Acyclic nucleoside phosphonate diesters

Patent metadata

Field	Value
Publication number	US-9775852-B2
Application number	US-201615179209-A
Country	US
Kind code	B2
Filing date	Jun 10, 2016
Priority date	Mar 15, 2013
Publication date	Oct 3, 2017
Grant date	Oct 3, 2017

Abstract

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.

First claim

What is claimed is:

1. A process for preparing a compound of Formula I comprising combining an alcohol R—OH, a coupling agent, a base, an organic solvent, and a compound of formula:

wherein
B Nuc is a naturally occurring purine or pyrimidine base;
X is hydrogen, C 1-6 alkyl, or C 1-6 heteroalkyl; and
L is a C 13-29 heteroalkyl or O-substituted glyceryl having the formula —CH 2 CH(OR 1 )—CH 2 (OR 2 ) (II), wherein R 1 and R 2 are independently alkyl or aryl;

thereby obtaining a compound of Formula I:

wherein
R is aryl, benzyl, heteroaryl, aryl(C 1-6 alkyl), or heteroaryl(C 1-6 alkyl).

2. The process of claim 1 , further comprising resolving the compound of Formula I to an optically active enantiomer or diastereomer of Formula I.

3. The process of claim 1 , wherein R—OH is benzyl alcohol.

4. The process of claim 1 , wherein the coupling agent is (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate.

5. The process of claim 1 , wherein the base is N,N-diisopropylethylamine.

6. The process of claim 1 , wherein the organic solvent is N,N-dimethylformamide.

7. A process for preparing a compound of Formula Ia comprising combining an alcohol R a —OH, a coupling agent, a base, an organic solvent, and a compound of formula:

wherein
B Nuc(a) is a naturally occurring purine, a naturally occurring pyrimidine, a non-naturally occurring purine or a non-naturally occurring pyrimidine;
X a is hydrogen, C 1-6 alkyl, a halogen substituted C 1-6 alkyl, a hydroxy substituted C 1-6 alkyl, or C 1-6 alkoxy; and
L a is C 12-24 alkyl, C 13-29 heteroalkyl, or a substituted glyceryl moiety, wherein the glyceryl moiety may be substituted with one or more groups selected from C 13-29 alkyl, C 13-29 heteroalkyl, aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl) and heterocycloalkyl(C 1-6 alkyl);

thereby obtaining a compound of Formula Ia:

wherein
R a is aryl, heteroaryl, aryl(C 1-6 alkyl), or heteroaryl(C 1 -6 alkyl).

8. The process of claim 7 , further comprising resolving the compound of Formula Ia to obtain an optically active enantiomer or diastereomer of Formula Ia.

9. The process of claim 7 , wherein R a —OH is benzyl alcohol.

10. The process of claim 7 , wherein the coupling agent is (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate.

11. The process of claim 7 , wherein the base is N,N-diisopropylethylamine.

12. The process of claim 7 , wherein the organic solvent is N,N-dimethylformamide.

13. A process for preparing a compound of Formula I comprising combining an alcohol L-OH, a coupling agent, a base, an organic solvent, and a compound of Formula 2-3

wherein
B Nuc is a naturally occurring purine or pyrimidine base;
X is hydrogen, C 1-6 alkyl, or C 1-6 heteroalkyl; and
R is aryl, benzyl, heteroaryl, aryl(C 1-6 alkyl), or heteroaryl(C 1-6 alkyl);

thereby obtaining a compound of Formula I:

wherein
L is C 13-29 heteroalkyl or O-substituted glyceryl having the formula —CH 2 CH(OR 1 )—CH 2 (OR 2 ), wherein R 1 and R 2 are independently alkyl or aryl.

14. The process of claim 13 , further comprising resolving the compound of Formula I to obtain an optically active enantiomer or diastereomer of Formula I.

15. The process of claim 13 , wherein L-OH is 2-(octadecyloxy)ethan-1-ol.

16. The process of claim 13 , wherein the coupling agent is (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate.

17. The process of claim 13 , wherein the base is N,N-diisopropylethylamine.

18. The process of claim 13 , wherein the organic solvent is N,N-dimethylformamide.

19. A process for preparing a compound of Formula Ia comprising combining an alcohol L a -OH, a coupling agent, a base, an organic solvent, and a compound of Formula 2-3a:

wherein
B Nuc (a) is a naturally occurring purine, a naturally occurring pyrimidine, a non-naturally occurring purine or a non-naturally occurring pyrimidine;
X a is hydrogen, C 1-6 alkyl, a halogen substituted C 1-6 alkyl, a hydroxy substituted C 1-6 alkyl, or C 1-6 alkoxy; and
R a is aryl, heteroaryl, aryl(C 1-6 alkyl), or heteroaryl(C 1-6 alkyl);

thereby obtaining a compound of Formula Ia:

wherein
L a is C 12-24 alkyl, C 13-29 heteroalkyl or a substituted glyceryl moiety, wherein the glyceryl moiety may be substituted with one or more groups selected from C 13-29 alkyl, C 13-29 heteroalkyl, aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl), or heterocycloalkyl(C 1-6 alkyl).

20. The process of claim 19 , further comprising resolving the compound of Formula Ia to obtain an optically active enantiomer or diastereomer of Formula Ia.

21. The process of claim 19 , wherein L a -OH is 2-(octadecyloxy)ethan-1-ol.

22. The process of claim 19 , wherein the coupling agent is (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate.

23. The process of claim 19 , wherein the base is N,N-diisopropylethylamine.

24. The process of claim 19 , wherein the organic solvent is N,N-dimethylformamide.

25. A process for preparing a compound of Formula I comprising combining a strong base, an organic solvent, a compound of Formula 3-1:

and a compound Formula 3-2:

wherein
Y is a leaving group;
B Nuc is a naturally occurring or modified purine or pyrimidine base;
X is hydrogen, C 1-6 alkyl, or C 1-6 heteroalkyl;
L is C 13-29 heteroalkyl or O-substituted glyceryl having the formula —CH 2 CH(OR 1 )—CH 2 (OR 2 ), wherein R 1 and R 2 are independently alkyl or aryl; and
R is aryl, heteroaryl, benzyl, aryl(C 1-6 alkyl), or heteroaryl(C 1-6 alkyl);

thereby obtaining a compound of Formula I:

26. The process of claim 25 , further comprising resolving the compound of Formula I to obtain an optically active enantiomer or diastereomer of Formula I.

27. The process of claim 25 , wherein Y is a leaving group selected from p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromo and iodo.

28. The process of claim 1 , wherein B NUC is guanine.

29. The process of claim 7 , wherein B NUC is guanine.

30. The process of claim 29 , wherein L a is C 13 -C 29 heteroalkyl.

Assignees

• Univ California

Inventors

• Hostetler Karl Y
• Beadle James R
• Valiaeva Nadejda

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P31/18

  for HIV · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/22

  for herpes viruses · CPC title