Process for preparing taxane derivatives, new derivatives obtain

Details Process for preparing taxane derivatives, new derivatives obtain Process for preparing taxane derivatives, new derivatives obtain

1993-05-21

1995-12-19

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549511, 548215, C07D30500, A61K 31335

Patent

active

054769540

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of FR91100928 filed Nov. 22, 1991.
The present invention relates to a process for preparing taxane derivatives of general formula: ##STR2## in which R represents a t-butoxy or phenyl radical, R.sub.1 represents a hydrogen atom or an acetyl radical and Ar represents an aryl radical.
Preferably, Ar represents an optionally substituted phenyl or .alpha.- or .beta.-naphthyl radical optionally substituted with one or more atoms or radicals selected from halogen (fluorine, chlorine, bromine, iodine) atoms and alkyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, mercapto, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, on the understanding that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and that the aryl radicals are phenyl or .alpha.- or .beta.-naphthyl radicals.
The present invention also relates to the new taxane derivatives of general formula (I) in which R.sub.1 represents a hydrogen atom, R represents a t-butoxy or phenyl radical and Ar represents a substituted phenyl radical or an optionally substituted .alpha.- or .beta.-naphthyl radical as stated above, that is to say the taxane derivatives of formula: ##STR3##
More especially, the invention relates to the new taxane derivatives of general formula (Ia) in which Ar represents a phenyl radical substituted with one or more identical or different atoms or radicals selected from halogen atoms and alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethyl radicals.
Still more especially, the invention relates to the products of general formula (II [sic]) in which Ar represents a phenyl radical substituted with a chlorine or fluorine atom, or with an alkyl (methyl), alkoxy (methoxy), dialkylamino (dimethylamino), acylamino (acetylamino) or alkoxycarbonylamino (t-butoxycarbonylamino) radical.
In EP-A-0,253,739, the preparation is described of taxol from Taxotere (4-acetoxy-2-benzoyloxy-5.beta.,20-epoxy-7.beta.,10.beta.-dihydroxy-9-oxo- 11-taxen-13.alpha.-yl (2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate), which can itself be obtained according to the process described in EP-A-0,336,841 by condensation of 3-t-butoxycarbonylamino-3-phenyl-2-(protected hydroxy) [sic] acid with appropriately protected 10-deacetylbaccatin III. Taxol and Taxotere possess antitumour and antileukemic properties. According to Chem. Abstr. 114 94569 q (1991), taxol metabolites which are derivatives hydroxylated on the phenyl ring at the 3'-position or on the phenyl ring of the benzoyl at the 2-position are markedly less active than taxol.
According to the invention, the taxane derivatives of general formula (I) may be obtained in the following manner: ##STR4## in which Ar is defined as above, Boc represents a t-butoxycarbonyl radical and R.sub.6 and R.sub.7, which may be identical or different, represent an alkyl radical containing 1 to 4 carbon atoms, optionally substituted with one or more aryl (phenyl) radicals, or an aryl (phenyl), or alternatively R.sub.6 and R.sub.7, together with the carbon atom to which they are linked, form a 4- to 7-membered ring, is condensed with a taxane derivative of general formula: ##STR5## in which R'.sub.1 represents an acetyl radical or a group protecting the hydroxyl function such as a 2,2,2-trichloroethoxycarbonyl radical and R.sub.2 represents a group protecting the hydroxyl function such as a 2,2,2-trichloro derivative of formula (III), the condensing agent being used in a stoichiometric amount relative to the acid of formula (II) and the activating agent being used in a stoichiometric amount relative to the taxane derivative of formula (III).
The product of general formula (IV) in which R'.sub.1 is defined as above and R.sub.2 represents a 2,2,2-trichloroethoxycarbonyl radical may be obtained by esterification of a taxane derivative of general formula (III) in which R'.sub.1 is defined as

REFERENCES:
patent: 4912039 (1990-03-01), Riordan

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