Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1997-04-21
1998-09-29
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 64, 549419, 552201, C07H 15252, A61K 3170, C07D30906, C07C 49747
Patent
active
058146083
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
Glycosidic derivatives of 8-fluoro-anthracyclinone of general formula (I) are described: ##STR3## wherein: R is chosen in the group consisting of H, OH, OR.sub.4 wherein R.sub.4 is chosen in the group consisting of CHO, COCH acyl derivative of a carboxylic acid containing up to 6 carbon atoms; formula (A) ##STR4## wherein R.sub.5 and R.sub.6, same or different, are chosen in the group consisting of: H, OH, NH.sub.2 and the symbol () indicates that the substituents R.sub.2, R.sub.3, R.sub.5 and R.sub.6 can be in the axial or equatorial configuration; and wherein the groups 8--F and 9--OH are in position cis; their pharmaceutically acceptable salts, procesess for their preparation and pharmaceutical compositions containing them.
STATE OF THE ART
Daunorubicin (daunomicin) and 4-demethoxydaunorubicin (idarubicin), and their derivatives containing an hydroxylated lateral chain (doxorubicin), are glycosides presenting well-known anti-tumoral properties; their preparation and use were already described (F. Arcamone "Doxorubicin: Anticancer Antibiotics" Medicinal Chemistry Series Vol. 17, Academic press 1981).
The 8-fluoro-anthracyclines are a class of anthracyclines already known (see for example: EP-A-0436474; EP-A-0457215; WO 95/09173) for their higher activity and selectivity in respect of the corresponding non-fluorinated compounds.
It has been surprisingly found, and this is an object of the present application, that when the two substituents 8--F and 9--OH have cis-stereochemistry, the corresponding derivatives are surprisingly more active, especially in respect of tumoral cells resistant against the already known compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention refers to glycosidic derivatives of 8-fluoroanthracyclinone of general formula ##STR5## wherein: R is chosen in the group consisting of H, OH, OR.sub.4 wherein R.sub.4 is chosen in the group consisting of CHO, COCH.sub.3, acyl derivative of a carboxylic acid containing up to 6 carbon atoms; formula (A) ##STR6## wherein R.sub.5 and R.sub.6, same or different, are chosen in the group consisting of: H, OH, NH.sub.2 and the symbol () indicates that the substituents R.sub.2, R.sub.3, R.sub.5 and R.sub.6 can be in the axial or equatorial configuration; and wherein the groups 8--F and 9--OH are in position cis; their pharmaceutically acceptable salts, process for their preparation and pharmaceutical compositions containing them.
More particularly the present invention refers to the following compounds: .dbd.NH.sub.2 ; R.sub.3 .dbd.OH) .dbd.R.sub.1 .dbd.R.sub.2 .dbd.H; R.sub.3 .dbd.NH.sub.2) (I: R.dbd.R.sub.1 .dbd.R.sub.2 .dbd.H; R.sub.3 .dbd.NH.sub.2) R.sub.2 .dbd.NH.sub.2; R.sub.3 .dbd.OH) R.dbd.R.sub.1 .dbd.H; R.sub.3 .dbd.A; R.sub.2 .dbd.R.sub.6 .dbd.OH; R.sub.5 .dbd.NH.sub.2) R.dbd.R.sub.1 H; R.sub.3 .dbd.A; R.sub.2 .dbd.R.sub.6 .dbd.OH; R.sub.5 .dbd.NH.sub.2) 4-demethoxy-8-(R)-fluoro-7-(2",3",4"-trideoxy-4"-amino-esapiranosyl-fucosy l)-daunorubicinone (I: R.dbd.R.sub.1 .dbd.R.sub.5 .dbd.H; R.sub.3 .dbd.A; R.sub.2 .dbd.OH; R.sub.6 .dbd.NH.sub.2) 4-demethoxy-8-(R)-fluoro-7-(2",3",4"-trideoxy-4"-amino-esapiranosyl-ramnos yl)-daunorubicinone (I: R.dbd.R.sub.1 .dbd.R.sub.5 .dbd.H; R.sub.3 .dbd.A; R.sub.2 .dbd.OH; R.sub.6 .dbd.NH.sub.2) R.dbd.R.sub.1 .dbd.H; R.sub.3 .dbd.A; R.sub.2 .dbd.R.sub.5 .dbd.R.sub.6 .dbd.OH) R.dbd.R.sub.1 .dbd.H; R.sub.3 A; R.sub.2 .dbd.R.sub.5 .dbd.R.sub.6 .dbd.OH) .dbd.NH.sub.2 ; R.sub.3 .dbd.OH) .dbd.H; R.sub.1 .dbd.OCH.sub.3 ; R.sub.3 .dbd.NH.sub.2) R.dbd.R.sub.2 .dbd.H; R.sub.1 .dbd.OCH.sub.3 ; R.sub.3 .dbd.NH.sub.2) R.sub.2 .dbd.NH.sub.2 ; R.sub.3 .dbd.OH) R.sub.1 .dbd.OCH.sub.3 ; R.sub.3 .dbd.A; R.sub.2 .dbd.R.sub.6 .dbd.OH; R.sub.5 .dbd.NH.sub.2) R.sub.1 .dbd.OCH.sub.3 ; R.sub.3 .dbd.A; R.sub.2 .dbd.R.sub.6 .dbd.OH; R.sub.5 .dbd.NH.sub.2) 8-(R)-fluoro-7-(2",3",4"-trideoxy-4"-amino-esapiranosyl-fucosyl)-daunorubi cinone (I: R.dbd.R.sub.5 .dbd.H; R.sub.1 .dbd.OCH.sub.3 ; R.sub.3 .dbd.A; R.sub.2 .dbd.OH; R.sub.6 .dbd.NH.sub.2) 8-(R)-fluoro-7-(2",3",4"-trideoxy-4"-amino-esapira
REFERENCES:
De Mesmaeker, Alain, et al., "A New Protected Form of Glucuronic Acid for the Synthesis of Labile 1-o-Acyl-.beta.-D-Glucurionides," Tetrahedron Letters, vol. 30, No. 29, pp. 3773-3776, 1989.
Arcamone, F. Doxorubicin: Anticancer Antibiotics. Medicinal Chemistry Series, vol. 17, Academic press, 1981. (entire book, not supplied).
Corey, E. J., "Cleavage of Allyloxycarbonyl Protecting Group from Oxygen and Nitrogen Under Mild Conditions by Nickel Carbonyl," J. Org. Chem., vol. 33, No. 18, pp. 3223-3224, 1973.
Albanese, Domenico, et al. "Tetrabutylammonium Dihydrogentrifluoride: An Effective Source of Fluoride Ion For Halofluorination of Alkenes," Gazzette Chimica Italiana, 121, pp. 537-541, 1991.
Lal. G. Sankar. "Site-Selective Fluorination of Organic Compounds Using Reagents), " J. Org. Chem., vol. 58, pp. 2791-2796, 1993.
Wong, C.M., et al, "Synthetic Studies of Hydronaphthacenic Antibiotics. I. The Synthesis of 4-Demethoxy-7-O-menthyl Daunomycinone," Department of Chemistry, University of Manitoba, Mar. 23, 1971, (7 pages).
Smith, Thomas H., et al, "Synthetic Approaches to Adriamycin, Degradation of Daunorubicin to Nonasymmetric Tetracyclic Ketone and Refunctionalization of the A-Ring to Adriamycin," Journal of the American Chemical Society, Mar. 31, 1976, pp. 1969-1971.
Kende, Andrew S., et al, "Total Synthesis of (.+-.)-Duanomycinone and (.+-.)-Carminomycinone," Journal of the American Chemical Society, Mar. 31, 1976, pp. 1967-1969.
Giolitti et al., Tetrahedron Letters, vol. 33,No. 12,pp. 1637-1640, 17 Mar. 1992.
Canfarini et al.,Tetrahedron Letters,vol. 34,No. 29,pp. 4697-4700, 16 Jul. 1993.
Chemical Abstracts,vol. 117,No.3,abst.no.27,045q,Jul. 20, 1992.
Animati Fabio
Arcamone Federico
Giannini Giuseppe
Lombardi Paolo
Monteagudo Edith
A. Menarini Industrie Farmaceutiche Riunite S.r.l.
Bristol-Myers Squibb S.p.A.
Rotman Alan L.
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