WO2001047520A1 - Thiazolidinedione derivatives in treatment of diabetes mellitus of type 2 - Google Patents

Thiazolidinedione derivatives in treatment of diabetes mellitus of type 2 Download PDF

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Publication number
WO2001047520A1
WO2001047520A1 PCT/GB2000/005007 GB0005007W WO0147520A1 WO 2001047520 A1 WO2001047520 A1 WO 2001047520A1 GB 0005007 W GB0005007 W GB 0005007W WO 0147520 A1 WO0147520 A1 WO 0147520A1
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WO
WIPO (PCT)
Prior art keywords
compound
insulin sensitiser
diabetes
treatment
thiazolidinedione
Prior art date
Application number
PCT/GB2000/005007
Other languages
French (fr)
Inventor
Robin Edward Buckingham
Original Assignee
Smithkline Beecham P.L.C.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to AU23827/01A priority Critical patent/AU2382701A/en
Publication of WO2001047520A1 publication Critical patent/WO2001047520A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • European Patent Application, Publication Number 0.306.228 relates to certain thiazolidinedione derivatives disclosed as having antihyperglycaemic and antihyperlipidaemic 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 'Compound (I)').
  • WO 94/05659 discloses certain salts of Compound (I) including the maleate salt at example 1 thereof.
  • the invention provides a method for the treatment of diabetes meilitus, especially Type 2 diabetes in a mammal, such as a human, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser.
  • an insulin sensitiser such as Compound (I)
  • a mammal in need thereof wherein the mammal is not suffering from heart failure.
  • the invention provides an insulin sensitiser.
  • an insulin sensitiser such as Compound (I) for use in the treatment of diabetes meilitus, especially Type 2 diabetes, wherein the recipient is not suffering from heart failure.
  • the invention provides the use of an insulin sensitiser.
  • an insulin sensitiser such as Compound (I)
  • Compound (I) for the manufacture of a medicament for the treatment of diabetes meilitus, especially Type 2 diabetes, wherein the recipient is not suffering from heart failure.
  • the method comprises the administration of 2 to 12 mg of Compound (I), especially when administered per day.
  • the method comprises the administration of 2 to 4, 4 to 8 or 8 to 12 mg of Compound (I) per day.
  • the method comprises the administration of 2 to 4mg of Compound
  • the method comprises the administration of 4 to 8mg of Compound (I), especially when administered per day.
  • the method comprises the administration of 2 mg of Compound (I), especially when administered per day.
  • the insulin sensitiser such as Compound (I) is administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate of the relevant pharmaceutically active agent. It will be understood that all pharmaceutically acceptable forms of the active agents per se are encompassed by this invention.
  • Suitable pharmaceutically acceptable forms of the other insulin sensitisers depend upon the particular agent used but include known pharmaceutically acceptable forms of the particular agent chosen. Such derivatives are found or are referred to in standard reference texts such as the British and US Pharmacopoeias. Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale 32nd Edition The Complete Drug Reference (London, The Pharmaceutical Press) or the above mentioned publications.
  • the insulin sensitiser of choice is prepared according to known methods, such methods are found or are referred to in standard reference texts, such as the British and US Pharmacopoeias. Remington's Pharmaceutical Sciences (Mack Publishing Co.). Martindale 32nd Edition The Complete Drug Reference (London, The Pharmaceutical Press) or the abovementioned publications.
  • Compound (I) or, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof may be prepared using known methods, for example those disclosed in EP 0306228 and WO 94/05659.
  • the disclosures of EP 0306228 and WO 94/05659 are incorporated herein by reference. Certain of the insulin sensitisers.
  • the term 'pharmaceutically acceptable embraces both human and veterinary use: for example the term 'pharmaceutically acceptable' embraces a veterinarily acceptable compound.
  • Glycaemic control may be characterised using conventional methods, for example by measurement of a typically used index of glycaemic control such as fasting plasma glucose or glycosylated haemoglobin (Hb Ale). Such indices are determined using standard methodology, for example those described in: Tuescher A, Richterich, P., Sau. med. Wschr. 101 (1971), 345 and 390 and Frank P.. 'Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements', Clinical Products 1988.
  • the active medicaments are preferably administered in pharmaceutical composition form. As indicated above, such compositions can include both medicaments or one only of the medicaments.
  • compositions may be prepared by admixing an insulin sensitiser.
  • an insulin sensitiser such as Compound (I) especially 2 to 12 mg thereof, and a pharmaceutically acceptable carrier therefor.
  • compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration.
  • 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.
  • composition of the invention is in the form of a unit dose.
  • compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
  • Suitable dosages including unit dosages of the Compound of formula (I) comprise 1. 2, 3, 4, 5, 6. 7, 8, 9, 10, 1 1 or 12 mg of Compound (I).
  • the medicaments may be administered from 1 to 6 times a day, but most preferably 1 or 2 times per day.
  • Particular dosages of Compound (I) are 2mg/day, 4mg/day, including 2mg twice per day, and 8 mg/day, including 4mg twice per day.
  • a suitable daily dose of pioglitazone is in the range of from 10 to 50mg, suitably 15mg to 45mg, in particular 15mg, 30mg or 45mg.
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agent can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the Compound (I) suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • the compositions are prepared and formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale 32nd Edition The Complete Drug Reference (London, The Pharmaceutical Press) or the above mentioned publications.
  • the present invention provides a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) especially 2 to 12 mg thereof, and a pharmaceutically acceptable carrier therefor, for use in the treatment of diabetes meilitus, especially Type 2 diabetes, especially Type 2 diabetes, wherein the recipient is not suffering from heart failure.

Abstract

A method for the treatment of diabetes mellitus, especially Type 2 diabetes in a mammal, such as a human, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, such as Compound (I) to a mammal in need thereof, wherein the mammal is not suffering from heart failure (or reduced cardiac reserve).

Description

THIAZOLIDINEDIONE DERTVAnVES IN TREATMENT OF DIABETES MELLTTUS OF TYPE 2
This invention relates to a method of treatment, in particular to a method for the treatment of diabetes meilitus, especially non-insulin dependent diabetes (NIDDM) or Type 2 diabetes.
European Patent Application, Publication Number 0.306.228 relates to certain thiazolidinedione derivatives disclosed as having antihyperglycaemic and antihyperlipidaemic 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 'Compound (I)'). WO 94/05659 discloses certain salts of Compound (I) including the maleate salt at example 1 thereof.
Compound (I) is an example of a class of anti-hyperglycaemic agents known as 'insulin sensitisers'. In particular Compound (I) is a thiazolidinedione insulin sensitiser. European Patent Applications. Publication Numbers: 0008203, 0139421 ,
0032128. 0428312, 0489663. 0155845, 0257781 , 0208420. 0177353, 0319189, 0332331, 0332332, 0528734, 0508740: International Patent Application, Publication Numbers 92/18501, 93/02079. 93/22445 and United States Patent Numbers 5104888 and 5478852, also disclose certain thiazolidinedione insulin sensitisers. Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in International Patent Applications. Publication Numbers WO 93/21166 and WO 94/01420. These compounds are herein referred to as 'acyclic insulin sensitisers1. Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number 5232945 and International Patent Applications. Publication Numbers WO 92/03425 and WO 91/19702. Further examples of insulin sensitiser are those disclosed in WO 97/31907 and GW262570. Other insulin sensitisers are those disclosed in European Patent Application, Publication Number 0533933, Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451. The above mentioned publications are incorporated herein by reference.
It is now indicated that Compound (I) is most beneficially used in the treatment of diabetes meilitus in patients identified as not suffering from heart failure.
Accordingly, the invention provides a method for the treatment of diabetes meilitus, especially Type 2 diabetes in a mammal, such as a human, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser. such as Compound (I) to a mammal in need thereof, wherein the mammal is not suffering from heart failure.
In another aspect the invention provides an insulin sensitiser. such as Compound (I) for use in the treatment of diabetes meilitus, especially Type 2 diabetes, wherein the recipient is not suffering from heart failure.
In a further aspect the invention provides the use of an insulin sensitiser. such as Compound (I), for the manufacture of a medicament for the treatment of diabetes meilitus, especially Type 2 diabetes, wherein the recipient is not suffering from heart failure.
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SUBSTTTUTE SHEET (RULE 25) Preferably the insulin sensitiser is used in the absence of any agent used specifically for the treatment of heart failure associated with diabetes, including such agents as endothelial antagonists, beta-blockers. ACE inhibitors or diuretics. A suitable thiazolidinedione insulin sensitiser is Compound (I). Other suitable thiazolidinedione insulin sensitisers include (+)-5-[[4-[(3,4- dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l-benzopyran-2-yl)methoxy]phenyl]methyl]- 2,4-thiazolidinedione (or troglitazone), 5-[4-[(l- methylcyclohexyl)methoxy]benzyl]thiazolidine-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 one particular aspect, the method comprises the administration of 2 to 12 mg of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 2 to 4, 4 to 8 or 8 to 12 mg of Compound (I) per day. Particularly, the method comprises the administration of 2 to 4mg of Compound
(I), especially when administered per day.
Particularly, the method comprises the administration of 4 to 8mg of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 8 to 12 mg of Compound (I), especially when administered per day.
Preferably, the method comprises the administration of 2 mg of Compound (I), especially when administered per day.
Preferably, the method comprises the administration of 4 mg of Compound (I), especially when administered per day. Preferably, the method comprises the administration of 8 mg of Compound (I), especially when administered per day.
It will be understood that the insulin sensitiser, such as Compound (I) is administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate of the relevant pharmaceutically active agent. It will be understood that all pharmaceutically acceptable forms of the active agents per se are encompassed by this invention.
Suitable pharmaceutically acceptable salted forms of Compound (I) include those described in EP 0306228 and WO 94/05659. A preferred pharmaceutically acceptable salt is a maleate.
Suitable pharmaceutically acceptable solvated forms of Compound (I) include those described in EP 0306228 and WO 94/05659. in particular hydrates.
Suitable pharmaceutically acceptable forms of the other insulin sensitisers depend upon the particular agent used but include known pharmaceutically acceptable forms of the particular agent chosen. Such derivatives are found or are referred to in standard reference texts such as the British and US Pharmacopoeias. Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale 32nd Edition The Complete Drug Reference (London, The Pharmaceutical Press) or the above mentioned publications.
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TTUTE SHEET RULE 26 The insulin sensitiser of choice is prepared according to known methods, such methods are found or are referred to in standard reference texts, such as the British and US Pharmacopoeias. Remington's Pharmaceutical Sciences (Mack Publishing Co.). Martindale 32nd Edition The Complete Drug Reference (London, The Pharmaceutical Press) or the abovementioned publications. For example Compound (I) or, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, may be prepared using known methods, for example those disclosed in EP 0306228 and WO 94/05659. The disclosures of EP 0306228 and WO 94/05659 are incorporated herein by reference. Certain of the insulin sensitisers. especially the thiazolidinedione insulin sensitisers. such as Compound (I), may exist in one of several tautomeric forms, all of which are encompassed by the term Compound (I) as individual tautomeric forms or as mixtures thereof. Certain of the insulin sensitisers, such as Compound (I) contain at lease one chiral carbon atom, and hence can exist in one or more stereoisomeric forms, all of which are encompassed in the method of the invention whether as individual isomers or as mixtures of isomers, including racemates.
"Heart failure" as used herein also may be referred to in the art as "reduced cardiac reserve" and can be diagnosed using conventional methodology, for example exercise tolerance testing. "Suffers from heart failure" in particular means suffers from chronic (congestive) heart failure syndrome which syndrome can be identified using known criteria for example those disclosed in reference texts such as Cecil Textbook of Medicine 19th Edition, W B Saunders Company for example at page 187.
As used herein the term 'pharmaceutically acceptable' embraces both human and veterinary use: for example the term 'pharmaceutically acceptable' embraces a veterinarily acceptable compound.
For the avoidance of doubt, when reference is made herein to scalar amounts, including mg amounts, of Compound (I) in a pharmaceutically acceptable form, the scalar amount referred to is made in respect of Compound (I) per se. For example 2 mg of Compound (I) in the form of the maleate salt is that amount of maleate salt which contains 2 mg of Compound (I). Similarly for the other insulin sensitisers. Diabetes meilitus is preferably Type 2 diabetes.
Glycaemic control may be characterised using conventional methods, for example by measurement of a typically used index of glycaemic control such as fasting plasma glucose or glycosylated haemoglobin (Hb Ale). Such indices are determined using standard methodology, for example those described 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 the method of the invention, the active medicaments are preferably administered in pharmaceutical composition form. As indicated above, such compositions can include both medicaments or one only of the medicaments.
Such compositions may be prepared by admixing an insulin sensitiser. such as Compound (I) especially 2 to 12 mg thereof, and a pharmaceutically acceptable carrier therefor.
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SUBSTTTUTE SHEET (RULE 26) Usually the compositions are adapted for oral administration. However, they may be adapted for other modes 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 obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.
Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth. or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate: disintegrants. for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
Suitable dosages including unit dosages of the Compound of formula (I) comprise 1. 2, 3, 4, 5, 6. 7, 8, 9, 10, 1 1 or 12 mg of Compound (I). In the treatment the medicaments may be administered from 1 to 6 times a day, but most preferably 1 or 2 times per day.
Particular dosages of Compound (I) are 2mg/day, 4mg/day, including 2mg twice per day, and 8 mg/day, including 4mg twice per day.
Suitable dosages including unit dosages of the other insulin sensitisers include the known dosages including unit doses for these compounds as described or referred to in reference text such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale 32nd Edition The Complete Drug Reference (London, The Pharmaceutical Press).
For example a suitable daily dose of pioglitazone is in the range of from 10 to 50mg, suitably 15mg to 45mg, in particular 15mg, 30mg or 45mg.
The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
Oral liquid preparations may be in the form of for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose. carboxymethylcellulose. aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate. or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil. oily esters such as esters of glycerine, propylene glycol. or ethyl
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SUBSnTUTE SHEET (RULE 26) alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agent can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the Compound (I) suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
Compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration.
Composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use. The compositions are prepared and formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale 32nd Edition The Complete Drug Reference (London, The Pharmaceutical Press) or the above mentioned publications. In particular, the present invention provides a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) especially 2 to 12 mg thereof, and a pharmaceutically acceptable carrier therefor, for use in the treatment of diabetes meilitus, especially Type 2 diabetes, especially Type 2 diabetes, wherein the recipient is not suffering from heart failure. It will be appreciated that the treatment of the present invention encompasses the use of an insulin sensitiser in monotherapy or in combination therapy, for example with other antidiabetic agents such as sulphonylureas, biguanides, for example metformin, or alpha glucosidase inhibitors with the above mentioned proviso with regard to an agent used specifically for the treatment of cardiac conditions associated with diabetes. No adverse toxicological effects have been established for the compositions or method of the invention in the abovementioned dosage ranges.
SUBSTTTUTE SHEET (RULE 26)

Claims

Claims:
1. A method for the treatment of diabetes meilitus, especially Type 2 diabetes in a mammal, such as a human, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, such as Compound (I) to a mammal in need thereof, wherein the mammal is not suffering from heart failure (or reduced cardiac reserve).
2. A method according to claiml, wherein the insulin sensitiser is used in the absence of any agent used specifically for the treatment of cardiac conditions associated with diabetes.
3. A method according to claim 1 or claim 2, wherein the insulin sensitiser is a thiazolidinedione insulin sensitiser.
4. A method according to claim 3, wherein the thiazolidinedione insulin sensitiser is
Compound (I).
5. A method according to claim 3, wherein the thiazolidinedione insulin sensitiser is 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl]thiazolidine-2,4-dione (or pioglitazone),
6. A method according to claim 3, wherein the thiazolidinedione insulin sensitiser is selected from the list consisting of: (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2, 5, 7, 8- tetramethyl-2H-l-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), 5-[4-[(l-methylcyclohexyl)methoxy]benzyl]thiazolidine-2,4-dione (or ciglitazone) and 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englitazone).
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SUBSTΠTΠΈ SHEET (RULE 26)
PCT/GB2000/005007 1999-12-24 2000-12-22 Thiazolidinedione derivatives in treatment of diabetes mellitus of type 2 WO2001047520A1 (en)

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GBGB9930696.1A GB9930696D0 (en) 1999-12-24 1999-12-24 Novel method of treatment

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007049050A2 (en) * 2005-10-27 2007-05-03 Heptahelix Ab Modulators of gpr40 for the treatment of diabetes
WO2007049050A3 (en) * 2005-10-27 2007-12-21 Heptahelix Ab Modulators of gpr40 for the treatment of diabetes

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