U.S. patent application number 11/932755 was filed with the patent office on 2008-05-08 for substituted triazoles as modulators of ppar and methods of their preparation.
This patent application is currently assigned to Metabolex Inc.. Invention is credited to Peng Cheng, Francine M. Gregoire, Jingyuan Ma, Vera A. Rakhmanova, Zuchun Zhao, Yan Zhu.
Application Number | 20080108630 11/932755 |
Document ID | / |
Family ID | 35451382 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108630 |
Kind Code |
A1 |
Zhu; Yan ; et al. |
May 8, 2008 |
SUBSTITUTED TRIAZOLES AS MODULATORS OF PPAR AND METHODS OF THEIR
PREPARATION
Abstract
The present invention is directed to certain novel triazole
compounds represented by Formula I and pharmaceutically acceptable
salts, solvates, hydrates, and prodrugs thereof. The present
invention is also directed to methods of making and using such
compounds and pharmaceutical compositions containing such compounds
to treat or control a number of diseases mediated by PPAR such as
glucose metabolism, lipid metabolism and insulin secretion,
specifically Type 2 diabetes, hyperinsulemia, hyperlipidemia,
hyperuricemia, hypercholesteremia, atherosclerosis, one or more
risk factors for cardiovascular disease, Syndrome X,
hypertriglyceridemia, hyperglycemia, obesity, and eating
disorders.
Inventors: |
Zhu; Yan; (Foster City,
CA) ; Ma; Jingyuan; (Fremont, CA) ; Cheng;
Peng; (Union City, CA) ; Zhao; Zuchun;
(Pleasanton, CA) ; Gregoire; Francine M.;
(Lafayette, CA) ; Rakhmanova; Vera A.; (Foster
City, CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Metabolex Inc.
3876 Bay Center Place
Hayward
CA
94545
|
Family ID: |
35451382 |
Appl. No.: |
11/932755 |
Filed: |
October 31, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11137678 |
May 24, 2005 |
7323480 |
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11932755 |
Oct 31, 2007 |
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60574426 |
May 25, 2004 |
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Current U.S.
Class: |
514/254.07 ;
514/359; 544/366; 548/255 |
Current CPC
Class: |
C07D 249/06 20130101;
A61P 9/10 20180101; A61P 3/04 20180101; A61P 3/10 20180101; A61P
9/00 20180101; C07D 409/10 20130101; A61P 3/06 20180101 |
Class at
Publication: |
514/254.07 ;
548/255; 544/366; 514/359 |
International
Class: |
A61K 31/497 20060101
A61K031/497; A61P 3/06 20060101 A61P003/06; A61P 3/10 20060101
A61P003/10; A61K 31/4192 20060101 A61K031/4192; C07D 403/06
20060101 C07D403/06; C07D 249/04 20060101 C07D249/04 |
Claims
1. A compound having the formula: ##STR89## wherein Ar.sup.1 is a
monocyclic or bicyclic aromatic ring system selected from the group
consisting of phenyl, naphthyl, imidazolyl, benzimidazoyl,
pyrrolyl, indolyl, thienyl, benzothienyl, furanyl, benzofuranyl,
and benzodioxole each of which is optionally substituted with from
one to five R.sup.7 substituents independently selected from the
group consisting of halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, --OR.sup.2, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.2-C.sub.8)alkenyl,
aryl(C.sub.2-C.sub.8)alkynyl, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2, --CO.sub.2R.sup.2,
--NR.sup.2R.sup.3, --NO.sub.2, --CN, --S(O).sub.r1R.sup.2,
--X.sup.1OR.sup.2, --X.sup.1COR.sup.2, --X.sup.1CO.sub.2R.sup.2,
--X NR.sup.2R.sup.3, --X.sup.1NO.sub.2, --X.sup.1CN, and
--X.sup.1S(O).sub.r1R.sup.2; Ar.sup.2 is a 6-membered monocyclic
aromatic ring selected from the group consisting of benzene,
pyridine, pyrazine, pyrimidine, pyridazine, triazine, each of which
is optionally substituted with from one to four R.sup.8
substituents independently selected from the group consisting of
halogen, (C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl,
--OR.sup.2, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.2-C.sub.8)alkenyl,
aryl(C.sub.2-C.sub.8)alkynyl, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2, --CO.sub.2R.sup.2,
--NR.sup.2R.sup.3, --NO.sub.2, --CN, --S(O).sub.r1R.sup.2,
--X.sup.2OR.sup.2, --X.sup.2COR.sup.2, --X.sup.2CO.sub.2R.sup.2,
--X.sup.2NR.sup.2R.sup.3, --X.sup.2NO.sub.2, X.sup.2CN, and
--X.sup.2S(O).sub.r1R.sup.2; L is a member selected from the group
consisting of a covalent bond and a linking group having from one
to six main chain atoms and having the formula
--Y.sup.1.sub.m1Y.sup.2.sub.m2Y.sup.3.sub.m3-- wherein L can be
attached to any available ring member of Ar.sup.2; K is a member
selected from the group consisting of: CH.sub.2, CH(CH.sub.3),
C(CH.sub.3).sub.2, --CH.dbd.CH.sub.2.sup.E, CH.dbd.CH.sub.2.sup.Z,
CH--CH, --OCH(CH.sub.3) and OC(CH.sub.3).sub.2, wherein E
represents the entgegen isomer and Z represents the zusammen
isomer; each Y.sup.1, Y.sup.2, and Y.sup.3 is a member
independently selected from the group consisting of
(CR.sup.4R.sup.5).sub.p, C.dbd.O, C.dbd.ONR.sup.2, C.dbd.NOR.sup.2,
NR.sup.2C.dbd.O, NR.sup.2, O, S(O).sub.r2, NR.sup.2SO.sub.2, and
SO.sub.2NR.sup.2; Z is selected from the group consisting of
CH.sub.2OR.sup.6, CO.sub.2R.sup.6, tetrazol-5-yl,
CONHSO.sub.2R.sup.2 and CHO; R.sup.1 is selected from the group
consisting of H, halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.4)alkyl; each R.sup.2 and R.sup.3 is a
member independently selected from the group consisting of H,
(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl,
--X.sup.3OR.sup.9, aryl, aryl(C.sub.1-C.sub.4)alkyl, and
heteroaryl, or optionally, if both present on the same substituent,
may be joined together to form a three- to eight-membered ring
system; each R.sup.4 and R.sup.5 is a member independently selected
from the group consisting of H, halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, OR.sup.2, aryl, heteroaryl, and
aryl(C.sub.1-C.sub.4)alkyl, or optionally, if both present on the
same substituent, may be joined together to form a three- to
eight-membered ring system, or if present on adjacent carbon atoms
are combined to form a double bond or triple bond between the atoms
to which they are attached; R.sup.6 is a member selected from the
group consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, --X OR.sup.2, --X NR.sup.2R.sup.3,
(C.sub.2-C.sub.8)alkenyl, (C.sub.3-C.sub.7)cycloalkyl,
heterocyclyl, aryl(C.sub.1-C.sub.4)alkyl; and
aryl(C.sub.2-C.sub.8)alkenyl; R.sup.9 is a member selected from the
group consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.4)alkyl, and
heteroaryl; each X.sup.1, X.sup.2, X.sup.3, and X.sup.4 is a member
independently selected from the group consisting of
(C.sub.1-C.sub.4)alkylene, (C.sub.2-C.sub.4)alkenylene, and
(C.sub.2-C.sub.4)alkynylene; the subscripts m1, m2, and m3 are each
integers of from 0 to 1; the subscripts r1 and r2 are integers of
from 0 to 2; the subscript p is an integer of from 1 to 2; and
pharmaceutically acceptable salts, solvates, hydrates and prodrugs
thereof.
2. A compound of claim 1, wherein Ar.sup.1 is benzodioxole or
phenyl optionally substituted with from one to three R.sup.7
substituents independently selected from the group consisting of
halogen, halo(C.sub.1-C.sub.8)alkyl, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, and --OR.sup.2.
3. A compound of claim 1, wherein Ar.sup.1 is ##STR90## wherein X
is a halogen; and the dashed line indicates the point of attachment
to the remainder of the molecule.
4. A compound of claim 3, wherein Ar.sup.1 is ##STR91## wherein the
dashed line indicates the point of attachment to the remainder of
the molecule.
5. A compound of claim 1, wherein R.sup.1 is selected from the
group consisting of (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, aryl and
heterocyclyl(C.sub.1-C.sub.4)alkyl.
6. A compound of claim 5, wherein R.sup.1 is selected from the
group consisting of CH.sub.3, CH(CH.sub.3).sub.2, CF.sub.3,
CF.sub.3CH.sub.2, phenyl and ##STR92## R.sup.10 is a halogen or
(C.sub.1-C.sub.8)alkoxy; and the dashed line indicates the point of
attachment to the remainder of the molecule.
7. A compound of claim 6, wherein R.sup.10 is Cl, Oi-Pr or
OCH.sub.3.
8. A compound of claim 5, wherein R.sup.1 is CH.sub.3.
9. A compound of claim 1, wherein Y.sup.1, Y.sup.2, and Y.sup.3 is
a member independently selected from the group consisting of
(CR.sup.4R.sup.5).sub.p, C.dbd.O, NR.sup.2, O, and S(O).sub.r2;
R.sup.2 is H; each R.sup.4 and R.sup.5 is a member independently
selected from the group consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C 1-C.sub.8)alkyl, or optionally, if both present on the same
substituent, may be joined together to form a three- to
eight-membered ring system or if present on adjacent carbon atoms
are combined to form a double bond or triple bond between the atoms
to which they are attached; and r2 is 0.
10. A compound of claim 9, wherein Y.sup.1 is
(CR.sup.4R.sup.5).sub.p, Y.sup.2 is CH.sub.2 or C.dbd.O and Y.sup.3
is NH, O, or S.
11. A compound of claim 9, wherein Y.sup.1 is CH.sub.2, Y.sup.2 is
(CH.sub.2).sub.2 and Y.sup.3 is O or S.
12. A compound of claim 1, wherein at least one of m1, m2, or m3 is
O.
13. A compound of claim 1, wherein L is a member selected from the
group consisting of: CH.sub.2, (CH.sub.2).sub.2, CH.sub.2S,
CH(CH.sub.3)S, C(CH.sub.3).sub.2S, (CH.sub.2).sub.2S,
CH(CH.sub.3)CH.sub.2S, --C(CH.sub.3).sub.2CH.sub.2S,
(CH.sub.2).sub.3S, CH.sub.2O, CH(CH.sub.3)O, C(CH.sub.3).sub.2O,
(CH.sub.2).sub.2O, CH(CH.sub.3)CH.sub.2O,
--C(CH.sub.3).sub.2CH.sub.2O, (CH.sub.2).sub.3S and
(C.dbd.O)NH.
14. A compound of claim 1, wherein each R.sup.4 and R.sup.5 is
independently H, CH.sub.3, CF.sub.3, or joined together to form a
three- to six-membered ring system selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
15. A compound of claim 14, wherein R.sup.4 and R.sup.5 are H.
16. A compound of claim 1, wherein Z is CO.sub.2R.sup.6.
17. A compound of claim 16, wherein R.sup.6 is H.
18. A compound of claim 1, wherein Ar.sup.2 is selected from the
group consisting of: (i) pyridine, optionally substituted with from
one to three R.sup.8 substituents; (ii) pyrazine, optionally
substituted with from one to two R.sup.8 substituents; (iii)
pyrimidine, optionally substituted with from one to two R.sup.8
substituents; (iv) pyridazine, optionally substituted with from one
to two R.sup.8 substituents; and (v) triazine, optionally
substituted with one R.sup.8 substituent wherein each R.sup.8
substituent is a member independently selected from the group
consisting of halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, --OR.sup.2, --X.sup.2OR.sup.2,
heterocyclyl, heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2,
--CO.sub.2R.sup.2, --NR.sup.2R.sup.3, --NO.sub.2,
X.sup.2NR.sup.2R.sup.3, --CN and --S(O).sub.r1R.sup.2.
19. A compound of claim 18, wherein Ar.sup.2 is selected from the
group consisting of: (i) pyridine, optionally substituted with from
one to three R.sup.8 substituents; (ii) pyrazine, optionally
substituted with from one to two R.sup.8 substituents; (iii)
pyrimidine, optionally substituted with from one to two R.sup.8
substituents; (iv) pyridazine, optionally substituted with from one
to two R.sup.8 substituents; and (v) triazine, optionally
substituted with from one to two R.sup.8 substituents wherein each
R.sup.8 substituent is a member independently selected from the
group consisting of halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, --OR.sup.2, --X.sup.2OR.sup.2,
heterocyclyl, heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2,
--CO.sub.2R.sup.2, --NR.sup.2R.sup.3, --NO.sub.2,
--X.sup.2NR.sup.2R.sup.3, --CN and --S(O).sub.r1R.sup.2.
20. A compound of claim 18, wherein Y.sup.1, Y.sup.2, and Y.sup.3
is a member independently selected from the group consisting of
(CR.sup.4R.sup.5).sub.p, C.dbd.O, NR.sup.2, O, and S(O).sub.r2;
R.sup.2 is H; and each R.sup.4 and R.sup.5 are members
independently selected from the group consisting of H,
(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl, or optionally,
if both present on the same substituent, may be joined together to
form a three- to eight-membered ring system or if present on
adjacent carbon atoms are combined to form a double bond or triple
bond between the atoms to which they are attached.
21. A compound of claim 20, wherein Y.sup.1 is
(CR.sup.4R.sup.5).sub.p, Y.sup.2 is CH.sub.2 or C.dbd.O and Y.sup.3
is NH, O, or S.
22. A compound of claim 20, wherein Y.sup.1 is CH.sub.2, Y.sup.2 is
(CH.sub.2).sub.2 and Y.sup.3 is O or S.
23. A compound of claim 18, wherein at least one of m1, m2, or m3
is O.
24. A compound of claim 18, wherein L is a member selected from the
group consisting of: CH.sub.2, (CH.sub.2).sub.2, CH.sub.2S,
CH(CH.sub.3)S, C(CH.sub.3).sub.2S, (CH.sub.2).sub.2S,
CH(CH.sub.3)CH.sub.2S, --C(CH.sub.3).sub.2CH.sub.2S,
(CH.sub.2).sub.3S, CH.sub.2O, CH(CH.sub.3)O, C(CH.sub.3).sub.2O,
(CH.sub.2).sub.2O, CH(CH.sub.3)CH.sub.2O,
--C(CH.sub.3).sub.2CH.sub.2O, (CH.sub.2).sub.3S and
(C.dbd.O)NH.
25. A compound of claim 18, wherein L is a member selected from the
group consisting of: CH.sub.2, CH(CH.sub.3), C(CH.sub.3).sub.2,
CH.dbd.CH.sub.2.sup.E, CH.dbd.CH.sub.2.sup.Z, CH.dbd.CH, OCH.sub.2,
--OCH(CH.sub.3) and OC(CH.sub.3).sub.2, wherein E represents the
entgegen isomer and Z represents the zusammen isomer.
26. A compound of claim 18, wherein each R.sup.4 and R.sup.5 is
independently H, CH.sub.3, CF.sub.3, or joined together to form a
three- to six-membered ring system selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
27. A compound of claim 26, wherein R.sup.4 and R.sup.5 are H.
28. A compound of claim 18, wherein each R.sup.8 substituent is a
member independently selected from the group consisting of halogen,
(C.sub.1-C.sub.8)alkyl, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, and
halo(C.sub.1-C.sub.8)alkyl.
29. A compound of claim 18, wherein Ar.sup.2 has the formula:
##STR93## each of which is optionally substituted with from one to
two R.sup.8 substituents each independently selected from the group
consisting of halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, --OR.sup.2, --X.sup.2OR.sup.2,
heterocyclyl, heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2,
--CO.sub.2R.sup.2, --NR.sup.2, R.sup.3, --NO.sub.2, --X
NR.sup.2R.sup.3, --CN and --S(O).sub.r1R.sup.2; wherein the dashed
line indicates the point of attachment to L.
30. A compound of claim 18, wherein Ar.sup.2 has the formula:
##STR94## each of which is optionally substituted with from one to
two R.sup.8 substituents each independently selected from the group
consisting of halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, --OR.sup.2, --X.sup.2OR.sup.2,
heterocyclyl, heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2,
--CO.sub.2R.sup.2, --NRR.sup.3, --NO.sub.2,
--X.sup.1NR.sup.2R.sup.3, --CN and --S(O).sub.r1R.sup.2; wherein
the dashed line indicates the point of attachment to L and the wavy
line indicates the point of attachment to K.
31. A compound of claim 1, wherein Ar.sup.2 is benzene optionally
substituted with from one to three R.sup.8 substituents each
independently selected from the group consisting of halogen,
(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, aryl(C.sub.1-C.sub.4)alkyl,
--OR.sup.2, --X.sup.2OR.sup.2, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2, --CO.sub.2R.sup.3,
--NR.sup.2R.sup.3, --NO.sub.2, --X.sup.2NR.sup.2R.sup.3, --CN and
--S(O).sub.r1R.sup.2.
32. A compound of claim 31, wherein Ar.sup.2 is benzene optionally
substituted with from one to two R.sup.8 substituents each
independently selected from the group consisting of halogen,
(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, aryl(C.sub.1-C.sub.4)alkyl,
--OR.sup.2, --X.sup.2OR.sup.2, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2, --CO.sub.2R.sup.2,
--NR.sup.2R.sup.3, --NO.sub.2, --X.sup.2NR.sup.2R.sup.3, --CN and
--S(O).sub.r1R.sup.2.
33. A compound of claim 31, wherein Y.sup.1, Y.sup.2, and Y.sup.3
is a member independently selected from the group consisting of
(CR.sup.4R.sup.5).sub.p, C.dbd.O, NR.sup.2, O, and S(O).sub.r2;
R.sup.2 is H; and each R.sup.4 and R.sup.5 are members
independently selected from the group consisting of H,
(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl, or optionally,
if both present on the same substituent, may be joined together to
form a three- to eight-membered ring system or if present on
adjacent carbon atoms are combined to form a double bond or triple
bond between the atoms to which they are attached.
34. A compound of claim 33, wherein Y.sup.1 is
(CR.sup.4R.sup.5).sub.p, Y.sup.2 is CH.sub.2 or C.dbd.O and Y.sup.3
is NH, O, or S.
35. A compound of claim 33, wherein Y.sup.1 is CH.sub.2, Y.sup.2 is
(CH.sub.2).sub.2 and Y.sup.3 is O or S.
36. A compound of claim 31, wherein at least one of m1, m2, or m3
is O.
37. A compound of claim 31, wherein L is a member selected from the
group consisting of: CH.sub.2, (CH.sub.2).sub.2, CH.sub.2S,
CH(CH.sub.3)S, C(CH.sub.3).sub.2S, (CH.sub.2).sub.2S,
CH(CH.sub.3)CH.sub.2S, --C(CH.sub.3).sub.2CH.sub.2S,
(CH.sub.2).sub.3S, CH.sub.2O, CH(CH.sub.3)O, C(CH.sub.3).sub.2O,
(CH.sub.2).sub.2O, CH(CH.sub.3)CH.sub.2O,
--C(CH.sub.3).sub.2CH.sub.2O, (CH.sub.2).sub.3S and
(C.dbd.O)NH.
38. A compound of claim 31, wherein each R.sup.4 and R.sup.5 is
independently H, CH.sub.3, CF.sub.3, or joined together to form a
three- to six-membered ring system selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
39. A compound of claim 38, wherein R.sup.4 and R.sup.5 are H.
40. A compound of claim 31, wherein each R.sup.8 substituent is
independently selected from the group consisting of H, halogen,
(C.sub.1-C.sub.8)alkyl, and halo(C 1-C.sub.8)alkyl.
41. A compound of claim 31, wherein Ar.sup.2 has the formula:
##STR95## wherein the dashed line indicates the point of attachment
to L and the wavy line indicates the point of attachment to K.
42. A compound of claim 41, wherein the compound is ##STR96##
43. A compound selected from the group consisting of:
2-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenoxy}-propionic acid;
3-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenyl}-acrylic-acid;
3-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenyl}-propionic acid;
2,2-Dimethyl-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2-
,3]triazol-4-ylmethylsulfanyl]-phenyl}-propionic acid;
{2-Bromo-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethylsulfanyl]-phenyl}-acetic
acid;-2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1-
,2,3] triazol-4-ylmethylsulfanyl]-phenyl}-propionic acid;
{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenyl}-acetic acid;
(2-Methyl-4-{1-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]-
triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid;
(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethoxy}-phenoxy)-acetic acid;
(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethoxy}-phenoxy)-acetic acid;
(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-y-
lmethyl]-amino}-phenoxy)-acetic acid;
1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenoxy}-cyclobutanecarboxylic acid;
1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenoxy}-cyclopentanecarboxylic acid;
1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenoxy}-cyclohexanecarboxylic acid;
(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethylsulfanyl}-phenoxy)-acetic acid;
(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethylsulfanyl}-phenoxy)-acetic acid;
(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazole-4--
carbonyl]-amino}-phenoxy)-acetic acid;
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenylsulfanyl}-acetic acid;
{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]--
3-propyl-phenyl}-acetic acid;
{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]--
phenyl}-acetic acid;
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methoxy]-phenyl}-propynoic acid;
2-{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl--
phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-propionic
acid;
2-{4-[5-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluorome-
thyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-propi-
onic acid;
2-{4-[5-[4-(4-Isopropoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-tri-
fluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenox-
y}-propionic acid;
2-{4-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid; and
2-{5-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl--
phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-p-
ropionic acid.
44. A compound selected from the group consisting of:
2-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenoxy}-propionic acid;
2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]t-
riazol-4-ylmethoxy]-phenoxy}-propionic acid;
2-[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-ph-
enoxy]-2-methyl-propionic acid;
2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]t-
riazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid;
2-Methyl-2-(2-methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,-
3]triazol-4-yl]-ethoxy}-phenoxy)-propionic acid;
(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethyl}-phenoxy)-acetic acid;
(2-Methyl-4-{1-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]-
triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid;
(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethoxy}-phenoxy)-acetic acid;
2-{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl--
phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-2-methyl-propionic
acid;
2-{4-[2-(4-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-2-
-methyl-phenoxy}-2-methyl-propionic acid;
2-{2-Chloro-4-[2-(4-chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy-
]-phenoxy}-2-methyl-propionic acid;
2-{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethoxy]-phenoxy}-2-methyl-propionic acid;
2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]t-
riazol-4-ylmethoxy]-phenoxy}-propionic acid;
2-[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-ph-
enoxy]-2-methyl-propionic acid; and
[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-phen-
oxy]-acetic acid;
(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethoxy}-phenoxy)-acetic acid;
(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethyl}-phenoxy)-acetic acid; and
2-Methyl-2-(2-methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,-
3]triazol-4-yl]-ethoxy}-phenoxy)-propionic acid.
45. A composition comprising one or more pharmaceutically
acceptable carriers, diluents, or excipients and a compound of
claim 1.
46. A method of modulating a condition selected from the group
consisting of: insulin resistance, leptin levels and peroxisome
proliferator activated receptor, comprising the step of contacting
the receptor with at least one compound of claim 1.
47. A method of treating a condition selected from the group
consisting of: hyperinsulemia, hyperlipidemia, hyperuricemia,
hypercholesteremia, atherosclerosis, one or more risk factors for
cardiovascular disease Syndrome X, hypertriglyceridemia,
hyperglycemia, obesity, eating disorders and Type 2 diabetes in a
subject, said method comprising administering to said subject a
therapeutically effective amount of a compound of claim 1.
48. A method of decreasing fibrinogen levels or LDLc in a subject,
said method comprising administering to said subject a
therapeutically effective amount of a compound of claim 1.
49. A method of shifting LDL particle size from small dense to
normal dense LDL in a subject, said method comprising administering
to said subject a therapeutically effective amount of a compound of
claim 1.
50. A method of suppressing appetite in a subject, said method
comprising administering to said subject a therapeutically
effective amount of a compound of claim 1.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. patent
application Ser. No. 11/137,678, filed May 24, 2005 and U.S.
Provisional Patent Application No. 60/574,426, filed May 25, 2004,
the content of which is incorporated herein by reference.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH AND DEVELOPMENT
[0002] NOT APPLICABLE
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISK
[0003] NOT APPLICABLE
BACKGROUND OF THE INVENTION
[0004] Peroxisome Proliferator-Activated Receptors (PPARs) are
implicated in a number of biological processes and disease states
including Type 2 diabetes, hyperinsulemia, hyperlipidemia,
hyperuricemia, hypercholesteremia, atherosclerosis, one or more
risk factors for cardiovascular disease, Syndrome X,
hypertriglyceridemia, hyperglycemia, obesity, eating disorders, and
suppressing appetite.
Diabetes, Hyperinsulemia, Hypertriglyceridemia, Hyperglycemia,
Atherosclerosis, and Cardiovascular Disease
[0005] Diabetes mellitus, commonly called diabetes, refers to a
disease process derived from multiple causative factors and
characterized by elevated levels of plasma glucose, referred to as
hyperglycemia. See, e.g., LeRoith, D. et al., (eds.), DIABETES
MELLITUS (Lippincott-Raven Publishers, Philadelphia, Pa. U.S.A.
1996), and all references cited therein. According to the American
Diabetes Association, diabetes mellitus is estimated to affect
approximately 6% of the world population. Uncontrolled
hyperglycemia is associated with increased and premature mortality
due to an increased risk for microvascular and macrovascular
diseases, including nephropathy, neuropathy, retinopathy,
hypertension, cerebrovascular disease, coronary heart disease, and
other cardiovascular diseases. Therefore, control of glucose
homeostasis is a critically important approach for the treatment of
diabetes.
[0006] There are two major forms of diabetes: Type 1 diabetes
(formerly referred to as insulin-dependent diabetes or IDDM); and
Type 2 diabetes (formerly referred to as non-insulin dependent
diabetes or NIDDM).
[0007] Type 1 diabetes is the result of an absolute deficiency of
insulin, the hormone which regulates glucose utilization. This
insulin deficiency is usually characterized by P-cell destruction
within the Islets of Langerhans in the pancreas, which usually
leads to absolute insulin deficiency. Type 1 diabetes has two
forms: Immune-Mediated Diabetes Mellitus, which results from a
cellular mediated autoimmune destruction of the .beta.-cells of the
pancreas; and Idiopathic Diabetes Mellitus, which refers to forms
of the disease that have no known etiologies.
[0008] Type 2 diabetes is a complex disease characterized by
defects in glucose and lipid metabolism. Typically there are
perturbations in many metabolic parameters including increases in
fasting plasma glucose levels, free fatty acid levels and
triglyceride levels (hypertriglyceridemia), as well as a decrease
in the ratio of HDL/LDL. One of the principal underlying causes of
diabetes is thought to be when muscle, fat and liver cells fail to
respond to normal concentrations of insulin (insulin resistance).
Insulin resistance may be due to reduced numbers of insulin
receptors on these cells, or a dysfunction of signaling pathways
within the cells, or both. Insulin resistance is characteristically
accompanied by a relative, rather than absolute, insulin
deficiency. Type 2 diabetes can range from predominant insulin
resistance with relative insulin deficiency to predominant insulin
deficiency with some insulin resistance.
[0009] The beta cells in insulin resistant individuals initially
compensate for this insulin resistance by secreting abnormally high
amounts of insulin (hyperinsulemia). Over time, these cells become
unable to produce enough insulin to maintain normal glucose levels,
indicating progression to Type 2 diabetes. When inadequate amounts
of insulin are present to compensate for insulin resistance and
adequately control glucose, a state of impaired glucose tolerance
develops. In a significant number of individuals, insulin secretion
declines further and the plasma glucose level rises, resulting in
the clinical state of diabetes. Type 2 diabetes can be due to a
profound resistance to insulin stimulating regulatory effects on
glucose and lipid metabolism in the main insulin-sensitive tissues:
muscle, liver and adipose tissue. This resistance to insulin
responsiveness results in insufficient insulin activation of
glucose uptake, oxidation and storage in muscle and inadequate
insulin repression of lipolysis in adipose tissue and of glucose
production and secretion in liver. In Type 2 diabetes, free fatty
acid levels are often elevated in obese and some non-obese patients
and lipid oxidation is increased.
[0010] Type 2 diabetes is brought on by a combination of genetic
and acquired risk factors--including a high-fat diet, lack of
exercise, and aging. Worldwide, Type 2 diabetes has become an
epidemic, driven by increases in obesity and a sedentary lifestyle,
widespread adoption of western dietary habits, and the general
aging of the population in many countries. In 1985, an estimated 30
million people worldwide had diabetes--by 2000, this figure had
increased 5-fold, to an estimated 154 million people. The number of
people with diabetes is expected to double between now and 2025, to
about 300 million.
[0011] Therapies aimed at reducing peripheral insulin resistance
are available. The most relevant to this invention are drugs of the
thiazolidinedione (TZD) class namely troglitazone, pioglitazone,
and rosiglitazone. In the US these have been marketed under the
names Rezulin.TM., Avandia.TM. and Actos.TM., respectively. The
principal effect of these drugs is to improve glucose homeostasis.
Notably in diabetics treated with TZDs there are increases in
peripheral glucose disposal rates indicative of increased insulin
sensitivity in both muscle and fat.
[0012] Premature development of atherosclerosis and increased rate
of cardiovascular and peripheral vascular diseases are
characteristic features of patients with diabetes, with
hyperlipidemia being an important precipitating factor for these
diseases.
Hyperlipidemia
[0013] Hyperlipidemia is a condition generally characterized by an
abnormal increase in serum lipids in the bloodstream and, as noted
above, is an important risk factor in developing atherosclerosis
and coronary heart disease. For a review of disorders of lipid
metabolism, see, e.g., Wilson, J. et al., (ed.), Disorders of Lipid
Metabolism, Chapter 23, Textbook of Endocrinology, 9th Edition,
(W.B. Sanders Company, Philadelphia, Pa. U.S.A. 1998; this
reference and all references cited therein are herein incorporated
by reference). Serum lipoproteins are the carriers for lipids in
the circulation. They are classified according to their density:
chylomicrons; very low-density lipoproteins (VLDL); intermediate
density lipoproteins (IDL); low density lipoproteins (LDL); and
high density lipoproteins (HDL). Hyperlipidemia is usually
classified as primary or secondary hyperlipidemia. Primary
hyperlipidemia is generally caused by genetic defects, while
secondary hyperlipidemia is generally caused by other factors, such
as various disease states, drugs, and dietary factors.
Alternatively, hyperlipidemia can result from both a combination of
primary and secondary causes of hyperlipidemia.
Hypercholesterolemia
[0014] Hypercholesterolemia, a form of hyperlipidemia, is
characterized by excessive high levels of blood cholesterol. The
blood cholesterol pool is generally dependant on dietary uptake of
cholesterol from the intestine and biosynthesis of cholesterol
throughout the body, especially the liver. The majority of the
cholesterol in plasma is carried on apolipoprotein B-containing
lipoproteins, such as the very-low-density lipoproteins (VLDL),
low-density lipoproteins (LDL), intermediate density lipoproteins
(IDL) and high density lipoproteins (HDL). Hypercholesterolemia is
characterized by elevated LDL cholesterol levels. The risk of
coronary artery disease in man increases when LDL and VLDL levels
increase. Conversely, high HDL levels are protective against
coronary artery disease (see Gordon, D. and Rifkind, B. N. Engl. J.
Med. 1989 321: 1311-15; and Stein, O. and Stein, Y. Atherosclerosis
1999 144: 285-303). Therefore, although it is desirable to lower
elevated levels of LDL, it is also desirable to increase HDL
levels.
[0015] Initial treatment for hypercholesterolemia is to place the
patients on a low fat/low cholesterol diet coupled with adequate
physical exercise, followed by drug therapy when LDL-lowering goals
are not met by diet and exercise alone. HMG-CoA reductase
inhibitors (statins) are useful for treating conditions associated
with high LDL levels. Other important anti-lipidemia drugs include
fibrates such as gemfibril and clofibrate, bile acid sequestrant
such as cholestyramine and colestipol, probucol, and nicotinic acid
analogs.
[0016] Elevated cholesterol levels are in turn associated with a
number of disease states, including coronary artery disease, angina
pectoris, carotid artery disease, strokes, cerebral
arteriosclerosis, and xanthoma.
Dyslipidemia
[0017] Dyslipidemia, or abnormal levels of lipoproteins in blood
plasma, is a frequent occurrence among diabetics, and has been
shown to be one of the main contributors to the increased incidence
of coronary events and deaths among diabetic subjects (see, e.g.,
Joslin, E. Ann. Chim. Med. (1927) 5: 1061-1079). Epidemiological
studies since then have confirmed the association and have shown a
several-fold increase in coronary deaths among diabetic subjects
when compared with nondiabetic subjects (see, e.g., Garcia, M. J.
et al., Diabetes (1974) 23: 105-11; and Laakso, M. and Lehto, S.
Diabetes Reviews (1997) 5(4): 294-315). Several lipoprotein
abnormalities have been described among diabetic subjects (Howard
B., et al., Atherosclerosis (1978) 30: 153-162).
Obesity
[0018] Obesity has reached epidemic proportions globally with more
than 1 billion adults overweight--at least 300 million of them
clinical obese- and is a major contributor to the global burden of
chronic diseases including cardiovascular disease problems,
conditions associated with insulin resistance such as Type 2
diabetes and certain types of cancers. The likelihood of developing
Type 2 diabetes and hypertension rises steeply with increasing body
fatness. Weight reduction leads to correction of a number of
obesity-associated endocrine and metabolic disorders.
[0019] Effective weight management for individuals and groups at
risk of developing obesity involves a range of long term
strategies. These include prevention, weight maintenance,
management of co-morbidities and weight loss. Existing treatment
strategies include caloric restriction programs, surgery (gastric
stapling) and drug intervention. The currently available
anti-obesity drugs can be divided into two classes: central acting
and peripheral acting. Three marketed drugs are Xenical (Orlistat),
Merida (Sibutramine) and Adipex-P (Phentermine). Xenical is a
non-systemic acting GI lipase inhibitor which is indicated for
short and long term obesity management. Merida reduces food intake
by re-uptake inhibition of primarily norepinephrine and serotonin.
Adipex-P is a phenteramine with sympathomimetic activities and
suppresses appetite. It is indicated only for short term use. A
more drastic solution to permanent weight loss is surgery and a
gastric by-pass which limits absorption of calories through massive
reduction in stomach size.
[0020] Carrying extra body weight and body fat go hand and hand
with the development of diabetes. People who are overweight (BMI
greater than 25) are at a much greater risk of developing type 2
diabetes than normal weight individuals. Almost 90% of people with
type 2 diabetes are overweight.
Syndrome X, Hyperuricemia, Eating Disorders, and Suppressing
Appetite
[0021] Syndrome X (including metabolic syndrome) is loosely defined
as a collection of abnormalities including hyperinsulinemia,
hyperuricemia, obesity, elevated levels of triglycerides,
fibrinogen, small dense LDL particles, and plasminogen activator
inhibitor 1 (PAI-1), and decreased levels of HDL-c. These
abnormalities are associated with eating disorders, particularly an
overactive appetite.
PPAR
[0022] PPARs are members of the nuclear receptor superfamily of
transcription factors, a large and diverse group of proteins that
mediate ligand-dependent transcriptional activation and repression.
They play a role in controlling expression of proteins that
regulate lipid metabolism. Furthermore, the PPARs are activated by
fatty acids and fatty acid metabolites. Three PPAR subtypes have
been isolated: PPAR.alpha., PPAR.beta. (also referred to as .delta.
or NUC1), and PPAR.gamma.. Each receptor shows a different pattern
of gene expression by binding to DNA sequence elements, termed PPAR
response elements (PPRE). In addition, each receptor show a
difference in activation by structurally diverse compounds. To
date, PPREs have been identified in the enhancers of a number of
genes encoding proteins that regulate lipid metabolism suggesting
that PPARs play a pivotal role in the dipogenic signaling cascade
and lipid homeostasis (Keller, H. and Wahli, W. Trends Endoodn.
Met. (1993) 4:291-296. PPAR.alpha. is found in the liver, heart,
kidney, muscle, brown adipose tissue and gut and is involved in
stimulating .beta.-oxidation of fatty acids. PPAR.alpha. is also
involved in the control of cholesterol levels in rodents and in
humans. Fibrates are weak PPAR.alpha. agonists that are effective
in the treatment of lipid disorders. In humans, they have been
shown to lower plasma triglycerides and LDL cholesterol. In
addition, PPAR.alpha. agonists have also been reported to prevent
diabetes and to improve insulin sensitivity and reduce adiposity in
obese and diabetic rodents (see Koh, E. H. et al. Diabetes (2003)
52:2331-2337; and Guerre-Millo, M. et al. J. Biol. Chem. (2000)
275: 16638-16642).
[0023] PPAR.beta. is ubiquitously expressed. Activation of
PPAR.beta. increases HDL levels in rodents and monkeys (see Oliver,
W. R. et al. PNAS (2001) 98:5306-5311; and Leibowitz, M. D. et al.
FEBS Letters (2000) 473:333-336). Moreover, PPAR.beta. has been
recently shown to be a key regulator of lipid catabolism and energy
uncoupling in skeletal muscle cells (Dressel, U. et al. Mol
Endocrinol. (2003) 17: 2477-2493). In rodents, activation of
PPAR.beta. induces fatty .beta.-oxidation in skeletal muscle and
adipose tissue, leading to protection against diet-induced obesity
and diabetes (see Wang, Y. X. et al. Cell (2003) 113:159-170; and
Tanaka et al. PNAS (2003) 100:15924-15929). In human macrophages,
PPAR.beta. activation also increases the reverse cholesterol
transporter ATP-binding cassette A1 and induces apolipoprotein
A1-specific cholesterol efflux (see Oliver, W. R. et al. PNAS
(2001) 98:5306-5311).
[0024] PPAR-.gamma. is expressed most abundantly in adipose tissue
and is thought to regulate adipocyte differentiation. Drugs of the
thiazolidinedione (TZD) class namely troglitazone, pioglitazone,
and rosiglitazone are potent and selective activators of
PPAR-.gamma.. In human, they increase insulin action, reduce serum
glucose and have small but significant effects on reducing serum
triglyceride levels in patients with type 2 diabetes.
[0025] Certain compounds that activate or otherwise interact with
one or more of the PPARs have been implicated in the regulation of
triglyceride and cholesterol levels in animal models. (See e.g.,
U.S. Pat. No. 5,859,501, and PCT publications WO 97/28149 and
99/04815.
[0026] Taken together, these data clearly indicate that PPARs
agonists are useful in treating hypertriglyceridemia,
hypercholesterolemia, obesity and type 2 diabetes.
[0027] Anti-lipidemia, anti-obesity and anti-diabetes agents are
still considered to have non-uniform effectiveness, in part because
of poor patient compliance due to unacceptable side effects. For
Anti-lipidemia and anti-obesity agents, these side effects include
diarrhea and gastrointestinal discomfort. For anti-diabetic agents,
they include weight gain, edema and hepatotoxicity. Furthermore,
each type of drug does not work equally well in all patients.
[0028] What is needed in the art are new compounds and methods
useful for modulating peroxisome proliferators activated receptor,
insulin resistance, fibrinogen levels, leptin levels, LDLc shifting
LDL particle size from small dense to normal dense LDL. What is
also needed in the art are new compounds and methods useful for
treating Type 2 diabetes, hyperinsulemia, hyperlipidemia,
hyperuricemia, hypercholesteremia, atherosclerosis, one or more
risk factors for cardiovascular disease, Syndrome X,
hypertriglyceridemia, hyperglycemia, obesity, eating disorders, and
suppressing appetite. The present invention fulfills this and other
needs by providing such compounds, compositions and methods for
modulating peroxisome proliferators activated receptor, insulin
resistance, fibrinogen levels, leptin levels, LDLc shifting LDL
particle size from small dense to normal dense LDL. The present
invention also provides compounds, compositions, and methods useful
for treating Type 2 diabetes, hyperinsulemia, hyperlipidemia,
hyperuricemia, hypercholesteremia, atherosclerosis, one or more
risk factors for cardiovascular disease, Syndrome X,
hypertriglyceridemia, hyperglycemia, obesity, eating disorders, and
suppressing appetite.
BRIEF SUMMARY OF THE INVENTION
[0029] In one aspect, the present invention provides compounds
having the formula: ##STR1## wherein Ar.sup.1 represents a
monocyclic or bicyclic aromatic ring system selected from the group
consisting of phenyl, naphthyl, imidazolyl, benzimidazoyl,
pyrrolyl, indolyl, thienyl, benzothienyl, furanyl, benzofuranyl,
and benzodioxole. Each of these rings can be optionally substituted
with from one to four R.sup.7 substituents.
[0030] In the above formula, the symbol Ar.sup.2 represents a
6-membered monocyclic aromatic ring. A variety of Ar.sup.2 aryl
groups provide compounds having the desired activity. In
particular, Ar.sup.2 aryl groups can be benzene, pyridine,
pyrazine, pyrimidine, pyridazine, triazine. Each of these rings can
be optionally substituted with from one to four R.sup.8
substituents.
[0031] Within Ar.sup.1 and Ar.sup.2, variables R.sup.7 and R.sup.8
represent from one to four substituents on their respective rings,
wherein each substituent present can be the same or different from
any other substituent. More particularly, R.sup.7 substituents are
independently selected from the group consisting of halogen,
(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl, --OR.sup.2,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.2-C.sub.8)alkenyl,
aryl(C.sub.2-C.sub.8)alkynyl, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2,
--C.sub.1-2R.sup.2, --NR.sup.2R.sup.3, --NO.sub.2, --CN,
--S(O).sub.r1R.sup.2, --X.sup.1OR.sup.2, --X.sup.1COR.sup.2,
--X.sup.1CO.sub.2R.sup.2, --X.sup.1NR.sup.2R.sup.3,
--X.sup.1NO.sub.2--X.sup.1CN, and --X.sup.1S(O).sub.r1R.sup.2. More
particularly, R.sup.8 substituents are independently selected from
the group consisting of halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, --OR.sup.2, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.2-C.sub.8)alkenyl,
aryl(C.sub.2-C.sub.8)alkynyl, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2, --CO.sub.2R.sup.2,
--NR.sup.2R.sup.3, --NO.sub.2, --CN, --S(O).sub.r1R.sup.2,
--X.sup.1OR.sup.2, --X.sup.2COR.sup.2, --X.sup.2CO.sub.2R.sup.2,
--X.sup.2NR.sup.2R.sup.3, --X.sup.2NO.sub.2--X.sup.2CN, and
--X.sup.1S(O).sub.r1R.sup.2. Within these designations, each
R.sup.2 and R.sup.3 is a member independently selected from the
group consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, --X.sup.3OR.sup.9, aryl,
aryl(C.sub.1-C.sub.4)alkyl, and heteroaryl, or optionally, if both
present on the same substituent, may be joined together to form a
three- to eight-membered ring system. R.sup.9 is a member selected
from the group consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, aryl, aryl(C.sub.1-C.sub.4)alkyl, and
heteroaryl. Each X.sup.1, X.sup.2, and X.sup.3 is a member
independently selected from the group consisting of
(C.sub.1-C.sub.4)alkylene, (C.sub.2-C.sub.4)alkenylene, and
(C.sub.2-C.sub.4)alkynylene. The subscript r1 is an integer of from
0 to 2.
[0032] Returning to formula I, L represents a covalent bond or a
linking group having from one to six main chain atoms and having
the formula --Y.sup.1.sub.m1Y.sup.2.sub.m2Y.sup.3.sub.m3-- wherein
L can be attached to any available ring member of Ar.sup.2.
[0033] Similarly, K represents either a covalent bond or a linking
group having from one to six main chain atoms and having the
formula --Y.sup.4.sub.m4 Y.sup.5.sub.m5Y.sup.6.sub.m6-- wherein K
can be attached to any available ring member of Ar.sup.2. Each
Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5, and Y.sup.6 represents
a member independently selected from the group consisting of
(CR.sup.4R.sup.5).sub.p, C.dbd.O, C.dbd.ONR.sup.2, C.dbd.NOR.sup.2,
NR.sup.2C.dbd.O, NR.sup.2, O, S(O).sub.r2, NR.sup.2SO.sub.2, and
SO.sub.2NR.sup.2; wherein R.sup.2 and R.sup.3 are as defined above.
Each R.sup.4 and R.sup.5 are members independently selected from
the group consisting of H, halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, OR.sup.2, aryl, heteroaryl, and
aryl(C.sub.1-C.sub.4)alkyl, or optionally, if both present on the
same substituent, may be joined together to form a three- to
eight-membered ring system, or if present on adjacent carbon atoms
are combined to form a double bond or triple bond between the atoms
to which they are attached. Each subscript m1-m6 is an integer of
from 0 to 1, the subscript r2 is an integer of from 0 to 2; and the
subscript p is an integer of from 1 to 2. More preferably the
subscript m1 and m6 is 0, the subscript r2 is 0; and the subscripts
m2-m4 are 1. More preferably the subscript p is 1.
[0034] Returning to formula I, Z is selected from the group
consisting of CH.sub.2OR.sup.6, CO.sub.2R.sup.6, CN, tetrazol-5-yl,
CONHSO.sub.2R.sup.2 and CHO; wherein R.sup.6 is a member selected
from the group consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, --X.sup.4OR.sup.2,
--X.sup.4NR.sup.2R.sup.3, (C.sub.2-C.sub.8)alkenyl,
(C.sub.3-C.sub.7)cycloalkyl, heterocyclyl,
aryl(C.sub.1-C.sub.4)alkyl, and aryl(C.sub.2-C.sub.8)alkenyl.
X.sup.4 is a member independently selected from the group
consisting of (C.sub.1-C.sub.4)alkylene,
(C.sub.2-C.sub.4)alkenylene, and (C.sub.2-C.sub.4)alkynylene.
R.sup.2 and R.sup.3 are as defined above.
[0035] The symbol R.sup.1 represents a member selected from the
group consisting of H, halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.4)alkyl.
[0036] In addition to compounds having formula I above, the present
invention further includes all salts thereof, and particularly,
pharmaceutically acceptable salts thereof. Still further, the
invention includes compounds that are single isomers of the above
formula (e.g., single enantiomers of compounds having a single
chiral center), as well as solvate, hydrate, and prodrug forms
thereof.
[0037] In other aspects, the present invention provides
compositions containing one or more compounds of Formula I, as well
as methods for the use of such compounds and compositions, either
alone or in combination with other pharmaceutical agents as
provided in detail below. In particular, the present invention
provides methods of using the compounds and/or compositions for the
treatment of Type 2 diabetes, hyperinsulemia, hyperlipidemia,
hyperuricemia, hypercholesteremia, atherosclerosis, one or more
risk factors for cardiovascular disease, Syndrome X,
hypertriglyceridemia, hyperglycemia, obesity, eating disorders, and
suppressing appetite. In addition, the present invention provides
methods of using the compounds and/or compositions for the
modulation of peroxisome proliferators activated receptor, insulin
resistance, fibrinogen levels, leptin levels, LDLc shifting LDL
particle size from small dense to nonmal dense LDL. Additionally,
the present invention provides methods of using the compounds
and/or compositions for the treatment of diseases modulated by any
of the isoforms of peroxisome proliferation activated receptor
(PPAR).
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] FIG. 1A-E illustrate a variety of preferred compounds of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0039] Abbreviations and Definitions
[0040] The abbreviations used herein are conventional, unless
otherwise defined:
[0041] AcOH: acetic acid; BPO: benzoyl peroxide; CBr.sub.4:
tetrabromomethane; Cs.sub.2CO.sub.3: cesium carbonate;
CH.sub.2Cl.sub.2: dichloromethane; CuCl.sub.2: copper chloride;
DIBAL: diisobutylaluminum hydride; DMSO: dimethyl sulfoxide; EtOAc:
ethyl acetate; H.sub.2: hydrogen; H.sub.2O: water; HBr: hydrogen
bromide; HCl: hydrogen chloride; KCN: potassium cyanide;
LiAlH.sub.4: lithium aluminum hydride; LiOH: lithium hydroxide;
MeCN: acetonitrile; MeOH: methanol; N.sub.2: nitrogen;
Na.sub.2CO.sub.3: sodium carbonate; NaHCO.sub.3: sodium
bicarbonate; NaNO.sub.2: sodium nitrite; NaOH: sodium hydroxide;
Na.sub.2S.sub.2O.sub.3: sodium bisulfate; Na.sub.2SO.sub.4: sodium
sulfate; NBS: N-bromosuccinamide; NH.sub.4Cl: ammonium chloride;
NH.sub.4OAc: ammonium acetate; NMR: nuclear magnetic resonance;
Pd/C: palladium on carbon; PPh.sub.3: triphenyl phosphine;
SOCl.sub.2: thionyl chloride; THF: tetrahydrofuran; TLC: thin layer
chromatography.
[0042] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below:
[0043] "Alkyl" refers to a linear saturated monovalent hydrocarbon
radical or a branched saturated monovalent hydrocarbon radical
having the number of carbon atoms indicated in the prefix. For
example, (C.sub.1-C.sub.8)alkyl is meant to include methyl, ethyl,
n-propyl, 2-propyl, n-butyl, 2-butyl, tert-butyl, pentyl, and the
like. For each of the definitions herein (e.g., alkyl, alkenyl,
alkoxy, araalkyloxy), when a prefix is not included to indicate the
number of main chain carbon atoms in an alkyl portion, the radical
or portion thereof will have six or fewer main chain carbon
atoms.
[0044] "Alkylene" refers to a linear saturated divalent hydrocarbon
radical or a branched saturated divalent hydrocarbon radical having
the number of carbon atoms indicated in the prefix. For example,
(C.sub.1-C.sub.6)alkylene is meant to include methylene, ethylene,
propylene, 2-methylpropylene, pentylene, and the like.
[0045] "Alkenyl" refers to a linear monovalent hydrocarbon radical
or a branched monovalent hydrocarbon radical having the number of
carbon atoms indicated in the prefix and containing at least one
double bond, but no more than three double bonds. For example,
(C.sub.2-C.sub.6)alkenyl is meant to include, ethenyl, propenyl,
1,3-butadienyl and the like.
[0046] "Alkynyl" means a linear monovalent hydrocarbon radical or a
branched monovalent hydrocarbon radical containing at least one
triple bond and having the number of carbon atoms indicated in the
prefix. The term "alkynyl" is also meant to include those alkyl
groups having one triple bond and one double bond. For example,
(C.sub.2-C.sub.6)alkynyl is meant to include ethynyl, propynyl, and
the like.
[0047] "Alkoxy", "aryloxy" or "araalkyloxy" refers to a radical
--OR wherein R is an alkyl, aryl or arylalkyl, respectively, as
defined herein, e.g., methoxy, phenoxy, benzyloxy, and the
like.
[0048] "Aryl" refers to a monovalent monocyclic or bicyclic
aromatic hydrocarbon radical of 6 to 10 ring atoms which is
substituted independently with one to four substituents, preferably
one, two, or three substituents selected from alkyl, cycloalkyl,
cycloalkyl-alkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,
acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy,
heteroalkyl, COR (where R is hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, phenyl or phenylalkyl), --(CR'R'').sub.n--COOR
(where n is an integer from 0 to 5, R' and R'' are independently
hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, phenyl or phenylalkyl) or
--(CR'R'').sub.n--CONR.sup.xR.sup.y (where n is an integer from 0
to 5, R' and R'' are independently hydrogen or alkyl, and R.sup.x
and R.sup.y are independently selected from hydrogen, alkyl,
cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). More
specifically the term aryl includes, but is not limited to, phenyl,
biphenyl, 1-naphthyl, and 2-naphthyl, and the substituted forms
thereof.
[0049] "Araalkyl" or "Aryl(C.sub.1-C.sub.x)alkyl" refers to the
radical --R.sup.xR.sup.y where R.sup.x is an alkylene group (having
eight or fewer main chain carbon atoms) and R.sup.y is an aryl
group as defined above. Thus, "araalkyl" refers to groups such as,
for example, benzyl, phenylethyl, 3-(4-nitrophenyl)-2-methylbutyl,
and the like. Similarly, "Araalkenyl" means a radical
--R.sup.xR.sup.y where Rx is an alkenylene group (an alkylene group
having one or two double bonds) and R.sup.y is an aryl group as
defined above, e.g., styryl, 3-phenyl-2-propenyl, and the like.
[0050] "Cycloalkyl" refers to a monovalent cyclic hydrocarbon
radical of three to seven ring carbons. The cycloalkyl group may
have one double bond and may also be optionally substituted
independently with one, two, or three substituents selected from
alkyl, optionally substituted phenyl, or --C(O)R.sup.z (where
R.sup.z is hydrogen, alkyl, haloalkyl, amino, mono-alkylamino,
di-alkylamino, hydroxy, alkoxy, or optionally substituted phenyl).
More specifically, the term cycloalkyl includes, for example,
cyclopropyl, cyclohexyl, cyclohexenyl, phenylcyclohexyl,
4-carboxycyclohexyl, 2-carboxamidocyclohexenyl,
2-dimethylaminocarbonyl-cyclohexyl, and the like.
[0051] "Cycloalkyl-alkyl" means a radical --R.sup.xR.sup.y wherein
R.sup.x is an alkylene group and R.sup.y is a cycloalkyl group as
defined herein, e.g., cyclopropylmethyl, cyclohexenylpropyl,
3-cyclohexyl-2-methylpropyl, and the like. The prefix indicating
the number of carbon atoms (e.g., C.sub.4-C.sub.10) refers to the
total number of carbon atoms from both the cycloalkyl portion and
the alkyl portion.
[0052] "Haloalkyl" refers to an alkyl group which is substituted
with one or more same or different halo atoms, e.g., --CH.sub.2Cl,
--CH.sub.2F, --CH.sub.2Br, --CFClBr, --CH.sub.2CH.sub.2Cl,
--CH.sub.2CH.sub.2F, --CF.sub.3, --CH.sub.2CF.sub.3,
--CH.sub.2CCl.sub.3, and the like, and further includes those alkyl
groups such as perfluoroalkyl in which all hydrogen atoms are
replaced by fluorine atoms. The prefix "halo" and the term
"halogen" when used to describe a substituent, refer to --F, --Cl,
--Br and --I.
[0053] "Haloalkoxy" refers to an alkoxy group which is substituted
with one or more same or different halo atoms, e.g.,
--CH.sub.3OCHCl, --CH.sub.3OCHF, --CH.sub.3OCHBr,
--CH.sub.3OCHCH.sub.2Cl, --CH.sub.3CH.sub.2OCHF,
--CH.sub.3OCHCF.sub.3, and the like.
[0054] "Heteroalkyl" means an alkyl radical as defined herein with
one, two or three substituents independently selected from cyano,
--OR.sup.w, --NR.sup.xR.sup.y, and --S(O).sub.nR.sup.z (where n is
an integer from 0 to 2), with the understanding that the point of
attachment of the heteroalkyl radical is through a carbon atom of
the heteroalkyl radical. R.sup.W is hydrogen, alkyl, cycloalkyl,
cycloalkyl-alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl,
carboxamido, or mono- or di-alkylcarbamoyl. R.sup.x is hydrogen,
alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or araalkyl. Ry is
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl,
alkoxycarbonyl, aryloxycarbonyl, carboxamido, mono- or
di-alkylcarbamoyl or alkylsulfonyl. R.sup.z is hydrogen (provided
that n is 0), alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl,
amino, mono-alkylamino, di-alkylamino, or hydroxyalkyl.
Representative examples include, for example, 2-hydroxyethyl,
2,3-dihydroxypropyl, 2-methoxyethyl, benzyloxymethyl, 2-cyanoethyl,
and 2-methylsulfonyl-ethyl. For each of the above, R.sup.w,
R.sup.x, R.sup.y, and R.sup.z can be further substituted by amino,
fluorine, alkylamino, di-alkylamino, OH or alkoxy. Additionally,
the prefix indicating the number of carbon atoms (e.g.,
C.sub.1-C.sub.10) refers to the total number of carbon atoms in the
portion of the heteroalkyl group exclusive of the cyano,
--OR.sup.w, --NR.sup.xR.sup.y, or --S(O).sub.nR.sup.z portions.
[0055] "Heteroaryl" means a monovalent monocyclic or bicyclic
radical of 5 to 12 ring atoms having at least one aromatic ring
containing one, two, or three ring heteroatoms selected from N, O,
or S, the remaining ring atoms being C, with the understanding that
the attachment point of the heteroaryl radical will be on an
aromatic ring. The heteroaryl ring is optionally substituted
independently with one to four substituents, preferably one or two
substituents, selected from alkyl, cycloalkyl, cycloalkyl-alkyl,
halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino,
mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl,
--COR (where R is hydrogen, alkyl, phenyl or phenylalkyl,
--(CR'R'').sub.n--COOR (where n is an integer from 0 to 5, R' and
R'' are independently hydrogen or alkyl, and R is hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl), or
--(CR'R'').sub.n--CONR.sup.xR.sup.y (where n is an integer from 0
to 5, R' and R'' are independently hydrogen or alkyl, and R.sup.x
and R.sup.y are, independently of each other, hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl). More
specifically the term heteroaryl includes, but is not limited to,
pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl,
imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl,
pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl,
benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl,
isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl,
isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and
the derivatives thereof.
[0056] "Heterocyclyl" or "cycloheteroalkyl" means a saturated or
unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in
which one to four ring atoms are heteroatoms selected from O, NR
(where R is independently hydrogen or alkyl) or S(O).sub.n (where n
is an integer from 0 to 2), the remaining ring atoms being C, where
one or two C atoms may optionally be replaced by a carbonyl group.
The heterocyclyl ring may be optionally substituted independently
with one, two, or three substituents selected from alkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,
cycloalkyl-alkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,
mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, --COR (where
R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or
phenylalkyl), --(CR'R'').sub.n--COOR (n is an integer from 0 to 5,
R' and R'' are independently hydrogen or alkyl, and R is hydrogen,
alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl or phenylalkyl), or
--(CR'R'').sup.n--CONR.sup.xR.sup.y (where n is an integer from 0
to 5, R' and R'' are independently hydrogen or alkyl, R.sup.x and
R.sup.y are, independently of each other, hydrogen, alkyl,
cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). More
specifically the term heterocyclyl includes, but is not limited to,
pyridyl, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl,
piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino,
2-pyrrolidon-1-yl, furyl, quinolyl, morpholino, thienyl,
benzothienyl, thiomorpholino, thiomorpholino-1-oxide,
thiomorpholino-1,1-dioxide, pyrrolidinyl, and the derivatives
thereof. The prefix indicating the number of carbon atoms (e.g.,
C.sub.3-C.sub.10) refers to the total number of carbon atoms in the
portion of the cycloheteroalkyl or heterocyclyl group exclusive of
the number of heteroatoms.
[0057] "Heterocyclylalkyl" or "Cycloheteroalkyl-alkyl" means a
radical --R.sup.xR.sup.y where R.sup.x is an alkylene group and
R.sup.y is a heterocyclyl group as defined herein, e.g.,
tetrahydropyran-2-ylmethyl,
4-(4-substituted-phenyl)piperazin-1-ylmethyl, 3-piperidinylethyl,
and the like.
[0058] The terms "optional" or "optionally" as used throughout the
specification means that the subsequently described event or
circumstance may but need not occur, and that the description
includes instances where the event or circumstance occurs and
instances in which it does not. For example, "heterocyclo group
optionally mono- or di-substituted with an alkyl group means that
the alkyl may but need not be present, and the description includes
situations where the heterocyclo group is mono- or disubstituted
with an alkyl group and situations where the heterocyclo group is
not substituted with the alkyl group.
[0059] "Optionally substituted" means a ring which is optionally
substituted independently with substituents.
[0060] For each of the definitions above, the term "di-alkylamino"
refers to an amino moiety bearing two alkyl groups that can be the
same, or different.
[0061] As used herein, the term "carboxylic acid equivalent" refers
to those moieties that are used as equivalents for a carboxylic
acid moiety. Such groups are generally known to one of skill in the
art (see, for example, The Practice of Medicinal Chemistry;
Wermuth, C. G., ed., Academic Press, New York, 1996, page 203).
Suitable isosteres or equivalents include --C(O)NHSO.sub.2R wherein
R can be alkyl, haloalkyl, heteroalkyl, araalkyl, aryl, heteroaryl,
heterocyclyl, alkoxy, haloalkoxy, aryloxy, alkylamino,
haloalkylamino, dialkylamino, dihaloalkylamino, arylamino,
diarylamino, araalkylamino, diaraalkylamino or other groups to
provide an overall acidic character to the moiety; sulfonic acids;
sulfinic acids; phosphonic acids; phosphinic acids; activated
sulfonamides (e.g., --SO.sub.2NHX wherein X is an electron
withdrawing group relative to an alkyl group, such as an acyl group
or aryl group; activated carboxamides (e.g., --C(O)NHCN);
hydroxamic acids (--C(O)NHOH); acidic heterocycles or substituted
heterocycles (e.g., tetrazoles, triazoles, hydroxypyrazoles,
hydroxyoxazoles, hydroxythiadiazoles); and acidic alcohols (e.g.,
--C(CF.sub.3).sub.2OH or --CH(CF.sub.3)OH). The term "carboxylic
acid equivalent" also refers to those moieties that may be
converted into a carboxylic acid moiety in vivo. Such groups are
generally known to one of skill in the art. While it is recognized
that these groups initially may be non-acidic, suitable in vivo
equivalents include aldehydes (CHO) and alcohols CH.sub.2OH and
esters CH.sub.2OR wherein R can be alkyl, alkenyl, cycloalkyl,
haloalkyl, heteroalkyl, araalkyl, aryl, heteroaryl, heterocyclyl,
arylalkyl, arylalkenyl, alkoxy, haloalkoxy, aryloxy, alkylamino,
haloalkylamino, dialkylamino, dihaloalkylamino, arylamino,
diarylamino, araalkylamino, diaraalkylamino, or other groups that
can be easily cleaved to provide a hydroxyl group that can be
oxidized in vivo to provide a carboxylic acid.
[0062] Compounds that have the same molecular formula but differ in
the nature or sequence of bonding of their atoms or the arrangement
of their atoms in space are termed "isomers". Isomers that differ
in the arrangement of their atoms in space are termed
"stereoisomers". Stereoisomers that are not mirror images of one
another are termed "diastereomers" and those that are
non-superimposable mirror images of each other are termed
"enantiomers". When a compound has an asymmetric center, for
example, it is bonded to four different groups, a pair of
enantiomers is possible. An enantiomer can be characterized by the
absolute configuration of its asymmetric center and is described by
the R- and S-sequencing rules of Cahn and Prelog, or by the manner
in which the molecule rotates the plane of polarized light and
designated as dextrorotatory or levorotatory (i.e., as (+) or
(-)-isomers respectively). A chiral compound can exist as either
individual enantiomer or as a mixture thereof. A mixture containing
equal proportions of the enantiomers is called a "racemic
mixture".
[0063] The compounds of this invention may exist in stereoisomeric
form if they possess one or more asymmetric centers or a double
bond with asymmetric substitution and, therefore, can be produced
as individual stereoisomers or as mixtures. Unless otherwise
indicated, the description is intended to include individual
stereoisomers as well as mixtures. The methods for the
determination of stereochemistry and the separation of
stereoisomers are well-known in the art (see discussion in Chapter
4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. March, John Wiley
and Sons, New York, 1992).
[0064] "Pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the
desired pharmacological activity of the parent compound. Such salts
include:
[0065] (1) acid addition salts, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
acid, glycolic acid, pyruvic acid, lactic acid, malonic acid,
succinic acid, malic acid, maleic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid,
glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,
glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid,
muconic acid, and the like; or
[0066] (2) salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic base such as ethanolamine, diethanolamine,
triethanolamine, trimethylamine, N-methylglucamine, and the
like.
[0067] "Prodrugs" means any compound which releases an active
parent drug according to Formula I in vivo when such prodrug is
administered to a mammalian subject. Prodrugs of a compound of
Formula I are prepared by modifying functional groups present in
the compound of Formula I in such a way that the modifications may
be cleaved in vivo to release the parent compound. Prodrugs include
compounds of Formula I wherein a hydroxy, amino, or sulfhydryl
group in a compound of Formula I is bonded to any group that may be
cleaved in vivo to regenerate the free hydroxyl, amino, or
sulfhydryl group, respectively. Examples of prodrugs include, but
are not limited to esters (e.g., acetate, formate, and benzoate
derivatives), amides, carbamates (e.g., N,N-dimethylaminocarbonyl)
of hydroxy functional groups in compounds of Formula I, and the
like.
[0068] "Protecting group" refers to a grouping of atoms that when
attached to a reactive group in a molecule masks, reduces or
prevents that reactivity. Examples of protecting groups can be
found in T. W. Greene and P. G. Wuts, PROTECTIVE GROUPS IN ORGANIC
CHEMISTRY, (Wiley, 2nd ed. 1991) and Harrison and Harrison et al.,
COMPENDIUM OF SYNTHETIC ORGANIC METHODS, Vols. 1-8 (John Wiley and
Sons. 1971-1996). Representative amino protecting groups include
formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ),
tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),
2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted
trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl
(FMOC), nitro-veratryloxycarbonyl (NVOC) and the like.
Representative hydroxy protecting groups include those where the
hydroxy group is either acylated or alkylated such as benzyl and
trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers,
trialkylsilyl ethers and allyl ethers.
[0069] Turning next to the compositions of the invention, the term
"pharmaceutically acceptable carrier or excipient" means a carrier
or excipient that is useful in preparing a pharmaceutical
composition that is generally safe, non-toxic and neither
biologically nor otherwise undesirable, and includes a carrier or
excipient that is acceptable for veterinary use as well as human
pharmaceutical use. A "pharmaceutically acceptable carrier or
excipient" as used in the specification and claims includes both
one and more than one such carrier or excipient.
[0070] With reference to the methods of the present invention, the
following terms are used with the noted meanings:
[0071] The terms "treating" or "treatment" of a disease
includes:
[0072] (1) preventing the disease, i.e., causing the clinical
symptoms of the disease not to develop in a mammal that may be
exposed to or predisposed to the disease but does not yet
experience or display symptoms of the disease,
[0073] (2) inhibiting the disease, i.e., arresting or reducing the
development of the disease or its clinical symptoms, or
[0074] (3) relieving the disease, i.e., causing regression of the
disease or its clinical symptoms.
[0075] The term "therapeutically effective amount" means the amount
of the subject compound that will elicit the biological or medical
response of a tissue, system, animal or human that is being sought
by the researcher, veterinarian, medical doctor or other clinician.
"A therapeutically effective amount" includes the amount of a
compound that, when administered to a mammal for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease and its severity and the age, weight, etc.,
of the mammal to be treated.
[0076] The term "patient" means all mammals, including humans.
Examples of patients include, but are not limited to, humans, cows,
dogs, cats, goats, sheep, pigs and rabbits.
[0077] The term "mammal" includes, without limitation, humans,
domestic animals (e.g., dogs or cats), farm animals (cows, horses,
or pigs), monkeys, rabbits, mice, and laboratory animals.
[0078] The term "insulin resistance" can be defined generally as a
disorder of glucose metabolism. More specifically, insulin
resistance can be defined as the diminished ability of insulin to
exert its biological action across a broad range of concentrations
producing less than the expected biologic effect. (see, e.g.,
Reaven, G. M. J Basic & Clin. Phys. & Pharm. (1998) 9:
387-406 and Flier, J. Ann Rev. Med. (1983) 34: 145-60). Insulin
resistant persons have a diminished ability to properly metabolize
glucose and respond poorly, if at all, to insulin therapy.
Manifestations of insulin resistance include insufficient insulin
activation of glucose uptake, oxidation and storage in muscle and
inadequate insulin repression of lipolysis in adipose tissue and of
glucose production and secretion in liver. Insulin resistance can
cause or contribute to polycystic ovarian syndrome, Impaired
Glucose Tolerance (IGT), gestational diabetes, hypertension,
obesity, atherosclerosis and a variety of other disorders.
Eventually, the insulin resistant individuals can progress to a
point where a diabetic state is reached. The association of insulin
resistance with glucose intolerance, an increase in plasma
triglyceride and a decrease in high-density lipoprotein cholesterol
concentrations, high blood pressure, hyperuricemia, smaller denser
low-density lipoprotein particles, and higher circulating levels of
plasminogen activator inhibitor-1), has been referred to as
"Syndrome X" (see, e.g., Reaven, G. M. Physiol. Rev. (1995) 75:
473-486).
[0079] The term "diabetes mellitus" or "diabetes" means a disease
or condition that is generally characterized by metabolic defects
in production and utilization of glucose which result in the
failure to maintain appropriate blood sugar levels in the body. The
result of these defects is elevated blood glucose, referred to as
"hyperglycemia." Two major forms of diabetes are Type 1 diabetes
and Type 2 diabetes. As described above, Type 1 diabetes is
generally the result of an absolute deficiency of insulin, the
hormone which regulates glucose utilization. Type 2 diabetes often
occurs in the face of normal, or even elevated levels of insulin
and can result from the inability of tissues to respond
appropriately to insulin. Most Type 2 diabetic patients are insulin
resistant and have a relative deficiency of insulin, in that
insulin secretion can not compensate for the resistance of
peripheral tissues to respond to insulin. In addition, many Type 2
diabetics are obese. Other types of disorders of glucose
homeostasis include Impaired Glucose Tolerance, which is a
metabolic stage intermediate between normal glucose homeostasis and
diabetes, and Gestational Diabetes Mellitus, which is glucose
intolerance in pregnancy in women with no previous history of Type
1 or Type 2 diabetes.
[0080] The term "secondary diabetes" is diabetes resulting from
other identifiable etiologies which include: genetic defects of (3
cell function (e.g., maturity onset-type diabetes of youth,
referred to as "MODY," which is an early-onset form of Type 2
diabetes with autosomal inheritance; see, e.g., Fajans, S. et al.
Diabet. Med. (1996) (9 Suppl 6): S90-5 and Bell, G. et al., Annu.
Rev. Physiol. (1996) 58: 171-86; genetic defects in insulin action;
diseases of the exocrine pancreas (e.g., hemochromatosis,
pancreatitis, and cystic fibrosis); certain endocrine diseases in
which excess hormones interfere with insulin action (e.g., growth
hormone in acromegaly and cortisol in Cushing's syndrome); certain
drugs that suppress insulin secretion (e.g., phenyloin) or inhibit
insulin action (e.g., estrogens and glucocorticoids); and diabetes
caused by infection (e.g. rubella, Coxsackie, and CMV); as well as
other genetic syndromes.
[0081] The guidelines for diagnosis for Type 2 diabetes, impaired
glucose tolerance, and gestational diabetes have been outlined by
the American Diabetes Association (see, e.g., The Expert Committee
on the Diagnosis and Classification of Diabetes Mellitus, Diabetes
Care, (1999) Vol 2 (Suppl 1): S5-19).
[0082] The term "hyperinsulinemia" refers to the presence of an
abnormally elevated level of insulin in the blood. Similarly, the
term "hyperuricemia" refers to the presence of an abnormally
elevated level of uric acid in the blood. The term "hyperlipidemia"
refers to the presence of an abnormally elevated level of lipids in
the blood. Hyperlipidemia can appear in at least three forms: (1)
hypercholesterolemia, i.e., an elevated cholesterol level; (2)
hypertriglyceridemia, i.e., an elevated triglyceride level; and (3)
combined hyperlipidemia, i.e., a combination of
hypercholesterolemia and hypertriglyceridemia.
[0083] The term "secretagogue" means a substance or compound that
stimulates secretion. For example, an insulin secretagogue is a
substance or compound that stimulates secretion of insulin.
[0084] The term "hemoglobin" or "Hb" refers to a respiratory
pigment present in erythrocytes, which is largely responsible for
oxygen transport. A hemoglobin molecule comprises four polypeptide
subunits (two .alpha. chain systems and two .beta. chain systems,
respectively). Each subunit is formed by association of one globin
protein and one heme molecule which is an iron-protoporphyrin
complex. The major class of hemoglobin found in normal adult
hemolysate is adult hemoglobin (referred to as "HbA"; also referred
to HbA.sub.0 for distinguishing it from glycated hemoglobin, which
is referred to as "HbA.sub.1," described infra) having
.alpha..sub.2.beta..sub.2 subunits. Trace components such as
HbA.sub.2 (.alpha..sub.2.beta..sub.2) can also be found in normal
adult hemolysate.
[0085] Among classes of adult hemoglobin HbAs, there is a glycated
hemoglobin (referred to as "HbA.sub.1," or "glycosylated
hemoglobin"), which may be further fractionated into HbA.sub.1a1,
HbA.sub.1a2, HbA.sub.1b, and HbA.sub.1c with an ion exchange resin
fractionation. All of these subclasses have the same primary
structure, which is stabilized by formation of an aldimine (Schiff
base) by the amino group of N-terminal valine in the .beta. subunit
chain of normal hemoglobin HbA and glucose (or, glucose-6-phosphate
or fructose) followed by formation of ketoamine by Amadori
rearrangement.
[0086] The term "glycosylated hemoglobin" (also referred to as
"HbA.sub.1c,", "GHb", "hemoglobin-glycosylated", "diabetic control
index" and "glycohemoglobin"; hereinafter referred to as
"hemoglobin Ar.sub.1c") refers to a stable product of the
nonenzymatic glycosylation of the .beta.-chain of hemoglobin by
plasma glucose. Hemoglobin A.sub.1c comprises the main portion of
glycated hemoglobins in the blood. The ratio of glycosylated
hemoglobin is proportional to blood glucose level. Therefore,
hemoglobin A.sub.1c rate of formation directly increases with
increasing plasma glucose levels. Since glycosylation occurs at a
constant rate during the 120-day lifespan of an erythrocyte,
measurement of glycosylated hemoglobin levels reflect the average
blood glucose level for an individual during the preceding two to
three months. Therefore determination of the amount of glycosylated
hemoglobin HbA.sub.1c can be a good index for carbohydrate
metabolism control. Accordingly, blood glucose levels of the last
two months can be estimated on the basis of the ratio of HbA.sub.1c
to total hemoglobin Hb. The analysis of the hemoglobin A.sub.1c in
blood is used as a measurement enabling long-term control of blood
glucose level (see, e.g., Jain, S. et al., Diabetes (1989) 38:
1539-1543; Peters A. et al., JAMA (1996) 276: 1246-1252).
[0087] The term "symptom" of diabetes, includes, but is not limited
to, polyuria, polydipsia, and polyphagia, as used herein,
incorporating their common usage. For example, "polyuria" means the
passage of a large volume of urine during a given period;
"polydipsia" means chronic, excessive thirst; and "polyphagia"
means excessive eating. Other symptoms of diabetes include, e.g.,
increased susceptibility to certain infections (especially fungal
and staphylococcal infections), nausea, and ketoacidosis (enhanced
production of ketone bodies in the blood).
[0088] The term "complication" of diabetes includes, but is not
limited to, microvascular complications and macrovascular
complications. Microvascular complications are those complications
which generally result in small blood vessel damage. These
complications include, e.g., retinopathy (the impairment or loss of
vision due to blood vessel damage in the eyes); neuropathy (nerve
damage and foot problems due to blood vessel damage to the nervous
system); and nephropathy (kidney disease due to blood vessel damage
in the kidneys). Macrovascular complications are those
complications which generally result from large blood vessel
damage. These complications include, e.g., cardiovascular disease
and peripheral vascular disease. Cardiovascular disease refers to
diseases of blood vessels of the heart. See. e.g., Kaplan, R. M. et
al., "Cardiovascular diseases" in HEALTH AND HUMAN BEHAVIOR, pp.
206-242 (McGraw-Hill, New York 1993). Cardiovascular disease is
generally one of several forms, including, e.g., hypertension (also
referred to as high blood pressure), coronary heart disease,
stroke, and rheumatic heart disease. Peripheral vascular disease
refers to diseases of any of the blood vessels outside of the
heart. It is often a narrowing of the blood vessels that carry
blood to leg and arm muscles.
[0089] The term "atherosclerosis" encompasses vascular diseases and
conditions that are recognized and understood by physicians
practicing in the relevant fields of medicine. Atherosclerotic
cardiovascular disease, coronary heart disease (also known as
coronary artery disease or ischemic heart disease), cerebrovascular
disease and peripheral vessel disease are all clinical
manifestations of atherosclerosis and are therefore encompassed by
the terms "atherosclerosis" and "atherosclerotic disease".
[0090] The term "antihyperlipidemic" refers to the lowering of
excessive lipid concentrations in blood to desired levels.
Similarly, the term "antiuricemic" refers to the lowering of
excessive uric acid concentrations in blood to desired levels.
[0091] The term "modulate" refers to the treating, prevention,
suppression, enhancement or induction of a function or condition.
For example, the compounds of the present invention can modulate
hyperlipidemia by lowering cholesterol in a human, thereby
suppressing hyperlipidemia.
[0092] The term "triglyceride(s)" ("TGs"), as used herein,
incorporates its common usage. TGs consist of three fatty acid
molecules esterified to a glycerol molecule and serve to store
fatty acids which are used by muscle cells for energy production or
are taken up and stored in adipose tissue.
[0093] Because cholesterol and TGs are water insoluble, they must
be packaged in special molecular complexes known as "lipoproteins"
in order to be transported in the plasma. Lipoproteins can
accumulate in the plasma due to overproduction and/or deficient
removal. There are at least five distinct lipoproteins differing in
size, composition, density, and function. In the cells of the small
of the intestine, dietary lipids are packaged into large
lipoprotein complexes called "chylomicrons", which have a high TG
and low-cholesterol content. In the liver, TG and cholesterol
esters are packaged and released into plasma as TG-rich lipoprotein
called very low density lipoprotein ("VLDL"), whose primary
function is the endogenous transport of TGs made in the liver or
released by adipose tissue. Through enzymatic action, VLDL can be
either reduced and taken up by the liver, or transformed into
intermediate density lipoprotein ("IDL"). IDL, is in turn, either
taken up by the liver, or is further modified to form the low
density lipoprotein ("LDL"). LDL is either taken up and broken down
by the liver, or is taken up by extrahepatic tissue. High density
lipoprotein ("HDL") helps remove cholesterol from peripheral
tissues in a process called reverse cholesterol transport.
[0094] The term "dyslipidemia" refers to abnormal levels of
lipoproteins in blood plasma including both depressed and/or
elevated levels of lipoproteins (e.g., elevated levels of LDL, VLDL
and depressed levels of HDL).
[0095] Exemplary Primary Hyperlipidemia include, but are not
limited to, the following:
[0096] (1) Familial Hyperchylomicronemia, a rare genetic disorder
which causes a deficiency in an enzyme, LP lipase, that breaks down
fat molecules. The LP lipase deficiency can cause the accumulation
of large quantities of fat or lipoproteins in the blood;
[0097] (2) Familial Hypercholesterolemia, a relatively common
genetic disorder caused where the underlying defect is a series of
mutations in the LDL receptor gene that result in malfunctioning
LDL receptors and/or absence of the LDL receptors. This brings
about ineffective clearance of LDL by the LDL receptors resulting
in elevated LDL and total cholesterol levels in the plasma;
[0098] (3) Familial Combined Hyperlipidemia, also known as multiple
lipoprotein-type hyperlipidemia; an inherited disorder where
patients and their affected first-degree relatives can at various
times manifest high cholesterol and high triglycerides. Levels of
HDL cholesterol are often moderately decreased;
[0099] (4) Familial Defective Apolipoprotein B-100 is a relatively
common autosomal dominant genetic abnormality. The defect is caused
by a single nucleotide mutation that produces a substitution of
glutamine for arginine which can cause reduced affinity of LDL
particles for the LDL receptor. Consequently, this can cause high
plasma LDL and total cholesterol levels;
[0100] (5) Familial Dysbetaliproteinemia, also referred to as Type
III Hyperlipoproteinemia, is an uncommon inherited disorder
resulting in moderate to severe elevations of serum TG and
cholesterol levels with abnormal apolipoprotein E function. HDL
levels are usually normal; and
[0101] (6) Familial Hypertriglyceridemia, is a common inherited
disorder in which the concentration of plasma VLDL is elevated.
This can cause mild to moderately elevated triglyceride levels (and
usually not cholesterol levels) and can often be associated with
low plasma HDL levels.
[0102] Risk factors in exemplary Secondary Hyperlipidemia include,
but are not limited to, the following: (1) disease risk factors,
such as a history of Type 1 diabetes, Type 2 diabetes, Cushing's
syndrome, hypothroidism and certain types of renal failure; (2)
drug risk factors, which include, birth control pills; hormones,
such as estrogen, and corticosteroids; certain diuretics; and
various .beta. blockers; (3) dietary risk factors include dietary
fat intake per total calories greater than 40%; saturated fat
intake per total calories greater than 10%; cholesterol intake
greater than 300 mg per day; habitual and excessive alcohol use;
and obesity.
[0103] The terms "obese" and "obesity" refers to, according to the
World Health Organization, a Body Mass Index (BMI) greater than
27.8 kg/m2 for men and 27.3 kg/m2 for wornen (BMI equals weight
(kg)/height (m2). Obesity is linked to a variety of medical
conditions including diabetes and hyperlipidemia. Obesity is also a
known risk factor for the development of Type 2 diabetes (See,
e.g., Barrett-Conner, E. Epidemol. Rev. (1989) 11: 172-181; and
Knowler, et al. Am. J. Clin. Nutr. (1991) 53:1543-1551).
General
[0104] The present invention derives from the discovery that
compounds of Formula I are useful in treating or controlling a
number of diseases associated with glucose metabolism, lipid
metabolism and insulin secretion. More particularly, the compounds
of the invention are useful in treating Type 2 diabetes,
hyperinsulemia, hyperlipidemia, hyperuricemia, hypercholesteremia,
atherosclerosis, one or more risk factors for cardiovascular
disease, Syndrome X, hypertriglyceridemia, hyperglycemia, obesity,
eating disorders, and suppressing appetite. Without intending to be
bound by theory, it is considered that the compounds of Formula I
operate via modulation of receptor interactions associated with one
or more isoforms of PPAR. As a result, the compounds will likely
have utility in treating other diseases states or conditions
associated with PPAR.
Compounds
[0105] In one aspect, the present invention provides compounds
having the formula: ##STR2## wherein Ar.sup.1 represents a
monocyclic or bicyclic aromatic ring system selected from the group
consisting of phenyl, naphthyl, imidazolyl, benzimidazoyl,
pyrrolyl, indolyl, thienyl, benzothienyl, furanyl, benzofuranyl,
and benzodioxole.
[0106] Ar.sup.2 represents 6-membered monocyclic aromatic ring
selected from the group consisting of benzene, pyridine, pyrazine,
pyrimidine, pyridazine, and triazine.
[0107] Returning to Formula I, Ar.sup.1 and Ar.sup.2 may have
substituents on their respective rings, wherein each substituted
present can be the same or different from any other substituent.
More particularly, Ar.sup.1 may have from 0 to 4 substituents, more
preferably from 0 to 3 substituents, and still more preferably, 0,
1 or 2 R.sup.7 substituents. R.sup.7 substituents are independently
selected from the group consisting of halogen,
(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl, --OR.sup.2,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.2-C.sub.8)alkenyl,
aryl(C.sub.2-C.sub.8)alkynyl, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2, --CO.sub.2R.sup.2,
--NR.sup.2R.sup.3, --NO.sub.2, --CN, --S(O).sub.r1R.sup.2--X.sup.2
OR.sup.2, --X.sup.1COR.sup.2, --X.sup.1CO.sub.2R.sup.2,
--X.sup.1NR.sup.2R.sup.3, --X.sup.1NO.sub.2, --X.sup.1CN, and
--X.sup.1S(O).sub.r1R.sup.2.
[0108] Ar.sup.2 may have from 0 to 4 substituents, more preferably
from 0 to 3 substituents, and still more preferably, 0, 1 or 2
R.sup.8 substituents. R.sup.9 substituents are independently
selected from the group consisting of halogen,
(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C8)alkyl, --OR.sup.2,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, aryl(C.sub.2-C.sub.8)alkenyl,
aryl(C.sub.2-C.sub.8)alkynyl, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2, --CO.sub.2R.sup.2,
--NR.sup.2R.sup.3, --NO.sub.2, --CN,
--S(O).sub.r1R.sup.2--X.sup.2OR.sup.2, --X.sup.2COR.sup.2,
--X.sup.2CO.sub.2R.sup.2, --X.sup.2NR.sup.2R.sup.3,
--X.sup.2NO.sub.2, --X.sup.2CN, and
--X.sup.2S(O).sub.r1R.sup.2.
[0109] L represents a member selected from the group consisting of
a covalent bond and a linking group having from one to six main
chain atoms and having the formula
--Y.sup.1.sub.m1Y.sup.2.sub.m2Y.sup.3.sub.m3-- wherein L can be
attached to any available ring member of Ar.sup.2; and each
Y.sup.1, Y.sup.2 and Y.sup.3 is a member independently selected
from the group consisting of (CR.sup.4R.sup.5).sub.p, C.dbd.O,
C.dbd.ONR.sup.2, C.dbd.NOR.sup.2, NR.sup.2C.dbd.O, NR.sup.2, O,
S(O).sub.r2, NR.sup.2SO.sub.2, and SO.sub.2NR.sup.2.
[0110] K represents a member selected from the group consisting of
a covalent bond and a linking group having from one to six main
chain atoms and having the formula
--Y.sup.4.sub.m4Y.sup.5.sub.m5Y.sup.6.sub.m6-- wherein K can be
attached to any available ring member of Ar.sup.2 and each Y.sup.4,
Y.sup.5 and Y.sup.6 is a member independently selected from the
group consisting of (CR.sup.4R.sup.5).sub.pC.dbd.O,
C.dbd.ONR.sup.2, C.dbd.NOR.sup.2, NR.sup.2C.dbd.O, NR.sup.2, O,
S(O).sub.2, NR.sup.2SO.sub.2, and SO.sub.2NR.sup.2.
[0111] Z represents a carboxylic acid equivalent and is selected
from the group consisting of CH.sub.2OR.sup.6, CO.sub.2R.sup.6, CN,
tetrazol-5-yl, CONHSO.sub.2R.sup.2 and CHO.
[0112] R.sup.1 represents a symbol selected from the group
consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.4)alkyl.
[0113] Each R.sup.2 and R.sup.3 represents a member independently
selected from the group consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, --X.sup.3OR.sup.9, aryl,
aryl(C.sub.1-C.sub.4)alkyl, heteroaryl, or optionally, if both
present on the same substituent, may be joined together to form a
three- to eight-membered ring system.
[0114] Each R.sup.4 and R.sup.5 represents members independently
selected from the group consisting of H, OR.sup.2, aryl,
heteroaryl, and aryl(C.sub.1-C.sub.4)alkyl, or optionally, if both
present on the same substituent, may be joined together to form a
three- to eight-membered ring system, or if present on adjacent
carbon atoms are combined to form a double bond or triple bond
between the atoms to which they are attached.
[0115] R.sup.6 is a member selected from the group consisting of H,
(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl,
--X.sup.4OR.sup.2, --X.sup.4NR.sup.2R.sup.3,
(C.sub.2-C.sub.8)alkenyl, (C.sub.3-C.sub.7)cycloalkyl,
heterocyclyl, aryl(C.sub.1-C.sub.4)alkyl and
aryl(C.sub.2-C.sub.8)alkenyl.
[0116] R.sup.9 is a member selected from the group consisting of H,
(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, and heteroaryl.
[0117] Each X.sup.1, X.sup.2, X.sup.3, and X.sup.4 is a member
independently selected from the group consisting of
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, and
(C.sub.2-C.sub.4)alkynyl.
[0118] The subscripts m1, m2, m3, m4, m5 and m6 are each integers
of from 0 to 1; the subscripts r1 and r2 are integers of from 0 to
2; and the subscript p is an integer of from 1 to 2.
[0119] In addition to compounds having formula I above, the present
invention further includes all salts thereof, and particularly,
pharmaceutically acceptable salts thereof. Still further, the
invention includes compounds that are single isomers of the above
formula (e.g., single enantiomers of compounds having a single
chiral center), as well as solvate, hydrate, and prodrug forms
thereof.
[0120] A number of other groups of embodiments are preferred and
are set forth below.
[0121] In a first group of embodiments, Ar.sup.1 is benzodioxole or
phenyl moiety optionally substituted with from one to three R.sup.7
substituents independently selected from the group consisting of
halogen, halo(C.sub.1-C.sub.8)alkyl, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, and --OR.sup.2.
[0122] The Ar.sup.1 phenyl group is preferably substituted with
from one to three R.sup.7 substituents independently selected from
halogen, (C.sub.1-C.sub.4)haloalkyl, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, or --OR.sup.2. Further
preferred within this embodiment is where Ar.sup.1 is ##STR3##
wherein X is a halogen; and still further preferred is where
Ar.sup.1 is ##STR4## wherein the dashed line indicates the point of
attachment to the remainder of the molecule.
[0123] Each R.sup.1 is preferably, selected from the group
consisting of (C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl,
aryl and heterocyclyl(C.sub.1-C.sub.4)alkyl. More preferably
R.sup.1 is selected from the group consisting of CH.sub.3,
CH(CH.sub.3).sub.2, CF.sub.3, CF.sub.3CH.sub.2, phenyl and ##STR5##
wherein R.sup.10 is a halogen or (C.sub.1-C.sub.8)alkoxy; and the
dashed line indicates the point of attachment to the remainder of
the molecule. Within this embodiment, R.sup.10 is preferably Cl,
Oi-Pr or OCH.sub.3. Most preferably R.sup.1 is CH.sub.3.
[0124] With regard to the linking groups L and K, preferred
embodiments are compounds wherein Y.sup.1, Y.sup.2, Y.sup.3,
Y.sup.4, Y.sup.5, and Y.sup.6 is a member independently selected
from the group consisting of (CR.sup.4R.sup.5).sub.p, C.dbd.O,
NR.sup.2, O, and S(O).sub.r2; R.sup.2 is H; each R.sup.4 and
R.sup.5 is a member independently selected from the group
consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, or optionally, if both present on the
same substituent, may be joined together to form a three- to
eight-membered ring system or if present on adjacent carbon atoms
are combined to form a double bond or triple bond between the atoms
to which they are attached; and r2 is 0. Compounds wherein Y.sup.1
is (CR.sup.4R.sup.5).sub.p, Y.sup.2 is CH.sub.2 or C.dbd.O and
Y.sup.3 is NH, O, or S are further preferred. Compounds within this
embodiment wherein Y.sup.1 is CH.sub.2, Y.sup.2 is (CH.sub.2).sub.2
and Y.sup.3 is 0 or S are still further preferred. In another
embodiment, compounds wherein at least one of m1, m2, or m3 is 0
are preferred.
[0125] L preferably is a member selected from the group consisting
of: CH.sub.2, (CH.sub.2).sub.2, --CH.sub.2S, CH(CH.sub.3)S,
C(CH.sub.3).sub.2S, (CH.sub.2).sub.2S, CH(CH.sub.3)CH.sub.2S,
C(CH.sub.3).sub.2CH.sub.2S, (CH.sub.2).sub.3S, CH.sub.2O,
--CH(CH.sub.3)O, C(CH.sub.3).sub.2O, (CH.sub.2).sub.2O,
CH(CH.sub.3)CH.sub.2O, C(CH.sub.3).sub.2CH.sub.2O,
(CH.sub.2).sub.3S and (C.dbd.O)NH.
[0126] In another embodiment, compounds, wherein Y.sup.4 is
CR.sup.4R.sup.5 or O, Y.sup.1 is CR.sup.4R.sup.5 and m6 is 0 are
preferred. Within this embodiment, compounds, wherein K is a member
selected from the group consisting of: --CH.sub.2--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2--, --CH.dbd.CH.sub.2.sup.E,
CH.dbd.CH.sub.2.sup.Z--, --CH.ident.CH--, --OCH.sub.2--,
--OCH(CH.sub.3)-- and --OC(CH.sub.3).sub.2-- are still further
preferred. In this embodiment, E represents the entgegen isomer and
Z represents the zusamen isomer.
[0127] With regard to groups R.sup.4 and R.sup.5 each is preferably
H, CH.sub.3, CF.sub.3, or joined together to form a three- to
six-membered ring system selected from the group consisting of
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Compounds,
wherein both R.sup.4 and R.sup.5 are H are even further
preferred.
[0128] In other preferred embodiments, Z represents a carboxylic
acid or its equivalent selected from the group consisting of
CH.sub.2OR.sup.6, CO.sub.2R.sup.6, CN, tetrazol-5-yl,
CONHSO.sub.2R.sup.2 and CHO. Preferred carboxylic acid equivalents
include tetrazol-5-yl. Still more preferably, Z is a carboxylic
acid. A further preferred group of embodiments are those in which Z
is CO.sub.2R.sup.6.
[0129] In one embodiment, Ar.sup.2 is preferably selected from the
group consisting of: (i) pyridine, optionally substituted with from
one to three R.sup.8 substituents; (ii) pyrazine, optionally
substituted with from one to two R.sup.8 substituents; (iii)
pyrimidine, optionally substituted with from one to two R.sup.8
substituents; (iv) pyridazine, optionally substituted with from one
to two R.sup.8 substituents; and (v) triazine, optionally
substituted with one R.sup.8 substituent. In this embodiment each
R.sup.8 substituent is preferably a member independently selected
from the group consisting of halogen, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
aryl(C.sub.1-C.sub.4)alkyl, --OR.sup.2, --X.sup.2OR.sup.2,
heterocyclyl, heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2,
--CO.sub.2R.sup.2, --NR.sup.2R.sup.3, --NO.sub.2, --X
NR.sup.2R.sup.3, --CN and --S(O).sub.r1R.sup.2. This embodiment
when Ar.sup.1 is benzodioxole or phenyl is especially preferred as
is this embodiment when L and K include the preferred embodiments
above. Within these embodiments, Ar.sup.2 is preferably selected
from the group having the formula: ##STR6## wherein the dashed line
indicates the point of attachment to K and the wavy line indicates
the point of attachment to L.
[0130] Each of the Ar.sup.2 groups is preferably substituted with
R.sup.8 substituents as defined above. When multiple substituents
are present, each is selected independently of the others.
[0131] Even further preferred are those embodiments in which
Ar.sup.2 is selected from ##STR7## wherein the dashed line
indicates the point of attachment to K and the wavy line indicates
the point of attachment to L.
[0132] In most preferred embodiments, Ar.sup.2 is benzene. In this
embodiment each R.sup.8 substituent is preferably a member
independently selected from the group consisting of halogen,
(C.sub.1-C.sub.9)alkyl, halo(C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, aryl(C.sub.1-C.sub.4)alkyl,
--OR.sup.2, --X.sup.2OR.sup.2, heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4)alkyl, --COR.sup.2, --CO.sub.2R.sup.2,
--NR.sup.2R.sup.3, --NO.sub.2, --X NR.sup.2R.sup.3, --CN and
--S(O).sub.r1R.sup.2. This embodiment when Ar.sup.1 is benzodioxole
or phenyl is especially preferred as is this embodiment when L and
K include the preferred embodiments above. Within these
embodiments, Ar.sup.2 is preferably selected from the group having
the formula: ##STR8##
[0133] wherein the dashed line indicates the point of attachment to
K and the wavy line indicates the point of attachment to L. The
compound: ##STR9## is especially preferred.
[0134] A variety of compounds have the desired activity. In
particular, one group of preferred compounds are provided in FIG.
1.
[0135] Still other preferred groups of embodiments are provided in
the Examples below. Examples of compounds of Formula I include
[0136]
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenoxy}-acetic acid; [0137]
2-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenoxy}-propionic acid; [0138]
3-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenyl}-acrylic acid; [0139]
{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsul-
fanyl]-phenoxy}-acetic acid; [0140]
{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenoxy}-acetic acid; [0141]
{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsul-
fanyl]-2-trifluoromethyl-phenoxy}-acetic acid; [0142]
{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsul-
fanyl]-2-trifluoromethoxy-phenoxy}-acetic acid; [0143]
3-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenyl}-propionic acid; [0144]
2,2-Dimethyl-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2-
,3]triazol-4-ylmethylsulfanyl]-phenyl}-propionic acid; [0145]
{2-Bromo-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethylsulfanyl]-phenyl}-acetic acid; [0146]
5-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenoxymethyl}-1H-tetrazole; [0147]
2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]t-
riazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid; [0148]
1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenoxy}-cyclopropanecarboxylic acid; [0149]
3-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenyl}-acrylic acid; [0150]
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenylsulfanyl}-acetic acid; [0151]
{2-Bromo-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethylsulfanyl]-phenoxy}-acetic acid; [0152]
{2-Methoxy-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-y-
lmethylsulfanyl]-phenoxy}-acetic acid; [0153]
{2,6-Dimethyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol--
4-ylmethylsulfanyl]-phenoxy}-acetic acid; [0154]
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenyl}-acetic acid; [0155]
2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]t-
riazol-4-ylmethylsulfanyl]-phenyl}-propionic acid; [0156]
{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenyl}-acetic acid; [0157]
(2-Methyl-4-{1-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]-
triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid; [0158]
{4-[5-Isopropyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl-
sulfanyl]-2-methyl-phenoxy}-acetic acid; [0159]
{2-Methyl-4-[5-propyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenoxy}-acetic acid; [0160]
{2-Methyl-4-[5-phenyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenoxy}-acetic acid; [0161]
{2-Methyl-4-[5-(2,2,2-trifluoro-ethyl)-2-(4-trifluoromethyl-phenyl)-2H-[1-
,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid; [0162]
{2-Methyl-4-[5-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]tri-
azol-4-ylmethylsulfanyl]-phenoxy}-acetic acid; [0163]
(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethoxy}-phenoxy)-acetic acid; [0164]
(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]
triazol-4-yl]-ethoxy}-phenoxy)-acetic acid; [0165]
(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-y-
lmethyl]-amino}-phenoxy)-acetic acid; [0166]
{4-[2-(4-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2--
methyl-phenoxy}-acetic acid; [0167]
{4-[2-(4-Bromo-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-m-
ethyl-phenoxy}-acetic acid; [0168]
{4-[2-(3-Chloro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-2-methyl-phenoxy}-acetic acid; [0169]
{4-[2-(3,4-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmet-
hylsulfanyl]-2-methyl-phenoxy}-acetic acid; [0170]
{4-[2-(4-Methoxy-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-
-methyl-phenoxy}-acetic acid; [0171]
{2-Methyl-4-[5-methyl-2-(4-trifluoromethoxy-phenyl)-2H-[1,2,3]triazol-4-y-
lmethylsulfanyl]-phenoxy}-acetic acid; [0172]
{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-2-methyl-phenoxy}-acetic acid; [0173]
[4-(2-Benzo[1,3]dioxol-5-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl-
)-2-methyl-phenoxy]-acetic acid; [0174]
{2-Methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenoxy}-acetic acid; [0175]
{4-[2-(3-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2--
methyl-phenoxy}-acetic acid; [0176]
{4-[2-(3-Bromo-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-m-
ethyl-phenoxy}-acetic acid; [0177]
1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenoxy}-cyclobutanecarboxylic acid; [0178]
1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]
triazol-4-ylmethylsulfanyl]-phenoxy}-cyclopentanecarboxylic acid;
[0179]
1-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-ylmethylsulfanyl]-phenoxy}-cyclohexanecarboxylic acid; [0180]
{2-Ethyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethylsulfanyl]-phenoxy}-acetic acid; [0181]
{2-Isopropyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-ylmethylsulfanyl]-phenoxy}-acetic acid; [0182]
{4-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-2-methyl-phenoxy}-acetic acid; [0183]
(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethylsulfanyl}-phenoxy)-acetic acid; [0184]
(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethylsulfanyl}-phenoxy)-acetic acid; [0185]
(2-Methyl-4-{[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazole-4--
carbonyl]-amino}-phenoxy)-acetic acid; [0186]
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenylsulfanyl}-acetic acid; [0187]
{4-[2-(4-Fluoro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2--
methyl-phenoxy}-acetic acid; [0188]
{4-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-2-methyl-phenoxy}-acetic acid; [0189]
{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmet-
hylsulfanyl]-2-methyl-phenoxy}-acetic acid; [0190]
{4-[2-(3,4-Dichloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl-
]-2-methyl-phenoxy}-acetic acid; [0191]
{4-[2-(3,4-Difluoro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl-
]-2-methyl-phenoxy}-acetic acid; [0192]
{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]--
3-propyl-phenyl}-acetic acid; [0193]
{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]--
phenyl}-acetic acid; [0194]
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methoxy]-phenyl}-propynoic acid; [0195]
2-{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethylp-
henyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-propionic
acid; [0196]
2-{4-[5-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-p-
henyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-propionic
acid; [0197]
{2-Ethyl-4-[5-[4-(4-methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluorom-
ethylphenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic
acid; [0198]
2-{4-[5-[4-(4-Isopropoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifl-
uoromethylphenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}--
propionic acid; [0199]
2-{4-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid; [0200]
{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-ph-
enyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic
acid; [0201]
2-{5-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluo-
romethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-2-
-methyl-propionic acid; [0202]
{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-thiophen-2-yl-phen-
yl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic
acid; [0203]
2-{4-[2-(4-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-
-2-methyl-phenoxy}-2-methyl-propionic acid; [0204]
2-{2-Chloro-4-[2-(4-chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy-
]-phenoxy}-2-methyl-propionic acid; [0205]
2-{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethoxy]-phenoxy}-2-methyl-propionic acid; [0206]
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methoxy]-phenoxy}-acetic acid; [0207]
2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]t-
riazol-4-ylmethoxy]-phenoxy}-propionic acid; [0208]
2-[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-ph-
enoxy]-2-methyl-propionic acid; [0209]
[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-phen-
oxy]-acetic acid; [0210]
(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethoxy}-phenoxy)-acetic acid; [0211]
(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethyl}-phenoxy)-acetic acid; and [0212]
2-Methyl-2-(2-methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,-
3]triazol-4-yl]-ethoxy}-phenoxy)-propionic acid.
[0213] Other examples of compounds include: [0214]
2-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
ylmethylsulfanyl]-phenoxy}-propionic acid; [0215]
{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmet-
hylsulfanyl]-2-methyl-phenoxy}-acetic acid; [0216]
{4-[2-(3,4-Dichloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl-
]-2-methyl-phenoxy}-acetic acid; [0217]
[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl)-2-meth-
yl-phenoxy]-acetic acid; [0218]
2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]t-
riazol-4-ylmethoxy]-phenoxy}-propionic acid; [0219]
2-[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-ph-
enoxy]-2-methyl-propionic acid; [0220]
2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]t-
riazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid; [0221]
2-Methyl-2-(2-methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,-
3]triazol-4-yl]-ethoxy}-phenoxy)-propionic acid; [0222]
(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethyl}-phenoxy)-acetic acid; [0223]
(2-Methyl-4-{1-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]-
triazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid; [0224]
(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-
-yl]-ethoxy}-phenoxy)-acetic acid; [0225]
{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-ph-
enyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic
acid and [0226]
2-{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl--
phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-2-methyl-propionic
acid.
[0227] A particularly preferred compound of the invention is:
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl-
methylsulfanyl]-phenoxy}-acetic acid.
[0228] All the preferred and most preferred compounds listed above
are selective hPPAR.delta. agonists.
Preparation of Compounds of the Invention
[0229] The compounds of the present invention can be prepared in a
number of ways familiar to one skilled in the art of organic
synthesis. The compounds outlined herein can be synthesized using
methods generally outlined in Scheme 1, along with methods
typically utilized by a synthetic chemist, and combinations or
variations of those methods, which are generally known to one
skilled in the art of synthetic chemistry. The synthetic route of
compounds in the present invention is not limited to the methods
outlined below. It is assumed one skilled in the art will be able
to use the schemes outlined below to synthesized compounds claimed
in this invention. Individual compounds may require manipulation of
the condition in order to accommodate various functional groups. A
variety of protecting groups generally known to one skilled in the
art may be required. Purification, if necessary can be accomplished
on a silica gel column eluted with the appropriate organic solvent
system. Also, reverse phase HPLC or recrystallization may be
employed.
[0230] The compounds of formula I can be prepared using methods
generally outlined in Scheme 1. ##STR10##
[0231] According to Scheme 1, electrophilic, aryl triazoles of
formula i (either commercially available or prepared according to
known methods or methods outlined below in Scheme 3) are condensed
with suitably substituted, nucleophilic aryl compounds II generally
in the presence of solvent and a non-nucleophilic base to provide
compound iii. Treatment of iii with a suitably substituted,
electrophilic carboxylic acid equivalent iv, generally in the
presence of solvent and a non-nucleophilic base, provides the
target compound v. Examples of suitable non-nucleophilic bases
include, but are not limited to, potassium carbonate, cesium
bicarbonate, sodium hydride, and the like.
[0232] For example, as shown in Scheme 2 aryl triazole 5A or 5C
(prepared as described below) is condensed with 4-mercaptophenol or
p-catechol in the presence of cesium carbonate to provide compound
15A. Treatment of 15A with bromo-acetic acid ethyl ester in the
presence of sodium hydride provides the target compound 16A.
Treatment of ester 16 with lithium hydroxide converts the ester to
carboxylic acid compound 100A.
[0233] Alternatively, as shown in Scheme 2 bromo-acetic acid ethyl
ester is condensed with 4-mercaptophenol or p-catechol in the
presence of cesium carbonate to provide compound 15B. Treatment of
15B with ZnI.sub.2, DEAD/PPh.sub.3 or diamide/PBu.sub.3 provides
the target compound 16B. Treatment of ester 16B with lithium
hydroxide converts the ester to carboxylic acid compound. ##STR11##
##STR12##
[0234] The synthesis of such triazole intermediates is illustrated
in Scheme 3 with intermediates in which Ar.sup.1 is
4-trifluoromethyl-benzene. Thus intermediates 5A-C can be prepared
by condensing trifluoromethylphenyl-hydrazine with a
2-hydroxyimino-3-oxo-butyric acid ester and treating with thionyl
chloride. Alternatively, trifluoromethylphenyl-diazonium
intermediate can be condensed with a 3-oxo-butyric acid ester and
treating with copper chloride Intermediate ester triazoles 3A and B
can be converted to the corresponding hydroxyl alkyl derivatives 4A
and B with lithium aluminum hydride or derivative 4C with an alkyl
anion such as methyl Grignard. Conversion to the alkyl bromide 5A,
alkyl chloride 5B, or alkyl triflate 5C, is accomplished by
treatment with hydrogen bromide, thionyl chloride or triflic
anhydride, respectively. Compounds 5A-C may then be use as noted in
Scheme 2. ##STR13## ##STR14##
[0235] Alternatively in certain embodiments, compounds of formula 5
can be converted into intermediates 9A or 9B by successive
treatment with potassium cyanide to form nitrile derivative 6,
hydrochloric acid in ethanol to form ester derivative 7, lithium
aluminum hydride to form hydroxylethyl derivative 8. Treatment with
triphenyl phosphine and carbon tetrabromide forms intermediate 9A,
while treatment with triphenyl phosphine and iodine forms
intermediate 9B.
[0236] Alternatively in certain embodiments, compounds of formula 3
can be converted into intermediate 14 by successive treatment with
diisobutyl aluminum hydride to form aldehyde derivative 10,
carbethoxymethylene-triphenylphosphorane to form ester derivative
11, hydrogen and palladium on carbon to form ester derivative 12,
lithium aluminum hydride to form hydroxylmethyl derivative 13, and
triphenyl phosphine and carbon tetrabromide to form intermediate
14.
[0237] These latter routes are particularly useful form
intermediates of formula i in Scheme 1 which have longer linking
groups K. By using the methods outlined above, target compounds
with linking groups of different lengths can be prepared as
outlined in Schemes 4 and 5. ##STR15##
[0238] Thus in Scheme 4,2-bromoethyl-triazole 9A serves as the
starting material. The acid chloride is treated with
4-mercaptophenol to provide substituted-triazole, 18. Treatment of
18 with the ethyl bromoacetate provides the target compound 19.
Treatment of ester 19 with lithium hydroxide converts the ester to
carboxylic acid compound 580.
[0239] Similarly in Scheme 5, compounds of formula I wherein
Y.sup.1 is CH.sub.2, Y.sup.2 is CH.sub.2CH.sub.2, and Y.sup.3 is S
can be prepared by treating 2-bromo propyl-triazole 14 with
4-mercaptophenol to provide substituted-triazole, 21. Treatment of
21 with the ethyl bromoacetate provides the target compound 22.
Treatment of ester 22 with lithium hydroxide converts the ester to
carboxylic acid compound 690. ##STR16##
[0240] Structural isomers, having the Y.sup.3 attached at either
the 2- or 3-position relative to the phenol hydroxyl group in
compound 100 can be prepared from the corresponding 2-, or
3-mercaptophenols.
[0241] Still further, the general schemes outlined in Schemes 1-5
can be used to prepare compounds of Formula I in which Ar.sup.2 is
another ring system. To obtain these compounds, the phenols are
replaced by the corresponding hydroxy-substituted ring system.
[0242] Likewise, the general schemes outlined in Schemes 1-5 can be
used to prepare compounds of Formula I in which L or K is an
alternatively functionalized linking group. To obtain these
compounds, mercapto phenols may be replaced with halo phenols or
halothiophenols and the resulting halogenated triazole
intermediates can be coupled with propynoic esters to give
unsaturated linking groups. ##STR17##
[0243] Thus in Scheme 6, aryl triazole 5A (prepared as described
above) is condensed with 4-bromo phenol in the presence of cesium
carbonate to provide compound 23. Treatment of 23 with propynoic
acid ethyl ester in the presence of a Pd/C catalyst provides the
target compound 24. Treatment of ester 24 with lithium hydroxide
converts the ester to carboxylic acid compound 680. The acid
compound can be hydrogenated to provide the Z-alkenoic acid
triazole, 230.
[0244] Alternatively in certain embodiments, the an alkylene or
E-alkenyl linker can be formed as is shown in Scheme 7. Aryl
triazole 5A (prepared as described above) is condensed with
4-hydroxybenzaldehyde in the presence of cesium carbonate to
provide compound 25A. Treatment of 25A with an appropriate Wittig
reagent provides the target compound 26A. Treatment of ester 26A
with lithium hydroxide converts the ester to the E-alkenoic acid
triazole, 120. Similarly, Aryl triazole 26B can prepared by
condensing with 4-benzaldehyde 25B with an appropriate Wittig
reagent to provide the target compound 26B. Hydrogenation of ester
26B converts the alkenyl compounds to the alkylenyl triazoles.
##STR18## ##STR19##
[0245] Alternatively in certain embodiments, triazoles with
saturated hydrocarbon linking groups can be formed as is shown in
Scheme 8. Thus aryl triazole 5A (prepared as described above) may
be condensed with an appropriately substituted 4-hydroxyphenyl
acetic acid in the presence of cesium carbonate to provide
compounds 660 and 670. ##STR20##
[0246] The carbon atoms on linkers L and K can also be
differentially substituted as is shown in Scheme 9. Thus triazole
ester 16 may be condensed with the appropriate alkyl halide in the
presence of sodium hydride to provide compounds 210, 220, 510, 520,
and 530. ##STR21## ##STR22##
[0247] Likewise, R.sup.1 can then be differentially substituted as
is shown in Scheme 10. Thus triazole ester 3A may be modified as
above with mercapto phenol and a halopropionate ester to provide
hydroxy methyl triazole ester 29. Hydroxymethyl triazole can then
be mesylated and condensed with the appropriate heterocyclic group,
such as 4-methoxyphenyl piperazine to provide the target compound
31. Treatment of ester 31 with lithium hydroxide converts the ester
to carboxylic acid compound 700. ##STR23##
[0248] Likewise, related compounds with different Ar.sup.1 and
Ar.sup.2 rings and different lengths and substitution of linkers L
and K can be prepared in a similar manner beginning with
appropriately substituted aryl compounds many of which are
available from commercial sources or can be prepared according to
literature methods. More specific details are provided in the
examples below. In each of Schemes 1-10, reaction conditions (e.g.,
amounts of reactants, solvents, temperatures and workup conditions)
can be selected using the Examples below as a guide.
[0249] Additionally, while the synthetic route is illustrated for
the preparation of electrophilic triazole compounds, the invention
is not so limited and synthetic routes are contemplated wherein the
triazole intermediates used are nucleophilic (compounds 4, 8, and
13) and the Ar.sup.2 containing intermediates are
electrophilic.
Preparation of Alcohols, Ethers, Nitrites, Amides, and
Aldehydes
[0250] The above general synthesis schemes are provided to
illustrate the prepared of compounds of Formula I in which Z is a
carboxylic acid or ester. Conversion of each of these groups into
the corresponding alcohols, ethers, nitrites, amides, or aldehydes
can be accomplished using methods generally known to one of skill
in the art. Several methods for reduction (and oxidation) are
provided below as illustrative of the processes used in preparing
additional compounds of the invention.
Conversion of Carboxylic Acids into Alcohols, Ethers, Nitrites,
Amides and Aldehydes.
[0251] The carboxylic acids of this invention can be converted into
the corresponding alcohols, ethers, nitrites, amides and aldehydes
by a number of methods, including the routes A-D shown in Scheme
11. The method to be used in a given case depends on the nature of
R, and the substituents thereon. A variety of useful methods are
described in Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS, VCH
Publishers Inc, New York (1989). In particular, methods are
described for converting acyl chlorides 32 to aldehydes 33 (p 620),
esters 31 to aldehydes 33 (p 621), esters 31 to carbinols 35 (p
549), carboxylic acids 31 to carbinols 35 (p 548), esters 31 to
amides 34 (p 987) and esters 31 to nitriles 36(p 988).
[0252] In method A, Scheme 11, a carboxylic acid 31 is first
converted into the corresponding acid chloride 32. This
transformation is effected by reacting the acid 31 with oxalyl
chloride, phosphorus pentachloride, or, preferably, thionyl
chloride. The reaction is conducted in an aprotic solvent such as
dichloromethane, tetrahydrofuran or, preferably,
1,2-dichloroethane. The acid chloride 32 is then converted into the
aldehyde 33 by chemical reduction, such as by the use of sodium
borohydride in DMF at -70.degree. C., as described in Tetrahedron
Lett. 22:11 (1981), or, more preferably by hydrogenation using 5%
palladium on barium sulfate as catalyst (see, for example, J. Amer.
Chem. Soc., 108:2608 (1986)). The reaction is conducted in an
aprotic solvent such as toluene or, preferably, xylene. The
aldehyde 33 is converted into the carbinol 35 by reduction, for
example by reaction with 9 BBN, lithium aluminum tritertiarybutoxy
hydride, or more preferably sodium borohydride, (see, J. Amer.
Chem. Soc. 71:122 (1949)). The reaction is conducted in aprotic
solvent such as ethanol, or preferably, isopropanol.
[0253] Alternatively ester 31 can be converted directly into the
aldehyde 3 by reduction, for example, by the use of sodium aluminum
hydride or preferably, diisobutyl aluminum hydride (see e.g.,
Synthesis, 617 (1975)). The reaction is conducted in a non-polar
solvent such as benzene or, preferably, toluene.
[0254] In method B, Scheme 11, ester 5 is converted into the amide
4 by transesterification with hydroxypyridine and the corresponding
amine (see, J.C.S.C. 89 (1969)). The reaction is conducted in an
ethereal solvent such as dioxane or, preferably,
tetrahydrofuran.
[0255] In method C, Scheme 11, ester 5 is converted into the
carbinol 4 by reduction with lithium aluminum hydride or,
preferably, with lithium borohydride (see, J. Amer. Chem. Soc.,
109:1186 (1987)). The reaction is conducted in an ethereal solvent
such as dioxane or, preferably, tetrahydrofuran.
[0256] Alternatively, carboxylic acid 31 can be converted into the
carbinol 35. This conversion is effected by reacting the carboxylic
acid with a reducing agent such as lithium aluminum hydride or,
preferably, with diborane, as described in ORGANIC SYNTHESES,
64:104 (1985). The reaction is conducted in an ethereal solvent
such as dioxane or, preferably, tetrahydrofuran.
[0257] The carbinol 35 (R.sup.6=H) can be converted into the ether
35 (R.sup.6=C.sub.1-C.sub.8). This transformation is effected by an
alkylation reaction, for example by reacting the carbinol 35 with
an alkyl chloride (C.sub.1-C.sub.8)Cl. The reaction is conducted in
an aprotic solvent such as dichloromethane or, preferably,
tetrahydrofuran, in the presence of an organic base such as
triethylamine or, preferably, pyridine.
[0258] In method D, Scheme 11, the ester 31 is converted into the
nitrile 36. This conversion is effected by reacting the ester with
a dehydrating agent such as dimethylaluminum nitride as described
in Tett. Lett., 4907 (1979). ##STR24##
[0259] Furthermore, the tetrazole derivatives may be conveniently
prepared by a general process wherein a compound like 36 is coupled
to an alcohol using the Mitsunobu protocol (Synthesis 1,
(1981).
[0260] Not all compound of formula I may be compatible with some of
the reaction conditions described in Examples. Such restrictions
are readily apparent to those skilled in the art of organic
synthesis, and alternative methods must then be used.
Isomeric Compounds
[0261] Certain of the compounds of the present invention possess
one or more chiral center and each center may exist in the R or S
configuration. The present invention includes all diastereomeric,
enantiomeric, and epimeric forms as well as the appropriate
mixtures thereof. For many compounds the present invention, a
single chiral center is present (at the carbon atom bearing
R.sup.2), resulting in racemic mixtures of enantiomers. As noted
above, the present invention further includes compounds,
compositions and methods wherein a single isomer (or single
enatiomer) is provided or used. Methods of preparing chiral
compounds are provided in the Examples. Alternatively, mixtures of
enantiomers can be separated into their individual isomers via
methods known in the art such as salt formation and crystallization
with chiral bases, chiral chromatography (e.g., HPLC using
commercially available columns for chiral resolution) and via
methods such as simulated moving bed chromatography (see, for
example, U.S. Pat. No. 5,518,625).
[0262] In certain preferred embodiments of the invention, the
(-)-isomer of the compound of formula I is used, which is
substantially free of its (+)-isomer. In this context,
"substantially free" refers to a compound that is contaminated by
less than about 20%, more preferably 10%, still more preferably 5%,
even more preferably 2% and most preferably less than about 1% of
the undesired isomer. In other preferred embodiments of the
invention, the (+)-isomer of the compound of formula I is used,
which is substantially free of its (-)-isomer.
[0263] Additionally, the compounds of the present invention may
exist as geometric isomers. The present invention includes all cis,
trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as
the appropriate mixtures thereof.
[0264] In some situations, compounds may exist as tautomers. All
tautomers are included within formula I and are provided by this
invention.
Solvate Forms of the Compounds of the Invention
[0265] In addition, the compounds of the present invention can
exist in unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of the present invention.
Prodrug Forms of the Compounds of the Invention
[0266] In some embodiments, the compounds of the invention are
present in a prodrug form. In particular, the invention also
provides, for example, compounds of Formula I in which CO.sub.2H is
esterified to form --CO.sub.2R.sup.6, wherein R.sup.6 is a member
selected from the group consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, --X.sup.4OR.sup.2,
--X.sup.4NR.sup.2R.sup.3, (C.sub.2-C.sub.8)alkenyl,
(C.sub.3-C.sub.7)cycloalkyl, heterocyclyl,
aryl(C.sub.1-C.sub.4)alkyl and aryl(C.sub.2-C.sub.8)alkenyl.
[0267] R.sup.2 and R.sup.3 are members independently selected from
the group consisting of H, (C.sub.1-C.sub.8)alkyl,
halo(C.sub.1-C.sub.8)alkyl, --X.sup.3OR.sup.9, aryl,
aryl(C.sub.1-C.sub.4)alkyl, heteroaryl, or optionally, if both
present on the same substituent, may be joined together to form a
three- to eight-membered ring system. Each X.sup.3 and X.sup.4 are
members independently selected from the group consisting of
(C.sub.1-C.sub.4)alkylene, (C.sub.2-C.sub.4)alkenylene, and
(C.sub.2-C.sub.4)alkynylene.
[0268] Esters of the compounds of the present invention may be
prepared as described herein or according to conventional
methods.
Pharmaceutical Compositions and Methods of Treating Diseases and
Conditions
[0269] In accordance with the present invention, a therapeutically
effective amount of a compound of Formula I can be used for the
preparation of a pharmaceutical composition useful for treating
diabetes, treating hyperlipidemia, treating hyperuricemia, treating
obesity, lowering triglyceride levels, lowering cholesterol levels,
raising the plasma level of high density lipoprotein, and for
treating, preventing or reducing the risk of developing
atherosclerosis.
[0270] The compositions of the invention can include compounds of
Formula I, pharmaceutically acceptable salts thereof, or a
hydrolysable precursor thereof. In general, the compound is mixed
with suitable carriers or excipient(s) in a therapeutically
effective amount. By a "therapeutically effective dose",
"therapeutically effective amount", or, interchangeably,
"pharmacologically acceptable dose" or "pharmacologically
acceptable amount", it is meant that a sufficient amount of the
compound of the present invention and a pharmaceutically acceptable
carrier, will be present in order to achieve a desired result,
e.g., alleviating a symptom or complication of Type 2 diabetes.
[0271] The compounds of Formula I that are used in the methods of
the present invention can be incorporated into a variety of
formulations for therapeutic administration. More particularly, the
compounds of Formula I can be formulated into pharmaceutical
compositions by combination with appropriate, pharmaceutically
acceptable carriers or diluents, and can be formulated into
preparations in solid, semi-solid, liquid or gaseous forms, such as
tablets, capsules, pills, powders, granules, dragees, gels,
slurries, ointments, solutions, suppositories, injections,
inhalants and aerosols. As such, administration of the compounds
can be achieved in various ways, including oral, buccal, rectal,
parenteral, intraperitoneal, intradermal, transdermal,
intratracheal administration. Moreover, the compound can be
administered in a local rather than systemic manner, in a depot or
sustained release formulation. In addition, the compounds can be
administered in a liposome.
[0272] The compounds of Formula I can be formulated with common
excipients, diluents or carriers, and compressed into tablets, or
formulated as elixirs or solutions for convenient oral
administration, or administered by the intramuscular or intravenous
routes. The compounds can be administered transdermally, and can be
formulated as sustained release dosage forms and the like.
Compounds of Formula I can be administered alone, in combination
with each other, or they can be used in combination with other
known compounds (see Combination Therapy below).
[0273] Suitable formulations for use in the present invention are
found in Remington's Pharmaceutical Sciences (Mack Publishing
Company (1985) Philadelphia, Pa., 17th ed.), which is incorporated
herein by reference. Moreover, for a brief review of methods for
drug delivery, see, Langer, Science (1990) 249:1527-1533, which is
incorporated herein by reference. The pharmaceutical compositions
described herein can be manufactured in a manner that is known to
those of skill in the art, i.e., by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or lyophilizing processes. The following
methods and excipients are merely exemplary and are in no way
limiting.
[0274] For injection, the compounds can be formulated into
preparations by dissolving, suspending or emulsifying them in an
aqueous or nonaqueous solvent, such as vegetable or other similar
oils, synthetic aliphatic acid glycerides, esters of higher
aliphatic acids or propylene glycol; and if desired, with
conventional additives such as solubilizers, isotonic agents,
suspending agents, emulsifying agents, stabilizers and
preservatives. Preferably, the compounds of the present invention
can be formulated in aqueous solutions, preferably in
physiologically compatible buffers such as Hanks's solution,
Ringer's solution, or physiological saline buffer. For transmucosal
administration, penetrants appropriate to the barrier to be
permeated are used in the formulation. Such penetrants are
generally known in the art.
[0275] For oral administration, the compounds of Formula I can be
formulated readily by combining with pharmaceutically acceptable
carriers that are well known in the art. Such carriers enable the
compounds to be formulated as tablets, pills, dragees, capsules,
emulsions, lipophilic and hydrophilic suspensions, liquids, gels,
syrups, slurries, suspensions and the like, for oral ingestion by a
patient to be treated. Pharmaceutical preparations for oral use can
be obtained by mixing the compounds with a solid excipient,
optionally grinding a resulting mixture, and processing the mixture
of granules, after adding suitable auxiliaries, if desired, to
obtain tablets or dragee cores. Suitable excipients are, in
particular, fillers such as sugars, including lactose, sucrose,
mannitol, or sorbitol; cellulose preparations such as, for example,
maize starch, wheat starch, rice starch, potato starch, gelatin,
gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose,
sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
If desired, disintegrating agents can be added, such as the
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate.
[0276] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions can be used, which can
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments can be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0277] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds can
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers can be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0278] For buccal administration, the compositions can take the
form of tablets or lozenges formulated in conventional manner.
[0279] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of an aerosol spray presentation from pressurized packs or
a nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or
from propellant-free, dry-powder inhalers. In the case of a
pressurized aerosol the dosage unit can be determined by providing
a valve to deliver a metered amount. Capsules and cartridges of,
e.g., gelatin for use in an inhaler or insufflator can be
formulated containing a powder mix of the compound and a suitable
powder base such as lactose or starch.
[0280] The compounds can be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. Formulations for injection can be presented in unit
dosage form, e.g., in ampules or in multidose containers, with an
added preservative. The compositions can take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and can contain formulator agents such as suspending, stabilizing
and/or dispersing agents.
[0281] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the active compounds in water-soluble
form. Additionally, suspensions of the active compounds can be
prepared as appropriate oily injection suspensions. Suitable
lipophilic solvents or vehicles include fatty oils such as sesame
oil, or synthetic fatty acid esters, such as ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions can
contain substances which increase the viscosity of the suspension,
such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, the suspension can also contain suitable stabilizers or
agents which increase the solubility of the compounds to allow for
the preparation of highly concentrated solutions. Alternatively,
the active ingredient can be in powder form for constitution with a
suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0282] The compounds can also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter, carbowaxes,
polyethylene glycols or other glycerides, all of which melt at body
temperature, yet are solidified at room temperature.
[0283] In addition to the formulations described previously, the
compounds can also be formulated as a depot preparation. Such long
acting formulations can be administered by implantation (for
example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds can be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0284] Alternatively, other delivery systems for hydrophobic
pharmaceutical compounds can be employed. Liposomes and emulsions
are well known examples of delivery vehicles or carriers for
hydrophobic drugs. In a presently preferred embodiment,
long-circulating, i.e., stealth liposomes can be employed. Such
liposomes are generally described in Woodle, et al., U.S. Pat. No.
5,013,556. The compounds of the present invention can also be
administered by controlled release means and/or delivery devices
such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899;
3,536,809; 3,598,123; and 4,008,719.
[0285] Certain organic solvents such as dimethylsulfoxide (DMSO)
also can be employed, although usually at the cost of greater
toxicity. Additionally, the compounds can be delivered using a
sustained-release system, such as semipermeable matrices of solid
hydrophobic polymers containing the therapeutic agent. Various
types of sustained-release materials have been established and are
well known by those skilled in the art. Sustained-release capsules
can, depending on their chemical nature, release the compounds for
a few hours up to over 100 days.
[0286] The pharmaceutical compositions also can comprise suitable
solid or gel phase carriers or excipients. Examples of such
carriers or excipients include but are not limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
[0287] Pharmaceutical compositions suitable for use in the present
invention include compositions wherein the active ingredients are
contained in a therapeutically effective amount. The amount of
composition administered will, of course, be dependent on the
subject being treated, on the subject's weight, the severity of the
affliction, the manner of administration and the judgment of the
prescribing physician. Determination of an effective amount is well
within the capability of those skilled in the art, especially in
light of the detailed disclosure provided herein.
[0288] For any compound used in the method of the present
invention, a therapeutically effective dose can be estimated
initially from cell culture assays or animal models.
[0289] Moreover, toxicity and therapeutic efficacy of the compounds
described herein can be determined by standard pharmaceutical
procedures in cell cultures or experimental animals, e.g., by
determining the LD.sub.50, (the dose lethal to 50% of the
population) and the ED.sub.50 (the dose therapeutically effective
in 50% of the population). The dose ratio between toxic and
therapeutic effect is the therapeutic index and can be expressed as
the ratio between LD.sub.50 and ED.sub.50. Compounds which exhibit
high therapeutic indices are preferred. The data obtained from
these cell culture assays and animal studies can be used in
formulating a dosage range that is not toxic for use in human. The
dosage of such compounds lies preferably within a range of
circulating concentrations that include the ED.sub.50 with little
or no toxicity. The dosage can vary within this range depending
upon the dosage form employed and the route of administration
utilized. The exact formulation, route of administration and dosage
can be chosen by the individual physician in view of the patient's
condition. (See, e.g., Fingl et al. 1975 In: The Pharmacological
Basis of Therapeutics, Ch. 1).
[0290] The amount of active compound that can be combined with a
carrier material to produce a single dosage form will vary
depending upon the disease treated, the mammalian species, and the
particular mode of administration. However, as a general guide,
suitable unit doses for the compounds of the present invention can,
for example, preferably contain between 100 mg to about 3000 mg of
the active compound. A preferred unit dose is between 500 mg to
about 1500 mg. A more preferred unit dose is between 500 to about
1000 mg. Such unit doses can be administered more than once a day,
for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2
times per day, so that the total daily dosage for a 70 kg adult is
in the range of 0.1 to about 250 mg per kg weight of subject per
administration. A preferred dosage is 5 to about 250 mg per kg
weight of subject per administration, and such therapy can extend
for a number of weeks or months, and in some cases, years. It will
be understood, however, that the specific dose level for any
particular patient will depend on a variety of factors including
the activity of the specific compound employed; the age, body
weight, general health, sex and diet of the individual being
treated; the time and route of administration; the rate of
excretion; other drugs which have previously been administered; and
the severity of the particular disease undergoing therapy, as is
well understood by those of skill in the area.
[0291] A typical dosage can be one 10 to about 1500 mg tablet taken
once a day, or, multiple times per day, or one time-release capsule
or tablet taken once a day and containing a proportionally higher
content of active ingredient. The time-release effect can be
obtained by capsule materials that dissolve at different pH values,
by capsules that release slowly by osmotic pressure, or by any
other known means of controlled release.
[0292] It can be necessary to use dosages outside these ranges in
some cases as will be apparent to those skilled in the art.
Further, it is noted that the clinician or treating physician will
know how and when to interrupt, adjust, or terminate therapy in
conjunction with individual patient response.
Combination Therapy
[0293] As noted above, the compounds of the present invention will,
in some instances, be used in combination with other therapeutic
agents to bring about a desired effect. Selection of additional
agents will, in large part, depend on the desired target therapy
(see, e.g., Turner, N. et al. Prog. Drug Res. (1998) 51: 33-94;
Haffner, S. Diabetes Care (1998) 21: 160-178; and DeFronzo, R. et
al. (eds.), Diabetes Reviews (1997) Vol. 5 No. 4). A number of
studies have investigated the benefits of combination therapies
with oral agents (see, e.g., Mahler, R. J. Clin. Endocrinol. Metab.
(1999) 84: 1165-71; United Kingdom Prospective Diabetes Study
Group: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin, C. W.,
(ed.), CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6th Edition
(Mosby--Year Book, Inc., St. Louis, Mo. 1997); Chiasson, J. et al.,
Ann. Intern. Med. (1994) 121: 928-935; Coniff, R. et al., Clin.
Ther. (1997) 19: 16-26; Coniff, R. et al., Am. J. Med. (1995) 98:
443-451; and Iwamoto, Y. et al., Diabet. Med. (1996) 13 365-370;
Kwiterovich, P. Am. J. Cardiol (1998) 82(12A): 3U-17U). These
studies indicate that diabetes and hyperlipidemia modulation can be
further improved by the addition of a second agent to the
therapeutic regimen. Combination therapy includes administration of
a single pharmaceutical dosage formulation which contains a
compound having the general structure of Formula I and one or more
additional active agents, as well as administration of a compound
of Formula I and each active agent in its own separate
pharmaceutical dosage formulation. For example, a compound of
Formula I and an HMG-CoA reductase inhibitor can be administered to
the human subject together in a single oral dosage composition,
such as a tablet or capsule, or each agent can be administered in
separate oral dosage formulations. Where separate dosage
formulations are used, a compound of Formula I and one or more
additional active agents can be administered at essentially the
same time (i.e., concurrently), or at separately staggered times
(i.e., sequentially). Combination therapy is understood to include
all these regimens.
[0294] An example of combination therapy that modulates (prevents
the onset of the symptoms or complications associated)
atherosclerosis, wherein a compound of Formula I is administered in
combination with one or more of the following active agents: an
antihyperlipidemic agent; a plasma HDL-raising agent; an
antihypercholesterolemic agent, such as a cholesterol biosynthesis
inhibitor, e.g., an hydroxymethylglutaryl (HMG) CoA reductase
inhibitor (also referred to as statins, such as lovastatin,
simvastatin, pravastatin, fluvastatin, and atorvastatin), an
HMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, or a
squalene synthetase inhibitor (also known as squalene synthase
inhibitor); an acyl-coenzyme A cholesterol acyltransferase (ACAT)
inhibitor, such as melinamide; probucol; nicotinic acid and the
salts thereof and niacinamide; a cholesterol absorption inhibitor,
such as .beta.-sitosterol; a bile acid sequestrant anion exchange
resin, such as cholestyramine, colestipol or dialkylaminoalkyl
derivatives of a cross-linked dextran; an LDL (low density
lipoprotein) receptor inducer; fibrates, such as clofibrate,
bezafibrate, fenofibrate, and gemfibrizol; vitamin B.sub.6 (also
known as pyridoxine) and the pharmaceutically acceptable salts
thereof, such as the HCl salt; vitamin B.sub.12 (also known as
cyanocobalamin); vitamin B.sub.3 (also known as nicotinic acid and
niacinamide, supra); anti-oxidant vitamins, such as vitamin C and E
and beta carotene; a beta-blocker; an angiotensin II antagonist; an
angiotensin converting enzyme inhibitor; and a platelet aggregation
inhibitor, such as fibrinogen receptor antagonists (i.e.,
glycoprotein IIb/IIIa fibrinogen receptor antagonists) and aspirin.
As noted above, the compounds of Formula I can be administered in
combination with more than one additional active agent, for
example, a combination of a compound of Formula I with an HMG-CoA
reductase inhibitor (e.g., lovastatin, simvastatin and pravastatin)
and aspirin, or a compound of Formula I with an HMG-CoA reductase
inhibitor and a .beta. blocker.
[0295] Another example of combination therapy can be seen in
treating obesity or obesity-related disorders, wherein the
compounds of Formula I can be effectively used in combination with,
for example, phenylpropanolamine, phenteramine, diethylpropion,
mazindol; fenfluramine, dexfenfluramine, phentiramine, .beta.-3
adrenoceptor agonist agents; sibutramine, gastrointestinal lipase
inhibitors (such as orlistat), and leptins. Other agents used in
treating obesity or obesity-related disorders wherein the compounds
of Formula I can be effectively used in combination with, for
example, neuropeptide Y, enterostatin, cholecytokinin, bombesin,
amylin, histamine H.sub.3 receptors, dopamine D.sub.2 receptors,
melanocyte stimulating hormone, corticotrophin releasing factor,
galanin and gamma amino butyric acid (GABA).
[0296] Still another example of combination therapy can be seen in
modulating diabetes (or treating diabetes and its related symptoms,
complications, and disorders), wherein the compounds of Formula I
can be effectively used in combination with, for example,
sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide,
tolazamide, glyburide, gliclazide, glynase, glimepiride, and
glipizide), biguanides (such as metformin), thiazolidinediones
(such as ciglitazone, pioglitazone, troglitazone, and
rosiglitazone); dehydroepiandrosterone (also referred to as DHEA or
its conjugated sulphate ester, DHEA-SO.sub.4); antiglucocorticoids;
TNF.alpha. inhibitors; .alpha.-glucosidase inhibitors (such as
acarbose, miglitol, and voglibose), pramlintide (a synthetic analog
of the human hormone amylin), other insulin secretogogues (such as
repaglinide, gliquidone, and nateglinide), insulin, as well as the
active agents discussed above for treating atherosclerosis.
[0297] A further example of combination therapy can be seen in
modulating hyperlipidemia (treating hyperlipidemia and its related
complications), wherein the compounds of Formula I can be
effectively used in combination with, for example, statins (such as
fluvastatin, lovastatin, pravastatin or simvastatin), bile
acid-binding resins (such as colestipol or cholestyramine),
nicotinic acid, probucol, betacarotene, vitamin E, or vitamin
C.
[0298] Additionally, an effective amount of a compound of Formula I
and a therapeutically effective amount of one or more active agents
selected from the group consisting of: an antihyperlipidemic agent;
a plasma HDL-raising agent; an antihypercholesterolemic agent, such
as a cholesterol biosynthesis inhibitor, for example, an HMG-CoA
reductase inhibitor, an HMG-CoA synthase inhibitor, a squalene
epoxidase inhibitor, or a squalene synthetase inhibitor (also known
as squalene synthase inhibitor); an acyl-coenzyme A cholesterol
acyltransferase inhibitor; probucol; nicotinic acid and the salts
thereof; niacinamide; a cholesterol absorption inhibitor; a bile
acid sequestrant anion exchange resin; a low density lipoprotein
receptor inducer; clofibrate, fenofibrate, and gemfibrozil; vitamin
B.sub.6 and the pharmaceutically acceptable salts thereof; vitamin
B.sub.12; an anti-oxidant vitamin; a .beta.-blocker; an angiotensin
II antagonist; an angiotensin converting enzyme inhibitor; a
platelet aggregation inhibitor; a fibrinogen receptor antagonist;
aspirin; phentiramines, .beta.-3 adrenergic receptor agonists;
sulfonylureas, biguanides, .alpha.-glucosidase inhibitors, other
insulin secretogogues, and insulin can be used together for the
preparation of a pharmaceutical composition useful for the
above-described treatments.
Kits
[0299] In addition, the present invention provides for kits with
unit doses of the compounds of Formula I, either in oral or
injectable doses. In addition to the containers containing the unit
doses will be an informational package insert describing the use
and attendant benefits of the drugs in alleviating symptoms and/or
complications associated with Type 2 diabetes as well as in
alleviating hyperlipidemia and hyperuricemia, or for alleviating
conditions dependent on PPAR. Preferred compounds and unit doses
are those described herein above.
[0300] For the compositions, methods and kits provided above, one
of skill in the art will understand that preferred compounds for
use in each are those compounds that are preferred above and
particularly those compounds provided in formula I in FIGS. 1A-1D.
Still further preferred compounds for the compositions, methods and
kits are those compounds provided in the Examples below.
EXAMPLES
Experimental Section
[0301] General Methods.
Intermediates
[0302] Synthesis of Intermediate Compound 3A ##STR25##
[0303] A solution of 4-trifluoromethyl-aniline hydrogen chloride in
AcOH, H.sub.2O, and concentrated HCl was cooled .ltoreq.5.degree.
C. and NaNO.sub.2 (1.2 eq) in H.sub.2O was added slowly to the
mixture. The resultant mixture was slowly added to a mixture of
ethyl acetoacetate (1 eq) and in EtOH and NaOAc in 1N
Na.sub.2CO.sub.3 at 0.degree. C. The resulting mixture was stirred
for 2 hrs and diluted with H.sub.2O, and then extracted with EtOAc.
The organic phases were combined and washed with H.sub.2O, brine,
dried over Na.sub.2SO.sub.4, and evaporated to give a crude
product, which was used in the next reaction without
purification.
[0304] To the crude product of the above reaction in ethanol was
added CuCl.sub.2.2H.sub.2O (2.2 eq.) and NH.sub.4OAc (10 eq). The
reaction mixture was refluxed for 12 hrs and then cooled to room
temperature. The reaction mixture was poured into a mixture of ice
and concentrated HCl. The reaction mixture was then filtered and
washed with 2N HCl. The resulting solid was purified by
recrystallization from ethanol to afford desired product. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.25 (2H, m), 7.76 (2H, m), 4.48
(2H, q, J=7.2), 2.63 (3H, s), 1.46 (3H, t, J=7.2). Synthesis of
Intermediate Compound 3B ##STR26##
[0305] A solution of 4-trifluoromethyl-aniline hydrogen chloride in
AcOH, H.sub.2O, and concentrated HCl was cooled .ltoreq.5.degree.
C. and NaNO.sub.2 (1.2 eq) in H.sub.2O was added slowly to the
mixture. The resultant mixture was slowly added to a mixture of
3-oxo-3-phenyl-propionic acid ethyl ester (1 eq) and in EtOH and
NaOAc in 1N Na.sub.2CO.sub.3 at 0.degree. C. The resulting mixture
was stirred for 2 hrs and diluted with H.sub.2O, and then extracted
with EtOAc. The organic phases were combined and washed with
H.sub.2O, brine, dried over Na.sub.2SO.sub.4, and evaporated to
give a crude product, which was used in the next reaction without
purification.
[0306] To the crude product of the above reaction in ethanol was
added CuCl.sub.2.2H.sub.2O (2.2 eq) and NH.sub.4OAc (10 eq). The
reaction mixture was refluxed for 12 hrs and then cooled to room
temperature. The reaction mixture was poured into a mixture of ice
and concentrated HCl. The reaction mixture was then filtered and
washed with 2N HCl. The resulting solid was purified by
recrystallization from ethanol to afford desired product 3B.
Synthesis of Intermediate Compound 4A ##STR27##
[0307] To a solution of compound 3A (3.5 g, 11.7 mmol) in anhydrous
THF (50 mL) was added LiAlH.sub.4 (0.89 g, 23.4 mmol) at 0.degree.
C. The reaction mixture was kept at 0.degree. C. for 2 hrs and then
quenched with 10% NaOH. The reaction mixture was filtered and
washed with EtOAc. The filtrate was concentrated to give 2.6 g of
compound 4A. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.12 (2H, d,
J=8.0), 7.71 (2H, d, J=8.0), 4.82 (2H, s), 2.43 (3H, s). Synthesis
of Intermediate Compound 4B ##STR28##
[0308] To compound 3B in anhydrous THF (50 mL) was added
LiAlH.sub.4 (2 eq) at 0.degree. C. The mixture was kept at
0.degree. C. for 2 hrs and quenched with 10% NaOH, filtered, washed
with EtOAc, and concentrated to give compound 4B. Synthesis of
Intermediate Compound 5A ##STR29##
[0309] A mixture of compound 4A (1.6 g,), 48% HBr (10 mL) and AcOH
(10 mL) was heated at 100.degree. C. for 2 hrs. The reaction
mixture was then cooled to room temperature, filtered, washed with
water, and air dried to give 1.1 g of compound 5A. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.14.about.8.11 (2H, m), 7.74.about.7.7
(2H, m), 4.57 (2H, s), 2.43 (3H, s). Synthesis of Intermediate
Compound 5B ##STR30##
[0310] To a solution of compound 4B in CH.sub.2Cl.sub.2 was added
SOCl.sub.2 (3 eq) at room temperature. The mixture was refluxed for
5 hrs, the mixture was cooled to room temperature and evaporated,
the residue was purified by chromatography to afford desired
product. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.22 (2H, d,
J=8.8 Hz), 7.9.about.7.87(2H, m), 7.74 (2H, d, J=8.8 Hz),
7.52.about.7.4(3H, m), 4.98 (2H, s). Synthesis of Intermediate
Compound 5C ##STR31##
[0311] To a solution of compound 4A in CH.sub.2Cl.sub.2 was added
SOCl.sub.2 (3 eq) at room temperature. The mixture was refluxed for
5 hrs, the mixture was cooled to room temperature and evaporated,
the residue was purified by chromatography to afford desired
product. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.12 (2H, d,
J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz), 4.72 (2H, s), 2.46 (3H, s).
[0312] The following compounds were made according to the procedure
above: Compound 5D ##STR32##
[0313] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.49 (2H, s), 7.81
(1H, s), 4.72 (2H, s), 2.47 (3H, s). Compound 5E ##STR33##
[0314] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.8.15(1H, d, J=2.8
Hz), 7.86 (1H, dd, J=8.8, 2.4 Hz), 7.52 (1H, d, J=8.4 Hz), 4.7 (2H,
s), 2.44 (3H, s). Compound 5F ##STR34##
[0315] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.09.about.8.04
(2H, m), 7.7.about.7.67(2H, m), 7.64.about.7.61(2H, m),
7.49.about.7.43(2H, m), 7.39.about.7.35(1H, m), 4.74 (2H, s), 2.46
(3H, s). Compound 5G ##STR35##
[0316] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.30 (1H, s), 8.21
(1H, m), 7.59 (2H, m), 4.72 (2H, s), 2.46 (3H, s). Compound 5H
##STR36##
[0317] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15 (2H, m), 7.72
(2H, m), 4.74 (2H, s), 3.20 (1H, m), 1.40 (6H, d, J=7.2 Hz).
Compound 5I ##STR37##
[0318] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.93 (2H, m), 7.42
(2H, m), 4.79 (2H, s), 2.41 (3H, s). Compound 5J ##STR38##
[0319] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.84 (2H, d, J=9.2
Hz), 7.50 (2H, d, J=9.2 Hz), 4.79 (2H, s), 2.41 (3H, s). Synthesis
of Intermediate Compound 6 ##STR39##
[0320] The mixture of compound 5A and KCN (2 eq) in ethanol was
refluxed for 6 hours. The volatiles were evaporated and the residue
was partitioned between EtOAc and water. The organic layer was
washed with brine, dried over Na.sub.2SO.sub.4, concentrated, and
purified by flash chromatography to give desired product 6. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.13.about.8.1(2H, m),
7.74.about.7.71 (2H, m), 3.85 (2H, s), 2.44 (3H, s). Synthesis of
Intermediate Compound 7A ##STR40##
[0321] To a saturated ethanolic solution of HCl was added compound
6 and the mixture was refluxed for 3 hrs. The solvent was
evaporated and the residue was partitioned between EtOAc and a pH 7
buffer solution. The organic phase was separated, washed with
brine, dried over Na.sub.2SO.sub.4, and evaporated. The residue was
purified by chromatography on silica gel to give the desired ester
7A. Synthesis of Intermediate Compound 7B ##STR41##
[0322] To a saturated methanolic solution of HCl was added compound
6 and the mixture was refluxed for 3 hrs. The solvent was
evaporated and the residue was partitioned between EtOAc and a pH 7
buffer solution. The organic phase was separated, washed with
brine, dried over Na.sub.2SO.sub.4, and evaporated. The residue was
purified by chromatography on silica gel to give the desired ester
7B. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.1.about.8.08(2H,
m), 7.69.about.7.766 (2H, m), 3.78 (2H, s), 3.73 (3H, s), 2.35 (3H,
s). Synthesis of Intermediate Compound 8 ##STR42##
[0323] To a solution of compound 7A or B in anhydrous THF was added
LiAlH.sub.4 (2 eq.) at 0.degree. C. The mixture was kept at
0.degree. C. for 2 hrs and then quenched with 10% NaOH. The
reaction mixture was then filtered and washed with EtOAc. The
filtrate was concentrated to give compound 8. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.98(2H, d, J=8.4 Hz), 7.59 (2H, d, J=8.4 Hz),
3.89 (2H, t, J=6 Hz), 3.83 (2H, t, J=6 Hz), 3.0.about.2.6(1H, br),
2.25 (3H, s). Synthesis of Compound 9A ##STR43##
[0324] To a solution of compound 8 and CBr.sub.4 was added
PPh.sub.3 at room temperature. The reaction mixture was stirred at
room temperature for 5 hrs. The volatiles were evaporated and the
resulting residue was purified by chromatography on silica gel to
give compound 9A. Synthesis of Compound 9B ##STR44##
[0325] To a solution of compound 8 (0.19 mg, 0.7 mmol), imidazole
(95 mg, 1.4 mmol), and PPh.sub.3 (367 mg, 1.4 mmol) in
CH.sub.2Cl.sub.2, was added 12 (215 mg, 1.4 mmol) at 0.degree. C.
The mixture was stirred overnight at room temperature, diluted with
EtOAc, and washed with aqueous Na.sub.2S.sub.2O.sub.3, brine, dried
over Na.sub.2SO.sub.4, and evaporated. The residue was purified by
chromatography on silica gel to give 0.22 g compound 9B. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.03(2H, dd, J=9.2, 0.8 Hz), 7.63
(2H, dd, J=9.2, 0.8 Hz), 3.41.about.3.37 (2H, m),
3.24.about.3.2(2H, m), 2.3 (3H, s). Synthesis of Intermediate
Compound 10A ##STR45##
[0326] To a solution of compound 3A in anhydrous CH.sub.2Cl.sub.2
was added DIBAL (1.1 eq) at -78.degree. C. under N.sub.2. The
mixture was stirred at -78.degree. C. for 4 hrs. The reaction
mixture was quenched with saturated NH.sub.4Cl and then filtered
through a plug of Celite. The filtrate was partitioned between
EtOAc and water. The organic phase was washed with brine, dried
over NaSO.sub.4, evaporated, and the residue was purified by
chromatography on silica gel to give compound 10A. Synthesis of
Intermediate Compound 10B ##STR46##
[0327] To a solution of compound 10A in anhydrous THF was added
MeMgBr (2 eq) at 0.degree. C. under N.sub.2 and The mixture was
allowed to warm to room temperature. The reaction mixture was
quenched with saturated NH.sub.4Cl and diluted with EtOAc. The
organic phase was washed with brine, dried over NaSO.sub.4,
evaporated, and the residue was purified by chromatography on
silica gel to give compound 10B. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.12(2H, 8.4 Hz), 7.71 (2H, d, J=9.2 Hz),
5.14.about.5.08(1H, m), 2.45 (3H, s), 2.09 (1H, d, J=6 Hz), 1.64
(3H, d, J=6.8 Hz). Synthesis of Intermediate Compound 10C
##STR47##
[0328] To a solution of compound 3A in anhydrous THF was added
MeMgBr (4 eq) at 0.degree. C. under N.sub.2 and The mixture was
allowed to warm to room temperature. The reaction mixture was
quenched with saturated NH.sub.4Cl and diluted with EtOAc. The
organic phase was washed with brine, dried over NaSO.sub.4,
evaporated, and the residue was purified by chromatography on
silica gel to give compound 10C. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.11(2H, 8.8 Hz), 7.7 (2H, d, J=8.8 Hz), 2.51 (3H, s), 2.29
91H, br), 1.68 (6H, s). Synthesis of Intermediate Compound 11
##STR48##
[0329] A mixture of aldehyde 10A and
(carbethoxymethylene)-triphenylphosphorane (1.1 eq) in toluene was
stirred at 100.degree. C. for 3 hrs. The solvent was evaporated and
the residue was purified by chromatography on silica gel to give
compound 11. Synthesis of Intermediate Compound 12 ##STR49##
[0330] A solution of 11 in MeOH was stirred with Pd/C 10% under
H.sub.2 at room temperature overnight. The reaction was filtered
through a plug of Celite. The filtrate was concentrated under
reduced pressure to give the desired compound 12. Synthesis of
Intermediate Compound 13 ##STR50##
[0331] To a solution of compound 12 in anhydrous THF was added
LiAlH.sub.4 (2 eq) at 0.degree. C. The reaction mixture was kept at
0.degree. C. for 2 hrs and then quenched with 10% NaOH. The
reaction mixture was then filtered and washed with EtOAc. The
filtrate was concentrated to give compound 13. Synthesis of
Intermediate Compound 14 ##STR51##
[0332] To a mixture of compound 13 and CBr.sub.4 was added
PPh.sub.3 at room temperature. The mixture was stirred at room
temperature for 5 hrs. The volatiles were evaporated and the
residue was purified by chromatography on silica gel to give
compound 14. Synthesis of Intermediate Compound 27 ##STR52##
[0333] To a solution of 3A (2.83 g, 10 mmol) in carbon
tetrachloride (100 mL) was added N-bromo succinimide (2.14 g, 12
mmol) and benzoyl peroxide (0.24 g, 1 mmol) at room temperature and
the mixture was refluxed for 5 hours. After cooling to 0.degree.
C., the mixture was filtered through Celite and the solvent was
evaporated to yield crude product. The crude product was dissolved
in MeCN (30 mL) and 4-mercapto-2-methylphenol (1.38 g, 10 mmol) and
cesium carbonate (3.26 g, 10 mmol) was added to the solution. The
mixture was allowed to stir at room temperature for 3 hours. The
mixture was filtered through Celite and washed with EtOAc,
evaporated and the residue was purified by chromatography to give
2.1 g of a white solid. Synthesis of Intermediate Compound 28
##STR53##
[0334] To a solution of compound 27 (2.1 g, 5 mmol) in anhydrous
THF (100 mL) was added LiAlH.sub.4 (0.38 g, 10 mmol) at 0.degree.
C. The mixture was kept at 0.degree. C. for 2 hrs and the reaction
was quenched with EtOH. The solvent was evaporated and the residue
was diluted with EtOAc, washed with 2N HCl, brine, and dried over
Na.sub.2SO.sub.4. The solvent was evaporated to yield 1.6 g of a
white solid. Synthesis of Intermediate Compound 29A ##STR54##
[0335] To a solution of compound 28 (0.75 g, 1 mmol) in toluene (10
mL) was added cesium carbonate (1.3 g, 4 mmol) and
2-bromo-2-methyl-propionic acid ethyl ester (0.8 g, 4 mmol) and the
mixture was heated to 97.degree. C. for 4 hours. The mixture was
cooled to room temperature, filtered through Celite, and washed
with EtOAc. The solvent was evaporated and the residue was purified
by chromatography to yield 0.45 g of the desired product. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.07(2H, d, J=8.8 Hz), 7.7 (2H,
d, J=8.8 Hz), 7.2.about.7.18(1H, m), 7.06.about.7.03(1H, m), 6.52
(1H, d, J=8.4 Hz), 4.74 (2H, d, J=6.4 Hz), 4.19 (2H, q, J=7.2 Hz),
4.17 (2H, s), 2.19 (1H, t, J=6.4 Hz), 2.15 (3H, s), 1.55 (6H, s),
1.2 (3H, t, J=7.2 Hz).
[0336] The following compounds were made according to the procedure
above: Compound 29B ##STR55##
[0337] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.07 (2H, d, J=8.4 Hz),
7.71 (2H, d, J=8.8 Hz), 7.21 (1H, s), 7.14 (1H, d, J=8.4 Hz), 6.58
(1H, d, J=8.4 Hz), 4.74 (2H, s), 4.6 (2H, s), 4.23 (2H, q, J=6.8
Hz), 4.17 (2H, s), 2.22 (3H, s), 1.27 (3H, t, J=6.8 Hz).
Compound 29C
[0338] ##STR56##
[0339] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.06(2H, d, J=8.8
Hz), 7.7 (2H, d, J=8.8 Hz), 7.26.about.7.24(2H, m),
6.75.about.6.71(2H, m), 4.74(2H, d, J=6.4 Hz), 4.182 (2H, q, J=7.2
Hz), 4.18 (2H, s), 4.15 (1H, t, J=6.4 Hz), 1.55 (6H, s), 1.2 (3H,
t, J=7.2 Hz).
Example 1A
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethylsulfanyl]-phenoxy}-acetic acid (Compound 100)
[0340] ##STR57##
[0341] To a mixture of compound 5A (500 mg, 1.56 mmol) and
4-mercapto-2-methyl-phenol (237 mg, 1.72 mmol) in MeCN (15 mL) was
added Cs.sub.2CO.sub.3 (560 mg, 1.72 mmol). The mixture was stirred
at room temperature for 4 hrs. TLC showed disappearance of compound
5A. Ethyl bromoacetate (0.2 mL, 2 mmol) was added followed by
addition of Cs.sub.2CO.sub.3 (717 mg, 2.2 mmol). The mixture was
stirred for another 4 hours. The mixture was then filtered through
Celite and washed with ethyl acetate. The solvent was evaporated
and the residue was purified by flash chromatography on silica gel
to give 610 mg of the desired ester.
[0342] To a solution of the ester in THF (5 mL) was added aqueous
LiOH (4 mL, 4 mmol). The mixture was stirred at room temperature
for 1 hr, acidified with 1N HCl, and then extracted with EtOAc. The
organic phase was washed with brine, dried, and concentrated. The
residue was recrystallized from hexanes and ethyl acetate to give
360 mg white solid. .sup.1H NMR (400 MHz, DMSO) .delta. 13.0 (1H,
br), 8.03 (2H, d, J=8.8 Hz), 7.87 (2H, d, J=8.8 Hz), 7.2.about.7.14
(2H, m), 6.76 (1H, d, J=8.4 Hz), 4.67 (2H, s), 4.2 (2H, s), 2.22
(3H, s), 2.1 (3H, s).
Example 1B
2-{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-y-
lmethylsulfanyl]-phenoxy}-propionic acid (Compound 110)
[0343] ##STR58##
[0344] The following compound was made according to the procedure
of Example 1A using compound 5A. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.03 (2H, d, J=8 Hz), 7.68 (2H, J=8 Hz), 7.2 (1H, d, J=1.6
Hz), 7.15 (1H, dd, J=8.8, 2 Hz), 6.61 (1H, d, J=8.4 Hz), 4.74 (1H,
q, J=7.2 Hz), 4.07 (2H, s), 2.24 (3H, s), 2.2 (3H, s), 1.65 (3H, d,
J=7.2 Hz).
Example 1C
{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmeth-
ylsulfanyl]-2-methyl-phenoxy}-acetic acid (Compound 630)
[0345] ##STR59##
[0346] The following compound was made according to the procedure
of Example 1A using compound 5D. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.39 (2H, s), 7.76 (1H, s), 7.24 (1H, d, J=2 Hz), 7.17 (1H,
dd, J=8.4, 2 Hz), 6.63 (1H, d, J=8.4 Hz), 4.66 (1H, s), 4.08 (2H,
s), 2.24 (3H, s), 2.27 (3H, s), 2.23 (3H, s).
Example 1D
{4-[2-(3,4-Dichloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-
-2-methyl-phenoxy}-acetic acid (Compound 640)
[0347] ##STR60##
[0348] The following compound was made according to the procedure
of Example 1A using compound 5E. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.05 (1H, d, J=2.4 Hz), 7.77 (1H, dd, J=8.8, 2.4 Hz), 7.48
(1H, d, J=8.4 Hz), 7.21 (d, J=2 Hz), 7.17 (1H, dd, J=8.4, 2.4 Hz),
6.63 (1H, d, J=8.4 Hz), 4.67 (2H, s), 4.05 (2H, s), 2.24 (3H, s),
2.23 (3H, s).
Example 1E
[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl)-2-methy-
l-phenoxy]-acetic acid
[0349] ##STR61##
[0350] The following compound was made according to the procedure
of Example 1A using compound 5F. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.98 (2H, d, J=9.2 Hz), 7.66 (2H, d, J=9.2 Hz),
7.63.about.7.6 (3H, m), 7.45 (2H, t, J=7.2 Hz), 7.36 (1H, t, J=7.2
Hz), 7.23 (1H, d, J=1.6 Hz), 7.18 (1H, dd, J=8.4, 2 Hz), 6.63 (1H,
d, J=8.8 Hz), 4.65 (2H, s), 4.09 (2H, s), 2.25 (3H, s), 2.23 (3H,
s).
Example 1F
2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]tr-
iazol-4-ylmethylsulfanyl]-phenoxy}-propionic acid (Compound
210)
[0351] ##STR62##
[0352] To a mixture of compound 5C (1.1 g, 4 mmol) and
4-mercapto-2-methyl-phenol (1.07 g, 4.4 mmol) in MeCN (15 mL) was
added CsCO.sub.3 (1.96 g, 6 mmol), the mixture was stirred at room
temperature for 4 hrs. TLC showed disappearance of compound 5C. The
mixture was filtrated through celite and washed with ethyl acetate,
the solvent was evaporated and the residue was purified by flash
chromatography on silica gel to give 1.2 g desired product.
[0353] To a solution of above compound (0.36 g, 1 mmol) in toluene
(10 mL) was added CsCO.sub.3 (0.65 g, 2 mmol) and ethyl
.alpha.-bromoisobutyrate (0.39 g, 2 mmol), the mixture was stirred
at 90.degree. C. for 4 hrs. The mixture was filtrated through
celite and washed with ethyl acetate, the solvent was evaporated
and the residue was purified by flash chromatography on silica gel
to give 0.42 g desired ester.
[0354] To a solution of the ester (0.34 g, in THF (5 mL) was added
aqueous LiOH (4 mL, 4 mmol), the mixture was stirred at room
temperature for 1 hr, acidified with 1N HCl, extracted with EtOAc.
The organic phase was washed with brine, dried and concentrated,
the residue was recrystallized from hexanes and ethyl acetate to
give 360 mg white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.05.about.8.02 (2H, m), 7.7.about.7.67 (2H, m), 7.21 (1H, d, J=2.4
Hz), 7.14.about.7.11 (1H, m), 6.71 (1H, d, J=8.8 Hz), 4.1 (2H, s),
2.27 (3H, s), 2.18 (3H, s), 1.59 (6H, s).
Example 1G
(2-Methyl-4-{1-methyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]t-
riazol-4-yl]-ethylsulfanyl}-phenoxy)-acetic acid
[0355] ##STR63##
[0356] To a solution of 10C (1.15 g, 4 mmol) in CH.sub.2Cl.sub.2
(10 mL) was added ZnI.sub.2 (1.28 g, 4 mmol) and solution
(4-Mercapto-2-methyl-phenoxy)-acetic acid (1.08 g, 4.8 mmol) in
CH.sub.2Cl.sub.2 (5 mL), the mixture was stirred at room
temperature for 20 hrs. The reaction was quenched with small amount
water, the solvent was evaporated and the residue was purified by
flash chromatography on silica gel to give 0.4 g desired ester.
[0357] To a solution of the ester (0.34 g, 0.69 mmol), in THF (3
mL) was added aqueous LiOH (1.4 mL, 1.4 mmol), the mixture was
stirred at room temperature for 1 hr, acidified with 1N HCl,
extracted with EtOAc. The organic phase was washed with brine,
dried and concentrated, the residue was recrystallized from hexanes
and ethyl acetate to give 0.18 g white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.98.about.7.96 (2H, m), 7.66.about.7.64 (2H,
m), 6.94.about.6.93 (1H, m), 6.9.about.6.87 (1H, m), 6.46 (1H, d,
J=8.8 Hz), 5.13 (2H, s), 4.54 (2H, s), 2.55 (3H, s), 1.72 (6H,
s).
Example 1H
{4-[5-Isopropyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyls-
ulfanyl]-2-methyl-phenoxy}-acetic acid
[0358] ##STR64##
[0359] The title compound was prepared from intermediate compound
5H, 4-mercapto-2-methylphenol and ethyl bromoacetate using the
procedure described above. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 13.02 (1H, br), 8.02 (2H, d, J=8.8 Hz), 7.87 (2H, d, J=8.8
Hz), 7.17 (2H, m), 6.76 (1H, d, J=8.8 Hz), 4.66 (2H, s), 4.22 (2H,
s), 3.09 (1H, m), 2.10 (3H, s), 1.25 (6H, d, J=7.2 Hz).
Example 1I
{4-[2-(4-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-m-
ethyl-phenoxy}-acetic acid
[0360] ##STR65##
[0361] The title compound was prepared from intermediate compound
5I, 4-mercapto-2-methyl-phenol and ethyl bromoacetate using the
procedure described above. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 13.00 (1H, br), 7.83 (2H, dd, J=7.2, 2.4 Hz), 7.55 (2H, dd,
J=7.2, 2.4 Hz), 7.14 (2H, m), 6.75 (11H, d, J=8.4 Hz), 4.66 (2H,
s), 4.17 (2H, s), 2.19 (3H, s), 2.10 (3H, s).
Example 1J
{4-[2-(4-Bromo-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-me-
thyl-phenoxy}-acetic acid
[0362] ##STR66##
[0363] The title compound was prepared from intermediate compound
5J, 4-mercapto-2-methylphenol and ethyl bromoacetate using the
procedure described above. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 13.00 (1H, br), 7.77 (2H, dd, J=6.8, 2.4 Hz), 7.68 (2H, dd,
J=7.2, 2.4 Hz), 7.15 (2H, m), 6.75 (1H, d, J=8.4 Hz), 4.66 (2H, s),
4.17 (2H, s), 2.19 (3H, s), 2.10 (3H, s).
Example 1K
{2-Methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethylsulfanyl]-phenoxy}-acetic acid
[0364] ##STR67##
[0365] The title compound was prepared from intermediate compound
5G, 4-mercapto-2-methyl-phenol and ethyl bromoacetate using the
procedure described above. .sup.1H NMR (400 MHz, DMSO) .delta.
12.98 (1H, br), 8.12 (1H, m), 8.05 (1H, s), 7.73 (2H, m), 7.19 (1H,
m), 7.14 (1H, m), 6.75 (1H, d, J=58.8 Hz), 4.65 (2H, s), 4.20 (2H,
s), 2.21 (3H, s), 2.10 (3H, s).
Example 1L
2-{4-[2-(4-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-
-methyl-phenoxy}-propionic acid
[0366] ##STR68##
[0367] The title compound was prepared from intermediate compound
5I, 4-mercapto-2-methylphenol and ethyl 2-bromopropionate using the
procedure described above. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.83 (2H, m), 7.55 (2H, m), 7.15 (2H, m), 6.69 (1H, d,
J=8.8 Hz), 4.77 (1H, q, J=6.4 Hz), 4.17 (2H, s), 2.18 (3H, s), 2.09
(3H, s), 1.47 (3H, d, J=6.4 Hz).
Example 1M
{2-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethylsulfanyl]-phenoxy}-acetic acid
[0368] ##STR69##
[0369] The title compound was prepared from intermediate compound
5A, 4-mercapto-2-chloro-phenol and ethyl 2-bromoacetate using the
procedure described above. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 13.12 (1H, br), 8.02 (2H, d, J=8.8 Hz), 7.86 (2H, d, J=8.8
Hz), 7.48 (1H, d, J=2.4 Hz), 7.28 (1H, dd, J=8.4, 2.4 Hz), 6.96
(1H, d, J=8.4 Hz), 4.78 (2H, s), 4.29 (2H, s), 2.26 (3H, s).
Example 1N
(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
yl]-ethylsulfanyl}-phenoxy)-acetic acid
[0370] ##STR70##
[0371] The title compound was prepared from intermediate compound
11, (4-Mercapto-2-methyl-phenoxy)-acetic acid using the procedure
described above. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.05(2H,
d, J=8.4 Hz), 7.68 (2H, d, J=8.4 Hz), 7.17.about.7.12(2H, m), 6.61
(1H, d, J=8 Hz), 4.64 (2H, s), 4.33 (1H, q, J=6.8 Hz), 2.31 (3H,
s), 2.2 (3H, s), 1.71 (3H, d, J=6.8 Hz).
Example 2
[0372] ##STR71##
(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
yl]-ethylsulfanyl}-phenoxy)-acetic acid (Compound 580)
[0373] To a mixture of compound 9B (114 mg, 0.3 mmol) and
4-mercapto-2-methyl-phenol (50 mg, 0.36 mmol) in MeCN (5 mL) was
added Cs.sub.2CO.sub.3 (98 mg, 0.3 mmol). The mixture was stirred
at room temperature for 4 hrs. TLC showed disappearance of compound
9B. Ethyl bromoacetate (67 mg, 0.4 mmol) was added followed by
addition of Cs.sub.2CO.sub.3 (130 mg, 0.4 mmol). The mixture was
stirred for another 4 hours. The mixture was then filtered through
Celite and washed with ethyl acetate. The volatiles were evaporated
and the residue was purified by flash chromatography on silica gel
to give 85 mg of the desired ester.
[0374] To a solution of the ester (80 mg) in THF (3 mL) was added
aqueous LiOH (1 mL, 1 mmol). The mixture was stirred at room
temperature for 1 hr, acidified with 1N HCl, and extracted with
EtOAc. The organic phase was washed with brine, dried and
concentrated. The residue was recrystallized from hexanes and ethyl
acetate to give 50 mg of a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 13.0 (1H, br), 8.06 (2H, d, J=8.8 Hz), 7.68
(2H, d, J=8.8 Hz), 7.2.about.7.14 (2H, m), 6.63 (1H, d, J=8.4 Hz),
4.63 (2H, s), 3.22.about.3.18 (2H, m), 2.98.about.2.93 (2H, m),
2.29 (3H, s), 2.23 (3H, s).
Example 3
{2-Methyl-4-[5-phenyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethylsulfanyl]-phenoxy}-acetic acid, (Compound 340)
[0375] ##STR72##
[0376] To a mixture of compound 5B (1 eq) and
4-mercapto-2-methyl-phenol (1.2 eq mmol) in MeCN (15 mL) was added
Cs.sub.2CO.sub.3 (1.2 eq). The mixture was stirred at room
temperature for 4 hrs. TLC showed disappearance of compound 5B.
Ethyl bromoacetate (1.5 eq) was added followed by addition of
Cs.sub.2CO.sub.3 (1.5 eq) and the mixture was stirred for another 4
hours. The mixture was filtered through Celite and washed with
ethyl acetate. The solvent was evaporated and the residue was
purified by flash chromatography on silica gel to give desired
ester.
[0377] To a solution of the ester in THF was added aqueous LiOH (3
eq). The mixture was stirred at room temperature for 1 hr,
acidified with 1N HCl, and extracted with EtOAc. The organic phase
was washed with brine, dried and concentrated. The residue was
recrystallized from hexanes and ethyl acetate to give the desired
acid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15 (2H, d, J=8.8
Hz), 7.81.about.7.78 (2H, m), 7.73 (2H, d, J=8.8 Hz), 7.5.about.7.4
(3H, m), 7.3.about.7.2 (2H, m), 6.61 (1H, d, J=8.8 Hz), 4.65 (2H,
s), 4.29 (2H, s), 2.21 (3H, s).
Example 4
{3-Propyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethoxy]-phenyl}-acetic acid (Compound 660)
[0378] ##STR73##
[0379] To a mixture of (4-hydroxy-3-propyl-phenyl)-acetic acid
methyl ester (125 mg, 0.6 mmol) and compound 5A (192 mg, 0.6 mmol)
in MeCN (5 mL) was added Cs.sub.2CO.sub.3 (234 mg, 0.72 mmol). The
mixture was stirred at room temperature for 4 hrs. The mixture was
filtered through Celite and washed with ethyl acetate. The solvent
was evaporated and the residue was purified by flash chromatography
on silica gel to give 150 mg of the desired ester.
[0380] To a solution of the ester in THF (2 mL) was added aqueous
LiOH (1.8 mL, 1.8 mmol), the mixture was stirred at room
temperature for 1 hr, acidified with 1N HCl, extracted with EtOAc.
The organic phase was washed with brine, dried and concentrated.
The residue was recrystallized from hexanes and ethyl acetate to
give 58 mg of a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.14 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.8 Hz),
7.07.about.7.12 (2H, m), 6.97 (1H, d, J=8.4 Hz), 5.19 (2H, s), 3.58
(2H, s), 2.57 (2H, t, J=7.6 Hz), 2.45 (3H, s), 1.52.about.1.64 (2H,
m), 0.92 (3H, t, J=7.2 Hz).
Example 5
{4-[2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-ac-
etic acid (Compound 670)
[0381] ##STR74##
[0382] To a mixture of (4-hydroxy-phenyl)-acetic acid methyl ester
(125 mg, 0.6 mmol) and compound 5A (192 mg, 0.6 mmol) in MeCN (5
mL) was added Cs.sub.2CO.sub.3 (234 mg, 0.72 mmol). The mixture was
stirred at room temperature for 4 hrs. The mixture was filtered
through Celite and washed with ethyl acetate. The solvent was
evaporated and the residue was purified by flash chromatography on
silica gel to give 150 mg desired ester.
[0383] To a solution of the ester in THF (2 mL) was added aqueous
LiOH (1.8 mL, 1.8 mmol), the mixture was stirred at room
temperature for 1 hr, acidified with 1N HCl, extracted with EtOAc.
The organic phase was washed with brine, dried and concentrated.
The residue was recrystallized from hexanes and ethyl acetate to
give 48 mg of white solid. .sup.1H NMR (400 MHz, DMSO) .delta. 12.2
(1H, br), 8.15 (2H, d, J=8.4 Hz), 7.91 (2H, d, J=8.4 Hz),
7.16.about.7.22 (2H, m), 6.98.about.7.02 (2H, m), 5.24 (2H, s),
3.48 (2H, s), 2.39 (3H, s).
Example 6A
2-Methyl-2-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]tr-
iazol-4-ylmethoxy]-phenoxy}-propionic acid (Compound 290)
[0384] ##STR75##
[0385] To a mixture of
2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester
(1 eq mmol) and compound 5C (1 eq) in MeCN (5 mL) was added
Cs.sub.2CO.sub.3 (1.2 eg). The mixture was stirred at room
temperature for 4 hrs. The mixture was filtered through Celite and
washed with ethyl acetate. The solvent was evaporated and the
residue was purified by flash chromatography on silica gel to give
the desired ester.
[0386] To a solution of the above compound in THF and methanol was
added aqueous LiOH (2 eq), the mixture was refluxed for 1 hr,
acidified with 1N HCl to about pH 5, extracted with EtOAc. The
organic phase was washed with brine, dried, and concentrated. The
residue was recrystallized from hexanes and ethyl acetate to give
desired acid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.97 (2H,
d, J=8.4 Hz), 7.65 (2H, d, J=8.4 HZ), 6.96.about.6.92 (2H, m), 6.51
(1H, d, J=8.4 Hz), 4.6 (2H, s), 2.55 (3H, s), 2.18 (3H, s), 1.73
(6H, s).
Example 6B
2-[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-phe-
noxy]-2-methyl-propionic acid
[0387] ##STR76##
[0388] The following compound was made according to the procedure
of Example 6B using compound 5F. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.08.about.8.05 (2H, m 7.7.about.7.66 (2H, m),
7.64.about.7.6 (2H, m), 7.48.about.7.44 (2Hm), 7.39.about.7.34 (1H,
m), 6.87.about.6.83 (2H, m), 6.77 (1H, dd, J=58.8, 3.2 Hz), 5.15
(2H, s), 4.09 (2H, s), 2.44 (3H, s), 2.24 (3H, s), 1.57 (6H,
s).
Example 6C
2-Methyl-2-(2-methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3-
]triazol-4-yl]-ethoxy}-phenoxy)-propionic acid
[0389] ##STR77##
[0390] To a solution of 10B (0.27 g, 1 mmol) and
2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester
(0.24 g, 1 mmol) in THF (10 mL) was added PBu.sub.3 (0.3 g, 1.5
mmol) and DIAMIDE (0.25 g, 1.5 mmol), the mixture was stirred at
room temperature for 20 hrs and the solvent was evaporated and the
residue was purified by flash chromatography on silica gel to give
0.35 g desired ester.
[0391] To a solution of the ester (0.35 g,), in THF (3 mL) and
methanol (3 mL) was added aqueous LiOH (2 mL, 2 mmol), the mixture
was refluxed for 2 hr, acidified with 1N HCl, extracted with EtOAc.
The organic phase was washed with brine, dried and concentrated,
the residue was recrystallized from hexanes and ethyl acetate to
give 0.25 g white solid .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.13.about.8.1 (2H, m), 7.72.about.7.69 (2H, m), 6.78 (1H, d, J=3.2
Hz), 6.75 (1H, d, J=8.8 Hz), 6.66 (1H, dd, J=8.8, 3.2 Hz), 5.55
(1H, q, J=6.8 Hz), 2.39 (3H, s), 2.18 (3H, s), 1.73 (3H, d, J=6.8
Hz).
Example 6D
(2-Methyl-4-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
yl]-ethoxy}-phenoxy)-acetic acid
[0392] ##STR78##
[0393] To a solution of 10B (0.39 g, 1.4 mmol) and
(4-Hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (0.35 g, 1.68
mmol) in CH.sub.2Cl.sub.2 (10 mL) was added PPh.sub.3 (0.73 g, 2.8
mmol) and DEAD (0.48 g, 2.8 mmol), the mixture was stirred at room
temperature for 20 hrs and the solvent was evaporated and the
residue was purified by flash chromatography on silica gel to give
0.3 g desired ester.
[0394] To a solution of the ester (0.3 g,), in THF (3 mL) was added
aqueous LiOH (2 mL, 2 mmol), the mixture was stirred at room
temperature for 1 hr, acidified with 1N HCl, extracted with EtOAc.
The organic phase was washed with brine, dried and concentrated,
the residue was recrystallized from hexanes and ethyl acetate to
give 0.2 g white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.13 (2H, d, J=8 Hz), 7.71 (2H, d, J=8 Hz), 6.86 (1H, d, J=2.4 Hz),
6.78 (1H, dd, J=8.8, 3.2 Hz), 6.7 (1H, d, J=8.8), 5.13 (2H, s),
4.63 (2H, s), 2.43 (3H, s), 2.18 (3H, s).
Example 6E
2-{4-[2-(4-Chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-
-phenoxy}-2-methyl-propionic acid
[0395] ##STR79##
[0396] The title compound was prepared from intermediate compound
51 and 2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl
ester using the procedure described above. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.93 (2H, dd, J=7.2, 2.0 Hz), 7.57 (2H, dd,
J=7.2, 2.0 Hz), 6.87 (1H, d, 3.2 Hz), 6.77 (1H, dd, J=8.8, 3.2 Hz),
6.69 (1H, d, J=8.8 Hz), 5.12 (2H, s), 2.34 (3H, s), 2.12 (3H, s),
1.42 (6H, s).
Example 6F
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethoxy]-phenoxy}-acetic acid
[0397] ##STR80##
[0398] The title compound was prepared from intermediate compound
5A and 2-(4-Hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester using
the procedure described above. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.14 (2H, d, J=8.8 Hz), 7.90 (2H, d, J=8.8 Hz), 6.89 (1H,
d, J=2.8 Hz), 6.80 (1H, dd, J=8.8, 2.8 Hz), 6.74 (1H, d, J=8.8 Hz),
5.16 (2H, s), 4.60 (2H, s), 2.38 (3H, s), 2.16 (3H, s).
Example 6G
[4-(2-Biphenyl-4-yl-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy)-2-methyl-pheno-
xy]-acetic acid
[0399] ##STR81##
[0400] The title compound was prepared from intermediate compound
5F and 2-(4-Hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester using
the procedure described above. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.07(2H, d, J=8.8 Hz), 7.68 (,d, J=8.8 Hz), 7.62 (2H, d,
J=7.6 Hz), 7.46 (2H, d, J=7.6 Hz), 7.36 (1H, t, J=7.6 Hz), 6.88
(1H, d, J=2.4 Hz), 6.8 (1H, dd, J=8.8, 2.8 Hz), 6.71 (1 h, d, J=9.2
Hz), 5.15 (2H, s), 4.63 (2H, s), 2.44 (3H, s), 2.28 (3H, s).
Example 6H
2-{2-Chloro-4-[2-(4-chloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-
-phenoxy}-2-methyl-propionic acid
[0401] ##STR82##
[0402] The title compound was prepared from intermediate compound
51 and 2-(4-Hydroxy-2-chloro-phenoxy)-2-methyl-propionic acid ethyl
ester using the procedure described above. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.95 (2H, dd, J=7.2, 2.0 Hz), 7.43 (2H, dd,
J=7.2, 2.0 Hz), 7.10 (1H, d, J=3.2 Hz), 7.07 (1H, d, J=8.8 Hz),
6.87 (1H, dd, J=8.8, 3.2 Hz), 5.14 (2H, s), 2.43 (3H, s), 1.59 (6H,
s).
Example 7A
2-{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-p-
henyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-pr-
opionic acid (Compound 700)
[0403] ##STR83##
[0404] To a solution of compound 29 (0.43 g, 0.84 mmol)
CH.sub.2Cl.sub.2(5 mL) was added methanesulfonyl chloride (0.1 g, 1
mmol) and triethyl amine (0.13 g, 1.26 mmol) at 0.degree. C. the
mixture was stirred at 0.degree. C. for 1 hour. The mixture was
diluted with EtOAc and washed with H.sub.2O and brine. The organic
phase was dried over Na.sub.2SO.sub.4 and evaporated to yield a
crude mesylate. To the crude mesylate in THF (10 mL) was added
4-methoxyphenyl piperazine (0.32 g, 1.68 mmol) and the mixture was
refluxed for 5 hours. After cooling to room temperature, the
solvent was evaporated and the residue was purified by
chromatography to produce 0.41 g desired product. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.08(2H, d, J=8.8 Hz), 7.69 (2H, d, J=8.8
Hz), 7.21 (1H, d, J=2 Hz), 7.09.about.7.06(1H, m), 6.916.87(2H, m),
6.85.about.6.82(2H, m), 6.53 (1H, d, J=8.8 Hz), 4.24 (2H, s), 4.2
(2H, q, J=7.2 Hz), 3.76 (3H, s), 3.65 (2H, s), 3.1.about.3.07 (4H,
m), 2.65.about.2.62(4H, m), 2.16 (3H, s), 1.56 (6H, s), 1.21 (3H,
t, J=7.2 Hz).
[0405] To a solution of the above compound in THF (4 mL) and
methanol (4 mL) was added aqueous LiOH (1.8 mL, 1.8 mmol), the
mixture was refluxed for 1 hr, acidified with 1N HCl to about pH 5,
extracted with EtOAc. The organic phase was washed with brine,
dried, and concentrated. The residue was recrystallized from
hexanes and ethyl acetate to give 360 mg of a white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.1(2H, d, J=8.8 Hz), 7.69 (2H,
d, J=8.8 Hz), 7.24 (1H, d, J=2 Hz), 7.02.about.6.98(3H, m),
6.86.about.6.83(2H, m), 6.72 (1H, d, J=8.4 Hz), 4.08 (2H, s), 3.76
(3H, s), 3.38 (2H, s), 3.2.about.3.1(4H, m), 2.76.about.2.68(4H,
m), 2.19 (3H, s), 1.62 (6H, s).
Example 7B
{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phe-
nyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic
acid
[0406] ##STR84##
[0407] The following compound was made from intermediate 29B
according to the procedure of Example 7A. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.1 (2H, d, J=8.8 Hz), 7.7 (2H, J=8.8 Hz), 7.22
(1H, d, J=12 Hz), 7.15 (1H, dd, J=8, 2 Hz), 7.03.about.7.0 (2H, m),
6.86.about.6.83 (2H, m), 6.68 (1H, d, J=8.4 Hz), 4.58 (2H, s), 4.11
(2H, s), 3.76 (3H, s), 3.5 (2H, s), 3.24.about.3.16 (4H, m),
2.84.about.2.76 (4H, m), 2.22 (3H, s).
Example 7C
2-{4-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-p-
henyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-2-methyl-propionic
acid
[0408] ##STR85##
[0409] The following compound was made from intermediate 29C
according to the procedure of Example 7A. .sup.1H NMR (400 MHz,
DMSO) .delta. 8.06 (2H, d, J=8.8 Hz), 7.88 (2H, J=8.8 Hz),
7.34.about.7.28 (2H, m), 6.86.about.6.82 (2H, m), 6.8.about.6.72
(4H, m), 4.3 (2H, s), 3.65 (3H, s), 3.58 (2H, s), 3.0.about.2.9
(4H, m), 2.55.about.2.45 (4H, m), 1.44 (6H, s).
Example 8
(2-Methyl-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4--
yl]-ethyl}-phenoxy)-acetic acid
[0410] ##STR86##
[0411] To a solution of
[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-trip-
henyl-phosphonium chloride (2.5 mmol) in THF (10 mL) was added BuLi
(2 mmol) at 0.degree. C. the solution was stirred at 0.degree. C.
for 30 min and cooled to -78C. A solution of
(4-Formyl-phenoxy)-acetic acid tert-butyl ester (0.24 g, 1 mmol) in
THF (5 mL) was added, the reaction was allowed to warm to room
temperature after 1 hr, quenched with EtOH, evaporated,
chromatography on silica gel to give 0.5 g desired trans
olefin.
[0412] The olefin (0.5 g) and 10% Pd/c in EtOAc (10 mL), was
stirred under H2 at room temperature overnight. The mixture was
filtrated through celite and washed with ethyl acetate, evaporated.
The residue was dissolved in CH.sub.2Cl.sub.2 (5 mL), and TFA (0.3
mL) was added at 0.degree. C. the mixture was allowed to warm to
room temperature and evaporated. The residue was recrystallized
from EtOAc/Hexane to afford 0.28 g desired product. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.1 (2H, d, J=8.8 Hz), 7.7 (2H, d,
J=8.8 Hz), 7.04 (1H, d, J=1.2 Hz), 6.96.about.6.97 (1H, dd, J=8.4,
2 Hz), 6.67 (1H, d, J=8 Hz), 4.67 (2H, s), 2.94 (4H, s), 2.27 (3H,
s), 2.2 (3H, s).
Example 9A
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethanesulfinyl]-phenoxy}-acetic acid
[0413] ##STR87##
[0414] To a solution of Compound 100 (eq) in CH.sub.2Cl.sub.2 was
added MCPBA (1.2 eg) at room temperature, the resulting mixture was
stirred for 2 hrs, evaporated and chromatography on silica gel to
give desired compound as a white solid. .sup.1H NMR (400 MHz, DMSO)
.delta. 8.01 (2H, d, J=8.4 Hz), 7.88 (2H, d, J=8.4 Hz),
7.34.about.7.28 (2H, m), 6.97 (1H, d, J=9.2 Hz), 4.77 (2H, s), 4.42
(1H, d, J=13.6 Hz), 4.27 (1H, d, J=13.6 Hz), 2.14 (3H, s), 2.09
(3H, s).
Example 9B
{2-Methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylm-
ethanesulfonyl]-phenoxy}-acetic acid
[0415] ##STR88##
[0416] To a solution of Compound 100 (1 eq) in CH.sub.2Cl.sub.2 was
added MCPBA (3 eg) at room temperature, the resulting mixture was
stirred for 6 hrs, evaporated and chromatography on silica gel to
give desired compound as a white solid. .sup.1H NMR (400 MHz, DMSO)
.delta. 7.99 (2H, d, J=8.8 Hz), 7.89 (2H, d, J=8.4 Hz),
7.56.about.7.5 (2H, m), 7.03 (1H, d, J=8.4 Hz), 4.85 (2H, s), 4.83
(2H, s), 2.18 (3H, s), 2.16 (3H, s).
Example 10
Measurement of PPAR.gamma., .delta., and .alpha. Transactivation
Activity
[0417] Chimeric receptors were constructed in which the yeast
transcription factor GAL4 DNA binding domain was fused to the
ligand binding domain of either mouse PPAR.gamma., mouse PPAR
.delta. or mouse PPAR .alpha. in order to assess the ability of the
compounds of the present invention to activate gene expression in a
PPAR-dependent manner. The chimeric receptor expression plasmids
(GAL4-mPPAR.gamma., GAL4-mPPAR .delta. and GAL4-PPAR .alpha.) and
the reporter plasmid containing 5.times. GAL4 binding site
(pFR-Luc, obtained from Stratagene) were transfected into HEK293T
cells using the Lipofectamine 2000 reagent (Invitrogen), according
to the manufacturers instructions. Six hours after transfection,
the culture medium was renewed and the cells were incubated for 20
hours in presence of either 1) DMSO (vehicle), 2) a compound of the
invention or 3) a reference compound for comparison. Rosiglitazone
(obtained from WDF Pharma) was used as a reference compound for the
PPARy assay; GW501516 (prepared as described in Sznaidman et al.
Bioorg. Med. Chem. Lett. (2003) 13:1517-1521) was used as a
reference compound for the PPAR .delta. assay and
[0418] GW7647 (obtained from Sigma) was used as a reference
compound for the PPAR .alpha. assay. Luciferase activity was
measured as a reporter of gene expression. Luciferase activity on
the cell lysates using the Steady-Glo reagent was measured
according to the manufacturers instructions. TABLE-US-00001 TABLE 1
Results of the PPARs transactivation assay for selected compounds
from FIG. 1. Gene Activation Assay: EC.sub.50 (.ltoreq.10 .mu.M)
Compounds PPAR alpha PPAR delta PPAR gamma 100 - + ND 660 ND + ND
670 - + ND 480 + + - 440 - + - 320 - + ND 110 + + + 210 + + 10 360
- + ND 340 + + ND 640 - + ND 580 + + ND ND: no activity detected @
30 .mu.M
[0419] As is apparent from the test results above, the compounds of
the invention are excellent modulators of PPAR.
[0420] While embodiments of the invention have been illustrated and
described, it is not intended that these embodiments illustrate and
describe all possible forms of the invention. Rather, the words
used in the specification are words of description rather than
limitation, and it is understood that various changes may be made
without departing from the spirit and scope of the invention.
* * * * *