Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-10-09
2004-09-07
Powers, Fiona T. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S373000, C546S176000, C548S159000, C548S181000, C548S222000, C548S425000, C548S430000, C548S464000, C548S466000, C548S467000, C548S492000
Reexamination Certificate
active
06787651
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to substituted indoles, pharmaceutical compositions containing such indoles, and their use in treating or preventing diseases or conditions mediated by the Peroxisome Proliferator Activated Receptor-&ggr; (PPAR-&ggr;).
BACKGROUND
Peroxisome Proliferator Activated Receptors (PPARs) belong to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. Willson, et al.,
Curr. Opin. Chem. Biol
., (1997), Vol. 1, pp 235-241. To date, three mammalian PPARs have been identified, namely PPAR-&agr;, PPAR-&ggr;, and PPAR-&dgr;.
PPARs regulate expression of target genes by binding to DNA response elements as heterodimers with the retinoid X receptor. These DNA response elements have been identified in the regulatory regions of a number of genes encoding proteins involved in lipid metabolism and energy balance. The biological role of the PPARs in the regulation of lipid metabolism and storage has been recently reviewed. Spiegelman,
Diabetes
, (1998), Vol. 47, pp. 507-514; Schoonjans, et al.,
Curr. Opin. Lipidol
., (1997), Vol. 8, pp 159-166; Brun, et al.,
Curr. Opin. Lipidol
., (1997), Vol. 8, pp 212-218.
Molecules that interact with PPAR-&ggr; may be useful in modulating PPAR-&ggr; mediated processes for the treatment or prevention of various diseases and conditions. For example, essential dietary fatty acids and certain of their eicosanoid metabolites are naturally occurring hormonal ligands for the PPAR-&ggr; receptor, which can promote adipogenesis through activation of the PPAR-&ggr; receptor. Kliewer, et al.,
Proc. Natl. Acad. Sci. USA
, (1997), Vol. 94, pp 4318-4323; Kliewer, et al.,
Cell
, (1995), Vol. 83, pp 813-819. Therefore, molecules that inhibit the adipogenic effects of endogenous PPAR-&ggr; hormones may be useful in the treatment of diseases caused by increased fat accumulation or lipid storage, such as osteoporosis, obesity and acne. Tontonoz, et al.,
Curr. Opin. Genet. Dev
., (1995), Vol. 5, pp 571-576. For example, it has been noted that the thiazolidinedione (TZD) class of PPAR-&ggr; ligands promotes adipogenesis in bone marrow and inhibits expression of markers of the osteoblast phenotype, such as alkaline phosphatase. Paulik, et al.,
Cell Tissue Res
., (1997), Vol. 290, pp 79-87. These effects may lead to low bone mineral density and osteoporosis. Similarly, it is known that TZDs can promote lipid accumulation in sebocytes. Rosenfield, et al.,
N. Dermatology
, (1998), Vol. 196, pp 43-46. These effects may lead to sebocyte differentiation and acne formation. Thus, molecules that block adipogenesis in adipocytes, pre-adipocytes, bone marrow, or sebocytes may have beneficial effects in the treatment of obesity, osteoporosis, or acne.
The PPAR-&ggr; receptor has been found in tissues other than adipose, and it is believed that synthetic PPAR-&ggr; ligands and natural PPAR-&ggr; hormones (natural ligands) may have beneficial effects in many other diseases including cardiovascular disease, inflammation, and cancer. Schoonjans, supra; Ricote, et al.,
Nature
, (1998), Vol. 391, pp 79-82; Mueller, et al.,
Mol. Cell
, (1998), Vol. 1, pp 465-470.
TZD PPAR-&ggr; ligands enhance the actions of insulin in man and reduce circulating glucose levels in rodent models of diabetes. The PPAR-&ggr; receptor is expressed in adipose tissue and plays a pivotal role in the regulation of adipocyte differentiation in vitro. TZD such as rosiglitazone induce adipocyte differentiation in vitro through activation of the PPAR-&ggr; receptor.
Although there are clearly therapeutic uses for PPAR-&ggr; ligands in the treatment of diseases of lipid metabolism and energy balance, it is possible that there will be side effects of these drugs. For example, PPAR-&ggr; ligands that promote adipocyte differentiation in vivo could lead to increased fat accumulation and weight gain. This side effect might offset the beneficial effects of a PPAR-&ggr; ligand in the treatment of diabetes or other diseases where obesity is a risk factor. Spiegelman, supra; Brun, supra.
There is precedent among other member of the steroid/retinoid receptor superfamily that synthetic ligands can be identified which mimic many of the beneficial effects but inhibit some of the detrimental side effects of the natural hormones. McDonnell,
Biochem. Soc. Trans
., (1998), Vol. 26, pp 54-60. These synthetic ligands have been given various labels, including antagonists, anti-hormones, partial agonists, selective receptor modulators, tissue selective ligands, and others. Katzenellenbogen, et al.,
Mol. Endocinol
., (1996), Vol. 10, pp 119-131. Compounds are needed that will modulate PPAR-&ggr; mediated processes for the treatment or prevention of diseases such as osteoporosis, cancer, etc. without the concommitant side-effects of natural hormones.
SUMMARY OF THE INVENTION
The invention provides compounds that modulate PPAR-&ggr; mediated processes, particularly substituted indole compounds, which can act as agonists or antagonists of PPAR-&ggr; and thereby modulate PPAR-&ggr; mediated processes. The invention further provides pharmaceutical compositions containing such compounds. Finally, the invention provides for methods of treating or preventing a PPAR-&ggr; mediated diseases or condition in a mammal by administering a compound of the invention.
The invention relates to compounds of the Formula I:
wherein
R
1
is R
8
—R
9
;
R
8
is selected from alkyl of 1-7 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, (CH
2
)
t
S(═O)
2
, and (CH
2
)
n
C(═O);
t
is 1-7;
n
is 0-8;
R
9
is selected from phenyl, cycloalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O,
wherein R
9
may be substituted with alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, halogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or Q—(CH
2
)
n
R
10
;
Q
is selected from NR
33
, NH, S and O;
R
10
is selected from cycloalkyl of 3-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, cycloalkenyl of 5-9 carbon atoms, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O;
R
33
is selected from alkyl of 1-8 carbon atoms, alkenyl of 1-8 carbon atoms and alkynyl of 1-8 carbon atoms;
X
is selected from NR
33
, NH, O, and S;
R
2
is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, and (CH
2
)
n
S(═O)
2
R
11
;
R
11
is selected from aryl of 5-14 carbon atoms and heteroaryl of 3-11 carbon atoms and 1-2 heteroatoms selected from N, S and O, with the proviso that R
11
is not isoxazole,
wherein R
11
may be substituted with alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or halogen;
R
3
is selected from:
(a) R
12
—R
13
, wherein
R
12
is selected from alkyl of 1-7 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, and C(═O), and
R
13
is selected from cycloalkyl of 3-7 carbon atoms, cycloalkenyl of 5-9 carbon atoms, heterocycloalkyl of 3-8 carbon atoms and 1-2 heteroatoms selected from N, S and O, and heterocycloalkenyl of 3-8 carbon atoms and 1-2 hetero atoms selected from N, S and O,
wherein R
13
may be substituted with alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1-8 carbon atoms and a number of halogen atoms up to the perhalo level, or halogen; or
(b) cycloalkyl of 3-9 carbon
Baryza Jeremy L.
Bullock William H.
Campbell Ann-Marie
Carley William
Coish Philip D. G.
Brink Robert H.
Powers Fiona T.
SmithKline Beecham Corporation
LandOfFree
Substituted indoles, pharmaceutical compounds containing... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted indoles, pharmaceutical compounds containing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted indoles, pharmaceutical compounds containing... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3262680