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|Title:||Prodrugs of phosphonates|
|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.|
|Inventor(s):||Starrett, Jr.; John E. (Middletown, CT), Mansuri; Muzammil M. (Cheshire, CT), Martin; John C. (Cheshire, CT), Tortolani; David R. (Meriden, CT), Bronson; Joanne J. (Madison, CT)|
|Assignee:||Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic (CZ) N/A (BE) Rega Stichting v.z.w. (N/A)|
|Filing Date:||Jun 07, 1995|
|Claims:||1. The compound having formula II ##STR25## wherein B is cytosine or Z; |
R.sup.1 and R.sup.2 are independently OH or OR.sup.4 provided that at least one of R.sup.1 or R.sup.2, is OR.sup.4, or one of R.sup.1 or R.sup.2 is linked to X to form a cyclic compound having Formula V ##STR26## * stereochemistry R, S, or RS; R.sup.13 is OR.sup.4 ;
X is CH.sub.2 OR.sup.6 (R, S or RS stereochemistry) or hydroxymethyl with the proviso that when X is CH.sub.2 OR.sup.6, then R.sup.1 and R.sup.2 may additionally be independently chosen from OH;
R.sup.6 is a hydrolyzable ester;
R.sup.4 is CH.sub.2 C(O)NR.sup.5.sub.2, CH.sub.2 C(O)OR.sup.5, CH.sub.2 OC(O)R.sup.5, CH(R.sup.5)OC(O)R.sup.5 (R, S, or RS stereochemistry), CH.sub.2 C(R.sup.5.sub.2 CH.sub.2 OH, or CH.sub.2 OR.sup.5 ; R.sup.4 may also be R.sup.5' ;
R.sup.5 is C.sub.1 -C.sub.20 alkyl, aryl or aryl-alkyl which is unsubstituted or is substituted by hydroxy, oxygen, nitrogen or halogen;
R.sup.5' is C.sub.4 -C.sub.20 alkyl, aryl or aryl-alkyl which is substituted by hydroxy, oxygen, nitrogen or halogen;
Z is ##STR27## O is independently H, Cl, NHR.sup.5, NR.sup.5.sub.2, NHC(O)R.sup.5, N(C(O)R.sup.5).sub.2, OH or NCHN(R.sup.5).sub.2 provided that when O is NCHN(R.sup.5).sub.2, then R.sup.5 is not CH.sub.3.
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.sup.5' is C.sub.4 -C.sub.20 alkyl, aryl or aryl-alkyl any one of which is substituted by hydroxy or halogen.
7. The compound of claim 1 wherein R.sup.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.