Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-10-06
1999-09-21
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5483581, A61K 31415, C07D49106
Patent
active
059554894
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to taxane derivatives prepared starting from 10-deacetyl-baccatine III, 14-hydroxy-10-deacetyl-baccatine III, 19-hydroxy-10-deacetylbaccatine III and their esters at C.sub.13, by reaction of the respective 10-dehydro-derivatives with hydrazine, hydroxylamine and derivatives thereof.
BACKGROUND ART
EP 253738 describes taxol derivatives bearing hydroxyls in positions 10 and 7 and a keto in position 9, which derivatives can be substituted by a isoserine residue in position 13; WO 94/25441 discloses anthrapyrazolones which can be used as anticancer agents, and a process for their synthesis; the "Journal of the American Chemical Society", vol. 93 No. 9, pages 2325-2327, reports the isolation and characterization of taxol derivatives having tumor inhibitory properties.
The novel compounds contain a pyrazoline group involving the C.sub.7 and C.sub.9 carbons. The esters at C.sub.13 with isoserine chains functionalized at C.sub.3 ' and at NH have cytotoxic activity on the cell lines of the most common-human tumors as well as in vivo anti-cancer activity. The compounds of the invention are potent cytotoxic agents, particularly active on cells resistant to known antiblastics and are strong apoptosis inducers on these cell lines, which activity is significantly important in the oncologic therapy.
SUMMARY OF THE INVENTION
The derivatives of the present invention have the following general formula (1) ##STR1## wherein R.sub.1 and R.sub.2 are hydrogen atoms or R.sub.1 is hydrogen and R.sub.2 is a hydroxy, alkoxy or acyloxy group, or R.sub.1 and R.sub.2 together form a cyclic carbonate or a cyclic thiocarbonate group of formula ##STR2## R.sub.3 is hydrogen or hydroxy; R.sub.4 is hydrogen or an isoserine residue of formula (2) ##STR3## wherein R.sub.5 is a C.sub.1 -C.sub.5 alkyl or C.sub.2 -C.sub.5 alkenyl group or an aryl residue, R.sub.6 has the same meanings as R.sub.5 or is a tert-butoxy group.
An aryl group is preferably a phenyl group. An alkoxy group is preferably a methoxy or ethoxy group. An acyloxy group is preferably an acetoxy group.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula (1) are prepared starting from a taxane of formula (3) ##STR4## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above, by reaction with hydrazine in alcohols, preferably in methanol.
The reaction yields two diastereomers in .alpha. and .beta. at C.sub.7 which can be separated by fractional crystallization or better by chromatography using for example silica gel columns and mixtures of ethyl acetate and hexane as eluents. In the reaction with hydrazine the isomer .beta. forms preferably in an about 8:2 ratio. Therefore the two isomer forms are also an object of the present invention. The reaction can be applied, besides to baccatine III or 14-.beta.-hydroxy-baccatine III or the corresponding carbonates or thiocarbonates prepared by reaction with phosgene or thiophosgene in pyridine (Italian patent appl. MI95A000533 and MI95O01022), also to the products already esterified at C.sub.13, such as paclitaxel, cephalomannine, docetaxel and their semi-synthetic analogues. The above mentioned products, after removing the acetate at C.sub.10 by treatment with hydrazine in methanol, are oxidized with copper acetate to 10-dehydro derivatives (see Italian patent applications cited above) which are directly converted into the corresponding pyrazoline derivatives by treatment with hydrazine. The conversion yields are nearly quantitative in the various steps. The pyrazoline derivatives can be used as such and have an activity comparable to or higher than the starting products as far as cytotoxicity is concerned. The obtained pyrazoline derivatives can be converted into the dihydro derivatives by catalytic hydrogenation or they can be derivatized at the nitrogen.
EXAMPLES
By way of example, the cytotoxicity of some of the prepared compounds is reported.
TABLE I ______________________________________
IC.sub.50 of compounds 2, 4, 5, 6, of paclitaxel
and of docetaxe
REFERENCES:
Journal of the American Chemical Society, vol. 93, No. 9, May 5, 1971, pp. 2325-2327, "Plant antitumor agents. VI The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia".
Indea S.p.A.
Ramsuer Robert W.
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