JP2001519382A - Use of thiazolidinedione for the treatment of hyperglycemia - Google Patents

Abstract

  (57) [Summary] A method of treating hyperglycemia wherein the plasma glucose concentration is within a range of ≤126 mg / dl from a high normal value, comprising the steps of: administering an effective non-toxic pharmaceutically acceptable amount of an insulin sensitizer to the hyperglycemia; A method comprising administering to a treatment.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to novel methods of treatment, especially to the treatment and / or prevention of certain hyperglycemia. European Patent Application Publication No. 0306228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycemic and hypolipidemic activity. E
Certain thiazolidinediones disclosed in P03086228 have 5- [4
-[2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (hereinafter referred to as 'compound (I)'). W
O94 / 05659 discloses certain salts of the compounds of compound (I), including maleates.

Compound (I) is an “insulin sensitizer” (or “insulin action promoter”)
Is an example of a series of anti-hyperglycemic agents known as. In particular, compound (I) is a thiazolidinedione insulin sensitizer. European Patent Application Publication Number: 0008203, 0139421, 00321
28,0428312,0489663,0155845,0257781,0
208420, 0177353, 0319189, 0332331, 03323
32, 0528734, 0508740; International Patent Application Publication No. 92/1850.
1, 93/02079, 93/22445 and U.S. Pat. Nos. 5,410,488 and 5,478,852 also disclose specific thiazolidinedione insulin sensitizers.

[0003] Another series of compounds that have been approved as having insulin sensitizer activity are those represented by the compounds disclosed in International Patent Application Publication Nos. WO93 / 21166 and WO94 / 01420. Such compounds are referred to herein as 'acyclic insulin sensitizers'. As other examples of acyclic insulin sensitizers, see US Pat. No. 5,232,945 and International Patent Application Publication No. WO 92/034.
25 and WO 91/19702.

[0004] Other examples of insulin sensitizers are described in European Patent Application Publication No. 053393.
3, compounds disclosed in Japanese Patent Application Publication No. 05271204 and US Pat. No. 5,264,451.

[0005] The Diabetes Committee and the Classification of Diabetes Mellitus (The Report of the Expe
rt Committee of the Diagnosis and Classification of Diabetes Mellitus)
According to Diabetes Care, vol 20 (7), 1997, 1183-1197), type II diabetes is characterized by a fasting plasma glucose concentration of ≧ 126 mg / dl (where fasting is at least 8 hours). Is defined as having no calories). The report also states that fasting serum glucose levels range from what is generally considered to be a normal plasma glucose level of about 110 mg / dl to hyperglycemia, which has been identified as having distinct type II diabetes characteristics. Describes how the progression of diabetes, characterized by increasing levels, generally occurs over several years. The report also refers to metabolic stages intermediate between diabetes, including normal glucose homeostasis and impaired glucose tolerance and impaired fasting glucose levels.

[0006] According to EP 0 306 228, Compound I is known to be useful in the treatment of hyperglycemia and therefore also in the treatment of glucose tolerance disorders. International Patent Application Publication No. WO 95/07694 also discloses that thiazolidinedione can be used to treat disorders of glucose tolerance to prevent or delay the onset of type II diabetes mellitus. However, EP 0 328 228 and WO 9
5/07694 does not mention the treatment of glycemia at any specified stage.

Compound (I) has been shown to be particularly effective in controlling glycemia in the hyperglycemia range from high normal to ≦ 126 mg / dl, thereby delaying or preventing further increases in blood glucose. . Therefore, the present invention provides a method for preparing a plasma glucose concentration of ≤126 mg / d from a high normal value.
A method of treating hyperglycemia, especially fasting hyperglycemia, in the range of 1 to 3, comprising administering an effective, non-toxic, pharmaceutically acceptable amount of an insulin sensitizer to a mammal in need thereof. Providing a method comprising: Therefore, the present invention provides a method for preparing a plasma glucose concentration of ≤126 mg / d from a high normal value.
An improved method of providing improved glycemic control in conditions characterized by hyperglycemia, particularly fasting hyperglycemia, in the range of 1 to thereby delay or prevent further exacerbation of hyperglycemia; A method comprising administering a toxic pharmaceutically acceptable amount of an insulin sensitizer to a mammal in need thereof. In a further aspect, the present invention provides a method wherein the plasma glucose concentration is> 126 mg / d.
A method for the prevention of hyperglycemia, especially fasting hyperglycemia, in the range of 1 to 3, comprising administering an effective, non-toxic, pharmaceutically acceptable amount of an insulin sensitizer to a mammal in need thereof. Providing a method comprising:

[0008] A group of conditions as defined herein is characterized by fasting hyperglycemia in which plasma glucose levels range from high normal to ≤126 mg / dl, as well as oral glucose. The tolerance test showed that the plasma glucose concentration was <1.
It is also characterized by hyperglycemia in the range of 40 mg / dl. Another group of conditions, as defined herein, is characterized by fasting hyperglycemia in which plasma glucose levels range from high normal to ≤126 mg / dl, as well as additional oral glucose tolerance. The test is characterized by hyperglycemia with plasma glucose levels ranging from 140 to 200 mg / dl.

A suitable insulin sensitizer is a thiazolidinedione insulin sensitizer. A suitable thiazolidinedione insulin sensitizer is compound (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[0010] Another suitable thiazolidinedione 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-methylcyclohexyl) methoxy] benzyl] thiazolidinedione-2, 4-dione (or ciglitazone), 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).

In certain embodiments, the methods of the present invention comprise administering 2 to 12 mg of Compound (I), especially when administered daily. In particular, the method comprises 2 to 4, 4 to 8 or 8 to 1 per day
Administering 2 mg of compound (I). In particular, the method comprises administering compound (I), especially when administered per day.
Or 4 mg. In particular, the method comprises administering Compound (I) in 4 to 8 mg, for example more than 4 mg, for example 4.1 mg to 8 mg, especially when administered per day. In particular, the method comprises administering compound (I), particularly when administered per day.
mg to 12 mg.

Preferably, the method comprises administering Compound (I), especially when administered daily.
2 mg is administered. Preferably, the method comprises administering compound (I), especially when administered daily.
4 mg is administered. Preferably, the method comprises administering compound (I), especially when administered daily.
8 mg is administered. .

[0013] The insulin sensitizer, such as compound (I), is suitably in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives, such as suitable pharmaceutically acceptable salts, esters and solvates thereof. Will be administered at Suitable pharmaceutically acceptable salt forms of insulin sensitizers such as compound (I) are described in the patents mentioned above and in patent applications related to compound (I), for example EP03062.
28 and WO94 / 05659. A preferred pharmaceutically acceptable salt of compound (I) is the maleate salt. Suitable pharmaceutically acceptable solvated forms of insulin sensitizers, such as compound (I), are described in the aforementioned patents and in patent applications such as EP 0306228 and WO 94/05659 relating to compound (I). And especially hydrates.

Insulin sensitizers such as compound (I), or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, are known in the art, for example, as described in the patents and compounds (I) above. Patent applications such as EP 0 306 228 and WO 94/0
5659. The aforementioned patents and patent applications, for example E
P03086228 and WO94 / 05659 are hereby incorporated by reference. Thiazolidinedione insulin sensitizers such as compound (I) exist as one of several tautomeric forms, all of which are encompassed herein as individual tautomeric forms or as mixtures thereof. You. Certain insulin sensitizers, such as compound (I), contain one or more chiral carbon atoms and may, therefore, exist in two or more stereoisomeric forms: , And mixtures of isomers, including racemates, are encompassed herein.

The term “pharmaceutically acceptable” as used herein includes both human and veterinary use: for example, the term “pharmaceutically acceptable” refers to a veterinarily acceptable compound Is included. The oral glucose tolerance test used herein is Diabete Care vol 20 (7),
1997, 1183-1197. As used herein, the term "high normal" hyperglycemia refers to, for example, the Diabetes Committee and the Report of the Expert Committee of Diabetes Mellitus.
Reference to the Diagnosis and Classification of Diabetes Mellitus), which is treated as generally understood in the art, usually refers to glycemia with a plasma glucose concentration of> 110 mg / dl.

In the method of the present invention, the active agent is preferably administered in the form of a pharmaceutical composition. As noted above, such compositions may include both or only one agent. Such pharmaceutical compositions may be prepared by mixing the insulin sensitizer, such as compound (I), especially 2 to 12 mg of the insulin sensitizer, with a pharmaceutically acceptable carrier. Usually, the composition is used for oral administration. However, such compositions may be used for other modes of administration, for example, parenteral, sublingual or transdermal. 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. Preferably, for consistency in administration, the compositions of the present invention are in unit dosage form.

Unit dosage forms for oral administration may be tablets and capsules and conventional excipients such as binders, for example syrups, acacia, gelatin, sorbitol, tragacanth gum or polyvinylpyrrolidine; For example, lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or sodium lauryl nitrate. Such a pharmaceutically acceptable wetting agent may be included.

The composition is preferably in a unit dosage form in an amount suitable for a daily dose. Suitable doses of the insulin sensitizer include those disclosed in the aforementioned patents and patent applications. Suitable doses of Compound (I), including unit doses, are 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11 or 12 mg. For treatments involving compounds other than compound (I), the dosages and formulations required for treatment are generally set forth in the above-cited patent publication, which is incorporated herein by reference. For example, administration of 200-800 mg troglitazone, such as 200, 300 or 400 mg troglitazone.

In treatment, the agent may be administered one to six times daily, but most preferably once or twice daily. Solid oral compositions can be prepared by conventional methods of mixing, filling or tableting. By means of a repeated mixing operation, the active ingredient can be distributed throughout the composition using a large amount of filler. Such operations are, of course, conventional in the art. The tablets may be coated according to methods known in standard pharmaceutical practice, especially with an enteric coating.

The oral liquid formulation may be in the form of, for example, an emulsion, syrup or elixir, or may be a dry product reconstituted with water or a suitable vehicle before use.
Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel, hardened edible oil; emulsifiers such as lecithin, sorbitan monooleate or acacia. Non-aqueous vehicles, which may include edible oils, for example, peanut oil, fractionated coconut oil, oily esters such as glycerin esters, propylene glycol or ethyl alcohol;
Preservatives, such as methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavoring or coloring agents may be included.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, which can be suspended or dissolved in the vehicle, depending on the concentration used. For preparing solutions, the compound can be dissolved in water for injection, filled into suitable vials or ampoules and sterile filtered before sealing. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can also be dissolved in the vehicle. To enhance stability, the composition may be frozen after filling into vials and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that Compound (I) is suspended in the vehicle instead of being dissolved and sterilization by filtration is not performed. The compound can also be sterilized by exposure to ethylene oxide before suspension in the sterile vehicle. Advantageously, the inclusion of a surfactant and wetting agent in the composition facilitates uniform distribution of the compound.

Depending on the method of administration, the composition may comprise from 0.1% to 99% by weight, preferably 10% by weight.
It may contain from 60 to 60% by weight of active ingredient. If desired, the composition may be packaged with instructions for use.

Compositions are described in standard references, such as British and US Pharmacopoeias, Remin
gton's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Ext
ra Pharmacopoeia (The Pharmaceutical Press, London) and Harry's Cosme
Prepared and formulated according to ticology (leonard Hill Books). Therefore, the present invention provides a method for preparing a plasma glucose concentration of ≤126 mg / d from a high normal value.
l for the manufacture of a medicament for the treatment of hyperglycemia, in particular fasting hyperglycemia, in the range
There is provided use of an insulin sensitizer such as compound (I), especially 2 to 12 mg thereof.

[0024] The present invention also provides a method wherein the plasma glucose concentration is high from normal to ≤126 mg / dl.
Used in the manufacture of a medicament for improving glycemic control in a condition characterized by hyperglycemia, in particular fasting hyperglycemia, and thus delaying or preventing further exacerbation of hyperglycemia There is provided use of an insulin sensitizer such as (I), especially 2 to 12 mg thereof. In yet a further aspect, the present invention provides a method wherein the plasma glucose concentration is> 126 m
It provides the use of an insulin sensitizer, such as compound (I), in particular 2 to 12 mg thereof, for the manufacture of a medicament for the prevention of hyperglycemia in the range of g / dl, especially fasting hyperglycemia. In particular, the present invention relates to a method in which the plasma glucose concentration is increased from a normal value to ≦ 126 mg / d.
for use in the treatment of hyperglycemia in the range of l, especially fasting hyperglycemia; or characterized by fasting hyperglycemia in the range from high normal to ≤126 mg / dl in plasma glucose levels To improve the glycemic control of symptoms, thereby delaying or preventing exacerbation of hyperglycemia; or when the plasma glucose concentration is> 126
mg / dl for the prevention of hyperglycemia, especially fasting hyperglycemia; Compound (I)
And a pharmaceutical composition comprising 2 to 12 mg of the insulin sensitizer, and a pharmaceutically acceptable carrier used therefor.

No detrimental toxicological effects are expected with the compositions or methods within the aforementioned dosage ranges of the present invention.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 417/12 C07D 417/12 // C07D 277/34 C07D 277/34 (C07D 417/12 (C07D 417 / 12 277: 34 277: 34 311: 58) 311: 58) (C07D 417/12 (C07D 417/12 213: 30 213: 30 277: 34) 277: 34) (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM) , AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX , NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Robin Edwin Buckingham UK, CEM 19.5 ADB, Essex, Harlow, Third Avenue, New Frontiers Science Park South, SmithKline Beecham Pharmaceuticals (72) Inventor Stephen Alistair Smith United Kingdom, CM 19.5 Adabrew, Essex, Harlow, Third Avenue, New Frontiers Science Park South, SmithKline Beecham Pharmaceutical F term (reference) 4C033 AD01 AD03 AD20 4C063 AA01 BB03 BB08 CC62 CC79 DD12 DD62 EE01 4C084 AA17 AA27 MA52 NA05 ZC352 4C086 AA01 BC82 GA02 GA08 GA10 MA01 MA02 MA04 MA05 MA52 NA05 ZC35

Claims (12)

[Claims] 1. The plasma glucose concentration is ≦ 126 mg / dl from a high normal value.
A method of treating hyperglycemia, which comprises administering an effective, non-toxic, pharmaceutically acceptable amount of an insulin sensitizer to the treatment of hyperglycemia. 2. The method according to claim 1, wherein the hyperglycemia is fasting hyperglycemia. 3. Hyperglycemia is characterized by a fasting plasma glucose concentration ranging from high normal to ≤126 mg / dl, and furthermore, an oral glucose tolerance test shows that the plasma glucose concentration 3. The method according to claim 2, characterized by hyperglycemia being <140 mg / dl. 4. Hyperglycemia is characterized by fasting plasma glucose concentrations ranging from high normal to ≤126 mg / dl, and furthermore, according to oral glucose tolerance tests, 3. The method according to claim 2, characterized by hyperglycemia ranging from 140 to <200 mg / dl. 5. The method according to claim 1, wherein the insulin sensitizer is a thiazolidinedione insulin sensitizer. 6. The method according to claim 1, wherein the insulin sensitizer is compound (I). 7. The method according to claim 6, wherein 2 to 12 mg of the compound (I) is administered per day. 8. An insulin sensitizer comprising (+)-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-methylcyclohexyl) methoxy] benzyl] thiazolidinedione-2,4-dione (or ciglitazone) ,
5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (or pioglitazone) and 5-[(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine] -2,
Claims: selected from the group consisting of 4-dione (or englitazone); or selected from its tautomeric forms, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof. 5. The method according to any one of 1 to 4. 9. The insulin sensitizer according to claim 1, which is in the form of a composition for oral administration.
9. The method according to any one of items 8 to 8. 10. The method according to claim 9, wherein the composition is in a unit dosage form. 11. The plasma glucose concentration is ≦ 126 mg / d from a high normal value.
Use of an insulin sensitizer in the manufacture of a medicament for the treatment of hyperglycemia in the range of 1. 12. The plasma glucose concentration is ≦ 126 mg / d from a high normal value.
A pharmaceutical composition comprising an insulin sensitizer and a pharmaceutically acceptable carrier for use in the treatment of hyperglycemia in the range of 1.