Method for treating or preventing inflammatory diseases

13 The method according to claim 8, wherein said P2Y receptor agonist is a dinucleoside polyphosphate of Formula III, or a pharmaceutically acceptable salt thereof:

• 12
• wherein:
• X is oxygen, methylene, dihalomethylene, or imido;
• n=0, 1 or2;
• m=0, 1 or 2;
• n+m=0,1, 2, 3 or 4;
• Z=H or OH;
• Z′=H or OH;
• Y=H or OH;
• Y′=H or OH;
• wherein at least one of Z, Z′, Y, or Y′ is OH;
• and
• B and B′ are each independently a purine residue or a pyrimidine residue, as defined in Formula IIIa and IIIb, respectively, linked through the 9- or 1-position, respectively:
• 13
• wherein:
• R11 is hydrogen, chlorine, amino, monosubstituted amino, disubstituted amino, alkylthio, arylthio, or aralkylthio, where the substituent on sulfur contains up to a maximum of 10 carbon atoms, with or without unsaturation;
• R12 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 absent;
• R12 and RX optionally taken together form a 5-membered fused imidazole ring of 1,N6-ethenoadenine derivatives, optionally substituted on the 4- or 5-positions of the etheno moiety with alkyl, aryl, nitroaryl, haloaryl, aralkyl or alkoxy moieties;
• R13 is hydrogen, azido, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, or aralkylthio, 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;
• or absent;
• and
• J is carbon or nitrogen, with the provision that when J is nitrogen, R13 is not present;
• 14
• wherein:
• R14 is oxo, hydroxy, mercapto, thione, amino, cyano, C7-12arylalkoxy, C1-6alkylthio, C1-6alkoxy, C1-6alkylamino or diC1-4alkylamino, wherein the alkyl groups are optionally linked to form a heterocycle;
• R15 is hydrogen, acetyl, benzoyl, alkyl, acyl, arylacyl, arylalkyl, 1-5alkanoyl, aroyl, or is absent when there is a double bond between N-3 and C-4;
• R16 is hydroxy, oxo, mercapto, thione, C1-4alkoxy, C7-12arylalkoxy, C1-6alkylthio, S-phenyl, arylthio, aralkylthio, arylalkylthio, triazolyl, amino, C1-5disubstituted amino, C1-6alkylamino, or di-C1-4alkylamino wherein said dialkyl groups are optionally linked to form a heterocycle or linked to form a substituted ring;
• or
• R15 and R16 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 C1-4alkyl, phenyl, arylalkyl, or nitrophenyl;
• R17 is hydrogen, hydroxy, cyano, nitro, C1-6alkyl, C2-8alkenyl, C2-8alkynyl, phenyl, halogen, CF3, allylamino, bromovinyl, ethyl propenoate, propenoic acid;
• or
• R16 and R17 together form a 5 or 6-membered saturated or unsaturated ring bonded through N or O or S at R16, said ring optionally contains functional substituents;
• and
• R18 is hydrogen, amino, alkylamino, acylamino, di-C1-4alkylamino, C1-4alkoxy, C7-12arylalkoxy, C1-4alkylthio, C7-12arylalkylthio, carboxamidomethyl, carboxymethyl, methoxy, methylthio, phenoxy, or phenylthio;
• provided that when R18 is amino or substituted amino, R17 is hydrogen;
• wherein the alkyl, alkenyl, alkynyl, and aryl groups are optionally substituted with lower alkyl, aryl, amino, mono- or dialkylamino, NO2, N3, cyano, hydroxy, carboxylic, amido, sulfonamido, sulphonic acid, phosphate, or halo groups.

The method according to claim 13, wherein said dinucleoside polyphosphate of general Formula III is a dinucleoside tetraphosphate selected from the group consisting of P1, P4-di(uridine 5′-)tetraphosphate;

• P1-(cytidine 5′)- P4-(uridine 5′-)tetraphosphate;
• P1, P4-di(adenosine 5′-)tetraphosphate;
• P1-(adenosine 5′)- P4-(uridine 5′-)tetraphosphate;
• P1-(adenosine 5′)- P4-(cytidine 5′-)tetraphosphate;
• P1, P4-di(ethenoadenosine)tetraphosphate;
• P1-(uridine 5′)- P4-(thymidine 5′-)tetraphosphate;
• P1-(adenosine 5′)- P4-(inosine 5′-)tetraphosphate;
• P1, P4-di(uridine 5′)-P2, P3-methylenetetraphosphate;
• P1, P4-di(uridine 5′)-P2, P3- difluoromethylenetetraphosphate;
• P1, P4-di(uridine 5′)-P2, P3-imidotetraphosphate;
• P1, P4-di(4-thiouridine 5′-)tetraphosphate;
• P1, P5-di(uridine 5′-)pentaphosphate;
• P1, P4-di(3, N4-ethenocytidine 5′-)tetraphosphate;
• P1, P4-di(imidazo[1,2-c]pyrimidine-5(6H)-one-2-(3-nitro)-phenyl-6-β-D-ribofuranoside 5′-) tetraphosphate;
• P1-(inosine 5′)-P4-(uridine 5′-) tetraphosphate;
• P1-(cytosine β-D-arabinofuranoside 5′)-P4-(uridine 5′-)tetraphosphate;
• P1-(uridine 5′)-P4-(xanthosine 5′-) tetraphosphate;
• P1-(2′-deoxyuridine 5′)-P4-(uridine 5′-)tetraphosphate;
• P1-(3′-azido-3′-deoxythymidine 5′)-P4-(uridine 5′-)tetraphosphate;
• P1, P4-di(3′-azido-3′-deoxythymidine 5′-) tetraphosphate;
• 2′(3′)-benzoyl-P1, P4-di(uridine 5′-)tetraphosphate;
• P1, P4-di[2′,(3′)-benzoyl uridine 5′-]tetraphosphate;
• P1-(2′-deoxyguanosine 5′)- P4-(uridine 5′-) tetraphosphate;
• P1-(2′-deoxyadenosine 5′)-P4-(uridine 5′-)tetraphosphate;
• P1-(2′-deoxyinosine 5′)-P4-(uridine 5′-) tetraphosphate;
• P1-(2′-deoxycytidine 5′)-P4-(uridine 5′-) tetraphosphate;
• P1-(4-thiouridine 5′)-P4-(uridine 5′-)tetra-phosphate;
• P1-(8-azaadenosine 5′)-P4-(uridine 5′-) tetraphosphate;
• P1-(6-mercaptopurine riboside 5′)-P4-(uridine 5′-) tetraphosphate;
• P1-(6-mercaptopurine riboside 5′)-P4-(2′-deoxyuridine 5′-)tetraphosphate;
• P1-(4-thiouridine 5′)-P4-(cytosine-β-D-arabinofuranoside 5′-) tetraphosphate;
• P1-(adenosine 5′)-P4-(4-thiomethyluridine 5′-)tetraphosphate;
• P1-(2′-deoxyadenosine 5′)-P4-(6-thiohexylpurine riboside 5′-)tetraphosphate;
• P1-(6-eicosanyloxypurine riboside 5′)-P4-(uridine 5′-) tetraphosphate.

The method according to claim 13, wherein said dinucleoside polyphosphate of general Formula III is a dinucleoside triphosphate selected from the group consisting of:

• P1P3-di(uridine 5′-)triphosphate;
• P1-(cytosine 5′)-P3-(uridine 5′-)triphosphate;
• P1,P3-di(adenosine 5′-) triphosphate;
• P1-(adenosine 5′)-P3-(uridine 5′-)triphosphate;
• P1-(adenosine 5′)-P3-(cytosine 5′-) triphosphate;
• P1,P3-di(ethenoadenosine)triphosphate;
• P1-(uridine 5′)-P3-(thymidine 5′-) triphosphate;
• P1-(adenosine 5′)-P3-(inosine 5′-)triphosphate;
• P1,P3-di(uridine 5′-)P2,P3-methylenetriphosphate;
• P1,P3-di(uridine 5′-P2,P3-difluoromethylenetriphosphate);
• P1,P3-di(uridine 5′-P2,P3-imidotriphosphate);
• P1,P3-di(4-thiouridine 5′-triphosphate);
• P1,P3-di(3,N4-ethenocytidine 5′-)triphosphate;
• P1, P3-di(imidazo[1,2-c]pyrimidine-5(6H)-one-2-(3-nitro)-phenyl-6-β-D-ribofuranoside 5′-)triphosphate;
• P1-(inosine 5′-)P3-(uridine 5′-) triphosphate;
• P1-(4-thiouridine 5′-)P3-(uridine 5′-) triphosphate;
• P1-(cytosine β-D-arabinofuranoside 5′-)P3-(uridine 5′) triphosphate;
• P1-(uridine 5′-)P3-(xanthosine 5′-) triphosphate;
• P1-(2′-deoxyuridine 5′-)-P3-(uridine 5′-)triphosphate;
• P1-(3′-azido-3′-deoxythymidine 5′-)-P3-( uridine 5′-) triphosphate;
• P1 ,P3-di(3′-azido-3′-deoxythymidine 5′-) triphosphate;
• 2′(3′)-benzoyl-P1,P3-di(uridine 5′-)triphosphate;
• P1,P3-di(2′, 3′-benzoyl uridine 5′-) triphosphate;
• P1-(2′-deoxyguanosine 5′-)P3-( uridine 5′-)triphosphate;
• P1-(2′-deoxyadenosine 5′-)P3-(uridine 5′-) triphosphate;
• P1-(2′-deoxyinosine 5′-)P3-(uridine 5′-triphosphate;
• P1-(2′-deoxycytidine 5′-)P3-(uridine 5′-)triphosphate;
• P1-(4-thiouridine 5′-)P3-(uridine 5′-)triphosphate;
• P1 -(8-azaadenosine-5 ′-)P3-(uridine 5′-) triphosphate;
• P1-(6-mercaptopurine riboside 5′-)P3-(uridine 5′-)triphosphate;
• P1-(6-mercaptopurine riboside 5′-) P3-(2′-deoxyuridine 5′-)triphosphate;
• P1-(4-thiouridine 5′-)P3-(arabinocytidine 5′-) triphosphate;
• P1-(adenosine 5′-)P3-(4-thiomethyluridine 5′-) triphosphate;
• P1-(2′-deoxyadenosine 5′-)P3-(6-thiohexylpurine riboside 5′-) tetraphosphate;
• and P1-(6-eicosanyloxypurine riboside 5′-)P3-(uridine 5′-) triphosphate.