WO2004028537A1 - Use of thiazolidinedione derivatives as aldose reductase inhibitors - Google Patents

Abstract

The present invention relates to the use of thiazolidinedione derivatives as aldose reductase inhibitors.

Description

Use of thiazolidinedione derivatives as aldose reductase inhibitors

The present invention relates to the use of thiazolidinedione derivatives as aldose reductase inhibitors.

Aldose reductase, referred to herein as AR, and also listed under the designations E.C.1.1.1.21 AR2 or AKR1 B1 , is a ubiquitous enzyme, which, after binding NADPH, catalyses the reduction of various aldehydes to their corresponding alcohols, for example converting glucose to sorbitol.

The advantage of developing aldose reductase inhibitors for the treatment of diabetic complications is well documented.

Specifically, regulating the level of glycaemia, especially by treatment with insulin, is not sufficient to block all the complications of diabetes, espe- cially the microvascular complications, such as neuropathies, nephropathies, retinopathies, etc. A cataract may especially develop in the context of diabetes, despite the glycaemia being under control.

There is thus a need for products that act directly on these complications. It has been shown that aldose reductase inhibitors make it possible to prevent or slow down the progress of diabetic complications (Oates and Mylari, 1999, Exp. Opin. Invest. Drugs 8(12): 2095-2119).

However, few compounds are currently developed in this respect.

Pfizer has described a certain number, such as Zopolrestat (US 4 939 140; US 5 990 111) and Sorbinil, the development of which was suspended. Epal- restat has been marketed by Ono, in Japan only, and Fidarestat is in clinical phase III for neuropathies, also in Japan.

Patent application WO 00/07582 moreover proposes to use certain thiazolidinedione derivatives, which are activators of the peroxisome prolif- erator-activated receptor y (PPARy), for the treatment or prevention of cataracts.

Patent application WO 97/22600 describes that certain other thiazolidinedione derivatives, PPARy also, show inhibitory activity on aldose reductase.

The inventors have now demonstrated, surprisingly, that derivatives of 5-phenoxyalkyl-2,4-thiazolidinedione type as described, for example, in patent application WO 97/47612 show inhibitory activity on aldose reductase. This property is all the more advantageous since it adds to the hypo- glycaemiant property already known for these compounds.

These compounds, which are not activators of the peroxisome prolif- erator-activated receptor y (PPARy), and consequently are less likely to cause hepatic toxicity, moreover show strong potential as antidiabetic agents.

It thus becomes possible to treat both diabetes, by lowering glycaemia, and diabetic complications, by acting directly via inhibition of aldose reductase.

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.

Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

The targeted compounds comprise the compounds of the formula (I):

in which A represents a saturated or unsaturated, linear or branched hydrocarbon-based group containing from 2 to 16 carbon atoms, D represents a homo-carbon-based or hetero-carbon-based, mono-, bi- or tricyclic aromatic structure possibly including one or more hetero atoms,

X represents a substituent of the aromatic structure, chosen from hydrogen, an alkyl group containing from 1 to 6 carbon atoms, an alkoxy group containing 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 ring structure comprising one or two rings optionally including one or two hetero atoms in the ring, for instance a phenyl or an α- or β-naphthyl, an arylalkyl 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 arylalkylaryl group in which the arylalkyl 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 sul- fone, a sulfonamide, a sulfamoyl, an alkylsulfonylamino, an acylamino or a trifluoromethoxy, n is an integer ranging from 1 to 3.

Among these compounds, those in which A represents a butyl radical and ₍χ₎n-fD~ . represents a 4-chlorophenyl group have moreover especially already been described.

In the text hereinabove, among the aromatic radicals D, homo-carbon- based structures that may be mentioned include the phenyl, α-naphthyl, β-naphthyl, anthracenyl and fluorenyl radicals. Among the heterocyclic aromatic radicals that may be mentioned are pyridyl and the quinolyl or carba- zolyl ring system.

D preferably represents a phenyl or naphthyl radical. Among the alkyl groups containing from 1 to 6 carbon atoms that may especially be mentioned are the methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, tert-butyl, pentyl and hexyl radicals. Among the alkoxy groups con- taining from 1 to 6 carbon atoms that may especially be mentioned are the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy radicals. Among the halogen groups that may especially be mentioned are fluorine, chlorine, bromine and iodine. The A chain is a linear or branched hydrocarbon-based chain containing from 2 to 16 carbon atoms, that is saturated or contains one or more ethylenic groups, optionally substituted by at least one hydroxyl radical or with a phenyl radical. Examples of linear alkyl radicals that may especially be mentioned include the divalent ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl and hexadecyl radicals. Among the branched alkyl chains that may especially be mentioned are the divalent 2-ethylhexyl, 2-methylbutyl, 2- methylpentyl, 1-methylhexyl and 3-methylheptyl radicals. Among the monohydroxyalkyl chains that are preferred are radicals containing 2 or 3 carbon atoms, such as 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl. Among the polyhydroxyalkyl chains that are preferred are radicals containing 3 to 6 carbon atoms and 2 to 5 hydroxyl radicals, such as 2,3- dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl or a pentaerythritol residue. Among the hydrocarbon-based chains containing from 2 to 16 carbon atoms and one or more ethylenic groups, mention may be made especially of the divalent allyl radical.

The divalent ethyl or propyl radical is preferred.

The present invention also relates to the tautomeric forms of the compounds of the general formula (I), to the enantiomers, diastereoisomers and epimers of these compounds, and also to the solvates thereof.

It may be conceived that the ketone functions borne by the thiazolidine ring can enolize and give rise to mono-enols.

The thiazolidinedione derivatives may be salified and be in the form of basic salts. Examples of basic salts of the compounds of the general formula (I) include pharmacologically acceptable salts, such as sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth, etc.). The amine salts that are not pharmacologically acceptable may serve as a means of identification, purifi- cation or resolution.

Among the compounds of the general formula (I) according to the invention, mention will be made more particularly, as compounds that are currently preferred, of: - 5-[3-(4-fluorophenoxy)propyl]thiazolidine-2,4-dione

- 5-(2-phenoxyethyl)thiazolidine-2,4-dione

- 5-[2-(4-fluoroρhenoxy)ethyl]thiazolidine-2,4-dione

- 5-{[1-hydroxy-2-(4-fluorophenoxy)]ethyl}thiazolidine-2,4-dione - 5-{[2-hydroxy-3-(4-fluorophenoxy)]propyl}thiazolidine-2,4-dione

- 5-[1 -methyl-2-phenoxyethyl]thiazolidine-2,4-dione

- 5-[2-(4-cyanophenoxy)ethyl)]thiazolidine-2,4-dione

- 5-[2-(2-fluorophenoxy)ethyl]thiazolidine-2,4-dione

- 5-[2-(2-naphthyloxy)ethyl]thiazolidine-2,4-dione and pharmacologically acceptable salts thereof.

These compounds have been described in patent application WO 97/47612.

It is preferred to use 5-[2-(4-cyanophenoxy)ethyl)]thiazolidine-2,4- dione, referred to herein as compound (1). The invention thus relates to the use of a compound of the formula (I) derived from thiazolidinedione, for the manufacture of a medicament for inhibiting aldose reductase.

Numerous applications derive therefrom, the medicament prepared being useful in preventing and/or treating any pathology against which an inhibition of aldose reductase is desired.

One of the preferred applications is the prophylactic treatment of cataracts.

A cataract is an opacification of the lens of the eye, which affects the visual acuity. A treatment of cataracts with aldose reductase inhibitors is already described, for example in patent US 6399 655.

The term "prophylactic" means total or partial protection against the formation of cataracts, by preventing the appearance of this phenomenon.

The compounds of the formula (I) are particularly useful for inhibiting age-related cataracts and diabetic cataracts. However, these compounds are also useful for the treatment of cataracts that are being or have been surgically treated, cataracts that form after surgical removal of an existing opacified lens, i.e. secondary cataracts, cataracts that arise after a detachment of the retina and surgery to repair this detached retina, cataracts associated with ocular or cranial trauma, cataracts associated with tumours, cataracts associated with exposure to radiation and cataracts associated with a toxicity.

The invention is also directed towards the prophylactic treatment of cataracts resulting from systemic disorders, for example galactosaemia, or Farry's disease, and dermatological disorders, such as atopy or ichthyosis.

The invention is also directed towards preventing the formation of cataracts caused by disorders of the central nervous system, such as neuro- fibromatosis, and local ocular diseases, such as glaucoma or degenerative myopia. The invention also relates to the prevention and/or treatment of reti- nopathy, neuropathy and nephropathy, in particular in diabetic patients (Tomlinson et ah, 1994, TIPS, 15: 293-297).

In general, the neuropathies may be autonomic or peripheral. In the case of an autonomic neuropathy, it may be, for example, cardiac neuropathy, gastric neuropathy or impotence.

Finally, the invention is directed towards preventing and/or treating myocardial reperfusion ischaemia (Hwang et al., 2000 FASEB Journal, 16(2): 243-5). Specifically, the reperfusion flow rate is increased by the inhibitory action of the compounds of the formula (I). The compound of the formula (I) can be used alone or in combination with at least one other active principle, for example another antidiabetic agent. Such a combination is particularly advantageous for the treatment of a complication in a diabetic patient, preferably a diabetic cataract. It may be, for example, insulin or a compound intended to reduce the hyperglycaemia of diabetes, especially of non-insulin-dependent diabetes (NIDDM).

The compound of the formula (I) and at least one other active principle may be combined in the same pharmaceutical composition.

Preferably, however, the compound of the formula (I) is used without being combined with another hypoglycaemiant agent, in particular not with insulin, especially when the patient is not diabetic.

Among the other hypoglycaemiant agents that may be mentioned are the 4-oxobutanoic acids as described in patent application WO 98/07681, glitazones, compounds that stimulate insulin secretion, such as sulfonyl- ureas, metformin, α-glucosidase inhibitors, etc. The medicament according to the invention is a pharmaceutical composition comprising, as active principle, at least one compound of the The invention also relates to the prevention and/or treatment of reti- nopathy, neuropathy and nephropathy, in particular in diabetic patients (Tomlinson et al., 1994, TIPS, 15: 293-297).

In general, the neuropathies may be autonomic or peripheral. In the case of an autonomic neuropathy, it may be, for example, cardiac neuropathy, gastric neuropathy or impotence.

Finally, the invention is also directed towards the use of a compound of the formula (I) for the manufacture of a medicament for the prevention of and/or treating myocardial reperfusion ischaemia (Hwang et al., 2000 FASEB Journal, 16(2): 243-5). Specifically, the reperfusion flow rate is increased by the inhibitory action of the compounds of the formula (I).

The compound of the formula (I) can be used alone or in combination with at least one other active principle, for example another antidiabetic agent. Such a combination is particularly advantageous for the treatment of a complication in a diabetic patient, preferably a diabetic cataract. It may be, for example, insulin or a compound intended to reduce the hyperglycaemia of diabetes, especially of non-insulin-dependent diabetes (NIDDM).

The compound of the formula (I) and at least one other active principle may be combined in the same pharmaceutical composition. Preferably, however, the compound of the formula (I) is used without being combined with another hypoglycaemiant agent, in particular not with insulin, especially when the patient is not diabetic.

Among the other hypoglycaemiant agents that may be mentioned are the 4-oxobutanoic acids as described in patent application WO 98/07681 , glitazones, compounds that stimulate insulin secretion, such as sulfonyl- ureas, metformin, α-glucosidase inhibitors, etc.

The medicament according to the invention is a pharmaceutical composition comprising, as active principle, at least one compound of the formula (I) with one or more pharmaceutically acceptable excipients or vehicles.

The expressions "excipients" and "pharmaceutically acceptable vehicle" mean any solvent, dispersing medium, absorption retarder, etc. that does not produce a side reaction, for example an allergic reaction, in humans or animals.

The dosage obviously depends on the active agent under consideration, the mode of administration, the therapeutic indication and the patient's age and condition. The unit dose of the compound of the formula (I) comprises from 12.5 to 200 mg of this compound (the dose depending especially on the active agents under consideration), preferably between 12.5 and 150 mg and even more preferably between 20 and 50 mg.

Taking one dose per day is preferred. The pharmaceutical compositions of the invention may be formulated so as to be administered to the patient via any route, for example via the oral or parenteral route.

When parenteral administration is envisaged, more particularly by injection, the compositions of the invention comprising the active principle(s) are in the form of injectable solutions and suspensions packaged in vials of bottles for slow perfusion. The injection may especially be performed sub- cutaneously, intramuscularly, intravenously or intra-vitreally.

When oral administration is envisaged, the compositions of the invention are in the form of gel capsules, effervescent tablets, coated or uncoated tablets, sachets, sugar-coated tablets, drinkable vials or solutions, micro- granules or sustained-release forms.

The forms for oral administration are prepared by mixing the active substance with various types of excipients or of vehicles, such as fillers, disintegration (or crumbling) agents, binders, dyes, flavour enhancers and the like, followed by shaping the mixture.

The dye can be any dye permitted for pharmaceutical use. Examples of flavour enhancers include cocoa powder, mint, borneol and cinnamon powder.

Examples of binders that may be mentioned are polyvinylpyrrolidone, hydroxypropylmethylcellulose, alginic acid, carbomer, carboxymethylcellu- lose, dextrin, ethylcellulose, starch, sodium alginate, polymethacrylate, maltodextrin, liquid glucose, magnesium aluminium silicate, hydroxyethyl- cellulose, hydroxypropylcellulose, ethylcellulose, methylcellulose and guar gum.

It is possible to use alginic acid, sodium carboxymethylcellulose, col- loidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, methylcellulose, microcrystalline cellulose, cellulose powder, pregelatinized starch, sodium alginate or sodium starch glyco- late as disintegration agent.

The fillers are, for example, cellulose, lactose, calcium hydrogen phosphate and microcrystalline cellulose.

The tablets can be obtained in a conventional manner by compressing granules in the presence of one or more lubricants. Suitable lubricants are calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogen- ated castor oil, hydrogenated plant oil, light mineral oil, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, stearyl sodium fumarate, stearic acid, talc and zinc stearate. These tablets can then be coated using polymers in solution or suspension, such as hydroxypropylmethylcellulose or ethylcellulose.

The granules used to do this are prepared, for example, by using the wet granulation process starting with a mixture of the active principles with one or more excipients, such as a binder, a crumbling agent (or disintegration agent) and a filler.

To obtain hard capsules, the mixture of the active principles with a suitable filler (for example lactose) is incorporated into empty gelatin cap- sules optionally in the presence of a lubricant, suc as magnesium stearate, stearic acid, talc or zinc stearate. Gel capsules or soft capsules are prepared by dissolving the active principles in a suitable solvent (for example polyethylene glycol), followed by incorporation into soft capsules.

The forms for parenteral administration are obtained in a conventional manner by mixing the active principle(s) with buffers, stabilizers, preserving agents, solubilizing agents, isotonicity agents and suspension agents. In accordance with the known techniques, these mixtures are subsequently sterilized and then packaged in the form of intravenous injections.

As buffer, a person skilled in the art can use buffers based on organophosphate salts.

Examples of suspension agents include methylcellulose, hydroxyethyl- cellulose, hydroxypropylcellulose, acacia and sodium carboxymethyi- cellulose.

Examples of solubilizing agents include castor oil solidified with poly- oxyethylene, polysorbate 80, nicotinamide or macrogol.

In addition, stabilizers that are useful according to the invention are sodium suifite and sodium metasulfite, while mention may be made of sodium p-hydroxybenzoate, sorbic acid, cresol and chlorocresol as preserving agents. For the preparation of an oral solution or suspension, the active principles are dissolved or suspended in a suitable vehicle with a dispersant, a humectant, a suspension agent (for example polyvinylpyrrolidone), a preserving agent (such as methylparaben or propylparaben), a flavour enhancer or a dye.

For the preparation of suppositories, the active principle(s) is (are) mixed in a manner that is known per se with a suitable base constituent, such as polyethylene glycol or semisynthetic glycerides.

For the preparation of microcapsules, the active principles are combined with suitable diluents, suitable stabilizers, agents that promote the sustained release of the active substances or any other type of additive for the formation of a central core which is then coated with a suitable polymer (for example a water-soluble resin or a water-insoluble resin). The techniques known to those skilled in the art will be used for this purpose. The microcapsules thus obtained are then optionally formulated in suitable dosage units.

Ocular administration may also be envisaged, in particular in the case of treating a cataract. The compound of the formula (I) is then in the form of an ophthalmic composition for local administration in the eye, for instance an eye lotion or an ophthalmic cream.

The ophthalmic composition may be an aqueous solution comprising distilled water or physiological saline solution, in which the compound of the formula (I) is dissolved. In this case, sodium salt or any other salt obtained by salification, for example with an amine of a compound of the formula (I) as defined above, is preferably used. Various additives may be incorporated into the ophthalmic composition if necessary, for example buffers, agents for maintaining isotonicity with the tears, preserving agents, thickeners, stabiliz- ers, antioxidants, pH regulators, chelating agents, etc.

The eye drops are prepared by aseptic manipulation, or sterilization is performed at a suitable stage in the preparation.

The ophthalmic creams may be prepared asepticaliy by mixing the active principle with a common base. The bases for ophthalmic creams are, for example, petroleum jelly, Jelene 50 or Plastibase, acrogol, etc. Surfactants may be added to increase the hydrophilicity. Additives, such as those described above, for example preserving agents, may be added if necessary. In general, for a local ophthalmic application, a satisfactory effect in adults is obtained by administering to the eye one drop of a preparation comprising from 0.001% to 10% and preferably from 0.01% to 1% by weight/volume of the compound of the invention or of a pharmaceutically acceptable salt thereof, several times, preferably one to six times a day, on each occasion preferably with one to four drops per eye, and, in the case of using an ophthalmic cream, by administering a preparation comprising from 0.001% to 10% and preferably from 0.01% to 1% by weight/volume of the compound of the invention or of a pharmaceutically acceptable salt thereof, with application to the eye preferably one to six times a day. The present invention also relates to a method for the prevention of and/or treating one of the pathologies mentioned above in a mammal requiring such a treatment, comprising the administration to the said mam- mal of a compound of the formula (I) in an amount that is effective to prevent and/or treat the pathology.

The figures and examples below illustrate the invention without limiting its scope.

KEY TO THE FIGURES:

Figure 1 is a graph showing the degree of opacity of the lens in streptozotocin (STZ) -responsive rats.

Figure 2 is a graph showing the number of cases of cataracts and the degree of opacification of the lens of treated rats versus control rats.

Figure 3 is a graph showing the number of rats with 0, 1 or 2 opacified eyes. EXAMPLES:

Example 1 : Effect of compound 1 on rat cataracts

During a study of the effect of compound 1 as described above, on:

- glycaemia, - feeding,

- body weight,

- mortality, in the case of rats treated with streptozotocin (model of type I diabetes), an unexpected result was demonstrated regarding the prevention of the appearance of cataracts in these rats.

MATERIALS AND METHODS: ♦ Products:

The streptozotocin (STZ) was obtained from Sigma-Aldrich (batch No. 100K1677, α-anomer = 79%). The other reagents were obtained from Sigma-Aldrich (sodium citrate) or from Choay (heparin). The solutions were prepared at the time of use.

♦ Animals:

The rats, male Wistar rats weighing from 290 to 310 g (8-9 weeks old), were obtained from Charles River/lffa-Credo. Upon their arrival (week

W[-1]), the rats were grouped in pairs in each cage. They were fed with a standard diet and were given water ad libitum. The protocol was started after a period of adaptation of six days following their arrival.

♦ Protocol:

In week W0, the rats received a single dose of 70 mg/kg of STZ (360 μl injected), administered intra-peritoneally early in the afternoon. The control rats received 360 μl of the vehicle (5 mM sodium citrate, pH 4.8). During week W0, a first blood sample was taken three days after the injec- tion of STZ to determine the plasmatic glycaemia. No loss was observed during this first week after injection of STZ.

After one week, the animals were divided up as follows (week W1): - "vehicle" group: 30 rats receiving standard feed ad libitum (A03, U.A.R., France); - "compound 1" group: 30 rats receiving feed comprising 1.1 g/kg

(0.1 % weight/weight) of compound 1.

The administration of compound 1 via the feed started on the Monday of W1.

♦ STZ-"responsive" animals:

The animals were classified according to whether they were "responsive" or "resistant" to STZ. The animals whose glycaemia was less than 18 mM, i.e. about 2.5 times the glycaemia value of the rats not treated with STZ of the said preliminary study (about 8 mM) and which weighed more than 330 g (after W2-W3) were considered as "resistant" (or "unresponsive"). From W2, these two criteria were equivalent and stable. In the "vehicle" group, three out of the four rats that died were "responsive". In the compound 1 test group, all four of the rats that died were "responsive".

For most of the animals, the "responsive" or "unresponsive" criteria could be attributed from W1 , and did not change from then onwards. However, in the two groups, the glycaemia measured at WO (i.e. 3 days after the STZ) was able to reach or exceed, albeit transiently, 18mM in certain animals (5/8 in the "vehicle" group; 3/8 in the compound 1 group).

♦ Quantification of the cataract

A substantial level of ocular opacification was reported from weeks W9/W 10 onwards.

Then, at W11 (CM), W12 (CM, TL) and W13 (CM), a visual quantification of the ocular affliction of each animal (i.e. of the number of eyes affected) was determined according to the following scale:

- 0 = no eyes affected, - 1 = only one eye affected,

- 2 = both eyes affected.

Furthermore, for each lens, the operator performed an in situ graded quantification of the level of opacity at the time of sacrifice (W13), according to the following scale: - 0 = no opacity,

- 1 = slightly opaque (and/or flaky),

- 2 = very opaque/dense/white.

After euthanasia, the lenses were removed, dry-transferred into Eppendorf tubes and stored in liquid nitrogen.

♦ Completion of the protocol:

At the end of the protocol, the animals were euthanased (isoflurane) for the final blood sample collection, before being sacrificed (lethal dose of pentobarbital). This sample collection was performed in two steps: (i) on a heparinized pipette as described above, to obtain plasma, and (ii) without anticoagulant, to obtain serum after coagulation in the tube.

♦ Data compilation and analysis:

The results are expressed in the form of a "mean ± standard error" of n determinations. For comparison of the means of two populations of values, the statistical significance was evaluated with Student's t test (bilateral), with a 5% threshold. For comparison of groups and kinetics, the significance was evaluated by 2-factor analysis of variance, without repeating the experiment (ANOVA, with a 5% threshold).

RESULTS: ♦ Cataracts and protective effect of compound 1 :

Cataracts: ocular opacification was observed from weeks W9/W10 onwards. This opacification appeared only in the STZ-" responsive" animals

(no STZ-" resistant" animal showed any detectable opacification). For each lens, the quantification (0, 1 or 2) of the level of opacity was determined in situ at the time of sacrifice (W 13) .

Figure 1 shows the mean opacity of the STZ-" responsive" animals.

The mean opacification of the lenses is almost completely abolished in the case of the animals treated with compound 1 (135 mg/kg/day) (0.06 ± 0.04, n = 34, versus; 1.00 ± 0.17, n = 38; p < 10^"6). In this group, only two lenses

(autologous) showed a median degree of opacification (value "1 "), whereas in the "vehicle" group, 17 lenses showed opacification.

Figure 2 shows the distribution of the levels of opacification in the two groups corresponding to the above means (at W13). Finally, the seriousness of the cataract was quantified on the basis of the number of eyes affected by opacification (i.e. only one eye, or both eyes). Figure 3 shows the results for W13 (similar results were obtained at W11 and at W12, not shown). An examination of Figure 3 shows that:

- half of the "vehicle" animals are afflicted with cataracts (five affected in one eye, four affected in both eyes), whereas the other half is spared (nine rats with no detectable ocular affliction);

- compound 1 considerably reduces the levels of ocular affliction (no animal affected bilaterally, and 16 out of 17 animals unaffected).

Example 2: in vitro test of aldose reductase inhibition

Materials and methods

Aldose reductase was extracted from the lens of male rats (Wistar, 200 to 240 g) according to the method described in Ward et al., 1990, Bio- chem. Pharmacol. 39(2): 337-346.

The lenses collected were homogenized in distilled water comprising 5 mM of 2-mercaptoethanol and 0.5 mM of EDTA, and then centrifuged. The supernatant was precipitated with ammonium sulfate at 40%, 50% and then 75% saturation. The supernatant was retained after the first two precipitations, and the AR activity was assayed on the pellet from the last step. The precipitate was dispersed in 75% saturated ammonium sulfate, at a rate of about 80 mg protein/cm³, and stored at -20°C.

The measurement of the aldose reductase activity was determined under the following conditions: 67 mM phosphate/NaOH, pH 6.2, 75 μM NADPH, 0.40 M lithium sulfate, 167 mM D-glucose and 5 μ\ of dimethyl sulfoxide per 3 cm³ of sample (containing the test compound). The reagents, including the enzyme at about 1.3 mg of protein/cm³, were incubated at 37°C for 10 minutes. The reaction was started by addition of L-glyceraldehyde. The enzymatic activity was measured by monitoring the disappearance of the NADPH by spectrophotometry (ε₃₄₀), with an NADPH extinction coefficient of 6.200/M/cm. Results

The compounds were first tested at 10^"5, 10^"6 and 10^"7 M. For the compounds that induced an inhibition of more than 30% at 10^"5 M, a more precise determination of their IC₅o (concentration inhibiting 50% of the AR activity) was performed.

The results are given in Table 1 below:

Table 1 : in vitro inhibition of rat lens aldose reductase

Compound 1 : 5-[2-(4-cyanophenoxy)ethyl]thiazolidine-2,4-dione Compound 2: 5-[2-(2-naphthyloxy)ethyl]thiazolidine-2,4-dione

Example 3: Preparation of a tablet

The following tablet formulations may be prepared: Formulation examples

1) 3)

5) 6)

Example 4: Preparation of an eye lotion

Formula No. 1

Formula No. 2

Claims

1. Use of a compound of the formula (I) derived from thiazolidinedione, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting aldose reductase, the compound of the formula (I) corresponding to the formula:

in which A represents a saturated or unsaturated, linear or branched hydrocarbon-based group containing from 2 to 16 carbon atoms,

D represents a homo-carbon-based or hetero-carbon-based, mono-, bi- or tricyclic aromatic structure possibly including one or more hetero atoms,

X represents a substituent of the aromatic structure, chosen from hydrogen, an alkyl group containing from 1 to 6 carbon atoms, an alkoxy group containing 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 ring structure comprising one or two rings optionally including one or two hetero atoms in the ring, such as, for example, a phenyl or an α- or β-naphthyl, an arylalkyl 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 arylalkylaryl group in which the arylalkyl 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 or a trifluoromethoxy, n is an integer ranging from 1 to 3.

2. Use according to Claim 1 , in which the medicament is intended for the prophylactic treatment of cataracts.

3. Used according to Claim 1 , in which the medicament is intended for the prevention of and/or treating retinopathy.

4. Use according to Claim 1 , in which the medicament is intended for the prevention of and/or treating neuropathy.

5. Use according to Claim 1 , in which the neuropathy is an autonomic neuropathy chosen from cardiac neuropathy, gastric neuropathy and impotence.

6. Use according to one of the preceding claims, in which the compound of the formula (I) is combined with another antidiabetic agent.

7. Use according to Claim 6, in which the antidiabetic agent is insulin.

8. Use according to one of the preceding claims, in which the medicament is intended for oral administration.

9. Use according to Claim 1 or 2, in which the medicament is intended for ocular administration.

10. Use according to Claim 1 , in which the medicament is intended for the prevention of and/or treating myocardial reperfusion ischaemia.

11. Use according to one of the preceding claims, in which the compound of the formula (I) is chosen from:

- 5-[3-(4-fluorophenoxy)propyl]thiazolidine-2,4-dione

- 5-(2-phenoxyethyl)thiazolidine-2,4-dione

- 5-[2-(4-fluorophenoxy)ethyl]thiazolidine-2,4-dione - 5-{[1 -hydroxy-2-(4-fluorophenoxy)]ethyl}thiazolidine-2,4-dione

- 5-{[2-hydroxy-3-(4-fluorophenoxy)]propyl}thiazolidine-2,4-dione

- 5-[1 -methyI-2-phenoxyethyl]thiazolidine-2,4-dione - 5-[2-(4-cyanophenoxy)ethyl)]thiazolidine-2,4-dione

- 5-[2-(2-fluorophenoxy)ethyl]thiazolidine-2,4-dione

- 5-[2-(2-naphthyloxy)ethyl]thiazolidine-2,4-dione and pharmacologically acceptable salts thereof.