EA002659B1 - Use 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)etoxy]benzyl]-thiazolidine-2,4-dione for treating hyperglycaemia - Google Patents

Abstract

1. A use of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]-benzyl]thiazolidine-2,4-dione (Compound (I)) or a tautomeric form thereof or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof for the treatment of hyperglycaemia in the range of from elevated normal to < 126mg/dl. 2. A method according to Claim 1, wherein the hyperglycaemia is fasting hyperglycaemia. 3. A method according to Claim 2, wherein the hyperglycaemia in the range of from elevated normal to < 126mg/dl is additionally characterized with level <140mg/dl following an oral glucose tolerance test. 4. A method according to Claim 2, wherein the hyperglycaemia in the range of from elevated normal to < 126mg/dl is additionally characterized with levels from <140mg/dl to <200mg/dl following an oral glucose tolerance test. 5. A method according to Claim 1, wherein 2 to 12 mg of Compound (I) is administered per day. 6. A method according to Claim 1, wherein Compound (I) is in the form of compositions adapted for oral administration. 7. A method according to Claim 6, wherein the composition is in unit dosage form.

Description

The present invention relates to a new method of treatment, in particular, to the method of treatment and / or prevention of hyperglycemia of some type.

European patent application, publication number 0306228, refers to some thiazolidinedione derivatives that are described as having hypoglycemic and hypolipidemic activity. One particular thiazolidinedione, disclosed in EP 0306228, represents 5 - [4 - [2 - (Ν - methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione (hereinafter referred to as compound (I )). AO 94/05659 discloses some salts of the compound (I), including maleate.

Compound (I) is an example of a class of antihyperglycemic agents known as insulin sensitizers (or insulin enhancers). Compound (I), in particular, is a thiazolidinedione insulin sensitizer.

European patent applications No. 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740, international patent applications No. 92/18501, 93/02079,

93/22445 and the patents of the United States No. 5104888 and 5478852 also disclose some thiazolidinedione insulin sensitizers.

Other series of compounds generally recognized as having activity of insulin sensitizers are compounds described in International patent applications No. AO 93/21166 and AO 94/01420. These compounds are referred to herein as acyclic insulin sensitizers. Other examples of acyclic insulin sensitizers are the compounds described in United States Patent No. 5232945 and International Patent Applications No. AO 92/03425 and AO 91/19702.

Examples of other insulin sensitizers are the compounds described in European patent application No. 0533933, in Japanese patent application No. 05271204 and in the United States patent No. 5264451.

The report of the expert committee on the diagnosis and classification of diabetes mellitus (E | abele Sag, vol. 20 (7), 1997, 1183-1197) notes that type 2 diabetes is characterized by fasting plasma glucose levels> 126 mg / dL (fasting is defined as lack of caloric intake for at least 8 hours). This report also describes how diabetes usually develops over a period of several years, characterized by an increase in fasting serum glycemia from levels usually considered normal - plasma glucose levels of about 110 mg / dl up to established hyperglycemia, which is characteristic of obvious diabetes 2 type This report also discusses the metabolic stages that are intermediate between normal glucose homeostasis and diabetes, including impaired glucose tolerance and impaired fasting glucose levels.

From EP 0306228 it is known that compound (I) is useful for the prevention of hyperglycemia and, therefore, for the treatment of impaired glucose tolerance. International Patent Application No. AO 95/07694 also describes that thiazolidinediones can be used to treat impaired glucose tolerance to prevent or delay the onset of type 2 diabetes. However, EP 0306228 and AO 95/07694 do not mention the treatment of any particular series of glycemic conditions.

Compound (I) has been shown to have a particularly beneficial effect on glycemic regulation within hyperglycemic conditions from elevated normal levels to <126 mg / dl, thereby preventing or delaying further increase in hyperglycemia.

Accordingly, the present invention provides a method for treating hyperglycemia, especially fasting hyperglycemia, in which plasma glucose levels range from elevated normal levels to <126 mg / dL; Said method comprises the administration of an effective non-toxic and pharmaceutically acceptable amount of insulin sensitizer to a mammal in need thereof.

Accordingly, the present invention provides a method for improving glycemic regulation in conditions that are characterized by hyperglycemia, especially fasting hyperglycemia, in which this improvement is provided by hyperglycemia with plasma glucose levels ranging from elevated normal levels to <126 mg / dL, delaying or preventing (warning) , thereby, a further increase in hyperglycemia; Said method comprises the administration of an effective non-toxic and pharmaceutically acceptable amount of insulin sensitizer to a mammal in need thereof.

In another aspect, the present invention provides a method for preventing hyperglycemia, especially fasting hyperglycemia, in which plasma glucose levels are in the range of> 126 mg / dL; Said method comprises the administration of an effective non-toxic and pharmaceutically acceptable amount of insulin sensitizer to a mammal in need thereof.

One particular group of conditions that are defined in this document, in addition to being characterized by fasting hyperglycemia 3 with plasma glucose levels ranging from elevated normal levels to <126 mg / dL, is also characterized by hyperglycemia, in which plasma glucose levels after oral administration glucose tolerance tests are <140 mg / dL.

In addition to the fact that it is characterized by fasting hyperglycemia with plasma glucose levels ranging from elevated normal levels to <126 mg / dL, another group of conditions defined herein is also characterized by hyperglycemia, in which plasma glucose levels after an oral test glucose tolerance ranges from 140 to <200 mg / dL.

A suitable insulin sensitizer is a thiazolidinedione insulin sensitizer.

A suitable thiazolidinedione insulin sensitizer is compound (I) or its tautomeric form, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate.

Other suitable thiazolidinedione insulin sensitizers include (+) - 5 [[4 - [(3,4-dihydro-6-hydroxy-2, 5,7,8-tetramethyl 2 H-1-benzopyran-2-yl) methoxy] phenyl] methyl ] -

2.4-thiazolidinedione (or troglitazone), 5- [4 - [(1methylcyclohexyl) methoxy] benzyl] thiazolidin-2,4-dione (or cyglitazone), 5- [4- [2- (5ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-

2.4-dione (or pioglitazone) or 5 - [(2-benzyl2,3-dihydrobenzopyran) -5-ylmethyl] thiazolidin-2,4-dione (or englitazone).

In one particular aspect, the method comprises the administration of from 2 to 12 mg of compound (I), especially when administered per day.

In particular, the method includes administration from 2 to 4, from 4 to 8, or from 8 to 12 mg of compound (I) per day.

Specifically, the method comprises the administration of 2 to 4 mg of compound (I), especially when administered daily.

Specifically, the method comprises the administration of 4 to 8 mg, such as doses greater than 4, for example, 4.1 to 8 mg, of compound (I), especially when administered daily.

Specifically, the method comprises the administration of from 8 to 12 mg of compound (I), especially when administered daily.

Preferably, the method comprises the administration of 2 mg of compound (I), especially when administered daily.

Preferably, the method comprises the administration of 4 mg of compound (I), especially when administered daily.

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

It should be understood that the insulin sensitizer, such as compound (I), is administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives, such as its pharmaceutically acceptable salts, esters and solvates, in a form that is convenient.

In a suitable embodiment, the pharmaceutically acceptable salt forms of insulin sensitizers, such as compound (I), include the forms described in the aforementioned patents and patent applications, such as EP 0306228 and \ νϋ 94/05659, for compound (I).

The preferred pharmaceutically acceptable salt of the compound (I) is maleate.

Suitable pharmaceutically acceptable solvated forms of insulin sensitizers, such as compound (I), include those described in the above patents and patent applications, such as EP 0306228 and νθ 94/05659, compounds (I), in particular, hydrates.

Insulin sensitizers, such as compound (I), or their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates can be obtained using known methods, for example, the methods described in the aforementioned patents and patent applications, such as EP 0306228 and νθ 94/05659 for compound (I). The descriptions of the above patents and patent applications, such as EP 0306228 and νθ 94/05659, are included in this document for information.

Thiazolidinedione insulin sensitizers, such as compound (I), can exist in one of several tautomeric forms, all of which are covered by the present invention, or as individual tautomeric forms, or mixtures thereof. Some insulin sensitizers, such as compound (I), contain one or more chiral carbon atoms, and therefore, can exist in two or more stereoisomeric forms; all such forms are embraced by the present invention regardless of whether they are individual isomers or mixtures of isomers, including racemates.

As used herein, the term pharmaceutically acceptable covers the use for both human and veterinary purposes; for example, the term pharmaceutically acceptable includes a compound that is also acceptable for veterinary purposes.

The oral glucose tolerance test, as used herein, is a test described in E.sub.Al5 Saga, vol. 20 (7), 1997, 1183-1197.

As used herein, the term elevated normal hyperglycemia should be interpreted in its generally accepted meaning, referring to the report of the expert committee on the diagnosis and classification of diabetes mellitus as an example, but usually interpreted as glycemia, in which plasma glucose levels are> 110 mg / dl.

In the method of the present invention, the active drugs are preferably administered in the form of a pharmaceutical composition. As indicated above, such compositions may include several drugs, or only one of the drugs.

Such compositions can be prepared by mixing an insulin sensitizer, such as compound (I), and especially from 2 to 12 mg of the latter, and a pharmaceutically acceptable carrier for it.

Typically, compositions are adapted for oral administration. However, they can be adapted for other routes of administration, for example, parenteral administration, sublingual or transdermal administration.

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

In order to ensure the constancy of administration, it is preferable that the composition of the present invention be prepared in the form of a unit dose or a dosage unit.

Dosage unit forms for oral administration may be tablets and capsules, and may contain conventional excipients, such as binding agents, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example, magnesium stearate; disintegrating agents, for example, starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

The compositions are preferably presented in unit dose form with an amount of the active ingredient suitable as a daily dose.

Suitable dosages of the insulin sensitizer include those described in the aforementioned patents and patent applications.

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

In the treatment in which compounds other than compound (I) are used, the dosages required and the finished forms of the compositions are those described in the aforementioned patents and patent applications, which, as mentioned above, are included in this document for information; The example includes the administration of 200-800 mg of troglitazone, for example, 200, 300 or 400 mg.

In the treatment of drugs can be administered from 1 to 6 times a day, but most preferably, from 1 to 2 times a day.

Solid oral compositions can be prepared by conventional methods of blending, filling or tableting. Repeated blending operations can be used to distribute the active agent in compositions containing large amounts of fillers. Such operations, of course, are well known to specialists. Tablets can be coated according to methods well known in conventional pharmaceutical practice, in particular, coated with an enteric coating.

Liquid oral preparations can be, for example, in the form of emulsions, syrups or elixirs, or can be a dry product to be redissolved in water or other suitable vehicle immediately before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifiers, for example, lecithin, sorbitan monooleate, or gum arabic; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl phydroxybenzoate or sorbic acid; and, if desired, conventional flavoring or coloring agents.

For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile vehicle, and depending on the concentration used, the compound can be suspended or dissolved in the vehicle. When preparing solutions, the compound can be dissolved in water for injection and sterilized by filtration before filling in suitable vials or ampoules and sealing. There are some advantages to dissolving excipients in the carrier, such as local anesthetics, preservatives and buffering agents. To enhance the stability, the composition can be frozen after filling in suitable vials and the water removed under vacuum. Parenteral suspensions are prepared by practically the same methods, except that compound (I) is suspended in a carrier instead of dissolution, and sterilization cannot be carried out by filtration. The compound can be sterilized by the action of ethylene oxide before suspending in a sterile vehicle. It is advantageous to include a surfactant or wetting agent in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0.1 to 99 wt.%, Preferably 10-60 wt.%, Of the active material, depending on the method of administration.

The composition may, if desired, be in the form of packaging provided with written or printed instructions for use.

Compositions are made and compiled into ready-made preparative forms according to the usual methods, such as those described in standard reference publications, for example, using the United Kingdom and the United States of America, K. etdop''8 Pharmaceuticals, Ciscadexia 5 (Mask RiSHYid Co.), Magdeba 1e Tye Ehtata Räygtastor Sepyas Co., Magypba1e Tye Eh1ta Ryagtastor Sepyas Co,. Rhegk) and Naggu'k So8teiko1o§u (Leoiath Ny1 Vaukk).

Accordingly, the present invention provides the use of an insulin sensitizer, such as compound (I), and especially from 2 to 12 mg, for the manufacture of a medicament for the treatment of hyperglycemia, especially fasting hyperglycemia, in which plasma glucose levels range from elevated normal levels up to <126 mg / dL.

The present invention also relates to the use of an insulin sensitizer, such as compound (I), and especially from 2 to 12 mg, for the manufacture of a medicament for improving glycemic control in conditions that are characterized by hyperglycemia, especially fasting hyperglycemia; wherein this improvement is provided at hyperglycemia with plasma glucose levels ranging from elevated normal levels to <126 mg / dL, delaying or preventing, thereby, a further increase in hyperglycemia.

In another aspect, the present invention relates to the use of an insulin sensitizer, such as compound (I), and especially from 2 to 12 mg, for the manufacture of a medicament for the prevention of hyperglycemia, especially fasting hyperglycemia, in which plasma glucose levels are> 126 mg / long

In particular, the present invention relates to a pharmaceutical composition comprising an insulin sensitizer, such as compound (I), and especially from 2 to 12 mg, and a pharmaceutically acceptable carrier thereof, for use in treating hyperglycemia, especially fasting hyperglycemia, in which glucose levels plasma levels range from elevated normal levels to <126 mg / dL or to improve glycemic regulation in conditions that are characterized by hyperglycemia, especially fasting hyperglycemia; wherein this improvement is provided for hyperglycemia with plasma glucose levels ranging from elevated normal levels to <126 mg / dL, thereby delaying or preventing further increases in hyperglycemia, or for the prevention of hyperglycemia, especially fasting hyperglycemia, in which glucose levels are plasma levels are> 126 mg / dl.

For compositions or methods of the present invention with the above mentioned dose ranges, there is no reason to expect any toxicological side effects.

Claims (7)

1. The use of 5- [4- [2- (P-methyl-L- (2pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4dione (compound (I)), or its tautomeric form, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate for treating hyperglycemia in the range from elevated normal levels to <126 mg / dl. 2. The use according to claim 1, wherein the hyperglycemia is fasting hyperglycemia. 3. The use according to claim 2, in which hyperglycemia in the range from elevated normal levels to <126 mg / dl is additionally characterized by a level of <140 mg / dl after an oral glucose tolerance test. 4. The use according to claim 2, in which hyperglycemia in the range from elevated normal levels to <126 mg / dl is additionally characterized by levels from 140 to <200 mg / dl after an oral glucose tolerance test. 5. The use according to claim 1, wherein the compound (I) is administered in an amount of 2-12 mg per day. 6. The use according to claim 1, wherein the compound (I) is used in the form of compositions adapted for oral administration. 7. The use according to claim 6, wherein the composition is in the form of a single dose. 4 ^) Eurasian Patent Organization, EAPO