Patent ID: 6596725
Filing Date: 2003-07-22
Classification: A61K,C07H

Abstract:
A method of treating edematous retinal disorders, retinal detachment, or retinal edema, in a subject in need thereof, said method comprising:administering to said subject a pharmaceutical composition comprising a P2Y receptor agonist or pharmaceutically acceptable salts thereof, in an amount effective to stimulate the removal of pathological fluid accumulation in intra-retinal and subretinal spaces associated with edematous retinal disorders, retinal detachment, or retinal edema, wherein said P2Y receptor agonist is a dinucleoside polyphosphate compound of Formula I: wherein:X is oxygen, methylene, difluoromethylene, or imido; n=0, 1 or 2; m=0, 1 or 2; n+m=0, 1, 2, 3 or 4; Z&boxH;OH or H; Zâ€²&boxH;OH or H; Y&boxH;H or OH; Yâ€²&boxH;H or OH; and B and Bâ€² are each independently a purine residue or a pyrimidine residue, as defined Formula Ia and Ib, respectively, linked through the 9- or 1-position, respectively: whereinR1 is selected from the group consisting of: hydrogen, chlorine, amino, monosubstituted amino, disubstituted amino, alkylthio, arylthio, or aralkylthio, where the substituent on sulfur contains up to a maximum of 20 carbon atoms, with or without unsaturation; R2 is selected from the group consisting of hydroxy, oxo, amino, mercapto, alkylthio, arylthio, aralkylthio, acylthio, alkyloxy, aryloxy, aralkyloxy, acyloxy, monosubstituted alkylamino, heterocyclic, monosubstituted cycloalkylamino, monosubstituted aralkylamino, monosubstituted arylamino, diaralkylamino, diarylamino, dialkylamino, acylamino, diacylamino, or NHRy; Rx is O or is absent; wherein R2 is NHRy, and Ry and Rx taken together form a 5-membered fused imidazole ring, optionally substituted on the 4- or 5-positions of the etheno moiety with alkyl, aryl or aralkyl moieties; R3 is hydrogen, azido, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, or aralkylthio; or A(C1-6 alkyl)OCONH(C1-6 alkyl)B-wherein A and B are independently amino, mercapto, hydroxy or carboxyl; or pharmaceutically acceptable esters, amides or salts thereof; J is carbon or nitrogen, with the provision that when J is nitrogen, R3 is not present; and wherein alkyls are straight-chain, branched or cyclic; wherein aryl groups are optionally substituted with lower alkyl, amino, alkylamino, NO2, N3, carboxylic, amido, sulfonamido, and halo groups; or wherein: R4 is selected from the group consisting of: hydrogen, oxo, hydroxy, mercapto, amino, cyano, C7-12 arylalkoxy, C1-6 alkylthio, C1-6 alkoxy, C1-6 alkylamino, and diC1-4 alkylamino, wherein the alkyl groups are optionally linked to form a heterocycle; R5 is selected from the group consisting of: hydrogen, acetyl, benzoyl, C1-6 alkyl, C1-5 alkanoyl, and aroyl; optionally R, is not present; R6 is selected from the group consisting of: hydroxy, oxo, mercapto, C1-4 alkoxy, C7-12 arylalkoxy, C1-6 alkylthio, S-phenyl, C1-5 disubstituted amino, triazolyl, C1-6 alkylamino, and di-C1-4 alkylamino wherein said dialkyl groups are optionally linked to form a heterocycle or linked to N3 to form a substituted ring; or R5 and R6 taken together form a 5-membered fused imidazole ring between positions 3 and 4 of the pyrimidine ring and form a 3, N4-ethenocytosine derivative, wherein said etheno moiety is optionally substituted on the 4- or 5-positions with C1-4 alkyl; phenyl; or phenyloxy; wherein at least one hydrogen of said C1-4 alkyl; phenyl or phenyloxy is optionally substituted with a moiety selected from the group consisting of: halogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, C6-10 aryl, C7-12 arylalkyl, carboxy, cyano, nitro, sulfonamido, sulfonate, phosphate, sulfonic acid, amino, C1-4 alkylamino, and di-C1-4 alkylamino wherein said dialkyl groups are optionally linked to form a heterocycle; R7 is selected from the group consisting of: hydrogen, hydroxy, cyano, nitro, and C2-8 alkenyl; wherein said alkenyl moiety is optionally linked through an oxygen to form a ring, wherein at least one hydrogen of said alkenyl moiety on the carbon adjacent to said oxygen is optionally substituted with a substituent selected from the group consisting of: C1-6 alkyl, phenyl, substituted C2-8 alkynyl, halogen, substituted C1-4 alkyl, CF3, C2-3 alkenyl, C2-3 alkynyl, allylamino, bromovinyl, ethyl propenoate, and propenoic acid; or R6 and R7 together form a 5 or 6-membered saturated or unsaturated ring bonded through N or O or S at R6, such ring optionally contains functional substituents; provided that when R8 is amino or substituted amino, R7 is hydrogen; and R8 is selected from the group consisting of hydrogen, amino, di-C1-4 alkylamino, C1-4 alkoxy, C7-12 arylalkoxy, C1-4 alkylthio, C7-12 arylalkylthio, carboxamidomethyl, carboxymethyl, methoxy, methylthio, phenoxy and phenylthio.