WO2004037248A2 - Modulation de l'activite des recepteurs actives par les proliferateurs de peroxysomes - Google Patents

Modulation de l'activite des recepteurs actives par les proliferateurs de peroxysomes Download PDF

Info

Publication number
WO2004037248A2
WO2004037248A2 PCT/EP2003/011710 EP0311710W WO2004037248A2 WO 2004037248 A2 WO2004037248 A2 WO 2004037248A2 EP 0311710 W EP0311710 W EP 0311710W WO 2004037248 A2 WO2004037248 A2 WO 2004037248A2
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
thιophen
pyrazol
pyrazole
thiophen
Prior art date
Application number
PCT/EP2003/011710
Other languages
English (en)
Other versions
WO2004037248A3 (fr
Inventor
Jacques Huck
Régis SALADIN
Michael Sierra
Evelyne Klotz
Original Assignee
Carex Sa
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 Carex Sa filed Critical Carex Sa
Priority to AU2003287965A priority Critical patent/AU2003287965A1/en
Publication of WO2004037248A2 publication Critical patent/WO2004037248A2/fr
Publication of WO2004037248A3 publication Critical patent/WO2004037248A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds, composil ions and methods useful for modulating nuclear receptors act.ivity in cells, and for treating and/or preventing various diseases and conditions mediated by said nuclear receptors, including metabolic or cell proliferative disorders. According [ ⁇ particular aspects, the present invention relates to compounds, compositions and methods useful for modujat nq activities of the Peroxisome Proliferator Activated Re.:o ⁇ l cu ⁇ ;
  • Receptor-gamma (PPAR-gamma) ligands which are useful m the modulation of blood glucose levels and in the increase of: insulin sensitivity in patients in need thereof.
  • the properties of the compounds and compositions of the invention make these PPAR ligands particularly useful in the treatment of those diseases and conditions including diabetes, atherosclerosis, hyperglycemia, dyslipidemia, obesity, syndrome X, insulin resistance, hypertension, neuropathy, microvascular diseases (e.g. retinopathy, nephropathy ) , macrovascular diseases (e.g. myocardial infarction, stroke, heart failure) in mammals.
  • PPAR-gamma Receptor-gamma
  • Diabetes mellitus refers to a disease process den veri from multiple causative factors and characterized by elevated levels of glucose in blood, or hyperglycemia .
  • Unconl col le hyperglycemia is associated with increased and promal ⁇ ⁇ morbidity and mortality mainly due to an increased ri k foi microvascular and macrovascular diseases. Therefore, control of glucose homeostasis is a critically important app. at foi the treatment of diabetes.
  • At least two types of diabetes mellitus have been identified : (l) the Type I diabetes, or Insulin Dependent Diabetes Mellitus (IDDM), which is the result of a complete lack of insulin, the hormone that regulates glucose utilization under normal physiological conditions, and (ii) the Type II diabetes, or Non Insulin Dependent Diabet r ⁇ - Mellitus (NIDDM) , which is due to a resistance to insuJ ui stimulatory or regulatory effects on glucose and lipjd metabolism in the main msulm-sensitive tissues, i.o skeletal muscle, liver and adipose tissue.
  • IDDM Insulin Dependent Diabetes Mellitus
  • NIDDM Non Insulin Dependent Diabet r ⁇ - Mellitus
  • Said resistance I o insulin responsiveness in Type II diabetes results in insufficient insulin activation of glucose uptake, oxLdai ion and storage in muscle and inadequate insulin repression ol lipolysis in adipose tissue and of glucose production and secretion m liver leading, directly or indirectly, lo diseases and conditions such as atherosclerosi , hyperglycemia, dyslipidemia, obesity, syndrome X, insulin resistance, hypertension, neuropathy, microvascular disease (e.g. retmopathy, nephropathy) , macrovascular diseases (e q myocardial infarction, stroke, heart failure).
  • atherosclerosi hyperglycemia
  • dyslipidemia dyslipidemia
  • obesity syndrome X
  • insulin resistance hypertension
  • neuropathy e.g. retmopathy, nephropathy
  • macrovascular diseases e q myocardial infarction, stroke, heart failure.
  • Type II or Non-Insulin Dependent Diabetes Mellitus constitutes 90 to 95% of all diabetic cases, and about 90% of these people are obese.
  • DM diabetes mellitus
  • Treatment of Type I diabetes involves administration of replacement doses of insulin, generally by the parenteral route.
  • treatment of Type II diabetes does not require admin LS I r t ion of insulin.
  • treatments have been proposed which were based on diet and lifestyle changes augmented by therapy with oral hypoglycemic agents.
  • oral hypoglycemic agents such as sulfonylur
  • pancreatic cells may lead to ma JOT adverse effects such as hypoglycemic reactions, including coma, which are highly unpredictable and prejudicial.
  • thiazolidmediones or T7Ds which act by improving insulin sensi ivity in adipose tissue, liver and muscle.
  • Treatments with sa ⁇ .d aqcnl- have been tested in several animal models of type ]I diahelo and resulted in complete correction of the elevated plasma levels of glucose, triglycerides and nonesterified free fatty acids without any occurrence of hypoglycemic reactions (Cheng Lai and Levme, 2000, Heart Dis., 2, 326-333).
  • thiazolidmediones are rosiglitazone, pioglitazone and troglitazone .
  • the nuclear receptors are activated by small lipophi 1 ⁇ r ligands and, in the activated state, function as transcr p on factors that can regulate the expression of genes involved in a broad range of developmental and physiological proeessr*- ranging from cell differentiation and development to lipid metabolism and energy homeostasis. They act by binding to DN/* response elements (REs) withm the promoter region of taiq t genes and regulate transcriptional activation of said gene c (for a review, see Escriva et al . , 2000, BioEssays, 22, 717 727) .
  • REs DN/* response elements
  • Peroxisome Proliferators Activated Receptors are transcription factors that belong to the nuclear hormone receptor superfamily.
  • the PPARs function as ligand-activat ed transcription factors that control the expression of target genes by binding as heterodimers with the retmoid X receplo ⁇ r
  • RXRs cognate sequences
  • PPREs cognate sequences
  • the first PPAR target genes ideni if Le were found to encode mainly enzymes involved in gluc si , lipid, and cholesterol metabolisms
  • furl In ⁇ investigations have shown that PPARs have pleiol ropu biological activities and wide-ranging medical applicat LOI ⁇ , extending from the treatment of metabolic disorders t o possible applications in inflammation and cancer (Spiegelman, 1998, Diabetes, 47, 507-514 ; Schoonjans et al . , 1997, Curr. Opin. Lipidol., 8, 159-166).
  • the PPAR subfamily includes three subtypes, i.e. PPAR- alpha, PPAR-beta and PPAR-gamma that have distinct tissue expression patterns and exert different physiological role ⁇ 5 PPAR-alpha (PPAR ⁇ or NR1C1) is highly expressed the liver, skeletal muscle, kidney and heart, and stimulates the expression of several enzymes involved in peroxisomal beta oxidation. In addition to being activated by a variety of medium and long-chain fatty acids, PPAR-alpha was found to be
  • the molecular target of the fibrate class of hypoli pi deiru r drugs such as clofibrate (i.e. 2- (4-chlorophenoxy ) 2 methylpropanoic acid ethyl ester), fenofibrate (i.e. 2- (4- (-1 chlorobenzoyl)phenoxy) -2-methylpropano ⁇ c acid ⁇ soprop ⁇ I ester), bezafibrate (i.e. 2-(4-(
  • PPAR-beta (PPAR ⁇ or NR1C2; also known as PPAR-del t , PPAR ⁇ , NUC-1 or FAAR) is ubiquitously expressed and its roJ r m mammalian physiology is still largely undefined. How ve- , , Oliver et al . (2001, Proc. Natl. Acad. Sci., 98, 5306-11) hav ⁇ recently demonstrated that PPAR-beta is implicated in t] regulation of reverse cholesterol transport and Michalik el al. (2000, Horm.
  • PPAR-beta is implicated in the control of keratmocyte proliferation and is necessary for rapid healing of a skm wound.
  • the human DNA sequences for the PPAR-beta has been cloned and is fu 1 J y described Schmidt et al . , 1992, Molecular Endocrinology, 6, 1634-1641, and is herein incorporated by reference.
  • PPAR-gamma (PPAR ⁇ or NR1C3) is most abundantly expressed adipose tissues, the large intestine, and cells of the monocyte lineage. PPAR-gamma plays a central role in adipogenesis , the regulation of fatty acid storage ridipoc tissue, insulin sensitization and m the control of circulating glucose levels. PPAR-gamma has been reported to affect cell proliferation, differentiation (e.g. adipocyte differentiation) and apoptosis pathways. Further evidence ⁇ -. accumulating that suggests an important role for PPAR-gamma in atherosclerosis, inflammation and cancer (for a review, Fa ⁇ jas et al., 2001, J. Mol.
  • PPAR-gamma ligands include prostagland s , fatty acids, N-(2- benzoylphenyl) tyrosine analogues, and the above disclosed thiazolidmediones (Lenhard, 2001, Receptors Channels , 7, 249-58) .
  • the DNA sequences for the PPAR-gamrna receptors have been described in Elbrecht, et al . , 1996, BBRC 224, 431 -4 , and are herein incorporated by reference (see also reference P37231 of NCBI data base) .
  • Literature provides numerous examples illustrating thai PPARs are closely involved in a wide array of diseases 01 pathological conditions which are associated with r el I , expressing these nuclear receptors.
  • Pl' ⁇ R " *-, 5 are useful as drug targets in methods for reducing blood glucose, cholesterol and triglyceride levels and aio accordingly explored for the treatment and/or prophylaxis of insulin resistance (Type II diabetes ; see for example WO 98/05331), impaired glucose tolerance, dyslipidemia, and other 0 disorders related to Syndrome X, also known as Metabolic
  • PPARs have been shown to be potential targets for the treatment of inflammatory diseases such as cutaneous disorder ⁇ -- (including acne vulga ⁇ s, cutaneous disorders with bar ⁇ ei dysfunction, cutaneous effects of aging, poor wound healing
  • !5 be useful for improving cognitive functions in neurologic diseases (Landreth and Heneka, 2001, Neurobiol . Aging, 22, 937-44) or in dementia, for treating diabetic complica ions, psoriasis, polycystic ovarian syndrome (PCOS) or for preventing and treating bone loss, e.g. osteoporosis ; or for 0 antiviral, antiproliferative or antitumoral treatments (see for example US 5,981,586 or US 6,291,496).
  • the PPARs have been shown to be exciting t argot r - for the development of therapeutic compounds likely to have utility at least in the treatment and/or prevention of diseases that involve insulin sensitivity, lipid and glucose homeostasis, such as diabetes mellitus, as well as vascular or inflammatory diseases or disorders.
  • the general problem underlying the invention is to develop new modulators of nuclear receptor activity, such as PPARs
  • PPARs and more specifically of PPAR-gamma
  • metabolic or cell proliferative disorders such as, for example, diseases and conditions related to increased 0 levels of lipids (e.g. hypertriglyceridemia and high levels of free fatty acids), hyperlipidemia, hyperi ns ⁇ l i neirn a , proliferation of the adipocytes, obesity, msulm resistance, insulin resistance leading to Type II diabetes and diabe ic complications thereof (e.g. Syndrome X), hypertension, atherosclerosis and coronary artery diseases.
  • diseases and conditions related to increased 0 levels of lipids e.g. hypertriglyceridemia and high levels of free fatty acids
  • hyperlipidemia e.g. hypertriglyceridemia and high levels of free fatty acids
  • hyperlipidemia e.g. hyperi ns ⁇ l i neirn a
  • proliferation of the adipocytes e.g. hypertension of the adipocyte
  • said compounds and compositions are able to lower one or more of the following biological entities .i patient: ' glucose, triglycerides, fatty acids, cholesterol, bile acid and the like, with better or equivalent efficacy and potency, but with lower toxicity and/or less undesirable side effects occurrence compared to known molecules in the art (e.g thiazolidinediones) .
  • Another objective of the present invention is to provide compounds of the general formula (I) and their derivatives, their analogues, their pharmaceutically acceptable solvates or salts and pharmaceutical compositions containing them or mixtures thereof which have agonist activity against PPAR- gamma, and preferably partial agonist activity against PPAR- gamma.
  • Another objective of the present invention is to provide compounds of the general formula (I) and their derivatives,- their analogues, their pharmaceutically acceptable solvates or salts and pharmaceutical compositions containing them or mixtures thereof having enhanced activities towards PPAR, especially PPAR gamma, without undesirable side effect or with limited undesirable side effect .
  • Yet another objective of the present invention is to provide a process for the preparation of compounds of the general formula (I) and their derivatives, their analogues, their pharmaceutically acceptable solvates or salts.
  • Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their derivatives, their analogues, their pharmaceutically acceptable solvates or salts or thei.r mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions . Still another objective of the present invention s to provide methods of treatment and/or prophylaxis of various diseases and conditions mediated or related to nuclear receptors, especially PPARs (more specially PPAR-gamma), which use the compounds or compositions as the active ingredient.
  • PPARs more specially PPAR-gamma
  • Another objective of the present invention is to provide methods of treatment and/or prophylaxis as above mentioned resulting, in the treated patient, in enhanced beneficial effects (e.g. lowering blood glucose levels and/or improving insulin sensitivity in adipose tissue, liver and skeletal muscle) without toxic effect or with limited toxic effect and /or without undesirable side effect or with limit ed undesirable side effects.
  • enhanced beneficial effects e.g. lowering blood glucose levels and/or improving insulin sensitivity in adipose tissue, liver and skeletal muscle
  • the present invention concerns compounds of the general formula (I):
  • R 1 is a moiety selected the group consisting of :
  • X is a moiety selected in the group consisting of O and S ; a, b, c and d are, independently from one another, an integer ranging from 0 to 4 ;
  • Ax, A 2 and A 3 are, independently from one another, a moiety selected in the group consisting of - CO- , -O- , -CH-, -CH 2 -, -NR 9 -, and -CHOH- where R 9 is as above mentioned; the moiety :
  • a 4 , A 5 , A 6 are, independently from one another, an atom selected in the group consisting of C, N, O and S ;
  • a ⁇ , As, A 9 and A ⁇ 0 are an atom selected in the group consisting of C, N, S and O ; the moiety :
  • a mono carbocyclic ring i.e. a cyclic carboalkyl, with A 7 , A 8 , A 9 and A 1 are C
  • a mono heterocyclic ring i.e. a cyclic heteroalkyl, with at least one A 7 , A 8 , Ar, and/or A 10 is selected in the group con i ing of N, S and O) ;
  • a bi- carbocyclic ring i.e. a bicycl ic carboalkyl with A 7 , A 8 , A 9 and A 10 are C
  • a bi- heterocyclic ring i.e. a bicyclic heteroalkyl with at least one cyclic ring is containing at least one A 7 , A 8 , A 9 and/or A 10 selected in the group consisting of N, S and O
  • a bi- heterocyclic ring i.e. a bicyclic heteroalkyl with at least one cyclic ring is containing at least one A 7 , A 8 , A 9 and/or A 10 selected in the group consisting of N, S and O
  • R 3 is a moiety selected in the group consisting of H, a Ci 4 alkyl moiety (esp. methyl) , - (CH 2 ) n -CONR 1 R , C0 2 R 4 , -COR 4 (esp. -CO-methyl or -CONH ? ) , -OR 4 (esp.
  • R 4 is a moiety selected m the group consisting of H, -
  • C n' H 2n' + 1 e.g. C ⁇ - 4 alkyl moiety such as methyl and ethyl
  • - (CH 2 ) n C0 2 H e.g. -NH 2
  • - (CH 2 ) n -TZD e.g. -OH
  • R 5 and R 13 are, independently from one another, a moiety selected in the group consisting of H, a Ci--** alkyl moiety (e.g. methyl and ethyl), -S0 2 CF 3 , and -SO-,* C n ,H 2n , +1 (e.g. S0 2 butyl) ;
  • R 6 and R 7 are, independently from one another, a moiety selected in the group consisting of H, an alkyl, more specifically a C-._ 4 alkyl moiety, a C 6 cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), or a C 7 cycloalkyl moiety (e.g. a cycloheptyl or a benzyl moiety) , -S0 2 CF 3 , -S0 2 -C n ⁇ 2n ⁇ +1 (e.g.
  • -S0 2 Butyl a benzyl moiety or phenyl moiety substituted at position 2 and/or 3 and/or 4 with a moiety selected in the-) group consisting of -0C n ⁇ 2 n ' + ⁇ . -Cl, -F, -(CH 2 ) n C0 2 H, - 0- (CH 2 ) r *C0 2 H, -(CH 2 ) n -TZD, -O- (CH 2 ) felicit-TZD, -CN, -NO ? , -C n .H2n ' +1 -CO-C n ⁇ 2n'+l , "S0?-C n X ⁇ o 1 , -NR -
  • R 8 and R 8* are, independently from one another, a moiety selected in the group consisting of H, -C n ⁇ 2n . + ⁇ , a C f , cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), -OC n , H n'+ ⁇ . -Cl, -F, -(CH 2 ) n C0 2 H, - CF 3 , - OCF 3 , -COCF 3 , -O- (CH 2 ) n C0 2 H, -(CH 2 ) n -TZD, -0- (CH 2 ) n -TZD ,
  • -CO-cyclohexyI or -CO-phenyl -0-(CH 2 ) n - cycloalkyl (e.g. -O- (CH 2 ) n -cyclohexyl or -O- (CH 2 ) n -phenyl) , -(CH 2 ) lake- cycloalkyl (e.g. - (CH 2 ) n -cyclohexyl or - (CH 2 ) n -phenyl ) , -NR 9 -S0 2 -C n ⁇ 2 n '+ ⁇ (e.g. -NR 9 -S0 2 butyl) ;
  • R 9 and R 9* are, independently from one another, a moiety selected in the group consisting of H, -CO-C n ⁇ 2n - ⁇ , - S0 2 -C n ⁇ 2n - +1 , and a C ⁇ _ 4 alkyl moiety;
  • R 10 and R 10* are, independently from one another, a moiety selected in the group consisting of H, an alkyl, more specifically a C-,- 4 alkyl moiety, a C 6 cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), or a C 7 cycloalkyl moiety (e.g.
  • R 11 and R 12 is, independently from one another, a moiety selected in the group consisting of H, a C l -,, alkyl moiety, - (CH 2 ) n -CONR 13 R 5 , -C0 2 R 4 , -COR 4 , -OR i
  • n is, independently from one another, an integer ranging from
  • n' is, independently from one another, an integer ranging from
  • the present invention concerns compounds of the general formula (I) :
  • R substituted mono carbocyclic ring i.e. cyclic carboalkyl, with A 7 , A 8 , A 9 and A 10 are C
  • a R 3 substituted mono heterocyclic ring ( .e. n cyclic heteroalkyl, with at least one A 7 , A 8 , A g and/or A ⁇ 0 is selected m the group consisting of N, S and 0) ;
  • a R 3 substituted bi- carbocyclic ring i.e. a bicyclic carboalkyl with A 7 , A 8 , A 9 and A ⁇ 0 are C
  • R J substituted bi- heterocyclic ring i.e. bicyclic heteroalkyl with at least one cyclic ring is containing at least one A 7 , A 8 , A 9 and/or A 10 selected in the group consisting of N, S and 0
  • said carbocyclic and/or heterocyclic ring can be unsaturated, or partially or completely saturated, and is containing from 5 to 10 atoms. Examples of said carbocyclic and/or heterocyclic rings are :
  • the present invention concerns compounds of the general formula (I) : or analogues, derivatives, solvates or salts thereof, wherein :
  • R 1 is a moiety selected in the group consisting of :
  • R 3 in R 1 is replaced with R 11 .
  • the present invention concerns compounds of the general formula (1) wherein W is N and A 4 , A 5 , A 6 are C.
  • the present invention concerns compounds of the general formula (I) wherein the moiety :
  • R 14 is a moiety selected in the group consisting of H, an alkyl, -C n ⁇ 2n - + ⁇ more specifically a C ⁇ _ 3 alkyl moiety, a C f) cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), or a
  • cycloalkyl moiety e.g. a cycloheptyl or a benzyl moiety
  • -CH-(CH 2 ) n e.g. -CO-cycloalkyl
  • - (CH 2 ) n -cycloalkyl e.g.
  • R 15 is a moiety selected in the group consisting of H, an alkyl, more specifically a C ⁇ - 3 alkyl moiety, a C 6 cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), or a C 7 cycloalkyl moiety (e.g. a cycloheptyl or a benzyl moiety), -CO-cycloalkyl (e.g. -CO-cyclohexyl or -CO-phenyl), -(CH,) n cycloalkyl (e.g. - (CH 2 ) n -cyclohexyl or - (CH 2 ) n -phenyl ) .
  • an alkyl moiety will have from 1 to 24 carbon atoms, with those moieties having 10 or fewer carbon atoms being preferred the present invention.
  • the alkyl moieties of the invention are lower alkyl.
  • a “lower alkyl” is a shorter alkyl chain having eight or fewer carbon atoms, preferably six or fewer carbon atoms, and even more preferably 4 or fewer carbon atoms (i.e. C-i ) .
  • a C-, 4 alkyl moiety according to the invention wil I have from 1 to 2 carbon atoms, with those moieties having 1 carbon atom being preferred m the present invention.
  • saturated alkyl moieties include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl , isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, (cyclohexyl) methyl , cyclopropylmethyl , n-pentyl, lsopenfyi, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, and the like.
  • An unsaturated alkyl moiety is one comprising one or more double bonds or triple bonds. Examples of unsaturated alkyl moieties include, but are not limited to, aromatic cycles such as for example phenyl
  • a mono carbocyclic ring i.e. a cyclic carboalkyl, with W, A 4 , A 5 and A 6 are C
  • a mono heterocyclic ring i.e. a cyclic heteroalkyl, with at least one A 4 , A 5 , A 6 and/or is as defined above and is not C
  • a bi- carbocyclic ring i.e. a bicyclic carboalkyl, with , A 4 , A 5 and As are C
  • a bi- heterocyclic ring i.e. a bicyclic heteroalkyl with at least one A 4 , A 5 , A s and/or is as defined above and is not C
  • a mono heterocyclic ring i.e. a cyclic heteroalkyl
  • a bi- heterocyclic ring i.e. a bicyclic heteroalkyl
  • the heterocyclic ring can further contain at least one additional hetero atom (i.e. at least one A 4 , A 5 or A 6 is not C) selected in the group consisting of N, S and O.
  • the substituting moiety R present in a cycle for example an aromatic cycle, such as for example the followings :
  • the substituting moiety is localized in position para or meta.
  • alkyl is intended to further include those derivatives of alkyl comprising at least one heteroatom, selected from the group consisting of 0, N and/or S (i.e. at least one carbon atom is replaced with one heteroatom) .
  • These alkyl derivatives are widely named "heteroalkyl” and as alkyl above described are intended to designate, by themselves or as part of another substituent, stable straight or branched chains, or cyclic moieties, or combinations thereof.
  • the nitrogen and sulfur atoms when present in the said heteroalkyl are further oxidized and/or the nitrogen heteroatom is guaternized.
  • the heteroatom may be placed at any position of the heteroalkyl moiety, including the position at which the alkyl moiety is attached to the remainder of the molecule.
  • cycloalkyl and heterocycloalkyl by themselves or as part of another substituent, are intended to designate cyclic versions of the above “alkyl” and “heteroalkyl", respectively. They include bicyclic, tricyclic and polycyclic versions thereof. According to one special embodiment, the term bicyclic (including both the carbo and hetero bicyclic) is intended to designate (1) the case wh ⁇ --*re two cycles are fused together, e.g. naphthalene, or ( 1) the case where one cycle is substituted with a second one, thereby forming a bicyclic structure, i.e. :
  • n is an integer ranging from 0 to 4, more particularly from 0 to 2, and preferably from 0 to 1. In preferred case it is 0.
  • C!_ 4 alkyl intended to designate a straight or branched chain, which may be fully saturated, mono- or polyunsaturated, having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, iso- propyl, and the like.
  • a C* ⁇ - alkyl moiety according to the invention will have from 1 to 2 carbon atoms, with those moieties having 1 carbon atom being preferred in the present invention.
  • An unsaturated alkyl moiety is one comprising one or more double bonds or triple bonds.
  • said structure isolated from R 2 can be as follows :
  • a, b and c are, independently from one another, an integer rangincj >5 from 0 to 2.
  • At least one - (NH) - moiety in the linker isolated from R 2 is replaced by at least one - (N) - moiety.
  • the linker isolated from R ,2 is selected in the group consisting i
  • the "linker" in compounds of formula I is selected in the group consisting of :
  • R 1 is
  • R 0 being H and R 8 being -Cl or -F.
  • R 5 ami R 9* are, independently from one another, selected in the group of ethyl and methyl moieties.
  • R d and/or R 10 is/are not an aromatic C 6 cycloalkyl. According to special embodiments of the invention, :
  • A is -NH- ; - A T IS -NH- and A 2 is -CO- ; or
  • Ai is -NH-
  • A? is -CO-
  • c is 0.
  • the above recitation describes a number of preferred moieties for the compounds of the present invention. Additionally, certain combinations of the above moieties will also be preferred.
  • the compounds according to the present invention include those having R 2 being :
  • R are selected in the group consisting of
  • the present invention concerns compounds as above described which are further substituted with at least one moiety R 16 in position 5 of the central pyrazole ring of Formula I :
  • R 16 being selected in the group consisting of -Cl, -F, -CF 3 , -OCF 3 , -C0CF 3 , a C ⁇ _ 4 alkyl moiety (particularly ethyl or methyl) .
  • the R 2 moiety can include at least one a e which is either secondary or preferably tertiary :
  • these amines are selected m the group consisting of : Dimethyl -a me; Diethyl - am ⁇ ne;D ⁇ sopropyl-amme ; Dibenzyl-amme; Benzyl-methyl-amme ; Methyl- (4-n ⁇ tro-phenyl) -amme; Methyl- (4-methoxy-phenyl ) - amme; Methyl- (4-chloro-phenyl) -amme; Methyl-phenyl-a i ne ; N,N, N ' - T ⁇ methyl -ethane- 1 , 2-d ⁇ amme; Methyl-p- tolyl -amme ;
  • Methoxy-phenyl) -piperazme 1 - (3-Methoxy-phenyl) -piperazme ; 1 -P ⁇ perazm-1 -yl-ethanone ; 1 -Benzyl-piperazme .
  • the compound of the invention is selected the group consisting m :
  • Morphol ⁇ n-4-yl- ( 1 -phenyl-3- thiophen- 2-yl- 1 H-pyrazol-4-yl) - methanone (CRX000166) ; 4 -Methyl -pipe ⁇ dm-1 -yl) - (1 -phenyl- 3 -thiophen- 2 -yl-1 H- pyrazol-4-yl) -methanone (CRX000170) ;
  • Th ⁇ ophene-2-carboxyl ⁇ c acid 1 -phenyl-3-th ⁇ ophen-2-yl- 1 H- pyrazol-4-yl) -amide (CRX000393) ;
  • the compound of the invention is selected in the group consisting in :
  • analogues, derivatives, solvates or salts of compounds of the present invention includes both the structural derivatives and analogues of said compounds, their pharmaceutically acceptable solvates or salts, their stereoisomers, ester, prodrug form, or, their polymorphs. All these type of compounds are herein designated by the generic term “compounds” .
  • the compounds of the present invention may be utilized m the form of a pharmaceutically acceptable salt thereof.
  • physiologicall acceptable salts of the compounds of the Invention include conventional salts prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • acid addition salts can be obtained by contacting the neutral fonn of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, formic, monohydrogencarbonic , phosphoric, monohydrogenphosphoric , dihydrogenphosphoric , perchloric, sulfuric, monohydrogensulfuric , hyd ⁇ odic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, lactic, propionic, isobutyric, palmoic, maleic, glutarmo, hydroxymaleic, malonic, benzoic, succinic, glycolic, suberic, fumaric, mandelic, phthalic, salicylic, benzenesulfom e , p tolylsulfonic , citric, tartaric, methanesul f on ⁇ e , hydroxynaphthoic , hydroiodic, and the like.
  • inorganic acids like hydroch
  • Examples of pharmaceutically acceptable base addition salts include sodium, potassium, lithium, calcium, aluminium, ammonium, barium, zinc, organic ammo, or magnesium salt, N, N 1 -dibenzylethylenedi am ⁇ ne , choline, diethanolamme, ethylenediamme, N-methylglucami ne, procame salts (e.g. chloroprocame) and the like. Also included are salts of am o acids such as argmate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66, 1-19). Finally, certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • t he compounds of the present invention may be utilized in the fonn of a pharmaceutically acceptable solvate thereof.
  • solvates may be prepared by conventional methods such as dissolving the compounds of the Invention m solvents such as methanol, ethanol and the like, preferably water.
  • References hereinafter to a compound according to the invention include both compounds of Formula presented above and their pharmaceutically acceptable salts and solvates.
  • the compounds of the invention may contain one or more chiral centers (stereocenters) and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • the present invention includes all possible stereoisomers including optical and geometric isomers of the-; above Formulae, and enantiomers. It further includes not only race ic compounds, or racemic mixture thereof, but also the optically active isomers as well.
  • a compound of the Invention When a compound of the Invention is desired as a single enantiomer, it may be obtained either by resolution of the final product or b / stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Additionally, in situations where tautomers of the compounds of the Invention are possible, the present invention is intended to include all tautomeric forms of the compound' . These terms and methods required for identifying and select inq the desired compounds are well known m the art. For example, diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographio techniques, and enantiomers may be separated from each other by the selective crystallization of the diastereomeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers may also be prepared synthetically from appropriate stereochemically pure starting materials, or by using stereoselective reactions.
  • the compounds of the present invention might be in a prodrug form.
  • a prodrug is most cases a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation withm the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. Therefore, prodrugs of a compound of the Invention is a compound which has chemically or metabolically cleavable groups and which readily undergoes chemical changes under physiological conditions to provide a compound of formula above described i n vi vo .
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, alkyl esters prepared by reaction of the parent acid compound wLth a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable am e.
  • Particularly preferred alkyl esters as prodrugs are formed from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-bul ⁇ l, morpholmoethyl, and N, N-diethylglycolamido .
  • Methyl ester prodrugs may be prepared by reaction of the acid form of a compound of general formula (I ) a medium such as methanol with an acid or base esterification catalyst (e.g., NaOH, H 2 S0 4 ) .
  • Ethyl ester prodrugs are prepared in similar fashion using ethanol m place of methanol. Details regarding prodrugs are available for example in US 5,498,729.
  • polymorphs of a compound of the Invention for example by crystallization of compound of formula described above under different conditions. For example, he can use different solvents or mixtures commonly used for crystall zation. Similarly, he can crystallize compounds of the Invention at different temperatures, according to various modes of coolincj, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques .
  • the compounds of the invention may be labeled in a variety of ways.
  • the compounds may contain radioactive labels e.g. radioactive isotopes such as, for example H 3 (tritium) or C 14 at one or more of the atoms that constitute compounds of the gene. a I formula presented above.
  • radioactively labelled compounds constitute very specific embodiments of the invention and may be administered systematically, or locally, to an animal, preferably a human.
  • These labelled compounds are useful, for example, for imaging the in vivo levels and/or localization of PPAR-beta in tissues and tissue sections e.g. by the use of well known techniques e.g. autoradiographic technigues oi scmtigraphy .
  • the compound may be labelled with any other type of label that allows detection of the substance, e.g. a fluorescent label or biotin, and the resulting compound can be used for the , -mi l i purpose as the radioactively labelled compound.
  • the compounds may be advantageously oined, covalent! y or noncovalently, directly or through a linker molecule, to a wide variety of other moieties, which may provide function as carriers, labels, ad uvents, coactivators , stabilizers, etc.
  • Such labeled and joined compounds are contemplated within the present invention.
  • composition comprising at least one compound of the general formula as above disclosed.
  • the compounds and compositions of the present invention arc further characterized by their properties towards nuclear receptor PPARs. More specifically, the Applicant has shown that the compounds of the Invention are first able to int i act with at least one PPAR receptor, more preferably with PPAR- gamma ; they are thus named PPAR or PPAR-gamma ligand, respectively. More preferred compounds are those, which are able to interact at least with the ligand binding domain (LBD) of a PPAR receptor, more preferably with the LBD of PPAR-gamma (i.e. ammo acids 195-475).
  • LBD ligand binding domain
  • the compounds of the invention are those which bind to the LBD of a PPAR receptor, more preferably PPAR- gamma, with an affinity of at least about 2 uM and more than about 1 nM, with concentrations in the range of about 10 up to 500 nM being preferred.
  • Biol., 176, 227-48 have disclosed an in vi tro screening test using the yeast two- hybrid system that is based on the ligand-dependent interaction of two proteins, a hormone receptor and a coactivator ;
  • Zhou et al . (2001, Methods, 25, 54-61) have disclosed a homogeneous time-resolved fluorescence (HlRhj energy transfer technology which is sensitive, homogeneous, and nonradioactive ;
  • Beaudet et al . (2001, Genome Res , 11, 600-8) have disclosed the AlphaScreenTM technology (Packard BioScience) which allows the development of high-throughput homogeneous proximity assays.
  • the full content of these papers is incorporated herein by reference.
  • FRET Fluorescence Resonance Energy Transfer
  • CARLA CoActivator-dependent Receptor Ligand Assay
  • GST-pull down assays or two-hybrid assays see Experimental Section
  • the compounds of the present invention are able to interact with said nuclear receptors and/or related LBD in a ligand-dependent fashion so as to effect transcriptional activation or so as to ⁇ nh ⁇ b ⁇ .1 oi silence transcription of genes which are transcript LOIUI! 1 modulated by the said nuclear receptors; i.e. the compounds and compositions of the present invention are able to modulate the transcriptional activity of PPAR receptors, more preferably PPAR-gamma, and thus the biological effects mediated by these nuclear receptors.
  • PPAR-gamma ability of compounds and compositions of the invention to specifically modulate the transcriptional activity of PPAR receptors, more preferably PPAR-gamma, may be first evaluated m vi tro for their ability to modulate PPAR receptor biological effects using biochemical assays (see, for example, the assays above mentioned; e.g. AlphaScreen 11,1 technology) or in cell-based assays.
  • biochemical assays see, for example, the assays above mentioned; e.g. AlphaScreen 11,1 technology
  • cell-based assays for example, a system for reconstilut nig ligand-dependent transcriptional control has been developed by Evans et al . , 1988, Science, 240, 889-95 and has been termed "co-transfection” or "cis-trans” assay. This assay is described in more detail m U.S.
  • the co- transfection assay provides a method to evaluate the ability of a compound to modulate the transcriptional response initiated by a nuclear receptor, for example PPAR.
  • the co- transfection assay is a functional, rapid assay that monitors hormone or ligand activity, is a good predictor of the in VJ v activity, and can be used to quantitate the pharmacological potency and utility of such ligands in treating various disease states (Berger et al., 1992, J. Steroid Biochem Molec . Biol., 41, 733-38).
  • the co-transfection assay involves the introduction of various plasmids by transient transfection into a mammalian cell : at least a plasmid which contains a nuclear receptor receptor cDNA (e.g.
  • PPAR gamma directs constitutive expression of the encoded receptor ; and at least a plasmid which contains a cDNA that encodes for a readily quantifiable protein, e.g., firefly luciferase or chloramphenicol acetyl transferase (CAT) , alkaline phosphatase (SPAP or SEAP), under control of a promoter containing a PPAR response element (PPRE) , which confers dependence on the transcription of the reporter.
  • CAT chloramphenicol acetyl transferase
  • SPAP alkaline phosphatase
  • SEAP alkaline phosphatase
  • This assay can be used to accurately measure efficacy and potency of interaction and modulating activity of a specific ligand compound.
  • the compounds and compositions can be evaluated for their ability to increase or decrease gene expression modulated by PPAR, using western-blot analysis.
  • Voegel et al . (1998, EMBO J. 17, 507-519) have proposed the use of transient transfection assays w th a GAL4 reporter plasmid and chimeras containing various peptide fragments linked to the GAL4 DBD (DNA Binding Domain) .
  • the compounds of the present invention achieve no activation of other PPAR isoform (e.g. PPAR alpha, PPAR beta) and other known target i.e. PXR, RXR , especially at a dose of 10 ⁇ M.
  • PPAR isoform e.g. PPAR alpha, PPAR beta
  • PXR, RXR a known target i.e. PXR, RXR
  • the compounds and compositions of the present invention are PPAR and/or PPAR l,BI) agonists.
  • the compounds and compositions of the present invention are PPAR-gamma and/or PPAR-gamma LBD agonists.
  • agonist is meant a compound or composition which when combined with an intracellular receptor stimulates or increases a reaction typical for the receptor, e.g., transcription activation activity.
  • said agonist is a PPAR-gamma agonist, i.e.
  • a PPAR ligand which potentiates, stimulates, induces or otherwise enhances the transcriptional activity of a PPAR-gamma receptor, e.g., such as by mimicking a natural physiological ligand for the receptor.
  • the compound and compositions of the present invention are PPAR ancl/oj PPAR LBD partial-agonists, and more particularly, the compounds and compositions of the present invention are PPAR-gamma and/or PPAR-gamma LBD partial-agonists.
  • a drug that produces less than the possible maximal effect i.e. the maximal effect produced by a full agonist, or reference molecule
  • partial agonist A drug that produces less than the possible maximal effect (i.e. the maximal effect produced by a full agonist, or reference molecule) is called partial agonist.
  • the partial agonist property of the compounds and compositions of the present invention can be defined by reference to rosiglitazone (AvandiaTM, Glaxo- SmithKlme) which is a full agonist.
  • the compounds and compositions of the present invention are partial agonists in the sense that their maximal efficacy (illustrated by their Vmax and/or Emax) is less than about 70% of the maximal efficacy (illustrated by Vmax and/or Emax) of the rosiglitazone measured under identical conditions (see the Experimental section).
  • their maximal efficacy is comprised between about 50% and about 10% of the rosiglitasone maximal efficacy, and m rather preferred embodiments it is comprised between about 30% and about 20% of the rosiglitasone maximal efficacy.
  • Potency and efficacy are the two key features in analyzing ligand agonist, including partial agonist, property.
  • Potency can be calculated through dose response experiment i n a given functional assay e.g. co-transfection assay. It represents the dose of compound necessary to achieve 50 % of maximal affect (EC50). This value is closely related to the Kd obtained a binding assay and therefore related to tl j affinity of the compound for the receptor. Identification of compounds with low potency is important to achieve target specificity and the development of low dosed pharmaceut ca L compositions to be administered into patients.
  • Efficacy determines the maximum effect that can be achieved in a functional assay that assesses the compound tested effect on the PPAR, and more particularly PPAR-gamma, in a co- transfection assay.
  • the Applicants postulate that too high level of efficacy can be associated with detrimental undesirable side effects.
  • the compounds and compositions of the present invention have a potency comprised between about 1 nM and 2 uM, with concentrations in the range of about 10 up to 500 nM being preferred.
  • the compounds and compositions of the present invention are both PPAR and/or PPAR LBD partial-agonists and PPAR and/or PPAR LBD antagonists. More particularly, the compounds and compositions of the present invention are both PPAR-gamma and/or PPAR-gamma LBD partial-agonists and PPAR-gamma and/or PPAR-gamrna T..P.D antagonists.
  • antagonist is meant a compound or composition which when combined with an nuclear receptor interferes or decreases a reaction typical for the receptor, e.g., transcription activation activity.
  • PPAR-gamma antagonist designates a PPAR-gamma ligand that gives greater than 50% inhibition of transactivation achieved by 100 nM rosiglitazone when tested in the cell-based reporter assay such as described in WO 01/17994.
  • PPAR antagonist designates a PPAR ligand which can inhibit the activity of a corresponding PPAR agonist. More generally, these agonist/antagonist/partial agonist activities may be measured by assays widely known to one skilled in the art such as for example those which are disclosed in WO99/50664 or WO96/41013.
  • the compounds and compositions of the invention are further characterized by their biological activities, and more specifically present beneficial activities towards glucose cellular uptake and/or adipogenesis .
  • beneficial activities e.g. thiazolidmediones
  • compounds that activate PPAR-gamma are further inducing adipocyte differentiation (i.e. adipogenic effect) and are thus resulting in body weight increase in treated patients. Therefore it is highly desirable that the next generation of such compounds are devoid of such activity.
  • PPAR-gamma e.g. thiazolidmediones
  • adipocyte differentiation i.e. adipogenic effect
  • the claimed compounds and compositions display at least about 50%, preferably at least about 60%, more preferably at least about 70 % and even more preferably at least about 80% of the rosiglitazone property towards glucose uptake. Ideally, i will be 100% or more. According to another preferred embodiment of the instant invention, the claimed compounds and compositions display less than about 50%, preferably less than about 40%, more preferably less than about 30 % and even more preferably less than about 20% of the rosiglitazone property towards adipogenesis .
  • nuclear receptors such as PPAR-gamma
  • PPAR-gamma achieve trancriptional activation or repression by binding to cognate sequences in the promoter regions of target genes (e.g. PPREs) and by recruiting numerous cofactor complexes whose activities range from chromatin remodeling, histone and cofactor modification, to basic transcription machinery recruitment (Glass, & Rosenfeld, 2000, Genes Dev., 14, 121-141).
  • target genes e.g. PPREs
  • cofactors may to a large extend determine the specificity of the action of nuclear receptors and integrate their action in a network of stirnul i whose proper orchestration leads to a specific cellular response.
  • PPAR cofactors have been identified so far. Some cofactors such as p300/CBP (Dowell et al . , 1997, J. Biol. Chem. 272, 33435-33433), SRC-1 (Onate et al . , 1995, Science 270, 1354-1357), TIF2 (GRIP- 2 ; Chakravarti et al., 1996, Nature, 383, 99-103), SRA (Lanz et al . , 1999, Cell, 97, 1/ 27), AIB-1 (Anzick et al . , 1997, Science, 277, 965-968), TRAP220/DRIP205 (i.e. PBP ; Zhu et al . , 1997, J. Biol. Che . 272, 25500-25506 ; Rachez et al . , 1999, Nature, 398, 824-828),
  • the 160-kDa protein (SRC 1 /TIF2/AIB-1 ) , CBP/p300 or TRAP220/DRIP205 ) interact directly with PPAR-gamma and potentiate nuclear receptoi transactivation function m a ligand-dependent fashion leading to biological action or side effects that can differ according to the ligand used (Adams et al . , 1997, J. Clin. Invest., 100, 3149-3153). Kodera et al . (2000, J. Biol.
  • Chem., 275, 33201- 33204 have examined whether interactions between PPAR- gamma and known cofactors were induced to the same extent by different classes of PPAR-gamma ligands (natural and synthetic) and concluded that the overall structure of PPAR- gamma and cofactors complexes may be different according to the ligands involved, resulting in the activation of a particular set of target gene promoters that exert different 5 biological actions.
  • SRC-1 The p160 family of cofactors, composed of SRC-1, TIF2 and SRC-3, is of notable interest for PPAR-gamma.
  • SRC-1 was initially isolated as a progesterone receptor (PR) coactivator (Onate et al . , 1995, Science, 270, 1354-1357) but has been
  • PR progesterone receptor
  • SRC-1 has an intrinsic histone acetyltransferase activity (Spencer et al.,1997, Nature, 389, 194-198) and is broadly expressed albeit at
  • SRC-1 has been shown to have two PPAR bin ing domains, each containing the LXXLL consensus receptor interaction motif (Heery et al . , 1997, Nature, 387, 733-736).
  • the compounds and compositions of the present invention are furthermore characterized by a restricted cofactor (s) recruitment pattern.
  • said pattern results actually in 0 distinct effects on the regulation of the transcriptional activity of said nuclear receptors allowing a very fine tuned regulation which results in the activation of speci tic metabolic processes as well as the elimination of unwanted side effects.
  • the compounds and compositions of the present invention are furthermore able to inhibit the interaction of PPAR receptor, more preferably PPAR receptor LBD, with cofactor TIF2 and that enhance the interaction of PPAR receptor, more preferably PPAR receptor LBD, with cofactor SRC-1.
  • said PPAR receptor is PPAR-gamma receptor.
  • Methods for measuring inhibition and/m enhancement of cofactor recruitment by ligands are detaUecl n* co-pending application EP 02291496.4 filed on June 14, 2002.
  • the AlphascreenTM method is a proximity assay that allow the measurement of the interaction of a nuclear receptor associated with a at least one ligand and with at least one cofactor.
  • the agonist / partial agonist / antagonist compounds of the invention when bound to PPAR-gamma will allow to recruit SRC1 to the LBD with an EC50 which is at least one log greater than the one for TIF2, with 2 log being preferred. This type of analysis is widespread practice of the one skilled in the art.
  • the compounds and compositions of the present invention due to their agonistic, particularly partial agonistic, or antagonistic property towards natural physiological ligands of the PPAR receptors, especially PPAR-gamma receptor, can SCJ c as pharmaceuticals for controlling the biological effects of PPAR-mediated transcriptional control and the attendant physiological effects produced thereby. More specifically they are capable of specifically modulating a cellular physiology to reduce an associated pathology or provide or enhance a prophylaxis .
  • the present invention further concerns a composition
  • a composition comprising at least one compound of the invention as disclosed above and a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent may be prepaied by conventional techniques, e.g. as described in Remington, 1995, The Science and Practise of Pharmacy, 19.sup.th Ed.
  • Typical compositions of the present invention are associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed withm a carrier which can be in the form of a capsule, sachet, paper, tablets, aerosols, solutions, suspensions or other container.
  • conventional technigues for the preparation of pharmaceutical compositions may be used.
  • the active compounds will usually be mixed with a carrier or a diluent, or diluted by a carrier or a diluent, or enclosed with a carrier or a diluent which may be in the form of a ampoule, capsule, sachet, paper, tablets, aerosols, solutions, suspensions or other container.
  • a carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compounds can be adsorbed on a granular solid container for example in a sachet.
  • liquid oral pharmaceutical compositions are in the form of, for example, suspensions, elixirs and solutions; solid oral pharmaceutical compositions are m the form of, for example, powders, capsules, caplets, gelcaps and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, m which case solid pharmaceutical carriers are obviously employed.
  • suitable carriers or diluents are, without being limited, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrm, amylose, magnesium stearate, talc, gelatin, agar, pectm, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides , pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone .
  • the carrier or diluent may include any sustained release material known m the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with wax.
  • the formulations may also include wetting agent r, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures wel I known in the art.
  • the active compounds ar prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vmyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to thos*-* skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • the compound of the present invention can also be administered m the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of lipids, including but not limited to amphipathic lipids such as phosphatidylchol es , sphmgomyel ns, phosphatidylethanolammes , phophatidylcholmes , cardiol i pi ns, phosphatidylsermes, phosphatidylglycerols , phospbati cl ⁇ c acids, phosphatidylmositols , diacyl trimethylammoni um propanes, diacyl dimethylammonium propanes, and stearyl amme, neutral lipids such as triglycerides, and combinations thereof.
  • amphipathic lipids such as phosphatidylchol es , sphmgomyel ns, phosphatidylethanolammes , phophatidylcholmes , cardiol i pi ns,
  • compositions of the invention can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the l ke, which do not deleteriously react with the active compounds.
  • the pharmaceutical compositions of the invention WLJ I typically be those which contain an effective amount of a compound of the invention.
  • an effective amount of a compound of the invention is a concentration of the sai compound that will produce a 50% (EC 50 ) increase in PPAR activity in a cell-based reporter gene assay, or a biochemic l peptide sensor assay such as the assays described above.
  • the pharmaceutical compositions herein may contain between about 0.1 mg and about 1000 mg, preferably about 100 to about 500 mg, even more preferably about 5 to about 50 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected.
  • the tablets or pills of the pharmaceutical composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an out i dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, alcohol and cellulose acetate.
  • composition of the present invention further comprises a natural or synthetic PPAR and/or RXR agonist or antagonist.
  • Naturally occurring ligands that modulate the activity of PPAR include but are not limited to, fatty acids such as arachidonic acid derivatives or metabolites such as eicosanoids (e.g. various isomeric forms of 8-hydroxytetraeno ⁇ c acid) and cyclopentenone prostaglandms
  • fatty acids such as arachidonic acid derivatives or metabolites such as eicosanoids (e.g. various isomeric forms of 8-hydroxytetraeno ⁇ c acid) and cyclopentenone prostaglandms
  • PPAR ligand is a prostaglandm J2 or delta-12-prostagland ⁇ n ⁇ ?
  • Synthetic ligands that modulate the activity of PPAR are for example antidyslipidemic fibrates (e.g. clofibrate,
  • N-2-L- tyrosine derivatives e.g. N-(2 Benzoylphenyl) -L-tyrosine ; Henke et al . , 1998, J. Med. Chem , 41, 5020-5036
  • FMOC-L-Leucine WO0200611
  • phenyl acetic acid derivatives Bohray et al . , 0 1998, J. Med. Chem., 41, 1619-1630.
  • RXR specific agonists include, but are not limited to, 9-c ⁇ •- retinoic acid, 4- ( 1 - (3 , 5 , 5 , 8 , 8-pentamethyl-5 , 6 , 7 , 8-tetrahyd ⁇ o- 2-naphthyl) -ethenyl) benzoic acid ( 3-methyl-TTNEB; LGD 1069), LG 100268 (i.e.
  • compositions of the present invention can further comprise additional agents.
  • additional agents are hypoglycemic agents (e.g.
  • sulfonylurea or/and biguamde derivatives insulin, insulin derivative, insulin secretagogue, insulin sensitizer, or insulin mimetic ; other examples are mitotic inhibitors, alkylatmg agents, antimetabolites, nucleic acid intercalating agents, topoisomerase inhibitors, agents which promote apoptosis, or agents which increase immune responses to tumors (e.g cytokmc chosen from alpha-, beta- and gamma-mterferon, mterleuki ns , and m particular IL-2, IL-4, IL-6, IL-10 or IL-12, tumour- necrosis factors (TNFs) and colony stimulating factors (for example GM-CSF, C-CSF and M-CSF) .
  • mitotic inhibitors alkylatmg agents, antimetabolites, nucleic acid intercalating agents, topoisomerase inhibitors, agents which promote apoptosis, or agents which increase immune responses to tumors (e.g
  • Literature provides to the skilled man with numerous examples of such additional agents.
  • the compounds and compositions containing the same of the present invention exhibit agonist, and preferably par ial- agonist activity toward PPAR receptors, and preferably toward ' PPAR-gamma receptor, which are important factors at the top of a gene cascade involved m differentiation of adipocyfer , synthesis, accumulation, metabolism and decomposition of lipids, control of glucose metabolism, and thermogenesis in the body.
  • a further aspect of the present invention is a method for the treatment of a mammal, including man, m particular in the treatment of diseases and conditions where modification of the effects of PPAR, preferably PPAR- gamma, is of therapeutic benefit, the method compr sing administering to the patient in need a therapeut cally effective amount of at least one compound of Formula (I), derivate thereof, or a pharmaceutically composition as above disclosed.
  • treatment herein extends to prophylaxis as well as the treatment of established diseases or symptoms.
  • Diseases and conditions where modification of the effects of PPAR is of therapeutic benefit means diseases or pathologic conditions wherein the observed disorder is associated initially with the deregulation, disturbance, hypersensitivity , or malfunctioning of cells expressing PPAR nuclear receptors, preferably PPAR-gamma receptor, or more specifically m which the disease or pathologic conditions is caused by one or more genes that are under the transcription control of PPARs, preferably of PPAR-gamma, or said disease or pathological condition causing genes are post-translational] / modified m response to PPARs. Examples of these cells are those from liver, skeletal muscle, kidney, heart, CNS, adipose tissues, intestine, or cells of the monocyte lineage.
  • said cell type is an adipocyte or pre- adipocyte.
  • a PPAR-responsive hyperproliferati-ve cell examples of these diseases or pathologic conditions are those associated with impaired metabolism of glucose, cholesterol or triglycerides.
  • diabetes is insulin resistance, Type II diabetes, Type I diabetes, impaired glucose tolerance, dyslipidem 1 a , hyperlipidemia, hypercholesterolemia, hypertriglycidern l , disorders related to the metabolic disease, Syndrome X including hypertension, obesity, hyperglycaemia, atherosclerosis, thrombosis, hyperlipidemia, coronary artery disease, heart failure and other cardiovascular disorders ; renal diseases including glomerulonephriti s , glomerulosclerosis , nephrotic syndrome, hypertensive nephrosclerosis ; neurologic diseases or dementia ; anorexia bulimia, anorexia nervosa ; inflammatory diseases such as cutaneous disorders (including acne vulga ⁇ s, psoriasis, cutaneous disorders with barrier dysfunction, cutaneous effects of aging, poor wound healing), diabetic complications, polycystic ovarian syndrome (PCOS) and bone loss, e.g.
  • PCOS polycystic ovarian syndrome
  • a method for treating obesity comprising administering to a patient m need of such treatment an amount of at least one compound or a composition of the invention effective to block cell differentiation to produce lipid-accumulatmg cells.
  • Obesity is a disease that had become highly prevalent m affluent societies and m the developing world and which is a manor cause of morbidity and mortality. It is characterized by a body mass index above 2 r > but those of skill in the art readily recognize that I lu invention method is not limited to those who fall withm t lu* above criteria.
  • lipid-accumulatmg cells such as, for example, mesenchymal cells (e.g., fibroblasts) .
  • amount of produce lipid-accumulatmg cells refers to levels of compound of the invention sufficient to provide circulating concentrat LO ⁇ S high enough to accomplish the desired effect. Such a concentration typically falls the range of about 10 nM up to 2 uM; with concentrations in the range of about 100 nM up to 500 nM being preferred. Since the activity of different compounds which fall with the definition of structure I as set forth above may vary considerably, and since individual subjects may present a wide variation in severity of symptoms, it is up to the practitioner to determine a subject's response to treatment and vary the dosages accordingly.
  • disease or pathologic condition according to the invention is diabetes or msulm resistance .
  • Insulin resistance is manifested by the diminished abili y of msulm to exert its biological action across a broad range of concentrations.
  • the body secretes abnormally high amounts of msulm to compensate for this defect.
  • diabetes mellitus has become a common problem and is associated with a variety of abnormalities including, but not limited to, obesity, hypertension, hyperlipidemia and renal complications.
  • ⁇ t is now increasingly being recognized that insulin resistance and hypermsulmemia contribute significantly to obesity, hypertension, atherosclerosis and Type II diabetes mellitus.
  • diabetes refers to all variant forms of diabetes mellitus (DM) , including Type I DM, Type II DM, gestational diabetes, juvenile diabetes, etc.
  • a method for modulating sulm- sensitivity and blood glucose levels m a patient comprising administering to a patient in need of such treatment an amount of at least one compound or composition of the invention in effective to lower the blood glucose level of said subject.
  • amount effective to lower blood glucose levels refers to levels of compound of the present invention sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a concentration typically falls in I he range of about 10 nM up to 2 uM; with concentrations in the range of about 100 nM up to 500 nM being preferred.
  • disease or pathologic condition according to the invention is hyperlipidemia.
  • Hyperlipidorm a is considered the primary cause of cardiovascular and other peripheral vascular diseases.
  • An increased risk of 5 cardiovascular disease is correlated with elevated plasma levels of LDL (Low Density Lipoprotem) and VLDL (Very Low Density Lipoprotem) as seen m hyperlipidemia.
  • LDL Low Density Lipoprotem
  • VLDL Very Low Density Lipoprotem
  • the diseases or pathologic conditions according to the invention also include cellular proliferation, growth, differentiation, or migration
  • a "cellular proliferation, growth, differentiation, or cell migration disorders” is a disorder which a cell increases number, size or content, in which a cell develops a specialized set of characteristics which differ from that of other cells, or in which a cell moves
  • the PPAR molecules of the present invention are involved signal transduction mechanisms, which are known to be involved in cellular growth, differentiation, and migration processes. Thus, the PPAR molecules may modulate cellular growth,
  • disorders may play a role in disorders characterized by aberrantly regulated growth, differentiation, or migration.
  • disorders include cancer, e.g., carcinomas, sarcomas, leukemias, and lymphoma s; Lumn angiogenesis and metastasis; skeletal dysplasia; hepatic 0 disorders; and hematopoietic and/or myeloproliferative disorders.
  • Exemplary disorders include, but not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma , osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcorna , lymphangiosarcoma, lymphangioendotheliosarcoma, synoviorna, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma , colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarc oma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcmomas , cystadenocarclnoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcmoma,
  • the disease or pathologic condition according to the invention is a disorder characterized by aberrant cell growth of PPAR-responsive cells such as hyperplastic or neoplastic disorders arising in adipose tissue, such as adipose cell tumors, e.g., lipoinar, fibrolipomas , lipoblastomas , lipomatosis, hi-bemoinas, hemangiomas and/or liposarcomas .
  • adipose cell tumors e.g., lipoinar, fibrolipomas , lipoblastomas , lipomatosis, hi-bemoinas, hemangiomas and/or liposarcomas .
  • the disease or pathologic condition according to the invention is a disorder characterized by aberrant cell growth of PPAR-responsive cells such as hyperplastic or neoplastic disorders of the hematopoietic system, e.g., leukemic cancers.
  • disease or pathologic condition according to the invention is an inflammatory disease including, but not limited to, T-lymphocyte activation and other T-lymphocyte-related disorders ; inflammatory cytok e (e.g. TNF-alpha, mterleukm (IL) - 1 -alpha, IL-1-beta, IL-2, IL-6) production ; activation of nuclear factors that promote transcription of genes encoding inflammatory cytokines Examples of these nuclear transcription factors include but are not restricted to, nuclear factor-kappaB (NF-kappaB) , activated protein- 1 (AP-1), nuclear factor of activated T cells (NFAT) .
  • Other examples of disease or pathologic condition according to the invention are chronic viral infections (e.g.
  • HIV HIV, CMV, HSV, HBV, HCV infections
  • neurodegenerative diseases e.g. Alzheimer ' disease, multiple sclerosis, Parkinson's disease
  • cardiovascular disease e.g. atherosclerosis, atherogene- ⁇ i , vascular restenosis, congestive heart failure
  • diseases oi conditions involving hypoxemia and hypoxic stress stroke, vascular occlusive disease, MI, atherosclerosis, retmitis, retinal vein occlusion, hypoxic retmopathy, macular degeneration
  • said methods for treating and/or preventing diseases or pathologic conditions associated with cell types that express PPAR receptors are not associated with side effects, and preferably are not associated with patient weigh ga , oedema, liver toxicity, haemadilution, etc
  • the present invention concerns a method oT treating and/or preventing diseases or conditions in a patient, comprising the step of administering to said individual a pharmacologically effective dose of a compound oi composition of the invention said administration resulting in improving the clinical status of said patient.
  • the term "patient” means a mammal, e.g., a primate, e.g., a human.
  • pharmaceutically effective dose an amount of a pharmaceutical compound or composition having a therapeutically relevant effect m the frame of treatment and/or prevention of conditions mediated by PPAR, preferably
  • a therapeutically relevant effect relieves to some extent one or more symptoms of conditions mediated by PPAR, preferably PPAR-gamma, in a patient or returns to normal either partially or completely one or more physiological o> biochemical parameters associated with or causative of said conditions, e.g. increasing the sensitivity of cellular response to circulating msulm, curing, reducing, or preventing one or more clinical symptoms of PPAR, preferably PPAR-gamma, related conditions, including, but not limited to, hyperglycemia, hyper sulmemia and hypertriglyceridemia.
  • a pharmaceutically effective dose of a compound or composition means an amount that increases the uptake of glucose by adipose tissue or muscle tissue.
  • a pharmaceutically effective dose of a compound or composition means an amount that increases the uptake of triglyceride by adipose tissue.
  • the compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 0.1 mg to about 70 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapeutic effect that is intended to be achieved, the form in which the dosage is administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge. Dosages and treatment schedules are readily attainable by routine experimentation to those having ordinary skill in this art. Generally, the compounds are dispensed in unit dosage form comprising from about 0.1 to about 100 mg of active ingredient together with a pharmaceutically acceptable carrier per u ⁇ l dosage .
  • the compounds or compositions of the present invention may be administered in a single daily dose, or the total daily
  • 5 dosage may be administered m divided doses of two, three oi four times daily.
  • the treatment can be adapted to administer the compounds or compositions of the invention in a single weekly or monthly dose.
  • the amount of a compound of the invention may be administered m divided doses of two, three oi four times daily.
  • the treatment can be adapted to administer the compounds or compositions of the invention in a single weekly or monthly dose.
  • compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0 01 mg/kg to about 30 mg/kg of body weight per day. Particularly, the range is from about 0.03 to about 15 mg/kg of body weight per day, and more particularly, from about 0.05 to about 10 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 2 times per day. Optimal dosages to be administered may be readily determined by those skilled the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • Toxicity and therapeutic efficacy of the compounds included in the compound or composition of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population) .
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effee t c may be used, special care should be taken to design a delivery system that targets such compounds to the site of affected tissue m order to minimize potential damage to unmfected cells and, thereby, leads to a reduction of side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use m humans.
  • the dosage of such compounds lies preferably withm a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may br formulated in animal models to achieve a circulating pla s ma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half- maxi al inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound which achieves a half- maxi al inhibition of symptoms
  • the route of administration of the compound or composition of the present invention may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous , intravenous, mtraurethral , intramuscular, tranasal, ophthalmic solution or an ointment, the oral or mtratumoral route being preferred.
  • the present invention further concerns compounds and compositions of the present invention for use in therapy. Similarly, it concerns the use of at least one compound or composition according of the present invention for the manufacture of a medicament for the treatment of diseases and conditions where modification of the effects of PPAR is of therapeutic benefit . Examples of these diseases and conditions are provided above.
  • the present invention concerns the use of at least one compound or composit ion according of the present invention for the manufacture of a medicament for the treatment of individuals requiring lower blood glucose levels, i.e. for the manufacture of a medicament for lowering blood glucose levels m a patient.
  • the present invention concerns the use of at least one compound or composition according of the present invention for the manufacture of a medicament for the treatment of individuals requiring an increased sensitivity to msulm, i.e. for the manufacture of a medicament for increasing msulm sensitivity in a patient.
  • the compounds and compositions of the present invention may also find use a variety of in vi tro and m vivo assay- , including diagnostic assays. For example, various allotypie
  • PPAR-gamma receptor gene expression processes may be distinguished m sensitivity assays with the subject compounds and compositions, or panels thereof.
  • labelled versions of the subject compounds and compositions e.g. in radioligand displacement assays.
  • the invention provides the compounds and compositions of the invention comprising a detectable label, which may be spectroscopic (e.g. fluorescent), radioactive, etc.
  • GAL4-hPPAR-gamma LBD plasmid expression vector encoding a chimeric construct comprising the GAL4 DBD (DN ⁇ Binding Domain) and the human PPAR-gamma LBD ; luciferase reporter plasmid : vector in which luciferase gene expression is placed under the control o a GAL4 response element ; - pCMV-betaGAL plasmid: control of transfection efficiency, it is a vector encoding the beta-galactosidase gene .
  • Rosiglitazone is a high affinity PPAR gamma ligand (Lehmann, et al . , 1995, J. Biol. Chem. 270, 12953-12956) and is a member of the thiazolidmedione class of compounds. Rosiglitazone possesses the capacity to activate PPAR-gamma m vi tro during transfection assays, to induce adipogenesis both in vi tro and m vivo (Fa ⁇ as et al., 1998, Curr. Opm. Cell Biol.
  • Cotransfection assay In order to test the ability of compounds of the invention to activate human PPAR-gamma, the following method can be used.
  • CV1 cells (5 10 4 cells/ well of a 96 wells plate) are grown in DMEM supplemented with L-Glutamme (2 mM) , penicillme / streptomycin, 10 % Fetal Calf Serum charcoal and dextran treated.
  • 1 ng of GAL4-hPPAR-gamma LBD plasmid is cotransfected with 4 ng of Luciferase reporter plasmid, 8 ng of pCMV-betaGAL as an internal transfection standard and 47 nq of pBSK as a carrier using Fugene reagent (Roche) .
  • CV1 cells (10 5 cells/ well of a 24 wells plate) are grown in DMEM supplemented with L-Glutamine (2mM), penicillme / streptomycin, 10% Fetal Calf Serum charcoal and dextran treated.
  • 8 ng of GAL4-TIF2 LBD plasmid is co-transfected with 8 ng of VP16-hPPAR gamma LBD, 8 ng of pSG5-RXR alpha, 32 ng of Luciferase reporter plasmid, 32 ng of pCMV- ⁇ GAL as an internal transfection standard and 302 ng of pBSK as a carrier using Fugene reagent (Roche).
  • 3T3L1 cells are grown to confluence at 37 °C, 5% C0 2 , in a 24 well plate in DMEM supplemented with L-Glutamine (2 mM) , penicillme / streptomycin, 10 % Calf Serum. Two days post confluency, cell are changed to DMEM supplemented with L-Glutamine (2 mM) , penicillme / streptomycin, 10 % Fetal Calf Serum.
  • Insulin (10 mg/ml) and either rosiglitazone at 1 ⁇ M or compounds of the invention at 10 ⁇ M, both in DMSO 0.25% final are then added to cells for 3 days. The same treatment is then repeated for an additional 2 days. Finally, cells are grown for another 2 days in DMEM supplemented with L-Glutamine (2 mM) , penicillme / streptomycin, 10 % Fetal Calf Serum.
  • Adipogenic effect is I hem quantified through the measurement of triglyceride content using the Triglyceride GPO Tinder test (SIGMA) . Data arc- expressed as a percent of rosiglitazone effect.
  • Insulin Stimulated Glucose Uptake (ISGU)
  • 3T3L1 cells are grown to confluence at 37°C, 5% C0 2 , in a 48 well plate in DMEM supplemented with L-Glutamine (2 mM) , penicillme / streptomycin, 10 % Calf Serum. Two days post confluency, cell are changed to DMEM supplemented with L- Glutamine (2 mM) , penicillme / streptomycin, 10 % Fetal Calf Serum (DMEM + 10% FCS), and an hormonal cocktail composed of : Insulin (10 ⁇ g/ml), IBMX (500 ⁇ M) and Dexamethasone (1 ⁇ M) for 3 days.
  • DMEM + 10% FCS and Insulin (10 ⁇ g/ml) are then treated for an additional 2 days with DMEM + 10% FCS and Insulin (10 ⁇ g/ml) . Finally, cells arc; grown for another 2 days in DMEM +10% FCS to complete adipocyte differentiation. Rosiglitazone at 10 ⁇ M or compounds of the invention at 10 ⁇ M, both in DMSO 0.25% final are then added everyday to cells for 3 days. Cells are rinsed w th serum-free DMEM twice and incubated for 3 hours at 37°C, 5' ⁇ C0 2 .
  • KRPH buffer (5 M phosphate, pH 7.4 (NaH 2 P0 4 -H 2 0 + Na 2 HP0 4 -7H 2 0) , 20 mM HEPES pH 7.4, 1 mM MgS0 4 , 1 mM CaCl 2 , 136 mM NaCl, 4.7 mM KCI).
  • Thr--' buffer is removed and the cells are incubated with or without 100 nM Insulin m KRPH buffer for 20 mmuts at 37°C.
  • I'ho buffer is replaced with 0.25 ⁇ Ci/well of [ 3H] -2-deoxy-D Glucose in KRPH buffer supplemented with 25 mM 2-deoxy 1) Glucose with incubation for 5 mmuts at room temperature. Supernatant is removed, cells washed four times with cold PBS and lysed with 0. IN NaOH. 400 ⁇ l of lysate is neutralized with 40 ⁇ l of IN HCl and added in a scintillation vial with 4 ml of Ready Safe Tm (Beckman Coulter) . The vials are mixed and counted. Data are expressed both for basal and insulin stimulated glucose uptake as a percent of rosiglitazone effect .
  • mice aged 8 weeks are treated twice a day by oral gavage in Carboxy Methyl Cellulose 1 % + Tween 80 0,1 with either vehicle alone, rosiglitazone at 10 mg/kg/day oi compounds of the invention at 10 mg/kg/day.
  • the hematocrit is quantified by measurement of percentage of Packed Red Cells Volume (PCV) in blood. Data are presented as a percentage of rosiglitazone effect.
  • PCV Red Cells Volume
  • mice aged 8 weeks are treated twice a day for 14 days by oral gavage Carboxy Methyl Cellulose 1% i Tween 80 0,1 % with either vehicle alone, rosiglitazone at 10 mg/kg/day or compounds of the invention at 10 mg/kg/day. Animals are bleed two days before initiation of the treatment and then at day 7 and at completion of the experiment (14 days treatment).
  • Plasma biochemical measurements include : total Cholesterol, HDL-Cholesterol , Triglycerides, Glucose, Non Esterified Fatty Acids, Insulin (-2, 7, 14 days) and liver enzymes for toxicity i.e Alkaline Phosphatase and Transaminases (ASAT, ALAT) at completion of the experiment. Additional measurement includes every other day body weight monitoring, food and water intake per cage. Every animal serve as his own control and results are expressed as percent changes.

Landscapes

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

Abstract

La présente invention concerne des composés, de compositions et des méthodes utiles pour moduler l'activité de récepteurs nucléaires dans des cellules, ou pour traiter et/ou prévenir diverses maladies et affections induites par lesdits récepteurs nucléaires, y compris des troubles du métabolisme ou des troubles dus à une prolifération cellulaire. Dans des aspects particuliers, l'invention concerne des composés, de compositions et des méthodes utiles pour moduler les activités des récepteurs activés par les proliférateurs de peroxysomes (PPAR) et pour traiter et/ou prévenir diverses maladies et affections induites par lesdits récepteurs nucléaires. Plus particulièrement, l'invention concerne des ligands des récepteurs gamma activés par les proliférateurs de peroxysomes (PPAR-gamma), qui sont utiles pour la modulation des taux glycémiques et l'augmentation de la sensibilité à l'insuline chez des patients. Les propriétés des composés et compositions de l'invention rendent ces ligands PPAR particulièrement utiles dans le traitement des maladies et affections telles que le diabète, l'athérosclérose, l'hyperglycémie, la dyslipidémie, l'obésité, le syndrome X, la résistance à l'insuline, l'hypertension, la neuropathie, les maladies microvasculaires (p. ex. la rétinopathie, la néphropathie), les maladies macrovasculaires (p. ex. l'infarctus du myocarde, l'accident vasculaire cérébral, la défaillance cardiaque) chez des mammifères.
PCT/EP2003/011710 2002-10-24 2003-10-22 Modulation de l'activite des recepteurs actives par les proliferateurs de peroxysomes WO2004037248A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003287965A AU2003287965A1 (en) 2002-10-24 2003-10-22 Modulation of peroxisome proliferator activated receptors activity

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
EP02360298 2002-10-24
EP02360298.0 2002-10-24
EP02360373 2002-12-20
EP02360373.1 2002-12-20
EP02360372 2002-12-20
EP02360372.3 2002-12-20
US45695403P 2003-03-25 2003-03-25
US60/456,954 2003-03-25
EP03360070.1 2003-06-11
EP03360070 2003-06-11
EP03360091 2003-07-24
EP03360091.7 2003-07-24

Publications (2)

Publication Number Publication Date
WO2004037248A2 true WO2004037248A2 (fr) 2004-05-06
WO2004037248A3 WO2004037248A3 (fr) 2004-06-03

Family

ID=32180796

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2003/011710 WO2004037248A2 (fr) 2002-10-24 2003-10-22 Modulation de l'activite des recepteurs actives par les proliferateurs de peroxysomes
PCT/EP2003/011855 WO2004043951A1 (fr) 2002-10-24 2003-10-24 Composes et compositions de modulation

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/011855 WO2004043951A1 (fr) 2002-10-24 2003-10-24 Composes et compositions de modulation

Country Status (2)

Country Link
AU (2) AU2003287965A1 (fr)
WO (2) WO2004037248A2 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089910A1 (fr) * 2003-04-05 2004-10-21 Merck Patent Gmbh Pyrazoles substitues en position 1,3 et 4 utilises en tant qu'antagonistes des recepteurs 5-ht pour le traitement de psychoses et de troubles neurologiques
WO2004108685A1 (fr) * 2003-06-04 2004-12-16 Aventis Pharma S.A. Produits aryl-heteroaromatiques, compositions les contenant et utilisation
EP1814582A1 (fr) * 2004-10-14 2007-08-08 Intercept Pharmaceuticals Inc. Procede de reduction d'effets secondaires indesirables induits par un medicament chez un patient
JP2008543970A (ja) * 2005-06-27 2008-12-04 エグゼリクシス， インコーポレイテッド ピラゾールベースのｌｘｒモジュレーター
JP2009197010A (ja) * 2005-08-26 2009-09-03 Iyaku Bunshi Sekkei Kenkyusho:Kk Ｐｐａｒアゴニスト活性を有する誘導体
US7842695B2 (en) 2003-04-05 2010-11-30 Merck Patent Gmbh Substituted pyrazole compounds
WO2010142628A1 (fr) * 2009-06-08 2010-12-16 Merck Serono S.A. Dérivés pyrazoles oxadiazoles en tant qu'agonistes de s1p1
US7960413B2 (en) 2003-04-05 2011-06-14 Merck Patent Gmbh Pyrazole compounds
US20120021074A1 (en) * 2009-03-23 2012-01-26 Merck Sharp & Dohme Corp. P2x3, receptor antagonists for treatment of pain
KR20140085526A (ko) * 2011-10-25 2014-07-07 이 아이 듀폰 디 네모아 앤드 캄파니 1,3-다이아릴 치환된 복소환식 살충제
EP2389171B1 (fr) * 2009-01-26 2016-03-30 Taipei Medical University Utilisation de composés ptérosine pour traiter le diabète et l'obésité
WO2016202935A1 (fr) 2015-06-19 2016-12-22 Bayer Pharma Aktiengesellschaft Inhibiteurs de transport du glucose
CN107438603A (zh) * 2015-04-22 2017-12-05 里格尔药品股份有限公司 吡唑化合物以及制备和使用该化合物的方法
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11370787B2 (en) 2019-08-30 2022-06-28 Rigel Pharmaceuticals, Inc. Pyrazole compounds, formulations thereof, and a method for using the compounds and/or formulations

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005061462A2 (fr) * 2003-12-19 2005-07-07 Neurogen Corporation Modulateurs de recepteurs neurokinine 3 : derives pyrazoles de diaryle
CA2560510C (fr) * 2004-03-18 2009-10-13 Pfizer Inc. Sulfamides n-(1-arylpyrazol-4yl) et leur utilisation en tant qu'anti-parasitaires
WO2007052843A1 (fr) * 2005-11-04 2007-05-10 Takeda Pharmaceutical Company Limited Compose amide heterocyclique et son utilisation
WO2007122970A1 (fr) * 2006-04-20 2007-11-01 Osaka University Ligand capable de se lier À un récepteur NUCLÉAIRE
US9315449B2 (en) 2008-05-15 2016-04-19 Duke University Substituted pyrazoles as heat shock transcription factor activators
WO2013019561A1 (fr) * 2011-07-29 2013-02-07 Karyopharm Therapeutics, Inc. Modulateurs de transport nucléaire et leurs utilisations
PL2736887T3 (pl) 2011-07-29 2018-03-30 Karyopharm Therapeutics, Inc. Modulatory transportu jądrowego zawierające ugrupowanie hydrazydu i ich zastosowania
CN103254133A (zh) * 2012-02-20 2013-08-21 南京大学 二芳基吡唑苯胺类化合物的制备及其在结肠癌治疗中的应用
LT2858991T (lt) 2012-05-09 2018-11-26 Biogen Ma Inc. Branduolinio transporto moduliatoriai ir jų panaudojimas
EP2968278B8 (fr) 2013-03-15 2019-05-22 Karyopharm Therapeutics Inc. Procédés de promotion de la cicatrisation d'une plaie à l'aide d'inhibiteurs de crm1
BR112015032071B1 (pt) 2013-06-21 2022-06-14 Karyopharm Therapeutics Inc Modulares do transporte nuclear e suas utilizações
CN111481553B (zh) 2014-08-15 2023-09-01 卡尔约药物治疗公司 赛灵克斯的多晶型物
EP3397634A1 (fr) 2015-12-31 2018-11-07 Karyopharm Therapeutics, Inc. Modulateurs de transport nucléaire et leurs utilisations
MA43529A (fr) 2015-12-31 2018-11-07 Karyopharm Therapeutics Inc Modulateurs de transport nucléaire et leurs utilisations
WO2017135786A1 (fr) * 2016-02-05 2017-08-10 연세대학교 산학협력단 Nouveau composé amide et son utilisation
WO2018098472A1 (fr) 2016-11-28 2018-05-31 Karyopharm Therapeutics Inc. Inhibiteurs de crm1 pour le traitement de l'épilepsie

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6294580B1 (en) * 1996-02-28 2001-09-25 Glaxo Wellcome Inc. Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma
US20010027200A1 (en) * 1998-01-29 2001-10-04 Tularik Inc. PPARgamma modulators
US20020151569A1 (en) * 1998-11-11 2002-10-17 Collins Jon Loren PPAR gamma ligands

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1507957A (en) * 1975-03-25 1978-04-19 Byk Gulden Lomberg Chem Fab Nitrofuryl-pyrazole derivatives methods for producing them and medicaments comprising them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6294580B1 (en) * 1996-02-28 2001-09-25 Glaxo Wellcome Inc. Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma
US20010027200A1 (en) * 1998-01-29 2001-10-04 Tularik Inc. PPARgamma modulators
US20020151569A1 (en) * 1998-11-11 2002-10-17 Collins Jon Loren PPAR gamma ligands

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRATENKO M K ET AL: "4-FUNCTIONALLY SUBSTITUTED 3-HETERYLPYRAZOLES: III. 3- ARYL(HETERYL)PYRAZOLE-4-CARBOXYLIC ACIDS AND THEIR DERIVATIVES" RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, CONSULTANTS BUREAU, US, vol. 37, no. 4, 2001, pages 552-555, XP009027046 ISSN: 1070-4280 *
LEHMANN J M ET AL: "AN ANTIDIABETIC THIAZOLIDINEDIONE IS A HIGH AFFINITY LIGAND FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPARGAMMA)" JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY OF BIOLOGICAL CHEMISTS, BALTIMORE, MD, US, vol. 270, no. 22, 2 June 1995 (1995-06-02), pages 12953-12956, XP000577082 ISSN: 0021-9258 cited in the application *

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7842695B2 (en) 2003-04-05 2010-11-30 Merck Patent Gmbh Substituted pyrazole compounds
WO2004089910A1 (fr) * 2003-04-05 2004-10-21 Merck Patent Gmbh Pyrazoles substitues en position 1,3 et 4 utilises en tant qu'antagonistes des recepteurs 5-ht pour le traitement de psychoses et de troubles neurologiques
US7566709B2 (en) 2003-04-05 2009-07-28 Merck Patent Gmbh 1,3,4-Substituted pyrazoles as 5-HT receptor antagonists for the treatment of psychoses and neurological disorders
US7960413B2 (en) 2003-04-05 2011-06-14 Merck Patent Gmbh Pyrazole compounds
WO2004108685A1 (fr) * 2003-06-04 2004-12-16 Aventis Pharma S.A. Produits aryl-heteroaromatiques, compositions les contenant et utilisation
EP1814582A1 (fr) * 2004-10-14 2007-08-08 Intercept Pharmaceuticals Inc. Procede de reduction d'effets secondaires indesirables induits par un medicament chez un patient
EP1814582A4 (fr) * 2004-10-14 2009-07-15 Intercept Pharmaceuticals Inc Procede de reduction d'effets secondaires indesirables induits par un medicament chez un patient
JP2008543970A (ja) * 2005-06-27 2008-12-04 エグゼリクシス， インコーポレイテッド ピラゾールベースのｌｘｒモジュレーター
JP2009197010A (ja) * 2005-08-26 2009-09-03 Iyaku Bunshi Sekkei Kenkyusho:Kk Ｐｐａｒアゴニスト活性を有する誘導体
EP2389171B1 (fr) * 2009-01-26 2016-03-30 Taipei Medical University Utilisation de composés ptérosine pour traiter le diabète et l'obésité
US20120021074A1 (en) * 2009-03-23 2012-01-26 Merck Sharp & Dohme Corp. P2x3, receptor antagonists for treatment of pain
EP2410858A1 (fr) * 2009-03-23 2012-02-01 Merck Sharp & Dohme Corp. Antagonistes du récepteur p2x3 pour le traitement de la douleur
EP2410858A4 (fr) * 2009-03-23 2012-08-22 Merck Sharp & Dohme Antagonistes du récepteur p2x3 pour le traitement de la douleur
US8946231B2 (en) 2009-03-23 2015-02-03 Merck Sharp & Dohme Corp. P2X3, receptor antagonists for treatment of pain
US8802663B2 (en) 2009-06-08 2014-08-12 Merck Serono Sa Pyrazole oxadiazole derivatives as S1P1 agonists
WO2010142628A1 (fr) * 2009-06-08 2010-12-16 Merck Serono S.A. Dérivés pyrazoles oxadiazoles en tant qu'agonistes de s1p1
AU2010257564B2 (en) * 2009-06-08 2016-09-29 Merck Serono S.A. Pyrazole oxadiazole derivatives as S1P1 agonists
JP2014530916A (ja) * 2011-10-25 2014-11-20 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニーＥ．Ｉ．Ｄｕ Ｐｏｎｔ Ｄｅ Ｎｅｍｏｕｒｓ Ａｎｄ Ｃｏｍｐａｎｙ １，３−ジアリール−置換複素環式有害生物防除剤
KR20140085526A (ko) * 2011-10-25 2014-07-07 이 아이 듀폰 디 네모아 앤드 캄파니 1,3-다이아릴 치환된 복소환식 살충제
KR101951976B1 (ko) 2011-10-25 2019-02-25 에프엠씨 코포레이션 1,3-다이아릴 치환된 복소환식 살충제
JP2017197544A (ja) * 2011-10-25 2017-11-02 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニーＥ．Ｉ．Ｄｕ Ｐｏｎｔ Ｄｅ Ｎｅｍｏｕｒｓ Ａｎｄ Ｃｏｍｐａｎｙ １，３−ジアリール−置換複素環式有害生物防除剤
CN107438603A (zh) * 2015-04-22 2017-12-05 里格尔药品股份有限公司 吡唑化合物以及制备和使用该化合物的方法
JP2018513177A (ja) * 2015-04-22 2018-05-24 ライジェル ファーマシューティカルズ， インコーポレイテッド ピラゾール化合物ならびにこの化合物を作製および使用するための方法
JP2021020924A (ja) * 2015-04-22 2021-02-18 ライジェル ファーマシューティカルズ， インコーポレイテッド ピラゾール化合物ならびにこの化合物を作製および使用するための方法
CN107438603B (zh) * 2015-04-22 2021-08-10 里格尔药品股份有限公司 吡唑化合物以及制备和使用该化合物的方法
CN113750094A (zh) * 2015-04-22 2021-12-07 里格尔药品股份有限公司 吡唑化合物以及制备和使用该化合物的方法
US11370808B2 (en) 2015-04-22 2022-06-28 Rigel Pharmaceuticals, Inc. Pyrazole compounds and methods for making and using the compounds
WO2016202935A1 (fr) 2015-06-19 2016-12-22 Bayer Pharma Aktiengesellschaft Inhibiteurs de transport du glucose
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11370787B2 (en) 2019-08-30 2022-06-28 Rigel Pharmaceuticals, Inc. Pyrazole compounds, formulations thereof, and a method for using the compounds and/or formulations

Also Published As

Publication number Publication date
AU2003282051A1 (en) 2004-06-03
WO2004037248A3 (fr) 2004-06-03
AU2003287965A8 (en) 2004-05-13
AU2003287965A1 (en) 2004-05-13
WO2004043951A1 (fr) 2004-05-27

Similar Documents

Publication Publication Date Title
WO2004037248A2 (fr) Modulation de l'activite des recepteurs actives par les proliferateurs de peroxysomes
EP1962838B1 (fr) Agonistes de recepteur de farnesoide x
RU2360902C2 (ru) Аллостерические модуляторы метаботропных глутаматных рецепторов
KR101712466B1 (ko) 신규의 에프엑스알(엔알 1에이치4) 결합 및 활성 조절 화합물
US7223791B2 (en) Function regulator for retinoid relative receptor
US7022725B2 (en) Isoxazole derivatives
JP5373788B2 (ja) Ｆｘｒを調節するための化合物および方法
CZ20023763A3 (cs) Derivát triazolu
BRPI0511703B1 (pt) composto, composição farmacêutica, e, métodos de tratar diabete melito tipo 2, de retardar o início do diabete melito tipo 2, de tratar hiperglicemia, diabete ou resistência à insulina, obesidade, síndrome x, um distúrbio lipídico, aterosclerose, e uma condição
EA033642B1 (ru) Соединения, модулирующие fxr (nr1h4)
CN104918936A (zh) 作为细胞凋亡信号调节激酶抑制剂的经取代的吡啶-2-甲酰胺化合物
EA011010B1 (ru) Соединения, модулирующие рецептор gpr40, фармацевтическая композиция, способ лечения заболеваний, чувствительных к модулированию рецептора gpr40 (варианты), способ модулирования функции gpr40 (варианты) и способ модулирования циркулирующей концентрации инсулина
KR20090005208A (ko) 옥사디아졸리딘디온 화합물
MXPA02004647A (es) Compuestos heterociclicos de 5 miembros que contienen nitrogeno.
WO2003099793A9 (fr) Derives 1,2-azole presentant une activite hypoglycemique et hypolipidemique
WO2002053547A1 (fr) Derives d'acide alcanoique, procede de production et utilisation correspondants
KR20120088738A (ko) 칼슘 방출-활성화 칼슘 통로의 조정제로서의 피라졸 유도체
KR20040040472A (ko) 이미다졸-4-카르복사미드 유도체, 그의 제법 및 비만치료를 위한 용도
WO2012138648A1 (fr) Compositions et procédés pour la modulation de récepteurs au lpa
EP3083631B1 (fr) Modulateurs de la voie wnt
KR20080058416A (ko) 피라졸 유도체, 당해 화합물을 함유하는 조성물 및사용방법
EP1394154A1 (fr) Derive heterocyclique a cinq membres d'acide alcanoique
US5374638A (en) Six membered ring fused imidazoles substituted with phenoxyphenylacetic acid derivatives used to treat asthma
AU2014244474B2 (en) Bicyclo [2.2.1] acid GPR120 modulators
WO2004072041A1 (fr) Tetrahydroquinoleines utilisees comme agonistes des recepteurs hepatiques

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP