Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-10-18
2000-12-26
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549313, 549318, A61K 3134, C07D30732
Patent
active
061660701
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel named Kodaistatins A, B, C and D, a process for their production and their use.
Increased rate of hepatic glucose output is a general feature of diabetes mellitus. In particular, there is a strong correlation between fasting plasma glucose level in non-insulin dependent diabetes mellitus (NIDDM) and hepatic glucose output. The two pathways by which glucose is produced in the liver are gluconeogenesis and glycogenolysis. The terminal steps of both pathways is catalysed by the microsomal glucose-6-phosphatase, a key enzyme in the homeostatic regulation of blood glucose levels. The level of this enzyme has also been known to be elevated in both experimental and pathological conditions of diabetes. Interference with this enzyme system should, therefore, result in a reduced hepatic glucose production.
Hepatic glucose-6-phosphatase is a multi component system comprised of at least three functional activities: a glucose-6-phosphate translocase (T1), a glucose-6-phosphate phosphohydrolase and a phosphate/pyrophosphate translocase (T2). The glucose-6-phosphate translocase facilitates transport of glucose-6-phosphate into the lumen of the endoplasmic reticulum (ER). The phosphohydrolase, with its active site situated on the lumenal surface of the ER, hydrolyses glucose-6-phosphate and releases glucose and phosphate into the lumen. While the efflux of phosphate is facilitated by the phosphate/pyrophosphate translocase, the exact mechanism of glucose efflux is still not clear.
The high degree of substrate specificity of glucose-6-phosphate translocase makes this a potential target for pharmacological intervention in the treatment of diabetes mellitus. Thus, amongst physiologically occurring sugar phosphates, only glucose-6-phosphate is transported by the transiocase. In contrast, the phosphatase is non-specific and is known to hydrolyse a variety of organic phosphate esters. described in the literature e.g. phlorrhizin [J. Biol. Chem., 242, 1955-1960 (1967)], 5,5'-dithio-bis-2-nitrobenzoic acid [Biochem. Biophys. Res. Commun., 48, 694-699 (1972)], 2,2'-diisothiocyanatostilbene and 2-isothiocyanato-2'-acetoxystilbene [J. Biol. Chem., 255, 1113-1119 (1980)]. The first therapeutically utilizable inhibitors of the glucose-6-phosphatase system have been proposed in European Patent Publication No's. 587087 (Application No. 93 114 260.8) and 587088 (Application No. 93 114261.6).
It has now been found, that Kodaistatins A, B, C and D have an enzyme inhibitory activity, in particular with respect to glucose-6-phosphate translocase.
Accordingly, a subject of the present invention is:
1) Kodaistatin A and Kodaistatin B, compounds of the molecular formula C.sub.35 H.sub.34 O.sub.11, and the pharmaceutically acceptable salts, esters, ethers and obvious chemical equivalents thereof.
Kodaistatin B has a hitherto unreported novel structure, formed by a o-hydroquinone, phenol, unsaturated y-lactone, dihydroxy-cyclopentenone and .alpha.,.beta.,.gamma.,.delta.-unsaturated carbonyl moieties and is a diastereomer of Kodaistatin A.
Kodaistatins A and B are compounds of formula I below: ##STR1## The present invention also to:
2) Kodaisatin C and Kodaisitantin D, compounds of the molecular formula C.sub.35 H.sub.34 O.sub.12, and the pharmaceutically acceptable salts, esters, ethers and obvious chemical equivalents thereof.
Kodaistatin C has a hitherto unreported novel structure, formed by o-hydroquinones, unsaturated .gamma.-lactone, dihydroxy-cyclopentenone and .alpha.,.beta.,.gamma.,.delta.-unsaturated carbonyl moieties. Kodaistatin D is a diastereomer of Kodaistatin C. The structural formulae of the Kodaistatins C and D differ from the structural formula I given above by the addition of an -OH group, most likely on the terminal phenyl A at position 6.
The present invention accordingly relates to all stereosomeric forms of Kodaistatin as well as to their mixtures. The single stereoisomeric forms can be isolated by known methods for example normal phase chromatography, anion-exchange chromatography, HPLC or s
REFERENCES:
patent: 5451573 (1995-09-01), Hemmerle et al.
Zoccoli, Michael A., "Effect of Two Inhibitors of Anion Transport on the Hydrolysis of Glucose 6-Phosphate by Rat Liver Microsomes", The Journal of Biological Chemistry, vol. 255 (3); 1113-1119 (Feb. 10, 1960).
Soodsma, James F., "The Inhibition by Phlorizin of Kidney Microsomal Inorganic Pyrophosphate-Glucose Phosphotransferase and Glucose 6-Phosphatase", The Journal of Biological Chemistry, vol. 242, (8); 1955-1960 (Apr. 25, 1967).
Wallin, Bruce K., "The Requirement For Membrane Integrity in the Inhibition of Hepatic Glucose 6-Phosphatase by Sulfhydryl Reagents and Taurocholate", Biochemical and Biophysical Research Communications, vol. 48, (3); 694-699 (Jun. 7, 1972).
Derwent Abstract XP-002061463.
Dalal Roda Maneck
Herling Andreas
Jayvanti Kenia
Kogler Herbert
Nadkarni Suresh Rudra
Aventis Pharma Deutschland GmbH
Owens Amelia
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