Hybrid antitumor compounds containing a cyclic enediyne and a DNA-binder
AssigneeBristol-Myers Squibb Company
InventorsMark D. Wittman, David Langley, John F. Kadow
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Abstract
The present invention provides novel antitumor agents which are hybrid molecules consisting of a cyclic enediyne unit attached to a DNA-binding unit via a linker unit, and having the general formula (I) D--(OCH.sub.2).sub.m --O--(CH.sub.2).sub.n --Ar--Y--CONH--B(I) wherein D is a cyclic enediyne; B is a residue capable of binding to the minor groove of DNA; n is 0 and m is 1, is or n is 1 and m is 0 or 1; Ar is an aromatic residue selected from the group consisting of phenyl, naphthyl, pyridyl, quinolinyl and indolyl; and Y is a direct bond, --CH.sub.2 -- or --CH.dbd.CH--; or a pharmaceutically acceptable salt thereof.
Claims13
compound having the formula
- D--(OCH.sub.2).sub.m --O--(CH.sub.2).sub.n --Ar--Y--CONH--B
- wherein D is a radical of the formula ##STR22## wherein is a double bond, a single bond, or an epoxy;
- one of R.sup.x or R.sup.y is hydrogen and the other is hydrogen or hydroxy;
- or R.sup.x and R.sup.y together is an oxo group;
- R.sup.w is hydrogen, --C(O) R.sup.s, --C(O)NR.sup.t R.sup.u or --C(O)OR.sup.v ;
- R.sup.z is hydrogen, hydroxy, --OC(O)R.sup.s, --OC(O)NR.sup.t R.sup.u or --OC(O)OR.sup.v ;
- R.sup.s is hydrogen, C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, C.sub.7-14 aralkyl or quinoxalyl;
- R.sup.t and R.sup.u are independently hydrogen, C.sub.1-8 alkyl, amino-substituted C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, C.sub.7-14 aralkyl, pyridyl or quinoxalyl;
- R.sup.v is C.sub.1-8 alkyl, halo-substituted C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, C.sub.6-10 aryl or C.sub.7-14 aralkyl;
- B is a radical of the formula ##STR23## wherein T, U, V and W are independently CH or N;
- p is 1 or 2;
- and Z is a group selected from --CH(CH.sub.3)CO.sub.2 R;
- --CH (CH.sub.3)CONHCH(CH.sub.3)CO.sub.2 R;
- --(CH.sub.2).sub.2 C(NH)NH.sub.2 ;
- --(CH.sub.2).sub.2 C(O)NH.sub.2 ;
- --(CH.sub.2).sub.q NR.sup.1 R.sup.2 ;
- and acridine-9-(1,4-phenylenediamine) radical of the formula ##STR24## wherein R is hydrogen or lower alkyl;
- q is 2 or 3;
- R.sup.1 and R.sup.2 are independently H, lower alkyl, hydroxy lower alkyl, or amino lower alkyl;
- n is 0 and m is 1, or n is 1 and m is 0 or 1;
- Ar is an aromatic residue selected from the group consisting of phenyl, naphthyl, pyridyl, quinolinyl and indolyl;
- and Y is a direct bond, --CH.sub.2 -- or CH.dbd.CH;
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.