Nucleoside prodrugs and uses related thereto

Patent metadata

Field	Value
Publication number	US-12049474-B2
Application number	US-202017637365-A
Country	US
Kind code	B2
Filing date	Aug 24, 2020
Priority date	Aug 22, 2019
Publication date	Jul 30, 2024
Grant date	Jul 30, 2024

Abstract

Disclosed are acyclic nucleoside prodrugs with improved metabolic stability and oral bioavailability. In general, the prodrugs are derivatives of acyclic nucleoside phosphonates containing a lipid-like moiety that can increase oral absorption and subsequent stability in the liver and plasma. Preferably, the lipid-like moiety can resist enzyme-mediated ω-oxidation, such as ω-oxidation catalyzed by cytochrome P450 enzymes. Also disclosed are pharmaceutical formulations of the acyclic nucleoside prodrugs. The acyclic nucleoside prodrugs and pharmaceutical formulations thereof can be used to treat viral infections, such as HIV infections, and/or viral-associated cancer, such as HPV-associated cancers.

First claim

What is claimed is:

1. A compound having a structure of Formula I or a pharmaceutically acceptable salt thereof:

wherein:
L is an acyclic nucleoside phosphonate;
W is a saturated C 1 -C 9 alkyl chain;
X is selected from the group consisting of substituted methylene or ethylene, —O—, —S—, —S(═O)—, and —S(O) 2 —;
Y is a saturated C 2 -C 20 alkyl chain; and
Z is selected from the group consisting of —C≡CCD 3 , —C≡CCH 2 F, —C≡CCHF 2 , —C≡CCF 3 , —C≡CC(CH 3 ) 3 ,

wherein * indicates the point of attachment to Y.

2. The compound of claim 1 , wherein L has a structure of Formula V:

wherein:
U is a nucleobase;
V is —O—R Y or —S—R Z ;
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, deuterium, halogen, azido, cyano, isocyano, nitrate, nitrosooxy, nitroso, nitro, formyl, carboxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, azo, acyl, optionally O-substituted hydroxyl, optionally S-substituted mercapto, sulfinyl, sulfonyl, sulfonate, optionally N-substituted amino, optionally N-substituted amide, optionally N-substituted sulfamoyl, optionally Si-substituted silyl, ester, carbonate ester, optionally substituted carbamate, optionally N-substituted aminooxy, and optionally N- and/or O-substituted hydroxyamino; and
R Y and R Z are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocarbocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

3. The compound of claim 2 , wherein L has a structure of Formula V′:

wherein U, R 3 , and R 4 are the same as defined in claim 2 .

4. The compound of claim 3 , wherein L is selected from the group consisting of:

5. The compound of claim 4 , wherein L is

6. The compound of claim 4 , wherein L is

7. The compound of claim 1 , wherein W is a linear C 1 -C 9 alkylene.

8. The compound of claim 7 , wherein W is CH 2 CH 2 — or CH 2 CH 2 CH 2 —.

9. The compound of claim 1 , wherein X is —CF 2 —, —O—, or —S—.

10. The compound of claim 1 , wherein Y is a linear C 2 -C 20 alkylene.

11. The compound of claim 10 , wherein Y is a linear C 8 -C 20 alkylene.

12. The compound of claim 1 , wherein Z is —C═CSi(CH 3 ) 3 .

13. The compound of claim 1 , wherein:
L is

W is —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —;
X is —CF 2 —, —O—, or —S—; and
Y is a linear C 8 -C 20 alkylene.

14. The compound of claim 13 , wherein the compound is selected from the group consisting of:
4,4-difluoro-18-(trimethylsilyl)octadec-17-yn-1-yl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
4,4,20,20,20-pentafluoroicos-18-yn-1-yl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((16, 16,16-trifluorohexadec-14-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-phenyldodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-(thiophen-2-yl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((13-(thiophen-2-yl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-(perfluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-(pyridin-3-yl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-cyclohexyldodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-(4-fluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-(3-fluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-(2-fluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-(2,4,6-trifluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((13-cyclopentyltridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((14-cyclopropyltetradec-13-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((10-(4-(tert-butyl)phenyl)dec-9-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((15, 15-dimethylhexadec-13-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((13-cyclobutyltridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((13-(1-methylsiletan-1-yl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((13-(ethyldimethylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((13-(triethylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((13-(triisopropylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((13-(tert-butyldimethylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((11-(dimethyl(phenyl)silyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((11-(dimethyl(perfluorophenyl)silyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-(dimethyl(3,3,3-trifluoropropyl)silyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((11-(cyclohexyldimethylsilyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((11-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate,
3-((12-(isobutyldimethylsilyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-

Assignees

• Univ Emory

Inventors

• Miller Eric
• Pribut Nicole
• D'Erasmo Michael
• Dasari Madhuri
• Giesler Kyle
• Iskandar Sabrina
• Liotta Dennis C

Classifications

• C07F9/65616 Primary

  containing the ring system [IMAGE cpc-sch-C07F-1006.gif] 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 title

• C07F9/6512

  having the nitrogen atoms in positions 1 and 3 · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title