Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-30
2004-08-03
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S311000, C514S312000, C514S313000, C514S314000, C544S238000, C546S153000, C546S159000, C546S160000, C546S161000, C546S168000
Reexamination Certificate
active
06770648
ABSTRACT:
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
The invention described herein was not made with the aid of any federally sponsored grants.
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), 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 plelotropic 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.
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 a substituted or unsubstituted aryl group; the letter X represents a divalent linkage selected from substituted or unsubstituted (C
1
-C
6
)alkylene, substituted or unsubstituted (C
1
-C
6
)alkylenoxy, substituted or unsubstituted (C
1
-C
6
)alkylenamino, substituted or unsubstituted (C
1
-C
6
)alkylene-S(O)
k
, —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 hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)heteroalkyl and aryl(C
1
-C
4
)alkyl 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 substituted or unsubstituted (C
1
-C
6
)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 hydrogen, substituted or unsubstituted (C
1
-C
8
)alkyl, substituted or unsubstituted (C
2
-C
8
)heteroalkyl and substituted or unsubstituted aryl(C
1
-C
4
)alkyl; and the subscripts m and n are independently integers of from 0 to 2.
The symbol R
1
represents a member selected from hydrogen, halogen, cyano, nitro, (C
1
-C
8
)alkyl, (C
1
-C
8
)alkoxy, —CO
2
R
14
, —C(O)NR
15
R
16
, —C(O)R
14
, —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 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 members independently selected from hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)heteroalkyl, aryl, and aryl(C
1
-C
4
)alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; and R
17
is a member selected from hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)heteroalkyl, aryl and aryl(C
1
-C
4
)alkyl. In each of the descriptions of, for example, alkyl, alkoxy and heteroalkyl, the groups can be substituted or unsubstituted.
The symbol R
2
represents a substituted or unsubstituted aryl group. Preferably, R
2
represents a phenyl, naphthyl, pyridazinyl or pyridyl group. More preferably, R
2
is a phenyl, naphthyl, pyridazinyl or pyridyl group substituted with from 0-3 substituents selected from halogen, —OCF
3
, —OH, —O(C
1
-C
8
)alkyl, —CN, —CF
3
, —C(O)—(C
1
-C
8
)alkyl, —(C
1
-C
8
)alkyl and —NH
2
.
The symbol R
3
represents a halogen, cyano, nitro or a substituted or unsubstituted (C
1
-C
8
)alkoxy group.
In another aspect, the present invention provides compounds of the formula above, as well as pharmaceutical compositions containing the compounds described above.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions:
The following abbreviations are used herein: PPAR&ggr;: peroxisome proliferator-activated receptor &ggr;; NIDDM: non-insulin-dependent diabetes mellitus; Et
3
N: triethylamine; MeGH: methanol; and DMSO: dimethylsulfoxide.
The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C
1
-C
10
means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkyl,” unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as “heteroalkyl,” “cycloalkyl” and “alkylene.” The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by —CH
2
CH
2
CH
2
CH
2
—. Typically, an alkyl group will have from 1 to 24 carbon atoms, with those groups having
Houze Jonathan B.
McGee Lawrence R.
Rubenstein Steven M.
Seaman D. Margaret
Townsend and Townsend / and Crew LLP
Tularik Inc.
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