Method for treating pain

A method of treating pain comprising administering to a subject a pharmaceutical composition comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, or amide or ester thereof:

• 14
• wherein:
• X1, X2, and X3 are independently oxygen, methylene, monochloromethylene, dichloromethylene, monofluoromethylene, difluoromethylene, or imido;
• T, W, and V are independently oxygen or sulfur;
• m=0, 1 or 2;
• n=0 or 1;
• p=0, 1, or 2;
• where the sum of m+n+p is from 0 to 5;
• each M is independently hydrogen or a pharmaceutically-acceptable inorganic or organic counterion;
• A=M, or
• A is a nucleoside residue which is defined as:
• 15
• and is linked to the phosphate chain via the 5′ position of the furanose or carbocycle;
• Z is H, F or OR1;
• Z is H, F or OR3;
• Y is H, F or OR2;
• Y is H, F or OR4;
• R1, R2, R3, and R4 are independently H or a residue according to Formulas II and/or III;
• provided that when A=M, at least one of Y and Z equals OQ(R5R6R7) under the definition of Formula II;
• or Y and Z taken together form a ring as defined in Formula III;
• further provided that when A is a nucleoside, at least one of Y, Y, Z, or Z equals OQ(R5R6R7) under the definition of Formula II;
• or either Y and Z taken together, or Y and Z taken together form a ring as defined in Formula III;
• D1 and D2 are independently O or C;
• 16
• wherein:
• Q is a carbon atom;
• R5, R6, and R7 are independently H, F, alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, or heterocyclic moiety, or
• R5 and R6, are taken together to form a carbocyclic or heterocyclic ring of 4 to 7 members, such that the moiety defined according to Formula II when attached to the oxygen is an ether;
• or
• R5 and R6 are taken together as oxygen or sulfur doubly bonded to Q, and R7 is alkyl, cycloalkyl, aralkyl, substituted aralkyl, aryl, or a heterocycle of 4 to 7 members, such that the moiety defined according to Formula II when attached to the oxygen is an ester or thioester;
• with the provision that when R5 and R6 are taken together as oxygen, and A=M, and X1=oxygen, then R7 is not benzoylbenzoyl;
• or
• R5 and R6 are taken together as oxygen or sulfur doubly bonded to Q, and R7 is amino or mono- or disubstituted amino, where the substituents are alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, or where the substituents on nitrogen form a heterocyclic ring of 4 to 7 members such that the moiety according to Formula II when attached to the oxygen is a carbamate or thiocarbamate;
• or
• R5 and R6 are taken together as oxygen or sulfur doubly bonded to Q, and R7 is alkoxy, cycloalkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy, such that the moiety according to Formula II when attached to the oxygen is a carbonate or thiocarbonate;
• 17
• wherein R1 and R2 and/or R3 and R4 are taken together to form Q;
• Q is a carbon atom;
• R8 and R9 are taken together as oxygen or sulfur doubly bonded to Q to form a cyclical carbonate or thiocarbonate;
• or R8 and R9 can be taken together to form a ring of 4 to 7 members, with or without substituents, with or without unsaturation and with or without heteroatoms in the ring, with the provision that when A=M, and X1=oxygen, said ring can have no more than two nitro groups as substituents or
• R8 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, substituted aralkyl, or heterocycle;
• R9 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, substituted aralkyl, heterocycle, alkyloxy, cycloalkyloxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy, such that Q is part of an acetal-, ketal- or ortho ester moiety;
• B and B′ are independently a purine or a pyrimidine residue according to Formulas IV or V which is linked to the sugar via the 9- or 1-position, respectively;
• 18
• wherein:
• R10 and R14 are independently hydroxy, oxo, amino, mercapto, alkylthio, alkyloxy, aryloxy, alkylamino, cycloalkylamino, aralkylamino, arylamino, diaralkylamino, diarylamino, N-alkyl-N-arylamino, or dialkylamino, where the alkyl and/or aryl groups are optionally linked to form a heterocycle;
• or
• R10 and R14 are independently acylamino, according to Formula VI;
• or
• when R10 or R14 has as its first atom nitrogen, R10 and R11 or R14 and R15 are taken together to form a 5-membered fused imidazole ring, optionally substituted on the imidazole ring of the etheno-compound with a substituted- or unsubstituted-alkyl, cycloalkyl, aralkyl, or aryl moiety, as described for R5-R9 above;
• J is carbon or nitrogen, with the provision that when J is nitrogen, R12 is not present;
• R11 is hydrogen, 0 or is absent;
• when present, R12 is hydrogen, alkyl, azido, amino, alkylamino, arylamino or aralkylamino, hydroxy, alkoxy, aryloxy or aralkyloxy, sulfhydryl, alkylthio, arythio or aralkylthio, or ω-X(C1-6alkyl)G-, wherein X is substituted- or unsubstituted-amino, mercapto, hydroxy or carboxyl and G is chosen from —O—, —S—, —NR18—, —N(CO)R18—, or N(CO)OR18—;
• R13 is hydrogen, chlorine, fluorine, hydroxy, amino, monosubstituted amino, disubstituted amino, alkylthio, trifluoroalkylthio, arylthio, or aralkylthio, where the substituent on sulfur contains up to a maximum of 20 carbon atoms, with or without unsaturation;
• R15 is hydrogen, or acyl;
• R16 is hydrogen, alkyl, halo, aryl, aralkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;
• 19
• wherein:
• W is oxygen or sulfur;
• R17 is amino or mono- or disubstituted amino such that the moiety according to Formula VI is a urea or thiourea;
• or
• R17 is alkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy, such that the moiety according to Formula VI is a carbamate or thiocarbamate;
• or
• R17 is alkyl, cycloalkyl, aralkyl, or aryl, with or without substituents or heteroatoms, such that the moiety according to Formula VI is an amide;
• and
• R18 is alkyl, cycloalkyl, aralkyl, aryl, with or without substituents or heteroatoms.