Prodrugs of phosphonates

• US 5,792,756 A
• Filed: 06/07/1995
• Issued: 08/11/1998
• Est. Priority Date: 09/14/1990
• Status: Expired due to Term

• Current Assignee: Institute Of Organic Chemistry And Biochemistry Of The Ascr, V.V.I., REGA Stichting VZW
• Original Assignee: Institute Of Organic Chemistry And Biochemistry Of The Ascr, V.V.I., REGA Stichting VZW
• Inventors: Tortolani, David R., Martin, John C., Bronson, Joanne J., Starrett, John E. Jr., Mansuri, Muzammil M.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US08/481,715
• Time in Patent Office: 1,161 Days
• Field of Search: 544/243, 514/86
• US Class Current: 514/86
• CPC Class Codes: A61P 31/12 Antivirals
• 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 9/6584 having one phosphorus atom as ring hetero atom

Abstract

There are disclosed novel oral prodrugs of phosphonate nucleotide analogs which are hydrolyzable under physiological conditions to yield compounds which are useful as antiviral agents, especially as agents effective against RNA and DNA viruses. They may also find use as antitumor agents.

Claims

1. The compound having formula II ##STR25## wherein B is cytosine or Z;

R¹ and R² are independently OH or OR⁴ provided that at least one of R¹ or R², is OR⁴, or one of R¹ or R² is linked to X to form a cyclic compound having Formula V ##STR26## * stereochemistry R, S, or RS;

R¹³ is OR⁴ ;

X is CH₂ OR⁶ (R, S or RS stereochemistry) or hydroxymethyl with the proviso that when X is CH₂ OR⁶, then R¹ and R² may additionally be independently chosen from OH;

R⁶ is a hydrolyzable ester;

R⁴ is CH₂ C(O)NR⁵₂, CH₂ C(O)OR⁵, CH₂ OC(O)R⁵, CH(R⁵)OC(O)R⁵ (R, S, or RS stereochemistry), CH₂ C(R⁵₂ CH₂ OH, or CH₂ OR⁵ ;

R⁴ may also be R^5'"'"' ;

R⁵ is C₁ -C₂₀ alkyl, aryl or aryl-alkyl which is unsubstituted or is substituted by hydroxy, oxygen, nitrogen or halogen;

R^5'"'"' is C₄ -C₂₀ alkyl, aryl or aryl-alkyl which is substituted by hydroxy, oxygen, nitrogen or halogen;

Z is ##STR27## O is independently H, Cl, NHR⁵, NR⁵₂, NHC(O)R⁵, N(C(O)R⁵)₂, OH or NCHN(R⁵)₂ provided that when O is NCHN(R⁵)₂, then R⁵ is not CH₃.

2. A method for the treatment of human cytomegalovirus viral infection in a mammal which comprises administering an antiviral effective non-toxic dose of a compound of claim 1 to the infected mammal for a treatment period of sufficient duration to mitigate said infection provided, however, that B is cytosine and X is hydroxymethyl.

3. The method of claim 2 wherein the compound is administered orally.

4. A pharmaceutical composition which comprises an antiviral effective amount of at least one compound of claim 1 in association with a pharmaceutically acceptable substantially non-toxic carrier or excipient.

5. The compound of claim 1 wherein B is cytosine.

6. The compound of claim 1 wherein R^5'"'"' is C₄ -C₂₀ alkyl, aryl or aryl-alkyl any one of which is substituted by hydroxy or halogen.

7. The compound of claim 1 wherein R^5'"'"' is aryl or aryl-alkyl which is unsubstituted or either of which is substituted by substituents independently selected from the group consisting of hydroxy, oxygen, nitrogen and halogen.