CA1256119A - Acetyldicarnitine - Google Patents
AcetyldicarnitineInfo
- Publication number
- CA1256119A CA1256119A CA000491773A CA491773A CA1256119A CA 1256119 A CA1256119 A CA 1256119A CA 000491773 A CA000491773 A CA 000491773A CA 491773 A CA491773 A CA 491773A CA 1256119 A CA1256119 A CA 1256119A
- Authority
- CA
- Canada
- Prior art keywords
- chloride
- acetyldicarnitine
- dichloride
- carnitine
- senile
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT
The present invention refers to a new derivative of carnitine. More particularly, the present invention refers to acetyldicarnitine dichloride, to a process for its preparation and to the pharmaceutical compositions containing this compound. The new compound is active on proteic metabolism, digestive secretions displaying an anabolic and antianoressic action.
It is also active on the senile and pre-senile cerebral involution syndromes and on cardiopathies.
The present invention refers to a new derivative of carnitine. More particularly, the present invention refers to acetyldicarnitine dichloride, to a process for its preparation and to the pharmaceutical compositions containing this compound. The new compound is active on proteic metabolism, digestive secretions displaying an anabolic and antianoressic action.
It is also active on the senile and pre-senile cerebral involution syndromes and on cardiopathies.
Description
~; ~
.
~256~19 . ' ACETYLDICARNITINE
1 The,present invention refers to an intermolecular ester of dicarnitine having a therapeutic action.
More particularly, the present invention refer$ to Acètyldicarnitine dichloride having the following general formula:
, CH3 ' CH3~-CH2-CH-CH2-cOOH ICH3 2 C1 , ' CH3 1_lCI_CH2_CIH CH2 CH 3 _ ' _ Further object of the present invention is a process for the preparation of Acetyldicarnitine dichloride.
According to the present invention, the preparation Of Acetyldicarnitine dichloride of formula I is essen-tially based on two alternative reactions. The former consists in transforming the acetylcarnitine chloride in the corresponding acyl chloride by treatment with thionyl chloride and further esterification with carnitine chloride in a single step.
According to the alternative reaction the starting compound is dicarnitine dichloride intermolecular ester of carnitine, obtained in a single step by treatment of ~.~
- - 2 - 1256~9 ; 1 carnitine chloride with thionyl chloride and further acetylation of the secondary free alcoholic group, in known manner, by reaction with acetic anhydride or acetyl chloride as an acylating agent.
The use of thionnyl chloride as acid catalyst and dehydrating agent is known in the literature.
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 to promote both the condensation of the two moles of carnitine and the acetylation of the obtained dicarnitine by further addition of acetic anhydride or acetyl chloride.
The reaction may be carried out in a single step starting from carnitine chloride or from acetylcarnitine, without isolation of the intermediate compounds so obtained.
An important object of the present invention consists 2Q in having found the peculiar conditions of the process of the invention. Consequently, an optimal control of these conditions is very important and critical. Furthermore, it has been found that an extended heating or high temperature cause the dehydration to ~-trimethylamino crotonic acid.
- 3 ~Z561~9 1 Moreover, the compound obtained by the process of the invention is rather labile 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 preferably carried out immedia~ely and very accurately. On th`e other hand, also the processes known in the literature require special accuracy.
Preferably, the process for preparing Acetyldicarni-tine dichloride of the invention is carried out starting from a mixture of acetylcarnitine chloride and freshly distilled thionyl chloride,in a molecular ratio of 1:1.5.
The mixture is allowed to stand under stirring for a period of 0.5-2 hours at room temperature. The acyl chloride of acetyl carnitine so obtained, dissolved in methylene chloride, is added with an equivalent quantity of carnitine chloride and allowed to stand for a period of 18-36 hours at 380-420C. The raw product so obtained is separated and purified in known manner.
Acute toxicity: Acetyldicarnitine dichloride of the invention is pratically a non toxic compound.
It has been found that LD50 by oral administration is higher than 20g/kg (body weight) in mice and higher than 15g/kg in rats. By intravenous administration, LD50 is higher than 0.75gikg in mice, higher than 1g/kg in rats and higher than 2.5g/kg in dogs.
, - 4 - 12 ~ 9 l Pharmacody amics By oral administration of Acetyldicarnitine dichloride at the dose of 100 mg/kg (body weight) in mice and senile rats (about 20 months aged) it was noticed an increase of curiosity and reactivity and an improvement of the 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 its meta-l~ bolism, it has been found that Acetyldicarnitinedichloride spilts off into L-acetyl-carnitine and L-carnitine in the organism.
Consequently, the compound of the present invention, . in addition to the pharmacological properties of L-carni-tine which, as known to the experts, activates the proteic metabolism and stimulates the digestive secre-tions 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 tvasculoPaties) and in cases of alte-ration of memory and attention in elderly men.
Furthermore, the compound of the present invention is active in the therapy of cardiopahies~ such as, for ~256119 1 example, acute and chronic myocardic ischemia, angina pectoris, latent and clear cardiac insufficiency and arhytmias~ L-acetildicarnitine is also endowed of a cardioprotective effect against damages on the heart induced by the use of anthracyclines antitumor drugs.
Furthermore, due to its most favourable pharmaco~inetic, the product has a higher bioavailability, resulting in a better effect in comparison with other available drugs.
Further scope of the present invention are the pharmaceutical compositions containing acetyldicarnitine dichloride.
The pharmaceutical compositions, administrable by oral or parenteral route, are active therapeutic agents for the treatment of the senile and pre-senile cerebral involution syndromes of primary Or secondary etiology, for the treatment of alteration of the memory and attention in elderly patients as well as of vascular diseases. The pharmaceutical compositions comprise a therapeutically effective amount of acetyldicarnitine dichloride and a pharmaceutically acceptable carrier and/or diluent for oral or intramuscular~ administration.
The suggested amount of acetyldicarnitine dichlo-ride for human patients is between 0.5 and 2.0 g pro die.
The following non-limitative examples illustrate the invention.
125~
1 'EXAMPLE 1 Prep'a'ration o'f L'-'a'cetylcarnitine chloride According to the method described in the litera-ture (Zegler et al. J. Org. Chem., 1967, p.3989) 50 ml of acetic acid were added with 8 g of acetyl chloride and maintained under stirriny for 3 hours, at 80C. After addition of 9.9 g of carnitine, the reaction mixture was allowed to stand under stirring for 1 hour, at 80C. A
very thick liquid obtained by distillation, in vacuo, was then added with 40 ml of boiling isopropanol.
The reaction mixture was filtered to remove the non-reacted carnitine and the product of the title precipitated slowly by addition of 50 ml of acetone. A
white crystalline solid was obtained.
(yield of 98~), m.p. 180-182C.
Ace*y'ldica'rnitine' dich'lo'r'ide 0.15 moles of freshly distilled thionyl chloride were added to 0.1 mole of L-acetylcarnitine chloride.
The mixture was allowed to stand under stirring for about 1 hour, at room temperature.
A~ter having removed the excess thionyl chloride by distillation under reduced pressure, the corresponding acyl chloride was obtained as a white spongy solid, which can be easily hydrolyzed in the air.
The acyl chloride so obtained was dissolved in 30 ml of anhydrous methylene chloride and then added with 0.105 moli of L-carnitine chloride. The resulting mixture ~2S6119 1 was allowed to stand under stirring for 24 hours at 40 C.
The reaction was followed by thin layer chromatography up to L-acetylc~rnitine acyl chloride completely disappeared.
After removing the solvent by evaporation unaer reduced pressure, the raw product was washed many times with small amounts of methylene chloride.
The white, spongy, very hygroscopic 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 by addition of acetone (300 ml) in the form of white, very hygroscopic solid which was washed more times wi~h small amounts of acetonitrile (about 20 ml) to remove all traces of esters.
The title compound was obtained (yield 90%):
IR (DMSO) ~max 1740, 1715 cm IR (KBr) ~max 3550, 2995, 2950, 2900, 1730 cm MS (field desorption) 347, 305, 287, 204, 162 m/e 'H-NMR (200 MHz, DMSO-d6, 22 C)
.
~256~19 . ' ACETYLDICARNITINE
1 The,present invention refers to an intermolecular ester of dicarnitine having a therapeutic action.
More particularly, the present invention refer$ to Acètyldicarnitine dichloride having the following general formula:
, CH3 ' CH3~-CH2-CH-CH2-cOOH ICH3 2 C1 , ' CH3 1_lCI_CH2_CIH CH2 CH 3 _ ' _ Further object of the present invention is a process for the preparation of Acetyldicarnitine dichloride.
According to the present invention, the preparation Of Acetyldicarnitine dichloride of formula I is essen-tially based on two alternative reactions. The former consists in transforming the acetylcarnitine chloride in the corresponding acyl chloride by treatment with thionyl chloride and further esterification with carnitine chloride in a single step.
According to the alternative reaction the starting compound is dicarnitine dichloride intermolecular ester of carnitine, obtained in a single step by treatment of ~.~
- - 2 - 1256~9 ; 1 carnitine chloride with thionyl chloride and further acetylation of the secondary free alcoholic group, in known manner, by reaction with acetic anhydride or acetyl chloride as an acylating agent.
The use of thionnyl chloride as acid catalyst and dehydrating agent is known in the literature.
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 to promote both the condensation of the two moles of carnitine and the acetylation of the obtained dicarnitine by further addition of acetic anhydride or acetyl chloride.
The reaction may be carried out in a single step starting from carnitine chloride or from acetylcarnitine, without isolation of the intermediate compounds so obtained.
An important object of the present invention consists 2Q in having found the peculiar conditions of the process of the invention. Consequently, an optimal control of these conditions is very important and critical. Furthermore, it has been found that an extended heating or high temperature cause the dehydration to ~-trimethylamino crotonic acid.
- 3 ~Z561~9 1 Moreover, the compound obtained by the process of the invention is rather labile 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 preferably carried out immedia~ely and very accurately. On th`e other hand, also the processes known in the literature require special accuracy.
Preferably, the process for preparing Acetyldicarni-tine dichloride of the invention is carried out starting from a mixture of acetylcarnitine chloride and freshly distilled thionyl chloride,in a molecular ratio of 1:1.5.
The mixture is allowed to stand under stirring for a period of 0.5-2 hours at room temperature. The acyl chloride of acetyl carnitine so obtained, dissolved in methylene chloride, is added with an equivalent quantity of carnitine chloride and allowed to stand for a period of 18-36 hours at 380-420C. The raw product so obtained is separated and purified in known manner.
Acute toxicity: Acetyldicarnitine dichloride of the invention is pratically a non toxic compound.
It has been found that LD50 by oral administration is higher than 20g/kg (body weight) in mice and higher than 15g/kg in rats. By intravenous administration, LD50 is higher than 0.75gikg in mice, higher than 1g/kg in rats and higher than 2.5g/kg in dogs.
, - 4 - 12 ~ 9 l Pharmacody amics By oral administration of Acetyldicarnitine dichloride at the dose of 100 mg/kg (body weight) in mice and senile rats (about 20 months aged) it was noticed an increase of curiosity and reactivity and an improvement of the 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 its meta-l~ bolism, it has been found that Acetyldicarnitinedichloride spilts off into L-acetyl-carnitine and L-carnitine in the organism.
Consequently, the compound of the present invention, . in addition to the pharmacological properties of L-carni-tine which, as known to the experts, activates the proteic metabolism and stimulates the digestive secre-tions 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 tvasculoPaties) and in cases of alte-ration of memory and attention in elderly men.
Furthermore, the compound of the present invention is active in the therapy of cardiopahies~ such as, for ~256119 1 example, acute and chronic myocardic ischemia, angina pectoris, latent and clear cardiac insufficiency and arhytmias~ L-acetildicarnitine is also endowed of a cardioprotective effect against damages on the heart induced by the use of anthracyclines antitumor drugs.
Furthermore, due to its most favourable pharmaco~inetic, the product has a higher bioavailability, resulting in a better effect in comparison with other available drugs.
Further scope of the present invention are the pharmaceutical compositions containing acetyldicarnitine dichloride.
The pharmaceutical compositions, administrable by oral or parenteral route, are active therapeutic agents for the treatment of the senile and pre-senile cerebral involution syndromes of primary Or secondary etiology, for the treatment of alteration of the memory and attention in elderly patients as well as of vascular diseases. The pharmaceutical compositions comprise a therapeutically effective amount of acetyldicarnitine dichloride and a pharmaceutically acceptable carrier and/or diluent for oral or intramuscular~ administration.
The suggested amount of acetyldicarnitine dichlo-ride for human patients is between 0.5 and 2.0 g pro die.
The following non-limitative examples illustrate the invention.
125~
1 'EXAMPLE 1 Prep'a'ration o'f L'-'a'cetylcarnitine chloride According to the method described in the litera-ture (Zegler et al. J. Org. Chem., 1967, p.3989) 50 ml of acetic acid were added with 8 g of acetyl chloride and maintained under stirriny for 3 hours, at 80C. After addition of 9.9 g of carnitine, the reaction mixture was allowed to stand under stirring for 1 hour, at 80C. A
very thick liquid obtained by distillation, in vacuo, was then added with 40 ml of boiling isopropanol.
The reaction mixture was filtered to remove the non-reacted carnitine and the product of the title precipitated slowly by addition of 50 ml of acetone. A
white crystalline solid was obtained.
(yield of 98~), m.p. 180-182C.
Ace*y'ldica'rnitine' dich'lo'r'ide 0.15 moles of freshly distilled thionyl chloride were added to 0.1 mole of L-acetylcarnitine chloride.
The mixture was allowed to stand under stirring for about 1 hour, at room temperature.
A~ter having removed the excess thionyl chloride by distillation under reduced pressure, the corresponding acyl chloride was obtained as a white spongy solid, which can be easily hydrolyzed in the air.
The acyl chloride so obtained was dissolved in 30 ml of anhydrous methylene chloride and then added with 0.105 moli of L-carnitine chloride. The resulting mixture ~2S6119 1 was allowed to stand under stirring for 24 hours at 40 C.
The reaction was followed by thin layer chromatography up to L-acetylc~rnitine acyl chloride completely disappeared.
After removing the solvent by evaporation unaer reduced pressure, the raw product was washed many times with small amounts of methylene chloride.
The white, spongy, very hygroscopic 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 by addition of acetone (300 ml) in the form of white, very hygroscopic solid which was washed more times wi~h small amounts of acetonitrile (about 20 ml) to remove all traces of esters.
The title compound was obtained (yield 90%):
IR (DMSO) ~max 1740, 1715 cm IR (KBr) ~max 3550, 2995, 2950, 2900, 1730 cm MS (field desorption) 347, 305, 287, 204, 162 m/e 'H-NMR (200 MHz, DMSO-d6, 22 C)
2.02 (s, 3H, COCH3) 2.7-2.8 (m, 4H, CH-CH2-COO-CH-CH2-COOH) OCOCH~
3.20 (s, 18H, 2 x N (CH3)3 3.8-4.1 (m, 4H, N -CH2-CH-CH2-COOCH-CH2-N
I
5.43 (m, 2H, -CH-CH2-COO-CH-CH2COOE~) 125S~l~
l EXAMPLE 2 .
Acetytdicarnitine dichloride 19.7 9 (0.1 moles) of carnitine~chloride and 35.7 9 (0.3 moles) of thionyl chloride were allowed to stand in a flask, under stirring, for about 8 hours, at 30C.
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 with hot isopropyl alcohol, filtered and after removing the unreacted carnitine and ~-trimethylamino-crotonic acid, if present, the fiItrate was allowed to crystalli~e.
The precipitate so obtained was then dissolved in 10.2 9 (0.1 moles) of acetic anhydride and the solution was allowed to stand under stirring for about 12 hours, at 40C~
The excess acetic anhydride and acetic acid was removed by distillation under reduced pressure on a water bath (40C).
2~ The viscous residue was dissolved in hot isopropyl alcohol and from the reaction mixture the title product was separated in known manner in the form of hygroscopic, white so!id.
.
25 Preparation of an injectable pharmaceutical composition _ 9 _ ~2 ~61 1~
l The preparation is carried out according to the conventional processes well known per se to those skilled in the art.
The preferred composition of an injectable form is:
acetyldicarnitine dichloride 500 mg glycine 750-mg distilled water 5 ml Preparation of an oral pharmaceutical composition 1~ The preparation is carried out according to the conventional processes well known per se to those skilled in the art.
The preferred composition of an orally administrable form tbottle of about 15 ml) is:
acetyldicarnitine dichloridel 9 70% sorbitol aqueous solution5 9 methyl p-hydroxybenzoate0,010 9 apricot essence 0,015 9 orange essence 0,025 9 distilled waterup to 10 ml vol.
I
5.43 (m, 2H, -CH-CH2-COO-CH-CH2COOE~) 125S~l~
l EXAMPLE 2 .
Acetytdicarnitine dichloride 19.7 9 (0.1 moles) of carnitine~chloride and 35.7 9 (0.3 moles) of thionyl chloride were allowed to stand in a flask, under stirring, for about 8 hours, at 30C.
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 with hot isopropyl alcohol, filtered and after removing the unreacted carnitine and ~-trimethylamino-crotonic acid, if present, the fiItrate was allowed to crystalli~e.
The precipitate so obtained was then dissolved in 10.2 9 (0.1 moles) of acetic anhydride and the solution was allowed to stand under stirring for about 12 hours, at 40C~
The excess acetic anhydride and acetic acid was removed by distillation under reduced pressure on a water bath (40C).
2~ The viscous residue was dissolved in hot isopropyl alcohol and from the reaction mixture the title product was separated in known manner in the form of hygroscopic, white so!id.
.
25 Preparation of an injectable pharmaceutical composition _ 9 _ ~2 ~61 1~
l The preparation is carried out according to the conventional processes well known per se to those skilled in the art.
The preferred composition of an injectable form is:
acetyldicarnitine dichloride 500 mg glycine 750-mg distilled water 5 ml Preparation of an oral pharmaceutical composition 1~ The preparation is carried out according to the conventional processes well known per se to those skilled in the art.
The preferred composition of an orally administrable form tbottle of about 15 ml) is:
acetyldicarnitine dichloridel 9 70% sorbitol aqueous solution5 9 methyl p-hydroxybenzoate0,010 9 apricot essence 0,015 9 orange essence 0,025 9 distilled waterup to 10 ml vol.
Claims (4)
1. Acetyldicarnitine dichloride having the general formula:
2. A therapeutic composition for the treatment of the senile and pre-senile cerebral involution syndromes of primary or secondary etiology, of the alteration of memory and attention in elderly patients as well as of vascular diseases and of the damages of heart induced by anthracyclines antitumor drugs, which comprises an effec-tive amount of the compound of claim 1 and a pharmaceuti-cally acceptable carrier and/or diluent for oral or parenteral administration.
3. A therapeutic composition according to claim 2, wherein the effective amount of acetyldicarnitine dichloride is between 0.5 and 2.0 g pro die.
4. Process for preparing acetyldicarnitine dichlori-de of formula l of claim 1, characterized in that a mixture of acetylcarnitine chloride and freshly distilled thionyl
4. Process for preparing acetyldicarnitine dichlori-de of formula l of claim 1, characterized in that a mixture of acetylcarnitine chloride and freshly distilled thionyl
Claim 4 continued chloride, in the molecular ratio 1:1.5, is allowed to stand under stirring for a period of 0.5-2 hours, at room temperature and, after removing the excess thionyl chloride, the resulting acyl chloride is dissolved in methylene chloride, added with an equivalent amount of carnitine chloride and the resulting reaction mixture is maintained for a period of 18-36 hours at a temperature of from 38 to 42 C, so obtaining the raw reaction product which is dissolved in hot isopropyl alcohol and the pure acetyldicarnitine dichloride is obtained by crystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000491773A CA1256119A (en) | 1985-09-27 | 1985-09-27 | Acetyldicarnitine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000491773A CA1256119A (en) | 1985-09-27 | 1985-09-27 | Acetyldicarnitine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1256119A true CA1256119A (en) | 1989-06-20 |
Family
ID=4131486
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000491773A Expired CA1256119A (en) | 1985-09-27 | 1985-09-27 | Acetyldicarnitine |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1256119A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896791A (en) * | 2012-12-25 | 2014-07-02 | 北京蓝贝望生物医药科技股份有限公司 | (R)-acetyl carnitine hydrochloride preparation method |
-
1985
- 1985-09-27 CA CA000491773A patent/CA1256119A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896791A (en) * | 2012-12-25 | 2014-07-02 | 北京蓝贝望生物医药科技股份有限公司 | (R)-acetyl carnitine hydrochloride preparation method |
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|---|---|---|---|
| MKEX | Expiry |