Method of preparing taxane derivatives

Details Method of preparing taxane derivatives Method of preparing taxane derivatives

1995-05-03

1997-04-01

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

056167393

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION OF THE INVENTION

The present invention relates to a new process for preparing taxane derivatives of general formula: ##STR2## which possess noteworthy antileukaemic and antitumour properties.
In the general formula (I): 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 a nitrogenous heterocycle radical, and Ar represents an aryl radical.
More especially, 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:
an unbranched or branched alkyl radical containing 1 to 8 carbon atoms, an 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 being optionally substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinyl radicals (optionally substituted at position 4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl, cyano or carboxyl radicals or alkyloxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms,
or a phenyl radical optionally substituted with one or more atoms or radicals chosen from alkyl radicals containing 1 to 4 carbon atoms or alkyloxy radicals containing 1 to 4 carbon atoms,
or a saturated or unsaturated 5- or 6-membered nitrogenous heterocyclic radical optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, radicals can be optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, and substituted with one or more atoms or radicals chosen from halogen (fluorine, chlorine, bromine, iodine) atoms and 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, on the understanding that the alkyl radicals and alkyl portions of the other radicals contain 1 to 4 carbon atoms, and that the alkenyl and alkynyl radicals contain 3 to 8 carbon atoms and the aryl radicals are phenyl or .alpha.- or .beta.-naphthyl radicals.
Of very special importance are 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.
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 0,253,738.
According to the process which is described in International Application PCT WO 92/09,589, the derivatives of general formula (I) may be obtained by:
condensation of an oxazolidine derivative of general formula: ##STR3## in which Ar is defined as above, Boc represents a t-butoxycarbonyl radical and R'.sub.2 and R'.sub.3, which may be identical or different, represent an alkyl radical containing 1 to 4 carbon atoms optionally substituted with one or more aryl radicals, or an aryl radical, or alternatively R'.sub.2 and R'.sub.3, together with the carbon atom to which they are linked, form a 4- to 7-membered ring, with protected 10-deacetylbaccatin III or baccatin III of general formula: ##STR4## in which G.sub.1 represents a group protecti

REFERENCES:
patent: 5015744 (1991-05-01), Holton
patent: 5136060 (1992-08-01), Holton
patent: 5175315 (1992-12-01), Holton
patent: 5319112 (1994-06-01), Kingston et al.
J. Med. Chem. vol. 34, No. 3, Mar. 1991, Washington, DC pp. 992-998, F. Gueritte-Voegelein et al.
Stud. Org. Chem. (New Trends in Nat. Prod. Chem. 1986), vol. 26, 1986, Amsterdam, pp. 219-235.

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