Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-27
2003-06-24
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S367000, C546S153000, C548S169000
Reexamination Certificate
active
06583157
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds that modulate the PAPAR&ggr; receptor and are useful in the diagnosis and treatment of type II diabetes (and complications thereof), hypercholesterolemia (and related disorders associated with abnormally high or low plasma lipoprotein or triglyceride levels) and inflammatory disorders.
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.
PAPAR&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 PAPAR&ggr; plays a pivotal role in the adipogenic signaling cascade. PAPAR&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 PAPAR&ggr; in adipocyte differentiation, several investigators have focused on the identification of PAPAR&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 PAPAR&ggr;-selective ligands. More recently, compounds that selectively activate murine PAPAR&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 PAPAR&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 PAPAR&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 PAPAR&ggr; activity, compositions containing them and methods for their use.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides methods of treating or preventing a metabolic disorder or an inflammatory condition. The methods typically involve administering to a subject in need thereof a therapeutically effective amount of a compound having the formula (I):
in which the symbol Ar
1
represents substituted or unsubstituted 2-benzothiazolyl or substituted or unsubstituted quinolinyl; X is a divalent linkage selected from —O—, —C(O)—, —CH(R
10
)—, —N(R
11
)—, and —S(O)
k
—, wherein R
10
is selected from hydrogen, cyano and (C
1
-C
4
)alkyl, R
11
is selected from hydrogen and (C
1
-C
8
)alkyl, and the subscript k is an integer of from 0 to 2; with the proviso that when Ar
1
is a substituted or unsubstituted 2-benzothiazolyl, then X is other than —S(O)
k
—.
The letter Y represents a divalent linkage having the formula —N(R
12
)—S(O)
2
—, wherein R
12
is hydrogen or (C
1
-C
8
)alkyl.
The symbol R
1
represents hydrogen, (C
2
-C
8
)heteroalkyl, halogen, (C
1
-C
8
)alkyl, (C
1
-C
8
)alkoxy, —C(O)R
14
, —CO
2
R
14
, —C(O)NR
15
R
16
, —S(O)
p
—R
14
, —S(O)
q
—NR
15
R
16
, —O—C(O)—R
17
or —N(R
14
)—C(O)—R
17
; wherein R
14
is selected from hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)heteroalkyl, aryl and aryl(C
1
-C
4
)alkyl; R
15
and R
16
are independently selected from hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)heteroalkyl, aryl, and aryl(C
1
-C4)alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R
17
is selected from (C
1
-C
8
)alkyl, (C
2
-C
8
)heteroalkyl, aryl and aryl(C
1
-C
4
)alkyl; the subscript p is an integer of from 0 to 3; and the subscript q is an integer of from 1 to 2.
R
2
is substituted or unsubstituted aryl; and
R
3
is selected from halogen and (C
1
-C
8
)alkoxy.
In another aspect, the present invention provides methods of treating or preventing a condition or disorder mediated by PAPAR&ggr; and methods for modulating PAPAR&ggr;.
In yet another aspect, the present invention provides compounds of formula I and pharmaceutical compositions containing compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
The abbreviations used herein are conventional, unless otherwise defined.
As used herein, “diabetes” refers to type I diabetes mellitus juvenile diabetes) or type II diabetes mellitus (non-insulin-dependent diabetes mellitus or NIDDM), preferably, type II diabetes mellitus.
The terms “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.
The terms “prevent”, “preventing” and “prevention” refer to a method of decreasing the probability or eliminating the possibility that a disease will be contracted.
As used herein, the term “PAPAR&ggr;-mediated condition or disorder” and the like refers to a condition or disorder characterized by inappropriate, e.g., less than or greater than normal, PAPAR&ggr; activity. A PAPAR&ggr; -mediated condition or disorder may be completely or partially mediated by inappropriate PAPAR&ggr; activity. However, a PAPAR&ggr;-mediated condition or disorder is one in which modulation of PAPAR&ggr; results in some effect on the underlying condition or disease (e.g., a PAPAR&ggr; antagonist results in some improvement in patient well-being in at least some patients). Exemplary PAPAR&ggr;-mediated conditions and disorders include metabolic disorders, e.g., diabetes, obesity, hyperglycemia, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia and dyslipidemia, and inflammatory conditions, e.g., rheumatoid arthritis and atherosclerosis.
The term “modulate” refers to the ability of a compound to increase or decrease the function, or activity, of PAPAR&ggr;. Modulation, as described herein, includes the inhibition or activation of PAPAR&ggr;, either directly or indirectly. Inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction, e.g., antagonists. Activators are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, sensitize or up regulate signal transduction, e.g., agonists.
The term “therapeutically effective amount” refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
The term “subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
The term “alky
Furukawa Noboru
Hagiwara Atsushi
Houze Jonathan B.
McGee Lawrence R.
Rubenstein Steven M.
Townsend and Townsend / and Crew LLP
Tularik Inc.
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