Seven-membered ring nucleosides

A compound of the general structural Formula (IV):

• wherein:
• X is O, S, SO2, N—R, CH—R, or C—R—R;
• R is H;
• C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl, each of which may be optionally substituted;
• CN, N3, halo, OH, CONH2, NH2, or amidino;
• R1 is OH, monophosphate, diphosphate, triphosphate, phosphoryl, a phosphate derivative, acyl, alkyl, O-acyl, O-alkyl, O-aryl, O-alkoxyalkyl, O-aryloxyalkyl, O-substituted alkyl, O-substituted alkenyl, O-substituted alkynyl, alkyl sulfonyl, aryl sulfonyl, alkenyl sulfonyl, aralkylsulfonyl, an amino acid residue, or any cleavable substitutent that in vivo provides OH;
• R2, R3, R4 and R5 each independently is H, OH, SH, NH2, halo, C1-10 alkylcarbonyl, monophosphate, diphosphate, triphosphate, phosphoryl, phosphate, phosphonate, phosphinate, phosphonoamidate, carbamate, phosphorothioate, phosphorodithioate, carbonyl, thiocarbonyl, aminoacyl, amidino, NO2, CN, N3, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamide, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, acyl, haloalkyl, haloalkenyl, haloalkynyl, cyclopropyl, O-alkyl, O-alkenyl;
• O-alkynyl;
• O-acyl;
• S-alkyl;
• S-alkenyl;
• S-alkynyl;
• S-acyl;
• NH-alkyl;
• N(alkyl)2;
• NH(alkenyl);
• N(alkenyl)2;
• NH(alkynyl);
• N(alkynyl)2;
• NH(acyl);
• N(acyl)2;
• CONH2;
• COOH;
• CONH-alkyl;
• CON(alkyl)2;
• COSH2;
• COSH-alkyl;
• COS(alkyl)2;
• C1-6 alkyl-O—C1-6 alkyl;
• C1-6 alkyl-O-alkenyl;
• C1-6 alkyl-O-alkynyl;
• C1-6 alkyl-S-alkyl;
• C1-6 alkyl-S-alkenyl;
• C1-6 alkyl-S-alkynyl;
• CH2CN;
• or CH2N3;
• and
• Each of R1′, R2′, R3′, R4′, R5′ and W independently is H, OH, C1-10 alkylcarbonyl, phosphoryl, phosphonate, phosphinate, phosphonoamidate, Cl, F, Br, I, CN, NO2, N3, NH2, acylamino, amido, amidino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbonyl, thiocarbonyl, acyl, haloalkyl, haloalkenyl, haloalkynyl, acyl, cyclopropyl, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, C1-6 alkyl-O—C1-6 alkyl, C1-6 alkyl-O-alkenyl, C1-6 alkyl-O-alkynyl, C1-6 alkyl-S-alkyl, C1-6 alkyl-S-alkenyl, C1-6 alkyl-S-alkynyl, CONH2, COOR, CH2CN, or CH2N3;
• and
• Each R2, R3, R4 and R5 and its corresponding R′ can form a spiro moiety;
• Each R2+R3, R3+R4, or R4+R5 independently may join to form a 3-6 membered ring that optionally has 1, 2 or 3 heteroatoms;
• Each R2′+R3′, R3′+R4′, or R4′+R5′ independently may join to form a 3-6 membered ring that optionally has 1, 2 or 3 heteroatoms;
• with the proviso that at least two of R2, R3, R4, R5 and W must be OH;
• with the additional proviso that W is OH only when X is CH—R or C—R—R for reasons of chemical stability;
• and
• with the further proviso that when any R1, R2, R3, R4 or R5 is OH or NH2, then its corresponding R1′, R2′, R3′, R4′ or R5′ may not also be OH or NH2;
• Base is selected from the group consisting of:
• wherein:
• Each occurrence of A, L, and T independently is C, CH, CH—R, N, NR, C-alkyl, O or S depending upon correct valence;
• or C-halo, C—C1-6 alkyl, C—C2-6 alkenyl, C—C2-6 alkynyl, C1-6 alkylamino, C—CF3, C—OH, C—NH2, C—NO2, C—CN, C—N3, C—COOR, or C—CONH2;
• D is CH, C—CN, C—NO2, N, C—C1-6 alkyl, C—CONH2, C—CONH—C1-6alkyl, C—CON(C1-6alkyl)(C1-6alkyl), C—NH2, C-alkoxy, C—OH, C-alkylamino, C—C(=NH)NH2,
• C—COOH, C—COO-alkyl, C—CSNH2, C—CSNH-alkyl, C—CSN(alkyl)2, C-di(C1-6 alkyl)amino, C-halo, C-heterocycle, wherein any alkyl optionally is substituted by from one to three substituents selected from the group consisting of alkoxy, hydroxyl, carboxy, halo and amino, and wherein heterocycle is a 5- or 6-membered ring having one to three heteroatoms;
• E is N or C-halo, C—C1-6 alkyl, C—C2-6 alkenyl, C—C2-6 alkynyl, C1-6 alkylamino, C—CF3, C—OH, C—NH2, C—NO2, C—CN, C—N3, C—COOR, or C—CONH2;
• Z is O or S;
• R6, R7, R8 and R9, each independently, is H, OH, SH, NH2, NO2, CN, N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylamino, di(C1-6 alkyl)amino, C3-6 cycloalkylamino, C3-6 cycloalkyl, halo, C1-6 alkoxy, carboxy, C1-6 alkoxycarbonyl, C1-6 alkylthio, C11-6 alkylsulfonyl, (C1-6 alkyl)0-2 aminomethyl, or CF3;
• R10 and R11 each independently is H, OH, SH, NH2, halo, C1-10 alkylcarbonyl, monophosphate, diphosphate, triphosphate, phosphoryl, phosphate, phosphonate, phosphinate, phosphonoamidate, carbamate, phosphorothioate, phosphorodithioate, carbonyl, thiocarbonyl, aminoacyl, amidino, NO2, CN, N3, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamide, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, acyl, haloalkyl, haloalkenyl, haloalkynyl, acyl, cyclopropyl, CONH2, COOH, CONH-alkyl, CON(alkyl)2, COSH2, COSH-alkyl, COS(alkyl)2, C1-6 alkyl-O—C1-6 alkyl, C1-6 alkyl-O-alkenyl, C1-6 alkyl-O-alkynyl, C1-6 alkyl-S-alkyl, C1-6 alkyl-S-alkenyl, C1-6 alkyl-S-alkynyl, CH2CN, or CH2N3;
• Q1 and Q2 each independently is N, N—R, O, S, SO, SO2, CH—R or C—R—R, depending upon the proper valence required;
• indicates the presence of a single or double bond;
• or
• a pharmaceutically acceptable salt, ester or prodrug, or a or tautomeric form thereof.

A process for the synthesis of a seven-membered ring nucleoside analogue:

• a. reacting a 2,3,5-tri-O-protected pentose to provide a 6-hydroxy-4, 5, 7-tri-O-protected methyl hept-2-enoate derivative;
• b. reducing the alkene from step a. to produce a 6-hydroxy-4,5,7-tri-O-protected methyl heptanoate;
• c. hydrolyzing the product from step b. to provide a 6-hydroxy-4,5, 7-tri-O-protected heptanoic acid derivative;
• d. cyclizing the product from step c. to provide a seven-membered lactone;
• e. reducing and acylating the lactone to provide a 2-O-acyl seven-membered ring ether;
• f. reacting the product of step e. with a nitrogen base to form a protected seven-membered ring nucleosise analogue.