Protein kinase c inhibitors
AssigneeEli Lilly and Company
InventorsWilliam F. Heath, Jr., Michael R. Jirousek, John H. McDonald, III, Christopher J. Rito
Life of this patent
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Abstract
This invention provides novel bis-indolemaleimide macrocycle derivatives of the formula: ##STR1## The invention further provides the preparation, pharmaceutical formulations and the methods of use for inhibiting Protein Kinase C in mammals.
Claims37
A compound of Formula:
- ##STR70## wherein:
- W is --O--, --S--, --SO--, --SO.sub.2 --, --CO--, C.sub.2 -C.sub.6 alkylene, substituted alkylene, C.sub.2 -C.sub.6 alkenylene, -aryl-, -aryl(CH.sub.2).sub.m O--, -heterocycle-, -heterocycle--(CH.sub.2).sub.m O--, -fused bicyclic-, -fused bicyclic--(CH.sub.2).sub.m O--, --NR.sub.3 --, --NOR.sub.3 --, --CONH--, or --NHCO--;
- X and y are independently C.sub.1 -C.sub.4 alkylene, substituted alkylene, or together X, y, and W combine to form --(CH.sub.2).sub.n --AA--;
- R.sub.1 is independently hydrogen, halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sub.4 R.sub.5, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sub.2 is hydrogen, CH.sub.3 CO--, NH.sub.2, or hydroxy;
- R.sub.3 is hydrogen, (CH.sub.2).sub.m aryl, C.sub.1 -C.sub.4 alkyl, --COO(C.sub.1 -C.sub.4 alkyl), --CONR.sub.4 R.sub.5, --(C.dbd.NH)NH.sub.2, --SO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (NR.sub.4 R.sub.5), or --SO.sub.2 (C.sub.1 -C.sub.4 alkyl);
- R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring;
- AA is an amino acid residue;
- m is independently 0, 1, 2, or 3;
- and
- n is independently 2, 3, 4, or 5;
- or
- a pharmaceutically acceptable salt or solvate thereof.
A compound selected from the group consisting of (R)-3,4-[(N,N'-1,1'-((2"-ethoxy)-3'"-((O)-4'"-(N,N-dimethylamino)-butane)- bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, (S)-3,4-[(N,N'-1,1'-((2"-ethoxy)-3'"-((O)-4'"-(N,N-dimethylamino)-butane )-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, a mixture thereof;
- or a pharmaceutically acceptable salt or solvate thereof.
A compound selected from the group consisting of (S)-3,4-[(N,N'-1,1'-((2"-ethoxy)-3'"-(O)-4'"-(N-pyrrolidine)-butane)-bis-( 3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, (R)-3,4-[(N,N'-1,1'-((2"-ethoxy)-3'"-(O)-4'"-(N-pyrrolidine)-butane)-bis-( 3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, a mixture thereof, or a pharmaceutically acceptable salt or solvent thereof.
A compound selected from the group consisting of (S)-3,4-[(N,N'-1,1'-((2"-ethoxy)-3" '-(O)-4'"-(N-phenylsulfonamido)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2 ,5-dione, (R)-3,4-[(N,N'-1,1'-((2"-ethoxy)-3'"-((O)-4'"-(N-phenylsulfonamido-butane) -bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, a mixture thereof, or a pharmaceutically acceptable salt or solvent thereof.
A compound of the Formula:
- ##STR73## wherein:
- V is --O--or N--CH.sub.3 ;
- W is --O--, --S--, --SO--, --SO.sub.2 --, --CO--, C.sub.2 -C.sub.6 alkylene, substituted alkylene, C.sub.2 -C.sub.6 alkenylene, -aryl-, -aryl(CH.sub.2).sub.m O--, -heterocycle-, -heterocycle--(CH.sub.2).sub.m O--, -fused bicyclic-, -fused bicyclic--(CH.sub.2).sub.m O--, --NR.sub.3 --, --NOR.sub.3 --, --CONH--, or --NHCO--;
- X and y are independently C.sub.1 -C.sub.4 alkylene, substituted alkylene, or together X, y, and W combine to form --(CH.sub.2).sub.n --AA--;
- R.sub.1 is independently hydrogen, halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sub.4 R.sub.5, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sub.3 is hydrogen, (CH.sub.2).sub.m aryl, C.sub.1 -C.sub.4 alkyl, --COO (C.sub.1 -C.sub.4 alkyl), --CONR.sub.4 R.sub.5, --(C.dbd.NH) NH.sub.2, --SO (C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (NR.sub.4 R.sub.5), or --SO.sub.2 (C.sub.1 -C.sub.4 alkyl);
- R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring;
- AA is an amino acid residue;
- m is independently 0, 1, 2, or 3;
- and
- n is independently 2, 3, 4, or 5.
Dependencies are inferred from the claim text.