Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-11
2003-04-01
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S369000, C546S269700, C548S187000, C548S183000
Reexamination Certificate
active
06541492
ABSTRACT:
The present invention relates to compounds that bind to and affect PPAR gamma. In another aspect, the present invention relates to methods for prevention or treatment of PPARgamma mediated diseases and conditions and to a method for prevention or treatment of osteoporosis.
Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example, Willson, T. M. and Wahli, W.,
Curr. Opin. Chem. Biol
., (1997), Vol. 1, pp 235-241.
Three mammalian PPARs have been identified which are termed PPAR-alpha, PPAR-gamma, and PPAR-delta. PPARs regulate expression of target genes by binding to DNA response elements as heterodimers with the retinoid X receptor. These DNA response elements (PPRE) 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. See, for example, Spiegelman, B. M.,
Diabetes
, (1998), Vol. 47, pp 507-514, Schoonjans, K., Martin, G., Staels, B., and Auwerx, J.,
Curr. Opin. Lipidol
., (1997), Vol. 8, pp 159-166, and Brun, R. P., Kim, J. B., Hu, E., and Spiegelman, B. M.,
Curr. Opin. Lipidol
., (1997), Vol. 8, pp 212-218.
PPAR-gamma ligands of the thiazolidinedione class (TZD) enhance the actions of insulin in man and reduce circulating glucose levels in rodent models of diabetes. The PPAR-gamma receptor is expressed in adipose tissue and plays a pivotal role the regulation of adipocyte differentiation in vitro. TZD such as rosiglitazone induce adipocyte differentiation in vitro through activation of the PPAR-gamma receptor. Thus, although there are clearly therapeutic uses for PPAR-gamma 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-gamma 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-gamma ligand in the treatment of diabetes or other diseases where obesity is a risk factor. See, for example, the Spiegelman and Brun articles cited above.
Essential dietary fatty acids and certain of their eicosanoid metabolites are naturally occurring hormones for the PPAR-gamma receptor. These hormones can promote adipogenesis through activation of the PPAR-gamma receptor. See, for example, Kliewer, S. A., et al.,
Proc. Natl. Acad. Sci. USA
, (1997), Vol. 94, pp 4318-4323, and Kliewer, S. A., et al.,
Cell
, (1995), Vol. 83, pp 813-819. Molecules that inhibit the adipogenic effects of endogenous PPAR-gamma hormones may be useful in the treatment of diseases caused by increased fat accumulation or lipid storage. See, for example, Tontonoz, P., Hu, E., and Spiegelman, B. M.,
Curr. Opin. Genet. Dev
., (1995), Vol. 5, pp 571-576. Examples of these diseases are obesity, osteoporosis, and acne. For example, it has also been noted that TZD promote adipogenesis in bone marrow and inhibit expression of markers of the osteoblast phenotype such as alkaline phosphatase. See, for example, Paulik, M. A. and Lenhard, J. M.,
Cell Tissue Res
., (1997), Vol. 290, pp 79-87. These effects may lead to low bone mineral density and osteoporosis. Compounds that promote osteogenesis activity may be useful in the treatment of osteoporosis. Similarly, it is known that the TZDs can promote lipid accumulation in sebocytes. See, for example, Rosenfield, R. L., Deplewski, D., Kentsis, A., and Ciletti,
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-gamma receptor has been found in tissues other than adipose, and it is believed that synthetic PPAR-gamma ligands and natural PPAR-gamma hormones (natural ligands) may have beneficial effects in many other diseases including cardiovascular disease, inflammation, and cancer. See, for example, the Schoonjans article cited above, Ricote, M. et al.,
Nature
, (1998), Vol. 391, pp 79-82, and Mueller, E. et al.,
Mol. Cell
, (1998), Vol. 1, pp 465-470.
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. See, for example, McDonnell, D. P.,
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. See, for example, Katzenellenbogen, J. A., O'Malley, B. W., and Katzenellenbogen, B. S.,
Mol. Endocinol
., (1996), Vol. 10, pp 119-131.
As used herein, a “PPARgamma ligand” is a compound that binds to human PPARgamma with a pKi of greater than 5 when tested in the binding assay described below. As used herein a “PPARgamma antagonist” is a PPARgamma ligand that gives greater than 50% inhibition of lipogenesis when tested in the adipocyte differentiation assay described below and greater than 50% inhibition of transactivation by rosiglitazone when tested in the cell-based reporter assay described below.
Briefly, in one aspect, the present invention discloses compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof,
where n is 2, 3, or 4,
R
1
is hexyl, heptyl, or C
4-6
alkyl-phenyl,
R
2
is butyl or benzyl optionally substituted with 1 or 2 halogen,
R
3
is butyl, benzyl optionally substituted with a trifluoromethyl group or with 1 to 3 halogen, —C
4
H
8
OH, p-pyridyl, o-pyridyl, ethylpropionate, propyl, ethyl acetate,
o-thiophenmethyl, 2,3-methylenedioxobenzyl, 2-thiazolemethyl, 2-furfuryl,
R
4
is —COOH, —NHC(O)NH
2
, —NHS(CH
3
)O
2
, —S(NH
2
)O
2
), hydantoin, —OH, —OCH
2
CO
2
H, —OCH
2
CONH
2
, —OCH
3
,
R
5
is hydrogen or R
5
and R
4
are bonded together to form a methylenedioxo ring.
In another aspect, the present invention discloses a method for prevention or treatment of a PPARgamma mediated disease or condition comprising administration of a therapeutically effective amount of a compound of this invention. As used herein, “a compound of the invention” means a compound of formula (I) or a pharmaceutically acceptable salt, or solvates thereof. Particular diseases or conditions are diabetes, obesity, dyslipidemia, metabolic syndrome, osteoporosis, acne, cardiovascular disease, inflammation or cancer.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, preferably in association with a pharmaceutically acceptable diluent or carrier.
In another aspect, the present invention discloses a method for prevention or treatment of osteoporosis comprising administration of a therapeutically effective amount of a PPARgamma antagonist.
In another aspect, the present invention provides a compound of the invention for use in therapy, and in particular, in human medicine.
In another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a PPARgamma mediated disease or condition. Particular diseases or conditions are diabetes, obesity, dyslipidemia, metabolic syndrome, osteoporosis, acne, cardiovascular disease, inflammation or cancer.
In another aspect, the present invention provides the use of a PPARgamma antagonist for the manufacture of a medicament for the treatment of osteoporosis.
In another aspect, the present invention provides a method for identifying compounds that will be useful for the treatment of a PPAR gamma mediated disease or condition, comprising the step of binding a compound of this invention to PPAR gamma.
In another aspect, the present invention provides
Collins Jon Loren
Holmes Christopher Patrick
Lenhard James Martin
Willson Timothy Mark
Brink Robert H.
Huang Evelyn Mei
SmithKline Beecham Corporation
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