Bishispidine compounds, processes for their production and pharm

Details Bishispidine compounds, processes for their production and pharm Bishispidine compounds, processes for their production and pharm

1996-10-18

1998-03-24

Davis, Zinna Northington

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549292, 549 13, 514336, 514397, 514408, 514444, 5462821, 5483355, 548518, C07D40506, C07D40906, A61K 31365

Patent

active

057313440

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/03116 filed Sep. 17, 1994, published as WO95/08547, Mar. 30, 1995.
The present invention concerns methylene-bishispidine derivatives, processes for their production and pharmaceutical agents that contain these compounds.
The invention concerns methylene-bishispidine derivatives of the general formula I ##STR1## in which A denotes hydrogen, C.sub.1 -C.sub.16 alkyl, C.sub.3 -C.sub.6 cycloalkyl, a group ##STR2## in which R.sub.1 -R.sub.5 simultaneously or independently of one another denote hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy, C.sub.1 -C.sub.6 acyloxy, C.sub.1 -C.sub.6 alkoxy, benzyloxy, halogen, cyano, carboxy, amino, phenyl, alkylthio, carboxyalkyl, heteroalkyl or an ester group, oxygen or sulphur, or sulphur
Z is .dbd.CR.sub.11 -- or nitrogen
in which halogen or carboxy and halogen, arylalkyl, carboxyl or carboxyl ester
The alkyl residues in the said alkyl, alkoxy, acyloxy, alkylthio, carboxyalkyl or heteroalkyl groups can be straight-chained or branched. A C.sub.1 -C.sub.6 alkyl residue in the present invention denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl or hexyl. Heteroalkyl denotes a C.sub.1 -C.sub.4 alkyl residue substituted by nitrogen, oxygen or sulphur. Arylalkyl denotes a phenyl group which is optionally substituted by halogen, hydroxy or methyl and is linked by a C.sub.1 -C.sub.4 alkyl residue. Carboxyalkyl is a carboxy group linked by a C.sub.1 -C.sub.4 alkyl residue. Halogen denotes fluorine, chlorine, bromine or iodine, preferably chlorine.
It was surprisingly found that compounds of formula I have valuable pharmacological properties. In particular they inhibit the formation of AGE (Advanced Glycosylation Endproducts) whose significance for the development of late diabetic complications has been shown (A. Cerami, Trends Biochem. Sci. 11, 311 (1986)).
Thus the non-enzymatic glycosylation of plasma proteins can be stimulated in vitro by incubating them with glucose the reinjection of these proteins leads in vivo to typical late diabetic damage (H. Vlassara et al., Diabetes 41, Suppl. 1, 9A (1992)). AGE are involved in the thickening of the glomerular basal membrane, a process which is responsible for renal insufficiency and renal failure. The non-enzymatic glycosylation of crystallin, a protein of the eye lens, leads to changes in the tertiary structure and polymerization by oxidation of SH groups to disulfides resulting in diabetic cataract formation (V. Monnier, Clin. Endocrinol. Metab. 11, 431 (1982)). The cross-linking of proteins caused by the end products of non-enzymatic glycosylation reduces the solubility of collagen and is involved in the sclerosis of blood vessels (H. Rosenburg et al., Biochem. Biophys. Res. Commun. 91 498 (1979)). A further consequence is the capture of low density lipoproteins (M. Brownlee et al., Science 232, 1629 (1986)). The localization of these LDL proteins on the endothelium is a strong stimulus for atherosclerotic processes (D. Steinberg et al., J. Clin. Invest, 88, 1785 (1991); D. Leake, Current Opinion in Lipidology, 2, 301 (1991)).
Compounds of formula I are therefore suitable for the prophylaxis and treatment of late diabetic damage (e.g. retinopathy, nephropathy and neuropathy) as well as for the prophylaxis and therapy of atherosclerosis and arteriosclerosis.
Preferred compounds of the general formula I are compounds in which A denotes hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.6 cycloalkyl or a group ##STR3## in which R.sub.1 and R.sub.5 are hydrogen.
Particularly preferred compounds of the general formula I are those in which R.sup.3 represents hydrogen, hydroxy, C.sub.1 -C.sub.4 alkoxy, cyano, carboxy or halogen, R.sup.2 and R.sup.4 independently of one another and independently of R.sup.3 denote hydrogen, hydroxy, C.sub.1 -C.sub.4 alkyloxy or C.sub.1 -C.sub.4 alkyl and R.sup.1 and R.sup.5 are hydrogen atoms.
Particularly preferred compounds of the general formula I are also those in which A denotes a group ##STR4## in which X is --CH.dbd.CH--, NH, --CH.dbd.N, oxygen or

REFERENCES:
Aminov et al, Chemical Abstracts, vol. 116, No. 12, Abstract No. 120, 411v, p. 20, 1992.

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