Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1997-07-31
2001-04-17
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S712000, C514S736000, C558S412000, C568S047000, C568S746000, C568S764000
Reexamination Certificate
active
06218431
ABSTRACT:
FIELD
This application claims the benefit of U.S. Provisional application No. 60/228,822.
BACKGROUND
The present invention concerns certain substituted pyridines, processes for the production thereof, and the use thereof in pharmaceutical products. It also concerns certain substituted biphenyls, processes for their production, pharmaceutical compositions containing them, and methods for their use.
7-(polysubstituted pyridyl) hept-6-enoates for the treatment of arteriosclerosis, lipoproteinemia, and hyperlipoproteinemia are known from U.S. Pat. No. 5,169,857. In addition, the production of 7-(4-aryl-3-pyridyl)-3,5-dihydroxy-hept-6-enoate is described in EP 325 130.
Glucagon is a peptide hormone whose main function is to increase hepatic glucose production. Insulin, on the other hand, functions to decrease glucose production. Together, these two hormones are necessary for maintaining a correct level of glucose in the blood.
Diabetes is a complex disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Diabetes is also associated with elevated glucagon levels. The heterogeneous nature of the disease requires different strategies to address the different abnormalities in metabolism found in affected individuals.
In the diabetic state (all forms of Type I and Type II), hyperglycemia often is associated with elevated glucagon levels. Accordingly, a means of treating all forms of diabetes is to block the glucagon receptor with a suitable antagonist, thereby inhibiting glucose production by the liver and reducing glucose levels in the patient.
Glucagon receptor antagonists, materials which block the action of endogenous glucagon, are known to have many and varied applications. Among these applications are the following:
1. Treatment of hyperglycemia associated with diabetes of any cause and associated with any other diseases or conditions. A glucagon receptor antagonist can be used either alone or in combination with any other therapies to treat hyperglycemia.
2. Treatment of impaired glucose tolerance (IGT).
3. Treatment of insulin resistance syndromes including those due to obesity, polycystic ovarian syndrome, “Syndrome X”, drugs and hormones, endocrinopathies and genetic syndromes.
4. To decrease free fatty acid levels and treat conditions associated with elevated free fatty acids levels such as insulin resistance, obesity, all or part of Syndrome X, Type I and II diabetes, hyperlipidemias and elevated hepatic glucose output associated with insulin resistance, Type I and Type II diabetes, obesity, and Syndrome X.
5. To treat conditions associated with genetic defects in insulin action due to alterations in insulin receptor structure and function or alterations in post receptor signal transduction. To treat diabetes associated with anti-insulin antibodies, drug induced diabetes, diabetes associated with endocrinopathies and diabetes associated with genetic syndromes.
6. To treat gestational diabetes mellitus.
7. To treat autoimmune and non autoimmune causes of Type I diabetes including those due to known genetic defects of the beta cell, pancreatic diseases, drug or toxin induced beta cell dysfunction, endocrinopathies, infectious causes, malnutrition associated and idiopathic Type I diabetes.
8. To prevent and treat diabetic ketoacidosis and decrease hepatic ketone body production
9. To treat hyperglycemia of exercise in diabetes.
10. To reduce fasting and postprandial glucose.
11. Treatment of insulin resistance in liver, muscle, and fat.
12. Treatment of conditions of hyperlipidemia.
13. To treat glucagonomas and all other conditions associated with elevated glucagon levels.
14. To treat conditions of increased futile cycling of glucose in the liver.
15. To increase insulin secretion.
16. To decrease glucose toxicity.
17. To decrease the renal prostaglandin response to protein and amino acids.
18. To decrease elevated GFR and albumin clearance due to diabetes or proteins or amino acids.
19. To decrease renal albumin clearance and excretion.
20. To treat acute pancreatitis.
21. To treat cardiovascular disease including causes of increased cardiac contractility.
22. To treat cardiac hypertrophy and its consequences.
23. As a diagnostic agent and as a diagnostic agent to identify patients having a defect in the glucagon receptor.
24. Treatment of gastrointestinal disorders, treatment of decreased gut motility.
25. As a therapy to increase gastric acid secretions.
26. To reverse intestinal hypomobility due to glucagon administration.
27. To reverse catabolism and nitrogen loss in states of negative nitrogen balance and protein wasting including all causes of Type I and Type II diabetes, fasting, AIDS, cancer, anorexia, aging and other conditions.
28. To treat any of the above conditions or diseases in post-operative or operative period.
29. To decrease satiety and increase energy intake.
Glucagon receptor antagonists of the prior art, such as those described in WO9518153-A and references cited therein, are predominantly peptide analogues of glucagon. They are susceptible to the actions of endogenous proteases, may precipitate antibody production and immune reactions and can be difficult and expensive to manufacture. Such peptides are usually unsuitable for oral delivery.
One non-peptide glucagon receptor antagonist has been reported (Collins, et al;
BioMed. Chem Lett.
1992, 2, 915-918). This quinoxaline derivative, CP-99,711, was shown to inhibit glucagon binding and glucagon action in rat liver membrane at micromolar concentrations.
It would be desirable to have inhibitors of CETP which possess valuable pharmacological properties that are superior to those of the state of the art. Certain of the substituted pyridine compounds of the invention are highly effective inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reverse cholesterol transport. They cause a reduction in LDL cholesterol levels in the blood, while at the same time increasing HDL cholesterol levels. They can therefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.
It would also be desirable to have readily prepared non-peptidic glucagon receptor antagonists which are metabolically more stable than peptidic antagonists of the prior art, and which afford good activity and bioavailability. Certain of the substituted pyridine compounds as well as the substituted biphenyls of the invention are highly effective inhibitors of the glucagon receptor. Accordingly, these compounds may be used to treat glucagon-mediated conditions such as those listed above.
SUMMARY
The present invention concerns substituted biaryl compounds which fall within the three general formulae (IA), (IB), and (IC) shown below. The definitions of these general formulae are given broadly in the following text. In the subsequent detailed description sections, each of these broad general formulae is discussed in more detail in terms of its preferred and most preferred molecular constituents, procedures for making, examples of particular materials made, testing procedures, and results obtained.
It should be noted that in the text below, and in the subsequent detailed description sections, the definitions of the various constituent and substituent groups apply only to the particular subset of the compounds of the invention then under consideration. The same symbols may have different definitions in connection with the other subsets of compounds.
The present invention concerns substituted pyridines of the general formula
in which
A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula —NR
1
R
2
,
wherein
R
1
and R
2
are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms,
D stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is substit
Cook, II James H.
Hertzog Donald L.
Kramss Richard H.
Ladouceur Gaetan H.
Lease Timothy G.
Bayer Corporation
Rotman Alan L.
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