Dinucleoside polyphosphate compositions and their therapuetic use as purinergic receptor agonists

A compound of Formula II:

• wherein:
• X is oxygen, methylene, dihalomethylene, or imido;
• n=0, 1 or 2;
• m=0, 1 or 2;
• n+m=0,1, 2, 3 or 4;
• Z=OH or H;
• Z′=OH or H;
• Y=OH or H;
• Y′=OH or H;
• and
• B and B′ are each independently a purine residue or a pyrimidine residue, as defined in Formula IIa or IIb, linked through the 9- or 1-position, respectively;
• and provided that at least one of B and B′ is a purine;
• R1 is hydrogen, chlorine, amino, monosubstituted amino, disubstituted amino, alkylthio, arylthio, or aralkylthio, wherein the substituent on sulfur contains up to a maximum of 20 carbon atoms, with or without unsaturation;
• R2 is hydroxy, alkenyl, oxo, amino, mercapto, thione, alkylthio, arylthio, aralkylthio, acylthio, alkyloxy, aryloxy, aralkyloxy, acyloxy, monosubstituted alkylamino, heterocyclic, monosubstituted cycloalkylamino, monosubstituted aralkylamino, monosubstituted arylamino, diaralkylamino, diarylamino, dialkylamino, acylamino, or diacylamino;
• Rx is O, H or is absent;
• R2 and Rx are optionally taken together to form a 5-membered fused imidazole ring of 1,N6-etheno adenine derivatives, optionally substituted on the 4- or 5-positions of the etheno moiety with alkyl, aryl or aralkyl moieties as defined below;
• J is nitrogen and R3 is not present;
• wherein the alkyls are straight-chain, branched or cyclic;
• the aryl groups are optionally substituted with lower alkyl, aryl, amino, mono- or dialkylamino, NO2, N3, cyano, carboxylic, amido, sulfonamido, sulphonic acid, phosphate, or halo groups;
• wherein:
• R4 is selected from the group consisting of oxo, hydroxy, mercapto, thione, 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, oxo, acetyl, benzoyl, C1-6 alkyl, C1-5 alkanoyl, aroyl, and absent;
• R6 is selected from the group consisting of:
• hydroxy, oxo, mercapto, thione, C1-4 alkoxy, C7-12 arylalkoxy, C1-6 alkylthio, amino, S-phenyl, arylthio, arylalkylthio, 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 form a substituted ring;
• or
• R5 and R6 taken together form a 5-membered fused imidazole ring of 3,N4-ethenocytosine derivatives between positions 3 and 4 of the pyrimidine ring, 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, C1-6 alkyl, phenyl, substituted C2-8 alkynyl, halogen, substituted C1-4 alkyl, CF3, C2-3 alkenyl, C2-3 alkynyl, allylamino, bromovinyl, ethyl propenoate, propenoic acid, and C2-8 alkenyl;
• 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;
• 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;
• provided that when R8 is amino or substituted amino, R7 is hydrogen.

A compound of Formula III:

• wherein:
• X is oxygen, methylene, dihalomethylene, or imido;
• n=0, 1 or 2;
• m=0, 1 or 2;
• n+m=0, 1, 2, 3 or 4;
• Z=O H or H;
• Z′=OH or H;
• Y=OH or H;
• Y′=OH or H;
• and B and B′ are each independently a purine residue or a pyrimidine residue, as defined in Formula IIIa or IIIb, linked through the 9- or 1-position, respectively;
• and provided that at least one of B and B′ is a purine:
• R1 is hydrogen, chlorine, amino, monosubstituted amino, disubstituted amino, alkylthio, arylthio, or aralkylthio, wherein the substituent on sulfur contains up to a maximum of 20 carbon atoms, with or without unsaturation;
• R2 is mercapto, thione, alkylthio, arylthio, aralkylthio, acylthio, alkyloxy, aryloxy, aralkyloxy, acyloxy, or di-substituted amino;
• Rx is O, H or is absent;
• R3 is hydrogen, azido, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, or aralkylthio as defined below;
• or T(C1-6alkyl)OCONH(C1-6alkyl)W wherein T and W 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;
• wherein the alkyls are straight-chain, branched or cyclic;
• the aryl groups are optionally substituted with lower alkyl, amino, monoalkylamino, dialkylamino, NO2, N3, cyano, carboxylic, amido, sulfonamido, sulphonic acid, phosphate, or halo groups;
• wherein:
• R4 is selected from the group consisting of:
• oxo, hydroxy, mercapto, thione, 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, oxo, acetyl, benzoyl, C1-6 alkyl, C1-5 alkanoyl, aroyl, and absent;
• R6 is selected from the group consisting of:
• hydroxy, oxo, mercapto, C1-4 alkoxy, C7-12 arylalkoxy, C1-6 alkylthio, amino, S-phenyl, arylthio, arylalkylthio, 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 form a 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, 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, and C2-8 alkenyl;
• 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 that themselves contain functionalities;
• 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 provided that when R8 is amino or substituted amino, R7 is hydrogen.