Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-09-12
1999-10-26
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549510, 549511, C07D26306, C07D30514
Patent
active
059731630
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
The present invention relates to novel derivatives having a taxane skeleton endowed with a marked anti-tumoural activity. The novel derivatives have the general structure 1: ##STR1## wherein R.sub.1 and R.sub.2 are hydrogen atoms, or R.sub.1 is a hydrogen atom and R.sub.2 is a hydroxyl or a acetyloxy group, or OR.sub.1 and R.sub.2 together form a cyclic carbonate group having the formula: ##STR2## R.sub.3, which can be .alpha.- or .beta.-oriented, is a hydrogen atom or an alkylsilyl group, preferably triethylsilyl (TES); R.sub.4 is hydrogen, or the residue ##STR3## or an isoserine residue of formula A: ##STR4## wherein R.sub.1 ' is a straight or branched alkyl or alkenyl group, containing one to five carbon atoms, or an aryl residue; R.sub.2 ' is a straight or branched alkyl or alkenyl group, containing one to five carbon atoms, or an aryl residue, or a tert-butoxy group.
The novel derivatives of general formula (1) are prepared by semisynthesis, starting from the natural syntons 10-deacetylbaccatine III (2) and 10-deacetyl-14.beta.-hydroxybaccatine III (3). They are selectively oxidized in position 10 and then esterified in position 13 with a suitable acylating agent which allows the introduction of the group R.sub.4. ##STR5##
When taxanes of natural or synthetic origin already contain the desired isoserine chain in position 13, the molecules of structure 1 can be obtained from these taxanes by selective oxidation in position 10. As described hereinafter, the selective oxidation in position 10 of 2, 3 and of the taxanes already containing the isoserine chain in position 13, can be obtained by treatment with copper (II) salts.
DETAILED DESCRIPTION OF THE INVENTION
As disclosed in U.S. Pat. No. 5,269,591, 10-Deacetylbaccatine III (2) and its 14.beta.-hydroxy (3) analogs can be recovered from suitably selected vegetable material.
However, it is one of the objects of the present invention, to synthesize taxane syntons containing an oxygenated function in position 14, which are useful for the preparation of compounds of structure 1, containing an oxygenated function in position 14, starting from 10-deacetylbaccatine III (2). In fact, it has surprisingly been found that, after protecting the hydroxyl in position 7 of compound 2 as a silyl ether, the oxidation to ketone of the carbon in 13 and the introduction of a .beta.-oriented alcohol function on the carbon in 14 take place by treatment with manganese dioxide. After protection of the hydroxyls in 10 and 14, for example as acetates, by treatment with hydrides, the 13-keto function is reduced to 13.alpha.-hydroxy.
The process, which is shown schematically below, leads to the formation of synton 4, which is used for the preparation of compounds with structure 1. ##STR6##
From synton 4, after removing the protective groups with known methods described in literature, for example using hydrochloric acid to remove the silyl group and a base to remove the acetate groups, 10-deacetyl-14.beta.-hydroxybaccatine III (3) is obtained. Therefore, as mentioned, in order to prepare compounds of formula 1, 10-deacetylbaccatine III (2), 10-deacetyl-14.beta.-hydroxybaccatine III (3), natural or semisynthetic, or other taxanes having an hydroxyl function at 10 and already containing in position 13 the isoserine chain represented by the group R.sub.4, must be available.
It has surprisingly been found that all these syntons, by treatment with copper (II) salts, preferably copper acetate, undergo a selective oxidation in position 10, without need for the protection of the other hydroxyl functions. For example, 10-deacetylbaccatine III (2), 10-deacetyl-14.beta.-hydroxybaccatine III (3) and the natural taxane 10-deacetyl-cephalomannine give the respective 10-keto derivatives 5-7 in yields from 75 to 85%. The oxidation generally requires protracted times (100-140 hours) and an oxidizer excess, and it is carried out at room temperature and in alcoholic solvent. ##STR7##
When, preparing the compound of formula 1 according to the present invention, the presen
REFERENCES:
Giovanni Appendino et al., Synthesis of Modified Baccatins via an Oxidation-Reduction Protocol, Tetrahedron Letters, vol. 36, No. 18 (May, 1995) pp. 3233-3236.
Giovanni Appendino et al., The Chemistry and Occurrence of Taxane Derivatives.XIII. The Oxidation of 10-Deacetylbaccatin III, Gazzetta Chimica Italiana, vol. 124, No. 6 (Jun., 1994) pp. 253-257.
Zhang Hongjie et al., Taxol Related Diterpenes From the Roots of Taxus Yunnanensis, Heterocycles, vol. 38, No. 5 (1994) pp. 975-998.
Bombardelli Ezio
De Bellis Paolo
Gabetta Bruno
Indena S.p.A.
Trinh Ba K.
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