Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-06-09
2004-05-04
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S262200, C548S269400
Reexamination Certificate
active
06730690
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase Type I (11&bgr;-HSD-1 or HSD-1), and methods of treatment using such compounds. The compounds are useful for the treatment of diabetes, such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, lipid disorders and other diseases and conditions.
BACKGROUND OF THE INVENTION
Diabetes is caused by multiple factors and is most simply characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state. There are two generally recognized forms of diabetes: type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), in which patients produce little or no insulin, the hormone which regulates glucose utilization, and type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), wherein patients produce insulin and even exhibit hyperinsulinemia (plasma insulin levels that are the same or even elevated in comparison with non-diabetic subjects), while at the same time demonstrating hyperglycemia. Type 1 diabetes is typically treated with exogenous insulin administered via injection. However, type 2 diabetics often develop “insulin resistance”, such that the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, namely, muscle, liver and adipose tissues, is diminished. Patients who are insulin resistant but not diabetic have elevated insulin levels that compensate for their insulin resistance, so that serum glucose levels are not elevated. In patients with NIDDM, the plasma insulin levels, even when they are elevated, are insufficient to overcome the pronounced insulin resistance, resulting in hyperglycemia.
Insulin resistance is primarily due to a receptor binding defect that is not yet completely understood. Resistance to insulin results in insufficient activation of glucose uptake, diminished oxidation of glucose and storage of glycogen in muscle, inadequate insulin repression of lipolysis in adipose tissue and inadequate glucose production and secretion by the liver.
Persistent or uncontrolled hyperglycemia that occurs in diabetics is associated with increased morbidity and premature and mortality. Abnormal glucose homeostasis is also associated both directly and indirectly with obesity, hypertension and alterations in lipid, lipoprotein and apolipoprotein metabolism. Type 2 diabetics are at increased risk of cardiovascular complications, e.g., atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
Many patients who have insulin resistance but have not developed type 2 diabetes are also at a risk of developing symptoms referred to as “Syndrome X”, or the “metabolic syndrome”. Syndrome X is characterized by insulin resistance, along with abdominal obesity, hyperinsulinemia, high blood pressure, low HDL and high VLDL. These patients, whether or not they develop overt diabetes mellitus, are at increased risk of developing the cardiovascular complications listed above.
Treatment of type 2 diabetes typically includes physical exercise and dieting. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic &bgr;-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate insulin-resistant tissues. However, dangerously low levels of plasma glucose can result, and an increased level of insulin resistance can ultimately occur.
Biguanides increase insulin sensitivity, resulting in some correction of hyperglycemia. However, many biguanides, e.g., phenformin and metformin, cause lactic acidosis, nausea and diarrhea.
The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) form a newer class of compounds with the potential for ameliorating hyperglycemia and other symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue, resulting in partial or complete correction of the elevated plasma levels of glucose substantially without causing hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR) gamma subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the glitazones. Newer PPAR agonists that are being developed for treatment of Type 2 diabetes and/or dyslipidemia are agonists of one or more of the PPAR alpha, gamma and delta subtypes.
There is a continuing need for new methods of treating diabetes and related conditions. The present invention meets this and other needs.
SUMMARY OF THE INVENTION
The present invention relates to a compound represented by Formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A and B may be taken separately or together;
when taken separately,
A represents halo, C
1-6
alkyl, OC
1-6
alkyl or phenyl, said alkyl, phenyl and the alkyl portion of OC
1-6
alkyl being optionally substituted with 1-3 halo groups; and
B represents represents H, halo, C
1-6
alkyl, —OC
1-6
alkyl, —SC
1-6
alkyl, C
2-6
alkenyl, phenyl or naphthyl, said alkyl, alkenyl, phenyl, naphthyl, and the alkyl portions of —OC
1-6
alkyl and —SC
1-6
alkyl being optionally substituted with 1-3 groups selected from halo, OH, CH
3
O, CF
3
and OCF
3
; and
when taken together,
A and B together represents (a) A
1-4
alkylene optionally substituted with 1-3 halo groups, and 1-2 R
a
groups wherein R
a
represents C
1-3
alkyl, OC
1-3
alkyl, C
6-10
arC
1-6
alkylene or phenyl optionally substituted with 1-3 halo groups, or (b) C
2-5
alkanediyl such that they form a 3-6 membered ring with the carbon atom to which they are attached, said ring optionally containing 1 double bond or 1-2 heteroatoms selected from O, S and N, said 3-6 membered ring being optionally substituted with C
1-4
alkylene, oxo, ethylenedioxy or propylenedioxy, and being further optionally substituted with 1-4 groups selected from halo, C
1-4
alkyl, haloC
1-4
alkyl, C
1-3
acyl, C
1-3
acyloxy, C
1-3
alkoxy, C
1-6
alkylOC(O)—, C
2-4
alkenyl, C
2-4
alkynyl, C
1-3
alkoxyC
1-3
alkyl, C
1-3
alkoxyC
1-3
alkoxy, phenyl, CN, OH, D, NH
2
, NHR
a
and N(R
a
)
2
wherein R
a
is as previously defined;
each R
1
represents H or is independently selected from the group consisting of: OH, halo, C
1-10
alkyl, C
1-6
alkoxy and C
6-10
aryl, said C
1-10
alkyl, C
6-10
aryl and the alkyl portion of C
1-6
alkoxy being optionally substituted with 1-3 halo, OH, OC
1-3
alkyl, phenyl or naphthyl groups, said phenyl and naphthyl being optionally substituted with 1-3 substituents independently selected from halo, OCH
3
, OCF
3
, CH
3
, CF
3
and phenyl, wherein said phenyl is optionally substituted with 1-3 halo groups,
or two R
1
groups taken together represent a fused C
5-6
alkyl or aryl ring, which may be optionally substituted with 1-2 OH or R
a
groups, wherein R
a
is as defined above;
R
2
and R
3
are taken together or separately;
when taken together, R
2
and R
3
represent (a) a C
3-8
alkanediyl forming a fused 5-10 membered non-aromatic ring optionally interrupted with 1-2 double bonds, and optionally interrupted by 1-2 heteroatoms selected from O, S and N; or (b) a fused 6-10 membered aromatic monocyclic or bicyclic group, said alkanediyl and aromatic monocyclic or bicyclic group being optionally substituted with 1-6 halo atoms, and 1-4 of OH, C
1-3
alkyl, OC
1-3
alkyl, haloC
1-3
alkyl, haloC
1-3
alkoxy, and phenyl, said phenyl being optionally substituted with 1-4 groups independently selected from halo, C
1-3
alkyl, OC
1-3
alkyl, and said C
1-3
alkyl and the C
1-3
alkyl portion of OC
1-3
alkyl being optionally substituted with 1-3 halo groups;
when tak
Balkovec James M.
Olson Steven H.
Zhu Yuping
Durette Philippe L.
Merck & Co. , Inc.
Ramsuer Robert W.
Winokur Melvin
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