Patent EA-001752-B1 (EA)
Title: Therapeutic treatment for vegf related occular diseases
Inventor: AIELLO LLOYD P
IPC: C07D487/22
Filed: 1997-05-01
Abstract: 1. A method for treating an ocular vascular disorder, selected from the group consisting of macular degeneration, macular edema, vascular retinopathy, iris neovascularization, retinal vein occlusion, histoplasmosis, and ischemic retinal disease which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of an inhibitor of the β isoenzyme of protein kinase C of the following formula   wherein: W is -O-, -S-, -SO-, -SO2-, -CO-, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl-, -aryl(CH2)mO-, -heterocycle-, -heterocycle-(CH2)mO-, -fused bicyclic-, -fused bicyclic-(CH2)mO-, -NR<3>-, -NOR<3>-, -CONH-, or -NHCO-; X and Y are independently C1-C4 alkylene, substituted alkylene, or together X, Y, and W are combined to form -(CH2)nAA-; R<1> radicals are hydrogen or up to four optional substituents independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, NR<4>R<5>, or -NHCO(C1-C4 alkyl); R<2> is hydrogen, CH3CO-, NH2, or hydroxy; R<3> is hydrogen, (CH2)maryl, C1-C4 alkyl, COO(C1-C4 alkyl),-CONR<4>R<5>, -(C=NH)NH2, -SO(C1-C4 alkyl), -SO2(NR<4>R<5>),or -SO2(C1-C4 alkyl); R<4> and R<5> are independently hydrogen, C1-C4 alkyl, phenyl, benzyl, or combined 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. 2. The method of Claim 1 wherein the inhibitor of the β isoenzyme of protein kinase C is a bis-indolylmaleimide or a macrocyclic bis-indolylmaleimide. 3. The method of Claim 1 wherein the inhibitor is isoenzyme selective and where the isoenzyme is selected from the group consisting of β-1 and β-2 isoenzymes. 4. The method of Claim 3 wherein the protein kinase C inhibitor has the following formula:   wherein: W is -O-, -S-, -SO-, -SO2-, -CO-, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl-, -aryl(CH2)mO-, -heterocycle-, -heterocycle-(CH2)mO-, -fused bicyclic-, -fused bicyclic-(CH2)mO-, -NR<3>-, -NOR<3>-, -CONH-, or -NHCO-; X and Y are independently C1-C4 alkylene, substituted alkylene, or together X, Y, and W are combined to form -(CH2)nAA-; R<1> radicals are hydrogen or up to four optional substituents independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, NR<4>R<5>, or -NHCO(C1-C4 alkyl); R<2> is hydrogen, CH3CO-, NH2, or hydroxy; R<3> is hydrogen, (CH2)maryl, C1-C4 alkyl, -COO(C1-C4 alkyl),-CONR<4>R<5>, -(C=NH)NH2, -SO(C1-C4 alkyl), -SO2(NR<4>R<5>),or -SO2(C1-C4 alkyl); R<4> and R<5> are independently hydrogen, C1-C4 alkyl, phenyl, benzyl, or combined 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   wherein Z is -(CH2)p- or -(CH2)p-O-(CH2)p-; R<4> is hydroxy, -SH, C1-C4 alkyl, (CH2)m aryl, -NH(aryl), -N(CH3) (CF3), -NH(CF3), or NR<5>R<6>; R<5> is hydrogen or C1-C4 alkyl; R<6> is hydrogen, C1-C4 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:   wherein Z is -(CH2)p-; R<4> is NR<5>R<6>, -NH(CF3), or -N(CH3) (CF3); R<5> and R<6> are independently H or C1-C4 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)]-l(H)-pyrrole-2,5-dione or its pharmaceutically acceptable acid salt. 8. The method of Claim 1 wherein the ocular vascular disorder is selected from the group consisting of macular degeneration, macular edema, vascular retinopathy, iris neovascularization, retinal vein occlusion, histoplasmosis, and ischemic retinal disease. 9. The method of Claim 1 wherein the ocular vascular disorder is selected from the group consisting of macular degeneration, macular edema, and retinal vein occlusion. 10. The method of Claim 8 wherein said vascular retinopathy is retinopathy of prematurity. 11. A method for inhibiting endothelial cell growth stimulated by VEGF which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of an inhibitor of the β isoenzyme of protein kinase C:   wherein: W is -O-, -S-, -SO-, -SO2-, -CO-, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl-, -aryl(CH2)mO-, -heterocycle-, -heterocycle-(CH2)mO-, -fused bicyclic-, -fused bicyclic-(CH2)mO-, -NR<3>-, -NOR<3>-, -CONH-, or -NHCO-; X and Y are independently C1-C4 alkylene, substituted alkylene, or together X, Y, and W are combined to form -(CH2)nAA-; R<1> radicals are hydrogen or up to four optional substituents independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, NR<4>R<5>, or -NHCO(C1-C4 alkyl); R<2> is hydrogen, CH3CO-, NH2, or hydroxy; R<3> is hydrogen, (CH2)maryl, C1-C4 alkyl, -COO(C1-C4 alkyl),-CONR<4>R<5>, -(C=NH)NH2, -SO(C1-C4 alkyl), -SO2(NR<4>R<5>),or -SO2(C1-C4 alkyl); R<4> and R<5> are independently hydrogen, C1-C4 alkyl, phenyl, benzyl, or combined 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. 12. A method for inhibiting VEGF stimulated capillary permeability associated with edema, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of an inhibitor of the β isoenzyme of protein kinase C of general formula    wherein: W is -O-, -S-, -SO-, -SO2-, -CO-, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl-, -aryl(CH2)mO-, -heterocycle-, -heterocycle-(CH2)mO-, -fused bicyclic-, -fused bicyclic-(CH2)mO-, -NR<3>-, -NOR<3>-, -CONH-, or -NHCO-; X and Y are independently C1-C4 alkylene, substituted alkylene, or together X, Y, and W are combined to form -(CH2)nAA-; R<1> radicals are hydrogen or up to four optional substituents independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, NR<4>R<5>, or -NHCO(C1-C4 alkyl); R<2> is hydrogen, CH3CO-, NH2, or hydroxy; R<3> is hydrogen, (CH2)maryl, C1-C4 alkyl, -COO(C1-C4 alkyl),-CONR<4>R<5>, -(C=NH)NH2, -SO(C1-C4 alkyl), -SO2(NR<4>R<5>), or -SO2(C1-C4 alkyl); R<4> and R<5> are independently hydrogen, C1-C4 alkyl, phenyl, benzyl, or combined 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.