US2008090860A1PendingUtilityA1
Retinoid x receptor modulators
Individually held — no corporate assignee on recordPriority: Mar 14, 2001Filed: Aug 23, 2007Published: Apr 17, 2008
Est. expiryMar 14, 2021(expired)· nominal 20-yr term from priority
Inventors:Kevin Matthew GardinierDouglas Linn GernertTimothy A. GreseDavid Andrew NeelChristopher M. MapesPierre-Yves MichellysMarcus F. Boehm
A61P 3/10A61P 3/06A61P 9/10A61P 37/08A61P 9/00A61P 43/00A61P 5/40A61P 31/04A61P 3/04A61P 29/00A61P 25/16A61P 35/00A61P 25/00A61P 25/28A61P 35/02C07D 307/85C07D 333/60C07D 261/20C07D 209/12A61P 17/14C07D 307/80C07D 231/56C07D 333/56C07D 217/16A61P 17/00C07D 333/70C07D 495/04A61P 13/10C07D 215/14C07D 471/04A61P 17/06A61P 13/08A61P 17/02
54
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention is directed to compounds represented by Structural Formula I and pharmaceutically acceptable salts, solvates and hydrates thereof: 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.
Claims
exact text as granted — not AI-modified1 . A compound represented by the following structural formula:
or a pharmaceutically acceptable salt, solvate and hydrate thereof, wherein:
R is H, F, Cl, Br, I, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 2 -C 3 alkenyl, C 2 -C 3 haloalkenyl, C 2 -C 3 alkynyl, C 2 -C 3 haloalkynyl, and C 1 -C 3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
R 1 and R 2 are each, independently, H, a halo, a C 1 -C 10 alkyl a C 3 -C 10 cycloalkyl, a C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl, or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy; or
R 1 and R 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 1 -C 6 alkyl groups; or
R and R 1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy substituents; and
R 3 is H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy;
R 4 is H, a halo, an aryl-C 1 -C 6 -alkyl, a C 1 -C 10 alkyl or a C 1 -C 10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, aryl, heteroaryl, a C 1 -C 6 alkoxy, an amino group represented by the formula NR 14 R 15 ; or
R 3 and R 4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy substituents; and
R 5 is H, a halo, or a C 1 -C 3 alkyl group which is optionally substituted with one or more halo;
R 6 is H or halo;
R 14 and R 15 are each, independently, H, a C 1 -C 6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
R 16 is OR 17 , OCH(R 17 )OC(O)R 18 , —NR 19 R 20 , or an aminoalkyl;
R 17 , R 18 and R 20 are each, independently, H or a C 1 -C 6 alkyl;
R 18 is a C 1 -C 6 alkyl;
ring A is:
a benzo[b]thiophenyl, optionally substituted with one or more substituents selected from a halo, a C 1 -C 6 alkyl, or a C 1 -C 6 alkoxy,
wherein:
2 . (canceled)
3 . The compound of claim 1 , wherein ring A is selected from the group consisting of:
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 α,β-unsaturated carbonyl group.
4 . The compound of claim 1 , wherein R 4 is a C 2 -C 5 alkoxy group which is optionally substituted with one or more fluoro.
5 . The compound of claim 1 , wherein R 5 is methyl and R 6 is H.
6 . The compound of claim 1 , wherein R 5 is methyl and R 6 is fluoro.
7 . The compound of claim 1 , wherein:
R 1 and R 3 are both isopropyl; and R 2 is H.
8 . The compound of claim 1 , wherein:
R 1 and R 3 are both t-butyl; and R 2 is H.
9 - 11 . (canceled)
12 . The compound of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt, solvate and hydrate thereof, wherein:
R 1 ′ and R 3 ′ are each, independently, H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, a C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl, or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkoxy;
R 4 ′ is H, a halo, an aryl-C 1 -C 6 -alkyl, a C 1 -C 10 alkyl or a C 1 -C 10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, aryl, heteroaryl, a C 1 -C 6 alkoxy, an amino group represented by the formula NR 14 R 15 ;
each R 9 is, independently, a halo or a C 1 -C 6 alkyl group;
R 10 is H, a halo or a C 1 -C 6 alkyl group; and
m is 0, 1, 2 or 3.
13 . The compound of claim 12 , wherein:
R 1 and R 3 are the same and are isopropyl or t-butyl; and R 5 is methyl.
14 . The compound of claim 13 , wherein R 4 is a C 2 -C 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-enoic 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-enoic 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]-prop-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]thien-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]thien-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}but-2-enoic acid; (E) 3-[4-(5-(2,2,2-trifluoroethoxy)-6-tert-butylindan-4-yl)-benzo[b]thien-2-yl]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]thien-2-yl}but-2-enoic acid; (E) 3-{4-[2-(3-fluoropropoxy)-3,5-di-(1,1-dimethylpropyl)phenyl]-benzo[b]thien-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}-but-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:
or a pharmaceutically acceptable salt, solvate and hydrate thereof, wherein:
R is H, F, Cl, Br, I, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 2 -C 3 alkenyl, C 2 -C 3 haloalkenyl, C 2 -C 3 alkynyl, C 2 -C 3 haloalkynyl, and C 1 -C 3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
R 1 and R 2 are each, independently, H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, a C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl, or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted within one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy; or
R 1 and R 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 1 -C 6 alkyl groups; or
R and R 1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy substituents; and
R 3 is H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy;
R 4 is H, a halo, an aryl-C 1 -C 6 -alkyl, a C 1 -C 10 alkyl or a C 1 -C 10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, aryl, heteroaryl, a C 1 -C 6 alkoxy, an amino group represented by the formula NR 14 R 15 ; or
R 3 and R 4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy substituents; and
R 5 is H, a halo, or a C 1 -C 3 alkyl group which is optionally substituted with one or more halo;
R 6 is H or halo;
R 14 and R 15 are each, independently, H, a C 1 -C 6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
R 16 is OR 17 , OCH(R 17 )OC(O)R 18 , —NR 19 R 20 , or an aminoalkyl;
R 17 , R 19 and R 20 are each, independently, H or a C 1 -C 6 alkyl;
R 18 is a C 1 -C 6 alkyl;
ring A is
a benzo[b]thiophenyl, optionally substituted with one or more substituents selected from a halo, a C 1 -C 6 alkyl, or a C 1 -C 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:
or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
R is H, F, Cl, Br, I, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 2 -C 3 alkenyl, C 2 -C 3 haloalkenyl, C 2 -C 3 alkynyl, C 2 -C 3 haloalkynyl, and C 1 -C 3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
R 1 and R 2 are each, independently, H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, a C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl, or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy; or
R 1 and R 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 1 -C 6 alkyl groups; or
R and R 1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy substituents; and
R 3 is H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy;
R 4 is H, a halo, an aryl-C 1 -C 6 -alkyl, a C 1 -C 10 alkyl or a C 1 -C 10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, aryl, heteroaryl, a C 1 -C 6 alkoxy, an amino group represented by the formula NR 14 R 15 ; or
R 3 and R 4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy substituents; and
R 5 is H, a halo, or a C 1 -C 3 alkyl group which is optionally substituted with one or more halo;
R 6 is H or halo;
R 14 and R 15 are each, independently, H, a C 1 -C 6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
R 16 is OR 17 , OCH(R 17 )OC(O)R 18 , —NR 19 R 20 , or an aminoalkyl;
R 17 , R 19 and R 20 are each, independently, H or a C 1 -C 6 alkyl;
R 18 is a C 1 -C 6 alkyl;
ring A is
a benzo[b]thiophenyl, optionally substituted with one or more substituents selected from a halo, a C 1 -C 6 alkyl or a C 1 -C 6 alkoxy.
69 . The method of claim 68 , further comprising the step of administering to said mammal a PPARγ agonist.
70 . The method of claim 68 , wherein R 4 is a C 2 -C 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:
or a pharmaceutically acceptable salt, solvate and hydrate thereof, wherein:
R 1 ′ and R 3 ′ are each, independently, H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, a C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl, or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkoxy;
R 4 ′ is H, a halo, an aryl-C 1 -C 6 -alkyl, a C 1 -C 10 alkyl or a C 1 -C 10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, aryl, heteroaryl, a C 1 -C 6 alkoxy, an amino group represented by the formula NR 14 R 15 ;
each R 9 is, independently, a halo or a C 1 -C 6 alkyl group;
R 10 is H, a halo or a C 1 -C 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]thiophene; 3-[7-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid; 2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophene; (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-enoic 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]thien-2-yl}-but-2-enoic acid; (E) 2-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-methylphenyl]-benzo[b]thien-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]thien-2-yl}but-2-enoic acid; (E) 3-{4-[2-(3-fluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid; (E) 3-{4-[2-(2,2-difluoroethyloxy)-3-(adamant-1-yl)-5-methylphenyl]-benzo[b]thien-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:
or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
R is H, F, Cl, Br, I, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 2 -C 3 alkenyl, C 2 -C 3 haloalkenyl, C 2 -C 3 alkynyl, C 2 -C 3 haloalkynyl, and C 1 -C 3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
R 1 and R 2 are each, independently, H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, a C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl, or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy; or
R 1 and R 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 1 -C 6 alkyl groups; or
R and R 1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy substituents; and
R 3 is H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy;
R 4 is H, a halo, an aryl-C 1 -C 6 -alkyl, a C 1 -C 10 alkyl or a C 1 -C 10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, aryl, heteroaryl, a C 1 -C 6 alkoxy, an amino group represented by the formula NR 14 R 15 ; or
R 3 and R 4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy substituents; and
R 5 is H, a halo, or a C 1 -C 3 alkyl group which is optionally substituted with one or more halo;
R 6 is H or halo;
R 14 and R 15 are each, independently, H, a C 1 -C 6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
R 16 is OR 17 , OCH(R 17 )OC(O)R 18 , —NR 19 R 20 , or an aminoalkyl;
R 17 , R 18 and R 20 are each, independently, H or a C 1 -C 6 alkyl;
R 18 is a C 1 -C 6 alkyl;
ring A is
a benzo[b]thiophenyl, optionally substituted with one or more substituents selected from a halo, a C_—C 6 alkyl, or a C 1 -C 6 alkoxy.
88 . The method of claim 87 , wherein R 4 is a C 2 -C 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:
or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
R 1 ′ and R 3 ′ are each, independently, H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, a C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl, or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkoxy;
R 4 ′ is H, a halo, an aryl-C 1 -C 6 -alkyl, a C 1 -C 10 alkyl or a C 1 -C 10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, aryl, heteroaryl C 1 -C 6 alkoxy, an amino group represented by the formula NR 14 R 15 ;
each R 9 is, independently, a halo or a C 1 -C 6 alkyl group;
R 10 is H, a halo or a C 1 -C 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]thiophene; 3-[7-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid; 2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophene; (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-enoic 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]thien-2-yl}-but-2-enoic acid; (E) 2-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-methylphenyl]-benzo[b]thien-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]thien-2-yl}but-2-enoic acid; (E) 3-{4-[2-(3-fluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid; (E) 3-{4-[2-(2,2-difluoroethyloxy)-3-(adamant-1-yl)-5-methylphenyl]-benzo[b]thien-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:
or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
R is H, F, Cl, Br, I, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 2 -C 3 alkenyl, C 2 -C 3 haloalkenyl, C 2 -C 3 alkynyl, C 2 -C 3 haloalkynyl, and C 1 -C 3 alkoxy, wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be optionally substituted;
R 1 and R 2 are each, independently, H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, a C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl, or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy; or
R 1 and R 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 1 -C 6 alkyl groups; or
R and R 1 taken together with the carbon atoms to which they are attached form an aryl, a heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloalkenyl ring wherein the aryl, heteroaryl, cycloalkyl and cyclolkenyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy substituents; and
R 3 is H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy;
R 4 is H, a halo, an aryl-C 1 -C 6 -alkyl, a C 1 -C 10 alkyl or a C 1 -C 10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, aryl, heteroaryl, a C 1 -C 6 alkoxy, an amino group represented by the formula NR 14 R 15 ; or
R 3 and R 4 taken together with the carbon atoms to which they are attached form an aryl, an heteroaryl, a C 5 -C 8 cycloalkyl or C 5 -C 8 cycloakenyl ring wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy substituents; and
R 5 is H, a halo, or a C 1 -C 3 alkyl group which is optionally substituted with one or more halo;
R 6 is H or halo;
R 14 and R 15 are each, independently, H, a C 1 -C 6 alkyl, or taken together with the nitrogen they are attached to can form a 5 to 8 membered heterocycle;
R 16 is OR 17 , OCH(R 17 )OC(O)R 18 , —NR 19 R 20 , or an aminoalkyl;
R 17 , R 19 and R 20 are each, independently, H or a C 1 -C 6 alkyl;
R 18 is a C 1 -C 6 alkyl;
ring A is
a benzo[b]thiophenyl optionally substituted with one or more substituents selected from a halo, a C 1 -C 6 alkyl, or a C 1 -C 6 alkoxy.
97 . The method of claim 96 , wherein R 4 is a C 2 -C 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:
or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:
R 1 ′ and R 3 ′ are each, independently, H, a halo, a C 1 -C 10 alkyl, a C 3 -C 10 cycloalkyl, a C 5 -C 10 cycloalkenyl, a 6 to 10 membered aryl, a 5 to 10 membered heteroaryl, an aryl-C 1 -C 6 -alkyl, or an amino group represented by the formula NR 14 R 15 , wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and arylalkyl are optionally substituted with one or more halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkoxy;
R 4 ′ is H, a halo, an aryl-C 1 -C 6 -alkyl, a C 1 -C 10 alkyl or a C 1 -C 10 alkoxy group wherein the arylalkyl, alkyl and alkoxy groups are optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, aryl, heteroaryl, a C 1 -C 6 alkoxy, an amino group represented by the formula NR 14 R 15 ;
each R 9 is, independently, a halo or a C 1 -C 6 alkyl group;
R 10 is H, a halo or a C 1 -C 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]thiophene; 3-[7-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid; 2-carboxy-4-(2-propoxy-3,5-di-tert-butylphenyl)-benzo[b]thiophene; (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-enoic 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]thien-2-yl}-but-2-enoic acid; (E) 2-{4-[2-(2,2,2-trifluoroethyloxy)-3-tert-butyl-5-methylphenyl]-benzo[b]thien-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]thien-2-yl}but-2-enoic acid; (E) 3-{4-[2-(3-fluoropropyloxy)-3-tert-butyl-5-ethylphenyl]-benzo[b]thien-2-yl}but-2-enoic acid; (E) 3-{4-[2-(2,2-difluoroethyloxy)-3-(adamant-1-yl)-5-methylphenyl]-benzo[b]thien-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)Join the waitlist — get patent alerts
Track US2008090860A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.