Esters of bis-(hydroxyalkylthio)-alkanes

Esters of acetylsalicylic acid with polyols of the formula: EQU HO -- A -- S -- (CH.sub.2).sub.n -- S -- A -- OH (I) in which n is an integer of from 5 to 15 and each A group represents a C.sub.2 -C.sub.6 linear or branched hydrocarbyl group which can contain an --OH group are particularly useful as hypolipidaemic, hypocholesterolaemic, anti-blood clotting and anti-atherosclerosis agents.

The present invention relates to certain esters of 
bis-(hydroxyalkylthio)-alkanes and to their therapeutic application, 
especially in the treatment of cardiovascular diseases. 
It is known that certain bis-(hydroxyalkylthio)-alkanes are useful as 
hypolipidaemic and hypocholesterolaemic agents (see, for example, British 
Pat. Specification No. 1,307,227, French Pat. Specification No. 2,146,138 
and British Pat. application No. 41381/74). 
It has now been discovered that particular esters of the said 
bis-(hydroxyalkylthio)-alkanes possess valuable therapeutic properties, 
especially in the cardio-vascular field. These compounds, which are novel 
per se, are esters of acetylsalicylic acid, as hereinafter defined, with 
the polyols of the formula 
EQU HO -- A -- S -- (CH.sub.2).sub.n -- S -- A -- OH (I) 
in which n is an integer from 5 to 15 and each A group represents a C.sub.2 
-C.sub.6 linear or branched hydrocarbyl group which can contain an OH 
group. 
The term "esters of acetylsalicyclic acid" as used herein includes both 
mono-acetylsalicylates of the polyol (I) which may be obtained by suitably 
protecting one --OH of the polyol (I), and the diacetylsalicylates of 
formula 
##STR1## 
in which A and n are as defined above. 
Examples of suitable groups for A are the --CH.sub.2 CH.sub.2 --, 
--CH(CH.sub.3)CH.sub.2 --, --CH.sub.2 CH(CH.sub.3)--, --C(CH.sub.3).sub.2 
CH.sub.2 --, --CH.sub.2 C(CH.sub.3).sub.2 --, --C(CH.sub.3).sub.2 
C(CH.sub.3).sub.2 --, --CH.sub.2 CHOHCH.sub.2 --, --CH(CH.sub.2 
OH)CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 -- and --CH.sub.2 
CH(CH.sub.3)CH.sub.2 -- groups. 
The acetylsalicylates of the invention can be prepared by methods known per 
se. The preferred method for the synthesis of the esters consists of 
reacting acetylsalicyloyl chloride with a polyol of the formula I in the 
presence of a base, especially an amine, under stoichiometric conditions, 
or in the presence of an excess of acetylsalicyloyl chloride. 
Particularly preferred bis-(hydroxyalkylthio)-alkanes of formula I which 
can be used to obtain the esters of the invention are those listed in 
Table I. 
Table I 
______________________________________ 
(CH.sub.2).sub.n [--S--A--OH].sub.2 
Code Number n A Melting Point 
______________________________________ 
LL 1,558 10 --CH.sub.2 CH.sub.2 -- 
70-71.degree. C 
LL 1,089 5 --CH.sub.2 CH.sub.2 -- 
85.degree. C 
-- 12 --CH.sub.2 CH.sub.2 -- 
78.degree. C 
CRL 40,055 10 --C(CH.sub.3).sub.2 CH.sub.2 -- 
&lt;50.degree. C 
CRL 40,077 8 --CH.sub.2 CH.sub.2 -- 
59.degree. C 
CRL 40,085 6 --CH.sub.2 CH.sub.2 -- 
47.degree. C 
CRL 40,116 9 --CH.sub.2 CH.sub.2 -- 
64.degree. C 
CRL 40,120 7 --CH.sub.2 CH.sub.2 -- 
50.degree. C 
CRL 40,122 10 --CH(CH.sub.3)CH.sub.2 -- 
47-48.degree. C 
CRL 40,155 10 --CH.sub.2 CHOHCH.sub.2 -- 
95.degree. C 
CRL 40,176 10 --CH(CH.sub.2 OH)CH.sub.2 CH.sub.2 -- 
73.degree. C 
CRL 40,193 9 -- CH(CH.sub.3)CH.sub.2 -- 
20.degree. C 
CRL 40,194 11 --CH.sub.2 CH.sub.2 -- 
73.degree. C 
______________________________________ 
Note: the melting points were determined on a Kofler bench (instantaneous 
melting point). 
The most useful esters from a therapeutic point of view are the 
diacetylsalicylates obtained from LL 1,558, i.e. 
3,14-dithia-1,16-hexadecanediol (alternative nomenclature: 
1,10-bis-(2-hydroxyethylthio)-decane) and from CRL 40,122 
2,15-dimethyl-3,14-dithia-1,16-hexadecanediol. 
The invention also provides a therapeutic composition comprising, as active 
ingredient, at least one acetylsalicylate of the invention in association 
with a physiologically acceptable excipient. The compound of the invention 
acts as a hypolipidaemic and hypocholesterolaemic agent. 
The invention is illustrated by the following Examples.

EXAMPLE 1 
1,16-Di-(O-acetylsalicyloyloxy)-3,14-dithiahexadecane 
alternative nomenclature: 
1,16-(3,14-dithiahexadecyl)di-(O-acetylsalicylate) 
##STR2## 
A solution of 8.5 g (0.042 mol) of acetylsalicyloyl chloride in 50 ml of 
benzene is run over the course of 1 hour into a suspension of 5.9 g (0.020 
mol) of 3,14-dithia-1,16-hexadecanediol (LL 1,558) and of 4.25 g (0.042 
mol) of triethylamine in 50 ml. of benzene. The reaction mixture is 
stirred for 3 hours at ambient temperature (15.degree.-25.degree. C.) and 
is diluted with diethyl ether. After washing the organic phase with water 
and with a potassium carbonate solution, drying it and evaporating the 
solvent, 14 g of a slightly pink limpid oil are obtained. 8.7 g of this 
oil are purified by passing it over a silica column and then by washing 
with a 50:50 v/v mixture of cyclohexane and diisopropyl ether, to give 3.1 
g of a white water-insoluble powder. 
Instantaneous melting point (Kofler) &lt; 40.degree. C. Yield = 39.5% 
EXAMPLE 2 
1,16-Di-(O-acetylsalicyloyloxy)-2,15-dimethyl-3,14-dithia-hexadecane 
alternative nomenclature: 1,16-(2,15-dimethyl-3,14-dithiahexadecyl) 
di-(O-acetylsalicylate) 
##STR3## 
On following the procedure indicated in Example 1 but replacing the 
3,14-dithia-1,16-hexadecanediol by 
2,15-dimethyl-3,14-dithia-1,16-hexadecanediol, 
1,16-di-(O-acetylsalicyloyloxy)-2,15-dimethyl-3,14-dithia-hexadecane is 
obtained. 
Pharmacological tests on animals and man show that the esters of the 
invention, especially the products of Examples 1 and 2, reduce the lipid 
and cholesterol levels in the blood. Additionally, they exhibit anti-blood 
clotting and anti-atherosclerosis properties. 
Preferably, the esters of the invention are administered orally as a 
therapeutic composition. The preferred dosage when treating or preventing 
cardio-vascular diseases is from 100 mg to 2000 mg of active ingredient 
per day for at least one week. 
The product of Example 1 has been successfully used in man as an anti-blood 
clotting and anti-atherosclerosis agent when 2 to 4 gelules or capsules 
(each containing 500 mg of active ingredient) have been administered to 
the patient each day.