Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-04
2002-04-09
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S032000, C549S035000, C549S039000
Reexamination Certificate
active
06369098
ABSTRACT:
BACKGROUND OF THE INVENTION
The peroxisome proliferator-activated receptors (PPARs) are members of the steroid/thyroid/retinoid nuclear receptor superfamily of ligand-activated transcription factors. Three subtypes of PPARs have been cloned from the mouse and human, i.e., PPAR&ggr; and PPAR&dgr;. In humans, PPAR&ggr; and PPAR&agr; are differentially expressed in organs and tissues (see, Willson et al.
J Med. Chem
. 43:527-50 (2000)).
Nuclear receptors like PPAR possess DNA binding domains (DBDs) that recognize specific DNA sequences (called response elements) located in the regulatory regions of their target genes (see, Mangelsdorf, et al.
Cell
83:835-839 (1995)); Perlmann, et al.
Cell
90:391-397 (1997)). Activation of PPARs modulates the expression of genes containing the appropriate respective perixosome proliferator response elements (PPRE) in its promoter region.
In the past, the genes regulated by PPARs were believed to be predominantly associated with lipid and glucose metabolism. Thiazolidinediones, which are a class of oral insulin-sensitizing agents that improve glucose utilization without stimulating insulin release, are selective PPAR agonists. U.S. Pat. No. 4,287,200, discloses certain thiazolidine derivatives having the ability to lower blood glucose levels. In addition, U.S. Pat. No. 4,572,912, discloses thiazolindinedione derivatives having the ability to lower blood lipid and blood glucose levels. These compounds were shown to have the ability to decrease the levels of blood lipid peroxides, blood triglycerides and blood cholesterol. A PPAR&ggr; antagonist that inhibits adipocyte differentiation has also been synthesized (see, Oberfield, et al.,
Proc Natl Acad Sci USA
96:6102-6 (1999)).
However, recent discoveries suggest that the genes regulated by PPAR receptors also play a role in other processes. Binding of ligands to PPARs induce changes in the transcriptional activity of genes that modulate inflammatory processes, angiogenesis, cellular proliferation and differentiation, apoptosis, and the activities of iNOS, MMPases and TIMPs. These findings suggest that regulation of the action of PPAR may have a therapeutic role in treating diseases such as occlusive vascular diseases (e.g. atherosclerosis), hypertension, neovascular diseases (e.g. diabetic retinopathy), inflammatory diseases (e.g. inflammatory bowel disease and psoriasis), and neoplastic diseases (carcinogenesis).
The precise contribution of each particular PPAR subtype to transcriptional activation of particular genes is difficult to predict. DNA response elements for both PPAR&agr; and PPAR&ggr; have been found in the promoter regions of a variety of genes, including a number involved in lipid and fatty acid metabolism. For example, in fetal rat brown adipocytes, expression of the uncoupling proteins UCP-1, UCP-2 and UCP-3 is controlled via both PPAR&agr; and PPAR&ggr; activation. Activation of PPAR&ggr; elicited 5- and 3-fold increases in UCP-1 and UCP-3, respectively. In contrast, activation of PPAR&agr; increased UCP-1 ten-fold, but decreased UCP-3. Interestingly, when both PPAR and were activated, a synergistic interaction occurred in regulation of UCP-3.
These differential and synergistic effects may be mediated by co-activator recruitment, suppression of co-repressor proteins, or direct interaction at the level of the PPRE (see, Teruel, et al.
Biochem Biophys Res Commun
. 273(2):560-4 (2000)). It is not known whether the nuclear receptor coactivators or corepressors identified to date are selective for particular PPAR receptors (see, Spiegelman, et al.,
Diabetes
47:507-514 (1998)). Many coactivators or corepressors have multiple modes of action and hence it is not clear which cofactors are more important for the function of any particular receptor (see, Puigserver, et al.
Science
286:1368-1371 (1999). Furthermore, the tremendous specificity of biological actions of the individual nuclear receptors (see, Spiegelman, et al.
Diabetes
47:507-514 (1998)), strongly suggests that the full spectrum of nuclear cofactors that regulate the transcriptional activity of PPAR&ggr; and/or PPAR&agr; remains to be defined.
Due to this lack of understanding of PPAR&ggr; and PPAR&agr;-related activity and mechanisms, as well as the differential expression of PPAR&ggr; and PPAR&agr; in cells, it is difficult to ascertain the potential effects of concurrent activation of PPAR gamma and alpha receptors on both cellular processes relevant to disease. For example, PPAR&agr; or PPAR&ggr; may either have similar or disparate effects. It is known that inflammatory activation of human aortic smooth-muscle cells is inhibited by PPAR&agr;, but not by PPAR&ggr;. Apoptosis in human monocyte-derived macrophages is induced by activation of either PPAR&agr; and PPAR&ggr; (see, Staels et al.
Nature
393:790-3 (1998)); Chinetti, et al.
J Biol Chem
. 273:25573-80 (1998)). However, PPAR&ggr; activation by troglitazone or 15-deoxy-&Dgr;-12-14-prostaglandin J2 protects cerebellar granule cells from cytokine-induced apoptotic cell death (see, Heneka, et al.
J Neuroimmunol
100:156-68 (1999)).
To summarize, PPAR subtypes exhibit differential patterns of tissue expression, different actions on different response elements, differential effects on co-activators and co-repressors, and differential regulation of access to the core transcriptional machinery. This complexity of PPAR regulation makes it extremely difficult to predict precisely which genes will ultimately be activated (transcribed) or inactivated (suppressed) as a result of activation by a particular combination of an agonist or an antagonist of PPAR&ggr; or PPAR&agr;. As a consequence, it is impossible to predict with certainty the way in which a tissue expressing PPAR&ggr; and PPAR&agr; may respond to a particular ligand, or whether a particular pathological state will be attenuated, arrested, accentuated or worsened by said ligand. This is especially the case in which a single ligand activates both PPAR&ggr; and PPAR&agr; to similar degrees.
In view of this complex interplay between PPAR&ggr; and PPAR&agr;, it is desirable to synthesize compounds, which bind both receptors and can take advantage of potential synergistic effects. For example, PPAR&ggr; and PPAR&agr; activation has been shown to inhibit proliferation (see, Ellis, et al.
Arch Dermatol
. 136:609-616 (2000)) and promote differentiation of epidermal keratinocytes, respectively (see, Komuves et al.
J Invest Dermatol
. 115:353-360 (2000)).
The syntheses of thiazolidine dithiolane derivatives with affinity for PPAR&ggr; have been described in WO 00/53601, published Sep. 14, 2000. Despite the advances of WO 00/53601, what is needed in the art are non-thiazolidinedione (non-TZD) dithiolane derivatives with high affinity for PPAR&ggr; that function either as PPAR&ggr; agonists, PPAR&ggr; antagonists, or mixed PPAR&ggr; agonist/antagonists. Methods to synthesize these non-TZD compounds with high affinity for both PPAR&ggr; and PPAR&dgr;, antagonists, mixed (partial) agonist/antagonists, or mixed PPAR&ggr;/PPAR&dgr; agonists are also needed. The present invention remedies such needs.
SUMMARY OF THE INVENTION
The present invention provides novel dithiolane derivatives which can be used to ameliorate PPAR&ggr;-mediated diseases such as inflammatory and proliferative diseases and those that are characterized by inappropriate activation of nuclear transcription factors.
As such, in one embodiment, the present invention provides compounds of Formula A:
In Formula A, R is a functional group including, but not limited to R or S or racemic 1,2-dithiolan-3-yl, or achiral 1,2-dithiolan-4-yl, R or S or racemic 1-(1,3-dithiopropanyl); R or S or racemic S,S′-Diacyl-[1-(1,3-dithiopropanyl)], R or S or racemic or achiral 2-(1,3-dithiopropanyl), R or S or racemic or achiral S,S′-Diacyl-[2-(1,3-dithiopropanyl)]; and optionally substituted 3R or 3S or racemic 3H-benzo[d]1,2-dithiolen-6-yl (or also named as a 3H-benzo[1,2]dithiol-6-yl) moieties. The term “diacyl” as use
Avery Mitchell A.
Pershadsingh Harrihar A.
Bethesda Pharmaceuticals, Inc.
Lambkin Deborah C.
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