to the brain increases. However, the overall effect on the blood circulation is also more significant than that of the well-known vincamine. Thanks to its pharmacological properties, the compounds manufactured according to the invention can be used in various vascular diseases, in the treatment of atherosclerosis, as well as in the treatment of hypertension. Claim 1. Invention of vincinic acid derivatives of general formula LHH5, where I. is ethyl, i-hydroxyethyl; t is hydroxyl on the group and hydrogen, if D is -oxyethyl; I and R. together form a carbon-carbon bond, or their salts, or their quaternary salts, characterized in that the vincic acid is reacted with ethylene halohydrin or in the presence of water-withdrawing agents with ethyl alcohol and the resulting desired product is taken in free form, in the form of salts or quaternary salts. 2. A method according to claim 1, characterized in that sulfuric or acetic acid or acetic anhydride is used as a dehydrating agent. Sources of information taken into account in the examination 1. Weigand-Hilgetag. Experimental methods in organic chemistry. M., 1968, p. 343-348.