Thiazolidinediones and drugs containing them

Details Thiazolidinediones and drugs containing them Thiazolidinediones and drugs containing them

1995-11-21

1997-02-04

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514342, 546146, 546175, 546122, 5462697, 5462704, 548181, 548183, C07D41712, A61K 31425

Patent

active

055998267

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/01619 filed May 19, 1994.
The present invention concerns thiazolidinediones, processes for their production and pharmaceutical agents which contain these compounds.
The invention concerns thiazolidinediones of the general formula I ##STR2## in which A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic ring with a maximum of 4 heteroatoms in which the heteroatoms can be the same or different and denote oxygen, nitrogen or sulphur and the heterocycles can if desired, carry an oxygen atom on one or several nitrogen atoms, C.sub.1 -C.sub.6 alkyl, mono- or disubstituted with C.sub.1 -C.sub.3 alkyl, CF.sub.3, C.sub.1 -C.sub.3 alkoxy, F, Cl or bromine, tolerated salts.
Similar compounds with anti-diabetic action have already been mentioned in the literature. Thus thiazolidine-diones with a hypoglycaemic action are described in the application U.S. Pat. No. 4,617,312 in which an alkoxy residue is absolutely necessary in the ortho position relative to the thiazolidinedione. The synthesis of 5-[4-(2-methyl-2-phenyl-propoxy)benzyl]thiazolidine-2,4-diones and their anti-diabetic action is presented in Chem. Pharm. Bull., 30, 3563, 1982. The U.S. Pat. Nos. 4,340,605, 4,725,610 and EP-A-389699 encompass 4-alkoxybenzylthiazolidine-diones with a hypoglycaemic action which are substituted by a heterocycle in the alkyl moiety. The European Application EP-A-332332 also claims an anti-diabetic action for benzyl-thiazolidinediones which can be substituted by various residues in the para position.
The U.S. Pat. No. 4,703,052 describes anti-diabetic derivatives which are linked with a bicycle in which, however, the aromatic ring of the bicycle which carries the thiazolidine residue may not contain any further substituent. The European Patent Applications EP-A-283035 and EP-A-299620 encompass benzoxazole-linked and benzofuran-linked thiazolidinediones with an anti-diabetic action.
It has now been surprisingly found that aromatic rings which are substituted in the same ring system by a thiazolidinedione residue and by a further substituent and to which in addition an aromatic five-membered or six-membered ring is condensed, have valuable pharmacological properties.
The compounds according to the invention are particularly suitable for the production of anti-diabetics for the oral treatment of diabetes mellitus and in particular of type II or type IIb. According to present knowledge an impairment in the utilization of insulin and glucose plays an important role in this as one of the main causes of diabetes of old age. This impairment in the utilization causes a hyperinsulinaemia which in turn is considered to be a risk factor for the development of macroangiopathic complications. Investigations on adipose type II diabetics showed that the substances according to the invention can be used to lower the level of glucose as well as of insulin. Due to their special mechanism of action the substances have some additional advantages: they do not cause hypoglycaemias and can lower the risk of arteriosclerosis in type II diabetics since they also reduce the insulin level. They are therefore also suitable for the prophylaxis of arteriosclerotic diseases. In addition they have a positive effect on elevated blood pressure values and lower the triglyceride and cholesterol level.
Preferred residues for the ring system A are carbocyclic rings with 5 or 6 carbon atoms or a heterocyclic five-membered or six-membered ring with 1 or 2 heteroatoms in which the heteroatoms can be the same or different and denote oxygen, nitrogen or sulphur.
The residues --CH.dbd.CH--, --N.dbd.CH-- or --CH.dbd.N-- are preferred for B.
W is preferably CH.sub.2, O CH(OH) or CO.
X preferably denotes S, O or NH.
Y preferably denotes N.
Preferred residues for R are naphthyl, pyridyl, furyl, thienyl or phenyl which if desired are mono- or disubstituted with methyl, CF.sub.3, methoxy, fluorine, chlorine or bromine.
Particularly preferred residues for A are carbocyclic aromatic rings with 6 carbon atoms or a heterocyclic

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