Acyclic nucleoside phosphonate diesters

• US 10,076,532 B2
• Filed: 06/08/2017
• Issued: 09/18/2018
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: US Department of Veterans Affairs (Government of the United States of America), Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Hostetler, Karl Y., Beadle, James R., Valiaeva, Nadejda
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US15/617,841
• Publication Number:
  US 20170304330A1
• Time in Patent Office: 467 Days
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• 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: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

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

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 CH₂F.

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 —

(CH₂)_1-6-O—

(CH₂)_11-21—

CH₃.

6. The compound of claim 5, wherein L^a is —

(CH₂)₂—

O—

(CH₂)₁₇—

CH₃.

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:

18. The compound of claim 17, wherein:

L^a is the C_13-29 heteroalkyl or —

CH₂CH(OR¹)—

CH₂(OR²), wherein R¹ and R² 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.