L'ACETYLSALICYLOYL-L-CARNITINE ET PROCEDE POUR SA PREPARATION

ACETYLSALICYLOYL L-CARNITINE AND PROCESS FOR ITS PREPARATION

Abrégé anglais

Novel 3-(2-acetoxybenzoyloxy)-4-
(trimethylammonio)-butyric acid betaine and its
pharmaceutically acceptable salts are disclosed. The
compounds are distinguished by high water solubility,
minimum toxicity and good gastric tolerance vis-a-vis
acetylsalicylic acid and can be prepared by acetylating the
corresponding salicylic acid ester of the carnitine.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. 3-(2-Acetoxybenzoyloxy)-4-(trimethylammonio)-
butyric acid betaine of the formula:
<IMG>
and pharmaceutically acceptable salts thereof.
2. (R)-(-)-3-(2-Acetoxybenzoyloxy)-4-
(trimethylammonio)-butyric-acid betaine of the formula:
<IMG>
and pharmaceutically acceptable salts thereof.
3. (S)-(+)-3-(2-Acetoxybenzoyloxy)-4-
(trimethylammonio)-butyric acid betaine of the formula:

<IMG>
and pharmaceutically acceptable salts thereof.
4. 3-(2-Acetoxybenzoyloxy)-4-(trimethylammonio)-
butyric acid betaine, or a pharmaceutically acceptable salt
thereof, for use as an active therapeutic component.
5. (R)-(-)-3-(2-Acetoxybenzoyloxy)-4-
(trimethylammonio) -butyric acid betaine, or a
pharmaceutically acceptable salt thereof, for use as an
active therapeutic component.
6. (S)-(+)-3-(2-Acetoxybenzoyloxy)-4-
(trimethylammonio)-butyric acid betaine or a
pharmaceutically acceptable salt thereof, for use as an
active therapeutic component.
7. 3-(2-Acetoxybenzoyloxy)-4-(trimethylammonio)-
butyric acid betaine, or a pharmaceutically acceptable salt
thereof, for use as an analgetic for the protection of the
gastric mucous membrane.
8. (R)-(-)-3-(2-Acetoxybenzoyloxy)-4-
(trimethylammonio)-butyric acid betaine, or a
pharmaceutically acceptable salt thereof, for use as an
analgetic for the protection of the gastric mucous
membrane.

9. (S)-(+)-3-(2-Acetoxybenzoyloxy)-4-
(trimethylammonio) -butyric acid betaine, or a
pharmaceutically acceptable salt thereof, for use as an
analgetic for the protection of the gastric mucous
membrane.
10. A process for the preparation of 3-(2-
acetoxybenzoyloxy)-4-(trimethylammonio)-butyric acid
betaine, which comprises acetylating 3-(2-
hydroxybenzoyloxy)-4-(trimethylammonio)-butyric acid
betaine.
11. A process according to claim 10, wherein the
acetylation is carried out with acetyl chloride or acetic
anhydride in the presence of a catalytic amount of H2SO4.
12. A process according to claim 10 or 11,
wherein the acetylation is carried out at a temperature
between 40°C and 100°C.

Description

1
This invention relates to the novel 3-(2-
acetoxybenzoyloxy)-4-(trimethylammonio)-butyric acid
betaine acetylsalicyloyl L-carnitine of the general
formula:
0
O
O
. C'3
I (z)
C''~'.~ H o ~ / W
~'3
in racemic and optically active form, and pharmaceutically
acceptable salts thereof, as well as to a new process for
its preparation. As an ester of acetylsalicylic acid with
carnitine (acetylsalicyloyl carnitine), 3-(2-
acetoxybenzoyloxy)-4-(trimethylammonio)-butyric acid
betaine is a salicylic acid derivative with promising
therapeutic properties.
Salicylic acid is used to a great extent as an
analgetic in the form of its acetyl derivative. Although
this acetyl derivative (known, inter alia, as Aspirin*) was
originally developed to reduce undesirable side-effects of
the previously known salicylic acid, it is nevertheless
burdened with some properties which limit its use. Among
these disadvantageous properties is, above all, its low
water solubility, especially in an acidic environment, such
as in gastric juice. The low solubility can lead to
precipitation of the active component in the stomach when
aqueous solutions are orally administered. This effect is
undesirable not only in persons having a sensitive or
already damaged gastric mucous membrane, as it may lead to
* Trade-mark

2~~I~~6
2
serious side-effects in these persons, but it also
generally delays the reabsorption, and thus postpones the
onset of the analgetic effect.
Moreover, acetylsalicylic acid can virtually only
be administered orally, and not parenterally, (e. g.
intravenously intraperitoneally) or topically. It is for
facilitating a quick response while protecting the
gastrointestinal tract that a parenteral application would
often be desirable.
Thus, the object of this invention is to provide
a salicylic acid derivative which has good water solubility
in an acidic environment, a high reabsorption rate and
minimum toxicity, and which can be administered both orally
and parenterally or topically and exhibits a quick
analgetic effect in all forms of administration.
Accordingly, the invention provides 3-(2-
acetoxybenzoyloxy)-4-(trimethylammonio)-butyric acid
betaine of formula I above. This compound has an
asymmetric carbon atom and can therefore occur in two
mirror-inverted optically active forms and as a racemic
mixture. All forms constitute a part of the invention,
however, the enantiomer with (R) configuration, which is
derived from the naturally occurring L-carnitine, is
preferred.
The advantageous physical and chemical
properties, such as high water solubility and a good pH
value of the solution, are, of course, also attained by the
(S) enantiomer and the racemate. However, L-carnitine is
known as an acyl-group transmitter in fat metabolism. It
is actively absorbed in most of the organs of the body via
high affinity transport systems and in cellular organelles
(mitochondria etc.) via antiport transporters.
There is reason to assume that acetylsalicyloyl
L-carnitine also reaches the cells and organelles via these
transport systems and that the onset of the analgetic
effect is thus accelerated.

3
Acyl L-carnitines continue to be easily
dissociated by enzymes of the individual cells, so that one
can expect a quick release of the salicylate radical.
Studies on rats have already shown an extremely
slight acute toxicity of acetylsalicyloyl L-carnitine.
However, dosages of up to 7.000 mg/kg body weight were
easily tolerated orally. Furthermore, there were no
harmful side-effects observed with intravenous and
intraperitoneal administration of therapeutic amounts.
The invention also provides for the production of
salts of the acetylsalicyloyl carnitine with
pharmaceutically acceptable acids.
According to the invention acetylsalicyloxy
carnitine is prepared by acetylating salicyloyl carnitine.
Acetyl chloride or acetic anhydride, in the presence of a
catalytic amount of HZSO~, is especially suitable as
acetylating agent.
Acetylation takes place advantageously in the
presence of acetic acid as solvent and in a temperature
range of from ~0°C to 100°C.
Previous experience has shown that, after a
reaction time of about 5 hours and after conventional
processing, acetylsalicylayl carnitine can be obtained in
good yield and with high purity.
It is also within the scope of the process of the
invention to subsequently convert the betaine into a
corresponding salt by addition of a pharmaceutically
acceptable acid.
The following Example illustrates the process
according to the invention.
Example
Acetylsalicyl~l L-carnitine HC1
0. 95 g of salicoyl L-carnitine HC1 ( [a D - -
31.2° (c=l, HZO); melting point: 185-187°C) were mixed with
35 2.35 g of acetyl chloride and 5.0 ml of acetic acid and
heated for 5 hours at 60°C. The reaction mixture was

4
subsequently evaporated under vacuum and the residue was
suspended with 10.0 ml acetic ester. The crystallized
product was rinsed with 5.0 ml of acetic ester and dried
under vacuum at 40°C. Thus, 0.95 g of white, crystalline
acetylsalicyloyl L-carnitine-HC1 was obtained having a
melting point of 154-158°C.
~H-NMR (DMSO-db, 300 MHz) d = 12.9 (br.s, 1H),
8.04 (d, 1H, J=1.9 Hz),
7.73 (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)p
[a] D~ - -41.7° (c=1, H20).
Gastric Tolerance Test on Rats (Ulcer Index
The (R)-(-)-3-(2-acetoxybenzoyloxy)-4
(trimethylammonio)-butyric acid betaine~HC1 (acetylsalicoyl
L-carnitine = ASC) was tested on male rats in comparison to
acetylsalicylic acid (ASA) by inducing gastric mucous
membrane charges based on the method of Okabe et al.,
Japan. J. Pharmacol. 1974, 24, 3&3 ff.
The test substances were administered p.o. to the
test rats in a 1% carboxymethyl cellulose suspension (1%
CMC ) .
The gastric mucous membrane changes were measured
by the Ulcer Index according to Chaumontet et al.,
Arzneimittelforschung [Pharmacological Research] 1978, 28,
2047-2178.

5
The results are shown in Table 1.
Table 1
Substance Ulcer Index Number of
(U. I.) Rats Tested
Comparison1% CMC 1 ml/250 63.00 10
g
Comparison ASA200 mgkg~ 300.00 20
Invention ASC200 mgkg~ 170.00 10
Invention ASC500 mgkg~~ 190.00 10
Invention 1000mgkg1 220.00 10
ASC
CMC - carboxymethyl cellulose
ASA - acetylsalicylic acid
ASC - acetylsalicoyl L-carnitine~HC1

Dessin représentatif