HU188095B - Process for preparing new esters of pyridine-carboxylic acid with high molecular weight - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel pyridine carboxylic acid esters of formula (I): wherein X and X1 are independently hydrogen, C1-4 alkanoyl or alkyl of the formula II, with the proviso that at least one of them is (II). , R 1 is hydrogen or C 1-4 alkyl, and n is 16-1000, and pharmaceutically acceptable acid addition salts thereof. These compounds can be prepared from esterification of the corresponding polyhydroxy compounds by pyridine carboxylic acids or a reactive derivative thereof. The compounds of formula (I) have valuable biological activity and may enhance the action of other biologically active compounds, and are therefore useful in cosmetic and pharmaceutical compositions. XO - (- CH2CHO -) - X1R, (I) 0 IIc (II) -1-

Description

This invention relates to novel high molecular weight pyridinecarboxylic acid esters. The pyridinecarboxylic acid esters and their acid addition salts obtainable by the process of the present invention show valuable biological activity.

U.S. Pat. Nos. 3,950,324, 4,017,502, and 4,111,075 disclose certain medicinal nicotinic acid derivatives. However, these compounds, which are different in structure from those obtainable by the process of the invention, can only be obtained by complex stepwise synthesis.

I have discovered that the new pyridinecarboxylic acid esters of the formula I are present in the formula

X and X 1 are independently hydrogen, alkyl having 1 to 4 carbon atoms in the alkyl moiety or II, with the proviso that at least one of them is represented by formula II, R 1 is hydrogen or C 1 to C 4 and pharmaceutically acceptable acid addition salts thereof, which are biologically active or biologically active, in particular in cosmetic and pharmaceutical compositions such as rheumatic ointment, anti-inflammatory and antihypertensive agents, and in dentifrice.

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts may be prepared according to the invention by reacting a polyhydroxy compound of formula (III) wherein R and n are as defined in formula (I) and R ₂ and R ₃ are as defined above. independently hydrogen or C 1-6 alkanoyl, provided that when X or X _{3 is} hydrogen, R ₃ or R ₂ is hydrogen - with at least 1 mole of pyridine carboxylic acid (IV) or with a reactive derivative and optionally a? The resulting free base of formula (I) is converted into the acid addition salt by treatment with a pharmaceutically acceptable acid.

In the compounds of formula (I), X is preferably hydrogen and X ₃ is preferably of formula (II), particularly preferably nicotinoyl. In the compounds of formula (I) and (III), R 1 is preferably hydrogen and n is preferably an integer from 25 to 500. When R1 is alkyl in these formulas, for example, methyl or ethyl may be mentioned. Preferably, X or X 1 in compounds of formula I and R ₂ or R _{3 in} formula III are preferably formyl, acetyl or propionyl.

Compounds of formula (III) are commercially available large-scale products. The pyridinecarboxylic acids of formula (IV), or their reactive derivatives, are well known in the art and are readily available.

In carrying out the process of the invention, the corresponding acid halides (preferably acid chlorides), their acid addition salts, acid anhydrides, mixed acid anhydrides, and reactive esters optionally substituted with 1 to 4 carbon atoms as the esterifying group may be used as reactive derivatives of the pyridine carbon 2 acids. containing an alkyl group. Of the latter, the appropriate ethyl and 2-hydroxyethyl esters are particularly noteworthy.

The process requires the use of at least 1 mole of pyridine carboxylic acid (IV) or a reactive derivative thereof per mole of compound (III). If the latter reactant is present in an amount of at least 2 moles, a final product of formula (I) may be formed wherein X and X1 are a group of formula (II). The reaction may be carried out in a solvent which is chemically inert to the reaction, such as an aromatic hydrocarbon such as benzene, but the solvent is optional. Because the polyhydroxy compound (III) itself can serve as a solvent, it is often desirable to use the latter compound in excess because the reaction to the compound (I) is carried out in such a good yield and selectivity that it is not necessary to isolate the product formed further purification, but the product solution obtained can be used directly.

In carrying out the process of the invention, the temperature is higher than the melting point of the polyhydroxy compound (III), preferably 160-190 ° C. The reaction time depends on the nature of the reactants and the reaction temperature, but is usually complete within 24 hours.

The acid addition salts of the pyridinecarboxylic acid esters of formula (I) may be prepared by physiologically acceptable organic and inorganic acids in known manner.

As mentioned above, the compounds of formula I have valuable biological activity per se and, in combination with other biologically active compounds, also exhibit potentiating properties. Freely soluble in water. The compounds of the formula I are furthermore unexpected in their properties, and are capable of containing about 10% of their actual weight by weight in water and / or alcoholic liquids, for example solutions in such solvents (e.g., dissolved surfactant or plant extract). ) without affecting their solid state or decreasing their melting point. At the same time, biologically active compounds which are poorly soluble in water are also shown to have a dissolution mediating effect. Thus, the compounds of formula (I) are very widely used in cosmetic and pharmaceutical formulations.

The following embodiments serve to illustrate the process of the present invention.

Example 1! Picolinic acid monoester of polyethylene glycol of molecular weight 500

188,095

150 g (0.1 mol) of a compound of formula III wherein R 1, R ₂ and R _{3 are} hydrogen and n is heated to 34,100 ° C and 11.4 g (0.05 mol) are added. picolinic anhydride, and while stirring, raise the temperature to 180 ° C and stir for ^λ / ζ hours. This gives 99% yield of a compound of formula I wherein R 1 and X are hydrogen and X 1 is picolinoyl. It is not necessary to clean or isolate the product. Its color is beige white, amorphous and has a freezing point of 40-44 'C. In its infrared spectrum, significant extinction is observed in the 1730-1740 cm ^-1 wavelength range. Average molecule. laser weight 1600. Freely soluble in water.

Example 2-

Isonicotinic acid monoester of polyethylene glycol of molecular weight 6000

The procedure described in Example 1 was followed, except that 60 g (0.01 mol) of a compound of formula III wherein ²⁵ R 1, R ₂ and R _{3 are} hydrogen and n is 136,

Reaction was with 1.78 g (0.01 mol) of isonicotinic acid hydrochloride. The acid number is reduced to near zero in 98% yield, without further isolation or purification, to give ³⁰ , wherein X and R1 are hydrogen and X is isonicotinoyl. It is an off-white color, freezing point 53-58 ° C, freely soluble in water and in ethanol. Infravö- ROS spectra of the 1730-1740 ^cm-1 shows a distinct extinction wave length in the range ^35, the 1710 cm ^-1 absorbance to the wavelength can not be detected. The average molecular weight of the product is 6100.

Example 3

Dinicotinic acid ester of polyethylene glycol of molecular weight 6000 and the hydrochloride salt of the latter

In the same manner as in Example 1, except that 60 g (0.01 mol) of a compound of the formula III in which R 1, R ₂ and R _{3 are} hydrogen and n is 136,

Nicotinic acid hydrochloride (3.56 g, 0.02 mol) was reacted. Reduction of the acid number to near zero after 50% yields, without further purification or isolation, the compound of formula I wherein R _{2 is} hydrogen and X and Xi are nicotinoyl.

The product is an off-white color with a melting point of 55-52 ° C, soluble in water and in ethanol. It has a marked extinction in its infrared spectrum at 1720-1740 cm '. The average molecular weight of the product is 6200.

If the reaction is carried out as described above, but the reaction is continued until the acid number of the mixture is reduced to 18 mg / g KOH, the corresponding hydrochloride salt is obtained. The resulting salt is an off-white color with a melting point of 53-59 ° C, freely soluble in water and in ethanol. 65

Example 4

Dinicotinic acid ester of polyethylene glycol of molecular weight 000

In the same manner as in Example 1, except that 350 g (0.01 mole) of a polyhydroxy compound of the formula III in which R 1, R ₂ and R _{3 are} hydrogen and n = 795 are heated until while melting, and at this temperature, 3.56 g (0.02 mole) of nicotinic acid chloride hydrochloride are added. When the acid chloride is homogeneously distributed in the melt, the temperature is raised to 180 ° C and maintained until the acid number drops to near zero. The compound of formula (I) is obtained in 99% yield, wherein X and X _are nicotinoyl and R 1 is hydrogen. Melting point 57-61 ° C, soluble in water and ethanol, white in color. In its infrared spectrum, a distinct extinction is observed in the wavelength range 1730-1740 cm ^-1 .

Example 5

50% solution of the picoline monoester of polyethylene glycol molecular weight 000 in the same polyethylene glycol

The procedure described in Example 1 was followed, except that 350 g (0.01 mol) of a polyhydroxy compound of the formula III in which R 1, R ₂ and R _{3 are} hydrogen and n is 795, 180 ° C. is reacted with 0.755 g (0.005 mol) of ethyl picolinic acid ester. During the reaction, ethanol is removed from the system. In a 98% yield, a 50% solid solution of the product of formula (I) in the parent polyhydroxy compound of formula (III) wherein X is a picolinoyl group, while X and R 1 is hydrogen and n is 795. % solid solution is white with a freezing point of 55-60 ° C.

Example 6

The acetate salt of a mixed acetyl and nicotinoyl ester of polyethylene glycol of molecular weight 6000 g (0.01 mole) of a compound of formula III wherein R _1; R ₂ and R _{3 are} hydrogen and heated above the melting point of n = 136 and then 1.78 g (0.01 mol) of nicotinic acid hydrochloride are added with stirring at a temperature in the region of 60 ° C. Wait until a homogeneous mixture is formed and then raise the temperature to [180 ° C] and maintain this temperature until the acid number drops to zero. It was then cooled to 60 ° C and acetic anhydride (1.02 g, 0.01 mol) was added. Upon completion of the reaction, the acetate salt of a compound of formula (I) is obtained wherein X is acetyl and X is nicotinoyl and R 1 is hydrogen. It is an off-white color, freezing point 53-58 ° C, freely soluble in water and in ethanol. Molecular weight 6200.

The compounds of formula (I) obtainable by the process of the invention are the preferred practical compounds

The use of 188,095 is illustrated by the soap-free skin cleanser described in the following embodiment, which is simultaneously anti-inflammatory, deodorant and biological protective.

Example 7

100 g of the compound of formula I prepared according to Example 4 are melted, then 2 g of titanium dioxide are added, followed by 10 g of sodium salt of dodecyl diglycol cholesterol sulfate and 4 g of tetradecyl diglycol ether sulfate sodium salt in 6 g of water. paste. After cooling, the resulting mixture is compressed into a mold.

Claims (6)

A process for the preparation of new pyridine carboxylic acid esters of the formula I in the formula X and X 1 are each independently hydrogen, alkyl having 1 to 4 carbon atoms in the alkyl moiety, or a group of formula II, provided that at least one of them is a group of formula II, R 1 is hydrogen; is hydrogen or C 1-4 alkyl and n is from 16 to 1000 - and pharmaceutically acceptable acid addition salts thereof, characterized in that a polyhydroxy compound of formula (III) wherein R and n are as defined in formula (I) and R ₂ and R ₃ are each independently hydrogen or C 1 -C 6 alkanoyl, provided that when X or X in formula I is R ₃ or R ₂ is hydrogen - is reacted with at least 1 mole of pyridine carboxylic acid of formula IV or a reactive derivative thereof and optionally converting the resulting free base of formula I into a pharmaceutically acceptable acid addition salt. 2. The method of claim 1 embodiment _{the 5} modes, characterized in that the compounds of formula (IV), reactive derivative of an acid halide, an acid addition salts thereof, acid anhydrides, mixed anhydrides and optionally substituted by hydroxy, C 1-4 tar _one talmazó alkyl észterezőcsoportként containing reactive esters. 3. A process according to claim 1 or 2 for the preparation of compounds of formula I wherein X and X1 are each represented by formula (II) wherein R and n are as defined in claim 1. ^{A process according to} claim ⁰ wherein at least 2 moles of the compound of formula (IV) or a reactive derivative thereof are used. _2Q 4. A process according to any one of the preceding claims wherein the polyhydroxy compound of formula (III) n = 25-500, wherein R 1 and R ₂ are as defined in claim 1, is used as starting material. ²⁰ A process for the preparation of a cosmetic composition, which process comprises the preparation of a compound of formula (I) according to claim 1 wherein X _1; X, R and n are as defined in claim 1 - ³⁰ or a pharmaceutically acceptable acid addition salt thereof in admixture with excipients conventionally used in the preparation of cosmetic compositions and / or excipients, and formed into cosmetic compositions. 6. A process for the preparation of a pharmaceutical composition comprising the compound of formula (I), wherein X 1, X, R _t and n are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof. mixed with excipients and / or excipients commonly used in the pharmaceutical field to form a pharmaceutical composition.