US 7,495,006 B2
2′ and 3′-substituted cyclobutyl nucleoside analogs for the treatment of viral infections and abnormal cellular proliferation
Dennis C. Liotta, Atlanta, Ga. (US); Shuli Mao, Atlanta, Ga. (US); and Michael Hager, Kennesaw, Ga. (US)
Assigned to Emory University, Atlanta, Ga. (US)
Filed on Dec. 08, 2005, as Appl. No. 11/301,326.
Claims priority of provisional application 60/634875, filed on Dec. 10, 2004.
Prior Publication US 2006/0223835 A1, Oct. 05, 2006
Int. Cl. A61K 31/505 (2006.01); A61K 31/506 (2006.01); A61K 31/513 (2006.01); A61K 31/52 (2006.01); A61K 31/522 (2006.01); C07F 9/113 (2006.01); C07F 9/117 (2006.01); C07D 239/47 (2006.01); C07D 239/48 (2006.01); C07D 473/02 (2006.01); C07D 473/04 (2006.01); C07D 473/18 (2006.01); C07D 473/26 (2006.01); C07D 473/32 (2006.01); C07D 473/34 (2006.01)
U.S. Cl. 514—263.23  [514/263.4; 514/274; 544/244; 544/276; 544/277; 544/312; 544/313; 544/314; 544/317] 39 Claims
 
1. A cyclobutyl nucleoside of the formula (I)-(IV):

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt, ester, salt of an ester, prodrug, salt of a prodrug, enantiomer, diastereomer, or tautomer thereof, wherein;
Base is a purine or pyrimidine base;
Z is independently phosphate selected from the group consisting of monophosphate, diphosphate, triphosphate and a stabilized phosphate prodrug, P(O)Z′Z″, CH2P(O)Z′Z″, alkyl, sulfonate ester, or sulfonyl
Z′ and Z″ each independently is OH, OAlkyl, OAryl, alkyl, aryl, SH, SAlkyl, SAryl, NH2, mono or di-alkylamino, mono- or di-arylamino, or a residue of an amino acid;
A is O, S, or CH2; or alternatively
A can be a covalent bond when Z is P(O)Z′Z″ or CH2P(O)Z′Z″;
R1, R2, and R3 are independently hydrogen, lower alkyl, halogenated lower alkyl, CF3, 2-Br-ethyl, lower alkenyl, halogenated lower alkenyl, Br-vinyl, lower alkynyl, halogenated lower alkynyl, halo, cyano, azido, NO2, NH2, —NH(lower alkyl), NH(acyl), N(lower alkyl)2, —N(acyl)2, OZ, O(lower alkyl), O(alkenyl), C(O)O(alkyl), C(O)O(lower alkyl); or alternatively,
R1 and R2 together are ═CH2 or ═CHY; or alternatively
R1 and R2 can come together to form a three-membered carbocyclic or heterocyclic ring, such as an epoxide ring; such that if R1 is H, then R2 is not CH2OH, and if R2 is H, then R1 is not CH2OH;
X is CH2, CHY, or S; and
Y is independently H, methyl, halogenated methyl, CF3, halogen, N3, cyano, or NO2.