CZ284755B6 - Betaine of 3-)2-acetoxybenzoyloxy(-4-)trimethylammonio)butyric acid and process for preparing thereof - Google Patents

Abstract

3-(2-Acetoxybenzoyloxy) -4-(trimethylammonio) -butyric acid betaine of formula (I) and its R-(-) and (S)-(+) enantiomers and pharmaceutically acceptable salts are new.

Description

3- (2-Acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine, process for its preparation

Technical field

The present invention relates to 3- (2-acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine of formula I

in racemic and optically active form, its pharmaceutically acceptable salts, and a process for its preparation. 3- (2-acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine is, as an acetylsalicylic acid ester with a carnitine (acetylsalicyloylcamitin), a salicylic acid derivative with very promising therapeutic properties.

BACKGROUND OF THE INVENTION

Salicylic acid in the form of its acetylderivative is widely used as an analgesic. Originally, this acetylderivative (known inter alia as Aspirin ^R ) was developed to reduce the disruptive side effects of the previously known salicylic acid. However, this derivative has some properties that limit its use. These unfavorable properties include, in particular, its low solubility in water, especially in an acidic environment, e.g. gastric juice. Low solubility may lead to precipitation of the active substance in the stomach when administered orally in aqueous solutions. This effect is undesirable not only in people with sensitive or damaged gastric mucosa, as it can cause serious side effects in these people. However, quite generally, the low solubility slows down the resorption and thus also the initiation of the analgesic effect. In addition, acetylsalicylic acid can be administered practically only orally, but not parenterally, e.g., intravenously or intraperitoneally or topically. Precisely because of the rapid initiation of action and / or gentle action on the gastrointestinal tract, parenteral administration would often be desirable.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a salicylic acid derivative which is soluble in water and in the acidic region, is readily absorbed, exhibits 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.

This object is achieved according to the invention, which is directed to betaine of 3- (2-acetoxybenzoyloxy) 4- (trimethylammonio) butyric acid. The compound has an asymmetric carbon atom and can therefore exist in two mirror optically active forms and as a racemic mixture. The enantiomer with the (R) -configuration that is derived from natural L-carnitine is preferred. Favorable physicochemical properties such as high water solubility and appropriate pH

L-carnitine is, however, known as an acyl group transporter in the metabolism of fats. It is actively received in most organs of the body through high-affinity transport systems. It is also taken up in cellular organelles (mitochondria, etc.) by an antiport transporter. It can be assumed that also acetylsalicyloyl-L-carnitine enters the cells and organ through these transport systems, and thus the onset of action is accelerated. Furthermore, the acyl-L-carnitines are readily cleaved by cellular enzymes, so that rapid release of the salicylate residue can be expected.

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

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

According to the invention, acetylsalicyloylcamitin is produced by acetylation of salicyloylcamitin. Acetyl chloride or acetic anhydride in the presence of a catalytic amount of sulfuric acid is particularly suitable as acetylating agent. Suitably, the acetylation is carried out in a temperature range of 40 ° C to 100 ° C in the presence of acetic acid as solvent.

Experience has shown that acetylsalicyloylcamitin can be obtained in good yield and high purity after about 5 hours reaction time and after usual working up. It is also within the scope of the invention to produce a process wherein the addition of a pharmaceutically acceptable acid further converts the betaine to the corresponding salt.

The following example illustrates an embodiment of the process of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Acetylsalicyloyl-L-carnitine.HCl

0.95 g of salicyloyl-L-kamitinu.HCl ([a] ^{20 =} -31.2 ° (c = l, H ₂ O) mp: 185-187 ° C) was mixed with 2.35 g of acetyl chloride and 5 1.0 ml of acetic acid and heated at 60 ° C for 5 hours. The reaction mixture was then evaporated in vacuo and the residue suspended with 10.0 ml of acetic acid ester. The crystalline product is washed with 5.0 ml of acetic acid ester and dried under vacuum at 40 ° C. 0.95 g of white crystalline acetylsalicyloyl-L-carnitine.HCl is obtained, mp 154-158 ° C.

1 H-NMR (DMSO-d ₆ , 300 MHz) δ = 12.9 (br.s, 1H), 8.04 (d, 1H, J = 1.9 Hz), 7.83 (t, 1H, J = 7.5 Hz), 7.46 (t, 1H, J = 7.6 Hz), 7.28 (d, 1H, J = 8.0 Hz), 5.70 (m, 1H), 4 , 08-3.83 (m, 2H), 3.20 (s, 9H), 2.93-2.78 (m, 2H), 2.33 (s, 3H), [α] _D ²⁰ = - 41.7 ° (c = 1, H ₂ O).

Test of gastric tolerance in rats (Ulcer index)

(R) - (-) - 3- (2-Acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid (acetylsalicyloyl-L-carnitine.HCl = ASC) was tested in male rats compared to acetylsalicylic acid (ASA). This assay is performed according to the method of Okabe et al., Japan. J.

-2GB 284755 B6

Pharmacol. 1974, 24, 363 et al., Which induce gastric mucosal changes. Test substances are administered to test rats p.o. in 1% carboxymethylcellulose suspension (1% CMC). Gastric mucosal changes are measured using the Ulcer Index of Chaumontet et al., Arzneimittelforschung 1978, 28 (II), Workbook 11, 2119-2121.

Table 1 shows the results.

Table 1

Substance Number of rats Ulver Index (U.I.) cf. 1% CMC 1 ml / 250 g 63.00 10 cf. ASA 200 mg.kg ^-1 300.00 20 May invention ASC 200 mg.kg ^-1 170.00 10 invention ASC 500 mg.kg ^-1 190.00 10 inventionASC 1000 mg.kg ^-1 220.00 10

CMC = carboxymethylcellulose,

ASA = acetyl salicylic acid,

ASC = acetylsalicyloyl-L-carnitine.HCl, cf. = comparison.

Claims (5)

PATENT CLAIMS A 3- (2-acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine of formula I and pharmaceutically acceptable salts thereof. (R) - (-) - 3- (2-acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine of formula II ^c- 3 and pharmaceutically acceptable salts thereof as compounds according to claim 1. (S) - (+) - 3- (2-Acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine of the formula III and pharmaceutically acceptable salts thereof as the compound according to claim 1. 4. 3- (2-Acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and its pharmaceutically acceptable salts for use as a therapeutically active agent. (R) - (-) - 3- (2-Acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and its pharmaceutically acceptable salts for use as a therapeutically active agent. (S) - (+) - 3- (2-Acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and its pharmaceutically acceptable salts for use as a therapeutically active agent. 7. 3- (2-Acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and its pharmaceutically acceptable salts for use as an gastric mucosal analgesic. (R) - (-) - 3- (2-Acetoxybenzoyloxy) -4-trimethylammonio) butyric acid betaine and its pharmaceutically acceptable salts for use as an gastric mucosal analgesic. (S) - ( ⁺ ) -3- (2-Acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine and its pharmaceutically acceptable salts for use as gastric mucosal analgesic. A process for preparing 3- (2-acetoxybenzoyloxy) -4- (trimethylammonio) butyric acid betaine, characterized in that 3- (2-hydroxybenzoyloxy) -4 (trimethylammonio) butyric acid betaine is acetylated. -4GB 284755 B6 Process according to claim 10, characterized in that acetyl chloride or acetic anhydride in the presence of catalytic amounts of sulfuric acid is used as acetylating agent. The method according to claim 10 or 11, characterized in that the acetylation is carried out at temperatures between 40 ° C and 100 ° C.