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WO1995021608A1 - Utilisation de sensibilisateurs a l'insuline dans le traitement de l'insuffisance renale - Google Patents

Utilisation de sensibilisateurs a l'insuline dans le traitement de l'insuffisance renale Download PDF

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Publication number
WO1995021608A1
WO1995021608A1 PCT/EP1995/000441 EP9500441W WO9521608A1 WO 1995021608 A1 WO1995021608 A1 WO 1995021608A1 EP 9500441 W EP9500441 W EP 9500441W WO 9521608 A1 WO9521608 A1 WO 9521608A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
formula
insulin sensitiser
group
substituted
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP1995/000441
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English (en)
Inventor
Robin Edwin Buckingham
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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
Priority claimed from GB9402624A external-priority patent/GB9402624D0/en
Priority claimed from GB9410214A external-priority patent/GB9410214D0/en
Priority claimed from GBGB9426019.7A external-priority patent/GB9426019D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Priority to JP7520956A priority Critical patent/JPH09512249A/ja
Priority to HU9602207A priority patent/HU224436B1/hu
Priority to EP95907653A priority patent/EP0777469A1/fr
Priority to AU15783/95A priority patent/AU700826B2/en
Priority to MX9603338A priority patent/MX9603338A/es
Publication of WO1995021608A1 publication Critical patent/WO1995021608A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/41—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to a novel method for the treatment of renal diseases.
  • Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in International Patent Applications, Publication Numbers WO93/21166 and WO94/01420. These compounds are herein referred to as 'acyclic insulin sensitisers'. Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number 5232945 and International Patent Applications, Publication Numbers WO92/03425 and WO91/19702.
  • insulin sensitisers examples include those disclosed in European Patent Application, Publication Number 0533933, Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451.
  • compounds having insulin sensitiser activity can prevent hydronephrosis and proteinuria, such as albuminuria, and that they are therefore of potential use in the treatment and/or prophylaxis of renal disease, especially renal disease associated with the development of Type II diabetes including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hype ⁇ ensive nephrosclerosis and end stage renal disease.
  • an insulin sensitiser upon nephropathy is also indicative that an insulin sensitising agent can be expected to prevent, reverse, stabilise or retard the progression of microalbuminuria to albuminuria.
  • microalbuminuria is considered to be a predictor of future nephropathy, especially in patients with clinical evidence of pre-diabetic insulin resistance syndrome, alternatively referred to as Syndrome X.
  • the present invention provides a method for the treatment and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease, and microalbuminuria which method comprises the administration of an effective, non-toxic amount of an insulin sensitiser to a human or non-human mammal in need thereof.
  • Particular insulin sensitisers include thiazolidinedione insulin sensitisers.
  • Particular insulin sensitisers include acyclic insulin sensitisers.
  • One favoured group of insulin sensitisers are the thiazolidinedione insulin sensitisers disclosed in EP 0306228 and WO94/05659.
  • the present invention provides a method for the treatment and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease, and microalbuminuria which method comprises the administration of an effective non-toxic amount of a compound of formula (I):
  • A* represents a substituted or unsubstituted aromatic heterocyclyl group
  • R! represents a hydrogen atom, an al yl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
  • R2 and R ⁇ each represent hydrogen, or R ⁇ and R ⁇ together represent a bond
  • a 2 represents a benzene ring having in total up to five substituents
  • n represents an integer in the range of from 2 to 6; to a human or non-human mammal in need thereof.
  • Suitable aromatic heterocyclyl groups of the compounds of formula (I) include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
  • Favoured aromatic heterocyclyl groups of the compounds of formula (I) include substituted or unsubstituted single ring aromatic heterocyclyl groups having 5 to 7 ring atoms, preferably 5 or 6 ring atoms.
  • aromatic heterocyclyl groups of the compounds of formula (I) comprise 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen.
  • Suitable values for A ⁇ when it represents a 5- membered aromatic heterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl.
  • Suitable values for A ⁇ when it represents a 6- membered aromatic heterocyclyl group include pyridyl or pyrimidinyl, especially pyridyl.
  • A* represents a moiety of formula (a), (b) or (c):
  • R6 and R ⁇ each independently represents a hydrogen or halogen atom, an alkyl or alkoxy group or a substituted or unsubstituted aryl group or when R ⁇ and R ⁇ are each attached to adjacent carbon atoms, then R ⁇ and R ⁇ together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R ⁇ and R ⁇ together is substituted or unsubstituted; and in the moiety of formula (a) X* represents oxygen or sulphur.
  • A* represents a moiety of the abovedefined formula (a).
  • Al represents a moiety of the abovedefined formula (b).
  • A* represents a moiety of the abovedefined formula (c).
  • a particular form of moiety (c) is a moiety (c'):
  • R° and R ⁇ are as defined in relation to formula (c).
  • R" and R ⁇ together represent a moiety of formula (d):
  • R ⁇ a and R ⁇ D each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R° a and R°b each independently represent hydrogen, halogen, alkyl or alkoxy.
  • R ⁇ a represents hydrogen.
  • R ⁇ D represents hydrogen.
  • R% a and R ⁇ b both represent hydrogen.
  • R ⁇ and R ⁇ each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, R ⁇ and R? each independently represent hydrogen, alkyl or phenyl.
  • R ⁇ and R? together represent the moiety of formula (d).
  • R ⁇ and R- 7 both represent hydrogen.
  • the five substituents of A ⁇ include three optional substituents.
  • Suitable optional substituents for the moiety A 2 include halogen, substituted or unsubstituted alkyl or alkoxy.
  • a preferred compound of formula (I) is 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy] benzyl] thiazolidine-2,4-dione or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, especially a maleic acid salt thereof, and/or a pharmaceutically acceptable solvate thereof.
  • a compound of formula (I) may exist in one of several tautomeric forms, all of which are encompassed in the method of the present invention. It will be appreciated that the present invention encompasses the administration of all of the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof, including any stereoisomeric forms thereof, whether as individual isomers or as mixtures of isomers.
  • Suitable substituents for any heterocyclyl group of the compounds of formula (I) include up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
  • suitable, favoured and preferred insulin sensitisers are the suitable, favoured and preferred compounds disclosed in European Patent Application, Publication Number 0533933, International Patent Application, Publication Number WO 93/02079 , Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451.
  • the term 'insulin sensitiser' relates to compounds which increase the biological response to insulin.
  • insulin sensitisers are indicated to lower elevated fasting plasma insulin concentrations and improve glycaemic control.
  • 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
  • 'halogen' refers to fluorine, chlorine, bromine and iodine; preferably chlorine.
  • 'alkyl' and 'alkoxy' relate to groups having straight or branched carbon chains,containing up to 12 carbon atoms.
  • acyl' includes alkylcarbonyl groups.
  • Suitable alkyl groups are C ⁇ - ⁇ alkyl groups, especially C ⁇ - alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.
  • Suitable substituents for any alkyl group include those indicated above in relation to the term "aryl”.
  • Suitable pharmaceutically acceptable salts include salts of carboxy groups and acid addition salts.
  • Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
  • Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane- sulphonate, a-keto glutarate and a-glycerophosphate, especially the maleate salt.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • active compounds disclosed in the above mentioned patent publications, and referred to herein as insulin sensitisers, including the specific examples disclosed therein, are conveniently prepared according to the methods disclosed in the said patent publications:
  • a compound of formula (I), or the tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof may be prepared using the processes described in EP 0306228 and WO94/05659.
  • salts and/or solvates of the compounds of formula (I) may be prepared and isolated according to conventional procedures for example sodium salts may be prepared by using sodium methoxide in methanol.
  • the present invention also provides an insulin sensitiser, such as a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease, and microalbuminuria.
  • an insulin sensitiser such as a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof
  • the present invention also provides an insulin sensitiser, such as a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the manufacture of a medicament for the treatment and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease, and microalbuminuria.
  • an insulin sensitiser such as a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof
  • the insulin sensitiser such as a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be administered er ⁇ -- or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition for the treatment and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease, and microalbuminuria
  • a pharmaceutical composition for the treatment and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease, and microalbuminuria
  • an insulin sensitiser such as a compound of the formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
  • the term 'pharmaceutically acceptable embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.
  • composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
  • compositions for oral administration are unit dosage forms such as tablets and capsules.
  • Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
  • the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
  • Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate or sucrose.
  • the composition will be formulated in unit dose form.
  • Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.
  • the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
  • an insulin sensitiser such as a compound of the formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg, generally about 0.5 to 10 mg. That is in the range of from 1.429 x 10 ⁇ 3 to 85.714 mg/kg/day, more usually about 1.429 x 10 "2 to 21.429 mg/kg/day, generally about 7.143 x 10 "3 to 0.1429 mg/kg/day.
  • the following Examples illustrate the invention but do not limit it in any way.
  • Obese Zucker rats are known to develop chronic nephropathy in addition to hyperlipidaemia, hyperinsulinaemia and peripheral insulin resistance (Kasiske et ⁇ / 1985).
  • 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzy-]thiazolidine-2,4- dione (herein after referred to as 'test compound') was administered to 2-3 month old obese Zucker fa/fa rats by dietary administration to provide a daily dose over a period of 3 months ranging from 2.0 - 7.0 ⁇ mole/kg body weight.
  • a group of age-matched obese Zucker fa/fa rats were given the same diet without the addition of the test compound, as was a group of lean Fa/? rats.
  • test compound Treatment with test compound resulted in a reduction in the incidence and degree of chronic nephropathy compared to the control group of Zucker fa/fa rats.
  • mild-moderate hydronephrosis was seen in 4/9 animals. Characteristically this involved dilation of the kidney pelvis. No hydronephrosis was seen in the rats treated with test compound.
  • the drug was given in the diet (50 ⁇ mole/kg of diet) from aged 6- 7weeks in Zucker fatty (fa/fa) rats, whilst in a second arm of the study, drug treatment as above was delayed until proteinuria had become established after 4 months, indicative of structural damage already present in the kidneys.
  • Urinary protein concentration was measured using the Bio-Rad protein assay as modified for use in a 96-well microtitre plate.
  • the assay is a dye-binding assay based on the differential colour change of a dye in response to various concentrations of protein (Bradford, Anal. Biochem., 72, 248, 1976). After a period of incubation with Dye Reagent, diluted urine samples are read at an optical density of 595 nm using a Molecular Devices multiplate reader.
  • NAG activity was assayed using a reagent kit on a Hitachi 717 analyser (both suppied by Boehringer Mannheim UK, Lewes). Enzyme activity was measured by monitoring the rate of chlorophenol (570 nm) released from the substrate chlorophenol red- ⁇ -D-glucosaminide.
  • results are given as mean values for the group ⁇ the standard error of the mean. Results have been analysed by one way ANOVA and significant differences from the Zucker fatty rat control group have been indicated by an asterisk.
  • Example 2 demonstrate that treatment of Zucker fatty (fa/fa) rats from the age of 6-7 weeks, for a period of 9 months, with BRL 49653 given via the diet, prevented the development of hypertension and markedly reduced both the elevation of urinary NAG activity and the rate of development of proteinuria.
  • BRL 49653 given via the diet

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  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
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  • Heart & Thoracic Surgery (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention se rapporte à un procédé de traitement et/ou à la prophylaxie des insuffisances rénales, y compris la néphropathie diabétique, la glomérulonéphrite, la glomérulosclérose, le syndrome néphrotique, la néphrosclérose hypertensive et l'insuffisance rénale au stade ultime ainsi que la microalbuminurie. Ce procédé consiste à administrer une dose efficace, non-toxique, d'un sensibilisateur à l'insuline à un être humain ou à un mammifère nécessitant ce traitement.
PCT/EP1995/000441 1994-02-10 1995-02-07 Utilisation de sensibilisateurs a l'insuline dans le traitement de l'insuffisance renale Ceased WO1995021608A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP7520956A JPH09512249A (ja) 1994-02-10 1995-02-07 腎臓疾患を治療するためのインスリンセンシタイザーの使用
HU9602207A HU224436B1 (hu) 1994-02-10 1995-02-07 Az 5-[4-{2-[N-metil-N-(2-piridil)-amino]-etoxi}-benzil]-2,4-dioxotiazolidin alkalmazása vesebetegségek kezelésére szolgáló gyógyszerkészítmények előállítására
EP95907653A EP0777469A1 (fr) 1994-02-10 1995-02-07 Utilisation de sensibilisateurs a l'insuline dans le traitement de l'insuffisance renale
AU15783/95A AU700826B2 (en) 1994-02-10 1995-02-07 Use of insulin sensitisers for treating renal diseases
MX9603338A MX9603338A (es) 1994-02-10 1995-02-07 Uso de sensibilizadores a la insulina para tratar enfermedades renales.

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB9402624.2 1994-02-10
GB9402624A GB9402624D0 (en) 1994-02-10 1994-02-10 Novel method
GB9410214A GB9410214D0 (en) 1994-05-21 1994-05-21 Novel method
GB9410214.2 1994-05-21
GB9426019.7 1994-12-22
GBGB9426019.7A GB9426019D0 (en) 1994-12-22 1994-12-22 Novel method

Related Child Applications (4)

Application Number Title Priority Date Filing Date
US08693190 A-371-Of-International 1996-10-11
US09329211 A-371-Of-International 1999-06-10
US32921199A Continuation 1994-02-10 1999-06-10
US09/863,534 Continuation US20010044458A1 (en) 1994-02-10 2001-05-23 Use of insulin sensitisers for treating renal diseases

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WO1995021608A1 true WO1995021608A1 (fr) 1995-08-17

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PCT/EP1995/000441 Ceased WO1995021608A1 (fr) 1994-02-10 1995-02-07 Utilisation de sensibilisateurs a l'insuline dans le traitement de l'insuffisance renale

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EP (1) EP0777469A1 (fr)
JP (1) JPH09512249A (fr)
CN (2) CN1083715C (fr)
AP (1) AP553A (fr)
AU (1) AU700826B2 (fr)
CA (1) CA2182986A1 (fr)
IL (1) IL112590A (fr)
MX (1) MX9603338A (fr)
SG (1) SG47100A1 (fr)
TW (1) TW475896B (fr)
WO (1) WO1995021608A1 (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055122A1 (fr) * 1997-06-05 1998-12-10 Smithkline Beecham Plc Composition renfermant de la 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
US5885997A (en) * 1996-07-01 1999-03-23 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US5889032A (en) * 1996-05-06 1999-03-30 Dr. Reddy's Research Foundation Heterocyclic compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US5889025A (en) * 1996-05-06 1999-03-30 Reddy's Research Foundation Antidiabetic compounds having hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
WO1999031095A1 (fr) * 1997-12-16 1999-06-24 Smithkline Beecham Plc Produit pharmaceutique constitue par un hydrate, sel de l'acide maleique, de formule 5-[4-[2- (n-methyl-n- (2-pyridyl)amino) ethoxy]benzyl] thiazolidine-2, 4-dione
US5919782A (en) * 1996-05-06 1999-07-06 Dr. Reddy's Research Foundation Heterocyclic compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US5985884A (en) * 1996-07-01 1999-11-16 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6011031A (en) * 1997-05-30 2000-01-04 Dr. Reddy's Research Foundation Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension: process for their preparation and pharmaceutical compositions containing them
US6011036A (en) * 1997-04-15 2000-01-04 Dr. Reddy's Research Foundation Heterocyclic compounds having antidiabetic hypolipidemic antihypertensive properties process for their preparation and pharmaceutical compositions containing them
US6114526A (en) * 1996-07-01 2000-09-05 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
WO2001012628A1 (fr) * 1999-08-17 2001-02-22 Smithkline Beecham P.L.C. Compositions pharmaceutiques contenant des derives de thiazolidinedione et procede de preparation
WO2001090356A1 (fr) * 2000-05-25 2001-11-29 Yamanouchi Pharmaceutical Co., Ltd. Promoteur de pgc-1 humain
US6372750B2 (en) 1996-07-01 2002-04-16 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compounds containing them and their use in the treatment of diabetes and related diseases
US6815457B1 (en) 1999-04-23 2004-11-09 Smithkline Beecham P.L.C. Thiazolidinedione derivative and its use as antidiabetic
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
USRE39266E1 (en) * 1996-07-01 2006-09-05 Dr. Reddy's Laboratories, Limited Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US7230109B2 (en) 1997-12-16 2007-06-12 Smithkline Beecham P.L.C. 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2, 4-dione, maleic acid salt, hydrate as pharmaceutical
EP1853258A4 (fr) * 2005-03-03 2008-05-07 Smithkline Beecham Corp Medicaments
WO2008134828A2 (fr) 2007-05-04 2008-11-13 Katholieke Universiteit Leuven Protection contre la dégénérescence tissulaire
CZ300081B6 (cs) * 1997-12-16 2009-01-28 Smithkline Beecham Plc Hydrát soli 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dionu s kyselinou maleinovou, zpusob jeho prípravy, farmaceutický prostredek s jeho obsahem a jeho použití
CZ301281B6 (cs) * 2000-08-04 2009-12-30 Smithkline Beecham P. L. C. Sul 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dionu a kyseliny L(+)vinné, zpusob její prípravy a použití a farmaceutická kompozice s jejím obsahem

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US5889025A (en) * 1996-05-06 1999-03-30 Reddy's Research Foundation Antidiabetic compounds having hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US5919782A (en) * 1996-05-06 1999-07-06 Dr. Reddy's Research Foundation Heterocyclic compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US5889032A (en) * 1996-05-06 1999-03-30 Dr. Reddy's Research Foundation Heterocyclic compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
USRE39266E1 (en) * 1996-07-01 2006-09-05 Dr. Reddy's Laboratories, Limited Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6372750B2 (en) 1996-07-01 2002-04-16 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compounds containing them and their use in the treatment of diabetes and related diseases
US5885997A (en) * 1996-07-01 1999-03-23 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US5985884A (en) * 1996-07-01 1999-11-16 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6114526A (en) * 1996-07-01 2000-09-05 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6573268B1 (en) 1996-07-01 2003-06-03 Dr. Reddy's Laboratories Ltd. Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6310069B1 (en) 1996-07-01 2001-10-30 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6780992B2 (en) 1996-07-01 2004-08-24 Dr. Reddy's Laboratories Ltd. Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6011036A (en) * 1997-04-15 2000-01-04 Dr. Reddy's Research Foundation Heterocyclic compounds having antidiabetic hypolipidemic antihypertensive properties process for their preparation and pharmaceutical compositions containing them
US6030973A (en) * 1997-04-15 2000-02-29 Dr. Reddy's Research Foundation Heterocyclic compounds having antidiabetic hypolipidemia and antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US6313113B1 (en) 1997-04-15 2001-11-06 Reddy-Cheminor, Inc. Heterocyclic compounds having antidiabetic, hypolipidemic and antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US6011031A (en) * 1997-05-30 2000-01-04 Dr. Reddy's Research Foundation Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension: process for their preparation and pharmaceutical compositions containing them
US6159966A (en) * 1997-05-30 2000-12-12 Reddy-Cheminor Inc. Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension: process for their preparation and pharmaceutical compositions containing them
AP1214A (en) * 1997-06-05 2003-10-08 Smithkline Beecham Plc Composition comprising 5-[4-[2-(n-methyl-n-2-pyridyl)amino) ethoxy} benzyl} thiazolidine-2, 4-dione.
WO1998055122A1 (fr) * 1997-06-05 1998-12-10 Smithkline Beecham Plc Composition renfermant de la 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
EA002384B1 (ru) * 1997-06-05 2002-04-25 Смитклайн Бичам Плс Композиция, включающая 5-[4-[2-(n-метил-n-(2-пиридил)амино)этокси]бензил]тиазолидин-2,4-дион
CZ299965B6 (cs) * 1997-12-16 2009-01-07 Smithkline Beecham Plc Hydrát soli 5-[4-[2-/N-methyl(2-pyridyl)amino/ethoxy]-benzyl]thiazolidin-2,4-dionu s kyselinou maleinovou jako farmaceutický prostredek
US7230109B2 (en) 1997-12-16 2007-06-12 Smithkline Beecham P.L.C. 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2, 4-dione, maleic acid salt, hydrate as pharmaceutical
CZ300081B6 (cs) * 1997-12-16 2009-01-28 Smithkline Beecham Plc Hydrát soli 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dionu s kyselinou maleinovou, zpusob jeho prípravy, farmaceutický prostredek s jeho obsahem a jeho použití
AP1365A (en) * 1997-12-16 2005-01-26 Smithkline Beecham Plc 5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy] benzyl] thiazolidine-2, 4-dione, maleic acid salt, hydrate as pharmaceutical.
WO1999031095A1 (fr) * 1997-12-16 1999-06-24 Smithkline Beecham Plc Produit pharmaceutique constitue par un hydrate, sel de l'acide maleique, de formule 5-[4-[2- (n-methyl-n- (2-pyridyl)amino) ethoxy]benzyl] thiazolidine-2, 4-dione
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
US7425557B2 (en) 1998-06-19 2008-09-16 Novartis Vaccines And Diagnostics, Inc. Inhibitors of glycogen synthase kinase 3
US6815457B1 (en) 1999-04-23 2004-11-09 Smithkline Beecham P.L.C. Thiazolidinedione derivative and its use as antidiabetic
WO2001012628A1 (fr) * 1999-08-17 2001-02-22 Smithkline Beecham P.L.C. Compositions pharmaceutiques contenant des derives de thiazolidinedione et procede de preparation
WO2001090356A1 (fr) * 2000-05-25 2001-11-29 Yamanouchi Pharmaceutical Co., Ltd. Promoteur de pgc-1 humain
CZ301281B6 (cs) * 2000-08-04 2009-12-30 Smithkline Beecham P. L. C. Sul 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dionu a kyseliny L(+)vinné, zpusob její prípravy a použití a farmaceutická kompozice s jejím obsahem
EP1853258A4 (fr) * 2005-03-03 2008-05-07 Smithkline Beecham Corp Medicaments
US7767682B2 (en) 2005-03-03 2010-08-03 Glaxosmithkline Llc Medicaments
US20110224264A1 (en) * 2005-03-03 2011-09-15 Kathleen Keating Brown Medicaments
WO2008134828A2 (fr) 2007-05-04 2008-11-13 Katholieke Universiteit Leuven Protection contre la dégénérescence tissulaire

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AU1578395A (en) 1995-08-29
CN1318372A (zh) 2001-10-24
EP0777469A1 (fr) 1997-06-11
CA2182986A1 (fr) 1995-08-17
MX9603338A (es) 1997-03-29
IL112590A (en) 2002-08-14
TW475896B (en) 2002-02-11
CN1145027A (zh) 1997-03-12
AP9500717A0 (en) 1995-04-30
CN1083715C (zh) 2002-05-01
IL112590A0 (en) 1995-06-29
JPH09512249A (ja) 1997-12-09
AP553A (en) 1996-11-06
SG47100A1 (en) 1998-03-20
AU700826B2 (en) 1999-01-14

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