[go: up one dir, main page]

WO2008010238A2 - Nouveaux composés antidiabétiques - Google Patents

Nouveaux composés antidiabétiques Download PDF

Info

Publication number
WO2008010238A2
WO2008010238A2 PCT/IN2007/000298 IN2007000298W WO2008010238A2 WO 2008010238 A2 WO2008010238 A2 WO 2008010238A2 IN 2007000298 W IN2007000298 W IN 2007000298W WO 2008010238 A2 WO2008010238 A2 WO 2008010238A2
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
ethoxy
phenyl
hex
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2007/000298
Other languages
English (en)
Other versions
WO2008010238A3 (fr
Inventor
Sudershan Kumar Arora
Neelima Sinha
Prathap S Nair
Ajay R. Tilekar
Nabendu N. Saha
Talha H. Khan
Reeba Vikramadithyan
Rajesh Gupta
Sai Kumar Chakka
Navnath Popat Karche
Prasad Purushottam Dixit
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lupin Ltd
Original Assignee
Lupin Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lupin Ltd filed Critical Lupin Ltd
Priority to GB0902845A priority Critical patent/GB2454615A/en
Priority to AU2007274598A priority patent/AU2007274598A1/en
Publication of WO2008010238A2 publication Critical patent/WO2008010238A2/fr
Publication of WO2008010238A3 publication Critical patent/WO2008010238A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D209/52—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 condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention 's related to novel compounds of the general formula (I), their stereoisomers, their racemates, their pharmaceutically acceptable salts, pharmaceutical compositions containing them.
  • the invention is also related to the process for preparation of compound of formula (I) and the intermediates involved in the process.
  • the compounds of the present invention are useful for lowering blood triglyceride, decreasing low-density lipoprotein cholesterol (LDL), lowering blood glucose, increasing high-density lipoprotein (HDL), lowering fatty acids and blood insulin.
  • LDL low-density lipoprotein cholesterol
  • HDL high-density lipoprotein
  • the compounds of the general formula (I) may be useful for the treatment and/or prophylaxis of metabolic disorders related to syndrome X that includes insulin resistance (type II diabetes), hypertension, obesity, hyperlipidemia, atherosclerosis, coronary heart disease and other, cardiovascular disorders. These compounds can be used for the treatment or prevention of certain renal diseases also such as glomerulosclerosis and nephrotic syndrome.
  • the compounds of the general formula (I) may also be useful as aldose reductase inhibitors or may be expected to improve cognitive functions in dementia. These compounds may also be useful for the treatment and/or prevention or to reduce the risk of complications related to diabetes, psoriasis, polycystic ovarian syndrome (PCOS), oestoporesis and arteriosclerosis.
  • Type-2 diabetes is associated with hypertriglyceridemia, low HDLc and more of small LDLc. This is due to peripheral insulin resistance and increased influx of free fatty acids to liver.
  • An elevated circulating level of low-density lipoprotein cholesterol (LDLc) forms a major risk factor for coronary artery disease (CAD).
  • LDLc low-density lipoprotein cholesterol
  • LDLc high-density lipoprotein cholesterol
  • TG triglycerides
  • Increased plasma levels of fatty acids might also play a pathological role in the disease.
  • Insulin resistance also decreases lipoprotein lipase (LpL) activity, the major mediator of VLDL clearance, which may to a certain extent contribute to elevated triglyceride levels.
  • LpL lipoprotein lipase
  • Improper treatment of diabetes can aggravate impaired glucose tolerance and insulin resistance and frank diabetes.
  • the present therapy for type-2 diabetes includes sulfonylureas, biguanides and insulin. Some of these treatments also lead to hypoglycemia or other associated side effects like lactic acidosis or increase in body weight.
  • thiazolidinediones as insulin sensitizers the glycemic control is satisfactory.
  • Thiazolinidines like Rosiglitazone and Pioglitazone are either used as monotherapy or in combination with insulin or any other antidiabeteic drugs.
  • Troglitazone the first in the class of thiazolidinedione was withdrawn from the market due to hepatotoxicity-associated deaths. Though it is considered to be idiosyncratic. Therefore, there is a need to develop safe drugs for treating insulin, diabetes and hyperlipidemia (Exp. Clin. Endocrinol. Diabetes, 109(4): S548-S559, 2001).
  • Intracellular processes that cause pathological events are thought to involve hyperglycemic damage to endothelial cells.
  • Patients with obesity, insulin resistance and diabetes have reduced endothelial function even without clinical evidence of cardiovascular disease (Steinberg et al., J. Clinical Invest. 97: 2601-2610, 1996; Caballero et al., Diabetes, 48: 1856-1862, 1999; Plump et al., J. Clinical Invest. 97: 2660-2671, 1996).
  • Microvascular diseases lead to characteristic pathological changes in the eyes and kidneys.
  • Metabolic syndrome is defined by the American Heart Association and the US National Heart, Lung and Blood Institute as "multiple, interrelated risk factors of metabolic origin that appear to directly promote the development of atherosclerotic cardiovascular disease".
  • the core metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, elevated plasma glucose, and proinflammatory state.
  • This constellation of risk factors is associated with the occurrence of type-2 diabetes. This clustering has also been associated with several other conditions like fatty liver, polycystic ovary disease, sleep apnoea, cholesterol gallstones and some forms of cancer.
  • Peroxisome proliferator activated receptors are ligand activated nuclear receptors that form heterodimers with the retinoid X receptor to affect the expression of genes involved in glucose, and lipid metabolism and inflammation.
  • PPAR alpha ligand activated nuclear receptors that form heterodimers with the retinoid X receptor to affect the expression of genes involved in glucose, and lipid metabolism and inflammation.
  • PPAR delta 3 subtypes - PPAR alpha, PPAR gamma and PPAR delta [Endocrine Reviews, 20(5): 649-688, 1999; J. Medicinal Chem., 43(4): 527-550, 2000; Cell MoI. Life Sci., 55(6-7), 932 - 943, 1999].
  • the endogenous ligands for these receptors are postulated to be fatty acids.
  • PPAR alpha controls liver and skeletal muscle lipid metabolism and glucose homeostasis. It influences intracellular lipid and carbohydrate metabolism through direct transcriptional control of genes involved in peroxisomal and mitochondrial ⁇ -oxidation pathways, FA uptake, and triglyceride catabolism.
  • preclinical data suggest a role of PPAR alpha in body weight control, supporting the use of PPAR alpha agonists to treat obesity.
  • the fibrate class of molecules forms the synthetic ligands for PPAR alpha, these drugs are known to lower triglycerides and increase HDL cholesterol.
  • Thiazolidinediones are the ligands for PPAR gamma and they are involved in glucose lowering and improving insulin sensitivity.
  • Dual agonists of PPAR alpha (to lower triglycerides and increase HDL cholesterol and decrease LDL cholesterol and VLDL cholesterol) and PPAR gamma (to lower glucose) have been generated in hope to treat metabolic syndrome and insulin resistance. Pharmacologically improving insulin resistance in people with obesity and diabetes may ultimately lead to decrease in CAD.
  • TNF alpha Proinflammatory cytokine TNF alpha has been reported to be involved in inducing insulin resistance. Fat is a site involved in the production of cytokines and other bioactive substances. Adiponectin is produced by fat and expression decreases with increased adiposity. Leptin is also produced by adipocytes. TNF alpha, IL-6, MCP-I, visfatin and PAI- 1 are expressed by activated macrophages and other other cells. TNF alpha, IL-6, resistin and other pro- or anti-inflammatory cytokines appear to participate in the induction of inflammatory state in obesity (Shoelson et al., J.Clinical investigation, 116: 1793-1801, 2006). This suggests that pharmacological decrease in inflammatory activity might downregulate the production of a number of proteins involved in the pathogenesis of insulin resistance, type-2 diabetes, and cardiovascular disease.
  • liver In addition to adipose tissue, the liver is affected by obesity. Inflammatory gene expression increases in liver with increasing adiposity (Nature Medicine 11: 183-190, 2005). Hepatocyte lipid accumulation (steatosis) might induce inflammatory response in liver similar to adipocyte due to fat accumulation. It might be possible to directly target inflammation with pharmacological interventions to treat and/or prevent insulin resistance and type-2 diabetes, CVD and other metabolic conditions.
  • PCT Application WO 2006057503 disclose several (hydroxyimino)-ethoxyphenyl propionic acid derivatives of general formula (Ha) as PPAR ⁇ and PP ARa agonist.
  • Bioorganic Medicinal Chemistry, 2006, 14(3), 866 discloses synthesis and evaluation of azaindole- ⁇ -alkyloxyphenylpropionic acid analogues as PPAR ⁇ / ⁇ agonists. Among them one compound of formula (Hd) was identified as a potent, selective PPAR ⁇ / ⁇ dual agonist.
  • PCT Application WO 2005087713 discloses preparation of tetrahydro- naphthalenylcarboxamide derivatives of formula (Hf) as RXR function modulators and RXR/PPAR heterodimer function modulators.
  • PCT Application WO 2004056740 discloses preparation of dimeric dicarbo-xylic acid derivatives of formula (Hi) as PPAR ⁇ agonist.
  • PCT Application WO 2004000789 discloses phenoxyalkanamide compounds of formula (Ilk) as PPAR receptor agonist.
  • PCT Application WO 2003070692 discloses preparation of 3- ⁇ henylpropionic acid derivatives of formula (Hm) for the treatment diabetes.
  • PCT Application WO 2003048130 discloses preparation of imidazolidinone derivatives of formula (Hn) as PPAR activated receptor agonists.
  • PCT Application WO 2002100813 discloses preparation of various analogs of substituted 3-phenyl-2-alkoxypropionic acid of the formula (Ho) as modulators of PPAR receptors for the treatment of diabetes and related conditions.
  • US Patent number 6369067 discloses some oxopyrimidine derivatives of formula (Hr) as antiobesity and hypocholesterolemic agents.
  • PCT Applications, WO 2001055085 and WO 2000063153 discloses synthesis of aryl- alkenyl-oxy-arylpropionic acid derivatives of formula (lit) and their use in the treatment of PPAR mediated disorders including diabetes and obesity.
  • US Patent number 5227490 discloses various benzenepropanoates of formula (Hx) as fibrinogen receptor antagonists.
  • the main objective of the present invention is therefore to provide novel compounds of the general formula (I), their stereoisomers, their racemates , their pharmaceutically acceptable salts, pharmaceutical compositions containing them, process and intermediates for the preparation of the above said compounds which may have agonist activity against PP ARa and/or PPAR ⁇ or PPAR ⁇ .
  • the compounds of the present invention may have the property to inhibit HMG CoA reductase optionally, which may be useful for the treatment of atherosclerosis.
  • It is thus basic object of the present invention is to develop novel compounds which are effective and useful to lower increased levels of lipids, to lower blood giucose, to improve insulin resistance, to reduce fatty acids and body weight, for the treatment and/ or prophylaxis of metabolic disorders related to syndrome X such as hypertension, obesity, hyperlipidemia, atherosclerosis, coronary artery disease especially for reducing the risk of ischemic heart disease and other cardiovascular disorders with better efficacy and lower toxicity.
  • the present invention provides novel organic compounds represented by the general formula (I), their stereoisomers, their racemates, their pharmaceutically acceptable salts, pharmaceutical compositions containing them or mixture thereof.
  • a further aspect of the present invention is to develop novel organic compounds represented by the general formula (I) useful for reducing blood glucose, lowering lipid levels, cholestrol and reducing body weight and also have some excellent effects in the treatment and/or prophylaxis of diseases caused by insulin resistance such as diabetes mellitus, Syndrome X, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, diabetic complications, for the treatment of atherosclerosis, coronary heart diseases, arteriosclerosis with better efficacy, potency, without or reduced toxicity.
  • diseases caused by insulin resistance such as diabetes mellitus, Syndrome X, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, diabetic complications, for the treatment of atherosclerosis, coronary heart diseases, arteriosclerosis with better efficacy, potency, without or reduced toxicity.
  • the present invention provides novel organic compounds of the general formula - (I), their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them or their mixture which may have agonist activity against PP ARa and/or PPAR ⁇ or PPAR ⁇ .
  • the compounds of the present invention may have the property to inhibit HMG CoA reductase optionally, which may be useful for the treatment of atherosclerosis.
  • the present invention provides a process for the preparation of novel organic compounds of the general formula (I), their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them.
  • a further aspect of the present invention is to provide novel intermediates, a process for their preparation and their use in methods of making compounds of the general formula
  • the ' present invention also provides pharmaceutical compositions containing compounds of the general formula (I), their stereoisomers, their pharmaceutically acceptable salts, their mixture in combination with the usual pharmaceutically acceptable carriers, diluents and solvents normally used in making such compositions.
  • pharmaceutically acceptable carriers e
  • the present invention relates to novel compounds of the general formula (I),
  • W is a group of formula (III) or (IV):
  • X is selected from the groups hydrogen; hydroxy; C ⁇ Csalkyl (straight or branched); Q-Csalkoxy (straight or branched); acyl; aralkyl group; heteroaralkyl group; C 3 - C 10 cycloalkyl group; C 4 -C 1 ocycloalkylmethyl group; alkoxyalkyl group; which may be substituted
  • (ethylenedioxy)benzene vii) aryl group such as substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl and the like; viii) aralkyl group which is substituted or unsubstituted wherein the alkyl moiety may have Ci-C 3 (straight or branched).
  • Preferred groups are benzyl; benzyl which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of halogen, Q-C ⁇ alkyl, Q-C ⁇ alkoxy, Ci- C t ⁇ thioalkyl, CrC ⁇ thioalkoxy, unsubstituted or substituted aralkoxyalkyl, unsubstituted or substituted thioaryloxy, nitro, amino, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, hydroxy, cyano; unsubstituted or substituted 1,2-
  • Examples thereof include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxypropyl groups; xii) substituted or unsubstituted acyl group, which include linear or branched alkanoyl group having 2 to 8 carbon atoms such as acetyl, propanoyl, isopropanoyl, butanoyl, pentanoyl, isopentanoyl, benzoyl, phenacyl and the like, which may be substituted; xiii) SO 2 R 6 ; where R 6 is Q-Cgalkyl (straight or branched), cycloalkyl having 3-10 ' carbon atoms, cycloalkylmethyl having 4-10 carbon atoms, phenyl, heteroaryl group which may be substituted as defined above; xiv) CONHR 7 or CSNHR 7 or CONHSO 2 R 7 ; where R 7 is Ci-Cgalkyl (straight or branched), cycl
  • R 2 is selected from group of i) hydrogen; ii) substituted or unsubstituted linear or branched preferably C 1 -
  • Qalkyl group such as methyl, ethyl, ⁇ -propyl, iso-pvopyl, n-bxxtyl, iso-butyl, pentyl, hexyl, octyl and the like; iii) C 3 -C 7 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl and the like; iv) aryl group such as substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl and the like; v) substituted or unsubstituted heterocyclyl groups.
  • substituted or unsubstituted heteroaryl group preferred groups are pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl and 1,2-ethylenedioxybenzene, quinolinyl, indolyl, benzoxazolyl, benzothiazolyl, pyrazolyl, benzimidazolyl, imidazolyl, thiadiazolyl, triazolyl, oxadiazolyl; vii) aralkyl group such as substituted or unsubstituted benzyl and substituted or unsubstituted phenethyl and the like.
  • R 3 is selected from groups consisting of i) hydrogen; ii) Q-Csalkyl (straight or branched), for example methyl, ethyl, ⁇ -propyl, iso- propyl, n-butyl, iro-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, which may be substituted; iii) cycloalkyl having 3-7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkyl groups having 3-5 carbon atoms are preferred and this group may be substituted; iv) cycloalkylmethyl having 4-10 carbon atoms, for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl and adamantylmethyl, which may be substituted; v) substituted or unsubstituted aryl group, for example phenyl and naphthyl; vi) substituted or unsubstituted heteroaryl group, preferred groups are pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl and 1,2-ethylenedioxybenzene, quinolinyl, indolyl, benzoxazolyl, benzothiazolyl, pyrazolyl, benzimidazolyl, imidazolyl, thiadiazolyl, triazolyl, oxadiazolyl;
  • QaIkOXyC 1 -C 6 alkyl group examples thereof include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxypropyl groups; , x) substituted or unsubstituted aryloxyalkyl group.
  • phenoxymethyl, phenoxyethyl, naphthyloxymethyl, naphthyloxyethyl and the like xi) substituted or unsubstituted acyl group, which include linear or branched alkanoyl group having 2 to 8 carbon atoms such as acetyl, propanoyl, isopropanoyl, butanoyl, benzoyl and the like; xii) Ci-Cealkoxycarbonyl group, the alkyl group may be substituted; xiii) substituted or unsubstituted heterocyclyl groups.
  • acyl group which include linear or branched alkanoyl group having 2 to 8 carbon atoms such as acetyl, propanoyl, isopropanoyl, butanoyl, benzoyl and the like
  • Ci-Cealkoxycarbonyl group the alkyl group may be substituted
  • aryloxycarbonyl group such as phenoxycarbonyl, naphthyloxycarbonyl
  • R 4 and R 5 are the same or different and are selected from i) hydrogen; ii) substituted or unsubstituted linear or branched preferably C 1 -
  • substituted or unsubstituted heteroaryl group preferred groups are pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl and 1,2-ethylenedioxybenzene, quinolinyl, indolyl, benzoxazolyl, benzotliiazolyl, pyrazolyl, benzimidazolyl, imidazolyl, thiadiazolyl, triazolyl, oxadiazolyl; viii) substituted or unsubstituted heteroaralkyl group, preferred groups are pyridinemethyl, furanmethyl, coumarinmethyl, oxazolemethyl and 1,4- benzodioxanmethyl; where R is selected from groups consisting of i) hydrogen; ii) COOC(CH 3 ) 3 (in case of W is fragment III, when R 1 is not an electron withdrawing group);
  • Preferred groups are benzyl; benzyl which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of halogen, Ci-C 12 alkyl, Q-Cnalkoxy, C 1 - C ⁇ thioalkyl, C 1 -C 12 ImOaIkOXy, unsubstituted or substituted aralkoxyalkyl, unsubstituted or substituted thioaryloxy, nitro, amino, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, hydroxy, cyano; unsubstituted or substituted 1,2- (ethylenedioxy)benzene; unsubstituted or substituted phenylethyl; ix) heteroaryl group which is unsubstituted or substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alk
  • C 6 alkoxyCrC 6 alkyl group examples thereof include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxypropyl groups; xii) substituted or unsubstituted acyl group, which include linear or branched alkanoyl group having 2 to 8 carbon atoms such as acetyl, propanoyl, isopropanoyl, butanoyl, pentanoyl, isopentanoyl, benzoyl, phenacyl and the like, which may be substituted; xiii) SO 2 R 6 ; where R 6 is Cj-Csalkyl (straight or branched), cycloalkyl having 3-10 carbon atoms, cycloalkylmethyl having 4-10 carbon atoms, phenyl, heteroaryl group which may be substituted as defined above; xiv) CONHR 7 or CSNHR 7 or CONHSO 2 R 7 ; where R 7 is d-
  • substituents in above definition include nitro, hydroxy, halogen, or unsubstituted or substituted groups selected from alkyl, alkylamino, alkylthio, cycloalkyl, hydroxyalkyl, amino, alkoxy, alkoxyalkyl, alkoxycarbonyl, cycloalkoxy, aryl, arylamino, aminoalkyl, heteroaryl, heterocyclyl, aralkyl, aralkoxyalkyl, heteroaralkyl, acyl, acyloxy, acylamino, aryloxy, thioalkyl groups, carboxylic acid or its derivatives, sulfonic acid or its derivatives.
  • Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Na, K, Ca, Mg, Fe, Cu, Zn, and trolamine. Salts may include an appropriate acid addition salts of various pharmaceutically acceptable acids disclosed in Berge SM et al., 'Pharmaceutical salts', a review article in Journal of Pharmaceutical Sciences, volume 66, page 1 — 19 (1977) and in Handbok of Pharmaceutical Salts Properties, selection, and use by P.Heinrich Stahl and Camille G.
  • Wermuth, Wiley-VCH (2002) such as sulphates, tartarates, borates, nitrates, benzoates, citrates, succinates, hydrohalides, salicylates, maleates hydroxy succinates, ascorbates, keto-glutarates, benzenesulfonates, glycerophosphates, hydroxynaphthoates and the like.
  • salts derived from organic bases such as betaine ⁇ N'-diacetylethylenediamine, 2-diethylarninoethanol, 2- diethylaminomethanol, caffeine, glucosamine, glucamine, iV-ethyl-morpholine, N- ethylpiperidine, morpholine, isopropylamine,hydrabamine, piperazine piperidine, procaine, methylglucamine, diethylamine, glycinol, trimethyl amine, tripropyl-amine, diethanolamine, tromethamine, adamentyl amine, ⁇ N'-diphenylethylenediamine, NJN'- dibenzylethylenediamine, iV-benzyl phenylethylamine, dicyclohexylamine, choline, choline hydroxide, metformin, phenylethylamine, benzylamine, thiamine, aminopyridine, amino
  • L 1 is selected from halogen, /7-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like
  • Base is selected from potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine
  • Rl ' is one methylene less Rl defined under definition iii, iv, v, viii, x, xi # Reduction was carried out using reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride
  • the compounds of the invention of formula (Ia) [which includes compounds of formula (IX), (X), (XI), (XIII) and (XIV).
  • Compound of formula (Ia) may also include compounds of formula (VII) and (VIII) if the protecting group, R 8 is the same as covered under the general definition of R 8 .] can be prepared as per Scheme 1.
  • L 1 is a leaving group such as halogen, jo-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and like in the presence of suitable inert solvent, for example, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as benzene and toluene, an ether type solvent such as diethyl ether, tetrahydrofuran and 1,4-dioxane, an aprotic polar solvent such as N,N'-dimethylformamide, iV-methyl- pyrrolidone and dimethyl sulfoxide, 1 acetonitrile, or a mixture thereof, in the presence of a suitable base such as potassium carbonate, sodium carbonate, cesium carbonate, .triethyl- amine, diisopropylethylamine at a temperature between 25-150 0 C for 1-24 h to obtain
  • Phase transfer catalyst such as tetraalkylammonium halides, potassium iodide and sodium iodide can be employed to increase the efficiency of the reaction.
  • the reaction is more effective under anhydrous conditions.
  • the inert atmosphere may be maintained by using inert gases such as nitrogen, argon or helium.
  • the reaction may also be effected in the presence of DMAP, HOBT, BINAP, palladium acetate.
  • the reaction temperature may be in range between -20 0 C to 100 0 C.
  • the duration of the reaction may range from 0.5-48 h.
  • the inert atmosphere may be employed by using inert gases such as nitrogen, argon or helium.
  • the above reaction may also be carried out by using mixed anhydride methodology.
  • Compound of (V ⁇ II) was then deprotected using standard methodology to obtain compound of formula (IX).
  • R 7 is C r C 8 alkyl (straight or branched), cycloalkyl having 3-10 carbon atoms, cycloalkylmethyl having 4-10 carbon atoms, phenyl which is unsubstituted or substituted with 1-5 substituents, arylalkyl group, heteroaryl group, heteroaralkyl group which may be substituted as defined above or R L, wherein, L is a leaving group such as halogen, hydroxy, or the like R 8 is same as defined other than defination (i) and (xiv), in the presence of solvents such as a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as benzene and toluene, an ether type solvent such
  • the reaction may be carried out in the presence of BINAP, palladium acetate.
  • the reaction temperature may be in range between —20 0 C to 100 0 C under inert atmosphere may be employed by using inert gases such as nitrogen, argon or helium.
  • compound of formula (VII) was first deprotected using standard methods to obtain compound of formula (XI). Which was further treated with compound R 1 L where all the symbols X, Y, Z, n are same as defined earlier, L represents CHO and R 1 is one methylene less R 1 defined under definition (iii), (iv), (v), (viii), (x), (xi); and may be selected from substituted or unsubstituted C 1 -C 8 alkyl (straight or branched); cycloalkyl having 3-10 carbon atoms; phenyl which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of halogen, CrC 12 alkyl, C 1 -Ci 2 alkoxy, C 1 -C 12 thioalkyl, nitro, amino, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, hydroxy, cyano, formyl, mono or dial
  • halogen Ci-C 4 alkyl, C 1 -C 4 alkoxy, haloalkoxy, perhaloalkoxy, haloalkyl, perhaloalkyl, nitro, cyano, mono or dialkylamino
  • preferred groups are pyridyl, thienyl, thiazolyl, furyl, pyrimidinyl, quinolinyl, indolyl, benzoxazolyl, benzothiazolyl, pyrazolyl, benzimidazolyl, imidazolyl, thiadiazolyl, triazolyl, oxadiazolyl; heteroaralkyl group which is substituted or unsubstituted, preferred groups are pyridinemethyl, benzofuranmethyl, benzothiophenemethyl, furanmethyl, thiophenemethyl,
  • alkoxyalkyl group which is preferably C 1 -C 6 alkoxy, C 1 -C 6 alkyl group, examples thereof include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxypropyl groups, in a suitable inert solvents, for example, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as benzene and toluene, an ether type solvent such as diethyl ether, tetrahydrofuran and 1,4-dioxane, a lower alcohol such as methanol, ethanol and 2- propanol, or a mixture thereof at a temperature between 0-120 0 C for 2-10 h to obtain compound of formula (XII), which was further reduced under a suitable condition using a reducing agent such as sodium borohydride,
  • the reaction may be carried out in the presence of BINAP, palladium acetate.
  • the reaction temperature may be in range between -20 0 C to 100 0 C.
  • the duration of the reaction may range from 0.5-48 h.
  • the inert atmosphere may be employed by using inert gases such as nitrogen, argon or helium.
  • Compounds of the formula (Ib) can be prepared using a variety of methods known in literature and known to those skilled in the art.
  • One such approach is by the reaction of compound (XV), wherein, R 8 comprises of electronegative groups selected from the groups covered under the general definition of R , and compound (VI) where L is hydroxy group, in a suitable inert solvent, for example, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as benzene and toluene, an ether type solvent such as diethyl ether, tetrahydrofuran and 1,4-dioxane, an aprotic polar solvent such as A ⁇ N'-dimethylformamide, iV-methylpyrrolidone and dimethyl sulfoxide, or a mixture ⁇ thereof, under a condition of the Mitsunobu reaction at a temperature between 0 0 C to the boiling point of a solvent used for 5 min to 48 h.
  • R 7 is Q-Csalkyl (straight or branched), cycloalkyl having 3-10 carbon atoms, cycloalkylmethyl having 4-10 carbon atoms, phenyl which is unsubstituted or substituted with 1-5 substituents, arylalkyl group, heteroaryl group, heteroaralkyl group which may be substituted as defined above or R 8 L, wherein R 8 is non-hydrogen substituents as covered under the general defination 'of R 8 other than defination (xiv), L is a leaving group such as halogen, hydroxy or the like in the presence of solvents such as a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as benzene and toluene, an ether
  • the reaction temperature may be in range between -20 0 C to 100 0 C.
  • the duration of the reaction may range from 0.5-48 h.
  • the inert atmosphere may be employed by using inert gases such as nitrogen, argon or helium.
  • compounds of formula (Ib) can be obtained by the reaction of compound (XV) and compound (VI) where L 1 is a leaving group such as halogen, p- toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and like in the presence of suitable inert solvent, for example, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as benzene and toluene, an ether type solvent such as diethyl ether, tetrahydrofuran and 1,4-dioxane, an aprotic polar solvent such as iVjiV'-dimethylformamide, N-methylpyrrolidon
  • the reaction may be effected in the presence of DMAP, HOBT.
  • the reaction may be carried out in the presence of BI ⁇ AP, palladium acetate.
  • the reaction temperature may be in range between -20 0 C to 100 0 C.
  • the duration of the reaction may range from 0.5- 48 h.
  • the inert atmosphere may be employed by using inert gases such as nitrogen, argon or helium.
  • the above reaction may also be carried out by using mixed anhydride methodology.
  • the starting material i.e. compound of formula (XV) can be synthesized as per reported procedure described in EP0413455; US2490714 and Synlett, 1097-1102 (1996) or a method described in reference examples, or in a similar manner thereto.
  • the compounds of the formula (Ia) or (Ib) where Z represents NR 4 R 5 and R 4 , R 5 are same as defined earlier, can be prepared by reacting the compounds of formula (Ia) or (Ib) where Z represents OR 2 , and R 2 is hydrogen or lower alkyl group with appropriate amines of the formula R 4 R 5 NH and R 4 , R 5 are same as defined earlier.
  • the compounds of formula (Ia) or (Ib) where Z represents OR 2 and R 2 represents hydrogen atom can be converted to acid halide by reacting with appropriate reagents known in literature such as thionyl chloride, oxalyl chloride and the like, followed by the reaction with aniines of the formula R 4 R 5 NH and R 4 , R 5 are same as defined earlier.
  • An alternative method can also be used by making mixed anhydrides from compounds of formula (Ia) or (Ib) where Z represents OR , and R represents hydrogen atom and all other symbols are same as defined earlier by treating with acid halides such as acetyl chloride, acetyl bromide, dichlorobenzoyl chloride, pivaloyl chloride and the like.
  • the reaction may be carried out in the presence of solvents, for example, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as xylene, benzene and toluene, in the presence of suitable base such as triethylamine, diisopropylethylamine and pyridine at a temperature between 0- 50 0 C.
  • solvents for example, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as xylene, benzene and toluene
  • suitable base such as triethylamine, diisopropylethylamine and pyridine
  • Coupling reagents generally used in conventional method, such as EDC/HOBT, DCC/DMAP, ethyl chloroformate, isobutyl chloroformate may be employed for activating the acids.
  • the acid halide or mixed anhydride or activated acids thus prepared can further be reacted with amines of the formula R 4 R 5 NH where R 4 , R 5 are same as defined earlier to provide the compounds of the formula (Ia) or (Ib) where Z represents NR 4 R 5 and all other symbols have the same meaning as defined earlier.
  • the pharmaceutically acceptable salts of the compounds of the present invention are readily prepared by reacting the acid forms with an appropriate base such as sodium hydroxide, sodium methoxide, potassium hydroxide, potassium methoxide, calcium hydroxide, magnesium hydroxide, triethanolamine and the like, in solvents such as chloroform, dichloromethane, diethyl ether, THF, dioxane, ethanol, methanol, /-butanol, isopropanol and toluene.
  • an appropriate base such as sodium hydroxide, sodium methoxide, potassium hydroxide, potassium methoxide, calcium hydroxide, magnesium hydroxide, triethanolamine and the like
  • solvents such as chloroform, dichloromethane, diethyl ether, THF, dioxane, ethanol, methanol, /-butanol, isopropanol and toluene.
  • acid addition salts of the compounds of the present invention are prepared by reacting with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, maleic acid, citric acid, tartaric acid, benzoic acid, succinic acid, salicylic acid, palmitic acid, /7-toluenesulfonic acid, ascorbic acid, benzene sulfonic acid and the like as described in Berge SM et al., 'Pharmaceutical salts', a review article in Journal of Pharmaceutical Sciences, volume 66, page 1 - 19 (1977) and in Handbok of Pharmaceutical Salts Properties, selection, and use by P.Heinrich Stahl and Camille G. Wermuth, Wiley-VCH (2002)]in solvents such as dichloromethane, THF, alcohols, diethyl ether, ethyl acetate, acetone and mixture thereof.
  • acids such as hydrochloric acid, hydrobromic acid, sulfuric acid
  • the stereoisomers of the compounds of the present invention may be prepared by combining the acid with an optically active amine, and separating the diastereomeric salt by fractional crystallization, or by reacting the acid with an optically active alcohol or amine, and separating the diastereomer esters or amides by column chromatography or fractional crystallization, followed by hydrolysis of separated isomers to yield the desired optically active acids.
  • the stereoisomers of the compounds can be prepared by using reactants in their single enantiomeric form, wherever possible, according to the methods given in literature or methods given in reference examples.
  • the present invention provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their stereoisomers or their pharmaceutically acceptable salts in combination with the usual pharmaceutically employed carriers, diluents and the like are useful for the treatment and/or prophylaxis of diseases such as hypertension, coronary heart disease, stroke, atherosclerosis, microvascular disease and associated disorders. These compounds are useful for treating hyperlipidemia, hyperglycemia, hypertriglyceridemia, hyperinsulinemia, lowering of LDL and VLDL, lowering of atherogenic lipoproteins like ApoB and increasing ApoAl and HDL cholesterol.
  • the compounds of the present treatment is useful in the treatment of insulin resistance (type- 2 diabetes), leptin resistance, obesity, impaired glucose tolerance, dyslipidemia, coronary artery disease and disorders associated with Syndrome X. These compounds may be useful in nephropathy and nephritic syndrome. (These compounds will be useful as Aldose reductase inhibitors for the treatment of macro vascular disorders like atheroscelrosis, and other diabetic complications like diabetic neuropathy, nephropathy and retinopathy. These compounds will be useful in treating disorders related to endothelial cell activation, psoriasis, polycystic ovary syndrome, inflammatory bowel syndrome, osteoporosis, pancreatitis, inflammation and for the treatment of cancer.
  • the compounds of the present invention are also useful in the treatment and/or prophylaxis of the above said diseases in combination with one or more the HMGCoA reductase inhibitors, hypolipidemic/ hypotriglyceridemic agents such as fibric acid derivatives, nicotinic acid derivatives, cholestyramine, cholesterol absorption inhibitors, probucol or their combinations.
  • HMGCoA reductase inhibitors such as fibric acid derivatives, nicotinic acid derivatives, cholestyramine, cholesterol absorption inhibitors, probucol or their combinations.
  • the present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their stereoisomers or their pharmaceutically acceptable salts and one or more HMGCoA reductase inhibitors, hypolipidemic/hypotriglyceridemic agents such as fabric acid derivatives, nicotinic acid derivatives, cholestyramine, cholesterol absorption inhibitors, probucol in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • HMGCoA reductase inhibitors such as fabric acid derivatives, nicotinic acid derivatives, cholestyramine, cholesterol absorption inhibitors, probucol in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the intermediates and the compounds of the present invention are obtained in pure form by applying methods ordinarily used in the synthetic organic chemistry such as crystallization using solvents such as diethyl ether, hexane, isopropyl ether, methanol, ethanol, isopropanol, ethyl acetate or their combinations or column chromatography using alumina or silica gel and eluting the column with solvents such as dichloromethane, ethyl acetate, hexane, chloroform, methanol, acetone and their combinations.
  • solvents such as diethyl ether, hexane, isopropyl ether, methanol, ethanol, isopropanol, ethyl acetate or their combinations
  • column chromatography using alumina or silica gel and eluting the column with solvents such as dichloromethane, ethyl acetate, hexane, chloroform, methanol,
  • Step 1 [(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(4-Chlorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid tert-butyl ester
  • Step 3 iV- ⁇ l ⁇ j ⁇ -S ⁇ -Chlorobenzy ⁇ -S-azabicyclofS.l.OJhex- ⁇ -yy ⁇ -nitrobenzene- suifonamide
  • Step 1 [(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(2-Fluorobenzoyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid tert- butyl ester
  • Step 2 [(l ⁇ ,5 ⁇ 5 6 ⁇ )-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]-(2-fluorophenyl)-methanone
  • Step 3 N-[(l ⁇ ,5 ⁇ 5 6 ⁇ )-3-(2-Fluorobenzoyl)-3-azabicyclo[3.1.0]hex-6-yl]-4-nitrobenzene sulfonamide
  • Step 1 [(l ⁇ ,5 ⁇ ,6 ⁇ )-[3-(2,4,5-Trifluorophenylcarbamoyl)-3-azabicyclo[3.1.0]hex-6-yl]]- carbamic acid tert-bv&yl ester
  • Step 2 (l ⁇ ,5 ⁇ ,6 ⁇ )-6-Amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid(2,4,5-trifluoro- phenyl)amide
  • Step 3 (l ⁇ ,5 ⁇ ,6 ⁇ )-6-(4-Nitrobenzenesulfonylamino)-3-azabicyclo[3.1.0]hexane-3- carboxylic acid(2,4,5-trifluorophenyl)amide
  • Step 1 [(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(5-Cyanopyridin-2-yl)-3-azabicyclo[3.1 .0]hex-6-yl]carbamic acid tert- butyl ester
  • Step 2 6-[(l ⁇ ,5 ⁇ ,6 ⁇ )-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]nicotinonitrile
  • Step 3 iV-[(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(5-Cyanopyridin-2-yl)-3-azabicyclo[3.1.0]hex-6-yl]-4-nitro- benzenesulfonamide
  • the DMF layer was concentrated to half of its volume under reduced pressure and diluted with water (4 times).
  • the solid separated out was filtered off and ethyl acetate (1500 ml) was added to the residue.
  • the combined ethyl acetate layer was washed with water (1 ⁇ 500 ml), brine (1 x200 ml), dried, over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the resulting residue was dissolved in chloroform (800 ml), washed with cold solution of 5% aqueous potassium hydroxide (2x250 ml) to remove unreacted 4-nitrophenol.
  • reaction mixture was allowed to come to room temperature and tetra- «-butyl-ammonium iodide (17.13 g, 0.04 mol) was added to it and stirred for 3 h at the same temperature. THF was removed under reduced pressure and water (400 ml) was added at 0 0 C. The reaction mixture was then extracted with ethyl acetate (3x500 ml).
  • Step 4 3-[4-(2-Benzyloxyethoxy)phenyl]-2-chloropropionic acid methyl ester
  • Step 5 3-[4-(2-Benzyloxyethoxy)phenyl]-2-hydroxypropionic acid To a mechanically stirred solution of 3-[4-(2-benzyloxyethoxy)phenyl]-2- chloropropionic acid methyl ester (128.6 g, 0.36 mol) in dioxane (742 ml) was added water (1.15 lit), calcium carbonate (36.93 g, 0.36 mol) and sodium hydroxide (15.49 g, 0.38 mol) at room temperature. The reaction mixture was then heated at reflux temperature for 18 h. Dioxane was removed under reduced pressure and the reaction mixture was acidified with 10% HCl to pR 3.
  • Step 6 3-[4-(2-Benzyloxyethoxy)phenyl]-2-hydroxypropionic acid ethyl ester
  • Step 7 3-[4-(2-Benzyloxyethoxy)phenyl]-2-(4-tert-butylphenoxy)propionic acid ethyl ester
  • reaction mixture was washed with water (2x150 ml) and the organic layer was dried over anhydrous Na 2 SO 4 .
  • the solvent was evaporated under reduced pressure to get a crude product that was purified by column chromatography over silica gel (100-200 mesh) using 40% dichloromethane-hexanesas an eluent to afford the title compound (22.16 g, 80%).
  • Step 10 [(2R), N(lS)]-2-(4-te ⁇ Butylphenoxy)-3-[4-(2-hydroxy ethoxy) phenyl] -iV-(2- hydroxy-l-phenylethyl)propionamide & [(2S), N(lS)]-2-(4-tert-Butylphenoxy)-3-[4-(2- hydroxyethoxy)phenyl]-N-(2-hydroxy- 1 -phenylethyl)propionamide
  • Step 12 (2S)-2-(4-fer ⁇ -Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester
  • reaction mixture was heated to 60-65 0 C for 1 h under stirring. The reaction mixture was allowed to come at room temperature. To this reaction mixture was added DMF (500 ml) followed by dropwise addition of benzyl chloride (83.8 g, 76.28-ml, 0.66 mol) at room temperature. Then reaction mixture was heated to 60 0 C for 2h under stirring. Grey coloured solid copper complex of O-benzyl-D-tyrosine was precipitated out. The reaction mixture was allowed come to at room temperature, and 300 ml of water was added to get free grey coloured solid.
  • DMF 500 ml
  • benzyl chloride 83.8 g, 76.28-ml, 0.66 mol
  • Reaction mixture was diluted with water (300 ml), extracted with ethyl acetate (3> ⁇ 600 ml). The combined organic layers were dried over sodium sulphate and concentrated under rteduced pressure to yield crude product.
  • the crude product was suspended in mixture of 400 ml of diisopropyl ether and 3 ml of ethyl acetate. Resulting solid was filtered, washed with diisopropyl ether (100 ' ml) and dried under vacuum to yield the pure title compound (40.4 g, 35%).
  • Step 4 (2S)-3-(4-Benzyloxyphenyl)-2-(4-/er/-butylphenoxy)propionic acid ethyl ester
  • reaction mixture was diluted with dichloromethane (300 ml) washed with water (1x5.0 ml), brine (1x50 ml), dried over sodium sulphate and concentrated under reduced pressure to get crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 70% dichloromethane- , hexanes as an eluent to yield the title compound (35.0 g, 79%).
  • the reaction mixture was cooled to 0 0 C and to this was added a solution of diethylazadicarboxylate (16.15 g, 14.18 ml, 92.84 mmol) in dry dichloromethane (50 ml) in a dropwise manner over a period of 20 min.
  • the resulting reaction mixture was stirred at room temperature for 4 h.
  • reaction mixture was diluted with dichloromethane (300 ml) washed with water (1x50 ml), brine (1x50 ml), dried over sodium sulphate and concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 80% dichloromethane- hexanes as an eluent to afford the title compound (26.0 g 71%).
  • Step 7 (2S)-2-(4-tert-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester
  • Step 1 (2R)-2-(4-tert-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]propionic acid
  • Step 2 (2R)-2-(4-tert-Butylphenoxy)-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester
  • Step 1 4-(2-Benzyloxyethoxy)benzaldehyde To a stirred suspension of 60% sodium hydride (pre-washed with hexanes; 4.29 g, 178 mmol) in dry THF (100 ml) was added a solution of 4-(2-hydroxyethoxy)benzadehyde (27.0 g, 162 mmol) in dry THF (100 ml) over a period of 30 min at 0-5 0 C. Reaction mixture was then stirred at same temperature for 2 h.
  • reaction mixture a solution of benzyl bromide (27.2 g, 16.2 ml, 162 mmol) in dry THF (400 ml) was added slowly over period of 0.5 h at same temperature under stirring. After the addition was completed, reaction mixture was allowed to come to room temperature and stirred for 8 h at same temperature. The reaction mixture was then cool in ice bath and quench with cold water (25 ml). THF was evaporated and the residue was diluted with water (300 ml) and extracted with ethyl acetate (2x250 ml).
  • Step 2 (E/Z)-3-[4-(2-Benzyloxyethoxy)phenyl]-2-ethoxyacrylic acid ethyl ester
  • Step 3 3-[4-2-(Benzyloxyethoxy)phenyl]-2-ethoxypropionic acid methyl ester
  • Step 5 [(2S), iV(lS)]-3-[4-(2-Benzyloxyethoxy)phenyl]-2-ethoxy-iV-(2-hydroxy-l-phenyl- thyl)propionamide and [(2R), N(lS)]-3-[4-(2-benzyloxyethoxy)phenyl] ⁇ 2-ethoxy-iV-(2- hydroxy- 1 -phenylethyl)propionamide
  • reaction mixture was cooled to room temperature and filtered through Celite bed, washed with ethanol (2x25 ml) and combined, filtrate was concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 60->80% ethyl acetate- hexanes as an eluent to afford the title compound (0.70 g, 88%).
  • Step 8 (2S)-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]propionic acid ethyl ester
  • Step 4 (2S)-2-Ethoxy-3-(4-hydroxyphenyl)propionic acid ethyl ester
  • (2S)-3-(4-benzyloxyphenyl)-2-ethoxypropionic acid ethyl ester 12.5 g, 0.038 mol
  • 10% Pd-C 10.0 g
  • reaction mixture was filtered through Celite bed, washed with ethanol (5x50 ml).
  • Step 5 (2S)-3-[4-(2-Benzyloxyethoxy)phenyl]-2-ethoxypropionic acid ethyl ester To a solution of (2S)-2-ethoxy-3-(4-hydroxyphenyl)propionic acid ethyl ester (8.0 g,
  • reaction mixture was diluted with dichloromethane (150 ml) washed with water (2x25 ml), brine (1x25 ml), dried over Na 2 SO 4 and concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate-hexanes as an eluent to afford the title compound (10.0 g, 80.0%).
  • Step 1 [(2R), N(lS)]-2-Ethoxy-3-[4-(2-hydroxyethoxy)phenyl]-N-(2-hydroxy-l-phenyl- ethyl)propionamide
  • reaction mixture was cooled to room temperature and filtered through Celite bed, washed with ethanol (2x25 ml) and combined filtrate was concentrated under reduced pressure to yield a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 2% methanol-dichloromethane as an eluent to yield the title compound (0.70 g, 88%).
  • Step 2 (2S)-3-[4-(3-Benzyloxypropoxy)phenyl]-2-ethoxypropionic acid ethyl ester
  • reaction mixture was stirred at same temperature for 4 h. After completion of reaction, reaction mixture was diluted with dichloromethane (50 ml), washed with water (2x10 ml), dried over Na 2 SO 4 and concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate-hexanes as an eluent to afford the title compound (1.6 g, 66%).
  • Step 4 3-[4-(2-Bromoethoxy)phenyl]-2-cyanopropionic acid ethyl ester
  • Step 1 N-((l ⁇ ,5 ⁇ ,6 ⁇ )-3-Benzyl-3-azabicyclo[3.1.0]hex-6- yl)-4-nitrobenzenesulfonamide
  • Step 2 (2S)-3-(4- ⁇ 2-[((l ⁇ ,5 ⁇ ,6 ⁇ )-3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-(4-nitrobenzene- sulfonyl)amino]ethoxy ⁇ phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester ⁇ Compound No 196)
  • Step 3 (2S)-3- ⁇ 4-[2-((l ⁇ ,5 ⁇ ,6 ⁇ )-3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylammo)ethoxy]- phenyl ⁇ -2-(4-tert-butylphenoxy)propionic acid ethyl ester (Compound No 197)
  • Step 4 (2S)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)tert-butoxy- carbonylamino]ethoxy ⁇ phenyl)-2-(4-terf-butylphenoxy)pro ⁇ ionic acid ethyl ester
  • reaction mixture was diluted with dichloromethane (50 ml), washed with water (2x20 ml). The combined organic laters were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to get crude product which was purified by column chromatography over silica gel (100-200 mesh) using 0.5-M.0% methanol-dichloromethane as an eluent to yield the title compound (5.0 g, 95%).
  • Step 5 (2S)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-(3-Azabicyclo[3.1.0]hex-6-yl)tert-butoxycarbonylamino]- ethoxy ⁇ phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester
  • Step 2 (2S)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ 5 6 ⁇ )-3-Benzyl-3-azabicyclo[3.1.0]hex-6-ylamino]ethoxy ⁇ - phenyl)-2-ethoxypropionic acid ethyl ester ⁇ Compound No 200)
  • Step 3 (2S)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-(3-Benzyl-3-azabicyclo[3.1.0]hex-6-yl)-f ⁇ rt-butoxy- carbonylamino]ethoxy ⁇ phenyl)-2-ethoxypropionic acid ethyl ester ⁇ Compound No 201)
  • reaction mixture was diluted with dichloromethane (20 ml), washed with water (2x10 ml). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to get crude product which was purified by column chromatography over silica gel (100-200 mesh) using 1.6->2.0% methanol-dichloromethane as an eluent to yield the title compound (1.217 g, 60%).
  • Step 4 (2S)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-(3-Azabicyclo[3.1.0]hex-6-yl)-f ⁇ rt-butoxycarbonylamino]- ethoxy ⁇ phenyl)-2-ethoxypropionic acid ethyl ester
  • reaction mixture was heated at 70 0 C for 6 h. After completion of reaction, reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (4x50 ml). The combined organic layers were washed with water (1x20 ml), brine (1x20 ml), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate-hexanes as an eluent to yield the title compound (7.76 g, 98%).
  • Step 2 3-(4-Benzyloxyphenyl)-2-(4-/ert-butylphenoxy)-2-methylpropionic acid methyl ester
  • reaction mixture was diluted with dichloromethane (50 ml) and washed with with water (2x10 ml), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate-hexanes as an eluent to yield the title compound (1.8 g, 63%).
  • Step 1 (2S)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-6-tert-Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3- yl]ethoxy ⁇ phenyl)-2-(4-tert-butylphenoxy)propionic acid ethyl ester ⁇ Compound No 12)
  • Step 2 (2S)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]ethoxy ⁇ phenyl)-2- '
  • Step 1 [(l ⁇ ,5 ⁇ ,6 ⁇ )-[3-(2,4,5-Trifluoromethylphenylcarbamoyl)-3-azabicyclo[3.1.0]hex-6- yl]]carbamic acid tert-butyl ester
  • reaction mixture was diluted with dichloromethane (20 ml), washed with water (2x20 ml), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to yield a crude product, which was crystallized by using 25:75 dichloromethane-hexanes to yield the title compound (3.30 g, 85%).
  • Step 3 (l ⁇ ,5 ⁇ ,6 ⁇ )-6-(4-Nitrobenzenesulfonylamino)-3-azabicyclo[3.1.0]hexane-3- carboxylic acid(4-trifluoromethylphenyl)amide
  • Step 2 (2S)-2-(4-tert-Butylphenoxy)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(4-chlorobenzyl)-3-azabicyclo- [3.1.0]hex-6-ylamino]ethoxy ⁇ phenyl)propionic acid ethyl ester (Compound No 10)
  • the reaction mixture was cooled to 0 0 C and added thiophenol (0.78 g, 0.75 ml, 7.1 mmol) drop wise under stirring. After being stirred for 3 h at room temperature, thiophenol (0.376 g, 0.35 ml, 3.4 mmol) and anhydrous potassium carbonate (0.5 g, 3.6 mmol) was added to the above reaction mixture and stirred for 2 h. After being stirred for another 2 h, this addition was repeated again with the same quantity of thiophenol and anhydrous potassium carbonate and stirred for further 3 h.
  • Step 3 (2S)-2-(4-tert-Butylphenoxy)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(4-chlorobenzyl)-3-azabicyclo-
  • the aqueous layer was neutralized by adding IM HCl at 0 0 C to p ⁇ 6 under stirring.
  • the resulting reaction mixture was stirred at 0 0 C for 0.5 h and the solid separated out was filtered through a Buchner funnel, washed with cold water (2x20 ml).
  • the solid so obtained was taken in 10% methanol-dichloromethane (100 ml) and sonicated for 5 min, the undissolved solid was filtered off through a buchner funnel. The filtrate was dried over anhydrous
  • Step 1 (2S)-2-(4-tert-Butylphenoxy)-3-[4-(2- ⁇ (l ⁇ ,5 ⁇ ,6 ⁇ )-(4-nitrobenzenesulfonyl)-[3- (2 5 4 5 5-trifluorobenzyl)-3-azabicyclo[3.1.0]hex-6-yl]amino ⁇ ethoxy)phehyl]propionic acid ethyl ester
  • reaction mixture was diluted with dichloromethane (500 ml), washed with water (200 ml), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to get a crude product which was purified by column chromatography over silica gel (100-200 mesh) using 0-> 1.5% acetone-dichloromethane as an eluent to yield the title compound (49.5 g, 83%).
  • Step 2 (2S)-2-(4-tert-Butylphenoxy)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(2,4,5-trifluorobenzyl)-3-aza- bicyclop.l.ojhex- ⁇ -ylaminojethoxyjpheny ⁇ propionic acid ethyl ester (Compound No 13)
  • reaction mixture was cooled at 0 0 C and added thiophenol (5.19 g, 4.7ml, 47.16 mmol). After being stirred at room temperature for 3 h, reaction mixture was poured into cold water (400 ml) and extracted with ethyl acetate (3x 200 ml).
  • Step 3 (2S)-2-(4-ter/-Butylphenoxy)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(2,4,5-trifluorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy ⁇ phenyl)propionic acid
  • Step 4 (2S)-2-(4-fert-Butylphenoxy)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ 5 6 ⁇ )-3-(2,4,5-triflurobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy ⁇ phenyl)propionic acid dihydrochloride
  • Step 1 (2S)-2-(4-tert-Butylphenoxy)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(2,4,5-trifluorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy ⁇ phenyl)propionic acid benzyl ester
  • Step 2 (2S)-2-(4-tert-Butylphenoxy)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(2 5 4,5-trifluorobenzyl)-3-aza- bicyclo ⁇ .l.Ojhex- ⁇ -ylaminojethoxylphenytypropionic acid benzyl ester dihydrochloride
  • Step 1 (2S)-2-(4-tert-Butylphenoxy)-3-(4- ⁇ 2-[(l ⁇ 5 5 ⁇ ,6 ⁇ )-3-(2,4 5 5-trifluorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy ⁇ phenyl)propionic acid 2-cyclopentylethyl ester
  • Step 2 (2S)-2-(4-fcrt-Butylphenoxy)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-3-(2,4,5-trifluorobenzyl)-3-aza- bicyclo[3.1.0]hex-6-ylamino]ethoxy ⁇ phenyl)propionic acid 2-cyclopentylethyl ester dihydro- chloride
  • Step 1 (2R)-2-(4-tert-Butylphenoxy)-3-(4- ⁇ 2-[(l ⁇ ,5 ⁇ ,6 ⁇ )-[3-(4-chlorobenzyl)-3-azabicyclo- [3.1.0]-hex-6-yl]-(4-nitrobenzenesulfonyl)amino]ethoxy ⁇ phenyl)propionic acid ethyl ester

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention porte sur de nouveaux composés antidiabétiques de formule générale (I) à usage médical dont les symboles sont définis dans la description, sur leurs sels pharmacocompatibles, sur leurs formes tautomères, sur leurs stéréoisomères, sur des préparations pharmaceutiques les contenant, sur leur procédé et leurs intermédiaires de fabrication, et sur leurs méthodes d'utilisation à des fins thérapeutiques pour le traitement du diabète de maladies associées.
PCT/IN2007/000298 2006-07-21 2007-07-20 Nouveaux composés antidiabétiques Ceased WO2008010238A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB0902845A GB2454615A (en) 2006-07-21 2007-07-20 Antidiabetic azabicyclo (3.1.0) hexan compounds
AU2007274598A AU2007274598A1 (en) 2006-07-21 2007-07-20 Antidiabetic azabicyclo [3. 1. 0] hexan compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN730KO2006 2006-07-21
IN730/KOL/2006 2006-07-21

Publications (2)

Publication Number Publication Date
WO2008010238A2 true WO2008010238A2 (fr) 2008-01-24
WO2008010238A3 WO2008010238A3 (fr) 2008-04-17

Family

ID=38812084

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000298 Ceased WO2008010238A2 (fr) 2006-07-21 2007-07-20 Nouveaux composés antidiabétiques

Country Status (3)

Country Link
AU (1) AU2007274598A1 (fr)
GB (1) GB2454615A (fr)
WO (1) WO2008010238A2 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
EP2133333A1 (fr) * 2008-06-13 2009-12-16 Les Laboratoires Servier Noveaux dérivés azabicycliques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
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
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
WO2013041621A1 (fr) 2011-09-20 2013-03-28 Basf Se Modulateurs à faible masse moléculaire du récepteur sensible au froid et au menthol trpm8, et leur utilisation
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
WO2013068486A1 (fr) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le diagnostic et le traitement de l'infertilité masculine
CN110237045A (zh) * 2019-07-11 2019-09-17 广西大学 一种胶囊剂
US11274082B2 (en) 2019-05-31 2022-03-15 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11458149B1 (en) 2019-05-31 2022-10-04 Ikena Oncology, Inc. TEAD inhibitors and uses thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9801992D0 (sv) * 1998-06-04 1998-06-04 Astra Ab New 3-aryl-2-hydroxypropionic acid derivative I
EP1618091A1 (fr) * 2003-04-09 2006-01-25 Ranbaxy Laboratories, Ltd. Derives d'azabicyclo hexane substitues en tant qu'antagonistes de recepteurs muscariniques

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
EP2133333A1 (fr) * 2008-06-13 2009-12-16 Les Laboratoires Servier Noveaux dérivés azabicycliques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2009150331A1 (fr) * 2008-06-13 2009-12-17 Les Laboratoires Servier Nouveaux derives azabicycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2932479A1 (fr) * 2008-06-13 2009-12-18 Servier Lab Nouveaux derives azabicycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
US7906547B2 (en) 2008-06-13 2011-03-15 Les Laboratoires Servier Azabicylic compounds, a process for their preparation and pharmaceutical compositions containing them
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
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
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
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
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
WO2013041621A1 (fr) 2011-09-20 2013-03-28 Basf Se Modulateurs à faible masse moléculaire du récepteur sensible au froid et au menthol trpm8, et leur utilisation
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
WO2013068486A1 (fr) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le diagnostic et le traitement de l'infertilité masculine
US11274082B2 (en) 2019-05-31 2022-03-15 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11458149B1 (en) 2019-05-31 2022-10-04 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
US11760728B2 (en) 2019-05-31 2023-09-19 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11925651B2 (en) 2019-05-31 2024-03-12 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
CN110237045A (zh) * 2019-07-11 2019-09-17 广西大学 一种胶囊剂

Also Published As

Publication number Publication date
AU2007274598A1 (en) 2008-01-24
GB2454615A (en) 2009-05-13
GB0902845D0 (en) 2009-04-08
WO2008010238A3 (fr) 2008-04-17

Similar Documents

Publication Publication Date Title
WO2008010238A2 (fr) Nouveaux composés antidiabétiques
JP2690006B2 (ja) 糖尿病及び肥満の治療のための選択的β３作働薬としての置換フェニルスルホンアミド
JP7637281B2 (ja) ラニフィブラノールの重水素化誘導体
JP4853965B2 (ja) アダマンタン誘導体およびアザビシクロオクタン誘導体およびアザビシクロノナン誘導体、ならびにこれらの調製方法およびｄｐｐ−ｉｖ阻害剤としてのこれらの使用
CN104125956B (zh) 作为11-β-羟基类固醇脱氢酶的抑制剂的环酰胺及其用途
AU2003211617A1 (en) Ester compound and medicinal use thereof
AU2015210833A1 (en) Dihydropyrrolopyridine inhibitors of ROR-gamma
MX2007001634A (es) Nuevo derivado de acido amino benzoico ciclico.
JP2025121901A (ja) ファルネソイドｘ受容体アゴニストの結晶質形態
TWI322143B (en) Carboxamide derivatives as muscarinic receptor antagonists
US6020371A (en) Antipicornaviral compounds compositions containing them and methods for their use
IL283823B2 (en) 7-phenoxy-n-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5h-pyrrolo[1,2-b][1,2,4]triazol-2-amine derivatives and related compounds as gamma-secretase modulators for the treatment of alzheimer's disease
US20030187068A1 (en) Substituted phenylpropionic acid derivatives
NO327257B1 (no) Nye heterocykliske oksimforbindelser, fremgangsmate for deres fremstilling og farmasoytiske sammensetninger inneholdende dem
JP2001187793A (ja) ブラジキニンアンタゴニストとしての５−員のヘテロアリール置換１，４−ジヒドロピリジン化合物
US20050282819A1 (en) Heterocyclic substituted indane derivatives and related compounds for the treatment of schizophrenia
WO2020152361A1 (fr) Dérivés de carbamate et leurs utilisations
EA018024B1 (ru) Фенантреноновые соединения, композиции и способы
CN114149341A (zh) 芳氧环己基酰胺类ampk激动剂及其制备方法和医药用途
Shaitanova et al. Synthesis of enantiomerically pure 4-polyfluoromethyl-4-hydroxy-homoprolines by intramolecular cyclization of 6-amino-5-polyfluoromethyl-hex-2-enoic acids
US20080114005A1 (en) Fibrate Compounds Having Ppar Agonist Activity
US20090036489A1 (en) Novel Cyclic Aminophenylalkanoic Acid Derivative
HK40110761A (en) Therapeutic uses of deuterated derivatives of lanifibranor
HK40110761B (en) Therapeutic uses of deuterated derivatives of lanifibranor
WO2025222049A1 (fr) Dérivés d'acide 2-((1-oxo-2,3-dihydro-1h-inden-5-yl)oxy)acétique et utilisations associées

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07805637

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2007274598

Country of ref document: AU

Ref document number: 632/KOLNP/2009

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 0902845

Country of ref document: GB

Kind code of ref document: A

Free format text: PCT FILING DATE = 20070720

WWE Wipo information: entry into national phase

Ref document number: 0902845.7

Country of ref document: GB

NENP Non-entry into the national phase

Ref country code: RU

ENP Entry into the national phase

Ref document number: 2007274598

Country of ref document: AU

Date of ref document: 20070720

Kind code of ref document: A

122 Ep: pct application non-entry in european phase

Ref document number: 07805637

Country of ref document: EP

Kind code of ref document: A2