Back to results
US 5,272,171 AGranted
Phosphonooxy and carbonate derivatives of taxol
AssigneeBristol-Myers Squibb Company
InventorsYasutsugu Ueda, Henry Wong, Vittorio Farina, Amarendra Mikkilineni, Dolatrai M. Vyas, Terrence Doyle
Life of this patent
Estimating the term…
Abstract
The present invention is directed to novel taxol derivatives useful as anti-tumor agents. Also provided by this invention is pharmaceutical formulations and methods of treating mammalian tumors with the compounds of this invention.
Claims52
A compound of formula I ##STR135## or a pharmaceutically acceptable salt thereof, in which R.sup.j is --COR.sup.2 in which R.sup.2 is t-butyloxy, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, or phenyl, optionally substituted with one to three same or different C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or --CF.sub.3 groups;
- R.sup.y is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, or a radical of the formula --W--R.sup.x in which W is a bond, C.sub.2-6 alkenediyl, or --(CH.sub.2).sub.t --, in which t is one to six;
- and R.sup.x is naphthyl, furyl, thienyl or phenyl, and furthermore R.sup.x can be optionally substituted with one to three same or different C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or --CF.sub.3 groups;
- R.sup.w is hydrogen, hydroxy, acetyloxy, --OC(.dbd.O)OY or --OZ;
- R.sup.1 is hydrogen, hydroxy, --OC(.dbd.O)OY or --OZ;
- R.sup.2 is hydroxy, --OC(.dbd.O)OY, --OC(.dbd.O)R or --OZ, with the proviso at least one of R.sup.1, R.sup.2 or R.sup.w is --OC(.dbd.O)OY or --OZ;
- R is C.sub.1-6 alkyl;
- Z is of the formula ##STR136## wherein R.sup.3 and R.sup.4 are independently hydrogen or C.sub.1-6 alkyl, or R.sup.3 and R.sup.4 taken together with the carbon atom to which they are attached form C.sub.3-6 cycloalkylidene;
- R.sup.5 is --OC(.dbd.O)R, --OP.dbd.O(OH).sub.2 or --CH.sub.2 OP.dbd.O(OH).sub.2 ;
- R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or hydrogen;
- or one of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is --OC(.dbd.O)R, --OP.dbd.O(OH).sub.2 or hydroxy, and the others are independently halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or hydrogen;
- but when R.sup.5 is --OC(.dbd.O)R, one of R.sup.6, R.sup.7, R.sup.8 or R.sup.9 must be --OP.dbd.O(OH).sub.2 ;
- Q is --(CH.sub.2).sub.q --, optionally substituted with one to six same or different C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl, or a carbon atom of said --(CH.sub.2).sub.q -- group can also be a part of C.sub.3-6 cycloalkylidene;
- q is 2 to 6;
- n is 0, and m is 1 or 0 when R.sup.5 is --CH.sub.2 OP.dbd.O(OH).sub.2 ;
- n is 1 or 0, and m is 1 when R.sup.5 is --OC(.dbd.O)R or --OP.dbd.O(OH).sub.2 ;
- Y is C.sub.1-6 alkyl (optionally substituted with --OP.dbd.O(OH).sub.2 or one to six same or different halogen atoms), C.sub.3-6 cycloalkyl, C.sub.2-6 alkenyl, or a radical of the formula ##STR137## in which D is a bond or --(CH.sub.2).sub.t --, optionally substituted with one to six same or different C.sub.1-6 alkyl;
- and R.sup.a, R.sup.b and R.sup.c are independently hydrogen, amino, C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, halogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
- and
- with the further proviso that R.sup.2 cannot be --OP.dbd.O(OH).sub.2 ;
- Y cannot be --CH.sub.2 CCl.sub.3 ;
- and R.sup.1 cannot be ##STR138##
18 more elements
A compound of formula I ##STR140## or a pharmaceutically acceptable salt thereof, in which R.sup.j is --COR.sup.z in which R.sup.z is t-butyloxy, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, or phenyl, optionally substituted with one to three same or different C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or --CF.sub.3 groups;
- R.sup.y is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, or a radical of the formula --W--R.sup.x in which W is a bond, C.sub.2-6 alkenediyl, or --(CH.sub.2).sub.t --, in which t is one to six;
- and R.sup.x is naphthyl, furyl, thienyl or phenyl, and furthermore R.sup.x can be optionally substituted with one to three same or different C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or --CF.sub.3 groups;
- R.sup.w is hydrogen, hydroxy, acetyloxy, --OC(.dbd.O)OY or --OZ;
- R.sup.1 is of the formula ##STR141## R.sup.2 is hydroxy, --OC(.dbd.O)OY, --OC(.dbd.O)R or --OZ;
- R is C.sub.1-6 alkyl;
- Z is of the formula ##STR142## wherein R.sup.3 and R.sup.4 are independently hydrogen or C.sub.1-6 alkyl, or R.sup.3 and R.sup.4 taken together with the carbon atom to which they are attached form C.sub.3-6 cycloalkylidene;
- R.sup.5 is --OC(.dbd.O)R, --OP.dbd.O(OH).sub.2 or --CH.sub.2 OP.dbd.O(OH).sub.2 ;
- R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or hydrogen;
- or one of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is --OC(.dbd.O)R, --OP.dbd.O(OH).sub.2 or hydroxy, and the others are independently halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or hydrogen;
- but when R.sup.5 is --OC(.dbd.O)R, one of R.sup.6, R.sup.7, R.sup.8 or R.sup.9 must be --OP.dbd.O(OH).sub.2 ;
- Q is --(CH.sub.2).sub.q --, optionally substituted with one to six same or different C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl, or a carbon atom of said --(CH.sub.2).sub.q -- group can also be a part of C.sub.3-6 cycloalkylidene;
- q is 2 to 6;
- n is 0, and m is 1 or 0 when R.sup.5 is --CH.sub.2 OP.dbd.O(OH).sub.2 ;
- n is 1 or 0, and m is 1 when R.sup.5 is --OC(.dbd.O)R or --OP.dbd.O(OH).sub.2 ;
- Y is C.sub.1-6 alkyl (optionally substituted with --OP.dbd.O(OH).sub.2 or one to six same or different halogen atoms), C.sub.3-6 cycloalkyl, C.sub.2-6 alkenyl, or a radical of the formula ##STR143## in which D is a bond or -(CH.sub.2).sub.t --, optionally substituted with one to six same or different C.sub.1-6 alkyl;
- and R.sup.a, R.sup.b and R.sup.c are independently hydrogen, amino, C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, halogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
- and
- with the further proviso that R.sup.2 cannot be --OP.dbd.O(OH).sub.2 ;
- and Y cannot be --CH.sub.2 CCl.sub.3.
16 more elements
Dependencies are inferred from the claim text.