WO2007047432A1 - Derives de sulfamide en tant que modulateurs de ppar - Google Patents

Derives de sulfamide en tant que modulateurs de ppar Download PDF

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Publication number
WO2007047432A1
WO2007047432A1 PCT/US2006/040079 US2006040079W WO2007047432A1 WO 2007047432 A1 WO2007047432 A1 WO 2007047432A1 US 2006040079 W US2006040079 W US 2006040079W WO 2007047432 A1 WO2007047432 A1 WO 2007047432A1
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Prior art keywords
optionally substituted
group
compound
recited
hydrogen
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PCT/US2006/040079
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English (en)
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James W. Malecha
Andrew K. Lindstrom
Sergio G. Duron
Steven P. Govek
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Kalypsys, Inc.
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Publication of WO2007047432A1 publication Critical patent/WO2007047432A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to novel sulfonyl-substituted bicyclic aryl derivatives and methods for treating various diseases by modulation of nuclear receptor mediated processes using these compounds, and in particular processes mediated by peroxisome proliferator activated receptors (PPARs).
  • PPARs peroxisome proliferator activated receptors
  • Peroxisome proliferators are a structurally diverse group of compounds which, when administered to mammals, elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes required for the ⁇ -oxidation cycle (Lazarow and Fujiki, Ann. Rev. Cell Biol. 1 :489-530 (1985); Vamecq and Draye, Ess ⁇ ys Biochem. 24: 1115-225 (1989); and Neiali et el.. Cancer Res.48:5316-5324 (1988)).
  • PPARs Compounds that activate or otherwise interact with one or more of the PPARs have been implicated in the regulation of triglyceride and cholesterol levels in animal models.
  • Compounds included in this group are the fibrate class of hypolipidemic drugs, herbicides, and phthalate plasticizers (Reddy and LaJwani, Criu Rev. Toxicol. 12:1-58 (1983)).
  • Peroxisome proliferation can also be elicited by dietary or physiological factors such as a high-fat diet and cold acclimatization.
  • Biological processes modulated by PPAR are those modulated by receptors, or receptor combinations, which are responsive to the PPAR receptor ligands. These processes include, for example, plasma lipid transport and fatty acid catabolism, regulation of insulin sensitivity and blood glucose levels, which are involved in hypoglycemia/hyperinsulinemia (resulting from, for example, abnormal pancreatic beta cell function, insulin secreting tumors and/or autoimmune hypoglycemia due to autoantibodies to insulin, the insulin receptor, or autoantibodies that are stimulatory to pancreatic beta cells), macrophage differentiation which lead to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, and adipocyte differentiation.
  • hypoglycemia/hyperinsulinemia resulting from, for example, abnormal pancreatic beta cell function, insulin secreting tumors and/or autoimmune hypoglycemia due to autoantibodies to insulin, the insulin receptor, or autoantibodies that are stimulatory to pancreatic beta cells
  • macrophage differentiation
  • Subtypes of PPAR include PPAR-alpha, PPAR-delta (also known as NUC! , PPAR-beta and FAAR) and two isoforms of PPAR-gamma. These PPARs can regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE's have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism
  • the receptor termed PPAR-alpha (or alternatively, PPAR ⁇ ) was subsequently shown to be activated by a variety of medium end long-chain fatty acids and to stimulate expression of the genes encoding rat acyl-CoA oxidase and hydratase- dehydrogenase (enzymes required for peroxisomal ⁇ -oxidation), as well as rabbit cytochrome P450 4A6, a fatty acid m-hydroxylase (Gottlich et al., Proc. Natl. Acad. Sci. USA 89:4653-4657 (1992); Tugwood et el., EMBO J 1 1:433-439 (1992); Bardot et al., Biochem.
  • PPAR-alpha or alternatively, PPAR ⁇
  • Activators of the nuclear receptor PPAR-gamma have been clinically shown to enhance insulin-action, to reduce serum glucose and to have small but significant effects on reducing serum triglyceride levels in patients with Type 2 diabetes. See, for example, D. E. Kelly et al., Citrr. Opfrt. Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D. Johnson Ct el., Ann. Pharmacather., 337-348, 32 (3), ( 1997); and M. repelnegger et al., Curr. Ther. Res. , 403-416, 58 (7), (1997).
  • PPAR-delta (or alternatively, PPAR ⁇ ) initially received much less attention than the other PPARs because of its ubiquitous expression and the unavailability of selective ligands.
  • genetic studies and recently developed synthetic PPAR-S agonists have helped reveal its role as a powerful regulator of fatty acid catabolism and energy homeostasis.
  • Studies in adipose tissue and muscle have begun to uncover the metabolic functions of PP AR- ⁇ .
  • Transgenic expression of an activated form of PPAR-S in adipose tissue produces lean mice that are resistant to obesity, hyperlipidemia and tissue steatosis induced genetically or by a high-fat diet The activated receptor induces genes required for fatty acid catabolism and adaptive thermogenesis.
  • PPAR- ⁇ is broadly expressed in the body and has been shown to be a valuable molecular target for treatment of dyslipidemi ⁇ and other diseases.
  • a potent and selective PPAR-delta compound was shown to decrease VLDL and increase HDL in a dose response manner (Oliver et al., Proc. Natl. Acad Sci. U S. /4.98: 5305, 2001 ).
  • PP ⁇ R-modulating drugs have been approved for use in humans.
  • Fenofibrate and gemfibrozil are PP ARa modulators: pioglitazone (Actos, Takeda Pharmaceuticals and EIi Lilly) and rosiglitazone (Avandia, GlaxcoSmithKline) are PPAR ⁇ modulators.
  • pioglitazone Actos, Takeda Pharmaceuticals and EIi Lilly
  • rosiglitazone Avandia, GlaxcoSmithKline
  • PPAR ⁇ modulators are PPAR ⁇ modulators.
  • al of these compounds have liabilities as potential carcinogens, having been demonstrated to have proliferative effects leading to cancers of various types (colon; bladder with PP ⁇ R ⁇ modulators and liver with PPARy modulators) in rodent studies. Therefore, a need exists to identify other modulators of PPARs which lack these liabilities.
  • Selective modulators of PPAR ⁇ may provide an opportunity for such improvements, and may even prove
  • the present invention provides a class of compounds useful as modulators of PPAR, having structural Formula (I)
  • A is selected from the group consisting ofaryl, heteroaryl, cycloalky], and heterocycloalkyl, any of which may be optionally substituted;
  • R 12 is selected from the group consisting of hydrogen, lower alfcyl, lower alkenyl, lower heteroalkyl, and lower alkoxy; R lz rnay join together with a carbon atom in G 1 to form a five to eight- membered carbocycle or het ⁇ rocycle, having structural Formula (II):
  • B is a saturated, partially saturated, or unsaturated hydrocarbon chain, optionally containing one or more heteroatoms, to form an optionally substituted five- to eight-membered carbocycle or heterocycle;
  • T is selected from the group consisting Of-C(O)OH, -C(O)NEb, and tetrazol ⁇ ;
  • G 1 is selected from the group consisting Of-(CR 1 R 2 )-- , -Z(CR 1 R 3 V-, - ⁇ CR'R 2 ), ⁇ -, - (CR 1 R 2 ⁇ (CR 1 RV;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, and lower perhaloalky I, or R 1 and R 2 together may form a cycloalkyl; -;
  • Y is S, -SO 2 N(RV or ' NS-";
  • W is O, S or -NR*; p is 2 to 6; m is 0, 1 or 2;
  • R* and R 1 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted heteroatkyl, optionally substituted cycloalkyl, lowerperbaloalkyl, lower perhaloalkoxy, nitro, cyano, NHj. and -C(O)OR", or R ⁇ and R 4 together may form a cycloalkyl;
  • R 1 ' is selected from the group consisting of hydrogen and optionally substituted lower alkyl
  • R s and R 6 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted heteroalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 7 and R 3 are each individually selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; and wherein said effect is selected from the group consisting of modulation of PPAR ⁇ , upregulation of expression ofGLUT4 in adipose tissue, reduction of expression of NPCl Ll, raising of HDL, lowering of LOLc, shifting of LDL particle size from small dense to normal LDL, inhibition of cholesterol absorption, reduction of triglycerides, decrease of insulin resistance, lowering of blood pressure, promotion of wound healing , reduction of scarring, and treatment of a PPAR ⁇ -mediated disease.
  • the compounds of the invention are selective modulators of PPAR ⁇ .
  • the present invention provides methods of, alone or in combination, raising HDL, lowering LDLc, shifting LDL particle size from small dense to normal LDL, and inhibiting cholesterol absorption, comprising the administration of a therapeutic amount of a compound of the invention.
  • the present invention provides methods for treating metabolic disorders and related conditions, in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound of formula (1) effective to reduce or prevent said disorders or conditions in the patient.
  • the invention provides for pharmaceutical compositions comprising the compounds of the invention, together with one or more pharmaceutically acceptable diluents or carriers, tn related aspects, the invention provides for pharmaceutical compositions comprising the compounds of the invention and one or more additional agents, for die treatment of metabolic disorders.
  • the compounds of the present invention have structural Formula (1) wherein:
  • T is -CO(O)H
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, lower alky I, lower alkoxy, and lower perhaloalkyl;
  • G 2 is -Y(CR 3 R + ) P W(CR 3 R 4 ),,, -;
  • W is O, or -NR 6 ; p is 2;
  • R 3 and R 4 are each hydrogen
  • A is optionally substituted phenyl
  • R 12 is hydrogen
  • R' and R 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;
  • the compounds of the invention wherein said aryl is optionally substituted with one or more of the following: halogen, pcrhaloalkyl, and perhaloalkoxy.
  • the compounds of the invention wherein said perhaloalkoxy is trifluoromethoxy.
  • the compounds of the invention wherein said trifluoromethoxy substitutes said aryl in the para position.
  • Ci is optionally substituted aryl.
  • G 3 is optionally substituted heteroaryl.
  • G 1 Is-N C(R 7 R 8 ).
  • the compounds of the invention wherein at least one R 7 and R s is optionally substituted aryl are optionally substituted aryl.
  • A is optionally substituted phenyl
  • R 12 joins together with a carbon atom in G' to form a five to eight-membered carbocycle or heterocycle;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl.
  • X 1 and X 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted lower alky I, optionally substituted cycloaikyl, optionally substituted heteroalkyl, optionally substituted cycloheteroalkyl, optionally substituted lower alkynyl, perhaloalky I, pcrhatoalkoxy, optionally substituted lower alkoxy, nitro, cyano, and NH 2 .
  • X 1 and X 2 are each hydrogen;
  • G 3 is optionally substituted aryl.
  • X i and X 2 are each hydrogen;
  • Q 3 is optionally substituted hetero ⁇ ryl.
  • X i and X 2 are each hydrogen;
  • the compounds of the present invention wherein at least one of R 7 and R a is optionally substituted aryl.
  • the compounds of the present invention wherein both R 7 and R 8 are optionally substituted aryl.
  • W is N; m is 1 ;
  • Xi and Xi are each hydrogen
  • R 3 and R* are hydrogen; and G 3 is optionally substituted aryl.
  • X' and X 2 each independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cyclonlkyl, optionally substituted heteroalkyl, optionally substituted cycioheteroalkyl, optionally substituted lower alkynyl, perhaloalkyl, perhafoalkoxy, optionally substituted lower alkoxy, nitro, cyano, and NJH-.
  • X ⁇ andX 2 areeach hydrogen
  • G 3 is optionally substituted aryl.
  • novel compounds disclosed herein can modulate at least one peroxisome proliferator-activated receptor (PPAR) function.
  • PPAR peroxisome proliferator-activated receptor
  • Compounds described herein may be activating both PPAR-delta and PPAR-gamma or PPAR-alpha and PPAR-delta, or all three PPAR subtypes, or selectively activating predominantly PPAR-gamma, PPAR-alpha or PPAR-delta.
  • the present invention discloses a method of modulating at least one peroxisome proliferator- activated receptor (PPAR) function comprising the step of contacting the PP ⁇ R with a compound of Formula I, as described herein.
  • PPAR peroxisome proliferator- activated receptor
  • the change in cell phenotype, cell proliferation, activity of the PPAR, expression of the PPAR or binding of the PPAR with a natural binding partner may be monitored.
  • Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.
  • the present invention describes methods of treating a PPAR-mediated disease or metabolic disorder comprising identifying a patient having said disease, and administering a therapeutically effective
  • the disease to be treated by the methods of the present invention is selected from the group consisting of obesity, diabetes, hyperinsuli ⁇ emia, metabolic syndrome X, polycystic ovary syndrome, climacteric, disorders associated with oxidative stress, inflammatory response to tissue injury, pathogenesis of emphysema, ischemia-associated organ injury, doxorubicin-induced cardiac injury, drug-induced hepatotoxicity, atherosclerosis, mid hypertoxic lung injury.
  • the present invention relates to a method of modulating at least one peroxisome proliferator-activated receptor (PPAR) function comprising the step of contacting the PPAR with a compound of Formula I, as described herein.
  • the change in cell phenotype, cell proliferation, activity of the PPAR, or binding of the PPAR with a natural binding partner may be monitored.
  • Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.
  • the PPAR may be selected from the group consisting of PPAR ⁇ , PPARS, and PPAR ⁇ .
  • the PPAR is PPARS.
  • the invention also discloses the use of a PPAR-delta modulator compound according to the invention for the manufacture of a medicament for raising HDL, lowering LDLc, shifting LDL particle size from small dense to normal LDL, or inhibiting cholesterol absorption.
  • the invention discloses methods of treatment of a PPAR-delta mediated disease or condition comprising administering a therapeutically effective amount of a compound according the present invention or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • the present invention discloses: methods for treating Type 2 diabetes, decreasing insulin resistance or lowering blood pressure in a subject; methods for treating atherosclerotic diseases including vascular disease, coronary heart disease, cerebrovascular disease and peripheral vessel disease in a subject; methods for treating cancers including colon, skin, and lung cancers in a subject; and methods for treating inflammatory diseases, including rheumatoid arthritis, asthma, osteoarthritis and autoimmune disease in a subject, ail comprising the administration of a therapeutic amount of a PPAR-delta modulator compound according to the present invention.
  • the invention further discloses compounds of the invention or pharmaceutical compositions thereof for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the modulation of a PPAR-delta.
  • Certain embodiments of the invention include the use of a PPAR-delta modulator compound having structural formula (I) for the manufacture of a medicament for the treatment of: Type 2 diabetes, or for decreasing insulin resistance or lowering blood pressure; atherosclerotic diseases including vascular disease, coronary heart disease, cerebrovascular disease and peripheral vessel disease; cancers including colon, skin, and lung cancers; and inflammatory diseases, including rheumatoid arthritis, asthma, osteoarthritis and autoimmune disease, in a patient in need thereof.
  • Another aspect of the invention are compounds of the invention or pharmaceutical compositions thereof for use in the treatment of disease or condition ameliorated by the modulation of a PPAR-delta wherein said PPAR-delta mediated disease or condition is dyslipidemia, metabolic
  • syndrome X heart failure, hypercholesteremia, cardiovascular disease, type I] diabetes rnellitus, type I diabetes, insulin resistance hyperlipidemia, obesity, anorexia bulimia, inflammation and anorexia nervosa.
  • Another aspect of the invention are compounds, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, or pharmaceutically acceptable salts thereof and having an ECJO value less than 5 ⁇ M as measured by a functional cell assay.
  • Another aspect of the invention are methods of modulating a peroxisome proliferator- acti vated receptor (PPAR) function comprising contacting said PPAR with a compound of the present invention and monitoring a change in cell phenotype, cell proliferation, activity of said PPAR, or binding of said PPAR with a natural binding partner.
  • PPAR peroxisome proliferator- acti vated receptor
  • Another aspect of the invention are method of modulating a peroxisome proliferator- activated receptor (PPAR) wherein the PPAR is selected from the group consisting of PPAR-alpha, PPAR-delta, and PPAR-gamma.
  • PPAR peroxisome proliferator- activated receptor
  • Another aspect of the invention are methods of treating a disease comprising identifying a patient in need thereof, and administering a therapeutically effective amount of a compound of (he present invention to said patient wherein said disease is selected from the group consisting of obesity, diabetes, hyperinsulinemia, metabolic syndrome X, polycystic ovary syndrome, climacteric, disorders associated with oxidative stress, inflammatory response to tissue injury, pathogenesis of emphysema, ischemia-associated organ injury, doxorubicin-induced cardiac injury, drug-induced hepatotoxicity, atherosclerosis, and hypertonic lung injury.
  • Another aspect of the invention are compounds which modulates a peroxisome proliferator- acti vated receptor (PPAR) function, preferably wherein said PPAR is selected from the group consisting of PPAR ⁇ , PPAR ⁇ , and PPARy.
  • PPAR peroxisome proliferator- acti vated receptor
  • Another aspect of the invention are compounds or composition for use in the treatment of a disease or condition ameliorated by the modulation of a PPAR such as PPAR ⁇ , PPAR ⁇ , and PPARy, wherein the disease or condition is dyslipidemia, metabolic syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type Il diabetes mellitus, type I diabetes, insulin resistance hyperlipidemia, obesity, anorexia bulimia, inflammation and anorexia nervosa.
  • a PPAR such as PPAR ⁇ , PPAR ⁇ , and PPARy
  • the disease or condition is dyslipidemia, metabolic syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type Il diabetes mellitus, type I diabetes, insulin resistance hyperlipidemia, obesity, anorexia bulimia, inflammation and anorexia nervosa.
  • Another aspect of the invention are compounds or compositions according for use in the manufacture of a medicament for the prevention or treatment of disease or condition ameliorated by the modulation of a PPAR such as PPAR ⁇ , PPAR ⁇ , and PPARy.
  • a PPAR such as PPAR ⁇ , PPAR ⁇ , and PPARy.
  • acyl refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, hetero ⁇ ryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon.
  • An “acetyl” group refers to a -C(O)CH.-) group.
  • An “alkylcarbonyl” or “alkanoyl” group refers to an olkyl group attached to the parent molecular moiety through a carbonyl group. Examples
  • acyl groups include formyl, alkanoyl and aroyl.
  • alkenyl refers to a straight-chain or branched- chain hydrocarbon radical having one or more double bonds and containing from 2 to 20, preferably 2 to 6, carbon atoms.
  • suitable alkenyl radicals include ethenyl, prope ⁇ yl, 2-methylpropenyl, 1 ,4-butadienyl and the like.
  • alkoxy refers to an alkyl ether radical, wherein the term alkyl is as defined below.
  • suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopnopoxy, n-butoxy, iso-buioxy, sec-butoxy, tert-butoxy, and the like.
  • alkyl refers to a straight-chain or branched- chain alkyl radical containing from I to and including 20, preferably I to 10, and more preferably 1 to 6, carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl end the like.
  • alkylene as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH 2 -).
  • alkylamino refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may he mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimeihylamino, N.N-ethylmethylamino and the like.
  • alkylidene refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
  • alkytthio refers to an alkyl thioether (K-S-) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.
  • alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthid, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.
  • alkynyl refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20, preferably from 2 to 6, more preferably from 2 to 4, carbon atoms.
  • Alkynylen ⁇ refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C ⁇ C-).
  • alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, buty ⁇ -l-yl, butyn-2-yl, penty ⁇ -l-yl, 3-methylbutyn-J-yl, hexyn-2-yl, and the like.
  • amino and “carbamoyl,”as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbo ⁇ yl group, or vice versa.
  • acylamino as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. ⁇ n example of an “acylamino” group is ⁇ cetylamino (CH 3 C(O)NH-).
  • amino refers to — NRR ' , wherein R and R " are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cyoloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted.
  • aryl as used herein, alone or in combination, means a c ⁇ rbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, ⁇ zutenyl, tetrahydrotiaphtbyl, and biphenyl.
  • arylalkenylTM or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alke ⁇ yl group.
  • arylalkoxy or “aralkoxy,” as used herein, aJone or in combination, refers to an aryj group attached to the parent molecular moiety through an alkoxy group.
  • arylalkyl or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • arylalkynyl or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
  • arylalka ⁇ oyl or “aralkanoyl” or “aroyl,”as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, ⁇ apthoyl, phenylacetyl, 3-phenylpropionyl (hydrocirmamoyl), 4-phenyIbutyryl, (2-naphthyl)acetyl, 4- chlor ⁇ hydrocinnamoyl, and the like.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxy.
  • benzo and "benz,” as used herein, alone or in combination, refer to the divalent radical derived from benzene. Examples include benzothiophene and benzimidazole.
  • carbnmic acid as used herein, alone or in combination, refers to an ester of carbnmic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
  • O-carbamyl refers to a -OC(O)NRR', group-with R and R' as defined herein.
  • N-carbamyl as used herein, alone or in combination, refers to a ROC(O)NR'- group, with R and R' as defined herein.
  • carbonyl when alone includes fortnyl [-C(O)H] and in combination is a -C(O)- group.
  • carboxy refers to -C(O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt.
  • An "O-carboxy” group refers to ⁇ RC(O)O- group, where R is as defined herein.
  • a “C-carboxy” group refers to a— C(O)OR groups where R is as defined herein.
  • cyano as used herein, alone or in combination, refers to -CN.
  • cycloalkyl refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 to 12, preferably five to seven, carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclope ⁇ tyl, cyclohexyl, cycioheptyl, octahydronaphthyl, 2,3-dihydro-I H-indenyl, adamantyl and the like.
  • Bicyclic and tricyclic as used herein are intended to include both fused ring systems, such as decahydonapthalene, octahydronaptbalene as well as the multicyclic (mu)ticentered) saturated or partially unsaturated type.
  • the latter type of isomer is exemplified in general by, bicyclo[1,t ,l] ⁇ entane, camphor, ad ⁇ mantane, and bicyclof3.2,l]oct ⁇ ne.
  • esters refers to a carboxy group bridging two moieties linked at carbon atoms.
  • ether refers to an oxy group bridging two moieties linked at carbon atoms.
  • halo or halogen, as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloaJkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have an iodo, bromo, chJoro or fluoro atom within the radical.
  • Dihnlo and poly haloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • h ⁇ loalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethy), chloromethy), dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromelhyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • "Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF 2 -), chloromethyiene (-CHC1-) and the like.
  • heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroator ⁇ s selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemizetJ.
  • N and S may be placed at ⁇ y interior position of the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH3.
  • heteroaryl refers to 3 to 7 membered, preferably 5 to 7 membered, unsaturated heteromonocyclic rings, or fused polycyclic rings in which at least one of the fused rings is unsaturated, wherein at least one atom is selected from the group consisting of O, S, and N.
  • the term also embraces fused polycyclic groups wherein heterocyclic radicals are fused with aryl radicals, wherein heteroaryl radicals are fused with other heteroaryl radicals, or wherein heteroaryl radicals are fused with cycloajkyl radicals.
  • heteroaryl groups include pyrrolyl, pyrroiinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyronyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl.
  • heterocycloalkyl and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic radical containing at least one, preferably I to 4, and more preferably I to 2 heteroatoms as ring members, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein there are preferably 3 to S ring members in each ring, more preferably 3 to 7 ring members in each ring, and most preferably S to 6 ring members in each ring.
  • Heterocycloalkyl and “heterooycle” are intended to include sulfones, sulfoxides, N-o ⁇ ides of tertiary nitrogen ring members, and c ⁇ rbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
  • Heterocycle groups of the invention are exemplified by aziridinyl, azetidinyl, 1,3-benzodioxoJyl, dihydroisoindolyl, dihydrois ⁇ quinolinyl, dihydrocinnoHny), dihydrobenzodioxinyl, dihydro[I,3]oxazolor4,5-b]pyridinyl, benzothiazolyj, dihydroindolyl, dihy-dropyridinyl, 1 ,3-diox ⁇ ny], 1,4- dioxanyl, 1 ,3-dioxolany I, isoi ⁇ dofi ⁇ yl, morpholi ⁇ yl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.
  • the heterocycle groups may be optionally substituted unless specifically prohibited.
  • hydrozi ⁇ yl refers to two amino groups joined by a single bond, i.e., -N-N-.
  • hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
  • m the man chain refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of this invention.
  • isocyanato refers to a -NCO group
  • isothiocyanato refers to a -NCS group
  • linear chain of atoms refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
  • lower means containing from 1 to and including 6 carbon atoms.
  • merc ⁇ ptyl as used herein, alone or m combination, refers to an RS- group, where R is as defined herein.
  • nitro refers to -NO 2 .
  • perhaloalkoxy refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms
  • p ⁇ rhaloslkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • sulfonate refers the -SO 3 H group and its anion as the sulfonic acid is used in salt formation.
  • thia and thio refer to a — S- group or an ether wherein the oxygen is replaced with sulfur.
  • the oxidized derivatives of the thio group namely sulfinyl and sulfo ⁇ yl, are included in the definition of thia and thio.
  • thiol as used herein, alone or in combination, refers to an -SH group.
  • thiocarbonyl when alone includes thioformyl -C(S)H and in combination is a -C(S)- group
  • N-thiocarbamyl refers to an ROC(S)NR'- group, with R and R' as defined herein
  • O-thiocarbamyl refers to a -OC(S)NRR', group with R and R'as defined herein
  • t ⁇ halomethanesulfonamido refers to a XjCS(O) S NR- group with X is a halogen and R as defined herein.
  • trihalomethanesulfonyl refers to a X 3 CS(O)r- group where X is a halogen
  • tnhalomethoxy refers to a X 3 CO- group where X is a halogen
  • t ⁇ substituted silyl refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include t ⁇ methysilyl, tert-butyldimethylsilyl, lriphenylsilyi and the like.
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyt would represent an alkoxy group attached to the parent molecule through an alkyi group
  • the term "optionally substituted” means the anteceding group may be substituted or uns ⁇ bstituted.
  • the substituenls of an "optionally substituted” group may include, without limitation, one or more substiruents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, loweralkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower hftloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy,
  • fiiranyl, lower carbamate, and lower urea Two substituents may be joined together to form a fused five-, six-, or seven-menbered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or cthylenedioxy.
  • An optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 3 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ).
  • R ox refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted.
  • R. and R' groups should be understood to be optionally substituted as defined herein.
  • every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other
  • the compounds of the present invention may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • E
  • Z
  • compounds may exist as tautomcrs; all tautomeric isomers are provided by this invention.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • bonds refers to a covalent linkage between two atoms, or two moieties when lhe atoms joined by the bond are considered to be part of larger substructure.
  • a bond may be single, double, or triple unless otherwise specified.
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • PPAR modulator is used herein to refer Io a compound that exhibits an IC 50 with respect to PPAR activity of no more than about 100 ⁇ M and more typically not more than about 50 .mu.M, as measured in the PPAR assay described generally hereinbelow.
  • ICs 0 is that concentration of inhibitor which reduces the activity of an enzyme (e.g., PPAR) to half-maximal level, Representative compounds of the present invention have been discovered to exhibit inhibitory activity against PPAR.
  • Compounds of the present invention preferably exhibit an ICJ 0 with respect to PPAR of no more than about 10 ⁇ M, more
  • patient means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits.
  • therapeutically effective amount refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease, condition or disorder being treated.
  • a therapeutically effective amount refers to that amount which has the effect of (I) reducing the blood glucose levels; (2) normalizing lipids, e.g. triglycerides, low-density lipoprotein; (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the disease, condition or disorder to be treated; and/or (4) raising HDL.
  • an “enhance” or “enhancing” means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • amounts effective for this use will depend on the severity and course of the disease, disorder or condition (including, but not limited to, metabolic disorders), previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. It is considered well within the skill of the art for one to determine such enfiancing-efFective amounts by routine experimentation.
  • substituent is a group that may be substituted with one or more grou ⁇ (s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heleroalicyclic, hydroxy, alkoxy, perhaloalkoxy,( ⁇ referobly perfluoroalkyloxy), mono or dihaloalkoxy, aryloxy, mercapto, ⁇ ikylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-c ⁇ rbamyl, N-carbar ⁇ yl, O-thiocarbamyl, N-thiocarbamyl, C- ⁇ mido, N- ami do, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocya ⁇ ato, thi
  • Molecular embodiments of the present invention may possess one or more chir ⁇ l centers and each center may exist in the R or S configuration.
  • the present invention includes all diastcreomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns. Additionally, the compounds of the present invention may exist as geometric
  • the present invention includes all cis, trans, syn, anti,
  • E
  • Z
  • isomers as well as the appropriate mixtures thereof.
  • compounds may exist as tautomers. All tautomersare included within Formula I and are provided by this invention.
  • the compounds of the present invention can exist in unsolvnted as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolv ⁇ ted forms for the purposes of the present invention.
  • the present invention relates to a method of treating a disease comprising identifying a patient in need thereof, and administering a therapeutically effective amount of a compound of Formula I, as described herein, to the patient.
  • PPAR ⁇ The third subtype of PPARs, PPAR ⁇ (PP ⁇ R ⁇ , NUCl), is broadly expressed in the body and has been shown to be a valuable molecular target for treatment of dyslipidemia and other diseases.
  • PPAR ⁇ PPAR ⁇ R ⁇ , NUCl
  • a potent and selective PPAR ⁇ compound was shown to decrease VLOL and increase HDL in a dose response manner (Oliver el al,, Proc, Natl. Acad. Sci. U. S. ⁇ .98: 5305, 200I).
  • the compounds of the invention are useful in the treatment of a disease or condition ameliorated by the modulation of an PPAR-delta.
  • Specific diseases and conditions modulated by PPAR-delta and for which the compounds and compositions are useful include but arc not limited to dyslipidemia, syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance hyperlipidemia, obesity, anorexia bulimia, inflammation and anorexia nervosa.
  • Other indications include reduction of scarring and wound healing.
  • the compounds of the invention may also be used (a) for raising H0L in a subject; (b) for treating Type 2 diabetes, decreasing insulin resistance or lowering blood pressure in a subject; (c) for decreasing LDLc in a subject; (d) for shifting LDL particle size from small dense to normal dense LDL in a subject; (e) for reducing cholesterol absorption or increasing cholesterol excretion in a subject; (f) for reducing the expression of NPCl L I in a subject; (g) for treating atherosclerotic diseases including vascular disease, coronary heart disease, cerebrovascular disease and peripheral vessel disease in a subject; and (h) for treating inflammatory diseases, including rheumatoid arthritis, asthma, osteoarthritis and autoimmune disease in a subject.
  • the compounds of the invention may also be used for treating, ameliorating, or preventing a disease or condition selected from the group consisting of obesity, diabetes, hyperinsulinemia, metabolic syndrome X, polycystic ovary syndrome, climacteric, disorders associated with oxidative stress, inflammatory response to tissue injury, pathogenesis of emphysema, ischemia-associated organ injury.
  • a disease or condition selected from the group consisting of obesity, diabetes, hyperinsulinemia, metabolic syndrome X, polycystic ovary syndrome, climacteric, disorders associated with oxidative stress, inflammatory response to tissue injury, pathogenesis of emphysema, ischemia-associated organ injury.
  • doxorubicin-induced cardiac injury drug-induced hepatotoxicity, atherosclerosis, and hyp ⁇ rtoxic lung injury.
  • compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease, condition or disorder mediated, modulated or involving the PPARs, including but not limited to metabolic diseases, conditions, or disorders, as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the disease, disorder or condition.
  • Amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. It is considered well within the skill of the art for one to determine such therapeutically effective amounts by routine experimentation (e.g., a dose escalation clinical trial).
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition mediated, modulated or involving the PPARs, including but not limited to metabolic diseases, conditions, or disorders, as described above.
  • a particular disease, disorder or condition mediated, modulated or involving the PPARs including but not limited to metabolic diseases, conditions, or disorders, as described above.
  • Such an amount is defined to be a "prophylactically effective amount or dose.”
  • the precise amounts also depend on the patient's state of health, weight, and the like. It is considered well within the skill of the art for one to determine such prophylactically effective amounts by routine experimentation (e.g., a dose escalation clinical trial).
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. When the symptoms have been alleviated to the desired level, treatment can cease. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub- doses per day.
  • therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • statin and/or other lipid lowering drugs for example MTP inhibitors and LDLR upregulators
  • antidiabetic agents e.g. metformin, sulfonylureas, or PPAR-gamma, PPAR-alph ⁇ and PPAR-alpha/gamma modulators (for example thiazolidinediones such as e.g. Pioglitazone and Kosiglitazone)
  • antihypertensive agents such as angiotensin antagonists, e.g., telmisartan, calcium channel antagonists, e.g. lacidtpine and ACE inhibitors, e.g., enalapril.
  • the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may vary from more than zero weeks to less than four weeks.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, pulmonary, ophthalmic or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising exctpients and auxiliaries which facilitate processing of the active compounds into preparations which can
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as HanJ ⁇ s's solution. Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as HanJ ⁇ s's solution. Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the agents of the invention may be formulated in aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more compound of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, macrocrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethy I cellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coalings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Jn addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets, lozenges, or gels formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetmfluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetmfluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetmfluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetmfluoroethane
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethy I cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilisers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • a suitable vehicle e.g., sterile pyrogen- free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. , containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolve ⁇ t system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be a 10% ethanol, 10% polyethylene glycol 300, 10% polyethylene glycol 40 castor oil (PEG-40 castor oil) with 70% aqueous solution.
  • This cosolvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a cosolvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • the identity of the cosolvent components may be varied: for example, other
  • low-toxicity nonpolar surfactants may be used instead of PEG-40 castor oil, the fraction size of polyethylene glycol 300 may be varied; other biocompatible polymers may replace polyethylene glycol, e g., polyvinyl pyrrolidone; and other sugars or polysaccharides maybe included in the aqueous solution.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emutsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as N-methylpyrrolidone also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • Salts useful with the compounds of the present invention include, without limitation, calcium acetate, hydrochloric acid, phosphoric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, magnesium acetate, and p-toluenesulfonic acid salts.
  • the salts can be prepared by contacting the compounds of the invention with an appropriate acid, either neat or in a suitable inert solvent, to yield the salt fomi3 of the invention.
  • the reaction sol ution was stirred at 150 0 C for 24h.
  • the solution was cooled to room temperature, diluted with water (20 mL) and extracted from ethyl acetate (1 x 10 mL).
  • the organic solution was dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the residue was purified by silica gel
  • N'-(5-EfIiyl-pyrimidii ⁇ -2-yl)-N'-(4-(ri ⁇ uoromethoxy-benzyl)-efha ⁇ e-I ⁇ -diamine To a solution of 20% trifluoroacetic acid (2 mL) in methylene chloride (10 mL) was added ⁇ 2-[(5-ethyl-pyrimidin-2-yl)- ⁇ 4- trifluoromethoxy-benzyl-amino]-ethyl ⁇ -carbamic acid tert-butyl ester (100 mg, 0.28 mmo!). The reaction solution was stirred at room temperature for 3h.
  • J2-(4-TrinuorDinethoxy-be ⁇ zylami ⁇ o)-ethyl]-carbamic acid tcrt-butyl ester To a solution of 4- (trifluoromethc»ty)-benzaldehyde (237 mg, 1.25 mmol) in methylene chloride (30 mL) was added N-(2- aminoethyl)carbamic acid tert-butyl ester (200 mg, 1.25 mmol). After 1 h sodium triacetoxy borohydride (527 mg, 2.50 mmol) was added and the reaction mixture was stirred at room temperature for 4h.
  • ⁇ -Pentyl-N'-(4-trifluoromethoxy-bet ⁇ zyl)-ethane-l,2-diamine A solution of f 2-[pemyl-(4- trifluoromethoxy-benzyl)-amino.]-ethyl ⁇ -carbamic acid tert-butyJ ester ( 130 mg, 0.32 mmol) and 20% trifluoroacetic acid (2 mL) in dichloromethane (10 mJL) was stirred at room temperature for 3h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and extracted with IN NaOH.
  • Step 3 o Thaodosia SimpWnB Page 38 of SS 2007-01-1300:21:39 (GMT) From: LaV ⁇ rn Hall
  • Methyl 4-sulfamoyl-2-3-dihydro-1H-indene-2-CBrboxylate Ammonia (3.5 mL, 2M in methanol, 7 mmol) was added to a solution of methyl 4-(chlorosulfonyl)-2,3-dihydro-lH-indene-2-carboxylate (825 mg, 3 mmol) and dichloromethane (15 mL) at room temperature.
  • Example I Step 4. 1 H NMR (400 MHz, DMSO-d6): ⁇ 12.81 (s. 1 H), 7.96 (t, 1 H), 7.76 (d, 1 H), 7.60 (d, 1H), 7.47 (d, 1H), 7.33 (t, lH), 6.52 (d, I H), 4.03 (m, 2H), 3.56-3.26 (m, 3H), 3.16 (m, 4H), 2.57 (s, 3H),
  • Methyl 5-(N-methylsulfamoyl)-2,3-dilrydro-1H-indene-2-carboxylate Methylamine (9 mL, 2M in THF, 18 mmol) was added to a solution of methyl 5-(chlorosulfonyl)-2,3-dihydro-1H-indene-2-carboxylate (1..6 g, 5.8 mmol) and dichlorometh ⁇ n ⁇ (20 mL) at room temperature.
  • tert-Butyl 2-(l,3-dioxoist>indoJi ⁇ -2-yloxy)ethyl(mr ⁇ hyl)carbamate 2-(Methylamino)ethanol (10.0 g, 133.1 mmol), triethylamine (55 mL, 394.6 mmol), and BoC 2 O (18 mL, 78.4 mmol) were mixed in DMF (50 mL). The reaction was stirred at room temperature for 1 h then dry loaded on SiO. and purified by flash chromatography to afford tert-bulyl 2-hydroxyethyl(methyl)carbamate (10.85 g).
  • tert-Butyl 2- hydroxyethyl(methyl)carbamate (10.85 g, 61.9 mmol) was then dissolved in THF (500 mL). To this solution was then added triphenylphosphine (18.20 g, 69.4 mmol), ⁇ /-hydroxyphthalamide (12.13 g, 74.4 mmol) and di-tert-butyl azodic ⁇ rboxylate (19.50 g, 84.7 mmol) at 0 "C.
  • tert-Butyl-2-(bis(4-(tri ⁇ uoromethy0phenyl)methyle ⁇ eaniinooxy)e «hyl(r ⁇ ethyl) carbamate Hydrazine monohydrate (240 ⁇ L, 4.9 mmol) was added to a solution of tert-butyl-2-(1,3- dioxoisoindolin-2-yloxy)etbyl(methyl)carbamate (1.0 g, 3.1 mmol) in EtOH (15 mL) at room temperature. When the deprotection was complete by TLC, the mixture was concentrated to afford an off-white solid which was then extracted with diethyl ether.
  • Compounds may be screened for functional potency in transient t ⁇ msfection assays in CV-I cells for their ability to activate the PPAR subtypes (transactiv ⁇ tion assay).
  • transactiv ⁇ tion assay A previously established chimeric receptor system was utilized to allow comparison of the relative transcriptional activity of the receptor subtypes on the same synthetic response element and to prevent endogenous receptor activation from complicating the interpretation of results. See, for example, Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A; Wilkinson, W.O.; Willson, T. M.; Kliewer, S.
  • An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor S (PP ARS), J. Biol. Chem., 1995, 270, 12953-6.
  • the ligand binding domains for murine end human PP ⁇ R-alpha, PPAR-gomma, and PPAR-delta are each fused to the yeast transcription factor GAL4 DNA binding domain.
  • CV-I cells were transiently transfected with expression vectors for the respective PPAR chimera along with a reporter construct containing four or five copies of the GAL4 DNA binding site driving expression of luciferase.
  • the cells are replated into multi-well assay plates and the media is exchanged to phenol-red free DME medium supplemented with 5% delipidated calf serum. 4 hours after replating, cells were treated with either compounds or I %
  • DMSO for 20-24 hours. Luciferase activity was then assayed with Britelite (Perkin Elmer ⁇ following the manufacturer's protocol and measured with either the Perkin Elmer Viewlux or Molecular Devices Acquest (see, for example, Kliewer, S. A., et. al. Cell 1995, 83, 813-819). Rosiglitazone is used as a positive control in the PPAR ⁇ assay, Wy ⁇ l4643 and GW7647 is used as a positive control in the PPAR ⁇ assay. GW50I5I6 is used as the positive control in the PPAR ⁇ assay.
  • Examples I -20 were assayed to measure their biological activity with respect to their efficacy for modulating PPAR-alpha, PPAR-gamma, and PPAR-ddta.
  • EC 50 values arc set forth below in Table I .

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Abstract

L'invention concerne des composés utilisés en tant que modulateurs de récepteurs activés par les inducteurs de la prolifération des péroxysomes (PPAR), des compositions pharmaceutiques les contenant, et des méthodes de traitement de maladie au moyen desdits composés.
PCT/US2006/040079 2005-10-12 2006-10-11 Derives de sulfamide en tant que modulateurs de ppar WO2007047432A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7863276B2 (en) 2005-10-25 2011-01-04 Kalypsys, Inc Salts of modulators of PPAR and methods of treating metabolic disorders
US7915253B2 (en) 2004-10-29 2011-03-29 Kalypsys, Inc Sulfonyl-substituted bicyclic compounds as modulators of PPAR
WO2012030165A2 (fr) 2010-08-31 2012-03-08 서울대학교산학협력단 Utilisation de la reprogrammation fœtale d'un agoniste des ppar δ
US9371307B2 (en) 2011-09-12 2016-06-21 The Johns Hopkins University Serine protease inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004092117A1 (fr) * 2003-04-07 2004-10-28 Kalypsys, Inc. Composes phenyle a substitution para-sulfonyle utilises en tant que modulateurs des ppar
WO2005016881A1 (fr) * 2003-08-02 2005-02-24 Bayer Healthcare Ag Derives bicycliques d'indoline-sulfonamides
WO2005115983A1 (fr) * 2004-04-07 2005-12-08 Kalypsys, Inc. Composes aryl sulfonamide et sulfonyl utilises comme modulateurs de ppar, et procedes de traitement de troubles metaboliques
WO2006055187A1 (fr) * 2004-10-29 2006-05-26 Kalypsys, Inc. Composes bicycliques a substitution sulfonyle, modulateurs des ppars

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004092117A1 (fr) * 2003-04-07 2004-10-28 Kalypsys, Inc. Composes phenyle a substitution para-sulfonyle utilises en tant que modulateurs des ppar
WO2005016881A1 (fr) * 2003-08-02 2005-02-24 Bayer Healthcare Ag Derives bicycliques d'indoline-sulfonamides
WO2005115983A1 (fr) * 2004-04-07 2005-12-08 Kalypsys, Inc. Composes aryl sulfonamide et sulfonyl utilises comme modulateurs de ppar, et procedes de traitement de troubles metaboliques
WO2006055187A1 (fr) * 2004-10-29 2006-05-26 Kalypsys, Inc. Composes bicycliques a substitution sulfonyle, modulateurs des ppars

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Title
WILLSON T M ET AL: "THE PPARS: FROM ORPHAN RECEPTORS TO DRUG DISCOVERY", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 43, no. 4, 24 February 2000 (2000-02-24), pages 527 - 550, XP001066309, ISSN: 0022-2623 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7915253B2 (en) 2004-10-29 2011-03-29 Kalypsys, Inc Sulfonyl-substituted bicyclic compounds as modulators of PPAR
US7863276B2 (en) 2005-10-25 2011-01-04 Kalypsys, Inc Salts of modulators of PPAR and methods of treating metabolic disorders
WO2012030165A2 (fr) 2010-08-31 2012-03-08 서울대학교산학협력단 Utilisation de la reprogrammation fœtale d'un agoniste des ppar δ
US9371307B2 (en) 2011-09-12 2016-06-21 The Johns Hopkins University Serine protease inhibitors

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