Claims
- 1. A method for inhibiting human immunodeficiency virus activation in an infected cell which comprises contacting the cell with a viral activation inhibiting amount of an inhibitor of the .beta. isozyme of protein kinase C.
- 2. The method of claim 1 wherein the inhibitor of the .beta. isozyme of protein kinase C is a bis-indolylmaleimides or a macrocyclic bis-indolylmaleimide.
- 3. The method of claim 1 wherein the inhibitor is isozyme selective and where the isozyme selectivity is selected from the group consisting of beta-1 and beta-2 isozymes.
- 4. The method of claim 3 wherein the protein kinase C inhibitor has the following formula: ##STR5## 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.sup.3 --, --NOR.sup.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.sup.1 s are hydrogen or up to four optional substituents independently selected from halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sup.4 R.sup.5, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sup.2 is hydrogen, CH.sub.3 CO--, NH.sub.2, or hydroxy;
- R.sup.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.sup.4 R.sup.5, --(C.dbd.NH)NH.sub.2, --SO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (NR.sup.4 R.sup.5), or --SO.sub.2 (C.sub.1 -C.sub.4 alkyl);
- R.sup.4 and R.sup.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, prodrug or ester thereof.
- 5. The method of claim 4 wherein the protein kinase C inhibitor has the following formula: ##STR6## wherein Z is --(CH.sub.2).sub.p -- or --(CH.sub.2).sub.p --O--(CH.sub.2).sub.p --; R.sup.4 is hydroxy, --SH, C.sub.1 -C.sub.4 alkyl, (CH.sub.2).sub.m aryl, --NH(aryl), --N(CH.sub.3) (CF.sub.3), --NH(CF.sub.3), or --NR.sup.5 R.sup.6 ; R.sup.5 is hydrogen or C.sub.1 -C.sub.4 alkyl; R.sup.6 is hydrogen, C.sub.1 -C.sub.4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof.
- 6. The method of claim 4 wherein the protein kinase C inhibitor has the following formula: ##STR7## wherein Z is --(CH).sub.p --; R.sup.4 is --NR.sup.5 R.sup.6, --NH(CF.sub.3), or --N(CH.sub.3) (CF.sub.3); R.sup.5 and R.sup.6 are independently H or C.sub.1 -C.sub.4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof.
- 7. The method of claim 4, wherein the protein kinase C inhibitor comprises (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 or its pharmaceutically acceptable acid salt.
- 8. A method of claim 7, wherein the pharmaceutically acceptable acid salt is selected from the hydrochloride sale and the mesylate salt.
- 9. A method for inhibiting human immunodeficiency virus replication in an infected cell which comprises contacting the cell with a viral replication inhibiting amount of an inhibitor of the .beta. isozyme of protein kinase C.
- 10. The method of claim 9 wherein the inhibitor of the .beta. isozyme of protein kinase C is a bis-indolylmaleimides or a macrocyclic bis-indolylmaleimides.
- 11. The method of claim 9 wherein the inhibitor is isozyme selective and where the isozyme selectivity is selected from the group consisting of beta-1 and beta-2 isozymes.
- 12. The method of claim 11 wherein the protein kinase C inhibitor has the following formula: ##STR8## 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.sup.3 --, --NOR.sup.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.sup.1 s are hydrogen or up to four optional substituents independently selected from halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sup.4 R.sup.5, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sup.2 is hydrogen, CH.sub.3 CO--, NH.sub.2, or hydroxy;
- R.sup.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.sup.4 R.sup.5, --(C.dbd.NH)NH.sub.2, --SO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (NR.sup.4 R.sup.5), or --SO.sub.2 (C.sub.1 -C.sub.4 alkyl);
- R.sup.4 and R.sup.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, prodrug or ester thereof.
- 13. The method of claim 12 wherein the protein kinase C inhibitor has the following formula: ##STR9## wherein Z is --(CH.sub.2).sub.p -- or --O--(CH.sub.2).sub.p --; R.sup.4 is hydroxy, --SH, C.sub.1 -C.sub.4 alkyl, (CH.sub.2).sub.m aryl, --NH(aryl), --N(CH.sub.3) (CF.sub.3), --NH(CF.sub.3), or --NR.sup.5 R.sup.6 ; R.sup.5 is hydrogen or C.sub.1 -C.sub.4 alkyl; R.sup.6 is hydrogen, C.sub.1 -C.sub.4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof.
- 14. The method of claim 12 wherein the protein kinase C inhibitor has the following formula: ##STR10## wherein Z is --(CH.sub.2).sub.p --; R.sup.4 is --NR.sup.5 R.sup.6, --NH(CF.sub.3), or --N(CH.sub.3) (CF.sub.3); R.sup.5 and R.sup.6 are independently H or C.sub.1 -C.sub.4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof.
- 15. The method of claim 12, wherein the protein kinase C inhibitor comprises (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 or its pharmaceutically acceptable acid salt.
- 16. A method of claim 15, wherein the pharmaceutically acceptable acid salt is selected from the hydrochloride salt and the mesylate salt.
- 17. A method for treating a mammal infected with human immunodeficiency virus which comprises administering to the mammal a therapeutically effective amount of an inhibitor of the .beta. isozyme of protein kinase C.
- 18. The method of claim 17 wherein the inhibitor of the .beta. isozyme of protein kinase C is a bis-indolylmaleimides or a macrocyclic bis-indolylmaleimides.
- 19. The method of claim 17 wherein the inhibitor is isozyme selective and where the isozyme selectivity is selected from the group consisting of beta-1 and beta-2 isozymes.
- 20. The method of claim 19 wherein the protein kinase C inhibitor has the following formula: ##STR11## 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.sup.3 --, --NOR.sup.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.sup.1 s are hydrogen or up to four optional substituents independently selected from halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sup.4 R.sup.5, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sup.2 is hydrogen, CH.sub.3 CO--, NH.sub.2, or hydroxy;
- R.sup.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.sup.4 R.sup.5, --(C.dbd.NH)NH.sub.2, --SO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (NR.sup.4 R.sup.5), or --SO.sub.2 (C.sub.1 -C.sub.4 alkyl);
- R.sup.4 and R.sup.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, prodrug or ester thereof.
- 21. The method of claim 20 wherein the protein kinase C inhibitor has the following formula: ##STR12## wherein Z is --(CH).sub.p -- or --(CH.sub.2).sub.p --O--(CH.sub.2).sub.p --; R.sup.4 is hydroxy, --SH, C.sub.1 -C.sub.4 alkyl, (CH.sub.2).sub.m aryl, --NH(aryl), --N(CH.sub.3) (CF.sub.3), --NH(CF.sub.3), or --NR.sup.5 R.sup.6 ; R.sup.5 is hydrogen or C.sub.1 -C.sub.4 alkyl; R.sup.6 is hydrogen, C.sub.1 -C.sub.4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof.
- 22. The method of claim 20 wherein the protein kinase C inhibitor has the following formula: ##STR13## wherein Z is --(CH.sub.2).sub.p --; R.sup.4 is --NR.sup.5 R.sup.6, --NH(CF.sub.3), or --N(CH.sub.3) (CF.sub.3); R.sup.5 and R.sup.6 are independently H or C.sub.1 -C.sub.4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof.
- 23. The method of claim 20, wherein the protein kinase C inhibitor comprises (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 or its pharmaceutically acceptable acid salt.
- 24. A method of claim 23, wherein the pharmaceutically acceptable acid salt is selected from the hydrochloride salt and the mesylate salt.
Parent Case Info
This application claims the priority benefits of the U.S. Provisional application Serial No. 60/024,873 filed Aug. 30, 1996.
US Referenced Citations (6)
Foreign Referenced Citations (2)
Number |
Date |
Country |
0 428 105 A2 |
May 1991 |
EPX |
0 657 411 A1 |
Feb 1994 |
EPX |