The present invention relates to a pharmaceutical composition comprising, as active principles, a derivative of 5-phenoxyalkyl-2, 4-thiazolidinedione type described in WO 97/47612 and an a-glucosidase inhibitor.

The invention also relates to the use of a derivative of 5-phenoxyalkyl-2, 4- thiazolidinedione type and an a-glucosidase inhibitor, for the preparation of a medicinal preparation for reducing hyperglycaemia, more particularly the hyperglycaemia of non-insulin-dependent diabetes.

Many thiazolidine-2, 4-dione derivatives have been described as anti-hyper- glycaemiants and hypolipaemiants and have thus been described as antidia- betic agents (Takeda, patent EP 193 256 and Sankyo patent EP 207 581).

These compounds are activators of the peroxisome proliferator-activated receptor-y (PPARy). cc-Glucosidase inhibitors are described as anti-hyperglycaemiants and are commonly used in the treatment of type 11 diabetes (NIDDM). a-Glucosidase inhibitors that may especially be mentioned include acarbose, miglitol and voglibose.

The combination of certain thiazolidinedione derivatives, such as pioglita- zone and troglitazone, which are PPARy activators, and of a-glucosidase inhibitors has already been described for the treatment of diabetes (SmithKline Beecham, patent application WO 98/57635).

Diabetes is a chronic disease that has a number of pathological manifesta- tions. It is accompanied by disorders of lipid and sugar metabolism and circulatory disorders. In many cases, diabetes tends to progress to a variety of pathological complications. Thus, it is necessary to find the treatment that is suited to each individual suffering from diabetes.

The specific combination of an a-glucosidase inhibitor with a 5-phenoxyalkyl- 2, 4-thiazolidinedione that has no activityion the transactivation of PPARy has not been described and offers particular advantages, especially the absence of weight gain and/or of haemodilution.

Thus, one aim of the present invention is to propose a composition for significantly improving the use of glucose.

An aim of the invention is also to propose a composition that is suitable for treating diabetes by displaying considerable action on the metabolic syn- drome of insulin resistance.

Finally, an aim of the invention is to propose a composition that is particularly suitable for diabetics at the various stages of the disease.

These aims and others are achieved by the present invention, which relates to a pharmaceutical composition comprising, as active principles, at least one a-glucosidase inhibitor and at least one compound of the formula (I), in combination with one or more pharmaceutically acceptable excipients.

This composition is particularly suitable for treating diabetes, more particu- larly non-insulin-dependent diabetes. It is particularly suitable for reducing the hyperglycaemia of non-insulin-dependent diabetes.

The compound of the formula (1) is defined as follows :

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 cyclic structure comprising one or two rings optionally including one or two hetero atoms in the ring, such as, for example, a phenyl or an a- or 0-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.

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

D preferably represents a phenyl or naphthyl radical.

Among the alkyl groups containing from 1 to 6 carbon atoms that may espe- cially be mentioned are the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,

tert-butyl, pentyl and hexyl radicals. Among the alkoxy groups containing 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 chain A 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 by 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-dihydroxy- propyl, 2,3, 4-trihydroxybutyl or 2,3, 4, 5-tetrahydroxypentyl or a pentaerythritol residue. Among the hydrocarbon-based chains containing from 2 to 16 car- bon atoms and one or more ethylenic groups, mention may be made espe- cially 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 is conceivable for the ketone functions borne by the thiazolidine ring to enolize and give rise to mono-enols.

The thiazolidinedione derivatives may be salifie 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 pharmacologi- cally acceptable may serve as a means of identification, purification or reso- lution.

Among the compounds of the general formula (I) according to the invention, the following will be mentioned more particularly as compounds that are currently preferred: - 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-{12-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.

The cc-glucosidase inhibitors that are thus anti-hyperglycaemiants are more particularly chosen from acarbose, miglitol, voglibose and emiglitate.

The compositions of the invention contain therapeutical effective amounts of the various active principles. The ratios of the respective amounts of a- glucosidase inhibitor and of compound of the formula (I) thus vary in consequence.

Preferably, the weight ratio of a-glucosidase inhibitor to the compound of the formula (I) ranges from 10-3 to 40, preferably from 10-3 to 10 and better still from 103to5.

The compositions of the invention are preferably administered parenterally, or better still orally, although the other routes of administration, for instance such as rectal administration, are not excluded.

If 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, microgranules or sustained-release forms.

If parenteral administration is envisaged, the compositions of the invention are in the form of injectable solutions and suspensions packaged in vials or bottles for slow venous infusion.

The forms for oral administration are prepared by mixing the active sub- stance with various types of excipients or of vehicles, such as fillers, disinte- gration (or crumbling) agents, binders, colorants, flavour enhancers and the like, followed by shaping the mixture.

The colorant can be any colorant 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, colloidal silicon dioxide, sodium croscarmellose, crospovidone, guar gum, magnesium aluminium silicate, methylcellulose, microcrystalline cellulose, cellulose powder, pregelatinized starch, sodium alginate or sodium starch glycolat as disintegration agent.

The fillers are, for example, cellulose, lactose, calcium hydrogen phosphate or 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 hydroxypropyl- methylcellulose or ethylcellulose.

The granules used to do this are prepared, for example, by 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 active principles with a suitable filler (for example lactose) is introduced into empty gelatine capsules, optionally in

the presence of a lubricant such 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 introduction into soft capsules.

The forms for parenteral administration are obtained in a conventional manner by mixing the active principles with buffers, stabilizers, preserving agents, solubilizing agents, tonicity 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 organo- phosphate salts.

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

Examples of solubilizing agents include castor oil solidified with polyoxy- ethylene, polysorbate 80, nicotinamide and macrogol.

In addition, stabilizers that are useful according to the invention are sodium sulfite 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 wetting agent, a suspension agent (for example polyvinylpyrrolidone), a preserving agent (such as methylparaben or propylparaben), a flavour enhancer or a colorant.

For the preparation of suppositories, the active principles are mixed in a manner that is known per se with a suitable base constituent, such as poly- ethylene 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 forma- tion of a central core that 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.

A subject of the present invention is also the use of an a-glucosidase inhibitor in combination with a compound of the formula (I) as defined above, for the preparation of a medicinal combination for treating diabetes, more particularly non-insulin-dependent diabetes.

According to another of its aspects, the invention relates to the use of glitazone in combination with the said compound of the formula (I) for the preparation of a medicinal combination for reducing the hyperglycaemia of non-insulin-dependent diabetes.

The present invention also relates to a process for treating diabetes, more particularly non-insulin-dependent diabetes, in a mammal, comprising the administration to the said mammal of the composition according to the present invention.

If the a-glucosidase inhibitor and the compound of the formula (I) are incor- porated into the same unit dose, the unit dose preferably comprises from

0.1 mg to 400 mg of a-glucosidase inhibitor (the dose depends especially on the active agents under consideration).

If the a-glucosidase inhibitor is chosen from miglitol and acarbose, the unit dose preferably comprises from 10 mg to 400 mg of a-glucosidase inhibitor.

If the a-glucosidase inhibitor is voglibose, the unit dose preferably comprises from 0.1 mg to 1 mg of voglibose.

The unit dose in this case advantageously comprises from 12.5 to 200 mg of a compound of the formula (I) (the dose depending especially on the active agents under consideration).

Naturally, the dosage depends on the active agent under consideration, the mode of administration, the therapeutic indication and the age and condition of the patient.

The daily dosage ranges particularly between 0.1 mg and 1 g of a- glucosidase inhibitor and between 25 and 200 mg of compound of the formula (I).

Specific, but non-limiting examples of the invention will now be presented.

The percentages given are expressed on a weight basis, except where otherwise mentioned.

Example 1 : A tablet having the composition below is prepared: 4- [2- (2, 4-Dioxothiazolidin-5-yl) ethoxy] benzonitrile* 50 mg 19.5% Acarbose 150 mg 58.4% Fine lactose powder 30 mg 11.7%

Hydroxypropylcellulose 12 mg 4.7% Sodium croscarmellose 12 mg 4. 7% Magnesium stearate 3 mg 1. 2% * also known as 5- [2- (4-cyanophenoxy) ethyl)] thiazolidine-2, 4-dione Example 2: A tablet having the composition below is prepared: 4- [2- (2, 4-Dioxothiazolidin-5-yl) ethoxy] benzonitrile 50 mg 11.4% Acarbose 300 mg 68.2% Fine lactose powder 45 mg 10.2% Hydroxypropylcellulose 20 mg 4.5% Sodium croscarmellose 20 mg 4.5% Magnesium stearate 5 mg 1. 1% Example 3: A tablet having the composition below is prepared: 4- [2- (2, 4-Dioxothiazolidin-5-yl) ethoxy] benzonitrile 100 mg 31.3% Acarbose 150 mg 46.9% Fine lactose powder 36 mg 11.3% Hydroxypropylcellulose 15 mg 4. 7% Sodium croscarmellose 15 mg 4.7% Magnesium stearate 4 mg 1.3% Example 4 : A tablet having the composition below is prepared: 4- [2- (2, 4-Dioxothiazolidin-5-yl) ethoxy] benzonitrile 1 00 mg 20.4% Acarbose 300 mg 61. 2% Fine lactose powder 44 mg 9% Hydroxypropylcellulose 20 mg 4. 1% Sodium croscarmellose 21 mg 4.3% Magnesium stearate 5 mg 1%

Example 5: A tablet having the composition below is prepared: 4- [2- (2, 4-Dioxothiazolidin-5-yl) ethoxy] benzonitrile 200 mg 46.0% Acarbose 150 mg 34.5% Fine lactose powder 42 mg 9.7% Hydroxypropylcellulose 18 mg 4. 1% Sodium croscarmellose 20 mg 4. 6% Magnesium stearate 5 mg 1. 1% Example 6: A tablet having the composition below is prepared: 4- [2- (2, 4-Dioxothiazolidin-5-yl) ethoxy] benzonitrile 200 mg 33.3% Acarbose 300 mg 50.0% Fine lactose powder 45 mg 7.5% Hydroxypropylcellulose 24 mg 4.0% Sodium croscarmellose 25 mg 4.2% Magnesium stearate 6 mg 1. 0%

PHARMACOLOGICAL STUDY The antidiabetic effect of the combination of 4-[2-(2, 4-dioxothiazolidin-5-yl)- ethoxy] benzonitrile (Compound A) * with acarbose was studied in n5STZ rats, an experimental model of non-insulin-dependent diabetes. This model is produced by intraperitoneal injection of steptozotocin (STZ) 80 mg/kg, five days after birth.

The characteristics of this model are: - hyperglycaemia - moderately diminished basal insulinaemia - glucose intolerance - insulin resistance * Compound A is also known as 5- [2- (4-cyanophenoxy) ethyl] thiazolidine-2, 4- dione > EXPERIMENTAL PROTOCOL 48 male n5STZ rats were used after a basal selection regarding the value of the hyperglycaemia after fasting for two hours, to homogenize the groups.

They were then divided into seven groups: - an n5STZ control group - a"normal"rat control group - a group treated orally with acarbose at 100 mg/kg - a group treated orally with acarbose at 400 mg/kg - a group treated orally with Compound A at 12.5 mg/kg - a group treated with acarbose 100 mg/kg and Compound A 12.5 mg/kg

a group treated with acarbose 400 mg/kg and Compound A 12.5 mg/kg The products were administered orally in the morning between 8 am and 9 am, for four days.

On the fourth day of treatment, a meal test was performed. This test consists of an oral administration of Eoprotine (milk powder, Milupa) at a rate of 10 kcal/kg of rat. The meal test is performed two hours after the final administration of product. The glycaemia and the insulinaemia are determined before the administration of Eoprotine, and then 10,20, 30,45, 60,90 and 120 minutes after gavage. Blood samples are taken from the tail of the conscious rats.

> RESULTS Table 1 Table 2 Table 1: Glycaemia (mmol/l) 0 min 10 min 20 min 30 min 45 min 60 min 90 min 120 min Control n5 STZ 9. 870. 35 15. 290. 4 18. 240. 76 19. 50. 91 19. 631. 2 18. 661. 4 16. 441. 6 12. 361. 7 Compound A 12. 5 mg/kg 9. 37 + 0. 72 16. 17 +1 19. 26 1. 1 20. 651. 5 20. 872. 2 20. 722. 4 20. 422. 7 17. 34+2. 7 Acarbose 100 mg/kg 9. 170. 28 14. 700. 7 16. 820. 91 17. 501. 2 17. 941. 3 18. 221. 4 17. 011. 5 15. 221. 6 Acarbose 400 mg/kg 8. 90. 92 13. 6510. 4 14. 841. 14 17. 890. 84 18. 651 18. 610. 7 16. 831. 1 14. 671. 7 Comp. A 12 5 mg/kg 8. 89+0. 27 13. 120. 5 14. 970. 81 16. 380. 87 17. 211. 3 18. 041. 5 16. 982. 3 14. 72. 2 + acarbose 100 mg/kg Comp ; A 125 mg/kg 8. 8iO. 45 12. 45+0. 5 14. 150. 92 14. 881. 05 15. 851. 5 15. 911. 5 14. 161. 2 13. 001. 2 + acarbose 400 mg/kg Table 2 : Insulinaemia (pmol/l) 0 min 10 min 20 min 30 min 45 min 60 min 90 min 120 min Control nt STZ 223 ñ 48 482 ñ 91 503 ñ 76 568 ñ 64 433 ñ 81 349 ñ 49 274 ñ 35 301 ñ 23 Compound A 12.5 mg/kg 199 ñ 49 372 ñ 93 501 ñ 138 427 ñ 88 368 ñ 51 324 ñ 56 307 ñ 39 270 ñ 40 Acarbose 100 mg/kg 188 ñ 25 392 ñ 53 493 ñ 92 387 ñ 73 343 ñ 58 324 ñ 67 256 ñ 68 239 ñ 64 Acarbose 400 mg/kg 201 ñ 32 309 ñ 36 325 ñ 47 371 ñ 51 364 ñ 56 353 ñ 57 241 ñ 41 220 ñ 49 Comp.A 12.5 mg/kg + acarbose 100 mg 186 ñ 32 355 ñ 49 389 ñ 43 317 ñ 36 281 ñ 61 312 ñ 33 270 ñ 33 284 ñ 42 Comp.A 12.5 mg /kg + acarbose 400 mg/kg 168 ñ 26 295 ñ 28 329 ñ 53 287 ñ 48 251 ñ 61 270 ñ 39 264 ñ 38 236 ñ 58

> COMMENTS After treatment for four days, the basal glycaemia of the n5STZ rats is not modified by the treatments with the products alone or in combination. As regards the kinetics of disappearance of the hyperglycaemia induced by the meal test, this study shows: Treatment with Compound A: At this low dose, Compound A does not modify the glucose disappearance kinetics (Figure 1). Indeed, the area under the curve (AUC) for glucose gly- caemia is slightly increased (+15%) after treatment. As regards the insulin response to glucose, this is slightly reduced by Compound A AUC (-8%).

However, none of the results is significant (Figures 2 and 3).

Treatment with acarbose : At the lowest dose used, of 100 mg/kg orally, acarbose does not modify the glucose disappearance kinetics. At the highest dosage, i. e. 400 mg/kg orally, acarbose significantly reduces the hyperglycaemia following the meal test, at times 10 and 20 minutes (Figure 4). Overall, the area under the curve for the glycaemia (AUC) is not modified (-2%) after treatment. As regards the insulin response to glucose, this is reduced by acarbose AUC (-20%). However, none of the results is significant (Figures 5 and 6).

Treatment with the combination Compound A and acarbose : The combination of acarbose at 400 mg/kg and of Compound A at 12.5 mg/kg induces a marked reduction in the hyperglycaemia peak induced by the meal test. The Compound A/acarbose combination significantly improves carbohydrate tolerance during the early phase of absorption. This

effect is accompanied by a marked reduction in insulin secretion (Figures 8 and 9).

Conclusion : Acarbose is a compound that inhibits the enzymatic activity of a-glucosidase and reduces the increase in the postprandial glucose. In this model of insulin-resistant diabetic rat, acarbose only very mildly reduces the post- prandial hyperglycaemia. In contrast, the combination of acarbose with a no- vel antidiabetic, 4- [2- (2, 4-dioxoxothiazolidin-5-yl) ethoxy] benzonitrile (Com- pound A), unexpectedly induces a synergistic effect with regard to the reduc- tion in the hyperglycaemia peak induced during a meal test. This beneficial effect is combined with a marked reduction in insulin secretion.