ZA200508362B - Alpha substituted carboxylic acid as PPAR modulators - Google Patents

Alpha substituted carboxylic acid as PPAR modulators Download PDF

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ZA200508362B
ZA200508362B ZA200508362A ZA200508362A ZA200508362B ZA 200508362 B ZA200508362 B ZA 200508362B ZA 200508362 A ZA200508362 A ZA 200508362A ZA 200508362 A ZA200508362 A ZA 200508362A ZA 200508362 B ZA200508362 B ZA 200508362B
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South Africa
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acid
methyl
oxazol
ethoxy
phenyl
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ZA200508362A
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Bailey Simon
Skalitzky Donald James
Zehnder Luke Raymond
Humphries Paul Stuart Wei-Guo
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Pfizer
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Description

-f-
Background of The Invention
This invention relates to alpha substituted carboxylic acids that modulate the activities of peroxisome proliferator-activated receptor (PPAR), preferably two or more of PPAR-a, PPAR-S, or PPAR-y, enabling them to be useful in modulation of blood giucose and the increase of insulin sensitivity in mammals. 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, efick dramatic increases in the size and number of hepatic and renal peroxisomes, as well 8s concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes required for the B-oxidation cycle. Chemicals included in this group are "45 the fibrate class of hypolipidermic drugs, herbicides, and phthaiste plasticizers (Reddy and Lawani, Crit. 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 ascciimatization. . ) Insight into the mechanism whereby peroxisome proiiferators exert their pleiotropic effects was provided by the identification of a member of the nuclear hormone receptor superfamily activated by these chemicals (Isseman and Green,
Nature, 347-845-850 (1990)). This receptor, termed PPAR-a, was subsequently shown to be activated by a variety of medium and long-chain fatty acids and to stimulate expression of the genes encoding rat acyl-CoA oxidase and hydrstase- dehydrogenase (enzymes required for peroxisomal B-oxidation), as well as rabbit cytochrome P450 4AS, a fatty acid O-hydroxylase.
PPAR-a activates transcription by binding to DNA sequence elements, termed peroxisome proiiferator response elements (PPRE), as a heterodimer with the retinoid X receptor. The retinoid X receptor is activated by 9-cis retinoic acid (see Kliewer, et al, Nature, 358.771-774 (1962), Gearing, et al., Proc. Natl. Acad.
Sci. USA, 80:1440-1444 (1993), Keller, et al., Proc. Natl. Acad. Sci. USA, 90:2160- 2164 (1993), Heyman, et al., Cell, 68.387-406 (1982), and Levin, et al., Nature, 355:350-361 (1992). Since the PPAR-a-RXR complex can be activated by peroxisome proiiferators and/or 9-cis retinoic acid, the retinoid and fatty acid signaling pathways are seen to converge in modulating lipid metabolism.
Since the discovery of PPAR-a, additional isoforms of PPAR have been identified, e.g., PPAR-5, or PPAR-y, which are spatially differentially expressed.
Each PPAR receptor shows a different pattem of tissue expression, and a2 differences in activation by structurally diverse compounds. PPAR-y, for instance, ls expressed most abundantly in adipose tissue and at lower levels in skeletal muscle, heart, iver, intestine, kidney, vascular endothelial and smooth muscie cetis as well as macrophages. Two isoforms of PPAR-y exist, identified as v and ys, respectively. PPAR-ymediates adipocyte signalling, %pid storage, and fat metabolism. Evidence gathered to date support the conclusion that PPAR-y is the primary, and perhaps the only, molecular target mediating the insulin sensitizing action of one class of antidiabetic agents, the thiazofidine 2,4 diones. in a monotherapeutic or combination therapy context, new and established oral antidiabetic agents are stil considered to have non-uniform and even limited effectiveness. The effectiveness of oral antidiabetic therapies may be limited, in part, because of poor or imited glyosmic 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 kinked to the administration of some thiazokidine 24 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.
As a result, there is 2 heed for antidiabetic agents that display combined
PPAR-a and PPAR-y activation which should lead to the discovery of efficacious glucose and triglyceride lowering drugs that have great potential in the treatment of type 2 diabetes and the metabolic syndrome (i.e., impaired glucose tolerance, insulin resistancem hyoertriglyceridemia and/or obesity).
Summary of The invention
The present invention provides novel compounds of Formula (1):
R!
Joi
R? 0) or a pharmaceutically acceptable sak or solvate thereof, wherein:
Ring Q is (Ce-Cio)aryl or {4-10)-membered heterocyclyl;
R' is H, halo, (CiCe)akyl, (Ci-Celakkoxy, CN, CF. -O-CFs, -0-SO(C-Co)alkyl, -0-80(CR"'R)(Ce-Crolaryl. {CRVR%){(Cy-Crolcycloalky-(CR''R"), ACR''R"WCs-CrlcycioalkyH(CR''R™)-0- , {CR"R™HCrCrHCR'R™:, ~(CRR™CeCrola{CR"R)O-,
-(CR"'R"?)(4-10)-membered heterocyclyHCR"'R'?\ of {CR''R™)-(4-10)- membered heterocyclyH(CR''R™)-O-; wherein the ring carbon stoms of R' are optionally substituted by 1 1 3 R™ groups; and the ring nitogen atoms of R' are optionally substituted by 1 to 3 (Cy-Coalkyt,
RE is H (Cr-Coakyl, «CR"R™){(CxCrocycloaliyl, {CR"R%) (Ce-Cro)aryl, or (CR''R™)(4-10)-membered heterocyclyl; and wherein the carbon atoms of RE are optionally substituted by 1 to 3 R™ groups; and the ring nitrogen atoms of R? are optionafly substituted by 1 to 3 (C,-Caalkyl;
R® is selected from the group consisting of.
A) t——RO——Ar'—AF—R® r*
Se M
B RY" AP—R® Re
RY R®? R’ s . o Lo ge—at— FR ( — rR" y) | R12
I 4 < R® da x
Y is -(C=0)- or -SOr;
Y* is NR™ or -O-; pis0, 1,002; each q, r, and t are independently 0, 1,2,3,4,0r 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 jis 0, 1,0r2;
Each R* is ~CR"R'),-, -(CR"R™), -S-(CR"R%), ~CR"'R"*)-NR"-, «CR" R'%),-NR"«CR"'R'3)-0-, {CR"R'),-O-(CR"'R'})NR"-, «CR"R"*)-O0-(CR"R'})\r, (CR"'R'}),-0-(CR"'R"*)-0-(CR"'R")sv, «CR''R'*)-CR"'=CR'’{CR"'R"*)y-, or -CH=CH-(CR''R'})-O-(CH2)~:
-lh =
Each R®is a bond or ~(CR"R%)p-Z-(CR"'R™),; Wherein Z is CR"'R%, -O- , NR'™-, or -S(O)r;
Each R° is -(C=O)OH, —C=OyOM’, -(C=OHCrCialyl,
L(CSO}O-(Cr-Calshyl, -C=OFNR™R", {C=OMNR™-SO-R", -SOrNH-R™, § .NH-SOrR', AC=0)}-NH-CaN, or R® has a formula:
N—N ..
Ny yA N 0 of H
M" is an alkali metal cation or an alkaline earth metal cation;
Each R' and R' is independently H, (CrCalakyl, (CrCaalkoxy.
LCR"R™(CsCro)cycioakyl, -CR"R™MCeCriary, ~(CR''R*MCe-CraarytO- {CR"R'’)4-10)-membered heterocyciyl of -(CR"'R"*){4-10)-membered heterocyciyt-O-;
Or R? and R® may optionally be taken together with the carbon to which they are attached to form a (Cs-Cio)cycloatiyl or a (3-10)-membered heterocyclyl;
Each of Ar’, A? A”, and Ar” represents (Cs-Cig)aryl or (5-10)-membered heterocyclyl; wherein the ring carbon atoms of each of Ar’, AZ, AP, and Ar’ are optionally substituted by 1 to 3 R*® 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 -
N(R'™)-, O, and S(O), wherein | is 0, 1, or 2, with the proviso that the ring does not contain two adjacent O or S(O), atoms, and wherein the carbon atoms of the ring A moiety are optionally substituted by 1 to 3 R"> groups;
R® is (Ci-Coalkyl, (CR''R™}Ce-Cioaryl or -(CR"'R"%),(4-10)}-membered heterocyclyl, wherein t is independently 0, 1, 2, 3, 4, or 5, wherein said R® groups are substituted with 1 to 3 groups independently selected from {CR"R'}),NR"R", {CR"'RJ)NR"(C, -Ce)alkanoyl, «CR"R"){O(CR" RR", and <CR"R"HR™; and wherein the heterocyclyl, aryl and alkyl moieties of the foregoing groups are optionally substituted with 1 to 3 R™ groups;
R™ and R"° sre independently H or (C,-Ce)alky!,
R" and R™ are independently H, (C+-Ca)alicyl, hydroxy, or (Ci-Ce)alkoxy,
R'™ is selected from H, (C+-Coalkyl, (C=O)-R", -SO,NR'*R™, or -S(O)(C4-Ce)atkyl;
Each R" and R™ are independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, (Ci-Ce)alkoxy, (Cr-Ciakyl, (CzCe)alkenyl, (CrCoalkynyl, -O-(CR"'R*),-0-(CR"'R")r, (C=O)
R" 4C=O}OR", -O{(C=O}R". -NR™(C=O}R", -NR'*(C=0)-0-R", -(C=O)-NR'"R'®, -NR"R', -NR"OR", -SO.NR'"R™, -S(O}(C:-Ce)akyl, -O-SO
RY, NR'%.SO-R", R'S (CR"R"™){Ce-Cro aryl), -(CR"'R"){4-10)-membered heterocyciyi, «CR"'R")q(C=0)(CR"'R"}(Ce-Crolaryl, -(CRVR™){(C=O)CR''R™)(4-10)-membered heterocyclyl, «(CRV'R'HO(CR"'R'})¢(Co-Cro)aryi, «CR"'R"O(CR"'R'})¢(4-10)-membered heterocyclyl, «(CR"'R'})SOxCR"'R™}{(Ce-CroJaryl, and -(CR"R")SOx(CR"'R"}){4-10)-membered heterocyclyl; 1 or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R™ and R'™ groups are optionally substituted with an oxo (=O) moiety, and the alkyl, alkenyl, alkynyl, ary! and heterocyclic moieties of the foregoing R" and R'> groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, triflucromethoxy, azido, OR", «C=0)R"™, +C=0)}-O-R", -0-(C=0)R", -NR"(C=0)-R", +C=O)-NR"R", NR'R", NR'OR", (Cr
Cgalkyl. (CrCoskenyl, (CrCodalynyl, «(CR'R™)}CeCularyl, and -(CR"'R'?){4-10)-membered heterocyclyl; each RY, R', and R' is independently selected from H, (Ci-Celalkyl, {CR"'R'}){Ce-Cro)aryl, and -(CR"'R')(4-10)-membered heterocyclyl; 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (=O) moiety, and the alkyl, aryl and heterocyclic moieties of the foregoing R™, R" and
R'™ groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, -NR''R", trifluoromethyl, trifuoromethoxy, (Ci-
Ce)alkyl, (CrCa)alkenyl, (C2-Ca)aliynyl, hydroxy, and (C-Ce) alkoxy;
RY is H, (C,-Ca)alkyl, -O-(C+-CaJakkyl, halo, CN, OH, CF, or -O-CFy; and wherein any of the above-mentioned substituents comprising a CH, (methyl), CH, (methylene), or CH (methine) group which is not attached to a haio,
SO or SO, group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, halo, (C+-C)alkyl, (C+-C.)akoxy, -NHz, -NH(Cy-
Ca)alkyl, and -N{(C+Ca)alkyl)z. in one embodiment, the invention relates to compounds of the Formula wherein R® is
A) RA — ATR" R®
Xe in another embodiment, the invention relates to compounds of the Formula wherein R® is
-8~
B) TN A —R RE x X
RACE.
Within this embodiment, preferred ~RL.Y-Y- are ~(CR"'R"),-0-(CR"'R")r(C=0)-NR"- or <{CR"'R")s-NR"’~(C=0)-O-.
In another embodiment, the invention relates to compounds of the Formula
IwhereinR’Is : 6 0) 0
In another embodiment, the invention relates to compounds of the Formula wherein R’ is rR"
Be
D) ——R* H, Re
R™ Xow in another embodiment, the invention relates to compounds of the Formula wherein ring Q is selected from the group consisting of 3 0 ON O—\ oO-N S N= N-N \J 4 N \ ’ & a 50 Sy [ex SN NS
FN IN N
‘SIT AXELEe. ge; . _/ . —_— . J , \=—=/ . and (0] .
In another embodiment, the invention relates to compounds of the Formula | wherein R' is H, halo, (C-Cy)akyl, (Ci-Co)alkoxy, CFs, -O-CF,, -0-S0(Cs-
Ce)akyl, -O-SOr(CR"'R"}{Ce-Cra)aryl, Of «CR"'R')(Cq-C1o)aryt-O-, wherein the ring carbon atoms of R' are optionally substituted by 1 to 3 R" groups. in another embodiment, the invention relates to compounds of the Formula 3 when RZ is H, phenyl, | CH °N
Sts [of sor OH, OH
FFs of 0) ne—o—{_ 4 3 . and on—{ Hb
N=N
In another embodiment, the invention relates to compounds of the Formula
R! | wherein OT.
CFs Fy O-«(Cs-Coakyl
CFs OQ Q 3,0, TT , R , : S02 (C1-Co)alkyl ; Ce-Cioaryl SOz(Ce-Cyo)aryl
R® I rR?
CH, CH
SUP oo al R® on R® Or rR?
CHs ole \ ® San ovo OO
Hy [)
A = OHO
Rr? oJ me—o—{ I+ J
CF, d 1] NN 1] ’ ¢ HN N . and —/ : in another embodiment, the invention relates to compounds of the Formula { wherein R* Is -CHzO-, -CHyO-CHy, -CHyCHzO-, -CH=CH-CHrO-, or -CHCHzCHZ-O-.
In another embodiment, the invention relates to compounds of the Formula wherein R*is ~(CH,)a-; wherein n is independently 0, 1, 2, or 3.
Ini another embodiment, the invention relates to compounds of the Formula wherein R® is a bond or <(CR''R™)-Z-(CR''R™),; wherein Z is -O-, -NR'®., or
S(O) wherein each m and s are independently 0, 1, 2, or 3; and wherein jis 0, 1, 1§ or2.
In another embodiment, the invention relates to compounds of the Formula wherein R®Is a bond, -O-, CH, -C(CHyH-, L(OH)H-, or -C(O-(C-Ce)akyhH-. in another embodiment, the invention relates to compounds of the Formula wherein R® is —(C=0)-OH. in another embodiment, the invention relates fo compounds of the Formula wherein R® is ~(C=0)-OM’, wherein M’ is selected from the group consisting of
Ca™, L* Na’and K'. in another embodiment, the invention relates to compounds of the Formula { wherein each R’ and R® is independently H, (C-Ca)atkyt, or (Ci-Co)alkoxy.
In another embodiment, the invention relates to compounds of the Formula wherein each R” and R® are taken together with the carbon to which they are attached to form a (3-7)-membered heterocyclyl. in another embodiment, the invention relates to compounds having a formula: o R2 . Rr! 4
N
: RA —ar'—AP—RY R®
De
Within this embodiment, the invention relates to compounds wherein said -Ar'-Ar- is selected from the group consisting of. 0-000
N= N =
O—0 OO 00
N=; N= po \ /
N N N NN N
O-O00--00—0 \ 7. \ 7". N—7
N "= a ;° a JR
San W : an a . wherein the ring carbon atoms of each of Ar' and Ar” are optionally substituted by 1 to 3 R"™ groups selected from the group consisting of halo, (C+
Cua)alkyl, and (C4-Colalkoxy.
Preferably, said —Ar'-Ar- is selected from the group consisting of.
N
= yo N ; and
Within this embodiment, specific compounds of the present invention are selected from the group consisting of
2-Methyt-2-({3'-[2-(5-methyt-2-phenyt-1 ,3-oxazol-4-yhethoxy}-1,1'-biphenyl- 3-yfoxy)propanoic acid; 2-Methyl-2-{(3'{[4-(triftuoromethyfbenzyfloxy)-1 ,*-biphenyi-3- yi)oxy]propanoic acid; 2-Methyk-2-{(3'-{2{1(6-methylpyridazin-3-yl)piperidin-4-yflethoxy}-1,1- biphenyi-3-yloxy]propanoic acid; 1-{{3"-[2-(5-Methyt-2-phenyi-1 ,3-oxazok4-ylethoxy}-1.1'-biphenyt-3- yljoxy)cyclobutanecarboxyhic acid; oT 2-({32-(5-Methyt-2-pheny}-1,3-oxazol-4-yl)ethoxy}-1,1'-biphenyt-3- yl)oxy)butanoic acid; 2-(3-{8-{2-(5-Methyi-2-phenyt-1 .3-oxazol-4-yl)ethoxylpyridin-2- yi}phenoxy)butanoic acid; 1-(3-{8-12-(5-Methyl-2-phenyt-1,3-0xazol-4-ylyethoxylpyridin-2- yljphenoxy)cyciobutanscarboxylic acid; 2-Methyl-2-(3-{B-12-(5-methy}-2-pheny}-1,3-0xazol-4-yljethoxylpyridin-2- yllphenoxy)propanoic acid; 2-Methyh-2-(3-{8-f2-(5-mettyi-2-phenyt-1 ,3-oxazol-4-yl)ethoxylpyrazin-2- yliphenoxy)propanoic acid; and and pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 1- ((3-{2-(5-Methyl-2-phenyt-1,3-oxazol4-yf)ethoxy}-1,1'-biphenyk-3- yfoxy)cyciobutanecarboxytic acid or the pharmaceutically acceptable saits thereof.
Within this embodiment, a specific compound of the present invention is 2- ({3-{2-(5-Methyt-2-phenyt-1,3-oxazoH4-yl)ethoxy}-1.1 “biphenyi-3-yfjoxy)butanoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- (3-{6-2-(5-Methy}-2-phenyi-1,3-oxazol-4-yl)ethoxylpyridin-2-yllphenoxy)butanoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 1- (3-{6-{2-(5-Methyl-2-phenyl-1 ,3-oxazol-4-ylethoxylpyridin-2- yfiphencxy)cyciobutanecarboxylic acd or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 1- [(3'{12-(3-fuorophenyl)-5-methyt-1, 3-oxazol4-ylimethoxy}biphenyi-3- yhoxylkyclobutanecarboxylic acid or the pharmaceutically acceptable saits thereof.
Within this embodiment, a specific compound of the present invention is 1- ({3-[3-(5-methyt-2-phenyi-1, 3-oxazol-4-yl)propoxylbiphenyt-3- ylloxy)cyclobutanecarbaxylic acid or the pharmaceutically acceptable salts thereof.
-41=-
Within this embodiment, a specific compound of the present invention is 1- [(3'{I5-(4-methoxyphenyi)-1 2.4-oxadiazol-3-yljmethoxy)biphenyt-3- yloxylcyclobutanecarboxytic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- [(3'2-{2-(3-Fluorophenyl)-5-methyk-1,3-oxazok4-yljethoxy}biphenyt-3-yloxy}-2- methylpropanoic acid or the pharmaceuticsily acceptable saits thereof.
Within this embodiment, a specific compound of the present invention is 2- methyl-2-{3"-{(S-methyl-2-phenyi-1 ,3-oxazol-4-y)methoxy]bipheny}-3- yl}oxy)propanoic acid or the pharmaceutically acceptable saits thereof.
Within this embodiment, a specific compound of the present invention is 2- ethoxy-3-{3-[2-(5-methyl-2-phenyt-1 ,3-oxazo+4-yhethoxylbiphenyi-3-yl}propanoic acid or the pharmaceutically acceptable salts thereof. in another embodiment, the invention relates to compounds having a formula: rR?
RA—Y—Y" AP —RS R® we XX,
R" R* FR ; wherein Y is -(C=0)- or -§O, Y* is NR", and pis 1.
Preferably, sach of R"' and R" are independently H.
Preferably, Ar” is phenyl.
Within this embodiment, specific compounds of the present invention are selected from the group consisting of 1-(3-{((2{3- (Trifluoromethyl)phenyilethaxy)carbonyl)amino]methyllphenoxy) cyclobutanecarboxytic acid; 2-(3-{I({2{3- (Trifiuoromethylphenyllethaxy}carbonyl)aminojmethyl}phenoxy)butanoic acid; 2-Methyt-2-(3-{[({2{3- (trifiuoromethyl)phenyljethoxy)carbonyf)aminojmethyf}phenoxy) propanoic acid; 2-Methyl-2-{3-{({[2-(5-methyl-2-pheny-1,3-0xaz0l-4- ylethoxyjcarbonyf}amino)methy] phenoxy)propanoic acid;
2-Methyt-2-(3-{1({14-(S-methyt-1,2,4-oxadiazol-3- yhbenzyljoxy)carbonyl)aminojmethyl} phenoxy)propanoic acid; 2-(3-[({[2-(5-Methyt-2-pheny}-1,3-oxazot-4- yhethoxylcarbonyljamino)methyfjohenoxy} butanoic acid, 1-{3-{({[2-(5-Methyt-2-phenyi-1,3-0xazol-4- : yl)ethoxy)carbonyljamino)methyflphenoxy} cyciobutanecarboxylic acid; 1{3-[({I3-(5-Methyl-2-pheny}-1,3-0xazol-4- yl)propoxylcarbonyfjamino)methyflphenoxy} cyclobutanecarboxylic acid; 2-{3-{({I3-(5-Methyl-2-phenyi-1,3-0xazol-4- yl)propoxy]carbonyfjamino)methyf] phenoxylbutanoic acid; 2-Methyt-2-{3-{({13-(5-methyl-2-phenyt-1 ,3-oxarol-4- yhpropoxyjcarbonyllamino) methyl] phenoxy}propanoic acid; and pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- Methyl-2-{3-{({12-(5-methyt-2-pheny}-1,3-0xazol-4- yl)ethoxyjcarbonyljaminc)methyfiphenoxy}propanoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- methyt-2-(3-{({(5-methy}-2-phenyt-1,3-oxazo-4- yl)methoxy)carbonyljamino)methyljphenoxy}propanolc acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- methyl-2-{4-[({[3-(5-methy}-2-phenyt-1,3-0xazoi-4- yl)propoxylcarbonyflamino)methyflphenoxy}propenoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- {3-fluoro-4-{({J2-(5-methyl-2-phenyl-1,3-0xazoH4- yl)ethoxy)carbonyljaminc)methyfjphenoxy})-2-methylpropanoic acid or the pharmaceutically acceptable sats thereof.
Within this embodiment, a specific compound of the present invention is 2- {3-{({12-(5-Methyl-2-phenyi-1,3-0xazol-4- yl)ethoxylcarbonyfjamino)methyfjphenoxy}butanoic acid or the pharmaceutically acceptable salts thereof.
43 ~-
Within this embodiment, a specific compound of the present invention is 2- {3-{({[(5-methy}-2-phenyt-1,3-0xazol-4- yhmethoxylcarbonyflaminojmethyfjphencxy}butanoic acid or the pharmaceutically acceptable salts thereof. \Within this embodiment, a specific compound of the present invention is 1- (3-{({[2-(5-Methyt-2-phenyt-1,3-0xazo-4- y)ethoxylcarbonyllaminojmethyliphenoxy)cyclobutanecarboxyfic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- methyl-2-(3-{({-(5-methyl-2-phenyi-1 ,3-0xazol-4- yDethyljaminojcarbonyfloxylmethyfjphenoxy)propancic acid or the pharmaceutically acceptable saits thereof.
Within this embodiment, a specific compound of the present invention is 2- ethoxy-3-{3-{({I3-(S-methy}-2-pheny}-1,3-oxazol-4- yhpropoxy)carbonyljamino)methyllphenyljpropancic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- ethoxy-3-{3-{({l2-(S-methy}-2-phenyt-1,3-0xazol-4- yhethoxyjcarbonyl}amino)methy(lphenyflpropancic acid or the pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to compounds having a formula: :
Rr? 0)
Ty
In ancther embodiment, ring A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
In another embodiment, ring A is selected from the group consisting of
XD 29! A Ro ag 108 Rr y S 108 Tea
R'® 'S Roe wherein — is an optional double bond. in another embodiment, ring A is selected from the group consisting of
J J N BIEN NR
BE) WEN :
R'“N—O 10s —NR'® XO 2 i wherein — is an optional double bond.
In ancther embodiment, ring A is selected from the group consisting of 1] Ral wherein — is an optional double bond.
Within this embodiment, Ar* is phenyl, naphthyl, pyridinyl, pyrimidinyl, or pyrazinyl.
Within this embodiment, specific compounds of the present invention are selected from the group consisting of e15= 1-{4-[2{5-methyl-2-phenyt-1 ,3-oxazol-4- yiethoxylbenzylicyclohexanecarboxylic acid; 1-44-[2-(5-methyl-2-phenyt-1 ,3-0X82Z0k-4~ yiyethoxylbenzylicyclopentanecarboxylic acid; 1-{4-[3«(S-methyt-2-phenyt-1 ,3-oxszol-4- ypropaxyjbenzyficyclopentanecarboxylic acid; 4-{4-[(5-methy}-2-phenyi-1 3-oxazoh4-ymethoxy]benzyijtetrahydro-2H- pyran-4-carboxylic acid; 4-{4-[2-(5-methy}-2-phenyt-1 ,3-oxazoh4-yl)ethoxylbenzyfjtetrahydro-2H- pyran-4-carboxylic acid; 1-{4-{2-(4-methoxy-1 1"-biphenyl-4-yljethoxylbenzyflcyclobutanecarboxyfic acid; 1-{4-f2-(4'-fioro-1 1-biphenyi-4-yliethoxylbenzylicyciobutanecarboxyfic acid; 1-{4-[2-(2'-methoxy-1,1"-biphenyi-4-yllethoxybenzyljcyciobutanecarboxylic acid; 1-{4-{2-{3-(trifworomethoxy)-1.1"-biphenyl-4- yilethoxy)benzyl)cyciobutanecarboxyfic scid; 1-(4-{2-{4-(6-methoxypyridin-3- yphenyflethoxy}benzyfcyciobutanecarboxylic acid; 1-(4-{244'{methyisuifonyl)-1,1'-biphenyt-4- yijethoxy}benzyf)cyclobutanecarboxyiic acid; 1-(4-{2-}4-(2,3-dihydro-1-benzofuran-8- yphenyfjethaxy)benzyl)cyclobutanecarboxylic ack; 1-{4-(2-{4'{(methyisulfonyl)amino}-1,1"-biphenyl-4- yllethoxy)benzyfjcyciobutanecarboxylic acid; 1-{4-[3-(5-methy}-2-phenyt-1 ,3-0xazol-4- yl)propoxylbenzyijcyciobutanecarboxylic acid, 1-{4-[(5-methyt-2-phenyl-1 ,3-oxazol-4- y))methoxyjbenzyfjcyciobutanecarboxylic acid; 1-{3-[2-(5-methyi-2-phenyi-1 ,3-oxazoi-4- yi)ethoxy benzyljcyciobutanecarboxylic acid, 1-{4-[2-(5-methy}-2-phenyh-1,3-0xazol-4- yhethoxylbenzyilcyclobutanecarboxytic acid; 3s 1-{4-{(2,5-dipheny}-1,3-oxazol-4-yl)methoxylbenzyl}cyclobutanecarboxylic add, 1-{4-[3-(2,5-diphenyt-1 3-oxazoH4-yl)propoxylbenzylicyclobutanecarboxylic acid,
«416 ~- 1-{44{(2,5-diphenyt-1,3-oxazol-4- y)methoxylphenoxy)cyclobutanecarboxylic acid; 1-{4-{3-(2,5-diphenyt-1 3-oxazo-4- ylipropoxylphenoxyjcyciobutanecarboxylic acid; 1-(4-2-§2-(1,1"-bipheny}-4-yl)-5-methy}-1,3-0xazol-4- yijethoxyjphenoxy)cyciobutanecarboxyfic acid; 1-{4-2-(5-methy}-2-phenyi-1,3-oxazol-4- yhethoxylphenoxy)cyclobutanecarboxylic acid; ~ 1-{4-[3-(5-methy}-2-pheny}-1,3-0xazok-4- yl)propoxylphenoxy)cyclobutanecarboxylic acid; 1-{4-{(5-methyl-2-phenyi-1,3-oxazol-4- } ymethoxylphenoxy}cyclobutanecarboxylic acid; 1-({8-[2-(5-methyi-2-phenyi-1 ,3-oxazol-4-yljethoxylpyridin-3- ylimethyf)cyciobutanecarboxytic acid; 16 1-{hydroxy{8-{2<(S-methyt-2-pheny-1 ,3-oxazol-4-yiyethoxylpyridin-3- ylimethylicyclobutanecarboxytic acid; 1-({8-[2-(5-methyl-2-phenyt-1 \3-oxazok4-yhethoxylpyridin-3- ylimethyl)cyclopentanecarboxyfic acid; 1-({842-(5-methy}-2-pheny}-1,3-oxazol-4-yljethoxy]pyridin-3- yl}methyi)cyclohexanecarboxylic acid, 2-({6-{2-(5-methyt-2-phenyt-1 ,3-oxazol-4-yl)ethoxy)pyridin-3- ylimethyi)tetrahydrofuran-2-carboxyfic acid; 2-({5{2-(5-methyl-2-phenyi-1 ,3-oxazol-4-ylyethoxy]pyridn-2- yljmethyi)tetrahydrofuran-2-carboxylic acid; and the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 1- {4{3-(5-methy-2-phenyt-1,3-0xazol-4-yfpropoxylbenzylicyclobutanecarboxylic acid or the pharmaceutically acceptable saits thereof.
Within this embodiment, a specific compound of the present invention is 1- {4-[2-(5-methyi-2-phenyl-1 ,3-oxazol-4-yl)ethoxybenzyficyclobutanecarboxylic acid or the pharmaceutically acceptable saits thereof.
Within this embodiment, a specific compound of the present invention is 2- ({8-[2-(5-methy}-2-pheny}-1,3-oxazol4-ylethoxylpyridin-3- yiimethyltetrahydrofuran-2-carboxyfic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- ({5-[2-(5-methyt-2-pheny}-1, 3-oxazol-4-yl)ethoxylpyridin-2-
ylimethyfjtetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
VWithin this embodiment, a specific compound of the present invention is 2- ({6-{2-(5-methyt-2-phenyt-1 3-oxazok4-yl)ethoxylpyridin-3-yjmethyf)tetrahydro-2H- pyran-2-carboxylic acid or the pharmaceutically acceptable sats thereof.
Within this embodiment, a specific compound of the present invention is 2- ((6-{2-{2-(3-chlorophenyl)-5-methyi-1 ,3-oxazol-4-yllethoxy}pyridin-3- y)methyihetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable
Within this embodiment, a specific compound of the present invention is 2- [(6-{2-{2-(3-methoxyphenyf)-5-methyt-1 3-oxazol4-yllethoxy)pyridin-3- y)methy(ketrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- (5-12-(5-Methy}-2-phenyl-oxazoi-4-yl)-ethoxy}-pyrazin-2-yimethyl}-tetrshydro-furan- 2-carboxylic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is - {4-2-(5-methyt-2-phenyh-1 ,3-oxazol-4-yl)ethoxylbenzyltetrahydrofuran-2-carboxylic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- {6-12-(5-Methyt-2-phenyl-oxazoi-4-yi)-sthoxy}-naphthalen-2-yimethyi}-tetrahydro- furan-2-carboxytic acid or the pharmaceutically scceptabie salts thereof. in another embodiment, the invention relates to compounds having a formula: ° rR? . 1”
R—\ 1 a : /
AE R®
Xo.
Within this embodiment, prefersbly the invention reistes to compounds having a formula:
R? 0}
R' 1 RY
R™ Xo .
Within this embodiment, preferably the invention relates to compounds having a formula:
Rr? 0 — =
C1 —, 6 rR Co R rR Xo .
Within this embodiment, preferably R° is methyl, ethyl, or benzyl. Preferably
R7isH.
Within this embodiment, a specific compound of the present invention is 2- ethoxy-3-{6-{2-(5-methyi-2-phenyt-1 ,3-oxazol-4-yfethoxylpyridin-3-yl}propanoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- methoxy-3-(6-{2-{5-methy}-2-(3-methyipheny)-1,3-oxazol-4-yljethoxy}pyridin-3- yi)propanoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- methoxy-3-{6-{2-(4-phenoxyphenylethoxylpyridin-3-yl}propanoic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2- ethoxy-3-{8-(2-{4-{(phenyisulfonyloxylphenyllethoxy)pyridin-3-yljpropancic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
Ethoxy-3-{5-[2-(5-methy}-2-phenyl-oxazol-4-yi)-ethoxy}-pyridin-2-yf}-propionic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
Methoxy-2-methyl-3-{6-{3-(5-methy}-2-phenyl-oxazol-4-yl)-propoxy}-pyridin-3-yi}- propionic acid or the pharmaceutically acceptable sats thereof. {
Within this embodiment, a specific compound of the presant invention is 2-
Methoxy-2-methyl-3-{5-{2-(5-ethyl-2-phenyl-oxazol-4-yl)-ethaxy}-pyridin-2-l}- propionic acid or the pharmaceutically acceptable saits thereof.
Within this embodiment, a specific compound of the present invention is 3- (6-{2-{2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yi}-ethoxy}-pyridin-3-yl)-2-methoxy-2- methyt-propionic ack or the pharmaceutically acceptable salts thereot.
Within this embodiment, a specific compound of the present invention is 2-
Methaxy-2-methyl-3-{8-[2-(5-methyi-2-phenyl oxazol-4-yl)-ethoxy}-pyridin-3-yi}- propionic acid or the pharmaceutically acceptable salts thereof.
Within this embodiment, a specific compound of the present invention is 2-
Methoxy-3-(6-{2-{2-(3-methoxy-phenyl)-5-methyl-oxazol-4-yl}-ethoxy}-pyridin-3-yi)- 2-methyi-proplonic 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 (1). in one embodiment, 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 (1).
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 (1).
The present invention also provides a method of treating hyperglycemia in a mammal comprising administering to the mammal in need thereof a therapeuticatly effective amount of a compound of Formula (1).
The present invention also provides a method of treating hyperlipidemia in a mammal comprising administering to the mamma! in need thereof a therapeutically effective amount of a compound of Formula (1).
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 (1).
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 (1).
-20~
The present invention also provides 2 method of treating hypertrigiyceridemia in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (1).
The present invention also provides a method of treating hyperinsulinemia in a memmal comprising edministering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (1).
The present invention aiso provides a method of treating a patient suffering from abnormal insulin andor evidence of glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, gtlucagon, or parathyroid hormone, comprising administering to said patient a therapeutically effective amount of a compound of Formula (1).
The present invention aiso 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 ().
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 (1).
The present invention aiso provides a method of modulating PPAR activity in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound of Formula (1).
The present invention aiso provides a method of lowering blood glucose in a mammal, comprising administering to a mammal an amount of a compound of
Formula (1) effective to lower blood ghicose levels.
The present invention also provides a method of modulating fat cell dffferentistion in a mammal, comprising administering to a mammal a therapeutically effective amount of a compound of Formula (1).
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 Formuia (1).
The present invention also provides a method of increasing insulin sensitivity in mammals, comprising administering to a mammal a therapeuticatly effective amount of a compound of Formula (1).
The present invention also provides a method of treating metabolic syndromes selected from the group consisting of galactosemia, maple syrup urine disease, phenyketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, giucose-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 caries thereof. Exemplary pharmaceutically acceptable carriers include carriers suitable for oral, intravenous, subcutaneous, intramuscular, intracutaneous, and the like administration. Administration in the form of creams, lotions, tablets, dispersible powders, granules, syrups, elixirs, sterile aqueous or non-aqueous solutions, suspensions or emulsions, and the like, is contemplated.
The PPAR agonists of the present invention may be administered in combination with other agents such as a-glucosidase inhibitors, aldose reductase inhibitors, bigusnide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin- converting enzyme inhibitors. in the above description, an o-glucosidase inhibitor is a medicament having action in inhibiting a digestive enzyme such ss amylase, maktase, o- dextrinase or sucrase, thereby retarding the digestion of starch or sucrose.
Examples of a-glucosidase inhibitors Include acarbose, N-(1,3-dihydroxy-2- propyl)variolamine (common name: voglibose) and migfitol.
In the above description, an aidose reductase inhibitor is a medicament which inhibits a rate-limiting enzyme of the first step of the polyol pathway, thereby inhibiting diabetic compiications. Examples include toirestat, epalrestat, 2,7- difiuoro-spiro(9H-fluoren-9,4 -imidazolidine)-2',5'-dione (common name: imirestat), 3-{(4-bromo-2-fluorophenyl)methyl}-7-chioro-3,4-dihydro-2,4-dioxo-1(2H)-qu inozolineacetic acid (common name: zenarestat), 8-fluoro-2, 3-dihydro-2,5'-dioxo- spiro{4H- 1-benzopyran-4 4 -imidazolidine}- 2-carboxamide (SNK-860), zopoirestat, sorbini and 1-{(3-bromo-2-benzofuranyl)suifonyl]-2,4-imidazolidinedione (M- 16209). in the above description, 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. in the above description, a statin base compound is a medicament which inhibits hydroxymethyigiutaryl CoA (HMG-CoA) reductase, thereby lowering the blood cholesterol level and examples include pravastatin and the sodium salt thereof, simvastatin, lovastatin, storvastatin and fluvastatin.
In the above description, a squalene synthesis inhibitor is a medicament for inhibiting squalene synthesis, thereby lowering the blood cholesterol level and examples include monopotassium (S)-a-[bis(2,2-dimethy*1-
oxopropaxy)methaxylphosphinyh-3-phenoxybenzene-butanesutfonate (BMS- in the above description, a fibrate base compound is a medicament for inhibiting synthesis and secretion of triglycerides in the liver and activating lipoprotein lipase, thereby lowering the trigiyceride level in the blood. Examples include bezsfibrate, beclobrate, binifibrate, ciprofibrate, dlinofibrats, clofibrate, clofibric acid, ethoffbrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate and theoftbrate. -
In the above description, 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- flucrophenylimethyt-1-piperazinyllethyll-7,7-diphenyl-2,4,6- heptatrienoic amide.
The above-described statin base compounds, squalene synthesis inhibitors, fiorate base compounds and LDL catabolism promolers can be repisced with another chemical effective for lowering the blood cholesterol or triglyceride jevel. Examples of such a medicament inciude nicotinic acid derivative preparations such as nicomol and niceritrol; antioxidants such as probucol; and ion exchange resin preparations such as cholestyramine. in the above description, an angiotensin-converting enzyme inhibitor is a medicament for inhibiting angictensin-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 cilazapri, enalaprilat, fosinopril, movettipril, perindopril, quinapril, spirapril, temocapril and trandolapi.
For the preparation of oral liquids, 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.
For the preparation of fluids for parenteral administration, suitable carriers include sterile aqueous Of non-aqueous solutions, suspensions, of emulsions.
Examples of non-aqueous solvents or vehicies are propylene glycol, polyethylene glycol, vegetable olis, such as olive oll and com ofl, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may aiso contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by fitration through a bacteria-retaining fitter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also bs manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.
Definitions
For purposes of the present invention, as described and claimed herein, the following terms are defined as follows:
The term “hai”, as used herein, uniess otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term “aky", as used herein, uniess otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
The term "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.
The term "alkynyl", as used herein, unless otherwise indicated, includes alkyt moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
The term "alkoxy", as used herein, unless otherwise indicated, includes O- alkyl groups wherein alkyl is as defined above.
The term "Me" means methyl, “Et” means ethyl, and “Ac” means acetyl.
The term “cycloalkyl”, as used herein, unless otherwise indicated refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to hersin 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. lustrative examples of cycloalkyl are derived from, but not fimited to, the following: a0 a OO A
CO Pal .
The term "aryl", as used herein, uniess otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
-24 ~
The term “4-10 membered heterocyclic”, as used herein, unless otherwise indicated, Includes aromatic and non-aromatic heterocyclic groups containing one 0 four heteroatoms each selected from O, S and N, wherein each heterocycic group has from 4-10 atoms in ks 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 S atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 4 membered heterocyclic group Is azetidiny! (derived from azetidine). An example of a § membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic hetarocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorphofino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepenyl, oxazepinyl, diazepinyl, thiszepinyl, 1.2,36-tstrahydropyridinyl, 2- pyrrolinyl, 3-pyrolinyl, indofinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithisnyi, dithiolany!, dihydropyranyl, dihydrothienyl, dihydrofuranyt, pyrazolidinyl, imidazoiinyl, imidazolidinyl, 3-azabicycio[3.1.0lhexanyl, 3- azabicyclo[4.1.0lheptanyl, 3H-indolyl and quinolizinyl. Exampies of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazoiyi, pyrazinyl, tetrazolyl, furyl, thienyi, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridaziny!, triazinyl, isoindoiyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanvi, benzofurazanyl, benzothiophenyi, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groupe, as derived from the groups sted above, may be C-attached or N-attached where such Is possible. For instance, a group derived from pymole may be pyrrok-1-y! (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yi (N-attached) or imidazol-3-yi (C- attached). The 4-10 membered heterocyciic may be optionally substituted on any ring carbon, sulfur, of nitrogen atom(s) by one to two oxo, per fing. An example of a heterocyclic group wherein 2 ring carbon atoms are substitited with oxo moieties is 1,1-dioxo-thiomorpholinyl. Other lllustrative examples of 4-10 membered heterocyclic are derived from, but not limited to, the following: i N
Ror
H ’ . HH No
N \ \ 0 x £003 . , . NN
SC 00 ky
H : : H H '
SOR
N° .
C5
TY and
Unless otherwise indicated, the term “oxo” refers to =O.
The term "~Ar'-A”%-", as used herein, unless otherwise indicated include two rings without any Kmitation of the order of attachments to R' and R’. For exampie, -Ar'-Ar- is defined as
OO
: then the —Ar'-Ar*- groups can be
R® R®
OG OT ad and i —Ar'-Ar- is defined as mr ro A goupa can
OF BO er - o =x i"
The phrase "pharmaceutically acceptable sait(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula (1). 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. The acids that may be used to prepare pharmaceutically acceptable acid addition saits of such basic compounds of formula (7) are those that form non-toxic acid addition salts, 1a, salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, dihydrochloride, edetate, edislyate, esiolate, esylate, ethyisuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyisuliate, mucsate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), paimitate, pantothenate, phospate/diphosphate, polygalacturcnate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teociate, tosylate, triethiodode, and valerate salts.
In the compounds of formula (7), where terms such as (CR''R™ or (CRVR'™), are used, R" and R" may vary with each teration of q or t above 1. For instance, where q or t is 2 the terms (CR''R™), or (CR"'R"’) may equal -CH,CHz, or -CH(CHa)C({CH2CH3)(CH2CH.CHy)-, Or any number of skmitar moleties falling within the scope of the definitions of R'* and R™. Further, as noted above, any substituents comprising a CH, (methyl), CH; (methylene), or CH (methine) group which is not attached to a halogeno, SO or SO; group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, C.-C, alkoxy and amines.
The term “treating”, as used herein, unless otherwise indicated, 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. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above.
The term “modulate” or “modulating”, as usad herein, refers to the ability of a modulstor for a member of the steroidfthyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a igand 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. 3s The term “obesity” or ‘obese’, as used herein, refers generally to individuals who are at least about 20-30% over the average weight for his/her age, sex and height. Technically, "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’. Those of skill in the art readily recognize that 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.
The term “Inflammatory disorders”, as used herein, refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocakinosis, gout, inflammatory bowel! disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.
The phrase “therapeutically effective amount”, as used herein, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissus, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
The phrase "amount . . . effective 10 lower blood glucose levels,” as used herein, refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a conceniration typically falls in the range of about 10 nM up 10 2 uM; with concentrations in the range of about 100 nM up to 500 nM being preferred. As noted previously, since the activity of different compounds which fall within the definition of Formuta (1) 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.
The phrase “insulin resistance’, as used herein, 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 Ussue. Insulin resistance occurs in many individuals with or without diabetes mellitus.
The phrase “insufin resistance syndrome”, as used herein, refers to the cluster of manifestations that include insulin resistance, hyperinsulinemia, non insulin depandent diabetes meliitus (NIDDM), arterial hypertension, central (visceral) obesity, and dyslipidemia.
The phrase "in combination with”, as used herein, means that the alpha substituted carboxylic acids compound of Formula (1) 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.
Thus, the sipha substituted carboxylic acids compound of Formuta (1) and the other agents may be administered simultaneously as elther as a single composition or as two separate compositions or sequentially as two separate compositions.

Claims (1)

  1. We Claim:
    1. A compound of formula OX R! (De R? 0) or a pharmaceutically acceptable saft or solvate thereof, wherein. Ring Q is (Cs-Cyo)aryl or (4-10)-membered heterocycly; R' is H, halo, (Ci-Coakyl, (Ci-Celakoxy, CN, CFs, -O-CFs, -O-SO~(Cr- Co)alkyl, -O-SOr(CR"'R'}{Ce-Crolaryl. -(CR"'R")(Cy-Cro)cycioalky-HCR"'R™). (CR"'R™)(Cx-Cro)cycloalky-CR'R")O-, {CR"R™J{(Ce-Cro)aryH(CR"R™}, HCR"'R™)(Ce-Cro)ary-(CR"'R")-O-, -CR"'R")(4-10)-membered heterocyclyl-(CR''R"™), or -(CR"'R")e(4-10)-membered heterocycly-(CR'R")-0-; wherein the ring carbon atoms of R' are optionally substituted by 1 to 3 R" groups; and the ring nitrogen atoms of R' are optionally substituted by 1 to 3 (C1-Ca)alkyl; RR is H, (CrCoakyl, -(CR"R)(CsCiolcycloalkyl, «(CR"R%) (Ce-Cro)ary, or {CR"'R")(4-10)-membered heterocyclyl; and wherein the carbon atoms of R? are optionally substituted by 1 to 3 R" groups; and the ring nitrogen atoms of R? are optionally substituted by 1 to 3 (Ci-Ca)akyl, R® is selected from the group consisting of: A) RA —AP—RS, RC X R® ; B) TTT ArP—R® RS gr X 4 12 7 R® rR" R R : 0 i gr—at—R RF
    RY . =X rR" Ap Le : ——R" —7 —C R® D) B
    XX . Y is -(C=0)- or -SOr; Y" is NR" or —O-;
    pis0,1,0r2;
    eachq,r, and t are independently 0. 1. 2, 3. 4,0r5;
    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;
    eachjis0,1,0r2;
    Each R* Is —CR"R%)e, -(CR"'R":8-(CR"R")r, ~CR"R™)-NR"-, -(CR"R")NR"~(CR"'R"*);-O-, {CR"R"),-O-(CR"'R'*)-NR""-, -(CR"'R'}),-O- ’ (CR"R)-, -(CR"R"),-0-(CR"'R"*x -O-(CR"'R"3)s-,
    -(CR"'R%),-CR"'=CR™-(CR"'R")x, or -CH=CH-(CR"'R"%)-0~(CH2)n-:
    Each Ris a bond or {CR"'R"2).-Z-(CR"'R"),; wherein Z is CR"R'%, -O- , -NR'™-, or -S(O)y:
    Each R® is -(C=0)-OH, (C=0)-OM’, «C=O}-(Cr-Caluliy, ~(C=0)-0-(Cs- Cojalkyl, -(C=0)-NR"R", {C=O}NRV-SO,R", -SOrNH-R™, NH-SOR™,
    -(C=O)-NH-CaN, or R® has a formula: 0 3 et I AH N o jor H M' is an alkali meta! cation or an alkaline earth metal cation; Each R’ and R° is independently H, (Ci-Coakyl, (Ci-Colalkoxy, -(CR"'R")}(CyCyo)cycloalkyl, «CR"'R)(Cs-Croanyl, -(CR''R™}(CeCio)arytO-, -(CR"'R')(4-10)-membered heterocyclyl or -(CR''R"?)(4-10)-membered heterocyciyt-O-;
    Or R’ and R® may optionally be taken together with the carbon to which they are attached to form a (Cx-Cio)cycioalkyl or a (3-10)-membered heterocyclyl;
    Each of Ar’, AZ, A”, and Ar* represents (Ce-Cro)ary! or (5-10)-membered heterocyclyl; wherein the ring carbon atoms of each of Ar', AP, Ar’, and Ar* are optionally substituted by 1 to 3 R* 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 - N(R'™)-, 0, and S(O), wherein j is 0, 1, or 2, with the proviso that the ring does not contain two adjacent O or S(O) atoms, and wherein the carbon atoms of the ring A moiety are optionally substituted by 1 to 3 R"™ groups;
    Ris (Cr-Coalkyl, (CR"'R™}Ce-Cro)aryl or ~(CR''R')(4-10)-membered heterocyclyl, wherein t is independently 0, 1, 2, 3, 4, or 5, wherein said R® groups are substituted with 1 fo 3 groups independently selected from -(CR''R");NR"*R",
    {CR"RHNR(C, Co)alkanoyi, «CR"R%);O(CR"R)R", and <CRYR')R™: and wherein the heterocyclyl, aryl and alkyl moieties of the foregoing groups are optionally substituted with 1 to 3 R'® groups; R®™ and R'° are independently H or (C,-Co)alkyl; RY and R™ are independently H, (C1-Co)alkyl, hydroxy, or (C-Ce)atkoxy, R'™ is selected from H, (Cs-Ca)alkyl, (C=O0)-R"*, -SO,NR"R", or -S(O)(C1-Ce)alkyl; Each R™ and R'* are independently selected from the group consisting of halo, cyano, nitro, trifiuoromethoxy, trifluoromethyl, azido, hydroxy, (Ci-Ce)alkoxy, (Cy-Cio)alkyl, (C-Celalkenyl, (C-Cealkynyl, -O-CR"'R'*)-0-(CR"'R"})y-, (C=0)- RY, {C=0)-O-R'®, -O-C=O}RY, -NR"(C=O}-R", -NR'(C=0)-0-R", -(C=0)-NR"R'®, -NR"R'®, -NROR™, -SO,NR'°R", -S(O}(Cy-Cojalkyl, -O-SO~ R“ -NR'SO,R" R“-CR"R“)CeCi aryl), -(CR"R")4-10)-membered heterocyclyl, {CR"R™),(C=0)(CR''R"}{Ce-Colaryl. -(CR'R'})(C=0)(CR"'R")(4-10)-membered heterocyclyl, -(CR"'R'2)0(CR"'R™)(Ce-Cio)aryl, «CR"'R'?O(CR"'R")(4-10)-membered heterocyclyl, «CR"'R")SO2(CR"'R™)(Ce-Cro)aryt, and -(CR"'R'};SO,CR"'R")4-10)-membered heterocyclyl; 1 or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R'™> and R'™ groups are optionally substituted with an oxo (=O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocycic moieties of the foregoing R"™ and R"** groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR', -(C=O)-R", «{C=0)-0-R", -O- (C=O)R"™, -NR'(C=0)-R", -(C=O}NR'*R'®, -NR"R™, -NR"OR", (Cs-Cojalkyl (CrCoikenyl, (CrColskynyl, -CR'R™CsCiaryl, and CR''R™)(4-10)- membered heterocyclyl; each R™ R', and R'" is independently selected from H, (C-Celalkyl. <(CR''R'}(Ce-Cro)aryl. and -(CR"'R')(4-10)-membered heterocyciyl. 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (=0) moiety, and the alkyl, aryl and heterocyclic moieties of the foregoing rR", R" and R™ groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, -NR''R"?, trifluoromethyl, trifluoromethoxy, (C+ Co)alkyl, (CCe)atikenyl, (C-Co)alkynyl, hydroxy, and (C4-Ce) alkoxy, R" is H, (Cs-Co)alkyl, -O-(C1-Ceakyl, halo, CN, OH, CF, or -O-CFy; and wherein any of the above-mentioned substituents comprising a CH, (methyl), CH, (methylene), or CH (methine) group which is not attached to a halo, SO or SO, group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, halo, (C1-Cu)alkyl, (C1-Ca)atkoxy, —NHa, -NH(Cs- Co)alkyl, and =N((C-Ce)atkyl)z.
    2. The compound according to claim 1 wherein Ris A RA —AP—RS X R®
    3. The compound according to claim 1 wherein Ris B) —RA—Y—Y" AP—RS R® Ne d xX rY R12 R’ R8
    4. The compound according to claim 1 wherein R’ is : I) : R* Art RS R®
    5. The compound according to claim 1 wherein R'is RY C3 / D) eT en R™ o—=R’
    6. The compound according to claim 2 having a formula: R2 O R'—4 N Ré—Ar'—AR—RS R® rR’ X RS. wherein said —Ar'-Ar- is selected from the group consisting of.
    N N 0-00-00 O00 OC y/, \_/ N= N N ==N 934 N / . N= ; \_/ : N N N N= J N N= C3 O00 {y—) : an = MN / N= N-O N—NR'® (=< O10 N== : N= and N= wherein the ring carbon atoms of each of Ar’ and Ar? are optionally substituted by 1 to 3 R' groups setected from the group consisting of halo, (C+ Ca)aikyl, and (C,-Cs)alkoXy.
    7. The compound according to claim 2 selected from the group consisting of 1-({3"-[2-(5-Methyi-2-pheny!-1 ,3-oxazol-4-yl)ethoxy}-1,1*-biphenyl- 3-ylJoxy)cyclobutanecarboxylic acid (Example A-4); 2-({3"-[2-(5-Methy}-2-phenyi-1 ,3-oxazot-4-ylethoxy}-1,1'-biphenyl- . 3-yljoxy)butanoic acid (Example A-5); 2-(3-{6-{2-(5-Methy}-2-pheny}-1,3-oxazol-4-yl)ethoxylpyridin-2- yi}phenoxy)butanoic acid (Example A-8). 1-(3-{6-{2-(5-Methy}-2-phenyl-1 3-0xazot-4-yl)ethoxylpyridin-2- yllphenoxy)cyclobutanecarboxylic acid (Example A-7), 14(3'-{I2-(3-fluorophenyi)-5-methyt-1, 3-oxazol-4- yljmethoxy}bipheny}-3-yljoxy]cyclobutanecarboxylic acid (Example A-11); 1-({3'{3-(5-methyi-2-phenyt-1, 3-oxazok4-yf)propoxypiphenyt-3- ylloxy)cyciobutanecarboxylic acid (Example A-12), 1-{(3'-{I5-(4-methoxyphenyl)-1 2 4-oxadiazol-3- ylImethoxy)biphenyl-3-yl)oxy]cyclobutanecarboxylic acid (Example A-17); 2-[(3'{2-{2-(3-Fluorophenyl)-5-methy}-1 ,3-oxazol-4- yijethoxy}biphenyt-3-yl)oxy}-2-methylpropanoic acid (Example A-21), 2-methyl-2-({3'{(5-methyl-2-phenyl-1,3-0xazol-4- yl)methoxy]biphenyt-3-yfjoxy)propanoic acid (Example A-24),
    2-ethoxy-3-{3"-{2-(5-methyl-2-phenyt-1 ,3-oxazol-4- yhethoxy]biphenyt-3-yljpropanoic acid (Example A-28), and the pharmaceutically acceptable salts thereof.
    8. The compound according to claim 3 having a formula: Rr? oO — 1 N 4 R TN AP—R® R® 5X Rd L. R’ R® : wherein Y is -(C30)- or -5O7, Y" is NR", and piis 1.
    8. The compound according to claim 3 selected from the group consisting of 2-Methyt-2-{3-{({2-(5-methyl-2-phenyt-1 ,3-OXazZOH-4- yljethoxylcarbonyilamino)methyljphenoxy}propanoic acid (Example B-5), 2-methy2-{3-{({[(5-methyi-2-phenyt-1 ,3-0XAZO-4- yl)methoxylcarbonytjamino)methy(jphenoxy}propanoic acid (Example B-6); 2-methyi-2-{4-[({13-(5-methyl-2-pheny}-1 ,3-0xazok4- yl)propoxylcarbonyljamino)methyfjphenoxy}propanoic acid (Example B-7); 2-{3-fluoro-4-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4- yhethoxylcarbonyflamino)methyljphenoxy}-2-methylpropanoic acid (Example B-9); 2-{3-{({]2-(5-Methy}-2-phenyi-1 .3-oxazol-4- yljethoxyicarbonyfjamino)methyfjphenaxy}butanoic acid (Example 8-13); 2-(34{({I(5-methyl-2-phenyl-1,3-0xazok-4- ylmethoxylcarbonyljamino)methyilphenoxy}butanoic acid (Example B-14), 1-{3-{({T2-(5-Methy\-2-phenyi-1,3-0xazok-4- yhethoxylcarbonyflamino)methyljphenoxy)cyclobutanecarboxylic acid (Example B-15); 2-methyh2-(3-{({2-(5-methyl-2-pheny}-1,3-0xazol-4- yiethyljaminojcarbonyijoxymethyf}phenoxy)propanoic acid (Example B- 21), 2-ethoxy-3-{3-[({3-(5-methyl-2-phenyl-1,3-0xazol-4- yi)propoxycarbonyljamino)methyfjphenyijpropanoic acid (Example B-23), 2-ethoxy-3-{3-{({[2-(5-methyt-2-pheny}-1,3-0xazol-4- yl)ethoxy]carbonyllaminojmethyllphenyflpropanoic acid (Example B-24), and the pharmaceutically acceptable salts thereof.
    10. The compound according to claim 4 having a formula: R? 0 R—Q\ EI g wherein said ring A is selected from the group consisting of cyclopropyl, cyclobuty!, cyclopentyl, cyclohexyl, XD X33 8) Re : 30 OVO py Rn . R'™ 7) RY x) R™ 0 H RW: R' 55 20 0 . X SL | ° ' Xr NR™ ; ! K J NR'® R : R © RSSN—NR'™ o a ~~
    ~ . .e Xr XO 1 ; 10a; . / RY R"h—0 —ire OL pe a) an wherein — is an optional double bond.
    1. The compound according to claim 4 selected from the group consisting of 1-{4-{3-(5-methyt-2-phenyt-1 3-oxazot-4- yi)propoxylbenzylicyclobutanecarboxytic acid (Example C-16), 1-{4-[2-(5-methyi-2-phenyt-1 ,3-0xazol-4- yl)ethoxy)benzyilcyciobutanecarboxylic acid (Example C-19), 2-({6-[2-(5-methyt-2-phenyt-1 ,3-oxazol-4-yl)ethoxylpyridin-3- yljmethyl)tetrahydrofuran-2-carboxylic acid (Example C-48); 2-({5-[2-(5-methyl-2-phenyl-1 ,3-oxazol4-yl)ethoxylpyridin-2- yimethyftetrahydrofuran-2-carboxyhc acid (Example C49); 2-({6-[2-(5-methyl-2-phenyl-1,3-0xazok-4-ylethoxypyridin-3- yl)methyl)tetrahydro-2H-pyran-2-carboxylic acid (Example C-56); 2{(6-{2-{2-(3-chlorophenyl)-5-methyt-1,3-0xazok4- yllethoxy}pyridin-3-yljmethyitetrahydrofuran-2-carboxylic acid (Exampie C- 59), 2-{(6-{2-[2-(3-methoxyphenyl)-5-methyt-1 3-oxazoh-4- yllethoxylpyridin-3-ymethyijtetrahydrofuran-2-carboxylic acid (Example C- 62), 2-{5-{2-(5-Methyl-2-phenyl-oxazol-4-yi)-ethoxy}-pyrazin-2- yimethyl}-tetrahydro-furan-2-carboxylic acid (Example C-77); -{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4- yi)ethoxyjbenzyljtetrahydrofuran-2-carboxylic acid (Example C-78); 2-{6-{2-(5-Methy}-2-phenyl-oxazol-4-yi)-ethoxy}-naphthalen-2-yimethyi}- tetrahydro-furan-2-carboxylic acid (Example C-91); and the pharmaceutically acceptable salts thereof.
    12. The compound according to claim 5 having a formula:
    R? 0) R—N\ 1 NM N R* — on R® WX R% o—=R" ior R? 0 — 1 A N — R® OK :
    13. The compound according to ciaim 12 selected from the group consisting of 2-ethoxy-3-{6-{2-(5-methyi-2-phenyi-1 ,3-oxazol-4-yl)ethoxy]pyridin- 3-ylipropanoic acid (Example D-1); 2-methoxy-3-(6-{2-[5-methyl-2-(3-methyiphenyl)-1 .3-oxazol-4- yllethoxy)pyridin-3-yi)propanoic acid (Example D-3); 2-methoxy-3-{8-[2-(4-phenoxyphenyl)ethoxy]pyridin-3-yljpropanoic acid (Example D-13); 2-ethoxy-3-[6-(2-{4-{(phenylsutfonyfoxy]phenyllethoxy)pyridin-3- yflpropanoic acid (Example D-17); 2-Ethoxy-3-{5-[2-(5-methy}-2-phenyl-oxazo-4-yf)-ethoxy}-pyridin-2- yl-propionic acid (Example D-23); 2-Methoxy-2-methyl-3-{8-[3-(5-methyt-2-phenyt-oxazoi-4-yl)- propoxy}-pyridin-3-yf}-propionic acid (Example D-27); 2-Methoxy-2-methyt-3-{5-{2-(S-methyi-2-phenyl-oxazol-4-yl)- ethoxy}-pyridin-2-yi}-propionic acid (Example D-28); 3-(8-{2-{2-(4-Chioro-phenyl)-5-methyi-oxazol-4-yl}-ethoxy}-pyridin- 3-yl)-2-methoxy-2-methyi-propionic acid (Example D-30); 2-Methoxy-2-methyl-3-{6-[2-(5-methyi-2-phenyl oxazol-4-yl)- ethoxy]-pyridin-3-yl}-propionic acid (Example D-35), 2-Methoxy-3-(8-{2-{2-(3-methoxy-phenyl)-5-methyi-oxazol-4-yi}- ethoxy}-pyridin-3-yi)-2-methyl-propionic acid (Example D-43); and the pharmaceutically acceptable salts thereof.
    PCT/1B2004/001159
    14. Use of an alpha substituted carboxylic acid compound according to claim 1 in the manufacture of a medicament for treating non-insulin dependent diabetes mellitus, polycystic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia, abnormal insulin and/or evidence of glucose disorders, insulin resistance syndrome, and PPAR-related disorders in a mammal.
    15. A composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier thereof, said compound is optionally in combination with other agents such as u-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, statin base compounds, squalene synthesis inhibitors, fibrate base compounds, LDL catabolism promoters and angiotensin-converting enzyme inhibitors.
    16. A substance or composition for use in a method of treating non- insulin dependent diabetes mellitus, polycystic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia, abnormal insulin and/or evidence of glucose disorders, insulin resistance syndrome, and PPAR-related disorders in a mammal, said substance or composition comprising an alpha substituted carboxylic acid compound according to claim 1, and said method comprising administering to the mammai in need thereof a therapeutically effective amount of said substance or composition 17 A compound according to any one of clams 1 to 13 substantially as herein described and illustratec 18 Use according to claim 14. substantially as herein described and illustrated.
    19. A composition according to claim 15, substantially as herein described and illustrated.
    20. A substance or composition for use in a method of treatment according to claim 16, substantially as herein described and illustrated. AMENDED SHEET
    PCT/1B2004/001159
    21. A new compound, a new use of a compound as claimed in claim 1, a new composition, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
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