WO1998052946A1 - Azolidinediones utilises dans le traitement du diabetes, de la dyslipidemie et de l'hypertension - Google Patents

Azolidinediones utilises dans le traitement du diabetes, de la dyslipidemie et de l'hypertension Download PDF

Info

Publication number
WO1998052946A1
WO1998052946A1 PCT/US1998/010612 US9810612W WO9852946A1 WO 1998052946 A1 WO1998052946 A1 WO 1998052946A1 US 9810612 W US9810612 W US 9810612W WO 9852946 A1 WO9852946 A1 WO 9852946A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
dione
thiazolidine
formula
ethoxy
Prior art date
Application number
PCT/US1998/010612
Other languages
English (en)
Inventor
Braj Bhushan Lohray
Vidya Bhushau Lohray
Ashok Channaveerappa Bajji
Shivaramayya Kalchar
Sekar Reddy Alla
Rajagopalan Ramanujam
Reeba K. Vikramadithyan
Original Assignee
Dr. Reddy's Research Foundation
Reddy-Cheminor Inc.
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 US08/982,910 external-priority patent/US6011031A/en
Application filed by Dr. Reddy's Research Foundation, Reddy-Cheminor Inc. filed Critical Dr. Reddy's Research Foundation
Priority to EP98923730A priority Critical patent/EP0977753A1/fr
Priority to AU75952/98A priority patent/AU7595298A/en
Priority to JP50737998A priority patent/JP2002515042A/ja
Publication of WO1998052946A1 publication Critical patent/WO1998052946A1/fr

Links

Classifications

    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to novel antidiabetic compounds, their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • This invention particularly relates to novel azohdinedione of the general formula (I), their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphs and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
  • the present invention also relates to a process for the preparation of the above said novel azohdinedione compounds, their analogues, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, and pharmaceutical compositions containing them.
  • This invention also relates to novel intermediates, processes for preparing the intermediates and processes for using the intermediates.
  • the azolidinediones of the general formula (I) defined above of the present invention are useful for the treatment and / or prophylaxis of hyperlipemia.
  • the azolidinediones of the formula (I) are useful for the treatment of insulin resistance associated with obesity and psoriasis.
  • the azolidinediones of the formula (I) can also be used to treat diabetic complications and can be used for treatment and / or prophylaxis of other diseases and conditions such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia.
  • PCOS polycystic ovarian syndrome
  • certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia.
  • Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations.
  • the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises and develops into diabetes.
  • diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin.
  • WO 95/07697 psoriasis (Patent Application No. WO 95/35108), dementia (Behavioral Brain Research (1996) 75 : 1 - 1 1) etc. may also have insulin resistance as a central pathogenic feature.
  • thiazolidinediones improve the bone mineral density and thus may be useful for the treatment of osteoporosis (EP-783888).
  • a number of molecular defects have been associated with insulin resistance. These include reduced expression of insulin receptors on the plasma membrane of insulin responsive cells and alterations in the signal transduction pathways that become activated after insulin binds to its receptor including glucose transport and glycogen synthesis.
  • U may represent the following groups:
  • R 1 and R 2 are the same or different and each represents hydrogen or C,-C 5 alkyl
  • R 3 represents hydrogen, acyl group, a (C,-C 6 ) alkoxycarbonyl group or aralkyloxycarbonyl group
  • R 4 - R 5 are same or different and each represent hydrogen, C, -C 5 alkyl or C, -C 5 alkoxy or R ⁇ R 5 together represent C,-
  • n 1, 2, or 3
  • W represents CH 2 , CO, CHOR 6 group in which R 6 represents any one of the items or groups defined for R 3 and may be the same or different from R 3 .
  • the main objective of the present invention is therefore, to provide novel azolidinedione compounds, their analogues, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or mixtures thereof.
  • Another objective of the present invention is to provide novel azolidinedione compounds, their analogues, their derivatives, their tautomeric forms, their stereoisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or mixtures thereof having enhanced activities, no toxic effect or reduced toxic effect.
  • Yet another objective of the present invention is to produce a process for the preparation of novel azolidinediones of the formula (I) as defined above, their tautomeric forms, their analogues, their derivatives, their stereoisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.
  • Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their analogues, their derivatives, their tautomers, their stereoisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or mixtures thereof in combination with suitable carriers, solvents, excipients, diluents and other media normally employed in preparing such compositions.
  • Yet another objective of the present invention is to provide a novel intermediate of the formula (III)
  • G represents -CHO, -N0 2 , -NH 2 or -CH 2 -CH(J)-COOR, where J represents halogen atom such as chlorine, bromine or iodine and R represents H or lower alkyl group such as a (C,-C 6 )alkyl, preferably (C,-C 3 )alkyl, more preferably methyl, ethyl or propyl; and R'-R 6 , n, m and Ar are as defined in formula (I) and a process for the preparation thereof.
  • Azolidinediones of the present invention have the general formula (I)
  • R 1 , R 2 , R 3 , R ⁇ R 5 , and R 6 may be same or different and represent hydrogen, halogen, hydroxy cyano, nitro or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxy carbonyl, aralkyloxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylmercapto, aralkoxycarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, mercaptoalky
  • R 9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and the like wherein these groups are defined as for R'-R 6 ;
  • Ar represents an optionally substituted divalent single or fused aromatic or -heterocyclic group,
  • R 7 represents hydrogen atom, hydroxy, alkoxy, halogen or lower alkyl such as
  • (C r C 6 )alkyl such as methyl, ethyl, propyl and the like, optionally substituted aralkyl group or forms a bond together with the adjacent group R 8 ;
  • R 8 represents hydrogen, hydroxy, alkoxy, halogen or lower alkyl group such as (C,-C 6 )alkyl such as methyl, ethyl, propyl and the like, optionally substituted aralkyl or R 8 forms a bond together with R 7 ;
  • B represents an oxygen atom or a sulfur atom;
  • Y represents an oxygen atom or a sulfur atom, n is an integer ranging from 1 to 4 and m is an integer of zero or one.
  • Suitable groups represented by R 1 - R 6 include hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro; substituted or unsubstituted (C r C 12 )alkyl group, especially, linear or branched (C,-C 6 )alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; cycloalkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and
  • NCH 3 (C 2 H 5 ), NHC 2 H 5 and the like; alkoxyalkyl group such as methoxymethyl, ethoxymethyl, ethoxyethyl and the like; aryloxyalkyl group such as H 5 OCH 2 ,
  • (C,-C 6 )alkylthio acyl group such as acetyl, propionyl or benzoyl, the acyl group may be substituted; acylamino groups such as NHCOCH 3 , NHCOC 2 H 5 , NHCOC 3 H 7 ,
  • NHCOC 6 H 5 aralkoxycarbonylamino group such as NHCOOCH 2 C 6 H 5 ,
  • carboxylic acid derivatives may be substituted; acyloxy group such as OOCMe,
  • OOCEt, OOCPh and the like which may optionally be substituted; sulfonic acid or its derivatives such as SO 2 NH 2 , S0 2 NHMe, S0 2 NMe 2 , S0 2 NHCF 3 and the like; the sulfonic acid derivatives may be substituted.
  • R'-R 6 All the groups represented by R'-R 6 may be substituted and, the substituents may be selected from the same groups represented by R'-R 6 and are defined in the same way.
  • Suitable cyclic structure formed by R 1 , R 2 together with carbon atoms to which they are attached contain 5 to 6 ring atoms, preferably, optionally substituted phenyl, pyridyl, furanyl, thienyl, pyrrolyl, and the like; substituents may be selected from the same groups represented by R 1 - R ⁇ and are defined in the same way.
  • Preferred substituents are halogen, (C,-C 6 )alkoxy, cyclo(C 3 -C 6 ) alkyl, cyclo(C 3 -C 6 )alkoxy, aryl, aralkyl, aralkoxy, heterocyclyl, hydroxy, acyl, acyloxy, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, amino, alkylamino, acylamino, aralkoxycarbonylamino, aminocarbonyl and the like.
  • Suitable X includes oxygen, sulfur or a group NR 9 as defined above.
  • X is preferably oxygen or sulfur.
  • the group represented by Ar includes substituted or unsubstituted divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl, hydrobenzopyranyl, pyrazolyl and the like.
  • the substituents on the group represented by A-r include linear or branched optionally halogenated (C,-C 6 )alkyl, optionally halogenated (C,-C 3 )alkoxy, halogen, acyl, amino, acylamino, thio, carboxylic and sulfonic acids and their derivatives.
  • the substituents are defined as they are for
  • Ar represents a substituted or unsubstituted divalent phenylene, naphthylene, benzofuranyl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl group.
  • Ar represents a divalent phenylene or benzofuranyl, which may be optionally substituted by methyl, halomethyl, methoxy or halomethoxy groups.
  • Suitable R 7 includes hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, (C,-C 3 )alkoxy; halogen atom such as fluorine, chlorine, bromine, or iodine; aralkyl such as C 6 H 5 CH 2 ,C 6 H 5 CH 2 CH 2 ,C 6 H 5 CH 2 CH 2 CH 2 , naphthylmethyl and the like, substituted aralkyl such as CH 3 C 6 H 4 CH 2 , Hal-C 6 H 4 CH 2 , CH 3 OC 6 H 4 CH 2 ,
  • Suitable R 8 may be a hydrogen atom, hydroxy, (C,-C 3 )alkoxy; halogen selected from fluorine, bromine, iodine and chlorine, lower alkyl group such as (C,-C 12 )alkyl, aralkyl such as C 6 H 5 CH 2 , C 6 H 5 CH 2 CH 2 , C 6 H 5 CH 2 CH 2 CH 2 , naphthylmethyl and the like, substituted aralkyl such as CH 3 C 6 H 4 CH 2 , Hal-C 6 H 4 CH 2 , CH 3 OC 6 H 4 CH 2 ,
  • R 7 and R 8 represent hydrogen atoms or R 7 and R 8 together represent a bond.
  • Suitable B group includes a hetero atom selected from O or S, preferably sulfur atom.
  • Suitable ring structure comprising B and Y include 2,4-dioxooxazolidin-5-yl,
  • Preferred ring structures comprising B include 2,4-dioxooxazolidin-5-yl and 2,4-dioxothiazolidin-5- yl groups.
  • the ring structure comprising B is a 2,4- dioxothiazolidin-5-yl group.
  • Suitable Y group is a heteroatom selected from O or S.
  • Suitable n is an integer ranging from 1 to 4,
  • n 1
  • Pharmaceutically acceptable salts forming part of this invention include salts of the azolidinedione moiety such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts, salts of carboxy group wherever appropriate, such as aluminum, alkali metal salts, alkaline earth metal salts, ammonium or substituted ammonium salts.
  • alkali metal salts like Li, Na, and K salts
  • alkaline earth metal salts like Ca and Mg salts
  • salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like
  • ammonium or substituted ammonium salts salts of carboxy group wherever appropriate, such as aluminum, alkali metal salts, alkaline earth metal salts, ammonium
  • Salts may include acid addition salts which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols. Particularly useful compounds according to the invention include :
  • G represents -CHO, -N0 2 -NH 2 or -CH 2 CH(J)-COOR, where J represents halogen atom such as chlorine, bromine or iodine and R represents H or an alkyl group, preferably (C r C 6 )alkyl group, more preferably (C,-C 3 )alkyl such as methyl, ethyl or propyl; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 may be same or different and represent hydrogen, halogen, hydroxy, cyano, nitro or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino
  • R 1 - R 6 , Ar, X, n and m are as defined above and G represents a CHO or a N0 2 group or a group -CH 2 -CH(J)-COOR, where J represents a halogen atom such as chlorine, bromine or iodine and R represents H or lower alkyl group as defined earlier.
  • the novel intermediate of the general formula (III) defined above where G is CHO or N0 2 group and m 1, can be prepared by reacting the compound of the general formula (IV),
  • R 1 - R 6 , X, n are as defined earlier and L 1 is a halogen atom such as chlorine, bromine or iodine or a leaving group such as methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate and the like with a compound of the formula (V)
  • reaction of compound of formula (IV) with the compound of formula (V) to produce a compound of formula (III) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like. Mixtures of solvents may be used.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar or He.
  • the reaction may be effected in the presence of a base such as K 2 C0 3 , N- ⁇ CO ⁇ NaH, or mixtures thereof.
  • the reaction temperature may range from 20 °C to 150 °C, preferably at a temperature in the range of 30 °C to 100 °C.
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.
  • L 2 -Ar-G (VII) where G is a CHO or N0 2 group and Ar is as defined earlier and L 2 represents a halogen atom such as chlorine or fluorine.
  • the reaction of compound of formula (VI) with a compound of formula (VII) to produce a compound of the formula (III) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N 2 , Ar, or He.
  • the reaction may be effected in the presence of a base such as K 2 CO 3 , Na 2 C0 3 or NaH or mixtures thereof.
  • the reaction temperature may range from 20 °C to 120 °C, preferably at a temperature in the range of 30 °C to 100 °C.
  • the duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours.
  • the novel intermediate of formula (III) defined above can also be obtained by the reaction of a compound of general formula (VI) defined above with a compound of general formula (V) defined earlier.
  • reaction of compound of general formula (VI) with a compound of general formula (V) may be carried out using suitable coupling agents such as dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such as PPh 3 / DEAD and the like.
  • suitable coupling agents such as dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such as PPh 3 / DEAD and the like.
  • the reaction may be carried out in the presence of solvents such as THF, DME, CH 2 C1 2 , CHC1 3 , toluene, acetonitrile, carbontetrachloride and the like.
  • solvents such as THF, DME, CH 2 C1 2 , CHC1 3 , toluene, acetonitrile, carbontetrachloride and the like.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar,
  • the reaction temperature may be in the range of 0 °C to 100 °C, preferably at a temperature in the range of 20 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
  • R' - R 6 and X are as defined earlier.
  • the reaction of compound of general formula (VIII) with a compound of general formula (IX) may be carried out neat or in the presence of solvents such as DMF, DMSO, CH 3 CN, EtOH, acetone or mixtures thereof.
  • solvents such as DMF, DMSO, CH 3 CN, EtOH, acetone or mixtures thereof.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar, or He.
  • the reaction may be effected in the presence of base such as K 2 C0 3 , Na 2 C0 3 , KOH, NaOH, NaH and the like or mixtures thereof.
  • the amount of base may range from 1 to 20 equivalents, preferably 1 to 10 equivalents.
  • the reaction may be carried out at a temperature in the range 20 °C to 180 °C, preferably at a temperature in the range 50 °C to 150 °C.
  • Duration of the reaction may range from 1 to 48 hours, preferably from 1 to 12 hours.
  • the amounts of the compound of general formula (VIII) and (IX) may range from 1 to 20 equivalents, preferably from 1 to 5 equivalents.
  • the reaction may be carried out in the presence of phase transfer catalysts such as quaternary ammonium halides or hydroxides such as tetrabutyl ammonium bromide, tetrabutylammonium hydroxide, benzyl trimethylammonium bromide, aliquat and the like.
  • the present invention provides a process for the preparation of novel azolidinediones of general formula (I), their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates wherein R 7 and R 8 together represent a bond and B represents a sulfur or oxygen atom and all symbols are as defined earlier which comprises: reacting the compound of general formula (III), where G is a CHO group with 2,4- thiazolidinedione, 2,4- oxazolidinedione or oxazolidone-4-oxo-2-thione to yield a compound of general formula (X)
  • R 7 and R 8 together represent a bond and removing the water formed during the reaction by conventional methods.
  • the reaction of the compound of the general formula (III) where G is a CHO group with 2,4-thiazolidinedione or 2,4-oxazolidinedione to yield a compound of general formula (X) may be carried out neat in the presence of sodium acetate or in the presence of a solvent such as benzene, toluene, methoxyethanol or mixtures thereof.
  • the reaction temperature may range from 80 °C to 140 °C depending upon the solvents employed and in the range from 80 °C to 180 °C when the reaction is carried out neat in the presence of sodium acetate.
  • Suitable catalyst such as piperidinium acetate or benzoate, sodium acetate or mixtures of catalysts may also be employed.
  • Sodium acetate can be used in the presence of solvent, but it is preferred that sodium acetate is used neat.
  • the water produced in the reaction may be removed, for example, by using Dean Stark water separator or by using water absorbing agents like molecular seives.
  • oxazolidine-4-oxo-2-thione is used to produce a compound of formula (X), wherein B represents oxygen atom and Y represents sulfur atom
  • the thio group may be converted to oxo group by oxidation using agents such as hydrogen peroxide or peroxyacids like mCPBA.
  • the compound of general formula (XI) represents the compound of general formula (I), wherein R 7 and R 8 represent hydrogen atom and all other symbols are as defined earlier.
  • the reduction of compound of the formula (X) to yield a compound of the general formula (XI) may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney Nickel and the like. Mixtures of catalysts may be used.
  • the reaction may be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. Mixtures of solvents may be used.
  • a pressure between atmospheric pressure and 80 psi may be employed.
  • the catalyst may be 5 - 10 % Pd/C and the amount of catalyst used may range from 50 - 300 % w/w.
  • the reaction may also be carried out by employing metal solvent reduction such as magnesium in methanol or sodium amalgam in methanol.
  • the reaction may also be carried out with alkali metal borohydrides such as LiBH 4 , NaBH 4 , KBH 4 and the like in the presence of cobalt salt such as CoCl 2 and ligands, preferably bidentated ligands such as 2, 2'-bipyridyl, 1, 10-phenanthroline, bisoximes and the like.
  • the compounds of the general formula (X) and general formula (XI) obtained above may be converted into pharmaceutically acceptable salts, or pharmaceutically acceptable solvates by conventional methods.
  • the compound of the general formula (I) where m represents 1 and all other symbols are as defined earlier can also be prepared by reacting a compound of the general formula (IV) defined above with a compound of general formula (XII)
  • reaction of compound of general formula (IV) with a compound of general formula (XII) to produce a compound of general formula (I) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N 2 , Ar or He.
  • the reaction may be effected in the presence of a base such as alkalis like sodium hydroxide or potassium hydroxide; alkali metal carbonates like sodium carbonate or potassium carbonate; alkali metal hydrides such as sodium hydride; organometallic bases like n-butyl lithium; alkali metal amides like sodamide, or mixtures thereof. Multiple solvents and bases can be used.
  • the amount of base may range from 1 to 5 equivalents, preferably 1 to 3 equivalents.
  • the reaction temperature may be in the range of 0 °C to 120 °C, preferably at a temperature in the range of 20 °C to 100 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 0.5 to 6 hours.
  • the removal of protecting groups may be carried out by conventional methods which include treatment with acid such as, hydrochloric acid, trifluoroacetic acid or bases such as, KOH, NaOH, Na 2 C0 3 , NaHC0 3 , 2 C0 3 and the like or mixtures thereof. These reagents may be used as aqueous solution or as solutions in alcohols like methanol, ethanol etc. Deprotection can also be effected by gaseous hydrogen in the presence of catalyst such as Pd/carbon or conventional transfer hydrogenation methods when the protecting group is a benzyl or substituted benzyl group.
  • acid such as, hydrochloric acid, trifluoroacetic acid or bases
  • KOH, NaOH, Na 2 C0 3 , NaHC0 3 , 2 C0 3 and the like or mixtures thereof may be used as aqueous solution or as solutions in alcohols like methanol, ethanol etc.
  • Deprotection can also be effected by gaseous hydrogen in the presence of catalyst such as Pd/
  • the reaction of compound of general formula (VI) with a compound of general formula (XII) to produce a compound of general formula (I) may be carried out using suitable coupling agents such as dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such as PPh 3 /DEAD and the like.
  • the reaction may be carried out in the presence of solvents such as THF, DME, CH 2 C1 2 , CHC1 3 , toluene, acetonitrile, carbontetrachloride and the like.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar, He.
  • the reaction may be effected in the presence of DMAP-HOBT and they may be used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents.
  • the reaction temperature may be in the range of 0 °C to 100 °C, preferably at a temperature in the range of 20 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
  • the compound of general formula (I), where R' - R 6 , X, n, m and Ar are as defined earlier and R 7 and R 8 represent hydrogen, B represents a sulfur atom and Y represents oxygen atom can be prepared by the reaction of compound of general formula (XIII)
  • R 1 - R 6 , X, Ar, m and n are as defined earlier, J is a halogen atom like chlorine, bromine or iodine and R is a lower alkyl group, with thiourea followed by treatment with an acid.
  • the reaction of compound of general formula (XIII) with thiourea is normally carried out in the presence of alcoholic solvent such as methanol, ethanol, propanol, isobutanol, 2-methoxybutanol, etc or DMSO or sulfolane.
  • the reaction may be conducted at a temperature in the range between 20 C C and the reflux temperature of the solvent used.
  • Bases such as NaOAc, KOAc, NaOMe, NaOEt etc. can be used.
  • the compound of general formula (XIV) can in turn be prepared by the conventional reduction of the novel intermediate (III) where G is N0 2 group and other symbols are as defined earlier.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guanidine and their derivatives etc. may also be used.
  • acid addition salts are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzene sulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid,
  • the term neat means the reaction is carried out without the use of solvent.
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
  • Various polymo ⁇ hs of the compounds of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • Polymo ⁇ hs may also be obtained by heating or melting the compound followed by gradual or slow cooling.
  • the presence of polymo ⁇ hs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder
  • the present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I), as defined above, their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment and / or prophylaxis of hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, insulin resistance and also diseases in which insulin resistance is the underlying pathophysiological mechanism such as type II diabetes, impaired glucose tolerance, dyslipidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis; insulin resistance associated with obesity and psoriasis, for treating diabetic complications and other diseases such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, n
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 1 to 25 %, preferably 1 to 15 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents.
  • the ingredients 1 to 3 are uniformly blended with water and granulated after drying under reduced pressure.
  • the ingredients 4 and 5 are mixed well with the granules and compressed by a tabletting machine to prepare 1000 tablets each containing 30 mg of active ingredient.
  • ingredients 1 -4 are uniformly moistened with an aqueous solution of 5 and granulated after drying under reduced pressure.
  • Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of ingredient 1.
  • the compound of the formula (I) as defined above are clinically administered to mammals, including man, via either oral or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or abso ⁇ tion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally.
  • the dosage is in the range of about 0. 10 to about 200 mg / kg body weight of the subject per day or preferably about 0. 10 to about 50 mg / kg body weight per day administered singly or as a divided dose.
  • the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds.
  • the injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
  • Step B A mixture of 2-(2,3-dihydro-l,4-benzoxazin-4-yl)ethyl methanesulfonate (5 g, 19.4 mmol) obtained above, p-hydroxy benzaldehyde (5.56 g, 29.1 mmol) and potassium carbonate (10.75 g) in dry dimethyl formamide (50 ml) was heated to 70 °C for 7 h. The reaction mixture was cooled to room temperature. Water (100 ml) was added to the mixture and extracted with ethyl acetate (2 x 100 ml). The organic extracts were washed with water (50 ml), brine (50 ml) and dried (Na 2 S0 4 ). The solvent was removed under reduced pressure to afford the title compound (4.0 g, 72 %) as a syrupy liquid.
  • Step A 2-(phenothiazin-10-yl)ethyl methanesulfonate : To a solution of (phenothiazin-l ⁇ -yl)ethanol (20.0 g, 82.0 mmol) in dichloromethane (150 ml) was added triethyl amine(24.9 g, 24 mmol) at 0 °C. Methanesulfonyl chloride (18.8 g, 160 mmol) in dichloromethane (50 ml) was added dropwise to the above reaction mixture at 0 °C. The reaction mixture was stirred for 3 h at 25 °C.
  • the title compound (1.0 g, 65 %) was prepared as a thick liquid from 2- (trifluoromethyl)phenothiazine (1.0 g, 3.7 mmol) and 4-(2-bromoethoxy)benzaldehyde (1.6 g, 7.49 mmol) by a similar procedure to that described in preparation 3.
  • mice C57 BL KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85 : 962-967), whereas heterozygous are lean and normoglycemic.
  • db/db model mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled.
  • the state of pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention were tested for blood sugar and triglycerides lowering activities.
  • the compounds of the present inventions showed blood sugar and triglycerides lowering activities through improved insulin resistance. This was demonstrated by the following in vivo experiments.
  • mice Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 35 to 60 grams, procured from the Jackson Laboratory, USA, were used in the experiment. The mice were provided with standard feed (National Institute of
  • the random blood sugar and triglyceride levels were measured by collecting blood (100 ⁇ l) through orbital sinus, using heparinised capillary in tubes containing
  • EDTA which was centrifuged to obtain plasma.
  • the plasma glucose and triglyceride levels were measured spectrometrically, by glucose oxidase and glycerol-3-P0 4 oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits, India,
  • Test compounds were suspended on 0.25 % carboxymethyl cellulose and administered to test group at a dose of 10 mg to 200 mg / kg through oral gavage daily for 6 days.
  • the control group received vehicle (dose 10 ml / kg).
  • Troglitazone 100 mg / kg, daily dose was used as a standard drug which showed 28 % reduction in random blood sugar level on 6th day.
  • the blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula:
  • Blood glucose level and triglycerides are also lowered at doses greater than 30 mg/kg. Normally, the quantum of reduction is dose dependent.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Psychiatry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Immunology (AREA)
  • Emergency Medicine (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés antidiabétiques, leurs formes tautomères, leurs dérivés, leurs analogues, leurs stéréoisomères, leurs polymorphes, leurs sels pharmaceutiquement acceptables, leurs solvates pharmaceutiquement acceptables, et des compositions pharmaceutiquement acceptables les contenant. La présente invention concerne également la préparation des composés antidiabétiques et leurs utilisations.
PCT/US1998/010612 1997-12-02 1998-05-26 Azolidinediones utilises dans le traitement du diabetes, de la dyslipidemie et de l'hypertension WO1998052946A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP98923730A EP0977753A1 (fr) 1997-12-02 1998-05-26 Azolidinediones utilises dans le traitement du diabetes, de la dyslipidemie et de l'hypertension
AU75952/98A AU7595298A (en) 1997-12-02 1998-05-26 Azolidinediones useful for the treatment of diabetes, dyslipidemia and hy pertension
JP50737998A JP2002515042A (ja) 1997-12-02 1998-05-26 糖尿病、異常脂血症（ｄｙｓｌｉｐｉｄｅｍｉａ）および高血圧の治療に有用なアゾリジンジオン（ａｚｏｌｉｄｉｎｅｄｉｏｎｅ）およびそれらを含有する組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/982,910 US6011031A (en) 1997-05-30 1997-12-02 Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension: process for their preparation and pharmaceutical compositions containing them
US08/982,910 1997-12-02

Publications (1)

Publication Number Publication Date
WO1998052946A1 true WO1998052946A1 (fr) 1998-11-26

Family

ID=25529626

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/010612 WO1998052946A1 (fr) 1997-12-02 1998-05-26 Azolidinediones utilises dans le traitement du diabetes, de la dyslipidemie et de l'hypertension

Country Status (4)

Country Link
EP (1) EP0977753A1 (fr)
JP (1) JP2002515042A (fr)
AU (1) AU7595298A (fr)
WO (1) WO1998052946A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020499A1 (fr) * 2000-09-04 2002-03-14 Dr. Reddy's Research Foundation Procede de preparation de 2-[3,4-dihydro-1,4-benzothiazin-4-yl]ethylmethane sulphonate
WO2002040460A1 (fr) * 2000-11-17 2002-05-23 Dr. Reddy's Research Foundation Methode de preparation de 2-[phenothiazin-10-yle] methanesulphonate d'ethyle
WO2002074758A3 (fr) * 2001-03-16 2003-03-20 Abbott Lab Nouvelles amines en tant que ligands des recepteurs de l'histamine 3 et leurs applications therapeutiques
FR2830012A1 (fr) * 2001-09-21 2003-03-28 Servier Lab Nouveaux derives heterocycliques, leur procede de preparation et les compositions pharamaceutiques qui les contiennent
WO2003059342A1 (fr) * 2002-01-11 2003-07-24 Abbott Laboratories Ligands de recepteur d'histamine-3 pour traiter des etats diabetiques
US6969730B2 (en) 2001-03-16 2005-11-29 Abbott Laboratories Amines as histamine-3 receptor ligands and their therapeutic applications
EP1765797A1 (fr) * 2004-06-24 2007-03-28 University of Kansas Center for Research, Inc. Derives de phenothiazine et leur methode d'utilisation
DE102007005045A1 (de) * 2007-01-26 2008-08-07 Sanofi-Aventis Phenothiazin Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5037842A (en) * 1990-06-05 1991-08-06 Pfizer Inc. Oxa- and thiazolidinedione hypoglycemic and hypocholesterolemic agents
EP0559571A1 (fr) * 1992-03-06 1993-09-08 Adir Et Compagnie Nouveaux dérivés de thiazolidine-2,4-dione, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
EP0593348A1 (fr) * 1992-10-12 1994-04-20 Adir Et Compagnie Nouveaux composés de thiazolidine dione, leur procédé de préparation et les compositions pharmaceutiques les contenant
EP0710659A1 (fr) * 1994-11-02 1996-05-08 Takeda Chemical Industries, Ltd. Dérivés d'oxazolidinedione, leur fabrication et leur application
JPH0912575A (ja) * 1995-06-28 1997-01-14 Sankyo Co Ltd ベンゾオキサジンおよびベンゾチアジン誘導体
EP0783888A1 (fr) * 1995-12-26 1997-07-16 Sankyo Company Limited Utilisation de la troglitazone et de thiazolidinediones apparentées dans la fabrication d'un médicament destiné au traitement et la prévention de l'ostéoporose
EP0787727A1 (fr) * 1996-01-31 1997-08-06 SS Pharmaceutical Co., Ltd. Dérivés de benzoazines ou leurs sels et compositions pharmaceutiques les contenant
WO1997037656A1 (fr) * 1996-04-04 1997-10-16 Takeda Chemical Industries, Ltd. Composition anticachexique

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5037842A (en) * 1990-06-05 1991-08-06 Pfizer Inc. Oxa- and thiazolidinedione hypoglycemic and hypocholesterolemic agents
EP0559571A1 (fr) * 1992-03-06 1993-09-08 Adir Et Compagnie Nouveaux dérivés de thiazolidine-2,4-dione, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
EP0593348A1 (fr) * 1992-10-12 1994-04-20 Adir Et Compagnie Nouveaux composés de thiazolidine dione, leur procédé de préparation et les compositions pharmaceutiques les contenant
EP0710659A1 (fr) * 1994-11-02 1996-05-08 Takeda Chemical Industries, Ltd. Dérivés d'oxazolidinedione, leur fabrication et leur application
JPH0912575A (ja) * 1995-06-28 1997-01-14 Sankyo Co Ltd ベンゾオキサジンおよびベンゾチアジン誘導体
EP0783888A1 (fr) * 1995-12-26 1997-07-16 Sankyo Company Limited Utilisation de la troglitazone et de thiazolidinediones apparentées dans la fabrication d'un médicament destiné au traitement et la prévention de l'ostéoporose
EP0787727A1 (fr) * 1996-01-31 1997-08-06 SS Pharmaceutical Co., Ltd. Dérivés de benzoazines ou leurs sels et compositions pharmaceutiques les contenant
WO1997037656A1 (fr) * 1996-04-04 1997-10-16 Takeda Chemical Industries, Ltd. Composition anticachexique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 97, no. 5 30 May 1997 (1997-05-30) *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020499A1 (fr) * 2000-09-04 2002-03-14 Dr. Reddy's Research Foundation Procede de preparation de 2-[3,4-dihydro-1,4-benzothiazin-4-yl]ethylmethane sulphonate
WO2002040460A1 (fr) * 2000-11-17 2002-05-23 Dr. Reddy's Research Foundation Methode de preparation de 2-[phenothiazin-10-yle] methanesulphonate d'ethyle
US6969730B2 (en) 2001-03-16 2005-11-29 Abbott Laboratories Amines as histamine-3 receptor ligands and their therapeutic applications
WO2002074758A3 (fr) * 2001-03-16 2003-03-20 Abbott Lab Nouvelles amines en tant que ligands des recepteurs de l'histamine 3 et leurs applications therapeutiques
EP2258694A1 (fr) * 2001-03-16 2010-12-08 Abbott Laboratories Amines en tant que ligands des recepteurs de l'histamine-3 et leurs applications thérapeutiques
US7538138B2 (en) 2001-03-16 2009-05-26 Abbott Laboratories Amines as histamine-3 receptor ligands and their therapeutic applications
JP2005500986A (ja) * 2001-03-16 2005-01-13 アボット・ラボラトリーズ ヒスタミン−３受容体リガンドとしての新規アミンおよびそれらの治療的適用
FR2830012A1 (fr) * 2001-09-21 2003-03-28 Servier Lab Nouveaux derives heterocycliques, leur procede de preparation et les compositions pharamaceutiques qui les contiennent
WO2003027108A1 (fr) * 2001-09-21 2003-04-03 Les Laboratoires Servier Derives heterocycliques et leur utilisation en tant qu'agents hypoglycemiants et hypolipemiants
WO2003059342A1 (fr) * 2002-01-11 2003-07-24 Abbott Laboratories Ligands de recepteur d'histamine-3 pour traiter des etats diabetiques
EP1765797A1 (fr) * 2004-06-24 2007-03-28 University of Kansas Center for Research, Inc. Derives de phenothiazine et leur methode d'utilisation
EP1765797A4 (fr) * 2004-06-24 2008-02-06 Univ Kansas Ct For Res Inc Derives de phenothiazine et leur methode d'utilisation
DE102007005045A1 (de) * 2007-01-26 2008-08-07 Sanofi-Aventis Phenothiazin Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DE102007005045B4 (de) * 2007-01-26 2008-12-18 Sanofi-Aventis Phenothiazin Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents

Also Published As

Publication number Publication date
EP0977753A1 (fr) 2000-02-09
JP2002515042A (ja) 2002-05-21
AU7595298A (en) 1998-12-11

Similar Documents

Publication Publication Date Title
EP0971917B1 (fr) Derives de thiazolidinedione et d'oxazolidinedione ayant des proprietes antidiabetiques, hypolipidemiques et antihypertenseurs
EP0981526B1 (fr) Nouveaux composes anti-diabetiques avec proprietes hypolipidemiantes et anti-hypertensives, procede pour les preparer et compositions pharmaceutiques contenant ces composes
US6310069B1 (en) Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6313113B1 (en) Heterocyclic compounds having antidiabetic, hypolipidemic and antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
EP0958296B1 (fr) Composes heterocycliques, leur procede de preparation, compositions pharmaceutiques les contenant et utilisation de ces composes dans le traitement du diabete et des maladies associees
EP0923580A1 (fr) Composes de thiazolidinedione presentant des proprietes antidiabetiques, hypolipidemiantes, antihypertensives, leur procede de preparation et compositions pharmaceutiques les contenant
US6159966A (en) Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension: process for their preparation and pharmaceutical compositions containing them
US7119198B2 (en) Tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them
US5885997A (en) Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US5889025A (en) Antidiabetic compounds having hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
WO1998052946A1 (fr) Azolidinediones utilises dans le traitement du diabetes, de la dyslipidemie et de l'hypertension
US5889032A (en) Heterocyclic compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
EP1036075B1 (fr) Oxalidinedione et thiazolidinedione a substitution, antidiabetiques, hypolipidemiques et antihypertenseurs
USRE39266E1 (en) Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6573268B1 (en) Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US5919782A (en) Heterocyclic compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
EP0894089B1 (fr) Nouveaux composes heterocycliques presentant des proprietes antidiabetiques, hypolipidemiantes, antihypertensives, leur procede de preparation et compositions pharmaceutiques les contenant
US6372750B2 (en) Heterocyclic compounds, process for their preparation and pharmaceutical compounds containing them and their use in the treatment of diabetes and related diseases

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
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)
WWE Wipo information: entry into national phase

Ref document number: 1998923730

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1998923730

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1998923730

Country of ref document: EP