Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1998-12-24
2000-08-15
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514255, 514656, 536 64, 552296, A61K 3170, A61K 31495, C07D295185, C07D29526, C07D295104
Patent
active
061037001
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of fluoro anthracyclinone and fluoro anthracycline derivatives as NMR imaging probes for monitoring amyloidotic diseases. The term amyloidosis indicates various diseases whose common characteristic is the tendency of particular proteins to aggregate and precipitate, as insoluble fibrils, into the extracellular space causing structural and functional damage to organs and tissues. The classification of amyloid and amyloidosis has been recently revised in Bulletin of the World Health Organisation 71(1): 105 (1993). All the different types of amyloid share the same ultrastructural organisation in anti-parallel .beta.-pleated sheets despite the fact that they contain a variety of widely differing protein subunits [see: Glenner G. G., New England Journal of Medicine 1980, vol. 302, p. 1283; Ghiso J. et al., Molecular Neurobiology 1994, vol. 8, p. 49].
The clinical course of the disease depends on the selectivity of organ involvement; the prognosis can be extremely unfavourable in case of heart infiltration (median survival <12 months) or more benign in case of kidney involvement (median survival approx. 5 years). The compounds of the formula A are able to interact with amyloid deposits and plaques and with fibrils of amyloid. Accordingly the present invention provides the use of a compound which is an anthracycline or anthracyclinone derivative of the general formula A: ##STR2## wherein: R.sub.1 is hydrogen, hydroxyl, halogen, C.sub.1 -C.sub.8 alkoxyl, amino which may be substituted by benzyl, acyl or trifluoroacetyl, or OSO.sub.2 (R.sub.4), wherein R.sub.4 is alkyl or aryl, each of which is unsubstituted or substituted by one or more fluorine atoms; by C.sub.1 -C.sub.16 alkyl, aryl, aralkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.8 cyclo-alkenyl which is unsubstituted or substituted by one or more fluorine atoms or trifluoromethyl groups, morpholino which may be substituted by C.sub.1 -C.sub.16 alkyl, aryl, aralkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.8 cyclo-alkenyl which is unsubstituted or substituted by one or more fluorine atoms or trifluoromethyl groups, piperazino which may be substituted by trifluoroacyl or trifluoromethanesulfonyl or aryl(trifluoromethyl), tetrahydropyridine, a group of formula B or C ##STR3## in which R.sub.5 is hydrogen or C.sub.1 -C.sub.6 alkyl, R.sub.6 represents COCF.sub.3 or SO.sub.2 CF.sub.3, n and m, which are the same or different, are each an integer of from 1 to 4, or a saccharide of formula D as below defined ##STR4## wherein R.sub.7 is hydrogen, hydroxyl, amino which is unsubstituted or substituted by acyl, trifluoroacetyl, trifluoromethansulfonyl, a residue of a naturally occurring amino acid, or a synthetic amino acid or a residue of di- or tri-peptide; hydroxyl, C.sub.1 -C.sub.4 alkoxyl, tetrahydropyranyl, halogen or OSO.sub.2 (R.sub.4) as above defined and the other of R.sub.8 and R.sub.9 represents hydrogen or amino which is unsubstituted or substituted by acyl, trifluoroacetyl or trifluoromethansulfonyl; unsubstituted or substituted by acyl, trifluoroacetyl, C.sub.1 -C.sub.16 alkyl, aryl or aralkyl which is unsubstituted or substituted by one or more fluorine atoms, morpholino, piperazino which may be substituted by trifluoroacyl or trifluoromethansulfonyl, tetrahydropyridine, a group of formula B or C as above defined, or a saccharide of formula D as above defined; anthracycline skeleton or carried by groups linked at different positions of the molecule; or a pharmaceutically acceptable salt thereof; for the diagnosis of amyloidosis or in the preparation of a composition for such a diagnosis.
When R.sub.7 is a residue of a naturally occurring amino acid, or a residue of a di- or tri-peptide, it is preferably in the form N-trifluoroacetyl or trifluoromethansufonyl.
Preferred compounds of formula A are those wherein: aminotrifluoromethanesulfonyl (NHSO.sub.2 CF.sub.3), aminotrifluoroacetyl, or O-mesyl [OSO.sub.2 CH.sub.3 ]; or substituted by one or more fluorin
REFERENCES:
patent: 5731313 (1998-03-01), Suarato et al.
patent: 5744454 (1998-04-01), Suarato et al.
Bandiera Tiziano
Caruso Michele
Fancelli Daniele
Lansen Jacqueline
Suarato Antonino
Pharmacia & Upjohn S.p.A.
Shah Mukund J.
Sripada Pavanaram K
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