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WO2004043951A1 - Composes et compositions de modulation - Google Patents

Composes et compositions de modulation Download PDF

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Publication number
WO2004043951A1
WO2004043951A1 PCT/EP2003/011855 EP0311855W WO2004043951A1 WO 2004043951 A1 WO2004043951 A1 WO 2004043951A1 EP 0311855 W EP0311855 W EP 0311855W WO 2004043951 A1 WO2004043951 A1 WO 2004043951A1
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Prior art keywords
phenyl
thiophen
pyrazole
carboxylic acid
pyrazol
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English (en)
Inventor
Jacques Huck
Régis SALADIN
Michael Sierra
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Carex SA
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Carex SA
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    • 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, compositions and methods useful for modulating nuclear receptors activity in cells, and for treating and/or preventing various diseases and conditions mediated by said nuclear receptors, including metabolic or cell proliferative disorders.
  • the present invention relates to compounds, compositions and methods useful for modulating activities of the Peroxisome Proliferator Activated Receptors (PPARs) and for treating and/or preventing various diseases and conditions mediated by said nuclear receptors. More specifically, it relates to Peroxisome Proliferator Activated Receptor-gamma (PPAR-gamma) ligands, which are useful in the modulation of blood glucose levels and in the increase of insulin sensitivity in patients in need thereof.
  • PPAR-gamma Peroxisome Proliferator Activated Receptor-gamma
  • 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.
  • 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.
  • Diabetes mellitus refers to a disease process derived from multiple causative factors and characterized by elevated levels of glucose in blood, or hyperglycemia. Uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality mainly due to an increased risk for microvascular and macrovascular diseases. Therefore, control of glucose homeostasis is a critically important approach for the treatment of diabetes.
  • At least two types of diabetes mellitus have been identified : (i) 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 Diabetes Mellitus (NIDDM) , which is due to a resistance to insulin stimulatory or regulatory effects . on glucose and • lipid metabolism in the main insulin-sensitive tissues, i.e. skeletal muscle, liver and adipose tissue.
  • IDDM Insulin Dependent Diabetes Mellitus
  • NIDDM Non Insulin Dependent Diabetes Mellitus
  • Said resistance to insulin responsiveness in Type II diabetes results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver leading, directly or indirectly, to diseases and conditions such as 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) .
  • diseases and conditions such as 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) .
  • Type II diabetes 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 administration of insulin.
  • treatments have been proposed which were based on diet and lifestyle changes augmented by the ⁇ apy with oral hypoglycemic agents.
  • oral hypoglycemic agents such as sulfonylurea (e.g. tolbutamide, glipizide) derivatives, which stimulate the pancreatic cells to secrete more insulin, may lead to major adverse effects such as hypoglycemic reactions, including coma, which are highly unpredictable and prejudicial.
  • thiazolidinediones or TZDs glitazones
  • TZDs glitazones
  • Treatments with said agents have been tested in several animal models of type II diabetes 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 Levine, 2000, Heart Dis., 2, 326-333) .
  • thiazolidinediones are rosiglitazone, pioglitazone and troglitazone.
  • thiazolidinediones exert their effects by binding to specific nuclear receptors, and more specifically to Peroxisome Proliferator Activated Receptor (PPAR) . It is furthermore recognized that they act as agonists of PPAR-gamma.
  • PPAR Peroxisome Proliferator Activated Receptor
  • the nuclear receptors are activated by small lipophilic ligands and, in the activated state, function as transcription factors that can regulate the expression of genes involved in a broad range of developmental and physiological processes ranging from cell differentiation and development to lipid metabolism and energy homeostasis. They act by binding to DNA response elements (REs) within the promoter region of target genes and regulate transcriptional activation of said genes (for a review, see Escriva et al . , 2000, BioEssays, 22, 717- 727) .
  • REs DNA response elements
  • Peroxisome Proliferators Activated Receptors are transcription factors that belong to the nuclear hormone receptor superfamily.
  • the PPARs function as ligand-activated transcription factors that control the expression of target genes by binding as heterodimers with the retinoid X receptors (RXRs) to cognate sequences (PPREs) in the promoter regions of their target genes.
  • RXRs retinoid X receptors
  • PPREs cognate sequences
  • 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 roles.
  • PPAR-alpha PPAR ⁇ or NR1C1
  • PPAR-alpha is highly expressed in the liver, skeletal muscle, kidney and heart, and stimulates the expression of several enzymes involved in peroxisomal beta- oxidation.
  • PPAR-alpha was found to be the molecular target of the fibrate class of hypolipidemic drugs, such as clofibrate (i.e.
  • PPAR-beta (PPAR ⁇ or NR1C2; also known as PPAR-delta, PPAR ⁇ , NUC-1 or FAAR) is ubiquitously expressed and its role in mammalian physiology is still largely undefined.
  • Oliver et al . 2001, Proc. Natl. Acad. Sci., 98, 5306-11
  • PPAR-beta is implicated in the regulation of reverse cholesterol transport
  • Michalik et al. 2000, Horm. Res., 54, 263-268
  • PPAR-beta is implicated in the control of keratinocyte proliferation and is necessary for rapid healing of a skin wound.
  • the human DNA sequences for the PPAR-beta has been cloned and is fully described in Schmidt et al . , 1992, Molecular Endocrinology, 6, 1634-1641, and is herein incorporated by reference.
  • PPAR-gamma (PPAR ⁇ or NR1C3) is most abundantly expressed in 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 in adipose tissue, insulin sensitization and in 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 is accumulating that suggests an important role for PPAR-gamma in atherosclerosis, inflammation and cancer (for a review, Fajas et al., 2001, J. Mol.
  • PPAR-gamma ligands include prostaglandins , fatty acids, N-(2- benzoylphenyl) tyrosine analogues, and the above disclosed thiazolidinediones (Lenhard, 2001, Receptors Channels , 7, 249-58) .
  • the DNA sequences for the PPAR-gamma receptors have been described in Elbrecht , et al . , 1996, BBRC 224, 431-437, and are herein incorporated by reference (see also reference P37231 of NCBI data base) .
  • PPARs are useful as drug targets in methods for reducing blood glucose, cholesterol and triglyceride levels and are accordingly explored for the treatment and/or prophylaxis o I: insulin resistance (Type II diabetes ; see for example WO 98/05331), impaired glucose tolerance, dyslipidemia, and other disorders related to Syndrome X, also known as Metabolic Disease Syndrome, (WO 97/25042, WO 97/10813, WO 97/28149 ; see also Kaplan et al . , 2001, J. Cardiovasc . Risk, 8, 211-7) including hypertension, obesity, atherosclerosis, thrombosis (Duez et al . , 2001, J. Cardiovasc.
  • PPARs have been shown to be potential targets for the treatment of inflammatory diseases such as cutaneous disorders (including acne vulgaris, cutaneous disorders with barrier dysfunction, cutaneous effects of aging, poor wound healing associated with altered signal transduction ; see Smith et al., 2001, J. Cutan. Med. Surg. , 5, 231-43), gastrointestinal diseases (WO 98/43081 ) or renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis ; similarly PPAR ligands should be useful for improving cognitive functions in neurologic diseases (Landreth and Heneka, 2001, Neurobiol .
  • the PPARs have been shown to be exciting targets 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 (and more specifically of PPAR-gamma) .
  • PPARs nuclear receptor activity
  • the Applicant has now identified compounds of general formula (I) below, their derivatives, their analogues, their pharmaceutically acceptable solvates or salts and pharmaceutical compositions containing them or mixtures thereof, which can be used tor the treatment and/or prophylaxis of various diseases and conditions mediated or related to nuclear receptors, especially PPARs (and more specifically of PPAR-gamma) , including metabolic or cell proliferative disorders such as, for example, diseases and conditions related to increased levels of lipids (e.g.
  • hypertriglyceridemia and high levels of free fatty acids hyperlipidemia, hyperinsulinemia, proliferation of the adipocytes, obesity, insulin resistance, insulin resistance leading to Type II diabetes and diabetic complications thereof (e.g. Syndrome X), hypertension, atherosclerosis and coronary artery diseases.
  • said compounds and compositions are able to lower one or more of the following biological entities in 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.
  • 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 limited 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 in the group consisting of :
  • C n ⁇ 2n , +1 (e.g. -NR 3 -S0 2 butyl) ; is a moiety selected in the group consisting of H, -C n /H 2 n '+ i (e.g. C1-.4 alkyl moiety such as methyl and ethyl), - (CH 2 ) n C0 2 H, -NH 2 , -(CH 2 ) n - TZD, -OH, -N(C n ,H 2n , + ⁇ ) 2 , -NR 9 -S0 2 CF 3 and -NR 9 - S0 2 -C n ⁇ 2n , +1 (e.g.
  • R 5 and R 13 are, independently from one another, a moiety selected in the group consisting of H, a C ⁇ _ 4 alkyl moiety (e.g. methyl and ethyl), - S0 2 CF 3 and -S0 2 -C n >H 2 n '+ i (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 ⁇ 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 lV H 2n , +1 (e.g.
  • R 9 and R 9* are, independently from one another, a moiety selected in the group consisting of H, —CO-C n' H n' i , —S0 —C n 'H 2 n '+ i i and a C-
  • Ai, A 2 , A 3 and A 4 are an atom selected in the group consisting of C, N, S and 0 ; the moiety :
  • a mono carbocyclic ring i.e. a cyclic carboalkyl, with Ai , A 2 , A 3 and A 4 are C
  • a mono heterocyclic ring i.e. a cyclic heteroalkyl, with at least one Ax , A 2 , A 3 and/or A 4 is selected m the group consisting of N, S and 0) ;
  • a bi- carbocyclic ring i.e. a bicyclic carboalkyl with A-i , A 2 , A 3 and A 4 are C
  • a bi- carbocyclic ring i.e. a bicyclic carboalkyl with A-i , A 2 , A 3 and A 4 are C
  • a bi- heterocyclic ring i.e. a bicyclic heteroalkyl with at least one cyclic ring is containing at least one A-, , A 2 , A 3 and/or A 4 selected in the group consisting of N, S arid 0
  • a bi- heterocyclic ring i.e. a bicyclic heteroalkyl with at least one cyclic ring is containing at least one A-, , A 2 , A 3 and/or A 4 selected in the group consisting of N, S arid 0
  • R 2 is a moiety selected m the group consisting of :
  • a, b, c and d are, independently from one another, an integer ranging from 0 to 4 ;
  • Y, G and Z are, independently from one another, a moiety selected in the group consisting of -CO-, -0- , -CH- , -CH(C n /H 2n'+ i)-. -C(C n >H 2n ⁇ +1 ) 2 -, -CH 2 -, -N-, -NR 9 - , -NR 7 -, -S0 2 -, -S(C n H 2n +1 ) - and -CHOH- where R 7 and R 9 are as above mentioned;
  • R and R is, independently from one another, a moiety selected in the group consisting of H, a C-i_ alkyl moiety, - (CH 2 ) n -CONR 13 R 5 , -C0 2 R 4 , -COR 4 , -OR 4 , - (CH 2 ) n -C0 2 R 4 , -
  • n is, independently from one another, an integer ranging from
  • n' is, independently from one another, an integer ranging from
  • R 8 and R 8* are, independently from one another, a moiety selected in the group consisting of H, -C n H 2n'+ ⁇ , a C s cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), -0C ThreadH 2n'+ 1 / -Cl, -F, -(CH 2 ) n C0 2 H, - CF 3 , -0CF 3 , -C0CF 3 , -0-
  • R 10 and R 10* are, independently from one another, a moiety selected m the group consisting of H, an alkyl, more specifically a C 1 -. 4 alkyl moiety, a C 6 cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), or a C 7 cycloalkyl moiety (e.g.
  • TZD is :
  • the present invention concerns compounds of the general formula (I) :
  • R substituted mono carbocyclic ring i.e. a cyclic carboalkyl, with Ai , A 2 , A 3 and A are C
  • a R 3 substituted mono heterocyclic ring i.e. a cyclic heteroalkyl, with at least one A-i , A 2 , A 3 and/or A 4 is selected in the group consisting of N, S and 0
  • a R 3 substituted mono heterocyclic ring i.e. a cyclic heteroalkyl, with at least one A-i , A 2 , A 3 and/or A 4 is selected in the group consisting of N, S and 0
  • a R 3 substituted bi- carbocyclic ring i.e. a bicyclic carboalkyl with Ai , A 2 , A 3 and A are C
  • a R 3 substituted bi- heterocyclic ring i.e. a bicyclic heteroalkyl with at least one cyclic ring is containing at least one Ax , A 2 , A 3 and/or A 4 selected in the group consisting of N, S and O.
  • said carbocyclic and/or heterocyclic ring (including both mono and bi) 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 .
  • alkyl as used herein, alone or in combination, is intended to designate a straight or branched chain, or cyclic carbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multi-moities .
  • an alkyl moiety will have from 1 to 24 carbon atoms, with those moieties having 10 or fewer carbon atoms being preferred in 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 ⁇ don 4 are a special embodiment of ⁇ C n ⁇ 2n '+ ⁇ .
  • a C ⁇ _ 4 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.
  • 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 , isopentyl, 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 and benzyl
  • 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 quaternized.
  • 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. Each of these cycles should be understood as being under either aromatic or non aromatic form.
  • n is an integer ranging from 0 to 4, more particularly from 0 to 2 , and preferably from 0 to 1. In special embodiment it is 0.
  • one or more of the (CH 2 ) n moiety of the Formula I is substituted with at least one methyl group. More specifically, said methyl substitutions occur on the (CH 2 ) n moiety comprised in the moiety selected in the group consisting of -(CH 2 ) n C0 2 H, -0- (CH 2 ) n C0 2 H, -(CH 2 ) n -TZD, -0- (CH 2 ) n -TZD.
  • _ alkyl is 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, n-butyl, sec-butyl, tert-butyl and the like.
  • a d_ 4 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 .
  • 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.
  • the compounds of formula I are :
  • At least one -(CH 2 )- moiety in the following structures (herein named the "linkers") isolated from R 2 :
  • said structure isolated from R 2 can be as follows :
  • At least one - (NH) - moiety in the linker isolated from R 2 is replaced by at least one -(N)- moiety.
  • those skilled in the art will be able to adapt the number and type of bounds accordingly.
  • a, b and c are, independently from one another, an integer ranging from 0 to 2.
  • the linker isolated from R 2 is selected in the group consisting in
  • the "linker" in compounds of formula I is selected in the group consisting of :
  • R is selected in the group consisting of :
  • R is
  • R 8 and/or R 10 is/are not an aromatic C ⁇ , cycloalkyl.
  • Z is -NH-.
  • Z is -CO-.
  • Z is -SO2-.
  • the C 6 cycloalkyl moiety e.g. a cyclohexyl or a phenyl moiety
  • the C 7 cycloalkyl moiety e.g. a cycloheptyl or a benzyl moiety
  • -(CH 2 ) n -C 6 cycloalkyl moiety, -(CH 2 ) n -C 7 cycloalkyl moiety, -0-(CH 2 ) n - C 6 cycloalkyl moiety or a -0- (CH 2 ) n -C 7 cycloalkyl moiety) is substituted, preferably at least with one moiety selected in the group consisting of R 8 and R 10 .
  • R 1 is :
  • R 11 and/or R 12 is selected in the group consisting in -Cl , -COOH and - CF 3 .
  • R 8* and/or R 10 * is selected in the group consisting in -CH 3 , -OCI-I 3 , -COCH 3 and halogen (-F or -Cl preferably) , -CF 3 , -OCF 3 , -COCF 3 , phenyl, -CH 2 -phenyl, -0-CH 2 -phenyl , -CONH 2 .
  • 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 : and having the following combinations of a, b, c, Y and Z in said A
  • a Y b z c 0 -CH 2 - 1 -CH 2 - or -CO- 0 0 -CH 2 - 1 -CO- 0 0 -CH 2 - 1 -CH 2 - 0 0 -NR 9 - 0 -CH 2 - or -CO- 1 0 -CH 2 - or -C0- 0 -NR 9 - 1 0 -CO- 0 -NH- 1 0 -NR 9 - 0 -CH 2 - or -CO- 0 0 -CH 2 - or -CO- 0 -NR 9 - 0 0 -CO- 0 -CH 2 - 0 0 -CH 2 - 0 -CO- 0 1 CH 2 - or -NR 9 - 0 -CH 2 - or -CO- 0 0 -CH 2 - or -CO- 0 -CH 2 - or -NR 9 -
  • the compound of the invention is selected in the group consisting in :
  • the compound of the invention is selected in the group consisting in :
  • the present invention concerns compounds as above described which are further substituted with at least one moiety R in position 5 of the central pyrazole ring of Formula I :
  • said moiety R 14 being selected in the group consisting in -Cl, -CF 3 , a C ⁇ _ alkyl moiety (particularly ethyl or methyl) .
  • R 2 moiety present in the compounds of the present invention are modified in such a way that the motif :
  • W is an atom selected in the group consisting of S, 0 and N.
  • analogues, derivatives, solvates or salts of compounds of the present invention include both the structural derivatives, equivalents 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” .
  • compositions of formula I may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature. General methods for preparing compounds according to the invention may also be prepared as described in the schemes that are presented in the Experimental Section. Those skilled in the art will recognize that the compounds of the present invention may be utilized in the form of a pharmaceutically acceptable salt thereof.
  • the physiologically acceptable salts of the compounds of Formula (I) include conventional salts prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form 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, monohydrogensulf ric, hydriodic, • or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, lactic, propionic, isobutyric, palmoic, maleic, glutamic, hydroxymaleic, malonic, benzoic, succinic, glycolic, suberic, fumaric, mandelic, phthalic, salicylic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, hydroxynaphthoic, hydroiodic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, lithium, calcium, aluminium, ammonium, barium, zinc, organic amino, or magnesium salt, N,N 1 -dibenzylethylenediamine, choline, diethanolamine, ethylenediamine, N-methylglucamine, procaine salts (e.g. chloroprocaine) and the like.
  • salts of amino acids such as arginate and the like
  • salts of organic acids like glucuronic or galactunoric acids and the like
  • 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.
  • solvates may be prepared by conventional methods such as dissolving the compounds of formula (I) in solvents such as methanol, ethanol and the like, preferably water.
  • references hereinafter to a compound according to the invention include both compounds of Formula (I) and their pharmaceutically acceptable salts and solvates.
  • the present invention includes all possible stereoisomers including optical and geometric isomers of Formula (I). It further includes not only racemic compounds, or racemic mixture thereof, but also the optically active isomers as well.
  • a compound of Formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate.
  • the present invention is intended to include all tautomeric forms of the compounds.
  • diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic 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 in most cases a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation within 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 general formula (I) 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 (I) in vivo .
  • 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 with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine.
  • Particularly preferred alkyl esters as prodrugs are formed from methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N- diethylglycolamido .
  • Methyl ester prodrugs may be prepared by reaction of the acid form of a compound of general formula (I ) in 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 in place of methanol. Details regarding prodrugs are available for example m US 5,498,729.
  • polymorphs of a compound of general formula (I) for example by crystallization of compound of formula (I) under- different conditions. For example, he can use different solvents or mixtures commonly used for crystallization. Similarly, he can crystallize compounds of general formula (I) at different temperatures, according to various modes of cooling, 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 calo ⁇ metry, powder X-ray diffraction or such other techniques .
  • the compounds of the invention may be labelled m a variety of ways.
  • the compounds may contain radioactive isotopes such as, for example H 3 (tritium) or C 14 at one or more of the atoms that constitute compounds of general formula (I).
  • the compounds may be advantageously joined, covalently or noncovalently, directly or through a linker molecule, to a wide variety of other moieties, which may provide function as carriers, labels, adjuvents, coactivators, stabilizers, etc.
  • Such labelled and joined compounds are contemplated within the present invention.
  • composition comprising at least one compound of the general formula (I) as above disclosed.
  • the compounds and compositions of the present invention are further characterized by their properties towards nuclear receptor PPARs. More specifically, the Applicant has shown that the compounds of general formula (I) are first able to interact with at least one PPAR receptor, more preferably with PPAR-gamma ; they are thus named PPAR or PPAR-gamma ligands, 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. amino acids 195-475 of P37231 available on NCBI web site) .
  • 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.
  • 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 inhibit or silence transcription of genes which are transcriptionally 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 in vi tro for their ability to modulate PPAR receptor biological effects using biochemical assays (see, for example, the assays above mentioned; e.g. AlphaScreenTM. technology) or in cell-based assays.
  • biochemical assays see, for example, the assays above mentioned; e.g. AlphaScreenTM. technology
  • cell-based assays for example, a system for reconstituting 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 in 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-gamma.
  • the co-transfection assay is a functional, rapid assay that monitors hormone or ligand activity, is a good predictor of the in vivo 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
  • PPRE PPAR response element
  • 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.
  • 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 LBD 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 compounds and compositions of the present invention are PPAR and/or 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- SmithKline) 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 in 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 m 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 in a binding assay and therefore related to the 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 pharmaceutical 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 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-gamma LBD 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 .
  • compounds that activate PPAR-gamma e.g. thiazolidinediones
  • 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, it will be 100% Or more.
  • 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.
  • the in vivo occurrence of undesirable side effects such as haemodilution, oedema, adipocyte differentiation, obesity increase, ... of the compounds of the invention can be predicted in vi tro for example by determining the cofactors recruitment profile of said compounds as described in EP1267171.
  • 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 stimuli whose proper orchestration leads to a specific cellular response.
  • TIF2 GRIP-2 ; Chakravarti et al . , 1996, Nature, 383, 99-103), SRA (Lanz et al . , 1999, Cell, 97, 17- 27), AIB-1 (Anzick et al . , 1997, Science, 277, 965-968), TRAP220/DRIP205 (i.e. PBP ; Zhu et al . , 1997, J. Biol. Chem. 272, 25500-25506 ; Rachez et al . , 1999, Nature, 398, 824-828), PGC-1 (Puigserver et al .
  • 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 shown later to also interact in a yeast two-hybrid system with the PPAR-gamma Ligand Binding Domain (Zhu et al, 1996, Gene Expression, 6, 185-195).
  • 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 different levels (Misiti et al . , 1998, Endocrinology , 139, 2493-2500) .
  • SRC-1 has been shown to have two PPAR binding 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 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 specific 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.
  • the compounds and compositions of the invention are additionally able to enhance the interaction of PPAR receptor, more preferably PPAR receptor LBD, with cofactor SRC-1.
  • PPAR receptor is PPAR-gamma receptor.
  • Methods for measuring inhibition and/or enhancement of cofactor recruitment by ligands are detailed in application EP 1267171.
  • 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 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 serve 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.
  • pharmaceutical compositions may be prepared by conventional techniques, e.g. as described in Remington, 1995, The Science and Practise of Pharmacy, 19.sup.th Ed.
  • 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 within a carrier which can be in the form of a capsule, sachet, paper, tablets, aerosols, solutions, suspensions or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, tablets, aerosols, solutions, suspensions or other container.
  • the carrier When the 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 in 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, in whic 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, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, 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 in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, 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 well known in the art.
  • the active compounds are 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 vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those 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 in 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 phosphatidylcholines , sphingomyelins , phosphatidylethanolamines, phophatidylcholines , cardiolipins , phosphatidylserines , phosphatidylglycerols, phosphatidic acids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyl dimethylammonium propanes , and stearylamine, neutral lipids such as triglycerides , and combinations thereof. They may either contain cholesterol or may be cholesterol-free.
  • amphipathic lipids such as phosphatidylcholines , sphingomyelins , phosphatidylethanolamines, phophatidylcholines , cardiolipins , phosphatidylserines , phosphat
  • 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 like, which do not deleteriously react with the active compounds .
  • compositions of the invention will 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 said compound that will produce a 50% (EC 50 ) increase in PPAR activity in a cell-based reporter gene assay, or a biochemical 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 outer 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-hydroxytetraenoic acid) and cyclopentenone prostaglandins (e.g. prostaglandins in the J and A series and their metabolites), long-chain fatty acids and their derivatives, e.g. 9- and 13-cis-hydroxyoctadecadienoic acid (HODE) (Nagy et al., 1998, Cell, 17, 93, 229-240 ; Chinetti et al . , 2001, Z.
  • fatty acids such as arachidonic acid derivatives or metabolites such as eicosanoids (e.g. various isomeric forms of 8-hydroxytetraenoic acid) and cyclopentenone prostaglandins (e.g. prostaglandins in the J and
  • said natural PPAR ligand is a prostaglandin J2 or delta- 12-prostaglandin J2 (PGJ2) metabolite, and more particularly it is 15-deoxy-delta- 12, 14-prostaglandin J2 [15-deoxy-Delta ( 12 , 14) -PGJ (2) or 15d- PGJ2] .
  • PGJ2 delta- 12-prostaglandin J2
  • Synthetic ligands that modulate the activity of PPAR are for example antidyslipidemic fibrates (e.g. clofibrate, fenofibrate, benzofibrate, ciprofibrate, gemfibrozil) , thiazolidine derivatives (e.g. thiazolidinediones), oxazolidine' ' derivatives (e.g. oxazolidinediones) , alpha- alkylthio, alpha-alkoxy and carboxylic acid derivatives of thiazolidines and oxazolidines (Hulin et al . 1996, J. Med.
  • antidyslipidemic fibrates e.g. clofibrate, fenofibrate, benzofibrate, ciprofibrate, gemfibrozil
  • thiazolidine derivatives e.g. thiazolidinediones
  • 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 . , 1998, J. Med. Chem., 41, 1619-1630.
  • RXR specific agonists include, but are not limited to, 9-cis- retinoic acid, 4- (1 - (3 , 5 , 5 , 8 , 8-pentamethyl-5 , 6 , 7 , 8-tetrahydro- 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 biguanide derivatives) , insulin, insulin derivative, insulin secretagogue, insulin sensitizer, or insulin mimetic ; other examples are mitotic inhibitors, alkylating agents, antimetabolites, nucleic acid intercalating agents, topoisomerase inhibitors, agents which promote apoptosis, or agents which increase immune responses to tumors (e.g cytokine chosen from alpha-, beta- and gamma-interferon, interleukins , and in 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) .
  • TNFs tumour necrosis factors
  • colony stimulating factors for example GM-CSF, C-CSF and M-CSF
  • the compounds and compositions containing the same of the present invention exhibit agonist, and preferably partial- agonist activity toward PPAR receptors, and preferably towards PPAR-gamma receptor, which are important factors at the top of a gene cascade involved in differentiation of adipocytes, 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, in particular in the treatment of diseases and conditions where modification of the effects of PPAR, preferably PPAR- gamma, is of therapeutic benefit, the method comprising administering to the patient in need a therapeutically effective amount of at least one compound of Formula (I) , 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 in 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-translationally modified in 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.
  • Another example is a PPAR-responsive hyperproliferative cell. Examples of these diseases or pathologic conditions are those associated with impaired metabolism of glucose, cholesterol or triglycerides .
  • insulin resistance Type II diabetes, Type I diabetes, impaired glucose tolerance, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglycidemia , 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 glomerulonephritis , glomerulosclerosis , nephrotic syndrome, hypertensive nephrosclerosis ; neurologic diseases or dementia ; anorexia bulimia, anorexia nervosa ; inflammatory diseases such as cutaneous disorders (including acne vulgaris, psoriasis, cutaneous disorders with barrier dysfunction, cutaneous effects of aging, poor wound healing), diabetic complications, polycystic ovarian syndrome (PCOS) and bone loss, e.g. osteoporosis ; gastrointestinal diseases ; viral, proliferative cells or tumoral diseases, such as cancers.
  • Syndrome X
  • a method for treating obesity comprising administering to a patient in need of such treatment an amount of at least one compound or a composition of the invention.
  • said amount is effective to block cell differentiation to produce lipid-accumulating cells.
  • Obesity is a disease that had become highly prevalent in affluent societies and in the developing world and which is a major cause of morbidity and mortality. It is characterized by a body mass index above 25 but those of skill in the art readily recognize that the invention method is not limited to those who fall within the above criteria.
  • lipid-accumulating cells such as, for example, mesenchymal cells (e.g., fibroblasts) .
  • amount of ... produce lipid-accumulating cells refers to levels of compound of the invention sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a concentration typically falls in 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 within 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 insulin resistance.
  • Insulin resistance is manifested by the diminished ability of insulin to exert its biological action across a broad range of concentrations.
  • the body secretes abnormally high amounts of insulin to compensate for this defect.
  • 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. It is now increasingly being recognized that insulin resistance and hyperinsulinemia contribute significantly to obesity, hypertension, atherosclerosis and Type II diabetes mellitus.
  • the association of insulin resistance with obesity, hypertension and angina pectoris has been described as a syndrome (Syndrome-X) in which insulin resistance plays the central role.
  • the term "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 insulin- sensitivity and blood glucose levels in a patient comprising administering to a patient in need of such treatment an amount of at least one compound or a composition of the invention in effective to lower the blood glucose level of said subject.
  • the phrase "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 ' 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.
  • disease or pathologic condition according to the invention is hyperlipidemia.
  • Hyperlipidemia is considered the primary cause of cardiovascular and other peripheral vascular diseases.
  • An increased risk of cardiovascular disease is correlated with elevated plasma levels of LDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) as seen in hyperlipidemia.
  • LDL Low Density Lipoprotein
  • VLDL Very Low Density Lipoprotein
  • the diseases or pathologic conditions according to the invention also include cellular proliferation, growth, differentiation, or migration disorders.
  • a "cellular proliferation, growth, differentiation, or cell migration disorders” is a disorder in which a cell increases in 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 closer to or further from a particular location or stimulus.
  • the PPAR molecules of the present invention are involved in signal transduction mechanisms, which are known to be involved in cellular growth, differentiation, and migration processes.
  • the -PPAR molecules may modulate cellular growth, differentiation, or migration, and may play a role in disorders characterized by aberrantly regulated growth, differentiation, or migration.
  • Such disorders include cancer, e.g., carcinomas, sarcomas, leukemias, and lymphomas ; tumor angiogenesis and metastasis; skeletal dysplasia; hepatic disorders; and hematopoietic and/or myeloproliferative disorders.
  • cancer e.g., carcinomas, sarcomas, leukemias, and lymphomas ; tumor angiogenesis and metastasis; skeletal dysplasia; hepatic disorders; and hematopoietic and/or myeloproliferative disorders.
  • Exemplary disorders include, but not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cyst denocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma,
  • 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., lipomas, fibrolipomas, lipoblasto as, lipomatosis, hibemomas , hemangiomas and/or liposarcomas .
  • adipose cell tumors e.g., lipomas, fibrolipomas, lipoblasto as, lipomatosis, hibemomas , 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 cytokine (e.g. TNF-alpha, interleukin (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) .
  • NF-kappaB nuclear factor-kappaB
  • AP-1 activated protein-1
  • NFAT nuclear factor of activated T cells
  • disease or pathologic condition are chronic viral infections (e.g. HIV, CMV, HSV, HBV, HCV infections), neurodegenerative diseases (e.g. Alzheimer's disease, multiple sclerosis, Parkinson's disease), cardiovascular disease (e.g. atherosclerosis, atherogenesis , vascular restenosis, congestive heart failure), diseases or conditions involving hypoxemia and hypoxic stress (stroke, vascular occlusive disease, MI, atherosclerosis, retinitis, retinal vein occlusion, hypoxic retinopathy, macular degeneration) .
  • chronic viral infections e.g. HIV, CMV, HSV, HBV, HCV infections
  • neurodegenerative diseases e.g. Alzheimer's disease, multiple sclerosis, Parkinson's disease
  • cardiovascular disease e.g. atherosclerosis, atherogenesis , vascular restenosis, congestive heart failure
  • diseases or conditions involving hypoxemia and hypoxic stress stroke, vascular occlusive disease, MI, atherosclerosis
  • 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 gain, oedema, liver toxicity, haemadilution, etc...
  • the present invention concerns a method of 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 or 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 in the frame of treatment and/or prevention of conditions mediated by PPAR, preferably PPAR-gamma.
  • 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 or biochemical parameters associated with or causative of said conditions, e.g.
  • 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.
  • 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.
  • 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 unit dosage .
  • the compounds or compositions of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the treatment can be adapted to administer the compounds or compositions of the invention in a single weekly or monthly dose.
  • doses employed for adult human treatment will typically be in the range of 0.02 - 5000 mg per adult human per day, e.g., 1- 1500 mg per adult human per day.
  • 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 active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • 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 in 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 effects may be used, special care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected 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 in humans.
  • the dosage of such compounds lies preferably within 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 be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half- maximal inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound which achieves a half- maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • the route of administration of the compound ox- 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, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral or intratumoral 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 composition according of the present invention for the manufacture of a medicament for the treatment of individuals requiring lower blood glucose levels.
  • the compounds and compositions of the present invention may also find use in a variety of in vi tro and in vivo assays, including diagnostic assays.
  • various allotypic PPAR-gamma receptor gene expression processes may be distinguished in sensitivity assays with the subject compounds and compositions, or panels thereof.
  • labeled 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.
  • Figure 2 Effect of CRX101338 on human PPAR-gamma in co- transfection assay. Squares and triangles designate respectively Rosiglitazone and CRX101338 effects.
  • Figure 3 Effect of CRX101338 on mouse 3T3L1 cell adipogenesis .
  • FIG. 4 Effect of CRX101338 on rosiglitazone induced mouse 3T3L1 cell adipogenesis
  • Figure 7 Effect of CRX000143 on basal and insulin Stimulated glucose uptake in mouse 3T3L1 adipocytes
  • FIG. 10 Effect of CRX000143 on Glucose (10A) and Triglycerides (10 B) plasma levels in diabetic db/db mice
  • GAL4-hPPAR-gamma LBD plasmid expression vector encoding a chimeric construct comprising the GAL4 DBD (DNA Binding Domain) and the human PPAR-gamma LBD ; luciferase reporter plasmid : vector in which luciferase gene expression is placed under the control of 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 thiazolidinedione class of compounds. Rosiglitazone possesses the capacity to activate PPAR-gamma in vi tro during transfection assays, to induce adipogenesis both in vi tro and in vivo (Fajas et al . , 1998, Curr. Opin. Cell Biol. 10, 165-173 ; Spiegelman, 1998, Diabetes 47, 507-514), and to improve insulin sensitivity in diabetic animals and humans (Glass et al . , 1997, Curr. Opin. Cell Biol. 9, 222-232) .
  • CV1 cells (5 10 4 cells/ well of a 96 wells plate) are grown in DMEM supplemented with L-Glutamine (2 mM) , penicilline / streptomycin, 10 % Fetal Calf Serum charcoal and dextran treated.
  • 1 ng of GAL4-hPPAR-gamma LBD plasmid is co- transfected with 4 ng of Luciferase reporter plasmid, 8 ng of pCMV-betaGAL as an internal transfection standard and 47 ng of pBSK as a carrier using Fugene reagent (Roche) .
  • DMEM fetal calf serum
  • penicilline / streptomycin 10 % Delipidated Fetal Calf Serum and cell are treated with increasing dose (1 10 ⁇ 10 M to 1 10 ⁇ 5 M) of either rosiglitazone or compounds of the invention for 24 hours.
  • Cells are then lysed with 100 ⁇ l lysis buffer (40 mM TRIS pH 7.8 , 2.14 mM MgCl2, 5.4 mM MgS04 , 0.2 mM EDTA, 66.6 mM DTT) and 50 ⁇ l are subject to luciferase assay whereas 30 ⁇ l are used for the betagal assay.
  • CV1 cells (10 5 cells/ well of a 24 wells plate) are grown in DMEM supplemented with L-Glutamine (2mM) , penicilline / streptomycin, 10% Fetal Calf Serum charcoal and dextran treated.
  • 8 ng of GAL4-TIF2 LBD plasmid is co-transfected with 8 ng of VPl6-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).- After 16 hours, medium is changed to DMEM supplemented with L-Glutamine (2mM) , penicilline / Streptomycin, 10% Delipidated Fetal Calf Serum and cells are treated with increasing dose (1.10 "10 M to 1 10 ⁇ 5 M) of either rosiglitazone or compounds of the invention for 24 hours.
  • lysis buffer 40mM TRIS pH 7.8, 2.14 mM MgCl2, 5.4 mM MgS04 , 0.2 mM EDTA, 66.6 mM DTT
  • 50 ⁇ l are subject to luciferase assay whereas 30 ⁇ l are used for betagal assay.
  • Data are presented in RLU (Relative Light .Unit) and EC50 were calculated using Prism software.
  • 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) , penicilline / streptomycin, 10 % Calf Serum. Two days post confluency, cell are changed to DMEM supplemented with L-Glutamine (2 mM) , penicilline / 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) , penicilline / streptomycin, 10 % Fetal Calf Serum. Adipogenic effect is then quantified through the measurement of triglyceride content using the Triglyceride GPO Tinder test (SIGMA) . Data are expressed as a percent of rosiglitazone effect.
  • SIGMA Triglyceride GPO Tinder test
  • 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) , penicilline / streptomycin, 10 % Calf Serum. Two days post confluency, cell are changed to DMEM supplemented with L- Glutamine (2 mM) , penicilline / 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.
  • the buffer is replaced with 0.25 ⁇ Ci/well of [3H] -2-deoxy-D- Glucose in KRPH buffer supplemented with 25 mM 2-deoxy-D- Glucose with incubation for 5 minuts at room temperature. Supernatant is removed, cells washed four times with cold PBS and lysed with 0.1N NaOH. 400 ⁇ l of lysate is neutralized with 40 ⁇ l of 1N 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 or 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 in Carboxy Methyl Cellulose 1 % + 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 include every other day body weight monitoring, food and water intake per cage. Every animals serve as his own control and results are expressed as percent changes .
  • EXAMPLE 1 The following compound was made as described in Figure 1. 1- (4-methoxyphenyl) -3- [l-phenyl-3- (thiophen-2- yl) -lH-pyrazol-4-yl]propen-l-one (C 23 H ⁇ 8 N 2 0 2 S)
  • Said compound has been named CRX101338.
  • CRX101338 has been synthesized according to the following protocol :
  • EXAMPLE 2 CRX101338 activates human PPAR-gamma.
  • CV1 cell lines were obtained from ATCC (Rockville, MD) . Cells were maintained in Dulbecco's modified Eagle's minimal essential medium (DMEM) supplemented with 10% fetal calf serum (FCS), L-glutamine (2 mM) , and antibiotics (penicillin/streptomycin) . In order to test the ability of CRX101338 to activate human PPAR-gamma, CV1 cells (5. 10 4 cells/ well of a 96 wells plate) were grown at 37 °C under a 5% C0 2 atmosphere in supplemented DMEM medium.
  • DMEM Dulbecco's modified Eagle's minimal essential medium
  • FCS fetal calf serum
  • L-glutamine L-glutamine
  • antibiotics penicillin/streptomycin
  • Co-transfection of CV1 cells was performed by adding in each well 1 ng of GAL4-hPPAR-gamma LBD plasmid, 4 ng of the luciferase reporter plasmid, 8 ng of pCMV-betaGAL and 47 ng of a plasmid carrier (e.g. pBSK) which allows to increase amount of total transfected DNA in order to improve transfection efficiency.
  • Said co-transfection is realized using the FuGENE 6 Transfection reagent (Roche) according to the manufacturer's instructions .
  • lysis buffer 40 mM TRIS pH 7.8, 2.14 mM MgCl2, 5.4 mM MgS04 , 0.2 mM EDTA, 66.6 mM DTT.
  • 50 ul of the lysate were subject to luciferase assay, whereas 30 ul of lysate were used for the beta-galactosidase assay.
  • Luciferase results were normalized to beta-galactosidase activity and data are presented in RLU (Relative Light Unit) .
  • FIG. 2 shows that CRX101338 is an agonist of human PPAR-gamma : it activates in a dose dependent manner the expression of luciferase gene.
  • CRX101338 shows good potency since the calculated EC50 is 130 nM, which is only 4 times higher than the one observed for rosiglitazone (40 nM) . The efficacy is thus about 30 % of the one observed with rosiglitazone. Accordingly, we can conclude that said compound has partial agonist property.
  • CRX101338 is a human PPAR-gamma partial agonist
  • 3T3L1 cells were grown to confluence in a 24 well plate in supplemented DMEM. Two days post confluence, cell medium was changed to fresh supplemented DMEM. Insulin (10 mg/ml) and either rosiglitazone at 1 uM or CRX101338 at 4 uM (both 0.25% final in DMSO) were then added to cells and the mixture was incubated for 3 days .
  • CRX101338 is a functional PPAR-gamma agonist since the compound induced adipocyte differentiation. Moreover, it confirms that CRX101338 is a partial PPAR-gamma agonist since it produced only 25% of rosiglitazone efficacy. EXAMPLE 4. CRX101338 is a human PPAR-gamma antagonist.
  • CRX101338 was tested in the mouse 3T3L1 differentiation assay. 4 uM of CRX101338 was added at initiation of the differentiation protocol on top of 1 uM rosiglitazone and Insulin (10 ug/ml) .
  • Example 2 After 3 days of incubation conducted as above described, the treatment disclosed in Example 2 was applied to cells and adipogenic effect was measured.
  • Figure 4 shows that CRX101338 is further a PPAR-gamma antagonist since it is able to inhibit adipocyte differentiation induced by rosiglitazone by about 68%.
  • Example 5.1 synthesis of compounds of general formula : l-aryl-3- (1-phenyl-3-aryl (heteryl) -lH-pyrazol-4-yl) -propenone
  • Example 5.2 synthesis of compounds of general formula 1-phenyl-3-aryl (heteryl) -lH-pyrazole-4-carboxamide
  • CV1 cells 5.10 4 cells/ well of a 96 wells plate) were grown at 37 °C in a 5% C0 2 atmospher in DMEM supplemented with L-Glutamine (2mM), penicilline / streptomycin, 10 % Fetal Calf Serum charcoal and dextran treated.
  • Per well 1 ng of the expression vector encoding a chimeric construct comprised of the GAL4 DBD and the human PPAR-gamma LBD (GAL4-hPPAR-gamma LBD plasmid) was co-transfected in CV1 cells with 4 ng of the reporter vector in which luciferase gene expression is under the control of a GAL4 response element, 8 ng of the expression vector encoding the beta-galactosidase gene as an internal transfection standard (pCMV-betaGAL) and 47 ng of pBSK as a carrier using Fugene reagent (Roche) according to the manufacturer's instruction.
  • a solution of phosphorus oxychloride (55 ml, 590 mmol) is added drop wise to a well stirred solution of DMF (55 ml) under argon at 0°C. The mixture is stirred between 0 and 10°C for 0.5 hour before adding 55 mL of DMF.
  • a solution of phosphorus oxychloride (29.9 ml, 320 mmol) is added dropwise to a well stirred solution of DMF (30 ml) under argon atmosphere at 0°C.
  • Intermediate 11 (44.7 g, 160 mmol) is added portionwise with DMF (20 ml aliquots) over 10 minutes to maintain the temperature between 0 and 10°C.
  • the reaction is heated to 60 °C for one hour. The mixture is allowed to cool, filtered off and the residue is washed with
  • the white solid (8.37 g, 74 %) is rapidly used "as is" in the next step.
  • CV1 cells (5 10 4 cells/ well of a 96 wells plate) were grown in DMEM supplemented with L-Glutamine (2 mM) , penicilline / streptomycin, 10 % Fetal Calf Serum charcoal and dextran treated.
  • 1 ng of GAL4-hPPAR-gamma LBD plasmid was co-transfected with 4 ng of Luciferase reporter plasmid, 8 ng of pCMV-betaGAL as an internal transfection standard and 47 ng of plasmid pBSK as a carrier using Fugene reagent (Roche) .
  • EC50 obtained for rosiglitazone was similar to the one described in the literature (40 nM) .
  • CRX000143 was shown to activate human PPAR-gamma with an EC50 of 141 nM.
  • CRX000143 is a human PPAR-gamma partial agonist that provokes reduced effect on adipogenesis in mouse 3T3L1 cells.
  • Figure 6 shows that CRX000143 activates PPAR-gamma and has an efficacy equivalent to 33 % of rosiglitazone.
  • CRX000143 was then tested in the- functional mouse 3T3L1 cell differentiation assay.
  • ' 3T3L1 cells were grown to confluence at 37°C, 5% C0 2 , in a 24 wells plate in DMEM supplemented with L-Glutamine (2 mM) , penicilline / streptomycin, 10 % Calf Serum. Two days post confluence, cell were changed to DMEM supplemented with L- Glutamine (2 mM) , penicilline / streptomycin, 10 % Fetal Calf Serum.
  • Insulin (10 mg/ml) and either rosiglitazone at 1 ⁇ M or CRXO 00143 at 10 ⁇ M, both in DMSO 0.25% final was then added to cells for 3 days. The same treatment was then repeated for an additional 2 days. Finally, cells were grown for another 2 days in DMEM supplemented with L-Glutamine (2 mM) , penicilline / streptomycin, 10 % Fetal Calf Serum. Adipogenic effect was then quantified through the measurement of triglyceride content using the Triglyceride GPO Tinder test (SIGMA) .
  • SIGMA Triglyceride GPO Tinder test
  • CRX000143 is a functional PPAR- gamma partial agonist CRX000143 presenting 25 % of rosiglitazone efficacy and only limited adipocyte differentiation.
  • EXAMPLE 10 CRX000143 is a human PPAR-gamma partial agonist that provokes basal and insulin stimulated glucose uptake in mouse 3T3L1 adipocytes cells . 3T3L1 cells were grown to confluence at 37°C, 5% C0 2 , in a 48 well plate in DMEM supplemented with L-Glutamine (2 mM) , penicilline / streptomycin, 10 % Calf Serum.
  • DMEM + 10% FCS fetal calf serum
  • an hormonal cocktail composed of : Insulin (10 ⁇ g/ml), IBMX (500 ⁇ M) and Dexamethasone (1 ⁇ M) for 3 days.
  • Cells were treated for an additional 2 days with DMEM + 10% FCS and Insulin (10 ⁇ g/ml). Finally, cells were grown for another 2 days in DMEM +10% FCS to complete 5 adipocyte differentiation.
  • Cells were rinsed twice with serum-free DMEM and incubated for 3 hours at 37 °C, 5% C0 2 - Cells were washed four times with KRPH ) buffer (5 mM 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 KCl) .
  • the buffer was removed and the cells were incubated with or without 100 nM Insulin in KRPH buffer for 20 minutes at 37°C.
  • the buffer was replaced with 0.25 ⁇ Ci/well of [3H]-2- deoxy-D-Glucose in KRPH buffer supplemented with 25 mM 2- deoxy-D-Glucose with incubation for 5 minuts at room temperature.
  • Supernatant was removed, cells washed four times with cold PBS and lysed with 0.1N NaOH. 400 ⁇ l of lysate was neutralized with 40 ⁇ l of 1N HCl and added in a scintillation vial with 4 ml of Ready Safe Tm (Beckman Coulter) . The vials were mixed and counted.
  • Figure 7 shows that CRX000143 induces both basal and insulin stimulated glucose uptake to a extent similar to rosiglitazone with, respectively, about 103% and 85 % of rosiglitazone efficacy.
  • CRX000143 is a human PPAR-gamma partial agonist showing antidiabetic activity, ameliorating lipid profile but showing reduced side effects .

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Abstract

L'invention concerne des composés, des compositions et des méthodes utilisés pour moduler l'activité de récepteurs nucléaires dans des cellules, et pour traiter et/ou prévenir des maladies et des états variés induits par lesdits récepteurs nucléaires, notamment les troubles de la prolifération cellulaire ou métaboliques. Selon des aspects particuliers, l'invention concerne des composés, des compositions et des méthodes utilisés pour moduler les activités des récepteurs activés par prolifération des peroxisomes (PPAR), et pour traiter et/ou prévenir des maladies et des états variés induits par lesdits récepteurs nucléaires. L'invention concerne, plus particulièrement, des ligands de PPAR-gamma utilisés pour moduler les niveaux de glucose sanguin et augmenter la sensibilité à l'insuline chez des patients qui en ont besoin. Les propriétés des composés et des compositions de l'invention rendent les ligands PPAR particulièrement utiles pour traiter des maladies et des états notamment 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 (par exemple, la rétinopathie, la néphropathie), et les maladies macrovasculaires (par exemple, l'infarctus du myocarde, un accident cérébrovasculaire, une insuffisance cardiaque) chez les mammifères.
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US9714226B2 (en) 2011-07-29 2017-07-25 Karyopharm Therapeutics Inc. Hydrazide containing nuclear transport modulators and uses thereof
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Publication number Priority date Publication date Assignee Title
DE10315569A1 (de) 2003-04-05 2004-10-14 Merck Patent Gmbh Substituierte Pyrazolverbindungen
DE10315573A1 (de) * 2003-04-05 2004-10-14 Merck Patent Gmbh Substituierte Pyrazole
DE10315571A1 (de) 2003-04-05 2004-10-14 Merck Patent Gmbh Pyrazolverbindungen
PE20050226A1 (es) * 2003-06-04 2005-05-18 Aventis Pharma Sa Productos aril-heteroaromaticos y composiciones que los contienen
US20060252670A1 (en) * 2004-10-14 2006-11-09 Intercept Pharmaceuticals Inc. Method of reducing drug-induced adverse side effects in a patient
WO2007002559A1 (fr) * 2005-06-27 2007-01-04 Exelixis, Inc. Modulateurs des lxr a base de pyrazoles
JP4324221B2 (ja) * 2005-08-26 2009-09-02 株式会社医薬分子設計研究所 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
AR076984A1 (es) * 2009-06-08 2011-07-20 Merck Serono Sa Derivados de pirazol oxadiazol
TW201321367A (zh) * 2011-10-25 2013-06-01 Du Pont 經１，３－二芳基取代之雜環殺蟲劑
BR112017022349B1 (pt) * 2015-04-22 2023-11-07 Rigel Pharmaceuticals, Inc Composto, composição o compreendendo, seus usos, e, método
TWI870449B (zh) 2019-08-30 2025-01-21 美商雷傑製藥公司 吡唑化合物，其配製物以及使用該化合物和/或配製物之方法
WO2022187303A1 (fr) 2021-03-03 2022-09-09 Rigel Pharmaceuticals, Inc. Procédé de traitement d'une maladie ou d'un état à l'aide d'un composé pyrazole ou d'une formulation associée
US12384775B2 (en) 2022-03-23 2025-08-12 Rigel Pharmaceuticals, Inc. Pyrimid-2-yl-pyrazole compounds as IRAK inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2612155A1 (de) * 1975-03-25 1976-10-14 Byk Gulden Lomberg Chem Fab Nitrofurylpyrazolderivate, verfahren zu deren herstellung und sie enthaltende arzneimittel
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2612155A1 (de) * 1975-03-25 1976-10-14 Byk Gulden Lomberg Chem Fab Nitrofurylpyrazolderivate, verfahren zu deren herstellung und sie enthaltende arzneimittel
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 (9)

* Cited by examiner, † Cited by third party
Title
ARGADE, N. D. ET AL: "Synthesis of some 5-(1,3-diphenyl-1H-pyrazol-4-yl)-3-(2-hydroxyphenyl)-4, dihydro-pyrazolines and 4-(1,3-diphenyl-1H-pyrazol-4-yl)-6-(2- hydroxyphenyl)-2-thionopyrimidines", INDIAN JOURNAL OF HETEROCYCLIC CHEMISTRY (2002), 12(1), 53-56, XP009027037 *
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 (TRANSLATION OF ZHURNAL ORGANICHESKO KHIMII) (2001), 37(4), 552-555, XP009027046 *
BRATENKO, M. K. ET AL: "4-Functionally substituted 3-heterylpyrazoles: IV. 1-Phenyl-3- aryl(heteryl)-5-(4-pyrazolyl)-2-pyrazolines", RUSSIAN JOURNAL OF ORGANIC CHEMISTRY (TRANSLATION OF ZHURNAL ORGANICHESKO KHIMII) (2001), 37(4), 556-559, XP009027047 *
CHARY, T. JAGAN MOHANA ET AL: "Synthesis of 1,3-diphenylpyrazoles with substituted thiazolidinone,.DELTA.2-1,2,4-oxadiazoline,.DELTA.2-pyrazoline of.DELTA.2-isoxazoline moiety at position-4", INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY (1992), 31B(8), 495-8, XP009027039 *
EL-EMARY, T. I. ET AL: "Synthesis and biological screening of new 1,3-diphenylpyrazoles with different heterocyclic moieties at position 4", PHARMAZIE (1999), 54(2), 106-111, XP001180007 *
EL-KHAWASS, EL SAYEDA M. ET AL: "Synthesis of novel pyrazolylpyrazole, pyrazolylthiadiazole and pyrazolylthiadiazoline derivatives as potential antiinflammatory agents", ALEXANDRIA JOURNAL OF PHARMACEUTICAL SCIENCES (1990), 4(1), 77-9, XP002966338 *
KARALE, B. K. ET AL: "Synthesis, characterization and antimicrobial activities of some 2-(1,3-diphenyl-1H-pyrazol-4-yl)-3-chlorochromones and 2-(1,3-diphenyl-1H-pyrazol-4-yl)-4-(2-hydroxyphenyl)-2,3-dihydro-1,5 benzothiazepines", KOREAN JOURNAL OF MEDICINAL CHEMISTRY (2000), 10(2), 84-91, XP009027040 *
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 *
REDDY, K. R. S. ET AL: "Search for physiologically active compounds. XXVII. Synthesis of 2-(1,3-diphenylpyrazol-4-yl)-3-methoxychromones", PROCEEDINGS - INDIAN ACADEMY OF SCIENCES, SECTION A (1975), 81(5), 197-20, XP009027032 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2005090313A1 (fr) * 2004-03-18 2005-09-29 Pfizer Limited Sulfamides n-(1-arylpyrazol-4l) et leur utilisation en tant qu'anti-parasitaires
US7687533B2 (en) 2004-03-18 2010-03-30 Pfizer Inc. N-(1-arylpyrazol-4l) sulfonamides and their use as parasiticides
US7803832B2 (en) 2004-03-18 2010-09-28 Pfizer Inc. N-(1-arylpyrazol-4L)sulfonamides and their use as parasiticides
WO2007052843A1 (fr) * 2005-11-04 2007-05-10 Takeda Pharmaceutical Company Limited Compose amide heterocyclique et son utilisation
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US20110112073A1 (en) * 2008-05-15 2011-05-12 Duke University Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof
US9718784B2 (en) 2008-05-15 2017-08-01 Duke University Substituted pyrazoles as heat shock transcription factor activators
US9315449B2 (en) * 2008-05-15 2016-04-19 Duke University Substituted pyrazoles as heat shock transcription factor activators
US8946231B2 (en) * 2009-03-23 2015-02-03 Merck Sharp & Dohme Corp. P2X3, receptor antagonists for treatment of pain
US20120021074A1 (en) * 2009-03-23 2012-01-26 Merck Sharp & Dohme Corp. P2x3, receptor antagonists for treatment of pain
EP2410858B1 (fr) * 2009-03-23 2016-09-07 Merck Sharp & Dohme Corp. Antagonistes du récepteur p2x3 pour le traitement de la douleur
US9717709B2 (en) 2010-11-12 2017-08-01 Duke University Substituted pyrazoles as heat shock transcription factor activators
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US9714226B2 (en) 2011-07-29 2017-07-25 Karyopharm Therapeutics Inc. Hydrazide containing nuclear transport modulators and uses thereof
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US12291508B2 (en) 2011-07-29 2025-05-06 Karyopharm Therapeutics Inc. Hydrazide containing nuclear transport modulators and uses thereof
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