U.S. patent application number 11/895278 was filed with the patent office on 2008-04-17 for retinoid x receptor modulators.
Invention is credited to Marcus F. Boehm, Kevin M. Gardinier, Douglas L. Gernert, Timothy A. Grese, Christopher M. Mapes, Pierre-Yves Michellys, David A. Neel.
Application Number | 20080090860 11/895278 |
Document ID | / |
Family ID | 23054229 |
Filed Date | 2008-04-17 |
United States Patent
Application |
20080090860 |
Kind Code |
A1 |
Gardinier; Kevin M. ; et
al. |
April 17, 2008 |
Retinoid x receptor modulators
Abstract
The present invention is directed to compounds represented by
Structural Formula I and pharmaceutically acceptable salts,
solvates and hydrates thereof: ##STR1## The invention is also
directed to pharmaceutical compositions, methods of use and methods
of making compounds represented by Structural Formula I and
pharmaceutically acceptable salts, solvates and hydrates
thereof.
Inventors: |
Gardinier; Kevin M.;
(Indianapolis, IN) ; Gernert; Douglas L.;
(Indianapolis, IN) ; Grese; Timothy A.;
(Indianapolis, IN) ; Neel; David A.; (Zionsville,
IN) ; Mapes; Christopher M.; (San Diego, CA) ;
Michellys; Pierre-Yves; (San Diego, CA) ; Boehm;
Marcus F.; (San Diego, CA) |
Correspondence
Address: |
HAMILTON, BROOK, SMITH & REYNOLDS, P.C.
530 VIRGINIA ROAD
P.O. BOX 9133
CONCORD
MA
01742-9133
US
|
Family ID: |
23054229 |
Appl. No.: |
11/895278 |
Filed: |
August 23, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10471330 |
Jan 16, 2004 |
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PCT/US02/08292 |
Mar 14, 2002 |
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11895278 |
Aug 23, 2007 |
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60275885 |
Mar 14, 2001 |
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Current U.S.
Class: |
514/300 ;
514/307; 514/379; 514/406; 514/419; 514/443; 514/469; 546/121;
546/144; 548/241; 548/356.5; 548/494; 549/469; 549/57; 549/58 |
Current CPC
Class: |
A61P 13/10 20180101;
C07D 471/04 20130101; A61P 43/00 20180101; A61P 17/14 20180101;
C07D 217/16 20130101; C07D 333/60 20130101; C07D 307/85 20130101;
A61P 13/08 20180101; A61P 3/06 20180101; A61P 29/00 20180101; C07D
333/70 20130101; C07D 231/56 20130101; A61P 35/00 20180101; A61P
9/00 20180101; A61P 9/10 20180101; A61P 17/02 20180101; A61P 25/16
20180101; C07D 307/80 20130101; C07D 261/20 20130101; A61P 25/00
20180101; A61P 3/10 20180101; C07D 495/04 20130101; A61P 25/28
20180101; A61P 31/04 20180101; A61P 17/00 20180101; C07D 215/14
20130101; A61P 37/08 20180101; C07D 333/56 20130101; A61P 5/40
20180101; A61P 3/04 20180101; A61P 17/06 20180101; C07D 209/12
20130101; A61P 35/02 20180101 |
Class at
Publication: |
514/300 ;
514/307; 514/379; 514/406; 514/419; 514/443; 514/469; 546/121;
546/144; 548/241; 548/356.5; 548/494; 549/469; 549/057;
549/058 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61K 31/343 20060101 A61K031/343; A61K 31/381 20060101
A61K031/381; A61K 31/405 20060101 A61K031/405; A61P 17/00 20060101
A61P017/00; A61P 3/06 20060101 A61P003/06; A61P 35/00 20060101
A61P035/00; C07D 209/18 20060101 C07D209/18; C07D 231/56 20060101
C07D231/56; C07D 471/04 20060101 C07D471/04; C07D 333/64 20060101
C07D333/64; C07D 333/52 20060101 C07D333/52; C07D 307/82 20060101
C07D307/82; C07D 261/20 20060101 C07D261/20; C07D 217/04 20060101
C07D217/04; A61P 9/00 20060101 A61P009/00; A61P 3/10 20060101
A61P003/10; A61P 25/28 20060101 A61P025/28; A61K 31/472 20060101
A61K031/472; A61K 31/416 20060101 A61K031/416; A61K 31/423 20060101
A61K031/423 |
Claims
1. A compound represented by the following structural formula:
##STR206## or a pharmaceutically acceptable salt, solvate and
hydrate thereof, wherein: R is H, F, Cl, Br, I, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.2-C.sub.3 alkenyl,
C.sub.2-C.sub.3 haloalkenyl, C.sub.2-C.sub.3 alkynyl,
C.sub.2-C.sub.3 haloalkynyl, and C.sub.1-C.sub.3 alkoxy, wherein
said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,
and alkoxy groups may be optionally substituted; R.sub.1 and
R.sub.2 are each, independently, H, a halo, a C.sub.1-C.sub.10
alkyl a C.sub.3-C.sub.10 cycloalkyl, a C.sub.5-C.sub.10
cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered
heteroaryl, an aryl-C.sub.1-C.sub.6-alkyl, or an amino group
represented by the formula NR.sub.14R.sub.15, wherein the alkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; or
R.sub.1 and R.sub.2 taken together with the carbon atoms to which
they are attached form a five or six membered carbocyclic ring
which is optionally substituted with one or more halo or
C.sub.1-C.sub.6 alkyl groups; or R and R.sub.1 taken together with
the carbon atoms to which they are attached form an aryl, a
heteroaryl, a C.sub.5-C.sub.8 cycloalkyl or C.sub.5-C.sub.8
cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and
cyclolkenyl are optionally substituted with one or more halo,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkoxy substituents; and R.sub.3 is H, a halo, a C.sub.1-C.sub.10
alkyl, a C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.10
cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered
heteroaryl, an aryl-C.sub.1-C.sub.6-alkyl or an amino group
represented by the formula NR.sub.14R.sub.15, wherein the alkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; R.sub.4
is H, a halo, an aryl-C.sub.1-C.sub.6-alkyl, a C.sub.1-C.sub.10
alkyl or a C.sub.1-C.sub.10 alkoxy group wherein the arylalkyl,
alkyl and alkoxy groups are optionally substituted with one or more
substituents selected from halo, C.sub.1-C.sub.6 alkyl, aryl,
heteroaryl, a C.sub.1-C.sub.6 alkoxy, an amino group represented by
the formula NR.sub.14R.sub.15; or R.sub.3 and R.sub.4 taken
together with the carbon atoms to which they are attached form an
aryl, an heteroaryl, a C.sub.5-C.sub.8 cycloalkyl or
C.sub.5-C.sub.8 cycloalkenyl ring wherein the aryl, heteroaryl,
cycloalkyl and cycloalkenyl are optionally substituted with one or
more halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkoxy substituents; and R.sub.5 is H, a halo, or a
C.sub.1-C.sub.3 alkyl group which is optionally substituted with
one or more halo; R.sub.6 is H or halo; R.sub.14 and R.sub.15 are
each, independently, H, a C.sub.1-C.sub.6 alkyl, or taken together
with the nitrogen they are attached to can form a 5 to 8 membered
heterocycle; R.sub.16 is OR.sub.17, OCH(R.sub.17)OC(O)R.sub.18,
--NR.sub.19R.sub.20, or an aminoalkyl; R.sub.17, R.sub.18 and
R.sub.20 are each, independently, H or a C.sub.1-C.sub.6 alkyl;
R.sub.18 is a C.sub.1-C.sub.6 alkyl; ring A is: ##STR207## a
benzo[b]thiophenyl, optionally substituted with one or more
substituents selected from a halo, a C.sub.1-C.sub.6 alkyl, or a
C.sub.1-C.sub.6 alkoxy, wherein:
2. (canceled)
3. The compound of claim 1, wherein ring A is selected from the
group consisting of: ##STR208## wherein: the symbol indicates a
single bond connecting ring A to the phenyl group; and the symbol
"[" indicates a single bond connecting ring A to the
.alpha.,.beta.-unsaturated carbonyl group.
4. The compound of claim 1, wherein R.sub.4 is a C.sub.2-C.sub.5
alkoxy group which is optionally substituted with one or more
fluoro.
5. The compound of claim 1, wherein R.sub.5 is methyl and R.sub.6
is H.
6. The compound of claim 1, wherein R.sub.5 is methyl and R.sub.6
is fluoro.
7. The compound of claim 1, wherein: R.sub.1 and R.sub.3 are both
isopropyl; and R.sub.2 is H.
8. The compound of claim 1, wherein: R.sub.1 and R.sub.3 are both
t-butyl; and R.sub.2 is H.
9-11. (canceled)
12. The compound of claim 1, wherein the compound is represented by
the following structural formula: ##STR209## or a pharmaceutically
acceptable salt, solvate and hydrate thereof, wherein: R.sub.1' and
R.sub.3' are each, independently, H, a halo, a C.sub.1-C.sub.10
alkyl, a C.sub.3-C.sub.10 cycloalkyl, a C.sub.5-C.sub.10
cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered
heteroaryl, an aryl-C.sub.1-C.sub.6-alkyl, or an amino group
represented by the formula NR.sub.14R.sub.15, wherein the alkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3 alkoxy;
R.sub.4' is H, a halo, an aryl-C.sub.1-C.sub.6-alkyl, a
C.sub.1-C.sub.10 alkyl or a C.sub.1-C.sub.10 alkoxy group wherein
the arylalkyl, alkyl and alkoxy groups are optionally substituted
with one or more substituents selected from halo, C.sub.1-C.sub.6
alkyl, aryl, heteroaryl, a C.sub.1-C.sub.6 alkoxy, an amino group
represented by the formula NR.sub.14R.sub.15; each R.sub.9 is,
independently, a halo or a C.sub.1-C.sub.6 alkyl group; R.sub.10 is
H, a halo or a C.sub.1-C.sub.6 alkyl group; and m is 0, 1, 2 or
3.
13. The compound of claim 12, wherein: R.sub.1 and R.sub.3 are the
same and are isopropyl or t-butyl; and R.sub.5 is methyl.
14. The compound of claim 13, wherein R.sub.4 is a C.sub.2-C.sub.5
alkoxy which is optionally substituted with one or more fluoro.
15-17. (canceled)
18. A compound selected from the group consisting of:
ethyl-2-carboxylate-7-(2-ethoxy-3,5-diisopropylbenzene)-benzo[b]thiophene-
;
2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophene;
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-
-but-2-enoic acid;
(E)-3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-en-
oic acid;
(E)-3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-
-but-2-enoic acid;
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-e-
noic acid;
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-
-but-2-enoic acid; (E)
2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-p-
rop-2-enoic acid; (E)
3-[4-(2-propyloxy-3,5-di-iso-propylphenyl)benzo[b]thien-2-yl]prop-2-enoic
acid;
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]benzo[b]th-
ien-2-yl}-but-2-enoic acid;
3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thien-
-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2--
yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-
-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3-fluoropropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl}-
but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethoxy)-3-(adamant-1-yl)-5-methylphenyl]benzo[b]thie-
n-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3,3-difluoropropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-
-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethoxy)-3-propyl-5-tert-butylphenyl]-benzo[b]thien-2-
-yl}but-2-enoic acid; (E)
3-{4-[2-(3,3-difluoropropoxy)-3-propyl-5-phenylphenyl]-benzo[b]thien-2-yl-
}but-2-enoic acid; (E)
3-[4-(2-(2,2,2-trifluoroethoxy)-3-phenyl-5-methylphenyl]-benzo[b]thienyl}-
but-2-enoic acid; (E)
3-{4-[2-(2-methylpropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl}-
but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethoxy)-4-tert-butylphenyl]-benzo[b]thien-2-yl}bu-
t-2-enoic acid; (E)
3-[4-(5-(2,2,2-trifluoroethoxy)-6-tert-butylindan-4-yl)-benzo[b]thien-2-y-
l]but-2-enoic acid; (E)
3-[4-(3,5-di-tert-butylphenyl)-benzo[b]thien-2-yl]but-2-enoic acid;
(E)
3-{4-[3,5-di-iso-propyl-2-(2,2,2-trifluoroethoxy)phenyl]-5-fluoro-benzo[b-
]thien-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3-methylbutoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}but--
2-enoic acid; (E)
3-{4-[2-(3,3,3-difluoropropoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2--
yl}but-2-enoic acid; (E)
3-{4-[2-(2-methylpropoxy)-3,5-di-tert-butylphenyl)-benzo[b]thien-2-yl]but-
-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-(1,1-dimethylpropyl)-phenyl]-benzo-
[b]thien-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]t-
hien-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3-fluoropropoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]thie-
n-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3-methylbutoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]thien-
-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3,3-difluoropropoxy)-3,5-di-(1,1-dimethylpropyl)-phenyl]-benzo[b-
]thiophene]but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-(dimethylphenylmethyl)phenyl]-benzo[b-
]thien-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethoxy)-3-tert-butyl-5-phenylphenyl]-benzo[b]thien-2-
-yl]but-2-enoic acid; (E)
3-{5-[2-(2,2-difluoroethoxy)-3-phenyl-5-tert-butylphenyl]-benzo[b]thien-2-
-yl}but-2-enoic acid;
3-[3-(2-butoxy-3,5-di-iso-propylphenyl)-1H-indol-5-yl]-but-2-enoic
acid;
3-{3-[2-(3-fluoropropoxy)-3,5-di-iso-propylphenyl]-benzo[b]thien-5-yl}-bu-
t-2-enoic acid;
3-[3-(2-hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-enoic
acid;
3-[3-(3,5-di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]-but-2-
-enoic acid; and a pharmaceutically acceptable salt, solvate and
hydrate thereof.
19. A pharmaceutical composition, comprising a pharmaceutically
acceptable carrier and at least one compound represented by the
following structural formula: ##STR210## or a pharmaceutically
acceptable salt, solvate and hydrate thereof, wherein: R is H, F,
Cl, Br, I, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 haloalkenyl,
C.sub.2-C.sub.3 alkynyl, C.sub.2-C.sub.3 haloalkynyl, and
C.sub.1-C.sub.3 alkoxy, wherein said alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be
optionally substituted; R.sub.1 and R.sub.2 are each,
independently, H, a halo, a C.sub.1-C.sub.10 alkyl, a
C.sub.3-C.sub.10 cycloalkyl, a C.sub.5-C.sub.10 cycloalkenyl, a 6
to 10 membered aryl, a 5 to 10 membered heteroaryl, an
aryl-C.sub.1-C.sub.6-alkyl, or an amino group represented by the
formula NR.sub.14R.sub.15, wherein the alkyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally
substituted within one or more halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; or R.sub.1 and
R.sub.2 taken together with the carbon atoms to which they are
attached form a five or six membered carbocyclic ring which is
optionally substituted with one or more halo or C.sub.1-C.sub.6
alkyl groups; or R and R.sub.1 taken together with the carbon atoms
to which they are attached form an aryl, a heteroaryl, a
C.sub.5-C.sub.8 cycloalkyl or C.sub.5-C.sub.8 cycloalkenyl ring
wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy
substituents; and R.sub.3 is H, a halo, a C.sub.1-C.sub.10 alkyl, a
C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.10 cycloalkenyl, a 6 to
10 membered aryl, a 5 to 10 membered heteroaryl, an
aryl-C.sub.1-C.sub.6-alkyl or an amino group represented by the
formula NR.sub.14R.sub.15, wherein the alkyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally
substituted with one or more halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; R.sub.4 is H,
a halo, an aryl-C.sub.1-C.sub.6-alkyl, a C.sub.1-C.sub.10 alkyl or
a C.sub.1-C.sub.10 alkoxy group wherein the arylalkyl, alkyl and
alkoxy groups are optionally substituted with one or more
substituents selected from halo, C.sub.1-C.sub.6 alkyl, aryl,
heteroaryl, a C.sub.1-C.sub.6 alkoxy, an amino group represented by
the formula NR.sub.14R.sub.15; or R.sub.3 and R.sub.4 taken
together with the carbon atoms to which they are attached form an
aryl, an heteroaryl, a C.sub.5-C.sub.8 cycloalkyl or
C.sub.5-C.sub.8 cycloalkenyl ring wherein the aryl, heteroaryl,
cycloalkyl and cycloalkenyl are optionally substituted with one or
more halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkoxy substituents; and R.sub.5 is H, a halo, or a
C.sub.1-C.sub.3 alkyl group which is optionally substituted with
one or more halo; R.sub.6 is H or halo; R.sub.14 and R.sub.15 are
each, independently, H, a C.sub.1-C.sub.6 alkyl, or taken together
with the nitrogen they are attached to can form a 5 to 8 membered
heterocycle; R.sub.16 is OR.sub.17, OCH(R.sub.17)OC(O)R.sub.18,
--NR.sub.19R.sub.20, or an aminoalkyl; R.sub.17, R.sub.19 and
R.sub.20 are each, independently, H or a C.sub.1-C.sub.6 alkyl;
R.sub.18 is a C.sub.1-C.sub.6 alkyl; ring A is ##STR211## a
benzo[b]thiophenyl, optionally substituted with one or more
substituents selected from a halo, a C.sub.1-C.sub.6 alkyl, or a
C.sub.1-C.sub.6 alkoxy.
20-67. (canceled)
68. A method for increasing HDL cholesterol levels and reducing
triglyceride levels in a mammal comprising administering to said
mammal a pharmaceutically effective amount of at least one compound
represented by the following structural formula: ##STR212## or a
pharmaceutically acceptable salt, solvate or hydrate thereof,
wherein: R is H, F, Cl, Br, I, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3
haloalkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.2-C.sub.3 haloalkynyl,
and C.sub.1-C.sub.3 alkoxy, wherein said alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be
optionally substituted; R.sub.1 and R.sub.2 are each,
independently, H, a halo, a C.sub.1-C.sub.10 alkyl, a
C.sub.3-C.sub.10 cycloalkyl, a C.sub.5-C.sub.10 cycloalkenyl, a 6
to 10 membered aryl, a 5 to 10 membered heteroaryl, an
aryl-C.sub.1-C.sub.6-alkyl, or an amino group represented by the
formula NR.sub.14R.sub.15, wherein the alkyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally
substituted with one or more halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; or R.sub.1 and
R.sub.2 taken together with the carbon atoms to which they are
attached form a five or six membered carbocyclic ring which is
optionally substituted with one or more halo or C.sub.1-C.sub.6
alkyl groups; or R and R.sub.1 taken together with the carbon atoms
to which they are attached form an aryl, a heteroaryl, a
C.sub.5-C.sub.8 cycloalkyl or C.sub.5-C.sub.8 cycloalkenyl ring
wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy
substituents; and R.sub.3 is H, a halo, a C.sub.1-C.sub.10 alkyl, a
C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.10 cycloalkenyl, a 6 to
10 membered aryl, a 5 to 10 membered heteroaryl, an
aryl-C.sub.1-C.sub.6-alkyl or an amino group represented by the
formula NR.sub.14R.sub.15, wherein the alkyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally
substituted with one or more halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; R.sub.4 is H,
a halo, an aryl-C.sub.1-C.sub.6-alkyl, a C.sub.1-C.sub.10 alkyl or
a C.sub.1-C.sub.10 alkoxy group wherein the arylalkyl, alkyl and
alkoxy groups are optionally substituted with one or more
substituents selected from halo, C.sub.1-C.sub.6 alkyl, aryl,
heteroaryl, a C.sub.1-C.sub.6 alkoxy, an amino group represented by
the formula NR.sub.14R.sub.15; or R.sub.3 and R.sub.4 taken
together with the carbon atoms to which they are attached form an
aryl, an heteroaryl, a C.sub.5-C.sub.8 cycloalkyl or
C.sub.5-C.sub.8 cycloalkenyl ring wherein the aryl, heteroaryl,
cycloalkyl and cycloalkenyl are optionally substituted with one or
more halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkoxy substituents; and R.sub.5 is H, a halo, or a
C.sub.1-C.sub.3 alkyl group which is optionally substituted with
one or more halo; R.sub.6 is H or halo; R.sub.14 and R.sub.15 are
each, independently, H, a C.sub.1-C.sub.6 alkyl, or taken together
with the nitrogen they are attached to can form a 5 to 8 membered
heterocycle; R.sub.16 is OR.sub.17, OCH(R.sub.17)OC(O)R.sub.18,
--NR.sub.19R.sub.20, or an aminoalkyl; R.sub.17, R.sub.19 and
R.sub.20 are each, independently, H or a C.sub.1-C.sub.6 alkyl;
R.sub.18 is a C.sub.1-C.sub.6 alkyl; ring A is ##STR213## a
benzo[b]thiophenyl, optionally substituted with one or more
substituents selected from a halo, a C.sub.1-C.sub.6 alkyl or a
C.sub.1-C.sub.6 alkoxy.
69. The method of claim 68, further comprising the step of
administering to said mammal a PPAR.gamma. agonist.
70. The method of claim 68, wherein R.sub.4 is a C.sub.2-C.sub.5
alkoxy group which is optionally substituted with one or more
fluoro.
71-73. (canceled)
74. The method of claim 68, wherein the compound is represented by
the following structural formula: ##STR214## or a pharmaceutically
acceptable salt, solvate and hydrate thereof, wherein: R.sub.1' and
R.sub.3' are each, independently, H, a halo, a C.sub.1-C.sub.10
alkyl, a C.sub.3-C.sub.10 cycloalkyl, a C.sub.5-C.sub.10
cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered
heteroaryl, an aryl-C.sub.1-C.sub.6-alkyl, or an amino group
represented by the formula NR.sub.14R.sub.15, wherein the alkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3 alkoxy;
R.sub.4' is H, a halo, an aryl-C.sub.1-C.sub.6-alkyl, a
C.sub.1-C.sub.10 alkyl or a C.sub.1-C.sub.10 alkoxy group wherein
the arylalkyl, alkyl and alkoxy groups are optionally substituted
with one or more substituents selected from halo, C.sub.1-C.sub.6
alkyl, aryl, heteroaryl, a C.sub.1-C.sub.6 alkoxy, an amino group
represented by the formula NR.sub.14R.sub.15; each R.sub.9 is,
independently, a halo or a C.sub.1-C.sub.6 alkyl group; R.sub.10 is
H, a halo or a C.sub.1-C.sub.6 alkyl group; and m is 0, 1, 2 or
3.
75. The method of claim 74, wherein the compound is selected from
the group consisting of:
ethyl-2-carboxylate-7-(2-ethoxy-3,5-di-iso-propylbenzene)-benzo[b]thiophe-
ne;
3-[7-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid;
2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophen-
e;
(E)-3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-
-enoic acid;
(E)-3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid;
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl-
]-but-2-enoic acid;
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-
-but-2-enoic acid;
2-fluoro-3-[4-(3,5-di-iso-propyl-2-propyloxyphenyl)benzo[b]thien-2-yl]but-
-2-enoic acid
3-[4-(3,5-di-iso-propyl-2-propyloxyphenyl)-benzo[b]thien-2-yl]but-2-enoic
acid;
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]benzo[b]th-
ien-2-yl}-but-2-enoic acid; (E)
2-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-methylphenyl]-benzo[b]th-
ien-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3,5-di-tert-butylphenyl]-benzo[b]thien--
2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thi-
en-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3-fluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-y-
l}but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethyloxy)-3-(adamant-1-yl)-5-methylphenyl]-benzo[b]t-
hien-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3,3-difluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-
-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethyloxy)-3-propyl-5-tert-butylphenyl]benzo[b]thien--
2-yl}but-2-enoic acid; (E)
3-{4-[2-(3,3-difluoropropyloxy)-3-propyl-5-phenylphenyl]-benzo[b]thien-2--
yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3-phenyl-5-methylbenzene]-benzo[b]thien-
-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2-methylpropyloxy)-3-tert-butyl-5-ethylphenyl]benzo[b]thien-2-yl-
}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-4-tert-butylphenyl]-benzo[b]thien-2-yl}-
but-2-enoic acid; and a pharmaceutically acceptable salt, solvate
and hydrate thereof.
76-86. (canceled)
87. A method for lowering blood glucose levels without altering
serum triglyceride levels in a mammal comprising administering to
said mammal a pharmaceutically effective amount of at least one
compound represented by the following structural formula:
##STR215## or a pharmaceutically acceptable salt, solvate or
hydrate thereof, wherein: R is H, F, Cl, Br, I, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.2-C.sub.3 alkenyl,
C.sub.2-C.sub.3 haloalkenyl, C.sub.2-C.sub.3 alkynyl,
C.sub.2-C.sub.3 haloalkynyl, and C.sub.1-C.sub.3 alkoxy, wherein
said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,
and alkoxy groups may be optionally substituted; R.sub.1 and
R.sub.2 are each, independently, H, a halo, a C.sub.1-C.sub.10
alkyl, a C.sub.3-C.sub.10 cycloalkyl, a C.sub.5-C.sub.10
cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered
heteroaryl, an aryl-C.sub.1-C.sub.6-alkyl, or an amino group
represented by the formula NR.sub.14R.sub.15, wherein the alkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; or
R.sub.1 and R.sub.2 taken together with the carbon atoms to which
they are attached form a five or six membered carbocyclic ring
which is optionally substituted with one or more halo or
C.sub.1-C.sub.6 alkyl groups; or R and R.sub.1 taken together with
the carbon atoms to which they are attached form an aryl, a
heteroaryl, a C.sub.5-C.sub.8 cycloalkyl or C.sub.5-C.sub.8
cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and
cyclolkenyl are optionally substituted with one or more halo,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkoxy substituents; and R.sub.3 is H, a halo, a C.sub.1-C.sub.10
alkyl, a C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.10
cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered
heteroaryl, an aryl-C.sub.1-C.sub.6-alkyl or an amino group
represented by the formula NR.sub.14R.sub.15, wherein the alkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; R.sub.4
is H, a halo, an aryl-C.sub.1-C.sub.6-alkyl, a C.sub.1-C.sub.10
alkyl or a C.sub.1-C.sub.10 alkoxy group wherein the arylalkyl,
alkyl and alkoxy groups are optionally substituted with one or more
substituents selected from halo, C.sub.1-C.sub.6 alkyl, aryl,
heteroaryl, a C.sub.1-C.sub.6 alkoxy, an amino group represented by
the formula NR.sub.14R.sub.15; or R.sub.3 and R.sub.4 taken
together with the carbon atoms to which they are attached form an
aryl, an heteroaryl, a C.sub.5-C.sub.8 cycloalkyl or
C.sub.5-C.sub.8 cycloalkenyl ring wherein the aryl, heteroaryl,
cycloalkyl and cycloalkenyl are optionally substituted with one or
more halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkoxy substituents; and R.sub.5 is H, a halo, or a
C.sub.1-C.sub.3 alkyl group which is optionally substituted with
one or more halo; R.sub.6 is H or halo; R.sub.14 and R.sub.15 are
each, independently, H, a C.sub.1-C.sub.6 alkyl, or taken together
with the nitrogen they are attached to can form a 5 to 8 membered
heterocycle; R.sub.16 is OR.sub.17, OCH(R.sub.17)OC(O)R.sub.18,
--NR.sub.19R.sub.20, or an aminoalkyl; R.sub.17, R.sub.18 and
R.sub.20 are each, independently, H or a C.sub.1-C.sub.6 alkyl;
R.sub.18 is a C.sub.1-C.sub.6 alkyl; ring A is ##STR216## a
benzo[b]thiophenyl, optionally substituted with one or more
substituents selected from a halo, a C_--C.sub.6 alkyl, or a
C.sub.1-C.sub.6 alkoxy.
88. The method of claim 87, wherein R.sub.4 is a C.sub.2-C.sub.5
alkoxy group which is optionally substituted with one or more
fluoro.
89-91. (canceled)
92. The method of claim 87, wherein the compound is represented by
the following structural formula: ##STR217## or a pharmaceutically
acceptable salt, solvate or hydrate thereof, wherein: R.sub.1' and
R.sub.3' are each, independently, H, a halo, a C.sub.1-C.sub.10
alkyl, a C.sub.3-C.sub.10 cycloalkyl, a C.sub.5-C.sub.10
cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered
heteroaryl, an aryl-C.sub.1-C.sub.6-alkyl, or an amino group
represented by the formula NR.sub.14R.sub.15, wherein the alkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3 alkoxy;
R.sub.4' is H, a halo, an aryl-C.sub.1-C.sub.6-alkyl, a
C.sub.1-C.sub.10 alkyl or a C.sub.1-C.sub.10 alkoxy group wherein
the arylalkyl, alkyl and alkoxy groups are optionally substituted
with one or more substituents selected from halo, C.sub.1-C.sub.6
alkyl, aryl, heteroaryl C.sub.1-C.sub.6 alkoxy, an amino group
represented by the formula NR.sub.14R.sub.15; each R.sub.9 is,
independently, a halo or a C.sub.1-C.sub.6 alkyl group; R.sub.10 is
H, a halo or a C.sub.1-C.sub.6 alkyl group; and m is 0, 1, 2 or
3.
93. The method of claim 92, wherein the compound is selected from
the group consisting of:
ethyl-2-carboxylate-7-(2-ethoxy-3,5-di-iso-propylbenzene)-benzo[b]thiophe-
ne;
3-[7-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid;
2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophen-
e;
(E)-3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-
-enoic acid;
(E)-3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid;
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl-
]-but-2-enoic acid;
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-
-but-2-enoic acid;
2-fluoro-3-[4-(3,5-di-iso-propyl-2-propyloxyphenyl)benzo[b]thien-2-yl]but-
-2-enoic acid
3-[4-(3,5-di-iso-propyl-2-propyloxyphenyl)-benzo[b]thien-2-yl]but-2-enoic
acid;
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]benzo[b]th-
ien-2-yl}-but-2-enoic acid; (E)
2-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-methylphenyl]-benzo[b]th-
ien-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3,5-di-tert-butylphenyl]-benzo[b]thien--
2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thi-
en-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3-fluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-y-
l}but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethyloxy)-3-(adamant-1-yl)-5-methylphenyl]-benzo[b]t-
hien-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3,3-difluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-
-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethyloxy)-3-propyl-5-tert-butylphenyl]benzo[b]thien--
2-yl}but-2-enoic acid; (E)
3-{4-[2-(3,3-difluoropropyloxy)-3-propyl-5-phenylphenyl]-benzo[b]thien-2--
yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3-phenyl-5-methylbenzene]-benzo[b]thien-
-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2-methylpropyloxy)-3-tert-butyl-5-ethylphenyl]benzo[b]thien-2-yl-
}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-4-tert-butylphenyl]-benzo[b]thien-2-yl}-
but-2-enoic acid; and a pharmaceutically acceptable salt, solvate
and hydrate thereof.
94-95. (canceled)
96. A method treating or preventing a disease or condition selected
from the group consisting of syndrome X, non-insulin dependent
diabetes mellitus, cancer, photoaging, acne, psoriasis, obesity,
cardiovascular disease, atherosclerosis, uterine leiomyomata,
inflamatory disease, neurodegenerative diseases, wounds and
baldness in a mammal comprising administering to said mammal a
pharmaceutically effective amount of at least one compound
represented by the following structural formula: ##STR218## or a
pharmaceutically acceptable salt, solvate or hydrate thereof,
wherein: R is H, F, Cl, Br, I, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3
haloalkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.2-C.sub.3 haloalkynyl,
and C.sub.1-C.sub.3 alkoxy, wherein said alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be
optionally substituted; R.sub.1 and R.sub.2 are each,
independently, H, a halo, a C.sub.1-C.sub.10 alkyl, a
C.sub.3-C.sub.10 cycloalkyl, a C.sub.5-C.sub.10 cycloalkenyl, a 6
to 10 membered aryl, a 5 to 10 membered heteroaryl, an
aryl-C.sub.1-C.sub.6-alkyl, or an amino group represented by the
formula NR.sub.14R.sub.15, wherein the alkyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally
substituted with one or more halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; or R.sub.1 and
R.sub.2 taken together with the carbon atoms to which they are
attached form a five or six membered carbocyclic ring which is
optionally substituted with one or more halo or C.sub.1-C.sub.6
alkyl groups; or R and R.sub.1 taken together with the carbon atoms
to which they are attached form an aryl, a heteroaryl, a
C.sub.5-C.sub.8 cycloalkyl or C.sub.5-C.sub.8 cycloalkenyl ring
wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy
substituents; and R.sub.3 is H, a halo, a C.sub.1-C.sub.10 alkyl, a
C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.10 cycloalkenyl, a 6 to
10 membered aryl, a 5 to 10 membered heteroaryl, an
aryl-C.sub.1-C.sub.6-alkyl or an amino group represented by the
formula NR.sub.14R.sub.15, wherein the alkyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally
substituted with one or more halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; R.sub.4 is H,
a halo, an aryl-C.sub.1-C.sub.6-alkyl, a C.sub.1-C.sub.10 alkyl or
a C.sub.1-C.sub.10 alkoxy group wherein the arylalkyl, alkyl and
alkoxy groups are optionally substituted with one or more
substituents selected from halo, C.sub.1-C.sub.6 alkyl, aryl,
heteroaryl, a C.sub.1-C.sub.6 alkoxy, an amino group represented by
the formula NR.sub.14R.sub.15; or R.sub.3 and R.sub.4 taken
together with the carbon atoms to which they are attached form an
aryl, an heteroaryl, a C.sub.5-C.sub.8 cycloalkyl or
C.sub.5-C.sub.8 cycloakenyl ring wherein the aryl, heteroaryl,
cycloalkyl and cycloalkenyl are optionally substituted with one or
more halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkoxy substituents; and R.sub.5 is H, a halo, or a
C.sub.1-C.sub.3 alkyl group which is optionally substituted with
one or more halo; R.sub.6 is H or halo; R.sub.14 and R.sub.15 are
each, independently, H, a C.sub.1-C.sub.6 alkyl, or taken together
with the nitrogen they are attached to can form a 5 to 8 membered
heterocycle; R.sub.16 is OR.sub.17, OCH(R.sub.17)OC(O)R.sub.18,
--NR.sub.19R.sub.20, or an aminoalkyl; R.sub.17, R.sub.19 and
R.sub.20 are each, independently, H or a C.sub.1-C.sub.6 alkyl;
R.sub.18 is a C.sub.1-C.sub.6 alkyl; ring A is ##STR219## a
benzo[b]thiophenyl optionally substituted with one or more
substituents selected from a halo, a C.sub.1-C.sub.6 alkyl, or a
C.sub.1-C.sub.6 alkoxy.
97. The method of claim 96, wherein R.sub.4 is a C.sub.2-C.sub.5
alkoxy group which is optionally substituted with one or more
fluoro.
98-100. (canceled)
101. The method of claim 96, wherein the compound is represented by
the following structural formula: ##STR220## or a pharmaceutically
acceptable salt, solvate or hydrate thereof, wherein: R.sub.1' and
R.sub.3' are each, independently, H, a halo, a C.sub.1-C.sub.10
alkyl, a C.sub.3-C.sub.10 cycloalkyl, a C.sub.5-C.sub.10
cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered
heteroaryl, an aryl-C.sub.1-C.sub.6-alkyl, or an amino group
represented by the formula NR.sub.14R.sub.15, wherein the alkyl,
cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3 alkoxy;
R.sub.4' is H, a halo, an aryl-C.sub.1-C.sub.6-alkyl, a
C.sub.1-C.sub.10 alkyl or a C.sub.1-C.sub.10 alkoxy group wherein
the arylalkyl, alkyl and alkoxy groups are optionally substituted
with one or more substituents selected from halo, C.sub.1-C.sub.6
alkyl, aryl, heteroaryl, a C.sub.1-C.sub.6 alkoxy, an amino group
represented by the formula NR.sub.14R.sub.15; each R.sub.9 is,
independently, a halo or a C.sub.1-C.sub.6 alkyl group; R.sub.10 is
H, a halo or a C.sub.1-C.sub.6 alkyl group; and m is 0, 1, 2 or
3.
102. The method of claim 101, wherein the compound is selected from
the group consisting of:
ethyl-2-carboxylate-7-(2-ethoxy-3,5-di-iso-propylbenzene)-benzo[b]thiophe-
ne;
3-[7-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid;
2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophen-
e;
(E)-3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-
-enoic acid;
(E)-3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid;
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl-
]-but-2-enoic acid;
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-
-but-2-enoic acid;
2-fluoro-3-[4-(3,5-di-iso-propyl-2-propyloxyphenyl)benzo[b]thien-2-yl]but-
-2-enoic acid
3-[4-(3,5-di-iso-propyl-2-propyloxyphenyl)-benzo[b]thien-2-yl]but-2-enoic
acid;
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]benzo[b]th-
ien-2-yl}-but-2-enoic acid; (E)
2-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-methylphenyl]-benzo[b]th-
ien-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3,5-di-tert-butylphenyl]-benzo[b]thien--
2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thi-
en-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3-fluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-y-
l}but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethyloxy)-3-(adamant-1-yl)-5-methylphenyl]-benzo[b]t-
hien-2-yl}but-2-enoic acid; (E)
3-{4-[2-(3,3-difluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-
-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2,2-difluoroethyloxy)-3-propyl-5-tert-butylphenyl]benzo[b]thien--
2-yl}but-2-enoic acid; (E)
3-{4-[2-(3,3-difluoropropyloxy)-3-propyl-5-phenylphenyl]-benzo[b]thien-2--
yl}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3-phenyl-5-methylbenzene]-benzo[b]thien-
-2-yl}but-2-enoic acid; (E)
3-{4-[2-(2-methylpropyloxy)-3-tert-butyl-5-ethylphenyl]benzo[b]thien-2-yl-
}but-2-enoic acid; (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-4-tert-butylphenyl]-benzo[b]thien-2-yl}-
but-2-enoic acid; and a pharmaceutically acceptable salt, solvate
and hydrate thereof.
103-112. (canceled)
Description
RELATED APPLICATION(S)
[0001] This application is a continuation of U.S. application Ser.
No. 10/471,330, having a 371(c) filing date of Jan. 16, 2004, which
is a U.S. National Stage of International Application No.
PCT/US02/08292, filed on Mar. 14, 2002, published in English, which
claims the benefit of U.S. Provisional Application No. 60/275,885,
filed on Mar. 14, 2001. The entire teachings of the above
application(s) are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The vitamin A metabolite, retinoic acid, has long been
recognized to induce a broad spectrum of biological effects. For
example, retinoic acid-containing products, such as Retin-A.RTM.
and Accutane.RTM., have found utility as therapeutic agents for the
treatment of various pathological conditions. In addition, a
variety of structural analogues of retinoic acid have been
synthesized that also have been found to be bioactive. Many of
these synthetic retinoids have been found to mimic many of the
pharmacological actions of retinoic acid, and thus have therapeutic
potential for the treatment of numerous disease states.
[0003] Medical professionals have become very interested in the
therapeutic applications of retinoids. Among their uses approved by
the FDA is the treatment of severe forms of acne and psoriasis as
well as cancers such as Kaposi's Sarcoma. A large body of evidence
also exists that these compounds can be used to arrest and, to an
extent, reverse the effects of skin damage arising from prolonged
exposure to the sun. Other evidence exists that these compounds
have clear effects on cellular proliferation, differentiation and
programmed cell death (apoptosis), and thus, may be useful in the
treatment and prevention of a variety of cancerous and
pre-cancerous conditions, such as acute promyleocytic leukemia
(APL), epithelial cancers, squamous cell carcinomas, including
cervical and skin cancers and renal cell carcinoma. Furthermore,
retinoids may have beneficial activity in treating and preventing
diseases of the eye, cardiovascular disease and other skin
disorders.
[0004] Major insight into the molecular mechanism of retinoic acid
signal transduction was gained in 1988, when a member of the
steroid/thyroid hormone intracellular receptor superfamily was
shown to transduce a retinoic acid signal. V. Giguere et al.,
Nature, 330:624-29 (1987); M. Petkovich et al., Nature, 330: 444-50
(1987); for a review, see R. M. Evans, Science, 240:889-95 (1988).
It is now known that retinoids regulate the activity of two
distinct intracellular receptor subfamilies: the Retinoic Acid
Receptors (RARs) and the Retinoid X Receptors (RXRs), including
their subtypes, RAR.alpha., .beta., .gamma. and RXR.alpha., .beta.,
.gamma.. All-trans-retinoic acid (ATRA) is an endogenous
low-molecular-weight ligand that modulates the transcriptional
activity of the RARs, while 9-cis retinoic acid (9-cis) is the
endogenous ligand for the RXRs. R. A. Heyman et al., Cell,
68:397-406 (1992); and A. A. Levin et al., Nature, 355:359-61
(1992).
[0005] Although both the RARs and RXRs respond to ATRA in vivo, due
to the in vivo conversion of some of the ATRA to 9-cis, the
receptors differ in several important aspects. First, the RARs and
RXRs are significantly divergent in primary structure (e.g., the
ligand binding domains of RAR.alpha. and RXR.alpha. have only
approximately 30% amino acid homology). These structural
differences are reflected in the different relative degrees of
responsiveness of RARs and RXRs to various vitamin A metabolites
and synthetic retinoids. In addition, distinctly different patterns
of tissue distribution are seen for RARs and RXRs. For example,
RXR.alpha. mRNA is expressed at high levels in the visceral
tissues, e.g., liver, kidney, lung, muscle and intestine, while
RAR.alpha. mRNA is not. Finally, the RARs and RXRs have different
target gene specificity.
[0006] RARs and RXRs regulate transcription by binding to response
elements in target genes that generally consist of two direct
repeat half-sites of the consensus sequence AGGTCA. It is believed
that RAR operates predominantly through a heterodimer complex with
RXR. RAR:RXR heterodimers activate transcription by binding to
direct repeats spaced by five base pairs. (a DR5) or by two base
pairs (a DR2). RXRs can also form homodimers. RXR:RXR homodimers
bind to a direct repeat with a spacing of one nucleotide (a DR1).
D. J. Mangelsdorf et al., "The Retinoid Receptors" in The
Retinoids. Biology, Chemistry and Medicine, M. B. Sporn, A. B.
Roberts and D. S. Goodman, Eds., Raven Press, New York, N.Y., 2nd
Edition (1994). For example, response elements have been identified
in the cellular retinal binding protein type II (CRBPII), which
consists of a DR1, and in Apolipoprotein AI genes that confer
responsiveness to RXR, but not to RAR. Further, RAR has also been
shown to repress RXR-mediated activation through the CRBPII RXR
response element (D. J. Manglesdorf et al., Cell, 66:555-61
(1991)). RXRs, however, act predominantly as coregulators, which
enhance the binding of all-trans retinoic acid, vitamin D.sub.3,
thyroid hormone, and peroxisome proliferator-activated receptors to
their response elements through heterodimerization. Also, RAR
specific target genes have been identified, including target genes
specific for RAR.beta. (e.g., PRE), that consist of a DR5. These
data indicate that two retinoic acid responsive pathways are not
simply redundant, but instead manifest a complex interplay.
[0007] RXR agonists in the context of an RXR:RXR homodimer display
unique transcriptional activity in contrast to the activity of the
same compounds through an RXR heterodimer. Activation of a RXR
homodimer is a ligand dependent event, i.e., the RXR agonist must
be present to bring about the activation of the RXR homodimer. In
contrast, RXR working through a heterodimer (e.g., RXR:RAR,
RXR:VDR) is often the silent partner, i.e., no RXR agonist will
activate the RXR-containing heterodimer without the corresponding
ligand for the heterodimeric partner. However, for other
heterodimers, (e.g., PPAR:RXR) a ligand for either or both of the
heterodimer partners can activate the heterodimeric complex.
Furthermore, in some instances, the presence of both an RXR agonist
and the agonist for the other heterodimeric partner (e.g.,
gemfibrizol for PPAR.alpha.: and TTNPB for RAR.alpha.) leads to at
least an additive, and often a synergistic enhancement of the
activation pathway of the other IR of the heterodimer pair (e.g.,
the PPAR.alpha. pathway). See e.g., WO 94/15902, published Jul. 21,
1994; R. Mukherjee et al., J. Steroid Biochem. Molec. Biol.,
51:157-166 (1994); and L. Jow and R. Mukherjee, J. Biol. Chem.,
270:3836-40 (1995).
[0008] RXR modulators which have been identified so far have
exhibited significant therapeutic utility, but they have also
exhibited some undesirable side effects. For instance, retinoids
have been shown to elevate triglycerides and suppress the thyroid
hormone axis (see, e.g., Sherman, S. I. et al., N. Engl. J. Med.
340(14):1075-1079 (1999). In addition, many retinoids have
undesirable side effects such as skin irritation, lipid and bone
toxicity, visual effects (including night blindness and dry eye)
and teratogenicity. Therefore, development of new compounds that
modulate RXR homo- and heterodimer activity while exhibiting fewer
side effects is desirable.
SUMMARY OF THE INVENTION
[0009] RXR modulators bind to RXR homo- or heterodimers and either
increase or decrease their ability to activate transcription of
genes that control cellular differentiation and proliferation.
Conditions mediated by retinoid X receptors include diabetes,
dermatologic diseases, inflammatory diseases, neurodegenerative
diseases, obesity, cardiovascular diseases, cancer and other
proliferative diseases, such as atherosclerosis, uterine
leiomyomata. In addition, RXR modulators can be used to promote
wound healing or to stimulate hair growth.
[0010] The present invention is directed to a class of compounds
that are RXR modulators. The compounds of the invention can be
represented by Structural Formula I and pharmaceutically acceptable
salts, solvates and hydrates thereof: ##STR2##
[0011] In Structural Formula I, R is selected from the group of
hydrogen, F, Cl, Br, I, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
haloalkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 haloalkenyl,
C.sub.2-C.sub.3 alkynyl, C.sub.2-C.sub.3 haloalkynyl, and
C.sub.1-C.sub.3 alkoxy, wherein said alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be
optionally substituted;
[0012] R.sub.1 and R.sub.2 are each, independently, H, a halo, a
C.sub.1-C.sub.10 alkyl, a C.sub.3-C.sub.10 cycloalkyl, a
C.sub.5-C.sub.10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10
membered heteroaryl, an aryl-C.sub.1-C.sub.6-alkyl, or an amino
group represented by the formula NR.sub.14R.sub.15, wherein the
alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are
optionally substituted with one or more halo, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; or
R.sub.1 and R.sub.2 taken together with the carbon atoms to which
they are attached form a five or six membered carbocyclic ring
which is optionally substituted with one or more halo or
C.sub.1-C.sub.6 alkyl groups. R.sub.14 and R.sub.15 are each,
independently, H, a C.sub.1-C.sub.6 alkyl, or taken together with
the nitrogen they are attached to can form a 5 to 8
heterocycle.
[0013] Alternatively, R and R.sub.1 taken together with the carbon
atoms to which they are attached form an aryl, a heteroaryl, a
C.sub.5-C.sub.8 cycloalkyl or C.sub.5-C.sub.8 cycloalkenyl ring in
which the aryl, heteroaryl, C.sub.5-C.sub.8 cycloalkyl or
C.sub.5-C.sub.8 cyclolkenyl are optionally substituted with one or
more halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkoxy substituents. Preferably, when R and R.sub.1
together with the carbon atoms to which they are attached form an
aryl or a heteroaryl, the aryl and heteroaryl have from five to six
atoms.
[0014] R.sub.3 is H, a halo, a C.sub.1-C.sub.10 alkyl, a
C.sub.3-C.sub.10 cycloalkyl, C.sub.5-C.sub.10 cycloalkenyl, a 6 to
10 membered aryl, a 5 to 10 membered heteroaryl, an
aryl-C.sub.1-C.sub.6-alkyl, or an amino group represented by the
formula NR.sub.14R.sub.15, wherein the alkyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally
substituted with one or more halo, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy.
[0015] R.sub.4 is H, a halo, an aryl-C.sub.1-C.sub.6-alkyl, a
C.sub.1-C.sub.10 alkyl or a C.sub.1-C.sub.10 alkoxy group wherein
the arylalkyl, alkyl, and alkoxy are optionally substituted with
one or more substituents selected from halo, C.sub.1-C.sub.6 alkyl,
aryl, heteroaryl, a C.sub.1-C.sub.6 alkoxy, an amino group
represented by the formula NR.sub.14R.sub.15. Preferably, the aryl
and the heteroaryl substituents each, independently, have from five
to ten atoms.
[0016] Alternatively, R.sub.3 and R.sub.4 taken together with the
carbon atoms to which they are attached form an aryl, an
heteroaryl, a C.sub.5-C.sub.8 cycloalkyl or C.sub.5-C.sub.8
cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and
cycloalkenyl are optionally substituted with one or more halo,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkoxy substituents. Preferably, when R.sub.3 and R.sub.4 together
with the carbon atoms to which they are attached form an aryl or a
heteroaryl, the aryl and heteroaryl have from five to ten
atoms.
[0017] R.sub.5 is H, a halo, or a C.sub.1-C.sub.3 alkyl group which
is optionally substituted with one or more halo.
[0018] R.sub.6 is H or halo.
[0019] R.sub.16 is OR.sub.17, OCH(R.sub.17)OC(O)R.sub.18,
--NR.sub.19R.sub.20, or an aminoalkyl.
[0020] R.sub.17, R.sub.18 and R.sub.20 are each, independently, H
or a C.sub.1-C.sub.6 alkyl.
[0021] R.sub.18 is a C.sub.1-C.sub.6 alkyl.
[0022] Ring A is a heteroaryl group represented by the following
structural formula: ##STR3##
[0023] In ring A, X.sub.1 and X.sub.2 are each, independently, O,
S, N, NH, or CH.
[0024] X.sub.3 is N or C.
[0025] X.sub.4 is CH or N.
[0026] p is 0 or 1.
[0027] However, when X.sub.1 is O or S, then X.sub.2 is CH or N and
p is 0.
[0028] Ring A is optionally substituted with one or more
substituents selected from a halo, a C.sub.1-C.sub.6 alkyl, or a
C.sub.1-C.sub.6 alkoxy.
[0029] In one embodiment, the present invention relates to a method
of modulating retinoid X receptor activity in a mammal by
administering to the mammal a pharmaceutically effective amount of
at least one compound represented by Structural Formula I, or
pharmaceutically acceptable salts, solvates and hydrates
thereof.
[0030] In another embodiment, the present invention relates to a
method of modulating RXR.alpha.:PPAR.alpha. heterodimer activity in
a mammal by administering to the mammal a pharmaceutically
effective amount of at least one compound represented by Structural
Formula I, or pharmaceutically acceptable salts, solvates and
hydrates thereof.
[0031] In another embodiment, the present invention relates to a
method of modulating RXR.alpha.:PPAR.alpha. heterodimer activity in
a mammal by administering to the mammal a pharmaceutically
effective amount of at least one compound represented by Structural
Formula I, or pharmaceutically acceptable salts, solvates and
hydrates thereof.
[0032] In another embodiment, the present invention relates to a
method of lowering blood glucose levels without altering serum
triglyceride levels in a mammal by administering to the mammal a
pharmaceutically effective amount of at least one compound
represented by Structural Formula I, or pharmaceutically acceptable
salts, solvates and hydrates thereof.
[0033] In another embodiment, the present invention relates to a
method of increasing HDL cholesterol levels and reducing
triglyceride levels in a mammal by administering to the mammal a
pharmaceutically effective amount of at least one compound
represented by Structural Formula I, or pharmaceutically acceptable
salts, solvates and hydrates thereof.
[0034] In another embodiment, the present invention relates to a
method of modulating lipid metabolism in a mammal by administering
to the mammal a pharmaceutically effective amount of at least one
compound represented by Structural Formula I, or pharmaceutically
acceptable salts, solvates and hydrates thereof.
[0035] In another embodiment, the present invention relates to a
method of treating or preventing a disease or condition in a
mammal, wherein the disease or condition are selected from the
group consisting of syndrome X, non-insulin dependent diabetes
mellitus, cancer, photoaging, acne, psoriasis, obesity,
cardiovascular disease, atherosclerosis, uterine leiomyomata,
inflamatory disease, neurodegenerative diseases, wounds and
baldness. The method involves administering to the mammal a
pharmaceutically effective amount of at least one compound
represented by Structural Formula I, or pharmaceutically acceptable
salts, solvates and hydrates thereof.
[0036] In another embodiment, the present invention also relates to
pharmaceutical compositions which include a pharmaceutically
acceptable carrier and at least one compound represented by
Structural Formula I, or pharmaceutically acceptable salts,
solvates and hydrates thereof.
[0037] In yet another embodiment, the present invention relates to
a method of making a compound represented by Structural Formula
I.
[0038] Compounds of the present invention and pharmaceutically
acceptable salts, solvates and hydrates thereof are expected to be
effective in treating diseases or conditions that are mediated by
retinoid X receptors or heterodimers of retinoid X receptors.
Therefore, compounds of the invention and pharmaceutically
acceptable salts, solvates and hydrates thereof are believed to be
effective in treating syndrome X, non-insulin dependent diabetes
mellitus, cancer, photoaging, acne, psoriasis, obesity,
cardiovascular disease, atherosclerosis, uterine leiomyomata,
inflamatory disease, neurodegenerative diseases, wounds and
baldness. In addition, compounds of the invention exhibit fewer
side effects than compounds currently used to treat these
conditions.
DETAILED DESCRIPTION OF THE INVENTION
[0039] As used herein, unless otherwise specified, alkyl groups
include straight chained or branched C.sub.1-C.sub.10 hydrocarbons,
which are completely saturated. Preferably, an alkyl group has from
1 to 6 carbon atoms.
[0040] The term "alkenyl" means a straight-chain or branched-chain
hydrocarbon radical having one or more carbon-carbon double-bonds
and having from 2 to about 10 carbon atoms. Examples of alkenyl
radicals include ethenyl, propenyl, 1,4-butadienyl and the like.
Preferably, an alkenyl group has from 1 to 6 carbon atoms.
[0041] The term "alkynyl" means a straight-chain or branched-chain
hydrocarbon radical having one or more carbon-carbon triple-bonds
and having from 2 to about 10 carbon atoms. Examples of alkynyl
radicals include ethynyl, propynyl, butynyl and the like.
Preferably, an alkynyl group has from 1 to 6 carbon atoms.
[0042] An alkoxy group is a C.sub.1-C.sub.6 alkyl which is linked
to a compound of the invention by an oxygen. The alkyl portion of
the C.sub.1-C.sub.6 alkoxy group can be straight chained or
branched and is completely saturated. Examples of alkoxy radicals
include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
iso-butoxy, sec-butoxy, tert-butoxy and the like.
[0043] Cycloalkyl groups, as used herein, include C.sub.3-C.sub.8
hydrocarbons, which are completely saturated.
[0044] The term "cycloalkenyl" includes optionally substituted
C.sub.5-C.sub.8 carbocyclic structures which have one or more
double bond but are not aromatic.
[0045] The terms "haloalkyl", "haloalkenyl" and "haloalkynyl"
include C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkenyl and
C.sub.1-C.sub.10 alkynyl structures, as described above, that are
substituted with one or more F, Cl, Br or I, or with combinations
thereof.
[0046] The term "carbocyclic" means a cycloalkyl, cycloalkenyl or
aryl wherein the cyclic moiety is composed of carbon atoms.
[0047] The term "heterocycle" includes optionally substituted,
saturated, unsaturated, or aromatic three- to eight-membered cyclic
structures wherein the cyclic moiety includes one to four
heteroatoms selected from oxygen, nitrogen, sulfur, or combinations
thereof.
[0048] As used herein, aryl groups have from one to ten carbon
atoms and include monocyclic aromatic ring systems (e.g. phenyl),
fused polycyclic aromatic ring systems (e.g. naphthyl and
anthracenyl) and aromatic ring systems fused to carbocyclic
non-aromatic ring systems (e.g., 1,2,3,4-tetrahydronaphthyl).
[0049] Heteroaryl groups, as used herein, are aromatic ring systems
having from five to ten atoms wherein from one to four of the atoms
are heteroatoms selected from nitrogen, sulfur or oxygen and the
remaining atoms are carbon atoms. Heteroaryl groups include
thienyl, benzo[b]furanyl, benzo[b]thienyl, indolyl,
thieno[2,3-c]pyridinyl, benzo[d]isoxazolyl, indazolyl,
imidazo[1,2-a]pyridinyl, isoquinolinyl, quinolinyl, pyridyl,
pyrrolyl, isoxazolyl, and pyrimidinyl.
[0050] An aryl-C.sub.1-C.sub.6-alkyl group, as used herein, is an
aryl substituent that is linked to a compound by an alkyl group
having from one to six carbon atoms.
[0051] An aminoalkyl group is an alkyl group having from one to six
carbon atoms which is substituted with at least one amine
represented by --NR.sub.19R.sub.20, in which R.sub.18 and R.sub.20
are each, independently, hydroden, a C.sub.1-C.sub.6 alkyl or
R.sub.18 and R.sub.20 taken together with the nitrogen to which
they are attached form a five or six membered heterocycloalkyl.
[0052] A heterocycloalkyl is a non-aromatic ring which contains
from one to four heteroatoms selected from oxygen, nitrogen or
sulfur (e.g., morpholine, piperidine, piperazine, pyrrolidine, and
thiomorpholine). Preferred heterocycloalkyl groups are morpholine
and piperidine.
[0053] The term "halo" includes to F, Cl, Br or I.
[0054] A carbonyl group is an aldehyde group represented by --CHO
or a ketone group represented by --C(O)--C.sub.1-C.sub.6-alkyl.
[0055] Phenol and amino protecting groups are known to those
skilled in the art. For examples of amino protecting groups see
Greene, et al., Protective Groups in Organic Synthesis (1991), John
Wiley & Sons, Inc., pages 309-405, the teachings of which are
incorporated herein by reference in their entirety. Preferably,
amines are protected as amides, carbamates or a phenylsulfonamide.
For examples of phenol protecting groups see Id., pages 143-174,
the teachings of which are incorporated herein by reference in
their entirety. A preferred phenol protecting group is a
methoxymethyl group.
[0056] The substituents of an "optionally substituted" structure
may include, but are not limited to, one or more of the following
preferred substituents: F, Cl, Br, I, CN, NO.sub.2, NH.sub.2,
NHCH.sub.3, N(CH.sub.3).sub.2, SH, SCH.sub.3, OH, OCH.sub.3,
OCF.sub.3, CH.sub.3, CF.sub.3, a C.sub.1-C.sub.6 alkyl, halo, a
C.sub.1-C.sub.6 alkoxy, a C.sub.1-C.sub.6 alkyl group which is
substituted with from one to thirteen halo substituents, or a
C.sub.1-C.sub.6 alkoxy group which is substituted with from one to
thirteen halo substituents. The maximum number of substituents that
a structure can have is dependent on the particular structure. A
person skilled in the art would be able to determine the maximum
number of substituents that a particular structure could have by
examining the structure of the structure. For example, a phenyl
group which is attached to a compound of the invention by one bond
can have from one to five substituents, whereas an indolyl group
which is attached to a compound of the invention by two bonds can
have from one to five substituents.
[0057] The term RXR modulator refers to a compound that binds to
one or more retinoid X receptors and modulates (i.e., increases or
decreases the transcriptional activity and/or biological properties
of the given receptor dimer) the transcriptional activity of an RXR
homodimer (i.e., RXR:RXR) and/or RXR in the context of a
heterodimer, including but not limited to heterodimer formation
with peroxisome proliferator activated receptors (e.g.,
RXR:PPAR.alpha.,.beta.,.beta.1 or .gamma.2), thyroid receptors
(e.g., RXR:TR.alpha. or .beta.), vitamin D receptors (e.g.,
RXR:VDR), retinoic acid receptors (e.g., RXR:RAR.alpha.,.beta. or
.gamma.), NGFIB receptors (e.g., RXR:NGFIB), NURR1 receptors (e.g.,
RXR:NURR1) LXR receptors (e.g., RXR:LXR.alpha.,.beta.), DAX
receptors (e.g., RXR:DAX), as well as other orphan receptors that
form heterodimers with RXR, as either an agonist, partial agonist
and/or antagonist. The particular effect of an RXR modulator as an
agonist, partial agonist and/or antagonist will depend upon the
cellular context as well as the heterodimer partner in which the
modulator compounds acts.
[0058] In a first preferred embodiment, compounds of the present
invention and pharmaceutically acceptable salts, solvates and
hydrates thereof, separately or with their respective
pharmaceutical compositions, have a benzo[b]furanyl ring A. This
group of compounds can be represented by Structural Formula II:
##STR4##
[0059] In Structural Formula II, R.sub.5, R.sub.6, and R.sub.16,
are as defined for Structural Formula I.
[0060] R.sub.1' and R.sub.3' are each, independently, H, a halo, a
C.sub.1-C.sub.10 alkyl, a C.sub.3-C.sub.10 cycloalkyl, a
C.sub.5-C.sub.10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10
membered heteroaryl, an aryl-C.sub.1-C.sub.6-alkyl or an amino
group represented by the formula NR.sub.14R.sub.15,
[0061] wherein the alkyl, cycloalkyl, cycloalkenyl, aryl,
heteroaryl and arylalkyl are optionally substituted with one or
more halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkoxy.
[0062] R.sub.4' is H, a halo, an aryl-C.sub.1-C.sub.6-alkyl, a
C.sub.1-C.sub.10 alkyl or a C.sub.1-C.sub.10 alkoxy group wherein
the arylalkyl, alkyl and alkoxy groups are optionally substituted
with one or more substituents selected from halo, C.sub.1-C.sub.6
alkyl, aryl, heteroaryl, a C.sub.1-C.sub.6 alkoxy, an amino group
represented by the formula NR.sub.14R.sub.15.
[0063] Each R.sub.7 is, independently, a halo or a C.sub.1-C.sub.6
alkyl group.
[0064] R.sub.8 is H, a halo or a C.sub.1-C.sub.6 alkyl group.
[0065] k is 0, 1, 2 or 3.
[0066] Examples of compounds having Structural Formula II include,
for instance, the compounds described in Examples 1-7, 9-10 and
22.
[0067] In a second preferred embodiment, compounds of the present
invention and pharmaceutically acceptable salts, solvates and
hydrates thereof, separately or with their respective
pharmaceutical compositions, have a benzo[b]thienyl ring A. This
group of compounds can be represented by Structural Formula III:
##STR5##
[0068] In Structural Formula III, R.sub.5, R.sub.6, and R.sub.16,
are as defined for Structural Formula I and R.sub.1', R.sub.3', and
R.sub.4' are defined as in Structural Formula II.
[0069] Each R.sub.9 is, independently, a halo or a C.sub.1-C.sub.6
alkyl group;
[0070] R.sub.10 is H, a halo or a C.sub.1-C.sub.6 alkyl group;
and
[0071] m is 0, 1, 2 or 3.
[0072] Examples of compounds having Structural Formula III include,
for instance, the compounds described in Examples 12, 14-21, 23-33
and 35-47.
[0073] In a third preferred embodiment, compounds of the present
invention and pharmaceutically acceptable salts, solvates and
hydrates thereof, separately or with their respective
pharmaceutical compositions, have an indolyl ring A. This group of
compounds can be represented by Structural Formula IV: ##STR6##
[0074] In Structural Formula IV, R.sub.5, R.sub.6, and R.sub.16,
are as defined for Structural Formula I and R.sub.1', R.sub.3', and
R.sub.4' are defined as in Structural Formula II.
[0075] R.sub.11 is H, a halo or a C.sub.1-C.sub.6 alkyl.
[0076] R.sub.12 is H or a C.sub.1-C.sub.6 alkyl.
[0077] Each R.sub.13 is, independently, a halo or a C.sub.1-C.sub.6
alkyl group.
[0078] q is 0, 1, 2 or 3
[0079] Examples of compounds having Structural Formula IV include,
for instance, the compounds described in Examples 48-52 and
63-65.
[0080] Compounds of the present invention include, but are not
limited to, the following group of compounds: [0081]
3-[5-(2-hydroxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-eno-
ic acid; [0082]
2-fluoro-3-[5-(2-methoxy-3,5-di-iso-propylphenyl)-benzo[b]furan-2-yl]-but-
-2-enoic acid; [0083]
2-fluoro-3-[7-(2-propoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]--
but-2-enoic acid ethyl ester; [0084]
3-[7-(2-ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid; [0085]
3-[7-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid; [0086]
3-[7-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid; [0087]
3-{7-[2-(3-fluoropropoxy)-3,5-di-iso-propylphenyl]-benzo[b]furan-2-yl}-bu-
t-2-enoic acid; [0088]
ethyl-2-carboxylate-7-(2-ethoxy-3,5-diisopropylbenzene)-benzo[b]thiophene-
; [0089]
3-{7-[2-(2,2-difluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]f-
uran-2-yl}-but-2-enoic acid; [0090]
(E)-2-fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[-
b]furan-2-yl}-but-2-enoic acid; [0091]
(E)-3-{7-[5,5,8,8,-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl]-be-
nzo[b]furan-2-yl}-but-2-enoic acid; [0092]
3-[7-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid; [0093]
2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophene;
[0094]
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thi-
en-2-yl}-but-2-enoic acid; [0095]
(E)-3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-en-
oic acid; [0096]
(E)-3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid; [0097]
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-e-
noic acid; [0098]
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-
-but-2-enoic acid; [0099] (E)
2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-p-
rop-2-enoic acid; [0100] (E)
3-[4-(2-propyloxy-3,5-di-iso-propylphenyl)benzo[b]thien-2-yl]prop-2-enoic
acid; [0101]
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]benzo[b]thien-2-y-
l}-but-2-enoic acid; [0102]
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]benzo[b]furan-2-y-
l}-but-2-enoic acid; [0103]
3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thien-
-2-yl}but-2-enoic acid; [0104] (E)
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2--
yl}but-2-enoic acid; [0105] (E)
3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-
-2-yl}but-2-enoic acid; [0106] (E)
3-{4-[2-(3-fluoropropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl}-
but-2-enoic acid; [0107] (E)
3-{4-[2-(2,2-difluoroethoxy)-3-(adamant-1-yl)-5-methylphenyl]benzo[b]thie-
n-2-yl}but-2-enoic acid; [0108] (E)
3-{4-[2-(3,3-difluoropropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-
-yl}but-2-enoic acid; [0109] (E)
3-{4-[2-(2,2-difluoroethoxy)-3-propyl-5-tert-butylphenyl]-benzo[b]thien-2-
-yl}but-2-enoic acid; [0110] (E)
3-{4-[2-(3,3-difluoropropoxy)-3-propyl-5-phenylphenyl]-benzo[b]thien-2-yl-
}but-2-enoic acid; [0111] (E)
3-[4-(2-(2,2,2-trifluoroethoxy)-3-phenyl-5-methylphenyl]-benzo[b]thienyl}-
but-2-enoic acid; [0112] (E)
3-{4-[2-(2-methylpropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl}-
but-2-enoic acid; [0113] (E)
3-{4-[2-(2,2,2-trifluoroethoxy)-4-tert-butylphenyl]-benzo[b]thien-2-yl}bu-
t-2-enoic acid; [0114] (E)
3-[4-(5-(2,2,2-trifluoroethoxy)-6-tert-butylindan-4-yl)-benzo[b]thien-2-y-
l]but-2-enoic acid; [0115] (E)
3-[4-(3,5-di-tert-butylphenyl)-benzo[b]thien-2-yl]but-2-enoic acid;
[0116] (E)
3-{4-[3,5-di-iso-propyl-2-(2,2,2-trifluoroethoxy)phenyl]-5-fluoro-benzo[b-
]thien-2-yl}but-2-enoic acid; [0117] (E)
3-{4-[2-(3-methylbutoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}but--
2-enoic acid; [0118] (E)
3-{4-[2-(3,3,3-difluoropropoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2--
yl}but-2-enoic acid; [0119] (E)
3-{4-[2-(2-methylpropoxy)-3,5-di-tert-butylphenyl)-benzo[b]thien-2-yl}but-
-2-enoic acid; [0120] (E)
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-(1,1-dimethylpropyl)-phenyl]-benzo-
[b]thien-2-yl}but-2-enoic acid; [0121] (E)
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]t-
hien-2-yl}but-2-enoic acid; [0122] (E)
3-{4-[2-(3-fluoropropoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]thie-
n-2-yl}but-2-enoic acid; [0123] (E)
3-{4-[2-(3-methylbutoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]thien-
-2-yl}but-2-enoic acid; [0124] (E)
3-{4-[2-(3,3-difluoropropoxy)-3,5-di-(1,1-dimethylpropyl)-phenyl]-benzo[b-
]thiophene]but-2-enoic acid; [0125] (E)
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-(dimethylphenylmethyl)phenyl]-benzo[b-
]thien-2-yl}but-2-enoic acid; [0126] (E)
3-{4-[2-(2,2-difluoroethoxy)-3-tert-butyl-5-phenylphenyl]-benzo[b]thien-2-
-yl}but-2-enoic acid; [0127] (E)
3-{5-[2-(2,2-difluoroethoxy)-3-phenyl-5-tert-butylphenyl]-benzo[b]thien-2-
-yl}but-2-enoic acid; [0128]
3-[3-(2-butoxy-3,5-di-iso-propylphenyl)-1H-indol-5-yl]-but-2-enoic
acid; [0129]
3-[3-(2-butoxy-3,5-di-iso-propylphenyl)-1-methyl-1H-indol-5-yl]-b-
ut-2-enoic acid; [0130]
3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid; [0131]
33-[3-(2-butoxy-3,5-di-tert-butyl-phenyl)-1H-indol-5-yl]-but-2-e-
noic acid; [0132]
3-[4-(2-butoxy-3,5-di-iso-propylphenyl)-1H-indol-2-yl]-but-2-enoic
acid; [0133]
3-[1-(2-butoxy-3,5-di-iso-propyl-phenyl)-isoquinolin-7-yl]-but-2(-
E)-enoic acid; [0134]
3-[4-(2-butoxy-3,5-di-iso-propyl-phenyl)-quinolin-6-yl]-but-2(E)-enoic
acid; [0135]
3-{3-[2-(3-fluoropropoxy)-3,5-di-iso-propylphenyl]-benzo[b]thien-5-yl}-bu-
t-2-enoic acid; [0136]
3-[3-(2-hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-enoic
acid; [0137]
3-[3-(3,5-di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]-but-2-enoic
acid; [0138]
3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-but-2-
-enoic acid; [0139]
3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-benzo[d]
isoxazol-5-yl]-but-2-enoic acid; [0140]
3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-1H-indazol-5-yl]-but-2-enoic
acid; [0141]
3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-but--
2-enoic acid; [0142]
3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-acry-
lic acid; [0143]
3-[3-(3,5-di-tert-butyl-2-propoxy-phenyl)-1H-indol-5-yl]-but-2-enoic
acid; [0144]
3-{3-[3,5-di-tert-butyl-2-(2,2-difluoro-ethoxy)-phenyl]-1H-indol-5-yl}-bu-
t-2-enoic acid; [0145]
3-{3-[3,5-di-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-indol-5-yl}-
-but-2-enoic acid, and
[0146] pharmaceutically acceptable salts, solvates and hydrates
thereof.
[0147] In one embodiment, ring A of compounds of the present
invention is a benzo[b]furanyl. These compounds include, but are
not limited to, the following group of compounds: [0148]
3-[5-(2-hydroxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-eno-
ic acid; [0149]
2-fluoro-3-[5-(2-methoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-
-enoic acid; [0150]
2-fluoro-3-[7-(2-propoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]--
but-2-enoic acid ethyl ester; [0151]
3-[7-(2-ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid; [0152]
3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid; [0153]
3-[7-(2-propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid; [0154]
3-{7-[2-(3-fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but--
2-enoic acid; [0155]
3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-b-
ut-2-enoic acid; [0156]
(E)-2-fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]-
furan-2-yl}-but-2-enoic acid; [0157]
(E)-3-{7-[5,5,8,8,-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl]-be-
nzo[b]furan-2-yl}-but-2-enoic acid; [0158]
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]furan-2--
yl}-but-2-enoic acid; and
[0159] pharmaceutically acceptable salts, solvates and hydrates
thereof.
[0160] In another embodiment, ring A of compounds of the present
invention is a benzo[b]thienyl. These compounds include but are not
limited to the following group of compounds: [0161]
ethyl-2-carboxylate-7-(2-ethoxy-3,5-di-iso-propylbenzene)-benzo[b]thiophe-
ne; [0162]
3-[7-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid; [0163]
2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophene;
[0164]
(E)-3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]--
but-2-enoic acid; [0165]
(E)-3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid; [0166]
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-e-
noic acid; [0167]
(E)-3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-
-but-2-enoic acid; [0168]
2-fluoro-3-[4-(3,5-di-iso-propyl-2-propyloxyphenyl)benzo[b]thien-2-yl]but-
-2-enoic acid [0169]
3-[4-(3,5-di-iso-propyl-2-propyloxyphenyl)-benzo[b]thien-2-yl]but-2-enoic
acid; [0170]
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]benzo[b]thien-2-y-
l}-but-2-enoic acid; [0171] (E)
2-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-methylphenyl]-benzo[b]th-
ien-2-yl}but-2-enoic acid; [0172] (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3,5-di-tert-butylphenyl]-benzo[b]thien--
2-yl}but-2-enoic acid; [0173] (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thi-
en-2-yl}but-2-enoic acid; [0174] (E)
3-{4-[2-(3-fluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-y-
l}but-2-enoic acid; [0175] (E)
3-{4-[2-(2,2-difluoroethyloxy)-3-(adamant-1-yl)-5-methylphenyl]-benzo[b]t-
hien-2-yl}but-2-enoic acid; [0176] (E)
3-{4-[2-(3,3-difluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-
-2-yl}but-2-enoic acid; [0177] (E)
3-{4-[2-(2,2-difluoroethyloxy)-3-propyl-5-tert-butylphenyl]benzo[b]thien--
2-yl}but-2-enoic acid; [0178] (E)
3-{4-[2-(3,3-difluoropropyloxy)-3-propyl-5-phenylphenyl]-benzo[b]thien-2--
yl}but-2-enoic acid; [0179] (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-3-phenyl-5-methylbenzene]-benzo[b]thien-
-2-yl}but-2-enoic acid; [0180] (E)
3-{4-[2-(2-methylpropyloxy)-3-tert-butyl-5-ethylphenyl]benzo[b]thien-2-yl-
}but-2-enoic acid; [0181] (E)
3-{4-[2-(2,2,2-trifluoroethyloxy)-4-tert-butylphenyl]-benzo[b]thien-2-yl}-
but-2-enoic acid; and
[0182] pharmaceutically acceptable salts, solvates and hydrates
thereof.
[0183] In another embodiment, ring A of compounds of the present
invention is an indolyl. These compounds include, but are not
limited to, the following group of compounds: [0184]
3-[3-(2-butoxy-3,5-di-iso-propyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid; [0185]
3-[3-(2-butoxy-3,5-di-iso-propylphenyl)-1-methyl-1H-indol-5-yl]--
but-2-enoic acid; [0186]
3-[3-(2-ethoxy-3,5-di-iso-propyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid; [0187]
3-[3-(2-butoxy-3,5-di-tert-butyl-phenyl)-1H-indol-5-yl]-but-2-en-
oic acid; [0188]
3-[4-(2-butoxy-3,5-di-iso-propylphenyl)-1H-indol-2-yl]-but-2-enoic
acid; [0189]
3-[3-(3,5-di-tert-butyl-2-propoxy-phenyl)-1H-indol-5-yl]-but-2-en-
oic acid; [0190]
3-{3-[3,5-di-tert-butyl-2-(2,2-difluoro-ethoxy)-phenyl]-1H-indol-5-yl}-bu-
t-2-enoic acid; [0191]
3-{3-[3,5-di-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-indol-5-yl}-
-but-2-enoic acid; and
[0192] pharmaceutically acceptable salts, solvates and hydrates
thereof.
[0193] In a fourth preferred embodiment, compounds represented by
Structural Formula I have a ring A that is selected from the group
consisting of an optionally substituted benzofuranyl, an optionally
substituted benzo[b]thiophenyl, an optionally substituted indolyl,
an optionally substituted thieno[2,3-c]pyridinyl, an optionally
substituted benzo[d]isoxazolyl, an optionally substituted
indazolyl, an optionally substituted imidazo[1,2-a]pyridinyl, an
optionally substituted isoquinolinyl, or an optionally substituted
quinolinyl.
[0194] In a fifth preferred embodiment, compounds represented by
Structural Formula I have a ring A that is selected from the
following groups: ##STR7## The symbol indicates a single bond
connecting ring A to the phenyl group, and the symbol "[" indicates
a single bond connecting ring A to the .alpha.,.beta.-unsaturated
carbonyl group.
[0195] In another embodiment, R.sub.4 of Structural Formula I or
R.sub.4 of preferred embodiments four and five is a C.sub.2-C.sub.5
alkoxy group which is optionally substituted with one or more
fluoro.
[0196] In another embodiment, R.sub.4' of preferred embodiments
one, two and three is a C.sub.2-C.sub.5 alkoxy group which is
optionally substituted with one or more fluoro.
[0197] In another embodiment, R.sub.5 is methyl and R.sub.6 is H in
anyone of the previous embodiments.
[0198] In another embodiment, R.sub.5 is methyl and R.sub.6 is
fluoro in anyone of the previous embodiments.
[0199] In another embodiment, R.sub.1 and R.sub.3 in anyone of the
previous embodiments in which they occur are the same.
[0200] In another embodiment, R.sub.1 and R.sub.3 in anyone of the
previous embodiments in which they occur are the same and are
iso-propyl or tert-butyl.
[0201] In another embodiment, R.sub.1' and R.sub.3' in anyone of
the previous embodiments in which they occur are the same.
[0202] In another embodiment, R.sub.1' and R.sub.3' in anyone of
the previous embodiments in which they occur are the same and are
iso-propyl or tert-butyl.
[0203] Compounds of Formula I are differentiated from previously
disclosed RXR modulators that have insulin sensitizing activity, in
that they cause little or no suppression of the thyroid axis and
little or no elevation of triglycerides. These compounds are
heterodimer selective modulators of RXR activity. They bind to RXR
with high affinity (K.sub.i<500 nM) and produce potent
synergistic activation of the RXR:PPA.gamma. heterodimer, but
preferably do not synergize with RAR agonists at the RXR:RAR
heterodimer. This synergistic activation of PPAR.gamma. in vitro is
contemplated to be a major determinant of the antidiabetic efficacy
of compounds in vivo.
[0204] Compounds of the present invention possess particular
application as RXR modulators and in particular as dimer-selective
RXR modulators including, but not limited to, RXR homodimer
antagonists, and agonists, partial agonists and antagonists of RXRs
in the context of a heterodimer.
[0205] In a second aspect, the present invention provides a method
of modulating processes mediated by RXR homodimers and/or RXR
heterodimers comprising administering to a patient an effective
amount of a compound of the invention as set forth above. Compounds
of the present invention also include all pharmaceutically
acceptable salts, as well as esters, and amides. As used in this
disclosure, pharmaceutically acceptable salts include, but are not
limited to: pyridine, ammonium, piperazine, diethylamine,
nicotinamide, formic, urea, sodium, potassium, calcium, magnesium,
zinc, lithium, cinnamic, methylamino, methanesulfonic, picric,
tartaric, triethylamino, dimethylamino, and
tris(hydroxymethyl)aminomethane. Additional pharmaceutically
acceptable salts are known to those skilled in the art.
[0206] Compounds of the present invention are useful in the
modulation of transcriptional activity through RXR in the context
of heterodimers other than RXR:RAR.alpha.,.beta.,.gamma. (e.g.,
RXR:PPAR.alpha.,.beta.,.gamma.; RXR:TR; RXR:VDR; RXR:NGFIB;
RXR:NURR1; RXR:LXR.alpha.,.beta., RXR:DAX), including any other
intracellular receptors (IRs) that form a heterodimer with RXR. For
example, application of compounds of the present invention to
modulate a RXR.alpha.:PPAR.alpha. heterodimer is useful to
increase, HDL cholesterol levels and reduce triglyceride levels.
Application of many of the same compounds of the present invention
to a RXR.alpha.:PPAR.gamma. heterodimer modulates a distinct
activity, i.e., modulation of adipocyte biology, including effects
on the differentiation and apoptosis of adipocytes, which will have
implications in the treatment and/or prevention of diabetes and
obesity. In addition, use of the modulator compounds of the present
invention with activators of the other heterodimer partner (e.g.,
fibrates for PPAR.alpha.: and thiazolidinediones for PPAR.gamma.)
can lead to a synergistic enhancement of the desired response.
Likewise, application of the modulator compounds of the present
invention in the context of a RXR.alpha.:VDR heterodimer will be
useful to modulate skin related processes (e.g., photoaging, acne,
psoriasis), malignant and pre-malignant conditions and programmed
cell death (apoptosis). Further, it will be understood by those
skilled in the art that the modulator compounds of the present
invention will also prove useful in the modulation of other
heteromer interactions that include RXR, e.g., trimers, tetramers
and the like.
[0207] In the context of an RXR homodimer, compounds of the present
invention function as partial agonists. Further, when the modulator
compounds of the present invention are combined with a
corresponding modulator of the other heterodimeric partner, a
surprising synergistic enhancement of the activation of the
heterodimer pathway can occur. For example, with respect to a
RXR.alpha.:PPAR.alpha. heterodimer, the combination of a compound
of the present invention with clofibric acid or gemfibrozil
unexpectedly leads to a greater than additive (i.e. synergistic)
activation of PPAR.alpha. responsive genes, which in turn is useful
to modulate serum cholesterol and triglyceride levels and other
conditions associated with lipid metabolism.
[0208] Whether acting on an RXR heterodimer pathway, or the RXR
homodimer pathway, it will also be understood by those skilled in
the art that the dimer-selective RXR modulator compounds of the
present invention will prove useful in any therapy in which
agonists, partial agonists and/or full antagonists of such pathways
will find application. Importantly, because compounds of the
present invention can differentially activate RXR homodimers and
RXR heterodimers, their effects will be tissue and/or cell type
specific, depending upon the cellular context of the different
tissue types in a given patient. For example, compounds of the
present invention will exert an RXR antagonist effect in tissues
where RXR homodimers prevail, and partial agonist or full agonist
activity on the PPAR pathway where RXR.alpha.:PPAR.alpha.
heterodimers prevail (e.g., in liver tissue). Thus, compounds of
the present invention will exert a differential effect in various
tissues in an analogous fashion to the manner in which various
classes of estrogens and antiestrogens (e.g., Estrogen, Tamoxifen,
Raloxifen) exert differential effects in different tissue and/or
cell types (e.g., bone, breast, uterus). See e.g., M. T. Tzukerman
et al., Mol. Endo, 8:21-30 (1994); D. P. McDonnell et al., Mol.
Endo., 9:659-669 (1995). However, in the present case, it is
believed that the differential effects of compounds of the present
invention are based upon the particular dimer pair through which
the compound acts, rather than through different transactiving
regions of the estrogen receptor in the case of estrogens and
antiestrogens. However, it is possible that they also function, in
part, by tissue selectivity.
[0209] The particular conditions that may be treated with compounds
of the present invention include, but are not limited to,
skin-related diseases, such as actinic keratoses, arsenic
keratoses, inflammatory and non-inflammatory acne, psoriasis,
ichthyoses and other keratinization and hyperproliferative
disorders of the skin, eczema, atopic dermatitis, Darriers disease,
lichen planus, prevention and reversal of glucocorticoid damage
(steroid atrophy), as a topical anti-microbial, as skin
pigmentation agents and to treat and reverse the effects of age and
photo damage to the skin. With respect to the modulation of
malignant and pre-malignant conditions, compounds may also prove
useful for the prevention and treatment of cancerous and
pre-cancerous conditions, including, premalignant and malignant
hyperproliferative diseases and cancers of epithelial origin such
as cancers of the breast, skin, prostate, cervix, uterus, colon,
bladder, esophagus, stomach, lung, larynx, oral cavity, blood and
lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias
and papillomas of the mucous membranes and in the treatment of
Kaposis sarcoma. In addition, the present compounds may be used as
agents to treat and prevent various cardiovascular diseases,
including, without limitation, diseases associated with lipid
metabolism such as dyslipidemias, prevention of restenosis and as
an agent to increase the level of circulating tissue plasminogen
activator (TPA), metabolic diseases such as obesity and diabetes
(i.e., non-insulin dependent diabetes mellitus and insulin
dependent diabetes mellitus), the modulation of differentiation and
proliferation disorders, as well as the prevention and treatment of
neurodegenerative diseases such as Alzheimer's disease, Parkinson's
disease and Amyotrophic Lateral Sclerosis (ALS), and in the
modulation of apoptosis, including both the induction of apoptosis
and inhibition of T-Cell activated apoptosis.
[0210] Furthermore, it will be understood by those skilled in the
art that compounds of the present invention, including
pharmaceutical compositions and formulations containing these
compounds, can be used in a wide variety of combination therapies
to treat the conditions and diseases described above. Thus,
compounds of the present invention can be used in combination with
modulators of the other heterodimeric partner with RXR (i.e., in
combination with PPAR.alpha. modulators, such as fibrates, in the
treatment of cardiovascular disease, and in combination with
PPAR.gamma. modulators, such thiazolidinediones, in the treatment
of diabetes, including non-insulin dependent diabetes mellitus and
insulin dependent diabetes mellitus, and with agents used to treat
obesity) and with other therapies, including, without limitation,
chemotherapeutic agents such as cytostatic and cytotoxic agents,
immunological modifiers such as interferons, interleukins, growth
hormones and other cytokines, hormone therapies, surgery and
radiation therapy.
[0211] By utilizing compounds of the present invention with
modulators of the other heterodimeric partner one is able to
utilize lower dosages of either or both modulators, thereby leading
to a significant decrease in the side-effects associated with such
modulators when employed alone at the strengths required to achieve
the desired effect. Thus, the modulator compounds of the present
invention, when utilized in combination therapies, provide an
enhanced therapeutic index (i.e., significantly enhanced efficacy
and/or decrease side-effect profiles) over utilization of compounds
by themselves.
[0212] Prodrugs are compounds of the present invention, which have
chemically or metabolically cleavable groups and become by
solvolysis or under physiological conditions compounds of the
invention which are pharmaceutically active in vivo. Prodrugs
include acid derivatives well known to practitioners of the art,
such as, for example, esters prepared by reaction of the parent
acidic compound with a suitable alcohol, or amides prepared by
reaction of the parent acid compound with a suitable amine. Simple
aliphatic or aromatic esters derived from acidic groups pendent on
compounds of this invention are preferred prodrugs. In some cases
it is desirable to prepare double ester type prodrugs such as
(acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.
Particularly preferred esters as prodrugs are methyl, ethyl,
propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl,
and N,N-diethylglycolamido.
[0213] Methyl ester prodrugs may be prepared by reaction of the
acid form of a compound of Formula I in a medium such as methanol
with an acid or base esterification catalyst (e.g., NaOH,
H.sub.2SO.sub.4). Ethyl ester prodrugs are prepared in similar
fashion using ethanol in place of methanol.
[0214] Morpholinylethyl ester prodrugs may be prepared by reaction
of the sodium salt of a compound of Structural Formula I (in a
medium such as dimethylformamide) with 4-(2-chloroethyl)morphine
hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis.
USA, Item No. C4,220-3).
[0215] The term "pharmaceutically acceptable" means that the
carrier, diluent, excipients and salt must be compatible with the
other ingredients of the formulation, and not deleterious to the
recipient thereof. Pharmaceutical formulations of the present
invention are prepared by procedures known in the art using well
known and readily available ingredients.
[0216] "Preventing" refers to reducing the likelihood that the
recipient will incur or develop any of the pathological conditions
described herein.
[0217] By virtue of its acidic moiety, a compound of Structural
Formula I forms salts with pharmaceutically acceptable bases. Such
a pharmaceutically acceptable salt may be made with a base which
affords a pharmaceutically acceptable cation, which includes alkali
metal salts (especially sodium and potassium), alkaline earth metal
salts (especially calcium and magnesium), aluminum salts, zinc
salts, and ammonium salts, as well as salts made from
physiologically acceptable organic bases such as methylamine,
dimethylamine, trimethylamine, ethylamine, diethylamine,
triethylamine, morpholine, pyridine, piperidine, piperazine,
picoline, nicotinamide, urea, tris(hydroxymethyl)aminomethane,
dicyclohexylamine, N,N'-dibenzylethylenediamine,
2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,
tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
N-benzyl-.beta.-phenethylamine, dehydroabietylamine,
N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine,
collidine, quinine, quinoline, and basic amino acid such as lysine
and arginine. These salts may be prepared by methods known to those
skilled in the art.
[0218] Compounds of Structural Formula I, which are substituted
with a basic group, may exist as salts with pharmaceutically
acceptable acids. The present invention includes such salts.
Examples of such salts include hydrochlorides, hydrobromides,
sulfates, methanesulfonates, nitrates, maleates, acetates,
citrates, cinnamates, picrate, formate, fumarates, tartrates [e.g.
(+)-tartrates, (-)-tartrates or mixtures thereof including racemic
mixtures], succinates, benzoates and salts with amino acids such as
glutamic acid.
[0219] Certain compounds of Structural Formula I and their salts
may also exist in the form of solvates, for example hydrates, and
the present invention includes each solvate and mixtures
thereof.
[0220] Certain compounds of Structural Formula I may exist in
different tautomeric forms or as different geometric isomers, and
the present invention includes each tautomer and/or geometric
isomer of compounds of Structural Formula I and mixtures
thereof.
[0221] Certain compounds of Structural Formula I may exist in
different stable conformational forms which may be separable.
Torsional asymmetry due to restricted rotation about an asymmetric
single bond, for example because of steric hindrance or ring
strain, may permit separation of different conformers. The present
invention includes each conformational isomer of compounds of
Structural Formula I and mixtures thereof.
[0222] Certain compounds of Structural Formula I may exist in
zwitterionic form and the present invention includes each
zwitterionic form of compounds of Structural Formula I and mixtures
thereof.
[0223] Certain compounds of Structural Formula I and their salts
may exist in more than one crystal form. Polymorphs of compounds
represented by Structural Formula I form part of this invention and
may be prepared by crystallization of a compound of Structural
Formula I under different conditions. For example, using different
solvents or different solvent mixtures for recrystallization;
crystallization at different temperatures; various modes of
cooling, ranging from very fast to very slow cooling during
crystallization. Polymorphs may also be obtained by heating or
melting a compound of Structural Formula I 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.
[0224] The language a "therapeutically effective amount" or
"pharmaceutically effective amount" is intended to include an
amount which is sufficient to mediate a disease or condition and
prevent its further progression or ameliorate the symptoms
associated with the disease or condition. Such an amount can be
administered prophylactically to a patient thought to be
susceptible to development of a disease or condition. Such amount
when administered prophylactically to a patient can also be
effective to prevent or lessen the severity of the mediated
condition. Such an amount is intended to include an amount which is
sufficient to modulate one or more retinoid X receptor, such as RXR
.alpha., RXR .beta., and/or RXR .gamma., which mediates a disease
or condition. Conditions mediated by retinoid X receptors include
diabetes, dermatologic diseases, inflammatory diseases,
neurodegenerative diseases, obesity, cardiovascular diseases,
cancer and other proliferative diseases, such as atherosclerosis,
uterine leiomyomata. In addition, RXR modulators can be used to
promote wound healing or to stimulate hair growth.
[0225] Compounds of Structural Formula I, and the pharmaceutically
acceptable salts, solvates and hydrates thereof, have valuable
pharmacological properties and can be used in pharmaceutical
preparations containing the compound or pharmaceutically acceptable
salts, esters or prodrugs thereof, in combination with a
pharmaceutically acceptable carrier or diluent. They are useful as
therapeutic substances in preventing or treating diabetes,
dermatologic diseases, inflammatory diseases, neurodegenerative
diseases, obesity, cardiovascular diseases, cancer,
atherosclerosis, uterine leiomyomata, wounds or hair loss in human
or non-human animals. Suitable pharmaceutically acceptable carriers
include inert solid fillers or diluents and sterile aqueous or
organic solutions. The active compound will be present in such
pharmaceutical compositions in amounts sufficient to provide the
desired dosage amount in the range described herein.
[0226] For oral administration, the compound or salts thereof can
be combined with a suitable solid or liquid carrier or diluent to
form capsules, tablets, pills, powders, syrups, solutions,
suspensions and the like.
[0227] The tablets, pills, capsules, and the like may also contain
a binder such as gum tragacanth, acacias, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch, alginic acid, a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose lactose
or saccharin. When a dosage unit form is a capsule, it may contain,
in addition to materials of the above type, a liquid carrier such
as a fatty oil.
[0228] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both. A syrup or elixir may
contain, in addition to the active ingredient, sucrose as a
sweetening agent, methyl and propylparabens as preservatives, a dye
and a flavoring such as cherry or orange flavor. Such compositions
and preparations should contain at least 0.1 percent of active
compound. The percentage of active compound in these compositions
may, of course, be varied and may conveniently be between about 2
percent to about 60 percent of the weight of the unit. The amount
of active compound in such therapeutically useful compositions is
such that an effective dosage will be obtained.
[0229] The active compounds can also be administered intranasally
as, for example, liquid drops or spray.
[0230] For parental administration compounds of the present
invention, or salts thereof can be combined with sterile aqueous or
organic media to form injectable solutions or suspensions. For
example, solutions in sesame or peanut oil, aqueous propylene
glycol and the like can be used, as well as aqueous solutions of
water-soluble pharmaceutically-acceptable salts of compounds.
Dispersions can also be prepared in glycerol, liquid polyethylene
glycols and mixtures thereof in oils. Under ordinary conditions of
storage and use, these preparations contain a preservative to
prevent the growth of microorganisms.
[0231] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that each syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against any contamination. The carrier can be solvent or
dispersion medium containing, for example, water, ethanol, polyol
(e.g. glycerol, propylene glycol and liquid polyethylene glycol),
propylene glycol and liquid polyethylene glycol), suitable mixtures
thereof, and vegetable oils. The injectable solutions prepared in
this manner can then be administered intravenously,
intraperitoneally, subcutaneously, or intramuscularly, with
intramuscular administration being preferred in humans.
[0232] The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of
administration, the condition being treated and the severity of the
condition being treated.
[0233] Preferably compounds of the invention or pharmaceutical
formulations containing these compounds are in unit dosage form for
administration to a mammal. The unit dosage form can be any unit
dosage form known in the art including, for example, a capsule, an
IV bag, a tablet, or a vial. The quantity of active ingredient
(viz., a compound of Structural Formula I or salts thereof) in a
unit dose of composition is a therapeutically effective amount and
may be varied according to the particular treatment involved. It
may be appreciated that it may be necessary to make routine
variations to the dosage depending on the age and condition of the
patient. The dosage will also depend on the route of administration
which may be by a variety of routes including oral, aerosol,
rectal, transdermal, subcutaneous, intravenous, intramuscular,
intraperitoneal and intranasal.
[0234] Pharmaceutical formulations of the invention are prepared by
combining (e.g., mixing) a therapeutically effective amount of a
compound of the invention together with a pharmaceutically
acceptable carrier or diluent. The present pharmaceutical
formulations are prepared by known procedures using well known and
readily available ingredients.
[0235] In making the compositions of the present invention, the
active ingredient will usually be admixed with a carrier, or
diluted by a carrier, or enclosed within a carrier which may be in
the form of a capsule, sachet, paper or other container. When the
carrier serves as a diluent, it may be a solid, lyophilized solid
or paste, semi-solid, or liquid material which acts as a vehicle,
or can be in the form of tablets, pills, powders, lozenges,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a
solid or in a liquid medium), or ointment, containing, for example,
up to 10% by weight of the active compound. Compounds of the
present invention are preferably formulated prior to
administration.
[0236] For the pharmaceutical formulations any suitable carrier
known in the art can be used. In such a formulation, the carrier
may be a solid, liquid, or mixture of a solid and a liquid. For
example, for intravenous injection compounds of the invention may
be dissolved in at a concentration of about 0.05 to about 5.0 mg/mL
in a 4% dextrose/0.5% Na citrate aqueous solution.
[0237] Solid form formulations include powders, tablets and
capsules. A solid carrier can be one or more substance which may
also act as flavoring agents, lubricants, solubilisers, suspending
agents, binders, tablet disintegrating agents and encapsulating
material.
[0238] Tablets for oral administration may contain suitable
excipients such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate, together with disintegrating agents, such as
maize, starch, or alginic acid, and/or binding agents, for example,
gelatin or acacia, and lubricating agents such as magnesium
stearate, stearic acid, or talc.
[0239] In powders the carrier is a finely divided solid which is in
admixture with the finely divided active ingredient. In tablets the
active ingredient is mixed with a carrier having the necessary
binding properties in suitable proportions and compacted in the
shape and size desired.
[0240] Advantageously, compositions containing the compound of
Structural Formula I or the salts thereof may be provided in dosage
unit form, preferably each dosage unit containing from about 1 to
about 500 mg be administered although it will, of course, readily
be understood that the amount of the compound or compounds of
Structural Formula I actually to be administered will be determined
by a physician, in the light of all the relevant circumstances.
[0241] Powders and tablets preferably contain from about 1 to about
99 weight percent of the active ingredient which is the novel
compound of this invention. Suitable solid carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium
carboxymethyl cellulose, low melting waxes, and cocoa butter.
[0242] The following pharmaceutical formulations 1 through 8 are
illustrative only and are not intended to limit the scope of the
invention in any way. "Active Ingredient", refers to a compound
according to Structural Formula I or salts thereof.
Formulation 1
[0243] Hard gelatin capsules are prepared using the following
ingredients: TABLE-US-00001 Quantity (mg/capsule) Active Ingredient
250 Starch, dried 200 Magnesium stearate 10 Total 460 mg
Formulation 2
[0244] A tablet is prepared using the ingredients below:
TABLE-US-00002 Quantity (mg/tablet) Active Ingredient 250
Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic
acid 5 Total 665 mg
The components are blended and compressed to form tablets each
weighing 665 mg.
Formulation 3
[0245] An aerosol solution is prepared containing the following
components: TABLE-US-00003 Weight Active Ingredient 0.25 Ethanol
25.75 Propellant 22 (Chlorodifluoromethane) 74.00 Total 100.00
The Active Ingredient is mixed with ethanol and the mixture added
to a portion of the propellant 22, cooled to 30.degree. C. and
transferred to a filling device. The required amount is then fed to
a stainless steel container and diluted with the remainder of the
propellant. The valve units are then fitted to the container.
Formulation 4
[0246] Tablets, each containing 60 mg of Active ingredient, are
made as follows: TABLE-US-00004 Active Ingredient 60 mg Starch 45
mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10%
solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg
The Active Ingredient, starch and cellulose are passed through a
No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution
containing polyvinylpyrrolidone is mixed with the resultant powder,
and the mixture then is passed through a No. 14 mesh U.S. sieve.
The granules so produced are dried at 50.degree. C. and passed
through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch,
magnesium stearate and talc, previously passed through a No. 60
mesh U.S. sieve, are then added to the granules which, after
mixing, are compressed on a tablet machine to yield tablets each
weighing 150 mg.
Formulation 5
[0247] Capsules, each containing 80 mg of Active Ingredient, are
made as follows: TABLE-US-00005 Active Ingredient 80 mg Starch 59
mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total
200 mg
The Active Ingredient, cellulose, starch, and magnesium stearate
are blended, passed through a No. 45 mesh U.S. sieve, and filled
into hard gelatin capsules in 200 mg quantities.
Formulation 6
[0248] Suppositories, each containing 225 mg of Active Ingredient,
are made as follows: TABLE-US-00006 Active Ingredient 225 mg
Saturated fatty acid glycerides 2,000 mg Total 2,225 mg
The Active Ingredient is passed through a No. 60 mesh U.S. sieve
and suspended in the saturated fatty acid glycerides previously
melted using the minimum heat necessary. The mixture is then poured
into a suppository mold of nominal 2 g capacity and allowed to
cool.
Formulation 7
[0249] Suspensions, each containing 50 mg of Active Ingredient per
5 mL dose, are made as follows: TABLE-US-00007 Active Ingredient 50
mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mL Benzoic acid
solution 0.10 mL Flavor q.v. Color q.v. Purified water to total 5
mL
The Active Ingredient is passed through a No. 45 mesh U.S. sieve
and mixed with the sodium carboxymethyl cellulose and syrup to form
a smooth paste. The benzoic acid solution, flavor and color are
diluted with a portion of the water and added, with stirring.
Sufficient water is then added to produce the required volume.
Formulation 8
[0250] An intravenous formulation may be prepared as follows:
TABLE-US-00008 Active Ingredient 100 mg Isotonic saline 1,000
mL
The solution of the above materials generally is administered
intravenously to a subject at a rate of 1 mL per minute.
Synthesis
[0251] In general, compounds of the invention can be prepared by
heating a triflate or halo substituted heteroaromatic compound (IX)
in an organic solvent with about 1 eq. to about 2 eq. of a
substituted phenylboronic acid (X) in the presence of about 0.01
eq. to about 0.1 eq. of tetrakis(triphenylphosphine) palladium(0)
and a base, such as sodium carbonate, to form a phenyl substituted
heteroaromatic compound (XI) (see Scheme I). The organic solvent
used is typically toluene or a mixture of toluene and an alcohol,
and reaction mixture is typically heated to about 60.degree. C. to
about 110.degree. C. for about 3 h to about 16 h. ##STR8##
[0252] Alternatively, R.sub.4 can be replaced by a protected
phenolic hydroxy group in compounds X and XI of Scheme I. In this
case, after addition of the substituted phenyl group to ring A, the
protecting group can be removed to form a phenolic hydroxy. The
phenolic hydroxy can then be reacted with an optionally substituted
C.sub.1-C.sub.9 alkyl iodide or an optionally substituted
C.sub.1-C.sub.9 alkyl bromide in the presence of cesium fluoride or
cesium carbonate to form a compound represented by Formula XI in
which R.sub.4 is an optionally substituted C.sub.1-C.sub.9 alkoxy
group.
[0253] When Z.sub.1 is a ketone or an aldehyde, the ketone or
aldehyde substituent of the (substituted phenyl)-heteroaromatic
ketone (XII) is converted to a .alpha.,.beta.-unsaturated ester via
a Horner-Emmons condensation with a trialkyl phosphonoacetate
(XIII) (see Scheme II). The reaction is typically carried out by
treating a solution of a trialkyl phosphonoacetate (XIII) in an
aprotic solvent such as dimethyl formamide (DMF) that has been
cooled to about -20.degree. C. to about 10.degree. C., with a
strong base, such as sodium hydride, for about 15 minutes to about
30 minutes to form an enol anion. The anion is then added to a
solution of the phenyl substituted heteroaromatic ketone or
aldehyde (XII) followed by heating the solution to about 20.degree.
C. to about 60.degree. C. for about 3 h to about 7 h. The reaction
is then quenched with water or saturated ammonium chloride solution
to form a (substituted phenyl)-heteroaromatic
.alpha.,.beta.-unsaturated ester (XIV).
[0254] The (substituted phenyl)-heteroaromatic
.alpha.,.beta.-unsaturated ester (XIV) is converted to a
(substituted phenyl)-heteroaromatic .alpha.,.beta.-unsaturated
carboxylic acid (XV) by a saponification reaction wherein the
.alpha.,.beta.-unsaturated ester (XIV) is treated with an aqueous
solution of an alkali metal hydroxide base, such as lithium
hydroxide. A water miscible organic solvent, such as
tetrahydrofuran, dioxane, and alcohols, can also be present in the
reaction mixture. Typically, the reaction is heated to about
50.degree. C. to about 80.degree. C. for about 1 h to about 4 h.
When the reaction is complete the reaction mixture is acidified
with an aqueous solution of HCl to a pH of about 1 to about 2, then
the product is extracted into an organic solvent. ##STR9##
[0255] Alternatively, the .alpha.,.beta.-unsaturated carboxylic
ester group can be added to the heteroaromatic compound before it
has been coupled with the substituted phenylboronic acid compound
(i.e., Z.sub.1 in Scheme I is an .alpha.,.beta.-unsaturated ester
represented by CR.sub.5.dbd.CR.sub.6--C(O)OR.sub.x). The starting
material in this embodiment is a halo substituted heteroaromatic
compound (XVI) that also has a substituent, such as a hydroxy or a
keto group, that can be converted into a triflate. The substituted
heteroaromatic compound (XVI) is reacted with an excess amount of
.alpha.,.beta.-unsaturated ester (XVII) (about 2 eq. to about 5
eq.) in an aprotic organic solvent in the presence of a catalytic
amount of palladium acetate (about 0.01 eq. to about 0.1 eq.) and
an aprotic base, such as a trialkyl amine (see Scheme III). The
reaction is typically heated for about 16 h to about 30 h at about
70.degree. C. to about 110.degree. C. to form a heteroaromatic
.alpha.,.beta.-unsaturated ester (XVIII). The hydroxy or ketone
group can then be converted to a triflate by reaction with
trifluoromethanesulfonic anhydride to form a triflate substituted
heteroaromatic compound (IX) which can be used reacted with a
substituted phenylboronic acid as shown in Scheme I. ##STR10##
[0256] A substituted phenyl boronic acid (X) can be prepared from a
substituted 2-iodophenol by forming a solution of the substituted
2-iodophenol (XIX), a base (e.g., potassium carbonate or cesium
carbonate) and an alkyl halide, alkyl mesylate, or alkyl tosylate
(XX) in a solvent (e.g., DMF or an alcohol) (see Scheme IV). The
solution contains with respect to the substituted 2-iodophenol
(XIX) about 1 eq. to about 2 eq. of the alkyl halide, alkyl
mesylate, or alkyl tosylate (XX) and about 1.5 eq. to about 2.5 eq.
of the base. The solution is stirred for about 2 h to about 6 h at
about room temperature to about 100.degree. C. to form a
2-alkoxy-1-iodobenzene (XXI).
[0257] A solution of an alkyl lithium is added to solution of the
2-alkoxy-1-iodobenzene (XXI) in a polar, aprotic solvent which is
kept at about -50.degree. C. to about -100.degree. C. The alkyl
lithium compound is present in about 1.2 eq. to about 2.5 eq. with
respect to the 2-alkoxy-1-iodobenzene (XXI). The suspension which
forms on addition of the alkyl lithium is stirred for about 30 min.
to about 1 h before adding about 2 eq. with respect to the alkyl
lithium of a trialkyl borate (e.g., trimethyl borate). The reaction
is allowed to warm to about -75.degree. C. to about 0.degree. C.
over a period of about 10 h to about 20 h. About 1 eq. to about 1.5
eq. with respect to the alkyl lithium of an acid, such as sulfuric
acid or hydrochloric acid, was added, and the reaction was stirred
for an additional period of about 20 min. to about 1 h to yield the
substituted phenyl boronic acid (X). ##STR11##
[0258] A compound in which ring A is a benzo[b]furanyl can be
synthesized from a triflate or halo substituted benzo[b]furan using
the method disclosed in Scheme I, or alternatively, it can be
synthesized by reacting a triflate or halo substituted
salicylaldehyde (XXII) with a substituted phenylboronic acid (X)
(see Scheme V). In this embodiment, the salicylaldehyde (XXII) and
about 0.01 eq. to about 0.1 eq. of palladium triphenyl phosphine is
dissolved in an organic solvent, such as toluene, benzene or
xylene, to form a salicylaldehyde solution having a concentration
of about 0.1 M to about 0.15 M. A solution having a concentration
of about 0.3 M to about 0.8 M of phenyl boronic acid (X) in
alcohol, such as ethanol, is added to the salicylaldehyde solution
(about 1.5 to about 2.5 molar equivalents of phenyl boronic acid is
added with respect to salicylaldehyde). Then a 2 N aqueous solution
of sodium carbonate is added (about 1 eq. to about 1.5 eq. with
respect to the phenyl boronic acid), and the reaction is refluxed
for about 1 h to about 5 h to form a
2-hydroxy-(substituted-phenyl)-benzaldehyde (XXIII).
[0259] The furanyl ring of the benzo[b]furanyl ring is formed by
dissolving the 2-hydroxy-(substituted-phenyl)-benzaldehyde (XXIII),
about 1 eq. to about 1.5 eq. of an .alpha.-halocarbonyl compound
represented by Formula XXIV and about 1.2 eq. to about 1.8 eq. of
cesium carbonate in an aprotic organic solvent, such as dimethyl
formamide (DMF). The solution is heated to about 50.degree. C. to
about 70.degree. C. for about 10 h to about 20 h to form a
(substituted phenyl)-2-carbonylbenzo[b]furan (XXV). An
.alpha.,.beta.-unsaturated carboxylic acid group can be added to
the (substituted phenyl)-2-carbonylbenzo[b]furan (XXV) by the
method depicted in Scheme II. ##STR12##
[0260] A compound in which ring A is a benzo[b]thienyl can be
synthesized from a triflate or halo substituted benzo[b]thienyl
using the method disclosed in Scheme I or, alternatively, it can be
synthesized from a fluorocarbonylbenzene (XXVI) (see Scheme VI). In
this embodiment, sodium hydride is added to a solution of an alkyl
thioglycolate (XXVII) in an aprotic solvent (e.g., DMF or an ether)
that has been cooled to about -20.degree. C. to about 11.degree. C.
About 5 min. to about 20 min. after addition of the sodium hydride,
fluorocarbonylbenzene (XXVI) is added to the reaction mixture, and
it is allowed to warm up to room temperature. Typically, the alkyl
thioglycolate (XXVII) is present in the reaction mixture in an
excess with respect to the fluorocarbonylbenzene (XXVI). The
reaction is complete in about 1 h to about 3 h to give a
thiophenyl-acetic acid alkyl ester (XXVIII).
[0261] The thiophenyl-acetic acid alkyl ester (XXVIII) is converted
to a thiophenyl-acetic acid (XXIX) via the saponification method
described for the third step of Scheme II. The thiophenyl-acetic
acid (XXIX) is then converted to an acid chloride via treatment
with thionyl chloride followed by a Friedel-Crafts acylation to
form a benzo[b]thien-3-one (XXX). In this reaction, a solution of
thiophenyl-acetic acid (XXIX) in an aprotic solvent (e.g.,
methylene chloride or dichloroethane) at room temperature is
treated with about 1.5 eq. to about 2.5 eq. of thionyl chloride.
Preferably, one drop of DMF is also added to the reaction. The
reaction mixture is heated to about 30.degree. C. to about
70.degree. C. for about 20 min. to about 1 h, then cooled to room
temperature. Preferably, after the reaction to form the acid
chloride is complete, dry nitrogen is bubbled through the reaction
mixture for about 5 min. to about 20 min. to remove traces of HCl
gas. About 0.1 eq. to about 0.5 eq. of a Friedel-Crafts catalyst is
added to the reaction mixture, and the reaction is heated to about
30.degree. C. to about 50.degree. C. for about 1 h to about 3 h to
form a benzo[b]thien-3-one (XXXI). Friedel-Crafts catalysts include
aluminum trichloride, aluminum tribromide, boron trifluoride,
ferric chloride, and zinc chloride. Aluminum trichloride is a
preferred Friedel-Crafts catalyst.
[0262] The benzo[b]thien-3-one (XXXI) is converted to a
trifluoromethanesulfonic acid benzo[b]thien-3-yl ester (XXXII) by
treating the benzo[b]thien-3-one (XXXI) in an aprotic solvent that
has been cooled to about -50.degree. C. to about -100.degree. C.
with a base such as lithium diisopropyl amine (LDA). About 20 min.
to about 45 min. after addition of the LDA,
N-phenyltrifluoromethanesulfonimide is added, and the reaction
mixture is allowed to warm up to room temperature. The reaction is
complete after about 45 min. to about 1.5 h to form the
trifluoromethanesulfonic acid benzo[b]thien-3-yl ester (XXXII).
[0263] The triflate group and the carbonyl group of the
trifluoromethanesulfonic acid benzo[b]thien-3-yl ester (XXXII) can
be further reacted to form compounds of the invention. The triflate
group can be reacted with a substituted phenylboronic acid to form
a 3-(substituted phenyl)-benzo[b]thiophene via the method depicted
in Scheme I, and the carbonyl group can be converted to an
.alpha.,.beta.-unsaturated carboxylic acid group via the method
depicted in Scheme II. ##STR13##
[0264] A 3-(substituted phenyl)-(.alpha.,.beta.-unsaturated
carboxy)-indole (XXXVI) can be prepared from an haloindole in which
the amino group has been protected with an amino protecting group,
such as a phenylsulfonamide or a carbamate (see Scheme VII). The
1-protected-haloindole (XXXII) is converted into a
1-protected-(.alpha.,.beta.-unsaturated carboxylic ester)-indole
(XXXIV) by treatment with a large excess (e.g., about 5 eq. to
about 10 eq.) of an .alpha.,.beta.-unsaturated ester (XXXIII) in
the presence of a palladium acetate catalyst and a base as
described in Scheme III.
[0265] A solution in an organic solvent of the
1-protected-(.alpha.,.beta.-unsaturated carboxylic ester)-indole
(XXXIV), N-iodosuccinamide (NIS) and an acid catalyst, such as
p-toluenesulfonic acid, is stirred for about 3 h to about 6 h at
room temperature to form a
1-protected-3-iodo-(.alpha.,.beta.-unsaturated carboxylic
ester)-indole (XXXV). About 1.5 eq. to about 2.5 eq. of
N-iodosuccinamide and about 0.1 eq. to about 0.2 eq of the acid
catalyst is present in the solution.
[0266] The iodo group can be reacted with a substituted
phenylboronic acid to form a 1-protected-3-(substituted
phenyl)-(.alpha.,.beta.-unsaturated carboxylic ester)-indole via
the method depicted in Scheme I. The ester group of the
1-protected-3-(substituted phenyl)-(.alpha.,.beta.-unsaturated
carboxylic ester)-indole can be converted to a carboxylic acid
group via a saponification reaction, and the indole nitrogen can be
deprotected to form a 3-(substituted
phenyl)-(.alpha.,.beta.-unsaturated carboxy)-indole (XXXVI).
##STR14##
[0267] A 2-(substituted phenyl)-(.alpha.,.beta.-unsaturated
carboxy)-indole (XLI) can also be prepared from a
1-protected-haloindole (XXXVII) (see Scheme VIII). A base, such as
LDA, is added to a solution of the 1-protected-haloindole (XXXVII)
in an aprotic solvent, such as an ether, which is maintained at
about -50.degree. C. to about -100.degree. C. About 1 h to about 2
h after the addition of the LDA, the solution is allowed to warm up
to about -20.degree. C. to about 110.degree. C. over a period of
about 30 min. to about 1 h. The solution is then cooled back down
to about -50.degree. C. to about -100.degree. C., then canulated
into a solution of chlorotrimethylsilane (TMSCl) in an aprotic
solvent which is also maintained at about -50.degree. C. to about
-100.degree. C. The reaction is allowed to warm to room temperature
and is continued for about 10 h to about 16 h to form a
1-protected-2-trimethylsilyl-haloindole (XXXVIII).
[0268] The trimethylsilyl group of the
1-protected-2-trimethylsilyl-haloindole (XXXVIII) is converted into
a carbonyl group via a Friedel-Crafts acylation reaction. The
Friedel-Crafts acylation is carried out by adding an anhydride or
an acid halide (XXXIX) to a mixture of a Friedel-Crafts catalyst in
an anhydrous solvent. After about 15 min. to about 30 min., the
mixture is cooled to about 10.degree. C. to about -10.degree. C.,
then the 1-protected-2-trimethylsilyl-haloindole (XXXVIII) is added
and the reaction. About 5 eq. to about 7 eq. of the Friedel-Crafts
catalyst and about 2.5 eq. to about 3.5 eq. of the anhydride or
acid chloride with respect to the
1-protected-2-trimethylsilyl-haloindole (XXXVIII) are present in
the reaction mixture. The reaction is allowed to warm to room
temperature and continued for about 45 min. to about 2 h to form a
1-protected-2-(carbonyl)-haloindole (XL).
[0269] The halo group and the alkyl ketone group of the
1-protected-2-(carbonyl)-haloindole (XL) can be further reacted to
form compounds of the invention. The halo group can be reacted with
a substituted phenylboronic acid to form a
1-protected-2-(carbonyl)-(substituted phenyl)-indole via the method
depicted in Scheme I, and the carbonyl group can be converted to an
.alpha.,.beta.-unsaturated carboxylic acid group via the method
depicted in Scheme II. Finally, the amino group is deprotected to
form a 2-(.alpha.,.beta.-unsaturated carboxy)-(substituted
phenyl)-indole (XLI). ##STR15##
[0270] Compounds of Formula I in which ring A is a isoquinoline or
an quinoline can be prepared from a halo-isoquinolin-1-one (XLII)
or a carbonyl-quinolin-4-one, respectively (see Scheme IXa which
depicts the method for the conversion of halo-isoquinolin-1-one and
IXb which depicts the method for the conversion of
carbonyl-quinolin-4-one). The halo group of the
halo-isoquinolin-1-one (XLII) is converted to an
.alpha.,.beta.-unsaturated carboxylic ester (XVII) via the method
depicted in Scheme III to form an (.alpha.,.beta.-unsaturated
carboxylic ester)-isoquinolin-1-one (XLIV). The carbonyl group of
the (.alpha.,.beta.-unsaturated carboxylic ester)-isoquinolin-1-one
(XLIV) is converted to a triflate group by adding about 1.1 eq. to
about 1.5 eq. trifluoromethane-sulfonic anhydride (Tf.sub.2O) to a
basic solution of the (.alpha.,.beta.-unsaturated carboxylic
ester)-isoquinolin-1-one (XLIV) which is maintained at about
0.degree. C. The reaction is complete in about 1 h to about 3 h to
form a 1-trifluoromethanesulfonyloxy-(.alpha.,.beta.-unsaturated
carboxylic ester)-isoquinoline (XLV). The triflate group can be
reacted with a substituted phenylboronic acid via the method
depicted in Scheme I to form a compound of Formula I in which ring
A is an isoquinoline. ##STR16##
[0271] Compounds of Formula I in which ring A is a quinoline can be
prepared from a carbonyl-quinolin-1-one (XLIII) via the method
depicted in Scheme IXb. The carbonyl-quinolin-4-one (XLI) is
converted to a triflate group by adding about 1.1 eq. to about 1.5
eq. trifluoromethanesulfonic anhydride (Tf.sub.2O) to a basic
solution of the carbonyl-quinolin-1-one (XLIII) which is maintained
at about 0.degree. C. The reaction is complete in about 1 h to
about 3 h to form a
1-trifluoromethanesulfonyloxy-carbonyl-quinoline (LXX). The
triflate group can be reacted with a substituted phenylboronic acid
(X) via the method depicted in Scheme I to form a (substituted
phenyl)-carbonyl-quinoline (LXXI). The carbonyl group of the
(substituted phenyl)-carbonyl-quinoline (LXXI) can be converted to
an .alpha.,.beta.-unsaturated carboxylic ester by adding the
(substituted phenyl)-carbonyl-quinoline (LXXI) to a solution of
2-lithio-1,1-difluoroethene (prepared by combining an alkyl lithium
with 1,1-difluoroethene at about -78.degree. C.) while maintaining
a temperature below -78.degree. C. The resulting alcohol is
isolated and immediately treated with methanol and H.sub.2SO.sub.4
to give a compound of Formula I in which ring A is a quinoline
(LXXII). ##STR17##
[0272] Compounds of Formula I in which ring A is a
thieno[2,3-c]pyridinyl can be prepared from a
2,3-thiophenedicarboxaldehyde (XLVI) (see Scheme X). The pyridinyl
ring is formed by cooling a solution of the
2,3-thiophenedicarboxaldehyde (XLVI) in an organic solvent to about
-10.degree. C. to about 10.degree. C., then adding about 1 eq. to
about 1.5 eq. of (1-acetylamino-2-oxo-propyl)-phosphonic acid
dimethyl ester (XLVII) and about 1 eq. to about 1.5 eq of a
hindered aprotic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU). The solution is allowed to come to room temperature and is
stirred for about 8 h to about 20 h to form
1-thieno[2,3-c]pyridin-5-yl-ethanone (XLVIII).
[0273] The 1-thieno[2,3-c]pyridin-5-yl-ethanone (XLVIII) dissolved
in a mixture of an organic solvent and a saturated bicarbonate
solution and treated with about 2 eq. to about a 4 eq. of bromine.
After stirring the mixture overnight at room temperature,
1-(3-bromo-thieno[2,3-c]pyridin-5-yl)-ethanone (XLIX) was
formed.
[0274] A substituted phenyl and a .alpha.,.beta.-unsaturated
carboxylic acid group can be added to the
1-(3-bromo-thieno[2,3-c]pyridin-5-yl)-ethanone by the method
described in Scheme I and Scheme II, respectively. ##STR18##
[0275] Compounds of Formula I in which ring A is a
benzo[d]isoxazole can be prepared from a substituted halobenzene or
a substituted trifluoromethanesulfonyloxybenzene (L) (see Scheme
XI). The substituted halobenzene or a substituted
trifluoromethanesulfonyloxybenzene (L) is dissolved in an aprotic
solvent, such as an ether, and then cooled to about -50.degree. C.
to bout -100.degree. C. About 1.5 eq. to about 2.5 eq. of an alkyl
lithium compound, such as t-butyl lithium, s-butyl lithium or
n-butyl lithium, is added, and the reaction is allowed to stir for
about 15 min. to about 1 h before a halo-2-fluorobenzaldehyde (LI)
is added to the reaction mixture. The reaction is allowed to warm
to room temperature and stirred for about 8 h to about 20 h to form
a halo-2-fluoro-phenyl)-(substituted phenyl)methanol (LII).
[0276] The alcohol group of the (halo-2-fluoro-phenyl)-(substituted
phenyl)methanol (LII) is oxidized to a ketone by adding a solution
of the (halo-2-fluoro-phenyl)-(substituted phenyl)methanol (LII) in
an organic solvent to a suspension of about 1 eq. to about 1.5 eq.
of pyridinium chlorochromate (PCC) at room temperature. After about
3 h to about 6 h, a (halo-2-fluoro-phenyl)-(substituted
phenyl)methanone (LIII) is formed.
[0277] To form the benzo[d]isoxazole ring, about 1 eq. of an oxime,
such as acetone oxime (LIV), is added to a mixture of about 1 eq.
of a hindered base, such as potassium t-butoxide in an ether. After
the mixture is stirred for about 15 min. to about 1 h at room
temperature, about 0.7 eq. to about 1 eq. of the
(halo-2-fluoro-phenyl)-(substituted phenyl)methanone (LIII) is
added, and the reaction is stirred for about 1 h to about 3 h. The
reaction is quenched with ammonium chloride, then extracted with an
organic solvent. The organic layer is dried over a drying agent
such as magnesium sulfate, then filtered and evaporated to a
residue. The residue is dissolved in a solution of 1:1 (vol:vol)
alcohol/1N HCl and refluxed for about 0.5 h to about 2 h to form a
halo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazole
(LV).
[0278] A .alpha.,.beta.-unsaturated carboxylic acid group can be
added to the halo-3-(substituted phenyl)-benzo[d]isoxazole (LV) by
the method described in Scheme III to form a compound represented
by Formula I in which ring A is a benzo[d]isoxazole. ##STR19##
[0279] Compounds of Formula I in which ring A is an indazole can be
prepared from a (halo-2-fluoro-phenyl)-(substituted
phenyl)methanone (LIII) (see Scheme XII). A hydrazone, such as
benzophenone hydrazone (LVI), is added to a solution of a hindered
base, such as potassium t-butoxide, in a polar organic solvent,
such as an ether. The hydrazone and the base are present in the
solution in about equal molar amounts. After stirring the mixture
for about 15 min. to about 1 h, about 0.7 eq. to about 1 eq. of the
(halo-2-fluoro-phenyl)-(substituted phenyl)methanone (LIII) is
added and the mixture is stirred for about 8 h to about 20 h at
room temperature. The reaction is quenched with ammonium chloride,
then extracted with an organic solvent. The organic layer is dried
over a drying agent, such as magnesium sulfate, then filtered and
evaporated to a residue. The residue is dissolved in a solution of
1:1 (vol:vol) alcohol/1N HCl and refluxed for about 0.5 h to about
2 h to form a halo-3-(substituted phenyl)-indazole (LVII).
[0280] A .alpha.,.beta.-unsaturated carboxylic acid group can be
added to the halo-3-(substituted phenyl)-indazole (LVII) by the
method described in Scheme III to form a compound represented by
Formula I in which ring A is an indazole. ##STR20##
[0281] Compounds of Formula I in which ring A is an
imidazo[1,2-a]pyridine can be prepared from a 2-amino-halo-pyridine
(LVIII) (see Scheme XIII). The halo group of the
2-amino-halo-pyridine can be substituted with an
.alpha.,.beta.-unsaturated carboxylic ester group via the method
depicted in Scheme III to form a
2-amino-(.alpha.,.beta.-unsaturated carboxylic ester)-pyridine
(LIX).
[0282] A haloacetaldehyde dialkyl acetal is refluxed in an aqueous
HCl solution to form haloacetaldehyde (LX). After about 15 min. to
about 1 h, the reaction is cooled to room temperature and sodium
bicarbonate is added until the reaction mixture is basic. About 0.7
eq. to about 1 eq. of 2-amino-(.alpha.,.beta.-unsaturated carboxyl
ester)-pyridine (LIX) is added to the reaction mixture, and the
reaction is allowed to stir for about 8 h to about 20 h to form an
(.alpha.,.beta.-unsaturated carboxyl ester)-imidazo[1,2-a]pyridine
(LXI).
[0283] The (.alpha.,.beta.-unsaturated carboxyl
ester)-imidazo[1,2-a]pyridine (LXI) is dissolved in an organic
solvent, and the mixture is cooled to about -10.degree. C. to about
10.degree. C. About 1 eq. to about 1.5 eq. of N-iodosuccinimide
(NIS) is added to the reaction mixture. After about 0.5 to about 2
h, 3-iodo-(.alpha.,.beta.-unsaturated carboxyl
ester)-imidazo[1,2-a]pyridine (LXII) is formed.
[0284] The iodo group of the 3-iodo-(.alpha.,.beta.-unsaturated
carboxyl ester)-imidazo[1,2-a]pyridine (LXII) can be converted to a
substituted phenyl group by the method described in Scheme I to
form a compound represented by Formula I in which ring A is an
imidazo[1,2-a]pyridine. ##STR21##
[0285] Alternatively, compounds of Formula I in which ring A is an
imidazo[1,2-a]pyridine can be prepared from a
2-amino-carboxyl-pyridine (LXIII) (see Scheme XIV). A
haloacetaldehyde dialkyl acetal is refluxed in an aqueous HCl
solution to form haloacetaldehyde (LX). After about 15 min. to
about 1 h, the reaction is cooled to room temperature and sodium
bicarbonate is added until the reaction mixture is basic. About 0.7
eq. to about 1 eq. of 2-amino-carboxyl-pyridine (LXIII) is added to
the reaction mixture and the reaction is allowed to stir for about
8 h to about 20 h to form a carboxy-imidazo[1,2-a]pyridine
(LXIV).
[0286] A solution of 1 eq. of the carboxy-imidazo[1,2-a]pyridine
(LXIV), about 2.5 eq. to about 3.5 eq. cesium carbonate and about 1
eq. to about 2 eq. of iodoalkane in an organic solvent is stirred
at room temperature for about 8 h to about 20 h to form a
(carboxylic ester)-imidazo[1,2-a]pyridine (LXV).
[0287] The (carboxylic ester)-imidazo[1,2-a]pyridine (LXV) is
dissolved in an organic solvent, and the mixture is cooled to about
-10.degree. C. to about 10.degree. C. About 1 eq. to about 1.5 eq.
of N-iodosuccinimide (NIS) is added to the reaction mixture. After
about 0.5 to about 2 h, 3-iodo-(carboxylic
ester)-imidazo[1,2-a]pyridine (LXVI) is formed.
[0288] The iodo group of the 3-iodo-(carboxylic
ester)-imidazo[1,2-a]pyridine (LXVI) can be replaced with a
substituted phenyl group by the method described in Scheme I to
form a 3-(substituted phenyl)-(carboxylic
ester)-imidazo[1,2-a]pyridine (LXVII).
[0289] The carboxylic ester group of the 3-(substituted
phenyl)-(carboxylic ester)-imidazo[1,2-a]pyridine (LXVII) is reduce
to an alcohol by treating a solution of 3-(substituted
phenyl)-(carboxylic ester)-imidazo[1,2-a]pyridine (LXVII) in an
aprotic organic solvent at about -50.degree. C. to about
-100.degree. C. with about 2.5 eq. to about 3.5 eq. of
diisobutylaluminum hydride (DIBAL-H). After about 3 h to about 6 h,
3-(substituted phenyl)-(hydroxymethyl)-imidazo[1,2-a]pyridine
(LXVIII) is formed.
[0290] The hydroxy group of 3-(substituted
phenyl)-(hydroxymethyl)-imidazo[1,2-a]pyridine (LXVIII) is oxidized
to an aldehyde by treating a solution of the 3-(substituted
phenyl)-(hydroxymethyl)-imidazo[1,2-a]pyridine (LXVIII) in an
organic solvent with about 1 eq. to about 2 eq. of
4-methylmorpholine N-oxide (NMO) and a catalytic amount (about 0.01
eq. to about 0.1 eq.) of tetrapropylammonium perruthenate (TRAP).
The reaction is stirred at room temperature for about 2 h to about
4 h to form of 3-(substituted
phenyl)-(aldehyde)-imidazo[1,2-a]pyridine (LXIX).
[0291] A .alpha.,.beta.-unsaturated carboxylic acid group can be
added to the 3-(substituted
phenyl)-(aldehyde)-imidazo[1,2-a]pyridine (LXIX) by the method
described in Scheme II to form a compound represented by Formula I
in which ring A is an imidazo[1,2-a]pyridine. ##STR22##
##STR23##
EXAMPLES
Example 1
3-[5-(2-Hydroxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-enoi-
c acid
[0292] ##STR24##
A.
2-Hydroxy-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzaldehyde
[0293] ##STR25##
[0294] To a mixture of 91 mg (0.078 mmol, 5%) of
Pd(PPh.sub.3).sub.4 and 252 mg (1.26 mmol) of 5-bromo
salicylaldehyde in 10 mL of dry toluene was added 685 mmol (2.5
mmol, 2 equivalents) of 2-methoxymethoxy-3-tert-butyl-5-ethyl
phenylboronic acid diluted in 5 mL of ethanol followed by 1.3 mL of
a 2N aqueous solution of Na.sub.2CO.sub.3. The mixture was stirred
at reflux for 3 hours and after cooling extracted with ethyl
acetate. The organic layer was dried over MgSO.sub.4 and evaporated
under reduced pressure. The residual oil was purified over silica
gel (eluent: ethyl acetate/hexane:10/90) to give 333 mg (0.969
mmol, yield: 77%) of
2-hydroxy-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzaldehyde
a pale brown oil. .sup.1H NMR (CDCl.sub.3), .delta.: 11.04 (s, 1H),
9.95 (s, 1H), 7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H),
7.19 (d, J=2.1 Hz, 1H), 7.06 (d, J=8.9 Hz, 1H), 6.98 (d, J=1.9 Hz,
1H), 4.52 (s, 2H), 3.29 (s, 3H), 2.64 (dd, J=15.2, 7.6 Hz, 2H),
1.47 (s, 9H), 1.26 (t, J=7.4 Hz, 3H).
B.
2-Acetyl-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzo[b]furan
[0295] ##STR26##
[0296] A mixture of 333 mg (0.969 mmol) of
2-hydroxy-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzaldehyde,
116 mg (1.26 mmol, 0.1 mL) of chloroacetone and 473 mg (1.45 mmol,
1.5 equivalents) of Cs.sub.2CO.sub.3 in 5 mL of dry DMF was heated
to 60.degree. C. overnight. After cooling, water was added (15 mL)
and the solution was extracted with ethyl acetate. The organic
layer was washed with water and brine, then dried over MgSO.sub.4.
Evaporation of the solvents followed by purification over a short
silica plug afforded
2-acetyl-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzo[b]furan
as a clear yellow oil (200 mg, 0526 mmol, yield: 54%). .sup.1H NMR
(CDCl.sub.3), .delta.: 7.85 (d, J=1.4 Hz, 1H), 7.68 (dd, J=8.7, 1.7
Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H), 7.02 (d,
J=2.3 Hz, 1H), 4.44 (s, 2H), 3.21 (s, 3H), 2.65 (m, 2H), 2.63 (s,
3H), 1.48 (s, 9H), 1.27 (t, J=7.7 Hz, 3H).
C.
3-[5-(2-Methoxymethoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]--
but-2-enoic acid ethyl ester
[0297] ##STR27##
[0298] To a mixture of 73 mg (1.52 mmol) of NaH in 2 mL of dry DMF
was added 287 mg (1.3 mmol, 0.25 mL) of triethylphosphonoacetate
diluted in 1 mL of dry DMF at 0.degree. C. After the gas evolution
ceased, the solution was stirred at this temperature for 15 minutes
and 195 mg (0.512 mmol) of
2-acetyl-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzo[b-
]furan diluted in 1 mL of dry DMF was added dropwise. The reddish
solution was heated to 40.degree. C. until completion (TLC
monitoring). After cooling, water was added and the mixture as
extracted with ethyl acetate. The organic layer was washed with
water and brine and dried over MgSO.sub.4. The solvents were
evaporated under reduced pressure, and the residual oil was
purified over silica gel (eluent: ethyl acetate/hexane:5/95) to
afford 58 mg (0.129 mmol, yield: 25%) of
3-[5-(2-methoxymethoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-bu-
tenoic acid ethyl ester as a clear yellow oil. .sup.1H NMR
(CDCl.sub.3), .delta.: 7.72 (d, J=1.1 Hz, 1H), 7.53 (dd, J=8.5, 1.7
Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 6.77
(broad s, 1H), 4.44 (s, 2H), 4.24 (dd, J=14.4, 7.2 Hz, 2H), 3.22
(s, 3H), 2.64 (dd, J=15.1, 7.5 Hz, 2H), 2.56 (s, 3H), 1.48 (s, 9H),
1.34 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.7 Hz, 3H).
D.
3-[5-(2-Methoxymethoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]--
but-2-enoic acid
[0299] ##STR28##
[0300] A mixture of 50 mg (0.111 mmol) of
3-[5-(2-methoxymethoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-bu-
t-2-enoic acid ethyl ester in 1 mL of THF, 1 mL of methanol and 0.5
mL of 2N aqueous LiOH solution was heated to 60.degree. C. until
completion (TLC monitoring). After cooling to room temperature the
solvents are evaporated, the mixture was acidified with 2N aqueous
HCl to pH=1-2 and extracted with ethyl acetate. The organic layer
was dried over MgSO.sub.4 and the solvents were removed under
reduced pressure. The crude acid is directly recrystallized from
petroleum ether to give 10 mg (0.023 mmol, yield: 21%) of
3-[5-(2-methoxymethoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-bu-
t-2-enoic acid as a yellow powder. .sup.1H NMR (CDCl.sub.3),
.delta.: 7.73 (broad s, 1H), 7.56 (dd, J=8.5, 1.7 Hz, 1H), 7.50 (d,
J=8.5 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 7.08 (broad s, 1H), 7.01 (d,
J=1.9 Hz, 1H), 6.70 (s, 1H), 4.45 (s, 2H), 3.22 (s, 3H), 2.64 (dd,
J=15.2, 7.6 Hz, 2H), 2.58 (s, 3H), 1.48 (s, 9H), 1.26 (t, J=7.6 Hz,
3H).
E.
3-[5-(2-Hydroxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-e-
noic Acid
[0301] A mixture of 9 mg (0.021 mmol) of
3-[5-(2-methoxymethoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-bu-
t-2-enoic acid in 0.5 mL of THF, 0.5 mL of methanol and 2 mL of 6 N
aqueous HCl was heated to 40.degree. C. overnight. The solvents
were evaporated and the aqueous layer was extracted with ethyl
acetate. The organic layer was dried over MgSO.sub.4 and the
solvents were removed under reduced pressure. The crude acid is
directly recrystallized from acetonitrile to afford 5 mg (0.013
mmol, yield: 62%) of
3-[5-(2-hydroxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-eno-
ic acid as a white solid. .sup.1H NMR (CDCl.sub.3), .delta.: 7.67
(s, 1H), 7.59 (dd, J=8.4, 2.0 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.14
(s, 1H), 7.09 (s, 1H), 6.94 (s, 1H), 6.73 (s, 1H), 3.80 (broad s,
1H), 2.64 (dd, J=15.2, 7.4 Hz, 2H), 2.59 (s, 3H), 1.45 (s, 9H),
1.25 (t, J=7.5 Hz, 3H).
Example 2
2-Fluoro-3-[5-(2-methoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2--
enoic acid
[0302] ##STR29##
A. 2-Acetyl-5-bromo benzo[b]furan
[0303] ##STR30##
[0304] A mixture of 5.0 g (24.9 mmol) of 5-bromo-salicylaldehyde,
3.0 g (32.3 mmol, 2.6 mL) of chloroacetone and 12 g (37.2 mmol) of
Cs.sub.2CO.sub.3 in 30 mL of dry DMF was heated to 60.degree. C.
overnight. After cooling at room temperature, water (100 mL) was
added and the mixture was extracted with ethyl acetate. The organic
layer was dried over MgSO.sub.4 and the solvents were removed under
reduced pressure. The crude product was directly recrystallized
from hexane to afford 4.14 g (17.3 mmol, yield: 70%) of
2-acetyl-5-bromo benzo[b]furan as a pale orange crystal. .sup.1H
NMR (CDCl.sub.3), .delta.: 7.84 (d, J=1.9 Hz, 1H), 7.56 (dd, J=9.0,
2.1 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.42 (s, 1H), 2.60 (s,
3H).
B. 2-Acetyl-5-[(2-methoxy-3,5-diisopropyl)-phenyl]benzo[b]furan
[0305] ##STR31##
[0306] To a mixture of 57 mg (0.049 mmol, 5%) of
Pd(PPh.sub.3).sub.4, 362 mg (1.26 mmol) of
2-acetyl-5-bromobenzo[b]furan and 297 mg (2.52 mmol) of
2-methoxy-3,5-diisopropyl phenylboronic acid in 10 mL of toluene,
and 5 mL of ethanol was added 1.3 mL of a 2N Na.sub.2CO.sub.3
aqueous solution. The mixture was heated to reflux for 3 hours and
after cooling (room temperature) extracted with ethyl acetate. The
organic layer was dried over MgSO.sub.4 and the solvents were
removed under reduced pressure. The crude product was filtrated
over a short silica plug (eluent: ethyl acetate/hexane:10/90) and
recrystallized from hexane to afford 309 mg (0.882 mmol, yield:
70%) of
2-acetyl-5-[(2-methoxy-3,5-diisopropyl)-phenyl]benzo[b]furan as a
white solid. .sup.1H NMR (CDCl.sub.3), .delta.: 7.91 (s, 1H), 7.74
(d, J=8.6 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.55 (s, 1H), 7.13 (d,
J=1.3 Hz, 1H), 7.05 (d, J=1.3 Hz, 1H), 3.40 (ddd, J=13.8, 6.8, 6.8
Hz, 1H), 3.30 (s, 3H), 2.92 (ddd., J=13.7, 6.9, 6.9 Hz, 1H), 2.63
(s, 3H), 1.29 (m, 6H).
C.
2-Fluoro-3-[5-(2-methoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-
-2-enoic acid ethyl ester
[0307] ##STR32##
[0308] To a mixture of 43 mg (0.89 mmol) of NaH in 1 mL of dry DMF
was added 216 mg (0.89 mmol, 0.15 mL) of triethyl
2-fluoro-2-phosphonoacetate diluted in 1 mL of dry DMF at 0.degree.
C. After the gas evolution ceased, the solution was stirred at this
temperature for 15 minutes and 103 mg (0.296 mmol) of
2-acetyl-5-[(2-methoxy-3,5-diisopropyl)-phenyl]benzo[b]furan
diluted in 1 mL of dry DMF was added dropwise. The reddish solution
was stirred to 0.degree. C. until completion (TLC monitoring).
After cooling, water was added and the mixture as extracted with
ethyl acetate. The organic layer was washed with water and brine
and dried over MgSO.sub.4. The solvents were evaporated under
reduced pressure, and the residual oil was purified over silica gel
(eluent: ethyl acetate/hexane:5/95) to afford 67 mg (0.157 mmol,
yield: 53%) of
2-fluoro-3-[5-(2-methoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-
-enoic acid ethyl ester (ratio E/Z=1/2) as a clear yellow oil.
.sup.1H NMR (CDCl.sub.3), .delta.: 7.80 (s, 1H), 7.59 (d, J=8.6 Hz,
1H), 7.49 (m, 1H), 7.29 (d, J=2.9 Hz, 1H), 7.15 (m, 2H), 4.33 (dd,
J=14.2, 7.1 Hz, 2H), 3.38 (m, 1H), 3.30 (s, 3H), 2.90 (m, 1H), 2.42
(d, J=3.2 Hz, 3H), 1.40 (t, J=7.1 Hz, 3H), 1.28 (m, 12H).
D.
2-Fluoro-3-[5-(2-methoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-
-2-enoic acid
[0309] A mixture of 60 mg (0.136 mmol) of
2-fluoro-3-[5-(2-methoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-
-enoic acid ethyl ester diluted in 1 mL of THF, 1 mL of methanol
and 0.5 mL of 2 N aqueous LiOH was heated to 40.degree. C. until
complete consumption of the ester. The solvents were evaporated and
the aqueous layer was extracted with ethyl acetate. The organic
layer was dried over MgSO.sub.4 and the solvents were removed under
reduced pressure. The crude acid is directly purified over
preparative HPLC (eluent: methanol/water +0.1% TFA: 10/90) to
afford 10 mg (0.024 mmol, yield: 18%) of the corresponding acid,
2-fluoro-3-[5-(2-methoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-
-enoic acid (30 mg -0.073 mmol, yield: 54% of the E isomer was also
isolated) as a pasty oil. .sup.1H NMR (CDCl.sub.3), .delta.: 7.83
(s, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.38 (d,
J=3.8 Hz, 1H), 7.11 (d, J=1.7 Hz, 1H), 7.06 (d, J=1.7 Hz, 1H), 4.33
(dd, J=14.2, 7.1 Hz, 2H), 3.40 (m, 1H), 3.31 (s, 3H), 2.92 (m, 1H),
2.63 (d, J=3.1 Hz, 3H), 1.31 (m, 12H).
Example 3
2-Fluoro-3-[7-(2-propoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-b-
ut-2-enoic acid ethyl ester
[0310] ##STR33##
A. 2-Acetyl-7-bromo benzo[b]furan
[0311] ##STR34##
[0312] A mixture of 5.0 g (24.9 mmol) of 3-bromo-salicylaldehyde,
3.0 g (32.3 mmol, 2.6 mL) of chloroacetone and 12 g (37.2 mmol) of
Cs.sub.2CO.sub.3 in 30 mL of dry DMF was heated to 60.degree. C.
overnight. After cooling at room temperature, water (100 mL) was
added and the mixture was extracted with ethyl acetate. The organic
layer was dried over MgSO.sub.4 and the solvents were removed under
reduced pressure. The crude product was directly recrystallized
from hexane to afford 2-acetyl-7-bromo benzo[b]furan as a pale
orange crystal.
B.
2-Acetyl-7-(2-propoxy-3-tert-butyl-5-ethylphenyl)benzo[b]furan
[0313] ##STR35##
[0314] To a mixture of 57 mg (0.049 mmol, 5%) of
Pd(PPh.sub.3).sub.4, 362 mg (1.26 mmol) of
2-acetyl-7-bromobenzo[b]furan and 2.52 mmol of
2-propoxy-3-tert-butyl-5-ethyl phenylboronic acid in 10 mL of
toluene, and 5 mL of ethanol was added 1.3 mL of a 2N
Na.sub.2CO.sub.3 aqueous solution. The mixture was heated to reflux
for 3 hours and after cooling (room temperature) extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and the
solvents were removed under reduced pressure. The crude product was
filtrated over a short silica plug (eluent: ethyl
acetate/hexane:10/90) and recrystallized from hexane to afford
2-acetyl-7-(2-propoxy-3-tert-butyl-5-ethylphenyl)benzo[b]furan as a
white solid.
C.
2-Fluoro-3-[7-(2-propoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl-
]-but-2-enoic acid ethyl ester
[0315] To a mixture of 43 mg (0.89 mmol) of NaH in 1 mL of dry DMF
was added 216 mg (0.89 mmol, 0.15 mL) of triethyl
2-fluoro-2-phosphonoacetate diluted in 1 mL of dry DMF at 0.degree.
C. After the gas evolution ceased, the solution was stirred at this
temperature for 15 minutes and 0.296 mmol of
2-acetyl-7-(2-propoxy-3-tert-butyl-5-ethylphenyl)benzo[b]furan
diluted in 1 mL of dry DMF was added dropwise. The reddish solution
was stirred to 0.degree. C. until completion (TLC monitoring).
After cooling, water was added and the mixture as extracted with
ethyl acetate. The organic layer was washed with water and brine
and dried over MgSO.sub.4. The solvents were evaporated under
reduced pressure, and the residual oil was purified over silica gel
(eluent: ethyl acetate/hexane:5/95) to afford
2-fluoro-3-[7-(2-propoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]--
but-2-enoic acid ethyl ester as a clear yellow oil. .sup.1H NMR
(CDCl.sub.3), .delta.: 7.52 (d, J=7.8 Hz, 1H), 7.52 (d, J=7.2 Hz,
1H), 7.39 (d, J=3.4 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.22 (d, J=2.1
Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 3.27 (t, J=6.2 Hz, 2H), 2.66 (dd,
J=15.1, 7.5 Hz, 1H), 2.54 (d, J=3.4 Hz, 3H), 1.46 (s, 9H), 1.27 (t,
J=7.7 Hz, 3H), 1.19 (m, 2H), 0.50 (t, J=7.4 Hz, 3H).
Example 4
3-[7-(2-Ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid
[0316] ##STR36##
A. 2-Acetyl-7-trifluoromethanesulfonate benzo[b]furan
[0317] ##STR37##
[0318] To a mixture of 4.84 g (27.5 mmol) of 2-acetyl-7-hydroxy
benzo[b]furan in 40 mL of dry CH.sub.2Cl.sub.2 and 10 mL of dry
triethylamine was added 10.9 g (30.5 mmol) of phenyltriflimide at
room temperature. The mixture was stirred at room temperature until
complexion (TLC monitoring) and water was added. The aqueous layer
was extracted with CH.sub.2Cl.sub.2 and the organic layer was dried
over MgSO.sub.4. Evaporation of the solvents gave the crude
triflate which was recrystallized from hexane to afford 8.0 g (26
mmol, yield: 95%) of 2-acetyl-7-trifluoromethanesulfonate
benzo[b]furan as a white solid. .sup.1H NMR (CDCl.sub.3), .delta.:
7.74 (d, J=7.7 Hz, 1H), 7.56 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.37
(t, J=8.0 Hz, 1H), 2.65 (s, 3H).
B. 2-Acetyl-7-(3,5-di-tert-butyl-2-ethoxyphenyl)-benzo[b]furan
[0319] ##STR38##
[0320] A mixture of 300 mg (1.08 mmol) of
3,5-di-tert-butyl-2-ethoxy phenylboronic acid, 498 mg (1.62 mmol)
of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan and 62 mg
(0.05 mmol) of Pd(PPh.sub.3).sub.4, 1 mL of 2N aqueous sodium
carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux.
After complexion (TLC), water was added and the solution was
extracted with ethyl acetate. The organic layer is dried over
MgSO.sub.4 and after evaporation of the solvents, the crude oil was
purified over a short silica plug (eluent: 10/90=ethyl
acetate/hexane) to afford 395 mg (1.00 mmol, yield: 93%/boronic
acid) of
2-acetyl-7-(3,5-di-tert-butyl-2-ethoxyphenyl)-benzo[b]furan as a
clear yellow pasty solid. .sup.1H NMR (CDCl.sub.3), .delta.: 7.72
(d, J=7.4 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.56 (s, 1H), 7.42 (s,
2H), 7.38 (d, J=7.6 Hz, 1H), 3.35 (dd, J=13.9, 7.0 Hz, 2H), 2.58
(s, 3H), 1.48 (s, 9H), 1.36 (s, 9H), 0.86 (t, J=7.0 Hz, 3H).
C.
3-[7-(2-Ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid ethyl ester
[0321] ##STR39##
[0322] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 200 mg (0.51 mmol)
of 2-acetyl-7-(3,5-di-tert-butyl-2-ethoxyphenyl)-benzo[b]furan
diluted in 3 mL of dry DMF was added dropwise. The red mixture was
slowly heated to 40.degree. C. until complexion. After cooling,
water was added and the solution was extracted 2 times with ethyl
acetate. The organic layers were combined, washed with water and
brine and dried over MgSO.sub.4. After evaporation of the solvents,
the crude oil is purified over a short plug of silica gel (eluent:
95/5 hexane/ethyl acetate) to afford 220 mg (0.476 mmol, yield:
93%) of
3-[7-(2-ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid ethyl ester as a pale yellow oil. .sup.1H NMR (CDCl.sub.3),
.delta.: 7.61 (d, J=7.4 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.46 (d,
J=2.4 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.03
(s, 1H), 6.62 (s, 1H), 4.17 (dd, J=14.4, 7.2 Hz, 2H), 3.37 (dd,
J=13.9, 7.0 Hz, 2H), 2.54 (s, 3H), 1.49 (s, 9H), 1.36 (s, 9H), 0.89
(t, J=6.9 Hz, 3H).
D.
3-[7-(2-Ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid
[0323] A mixture of 210 mg (0.450 mmol) of
3-[7-(2-ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH
(2N aqueous) was refluxed for 2 hours. After cooling at room
temperature, the mixture was acidified to pH=2 and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
3-[7-(2-Ethoxy-3,5-di-tert-butylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid was isolated as a white solid. .sup.1H NMR (CDCl.sub.3),
.delta.: 7.62 (d, J=7.4 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.44 (d,
J=2.1 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.10
(s, 1H), 6.63 (s, 1H), 3.37 (dd, J=13.8, 6.9 Hz, 2H), 2.56 (s, 3H),
1.48 (s, 9H), 1.37 (s, 9H), 0.88 (t, J=6.9 Hz, 3H).
Example 5
3-[7-(2-Ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid
[0324] ##STR40##
A. 2-Ethoxy-1-iodo-3,5-diiosopropyl-benzene
[0325] ##STR41##
[0326] 2-Iodo-4,6-diisopropyl-phenol (6.08 g, 20 mmol), cesium
carbonate (13 g, 40 mmol) and iodoethane (2.43 ml, 30 mmol) were
reacted in dimethylformamide (100 mL) at room temperature. The
reaction was diluted with water (100 mL)/hexane (30 mL). The solids
were dissolved and the water layer separated and extracted with
hexane (15 mL). The hexane portions were combined, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo to provide (6.50 g,
98%) of a yellow oil. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta.
7.46 (d, 1H, J=2.1), 7.05 (d, 1H, J=2.1), 3.83, (t, 2H, J=6.6),
3.31 (sep, 1H, J=6.9), 2.81 (sep, 1H, J=6.9), 1.82 (m, 2H), 1.55
(m, 2H), 1.22 (d, 6H, J=6.9), 1.21 (d, 6H, J=6.9).
B. (2-Ethoxy-3,5-diisopropylphenyl)-boronic acid
[0327] ##STR42##
[0328] 2-Ethoxy-1-iodo-3,5-diiosopropyl-benzene (56 mmol) was
dissolved in anhydrous THF (250 mL) under nitrogen and cooled to
-75.degree. C. to in a dry ice/acetone bath. t-Butyl lithium (72.6
mL, 123 mmol, 1.7 M in pentane) was added over 21 min at
-73.degree. C. and the suspension was stirred for 40 min. Trimethyl
borate (27.6 mL, 246 mmol) was added at -73.degree. C. The dry ice
bath was left in place and the reaction allowed to warm to
12.degree. C. overnight. The reaction was stirred 30 min with 1N
H.sub.2SO.sub.4 (125 mL) and then diluted into water (125 mL)/EtOAc
(175 mL). The organic phase was separated and washed with 10%
aqueous NaHCO.sub.3, dried (Na.sub.2SO.sub.4) and concentrated in
vacuo to provide 15.7 g of a viscous yellow oil. The oil was passed
over a large silica pad with a gradient elution of hexane, (95:5)
hexane:ethyl acetate, (9:1) hexane:ethyl acetate and (4:1)
hexane:ethyl acetate. The product came off in (95:5) and (9:1)
hexane:ethyl acetate providing (54.8 g, 70%) as a yellow solid. Mp:
86-89.degree. C. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.52
(d, 1H, J=2.4), 7.24 (d, 1H, J=2.4), 6.27 (s, 2H), 3.89 (q, 2H,
J=7.0), 3.26 (sep, 1H, J=6.9), 2.90 (sep, 1H, J=6.9), 1.46 (t, 3H,
J=7.0), 1.26 (d, 6H, J=6.9), 1.25 (d, 6H, J=6.9).
C. 2-Acetyl-7-(3,5-diisopropyl-2-ethoxyphenyl)-benzo[b]furan
[0329] ##STR43##
[0330] A mixture of 1.08 mmol of 3,5-diisopropyl-2-ethoxy
phenylboronic acid, 498 mg (1.62 mmol) of
2-acetyl-7-trifluoromethanesulfonate benzo[b]furan (see Example 4,
step A) and 62 mg (0.05 mmol) of Pd(PPh.sub.3).sub.4, 1 mL of 2N
aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was
heated to reflux. After complexion (TLC), water was added and the
solution was extracted with ethyl acetate. The organic layer is
dried over MgSO.sub.4 and after evaporation of the solvents, the
crude oil was purified over a short silica plug (eluent:
10/90=ethyl acetate/hexane) to afford
2-acetyl-7-(3,5-diisopropyl-2-ethoxyphenyl)-benzo[b]furan as a
clear yellow pasty solid.
D.
3-[7-(2-Ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid Ethyl Ester
[0331] ##STR44##
[0332] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-7-(3,5-diisopropyl-2-ethoxyphenyl)-benzo[b]furan diluted
in 3 mL of dry DMF was added dropwise. The red mixture was slowly
heated to 40.degree. C. until complexion. After cooling, water was
added and the solution was extracted 2 times with ethyl acetate.
The organic layers were combined, washed with water and brine and
dried over MgSO.sub.4. After evaporation of the solvents, the crude
oil is purified over a short plug of silica gel (eluent: 95/5
hexane/ethyl acetate) to afford
3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid ethyl ester as a pale yellow oil.
E.
3-[7-(2-Ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid
[0333] A mixture of 0.450 mmol of
3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH
(2N aqueous) was refluxed for 2 hours. After cooling at room
temperature, the mixture was acidified to pH=2 and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
3-[7-(2-Ethoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid was isolated as a white solid. .sup.1H-NMR (CDCl.sub.3),
.delta.: 7.65 (d, J=7.5 Hz, 1H, Ar--H), 7.56 (d, J=7.7 Hz, 1H,
Ar--H), 7.33 (d, J=2.0 Hz, 1H, Ar--H), 7.29 (t, J=7.6 Hz, 1H,
Ar--H), 7.16 (d, J=2.0 Hz, 1H, Ar--H), 7.11 (s, 1H, furan-H), 6.60
(s, 1H, C.dbd.C--H), 3.43 (m, 3H, CH.sub.3--CH--CH.sub.3,
O--CH.sub.2--CH.sub.3), 2.95 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.57
(s, 3H, C.dbd.C--CH.sub.3), 1.31 (d, J=6.9 Hz, 12H,
CH.sub.3--CH--CH.sub.3), 0.97 (t, J=7.0 Hz, 3H,
O--CH.sub.2--CH.sub.3).
Example 6
3-[7-(2-propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid
[0334] ##STR45##
A. 2-Acetyl-7-(3,5-diisopropyl-2-propoxyphenyl)-benzo[b]furan
[0335] ##STR46##
[0336] A mixture of 1.08 mmol of
(3,5-diisopropyl-2-propoxy-phenyl)-boronic acid, 498 mg (1.62 mmol)
of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan (see Example
4, step A) and 62 mg (0.05 mmol) of Pd(PPh.sub.3).sub.4, 1 mL of 2N
aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was
heated to reflux. After complexion (TLC), water was added and the
solution was extracted with ethyl acetate. The organic layer is
dried over MgSO.sub.4 and after evaporation of the solvents, the
crude oil was purified over a short silica plug (eluent:
10/90=ethyl acetate/hexane) to afford
2-acetyl-7-(3,5-diisopropyl-2-propoxyphenyl)-benzo[b]furan as a
clear yellow pasty solid.
B.
3-[7-(2-Propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid ethyl ester
[0337] ##STR47##
[0338] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-7-(3,5-di-isopropyl-6-propoxybenzene)-benzo[b]furan
diluted in 3 mL of dry DMF was added dropwise. The red mixture was
slowly heated to 40.degree. C. until complexion. After cooling,
water was added and the solution was extracted 2 times with ethyl
acetate. The organic layers were combined, washed with water and
brine and dried over MgSO.sub.4. After evaporation of the solvents,
the crude oil is purified over a short plug of silica gel (eluent:
95/5 hexane/ethyl acetate) to afford
3-[7-(2-propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid ethyl ester as a pale yellow oil.
C.
3-[7-(2-Propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid
[0339] A mixture of 0.450 mmol of
3-[7-(2-propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH
(2N aqueous) was refluxed for 2 hours. After cooling at room
temperature, the mixture was acidified to pH=2 and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
3-[7-(2-Propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid was isolated as a white solid. .sup.1H-NMR (CDCl.sub.3),
.delta.: 7.61 (d, J=7.1 Hz, 1H, Ar--H), 7.56 (d, J=7.8 Hz, 1H,
Ar--H), 7.28 (m, 2H, Ar--H, Ar--H), 7.16 (d, J=2.2 Hz, 1H, Ar--H),
7.10 (s, 1H, furan-H), 6.60 (s, 1H, C.dbd.C--H), 3.43 (m, 1H,
CH.sub.3--CH--CH.sub.3), 3.30 (t, J=6.4 Hz, 2H,
O--CH.sub.2--CH.sub.2--CH.sub.3), 2.95 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.56 (s, 3H, C.dbd.C--CH.sub.3), 1.32 (m,
14H, CH.sub.3--CH--CH.sub.3, O--CH.sub.2--CH.sub.2--CH.sub.3), 0.64
(t, J=7.4 Hz, 3H, O--CH.sub.2--CH.sub.2--CH.sub.3).
Example 7
3-{7-[2-(3-Fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-
-enoic acid
[0340] ##STR48##
A.
Acetyl-7-[3,5-diisopropyl-2-(3-fluoropropoxy)phenyl]-benzo[b]furan
[0341] ##STR49##
[0342] A mixture of 1.08 mmol of
3,5-diisopropyl-2-(3-fluoropropoxy)phenylboronic acid, 498 mg (1.62
mmol) of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan (see
Example 4, step A) and 62 mg (0.05 mmol) of Pd(PPh.sub.3).sub.4, 1
mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL
ethanol was heated to reflux. After complexion (TLC), water was
added and the solution was extracted with ethyl acetate. The
organic layer is dried over MgSO.sub.4 and after evaporation of the
solvents, the crude oil was purified over a short silica plug
(eluent: 10/90=ethyl acetate/hexane) to afford
2-acetyl-7-[3,5-diisopropyl-2-(3-fluoropropoxy)phenyl]-benzo[b]furan
as a clear yellow pasty solid.
B.
3-{7-[2-(3-Fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-bu-
t-2-enoic acid ethyl ester
[0343] ##STR50##
[0344] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-7-[3,5-diisopropyl-2-(3-fluoropropoxy)phenyl]-benzo[b]furan
diluted in 3 mL of dry DMF was added dropwise. The red mixture was
slowly heated to 40.degree. C. until complexion. After cooling,
water was added and the solution was extracted 2 times with ethyl
acetate. The organic layers were combined, washed with water and
brine and dried over MgSO.sub.4. After evaporation of the solvents,
the crude oil is purified over a short plug of silica gel (eluent:
95/5 hexane/ethyl acetate) to afford
3-{7-[2-(3-fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-y-
l}-but-2-enoic acid ethyl ester as a pale yellow oil.
C.
3-{7-[2-(3-Fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-bu-
t-2-enoic acid
[0345] A mixture of 0.450 mmol of
3-{7-[2-(3-fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but--
2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of
LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room
temperature, the mixture was acidified to pH=2 and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
3-{7-[2-(3-Fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but--
2-enoic acid was isolated as a white solid. .sup.1H-NMR
(CDCl.sub.3), 7.58 (d, J=6.7 Hz, 1H, Ar--H), 7.56 (d, J=6.2 Hz, 1H,
Ar--H), 7.29 (t, J=7.6 Hz, 1H, Ar--H), 7.28 (d, J=2.2 Hz, 1H,
Ar--H), 7.17 (d, J=2.1 Hz, 1H, Ar--H), 7.11 (s, 1H, furan-H), 6.59
(s, 1H, C.dbd.C--H), 4.25 (dt, J=47.1 Hz, J=6.1 Hz, 2H,
O--CH.sub.2--CH.sub.2--CH.sub.2F), 3.46 (t, J=5.9 Hz, 2H,
O--CH.sub.2--CH.sub.2--CH.sub.2F), 3.38 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.95 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.56
(s, 3H, C.dbd.C--CH.sub.3), 1.70 (m, 2H,
O--CH.sub.2--CH.sub.2--CH.sub.2F), 1.32 (d, J=5.7 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.30 (d, J=6.6 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 8
Ethyl-2-carboxylate-7-(2-ethoxy-3,5-diisopropylbenzene)-benzo[b]thiophene
[0346] ##STR51##
[0347] A mixture of 300 mg (1.2 mmol) of
2-ethoxy-3,5-diisopropylphenylboronic acid, 265 mg (0.8 mmol) of
ethyl-2-carboxylate-7-iodo benzo[b]thiophene, 46 mg (0.04 mmol)
Pd(PPh.sub.3).sub.4, 6 mL of toluene, 3 mL of absolute ethanol and
0.8 mL of a 2N Na.sub.2CO.sub.3 aqueous solution was refluxed for 5
hours. After cooling at room temperature, water was added and the
mixture was extracted with ethyl acetate. The organic layer were
dried over MgSO.sub.4 and after evaporation, the crude oil was
purified over silica gel (eluent: 10/90 ethyl acetate/hexane) to
afford 284 mg (0.692 mmol, yield=86%) of
ethyl-2-carboxylate-7-(2-ethoxy-3,5-diisopropylbenzene)-benzo[b]thiophene-
. .sup.1H-NMR (CDCl.sub.3), .delta.: 8.12 (s, 1H), 7.85 (dd, J=7.8,
0.9 Hz, 1H), 7.55 (d, J=6.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.19
(d, J=2.2 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 4.38 (dd, J=14.1, 7.0
Hz, 2H), 3.43 (dt, J=13.8, 6.9 Hz, 1H), 3.33 (dd, J=14.0, 7.0 Hz,
2H), 2.92 (dt, J=13.8, 6.9 Hz, 1H), 1.38 (t, J=7.2 Hz, 3H), 1.28
(m, 12H), 0.88 (t, J=7.1 Hz, 3H).
Example 9
3-{7-[2-(2,2-Difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-bu-
t-2-enoic acid
[0348] ##STR52##
A.
2-Acetyl-7-[3,5-diisopropyl-2-(2,2-difluoroethoxy)phenyl]-benzo[b]furan
[0349] ##STR53##
[0350] A mixture of 1.08 mmol of
3,5-diisopropyl-2-(2,2-difluoroethoxy)phenylboronic acid, 498 mg
(1.62 mmol) of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan
(see Example 4, step A) and 62 mg (0.05 mmol) of
Pd(PPh.sub.3).sub.4, 1 mL of 2N aqueous sodium carbonate in 9 mL of
toluene and 4 mL ethanol was heated to reflux. After complexion
(TLC), water was added and the solution was extracted with ethyl
acetate. The organic layer is dried over MgSO.sub.4 and after
evaporation of the solvents, the crude oil was purified over a
short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford
2-acetyl-7-[3,5-diisopropyl-2-(2,2-difluoroethoxy)phenyl]-benzo[b]furan
as a clear yellow pasty solid.
B.
3-{7-[2-(2,2-Difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-
-but-2-enoic acid ethyl ester
[0351] ##STR54##
[0352] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-7-[3,5-diisopropyl-2-(2,2-difluoroethoxy)phenyl]-benzo[b]furan
diluted in 3 mL of dry DMF was added dropwise. The red mixture was
slowly heated to 40.degree. C. until complexion. After cooling,
water was added and the solution was extracted 2 times with ethyl
acetate. The organic layers were combined, washed with water and
brine and dried over MgSO.sub.4. After evaporation of the solvents,
the crude oil is purified over a short plug of silica gel (eluent:
95/5 hexane/ethyl acetate) to afford
3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan--
2-yl}-but-2-enoic acid ethyl ester as a pale yellow oil.
C.
3-{7-[2-(2,2-Difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-
-but-2-enoic acid
[0353] A mixture of 0.450 mmol of
3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-b-
ut-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL
of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at
room temperature, the mixture was acidified to pH=2 and extracted
with ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
3-{7-[2-(2,2-Difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-b-
ut-2-enoic acid was isolated as a white solid. .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 7.60 (d, J=7.1 Hz, 1H, Ar--H), 7.57 (d,
J=7.4 Hz, 1H, Ar--H), 7.32 (d, J=2.3 Hz, 1H, Ar--H), 7.31 (t, J=7.6
Hz, 1H, Ar--H), 7.18 (d, J=2.2 Hz, 1H, Ar--H), 7.11 (s, 1H,
furan-H), 6.58 (s, 1H, C.dbd.C--H), 5.54 (tt, J=55.3 Hz, J=4.2 Hz,
1H, O--CH.sub.2--CF.sub.2H), 3.54 (dt, J=13.6 Hz, J=4.2 Hz, 2H,
O--CH.sub.2--CF.sub.2H), 3.42 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.96
(m, 1H, CH.sub.3--CH--CH.sub.3), 2.57 (s, 3H, C.dbd.C--CH.sub.3),
1.32 (d, J=6.8 Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.31 (d, J=6.8 Hz,
6H, CH.sub.3--CH--CH.sub.3).
Example 10
(E)-2-Fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]f-
uran-2-yl}-but-2-enoic acid
[0354] ##STR55##
A.
2-Fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]fu-
ran-2-yl}-but-2-enoic acid ethyl ester
[0355] ##STR56##
[0356] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl 2-fluoro-2-phosphonoacetate (diluted in 1 mL of dry
DMF) at 0.degree. C. After the gas evolution has ceased, 0.51 mmol
of
2-acetyl-7-[3,5-diisopropyl-2-(2,2-difluoroethoxy)phenyl]-benzo[b]furan
(see Example 9, step A) diluted in 3 mL of dry DMF was added
dropwise. The red mixture was slowly heated to 40.degree. C. until
complexion. After cooling, water was added and the solution was
extracted 2 times with ethyl acetate. The organic layers were
combined, washed with water and brine and dried over MgSO.sub.4.
After evaporation of the solvents, the crude oil is purified over a
short plug of silica gel (eluent: 95/5 hexane/ethyl acetate) to
afford
2-fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]fura-
n-2-yl}-but-2-enoic acid ethyl ester as a pale yellow oil.
B.
2-Fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]fu-
ran-2-yl}-but-2-enoic acid
[0357] A mixture of 0.450 mmol of
2-fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]fura-
n-2-yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol
and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After
cooling at room temperature, the mixture was acidified to pH=2 and
extracted with ethyl acetate. The organic layer was dried over
MgSO.sub.4 and after evaporation of the solvents, the crude acid
was recrystallized from acetonitrile.
2-Fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]fura-
n-2-yl}-but-2-enoic acid was isolated as a white solid. .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 7.65 (d, J=8.1 Hz, 1H, Ar--H), 7.58
(d, J=7.3 Hz, 1H, Ar--H), 7.41 (d, J=3.0 Hz, 1H, furan-H), 7.34 (t,
J=7.6 Hz, 1H, Ar--H), 7.31 (d, J=2.2 Hz, 1H, Ar--H), 7.17 (d, J=2.2
Hz, 1H, Ar--H), 5.52 (tt, J=55.2 Hz, J=4.1 Hz, 1H,
O--CH.sub.2--CF.sub.2H), 3.52 (dt, J=13.6 Hz, J=4.1 Hz, 2H,
O--CH.sub.2--CF.sub.2H), 3.41 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.95
(m, 1H, CH.sub.3--CH--CH.sub.3), 2.56 (d, J=3.5 Hz, 3H,
C.dbd.C--CH.sub.3), 1.31 (d, J=6.7 Hz, 6H, CH.sub.3--CH--CH.sub.3),
1.29 (d, J=6.8 Hz, 6H, CH.sub.3--CH--CH.sub.3).
Example 11
(E)-3-{7-[5,5,8,8,-Tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl]-ben-
zo[b]furan-2-yl}-but-2-enoic acid
[0358] ##STR57##
A.
2-Acetyl-7-(5,5,8,8,-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl-
)-benzo[b]furan
[0359] ##STR58##
[0360] A mixture of 1.08 mmol of
(5,5,8,8,-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl)-boronic
acid, 498 mg (1.62 mmol) of 2-acetyl-7-trifluoromethanesulfonate
benzo[b]furan (see Example 4, step A) and 62 mg (0.05 mmol) of
Pd(PPh.sub.3).sub.4, 1 mL of 2N aqueous sodium carbonate in 9 mL of
toluene and 4 mL ethanol was heated to reflux. After complexion
(TLC), water was added and the solution was extracted with ethyl
acetate. The organic layer is dried over MgSO.sub.4 and after
evaporation of the solvents, the crude oil was purified over a
short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford
2-acetyl-7-(5,5,8,8,-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl)--
benzo[b]furan as a clear yellow pasty solid.
B.
(E)-3-{7-[5,5,8,8,-Tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl]--
benzo[b]furan-2-yl}-but-2-enoic acid ethyl ester
[0361] ##STR59##
[0362] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-7-(5,5,8,8,-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl)--
benzo[b]furan diluted in 3 mL of dry DMF was added dropwise. The
red mixture was slowly heated to 40.degree. C. until complexion.
After cooling, water was added and the solution was extracted 2
times with ethyl acetate. The organic layers were combined, washed
with water and brine and dried over MgSO.sub.4. After evaporation
of the solvents, the crude oil is purified over a short plug of
silica gel (eluent: 95/5 hexane/ethyl acetate) to afford
(E)-3-{7-[5,5,8,8,-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl]-be-
nzo[b]furan-2-yl}-but-2-enoic acid ethyl ester as a pale yellow
oil.
C.
(E)-3-{7-[5,5,8,8,-Tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphth-2-yl]--
benzo[b]furan-2-yl}-but-2-enoic acid
[0363] A mixture of 0.450 mmol of
3-[7-(2-propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH
(2N aqueous) was refluxed for 2 hours. After cooling at room
temperature, the mixture was acidified to pH=2 and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
3-[7-(2-Propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic
acid was isolated as a white solid. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.55 (m, 2H, Ar--H), 7.54 (s, 1H, Ar--H), 7.28
(t, J=7.6 Hz, 1H, Ar--H), 7.10 (s, 1H, furan-H), 6.94 (s, 1H,
Ar--H), 6.62 (s, 1H, C.dbd.C--H), 4.06 (q, J=6.9 Hz, 2H,
O--CH.sub.2--CH.sub.3), 2.56 (s, 3H, C.dbd.C--CH.sub.3), 1.74 (s,
4H, ring-CH.sub.2), 1.37 (s, 6H, ring-CH.sub.3), 1.33 (s, 6H,
ring-CH.sub.3), 1.27 (t, J=6.9 Hz, 3H, O--CH.sub.2--CH.sub.3).
Example 12
3-[7-(2-Ethoxy-3,5-diisopropylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid
[0364] ##STR60##
A.
2-Acetyl-7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thiophene
[0365] ##STR61##
[0366] To mixture of 280 mg (0.69 mmol) of
ethyl-2-carboxylate-7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thiophene
in 5 mL of dry ether was added 0.7 mL of a 1.0 M lithium aluminum
hydride solution at 0.degree. C. After complexion of the reaction,
the mixture was carefully quenched with 0.5 mL of cold water
followed by 1 mL of a 1N aqueous NaOH solution. The precipitate was
filtered over celite, washed 2 times with ethyl acetate and the
organic layer dried over MgSO.sub.4. After filtration and
evaporation of the solvents, the crude alcohol was diluted in 3 mL
of CH.sub.2Cl.sub.2 and 121 mg (1.03 mmol) of 4-methylmorpholine
N-oxide (NMO) followed by 15 mg of tetrapropylammonium perruthenate
(TPAP) (0.04 mmol) were successively added. The dark mixture is
stirred at room temperature until complexion (TLC monitoring) and
filtrated over silica gel. The gel was washed 2 times with
CH.sub.2Cl.sub.2 and the solvents removed over reduced pressure.
The crude aldehyde was dissolved in 5 mL of dry ether and the
cooled to 0.degree. C. Methyl magnesium bromide (1 mL, 3 mmol) was
then added dropwise. After complexion (TLC monitoring), and
work-up, the crude alcohol was oxidized to the ketone using the
same protocol previously described (NMO/TPAP in CH.sub.2Cl.sub.2).
Purification over silica gel (eluent: ethyl acetate/hexane:5/95)
gave 125 mg (0.238 mmol, yield: 41% over 5 steps) of
2-acetyl-7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thiophene as
orange crystals. .sup.1H-NMR (CDCl.sub.3), .delta.: 8.01 (s, 1H),
7.87 (broad d, J=8.0 Hz, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.48 (t,
J=7.6 Hz, 1H), 7.18 (dd, J=6.8, 2.2 Hz, 1H), 3.43 (dt, J=13.8, 6.9
Hz, 1H), 3.33 (dd, J=14.0, 6.9 Hz, 2H), 2.92 (dt, J=13.8, 6.9 Hz,
1H), 2.66 (s, 3H), 1.28 (m, 12H), 0.89 (t, J=7.0 Hz, 3H).
B.
3-[7-(2-Ethoxy-3,5-diisopropylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid ethyl ester
[0367] ##STR62##
[0368] To a mixture of 38 mg (0.79 mmol) of NaH in 1 mL of dry DMF
was added dropwise a solution of 148 mg (0.66 mmol, 0.13 mL) of
triethylphosphonoacetate at 0.degree. C. After 10 minutes, 125 mg
of 2-acetyl-7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thiophene
(diluted in 2 mL of dry DMF) was added slowly and the mixture is
warmed-up to 40.degree. C. After complexion of the reaction (TLC),
and work-up, the crude ester was purified over a short pad of
silica gel (eluent: ethyl acetate/hexane:95/5) to afford 87 mg
(0.193 mmol, yield=59%) of
3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid ethyl ester (ratio E/Z=85/15)1. .sup.1H-NMR (CDCl.sub.3),
.delta.: 7.73 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J=1.0 Hz,
1H), 7.43 (t, J=7.9 Hz, 1H), 7.17 (m, 2H), 6.29 (s, 1H), 4.19 (dd,
J=14.5, 7.3 z, 2H), 3.44 (dt, J=13.7, 6.9 Hz, 1H), 3.36 (dd,
J=14.0, 7.0 Hz, 2H), 2.92 (dt, J=13.7, 6.8 Hz, 1H), 2.66 (s, 3H),
1.28 (m, 12H), 0.90 (t, J=7.0 Hz, 3H).
C.
3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid
[0369] A mixture of 0.450 mmol of
3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH
(2N aqueous) was refluxed for 2 hours. After cooling at room
temperature, the mixture was acidified to pH=2 and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile to afford 30 mg (0.07 mmol,
yield=40%)
3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid was afforded as white solid. .sup.1H-NMR (CDCl.sub.3),
.delta.: 7.75 (d, J=7.9 Hz, 1H), 7.65 (s, 1H), 7.48 (d, J=6.4 Hz,
1H), 7.42 (t, J=7.7 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.17 (d, J=2.3
Hz, 1H), 6.32 (s, 1H), 3.43 (dt, J=13.8, 6.9 Hz, 1H), 3.36 (dd,
J=14.0, 7.0 Hz, 2H), 2.93 (dt, J=13.8, 6.9 Hz, 1H), 2.69 (s, 3H),
1.28 (m, 12H), 0.92 (t, J=6.9 Hz, 3H).
Example 13
2-Carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophene
[0370] ##STR63##
A. 2-(Ethyl
carboxylate)-4-(2-hydroxy-3,5-di-tert-butylphenyl)benzo[b]thiophene
[0371] ##STR64##
[0372] A mixture of 2.42 g (8.22 mmol) of 3,5
di-tert-butyl-2-methoxymethyl phenylboronic acid, 1.52 g (5.0 mmol)
of ethyl-4-iodo-benzo[b]thiophene-2-carboxylate, 288 mg (0.25 mmol,
5%) Pd(PPh.sub.3).sub.4 diluted in 10 mL of ethanol, 20 mL of
toluene and 5 mL of 2N Na.sub.2CO.sub.3 aqueous solution was
refluxed until complexion of the reaction. After work-up, the
solvents are removed under reduced pressure and the crude product
is directly hydrolyzed with aqueous 6N HCl in THF at 40.degree. C.
After cooling at room temperature, the mixture was extracted with
ethyl acetate and the organic layer dried over MgSO.sub.4. After
evaporation of the solvents, the crude phenol was recrystallized
from ethyl acetate/methanol (ratio: 10/1) to afford 1.23 g (3 mmol,
yield: 60%) of 2-(ethyl
carboxylate)-4-(2-hydroxy-3,5-di-tert-butylphenyl)benzo[b]thiophene
as a pale orange powder. .sup.1H-NMR (CDCl.sub.3), .delta.: 7.925
(d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.56 (d, J=7.4 Hz, 1H), 7.46 (t,
J=7.3 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 4.98
(s, 1H), 4.35 (dd, J=14.1, 7.0 Hz, 2H), 1.54 (s, 9H), 1.46 (s,
9H).
B. 2-(Ethyl
carboxylate)-4-(2-propoxy-3,5-di-tert-butylphenyl)benzo[b]thiophene
[0373] ##STR65##
[0374] To a mixture of 284 mg (0.691 mmol) of 2-(ethyl
carboxylate)-4-(2-hydroxy-3,5-di-tert-butylphenyl)benzo[b]thiophene
and 102 mg (0.075 mL, 0.83 mmol) of 1-bromopropane in 2 mL of dry
DMF was added 338 mg (1.04 mmol) of Cs.sub.2CO.sub.3. After
complexion of the reaction, 10 mL of a1/9 mixture of ethyl
acetate/hexane was added and the solution was filtrated over a
short pad of silica gel. The pad was washed 2 times with a 1/9
mixture of ethyl acetate/hexane and the solvents were evaporated
under reduced pressure to afford 303 mg (0.669 mmol, yield: 97%) of
2-(ethyl
carboxylate)-4-(2-propoxy-3,5-di-tert-butylphenyl)benzo[b]thiophene.
.sup.1H-NMR (CDCl.sub.3), .delta.: 7.95 (s, 1H), 7.83 (d, J=7.8 Hz,
1H), 7.51 (d, J=7.4 Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 7.41 (d, J=2.5
Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 4.36 (m, 2H), 3.23 (m, 1H), 3.16
(m, 1H), 1.47 (s, 9H), 1.33 (s, 9H), 1.14 (m, 2H), 0.42 (t, J=7.5
Hz, 3H).
C.
2-Carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophene
[0375] A mixture of 0.450 mmol of 2-(ethyl
carboxylate)-4-(2-propoxy-3,5-di-tert-butylphenyl)benzo[b]thiophene,
3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was
refluxed for 2 hours. After cooling at room temperature, the
mixture was acidified to pH=2 and extracted with ethyl acetate. The
organic layer was dried over MgSO.sub.4 and after evaporation of
the solvents, the crude acid was recrystallized from acetonitrile
to afford 200 mg (0.47 mmol, yield=70%) of
2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophene
was afforded as white solid. .sup.1H-NMR (CDCl.sub.3), .delta.:
8.05 (s, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.55 (t, J=7.4 Hz, 1H), 7.49
(d, J=7.2 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H),
3.25 (m, 1H), 3.17 (m, 1H), 1.47 (s, 9H), 1.34 (s, 9H), 1.15 (m,
2H), 0.43 (t, J=7.2 Hz, 3H). (LG101564)
Example 14
3-{4-[2-(2,2-Difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}--
but-2-enoic acid
[0376] ##STR66##
A. 2-Acetyl-4-iodo benzo[b]thiophene
[0377] ##STR67##
[0378] A mixture of 2.53 g (10.1 mmol) of 2-fluoro-6-iodo
benzaldehyde, 1.0 g (11.1 mmol) of mercapto-2-propanone and 3.5 mL
(2.5 g, 25 mmol) of Et.sub.3N in 15 mL of DMSO was heated to
80.degree. C. overnight. After cooling to room temperature, water
was added and the mixture was extracted with ethyl acetate. The
organic layer was washed with water (2 times), brine and dried over
MgSO.sub.4. After evaporation of the solvents, the crude product
was purified over silica gel column chromatography to afford 1.85 g
(6.12 mmol, yield: 61%) of 2-acetyl-4-iodo benzo[b]thiophene as an
orange powder. .sup.1H-NMR (CDCl.sub.3), .delta.: 7.97 (s, 1H),
7.83 (d, J=7.9 Hz, 2H), 7.16 (t, J=7.9 Hz, 1H), 2.70 (s, 3H).
B.
2-Acetyl-4-(2-methoxymethoxy-3,5-di-tert-butylphenyl)benzo[b]thiophene
[0379] ##STR68##
[0380] A mixture of 620 mg (2.1 mmol)
3,5-di-tert-butyl-2-methoxymethoxy phenylboronic acid, 377 mg (1.24
mmol) of 2-acetyl-4-iodo benzo[b]thiophene, 72 mg (0.105 mmol, 5%)
Pd(PPh.sub.3).sub.4 6 mL of ethanol, 1.25 mL of Na.sub.2CO.sub.3 in
8 mL of toluene was heated to reflux for 12 hours. After cooling
and work-up, the crude product was purified over a short silica gel
plug (eluent: ethyl acetate/hexane:10/90) to give 368.6 mg (0.868
mmol, yield: 70%) of pure
2-acetyl-4-(2-methoxymethoxy-3,5-di-tert-butylphenyl)benzo[b]thiophene
as a clear oil. .sup.1H-NMR (CDCl.sub.3), .delta.: 7.84 (d, J=7.9
Hz, 1H), 7.79 (s, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.46 (d, J=2.6 Hz,
1H), 7.44 (d, J=2.6 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 4.47 (d, J=4.5
Hz, 1H), 4.06 (dd, J=14.2, 7.0 Hz, 2H), 2.81 (s, 3H), 2.54 (s, 3H),
2.02 (s, 3H), 1.49 (s, 9H), 1.33 (s, 9H), 1.23 (t, J=7.3 Hz,
3H).
C.
2-Acetyl-4-(2-hydroxy-3,5-di-tert-butylphenyl)benzo[b]thiophene
[0381] ##STR69##
[0382] A slurry of 365 mg (0.859 mmol) of
2-acetyl-4-(2-methoxymethoxy-3,5-di-tert-butylphenyl)benzo[b]thiophene
into a mixture of 5 mL of THF and 5 mL of aqueous 6N HCl was heated
to 50.degree. C. overnight. After cooling, the THF was evaporated
and the aqueous solution was extracted with ethyl acetate. The
organic layer was dried over MgSO.sub.4 and evaporated under
reduced pressure. The crude
2-acetyl-4-(2-hydroxy-3,5-di-tert-butylphenyl)benzo[b]thiophene was
directly used in the next step. .sup.1H-NMR (CDCl.sub.3), .delta.:
7.92 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.58 (t, J=7.4 Hz, 1H), 7.47
(d, J=2.6 Hz, 1H), 7.42 (d, J=2.3 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H),
5.03 (s, 1H), 2.57 (s, 3H), 1.48 (s, 9H), 1.34 (s, 9H).
D.
3-{4-[2-(2,2-Difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-y-
l}-but-2-enoic acid ethyl ester
[0383] ##STR70##
[0384] A mixture of the crude
2-acetyl-4-(2-hydroxy-3,5-di-tert-butylphenyl)benzo[b]thiophene,
142.0 mg (1 mmol) of 2-bromo-1,1-difluoroethane and 410 mg (2.7
mmol) of CsF in 10 mL of dry DMF was stirred at room temperature
overnight. After work-up the crude oil was filtrated over a short
pad of silica gel (eluent: 10/90 ethyl acetate/hexane) to give
2-acetyl-4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thiop-
hene as an oil, directly used without further purification. The
crude ketone was treated with the anion of triethylphosphonoacetate
(previously prepared from 336 mg of triethylphosphonoacetate and 86
mg of NaH in 3 mL of dry DMF) at 60.degree. C. After completion of
the reaction (TLC monitored) and work-up, the crude ester was
purified over silica gel column (eluent: 5/95 ethyl acetate/hexane)
to afford 315 mg (0.65 mmol, yield: 75%, 2 steps) of pure
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-
-but-2-enoic acid ethyl ester as an oil. .sup.1H-NMR (CDCl.sub.3),
.delta.: 7.80 (dd, J=7.2, 1.6 Hz, 1H), 7.43 (m, 4H), 7.23 (d, J=2.5
Hz, 1H), 6.29 (s, 1H), 5.17 (dt, J=55.4, 4.1 Hz, 1H), 4.21 (dd,
J=14.4, 7.2 Hz, 2H), 3.50 (m, 2H), 2.57 (s, 3H), 1.47 (s, 9H), 1.34
(s, 9H), 1.31 (t, J=7.0 Hz).
E.
3-{4-[2-(2,2-Difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-y-
l}-but-2-enoic acid
[0385] A mixture of 0.450 mmol of
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-
-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1
mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at
room temperature, the mixture was acidified to pH=2 and extracted
with ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, and the crude acid was
recrystallized from acetonitrile to afford 192 mg (0.378 mmol,
yield: 58%) of
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-
-but-2-enoic acid was isolated as a white solid. .sup.1H NMR
(CDCl.sub.3), .delta.: 7.81 (dd, J=7.3, 1.5 Hz, 1H), 7.45 (m, 4H),
7.21 (d, J=2.4 Hz, 1H), 6.33 (s, 1H), 5.19 (dt, J=55.5, 4.3 Hz,
1H), 3.51 (m, 2H), 2.59 (s, 3H), 1.48 (s, 9H), 1.35 (s, 9H).
Example 15
(E)-3-[4-(2-Propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid
[0386] ##STR71##
A.
2-Acetyl-4-(2-Propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene
[0387] ##STR72##
[0388] A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-propoxy
phenylboronic acid, 1.62 mmol of 2-acetyl-4-iodo benzo[b]thiophene
(see Example 14, step A) and 62 mg (0.05 mmol) of
Pd(PPh.sub.3).sub.4, 1 mL of 2N aqueous sodium carbonate in 9 mL of
toluene and 4 mL ethanol was heated to reflux. After complexion
(TLC), water was added and the solution was extracted with ethyl
acetate. The organic layer is dried over MgSO.sub.4 and after
evaporation of the solvents, the crude oil was purified over a
short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford
2-acetyl-4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene.
B.
3-[4-(2-Propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoi-
c acid ethyl ester
[0389] ##STR73##
[0390] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene
diluted in 3 mL of dry DMF was added dropwise. The red mixture was
slowly heated to 40.degree. C. until complexion. After cooling,
water was added and the solution was extracted 2 times with ethyl
acetate. The organic layers were combined, washed with water and
brine and dried over MgSO.sub.4. After evaporation of the solvents,
the crude oil is purified over a short plug of silica gel (eluent:
95/5 hexane/ethyl acetate) to afford
3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid ethyl ester.
C.
3-[4-(2-Propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoi-
c acid
[0391] A mixture of 0.450 mmol of
3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH
(2N aqueous) was refluxed for 2 hours. After cooling at room
temperature, the mixture was acidified to pH=2 and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
3-[4-(2-Propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid was isolated as a white solid. .sup.1H NMR (CDCl.sub.3),
.delta.: 7.76 (dd, J=5.9, 2.6 Hz, 1H), 7.50 (s, 1H), 7.42 (m, 2H),
7.17 (d, J=2.3 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.32 (s, 1H), 3.41
(dt, J=13.7, 6.9 Hz, 1H), 3.26 (m, 1H), 3.18 (m, 1H), 2.93 (dt,
J=13.7, 6.8 Hz, 1H), 2.61 (s, 3H), 1.29 (m, 14H), 0.52 (t, J=7.5
Hz, 3H).
Example 16
(E)-3-[4-(2-Ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoi-
c acid
[0392] ##STR74##
A.
2-Acetyl-4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene
[0393] ##STR75##
[0394] A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-ethoxy
phenylboronic acid, 1.62 mmol of 2-acetyl-4-iodo benzo[b]thiophene
(see Example 14, step A) and 62 mg (0.05 mmol) of
Pd(PPh.sub.3).sub.4, 1 mL of 2N aqueous sodium carbonate in 9 mL of
toluene and 4 mL ethanol was heated to reflux. After complexion
(TLC), water was added and the solution was extracted with ethyl
acetate. The organic layer is dried over MgSO.sub.4 and after
evaporation of the solvents, the crude oil was purified over a
short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford
2-acetyl-4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene.
B.
3-[4-(2-Ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid ethyl ester
[0395] ##STR76##
[0396] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene
diluted in 3 mL of dry DMF was added dropwise. The red mixture was
slowly heated to 40.degree. C. until complexion. After cooling,
water was added and the solution was extracted 2 times with ethyl
acetate. The organic layers were combined, washed with water and
brine and dried over MgSO.sub.4. After evaporation of the solvents,
the crude oil is purified over a short plug of silica gel (eluent:
95/5 hexane/ethyl acetate) to afford
3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid ethyl ester.
C.
3-[4-(2-Ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid
[0397] A mixture of 0.450 mmol of
3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH
(2N aqueous) was refluxed for 2 hours. After cooling at room
temperature, the mixture was acidified to pH=2 and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
3-[4-(2-Ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid was isolated as a white solid. .sup.1H NMR (CDCl.sub.3),
.delta.: 7.77 (dd, J=5.9, 3.6 Hz, 1H), 7.51 (s, 1H), 7.43 (m, 2H),
7.17 (d, J=2.2 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 6.32 (s, 1H), 3.43
(dt, J=13.8, 6.9 Hz, 1H), 3.33 (m, 2H), 2.93 (dt, J=13.7, 6.9 Hz,
1H), 2.61 (s, 3H), 1.29 (m, 12H), 0.85 (t, J=7.4 Hz, 3H).
Example 17
(E)-3-[4-(2-n-Butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-en-
oic acid
[0398] ##STR77##
A. 2-n-Butoxy-1-iodo-3,5-diiosopropyl-benzene
[0399] ##STR78##
[0400] 2-Iodo-4,6-diisopropyl-phenol (60.8 g, 0.2 mol),
1-bromobutane (41.1 g, 0.3 mol), and powdered potassium carbonate
(55.3 g, 0.4 mol) were combined in ethanol (366 mL). The mixture
was heated at reflux for 4 h and then diluted with water (1
L)/hexane (300 mL). The solids were dissolved and the water layer
separated and extracted with hexane (150 mL). The hexane portions
were combined, dried (Na.sub.2SO.sub.4), and concentrated in vacuo
to provide 70.63 g (98%) of an orange oil. .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 7.46 (d, 1H, J=2.1), 7.05 (d, 1H, J=2.1),
3.83, (t, 2H, J=6.6), 3.31 (sep, 1H, J=6.9), 2.81 (sep, 1H, J=6.9),
1.82 (m, 2H), 1.55 (m, 2H), 1.22 (d, 6H, J=6.9), 1.21 (d, 6H,
J=6.9).
B. (2-n-Butoxy-3,5-di-iso-propylphenyl)-boronic acid
[0401] ##STR79##
[0402] 2-n-Butoxy-1-iodo-3,5-diiosopropyl-benzene (20.16 g, 56
mmol) was dissolved in anhydrous THF (250 mL) under nitrogen and
cooled to -75.degree. C. to in a dry ice/acetone bath. t-Butyl
lithium (72.6 mL, 123 mmol, 1.7 M in pentane) was added over 21 min
at -73.degree. C. and the suspension was stirred for 40 min.
Trimethyl borate (27.6 mL, 246 mmol) was added at -73.degree. C.
The dry ice bath was left in place and the reaction allowed to warm
to 12.degree. C. overnight. The reaction was stirred 30 min with 1N
H.sub.2SO.sub.4 (125 mL) and then diluted into water (125 mL)/ethyl
acetate (175 mL). The organic phase was separated and washed with
10% aqueous NaHCO.sub.3, dried (Na.sub.2SO.sub.4) and concentrated
in vacuo to provide 15.7 g of a viscous yellow oil. The oil was
passed over a large silica pad with a gradient elution of hexane,
(95:5) hexane:ethyl acetate, (9:1) hexane:ethyl acetate and (4:1)
hexane:ethyl acetate. The product came off in (95:5) and (9:1)
hexane:ethyl acetate providing 11.3 g (73%) of product. Mp:
73-78.degree. C. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.52
(d, 1H, J=2.4), 7.24 (d, 1H, J=2.4), 6.25 (s, 2H), 3.81, (t, 2H,
J=6.8), 3.27 (sep, 1H, J=6.9), 2.90 (sep, 1H, J=6.9), 1.83 (m, 2H),
1.54 (m, 2H), 1.26 (d, 6H, J=6.9), 1.25 (d, 6H, J=6.9).
C.
2-Acetyl-4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene
[0403] ##STR80##
[0404] A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-n-butoxy
phenylboronic acid, [0405] 1.62 mmol of 2-acetyl-4-iodo
benzo[b]thiophene (see Example 14, step A) and 62 mg (0.05 mmol) of
Pd(PPh.sub.3).sub.4, 1 mL of 2N aqueous sodium carbonate in 9 mL of
toluene and 4 mL ethanol was heated to reflux. After complexion
(TLC), water was added and the solution was extracted with ethyl
acetate. The organic layer is dried over MgSO.sub.4 and after
evaporation of the solvents, the crude oil was purified over a
short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford
2-acetyl-4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene.
D.
3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid ethyl ester
[0406] ##STR81##
[0407] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene
diluted in 3 mL of dry DMF was added dropwise. The red mixture was
slowly heated to 40.degree. C. until complexion. After cooling,
water was added and the solution was extracted 2 times with ethyl
acetate. The organic layers were combined, washed with water and
brine and dried over MgSO.sub.4. After evaporation of the solvents,
the crude oil is purified over a short plug of silica gel (eluent:
95/5 hexane/ethyl acetate) to afford
3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid ethyl ester.
E.
3-[4-(2-n-Butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-eno-
ic acid
[0408] A mixture of 0.450 mmol of
3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH
(2N aqueous) was refluxed for 2 hours. After cooling at room
temperature, the mixture was acidified to pH=2 and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic
acid was isolated as a white solid. .sup.1H-NMR (CDCl.sub.3),
.delta.: 7.76 (dd, J=6.8, 2.9 Hz, 1H), 7.48 (s, 1H), 7.43 (m, 2H),
7.16 (d, J=2.2 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.32 (s, 1H), 3.39
(dt, J=13.8, 6.8 Hz, 1H), 3.32 (m, 2H), 2.93 (dt, J=13.7, 6.8 Hz,
1H), 2.60 (s, 3H), 1.29 (m, 14H), 0.95 (m, 2H), 0.57 (t, J=7.5 Hz,
3H).
Example 18
(E)-3-[4-(2-n-Butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]--
but-2-enoic acid
[0409] ##STR82##
A.
2-Acetyl-4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thiophe-
ne
[0410] ##STR83##
[0411] A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-n-butoxy
phenylboronic acid, 1.62 mmol of
2-acetyl-4-iodo-5-fluorobenzo[b]thiophene and 62 mg (0.05 mmol) of
Pd(PPh.sub.3).sub.4, 1 mL of 2N aqueous sodium carbonate in 9 mL of
toluene and 4 mL ethanol was heated to reflux. After complexion
(TLC), water was added and the solution was extracted with ethyl
acetate. The organic layer is dried over MgSO.sub.4 and after
evaporation of the solvents, the crude oil was purified over a
short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford
2-acetyl-4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thiophene-
.
B.
3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-b-
ut-2-enoic acid ethyl ester
[0412] ##STR84##
[0413] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thiophene
diluted in 3 mL of dry DMF was added dropwise. The red mixture was
slowly heated to 40.degree. C. until complexion. After cooling,
water was added and the solution was extracted 2 times with ethyl
acetate. The organic layers were combined, washed with water and
brine and dried over MgSO.sub.4. After evaporation of the solvents,
the crude oil is purified over a short plug of silica gel (eluent:
95/5 hexane/ethyl acetate) to afford
3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2--
yl]-but-2-enoic acid ethyl ester.
C.
3-[4-(2-n-Butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-b-
ut-2-enoic acid
[0414] A mixture of 0.450 mmol of
3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-but-
-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL
of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at
room temperature, the mixture was acidified to pH=2 and extracted
with ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
3-[4-(2-n-butoxy-3,5-di-iso-propylphenyl)-5-fluorobenzo[b]thien-2-yl]-but-
-2-enoic acid was isolated as a white solid. .sup.1H-NMR
(CDCl.sub.3), .delta.: 7.71 (dd, J=8.7, 4.4 Hz, 1H), 7.26 (t,
J=16.7 Hz, 2H), 7.20 (d, J=1.8 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H),
3.39 (dt, J=13.8, 6.9 Hz, 1H), 3.33 (t, J=6.3 Hz, 2H), 2.93 (dt,
J=13.7, 6.8 Hz, 1H), 2.57 (s, 3H), 1.28 (m, 12H), 1.22 (m, 2H),
0.96 (m, 2H), 0.57 (t, J=7.2 Hz, 3H).
Example 19
(E)
2-Fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl-
]-prop-2-enoic acid
[0415] ##STR85##
A.
2-Formyl-4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene
[0416] ##STR86##
[0417] A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-n-propoxy
phenylboronic acid, 1.62 mmol of 2-formyl-4-iodo-benzo[b]thiophene
and 62 mg (0.05 mmol) of Pd(PPh.sub.3).sub.4, 1 mL of 2N aqueous
sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to
reflux. After complexion (TLC), water was added and the solution
was extracted with ethyl acetate. The organic layer is dried over
MgSO.sub.4 and after evaporation of the solvents, the crude oil was
purified over a short silica plug (eluent: 10/90=ethyl
acetate/hexane) to afford
2-formyl-4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene.
B.
2-Fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-
-prop-2-enoic acid ethyl ester
[0418] ##STR87##
[0419] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonofluoroacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-formyl-4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene
diluted in 3 mL of dry DMF was added dropwise. The red mixture was
slowly heated to 40.degree. C. until complexion. After cooling,
water was added and the solution was extracted 2 times with ethyl
acetate. The organic layers were combined, washed with water and
brine and dried over MgSO.sub.4. After evaporation of the solvents,
the crude oil is purified over a short plug of silica gel (eluent:
95/5 hexane/ethyl acetate) to afford
2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien--
2-yl]-prop-2-enoic acid ethyl ester.
C. (E)
2-Fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-
-yl]-prop-2-enoic acid
[0420] A mixture of 0.450 mmol of
2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-p-
rop-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1
mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at
room temperature, the mixture was acidified to pH=2 and extracted
with ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile.
(E)-2-Fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-y-
l]-prop-2-enoic acid was isolated as a white solid. .sup.1H-NMR
(CDCl.sub.3), .delta.: 7.83 (d, J=7.7 Hz, 1H), 7.49 (broad s, 1H),
7.46 (s, 1H), 7.42 (t, J=7.0 Hz, 2H), 7.18 (d, J=2.1 Hz, 1H), 7.00
(d, J=2.1 Hz, 1H), 3.42 (dt, J=13.7, 6.8 Hz, 1H), 3.32 (m, 1H),
3.19 (m, 1H), 2.92 (dt, J=13.8, 6.9 Hz, 1H), 1.29 (m, 14H), 1.22
(m, 2H), 0.45 (t, J=7.3 Hz, 3H).
Example 20
(E)
3-[4-(2-propyloxy-3,5-di-iso-propylphenyl)benzo[b]thien-2-yl]prop-2-en-
oic acid
[0421] ##STR88##
A.
3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-e-
noic acid ethyl ester
[0422] ##STR89##
[0423] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-formyl-4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene
(see Example 19, step A) diluted in 3 mL of dry DMF was added
dropwise. The red mixture was slowly heated to 40.degree. C. until
complexion. After cooling, water was added and the solution was
extracted 2 times with ethyl acetate. The organic layers were
combined, washed with water and brine and dried over MgSO.sub.4.
After evaporation of the solvents, the crude oil is purified over a
short plug of silica gel (eluent: 95/5 hexane/ethyl acetate) to
afford
3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-eno-
ic acid ethyl ester.
B. (E)
3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-
-2-enoic acid
[0424] A mixture of 0.450 mmol of
3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-eno-
ic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH
(2N aqueous) was refluxed for 2 hours. After cooling at room
temperature, the mixture was acidified to pH=2 and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4 and
after evaporation of the solvents, the crude acid was
recrystallized from acetonitrile. (E)
3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-eno-
ic acid was isolated as a white solid. .sup.1H-NMR
(CD.sub.3COCD.sub.3), .delta.: 7.95 (d, J=7.9 Hz, 1H), 7.92 (d,
J=15.9 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.49 (s, 1H), 7.42 (dd,
J=7.4, 1.0 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H),
6.27 (d, J=15.9 Hz, 1H), 3.45 (dt, J=13.6, 6.8 Hz, 1H), 3.35 (m,
2H), 2.93 (dt, J=13.7, 6.8 Hz, 1H), 2.05 (m, 2H), 1.30 (d, J=6.9
Hz, 6H),), 1.28 (d, J=6.9 Hz, 6H), 0.49 (t, J=7.2 Hz, 3H).
Example 21
3-{4-[2-(2,2,2-Trifluoroethoxy)-3,5-di-ispropylphenyl]benzo[b]thien-2-yl}--
but-2-enoic acid
[0425] ##STR90##
A.
2-Acetyl-4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]-
thiophene
[0426] ##STR91##
[0427] A mixture of 1.08 mmol of
3,5-di-iso-propyl-2-(2,2,2-trifluoroethoxy)-phenylboronic acid,
1.62 mmol of 2-acetyl-4-iodo-benzo[b]thiophene and 62 mg (0.05
mmol) of Pd(PPh.sub.3).sub.4, 1 mL of 2N aqueous sodium carbonate
in 9 mL of toluene and 4 mL ethanol was heated to reflux. After
complexion (TLC), water was added and the solution was extracted
with ethyl acetate. The organic layer is dried over MgSO.sub.4 and
after evaporation of the solvents, the crude oil was purified over
a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford
2-acetyl-4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]th-
iophene.
B.
3-{4-[2-(2,2,2-Trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]thien--
2-yl}-but-2-enoic acid ethyl ester
[0428] ##STR92##
[0429] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]th-
iophene diluted in 3 mL of dry DMF was added dropwise. The red
mixture was slowly heated to 40.degree. C. until complexion. After
cooling, water was added and the solution was extracted 2 times
with ethyl acetate. The organic layers were combined, washed with
water and brine and dried over MgSO.sub.4. After evaporation of the
solvents, the crude oil is purified over a short plug of silica gel
(eluent: 95/5 hexane/ethyl acetate) to afford
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]t-
hien-2-yl}-but-2-enoic acid ethyl ester.
C.
3-{4-[2-(2,2,2-Trifluoroethoxy)-3,5-di-iso-propylphenyl]-5-fluorobenzo[-
b]thien-2-yl}-but-2-enoic acid
[0430] A mixture of 0.450 mmol of
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]thien-2--
yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and
1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling
at room temperature, the mixture was acidified to pH=2 and
extracted with ethyl acetate. The organic layer was dried over
MgSO.sub.4 and after evaporation of the solvents, the crude acid
was recrystallized from acetonitrile.
3-{4-[2-(2,2,2-Trifluoroethoxy)-3,5-di-iso-propylphenyl]-5-fluorobenzo[b]-
thien-2-yl}-but-2-enoic acid was isolated as a white solid.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.81 (dd, J=8.9 Hz, J=1.7
Hz, 1H), 7.45 (m, 3H), 7.20 (d, J=2.0 Hz, 1H), 7.07 (d, J=2.1 Hz,
1H), 6.34 (s, 1H), 3.51 (m, 2H), 3.45 (m, 1H), 2.94 (m, 1H), 2.61
(s, 3H), 1.31 (d, J=6.9 Hz, 6H), 1.28 (d, J=6.9 Hz, 6H).
Example 22
3-{4-[2-(2,2,2-Trifluoroethoxy)-3,5-di-iso-propylphenyl]benzo[b]furan-2-yl-
}-but-2-enoic acid
[0431] ##STR93##
A.
2-Acetyl-4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]-
furan
[0432] ##STR94##
[0433] A mixture of 1.08 mmol of
3,5-di-iso-propyl-2-(2,2,2-trifluoroethyoxy)-phenylboronic acid,
1.62 mmol of 2-acetyl-7-trifluoromethanesulfonate benzo[b]furan and
62 mg (0.05 mmol) of Pd(PPh.sub.3).sub.4, 1 mL of 2N aqueous sodium
carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux.
After complexion (TLC), water was added and the solution was
extracted with ethyl acetate. The organic layer is dried over
MgSO.sub.4 and after evaporation of the solvents, the crude oil was
purified over a short silica plug (eluent: 10/90=ethyl
acetate/hexane) to afford
2-acetyl-4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]fu-
ran.
B.
3-{4-[2-(2,2,2-Trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]furan--
2-yl}-but-2-enoic acid ethyl ester
[0434] ##STR95##
[0435] To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil)
in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents)
of triethyl phosphonoacetate (diluted in 1 mL of dry DMF) at
0.degree. C. After the gas evolution has ceased, 0.51 mmol of
2-acetyl-4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]fu-
ran diluted in 3 mL of dry DMF was added dropwise. The red mixture
was slowly heated to 40.degree. C. until complexion. After cooling,
water was added and the solution was extracted 2 times with ethyl
acetate. The organic layers were combined, washed with water and
brine and dried over MgSO.sub.4. After evaporation of the solvents,
the crude oil is purified over a short plug of silica gel (eluent:
95/5 hexane/ethyl acetate) to afford
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]f-
uran-2-yl}-but-2-enoic acid ethyl ester.
C.
3-{4-[2-(2,2,2-Trifluoroethoxy)-3,5-di-iso-propylphenyl]-5-fluorobenzo[-
b]furan-2-yl}-but-2-enoic acid
[0436] A mixture of 0.450 mmol of
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]furan-2--
yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and
1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling
at room temperature, the mixture was acidified to pH=2 and
extracted with ethyl acetate. The organic layer was dried over
MgSO.sub.4 and after evaporation of the solvents, the crude acid
was recrystallized from acetonitrile.
3-{4-[2-(2,2,2-Trifluoroethoxy)-3,5-di-iso-propylphenyl]-5-fluorobenzo[b]-
furan-2-yl}-but-2-enoic acid was isolated as a white solid.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.60 (d, J=6.9 Hz, 1H),
7.58 (d, J=6.2 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H), 7.32 (t, J=7.6 Hz,
1H), 7.19 (d, J=2.1 Hz, 1H), 7.11 (s, 1H), 6.59 (s, 1H), 3.64 (dd,
J=8.5 Hz, 2H), 3.45 (m, 1H), 2.96 (m, 1H), 2.57 (s, 3H), 1.32 (d,
J=6.8 Hz, 6H), 1.31 (d, J=6.7 Hz, 6H).
Example 23
3-{4-[2-(2,2,2-Trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thien--
2-yl}but-2-enoic acid
[0437] ##STR96##
A. 2-Acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)
benzo[b]thiophene
[0438] ##STR97##
[0439] To a mixture of 5.0 g (16.5 mmol)
2-acetyl-4-iodobenzo[b]thiophene and 675 mg (0.82 mmol) of
PdCl.sub.2dppf in a mixture of 55 mL of dry dioxane and 6.8 mL of
dry triethylamine was added dropwise 3.6 mL (3.2 g, 24.8 mmol) of
4,4,5,5-tetramethyl-1,3,2-dioxaborolane. When the vigorous gas
evolution has stopped, the mixture was stirred 3 hours at
80.degree. C. When the reaction was complete (TLC monitoring),
water (1 mL) was added carefully to hydrolyze the remaining
boronate and the solvents were removed under reduced pressure. The
remaining brownish solid was disolved in 10 mL of a 1/10 mixture of
methylene chloride-hexane and purified over a silica plug (eluent:
methylene chloride/hexane, 1/10). After removal of the solvents,
the crude boronate was recrystallized from hexanes to afford 3.6 g
(11.9 mmol, yield: 74%) of
2-acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)
benzo[b]thiophene as a bright yellow crystal. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.58 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.92 (d,
J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 2.70 (s, 3H), 1.41 (s,
12H).
B.
2-Acetyl-4-(2-hydroxy-3-tert-butyl-5-methylphenyl)benzo[b]thiophene
[0440] ##STR98##
[0441] A mixture of 240 mg (0.86 mmol) of
2-tert-butyl-4-methyl-6-iodophenol, 260 mg (0.86 mmol) of
2-acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)
benzo[b]thiophene, 25 mg (0.03 mmol) of PdCl.sub.2dppf, 0.9 ml of a
2N Na.sub.2CO.sub.3 aqueous solution in 6 ml of dry ethylene glycol
dimethyl ether was heated to reflux for 5 hours. After cooling at
room temperature, the solvents were removed under reduced pressure
and the crude phenol was purified using silica gel column
chromatography (eluent: 15/85 ethyl acetate/hexanes) to give 211 mg
(0.63 mmol, yield: 72%) of
2-acetyl-4-(2-hydroxy-3-tert-butyl-5-methylphenyl)benzo[b]thiophene.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92 (d, J=7.7 Hz, 1H),
7.71 (s, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.20
(d, J=1.9 Hz, 1H), 6.95 (d, J=1.9 Hz, 1H), 4.95 (s, 1H), 2.57 (s,
3H), 2.35 (s, 3H), 1.46 (s, 9H).
C.
2-Acetyl-4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo-
[b]thiophene
[0442] ##STR99##
[0443] A mixture of 211 mg (0.63 mmol) of
2-acetyl-4-(2-hydroxy-3-tert-butyl-5-methylphenyl)benzo[b]thiophene,
0.1 ml (132 mg, 0.81 mmol) of 1,1,1-trifluoro-2-bromoethane and 304
mg (0.94 mmol) of Cs.sub.2CO.sub.3 in 2.5 ml of dry DMF was heated
at 60.degree. C. in a pressure tube overnight. After cooling at
room temperature, 10 mL of a 5/95 ethyl acetate/hexane solution was
added and the remaining mixture was stirred for 5 minutes. The
solution was filtrated through a silica plug (eluent: 5/95 ethyl
acetate/hexane) and the solvents were removed under pressure. 188
mg (0.44 mmol, yield: 71%) of
2-acetyl-4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b-
]thiophene was isolated as an oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.89 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 7.54 (t,
J=7.8 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.26 (d, J=1.9 Hz, 1H), 7.06
(d, J=1.9 Hz, 1H), 3.63 (m, 1H), 3.52 (m, 1H), 2.56 (s, 3H), 2.38
(s, 3H), 1.48 (s, 9H).
D.
3-{4-[2-(2,2,2-Trifluoroethoxy)-3-tert-butyl-5-methylphenyl]-benzo[b]th-
ien-2-yl}but-2-enoic acid ethyl ester
[0444] ##STR100##
[0445] To a mixture of 33 mg (0.79 mmol) of NaH in 2 ml of dry DMF
was added dropwise 0.13 mL (148 mg, 0.66 mmol) of
triethylphosphonoacetate at 0.degree. C. The solution was stirred
for 10 minutes at 0.degree. C., then 185 mg (0.44 mmol) of
2-acetyl-4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b-
]thiophene diluted in 2 ml of dry DMF was added dropwise. The
reddish solution was stirred at 60.degree. C. until the reaction
was complete (TLC monitoring). After cooling to room temperature
and work-up, the crude ester was purified using silica gel column
chromatography to afford 198 mg (0.41 mmol, yield: 94%) of
3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]-benzo[b]thie-
n-2-yl}but-2-enoic acid ethyl ester as an oil. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.81(d, J=7.9 Hz, 1H), 7.43 (t, J=7.9 Hz,
1H), 7.39 (d, J=7.8 Hz, 1H), 7.37 (s, 1H), 7.24 (d, J=1.6 Hz, 1H),
7.06 (d, J=1.6 Hz, 1H), 6.29 (s, 1H), 4.21 (dd, J=14.1, 7.0 Hz,
2H), 3.64 (m, 1H), 3.51 (m, 1H), 2.57 (s, 3H), 2.37 (s, 3H), 1.47
(s, 9H), 1.32 (t, J=7.2 Hz, 3H).
E.
3-{4-[2-(2,2,2-Trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thi-
en-2-yl}but-2-enoic acid
[0446] A mixture of 198 mg (0.41 mmol) of
3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thien-
-2-yl}but-2-enoic acid ethyl ester dissolved in 4 mL of methanol, 5
mL of THF and 1 mL of a 2N aqueous solution of LiOH was heated to
reflux for 2 hours. After cooling at room temperature and acidic
work-up, the crude acid was purified using preparative HPLC
(kromosil column, eluent: 8/92 water/methanol +0.1% TFA).
Collection of the desired fractions, evaporation of the solvents
and recrystallization from acetonitrile affords 110 mg (0.23 mmol,
yield: 58%) of
3-{4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thien-
-2-yl}but-2-enoic acid as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) d: 7.80 (d, J=8.2 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.40
(s, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.24 (d, J=1.9 Hz, 1H), 7.06 (d,
J=1.9 Hz, 1H), 6.32 (s, 1H), 3.61 (m, 1H), 3.58 (m, 1H), 2.58 (s,
3H), 2.37 (s, 3H), 1.46 (s, 9H).
[0447] Examples 24-47 were synthesized using the method described
in Example 23.
Example 24
(E)
3-{4-[2-(2,2,2-Trifluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-
-2-yl}but-2-enoic acid
[0448] ##STR101##
[0449] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.82 (dd, J=6.7,
2.2 Hz, 1H), 7.46 (m, 3H), 7.45 (s, 1H), 7.23 (d, J=2.3 Hz, 1H),
6.33 (s, 1H), 3.60 (m, 2H), 2.59 (s, 3H), 1.48 (s, 3H), 1.33 (s,
9H).
Example 25
(E)
3-{4-[2-(2,2,2-Trifluoroethoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]th-
ien-2-yl}but-2-enoic acid
[0450] ##STR102##
[0451] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.81 (d, J=7.7
Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J=7.7 Hz,
1H), 7.39 (d, J=2.1 Hz, 1H), 7.08 (d, J=2.1 Hz, 1H), 6.32 (s, 1H),
3.62 (m, 1H), 3.55 (m, 1H), 2.65 (dd, J=15.1, 7.5 Hz, 2H), 2.59 (s,
3H), 1.47 (s, 9H), 1.27 (t, J=7.5 Hz, 3H).
Example 26
(E)
3-{4-[2-(3-fluoropropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2--
yl}but-2-enoic acid
[0452] ##STR103##
[0453] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.78 (d, J=7.7
Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J=7.7 Hz,
1H), 7.23 (d, J=2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.32 (s, 1H),
4.12 (m, 1H), 3.95 (m, 1H), 3.47 (m, 1H), 3.35 (m, 1H), 2.67 (dd,
J=15.2, 7.6 Hz, 2H), 2.58 (s, 3H), 1.55 (m, 2H), 1.46 (s, 9H), 1.27
(t, J=7.4 Hz, 3H).
Example 27
(E)
3-{4-[2-(2,2-difluoroethoxy)-3-(adamant-1-yl)-5-methylphenyl]benzo[b]t-
hien-2-yl}but-2-enoic acid
[0454] ##STR104##
[0455] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.80 (d, J=7.9
Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.41 (s, 1H), 7.40 (d, J=7.9 Hz,
1H), 7.18 (d, J=1.6 Hz, 1H), 7.05 (d, J=1.6 Hz, 1H), 6.33 (s, 1H),
5.17 (dt, J=55.4, 3.8 Hz, 1H), 3.52 (m, 1H), 3.45 (m, 1H), 2.59 (s,
3H), 2.37 (s, 3H), 2.12 (m, 9H), 1.79 (m, 6H).
Example 28
(E)
3-{4-[2-(3,3-difluoropropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thie-
n-2-yl}but-2-enoic acid
[0456] ##STR105##
[0457] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.80 (d, J=7.9
Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.42 (s, 1H), 7.41 (d, J=7.9 Hz,
1H), 7.23 (d, J=1.9 Hz, 1H), 7.07 (d, J=1.9 Hz, 1H), 6.33 (s, 1H),
5.35 (dt, J=56.9, 4.7 Hz, 1H), 3.51 (m, 1H), 3.42 (m, 1H), 2.67
(dd, J=15.1, 7.5 Hz, 2H), 2.58 (s, 3H), 1.65 (m, 2H), 1.46 (s, 9H),
1.27 (t, J=7.4 Hz, 3H).
Example 29
(E)
3-{4-[2-(2,2-difluoroethoxy)-3-propyl-5-tert-butylphenyl]-benzo[b]thie-
n-2-yl}but-2-enoic acid
[0458] ##STR106##
[0459] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.81 (d, J=7.8
Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.45 (s, 1H), 7.42 (t, J=7.8 Hz,
1H), 7.27 (d, J=2.2 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 6.33 (s, 1H),
5.43 (dt, J=55.4, 4.2 Hz, 1H), 3.48 (m, 2H), 2.70 (t, J=7.7 Hz,
2H), 2.60 (s, 3H), 1.70 (m, 2H), 1.34 (s, 9H), 1.03 (t, J=7.3 Hz,
3H). (LG101646)
Example 30
(E)
3-{4-[2-(3,3-difluoropropoxy)-3-propyl-5-phenylphenyl]-benzo[b]thien-2-
-yl}but-2-enoic acid
[0460] ##STR107##
[0461] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.81 (d, J=7.8
Hz, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.50 (d, J=1.8 Hz, 1H), 7.43 (m,
6H), 7.33 (t, J=6.9 Hz, 1H), 6.33 (s, 1H), 5.45 (dt, J=56.9, 4.7
Hz, 1H), 3.55 (m, 1H), 3.42 (m, 1H), 2.73 (t, J=7.7 Hz, 2H), 2.58
(s, 3H), 1.72 (m, 4H), 1.38 (m, 2H), 1.05 (t, J=7.4 Hz, 3H).
Example 31
(E)
3-[4-(2-(2,2,2-trifluoroethoxy)-3-phenyl-5-methylphenyl]-benzo[b]thien-
yl}but-2-enoic acid
[0462] ##STR108##
[0463] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.81 (d, J=7.8
Hz, 1H), 7.62 (d, J=7.4 Hz, 2H), 7.52 (s, 1H), 7.45 (td, J=7.5, 2.4
Hz, 2H), 7.39 (m, 3H), 7.28 (d, J=1.8 Hz, 1H), 7.21 (d, J=1.8 Hz,
1H), 6, 36 (s, 1H), 2.66 (s, 3H), 2.44 (s, 3H).
Example 32
(E)
3-{4-[2-(2-methylpropoxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2--
yl}but-2-enoic acid
[0464] ##STR109##
[0465] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.77 (d, J=7.7
Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.44 (s, 1H), 7.40 (t, J=7.7 Hz,
1H), 7.22 (d, J=2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.30 (s, 1H),
3.15 (dd, J=8.9, 6.1 Hz, 1H), 2.95 (dd, J=8.9, 6.1 Hz, 1H), 2.67
(dd, J=15.1, 7.5 Hz, 2H), 2.59 (s, 3H), 1.27 (s, 9H), 1.41 (m, 1H),
1.27 (t, J=7.7 Hz, 3H), 0.49 (d, J=6.7 Hz, 3H), 0.35 (d, J=6.7 Hz,
3H).
Example 33
(E)
3-{4-[2-(2,2,2-trifluoroethoxy)-4-tert-butylphenyl]-benzo[b]thien-2-yl-
}but-2-enoic acid
[0466] ##STR110##
[0467] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.52 (d, J=7.9
Hz, 1H), 8.17 (s, 1H), 8.15 (t, J=7.9 Hz, 1H), 8.05 (d, J=7.9 Hz,
2H), 7.99 (s, 1H), 7.97 (dd, J=7.9, 1.4 Hz, 1H), 7.84 (d, J=1.9 Hz,
1H), 7.06 (s, 1H), 4.90 (d, J=8.2 Hz, 1H), 4.86 (d, J=8.2 Hz, 1H),
3.35 (s, 3H), 2.14 (s, 9H).
Example 34
(E)
3-[4-(5-(2,2,2-trifluoroethoxy)-6-tert-butylindan-4-yl)-benzo[b]thien--
2-yl]but-2-enoic acid
[0468] ##STR111##
[0469] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.81 (d, J=7.9
Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.33 (s,
1H), 7.25 (s, 1H), 6.32 (s, 1H), 3.61 (m, 2H), 2.96 (t, J=7.4 Hz,
2H), 2.75 (m, 1H), 2.57 (s, 3H), 2.51 (m, 1H), 2.05 (m, 2H), 1.44
(s, 9H).
Example 35
(E) 3-[4-(3,5-di-tert-butylphenyl)-benzo[b]thien-2-yl]but-2-enoic
acid
[0470] ##STR112##
[0471] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.76 (m, 2H),
7.44 (m, 5H), 6.34 (s, 3H), 2.62 (s, 3H), 1.40 (s, 18H).
Example 36
(E)
3-{4-[3,5-di-iso-propyl-2-(2,2,2-trifluoroethoxy)phenyl]-5-fluoro-benz-
o[b]thien-2-yl}but-2-enoic acid
[0472] ##STR113##
[0473] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.77 (m, 1H),
7.25 (m, 4H), 7.06 (d, J=2.3 Hz, 1H), 6.32 (s, 1H), 3.63 (m, 2H),
3.42 (m, 1H), 2.95 (m, 1H), 2.58 (s, 3H), 1.31 (d, J=6.9 Hz, 6H),
1.28 (d, J=6.8 Hz, 6H).
Example 37
(E)
3-{4-[2-(3-methylbutoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}b-
ut-2-enoic acid
[0474] ##STR114##
[0475] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.76 (d, J=6.9
Hz, 1H), 7.46 (m, 3H), 7.41 (d, J=2.3 Hz, 1H), 7.19 (d, J=2.3 Hz,
1H), 6.31 (s, 1H), 3.29 (m, 2H), 2.59 (s, 3H), 1.47 (s, 9H), 1.34
(s, 9H), 1.21 (m, 1H), 0.99 (q, J=6.7 Hz, 2H), 0.54 (d, J=6.6 Hz,
3H), 0.41 (d, J=6.6 Hz, 3H).
Example 38
(E)
3-{4-[2-(3,3,3-difluoropropoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-
-2-yl}but-2-enoic acid
[0476] ##STR115##
[0477] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.80 (d, J=7.6 Hz,
1H), 7.45 (m, 4H), 7.21 (d, J=2.4 Hz, 1H), 6.33 (s, 1H), 5.39 (tt,
J=56.8 Hz, J=4.7 Hz, 1H), 3.44 (m, 2H), 2.59 (s, 3H), 1.70 (m, 2H),
1.46 (s, 9H), 1.35 (s, 9H).
Example 39
(E)
3-{4-[2-(2-methylpropoxy)-3,5-di-tert-butylphenyl)-benzo[b]thien-2-yl]-
but-2-enoic acid
[0478] ##STR116##
[0479] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.77 (d, J=7.7 Hz,
1H), 7.43 (m, 4H), 7.19 (d, J=2.4 Hz, 1H), 6.30 (s, 1H), 3.14 (m,
1H), 2.94 (m, 1H), 2.59 (s, 3H), 1.47 (s, 9H), 1.40 (m, 1H), 1.34
(s, 9H), 0.50 (d, J=6.7 Hz, 3H), 0.36 (d, J=6.6 Hz, 3H).
Example 40
(E)
3-{4-[2-(2,2,2-trifluoroethoxy)-3,5-di-(1,1-dimethylpropyl)-phenyl]-be-
nzo[b]thien-2-yl}but-2-enoic acid
[0480] ##STR117##
[0481] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.81 (d, J=7.0 Hz,
1H), 7.45 (m, 3H), 7.31 (d, J=2.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H),
6.32 (s, 1H), 3.58 (m, 2H), 2.59 (s, 3H), 1.96 (m, 1H), 1.80 (m,
1H), 1.65 (q, J=7.5 Hz, 2H), 1.45 (s, 3H), 1.43 (s, 3H), 1.31 (s,
3H), 1.30 (s, 3H), 0.75 (t, J=7.5 Hz, 3H), 0.73 (t, J=7.5 Hz,
3H).
Example 41
(E)
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[-
b]thien-2-yl}but-2-enoic acid
[0482] ##STR118##
[0483] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.81 (d, J=7.6
Hz, 1H), 7.45 (m, 3H), 7.29 (d, J=2.1 Hz, 1H), 7.15 (d, J=2.2 Hz,
1H), 6.33 (s, 1H), 5.13 (tt, J=55.3 Hz, J=4.2 Hz, 1H), 3.49 (m,
2H), 2.59 (s, 3H), 1.93 (m, 1H), 1.81 (m, 1H), 1.64 (q, J=7.4 Hz,
2H), 1.44 (s, 3H), 1.42 (s, 3H), 1.30 (s, 6H), 0.74 (t, J=7.2 Hz,
3H), 0.73 (t, J=7.3 Hz, 3H).
Example 42
(E)
3-{4-[2-(3-fluoropropoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]t-
hien-2-yl}but-2-enoic acid
[0484] ##STR119##
[0485] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.78 (d, J=7.6
Hz, 1H), 7.44 (m, 3H), 7.28 (d, J=2.3 Hz, 1H), 7.13 (d, J=2.3 Hz,
1H), 6.32 (s, 1H), 4.00 (m, 2H), 3.36 (m, 2H), 2.59 (s, 3H), 1.98
(m, 1H), 1.78 (m, 1H), 1.64 (q, J=7.5 Hz, 2H), 1.44 (s, 3H), 1.42
(s, 3H), 1.30 (s, 6H), 0.74 (t, J=7.4 Hz, 3H), 0.72 (t, J=7.4 Hz,
3H).
Example 43
(E)
3-{4-[2-(3-methylbutoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]th-
ien-2-yl}but-2-enoic acid
[0486] ##STR120##
[0487] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.76 (d, J=7.4
Hz, 1H), 7.43 (m, 3H), 7.26 (d, J=2.1 Hz, 1H), 7.12 (d, J=2.3 Hz,
1H), 6.31 (s, 1H), 3.26 (m, 2H), 2.59 (s, 3H), 2.00 (m, 1H), 1.78
(m, 1H), 1.64 (q, J=7.4 Hz, 2H), 1.43 (s, 3H), 1.41 (s, 3H), 1.29
(s, 6H), 1.21 (m, 1H), 0.96 (q, J=6.7 Hz, 2H), 0.74 (t, J=7.3 Hz,
3H), 0.72 (t, J=7.3 Hz, 3H), 0.54 (d, J=6.6 Hz, 3H), 0.41 (d, J=6.6
Hz, 3H).
Example 44
(E)
3-{4-[2-(3,3-difluoropropoxy)-3,5-di-(1,1-dimethylpropyl)-phenyl]-benz-
o[b]thiophene]but-2-enoic acid
[0488] ##STR121##
[0489] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.80 (d, J=7.9
Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.41 (d, J=6.2 Hz, 1H), 7.40 (s,
1H), 7.28 (d, J=2.3 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 6.32 (s, 1H),
5.36 (tt, J=56.8 Hz, J=4.7 Hz, 1H), 3.41 (m, 2H), 2.58 (s, 3H),
1.95 (m, 1H), 1.76 (m, 1H), 1.64 (q, J=7.3 Hz, 2H), 1.52 (m, 2H),
1.43 (s, 3H), 1.41 (s, 3H), 1.30 (s, 6H), 0.74 (t, J=7.5 Hz, 3H),
0.72 (t, J=7.5 Hz, 3H).
Example 45
(E)
3-{4-[2-(2,2-difluoroethoxy)-3,5-di-(dimethylphenylmethyl)phenyl]-benz-
o[b]thien-2-yl}but-2-enoic acid
[0490] ##STR122##
[0491] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.73 (d, J=7.9
Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.32 (m,
5H), 7.24 (m, 6H), 7.14 (m, 2H), 6.28 (s, 1H), 4.34 (tt, J=55.4 Hz,
J=4.3 Hz, 1H), 2.55 (s, 3H), 2.36 (m, 1H), 2.25 (m, 1H), 1.77 (s,
9H), 1.67 (s, 3H).
Example 46
(E)
3-{4-[2-(2,2-difluoroethoxy)-3-tert-butyl-5-phenylphenyl]-benzo[b]thie-
n-2-yl]but-2-enoic acid
[0492] ##STR123##
[0493] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.84 (dd, J=6.7
Hz, J=2.2 Hz, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.59 (d, J=7.4 Hz, 2H),
7.47 (m, 6H), 7.35 (t, J=7.3 Hz, 1H), 6.34 (s, 1H), 5.19 (tt,
J=55.4 Hz, J=4.2 Hz, 1H), 3.54 (m, 2H), 2.60 (s, 3H), 1.53 (s,
9H).
Example 47
(E)
3-{5-[2-(2,2-difluoroethoxy)-3-phenyl-5-tert-butylphenyl]-benzo[b]thie-
n-2-yl}but-2-enoic acid
[0494] ##STR124##
[0495] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.83 (m, 1H),
7.62 (d, J=7.4 Hz, 2H), 7.55 (s, 1H), 7.47 (m, 5H), 7.40 (m, 2H),
6.36 (s, 1H), 5.06 (tt, J=55.5 Hz, J=4.2 Hz, 1H), 3.29 (m, 2H),
2.66 (s, 3H), 1.39 (s, 9H).
Example 48
3-[3-(2-Butoxy-3,5-di-iso-propylphenyl)-1H-indol-5-yl]-but-2-enoic
acid
[0496] ##STR125##
A. 1-Benzenesulfonyl-5-iodo-1H-indole
[0497] ##STR126##
[0498] 5-Iodoindole (9.72 g, 40 mmol), tetrabutylammonium hydrogen
sulfate (1.36 g, 4 mmol) and benzene sulfonyl chloride (5.1 mL, 40
mmol) was dissolved in a biphasic mixture of toluene (240 mL)/2.5 N
NaOH (480 mL) and stirred vigorously for 16 h. The two layers were
separated and the toluene was washed with water (3.times.300 mL),
brine (250 mL), dried (Na.sub.2SO.sub.4), filtered and evaporated
in vacuo to provide 14.9 g of a reddish brown oil. The material was
passed over a silica pad with (9:1) hexane:ethyl acetate to provide
14.0 g (91%) of a brown gum. .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 7.90-7.86 (m, 3H), 7.79 (d, 1H, J=8.7), 7.63-7.55 (m, 3H),
7.51-7.45 (m, 2H), 6.61 (1H, d, J=3.8).
B. 3-(1-Benzenesulfonyl-1H-indol-5-yl)-but-2-enoic acid methyl
ester
[0499] ##STR127##
[0500] 5-Iodo-N-benzenesulfonylindole (18.09 g, 47 mmol), methyl
crotonate (40 mL, 378 mmol), triethylamine (145 mL), and palladium
acetate (2.65 g, 11.8 mmol) were combined in DMF (600 mL). The
reaction was heated at 100.degree. C. for 4 h. TLC (3:1)
hexane:ethyl acetate showed iodide still present. Methyl crotonate
(25 mL) and dichlorobis(triphenylphosphine) palladium(II) (3.31 g,
4.7 mmol) was added. The reaction was heated for an additional 4 h
and then at room temperature for 13 h at which time starting
material was virtually gone. The solids were allowed to settle and
most of the liquid decanted off. The remaining portion was filtered
through a pad of celite to remove the solids and the volume reduced
somewhat in vacuo. The solution was diluted with water (1 L) and
washed with diethyl ether (3.times.500 mL). The organic portion was
washed with 1N HCl (2.times.500 mL), brine (2.times.500 mL), dried
(MgSO.sub.4), filtered and evaporated in vacuo to provide 18.3 g of
a dark brown oil. The material was purified preparatively in two
runs on a Waters 2000LC using a gradient elution of (98:2) ethyl
acetate:hexane to 66:34 ethyl acetate:hexane to give 6.79 g (40%).
Mp: 80-85.degree. C. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta.
7.90 (d, 1H, J=8.7), 7.84-7.81 (m, 2H), 7.57 (d, 1H, J=1.6),
7.52-7.35 (m, 5H), 6.60 (m, 1H), 6.07, (d, 1H, J=1.2), 3.68, (s,
3H), 2.53 (d, 3H, J=1.2). MS [EI+] 356 (M+H).sup.+.
[0501] Anal. Calcd for C.sub.19H.sub.17NO.sub.4S: C, 64.21; H,
4.82; N, 3.94. Found: C, 64.06; H, 4.63; N, 4.04.
C. 3-(1-Benzenesulfonyl-3-iodo-1H-indol-5-yl)-but-2-enoic acid
methyl ester
[0502] ##STR128##
[0503] 3-(1-Benzenesulfonyl-1H-indol-5-yl)-but-2-enoic acid methyl
ester (6.78 g, 19.1 mmol), N-iodosuccinimide (6.45 g, 28.7 mmol)
and p-toluenesulfonic acid monohydrate (0.55 g, 2.87 mmol) were
dissolved in dichloromethane (50 mL) and stirred for 4 h. The
reaction was diluted with diethyl ether (250 mL) and washed with
10% Na.sub.2S.sub.2O.sub.3 (2.times.100 mL). The aqueous layers
were combined and backwashed with ether and then the combined
organic portions washed with water (200 mL, brine (200 mL), dried
(MgSO.sub.4), filtered, and evaporated to give 9.56 g reddish foam.
The foam was passed over a pad of Florosil in a 2 L sintered glass
funnel using (9:1) hexane:ethyl acetate. Fractions containing
product were concentrated. The reside was redissolved in
hexane:ethyl acetate and the volume reduced in vacuo. The resulting
solids were filtered and dried to give 4.08 g (44%) of a light pink
solid. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.00-7.92 (m,
3H), 7.75 (s, 1H), 7.54-7.48 (m, 5H), 6.20 (d, 1H, J=1.3), 3.79 (s,
3H), 2.65 (d, 3H, J=1.2).
D.
3-[1-Benzenesulfonyl-3-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol-5-yl]-
-but-2-enoic acid methyl ester
[0504] ##STR129##
[0505] 3-(1-Benzenesulfonyl-3-iodo-1H-indol-5-yl)-but-2-enoic acid
methyl ester (653 mg, 1.35 mmol) and
(2-butoxy-3,5-diisopropylphenyl)-boronic acid (415 mg, 1.49 mmol)
were dissolved in toluene (8 mL) under a nitrogen atmosphere.
Tetrakis(triphenylphosphine) palladium (172 mg, 0.15 mmol) and 2N
Na.sub.2CO.sub.3 (2.7 mL) was added and the biphasic mixture
stirred at 80.degree. C. for 6 h. The reaction was judged complete
by TLC (9:1) in hexane:ethyl acetate but was allowed to stir
overnight at room temperature. The reaction was diluted with water
(5 mL)/ethyl acetate (15 mL). The layers were separated and the
aqueous washed with ethyl acetate (10 mL). The organic portions
were passed through a pad of Celite, dried (MgSO.sub.4), filtered
and concentrated in vacuo to provide 1.20 g of a dark brown oil.
Chromatography (SiO.sub.2, hexanes/ethyl acetate) provided 294 mg
(37%) of a yellow foam. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta.
8.06 (d, 1H, J=8.7), 7.94 (m, 2H), 7.80 (s, 1H), 7.75 (d, 1H,
J=1.7), 7.56-7.45 (m, 4H), 7.13 (m, 2H), 6.14 (d, 1H, J=1.2), 3.75
(s, 3H), 3.39 (sep, 1H, J=6.9), 3.29 (t, 2H, J=6.3), 2.93 (sep, 1H,
J=6.9), 2.60 (d, 3H, J=1.2), 1.29 (d, 7H, J=6.9), 1.27 (d, 7H,
J=6.9), 1.22 (m, 2H), 0.62 (t, 3H, J=7.2). MS [EI+] 588
(M+H).sup.+.
E.
3-[3-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid
[0506]
3-[1-Benzenesulfonyl-3-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol--
5-yl]-but-2-enoic acid methyl ester (130 mg, 0.22 mmol) was
dissolved in methanol (3.5 mL)/dioxane (3.5 mL) and treated with
2.5N KOH (2.5 mL) at 60.degree. C. for 8 h. Diluted with 1N HCl (10
mL) and extracted with ethyl acetate (3.times.10 mL). The combined
organic portions were washed with water, brine, dried (MgSO.sub.4),
filtered and concentrated in vacuo to provide 151 mg of a yellow
oil. The material was purified using radial chromatography by
elution with hexane/ethyl acetate gradient to provide 51 mg (54%)
of a yellow foam. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.32
(bs, 1H), 8.02 (s, 1H), 7.55 (d, 1H, J=2.3), 7.40 (s, 2H), 7.28 (d,
1H, J=2.2), 7.09 (d, 1H, J=2.2), 6.26 (d, 1H, J=1.0), 3.44 (m, 3H),
2.95 (sep, 1H, J=6.9), 2.70 (d, 3H, J=0.9), 1.41 (m, 2H), 1.32-1.19
(m, 14H), 0.75 (t, 3H, J=7.3). MS [EI+] 434 (M+H).sup.+ [EI-] 432
(M-H).sup.+. HPLC [MetaSil AQ C18 (0.46.times.15 cm) 5-90%
CH.sub.3CN(0.1% TFA) in H.sub.2O(0.1% TFA)], 21.973 min.
>99%.
Example 49
3-[3-(2-Butoxy-3,5-diisopropylphenyl)-1-methyl-1H-indol-5-yl]-but-2-enoic
acid
[0507] ##STR130##
A.
3-[3-(2-Butoxy-3,5-diisopropylphenyl)-1-methyl-1H-indol-5-yl]-but-2-eno-
ic acid methyl ester
[0508] ##STR131##
[0509]
3-[3-(2-Butoxy-3,5-diisopropyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid (129 mg, 0.30 mmol), cesium carbonate (293 mg, 0.90 mmol), and
iodomethane (0.041 mL, 65 mmol) were combined in DMF (6 mL) and
heated at 40.degree. C. for 2 h. The reaction was diluted with
water and extracted with ethyl acetate (2.times.). The organic
portions were combined and washed with brine, dried (MgSO.sub.4),
filtered and concentrated in vacuo to provide 139 mg of a yellow
oil. The material was purified using radial chromatography by
elution with (95:5) hexane:ethyl acetate to provide 119 mg (86%) of
product. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.00 (d, 1H,
J=1.4), 7.45 (dd, 1H, J=1.7, 8.7), 7.41 (s, 1H), 7.34 (d, 1H,
J=8.7), 7.28 (d, 1H, J=2.3), 7.07 (d, 1H, J=2.3), 6.22 (d, 1H,
J=1.2), 3.86 (s, 3H), 3.76 (s, 3H), 3.44 (m, 3H), 2.94 (sep, 1H,
J=6.9), 2.68 (d, 3H, J=1.0), 1.44 (m, 2H), 1.30-1.19 (m, 14H), 0.76
(t, 3H, J=7.3). MS [EI+] 462 (M+H).sup.+.
B.
3-[3-(2-Butoxy-3,5-diisopropylphenyl)-1-methyl-1H-indol-5-yl]-but-2-eno-
ic acid
[0510]
3-[3-(2-Butoxy-3,5-diisopropylphenyl)-1-methyl-1H-indol-5-yl]-but--
2-enoic acid methyl ester (119 mg, 0.26 mmol) was dissolved in
methanol (2.5 mL)/dioxane (2.5 mL) and treated with 1N NaOH (2.5
mL) at 60.degree. C. for 3 h. The reaction was diluted with 1N HCl
(3 mL) and extracted with ethyl acetate (3.times.10 mL). The
combined organic portions were washed with brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo to provide 134 mg
of residue. The material was purified using radial chromatography
by elution with hexane:ethyl acetate gradient to provide 60 mg
(52%) of a light yellow solid. .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 8.05 (d, 1H, J=1.4), 7.49 (dd, 1H, J=1.6, 8.7), 7.44 (s,
1H), 7.38 (d, 1H, J=8.7), 7.07 (d, J=2.3), 7.30 (d, 1H, J=2.2),
7.10 (d, 1H, J=2.2), 3.89 (s, 3H), 3.47 (m, 3H), 2.97 (sep, 2H,
J=6.9), 2.73 (s, 3H), 1.46 (m, 2H), 1.34-1.22 (m, 14H), 0.78 (t,
3H, J=7.3). MS [EI+] 448 (M+H).sup.+ [EI-] 446.
[0511] Anal. Calcd for C.sub.29H.sub.37NO.sub.3: C, 77.82; H, 8.33;
N, 3.13. Found: C, 77.50; H, 8.28; N, 3.15.
Example 50
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid
[0512] ##STR132##
A.
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid methyl ester
[0513] ##STR133##
[0514] 3-(1-Benzenesulfonyl-3-iodo-1H-indol-5-yl)-but-2-enoic acid
methyl ester (226 mg, 0.47 mmol) (see Example 23, step C),
(2-ethoxy-3,5-diiosopropylphenyl)-boronic acid (129 mg, 0.52 mmol)
and tetrakis(triphenylphosphine) palladium (54 mg, 0.05 mmol) were
combined in toluene (3 mL)/2N Na.sub.2CO.sub.3 (1 mL) and heated at
80.degree. C. After 4.5 h, the reaction was diluted with
water/ethyl acetate and the layers were separated. The aqueous
layer was washed with ethyl acetate. The organic portions were
combined washed with brine, dried (MgSO.sub.4), filtered and
evaporated in vacuo to provide 337 mg as a dark brown oil. The
material was purified by column chromotagraphy using (9:1)
hexane:ethyl acetate. Further purification was accomplished by
radial chromatography using (99:1) hexane:ethyl acetate and (95:5)
hexane:ethyl acetate to provide 93 mg (35%) of a yellow solid.
.sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.08 (d, 1H, J=8.7),
7.93 (m, 2H), 7.92 (s, 1H), 7.78 (d, 1H, J=1.7), 7.56-7.45 (m, 4H),
7.14 (s, 2H), 6.15 (d, 1H, J=1.2), 3.74 (s, 3H), 3.38 (m, 3H), 2.92
(sep, 1H, J=6.9), 2.60 (d, 3H, J=1.2), 1.29 (d, 7H, J=6.9), 1.27
(d, 6H, J=6.9), 0.91 (t, 3H, J=7.0). MS [EI+] 560 (M+H).sup.+.
B.
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid
[0515]
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid methyl ester (77 mg, 0.14 mmol) was dissolved in methanol (1
mL)/dioxane (1 mL) and treated with 1N NaOH (1 mL) at 55.degree. C.
for 5 h. Diluted with 1N HCl (3 mL)/water (10 mL) and extracted
with ethyl acetate (3.times.10 mL). The combined organic portions
were washed with brine (2.times.10 mL), dried (MgSO.sub.4),
filtered and concentrated in vacuo to provide 68 mg. The material
was purified by radial chromatography using a hexane/ethyl acetate
gradient to provide 34 mg (62%) of a yellow foam. .sup.1H NMR (250
MHz, CDCl.sub.3): .delta. 8.33 (bs, 1H), 8.04 (s, 1H), 7.58 (d, 1H,
J=2.4), 7.44 (s, 1H), 7.29 (d, 1H, J=2.2), 7.09 (d, 1H, J=2.2),
6.27 (s, 1H), 3.56-3.38 (m, 3H), 2.95 (sep, 1H, J=6.9), 2.70 (s,
3H), 1.32 (s, 12H, J=6.9), 1.08 (t, 3H, J=7.0). MS [EI-] 404
(M-H).sup.+.
Example 51
3-[3-(2-Butoxy-3,5-di-tert-butyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid
[0516] ##STR134##
A. 1-Butoxy-2,4-di-tert-butyl-benzene
[0517] ##STR135##
[0518] 2,4-Di-tert-butylphenol (10.3 g, 50 mmol), cesium carbonate
(32.6 g, 100 mmol) and 1-iodobutane (6 ml, 52.5 mmol) were combined
and stirred in dimethylformamide (250 mL) at room temperature for
24 h. The reaction was diluted with water (250 mL) and washed with
50% hexane/diethyl ether (400 mL, 2.times.200 mL). The organic
portions were combined, washed with water (2.times.250 mL), dried
(MgSO.sub.4), filtered and evaporated in vacuo to provide 12.2 g of
a yellow oil. The material was passed over a silica pad with hexane
to give 11.26 g (86%) of a clear oil. .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 7.38 (d, 1H, J=2.5), 7.22 (dd, 1H, J=2.6,
J=8.5), 6.84 (d, J=8.5), 4.02 (t, 2H, J=6.4), 1.87 (m, 2H), 1.59
(m, 2H), 1.46 (s, 9H), 1.36 (s, 9H), 1.04 (t, 3H, J=7.3).
B. 2-Butoxy-1,5-di-tert-butyl-3-iodo-benzene
[0519] ##STR136##
[0520] 1-Butoxy-2,4-di-tert-butyl-benzene (11.21 g, 42.7 mmol),
N-iodosuccinimide (11.53 g, 51.2 mmol) and p-toluenesulfonic acid
monohydrate (1.62 g, 8.5 mmol) were combined in dichloromethane
(100 mL) and stirred at room temperature for 62 h. TLC (hexane)
showed the reaction was not yet complete. Additional
N-iodosuccinimide (4.8 g, 21.3 mmol) and p-toluenesulfonic acid
monohydrate (1.62 g, 8.5 mmol) were added and the reaction stirred
at 35.degree. C. for 6 h. TLC showed the reaction was completed. It
was washed with a 10% Na.sub.2S.sub.2O.sub.3 solution (3.times.100
mL). The aqueous was backwashed with dichloromethane (100 mL) and
then the combined organic portions washed with water (100 mL) dried
(MgSO.sub.4), filtered and evaporated in vacuo to provide 16.42 g
yellow oil. The material was passed over a silica pad with hexane
and 99 hexane/1 ethyl acetate to provide 15.93 g (96%) of a pale
yellow oil. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.68 (d, 1H,
J=2.4), 7.36 (d, 1H, J=2.4), 4.00 (t, 2H, J=6.8), 1.92 (m, 2H),
1.58 (m, 2H), 1.42 (s, 9H), 1.31 (s, 9H), 1.04 (t, 3H, J=7.3). MS
[EI+] 275 (M+H).sup.+(-2tBu).
C. (2-Butoxy-3,5-di-tert-butylphenyl)-boronic acid
[0521] ##STR137##
[0522] 2-Butoxy-1,5-di-tert-butyl-3-iodo-benzene (3.88 g, 10 mmol)
was dissolved in anhydrous 1,2-dimethoxy-ethane (55 mL under a
nitrogen atmosphere. The solution was cooled to -75.degree. C. and
t-butyl lithium (14.7 mL, 25 mmol, 1.7M in pentane) was added
dropwise over 20-25 min at -72.degree. C. to -69.degree. C. The
reaction was stirred at -72.degree. C. for 45 min and then treated
with trimethyl borate (5.7 mL, 50 mmol). The reaction was kept cold
for 1 h and then the bath was removed and the reaction allowed to
warm to room temperature over 24 h. It was treated with 1N
hydrochloric acid (35 mL) and stirred for 30 min. The reaction was
then diluted with water (200 mL) and extracted with ethyl acetate
(150 mL, 2.times.100 mL). The combined organic portions were washed
with bicarbonate solution (100 mL), water (150 mL), brine (150 mL),
dried (Na.sub.2SO.sub.4), filtered and evaporated in vacuo to
provide 3.0 g of an oil. The material was purified by flash
chromotography (eluet: (9:1) hexane:ethyl acetate and (4:1)
hexane:ethyl acetate) to provide 2.04 g (67%) of a white solid. Mp:
82-91.degree. C. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.66
(d, 1H, J=2.6), 7.48 (d, 1H, J=2.6), 5.75 (s, 1H), 3.84 (t, 2H,
J=7.1), 1.84 (m, 2H), 1.47 (m, 2H), 1.42 (s, 9H), 1.33 (s, 9H),
2.66 (t, 3H, J=7.3). MS [EI+] 307 (M+H).sup.+ [EI-] 305
(M-H).sup.+.
D.
3-[1-Benzenesulfonyl-3-(2-butoxy-3,5-di-tert-butyl-phenyl)-1H-indol-5-y-
l]-but-2-enoic acid methyl ester
[0523] ##STR138##
[0524] 3-(1-Benzenesulfonyl-3-iodo-1H-indol-5-yl)-but-2-enoic acid
methyl ester (400 mg, 0.83 mmol) (see Example 23, step C) and
(2-butoxy-3,5-di-tert-butylphenyl)-boronic acid (415 mg, 1.49 mmol)
were dissolved in toluene (6 mL) under a nitrogen atmosphere.
Tetrakis(triphenylphosphine) palladium (96 mg, 0.083 mmol) and 2N
Na.sub.2CO.sub.3 (2.0 mL) were added and the biphasic mixture
stirred at 80.degree. C. for 5 h. TLC (9 hexane/1 EtOAc, 3.times.)
showed the iodide still present and additional palladium catalyst
(90 mg) was added and the reaction stirred at 80.degree. C. for 18
h. The reaction was allowed to cool to room temperature and the
aqueous layer was washed with ethyl acetate. The layers were
separated and the aqueous washed with EtOAc (2.times.10 mL). The
organic portions were washed with brine, dried (MgSO.sub.4),
filtered and concentrated in vacuo to provide 750 mg of a residue.
The material was purified by column and radial chromatography
(SiO.sub.2, hexane/ethyl acetate gradient) to provide 192 mg (31%)
of a yellow foam. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.07
(d, 1H, J=8.7), 7.95 (m, 2H), 7.71 (m, 2H), 7.53-7.39 (m, 5H), 7.22
(d, 1H, J=2.5), 6.15 (d, 1H, J=1.2), 3.75 (s, 3H), 3.27 (t, 2H,
J=6.4), 2.58 (d, 3H, J=1.1), 1.45 (s, 9H), 1.34 (s, 9H), 1.09 (m,
2H), 0.83 (m, 2H), 0.47 (t, 3H). MS [EI+] 616 (M+H).sup.+.
E.
3-[3-(2-butoxy-3,5-di-tert-butyl-phenyl)-1H-indol-5-yl]-but-2-enoic
acid
[0525]
3-[1-Benzenesulfonyl-3-(2-butoxy-3,5-di-tert-butyl-phenyl)-1H-indo-
l-5-yl]-but-2-enoic acid methyl ester (187 mg, 0.3 mmol) was
dissolved in methanol (2 mL)/dioxane (3.5 mL) and treated with 1N
NaOH (2 mL) at 60.degree. C. for 4 h. Diluted with 1N HCl (3 mL)
and extracted with ethyl acetate (3.times.10 mL). The combined
organic portions were washed with water (10 mL), brine (10 mL),
dried (MgSO.sub.4), filtered and concentrated in vacuo to provide
160 mg of an orange solid. The material was purified using radial
chromatography (eluet: hexane/ethyl acetate gradient) to provide 85
mg (62%) of a yellow foam. .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 8.24 (bs, 1H), 7.88 (s, 1H), 7.40-7.35 (m, 3H), 7.28 (d,
2H), 6.18 (s, 1H), 3.37 (t, 2H, J=6.5), 2.61 (s, 3H), 1.41 (s, 9H),
1.28 (s, 9H), 1.19-0.98 (m, 4H), 0.56 (t, 3H, J=7.2). MS [EI+] 462
(M+H).sup.+, [EI-]460 (M-H).sup.+. Anal. Calcd for
C.sub.30H.sub.39NO.sub.3: C, 78.05; H, 8.52; N, 3.03. Found: C,
78.10; H, 8.30; N, 3.02.
Example 52
3-[4-(2-Butoxy-3,5-diisopropylphenyl)-1H-indol-2-yl]-but-2-enoic
acid
[0526] ##STR139##
A. 1-Benzenesulfonyl-4-bromo-1H-indole
[0527] ##STR140##
[0528] 5-Bromoindole (9.76 g, 50 mmol), tetrabutylammonium hydrogen
sulfate (1.70 g, 5 mmol) and benzene sulfonyl chloride (6.7 mL, 50
mmol) was dissolved in a biphasic mixture of toluene (300 mL)/2.5 N
NaOH (600 mL) and stirred vigorously for 2.5 h. The aqueous layer
was separated and washed with ethyl acetate (2.times.250 mL). All
organic portions were combined and washed with water (3.times.250
mL), brine (250 mL), dried over MgSO.sub.4, filtered and evaporated
in vacuo to provide 16.5 g of crude product. The crude product was
triturated in diethyl ether and filtered to give 12.49 g of a light
pink solid. The filtrate was concentrated and triturated in hexane
to give 2.10 g of a brick red solid for a combined yield of 87%.
.sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.98 (d, 1H, J=8.3),
7.90 (m, 2H), 7.66 (d, 1H), 7.56-7.41 (m, 4H), 7.24 (t, 1H, J=8.0)
6.76 (1H, d, J=3.8). MS [EI+] 335, 337 (M).sup.+.
B. 1-Benzenesulfonyl-4-bromo-2-trimethylsilanyl-1H-indole
[0529] ##STR141##
[0530] Anhydrous THF (12 mL) was placed in an oven-dried 3-neck,
reaction flask under nitrogen and cooled to -73.degree. C. in a dry
ice/acetone bath. Lithium diisopropylamide (2.0M, 3.0 mL, 6 mmol)
was added followed by addition of a solution of
4-bromo-benzenesulfonylindole (1.92 g, 5.7 mmol) in anhydrous THF
(10 mL) over a period of 10 min at -73.degree. C. to -70.degree. C.
The reaction was stirred at -73.degree. C. for 1.5 h and then
placed in an ice/brine bath and allowed to warm to -5.degree. C.
over 50 min. Chlorotrimethylsilane (3.0 mL, 1.2 mmol) was dissolved
in anhydrous THF (10 mL) in a separate 3-neck roundbottom flask
under nitrogen and cooled to -73.degree. C. with a dry ice/acetone
bath. The indolyl lithium species was cooled back down to
-73.degree. C. and cannulated into the chlorotrimethyl silane while
the temperature was maintained at -72.degree. C. to -68.degree. C.
After the addition was complete, the bath was left in place, and
the reaction allowed to gradually warm to room temperature
overnight. The reaction was poured slowly into ethyl acetate (150
mL) and washed with 3-5% aqueous NaHCO.sub.3 solution (50 mL). The
organic layer was washed with more aqueous NaHCO.sub.3 (50 mL) and
then the bicarbonate layer was backwashed with ethyl acetate (50
mL). The combined organic layers were washed with water (100 mL),
brine (100 mL), dried over MgSO.sub.4, filtered and evaporated in
vacuo to provide 2.27 g of a yellow oil. The material was purified
chromotagraphically using (99:1) hexane:ethyl acetate followed by
(9:1) hexane:ethyl acetate to elute the product. Obtained 1.56 g
(67%) of a clear oil. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta.
7.83 (d, 1H, J=8.4), 7.65 (m, 2H), 7.53 (m, 1H), 7.51-7.35 (m, 3H),
7.10 (t, 1H, J=8.2), 7.00 (s, 1H), 0.48 (s, 9H). MS [EI+] 408, 410
(M+H).sup.+, [EI-] 407, 408.
C. 1-(1-Benzenesulfonyl-4-bromo-1H-indol-2-yl)-ethanone
[0531] ##STR142##
[0532] To a suspension of aluminum chloride (3.04 g, 22.8 mmol) in
anhydrous CH.sub.2Cl.sub.2 25 mL) under nitrogen was added acetic
anhydride (1.1 mL, 11.4 mmol). The mixture was stirred for 20 min
and then cooled in an ice bath. A solution of
2-trimethylsilyl-4-bromo-benzenesulfonylindole (1.55 g, 3.8 mmol)
in CH.sub.2Cl.sub.2 was added slowly. The ice bath was removed
after 5 min and the reaction allowed to warm to room temperature.
After 1 h the reaction was judged complete by TLC (9:1)
hexane:ethyl acetate. Ice was added, the biphasic mixture stirred
for 20 min and then diluted into water (25 mL)/CH.sub.2Cl.sub.2.
The layers were separated and the aqueous layer was washed with
CH.sub.2Cl.sub.2 (2.times.50 mL). The combined organic portions
were washed with saturated NaHCO.sub.3 solution (100 mL), brine
(100 mL), dried over MgSO.sub.4, filtered and evaporated in vacuo
to provide 1.28 g of a pink solid. The material was purified by
column chromatography using (99:1) hexane:ethyl acetate followed by
(5:1) hexane:ethyl acetate to provide 1.15 g (yield=80%) of product
as an off-white solid. Mp: 142-146.degree. C. .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 8.16 (d, 1H, J=8.5), 8.02 (m, 2H), 7.63-7.48
(m, 4H), 7.35 (t, 1H, J=8.3), 7.22 (s, 1H), 2.69 (s, 3H). MS [EI+]
378, 380 (M+H).sup.+.
D. 3-(1-Benzenesulfonyl-4-bromo-1H-indol-2-yl)-but-2-enoic acid
methyl ester
[0533] ##STR143##
[0534] Methyldiethylphosphonoacetate (366 mg, 0.97 mmol) was
dissolved in DMF (8 mL) under nitrogen, cooled in an ice bath, and
treated with potassium t-butoxide (434 mg, 3.87 mmol). The ice bath
was removed and allowed to warm to room temperature over 30 min.
1-(1-Benzenesulfonyl-4-bromo-1H-indol-2-yl)-ethanone (366 mg, 0.97
mmol) dissolved in DMF (4 mL) was added and the reaction heated at
50.degree. C. for 1.5 h. The reaction was allowed to cool and
poured into ethyl acetate/saturated ammonium chloride solution. The
aqueous was washed with more ethyl acetate. Then the pH was lowered
and the aqueous washed a third time with ethyl acetate. The organic
portions were washed with brine, dried (MgSO.sub.4), filtered and
evaporated to give 3.24 g brown oil. The material was purified by
column chromatography using (5:1) hexane:ethyl acetate to give 207
mg (28%) of a crude foam. The material was used without further
purification. MS [EI+] 434, 436 (M+H).sup.+.
E.
3-[1-Benzenesulfonyl-4-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol-2-yl]-
-but-2-enoic acid methyl ester
[0535] ##STR144##
[0536] 3-(1-Benzenesulfonyl-4-bromo-1H-indol-2-yl)-but-2-enoic-acid
methyl ester (117 mg, 0.27 mmol) and
2-butoxy-3,5-diisopropylphenyl-boronic acid (150 mg, 54 mmol) (see
Example 17, step B) were dissolved in toluene (2 mL) under a
nitrogen atmosphere. Tetrakis(triphenylphosphine) palladium (31 mg,
0.027 mmol) and 2N Na.sub.2CO.sub.3 (0.7 mL) were added and the
biphasic mixture stirred at 75.degree. C. for 16 h. The reaction
was diluted with water/ethyl acetate. The layers were separated and
the aqueous layer was washed with ethyl acetate. The organic
portions were passed through a pad of Celite, dried (MgSO.sub.4),
filtered and concentrated in vacuo to provide 243 mg of a crude
black oil. Radial chromatography using (99:1) hexane:ethyl acetate
provided 76 mg (48%) of product. .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 8.15 (d, 1H, 8.2), 7.66 (m, 2H), 7.46-7.27 (m, 5H), 7.11
(d, 1H, J=2.2), 6.90 (d, 1H, J=2.2), 6.54 (s, 1H), 6.05 (d, 1H,
J=1.2), 3.80 (s, 3H), 3.36 (sep, 1H, J=6.9), 3.04 (t, 2H, J=6.0),
2.88 (sep, 1H, J=6.9), 2.61 (d, 3H, J=1.2), 1.25 (d, 6H, J=6.9),
1.24 (d, 6H, J=6.9), 1.08-0.87 (m, 4H), 0.62 (t, 3H, J=7.0). MS
[EI+] 588 (M+H).sup.+ [EI-] 586 (M-H).sup.+.
F.
3-[1-Benzenesulfonyl-4-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol-2-yl]-
-but-2-enoic acid
[0537] ##STR145##
[0538]
3-[1-Benzenesulfonyl-4-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol--
2-yl]-but-2-enoic acid methyl ester (74 mg, 0.126 mmol) was
dissolved in methanol (1 mL)/dioxane (1 mL) and treated with 1N
NaOH (1 mL, 1 mmol) at 60.degree. C. for 2 h. The reaction was
diluted with 1N HCl (3 mL)/water (10 mL) and extracted with ethyl
acetate (3.times.10 mL). The organic portions were washed with
water (10 mL), brine (10 mL), dried (MgSO.sub.4), filtered and
evaporated in vacuo to provide 78 mg of a yellow oil. The material
was purified using radial chromotagraphy with a gradient of
hexane/ethyl acetate to provide 42 mg (58%) of a yellow amorphous
foam. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.08 (d, 1H, 8.2),
7.58 (m, 2H), 7.42-7.21 (m, 5H), 7.03 (d, 1H, J=2.2), 6.82 (d, 1H,
J=2.2), 6.49 (s, 1H), 6.00 (bs, 1H), 3.28 (sep, 1H, J=6.9), 2.96
(t, 2H, J=6.0), 2.81 (sep, 1H, J=6.9), 1.18 (d 6H, J=6.9), 1.17 (d,
6H, J=6.9). MS [EI+] 574, (M+H).sup.+, [EI-] 572 (M-H).sup.+.
G.
3-[4-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol-2-yl]-but-2-enoic
acid
[0539]
3-[1-Benzenesulfonyl-4-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol--
2-yl]-but-2-enoic acid (32 mg, 0.056 mmol) was dissolved in ethanol
(1 mL)/dioxane (1 mL) and treated with 2.5N KOH (1 mL, 1 mmol) at
70-75.degree. C. for 24 h. The reaction was neutralized with 1N HCl
and extracted with ethyl acetate (3.times.10 mL). The organic
portions were washed with water (10 mL), brine (10 mL), dried over
MgSO.sub.4, filtered and evaporated in vacuo to provide 25 mg of a
residue. The material was purified using radial chromatography with
a gradient of hexane/ethyl acetate to provide 13 mg (53%) of a
yellow amorphous foam. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta.
8.26 (bs, 1H), 7.26-7.15 (m, 3H), 7.06 (m, 2H), 6.83 (s, 1H), 6.11
(s, 1H), 3.37 (m, 1H), 3.22 (t, 2H, J=6.3), 2.86 (m, 1H), 2.55 (s,
3H), 1.23 (m, 14H), 0.95 (m, 2H), 0.54 (t, 3H, J=7.2). MS [EI+]
434, (M+H).sup.+, [EI-] 432 (M-H).sup.+.
Example 53
3-[1-(2-Butoxy-3,5-diisopropyl-phenyl)-isoquinolin-7-yl]-but-2(E)-enoic
acid
[0540] ##STR146##
A. 3-(1-Oxo-1,2-dihydro-isoquinolin-7-yl)-but-2(E)-enoic acid
methyl ester
[0541] ##STR147##
[0542] To a solution of 7-bromo-2H-isoquinolin-1-one (272 mg, 1.21
mmol) in DMF (4.0 mL) was added trans-methylcrotonate (0.40 mL, 3.8
mmol), triethylamine (0.70 mL, 5.04 mmol), and palladium acetate
(79 mg, 0.35 mmol). The solution was sparged with N.sub.2 for 5 min
then stirred overnight at 90.degree. C. under N.sub.2 atm.
Additional trans-methylcrotonate (0.40 mL, 3.8 mmol) and
dichlorobis(triphenylphospine) palladium(II) (180 mg, 0.26 mmol)
were added, and the mixture was stirred at 100.degree. C. for 6 h
under N.sub.2 atm. The mixture was cooled to room temperature,
diluted with H.sub.2O, and extracted with ethyl acetate (50 mL).
The organic layer was separated and washed with H.sub.2O
(2.times.25 mL), saturated NaHCO.sub.3 (25 mL) and brine (25 mL)
then dried, filtered, and concentrated. The crude material was
purified by flash chromatography (50% to 75% ethyl acetate/hexanes)
to give 3-(1-oxo-1,2-dihydro-isoquinolin-7-yl)-but-2(E)-enoic acid
methyl ester (112 mg, 38% yield) as a white solid. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 11.42 (br s, 1H), 8.53 (d, 1H, J=1.5),
8.40 (d, 1H, J=8.3), 7.78 (dd, 1H, J=2.0, 8.3), 7.55 d (d, 1H,
J=8.3), 6.56 (d, 1H, J=6.8), 6.28 (d, 1H, J=1.0), 3.76 (s, 3H),
2.66 (d, 3H, J=1.0). MS [EI+] 244 (M+H).sup.+, [EI-] 242
(M-H).sup.-.
B.
3-(1-Trifluoromethanesulfonyloxy-isoquinolin-7-yl)-but-2(E)-enoic
acid methyl ester
[0543] ##STR148##
[0544] To a 0.degree. C. solution of
3-(1-oxo-1,2-dihydro-isoquinolin-7-yl)-but-2(E)-enoic acid methyl
ester (112 mg, 0.46 mmol) in (2:1) CH.sub.2Cl.sub.2:pyridine (3 mL)
was added trifluoromethanesulfonic anhydride (0.09 mL, 0.6 mmol).
The solution was stirred at 0.degree. C. for 2 h then poured into
brine (25 mL) and extracted with ethyl acetate (30 mL). The organic
layer was separated and dried, filtered, and concentrated to give
crude material which was purified by flash chromatography to give
3-(1-trifluoromethanesulfonyl-oxy-isoquinolin-7-yl)-but-2(E)-enoic
acid methyl ester (98 mg, 56% yield) as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 8.21 (d, 1H, J=8.3), 8.15 (s, 1H),
7.90 (m, 2H), 7.70 (dd, 1H, J=1.1, 8.3), 6.26 (m, 1H), 3.78 (s,
3H), 2.67 (d, 3H, J=1.5). MS [EI+] 376 (M+H).sup.+.
C.
3-[1-(2-Butoxy-3,5-diisopropyl-phenyl)-isoquinolin-7-yl]-but-2(E)-enoic
acid methyl ester
[0545] ##STR149##
[0546] To a solution of
3-(1-trifluoromethanesulfonyl-oxy-isoquinolin-7-yl)-but-2(E)-enoic
acid methyl ester (96 mg, 0.26 mmol) and
(2-butoxy-3,5-diisopropyl-phenyl)-boronic acid (97 mg, 0.35 mmol)
(see Example 17, step B) in toluene (3 mL) was added 2N
Na.sub.2CO.sub.3 (0.58 mmol) and tetrakis(triphenylphosphine)
palladium(0) (80 mg, 0.069 mmol). The mixture was stirred at
80.degree. C. for 1.5 h under N.sub.2 atm. The mixture was then
poured into brine (25 mL) and extracted with ethyl acetate (30 mL).
The organic phase was dried, filtered, and concentrated. The crude
material was purified by flash chromatography (0 to 10% ethyl
acetate:hexanes) to give
3-[1-(2-butoxy-3,5-diisopropyl-phenyl)-isoquinolin-7-yl]-but-2(E)-enoic
acid methyl ester (66 mg, 55% yield) as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 8.62 (d, 1H, J=5.9), 7.93 (m, 1H),
7.82 (d, 1H, J=8.8), 7.75 (d, 1H, J=8.8), 7.62 (d, 1H, J=5.9), 7.22
(d, 1H, J=2.4), 7.16 (d, 1H, J=2.4), 6.20 (d, 1H, J=1.5), 3.72 (s,
3H), 3.37 (m, 2H), 3.07 (m, 1H), 2.93 (m, 1H), 2.54 (d, 3H, J=1.5),
1.27 (m, 12H), 1.01 (m, 2H), 0.70 (m, 2H), 0.43 (t, 3H, J=7.8).
.sup.13C NMR (63 MHz): .delta. 167.1, 160.6, 155.0, 152.4, 144.3,
143.0, 141.6, 140.1, 136.2, 132.1, 131.3, 127.8, 127.2, 126.7,
126.6, 125.5, 119.4, 117.6, 73.9, 51.1, 33.8, 31.8, 27.0, 24.4,
24.1, 23.9, 23.1, 18.5, 17.8, 13.4. MS (EI+) 460 (M+H).sup.+.
D.
3-[1-(2-Butoxy-3,5-diisopropyl-phenyl)-isoquinolin-7-yl]-but-2(E)-enoic
acid
[0547] To a solution of
3-[1-(2-butoxy-3,5-diisopropyl-phenyl)-isoquinolin-7-yl]-but-2(E)-enoic
acid methyl ester (66 mg, 0.14 mmol) in methanol (1.0 mL) was added
1N NaOH (0.58 mL). The solution was stirred at 45.degree. C.
overnight. The solution was neutralized with 1N HCl solution,
diluted with H.sub.2O (20 mL) and extracted with ethyl acetate
(3.times.20 mL). The organic layers were combined and washed with
brine (20 mL), dried, filtered, and concentrated. The crude
material was purified by flash chromatography (20% to 40% ethyl
acetate:hexanes) to give
3-[1-(2-butoxy-3,5-diisopropyl-phenyl)-isoquinolin-7-yl]-but-2(E)-enoic
acid (37 mg, 58% yield) as a white solid. mp 149.8.degree. C.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.65 (d, 1H, J=5.9),
7.95 (s, 1H), 7.84 (d, 1H, J=8.8), 7.77 (d, 1H, J=7.3), 7.65 (d,
1H, J=5.4), 7.22 (d, 1H, J=2.0), 7.17 (s, 1H), 6.22 (s, 1H), 3.37
(m, 2H), 3.06 (m, 1H), 2.93 (m, 1H), 2.56 (s, 3H), 1.27 (m, 12H),
1.02 (m, 2H), 0.75 (m, 2H), 0.44 (t, 3H, J=7.3). .sup.13C NMR (63
MHz): .delta. 171.0, 160.5, 156.3, 152.4, 144.3, 142.5, 141.6,
140.2, 136.4, 131.6, 128.1, 127.4, 126.9, 126.7, 125.6, 119.7,
117.9, 74.0, 33.8, 31.8, 27.0, 24.4, 24.3, 24.0, 23.0, 18.5, 18.0,
13.4. MS [EI+] 446 (M+H).sup.+. Analytical
(C.sub.29H.sub.35NO.sub.3): Calculated C, 78.17; H, 7.92; N, 3.14.
Found: C, 78.12; H, 8.14; N, 3.13.
Example 54
3-[4-(2-Butoxy-3,5-diisopropyl-phenyl)-quinolin-6-yl]-but-2(E)-enoic
acid
[0548] ##STR150##
A. Trifluoro-methanesulfonic acid 6-acetyl-quinolin-4-yl ester
[0549] ##STR151##
[0550] To a 0.degree. C. solution of
6-acetyl-1H-quinolin-4-one.sup.1 (507 mg, 2.71 mmol) in (7:3)
CH.sub.2Cl.sub.2:pyridine (10 mL) was added
trifluoromethane-sulfonic anhydride (0.55 mL, 3.27 mmol). The
solution was stirred at 0.degree. C. for 2 h under N.sub.2 atm. The
solution was quenched by addition of saturated NaHCO.sub.3 (50 mL).
The mixture was extracted with ethyl acetate (50 mL) and the
organic phase was washed with brine (50 mL) then dried, filtered,
and concentrated. The crude trifluoro-methanesulfonic acid
6-acetyl-quinolin-4-yl ester (648 mg, 75% yield) was used without
further purification in the subsequent step. Mp 94.0.degree. C.
.sup.1 6-Acetyl-1H-quinolin-4-one was prepared according to Cassis,
et al., Synthetic Communications (1985), 15(2):125.
B.
1-[4-(2-Butoxy-3,5-diisopropyl-phenyl)-quinolin-6-yl]-ethanone
[0551] ##STR152##
[0552] To a solution of trifluoro-methanesulfonic acid
6-acetyl-quinolin-4-yl ester (321.7 mg, 1.008 mmol) and
(2-butoxy-3,5-diisopropyl-phenyl)-boronic acid (315.3 mg, 1.133
mmol) (see Example 17, step B) in toluene (10 mL) was added 2N
Na.sub.2CO.sub.3 (1.1 mL) and Pd(PPh.sub.3).sub.4 (117.1 mg, 0.101
mmol). The solution was stirred at 80.degree. C. for 2 h under
N.sub.2 atm. The mixture was poured into brine (30 mL) and
extracted with ethyl acetate (30 mL). The organic phase was dried,
filtered, and concentrated. The crude material was purified by
flash chromatography (2:8) ethyl acetate:hexanes to give
1-[4-(2-butoxy-3,5-diisopropyl-phenyl)-quinolin-6-yl]-ethanone (378
mg, 93% yield) as a light yellow crystalline solid. Mp
132.8.degree. C. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.01
(d, 1H, J=4.4), 8.40 (d, 1H, J=2.0), 8.25 (2d, 1H, J=2.0, 8.8),
8.16 (d, 1H, J=8.8), 7.50 (d, 1H, J=4.4), 7.24 (m, 1H), 7.00 (d,
1H, J=2.4), 3.36 (m, 1H), 3.26 (m, 1H), 3.16 (m, 1H), 2.94 (m, 1H),
2.58 (s, 3H), 1.29 (m, 12H), 1.10 (m, 2H), 0.79 (m, 2H), 0.47 (t,
3H, J=7.3). .sup.13C NMR (75 MHz, DMSO-d.sub.6): .delta. 197.1,
152.3, 151.6, 149.6, 147.2, 144.2, 141.6, 134.0, 129.7, 128.5,
127.2, 126.5, 125.4, 123.0, 73.0, 33.0, 31.1, 26.4, 24.0, 23.9,
23.8, 23.0, 17.9, 12.9. IR (CHCl.sub.3, cm.sup.-1): 2963, 2934,
2872, 1681. MS [EI+] 404 (M+H).sup.+. Analytical
(C.sub.27H.sub.33NO.sub.2): Calculated C, 80.36; H, 8.24; N, 3.47.
Found: C, 79.98; H, 8.57; N, 3.46.
C.
3-[4-(2-Butoxy-3,5-diisopropyl-phenyl)-quinolin-6-yl]-but-2(E)-enoic
acid methyl ester
[0553] ##STR153##
[0554] To a solution of 1,1-difluoroethylene (4.5 mL, 0.5M in 8:2
THF:Et.sub.2O) at -100.degree. C. was added dropwise a solution of
sec-butyl lithium (1.1 mL, 1.3 M in cyclohexane) via syringe. The
solution was stirred at -100.degree. C. for 10 min. A solution of
1-[4-(2-butoxy-3,5-diisopropyl-phenyl)-quinolin-6-yl]-ethanone (426
mg, 1.06 mmol) in (8:2) THF:Et.sub.2O (5 ml) was added to the above
solution via cannula. The reaction solution was stirred at
-100.degree. C. for 10 min then warmed to -78.degree. C. for 15
min. The reaction was quenched by addition of a few drops of
saturated NaHCO.sub.3. The mixture was diluted with additional
saturated NaHCO.sub.3 and extracted with diethyl ether (2.times.30
mL). The organic phases were combined, dried, and concentrated to
give an oil which was dissolved in methanol (10 mL) and 4 drops of
concentrated H.sub.2SO.sub.4. The yellow solution was stirred at
room temperature for 1 h then poured into saturated NaHCO.sub.3 (30
mL) and extracted with ethyl acetate (3.times.25 mL). The organic
phases were combined, washed with brine (20 mL) then dried,
filtered, and concentrated to give
3-[4-(2-butoxy-3,5-diisopropyl-phenyl)-quinolin-6-yl]-but-2(E)-enoic
acid methyl ester (430 mg, 89% yield) which was used without
further purification. Mp 104.7.degree. C. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.92 (d, 1H, J=4.4), 8.11 (d, 1H, J=8.8), 7.88
(d, 1H, J=2.0), 7.80 (dd, 1H, J=2.0, 8.8), 7.45 (d, 1H, J=4.4),
7.22 (dd, 1H, J=2.0, 4.4), 6.99 (d, 1H, J=2.4), 6.21 (m, 1H), 3.72
(s, 3H), 3.36 (q, 1H, J=6.8), 3.24 (m, 1H), 3.17 (m, 1H), 2.92 (q,
1H, J=6.8), 2.56 (d, 3H, J=1.5), 1.27 (m, 12H), 1.11 (m, 2H), 0.81
(m, 2H), 0.48 (t, 3H, J=7.3). .sup.13C NMR (75 MHz): .delta. 167.1,
155.1, 152.2, 150.3, 148.6, 147.3, 144.3, 142.2, 139.5, 130.2,
129.6, 127.2, 126.6, 125.4, 125.2, 122.6, 117.6, 73.6, 51.0, 33.8,
31.8, 29.6, 26.9, 24.2, 24.0, 23.3, 18.5, 17.8, 13.3. IR
(CHCl.sub.3, cm.sup.-1): 2963, 2934, 2872, 1712. MS [EI+] 460
(M+H).sup.+. Analytical (C.sub.30H.sub.37NO.sub.3): Calculated C,
78.40; H, 8.11; N, 3.05. Found: C, 78.64; H, 8.46; N, 3.13.
D.
3-[4-(2-Butoxy-3,5-diisopropyl-phenyl)-quinolin-6-yl]-but-2(E)-enoic
acid
[0555] To a solution of
3-[4-(2-butoxy-3,5-diisopropyl-phenyl)-quinolin-6-yl]-but-2(E)-enoic
acid methyl ester (349 mg, 0.759 mmol) in methanol (6 mL) at room
temperature was added aqueous 1N NaOH (3 mL, 3 mmol). The white
suspension was stirred at room temperature for 1 h then at
45.degree. C. overnight. The clear solution was concentrated,
diluted with water (25 mL) and treated with aqueous 1N HCl until
solution achieved pH 2. The resulting mixture was extracted with
ethyl acetate (3.times.30 mL). The organic phases were combined and
washed with brine (30 mL) then dried, filtered, and concentrated.
The crude material was purified by flash chromatography twice (1:1)
ethyl acetate:hexanes) to give
3-[4-(2-butoxy-3,5-diisopropyl-phenyl)-quinolin-6-yl]-but-2(E)-enoic
acid (250 mg, 74%) as a white amorphous solid. Mp 195.3.degree. C.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.96 (s, 1H), 8.15 (d,
1H, J=8.8), 7.92 (s, 1H), 7.83 (d, 1H, J=8.8), 7.48 (d, 1H, J=3.4),
7.23 (m, 1H), 7.00 (s, 1H), 6.27 (s, 1H), 3.37 (m, 1H), 3.25 (m,
1H), 3.20 (m, 1H), 2.93 (m, 1H), 2.60 (s, 3H), 1.29 (m, 12H), 1.26
(m, 2H), 0.83 (m, 2H), 0.49 (t, 3H, J=7.3). .sup.13C NMR (63 MHz):
.delta. 170.0, 157.0, 152.2, 150.3, 148.4, 147.7, 144.4, 142.3,
139.6, 130.2, 129.4, 127.4, 126.7, 125.6, 125.4, 122.7, 117.4,
73.6, 33.8, 31.9, 27.0, 24.3, 24.1, 24.0, 23.4, 18.6, 18.1, 13.4.
IR (CHCl.sub.3, cm.sup.-1): 2963, 2934, 2872, 1689. MS [EI+] 446
(M+H).sup.+, [EI-] 444 (M-H).sup.-. Analytical
(C.sub.29H.sub.35NO.sub.3): Calculated C, 78.17; H, 7.92; N, 3.14.
Found C, 77.87; H, 8.09; N, 3.17.
Example 55
3-{3-[2-(3-Fluoropropoxy)-3,5-di-iso-propylphenyl]-benzo[b]thien-5-yl}-but-
-2-enoic acid
[0556] ##STR154##
A. (4-Acetyl-phenylsulfanyl)-acetic acid methyl ester
[0557] ##STR155##
[0558] Methyl thioglycolate was dissolved in DMF (10 ml) and this
mixture was cooled to 0.degree. C. under an atmosphere of nitrogen.
NaH (750 mg of 60% mineral oil dispersion, 18.1 mmol) was then
added in one portion. After 5 min., the ice bath was removed and
p-fluoroacetophenone (1 ml, 8.2 mmol) was added in one portion. The
reaction mixture stirred at ambient temperature for 1 hr then
diluted with ethyl acetate (50 ml) and washed with water. The
aqueous layer was extracted with ethyl acetate (2.times.50 ml) and
the combined organics dried over MgSO.sub.4 and concentrated in
vacuo to yield (4-acetyl-phenylsulfanyl)-acetic acid methyl ester,
as a white waxy solid (1.48 g, 80%). .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 7.80 (d, 2H, J=9.4), 7.32 (d, 2H, J=9.4), 3.71
(s, 2H), 3.67 (s, 3H), 2.50 (s, 3H). MS [EI+] 225 (M+H).sup.+.
B. (4-Acetyl-phenylsulfanyl)-acetic acid
[0559] ##STR156##
[0560] (4-Acetyl-phenylsulfanyl)-acetic acid methyl ester (1.48 g,
6.6 mmol) is dissolved in THF (40 ml). To this solution is added
LiOH (415 mg, 9.9 mmol) in water (10 ml), and the mixture was
stirred at ambient temperature overnight. The mixture was acidified
to pH 5 using 1N HCl and then extracted with ethyl acetate
(3.times.25 ml). The combined organic layers were dried over
MgSO.sub.4 and concentrated in vacuo to yield
(4-acetyl-phenylsulfanyl)-acetic acid as a white solid (1.27 g,
91%). .sup.1H NMR (250 MHz, DMSO): .delta. 7.89 (d, 2H, J=9.4),
7.41 (d, 2H, J=9.4), 3.96 (s, 2H), 2.55 (s, 3H). MS [EI-] 209
(M-H).sup.-.
C. 5-Acetyl-benzo[b]thiophen-3-one
[0561] ##STR157##
[0562] (4-Acetyl-phenylsulfanyl)-acetic acid (1.0 g, 4.8 mmol) is
suspended in dichloroethane, under nitrogen at ambient temperature.
To this is added thionyl chloride (0.694 ml, 9.6 mmol) followed
immediately by 1 drop of DMF. After maintaining the reaction
mixture at 50.degree. C. for 30 min., the mixture became
homogenous. After cooling to ambient temperature, nitrogen was
bubbled into the mixture to remove any trace gasses (10 min.), then
aluminum trichloride (1.9 g, 14.4 mmol) was added in 4 portions
which caused the reaction temperature to raise to 40.degree. C.
After the reaction had cooled to ambient temperature (2 hr), the
reaction mixture was poured into 200 mL of and ice/water mixture
and extracted with dichloromethane (3.times.100 ml). The combined
organic layers were washed with saturated bicarbonate solution, and
brine, then dried over MgSO.sub.4, filtered and concentrated in
vacuo to yield 5-acetyl-benzo[b]thiophen-3-one as a red brown solid
(720 mg, 79%). This material was used without further purification.
.sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.23 (d, 1H, J=2.1),
8.15 (dd, 1H, J=7.5, J=2.1), 7.48 (d, 1H, J=7.5), 3.83 (s, 2H),
2.56 (s, 3H). MS [EI+] 193 (M+H).sup.+, [EI-]191 (M-H).sup.-.
D. Trifluoro-methanesulfonic acid 5-acetyl-benzo[b]thiophen-3-yl
ester
[0563] ##STR158##
[0564] 5-Acetyl-benzo[b]thiophen-3-one (720 mg, 3.7 mmol) was
dissolved in THF under nitrogen and cooled to -78.degree. C. with a
dry ice acetone bath. 2.8 ml of a 2M lithium diisopropylamide
solution (5.6 mmol) was added to this mixture. After 30 min.,
N-phenyltrifluoromethane-sulfonimide (2.68 g, 7.5 mmol) was added.
The dry ice acetone bath was removed and after 1 hr the reaction
had warmed to ambient temperature and was and concentrated in
vacuo. The residue was then purified by chromatography
(chromatotron, 4.mu. plate, 0-10% ethyl acetate in hexanes) to
provide trifluoro-methanesulfonic acid
5-acetyl-benzo[b]thiophen-3-yl ester as a clear oil (788 mg, 65%).
.sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.29 (d, 1H, J=1.2),
8.01 (dd, 1H, J=7.8, J=1.2), 7.85 (d, 1H, J=7.8), 7.44 (s, 1H),
2.64 (s, 3H).
E.
1-[3-(3,5-Diisopropyl-2-methoxymethoxy-phenyl)-benzo[b]thiophen-5-yl]-e-
thanone
[0565] ##STR159##
[0566] 3,5-Diisopropyl-2-methoxymethoxy-phenyl-boronic acid (470
mg, 1.8 mmol) was dissolved in toluene (15 ml) and ethanol (15 ml).
Trifluoro-methanesulfonic acid 5-acetyl-benzo[b]thiophen-3-yl ester
(320 mg, 0.99 mmol), tetrakis(triphenylphosphine)palladium(0) (114
mg, 0.1 mmol) followed by some 2M sodium carbonate solution (1.98
mmol) was added to this solution. The reaction was then heated
overnight, then poured into brine (20 ml) and extracted with ethyl
acetate (2.times.20 ml). The organic layers were then dried over
MgSO.sub.4 and concentrated in vacuo. The residue was purified by
chromatography (chromatotron, 411 plate, 0-10% ethyl acetate in
hexanes) to give
1-[3-(3,5-diisopropyl-2-methoxymethoxy-phenyl)-benzo[b]thiophen-5-yl]-eth-
anone as a yellow oil (228 mg, 58%). An analytical sample was
obtained by preparatory thin layer chromatography (5% ethyl acetate
in hexanes). .sup.1HNMR (250 MHz, CDCl.sub.3): .delta. 8.23 (s,
1H), 7.85-7.97 (m, 2H), 7.48 (s, 1H), 7.14 (d, 1H, J=1.2), 7.04 (d,
1H, J=1.2), 4.41 (s, 2H), 3.40 (m, 1H), 2.95 (s, 3H), 2.86 (m, 1H),
2.55 (s, 3H), 1.26 (s, 3H), 1.23 (s, 3H), 1.21, (s, 3H), 1.18 (s,
3H).
F.
3-[3-(3,5-Di-iso-propyl-2-methoxymethoxyphenyl)-benzo[b]thien-5-yl]-but-
-2-enoic acid methyl ester
[0567] ##STR160##
[0568] Sodium hydride (13 mg, 60% mineral oil dispersion, 0.33
mmol) was suspended in dry DMF (5 ml) at 0.degree. C. under
nitrogen atmosphere. Methyl diethyl phosphonoacetate (0.061 ml,
0.33 mmol) was added, and the reaction was stirred for 30 min.,
then time
1-[3-(3,5-diisopropyl-2-methoxymethoxy-phenyl)-benzo[b]thiophen-5-yl]-eth-
anone (110 mg, 0.28 mmol) was added. The ice bath was removed, and
after 1 h the reaction was heated to 50.degree. C. After 5 h, the
reaction was quenched with saturated ammonium chloride solution and
extracted with ethyl acetate (2.times.5 ml). The residue was then
purified by chromatography (chromatotron, 2.mu. plate, 0-10% ethyl
acetate in hexanes) to give
3-[3-(3,5-di-iso-propyl-2-methoxymethoxyphenyl)-benzo[b]thien-5-yl]-but-2-
-enoic acid methyl ester as a white solid (33.2 mg, 26%). .sup.1H
NMR (250 MHz, CDCl.sub.3): .delta. 7.78 (d, 1H, J=7.2), 7.74 (d,
1H, J=0.6), 7.37-7.45 (m, 2H), 7.10 (d, 1H, J=1.2), 7.02 (d, 1H,
J=1.2), 6.11 (d, 1H, J=0.5), 4.38 (s, 2H), 3.66 (s, 3H), 3.40 (m, 1
h), 2.96 (s, 3H), 2.87 (m, 1H), 2.54 (d, 3H, J=0.5), 1.25 (s, 3H),
1.23 (s, 3H), 1.21 (s, 3H), 1.19 (s, 3H). MS [EI+] 470
(M+H.sub.2O).sup.+.
G.
3-[3-(2-Hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-enoi-
c acid methyl ester
[0569] ##STR161##
[0570]
3-[3-(3,5-Di-iso-propyl-2-methoxymethoxy-phenyl)-benzo[b]thien-5-y-
l]-but-2-enoic acid methyl ester (15 mg, 0.033 mmol) was dissovlved
in methanol (5 ml) and 2 drops of concentrated HCl was added. This
mixture was stirred at ambient temperature for 4 h then
concentrated in vacuo. The residue was passed over a silica gel
plug (50% ethyl acetate in hexane) to yield a quatitative amount of
3-[3-(2-hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-enoic
acid methyl ester as a white solid which was used without further
purification. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.96 (d,
1H, J=11.2), 7.77 (d, 1H, J=0.6), 7.75-7.61 (m, 2H), 7.18 (d, 1H,
J=3.1), 7.05 (d, 1H, J=3.1), 6.20 (d, 1H, J=1.2), 5.05 (bs, 1H),
3.77 (s, 3H), 3.38 (m, 1H), 2.94 (m, 1H), 2.62 (d, 3H, J=1.2), 1.36
(s, 3H), 1.34 (s, 3H), 1.33 (s, 3H), 1.31 (s 3H). MS [EI+] 426
(M+H.sub.2O).sup.+, [EI-] 407 (M-1).sup.-.
H.
3-{3-[2-(3-Fluoropropoxy)-3,5-di-iso-propylphenyl]-benzo[b]thien-5-yl}b-
ut-2-enoic acid methyl ester
[0571] ##STR162##
[0572]
3-[3-(2-Hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-
-enoic acid methyl ester (15 mg, 0.037 mmol) was dissolved in 1 ml
of DMF. Cesium fluoride (22.3 mg, 0.14 mmol), followed by
1-bromo-3-fluoropropane (0.004 ml, 0.044 mmol) was added, and the
reaction was stirred under a nitrogen atmosphere at ambient
temperature overnight. Then 2 mL of water was added, and the
mixture extracted with ethyl acetate (2.times.5 ml). The combined
organics were washed with brine, then dried over MgSO.sub.4 and
concentrated in vacuo to yield
3-{3-[2-(3-fluoropropoxy)-3,5-di-iso-propylphenyl]-benzo[b]thien-5-yl}but-
-2-enoic acid methyl ester as a white solid (14.8 mg, 83%). .sup.1H
NMR (250 MHz, CDCl.sub.3): .delta. 7.81 (d, 1H, J=10.0), 7.74 (d,
1H, J=1.2), 7.45 (s, 1H), 7.43 (dd, 1H, J=7.5, J=1.2), 7.11 (d, 1H,
J=3.1), 7.04 (d, 1H, J=3.1), 6.12 (d, 1H, J=0.62), 4.10 (dt, 2H,
J=50.0, J=6.25), 3.68 (s, 3H), 3.38 (t, 2H, J=6.25), 3.30 (m, 1H),
2.86 (m, 1H), 2.55 (d, 3H, J=0.62), 1.58 (dq, 2H, J=25.0, J=6.25),
1.25 (s, 3H), 1.22 (s, 6H), 1.20 (s, 3H).
I.
3-{3-[2-(3-Fluoropropoxy)-3,5-di-iso-propylphenyl]-benzo[b]thien-5-yl}--
but-2-enoic acid
[0573]
3-{3-[2-(3-Fluoropropoxy)-3,5-di-iso-propylphenyl]-benzo[b]thien-5-
-yl}but-2-enoic acid methyl ester (14.8 mg, 0.031 mmol) was
dissolved in methanol (1 ml) and 1N NaOH solution (1 ml), then
heated to 60.degree. C. for 2 h. The reaction was brought to pH=4
with 1N HCl solution, then extracted with ethyl acetate (3.times.5
ml). The combined organic layers were washed with brine, then dried
over MgSO.sub.4 and concentrated in vacuo to yield a white solid
(13.7 mg, 96%). .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.81 (d,
1H, J=10.0), 7.74 (d, 1H, J=1.2), 7.45 (s, 1H), 7.43 (dd, 1H,
J=7.5, J=1.2), 7.11 (d, 1H, J=3.1), 7.04 (d, 1H, J=3.1), 6.12 (d,
1H, J=0.62), 4.10 (dt, 2H, J=50.0, J=6.25), 3.38 (t, 2H, J=6.25),
3.30 (m, 1H), 2.86 (m, 1H), 2.55 (d, 3H, J=0.62), 1.58 (dq, 2H,
J=25.0, J=6.25), 1.25 (s, 3H), 1.22 (s, 6H), 1.20 (s, 3H). MS [EI+]
437 (M+H--H.sub.2O).sup.+, [EI-] 453 (M-1).sup.-. HPLC [MetaSil AQ
C18 (0.46.times.25 cm) 95% CH.sub.3CN(0.1% TFA) in H.sub.2O(0.1%
TFA)] 5.262 min.
Example 56
3-[3-(2-Hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-enoic
acid
[0574] ##STR163##
[0575]
3-[3-(3,5-Di-iso-propyl-2-methoxymethoxyphenyl)-benzo[b]thien-5-yl-
]-but-2-enoic acid methyl ester (15 mg, 0.033 mmol) (see Example
55, step F) was dissolved in MeOH (2 ml) and 1N NaOH (2 ml). The
mixture was then stirred at 60.degree. C. for 2 h, then cooled to
ambient temperature and brought to pH 2 with 1N HCl. The reaction
mixture was allowed to stir for 1 h, it was extracted with ethyl
acetate (3.times.5 mL) and the organic layers were dried over
MgSO.sub.4 and concentrated in vacuo. The residue was purified by
silica gel chromatography (10% ethyl acetate in hexanes) to give
3-[3-(2-hydroxy-3,5-diisopropyl-phenyl)-benzo[b]thien-5-yl]-but-2-
-enoic acid as a white solid (11.7 mg, 89%). .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 7.89 (d, 1H, J=8.75), 7.70 (d, 1H, J=0.62),
7.50 (m, 2H), 7.08 (d, 1H, J=1.2), 6.95 (d, 1H, J=1.2), 6.14 (bs,
1H), 3.29 (m, 1H), 2.85 (m, 1H), 2.55 (s, 3H), 1.27 (s, 3H), 1.25
(s, 3H), 1.23 (s, 3H), 1.20 (s, 3H). MS [EI+] 395
(M+H--H.sub.2O).sup.+, [EI-] 393 (M-1).sup.-. HPLC [MetaSil AQ C18
(0.46.times.25 cm) 95% CH.sub.3CN(0.1% TFA) in H.sub.2O(0.1% TFA)]
4.388 min.
Example 57
3-[3-(3,5-Di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]-but-2-enoic
acid
[0576] ##STR164##
A.
3-[3-(3,5-Di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]-but-2-enoi-
c acid methyl ester
[0577] ##STR165##
[0578]
3-[3-(2-Hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-
-enoic acid methyl ester (100 mg, 0.24 mmol) was dissolved in DMF
(5 ml), and iodomethane (0.0183 ml, 0.29 mmol) and cesium fluoride
(149 mg, 0.98 mmol) were added to this solution. The reaction was
stirred at ambient temperature under nitrogen overnight, then water
(2 ml) was added and the mixture extracted with ethyl acetate
(2.times.5 mL). The combined organics were washed with brine, then
dried over MgSO.sub.4 and concentrated in vacuo to yield
3-[3-(3,5-di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]
but-2-enoic acid methyl ester as a pale yellow solid (101 mg, 98%).
.sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.85 (d, 1H, J=6.2),
7.80 (s, 1H), 7.46 (s, 1H), 7.40 (dd, 1H, J=0.6, J=8.8), 7.09 (d,
1H, J=1.2), 7.03 (d, 1H, J=1.2), 6.12 (d, 1H, J=0.6), 3.65 (s, 3H),
3.32 (m, 1H), 3.18 (s, 3H), 2.85 (m, 1H), 2.53 (d, 3H, J=0.6), 1.24
(s, 3H), 1.22 (s, 6H), 1.18 (s, 3H).
B.
3-[3-(3,5-Di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]-but-2-enoi-
c acid
[0579]
3-[3-(3,5-Di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]-but-2-
-enoic acid methyl ester (100 mg, 0.24 mmol) was dissolved in
methanol (5 ml) and 1N NaOH solution (5 ml), then heated to
60.degree. C. for 2 h. The reaction was brought to pH 6 with 1N HCl
solution, then extracted with ethyl acetate (3.times.10 mL). The
combined organics were washed with brine, then dried over
MgSO.sub.4 and concentrated in vacuo. The residue was purified by
silica gel chromatography (10% ethyl acetate in hexanes) to yield a
white solid (59.5 mg, 59%). .sup.1HNMR (250 MHz, CDCl.sub.3):
.delta. 7.82 (d, 1H, J=6.2), 7.80 (s, 1H), 7.48 (s, 1H), 7.44 (dd,
1H, J=0.6, J=8.8), 7.10 (d, 1H, J=1.2), 7.04 (d, 1H, J=1.2), 6.16
(d, 1H, J=0.6), 3.34 (m, 1H), 3.21 (s, 3H), 2.87 (m, 1H), 2.56 (d,
3H, J=0.6), 1.26 (s, 3H), 1.23 (s, 6H), 1.20 (s, 3H). MS [EI+] 409
(M+H--H.sub.2O).sup.+, [EI-] 407 (M-1).sup.-. HPLC [MetaSil AQ C18
(0.46.times.25 cm) 95% CH.sub.3CN(0.1% TFA) in H.sub.2O(0.1% TFA)]
5.695 min.
Example 58
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-but-2-en-
oic acid
[0580] ##STR166##
A. 1-Thieno[2,3-c]pyridin-5-yl-ethanone
[0581] ##STR167##
[0582] A solution of 2,3-thiophenedicarboxaldehyde (600 mg, 4.28
mmol) in dichloromethane (50 ml) was cooled to 0.degree. C. under
an atmosphere of nitrogen. (1-Acetylamino-2-oxo-propyl)-phosphonic
acid dimethyl ester (1.05 g, 4.70 mmol) was added [literature
procedure: Kitamura, et al. Tet. Lett., 36(32), 1995, pp.
5769-5772], followed by DBU (0.471 ml, 4.70 mmol), and the mixture
allowed to warm to ambient temperature overnight, then concentrated
in vacuo, and the residue was then purified by flash chromatography
(0-50% ethyl acetate in hexanes) to provide
1-thieno[2,3-c]pyridin-5-yl-ethanone as a white solid (326 mg,
43%). .sup.1HNMR (250 MHz, CDCl.sub.3): .delta. 9.20 (s, 1H), 8.50
(d, 1H, J=1.02), 7.80 (d, 1H, J=5.36), 7.51 (d, 1H, J=5.36), 2.81
(s, 3H).
B. 1-(3-Bromo-thieno[2,3-c]pyridin-5-yl)-ethanone
[0583] ##STR168##
[0584] An aqueous aturated sodium bicarbonate solution (10 ml) and
water (10 ml) was added to a solution of
1-thieno[2,3-c]pyridin-5-yl-ethanone (600 mg, 3.39 mmol) in carbon
tetrachloride (5 ml). Bromine (0.523 ml, 10.2 mmol) was added and
the reaction was stirred overnight. The biphasic mixture was
allowed to separate and the organic layer was diluted with
dichloromethane (25 ml) and washed with 10% sodium sulfide (in
ammonium hydroxide) (1.times.20 mL), and brine (1.times.20 mL). The
organic layer was dried over MgSO.sub.4 and concentrated in vacuo.
The residue was then purified by chromatography (chromatotron,
4.mu. plate, 0-200% ethyl acetate in hexanes) to yield
1-(3-bromo-thieno[2,3-c]pyridin-5-yl)-ethanone as a white solid
(311.3 mg, 36%). .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 9.20
(s, 1H), 8.54 (s, 1H), 7.30 (s, 1H), 7.30 (s, 1H), 2.85 (s, 3H). MS
[EI+] 255 & 257 (M+H).sup.+.
C.
1-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-ethan-
one
[0585] ##STR169##
[0586] 2-Ethoxy-3,5-diisopropyl-phenyl-boronic acid (586 mg, 2.34
mmol) was dissolved in toluene (10 ml).
1-(3-Bromo-thieno[2,3-c]pyridin-5-yl)-ethanone (310 mg, 1.21 mmol),
and tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol)
followed by 2M sodium carbonate solution (2.34 ml) was added to
this solution. This mixture was then heated to 90.degree. C.
overnight, then poured into brine (20 ml) and extracted with ethyl
acetate (2.times.20 mL). The organic layers were dried over
MgSO.sub.4 and concentrated in vacuo. The residue was then purified
by chromatography (chromatotron, 4.mu. plate, 10% ethyl acetate in
hexanes) to give a
1-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-ethanon-
e as a white solid (422.2 mg, 91%). .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 9.14 (s, 1H), 8.38 (s, 1H), 7.80 (s, 1H), 7.13
(d, 1H, J=1.9), 6.98 (d, 1H, J=1.9), 3.33 (m, 1H), 3.28 (q, 2H,
J=7.5), 2.87 (m, 1H), 2.74 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H),
1.22 (s, 3H), 1.20 (s, 3H), 0.85 (t, 3H, J=7.5). MS [EI+] 382
(M+H).sup.+.
D.
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-but-2-
-enoic acid methyl ester
[0587] ##STR170##
[0588] Methyl diethyl phosphonoacetate (0.606 ml, 3.3 mmol) was
added to a suspension of sodium hydride (132 mg, 60% mineral oil
dispersion, 3.3 mmol) in dry DMF (10 ml) under nitrogen atmosphere
which was maintained at 0.degree. C. After the suspension had
stirred for 30 min.,
1-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-ethanon-
e (420 mg, 1.1 mmol) was added and the cold bath removed. The
reaction was allowed to stir overnight at room temperature, then
was quenched with saturated ammonium chloride solution and
extracted with ethyl acetate (2.times.10 mL). The residue was then
purified by chromatography (chromatotron, 4.mu. plate, 0-10% ethyl
acetate in hexanes) to give
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-but-2-e-
noic acid methyl ester as a white solid (294.9 mg, 61%). .sup.1H
NMR (250 MHz, CDCl.sub.3): .delta. 9.06 (s, 1H), 7.36 (s, 1H), 7.23
(s, 1H), 7.10 (d, 1H, J=6.2), 7.00 (d, 1H, J=6.2), 6.80 (d, 1H,
J=0.12), 3.67 (s, 3H), 3.35 (m, 1H), 3.28 (q, 2H, J=8.8), 2.36 (m,
1H), 2.58 (d, 3H, J=0.12), 1.24 (s, 3H), 1.21 (s, 3H), 1.20 (s,
3H), 1.18 (s, 3H), 0.83 (t, 3H, J=8.75). MS [EI+] 438
(M+H).sup.+.
E.
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-but-2-
-enoic acid
[0589] A solution of
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-but-2-e-
noic acid methyl ester (295 mg, 0.675 mmol) in methanol (5 ml) and
1N NaOH solution (5 ml) was heated to 60.degree. C. for 2 h, then
brought to pH=4 with 1N HCl solution and extracted with ethyl
acetate (3.times.5 mL). The combined organic layers were washed
with brine, then dried over MgSO.sub.4 and concentrated in vacuo to
yield a white crystals (203.4 mg, 71%). .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 9.24 (d, 1H, J=0.62), 8.00 (d, 1H, J=0.62),
7.86 (s, 1H), 7.23 (d, 1H, J=1.2), 7.13 (d, 1H, J=1.2), 6.94 (d,
1H, J=0.62), 3.45 (m, 1H), 3.40 (q, 2H, J=7.5), 3.00 (m, 1H), 2.72
(d, 3H, J=0.62), 1.36 (s, 3H), 1.34 (s, 3H), 1.33, (s, 3H), 1.31
(s, 3H), 0.97 (t, 3H, J=7.5). MS [EI+] 424 (M+H).sup.+. HPLC [YMC
ODS-A (0.46.times.50 mm) 5%-95% CH.sub.3CN(0.1% TFA) in
H.sub.2O(0.1% TFA) in 12 min.] 10.068 min.
Example 59
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazol-5-yl]-but-2-enoic
acid
[0590] ##STR171##
A.
(5-Bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanol
[0591] ##STR172##
[0592] 1-Bromo-2-ethoxy-3,5-diisopropyl-benzene (2.0 g, 7.01 mmol)
was dissolved in ethylene glycol dimethyl ether (20 ml) and the
mixture cooled to -78.degree. C. t-Butyl lithium (8.66 ml, 1.7M,
14.7 mmol) dropwise to the mixture over 30 min., then the reaction
was stirred for an additional 30 min. before
5-bromo-2-fluorobenzaldehyde (1.57 g, 7.71 mmol) was added in one
portion. The reaction was allowed to warm to ambient temperature,
then stirred overnight. The mixture was poured into saturated
ammonium chloride solution (100 mL), and extracted with ethyl
acetate (3.times.50 mL). The combined organic layers were dried
over MgSO.sub.4 and concentrated in vacuo. The residue was purified
flash column (5% ethyl acetate in hexanes) to give
(5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanol,
as a pale yellow oil (1.88 g, 66%). .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 7.73 (dd, 1H, J=1.2, J=7.5), 7.42 (m, 1H),
7.11 (d, 1H, J=1.2), 6.95 (t, 1H, J=7.5), 6.85 (d, 1H, J=1.2), 6.35
(d, 1H, J=6.2), 3.84 (q, 2H, J=6.9), 3.30 (m, 1H), 3.07 (d, 1H,
J=6.2), 2.85 (m, 1H), 1.47 (t, 3H, J=6.9), 1.25 (s, 6H), 1.20 (s,
6H). MS [EI+] 431, 433 (M+Na).sup.+.
B.
(5-Bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanone
[0593] ##STR173##
[0594]
(5-Bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methan-
ol (1.88 g, 4.6 mmol) was dissolved in dichloromethane (5 ml) and
added to a suspension of pyridinium chlorochromate (1.1 g, 5.1
mmol) in dichloromethane (20 ml). After stirring at ambient
temperature under and atmosphere of nitrogen for 4 h the reaction
was diluted with ether (50 mL) and filtered through a plug of
florosil. The remaining solvent was evaporated to yield
(5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanone
as yellow crystals (1.75 g, 94%). .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 7.81 (dd, 1H, J=3.1, J=6.9), 7.62 (m, 1H),
7.33 (d, 1H, J=2.5), 7.28 (d, 1H, J=2.5), 7.02 (dd, 1H, J=11.2,
J=9.4), 3.67 (q, 2H, J=6.9), 3.34 (m, 1H), 2.95 (m, 1H), 1.31 (s,
3H), 1.28 (s, 6H), 1.25 (s, 3H), 1.02 (t, 3H, J=6.9). MS [EI+] 407,
409 (M+H).sup.+.
C.
5-Bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazole
[0595] ##STR174##
[0596] Acetone oxime (172 mg, 2.35 mmol) was added to a solution of
potassium t-butoxide (264 mg, 2.35 mmol) in 10 ml of THF. This was
stirred for 30 min. at ambient temperature under a nitrogen
atmosphere, then a solution of
(5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanone
(800 mg, 1.96 mmol) in THF was added. After 2 hrs., the reaction
was quenched with saturated ammonium chloride solution (20 mL) and
extracted with ether (2.times.20 mL). The organic layers were
combined, dried over MgSO.sub.4 and evaporated. The residue was
dissolved in ethanol (10 mL) and 1N HCl solution (10 mL) and
refluxed for 1 h. The reaction mixture was portioned between ether
and water after cooling to room temperature. The organic layer was
dried over MgSO.sub.4 and evaporated. The residue was purified by
silica gel column (10% ethyl acetate in hexanes) to give
5-bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazole as a
clear oil (313.2 mg, 40%). .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 7.97 (d, 1H, J=2.5), 7.60 (dd, 1H, J=2.5, J=9.4), 7.45 (d,
1H, J=9.4), 7.27 (d, 1H, J=1.2), 7.24 (d, 1H, J=1.2), 3.49 (q, 2H,
J=7.5), 3.38 (m, 1H), 2.88 (m, 1H), 1.25 (s, 3H), 1.23 (s, 6H),
1.20 (s, 3H), 0.95 (t, 3H, J=7.5). MS [EI+] 402, 404
(M+H).sup.+.
D.
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazol-5-yl]-but-2-eno-
ic acid methyl ester
[0597] ##STR175##
[0598] Methyl crotonate (0.087 ml, 0.82 mmol),
tris(dibenzylideneacetone)-dipalladium(0) (6.8 mg, 0.007 mmol),
tri-o-tolylphosphine (91 mg, 0.30 mmol), and triethyl amine (0.208
ml, 1.5 mmol) was added to a solution of
5-bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazole (300
mg, 0.75 mmol) in DMF (5 ml). The reaction mixture was then heated
to 120.degree. C. under an atmosphere of nitrogen. After 12 h, the
reaction was cooled and poured into brine, then extracted with
ethyl acetate (2.times.10 mL). The organic layer was dried over
MgSO.sub.4 and evaporated to a residue. The residue was purified by
silica gel chromatography (5% ethyl acetate in hexanes) to give
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazol-5-yl]-but-2-enoic
acid methyl ester as a clear oil (99.6 mg, 32%). .sup.1H NMR (250
MHz, CDCl.sub.3): .delta. 7.89 (d, 1H, J=0.62), 7.61 (dd, 1H,
J=2.5, J=9.4), 7.51 (d, 1H, J=9.4), 7.28 (d, 1H, J=1.2), 7.23 (d,
1H, J=1.2), 6.07 (d, 1H, J=0.62), 3.67 (s, 3H), 3.48 (q, 2H,
J=7.5), 3.37 (m, 1H), 2.87 (m, 1H), 2.54 (d, 3H, J=0.62), 1.25 (s,
3H), 1.22 (s, 6H), 1.19 (s, 3H), 0.90 (t, 3H, J=7.5). MS [EI+] 422
(M+H).sup.+.
E.
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazol-5-yl]-but-2-eno-
ic acid
[0599] A solution of
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-benzo[d]isoxazol-5-yl]-but-2-enoic
acid methyl ester (99.6 mg, 0.24 mmol) in 2 mL of methanol and 2 ml
of 1N NaOH solution was heated this mixture to 60.degree. C. for 3
h, then cooled and brought to pH 2 with 1N HCl. The reaction
mixture was extracted with ethyl acetate (2.times.10 mL), and the
organic layers were dried over MgSO.sub.4 and evaporated to a
residue. The residue was purified by silica gel chromatography (50%
ethyl acetate in hexanes) to give a clear oil, which solidified
upon standing to a waxy solid (12.1 mg, 13%). .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 7.92 (d, 1H, J=0.62), 7.65 (dd, 1H, J=2.1,
J=9.4), 7.55 (d, 1H, J=9.4), 7.30 (d, 1H, J=1.2), 7.24 (d, 1H,
J=1.2), 6.12 (bs, 1H), 3.50 (q, 2H, J=7.5), 3.39 (m, 1H), 2.90 (m,
1H), 2.58 (bs, 3H), 1.26 (s, 3H), 1.23 (s, 6H), 1.20 (s, 3H), 0.90
(t, 3H, J=7.5). MS [EI+] 408 (M+H)+MS [EI-] 406 (M-H).sup.-.
Example 60
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-1H-indazol-5-yl]-but-2-enoic
acid
[0600] ##STR176##
A. 5-Bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indazole
[0601] ##STR177##
[0602] Benzophenone hydrazone (232 mg, 1.2 mmol) was added to a
solution of potassium t-butoxide (132 mg, 1.2 mmol) in 10 ml of
THF. After stirring for 30 min. at ambient temperature under a
nitrogen atmosphere, a solution of
(5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanone
(400 mg, 1.0 mmol) in THF (10 mL) was added and the reaction was
stirred for 12 h, then quenched with saturated ammonium chloride
solution (20 mL) and extracted with ether (2.times.20 mL). The
organic layers were combined, dried over MgSO.sub.4 and evaporated
to a residue. The residue was dissolved in ethanol (10 mL) and 1N
HCl solution (10 mL) and refluxed for 1 h. After cooling, the
reaction was partitioned between ether and water. The organic layer
was dried over MgSO.sub.4 and evaporated to a residue. The residue
was purified by silica gel column (10% ethyl acetate in hexanes) to
give 5-bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indazole as a
clear oil (61.8 mg, 16%). .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 7.87 (bs, 1H), 7.22-7.02 (m, 3H), 6.55 (bd, 1H, J=9.4),
3.32 (m, 1H), 3.26 (q, 2H, J=7.5), 2.73 (m, 1H), 1.05 (s, 6H), 1.03
(s, 6H), 0.77 (t, 3H, J=7.5). MS [EI+] 401, 403 (M+H).sup.+.
B.
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-1H-indazol-5-yl]-but-2-enoic
acid methyl ester
[0603] ##STR178##
[0604] Methyl crotonate (0.017 mL, 0.17 mmol),
tris(dibenzylideneacetone)-dipalladium(0) (1.3 mg, 0.001 mmol),
tri-o-tolylphosphine (18.2 mg, 0.06 mmol), and triethyl amine
(0.042 mL, 0.30 mmol) were added to a solution of
5-bromo-3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indazole (60 mg,
0.15 mmol) in DMF (1 mL). The reaction mixture was then heated to
120.degree. C. under an atmosphere of nitrogen for 12 hrs., then
cooled, poured into brine and extracted with ethyl acetate
(2.times.5 mL). The organic was dried over MgSO.sub.4 and
evaporated to give
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indazol-5-yl]-but-2-enoic
acid methyl ester as a clear oil which was used without further
purification. MS [EI+] 421 (M+H)+MS [EI-] 419 (M-H).sup.-.
C.
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-1H-indazol-5-yl]-but-2-enoic
acid
[0605] A solution of
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indazol-5-yl]-but-2-enoic
acid methyl ester in 2 ml of methanol and 2 ml of 1N NaOH solution
was heated to 60.degree. C. for 3 h, then cooled and brought to pH
7 with 1N HCl. The reaction mixture was extracted with ethyl
acetate (2.times.10 mL), and the organic layers were dried over
MgSO.sub.4 and evaporated to a residue. The residue was purified by
silica gel chromatography (50% ethyl acetate in hexanes) to give a
white solid (6.1 mg, 10%). .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 7.97 (bs, 1H), 7.60-6.90 (m, 4H), 6.12 (d, 1H, J=0.62),
3.32 (q, 2H, J=6.9), 3.27 (m, 1H), 2.80 (m, 1H), 2.51 (d, 3H,
J=0.62), 1.20 (s, 3H), 1.16 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H),
0.80 (t, 3H, J=6.9). MS [EI+] 407 (M+H).sup.+ MS [EI-] 405
(M-H).sup.-.
Example 61
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-but-2-e-
noic acid
[0606] ##STR179##
A. 3-(6-Amino-pyridin-3-yl)-but-2-enoic acid methyl ester
[0607] ##STR180##
[0608] Methyl crotonate (1.35 ml, 12.8 mmol),
tris(dibenzylideneacetone)-dipalladium(0) (106 mg, 0.12 mmol),
tri-o-tolylphosphine (1.41 g, 4.6 mmol), and triethylamine (3.22
ml, 23.1 mmol) were added to a solution of 2-amino-5-bromo pyridine
(2 g, 11.6 mmol) in DMF (25 mL). The reaction mixture was heated to
120.degree. C. in a nitrogen atmosphere overnight, then cooled to
ambient temperature and diluted with ethyl acetate (50 mL). The
reaction was filtered, then washed with saturated ammonium chloride
solution (2.times.25 mL), and the organic layer dried over
MgSO.sub.4 and concentrated in vacuo. The residue was then purified
by flash column (2% methanol in dichloromethane) to give
3-(6-amino-pyridin-3-yl)-but-2-enoic acid methyl ester as a yellow
solid (904.7 mg, 41%). .sup.1H NMR (250 MHz, DMSO): .delta. 8.22
(d, 1H, J=3.1), 7.68 (dd, 1H, J=7.5, J=3.1), 6.46 (d, 1H, J=7.5),
6.40 (bs, 2H), 6.11 (d, 1H, J=0.62), 3.65 (s, 3H), 2.48 (d, 3H,
J=0.62). MS [EI+] 193 (M+H).sup.+.
B. 3-Imidazo[1,2-a]pyridin-6-yl-but-2-enoic acid methyl ester
[0609] ##STR181##
[0610] Bromoacetaldehyde dimethyl acetal (0.692 mL, 5.85 mmol) was
refluxed in a solution of water (10 mL) and concentrated HCl (0.1
mL) for 30 min. The reaction was cooled to ambient temperature, and
sodium bicarbonate (629 mg, 7.49 mmol) was added in several
portions. After the addition was complete,
3-(6-amino-pyridin-3-yl)-but-2-enoic acid methyl ester (900 mg,
4.68 mmol) was added, and the reaction stirred overnight. During
this time, the reaction became homogenous. After extracting the
reaction mixture with ethyl acetate (3.times.20 mL), the organic
layers were combined, dried over MgSO.sub.4 and concentrated in
vacuo. The residue was purified by chromatography (chromatotron,
4.mu. plate, 50% ethyl acetate in hexanes) to yield
3-imidazo[1,2-a]pyridin-6-yl-but-2-enoic acid methyl ester as an
off white solid (223.3 mg, 22%). .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 8.32 (bs, 1H), 7.58-7.70 (m, 3H), 7.35 (dd, 1H, J=7.5,
J=3.1), 6.24 (d, 1H, J=0.62), 3.31 (s, 3H), 2.64 (d, 3H, J=0.62).
MS [EI+] 217 (M+H).sup.+.
C. 3-(3-Iodo-imidazo[1,2-a]pyridin-6-yl)-but-2-enoic acid methyl
ester
[0611] ##STR182##
[0612] N-iodosuccinimide (252 mg, 1.12 mmol) was added to a mixture
of 3-imidazo[1,2-a]pyridin-6-yl-but-2-enoic acid methyl ester (220
mg, 1.02 mmol) in acetonitrile (10 mL) which had been cooled to
0.degree. C. under nitrogen atmosphere. The mixture was stirred for
1 h, then diluted with ethyl acetate (30 mL) and washed with
saturated sodium bicarbonate solution (2.times.10 mL), and brine
(1.times.15 mL). The organic layers were combined, dried over
MgSO.sub.4 and concentrated in vacuo. The residue was purified by
chromatography (chromatotron, 4.mu. plate, 50% ethyl acetate in
hexanes) to yield 3-(3-iodo-imidazo[1,2-a]pyridin-6-yl)-but-2-enoic
acid methyl ester as a pale yellow solid (168.1 mg, 48%). .sup.1H
NMR (250 MHz, CDCl.sub.3): .delta. 8.27 (bs, 1H), 7.77 (s, 1H),
7.64 (d, 1H, J=9.4), 7.41 (dd, 1H, J=9.4, J=1.6), 6.27 (d, 1H,
J=0.62), 3.84 (s, 3H), 2.68 (d, 3H, J=0.62). MS [EI+] 343
(M+H).sup.+.
D.
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-but--
2-enoic acid methyl ester
[0613] ##STR183##
[0614] 3-(3-Iodo-imidazo[1,2-a]pyridin-6-yl)-but-2-enoic acid
methyl ester (168 mg, 0.49 mmol),
tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol),
followed by 2M sodium carbonate solution (1 ml) were added to a
solution of 2-ethoxy-3,5-diisopropyl-phenyl-boronic acid (246 mg,
0.98 mmol) (see Example 5, step B) in toluene (10 mL). The reaction
mixture was heated to 90.degree. C. overnight, then poured into
brine (20 mL) and extracted with ethyl acetate (2.times.20 mL). The
organic layers were combined, dried over MgSO.sub.4 and
concentrated in vacuo. The residue was purified by chromatography
(chromatotron, 2.mu. plate, 50% ethyl acetate in hexanes) to give a
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-but-2--
enoic acid methyl ester as a yellow oil (157.5 mg, 76%). .sup.1H
NMR (250 MHz, CDCl.sub.3): .delta. 8.19 (bs, 1H), 7.75 (s, 1H),
7.68 (d, 1H, J=9.4), 7.42 (dd, 1H, J=9.4, J=1.2), 7.25 (d, 1H,
J=2.5), 7.15 (d, 1H, J=2.5), 6.24 (d, 1H, J=0.62), 3.28 (s, 3H),
3.44 (m, 1H), 3.35 (q, 2H, J=8.1), 2.97 (m, 1H), 2.59 (d, 3H,
J=0.62), 1.35 (s, 3H), 1.33 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H),
1.29 (t, 3H, J=8.1). MS [EI+] 421 (M+1).sup.+.
E.
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-but--
2-enoic acid
[0615] A solution of
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-but-2--
enoic acid methyl ester (157 mg, 0.37 mmol) in methanol (2 mL) and
1N NaOH solution (2 mL) was heated to 40.degree. C. for 2 hrs. The
reaction was brought to pH=7.5 with 1N HCl solution, then extracted
with ethyl acetate (3.times.5 mL). The combined organic layers were
washed with brine, then dried over MgSO.sub.4 and concentrated in
vacuo. The residue was then purified by chromatography
(chromatotron, 2.mu. plate, 20% methanol in dichloromethane) to
yield a white solid (118.1 mg, 78%). .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 8.19 (bs, 1H), 7.75 (s, 1H), 7.68 (d, 1H,
J=9.4), 7.42 (dd, 1H, J=9.4, J=1.2), 7.25 (d, 1H, J=2.5), 7.15 (d,
1H, J=2.5), 6.24 (d, 1H, J=0.62), 3.44 (m, 1H), 3.35 (q, 2H,
J=8.1), 2.97 (m, 1H), 2.59 (d, 3H, J=0.62), 1.35 (s, 3H), 1.33 (s,
3H), 1.32 (s, 3H), 1.30 (s, 3H), 1.29 (t, 3H, J=8.1). MS [EI+] 407
(M+1).sup.+, [EI-] 405 (M-1).sup.-. HPLC [YMC ODS-A (0.46.times.50
mm) 5%-95% CH.sub.3CN(0.1% TFA) in H.sub.2O(0.1% TFA) in 12 min.]
7.857 min.
Example 62
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-acrylic
acid
[0616] ##STR184##
A. Imidazo[1,2-a]pyridine-6-carboxylic acid
[0617] ##STR185##
[0618] Concentrated HCL (1.5 mL) was added to a solution of
bromoacetaldehyde dimethylacetal in water (50 mL), and the reaction
refluxed for 30 min. The reaction mixture was then cooled in an ice
bath, and sodium bicarbonate (10 g, 0.12 mol) was added slowly.
After the addition was complete, 6-aminonicotinic acid (10 g, 0.072
mol) was added, and the reaction stirred at ambient temperature
overnight. The reaction was then filtered, and the solid washed
with water, and dried in vaccuo to give
imidazo[1,2-a]pyridine-6-carboxylic acid as a white solid (2.61 g,
22%). .sup.1H NMR (250 MHz, DMSO): .delta. 9.30 (s, 1H), 8.13 (s,
1H), 7.68 (s, 1H), 7.64 (s, 2H).
B. Imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester
[0619] ##STR186##
[0620] Cesium carbonate (15.7 g, 48.2 mmol) and iodomethane (1.50
ml, 24.2 mmol) were added to a solution of
imidazo[1,2-a]pyridine-6-carboxylic acid (2.61 g, 16.1 mmol) in DMF
(100 ml). The reaction was stirred at ambient temperature
overnight, then poured into brine (100 ml) and extracted with ethyl
acetate (3.times.100 mL). The combined organics were washed with
saturated sodium bicarbonate solution (25 mL), and a 1N HCl
solution (25 mL) then dried over MgSO.sub.4 and evaporated to give
imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester as a yellow
solid (1.1 g, 39%). .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.96
(s, 1H), 7.8-7.6 (m, 4H), 3.98 (s, 3H). MS [EI+] 177
(M+H).sup.+.
C. 3-Iodo-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester
[0621] ##STR187##
[0622] N-iodosuccinamide (1.55 g, 6.89 mmol) was added to a
solution of imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester
(1.1 g, 6.24 mmol) in acetonitrile (50 mL) which had been cooled to
0.degree. C. under a nitrogen atmosphere. The reaction stirred for
1 hr, then concentrated in vaccuo to a residue. The residue was
dissolved in ethyl acetate (50 mL) and washed with 10% sodium
bisulfate (2.times.10 mL) and brine (1.times.20 mL), then the
organic layers were dried over MgSO.sub.4 and evaporated to give
3-iodo-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester as a
pale yellow solid (1.79 g, 95%). .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 8.91 (s, 1H), 7.85 (dd, 1H, J=2.5, J=10), 7.80 (s, 1H),
7.69 (d, 1H, J=10), 4.01 (s, 3H).
D.
3-(2-Ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridine-6-carboxylic
acid methyl ester
[0623] ##STR188##
[0624] 3,5-Diisopropyl-2-methoxymethoxy-phenyl-boronic acid (455
mg, 1.83 mmol), followed by
tetrakis(triphenylphosphine)palladium(0) (191 mg, 0.16 mmol), and
2M sodium carbonate solution (3.31 ml, 3.32 mmol) were added to a
solution of 3-iodo-imidazo[1,2-a]pyridine-6-carboxylic acid methyl
ester (500 mg, 1.66 mmol) in toluene (10 mL). This reaction was
then heated to 80.degree. C. overnight, then cooled to ambient
temperature and partitioned between brine (10 mL) and ethyl acetate
(50 mL). The organic layer was dried over MgSO.sub.4 and evaporated
to a residue. The residue was purified by silica gel chromatography
(5% MeOH in dichloromethane) to yield
3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridine-6-carbox-
ylic acid methyl ester as a yellow solid (411 mg, 65%). .sup.1H NMR
(250 MHz, CDCl.sub.3): .delta. 8.71 (s, 1H), 7.70 (m, 1H), 7.62 (m,
1H), 7.41 (m 1H), 7.19 (d, 1H, J=1.2), 7.08 (d, 1H, J=1.2), 3.85
(s, 3H), 3.38 (m, 1H), 3.29 (q, 2H, J=6.8), 2.90 (m, 1H), 1.28 (s,
3H), 1.26 (s, 6H), 1.24 (s, 3H), 0.75 (t, 3H, J=6.8). MS [EI+] 381
(M+H).sup.+.
E.
[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-methan-
ol
[0625] ##STR189##
[0626] Diisobutylaluminum hydride (2.4 ml, 1 M soln., 2.4 mmol) was
added dropwise to a solution of
3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridine-6-carboxylic
acid methyl ester (300 mg, 0.79 mmol) in dichloromethane (10 mL)
which had been cooled to -78.degree. C. under a nitrogen
atmosphere. After the addition was complete, the reaction was kept
at -78.degree. C. for 4 h, then quenched with methanol (10 mL).
After addition of the methanol, the mixture was poured into water,
filtered and the solution evaporated to a residue. The residue was
purified by silica gel chromatography (2.5% MeOH in
dichloromethane) to give
[3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-methanol
as a clear glass (102 mg, 38%). .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 8.01 (s, 1H), 7.70 (bs, 1H), 7.64 (d, 1H, J=9.4), 7.24 (m,
2H), 7.12 (d, 1H, J=0.62), 4.73 (s, 1H), 3.45 (m, 1H), 3.35 (q, 2H,
J=7.0), 1.34 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H),
0.84 (t, 3H, J=7.0). MS [EI+] 353 (M+H).sup.+.
F.
3-(2-Ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridine-6-carbaldehy-
de
[0627] ##STR190##
[0628] Tetrapropylammonium perruthenate (24 mg, 0.07 mmol) and
4-methylmorpholine N-oxide (239.3 mg, 2.04 mmol) were added to a
solution of
[3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-metha-
nol (480 mg, 1.36 mmol) in dichloromethane under an atmosphere of
nitrogen. After 3 h, the reaction was filtered through celite and
evaporated. The residue used without further purification.
G.
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-acry-
lic acid methyl ester
[0629] ##STR191##
[0630] Sodium hydride (163.3 mg, 4.1 mmol) was added to a solution
of methyl diethyl phosphoacetate (0.75 ml, 4.1 mmol) in DMF (10 ml)
which had been cooled to 0.degree. C. under a nitrogen atmosphere.
The reaction stirred for 30 min., then
3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridine-6-carbaldehyde
(477 mg, 1.4 mmol) was added, and the reaction was allowed to stir
at ambient temperature overnight. The reaction was then poured into
brine (30 mL) and extracted with ethyl acetate (3.times.10 mL). The
combined organic layers were dried over MgSO.sub.4 and evaporated
to a residue. The residue was purified by silica gel chromatography
to give
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-acryli-
c acid methyl ester as a pale yellow solid (288 mg, 52%). .sup.1H
NMR (250 MHz, CDCl.sub.3): .delta. 8.02 (s, 1H), 7.64 (d, 2H,
J=0.6), 7.57 (d, 1H, J=7.5), 7.39 (dd, 1H, J=0.6, J=7.5), 7.17 (d,
1H, J=1.2), 7.04 (d, 1H, J=1.2), 6.35 (d, 1H, J=16.9), 3.74 (s,
3H), 3.37 (m, 1H), 3.26 (q, 2H, J=7.2), 2.88 (m, 1H), 1.26 (s, 3H),
1.23 (s, 6H), 1.20 (s, 3H), 0.72 (t, 3H, J=7.2).
H.
3-[3-(2-Ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-acry-
lic acid
[0631] A solution of
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-acryli-
c acid methyl ester (288 mg, 0.71 mmol) in MeOH (5 ml) and 1N NaOH
(5 ml) was heated to 40.degree. C. for 2 h. The reaction was
cooled, then brought to pH 7.5 with solid ammonium chloride and
extracted with ethyl acetate (2.times.10 mL). The combined organic
layers were then dried over MgSO.sub.4 and evaporated to a residue.
The residue was purified by silica gel chromatography (10% MeOH in
dichloromethane) to give
3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-imidazo[1,2-a]pyridin-6-yl]-acryli-
c acid as a white solid (65 mg, 23%). .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 8.02 (s, 1H), 7.64 (m, 2H), 7.57 (d, 1H,
J=7.5), 7.39 (m, 1H), 7.17 (d, 1H, J=1.2), 7.04 (d, 1H, J=1.2),
6.35 (d, 1H, J=16.9), 3.37 (m, 1H), 3.26 (q, 2H, J=7.2), 2.88 (m,
1H), 1.26 (s, 3H), 1.23 (s, 6H), 1.20 (s, 3H), 0.72 (t, 3H, J=7.2).
MS [EI+] 393 (M+H).sup.+.
Example 63
3-[3-(3,5-Di-tert-butyl-2-propoxy-phenyl)-1H-indol-5-yl]-but-2-enoic
acid
[0632] ##STR192##
A. 1-Bromo-3,5-di-tert-butyl-2-propoxy-benzene
[0633] ##STR193##
[0634] A solution of 2-bromo-4,6-di-tert-butyl-phenol (18.58 g, 65
mmol) in DMF (200 mL) was added to a stirred slurry of sodium
hydride in anhydrous DMF (500 mL) precooled to -7.degree. C. over
15 min. The resulting reaction mixture was stirred at <0.degree.
C. for 0.5 h. n-Propyl iodide was added and stirring of the olive
green reaction mixture was continued for 18 h. after removal of the
ice bath. The reaction was quenched with de-ionized water (2.5 L),
1 M HCl (250 mL) and 5% LiCl solution (250 mL). The resulting
mixture was extracted with ethyl acetate (2.times.250 mL). Sodium
chloride (q.s. to saturation) was added to facilitate the
separation. The aqueous layer was extracted with hexane (200 mL).
The combined organic layers were washed with 5% LiCl (2.times.200
mL) dried (MgSO.sub.4) and filtered. The solvent was removed under
vacuum to give a viscous oil which was a 2:1 ration of product to
DMF. The residue was dissolved in hexane (100 mL) and the solution
was washed with 5% LiCl solution (3.times.30 mL). The hexane
solution was dried (MgSO.sub.4), filtered, and the hexane was
removed under vacuum to give a light brown oil which crystallized
on standing to give a tan solid (21.23 g, 99%). The product may be
purified by sublimation at 150.degree. C. at 0.5 torr to give a
light yellow solid. NMR (250 MHz, CDCl.sub.3): .delta. 7.32 (d, 1H,
J=2.4 Hz), 7.20 (d, 1H, J=2.4), 3.92 (t, 2H, J=6.8), 1.82 (sex,
2H), 1.00 (t, 3H, J=7.4). MS [EI+] 326, 328 (M+H).sup.+.
B. (2-Propoxy-3,5-di-tert-butylphenyl)-boronic acid
[0635] ##STR194##
[0636] 1-Bromo-3,5-di-tert-butyl-2-propoxy-benzene (6.55 g, 20
mmol) was dissolved in anhydrous 1,2-dimethoxy-ethane (125 mL under
a nitrogen atmosphere. The solution was cooled to -75.degree. C.
and t-butyl lithium (30 mL, 50 mmol, 1.7M in pentane) was added
dropwise over 20 min at -73.degree. C. to -68.degree. C. The
reaction was stirred at -74.degree. C. for 1 h and then treated
with trimethyl borate (11.4 mL, 100 mmol). The reaction was kept
cold for 1 h and then the bath was removed and the reaction allowed
to warm to room temperature over 24 h. It was treated with 1N
hydrochloric acid (70 mL) and stirred for 30 min. The reaction was
then diluted with water (150 mL) and extracted with ethyl acetate
(300 mL, 2.times.150 mL). The combined organic portions were washed
with bicarbonate solution (150 mL), water (150 mL), brine
(2.times.150 mL), dried (Na.sub.2SO.sub.4), filtered and evaporated
in vacuo to provide 6.33 g of a yellow semi-solid. The material was
purified by flash chromotography (eluet: (9:1) hexane:ethyl acetate
and (3:1) hexane:ethyl acetate) to provide 3.34 g (57%) of a white
solid. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.67 (d, 1H,
J=2.6), 7.49 (d, 1H, J=2.6), 5.91 (m, 1H), 3.82 (t, 2H, J=7.1),
1.89 (m, 2H), 1.42 (s, 9H), 1.33 (s, 9H), 2.63 (t, 3H, J=7.4). MS
[EI+] 293 (M+H).sup.+ [EI-] 291 (M-H).sup.+.
C.
3-[1-Benzenesulfonyl-3-(3,5-di-tert-butyl-2-propoxy-phenyl)-1H-indol-5--
yl]-but-2-enoic acid methyl ester
[0637] ##STR195##
[0638] 3-(1-Benzenesulfonyl-3-iodo-1H-indol-5-yl)-but-2-enoic acid
methyl ester (722 mg, 1.5 mmol) (see Example 23, step C) and
(2-propoxy-3,5-di-tert-butylphenyl)-boronic acid (526 mg, 1.8 mmol)
were dissolved in toluene (15 mL) under a nitrogen atmosphere.
Tetrakis(triphenylphosphine) palladium (347 mg, 0.3 mmol) and 2N
Na.sub.2CO.sub.3 (10 mL) were added and the biphasic mixture
stirred at 80.degree. C. for 24 h. The reaction was allowed to cool
to room temperature and the toluene portion was passed through a
pad of celite, washing liberally with ethyl acetate. The aqueous
portion was washed with ethyl acetate (2.times.) and the combined
organics dried (Na.sub.2SO.sub.4), filtered, and evaporated in
vacuo to give a black oil. The material was passed over a silica
pad with (4:1) hexane:ethyl acetate to give 875 mg of a brown oil
and then purified further by column chromotography (eluet: (9:1)
hexane:ethyl acetate and (4:1) hexane:ethyl acetate) to provide 183
mg (20%) of a yellow oil. .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 8.07 (d, 1H, 8.7), 7.94 (m, 2H) 7.72 (m, 2H), 7.53-7.39 (m,
5H), 7.21 (d, 1H, J=2.5), 6.15 (d, 1H, J=1.2), 3.74 (s, 3H), 3.22
(t, 2H, J=6.5) 2.57 (d, 3H, J=1.1), 1.45 (s, 9H), 1.34 (s, 9H),
1.02 (m, 2H) 0.39 (t, 3H, J=7.4). MS [EI+] 602 (M+H).sup.+.
D.
3-[3-(3,5-Di-tert-butyl-2-propoxy-phenyl)-1H-indol-5-yl]-but-2-enoic
acid
[0639]
3-[1-Benzenesulfonyl-3-(3,5-di-tert-butyl-2-propoxy-phenyl)-1H-ind-
ol-5-yl]-but-2-enoic acid methyl ester (171 mg, 0.28 mmol) was
dissolved in methanol (1.5 mL)/dioxane (3 mL) and treated with 1N
NaOH (2 mL) at 60.degree. C. for 4 h. The reaction was diluted with
1N HCl (10 mL) and extracted with ethyl acetate (3.times.15 mL).
The combined organic portions were washed with water (10 mL), brine
(10 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to
provide 160 mg of a brown solid. The material was purified using
radial chromatography (eluent: hexane/ethyl acetate gradient) to
provide 73 mg (58%) of a yellow foam. Mp. 105-115.degree. C.
.sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.31 (bs, 1H), 7.98 (bs,
1H, 8.7), 7.92 (m, 2H) 7.70 (m, 2H), 7.47-7.35 (m, 5H), 6.27 (bs,
1H), 3.42 (t, 2H, J=6.4) 2.68 (d, 3H, J=1.0), 1.49 (s, 9H), 1.37
(s, 9H), 1.32 (m, 2H) 0.68 (t, 3H, J=7.4). MS [EI+] 448
(M+H).sup.+, [EI-] 446 (M-H).sup.+. Analytical
(C.sub.29H.sub.37NO.sub.3): Calculated C, 77.81; H, 8.33; N, 3.13.
Found: C, 77.89; H, 8.68; N, 2.94.
Example 64
3-{3-[3,5-Di-tert-butyl-2-(2,2-difluoro-ethoxy)-phenyl]-1H-indol-5-yl}-but-
-2-enoic acid
[0640] ##STR196##
A. 2,4-Di-tert-butyl-1-(2,2-difluoro-ethoxy)-benzene
[0641] ##STR197##
[0642] 2,4-Di-tert-butylphenol (6.72 g, 32.6 mmol), cesium
carbonate (21.2 g, 65.2 mmol) and methanesulfonic acid 2,2-difluoro
ethyl ester (5.72 g, 35.8 mmol) were combined and stirred in
dimethylformamide (100 mL) at room temperature for 2 days. The
reaction was diluted with water (100 mL) and washed with 50%
hexane/diethyl ether (3.times.100 mL). The organic portions were
washed with water (200 mL), dried (MgSO.sub.4), filtered and
evaporated in vacuo to provide 7.93 g of a yellow oil. The oil was
passed over a silica pad with 1% ethyl acetate/hexane to provide
6.84 g (78%) of a clear oil. .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 7.37 (d, 1H, J=2.5 Hz), 7.19 (dd, 1H, J=8.5, J=2.5), 6.74
(d, 1H, J=8.5), 6.16 (tt, 1H, J=55.3, J=4.1), 4.20 (td, 2H, J=13.2,
J=4.1), 1.40 (s, 9H), 1.29 (s, 9H).
B. 1,5-Di-tert-butyl-2-(2,2-difluoro-ethoxy)-3-iodo-benzene
[0643] ##STR198##
[0644] 2,4-Di-tert-butyl-1-(2,2-difluoro-ethoxy)-benzene (6.75 g,
25 mmol), N-iodosuccinimide (6.74 g, 30 mmol) and p-toluenesulfonic
acid monohydrate (1.90 g, 10 mmol) were combined in dichloromethane
(75 mL) and heated at 38.degree. C. for 7 h. TLC (hexanes)
indicated a small amount of starting material still present and the
reaction was treated with additional N-iodosuccinimde (0.33 g).
After 4 h the reaction was washed with 10% Na.sub.2S.sub.2O.sub.3
solution (50 mL). The aqueous was backwashed with dichloromethane
(100 mL) and then the combined organic portions washed with water
(75 mL) and the combined organic portions washed with water (100
mL), dried (MgSO.sub.4), filtered and evaporated in vacuo to
provide an orange oil (9.92 g). The material was purified by flash
chromatography using hexane to give 8.88 g (90%) of a light pink
oil which solidified over time. .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 7.66 (d, 1H, J=2.4), 7.36 (d, 1H, J=2.4), 6.29 (tt, 1H,
J=55.3, J=4.3), 4.24 (td, 2H, J=13.2, J=4.3), 1.40 (s, 9H), 1.29
(s, 9H).
C.
2-(2,2-difluoro-ethoxy)-3,5-di-tert-butylphenyl)-boronic-acid
[0645] ##STR199##
[0646] 1,5-Di-tert-butyl-2-(2,2-difluoro-ethoxy)-3-iodo-benzene
(3.96 g, 10 mmol) was dissolved in anhydrous diethyl ether (100 mL)
in an oven-dried flask under nitrogen. N,N,N',N'-Tetramethyl
ethylenediamine (2.3 mL, 15 mmol) was added and the reaction cooled
in a dry ice/acetone bath. At -76.degree. C. to -73.degree. C. was
added over 5 min n-butyl lithium (6 mL, 15 mmol, 2.5M in hexane).
The reaction was stirred at -75.degree. C. for 15 min and then
treated slowly with trimethyl borate (3.4 mL, 30 mmol). The
reaction was stirred at -75.degree. C. for 1 h. The dry ice/acetone
bath was replace with an ice bath and the reaction was allowed to
warm to 0.degree. C. over 40 min. 1N hydrochloric acid (50 mL) was
added and after 5 min the ice bath was removed and stirring allowed
to continue for 1 h. The aqueous and organic layers were separated
and the aqueous layer was washed with ethyl acetate (2.times.150
mL). The combined organic portion was washed with brine (150 mL),
dried (MgSO.sub.4), filtered and evaporated in vacuo to provide an
oil (4.01 g). The material was purified by flash chromatography
using (9:1) hexane:ethyl acetate and (4:1) hexane:ethyl acetate to
give 1.32 g (42%) of a white solid. .sup.1H NMR (250 MHz,
CDCl.sub.3): .delta. 7.69 (d, 1H, J=2.6), 7.53 (d, 1H, J=2.6), 6.29
(tt, 1H, J=55.3, J=4.3), 4.24 (td, 2H, J=13.2, J=4.3), 1.40 (s,
9H), 1.29 (s, 9H). MS [EI-] 313 (M-H).sup.+.
D.
3-{1-Benzenesulfonyl-3-[3,5-di-tert-butyl-2-(2,2-difluoro-ethoxy)-pheny-
l]-1H-indol-5-yl}-but-2-enoic acid methyl ester
[0647] ##STR200##
[0648] 3-(1-Benzenesulfonyl-3-iodo-1H-indol-5-yl)-but-2-enoic acid
methyl ester (400 mg, 0.83 mmol) (see Example 23, step C) and
2-(2,2-difluoro-ethoxy)-3,5-di-tert-butylphenyl)-boronic acid (565
mg, 1.8 mmol) were dissolved in toluene (15 mL) under a nitrogen
atmosphere. Tetrakis(triphenylphosphine) palladium (173 mg, 0.15
mmol) and 2N Na.sub.2CO.sub.3 (15 mL) were added and the biphasic
mixture stirred at 80.degree. C. for 5 h. The layers were separated
and the aqueous washed with EtOAc (2.times.25 mL). The organic
portions were washed with brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo to provide 1.31 g of a black oil. The
material was purified by flash chromatography using (9:1)
hexane:ethyl acetate and (4:1) hexane:ethyl acetate to give 543 mg
(58%) of an oil. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.09
(d, 1H, J=8.7), 7.93 (m, 2H) 7.76 (s, 1H), 7.67 (d, 1H, J=1.6),
7.54-7.42 (m, 5H), 7.24 (d, 1H, J=2.5), 6.15 (d, 1H, J=1.2), 5.26
(tt, 1H, J=55.3, J=4.3), 3.74 (s, 3H), 3.53 (td, 2H, J=13.5,
J=4.2), 2.58 (d, 3H, J=1.1), 1.46 (s, 9H), 1.34 (s, 9H). MS [EI+]
624 (M+H).sup.+.
E.
3-{3-[3,5-Di-tert-butyl-2-(2,2-difluoro-ethoxy)-phenyl]-1H-indol-5-yl}--
but-2-enoic acid
[0649]
3-{1-Benzenesulfonyl-3-[3,5-di-tert-butyl-2-(2,2-difluoro-ethoxy)--
phenyl]-1H-indol-5-yl}-but-2-enoic acid methyl ester (493 mg, 0.79
mmol) was dissolved in methanol (4 mL)/dioxane (8 mL) and treated
with 1N NaOH (5.5 mL) at 60.degree. C. for 4 h. Diluted with 1N HCl
(25 mL) and extracted with ethyl acetate (3.times.25 mL). The
combined organic portions were washed with water (50 mL), brine (50
mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to
provide crude material. The material was purified using radial
chromatography by elution with hexane/ethyl acetate gradient to
provide 158 mg (43%) of a light yellow solid. Mp. 135-145.degree.
C. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.40 (bs, 1H), 7.92
(s, 1H), 7.47 (m, 3H), 7.39 (m, 2H), 6.26 (d, J=1.1), 5.49 (tt, 1H,
J=55.3, J=4.3), 3.69 (td, 2H, J=14.0, J=4.0), 2.68 (d, 3H, J=1.0),
1.50 (s, 9H), 1.37 (s, 9H). MS [EI-] 468 (M-H).sup.+. Analytical
(C.sub.28H.sub.33NO.sub.3): Calculated C, 71.62; H, 7.08; N, 2.98.
Found: C, 69.95; H, 7.38; N, 2.70.
Example 65
3-{3-[3,5-Di-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-indol-5-yl}--
but-2-enoic acid
[0650] ##STR201##
A. 2,4-Di-tert-butyl-1-(2,2,2-trifluoro-ethoxy)-benzene
[0651] ##STR202##
[0652] 2,4-Di-tert-butylphenol (6.19 g, 30 mmol), cesium carbonate
(19.5 g, 60 mmol) and 2-bromo-1,1,1-trifluoroethane (7.3 mL, 60
mmol) were combined and stirred in anhydrous dimethylformamide (75
mL) at 50.degree. C. for 2 days. The reaction was judged to be
incomplete by TLC (hexane) and additional
2-bromo-1,1,1-trifluoroethane (4.8 mL, 53 mmol) was added and
stirring continued at 50.degree. C. for 12 h. At that time there
was still a minor amount of unreacted phenol. The reaction was
diluted with water (100 mL) and washed with 50% hexane/diethyl
ether (3.times.150 mL). The organic portions were washed with water
(100 mL), dried (Na.sub.2SO.sub.4), filtered and evaporated in
vacuo to provide 8.15 g of a yellow oil. The oil was passed over a
silica pad with hexane to provide 5.17 g (60%) of a clear oil.
.sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.39 (d, 1H, J=2.5 Hz),
7.20 (dd, 1H, J=8.5, J=2.5), 6.70 (d, 1H, J=8.5), 4.35 (q, 2H,
J=8.2), 1.41 (s, 9H), 1.32 (s, 9H).
B. 1,5-Di-tert-butyl-3-iodo-2-(2,2,2-trifluoro-ethoxy)-benzene
[0653] ##STR203##
[0654] 2,4-Di-tert-butyl-1-(2,2,2-trifluoro-ethoxy)-benzene (5.06
g, 17.5 mmol), N-iodosuccinimide (4.74 g, 21 mmol) and
p-toluenesulfonic acid monohydrate (1.33 g, 7 mmol) were combined
in dichloromethane (50 mL) and heated at 38.degree. C. for 19 h.
The reaction was washed with 10% Na.sub.2S.sub.2O.sub.3 solution
(2.times.40 mL). The aqueous was backwashed with dichloromethane
(70 mL) and then the combined organic portions washed with water
(75 mL) and the combined organic portions washed with water (100
mL), dried (MgSO.sub.4), filtered and evaporated in vacuo to
provide a yellow oil (6.96 g). The material was purified by flash
chromatography using hexane to give 5.85 g (81%) of a light pink
oil. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.67 (d, 1H,
J=2.4), 7.37 (d, 1H, J=2.4), 4.45 (q, 2H, J=8.2), 1.40 (s, 9H),
1.30 (s, 9H).
C. 2-(2,2,2-Trifluoro-ethoxy)-3,5-di-tert-butylphenyl-boronic
acid
[0655] ##STR204##
[0656] 1,5-Di-tert-butyl-3-iodo-2-(2,2,2-trifluoro-ethoxy)-benzene
(3.17 g, 7.7 mmol) was dissolved in anhydrous diethyl ether (75 mL)
in an oven-dried flask under nitrogen. N,N,N',N'-Tetramethyl
ethylenediamine (1.73 mL, 11.5 mmol) was added and the reaction
cooled in a dry ice/acetone bath. At -76.degree. C. to -73.degree.
C. was added over 5 min n-butyl lithium (4.6 mL, 11.5 mmol, 2.5M in
hexane). The reaction was stirred at -75.degree. C. for 15 min and
then treated slowly with trimethyl borate (2.6 mL, 23 mmol). The
reaction was stirred at -75.degree. C. for 1 h. The dry ice/acetone
bath was replace with an ice bath and the reaction was allowed to
warm to 0.degree. C. over 40 min. 1N hydrochloric acid (50 mL) was
added and after 5 min the ice bath was removed and stirring allowed
to continue for 1 h. The aqueous and organic layers were separated
and the aqueous layer was washed with ethyl acetate (2.times.75
mL). The combined organic portion was washed with brine (100 mL),
dried (MgSO.sub.4), filtered and evaporated in vacuo to provide a
yellow gum. The material was purified by flash chromatography using
(9:1) hexane:ethyl acetate and then (4:1) hexane:ethyl acetate to
give 1.28 g (50%) of an off-white solid.
[0657] .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.65 (d, 1H,
J=2.6), 7.51 (d, 1H, J=2.6), 5.34 (bs, 1H), 4.24 (2H, J=8.2), 1.42
(s, 9H), 1.33 (s, 9H). MS [EI-] 331 (M-H).sup.+. MS [EI-] 331
(M-H).sup.+.
D.
3-{-Benzenesulfonyl-3-[3,5-di-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phe-
nyl]-1H-indol-5-yl}-but-2-enoic acid methyl ester
[0658] ##STR205##
[0659] 3-(1-Benzenesulfonyl-3-iodo-1H-indol-5-yl)-but-2-enoic acid
methyl ester (587 mg, 1.22 mmol) (see Example 23, step C) and
2-(2,2,2-trifluoro-ethoxy)-3,5-di-tert-butylphenyl-boronic acid
(445 mg, 1.34 mmol) were dissolved in toluene (12 mL) under a
nitrogen atmosphere. Tetrakis(triphenylphosphine) palladium (282
mg, 0.24 mmol) and 2N Na.sub.2CO.sub.3 (8 mL) were added and the
biphasic mixture stirred at 80.degree. C. for 6 h. The layers were
separated and the aqueous washed with EtOAc (2.times.25 mL). The
organic portions were washed with brine, dried (MgSO.sub.4),
filtered and concentrated in vacuo to provide 1.20 g of a black
oil. The material was purified by flash chromatography (eluent:
(9:1) hexane:ethyl acetate and (4:1) hexane:ethyl acetate) to
provide 195 mg (25%) of a yellow gum.
[0660] .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.08 (d, 1H,
J=8.7), 7.93 (m, 2H), 7.78 (s, 1H), 7.66 (d, 1H, J=1.6), 7.55-7.43
(m, 5H), 7.25 (d, 1H, J=2.5), 6.14 (d, 1H, J=1.2), 3.74 (s, 3H),
3.65 (q, 2H, J=8.4), 2.58 (d, 3H, J=1.2), 1.47 (s, 9H), 1.34 (s,
9H). MS [EI+] 642 (M+H).sup.+.
E.
3-{3-[3,5-Di-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-indol-5-y-
l}-but-2-enoic acid
[0661]
3-{1-Benzenesulfonyl-3-[3,5-di-tert-butyl-2-(2,2,2-trifluoro-ethox-
y)-phenyl]-1H-indol-5-yl}-but-2-enoic acid methyl ester was
dissolved in methanol (1.5 mL)/dioxane (3 mL) and treated with 1N
NaOH (2.0 mL) at 60.degree. C. for 2.5 h. Diluted with 1N HCl (15
mL) and extracted with ethyl acetate (3.times.15 mL). The combined
organic portions were washed with water (30 mL), brine (30 mL),
dried (MgSO.sub.4), filtered and concentrated in vacuo to provide
145 mg of crude material. The material was purified using radial
chromatography by (eluet: hexane/ethyl acetate gradient) to provide
72 mg (53%) of a pale yellow solid. Mp. 146-153.degree. C. .sup.1H
NMR (250 MHz, CDCl.sub.3): .delta. 8.43 (bs, 1H), 7.95 (s, 1H),
7.53 (d, 1H, J=2.4), 7.46 (m, 3H), 7.38 (d, 1H, J=2.5), 6.26 (d,
1H, J=1.1), 3.86 (q, 2H, J=8.6), 2.69 (d, 3H, J=1.0), 1.49 (s, 9H),
1.37 (s, 9H). MS [EI+] 488 (M+H).sup.+, [EI-] 486 (M-H).sup.+.
Analytical (C.sub.29H.sub.37NO.sub.3): Calculated C, 68.98; H,
6.62; N, 2.87. Found: C, 66.45; H, 6.85; N, 2.59.
Example 66
Evaluation of Activity In Vivo
[0662] Rodents that are genetically defective in the leptin pathway
are commonly used as animal models of non-insulin dependant
diabetes mellitus (NIDDM). db/db mice and ZDF rats develop frank
diabetes that progresses to include .beta.-cell failure and the
accompanying precipitous drop in plasma insulin levels. Both
strains are profoundly obese, hyperglycemic, hyperinsulinemic, and
hypertriglyceridemic. fa/fa rats, on the other hand, are obese and
insulin resistant but do not develop frank diabetes and the
associated hyperglycemia. All three rodent models were used to
examine the efficacy of oral dosing with compounds of the invention
on diabetes, insulin sensitivity, food consumption and body weight
gain.
[0663] All animal experiments were conducted in a United States
Department of Agriculture registered facility in accordance with
NIH guidelines for the care and use of laboratory animals. Mice
(obtained from Jackson Laboratory), ZDF rats (obtained from Genetic
Models Inc.) and fa/fa rats (obtained from either Charles River, or
Harlan) were maintained on 12-hour light/dark cycle. Mice (age
28-42 days) were caged in groups of 5-6. Rats (age 7 weeks) were
housed individually. All animals were allowed ad libitum access to
water and food (Purina 5015 for mice and 5008 for rats). Compounds
were administered at the specified doses by oral gavage on the
morning of each day of any experiment. Blood samples were obtained
3 hours after dosing from fed animals under anesthesia and
collected into heparinized capillary tubes from the tail vein.
[0664] Mice transgenic for the human apolipoprotein A-I gene
(obtained from Jackson Laboratory) were used to evaluate
PPAR.alpha. mediated effects on high density lipoprotein (HDL)
cholesterol. The mice were handled as described above for db/db
mice, except that they were fed Purina 5001.
[0665] Compounds that are full agonists at the RXR homodimer, such
as LG100268, are efficacious insulin sensitizers in rodent models
of NIDDM and, thus, lower blood glucose levels. However, such
compounds raise triglycerides and suppress the thyroid hormone axis
in these animals. On the other hand, full antagonists have no
effect on glucose, triglycerides or the thyroid status in these
same model systems. We have identified a specific subset of
rexinoids that maintain the desirable insulin sensitizing activity
and eliminate both the suppression of the thyroid axis and
triglyceride elevations (see Table 1 for glucose and triglyceride
data for animals treated with a compound of the invention compared
to animals treated with LG 100268). These compounds are heterodimer
selective modulators of RXR activity. They bind to RXR with high
affinity (K.sub.i<55 nM) and produce potent synergistic
activation of the RXR:PPAR.gamma. heterodimer. This synergistic
activation of PPAR.gamma. in vitro is presumably a major
determinant of the antidiabetic efficacy of compounds in vivo. To
eliminate the undesirable increases in triglycerides and
suppression of T4, the modulators must not significantly activate
RXR:RAR heterodimers and must have substantial RXR:RAR antagonist
activity. Examples 14, 15, 5, and 18 in Table 1 clearly demonstrate
that compounds of the invention do not activate RXR:RAR
heterodimers.
[0666] When administered to obese, insulin resistant db/db mice
(100 mg/kg by daily oral gavage for 14 days), compounds of the
invention lower plasma glucose. However, unlike full agonists
(e.g., LG100268), they do not increase triglycerides.
[0667] Four week old db/db mice are essentially normoglycemic, they
have not yet developed hyperglycemia. Treatment of such mice with a
compound of the invention (30 mg/kg by daily oral gavage) prevents
the development of hyperglycemia. This treatment is expected to
successfully control plasma glucose levels for up to 11 weeks (when
the mice are 15 weeks old).
[0668] Treatment of 7 week old db/db mice with metformin (300 mg/kg
by daily oral gavage) lowers plasma glucose. However the maximum
effect is seen following the first week of treatment. Over 3
subsequent weeks the efficacy of metformin decreases. At this
point, treatment with metformin plus the addition of a compound of
the invention (100 mg/kg by daily oral gavage) is expected to
lowered plasma glucose to the level of age matched lean. Thus, the
RXR modulator could be efficacious in cases of secondary failure of
metformin.
[0669] To determine whether compounds of the invention produce
insulin sensitization, compounds of the invention can be
administered to insulin resistant fa/fa rats (100 mg/Kg by daily
oral gavage for 14 days. In response to the oral glucose challenge,
both insulin and glucose is expected to rise significantly less in
animals treated with a compound of the invention than in untreated
control animals. Animals treated with a compound of the invention
are expected to consume the same amount of food and gain the same
amount of weight as vehicle treated control animals. When fa/fa
animals are treated with a thiazolinedione insulin sensitizer, they
consume significantly more food and gain significantly more weight
than control animals. In contrast, animals treated with a
combination of the thiazolidinedione and a compound of the
invention are expected to consume the same amount of food and gain
the same amount of weight as the control animals. Compounds of the
invention are expected to block the thiazolidinedione induced
increases in both food consumption and body weight gain.
[0670] When administered to transgenic mice carrying the human apo
A-I gene, compounds of the invention are expected to increase HDL
cholesterol. However, unlike LG 100268 which also raises
triglycerides, compounds of the invention do not raise
triglycerides (see Examples 14, 15, 5, and 18 of Table 1).
Compounds of the invention that are not RXR:RAR heterodimer agonist
and have greater than 50% RXR:RAR antagonists activity do not raise
triglycerides in the transgenic mouse model, consistent with their
heterodimer selectivity. This effect is consistent with activation
of PPAR.alpha. and, in fact, in vivo these compounds synergize with
the weak PPAR.alpha. agonist fenofibrate. TABLE-US-00009 TABLE 1
Modulation of RXR activity using compounds of the invention. Bind
PPAR.gamma. RXR.alpha. CV-1 RXR:RXR RXR:RAR db/db mouse K.sub.i (%)
CV-1 (%) CV-1 (%) Glu. Trigs. Compound (nM) Synergy Ag Antag Ag. (D
7) (D 3) LG100268 3 183 73 -- 6 73 195 Ex. 14 12 67 1 79 2 35 139
Ex. 15 14 109 4 81 6 20 98 Ex. 5 22 140 33 10 3 17 104 Ex. 18 54 40
1 86 4 38 105 NC: "no change" NT: "not tested K.sub.i = Determined
from IC.sub.50 values by the Cheng-Prussof equation using tritiated
LGD1069. Synergy = Efficacy calculated as the maximal response in
presence of 100 nM BRL49653 (RXR:PPAR.gamma.) relative to maximal
response of BRL49653 alone. Ag. = Efficacy calculated as the
maximal response relative to maximal response of ATRA. Antag. =
Efficacy calculated as the maximal repression (100%) in the
presence of 32 nM LGD1069 (RXR:RXR) or 10 nM TTNPB (RXR:RAR). Glu.
= Plasma glucose as a % correction relative to lean values on day 7
of treatment with 30 mg/kg/day. Trigs. = Plasma triglycerides as a
% of control values on day 3 of treatment with 30 mg/kg/day.
Example 67
Evaluation of Teratogenicity In Vivo
[0671] Teratogenicity is commonly evaluated by examination of
fetuses obtained by cesarean section from pregnant mice dosed daily
with test compound between gestation days 6-18. A blind study can
be conducted using time-mated female Crl:CD-1.RTM. (ICR)BR mice to
evaluate potential developmental toxicity (teratogenicity)
following administration of a compound of the invention at either
30 or 200 mg/kg-day by daily oral gavage for the specified 12 days
of gestation. Each test group consists of 7-8 pregnant females and
produced approximately 100 live fetuses per test group. As a
positive control, pregnant female mice are treated with the
retinoid LG100268 at a dose of either 30 mg/kg-day or 100
mg/kg-day. Teratogenicity can be observed in fetuses from mice
treated with the LG100268 at both dosage groups. In contrast, no
teratogenic effects are expected to be observed in fetuses from
mice treated with a compound of the invention. Compared to controls
dosed with vehicle, no effects are expected to be observed on the
number of Corpora lutea, implantation sites, live or dead fetuses,
early or late resorptions, fetal weight or sex, gross external
morphology or visceral morphology of the cranial region in fetuses
from mice treated with a compound of the invention at either dose.
The highest dose of a compound of the invention tested (200
mg/kg-day) is twice the dose required to produce maximum
antidiabetic activity in db/db mice (100 mg/kg-day).
EQUIVALENTS
[0672] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
details may be made therein without departing from the scope of the
invention encompassed by the appended claims.
* * * * *