Nucleotide analogs

• US 5,886,179 A
• Filed: 12/29/1995
• Issued: 03/23/1999
• Est. Priority Date: 09/17/1993
• Status: Expired due to Term

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Jones, Robert J., Arimilli, Murty N., Lee, William A., Bischofberger, Norbert W., Prisbe, Ernest J.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US08/581,147
• Time in Patent Office: 1,180 Days
• Field of Search: 514/86, 514/79, 514/84, 544/243, 544/179, 544/182, 544/195
• US Class Current: 544/243
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: C07F 9/657181 the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
• CPC Class Codes: C07F 9/65742 non-condensed with carbocyclic rings or heterocyclic rings or ring systems
• CPC Class Codes: C07F 9/65744 condensed with carbocyclic or heterocyclic rings or ring systems
• CPC Class Codes: C07F 9/65785 the ring phosphorus atom and, at least, one ring sulfur atom being part of a thiophosphonic acid derivative
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Nucleotide phosphonate esters characterized by the presence of an ester linked group which is bonded to the phosphorus atom of phosphonate nucleotide analogs are disclosed. The analogs comprise an ester bond that is hydrolyzed in vivo to yield a corresponding phosphonate nucleotide analog. Methods and intermediates for their synthesis and use are described.

Claims

1. A compound having the structure of formula (1) ##STR36## wherein B is 5-fluorocytosin-1-yl, 5-methylcytosin-1-yl, or a heterocyclic base having the structure (a) ##STR37## R is --S(O)₂ N(R³)₂ ;

each R¹ is independently hydrogen, cyano, nitro, alkyl, O-alkyl, --C(O)R³, --S(O)₂ OH, --N(R³)₂ or --CHO;

each R³ is independently hydrogen, alkyl, phenyl, phenyl substituted with C_1-20 alkyl, --CH₂ C₆ H₅ or --CH₂ CH₂ C₆ H₅, but when R¹ is --N(R³)₂, one R³ is hydrogen and the other R³ is C_2-6 alkyl or when R¹ is --N(R³)₂, both R³ are the same and are C_2-6 alkyl;

R⁶ is --NH₂, --NHR⁷, --NHR⁸, --N═

CHN(R⁷)₂ or --N═

C(CH₃)N(R⁷)₂ ;

R⁷ is C₁ -C₆ alkyl;

R⁸ is a protecting group; and

each R⁹ independently is N or CH.