AU662658B2

AU662658B2 - New thiazolidinedione compounds, a process for their preparation and pharmaceutical compositions containing them

Info

Publication number: AU662658B2
Application number: AU48905/93A
Authority: AU
Inventors: Yves Charton; Jacques Duhault; Joseph Espinal; Gilbert Regnier
Original assignee: ADIR SARL
Current assignee: Les Laboratoires Servier SAS
Priority date: 1992-10-12
Filing date: 1993-10-11
Publication date: 1995-09-07
Anticipated expiration: 2013-10-11
Also published as: CA2108064A1; FR2696743A1; FR2696743B1; EP0593348B1; DK0593348T3; ES2117114T3; JP2948076B2; DE69317621T2; NZ248905A; ATE164374T1; ZA937552B; JPH07309852A; AU4890593A; EP0593348A1; GR3026633T3; DE69317621D1; CA2108064C

Abstract

New thiazolidinedione compounds of formula: <IMAGE> in which Ar, A, X and B are as defined in the description, their enantiomers, diastereoisomers and pharmaceutically acceptable acid addition salts. They can be used in therapeutics, especially in the treatment of insulin-resistant states and/or of non-insulinopenic diabetes, possibly in association with hypertension (high blood pressure).

Description

-l

AUSTRALIA

Patents Act 1990 F-'UU/U1 1 28/V01I Rogulation 3.2(2)

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT .0 .9

I

49.9 o 49 *0 9 9, 9 4*4~ .4 49 4 4 *09* .9 till

'LI

Application Number: Lodged: Invention Title: NEW THIAZOLIDINEDIONE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING

THEM

I~ C The following statement is a full description of this invention, including the best method of performing it known to us- 7 L The present invention relates to new thiazolidinedione compounds, a process for their preparation and pharmaceutical compositions containing them.

It relates more especially to thiazolidinedione compounds of formula I 0 I NH Ar-A-X--B- -CH2- H s

(I)

0 wherein Ar represents a) a polymethylene ring containing from 5 to 7 carbon atoms which is optionally substituted by one or more alkyl radicals having from 1 to 5 carbon atoms, b) a mono-, bi- or tri-cyclic hydrocarbon radical such as, for example, a phenyl, naphthyl, fluorenyl, f 1 dibenzocycloheptenyl or biphenylyl radical, each of which is optionally mono- or poly-substituted by a halogen atom, such as, for example, a fluorine, Schlorine or bromine atom, a trifluoromethyl radical, a straight-chain or branched alkyl, alkoxy or alkylthio radical each having from 1 to 5 carbon L L atoms, an acyloxy radical, a hydroxy radical or a radical of the formula R 1 R1 or -S02 N in each of which R2 R2

R

1 and R 2 which are the same or different, each i

'I

2 represents a hydrogen atom, or a straight-chain or branched alkyl radical having from 1 to 5 carbon atoms, or R 1 and R 2 together with the nitrogen atom to which they are bonded, represent a heterocycle having from 4 to 7 ring members optionally including (in addition to the nitrogen atom) an oxygen or sulphur atom, or c) a mono-, bi- or tri-cyclic heterocyclic radical containing 1 or 2 hetero atoms selected from nitrogen, oxygen and sulphur atoms, such as, for example, a furyl, thienyl, pyrrolinyl, pyridyl, pyrazinyl, oxazolyl, thiazolyl, indolyl, imidazolyl, chromanyl or xanthenyl radical, each of which is optionally substituted by an oxo radical and/or by one or more halogen atoms or alkyl radicals (having from 1 to 5 carbon atoms) or phenyl radicals, each phenyl radical itself optionally being substituted by one or more halogen atoms or trifluoromethyl

C

l radicals or alkyl or alkoxy radicals each having from 1 to 5 carbon atoms S A represents a single bond, a hydrocarbon chain having 2 or S3 carbon atoms and including a double bond, or a chain of the

CH

3 formula -(CH2)m- -CH-(CH2)m-l- CH3 R R" -O-(CH2)m- or -S-(CH 2 wherein m is an integer from 1 to 3 and R' and which are the same or different, each represents a hydrogen atom or a straight-chain or branched alkyl radical having from 1 to 5 carbon atoms; i r~: 3 X represents an oxygen atom, -CONR- or -SO 2 NR- wherein R represents a hydrogen atom or a straight-chain or branched alkyl radical having from 1 to 5 carbon atoms and optionally including a double bond, or, when A represents a single bond and Ar represents a phenyl radical, R may also represent a carbonyl radical bonded to Ar by its free bond such that Ar-A-X together form a phthalimido radical; B represents a saturated hydrocarbon chain having from 1 to 6 carbon atoms which is optionally branched and/or substituted by a hydroxy radical or an oxo radical; and also the enantiomers and, when B is branched, the corresponding diastereoisomers.

The prior art is illustrated especially by the patent applications EP 008203, WO 8607056, EP 207581, WO 8504171 and WO 9207850 which relate to thiazolidine-2,4-dione compounds which can be used as antidiabetic agents.

Apart from the fact that the compounds of the present invention are new, they differ from the previously known thiazolidine-2,4-dione compounds in the intensity of their pharmacological properties.

Insulin resistance and the lack of secretion of insulin are responsible for the glucose intolerance observed in patients having non-insulin-dependent diabetes.

The therapeutic agents currently available essentially allow correction of the lack of insulin secretion without necessarily improving the sensitivity to insulin of peripheral tissues (muscles, adipose tissue).

Thiazolidine-2,4-dione compounds are capable of causing a -4reduction in glycaemia and of improving glucose tolerance in non-insulin-dependent diabetic models without causing an increase in the secretion of insulin.

The compounds of the present invention have the advantage of being especially powerful (more especially compared with ciglitazone, a reference compound belonging to the same chemical class) whilst at the same time not exhibiting harmful haematological effects, as will be demonstrated by the pharmacological study described hereinafter.

The compounds of the present invention may thus be used in the treatment of conditions of insulin resistance and/or of non-insulin-dependent diabetic conditions, making it possible to obtain a better control of glycaemia but with a reduced level of circulating insulin. The prevention of that relative hyperinsulinaemia, associated with a reduction in circulating e* triglycerides resulting from the action of those com- S. pounds, may assist in reducing the risks of macro- .Tc angiopathy.

The same compounds may furthermore be used in the treatment of hypertension in older patients exhibiting I .Tinsulin resistance which may or may not be associated with other metabolic anomalies.

srC. C ?citt The present invention relates also to pharmaceutical compositions comprising as active ingredient a compound of formula I or a physiologically tolerable salt thereof, t mixed with or in association with one or more appropriate pharmaceutical excipients.

The pharmaceutical compositions so obtained are generally in dosage form containing from 100 to 200 mg of active 5 ingredient. They may, for example, be in the form of tablets, dragdes, gelatin capsules, suppositories or injection or drinkable solutions, and may be administered by the oral, rectal or parenteral route.

The dosage may vary, especially in accordance with the age and weight of the patient, the administration route, the nature of the disorder, and associated treatments, and ranges from 100 to 200 mg of active ingredient from 2 to 3 times per day.

Tb.,presenti.nent.ion relates also to a process for the preparation of compounds of formula I characterised in that either, A) a compound of formula II

H

Ar-A-X-B- -CH2-C-COOCH 3 (II)

'B

Hal wherein Ar, A, X and B are as defined hereinbefore and Hal represents a chlorine or bromine atom, is reacted with thiourea (H 2

N-C-NH

2

I

and the imine so obtained of formula III: 0 l Ar-A-X-B- -CH2-

NH

wherein Ar, A, X and B are as defined hereinbefore, is hydrolysed;

-M

-6or, B) a compound of formula IV Ar-A-X' (IV) wherein Ar and A are as defined hereinbefore and X' represents COC1, S02C, an activated ester or is reacted with a compound of formula V 0

NH

R'HN-B CH2 SS

(V)

0 wherein B is as defined hereinbefore and R' represents a hydrogen atom or a straightchain or branched alkyl radical having from 1 to 5 carbon atoms.

Method A, described by T. Sohda et al, Chem. Pharm.

Bull., 30 (10) 3580-3600 (1982), is especially suitable for the preparation of compounds I if carried out in an appropriate solvent such as, for example, methanol, ethanol, sulfolaneR or dimethylformamide, heating the mixture of compound II and thiourea at 100-120 C for from 6 to 10 hours and then hydrolysing compound III by means of a strong acid, such as HC1 or H 2

SO

4 The starting materials of formula II were prepared from "S amines of formula Ar-A-X-B-/ \NH2 -0I 1,

I

l *d(

I

I I (Cc tIcr

C

w r 3

M

c t t 0 o a r p.

i i 7 hich were themselves obtained by hydrogenating coresponding nitrated compounds under a pressure of x10 5 Pa in the presence of Raney nickel.

ethod B is advantageously carried out by reacting the ompounds IV and V at a temperature of 20-25°C for from 8 o 15 hours in a suitable solvent, such as, for example, etrahydrofuran, dimethylformamide or acetonitrile, alone r in the form of a mixture, in the presence of an cceptor for the acid formed during the course of the eaction.

wai n That acceptor may be, for example, triethylamine or an excess of the compound V used for the synthesis.

Furthermore, compounds of formula I wherein the group Ar is substituted, inter alia, by a hydroxy radical, may also be prepared by hydrolysing corresponding acyloxy compounds in the presence of sodium hydroxide solution.

Compounds I prepared in accordance with method A or B may be purified by crystallisation from appropriate customary organic solvents or by flash chromatography on an Amicon silica support (35- 7 0A) using as eluant appropriate solvents such as CH 2 C12, CH 2 C12/acetone (95:5), toluene/ethanol under a pressure of 0.5 to 1 atmosphere of nitrogen.

The compounds of formula I may be converted into addition salts with acids, which salts, as such, form part of the invention. There may be mentioned as acids that can be used for the formation of those salts, for example, in the mineral series, hydrochloric, hydrobromic, nitric, sulphuric and phosphoric acid and, in the organic series, acetic, propionic, maleic, fumaric, tartaric, oxalic, benzoic, methanesulphonic and isethionic acid.

Bc 8 The following Examples illustrate the present invention.

Unless specified otherwise, the melting points are determined using a Kofler hot plate.

Example 1 5-{4-[2-(2-methoxy-5-chlorobenzamido)ethyl]benzyl}thiazolidine-2,4-dione.

Cl 1

CO-NH-CH

2

-CH

2 CH 2 NH

OCH

3 S3 0 0 A mixture of 4.1 g of methyl 3-{4-[2-(2-methoxy-5chlorobenzamido)ethyl]phenyl)-2-chloropropionate (oil) and 1.52 g of thiourea are heated for 10 hours at 120°C in 40 ml of sulfolaneR. The imine formed is hydrolysed I by adding 14 ml of 2N HC1 to the mixture and heating the i whole at 100C for 8 hours. When the reaction is como plete, the whole is diluted with 600 ml of water and the, aqueous portion is decanted off. The gummy product is extracted with CH 2 Cl 2 and.the organic solution is washed with water. After evaporation of the solvent, the residue is purified on 90 g of silica by flash chromatography using a mixture of CH 2 C1 2 and methanol (95:5) as eluant. The evaporated eluates yield 2.6 g of the 0c« desired compound in crystallised form, m.p. 182°C.

u

'I

c I I__LII_ CI~1 C~-L~-XLL^i I I~(II- IUIIIC1~5 -9- Example 2 2-(4-hydroxy-3,5-di-tert-butylbenzamido)ethyl ]benzyl thiazolidine-2, 4-dione CH3 0 H3C-C CO-NH-CH I 2-CH2- CH2

NH

H

3 C

OCH

3 S 0 OH O H3C-C-CH 3

CH

3 1.9 g of 1, 1-carbonyldiimidazole is added to a solution of 3 g of 4-hydroxy-3,5-di-tert-butylbenzoic acid in 150 ml of anhydrous tetrahydrofuran and the solution is stirred at room temperature for 8 hours. 3 g of 5-[4- (2-aminoethyl) benzyl]thiazolidine-2,4-dione (melting at 1 *0 200'C) are then added and the mixture is stirred at room temperature for 15 hours. The solvent is then evaporated off and the residue is taken up in a mixture of 10 Na 2

CO

3 in CH 2 C1 2 The precipitate is filtered and then purified by flash chromatography on 180 g of silica using a mixture of CH2C1 2 and methanol (97:3) as eluant.

After evaporation of the eluates, 3 g of the desired *t compound in amorphous form are collected. The aminoethyl) benzyl]thiazolidine-2, 4-dione starting material was prepared by the method according to SOHDA et al from methyl (2-acetamidoethyl)phenyl]-2-chloropropionate (oil).

Cf 4i I ii i 10 Example 3 (R,,S)-5-(4-[2-(salicyloylamino)ethyl]benzyl)thiazolidine- 2,4-dione.

0

OH

CO-NH-CH2-CH2- CH2 NH

S

0 2.3 g of acetylsalicyloyl chloride are added to a solution of 3 g of 5-[4-(2-aminoethyl)benzyl]thiazolidine-2,4-dione and 1.16 g of triethylamine in 50 ml of anhydrous dimethylformamide and the mixture is stirred at room temperature for 15 hours.

The dimethylformamide is then evaporated off and the residue is taken up in CH 2 C12 and water.

The organic phase is separated off and then evaporated under reduced pressure. 5.3 g of an oily residue are obtained which are chromatographed on 170 g of silica using a mixture of CH 2 C1 2 and acetone (90:10) as eluant.

S. Evaporation of the eluates leaves 3 g of amorphous product which is dissolved in 50 ml of ethanol and then hydrolysed in the presence of 8.5 ml of N NaOH at room temperature for 5 hours. The solvent is then evaporated off, the product is taken up in N HC1 and the resulting white crystals are suction-filtered.

1.9 g of the desired compound are obtained. M.p. 184°C.

Examples 4 to The following compounds were prepared by operating analogously to the methods described above 4) 5-{4-[2-(phthalimido)ethyl]benzyl}thiazolidine-2,4dione, m.p. 180 C.

5-(4-12-(diphenylacetylamino)ethyl]benzyllthiazolidine-2, 4-dione, amorphous product.

6) ,3-diphenylpropionamido)ethyl]benzyl~thiazolidine-2,4-dione, m.p. 148*C.

7) V zyl)thiazolidine-2,4-dione, m.p. :182 0

C.

8) (R,S)-5-(4-[2-(4-methoxyphenylsulphamoy)ethyl]beizyl~thiazolidirie-2,4-dione, m.p. :143 0

C.

9) (R,Si)-5-{4-[2-(3-trifluoromethylbenzamido)ethyl]benji0 zyl~thiazolidine-2,4-dione, m.p. 130' 0

C.

(ER~)-5-(4-[2-(3,4-dichlorobenzamido)ethyl]ben- Vt zyl)thiazolidine-2,4-dione, m.p. :170 0

C.

11) (R,fi)-5-{4-[2-(phenylacetylamino)ethyl]benzy1}thiazolidine-2,4-dione, m.p. :128*C.

12) (,a--4[-peoyctlmn~ty~ezltiz, olidine-2,4-diong, m.p. :138*C.

4 13) (R,a)-5-(4-[2-(cyclopentylcarbonylamino)ethyl]benzyl~thiazolidine-2,4-dione, m.p. :154 0

C.

C C tC 14) (R,fi)-5-{4-[2-(ffur-2-ylcarbonylamino)ethy]benzyl~thiazolidine-2,4-dione, m.p. :150 0

C.

(R,S)-5-(4-[2-(5-methy1-1,2-oxazo1-3-ylcarbony1amino)ethyljbenzyl)thiazolidine-2,4-dione, m.p. :148 0

C.

16) (R,fi)-5--4-[2-(2-hydroxy-5-chlorobenzamido)ethyl]benzyl)thiazolidine-2,4-dione, m.p. 242-244*C.

12 *17) 2-(2-amino-5-chlorobenzamido) ethyl ben zyl) thiazolidine-2,4-dione, m.p. (cap) 196-200 0

C.

18) 2-(2-dimethylamino-5-chlorobenzamido) ethyl] benzyl)thiazolidine-2,4-dione, m.p. (cap): 162-164 0

C.

19) 2-(5-methoxyindol-2-ylcarbonylamino) -ethyl] benzyl1thiazolidine-2,4-dione, m.p. 232-236 0

C.

-5-f 2-(pyrid-3-ylcarbonylamino) ethyl Ibenzyl)thiazolidine-2,4-dione, rn.p. (cap): 238-240 0

C.

21) (pyr id-4-ylcarbonylami no) ethyl benzyl) thiazolidine-2,4-dione, m.p. (cap): 278-280 0

C.

22) (R,S)-5-t4-[2-(cinnamylcarbonylamino)ethyljbenzyl)thiazolidine-2,4-dione, m.p. (cap): 76-78 0

C.

23) (RS-5-(4-f 2-(3-phenylthiopropionamido) ethyl] benzyll V thiazolidine-2,4-dione, m.p. (cap): 76-78 0

C.

24) 5 f 2- 57 8- te t rame thy 1- 6-hydr o xy chroman-2-ylcarbonylamino) ethyl Ibenzyl) thiazol idine- 2, 4-di one, S amorphous product.

(R,S)-5-{4-[2--(pyrazin-2-ylcarbonylamino)ethyljbenzyl} thiazolidine-2,4-dione, m.p. 198-2001C.

26) [2-(pyrid-2-ylcarbonylamino) ethyl jbenzyl~thiazolidine-2,4-dione, m.p. 160 0

C.

27) (indol-2-ylcarbonylamino) ethyl) benzyl) thiaz- Solidine-2,4-dione, m.p. 256 0

C.

13 28) -dime thylami no ben zami do) ethyllIben zyl) thiazolidine-2,4-dione, m.p. :1800C.

29) (R,S)-5-(4-[2-(2-piperidino-.5-chlorobenzamido)ethyl] benzyl~thiazolidine-2,4-dione, m.p. 164-166 0

C.

530) (R,S)-5-(4--12-(fur-3-ylcarbonylamino)ethyllbenzyl)thiazolidine-2,4-dione, m.p. 176--1780C.

31) 5-miethyl-2-phenyloxazol-4-ylcarbonylamino) ethyl Ibenzy1}thiazolidine-2,4- -dione, m.p. (cap) 178- 18000.

32) 5-methyl-2-phenyloxazol-4-ylacetylamino) ethyl benzyl) thiazolidine-2, 4-dione, m.p. (cap) 146- 15000.

33) (R,S)-5-(4-[3-(2-methoxy-5-chlorobenzamido)propyljbenzyl) thiazolidine-2,4-dione, m.p. (cap) :142 0

C.

34) 2- (2--methoxy-5-trif luoromethylbenzamido) ethylj benzyl)thiazolidine-2,4-dione, m.p. (cap) with decomposition >160 0

C.

thazldie2,-ioe (cp 5012C thiazolidine-2,4-dione, m.p. (cap) ;150-152 0

C.

:~o36) (R,S)-5-(4-[2(5-chloro-2-methoxyenaoethyldobenzyl} benlthiazolidine-2,4-dione, m.p. (cap) 116118 0

C.

S38) (a,g)-5-{4-[2-(4-amino--chloro-2-methoxybenzamido)ethylI L cc 25 benzyllthiazolidine-2,4-dione, m.p. (cap) of the 14 corresponding hydrochloride :125-1301C.

39) (R,S)-5-{4-[i-oxo-2-(5-chloro-2-methoxybenzamido) -ethyl]I benzyllthiazolidine-2,4-dione, M.p. (cap) 190-192 0

C.

.5 4 1l- hyd roxy 2- 5 -c hlo r o- 2-me th o xy ben za m id o ethyl]benzyl~thiazolidine-2,4-dione, m.p. (cap) :175-178*C.

41) S) -5-f 5-di -ter t -butyl -4 -hydroxyphenoxy) -ethyl] benzyl)thiazolidine-2,4-dione, m.p. (cap) 118-120 0

C.

42) (RS-5-f{4- 2-(3-ethyl-4-methyl-2-oxo-3-pyrrolin-l- LIylcarbonylamino)ethyllbenzyl~thiazolidine-2,4-dione, M.P.

1 10 (cap) :178-180 0

C.

43) 4-dimethoxyphenyl )prop-2-enoylamino) ethyl benzyl) thiazolidine-2, 4-dione, rn.p. (cap) ;178- 180 0

C.

44) (R,S)-5-{4-12-(3-(3,4-methylenedioxyphenyl)prop-2-enoyl- Samino) ethyl benzyl) thiazolidine-2, 4-dione rn.p. (cap) 155- K> 45) (R,S)-5-{4-[2--(xanthen-9-ylcarbonylarnino)ethyl]benzyl) Sthiazolidine-2,4-dione, m.p. (cap) :138-140 0

C.

46) 2- (2,6-dimethylphenyl) acetylami no) ethyl] benzyl~thiazolidine-2,4-dione, m.p. :182 0

C.

47) (R,S)-5-{4-[2-(l0,11-dihydro-5H-dibenzo[a,dlcyclohepten-5ylcarbonylamino)ethyllbenzyl~thiazolidine-2, 4-diane, m.p.

(cap) :180-182 C.

t C 49 48) 2- (4-hydroxY-3--methoxyphenyl)prop-2-enoyl- *amino) ethyl Ibenzyl Ithiazolidine-2, 4-dion'e, m.p. (Qap) :172- 176 0

C.

49) (R,S)-5-{4-[2-(fluoren-9-ylcarbonylamino)ethyllbenzyl) 5thiazolidine-2,4-dione, m.p. (cap) :180-184 0

C.

(R,S)-5-{4-[2-(3-(4-acetoxy-3-methoxyphenyl)prop-2-enoylamino)ethyllbenzyl)thiazolidine-2,4-dione, m.p. (cap): 135- 1400C.

Example 51 PHARMACOLOGICAL STUDY A/ Study of the activity of the compounds of the invention on a non insulin-dependent diabetic model (NIDDM) The animals (ob/ob mice) are treated each day, for 4 days, by the oral administration of the compounds of the invention suspended in a 20 Senegal gum solution.

Before and after treatment, that is to say on dO and on blood is taken by piercing the orbital sinus and the glycaemia is determined.

Table 1 shows the doses of the different compounds that need to be administered to obtain the same hypoglycaemic effect (base 100).

SC CC L I t 16 Table 1 Doses causing the same hypoglycaemic effect in ob/ob mice

I

I.

cc *r I tr

C

C L C Compounds Dose mg/kg/day Hypoglycaemic for 4 days activity ciglitazone 50-100 100 Example 1 =10 100 Example 3 25 100 Example 4 10 100 Example 6 10 100 Example 7 25 100 Example 14 10 100 Example 15 25 100 Example 25 10 100 Example 28 10 100 Example 33 25 100 Example 35 20 100 Example 36 20 100 Example 40 50 100 Example 41 50 100 Example 43 25 100 Example 44 10 100 Example 45 15 100 Example 46 40 100 4" 04 17 B/ Study of the activity of the compounds of the invention on a model having reduced glucose tolerance associated with hyperinsulinaemia and hyperlipaemia.

The animals (Zucker Fa/Fa male rats) are treated each day, for 10 days, by the oral administration of the compounds of the invention at a dose of 5 mg/kg/day suspended in a 20 Senegal gum solution. On the 11th day the animals are sacrificed and blood is collected in order to determine glycaemia, plasma triglycerides and immuno-reactive insulin. The animals are also weighed before and after treatment.

Under those conditions the compounds of the invention do not have any influence on the level of circulating glucose but decrease the level of triglycerides (TG) and free fatty acids (FFA) in the plasma and also the level of immuno-reactive insulin. The activity is the same as, or superior to, that of other reference thiazolidinedione tc compounds.

STable 2 Pharmacological study of Zucker Fa/Fa male rats cc ccE.* 3 ct t t c cccr C I Dose Weight Glycaemia Plasma TG FFA (mg/kg/day) AP insulin for 10 days dl-d Control 0 +100 100 100 100 100 pioglitazone 5 +320 115 49 35 57 Example 1 5 +112 113 71 94 83 Example 4 5 +132 108 72 78 108 Example 28 5 +103 99 75 89 110 Administered per os to male SDCD rats weighing 175 g, contrary to pioglitazone the compounds are without effect 18 on the specified elements of the blood and the plasma volume: Table 3 (control values 100) Duration of White Red Haemato- Haemotreatment corpuscles corpuscles crit globin 8 days pioglitazone: 100 mg/kg/d 46 37 26 29'% Example 1: 100 mg/kg/d 11 11 250 mg/kg/d 4 11 4 4% 1 it i t r r1

S

tt4i t t€

LP

¢C,

t i .1 I Ci S S

Claims

22- 0 I 7 N H Ar-A-X-B- \-CH2- H s (III) NH i wherein Ar, A, X and B are as defined hereinbefore, j is hydrolysed; or, B) a compound of formula IV Ar-A-X' (IV) wherein Ar and A are as defined in claim 1 and X' represents COC1, SO 2 Cl, an activated ester lo Ar-A-x c-OMPr-1SnA C #i4halc a(hydrd- radc*Ca( is reacted with a compound of formula V 0 o I N H R'HN-B/ \CH2 (v) 0 wherein B is as defined in claim 1 and R' represents a hydrogen atom or a straight- chain or branched alkyl radical having from 1 to carbon atoms; and, if desired, the isomers of the compounds so obtained are separated by conventional methods of separation and/or the said compounds are converted into their addition salts with a pharmaceutically acceptable acid. f 6) Pharmaceutical compositions containing as active ingredient at least one compound according to any one of Sclaims 1 to 4, alone or in combination with one or more (,,it79) 23 appropriate pharmaceutical excipients. 7) A method of treating conditions of insulin resistance and/or non-insulin- dependent diabetes which may or may not be associated with hypertension comprising administering to a patient requiring such treatment a pharmaceutically effective amount of a compound as claimed in any one of claims 1 to 4 in adjunct with suitable excipients. DATED this 29th day of June, 1995 ADIR ET COMPAGNIE WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA j t i-- t. C t TIL t 't C -i r I--I 0 i 5*9* a a a ABSTRACT NEW THIAZOLIDINEDIONE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM ADIR ET COMPAGNIE 1 rue Carle H6bert F 92415 COURBEVOIE CEDEX New thiazolidinedione compounds of formula 0 \-NH Ar-A-X-B-/ -CH2< K 0 0 ''at t 4-C wherein Ar, A, X and B are as defined in the description, their enantiomers, diastereoisomers and pharmaceutically k t acceptable acid addition salts. They may be used therapeutically especially in the treatment of conditions of insulin resistance and/or non-insulin- dependent diabetes which may or may not be associated with hypertension.