Nucleotide analogs

• US 6,225,460 B1
• Filed: 02/10/1999
• Issued: 05/01/2001
• Est. Priority Date: 09/17/1993
• Status: Expired due to Term

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Lee, William A., Bischofberger, Norbert W., Louie, Michael S., Jones, Robert J., McGee, Lawrence R., Lin, Kuei-Ying, Arimilli, Murty N., Cundy, Kenneth C., Prisbe, Ernest J.
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): Lukton, David
• Application Number:
  US09/247,497
• Time in Patent Office: 811 Days
• Field of Search: 536/25.34, 536/27.14, 536/27.21, 536/26.1, 562/553
• US Class Current: 536/26.1
• 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 analogs characterized by the presence of an amidate linked amino acid or an ester linked group which is bonded to the phosphorus atom of phosphonate nucleotide analogs are disclosed. The analogs comprise a phosphoamidate or 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 included for antiviral use having the formula Id

wherein L¹ is of the formula III

 

wherein L² is OR, SR or independently is L¹;

wherein n and n1 are 1;

R is N-ethylmorpholino, pivaloyloxymethyl, phenyl, benzyl, isopropyl, t-butyl, ethyl, isopropyl, butyl, adamantoyloxymethyl, 3-methoxyphenyl, 2-carboethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2-ethoxyphenyl, 3-dimethylaminophenyl, 4-trifluoromethylbenzyl, 2-ethylsalicyl, —

O—

CH₂—

O—

C(O)—

C₁₀H₁₅, —

C₆H₄—

CH₂—

N(CH₃)₂, —

CH₂—

CH₂F, —

CH₂—

CH₂Cl, —

CH₂—

CF₃, —

CH₂—

CCl₃, R⁵, NHR⁶ or N(R⁶)₂;

 

wherein,

R⁵ is CH₂C(O)N(R⁶)₂, CH₂C(O)OR⁶, CH₂OC(O)R⁶, CH(R⁶)OC(O)R⁶, CH₂C(R⁶)₂CH₂OH, or CH₂OR⁶, and

R⁶ is C₁-C₂₀ alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (1 to 5 halogen atoms), C₆-C₂₀ aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (1 to 5 halogen atoms) or C₇-C₂₀ aryl-alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (1 to 5 halogen atoms);

R¹ is H, methyl, ethyl, isopropyl, phenyl or benzyl;

R² is H;

R³ is H, —

CH₃, —

CH(CH₃)₂, —

CH₂—

CH(CH₃)₂, —

CHCH₃—

CH₂—

CH₃, —

CH₂—

CH₆H₅, —

CH₂CH₂—

S—

CH₃, —

CH₂OH, —

CH(OH)—

CH₃, —

CH₂—

SH, —

CH₂—

C₆H₄OH, —

CH₂—

CO—

NH₂, —

CH₂—

CH₂—

CO—

NH₂, —

CH₂—

COOH, —

CH₂—

CH₂—

COOH, —

(CH₂)₄—

NH₂, —

(CH₂)₃—

NH—

C(NH₂)—

NH₂, 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl or ethoxyphenyl;

R⁴ is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, phenyl, benzyl, 1-pyridyl, 3-pyridyl, 1-pyrimidinyl, pivaloyloxymethyl, N-ethylmorpholino, N-2-propylmorpholino, methoxyethyl, 4-N-methylpiperidyl, 3-N-methylpiperidyl, 1-ethylpiperazinyl 2-, 3-, and 4-N,N-dimethylaminophenyl or 2-, 3-, or 4-N,N-diethylaminophenyl;

Z is —

CH₂—

O—

CH₂—

CH₂—

, —

CH₂—

O—

CH₂—

CH(CH₂OH)—

, —

CH₂—

O—

CH₂—

CH(CH₂F)—

, —

CH₂—

O—

CH₂—

CH(CH₃)—

, —

CH₂—

O—

CH₂—

CH(CH═

CH₂)—

or —

CH₂—

O—

CH₂—

CH(CH₂N₃)—

, or is of formula IV or V

 

wherein

R²⁵ and R²⁹ are O;

R²⁶ is CH;

R²⁷ and R²⁸ are H; and

B is adenin-9-yl, 1-deazaadenin-9-yl, 3-deazaadenin-9-yl, 7-deaza-8-azaadenin-9-yl, 8-azaadenin-9-yl, guanin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl, thymin-1-yl, cytosin-1-yl, 5-fluorocytosin-1-yl, 6-azacytosin-1-yl, 5-methylcytosin-1-yl, 5-bromovinyluracil-1-yl, 5-fluorouracil-1-yl or 5-trifluoromethyluracil-1-yl.

2. A compound having the structure

wherein L² is —

OC₆H₅, L¹ is —

NH—

CH(CH₃)—

C(O)—

OR⁴, Z is —

CH₂—

O—

CH(CH₃)—

CH₂—

, B is adenin-9-yl and R⁴ is H, propyl, isopropyl, t-butyl, phenyl, benzyl, 1-pyridinyl, 1-pyrimidinyl, N-ethylmorpholino, methoxyethyl, 4-hydroxy-N-methylpiperidinyl, 3-hydroxy-N-methylpiperidinyl or 1-ethylpiperazinyl.