WO2005100331A2 - Agents antidiabetiques - Google Patents

Agents antidiabetiques Download PDF

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Publication number
WO2005100331A2
WO2005100331A2 PCT/IB2005/000998 IB2005000998W WO2005100331A2 WO 2005100331 A2 WO2005100331 A2 WO 2005100331A2 IB 2005000998 W IB2005000998 W IB 2005000998W WO 2005100331 A2 WO2005100331 A2 WO 2005100331A2
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WO
WIPO (PCT)
Prior art keywords
compound
dione
prop
ynyl
thiazolidine
Prior art date
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PCT/IB2005/000998
Other languages
English (en)
Other versions
WO2005100331A3 (fr
Inventor
Mohammad Salman
Jitendra Sattigeri
Dharam Vir
Vija Dattatraya Gangan
Original Assignee
Ranbaxy Laboratories Limited
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Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2005100331A2 publication Critical patent/WO2005100331A2/fr
Publication of WO2005100331A3 publication Critical patent/WO2005100331A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to alkynyl derivatives, which have PPAR agonist activity and hence can be used as antidiabetic compounds.
  • Compounds disclosed herein can be used for the treatment of diabetes and diabetes-associated complications, for the treatment of diseases and conditions in which insulin resistance is the central pathophysiological mechanism, for the treatment of diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndorme, hypertensive nephrosclerosis, polycystic ovarian syndrome, eating disorders, psoriasis, obesity, for improving cognitive functions in dementia and as aldose reductase inhibitors.
  • Processes for the preparation of such compounds, pharmaceutical compositions containing such compounds, and the methods for treating diabetes mellitus and the diseases and conditions mediated through insulin resistance are provided. Background of the Invention
  • Type 2 insulin-resistant diabetes mellitus [also known as non-insulin dependent diabetes mellitus] afflicts an estimated 6% of the adult population in western society and is expected to continue to grow at a rate of 6% per annum worldwide.
  • Type 2 diabetes is a complex metabolic disorder and is characterized by hyperglycemia. This results from contribution of impaired insulin secretion from pancreas and insulin resistance mainly in muscle and liver. Insulin resistant individuals in addition to being hyperglycemic, exhibit a constellation of closely related clinical indications, which include obesity, hypertension, dyslipidemia, and premature atherosclerosis. In fact, 80% of diabetic mortality arises from atherosclerotic cardiovascular disease (ASCVD). Uncontrolled hyperglycemia can further lead to late stage complications such as nephropathy, neuropathy and retinopathy.
  • ASCVD atherosclerotic cardiovascular disease
  • Non-pharmacological approaches to lower high blood sugar include a strict control of diet followed by vigorous exercise.
  • pharmacological agents are also available as hypoglycemic agents including insulin secretagogues - sulphonyl ureas (glimeperide) and non sulphonyl ureas (repaglinide)- which increase insulin secretion from pancreatic cells; biguanides - metformin - which lower hepatic glucose production; and ⁇ - glucosidase inhibitors - acarbose - which delays intestinal absorption of carbohydrate.
  • PPAR Peroxisome-Proliferator- Activated Receptor
  • PPAR ⁇ is abundantly expressed in adipose tissues.
  • Direct activation of PPAR y leads to induction of adipocyte genes such as for fatty acid transporter 1 which in turn contributes to lowering of triglycerides and free fatty acid levels.
  • FFA is a potential mediator of insulin resistance
  • lowering of FFA levels contributes to efficacy of PPAR ⁇ activation in increasing insulin sensitivity and consequently glucose uptake in skeletal muscle cell.
  • Glitazones - rosiglitazone and pioglitazone - belongs to this class of drug and are now proven insulin sensitisers [Moller, D.E.; Nature, 2001, 414(6865), 821-827]
  • WO 03/018553 discloses compounds, pharmaceutical compositions containing such compound, processes for preparing such compounds, and their use as reported antidiabetic agents.
  • WO 01/14351 and WO 01/14352 disclose substituted benzylthiazolidine-2,4-dione derivatives allegedly capable of serving as ligands of the human peroxisome proliferator- activated receptor (PPAR), enhancing the transcriptional activity of the receptor and showing effects of lowering blood sugar level and lowering lipid level.
  • PPAR peroxisome proliferator- activated receptor
  • WO 01/14349 discloses benzylthiazolidine-2,4-dione derivatives which are described as binding as ligands to human peroxisome proliferator-activated receptor (PPAR), thereby activating the receptor and exerting antihyperglycemic and antihyperlipidemic effects.
  • European Patent 684242 discloses isoxazolidinedione derivatives, which are described as having b-ypoglycemic action and hyperlipidemic action, and being useful as therapeutic agents for diabetes and the complication thereof.
  • 6,008,237 discloses substituted 5-aryl-2,4- thiazolidinedione which are described as being potent agonists of PPAR, and therefore useful in the treatment, control or prevention of diabetes, hyperglycemia, hyperlipidemia, atherosclerosis, obesity, vascular restenosis, and other PPAR ⁇ , ⁇ and/or ⁇ mediated diseases, disorders and conditions.
  • U.S. Patent No. 5,260,445 discloses certain substituted thiazolidinedione derivatives and their use in medicine.
  • U.S. Patent No. 5,965,589 discloses novel thiazolidinedione derivatives described as having hypoglycemic activity, blood lowering activity, and antidiabetic action.
  • 5,910,592 discloses substituted thaizolidinedione derivatives and their use in medicine.
  • U.S Patent No. 5,885,997 discloses 5 novel azolidinedione derivatives, which are described as being useful for the treatment of diabetes and related diseases.
  • the present invention relates to alkynyl derivatives, which have PPA-R agonist activity and hence can be used as antidiabetic compounds, and processes for the syntheses of these
  • compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers or diluents, can be used for the treatment of diabetes mellitus and the disease or condition mediated through insulin resistance.
  • A can represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl, acylo-xy, aryl or heterocycle.
  • W can represent sulphur, oxygen, or NR 3 , wherein R 3 can represent hydrogen or alkyl.
  • X can represent wherein n is an integer 0 to 3, and Ri can represent hydrogen or alkyl, with the pro ⁇ so that when X is — (CH 2 )rf
  • U-V can not be R 2 CH-CH, unless A is acyloxy, such as acetyloxy, for example.
  • B can represent aryl or heterocycle.
  • Y can represent (CH 2 ) n wherein n represents an integer 0 to 3.
  • R can represent hydrogen, alkyl, cycloalkyl, aryl or heterocycle.
  • alkyl refers to straight or branched saturated hydrocarbon having one to six carbon atom(s).
  • One or more hydrogen atom(s) of alkyl can optionally be replaced by halogen, hydroxy, cyano, or -NR 5 Re, wherein R 5 and Re are selected from hydrogen and alkyl.
  • alkyl include, but are not limited to, methyl, ethyl, p-ropyl, isopropyl and butyl, and the like.
  • alkenyl or “alkynyl” stands for unsaturated hydrocarbon having two to six carbon atoms.
  • One or more hydrogen of sa-dd alkenyl or alkynyl can be replaced by halogen.
  • alkenyl and alkynyl include, but are not limited to, ethylene, propylene, ethynyl and propynyl, and the like.
  • cycloalkyl refers to saturated carbocyclic ring having three to seven carbon atoms.
  • examples of cycloakyl include, but are not limited to, cyclopropyl, cyclobutyl and cyclopentyl, and the like.
  • cycloalkenyl refers to unsaturatecd carbocyclic ring having three to seven carbon atoms.
  • Examples of cycloakenyl include, but are not limited to, cyclopropenyl and cyclobutenyl, and the like.
  • cycloalkenyl may optionally be substituted with halogen, hydroxy, cyano, nitro or -LNER 5 R 6 , wherein R 5 and R 6 are selected from hydrogen and alkyl.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • acyl and acyloxy refers to COR 7 and OCOR 7 wherein R 7 represents alkyl or aryl.
  • alkoxy refers to O-R 7 wherein R 7 represents alkyl or aryl.
  • thioalkyl refers to -S-R 7 wherein R 7 refers to alkyl or aryl.
  • cycloalkoxy refers to 0-R 8 wherein R 8 represents cycloalkyl or cycloalkenyl.
  • haloakyl refers to alkyl of which one or more hydrogen (s) is/are replaced by halogen.
  • aryl stands for an aromatic radical having 6 to 14 carbon, atoms. Examples of aryl include, but are not limited to, phenyl, napthyl, anthryl and biphexiyl, and the like.
  • heterocycle refers to non-aromatic, aromatic or aromatic fused with aromatic or non-aromatic ring system having one or more heteroatom (s) in either the aromatic or the non-aromatic part wherein the said hetero atom (s) is/ are selected from the group comprising of nitrogen, sulphur and oxygen and the ring system includes mono, bi or tricyclic.
  • One or more carbon atom (s) of non-aromatic fused with aromatic ring is/are replaced by carbonyl or sulfonyl group.
  • heterocycles include, but not limited to, benzoxazinyl, benzthiazinyl, benzimidazolyl, carbazolyl, Indolyl, phenoxazinyl and phenothiazinyl, isoxazolyl and pyridinyl, and the like.
  • the aryl and heterocycle may optionally be substituted with one or more substituent(s) independently selected from the group comprising of halogen, hydroxy, nitro, mercapto, cyano, alkyl, aryl, haloalkyl, alkox-y, haloalkoxy, thioalkyl, cycloalkoxy, -NR 5 R 6 , -CONRsRe, -COOR 6 , -OCOR 6 , -COR 6 , -
  • polymorphs includes all crystalline forms for compounds described herein.
  • some of the compounds described herein may form solvates with water (for example, hydrate, hemihydrate or sesquihydrate) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
  • pharmaceutically acceptable salts denotes salts of the free base, whicra possess the desired pharmacological activity of the free base.
  • Suitable pharmaceutically acceptable salts may be prepared from an inorganic or organic acid.
  • inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric acid and the like.
  • organic acids include, but are not limited to, aliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, stearic, algenic, beta-hydroxybutyric, cyclohexylaminosulfonic, galactaric, galacturonic acid and the like.
  • organic acids include, but are not limited to, aliphatic, aromatic, heterocyclic, carboxylic and sulfonic
  • reaction of a compound of Formula II with a compound of Formula III can be carried out in the presence of an organic base such as, for example, triethylamine, diethylamine, tributylamine, 4-dimethylaminopyridme or pyridine.
  • organic base such as, for example, triethylamine, diethylamine, tributylamine, 4-dimethylaminopyridme or pyridine.
  • a coupling agent such as, for example, l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, ⁇ -methyl morpholine or hydroxy benzotriazole.
  • the condensation of a compound of Formula IN with thiazolidinedione of Formula N to give a compound of Formula VI can be carried out in a solvent such as, for example, methanol, ethanol, tetrahydrofuran, acetonitrile, dimethylformamide or toluene.
  • the condensation of a compound of Formula IN with thiazolidinedione of Formula N can be carried out in the presence of organic base such as, for example, pyridine, piperidine, triethylamine or diethylamine.
  • organic base such as, for example, pyridine, piperidine, triethylamine or diethylamine.
  • the condensation of a compound of Formula IV with thiazolidinedione of Formula N can be carried out in the presence of an organic acid such as, for example, acetic acid, dichloroacetic acid or benzoic acid.
  • the reduction of a compound of Formula NI to give a compound of Formula VII can be carried out in a solvent such as, for example, methanol, ethanol, tetrahydrofuran or acetonitrile.
  • the reduction of a compound of Formula VI can be carried out in the presence of a reducing agent such as, for example, sodium borohydrate, cyanoborohydride or sodium triaacetoxyborohydride.
  • compositions comprising, as an active ingredient, at least one of the disclosed compounds or a pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or diluent are disclosed.
  • Compounds disclosed herein may be administered to human or animal for treatment by any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral (rectal, subcutaneous, intravenous, intrauethral, intramascular, intranasal), preferred route is oral.
  • the pharmaceutical composition of the present invention comprises a pharmaceutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers is intended to included non-toxic, inert solid, semi-solid or liquid filler, diluents, encapsulating material or formulation of any type.
  • Solid form preparations for oral administration include capsules, tablet, pills, powder, granules, sachets and suppositories.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate; binders such as carboxymethyl cellulose, alginates, gelatins, polyvinylpyrolidinone, acacia; disintegrating agents such as agar-agar, calcium carbonate, alginic acid, certain silicates and sodium carbonate; absorption acceptors such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate; adsorbents such as kaolin; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate and mixture thereof.
  • the dosage form may also comprise buffering agents.
  • the solid preparation of tablets, capsules, pills, granules can be prepared with coating and shells such as enteric coating and other coatings well known in the pharmaceutical formulating art.
  • Liquid form preparations for oral administration can include pharmaceutically acceptable emulsions, solution, suspensions, syrup and elixir.
  • the active compound is mixed with water or other solvent, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (such as cottonseed, groundnut, corn, germ, olive, custard sesame oil), glycerol, and fatty acid esters of Sorbitan and mixture thereof.
  • solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (
  • the oral composition can also include adjuvants such as wetting agents, emulsiying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
  • adjuvants such as wetting agents, emulsiying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
  • injectible preparations such as sterile injections or aqueous solutions may be formulated according to the art using suitable dispersing or wetting and suspending agent.
  • suitable dispersing or wetting and suspending agent are water, Ringer's solutions, and isotonic sodium chloride.
  • the formulations disclosed herein may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known to the art.
  • Example 2 Preparation of compound of Formula IN In a 3-neck round-bottomed flask fitted with ⁇ 2 inlet, septum and a guard tube were placed triflate of Formula II (1 eq), Et 3 N (2 eq), Pdcl 2 (pph 3 ) 2 , (0.05 eq), PPh 3 (0.1 eq), Cul (0.1 eq) and dimethylformamide. The reaction mixture was heated to 70°C and at this temperature was added the compound of Formula III (1.2 eq) as a solution in dimethyl formamide slowly over a period of about 30 min, and heated till completion of reaction. Reaction mixture was poured in water and extracted with dichloromethane.
  • Compound No. 26 5-r4- ⁇ 3-(dibenzorb.flazepin-5-vDprop-l-vnyljbenzvnthiazolidine-2,4- dione; MS (+ve ion mode): m/z 437 (M ⁇ +l).
  • Compound No. 27 5-[4- ⁇ 3-(2,3-dihydro-l,4-benzoxazin-4-yl)prop-l-ynyl ⁇ benzyl] thiazolidine-2,4-dione; MS (+ve ion mode): m/z 379 (MT ⁇ +l).
  • Example 5 Coactivator-dependent receptor ligand assays (CARLA) for PPAR ⁇ / ⁇ / ⁇ in a homogeneous time resolved-fluorescence resonance energy transfer (TR-FRET) format
  • CARLA coactivator-dependent receptor ligand assay
  • the functional and binding assays for the PPAR ⁇ , PPAR ⁇ and PPAR ⁇ are a variation of the coactivator-dependent receptor ligand assay (CARLA) (Krey et al., (1997) Mol. Endocrinol., 11:779-791).
  • the present CARLA assays used a TR-FRET detection method previously reviewed (Hemmila I. LANCE, (1999) J. Biomol. Screening, 4:303-307; Mathis G., (1999) J. Biomol. Screening, 4:309-313).
  • GST glutathione-S- transferase
  • the biotinylated SRC-1 peptide was prepared by standard solid-phase peptide synthetic methods.
  • the GST-PPAR LBDs were expressed in pGEX vectors (Amersham Pharmacia) in the E. c ⁇ li strain BL21(DE3) using standard expression conditions at 18 °C. In some cases, the GST-PPAR LBDs were co-expressed with groESL.
  • the GST fusion proteins were purified on glutathione sepharose affinity columns (Amersham Pharmacia) using the method described by the manufacturer.
  • the assay buffer contained 50 mM Tris pH 7.4, 50 mM KCl, 0.1%) BSA, and 1 mM DTT.
  • the assay was carried out in black half area 96-well plates in a final volume of 25 ⁇ l. After mixing all components, the reaction mixture sat for 3 hours at room temperature before reading the TR-FRET signal on a Wallac Victor 2 plate reader (measuring the ratio of signals at 665 nm and 620 nm). EC 50 values were estimated with the Excel add-in program XLFit (ID Business Solutions, Guildford, Surrey, UK) utilizing a 4-parameter logistic equation.
  • EC50 values for PPAR , PPAR ⁇ , and PPAR ⁇ were determined with respect to compounds numbered 14, 18-23 and 26-29.
  • the ED50 values ranged from about 30 ⁇ M to about 5 ⁇ M, for example from about 10 ⁇ M to about 5 ⁇ M.
  • the ED50 values ranged from about 6 ⁇ M to about 0.06 ⁇ M, for example from about 1.0 M to about 0.06 ⁇ M, or from about 0.2 ⁇ M to about 0.06 ⁇ M.
  • the ED50 values ranged from about 30 ⁇ M to about 2.4 ⁇ M, for example from about 10 ⁇ M to about 2.4 ⁇ M.

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

Abstract

La présente invention concerne des dérivés d'alcynyle qui ont une activité d'agoniste de PPAR et peuvent de ce fait être utilisés comme composés antidiabétiques. Les composés de l'invention peuvent être utilisés pour traiter le diabète et des troubles associés au diabète, pour traiter des maladies et des états pathologiques dans lesquels la résistance à l'insuline est le mécanisme pathophysiologique central, pour traiter des maladies et des états pathologiques tels que le diabète de type II, la dyslipidémie, l'hypertension, les troubles cardiaques coronariens, les troubles cardio-vasculaires, l'athérosclérose, la néphropathie diabétique, la glomérulonéphrite, la glomérularsclérose, le syndrome néphrotique, la néphrosclérose hypertensive, le syndrome ovarien polycystique, les troubles de l'alimentation, le psoriasis, l'obésité, pour améliorer des fonctions cognitives dans le cadre de démences, et en tant qu'inhibiteurs d'aldose réductase. L'invention a également pour objet des procédés pour préparer ces composés, des compositions pharmaceutiques qui les contiennent, et des procédés pour traiter le diabète sucré et les troubles et états pathologiques liés à la résistance à l'insuline.
PCT/IB2005/000998 2004-04-14 2005-04-14 Agents antidiabetiques WO2005100331A2 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0283035A1 (fr) * 1987-03-18 1988-09-21 Tanabe Seiyaku Co., Ltd. Dérivés de benzoxazole et leur préparation
WO1996005186A1 (fr) * 1994-08-10 1996-02-22 Takeda Chemical Industries, Ltd. Derives de la thiazolidindione, leur procede d'obtention et leurs utilisations
EP0780389A1 (fr) * 1995-12-22 1997-06-25 Tobishi Pharmaceutical Co., Ltd. Dérivés de thiazolidinedione, procédé de préparation et compositions pharmaceutiques les contenant
WO2004007491A1 (fr) * 2002-07-10 2004-01-22 Applied Research Systems Ars Holding N.V. Derives de benzene a fusion azolidinone-vinyle
WO2005058813A2 (fr) * 2003-12-17 2005-06-30 Ranbaxy Laboratories Limited Agents antidiabetiques

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10195063A (ja) * 1996-10-21 1998-07-28 Dai Ichi Seiyaku Co Ltd エチニルチアゾール誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0283035A1 (fr) * 1987-03-18 1988-09-21 Tanabe Seiyaku Co., Ltd. Dérivés de benzoxazole et leur préparation
WO1996005186A1 (fr) * 1994-08-10 1996-02-22 Takeda Chemical Industries, Ltd. Derives de la thiazolidindione, leur procede d'obtention et leurs utilisations
EP0780389A1 (fr) * 1995-12-22 1997-06-25 Tobishi Pharmaceutical Co., Ltd. Dérivés de thiazolidinedione, procédé de préparation et compositions pharmaceutiques les contenant
WO2004007491A1 (fr) * 2002-07-10 2004-01-22 Applied Research Systems Ars Holding N.V. Derives de benzene a fusion azolidinone-vinyle
WO2005058813A2 (fr) * 2003-12-17 2005-06-30 Ranbaxy Laboratories Limited Agents antidiabetiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ARAKAWA K ET AL: "NOVEL BENZOXAZOLE 2,4-THIAZOLIDINEDIONES AS POTENT HYPOGLYCEMIC AGENTS.SYNTHESIS AND STRUCTURE-ACTIVITY AND RELATIOSHIPS" CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, TOKYO, JP, vol. 45, no. 12, 1997, pages 1984-1993, XP002967722 ISSN: 0009-2363 *
PATENT ABSTRACTS OF JAPAN vol. 1998, no. 12, 31 October 1998 (1998-10-31) -& JP 10 195063 A (DAI ICHI SEIYAKU CO LTD), 28 July 1998 (1998-07-28) *

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