WO2003053974A1 - Nouveaux composes et leur utilisation en medecine, procede de preparation de ceux-ci et compositions pharmaceutiques les contenant - Google Patents

Nouveaux composes et leur utilisation en medecine, procede de preparation de ceux-ci et compositions pharmaceutiques les contenant Download PDF

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WO2003053974A1
WO2003053974A1 PCT/IB2002/005442 IB0205442W WO03053974A1 WO 2003053974 A1 WO2003053974 A1 WO 2003053974A1 IB 0205442 W IB0205442 W IB 0205442W WO 03053974 A1 WO03053974 A1 WO 03053974A1
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substituted
compound
formula
alkyl
aralkyl
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PCT/IB2002/005442
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Saibal Kumar Das
Debnath Bhuniya
Gurram Ranga Madhavan
Javed Iqbal
Ranjan Chakrabarti
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Dr. Reddy's Laboratories Ltd.
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Priority to AU2002348829A priority Critical patent/AU2002348829A1/en
Priority to US10/499,852 priority patent/US20050096331A1/en
Publication of WO2003053974A1 publication Critical patent/WO2003053974A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers

Definitions

  • the present invention relates to novel antidiabetic, hypolipidemic, 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 alkyl carboxylic acids of the general formula (I), 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.
  • the present invention also relates to a process for the preparation of the above said compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
  • the present invention also relates to novel intermediates, processes for their preparation, their use in the preparation of compounds of formula (I) and their use as antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds.
  • 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 hyperlipidemia, hyperglycemia, hypercholesterolemia, lowering of atherogenic lipoproteins, VLDL (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 leptin resistance, 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 inhibitor; cholesterol absorption inhibitor; antiobesity drug; lipoprotein disorder treatment drug; hypoglycemic agent; insulin; biguanide; sulfonylurea; thiazolidinedione; dual PPAR ⁇ and ⁇ agonists or a mixture thereof.
  • Atherosclerosis and other peripheral vascular diseases effect the quality of life of millions of people. Therefore, considerable attention has been directed towards understanding the etiology of hypercholesterolemia and hyperlipidemia and development of effective therapeutic strategies.
  • 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. There is clearly a definite cause and effect-relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most of the cholesterol is present in the esterif ⁇ ed forms with various lipoproteins such as Low density lipoprotein (LDL), Intermediate density lipoprotein (IDL), High density lipoprotein (HDL) and partially as Very low density lipoprotein (VLDL).
  • LDL Low density lipoprotein
  • IDL Intermediate density lipoprotein
  • HDL High density lipoprotein
  • VLDL Very low density lipoprotein
  • HDL hypercholesterolemia and coronary heart diseases
  • Obesity is a disease highly prevalent in affluent societies and in the developing world and is a major cause of morbidity and mortality. It is a state of excess body fat accumulation. The causes of obesity are unclear. It is believed to be of genetic origin or promoted by an interaction between the genotype and environment. Irrespective of the cause, the result is fat deposition due to imbalance between the energy intake versus energy expenditure. Dieting, exercise and appetite suppression have been a part of obesity treatment. There is a need for efficient therapy to fight this disease since it may lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility and many other psychological and social problems. Diabetes and insulin resistance is yet another disease which severely effects the quality of large population in the world.
  • 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 raises 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., 75 (1985) 809 - 817; N. Engl. J. Med 317 (1987) 350-357; J. Clin. Endocrinol. Metab., 66 (1988) 580 - 583; J. Clin. Invest., 68 (1975) 957 - 969) and other renal complications (patent publication No.
  • Hyperlipidemia is the primary cause for cardiovascular (CVD) and other peripheral vascular diseases.
  • High risk of CVD is related to the higher LDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) seen in hyperlipidemia.
  • LDL Low Density Lipoprotein
  • VLDL Very Low Density Lipoprotein
  • Patients having glucose intolerance/insulin resistance in addition to hyperlipidemia have higher risk of CVD.
  • Numerous studies in the past have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and VLDL 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, 135 (1994) 798-800) and energy homeostasis (Cell, 83 (1995) 803-812), whereas the alpha, ( ⁇ ) isoform of PPAR (PPAR ⁇ ) mediates fatty acid oxidation (Trend. Endocrin. Metab., 4 (1993) 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol. 5 (1995) 618 - 621).
  • PPAR ⁇ agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that compounds which are agonists for both PPAR ⁇ and PPAR ⁇ are suggested to be useful for the treatment of syndrome X (WO 97/25042). Similar effect between the insulin sensitizer (PPAR ⁇ agonist) and HMG CoA 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, 87 (1996) 377-389). Ligand activation of PPAR is sufficient to cause complete terminal differentiation (Cell, 79 (1994) 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 and 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. Sci, 94 (1997) 237-241) and inhibition of expression of prostate cancer tissue (Cancer Research 58 (1998) 3344-3352). This would be useful in the treatment of certain types of cancer, which express PPAR ⁇ and could lead to a quite nontoxic chemotherapy.
  • 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 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).
  • X represents O or S ;
  • the groups Rl, R ⁇ and group R ⁇ 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, alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbon
  • Ar 1 and Ar 2 are independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylcyclenyl or fused heteroarylheterocyclyl;
  • B is O, S, NR 19 , a chemical bond, C(O), N(R 20 )C(O) or C(O)N(R 20 );
  • E is a chemical bond or an ethylene group;
  • a is 0-6;
  • b is 0-4;
  • c is
  • R a represents 2-benzoxazolyl or 2-pyridyl and R D represent CF3, CH2OCH3 or CH3.
  • R D 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 (II f).
  • X-Y-Z-Aryl-A-B (II k) aryl is a 6 membered aromatic ring containing 0, 1, 2 or 3 nitrogen atoms and either unsubstituted or substituted with R 8 and R 9 ;
  • Y is selected from Co- 8 alkyl, C 4 _ ⁇ o cycloalkyl, Co- 8 alkyl-NR 3 -CO-Co-8 alkyl, Co.
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are independently selected from hydrogen, fluorine, (C ⁇ - 8 ) alkyl, hydroxy, hydroxy(C ⁇ - 6 ) alkyl, carboxy(Co-6)alkyl, (C ⁇ -6)alkyloxy, aryl(Co- 6 )alkyloxy, (C 3 - 8 )cycloalkyl, aryl(Co- 6 )alkyl, (C ⁇ - 6 )alkylcarbonyloxy, (Co- 6 )alkylamino(Co- 6 )alkyl and the like;
  • R 12 is selected from hydroxy, (C ⁇ - 8 ) alkyloxy, aryl (Co- 6 ) alkyl and the like; An example of these compounds is shown in formula (II 1)
  • R 1 is chosen from hydrogen, C ⁇ - 6 alkyl, aryl C 4 - ⁇ o alkyl, aryl, carboxy, C ⁇ - 6 alkyloxy, carboxy Co- 6 alkyl, carboxy C ⁇ - 6 alkyloxy, hydroxy Co-6 alkyl, C ⁇ - 4 alkylsulfonyl Co-6 alkyl, Co- 4 alkylamino Co-6 alkyl, aryl Co-io alkylamino Co-6 alkyl, C2-10 acylamino Co-6 alkyl, - carboalkoxy Co- 6 alkyl halogen, R 2 is independently chosen from hydrogen, halogen, hydroxy, C ⁇ - 6 alkyl, wherein the alkyl group is substituted or unsubstituted, Ci- 6 alkyloxy, aryl Co- 4 alkyl, aryl Co- 6 alkyloxy and the like; R 3 hydrogen, -6 alkyl, aryl Ci- ⁇ o alkyl; Z is NR R
  • Another objective of the present invention is to provide novel alkyl carboxylic 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
  • Another objective of the present invention is to provide novel alkyl carboxylic 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
  • Yet another objective of the present invention is to provide a process for the preparation of alkyl carboxylic 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 use of the intermediates in processes for preparation of allcyl carboxylic acids of formula (I), their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their salts and their pharmaceutically acceptable solvates and their use as antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds.
  • R represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, alkanoyloxy, aroyl, aralkanoyl, heterocyclyl, heteroaryl, heteroaralkyl groups or (C ⁇ -C ⁇ 2 )alkylcarboxylic acid or its derivative
  • R and R , R , 10 when attached to carbon atom may be same or different and represent 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, alkanoylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbon
  • Suitable groups represented by R 1 may be selected from hydrogen, hydroxy, ( - C 6 ) alkyl groups such as methyl, ethyl, propyl and the like; (Ci-C ⁇ ) alkoxy such as methoxy, ethoxy, propoxy and the like; halogen atom such as fluorine, chlorine, bromine or iodine; (C 2 -C ⁇ o) alkanoyl group such as acetyl, propanoyl, butanoyl, pentanoyl, benzoyl and the like; aralkyl such as benzyl, phenethyl and the like, which may be unsubstituted or substituted or R 1 together with R 7 forms a bond.
  • the substituents are selected from halogen, hydroxy or alkyl groups.
  • Suitable groups represented by R 2 may be selected from hydrogen, hydroxy, halogen atom such as chlorine, bromine, iodine or fluorine; linear or branched (Cj-Cie) alkyl, preferably (C ⁇ -C ⁇ 2 ) alkyl group such as methyl, ethyl, 72-propyl, z-propyl, n-butyl, i- butyl, pentyl, hexyl, heptyl, octyl and the like, the alkyl group may be substituted; (Q- C ⁇ o)alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy, hexyloxy, octyloxy and the like, which may be substituted; (C 3 -C 7 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
  • 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 arakyl group may be substituted; aryloxy group such as phenoxy, naphthyloxy and the like, the aryloxy group may be substituted; aralkoxy group such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy and the like, the aralkoxy group may be substituted; heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl and the like, the heteroaryl group may be substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; heteroaryloxy and heteroaralkoxy, where
  • the substituents may be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, alkanoyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives or sulfonic acid or its derivatives.
  • Suitable groups represented by R 3 may be selected from hydrogen, linear or branched (C ⁇ -C ⁇ 6 )alkyl, preferably (C ⁇ -C ⁇ 2 )alkyl group such as methyl, ethyl, ?z-propyl, i- propyl, 7z ⁇ butyl, z ' -butyl, pentyl, hexyl, heptyl, octyl and the like, the alkyl group may be substituted; (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; heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl and the like, the heteroaryl group may be substituted; heteroaral
  • the substituents on R may be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, alkanoyl, alkanoyloxy, hydroxyalkyl, amino, alkanoylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives such as amides, like CONH 2 , CONHMe, CONMe 2 , CONHEt, CONEt 2 , CONHPh and the like, or esters such as COOCH 3 , COOC 2 H 5 , COOC 3 H 7 and the like, the carboxylic acid derivatives
  • Suitable groups represented by R 4 , R 5 and R 6 may be selected from hydrogen, substituted or unsubstituted linear or branched (Ci-Cie) alkyl, preferably (C ⁇ -C ⁇ 2 ) alkyl group such as methyl, ethyl, 7i-propyl, /-propyl, n-butyl, /-butyl, pentyl, hexyl, heptyl, octyl and the like; hydroxy(C ⁇ -Ce) alkyl such as hydroxymethyl, hydroxyethyl, hydroxybutyl and the like; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl group such as benzyl, phenethyl, phenyl propyl, phenyl butyl, phenyl pentyl, phenyl hexyl, phenyl hepty
  • 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, hydroxyalkyl, amino, arylamino, aminoalkyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives such as amides, like CONH 2 , CONHMe, CONMe 2 , CONHEt, CONEt 2 , CONHPh and the like, or esters such as COOCH 3 , COOC 2 H 5 , COOC 3 H 7 and the like, the carboxylic acid derivatives may be substituted; sulfonic acid or its derivatives such as SO 2 NH 2 , SO 2 NHMe,
  • Suitable ring structures formed by R 3 and R 4 together may be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like.
  • Suitable groups represented by R 7 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 ⁇ -C 3 )alkoxy such as methoxy, ethoxy, propoxy and the like; substituted or unsubstituted aralkyl such as benzyl, phenethyl and the like or R 7 together with R 1 represents a bond.
  • the substituents may be selected from hydroxy, halogen atom, nitro or amino groups.
  • Suitable groups represented by R 8 , R 9 and R 10 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 (Q- C ⁇ o)alkyl group, such as methyl, ethyl, n-propyl, z ' -propyl, «-butyl, /-butyl, t-butyl, n- pentyl, /-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 ⁇ -Ce
  • 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, thioalkyl groups, carboxylic acid or sulfonic acid.
  • Suitable groups represented by Ar may be selected from substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like.
  • the substituents on the group represented by Ar may be selected from linear or branched optionally halogenated (C ⁇ -C 6 )alkyl, optionally halogenated (C ⁇ -C 3 )alkoxy, halogen, acyl, amino, acylamino, thio or carboxylic or sulfonic acids and their derivatives.
  • the substituents are defined as they are for R 8 -R 10 .
  • Ar represent substituted or unsubstituted divalent, phenylene, naphthylene, benzofuryl, pyrrolyl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups.
  • Suitable n is an integer ranging from 1-4.
  • Suitable m and p are integers ranging from 0-4.
  • salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, betaine, caffeine, 2- diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, theobromine, glycinol, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, adamentyl amine, diethanolamine, meglumine, ethylenediamine, N,N'-diphenylethylenediamine, N,N'- dibenzylethylenediamine, N-benzy
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succmates, palmoates, methanesulfonates, 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 include :
  • the compounds of general formula (I) where Y represents C ⁇ R 7 group, R 7 and R 1 together represent a bond, G is O or S; Z represents oxygen atom; and all other symbols are as defined earlier, can be prepared by any of the following routes shown in Scheme-I below.
  • Route 1 The reaction of a compound of the general formula (Ilia) where all symbols are as defined earlier with a compound of formula (Illb) where R 11 represents (C ⁇ -C 6 )alkyl, R represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and all other symbols are as defined earlier to yield compound of general formula (I) where R 2 represents substituted or unsubstituted groups selected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and all other symbols are as defined above may be carried out in the presence of a base such as alkali metal hydrides like NaH or KH; organohthiums such as LDA, TMEDA and the like; alkoxides such as NaOMe, NaOEt, t-BuO " K + and the like or mixtures thereof.
  • a base such as alkali metal hydrides like NaH or KH
  • 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 (Illb) 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 Ha ⁇ " Ph 3 P + CH-(OR)CO 2 R 3 under similar reaction conditions as described above.
  • the reaction may be carried out in an inert atmosphere that may be maintained by using inert gases such as N 2 , argon, He and the like.
  • 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, organic base like triethyl amine 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 tetraalkylammonium 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 - 150 °C, preferably at a temperature in the range of 15 °C - 100 °C.
  • the duration of the reaction may range from 0.25 to 72 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 (Ille) where R 1 represents hydrogen atom and all other symbols are as defined earlier may be carried out in the presence of a base.
  • 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 carried out in an inert atmosphere that may be maintained by using inert gases such as N 2 , Ar, or He and the reaction is more effective under anhydrous conditions. Temperature in the range of -80 °C to 35 °C may be used.
  • the ⁇ -hydroxy product initially produced may be dehydrated under conventional dehydration conditions such as treating with p-TSA in solvents such as benzene or toluene.
  • solvents such as benzene or toluene.
  • the nature of solvent and dehydrating agent is not critical.
  • Temperature in the range of 20 °C to reflux temperature of the solvent used may be employed, preferably at reflux temperature of the solvent by continuous removal of water using a Dean-Stark water separator.
  • R and R 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.
  • the reaction may be carried out in an inert atmosphere that 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 K 2 CO 3 , Na 2 CO 3 or NaH or mixtures thereof.
  • Acetone may be used as solvent when Na 2 CO 3 or K 2 CO 3 is used as a base.
  • the reaction temperature may range from 0 °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 48 hours, preferably from 2 to 12 hours.
  • the compound of formula (Hit) can be prepared according to a known procedure by Wittig Homer reaction between the hydroxy protected aryl aldehyde such as benzyloxyaryl aldehyde and compound of formula (Illb), followed by deprotection.
  • Route 5 The reaction of compound of general formula (Illh) where A is as defined earlier and Hal represents halogen atom such as chlorine, bromme, fluorine or iodine, with compound of formula (Illi) where R 1 and R together represent a bond and all other symbols are as defined earlier to yield the 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; organohthiums such as TMEDA, LDA and the like; alkoxides such as NaOMe, NaOEt, t-BuO " K and the like or mixtures thereof.
  • a base such as alkali metal hydrides like NaH or KH
  • organohthiums such as TMEDA, LDA and the like
  • alkoxides such as NaOMe, NaOEt, t-BuO " K 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.
  • the reaction temperature may range from -78 °C to 120 °C, preferably at a temperature in the range of -10 °C to 80 °C.
  • the reaction is more effective under anhydrous conditions.
  • Route 6 The reaction of compound of general formula (IIIj) where all symbols are as defined earlier with a compound of general formula (lllf) where R 1 and R 7 together represent a bond and all other symbols are as defined earlier may be carried out using suitable coupling agents such as EDCI, dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPh 3 / DEAD or DIAD and the like.
  • the reaction may be carried out in the presence of solvents such as THF, DME, CH 2 C1 2 , CHCI3, 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 -20 °C to 100 °C, preferably at a temperature in the range of 0 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
  • the above condensation may also be made using mixed anhydride methodology.
  • Route 7 The reaction of a compound of formula (Illk) where all symbols are as defined earlier with a compound of formula (III1) where R represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and where R 3 is as defined earlier excluding hydrogen to yield compound of general formula (I) where R 2 represents substituted or unsubstituted groups selected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and all other symbols are as defined above may be carried out neat in the presence of a base such as alkali metal hydrides like NaH, KH or organohthiums like CR_Li, BuLi, TMEDA, LDA and the like or alkoxides such ' as NaOMe, NaOEt, t-BuO " K + and the like or mixtures thereof.
  • a base such as alkali metal hydrides like NaH, KH or organohthiums like
  • 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. The reaction is more effective under anhydrous condition.
  • Route 8 The compound of general formula (IIIc) where B represents pyrazolopyrimidine or imidazolopyrimidine of the formula given below : .
  • enol form reacts with compound of general formula (Illm) which represents compound of formula (Illi) when G represents oxygen, R 1 and R 7 together represent a bond and all other symbols are as defined earlier to produce compound of formula (I) where all symbols are as defined above.
  • suitable coupling agents such as EDCI, dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPI1 3 / DEAD or DIAD 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, carbon tetrachloride and the like.
  • solvents such as THF, DME, CH 2 C1 2 , CHCI 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 -20 °C to 100 °C, preferably at a temperature in the range of 0 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 120 hours, preferably from 6 to 24 hours.
  • X, R 2 , R 3 , n, Ar and A are as defined earlier, G is O or S and Z represents oxygen atom
  • G is O or S and Z represents oxygen atom
  • Route 9 The reduction of compound of the formula (INa) which represents a compound of formula (I) where R 1 and R 7 together represent a bond and Z represents oxygen atom 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 5 each represent hydrogen atom and all symbols are as defined earlier, may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd(OH) 2 /C, Pd/C, Rh C, Pt/C, Ra- ⁇ i, and the like. Mixtures of catalysts may be used.
  • a catalyst such as Pd(OH) 2 /C, Pd/C, Rh C, Pt/C, Ra- ⁇ i, and the like. Mixtures of catalysts may be used.
  • the reaction may be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate, 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 reaction temperature may range from 20 °C - 120 °C, preferably at a temperature in the range of 25 °C - 100 °C.
  • the duration of the reaction may range from 1 to 48 hours, preferably from 2 to 6 hours.
  • the hydrogenation may be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of formula (I) in optically active form.
  • the metal catalyst may contain Rhodium, Ruthenium, Indium and the like.
  • the chiral ligands may preferably be chiral phosphines such as optically pure enantiomers of 2,3-bis(diphenylphosphino)butane, 1 ,2-bis(diphenylphosphino) ethane, l,2-bis(2- methoxyphenyl phenylphosphino)ethane, 2,3-isopropylidene-2,3-dihydroxy-l ,4- bis(diphenylphosphmo)butane and the like.
  • Any suitable chiral catalyst may be employed which would give required optical purity of the product (I) (Ref: Principles of Asymmetric Synthesis, Tetrahedron Series Nol 14, pp311-316, Ed. Baldwin J
  • Route 10 The reaction of compound of formula (INb) where L 1 is a leaving group such as halogen atom, /?-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like, R 3 is as defined earlier excluding hydrogen and all other symbols are as defined earlier with an alcohol of general formula (IVc), where R represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and all other symbols are as defined earlier to yield compound of general formula (I) where R 2 represents substituted or unsubstituted groups selected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and all symbols earlier may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere that 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 KOH, NaOH, NaOMe, NaOEt, t-BuO " K + or NaH or mixtures thereof.
  • Phase transfer catalysts such as tetraalkyl ammonium halides or bisulphates 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 24 hours, preferably from 2 to 6 hours.
  • the reaction may be carried out in an inert atmosphere that 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 Na 2 CO 3 , K 2 CO 3 , NaH.and the like or mixtures thereof.
  • Acetone may be used as a solvent when Na 2 CO 3 or K 2 CU 3 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 48 hours, preferably from 2 to 12 hours.
  • the compound of formula (lllf) may be prepared by using Wittig Homer reaction between the protected hydroxyaryl aldehyde and compound of formula (Illb) followed by reduction of the double bond and deprotection.
  • Route 12 The reaction of compound of general formula (IIIj) defined earlier with a compound of general formula (lllf) where all symbols are as defined above may be carried out using suitable coupling agents such as EDCI, dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPh 3 / DEAD or DIAD 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 -20 °C to 100 °C, preferably at a temperature in the range of 0 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.
  • the above condensation may also be made using mixed anhydride methodology.
  • Route 13 The reaction of compound of formula (IVd), which represents a compound of formula (I), when R 2 represents hydroxy group and all other symbols are as defined above with a compound of formula (IVe) where R represents substituted or unsubstituted groups selected from allcyl, aryl, aralkyl, heteroaryl or heteroaralkyl and L 2 is a halogen atom to yield compound of general formula (I) where R 2 represents substituted or unsubstituted groups selected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and all symbols are as defined earlier may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like.
  • solvents such as THF, DMF, DMSO, DME 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 a base such as KOH, NaOH, NaOMe, t-BuO " K + , NaH, KH and the like.
  • Phase transfer catalyst such as tetraalkyl ammonium halides or bisulphates or hydroxides may be employed.
  • the reaction temperature may range from 20 °C to 150 °C, preferably at a temperature in the range of 25 °C to 100 °C.
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.
  • Route 14 The reaction of compound of general formula (Illh) where Hal represents halogen atom and A is as defined earlier with the compound of formula (Illi) where all other symbols are as defined earlier to yield the 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; organohthiums such as TMEDA, LDA and the like; alkoxides such as NaOMe, NaOEt, t-BuO " K 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.
  • the reaction temperature may range from -78 °C to 120 °C, preferably at a temperature in the range of -10 °C to 80 °C. The reaction is more effective under anhydrous conditions.
  • reaction may be carried out using suitable coupling agents such as EDCI, dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPh 3 / DEAD or DIAD and the like.
  • suitable coupling agents such as EDCI, dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPh 3 / DEAD or DIAD 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, carbon tetrachloride and the like.
  • solvents such as THF, DME, CH 2 C1 2 , CHCI 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 in the range of 20 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 120 hours, preferably from 6 to 24 hours.
  • Route 16 The reaction of a compound of the general formula (Ilia) as defined above with a compound of formula (Hie) where R 1 represents hydrogen atom and all other symbols are as defined earlier may be carried out in the presence of base.
  • the base is not critical. Any base normally employed for aldol condensation reaction may be employed, metal hydride such as NaH or KH; metal alkoxides such as NaOMe, t-BuOTC * or NaOEt; metal amides such as LiNH 2 , LiN(iPr) 2 . Aprotic solvent such as THF may be used. Inert atmosphere may be employed such as N 2 or argon or He and the reaction is more effective under anhydrous conditions.
  • the reaction may be carried out in an inert atmosphere that 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 LDA, TMEDA; 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.
  • 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 18 The conversion of compound of formula (IVf) where all symbols are as defined earlier to a compound of formula (I) may be carried out either in the presence of base or acid and the selection of base or acid is not critical. Any base normally used for hydrolysis of nitrile to acid may be employed, metal hydroxides such as NaOH or KOH in an aqueous solvent or any acid normally used for hydrolysis of nitrile to ester may be employed such as HC1 in an excess of alcohol such as methanol, ethanol, propanol etc.
  • 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 °C to reflux temperature of the solvent used. The duration of the reaction may range from 0.25 to 48 hrs.
  • Route 19 The reaction of a compound of formula (IVg) where R 3 is as defined earlier excluding hydrogen and all other symbols are as defined earlier with a compound of formula (IVc) where R represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and L 2 is a halogen atom to yield compound of general formula (I) where R 2 represents substituted or unsubstituted groups selected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and all other symbols are as defined earlier (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 ROH 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 ROH 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 N 2 , Ar, He and the like.
  • the duration of the reaction may range from 0.5 to 24 h, preferably from 0.5 to 6 h.
  • the compound of general formula (I) represents O or S qr NR 6 group where R 6 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups;
  • X represents NHR 5 , -CO(CH 2 ) p NR 5 (CH 2 ) m -, -(CH 2 ) p O-, -(CH 2 ) p NR 5 CO- where m and p are as defined earlier; G is O or S and Z represents oxygen atom; R , R , R , A, n and Ar are as defined earlier, can be prepared by any of the following routes shown in Scheme-Ill below.
  • Route 20 The reaction of compound of formula (Va) where all symbols are as defined earlier with compound of formula (Vb) where L is a leaving group such as halogen atom, / 5-toluenesulfonate, methanesulfonate, frifluoromethanesulfonate and the like, 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; organic base like triethyl amine, lutidine, collidine and the like or mixtures thereof.
  • aprotic solvents such as THF, DMF, DMSO, DME and the like
  • organic base like triethyl amine, lutidine, collidine and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere that 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 K ⁇ CO j , Na 2 CO 3j NaH, KH and the like or mixtures thereof.
  • Acetone may be used as solvent when Na 2 CO 3 or K 2 CO 3 is used as a base.
  • the reaction temperature may range from 0 °C - 120 °C, preferably at a temperature in the range of 25 °C - 100 °C.
  • the duration of the reaction may range from 1 to 96 hours, preferably from 2 to 24 hours.
  • the reaction may be carried out in an inert atmosphere that may be maintained by using inert gases such as N 2 , argon, He and the like.
  • the reaction may be effected in the presence of a base such as alkalis like isodium 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-BuLi, TMEDA (N,N,N',N'- tetramethylethylenediamine), LDA; alkali metal amides like sodamide, organic base like triethyl amine, lutidine, coUidine or mixtures thereof.
  • a base such as alkalis like isodium 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-BuLi, T
  • 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 tetraalkylammonium halide or sulphonates or hydroxide may be added.
  • Additives such as alkali metal halides like LiBr may be added.
  • the reaction may be carried out at a temperature in the range of 0 °C - 150 °C, preferably at a temperature in the range of 15 °C - 100 °C.
  • the duration of the reaction may range from 0.25 to 72 hours, preferably from 0.25 to 24 hours.
  • Route 22 The reaction of compound of formula (Vc) where L ! represents a leaving group such as halogen atom, -toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like, and all other symbols are as defined earlier with compound of formula (Hit) 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 aprotic solvents such as THF, DMF, DMSO,
  • the reaction may be carried out in an inert atmosphere that 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 K 2 CO 3 , Na 2 CO 3 or NaH,
  • reaction temperature may range from 0 °C - 120
  • the duration of the reaction may range from 1 to 72 hours, preferably from 2 to 24 hours.
  • Route 23 The reaction of compound of general formula (Illh) where A is as defined earlier and Hal represents halogen atom with the compound of formula (Illi) where all 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; organohthiums such as TMEDA, LDA and the like; alkoxides such as NaOMe, NaOEt, t-BuO ⁇ K + 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.
  • the reaction temperature may range from -78 °C to 120 °C, preferably at a temperature in the range of -10 °C to 80 °C. The reaction is more effective under anhydrous conditions.
  • Route 24 The reaction of compound of formula (Vd) where all symbols are as defined earlier with a compound of general formula (Hit) where all symbols are as defined earlier may be carried out using pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate and the like.
  • the reaction may be carried out in the presence of solvents such as CH 2 C1 2 , DMF, THF and the like or mixtures thereof.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar, He and the like.
  • the reaction may be carried out in the presence of bases like triethyl amine, lutidine, coUidine and the like.
  • the reaction temperature may be in the range of -20 °C to 80 °C, preferably at a temperature in the range of 0 °C to 50 °C.
  • the duration of the reaction may range from 0.5 to 24 hours, preferably from 0.5 to 12 hours. This reaction can also be carried out by a method described in Route 25.
  • the reaction may be carried out in the presence of solvents such as THF, DME, CH 2 C1 2 , CHCI 3 , toluene, acetonitrile, carbon tetrachloride and the like.
  • solvents such as THF, DME, CH 2 C1 2 , CHCI 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 -20 °C to 100 °C, preferably at a temperature in the range of 0 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 48 hours, preferably from 6 to 18 hours.
  • Route 26 The conversion of compound of formula (IVf) where all symbols are as defined earlier to a compound of formula (I) may be carried out either in the presence of base or acid and the selection of base or acid is not critical. Any base normally used for hydrolysis of nitrile to acid may be employed, metal hydroxides such as NaOH or KOH in an aqueous solvent, or any acid normally used for hydrolysis of nitrile to ester may be employed such as HC1 in an excess of alcohol such as methanol, ethanol, propanol etc.
  • 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 °C to reflux temperature of the solvent used.
  • Route 27 The reaction of compound of general formula (IIIj) where A, G and n are as defined earlier with a compound of general formula (lllf) where all symbols are as defined earlier may be carried out using suitable coupling agents such as EDCI, dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPh 3 / DEAD or DIAD and the like.
  • suitable coupling agents such as EDCI, dicyclohexyl urea, triarylphosphine/ dialkylazadicarboxylate such as PPh 3 / DEAD or DIAD 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, 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 -20 °C to 100 °C, preferably at a temperature in the range of 0 °C to 80 °C.
  • the duration of the reaction may range from 0.5 to 48 hours, preferably from 6 to 18 hours.
  • the above condensation may also be made using mixed anhydride methodology as described in Route 24.
  • the compound of formula (I) where R 3 represents hydrogen atom may be prepared by hydrolysing, using conventional methods, a compound of formula (I) where R 3 represents all groups defined earlier excluding hydrogen.
  • the hydrolysis may be carried out in the presence of a base such as Na 2 CO 3 , K 2 CO 3 , NaOH, KOH, LiOH and the like and a suitable solvent such as methanol, ethanol, dioxane, water and the like or mixtures thereof. THF is used as solubilizing agent wherever necessary.
  • the reaction may be carried out at a temperature in the range of 20 °C to reflux temperature of the solvent, preferably at 25 °C to reflux temperature.
  • the reaction time may range from 1 to 48 h, preferably from 1 to 12 h.
  • the compound of general formula (I) where Z represents oxygen and R represents hydrogen or lower alkyl group may be converted to compound of formula (I), where Z represents NR 4 by reaction with appropriate amines of the formula NHR 3 R 4 , where R 3 and R 4 are as defined earlier to yield a compound of formula (I) where Z represents NR 4 and all otlier symbols are as defined earlier.
  • mixed anhydrides may be prepared from compound of formula (I) where ZR 3 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 pyridine, triethylamine, diisopropyl ethylamine and the like.
  • Coupling reagents such as DCC/DMAP, DCC/HOBt, EDCI/HOBt, ethylchloroformate, isobutylchloroformate can also be used to activate the acid.
  • Solvents such as halogenated hydrocarbons like CHC1 3 or 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 at a temperature in the range of 0 °C to room temperature.
  • the acid halide or mixed anhydride or activated acid obtained by coupling reagents described above thus prepared may further be treated with appropriate amines of the formula NHR 3 R 4 where R 3 and R 4 are as defined earlier to yield a compound of formula (I) where Z represents NR 4 and all other symbols are as defined earlier.
  • R 1 represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted or unsubstituted aralkyl groups
  • R 2 represents hydrogen, hydroxy, halogen, substituted or unsubstituted groups selected from alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups
  • R represents hydrogen or substituted or unsubstituted groups selected from all
  • Route 28 The reduction of compound of the formula (IIIf-1) where all symbols are as defined above to yield compound of the general formula (lllf) where R 5 represents hydrogen; and all other symbols are as defined above 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 carried out in the presence of solvents such as dioxane, acetic acid, ethyl acetate, alcohol such as methanol, ethanol and the like or mixture thereof. A pressure between atmospheric pressure and 40 to 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 or samarium in alcohol or sodium amalgam in alcohol, preferably methanol.
  • metal solvent reduction such as magnesium or samarium in alcohol or sodium amalgam in alcohol, preferably methanol.
  • R 1 and R 2 represent double bond
  • the hydrogenation may be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of formula (lllf) in optically active form.
  • the metal catalyst may contain Rhodium, Ruthenium, Indium and the like.
  • the chiral ligands may preferably be chiral phosphines such as optically pure enantiomers of 2,3-bis(diphenylphosphino)butane, 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) (Ref: Principles of Asymmetric Synthesis, Tetrahedron Series Vol 14, pp311- 316, Ed. Baldwin I. E.).
  • Route 29 The reaction of compound of formula (IIIf-2) with compound of formula (Illf- 3) to give a compound of formula (lllf) where R 5 represents alkyl group and all other symbols are as defined above may be carried out iii two steps the first step being the imine formation, followed by reduction. Formation of imine may be carried out in solvents such as MeOH, EtOH, z'-PrOH and the like. The reaction may be effected in the presence of a promoter such as NaOAc, KOAc and the like or the mixtures thereof. The temperature of reaction may range from room temperature to the reflux temperature of the solvent used. The reaction time may be 2 h to 24 h, preferably in the range 2 h to 12 h.
  • the imine can also be obtained by the reaction of a compound of general formula (IIIf-2) with a compound of formula (IIIf-3) using solvents such as CH 2 C1 2 , CHCI3, chlorobenzene, benzene, THF, in the presence of catalyst such as p-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF 3 -OEt 2 and the like.
  • the reaction may also be carried out in presence of activated molecular sieves.
  • the temperature of the reaction may range from 10 °C to 100 °C, preferably at a temperature in the range from 10 °C to 60 °C.
  • the reaction time may be 1 h to 48 h.
  • the imine product thus obtained above may be reduced by using Na(CN)BH 3 -HCl
  • Route30 The conversion of compound of formula (IIIf-4) to a compound of formula (lllf) where R 5 represents hydrogen, and all other symbols are as defined above may be carried out in two steps the first step being the imine formation, followed by reduction.
  • Formation of imine may be carried out in solvents such as MeOH, EtOH, z ' -PrOH and the like using hydroxylamine hydrochloride.
  • the reaction may be effected in the presence of a promoter such as NaOAc, KOAc and the like or the mixtures thereof.
  • the temperature of reaction may range from room temperature to the reflux temperature of the solvent used.
  • the reaction time may be 2 h to 24 h, preferably in the range 2 h to 12 h.
  • the imine product thus obtained above may be reduced by using Na(CN)BH 3 -HCl
  • the reaction may be carried out in the presence of solvents such as methanol, ethanol water and the like.
  • solvents such as methanol, ethanol water and the like.
  • the temperature of reaction may range from -20 °C to the reflux temperature of the solvent used.
  • the reaction time may be 1 h to 48.
  • Route 31 The reduction of compound of the formula (IIIf-5) to yield compound of the general formula (lllf) where R 5 represents hydrogen and all other symbols are as defined above may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate 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 1-50 % w/w.
  • a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel 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. A pressure between atmospheric pressure and 80 ps
  • the reaction may also be carried out by employing metal solvent reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol or ethanol.
  • metal solvent reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol or ethanol.
  • the hydrogenation may be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of formula (lllf) in optically active form.
  • the metal catalyst may contain Rhodium, Ruthenium, Indium and the like.
  • the chiral ligands may preferably be chiral phosphines such as ⁇ optically pure enantiomers of 2,3-bis(diphenylphosphino)butane, 2,3-isopropylidene-2,3- dihy droxy- l,4-bis(diphenylphosphino) butane and the like.
  • chiral phosphines such as ⁇ optically pure enantiomers of 2,3-bis(diphenylphosphino)butane, 2,3-isopropylidene-2,3- dihy droxy- l,4-bis(diphenylphosphino) butane and the like.
  • the compound of formula (lllf) where R 2 represents substituted or unsubstituted groups selected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy; X represents NHR 5 , Y represents O, S, NR 6 or CHR 7 , Z is as defined above excluding NH and all other symbols are as defined above may be prepared by diazotizing the compound of formula (IIIf-6) to a compound of formula (IIIf-7) and reducing the compound of formula (IIIf-7) to yield compound of formula (Hit).
  • alkyl sulfates such as diethyl sulphate, dimethylsulphate and the like or alkyl halides such as ethyl iodide, methyliodide and the like
  • solvents such as hydrocarbons like toluene, benzene and the like or DMF, DMSO, methyl isobutyl ketone (MIBK) and the like
  • alkali bases such as sodium carbonate, potassium carbonate, sodium methoxide, sodium hydride, potassium hydride and the like.
  • the reduction of compound of the formula (IIIf-7) to yield a compound of the general formula (lllf) where R 5 represents hydrogen atom and all other symbols are as defined earlier may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate 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 1-50 % w/w.
  • the reaction may also be carried out by employing metal solvent reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol.
  • metal solvent reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol.
  • the hydrogenation may also be carried out using ammonium formate, cyclohex-l,4-diene type of hydrogen donor under pd/c conditions using solvents such as methanol, ethanol, ethyl acetate and the like.
  • the compound of formula (lllf) where R 2 represents substituted or unsubstituted groups selected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy; X represents NHR 5 , Z is as defined above excluding NH and all other symbols are as defined above may be prepared by diazotizing and reducing the compound of formula (IIIf-6) to a compound of formula (Illf- 8) and etherifying the compound of formula (IIIf-8) to yield compound of formula (lllf).
  • the diazotization of the compound of the formula (IIIf-6) where all symbols are as defined above to obtain compound of formula (IIIf-8) may be carried out using diazotizing agent such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like under aqueous acidic conditions using acids such as sulfuric acid, HC1, acetic acid and the like, in an organic solvent such as alcohols such as methanol, ethanol, propanol and the like; 1,4-dioxane, THF, acetone and the like. Reducing the residue obtained using gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like.
  • diazotizing agent such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like
  • acids such as sulfuric acid, HC1, acetic acid and the like
  • organic solvent such as alcohol
  • the reduction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like.
  • solvents such as dioxane, acetic acid, ethyl acetate 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 1-50 % w/w.
  • the reaction may also be carried out by employing metal solvent reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol.
  • the hydrogenation may also be carried out using ammonium formate, cyclohex-l,4-diene type of hydrogen donor under pd/c conditions using solvents such as methanol, ethanol, ethyl acetate and the like.
  • Etherification of compound of formula (IIIf-8) to yield compound of formula (lllf) where R 2 represents substituted or unsubstituted groups selected from alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy and all other symbols are as defined earlier may be carried out using alkyl sulfates such as diethyl sulphate, dimethylsulphate and the like or alkyl halides such as ethyl iodide, methyliodide and the like, in solvents such as hydrocarbons like toluene, benzene and the like or DMF, DMSO, methyl isobutyl ketone (MIBK) and the like, in the presence of alkali bases such as sodium carbonate, potassium carbonate, sodium methoxide, sodium hydride, potassium hydride and the like.
  • alkyl sulfates such as diethyl sulphate, dimethylsulphate and the like or alkyl hal
  • reaction of a compound of the general formula (Illb) where all symbols are as defined above with a compound of formula (IIIf-9) where R 12 represents (C ⁇ -C ⁇ )alkyl group to yield compound of formula (IIIf-10) may be carried out in the presence of a base such as metal hydride like NaH or KH; organolithiums such as CHsLi, BuLi and the like; alkoxides such as NaOMe, NaOEt, t-BuO " K + and the like or mixtures thereof.
  • the reaction may be carried out in the presence of solvents such as diethyl ether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide 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 reduction of compound of the formula (IIIf-10) to yield a compound of the formula (IIIf-2) may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts may be used.
  • the reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate 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 1-50 % w/w.
  • the reaction may also be carried out by employing metal solvent reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol followed by an acidic work up.
  • metal solvent reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol followed by an acidic work up.
  • the hydrogenation may be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of formula (I) in optically active form.
  • the metal catalyst may contain Rhodium, Ruthenium, Indium and the like.
  • the chiral ligands may preferably be chiral phosphines such as optically pure enantiomers of 2,3- bis(diphenylphosphino)butane, 2,3-isopropylidene-2,3-dihydroxy-l,4- bis(diphenylphosphino) butane and the like.
  • reaction of a compound of general formula (IIIf-2) with a compound of formula (IIIf-3) where R 5 is as defined above to yield compound of formula (lllf) may be carried out using solvents such as CH 2 C1 2 , CHCI 3 , chlorobenzene, benzene, THF, in the presence of catalyst such as p-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF 3 -OEt 2 and the like.
  • the reaction may also be carried out using activated molecular sieves.
  • the temperature of the reaction may range from 10 °C to 100 °C, preferably at a temperature in the range from 10 °C to 60 °C.
  • the imine product initially produce may be reducing using Na(CN)BH 3 -HCl (ref: Hutchins, R. O. et al. J. Org. Chem. 1983, vol. 48, 3433-3428), H 2 -Pd/C, H 2 -Pt/C, H 2 -Ph C and the like in solvents such as methanol, ethanol and the like.
  • reaction of compound of formula (IIIf-2) to yield compound of formula (lllf) where R 5 represents hydrogen, m is 1, and all other symbols are as defined above may be carried out using substituted or unsubstituted hydroxyl amine followed by treating with TiCl 3 as reagent and a reducing agent such asNaCNBH 3 , or NaBH .
  • a reducing agent such asNaCNBH 3 , or NaBH .
  • the coactivators like ammonium acetate can be used.
  • the reaction may be carried out in the presence of solvents such as methanol, ethanol, water and the like or mixtures thereof.
  • the temperature of reaction may range from -20 °C to the reflux temperature of the solvent used.
  • the reaction time may be 1 h to 48.
  • reaction of compound of formula (IIIf-2) to yield compound of formula (lllf) where R 5 represents hydrogen, m is 1, and all other symbols are as defined above may be carried out using NH 3 /methanol, NH3/ethanol or NH3/isopropanol in presence of Pd/C, Ra-Ni and the like as catalyst and atmospheric pressure to 80 psi pressure of hydrogen gas.
  • the reaction temperature may range from room temperature to 60 °C.
  • the duration of reaction may range from 2 h to 48.
  • L 1 is a leaving group such as halogen atom, ⁇ >-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate
  • R 1 represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted or unsubstituted aralkyl groups
  • R 2 represents hydrogen, hydroxy, halogen, substituted or unsubstituted groups selected from alkyl, cycloalkyl, cycloallcylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxy
  • the compound of formula (Hid) where X represents -CO(CH 2 ) p NR 5 (CH 2 ) m -, -(CH 2 ) p NR 5 CO-; all symbols are as defined above may be prepared by a process which comprises, reacting the compound of formula (lllf)
  • reaction of compound of formula (lllf) with compound of formula (IIId-1) where may be carried out in the presence of solvents such as DCM, DCE, THF, DMF, DMSO, DME and the like or mixtures thereof.
  • solvents such as DCM, DCE, THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere that 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 triethyl amine, lutidine, coUidine and the like or mixtures thereof
  • the reaction temperature may range from -20 °C - 120 °C.
  • duration of the reaction may range from 1 to 48 hours, preferably from 2 to 12 hours.
  • L 1 is a leaving group such as halogen, p-toluenesulfonate, methanesulfonate,' trifluoromethanesulfonate;
  • R 1 represents hydrogen;
  • R 2 represents hydrogen, hydroxy, halogen, substituted or unsubstituted groups selected from alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups;
  • R 3 represents hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, cycloalkylalkyl, al
  • the compound of formula (Hid) where X represents -CO(CH 2 ) p NR 5 (CH 2 ) m -, -(CH 2 ) p NR 5 CO-; all symbols are as defined above may be prepared by a process which comprises, reacting the compound of formula (Hit)
  • reaction of compound of formula (Hit) with compound of formula (IIId-1) where may be carried out in the presence of solvents such as DCM, DCE, THF, DMF, DMSO, DME and the like or mixtures thereof.
  • solvents such as DCM, DCE, THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere that 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 triethyl amine, lutidine, coUidine and the like or mixtures thereof.
  • the reaction temperature may range from -20 °C - 120 °C.
  • the duration of the reaction may range from 1 to 48 hours, preferably from 2 to 12 hours.
  • L 1 is a leaving group such as halogen, -toluenesulfonate, methanesulfonate, trifluoromethanesulfonate;
  • R 1 represents hydrogen;
  • R 2 represents hydrogen, hydroxy, halogen, substituted or unsubstituted groups selected from alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups;
  • R 3 represents hydrogen or substituted or unsubstitute
  • the compound of formula (Hid) where X represents -CO(CH 2 ) p NR 5 (CH 2 ) m -, -(CH 2 ) p NR 5 CO-; all symbols are as defined above may be prepared by a process which comprises, reacting the compound of formula (lllf)
  • reaction of compound of formula (lllf) with compound of formula (IIId-1) where may be carried out in the presence of solvents such as DCM, DCE, THF, DMF, DMSO, DME and the like or mixtures thereof.
  • solvents such as DCM, DCE, THF, DMF, DMSO, DME and the like or mixtures thereof.
  • the reaction may be carried out in an inert atmosphere that 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 triethyl amine, lutidine, coUidine and the like or mixtures thereof.
  • the reaction temperature may range from -20 °C - 120 °C.
  • the duration of the reaction may range from 1 to 48 hours, preferably from 2 to 12 hours.
  • Ar represents substituted or unsubstituted, divalent, single or fused, aromatic, heteroaromatic or heterocyclic group
  • G represents O or S
  • X represents O, NHR 5 , -CO(CH 2 ) p NR 5 (CH 2 ) m -, (CH 2 ) p O, -(CH 2 ) p NR 5 CO-;
  • R 5 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups
  • n is an integer in the range
  • R and R 9 , R 10 when attached to carbon atom may be same or different and represent 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, alkanoylamino, monoalkylamino, diaUcylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alk
  • L 1 is a leaving group such as halogen atom, /?-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like;
  • R 1 represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted or unsubstituted aralkyl groups;
  • R 3 represents hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups;
  • Z represents oxygen or NR , where R represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, a
  • R and R 9 , R 10 when attached to carbon atom may be same or different and represent 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, alkanoylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbony
  • R 1 represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy, acyl, substituted or unsubstituted aralkyl groups
  • R 2 represents hydrogen, hydroxy, halogen, substituted or unsubstituted groups selected from alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, alkanoyl, alkanoyloxy, aroyl, aralkyl, aryloxy, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl groups
  • Ar represents substituted or unsubstituted, divalent, single or
  • R 5 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups
  • Y represents O, S, NR 6 or CHR 7
  • R 6 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups
  • R 7 represents hydrogen atom, halogen, hydroxy, alkyl, alkoxy, substituted or unsubstitute
  • R and R , R when attached to carbon atom may be same or different and represent 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, alkanoylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamin
  • R 3 represents hydrogen or substituted or unsubstituted groups selected from allcyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups
  • Z represents oxygen or NR 4 , where R 4 represents hydrogen or substituted or unsubstituted groups selected from allcyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, alkanoyl, aroyl, aralkanoyl, heterocyclyl, heteroaryl or heteroaralkyl groups or R 3 and R 4 together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, a nitrogen atom and which may optionally contain one or two additional heteroatoms selected from oxygen, sulfur or nitrogen;
  • Ar represents substituted or unsubsti
  • R and R 9 , R 10 when attached to carbon atom may be same or different and represent 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, alkanoylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbon
  • 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 tertiarybutyldimethylsilyl, methoxymethyl, triphenyl methyl, benzyloxycarbonyl, THP etc, to protect hydroxyl or phenolic hydroxy group; N-Poc, Boc, N-Cbz, N-Fmoc, benzophenoneimine etc, for protection of amino or anilino group, acetal protection for aldehyde, ketal protection for ketone and the like.
  • 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 compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium hydroxide, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol, toluene etc. Mixtures of solvents may be used.
  • Organic bases like lysine, arginine, diethanolamine, choline, guanidine, adamentyl amine 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 and the like. Mixtures 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
  • stereoisomers of the compounds fo ⁇ ning 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.
  • Various polymorphs of a 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. Polymorphs may also 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. Polymorphs may also
  • polymorphs 15 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 calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention provides a pharmaceutical composition, containing the
  • Atherosclerosis 25 atherosclerosis, stroke, peripheral vascular diseases and related disorders.
  • These compounds are useful for the treatment of hyperlipemeia, hyperglycemia, familial hypercholesterolemia, hyperrriglyceridemia, lowering of atherogenic lipoproteins, VLDL and LDL.
  • the compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome,
  • 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, retinopathy, arteriosclerosis, xanthoma, 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, probucol or their combination.
  • HMG CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol or their combination.
  • 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 hyperlipidemia such as lovastatin, pravastatin, simvastatin, fluvastatm, atorvastatin, cerivastatin and their analogs thereof.
  • Suitable fibric acid derivative may be gemfibrozil, clofibrate, fenofibrate, ciprofibrate, benzafibrate and their analogs thereof.
  • 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 or their pharmaceutically acceptable solvates and one or more HMG CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, 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.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compound of formula (I) 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 compound formula (I) 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.
  • Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions.
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the preparation may contain the compound of formula (I), of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.
  • Tablets, dragees or capsules having talc and / or a carbohydrate carried binder or the like are particularly suitable for any oral application.
  • carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet production method is exemplified below :
  • the ingredients 1 to 3 are uniformly blended with water and granulated after drying under reduced pressure.
  • the ingredient 4 and 5 are mixed well with the granules and compressed by a tabletting machine to prepare 1000 tablets each containing 30 mg of active ingredient.
  • ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and granulated after drying under reduced pressure.
  • Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of ingredient 1.
  • the compound of the formula (I) as defined above are clinically administered to mammals, including man, via either oral, nasal, pulmonary, transdermal or parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, infranasal, ophthalmic solution or an ointment.
  • Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection.
  • 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.
  • Br OOEt Red phosphorous (455 mg, 14.7 mmol) was added to valeric acid (15 g, 14.7 mmol) followed by drop wise addition of bromine (15 mL, 294 mmol) at room temperature. After complete addition, the reaction mixture was heated to 100 °C for 6 h. The excess bromine was then removed using water aspirator at the same temperature. Ethanol (25 mL) was added to the residue and refluxed for overnight. The reaction mixture was cooled to room temperature and poured into water (45 mL) when oil separated. The oil was washed with water, saturated sodium bicarbonate and water, dried (Na 2 S0 4 ) and distilled under reduced pressure to obtain the title compound (26.2 g, 85%) as colorless oil.
  • reaction mixture was dumped into ice water and extracted with toluene.
  • the combined organic extracts were washed with water and the solvent was removed under reduced pressure to afford S(-)-ethyl 2- ethoxy-3-(4-benzyloxyphenyl)propionate (41-42 g, 98-99 %).
  • Step-vi A mixture of S(-)-ethyl 2-ethoxy-3-(4-benzyloxyphenyl)propionate (40 g) obtained in step (v) above, 5 % Pd/C catalyst (8 g) and tetrahydrofuran (120 ml) was subjected to hydrogenation at room temperature and 50-60 psi of hydrogen pressure for a period of 8- 12 hours. After completion of the reaction, the catalyst was filtered off and the solvent was removed under reduced pressure to afford S(-)-ethyl 2-ethoxy-3-(4- hydroxyphenyl)propionate (28-29 g, 97-98 %) ⁇ Step-vii:
  • Step i A solution of triethyl-2-ethoxyphosphonoacetate prepared (5.61 g, 20.89 mmol) in dry tetrahydrofuran (20 mL) was added slowly to a stirred ice cooled suspension of sodium hydride (60 % dispersion of oil) (1 g, 42 mmol) in dry tetrahydrofuran (10 mL), under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min. prior to the addition of a 4-(2-bromoethoxy)benzaldehyde (4.0 g, 17.4 mmol) in dry tetrahydrofuran (30 mL).
  • sodium hydride 60 % dispersion of oil
  • Method B To a solution of ethyl 3-[4-(2-bromoethoxy) ⁇ henyl]-2-ethoxypropanoate obtained in step ii. above (2.5 g, 7.25 mmol) in methanol (40 mL) was added a solution of sodium carbonate (3.84 g, 36.2 mmol) in water (20 mL), and stirred the reaction mixture for 24 h at room temperature. Methanol was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL) to remove impurities, if any.
  • the aqueous layer was cooled to 0 °C and acidified with 2N HC1 solution to pH ⁇ 2 and extracted with ethyl acetate (2 x 200 mL).
  • the organic extracts were washed with brine, dried (Na 2 SO 4 ) and evaporated to dryness to give the crude intermediate (2.2 g, 96%).
  • the crude residue (2.2 g) was dissolved in potassium hydroxide solution (1.56 g in 20 mL of water) and the reaction mixture was stirred at room temperature for 96 h.
  • the reaction mixture was cooled to 0 °C and acidified with 2N HC1 solution to pH ⁇ 2 and extracted with ethyl acetate (3 x 100 mL).
  • Step i Sodium (11.5 g, 500 mmol) was added to ethanol (130 mL) in portions at room temperature with vigorous stirring. After sodium got dissolved, the solution was cooled to 0 °C. Methyl propyl ketone (53.0 mL, 500 mmol) was added dropwise and the stirring was continued for further 15 - 20 min. Diethyl oxalate (68.0 mL, 500 mmol) was added dropwise to the resulting solution at 0 °C and the stirring was continued for another 15 min at 0 °C. The reaction mixture was then allowed to attain room temperature and the stirring was continued for further 12 h at this temperature. The reaction mixture was then kept in refrigerator for 24 h. The solvent was removed under vacuum at room temperature.
  • Dimethyl sulfate (6.0 g, 48.35 mmol) was added to the pyrazole ester obtained in step ii. above (16.0 g, 88 mmol) and the reaction mixture was heated at 160 °C for 2 h. The reaction mixture was cooled to ⁇ 90 °C and 5N sodium hydroxide solution (64 mL) was added and the reaction mixture was stirred at 80 - 90 °C for 30 min. The reaction mixture was cooled in an ice bath and was acidified to pH 4 with 2N hydrochloric acid resulting precipitation of the product.
  • 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 step iii. above 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 crushed ice.
  • Cyclopropane carboxylic acid (600 mg, 6.97 mmol) was refluxed in thionyl chloride (1.01 mL, 1.64 mmol) for 2 h. Excess thionyl chloride was distilled off and the acid chloride was cooled to 0 °C.
  • thionyl chloride was distilled off and the acid chloride was cooled to 0 °C.
  • 4-amino-l-methyl-3-propyl-lH-5- pyrazole carboxamide (prepared as disclosed in our US application No. 09/507,373) (1.0 g, 5.49 mmol) in xylene (10 mL)
  • cyclopropane carboxylic acid (5 mL) was added and cooled in ice bath.
  • Triethyl amine was added to the above mixture and stirred for 20 min. This mixture was then added to acid chloride at 0 °C and stirred at room temperature for 1 h. The reaction mixture was refluxed for 48 h and the solvents were removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with water, brine, dried (Na 2 SO 4 ) and concentrated. The crude compound was purified by silica gel column chromatography using 30% ethyl acetate in pet ether to yield the title compound (1.22 g, 45%) as a white solid, mp 228-230 °C.
  • reaction mixture was diluted with ethyl acetate (400 mL) and washed the organic layer successively with water (3 x 300 mL) and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound (23.0 g, 92%) as a gummy mass.
  • the title compound (1.45 g, 78%) was obtained from ethyl 6-[4-(l- ethoxycarbonylbutoxy)anilino]hexanoate (1.55 g, 4.1 mmol) obtained in preparation 15 by reacting with chloroacetyl chloride (0.47 mL, 6.13 mmol) using dichloromethane (18 mL) in presence of triethyl amine (1.7 mL, 12.27 mmol) at room temperature for 16 h by following the similar procedure as described in preparation 4.
  • the title compound (3.2 g, 55%) was synthesized by hydrogenating ethyl 2-ethoxy-3-[4- nitrophenyl]propeonate obtained in preparation 17 (6.5 g, 24.4 mmol) by passing hydrogen gas at 60 psi, taken in dioxane (65 mL), in presence of 10% Pd-C (2.6 g) at room temperature for 36 h by following the same procedure as described in preparation 14. !
  • the title compound (1.35 g, 36.4%) was obtained as a liquid from ethyl 2-(4- aminophenoxy)pentanoate (2.0 g, 8.4 mmol), obtained in preparation 14, by reacting with ethyl 4-(4-bromobutyl)benzoate (2.65 g, 9.82 mmol) using anhydrous potassium carbonate (3.5 g, 25.31 mmol) at room temperature for 60 h following a similar procedure as described in the preparation 13.
  • the title compound (1.4 g, 88%) was obtained from ethyl 2-[4- ⁇ 4-(4- ethoxycarbonylphenyl)butylamino ⁇ phenoxy]pentanoate (1.35 g, 3.07 mmol), obtained in preparation 21, by reacting with chloroacetyl chloride (0.28 mL, 3.68 mmol) using dichloromethane (20 mL) in presence of triethyl amine (1.08 mL, 7.67 mmol) at room temperature for 40 h by following the similar procedure as described in preparation 4.
  • the title compound (230 g, 38%) was obtained by condensing l-methyl-3-propyl-5- cyclopropyl-lH-pyrazolo[4,3-d]pyrimidin-7-one (200 mg, 0.86 mmol) obtained in preparation 12 with ethyl (2S)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate (357 mg,
  • the title compound (400 mg, 55%) was obtained by condensing 5 -ethyl- 1 -methyl-3 - propyl-6,7-dihydro-lH-pyrazolo[4,3-d]-pyrimidin-7-one obtained in preparation 23 (250 mg, 1.14 mmol) with ethyl 6-chloromethyl[4-(l- ethyloxycarbonylbutoxy)phenyl]carboxamidohexanoate, obtained in preparation 16, in dry N,N-dimethylformamide (10 mL) in the presence of anhydrous K 2 CO 3 (470 mg, 3.41 mmol) at room temperature for 96 h following a similar procedure as described in example 1.
  • the title compound (530 mg, 86%) was obtained by condensing 5-ethyl-l-methyl-3- propyl-6,7-dihydro-lH-pyrazolo[4,3-d]-pyrimidin-7-one obtained in preparation 23 (193 mg, 0.88 mmol) with ethyl 2-[4-chloromethyl ⁇ 4-(4- ethyloxycarbonylphenyl)butyl ⁇ carboxamidophenoxy] pentanoate (530 mg, 1.03 mmol), obtained in preparation 22, in dry N,N-dimethylformamide (8 mL) in the presence of anhydrous K 2 CO 3 (358 mg, 2.59 mmol) at room temperature for 48 h following a similar procedure as described in example 1.
  • the compounds of the present invention lowered random blood sugar level, triglyceride, total cholesterol, LDL, VLDL and increased HDL. This was demonstrated by in vitro as well as in vivo animal experiments.
  • Ligand binding domain of hPPAR ⁇ was fused to DNA binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector. Using superfect (Qiagen,
  • transfecting reagent HEK-293 cells were transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter.
  • Luciferase activity as a function of compound binding/activation capacity of PPAR ⁇ was measured using Packard Luclite kit (Packard, USA) in Top Count (Ivan
  • Ligand binding domain of hPPAR ⁇ l was fused to DNA binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector. Using lipofectamine (Gibco
  • transfecting reagent HEK-293 cells were transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter.
  • Luciferase activity as a function of drug binding/activation capacity of PPAR ⁇ l 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 P0 4 , 4 M 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.
  • 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 (NTN), India) and acidified water, ad libitum.
  • NTN National Institute of Nutrition
  • 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 0.1 mg to 30 mg / kg through oral gavage daily for 6 days.
  • the control group received vehicle (dose 10 ml / kg).
  • 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 spectrometrically, by glucose oxidase and glycerol-3-P0 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.
  • mice were obtained at 5 weeks of age from Bomholtgard, Denmark and were used at 8 weeks of age.
  • Zucker fa/fa fatty rats were obtained from IffaCredo, France at 10 weeks of age and were used at 13 weeks of age.
  • the animals were maintained under 12 hour light and dark cycle at 25 + 1 °C.
  • Animals were given standard laboratory chow (NTN, India) and water, ad libitum (Fujiwara, T., Yoshioka, S., Yoshioka, T., Ushiyama, I and Horikoshi, H. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 1988, 37 : 1549 - 1558).
  • the test compounds were administered at 0.1 to 30 mg/kg/day dose for 9 days.
  • the control animals received the vehicle (0.25 % carboxymethylcellulose, dose 10 ml/kg) through oral gavage.
  • 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, India).
  • the plasma free fatty acid was measured using a commercial kit from Boehringer Mannheim, Germany.
  • the plasma insulin was measured using a RIA kit (BARC, India). The reduction of various parameters examined are calculated according to the formula given below.
  • 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.
  • Plasma triglyceride and Cholesterol lowering activity in hypereholesterolemic rat models Plasma triglyceride and Cholesterol lowering activity in hypereholesterolemic rat models
  • 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 hypereholesterolemic 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., Bonnefis, M. T., Rey, C and Infante, R. Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normal 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/l g).
  • the blood samples were collected in fed state 1 hour after drug 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 VLDL 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. c) Plasma triglyceride and total cholesterol lowering activity in Swiss albino mice and Guinea pigs
  • SAM Male Swiss albino mice
  • Male Guinea pigs were obtained from NIN and housed in DRF animal house. All these ammals 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.
  • the 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.
  • test compounds were administered orally at 1 to 30 mg/kg/day dose for 15 days.
  • Control group animals were treated with vehicle (Mill Q water, dose 10 ml/kg/day).
  • Body weights were measured on every 3 r day.
  • LDL and VLDL cholesterol levels were calculated according to the formula :
  • Triglyceride LDL cholesterol in mg/dl [ Total cholesterol - HDL cholesterol - ] mg/dl
  • VLDL cholesterol in mg/dl [Total cholesterol - HDL cholesterol - LDL cholesterol] mg/dl.

Abstract

La présente invention concerne de nouveaux composés antidiabétiques, hypolipidémiants, anti-obésité et hypocholestérolémiques, leurs dérivés, leurs analogues, leurs formes tautomériques, leurs stéréoisomères, leurs formes polymorphes, leurs sels acceptables d'un point de vue pharmaceutique, leurs solvates acceptables d'un point de vue pharmaceutique, et des compositions acceptables d'un point de vue pharmaceutique les contenant. La présente invention concerne, plus particulièrement, de nouveaux acides carboxyliques d'alkyle représentés par la formule générale (I), leurs dérivés, leurs analogues, leurs formes tautomériques, leurs stéréoisomères, leurs formes polymorphes, leurs sels acceptables d'un point de vue pharmaceutique, leurs solvates acceptables d'un point de vue pharmaceutique, et des compositions acceptables d'un point de vue pharmaceutique les contenant.
PCT/IB2002/005442 2001-12-21 2002-12-17 Nouveaux composes et leur utilisation en medecine, procede de preparation de ceux-ci et compositions pharmaceutiques les contenant WO2003053974A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056740A1 (fr) * 2002-12-20 2004-07-08 Novo Nordisk A/S Derives d'acide dicarboxylique en tant qu'agonistes ppar
WO2005040102A2 (fr) * 2003-10-28 2005-05-06 Dr. Reddy's Laboratories Ltd. Nouveaux composes et leur utilisation en medecine, leur procede de preparation et compositions pharmaceutiques les contenant
EP1555021A1 (fr) * 2004-01-16 2005-07-20 National Health Research Institutes Combinaisons d'un inhibiteur de la voie du mévalonate et d'un agoniste PPAR-gamma pour le traitement du cancer
WO2006016517A1 (fr) * 2004-08-13 2006-02-16 Kaneka Corporation Procédé de production d’arylalcanoïque 2-substituant-oxy-3-(4-substituant-oxyphénil) optiquement actif
KR100827353B1 (ko) * 2006-10-13 2008-05-06 재단법인서울대학교산학협력재단 2-에톡시프로피온산 유도체 또는 이의 약학적으로허용가능한 염, 이의 제조방법 및 이를 유효성분으로함유하는 당뇨병 예방 및 치료제
US7816385B2 (en) 2002-12-20 2010-10-19 High Point Pharmaceuticals, Llc Dimeric dicarboxylic acid derivatives, their preparation and use
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
CN102274753A (zh) * 2011-05-16 2011-12-14 南京理工大学 一种细菌纤维素负载纳米钯催化剂制备方法
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
US10959970B2 (en) 2009-02-16 2021-03-30 Nogra Pharma Limited Methods of treating hair related conditions
US11046641B2 (en) 2012-02-09 2021-06-29 Nogra Pharma Limited Methods of treating fibrosis
US11905232B2 (en) 2019-02-08 2024-02-20 Nogra Pharma Limited Process of making 3-(4′-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof

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EP0254590A2 (fr) * 1986-07-24 1988-01-27 Yamanouchi Pharmaceutical Co. Ltd. Dérivés de aryl-di(thio)éther comme médicaments antitumoraux
WO1994013650A1 (fr) * 1992-12-04 1994-06-23 Smithkline Beecham Plc Derives heterocycliques et leur utilisation comme produits pharmaceutiques

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US4654348A (en) * 1984-04-04 1987-03-31 Nissan Chemical Industries Ltd. Pyrazolo[4,3-d]pyrimidine derivative, process for its production, antihyperlipidemic agent containing it, its intermediate, and process for the production of the intermediate
EP0254590A2 (fr) * 1986-07-24 1988-01-27 Yamanouchi Pharmaceutical Co. Ltd. Dérivés de aryl-di(thio)éther comme médicaments antitumoraux
EP0397290A1 (fr) * 1986-07-24 1990-11-14 Yamanouchi Pharmaceutical Co. Ltd. Dérivés, leur préparation et composition pharmaceutique les contenant
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7816385B2 (en) 2002-12-20 2010-10-19 High Point Pharmaceuticals, Llc Dimeric dicarboxylic acid derivatives, their preparation and use
WO2004056740A1 (fr) * 2002-12-20 2004-07-08 Novo Nordisk A/S Derives d'acide dicarboxylique en tant qu'agonistes ppar
WO2005040102A2 (fr) * 2003-10-28 2005-05-06 Dr. Reddy's Laboratories Ltd. Nouveaux composes et leur utilisation en medecine, leur procede de preparation et compositions pharmaceutiques les contenant
WO2005040102A3 (fr) * 2003-10-28 2006-03-23 Reddys Lab Ltd Dr Nouveaux composes et leur utilisation en medecine, leur procede de preparation et compositions pharmaceutiques les contenant
EP1555021A1 (fr) * 2004-01-16 2005-07-20 National Health Research Institutes Combinaisons d'un inhibiteur de la voie du mévalonate et d'un agoniste PPAR-gamma pour le traitement du cancer
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2006016517A1 (fr) * 2004-08-13 2006-02-16 Kaneka Corporation Procédé de production d’arylalcanoïque 2-substituant-oxy-3-(4-substituant-oxyphénil) optiquement actif
KR100827353B1 (ko) * 2006-10-13 2008-05-06 재단법인서울대학교산학협력재단 2-에톡시프로피온산 유도체 또는 이의 약학적으로허용가능한 염, 이의 제조방법 및 이를 유효성분으로함유하는 당뇨병 예방 및 치료제
US10959970B2 (en) 2009-02-16 2021-03-30 Nogra Pharma Limited Methods of treating hair related conditions
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
CN102274753A (zh) * 2011-05-16 2011-12-14 南京理工大学 一种细菌纤维素负载纳米钯催化剂制备方法
US11046641B2 (en) 2012-02-09 2021-06-29 Nogra Pharma Limited Methods of treating fibrosis
US11753365B2 (en) 2012-02-09 2023-09-12 Nogra Pharma Limited Methods of treating fibrosis
US11905232B2 (en) 2019-02-08 2024-02-20 Nogra Pharma Limited Process of making 3-(4′-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof

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