Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-08-05
1999-06-29
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549 34, 549 40, 549 41, 549229, 549432, 514439, 514443, 514467, C07D32710, C07D31770, A61K 3138, A61K 31335
Patent
active
059170565
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to 10-deacetyl-14.beta.-hydroxybaccatine III of formula 1: ##STR1## wherein X is a >C=S, >C=NH or >S=O group; alkylsilyloxy (preferably triethylsilyloxy, O-TES), dichloromethoxycarbonyl group, or, with the carbon atom to which is connected, it forms a keto group; ##STR2## R.sub.4 is a straight or branched alkyl or alkenyl group, having 1-5 carbon atoms, or an aryl group; group, or a tert-butoxy group.
BACKGROUND ART
Paclitaxel (taxol), as it is already well-known, is a diterpenoid extracted from plants of the Taxus genus having anticancerogenic activity on different forms of human tumours. Its clinical use still involves some drawbacks such as cardiotoxicity and a poor water solubility, which makes its administration complex. Moreover, paclitaxel induces resistance quickly. Due to these reasons, researches have been in progress for some years aiming at synthesizing novel paclitaxel analogues which cause less adverse effects compared with the parent molecule.
SUMMARY OF THE INVENTION
Now it has been found that the compounds having the above reported formula 1, in addition to having a remarkable cytotoxic and antitumour activity, are free from the drawbacks of paclitaxel mentioned above.
According to the invention, the compounds of formula 1 are obtained by semisynthesis, starting from 10-deacetyl-14.beta.-hydroxybaccatine. III which, upon protection of the hydroxyls at 7- and 10-, is reacted a) with thiophosgene in pyridine, thereby obtaining the corresponding 1,14-thiocarbonate, (1, with X=>C=S) or b) with thionyl chloride in the presence of tertiary bases (in which case a 1,14-sulfite will be obtained), (1, with X=>S=O) or c) with cyanogen bromide (after conversion of the hydroxyls at 1- and 14- into the corresponding lithium alkoxides), in order to obtain the iminocarbonate (1, with X=>C=NH). The operative details will be reported in the examples, and of course those skilled in the art will make use of well known variations when carrying out the process, without however departing from the original inventive scope.
DETAILED DESCRIPTION OF THE INVENTION
The resulting thiocarbonates, sulfites and iminocarbonates are esterified at the hydroxyl at C.sub.13 with the suitably activated isoserine chains of formula 2, according to what reported in literature for the semisynthesis of paclitaxel and analogues thereof (see, for ex. EP-A 400,971; Fr. Dem. 86, 10400; E. Didier et. al. Tetrahedron Letters 35, 2349 (1994); E. Didier et al. ibid. 35, 3063 (1994)). Preferably the isoserine chains are used in the oxazolinedicarboxylic acid activated form corresponding to the formula 3: ##STR3## wherein R.sub.4 and R.sub.5 have the meanings defined above.
Alternatively to this synton, the analogous compound wherein the ketalizing acetone can be replaced by 1,3-bromoacetone, hexachloroacetone, chloral or an aromatic aldehyde, preferably p-methoxy benzaldehyde or o,p-dimethoxy benzaldehyde, can be used. The esterification of the oxazolidinecarboxylic acids with the taxane syntons and the subsequent elimination of the protecting groups are carried out as described in literature for the synthesis of paclitaxel and the analogues thereof.
The compounds of formula 1 wherein R.sub.2 forms a keto group with C.sub.10 can be obtained analogously, starting from 14.beta.-hydroxy-10-dehydrobaccatine III.
Among the compounds of formula 1, particularly active proved to be .beta.-hydroxybaccatine III 1,14-thiocarbonate (5), 4.beta.-hydroxybaccatine III 1,14-thiocarbonate (6), oxybaccatine III 1,14-thiocarbonate III (7); active and with a different solubility in water proved to be the analogous derivatives having as substituents at the 1,14 hydroxyls the >C=NH group or the >S=O group. The compounds oxybaccatine III 1,14-iminocarbonate (8) and oxybaccatine-III 1,14-sulfite (9) showed advantages compared with the compounds of the prior art in terms of both activity and tolerability.
EXAMPLES
The cytotoxicity data of the compounds 5, 8 and 9 compared with those o
REFERENCES:
Chen et al, Tetrahedron Letters, 34 (20), pp. 3205-3206, 1993.
I. Ojima et al., "Structure-Activity Relationships of New Taxoids Derived from 14.beta.-Hydroxy-10-deacetylbaccatin III", J. Med. Chem., vol. 37 (1994) pp. 1408-1410.
I. Ojima et al., "Synthesis and Biological Activity of 14-Hydroxydocetaxel", Bioorg. Med. Chem. Lett., vol. 4, No. 13 (1994) pp. 1571-1576.
J. Kant et al., "Synthesis and Antitumor Properties of Novel 14-.beta.-Hydroxytaxol and Related Analogues", Bioorg. Med. Chem. Lett., vol. 4, No. 13 (1994) pp. 1565-1570.
E. Didier et al., "2-Monosubstituted-1,3-Oxazolidines as Improved Protective Groups of N-Boc-Phenylisoserine in Docetaxel Preparation", Tetrahedron Lett., vol. 35, No. 15 (1994) pp. 2349-2352.
E. Didier et al., "Expeditious Semisynthesis of Docetaxel Using 2-Trichloromethyl-1,3-Oxazolidine as Side-Chain Protection", Tetrahedron Lett., vol. 35, No. 19 (1994) pp. 3063-3064.
Indena S.p.A.
Trinh Ba K.
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