U.S. patent application number 10/692561 was filed with the patent office on 2005-04-14 for novel compounds, their preparation and use.
Invention is credited to Havranek, Miroslav, Jeppesen, Lone, Pettersson, Ingrid, Pihera, Pavel, Sauerberg, Per.
Application Number | 20050080115 10/692561 |
Document ID | / |
Family ID | 34426533 |
Filed Date | 2005-04-14 |
United States Patent
Application |
20050080115 |
Kind Code |
A1 |
Jeppesen, Lone ; et
al. |
April 14, 2005 |
Novel compounds, their preparation and use
Abstract
Novel compounds of the general formula (I), the use of these
compounds as pharmaceutical compositions, pharmaceutical
compositions comprising the compounds and methods of treatment
employing these compounds and compositions. The present compounds
may be useful in the treatment and/or prevention of conditions
mediated by Peroxisome Proliferator-Activated Receptors (PPAR), in
particular the PPAR.delta. suptype.
Inventors: |
Jeppesen, Lone; (Virum,
DK) ; Pettersson, Ingrid; (Frederiksberg, DK)
; Sauerberg, Per; (Farum, DK) ; Pihera, Pavel;
(Praha, CZ) ; Havranek, Miroslav; (Praha,
CZ) |
Correspondence
Address: |
NOVO NORDISK, INC.
PATENT DEPARTMENT
100 COLLEGE ROAD WEST
PRINCETON
NJ
08540
US
|
Family ID: |
34426533 |
Appl. No.: |
10/692561 |
Filed: |
October 24, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60423644 |
Nov 4, 2002 |
|
|
|
Current U.S.
Class: |
514/357 ;
514/408; 514/485; 514/522; 514/532; 546/335; 548/571; 558/410;
560/24 |
Current CPC
Class: |
C07D 307/38 20130101;
C07D 333/18 20130101; C07D 333/54 20130101; C07D 409/14 20130101;
A61P 3/04 20180101; A61P 3/08 20180101; A61P 3/10 20180101; C07C
323/20 20130101 |
Class at
Publication: |
514/357 ;
514/408; 514/485; 514/522; 514/532; 546/335; 548/571; 558/410;
560/024 |
International
Class: |
A61K 031/44; A61K
031/40; A61K 031/235; A61K 031/325 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 28, 2002 |
DK |
2002 01629 |
Claims
What is claimed is:
1. A compound of the general formula (I): 27wherein X.sub.1 is aryl
or heteroaryl each of which is optionally substituted with one or
more substituents selected from halogen, hydroxy, cyano, amino or
carboxy; or C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, C.sub.1-6-alkoxy, C.sub.3-6-cycloalkoxy, aryloxy,
aralkoxy, heteroaralkoxy, C.sub.1-6-alkylthio, arylthio,
C.sub.3-6-cycloalkylthio, C.sub.1-6-alkylcarbonyl, arylcarbonyl,
C.sub.1-6-alkylsulfonyl, arylsulfonyl, C.sub.1-6-alkylsulfonyloxy,
arylsulfonyloxy, C.sub.1-6-alkylamido, arylamido,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylamino,
C.sub.1-6-dialkylamino or C.sub.3-6-cycloalkylamino each of which
is optionally substituted with one or more halogens; and X.sub.2 is
arylene or heteroarylene each of which is optionally substituted
with one or more substituents selected from halogen, hydroxy,
cyano, amino or carboxy; or C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.1-6-alkoxy,
C.sub.3-6-cycloalkoxy, C.sub.1-6-alkylthio,
C.sub.3-6-cycloalkylthio, C.sub.1-6-alkylamino,
C.sub.1-6-dialkylamino or C.sub.3-6-cycloalkylamino each of which
is optionally substituted with one or more halogens; and X.sub.3 is
aryl or heteroaryl each of which is optionally substituted with one
or more substituents selected from halogen, hydroxy, cyano, amino
or carboxy; or C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, aralkyl, heteroaralkyl,
C.sub.1-6-alkoxy, C.sub.3-6-cycloalkoxy, aryloxy, aralkoxy,
heteroaralkoxy, C.sub.1-6-alkylthio, arylthio,
C.sub.3-6-cycloalkylthio, C.sub.1-6-alkylcarbonyl, arylcarbonyl,
C.sub.1-6-alkylsulfonyl, arylsulfonyl, C.sub.1-6-alkylsulfonyloxy,
arylsulfonyloxy, C.sub.1-6-alkylamido, arylamido,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylamino,
C.sub.1-6-dialkylamino or C.sub.3-6-cycloalkylamino each of which
is optionally substituted with one or more halogens; and Ar is
arylene which is optionally substituted with one or more
substituents selected from halogen, hydroxy or cyano; or
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,
C.sub.1-6-alkoxy, C.sub.3-6-cycloalkoxy, aryloxy, aralkoxy,
heteroaralkoxy, C.sub.1-6-alkylthio, arylthio or
C.sub.3-6-cycloalkylthio each of which is optionally substituted
with one or more halogens; and Y.sub.1 is O or S; and Y.sub.2 is O
or S; and Z is --(CH.sub.2).sub.n-- wherein n is 1, 2 or 3; and
R.sub.1 is hydrogen, halogen or a substituent selected from
C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, aralkyl, heteroaralkyl, C.sub.1-6-alkoxy,
C.sub.3-6-cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy,
C.sub.1-6-alkylthio, arylthio or C.sub.3-6-cycloalkylthio each of
which is optionally substituted with one or more halogens; and
R.sub.2 is hydrogen, C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, C.sub.4-6-alkenynyl or aryl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable
solvate, tautomeric form, stereoisomer, mixture of stereoisomers,
racemic mixture, or polymorphs thereof.
2. A compound according to claim 1, wherein X.sub.1 is aryl or
heteroaryl optionally substituted with one or more substituents
selected from halogen; or C.sub.1-6-alkyl, aryl, C.sub.1-6-alkoxy,
C.sub.1-6-alkylsulfonyl or C.sub.1-6-alkylsulfonyloxy each of which
is optionally substituted with one or more halogens.
3. A compound according to claim 2, wherein X.sub.1 is phenyl,
furyl, thienyl, benzothienyl or benzofuranyl optionally substituted
with one or more substituents selected from halogen; or
C.sub.1-6-alkyl, aryl, C.sub.1-6-alkoxy, C.sub.1-6-alkylsulfonyl or
C.sub.1-6-alkylsulfonyloxy each of which is optionally substituted
with one or more halogens.
4. A compound according to claim 3, wherein X.sub.1 is phenyl
optionally substituted with one or more substituents selected from
halogen, C.sub.1-6-alkyl, aryl or perhalomethyl.
5. A compound according to claim 4, wherein X.sub.1 is phenyl
optionally substituted with one or more substituents seleced from
phenyl or trifluoromethyl.
6. A compound according to claim 5, wherein X, is phenyl.
7. A compound according to claim 3, wherein X, is furyl, thienyl,
benzothienyl or benzofuranyl with one or more substituents seleced
from halogen, C.sub.1-6-alkyl, aryl or perhalomethyl.
8. A compound according to claim 7, wherein X.sub.1 is furyl
optionally substituted with one or more substituents seleced from
halogen, C.sub.1-6-alkyl, phenyl or trifluoromethyl.
9. A compound according to claim 7, wherein X.sub.1 is thienyl
optionally substituted with one or more substituents seleced from
halogen, C.sub.1-6-alkyl, phenyl or trifluoromethyl.
10. A compound according to claim 7, wherein X.sub.1 is
benzothienyl optionally substituted with one or more substituents
seleced from halogen, C.sub.1-6-alkyl, phenyl or
trifluoromethyl.
11. A compound according to claim 1, wherein X.sub.2 is arylene or
heteroarylene optionally substituted with one or more substituents
selected from halogen; or C.sub.1-6-alkyl or C.sub.1-6-alkoxy each
of which is optionally substituted with one or more halogens.
12. A compound according to claim 11, wherein X.sub.2 is phenylene
optionally substituted with one or more substituents selected from
halogen; or C.sub.1-6-alkyl or C.sub.1-6-alkoxy each of which is
optionally substituted with one or more halogens.
13. A compound according to claim 12, wherein X.sub.2 is phenylene
optionally substituted with one or more halogens.
14. A compound according to claim 13, wherein X.sub.2 is
phenylene.
15. A compound according to claim 11, wherein X.sub.2 is
benzofuranylene optionally substituted with one or more
substituents selected from halogen; or C.sub.1-6-alkyl or
C.sub.1-6-alkoxy each of which is optionally substituted with one
or more halogens.
16. A compound according to claim 15, wherein X.sub.2 is
benzofuranylene optionally substituted with C.sub.1-6-alkyl.
17. A compound according to claim 1, wherein X.sub.3 is aryl or
heteroaryl optionally substituted with one or more substituents
selected from halogen; or C.sub.1-6-alkyl, C.sub.1-6-alkoxy,
C.sub.1-6-alkylsulfonyl or C.sub.1-6-alkylsulfonyloxy each of which
is optionally substituted with one or more halogens.
18. A compound according to claim 17, wherein X.sub.3 is phenyl,
furyl, thienyl, benzothienyl or benzofuranyl optionally substituted
with one or more substituents selected from halogen; or
C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-alkylsulfonyl or
C.sub.1-6-alkylsulfonyloxy each of which is optionally substituted
with one or more halogens.
19. A compound according to claim 18, wherein X.sub.3 is phenyl
optionally substituted with one or more halogens.
20. A compound according to claim 18, wherein X.sub.3 is phenyl
optionally substituted with one or more substituents selected from
C.sub.1-6-alkyl or perhalomethyl.
21. A compound according to claim 18, wherein X.sub.3 is
phenyl.
22. A compound according to claim 18, wherein X.sub.3 is furyl,
thienyl, benzothienyl or benzofuranyl optionally substituted with
one or more substituents selected from halogen, C.sub.1-6-alkyl or
perhalomethyl.
23. A compound according to claim 22, wherein X.sub.3 is furyl
optionally substituted with one or more substituents selected from
halogen, C.sub.1-6-alkyl or trifluoromethyl.
24. A compound according to claim 22, wherein X.sub.3 is thienyl
optionally substituted with one or more substituents selected from
halogen, C.sub.1-6-alkyl or trifluoromethyl.
25. A compound according to claim 22, wherein X.sub.3 is
benzothienyl optionally substituted with one or more substituents
selected from halogen, C.sub.1-6-alkyl or trifluoromethyl.
26. A compound according to claim 22, wherein X.sub.3 is
benzofuranyl optionally substituted with one or more substituents
selected from halogen, C.sub.1-6-alkyl or trifluoromethyl.
27. A compound according to claim 1, wherein Ar is phenylene which
is optionally substituted with one or more substituents selected
from halogen, hydroxy or cyano; or C.sub.1-6-alkyl,
C.sub.3-6-cycloalkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, C.sub.1-6-alkoxy,
C.sub.3-6-cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy,
C.sub.1-6-alkylthio, arylthio or C.sub.3-6-cycloalkylthio each of
which is optionally substituted with one or more halogens.
28. A compound according to claim 27, wherein Ar is phenylene which
is optionally substituted with one or more substituents selected
from halogen; or C.sub.1-6-alkyl, C.sub.1-6-alkoxy, aryloxy or
aralkoxy each of which is optionally substituted with one or more
halogens.
29. A compound according to claim 28, wherein Ar is phenylene which
is optionally substituted with methyl.
30. A compound according to claim 29, wherein Ar is phenylene.
31. A compound according to claim 1, wherein Y.sub.1 is S.
32. A compound according to claim 1, wherein Y.sub.2 is O.
33. A compound according to claim 1, wherein n is 1.
34. A compound according to claim 1, wherein R.sub.1 is hydrogen or
a substituent selected from C.sub.1-6-alkyl, aralkyl,
C.sub.1-6-alkoxy, aryloxy, aralkoxy each of which is optionally
substituted with one or more halogens.
35. A compound according to claim 34, wherein R.sub.1 is hydrogen
or a substituent selected from C.sub.1-6-alkyl or C.sub.1-6alkoxy
each of which is optionally substituted with one or more
halogens.
36. A compound according to claim 35, wherein R.sub.1 is
hydrogen.
37. A compound according to claim 1, wherein R.sub.2 is
hydrogen.
38. A compound according to claim 1, wherein R.sub.2 is methyl or
ethyl.
39. A compound according to claim 1, which is selected from the
following: (E/Z)
{4-[3-Biphenyl-4-yl-3-(4-bromo-phenyl)-allylsulfanyl]-phenoxy}-acet-
ic acid, and (E/Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-
-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; or a
pharmaceutically acceptable salt, pharmaceutically acceptable
solvate, tautomeric form, stereoisomer, mixture of stereoisomers,
racemic mixture, or polymorphs thereof.
40. A compound according to claim 1, which is selected from the
following:
{4-[3-(4-Bromo-phenyl)-3-[1,1';4',1"]terphenyl-4"-yl-allylsulfanyl]-2-met-
hyl-phenoxy}-acetic acid;
(E/Z)-[2-Methyl-4-[3-[5-(5-methylthiophen-2-yl)b-
enzo[b]furan-2-yl]-3-(thiophen-2-yl)allylsulfanyl]phenoxy]acetic
acid;
(E/Z)-[4-[3-(Biphenyl-4-yl)-3-(furan-2-yl)allylsultanyl]-2-methylphenoxy]-
acetic acid;
(E/Z)-[4-[3-(Benzo[b]thiophen-3-yl)-3-(biphenyl-4-yl)allylsul-
fanyl]-2-methylphenoxy]acetic acid;
[4-[(3-Benzo[b]thiophen-2-yl)-3-(biphe-
nyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy]-acetic acid; and
(E/Z)-[4-[3-(4-Biphenylyi)-3-(5-methylthiophen-2-yl)allylsulfanyl]-2-meth-
ylphenoxy]acetic acid; or a pharmaceutically acceptable salt,
pharmaceutically acceptable solvate, tautomeric form, stereoisomer,
mixture of stereoisomers, racemic mixture, or polymorphs
thereof.
41. A compound according to claim 1, which is selected from the
following: (E)
{4-[3-Biphenyl-4-yl-3-(2-fluoro-phenyl)-allylsulfanyl]-phenoxy}-aceti-
c acid; (Z)
{4-[3-Biphenyl-4-yl-3-(2-fluoro-phenyl)-allylsulfanyl]-phenoxy-
}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(2-chloro-phenyl)-allylsulfanyl]--
phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(2-chloro-phenyl)-allylsul-
fanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(2-bromo-phenyl)-al-
lylsulfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(2-bromo-phen-
yl)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(2-iodo-
-phenyl)-allylsulfanyl]-phenoxy)-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(2-
-iodo-phenyl)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(2-methoxy-phenyl)-allysulfanyl]-phenoxy}-acetic
acid; (Z)
{4-[3-Biphenyl-4-yl-3-(2-methoxy-phenyl)-allylsulfanyl]-phenoxy-
}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(2-trifluoromethoxy-phenyl)-allyl-
sulfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(2-trifluorometh-
oxy-phenyl)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(2-methyl-phenyl)-allylsulfanyl]-phenoxy}-acetic
acid; (Z)
{4-[3-Biphenyl-4-yl-3-(2-methyl-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(2-trifluoromethyl-phenyl)-allylsu-
lfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(2-trifluoromethyl-
-phenyl)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(3-
-fluoro-phenyl)-allylsulfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(3-fluoro-phenyl)-allylsulfanyl]-phenoxy}-acetic
acid; (E)
{4-[3-Biphenyl-4-yl-3-(3-chloro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(3-chloro-phenyl)-allylsulfanyl]-p-
henoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(3-bromo-phenyl)-allylsulfa-
nyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(3-bromo-phenyl)-ally-
lsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(3-iodo-phenyl)-
-allylsulfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(3-iodo-ph-
enyl)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4[3-Biphenyl-4-yl-3-(3-met-
hoxy-phenyl)-allylsulfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(3-methoxy-phenyl)-allylsulfanyl]-phenoxy}-acetic
acid; (E)
{4-[3-Biphenyl-4-yl-3-(3-trifluoromethoxy-phenyl)-allylsulfanyl-
]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(3-trifluoromethoxy-phen-
yl)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-37(3-meth-
yl-phenyl)-allylsulfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(3-methyl-phenyl)-allylsulfanyl]-phenoxy}-acetic
acid; (E)
{4-[3-Biphenyl-4-yl-3-(3-trifluoromethyl-phenyl)-allylsulfanyl]-
-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(3-trifluoromethyl-phenyl-
)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(4-fluoro-
-phenyl)-allylsulfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(4-
-fluoro-phenyl)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(4-chloro-phenyl)-allylsulfanyl]-phenoxy}-acetic
acid; (Z)
{4-[3-Biphenyl-4-yl-3-(4-chloro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid; (E/Z)
{4-[3-Biphenyl-4-yl-3-(4-bromo-phenyl)-allylsulfanyl]--
phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(4-bromo-phenyl)-allylsulf-
anyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(4-bromo-phenyl)-all-
ylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(4-iodo-phenyl-
)-allylsulfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(4-iodo-p-
henyl)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(4-m-
ethoxy-phenyl)-allylsulfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(4-methoxy-phenyl)-allylsulfanyl]-phenoxy}-acetic
acid; (E)
{4-[3-Biphenyl-4-yl-3-(4-trifluoromethoxy-phenyl)-allylsulfanyl-
]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(4-trifluoromethoxy-phen-
yl)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-Biphenyl-4-yl-3-(4-meth-
yl-phenyl)-allylsulfanyl]-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(4-methyl-phenyl)-allylsulfanyl]-phenoxy}-acetic
acid; (E)
{4-[3-Biphenyl-4-ya-3-(4-trifluoromethyl-phenyl)-allylsulfanyl]-
-phenoxy}-acetic acid; (Z)
{4-[3-Biphenyl-4-yl-3-(4-trifluoromethyl-phenyl-
)-allylsulfanyl]-phenoxy}-acetic acid; (E)
{4-[3-(4-Fluoro-phenyl)-3-(2'-t-
rifluoromethyl-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic
acid; (Z)
{4-[3-(4-Fluoro-phenyl)-3-(2'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid; (E/Z)
{4-[3-(4-Fluoro-phenyl)--
3-(3'-trifluoromethyl-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acet-
ic acid; (E)
{4-[3-(4-Fluoro-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)--
allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Fluoro-phenyl)--
3-(3'-trifluoromethyl-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acet-
ic acid; (E)
{4-[3-(4-Fluoro-phenyl)-3-(4'-trifluoromethyl-biphenyl-4-yl)--
allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Fluoro-phenyl)--
3-(4'-trifluoromethyl-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acet-
ic acid; (E)
{4-[3-(4-Fluoro-phenyl)-3-(3'-chloro-biphenyl-4-yl)-allylsulf-
anyl]-2-methyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Fluoro-phenyl)-3-(3'-chl-
oro-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid;
(E)
{4-[3-(4-Fluoro-phenyl)-3-(4'-chloro-biphenyl-4-yl)-allylsulfanyl]-2-meth-
yl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Fluoro-phenyl)-3-(4'-chloro-biphenyl-
-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Fluoro-phenyl)-3-(3'-methoxy-biphenyl-4-yl)-allylsulfanyl]-2-met-
hyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Fluoro-phenyl)-3-(3'-methoxy-biphen-
yl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Fluoro-phenyl)-3-(4'-methoxy-biphenyl-4-yl)-allylsulfanyl]-2-met-
hyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Fluoro-phenyl)-3-(4'-methoxy-biphen-
yl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Chloro-phenyl)-3-(2'-trifluoromethyl-biphenyl-4-yl)-allylsulfany-
l]-2-methyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Chloro-phenyl)-3-(2'-triflu-
oromethyl-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic
acid; (E/Z)
{4-[3-(4-Chloro-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-allyls-
ulfanyl]-2-methyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Chloro-phenyl)-3-(3'--
trifluoromethyl-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic
acid; (Z)
{4-[3-(4-Chloro-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Chloro-phenyl)-3--
(4'-trifluoromethyl-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic
acid; (Z)
{4-[3-(4-Chloro-phenyl)-3-(4'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Chloro-phenyl)-3--
(3'-chloro-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic
acid; (Z)
{4-[3-(4-Chloro-phenyl)-3-(3'-chloro-biphenyl-4-yl)-allylsulfanyl]-2--
methyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Chloro-phenyl)-3-(4'-chloro-biph-
enyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Chloro-phenyl)-3-(4'-chloro-biphenyl-4-yl)-allylsulfanyl]-2-meth-
yl-phenoxy}-acetic acid; (E)
{4-[3-(4-Chloro-phenyl)-3-(3'-methoxy-bipheny-
l-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Chloro-phenyl)-3-(3'-methoxy-biphenyl-4-yl)-allylsulfanyl]-2-met-
hyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Chloro-phenyl)-3-(4'-methoxy-biphen-
yl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Chloro-phenyl)-3-(4'-methoxy-biphenyl-4-yl)-allylsulfanyl]-2-met-
hyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Bromo-phenyl)-3-(2'-trifluoromethyl-
-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Bromo-phenyl)-3-(2'-trifluoromethyl-biphenyl-4-yl)-allylsulfanyl-
]-2-methyl-phenoxy}-acetic acid; (E/Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-triflu-
oromethyl-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic
acid; (E)
{4-[3-(4-Bromo-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-allylsulfanyl-
]-2-methyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-trifluor-
omethyl-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic
acid; (E)
{4-[3-(4-Bromo-phenyl)-3-(4'-trifluoromethyl-biphenyl-4-yl)-allylsulfanyl-
]-2-methyl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Bromo-phenyl)-3-(4'-trifluor-
omethyl-biphenyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic
acid; (E)
{4-[3-(4-Bromo-phenyl)-3-(3'-chloro-biphenyl-4-yl)-allylsulfanyl]-2-methy-
l-phenoxy}-acetic acid; (Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-chloro-biphenyl-4-
-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Bromo-phenyl)-3-(4'-chloro-biphenyl-4-yl)-allylsulfanyl]-2-methy-
l-phenoxy}-acetic acid; (Z)
{4-[3-(4-Bromo-phenyl)-3-(4'-chloro-biphenyl-4-
-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Bromo-phenyl)-3-(3'-methoxy-biphenyl-4-yl)-allylsulfanyl]-2-meth-
yl-phenoxy}-acetic acid; (Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-methoxy-biphenyl-
-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; (E)
{4-[3-(4-Bromo-phenyl)-3-(4'-methoxy-biphenyl-4-yl)-allylsulfanyl]-2-meth-
yl-phenoxy}-acetic acid; and (Z)
{4-[3-(4-Bromo-phenyl)-3-(4'-methoxy-biph-
enyl-4-yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid; or a
pharmaceutically acceptable salt, pharmaceutically acceptable
solvate, tautomeric form, stereoisomer, mixture of stereoisomers,
racemic mixture, or polymorphs thereof.
42. A compound according to claim 1, which is a PPAR.delta.
agonist.
43. A compound according to claim 42, which is a selective
PPAR.delta. agonist.
44. A pharmaceutical composition comprising, as an active
ingredient, at least one compound according to claim 1, together
with one or more pharmaceutically acceptable carriers or
excipients.
45. A pharmaceutical composition according to claim 44 in unit
dosage form, comprising from about 0.05 mg to about 1000 mg,
preferably from about 0.1 to about 500 mg of and especially
preferred from about 0.5 mg to about 200 mg per day of compound
according to claim 1.
46. A pharmaceutical composition for the treatment and/or
prevention of conditions mediated by nuclear receptors, in
particular the Peroxisome Proliferator-Activated Receptors (PPAR),
the composition comprising a compound according to claim 1 together
with one or more pharmaceutically acceptable carriers or
excipients.
47. A pharmaceutical composition for the treatment and/or
prevention of type I diabetes, type II diabetes, impaired glucose
tolerance, insulin resistance or obesity comprising a compound
according to claim 1 together with one or more pharmaceutically
acceptable carriers or excipients.
48. A pharmaceutical composition according to any one of the claim
44 for oral, nasal, transdermal, pulmonal, or parenteral
administration.
49. A method for the treatment and/or prevention of conditions
mediated by nuclear receptors, in particular the Peroxisome
Proliferator-Activated Receptors (PPAR), the method comprising
administering to a subject in need thereof an effective amount of a
compound according to claim 1 or a pharmaceutical composition
comprising the same.
50. A method for the treatment and/or prevention of type I
diabetes, type II diabetes, impaired glucose tolerance, insulin
resistance or obesity, the method comprising administering to a
subject in need thereof an effective amount of a compound according
to claim 1 or of a pharmaceutical composition comprising the
same.
51. The method according to claim 49 wherein the effective amount
of the compound according to claim 1 is in the range of from about
0.05 mg to about 1000 mg, preferably from about 0.1 to about 500 mg
of and especially preferred from about 0.5 mg to about 200 mg per
day.
52. The method according to claim 50 wherein the effective amount
of the compound according to claim 1 is in the range of from about
0.05 mg to about 1000 mg, preferably from about 0.1 to about 500 mg
of and especially preferred from about 0.5 mg to about 200 mg per
day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. 119 of
Danish application no. PA 2002 01629 filed Oct. 28, 2002 and U.S.
application No. 60/423,644 filed Nov. 4, 2002, the contents of each
of which are fully incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to novel compounds, to the use
of these compounds as pharmaceutical compositions, to
pharmaceutical compositions comprising the compounds and to a
method of treatment employing these compounds and compositions.
More specifically, the compounds of the invention can be utilised
in the treatment and/or prevention of conditions mediated by the
Peroxisome Proliferator-Activated Receptors (PPAR), in particular
the PPAR.delta. subtype.
BACKGROUND OF THE INVENTION
[0003] Coronary artery disease (CAD) is the major cause of death in
Type 2 diabetic and metabolic syndrome patients (i.e. patients that
fall within the `deadly quartet` category of impaired glucose
tolerance, insulin resistance, hypertriglyceridaemia and/or
obesity).
[0004] The hypolipidaemic fibrates and antidiabetic
thiazolidinediones separately display moderately effective
triglyceride-lowering activities although they are neither potent
nor efficacious enough to be a single therapy of choice for the
dyslipidaemia often observed in Type 2 diabetic or metabolic
syndrome patients. The thiazolidinediones also potently lower
circulating glucose levels of Type 2 diabetic animal models and
humans. However, the fibrate class of compounds are without
beneficial effects on glycaemia. Studies on the molecular actions
of these compounds indicate that thiazolidinediones and fibrates
exert their action by activating distinct transcription factors of
the peroxisome proliferator activated receptor (PPAR) family,
resulting in increased and decreased expression of specific enzymes
and apolipoproteins respectively, both key-players in regulation of
plasma triglyceride content. Fibrates, on the one hand, are
PPAR.alpha. activators, acting primarily in the liver.
Thiazolidinediones, on the other hand, are high affinity ligands
for PPAR.gamma. acting primarily on adipose tissue.
[0005] Adipose tissue plays a central role in lipid homeostasis and
the maintenance of energy balance in vertebrates. Adipocytes store
energy in the form of triglycerides during periods of nutritional
affluence and release it in the form of free fatty acids at times
of nutritional deprivation. The development of white adipose tissue
is the result of a continuous differentiation process throughout
life. Much evidence points to the central role of PPAR.gamma.
activation in initiating and regulating this cell differentiation.
Several highly specialised proteins are induced during adipocyte
differentiation, most of them being involved in lipid storage and
metabolism. The exact link from activation of PPAR.gamma. to
changes in glucose metabolism, most notably a decrease in insulin
resistance in muscle, has not yet been clarified. A possible link
is via free fatty acids such that activation of PPAR.gamma. induces
Lipoprotein Lipase (LPL), Fatty Acid Transport Protein (FATP) and
Acyl-CoA Synthetase (ACS) in adipose tissue but not in muscle
tissue. This, in turn, reduces the concentration of free fatty
acids in plasma dramatically, and due to substrate competition at
the cellular level, skeletal muscle and other tissues with high
metabolic rates eventually switch from fatty acid oxidation to
glucose oxidation with decreased insulin resistance as a
consequence.
[0006] PPAR.alpha. is involved in stimulating P-oxidation of fatty
acids. In rodents, a PPAR.alpha.-mediated change in the expression
of genes involved in fatty acid metabolism lies at the basis of the
phenomenon of peroxisome proliferation, a pleiotropic cellular
response, mainly limited to liver and kidney and which can lead to
hepatocarcinogenesis in rodents. The phenomenon of peroxisome
proliferation is not seen in man. In addition to its role in
peroxisome proliferation in rodents, PPAR.alpha. is also involved
in the control of HDL cholesterol levels in rodents and humans.
This effect is, at least partially, based on a PPAR.alpha.-mediated
transcriptional regulation of the major HDL apolipoproteins, apo
A-I and apo A-II. The hypotriglyceridemic action of fibrates and
fatty acids also involves PPAR.alpha. and can be summarised as
follows: (I) an increased lipolysis and clearance of remnant
particles, due to changes in lipoprotein lipase and apo C-III
levels, (II) a stimulation of cellular fatty acid uptake and their
subsequent conversion to acyl-CoA derivatives by the induction of
fatty acid binding protein and acyl-CoA synthase, (III) an
induction of fatty acid .beta.-oxidation pathways, (IV) a reduction
in fatty acid and triglyceride synthesis, and finally (V) a
decrease in VLDL production. Hence, both enhanced catabolism of
triglyceride-rich particles as well as reduced secretion of VLDL
particles constitutes mechanisms that contribute to the
hypolipidemic effect of fibrates.
[0007] PPAR.delta. activation was initially reported not to be
involved in modulation of glucose or triglyceride levels. (Berger
et al., j. Biol. Chem., 1999, Vol 274, pp. 6718-6725). Later it has
been shown that PPAR.delta. activation leads to increased levels of
HDL cholesterol in dbldb mice (Leibowitz et al. FEBS letters 2000,
473, 333-336). Further, a PPAR.delta. agonist when dosed to
insulin-resistant middle-aged obese rhesus monkeys caused a
dramitic dose-dependent rise in serum HDL cholesterol while
lowering the levels of small dense LDL, fasting triglycerides and
fasting insulin (Oliver et al. PNAS 2001, 98, 5306-5311). The same
paper also showed that PPAR.delta. activation increased the reverse
cholesterol transporter ATP-binding cassette A1 and induced
apolipoprotein A1-specific cholesterol efflux. The involvement of
PPAR.delta. in fatty acid oxidation in muscles was further
substantiated in PPAR.alpha. knock-out mice. Muoio et al. (J. Biol.
Chem. 2002, 277, 26089-26097) showed that the high levels of
PPAR.delta. in skeletal muscle can compensate for deficiency in
PPAR(X. Taken together these observations suggest that PPAR.delta.
activation is useful in the treatment and prevention of
cardiovascular diseases and conditions including atherosclerosis,
hypertriglyceridemia, and mixed dyslipidaemia (WO 01/00603).
[0008] A number of PPAR.delta. compounds have been reported to be
useful in the treatment of hyperglycemia, hyperlipidemia and
hypercholesterolemia (WO 02/59098, WO 01/603, WO 01/25181, WO
02/14291, WO 01/79197, WO 99/4815, WO 97/28149, WO 98/27974, WO
97/28115, WO 97/27857, WO 97/28137, WO 97/27847).
[0009] Glucose lowering as a single approach does not overcome the
macrovascular complications associated with Type 2 diabetes and
metabolic syndrome. Novel treatments of Type 2 diabetes and
metabolic syndrome must therefore aim at lowering both the overt
hypertriglyceridaemia associated with these syndromes as well as
alleviation of hyperglycaemia.
[0010] This indicate that research for compounds displaying various
degree of PPAR.alpha., PPAR.gamma. and PPAR.delta. activation
should lead to the discovery of efficacious triglyceride and/or
cholesterol and/or glucose lowering drugs that have great potential
in the treatment of diseases such as type 2 diabetes, dyslipidemia,
syndrome X (including the metabolic syndrome, i.e. impaired glucose
tolerance, insulin resistance, hypertrigyceridaemia and/or
obesity), cardiovascular diseases (including atherosclerosis) and
hypercholesteremia.
[0011] In WO 97/48674, various antimicrobial diaryls has been
described as anti-infective agents. The invention comprises
compounds of the formula: 1
[0012] wherein L may be selected from the group consisting of N, CH
and C; G, E may independently be selected from i.a. phenyl,
substituted phenyl (the substituents being halogen, alkyl or
alkoxy), phenylC.sub.1-4-alkyl, substituted phenylC.sub.1-4-alkyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl and 3-thienyl; J may be
CH or O; X may be selected from the group consisting of is O, S,
NR, and C(O)NR; Ar may be aryl or substituted aryl (the
substituents being halogen, alkyl or alkoxy); W may be O or S; A
may be selected from the group consisting of i.a. NRR, amidino,
COOH; CHRCOOH, CH.dbd.CHR, CH.dbd.C(COOH).sub.2; m, n may
independently be 0-6; and q, p may independently be 0 or 1.
[0013] Definitions
[0014] In the structural formulas given herein and throughout the
present specification the following terms have the indicated
meaning:
[0015] The term "C.sub.1-6-alkyl" as used herein, alone or in
combination, represent a linear or branched, saturated hydrocarbon
chain having the indicated number of carbon atoms. Representative
examples include, but are not limited to methyl, ethyl, n-propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, hexyl, isohexyl and the like.
[0016] The term "C.sub.1-6-alkylcarbonyl as used herein, represents
a "C.sub.1-6-alkyl" group as defined above having the indicated
number of carbon atoms linked through a carbonyl group.
Representative examples include, but are not limited to,
methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl,
butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl,
tertbutylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl,
neopentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl,
isohexylcarbonyl and the like.
[0017] The term "C.sub.1-6-alkylsulfonyl" as used herein refers to
a monovalent substituent comprising a "C.sub.1-6-alkyl" group as
defined above linked through a sulfonyl group. Representative
examples include, but are not limited to, methylsulfonyl,
ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl,
n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,
tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl,
neopentylsulfonyl, tert-pentylsulfonyl, n-hexylsulfonyl,
isohexylsulfonyl and the like.
[0018] The term "C.sub.1-6-alkylsulfonyloxy" as used herein refers
to a monovalent substituent comprising a "C.sub.1-6-alkyl" group as
defined above linked through a sulfonyloxy group. Representative
examples include, but are not limited to, methylsulfonyloxy,
ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy,
n-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy,
tert-butylsulfonyloxy, n-pentylsulfonyloxy, isopentylsulfonyloxy,
neopentylsulfonyloxy, tert-pentylsulfonyloxy, n-hexylsulfonyloxy,
isohexylsulfonyloxy and the like.
[0019] The term "C.sub.1-6alkylamido" as used herein, refers to an
acyl group linked through an amino group; Representative examples
include, but are not limited to acetylamino, propionylamino,
butyrylamino, isobutyrylamino, pivaloylamino, valerylamino and the
like.
[0020] The term "C.sub.3-6-cycloalkyl" as used herein, alone or in
combination, represent a saturated monocyclic hydrocarbon group
having the indicated number of carbon atoms. Representative
examples include, but are not limited to cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and the like.
[0021] The term "C.sub.2-6-alkenyl" as used herein, represent an
olefinically unsaturated branched or straight hydrocarbon group
having from 2 to the specified number of carbon atoms and at least
one double bond. Representative examples include, but are not
limited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl,
1,3-butadienyl, 1-butenyl, hexenyl, pentenyl and the like.
[0022] The term "C.sub.2-6-alkynyl" as used herein, represent an
unsaturated branched or straight hydrocarbon group having from 2 to
the specified number of carbon atoms and at least one triple bond.
Representative examples include, but are not limited to,
1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,
2-pentynyl and the like.
[0023] The term "C.sub.4-6-alkenynyl" as used herein, represent an
unsaturated branched or straight hydrocarbon group having from 4 to
the specified number of carbon atoms and both at least one double
bond and at least one triple bond. Representative examples include,
but are not limited to, 1-penten-4-ynyl, 3-penten-1-ynyl,
1,3-hexadiene-5-ynyl and the like.
[0024] The term "C.sub.1-6-alkoxy" as used herein, alone or in
combination, refers to a straight or branched configuration linked
through an ether oxygen having its free valence bond from the ether
oxygen. Examples of linear alkoxy groups are methoxy, ethoxy,
propoxy, butoxy, pentoxy, hexoxy and the like. Examples of branched
alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy,
isohexyloxy and the like.
[0025] The term "C.sub.3-6-cycloalkoxy" as used herein, alone or in
combination, represent a saturated monocyclic hydrocarbon group
having the indicated number of carbon atoms linked through an ether
oxygen having its free valence bond from the ether oxygen. Examples
of cycloalkoxy groups are cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy, cyclohexyloxy and the like.
[0026] The term "C.sub.1-6-alkylthio" as used herein, alone or in
combination, refers to a straight or branched monovalent
substituent comprising a "C.sub.1-6-alkyl" group as defined above
linked through a divalent sulfur atom having its free valence bond
from the sulfur atom and having 1 to 6 carbon atoms. Representative
examples include, but are not limited to, methylthio, ethylthio,
propylthio, butylthio, pentylthio and the like.
[0027] The term "C.sub.3-6-cycloalkylthio" as used herein, alone or
in combination, represent a saturated monocyclic hydrocarbon group
having the indicated number of carbon atoms linked through a
divalent sulfur atom having its free valence bond from the sulfur
atom. Examples of cycloalkoxy groups are cyclopropylthio,
cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
[0028] The term "C.sub.1-6-alkylamino" as used herein, alone or in
combination, refers to a straight or branched monovalent
substituent comprising a "C.sub.1-6-alkyl" group as defined above
linked through amino having a free valence bond from the nitrogen
atom. Representative examples include, but are not limited to,
methylamino, ethylamino, propylamino, butylamino, pentylamino and
the like.
[0029] The term "C.sub.1-6-alkylaminocarbonyl" as used herein
refers to a monovalent substituent comprising a
C.sub.1-monoalkylamino group linked through a carbonyl group such
as e.g. methylaminocarbonyl, ethylaminocarbonyl,
n-propylaminocarbonyl, isopropylaminocarbonyl,
n-butylaminocarbonyl, sec-butylaminocarbonyl,
isobutylaminocarbonyl, tert-butylaminocarbonyl,
n-pentylaminocarbonyl, 2-methylbutylaminocarbony- l,
3-methylbutylaminocarbonyl, n-hexylaminocarbonyl,
4-methylpentylaminocarbonyl, neopentylaminocarbonyl,
n-hexylaminocarbonyl and 2-2-dimethylpropylaminocarbonyl and the
like.
[0030] The term "C.sub.3-6-cycloalkylamino" as used herein, alone
or in combination, represent a saturated monocyclic hydrocarbon
group having the indicated number of carbon atoms linked through
amino having a free valence bond from the nitrogen atom.
Representative examples include, but are not limited to,
cyclopropylamino, cyclobutylamino, cyclopentylamino,
cyclohexylamino and the like.
[0031] The term "C.sub.1-6-alkoxyC.sub.1-6-alkyl" as used herein,
alone or in combination, refers to a "C.sub.1-6-alkyl" group as
defined above whereto is attached a "C.sub.1-6-alkoxy" group as
defined above. Representative examples include, but are not limited
to, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the
like.
[0032] The term "aryl" as used herein refers to an aromatic
monocyclic or an aromatic fused bi- or tricyclic hydrocarbon group.
Representative examples include, but are not limited to, phenyl,
naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like.
[0033] The term "arylene" as used herein refers to divalent
aromatic monocyclic or a divalent aromatic fused bi- or tricyclic
hydrocarbon group. Representative examples include, but are not
limited to, phenylene, naphthylene and the like.
[0034] The term "arylcarbonyl" as used herein represents an "aryl"
group as defined above linked through a carbonyl group.
Representative examples include, but are not limited to,
phenylcarbonyl, naphthylcarbonyl, anthracenylcarbonyl,
phenanthrenylcarbonyl, azulenylcarbonyl and the like.
[0035] The term "arylsulfonyl" as used herein refers to an "aryl"
group as defined above linked through a sulfonyl group.
Representative examples include, but are not limited to,
phenylsulfonyl, naphthylsulfonyl, anthracenylsulfonyl,
phenanthrenylsulfonyl, azulenylsulfonyl, and the like.
[0036] The term "arylsulfonyloxy" as used herein refers to an
"aryl" group as defined above linked through a sulfonyloxy group.
Representative examples include, but are not limited to,
phenylsulfonyloxy, naphthylsulfonyloxy, anthracenylsulfonyloxy,
phenanthrenylsulfonyloxy, azulenylsulfonyloxy, and the like.
[0037] The term "arylamido" as used herein refers to an
arylcarbonyl group linked through an amino group. Representative
examples include, but are not limited to phenylcarbonylamino,
naphthylcarbonylamino, anthracenylcarbonylamino,
phenanthrenylcarbonylamino, azulenylcarbonylamino and the like.
[0038] The term "halogen" means fluorine, chlorine, bromine or
iodine.
[0039] The term "perhalomethyl" means trifluoromethyl,
trichloromethyl, tribromomethyl or triiodomethyl.
[0040] The term "perhalomethoxy" means trifluoromethoxy,
trichloromethoxy, tribromomethoxy or triiodomethoxy.
[0041] The term "C.sub.1-6-dialkylamino" as used herein refers to
an amino group wherein the two hydrogen atoms independently are
substituted with a straight or branched, saturated hydrocarbon
chain having the indicated number of carbon atoms. Representative
examples include, but are not limited to, dimethylamino,
N-ethyl-N-methylamino, diethylamino, dipropylamino,
N-(n-butyl)-N-methylamino, di(n-pentyl)amino and the like.
[0042] The term "acyl" as used herein refers to a monovalent
substituent comprising a "C.sub.1-6-alkyl" group as defined above
linked through a carbonyl group. Representative examples include,
but are not limited to, acetyl, propionyl, butyryl, isobutyryl,
pivaloyl, valeryl and the like.
[0043] The term "heteroaryl" as used herein, alone or in
combination, refers to a monovalent substituent comprising a 5-7
membered monocyclic aromatic system or a 8-10 membered bicyclic
aromatic system containing one or more heteroatoms selected from
nitrogen, oxygen and sulfur, e.g. furyl, thienyl, pyrrolyl,
imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl,
thiadiazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinnyl,
indolyl, benzimidazolyl, benzofuranyl, benzothienyl, pteridinyl and
purinyl and the like.
[0044] The term "heteroarylene" as used herein, alone or in
combination, refers to divalent 5-7 membered monocyclic aromatic
system or a 8-10 membered bicyclic aromatic system containing one
or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g.
furylene, thienylene, pyrrolylene, imidazolylene, pyrazolylene,
triazolylene, pyrazinylene, pyrimidinylene, pyridazinylene,
isothiazolylene, isoxazolylene, oxazolylene, oxadiazolylene,
thiadiazolylene, quinolylene, isoquinolylene, quinazolinylene,
quinoxalinnylene, indolylene, benzimidazolylene, benzofuranylene,
pteridinylene and purinylene and the like.
[0045] The term "heteroaryloxy" as used herein, alone or in
combination, refers to a heteroaryl as defined herein linked to an
oxygen atom having its free valence bond from the oxygen atom e.g.
pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy,
pyrazinyloxy, pyrimidinyloxy, pyridazinyloxy, isothiazolyloxy,
isoxazolyloxy, oxazolyloxy, oxadiazolyloxy, thiadiazolyloxy,
quinolinyloxy, isoquinolinyloxy, quinazolinyloxy, quinoxalinyloxy,
indolyloxy, benzimidazolyloxy, benzofuranyloxy, pteridinyloxy and
purinyloxy and the like.
[0046] The term "aralkyl" as used herein refers to a straight or
branched saturated carbon chain containing from 1 to 6 carbons
substituted with an aromatic carbohydride. Representative examples
include, but are not limited to, benzyl, phenethyl, 3-phenylpropyl,
1-naphthylmethyl, 2-(1-naphthyl)ethyl and the like.
[0047] The term "aryloxy" as used herein refers to phenoxy,
1-naphthyloxy, 2-naphthyloxy and the like.
[0048] The term "aralkoxy" as used herein refers to a
C.sub.1-6-alkoxy group substituted with an aromatic carbohydride,
such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy,
2-(1-naphtyl)ethoxy and the like.
[0049] The term "heteroaralkyl" as used herein refers to a straight
or branched saturated carbon chain containing from 1 to 6 carbons
substituted with a heteroaryl group; such as (2-furyl)methyl,
(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,
(2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like.
[0050] The term "heteroaralkoxy" as used herein refers to a
heteroarylalkyl as defined herein linked to an oxygen atom having
its free valence bond from the oxygen atom. Representative examples
include, but are not limited to, (2-furyl)methyloxy,
(3-furyl)methyloxy, (2-thienyl)methyloxy, (3-thienyl)methyloxy,
(2-pyridyl)methyloxy, 1-methyl-1-(2-pyrimidyl)ethyloxy and the
like.
[0051] The term "arylthio" as used herein, alone or in combination,
refers to an aryl group linked through a divalent sulfur atom
having its free valence bond from the sulfur atom, the aryl group
optionally being mono- or polysubstituted with C.sub.1-6-alkyl,
halogen, hydroxy or C.sub.1-6alkoxy. Representative examples
include, but are not limited to, phenylthio, (4-methylphenyl)-thio,
(2-chlorophenyl)thio and the like.
[0052] Certain of the above defined terms may occur more than once
in the structural formulae, and upon such occurrence each term
shall be defined independently of the other.
[0053] The term "optionally substituted" as used herein means that
the groups in question are either unsubstituted or substituted with
one or more of the substituents specified. When the groups in
question are substituted with more than one substituent the
substituents may be the same or different.
DESCRIPTION OF THE INVENTION
[0054] The present invention relates to compounds of the general
formula (I): 2
[0055] wherein X.sub.1 is aryl or heteroaryl each of which is
optionally substituted with one or more substituents selected
from
[0056] halogen, hydroxy, cyano, amino or carboxy; or
[0057] C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl,
C.sub.1-6-alkoxy, C.sub.3-6-cycloalkoxy, aryloxy, aralkoxy,
heteroaralkoxy, C.sub.1-6-alkylthio, arylthio,
C.sub.3-6-cycloalkylthio, C.sub.1-alkylcarbonyl, arylcarbonyl,
C.sub.1-6-alkylsulfonyl, arylsulfonyl, C.sub.1-6-alkylsulfonyloxy,
arylsulfonyloxy, C.sub.1-6-alkylamido, arylamido,
C.sub.1-6-alkylaminocarbonyl, C.sub.1-6-alkylamino,
C.sub.1-6-dialkylamino or C.sub.3-6-cycloalkylamino each of which
is optionally substituted with one or more halogens; and
[0058] X.sub.2 is arylene or heteroarylene each of which is
optionally substituted with one or more substituents selected
from
[0059] halogen, hydroxy, cyano, amino or carboxy; or
[0060] C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, C.sub.1-6-alkoxy, C.sub.3-6-cycloalkoxy,
C.sub.1-6-alkylthio, C.sub.3-6-cycloalkylthio,
C.sub.1-6-alkylamino, C.sub.1-6-dialkylamino or
C.sub.3-6-cycloalkylamino each of which is optionally substituted
with one or more halogens; and
[0061] X.sub.3 is aryl or heteroaryl each of which is optionally
substituted with one or more substituents selected from
[0062] halogen, hydroxy, cyano, amino or carboxy; or
[0063] C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, aralkyl, heteroaralkyl, C.sub.1-6-alkoxy,
C.sub.3-6-cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy,
C.sub.1-6-alkylthio, arylthio, C.sub.3-6-cycloalkylthio,
C.sub.1-6-alkylcarbonyl, arylcarbonyl, C.sub.1-alkylsulfonyl,
arylsulfonyl, C.sub.1-6-alkylsulfonyloxy, arylsulfonyloxy,
C.sub.1-6-alkylamido, arylamido, C.sub.1-6-alkylaminocarbonyl,
C.sub.1-6-alkylamino, C.sub.1-6-dialkylamino or
C.sub.3-6-cycloalkylamino each of which is optionally substituted
with one or more halogens; and
[0064] Ar is arylene which is optionally substituted with one or
more substituents selected from
[0065] halogen, hydroxy or cyano; or
[0066] C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,
C.sub.1-6-alkoxy, C.sub.3-6-cycloalkoxy, aryloxy, aralkoxy,
heteroaralkoxy, C.sub.1-6 alkylthio, arylthio or
C.sub.3-6-cycloalkylthio each of which is optionally substituted
with one or more halogens; and
[0067] Y.sub.1 is O or S; and
[0068] Y.sub.2 is O or S; and
[0069] Z is --(CH.sub.2).sub.n-- wherein n is 1, 2 or 3; and
[0070] R.sub.1 is hydrogen, halogen or a substituent selected
from
[0071] C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, aralkyl, heteroaralkyl, C.sub.1-6-alkoxy,
C.sub.3-6-cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy,
C.sub.1-6-alkylthio, arylthio or C.sub.3-4-cycloalkylthio each of
which is optionally substituted with one or more halogens; and
[0072] R.sub.2 is hydrogen, C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl,
C.sub.2-4-alkenyl, C.sub.2-6-alkynyl, C.sub.4-6-alkenynyl or aryl;
or
[0073] a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable solvate thereof, or any tautomeric
forms, stereoisomers, mixture of stereoisomers including a racemic
mixture, or polymorphs.
[0074] In one embodiment, the present invention is concerned with
compounds of formula (I) wherein X.sub.1 is aryl optionally
substituted with one or more substituents selected from
[0075] halogen; or
[0076] C.sub.1-6-alkyl, aryl, C.sub.1-6-alkoxy,
C.sub.1-6-alkylsulfonyl or C.sub.1-6-alkylsulfonyloxy each of which
is optionally substituted with one or more halogens.
[0077] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is aryl optionally
substituted with one or more substituents selected from
[0078] halogen; or
[0079] C.sub.1-6-alkyl or aryl optionally substituted with one or
more halogens.
[0080] In another embodiment, the present invention is concerned
with compounds of fomula (I) wherein X.sub.1 is aryl optionally
substituted with one or more halogens, phenyl or perhalomethyl.
[0081] In another embodiment, the present invention is concerned
with compounds of fomula (I) wherein X, is aryl.
[0082] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is phenyl optionally
substituted with one or more substituents selected from
[0083] halogen; or
[0084] C.sub.1-6-alkyl, aryl, C.sub.1-6-alkoxy,
C.sub.1-6-alkylsulfonyl or C.sub.1-6-alkylsulfonyloxy each of which
is optionally substituted with one or more halogens.
[0085] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is phenyl optionally
substituted with one or more substituents selected from
[0086] halogen; or
[0087] C.sub.1-6-alkyl or aryl optionally substituted with one or
more halogens.
[0088] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is phenyl optionally
substituted with one or more halogens.
[0089] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is phenyl optionally
substituted with one or more of phenyl.
[0090] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is phenyl optionally
substituted with one or more of perhalomethyl.
[0091] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is phenyl.
[0092] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is heteroaryl
optionally substituted with one or more substituents selected
from
[0093] halogen; or
[0094] C.sub.1-6-alkyl, aryl, C.sub.1-6-alkoxy,
C.sub.1-6-alkylsulfonyl or C.sub.1-6-alkylsulfonyloxy each of which
is optionally substituted with one or more halogens.
[0095] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is heteroaryl
optionally substituted with one or more substituents selected
from
[0096] halogen; or
[0097] C.sub.1-6-alkyl or aryl optionally substituted with one or
more halogens.
[0098] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is heteroaryl
optionally substituted with one or more halogens.
[0099] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is heteroaryl
optionally substituted with one or more of C.sub.1-6-alkyl or
perhalomethyl.
[0100] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is heteroaryl.
[0101] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is furyl, thienyl,
benzothienyl or benzofuranyl optionally substituted with one or
more halogens.
[0102] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.1 is furyl, thienyl,
benzothienyl or benzofuranyl optionally substituted with one or
more of C.sub.1-6-alkyl.
[0103] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is arylene optionally
substituted with one or more substituents selected from
[0104] halogen; or
[0105] C.sub.1-6-alkyl or C.sub.1-6-alkoxy each of which is
optionally substituted with one or more halogens.
[0106] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is arylene optionally
substituted with one or more halogens.
[0107] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is arylene optionally
substituted with one or more of C.sub.1-6-alkyl.
[0108] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is arylene.
[0109] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is phenylene
optionally substituted with one or more substituents selected
from
[0110] halogen; or
[0111] C.sub.1-6-alkyl or C.sub.1-6-alkoxy each of which is
optionally substituted with one or more halogens.
[0112] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is phenylene
optionally substituted with one or more halogens.
[0113] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is phenylene
optionally substituted with one or more of C.sub.1-6-alkyl.
[0114] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is phenylene.
[0115] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is heteroarylene
optionally substituted with one or more substituents selected
from
[0116] halogen; or
[0117] C.sub.1-6-alkyl or C.sub.1-6-alkoxy each of which is
optionally substituted with one or more halogens.
[0118] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is heteroarylene
optionally substituted with one or more halogens.
[0119] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is heteroarylene.
[0120] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.2 is
benzofuranylene.
[0121] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is aryl optionally
substituted with one or more substituents selected from
[0122] halogen; or
[0123] C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-alkylsulfonyl
or C.sub.1-6-alkylsulfonyloxy each of which is optionally
substituted with one or more halogens.
[0124] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is aryl optionally
substituted with one or more substituents selected from
[0125] halogen; or
[0126] C.sub.1-6-alkyl optionally substituted with one or more
halogens.
[0127] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is aryl.
[0128] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is phenyl optionally
substituted with one or more substituents selected from
[0129] halogen; or
[0130] C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-alkylsulfonyl
or C.sub.1-6-alkylsulfonyloxy each of which is optionally
substituted with one or more halogens.
[0131] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is phenyl optionally
substituted with one or more substituents selected from
[0132] halogen; or
[0133] C.sub.1-6-alkyl optionally substituted with one or more
halogens.
[0134] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is phenyl optionally
substituted with one or more halogens.
[0135] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is phenyl.
[0136] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is heteroaryl
optionally substituted with one or more substituents selected
from
[0137] halogen; or
[0138] C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-alkylsulfonyl
or C.sub.1-6-alkylsulfonyloxy each of which is optionally
substituted with one or more halogens.
[0139] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is heteroaryl
optionally substituted with one or more substituents selected
from
[0140] halogen; or
[0141] C.sub.1-6-alkyl optionally substituted with one or more
halogens.
[0142] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is heteroaryl
optionally substituted with one or more halogens.
[0143] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is heteroaryl
optionally substituted with one or more of C.sub.1-6-alkyl.
[0144] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is heteroaryl.
[0145] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is furyl, thienyl,
benzothienyl or benzofuranyl optionally substituted with one or
more halogens.
[0146] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is furyl, thienyl,
benzothienyl or benzofuranyl optionally substituted with one or
more of C.sub.1-6-alkyl.
[0147] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein X.sub.3 is furyl, thienyl,
benzothienyl or benzofuranyl.
[0148] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Ar is phenylene which is
optionally substituted with one or more substituents selected
from
[0149] halogen, hydroxy or cyano; or
[0150] C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,
C.sub.1-6-alkoxy, C.sub.3-6-cycloalkoxy, aryloxy, aralkoxy,
heteroaralkoxy, C.sub.1-6-alkylthio, arylthio or
C.sub.3-6-cycloalkylthio each of which is optionally substituted
with one or more halogens.
[0151] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Ar is phenylene which is
optionally substituted with one or more substituents selected
from
[0152] halogen; or
[0153] C.sub.1-6-alkyl, aryl, C.sub.1-6-alkoxy, aryloxy or aralkoxy
each of which is optionally substituted with one or more
halogens.
[0154] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Ar is phenylene which is
optionally substituted with one or more halogens.
[0155] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Ar is phenylene which is
optionally substituted with one or more C.sub.1-6-alkyl optionally
substituted with one or more halogens.
[0156] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Ar is phenylene which is
optionally substituted with one or more C.sub.1-6-alkoxy optionally
substituted with one or more halogens.
[0157] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Ar is phenylene which is
optionally substituted with one or more aryl optionally substituted
with one or more halogens.
[0158] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Ar is phenylene which is
optionally substituted with methyl.
[0159] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Ar is phenylene which is
optionally substituted with metoxy.
[0160] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Ar is phenylene which is
optionally substituted with one or more of phenyl.
[0161] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Ar is phenylene.
[0162] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Y.sub.1 is S.
[0163] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Y.sub.1 is O.
[0164] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Y.sub.2 is O.
[0165] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein Y.sub.2 is S.
[0166] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein n is 1.
[0167] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein R.sub.1 is hydrogen or a
substituent selected from
[0168] C.sub.1-6-alkyl, aralkyl, C.sub.1-6-alkoxy, aryloxy,
aralkoxy each of which is optionally substituted with one or more
halogens.
[0169] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein R.sub.1 is hydrogen or a
substituent selected from
[0170] C.sub.1-6-alkyl, C.sub.1-6-alkoxy each of which is
optionally substituted with one or more halogens.
[0171] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein R.sub.1 is hydrogen.
[0172] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein R.sub.1 is methoxy or
ethoxy.
[0173] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein R.sub.2 is hydrogen.
[0174] In another embodiment, the present invention is concerned
with compounds of formula (I) wherein R.sub.2 is methyl or
ethyl.
[0175] In another embodiment, the present invention is concerned
with compounds of formula I wherein alkyl is methyl or ethyl.
[0176] In another embodiment, the present invention is concerned
with compounds of formula I wherein alkenyl is vinyl or
1-propenyl.
[0177] In another embodiment, the present invention is concerned
with compounds of formula I wherein alkynyl is 1-propynyl.
[0178] In another embodiment, the present invention is concerned
with compounds of formula I wherein alkenynyl is
1-pentene-4-yne.
[0179] In another embodiment, the present invention is concerned
with compounds of formula I wherein alkoxy is methoxy, ethoxy,
isopropoxy or cyclopropoxy.
[0180] In another embodiment, the present invention is concerned
with compounds of formula I wherein aryl is phenyl.
[0181] In another embodiment, the present invention is concerned
with compounds of formula I wherein arylene is phenylene.
[0182] In another embodiment, the present invention is concerned
with compounds of formula I wherein halogen is bromine, fluorine or
chlorine.
[0183] In another embodiment, the present invention is concerned
with compounds of formula I wherein perhalomethyl is
trifluoromethyl.
[0184] In another embodiment, the present invention is concerned
with compounds of formula I wherein perhalomethoxy is
trifluoromethoxy, In another embodiment, the present invention is
concerned with compounds of formula I wherein heteroaryl is furyl
or thienyl.
[0185] In another embodiment, the present invention is concerned
with compounds of formula I wherein aralkyl is benzyl.
[0186] In another embodiment, the present invention is concerned
with compounds of formula I wherein aryloxy is phenoxy.
[0187] In another embodiment, the present invention is concerned
with compounds of formula I wherein aralkoxy is benzyloxy.
[0188] In another embodiment, the present invention is concerned
with compounds of formula I wherein the substituents R.sub.1 and
X.sub.3 are arranged in a trans-configuration.
[0189] In another embodiment, the present invention is concerned
with compounds of formula I wherein the substituents R.sub.1 and
X.sub.3 are arranged in a cis-configuration.
[0190] In another embodiment, the present invention is concerned
with compounds of formula I which are PPAR.delta. agonists.
[0191] In another embodiment, the present invention is concerned
with compounds of formula I which are selective PPAR.delta.
agonists.
[0192] Examples of specific compounds of the invention are:
[0193] (E/Z)
{4-[3-Biphenyl-4-yl-3-(4-bromo-phenyl)-allylsulfanyl]-phenoxy-
}-acetic acid,
[0194] (E/Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-a-
llylsulfanyl]-2-methyl-phenoxy}-acetic acid; or
[0195] a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable solvate thereof, or any tautomeric
forms, stereoisomers, mixture of stereoisomers including a racemic
mixture, or polymorphs.
[0196] Other examples of specific compounds of the invention
are:
[0197]
{4-[3-(4-Bromo-phenyl)-3-[1,1';4',1"]terphenyl-4"-yl-allylsulfanyl]-
-2-methyl-phenoxy}-acetic acid,
[0198]
(E/Z)-[2-Methyl-4-[3-[5-(5-methylthiophen-2-yl)benzo[b]furan-2-yl]--
3-(thiophen-2-yl)allyl-sulfanyl]phenoxy]acetic acid,
[0199]
(E/Z)-[4-[3-(Biphenyl-4-yl)-3-(furan-2-yl)allylsulfanyl]-2-methylph-
enoxy]acetic acid,
[0200]
(E/Z)-[4-[3-(Benzo[b]thiophen-3-yl)-3-(biphenyl-4-yl)allylsulfanyl]-
-2-methylphenoxy]acetic acid,
[0201]
[4-[(3-Benzo[b]thiophen-2-yl)-3-(biphenyl-4-yl)-allylsulfanyl]-2-me-
thyl-phenoxy]-acetic acid,
[0202]
(E/Z)-[4-[3-(4-Biphenylyl)-3-(5-methylthiophen-2-yl)allylsulfanyl]--
2-methylphenoxy]acetic acid,
[0203] or a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable solvate thereof, or any tautomeric
forms, stereoisomers, mixture of stereoisomers including a racemic
mixture, or polymorphs.
[0204] Other examples of specific compounds of the invention
are:
[0205] (E)
{4-[3-Biphenyl-4-yl-3-(2-fluoro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0206] (Z)
{4-[3-Biphenyl-4-yl-3-(2-fluoro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0207] (E)
{4-[3-Biphenyl-4-yl-3-(2-chloro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0208] (Z)
{4-[3-Biphenyl-4-yl-3-(2-chloro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0209] (E)
{4-[3-Biphenyl-4-yl-3-(2-bromo-phenyl)-allylsulfanyl]-phenoxy}--
acetic acid;
[0210] (Z)
{4-[3-Biphenyl-4-yl-3-(2-bromo-phenyl)-allylsulfanyl]-phenoxy}--
acetic acid;
[0211] (E)
{4-[3-Biphenyl-4-yl-3-(2-iodo-phenyl)-allylsulfanyl]-phenoxy}-a-
cetic acid;
[0212] (Z)
{4-[3-Biphenyl-4-yl-3-(2-iodo-phenyl)-allylsulfanyl]-phenoxy}-a-
cetic acid;
[0213] (E)
{4-[3-Biphenyl-4-yl-3-(2-methoxy-phenyl)-allylsulfanyl]-phenoxy-
}-acetic acid;
[0214] (Z)
{4-[3-Biphenyl-4-yl-3-(2-methoxy-phenyl)-allylsulfanyl]-phenoxy-
}-acetic acid;
[0215] (E)
{4-[3-Biphenyl-4-yl-3-(2-trifluoromethoxy-phenyl)-allylsulfanyl-
]-phenoxy}-acetic acid;
[0216] (Z)
{4-[3-Biphenyl-4-yl-3-(2-trifluoromethoxy-phenyl)-allylsulfanyl-
]-phenoxy}-acetic acid;
[0217] (E)
{4-[3-Biphenyl-4-yl-3-(2-methyl-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0218] (Z)
{4-[3-Biphenyl-4-yl-3-(2-methyl-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0219] (E)
{4-[3-Biphenyl-4-yl-3-(2-trifluoromethyl-phenyl)-allylsulfanyl]-
-phenoxy}-acetic acid;
[0220] (Z)
{4-[3-Biphenyl-4-ya-3-(2-trifluoromethyl-phenyl)-allylsulfanyl]-
-phenoxy}-acetic acid;
[0221] (E)
{4-[3-Biphenyl-4-yl-3-(3-fluoro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0222] (Z)
{4-[3-Biphenyl-4-yl-3-(3-fluoro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0223] (E)
{4-[3-Biphenyl-4-yl-3-(3-chloro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0224] (Z)
{4-[3-Biphenyl-4-yl-3-(3-chloro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0225] (E)
{4-[3-Biphenyl-4-yl-3-(3-bromo-phenyl)-allylsulfanyl]-phenoxy}--
acetic acid;
[0226] (Z)
{4-[3-Biphenyl-4-yl-3-(3-bromo-phenyl)-allylsulfanyl]-phenoxy}--
acetic acid;
[0227] (E)
{4-[3-Biphenyl-4-yl-3-(3-iodo-phenyl)-allylsulfanyl]-phenoxy}-a-
cetic acid;
[0228] (Z)
{4-[3-Biphenyl-4-yl-3-(3-iodo-phenyl)-allylsulfanyl]-phenoxy}-a-
cetic acid;
[0229] (E)
{4-[3-Biphenyl-4-yl-3-(3-methoxy-phenyl)-allylsulfanyl]-phenoxy-
}-acetic acid;
[0230] (Z)
{4-[3-Biphenyl-4-yl-3-(3-methoxy-phenyl)-allylsulfanyl]-phenoxy-
}-acetic acid;
[0231] (E)
{4-[3-Biphenyl-4-ya-3-(3-trifluoromethoxy-phenyl)-allylsulfanyl-
]-phenoxy}-acetic acid;
[0232] (Z)
{4-[3-Biphenyl-4-yl-3-(3-trifluoromethoxy-phenyl)-allylsulfanyl-
]-phenoxy}-acetic acid;
[0233] (E)
{4-[3-Biphenyl-4-yl-3-(3-methyl-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0234] (Z)
{4-[3-Biphenyl-4-yl-3-(3-methyl-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0235] (E)
{4-[3-Biphenyl-4-yl-3-(3-trifluoromethyl-phenyl)-allylsulfanyl]-
-phenoxy}-acetic acid;
[0236] (Z)
{4-[3-Biphenyl-4-yl-3-(3-trifluoromethyl-phenyl)-allylsulfanyl]-
-phenoxy}-acetic acid;
[0237] (E)
{4-[3-Biphenyl-4-yl-3-(4-fluoro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0238] (Z)
{4-[3-Biphenyl-4-yl-3-(4-fluoro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0239] (E)
{4-[3-Biphenyl-4-yl-3-(4-chloro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0240] (Z)
{4-[3-Biphenyl-4-yl-3-(4-chloro-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0241] (E/Z)
{4-[3-Biphenyl-4-yl-3-(4-bromo-phenyl)-allylsulfanyl]-phenoxy-
}-acetic acid;
[0242] (E)
{4-[3-Biphenyl-4-yl-3-(4-bromo-phenyl)-allylsulfanyl]-phenoxy}--
acetic acid;
[0243] (Z)
{4-[3-Biphenyl-4-yl-3-(4-bromo-phenyl)-allylsulfanyl]-phenoxy}--
acetic acid;
[0244] (E)
{4-[3-Biphenyl-4-yl-3-(4-iodo-phenyl)-allylsulfanyl]-phenoxy}-a-
cetic acid;
[0245] (Z)
{4-[3-Biphenyl-4-yl-3-(4-iodo-phenyl)-allylsulfanyl]-phenoxy}-a-
cetic acid;
[0246] (E)
{4-[3-Biphenyl-4-yl-3-(4-methoxy-phenyl)-allylsulfanyl]-phenoxy-
}-acetic acid;
[0247] (Z)
{4-[3-Biphenyl-4-yl-3-(4-methoxy-phenyl)-allylsulfanyl]-phenoxy-
}-acetic acid;
[0248] (E)
{4-[3-Biphenyl-4-yl-3-(4-trifluoromethoxy-phenyl)-allylsulfanyl-
]-phenoxy}-acetic acid;
[0249] (Z)
{4-[3-Biphenyl-4-yl-3-(4-trifluoromethoxy-phenyl)-allylsulfanyl-
)-phenoxy}-acetic acid;
[0250] (E)
{4-[3-Biphenyl-4-yl-3-(4-methyl-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0251] (Z)
{4-[3-Biphenyl-4-yl-3-(4-methyl-phenyl)-allylsulfanyl]-phenoxy}-
-acetic acid;
[0252] (E)
{4-[3-Biphenyl-4-ya-3-(4-trifluoromethyl-phenyl)-allylsulfanyl]-
-phenoxy}-acetic acid;
[0253] (Z)
{4-[3-Biphenyl-4-yl-3-(4-trifluoromethyl-phenyl)-allylsulfanyl]-
-phenoxy}-acetic acid;
[0254] (E)
{4-[3-(4-Fluoro-phenyl)-3-(2'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0255] (Z)
{4-[3-(4-Fluoro-phenyl)-3-(2'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0256] (E/Z)
{4-[3-(4-Fluoro-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)--
allylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0257] (E)
{4-[3-(4-Fluoro-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0258] (Z)
{4-[3-(4-Fluoro-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0259] (E)
{4-[3-(4-Fluoro-phenyl)-3-(4'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0260] (Z)
{4-[3-(4-Fluoro-phenyl)-3-(4'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0261] (E)
{4-[3-(4-Fluoro-phenyl)-3-(3'-chloro-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0262] (Z)
{4-[3-(4-Fluoro-phenyl)-3-(3'-chloro-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0263] (E)
{4-[3-(4-Fluoro-phenyl)-3-(4'-chloro-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0264] (Z)
{4-[3-(4-Fluoro-phenyl)-3-(4'-chloro-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0265] (E)
{4-[3-(4-Fluoro-phenyl)-3-(3'-methoxy-biphenyl-4-yl)-allylsulfa-
nyl]-2-methyl-phenoxy}-acetic acid;
[0266] (Z)
{4-[3-(4-Fluoro-phenyl)-3-(3'-methoxy-biphenyl-4-yl)-allylsulfa-
nyl]-2-methyl-phenoxy}-acetic acid;
[0267] (E)
{4-[3-(4-Fluoro-phenyl)-3-(4'-methoxy-biphenyl-4-yl)-allylsulfa-
nyl]-2-methyl-phenoxy}-acetic acid;
[0268] (Z)
{4-[3-(4-Fluoro-phenyl)-3-(4'-methoxy-biphenyl-4-yl)-allylsulfa-
nyl]-2-methyl-phenoxy}-acetic acid;
[0269] (E)
{4-[3-(4-Chloro-phenyl)-3-(2'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0270] (Z)
{4-[3-(4-Chloro-phenyl)-3-(2'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0271] (E/Z)
{4-[3-(4-Chloro-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)--
allylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0272] (E)
{4-[3-(4-Chloro-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0273] (Z)
{4-[3-(4-Chloro-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0274] (E)
{4-[3-(4-Chloro-phenyl)-3-(4'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0275] (Z)
{4-[3-(4-Chloro-phenyl)-3-(4'-trifluoromethyl-biphenyl-4-yl)-al-
lylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0276] (E)
{4-[3-(4-Chloro-phenyl)-3-(3'-chloro-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0277] (Z)
{4-[3-(4-Chloro-phenyl)-3-(3'-chloro-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0278] (E)
{4-[3-(4-Chloro-phenyl)-3-(4'-chloro-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0279] (Z)
{4-[3-(4-Chloro-phenyl)-3-(4'-chloro-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0280] (E)
{4-[3-(4-Chloro-phenyl)-3-(3'-methoxy-biphenyl-4-yl)-allylsulfa-
nyl]-2-methyl-phenoxy}-acetic acid;
[0281] (Z)
{4-[3-(4-Chloro-phenyl)-3-(3'-methoxy-biphenyl-4-yl)-allylsulfa-
nyl]-2-methyl-phenoxy}-acetic acid;
[0282] (E)
{4-[3-(4-Chloro-phenyl)-3-(4'-methoxy-biphenyl-4-yl)-allylsulfa-
nyl]-2-methyl-phenoxy}-acetic acid;
[0283] (Z)
{4-[3-(4-Chloro-phenyl)-3-(4'-methoxy-biphenyl-4-yl)-allylsulfa-
nyl]-2-methyl-phenoxy}-acetic acid;
[0284] (E)
{4-[3-(4-Bromo-phenyl)-3-(2'-trifluoromethyl-biphenyl-4-yl)-all-
ylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0285] (Z)
{4-[3-(4-Bromo-phenyl)-3-(2'-trifluoromethyl-biphenyl-4-yl)-all-
ylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0286] (E/Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-a-
llylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0287] (E)
{4-[3-(4-Bromo-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-all-
ylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0288] (Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-all-
ylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0289] (E)
{4-[3-(4-Bromo-phenyl)-3-(4'-trifluoromethyl-biphenyl-4-yl)-all-
ylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0290] (Z)
{4-[3-(4-Bromo-phenyl)-3-(4'-trifluoromethyl-biphenyl-4-yl)-all-
ylsulfanyl]-2-methyl-phenoxy}-acetic acid;
[0291] (E)
{4-[3-(4-Bromo-phenyl)-3-(3'-chloro-biphenyl-4-yl)-allylsulfany-
l]-2-methyl-phenoxy}-acetic acid;
[0292] (Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-chloro-biphenyl-4-yl)-allylsulfany-
l]-2-methyl-phenoxy}-acetic acid;
[0293] (E)
{4-[3-(4-Bromo-phenyl)-3-(4'-chloro-biphenyl-4-yl)-allylsulfany-
l]-2-methyl-phenoxy}-acetic acid;
[0294] (Z)
{4-[3-(4-Bromo-phenyl)-3-(4'-chloro-biphenyl-4-yl)-allylsulfany-
l]-2-methyl-phenoxy}-acetic acid;
[0295] (E)
{4-[3-(4-Bromo-phenyl)-3-(3'-methoxy-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0296] (Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-methoxy-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0297] (E)
{4-[3-(4-Bromo-phenyl)-3-(4'-methoxy-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid;
[0298] (Z)
{4-[3-(4-Bromo-phenyl)-3-(4'-methoxy-biphenyl-4-yl)-allylsulfan-
yl]-2-methyl-phenoxy}-acetic acid; or
[0299] a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable solvate thereof, or any tautomeric
forms, stereoisomers, mixture of stereoisomers including a racemic
mixture, or polymorphs.
[0300] The present invention also encompasses pharmaceutically
acceptable salts of the present compounds. Such salts include
pharmaceutically acceptable acid addition salts, pharmaceutically
acceptable base addition salts, pharmaceutically acceptable metal
salts, ammonium and alkylated ammonium salts. Acid addition salts
include salts of inorganic acids as well as organic acids.
Representative examples of suitable inorganic acids include
hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric
acids and the like. Representative examples of suitable organic
acids include formic, acetic, trichloroacetic, trifluoroacetic,
propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic,
maleic, malic, malonic, mandelic, oxalic, picric, pyruvic,
salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric,
ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,
gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,
p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids,
sulphates, nitrates, phosphates, perchlorates, borates, acetates,
benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarates
and the like. Further examples of pharmaceutically acceptable
inorganic or organic acid addition salts include the
pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977,
66, 2, which is incorporated herein by reference. Examples of metal
salts include lithium, sodium, potassium, magnesium, zinc, calcium
salts and the like. Examples of amines and organic amines include
ammonium, methylamine, dimethylamine, trimethylamine, ethylamine,
diethylamine, propylamine, butylamine, tetramethylamine,
ethanolamine, diethanolamine, triethanolamine, meglumine,
ethylenediamine, choline, N,N'-dibenzylethylenediamine,
N-benzylphenylethylamine, N-methyl-D-glucamine, guanidine and the
like. Examples of cationic amino acids include lysine, arginine,
histidine and the like.
[0301] The pharmaceutically acceptable salts are prepared by
reacting the compound of formula I with 1 to 4 equivalents of a
base such as sodium hydroxide, sodium methoxide, sodium hydride,
potassium t-butoxide, calcium hydroxide, magnesium hydroxide and
the like, in solvents like ether, THF, methanol, t-butanol,
dioxane, isopropanol, ethanol etc. Mixture of solvents may be used.
Organic bases like lysine, arginine, diethanolamine, choline,
guandine and their derivatives etc. may also be used.
Alternatively, acid addition salts wherever applicable are prepared
by treatment with acids such as hydrochloric acid, hydrobromic
acid, nitric acid, sulfuric acid, phosphoric acid,
p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric
acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic
acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic
acid, tartaric acid and the like in solvents like ethyl acetate,
ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may
also be used.
[0302] The stereoisomers of the compounds forming part of this
invention may be prepared by using reactants in their single
enantiomeric form in the process wherever possible or by conducting
the reaction in the presence of reagents or catalysts in their
single enantiomer form or by resolving the mixture of stereoisomers
by conventional methods. Some of the preferred methods include use
of microbial resolution, enzymatic resolution, resolving the
diastereomeric salts formed with chiral acids such as mandelic
acid, camphorsulfonic acid, tartaric acid, lactic acid, and the
like wherever applicable or chiral bases such as brucine, (R)- or
(S)-phenylethylamine, cinchona alkaloids and their derivatives and
the like. Commonly used methods are compiled by Jaques et al in
"Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981).
More specifically the compound of formula I may be converted to a
1:1 mixture of diastereomeric amides by treating with chiral
amines, aminoacids, aminoalcohols derived from aminoacids;
conventional reaction conditions may be employed to convert acid
into an amide; the dia-stereomers may be separated either by
fractional crystallization or chromatography and the stereoisomers
of compound of formula I may be prepared by hydrolysing the pure
diastereomeric amide.
[0303] Various polymorphs of compound of general formula I forming
part of this invention may be prepared by crystallization of
compound of formula I under different conditions. For example,
using different solvents commonly used or their mixtures for
recrystallization; crystallizations at different temperatures;
various modes of cooling, ranging from very fast to very slow
cooling during crystallizations. Polymorphs may also be obtained by
heating or melting the compound followed by gradual or fast
cooling. The presence of polymorphs may be determined by solid
probe nmr spectroscopy, ir spectroscopy, differential scanning
calorimetry, powder X-ray diffraction or such other techniques.
[0304] The invention also encompasses prodrugs of the present
compounds, which on administration undergo chemical conversion by
metabolic processes before becoming active pharmacological
substances. In general, such prodrugs will be functional
derivatives of the present compounds, which are readily convertible
in vivo into the required compound of the formula (I). Conventional
procedures for the selection and preparation of suitable prodrug
derivatives are described, for example, in "Design of Prodrugs",
ed. H. Bundgaard, Elsevier, 1985.
[0305] The invention also encompasses active metabolites of the
present compounds.
[0306] The invention also relates to pharmaceutical compositions
comprising, as an active ingredient, at least one compound of the
formula I or any optical or geometric isomer or tautomeric form
thereof including mixtures of these or a pharmaceutically
acceptable salt thereof together with one or more pharmaceutically
acceptable carriers or diluents.
[0307] Furthermore, the invention relates to the use of compounds
of the general formula I or their tautomeric forms, their
stereoisomers, their polymorphs, their pharmaceutically acceptable
salts or pharmaceutically acceptable solvates thereof for the
preparation of a pharmaceutical composition for the treatment
and/or prevention of conditions mediated by nuclear receptors, in
particular the Peroxisome Proliferator-Activated Receptors (PPAR)
such as the conditions mentioned above.
[0308] In another aspect, the present invention relates to a method
of treating and/or preventing Type I or Type II diabetes.
[0309] In a still further aspect, the present invention relates to
the use of one or more compounds of the general formula I or
pharmaceutically acceptable salts thereof for the preparation of a
pharmaceutical composition for the treatment and/or prevention of
Type I or Type II diabetes.
[0310] In a still further aspect, the present compounds are useful
for the treatment and/or prevention of IGT.
[0311] In a still further aspect, the present compounds are useful
for the treatment and/or prevention of Type 2 diabetes.
[0312] In a still further aspect, the present compounds are useful
for the delaying or prevention of the progression from IGT to Type
2 diabetes.
[0313] In a still further aspect, the present compounds are useful
for the delaying or prevention of the progression from non-insulin
requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
[0314] In another aspect, the present compounds reduce blood
glucose and triglyceride levels and are accordingly useful for the
treatment and/or prevention of ailments and disorders such as
diabetes and/or obesity.
[0315] In still another aspect, the present compounds are useful
for the treatment and/or prophylaxis of insulin resistance (Type 2
diabetes), impaired glucose tolerance, dyslipidemia, disorders
related to Syndrome X such as hypertension, obesity, insulin
resistance, hyperglycaemia, atherosclerosis, hyperlipidemia,
coronary artery disease, myocardial ischemia and other
cardiovascular disorders.
[0316] In still another aspect, the present compounds are effective
in decreasing apoptosis in mammalian cells such as beta cells of
Islets of Langerhans.
[0317] In still another aspect, the present compounds are useful
for the treatment of certain renal diseases including
glomerulonephritis, glomerulosclerosis, nephrotic syndrome,
hypertensive nephrosclerosis.
[0318] In still another aspect, the present compounds may also be
useful for improving cognitive functions in dementia, treating
diabetic complications, psoriasis, polycystic ovarian syndrome
(PCOS) and prevention and treatment of bone loss, e.g.
osteoporosis.
[0319] In yet another aspect, the invention also relates to the use
of the present compounds, which after administration lower the
bio-markers of atherosclerosis like, but not limited to, c-reactive
protein (CRP), TNF.alpha. and IL-6.
[0320] The present compounds may also be administered in
combination with one or more further pharmacologically active
substances eg., selected from antiobesity agents, antidiabetics,
antihypertensive agents, agents for the treatment and/or prevention
of complications resulting from or associated with diabetes and
agents for the treatment and/or prevention of complications and
disorders resulting from or associated with obesity.
[0321] Thus, in a further aspect of the invention the present
compounds may be administered in combination with one or more
antiobesity agents or appetite regulating agents.
[0322] Such agents may be selected from the group consisting of
CART (cocaine amphetamine regulated transcript) agonists, NPY
(neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin
antagonists, TNF (tumor necrosis factor) agonists, CRF
(corticotropin releasing factor) agonists, CRF BP (corticotropin
releasing factor binding protein) antagonists, urocortin agonists,
.beta.3 agonists, MSH (melanocyte-stimulating hormone) agonists,
MCH (melanocyte-concentrating hormone) antagonists, CCK
(cholecystokinin) agonists, serotonin re-uptake inhibitors,
serotonin and noradrenaline re-uptake inhibitors, mixed serotonin
and noradrenergic compounds, 5HT (serotonin) agonists, bombesin
agonists, galanin antagonists, growth hormone, growth hormone
releasing compounds, TRH (thyreotropin releasing hormone) agonists,
UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists,
DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors,
RXR (retinoid X receptor) modulators or TR .beta. agonists.
[0323] In one embodiment of the invention the antiobesity agent is
leptin.
[0324] In another embodiment the antiobesity agent is
dexamphetamine or amphetamine.
[0325] In another embodiment the antiobesity agent is fenfluramine
or dexfenfluramine.
[0326] In still another embodiment the antiobesity agent is
sibutramine.
[0327] In a further embodiment the antiobesity agent is
orlistat.
[0328] In another embodiment the antiobesity agent is mazindol or
phentermine.
[0329] Suitable antidiabetics comprise insulin, GLP-1 (glucagon
like peptide-1) derivatives such as those disclosed in WO 98/08871
to Novo Nordisk A/S, which is incorporated herein by reference as
well as orally active hypoglycaemic agents.
[0330] The orally active hypoglycaemic agents preferably comprise
sulphonylureas, biguanides, meglitinides, glucosidase inhibitors,
glucagon antagonists such as those disclosed in WO 99/01423 to Novo
Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists,
potassium channel openers such as those disclosed in WO 97/26265
and WO 99/03861 to Novo Nordisk A/S which are incorporated herein
by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors,
inhibitors of hepatic enzymes involved in stimulation of
gluconeogenesis and/or glycogenolysis, glucose uptake modulators,
compounds modifying the lipid metabolism such as antihyperlipidemic
agents and antilipidemic agents as HMG CoA inhibitors (statins),
compounds lowering food intake, RXR agonists and agents acting on
the ATP-dependent potassium channel of the .beta.-cells.
[0331] In one embodiment of the invention the present compounds are
administered in combination with insulin.
[0332] In a further embodiment the present compounds are
administered in combination with a sulphonylurea eg. tolbutamide,
glibenclamide, glipizide or glicazide.
[0333] In another embodiment the present compounds are administered
in combination with a biguanide eg. mefformin.
[0334] In yet another embodiment the present compounds are
administered in combination with a meglitinide eg. repaglinide or
senaglinide.
[0335] In a further embodiment the present compounds are
administered in combination with an .alpha.-glucosidase inhibitor
eg. miglitol or acarbose.
[0336] In another embodiment the present compounds are administered
in combination with an agent acting on the ATP-dependent potassium
channel of the .beta.-cells eg. tolbutamide, glibenclamide,
glipizide, glicazide or repaglinide.
[0337] Furthermore, the present compounds may be administered in
combination with nateglinide.
[0338] In still another embodiment the present compounds are
administered in combination with an antihyperlipidemic agent or
antilipidemic agent eg. cholestyramine, colestipol, clofibrate,
gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156,
LY-518674, LY-519818, MK-767, atorvastatin, fluvastatin,
lovastatin, pravastatin, simvastatin, cerivastin, acipimox,
ezetimibe, probucol, dextrothyroxine or nicotinic acid.
[0339] In yet another embodiment the present compounds are
administered in combination with a thiazolidinedione e.g.
troglitazone, ciglitazone, pioglitazone or rosiglitazone.
[0340] In a further embodiment the present compounds are
administered in combination with more than one of the
above-mentioned compounds eg. in combination with a sulphonylurea
and mefformin, a sulphonylurea and acarbose, repaglinide and
metformin, insulin and a sulphonylurea, insulin and metformin,
insulin, insulin and lovastatin, etc.
[0341] Furthermore, the present compounds may be administered in
combination with one or more antihypertensive agents. Examples of
antihypertensive agents are .beta.-blockers such as alprenolol,
atenolol, timolol, pindolol, propranolol and metoprolol, ACE
(angiotensin converting enzyme) inhibitors such as benazepril,
captopril, enalapril, fosinopril, lisinopril, quinapril and
ramipril, calcium channel blockers such as nifedipine, felodipine,
nicardipine, isradipine, nimodipine, diltiazem and verapamil, and
.alpha.-blockers such as doxazosin, urapidil, prazosin and
terazosin. Further reference can be made to Remington: The Science
and Practice of Pharmacy, 19.sup.th Edition, Gennaro, Ed., Mack
Publishing Co., Easton, Pa., 1995.
[0342] It should be understood that any suitable combination of the
compounds according to the invention with one or more of the
above-mentioned compounds and optionally one or more further
pharmacologically active substances are considered to be within the
scope of the present invention.
[0343] The present invention also relates to a process for the
preparation of the above said novel compounds, their derivatives,
their analogs, their tautomeric forms, their stereoisomers, their
polymorphs, their pharmaceutically acceptable salts or
pharmaceutically acceptable solvates.
[0344] Pharmaceutical Compositions
[0345] The compounds of the invention may be administered alone or
in combination with pharmaceutically acceptable carriers or
excipients, in either single or multiple doses. The pharmaceutical
compositions according to the invention may be formulated with
pharmaceutically acceptable carriers or diluents as well as any
other known adjuvants and excipients in accordance with
conventional techniques such as those disclosed in Remington: The
Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack
Publishing Co., Easton, Pa., 1995. The compositions may appear in
conventional forms, for example capsules, tablets, aerosols,
solutions, suspensions or topical applications.
[0346] Typical compositions include a compound of formula I or a
pharmaceutically acceptable acid addition salt thereof, associated
with a pharmaceutically acceptable excipient which may be a carrier
or a diluent or be diluted by a carrier, or enclosed within a
carrier which can be in the form of a capsule, sachet, paper or
other container. In making the compositions, conventional
techniques for the preparation of pharmaceutical compositions may
be used. For example, the active compound will usually be mixed
with a carrier, or diluted by a carrier, or enclosed within a
carrier which may be in the form of a ampoule, capsule, sachet,
paper, or other container. When the carrier serves as a diluent, it
may be solid, semi-solid, or liquid material which acts as a
vehicle, excipient, or medium for the active compound. The active
compound can be adsorbed on a granular solid container for example
in a sachet. Some examples of suitable carriers are water, salt
solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated
castor oil, peanut oil, olive oil, gelatine, lactose, terra alba,
sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin,
agar, pectin, acacia, stearic acid or lower alkyl ethers of
cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid
monoglycerides and diglycerides, pentaerythritol fatty acid esters,
polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
Similarly, the carrier or diluent may include any sustained release
material known in the art, such as glyceryl monostearate or
glyceryl distearate, alone or mixed with a wax. The formulations
may also include wetting agents, emulsifying and suspending agents,
preserving agents, sweetening agents or flavouring agents. The
formulations of the invention may be formulated so as to provide
quick, sustained, or delayed release of the active ingredient after
administration to the patient by employing procedures well known in
the art.
[0347] The pharmaceutical compositions can be sterilized and mixed,
if desired, with auxillary agents, emulsifiers, salt for
influencing osmotic pressure, buffers and/or colouring substances
and the like, which do not deleteriously react with the active
compounds.
[0348] The route of administration may be any route, which
effectively transports the active compound to the appropriate or
desired site of action, such as oral, nasal, pulmonary, transdermal
or parenteral e.g. rectal, depot, subcutaneous, intravenous,
intraurethral, intramuscular, intranasal, ophthalmic solution or an
ointment, the oral route being preferred.
[0349] If a solid carrier is used for oral administration, the
preparation may be tabletted, placed in a hard gelatin capsule in
powder or pellet form or it can be in the form of a troche or
lozenge. If a liquid carrier is used, the preparation may be in the
form of a syrup, emulsion, soft gelatin capsule or sterile
injectable liquid such as an aqueous or non-aqueous liquid
suspension or solution.
[0350] For nasal administration, the preparation may contain a
compound of formula I dissolved or suspended in a liquid carrier,
in particular an aqueous carrier, for aerosol application. The
carrier may contain additives such as solubilizing agents, e.g.
propylene glycol, surfactants, absorption enhancers such as
lecithin (phosphatidylcholine) or cyclodextrin, or preservatives
such as parabenes.
[0351] For parenteral application, particularly suitable are
injectable solutions or suspensions, preferably aqueous solutions
with the active compound dissolved in polyhydroxylated castor
oil.
[0352] Tablets, dragees, or capsules having talc and/or a
carbohydrate carrier or binder or the like are particularly
suitable for oral application. Preferable carriers for tablets,
dragees, or capsules include lactose, corn starch, and/or potato
starch. A syrup or elixir can be used in cases where a sweetened
vehicle can be employed.
[0353] A typical tablet which may be prepared by conventional
tabletting techniques may contain:
1 Core: Active compound (as free compound or salt thereof) 5 mg
Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst.
(Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium
stearate Ad. Coating: HPMC approx. 9 mg *Mywacett 9-40 T approx.
0.9 mg *Acylated monoglyceride used as plasticizer for film
coating.
[0354] If desired, the pharmaceutical composition of the invention
may comprise the compound of formula (I) in combination with
further pharmacologically active substances such as those described
in the foregoing.
[0355] The compounds of the invention may be administered to a
mammal, especially a human in need of such treatment, prevention,
elimination, alleviation or amelioration of diseases related to the
regulation of blood sugar.
[0356] Such mammals include also animals, both domestic animals,
e.g. household pets, and non-domestic animals such as wildlife.
[0357] The compounds of the invention are effective over a wide
dosage range. A typical oral dosage is in the range of from about
0.001 to about 100 mg/kg body weight per day, preferably from about
0.01 to about 50 mg/kg body weight per day, and more preferred from
about 0.05 to about 10 mg/kg body weight per day administered in
one or more dosages such as 1 to 3 dosages. The exact dosage will
depend upon the frequency and mode of administration, the sex, age,
weight and general condition of the subject treated, the nature and
severity of the condition treated and any concomitant diseases to
be treated and other factors evident to those skilled in the
art.
[0358] The formulations may conveniently be presented in unit
dosage form by methods known to those skilled in the art. A typical
unit dosage form for oral administration one or more times per day
such as 1 to 3 times per day may contain of from 0.05 to about 1000
mg, preferably from about 0.1 to about 500 mg, and more preferred
from about 0.5 mg to about 200 mg.
[0359] Any novel feature or combination of features described
herein is considered essential to this invention.
EXAMPLES
[0360] The following examples and general procedures refer to
intermediate compounds and final products identified in the
specification and in the synthesis schemes. The preparation of the
compounds of the present invention is described in detail using the
following examples. Occasionally, the reaction may not be
applicable as described to each compound included within the
disclosed scope of the invention. The compounds for which this
occurs will be readily recognised by those skilled in the art. In
these cases the reactions can be successfully performed by
conventional modifications known to those skilled in the art, that
is, by appropriate protection of interfering groups, by changing to
other conventional reagents, or by routine modification of reaction
conditions. Alternatively, other reactions disclosed herein or
otherwise conventional will be applicable to the preparation of the
corresponding compounds of the invention. In all preparative
methods, all starting materials are known or may easily be prepared
from known starting materials. The structures of the compounds are
confirmed nuclear magnetic resonance (NMR). NMR shifts (.delta.)
are given in parts per million (ppm. Mp is melting point and is
given in .degree. C.
[0361] The abbreviations as used in the examples have the following
meaning:
[0362] THF: tetrahydrofuran
[0363] DMSO: dimethylsulfoxide
[0364] CDCl.sub.3: deutorated chloroform
[0365] DMF: N,N-dimethylformamide
[0366] min: minutes
[0367] h: hours
[0368] General Procedure (A)
[0369] Step A:
[0370] Reacting a compound of formula (II) 3
[0371] wherein X.sub.2 and X.sub.3 are defined as above and wherein
HIg is bromine or iodine, through a Wittig-like process with for
example (EtO).sub.2PO(CHR.sub.1)COOR.sub.6, wherein R.sub.6 is an
alkyl group and R.sub.1 is defined as above, in the presence of a
base such as sodium hydride, EtONa and the like to give a compound
of formula (III) 4
[0372] wherein X.sub.2, X.sub.3, R.sub.1 and R.sub.6 are defined as
above and wherein HIg is bromine or iodine, and
[0373] Step B:
[0374] Reducing the compound of formula (III) wherein X.sub.2,
X.sub.3, R.sub.1 and R.sub.6 are defined as above and wherein HIg
is bromine or iodine with a suitable reagent such as
diisobutylaluminium hydride, to give a compound of formula (IV)
5
[0375] wherein X.sub.2, X.sub.3 and R.sub.1 are defined as above
and wherein HIg is bromine or iodine, and
[0376] Step C:
[0377] Reacting the compound of formula (IV), wherein X.sub.2,
X.sub.3 and R.sub.1 are defined as above and wherein HIg is bromine
or iodine, (except that when X.sub.2 or X.sub.3 are substituted
with hydroxy, this functionality has to be protected) with a
compound of formula (V) 6
[0378] wherein Y.sub.1, Ar, Y.sub.2, Z and R.sub.2 are defined as
above, except that R.sub.2 is not hydrogen under Mitsunobu
conditions, using a reagent such as
triphenylphosphine/diethylazodicarboxylate and the like to obtain a
compound of formula (VI) 7
[0379] wherein X.sub.2, X.sub.3, Y.sub.1, Y.sub.2, Ar, Z, R.sub.1
and R.sub.2 are defined as above, except that R.sub.2 is not
hydrogen and wherein HIg is bromine or iodine, and
[0380] Step D:
[0381] Reacting a compound of formula (VI) wherein X.sub.2,
X.sub.3, Y.sub.1, Y.sub.2, Ar, Z, R.sub.1 and R.sub.2 are defined
as above, and wherein HIg is bromine or iodine, with an boronic
acid or with a tributyltin derivative of X.sub.1 under appropriate
coupling conditions as
Pd2(dba).sub.3/Pd(P(t-Bu).sub.3).sub.2/KF/THF, to give a compound
of formula (I), wherein X.sub.1, X.sub.2, X.sub.3, Y.sub.1,
Y.sub.2, Ar, Z, R.sub.1 and R.sub.2 are defined as above, except
that R.sub.2 is not hydrogen.
[0382] General Procedure (B)
[0383] Step A:
[0384] By chemical or enzymatic saponification of a compound of
formula (I) wherein X.sub.1, X.sub.2, X.sub.3, Y.sub.1, Y.sub.2,
Ar, Z, R.sub.1 and R.sub.2 are defined as above, except that
R.sub.2 is not hydrogen to give a compound of formula (I) wherein
X.sub.1, X.sub.2, X.sub.3, Y.sub.1, Y.sub.2, Ar, Z, R.sub.1 and
R.sub.2 are defined as above, except that R.sub.2 is hydrogen.
[0385] General Procedure (C)
[0386] Step A:
[0387] By chemical or enzymatic saponification of a compound of
formula (VI) wherein X.sub.2, X.sub.3, Y.sub.1, Y.sub.2, Ar, Z,
R.sub.1 and R.sub.2 are defined as above, except that R.sub.2 is
not hydrogen and wherein HIg is bromine or iodine to give a
compound of formula (VI) wherein X.sub.1, X.sub.2, X.sub.3,
Y.sub.1, Y.sub.2, Ar, Z, R.sub.1 and R.sub.2 are defined as above,
except that R.sub.2 is hydrogen and wherein HIg is bromine or
iodine, and
[0388] Step B:
[0389] Reacting an compound of formula (VI) wherein X.sub.2,
X.sub.3, Y.sub.1, Y.sub.2, Ar, Z, R.sub.1 and R.sub.2 are defined
as above, except that R.sub.2 is hydrogen and wherein HIg is
bromine or iodine, with an boronic acid derivative of X.sub.1 under
appropriate coupling conditions as
Pd2(dba).sub.3/Pd(P(t-Bu).sub.3).sub.2/KF/THF, to give a compound
of formula (I), wherein X.sub.1, X.sub.2, X.sub.3, Y.sub.1,
Y.sub.2, Ar, Z, R.sub.1 and R.sub.2 are defined as above, except
that R.sub.2 is hydrogen.
[0390] General Procedure (D)
[0391] Step A:
[0392] Reacting a compound of formula (VII) 8
[0393] wherein X.sub.1, X.sub.2 and X.sub.3 are defined as above,
through a Wittig-like process with for example
(EtO).sub.2PO(CHR.sub.1)COOR.sub.6- , wherein R.sub.6 is an alkyl
group and R.sub.1 is defined as above, in the presence of a base
such as sodium hydride, EtONa and the like to give a compound of
formula (VIII) 9
[0394] wherein X.sub.1, X.sub.2, X.sub.3, R.sub.1 and R.sub.6 are
defined as above, and
[0395] Step B:
[0396] Reducing the compound of formula (VIII) wherein X.sub.1,
X.sub.2, X.sub.3, R.sub.1 and R.sub.6 are defined as above, with a
suitable reagent such as diisobutylaluminium hydride, to give a
compound of formula (IX) 10
[0397] wherein X.sub.1, X.sub.2, X.sub.3 and R.sub.1 are defined
as, and
[0398] Step C:
[0399] Reacting the compound of formula (IX), wherein X.sub.1,
X.sub.2, X.sub.3 and R.sub.1 are defined as above, (except that
when X.sub.1, X.sub.2 or X.sub.3 are substituted with hydroxy, this
functionality has to be protected) with a compound of formula (V)
wherein Y.sub.1, Ar, Y.sub.2, Z and R.sub.2 are defined as above,
except that R.sub.2 is not hydrogen under Mitsunobu conditions,
using a reagent such as triphenylphosphine/diethylazodicarboxylate
and the like to obtain a compound of formula (I), wherein X.sub.1,
X.sub.2, X.sub.3, Y.sub.1, Y.sub.2, Ar, Z, R.sub.1 and R.sub.2 are
defined as above, except that R.sub.2 is not hydrogen.
[0400] General Procedure (E)
[0401] Step A:
[0402] Converting the --OH functionality in the compound of formula
(IX), wherein X.sub.1, X.sub.2, X.sub.3 and R.sub.1 are defined as
above, to an appropriate leaving group (L) such as
p-toluenesulfonate, methanesulfonate, halogen (for example by
methods according to: Houben-Weyl, Methoden der organischen Chemie,
Alkohole III, 6/1b, Thieme-Verlag 1984, 4th Ed., pp. 927-939;
Comprehensive Organic Transformations. A guide to functional group
preparations, VCH Publishers 1989, 1.sup.st Ed., pp. 353-363 and J.
Org. Chem., Vol. 36 (20), 3044-3045, 1971), triflate and the like,
to give a compound of formula (X) 11
[0403] wherein, X.sub.1, X.sub.2, X.sub.3, R. and L are defined as
above.
[0404] Step B:
[0405] Reacting the compound of formula (X) wherein L is a leaving
group such as p-toluenesulfonate, methanesulfonate, halogen,
triflate and the like and wherein X.sub.1, X.sub.2, X.sub.3 and
R.sub.1 are defined as above, with a compound of formula (V)
wherein Y.sub.1, Ar, Y.sub.2, Z and R.sub.2 are defined as above,
except that R.sub.2 is not hydrogen, to give a compound of formula
(I) wherein X.sub.1, X.sub.2, X.sub.3, Y.sub.1, Y.sub.2, Ar, Z,
R.sub.1 and R.sub.2 are defined as above, except that R.sub.2 is
not hydrogen.
[0406] General Procedure (F)
[0407] Step A:
[0408] Reacting a compound of formula (XI) 12
[0409] wherein X.sub.1 and X.sub.2 are as defined above, with
carbon tetrabromide and triphenylphosphine to give a compound of
formula (XII) 13
[0410] wherein X.sub.1 and X.sub.2 are as defined above.
[0411] Step B:
[0412] Reacting the compound of formula (XII), wherein X.sub.1 and
X.sub.2 are as defined above, with paraformaldehyde in the presence
of a strong base like BuLi, to give a compound of formula (XIII)
14
[0413] wherein X.sub.1 and X.sub.2 are as defined above.
[0414] Step C:
[0415] Reducing the compound of formula (XIII), wherein X.sub.1 and
X.sub.2 are as defined above, with LiAlH in the presence of a base,
like sodium methoxide, followed by treatment with dimethylcarbonate
and iodine to give a compound of formula (XIV) 15
[0416] wherein X.sub.1 and X.sub.2 are as defined above.
[0417] Step D:
[0418] Converting the hydroxyl function in the compound of formula
(XIV) to a leaving group (L), as described under the General
procedure B, to give a compound of formula (XV) 16
[0419] wherein X.sub.1, X.sub.2 and L are as defined above.
[0420] Step E:
[0421] Reacting the compound of formula (XV), wherein L is a
leaving group, such as p-toluenesulfonate, methanesulfonate,
halogen, triflate and the like, and wherein X.sub.1 and X.sub.2 are
as defined above, with the compound of formula (V), wherein
Y.sub.1, Ar, Y.sub.2, Z and R.sub.2 are as defined above, except
that R.sub.2 is not hydrogen, to give a compound of formula (XVI)
17
[0422] wherein X.sub.1, X.sub.2, Y.sub.1, Y.sub.2, Ar, Z and
R.sub.2 are as defined above, except that R.sub.2 is not
hydrogen.
[0423] Step F:
[0424] Reacting the compound of formula (XVI), wherein X.sub.1,
X.sub.2, Y.sub.1, Y.sub.2, Ar, Z and R.sub.2 are defined as above,
except that R.sub.2 is not hydrogen, with X.sub.2-tributyltin in
the presence of a palladium catalyst, like Pd.sub.2(dba).sub.3, and
tri(t.-butyl)phosphine to give the compound of formula (I), wherein
X.sub.1, X.sub.2, X.sub.3, Y.sub.1, Y.sub.2, Ar, Z, R.sub.1 and
R.sub.2 are defined as above, except that R.sub.1 is hydrogen and
R.sub.2 is not hydrogen.
[0425] General Procedure (G)
[0426] Step A:
[0427] Reacting a compound of formula X.sub.1-X.sub.2-halogen,
wherein X.sub.1 and X.sub.2 are as defined above, under Heck like
conditions with propargylalcohol in the presence of a palladium
catalyst, like Pd.sub.2(dba).sub.3, and cubber(I) to give the
compound of formula (XIII), wherein X.sub.1 and X.sub.2 are as
defined above.
[0428] General Procedure (H)
[0429] Step A:
[0430] Reacting the compound of formula (XIV), wherein X.sub.1 and
X.sub.2 are defined as above, with X.sub.3-tributyltin in the
presence of a palladium catalyst, like Pd.sub.2(dba).sub.3, and
tri(t.-butyl)phosphine to give a compound of formula (XVII) 18
[0431] wherein X, X.sub.2 and X.sub.3, are defined as above.
[0432] Using a combination of the above methods, or methods
analogous hereof, various compounds may be made within the scope of
the present invention.
[0433] The present invention is further exemplified by the
following examples, which illustrate the preparation of the
compounds according to the invention. The examples are, however,
not intended to limit the scope of the invention in any way.
Example 1
(E/Z)
{4-[3-Biphenyl-4-yl-3-(4-bromo-phenyl)-allylsulfanyl]-phenoxy}-aceti-
c Acid
[0434] 19
[0435] General Procedure A:
[0436] Step A:
[0437] To a solution of NaH (3.53 g, 88.2 mmol) in dry toluene (300
ml) was added dropwise at 0.degree. C. a solution of
trietylphosphonoacetate (13.2 g, 58.8 mmol) in toluene (100 ml).
The reaction mixture was stirred for 30 min. after which a solution
of 4,4-dibromobenzophenone (10.0 g, 29.4 mmol) in THF (100 ml) was
added. The reaction mixture was stirred for 48 h. Ethanol (10 ml)
and water (300 ml) were added and the mixture was extracted with
ethyl acetate-methanol (2%, 2.times.150 ml). The combined organic
phases were washed with brine, dried with MgSO.sub.4, filtered and
evaporated. The residue was purified by column chromatography
(eluent: ether) to give ethyl 3,3-bis-(4-bromophenyl)-acry- late as
a gum. Crystallization from hexanes gave white crystals in 8.77 g
(73%) yield.
[0438] .sup.1H NMR (CDCl.sub.3, 300 MHz); .delta. 1.20 (3H, t),
4.05 (2H, q), 6.35 (1H, s), 7.0-7.1 (4H, m), 7.40-7.52 (4H, m).
[0439] Step B:
[0440] Ethyl 3,3-bis-(4-bromophenyl)-acrylate (8.75 g, 21.3 mmol)
was dissolved in dry THF (35 ml). DIBAL-H (1.5 M in toluene, 43 ml,
64.0 mmol) was added at -15.degree. C. and the reaction mixture was
stirred for 30 min. A solution of ammonium chloride in water was
added and the mixture was extracted with ethyl acetate (3.times.50
ml). The combined organic phases were washed with brine, dried with
MgSO.sub.4, filtered and evaporated to give
3,3-bis-(4-bromophenyl)-pro-2-en-1-ol in 6.0 g (76%) yield.
[0441] .sup.1H NMR (CDCl.sub.3, 300 MHz); .delta. 1.15 (1H, br s),
4.16-4.20 (2H, dd), 6.25 (1H, t), 7.0-7.1 (4H, m), 7.40-7.52 (4H,
m).
[0442] Step C:
[0443] 3,3-Bis-(4-bromophenyl)-pro-2-en-1-ol (2.98 g, 8.1 mmol) and
tributylphosphine (2.4 g, 12.1 mmol) were dissolved in dry THF (150
ml) and cooled to 0.degree. C. under an atmosphere of nitrogen.
1,1'-(Azodicarbonyl)dipiperidine (ADDP) (3.1 g, 12.1 mmol) was
added and the reaction mixture was stirred for 5 min.
(4-Mercapto-2-methyl-phenoxy)- -acetic acid methyl ester (2.06 g,
9.7 mmol) was slowly added (5 min) and the stirring continued for 2
h at 0.degree. C. Water (100 ml) was added and the mixture was
extracted with dichloromethane (2.times.150 ml). The combined
organic phases were dried with MgSO.sub.4, filtered and evaporated.
The residue was purified by column chromatography
(eluent:dichloromethane) to give 4.0 g (88%) of
{4-[3,3-bis-(4-bromo-phen-
yl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester.
[0444] .sup.1H NMR (CDCl.sub.3, 300 MHz); .delta. 2.20 (3H, s),
3.44 (2H, d), 3.78 (3H, s), 4.64 (2H, s), 6.11 (1H, t), 6.55 (1H,
d), 6.73 (2H, d), 6.98 (2H, d), 7.10 (2H, bs), 7.38 (2H, d), 7.43
(2H, d).
[0445] General Procedure C:
[0446] Step A:
[0447] A solution of
{4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl--
phenoxy}-acetic acid methyl ester (530 mg, 0.94 mmol) in ethanol
(20 ml) and 1 M NaOH (2.0 ml, 2.0 mmol) was stirred at room temp.
for 2 h. The reaction mixture added water (20 ml) and 1N HCl (3.0
ml). The water phase was extracted dichloromethane (2.times.50 ml)
and the combined organic phases dried with MgSO.sub.4, filtered and
evaporated to give 482 mg (93%) of
{4-[3,3-bis-(4-bromophenyl)-allylsulfanyl]-2-methyl-phenoxy}-ace-
tic acid.
[0448] .sup.1H NMR (CDCl.sub.3, 300 MHz); .delta.2.20 (3H, s), 3.45
(2H, d), 4.68 (2H, s), 6.10 (1H, t), 6.58 (1H, d), 6.75 (2H, d),
6.98 (2H, d), 7.10-7.13 (2H, m), 7.38 (2H, d), 7.43 (2H, d).
[0449] Step B:
[0450] A mixture of
{4-[3,3-bis-(4-bromophenyl)-allylsulfanyl]-2-methyl-ph-
enoxy}-acetic acid (97 mg, 0.177 mmol), phenylboronic acid (47 mg,
389 mmol), KF (34 mg, 0.584 mmol), Pd.sub.2(dba).sub.3 (10 mg,
0.011 mmol) and Pd(P(t-Bu).sub.3).sub.2 (11 mg, 0.021 mmol) was
evacuated for air and kept under nitrogen. THF (2 ml) was added and
the reaction mixture was stirred at room temperature for 4 hours. A
saturated aqueous NH.sub.4Cl (5 ml) solution was added, and the
mixture was extracted with methylene chloride (2.times.20 ml). The
combined organic phases were dried and purified on column
chromatography using methylene chloride: THF (8:3) as eluent. The
isolated products were further purified on HPLC using
acetonitril:water (4:6) increasing to pure acetonitril as eluent.
The title product was isolated as an E/Z mixture in 4 mg yield.
[0451] .sup.1H NMR (CDCl.sub.3, 400 MHz); .delta. 7.60-6.75 (m,
15H); 6.47 (d, J=7 Hz, 1H); 6.16 (t, J=7 Hz, 0.7H); 6.07 (t, J=7
Hz, 0.3H); 4.37 (s, 2H); 3.53 (d, J=7 Hz, 0.6H); 3.45 (d, J=7 Hz,
1.4H); 2.07 (s, 3H).
Example 2
(E/Z)
{4-[3-(4-Bromo-phenyl)-3-(3'-trifluoromethyl-biphenyl-4-yl)-allylsul-
fanyl]-2-methyl-phenoxy}-acetic Acid
[0452] 20
[0453] General Procedure C:
[0454] Step B:
[0455] A mixture of
{4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl-p-
henoxy}-acetic acid (described above) (231 mg, 0.421 mmol),
3-(trifluoromethyl)phenylboronic acid (203 mg, 1.07 mmol), KF (81
mg, 1.39 mmol), Pd.sub.2(dba).sub.3 (23 mg, 0.025 mmol) and
Pd(P(t-Bu).sub.3).sub.2 (26 mg, 0.051 mmol) was evacuated for air
and kept under nitrogen. THF (5 ml) was added and the reaction
mixture was stirred at 50.degree. C. overnight. A saturated aqueous
NH.sub.4Cl (5 ml) solution was added, and the mixture was extracted
with methylene chloride (2.times.20 ml). The combined organic
phases were dried an evaporated. The isolated products were further
purified on HPLC using acetonitril:water (4:6) increasing to pure
acetonitril as eluent. The title product was isolated as an E/Z
mixture in 95 mg (37%) yield.
[0456] .sup.1H NMR (CDCl.sub.3, 400 MHz); .delta. 7.87-7.00 (m,
13H), 6.84 (d, J=8 Hz, 1H), 6.60 (d, J=8 Hz, 1H), 6.21 (t, J=6 Hz,
0.3H), 6.14 (t, J=6 Hz, 0.6H), 4.66 (s, 2H), 3.55 (d, J=7 Hz,
1.4H), 3.51 (d, J=7 Hz, 0.6H), 2.21 (s, 1H), 2.19 (s, 2H).
Example 3
{4-[3-(4-Bromo-phenyl)-3-[1,1';4',1"]terphenyl-4"-yl-allylsulfanyl]-2-meth-
yl-phenoxy}-acetic Acid
[0457] 21
[0458] General Procedure C:
[0459] Step B:
[0460] A mixture of
{4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl-p-
henoxy}-acetic acid (example 1) (225 mg, 0.410 mmol),
4-biphenylboronic acid (163 mg, 0.82 mmol), KF (79 mg, 1.35 mmol),
Pd.sub.2(dba).sub.3 (23 mg, 0.025 mmol) and Pd(P(t-Bu).sub.3).sub.2
(25 mg, 0.049 mmol) was evacuated for air and kept under nitrogen.
THF (6 ml) was added and the reaction mixture was stirred at
70.degree. C. overnight. A saturated aqueous NH.sub.4Cl (5 ml)
solution was added, and the mixture was extracted with methylene
chloride (2.times.20 ml). The combined organic phases were dried an
evaporated. The isolated products were further purified on column
chromatography using methylene chloride:THF (40:1) as eluent. The
isolated products were further purified on HPLC using
acetonitril:water (7:3) increasing to pure acetonotril as eluent.
The title product was isolated as an E/Z mixture in 40 mg (16%)
yield.
[0461] .sup.1H NMR (CDCl.sub.3, 400 MHz); .delta. 7.70-6.97 (m,
xxH), 6.83 (d, 1H), 6.57 (d, 1H), 6.20 (t, 1/3H), 6.12 (t, 2/3H),
4.64 (s, 2/3H), 4.63 (s, 4/3H), 3.57 (d, 4/3), 3.47 (d, 2/3H), 2.18
(s, 2/3H), 2.17 (s, 4/3H).
Example 4
General Procedure (A)
(E/Z)-[2-Methyl-4-[3-[5-(5-methylthiophen-2-yl)benzo[b]furan-2-yl]-3-(thio-
phen-2-yl)allylsulfanyl]phenoxy]acetic Acid
[0462] 22
[0463] Potassium carbonate (12.0 g, 0.087 mol) and subsequently
2-bromo-1-(thiophen-2-yl)ethanone (7.0 g, 0.034 mol; prepared as
described in J.Med.Chem. 30, 1497 (1987)) were added to a stirred
solution of 5-bromosalicylaldehyde (6.9 g, 0.034 mol) in acetone
(150 mL). The mixture was stirred at ambient temperature for 30 min
at first and then refluxed for 1 h. Solid mass was filtered off,
washed with hot acetone (2.times.50 mL) and the filtrate was
evaporated in vacuo. The residue (11.3 g) was crystallized from
ethanol (15 mL) giving
(5-bromobenzo[b]furan-2-yl)-(thiophen-2-yl)methanone. Yield: 8.0 g
(77%). M.p. 84-86.degree. C. R.sub.F (SiO.sub.2, hexane/ethyl
acetate 3:1) 0.70.
[0464] Step A:
[0465] In atmosphere of nitrogen, 2M solution of lithium
diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (33 mL,
66.0 mmol) was added dropwise to an ice-water cooled solution of
triethyl phosphonoacetate (12 mL, 60.0 mmol) in tetrahydrofuran
(180 mL). The mixture was stirred at ambient temperature for 30
min, a solution of the above methanone (9.2 g, 30.0 mmol) in
tetrahydrofuran (92 mL) was added dropwise and the whole mixture
was stirred at ambient temperature for 39 h. The mixture was
diluted with dichloromethane (150 mL), washed with water (150 mL)
and the aqueous layer was extracted with dichloromethane (100 mL).
The combined organic layers were washed with water (200 mL), brine
(200 mL), dried over anhydrous magnesium sulfate and evaporated in
vacuo. Purification by column chromatography (silica gel Fluka 60,
hexane/ethyl acetate 9:1) of the obtained residue gave
(E/Z)-3-(5-bromobenzo[b]furan-2-yl)-3-(thiophen- -2-yl)acrylic acid
ethyl ester as an yellow oil.
[0466] Yield: 8.0 g (71%). R.sub.F (SiO.sub.2, hexane/ethyl acetate
9:1) 0.30.
[0467] Step B:
[0468] In atmosphere of nitrogen, a solution of anhydrous aluminum
chloride (1.03 g, 7.71 mmol) in dry ether (39 mL) was added
dropwise to a suspension of lithium aluminum hydride (0.88 g, 23.1
mmol) in dry ether (74 mL) at -15.degree. C. The mixture was
stirred for 30 min allowing the reaction temperature to reach
0.degree. C. The suspension was cooled at -15.degree. C. again, a
solution of the above ester (2.90 g, 7.71 mmol) in dry ether (39
mL) was added dropwise and the resulting mixture was stirred for 1
h under cooling. Water (0.6 mL), 10% aqueous solution of sodium
hydroxide (0.6 mL) and water (1.8 mL) were added dropwise to the
cold mixture; the segregated precipitate was filtered off and
washed with ether (70 mL). The combined ethereal layers were washed
with water (2.times.50 mL), brine (2.times.50 mL), dried over
anhydrous magnesium sulfate and evaporated in vacuo. The obtained
crude product was purified by column chromatography (silica gel
Fluka 60, hexane/ethyl acetate 4:1) yielding
(E/Z)-3-(5-bromobenzo[b]furan-2-yl)-3-(thiophen-2-yl)prop-2-en-1-
-ol as a white crystalline solid.
[0469] Yield: 1.61 g (62%). R.sub.F (SiO.sub.2, hexane/ethyl
acetate 4:1) 0.30.
[0470] .sup.1H NMR spectrum of the main isomer (250 MHz,
CDCl.sub.3): 7.71 (dd, J=1.8 and 0.7 Hz, 1H); 7.43 (dd, J=8.8 and
1.9 Hz, 1H); 7.37 (dm, J=8.8 Hz, 1H); 7.29 (dd, J=5.1 and 1.2 Hz,
1H); 7.10 (m, 1H); 7.03 (m, 1H); 6.76 (s, 1H); 6.35 (t, J=6.6 Hz,
1H); 4.60 (d, J=6.6 Hz, 2H).
[0471] Procedure Analogues to "General Procedure E, Step A-B")
[0472] In atmosphere of nitrogen, tetrabromomethane (1.48 g, 4.46
mmol) was added to an ice-cooled solution of the above hydroxy
derivative (1.00 g, 2.98 mmol) and triphenylphosphine (1.25 g, 4.77
mmol) in dry methylene chloride (40 mL). The reaction mixture was
stirred for 2 h at ambient temperature, quickly filtered through a
short path of silica gel and the filtrate was evaporated in vacuo.
In atmosphere of nitrogen, tetrahydrofuran (38 mL),
N,N-diisopropylethylamine (0.94 mL, 5.40 mmol) and a solution of
ethyl (4-mercapto-2-methylphenoxy)acetate (1.27 g, 5.61 mmol) in
tetrahydrofuran (2 mL) were added to the residue. The reaction
mixture was stirred overnight, filtered, the precipitated solid was
washed with tetrahydrofuran (10 mL) and the collected organic
solutions were evaporated in vacuo. The residue was purified by
column chromatography (silica gel Merck 60, hexane/ethyl acetate
15:1) yielding
(E/Z)-[4-[3-(5-bromobenzo[b]furan-2-yl)-3-(thiophen-2-yl)allylsulfanyl]-2-
-methylphenoxy]acetic acid ethyl ester.
[0473] Yield: 1.4 g (87%). R.sub.F (SiO.sub.2, hexane/ethyl acetate
4:1) 0.50.
[0474] .sup.1H NMR spectrum (250 MHz, CDCl.sub.3): 7.60-6.27 (m,
9H); 6.73 and 6.22 (t, J=8.3 Hz, 1H); 6.59 and 6.46 (d, J=8.3 Hz,
1H); 4.60 and 4.53 (s, 2H); 4.24 and 4.12 (q, J=7.2 Hz, 2H); 3.86
and 3.62 (d, J=8.3 Hz, 2H); 2.21 and 2.08 (s, 3H); 1.28 and 1.27
(t, J=7.2 Hz, 3H).
[0475] General Procedure A:
[0476] Step D:
[0477] To a solution of
(E/Z)-[4-[3-(5-bromobenzo[b]furan-2-yl)-3-(thiophe-
n-2-yl)allylsulfanyl]-2-methylphenoxy]acetic acid ethyl ester (330
mg, 0.607 mmol) and tributyl-(5-methylthiophen-2-yl)tin (250 mg,
0.644 mmol, prepared in 69% yield according to J. Med. Chem. 44,
3355 (2001)) in dry N,N-dimethylformamide (15 mL)
tris(dibenzylideneacetone)-dipalladium chloroform complex (19.5 mg,
0.019 mmol) was added. Traces of moisture and oxygen were removed
and 0.20M solution of tri(tert.butyl)phosphine in cyclohexane (0.4
mL, 0.080 mmol) was added under atmosphere of nitrogen and the
whole mixture was stirred at 50.degree. C. for 3 h. The mixture was
diluted with ethyl acetate (50 mL), washed with water (40 mL),
brine (40 mL), 10% aqueous solution of potassium fluoride (40 mL)
and brine (50 mL). The organic solution was dried with anhydrous
sodium sulfate and its evaporation gave an oil that was purified by
column chromatography (silica gel Fluka 60, hexane/ethyl acetate
16:1) yielding
(E/Z)-[2-methyl-4-[3-[5-(5-methylthiophen-2-yl)benzo[b]furan-2-yl]-3-(thi-
ophen-2-yl)allylsulfanyl]phenoxy]acetic acid ethyl ester as an
yellow oil.
[0478] Yield: 256 mg (75%). R.sub.F (SiO.sub.2, hexane/ethyl
acetate 16:1) 0.30.
[0479] .sup.1H NMR spectrum (250 MHz, CDCl.sub.3): 7.68-6.30 (m,
11H); 6.21 (t, J=8.3 Hz, 1H); 6.59 and 6.47 (d, J=8.3 Hz, 1H); 4.60
and 4.52 (s, 2H); 4.23 and 4.12 (q, J=7.2 Hz, 2H); 3.91 and 3.63
(d, J=8.2 Hz, 2H); 2.51 and 2.49 (s, 3H); 2.22 and 2.09 (s, 3H);
1.26 and 1.25 (t, J=7.2 Hz, 3H).
[0480] General Procedure B:
[0481] Step A:
[0482] To an ice-water cooled solution of the above ester (144 mg,
0.257 mmol) in a mixture tetrahydrofuran/methanol/water (5:1:1, 7
mL) lithium hydroxide monohydrate (16 mg, 0.381 mmol) was added.
The resulting solution was stirred for 70 min under cooling and
subsequently a diluted solution of tartaric acid (5 mL) was added
followed by addition of ether (20 mL). The layers were separated,
the aqueous layer was extracted with ether (10 mL) and the combined
ethereal layers were washed with water (3.times.10 mL) and brine
(2.times.10 mL) and dried with anhydrous sodium sulfate. The oil
obtained by evaporation of the organic solution was purified by
column chromatography (silica gel Fluka 60, chloroform/methanol
99:1-98:2) yielding the title compound. Yield: 25 mg (18%). M.p. -
- - (foam). R.sub.F (SiO.sub.2, methylene chloride/methanol 85:15)
0.25.
[0483] L-Lysine (6 mg, 0.041 mmol) was added to a solution of the
above acid (25 mg, 0.047 mmol) in dry methanol (3 mL). The mixture
was stirred for 2 h, evaporated in vacuo and the residue twice
triturated with anhydrous ether yielding the L-lysinate of the
title acid.
[0484] Yield: 20 mg (63%). M.p. 142-161.degree. C. (amorphous).
[0485] .sup.1H NMR spectrum (250 MHz, DMSO-d.sub.6): 7.81-6.21 (m,
.about.13H); 4.38 and 4.34 (s, 2H); 3.88 and 3.68 (d, .about.2H);
3.16 (m, .about.1H); 2.75 (m, 2H); 2.47 and 2.45 (d, .about.3H);
2.10 and 1.96 (s, 3H); 1.70-1.25 (m, .about.6H).
Example 5
General Procedure (F)
(E/Z)-[4-[3-(Biphenyl-4-yl)-3-(furan-2-yl)allylsulfanyl]-2-methylphenoxy]a-
cetic Acid
[0486] 23
[0487] Step A:
[0488] Tetrabromomethane (21.8 g, 166 mmol) was added to a cooled
solution of biphenyl-4-carbaldehyde (10.0 g, 54.9 mmol) and
triphenylphosphine (35.5 g, 131.8 mmol) in dry methylene chloride
(100 mL). Reaction mixture was stirred for 3 h at ambient
temperature and saturated solution of sodium hydrogen carbonate (50
mL) was added. The organic layer was washed with water (50 mL),
dried with anhydrous magnesium sulfate and subsequently evaporated
in vacuo. The crude product was twice re-crystallized from methanol
giving 1,1-dibromo-2-(4-biphenylyl)ethene as a white solid.
[0489] Yield: 14.9 g (80%). R.sub.F (SiO.sub.2, hexane) 0.80.
[0490] Step B:
[0491] The above bromo derivative (3.0 g, 8.9 mmol) was dissolved
in dry tetrahydrofuran (100 mL) and under inert atmosphere cooled
to -78.degree. C. 2M Solution of n-butyllithium (12 mL, 22 mmol)
was added dropwise to the solution and the reaction mixture was
stirred for 2 h under cooling. Finely powdered paraformaldehyde
(0.7 g, 22 mmol) was added to the mixture and it was stirred for 3
h at -60.degree. C. slowly increasing the reaction temperature to
ambient temperature. Brine (50 mL) was added and reaction mixture
was extracted with ether (4.times.50 mL). The collected organic
layers were dried with anhydrous magnesium sulfate and subsequently
evaporated in vacuo. The residue was purified by column
chromatography (silica gel Merck 60, hexane/ethyl acetate 1:0-3:1)
yielding 3-(4-biphenylyl)-prop-2-yn-1-ol.
[0492] Yield: 4.1 g (74%). R.sub.F (SiO.sub.2, hexane/ethyl acetate
4:1) 0.45.
[0493] .sup.1H NMR spectrum (250 MHz, CDCl.sub.3): 7.63-7.30 (m,
9H); 4.52 (s, 2H).
[0494] Step C:
[0495] A solution of the above alkyne (1.0 g, 4.8 mmol) in dry
tetrahydrofuran (20 mL) was added dropwise to an ice-cooled
solution of lithium aluminum hydride (380 mg, 10 mmol) and sodium
methoxide (10 mg, 250 .mu.mol, 5%) in dry tetrahydrofuran (10 mL)
under inert atmosphere. The reaction mixture was stirred for 3 h, a
solution of dimethyl carbonate (900 mg, 10 mmol) in dry
tetrahydrofuran (10 mL) was added dropwise at 0.degree. C. and the
reaction mixture was stirred for further 2 h. A solution of iodine
(2.5 g, 10 mmol) in tetrahydrofuran (10 mL) was added and the
resulting mixture was allowed to stand overnight in fridge.
Methanol (5 mL) was added and reaction mixture was stirred for 0.5
h. Saturated aqueous solution of sodium thiosulfate (25 mL) and
brine (100 mL) were added and the heterogenous mixture was
extracted with ether (4.times.100 mL). The collected organic
solutions were dried with anhydrous magnesium sulfate and
subsequently evaporated in vacuo. The residue was purified by
column chromatography (silica gel Merck 60, hexane/methylene
chloride 9:1--methylene chloride/methanol 3:1) yielding
(Z)-3-(4-biphenylyl)-3-iodoprop-2-en-1-ol.
[0496] Yield: 1.3 g (80%). R.sub.F (SiO.sub.2, hexane/ethyl acetate
4:1) 0.50.
[0497] Step D-E:
[0498] A solution of tetrabromethane (1.0 g, 3.0 mmol) in dry
methylene chloride (20 mL) was added dropwise to an ice-cooled
solution of the above hydroxy derivative (0.6 g, 2.0 mmol) and
triphenylphosphine (0.8 g, 3.0 mmol) in dry methylene chloride (50
mL). The reaction mixture was stirred for 2 h at ambient
temperature, N,N-diisopropylethylamine (250 mg, 2 mmol) and a drop
of water were added, the solution was stirred for further 0.5 h and
evaporated in vacuo. In atmosphere of nitrogen, tetrahydrofuran (25
mL), N,N-diisopropylethylamine (390 .mu.L, 3.0 mmol) and ethyl
(4-mercapto-2-methylphenoxy)acetate (560 mg, 2.5 mmol) were added
to the residue. The reaction mixture was stirred overnight,
filtered through a short path of silica gel and the filtrate was
evaporated in vacuo. The residue was purified by column
chromatography (silica gel Merck 60, hexane/ethylacetate 1:0-9:1)
yielding ethyl
(Z)-[4-[3-(4-biphenylyl)-3-iodoprop-2-enylsulfanyl]-2-methylphenoxy]aceta-
te.
[0499] Yield: 0.5 g (50%). R.sub.F (SiO.sub.2, hexane/ethyl acetate
4:1) 0.50.
[0500] Step F:
[0501] To a solution of ethyl
(Z)-[4-[3-(biphenyl-4-yl)-3-iodoallylsulfany-
l]-2-methylphenoxy]-acetate (424 mg, 0.779 mmol) and
tributyl-(furan-2-yl)tin (283 mg, 0.792 mmol, prepared in 78% yield
according to Morimoto et al.: J.Med.Chem. 44, 3355 (2001)) in dry
N,N-dimethylformamide (8 mL) Pd.sub.2(dba).sub.3.CHCl.sub.3 (23.8
mg, 0.023 mmol) was added. Traces of moisture and oxygen were
removed and 0.20M solution of tri(tert.butyl)phosphine in
cyclohexane (0.46 mL, 0.092 mmol) was added under atmosphere of
nitrogen and the whole mixture was stirred at room temperature for
15 min and for further 3 h at 60.degree. C. The dark solution was
poured into 10% aqueous solution of potassium fluoride (15 mL) and
subsequently ethyl acetate (50 mL) was added. The layers were
separated, the aqueous layer was washed with ethyl acetate
(2.times.15 mL) and the collected organic layers were washed with
brine (2.times.20 mL), 10% solution of potassium fluoride
(2.times.10 mL), water (2.times.10 mL) and brine (2.times.10 mL).
The organic solution was dried with anhydrous sodium sulfate and
its evaporation gave an oil that was purified by column
chromatography (silica gel Fluka 60, hexane/ethyl acetate 10:1+0.1%
of triethylamine) yielding 330 mg of crude ethyl
(Z)-[4-[3-(Biphenyl-4-yl)-3-(furan-2-yl)allylsulfanyl]-2-methylphenoxy]ac-
etate.
[0502] Crude yield: 330 mg (88%). R.sub.F=0.25 (SiO.sub.2,
hexane/ethyl acetate 10:1).
[0503] .sup.1H NMR spectrum (250 MHz, CDCl.sub.3): 7.61-7.15 (m,
12H); 6.59 (d, J=8.3 Hz, 1H); 6.40 (dd, J=3.4 and 1.9 Hz, 1H); 6.19
(d, J=3.4 Hz, 1H); 5.88 (t, J=7.9 Hz, 1H); 4.58 (s, 2H); 4.23 (q,
J=7.2 Hz, 2H); 3.96 (d, J=8.0 Hz, 2H); 2.21 (s, 3H); 1.26 (t, J=7.2
Hz, 3H).
[0504] General Procedure B:
[0505] Step A:
[0506] To a solution of the above ester (330 mg, 0.681 mmol) in a
mixture of tetrahydrofuran/methanol (1:3, 8 mL) a solution of
lithium hydroxide monohydrate (42 mg, 1.00 mmol) in distilled water
(0.5 mL) was added. The resulting solution was stirred for 30 min
and subsequently evaporated in vacuo. The residue was diluted with
water (30 mL), neutralized with acetic acid (60 mg, 1.00 mmol) and
extracted with ether (3.times.25 mL). The collected organic layers
were washed with water (15 mL) and brine (2.times.15 mL) and dried
with anhydrous sodium sulfate. The oil obtained by its evaporation
was purified by column chromatography (silica gel Fluka 60,
chloroform+3-15% of methanol) yielding 161 mg of approximately
equimolar mixture of both isomers of
(E/Z)-[4-[3-(Biphenyl-4-yl)-3-(furan-
-2-yl)allylsulfanyl]-2-methylphenoxy]acetic acid.
[0507] Yield: 161 mg (52%). M.p.: - - - (oil). R.sub.F=0.30
(SiO.sub.2, chloroform/methanol 85:15).
[0508] .sup.1H NMR spectrum (250 MHz, DMSO-d.sub.6): 7.74-7.07 (m,
12H); 6.75 (d, 1H); 6.57 and 6.46 (dd, 1H); 6.35 and 5.92 (d, 1H);
6.28 and 5.93 (t, 1H); 4.62 and 4.59 (s, 2H); 3.93 and 3.53 (d,
2H); 2.14 and 2.11 (s, 3H).
[0509] The above acid (155 mg, 0.339 mmol) was dissolved in minimal
amount of dry methylene chloride (about 1 mL), the formed solution
was diluted with absolute methanol (8 mL) and L-lysine (47 mg,
0.321 mmol) was added. The reaction mixture was stirred at room
temperature for 3 h, evaporated in vacuo and the residue was
triturated with anhydrous ether (2.times.8 mL) yielding 140 mg of
the L-lysinate of the title acid.
[0510] Yield: 140 mg (68%). M.p.: 135-150.degree. C.
(amorphous).
[0511] .sup.1H NMR spectrum (250 MHz, DMSO-d.sub.6): 7.73-6.63 (m,
13H); 6.55 and 6.43 (dd, 1H); 6.33 and 5.90 (d, 1H); 6.25 and 5.91
(t, 1H); 4.26 and 4.24 (s, 2H); 3.88 and 3.49 (d, 2H); 3.25 (m,
1H); 2.71 (m, 2H); 2.10 and 2.08 (s, 3H); 1.79-1.27 (m, 6H).
Example 6
General Procedure (F)
(E/Z)-[4-[3-(Benzo[b]thiophen-3-yl)-3-(biphenyl-4-yl)allylsulfanyl]-2-meth-
ylphenoxy]acetic Acid
[0512] 24
[0513] Step F:
[0514] To a solution of ethyl
(Z)-[4-[3-(biphenyl-4-yl)-3-iodoallylsulfany-
l]-2-methylphenoxy]-acetate (307.4 mg, 0.565 mmol; example 5, step
D-E) and (benzo[b]thiophen-3-yl)-tributyltin (242.4 mg, 0.573 mmol;
prepared in 71% yield according to Morimoto et al.: J.Med.Chem. 44,
3355 (2001)) in dry N,N-dimethylformamide (3 mL)
Pd.sub.2(dba).sub.3.CHCl.sub.3 (17.9 mg, 0.0173 mmol) was added.
Traces of moisture and oxygen were removed and 0.20 M solution of
tri(tert.butyl)phosphine in cyclohexane (0.367 mL, 0.073 mmol) was
added under atmosphere of nitrogen and the whole mixture was
stirred at 86.degree. C. for 6 h. The dark solution was poured into
10% aqueous solution of potassium fluoride (20 mL) and subsequently
ethyl acetate (30 mL) was added. The layers were separated, the
aqueous layer was washed with ethyl acetate (2.times.15 mL) and the
collected organic layers were washed with brine (10 mL), 10%
solution of potassium fluoride (20 mL), water (20 mL) and brine (20
mL). The organic solution was dried with anhydrous sodium sulfate
and its evaporation gave an oil that was purified by column
chromatography (silica gel Fluka 60, hexane/ethyl acetate 9:1)
yielding 224 mg of crude ethyl (Z)-[4-[3-(Benzo[b]thiophen-3-
-yl)-3-(biphenyl-4-yl)allylsulfanyl]-2-methylphenoxy]acetate.
[0515] Yield: 224 mg (71%). R.sub.F=0.30 (SiO.sub.2, hexane/ethyl
acetate 9:1).
[0516] .sup.1H NMR spectrum (250 MHz, CDCl.sub.3): 6.61-7.60 (m,
16H); 6.59 (d, 1H); 6.28 (t, 1H); 4.61 (s, 2H); 4.24 (q, 2H); 3.75
(d, 2H); 2.19 (s, 3H); 1.26 (t, 3H).
[0517] General Procedure B:
[0518] Step A:
[0519] To a solution of the above ester (222 mg, 0.403 mmol) in a
mixture of tetrahydrofuran/ethanol (1:1, 16.8 mL) 0.968M solution
of lithium hydroxide monohydrate (0.52 mL, 0.503 mmol) was added.
The resulting solution was stirred for 2 h and subsequently
evaporated in vacuo. The residue was diluted with water (10 mL),
acidified with 1M hydrochloric acid to pH 2-3 and extracted with
ether (40+15 mL). The collected organic layers were washed with
water (25 mL) and brine (30 mL) and dried with anhydrous magnesium
sulfate. The oil obtained by its evaporation was purified by column
chromatography (silica gel Fluka 60, chloroform+3-15% of methanol)
yielding 87.5 mg of a mixture of both isomers of
(E/Z)-[4-[3-(benzo[b]thiophen-3-yl)-3-(biphenyl-4-yl)allylsulfanyl]-2-met-
hylphenoxy]acetic acid.
[0520] Yield: 87.5 mg (42%). R.sub.F=0.10 (SiO.sub.2,
chloroform+15% methanol).
[0521] The above acid (87.5 mg, 0.167 mmol) was dissolved in
minimal amount of dry methylene chloride (about 2 mL), the formed
solution was diluted with absolute methanol (5 mL) and L-lysine
(23.5 mg, 0.161 mmol) was added. The reaction mixture was stirred
at room temperature for 4.5 h, evaporated in vacuo and the residue
was triturated with anhydrous ether (2.times.5 mL) yielding 50.6 mg
of the L-lysinate of the title acid.
[0522] Yield: 50.6 mg (45%). M.p.: 125-145.degree. C.
(amorphous).
[0523] .sup.1H NMR spectrum (250 MHz, DMSO-d.sub.6): 8.00-6.63 (m,
17H); 6.31 (t, 1H); 4.22+4.21 (s, 2H); 3.74+3.51 (d, 2H); 3.18 (bt,
1H); 2.71 (bt, 2H); 2.10+2.08 (s, 3H); 1.80-1.30 (m, 6H).
Example 7
General Procedure (F)
[4-[(3-Benzo[b]thiophen-2-yl)-3-(biphenyl-4-yl)-allylsulfanyl]-2-methyl-ph-
enoxy]-acetic Acid
[0524] 25
[0525] Step F:
[0526] To a solution of ethyl
(Z)-[4-[3-(biphenyl-4-yl)-3-iodoallylsulfany-
l]-2-methylphenoxy]-acetate (419 mg, 0.770 mmol; example 5, step
D-E) and (benzo[b]thiophen-2-yl)-tributyltin (335 mg, 0.792 mmol,
prepared according to Morimoto et al.: J.Med.Chem. 44, 3355 (2001))
in dry N,N-dimethylformamide (9 mL) Pd.sub.2(dba).sub.3.CHCl.sub.3
(23.1 mg, 0.023 mmol) was added. Traces of moisture and oxygen were
removed and 0.20M solution of tri(tert.butyl)phosphine in
cyclohexane (0.39 mL, 0.098 mmol) was added under atmosphere of
nitrogen and the whole mixture was stirred at 50.degree. C. for 10
h and then left stand overnight. The dark solution was poured into
10% aqueous solution of potassium fluoride (30 mL) and subsequently
ethyl acetate (40 mL) was added. The layers were separated, the
aqueous layer was washed with ethyl acetate (2.times.15 mL) and the
collected organic layers were washed with brine (10 mL), 10%
solution of potassium fluoride (20 mL), water (20 mL) and brine (20
mL). The organic solution was dried with anhydrous sodium sulfate
and its evaporation gave an oil that was purified by column
chromatography (silica gel Fluka 60, hexane/ethyl acetate
93:7).
[0527] Yield 190 mg (45%) of crude ethyl
(Z)-[4-[(3-Benzo[b]thiophen-2-yl)-
-3-(biphenyl-4-yl)-allylsulfanyl]-2-methylphenoxy]acetate.
R.sub.F=0.35 (SiO.sub.2, hexane/ethyl acetate 9:1).
[0528] .sup.1H NMR spectrum (250 MHz, CDCl.sub.3): 6.61-7.60 (m,
16H); 6.59 (d, 1H); 6.28 (t, 1H); 4.61 (s, 2H); 4.24 (q, 2H); 3.75
(d, 2H); 2.19 (s, 3H); 1.26 (t, 3H).
[0529] General Procedure B:
[0530] Step A:
[0531] To a solution of the above ester (190 mg, 0.345 mmol) in a
mixture of tetrahydrofuran/ethanol (1:1, 16 mL) a solution of
lithium hydroxide monohydrate (17.7 mg, 0.422 mmol) in water (0.15
mL) was added. The resulting solution was stirred for 2 h and
subsequently evaporated in vacuo. The residue was diluted with
water (10 mL), acidified with 1M hydrochloric acid to pH 2-3 and
extracted with ether (30+15 mL). The collected organic layers were
washed with water (2.times.15 mL) and brine (30 mL) and dried with
anhydrous magnesium sulfate. The oil obtained by its evaporation
was purified by column chromatography (silica gel Fluka 60,
toluene/methanol/acetic acid 100:5:1) yielding 66 mg of mixture of
both isomers of
(E/Z)-[4-[(3-benzo[b]thiophen-2-yl)-3-(biphenyl-4-yl)-all-
ylsulfanyl]-2-methyl-phenoxy]-acetic acid. Yield: 87.5 mg (49%).
RF=0.10 (SiO.sub.2, chloroform+15% methanol).
[0532] The above acid (66 mg, 0.126 mmol) was dissolved in methanol
(5 mL) and L-lysine (18.4 mg, 0.126 mmol) was added. The reaction
mixture was stirred at room temperature for 1 h, evaporated in
vacuo and the residue was triturated with anhydrous ether
(3.times.5 mL) yielding 67 mg (78%) of the L-lysinate of the title
acid. M.p.: 140-155.degree. C. (amorphous).
[0533] .sup.1H NMR spectrum (250 MHz, DMSO-d.sub.6): 7.98-6.82 (m,
.about.17); 6.12 (t, 1H); 4.32 (s, .about.2H); 3.90 (m, .about.2H);
3.20 (t, 1H); 2.73 (m, .about.2H); 2.16 (s, .about.3H); 1.78-1.30
(m, .about.6H).
Example 8
General Procedure (F)
(E/Z)-[4-[3-(4-Biphenylyl)-3-(5-methylthiophen-2-yl)allylsulfanyl]-2-methy-
lphenoxy]acetic Acid
[0534] 26
[0535] Step F:
[0536] To a solution of ethyl
(Z)-[4-[3-(4-biphenylyl)-3-iodoallylsulfanyl-
]-2-methylphenoxy]-acetate (240 mg, 0.441 mmol; Example 5, Step
D-E) and tributyl-(5-methylthiophen-2-yl)tin (180 mg, 0.461 mmol,
prepared in 86% yield according to Morimoto et al.: J.Med.Chem. 44,
3355 (2001)) in dry N,N-dimethylformamide (5 mL)
tris(dibenzylideneacetone)dipalladium chloroform complex (13.5 mg,
0.013 mmol) was added. Traces of moisture and oxygen were removed
and 0.25M solution of tri(tert-butyl)phosphine in cyclohexane (0.2
mL, 0.050 mmol) was added under atmosphere of nitrogen and the
whole mixture was stirred at 50.degree. C. for 3 h. The dark
solution was diluted with ethyl acetate (30 mL) and washed with
brine (2.times.10 mL), water (2.times.10 mL), 10% solution of
potassium fluoride (2.times.10 mL), 10% solution of sodium
pyrosulfite (10 mL), 0.1 M hydrochloric acid (2.times.10 mL), water
(10 mL), 10% solution of sodium hydrogencarbonate (2.times.10 mL)
and brine (10 mL). The organic solution was dried with anhydrous
sodium sulfate and its evaporation gave an oil. The crude product
was purified by column chromatography (silica gel Fluka 60,
hexane/ethyl acetate 8:1) yielding ethyl
(Z)-[4-[3-(4-biphenylyl)-3-(5-methylthiophen-2-yl)allylsulfanyl]-2-methyl-
phenoxy]acetate.
[0537] Yield: 190 mg (84%). R.sub.F (SiO.sub.2, hexane/ethyl
acetate 8:1) 0.30.
[0538] .sup.1H NMR spectrum (250 MHz, CDCl.sub.3): 7.60-7.10 (m,
11H); 6.63 (m, 3H); 6.06 (t, J=7.8 Hz, 1H); 4.60 (s, 2H); 4.23 (q,
J=7.1 Hz, 2H); 3.77 (d, J=7.8 Hz, 2H); 2.48 (s, 3H); 2.23 (s, 3H);
1.26 (t, J=7.1 Hz, 3H).
[0539] General Procedure B:
[0540] Step A:
[0541] To a solution of the above ester (260 mg, 0.505 mmol) in a
mixture tetrahydrofuran/ethanol (1:1, 6 mL) a solution of lithium
hydroxide monohydrate (26 mg, 0.620 mmol) in distilled water (0.4
mL) was added. The resulting solution was stirred for 2 h and
subsequently evaporated in vacuo. The residue was diluted with
water (30 mL), acidified with 1 M hydrochloric acid to pH 3 and
extracted with ether (3.times.20 mL). The collected organic layers
were washed with water (20 mL) and 10% solution of potassium
carbonate (3.times.20 mL). The alkaline solutions were collected,
acidified with 1 M hydrochloric acid to pH 3 and extracted with
ether (3.times.20 mL) again. The collected organic solutions were
washed with water (20 mL) and brine (2.times.20 mL) and dried with
anhydrous sodium sulfate. The oil obtained by its evaporation was
purified by column chromatography (silica gel Fluka 60,
chloroform/methanol 10:1) yielding the title compound as
approximately equimolar mixture of both isomers.
[0542] Yield: 140 mg (60%). M.p. - - - (foam). R.sub.F (SiO.sub.2,
methylene chloride/methanol 9:1) 0.25.
[0543] .sup.1H NMR spectrum (250 MHz, DMSO-d.sub.6): 7.74-6.44 (m,
14H); 6.09 and 6.06 (t, 1H); 4.71 and 4.69 (s, 2H); 4.13 and 3.76
(d, 2H); 2.46 and 2.41 (s, 3H); 2.16 and 2.12 (s, 3H).
[0544] L-Lysine (42 mg, 0.287 mmol) was added to a solution of the
above acid (140 mg, 0.288 mmol) in a mixture of dry methanol and
ether (2:1, 6 mL). The formed suspension was evaporated and the
residue was re-dissolved in a mixture of dry methanol and acetone
(3:1, 4 mL). The formed solution was stirred for 2 h, evaporated in
vacuo and the residue was repeatedly triturated with anhydrous
ether yielding the L-lysinate of the title acid.
[0545] Yield: 170 mg (93%). M.p.: 129-138.degree. C.
(amorphous).
[0546] .sup.1H NMR spectrum (250 MHz, DMSO-d.sub.6): 7.75-6.45 (m,
14H); 6.08 and 6.04 (t, 1H); 4.28 (bs, 2H); 3.72 and 3.42 (d, 2H);
3.23 (bs, 1H); 2.74 (bs, 2H); 2.46 and 2.41 (s, 3H); 2.14 and 2.10
(s, 3H); 1.70-1.35 (m, 6H).
[0547] Pharmacological Methods
[0548] In Vitro PPAR Alpha, PPAR Gamma and PPAR Delta Activation
Activity
[0549] The PPAR transient transactivation assays are based on
transient transfection into human HEK293 cells of two plasmids
encoding a chimeric test protein and a reporter protein
respectively. The chimeric test protein is a fusion of the DNA
binding domain (DBD) from the yeast GAL4 transcription factor to
the ligand binding domain (LBD) of the human PPAR proteins. The
PPAR-LBD moiety harbored in addition to the ligand binding pocket
also the native activation domain (activating function 2=AF2)
allowing the fusion protein to function as a PPAR ligand dependent
transcription factor. The GAL4 DBD will direct the chimeric protein
to bind only to Gal4 enhancers (of which none existed in HEK293
cells). The reporter plasmid contained a Gal4 enhancer driving the
expression of the firefly luciferase protein. After transfection,
HEK293 cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The
fusion protein will in turn bind to the Gal4 enhancer controlling
the luciferase expression, and do nothing in the absence of ligand.
Upon addition to the cells of a PPAR ligand luciferase protein will
be produced in amounts corresponding to the activation of the PPAR
protein. The amount of luciferase protein is measured by light
emission after addition of the appropriate substrate.
[0550] Cell Culture and Transfection
[0551] HEK293 cells were grown in DMEM+10% FCS. Cells were seeded
in 96-well plates the day before transfection to give a confluency
of 50-80% at transfection. A total of 0.8 .mu.g DNA containing 0.64
.mu.g pM1.alpha./.gamma.LBD, 0.1 .mu.g pCMV.beta.Gal, 0.08 .mu.g
pGL2(Gal4).sub.5 and 0.02 .mu.g pADVANTAGE was transfected per well
using FuGene transfection reagent according to the manufacturers
instructions (Roche). Cells were allowed to express protein for 48
h followed by addition of compound.
[0552] Plasmids: Human PPAR .alpha., .gamma. and .delta. was
obtained by PCR amplification using cDNA synthesized by reverse
transcription of mRNA from human liver, adipose tissue and
plancenta respectively. Amplified cDNAs were cloned into pCR2.1 and
sequenced. The ligand binding domain (LBD) of each PPAR isoform was
generated by PCR (PPAR.alpha.: aa 167-C-terminus; PPAR.gamma.: aa
165-C-terminus; PPAR.delta.: aa 128-C-terminus) and fused to the
DNA binding domain (DBD) of the yeast transcription factor GAL4 by
subcloning fragments in frame into the vector pM1 (Sadowski et al.
(1992), Gene 118, 137) generating the plasmids pM1.alpha.LBD,
pM1.gamma.LBD and pM1.delta.. Ensuing fusions were verified by
sequencing. The reporter was constructed by inserting an
oligonucleotide encoding five repeats of the GAL4 recognition
sequence (5.times.CGGAGTACTGTCCTCCG(AG)) (Webster et al. (1988),
Nucleic Acids Res. 16, 8192) into the vector pGL2 promotor
(Promega) generating the plasmid pGL2(GAL4).sub.5. pCMV.beta.Gal
was purchased from Clontech and pADVANTAGE was purchased from
Promega.
[0553] In Vitro Transactivation Assay
[0554] Compounds: All compounds were dissolved in DMSO and diluted
1:1000 upon addition to the cells. Compounds were tested in
quadruple in concentrations ranging from 0.001 to 300 .mu.M. Cells
were treated with compound for 24 h followed by luciferase assay.
Each compound was tested in at least two separate experiments.
[0555] Luciferase assay: Medium including test compound was
aspirated and 100 .mu.l PBS incl. 1 mM Mg++ and Ca++ was added to
each well. The luciferase assay was performed using the LucLite kit
according to the manufacturers instructions (Packard Instruments).
Light emission was quantified by counting on a Packard LumiCounter.
To measure O-galactosidase activity 25 .mu.L supernatant from each
transfection lysate was transferred to a new microplate.
.beta.-galactosidase assays were performed in the microwell plates
using a kit from Promega and read in a Labsystems Ascent Multiscan
reader. The .beta.-galactosidase data were used to normalize
(transfection efficiency, cell growth etc.) the luciferase
data.
[0556] Statistical Methods
[0557] The activity of a compound is calculated as fold induction
compared to an untreated sample. For each compound the efficacy
(maximal activity) is given as a relative activity compared to
Wy14,643 for PPAR.alpha., Rosiglitazone for PPAR.gamma. and
Carbacyclin for PPAR.delta.. The EC50 is the concentration giving
50% of maximal observed activity. EC50 values were calculated via
non-linear regression using GraphPad PRISM 3.02 (GraphPad Software,
San Diego, Calif.). The results were expressed as means.+-.SD.
Sequence CWU 1
1
1 1 95 DNA Kluyveromyces lactis 1 cggagtactg tcctccgagc ggagtactgt
cctccgagcg gagtactgtc ctccgagcgg 60 agtactgtcc tccgagcgga
gtactgtcct ccgag 95
* * * * *