WO2003047627A1 - Composition pharmaceutique comprenant un inhibiteur de l'alpha-glucosidase ainsi qu'un derive de la thiazolidinedione, et son utilisation pour traiter le diabete - Google Patents

Composition pharmaceutique comprenant un inhibiteur de l'alpha-glucosidase ainsi qu'un derive de la thiazolidinedione, et son utilisation pour traiter le diabete Download PDF

Info

Publication number
WO2003047627A1
WO2003047627A1 PCT/EP2002/010633 EP0210633W WO03047627A1 WO 2003047627 A1 WO2003047627 A1 WO 2003047627A1 EP 0210633 W EP0210633 W EP 0210633W WO 03047627 A1 WO03047627 A1 WO 03047627A1
Authority
WO
WIPO (PCT)
Prior art keywords
dione
thiazolidine
ethyl
compound
fluorophenoxy
Prior art date
Application number
PCT/EP2002/010633
Other languages
English (en)
Inventor
Gérard Moinet
Gérard Botton
Didier Mesangeau
Original Assignee
Merck Patent Gmbh
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 Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to AU2002338753A priority Critical patent/AU2002338753A1/en
Publication of WO2003047627A1 publication Critical patent/WO2003047627A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, as active principles, a derivative of 5-phenoxyalkyl-2,4-thiazolidinedione type described in WO 97/47612 and an ⁇ -glucosidase inhibitor.
  • the invention also relates to the use of a derivative of 5-phenoxyalkyl-2,4- 10 thiazolidinedione type and an ⁇ -glucosidase inhibitor, for the preparation of a medicinal preparation for reducing hyperglycaemia, more particularly the hyperglycaemia of non-insulin-dependent diabetes.
  • thiazolidine-2,4-dione derivatives have been described as anti-hyper- 15 glycaemiants and hypolipaemiants and have thus been described as antidia- betic agents (Takeda, patent EP 193 256 and Sankyo patent EP 207581). These compounds are activators of the peroxisome proliferator-activated receptor- ⁇ (PPAR ⁇ ).
  • PPAR ⁇ peroxisome proliferator-activated receptor- ⁇
  • ⁇ -Glucosidase inhibitors are described as anti-hyperglycaemiants and are commonly used in the treatment of type II diabetes (NIDDM).
  • ⁇ -Glucosidase inhibitors that may especially be mentioned include acarbose, miglitol and voglibose.
  • Diabetes is a chronic disease that has a number of pathological manifestations. It is accompanied by disorders of lipid and sugar metabolism and circulatory disorders. In many cases, diabetes tends to progress to a variety of pathological complications. Thus, it is necessary to find the treatment that is suited to each individual suffering from diabetes.
  • one aim of the present invention is to propose a composition for significantly improving the use of glucose.
  • An aim of the invention is also to propose a composition that is suitable for treating diabetes by displaying considerable action on the metabolic syndrome of insulin resistance.
  • an aim of the invention is to propose a composition that is particularly suitable for diabetics at the various stages of the disease.
  • a pharmaceutical composition comprising, as active principles, at least one ⁇ -glucosidase inhibitor and at least one compound of the formula (I), in combination with one or more pharmaceutically acceptable excipients.
  • This composition is particularly suitable for treating diabetes, more particularly non-insulin-dependent diabetes. It is particularly suitable for reducing the hyperglycaemia of non-insulin-dependent diabetes.
  • A represents a saturated or unsaturated, linear or branched hydrocarbon-based group containing from 2 to 16 carbon atoms
  • D represents a homo-carbon-based or hetero-carbon-based, mono-, bi- or tricyclic aromatic structure possibly including one or more hetero atoms,
  • X represents a substituent of the aromatic structure, chosen from hydrogen, an alky! group containing from 1 to 6 carbon atoms, an alkoxy group containing from 1 to 6 carbon atoms, an alkoxyalkyl group, in which the alkoxy and alkyl groups are defined as above, an aryl group, defined as an aromatic cyclic structure comprising one or two rings optionally including one or two hetero atoms in the ring, such as, for example, a phenyl or an ⁇ - or ⁇ -naphthyl, an arylalkyl group, in which the alkyl group is defined as above and the aryl group is defined as above and optionally comprises one or more substituents, an arylalkylaryl group, in which the arylalkyl and aryl fractions are defined as above, a halogen, a trifluoromethyl, a cyano, a hydroxyl, a nitro, an amino, a carboxyl, an alkoxycarbony
  • homo-carbon-based structures that may be mentioned include the phenyl, ⁇ -naphthyl, ⁇ -naphthyl, anthracenyl and fluorenyl radicals.
  • heterocyclic aromatic radicals that may be mentioned are pyridyl and the quinolyl or carbazolyl ring.
  • D preferably represents a phenyl or naphthyl radical.
  • alkyl groups containing from 1 to 6 carbon atoms that may especially be mentioned are the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl radicals.
  • alkoxy groups containing from 1 to 6 carbon atoms that may especially be mentioned are the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy radicals.
  • halogen groups that may especially be mentioned are fluorine, chlorine, bromine and iodine.
  • the chain A is a linear or branched hydrocarbon-based chain containing from 2 to 16 carbon atoms, that is saturated or contains one or more ethylenic groups, optionally substituted by at least one hydroxyl radical or by a phenyl radical.
  • linear alkyl radicals that may especially be mentioned include the divalent ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl and hexadecyl radicals.
  • branched alkyl chains that may especially be mentioned are the divalent 2-ethylhexyl, 2-methylbutyl, 2- methylpentyl, 1 -methylhexyl and 3-methyiheptyl radicals.
  • monohydroxyalkyl chains that are preferred are radicals containing 2 or 3 carbon atoms, such as 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl.
  • radicals containing 3 to 6 carbon atoms and 2 to 5 hydroxyl radicals such as 2,3-dihydroxy- propyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl or a pentaerythritol residue.
  • hydrocarbon-based chains containing from 2 to 16 carbon atoms and one or more ethylenic groups mention may be made especially of the divalent allyl radical.
  • the divalent ethyl or propyl radical is preferred.
  • the present invention also relates to the tautomeric forms of the compounds of the general formula (I), to the enantiomers, diastereoisomers and epimers of these compounds, and also to the solvates thereof. It is conceivable for the ketone functions borne by the thiazolidine ring to enolize and give rise to mono-enols.
  • the thiazolidinedione derivatives may be salified and be in the form of basic salts.
  • Examples of basic salts of the compounds of the general formula (I) include pharmacologically acceptable salts, such as sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth, etc.).
  • pharmacologically acceptable salts such as sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth, etc.).
  • the amine salts that are not pharmacologically acceptable may serve as a means of identification, purification or resolution.
  • ⁇ -glucosidase inhibitors that are thus anti-hyperglycaemiants are more particularly chosen from acarbose, miglitol, voglibose and emiglitate.
  • the compositions of the invention contain therapeutically effective amounts of the various active principles. The ratios of the respective amounts of ⁇ - glucosidase inhibitor and of compound of the formula (I) thus vary in consequence.
  • the weight ratio of ⁇ -glucosidase inhibitor to the compound of the formula (I) ranges from 10 "3 to 40, preferably from 10 "3 to 10 and better still from 10 "3 to 5.
  • compositions of the invention are preferably administered parenterally, or better still orally, although the other routes of administration, for instance such as rectal administration, are not excluded.
  • compositions of the invention are in the form of gel capsules, effervescent tablets, coated or uncoated tablets, sachets, sugar-coated tablets, drinkable vials or solutions, microgranules or sustained-release forms.
  • compositions of the invention are in the form of injectable solutions and suspensions packaged in vials or bottles for slow venous infusion.
  • the forms for oral administration are prepared by mixing the active substance with various types of excipients or of vehicles, such as fillers, disinte- gration (or crumbling) agents, binders, colorants, flavour enhancers and the like, followed by shaping the mixture.
  • the colorant can be any colorant permitted for pharmaceutical use.
  • flavour enhancers include cocoa powder, mint, borneol and cinnamon powder.
  • binders that may be mentioned are polyvinylpyrrolidone, hydroxypropylmethylcellulose, alginic acid, carbomer, carboxymethylcellu- lose, dextrin, ethylcellulose, starch, sodium alginate, polymethacrylate, maltodextrin, liquid glucose, magnesium aluminium silicate, hydroxyethyl- cellulose, hydroxypropylcellulose, ethylcellulose, methylcellulose and guar gum.
  • alginic acid sodium carboxymethylcellulose, colloidal silicon dioxide, sodium croscarmellose, crospovidone, guar gum, magnesium aluminium silicate, methylcellulose, microcrystalline cellulose, cellulose powder, pregelatinized starch, sodium alginate or sodium starch glycolate as disintegration agent.
  • the fillers are, for example, cellulose, lactose, calcium hydrogen phosphate or microcrystalline cellulose.
  • the tablets can be obtained in a conventional manner by compressing granules in the presence of one or more lubricants.
  • Suitable lubricants are calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogen- ated castor oil, hydrogenated plant oil, light mineral oil, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, stearyl sodium fumarate, stearic acid, talc and zinc stearate.
  • These tablets can then be coated using polymers in solution or suspension, such as hydroxypropylmethylcellulose or ethylcellulose.
  • the granules used to do this are prepared, for example, by the wet granulation process starting with a mixture of the active principles with one or more excipients such as a binder, a crumbling agent (or disintegration agent) and a filler.
  • excipients such as a binder, a crumbling agent (or disintegration agent) and a filler.
  • the mixture of active principles with a suitable filler for example lactose
  • a suitable filler for example lactose
  • a lubricant such as magnesium stearate, stearic acid, talc or zinc stearate.
  • Gel capsules or soft capsules are prepared by dissolving the active principles in a suitable solvent (for example polyethylene glycol), followed by introduction into soft capsules.
  • a suitable solvent for example polyethylene glycol
  • parenteral administration is obtained in a conventional manner by mixing the active principles with buffers, stabilizers, preserving agents, solubilizing agents, tonicity agents and suspension agents. In accordance with the known techniques, these mixtures are subsequently sterilized and then packaged in the form of intravenous injections.
  • buffer a person skilled in the art can use buffers based on organo- phosphate salts.
  • suspension agents examples include methylcellulose, hydroxyethyl- cellulose, hydroxypropylcellulose, acacia and sodium carboxymethyl- cellulose.
  • solubilizing agents examples include castor oil solidified with polyoxy- ethylene, polysorbate 80, nicotinamide and macrogol.
  • stabilizers that are useful according to the invention are sodium sulfite and sodium metasulfite, while mention may be made of sodium p- hydroxybenzoate, sorbic acid, cresol and chlorocresol as preserving agents.
  • the active principles are dissolved or suspended in a suitable vehicle with a dispersant, a wetting agent, a suspension agent (for example polyvinylpyrrolidone), a preserving agent (such as methylparaben or propylparaben), a flavour enhancer or a colorant.
  • the active principles are mixed in a manner that is known per se with a suitable base constituent, such as polyethylene glycol or semisynthetic glycerides.
  • the active principles are combined with suitable diluents, suitable stabilizers, agents that promote the sustained release of the active substances or any other type of additive for the formation of a central core that is then coated with a suitable polymer (for example a water-soluble resin or a water-insoluble resin).
  • suitable polymer for example a water-soluble resin or a water-insoluble resin.
  • microcapsules thus obtained are then optionally formulated in suitable dosage units.
  • a subject of the present invention is also the use of an ⁇ -glucosidase inhibitor in combination with a compound of the formula (I) as defined above, for the preparation of a medicinal combination for treating diabetes, more particularly non-insulin-dependent diabetes.
  • the invention relates to the use of glitazone in combination with the said compound of the formula (I) for the preparation of a medicinal combination for reducing the hyperglycaemia of non-insulin-dependent diabetes.
  • the present invention also relates to a process for treating diabetes, more particularly non-insulin-dependent diabetes, in a mammal, comprising the administration to the said mammal of the composition according to the present invention.
  • the unit dose preferably comprises from 0.1 mg to 400 mg of ⁇ -glucosidase inhibitor (the dose depends especially on the active agents under consideration).
  • the unit dose preferably comprises from 10 mg to 400 mg of ⁇ -glucosidase inhibitor. If the ⁇ -glucosidase inhibitor is voglibose, the unit dose preferably comprises from 0.1 mg to 1 mg of voglibose.
  • the unit dose in this case advantageously comprises from 12.5 to 200 mg of a compound of the formula (I) (the dose depending especially on the active agents under consideration).
  • the dosage depends on the active agent under consideration, the mode of administration, the therapeutic indication and the age and condition of the patient.
  • the daily dosage ranges particularly between 0.1 mg and 1 g of ⁇ - glucosidase inhibitor and between 25 and 200 mg of compound of the formula (I).
  • a tablet having the composition below is prepared:
  • a tablet having the composition below is prepared:
  • a tablet having the composition below is prepared:
  • a tablet having the composition below is prepared:
  • a tablet having the composition below is prepared:
  • a tablet having the composition below is prepared:
  • the characteristics of this model are: hyperglycaemia - moderately diminished basal insulinaemia glucose intolerance insulin resistance
  • an n5STZ control group a "normal" rat control group a group treated orally with acarbose at 100 mg/kg a group treated orally with acarbose at 400 mg/kg a group treated orally with Compound A at 12.5 mg/kg a group treated with acarbose 100 mg/kg and Compound A 12.5 mg/kg a group treated with acarbose 400 mg/kg and Compound A 12.5 mg/kg
  • the products were administered orally in the morning between 8 am and 9 am, for four days.
  • a meal test was performed. This test consists of an oral administration of Eoprotine (milk powder, Milupa) at a rate of 10 kcal/kg of rat. The meal test is performed two hours after the final administration of product. The glycaemia and the insulinaemia are determined before the administration of Eoprotine, and then 10, 20, 30, 45, 60, 90 and 120 minutes after gavage. Blood samples are taken from the tail of the conscious rats.
  • Eoprotine milk powder, Milupa
  • the meal test is performed two hours after the final administration of product.
  • the glycaemia and the insulinaemia are determined before the administration of Eoprotine, and then 10, 20, 30, 45, 60, 90 and 120 minutes after gavage. Blood samples are taken from the tail of the conscious rats.
  • acarbose does not modify the glucose disappearance kinetics.
  • acarbose significantly reduces the hyperglycaemia following the meal test, at times 10 and 20 minutes (Figure 4).
  • AUC area under the curve for the glycaemia
  • acarbose at 400 mg/kg and of Compound A at 12.5 mg/kg induces a marked reduction in the hyperglycaemia peak induced by the meal test.
  • the Compound A/acarbose combination significantly improves carbohydrate tolerance during the early phase of absorption. This effect is accompanied by a marked reduction in insulin secretion ( Figures 8 and 9).
  • Acarbose is a compound that inhibits the enzymatic activity of ⁇ -glucosidase and reduces the increase in the postprandial glucose.
  • acarbose only very mildly reduces the postprandial hyperglycaemia.
  • the combination of acarbose with a novel antidiabetic, 4-[2-(2,4-dioxoxothiazolidin-5-yl)ethoxy]benzonitrile (Com- pound A)
  • Com- pound A unexpectedly induces a synergistic effect with regard to the reduction in the hyperglycaemia peak induced during a meal test. This beneficial effect is combined with a marked reduction in insulin secretion.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant, comme principes actifs, un dérivé de type 5-phénoxyalkyl-2,4-thiazolidinedione ainsi qu'un inhibiteur de l'α-glucosidase, en association avec un ou plusieurs excipients pharmaceutiquement acceptables. Ces compositions conviennent en particulier pour traiter le diabète.
PCT/EP2002/010633 2001-12-03 2002-09-21 Composition pharmaceutique comprenant un inhibiteur de l'alpha-glucosidase ainsi qu'un derive de la thiazolidinedione, et son utilisation pour traiter le diabete WO2003047627A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002338753A AU2002338753A1 (en) 2001-12-03 2002-09-21 Pharmaceutical composition comprising an alpha-glucosidase inhibitor and a thiazolidinedione derivative, and a use thereof for treating diabetes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0115602A FR2832930A1 (fr) 2001-12-03 2001-12-03 Composition pharmaceutique comprenant un inhibiteur d'alpha-glucosidase et un derive de thiazolidinedione et son utilisation pour la preparation de medicaments destines a traiter le diabete
FR01/15602 2001-12-03

Publications (1)

Publication Number Publication Date
WO2003047627A1 true WO2003047627A1 (fr) 2003-06-12

Family

ID=8870050

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/010633 WO2003047627A1 (fr) 2001-12-03 2002-09-21 Composition pharmaceutique comprenant un inhibiteur de l'alpha-glucosidase ainsi qu'un derive de la thiazolidinedione, et son utilisation pour traiter le diabete

Country Status (4)

Country Link
AU (1) AU2002338753A1 (fr)
FR (1) FR2832930A1 (fr)
TW (1) TW200300682A (fr)
WO (1) WO2003047627A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998057635A1 (fr) * 1997-06-18 1998-12-23 Smithkline Beecham Plc Traitement du diabete a l'aide de thiazolidinedione et d'un inhibiteur des alpha-glucosidases
WO1999003478A1 (fr) * 1997-07-18 1999-01-28 Smithkline Beecham P.L.C. Traitement du diabete avec du thiazolidinedione, un secretagogue d'insuline et un inhibiteur d'alpha glucosidase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998057635A1 (fr) * 1997-06-18 1998-12-23 Smithkline Beecham Plc Traitement du diabete a l'aide de thiazolidinedione et d'un inhibiteur des alpha-glucosidases
WO1999003478A1 (fr) * 1997-07-18 1999-01-28 Smithkline Beecham P.L.C. Traitement du diabete avec du thiazolidinedione, un secretagogue d'insuline et un inhibiteur d'alpha glucosidase

Also Published As

Publication number Publication date
FR2832930A1 (fr) 2003-06-06
AU2002338753A1 (en) 2003-06-17
TW200300682A (en) 2003-06-16

Similar Documents

Publication Publication Date Title
EP1448181B1 (fr) Composition pharmaceutique contenant une combinaison de metformine et d'un acide 4-oxobutanoique et son utilisation pour traiter le diabete
US20040014797A1 (en) Pharmaceutical composition comprising metformin and a 5-phenoxyalkyl-2,4-thiazolidinedione-type derivative
WO2003047627A1 (fr) Composition pharmaceutique comprenant un inhibiteur de l'alpha-glucosidase ainsi qu'un derive de la thiazolidinedione, et son utilisation pour traiter le diabete
WO2003041706A1 (fr) Composition pharmaceutique comprenant une glitazone et un derive de thiazolidinedione, et utilisation de celle-ci dans le traitement du diabete
US20040097567A1 (en) Pharmaceutical composition
WO2003047574A1 (fr) Composition pharmaceutique renfermant un derive de type 5-phenoxyalkyl-2,4-thiazolidinedione et un acide 4-oxobutanoique
AU2002247755A1 (en) Pharmaceutical composition for the treatment of diabetes comprising a 5-phenoxyalkal-2,4-thiazolidinedione derivative and a compound that stimulates insulin secretion
US20050070553A1 (en) Pharmaceutical composition comprising an alpha-glucosidase inhibitor and a 4-oxobutanoic acid, and the use thereof for treating diabetes
US20050085489A1 (en) Pharmaceutical composition comprising a glitazone and a 4-oxobutanoic acid, and the use thereof for treating diabetes
WO2010047369A1 (fr) Agent destiné au traitement de la néphropathie diabétique
JPH07277966A (ja) 心肥大の予防および治療剤
WO2004028537A1 (fr) Utilisation de derives de thiazolidinedione en tant qu'inhibiteurs d'aldose reductase
FR2838968A1 (fr) Association d'insuline et d'un derive de thiazolidinedione et son utilisation pour traiter le diabete

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP