Prodrugs of phosphonates

• US 5,663,159 A
• Filed: 10/11/1994
• Issued: 09/02/1997
• 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: Bronson, Joanne J., Tortolani, David R., Martin, John C., Starrett, John E. Jr., Mansuri, Muzammil M.
• Primary Examiner(s): Berch, Mark L.
• Application Number:
  US08/320,632
• Time in Patent Office: 1,057 Days
• Field of Search: 544/244, 514/181
• US Class Current: 514/181
• 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. Antivirally active compounds or intermediates therefor of the formula I or V ##STR25## wherein B represents adenyl (A), guanyl (G), or 2,6-diaminopurinyl (DAP);

R¹ and R² are independently each OR⁴

R³ represents ##STR26## X represents hydrogen, methyl or hydroxymethyl;

R⁴ represents a physiologically hydrolyzable group selected from the group consisting of CH₂ OC(O)R⁵ and CH(R⁵)OC(O)R⁵ (R, S, or RS stereochemistry); and

R⁵ represents C₁ -C₂₀ alkyl, aryl or aryl-alkyl which may be substituted or unsubstituted by hydroxy or halogen.

3. The compound of claim 1 wherein X is H and R⁵ is C₁ -C₂₀ alkyl.

5. The compound of claim 1 wherein X is H.

6. The compound of claim 1 wherein X is hydroxymethyl or methyl.

7. The compound of claim 1 wherein B is adenyl.

8. The compound of claim 7 wherein X is H and R⁴ is CH₂ OC(O)R⁵.

9. The compound of claim 1 which is 9-(2-phosphonylmethoxy) ethyladenine di(pivaloyloxymethyl)ester.

10. The compound of claim 1 which is 9-(2-phosphonylmethoxy) ethyladenine di(propionyloxymethyl)ester.

11. The compound of claim 1 which is 9-(2-phosphonylmethoxy) ethyladenine di(isobutyryloxymethyl)ester.

12. The compound of claim 1 which is 9-(2-phosphonylmethoxy) ethyladenine di(benzoyloxymethyl)ester.

13. A composition comprising the compound of claim 1 in association with a pharmaceutically acceptable substantially nontoxic carrier or excipient.

2. Antivirally active compounds or intermediates therefor of Formula III ##STR27## wherein B represents adenyl (A), guanyl (G), or diaminopurinyl (DAP);

R⁷ is OH;

X represents hydrogen, methyl or hydroxymethyl;

R¹ is OR⁴ ;

R⁴ represents a physiologically hydrolyzable group selected from the group consisting of CH₂ OC(O)R⁵ and CH(R⁵)OC(O)R⁵ (R, S, or RS stereochemistry); and

R⁵ represents C₁ -C₂₀ alkyl, aryl or aryl-alkyl which may be substituted or unsubstituted by hydroxy or halogen.

4. The compound of claim 2 wherein X is H or hydroxymethyl.

14. The compound of claim 2 wherein X is H.

15. The compound of claim 2 wherein X is hydroxymethyl or methyl.

16. The compound of claim 2 wherein R⁴ is CH₂ OC(O)R⁵.

17. The compound of claim 2 which is 9-(2-phosphonylmethoxy) ethyladenine mono(pivaloyloxymethyl)ester.

18. A method for the treatment of HSV-2, HCMV or HIV in a mammal which comprises orally administering to the mammal an antiviral effective non-toxic dose of 9-(2-phosphonylmethoxy) ethyladenine di(pivaloyloxymethyl)ester for a treatment period of sufficient duration to mitigate said infection.