CS252496B2 - Process for producing acetyldicarnitine dichloride - Google Patents

Abstract

The invention relates to a method for producing acetyldicarnitine dichloride of the general formula I by allowing a mixture of acetylcarnitine chloride and thionyl chloride to stand under stirring, after removing excess thionyl chloride, the resulting acyl chloride is dissolved, carnitine chloride is added, after which the crude reaction product thus obtained is dissolved in hot isopropyl alcohol and crystallized to pure acetyldicarnitine dichloride. The new compound is effective in protein metabolism and digestive secretion, and is characterized by anabolic and antinorectic effects. The compound is also effective in senile and presenile cerebral involution syndromes and in cardiopathies.

Description

(54) A method for producing acetyldicarnitine dichtoride

The present invention relates to a process for the preparation of an acetyldicarnitine dichloride of the formula (I) by allowing a mixture of acetylcarnitine chloride and thionyl chloride to stand while stirring. pure acetyldicarnitine dichloride.

The novel compound is effective in protein metabolism and digestive secretion, with anabolic and antinorectic activity. The compound is also effective in senile and presenile cerebral involutional syndromes and in cardiopathies.

The present invention relates to a process for the production of an intermolecular dicarnitine ester having therapeutic efficacy.

In particular, the invention relates to a process for the preparation of acetyldicarnitine dichloride of the formula I

Cl · © I

CH ₃ - N - CH ₂ - CH - CH ₂ - COOH ch ₃

Cl

CH,

- C - CH, - CH - CH, - N - CH,

I £ h

- C - CH,

The preparation of the acetyldicarnitine dichloride of the formula I according to the invention is essentially based on two alternative reactions. The former consists in converting acetylcarnitine chloride into the corresponding acyl chloride by the action of thionyl chloride and subsequent esterification with carnitine chloride in a single step.

According to an alternative reaction, the starting material is the dicarnitine dichloride intermolecular ester obtained in a single step by the action of carnitine chloride on thionyl chloride and further acetylation of the secondary free alcohol group in a known manner by reaction with acetic anhydride or acetyl chloride as acylating agent.

The use of thionyl chloride as an acid catalyst is known in the literature.

Conversion of the carboxyl group to the corresponding acyl halide and subsequent easier esterification with the alcoholic substrate present in the reaction mixture is a very characteristic and important synthesis capable of facilitating the condensation of 2 carnitine molecules and the acetylation of the dicarnitine obtained by further addition of acetic anhydride or acetyl chloride.

The reaction can be carried out in a single step starting from carnitine chloride or acetylcarnitine without isolation of the thus obtained intermediate compounds.

An important object of the invention is to find the characteristic conditions of the process according to the invention. Consequently, optimum management of these conditions is very important and critical.

Further, prolonged heating or high temperature has been found to cause dehydration to produce gamma-trimethylaminocrotonic acid.

Moreover, the compound obtained by the process of the invention is rather unstable and readily hydrolyses under acidic conditions, so that its separation from the reaction mixture is very critical.

It has been found that its insulation is preferably carried out immediately and very precisely. On the other hand, methods known from the literature also require particular precision.

Preferably, the process for preparing acetyldicarnitine dichloride is carried out from a 1: 1.5 molar ratio of acetylcarnitine chloride and freshly distilled thionyl chloride.

The mixture was allowed to stir for 0.5 to 2 hours at room temperature. The acetylcarnitine acetyl chloride thus obtained, dissolved in methylene chloride, is added to an equivalent amount of carnitine chloride and allowed to stand for 18 to 36 hours at 38 to 42 ° C. The crude product thus obtained is separated and purified in a known manner.

Acute Toxicity: Acetyldicarnitine dichloride produced according to the invention is a practically non-toxic compound.

It was found that the LD _5Q after oral administration is higher than 20 g / kg body weight in mice and higher than 15 g / kg in rats. Following intravenous administration, the LD _{50 is} greater than 0.75 g / kg in mice and greater than 1 g / kg in rats, and greater than 2.5 g / kg in dogs.

Pharmacodynamics

Following oral administration of acetyldicarnitine dichloride at 100 mg / kg body weight in mice and adult rats (about 20 months of age), differences and reactivity and improved motor coordination were noted.

Based on pharmacological experiments carried out to determine the pharmacokinetic characteristics of the product produced according to the invention and to study its metabolism, it has been found that acetylcarnitine dichloride is cleaved into L-acetylcarnitine and L-carnitine in the body.

Thus, in addition to the pharmacological properties of L-carnitine, which is known to those skilled in the art to activate protein metabolism and stimulate digestive secretion with an anabolic and antianorexic reactions, the compound produced according to the invention exhibits some original and unexpected properties

The compound produced according to the invention is particularly effective in the treatment of senile and presenile cerebral involution syndromes of primary and secondary etiology (vasculopathy) and in cases of memory alteration and attention in the elderly.

Further, the compound produced according to the invention is effective in the treatment of cardiopathies, for example in acute and chronic myocardial ischemia, angina pectoris, latent and distinct cardiac insufficiency, and arrhythmias. L-acetyldicarnitine also has a cardioprotective effect against heart damage induced by the use of anthracycline antitumor drugs. Further, due to its very favorable pharmacacocytic properties, the product has a higher bioavailability, resulting in a better effect compared to other available drugs.

The present invention further provides pharmaceutical compositions comprising acetyldicarnitine dichloride.

Pharmaceutical preparations applicable orally or parenterally are effective drugs for the treatment of senile and presenile brain involution syndromes of primary or secondary etiology, for the treatment of memory and attention alteration in the elderly as well as in vascular diseases. The pharmaceutical compositions comprise a therapeutically effective amount of acetyldicarnitine dichloride and a pharmaceutically acceptable carrier and / or diluent for oral or parenteral administration.

The proposed amount of acetyldicarnitine dichloride for humans ranges from 0.5 to 2.0 g per day.

The following examples illustrate the invention but do not limit it in any way.

He did

Preparation of L-acetylcarnitine chloride

According to the method described in the literature (Ziegler et al., J. Org. Chem., 1967, p.

989), 50 ml of acetic acid was mixed with 8 g of acetyl chloride and kept under stirring 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 an additional hour with stirring. The very thick liquid obtained by distillation in vacuo was then added to 40 ml of boiling isopropyl alcohol.

The reaction mixture was filtered to remove unreacted carnitine and the title product was precipitated by the slow addition of 50 mL acetone. A white crystalline solid was obtained. Yield: 98%. Melting point: 180-182 ° C.

Acetyldicarnitine dichloride

0.15 mol of freshly distilled thionyl chloride was added to 0.1 mol of L-acetylcarnitine chloride.

The reaction mixture was allowed to stand with stirring for about 1 hour at room temperature.

After removal of the excess thionyl chloride by distillation under reduced pressure, the corresponding acyl chloride was obtained as a colorless spongy fluffy solid which was easily hydrolyzed in air.

The acyl chloride thus obtained was dissolved in 30 ml of anhydrous methylene chloride and then added to 0.15 moles of L-carnitine chloride. The resulting reaction mixture was allowed to stand with stirring for a further 24 hours at 40 ° C. The reaction mixture was monitored by thin layer chromatography until L-acetylcarnitine-acyl chloride disappeared completely.

After removal of the solvent by evaporation under reduced pressure, the crude product was washed many times with a small amount of methylene chloride.

The white, spongy, very hygroscopic solid thus obtained was dissolved in a minimum amount of isopropyl alcohol (about 150 ml) and then the solution was filtered to remove unreacted carnitine and acetylcarnitine.

The product precipitated from the filtrate (by the addition of 300 ml of acetone) as a white, very hygroscopic solid was washed several times with a small amount of acetoneitrile (about 20 ml) to remove any traces of esters.

The title compound was obtained in 90% yield:

IC (dimethylsulfoxide, hereinafter DMSO) max. 1,740, 1,715 cm

IC (KBr) max 3,550, 2,995, 2,950, 2,900, 1,730 cm ^-1

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

2.02 (s, 3H, _{COCH3) (}

2.7 to 2.8 (m, 4H, CH - _CH2 - COO- CH - CH ₂ - COOH

ÍCOCH ₃

3.20 (s, 18H, 2 * N ⁺ (CH3) ₃ + L, 1 +)

3.8 to 4.1 (m, 4H, N - _CH2 - CH - CH ₂ - COO - CH ₂ - N ₃ OCOCH

OCOCHI ³ I

5.43 (m, 2H, CH - CH ₂ - COO - CH - CH ₂ COOH)

Example 2

Acetylcarnitine dichloride

19.7 g (0.1 mol) of carnitine chloride and 35.7 g (0.3 mol) of thionyl chloride were mixed in a reaction flask and stirred for 8 hours at 30 ° C.

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

The crude product was dissolved in isopropanol at 33 ° C, filtered, and after removal of unreacted carnitine and gamma-trimethylaminocrotonic acid, the filtrate was allowed to crystallize.

The precipitate thus obtained was dissolved in 10.2 g (0.1 mol) acetic anhydride and the solution was stirred for about 12 hours at 40 ° C.

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

The viscous residue was dissolved in isopropanol at 33 ° C and the title compound was isolated from the reaction mixture in a known manner as a hygroscopic colorless solid.

Example 3

Preparation of an injectable pharmaceutical preparation

The preparation is carried out by conventional methods known in the art.

A preferred preparation of the injectable form has the following composition:

acetyldicarnitine dichloride 500 mg glycine 750 mg distilled water 5 ml

Example4

Preparation of an oral pharmaceutical preparation

The preparation is carried out by conventional methods known in the art.

Preferred orally administrable formulation (about 15 ml vial):

acetyldicarnitine dichloride i g 70% aqueous sorbitol solution 5 g methyl [p-hydroxybenzoate] 0.010 apricot essence 0.015 orange essence 0,025 distilled water to volume 10 ml.

A process for the preparation of the acetyldicarnitine dichloride of the formula I

Claims (1)

SUBJECT VYNALEZU CHCHch ₃ I® O - C - CH - CH - CH - N - CH 2 5 CH0 - C - CH 2 Cl (I) wherein the mixture of acetylcarnitine chloride of formula II (CH3) ₃ N - CH ₂ - CH - CH ₂ - COOH (II) OCOCH, and freshly distilled thionyl chloride at a molar ratio of 1: 1.5 are allowed to stand with stirring for 0.5 to 2 hours at room temperature, after removal of excess thionyl chloride, the obtained acyl chloride is dissolved in methylene chloride, an equivalent amount of darnitine chloride is added. The reaction mixture is maintained at 38-42 ° C for 18-36 hours, the crude reaction product thus obtained is dissolved in isopropanol at 25-42 ° C and pure acetyldicarnitine dichloride is obtained by crystallization.