Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-06-25
1998-02-17
Trinh, Ba K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549510, 549511, A61K 31335, C07D30514
Patent
active
057191778
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP 95/04302 dated Nov. 2, 1995.
The present invention is directed to new taxane derivatives endowed with antitumour activity, to a process for their preparation and to pharmaceutical compositions containing them.
The taxane family of direrpenes includes Paclitaxel (also named taxol in several publications), isolated and characterized from an extract of bark of Taxus brevifolia L., and Cephalomannine (see J. Chem. Soc. Chem. Comm. 102, 1979); other taxane analogues are also known and were prepared by semisynthesis starting from 10-deacetyl baccatin III, extracted from the needles of Taxus baccata L. (see Wani et al., J. Am. Chem. Soc. 93, 2325, 1971; Lovelle et al., Proc. Am. Assoc. Cancer Res. 31, 417, 1990). Particularly, paclitaxel is a very potent anticancer drug and is already applied with success to the treatment of platinum-resistant ovarian cancer. Nevertheless there is a continuous need for more potent compounds having the broadest possible spectrum of activity on different cancer types.
The present invention provides taxane derivatives modified at the 13-position of the taxane skeleton (taxol numbering). More especially, the invention provides taxane derivatives of the formula I: ##STR1## wherein: R represents a hydrogen atom or a hydroxy group, or taken together with R.sub.3, a bond; hydrogen, or a bond, or R.sub.b is azido or amino group and R.sub.c is hydrogen atom; --OCOR', --OR', --OSO.sub.2 R', --OCONR'R", --OCONHR' or --OCOOR' wherein R' and R" are each independently C.sub.1 -C.sub.6 alkyl, preferably methyl, phenyl-C.sub.2 -C.sub.6 alkenyl or phenyl-C.sub.2 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.6 alkynyl or a phenyl group, optionally substituted with one, two or three substituents which may be the same or different and which are selected from a halogen atom and C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy and --CF.sub.3 groups; and either A--N.dbd., as pure E or pure Z isomers or as a mixture of both E and Z isomers, wherein A represents: dimethylamino group, or 3-phenylserine, .beta.-alanine and the like, optionally protected at the amino group as a N-benzoyl derivative or as a carbamate, or ##STR2## wherein: R.sub.4 is a C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 cycloalkyl group or a phenyl or heteroaryl group, optionally substituted with one, two or three substituents which may be the same or different and which are selected from a halogen atom and C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or --CF.sub.3 groups; and alkyl, preferably tert-butyl or n-pentyl, C.sub.2 -C.sub.6 alkenyl, preferably 1-methyl-1-propenyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.6 alkynyl or a phenyl group, optionally substituted with one, two or three substituents which may be the same or different and which are selected from a halogen atom and C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy and --CF.sub.3 groups; or and n is 0 or 1, or represents hydrogen, or, taken with R, a bond; and pharmaceutically acceptable salts thereof.
The R.sub.2 substituent may be in the R or S configuration. Alternatively the R.sub.2 substituent may be in both the R and S configurations i.e. a mixture of stereoisomers is present.
A C.sub.1 -C.sub.6 alkyl group is a straight or branched alkyl group, preferably a C.sub.1 -C.sub.4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl. A C.sub.2 -C.sub.6 alkenyl group is a straight or branched alkenyl group, preferably a C.sub.2 -C.sub.5 alkenyl group such as vinyl, allyl, crotyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl, butenyl or pentenyl. A C.sub.3 -C.sub.6 cycloalkyl group is a saturated carbocyclic group of 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
A halogen is preferably fluorine, chlorine, bromine or iodine.
The heteroaryl group is preferably a 3- to 6-membered, saturated or unsaturated heterocyclyl ring which contains at least one, for example 1, 2 or 3, heteroatoms selected from O, S and N an
Bassini Domenico Fusar
Ceccarelli Walter
Ciomei Marina
Menichincheri Maria
Mongelli Nicola
Pharmacia S.p.A.
Trinh Ba K.
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