2-alkenylene-thieno-1,2-thiazole derivatives with lipid-lowering activity

The invention relates to new thieno-1,2-thiazole derivatives of the formula ##STR1## wherein A, with the two carbon atoms of the thiazole ring, forms a group of the formula ##STR2## and the broken line indicates the double bond present in the thieno structures of the formulae IIa and IIb, n denotes the integer 2, 3 or 4, R denotes hydrogen or lower alkyl, R.sub.1 denotes hydrogen, lower alkyl, halogen, trifluoromethyl, lower alkoxy or lower alkylthio and R.sub.2 denotes hydrogen, lower alkyl or halogen; and the pharmaceutically acceptable salts of compounds of the formula I wherein R denotes hydrogen, a process for their preparation, pharmaceutical products containing these compounds, and their use in medicaments. The compounds of the formula I and salts thereof have a lipid-lowering action.

The invention relates to new thieno-1,2-thiazole derivatives of the formula 
##STR3## 
wherein A, with the two carbon atoms of the thiazole ring, forms a group 
of the formula 
##STR4## 
and the broken line indicates the double bond present in the thieno 
structures of the formulae IIa and IIb, n denotes the integer 2, 3 or 4, R 
denotes hydrogen or lower alkyl, R.sub.1 denotes hydrogen, lower alkyl, 
halogen, trifluoromethyl, lower alkoxy or lower alkylthio and R.sub.2 
denotes hydrogen, lower alkyl or halogen; and the pharmaceutically usable 
salts of compounds of the formula I wherein R denotes hydrogen, a process 
for their preparation, pharmaceutical products containing these compounds, 
and their use in medicaments. 
The expression "lower alkyl" used in this description designates 
straight-chain or branched saturated hydrocarbon radicals with 1 to 4 
carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl, sec.-butyl or tert.-butyl (1,1-dimethylethyl). The 
expression "lower alkox)" represents an alkyl ether group in which the 
alkyl radical has the above meaning, for example methoxy, ethoxy, propoxy, 
isopropoxy, butoxy, isobutoxy, sec.-butoxy or tert.-butoxy, and the 
designation "lower alkylthio" represents an alkylthio ether group with the 
abovementioned meaning for the alkyl radical, such as methylthio, 
ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, 
sec.-butylthio or tert.-butylthio. The term "halogen" designates chlorine, 
bromine, fluorine or iodine. 
In a preferred class of compounds of the formula I, n denotes the number 2 
or 3, the number 2 being particularly preferred. R preferably represents 
hydrogen, 1,1-dimethylethyl or ethyl, R again particularly preferably 
denoting hydrogen. 
In another preferred class of compounds of the formula I, A denotes the 
thieno group of the formula IIc. In compounds of the formula I wherein A 
represents a group of the formula IIa, R.sub.1 preferably represents 
hydrogen, and in compounds of the formula I wherein A denotes a group of 
the formula IIb, R.sub.2 is preferably hydrogen or chlorine. 
The thieno-1,2-thiazole derivatives of the formula I and salts thereof are 
prepared, according to the invention, by methods which are known per se, 
preferably by a process in which 
(a) a compound of the formula 
##STR5## 
wherein A has the meaning given in the case of formula I, is converted 
into its alkali metal salt and this is reacted with a compound of the 
formula 
EQU X--(CH.sub.2).sub.n --COOR IV 
wherein n and R have the meaning given in the case of formula I and X 
represents a reactive leaving group, after which 
(b) if appropriate, a compound of the formula I thus obtained, wherein R 
denotes 1,1-dimethylethyl, is converted into a compound of the formula I 
wherein R denotes hydrogen by heating in a solvent which is inert in the 
reaction, in the presence of catalytic amounts of a strong acid, and 
(c) if desired, a free acid of the formula I obtained in process step (a) 
or (b), wherein R denotes hydrogen, is converted into a pharmaceutically 
acceptable salt with inorganic or organic bases. 
The anhydrous alkali metal salts of compounds of the formula III can be 
prepared in the customary manner, for example by treating a compound cf 
the formula III with calculated amounts of aqueous alkali metal hydroxide 
solution, preferably sodium hydroxide solution or potassium hydroxide 
solution, or with the calculated amount of an alcoholic alkali metal 
alcoholate solution, preferably an alcoholic sodium methylate, sodium 
ethylate or potassium ethylate solution, and obtaining the alkali metal 
salts in the dry residue by evaporating the resulting solution. 
The alkali metal salts for the process according to the invention can also 
be prepared in situ in a particularly simple and advantageous manner by 
adding the calculated amount of sodium hydride, for example a sodium 
hydride suspension in white oil, to a solution of the compound of the 
formula III in an aprotic polar solvent, which can also be used in the 
subsequent reaction of the alkali metal salt with a compound of the 
formula IV, for example in dimethylformamide, dimethyl sulfoxide, dimethyl 
acetamide, hexamethylphosphoric acid triamide and the like. 
The leaving group designated by the symbol X in formula IV is preferably a 
halogen atom which can easily be split off, such as chlorine, bromine or 
iodine, or an sulfonic acid ester group. such as tosyloxy or mesyloxy, or 
the like. 
The reaction of the alkali metal salts of compounds of the formula III with 
the compounds of the formula IV by process step (a) can be carried out in 
the presence or absence of a solvent which is inert in the reaction. The 
reaction is advantageously carried out in a polar aprotic solvent in which 
the alkali metal salts are readily soluble, the solvents mentioned above 
for the preparation of the alkali metal salts being preferably suitable. 
The reaction is preferably carried out by warming, temperatures of 
80.degree. to 140.degree. C. with a temperature optimum at about 
100.degree. C. being particularly preferred. Depending on the reaction 
temperature and the reactivity of the particular reaction partners 
employed, in particular on the nature of the leaving group X, the reaction 
time is between a few hours and several days. 
The tert.-butyl esters of the formula I obtained in this reaction, in which 
R represents a 1,1-dimethylethyl radical, can, if desired, be converted 
into the free acids of the formula I wherein B denotes hydrogen by process 
step (b). The 1,1-dimethylethyl group is advantageously split off in the 
form of isobutylene to form the free carboxyl group by dissolving the 
starting compound of the formula I (R=1,1-dimethylethyl) in an aprotic 
solvent which is inert in the reaction, preferably an aromatic 
hydrocarbon, such as benzene, toluene or xylene, and heating the solution 
in the presence of catalytic amounts of a strong acid. Strong acids which 
are partly or completely soluble in the solvents mentioned, for example 
benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and the 
like, are preferably used for this purpose. The reaction temperature at 
which the splitting off of the 1,1-dimethylethyl group is carried out can 
be chosen virtually as desired within a wide temperature range above room 
temperature, the reflux temperature of the reaction mixture having proved 
to be particularly advantageous. 
The reaction time depends on the reaction temperature and is, for example, 
about 90 minutes when the reaction mixture in toluene is heated under 
reflux. Compounds of the formula I obtained in the reactions in process 
step (a) or (b) which have a free carboxyl group can be converted into 
their pharmaceutically usable salts in the customary manner with inorganic 
or organic bases. The salt formation can be carried out, for example, by 
dissolving the compounds mentioned of the formula I (R=H) in a suitable 
solvent, for example water or a lower aliphatic alcohol, adding an 
equivalent amount of the desired base, ensuring thorough mixing and, when 
salt formation has ended, distilling off the solvent in vacuo. If 
appropriate, the salts can be recrystallized after isolation. 
Examples of pharmaceutically usable salts are metal salts, in particular 
alkali metal or alkaline earth metal salts, such as sodium, potassium, 
magnesium or calcium salts. Other harmaceutically usable salts are, for 
example, also ammonium salts which readily crystallize. The latter are 
derived from ammonia or organic amines, for example mono-, di- or 
tri-lower (alkyl, cycloalkyl or hydroxyalkyl)-amines, lower alkylene 
diamines or (hydroxylower alkyl or aryl-lower alkyl)-lower alkylammonium 
bases, for example methylamine, diethylamine, triethylamine, 
dicyclohexylamine, triethanolamine, ethylenediamine, 
tris(hydroxymethyl)-aminomethane, benzyl-trimethylammonium hydroxide and 
the like. 
The starting compounds of the formula IV are known from the literature. The 
starting compounds of the formula III used for the process according to 
the invention are either likewise known from the literature (German 
Offenlegungsschrift Nos. 2,534,689, 2,839,266 and 2,749,640), or they can 
be prepared in a manner which is known per se, starting from known 
products. In particular, they can be synthesized in accordance with the 
following equation by customary chemical methods of working with which any 
expert is familiar. 
The starting compounds of the formulae V and VII shown in the equation are 
known from the literature (German Offenlegungsschrift Nos. 2,537,070, 
2,835,760, 2,838,851, and European Patent No. A-103,142). Unless stated 
otherwise, A, R.sub.1 and R.sub.2 in the following equation have the 
meaning given in the case of formula I. 
##STR6## 
The compounds of the formula I and their pharmaceutically usable salts show 
useful pharmacological properties in animal experiments. In particular, 
they effect a marked reduction in the blood level values of cholesterol 
and triglycerides and, on the basis of these lipid-lowering properties, 
can be used in human medicine for the treatment and prophylaxis of 
diseases caused by an increased level of cholesterol and/or triglycerides 
in the blood. Such diseases are primarily cardiovascular disorders, inter 
alia thrombosis, arteriosclerosis, myoardial infarction and angina 
pectoris. These actions can be demonstrated by in vitro experiments or in 
vivo animal experiments, preferably on mammals, for example guineapigs, 
mice, rats, cats, dogs or monkeys. The compounds mentioned can be 
administered to these animals enterally or parenterally, and in view of 
human administration in particular also orally. 
The following test method, inter alia, is used to investigate the 
lipid-lowering properties of compounds of the general formula I. 
The test substances are suspended in each case in freshly prepared 1% 
strength carboxymethylcellulose and are administered intraperitoneally 
once daily in constant doses of 20 mg/kg with a unit administration volume 
of 10 ml/kg over a period of 14 days to male mice (strain: OF 1, Swiss, 
SPF; weight at the start of the experiment: about 25 g) which have free 
access to a standard diet and drinking water. The control group receives 
only 10 ml/kg of 1% strength carboxymethylcellulose. 
4 hours after the last administration of the test substances or of the 
carboxymethylcellulose, in the control group, the animals are sacrificed 
by exsanguination via the aorta carotis. EDTA (ethylenediaminetetraacetic 
acid) plasma is obtained from the test animals to determine the blood 
level values of lipids. 
ANALYTICAL METHODS 
Cholesterol is determined both by the conventional method 
(Liebermann-Burchard color test; Zbl. Pharm, 124 (7), 396 et seq.) and by 
a completely enzymatic method (Celichrome cholesterol; test system: Chemie 
Linz AG, Diagnostica; Linz, Austria). 
The triglycerides are determined completely enzymatically (Triglyceride 
iodonitrotetrazolium violet; test system: Chemie Linz AG, Diagnostica; 
Linz, Austria). 
In this test, compounds of the general formula I exhibit powerful 
lipid-lowering properties. For example, 
2,3-dihydro-3-oxo-thieno(3,4-d)-1,2-thiazole-propionic acid 1,1-dioxide at 
a dosage of 20 mg/kg intraperitoneally effects a 9.2% reduction in the 
blood level value of cholesterol and a 7.8% reduction in the blood level 
value of triglycerides in comparison with the control group. 
The compounds of the general formula I can be used as medicines, for 
example in the form of pharmaceutical products which contain them mixed 
with a pharmaceutical organic or inorganic inert auxiliary and/or 
excipient suitable for enteral or parenteral administration, such as, for 
example, pharmaceutically acceptable solvents, gelatin, gum arabic, 
lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene 
glycols, vaseline and the like. 
The pharmaceutical products can be in a solid form, for example as tablets, 
coated tablets, suppositories, capsules and the like, or in a liquid form, 
for example as solutions, suspensions or emulsions. If appropriate, they 
are sterilized and contain auxiliaries, such as preservatives, stabilizers 
or emulsifying agents, salts for modifying the osmotic pressure and the 
like. 
In particular, pharmaceutical products can contain the compounds according 
to the invention in combination with other therapeutically useful 
substances. The compounds according to the invention can be formulated to 
combination products with these, together with the abovementioned 
auxiliaries and/or excipients.

The following examples illustrate the invention in more detail: 
EXAMPLE 1 
10.0 g (0.053 mol) of thieno(2,3-d)-1,2-thiazol-3(2H)-one 1,1-dioxide are 
suspended in 100 ml of dry dimethylformamide, 2.54 g (0.053 mol) of a 50% 
strength sodium hydride suspension washed with benzene are added, the 
solid is dissolved at 70.degree. C., while stirring (10 minutes), the 
solution is cooled to 30.degree. C., 12.16 g (0.058 mol) of 
1,1-dimethylethyl 3-bromopropionate are added and the mixture is heated at 
100.degree. C. for 3 hours. It is then evaporated in vacuo, the residue is 
partitioned between NaHCO.sub.3 solution and CH.sub.2 Cl.sub.2 and the 
organic phase is separated off, dried with Na.sub.2 SO.sub.4 and 
evaporated. The crystalline residue, which consists of 
1,1-dimethylethyl-2,3-dihydro-3-oxo-thieno-(2,3-d)-1,2-thiazole propionate 
1,1-dioxide can be recrystallized from diisopropyl ether. 
Yield: 11 g (65.5%). 
Melting point (diisopropyl ether): 66.degree.-67.degree. C. of colorless 
crystals. 
EXAMPLE 2 
10.0 g (0.053 mol) of thieno(3,2-d)-1,2-thiazol-3(2H)-one 1,1-dioxide are 
suspended in 100 ml of dry dimethyl sulfoxide and reacted at 95.degree. C. 
for 4 hours in a manner analogous to that described in Example 1. 
1,1-dimethylethyl-2,3-dihydro-3-oxo-thieno(3,2-d)-1,2-thiazole propionate 
1,1-dioxide is obtained in a yield of 67%. 
Melting point (diisopropyl ether): 72.degree.-74.degree. C. 
EXAMPLE 3 
10 g (0.053 mol) of thieno(3,4-d)-1,2-thiazol-3(2H)-one 1,1-dioxide are 
suspended in 100 ml of dry dimethylacetamide and reacted at a reaction 
temperature of 110.degree. C. for 3 hours in a manner analogous to that 
described in Example 1. 
1,1-dimethylethyl-2,3-dihydro-3-oxo-thieno(3,4-d)-1,2-thiazole propionate 
1,1-dioxide is obtained in a yield of 62%. 
Melting point (diisopropyl ether): 94.degree.-95.degree. C. 
EXAMPLE 4 
10 g (0.045 mol) of 5-chloro-thieno(3,2-d)-1,2-thiazol-3(2H)-one 
1,1-dioxide are reacted with 10.03 g (0.048 mol) of 1,1-dimethylethyl 
3-bromopropionate in a manner analogous to that described in Example 1. 
1,1-Dimethylethyl-5-chloro-2,3-dihydro-3-oxo-thieno(3,2-d)-1,2-thiazole 
propionate 1,1-dioxide is obtained in a yield of 60%. 
Melting point (diisopropyl ether): 115.degree.-116.degree. C. 
EXAMPLE 5 
A solution of 2.12 g (0.053 mol) of sodium hydroxide in 150 ml of water are 
added to 10 g (0.053 mol) of thieno(2,3-d)-1,2-thiazol-3(2H)-one and the 
mixture is stirred until a solution which is virtually free from residue 
is obtained. Small amounts of undissolved constituents are filtered off 
and the dry residue is prepared by evaporating off the water in vacuo. The 
alkali metal salt thus obtained is finely powdered and dried to constant 
weight under a high vacuum. This salt is suspended in 100 ml of dry 
dimethylformamide and dissolved at 80.degree. C., while stirring, the 
solution is cooled to 30.degree. C., 7.92 g (0.058 mol) of ethyl 
3-chloropropionate are added and the mixture is heated at 100.degree. C. 
for 4 hours 15 minutes. 
The reaction mixture is worked up as descried in Example 1. Ethyl 
2,3-dihydro-3-oxo-thieno(2,3-d)-1,2-thiazole-propionate 1,1-dioxide is 
obtained in a yield of 65%. 
Melting point (diisopropyl ether): 62.degree.-63.degree. C. 
EXAMPLE 6 
A solution of 3.61 g (0.053 mol) of sodium ethylate in 120 ml of dry 
ethanol is added to 10 g (0.053 mol) of 
thieno(3,2-d)-1,2-thiazol-3(2H)-one and the mixture is stirred until a 
clear solution is obtained. The dry residue is prepared by evaporating off 
the solvent in vacuo. The sodium salt thereby obtained is finely powdered, 
dried to constant weight, subsequently suspended in 100 ml of dry 
dimethylformamide and dissolved at 80.degree. C., while stirring, the 
solution is cooled to 30.degree. C. and 10.49 g (0.058 mol) of ethyl 
3-bromopropionate are added. The mixture is heated at 100.degree. C. for a 
further 3 hours to bring the reaction to completion. 
The reaction mixture is worked up as described in Example 1. Ethyl 
2,3-dihydro-3-oxo-thieno(3,2-d)-1,2-thiazole-propionate 1,1-dioxide is 
obtained in a yield of 60%. 
Melting point (diisopropyl ether): 95.degree.-96.degree. C. 
EXAMPLE 7 
10 g (0.053 mol) of thieno(3,4-d)-1,2-thiazol- 3(2H)-one 1,1-dioxide are 
suspended in 100 ml of dry dimethylacetamide and treated with sodium 
hydride in a manner analogous to that described in Example 1, and the 
mixture is reacted with 10.49 g (0.058 mol) of ethyl 3-bromopropionate at 
110.degree. C. for 2 hours 40 minutes. Ethyl 
2,3-dihydro-3-oxo-thieno(3,4-d)-1,2-thiazole propionate 1,1-dioxide is 
obtained in a yield of 65%. 
Melting point (diisopropyl ether): 105.degree.-107.degree. C. 
EXAMPLE 8 
10.8 g of 1,1-dimethylethyl 
2,3-dihydro-3-oxothieno(2,3-d)-1,2-thiazole-propionate 1,1-dioxide are 
dissolved in 110 ml of dry toluene, 113 mg of p-toluenesulfonic acid are 
added and the reaction mixture is heated under reflux for 90 minutes. 
After cooling, colorless crystals consisting of 
2,3-dihydro-3-oxo-thieno(2,3-d)1,2-thiazole-propionic acid 1,1-dioxide are 
filtered off with suction and recrystallized from ethanol. 
Yield: 79% 
Melting point: 133.degree.-135.degree. C. 
EXAMPLE 9 
2,3-Dihydro-3-oxo-thieno(3,2-d)-1,2-thiazolepropionic acid 1,1-dioxide are 
obtained in a yield of 85% by reaction, analogously to Example 8, of 
1,1-dimethylethyl 2,3-dihydro-3-oxo-thieno(3,2-d)-1,2-thiazole-propionate 
1,1-dioxide in 120 ml of dry benzene while heating under reflux. 
Melting point (water): 140.degree.-142.degree. C. 
EXAMPLE 10 10.8 g of 1,1-dimethylethyl 
2,3-dihydro-3-oxothieno(3,4-d)-1,2-thiazole-propionate 1,1-dioxide are 
dissolved in 100 ml of dry toluene, 110 mg of benzenesulfonic acid are 
added and the reaction mixture is heated under reflux for 95 minutes. 
2,3-Dihydro-3-oxo-thieno(3,4-d)1,2-thiazole-propionic acid 1,1-dioxide is 
obtained in a yield of 78%. 
Melting point (water): 173.degree.-176.degree. C. 
EXAMPLE 11 
8 g of 1,1-dimethylethyl 
5-chloro-2,3-dihydro-3-oxo-thieno(3,2-d)-1,2-thiazole-propionate 
1,1-dioxide are dissolved in 90 ml of dry toluene, 95 mg of 
methanesulfonic acid are added and the reaction mixture is heated at 
115.degree. C. for 105 minutes, while stirring. 
5-Chloro-2,3-dihydro-3-oxo-thieno(3,2-d)-1,2-thiazole-propionic acid 
1,1-dioxide are obtained in a yield of 82%. 
Melting point (ethanol): 195.degree.-197.degree. C.