S1P3 Receptor Inhibitors for Treating Conditions of the Eye

A method for treating a condition of the eye selected from the group consisting of non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema, uveitis, retinitis, choroiditis, Behcet's disease, birdshot retinochoroidopathy, infectious uveitis, intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome, retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telanqiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, anqioid streaks, familial exudative vitreoretinopathy, Eales disease, sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, conditions caused by laser, conditions caused by photodynamic therapy, photocoaqulation, hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy, proliferative vitreal retinopathy, epiretinal membranes, proliferative diabetic retinopathy;

• ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associate with HIV infection, uveitic disease associate with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, myiasis, retinitis piqmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best's disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsbv's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma elasticum, retinal detachment, macular hole, giant retinal tear, retinal disease associated with tumors, congenital hypertrophy of the retinal pigmented epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, and intraocular lymphoid tumors, punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal piqement epitheliitis, the method comprising the step of administering to a patient in need of such treatment a compound represented by the general formula I:
• or a pharmaceutically acceptable salt thereof, wherein
• X is NR5, O, S;
• Z is O or S;
• n is 0 or an integer of from 1 to 4;
• o is 0 or an integer of from 1 to 3;
• p is 0 or an integer of from 1 to 4;
• A is (C(R5)2)m, wherein
• m is 0 or an integer of from 1 to 6;
• R5 is selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, aryl, wherein said aryl is a carbocyclic aryl or heterocyclic aryl group wherein said carbocylic aryl comprises from 6 to 20 atoms and said heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, halo, C1 to C12 haloalkyl, hydroxyl, C1 to C12 alkoxy, C1 to C12 alkylcarbonyl, formyl, oxycarbonyl, carboxy, C1 to C12 alkyl carboxylate, C1 to C12 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl and sulfonyl groups;
• Y is a carbocyclic aryl or heterocyclic aryl group wherein said carbocylic aryl comprises from 6 to 20 atoms and said heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein said aryl may be bonded to A at any position;
• R1, R2, R3, R4 are selected from the group consisting of hydrogen;
• straight or branched chain alkyl having 1 to 12 carbons;
• cycloalkyl having 3 to 6 carbons;
• alkenyl having 2 to 6 carbons and 1 or 2 double bonds;
• alkynyl having 2 to 6 carbons and 1 or 2 triple bonds;
• aryl wherein said aryl is a carbocyclic aryl or heterocyclic aryl group wherein said carbocylic aryl comprises from 6 to 20 atoms and said heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
• halo;
• C1 to C12 haloalkyl;
• hydroxyl;
• C1 to C12 alkoxy;
• C3 to C20 arylalkyloxy;
• C1 to C12 alkylcarbonyl;
• formyl;
• oxycarbonyl;
• carboxy;
• C1 to C12 alkyl carboxylate;
• C1 to C12 alkyl amide;
• aminocarbonyl;
• amino;
• cyano;
• diazo;
• nitro;
• thio;
• sulfoxyl;
• sulfonyl groups;
• or a group selected from the group consisting of
• wherein R is CO2H or PO3H2, p is an integer of 1 or 2 and q is 0 or an integer of 1 to 5 and s is 0 or an integer of 1 or 2;
• provided that, if Y is phenyl, it must be substituted with at least one R4 group that is not hydrogen.

A method of treating a conditions of the eye selected from the group consisting of non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema, uveitis, retinitis, choroiditis, Behcet's disease, birdshot retinochoroidopathy, infectious uveitis, intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiqinous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome, retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telanqiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, anqioid streaks, familial exudative vitreoretinopathy, Eales disease, sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, conditions caused by laser, conditions caused by photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy, proliferative vitreal retinopathy, epiretinal membranes, proliferative diabetic retinopathy;

• ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associate with HIV infection, uveitic disease associate with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, myiasis, retinitis piqmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best's disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsbv's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma elasticum, retinal detachment, macular hole, giant retinal tear, retinal disease associated with tumors, congenital hypertrophy of the retinal pigmented epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, and intraocular lymphoid tumors, punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal piqement epitheliitis, the method comprising the step of administering to a patient in need of such treatment a compound represented by the general formula IV:
• or a pharmaceutically acceptable salt thereof, wherein
• X is selected from the group consisting of CR3 and N;
• Y is selected from the group consisting of CR3 and N;
• Z is selected from the group consisting of CR3 and N;
• at least one of X, Y and Z is N;
• W is NR3 or 0;
• R1 is an aryl group;
• R2 is an aryl group;
• R3 is selected from the group consisting of H and alkyl;
• and 2 of said R3 groups may together with N may form a heterocylic ring having from 2 to 6 carbon atoms;
• R4 is selected from the group consisting of H, alkyl, OR3, and N(R3)2;
• a is 0 or an integer of from 1 to 6;
• b is 0 or 1;
• c is 0 or an integer of from 1 to 6;
• d is 0 or 1;
• e is 0 or 1;
• u is 0 or 1;
• v is 0 or an integer of from 1 to 2;
• x is 0 or 1;
• y is 0 or an integer of from 1 to 3;
• z is 0 or an integer of from 1 to 3;
• provided, however, that when d is 0, e is 1, and when e is 0, d is 1.