KR20010021952A - Treatment of Diabetes with Thiazolidinedione, Insulin Secretagogue and Alpha Glucocidase Inhibitor - Google Patents

Abstract

Administering a pharmaceutically acceptable non-toxic effective amount of an insulin sensitiser, an insulin secretagogue, and an alpha glucosidase inhibitor antihyperglycemic agent to a mammal in need thereof. A method of treating diabetes and diseases associated with diabetes in said mammal; And compositions for use in such methods.

Description

Treatment of Diabetes with Thiazolidinedione, Insulin Secretagogue and Alpha Glucocidase Inhibitor

Insulin secretagogues are compounds that promote increased insulin secretion by pancreatic beta cells.

Sulfonylureas are well known examples of insulin secretagogues. Sulfonylurea acts as an antihyperglycemic agent and is used in the treatment of type 2 diabetes. Examples of sulfonylureas include glybenclamide, glyphizide, glyclazide, glymepiride, tolazamide or tolbutamide.

Alpha glucosidase inhibitor antihyperglycemic agents such as acarbose, emigritate and miglytol are commonly used in the treatment of type II diabetes.

European Patent Application Publication No. 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having antihyperglycemic and hypolipidemic activity. One particular thiazolidinedione disclosed in EP 0306228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4 -Dione (hereinafter referred to as 'compound (I)'). WO 94/05659 discloses certain salts of compound (I), including maleate.

Compound (I) is an example of a class of antihyperglycemic agents known as 'insinsitisers'. In particular, compound (I) is a thiazolidinedione insulin sensitizer.

European Patent Application Publication No. 0008203, No. 039421, No. 032128, No. 0428312, No. 0489663, No. 055845, No. 0778,1, No. 0206020, No. 0177353, No. 0319189, 0303331, 0332332, 0528734, and 00508740; International Patent Application Publication Nos. 92/18501, 93/02079, 93/22445, and US Pat. Nos. 5,104,888 and 55,547,52 also disclose specific thiazolidinedione insulin sensitizers.

Other classes of compounds generally recognized to have insulin sensitizer activity are those represented by the compounds disclosed in WO 93/21166 and WO 94/01420. These compounds are referred to herein as 'acyclic insulin sensitizers'. Other examples of acyclic insulin sensitizers are those disclosed in US Pat. No. 52,2945 and WO 92/03425 and WO 91/19702.

Examples of other insulin sensitizers are those disclosed in European Patent Application Publication No. 0533933, Japanese Patent Application Publication No. 05271204, and US Patent No. 52,4451.

The aforementioned patent documents are incorporated herein by reference.

The present invention relates to a method of treatment, in particular a method of treating diabetes, in particular insulin independent diabetes (NIDDM) or type 2 diabetes and diseases associated with diabetes.

Surprisingly, the compound (I) in combination with an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycemic agent provides a particularly beneficial effect on glycemic control, and therefore such complexes are associated with diabetes, in particular type 2 diabetes and diabetes mellitus. It has been shown to be particularly useful in the treatment of related diseases. This method of treatment has also been shown to have minimal side effects.

Accordingly, the present invention provides a non-toxic effective amount of an insulin sensitizer, an insulin secretagogue and an alpha glucosidase inhibitor in a mammal, such as a person in need of treatment for diabetes, in particular type 2 diabetes and a disease associated with diabetes. Provided is a method of treating diabetes in a mammal, in particular type 2 diabetes and a disease associated with diabetes, comprising administering a blood sugar agent.

The methods of the present invention include co-administration or sequential administration of insulin sensitizers, insulin secretagogues and alpha glucosidase inhibitor antihyperglycemic agents.

Co-administration includes administration of formulations containing insulin sensitizers, insulin secretagogues and alpha glucosidase inhibitor antihyperglycemic agents or essentially simultaneous administration of separate formulations of each medicament.

In another aspect of the invention the use of an insulin sensitizer, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycemic agent such as compound (I) in the preparation of a composition for treating diabetes, in particular type 2 diabetes and diseases associated with diabetes To provide.

Suitable insulin sensitizers are thiazolidinedione insulin sensitizers.

Suitable thiazolidinedione insulin sensitizers are compound (I).

Other suitable thiazolidinedione insulin sensitizers are (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzo Pyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4-[(1-methylcyclohexyl) methoxy] benzyl] thiazolidine-2 , 4-dione (or cyglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (or pioglitazone) or 5- [(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine-2,4-dione (or englitazone).

Suitable insulin secretagogues include sulfonylureas.

Suitable sulfonylureas include glybenclamide, glipizide, glyclazide, glymepiride, tolazamide or tolbutamide.

Other sulfonylureas include acetohexamide, carbutamide, chlorpropamide, glyborneuride, glyquidone, glycentide, glysolamide, glyoxepide, glyclopiamide and glycyramide.

Other suitable insulin secretagogues include repaglinide.

Suitable alpha glucosidase inhibitor antihyperglycemic agents are acarbose.

Other suitable alpha glucosidase inhibitor antihyperglycemic agents are emiglytate and miglytol.

In one particular aspect, the methods of the present invention comprise administering from 2 to 12 mg of compound (I), especially when administered per day.

In particular, the method of the present invention comprises administering 2 to 4 mg, 4 to 8 mg or 8 to 12 mg of compound (I) per day.

In particular, the methods of the invention comprise administering 2 to 4 mg of compound (I), especially when administered per day.

In particular, the methods of the present invention comprise administering from 4 to 8 mg of compound (I), especially when administered per day.

In particular, the method of the invention comprises administering 8 to 12 mg of compound (I), especially when administered per day.

Preferably, the method of the invention comprises administering 2 mg of compound (I), especially when administered per day.

Preferably, the methods of the present invention comprise administering 4 mg of compound (I), especially when administered per day.

Preferably, the method of the invention comprises administering 8 mg of compound (I), especially when administered per day.

Insulin sensitizers, insulin secretagogues and alpha glucosidase inhibitor antihyperglycemic agents such as compound (I) each comprise pharmaceutically acceptable derivatives such as salts, esters and solvates thereof which are suitably pharmaceutically acceptable. It will be understood that it will be administered in a pharmaceutically acceptable form. In some cases, the names used herein for the relevant insulin secretagogues and alpha glucosidase inhibitor antihyperglycemic agents may relate to a particular pharmaceutical form of the active agent concerned: that is, all pharmaceutically acceptable forms of the active agent themselves. It will be understood that is included in the present invention.

Suitable pharmaceutically acceptable chloride forms of insulin sensitizers such as compound (I) include those described for compound (I) in the aforementioned patents and patent applications, such as EP 0306228 and WO 94/05659. Preferred pharmaceutically acceptable salts for compound (I) are maleates.

Suitable pharmaceutically acceptable solvate forms of insulin sensitizers such as compound (I) are those described for compound (I) in the aforementioned patents and patent applications such as EP 0306228 and WO94 / 05659, in particular Hydrates.

Suitable pharmaceutically acceptable forms of insulin secretagogues and alpha glucosidase inhibitor antihyperglycemic agents depend on the particular compound used, but include known pharmaceutically acceptable forms of the particular compound selected. Such derivatives are described in the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (e.g., page 31, page 341 and pages cited therein). Or reference is found in standard references.

Insulin sensitizers such as compound (I) or pharmaceutically acceptable salts thereof or pharmaceutically acceptable solvates thereof are known methods, for example those mentioned above such as EP 0306228 and WO 94/05659. It can be prepared using the method disclosed for compound (I) in patents and patent applications. The disclosures of the aforementioned patents and patent applications, such as EP 0306228 and WO94 / 05659, are incorporated herein by reference.

Compound (I) may exist in one of several tautomeric forms, all of which are included in the term compound (I) as individual tautomeric forms or as mixtures thereof. Since compound (I) contains chiral carbon atoms, it may exist in up to two stereoisomeric forms, and the term compound (I) includes both of these isomeric forms as individual isomers or as a mixture of isomers including racemates. do.

Selected insulin secretagogues and alpha glucosidase inhibitor antihyperglycemic agents are prepared according to known methods, which are described in British and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra. Or is referenced in standard reference literature such as Pharmacopoeia (London, The Pharmaceutical Press) (see, eg, page 31, page 341 and page mentioned herein).

As used herein, the term 'diabetes related diseases' includes diseases associated with diabetes itself and complications associated with diabetes. Diseases related to diabetes also include diseases associated with prediabetes conditions.

As used herein, the term 'diseases associated with pre-diabetic conditions' includes diseases such as insulin resistance (including genetic insulin resistance), impaired glucose tolerance and hyperinsulinemia.

'Diseases associated with diabetes itself' include hyperglycemia and insulin resistance (including acquired insulin resistance). Another disease associated with diabetes itself includes hypertension and cardiovascular disease, especially those associated with atherosclerosis and insulin resistance. Diseases associated with insulin resistance include polycystic ovary syndrome and steroid induced insulin resistance and gestational diabetes.

'Diabetes-related complications' include kidney disease, in particular kidney disease, neuropathy and retinopathy associated with type 2 diabetes.

Renal diseases associated with type 2 diabetes include nephropathy, glomerulonephritis, glomerulosclerosis, hypertensive neurosis and late stage renal disease. Other kidney diseases associated with type 2 diabetes include nephrotic syndrome.

For the sake of clarity, when referring to the scalar amount (including mg amount) of Compound (I) in pharmaceutically acceptable form herein, the scalar amount mentioned is for Compound (I) itself: ie for example , 2 mg of compound (I) in maleate form is the amount of maleate containing 2 mg of compound (I).

Diabetes is preferably type 2 diabetes.

Particularly beneficial effects on glycemic control provided by the treatment methods of the present invention appear to be synergistic compared to the expected control over the sum of the effects of the individual active agents.

Glucose control can be characterized by measuring conventionally used blood glucose control indexes, such as, for example, fasting blood glucose or glycosylated hemoglobin (HbAlc). Such indices are standard methods, for example, in Tuescher A., Richterich, P., Schweiz. med. Wschr. 101 (1971), 345, and 390, and Frank P., Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements, Clinical Products 1988.

In a preferred aspect, the dosage level of each active agent when used in accordance with the treatment methods of the present invention will be less than that required for pure additive effects in blood glucose control.

Suitably, the insulin sensitizer is a first dose.

Suitably, the insulin secretagogue is a second dose.

Suitably, the alpha glucosidase inhibitor is a third agent.

The treatment methods of the present invention will improve levels of enhanced glycosylation end products (AGEs), leptin and serum lipids (including total cholesterol, HDL-cholesterol, LDL-cholesterol) compared to individual agents (in their proportions). It has also been shown that it will improve serum lipids (including total cholesterol, HDL-cholesterol, LDL-cholesterol), including improvement in ratios, in particular in ratios.

As used herein, the term 'pharmaceutically acceptable' encompasses both human and veterinary uses; For example, the term 'pharmaceutically acceptable' encompasses veterinary acceptable compounds.

In the methods of the invention, the active agents are preferably administered in the form of pharmaceutical compositions. As noted above, such compositions may include all medicaments or only one of the medicaments.

Thus, in one aspect the present invention also provides a pharmaceutical composition comprising an insulin sensitizer, such as compound (I), in particular 2-12 mg, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. To provide.

Such compositions can be prepared by mixing insulin sensitizers, such as compound (I), in particular 2-12 mg, insulin secretagogues and alpha glucosidase inhibitor antihyperglycemic agents with pharmaceutically acceptable carriers.

In general, the composition is suitable for oral administration. However, it may be suitable for other modes of administration, for example, parenteral, sublingual or transdermal.

The composition may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders or liquid preparations, for example oral or sterile parenteral solutions or suspensions.

In order to achieve consistency of administration, the compositions of the present invention are preferably in unit dosage form.

Unit dosage form forms for oral administration may be tablets and capsules and may include binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; Fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Tableting lubricants such as magnesium stearate; Disintegrants such as starch, polyvinylpyrrolidone, sodium glycolate starch or microcrystalline cellulose; Or pharmaceutically acceptable wetting agents, for example conventional excipients such as sodium lauryl sulfate.

The composition is preferably in unit dosage form for an appropriate daily administration.

Suitable dosage forms for insulin sensitizers include those disclosed in the aforementioned patents and patent applications.

Suitable dosage forms (including unit dosage forms) of compound (I) include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of compound (I).

At the time of treatment, the medicament may be administered 1 to 6 times a day, most preferably once or twice a day.

Specific dosages of compound (I) are 2 mg / day, 4 mg / day (including 2 mg twice daily) and 8 mg / day (including 4 mg twice daily).

Suitable dosage forms (including unit dosage forms) of insulin secretagogues or alpha glucosidase inhibitor antihyperglycemic agents such as sulfonylureas are described in the British and US Pharmacopeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Including unit dosages for these compounds, as described or referred to in references such as Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see, e.g., page 31, page 341 and pages mentioned herein). Known dosage forms.

Thus, for sulfonylureas, typical daily dosages of glybenclamide range from 2.5 to 20 mg, eg, 10 mg twice daily or 20 mg once daily; Typical daily doses of glipizide range from 2.5 to 40 mg; Typical daily dosages of glyclazid range from 40 to 320 mg; Typical daily doses of tolazamide range from 100 to 1000 mg; Typical daily dosages of tolbutamide range from 1000 to 3000 mg; Typical daily doses of chlorpropamide range from 100 to 500 mg; Typical daily dosages of glycidone range from 15 to 180 mg.

Repaglinide can generally be administered in amounts ranging from 0.5 mg to 4 mg, typically with food up to a typical maximum daily dose of 16 mg per day.

With respect to alpha glucosidase inhibitor antihyperglycemic agents, typical daily doses of acarbose range from 50 to 600 mg per day, for example 100 mg or 200 mg.

Solid oral compositions can be prepared by conventional blending, filling or tableting methods. The blending operation can be repeated to distribute the active agent throughout the composition using a large amount of filler. Such work is of course common in the art. Tablets may be coated according to methods well known in standard pharmaceutical practice, in particular with enteric coatings.

Oral liquid compositions may be in the form of emulsions, syrups or elixirs, or may be provided as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations include suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hardened edible fats; Emulsifiers such as lecithin, sorbitan monooleate or acacia; Non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters (eg esters of glycerin, propylene glycol or ethyl alcohol); Preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; And, if desired, conventional additives such as conventional flavoring or coloring agents.

For parenteral administration, the fluid unit dosage forms may be prepared using the compound and sterile vehicle and may be suspended or dissolved in the vehicle, depending on the concentration used. In the preparation of solutions, the compounds may be dissolved in water for injection, sterile filtered and then filled and sealed in suitable vials or ampoules. Advantageously, adjuvants such as local anesthetics, preservatives and buffers can be dissolved in the vehicle. To enhance stability, the composition can be filled into a vial and freeze after removing the water under vacuum. Parenteral suspensions are prepared in substantially the same manner except that compound (I) is suspended instead of dissolved in the vehicle and cannot be sterilized by filtration. The compound can be sterilized by exposure to ethylene oxide and then suspended in a sterile vehicle. Advantageously, surfactants or wetting agents are included in the composition to facilitate uniform distribution of the compound.

The composition may contain 0.1 to 99% by weight, preferably 10 to 60% by weight of active substance, depending on the method of administration.

If desired, the composition may be in the form of a pack with written or printed instructions for use.

The compositions are described in standard references, such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press; see, eg, 31 pages 341). And pages cited therein) and Harry's Cosmeticology (Leonard Hill Books).

The present invention is also intended for use as an active therapeutic agent containing insulin sensitizers such as compound (I), in particular 2 to 12 mg, insulin secretagogues and alpha glucosidase inhibitor antihyperglycemic agents and pharmaceutically acceptable carriers. Provide a pharmaceutical composition.

The present invention also provides the use of an insulin sensitizer, such as compound (I), in particular 2-12 mg, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycemic agent in the manufacture of a medicament for the treatment of diabetes and diseases associated with diabetes. do.

In particular, the present invention relates to diabetes mellitus and diabetes mellitus, containing insulin sensitizers such as compound (I), in particular 2 to 12 mg, insulin secretagogues and alpha glucosidase inhibitor antihyperglycemic agents and pharmaceutically acceptable carriers Provided is a pharmaceutical composition for treating a disease.

The range of 2 to 4 mg ranges from 2.1 to 4, 2.2 to 4, 2.3 to 4, 2.4 to 4, 2.5 to 4, 2.6 to 4, 2.7 to 4, 2.8 to 4, 2.9 to 4, or 3 to 4 mg. It includes.

The range of 4 to 8 mg is 4.1 to 8, 4.2 to 8, 4.3 to 8, 4.4 to 8, 4.5 to 8, 4.6 to 8, 4.7 to 8, 4.8 to 8, 4.9 to 8, 5 to 8, 6 to 8 Or in the range of 7 to 8 mg.

The range of 8 to 12 mg is 8.1 to 12, 8.2 to 12, 8.3 to 12, 8.4 to 12, 8.5 to 12, 8.6 to 12, 8.7 to 12, 8.8 to 12, 8.9 to 12, 9 to 12, 10 to 12 Or 11 to 12 mg.

No toxic side effects are seen in the above-mentioned dosage ranges for the compositions of the invention or the methods of the invention.

Composition of Compound (I)

Preparation of Concentrates: A tableting concentrate was prepared using the following materials.

ingredient Volume (%) Compound (I) as milled maleate 13.25 (pure maleate) Sodium glycolate starch 5.00 Hydroxypropyl methylcellulose 2910 5.00 Microcrystalline Cellulose (Avicel PH102) 20.0 Lactose Monohydrate, Rule Grade Up to 100 Purified water * * Removed during machining

The concentrate was then formulated into tablets using:

Amount (mg / tablet) Tablet concentration 1.0 mg 2.0 mg 4.0 mg 8.0 mg Active Ingredients: Compound (I) Maleate Concentrate Granule 10.00 20.00 40.00 80.00 Other Ingredients: Sodium Glycolate Starch Microcrystalline Cellulose (Avicel PH102) Lactose Monohydrate (Pharmatose DCL15) Magnesium Stearate 6.9627.85104.440.75 6.4625.8596.940.75 5.4621.8581.940.75 10.9243.70163.881.50 Total weight of tablet core 150.0 150.0 150.0 300.0 Total weight of Opadry film coated tablets 4.5154.5 4.5154.5 4.5154.5 9.0309.0

Compositions for other active agents are as described in the documents cited above.

Claims (22)

Administering a pharmaceutically acceptable non-toxic effective amount of an insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycemic agent to a mammal in need thereof. A method of treating diabetes in a mammal and a disease associated with diabetes. The method according to claim 1, wherein the insulin secretagogue is glybenclamide, glipizide, glyclazide, glymepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide, glybornuri De, glycidone, glycentide, glysolamide, glyoxepide, glyclopiamide, glycyramid or repaglinide. 2. The method of claim 1, wherein said alpha glucosidase inhibitor antihyperglycemic agent is acarbose, emiglytate and miglytol. The method according to any one of claims 1 to 3, wherein the insulin sensitizer is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine- 2,4-dione (Compound I). The method of any one of claims 1 to 4 comprising administering from 2 to 12 mg of compound (I). 6. The method of claim 1, comprising administering 2-4 mg, 4-8 mg or 8-12 mg of compound (I). 7. The method of any one of claims 1 to 6 comprising administering 2 to 4 mg of compound (I). The method of any one of claims 1 to 6, comprising administering 4-8 mg of compound (I). The method of any one of claims 1 to 6 comprising administering 8 to 12 mg of compound (I). The method of any one of claims 1 to 6 comprising administering 2 mg of compound (I). The method of any one of claims 1 to 6 comprising administering 4 mg of compound (I). The method of any one of claims 1 to 6 comprising administering 8 mg of compound (I). The method of claim 1, wherein the insulin sensitizer is (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzo Pyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4-[(1-methylcyclohexyl) methoxy] benzyl] thiazolidine-2 , 4-dione (or cyglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (or pioglitazone) or 5- [(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine-2,4-dione (or englitazone); Or a pharmaceutically acceptable form thereof. A pharmaceutical composition comprising an insulin sensitizer, an insulin secretagogue, an alpha glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. 15. The composition of claim 14, wherein said insulin secretagogue is sulfonylurea. 16. The method according to claim 14 or 15, wherein the insulin secretagogue is glybenclamide, glipizide, glyclazide, glymepiride, tolazamide or tolbutamide, acetohexamide, carbutamide, chlorpropamide , Glyborneuride, glycidone, glycentide, glysolamide, glyoxepide, glyclopiamide, glycyramid or repaglinide. 15. The composition of claim 14, wherein said alpha glucosidase inhibitor antihyperglycemic agent is acarbose, emiglytate and miglytol. 18. The composition according to any one of claims 14 to 17, wherein said insulin sensitizer is compound (I). 18. The composition according to any one of claims 14 to 17, comprising 2 to 12 mg of compound (I). A pharmaceutical composition for use as an active therapeutic agent comprising an insulin sensitizer, an insulin secretagogue and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating diabetes and diseases associated with diabetes, comprising an insulin sensitizer, an insulin secretagogue, an alpha glucosidase inhibitor antihyperglycemic agent and a pharmaceutically acceptable carrier. The method according to any one of claims 14, 20 or 21, wherein the insulin sensitizer is (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5, 7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4-[(1-methylcyclo Hexyl) methoxy] benzyl] thiazolidine-2,4-dione (or cyglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine- 2,4-dione (or pioglitazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine-2,4-dione (or englitazone); Or a pharmaceutically acceptable form thereof.