SK280172B6 - Salicyloylcarnitine and method of its preparation - Google Patents

Abstract

Disclosed is a betaine of 3-(2-acetoxybenzoyloxy)-4- -(trimethylamonio)butyric acid of formula (I) in a racemic or optically active form and the pharmaceutically acceptable salts thereof which exhibit, in respect to acetylsalicylic acid, high water solubility, lower toxicity and good gastric tolerability and can be obtained in 3 stages from carnitine hydrochloride and o-methoxybenzoyl chloride.

Description

Technical field

The present invention relates to 3- (2-hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine in racemic and optically active form, to pharmaceutically acceptable salts thereof, and to a process for its preparation. 3- (2-hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine is, as a salicylic acid ester with carnitine (salicyloylcamitin) a derivative of salicylic acid with very promising therapeutic properties.

BACKGROUND OF THE INVENTION

Salicylic acid in the form of its acetylderivative is widely used as an analgesic. Initially, this acetylderivative (also known as Aspirin® has been developed to reduce the disturbing side effects of the previously known salicylic acid. Nevertheless, this derivative has some limitations on its use. Low solubility may cause precipitation of the active substance in the stomach when administered orally with aqueous solutions, which is undesirable not only in people with sensitive or damaged gastric mucosa, as it can cause serious side effects in these persons. In general, however, the low solubility slows down the resorption and hence the initiation of the analgesic effect.In addition, acetylsalicylic acid can only be administered orally, but not parenterally, for example intravenously or intraperitoneally or topically. a rapid onset of action and / or a sensitive action on the gastrointestinal tract would often require parenteral administration.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a salicylic acid derivative which is well soluble in both the water and acidic regions, is readily absorbed, has as little toxicity as possible and can be administered both orally, parenterally or topically. In all forms of administration, this derivative should be rapidly analgesic.

The object of the present invention is to provide a 3- (2-hydroxybenzoyloxy) -4- (trimethylammonio-butyric acid betaine) betaine which has an asymmetric carbon atom and can therefore exist in two mirror optically active forms and as a racemic mixture. Favorable physicochemical properties, such as high water solubility and a suitable pH of the solution, are also achieved with the (S) -enantiomer and with the racemate. Known as acyl group transporter for fat metabolism, it is actively taken up by most of the body's organs using high-affinity transport systems, and is also received by cellular organelles (mitochondria, etc.) using an antiport transporter.

It is also believed that salicyloyl-L-carnitine also enters cells and organelles by these delivery systems, thereby accelerating the onset of action. Acyl-L-carnitines are further cleaved by cellular enzymes so that rapid release of the salicylate residue can be envisaged.

Experiments in rats have already shown extremely low acute toxicity of salicyloyl-L-carnitine. Doses of up to 1000 mg / kg body weight administered orally are tolerated without difficulty and no harmful side effects are observed with intravenous and intraperitoneal administration of therapeutic doses.

The first study compared the analgesic effect of salicyloyl-L-carnitine with aspirin following oral, intraperitoneal and intravenous administration to rats. When administered orally, salicyloyl-L-carnitine showed a delayed effect of 1.5 hours over acetylsalicylic acid, while intraperitoneal and intravenous administration showed a pronounced analgesic effect as early as 10 to 15 min.

Of course, the invention also includes the formation of salts of salicyloylcamitin with pharmaceutically acceptable acids and the use of the compounds in this form.

According to the invention, salicyloylcamitin is produced by first converting a carnitine hydrohalide, preferably hydrochloride, to an ester with 2-methoxybenzoyl halide (o-anisoyl halide), preferably with acid chloride, to the corresponding 3- (2-methoxybenzoyloxy) -4- (trimethylammonio) betaine hydrohalide ) butyric (o-anisoylkanitin hydrohalide).

Suitably a polar protic solvent which is inert against hydrogen chloride is used as the solvent. Low aliphatic carboxylic acids, such as acetic acid or formic acid, are preferred, and trichloroacetic acid is particularly preferred. The reaction temperature in this solvent is preferably 50 to 90 ° C, the reaction time is 1 to 4 hours.

Subsequent treatment with an excess of hydrogen bromide in glacial acetic acid converts the methoxy group to the hydroxy group. The reaction with hydrogen bromide is conveniently carried out at 20 to 80 ° C. Excess hydrogen bromide yields the title compound as the hydrobromide, which can be isolated in crystalline form. For use in pharmaceuticals, the hydrobromide is conveniently converted to free betaine by means of a base. For reasons of solubility, this is preferably carried out with a weakly basic anion exchange resin. Indeed, the use of the free base would also give rise to a salt having similar solubility to betaine and would be difficult to separate. A weakly basic anion exchanger bearing a primary, secondary or tertiary amino group as a functional group is further advantageous because it does not hydrolyze the ester group. product, nor does it bind the product by a weakly acidic phenolic function.

The process described is, of course, suitable for the preparation of both racemic and optically active salicyloylcarnitine according to the starting material.

It is also within the scope of the process of the invention to convert the betaine upon addition of a pharmaceutically acceptable acid to the corresponding salt.

The following examples illustrate an embodiment of the production method of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

(R) - (-) - 3- (Methoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine hydrochloride (o-anisoyl-L-carnitine hydrochloride)

61.8 g of L-carnitine hydrochloride are dissolved in 152.0 g of trichloroacetic acid at 80 ° C. Within 30 min. 80.0 g of 2-methoxybenzoyl chloride is added dropwise at 80 ° C. The reaction mixture was stirred at the same temperature for 90 minutes, cooled to 30 ° C and treated with 500 ml diethyl ether and 200 ml ethyl acetate with stirring. The mixture was stirred for 30 min. The mixture is heated to reflux, whereby the product crystallizes. The crude product is filtered and dried (yield of crude product:

SK 280172 Β6

112.6 g), then suspended in 200 ml of isopropanol at 80 ° C, filtered and washed twice with 50 ml of isopropanol on the filter.

Yield: 75.7 g (73.0%) of colorless crystals, mp: 186-190 ° C [α] _D ²⁰ = -28.8 ° C (c = 1, H ₂ O).

@ 1 H-NMR (DMSO-d6, 300 MHz) _.delta . = 7.02-7.75 (m, 4H),

5.67 - 5.75 (m, 1H);

3.78-4.02 (m, 2H), 3.84 (s, 3H),

3.22 (s, 9H);

2.80 - 2.90 (m, 2H);

Example 2

(R) - (-) - 3- (Hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine hydrobromide (salicyloyl-L-carnitine hydrobromide)

24.0 g of o-anisoyl-L-carnitine hydrochloride (prepared according to Example 1) are dissolved in 200 ml of a 30% solution of hydrogen bromide in glacial acetic acid and stirred for 6 hours. at 60 ° C. The reaction mixture is then evaporated in vacuo and the residue is suspended in 200 ml of diethyl ether and filtered. The crystalline crude product is recrystallized twice from 110 ml of warm isopropanol.

Yield: 14.0 g (50.2%) of colorless crystals Melting point: 173-175 ° C [α] _D ²⁰ = -27.2 ° C (c = 1, H ₂ O).

Example 3

(R) - (-) - 3- (Hydroxybenzoyloxy) -4- (trimethylammonio-butyric acid betaine) (salicyloyl-L-carnitine) betaine

13.0 g of salicyloyl-L-carnitine hydrobromide (prepared according to Example 2) are dissolved in 130 ml of water. The solution is filtered through a column packed with 58 g of weakly basic anion exchange resin (Amberlit® IRA-93) and concentrated in vacuo. Addition of 60 ml of acetone precipitates the product. The crystalline product is filtered off and dried under vacuum at 40 ° C.

Yield: 10.0 g (quantitative) of colorless crystals M.p .: 120-122 ° C.

[α] _D ²⁰ = -25.0 ° C (c = 1, H ₂ O)

Elemental analysis: calculated: C 59.5 H 6.9 N 4.9 BCl Cl found: C 59.8 H 6.8 A 5.0 Br <0.1

CCA 1

Rat gastric tolerance test (Ulcer index)

(R) - (-) - 3- (2-hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid (salicyloyl-L-carnitine = SC) betaine was tested in male rats compared to acetylsalicylic acid (ASA). This test is performed according to the method of Okabe et al., Japan. J. Pharmacol. 1974, 24, 363 et seq., Which induce gastric mucosal changes.

Test substances are administered to test rats p. about. in a 1% carboxymethyl cellulose suspension (1% CMC). Changes in the gastric mucosa were measured using the Ulcer Index of Chaumontet et al., Arzneimittelforschung 1978, 28 (II), workbook 11, 2119-2121.

Table 1

substance Ulcer index (U.I.) Number of rats Comp. 1% CMC 1 ml / 250 g 63.00 10 Comp. ASA 200 mg.kg- ¹ 300.00 20 invention SC 200 mg.kg ^-1 144.00 10 invention SC 500 mg.kg ^-1 200.00 10 invention SC 1000 ing.kg ^-1 200.00 10

CMC = carboxymethylcellulose ASA = acetylsalicylic acid SC = salicyloyl-L-carnitine cf. = comparison

PATENT CLAIMS

Claims (17)

A 3- (2-hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine of formula (I) and pharmaceutically acceptable salts thereof. 2. Betaine (R) - (-) - 3- (2-hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid of formula (II) CH ₃ and pharmaceutically acceptable salts thereof as compounds according to of claim 1. (S) - (+) - 3- (2-Hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine of formula (III) and pharmaceutically acceptable salts thereof as compounds according to claim 1. 4. 3- (2-Hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and salts thereof for use as a therapeutically active agent. (R) - (-) - 3- (2-Hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and salts thereof for use as a therapeutically active substance. (S) - (+) - 3- (2-Hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and salts thereof for use as a therapeutically active agent. 7. 3- (2-Hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and its salts for use as gastric mucosal analgesic. (R) - (-) - 3- (2-Hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and its salts for use as gastric mucosal analgesic. SK 280172 Β6 (S) - (+) - 3- (2-Hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and its salts for use as gastric mucosal analgesic. 3- (2-Methoxybenzoyloxy) -4- (trimethylammoniumbutyric acid) betaine and its salts as intermediates for the production of the compounds according to claim 1. (R) - (-) - 3- (2-methoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and its salts as intermediates for the production of the compounds according to claim 1. (S) - (+) - 3- (2-methoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and its salts as intermediates for the production of the compounds according to claim 1. 13. A process for the preparation of 3- (2-hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine, characterized in that in the first step the 3-hydroxy-4- (trimethylammonio) butyric acid betaine hydrohalide is esterified with 2-methoxybenzoyl halide to form 3- (2-methoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine halide which is demethylated with hydrogen bromide in acetic acid to give 3- (2-hydroxybenzoyloxy) -4- (trimethylammonio) butyric acid hydrobromide and deprotonates with base to betaine. Process according to claim 13, characterized in that 3-hydroxy-4- (trimethylammonio) butyric acid betaine hydrohalide is hydrochloride. Process according to claim 13 or 14, characterized in that acid chloride is used as the 2-methoxybenzoyl halide. Method according to one of claims 13 to 16 15, characterized in that a weakly basic anion exchanger is used as the base. Method according to one of claims 13 to 17 16, characterized in that the starting material used is the (R) -2-hydroxy-4- (trimethylammonio) butyric acid betaine hydrohalide, L-carnitine hydrohalide.