HU194158B - Process for producing acetyl-dicarnitine-dichloride and pharmaceutical compositions containing them as active components - Google Patents

Abstract

Acetyl dicarnitine dichloride (I) is new. - (I) is prepd. by either of the following routes: a) acetyl carnitine is converted to the acyl chloride by treatment with thionyl chloride, and this is then treated with carnitine chloride. (b) dicarnitine dichloride is prepd. from carnitine chloride by treatment with thionyl chloride, and this is then acetylated with acetyl chloride or acetic anhydride. These reactions may be effected without purifn. of the intermediates.

Description

The present invention relates to a process for the preparation of an intermolecular dicarnitine ester which has a therapeutic effect.

More particularly, the present invention relates to a process for the preparation of the novel acyldicarnitine dichloride of formula (I) and pharmaceutical compositions containing it as an active ingredient.

According to the invention, the preparation of acetyldicarnitine dichloride of formula (I) is essentially based on two alternative reactions. One such reaction consists in treating the acetyl-carnitine chloride with thionyl chloride to convert it to the corresponding acid chloride, followed by one-step esterification with carnitine chloride.

Alternatively, the starting material is dicamitine dichloride, an intermolecular ester of carnitine, which is prepared in a single step by treating carnitine chloride with thionyl chloride, followed by acetylation of the free secondary alcoholic hydroxyl group in a known manner, with acetyl chloride as the acetyl chloride. or by reaction with acetic anhydride.

The use of thionyl chloride as a catalyst and dehydrating agent is known in the art.

The conversion of the carbonyl group to the corresponding acid halide and subsequent easier esterification with the alcoholic substrate present in the reaction is a unique and important synthesis method that can promote both the carnitine ε condensation of the two molecules and the resulting dicamitine acetylide or acetic acid more.

The reaction may be carried out in one step starting from the carnitine chloride or acetylcarnitine without isolation of the intermediates thus obtained.

An important object of the invention is to determine the specific conditions of the process according to the invention. As a result, optimal control of these conditions is very important and critical. Further, it has been found that prolonged heating or high temperature leads to dehydration of gamma-trimethylaminocrotonic acid.

In addition, the compound obtained by the process of the invention is quite labile and is readily hydrolyzed under acidic conditions, so isolation from the reaction mixture is very critical. It has been found that the isolation is preferably carried out immediately and very thoroughly. On the other hand, the procedures known in the literature also require particular precision.

The process for preparing the acetyldicamitin dichloride according to the invention is preferably carried out starting from a 1: 1.5 molar mixture of acetylcarnitine chloride and freshly distilled thionyl chloride.

The mixture was allowed to stand at room temperature for 0.5 to 2 hours with stirring. The resulting acetylcarnitine acid chloride is dissolved in methylene chloride, an equivalent amount of carnitine chloride is added and the mixture is allowed to stand at 38-42 ° C for 18-36 hours. The crude product thus obtained is isolated and purified in known manner.

Acute Toxicity: The acetyldecafnithine dichloride of the present invention is substantially non-toxic.

We found that the LD _S0 value for oral administration is greater than 20 g / kg (body weight) in mice and greater than 15 g / kg in rats. For intravenous administration, the LD ₁₀₀ is greater than 0.75 g / kg in the mouse, 1 g / kg in the rat and 2.5 g / kg in the dog.

Pharmacodynamics (Pharmacology)

Oral administration of acetyldicamitin dichloride at a dose of 100 mg / kg body weight in mice and senile mice (about 20 months of age) has been shown to increase interest and reactivity and improve motor coordination.

Based on pharmacological studies carried out to determine the pharmacokinetic properties of the product of the invention and study its metabolism, we have found that acetyldicarnitine dichloride in the body is converted to Lacetylcarnitine and L-carnitine. decompose.

Consequently, in addition to the pharmacological properties of L-carnitine, which are known to one of skill in the art, the compound of the present invention activates protein metabolism and stimulates the secretion of digestive juices, while exhibiting anabolic and antianorxic properties, exhibits certain original and unexpected properties.

In particular, the compound of the present invention is particularly active in the treatment of primary and secondary aetiology, senile and pre-senile cerebral regression (vascular disease), and in memory and attention impairment in the elderly.

The compound of the present invention is also active in the treatment of certain cardiac disorders, e.g. acute and chronic myocardial ischaemia, angina pectm ris, latent and manifest heart failure, and arrhythmias. L-acetyldicarnitine also has a cardioprotective effect on cardiac damage induced by the use of anthracycline-type anticancer agents. In addition, due to its very good pharmacological properties, the product has a higher bioavailability and this results in better results than other drugs available.

The present invention also relates to the manufacture of a medicament containing acetol dicarnitine dichloride. Pharmaceutical compositions for oral or parenteral administration are active therapeutic agents for the treatment of primary and secondary aetiologies of senile and pre-senile cerebral regression, for the treatment of memory and attention in elderly patients, and for cardiovascular disease. The pharmaceutical compositions comprise a pharmaceutically effective amount of acetyldicamitin dichloride in the presence of a pharmaceutically acceptable carrier and / or diluent for oral or intramuscular administration.

The recommended amount of acetyldicamitin dichloride in human medicine is 0.5-2.0 g / day.

Example I

Preparation of L-acetylcamityl chloride

According to the method described in the literature (Ziegler et al.

J. Org.Chem. 1967, p. 3989) Acetic acid (50 ml) was mixed with acetyl chloride (8 g) and the mixture was stirred at 80 ° C for 3 hours. After addition of 9.9 g of carnitine, the reaction mixture was allowed to stand at 80 ° C for 1 hour with stirring. Vacuum distillation gives a very thick liquid which is mixed with 40 ml of hot isopropanol.

To remove unreacted carnitine, the reaction mixture was filtered and the title product precipitated by slowly adding 50 ml of acetone. A white crystalline solid is obtained. Yield 98%, m.p. 180-182 ° C.

-2194.158

Acct il-Dicarite Injection Chlorides

Freshly distilled thionyl chloride (0.15 mL) was added to 0.1 mol of L-acetylcarnitine chloride.

The mixture was stirred at room temperature for approx. Allow to stand for 1 hour.

Excess thlonyl chloride is removed by distillation under reduced pressure to give the corresponding acid chloride in the form of a spongy white substance which is readily hydrolyzed in air.

The acid chloride thus obtained was dissolved in 30 ml of anhydrous methylene chloride and 0.105 mol of L-carnitine chloride were added. The resulting mixture was allowed to stand at 40 ° C for 24 hours with stirring. The reaction was monitored by TLC until the L-acetylcarnitinic acid chloride disappeared completely.

The solvent was removed by distillation under reduced pressure. The crude product was washed several times with a small amount of methylene chloride.

The resulting white, spongy, high hygroscopic solid is dissolved in a minimum amount (about 150 mL) of isopropanol and the solution is spun to remove unreacted carnitine and acetylcarnitine.

The product was precipitated from the filtrate by the addition of acetone (300 mL). A white, very hygroscopic solid is obtained, which is washed several times with a small amount (about 20 ml) of acetonitrile to remove all traces of ester.

Yield: 90%. IR (DMSO): delta _today "1740.1715 ^cm-1 IR (KBr): delta _{of the} '3550, 2995, 2950, 2900,

1730 cm '

MS (space-desorption): 347, 305, 287, 204, 162 m / e 1 H-NMR (200 MHz, DMSO-d ₆ , 22 ° C)

2.02 fs. 3H.-C0CH,) |

2.7-2.8 (m, 4H, -CH-CH ₃ -COO-CH-CH ₂ -COOH)

OCOCH ₃ 3.20 (s, 18H, 2xN 1 CH ₃ ) ₃

3.8- 4.1 (m, 4H, N + -CH ₂ -CH-CH ₂ -COOCH CH ~~ I _r N ⁺ _p-COCH3

5.43 (m, 2H, CH = CH-CH ₂ -COO-CH ₂ -COOH) π r ~

0C0CH ₃

Example 2

Ace til dicarnitine dichloride

Carnitine chloride (19.7 g, 0.1 mol) and thionyl chloride (35.7 g, 0.3 mol) in a flask were stirred for ca. Leave for 8 hours at 30 ° C.

The excess thionyl chloride was removed under reduced pressure. After adding 10 ml of water, the reaction mixture was evaporated to dryness.

The crude product is taken up in hot isopropanol, the solution is filtered and, after removal of any unreacted carnitine and gamma-trimethylaminocrotonic acid that may be present, the filtrate is allowed to crystallize.

The resulting precipitate was then dissolved in 10.2 g (0.1 mol) of acetic anhydride and the solution was stirred with stirring for ca. Allow to stand for 12 hours at 40 ° C.

Excess acetic anhydride and acetic acid were removed by distillation under reduced pressure in a water bath (40 ° C).

The viscous residue is dissolved in hot isopropanol and the title product is isolated from the reaction mixture in a known manner as a hygroscopic white solid. Yield 94%.

Example 2

Preparation of an injectable pharmaceutical composition

The preparation is carried out according to conventional methods well known to those skilled in the art.

The preferred composition of the injectable form is:

acetyl dicarnitine dichloride 500 mg glycine 750 mg distilled water 5 ml

Example 4

Preparation of an oral dosage form

The preparation is carried out according to conventional methods well known to those skilled in the art.

Preferred composition for oral administration (about 15 ml glass): acetyl chloride dikarnitin 70% Sorbitol, aqueous solution p-Bidroxybenzoic acid methyl ester peach essence orange essence distilled water 1g 5g 0.01 g to 0.015 g to 0.025 g to 10 ml Claims

A process for the preparation of a novel acetyldicamitinic di-formula (I)

Claims (2)

A process for the preparation of a novel acetyldicamitine dichloride of formula (I), characterized in that a) A 1: 1.5 molar mixture of acetyl carnitine chloride and freshly distilled thionyl chloride was stirred at room temperature for 0.5-2 hours and after removal of the excess thionyl chloride, the resulting acid chloride was dissolved in methylene chloride and an equal amount of carnitine chloride was added. The reaction mixture is kept at 38-42 ° C for 18-36 hours, and the crude reaction product thus obtained is dissolved in spinning isopropanol and crystallized with pure acetyldicarnitine dichloride, or b) Reaction of the carnitine with excess freshly distilled thionyl chloride, while stirring the reaction mixture with acetyl anhydride or acetyl chloride for 10-14 hours at 35-45 ° C, followed by isolation of the final product by crystallization. 2. A method for the preparation of a medicament for the treatment of senile and preseneal cerebral regression of primary and secondary etiology, memory and attention impairment in the elderly, vascular complaints, and cardiac disorders induced by anticancer agents having antitumor activity, characterized in that: Acetyl dicarnitine dichloride of the formula (I) prepared according to the invention is mixed with the pharmaceutically acceptable carrier and / or diluent as an active ingredient.