Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-20
2001-03-13
Rotman, Alan L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S294000, C546S295000, C514S345000, C514S351000
Reexamination Certificate
active
06200995
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
The invention described herein was not made with the aid of any federally sponsored grants.
1. Field of the Invention
The present invention relates to compounds that modulate the PPAR&ggr; receptor and are useful in the diagnosis and treatment of type II diabetes (and complications thereof) and inflammatory disorders.
2. Background of the Invention
The peroxisome proliferator-activated receptors (PPARs) are transducer proteins belonging to the steroid/thyroid/retinoid receptor superfamily. The PPARs were originally identified as orphan receptors, without known ligands, but were named for their ability to mediate the pleiotropic effects of fatty acid peroxisome proliferators. These receptors function as ligand-regulated transcription factors that control the expression of target genes by binding to their responsive DNA sequence as heterodimers with RXR. The target genes encode enzymes involved in lipid metabolism and differentiation of adipocytes. Accordingly, the discovery of transcription factors involved in controlling lipid metabolism has provided insight into regulation of energy homeostasis in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes and dyslipidemia.
PPAR&ggr; is one member of the nuclear receptor superfamily of ligand-activated transcription factors and has been shown to be expressed in an adipose tissue-specific manner. Its expression is induced early during the course of differentiation of several preadipocyte cell lines. Additional research has now demonstrated that PPAR&ggr; plays a pivotal role in the adipogenic signaling cascade. PPAR&ggr; also regulates the ob/leptin gene which is involved in regulating energy homeostasis, and adipocyte differentiation which has been shown to be a critical step to be targeted for anti-obesity and diabetic conditions.
In an effort to understand the role of PPAR&ggr; in adipocyte differentiation, several investigators have focused on the identification of PPAR&ggr; activators. One class of compounds, the thiazolidinediones, which were known to have adipogenic effects on preadipocyte and mesenchymal stem cells in vitro, and antidiabetic effects in animal models of non-insulin-dependent diabetes mellitus (NIDDM) were also demonstrated to be PPAR&ggr;-selective ligands. More recently, compounds that selectively activate murine PPAR&ggr; were shown to possess in vivo antidiabetic activity in mice.
Despite the advances made with the thiazolidinedione class of antidiabetes agents, unacceptable side effects have limited their clinical use. Accordingly, there remains a need for potent, selective activators of PPAR&ggr; which will be useful for the treatment of NIDDM and other disorders related to lipid metabolism and energy homeostasis. Still further, compounds that block PPAR&ggr; activity would be useful for interfering with the maturation of preadipocytes into adipocytes and thus would be useful for the treatment of obesity and related disorders associated with undesirable adipocyte maturation. Surprisingly, the present invention provides compounds that are useful as activators as well as antagonists of PPAR&ggr; activity and compositions containing them, along with methods for their use.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention provides methods of modulating conditions which are mediated by PPAR&ggr;. The methods typically involve contacting the host with a PPAR&ggr;-modulating amount of a compound having the formula:
in which the symbol Ar
1
represents an aryl group; the letter X represents a divalent linkage selected from the group consisting of —(C
1
-C
6
)alkylene, —(C
1
-C
6
)alkylenoxy, —O—, —C(O)—, —N(R
11
)—, —N(R
11
)C(O)—, —S(O)
k
— and a single bond, in which R
11
is a member selected from the group consisting of hydrogen, alkyl, heteroalkyl and arylalkyl and the subscript k is an integer of from 0 to 2. The letter Y, in the above formula represents a divalent linkage selected from the group consisting of alkylene, —O—, —C(O)—, —N(R
12
)—S(O)
m
—, —N(R
12
)—S(O)
m
—N(R
13
)—, —N(R
12
)C(O)—, —S(O)
n
—, a single bond, and combinations thereof in which R
12
and R
13
are members independently selected from the group consisting of hydrogen, alkyl, heteroalkyl and arylalkyl; and the subscripts m and n are independently integers of from 0 to 2.
The symbol R
1
represents a member selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, —CO
2
R
14
, —C(O)R
14
, —C(O)NR
15
R
16
, —S(O)
p
—R
14
, —S(O)
q
—NR
15
R
16
, —O—C(O)—OR
17
, —O—C(O)—R
17
, —O—C(O)—NR
15
R
16
, —N(R
14
)—C(O)—NR
15
R
16
, —N(R
14
)—C(O)—R
17
and —N(R
14
)—C(O)—OR
17
, in which R
14
is a member selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and arylalkyl, and R
15
and R
16
are members independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, and arylalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring. The symbol R
17
represents a member selected from the group consisting of alkyl, heteroalkyl, aryl and arylalkyl. Additionally, for the R
1
groups described above, the subscript p is an integer of from 0 to 3, and the subscript q is an integer of from 1 to 2.
The symbol R
2
represents a member selected from the group consisting of alkyl, heteroalkyl, aryl and arylalkyl.
In another aspect, the present invention provides compounds of the formula above, as well as pharmaceutical compositions containing the compounds described above.
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Chen Jin-Long
Cushing Timothy D.
De la Brouse-Elwood Fabienne
Flygare John A.
Houze Jonathan B.
Rotman Alan L.
Townsend and Townsend / and Crew LLP
Tularik Inc.
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