CS225009B1 - Diacylglycerol esters of all-trans-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid; mixtures thereof and processes for their preparation - Google Patents

Abstract

The invention relates to new substances - diacylglycerol esters of all-trans-9-(4-methoxy- -2,3,6-trimethylphenyl) -3,7-ditaethyl-2,4,6,8- -nonenetetraenoic acid, their mixtures and the method of their preparation. All-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid in the form of ethyl ester is used in the oral treatment of a number of skin diseases, such as pustular and erythrodermic psoriasis and various keratoses. Diacylglycerol esters of this acid, due to their affinity with natural fats, guarantee perfect resorption of the active ingredient by a living organism. They are prepared by the action of sodium diacylglycerols or their mixtures on the imidezolid of the corresponding acid.

Description

The present invention relates to diacylglyerole esters of all-tran8-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-nonetetreeic acid, and mixtures thereof, and a process for their preparation.

Ell-trans-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester is an active ingredient used in the oral therapy of a number of skin diseases accompanied by excessive keratinization, such as erythrodermic and pustular psoriasis, and various dys-, para- and hyperkeratoses (Experientia, 34, 1 105 1978). It has been shown that agents of this type can be used to prevent the transformation of normal cells into cancer cells (Center Chemotherapy and Pharmacology 3, 207, 1979). The low resorbability of said ethyl ester leads to the search for new derivatives to overcome this disadvantage.

Such substances are diaoylglycerol esters of all-trens-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-nonatetreenic acid of formula X

CH

CH, CH,

COOA (I), <

where A is bu3

-CH,

I ₂

CHORUS'

CHgOR ³ or

CH ² OR ^d and s

-CH

CHgOR ³ wherein R ² , R ³ is CH ₃ (CH ₂ ), ₄ CO-,

CH ₃ (CH ₂ ), ₆ CO- or CH ₃ (CH ₂ ) ₇ CH = CH (CH ₂ ) ₇ co-, which are the subject of the invention. These compounds are so close to natural fats that their resorption, and thus perfect resorption of the active part, is guaranteed.

The present invention further provides a process for the preparation of these compounds, i.e., all-trens-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-none-tetranic diacylglyerole esters. of an acid of formula I, characterized in that sodium di-O-acylglycerate of the formula II or III is reacted

CH, ON and CH, OR ²

I I

CROP ² (II) CHONa (III),

I 3 I 3

CHgOR · ³ CHgOR · ³ where R ² , R ³ = CH ₃ (CH ₂ ) _for CO- (palmitoyl)

CH ₃ (CH ₂ ), gCO- (steeroyl)

CH ₃ (CH ₂ ) ₇ CH = CH (CH ₂ ) ₇ CO- (oleoyl) with imidazolidone all-trena-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2, 4,6-nonetetraenoic acid of formula IV

in an inert solvent at a temperature of 60 to 80 ° C, preferably in benzene.

The process of the present invention is a novel approach to the preparation of triecyl glycerols which are prepared according to prior art (Advens in Lipid Research 14, 231, 1976) for a 3-7 day reaction of diacylglyeeroles and fatty acid chloride in pyridine. The process of the invention provides practically theoretical yields of compounds of formula I in the reaction, lasting about 30 min. The preparation of the compounds of formula (I) is carried out by treating with 1.1 to 1.3 equivalents of the compounds of formula (II) or (III) or 1 equivalent of formula (IV) in an inert solvent. Benzene is preferably used as the inert solvent. The reaction is carried out at a temperature of 60 to 80 ° C, preferably from the reflux temperature of benzene (80 ° C). From this temperature, a practically quantitative yield of the compound of formula I is obtained in 20 min. Isolation of the products of formula (I) is accomplished by first removing sodium ions and imidazole by shaking to 0.1-0.2 mol / L phosphoric acid, then evaporating the benzene solution and purifying the residue by chromatography on a silica gel column in chloroform- hexane (4: 1) wherein the compounds of Formula I are eluted in the first yellow colored eluate.

Both the pure 1,2-di-O-acylglycerates (formula III), or 1,3-di-O-ecylglycerates (formula IV), or the sodium salts of their mixtures, obtained by partial hydrolysis of the natural fat. In all cases, the reaction of the invention results in triacylglycerols, analogous to natural fats, which are in fact a mixture of triacylglycerols. Both the chemically pure triecylglycerol derivatives of formula I and mixtures thereof meet the requirement of physiological resorbability, serving as a chemical vehicle for the introduction of active all-trans-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2 Of 4,6,8-nonatetreenic acid to a living organism. Since the properties of the starting diacylglyeeroles are practically identical and because the properties of the final triecylglycerols are also identical, the preparation procedure is identical for all types R and R. The preparation process is illustrated by the following examples.

Example 1

To a solution of 2.63 g of imidezolide IV in 30 ml of benzene is added a solution of 5.3 g of 1,2-di-O-palmitoyl glycerate in 50 ml of benzene and the mixture is refluxed for 20 min. The mixture was cooled to room temperature, 100 ml of 0.2 mol / L phosphoric acid and 20 ml of ethanol were added and stirred for 20 minutes. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in 30 ml of 4: 1 chloroformwhexane and loaded onto a silica gel column (6.6 x 30 cm) mixed in the same solvent mixture. The column is eluted with the same mixture. The yellow colored eluent, eluting with the third liter of the mixture, was evaporated. 6 g (97%) of 1,2-di-O-palmitoyl-3-O (all-trans-9 ...) glycerol are obtained, m.p. 49-51 ° C.

R f (Silufol 11, 254 ' ^chloro: fmr) = 0.88

Example 2

To a solution of 2.63 g ^- imidezolidu formula IV in 30 ml of benzene was added a solution of 5.5 g of 1,3-di-O-stearoyl sodium glycerate in 50 ml of benzene. In the same manner as in Example 5, 5.9 g (95%) of 1,3-di-O-stearoyl-2-O- (all-trans-9 ...) glffcerol of m.p.

Hp (Silufol UV ₂₅₄ , chloroform) = 0.90.

Example 3

To a solution of 2.63 imidazolidate of formula IV in 30 ml of benzene is added a solution of 5.5 g of a mixture of sodium salts of 1,2-di-O-oleoylglycerol and 1,3-di-O-oleoylglycerol. 6 g of an oily mixture of 1,2-dl-O-oleoyl-3- (ell-trans-9 -...) glycerol β 1,3-di-O-oleoyl-3- (all-trans-9 ...) -glyeerole of R 1, (Silufol? 254 'chloroform) = 0.88.

Claims (4)

). Disoylglycerol esters of all-trans-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8-nonatetraenoic acid of the formula I ch ₃ . CH ₃ o wherein A is-CH₂ bu5 CROP ^{2 -} CH ¹ 3 i 3 CH ₂ OR ^j ch ₂ or ^j Where R ² , R ³ is CH ₃ (CH ₂ ), ₄ COCH ₃ (CH ₂ ) ₁₆ CO- or ch ₃ (ch ₂ ) ₇ ch = ch (CH ₂ ) _? C0-. 2. Mixtures of dlacylglycerol esters according to run 1. COOA or CH-, ΟϊΓ (I), 3. A process for the preparation of diacylglycerol esters and mixtures thereof according to claim 1, characterized in that the sodium 1,2-di-O-acylglycerate of the chemical formula II or the sodium 1,3-di-O-acylglycerate of the chemical formula III or its mixtures CH, ON and CH.OR ² li CROP ^{2 (II)} CHONA (III) 3 CH ₂ OR ^j CH ₂ OR ^j Wherein R, R have the same meaning as above, with imldazolidone all-trens-9- (4-methoxy-2,3,6-trimethylphenyl) -3,7-dimethyl-2,4,6,8- nonetetraenoic acid of the formula IV (IV) in an inert solvent at a temperature of 60 to 80 ° C. 4. The process of claim 3 wherein the inert solvent is benzene.