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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/63—One oxygen atom
  • C07D213/65—One oxygen atom attached in position 3 or 5
  • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
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  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/14—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
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  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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  • 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
  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • 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
  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
  • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
  • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
  • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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  • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C62/30—Unsaturated compounds
  • C07C62/34—Unsaturated compounds containing ether groups, groups, groups, or groups
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
  • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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  • 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
  • C07D401/02—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 two hetero rings
  • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • 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
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • 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
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  • 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
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

• This invention relates to alpha substituted carboxylic acids that modulate the activities of peroxisome proliferator-activated receptor (PPAR), preferably two or more of PPAR- ⁇ , PPAR- ⁇ , or PPAR-y, enabling them to be useful in modulation of blood glucose and the increase of insulin sensitivity in mammals.
• PPAR peroxisome proliferator-activated receptor
• This invention also relates to treatment of PPAR related disorders, such as diabetes, dyslipidemia, obesity and inflammatory disorders.
• Peroxisome proliferators are a structurally diverse group of compounds which, when administered to rodents, 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.
• Chemicals included in this group are the fibrate class of hypolipidermic drugs, herbicides, and phthalate piasticizers
• Peroxisome proliferation can also be elicited by dietary or physiological factors such as a high-fat diet and cold acclimatization.
• PPAR- ⁇ activates transcription by binding to DNA sequence elements, termed peroxisome prolrferator response elements (PPRE), as a heterodimer with the retinoid X receptor.
• PPRE peroxisome prolrferator response elements
• the retinoid X receptor is activated by 9-cis retinoic acid (see Kliewer, et al., Nature, 358:771-774 (1992), Gearing, et al., Proc. Natl. Acad. Sci. USA, 90:1440-1444 (1993), Keller, et al., Proc. Natl. Acad. Sci.
• PPAR- ⁇ PPAR- ⁇
• PPAR-y PPAR-y
• PPAR- ⁇ PPAR- ⁇
• PPAR- ⁇ PPAR- ⁇
• PPAR-y PPAR-y
• PPAR- ⁇ PPAR- ⁇
• PPAR- ⁇ PPAR- ⁇ mediates adipocyte signalling, lipid storage, and fat metabolism.
• Evidence gathered to date support the conclusion that PPAR- ⁇ is the primary, and perhaps the only, molecular target mediating the insulin sensitizing action of one class of antidiabetic agents, the thiazolidine 2,4 diones.
• oral antidiabetic therapies may be limited, in part, because of poor or limited glycemic control, or poor patient compliance due to unacceptable side effects. These side effects include edema, weight gain, or even more serious complications. For instance, hypoglycemia is observed in some patients taking sulfonylureas. Metformin, a substituted biguanide, can cause diarrhea and gastrointestinal discomfort. Finally, edema, weight gain, and in some cases, hepatoxicity, have been linked to the administration of some thiazolidine 2,4 dione antidiabetic agents. Combination therapy using two or more of the above agents is common, but generally only leads to incremental improvements in glycemic control.
• Ring Q is (C 6 -C ⁇ 0 )aryl or (4-10)-membered heterocyclyl;
• R 1 is H, halo, (d-C ⁇ Jalkyl, (C C ⁇ )alkoxy, CN, CF 3 , -0-CF 3 , -0-S0 2 -(C,-C 8 )alkyl, -0-S0 2 -(CR 11 R 12 ) t (C 6 -C 10 )aryl,
• R 2 is H, (C Ca)alkyl, -(CR 11 R 12 ),-(C 3 -C 10 )cycloalkyl, -(CR 11 R 12 ),- (C 6 -C 10 )aryl, or -(CR 11 R 12 ),(4-10)-membered heterocyclyl; and wherein the carbon atoms of R 2 are optionally substituted by 1 to 3 R 13 groups; and the ring nitrogen atoms of R 2 are optionally substituted by 1 to 3 (C ⁇ -C 8 )alkyl;
• R 3 is selected from the group consisting of:
• Y" is NR 10 or-O-; p is 0, 1 , or 2; each q, r, and t are independently 0, 1 , 2, 3, 4, or 5; each n is independently 0, 1, 2, 3, or 4; each k is independently 1 , 2, or 3; each m and s are independently 0, 1, 2, or 3; each j is 0, 1 , or 2;
• Each R 4 is -(CR 11 R 12 ) n -, -(CR 11 R 12 ) n -S-(CR 11 R 12 ) n -, -(CR 11 R 12 ) n -NR 10 -, -(CR 11 R 12 ) n -NR 10 -(CR 11 R 12 ) n -0-, -(CR 11 R 12 ) n -0-(CR 11 R 12 ) k -NR 10 -,
• Each R 5 is a bond or -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CR 11 R 12 -, -0- , -NR 10a -, or -S(O) r ;
• M * is an alkali metal cation or an alkaline earth metal cation;
• Each R 7 and R ⁇ is independently H, (C C 8 )alkyl, (C r C 8 )alkoxy, -(CR 11 R 1 ),(C 3 -C 10 )cycloalkyl, -(CR 11 R 12 ) t (C 6 -C 10 )aryl, -(CR ⁇ R ⁇ Md-dcOaryl-O-, -(CR 11 R 12 ) t (4-10)-membered heterocyclyl or -(CR 11 R 12 ),(4-10)-membered heterocyclyl-O-;
• R 7 and R 8 may optionally be taken together with the carbon to which they are attached to form a (C 3 -C ⁇ 0 )cycloalkyl or a (3-10)-membered heterocyclyl;
• Each of Ar 1 , Ar 2 , Ar 3 , and Ar" represents (C 6 -C ⁇ 0 )aryl or (5-10)-membered heterocyclyl; wherein the ring carbon atoms of each of Ar 1 , Ar 2 , Ar 3 , and Ar 4 are optionally substituted by 1 to 3 R 13 groups;
• Ring A represents a 3, 4, 5, 6 or 7-membered ring optionally containing 1 to 4 heteroatoms which may be the same or different and which are selected from -
• R 9 is (d-C 8 )alkyl, -(CR 11 R 12 ),(C 6 -C 10 )aryl or -(CR 11 R 12 ),(4-10)-membered heterocyclyl, wherein t is independently 0, 1, 2, 3, 4, or 5, wherein said R 9 groups are substituted with 1 to 3 groups independently selected from -(CR 11 R 12 ) q NR 10 R 11 , -(CR 11 R 12 ) q NR 10 (d-C 6 )alkanoyl, -(CR 11 R 12 ) q O(CR 1 R 12 ) r R 10 , and -(CR 11 R 12 ) q R 10 ; and wherein the heterocyclyl, aryl and alkyl moieties of the foregoing groups are optionally substituted with 1 to 3 R 13 groups;
• R 9a and R 10 are independently H or (C ⁇ -C 8 )alkyl;
• R 11 and R 12 are independently H, (d-C 8 )alkyl, hydroxy, or (d-C 6 )alkoxy;
• Each R 13 and R 13a are independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, (d-C 6 )alkoxy, (d-C 10 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, -0-(CR 11 R 12 ) k -0-(CR 11 R 12 ) n -.
• R 14 , R 15 and R 16 groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, -NR R , trifluoromethyl, trifluoromethoxy, (C '1-
• R 17 is H, (C C 8 )alkyl, -0-(C C 8 )alkyl, halo, CN, OH, CF 3 , or-0-CF 3 ; and wherein any of the above-mentioned substituents comprising a CH 3
• the invention relates to compounds of the Formula
• the invention relates to compounds of the Formula I wherein R 3 is
• the invention relates to compounds of the Formula
• the invention relates to compounds of the Formula I wherein ring Q is selected from the group consisting of
• the invention relates to compounds of the Formula I wherein R 1 is H, halo, (d-C 8 )alkyl, (C C 8 )alkoxy, CF 3 , -0-CF 3 , -0-S0 2 -(d- C 8 )alkyl, -O-SO 2 -(CR 11 R 12 ),(C 6 -C 10 )aryl, or -(CR ⁇ R ⁇ MCe-doJaryl-O-, wherein the ring carbon atoms of R 1 are optionally substituted by 1 to 3 R 13 groups.
• the invention relates to compounds of the Formula
• the invention relates to compounds of the Formula
• R 4 is -(CH 2 ) n -; wherein n is independently 0, 1, 2, or 3.
• the invention relates to compounds of the Formula I wherein R 5 is a bond or -(CR 11 R 1 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -0-, -NR 10a -, or -S(0) j -; wherein each m and s are independently 0, 1, 2, or 3; and wherein j is 0, 1, or 2.
• the invention relates to compounds of the Formula I wherein R 5 is a bond, -0-, -CH 2 -, -C(CH 3 )H-, -C(OH)H-, or -C(0-(d-C 8 )alkyl)H-.
• M + is selected from the group consisting of Ca + ⁇ Li ⁇ Na + and K*.
• the invention relates to compounds of the Formula I wherein each R 7 and R 8 is independently H, (C ⁇ -C 8 )alkyl, or (C ⁇ -C 8 )alkoxy. ln another embodiment, the invention relates to compounds of the Formula I wherein each R 7 and R 8 are taken together with the carbon to which they are attached to form a (3-7)-membered heterocyclyl.
• the invention relates to compounds having a formula:
• the invention relates to compounds wherein said -A ⁇ -Ar 2 - is selected from the group consisting of:
• R 13 groups selected from the group consisting C 8 )alkyl, and (d-C 8 )alkoxy.
• said -A ⁇ -Ar 2 - is selected from the group consisting of:
• specific compounds of the present invention are selected from the group consisting of 2-Methyl-2-( ⁇ 3'-[2-(5-methyl-2-phenyl-1 ,3-oxazol-4-yl)ethoxy]-1 , 1 '-biphenyl- 3-yI ⁇ oxy)propanoic acid;
• a specific compound of the present invention is 2- ( ⁇ 3'-[2-(5- ethyl-2-phenyl-1 ,3-oxazol-4-yl)ethoxy]-1 , 1 '-biphenyl-3-yl ⁇ oxy)butanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- (3- 6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl ⁇ phenoxy)butanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 1- (3- ⁇ 6-[2-(5- ethyl-2-phenyl-1 ,3-oxazol-4-yl)ethoxy]pyridin-2- yl ⁇ phenoxy)cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 1- t(3'- ⁇ [5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy ⁇ biphenyl-3- yl)oxy]cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- [(3'- ⁇ 2-[2-(3-Fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy ⁇ biphenyl-3-yl)oxy]-2- methylpropanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- methyl-2-( ⁇ 3'-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]biphenyl-3- yl ⁇ oxy)propanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ethoxy-3- ⁇ 3 , -[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]biphenyl-3-yl ⁇ propanoic acid or the pharmaceutically acceptable salts thereof.
• the invention relates to compounds having a formula:
• Y" is NR 10
• p is 1.
• each of R 11 and R 12 are independently H.
• Ar 3 is phenyi.
• a specific compound of the present invention is 2- ethyl-2- ⁇ 3-t( ⁇ [2-(5-methyl-2-phenyl- 1 ,3-oxazol-4- yl)ethoxy]carbonyl ⁇ amino)methyl]phenoxy ⁇ propanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- methyl-2- ⁇ 3-[( ⁇ [(5-methyl-2-phenyl-1,3-oxazol-4- yl)methoxy]carbonyl ⁇ amino)methyl]phenoxy ⁇ propanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- methyl-2- ⁇ 4-[( ⁇ [3-(5-methyl-2-phenyl-1,3-oxazol-4- yl)propoxy]carbonyl ⁇ amino)methyl]phe ⁇ oxy ⁇ propanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2-
• a specific compound of the present invention is 2-(2-(5-methyl-2-phenyl-1,3-oxazol-4- yl)ethoxy]carbonyl ⁇ amino)methyl]phenoxy ⁇ -2-methylpropanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2-
• a specific compound of the present invention is 2- ⁇ 3-[( ⁇ [(5-methyl-2-phenyl-1,3-oxazol-4- yl)methoxy]carbonyl ⁇ amino)methyr]phenoxy ⁇ butanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 1- ⁇ 3-[( ⁇ [2-(5-Methyl-2-phenyl-1,3-oxazol-4- yl)ethoxy]carbonyl ⁇ amino)methyl]phenoxy ⁇ cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- methyl-2-(3- [( ⁇ I2-(5-methyl-2-phenyl-1,3-oxazol-4- yl)ethyl]amino ⁇ carbonyl)oxy]methyf ⁇ phenoxy)propanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ethoxy-3- ⁇ 3-[( ⁇ [3-(5-methyl-2-phenyl-1,3-oxazol-4- yl)pro ⁇ oxy]carbonyl ⁇ amino)methyl]phenyl ⁇ propanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ethoxy-3- ⁇ 3-[( ⁇ [2-(5-methyl-2-phenyl-1 l 3-oxazol-4- yl)ethoxy]carbonyl ⁇ amino)methyl]phenyl ⁇ propanoic acid or the pharmaceutically acceptable salts thereof.
• the invention relates to compounds having a formula:
• ring A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• ring A is selected from the group consisting of
• ring A is selected from the group consisting of
• ⁇ is an optional double bond.
• ring A is selected from the group consisting of
• Ar 4 is phenyi, naphthyl, pyridinyl, pyrimidinyl, or pyrazinyl.
• specific compounds of the present invention are selected from the group consisting of 1- ⁇ 4-[2-(5-methyl-2-phenyl-1,3-oxazol-4- yl)ethoxy]benzy! ⁇ cyclohexanecarboxylic acid;
• a specific compound of the present invention is 1- ⁇ 4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]benzyl ⁇ cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 1- ⁇ 4-f2-(5-methyl-2-pheny!-1 ,3-oxazol-4-yl)ethoxy]benzyl ⁇ cyclobutanecarboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ( ⁇ 6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3- yl ⁇ methyl)tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ( ⁇ 5-[2-(5-methyl-2-phenyl-1 , 3-oxazol-4-yl)ethoxy]pyridin-2- yl ⁇ methyl)tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ( ⁇ 6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl ⁇ methyl)tetrahydro-2 + pyran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- [(6- ⁇ 2-[2-(3-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy ⁇ pyridin-3- yl)methyl]tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- [(6- ⁇ 2-[2-(3-methoxyphenyl)-5-methyl-1 ,3-oxazol-4-yl]ethoxy ⁇ pyridin-3- yl)methyl]tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ⁇ 5-[2-(5- ethyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazin-2-ylmethyl ⁇ -tetrahydro-furan- 2-carboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is - ⁇ 4-t2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl ⁇ tetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ⁇ 6-[2-(5- ethyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-2-ylmethyl ⁇ -tetrahydro- furan-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
• the invention relates to compounds having a formula:
• the invention relates to compounds having a formula:
• the invention relates to compounds having a formula:
• R 9 is methyl, ethyl, or benzyl.
• R 51 ⁇ 7' i:.s. H.
• a specific compound of the present invention is 2- ethoxy-3- ⁇ 6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl ⁇ propanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- methoxy-3-(6- ⁇ 2-[5-methyl-2-(3-methylphenyl)-1,3-oxazol-4-yl]ethoxy ⁇ pyridin-3- yl)propanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- methoxy-3- ⁇ 6-[2-(4-phenoxyphenyl)ethoxy]pyridin-3-yl ⁇ propanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ethoxy-3-[6-(2- ⁇ 4-[(phenylsulfonyl)oxy]pheny ⁇ ethoxy)pyridin-3-yl]propanoic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2-
• a specific compound of the present invention is 2- Methoxy-2-methyl-3- ⁇ 6-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-pyridin-3-yl ⁇ - propionic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- Methoxy-2-methyl-3- ⁇ 5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-2-yl ⁇ - propionic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 3- (6- ⁇ 2-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy ⁇ -pyridin-3-yl)-2-methoxy-2- methyl-propionic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ethoxy-2-methyl-3- ⁇ 6-[2-(5-methyl-2-phenyl oxazol-4-yl)-ethoxy]-pyridin-3-yl ⁇ - propionic acid or the pharmaceutically acceptable salts thereof.
• a specific compound of the present invention is 2- ethoxy-3-(6- ⁇ 2-[2-(3-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy ⁇ -pyridin-3-yl)- 2-methyl-propionic acid or the pharmaceutically acceptable salts thereof.
• the present invention also provides a method of treating non-insulin dependent diabetes mellitus in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I).
• said mammal has an impaired glucose tolerance.
• the present invention also provides a method of treating polycystic ovarian syndrome in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating obesity in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of reducing body weight in an obese mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating hyperglycemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating hyperlipidemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating hypercholesteremia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating atherosclerosis in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating hypertriglyceridemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating hyperinsulinemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating a patient suffering from abnormal insulin and/or evidence of glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating insulin resistance syndrome in humans comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating PPAR-related disorders in humans comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of modulating PPAR activity in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of lowering blood glucose in a mammal, comprising administering to a mammal an amount of a compound of Formula (I) effective to lower blood glucose levels.
• the present invention also provides a method of modulating fat cell differentiation in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of modulating processes mediated by PPAR in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of increasing insulin sensitivity in mammals, comprising administering to a mammal a therapeutically effective amount of a compound of Formula (I).
• the present invention also provides a method of treating metabolic syndromes selected from the group consisting of galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-6- phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.
• the present invention also provides a composition comprising at least one modulator of PPAR of Formula (I) and a pharmaceutically acceptable carrier thereof.
• Exemplary pharmaceutically acceptable carriers include carriers suitable for oral, intravenous, subcutaneous, intramuscular, intracutaneous, and the like administration.
• the PPAR agonists of the present invention may be administered in combination with other agents such as ⁇ -glucosidase inhibitors, afdose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin- converting enzyme inhibitors.
• agents such as ⁇ -glucosidase inhibitors, afdose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin- converting enzyme inhibitors.
• an ⁇ -glucosidase inhibitor is a medicament having action in inhibiting a digestive enzyme such as amylase, maltase, ⁇ - dextrinase or sucrase, thereby retarding the digestion of starch or sucrose.
• ⁇ -glucosidase inhibitors examples include acarbose, N-(1,3-dihydroxy-2- propyl)variolamine (common name: voglibose) and miglitol.
• an aldose reductase inhibitor is a medicament which inhibits a rate-limiting enzyme of the first step of the polyol pathway, thereby inhibiting diabetic complications.
• examples include tolrestat, epalrestat, 2,7- difluoro-spiro(9H-fluoren-9,4'-imidazolidine)-2 , ,5'-dione (common name: imirestat), 3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-qu inozolineacetic acid (common name: zenarestat), 6-fluoro-2,3-dihydro-2,5'-dioxo- spiro[4H-1-benzopyran-4,4'-imidazolidine]- 2-carboxamide (SNK-860), zopolrestat, sorbinil and 1- ⁇ (3-bromo-2-benzofur
• a biguanide preparation is a medicament having effects in anaerobic glycolysis promotion, insulin action reinforcement at the periphery, intestinal glucose absorption inhibition, hepatic gluconeogenesis inhibition and fatty-acid oxidation inhibition and examples include phenformin, metformin and buformin.
• a statin base compound is a medicament which inhibits hydroxymethylglutaryl CoA (HMG-CoA) reductase, thereby lowering the blood cholesterol level and examples include pravastatin and the sodium salt thereof, simvastatin, lovastatin, atorvastatin and fluvastatin.
• HMG-CoA hydroxymethylglutaryl CoA
• a squalene synthesis inhibitor is a medicament for inhibiting squalene synthesis, thereby lowering the blood cholesterol level and examples include monopotassium (S)- ⁇ -[bis(2,2-dimethyl-1- oxopropoxy)methoxy]phosphinyl-3-phenoxybenzene-butanesulfonate (BMS-
• a fibrate base compound is a medicament for inhibiting synthesis and secretion of triglycerides in the liver and activating lipoprotein lipase, thereby lowering the triglyceride level in the blood.
• examples include bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibric acid, ethofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate and theofibrate.
• a LDL catabolism promoter is a medicament for increasing LDL (low-density lipoprotein) receptors, thereby lowering the blood cholesterol level and examples include compounds described in Japanese Patent Application Kokai Hei 7-316144 or salts thereof, more specifically, N-[2-[4-bis(4- fluorophenyl)methyl-1 -piperazinyl]ethyl]-7,7-diphenyl-2,4,6- heptatrienoic amide.
• statin base compounds, squalene synthesis inhibitors, fibrate base compounds and LDL catabolism promoters can be replaced with another chemical effective for lowering the blood cholesterol or triglyceride level.
• examples of such a medicament include nicotinic acid derivative preparations such as nicomol and niceritrol; antioxidants such as probucol; and ion exchange resin preparations such as cholestyramine.
• an angiotensin-converting enzyme inhibitor is a medicament for inhibiting angiotensin-converting enzyme, thereby lowering the blood pressure and at the same time, partially lowering the blood sugar level of a patient suffering from diabetes.
• Examples include captopril, enalapril, alacepril, delapril, ramipril, lisinopril, imidapril, benazepril, ceronaprill cilazapril, enalaprilat, fosinopril, moveltipril, perindopril, quinapril, spirapril, temocapril and trandolapril.
• suitable carriers include emulsions, solutions, suspensions, syrups, and the like, optionally containing additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents, and the like.
• suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
• non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
• Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by inco ⁇ orating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.
• adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by inco ⁇ orating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.
• halo as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
• alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
• alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety.
• alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
• alkoxy as used herein, unless otherwise indicated, includes O- alkyl groups wherein alkyl is as defined above.
• Me means methyl
• Et means ethyl
• Ac means acetyl
• cycloalkyi refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, preferably 5-8 ring carbon atoms.
• exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
• Illustrative examples of cycloalkyi are derived from, but not limited to, the following:
• aryl includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyi or naphthyl.
• 4-10 membered heterocyclic includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
• Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
• the heterocyclic groups include benzo-fused ring systems.
• An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
• An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl.
• non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2- pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazoiinyl, di
• aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyi, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
• a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached).
• a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C- attached).
• the 4-10 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring.
• heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl.
• 4-10 membered heterocyclic are derived from, but not limited to, the following:
• -A ⁇ -Ar 2 - as used herein, unless otherwise indicated include two rings without any limitation of the order of attachments to R 4 and R 5 . For example, if
• phrases "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula (I).
• the compounds of formula (I) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula (I) are those that form non-toxic acid addition salts, Le., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, alate, maleate, mandelate, mesylate, methylsulfate
• R 11 and R 12 may vary with each iteration of q or t above 1. For instance, where q or t is 2 the terms (CR 11 R 12 ) q or (CR ⁇ R 12 ⁇ may equal -CH 2 CH 2 -, or -CH(CH 3 )C(CH 2 CH 3 )(CH 2 CH 2 CH 3 )-, or any number of similar moieties falling within the scope of the definitions of R 11 and R 12 .
• any substituents comprising a CH 3 (methyl), CH 2 (methylene), or CH (methine) group which is not attached to a halogeno, SO or S0 2 group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, d-C 4 alkoxy and amines.
• treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
• treatment refers to the act of treating as “treating” is defined immediately above.
• modulate refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
• modulator refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
• hormone expression control or to repress expression of gene(s) maintained under such control.
• “obese” is defined, for males, as individuals whose body mass index is greater than 27.8 kg/m, and for females, as individuals whose body mass index is greater than 27.3 kg/m 2 .
• the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity.
• Inflammatory disorders refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.
• therapeutically effective amount refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
• amount . . . effective to lower blood glucose levels refers to levels of compound 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 ⁇ M; with concentrations in the range of about 100 nM up to 500 nM being preferred.
• concentrations typically falls in the range of about 10 nM up to 2 ⁇ M; with concentrations in the range of about 100 nM up to 500 nM being preferred.
• the activity of different compounds which fall within the definition of Formula (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.
• insulin resistance refers to the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus.
• insulin resistance syndrome refers to the cluster of manifestations that include insulin resistance, hyperinsulinemia, non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, and dyslipidemia.
• NIDDM non insulin dependent diabetes mellitus
• the phrase "in combination with”, as used herein, means that the alpha substituted carboxylic acids compound of Formula (I) may be administered shortly before, shortly after, concurrently, or any combination of before, after, or concurrently, with such other agents as described in the previous paragraphs.
• the alpha substituted carboxylic acids compound of Formula (I) and the other agents may be administered simultaneously as either as a single composition or as two separate compositions or sequentially as two separate compositions.
• Certain compounds of formula (I) may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula (I), and mixtures thereof, are considered to be within the scope of the invention.
• the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof.
• the compounds of formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof. ⁇
• Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini, et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
• the subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 7 0, 31 P, 2 P, 35 S, 18 F, and 36 CI, respectively.
• Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
• isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are inco ⁇ orated, are useful in drug and/or substrate tissue distribution assays.
• Tritiated, i.e., 3 H, and carbon-14, i.e., 1 C, isotopes are particularly preferred for their ease of preparation and detectability.
• substitution with heavier isotopes such as deuterium, i.e., H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
• Isotopically labelled compounds of Formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
• This invention also encompasses pharmaceutical compositions containing and methods of treating bacterial infections through administering prodrugs of compounds of the formula 1.
• Compounds of formula 1 having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
• Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of formula 1.
• the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
• Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 79, 115.
• Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
• R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -0-, -NR 10 ⁇ or -S(0) r ; wherein m and s are independently 0, 1 , 2, or 3; and wherein j is 0, 1 , or 2
• R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -0-, -NR 10a -, or -S(0) r ; wherein each m and s are independently 0, 1, 2, or 3; and wherein j is 0, 1 , or 2
• R 5 Is ⁇ CR' , R ,2 ) m -Z-(CR 1, R 12 ),; wherein Z is -CH r ; wherein each m and s are independently 0. 1. 2. or 3.
• R 5 is -(CR 1 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CH 2 -; wherein each and s are independently 0, 1, 2, or 3.
• R 5 is -(CR 11 R 12 )m-Z-(CR 11 R 12 )s; wherein Z is -CH 2 -; wherein each m and s are independently 0, 1, 2, or 3.
• R 5 is -(CR 1 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -0-, -NR 10a -, or -S(0) r ; wherein each m and s are independently 0, 1 , 2, or 3; and wherein j is 0, 1 , or 2.
• the compound of formula la may be prepared by hydrolysis of compounds Ha, wherein the group C0 2 R is a hydrolyzable ester group such as methyl ester (C0 2 -CH 3 ) or ethyl ester (C0 2 -CH 2 CH 3 ), by alkali metal hydroxides (e.g. NaOH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF, aqueous methanol or combinations thereof) at a temperature between 0 and 100 degrees or by heating in a microwave synthesizer.
• a suitable solvent e.g. aqueous THF, aqueous methanol or combinations thereof
• Compound IVa can be obtained by alkylation of compound Va, wherein Lv 1 is as described above, with compound Via, wherein Lv 2 is CI, Br, I, or triflate.
• the compound of formula Ilia which is used in Scheme 1, may be obtained from compounds Vila, wherein Lv 3 is CI, Br, I, or triflate, by palladium(O) mediated coupling reactions with a reagent such as pinacolatodiborane.
• Compounds Vila, wherein Lv 3 is as described above can be obtained by alkylation of compounds Villa, wherein Lv 3 is as described above, with compound IXa, wherein Lv 4 is CI, Br, I, or triflate.
• esters Ha which is used in Scheme 1, wherein the group C0 2 R is as described above, may also be prepared by alkylation of compound Xa, wherein the group C0 2 R is as described above, with compound Via, wherein Lv 2 is as described above in the description of Scheme 1.
• Compounds Xa may be obtained from compound Xla, wherein the group C0 2 R is as described above, by reacting compound Xla with a deprotecting agent, such as with hydrogen gas over a metal catalyst (e.g. palladium on carbon) in a suitable solvent (e.g. THF, methanol, ethanol) at a temperature between 0 degrees Celcius and 100 degrees Celcius.
• a deprotecting agent such as with hydrogen gas over a metal catalyst (e.g. palladium on carbon) in a suitable solvent (e.g. THF, methanol, ethanol) at a temperature between 0 degrees Celcius and 100 degrees Celcius.
• (CR 1 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -O-, -NH 10 ⁇ or -S(0) r ; wherein each m and s are independently 0, 1, 2, or 3; and wherein j is 0, 1, or 2; may be prepared by hydrolysis of compounds lib, wherein R 5 is as described in the compounds of formula lb and the group C0 2 R is as described above, by an alkali metal hydroxide (e.g. Na OH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF, aqueous methanol or combinations thereof) at a temperature 0 degrees Celcius and 100 degrees Celcius.
• a suitable solvent e.g. aqueous THF, aqueous methanol or combinations thereof
• Compounds of formula lib wherein R 5 is as described in the compounds of formula lb, may be prepared by reaction of compounds lllb, wherein R 5 is as described in the compounds of formula lib and the group C0 2 R is as described above, with an activated acylating agent such as Vlb in a suitable solvent (e.g. THF, acetonitrile, dioxane, toluene) at a temperature between 0 degrees Celcius and 100 degrees Celcius.
• a suitable solvent e.g. THF, acetonitrile, dioxane, toluene
• Compounds IVb may be obtained from compound Vb by reacting compound Vb with compound Vlb, wherein Lv 6 is a leaving group.
• Suitable compound Vlb includes N,N'-carbonyl diimidazole.
• compounds of formula 1Mb which is used in Scheme 4, wherein R 5 is as described in the description of Scheme 4 and the group C0 2 R is as described above, may be prepared by reacting compound Vllb wherein R 5 is as described in the previous paragraph, with an appropriate electrophile of formula Lv 6 -C(R 7 R 8 )-C00R, wherein Lv 6 is a leaving group such as halo, in the presence of a base (e.g. cesium carbonate, potassium carbonate) in a suitable solvent (e.g. THF, DMF, acetonitrile, or DMSO) at a temperature between 0 degrees Celcius and 100 degrees Celcius.
• Suitable electrophiles of formula Lv 6 - C(R 7 R 8 )-COOR include methyl 2-bromo-2-methyl propanoate.
• Compounds Vllb are commercially available or can be made by those skilled in the art.
• compounds of formula lc, wherein R 5 is - (CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CH r . may be prepared by hydrolysis of compounds He, wherein the group C0 2 R is as described above, by alkali metal hydroxides (e.g. NaOH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF, aqueous methanol or combinations thereof) at a temperature between 0 degrees Celcius and 100 degrees Celcius or by heating in a microwave synthesizer.
• alkali metal hydroxides e.g. NaOH, LiOH, KOH
• a suitable solvent e.g. aqueous THF, aqueous methanol or combinations thereof
• Compounds He may be prepared by alkylation of compound lllc, wherein Lv 5 is a leaving group, with compound IVc (when Lv 7 is iodide, bromide, chloride or other leaving group).
• Compounds Vc may be prepared from compounds Vic by reacting compounds Vlllc with a reducing agent, such as sodium borohydride.
• a reducing agent such as sodium borohydride.
• compounds of formula He wherein R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) 8 ; wherein Z is -CH 2 -, may be prepared by the reductive deoxygenation of compound Vlllc using a silane and an acid source, typically triethylsilane and trifluoroacetic acid.
• Compounds Vlllc may be obtained by addition of compound lllc to compound Vic.
• Mitsunobu-type conditions e.g. triphenyl phosphine and diethylazodicarboxylate.
• Compounds IXc can be prepared by deprotection of protected compounds Xc.
• Suitable protecting groups can include allyl, benzyl etc.
• Compound XIVc can be prepared by reacting compound XVc with (C-0)CI 2 in a polar aprotic solvents such as dimethylformamide.
• Compound XVc can be prepared by reacting compound Xllc with a reducing agent, such as sodium borohydride.
• a reducing agent such as sodium borohydride.
• Compounds Xlllc may be prepared by the method described in Scheme 6.
• the compound of formula lc wherein R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -0-, -NR 10a -, or -S(0) r ; wherein each m and s are independently 0, 1, 2, or 3; and wherein j is 0, 1, or 2; may be prepared by hydrolysis of compounds He by alkali metal hydroxides (e.g.
• a suitable solvent e.g. aqueous THF, aqueous methanol or combinations thereof
• a suitable solvent e.g. aqueous THF, aqueous methanol or combinations thereof
• a base e.g. cesium carbonate, potassium carbonate or potassium f-butoxide
• compounds of formula Id may be prepared by hydrolysis of compounds lid by alkali metal hydroxides (e.g. NaOH, LiOH, KOH) in a suitable solvent (e.g. aqueous THF, aqueous methanol or combinations thereof) at a temperature between 0 degrees Celcius and 100 degrees Celcius.
• a suitable solvent e.g. aqueous THF, aqueous methanol or combinations thereof
• Compounds of formula lid may be prepared by reaction of compounds Hid with an appropriate hydrogenation agent such as hydrogen gas over a metal catalyst (e.g., palladium on carbon) in a suitable solvent (e.g. THF, methanol, ethanol) at a temperature between 0 degrees Celcius and 100 degrees Celcius.
• Compounds of formula Hid may be prepared by reaction of compounds IVd with an appropriate triphenyl phosphine reagent having a formula: (C 6 H 5 ) 3 P + -CH(OR 9 )(COOR) Cr in a Wittig reaction.
• Suitable triphenyl phosphine reagents include 1,2-diethoxy-2- oxoethyl)(triphenyl) phosphonium chloride.
• Compounds of formula IVd may be prepared by reaction of compounds Vd as described in Scheme 9.
• Compounds of formula Vd may be prepared by reaction of compounds Vld and Vlld as described in Scheme 9.
• compounds of formula lid may be prepared by the methods of Scheme 13.
• alkylation of enolate anion of methyl 2- methoxy propanoate with a benzyl halide IXd affords compounds Vllld.
• Compounds Vllld can be elaborated to compounds lid by e.g. palladium mediated coupling reaction.
• Compounds lid may also be prepared from compounds Xd.
• Compounds Xd can be prepared from compounds Xlld by a sequence of reactions such as (i) palladium mediated coupling reaction to form compounds Xld, and (ii) reduction of the ester to alcohol, and (iii) halide formation to form compounds lid.
• any of the above compounds of formula I and any of the compounds in the schemes 1-13 above can be converted into another analogous compound by standard chemical manipulations. These chemical manipulations are known to those skilled in the art and include a) removal of a protecting group by methods outlined in T. W. Greene and P.G.M.
• the compounds of the present invention may have asymmetric carbon atoms.
• Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
• Enanfjomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers; or by chromatographic separation using chiral stationary or mobile phase. All such isomers, including diastereomeric mixtures and pure enant j omers are considered as part of the invention.
• the compounds of formulas (I) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula (I) from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the tatter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
• the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
• the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
• Those compounds of formula (I) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
• the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non- toxic base salts with the acidic compounds of formula (I).
• Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
• salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
• they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
• stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
• the compounds of the present invention are modulators of PPAR, preferably PPAR ⁇ and ⁇ .
• the compounds of the present invention can modulate processes mediated by PPAR- ⁇ , which refers to biological, physiological, endocrinological, and other bodily processes which are mediated by receptor or receptor combinations which are responsive to the PPAR agonists described herein (e.g., diabetes, hyperiipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts and coronary artery diseases and the like), arteriosclerosis, pregnancy diabetes, poiycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heart disease and the like), cell injury (e.g.
• inflammatory diseases e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, GI ulcer, cachexia, autoimmune diseases, pancreatitis and the like
• cancer e.g. arthrosteitis, pain, pyrexia, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergosis, asthma, GI ulcer, cachexia, autoimmune diseases, pancreatitis and the like
• Modulation of such processes can be accomplished in vitro or in vivo. In vivo modulation can be carried out in a wide range of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like.
• the compounds of the present invention may also be useful in the treatment of other metabolic syndromes associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycys ' itic ovarian syndrome, obesity, hyperglycemia, hyperiipidemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman's Medical Dictionary (Xth Ed.).
• the in vitro activity of the compounds of formula (I) may be determined by the following procedure.
• SPA Scintillatian Proximity Assay
• 3H labeled darglitazone for PPAR- ⁇
• GW2331 for PPAR- ⁇
• the PPAR-bound 3H labeled ligand can be displaced by an unlabeled compound.
• the Ki of the compound can be then determined by the extent of displacement at various compound concentrations.
• SPA polylysine beads which can be purchased from Amersham Bioscience.
• the alpha substituted carboxylic acids compounds of Formula (I) may be provided in suitable topical, oral and parenteral pharmaceutical formulations for use in the treatment of PPAR mediated diseases.
• the compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixars.
• the compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations. Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets.
• these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period.
• a pharmaceutically acceptable enteric coating such as glyceryl monostearate or glyceryl distearate
• Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
• the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
• Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension.
• excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occuring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
• This suspension may be formulated according to know methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
• the sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
• accetable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• the alpha substituted carboxylic acids compounds of Formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non- irritating excipient that is solid at about room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non- irritating excipient include cocoa butter and other glycerides.
• topical use preparations for example, creams, ointments, jellies solutions, or suspensions, containing the compounds of the present invention are employed.
• the alpha substituted carboxylic acids compounds of Formula (I) may also be administered in the form of liposome delivery systems such as small constitutionalamellar vesicles, large constitutionalamellar vesicles and multimellar vesicles.
• Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines.
• Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight.
• a preferred dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
• HPLC chromatography is referred to in the preparations and examples below, the general conditions used, unless otherwise indicated, are as follows.
• the column used is a ZORBAXTM RXC18 column (manufactured by Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter.
• the samples are run on a Hewlett Packard- 1100 systemA gradient solvent method is used running 100 percent ammonium acetate / acetic acid buffer (0.2 M) to 100 percent acetonitrile over 10 minutes.
• the system then proceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes.
• the flow rate over this period is a constant 3 ml / minute.
• Et means ethyl
• AC means acetyl
• Me means methyl
• ETOAC or "ETOAc” means ethyl acetate
• THF means tetrahydrofuran
• Bu means butyl.
• Example A-3 2-Methyl-2-f ( 3'-f2-ri- ( 6-methylPyridazin-3-yl)piperidin-4-vnethoxyV1.1'-biphenyl-3- vDoxylpropanoic acid
• Example A-4 1- «3'-r2-(5-Methyl-2-phenyl-1.3-oxazol-4-yltethoxy1-1.1'-biphenyl-3- yl ⁇ oxy)cvclobutanecarboxylic acid
• the ethereal layer was removed and the aqueous layer acidified to pH 2 with 1 N hydrochloric acid at 0 °C and stirred for 20 min.
• the white precipitate was collected by filtration and washed with ice-cold water. After drying at 40 °C under high vacuum the title compound was afforded as a white crystalline solid (0.091 g, 70%).
• Examples B-2 to B-29 were prepared by procedures analogous to that used for Example B-1.
• methyl ester b-21q was prepared by reacting compound b-21f with compound b-21c in yields ranging from 60 to 90%.
• Triethylsilane (1.03 g, 8.86 mmol) was added to a solution of methyl 1 -(hydroxyl ⁇ 4- [2-(5-methyl-2-phenyl-1,3-oxazol-4- yl)ethoxy]phenyl ⁇ methyl)cyclohexanecarboxylate (0.797 g, 1.77 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) at room temperature. The resulting mixture was stirred for 1 hour then evaporated in vacuo and azeotroped with heptane.
• Examples C-2 to C-5 were prepared by procedures analogous to those used for Example C-1 with the exception that the final hydrolysis step was carried out by dissolving the crude residue in dimethyl sulfoxide (75 mo/mD and 6N sodium hydroxide (1 mL) and heating at 150 °C for 10 minutes in a microwave synthesizer.
• Example C-6 or by stirring a solution of the ester with sodium or lithium hydroxide in agueous methanol. aqueous ethanol, agueous tetrahydrofuran or mixtures thereof at temperatures between 20 °C and 75°C.
• Lithium hydroxide monohydrate (993 mg, 21.1 mmol) was added to a solution of 10 (4S)-4-benzyl-3- ⁇ [2-( ⁇ 6-t2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3- yl ⁇ methyl)tetrahydrofuran-2-yl]carbonyl ⁇ -1,3-oxazolidin-2-one (600 mg, 1.06 mmol) in a mixture of tetrahydrofuran:methanol:water (1:1:1, 12 mL). The mixture was stirred at 50°C for 4.5 hours, then cooled to ambient temperature and stirred for 2 days.
• Example C-48b Enantiomer 2 of 2-( ⁇ 6-r2-(5-methyl-2-phenyl-1.3-oxazol-4-v ethoxylPyridin-3- yllmethvhtetrahvdrofuran-2-carboxylic acid
• Enantiomer 2 was prepared using a similar sequence of reactions to those described for enantiomer 1, except starting from (4R)-4-benzyl-1 ,3-oxazolidin-2- one.
• Preparations c-14 to c-35 were prepared using analogous procedures to those used for Preparation c-1.
• Preparation c-36 Ethyl 1 -(4-r2-(4'-methoxy-1.1 '-biphenyl-4-yl)ethoxy1benzyl)cvclobutanecarboxylate
• Oxalyl chloride (0.30 mL, 3.44 mmol) was added to a solution of ⁇ 6-[2-(5-methyl-2- phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl ⁇ methanol (Preparation 26) (0.97 g, 3.13 mmol) in dichloromethane (30 mL) and ⁇ /, ⁇ /-dimethyl formamide (3 L) at 0 °C. The mixture was warmed to ambient temperature and stirred for 1 hour then evaporated. The residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
• 9-Borabicyclononane (4.2 mL of a 0.5M solution in tetrahydrofuran, 2.07 mmol) was added to a yellow solution of 4-allyl-5-methyl-2-phenyl-oxazole (0.21 g, 1.04 mmol) in dry tetrahydrofuran (1 mL).
• Tetrabutylammonium fluoride (2.8 mL of a 1M solution in tetrahydrofuran, 2.78 mmol) was added dropwise to a solution of 2-(fert-butyl-dimethyl-silanyloxymethyl)- 5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazine ( ⁇ 1.39 mmol) in dry tetrahydrofuran (20 mL). The mixture was stirred at ambient temperature for 16 hours and then quenched with water (1 mL), and acidified to pH 5 with 1M aqueous acetic acid solution.
• n-Butyllithium (22.6 mL of a 2.5M solution in hexanes, 56.4 mmol) was added dropwise to a solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (10.0 g, 56.4 mmol) in tetrahydrofuran (200 mL) at -78°C. The mixture was stirred for 30 minutes then a solution of tetrahydrofuran-2-carbonyl chloride (9.12 g, 67.7 mmol) in tetrahydrofuran (25 mL) was added. The mixture was stirred at -78°C for 30 minutes, warmed to 0 C C over 1 hour and quenched with saturated ammonium chloride solution.
• Trifluoroacetic anhydride (1.55 g, 7.38 mmol) was added slowly, with a rate of one drop every 10 seconds, to an ice-cold solution (0 °C) of tetrahydro-furan-2- carboxylic acid amide (0.77 g, 6.71 mmol) and pyridine (1.06 g, 13.42 mmol) in anhydrous 1,4-dioxane (10 mL).
• the addition of trifluoroacetic anhydride was monitored to keep the internal temperature below 5 °C and was completed after 20 minutes. The resulting mixture was allowed to warm to ambient temperature, and stirred for 3 hours.
• Lithium hydroxide monohydrate (180 mg, 4.31 mmol) was added to a solution of ethyl 2-ethoxy-3- ⁇ 6-[2-(5-methyl-2-phenyl- 1 , 3-oxazol-4-yl)ethoxy]pyridin-3- yljpropanoate (183 mg, 0.431 mmol) in a mixture of tetrahydrofuran:methanol:water (1:1:1, 6 mL). The mixture was stirred 18 hours then the volatile components were removed by evaporation. The aqueous phase was acidified with 3M hydrochloric acid and extracted with ethyl acetate.
• Examples D-2 to D-45 were prepared by procedures analogous to those used for Example D-1 by stirring a solution of the ester with sodium or lithium hydroxide in aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran or mixtures thereof at temperatures between 20 °C and 75°C.
• Phosphorous tribromide (100 mmol, 27.1 g, 2.0 eq.) was added carefully to 2- chloro-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 eq.). The pyridine clumped together and the mixture was heated to 160 °C. Within 5 minutes of
• the compounds of the invention have been tested for activities against PPAR- gamma and PPAR-alpha. The activities are tabulated below in Ki ( ⁇ m).
• E/M is defined as enantiomeric mixture, including racemic mixture.
• S/E is defined as single enantiomer.
• E/M is defined as enantiomeric mixture, including racemic mixture.
• S/E is defined as single enantiomer
• E/M is defined as enantiomeric mixture, including racemic mixture.
• S/E is defined as single enantiomer

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