Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2002-02-11
2002-10-22
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S169000, C514S179000, C552S549000, C552S550000
Reexamination Certificate
active
06468975
ABSTRACT:
This application is a 371 of PCT/EP00/02429 filed Mar. 18, 2000.
FIELD OF THE INVENTION
This invention relates to novel compounds that are liver selective glucocorticoid receptor antagonists, to methods of preparing such compounds, and to methods for using such compounds in the regulation of metabolism, especially lowering serum glucose levels.
BACKGROUND OF THE INVENTION
Glucocorticoid Receptor Antagonists
A major problem with both Type 2 and Type 1 diabetes is that there is excessive and inappropriate production of glucose by the liver. This abnormality is the primary cause of fasting hyperglycemia and occurs in addition to defects in regulation of insulin release and in peripheral sensitivity to insulin. Thus, agents that decrease liver glucose production would be beneficial for treating both Type 2 and also Type 1 diabetes.
Intensive treatment of the hyperglycemia of Type 1 diabetes mellitus has been shown to markedly decrease the development of ocular, renal and neuropathic complications, and there is evidence that intensive treatment is also beneficial for Type 2 diabetes. The available data also indicate that most patients are currently not receiving ideal and state-of-the-art treatment for either Type 2 or Type 1 diabetes. This inadequacy exists in spite of the availability of several different types of preparations of insulin for treatment of both Type 2 and Type 1 diabetes, and of a number of additional modalities, including agents that stimulate insulin release (e.g., sulfonylureas), influence liver glucose production (e.g., metformin), affect the sensitivity to insulin (e.g., troglitazone) and glucose absorption (e.g., a-glucosidase inhibitors). In spite of the availabilitn of several different orally active agents that lower blood glucose levels, many patients with Type 2 diabetes also require insulin for control of their blood sugar levels. Overall, insulin usage in Type 2 diabetes exceeds that for Type 1 diabetes, and there is general agreement that there is a need for additional oraily active agents to treat Type 2 diabetes.
The glucocorticoid secretions of the adrenal gland (dominantly cortisol in humans) were so-named because of their ability to regulate glucose metabolism. These steroids stimulate the production of glucose in the liver by promoting gluconeogenesis, which is the biosynthesis or new glucose (i.e. not glucose from glycogen). Thus, in glucocorticoid insufficiency there is a tendency to hypoglycemia, Wvith decreased liver glucose production. Further development of Addison's disease in the diabetic generally leads to lowered glucose levels. Conversely, glucocorticoid excess can Drovoke frank diabetes in individuals with latent diabetes mellitus, and generaily aggravates glycemic control in established diabetics. Similar influences have been observed in various animal models.
The increased glucose production in response to glucocorticoids is due to effects on a number of proteins. Important among these are effects on various transaminases that convert amino acids to glucose precursors, and induction of glucose-6 phosphatase and phosphoenolpyruvate carboxy-kinase (PEPCK). Even a modest increase of PEPCK, as obtained in transgenic mice, gives rise to hyperglycemia. In mice with Type 2 diabetes and increased levels of corticosterone (the endogenous glucocorticoid of that species) there is increased expression of PEPCK. This over expression of PEPCK can be repressed by treatment with the GR antagonist RU486 with a concomitant decrease in the hyperglycemia.
The considerations outlined above indicate that if actions of endogenous glucocorticoids on liver glucose production could be blocked in a specific manner, glycemic control could be improved for the benefit of the diabetic patients. However, to date, all means to block glucocorticoid action have been general. Thus, adrenalectomy leaves the patient with frank adrenal insufficiency and the problems of Addison's disease. Blockade of adrenal steroid production, for example by metyrapone, or of glucocorticoid action, for example with RU486 is ordinarily of limited duration of effectiveness and when it is effective also results in generalized adrenal insufficiency. Long term, compensatory ACTH hypersecretion and increased cortisol release that override the block generally overcome these treatments. By contrast, a liver-specific GR antagonist would not have these problems, should counter-act the increased liver glucose production in diabetes mellitus and should be useful for treatment of Type 2 diabetes.
A liver selective GR antagonist offers a number of advantages. First, it would decrease liver glucose production. This action will have a significant effect on glycemic control. In fact, excessive liver glucose production can be the major defect in Type 2 diabetes. Secondly, such a drug should enhance insulin sensitivity because of the overall improvement in the metabolic milieu and the amelioration of the hyperglycemia-induced defects in insulin action and secretion. The decreased demand on &bgr;-cell secretion, as a result of a reduction in glycemia, would retard the progressive &bgr;-cell dvsfunction characteristic of Type 2 diabetes. Another advantage of GR antagonist treatment compared with sulfonylurea or insulin treatment is that the patient would run a lower risk of hypoglycemia.
Previous efforts to block glucocorticoid action in diabetes have been hampered by the fact that any compounds used would generally block glucocorticoid action in all tissues and would lead to the potential problems of glucocorticoid insufficiency, such as hypotension, shock and uitimately death if the organism is exposed to sufficiently strong stress conditions. In contrast, a liver-selective GR-antagonist with minimal effects outside the liver could be used as a front line therapy for Type 2 diabetes, or could be used in conjunction with other existing therapies.
A strategy for obtaining liver selective compounds is to conjugate them with a bile acid such as cholate. This strategy has been recently reviewed by Kramer and Wess (Kramer, W.; Wess, G.; “Bile acid transport systems as pharmaceutical targets”;
Eur. J. Clin. Invest
. 1996, 26, 715-732). For example, bile acid conjugates have been prepared wvith the thyroid hormone T; and with HNIG-CoA reductase inhibitors. Both classes of conjugates were shown to reduce serum cholesterol levels while minimizing undesirable peripheral effects. These results demonstrate that bile acid conjugates are liver selective and are capable of delivering therapeutically useful concentrations of drug to the liver. An intriguing aspect of bile acid conjugates is that they are absorbed, excreted, and re-absorbed up to 12 times. Therefore bile acids represent an extremely efficient sustained release delivery mechanism.
While the bile acid conjugate strategy has previously been applied to several classes of drugs, it has not previously been applied to glucocorticoid ligands. For a glucocorticoid bile acid conjugate to be effective, it must maintain high affinity for both the glucocorticoid receptor and bile acid transporters and means to achieve this are non-obvious to those skilled in-the-art.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, compounds are provided which are glucocorticoid ligands, and have the general formula I:
in which:
R is a hydrogen atom, an aliphatic hydrocarbon, an aromatic hydrocarbon, carboxylic acid or ester thereof, alkenyl carboxylic acid or ester thereof, hydroxy, halogen, or cyano halogen, or cyano, or a pharmaceutically acceptable salt thereof;
W is a methine carbon atom (CH) having the R, S, or racemic stereocheristrv;
X and Z are the same or are different and are a bond, an amide (—CONR′— or —NR′CO—), an amine (—NR′—), an ether (—O—), or a thioether (—S—) and R′ is a hydrogen atom, an aliphatic hydrocarbon, or an aromatic hydrocarbon;
The subscripts n, o are the same or are different and are intergrers from one (1) to six (6), and mn in an integer from zero (0) to six (6);
Y is hydroxyl group, carboxylic
Apelqvist Theresa
Koehler Konrad
Wu Jinchang
Badio Barbara P.
Garabedian Todd E.
Karo Bio AB
Wiggin & Dana LLP
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