Process for the preparation of taxane derivatives

Details Process for the preparation of taxane derivatives Process for the preparation of taxane derivatives

1995-04-05

1997-04-15

Trinh, Ba K.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549511, C07D30514

Patent

active

056211210

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FR93/00969 filed Oct. 4, 1993.


DESCRIPTION OF THE INVENTION

The present invention relates to a new process for the preparation of taxane derivatives of general formula: ##STR2## which have notable antileukaemic and antitumour properties.
In the general formula (I), R represents a hydrogen atom or an acetyl radical, R.sub.1 represents a benzoyl radical or a radical R.sub.2 --O--CO-- in which R.sub.2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or nitrogen-containing heterocyclyl radical, and Ar represents an aryl radical.
More particularly, R represents a hydrogen atom or an acetyl radical and R.sub.1 represents a benzoyl radical or a radical R.sub.2 --O--CO-- in which R.sub.2 represents: alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 10 carbon atoms, these radicals optionally being substituted by one or a number of substituents chosen from the halogen atoms and the hydroxyl radical, alkyloxy radical containing I to 4 carbon atoms, dialkylamino radical, each alkyl part of which contains 1 to 4 carbon atoms, piperidino radical, morpholino radical, 1-piperazinyl radical (optionally substituted in the 4-position by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical, the alkyl part of which contains 1 to 4 carbon atoms), cycloalkyl radical containing 3 to 6 carbon atoms, cycloalkenyl radical containing 4 to 6 carbon atoms, phenyl radical, cyano radical, carboxyl radical or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms, radicals chosen from the alkyl radicals containing 1 to 4 carbon atoms or the alkyloxy radicals containing 1 to 4 carbon atoms, containing 5 or 6 members, optionally substituted by one or a number of alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may optionally be substituted by one or a number of alkyl radicals containing 1 to 4 carbon atoms, and substituted by one or a number of atoms or radicals chosen from the halogen atoms (fluorine, chlorine, bromine or iodine) and the alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano and trifluoromethyl radicals, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 3 to 8 carbon atoms and the aryl radicals are phenyl or .alpha.- or .beta.-naphthyl radicals.
The products of general formula (I) in which R (represents a hydrogen atom or an acetyl radical, R.sub.1 represents a benzoyl or t-butoxycarbonylamino radical and Ar represents a phenyl radical are very particularly anvantageous.
The products of general formula (I) in which R.sub.1 represents a benzoyl radical correspond to taxol and to 10-deacetyltaxol and the products of general formula (I) in which R.sub.1 represents a t-butoxycarbonyl radical correspond to those which form the subject of European Patent EP 0,253,738.
According to the process which is described in International Application PCT WO 92/09589, the derivatives of general formula (I) can be obtained by: ##STR3## in which Ar is defined as above, Boc represents the t-butoxycarbonyl radical and R'.sub.2 and R'.sub.3, which are identical or different, represent an alkyl radical containing 1 to 4 carbon atoms, optionally substituted by one or a number of aryl radicals, or an aryl radical, or else R'.sub.2 and R'.sub.3 form, together with the carbon: atom to which they are bonded, a ring having from 4 to 7 members, with the protected baccatin IIT or 10-deacetylbaccatin (III of general formula: ##STR4## in which G.sub.

REFERENCES:
patent: 5319112 (1994-06-01), Kingston et al.
Voegelein et al, J. Med. Chem., vol. 34, No. 3, 1991, pp. 992-998.

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