Amino acid phenoxy ethers

Details Amino acid phenoxy ethers Amino acid phenoxy ethers

2003-01-31

2004-09-21

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S376000, C548S183000, C548S227000

Reexamination Certificate

active

06794401

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel amino acid phenyl ethers for the treatment of immunological diseases, inflammation, obesity, hyperlipidemia, hypertension, neurological diseases and diabetes.
BACKGROUND OF THE INVENTION
The principal elements of the immune system are macrophages or antigen-presenting cells, T cells and B cells. The role of other immune cells such as NK cells, basophils, mast cells and dendritic cells are known, but their role in primary immunologic disorders is uncertain. Macrophages are important mediators of both inflammation and providing the necessary “help” for T cell stimulation and proliferation. Most importantly macrophages make IL 1, IL 12 and TNF-&agr; all of which are potent pro-inflammatory molecules and also provide help for T cells. In addition, activation of macrophages results in the induction of enzymes, such as cyclooxygenase II (COX-2), inducible nitric oxide synthase (iNOS) and production of free radicals capable of damaging normal cells. Many factors activate macrophages, including bacterial products, superantigens and interferon gamma (IFN &ggr;). It is believed that phosphotyrosine kinases (PTKs) and other undefined cellular kinases are involved in the activation process.
Cytokines are molecules secreted by immune cells that are important in mediating immune responses. Cytokine production may lead to the secretion of other cytokines, altered cellular function, cell division or differentiation. Inflammation is the normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality. The cytokine tumor necrosis factor-alpha (TNF-&agr;) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory disease. TNF-&agr; is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-&agr; participates in the protective inflammatory response by activating leukocytes and promoting their migration to extravascular sites of inflammation (Moser et al., J Clin Invest, 83:444-55, 1989). At higher concentrations, TNF-&agr; can act as a potent pyrogen and induce the production of other pro-inflammatory cytokines (Haworth et al., Eur J Immunol, 21:2575-79, 1991; Brennan et al., Lancet, 2:244-7, 1989). TNF-&agr; also stimulates the synthesis of acute-phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF-&agr; mediates the cytokine cascade that leads to joint damage and destruction (Arend et al., Arthritis Rheum, 38:151-60, 1995). Inhibitors of TNF-&agr;, including soluble TNF receptors (etanercept) (Goldenberg, Clin Ther, 21:75-87, 1999) and anti-TNF-&agr; antibody (infliximab) (Luong et al., Ann Pharmacother, 34:743-60, 2000), have recently been approved by the U.S. Food and Drug Administration (FDA) as agents for the treatment of rheumatoid arthritis.
Elevated levels of TNF-&agr; have also been implicated in many other disorders and disease conditions, including cachexia, septic shock syndrome, osteoarthritis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis etc.
Excessive production of IL-6 is implicated in several disease states, it is highly desirable to develop compounds that inhibit IL-6 secretion.
The cytokine IL-1&bgr; also participates in the inflammatory response. It stimulates thymocyte proliferation, fibroblast growth factor activity, and the release of prostaglandin from synovial cells.
Elevated or unregulated levels of the cytokine IL-1&bgr; have been associated with a number of inflammatory diseases and other disease states, including but not limited to adult respiratory distress syndrome, allergy, Alzheimer's disease etc.
Since overproduction of IL-1&bgr; is associated with numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL-1&bgr;.
It will be appreciated from the foregoing that, while there have been extensive prior efforts to provide compounds for inhibiting, for example, TNF-&agr;, IL-1, IL-6, COX-2 or other agents considered responsible for immune response, inflammation or inflammatory diseases, e.g. arthritis, there still remains a need for new and improved compounds for effectively treating or inhibiting such diseases.
There appears to be a correlation of TNF-&agr; to adipogenesis (obesity) and other metabolic disorders such as diabetes mellitus. Although, in the past two decades there has been an explosive increase in number of people diagnosed with diabetes worldwide [Amos A., McCarty, D., Zimmet, P. (1997) Diabetic Med. 14, S1-S85; King, H., Aubert, R., Herman, W. (1998) Diabetes Care, 21, 1414-1431], there has been relatively little development of new therapeutics for the treatment of diabetes and its associated conditions [Moller, D. E. (2001) Nature 414, 821-827]. Diabetes exists in two types: insulin dependent Type-I and non-Insulin dependent (insulin-resistant) Type-I. Type-II insulin-resistant diabetes mellitus accounts for 90-95% of all diabetes. This syndromic metabolic disorder currently affects more than 150 million people worldwide and is projected to grow to 300 million by year 2005 [Amos, A., McCarty, D., Zimmet, P. (1997) Diabetic Med. 14, S1-S85; Kopelman, P. G. Hitaman, G. A. (1998) Lancet, 352, SIV5). The main force driving this increase in incidence of type II diabetes is an increase in obesity, the single most important contribution to the pathogenesis of type II diabetes [Kopelman, P. G., Hitaman, G. A. (1998) Lancet, 352, SIV5].
At present, therapy for type II diabetes relies mainly on several approaches intended to reduce the hyperglycemia itself. These are: sulfonylureas and related insulin secretogens that are known to release more insulin from pancreatic &bgr; cells; metformin, that acts to reduce hepatic glucose production; peroxisome proliferator-activated receptor (PPAR) agonists that enhances insulin action; a-glucosidase inhibitors that slow down absorption of glucose from the gut; and insulin itself, that suppresses glucose production and augments glucose utilization (summarized in table I below). All of these therapies have limited efficacy, limited tolerability and significant mechanism-based side effects. Of particular concern is the tendency for most treatment to enhance body weight gain. Several current treatments for type II diabetes are associated with episodes of hypoglycemia, and few of the available therapies adequately address underlying defects such as obesity and a phenomenon known as insulin resistance. Among these oral medications, sulfonylureas represent the oldest and widely used form of treatment. Many patients who respond to sulfonylureas initially become refractory to the treatment over time (secondary failure). Besides glucose level and obesity, type II diabetes is now linked with high level of triglycerides and cholesterol. Therefore, there is a need for new classes of drugs addressing the underlying issue of metabolic defects (increasingly known as Syndrome-X) such as obesity, hyperglycemia and hyperlipidemic conditions to address type II diabetes and its associated condition.
TABLE 1
Current Therapeutic agents for Type II Diabetes
Deli-
Target Site
Adverse
Drug class
very
Molecular
of Action
Events
Insulin
Intra-
Insulin
Liver, Muscle,
Weight gain
mus-
receptor
Fat
Hypoglycemia
cular
Sulfonylureas
Oral
SU receptors
Pancreatic &bgr;
Weight gain
(glibenclamide)
K+/
cells
Hypoglycemia
(repaglinide)
ATP channel
(nateglinide)
Metformin
Oral
Unknown
Liver (muscle)
GI disturbance
(biguanides)
Lactic acidosis
&agr;-Glucosidase
Oral
&agr;-Gluco-
Intestine
GI disturbance
Inhibitors
sidase
(Acarbose)
PPAR-agonist
Oral
PPAR-
Fat, Muscle,
Weight gain
(Rosiglitazone)
gamma
Liver
Anaemia
(Pioglitazone)
Oedema
SUMMARY OF THE INVENTION
The present invention, relates to novel amino acid phenyl ethers of formula (I)
their derivatives, their analogs, the

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