Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-16
2004-03-16
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S562000, C514S567000, C514S364000, C514S417000, C514S445000, C514S452000, C514S366000, C514S381000, C514S375000, C548S481000, C548S131000, C548S180000, C548S163000, C548S151000, C548S224000, C548S253000, C549S063000, C549S365000, C549S366000, C562S430000, C562S439000
Reexamination Certificate
active
06706744
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to agents that act to antagonize the action of the glucagon peptide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists.
BACKGROUND OF THE INVENTION
Glucagon is a key hormonal agent that, in co-operation with insulin, mediates homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.
Glucagon is produced in the alpha islet cells of the pancreas and insulin in the beta islet cells. Diabetes mellitus is a common disorder of glucose metabolism. The disease is characterized by hyperglycemia and may be classified as Type 1 diabetes, the insulin-dependent form, or Type 2 diabetes, which is non-insulin-dependent in character. Subjects with Type 1 diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin. However, in some patients with Type 1 or Type 2 diabetes, absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state. Both in healthy control animals as well as in animal models of Type 1 and Type 2 diabetes, removal of circulating glucagon with selective and specific anti-bodies has resulted in reduction of the glycemic level (Brand et al., Diabetologia 37, 985 (1994); Diabetes 43, [suppl 1], 172A (1994); Am. J. Physiol. 269, E469-E477 (1995); Diabetes 44 [suppl 1], 134A (1995); Diabetes 45, 1076 (1996)). These studies suggest that glucagon suppression or an action that antagonizes glucagon could be a useful adjunct to conventional treatment of hyperglycemia in diabetic patients. The action of glucagon can be suppressed by providing an antagonist or an inverse agonist, i.e. substances that inhibit or prevent glucagon-induced responses. The antagonist can be peptidic or non-peptidic in nature.
Native glucagon is a 29 amino acid peptide having the sequence:
His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-OH.
Glucagon exerts its action by binding to and activating its receptor, which is part of the Glucagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family (Jelinek et al., Science 259, 1614, (1993)). The receptor functions by activating the adenylyl cyclase second messenger system and the result is an increase in cAMP levels.
Peptide antagonists of peptide hormones are often quite potent. However, they are generally known not to be orally available because of degradation by physiological enzymes, and poor distribution in vivo. Therefore, orally available non-peptide antagonists of peptide hormones are generally preferred. Among the non-peptide glucagon antagonists, a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethylamino]-6,7-dichloroquinoxaline was found to displace glucagon from the rat liver receptor (Collins, J. L. et al., Bioorganic and Medicinal Chemistry Letters 2(9):915-918 (1992)). WO 94114426 (The Wellcome Foundation Limited) discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists. U.S. Pat. No. 4,359,474 (Sandoz) discloses the glucagon inhibiting properties of 1-phenyl pyrazole derivatives. U.S. Pat. No. 4,374,130 (Sandoz) discloses substituted disilacyclohexanes as glucagon inhibiting agents. WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as glucagon antagonists. U.S. Pat. No. 5,776,954 (Merck & Co., Inc.) discloses substituted pyridyl pyrroles as glucagon antagonists and WO 98121957, WO 98/22108, WO 98122109 and U.S. Pat. No. 5,880,139 (Merck & Co., Inc.) disclose 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. Furthermore, WO 97/16442 and U.S. Pat. No. 5,837,719 (Merck & Co., Inc.) disclose 2,5-substituted aryl pyrroles as glucagon antagonists. WO 98/24780, WO 98/24782, WO 99/24404 and WO 99/32448 (Amgen Inc.) disclose substituted pyrimidinone and pyridone compounds and substituted pyrimidine compounds, respectively, which are stated to possess glucagon antagonistic activity. Madsen et al. (J. Med. Chem. 1998 (41) 5151-7) discloses a series of 2-(benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethanones as competitive human glucagon receptor antagonists. WO 99/01423 and WO 00/39088 (Novo Nordisk A/S) disclose different series of alkylidene hydrazides as glucagon antagonists/inverse agonists. These known glucagon antagonists differ structurally from the present compounds.
DESCRIPTION OF THE INVENTION
The present invention is based on the unexpected observation that compounds belonging to the series of the compounds disclosed below have a high binding affinity for the glucagon receptor and act to antagonize the action of glucagon.
The present invention relates to a compound selected from:
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the invention the compound is selected from
3-{4-[1-(4-cyclohexylphenyl)-3-(3-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohexylphenyl)-3-(3-trifluoromethylphenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohexylphenyl)-3-(3-bromophenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3-bromophenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohexylphenyl)-3-(3-trifluoromethyl-5-fluorophenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohexylphenyl)-3-(3-trifluoromethyl-5-cyanophenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3-methylsulfonyl-4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohexylphenyl)-3-(3-hydroxymethyl-4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3-hydroxymethyl-4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohexylphenyl)-3-(3-methylthiophenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3-methylthiophenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[3-[1(S)-(4-chlorophenyl)ethyl]1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[3-biphenyl-2-ylmethyl-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohexylphenyl)-3-(2,2,4,4-tetrafluorobenzo[1,3]dioxin-6-yl)ureidomethyl]benzoyl-amino}propionic acid
3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(2,2,4,4-tetrafluorobenzo[1,3]dioxin-6-yl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohexylphenyl)-3-(3,3,4,4-tetrafluorobenzo[1,4]dioxin-6-yl)ureidomethyl]benzoyl-amino}propionic acid
3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,3,4,4-tetrafluorobenzo[1,4]dioxin-6-yl)ureidomethyl]benzoylamino}propionic acid
3-{4-[1-(4-cyclohexylphenyl)-3-(6-trifluoromethoxybenzothiazol-2-yl)ureidomethyl]benzoyl-amino}propionic acid
3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(6-trifluoromethoxybenzothiazol-2-yl)ureidomethyl]benzoylamino}propionic acid
3-{4-[3-(3-cyano-5-trifluoromethylphenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoyl-amino}propionic acid
as well as any optical or
Lau Jesper
Ling Anthony
Madsen Peter
Began, Esq. Marc A.
Boak, Esq. Richard W.
Green, Esq. Reza
Novo Nordisk A S
Stockton Laura L.
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