SU1068035A3 - Process for preparing polysubstituted esters of -alkylaminobenzoic acid - Google Patents

Abstract

A METHOD FOR OBTAINING POLYMIDATED ETHERS 4-ALKYLAMINO-BENZOIC ACID of the general formula O X Y Kjp-NH-C-0-CH-C-CH-K5 Rj 2 where R is unbranched Cf, H2,., Where, R, R2 and Kj are chosen groups, 1 cent of hydrogen or -oxyalkyl, X and Y, identical or different, selected from the group consisting of hydrogen, hydroxyl, in addition to the compound R NHArCOOCHjCHjCKy, characterized in that they react the alkylaminobenzoic acid of the general formula soon with POLI substituted alkyl6 alcohol of the general formula X 9 HO — CH — C — CH — RI RI 1 kg sl in the presence of p-toluenesulfonic acid, or hydride n three or boron fluoride etherate, preferably in an organic solvent at 60 120 ° C.

Description

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The invention relates to a process for the preparation of new derivatives of polysameded 4-alkylaminobenzoic acid esters of the general formula (I) KiplJHc-0-cn-cc-cc, R i ft where R is unbranched alkyl where n is 8-19; R, Rg are selected from the group consisting of hydrogen or hydroxyalkyl X and Y are the same or different - selected from the group consisting of hydrogen, hydroxyl, except for the compound P MI / gCOOCH2CK CH3, which have lipid-lowering activity and serum level of lipids. . A known method for producing meta-derivatives of benzric acid of the general formula (II) GOOR. CH-CH-1T where R is hydrogen, OXI-, lower a kil - and alkyloxy; hydrogen, lower alkyl; aralkyl, lower alkyl, ny alkyl alkylaryl; hydrogen, lower, alkyl, aralkyl, lower alkoxy etc. lower alkyl, aralkyl, ny alkyl alkyl, aryl, etc. with g- together with the nitrogen atom are five- or six-membered saturated heterocycle, etc. or their salts, consisting in the interaction of the corresponding acid or its derivative with an alcohol of general formula R, OH, the process is carried out in the presence of a strong acid, in particular aryl or alkylsulfonic acid, at a temperature from 40 ° C to the boiling point of the reaction mixture 1. The goal the invention is the preparation of novel compounds with hypolipidemic activity. The goal is achieved with the process, which consists in the interaction of polysubstituted alkyl-alcohol alcohols of general formula (III) X 9 NOGCH-C-SK-Kz Ri Co with 4-acyl amino benzoic acids of general formula (IV) where R, H, R, R have the indicated value. The process is carried out at a temperature of 60-120 ° C, preferably in an organic solvent in the presence of p-toluenesulfonic acid, or sodium hydride, or boron fluoride etherate. Example. 2,3-Dioxyprop4- (n-hexadecylamino) benzoate. A mixture consisting of 722 ml of 4- (n-hexadecylamino) benzoic acid, 736 ml of glycerin and 412 ml of p-toluenesulfonic acid, is heated for 4 hours at 120 ° C, allowed to cool, and then it is treated with ether and 2 % aqueous solution of sodium carbonate. As a result of filtration, a white solid is obtained, recrystallized from chloroform, which gives 2,3-dioxypropyl-4- (-hexadecylamine) benzoate, etc. 125 ° C. Example 2 2,3-Dioxypropyl 4- (n-hexadecylamino) benzoate. A solution consisting of 11.8 4- (nhexadecylamino) benzoic acid, 1.00 g of glycerin and 5.35 ml of fluoride boron etherate in 200 ml of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml etherate fluoride boron, and refluxing continued for another 120 hours. Dilution with water and methylene chloride followed by filtration gives 2,3-dioxypropyl-4- (n-hexadecylamino) benzoate as a white solid. The yield of the target product 50%, so pl, 112-113 ° C. Froze 2-hydroxypropyl-4- (nhexadecylamino) benzoate. A solutionX consisting of 7.2 g of 4- (n-hexadecylamino) benzoic acid, 15.2 g of 1,2-dioxypropane and 3.9 ml of boron fluoride etherate is stirred under nitrogen at 115 ° C for 19 hours. Grow; The ora is cooled, diluted with methylene chloride and placed in a refrigerator (freezer) overnight. The solid is collected, washed with hexane and dried in an oven, and a white solid is obtained. It is recrystallized from hexane and chromatographed on alumina using chloroform. This method gives 2-hydroxypropyl-4- (n-hexadecylamino) benzoate in the form of a white solid with mp 91-93 ° C. The same product is obtained. In the case when instead of boron fluoride etherate, 5.16 g of para-toluene sulfonic acid is used as a catalyst. EXAMPLE 4 (2,2-dioxymethyl-3-scsi) propyl-4 - (n-hexadecylamino) benzoate. A mixture consisting of 3.62 g of 4- (and hexyldecylamino) benzoic acid, 5.44 pentaerythritol, 7.60 g of para-toluenesulfonic acid and 100 ml of toluene is stirred under reflux for 3 days, the water that forms during the reaction, it is collected in a Dean-Stark trap. The mixture is extracted with aqueous sodium carbonate and the organic layer is separated, dried on anhydrous magnesium sulphate and evaporated. Crystallization from chloroform gives (2,. 2-dioxymethyl-3-hydroxy) propyl-4- (n-hexadecylamino) benzoate with a yield of 55%, so pl. 247-250 ° C. EXAMPLE 5 (2, 3-Dioxy-1-oxy methyl / propyl-4- (i-hexadecylamino) benzoate. Mixture consisting of 3.62 g of 4- (nhexadecylamino) benzoic acid, 4.88 g of meso-erythritol, 7.60 g of para-toluenesulfonic acid and .100 ml of toluene, stirred under reflux for a day and the water is collected in a DinaStark trap. The mixture is treated with an aqueous solution of sodium carbonate and dimethoxyethane. are dried, dried over anhydrous magnesium sulphate and evaporated. Crystallization from chloroform gives (2, 3-dioxy-1-hydroxymethyl) ex opil-4- (n-hexadecylamino) benzoate in the form of a white solid with mp 123-125 ° C. Example 6. 2, 3.4, 5, 6-Pen taoxyhexyl-4- (n- hexadecylamino) benzoate. By the method described above, 3.62 g of 4- (n-hexadecylamino) benzoic acid, 1.82 g of mannitol and 2.06 g of para-toluene sulfonic acid are reacted, resulting in a mixture of mono- and bis-acylated products. The pure 2,3,4,5,6-pentaoxyhexyl-4- (n-hexadecylates no) benzoate is separated from the mixture by adsorption chromatography using silica gel as the adsorbent. The yield of the target product is 17%, so pl. 121-123 C. Example7. 2, 3-Dioxypropyl-4- (n-nonadecylamino) benzoate. A solution consisting of 8.05 g of 4- (n-nonadecylamino) benzoic acid in 25 ml of hexamethylphosphoramide is treated with sodium hydride and then 1-llor-2, 3-propanediol. Get 2, 3-dioxypropyl-4- (n-nonadecylamine benzoate in the form of a solid white color. The yield of the target product is 51%, mp. 105-106 ° C. Example 8. 2,3-Dioxypropyl4- (n- Octylamine) benzoate. A solution consisting of 4- (n-octylamino) benzoic acid (4, .97 g) in 25 ml of hexamethylphosphoramide is treated with sodium hydride and then 1-chloro-2,3-propanediol. White crystals are obtained 2 , 3-dioxypropyl-4- (n-octylamino) benzoate. Example 9. 2,3-Dioxypropyl 4- (n-tridecylamino) benzoate. A solution consisting of 6.36 g of 4- (n-tridecylamino) benzoic acid in 25 ml hexamethylphosphorus Mida, treated with sodium hydride and 1-chloro-2,3-propanediol. 2, 3-dioxypropyl-4- (n-tridecylamino) benzoate is obtained in the form of a white solid with a yield of 29%, mp 106-107 ° C. These compounds have a hypolipidemic activity and the ability to lower serum lipid levels. These lipid-lowering properties are useful in the treatment of atherosclerosis. Atherosclerosis is a type of arteriosclerosis in which cholesterol and lipoid materials precipitate in the form of plaque in the intima of large and medium arteries. Arteriosclerosis is associated with degeneration of the arterial walls as a result of an action that is not yet completely understood. There is a statistical correlation between hypercholesterinemia and the incidence of cardiovascular diseases, in particular ischemic heart disease. Previously, the level of cholesterol in the blood was reduced by oral administration of various substances, which are usually referred to as hypocholesteremic drugs, enhancing the action of other drugs. Such substances are lecithin, cottonseed oil and corn oil. The proposed compounds exhibit a stronger hypocholesteremic effect than the above-mentioned reinforcing drugs and synthetic drugs. In addition, these compounds have the ability to reliably and effectively stop the development of atheromatous diseases in the aorta of warm-blooded animals, which provides an important additional tool in the fight against atherosclerosis. These compounds are hypolipidemic agents. OHIs have lipid-lowering activity, as determined by the following animal experiments. The studied compounds are administered orally along with food to groups of 4 male rats, species CFE. A control group of 8 rats was fed a clean stern; the test groups received semi-finished feed with the addition of prescriptive e and x compounds. After 6 days or 4 weeks, the animals were sacrificed and the serum sterol concentrations in milligrams per 100 were determined by the saponification and extraction of R. Trinder and the colorimetric determination of Zlatkis, or by the extraction method X. X. Leffler and colorimetric determination of Zlatkis by a general method, respectively modified for use with an automatic mechanical analyzer. Evaluation of serum triglycerides was performed according to the automated method of Kessler and Lederer.

When conducting these tests, a compound is considered to have hypolipidemic activity if it lowers the serum sterol concentration below the concentration of the control group and / or lowers the triglyceride concentration lower than that of the control group, the table shows some of the proposed compounds and the extent to which they decrease the serum concentration. sterols and triglycerides after 6-day and 4-week periods of dosing.

2, 3-Dioxypropi-4- (n-hexadecylano) benzoate

2,3-Epoxypropyl-4- (i-hexadecylamino) benzoate

2,3-Dioxypropyl-4- (n-hexadecylamino) bezoate hydrochloride

2-Acetoxy-3-hydroxypropyl-4- (n-hexadecylamino) benzoate

2,3- (Isopropylidenedioxy) -pro LIL-4- (n-hexade1-amino) benzoate

57 62 45 24 19

57 45 23

31 28 23

47 40 26

68

52

29

32

2-Phenyl-1,3-dioxolan-4-ylmethyl-4- (n-hexadecylamino) benzoate

2-hydroxypropyl-4- (N.-hex decylamino) benzoate

0.1 0.03 0.1 0, 03 0.01 Similar tests were carried out in mice. The methods of lipid analysis are the same as in the study of rats using 2,3-diox-4- (n-hexadecadecylamino) benzoate at 1 week trial the following: Amount of compound 0.03 0, in diet Reduced sterol in serum,% Reduced triglycerides in serum,%

Table continuation

50

53.

33

26

40

62 19

42 26 23

28 The proposed compounds show the ability to stop the development of atheromatous diseases when used in rabbits as experimental animals. Atheromatous diseases are induced by mexaHH4eckoro light surface damage, rabbit aorta. After the introduction of the feed with the addition of cholesterol, followed by the introduction of the feed containing these compounds, histological and. biochemical analyzes of aortic tissue and measurement of the degree and severity of diseases. The use of 2,3-dioxypropyl-4- {| hexadecylamino) benzoate gives a positive effect. The amount of sterol deposited in the aorta of treated rabbits is reduced by 40% in the thoracic segment and by 36% of the abdominal segment of the aorta compared with control rabbits. The degree of atheromatous lesion, measured by the percentage of aorta with such lesions, is reduced by 95% in the thoracic segment and by 75% in the abdominal segment compared to control rabbits.

The ability to lower the level of serum lipids and reduce the deposition of lipids on the walls of the aorta increases in direct proportion to the extent of absorption from the intestine. The concentration of radiolabelled drug isotopes is 4 times higher in the bloodstream at 2, 3 D-hydroxy-propyl 4- (n-hexadecylamino) benzoate than with the corresponding acid.

The proposed compounds give a comparable effect on serum lipids at doses in rats of only 0.1-0.01%. Consequently, the dose limits should be approximately 50 mg - 1 g / day - in a single or in divided doses per 50 kg. body weight. The effective. The limits of the compounds proposed should be about 0.5 to 40 mg / kg / day.

Lipid-lowering agents may be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or in hard or soft gelatin capsules, or in tablets, or they may be taken directly with dietary foods. For oral therapeutic administration, the proposed active compounds are mixed with excipients and used in the form of tablets, capsules / elixirs, suspensions, syrups, wafers, chewing gum. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compositions and preparations may vary from 5 to 75% or more by weight per unit.

Claims (1)

METHOD FOR PRODUCING POLYMESTERED ETHERS 4 — ALKYLAMINO — BENZOIC ACID of the general formula 0 XU / W \ ^{11 1 1} R 0 -CI- s- CH-R s Rf R ₂ where Id is unbranched C _n H _{2n +} ^, where n = 8-19, R ^, R ₂ and R ₃ are selected from the group consisting of hydrogen or C ^ -Cy-oxyalkyl, X and Y, the same or different, are selected from the group consisting of hydrogen, hydroxyl, except for the compound ^ NWArCOOCHjCHjCHy, characterized in that the alkylamino-benzoic acid of the general formula is reacted with a polysubstituted alkyl alcohol alcohol of the general formula X y H0-CH-C-CH-R, II Ri in the presence of η-toluenesulfonic acid, or sodium hydride, or boron fluoride etherate, preferably in an organic solvent at 60 to 120 ° C. SB with SL '1068035