Thiazolidone-2 derivatives, 4-diketone substituted, method...

Details Thiazolidone-2 derivatives, 4-diketone substituted, method... Thiazolidone-2 derivatives, 4-diketone substituted, method...

1998-12-07

2002-08-20

Gerstl, Robert (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S183000

Reexamination Certificate

active

06437143

ABSTRACT:

The present invention relates to the field of chemistry and more particularly to that of therapeutic chemistry.
More precisely, the subject of the present invention is new 2,4-thiazolidinedione derivatives, namely 5-phenoxyalkyl-2,4-thiazolidinediones, processes for producing them, their use and antidiabetic agents and in the treatment of the metabolic syndrome of insulin resistance, and the pharmaceutical compositions containing them.
Numerous 2,4-thiazolidinedione derivatives have already been described as antidiabetic agents (Takeda, Patent EP 193 256, Sankyo Patent EP 207 581).
The compounds previously described were mainly thiazolidinediones substituted at the 5 position by a benzyl radical, that is to say compounds having an alkylene chain containing only one carbon atom between the thiazolidine ring and an aryl group.
The structure of these compounds comprised in general variations on the substituent carried by the aryl ring of the benzyl radical.
Compounds possessing the structures previously described and exhibiting notable hypoglycaemic and hypotriglyceridaemic activities had as linkage at the 5 position the group R—O—Ar—CH
2
—.
These variations affected exclusively the R substituent carried by the oxygen at the para position of the phenyl.
Some of these compounds, beside their pharmacological properties, manifest hepatotoxicity phenomena (Takashi Sohda, Chem. Pharm. Bull 30 (1982) 3580).
It is known that, in non-insulin-dependent diabetes, a decrease in the efficacy of insulin leads to hyperglycaemia.
The decrease in the “activity” of insulin is linked, on the one hand, to a pancreatic defect in the insulin response to glucose and, on the other hand, to a hepatic and peripheral (muscles—adipose tissues) insulin resistance.
Some current antidiabetic therapies stimulate mainly insulin secretion, without enhancing insulin resistance, and have as major defect, in the long term, the worsening of the diabetes by depletion of the &bgr;-pancreatic cells.
Other antihyperglycaemics such as Metformin and the compounds having the 2,4-thiazolidinedione structure enhance the sensitivity to insulin.
These thiazolidinediones reduce glycemia without stimulating the secretion of insulin and prove more active in insulin resistance with hyperinsulinism.
The compounds of the present invention are new and differ from other 2,4-thiazolidinedione derivatives in properties which the compounds of the prior art did not possess: absence of effect on the secretion of insulin, action on insulin resistance, absence of hepato toxic effect, activity in diabetics in the case of diabetes without hyperinsulinism.
The subject of the present invention is specifically the new 5-phenoxyalkyl-2,4-thiazolidinediones corresponding to the general formula I:
in which
A represents a linear or branched alkylene group comprising from 2 to 16 carbon atoms
D represents a homo- or heterocarbon mono-, di- or tricyclic aromatic structure which may include one or more heteroatoms
X represents a substituent of the aromatic structure, chosen from hydrogen, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an alkoxyalkyl group in which the alkoxy and alkyl groups are defined as above, an aryl group defined as an aromatic cyclic structure comprising one or two rings optionally including one or two heteroatoms in the ring such as for example a phenyl or an &agr;- or &bgr;-naphthyl, an aralkyl group in which the alkyl group is defined as above and the aryl group is defined as above and optionally comprises one or more substituents, an aralkylaryl group whose aralkyl and aryl fractions are defined as above, a halogen, a trifluoromethyl, a cyano, a hydroxyl, a nitro, an amino, a carboxyl, an alkoxycarbonyl, a carboxamide, a sulfonyl, a sulfone, a sulfonamide, a sulfamoyl, an alkylsulfonylamino, an acylamino, a trifluoromethoxy
n is an integer ranging from 1 to 3 with the proviso that if A represents the butyl radical,
 does not represent the 4-chlorophenyl group.
In the preceding text, among the aromatic radicals D, there may be mentioned as homocarbon structure the phenyl, &agr;-naphthyl, &bgr;-naphthyl or fluorenyl radical.
Among the heterocyclic aromatic radicals, there may be mentioned pyridyl, the quinolyl ring or carbazolyl.
As regards the invention, an alkyl group is defined as having from 1 to 6 carbon atoms and especially a methyl, ethyl, propyl, isopropy, butyl, isobutyl, tert-butyl or pentyl radical and the like, an alkoxy group is defined as having from 1 to 6 carbon atoms and especially a methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy radical and the like, a halogen group is defined as being fluorine, chlorine, bromine or iodine.
The alkylene chain A is a linear or branched hydrocarbon chain having from 2 to 16 carbon atoms, which is saturated or has one or more ethylene bonds, optionally substituted with a hydroxyl radical or with a phenyl radical. An example of such a chain will be an ethylene or propylene radical.
The present invention also relates to tautomeric forms of the compounds of general formula I, to the enantiomers, diastereoisomers and epimers of these compounds, as well as their solvates.
It can be envisaged that the ketone functions carried by the thiazolidine ring may become enolized and give rise to monoenols.
The thiazolidinedione derivatives of general formula I which possess an acidic proton on the nitrogen of the thiazolidinedione ring may, in this case, be salified and exist in the form of basic salts.
Examples of basic salts of the compounds of general formula I include the pharmacologically acceptable salts, such as the sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth and the like). The amine salts which are not pharmacologically acceptable may serve as means for identification, purification or resolution.
Among the compounds of general formula I according to the invention, there may be mentioned more particularly, as compounds currently preferred:
5-[3-(4-fluorophenoxy)propyl]-2,4-thiazolidinedione
5-(2-phenoxyethyl)-2,4-thiazolidinedione
5-[2-(4-fluorophenoxy)ethyl]-2,4-thiazolidinedione
5-{[1-hydroxy-2-(4-fluorophenoxy)]ethyl}-2,4-thiazolidinedione
5-{[2-hydroxy-3-(4-fluorophenoxy)]propyl}-2,4-thiazolidinedione
5-[1-methyl-2-phenoxyethyl]-2,4-thiazolidinedione
5-[2-(4-cyanophenoxy)ethyl]-2,4-thiazolidinedione
5-[2-(2-fluorophenoxy)ethyl]-2,4-thiazolidinedione
5-[2-(2-naphthyloxy)ethyl]-2,4-thiazolidinedione
and their pharmacologically acceptable salts.
The invention also relates to the processes for producing the 5-phenoxyalkyl-2,4-thiazolidinedione of general formula I.
A process of synthesis according to the invention, (route A), is a malonic synthesis, which consists in that a compound of formula II:
in which X, D and n are defined as above,
is subjected to the action of a dihaloalkyl of formula III:
in which
Hal represents a chlorine or bromine atom,
A is an alkylene radical defined as above,
in the presence of a basic agent, to form a compound of general formula IV:
in which X, D, n and A are defined as above,
which is subjected to the action of a dialkyl malonate of formula V:
in which R
1
and R′
1
are alkyl radicals,
in the presence of an alkali metal alcoholate, to form a compound of general formula VI:
in which X, D, n, A, R
1
and R′
1
are defined as above,
which is subjected to halogenation by the action of a halogenating agent to form the compound of general formula VII:
in which
Hal represents a chlorine or bromine atom,
X, D, n, A, R
1
and R′
1
are defined as above.
The malonic compound VI may be halogenated with an N-haloamide or an N-haloimide after formation of the anion, as for example by the action of sodium hydride in tetrahydrofuran.
The dialkyl diester of general formula VII is decarboxylated and saponified by heating in an acidic mixture consisting especially of hydrochloric acid and aceti

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