[go: up one dir, main page]

WO2004043951A1 - Pyrazole derivatives as modulators of peroxisome proliferator activated receptors - Google Patents

Pyrazole derivatives as modulators of peroxisome proliferator activated receptors Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
thiophen
pyrazole
carboxylic acid
pyrazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2003/011855
Other languages
French (fr)
Inventor
Jacques Huck
Régis SALADIN
Michael Sierra
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Carex SA
Original Assignee
Carex SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Carex SA filed Critical Carex SA
Priority to AU2003282051A priority Critical patent/AU2003282051A1/en
Publication of WO2004043951A1 publication Critical patent/WO2004043951A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds, 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 .

Landscapes

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

Abstract

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. According to particular aspects, 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 disease and conditions mediated by said nuclear receptors. More specifically, it relates to Peroxigome 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. 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.

Description

PYRAZOLE DERIVATIVES AS MODULATORS OP PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR S
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. According to particular aspects, 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. 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.
The following description is provided to aid in understanding the invention but is not admitted to be prior art to the invention. 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. 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) . In addition, it has been shown that excess body weight is directly associated with risk of cancer at several organ sites, including colon, breast (in postmenopausal women) , endometrium, oesophagus, and kidney (Bianchini et al . , 2002, Lancet Oncol., 3, 565-574). Type II or Non-Insulin Dependent Diabetes Mellitus • (Type II diabetes) constitutes 90 to 95% of all diabetic cases, and about 90% of these people are obese.
The primary aim of treatment for both forms of diabetes mellitus (DM) is the same, namely, the reduction of blood glucose levels to as near normal as possible. Treatment of Type I diabetes involves administration of replacement doses of insulin, generally by the parenteral route. In contrast, treatment of Type II diabetes does not require administration of insulin. Initially, treatments have been proposed which were based on diet and lifestyle changes augmented by theι~apy with oral hypoglycemic agents. However, while physical exercise and reductions in dietary intake of calories can improve the diabetic condition, compliance with this treatment is very poor because of sedentary lifestyles and excess food consumption, especially high fat containing food. Additionally, treatment with 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.
Thus, new class of drugs for the treatment of type II diabetes have been developed, i.e. thiazolidinediones or TZDs (glitazones) , which act by improving insulin sensitivity in adipose tissue, liver and muscle. 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) . Examples of these thiazolidinediones are rosiglitazone, pioglitazone and troglitazone. However, while offering attractive therapeutic effects, these compounds suffer from numerous serious undesirable side effects including hemodilution (including oedema) , liver toxicity, body weight increase (including body fat increase, plasma volume increase, cardiac hypertrophy, increase of the adipocyte differentiation leading to increase obesity) , modest but significant LDL-chol increase, anaemia (for a review, see Lebovitz, 2002, Diabetes Metab. Res. Rev., 18, Suppl 2, S23-9) .
It has been shown that 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.
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) .
Peroxisome Proliferators Activated Receptors (PPARs) 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. The first PPAR target genes identified were found to encode mainly enzymes involved in glucose, lipid, and cholesterol metabolisms. However, further investigations have shown that PPARs have pleiotropic biological activities and wide-ranging medical applications, extending from the treatment of metabolic disorders to possible applications in inflammation and cancer (Spiegelman, 1998, Diabetes, 47, 507-514 ; Schoonjans et al . , 1997, Curr. Opin. Lipidol., 8, 159-166). Those skilled in the art will appreciate the numerous additional examples of PPAR mediated diseases and pathologic conditions that have been described in the literature. As indicated above, the discovery that these transcription factors are involved in the control of lipid metabolism has provided new insights into the regulation of vertebrate energy homeostasis, and further has provided new molecular targets for the development of therapeutic agents for disorders such as diabetes, obesity, dyslipidemia, cardiovascular disease and related conditions.
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 (PPARα or NR1C1) is highly expressed in the liver, skeletal muscle, kidney and heart, and stimulates the expression of several enzymes involved in peroxisomal beta- oxidation. In addition to being activated by a variety of medium and long-chain fatty acids, PPAR-alpha was found to be the molecular target of the fibrate class of hypolipidemic drugs, such as clofibrate (i.e. 2- (4-chlorophenoxy) -2- methylpropanoic acid ethyl ester), fenofibrate (i.e. 2- (4- (4- chlorobenzoyl) phenoxy) -2-methylpropanoic acid isopropyl ester), bezafibrate (i.e. 2- (4- (4- chlorobenzoylaminoethyl) phenoxy) -2-methylpropanoic acid) , ciprofibrate (i.e. 2-(4-(2,2- dichlorocyclopropyl) phenoxy) isobutyric acid) , beclofibrate and etofibrate, as well as gemfibrozil (i.e. 2- (2,4- dimethylphenoxypropyl) -2-methylpropanoic acid) (Fruchart, 2001, Am. J. Cardiol., 88, 24N-29N) . Examples of PPAR-alpha ligands are provided in US 6,071,955.
PPAR-beta (PPARβ or NR1C2; also known as PPAR-delta, PPARδ, NUC-1 or FAAR) is ubiquitously expressed and its role in mammalian physiology is still largely undefined. However, Oliver et al . (2001, Proc. Natl. Acad. Sci., 98, 5306-11) have recently demonstrated that PPAR-beta is implicated in the regulation of reverse cholesterol transport and Michalik et al. (2000, Horm. Res., 54, 263-268) have shown that 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 (PPARγ 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. Endo., 27, 1-9 or Rosen et al . , 2000, Genes & Dev 14, 1293-1307, herein incorporated by reference). 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) . For a general review on PPAR-gamma, see Houseknecht et al . , 2002, Domestic Animal Endocrinology, 22, 1-23 which is herein incorporated by reference in its entirety. Literature provides numerous examples illustrating that PPARs are closely involved in a wide array of diseases or pathological conditions which are associated with cells expressing these nuclear receptors. More specifically, 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. Risk, 8, 185-186), coronary artery disease and other cardiovascular disorders. Further, 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 . Aging, 22, 937-44) or in dementia, for treating diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS) or for preventing and treating bone loss, e.g. osteoporosis ; or for antiviral, antiproliferative or antitumoral treatments (see for example US 5,981,586 or US 6,291,496).
Thus, 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.
Although, as stated above, while the responses observed in the context of these various treating and/or preventing methods, are encouraging, they are not fully satisfactory treatments because of the occurrence of undesirable side effects (see above and Haskins et al . , 2001, Arch Toxicol. , 75, 425-438 ; Yamamoto et al . , 2001, Life Sci., 70, 471-482 ; Scheen, 2001, Diabetes Metab., 27, 305-313 ; Gale, 2001, Lancet, 357, 1870-1875 ; Forman et al . , 2000, Ann. Intern. Med., 132, 118-121 or Al-Salman et al . , 2000, Ann. Intern. Med., 132, 121-124). Thus, it is still desirable to have novel improved products and/or novel methods which enable the treatment and/or the prevention of diseases or conditions associated with cell types that express nuclear receptors, in particular the PPARs, and more specifically the PPAR-gamma.
The general problem underlying the invention is to develop new modulators of nuclear receptor activity, such as PPARs (and more specifically of PPAR-gamma) . 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. More specifically, 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.
Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their derivatives, their analogues, their pharmaceutically acceptable solvates or salts or then- mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions . Still another objective of the present invention is to provide methods of treatment and/or prophylaxis of various diseases and conditions mediated or related to nuclear receptors, especially PPARs (more specially PPAR-gamma), which use the compounds or compositions as the active ingredient.
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.
Further objectives will become apparent from reading the following description.
According to a first embodiment, the present invention concerns compounds of the general formula (I) :
Figure imgf000011_0001
or analogues, derivatives, solvates or salts thereof, wherein :
R1 is a moiety selected in the group consisting of :
(i)
Figure imgf000011_0002
(ϋ)
Figure imgf000012_0001
Figure imgf000012_0002
(iv) H, CF3, -(CH2)n-R3 and -Cn,H2n , +1
with is a moiety selected in the group consisting of H, a Cι_ alkyl moiety (esp. methyl) ,
(CH2)n-CONR13R5, -C02R4, -COR4 (esp. -CO- methyl or -CONH ) , -OR4 (esp. -O-methyl), -
(CH2)n-C02R4, -(CH2)n-COR4, -(CH2)n-OR4, -NR13R5,
(CH2)n-NR13R5, -NH-COR" , - (CH2)n-NH-COR4, - - CI, -F, -(CH2)nC02H, -0-
(CH2)nC02H, -(CH2)n-TZD, -0- (CH2) n-TZD, -CN, - N02, -OH, -OCF3, -COCF3, -CF3, -N (Cn ,H2n'.1 ) 2,
S02-N(R9) (R9*) , -NR9-S02CF3, and -NR -SO?
CnΗ2n,+1 (e.g. -NR3-S02butyl) ; is a moiety selected in the group consisting of H, -Cn/H2n'+i (e.g. C1-.4 alkyl moiety such as methyl and ethyl), - (CH2) nC02H, -NH2, -(CH2)n- TZD, -OH, -N(Cn,H2n,+ι)2, -NR9-S02CF3 and -NR9- S02-CnΗ2n,+1 (e.g. -NR9-S02butyl) ; R5 and R13 are, independently from one another, a moiety selected in the group consisting of H, a Cι_4 alkyl moiety (e.g. methyl and ethyl), - S02CF3 and -S02-Cn>H2n'+i (e.g. S02butyl) ;
R6 and R7 are, independently from one another, a moiety selected in the group consisting of H, an alkyl, more specifically a Cι_4 alkyl moiety, a Cβ cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety) , or a C7 cycloalkyl moiety (e.g. a cycloheptyl or a benzyl moiety) , -S02CF3 , -S02-ClVH2n,+1 (e.g. -S02Butyl) , a benzyl moiety or phenyl moiety substituted at position 2 and/or 3 and/or 4 with a moiety selected in the group consisting of -OCn ,H2n,+1 , -CI, -F, -(CH2)nC02H, -0-(CH2)nC02H, -(CH2)n-TZD, -O- (CH2) n-TZD, -CN, -N02, -CnΗ2n'+ι , -CO-CnΗ2n'+ι , -S02-Cn ,H2n , +1 , -NR9-S02CF3, -NR9-S02-Cn ,H2n , ,,, (e.g. -NR9-S02butyl) , -OCF3, -COCF3, -CF3;
R9 and R9* are, independently from one another, a moiety selected in the group consisting of H, —CO-Cn'Hn' i , —S0 —Cn'H2n'+i i and a C-|_4 alkyl moiety ;
Ai, A2, A3 and A4 are an atom selected in the group consisting of C, N, S and 0 ; the moiety :
Figure imgf000013_0001
is intended to designate :
(i) a mono carbocyclic ring (i.e. a cyclic carboalkyl, with Ai , A2, A3 and A4 are C) ; (11) a mono heterocyclic ring (i.e. a cyclic heteroalkyl, with at least one Ax , A2, A3 and/or A4 is selected m the group consisting of N, S and 0) ;
(in) a bi- carbocyclic ring (i.e. a bicyclic carboalkyl with A-i , A2, A3 and A4 are C) ;
(iv) a bi- heterocyclic ring (i.e. a bicyclic heteroalkyl with at least one cyclic ring is containing at least one A-, , A2, A3 and/or A4 selected in the group consisting of N, S arid 0) ;
R2 is a moiety selected m the group consisting of :
Figure imgf000014_0001
(ii!
Figure imgf000014_0002
(iii)
Figure imgf000014_0003
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(Cn/H2n'+i)-. -C(Cn>H2n<+1)2-, -CH2-, -N-, -NR9- , -NR7-, -S02-, -S(CnH2n +1) - and -CHOH- where R7 and R9 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, - (CH2)n-CONR13R5, -C02R4, -COR4, -OR4, - (CH2) n-C02R4, -
(CH2)n-COR4, -(CH2)n-OR4, -NR13R5, - (CH2) n-NR13R5, -NH-COR4 , - (CH2)n-NH-COR4' -OCn ,H2n'+ι, -Cl, -F, -(CH2)nC02H, -O-
(CH2)nC02H, -(CH2)n-TZD, -O- (CH2) n-TZD, -CN, -N02, -OH, OCF3, -COCF3 , -CF3, -N(CnH2n'+ι)2. - S02-N(R9) (R9*) , -NR9-S02CF3, -NR9-S02-Cn,H2n.+ι (e.g. -NR9-S02butyl) , and :
Figure imgf000015_0001
with in all the above : n is, independently from one another, an integer ranging from
0 to 6, n' is, independently from one another, an integer ranging from
1 to 4, preferably from 1 to 3 and preferably from 1 to 2 ;
R8 and R8* are, independently from one another, a moiety selected in the group consisting of H, -CnH2n'+ι , a Cs cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), -0C„H2n'+1/ -Cl, -F, -(CH2)nC02H, - CF3, -0CF3, -C0CF3, -0-
(CH2)nC02H, -(CH2) n-TZD, -0- (CH2) n-TZD, -CH-(CH2)n , -(CH2)n- N(R9)(R9*), -CN, -N02, -(CH2)n-CO-Cn'H2n' +i, - (CH2) n-C0-N (R9) (R9*) , - S02-N(R9) (R9*) , -NR9-S02CF3, - (CH2) n-CO-cycloalkyl (e.g. - CO-cyclohexyl or -CO-phenyl) , -0-(CH2)n- cycloalkyl (e.g. -0- (CH2)n-cyclohexyl or -0- (CH2) n-phenyl) , - (CH2) n-cycloalkyl
(e.g. - (CH2)n-cyclohexyl or - (CH2) n-phenyl) , -NR9-S02-CnΗ2n>+ι
(e.g. -NR9-S02butyl) ; R10 and R10* are, independently from one another, a moiety selected m the group consisting of H, an alkyl, more specifically a C1-.4 alkyl moiety, a C6 cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), or a C7 cycloalkyl moiety (e.g. a cycloheptyl or a benzyl moiety), -Cl, -OCn>Hn'+ι , - CF3, -OCF3, -COCF3, -CN, -N02 ; and TZD is :
Figure imgf000016_0001
According to one special embodiment, the present invention concerns compounds of the general formula (I) :
R
Figure imgf000016_0002
or analogues, derivatives, solvates or salts thereof, wherein : the R1 moiety :
Figure imgf000016_0003
is intended to designate (i) a R substituted mono carbocyclic ring (i.e. a cyclic carboalkyl, with Ai , A2, A3 and A are C) ;
(ii) a R3 substituted mono heterocyclic ring (i.e. a cyclic heteroalkyl, with at least one A-i , A2, A3 and/or A4 is selected in the group consisting of N, S and 0) ;
(iii) a R3 substituted bi- carbocyclic ring (i.e. a bicyclic carboalkyl with Ai , A2, A3 and A are C) ;
(iv) a R3 substituted bi- heterocyclic ring (i.e. a bicyclic heteroalkyl with at least one cyclic ring is containing at least one Ax , A2, A3 and/or A4 selected in the group consisting of N, S and O) .
Additionally, 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 :
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
furane thiophene pyrrole p oyridine
Figure imgf000019_0002
1 ,2,4-triazole oxazole isothiazole 1 ,2,3-oxadiazole
Figure imgf000019_0003
1 ,2,3-triazole -A isoxazole thiazole 1 ,2,4-oxadiazole
Figure imgf000019_0004
pyrazole 1 ,2,5-oxadiazole 1 ,3,4-oxadiazole 1 ,2,5-oxathiazole
Figure imgf000019_0005
pyridazine pyrimidine pyrazine 1 ,2,5-oxathiazine
Figure imgf000019_0006
s-triazine as-triazine v-triazine
Figure imgf000019_0007
According to another special embodiment, the present invention concerns compounds of the general formula (I):
Figure imgf000020_0001
or analogues, derivatives, solvates or salts thereof, wherein :
R1 is a moiety selected in the group consisting of :
Figure imgf000020_0002
Figure imgf000020_0003
Figure imgf000020_0004
Figure imgf000020_0005
with X is a moiety selected in the group consisting of 0, N and S ; and the other substituting moieties being as defined above . Alternatively, R3 in R1 is replaced with R11.
According to the present invention, the term "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 . Typically, 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. In rather preferred embodiment, 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. Cι„4) . They are a special embodiment of ~CnΗ2n'+ι. Typically, a Cι_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. Examples of 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 .
Additionally, the term "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. According to specific embodiment, 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.
The terms "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.
It should be noticed that the compounds of formula. I are comprising several moieties which can be repeated n times (e.g. -0- (CH2) nC02H) ; it should be understood that each n value throughout the formula I in a particular compound can be chosen independently from one another. According to special embodiments of the invention, 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.
According to one special embodiment, one or more of the (CH2)n moiety of the Formula I is substituted with at least one methyl group. More specifically, said methyl substitutions occur on the (CH2)n moiety comprised in the moiety selected in the group consisting of -(CH2)nC02H, -0- (CH2) nC02H, -(CH2)n-TZD, -0- (CH2)n-TZD.
According to the present invention, the term C-|_ 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. Typically, 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 .
According to one special embodiment, at least one cycle designated in Formula I with :
Figure imgf000023_0001
is under the form of an aromatic cycle
Figure imgf000023_0002
According to the present invention, the substituting moiety R present in a cycle (or cycloalkyl), for example an aromatic cycle, such as for example the followings :
Figure imgf000023_0003
can be localized in position para, meta and/or ortho of said cycle. In preferred embodiment, the substituting moiety is localized in position para or meta.
In preferred embodiments, the compounds of formula I are :
Figure imgf000024_0001
and R is
Figure imgf000024_0002
According to special embodiments, at least one -(CH2)- moiety in the following structures (herein named the "linkers") isolated from R2:
■fiirγ' z rt
Figure imgf000024_0003
is replaced by at least one - (CH) - moiety. In this special case, those skilled in the art will be able to adapt the number and type of bounds accordingly. For example, said structure isolated from R2 can be as follows :
Figure imgf000024_0004
According to special embodiments, at least one - (NH) - moiety in the linker isolated from R2 is replaced by at least one -(N)- moiety. In this special case, those skilled in the art will be able to adapt the number and type of bounds accordingly.
According to special embodiments of the invention, a, b and c are, independently from one another, an integer ranging from 0 to 2.
According to special embodiments of the invention, the linker isolated from R2 is selected in the group consisting in
Figure imgf000025_0001
According to particular embodiments of the invention, the "linker" in compounds of formula I is selected in the group consisting of :
Figure imgf000026_0001
According to special embodiments of the invention, in compounds of formula I, when the following structure isolated from R^
Figure imgf000026_0002
IS
Figure imgf000026_0003
with a is 0
R' is
Figure imgf000026_0004
According to another special embodiments of the invention, in compounds of formula I, when the following structure isolated from R2 :
Figure imgf000026_0005
IS
Figure imgf000027_0001
with a is 0
Figure imgf000027_0002
or
Figure imgf000027_0003
According to special embodiments of the invention, R is selected in the group consisting of :
Figure imgf000027_0004
O
J. N
O
\ •
Figure imgf000027_0005
According to special embodiments of the invention, R is
H.
According to special embodiments of the invention, R8 and/or R10 is/are not an aromatic Cς, cycloalkyl. According to special embodiments of the invention, Z is -NH-.
According to special embodiments of the invention, Z is -CO-.
According to special embodiments of the invention, Z is -SO2-.
According to special embodiments of the invention, the C6 cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety) or the C7 cycloalkyl moiety (e.g. a cycloheptyl or a benzyl moiety), alone or in combination (e.g. -(CH2)n-C6 cycloalkyl moiety, -(CH2)n-C7 cycloalkyl moiety, -0-(CH2)n- C6 cycloalkyl moiety or a -0- (CH2) n-C7 cycloalkyl moiety) is substituted, preferably at least with one moiety selected in the group consisting of R8 and R10.
According to special embodiments of -the invention, R1 is :
Figure imgf000028_0001
According to special embodiments of the invention, R11 and/or R12 is selected in the group consisting in -Cl , -COOH and - CF3.
According to special embodiments of the invention, R8* and/or R10* is selected in the group consisting in -CH3 , -OCI-I3, -COCH3 and halogen (-F or -Cl preferably) , -CF3 , -OCF3, -COCF3, phenyl, -CH2-phenyl, -0-CH2-phenyl , -CONH2.
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. For example, in one group of embodiments, the compounds according to the present invention- include those having R2 being :
Figure imgf000029_0001
and having the following combinations of a, b, c, Y and Z in said A
a Y b z c 0 -CH2- 1 -CH2- or -CO- 0 0 -CH2- 1 -CO- 0 0 -CH2- 1 -CH2- 0 0 -NR9- 0 -CH2- or -CO- 1 0 -CH2- or -C0- 0 -NR9- 1 0 -CO- 0 -NH- 1 0 -NR9- 0 -CH2- or -CO- 0 0 -CH2- or -CO- 0 -NR9- 0 0 -CO- 0 -CH2- 0 0 -CH2- 0 -CO- 0 1 CH2- or -NR9- 0 -CH2- or -CO- 0 0 -CH2- or -CO- 0 -CH2- or -NR9- 1 0 -NR9- 0 -CH2- or -CO- 2 0 -CH2- 0 -CH2- 0 0 -CH- 1 -CO- 0 with(-CH-)b
1 -CH- 0 -CO- 0 with(-CH-)
According to particular embodiments, the compound of the invention is selected in the group consisting in :
1 - (4-methoxy-phenyl) -3- [1 -phenyl-3- (thiophen-2-yl) -1H- pyrazol-4-yl]propen-1 -one (CRX101338) ,
1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-pyridin-3-yl-lH-pyrazol- 4-yl) -propenone (CRX000143),
1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-pyridin-4-yl-1 H-pyrazol- 4-yl) -propenone (CRX000144), 3- [3- (4-Methoxy-phenyl) -1 -phenyl- 1 H-pyrazol-4-yl] -1 -phenyl- propenone (CRX156707),
1 - (4-Chloro-phenyl) -3- (1 , 3-diphenyl-1 H-pyrazol-4-yl) - propenone (CRX156701)
1 - (4-methoxy-phenyl) -3- [1 -phenyl-3- (thiophen-3-yl) -1H- pyrazol-4-yl]propen-1 -one (CRX000270) ,
1 -phenyl-3- (1 -phenyl-3-pyridin-3-yl-1 H-pyrazol-4-yl) - propenone ,
1 - (4-ethyl-phenyl) -3- (1 -phenyl- 3-pyridin-3-yl-1 H-pyrazol-4- yl) -propenone,
3- (1 , 3-diphenyl-1 H-pyrazol-4-yl) -1 - (4-methoxyphenyl) propenone (CRX156023),
1 - (4-ethyl-phenyl) -3- (1 -phenyl-3-pyridin-3-yl-1 H-pyrazol-4- yl) -propenone,
3- (4-chloro-phenyl) -1 -phenyl-lH-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide,
3- (4-chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-acetyl-phenyl ) -amide ,
1 , 3-diphenyl-1 H-pyrazole-4-carboxylic acid (4-methoxyphenyl) -amide,
1 -phenyl-3-p-tolyl-1 H-pyrazole-4-carboxylic acid (4-methoxy- phenyl-amide,
3- (3 , 4-dimethoxy-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-chloro-phenyl) -amide,
1 -Phenyl-3-m-tolyl-1 H-pyrazole-4-carboxylic acid (4-methoxyphenyl) -amide (CRX000314),
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid benzylamide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methyl-benzyl) -amide, 1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- methyl-benzyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- chloro-benzyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- chloro-benzyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methoxy-benzyl) -amide,
1- phenyl -3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid cyclohexyl-amide ,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid cyclohexylmethyl-amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- methoxy-benzyl) amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- trifluoromethyl-benzyl) amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- trifluoromethyl-benzyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid phenyl-amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- chloro-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- chloro-phenyl) -amide (CRX000186) ,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- trifluoromethyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- trifluoromethyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- nitro-phenyl) -amide, 1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- nitro-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid phenetyl-amide,
1- phenyl -3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid 2- (4-chloro-phenyl) -ethyl] -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -ethyl] -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3-chloro-phenyl) -ethyl] -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid methoxy-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid 4- methoxy-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid benzyloxy-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid methyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid methyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 4- butyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid cyclohexyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 2- (3-methoxy-phenyl) -ethyl] -amide,
1- phenyl -3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid acetyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 4- carbamoyl-phenyl) -amide, 1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- dimethylamino-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- carbamoyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid biphenyl-4-yl amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- benzoyl-phenyl) -amide,
1 -phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- sulfamoyl-phenyl) -amide,
1 -phenyl-3-pyridin-2-yl-1H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide,
1 -phenyl-3-pyridin-3-yl-1 H-pyrazole-4-carboxylic acid(4- methoxy-phenyl) -amide,
1 -phenyl-3-p'yridin-4-yl-lH-pyrazole-4-carboxylic acid(4- methoxy-phenyl) -amide,
3- (3-chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide,
3- ( 2-chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide,
3- (4-trifluoromethyl-phenyl) -1 -phenyl-1 H-pyrazole-4- carboxylic acid (4-methoxy-phenyl) -amide ,
3- (3-trifluoromethyl-phenyl) -1 -phenyl-1 H-pyrazole-4- carboxylic acid (4-methoxy-phenyl) -amide ,
3- (2-trifluoromethyl-phenyl) -1 -phenyl-1 H-pyrazole-4- carboxylic acid (4-methoxy-phenyl) -amide ,
3- (3-methyl-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide,
3- (4-methoxy-phenyl) -1 -phenyl-1 H-pyrazole-4 -carboxylic acid (4-methoxy-phenyl) -amide, 3-furan-2-yl-1 -phenyl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide,
3- (4-methyl-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide,
3- ( 3 , 4-Dimethoxy-phenyl) - 1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid pyridin- 2-ylamide ,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid pyridin-3-ylamide ,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid pyridin-4-ylamide,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (pyridin-2-ylmethyl) -amide,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic ' acid (pyridin-3-ylmethyl) -amide,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (pyridin-4-ylmethyl) -amide .
According' to another particular embodiments, the compound of the invention is selected in the group consisting in :
1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl)-propan-1-one (CRX000141)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- carbamoyl-phenyl) -amide (CRX000142)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- trifluoromethyl-phenyl) -amide (CRX000145)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- acetyl-phenyl) -amide (CRX000146)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- benzyloxy-phenyl) -amide (CRX000149) 1 -Phenyl-3-pyridin-3-yl-1 H-pyrazole-4-carboxylic acid (4- ethoxy-pheny1 ) -amide (CRXO00151)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid benzylamide (CRX000155)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid phenethyl-amide (CRX000156)
1 -Phenyl-3-pyridin-4-yl-1H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide (CRX000158)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid methyl-phenyl-amide (CRX000165)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -methyl-amide (CRX000167 )
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- carbamoyl-phenyl) -amide (CRX000172)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid p- tolylamide (CRX000174)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methoxy-pheny1) -amide (CRXO00176)
1 -Phenyl-3- (4-trifluoromethyl-phenyl) -lH-pyrazole-4- carboxylic acid (4-methoxy-phenyl) -amide (CRX000181)
1 -Phenyl-3- (2-trifluoromethyl-phenyl) -1 H-pyrazole-4- carboxylic acid (4-methoxy-phenyl) -amide (CRX000182)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid phenylamide (CRX000183)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 4- methoxy-benzylamide (CRX000184)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- dimethylamino-phenyl) -amide (CRX000185)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- chloro-phenyl) -amide (CRX000188)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid m- tolylamide (CRX000189)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid (3- trifluoromethyl-phenyl) -amide (CRX000190) 1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid 4- trifluoromethyl-benzylamide (CRX000203)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid [2- (4-chloro-phenyl) -ethyl] -amide (CRX000205)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- butyl-phenyl) -amide (CRX000206)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (2- phenoxy-ethyl) -amide (CRX000207)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 4- chloro-benzylamide (CRX000208)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 3- chloro-benzylamide (CRX000209)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 3- methyl-benzylamide (CRX000210)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 4- methyl-benzylamide (CRX000211 )
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic 'acid (3- methoxy-phenyl) -amide (CRX000212)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid [2- (3-chloro-phenyl) -ethyl] -amide (CRX000213)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- benzoyl-phenyl) -amide (CRX000214)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid [2- (4-methoxy-phenyl) -ethyl] -amide (CRX000215)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid [2- (3-methoxy-phenyl) -ethyl] -amide (CRX000216)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid (4- cyclohexyl-phenyl) -amide (CRX000218)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid cyclohexylmethyl-amide (CRXO00220)
3-Furan-2-yl-1 -phenyl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide (CRXO00233)
3-Furan-2-yl-1 -phenyl-1 H-pyrazole-4-carboxylic acid 4- methoxy-benzylamide (CRX000234) 1 - (4-Methoxy-phenyl) -3- (3-methyl-1 -phenyl-1 H-pyrazol-4-yl) - propenone (CRXO00235)
3- (2-Chloro-phenyl) -1 -phenyl-1H-pyrazole-4-carboxylic acid 4-methoxy-benzylamide (CRX000237)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid methyl-p-tolyl-amide (CRX000245)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid (3- chloro-phenyl) -methyl-amide (CRX000246)
4- (4-Methoxy-benzyloxymethyl) -1 -phenyl-3-thiophen-2-yl-1 H- pyrazole (CRX000248)
3- (2-Chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide (CRX000254)
3- (3-Chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide (CRX000255)
3- [3- (4-Chloro-phenyl) -1 -phenyl-1 H-pyrazol-4-yl] -1 - (4- methoxy-phenyl) -propenone (CRX000256)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid 3- methoxy-benzylamide (CRX000261 )
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid cyclohexylamide (CRXO00263)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid biphenyl-4-ylamide (CRX000264)
1 - (4-Methoxy-phenyl) -3- [3- (4-methoxy-phenyl) -1 -phenyl- 1H- pyrazol-4-yl] -propenone (CRX000273)
4-Methyl-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRXO 00275)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid ethyl-phenyl-amide (CRX000276)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid benzyl-phenyl-amide (CRX000277)
3-Methyl-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRXO00278)
(4-Methoxy-benzyl) - ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethylene) -amine (CRX000281 ) 1 - (4-Methoxy-phenyl) -3- ( 1 -phenyl-1 H-pyrazol-4-yl) -propenone (CRX000284)
1 - (4-Methoxy-phenyl) -3- [3- (1 -methyl-1 H-pyrrol-3-yl) -1 - phenyl-1 H-pyrazol-4-yl] -propenone (CRX000285)
3- (3-Furan-2-yl-1 -phenyl-1 H-pyrazol-4-yl) -1 - (4-methoxyphenyl) -propenone (CRX000287)
(4-Methoxy-benzyl) - (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -amine (CRXO 00291)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid methyl-phenethyl-amide (CRX000303)
N- ( 1 -Phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) -2-m-tolyl- acetamide (CRX000304)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid (3,4- dichloro-phenyl) -methyl-amide (CRX000305)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- sulfamoyl-phenyl) -amide (CRX000308)
1 -Phenyl-3-m-tolyl-1 H-pyrazole-4-carboxylic acid 4 methoxy- benzylamide (CRXO00315)
3-Methoxy-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRX000332)
N- (1 -Phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl) -3- trifluoromethyl-benzamide (CRX000336)
3-Chloro-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRX000338)
Benzyl-methyl- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -amine (CRX000342)
1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-m-tolyl-1 H-pyrazol-4-yl) - propenone (CRXO00347)
4- [3- (4-Methoxy-phenyl) -3-oxo-propenyl] -1 -phenyl- 1H- pyrazole-3-carboxylic acid benzylamide (CRX000349)
(4-Methoxy-benzyl) -methyl- (1 -phenyl-3-thiophen-2-yl-1 H- pyrazol-4-ylmethyl) -amine (CRX000350)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid [2- (4-methoxy-phenyl) -2-oxo-ethyl] -amide (CRX000357) 1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid 3- trifluoromethyl-benzylamide (CRX000358)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid ethyl-m-tolyl-amide (CRX000359)
N- (4-Methoxy-benzyl) -N- (1 -phenyl-3-thiophen-2-yl-lH-pyrazol- 4-ylmethyl) -methanesulfonamide (CRX000362)
4-Methoxy-N- (2-phenyl-5-thiophen-2-yl-2H-pyrazol-3-yl) - benzamide (CRXO00365)
N- (1 -Phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl) -4- trifluoromethyl-benzamide (CRXO 00378)
N- (1 -Phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl) -2-p-tolyl- acetamide (CRX000379)
(1 -Phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) -carbamic acid benzyl ester (CRX000382)
3-Phenyl-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - propionamide (CRX000383)
4-Methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRX000392)
2- (3-Chloro-phenyl) -N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl)-acetamide (CRX000394)
4-Acetyl-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRX000395)
N- (1 -Phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) -benzamide (CRX000396)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid methyl- (2-trifluoromethyl-phenyl) -amide (CRX000401 )
4-Dimethylamino-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- yl) -benzamide (CRX000402)
4- [3- (4-Methoxy-phenyl) -propenyl] -1 -phenyl-3-thiophen-2-yl- iH-pyrazole (CRX000417)
2- (4-Methoxy-phenyl) -N- (2-phenyl-5-thiophen-2-yl-2H-pyrazol- 3-yl) -acetamide (CRX000418)
4-Methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000432) 2- (4-Methoxy-phenyl) -N- (1 -phenyl- 3-thiophen-2-yl- 1 H-pyrazol- 4-ylmethyl) -acetamide (CRX000433)
1 - (4-Chloro-phenyl) -3-phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide (CRX000434)
3- (4-Methoxy-phenyl) -N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-ylmethyl) -propionamide (CRX000443)
4-Methoxy-N- (1 -phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl) - benzenesulfonamide (CRX000444)
4-Methoxy-N-methyl-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- yl) -benzenesulfonamide (CRX000454)
1 -Phenyl-3- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - propenone (CRX000478)
4-Methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzenesulfonamide (CRX000506)
C-Phenyl-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - methanesulfonamide (CRX000509)
4-Methoxy-N- (1 -methyl-3-thiophen-2-yl-1H-pyrazol-4- yl ethyl) -benzamide (CRX000510)
1 -Benzyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide (CRX000511 )
1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl- 1 H-pyrazol- 4-yl)-butan-1-one (CRX000512)
3-Methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000515)
4-Fluoro-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylme thyl) - benzamide (CRX000516)
N- ( 1 -Benzyl- 3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) -4- methoxy-benzamide (CRX000523)
1 - (4-Methoxy-phenyl) -3- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl)-heptan-1-one (CRX000524)
4-Methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazole-4- carbonyl) -benzamide (CRX000533)
3 , 4-Dimethoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000537) N- ( 1 -Phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - nicotinamide (CRX000538)
N- ( 1 -Benzyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) -3- methoxy-benzamide (CRX000539)
N- (1 -Phenyl-3-thiophen-2-yl-1H-pyrazol-4-ylmethyl) -2- trifluoromethoxy-benzamide (CRXO00544)
3 , 4-Dichloro-N- (1 -phenyl- 3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000545)
N- (1 , 3-Diphenyl-1 H-pyrazol-4-ylmethyl) -4-methoxy-benzamide (CRX000546)
N- [1 - (4-Chloro-phenyl) -3-phenyl-1 H-pyrazol-4-ylmethyl] -4- methoxy-benzamide (CRX000547)
4-Hydroxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000549)
2-Fluoro-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) ■ benzamide (CRXO00555)
2-Methoxy-N- ( -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000556)
3 , 5-Dimethoxy-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000557)
4-Chloro-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - benzamide (CRX000571)
N- ( 1 -Phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) -4- trifluoromethoxy-benzamide (CRXO00572)
3-Chloro-4-methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000573)
3-Chloro-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - benzamide (CRX000574)
N- ( 1 -Phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) -3- trifluoromethyl-benzamide (CRXO00576)
N- (1 -Phenyl-3-thiophen-2-yl-lH-pyrazol-4-ylmethyl) -4- trifluoromethyl-benzamide (CRXO00579)
3-Fluoro-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - 4-trifluoromethyl-benzamide (CRXO00580) N- ( 1 -Phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - terephthalamic acid (CRX000581 )
3- [1 - (3, 5-Bis-trifluoromethyl-phenyl) -3-thiophen-2-yl- 1 H- pyrazol-4-yl] -1 - (4-methoxy-phenyl) -propenone (CRX000582)
2-Fluoro-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - 4-trifluoromethyl-benzamide (CRX000587)
4-Methoxy-N- (1 -phenyl-3-m-tolyl-1 H-pyrazol-4-ylmethyl) - benzamide (CRX000588)
2 , 4-Dimethoxy-N- ( 1 -phenyl-3-thiophen- 2-yl- 1 H-pyrazol-4- ylmethyl) -benzamide (CRX000600)
1 - (4-Methoxy-phenyl) -3- [3-thiophen-2-yl-1 - (4- trifluoromethyl-benzyl) -1 H-pyrazol-4-yl] -propenone (CRX000603)
3- [1 - (4-Fluoro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- methoxy-phenyl) -propenone (CRX000604)
N- [3- (4-Chloro-phenyl) -1 -phenyl-1 H-pyrazol-4-ylmethyl] -4- methoxy-benzamide (CRX000608)
N- (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl-1 H'-pyrazol- 4-yl) -acrylamide (CRX000609)
3- [3- (4-Fluoro-phenyl) -1 -phenyl-1 H-pyrazol-4-yl] -1 - (4- methoxy-phenyl) -propenone (CRX000610)
N- (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl) -propionamide (CRX000618)
1 -Phenyl-2- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylamino) - ethanol (CRX000620)
N- (4-Methoxy-phenyl) -2- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl) -acetamide (CRX000621 )
1 - (4-Fluoro-phenyl) -3- [3-pyridin-3-yl-1 - (4-trifluoromethyl- phenyl) -lH-pyrazol-4-yl] -propenone (CRX000622)
1 - (4-Chloro-phenyl) -3- [3-pyridin-3-yl-1 - (4-trifluoromethyl- phenyl) -1H-pyrazol-4-yl] -propenone (CRX000623)
1 - (4-Methoxy-phenyl) -3- [3-pyridin-3-yl-1 - (4-trifluoromethyl- phenyl) -1H-pyrazol-4-yl] -propenone (CRX000624)
2-Acetyl-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - benzamide (CRX000625) 3- [1 - (4-Chloro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- fluoro-phenyl) -propenone (CRX000626)
1 - (4-Chloro-phenyl) -3- [1 - (4-chloro-phenyl) -3-pyridin-3-yl- lH-pyrazol-4-yl] -propenone (CRX000627)
3- [1 - (4-Chloro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- methoxy-phenyl) -propenone (CRXO 00629)
3- [3-Pyridin-3-yl-1 - (4-trifluoromethyl-phenyl) -1 H-pyrazol-4- yl] -1 - (4-trifluoromethyl-phenyl) -propenone (CRX000631 )
1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl) -propan-1 -ol (CRX000632)
Phenyl- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) -methanone (CRX000636)
3- [3-Pyridin-3-yl-1 - (4-trifluoromethyl-phenyl) -1 H-pyrazol-4- yl] -1 - (4-trifluoromethoxy-phenyl) -propenone (CRX000637)
3- [1 - (4-Chloro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- trifluoromethoxy-phenyl) -propenone (CRX000638)
3- [1 - (4-Chloro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- trifluoromethyl-phenyl) -propenone (CRX000640)
1 - (4-Fluoro-phenyl) -3- [1 - (4-fluoro-phenyl) -3-pyridin-3-yl- lH-pyrazol-4-yl] -propenone (CRX000641 )
3- [1 - (4-Fluoro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- trifluoromethoxy-phenyl) -propenone (CRX000642)
1 - (4-Chloro-phenyl) -3- [1 - (4-fluoro-phenyl) -3-pyridin-3-yl- 1H-pyrazol-4-yl] -propenone (CRX000643)
3-Isopropylsulfanyl-1 - (4-methoxy-phenyl) -3- (1 -phenyl-3- thiophen-2-yl-lH-pyrazol-4-yl) -propan-1 -one (CRX000644)
1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl) -prop-2-en-1-ol (CRX000645)
3- [1 - (4-Fluoro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- trifluoromethyl-phenyl) -propenone (CRX000648)
4- [4- (4-Methoxy-phenylcarbamoyl) -3-thiophen-2-yl-pyrazol-1 - yl] -benzoic acid ethyl ester (CRX000790)
3- (4-Fluoro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid [4- (pyridin-2-ylmethoxy) -phenyl] -amide (CRX000871 ) . According to another embodiment, 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 :
Figure imgf000044_0001
said moiety R14 being selected in the group consisting in -Cl, -CF3, a Cι_ alkyl moiety (particularly ethyl or methyl) .
Examples of these specific 5-substituted compounds are :
5-chloro-3-methyl-1 -phenyl-1 H-pyrazole-4-carboxylic acid cyclohexylmethyl-amide,
5-chloro-3-methyl-1 -phenyl-1 H-pyrazole-4-carboxylic acid (3- chloro-2-methyl-phenyl) -amide,
5-methyl-1 , 3-diphenyl-1 H-pyrazole-4-carboxylic acid cyclohexylamide .
According to another alternative, the R2 moiety present in the compounds of the present invention are modified in such a way that the motif :
Figure imgf000044_0002
is replaced with a motif selected in the group consisting of
Figure imgf000045_0001
with W is an atom selected in the group consisting of S, 0 and N.
Examples of these compounds of the invention comprising heterocycles are :
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid pyridin-2-ylamide,
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid pyridin-3-ylamide ,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid pyridin-4-ylamide ,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (pyridin-2-ylmeth.yl) -amide,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (pyridin-3-ylmethyl) -amide,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (pyridin-4-ylmethyl) -amide.
The terms "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" .
Compounds 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. Other acids such as oxalic, while not considered as pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. When compounds of the present invention contain relatively acidic functionalities, 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. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, lithium, calcium, aluminium, ammonium, barium, zinc, organic amino, or magnesium salt, N,N1-dibenzylethylenediamine, choline, diethanolamine, ethylenediamine, N-methylglucamine, procaine salts (e.g. chloroprocaine) and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66, 1-19). Finally, certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
Similarly, those skilled in the art will recognize that the compounds of the present invention may be utilized in the form of a pharmaceutically acceptable solvate thereof. These 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.
Additionally, those skilled in the art will recognize that stereocenters exist in compounds of Formula (I). Accordingly, 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. When 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. Additionally, in situations where tautomers of the compounds of Formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds. These terms and methods required for identifying and selecting the desired compounds are well known in the art. For example, 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.
In special embodiments, e.g in the case of the -COOH being present, 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, for example, 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, H2 S04) . 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.
Those skilled m the art are further able to prepare various 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 caloπmetry, powder X-ray diffraction or such other techniques .
According to special embodiments, the compounds of the invention may be labelled m a variety of ways. For example, the compounds may contain radioactive isotopes such as, for example H3 (tritium) or C14 at one or more of the atoms that constitute compounds of general formula (I). Similarly, 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.
The invention further concern 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) . In even more preferred embodiments, 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.
Methods and conditions for testing or measuring the interacting and/or binding property of compounds (e.g. ligands) with nuclear receptors and/or LBD are widely disclosed and implemented in the art : for examples, Glickman et al . , 2002, J. Biomolecular Screening, 7, 3-10 or Lehmann et al., 1995, J. Biol. Chem., 270, 12953-12956. For example, Le Douarin et al . , (2001, Methods Mol. Biol., 176, 227-48) have disclosed an in vi tro screening test using the yeast two- hybrid system that is based on the ligand-dependent interaction of two proteins, a hormone receptor and a coactivator ; Zhou et al . , (2001, Methods, 25, 54-61) have disclosed a homogeneous time-resolved fluorescence (HTRF) energy transfer technology which is sensitive, homogeneous, and nonradioactive ; Beaudet et al . , (2001, Genome Res., 11, 600-8) have disclosed the AlphaScreen™ technology (Packard BioScience) which allows the development of high-throughput homogeneous proximity assays. The full content of these papers is incorporated herein by reference. Specific examples of said standard procedures available in the art are the Fluorescence Resonance Energy Transfer (FRET) , the CoActivator-dependent Receptor Ligand Assay (CARLA) and the GST-pull down assays or two-hybrid assays (see Experimental Section). According to another embodiment, 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.
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. AlphaScreen™. technology) or in 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. 4,981,784 and US 5,071,773, which are incorporated herein by reference. Also see Heyman et al., 1992, Cell, 68, 397-406, Kliewer et al . , 1995, Cell 83, 813-819 , Lehmann et al . , 1995, J. Biol. Chem., 270, 12953- 12956, or Lehnman et al . 1997, J. Biol. Chem., 272, 3137-3140. 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). Briefly, 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) and 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. This assay can be used to accurately measure efficacy and potency of interaction and modulating activity of a specific ligand compound. Alternatively, the compounds and compositions can be evaluated for their ability to increase or decrease gene expression modulated by PPAR, using western-blot analysis.
Alternatively, Voegel et al . (1998, EMBO' J. 17, 507-519) have proposed the use of transient transfection assays with a GAL4 reporter plasmid and chimeras containing various peptide fragments linked to the GAL4 DBD (DNA Binding Domain) .
According to special embodiments, 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 μM.
It is further possible to analyze the modulating properties of the compounds and compositions of the present invention in vivo, in established animal models. These models are particularly useful to evaluate the effects of said compounds and compositions on plasma levels of glucose, insulin, total cholesterol, triglycerides and non-esterified free fatty acids (NEFA's), on weight variation, on oedema or hepatotoxicity occurrence, etc... These models are well known in the art (e.g. db/db mice, Zucker fa/fa rat, KKY or KKAY mice, NOD or non- obese diabetic mice, DIO models...). According to a specific embodiment, the compounds and compositions of the present invention are PPAR and/or PPAR LBD agonists. According to a preferred embodiment, the compounds and compositions of the present invention are PPAR-gamma and/or PPAR-gamma LBD agonists. By "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. In one embodiment, 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.
According to another preferred embodiment, 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) is called partial agonist.
For example, the partial agonist property of the compounds and compositions of the present invention can be defined by reference to rosiglitazone (Avandia™, Glaxo- SmithKline) which is a full agonist. According to special embodiments, 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). In preferred embodiments, 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 Applicants postulate that too high level of efficacy can be associated with detrimental undesirable side effects. Thus, they proposed to seek for potent PPAR ligands, especially PPAR-gamma ligands, with reduced efficacy (compared to rosiglitazone for example) which should result in safer drugs.
According to special embodiments, 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.
According to other embodiments, 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. By "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. The term "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. As general definition, "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 . For example, it has been shown that compounds that activate PPAR-gamma (e.g. thiazolidinediones) are further inducing adipocyte differentiation (i.e. adipogenic effect) and are thus resulting in body weight increase in treated patients. Therefore it is highly desirable that the next generation of such compounds are devoid of such activity. These activities can be appreciated using methods widely used in the art (see for example tests in the mouse 3T3L1 in Mukherjee et al . , 2000, Mol. Endo., 14, 1425-1433). More spe'cifically, these activities are appreciated with reference to a molecule which has already been identified in the art, such as rosiglitazone (also named BRL49653 ; see Lehmann et al . , 1995, J. Biol. Chem., 270, 12953-12956 for the chemical structure details). According to a preferred embodiment of the invention, 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. According to another preferred embodiment of the instant invention, the claimed compounds and compositions display less than about 50%, preferably less than about 40%, more preferably less than about 30 % and even more preferably less than about 20% of the rosiglitazone property towards adipogenesis.
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.
It is actually now widely acknowledged that nuclear receptors, such as 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). These 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. Hence, the determination of the multiple partnerships in which each nuclear receptor is engaged, as a function of time and cell type, is a crucial aspect leading to a better understanding of the activity of nuclear receptors on transcriptional regulation. For instance, it is known that for certain hormones, such as estrogen, the response to the hormone is determined almost to the same extent by the presence of the respective nuclear hormone receptor, as by the presence of the cofactors, which interact with the receptors. Various PPAR cofactors have been identified so far. Some cofactors such as p300/CBP (Dowell et al . , 1997, J. Biol. Chem. 272, 33435-33433), SRC-1 (Onate et al . , 1995, Science 270, 1354-1357), TIF2 (GRIP-2 ; Chakravarti et al . , 1996, Nature, 383, 99-103), SRA (Lanz et al . , 1999, Cell, 97, 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 . , 1998, Cell 92, 829-839), PRIP (Zhu et al., 2000, J. Biol. Chem. 275, 13510-13516), PGC-2 (Castillo et al . , 1999, Embo J. , 18, 3676-3687), ARA70 (Heinlein et al . , 1999, J. Biol. Chem. 274, 16147-16152), RIP140 (Treuter et al . , 1998, Mol. Endocrinol. 12, 864-881), enhance their transcriptional activity, whereas SMRT (Lavinsky et al., 1998, Proc. Natl. Acad. Sci. USA 95, 2920-2925) and N- CoR (Dowell et al . , J. Biol. Chem 274, 15901-15907) repress it. Additionally, it has been shown that members of the PPAR- gamma cofactor family (e.g. the 160-kDa protein (SRC- 1 /TIF2/AIB-1 ) , CBP/p300 or TRAP220/DRIP205) interact directly with PPAR-gamma and potentiate nuclear receptor transactivation function in a ligand-dependent fashion leading to biological action or side effects that can differ according to the ligand used (Adams et al . , 1997, J. Clin. Invest., 100, 3149-3153). Kodera et al . (2000, J. Biol. Chem., 275, 33201- 33204) have examined whether interactions between PPAR- gamma and known cofactors were induced to the same extent by different classes of PPAR-gamma ligands (natural and synthetic) and concluded that the overall structure of PPAR- gamma and cofactors complexes may be different according to the ligands involved, resulting in the activation of a particular set of target gene promoters that exert different biological actions.
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). Like CBP/p300, 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 related members of the p160 family of cofactors, TIF2 (Voegel et al . , 1998, EMBO J. 17, 507-519) and SRC-3 (Torchia, et al . , 1997, Nature, 387, 677-684), have been shown to also interact with PPAR-gamma in a manner similar to SRC-1.
The Applicant has now investigated ' whether these different p160 family members can be specifically recruited by the compounds and compositions of the invention. Thus, according to special embodiments, the compounds and compositions of the present invention are furthermore characterized by a restricted cofactor (s) recruitment pattern. In preferred embodiments, 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. In more specific embodiments, 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. According to another embodiment, 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. Preferably, said 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 Alphascreen™ 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. In a preferred embodiment, 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 .
Accordingly, the present invention further concerns a composition comprising at least one compound of the invention as disclosed above and a pharmaceutically acceptable carrier or diluent. These 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.
Typical compositions of the present invention are associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, tablets, aerosols, solutions, suspensions or other container. In making the combination products, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compounds will usually be mixed with a carrier or a diluent, or diluted by a carrier or a diluent, or enclosed within a carrier or a diluent which may be in the form of a ampoule, capsule, sachet, paper, tablets, aerosols, solutions, suspensions or other container. 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. Typically, 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.
Some examples of 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 .
Similarly, 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. In one embodiment, 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. These can be prepared according to methods known to those skilled in the art, for example, as described in US 4,522,811. The pharmaceutical 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 .
The pharmaceutical compositions of the invention will typically be those which contain an effective amount of a compound of the invention. In general, an effective amount of a compound of the invention is a concentration of the said compound that will produce a 50% (EC50) increase in PPAR activity in a cell-based reporter gene assay, or a biochemical peptide sensor assay such as the assays described above.
For example, 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. For example, 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. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, alcohol and cellulose acetate.
Alternatively, the 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, preferably the PPAR-gamma, 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. Kardiol, 90, Suppl 3, 125-32). Diterpene acids and auronols (e.g. pseudolaric acids A and B) isolated from Pseudolarix kaempferi (Pan et al . , 1990, Planta. Med., 56, 383-385; Li et al . , 1999, J. Nat. Prod., 62, 767-769) have also been shown to activate PPAR-gamma and are expected to be useful in the practice of this invention. In one embodiment, 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] .
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. Chem., 39, 3897-3907), 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 (Berger et al . , 1999, J. Biol. Chem., 274, 6718- 6725) and indole-thiazolidinedione derivatives (Lohray et al . , 1998, J. Med. Chem., 41, 1619-1630).
Compounds disclosed or described in the following articles, patents and patent applications which have RXR agonist activity are incorporated by reference herein: US 5,399,586 and 5,466,861, WO96/05165, WO94/15901, W093/11755, WO94/15902, W093/21146, Boehm, et al . 1994, J. Med. Chem., 38, 3146-3155, Boehm, et al . 1994, J. Med. Chem., 37, 2930-2941, Antras et al . , 1991, J. Biol. Chem., 1266, 1157-1161. 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. 2- [1 - (3 , 5 , 5 , 8 , 8-pentamethyl-5 , 6 , 7 , 8- tetrahydro-2-naphthyl) -cyclopropyl] -pyridine-5-carboxylic acid) , 4- [ (3,5, 5, 8, 8-pentamethyl-5 , 6 , 7 , 8-tetrahydro-2- naphthy) -2-carbonyl] -benzoic acid, ( (E) -2- (2- ( (5 , 6 , 7 , 8-tetra- hydro-3, 5,5,8, 8-penta ethyl-2-naphthyl) propen-1 - yl) -4- thiophenecarboxylic acid) (AGN 191701), 2- (5 , 6 , 7 , 8-tetra- hydro-5, 5,8, 8-tetramethyl-2-naphthyl) -2- (carboxyphenyl) -1 , 3- dioxolane (SR 11237), 4- (5H-2 , 3- (2 , 5-dimethyl-2 , 5-hemano) -5- methyl-dibenzo (b,e) ( 1 , 4) diazepin-11 -yl) -benzoic acid (HX600) or thiadiazepin analogues thereof, 3 , 7 , 11 , 15-tetramethyl hexadecanoic acid (phytanic acid), 6- ( 1 - (3 , 5, 5 , 8 , 8- pentamethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl) cyclopropyl) nicotinic acid, ALRT 1057 (i.e. 9-cis retinoic acid, 2- (4- carboxyphenyl) -2- (5, 6, 7 , 8-tetrahydro-5, 5,8, 8-tetramethyl-2- naphthalen yl) -1 , 3-dithiane (SR11203), 4- (2-methyl) -1 - (5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2- naphthalenyl) propenyl) benzoic acid (SR11217), and the like or a pharmaceutically acceptable salt thereof.
Likewise, the compositions of the present invention can further comprise additional agents. Examples of such 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) . Literature provides to the skilled man with numerous examples of such additional agents.
The compounds and compositions containing the same of the present invention exhibit agonist, and preferably 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.
Accordingly, the compounds and compositions of the present invention are specially adapted to cure, improve or prevent one or more symptoms of diseases or pathologic conditions associated with cells types that express PPAR nuclear receptors. Thus, 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. It will be appreciated by those skilled in the art that the term "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. In preferred embodiment, 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 . More specifically, it is 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.
According to one embodiment of the present invention, there is provided a method for treating obesity, said method comprising administering to a patient in need of such treatment an amount of at least one compound or a composition of the invention. Preferably, 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. Thus there is a strong need for efficient therapy to- treat this disease which has been identified as a leading cause of coronary heart disease, Type II diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility and many other psychological and social problems. Additionally, obesity contributes to insulin resistance and diabetes.
Those of skill in the art recognize that there are numerous cell types which are capable of differentiation to produce "lipid-accumulating cells," such as, for example, mesenchymal cells (e.g., fibroblasts) . The terms "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.
In another embodiment, 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. During early stages of insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect. Within developed countries, 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.
Accordingly, in still another embodiment of the present invention, there is provided a method for modulating insulin- sensitivity and blood glucose levels in a patient, said method 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. As employed herein, 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. As noted previously, since the activity of different compounds of the present invention 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.
In another embodiment, 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. Numerous studies have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and VLDL and increasing HDL cholesterol leads to a significant reduction of cardiac events .
In yet another embodiment, the diseases or pathologic conditions according to the invention also include cellular proliferation, growth, differentiation, or migration disorders. As used herein, 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. Thus, 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. 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, Wilms ' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.
In other embodiments, 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 .
In still other embodiments, 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.
In another embodiment, 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) .
Other examples of disease or pathologic condition according to the invention 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) .
In preferred embodiment, 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...
Alternatively, 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.
According to the present invention, the term "patient" means a mammal, e.g., a primate, e.g., a human.
By "pharmaceutically effective dose" is meant 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. increasing the sensitivity of cellular response to circulating insulin, curing, reducing, or preventing one or more clinical symptoms of PPAR, preferably PPAR-gamma, related conditions, including, but not limited to, hyperglycemia, hyperinsulinemia and hypertriglyceridemia. In a preferred embodiment, a pharmaceutically effective dose of a compound or composition means an amount that increases the uptake of glucose by adipose tissue or muscle tissue. In another preferred embodiment, a pharmaceutically effective dose of a compound or composition means an amount that increases the uptake of triglyceride by adipose tissue. The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 0.1 mg to about 70 mg per day. In choosing a regimen for patients it may frequently be necessary to begin with a dosage of about 2 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about Q .1 to about 10 mg per day. The exact dosage will depend upon the mode of administration, on the therapeutic effect that • is intended to be achieved, the form in which the dosage is administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge. Dosages and treatment schedules are readily attainable by routine experimentation to those having ordinary skill in this art. Generally, the compounds are dispensed in unit dosage form comprising from about 0.1 to about 100 mg of active ingredient together with a pharmaceutically acceptable carrier per 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. Similarly, the treatment can be adapted to administer the compounds or compositions of the invention in a single weekly or monthly dose. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, 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. For oral administration, the 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. For any compound used in the method of the invention, 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. Such information can be used to more accurately determine useful doses in humans. 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.
According to a preferred embodiment, 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.
Compounds of the general formula (I) above described can be prepared using readily available starting materials or known intermediates.
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. For example, various allotypic PPAR-gamma receptor gene expression processes may be distinguished in sensitivity assays with the subject compounds and compositions, or panels thereof. In certain assays and in in vivo distribution studies, it is desirable to use labeled versions of the subject compounds and compositions, e.g. in radioligand displacement assays. Accordingly, the invention provides the compounds and compositions of the invention comprising a detectable label, which may be spectroscopic (e.g. fluorescent), radioactive, etc.
All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation. Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practised otherwise than as specifically described. Accordingly, those skilled in the art will recognize, or able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims .
These and other embodiments are disclosed or are obvious from and encompassed by the description and examples of the present invention. Further literature concerning any one of the methods, uses and compounds to be employed in accordance with the present invention may be retrieved from public libraries, using for example electronic devices. For example the public database "Medline" may be utilized which is available on Internet, e.g. under http : //www . ncbi . nlm . nih . gov/PubMed/medline . html . Further databases and addresses, such as http://www.ncbi.nlm.nih.gov/, http: //www. infobiogen. fr/ , http: //www. fmi . ch/biology/research_ tools.html, http://www.tigr.org/, are known to the person skilled in the art and can also be identified/located using, e.g., http://www.lycos.com. An overview of patent information in biotechnology and a survey of relevant sources of patent information useful for retrospective searching and for current awareness are given in Berks, TIBTECH 12 (1994), 352-364. FIGURE LEGENDS
Figure 1 : Synthesis of compound CRX101338
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 .
Figure 4 : Effect of CRX101338 on rosiglitazone induced mouse 3T3L1 cell adipogenesis
Figure 5 : Effect of CRX000143 on human PPAR-gamma in co-transfection assay (CV1 cells)
Figure 6 : Effect of CRX000143 on mouse 3T3L1 cell adipogenesis
Figure 7 : Effect of CRX000143 on basal and insulin Stimulated glucose uptake in mouse 3T3L1 adipocytes
Figure 8 : Effect of CRX000143 on body weight
Figure 9 : Effect of CRX000143 on Packed Red Cells Volume in diabetic db/db mice.
Figure 10 : Effect of CRX000143 on Glucose (10A) and Triglycerides (10 B) plasma levels in diabetic db/db mice
EXAMPLES Material
Plasmids :
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 : 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) .
In vitro assay Cotransfection assay
In order to test the ability of compounds of the invention to activate human PPAR-gamma, the following method can be used. CV1 cells (5 104 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) . After 16 hours, medium is changed to DMEM supplemented with L-Glutamine (2 mM) , 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 μl 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 μl are subject to luciferase assay whereas 30 μl are used for the betagal assay. Data are presented in RLU (Relative Light Unit) and EC50 were calculated using Prism software. Similar protocol can be used for testing the activity of compounds of the invention on human PPAR-alpha (using for example GW2433 as reference compound, Brown et al . 1997, J. Chem. Biol., 4,909-18)) and human PPAR-beta (using for example GW1516 as reference compound, Oliver et al. , 2001, Proc. Natl. Acad. Sci., 98, 5306-11).
Mammalian two hybrid
In order to test the ability of compounds of the invention to recruit the co-activator TIF2 , the following method can be used. CV1 cells (105 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-βGAL 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. Cells are then lysed with 100 μl lysis buffer (40mM TRIS pH 7.8, 2.14 mM MgCl2, 5.4 mM MgS04 , 0.2 mM EDTA, 66.6 mM DTT) and 50 μl are subject to luciferase assay whereas 30 μl are used for betagal assay. Data are presented in RLU (Relative Light .Unit) and EC50 were calculated using Prism software.
Adipocyte differentiation
To test the effect of compounds of the invention on adipogenesis, the well described mouse preadipocyte 3T3L1 cell system can be implemented. 3T3L1 cells are grown to confluence at 37°C, 5% C02, 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 μM or compounds of the invention at 10 μM, 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.
Insulin Stimulated Glucose Uptake (ISGU)
3T3L1 cells are grown to confluence at 37°C, 5% C02, 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 μg/ml), IBMX (500 μM) and Dexamethasone ' (1 μM) for 3 days. Cells are then treated for an additional 2 days with DMEM + 10% FCS and Insulin (10 μg/ml). Finally, cells are grown for another 2 days in DMEM +10% FCS to complete adipocyte differentiation. Rosiglitazone at 10 μM or compounds of the invention at 10 μM, both in DMSO 0.25% final are then added everyday to cells for 3 days. Cells are rinsed with serum-free DMEM twice and incubated for 3 hours at 37 °C, 5% C02- Cells are then washed four times with KRPH buffer (5 mM phosphate, pH 7.4 (NaH2P04-H20 + Na2HP0-7H20) , 20 mM HEPES pH 7.4, 1 mM MgS0 , 1 mM CaCl2, 136 mM NaCl, 4.7 mM KCl). The buffer is removed and the cells are incubated with or without 100 nM Insulin in KRPH buffer for 20 minuts at 37°C. The buffer is replaced with 0.25 μCi/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 μl of lysate is neutralized with 40 μl of 1N HCl and added in a scintillation vial with 4 ml of Ready SafeTm (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 .
In vivo assay
Hematocrit Assay
Male C57B6J 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. On the fifth day of treatment, 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 .
Anti-diabetic activity in db/άb mouse
Male Diabetic db/db 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 (C23Hι8N202S)
MM: 386,48 g.mol""1 MS (ESI+) : 387 RMN A (400 MHz, CDC13) δ (ppm): 3.88 (s, 3H) , 6.96 (m, 2H) , 7.16 (m, IH) , 7.37 (m, 1H), 7.40-7.52 (m, 4H) , 7.80 (m, 2H) , 7.98-8.03 (m, 3H) , 8.33 (s, 1H) .
Said compound has been named CRX101338.
More specifically, CRX101338 has been synthesized according to the following protocol :
Intermediate 1 : N-phenyl -N' - (l-thiophen-2-yl- ethylidene) -hydrazine
A solution of 1 -thiophen-2-yl-ethanone (1.08 ml, 9.9 mmol), phenyl-hydrazine (1ml, 9.86 mmol), and 5 drops of acetic acid in ethanol were heated at 80°C. After 6 hours, the solution was evaporated and diluted in ammonium hydroxyde (20 ml) . The solution was filtered and washed with water to give intermediate 1 (2.326g, quantitative) which was used without further purification.
Analytical data
C12H12Ν2S
MM: 216.31 g.mol"1
Mp : 96.4 - 97.5°C
Intermediate 2 : l-phenyl-3-thiophen-2-yl-lH- pyrazole-4-carbaldehyde
To a well stirred solution of DMF (2.2 ml) under argon at 0°C, was added dropwise a solution of phosphorus oxychloride (0.86 ml, 9.23 mmol). The mixture was stirred between 0 and 10°C for 0.5 hour. A solution of intermediate 1 (1 g, 4.62 mmol) in DMF (1.7 ml) was slowly added over 10 minutes. The mixture was stirred between 0 and 10°C for 1 hour and then an additional 2 hours at 60 °C. The mixture was cooled and neutralized with sodium carbonate to pH8. The precipitate was filtered, washed with water and recrystallized in methylene chloride to obtain a beige solid (878 mg, 75%) .
Analytical data
C1 4H1 0N2OS
MM: 254.31 g.mol"1
Mp : 98.3 - 98.7°C (lit. 94°C)
- 1- (4-methoxy-phenyl) -3- (l-phenyl-3-thiophen-2-yl-lH- pyrazol-4-yl) -propenone (CRX101338)
Figure imgf000083_0001
To a solution of Intermediate 2 (878 mg, 3.45 mmol) in 15 ml of 2-propanol was added 1 - (4-methoxy-phenyl) ethanone (519 mg, 33.46 mmol) while stirring at room temperature. The reaction mixture was heated to 50°C, and 1 ml of 20% aqueous sodium hydroxide was added. The mixture was stirred at 50°C for 0.5 hour then cooled to room temperature and stirred for an additional 3 hours. The separated precipitate was filtered off and crystallized from 2-propanol to afford example 1 (892 mg, 67%) as a yellow solid.
Analytical data
C23H18N202S
MM: 386,48 g.mol"1 MS (ESI+) : 387
Mp : 120°C
RMN 1H (300 MHz, DMSO) δ (ppm): 3.89 (s, 3H) , 7.12 (d, 2H, 9.00
Hz), 7.27 (m, 1H), 7.43 (m, 1H), 7.48 (m, 1H), 7.60 (t, 2H,
7.53 Hz), 7.73 (dd, 1H, 5.10 and 0.96 Hz), 7.81-7.96 (m, 4H) ,
8.13 (d, 2H, 8.85 Hz) .
EXAMPLE 2 : CRX101338 activates human PPAR-gamma.
The 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. 104 cells/ well of a 96 wells plate) were grown at 37 °C under a 5% C02 atmosphere in supplemented DMEM medium.
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 .
After 16 hours of cell growth, the medium was changed by fresh DMEM supplemented. Cells were then treated with increasing doses (from 1.10"10 M to 1.10"5 M, see Figure 2) of either rosiglitazone or compound CRX101338 and incubated for 24 hours as mentioned above.
Cells were lysed with 100 ul 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) .
Figure 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.
EXAMPLE 3. CRX101338 is a human PPAR-gamma partial agonist
To confirm the partial agonist activity of CRX101338, said compound was then tested in the mouse 3T3L1 cell differentiation functional assay (i.e. adipogenic effect measurement) .
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 .
The same treatment was repeated for an additional 2 days. Finally, cells were grown for other 2 days in supplemented DMEM and the adipogenic effect of the tested ligands was quantified through the measurement of triglyceride content using the Triglyceride GPO Tinder test (SIGMA) . Figure 3 confirms that 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.
Additionally the ability of CRX101338 to antagonize a PPAR- gamma ligand 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) .
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. Synthesis of "pyrazole 1,3,4" compounds of the invention .
The general synthesis protocol is as follows :
Intermediate 3 : N-phenyl-N' - [ (1-aryl (heteryl) ) - ethylidene] -hydrazine
Figure imgf000086_0001
A solution of the aryl methyl ketone (R1-CO-CH3) (1 eq) , phenyl-hydrazine (1 eq) , and 5 drops of acetic acid in ethanol were heated at 80°C. After 6 hours, the solution was evaporated and diluted in ammonium hydroxide. The solution was filtered and washed with water to give intermediate 3 (quantitative) which was used without further purification. Intermediate 4 : 1-phenyl-3-aryl (heteryl) -lH-pyrazole- 4-carbaldehyde
Figure imgf000087_0001
To a well stirred solution of DMF (2.2 ml) under argon at 0°C, was slowly added a solution of phosphorus oxychloride (9.23 mmol). The mixture was stirred between 0 and 10°C for 0.5 hour. A solution of intermediate 3 (4.62 mmol) in DMF (1.7 ml) was slowly added over 10 minutes. The mixture was stirred between 0 and 10°C for 1 hour and then an additional 2 hours at 60 °C. The mixture was cooled and neutralized with sodium carbonate to pH=8. The precipitate was filtered, washed with water and recrystallized in methylene chloride.
Intermediate 5 : l-phenyl-3-aryl (heteryl) -iH-pyrazole- 4-σarboxylic acid
Figure imgf000087_0002
To a stirred suspension of 50 mmol of intermediate 4 in 50 ml of 50% aqueous pyridine, cooled in a water bath, was added by small portions of potassium permanganate (7.9 g, 50 mmol) over 1 hour maintaining the temperature of the reaction at 20°C. The mixture was stirred till the violet color disappeared, the manganese dioxide precipitate was filtered, washed with 5% sodium hydroxide, and to the filtrate was added diluted hydrochloric acid. The precipitate of the carboxylic acid was filtered, dried, and recrystallized from glacial acetic acid.
Intermediate 6 : 1-phenyl-3-aryl (heteryl) -lH-pyrazole- 4-carbonyl chloride
Figure imgf000088_0001
To a suspension of intermediate 5 (2 mmol) in anhydrous toluene (15 ml) was added thionyl chloride (50 mmol), 3-4 drops of • dimethylformamide, and the mixture was heated to 110°C for 2 hours. Then the excess of thionyl chloride and solvent were removed under vacuum, the residue was washed with hexane and crystallized from a mixture toluene-hexane (3:1).
Example 5.1 : synthesis of compounds of general formula : l-aryl-3- (1-phenyl-3-aryl (heteryl) -lH-pyrazol-4-yl) -propenone
Figure imgf000088_0002
To a solution of intermediate 4 (1 eq) in 2-propanol was added aryl-ethanone R8 -CO-CH3 (1 eq) while stirring at room temperature. The reaction mixture was heated to 50 °C, and 1 ml of 20% aqueous sodium hydroxide was added. The mixture was
$7 stirred at 50 °C for 0.5 hour then cooled to room temperature and stirred for an additional 3 hours. The separated precipitate was filtered off and crystallized from 2-propanol to afford the compound.
This synthesis protocol has been used for preparing the following compounds of the invention :
Figure imgf000089_0002
Example 5.2 : synthesis of compounds of general formula 1-phenyl-3-aryl (heteryl) -lH-pyrazole-4-carboxamide
Figure imgf000089_0001
To a solution of intermediate 6 (2.5 mmol) in toluene (10 ml) while stirring was added the amine (NR16R ) (2.5 mmol) and triethylamine (0.4 ml). The mixture was heated to 110°C for 3 hours and left standing at room temperature for 12 hours. The solvent was evaporated, the residue was treated with water, filtered, dried, and crystallized from an appropriate solvent.
This synthesis protocol has been used for preparing the following compounds of the invention :
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
EXAMPLE 6. Compounds of the pyrazole 1,3,4 family activates human PPAR-gamma
In order to test the ability of the above described CRX101338, CRX156018, CRX156020, CRX156023, CRX156048, CRX156050, CRX156054, CRX143878, CRX143894 to activate human PPAR-gamma, CV1 cells (5.104 cells/ well of a 96 wells plate) were grown at 37 °C in a 5% C02 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. After 16 hours cell growth, the medium was changed to DMEM supplemented with L-Glutamine (2 mM) , penicilline / streptomycin, 10 % Delipidated Fetal Calf Serum. Cells were then treated with increasing doses (from 1.10M to 1.10 M see Figure 1) of either rosiglitazone or test compounds and incubated for 24 hours at 37 °C. Cells were lysed with 100 mul lysis buffer (40 mM TRIS pH 7.8 , 2.14 mM MgC12, 5.4 mM MgS04, 0.2 mM EDTA, 66.6 mM DTT) and 50 mul of lysate were subject to luciferase assay whereas 30 mul of lysate were used for the beta-galactosidase assay. Luciferase results were normalized to beta-galactosidase activity. Potency and efficacy was then calculated for each compound and are presented in table 1. Potency calculation derive from dose response experiment. It represent 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. Efficacy determine the maximum effect that can be achieved (Vmax) . The effect of compounds of the pyrazole 1,3,4 serie on human PPAR gamma tested by cotransfection assay is presented below :
Figure imgf000098_0002
EXAMPLE 7. Synthesis of "enone" compounds of the invention .
The general synthesis protocol is as follows :
Example 7.1 : synthesis of intermediate compounds
Intermediate 7 : N- (4-Flύoro-phenyl) -N' - (1 -pyridin-3- yl-ethylidene) -hydrazine
Figure imgf000098_0001
To 3-acetylpyridine (37.3 g, 308 mmol) in ethanol (1 L)are added 4-fluorophenyl-hydrazine hydrochloride (50 g, 308 mmol) and acetic acid (10 mL) . The mixture is heated at 80°C for 12 hours. The solution is evaporated to dryness, diluted in ammonium hydroxide (20 ml) and extracted with methylene chloride to afford N- (4-Fluoro-phenyl) - '-( 1 -pyridin-3-yl- ethylidene) -hydrazine (67.5 g, 96%) which can be used without further purification. Analytical data C13Hι2N3F
MM: 229.26 g.mol"1 Mp : 114-115°C Intermediate 8 : 1- (4-Fluoro-phenyl) -3-pyridin-3~yl- lH-pyrazole-4-carbaldehyde
Figure imgf000099_0001
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 intermediate 7 (67.5 g, 294 mmol) in DMF (75 ml) is slowly added over 10 minutes to maintain the temperature between 0 and 10°C. The reaction is stirred an additional 1 hour at this temperature and then an additional 3 hours at 60 °C. The mixture is cooled and neutralized with sodium carbonate to pH=8. The solution is extracted with methylene chloride to obtain 1 - (4-Fluoro-phenyl) -3-pyridin-3-yl-1 H-pyrazole-4- carbaldehyde as beige solid (68.8 g, 87%) .
Analytical data
C15H10N3OF
MM: 267.26 g.mol"1
Mp : 196-197°C
Intermediate 9 : 3-{1 - [ (4-chlorophenyl) - hydrazono] ethyl}pyridinium chloride
Figure imgf000100_0001
To a suspension of 4-chlorophenylhydrazine hydrochloride (40 g, 223 mmol) in 750 mL ethanol were added 3-acetylpyridme (25 mL, 227 mmol) and 5 drops of acetic acid. After 15 hours at 80 °C followed by a partial concentration of the mixture, the precipitate was filtered, washed with ethanol and dried under reduced pressure to give 3- {1 -[ (4-chlorophenyl) - hydrazono] -ethyl}pyridinium chloride as a yellow solid (55.9 g, 87 %) . Analytical data C13H13C12N3 MM: 282.17 g.mol"1
RMN 1H (400Mhz, DMSO-d6) δ (ppm) : 2.36 (s, 3H, CH3) , 7.29 (d, 1H, J = 8.48, Harora) , 7.39 (d, 1H, J = 9.08, Harom) , 8.00 (dd, 1H, J, = 8.48, J2 = 8.20, Harom) , 7.48-7.51 (m, 3H, Harora) , 8.78 (d, 1H,J = 5.52, Harora) , 8.86 (dd, 1H, J, = 8.20, J2 = 8.16, Harom) , 9.14 ( s, 1H, Hpyrazoie)
Intermediate 10 : 1 - (4-chlorophenyl) -3-pyridin-3-yl- 1 H-pyrazole-4-carbaldehyde
Figure imgf000100_0002
To a well stirred solution of DMF (50 ml) under argon at 0°C, was added dropwise a solution of phosphorus oxychloride (20 ml, 214.6 mmol). The mixture was stirred between 0 and
10°C for 0.5 hour. A solution of intermediate 9 (28.7 g, 101.5 mmol) in DMF (150 ml) was slowly added over 10 minutes. The mixture was stirred between 0 and 10°C for 1 hour and then an additional 2 hours at 60°C. The mixture was cooled, filtered and washed with DMF. The off-white solid was suspended in water and the solution was neutralized with sodium carbonate to pH=8. The precipitate was filtered, washed with water and dried at 40°C under reduced pressure to give 1-(4- chlorophenyl) -3-pyridin-3-yl-1 H-pyrazole-4-carbaldehyde as a slightly yellow solid (13.5 g, 47 %) .
Analytical data
Cl5H10ClN3O
MM: 283.72 g.mol"1
Mp : 222.2 °C
MS (ESI+) : 284.3 ;(ESI-): 282.4
Intermediate 11: N- ( 1 -Pyridin-3-yl-ethyl'idene) -N ' - (4- trifluoromethyl-phenyl) -hydrazine
Figure imgf000101_0001
To 3-acetylpyridine (20.6 g, 170 mmol) in ethanol (300 mL) are added (4-Trifluoromethyl-phenyl) -hydrazine (30 g, 170 mmol) and acetic acid (1 mL) . The mixture is heated at 60°C for 12 hours. The reaction mixture is treated with ammonium hydroxide 30% (100 ml) and then evaporated to dryness. The residue is washed with water to afford N- ( 1 -Pyridin-3-yl- ethylidene) -N '- (4-trifluoromethyl-phenyl) -hydrazine (44.7 g, 94%) which can be used without further purification. Analytical data Cι4H12F3N3
MM: 279.27 g.mol"1 MS (ESI+) : 280, MS (ESI-): 278 Intermediate 12 3-Pyridin-3-yl-l- ( 4 - trifluoromethyl-phenyl) -lH-pyrazole-4-carbaldehyde
Figure imgf000102_0001
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
DMF. The solid is dissolved in water and the solution neutralized with sodium carbonate to pH=8. The precipitate is filtered off and washed with water to obtain 3-Pyridin-3-yl-1 -
(4-trifluoromethyl-phenyl) -1 H-pyrazole-4-carbaldehyde as a white off solid in a 36% yield.
Analytical data
Cl6H10F3N3O
MM: 317.27 g.mol"1
MS (ESI+) : 318, MS (ESI-): 316
Intermediate 13 : [2- (4-Fluorophenyl) -2-oxoethyl] - triphenylphosphonium bromide
10'
Figure imgf000103_0001
To triphenylphosphine (6.30g, 24.0 mmol) in anhydrous diethtylether is added very slowly a solution of 4- fluorophenacylbromide (5.13 g, 23.6 mmol) in 10 mL diethyl ether. After 45 minutes stirring at room temperature, the precipitate is rapidly filtered, washed with ether and dried under reduced pressure.
Due to its apparently high hygroscopy, the white solid (8.37 g, 74 %) is rapidly used "as is" in the next step.
Intermediate 14: [2- (4-Chlororophenyl) -2-oxoethyl] triphenylphosphonium bromide
Figure imgf000103_0002
To triphenylphosphine (6.30g, 24.0 mmol) in anhydrous diethtylether is added very slowly a solution of 4- chlorophenacylbromide (23.6 mmol) in 10 mL diethyl ether. After 45 minutes stirring at room temperature, the precipitate is rapidly filtered, washed with ether and dried under reduced pressure to afford [2- (4-Chlororophenyl) -2-oxoethyl] - triphenylphosphonium bromide as a white solid.
Intermediate 15; [2- (4-trifluoromethylphenyl) -2- oxoethyl] -triphenylphosphonium bromide
Figure imgf000104_0001
To triphenylphosphine (6.30g, 24.0 mmol) in anhydrous diethtylether is added very slowly a solution of 4- trifluoromethylphenacylbromide (23.6 mmol) in 10 mL diethyl ether. After 45 minutes stirring at room temperature, the precipitate is rapidly filtered, washed with ether and dried under reduced pressure to afford [2- (4-trifluoromethylphenyl) - 2-oxoethyl] -triphenylphosphonium bromide as a white solid.
Intermediate 16: [2- (4-methoxy-phenyl) -2-oxoethyl] - triphenylphosphonium bromide
Figure imgf000104_0002
To triphenylphosphine (6.30g, 24.0 mmol) in anhydrous diethtylether is added very slowly a solution of 4-methoxy- phenacylbromide (23.6 mmol) in 10 mL diethyl ether. After 45 minutes stirring at room temperature, the precipitate is rapidly filtered, washed with ether and dried under reduced pressure to afford [2- (4-methoxy-phenyl) -2-oxoethyl] - triphenylphosphonium bromide as a white solid.
Intermediate 17 : [2- (4-trifluoromethoxy-phenyl) -2- oxoethyl] -triphenylphosphonium bromide
Figure imgf000105_0001
To triphenylphosphine (6.30g, 24.0 mmol) in anhydrous diethtylether is added very slowly a solution of 4- trifluoromethoxy-phenacylbromide (23.6 mmol) in 10 mL diethyl ether. After 45 minutes stirring at room temperature, the precipitate is rapidly filtered, washed with ether and dried under reduced pressure to afford [2- (4-trifluoromethoxy- phenyl) -2-oxoethyl] -triphenylphosphonium bromide as a white solid.
Intermediate 18: N-Phenyl-N ' - (1 -pyridin-3-yl-ethylid ene) -hydrazine
Figure imgf000105_0002
To 3-acetylpyridine (30 g, 248 mmol) in ethanol (700 mL) are added phenylhydrazine (26.8 g, 248 mmol) and acetic acid
(1 mL) . The mixture is heated at 60°C for 12 hours The reaction mixture is treated with ammonium hydroxide 30% (100 ml) and then evaporated to dryness. The residue is washed with hexane to afford N-Phenyl-N' -( 1 -pyridin-3-yl-ethylidene) - hydrazine (51.4 g, 98%) which can be used without further purification.
Analytical data
C1 3H1 3N3
MM : 2 1 1 . 27 g . mol" 1
MS ( ESI + ) : 2 1 2
Intermediate 19 1 -Phenyl-3-pyridin-3-yl-1 H-pyrazole
10- •4-carbaldehyde
Figure imgf000106_0001
A solution of phosphorus oxychloride (43.2 ml, 463 mmol) is added dropwise to a well stirred solution of DMF (95 ml) under argon atmosphere at 0°C. Intermediate 18 (49 g, 232 mmol) is added portionwise with DMF (150 ml) over 20 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 DMF. The solid is dissolved in water and the solution neutralized with sodium carbonate to pH=8. The precipitate is filtered off and washed with water to obtain 1 -Phenyl-3-pyridin-3-yl-1 H- pyrazole-4-carbaldehyde as a white off solid (25.1 g, 43%)
Analytical data
C15H1 1 N3O
MM : 249 . 27 g . mol" 1
MS ( ESI+ ) : 250
Example 7 .2 : synthesis of compounds of general formula
Figure imgf000106_0002
To a solution of the reactant "phosphonium salt" intermediate (ph. Int.) (5.4 mmol) m 30 mL anhydrous methanol was added a 0.5 M solution of MeONa in methanol (6 mmol) . After stirring during 25 minutes at room temperature, the mixture was condensed to dryness, twice coevaporated with toluene and suspended m 30 mL toluene.
To this suspension, the reactant "aldehyde" intermediate (aid. Int.) (2.7 mmol) was very slowly added directly as a powder. After stirring overnight at 110 °C, the mixture was concentrated and purified by flash chromatography on silica gel to give the product as a solid.
This synthesis protocol has been used for preparing the following compounds of the invention :
Figure imgf000108_0001
Figure imgf000109_0001
10!
Figure imgf000110_0001
Figure imgf000111_0002
EXAMPLE 8. CRX000143 activates human PPAR-gamma
1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-pyridin-3-yl- 1 H- pyrazol-4-yl) -propenone (CRX000143) is of formula :
Figure imgf000111_0001
In order to test the ability of CRX000143 to activate human PPAR-gamma, CV1 cells (5 104 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) . After 16 hours, medium was changed to DMEM supplemented with L-Glutamine (2 mM) , penicilline / streptomycin, 10 % Delipidated Fetal Calf Serum and cell were treated with increasing dose (1 10"10 M to 1 10"5 M) of either rosiglitazone or CRX000143 for 24 hours. Cells were then lysed with 100 μl lysis buffer and 50 μl were subject to luciferase assay whereas 30 μl were used for the betagal assay. Data are presented in RLU (Relative Light Unit) and EC50 were calculated using Prism software.
As shown in figure 5, EC50 obtained for rosiglitazone was similar to the one described in the literature (40 nM) . In the same experiment; CRX000143 was shown to activate human PPAR-gamma with an EC50 of 141 nM. '
EXAMPLE 9. 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. To confirm its partial agonist activity, CRX000143 was then tested in the- functional mouse 3T3L1 cell differentiation assay.' 3T3L1 cells were grown to confluence at 37°C, 5% C02, 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 μM or CRXO 00143 at 10 μM, 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) .
Figure 6 confirms that 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% C02, in a 48 well plate in DMEM supplemented with L-Glutamine (2 mM) , penicilline / streptomycin, 10 % Calf Serum. Two days post confluence, cell medium was 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 μg/ml), IBMX (500 μM) and Dexamethasone (1 μM) for 3 days. Cells were treated for an additional 2 days with DMEM + 10% FCS and Insulin (10 μg/ml). Finally, cells were grown for another 2 days in DMEM +10% FCS to complete 5 adipocyte differentiation.
Rosiglitazone at 10 μM or CRX000143 at 10 μM, both in DMSO 0.25% final, was added everyday to cells for 3 days. Cells were rinsed twice with serum-free DMEM and incubated for 3 hours at 37 °C, 5% C02- Cells were washed four times with KRPH ) buffer (5 mM phosphate, pH 7.4 (NaH2P04-H20 + Na2HP04-7H20) , 20 mM HEPES pH 7.4, 1 mM MgS04, 1 mM CaCl2, 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 μCi/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 μl of lysate was neutralized with 40 μl of 1N HCl and added in a scintillation vial with 4 ml of Ready SafeTm (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.
EXAMPLE 11. CRX000143 is a human PPAR-gamma partial agonist showing antidiabetic activity, ameliorating lipid profile but showing reduced side effects .
Male Diabetic db/db mice 8 weeks old were 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 CRX000143 at 10 mg/kg/day. As shown in Figure 8, animal treated with rosiglitazone gained more weight over the time of the experiment as compared to vehicle (17,8 +/- 3,8 vs. 10 +/- 3,2; p = 0,0007) whereas animals treated with CRX000143 did not gain extra weight compared to vehicle (7,6 +/- 2,8 vs 10 +/- 3,2, ns) .
At the completion of the experiment, the hematocrit was quantified by measurement of percentage of Packed Red Cells Volume- (PCV) in blood. As shown in Figure 9, Rosiglitazone provokes a significant reduction in PCV (54,1 +/- 1,2 vs. 57,8 +/- 2,6 for vehicle, p=0,004), whereas CRX000143 effect is only 32% of the one for rosiglitazone (56,6 +/- 1,9 vs. 57,8 +/- 2,6 for vehicle, ns) . As shown in Figure 10A, when plasma parameters were analyzed 7 days after initiation of the treatment, CRX000143 shows similar effect on plasma glucose levels compared to rosiglitazone (+16 ± 12, -8 + 7 and -10 ± 27, respectively, for vehicle, rosiglitazone and CRX000143 treated animals, p=0,0004 and 0,03 respectively for rosiglitazone and CRX000143 compared to vehicle).
As shown in Figure 10B, a similar pattern was obtained when plasma triglycerides (TG) were measured with an effect for vehicle, rosiglitazone and CRX000143 of +26 ±'37, -49 ± 16, -12 ± 13, respectively (p=0,0004 and 0,02, respectively, for rosiglitazone and CRX000143. compared to vehicle). In addition to triglycerides, both rosiglitazone and CRX000143 have a positive effect on plasma HDL-Cholesterol (respectively + 6,6 ± 6,7 and 5,7 ±10 vs. -0,4 ± 6,8 for vehicle).
EXAMPLE 12 . Synthesis of CRX000790
Intermediate 20 : 4- [N' - (l-Thlophen-2-yl-ethylldene) - hydrazlno] -benzole acid ethyl ester
Figure imgf000115_0001
To a suspension of 4-hydrazinobenzoic acid (2.02 g, 13 mmol) in 15 mL ethanol were added 3-acetylthiophene (1.5 mL, 13 mmol) and concentrated sulfuric acid (3 mL) . After 12 hours at 80 °C the mixture was partially concentrated and diluted in ammonium hydroxide (20 ml) . The resulting precipitate was filtered, washed with water and dried under reduced pressure to give a yellow solid (3.22 g, 86 %) .
Analytical data
C15Hl6N202S
MW: 288.36 g.mol"1 MS (ESI+) : 289.3 ;(ESI-): 287.4
1H NMR (400 MHz, CDC13) δ (ppm) : 1.42 (t, 3H, J = 1.48, CH3) , 2.28 (s, 3 H, CH3) , 4.39 (q, 2H, J = 7.00, CH2) ,7.03 (dd, 1H, J = 4.96, Harom) , 7.15-7.19 (m, 3H, Harom) , 7.30 (dd, 1H, J = 4.96, Harom) , 7.60 (s, 1H, Hpyrazole) , 7.97-8.01 (t, 2H, Harom) - Intermediate 21 : 4- (4-Formyl-3-thiophen-2-yl- pyrazol-1-yl) -benzoic acid ethyl ester
Figure imgf000116_0001
To a well stirred solution of DMF (10 ml) under argon at 0°C, was added dropwise a solution of phosphorus oxychloride (3.6 ml, 38.6 mmol). The mixture was stirred between 0 and 10°C for 0.5 hour. A solution of intermediate 20 (5.59 g, 19.3 mmol) in DMF (20 ml) was slowly added over 10 minutes. The mixture was stirred between 0 and 10°C for 1 hour, at room temperature for 1 hour and then additional 2 hours at 60 °C. The mixture was cooled and neutralized with sodium carbonate to pH=8. The precipitate was filtered, washed with water and dried at 40 °C under reduced pressure to give a slightly brown solid (4.5 g, 71 %) .
Analytical data
Cι7H14N203S
MW: 326.37 g.mol"1
MS (+APCI) : 327.1
1H NMR (400MHz, CDCl3) δ (ppm) : 1.41 (t, 3H, J = 4.76, CH3) ,
4.43(q, 2H, J = 6.96, CH2) , 7.18 (dd, 1H, J = 5.12, Harora) , 7.46
(dd, 1H, J = 5.12, Harom) ,7.87 (d, 2H, J = 8.80, Harora) , 7.95 (dd,
1H, Harom) , 8.19 (d, 2H, J = 8.76, Harom) , 8.59 (s, 1H, Hpyrazole) ,
10.17 (s, 1H, Hald)
Intermediate 22 : 1- (4-Ethoxyσarbonyl -phenyl) -3- thiophen-2-yl-lH-pyrazole-4-carboxylic acid
Figure imgf000117_0001
To a well stirred solution of Intermediate 21 (4.52 g, 13.8 mmol) in THF (40 mL) was added tert-butanol (40 mL) , 1,3-
> dimethylbut-2-ene (11 mL, 103.5 mmol) and a mixture of sodium hypochlorite (12.5 g, 138 mmol) and sodium hydrogenophosphate
(12.4 g, 103.5 mmol) in water (40 mL) . The mixture was stirred at room, temperature for -2.5 hours. After decantation, the organic phase was concentrated, diluted in ethyl acetate,
) washed with water and brine, then dried on sodium sulfate, filtered and concentrated to give a white solid (1.54 g, 33 %) •
Analytical data 5 C17H14N204S
MW: 342.37 g.mol"1 MS (ESI-) : 341.5 ; (ESI+) : 343.3
1H NMR (400MHz, CDCl3) δ (ppm) : 1.5 (t, 3H, J = 7.04, CH3) ,
4.43(q, 2H, J = 7.04, CH2) , 7.18 (dd, 1H, J = 4.96, Harom) , 7.65 (dd, 1H, J = 4.96, Harom) ,8.12 (m, 4H, Harom) , 8.19 (dd, 1H, J =
3.52, Harora) i 9.23 (S, In, Hpyrazole/
Intermediate 23: 4- (4-Chloroσarbonyl-3-thiophen-2-yl- pyrazol-1-yl) -benzoic acid ethyl ester
Figure imgf000118_0001
To a suspension of intermediate 22 (0.88 mmol) in anhydrous toluene (15 ml) was added thionyl chloride (17.6 mmol), the mixture was heated to 110°C overnight and then the excess of thionyl chloride and solvent were removed under vacuum'.' The crude product was used without purification.
Synthesis of 4- [4- (4-Methoxy-phenylcarbamoyl) -3-thiophen- 2-yl-pyrazol-l-yl] -benzoic acid ethyl ester [CRX000790]
Figure imgf000118_0002
To a solution of intermediate 23 (0.88 mmol) in toluene
(10 ml) while stirring were added the 4-methoxyaniline (0.70 mmol) and triethylamine (2.64 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was diluted in EtOAc and washed with HCl 1N. The organic phase was separated and washed with satured NaHC03 solution, then dried (Na2S04) , filtered and evaporated. The crude product was purified by silica gel chromatography (heptane/EtOAc 8:2) to afford the title compound (30 %) as a pale brown solid.
Analytical data C24H21N304S MW: 447.52 g.mol"1
MS (ESI-, M+HCOO") : 492.1
1H NMR (400 MHz, CDC13) δ (ppm) : 1.45 (t, J = 7.0 Hz, 3H,
CH3) , 3.82 (s, 3H, OCH3) , 4.43 (q, J = 7.0 Hz, 2H, OCH2) , 6.88
(d, J = 5.6 Hz, 2Harθm) , 7.24 (t, J = 4.6 Hz, lHarora), 7.39 (d, J = 8.8 Hz, 2Harom) , 7.56 (d, J = 5.3 Hz, lHarom), 7.63 (d, J = 3.5
Hz, 1Harom), 7.76 (s, 1Harom), 7.87 (d, J = 8,5 Hz, 2Harom) , 8.19
(d, J = 8.5 Hz, 2Harom) , 8.62 (s, Hpyrazoιe) .
11.

Claims

1. A compound of the following general formula (I]
Figure imgf000120_0001
or analogues, derivatives, solvates or salts thereof, wherein ■ :
R1 is a moiety selected in the group consisting of : (i)
Figure imgf000120_0002
(ϋ)
Figure imgf000120_0003
Figure imgf000120_0004
( iv) H , CF3 , - ( CH2 ) n-R3 and - Cn,H 2n' + 1
with :
R3 is a moiety selected in the group consisting of H, a C!_4 alkyl moiety (esp. methyl),
(CH2)n-CONR13R5, -C02R4, -COR4 (esp. -CO- methyl or -CONH2) , -OR4 (esp. -O-methyl) , -
(CH2)n-C02R4, -(CH2)n-COR4, -(CH2)n-OR4, -NR13R5,
- (CH2)n-NR13R5, -NH-COR4 , - (CH2) n-NH-COR4, - - Cl, -F, -(CH2)nC02H, -0-
(CH2)nC02H, -(CH2)n-TZD, -O- (CH2) n-TZD, -CN, - N02, -OH, -OCF3, -COCF3, -CF3, -N(CnΗ2n'+ι.
2.
- S02-N(R9) (R9*) , -NR9-S02CF3, and -NR9-S02- CnΗ2n,+1 (e.g. -NR9-S02butyl) ; R4 is a moiety selected in the group consisting of H, -Cn/H2n'+i (e.g. C-|_ alkyl moiety such as methyl and ethyl), -(CH2)nC02H, -NH2 ', -(CH2)n- TZD, -OH, -N(Cn'H2n'+i)2/ -NR9-S02CF3 and -NR9- S02-Cn,H2n'+i (e.g. -NR9-S02butyl) ; R5 and R13 are, independently from one another, a moiety selected in the group consisting of H, a Cι_ alkyl moiety (e.g. methyl and ethyl) , - S02CF3 and -S02-Cn>H2n'+ι (e.g. S02butyl) ;
R6 and R7 are, independently from one another, a moiety selected in the group consisting of H, an alkyl, more specifically a C-ι_ alkyl moiety, a C5 cycloalkyl moiety (e.g. a cyclohexyl or a' phenyl moiety) , or a C7 cycloalkyl moiety (e.g. a cycloheptyl or a benzyl moiety) , -S02CF3, -S02-CnΗ2n''+ι (e.g.
-S02Butyl) , a benzyl moiety or phenyl moiety substituted at position 2 and/or 3 and/or 4 with a moiety selected in the group consisting of -OCn,H2n>+1 , -Cl, -F, -(CH2)nC02H, -0-(CH2)nC02H, -(CH2)n-TZD, -0- (CH2) n-TZD , -CN, -N02, -Cn,H2n'+ι , -C0-Cn H2n'+ι -S02-Cn,H2n^+ι , -NR9-S02CF3, -NR9-S02-Cr,,H2n,+ 1 (e.g. -NR9-S02butyl) , -OCF3, -COCF3, -CF3;
R9 and R9* are, independently from one another, a moiety selected in the group consisting of H, -CO-Cn/H2n , +ι , -S02-Cn/H2n.+1 , and a C1_4 alkyl moiety ; Ai , A2, A3 and A4 are an atom selected in the group consisting of C, N, S and 0 ; the moiety :
Figure imgf000122_0001
is intended to designate :
(v) a mono carbocyclic ring (i.e. a cyclic carboalkyl, with A-i , A2, A3 and A4 are C) ;
(vi) a mono heterocyclic ring (i.e. a cyclic heteroalkyl, with at least one A-i , A2, A3 and/or A is selected in the group consisting of N, S and 0) ;
(vii) a bi- carbocyclic ring (i.e. a bicyclic carboalkyl with A3, A and A5 are C) ; (viii) a bi- heterocyclic ring (i.e. a bicyclic heteroalkyl with at least one cyclic ring is containing at least one A3, A and/or A5 selected in the group consisting of N, S and 0) ; selected in the group consisting of :
Figure imgf000123_0001
(ϋ)
Figure imgf000123_0002
!ϋi)
Figure imgf000123_0003
with : 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„,H2n' +ι)-, -C(Cn ,H2„, +1)2-, -CH2-, -N- , -NR9-, -NR7-, -S02-, -S (CnH2n/+ ) - and -CHOH- where R7 and R9 are as above mentioned;
R ,11 and R12 is a moiety selected in the group consisting of H, a
,13π5 d-4 alkyl moiety, - (CH2) n-CONR-' JR°, -C02R\ -COR", -OR"
;CH2)n-C02R4, -
Figure imgf000123_0004
- (CH2)n-NR ,1I3J-R53
NH-COR* - (CH2) n-NH-COR4' -OCn,H2n- + 1 -Cl, -F, -(CH2)nC02H,
-0- (CH2)nC02H, - (CH2) n-TZD, -O- (CH2) n-TZD, -CN, -N02, -OH,
-0CF3, -COCF3 , -CF3, -N(Cn,H2n,+1)2, - S02-N(R9) (R9*) , -NR9-S02CF3, -NR9-S02-CnΗ2n/+ι (e.g. -NR9-S02butyl) , and :
Figure imgf000123_0005
with in all the above : n is, independently from one another, an integer ranging from
0 to 6, n' is, independently from one another, an integer ranging from
1 to 4, preferably from 1 to 3 and preferably from 1 to 2 ;
R8 and R8 are, independently from one another, a moiety selected in the group consisting of H, -Cn.H2n.+1 , a C6 cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), -OCn/H2n'+ι , -Cl, -F, -(CH2)nC02H, - CF3, -0CF3, -C0CF3, -0-
(CH2)nC02H, -(CH2) n-TZD, -0- (CH2) n-TZD, -CH-(CH2)n , -(CH2)n- N(R9) (R9*) , -CN, -NC-2, -(CH2)n-CO-C„,H2n' + ι. - (CH2) n-CO-N (R9) (R9*) , - S02-N(R9) (R9*) , -NR9-S02CF3, - (CH2) n-CO-cycloalkyl (e.g. -
CO-cyclohexyl or -CO-phenyl) , -0-(CH2)n- cycloalkyl (e.g.
-0- (CH2) n-cyclohexyl or -0- (CH2) n-phenyl) , - (CH2) n-cycloalkyl
(e.g. - (CH2) n-cyclohexyl or - (CH2) n-phenyl) , • -NR9-S02-Cn,H2n , ι
(e.g. -NR9-S02butyl) ;
R10 and R10* are, independently from one another, a moiety selected in the group consisting of H, an alkyl, more specifically a Cι_4 alkyl moiety, a C6 cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety), or a C7 cycloalkyl moiety (e.g. a cycloheptyl or a benzyl moiety) , -Cl, -0CnΗn'+ι - CF3, -0CF3, _ -C0CF3,-CN, -N02 ; and TZD is
Figure imgf000124_0001
The compound of claim 1 wherein the R1 moiety
Figure imgf000125_0001
is intended to designate
(v) a R substituted mono carbocyclic ring (i.e. a cyclic carboalkyl, with Ai , A2, A3 and A4 are C) ;
(vi) a R3 substituted mono heterocyclic ring (i.e. a cyclic heteroalkyl, with at least one A-i , A2, A3 and/or A is selected in the group consisting of N, S and 0) ;
(vii) a R 3J substituted bi- carbocyclic ring (i.e. a bicyclic carboalkyl with A3, A4 and A5 are C) ;
(viii) a R3 substituted bi- heterocyclic ring (i.e. a bicyclic heteroalkyl with at least one cyclic ring is containing at least one A , A4 and/or A5 selected in the group consisting of N, S and O) .
3. The compound of claim 1 or 2 wherein the R1 moiety is selected in the group consisting of :
Figure imgf000125_0002
Figure imgf000125_0003
Figure imgf000125_0004
Figure imgf000126_0001
with X is a moiety selected in the group consisting of 0, N and S .
4. The compound of claims 1 to 3 wherein the linker in structure Rι2 is selected in the group consisting in
Figure imgf000126_0002
Figure imgf000126_0003
5. A compound of claims 1 to 4 selected in the group consisting in :
1 - (4-methoxy-phenyl) -3- [1 -phenyl-3- (thiophen-2-yl) -1H- pyrazol-4-yl]propen-1 -one (CRX101338) , 1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-pyridin-3-yl-1 H-pyrazol- 4-yl) -propenone (CRX000143),
1 - (4-Methoxy-phenyl) -3- ( 1 -phenyl-3-pyridin-4-yl-1 H-pyrazol- 4-yl) -propenone (CRX000144),
3- [3- (4-Methoxy-phenyl) -1 -phenyl-lH-pyrazol-4-yl] -1 -phenyl- propenone (CRX156707),
1 - (4-Chloro-phenyl) -3- (1 , 3-diphenyl-1 H-pyrazol-4 -yl) - propenone (CRX156701)
1 - (4-methoxy-phenyl) -3- [1 -phenyl-3- (thiophen- 3-yl) -1H- pyrazol-4-yl]propen-1-one (CRX000270) , i 1 -phenyl-3- (1 -phenyl-3-pyridin-3-yl-1H-pyrazol-4-yl) - propenone,
1 - (4-ethyl-phenyl) -3- (1 -phenyl-3-pyridin-3-yl-1 H-pyrazol-4- yl) -propenone,
3- ( 1 , 3-diphenyl-1 H-pyrazol-4-yl) -1 - (4-methoxy- ) phenyl) propenone (CRX156023),
1 - (4-ethyl-phenyl) -3- (1 -phenyl-3-pyridin-3-yl-lH-pyrazol-4- yl) -propenone,
3- (4-chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide, 3- (4-chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-acetyl~phenyl) -amide,
1 , 3-diphenyl-1 H-pyrazole-4-carboxylic acid (4-methoxyphenyl) -amide ,
1 -phenyl-3-p-tolyl-1 H-pyrazole-4-carboxylic acid (4-methoxy- phenyl-amide,
3- (3 , 4-dimethoxy-phenyl) -1 -phenyl- 1 H-pyrazole-4-carboxylic acid (4-chloro-phenyl) -amide, 1 -Phenyl-3-m-tolyl-1H-pyrazole-4-carboxylic acid (4-methoxyphenyl) -amide (CRX000314),
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid benzylamide, 1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methyl-benzyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- methyl-benzyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- chloro-benzyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- chloro-benzyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methoxy-benzyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid cyclohexyl-amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid cyclohexylmethyl-amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- methoxy-benzyl) amide,
1- phenyl -3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid (4- trifluoromethyl-benzyl) amide,
1- phenyl -3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid (3- trifluoromethyl-benzyl) -amide, 1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid phenyl-amide ,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- chloro-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- chloro-phenyl) -amide (CRX000186) , 1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- trifluoromethyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- trifluoromethyl-phenyl) -amide, 1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- nitro-phenyl) -amide, *
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- nitro-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid phenetyl-amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid [2- (4-chloro-phenyl) -ethyl] -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid [2- ( 4-methoxy-phenyl) -ethyl] -amide,
1- phenyl -3-thiophen-2-yl-1 H-py'razole-4-carboxylic acid [2- (3-chloro-phenyl) -ethyl] -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- methoxy-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- benzyloxy-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methyl-phenyl) -amide, 1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- methyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid (4- butyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- cyclohexyl-phenyl) -amide, 1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid [2- (3-methoxy-phenyl) -ethyl] -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- acetyl-phenyl) -amide,
5 1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- carbamoyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid (4- dimethylamino-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- ■"1 carbamoyl-phenyl) -amide,
1- phenyl -3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid biphenyl-4-yl amide,
1- phenyl -3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- benzoyl-phenyl) -amide, i 1 -phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- sulfamoyl-phenyl) -amide,
1 -phenyl-3-pyridin- 2-yl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide,
1 -phenyl-3-pyridin-3-yl-1 H-pyraz.ole-4-carboxylic acid (4- ) methoxy-phenyl) -amide,
1 -phenyl-3-pyridin-4-yl-1H-pyrazole-4-carboxylic acid(4- methoxy-phenyl) -amide,
3- (3-chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide,
25 3- (2-chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide,
3- (4-trifluoromethyl-phenyl) -1 -phenyl-1 H-pyrazole-4- carboxylic acid (4-methoxy-phenyl) -amide,
3- (3-trifluoromethyl-phenyl) -1 -phenyl-1 H-pyrazole-4- 30 carboxylic acid (4-methoxy-phenyl) -amide, 3- (2-trifluoromethyl-phenyl) -1 -phenyl-1 H-pyrazole-4- carboxylic acid (4-methoxy-phenyl) -amide,
3- (3-methyl-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl ) -amide ,
5 3- (4-methoxy-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid ( 4-methoxy-phenyl ) -amide ,
3-furan-2-yl-1 -phenyl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide,
3- (4-methyl-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid Λ) (4-methoxy-phenyl) -amide,
3- (3, 4-Dimethoxy-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide,
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid pyridin- 2-ylamide,
5 1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid pyridin-3-ylamide ,
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid pyridin-4-ylamide,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid . (pyridin-2-ylmethyl) -amide,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (pyridin-3-ylmethyl) -amide,
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (pyridin-4-ylmethyl) -amide 5 1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl) -propan-1 -one (CRX000141)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- carbamoy1-phenyl) -amide (CRXO00142)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid (4- 0 trifluoromethyl-phenyl) -amide (CRX000145) 1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid (4- acetyl-phenyl) -amide (CRX000146)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid (4- benzyloxy-phenyl) -amide (CRX000149) 1 -Phenyl-3-pyridin-3-yl-1H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide (CRX000151 )
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid benzylamide (CRX000155)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid phenethyl-amide (CRX000156)
1 -Phenyl-3-pyridin-4-yl-lH-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide (CRX000158)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid methyl-phenyl-amide (CRX000165)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -methyl-amide (CRX000167 )
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- carbamoyl-phenyl) -amide (CRX000172)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid p- tolylamide (CRX000174)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide (CRX000176)
1 -Phenyl-3- (4-trifluoromethyl-phenyl) -1 H-pyrazole-4- carboxylic acid (4-methoxy-phenyl) -amide (CRX000181) 1 -Phenyl-3- ( 2-trifluoromethyl-phenyl) -1 H-pyrazole-4- carboxylic acid (4-methoxy-phenyl) -amide (CRX000182)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid phenylamide (CRX000183)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 4- methoxy-benzylamide (CRX000184)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid (4- dimethylamino-phenyl) -amide (CRX000185)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- chloro-phenyl) -amide (CRX000188) 1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid m- tolylamide (CRX000189)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid (3- trifluoromethyl-phenyl) -amide (CRX000190) 1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid 4- trifluoromethyl-benzylamide (CRX000203)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid [2- (4-chloro-phenyl) -ethyl] -amide (CRX000205)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- butyl-phenyl) -amide (CRX000206)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (2- phenoxy-ethyl) -amide (CRX000207)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid 4- chloro-benzylamide (CRX000208)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 3- chloro-benzylamide (CRX000209)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 3- methyl-benzylamide (CRX000210)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid 4- methyl-benzylamide (CRX000211 )
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (3- methoxy-phenyl ) -amide (CRXO00212)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid [2- (3-chloro-phenyl) -ethyl] -amide (CRX000213) 1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- benzoyl-phenyl) -amide (CRX000214)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid [2- (4-methoxy-phenyl) -ethyl] -amide (CRX000215)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid [2- (3-methoxy-phenyl) -ethyl] -amide (CRX000216)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- cyclohexyl-phenyl) -amide (CRX000218)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid cyclohexylmethyl-amide (CRX000220) 3-Furan-2-yl-1 -phenyl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide '(CRX000233)
3-Furan-2-yl-1 -phenyl-1 H-pyrazole-4-carboxylic acid 4- methoxy-benzylamide (CRX000234) 1 - (4-Methoxy-phenyl) -3- (3-methyl-1 -phenyl-1 H-pyrazol-4-yl) - propenone (CRX000235)
3- (2-Chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid 4-methoxy-benzylamide (CRX000237)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid methyl-p-tolyl-amide (CRX000245)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid (3- chloro-phenyl) -methyl-amide (CRX000246)
4- (4-Methoxy-benzyloxymethyl) -1 -phenyl-3-thiophen-2-yl-1 H- pyrazole (CRX000248)
3- (2-Chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide (CRX00025 )
3- (3-Chloro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide (CRX000255)
3- [3- (4-Chloro-phenyl) -1 -phenyl-1 H-pyrazol-4-yl] -1 - (4- methoxy-phenyl) -propenone (CRX000256)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid 3- methoxy-benzylamide (CRXO00261 )
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid cyclohexylamide (CRX000263) 1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid biphenyl-4-ylamide (CRX000264)
1 - (4-Methoxy-phenyl) -3- [3- (4-methoxy-phenyl) -1 -phenyl- 1H- pyrazol-4-yl] -propenone (CRX000273)
4-Methyl-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRXO00275)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid ethyl-phenyl-amide (CRX000276)
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid benzyl-phenyl-amide (CRX000277) 3-Methyl-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRX000278)
(4-Methoxy-benzyl) - (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethylene) -amine (CRX000281 ) 1 - (4-Methoxy-phenyl) -3- (1 -phenyl-1 H-pyrazol-4-yl) -propenone (CRX000284)
1 - (4-Methoxy-phenyl) -3- [3- (1 -methyl- 1 H-pyrrol-3-yl) -1 - phenyl-1 H-pyrazol-4-yl] -propenone (CRX000285)
3- (3-Furan-2-yl-1 -phenyl-1 H-pyrazol-4-yl) -1 - (4-methoxy- phenyl) -propenone (CRX000287)
(4-Methoxy-benzyl) - ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -amine (CRX000291 )
1 -Phenyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid methyl-phenethyl-amide (CRX000303) i N- ( 1 -Phenyl-3-thiophen- 2-yl-1 H-pyrazol-4-yl) -2-m-tolyl- aceta ide (CRX000304)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid (3,4- dichloro-phenyl) -methyl-amide (CRX000305)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid (4- ) sulfamoyl-phenyl) -amide (CRX000308)
1 -Phenyl-3-m-tolyl-1 H-pyrazole-4-carboxylic acid 4-methoxy- benzylamide (CRX000315)
3-Methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRXO00332) N- (1 -Phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl) -3- trifluoromethyl-benzamide (CRX000336)
3 -Chloro-N- (1 -phenyl-3-thiophen- 2-yl-1 H-pyrazol-4-yl) - benzamide (CRXO00338)
Benzyl-methyl- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethy1) -amine (CRXO00342)
1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-m-tolyl-1 H-pyrazol-4-yl) - propenone (CRX000347)
4- [3- (4-Methoxy-phenyl) -3-oxo-propenyl] -1 -phenyl-1 H- pyrazole-3-carboxylic acid benzylamide (CRX000349) (4-Methoxy-benzyl) -methyl- (1 -phenyl-3-thiophen-2-yl-1 H- pyrazol-4-ylmethyl) -amine (CRX000350)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid [2- (4-methoxy-phenyl) -2-oxo-ethyl] -amide (CRX000357) 1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid 3- trifluoromethyl-benzylamide (CRX000358)
1 -Phenyl-3-thiophen-2-yl-lH-pyrazole-4-carboxylic acid ethyl-m-tolyl-amide (CRX000359)
N- (4-Methoxy-benzyl) -N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-ylmethyl) -methanesulfonamide (CRX000362)
4-Methoxy-N- (2-phenyl-5-thiophen-2-yl-2H-pyrazol-3-yl) - benzamide (CRX000365)
N-(1~Phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl) -4- trifluoromethyl-benzamide (CRXO00378) i N- (1 -Phenyl-3-thiophen-2-yl-lH-pyrazol-4-yl) -2-p-tolyl- acetamide (CRX000379)
(1 -Phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl) -carbamic acid benzyl ester (CRX000382)
3-Phenyl-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - ) propionamide (CRX000383)
4-Methoxy-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRXO00392)
2- (3-Chloro-phenyl) -N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl)-acetamide (CRX000394) 4-Acetyl-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzamide (CRXO00395)
N- (1 -Phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl) -benzamide (CRX000396)
1 -Phenyl-3-thiophen-2-yl-1H-pyrazole-4-carboxylic acid methyl- (2-trifluoromethyl-phenyl) -amide (CRX000401 )
4-Dimethylamino-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- yl) -benzamide (CRX000402)
4- [3- (4-Methoxy-phenyl) -propenyl] -1 -phenyl-3-thiophen-2-yl- iH-pyrazole (CRX000417) 2- (4-Methoxy-phenyl) -N- ( 2-phenyl-5-thiophen-2-yl-2H-pyrazol- 3-yl)-acetamide (CRX000418)
4-Methoxy-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000432) 5 2- (4-Methoxy-phenyl) -N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-ylmethyl) -acetamide (CRX000433)
1 - (4-Chloro-phenyl) -3-phenyl-1 H-pyrazole-4-carboxylic acid (4-methoxy-phenyl) -amide (CRXO00434)
3- (4-Methoxy-phenyl) -N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-ylmethyl) -propionamide (CRX000443)
4-Methoxy-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-yl) - benzenesulfonamide (CRX000444)
4-Methoxy-N-methyl-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- yl) -benzenesulfonamide (CRX000454) 5 1 -Phenyl-3- (1 -phenyl-3-thiophen-2-yl-1H-pyrazol-4-yl) - • propenone (CRX000478)
4-Methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzenesulfonamide (CRX000506)
C-Phenyl-N- (1 -phenyl-3-thiophen-2-yl-lH-pyrazol-4-yl) - ) methanesulfonamide (CRX000509)
4-Methoxy-N- ( 1 -methyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000510)
1 -Benzyl-3-thiophen-2-yl-1 H-pyrazole-4-carboxylic acid (4- methoxy-phenyl) -amide (CRX000511 ) 1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl) -butan-1-one (CRX000512)
3-Methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000515)
4-Fluoro-N- ( 1 -phenyl- 3-thiophen- 2 -yl- 1 H-pyrazol-4-ylmethyl ) - benzamide (CRX00051 6 )
N- (1 -Benzyl-3-thiophen-2-yl-1H-pyrazol-4-ylmethyl) -4- methoxy-benzamide (CRX000523)
1 - (4-Methoxy-phenyl) -3- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl) -heptan-1-one (CRX000524) 4-Methoxy-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazole-4- carbonyl) -benzamide (CRX000533)
3 , 4-Dimethoxy-N- ( 1 -phenyl-3-thiophen- 2-yl- 1 H-pyrazol-4- ylmethyl) -benzamide (CRX000537) 5 N- (1 -Phenyl- 3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - nicotinamide (CRX000538)
N- (1 -Benzyl- 3-thiophen- 2-yl- 1 H-pyrazol-4-ylmethyl) -3- methoxy-benza ide (CRX000539)
N- (1 -Phenyl- 3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - 2- 0 trifluoromethoxy-benzamide (CRX000544)
3 , 4-Dichloro-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000545)
N- (1 , 3-Diphenyl-1 H-pyrazol-4-ylmethyl) -4-methoxy-benzamide (CRX000546) 5 N- [1 - (4-Chloro-phenyl) -3-phenyl-1 H-pyrazol-4-ylmethyl] -4- methoxy-benzamide (CRX000547)
4-Hydroxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000549)
2-Fluoro-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - ) benzamide (CRX000555)
2-Methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000556)
3 , 5-Dimethoxy-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000557) 4-Chloro-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - benzamide (CRX000571)
N- (1 -Phenyl-3-thiophen-2-yl-lH-pyrazol-4-ylmethyl) -4- trifluoromethoxy-benzamide (CRXO00572)
3-Chloro-4-methoxy-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000573)
3-Chloro-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - benzamide (CRX000574)
N- (1 -Phenyl-3-thiophen- 2-yl-1 H-pyrazol-4-ylmethyl) -3- trifluoromethyl-benzamide (CRXO00576) N- (1 -Phenyl-3-thiophen-2-yl-lH-pyrazol-4-ylmethyl) -4- trifluoromethyl-benzamide (CRXO00579)
3-Fluoro-N- (1 -phenyl-3-thiophen-2-yl-1H-pyrazol-4-ylmethyl) 4-trifluoromethyl-benzamide (CRXO00580) N- (1 -Phenyl-3-thiophen-2-yl-1H-pyrazol-4-ylmethyl) - terephthalamic acid (CRX000581 )
3- [1 - (3, 5-Bis-trifluoromethyl-phenyl) -3-thiophen- 2-yl- 1H- pyrazol-4-yl] -1 - (4-methoxy-phenyl) -propenone (CRX000582)
2-Fluoro-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl) - 4-trifluoromethyl-benzamide (CRX000587)
4-Methoxy-N- (1 -phenyl-3-m-tolyl-1 H-pyrazol-4-ylmethyl) - benzamide (CRX000588)
2 , 4-Dimethoxy-N- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4- ylmethyl) -benzamide (CRX000600) > 1 - (4-Methoxy-phenyl) -3- [3-thiophen-2-yl-1 - (4- trifluoromethyl-benzyl) -1H-pyrazol-4-yl] -propenone (CRX000603)
3- [1 - (4-Fluoro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- methoxy-phenyl) -propenone (CRX000604)
N- [3- (4-Chloro-phenyl) -1 -phenyl-1 H-pyrazol-4-ylmethyl] -4- ) methoxy-benzamide (CRX000608)
N- (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl) -acrylamide (CRX000609)
3- [3- (4-Fluoro-phenyl) -1 -phenyl-1 H-pyrazol-4-yl] -1 - (4- methoxy-phenyl) -propenone (CRX000610) N- (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl)-propionamide (CRX000618)
1 -Phenyl-2- ( 1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylamino) - ethanol (CRX000620)
N- (4-Methoxy-phenyl) -2- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl) -acetamide (CRX000621)
1 - (4-Fluoro-phenyl) -3- [3-pyridin-3-yl-1 - (4-trifluoromethyl- phenyl) -1H-pyrazol-4-yl] -propenone (CRX000622)
1 - (4-Chloro-phenyl) -3- [3-pyridin-3-yl-1 - (4-trifluoromethyl- phenyl) -1H-pyrazol-4-yl] -propenone (CRX000623) 1 - (4-Methoxy-phenyl) -3- [3-pyridin-3-yl-1 - (4-trifluoromethyl- phenyl) -1H-pyrazol-4-yl] -propenone (CRX000624)
2-Acetyl-N- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol-4-ylmethyl ) - benzamide (CRX000625) 5 3- [1 - (4-Chloro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- fluoro-phenyl) -propenone (CRX000626)
1 - (4-Chloro-phenyl) -3- [1 - (4-chloro-phenyl) -3-pyridin-3-yl- 1H-pyrazol-4-yl] -propenone (CRX000627)
3- [1 - (4-Chloro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- methoxy-phenyl) -propenone (CRX000629)
3- [3-Pyridin- 3-yl-1 - (4-trifluoromethyl-phenyl) -1 H-pyrazol-4- yl] -1 - (4-trifluoromethyl-phenyl) -propenone (CRX000631 )
1 - (4-Methoxy-phenyl) -3- ( 1 -phenyl- 3-thiophen- 2-yl-1 H-pyrazol- 4-yl) -propan-1 -ol (CRX000632) j Phenyl- (1 -phenyl-3-thiophen- 2-yl-1 H-pyrazol-4-yl) -methanone (CRX000636) .
3- [3-Pyridin- 3-yl-1 - (4-trifluoromethyl-phenyl) -1 H-pyrazol-4- yl] -1 - (4-trifluoromethoxy-phenyl) -propenone (CRX000637)
3- [1 - (4-Chloro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- ) trifluoromethoxy-phenyl) -propenone (CRX000638)
3- [1 - (4-Chloro-phenyl) - 3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- trifluoromethyl-phenyl) -propenone (CRX000640)
1 - (4-Fluoro-phenyl) -3- [1 - (4-fluoro-phenyl) -3-pyridin-3-yl- 1H-pyrazol-4-yl] -propenone (CRX000641 ) 3- [1 - (4-Fluoro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- trifluoromethoxy-phenyl) -propenone (CRX000642)
1 - (4-Chloro-phenyl) -3- [1 - (4-fluoro-phenyl) - 3-pyridin- 3-yl- lH-pyrazol-4-yl] -propenone (CRX000643)
3-Isopropylsulfanyl-1 - (4-methoxy-phenyl) -3- (1 -phenyl-3- thiophen-2-yl-1H-pyrazol-4-yl) -propan-1 -one (CRX000644)
1 - (4-Methoxy-phenyl) -3- (1 -phenyl-3-thiophen-2-yl-1 H-pyrazol- 4-yl)-prop-2-en-1-ol (CRX000645)
3- [1 - (4-Fluoro-phenyl) -3-pyridin-3-yl-1 H-pyrazol-4-yl] -1 - (4- trifluoromethyl-phenyl) -propenone (CRX000648) 4- [4- (4-Methoxy-phenylcarbamoyl) -3-thiophen-2-yl-pyrazol-1 - yl] -benzoic acid ethyl ester (CRX000790)
3- (4-Fluoro-phenyl) -1 -phenyl-1 H-pyrazole-4-carboxylic acid [4- (pyridin-2-ylmethoxy) -phenyl] -amide (CRX000871 ) .
6. A PPAR-gamma agonist having the structure of compound of claims 1 to 5.
7. A composition comprising at least one compound of claims 1 to 6.
8. A method for treating obesity, said method comprising administering to a patient in need of such treatment an amount of at least one compound or a composition of claims 1-7.
9. A method for treating diabetes, said method comprising administering to a patient in need of such treatment an amount of at least one compound or a composition of claims 1-7.
10. A method for modulating insulin-sensitivity and blood glucose levels in a patient, said method comprising administering to a patient in need of such treatment an amount of compound or a composition of claims 1-7.
PCT/EP2003/011855 2002-10-24 2003-10-24 Pyrazole derivatives as modulators of peroxisome proliferator activated receptors Ceased WO2004043951A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003282051A AU2003282051A1 (en) 2002-10-24 2003-10-24 Pyrazole derivatives as modulators of peroxisome proliferator activated receptors

Applications Claiming Priority (12)

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

Publications (1)

Publication Number Publication Date
WO2004043951A1 true WO2004043951A1 (en) 2004-05-27

Family

ID=32180796

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2003/011710 Ceased WO2004037248A2 (en) 2002-10-24 2003-10-22 Modulation of peroxisome proliferator activated receptors activity
PCT/EP2003/011855 Ceased WO2004043951A1 (en) 2002-10-24 2003-10-24 Pyrazole derivatives as modulators of peroxisome proliferator activated receptors

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/011710 Ceased WO2004037248A2 (en) 2002-10-24 2003-10-22 Modulation of peroxisome proliferator activated receptors activity

Country Status (2)

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

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005090313A1 (en) * 2004-03-18 2005-09-29 Pfizer Limited N-(1-arylpyrazol-4l)sulfonamides and their use as parasiticides
WO2005061462A3 (en) * 2003-12-19 2005-11-17 Neurogen Corp Diaryl pyrazole derivatives and their use as neurokinin-3 receptor modulators
WO2007052843A1 (en) * 2005-11-04 2007-05-10 Takeda Pharmaceutical Company Limited Heterocyclic amide compound and use thereof
WO2007122970A1 (en) * 2006-04-20 2007-11-01 Osaka University Ligand capable of binding to nuclear receptor
US20110112073A1 (en) * 2008-05-15 2011-05-12 Duke University Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof
US20120021074A1 (en) * 2009-03-23 2012-01-26 Merck Sharp & Dohme Corp. P2x3, receptor antagonists for treatment of pain
CN103254133A (en) * 2012-02-20 2013-08-21 南京大学 Preparation method of diarylpyrazolylaniline compounds, and application of compounds in colorectal cancer treatment
JP2014521653A (en) * 2011-07-29 2014-08-28 カリオファーム セラピューティクス，インコーポレイテッド Nuclear transport regulators and uses thereof
WO2016202935A1 (en) 2015-06-19 2016-12-22 Bayer Pharma Aktiengesellschaft Glucose transport inhibitors
US9714226B2 (en) 2011-07-29 2017-07-25 Karyopharm Therapeutics Inc. Hydrazide containing nuclear transport modulators and uses thereof
WO2017135786A1 (en) * 2016-02-05 2017-08-10 연세대학교 산학협력단 Novel amide compound and use thereof
US9738624B2 (en) 2013-06-21 2017-08-22 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
US9861614B2 (en) 2012-05-09 2018-01-09 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
US10202366B2 (en) 2013-03-15 2019-02-12 Karyopharm Therapeutics Inc. Methods of promoting wound healing using CRM1 inhibitors
US10519139B2 (en) 2014-08-15 2019-12-31 Karyopharm Therapeutics Inc. Polymorphs of Selinexor
US10526295B2 (en) 2015-12-31 2020-01-07 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
US10709706B2 (en) 2015-12-31 2020-07-14 Karopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11602530B2 (en) 2016-11-28 2023-03-14 Biogen Ma Inc. CRM1 inhibitors for treating epilepsy

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10315571A1 (en) 2003-04-05 2004-10-14 Merck Patent Gmbh pyrazole
DE10315573A1 (en) * 2003-04-05 2004-10-14 Merck Patent Gmbh Substituted pyrazoles
DE10315569A1 (en) 2003-04-05 2004-10-14 Merck Patent Gmbh Substituted pyrazole compounds
AR044586A1 (en) * 2003-06-04 2005-09-21 Aventis Pharma Sa ARIL PRODUCTS - HETEROAROMATICOS, COMPOSITIONS THAT CONTAIN THEM AND THEIR USE
US20060252670A1 (en) * 2004-10-14 2006-11-09 Intercept Pharmaceuticals Inc. Method of reducing drug-induced adverse side effects in a patient
MX2008000141A (en) * 2005-06-27 2008-04-07 Exelixis Inc Imidazole based lxr modulators.
CN101296914B (en) * 2005-08-26 2012-07-18 盐野义制药株式会社 Derivatives with PPAR agonistic activity
CA2749931C (en) * 2009-01-26 2018-03-06 Taipei Medical University Use of pterosin compounds for treating diabetes and obesity
AR076984A1 (en) * 2009-06-08 2011-07-20 Merck Serono Sa DERIVATIVES OF PIRAZOL OXADIAZOL
TW201321367A (en) * 2011-10-25 2013-06-01 Du Pont Heterocyclic insecticide substituted by 1,3-diaryl
PL3286181T3 (en) * 2015-04-22 2021-08-02 Rigel Pharmaceuticals, Inc. Pyrazole compounds and method for making and using the compounds
MX2022002292A (en) 2019-08-30 2022-06-02 Rigel Pharmaceuticals Inc Pyrazole compounds, formulations thereof, and a method for using the compounds and/or formulations.
WO2022187303A1 (en) 2021-03-03 2022-09-09 Rigel Pharmaceuticals, Inc. A method for treating a disease or condition using a pyrazole compound or formulation thereof
JP2025513716A (en) 2022-03-23 2025-04-30 ライジェル・ファーマシューティカルズ・インコーポレイテッド 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 (en) * 1975-03-25 1976-10-14 Byk Gulden Lomberg Chem Fab NITROFURYL PYRAZOLE DERIVATIVES, METHOD FOR MANUFACTURING THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM
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 (en) * 1975-03-25 1976-10-14 Byk Gulden Lomberg Chem Fab NITROFURYL PYRAZOLE DERIVATIVES, METHOD FOR MANUFACTURING THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM
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 *

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005061462A3 (en) * 2003-12-19 2005-11-17 Neurogen Corp Diaryl pyrazole derivatives and their use as neurokinin-3 receptor modulators
WO2005090313A1 (en) * 2004-03-18 2005-09-29 Pfizer Limited N-(1-arylpyrazol-4l)sulfonamides and their use as parasiticides
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 (en) * 2005-11-04 2007-05-10 Takeda Pharmaceutical Company Limited Heterocyclic amide compound and use thereof
WO2007122970A1 (en) * 2006-04-20 2007-11-01 Osaka University Ligand capable of binding to nuclear receptor
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
US20120021074A1 (en) * 2009-03-23 2012-01-26 Merck Sharp & Dohme Corp. P2x3, receptor antagonists for treatment of pain
US8946231B2 (en) * 2009-03-23 2015-02-03 Merck Sharp & Dohme Corp. P2X3, receptor antagonists for treatment of pain
EP2410858B1 (en) * 2009-03-23 2016-09-07 Merck Sharp & Dohme Corp. P2x3 receptor antagonists for treatment of pain
US9717709B2 (en) 2010-11-12 2017-08-01 Duke University Substituted pyrazoles as heat shock transcription factor activators
US9156775B2 (en) 2010-11-12 2015-10-13 Duke University Substituted 1,3-thiazoles as heat shock transcription factor 1 activators
US9447058B2 (en) 2010-11-12 2016-09-20 Duke University Substituted 1,3-thiazoles as heat shock transcription factor 1 activators
US11034660B2 (en) 2011-07-29 2021-06-15 Karyopharm Therapeutics Inc. Hydrazide containing nuclear transport modulators and uses thereof
US10173987B2 (en) 2011-07-29 2019-01-08 Karyopharm Therapeutics Inc. Hydrazide containing nuclear transport modulators and uses thereof
US12291508B2 (en) 2011-07-29 2025-05-06 Karyopharm Therapeutics Inc. Hydrazide containing nuclear transport modulators and uses thereof
JP2014521653A (en) * 2011-07-29 2014-08-28 カリオファーム セラピューティクス，インコーポレイテッド Nuclear transport regulators and uses thereof
US11787771B2 (en) 2011-07-29 2023-10-17 Karyopharm Therapeutics Inc. Hydrazide containing nuclear transport modulators and uses thereof
US9714226B2 (en) 2011-07-29 2017-07-25 Karyopharm Therapeutics Inc. Hydrazide containing nuclear transport modulators and uses thereof
US10544108B2 (en) 2011-07-29 2020-01-28 Karyopharm Therapeutics Inc. Hydrazide containing nuclear transport modulators and uses thereof
CN103254133A (en) * 2012-02-20 2013-08-21 南京大学 Preparation method of diarylpyrazolylaniline compounds, and application of compounds in colorectal cancer treatment
US10617677B2 (en) 2012-05-09 2020-04-14 Biogen Ma Inc. Nuclear transport modulators and uses thereof
US10058535B2 (en) 2012-05-09 2018-08-28 Biogen Ma Inc. Nuclear transport modulators and uses thereof
US10335393B2 (en) 2012-05-09 2019-07-02 Biogen Ma Inc. Nuclear transport modulators and uses thereof
JP2018172444A (en) * 2012-05-09 2018-11-08 カリオファーム セラピューティクス，インコーポレイテッド Nuclear transport regulators and uses thereof
US11318120B2 (en) 2012-05-09 2022-05-03 Biogen Ma Inc. Nuclear transport modulators and uses thereof
US9861614B2 (en) 2012-05-09 2018-01-09 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
US10925859B2 (en) 2012-05-09 2021-02-23 Biogen Ma Inc. Nuclear transport modulators and uses thereof
US10202366B2 (en) 2013-03-15 2019-02-12 Karyopharm Therapeutics Inc. Methods of promoting wound healing using CRM1 inhibitors
US9738624B2 (en) 2013-06-21 2017-08-22 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
US10407405B2 (en) 2013-06-21 2019-09-10 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
US11945794B2 (en) 2013-06-21 2024-04-02 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
US11124493B2 (en) 2013-06-21 2021-09-21 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
US11753401B2 (en) 2014-08-15 2023-09-12 Karyopharm Therapeutics Inc. Polymorphs of Selinexor
US11078190B2 (en) 2014-08-15 2021-08-03 Karyopharm Therapeutics Inc. Polymorphs of selinexor
US11746102B2 (en) 2014-08-15 2023-09-05 Karyopharm Therapeutics Inc. Polymorphs of selinexor
US11807629B2 (en) 2014-08-15 2023-11-07 Karyopharm Therapeutics Inc. Polymorphs of Selinexor
US10519139B2 (en) 2014-08-15 2019-12-31 Karyopharm Therapeutics Inc. Polymorphs of Selinexor
US12371420B2 (en) 2014-08-15 2025-07-29 Karyopharm Therapeutics Inc. Polymorphs of Selinexor
WO2016202935A1 (en) 2015-06-19 2016-12-22 Bayer Pharma Aktiengesellschaft Glucose transport inhibitors
US10709706B2 (en) 2015-12-31 2020-07-14 Karopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
US10526295B2 (en) 2015-12-31 2020-01-07 Karyopharm Therapeutics Inc. Nuclear transport modulators and uses thereof
KR101857714B1 (en) * 2016-02-05 2018-05-15 연세대학교 산학협력단 Novel amide compounds and use thereof
WO2017135786A1 (en) * 2016-02-05 2017-08-10 연세대학교 산학협력단 Novel amide compound and use thereof
US11602530B2 (en) 2016-11-28 2023-03-14 Biogen Ma Inc. CRM1 inhibitors for treating epilepsy
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Also Published As

Publication number Publication date
AU2003287965A1 (en) 2004-05-13
AU2003287965A8 (en) 2004-05-13
WO2004037248A2 (en) 2004-05-06
WO2004037248A3 (en) 2004-06-03
AU2003282051A1 (en) 2004-06-03

Similar Documents

Publication Publication Date Title
WO2004043951A1 (en) Pyrazole derivatives as modulators of peroxisome proliferator activated receptors
TWI404712B (en) Benzoazepin-oxy-acetic acid derivatives as ppar-delta agonists used for the increase of hdl-c, lower ldl-c and lower cholesterol
EP1533292B1 (en) Dibenzylamine compound and medicinal use thereof
US7319109B2 (en) Farnesoid X receptor agonists
JP5299810B2 (en) Compounds, pharmaceutical compositions and methods for use in the treatment of metabolic disorders
JP4733153B2 (en) Pyrazole derivatives, compositions containing such compounds and methods of use
RU2252939C2 (en) 5-membered n-heterocyclic compounds with hypoglycemic and hypolipidemic activity
JP2009507846A (en) PPAR active compounds
KR20010034586A (en) Carboxylic acid derivatives and drugs containing the same as the active ingredient
NO323643B1 (en) Diarylic acid derivatives, pharmaceutical compositions comprising them and their use in the preparation of pharmaceutical preparations
WO2004024162A1 (en) 2-amino-4-quinazolinones as lxr nuclear receptor binding compounds
CA2497901A1 (en) Furan or thiophene derivative and medicinal use thereof
US5374638A (en) Six membered ring fused imidazoles substituted with phenoxyphenylacetic acid derivatives used to treat asthma
CN101663298A (en) Thiazole derivatives as modulators of g protein-coupled receptors
KR20070041560A (en) Arilidene for the Treatment of Estrogen-related Receptor-alpha-Mediated Diseases
ES2300587T3 (en) DERIVATIVES OF PHENYLLOAXIALCANOIC ACID AS HPPAR ACTIVATORS.
WO2004072046A2 (en) Quinoline derivatives and their use for modulation of lxr activity
WO2004072041A1 (en) Tetrahydroquinolines as agonists of liver- x receptors
JP6937524B2 (en) Amide compounds and their use
KR20080058416A (en) Pyrazole derivatives, compositions containing such compounds and methods of use
JP2003535084A (en) Benzamide derivatives and their use as apo B-100 and MTP inhibitors
AU2007298540A1 (en) 3 -amino- pyridine derivatives for the treatment of metabolic disorders
US6034106A (en) Oxadiazole benzenesulfonamides as selective β3 Agonist for the treatment of Diabetes and Obesity
Kim et al. Synthesis and biological activity of annulated pyrazoles as selective COX-2 inhibitors. I.
KR100484526B1 (en) Thione derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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

AL Designated countries for regional patents

Kind code of ref document: A1

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

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

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP