GB2180533A

GB2180533A - Acetyldicarnitine dichloride

Info

Publication number: GB2180533A
Application number: GB08523376A
Authority: GB
Inventors: Giorgio Francia
Original assignee: CHEMIOSYNTEX Srl
Current assignee: CHEMIOSYNTEX Srl
Priority date: 1984-03-28
Filing date: 1985-09-21
Publication date: 1987-04-01
Also published as: ZA857051B; SE458857B; IT1237343B; FR2588001B1; FR2588001A1; AU575995B2; IT8420277A0; AT382365B; JPS6272655A; SE8504191L; CH663784A5; GB8523376D0; DE3533877A1; GB2180533B; SE8504191D0; ATA272385A; NL8502578A; BE903270A; AU4737985A

Abstract

<IMAGE> Acetyldicarnitine dichloride activates the proteic metabolism and stimulates digestive secretions, displaying an anabolic and antianorexic action. It is also active on the senile and pre-senile cerebral involution syndromes and on cardiopathies. It may be prepared from carnitine chloride either (i) by treatment with thionyl chloride to form the intermolecular ester, dicarnitine dichloride, followed by acetylation or (ii) by esterification using the acyl chloride obtained from acetylcarnitine chloride by treatment with thionyl chloride. Pharmaceutical compositions containing it are described.

Description

SPECIFICATION Acetyldicarnitine chloride The invention relates to a derivative of an intermolecular ester of carnitine chloride, to processes for its preparation and to pharmaceutical compositions containing it.

The invention provides acetyldicarnitine dichloride, which has the formula

The invention further provides two processes for the preparation of acetyldicarnitine dichloride.

In the first process, acetylcarnitine chloride is converted into its acyl chloride by treatment with thionyl chloride, and the acyl chloride is used to esterify carnitine chloride. In the second process, carnitine chloride is treated with thionyl chloride to form dicarnitine dichloride, and the free secondary alcohol group thereof is then acetylated by reaction with acetic anhydride or acetyl chloride.

The transformation of the carboxyl group into the corresponding acyl halide and the consequent easier esterification with the alcoholic substratum present in the reaction mixture, represents a very peculiar and important synthesis capable of promoting both the condensation of the two moles of carnitine and the acetylation of the resulting dicarnitine by further addition of acetic anhydride or acetyl chloride.

Either process may be carried out without isolation of the intermediate compounds.

Control of the reaction conditions is important. It has been found that extended heating or high temperature causes dehydration of carnitine chloride to -trimethylamino crotonic acid.

In carrying out the first process of the invention, it is preferable that a mixture of acetylcarnitine chloride and freshly distilled thionyl chloride, in the molecular ratio 1:1.5, is stirred for a period of from 0.5 to 2 hours at room temperature, the excess thionyl chloride is removed, the resulting acyl chloride is dissolved in methylene dichloride, an equivalent amount of carnitine chloride is added and the reaction mixture is maintained for a period of from 18 to 36 hours at a temperature of from 38 to 42"C.

In carrying out the second process of the invention, it is preferable that a mixture of carnitine chloride and thionyl chloride, in the molecular ratio 1:3, is stirred for a period of from 6 to 10 hours at a temperature of from 25 to 35"C, the excess thionyl chloride is removed, and the resulting dicarnitine dichloride is dissolved in two equivalents of acetic anhydride or acetyl chloride and maintained under stirring for a period of from 8 to 16 hours at a temperature of from 38 to 42"C.

Moreover, the compound obtained by the process of the invention is rather labiie and it is easily hydrolized in acidic medium, so that its separation from the reaction mixture is very critical. It has been found that the isolation is preferabiy carried out immediately and very accurately. Isolation is suitably effected by dissolving the crude acetyldicarnitine dichloride in isopropanol and either crystallizing the pure compound therefrom or precipiting the pure compound therefrom by adding acetone.

Acute toxicity Acetyldicarnitine dichloride has been found to be pratically non toxic, having an LD50 by oral administration of higher than 20g/kg body weight in mice and higher than 1 5g/kg body weight in rats. By intravenous administration, its LD50 is higher than 0.75g/kg body weight in mice, higher than 1g/kg body weight in rats and higher than 2.5g/kg body weight in dogs.

Pharmacodynamics On oral administration of acetyldicarnitine dichloride at the dose of 100 mg/kg body weight in mice and senile rats (aged about 20 months) there was noticed an increase of curiosity and reactivity and an improvement of motory coordination.

On the ground of the pharmacological trials carried out to establish the pharmacokinetic characteristics of the product of the invention and to study the metabolism, it has been found that acetyldicarnitine dichloride splits off into L-acetyl-carnitine and L-carnitine in the organism.

Consequently, the compound of the present invention, in addition to the pharmacological proper ties of L-carnitine which is known to activate the proteic metabolism and stimulate digestive secretion with an anabolic and antianorexic action, shows some original and unexpected properties.

More particularly, the compound of the invention is expecially active in the treatment of the senile and pre-senile cerebral involution syndromes of primary and secondary etiology (vasculopathies) and in cases of alteration of memory and attention in elderly men.

Furthermore, the compound of the invention is active in the therapy of cardiopathies, such as, for example, acute and chronic myocardic ischemia, angina pectoris, latent and clear cardiac insufficiency and arhytmias. L-acetyldicarnitine dichloride is also endowed with a cardioprotective effect against damage to the heart induced by the use of anthracycline antitumour drugs.

Furthermore, due to its most favourable pharmacokinetic properties, the compound has a higher bioavailability, resulting in a better effect in comparison with other available drugs.

The invention accordingly further comprises a pharmaceutical composition comprising acetyldicarnitine dichloride in admixture with a pharmaceutically acceptable diluent or carrier.

A pharmaceutical composition according to the invention in injectable form may suitably comprise: acetyldicarnitine dichloride 500 mg glycine 750 mg distilled water 5 ml A pharmaceutical composition according to the invention in orally administrable form may suitably comprise: acetyldincarnitine dichloride 1000 mg 70% sorbitol aqueous solution 5000 mg methyl phydroxybenzoate 10 mg apricot essence 15 mg orange essence 25 mg distilled water up to 10 ml vol.

The suggested amount of acetyldicarnitine dichloride for human patients is between 0.5 and 2.0 g pro die.

The following Examples illustrate the invention.

EXAMPLE 1 Preparation of L-acetylcarnitine chloride Following the method described by Ziegler et al in J. Org. Chem., 1967, p. 3989, 89 of acetyl chloride was added to 50 ml of acetic acid and the mixture was maintained under stirring for 3 hours at 80"C. After addition of 9.9 g of carnitine, the reaction mixture was stirred for 1 hour at 80"C. The mixture was then distilled in vacuo giving a very thick liquid, to which 40 mol of boiling isopropanol was added.

The reaction mixture was filtered to remove unreacted carnitine and the title product precipitated slowly on addition of 50 ml of acetone. A white crystalline solid was obtained, yield 98%, m.p. 180"-182"C.

Acetyldicarnitine chloride 0.15 mole of freshly distilled thionyl chloride was added to 0.1 mole of L-acetylcarnitine chloride. The mixture was allowed to stand under stirring for about 1 hour at room temperature.

After removing the excess thionyl chloride by distillation under reduced pressure, the corresponding acyl chloride was obtained as a white spongy solid, readily hydrolyzed in air.

The acyl chloride so obtained was dissolved in 30 ml of anhydrous methylene dichloride.

0.105 mole of L-carnitine chloride was added and the resultant mixture was allowed to stand under stirring for 24 hours at 40 C. The reaction was followed by thin layer chromatography until the L-acetylcarnitine acyl chloride had completely disappeared.

After removing the solvent by evaporation under reduced pressure, the raw product was washed many times with small amounts of methylene dichloride. The white, spongy, very hydroscopic solid compound so obtained was dissolved in the minimum quantity of isopropanol (about 150 ml) and then filtered to remove the unreacted carnitine and acetyl carnitine. From the filtrate the product precipitated on addition of acetone (300 ml) in the form of a white, very hydroscopic solid which was washed more times with small amounts of acetonitrile (about 20 ml) to remove all traces of esters. The title compound was obtained (yield 90%).

IR (DMSO) os max 1740, 1715 cam~' IR (KBr) a max 3550, 2995, 2950, 2900, 1730 cm-' MS (field desorption) 347, 305, 287, 204, 162 m/e 1H-NMR (200 MHz, DMSO-d6, 22"C) 2.02 (s, 3H, COCH3)

3.20 (s, 18H, 2XN+(CH3)3)

EXAMPLE 2 A cetyldicarnitine chloride 19.7 g (0.1 mole) of carnitine chloride and 35.7 g (0.3 mole) of thionyl chloride were allowed to stand in a flask, under stirring, for about 8 hours at 30"C. The excess thionyl chloride was removed under reduced pressure. After addition of 10 ml of water the reaction mixture was evaporated to dryness. The raw product was taken up in hot isopropanol and filtered. After removing the unreacted carnitine and y-trimethylamino-crotonic acid, if present, the filtrate was allowed to crystallize. The precipitate so obtained was then dissolved in 10.2 g (0.1 mole) of acetic anhydride and the solution was allowed to stand under stirring for about 12 hours at 40"C. The excess acetic anhydride and acetic acid was removed by distillation under reduced pressure on a water bath (40"C). The viscous residue was dissolved in hot isopropanol and from the reaction mixture the title product was separated in known manner in the form of a hydroscopic white solid.

Claims

1. Acetyldicarnitine dichloride, which has the formula:

2. A process for the preparation of acetyldicarnitine dichloride, the process comprising converting acetylcarnitine chloride into its acyl chloride by treatment with thionyl chloride, and esterifying carnitine chloride with the acyl chloride.

3. A process according to claim 2 in which a mixture of acetylcarnitine chloride and freshly distilled thionyl chloride, in the molecular ratio 1:1.5, is stirred for a period of from 0.5 to 2 hours at room temperature, the excess thionyl chloride is removed, the resulting acyl chloride is dissolved in methylene dichloride, an equivalent amount of carnitine chloride is added and the reaction mixture is maintained for a period of from 18 to 36 hours at a temperature of from 38 to 42"C.

4. A process for the preparation of acetyldicarnitine dichloride, the process comprising treating carnitine chloride with thionyl chloride and acetylating the free secondary alcohol group of the resultant dicarnitine dichloride by reaction with acetic anhydride or acetyl chloride.

5. A process according to claim 4 in which a mixture of carnitine chloride and thionyl chloride, in the molecular ratio 1:3, is stirred for a period of from 6 to 10 hours at a temperature of from 25 to 35"C, the excess thionyl chloride is removed, and the resulting dicarnitine dichloride is dissolved in two equivalents of acetic anhydride or acetyl chloride and maintained under stirring for a period of from 8 to 16 hours at a temperature of from 38 to 42"C.

6. A process according to any of claims 2 to 5 further comprising isolating the acetyldicarnitine dichloride by dissolution in isopropanol and crystallization therefrom or precipitation therefrom by addition of acetone.

7. A process according to claim 2, the process being substantially as described herein with reference to Example 1.

8. A process according to claim 4, the process being substantially as described herein with reference to Example 2.

9. A pharmaceutical composition comprising acetyldicarnitine dichloride in admixture with a pharmaceutically acceptable diluent or carrier.