WO2008035359A2 - Acide oxyminophénoxyalcanoïque et dérivés de l'acide phenylalcanoïque - Google Patents

Acide oxyminophénoxyalcanoïque et dérivés de l'acide phenylalcanoïque Download PDF

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WO2008035359A2
WO2008035359A2 PCT/IN2007/000226 IN2007000226W WO2008035359A2 WO 2008035359 A2 WO2008035359 A2 WO 2008035359A2 IN 2007000226 W IN2007000226 W IN 2007000226W WO 2008035359 A2 WO2008035359 A2 WO 2008035359A2
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ethyl
methyl
phenoxy
acetate
phenyl
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WO2008035359A3 (fr
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Braj Bhushan Lohray
Vidya Bhushan Lohray
Harikishore Pingali
Pankaj Ramanbhai Patel
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Cadila Healthcare Limited
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • A—HUMAN NECESSITIES
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    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • 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
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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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    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole 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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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
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    • 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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    • 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
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel oximinophenoxyalkanoic acid and phenylalkanoic acid 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 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. These compounds of general formula (I) are useful for the treatment and/or prophylaxis of metabolic disorders loosely defined as 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.
  • NIDDM non- insulin dependent diabetes mellitus
  • 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.
  • 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.
  • 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
  • Hyperlipidaemia has been recognized as the major risk factor in causing cardiovascular diseases due to atherosclerosis.
  • Atherosclerosis and other such peripheral vascular diseases affect the quality of life of a large population in the world.
  • the therapy aims to lower the elevated plasma LDL cholesterol, low-density lipoprotein and plasma triglycerides in order to prevent or reduce the risk of occurrence of cardiovascular diseases.
  • the detailed etiology of atherosclerosis and coronary artery diseases is discussed by Ross and Glomset [New Engl. J. Med., 295, 369-377 (1976)].
  • Plasma cholesterol is generally found esterified with various serum lipoproteins and numerous studies have suggested an inverse relationship between serum HDL- cholesterol level and risk for occurrence of cardiovascular disease.
  • Diabetes is associated with a number of complications and also affect a large population. This disease is usually associated with other diseases such as obesity, hyperlipidemia, hypertension and angina. It is well established that improper treatment can aggravate impaired glucose tolerance and insulin resistance, thereby leading to frank diabetes. Further, patients with insulin resistance and type 2 diabetes often have raised triglycerides and low HDL-cholesterol concentrations and therefore, have greater risk of cardiovascular diseases.
  • the present therapy for these diseases includes sulfonylureas and biguanides along with insulin. This type of drug therapy may lead to mild to severe hypoglycemia, which may lead to coma or in some cases may lead to death, as a result of unsatisfactory glycaemic control by these drugs.
  • thiazolidinediones drugs having insulin- sensitizing action.
  • Thiazolidinediones like troglitazone, rosiglitazone and pioglitazone are prescribed alone or in combination with other anti-diabetic agents. These are useful in treating diabetes, lipid metabolism but are suspected to have tumor- inducing potential and cause hepatic dysfunction, which may lead to liver failure. Further, serious undesirable side-effects have occurred in animal and/or human studies which include cardiac hypertrophy, hema dilution and liver toxicity in a few glitazones progressing to advanced human trials. The drawback is considered to be idiosyncratic.
  • Obesity is another major health problem being associated with increased morbidity and mortality. It is a metabolic disorder, in which excess of fat is accumulated in the body. Although, its etiology is unclear, the general feature includes excess of calorie intake than it is consumed.
  • Various therapies such as dieting, exercise, appetite suppression, inhibition of fat absorption etc. have been used to combat obesity. However, more efficient therapies to treat this abnormality is essential as obesity is closely related to several diseases such as coronary heart disease, stroke, diabetes, gout, osteoarthritis, hyperlipidaemia and reduced fertility. It also leads to social and psychological problems [Nature Reviews: Drug Discovery: 1(4), 276-86 (2002)].
  • PPAR Peroxisome Proliferator Activated Receptor
  • PPARoc, PPAR ⁇ and PPAR ⁇ have been identified as subtypes of PPARs. Extensive reviews regarding PPAR, their role in different diseased conditions are widely published [Endocrine Reviews, 20(5), 649-688 (1999); J. Medicinal Chemistry, 43(4), 58-550 (2000); Cell, 55, 932-943 (1999); Nature, 405, 421-424 (2000); Trends in Pharmacological ScI, 469-473 (2000)].
  • PPAR ⁇ activation has been found to play a central role in initiating and regulating adipocyte differentiation [Endocrinology 135, 798-800, (1994)] and energy homeostasis, [Cell, 83, 803-812 (1995); Cell, 99, 239-242 (1999)].
  • PPAR ⁇ agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristic of a more differentiated, less malignant state.
  • adipocyte differentiation several highly specialized proteins are induced, which are being involved in lipid storage and metabolism.
  • PPAR ⁇ activation leads to expression of CAP gene [Cell Biology, 95, 14751- 14756, (1998)], however, the exact link from PPAR ⁇ activation to changes in glucose metabolism and decrease in insulin resistance in muscle has not been clear.
  • PPAR ⁇ is involved in stimulating ⁇ -oxidation of fatty acids [Trends Endocrine. Metabolism, 4, 291-296 (1993)] resulting in plasma circulating free fatty acid reduction [Current Biol, 5, 618-621 (1995)].
  • role of PPAR ⁇ activation in the terminal differentiation of adipocyte precursors has been implicated in the treatment of cancer.
  • PPAR ⁇ is broadly expressed in the body and has been shown to be a valuable molecular target for treatment of dyslipidimia, inflammation, wound healing and other diseases.
  • PPAR ⁇ agonists have been found useful in the treatment of obesity (WO 97/36579).
  • Dual PPAR ⁇ and ⁇ agonists have been suggested to be useful for Syndrome X (WO 97/25042).
  • PPAR delta compound was shown to decrease VLDL and increase HDL in a dose dependent manner (Proc. Natl. Acad. Sci.U.S.A. 98, 5305, 2001).
  • PPAR ⁇ agonists and HMG-CoA reductase inhibitors have exhibited synergism and indicated the usefulness of the combination in the treatment of atherosclerosis and xanthoma (EP 0753 298).
  • Leptin is a protein when bound to leptin receptors is involved in sending satiety signal to the hypothalamus. Leptin resistance would therefore lead to excess food intake, reduced energy expenditure, obesity, impaired glucose tolerance and diabetes [Science, 269, 543-46(1995)]. It has been reported that insulin sensitizers lower plasma leptin concentration [Proc. Natl. Acad. ScL 93, 5793-5796 (1996): WO 98/02159)].
  • hypocholesterolemic useful as hypocholesterolemic, hypolipidaemic, hypolipoproteinemic, anti-obesity and antihyperglycemic agents which may have additional body weight lowering effect and beneficial effect in the treatment and/or prophylaxis of diseases caused by hyperlipidaemia, diseases classified under Syndrome X, atherosclerosis, inflamation and wound healing and methods for their preparation.
  • the main objective of the present invention is to provide novel substituted oximinophenoxyalkanoic acid and phenylalkanoic acid and their 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.
  • 'A' represents an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups
  • 'A' is selected from optionally substituted aryl or heterocyclyl groups
  • the aryl group may be selected from monocyclic or bicyclic aromatic groups; in a still further embodiment, the aryl group is an optionally substituted phenyl group.
  • the heterocyclyl group may be selected from single or fused mono, bi or tricyclic aromatic or non-aromatic radicals containing one or more hetero atoms selected from
  • the heterocyclyl group may be selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, indolinyl, indolyl, pyrazolyl, quinazolinyl, quinazolinonyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, benzoxazine, benzoxazinone, oxazolidinone groups;
  • 'W represents substituted or unsubstituted linear or branched (Ci-C ⁇ )alkyl, (C 2 -
  • C 6 alkenyl groups
  • 'W is selected from (Ci-C 3 )alkyl or (C 2 -C 4 )alkenyl groups
  • Ri represents optionally substituted linear or branched (C]-C 6 )alkyl, (C 3 -C ⁇ )cycloalkyl, aryl, aralkyl groups;
  • the aryl group represents optionally substituted phenyl group;
  • R 2 represents hydrogen, linear or branched substituted or unsubstituted (Ci-Ce)alkyl ;
  • R 3 at each occurrence independently represents hydrogen, halo, optionally substituted groups selected from linear or branched (Ci-C 3 )alkyl, halo(C]-C 3 )alkyl, (Ci-C 3 )alkoxy, thio(Ci-C 3 )alkyl, sulfenyl derivatives, sulfonyl derivatives;
  • R 4 and R 5 may be same or different and independently represents H or (Ci-Ce)alkyl;
  • X represents either a bond or oxygen or the group -CH 2 -;
  • the substituents may be independently selected from hydroxyl, oxo, halo, thio, amino, or substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, acyl, arylamino, aralkylamino, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, sulfenyl derivatives, sulfonyl derivative
  • the substituents on A or Ri may be independently selected from hydroxyl, oxo, halo, thio, amino, or substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, aryloxy, acyl, hydroxyalkyl, alkoxyalkyl, alkylthio, arylthio, alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, sulfenyl derivatives, sulfonyl derivatives.
  • radicals described above may be selected from:
  • alkyl 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, wo-propyl, n-butyl, sec-butyl, tert-butyl, amyl, /-amyl, «-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, 2-hexenyl, 3-hexenyl, 4-hexenyl and the like;
  • the "alkenyl” group includes dienes and trienes of straight and branched chains;
  • 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;
  • alkoxy 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, n- propoxy, ⁇ opropoxy, «-butoxy, ⁇ -butoxy, w ⁇ -butoxy, pentyloxy, hexyloxy, 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, perfluoro(Ci-C6)alkyl such as fluoromethyl, di
  • 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, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyra ⁇ onyl, benzodihydrofuranyl,
  • the "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 L methyl anilino and the like;
  • 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
  • hydroxyalkyl 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;
  • alkoxyalkyl 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,
  • 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 "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 -SO 2 -, or R x SO 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.
  • Suitable groups and substituents on the groups may be selected from those described anywhere in the specification. Particularly useful compounds may be selected from Ethyl-[4-( 1 -hydroxyimino-propyl)-phenoxy]-acetate; Ethyl-[4-(l-hydroxyimino-butyl)-phenoxy]-acetate; Ethyl-[4-(l-hydroxyimino-ethyl)-2-methyl-phenoxy]-acetate; Ethyl-[4-(hydroxyimino-phenyl-methyl)-2-methyl-phenoxy]-acetate; 26
  • novel compounds of this invention may be prepared using the reactions and techniques described in the following section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. 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.
  • Scheme: 1 The compounds of general formula (I) wherein all the symbols are as defined earlier, may be prepared by reactions outlined in Scheme 1 below which comprises:
  • the reaction may be carried out in presence of solvent(s) such as acetone, tetrahydrofuran, dimethyl sulfoxide, dioxane, acetonitrile, dimethyl formamide, dimethoxy ethane, benzene, toluene, petroleum ether, heptane, hexane, 2-butanone, xylene, alcohols such as methanol, ethanol, propanol, butanol, iso-butanol, tert-butanol, pentanol and the like or mixtures thereof.
  • solvent(s) such as acetone, tetrahydrofuran, dimethyl sulfoxide, dioxane, acetonitrile, dimethyl formamide, dimethoxy ethane, benzene, toluene, petroleum ether, heptane, hexane, 2-butanone, xylene, alcohols such as methanol, ethanol
  • Base(s) such as alkali metal carbonates such as K2CO3, Na 2 CO 3 , CsCO 3 , and the like; or alkali metal hydroxides such as NaOH, KOH and the like, may be used during this reaction.
  • Alkali metal hydride(s) such as NaH, KH can be used whenever solvent employed is not protic or contain carbonyl group.
  • the reaction may be carried out at a temperature in the range 0 0 C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
  • Method B The compound of formula (Ia) may be hydrolysed to compound of formula (I) using suitable base(s) e.g., NaOH, LiOH, KOH and the like. Reaction may be conducted in suitable solvents e.g., alcohols like methanol, ethanol and the like, THF, water or the mixtures thereof. The reaction may be carried out at a temperature in the range 20 0 C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
  • Method C The intermediate of the formula (VI) may be converted to its corresponding oxime (III) by treating with hydroxylamine hydrochloride in the presence of a base(s) like NaOH, NaOAc and the like.
  • Reaction may be conducted in a suitable solvent system which is preferably a mixture of water and alcohol(s) like ethanol. Reaction may be carried out at a temperature in the range of 20 0 C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
  • a suitable solvent system which is preferably a mixture of water and alcohol(s) like ethanol. Reaction may be carried out at a temperature in the range of 20 0 C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.
  • Example 11 Ethyl-[4-( 1 -hydroxyimino-ethyl)-phenyl]-acetate.
  • Example 12 Ethyl- ⁇ 4-[l-(3-methyl-4-oxo-3,4-dihydro-quinazolin-2-ylmethoxyimino)-propyl]- phenoxy ⁇ -acetate.
  • Example 12 with appropriate variations of reactants, reaction conditions and quantities of reagents.
  • Example 21 Ethyl- ⁇ 4-[l-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxyimino)-propyl]-phenoxy ⁇ - acetate.
  • Example 22 Ethyl- ⁇ 4-[l-(4-trifluoromethyl-benzyloxyimino)-propyl]-phenoxy ⁇ -acetate.
  • Example 23 Example 23
  • Example 25 Ethyl- ⁇ 2-methyl-4-[l-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxyimino)-ethyl]-phenoxy ⁇ - acetate.
  • Example 32 Ethyl- ⁇ 4-[l-(2-indpl-l-yl-ethoxyimino)-ethyl]-2-methyl-phenoxy ⁇ -acetate.
  • Example 33 Ethyl- ⁇ 4-[l-(2-indpl-l-yl-ethoxyimino)-ethyl]-2-
  • Example 40 Ethyl-(4- ⁇ cyclohexyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol- 5ylmethoxyimino]-methyl ⁇ -2-methyl-phenoxy)-acetate.
  • Example 42 Ethyl- ⁇ 4-[ 1 -(2-carbazol-9-yl-ethoxyimino)-2-phenyl-ethyl]-2-methyl-phenoxy ⁇ - acetate.
  • Example 49 Ethyl- ⁇ 4-[cyclohexyl-(2-indol- 1 -yl-ethoxyimino)-methyl] -2 -methyl -phenoxy ⁇ -acetate.
  • Example 50 Ethyl- ⁇ 4-[cyclohexyl-(2-indol- 1 -yl
  • Example 60 ⁇ 4-[l -(2 -p-Tolyl-ethoxyimino)-propyl]-phenoxy ⁇ -acetic acid.
  • Example 61 (4- ⁇ 1 -[2-(4-Methoxy-phenyl)-ethoxyimino]-propyl ⁇ -phenoxy)-acetic acid.
  • Example 65 ⁇ 4-[l-(5-Methyl-2-p-tolyl-oxazol-4-ylmethoxyimino)-propyl]-phenoxy ⁇ -acetic acid.
  • Example 70 ⁇ 2-Methyl-4-[l-(5-methyl-2-phenyl-oxazol-4-ylmethoxyimino)-ethyl]-phenoxy ⁇ -acetic acid.
  • Example 77 ⁇ 4-[l-(2-Indol-l-yl-ethoxyimino)-ethyl]-2-methyl-phenoxy ⁇ -acetic acid.
  • Example 81 ⁇ 2-Methyl-4-[l-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxyimino)-2-phenyl-ethylj- phenoxy ⁇ -acetic acid.
  • Example 83 ⁇ 2-Methyl-4-[(5-methyl-2-p-tolyl-oxazol-4-ylmethoxyimino)-phenyl-methyl]- phenoxy ⁇ -acetic acid.
  • Example 88 ⁇ 4-[l-(2-Indol- 1 -yl-ethoxyimino)-2-phenyl-ethyl]-2-methyl-phenoxy ⁇ -acetic acid.
  • Example 92 ⁇ 4-[l-(2-Indol-l-yl-ethoxyimino)-butyl]-2-methyl-phenoxy ⁇ -acetic acid.
  • Example 103 2-Methyl-4-[2-thiophen-3-yl-l-(4-trifluoromethyl-benzyloxyimino)-ethyl]-phenoxy ⁇ - acetic acid.
  • the compounds of the present invention are therefore suitable as hypocholesterolemic, hypolipidaemic, hypolipoproteinemic, anti-obesity and antihyperglycemic agents which may have additional body weight lowering effect.
  • 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 (1) according to this invention.
  • the quantity of active component that is, the compounds of formula (1) 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.

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Abstract

La présente invention concerne un acide oxyminophénoxyalcanoïque et l'acide phénylalcanoïque de la formule générale (I) leurs formes tautomères, leurs stéréoisomères, leurs sels pharmaceutiquement acceptables, les compositions pharmaceutiques les contenant, leurs procédés de préparation, l'utilisation de ces composés en médicine et les intermédiaires impliqués dans leur préparation.
PCT/IN2007/000226 2006-06-12 2007-06-05 Acide oxyminophénoxyalcanoïque et dérivés de l'acide phenylalcanoïque WO2008035359A2 (fr)

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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010084512A1 (fr) * 2008-12-24 2010-07-29 Cadila Healthcare Limited Nouveaux dérivés d'oxime
WO2010049946A3 (fr) * 2008-10-27 2010-07-29 Cadila Healthcare Limited Ligands des récepteurs thyroïdiens
WO2010110479A1 (fr) * 2009-03-26 2010-09-30 日本ケミファ株式会社 Activateur pour récepteur activé par des proliférateurs de peroxisomes
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
JP2014504590A (ja) * 2010-12-28 2014-02-24 カディラ ヘルスケア リミティド 脂質異常症の治療に適したヘテロ環式化合物
WO2014192023A1 (fr) * 2013-05-22 2014-12-04 Cadila Healthcare Limited Nouveaux composés appropriés pour le traitement de la dyslipidémie
WO2015107541A1 (fr) * 2013-12-16 2015-07-23 Cadila Healthcare Limited Dérivés d'oximino pour le traitement de la dyslipidémie
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
KR20200090649A (ko) * 2020-06-29 2020-07-29 고려대학교 산학협력단 옥시이미노메틸벤젠 유도체

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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010049946A3 (fr) * 2008-10-27 2010-07-29 Cadila Healthcare Limited Ligands des récepteurs thyroïdiens
CN102197019A (zh) * 2008-10-27 2011-09-21 卡迪拉保健有限公司 甲状腺受体配体
JP2012506854A (ja) * 2008-10-27 2012-03-22 カディラ・ヘルスケア・リミテッド 甲状腺受容体リガンド
WO2010084512A1 (fr) * 2008-12-24 2010-07-29 Cadila Healthcare Limited Nouveaux dérivés d'oxime
US8742117B2 (en) 2008-12-24 2014-06-03 Cadila Healthcare Limited Oxime derivatives
WO2010110479A1 (fr) * 2009-03-26 2010-09-30 日本ケミファ株式会社 Activateur pour récepteur activé par des proliférateurs de peroxisomes
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
JP2014504590A (ja) * 2010-12-28 2014-02-24 カディラ ヘルスケア リミティド 脂質異常症の治療に適したヘテロ環式化合物
US8822414B2 (en) * 2010-12-28 2014-09-02 Cadila Healthcare Limited Heterocyclic compounds suitable for the treatment of dyslipidemia
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014192023A1 (fr) * 2013-05-22 2014-12-04 Cadila Healthcare Limited Nouveaux composés appropriés pour le traitement de la dyslipidémie
WO2015107541A1 (fr) * 2013-12-16 2015-07-23 Cadila Healthcare Limited Dérivés d'oximino pour le traitement de la dyslipidémie
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
KR20200090649A (ko) * 2020-06-29 2020-07-29 고려대학교 산학협력단 옥시이미노메틸벤젠 유도체
KR102209201B1 (ko) * 2020-06-29 2021-02-01 고려대학교 산학협력단 옥시이미노메틸벤젠 유도체

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