Acyclic nucleoside phosphonate diesters
The present disclosure relates, inter alia, to compositions and methods for treating viral diseases and cancer. There are disclosed lipophilic antiviral and anticancer acyclic nucleoside phosphonate diesters, preparation thereof, and methods of using the compounds to treat viral diseases and cancer.
1. A compound of Formula (Ia), or a pharmaceutically acceptable salt thereof:
wherein:
B Nuc is guanine, adenine, cytosine, thymine, uracil, or 2,6-diaminopurine;
L a is —(CH 2 ) 1-6 O(CH 2 ) 11-21 CH 3 ;
R a is selected from aryl, heteroaryl, heterocycloalkyl, aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl), and heterocycloalkyl(C 1-6 alkyl); and
X a is hydrogen.
2. The compound of claim 1 , wherein L a is —(CH 2 ) 2 O(CH 2 ) 17 CH 3 .
3. The compound of claim 1 , wherein L a is —(CH 2 ) 3 O(CH 2 ) 15 CH 3 .
4. The compound of claim 1 , wherein B Nuc(a) is guanine.
5. The compound of claim 1 , wherein B Nuc(a) is adenine.
6. The compound of claim 1 , wherein B Nuc(a) is cytosine, thymine, or uracil.
7. The compound of claim 1 , wherein B Nuc(a) is 2,6-diaminopurine.
8. The compound of claim 1 , wherein R a is aryl(C 1-6 alkyl).
9. The compound of claim 8 , wherein L a is —(CH 2 ) 2 O(CH 2 ) 17 CH 3 .
10. The compound of claim 8 , wherein L a is —(CH 2 ) 3 O(CH 2 ) 15 CH 3 .
11. The compound of claim 8 , wherein aryl(C 1-6 alkyl) is benzyl.
12. The compound of claim 1 , wherein R a is aryl.
13. The compound of claim 12 , wherein L a is —(CH 2 ) 2 O(CH 2 ) 17 CH 3 .
14. The compound of claim 12 , wherein L a is —(CH 2 ) 3 O(CH 2 ) 15 CH 3 .
15. The compound of claim 12 , wherein aryl is phenyl.
16. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.
17. The pharmaceutical composition of claim 16 , in a topical dosage form.
18. The pharmaceutical composition of claim 17 , in a cream, a gel, or an ointment.
19. A method of treating a disorder selected from the group consisting of human papilloma virus, cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, and anal intraepithelial neoplasia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein the disorder is human papilloma virus.
21. The method of claim 20 , wherein the human papilloma virus is human papilloma virus type 52, type 58, type 16, type 18, or type 11.
22. The method of claim 19 , wherein the disorder is cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, or anal intraepithelial neoplasia.
23. The method of claim 19 , wherein the subject is a human.