EP1363914A1 - Aryl substituted alkylcarboxylic acids as hypocholesterolemic agents - Google Patents

Aryl substituted alkylcarboxylic acids as hypocholesterolemic agents

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Publication number
EP1363914A1
EP1363914A1 EP02711126A EP02711126A EP1363914A1 EP 1363914 A1 EP1363914 A1 EP 1363914A1 EP 02711126 A EP02711126 A EP 02711126A EP 02711126 A EP02711126 A EP 02711126A EP 1363914 A1 EP1363914 A1 EP 1363914A1
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EP
European Patent Office
Prior art keywords
substituted
compound
ethoxy
formula
aralkyl
Prior art date
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Application number
EP02711126A
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German (de)
English (en)
French (fr)
Inventor
Kumar Das Dr. Reddy's Research Foundation SAIBAL
Papi Reddy Dr. Reddy's Research Foundation PURMA
Venkateswarlu Dr. Reddy's Res. Foundation AKELLA
Rajagopalan Dr. Reddy's Res. Found. RAMANUJAM
Chakrabarti Dr. Reddy's Res. Foundation RANJAN
Braj Bhushan Dr. Reddy's Res. Foundation LOHRAY
Vidya Bhushan Dr. Reddy's Res. Foundation LOHRAY
Bheema Rao Dr. Reddy's Res. Foundation PARASELLI
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Dr Reddys Laboratories Ltd
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Dr Reddys Laboratories Ltd
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Publication of EP1363914A1 publication Critical patent/EP1363914A1/en
Withdrawn legal-status Critical Current

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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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    • 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
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    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel ⁇ -aryl- ⁇ -oxysubstituted alkylcarboxylic acids of the general formula (I), their derivatives, then- analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • the present invention also relates to a process for the preparation of the above said novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their ' polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
  • the present invention also relates to novel intermediates, processes for their preparation and their use in the preparation of compounds of formula (I).
  • the compounds of the present invention lower plasma glucose, triglycerides, lower total cholesterol (TC) and increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL), which have a beneficial effect on coronary heart disease and atherosclerosis.
  • TC total cholesterol
  • HDL high density lipoprotein
  • LDL low density lipoprotein
  • the compounds of general formula (I) are useful in reducing body weight and for the treatment and/or prophylaxis of diseases such as atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of hyperglycemia, hyperiipidemia, hypercholesterolemia, lowering of atherogenic lipoproteins, NLDL (very low density lipoprotein) and LDL.
  • the compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy.
  • the compounds of general formula (I) are also useful for the treatment and/or prophylaxis of type 2 diabetes, leptin resistance, atherosclerosis, impaired glucose tolerance, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.
  • These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, eating disorders, inflammation and for the treatment of cancer.
  • PCOS polycystic ovarian syndrome
  • the compounds of the present invention are also useful in the treatment and or prophylaxis of the above said diseases in combination/concomittant with one or more HMG CoA reductase inhibitors, hypolipidemic/hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol and probucol.
  • Hypercholesterolemia has been defined as plasma cholesterol level that exceeds arbitrarily defined value called "normal” level. Recently, it has been accepted that "ideal" plasma levels of cholesterol are much below the "normal” level of cholesterol in the general population and the risk of coronary artery disease (CAD) increases as cholesterol level rises above the "optimum” (or “ideal”) value.
  • CAD coronary artery disease
  • LDL Low density lipoprotein
  • IDL intermediate density lipoprotein
  • HDL High density lipoprotein
  • NLDL Very low density lipoprotein
  • Diabetes and insulin resistance is yet another disease which severely effects the quality of a large population in the world. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, 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, hyper- lipidemia (J. Clin. Invest., (1985) 75 : 809 - 817; N. Engl. J. Med. (1987) 317: 350-357; J. Clin. Endocrinol.
  • High risk of CND is related to the higher LDL (Low Density Lipoprotein) and NLDL (Very Low Density Lipoprotein) seen in hyperiipidemia. Patients having glucose intolerance/insulin resistance in addition to hyperiipidemia have higher risk of CND. Numerous studies in the past have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and NLDL and increasing HDL cholesterol help in preventing cardiovascular diseases.
  • Peroxisome proliferator activated receptors are members of the nuclear receptor super family.
  • the gamma ( ⁇ ) isoform of PPAR (PPAR ⁇ ) has been implicated in- regulating differentiation of adipocytes (Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell, (1995) 83: 803-812), whereas the alpha ( ⁇ ) isoform of PPAR (PPAR ⁇ ) mediates fatty acid oxidation (Trend. Endocrin. Metab., (1993) 4: 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol. (1995) 5: 618 -621).
  • PPAR ⁇ agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that there exists synergism for the molecules, which are agonists for both PPAR ⁇ and PPAR ⁇ and suggested to be useful, for the treatment of syndrome X (WO 97/25042). Similar synergism between the insulin sensitizer (PPAR ⁇ agonist) and HMG Co A reductase inhibitor has been observed which may be useful for the treatment of atherosclerosis and xanthoma (EP 0 753 298).
  • PPAR ⁇ plays an important role in adipocyte differentiation (Cell, (1996) 87, 377-389). Ligand activation of PPAR is sufficient to cause complete terminal differentiation (Cell, (1994) 79, 1147- 1156) including cell cycle withdrawal. PPAR ⁇ is consistently expressed in certain cells and activation of this nuclear receptor with PPAR ⁇ agonists would stimulate the terminal differentiation of adipocyte precursors ai d cause morphological and molecular changes characteristics of a more differentiated, less malignant state (Molecular Cell, (1998), 465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad.
  • Leptin resistance is a condition wherein the target cells are unable to respond to leptin signal. This may give rise to obesity due to excess food intake and reduced energy expenditure and cause impaired glucose tolerance, type 2 diabetes, cardiovascular diseases and such other interrelated complications.
  • Kallen.et al Proc. Natl. Acad. Sci. (1996) 93, 5793-5796) have reported that insulin sensitizers which perhaps due to the PPAR agonist expression and therefore lower plasma leptin concentrations.
  • compounds having insulin sensitizing property also possess leptin sensitization activity. They lower the circulating plasma leptin concentrations by improving the target cell response to leptin (WO/98/02159).
  • R a represents 2- benzoxazolyl or 2-pyridyl and Rb represent CF3, CH2OCH3 or CH3.
  • Rb represent CF3, CH2OCH3 or CH3.
  • a typical example is (S)-3-[4-[2-[N-(2-benzoxazolyl)-N- methylamino] ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid (Ilf).
  • X represents O or S ;
  • the groups Rl, R2 and group R3 when attached to the carbon atom, may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, all ylammo, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryl
  • (CH2)n-O- may be attached either through nitrogen atom or through carbon atom where n is an integer ranging from 1 - 4;
  • Ar represents an optionally substituted divalent single or fused aromatic or heterocyclic group;
  • R 4 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aralkyl group or forms a bond together with the adjacent group R 5 ;
  • R 5 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aralkyl or R 5 forms a bond together with R 4 ;
  • R 6 may be hydrogen, optionally substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups, with a
  • R and R together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen.
  • EP 0903343 discloses compounds of general formula (Ilk)
  • A is an alkylene, alkyleneoxy or alkylenecarbonyl
  • X is O, S, NH or CH 2
  • Y 1 is an amino, hydroxylamino, hydroxyalkylamino, monoalkylamino, dialkylamino, cyclic amino, hydroxy or lower alkoxy group
  • R 1 is a hydrogen atom, lower alkyl, hydroxyalkyl group, alkoxyalkyl, halogenalkyl or COY 2 , where Y is amino, hydroxyamino, hydroxyalkylamino, monoalkylamino, dialkylamino, cyclic amino, hydroxy or lower alkoxy group
  • R 2 is lower alkyl, hydroxyalkyl, alkoxyalkyl or halogenalkyl group, COY 2 or a phenyl, pyridyl or aralkyl which may be substituted and R is a hydrogen or halogen, alkyl, alkoxy, halogenalkyl,
  • R 4 is a hydrogen, halogen, alkyl, alkoxy, halogenalkyl, amino, hydroxy, cyano, carbonyl, acyl, nitro, carboxy or sulfonamide, phenyl or benzyl which may be substituted;
  • R 5 is a hydrogen, alkyl, aryl, aralkyl or pyridyl which may be substituted;
  • R 6 is hydrogen or lower alkyl group
  • R 7 is a lower alkyl, phenyl or aralkyl groups;
  • Z 1 is O, S, CH 2 or NR 5 , Z 2 is N or CH and m is an integer of 1 to 4.
  • the main objective of the present invention is therefore, to provide novel ⁇ -aryl- ⁇ -oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, 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 ⁇ -aryl- ⁇ - oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against PPAR ⁇ and/or PPAR ⁇ , and optionally inhibit HMG CoA reductase, in addition to having agonist activity against PPAR ⁇ and/or PPAR ⁇ .
  • Another objective of the present invention is to provide novel ⁇ -aryl- ⁇ - oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, 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, without toxic effect or with reduced toxic effect.
  • Yet another objective of the present invention is a process for the preparation of novel ⁇ -aryl- ⁇ -oxysubstituted alkylcarboxylic acids of formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, 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 analogs, their derivatives, their tautomers, their stereoisomers, their polymorphs, their salts, solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • Another objective of the present invention is to provide novel intermediates, a process for their preparation and their use in the preparation of ⁇ -aryl- ⁇ -oxysubstituted alkyl carboxylic acids of formula (I), their derivatives, their analogs; their tautomers, their stereoisomers, their polymorphs, their salts and their pharmaceutically acceptable solvates.
  • R represents hydrogen atom, halogen, hydroxy, lower alkyl, alkoxy, substituted or unsubstituted aralkyl group or forms a bond together with the adjacent group R 2 ;
  • R 2 represents hydrogen, hydroxy, halogen, lower alkyl, alkoxy, alkanoyl, aroyl, aralkanoyl, substituted or unsubstituted aralkyl or R 2 forms a bond together with R 1 ;
  • R 3 may be hydrogen atom or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, alkanoyl, aroyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups, with a provision that R 3 does not represent hydrogen when R 4 represents hydrogen or lower alkyl group;
  • X represents O or S
  • R ⁇ when attached to the carbon atom represents hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl, aroyl, alkanoyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxy carbonylamino,
  • R and R when attached to carbon atom may be same or different and represent hydrogen, halogen, hydroxy, cyano, nitro, formyl or substituted or unsubstituted groups selected from alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxyalkyl, thioalkyl, alkylthio groups;
  • R and R when attached to nitrogen may be same or different and represent hydrogen, hydroxy or substituted or unsubstituted groups selected from alkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, arylamino groups.
  • Suitable groups represented R 1 may be selected from hydrogen, hydroxy, halogen atom such as fluorine, chlorine, bromine or iodine; lower alkyl groups such as methyl, ethyl, propyl and the like; ( -C 3 )alkoxy such as methoxy, ethoxy, propoxy and the like; substituted or unsubstituted aralkyl such as benzyl, phenethyl and the like or R 1 together with R 2 represent a bond.
  • the substituents may be selected from hydroxy, halogen atom, nitro or amino groups.
  • Suitable groups represented R 2 may be selected from hydrogen, hydroxy, halogen atom such as fluorine, chlorine, bromine, iodine; lower alkyl groups such as methyl, ethyl, propyl and the like; ( -C 3 )alkoxy such as methoxy, ethoxy, propoxy and the like; linear or branched (C 2 -C 10 )alkanoyl group such as acetyl, propanoyl, butanoyl, pentanoyl and the like; aroyl such as benzoyl, substituted benzoyl and the like; aralkanoyl groups such as phenylacetyl, phenylpropanoyl and the like; substituted or unsubstituted
  • R and R represent hydrogen atom or R and R together represent a bond.
  • Suitable groups represented by R 3 may be selected from hydrogen, substituted or unsubstituted, linear or branched (C C ⁇ 6 )alkyl, preferably ( - C 12 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; substituted or unsubstituted, linear or branched(C -C 16 )alkanoyl group such as acetyl, propanoyl, butanoyl, octanoyl, decanoyl and the like; aroyl such as benzoyl, substituted benzoyl and the like; (C 3 -C 7 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, the cyclo
  • the substituents may be selected from halogen, hydroxy or nitro or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, alkanoyl, alkanoyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.
  • Suitable groups represented by R 4 may be selected from hydrogen, substituted or unsubstituted, linear or branched (CrC 16 )alkyl, preferably (
  • C 12 alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; (C 3 -C 7 )cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl group such as benzyl, phenethyl and the like, the aralkyl group may be substituted; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl and the like, the heterocycl
  • Suitable groups represented by R 5 may be selected from hydrogen, substituted or unsubstituted, linear or branched (CrC 16 )alkyl, especially, ( - C 12 )alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, lieptyl, octyl and the like; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; hydroxy(C ⁇ -C 6 )alkyl, which may be substituted; substituted or unsubstituted, linear or branched(C 2 -C 6 )alkanoyl group such as acetyl, propanoyl, butanoyl and the like; aralkyl group such as benzyl,
  • the substituents may be selected from halogen, hydroxy, amino, nitro or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, aryl, aralkyl group.
  • Suitable ring structures formed by R 4 and R 5 together may be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolinyl, diazolinyl and the like.
  • Suitable substituents on the cyclic structure formed by R 4 and R 5 taken together may be selected from halogen, hydroxy, alkyl, oxo, aralkyl and the like.
  • Suitable n is an integer ranging from 1 to 4, preferably n represents an integer of 1 or 2.
  • Suitable groups represented by Ar include substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyridyl, quinolinyl, benzo furyl, dihydrobenzo furyl, benzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like.
  • the substituents on the group represented by Ar may be selected from optionally halogenated substituted or unsubstituted linear or branched (C ⁇ -C )alkyl, optionally halogenated ( -C 3 )alkoxy, halogen, alkanoyl, amino, acylamino, thio or carboxylic or sulfonic acids and their derivatives.
  • Ar represents substituted or unsubstituted divalent phenylene, naphthylene, benzofuryl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl.
  • Ar is represented by divalent phenylene or naphthylene, which may be substituted or unsubstituted by methyl, halomethyl, methoxy or halomethoxy groups.
  • Suitable groups represented by R 6 when attached to carbon atom may be selected from hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro, formyl; substituted or unsubstituted ( - C 12 )alkyl group, especially, linear or branched (Ci-C 10 )alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso- pentyl, hexyl, heptyl, octyl and the like; cyclo(C 3 -C 6 )alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; (C]-C 6 )alk
  • the substituents may be selected from halogen, hydroxy, nitro or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, alkanoyl, alkanoyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives or sulfonic acid or its derivatives.
  • substituents on R represents halogen atom such as fluorine, chlorine, bromine, hydroxy group, optionally halogenated groups selected from alkyl group such as methyl, ethyl, isopropyl, n-propyl, n-butyl; cycloalkyl group such as cyclopropyl; aryl group such as phenyl; aralkyl group such as benzyl; (CrC 3 )alkoxy, benzyloxy, alkanoyl or alkanoyloxy groups.
  • halogen atom such as fluorine, chlorine, bromine, hydroxy group
  • optionally halogenated groups selected from alkyl group such as methyl, ethyl, isopropyl, n-propyl, n-butyl
  • cycloalkyl group such as cyclopropyl
  • aryl group such as phenyl
  • aralkyl group such as benzyl
  • Suitable groups represented by R 6 when attached to nitrogen atom may be selected from hydrogen, hydroxy, formyl; substituted or unsubstituted ( - C 12 )alkyl group, especially, linear or branched ( -C 6 )alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso- pentyl, hexyl and the like; cyclo(C 3 -C 6 )alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; ( -C 6 )alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso- propyloxy and the like, the alkoxy group may be substituted; cycl
  • preferred substituents may be selected from halogen such as fluorine, chlorine; hydroxy, alkanoyl, alkanoyloxy, amino groups.
  • Suitable groups represented by R 7 and R 8 when attached to carbon atom may be selected from hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro, formyl; substituted or unsubstituted (C]-C ⁇ 2 )alkyl group, especially, linear or branched ( -C ⁇ o)alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso- pentyl, hexyl, heptyl, octyl and the like; ( rC 6 )alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, the alkoxy group may be substituted; aryl group such as phenyl, naphthyl and
  • the substituent may be selected from halogen, hydroxy, nitro or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, hydroxyalkyl, amino, arylamino, aminoalkyl, alkylamino, alkoxyalkyl, alkylthio, thioallcyl groups, carboxylic acid or sulfonic acid.
  • R 7 and R 8 represent halogen atom such as fluorine, chlorine or bromine; hydroxy group, optionally halogenated groups selected from alkyl group such as methyl, ethyl, isopropyl, n-propyl, n- butyl and the like; cycloalkyl group such as cyclopropyl; aryl group such as phenyl; aralkyl group such as benzyl; (C C 3 )alkoxy or benzyloxy groups.
  • halogen atom such as fluorine, chlorine or bromine
  • hydroxy group optionally halogenated groups selected from alkyl group such as methyl, ethyl, isopropyl, n-propyl, n- butyl and the like
  • cycloalkyl group such as cyclopropyl
  • aryl group such as phenyl
  • aralkyl group such as benzyl
  • Suitable groups represented by R 7 and R 8 when attached to nitrogen atom may be selected from hydrogen, hydroxy, substituted or unsubstituted (C r C l2 )alkyl group, especially, linear or branched ( -C ⁇ o)alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso- pentyl, hexyl, heptyl, octyl and the like; ( -C 6 )alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, the alkoxy group may be substituted; aryl group such as phenyl and the like, the aryl group may be substituted; aryloxy group such as phenoxy and the like, the aryloxy group may be substituted;
  • NHC 3 H 7 , NHC 6 H 13 and the like which may be substituted; (C r C 6 )dialkylamino group such as N(CH 3 ) , NCH 3 (C 2 H 5 )and the like, which may be substituted; arylamino group such as HNC 6 H 5 , NCH 3 (C 6 H 5 ), NHC 6 H CH 3 , NHC 6 H 4 -Hal and the like, which may be substituted.
  • preferred substituents may be selected from halogen atom such as fluorine, chlorine; hydroxy, alkyl, alkanoyl, alkanoyloxy, amino groups.
  • Pharmaceutically acceptable salts forming part of this invention include salts of the carboxylic acid 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 diethanolamine, choline and the like; chiral bases like alkylphenylamine, phenyl glycinol and the like, salts of natural amino acids such as lysine, arginine, guanidine, methionine, alanine, valine and the like; unnatural amino acids such as D-isomers or substituted amino acids; ammonium or substituted ammonium salts and aluminum 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 diethanolamine, choline and the like
  • chiral bases like alkylphenylamine, phenyl glycinol and the like
  • Salts may include acid addition salts where appropriate 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 present invention includes:
  • Route (1) The reaction of a compound of the general formula (Ilia) where A, Ar and n are as defined earlier with a compound of formula (Illb) where R represents (C 1 -C 6 )alkyl and all other symbols are as defined earlier to yield compound of general formula (I) where all symbols are as defined above may be carried out in the presence of a base such as alkali metal hydrides like NaH or. KH; organolithiums such as CH 3 Li, BuLi and the like; alkoxides such as NaOMe, NaOEt, K + BuO " and the like or mixtures thereof.
  • a base such as alkali metal hydrides like NaH or. KH; organolithiums such as CH 3 Li, BuLi and the like; alkoxides such as NaOMe, NaOEt, K + BuO " and the like or mixtures thereof.
  • the reaction may be carried out in the presence of solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof.
  • HMPA may be used as • cosolvent.
  • the reaction temperature may range from -78 °C to 50 °C, preferably at a temperature in the range of -10 °C to 30 °C.
  • the reaction is more effective under anhydrous conditions.
  • the compound of general formula (Iilb) may be prepared by Arbuzov reaction.
  • the compound of formula (I) may be prepared by reacting the compound of formula (Ilia) where all symbols are as defined earlier with Wittig reagents such as HalTh 3 P + CH-(OR 3 )CO 2 R 4 . under similar reaction conditions as described above.
  • Wittig reagents such as HalTh 3 P + CH-(OR 3 )CO 2 R 4 .
  • Route (2) The reaction of a compound of general formula (IIIc) where A is as defined earlier with a compound of general formula (Hid) where L 1 is a leaving group such as halogen atom, p-toluenesulfonate, methanesulfonate,
  • the reaction may be effected in the presence of a base such as alkalis like sodium hydroxide or potassium hydroxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal hydrides such as sodium hydride or potassium hydride; organometallic bases like n-butyl lithium; alkali metal amides like sodamide or mixtures thereof.
  • the amount of base may range from 1 to 5 equivalents, based on the amount of the compound of formula (IIIc), preferably the amount of base ranges from 1 to 3 equivalents.
  • Phase transfer catalysts such as tetraallcylammonimn halide or hydroxide may be added.
  • Additives such as alkali metal halides such as LiBr may be added.
  • the reaction may be carried out at a temperature in the range of 0 °C to 150 °C, preferably at a temperature in the range of 15 °C to 100 °C.
  • the duration of the reaction may range from 0.25 to 48 hours, preferably from 0.25 to 24 hours.
  • Route (3) The reaction of a compound of the general formula (Ilia) where all symbols are as defined earlier, with a compound of formula (Hie) where R represents hydrogen atom and all other symbols are as defined earlier may be carried out in the presence of a base.
  • the nature of the base is not critical. Any base normally employed for aldol condensation reaction may be employed; bases like metal hydride such as NaH, KH, metal alkoxides such as NaOMe, t-
  • BuO " K + , NaOEt, metal amides such as LiNH 2 ,- LiN(ipr) 2 may be used.
  • Aprotic solvents such as THF, ether, dioxane may be used. The reaction may be
  • Route (4) The reaction of compound of fomiula (Illg) where A and n are as defined earlier and L represents a leaving group such as halogen atom, p- toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like, preferably a halogen atom with compound of formula (Illf) where R 1 and R 2 together represent a bond and all other symbols are as defined earlier to produce a compound of the formula (I) defined above may be carried out in the presence of aprotic solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • aprotic 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, He and the like. ' The reaction may be effected in the presence- of a base such as K2CO3, Na2CO3 or NaH or mixtures thereof. Acetone may be used as solvent when Na 2 CO 3 or K CO 3 is used as a base.
  • the reaction temperature may range from
  • the compound of formula (Illf) can be prepared according to known procedure by a Wittig Horner reaction between the hydroxy protected aryl aldehyde such as benzyloxyaryl aldehyde and compound of formula (nib), followed by deprotection.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar, He and the like.
  • 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.
  • R and R together represent a bond may be carried out neat in the presence of a base such as alkali metal hydrides like NaH, KH or organolithiums like CH 3 Li, BuLi and the like dr alkoxides such as NaOMe, NaOEt, t-BuO " K + and the like or mixtures thereof.
  • the reaction may be carried out in the presence of aprotic solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof.
  • HMPA may be used as cosolvent.
  • the reaction temperature may range from -78 °C to 100 °C, preferably at a temperature in the range of -10 °C to 50 °C.
  • Route 7 The reduction of compound of the formula (IVa) which represents a compound of formula (I) where R 1 and R 2 together represent a bond and Y represent oxygen atoni and all other symbols are as defined earlier, obtained as described earlier(Scheme-I), to yield a compound of the general formula (I) where R 1 and R 2 each represent hydrogen atom and all symbols are as defined
  • the reaction 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, alcohol such as methanol, ethanol and the like. A pressure between atmospheric pressure and 80 psi may be employed.
  • the catalyst may be preferably 5 - 10 % Pd/C and the amount of catalyst used may range from 5 - 100 % w/w.
  • the reaction may also be carried out by employing metal solvent reduction such as magnesium in alcohol or sodium amalgam in alcohol, preferably methanol.
  • the hydrogenation may be carried out in the " presence of metal catalysts containing chiral ligands to obtain a compound of
  • the metal catalyst may contain Rhodium,
  • the chiral ligands may preferably be chiral phosphines such as optically pure enantiomers of 2,3-r bis(diphenylphosphino)butane, l,2-bis(diphenylphosphino)ethane, l,2-bis(2- methoxyphenyl phenylphosphino)ethane, 2,3-isopropylidene-2,3-dihydroxy- l,4-bis(diphenylphosphino) butane and the like. Any suitable chiral catalyst may be employed which would give required optical purity of the product (I)
  • Route 8 The reaction of compound of formula (INb) where R 4 is as defined earlier excluding hydrogen all other symbols are as defined earlier and L 3 is a leaving group such as halogen atom with an alcohol of general formula (INc), where R 3 is as defined earlier excluding hydrogen to produce a compound of the formula (I) defined earlier 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 ⁇ , Ar, He and the like.
  • the reaction may be effected in the presence of a base such as KOH, NaOH, NaOMe, NaOEt, t- BuO " K + or NaH or mixtures thereof.
  • Phase transfer catalysts such ' as tefraalkylammonium halides or hydroxides may be employed.
  • 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 to 12 hours, preferably from 2 to 6 hours.
  • the compound of general formula (INb) where R 4 represents hydrogen or lower alkyl group and its preparation has been disclosed in our US patent ⁇ os. 5,885,997 and 5,985,884.
  • the reaction of compound of formula (Illg) defined earlier with compound of formula (Illf) where all symbols are as defined earlier to produce a compound of the formula (I) defined above 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, He and the like.
  • the reaction may be effected in the presence of a base such as K2CO3, Na2CO3 NaH and the like or mixtures thereof.
  • Acetone may be used as' a solvent when K2CO3 or Na2CO3 is used as a base.
  • the reaction temperature may range from 20 °C - 120 °C, preferably at a temperature in the range of 30 °C - 80
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours.
  • the compound of formula (Illf) may be prepared by Wittig Horner reaction between the protected hydroxy aryl aldehyde and compound of formula (Illb) followed by reduction of the double bond and deprotection. Alternatively, the compound of formula (Illf) may be prepared by following a procedure disclosed in WO 94/01420.
  • Route 10 The reaction of compound of general formula (lllh) defined earlier with a compound of general formula (Illf) where all symbols are as defined above may be carried out using suitable coupling agents such as dicyclohexyl urea, triarylphosphme/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, carbon tetrachloride and the like.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar, He and the like.
  • 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 hi 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 formula (INd) represents a compound of formula (I) where R represents hydrogen atom and all other symbols are as defined earlier.
  • Route 12 The reaction of a compound of the general formula (Ilia) as defined above with a compound of formula (Hie) where R represents hydrogen atom and all other symbols are as defined earlier may be carried out under conventional conditions.
  • the base is not critical. Any base nomially employed for aldol condensation reaction may be employed, metal hydride such as ⁇ aH or KH; metal alkoxides such as ⁇ aOMe, t-BuOT * or ⁇ aOEt; metal amides such as Li ⁇ H 2 , LiN(iPr) 2 .
  • Aprotic solvent such as THF may be used.
  • Inert atmosphere may be employed such as argon and the reaction is more effective under anhydrous conditions.
  • ⁇ -hydroxy aldol product may be dehydroxylated using conventional methods, conveniently by ionic hydrogenation technique such as • by treating with a trialkyl silane in the presence of an acid such as trifluoroacetic acid.
  • Solvent such as CH 2 C1 2 may be used.
  • reaction proceeds at 25 °C. Higher temperature may be employed if the reaction is slow.
  • Route 13 The reaction of a compound of general formula (IIIc) where all symbols are as defined earlier with a compound of general formula (Hid) where L 1 is a leaving group such as halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like, preferably a halogen atom and all other symbols are as defined earlier to produce a compound of general formula (I) where all symbols are as defined above may be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a combination thereof.
  • solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a combination thereof.
  • the reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N 2 , Ar, He and the like.
  • the reaction may be effected in the presence of a base such as alkalis like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate or potassium carbonate; alkali metal hydrides such as sodium hydride or potassium hydride; organometallic bases like n-butyl lithium; alkali metal amides like sodamide or mixtures thereof.
  • the amount of base may range from 1 to 5 equivalents, based on the amount of the compound of fomiula (IIIc), preferably the amount of base ranges from 1 to 3 equivalents.
  • Additives such as alkali metal halides such as LiBr may be added.
  • the reaction may be carried out at a temperature in the range of 0 °C to
  • the reaction may be carried out at a temperature in the range of 0 °C to reflux temperature of the solvent used, preferably at a temperature in the range of 25 °Q to reflux temperature of the solvent used.
  • the duration of the reaction may range from 0.25 to 48 hrs.
  • Route 15 The reaction of a compound of formula (INg) where R is as . defined earlier excluding hydrogen and all symbols are as defined earlier with a compound of fomiula (IVc) where R is as defined earlier excluding hydrogen to produce a compound of formula (I) (by a rhodium carbenoid mediated insertion reaction) may be carried out in the presence of rhodium (II) salts such as rhodium (II) acetate.
  • rhodium (II) salts such as rhodium (II) acetate.
  • the reaction may be carried out in the presence of solvents such as benzene, toluene, dioxane, ether, THF and the like or a combination thereof or when practicable in the presence of R OH as solvent at any temperature providing a convenient rate of formation of the required product, generally at an elevated temperature, - such as reflux temperature of the solvent.
  • solvents such as benzene, toluene, dioxane, ether, THF and the like or a combination thereof or when practicable in the presence of R OH as solvent at any temperature providing a convenient rate of formation of the required product, generally at an elevated temperature, - such as reflux temperature of the solvent.
  • the inert atmosphere may be maintained by using inert gases such as ⁇ 2 , Ar, He and the like.
  • the duration of the reaction may be range from 0.5 to 24 h, preferably from 0.5 to 6 h.
  • the compound of general formula (I) where R 4 represents hydrogen atom may be prepared by hydrolysing using conventional methods, a compound of formula (I) where R 4 represents all groups defined earlier except hydrogen.
  • the hydrolysis may ' be carried out in the presence of a base such as Na 2 CO 3 and a suitable solvent such as methanol, ethanol, water and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 20-120 °C, preferably at 25-30 °C.
  • the reaction time may range from 2 to 48 h, preferably from 4 to 12 h.
  • the compound of general fomiula (I) where Y represents oxygen and R is as defined earlier may be converted to compound of formula (I), where Y represents NR 5 by reaction with appropriate amines.
  • mixed anhydrides may be prepared from compound of formula (I) where YR 4 represents OH and all other symbols are as defined earlier, by treating with acid halides such acetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chloride and the like.
  • the reaction may be carried out in the presence of suitable base such as pyridine. triethylamine, diisopropyl ethylamine and the like. Solvents such as halogenated hydrocarbons like CHC1 3 , CH 2 C1 2 , hydrocarbons such as benzene, toluene, xylene and the like may be used.
  • the reaction may be carried out at a temperature in the range of -40 °C to 40 °C, preferably 0 °C to 20 °C.
  • the acid halide or mixed anhydride thus prepared may further be treated with appropriate amines.
  • R 1 represents hydrogen atom, halogen, hydroxy, lower alkyl, alkoxy, substituted or unsubstituted aralkyl group or forms a bond together with the adjacent group R 2 ;
  • R 2 represents hydrogen, hydroxy, halogen, lower alkyl, alkoxy, alkanoyl, aroyl, aralkanoyl, substituted or unsubstituted aralkyl or R 2 forms a bond together with R 1 ;
  • R 3 may be hydrogen atom or substituted - or unsubstituted groups selected from alkyl, cycloalkyl, aryl, alkanoyl, aroyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups, n is an integer ranging from 1- 4;
  • Ar represents substituted or unsubsti
  • X represents O or S
  • R ⁇ when attached to the carbon atom represents hydrogen, halogen, hydroxy, nitro, cyano, fonnyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl, aroyl, alkanoyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarb ⁇ nyla
  • reaction of a compound of formula (Ilia) where all symbols are as defined earlier with a compound of formula (INh) where R 3 is as defined earlier excluding hydrogen and Hal represent a halogen atom such as Cl, Br, I to produce a compound of formula (INi) where all symbols are defined earlier and R 3 is as defined earlier excluding hydrogen may be carried out under conventional conditions in the presence of a base.
  • the base is not critical. Any base normally employed for Wittig reaction may be employed, metal hydride such as ⁇ aH, KH, metal alkoxides such as ⁇ aOMe, K l BuO " , ⁇ aOEt, metal amides such as Li ⁇ H 2 , LiN(iPr) 2 .
  • Aprotic solvent such as THF, DMSO, dioxane, DME and the like may be used. Mixture of solvents may be used. HMPA may be used as cosolvent. Inert atmosphere may be employed such as argon and the reaction is more effective under anhydrous conditions. Temperature in the range of -80 °C to 100 °C may be used.
  • the compound of fomiula (INi) where all symbols are as defined earlier and R 3 is as defined earlier excluding hydrogen may be converted to a compound of formula (INj) where all symbols are as defined earlier, by treating with an alcohol under anhydrous conditions in the presence of a strong anhydrous acid such as p-toluenesulfonic acid.
  • a strong anhydrous acid such as p-toluenesulfonic acid.
  • the compound of formula (INj) defined above upon treatment with trialkylsilyl cyanide such as trimethylsilyl cyanide produces a compound of formula (INf) where all symbols are as defined earlier.
  • R 1 represents hydrogen atom,- halogen, hydroxy, lower alkyl, alkoxy, substituted or unsubstituted aralkyl group
  • R 4 may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups
  • n is an integer ranging from 1- 4
  • Ar represents substituted or unsubstituted, divalent, single or fused, aromatic or heterocychc group
  • A represents a cyclic structure given below :
  • R6 when attached to the carbon atom represents hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkanoyl, aroyl, alkanoyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, ary
  • R 2 is hydrogen atom and all other symbols are as defined earlier, with an appropriate diazotizing agent.
  • the diazotization reaction may be under conventional conditions.
  • a suitable diazotizing agent is an alkyl nitrile, such as iso-amyl nitrile.
  • the reaction may be carried out in presence of solvents such as THF, dioxane, ether, benzene and the like or a combination thereof. Temperature in the range of -50 °C to 80 °C may be used.
  • 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 duration of the reaction may range from 1 to 24 h, preferably, 1 to 12 h.
  • the compound of formula (INk) may also be prepared by a reaction between (IIHi) where all symbols are as defined earlier and a compound of formula (INI)
  • R 2 is hydrogen atom and all other symbols are as defined earlier.
  • reaction of compound of formula (lllh) where all symbols are as defined earlier and a compound of formula (INI) where all symbols are as defined earlier may be carried out in the presence of solvents such as THF,
  • the reaction may be carried out in an inert atmosphere which is maintained by using inert gases such as N2, Ar or He.
  • the reaction may be effected in the presence of a base such as K2CO3, Na2CO3 or NaH or mixtures thereof.
  • Acetone may be used as a solvent when K2CO3 or Na2CO3 is used as a base.
  • 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 to 24 hours, preferably from 2 to 12 hours.
  • any reactive group in the substrate molecule may be protected according to conventional chemical practice.
  • Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the pharmaceutically acceptable salts are prepared by reacting the compounds of formula (I) wherever applicable 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, tromethamine, guanidine and their derivatives etc. may also be used.
  • acid addition salts wherever applicable 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, benzenesulfonic 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, ascorbic
  • 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 wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
  • polymorphs of compounds of general formula (I) and (Illm) fonning 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 crystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorrmetry, powder X- ray diffraction or such other techniques.
  • the present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, 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 diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of familial hypercholesterolemia, hypertriglyceridemia, lowering of atherogenic lipoproteins, NLDL and LDL.
  • the compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy.
  • the compounds of general formula (I) are also useful for the treatment / prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease, and other cardiovascular disorders.
  • These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma and for the treatment of cancer.
  • PCOS polycystic ovarian syndrome
  • the compounds of the present inventions are useful in the treatment and / or prophylaxis of the above said diseases in combination / concomittant with one or more HMG CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol.
  • HMG CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol.
  • the compounds of the present invention in combination with HMG CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents can be administered together or within such a period to act synergistically.
  • the HMG CoA reductase inhibitors may be selected from those used for the treatment or prevention .of hyperiipidemia such as lovastatin, provastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin and their analogs thereof.
  • Suitable f ⁇ bric acid derivative may be gemfibrozil, clofibrate, fenofibrate, ciprofibrate, benzafibrate and their analogs thereof.
  • 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 20 %, preferably 1 to 10 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • 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 absorption following oral administration is impaired, as by disease or other abnormality, it is essential that the drag be administered parenterally.
  • the dosage is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 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 salts with base 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.
  • Nitrating agent was prepared by adding 90 % nitric acid (7.18 mL) to concentrated sulphuric acid (13.8 mL) at 75-78 °C.
  • l-Methyl-3-propyl-lH-5- pyrazole carboxylic acid (11.5 g, 68.4 mmol) obtained in preparation 3, was added to the nitrating agent portion wise with stirring so that the temperature is maintained at ⁇ 85 °C. After the complete addition, the mixture was heated at 100 °C for 2 h. The reaction mixture was cooled and poured into crashed ice. The suspension was filtered cold (10 °C) and the solids were washed with ice cold brine and dried to yield the title compound (5.0 g, 34 %).
  • the reaction mixture was stirred at room temperature for 8 h, diluted with water and extracted with ethyl acetate (3 X 10 mL). The combined organic extracts were washed with water, brine, dried ( ⁇ a 2 SO 4 ) and evaporated to dryness.
  • the title compound (150 mg, 68 %) was obtained by purifying over silica gel column using 20 % ethyl acetate in pet. ether as eluent, mp 112 °C.
  • the compounds of the present invention lowered random blood sugar level, triglyceride, total cholesterol, LDL, NLDL and increased HDL. This was demonstrated by in vitro as well as in vivo animal experiments.
  • Ligand binding domain of hPPAR ⁇ was fused to D ⁇ A binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector.
  • superfect Qiagen, Germany
  • HEK-293 cells were transfected ith this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter.
  • Compound was added at different concentrations after 42 hrs of transfection and incubated overnight.
  • Luciferase activity as a function of compound binding/activation capacity of PPAR ⁇ was measured using Packard Luclite kit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Ho His. Gene. 1992. 118 : 137 —141; Superfect Transfection Reagent Handbook. February 1997. Qiagen, Germany).
  • hPPAR ⁇ activity Ligand binding domain of hPPAR ⁇ l was fused to DNA binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector. Using lipofectamine (Gibco BRL, USA) as transfecting reagent HEK-293 cells were transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter. Compound was added at 1 ⁇ M concentration after 48 hrs of transfection and incubated overnight.
  • Luciferase activity as a function of drug binding/activation capacity of PPAR ⁇ 1 was measured using Packard Luclite kit (Packard, USA) in Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 118 : 137 —141; Guide to Eukaryotic Transfections with Cationic Lipid Reagents. Life Technologies, GIBCO BRL, USA).
  • Liver microsome bound reductase was prepared from 2% cholestyramine fed rats at mid-dark cycle. Spectrophotometric assays were carried out in 100 mM KH 2 PO 4 , 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 ⁇ g of liver microsomal enzyme. Total reaction mixture volume was kept as 1 ml. Reaction was started by addition of HMG CoA. Reaction mixture was incubated at 37 °C for 30 min and decrease in absorbance at 340 nm was recorded. Reaction mixture without substrate was used as blank (Goldstein, J. L and Brown, M. S. Progress in understanding the LDL receptor and HMG CoA reductase, two membrane proteins that regulate the plasma cholesterol. J. Lipid Res. 1984, 25: 1450 - 1461). The test compounds inhibited the HMG CoA reductase enzyme.
  • 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.
  • mice of 8 to 14 weeks age having body weight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animal house, were used in the experiment.
  • the mice were provided with standard feed (National Institute of Nutrition (NIN), India) and acidified water, ad libitum.
  • the animals having more than 350 mg / dl blood sugar were used for testing.
  • the number of animals in each group was 4.
  • Test compounds were suspended on 0.25 % carboxymethyl cellulose and administered to test group at a dose of 0.001 mg to 30 mg / kg through oral gavage daily for 6 days.
  • the control group received vehicle (dose 10 ml / kg). On 6th day the blood samples were collected one hour after administration of test compounds ' / vehicle for assessing the biological activity.
  • 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 spectromexrically, by glucose oxidase and glycerol-3-PO 4 oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits, India) methods respectively.
  • the blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula. No adverse effects were observed for any of the mentioned compounds of invention in the above test.
  • mice were obtained at 5 weeks of age from Bomholtgard,
  • test compounds were administered at 0.1 to 30 mg/kg/day dose for the test compounds.
  • the blood samples were collected in fed state 1 hour after drug administration on 0 and 9 day of treatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for triglyceride, glucose, free fatty acid, total cholesterol and insulin estimations. Measurement of plasma triglyceride, glucose, total cholesterol were done using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division kits, Hyderabad, India).
  • the plasma free fatty acid was measured using a commercial kit form Boehringer Mannheim, Germany.
  • the plasma insulin was measured using a RIA kit (BARC, India). The reduction of various parameters exammed are calculated according to the formula.
  • mice oral glucose tolerance test was performed after 9 days treatment. Mice were fasted for 5 hrs and challenged with 3 gm/kg of glucose orally. The blood samples were collected at 0, 15, 30, 60 and 120 min for estimation of plasma glucose levels.
  • mice Male Sprague Dawley rats (NIN stock) were bred in DRF animal house. Animals were maintained under 12 hour light and dark cycle at 25 ⁇ 1 °C. Rats of 180 - 200 gram body weight range were used for the experiment. Animals were made hypercholesterolemic by feeding 2% cholesterol and 1% sodium cholate mixed with standard laboratory chow [National Institute of Nutrition (NIN), India] for 6 days. Throughout the experimental period the animals were maintained on the same diet (Petit, D., Bonnef ⁇ s, M. T., Rey, C and Infante, R. Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normo- and hyperlipidemic rats. Atherosclerosis. 1988. 74 : 215 - 225).
  • test compounds were administered orally at a dose 0.1 to 30 mg/kg/day for 3 days.
  • Control group was treated with vehicle alone (0.25 % Carboxymethylcellulose; dose 10 ml/kg).
  • the blood samples were collected in fed state 1 hour after drag administration on 0 and 3 day of compound treatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for total cholesterol, HDL and triglyceride estimations. Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India). LDL and NLDL cholesterol were calculated from the data obtained for total cholesterol, HDL and triglyceride. The reduction of various parameters examined are calculated according to the formula. CHOLESTEROL LOWERING ACTIVITY IN MALE SPRAGUE
  • SAM Male Swiss albino mice
  • Male Guinea pigs were obtained from NIN and housed in DRF animal house. All these animals were maintained under 12 hour light and dark cycle at 25 + 1 °C. Animals were given standard laboratory chow (NIN, India) and water, . ad libitum. SAM of 20 - 25 g body weight range and Guinea pigs of 500 - 700 g body weight range were used (Oliver, P., Plancke, M. O., Marzin, D., Clavey, V., Sauzieres, J and Fruchart, J. C. Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levels in normal and hyperlipidemic mice. Atherosclerosis. 1988. 70 : 107 - 114).
  • test compounds were administered orally to Swiss albino mice at 0.3 to 30 mg/kg/day dose for 6 days. Control mice were treated with vehicle (0.25% Carboxymethylcellulose; dose 10 ml/kg). The test compounds were administered orally to Guinea pigs at 0.3 to 30 mg/kg/day dose for 6 days. Control animals were treated with vehicle (0.25% Carboxymethylcellulose; dose 5 ml/kg).
  • the blood samples were collected in fed state 1 hour after drug administration on 0 and 6 day of treatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample .was separated for triglyceride and total cholesterol (Wieland, O. Methods of Enzymatic analysis. Bergermeyer, H. O., Ed., 1963. 211 - 214; Trinder, P. Ann. Clin. Biochem. 1969. 6 : 24 - 27).
  • Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Reddy's Diagnostic Division, India).
  • NLDL cholesterol in mg/dl [Total cholesterol - HDL cholesterol - LDL cholesterol] mg/dl.

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US7223761B2 (en) 2003-10-03 2007-05-29 Amgen Inc. Salts and polymorphs of a potent antidiabetic compound
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
EP1793828A4 (en) * 2004-09-06 2009-09-02 Reddys Lab Ltd Dr FIBRATE CONNECTION WITH PRAR AGONIST ACTIVITY
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