OA11519A - Use of thiazolidinediones for the treatment of hyperglycaemia. - Google Patents

Use of thiazolidinediones for the treatment of hyperglycaemia. Download PDF

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Publication number
OA11519A
OA11519A OA1200000107A OA1200000107A OA11519A OA 11519 A OA11519 A OA 11519A OA 1200000107 A OA1200000107 A OA 1200000107A OA 1200000107 A OA1200000107 A OA 1200000107A OA 11519 A OA11519 A OA 11519A
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Prior art keywords
hyperglycaemia
glucose levels
insulin sensitiser
plasma glucose
range
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Application number
OA1200000107A
Inventor
Robin Edwin Buckingham
Stephen Alistair Smith
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Smithkline Beecham Plc
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Publication of OA11519A publication Critical patent/OA11519A/en

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    • 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
    • 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
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A method for the treatment of hyperglycaemia wherein plasma glucose levels in the range of from > 126 mg/dl to 140 mg/dl, which method comprises administering an effective nontoxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.

Description

1 011519
NOVEL METHOD OF TREATMENT
This invention relates to a method of treatment, in particular to a method for thetreatment of a certain, specified hyperglycaemia. 5 European Patent Application, Publication Number 0,306,228 relates to certain thiazolidinedione dérivatives disclosed as having hypoglycaemic and hypolipidaemicactivity. 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)').WO94/05659 discloses certain salts of Compound (I) including the maleate sait. 10 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 15 92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852, also disclose certain thiazolidinedione insulin sensitisers.
Another sériés of compounds generally recognised as having insulin sensitiseractivity are those typified by the compounds disclosed in International PatentApplications, Publication Numbers WO93/21166 and W094/01420. These compounds 20 are herein referred to as 'acyclic insulin sensitisers'. Other examples of acyclic insulinsensitisers are those disclosed in United States Patent Number 5232945 and InternationalPatent Applications, Publication Numbers WO92/03425 and WO91/19702.
Examples of other insulin sensitisers are those disclosed in European PatentApplication, Publication Number 0533933, Japanese Patent Application Publication 25 Number 05271204 and United States Patent Number 5264451.
The Report of the Expert Committee of the Diagnosis and Classification of
Diabètes Mellitus (Diabètes Care, vol 20(7), 1997, 1183-1197) States that Type 2 diabètesis characterised by fasting plasma glucose levels of > 126mg/dl (where fasting is defïnedas no calorific intake for at least 8 hours). It is also described therein how the 30 development of diabètes commonly occurs over a period of several years characterised bya rise in fasting sérum glycaemia levels from levels generally considered to be normal -plasma glucose levels of approximately 1 lOmg/dl - through to the stated hyperglycaemiacharacteristic of ffank Type 2 diabètes. The Report also refers to metabolic stagesintermediate between normal glucose homeostasis and diabètes, including impaired 35 glucose tolérance and impaired fasting glucose.
It is known from EP0306228 that Compound I is useful in the prophyIaxis of hyperglycaemia and hence for the treatment of impaired glucose tolérance. InternationalPatent Application, Publication number WO 95/07694 also discloses that 2 011519 thiazolidinediones can be used to treat impaired glucose tolérance to prevent or delay theonset of Type 2 diabètes mellitus. However, EP0306228 and WO 95/07694 do notdisclose the treatment of any particular range of glycaemias.
It is now surprisingly indicated that Compound (I) provides a particularly5 bénéficiai effect on glycaemic control in the range of hyperglycaemia from >126mg/dl to 140mg/dl, thereby delaying or preventing fiirther élévation of the hypergylcaemia.Accordingly, the invention provides a method for the treatment of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are inthe range of ffom >126mg/dl to 140mg/dl, which method comprises administering an 10 effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to amammal in need thereof.
In a further aspect the invention provides a method for improving glycaemiccontrol in conditions characterised by hyperglycaemia, especially fastinghyperglycaemias, wherein the improvement is provided wherein plasma glucose levels 15 are in the range of from >126mg/dl to 140mg/dl, thereby delaying or preventing furtherélévation of the hypergylcaemia, which method comprises administering an effectivenon-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammalin need thereof.
In yet a further aspect, the invention provides a method for the prophylaxis of 20 hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are>140mg/dl, which method comprises administering an effective non-toxic andpharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.
One particular group of conditions defined herein, in addition to beingcharacterised by hyperglycaemia wherein fasting plasma glucose levels are in the range of 25 from >126mg/dl to 140mg/dl are further characterised by hyperglycaemia wherein plasmaglucose levels following an oral glucose tolérance test are <140mg/dl. A further group of conditions defined herein are those wherein in addition tobeing characterised by hyperglycaemia wherein fasting plasma glucose levels are in therange of from >126mg/dl to 140mg/dl, are further characterised by hyperglycaemias 30 wherein plasma glucose levels following an oral glucose tolérance test are in the range offrom 140 to <200 mg/dl.
Suitably the hyperglycaemia is that associated with the Type 2 diabètes mellitussyndrome. A suitable insulin sensitiser is a thiazolidinedione insulin sensitiser. 35 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] 011519 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 thé administration of 2 to 12 mg5 of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 2 to 4,4 to 8 or 8 to 12mg of Compound (I) per day.
Particularly, the method comprises the administration of 2 to 4mg of Compound(I), especially when administered per day. 10 Particularly, the method comprises the administration of 4 to 8mg, such as greater than 4 for example 4.1, to 8 mg, of Compound (I), especially when administeredper day.
Particularly, the method comprises the administration of 8 to 12 mg ofCompound (I), especially when administered per day. 15 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), 20 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 pharmaceuticallyacceptable dérivatives such as pharmaceutically acceptable salts, esters and solvatésthereof, as appropriate. 25 Suitable pharmaceutically acceptable salted forms of the insulin sensitisers, such as Compound (I), include those described in the above mentioned patents and patentapplications such as in EP 0306228 and WO94/05659 for Compound (I). A preferred pharmaceutically acceptable sait for Compound (I) is a maleate.Suitable pharmaceutically acceptable solvated forms of the insulin sensitisers, 30 such as Compound (I), include those described in the above mentioned patents and patentapplications, such as in EP 0306228 and WO94/05659 for Compound (I), in particularhydrates.
The thiazolidinedione insulin sensitisers, such as Compound (I), may exist in oneof several tautomeric forms, ail of which are encompassed herein either as individual 35 tautomeric forms or as mixtures thereof. Certain of the insulin sensitisers, such asCompound (I), contain one or more chiral carbon atom, and hence can exist in two ormore stereoisomeric forms: Ail such forms are encompassed herein whether as individualisomers or as mixtures of isomers, including racemates. 4 011519
As used herein the term 'pharmaceutically acceptable' embraces both hüman andveterinary use: for example the term 'pharmaceutically acceptable' embraces a veterinarilyacceptable compound.
As used herein the oral glucose tolérance test is that referenced in Diabètes Care5 1997, vol 20(7), 1183-1197.
As used herein ’elevated normal' hyperglycaemia is to be taken as generallyunderstood in the art, with reference for example to the Report of the Expert Committeeof the Diagnosis and Classification of Diabètes Mellitus but is usually taken to meanglycaemias wherein plasma glucose levels are >1 lOmg/dl. 10 Suitably, plasma glucose levels are fasting plasma glucose levels.
In the method of the invention, the active médicaments are preferablyadministered in pharmaceutical composition form. As indicated above, suchcompositions can include both médicaments or one only of the médicaments.
Such compositions may be prepared by admixing an insulin sensitiser, such as15 Compound (I) and especially 2 to 12 mg thereof, and a pharmaceutically acceptable carrier therefor.
Usually the compositions are adapted for oral administration. However, theymay be adapted for other modes of administration, for example parentéral administration,sublingual or transdermal administration. 20 The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid préparations, such as oral orstérile parentéral solutions or suspensions.
In order to obtain consistency of administration it is preferred that a compositionof the invention is in the form of a unit dose. 25 Unit dose présentation 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, forexample magnésium stéarate; disintegrants, for example starch, polyvinylpyrrolidone, 30 sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptablewetting agents such as sodium lauryl sulphate.
The compositions are preferably in a unit dosage form in an amount appropriatefor the relevant daily dosage.
Suitable dosages for the insulin sensitisers include those disclosed in the above 35 mentioned patents and patent applications.
Suitable dosages,· including unit dosages, of Compound (I) comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I). 5 011519
In the treatment the médicaments may be administered from 1 to 6 times a day,but most preferably 1 or 2 times per day.
In the treatment involving compounds other than Compound (I), the requireddosages and formulations are generally as described in the above mentioned patent 5 publications which as stated above are incorporated by reference herein: An exampleincludes the administration of 200-800mg of Troglitazone, for example 200, 300 or400mg.
The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may be used to distribute 10 the active agent throughout those compositions employing large quantities of fillers.
Such operations are of course conventional in the art. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice, in particular with anenteric coating.
Oral liquid préparations may be in the form of, for example, émulsions, syrups, 15 or élixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid préparations may contain conventional additivessuch as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminium stéarate gel, hydrogenatededible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; 20 non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycérine, propylene glycol, or ethylalcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid;and if desired conventional flavouring or colouring agents.
For parentéral administration, fluid unit dosage forms are prepared utilizing the 25 compound and a stérile vehicle, and, depending on the concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions the compound can bedissolved in water for injection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, apreservative and buffering agents can be dissolved in the vehicle. To enhance the 30 stability, the composition can be frozen after filling into the vial and the water removedunder vacuum. Parentéral suspensions are prepared in substantially the same manner,except that the médicament is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can be sterilized byexposure to ethylene oxide before suspending in the stérile vehicle. Advantageously, a 35 surfactant or wetting agent is included in the composition to facilitate uniformdistribution of the compound.
Compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending upon the method of administration. 6 011519
The composition may, if desired, be in the form of a pack accompanied bywritten or printed instructions for use.
The compositions are prepared and formulated according to conventionalmethods, such as those disclosed in standard reference texts, for example the British and 5 US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.),Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry'sCosmeticology (Leonard Hill Books).
The invention also provides the use of an insulin sensitiser, such as Compound(I) and especially 2 to 12 mg thereof, for the manufacture of a médicament for the 10 treatment of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucoselevels are in the range of from >126mg/dl to 140mg/dl.
In addition, the invention also provides the use of an insulin sensitiser, such asCompound (I) and especially 2 to 12 mg thereof, for the manufacture of a médicament forimproving glycaemic control in conditions characterised by hyperglycaemia, especially 15 fasting hyperglycaemia, the improvement being provided wherein plasma glucose levels are in the range of from >126mg/dl to 140mg/dl, thereby delaying or preventing furtherélévation of the hypergylcaemia.
In yet a further aspect, the invention provides the use of an insulin sensitiser,such as Compound (I) and especially 2 to 12 mg thereof, for the manufacture of a 20 médicament for the prophylaxis of hyperglycaemia, especially fasting hyperglycaemia,wherein plasma glucose levels are >140mg/dl.
The présent invention also provides a pharmaceutical composition comprising aninsulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, and apharmaceutically acceptable carrier therefor, for use in the treatment of hyperglycaemia, 25 especially fasting hyperglycaemia, wherein plasma glucose levels are in the range of from>126mg/dl to 140mg/dl or for the improvement of glycaemic control in conditionscharacterised by fasting hyperglycaemia, the improvement being provided in the range ofhyperglycaemia wherein plasma glucose levels are in the range of from >126mg/dl to140mg/dl, thereby delaying or preventing further élévation of the hypergylcaemia or for 30 the prophylaxis of hyperglycaemia, especially fasting hyperglycaemia, wherein plasmaglucose levels are >140mg/dl.
No adverse toxicological effects are expected for the compositions or methods of theinvention in the above mentioned dosage ranges.

Claims (11)

  1. 7 Claims: 011519
    1. A method for the treatment of hyperglycaemia wherein plasma glucose levels arein the range of from >126mg/dl to 140mg/dl, which method comprises administering an 5 effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to amammal in need thereof.
  2. 2. A method according to claim 1, wherein the hyperglycaemia is fastinghyperglycaemia.
  3. 3. A method according to claim 2, wherein the hyperglycaemia is characterised by 10 fasting plasma glucose levels in the range of from >126mg/dl to 140mg/dl and is further characterised by hyperglycaemia wherein plasma glucose levels following an oral glucosetolérance test are <140mg/dl.
  4. 4. A method according to claim 2, wherein the hyperglycaemia is characterised byfasting plasma glucose levels in the range of from >126mg/dl to 140mg/dl, and is further 15 characterised by hyperglycaemias wherein plasma glucose levels following an oralglucose tolérance test are in the range of from 140 to <200 mg/dl.
  5. 5. A method according to any one of claims 1 to 4, wherein the insulin sensitiser isa thiazolidinedione insulin sensitiser.
  6. 6. A method according to any one of claims 1 to 5, wherein the insulin sensitiser is 20 Compound (I).
  7. 7. A method according to claim 6, wherein 2 to 12 mg of Compound (I) isadministered per day.
  8. 8. A method according to any one of claims 1 to 4, wherein the insulin sensitiser isselected from the list consisting of: (+) -5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8- 25 tetramethyl-2H-1 -benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (ortroglitazone), 5-[4-[(l-methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (orciglitazone), 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (orpioglitazone) and 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englitazone); or a tautomeric form thereof, or a pharmaceutically acceptable sait 30 thereof, or a pharmaceutically acceptable solvaté thereof.
  9. 9. A method according to any one of claims 1 to 8, wherein the insulin sensitiser isin the form of a compositions adapted for oral administration.
  10. 10. A method according to claim 9, wherein the composition is in unit dosage form. 11 The use of an insulin sensitiser for the manufacture of a médicament for the 35 treatment of hyperglycaemia wherein plasma glucose levels are in the range of from >126mg/dl to 140mg/dl. 8 011519
  11. 12. A pharmaceutical composition comprising an insulin sensitiser and apharmaceutically acceptable carrier, for use in the treatment of hyperglycaemia whereinplasma glucose levels in the range of from >126mg/dl to 140mg/dl.
OA1200000107A 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia. OA11519A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9721692.3A GB9721692D0 (en) 1997-10-13 1997-10-13 Novel treatment
PCT/GB1998/003067 WO1999018944A1 (en) 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia

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OA11519A true OA11519A (en) 2004-02-09

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EP (1) EP1023057A1 (en)
JP (1) JP2001519383A (en)
KR (1) KR20010024482A (en)
CN (1) CN1281358A (en)
AP (1) AP1223A (en)
AU (1) AU9547198A (en)
BG (1) BG104405A (en)
BR (1) BR9815220A (en)
CA (1) CA2305289A1 (en)
CZ (1) CZ20001298A3 (en)
EA (1) EA200000418A1 (en)
GB (1) GB9721692D0 (en)
HR (1) HRP20000256A2 (en)
HU (1) HUP0003673A3 (en)
ID (1) ID24439A (en)
IL (1) IL135515A0 (en)
NO (1) NO20001897L (en)
OA (1) OA11519A (en)
PL (1) PL339804A1 (en)
SK (1) SK5322000A3 (en)
TR (1) TR200000957T2 (en)
UA (1) UA66809C2 (en)
WO (1) WO1999018944A1 (en)
YU (1) YU28700A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
TR200100207T2 (en) * 1998-07-21 2001-05-21 Smithkline Beecham P.L.C. The use of substance enhancing glucose uptake for the reduction of apoptosis

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG59988A1 (en) * 1987-09-04 1999-02-22 Beecham Group Plc Substituted thiazolidinedione derivatives
GB9218830D0 (en) * 1992-09-05 1992-10-21 Smithkline Beecham Plc Novel compounds
US5457109A (en) * 1993-09-15 1995-10-10 Warner-Lambert Company Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of disease states at risk for progressing to noninsulin-dependent diabetes mellitus

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AP1223A (en) 2003-11-13
IL135515A0 (en) 2001-05-20
JP2001519383A (en) 2001-10-23
UA66809C2 (en) 2004-06-15
NO20001897D0 (en) 2000-04-12
NO20001897L (en) 2000-06-09
WO1999018944A1 (en) 1999-04-22
SK5322000A3 (en) 2000-09-12
TR200000957T2 (en) 2000-08-21
EA200000418A1 (en) 2000-10-30
CZ20001298A3 (en) 2001-08-15
AP2000001788A0 (en) 2000-06-30
HUP0003673A3 (en) 2001-12-28
CA2305289A1 (en) 1999-04-22
PL339804A1 (en) 2001-01-02
YU28700A (en) 2003-10-31
HRP20000256A2 (en) 2000-12-31
BR9815220A (en) 2000-11-14
KR20010024482A (en) 2001-03-26
EP1023057A1 (en) 2000-08-02
AU9547198A (en) 1999-05-03
HUP0003673A2 (en) 2001-10-28
CN1281358A (en) 2001-01-24
ID24439A (en) 2000-07-20
GB9721692D0 (en) 1997-12-10
BG104405A (en) 2000-12-29

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