WO2014192023A1 - Nouveaux composés appropriés pour le traitement de la dyslipidémie - Google Patents

Nouveaux composés appropriés pour le traitement de la dyslipidémie Download PDF

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WO2014192023A1
WO2014192023A1 PCT/IN2014/000337 IN2014000337W WO2014192023A1 WO 2014192023 A1 WO2014192023 A1 WO 2014192023A1 IN 2014000337 W IN2014000337 W IN 2014000337W WO 2014192023 A1 WO2014192023 A1 WO 2014192023A1
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oxy
ethyl
imino
phenoxy
ethanone
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PCT/IN2014/000337
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English (en)
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Ranjit C. Desai
Harikishor PINGALI
Vrajesh PANDYA
Pankaj Makadia
Pankaj Patel
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Cadila Healthcare Limited
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
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    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
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    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
    • C07C251/52—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

Definitions

  • the present invention relates to compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.
  • the present invention is directed towards compounds which can be used to treat diseases such as Hyperlipidemia and also have a beneficial effect on cholesterol.
  • the compounds of the general formula (I) lower blood glucose, lower or modulate triglyceride levels and/or cholesterol levels and/or low-density lipoproteins (LDL) and raises the high-density lipoproteins (HDL) plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) is beneficial.
  • LDL low-density lipoproteins
  • HDL high-density lipoproteins
  • the compounds of general formula (I) are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions such as artereosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders.
  • Syndrome X The characteristic features of Syndrome X include initial insulin resistance followed by hyperinsulinemia, dyslipidemia and impaired glucose tolerance.
  • the glucose intolerance can lead to non-insulin dependent diabetes mellitus (NIDDM, Type 2 diabetes), which is characterized by hyperglycemia, which if not controlled may lead to diabetic complications or metabolic disorders caused by insulin resistance. Diabetes is no longer considered to be associated only with glucose metabolism, but it affects anatomical and physiological parameters, the intensity of which vary depending upon stages/duration and severity of the diabetic state.
  • NIDDM non-insulin dependent diabetes mellitus
  • the compounds of this invention are also useful in prevention, halting or slowing progression or reducing the risk of the above mentioned disorders along with the resulting secondary diseases such as cardiovascular diseases, like arteriosclerosis, atherosclerosis; diabetic retinopathy, diabetic neuropathy ' and renal disease including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal diseases, ; like microalbuminuria and albuminuria, which may be result of hyperglycemia or hyperinsulinemia.
  • cardiovascular diseases like arteriosclerosis, atherosclerosis
  • the compounds of the present invention can be useful as aldose reductase inhibitors; for improving cognitive functions in dementia, and in the treatment and/or prophylaxis of disorders such as psoriasis, polycystic ovarian syndrome (PCOS), cancer, osteoporosis, leptin resistance, inflammation and inflammatory bowel diseases, wound healing, xanthoma, pancreatitis, myotonic dystrophy, endothelial cell dysfunction and hyperlipidemia.
  • disorders such as psoriasis, polycystic ovarian syndrome (PCOS), cancer, osteoporosis, leptin resistance, inflammation and inflammatory bowel diseases, wound healing, xanthoma, pancreatitis, myotonic dystrophy, endothelial cell dysfunction and hyperlipidemia.
  • disorders such as psoriasis, polycystic ovarian syndrome (PCOS), cancer, osteoporosis, leptin resistance, inflammation and inflammatory bowel diseases, wound healing
  • LDL cholesterol levels in the plasma Increase cardiovascular risk and reduction in the levels of LDL would decrease CVD risk by a comparable percentage (PNAS, 2009, 106, 9546-9547).
  • Clearance of LDL cholesterol from plasma is through the action of LDL receptors in the liver and LDL receptors are cell surface glycoproteins that.bind to apoliporpotein B 100.(apoB100) on LDL particles with high affinity and mediate their ehdocytic uptake (Journal of Biological Chemistry, 2009, 284, 10561-10570). Defect in hepatic cholesterol clearance and elevated levels of plasma LDL cholesterol that result from the mutations cause familial hypercholesterolemia.
  • Such mutations are identified in the human LDL receptor and later in apolipoprotein-B (Nature Structural and Molecular Biology, 2007, 14, 413- 419). Recently, mutations within certain subtypes .of the pro-protein convertase subtilisin/ gene such as the subtype nine (hereinafter "the gene") were found to represent a third class of mutations associated with autosomal dominant hypercholesterolemia (ADH). The discovery, etiology and functions of this subtype gene is discussed in details in Nature Genetics, 2003, 34, 154-156, Trends in Biochemical Sciences, 2008, 33, 426-434 etc..
  • the main objective of the present invention is to provide novel substituted oximino derivatives represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof.
  • compositions containing compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • the present invention relates to compounds of the general formula
  • ⁇ ' represents an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups
  • f A' is selected from optionally substituted aryl or heterocyclyl groups
  • the aryl group may be selected from substituted or unsubstituted monocyclic or bicyclic aromatic groups
  • the aryl group is an optionally substituted phenyl group.
  • the heterocyclyl group when ' ⁇ ' represents a heterocyclyl group, may be selected from single or fused mono, bi or tricyclic aromatic or non- aromatic groups containing one or more hetero atoms selected from O, N or S;
  • the heterocyclyl group may be selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyr, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl> benzimidazolyl, benzotriazolyl, phthalazynil, nap
  • 'Y' represents either a bond or substituted or unsubstituted linear or branohed (Ci-C 6 )alkyl, (C 2 -C )alkeriyl groups or the groups represented by '-U(CH 2 ) m -' wherein U represents 0, S(0) 0 , NR 4 ; 'm' represents integers from 2 to 4, ⁇ ' represents integers from 0 to 2 and R4 represents H, substituted or unsubstituted linear or branched (Ci- C 6 )alkyl; 'V represents either a bond, or may be selected from O, S(0) 0 , NR 4 or S0 2 NR 4 ; wherein R is as defined earlier;
  • 'X' represents C or N
  • 'W represents substituted or unsubstituted linear or branched (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl groups;
  • 'Z' represents substituted or unsubstituted linear or branched (Ci-C 6 )alkyl, (C - C 6 )alkenyl groups or an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups;
  • 'Z' is selected from optionally substituted aryl or heterocyclyl groups; . , v
  • the aryl group may be selected from substituted or unsubstituted monocyclic or bicyclic aromatic groups
  • the aryl group is an optionally substituted phenyl or naphthyl group.
  • the heterocyclyl group may be selected from single or fused mono or bi cyclic aromatic groups containing one or more hetero atoms selected from O, N or S; ⁇ >
  • the heterocyclic group may be selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2- oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, tetrahydropyran, dihydrofuran, tetrahydrofuran, dihydrothiazole, ⁇ benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydr
  • Ri represents hydrogen, optionally substituted, (Ci-C6)alkyl, (C3-C 6 )cycloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl groups;
  • R 2 represents hydrogen, or the groups selected from (Ci-C 6 )alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, (Q-Ceialkoxy, hydroxy, hydroxyalkyl, thio(Ci-C6)aIkyl, amino, aminoalkyl, alkylamino, each of which may be. optionally substituted;
  • R 3 at each occurrence independently represents hydrogen, halogen, (Ci- C 3 )alkyl, halo(Ci-C 3 )alkyl, (Ci-C 3 )alkoxy, thio(Ci-C 3 )alkyl, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, sulfenyl derivatives, sulfonyl derivatives;
  • 'n' represents integers from 0-3;
  • Ri and R 2 wherever possible, together may form 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(0) 0 ; -
  • the substituents at each occurrence may be independently selected from hydroxyl, oxo, halo, thiol, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino,.
  • the substituents at each occurrence may be independently selected from hydroxyl oxo, halo, thiol, nitro, amino, cyano, acyl, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, alkylsulfonylamino, alkyl
  • the substituents on any of A, Z, W, Ri, R 2 or R 3 are further substituted, the substituents may be selected from one or more groups described above.
  • radicals described above may be selected from: ⁇ ⁇ ⁇ - the "alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, «-propyl, iso-pro pyl, «-butyl, sec-butyl, tert-butyl, amyl, i-amyl, H-pentyl, n- hexyl, and the like;
  • the "alkenyl” group used either alone or in combination with other radicals is selected from a radical containing from two to six carbons, more preferably groups selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
  • alkenyl includes dienes and trienes of straight and branched chains
  • the "cycloalkyl", or ⁇ alicyclic” group used either alone or in combination with other radicals is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
  • the "cycloalkenyl” group used either alone or in combination with other radicals are preferably selected from cyclopropenyl, 1-cyclobutenyl, 2-cylobutenyl, 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl,
  • alkoxy group used either alone or in combination with other radicals is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, w-propoxy, wo-propoxy, «-butoxy, i-butoxy, /so-butoxy, pentyloxy, hexyloxy, and the like;
  • the "cycloalkoxy” group used either alone or in combination with other radicals is selected from a cyclic radical containing three to seven carbons, more preferably cyclopropyloxy, cyclobutylxoy, cyclopentyioxy, cyclohexyloxy and the like;
  • the terms "bicycloalkyloxy” means more than one cycloalkyl groups fused together;
  • the "alkenoxy” group used either alone or in combination with other radicals is selected from groups containing an alkenyl radical, as defined above, attached to an oxygen atom, more preferably selected from vinyloxy, allyloxy, butenoxy, pentenoxy, hexenoxy, and the like;
  • haloalkyl is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoroCQ-C ⁇ alkyl such as fiuoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
  • perhaloalkyl more preferably, perfluoroCQ-C ⁇ alkyl such as fiuoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
  • haloalkoxy is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like;
  • the "aryl” or “aromatic” group used either alone or in combination with other radicals is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like;
  • aryloxy group used either alone or in combination with other radicals is selected from groups containing an aryl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenyloxy, and the like;
  • heterocyclyl or “heterocyclic” group used either alone or in combination with other radicals, is selected from suitable aromatic or non-aromatic radicals containing one or more hetero atoms selected from O, N or S.
  • the non-aromatic radicals may be saturated, partially saturated or unsaturated mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2- oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2- oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thi
  • heterocycloxy is selected from suitable heterocyclyl, heterocylylalkyl groups respectively, as defined above, attached to an oxygen atom;
  • acyl group used either alone or in combination with other radicals is selected from a radical containing one to eight carbons, more preferably selected from formyl, acetyl, propanoyl, butanoyl, wo-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted;
  • acyloxy used either alone or in combination with other radicals, is selected from a suitable acyl group, as defined above, directly attached to an oxygen atom, more preferably such groups are selected from acetyloxy, propionyloxy, butanoyloxy, wo-butanoyloxy, benzoyloxy and the like;
  • the "acylamino" group used either alone or in combination with other radicals is selected from a suitable acyl group as defined earlier, attached to an amino radical, more preferably such groups are selected from CH 3 CONH, C 2 H 5 CONH, C 3 H 7 CONH, QH 9 CONH, C 6 H 5 CONH and the like, which may be substituted;
  • - the "mono-substituted amino” group used either alone or in combination with other radicals represents an amino group substituted with one group selected from (Q- C 6 )alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from methylamine, ethylamine, n- propylamine, n-butylamine, n-pentylamine and the like;
  • the 'disubstituted amino" group used either alone or in combination with other radicals represents an amino group, substituted with two radicals that may be same or different and may
  • arylamino used either alone or in combination with other radicals, represents an aryl group, as defined above, linked through amino having a free valence bond from the nitrogen atom, more preferably the groups are selected from phenylamino, naphthylamino, N-methyl anilino and the like;
  • carboxylic acid used alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic acid such as esters and amides;
  • the "ester” group used alone or in combination with other radicals denotes -COO- group, and includes carboxylic acid derivatives, more preferably the ester moieties are selected from alkoxycarbonyl; * such as methoxycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may optionally be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may optionally be substituted; heterocyclyloxycarbonyl, where the heterocyclic group, as defined earlier, which may optionally be substituted; the "amide" group used alone or in combination with other radical
  • the "aminocarbonyl” group used either alone or in combination with other radicals may be selected from 'aminocarbonyl', 'aminocarbonylalkyl", "n- alkylaminocarbonyl", “N-arylaminocarbonyl”, “ ⁇ , ⁇ -dialkylaminocarbonyl”, “N- alkyl-N-arylaminocarbonyl”, “N-alkyl-N-hydroxyaminocarbonyl”, and "N-alkyl- N-hydroxyaminocarbonylalkyl", each of them being optionally substituted.
  • N-alkylaminocabonyl and “ ⁇ , ⁇ -dialkylaminocarbonyl” denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical and with two alkyl radicals, respectively. Preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to aminocarbonyl radical.
  • N-arylaminocarbonyl and “N-alkyl-N- arylaminocarbonyl” denote amiocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl, and one aryl radical.
  • aminocarbonylalkyl includes alkyl radicals substituted with aminocarbonyl radicals;
  • hydroxyalkyl group used either alone or in combination with other radicals is selected from an alkyl group, as defined above, substituted with one or more hydroxy radicals, more preferably the groups are selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like;
  • aminoalkyi used alone or in combination with other radicals, denotes an amino (-NH 2 ) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyi.
  • alkylamino used herein, alone or in combination with other radicals, denotes an alkyl radical, as defined above, attached to an amino group, which may be substituted, such as mono- and di-substituted alkylamino;
  • alkoxyalkyl used alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group as defined above, more preferably the groups may be selected from methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like;
  • alkylthio denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, ethylthio, propylthio,
  • thioalkyl used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula -SR.', where R' represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted.
  • alkoxycarbonylamino used alone or in combination with other radicals, is selected from a suitable alkoxycarbonyl group, as defined above, attached to an amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like;
  • the "arylthio" group used either alone or in combination with other radicals denotes a comprising an aryl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from phenylthio, naphthylthio, tetrahydronaphthylthio, indanethio, biphenylthio, and the like;
  • the "heterocyclylthio" group used either alone or in combination with other radicals denotes a comprising an heterocyclyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from aziridinylthio, azetidinylthio, pyrrolidinylthio, imidazolidinylthio, piperidinylthio, piperazinylthio, 2- oxopiperidinylthio, 4-oxopiperidinylthio, 2-oxopiperazinylthio, 3- oxopiperazinylthio, morpholinylthio, thiomorpholinylthio, 2-oxomorpholinylthio, azepinylthio, diazepinylthio, oxapinylthio, thiazepinylthio, oxazolidinylthio,
  • alkoxycarbonylamino used alone or in combination with other radicals, is selected from a suitable alkoxycarbonyl group, as defined above, attached to an amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like;
  • aminocarbonylamino is a carbonylamino (-CONH 2 ) group, attached to amino(NH 2 ), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above;
  • the "alkylamidino” group represents an alkyl radical, as described above, attached to an amidino group
  • the "alkoxyamino” group used either alone or in combination with other radicals represents a suitable alkoxy group as defined above, attached to an amino group
  • the "hydroxyamino” group used either alone or in combination with other radicals represents a -NHOH moiety, and may be optionally substituted with suitable groups selected from those described above;
  • the "sulfenyl” group or “sulfenyl derivatives” used alone or in combination with other radicals represents a bivalent group, -SO- or R x SO, where R x is an optionally substituted alkyl, aryl, heteroaryl, heterocyclyl, group selected from those described above;
  • the "sulfonyl” group or “sulfones derivatives” used either alone or in combination with other radicals, with other terms such as alkylsulfonyl, represents a divalent radical -S0 2 -, or R x S0 2 -, where R x is as defined above.
  • the groups may be selected from “alkylsulfonyl” wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, "arylsulfonyl” wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.
  • sulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like
  • arylsulfonyl wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in
  • Such administration encompasses coadministration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient.
  • administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • therapeutic effective is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.
  • therapeuticically acceptable refers to those compounds (or their salts, prodrugs, tautomers, zwitterionic formsj etc.) which are suitable for use in patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • patient means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
  • Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
  • Particularly useful compounds may be selected from:
  • novel compounds of this invention may be prepared using the reactions and techniques as shown in scheme below and described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. It will also be well appreciated that one or more of the reactants may be protected and deprotected for facile synthesis by techniques known to persons skilled in the art. It will also be appreciated that one or more of the compounds of the present invention may exist in stereoisomeric and/or diastereomeric forms.
  • Such stereoisomers and/or diastereoisomers as well as their optical antipodes are to be construed to be within the scope of the present invention. It will also be well appreciated that one or more of these compounds may be converted to their salts and other derivatives based on the specific groups present on the compounds, which can be well comprehended by persons skilled in the art. Such salts and/or other derivatives, as the case may be should also be construed to be within the scope of the present invention.
  • the compounds of formula V wherein all the symbols are as defined earlier may be prepared by using appropriate starting materials IV wherein all the symbols are as defined earlier, using hydrazine hydrate as a deprotecting agent.
  • the reaction may be carried out neat or in presence of suitable protic solvent(s) such as methanol, ethanol, butanol and the like or suitable aprotic solvent(s) such as toluene, tetrahydrofuran, dichloromethane and the like or suitable mixtures thereof.
  • suitable protic solvent(s) such as methanol, ethanol, butanol and the like or suitable aprotic solvent(s) such as toluene, tetrahydrofuran, dichloromethane and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours;
  • the compounds of the formula VII wherein all the symbols are as defined earlier may be prepared by reacting appropriate ketones VI with oxyamine compounds of formula V wherein all the symbols are as defined earlier in the presence of a base(s) like NaOH, NaOAc, pyridine and the like.
  • the reaction may be carried out in presence of suitable solvent(s) such as methanol, ethanol, butanol, water and the like or suitable mixtures thereof.
  • suitable solvent(s) such as methanol, ethanol, butanol, water and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
  • Compounds of general formula I wherein all the symbols are as defined earlier may be prepared by reacting the compounds of general formula VII with compounds of formula VIII wherein all the symbols are as defined earlier using suitable inorganic base(s) such as NaOH, KOH, K 2 C0 3 , Cs 2 C0 3 and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like.
  • suitable inorganic base(s) such as NaOH, KOH, K 2 C0 3 , Cs 2 C0 3 and the like
  • organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like.
  • reaction may be carried out in presence of suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dimethylformamide (DMF), dichloromethane and the like or mixtures thereof by means of the methods available in the literature for standard nucleophilic substitution reaction;
  • suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dimethylformamide (DMF), dichloromethane and the like or mixtures thereof by means of the methods available in the literature for standard nucleophilic substitution reaction;
  • suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dimethylformamide (DMF), dichlor
  • Compounds of general formula XII wherein all the symbols are as defined earlier may be prepared by reacting the compounds of general formula VI wherein all the symbols are as defined earlier and the compounds of general formula XI using suitable inorganic base(s) such as NaOH, KOH, 2C03, Cs2C03 and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like.
  • suitable inorganic base(s) such as NaOH, KOH, 2C03, Cs2C03 and the like
  • organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like.
  • reaction may be carried out in presence of suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dimethylformamide (DMF), dichloromethane and the like or mixtures thereof by means of the methods available in the literature for standard nucleophilic substitution reaction;
  • suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dimethylformamide (DMF), dichloromethane and the like or mixtures thereof by means of the methods available in the literature for standard nucleophilic substitution reaction;
  • compounds of general formula XII wherein all the symbols are as defined earlier may be prepared by coupling of compounds of formula IX wherein all the symbols are as defined earlier and compounds of general formula X wherein all other symbols are as defined using suitable inorganic base(s) such as NaOH, KOH, K2C03, Cs2C03 and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like.
  • suitable inorganic base(s) such as NaOH, KOH, K2C03, Cs2C03 and the like
  • organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like.
  • reaction may be carried out in presence of suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dimethylformamide (DMF), dichloromethane and the like or mixtures thereof;
  • suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dimethylformamide (DMF), dichloromethane and the like or mixtures thereof;
  • Compounds of general formula XIII wherein all the symbols are as defined earlier may be prepared by reacting compounds of general formula XII wherein all the symbols are as defined earlier with hydro xylamine hydrochloride in the presence of a base(s) like NaOH, NaOAc, pyridine and the like.
  • the reaction may be carried out in presence of suitable solvent(s) such as methanol, ethanol, butanol, water and the like or suitable mixtures thereof.
  • suitable solvent(s) such as methanol, ethanol, butanol, water and the like or suitable mixtures thereof.
  • the reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours;
  • Compounds of general formula XIV wherein all the symbols are as defined earlier may be prepared by reacting the compounds of general formula XIII with compounds of formula II wherein all the symbols are as defined earlier using suitable inorganic base(s) such as NaOH, KOH, K2C03, Cs2C03 and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like.
  • suitable inorganic base(s) such as NaOH, KOH, K2C03, Cs2C03 and the like
  • organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like.
  • reaction may be carried out in presence of suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dichloromethane and the like or mixtures thereof by means of the methods available in the literature for standard nucleophilic substitution;
  • suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dichloromethane and the like or mixtures thereof by means of the methods available in the literature for standard nucleophilic substitution;
  • Compounds of general formula XV wherein all the symbols are as defined earlier may be prepared by the hydrolysis of compounds of general formula XIV wherein all the symbols are as defined earlier under suitable condition; vi.
  • the compounds of formula XVI wherein all the symbols are as defined earlier may be prepared by coupling reaction of corresponding acids of general formula XIV wherein all the symbols are as defined earlier and ⁇ , ⁇ - dimethylhydroxylamine under suitable conditions such as those generally described in Tetrahedron, 2005, 61(46), 10827-10852 with suitable modifications and alterations as are well known to a skilled person.
  • the reaction may be carried out in presence of reagents(s) such as N-(3- dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride (EDC1) & 1- Hydroxybenzotriazole (HOBT), and the like.
  • reagents(s) such as N-(3- dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride (EDC1) & 1- Hydroxybenzotriazole (HOBT), and the like.
  • EDC1 N-(3- dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride
  • HOBT 1- Hydroxybenzotriazole
  • the reaction may be carried in suitable solvent(s) such as dimethyl formamide, tetrahydrofuran, dichloromethane and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and
  • composition is provided by employing conventional techniques.
  • composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.
  • the quantity of active component that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
  • the compound of the present invention may be used alone or in combination with a second medicament as may be necessary depending on the condition of the patient, the severity of the disease and such other conditions which are well known to a skilled practitioner.
  • Such second medicament when required may be selected from a HMG-Co-A reductase inhibitor, angiotensin converting enzyme (ACE) inhibitor, calcium channel blocker, aldosterone synthase inhibitor, aldosterone antagonist, dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, endothelin antagonist, angiotensin II receptor blocker (ARB) including their pharmaceutically acceptable salts as well as a combination of one or more medicines from any of these classes along with the compound of formula (I) of the present invention.
  • ACE angiotensin converting enzyme
  • ARB angiotensin II receptor blocker
  • Step4 -l-phenyl-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl) phenoxy) ethanone
  • l-(4-hydroxyphenyl)ethanone 0-(4-(trifluoromethyl)benzyl) oxime 300 mg, 0.970 mmol
  • DMF 5 ml
  • 2-chloro-l-phenylethanone 180 mg, 1.164 mmol
  • reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined organic layer was washed with water & brine, dried over Na 2 S0 4 and evaporated under vacuum to yield 500 mg crude product as sticky solid.
  • the crude product was purified by column chromatography (230-400 silica gel column, Eluent: 4% EtOAc in Hexane) to yield 200 mg, (47.1 %) of pure product as white crystalline solid.
  • Step 3 Methyl 2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)pyridin-2- yl)oxy)acetate
  • Step 4 2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)pyridin-2-yl)oxy)acetic acid
  • a solution of the product of step 3 (2.0 gm, 5.2 mmoles) in a mixture of THF (12 mL), methanol (4 mL) and water (4 mL)
  • lithium hydroxide (440 mg, 10.5 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure.
  • the residue was dissolved in water, acidified with IN HC1 and extracted with ethyl acetate.
  • the ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 1.7 gm (88%) of title product as white solid.
  • Step 5 N-methoxy-N-methyl-2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy)imino) ethyl) pyridin-2-yl)oxy)acetamide.
  • reaction mixture was stirred at 30 °C for 22 hours.
  • the reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (3 x 15 mL).
  • the combined organic layer was washed with water & brine, dried over Na 2 S0 4 and evaporated under vacuum to yield N-methoxy-N-methyl-2-((5- (l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)pyridin-2-yl)oxy)acetamide as yellow liquid.
  • Step 6 l-cyclopropyl-2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl) pyridin- 2-yl)oxy)ethanone.
  • N-methoxy-N-methyl-2-((5-(l-(((4-(trifluoromethyl) benzyl) oxy)imino)ethyl)pyridin-2-yl)oxy)acetamide (0.400 g, 0.972 mmol) in THF (10.00 ml)
  • freshly prepared cyclopropyl magnesium bromide using magnesium (0.236 g, 9.72 mmol) and cyclopropyl bromide (0.779 ml, 9.72 mmol) in Diethyl ether (15 ml) was added in portions at 0°C.
  • the reaction mixture was stirred at 0 °C for one hour.
  • the reaction mixture was poured into saturated solution of NH 4 C1 (25 mL) and extracted with ethyl acetate.
  • the organic layer was washed with water & brine, dried over Na 2 S0 4 and evaporated under vacuum to yield crude product as yellow liquid.
  • the crude product was purified by column chromatography (230-400 silica gel column, Eluent: 15 % EtOAc in Hexane) to yield 0.275 g, (71.6 %) of pure product as white solid.
  • Step 1 l-(4-(benzyloxy)-2-hydroxyphenyl)ethanone.
  • Step 2 Ethyl 2-(l-(4-(benzyloxy)-2-hydroxyphenyl)ethylidene)hydrazine carboxylate.
  • Step 4 Ethyl 2-acetyl-5-hydroxybenzoate.
  • a solution of ethyl 2-acetyl-5-(benzyIoxy)benzoate 1.0 g, 3.35 mmol
  • ammonium formate 0.45 g, 13.41 mmol
  • the reaction mixture was refluxed for 1 hour.
  • the reaction mixture was cooled to 30°C and the catalyst was filtered off, washed with excess ethyl acetate (20 ml). Filtrate was washed with water (3 X 20 ml), dried ovec Na 2 S0 4 and evaporated under vacuum to yield 0.6 g (86 %) of product as pale red liquid.
  • Step 6 Ethyl 5-(2-oxo-2-phenylethoxy)-2-(l-(((4-(trifluoromethyl)benzyl)oxy)imino) ethyl)benzoate.
  • Step 1 l-(4-(3,3,3-trifiuoro-2-hydroxypropoxy)phenyl)ethanone 0-(4-trifluoromethyl) benzyl) oxime
  • Step 2 l,l,l-trifluoro-3-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl) phenoxy) propan-2-one
  • Example 1-4 The following examples were prepared following the general procedures given in Example 1-4, with suitable modifications, alterations and other process variations which are within the scope of a person skilled in the art.
  • Example 60 1 -(5-Methylfuran-2-yl)-2-(4-( 1 -(((2,4,6-triisopropylbenzyl)oxy)imino) ethyl)phenoxy) ethanone
  • the compounds of the present invention lowered LDL cholesterol(LDL-c), and total cholesterol (TC). This was demonstrated by in vivo animal experiments.
  • the compounds described herein may be administered at least one of the compounds described herein or a pharmaceutically acceptable salt, ester, or prodrug thereof in combination with another therapeutic agent.
  • a combination therapy Several reasons can be attributed for using a combination therapy depending on the need of the patient.
  • one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent.
  • the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • another therapeutic agent which also includes a therapeutic regimen
  • the use of combination therapy may be envisaged for all such situations.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or. the patient may experience a synergistic benefit.
  • combination therapies include use of certain compounds disclosed herein with agents found in the following pharmaco- therapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present.
  • combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.
  • compounds disclosed herein may, if necessary, be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide- 1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-1 19 inhibitors, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR.delta agonist, HMG- CoA reductase inhibitors, cholesterol-lowering drugs, renin inhibitors, anti-thrombotic and anti-platelet agents and anti-obesity agents.
  • compounds disclosed herein may be, if necessary, administered with an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), acarbose, miglitol, voglibose, Exendin-4, , vildagliptin, Liraglutide, naliglutide, saxagliptin, pioglitazone, rosiglitazone, HMG-CoA reductase inhibitors (for example, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin,i rosuvastatin, pitavastatin and like), cholesterol-lowering drugs (for example, fibrates which include: f

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Abstract

La présente invention concerne des composés de formule générale (I), leurs formes tautomères, leurs stéréoisomères, leurs sels pharmaceutiquement acceptables, des compositions pharmaceutiques les contenant, leurs procédés de préparation, l'utilisation de ces composés en médecine et les intermédiaires impliqués dans leur préparation. Les composés de la présente invention peuvent être utilisés pour traiter des maladies telles que l'hyperlipidémie et ont également un effet bénéfique sur le cholestérol.
PCT/IN2014/000337 2013-05-22 2014-05-20 Nouveaux composés appropriés pour le traitement de la dyslipidémie WO2014192023A1 (fr)

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CN109776415A (zh) * 2019-03-07 2019-05-21 福建南方济民医药研发中心有限公司 一种Roxadustat中间体的制备方法
WO2020122380A1 (fr) * 2018-12-13 2020-06-18 고려대학교 산학협력단 Composition pharmaceutique pour la prévention ou le traitement de troubles liés au rythme circadien, comprenant un dérivé d'oxyiminométhylbenzene en tant que principe actif
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WO2020122380A1 (fr) * 2018-12-13 2020-06-18 고려대학교 산학협력단 Composition pharmaceutique pour la prévention ou le traitement de troubles liés au rythme circadien, comprenant un dérivé d'oxyiminométhylbenzene en tant que principe actif
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CN109776415B (zh) * 2019-03-07 2020-11-17 福建南方制药股份有限公司 一种Roxadustat中间体的制备方法
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