Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-12-02
2000-08-22
Riley, Jezia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 18, 514419, 5142352, 514323, 514330, 514385, 548100, A01N 4338, A01N 4340, A01N 4352, A61K 31405
Patent
active
061073296
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to glycogen phosphorylase inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia in mammals.
In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas (e.g. Chlorpropamide.TM. (Pfizer), Tolbutamide.TM. (Upjohn), Acetohexamide.TM. (E. I. Lilly), Tolazamide.TM. (Upjohn)) and biguanides (e.g. Phenformin.TM. (Ciba Geigy), Metformin.TM. (G. D. Searle)) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in about 10% of diabetic patients in which synthetic hypoglycemic agents are not effective Type I diabetes, insulin dependent diabetes mellitus), requires multiple daily doses, usually by self injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral agents, e.g. sulfonylureas, and in more severe cases, insulin. However, the clinically available hypoglycemics can have other side effects which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may have fewer side effects or succeed where others fail, is clearly evident.
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well known. The earliest stage in this sequence is the formation of "fatty streaks" in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Further, it is postulated that most of the cholesterol found within the fatty streaks, in turn, give rise to development of the "fibrous plaque", which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extra cellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the "complicated lesion" which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of "normal" are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at particular high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of excep
REFERENCES:
patent: 4764610 (1988-08-01), Zimmerman
patent: 4836846 (1989-06-01), Zimmerman
patent: 4902708 (1990-02-01), Kim
patent: 4904846 (1990-02-01), Oscadal
patent: 4933325 (1990-06-01), Hansen, Jr. et al.
patent: 4997950 (1991-03-01), Murphy et al.
patent: 5034376 (1991-07-01), Hoover et al.
patent: 5064853 (1991-11-01), Gasc et al.
patent: 5089638 (1992-02-01), Freidinger
patent: 5128346 (1992-07-01), Nadzan et al.
patent: 5219859 (1993-06-01), Festal et al.
patent: 5250517 (1993-10-01), Branca et al.
patent: 5346907 (1994-09-01), Kerwin, Jr. et al.
Joachim Pigulla, et al., Arch. Pharm. (Weinheim) 312:12-18, 1979, "Preparation of indole-2-carboxamides and esters of (indol-2-yl-carbonylamino)carboxylic acids by the imidazolide method".
Joachim Pigulla, et al., Liebigs Ann. Chem. 1978:1390-1398, "Azepinoindoles, III.sup.1 Synthesis of azepino[3,4-b]indolediones by cyclization of N-(2-indolylcarbonyl)-.beta.-amino acids.sup.2 ".
James F. Kerwin, Jr., et. al., J. Med. Chem. 1991, 34, 3350-3359, Cholecystokinin Antagonists: (R)-Tryptophan-Based Hybrid Antagonists of High Affinity and Selectivity for CCK-A Receptors.
Martin, J.L. et al. "Biochemistry" 1991, 30, 10101.
Kasvinsky, P. J. et al. "J. Biol. Chem." 1978, 253, 3343-3351 and 9102-9106.
Blundell, T. B. et al. "Diabetologia" 1992, 35, Suppl. 2, S69-S76.
Nadzan, A. M. et al. "Design of Cholecystokinin Analogs with High Affinity and Selectivity for Brain CCK Receptors" pp. 100-102.
Chemical abstr., vol. 90, No. 19, May 7, 1979 (Columbus, Ohio, USA p. 587, col. 2, the abstract No. 151917p, Pigulla, J. et al., "Preparation of indole-2-carboxamides and esters of (indole-2-ylcarbonylamino)carboxylic acids by the imidazolide method," Arch. Pharm. (Weinhem, Ger.) 1979, 312(1), 12-18 (Ger.).
Chemical Abstr., vol. 90, No. 3, Jan. 15, 1979 (Columbus, OH, USA), p. 636, col. 1, the abstract No. 22858w, Pigulla, J. et al., "Azepinoindoles, III. Cyclization of N-(2-indolylcarbonyl)-.beta.-amino acids to azepino[3,4-b]indolediones", Justus Liebigs Ann. Chem. 1978, (9), 1390-8.
Allard, M. F. et al. "Am. J. Physiol." 1994, 267, H66-H74.
Farris P. L. et al. ,Science 1984, vol. 226, pp. 1215-1217, "Morphine Analgesia Potentiated but Tolerance Not Affected by Active Immunization Against Sholecystokinin".
Bock, Mark G., et al. "J. Med. Chem." 1989, 32, pp. 13-16, "Benzodiazepine Gastrin and Brain Cholecystokinin Receptor Ligands: L-365,260".
Shroff, James R. et al. "J. Med. Chem." 1982, 25, pp. 359-362, "Chemistry and Hypoglycemic Activity of N-[[(Dialkylamino)alkoxy]phenyl]benzamidines".
Burn, Peter et al. "J. Med. Chem." 1982, 25, pp. 363-368, "Synthesis and Dopaminergic Properties of Some exo- and endo-2-Aminobenzonorbornenes Designed as Rigid Analogues of Dopamine".
73:110093x, Saito et al., Chemistry of diborance and sodium borohydride. VII. Reduction of .alpha.-amino acid amides with sodium borohydride., vol. 73, 1970.
86:16946z, Grathwohl et al., The X-Pro peptide bond as an NMR probe for conformational studies of flexible linear peptides., vol. 86, 1977.
98:4791e, Brantl, Victor, Pharmacologically active peptides containing N-terminal phenylalanine. vol. 98, 1983.
103:215774m, Ando et al., Syntheses of cyclic decapeptides with four ornithyl residues related to gramicidin S., vol. 103, 1985.
104:221198p, Okada et al., Inhibition of .alpha.-chymotrypsin by Suc-L-Tyr-D-Leu-D-Phe-pNA, a stereoisomer of a specific substrate., vol. 104, 1986.
108:150948c, Tsuge et al., Lithium bromide-triethylamine induced cyclo addition of N-alkylidene 2-amino esters and amides to electro n-deficient olefins with high regio- and stereoselectivity., vol. 108, 1988.
114:94966s, Weiss et al, Effects of amino acid amides and aminothiols on 3-mercaptoproprionic acid-induced convulsions and phency clidine-induced hyperactivity in mice., vol. 114, 1991.
Hoover Dennis J.
Hulin Bernard
Martin William H.
Phillips Douglas
Treadway Judith L.
Benson Gregg C.
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
Riley Jezia
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