EP0923580A1 - Composes de thiazolidinedione presentant des proprietes antidiabetiques, hypolipidemiantes, antihypertensives, leur procede de preparation et compositions pharmaceutiques les contenant - Google Patents

Composes de thiazolidinedione presentant des proprietes antidiabetiques, hypolipidemiantes, antihypertensives, leur procede de preparation et compositions pharmaceutiques les contenant

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Publication number
EP0923580A1
EP0923580A1 EP97924560A EP97924560A EP0923580A1 EP 0923580 A1 EP0923580 A1 EP 0923580A1 EP 97924560 A EP97924560 A EP 97924560A EP 97924560 A EP97924560 A EP 97924560A EP 0923580 A1 EP0923580 A1 EP 0923580A1
Authority
EP
European Patent Office
Prior art keywords
dione
thiazolidine
methoxy
compound
pyrrolidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP97924560A
Other languages
German (de)
English (en)
Inventor
Vidya Bhushan Lohray
Braj Bhushan Lohray
Sekar Reddy Alla
Rao Bheema Paraselli
Rajagopalan 28 Vishaal Towers RAMANUJAM
Ranjan Chakrabarti
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys 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 US08/687,840 external-priority patent/US5801173A/en
Application filed by Dr Reddys Research Foundation, Reddy Cheminor Inc filed Critical Dr Reddys Research Foundation
Publication of EP0923580A1 publication Critical patent/EP0923580A1/fr
Ceased legal-status Critical Current

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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
    • C07D417/14—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
    • 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
    • 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
    • A61P3/06—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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • 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

Definitions

  • the present invention relates to novel antidiabetic compounds, their tautomeric forms, their derivatives, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • This invention particularly relates to novel thiazoiidinedione derivatives of the general formula (I), their tautomeric forms, their derivatives, 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, thiazoiidinedione derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, novel intermediates and pharmaceutical compositions containing them.
  • the thiazoiidinedione derivatives of the general formula (I) defined above of the present invention are useful for the treatment and / or prophylaxis of diseases or conditions in which insulin resistance is the underlying pathophysiological mechanism. Examples of these diseases and conditions are type II diabetes, impaired glucose tolerance, dyslipidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis.
  • the thiazoiidinedione derivatives of the formula (I) are useful for the treatment of insulin resistance associated with obesity and psoriasis.
  • the thiazoiidinedione derivatives 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
  • 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. Invest., (1985) 75: 809-817; N. Engl. J. Med. (1987) 317: 350-357; J. Clin. Endocrinol. Metab., (1988) 66: 580-583; J. Clin. Invest., (1975) 68: 957-969) and other renal complications (See Patent Application No.
  • 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 and 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,-C 4 alkenedioxy group
  • n is 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 .
  • NIDDM non-insulin-dependent-diabetes mellitus
  • the main objective of the present invention is therefore, to provide novel thiazoiidinedione derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically, acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or their mixtures.
  • Another objective of the present invention is to provide novel thiazoiidinedione derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, no toxic effect or reduced toxic effect.
  • A represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted five membered heterocyclic group with one hetero atom selected from nitrogen, oxygen or sulfur, which is single or fused or a substituted or unsubstituted six membered heterocyclic group with one or more nitrogen atoms, which is single or fused, which may or may not contain one or more oxo group on the ring
  • B and D represent substituted or unsubstituted hydrocarbon linking group between N and X which may or may not contain one or more double bonds
  • X represents either a CH 2 group or a hetero atom selected from the group of nitrogen, oxygen or sulfur
  • Ar represents an optionally substituted divalent aromatic or heterocyclic group
  • R 1 and R 2 can be the same or different and represent hydrogen atom, lower alkyl, halogen, alkoxy or hydroxy groups or R 1 and R 2 together represent a bond and p is an integer ranging from 0-4.
  • A may be a six membered heterocyclic group which contains 1-3 nitrogen atoms and A may be a single or fused ring which is substituted or unsubstituted and may contain up to 3 oxo groups.
  • Suitable aromatic groups represented by A include phenyl, naphthyl, phenanthryl, preferably, phenyl and naphthyl group
  • suitable heterocyclic groups represented by A include furyl, pyrrolyl, thienyl, pyridyl, quinolyl, 4-pyridone-2-yl, pyrimidyl, 4-pyrimidone-2-yl, pyridazyl, and 3-pyridazone-2-yl groups, pthalazinyl, phthalazinonyl, quinoxalinyl, quinoxalonyl, quinazolinyl, quinazolinonyl, azaindolyl, naphtharidinyl, carbazolyl, indolyl, benzofuranyl, pyrimidonyl, and the like.
  • Preferred groups represented by A include pyridyl, quinolyl, indolyl, benzofuranyl, pyrimidonyl, quinazolinonyl groups. More preferred groups represented by A include pyridyl and quinolyl groups.
  • One or more of the suitable substituents on the aromatic and heterocyclic group represented by A include hydroxy, amino group, halogen atoms such as chlorine, fluorine, bromine, or iodine, substituted or unsubstituted (C,-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, pentyl, hexyl and the like; cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; cycloalkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like; aryl group such as phenyl or naphthy
  • the substituents selected are from the same groups as those groups that substitute A and may be selected from halogen, hydroxy, or nitro, or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.
  • the substituents on the adjacent carbon atoms on the group represented by A along with the carbon atoms to which they are attached may also form a substituted or unsubstituted, aromatic, saturated or unsaturated 5-7 membered cyclic structure which may be carbocyclic or heterocyclic wherein one or more hetero atoms are selected from N, O, and S, such as phenyl, naphthyl, thienyl, furyl, oxazolyl, thiazolyl, furyl, imidazolyl, azacyclobutyl, isoxazolyl, azepinyl and the like, preferably, phenyl, furyl and imidazolyl groups.
  • the substituents on such cyclic structure may be selected from the same group that may substitute the aromatic and heterocyclic group represented by A.
  • Suitable hydrocarbon linking group between N and X represented by B may contain 1-4 carbon atoms, 1-2 being preferred and suitable linking group between N and X represented by D may represent either a bond or contain 1-4 carbon atoms, 1- 2 being preferred.
  • the compounds according to formula (I) always have a linking group B and a linking group D.
  • the linking group D having no carbon atom means that the linking group D represents a bond.
  • B and D may contain no double bond or contain one to two double bonds, no double bond or one double bond being preferred.
  • the substituents on the B and D include hydroxy; amino groups; halogen such as chlorine, bromine, or iodine; optionally substituted linear or branched (C,-C 12 )alkyl, especially (C,-C 6 )alkyl group such as methyl, hydroxymethyl, aminomethyl, methoxymethyl, trifluoromethyl, ethyl, isopropyl, hexyl etc; (C 3 -C 6 )cycloalkyl groups such as cyclopropyl, fluorocyclopropyl, cyclobutyl, cyclopentyl, fluorocyclopentyl, cyclohexyl, fluorocyclohexyl and the like; (C,-C 6 )alkoxy, (C 3 -C 6 ) cycloalkoxy, aryl such as phenyl; heterocyclic groups such as furyl, thienyl and the like; (C 2 -C 6 ) acyl
  • Preferred ring structures include phenyl, naphthyl, pyridyl, thienyl, furyl, oxazolyl, thiazolyl, furyl, isoxazolyl, azepinyl and the like.
  • the substituents on such cyclic structure may be selected from the same group that may substitute the aromatic or heterocyclic group represented by A.
  • Suitable X includes CH 2 , O, N or S group, preferably CH 2 and O.
  • Preferred ring structures comprising a nitrogen atom, linking groups represented by B and D, and X are pyrrolidinyl, piperidinyl, piperazinyl, aziridinyl and morpholinyl groups.
  • the ring structures comprising a nitrogen atom, linking groups represented by B and D, and X are a pyrrolidinyl group, morpholinyl or aziridinyl group.
  • the group represented by Ar includes divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, pyrazolyl and the like.
  • the substituents on Ihe group represented by Ar include linear or branched optionally halogenated (C,-C 5 )alkyl and optionally halogenated (C,-C 3 )alkoxy, halogen, acyl, amino, acylamino, thio, carboxylic and sulfonic acids and their derivatives.
  • Ar represents substituted or unsubstituted divalent phenylene, naphthylene, benzofuranyl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups.
  • Ar is represented by divalent phenylene or naphthylene, which may be optionally substituted by methyl, halomethyl, methoxy or halomethoxy groups.
  • Suitable R l and R 2 include hydrogen, lower alkyl groups such as methyl, ethyl or propyl; halogen atoms such as fluorine, chlorine, bromine or iodine; (C,- C 3 )alkoxy, hydroxy or R 1 and R 2 together represent a bond; preferably both R 1 and R 2 are hydrogen or together represent a bond.
  • Suitable p is an integer ranging from 0-4, preferably 0-2. When p is zero, (CH 2 ) p represents a bond; the ring structure comprising N, X and the linking groups B and D is directly linked to oxygen atom.
  • Pharmaceutically acceptable salts forming part of this invention include salts of the thiazoiidinedione 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, ammoni
  • 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 die like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Particularly useful compounds according to the invention include:
  • a process for the preparation of novel thiazoiidinedione derivatives of formula (I) , their stereoisomers, their polymo ⁇ hs, their tautomeric forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates which comprises, (a) reacting a compound of general formula (III) A— L 1 (III) where A is as defined above and L 1 is a halogen atom such as chlorine, bromine or iodine; a thioalkyl group such as thiomethyl group, or a group capable of coupling with an amine nitrogen atom, with a compound of general formula (IV)
  • R a is a hydroxy group or a group which can be converted to a hydroxy group or a leaving group such as OMs, OTs, Cl, Br or I, by conventional methods, to yield a compound of general formula (V)
  • the reaction of compound of general formula (III) with a compound of general formula (IV) to yield a compound of general formula (V) may be carried out in neat or in the presence of solvents such as DMF, DMSO, acetone, CH 3 CN, THF, pyridine or ethanol. Mixture of solvents may be used.
  • the reaction may be carried out in an inert atmosphere.
  • 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 CO 3 , NajCOj, KOH, NaOH, NaH and the like or mixture 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. - 150°C. Duration of the reaction may range from 1 to 48 hours, preferably from 1 to 12 hours. In the reaction, the ratio of the compound of general formula (III) and (IV) may range from 1 to 20 equivalents, preferably from 1 to 5 equivalents. (b) reacting the compound of general formula (V) where R a is a hydroxy group with a compound of general formula (VI)
  • R b — Ar— CHO (VI) where Ar is as defined earlier and R b is a halogen atom such as chlorine or fluorine, or R b is a hydroxy group to yield a compound of general formula (VII)
  • the reaction of compound of general formula (V) where R a is a hydroxy group with the compound of general formula (VI) where R b is a halogen atom to give a compound of general formula (VII) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or a mixture thereof.
  • the reaction may be carried out in an inert atmosphere.
  • 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 CO 3 , Na 2 CO 3 , or NaH. Mixture of bases may be used.
  • the reaction temperature may range from 20°C. to 120°C, preferably at a temperature in the range of 30°C. to 80°C.
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours.
  • reaction of compound of general formula (V) where R a is a hydroxy group with the compound of general formula (VI) where R b is a hydroxy group may be carried out using suitable coupling agents such as dicyclohexyl urea, triarylphosphine / dialkylazodicarboxylate such as PPh 3 /DEAD and the like.
  • suitable coupling agents such as dicyclohexyl urea, triarylphosphine / dialkylazodicarboxylate 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 or a mixture thereof.
  • solvents such as THF, DME, CH 2 C1 2 , CHC1 3 , toluene, acetonitrile, carbontetrachloride-
  • 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 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 50°C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
  • reaction between the compound of general formula (VII) with 2,4- thiazoiidinedione to give a compound of general formula (VIII) in step (c) may be carried out neat in the presence of sodium acetate or in the presence of a solvent such as benzene, toluene, methoxyethanol or a mixture thereof.
  • the reaction temperature may range from 80°C. to 140°C. depending upon the solvents employed.
  • a suitable catalyst such as piperidinium acetate or benzoate, or sodium acetate may also be employed.
  • 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 sieves etc. And if desired,
  • step (d) reducing the compound of general formula (VIII) obtained in step (c) by known methods, to obtain the compound of general formula (IX)
  • the reduction of compound of the formula (VIII) obtained in " step (c) to yield a compound of the general formula (IX) may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and the like. Mixtures of catalysts may be used. The reaction may also 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.
  • metal solvent reduction such as magnesium in methanol or sodium amalgam in methanol.
  • alkali metal borohydrides such as LiBH 4 , NaBH 4 , KBH 4 and the like
  • cobalt salt such as CoCl 2 and ligands, preferably bidentated ligands such as 2, 2'- bipyridyl, 1,10-phenanthroline, bisoximes and the like.
  • (VII) can be prepared by converting the compound of general formula (V) to a compound of general formula (X) where A, B, D, X and p are as defined earlier and L 2 is a leaving group such as halide group like chloride, bromide or iodide, or methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate and the like and further reaction of the compound of general formula (X) with a compound of general formula (VI) where Ar is as defined earlier and R b is a hydroxy group.
  • the compound of general formula (V) may be converted to a compound of general formula (X) using halogenating agents such as thionyl chloride, CBr 4 /PPh 3 , CCl 4 /PPh 3 , phosphorus halides or by using p-toluenesulfonyl chloride, metharfesulfonyl chloride, trifluoromethanesulfonyl chloride or anhydride in neat or in the presence of a base such as pyridine, DMAP, triethylamine etc. Mixture of bases may be used. These reagents may be used in 1-4 equivalents, preferably 1 to 2 equivalents. Temperature in the range -10°C. to 100°C. may be employed, preferably from 0°C. to 60°C. The reaction may be conducted for 0.5 to 24 hours, preferably from 1 to 12 hours.
  • halogenating agents such as thionyl chloride, CBr 4 /PPh 3 ,
  • the reaction may be carried out in an inert atmosphere.
  • 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 CO 3 , Na 2 CO 3 , or NaH or their mixture.
  • the reaction temperature may range from 20°C. - 120°C, preferably at a temperature in the range of 30°C. -80°C.
  • the duration of the reaction may range from 1-24 hours, preferably from 2 to 12 hours.
  • the compound of general formula (VII) can also be prepared by reacting a compound of general formula (XI)
  • the reaction of compound of general formula (XI) with a compound of general formula (III) may be carried out neat or in the presence of solvents such as DMF, DMSO, acetone, acetonitrile, ethanol and the like or mixture thereof.
  • the reaction may be carried out in an inert atmosphere.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar or He.
  • the reaction may be effected in neat or in the presence of base such as K 2 CO 3 , NajCOj, KOH, NaOH, NaH and the like or mixture thereof.
  • the amount of base may range from 1 to 20 equivalents, preferably 1-10 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. -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 (III) and (XI) may range from 1 to
  • the compound of general formula (XI) in turn can be prepared by reacting a compound of general formula (XII)
  • the reaction may be carried out in an inert atmosphere.
  • 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 CO 3 , Na 2 CO 3 , NaH or a mixture thereof.
  • the reaction temperature may range from 20°C. to 120°C, preferably at a temperature in the range of 30°C. to 80°C.
  • the duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours.
  • the N-protecting group R 3 is usually removed either by acid treatment or by hydrogenation or in the presence of a suitable base depending upon the nature of the protecting group employed.
  • the compound of the general formula (I), their tautomeric forms, their stereoisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates can also be prepared by reacting a compound of the general formula (V) where R a is OH group obtained and defined above with a compound of general formula (XIII).
  • R', R 2 and Ar are as defined earlier and R 4 is hydrogen or a nitrogen protecting group such as acyl or triarylmethyl group.
  • reaction of compound of general formula (V) with a compound of general formula (XIII) 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 , CHCI 3 , toluene, acetonitrile, carbontetrachloride and the like.
  • the reaction may be carried out in an inert atmosphere.
  • 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 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 the general formula (I), their tautomeric forms, their stereoisomers, their polymo ⁇ hs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates can also be prepared by reacting a compound of the general formula (X) obtained and defined above with a compound of general formula (XIII) as defined above.
  • reaction of compound of general formula (X) with a compound of general formula (XIII) 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 mixture thereof.
  • solvents such as THF, DMF, DMSO, DME and the like or mixture thereof.
  • the reaction may be carried out in an inert atmosphere which is 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 mixture thereof. Multiple solvents and bases can be used.
  • the amount of base may range from l 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 2 to 12 hours.
  • the compound of general formula (I) defined above can be obtained by reacting a compound of general formula (XIV)
  • the reaction of compound of general formula (XIV) with the compound of general formula (III) to produce a compound of general formula (I) may be carried out neat or in the presence of solvents such as DMF, DMSO, acetone, acetonitrile, ethanol and THF or mixture thereof.
  • the reaction may be carried out in an inert atmosphere.
  • 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 CO 3 , Na ⁇ O j , KOH, NaOH, NaH and the like or a mixture thereof.
  • the amount of base may range from 1 to 20 equivalents, preferably 1 to 6 equivalents.
  • the reaction may be carried out at a temperature in the range 20°C.
  • the amounts of the compounds of general formula (III) and (XIV) may range from 1 to 20 equivalents, preferably from 1 to 5 equivalents.
  • the reaction of compound of general formula (XIII) with the compound of general formula (XV) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or a mixture thereof.
  • the reaction may be carried out in an inert atmosphere.
  • 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 CO 3 , Na 2 CO 3 , NaH or their mixture.
  • the reaction temperature may range from 20°C. to 120°C, preferably at a temperature in the range of 30°C. to 80°C.
  • the duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours.
  • the compound of the general formula (XIV) where R 1 and R 2 together represent a bond can also be prepared by reacting a compound of general formula (XVI)
  • the reaction between the compound of general formula (XVI) with 2,4- thiazolidinedione may be carried out neat in the presence of sodium acetate or in the presence of a solvent such as benzene, toluene, or methoxyethanol.
  • the reaction temperature may range from 80°C. to 140°C. depending upon the solvents employed.
  • a suitable catalyst such as piperidinium acetate or benzoate or sodium acetate may also be employed.
  • 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 sieves.'
  • the compound of general formula (I) where A, B, D, X, p and Ar are as defined earlier can be prepared by the reaction of compound of general formula (XVII)
  • 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.
  • reaction of compound of general formula (XVII) 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.
  • 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. and the reflux temperature of the solvent used.
  • Bases such as NaOAc, KOAc, NaOMe, NaOEt etc. can be used.
  • the reaction is normally followed by treatment with a mineral acid such as hydrochloric acid at 20°C. - 100°C.
  • the compound of general formula (XVIII) can in turn be prepared by the conventional reduction of the novel intermediate (XIX) where all symbols are as i defined earlier.
  • novel intermediate of general formula (XIX) can be prepared by the reaction of compound of general formula (V)
  • (XX) to produce a compound of the formula (XIX) 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 is 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 CO 3 or NaH or mixtures thereof.
  • the reaction temperature may range from 20°C. - 120°C, preferably at a temperature in the range of 30°C. - 100°C.
  • the duration of the reaction may range from 1 - 12 hours, preferably from 2 to 6 hours.
  • the compound of general formula (XIX) can also be prepared by reacting a compound of general formula (XXI)
  • the reaction of compound of general formula (XXI) with a compound of general formula (III) may be carried out neat or in the presence of solvents such as DMF, DMSO, acetone, acetonitrile or ethanol. Mixture 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 neat or in the presence of base such as K 2 CO 3 , Na ⁇ O j , KOH, NaOH, NaH and the like or mixture thereof.
  • the amount of base may range from 1 to 20 equivalents, preferably 1-10 equivalents.
  • the reaction may be carried out at a temperature in the range of 20°C. to 180°C, preferably at a temperature in the range of 50°C.
  • the amount of the compound of general formula (III) and (XXI) may range from 1 to 20 equivalents, preferably from 1 to 9 equivalents.
  • the compound of general formula (XXI) in turn can be prepared by reacting a compound of general formula (XII)
  • the reaction may be effected in the presence of a base such as K 2 CO 3 , Na 2 CO 3 , or NaH.
  • the reaction temperature may range from 20°C. to 120°C, preferably at a temperature in the range of 30°C. to 80°C.
  • the duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours.
  • the N-protecting group R 3 is usually removed either by acid treatment or by hydrogenation or in the presence of a suitable base depending upon the nature of the protecting group employed.
  • deprotection methods include treatment with acid such as, hydrochloric acid, trifluoroacetic acid or bases such as, KOH, NaOH, NajCO j , NaHCO 3 , or K 2 CO 3 and the like. 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 a substituted benzyl group.
  • 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-toluenesulphonic 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-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascor
  • 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.
  • polymo ⁇ hs of compound 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 fast cooling. The presence of polymo ⁇ hs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray data or such other techniques.
  • the present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I), as defined above, their tautomeric forms, 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 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, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders, as aldose reductase inhibitors and for improving
  • 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 or solvents.
  • Tablet Production Example a) 1) Active ingredient 30 g
  • the ingredients 1 to 4 are uniformly moistened with an aqueous solution of ingredient 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 active 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.
  • 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 flavorants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions or suspensions For example, 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 title compound (2.9 g, 15 %) was prepared as a thick liquid from 2- chloropyridine (40 g ) and L-prolinol (10 g) by an analogous procedure to that described in preparation 1.
  • the title compound (0.3 g, 100%) was prepared as a thick liquid from
  • the title compound (33.0 g, 72%) was prepared as a thick liquid from 2- chloropyridine (54.32 g) and 2-hydroxymethyl mo ⁇ holine (28.0 g) by a similar procedure to that described in preparation 1.
  • Method B The title compound (0.12 g, 15%) was prepared as a white solid from ethyl 2-bromo-3-[4-[[l-(lepidin-2-yl)-(2S)-pyrrolidin-2-yl]methoxy]phenyl]propanoate
  • mice progressively develop 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 invention showed blood sugar and triglycerides lowering activities through improved insulin resistance. This was demonstrated by the following in vivo experiments.
  • mice of 8 to 14 weeks age having body weight range of 35 to 60 grams, procured from the Jackson Laboraotory, USA, were used in the experiment.
  • the mice were provided with standard feed (National Institute of Nutrition, Hyderabad, India) and acidified water, ad libitum.
  • the animals having more than 300 mg / dl blood sugar were used for testing.
  • the number of animals in each group was 4.
  • 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 glyceroI-3- PO 4 oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits, India) methods respectively.
  • the blood samples were collected one hour after administration of test compounds / vehicle for assessing the biological activity.
  • Test compounds were suspended on 0.25 % carboxymethyl cellulose or water (for water soluble compounds) and administered to test group at a dose of 10 to 30 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: DT/DC
  • ZC Zero day control group value
  • DC Zero day treated group value
  • TC Control group value on test day
  • DT Treated group value on the test day
  • Groups of 20 rats consisting of 10 males and 10 females, weighing between 120 to 140 gm, received orally 100 mg/ kg of compound of Example 6 for 28 days. The behavioral changes and body weights were monitored daily. The rats were sacrificed on the 29th day and blood was collected for hematological and biochemical estimations. All vital organs were examined both macroscopically and microscopically. The compound of example 6 at 100 mg / kg dose did not produce any mortality. At the end of 28 days treatment no significant deviations from the control were observed in hematological and biochemical parameters. No gross macroscopic and microscopic changes of heart, lungs, bone marrow, kidneys and spleen were observed.

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Abstract

L'invention concerne de nouveaux composés antidiabétiques de thiazolidinedione, leurs formes tautomères, leurs dérivés, leurs stéréoisomères, leurs polymorphes, leurs sels pharmaceutiquement acceptables, leurs solvates pharmaceutiquement acceptables et des compositions pharmaceutiquement acceptables les contenant, des procédés de préparation des composés antidiabétiques et leurs utilisations.
EP97924560A 1996-07-26 1997-05-02 Composes de thiazolidinedione presentant des proprietes antidiabetiques, hypolipidemiantes, antihypertensives, leur procede de preparation et compositions pharmaceutiques les contenant Ceased EP0923580A1 (fr)

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US08/687,840 US5801173A (en) 1996-05-06 1996-07-26 Heterocyclic compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US687840 1996-07-26
PCT/US1997/007415 WO1997041120A1 (fr) 1996-07-26 1997-05-02 Composes de thiazolidinedione presentant des proprietes antidiabetiques, hypolipidemiantes, antihypertensives, leur procede de preparation et compositions pharmaceutiques les contenant

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AU2995497A (en) 1997-11-19
CN1221417A (zh) 1999-06-30
JP2000514041A (ja) 2000-10-24
WO1997041120A1 (fr) 1997-11-06

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