Antidiabetic agents

Details Antidiabetic agents Antidiabetic agents

2003-03-17

2004-04-06

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S137000, C544S369000, C546S271400, C548S236000

Reexamination Certificate

active

06716842

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds that are useful as antidiabetic agents.
BACKGROUND OF THE INVENTION
Type II diabetes, or non-insulin dependent diabetes (NIDDM) is a significant healthcare problem whose incidence is on the rise. Between 1990 and 1998, the prevalence of NIDDM in the United States increased by 33 percent, to about 13 million persons. An additional 5 million persons are presumed to have undiagnosed NIDDM, while another 14 million persons have impaired glucose tolerance. Direct medical costs associated with diabetes were $44 billion in 1997, due mainly to hyperglycemia-related diabetic complications, including diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation, and glaucoma.
NIDDM is one of a number of disease states associated with the phenomenon of insulin resistance. Insulin resistance is defined as the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus. Insulin resistance syndrome (hereinafter IRS) refers to the cluster of manifestations that include insulin resistance; hyperinsulinemia; non insulin dependent diabetes mellitus (NIDDM); arterial hypertension; central (visceral) obesity; and dyslipidemia.
The primary goal of IRS therapy and thus diabetes therapy is to lower blood glucose levels so as to prevent acute and long-term disease complications. For some persons, modified diet and increased exercise may be a successful therapeutic option for achieving the goal of glucose control. When modified diet and increased exercise are not successful, drug therapy using oral antidiabetic agents is initiated.
To date, a number of oral antidiabetic agents have been developed. For instance, sulfonylureas are generally used to stimulate insuln. The biguanide metformin is generally used to improve insulin sensitivity and to decrease hepatic glucose output. Acarbose is used to limit postprandial hyperglycemia, Thiazolidine 2,4 diones are used to enhance insulin action.
New drug therapies for the treatment of NIDDM have focused in part on the discovery of new Peroxisome Proliferator Activation Recpetor (PPAR) agonists. PPARs are members of the nuclear receptor superfamily of transcription factors that includes steroid, thyroid, and vitamin D receptors. PPARs play a role in controlling expression of proteins that regulate lipid metabolism. There are three PPAR subtypes: PPAR&agr;, PPAR&dgr;, and PPAR&ggr;.
Each PPAR receptor shows a different pattern of tissue expression, and differences in activation by structurally diverse compounds. PPAR&ggr;, for instance, is expressed most abundantly in adipose tissue and at lower levels in skeletal muscle, heart, liver, intestine, kidney, vascular endothelial and smooth muscle cells as well as macrophages. Two isoforms of PPAR&ggr; exist, identified as &ggr;
1
and &ggr;
2
, respectively. PPAR&ggr; mediates adipocyte signalling, lipid storage, and fat metabolism. Evidence gathered to date support the conclusion that PPAR&ggr; is the primary, and perhaps the only, molecular target mediating the insulin sensitizing action of one class of antidiabetic agents, the thiazolidine 2,4 diones.
In a monotherapeutic or combination therapy context, new and established oral antidiabetic agents are still considered to have non-uniform and even limited effectiveness. The effectivieness of oral antidiabetic therapies may be limited, in part, because of poor or limited glycemic control, or poor patient compliance due to unacceptable side effects. These side effects include edema weight gain, or even more serious complications. For instance, hypoglycemia is observed in some patients taking sulfonylureas. Metformin, a substituted biguanide, can cause diarrhea and gastrointestinal discomfort. Finally, edema, weight gain, and in some cases, hepatoxicity, have been linked to the administration of some thiazolidine 2,4 dione antidiabetic agents. Combination therapy using two or more of the above agents is common, but generally only leads to incremental improvements in glycemic control.
As a result, there is a need for oral antidiabetic agents that can be used alone or in combination, and that do not give rise to side effects such as fluid retention, peripheral edema, weight gain, or more severe complications.
SUMMARY OF THE INVENTION
These and other needs are met by the current invention which is a compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
X is a tether 2 to 5 atoms in length,
wherein 0, 1, 2, or 3 of the atoms of the tether are O, S, or NR
1
, wherein R
1
is H or (C
1
-C
6
)alkyl, and wherein the other atoms are CR
2
R
3
, CR
4
═CR
5
, or C≡C, wherein R
2
and R
3
taken together are ═O, or R
2
-R
5
are each independently H or (C
1
-C
6
)alkyl;
R′ is H,
C
1
-C
7
alkyl and substituted alkyl,
C
2
-C
7
alkenyl and substituted alkenyl,
C
2
-C
7
alkynyl and substituted alkynyl,
C
3
-C
7
cycloalkyl and substituted cycloalkyl,
aryl and substituted aryl,
heterocyclic and substituted heterocyclic,
heteroaryl and substituted heteroaryl,
halo,
NO
2
,
NO,
CN,
OR
a
,
 wherein R
a
is H,
C
1
-C
7
alkyl and substituted alkyl,
C
2
-C
7
alkenyl and substituted alkenyl,
C
3
-C
7
cycloalkyl and substituted cycloalkyl,
aryl and substituted aryl,
heteroaryl and substituted heteroaryl, or
heterocycloalkyl and substituted heterocycloalkyl;
E is COR
6
, wherein R
6
is (C
1
-C
6
)alkyl, OH, (C
1
-C
6
)alkoxy, NR
7
R
8
,
wherein R
7
and R
8
are each independently H or (C
1
-C
6
)alkyl, or
one of R
7
and R
8
is H or (C
1
-C
6
)alkyl and the other is SO
2
R
9
,
wherein R
9
is H or (C
1
-C
6
)alkyl, or E is substituted heteroaryl or
What is also provided is a compound of formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R″ is H,
C
1
-C
7
alkyl and substituted alkyl,
C
2
-C
7
alkenyl and substituted alkenyl,
C
2
-C
7
alkynyl and substituted alkynyl,
C
3
-C
7
cycloalkyl and substituted cycloalkyl,
aryl and substituted aryl,
heterocyclic and substituted heterocyclic, and
heteroaryl and substituted heteroaryl;
E is COR
6
, wherein R
6
is (C
1
-C
6
)alkyl, OH, (C
1
-C
6
)alkoxy, NR
7
R
8
,
wherein R
7
and R
8
are each independently H or (C
1
-C
6
)alkyl, or
one of R
7
and R
8
is H or (C
1
-C
6
)alkyl and the other is SO
2
R
9
,
wherein R
9
is H or (C
1
-C
6
)alkyl, or E is substituted heteroaryl or
What is also provided is a compound which is:
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyridin-2-ylmethoxy)-phenyl]-propionic acid;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(hydroxy)-phenyl]-propionic acid;
3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester;
3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyridin-3-ylmethoxy)-phenyl]-propionic acid;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(methoxy)-phenyl]-propionic acid;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyridin-4-ylmethoxy)-phenyl]-propionic acid;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyridin-4-ylmethoxy)-phenyl]-propionic acid;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(phenyloxy)-phenyl]-propionic acid;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(phenyloxy)-phenyl]-propionic acid;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(cyclohexyloxy)-phenyl]-propionic acid;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(cyclohexylmethoxy)-phenyl]-propionic acid;
3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(cyclopentylmet

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