Acyclic nucleoside phosphonate diesters

Patent metadata

Field	Value
Publication number	US-10076532-B2
Application number	US-201715617841-A
Country	US
Kind code	B2
Filing date	Jun 8, 2017
Priority date	Mar 15, 2013
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

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 compound of Formula (Ia) or a pharmaceutically acceptable salt thereof:

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

2. The compound of claim 1 , wherein: B Nuc(a) is a naturally occurring purine; L a is the C 13-29 heteroalkyl; and R a is the C 1-6 alkyl or the substituted or unsubstituted aryl.

3. The compound of claim 1 , wherein X a is methyl, methoxy, or CH 2 F.

4. The compound of any one of claim 1 , wherein L a is the C 13-29 heteroalkyl.

5. The compound of claim 4 , wherein L a is —(CH 2 ) 1-6 -O—(CH 2 ) 11-21 —CH 3 .

6. The compound of claim 5 , wherein L a is —(CH 2 ) 2 —O—(CH 2 ) 17 —CH 3 .

7. The compound of claim 1 , wherein R a is the unsubstituted aryl.

8. The compound of claim 7 , wherein R a is phenyl or benzyl.

9. The compound of claim 1 , wherein B Nuc(a) is:

10. The compound of claim 1 , wherein the compound of Formula (Ia) has the structure:

11. The compound of claim 1 , wherein the compound of Formula (Ia) has the structure:

12. The compound of claim 1 , wherein the compound of Formula (Ia) is:

13. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

14. A method for treating HIV or hepatitis B in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 1 to the patient to treat the HIV or the hepatitis B.

15. A method of treating HIV in a patient in need thereof, the method comprising administering a therapeutically effective amount of the compound of claim 12 to the patient to treat the HIV.

16. A method for treating HIV or hepatitis B in a patient in need thereof, the method comprising administering a therapeutically effective amount of the composition of claim 13 to the patient to treat the HIV or the hepatitis B.

17. A compound of Formula (Ia) or a pharmaceutically acceptable salt thereof:

wherein:
B Nuc(a) is adenine-9-yl;
L a is a C 12-24 alkyl, a C 13-29 heteroalkyl, or a glyceryl moiety substituted with one or more groups selected from a C 13-29 alkyl, a C 13-29 heteroalkyl, a substituted or unsubstituted aryl(C 1-6 alkyl), a substituted or unsubstituted heteroaryl(C 1-6 alkyl), and a substituted or unsubstituted heterocycloalkyl(C 1-6 alkyl);
R a is a C 1-6 alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl(C 1-6 alkyl), a substituted or unsubstituted heteroaryl(C 1-6 alkyl) and a substituted or unsubstituted heterocycloalkyl(C 1-6 alkyl); and
X a is hydrogen or a hydroxy substituted C 1-6 alkyl.

18. The compound of claim 17 , wherein: L a is the C 13-29 heteroalkyl or —CH 2 CH(OR 1 )—CH 2 (OR 2 ), wherein R 1 and R 2 are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl; R a the C 1-6 alkyl or the substituted or unsubstituted aryl; and X a is hydrogen.

19. A pharmaceutical composition comprising the compound of claim 17 and a pharmaceutically acceptable excipient.

20. A method for treating HIV or hepatitis B in a patient in need thereof, the method comprising administering a therapeutically effective amount of the composition of claim 17 to the patient to treat the HIV or the hepatitis B.

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

• A61P31/22

  for herpes viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P35/02

  specific for leukemia · CPC title