Oral formulations of CD73 compounds
Oral formulations comprising a compound of Formula (I) and a chelating agent are provided, wherein compounds of Formula (I) have the structure: wherein, W, X, Y, Z, R a , R c , and each R g are as defined herein. Also provided are methods of preparation, methods of use, and specific dosage forms.
1. An oral formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and inositol hexaphosphate or an ionized salt thereof, wherein the compound of Formula (I) has the structure:
wherein,
W is selected from the group consisting of CR e and N;
X is selected from the group consisting of O, CH 2 , and S;
each of Y and Z is independently selected from the group consisting of CH and N:
R g is H or the two R 9 groups are combined to form an acetonide;
R a is selected from the group consisting of NH 2 , NHR 1 , and NR 1 R 2 ;
R c is selected from the group consisting of H, halogen, haloalkyl, NH 2 , NHR 3 , NR 3 R 4 , R 3 , OH, OR 3 , SR 3 , SO 2 R 3 , —X 1 —NH 2 , —X 1 —NHR 3 , —X 1 —NR 3 R 4 , —X 1 —OH, —X 1 —OR 3 , —X 1 —SR 3 , and —X 1 —SO 2 R 3 ;
R e is selected from the group consisting of H, halogen, and optionally substituted C 1 -C 6 alkyl;
each X 1 is C 1 -C 4 alkylene; and
each R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 7 cycloalkylC 1 -C 4 alkyl-, optionally substituted 4-7 membered heterocycloalkyl, optionally substituted 4-7 membered heterocycloalkylC 1 -C 4 alkyl-, optionally substituted aryl, optionally substituted arylC 1 -C 4 alkyl-, optionally substituted heteroaryl, and
optionally substituted heteroarylC 1 -C 4 alkyl-, or when R 1 and R 2 or R 3 and R 4 are attached to the same nitrogen, they combine to form a 4- to 7-membered heterocyclic ring.
2. The oral formulation of claim 1 , wherein X is O.
3. The oral formulation of claim 1 , wherein R 9 is H.
4. The oral formulation of any one of claim 1 , wherein R a is NHR 1 and R 1 is selected from the group consisting of optionally substituted arylC 1 -C 4 alkyl- and optionally substituted heteroarylC 1 -C 4 alkyl-.
5. The oral formulation of claim 1 , wherein R a is NHR 1 and R 1 is optionally substituted arylC 1 -C 4 alkyl-.
6. The oral formulation of claim 1 , wherein R c is selected from the group consisting of H, halogen, and haloalkyl.
7. The oral formulation of claim 1 , wherein R c is halogen.
8. The oral formulation of claim 1 , wherein R e is H.
9. The oral formulation of claim 1 , wherein the compound of Formula (I), or the pharmaceutically acceptable salt thereof, has a structure selected from the group consisting of
10. The oral formulation of claim 1 , wherein the compound of Formula (I), or the pharmaceutically acceptable salt thereof, has the structure
11. The oral formulation of claim 1 , wherein, the inositol hexaphosphate or an ionized salt thereof is a partially ionized inositol hexaphosphate salt.
12. The oral formulation of claim 11 , wherein the partially ionized inositol hexaphosphate salt is hexasodium inositol hexaphosphate.
13. The oral formulation of claim 11 , wherein the partially ionized inositol hexaphosphate salt is an inositol hexaphosphate salt having not less than 5 mol sodium per mol of inositol phosphate.
14. The oral formulation of claim 11 , wherein the partially ionized inositol hexaphosphate salt is an inositol hexaphosphate salt having not less than 4 mol sodium per mol of inositol phosphate.
15. The oral formulation of claim 11 , wherein the partially ionized inositol hexaphosphate salt is an inositol hexaphosphate salt having not less than 3 mol sodium per mol of inositol phosphate.
16. The oral formulation of claim 11 , wherein the partially ionized inositol hexaphosphate salt is an inositol hexaphosphate salt having not less than 2 mol sodium per mol of inositol phosphate.
17. The oral formulation of claim 1 , wherein the inositol hexaphosphate or an ionized salt thereof is a fully ionized inositol hexaphosphate salt.
18. The oral formulation of claim 1 , having a molar ratio of inositol hexaphosphate or an ionized salt thereof to compound of Formula (I) of from about 1:1 to 10:1.
19. The oral formulation of claim 18 , wherein the ratio of inositol hexaphosphate or an ionized salt thereof to compound of Formula (I) is from about 3:1 to 10:1.
20. The oral formulation of claim 18 , wherein the ratio of inositol hexaphosphate or an ionized salt thereof to compound of Formula (I) is from about 1:1 to 7:1.
21. The oral formulation of claim 19 , wherein the ratio of inositol hexaphosphate or an ionized salt thereof to compound of Formula (I) is from about 1:1 to 5:1.
22. The oral formulation of claim 19 , wherein the ratio of inositol hexaphosphate or an ionized salt thereof to compound of Formula (I) is about 3.5:1.
23. A method of treating a disease, disorder, or condition, mediated at least in part by CD73, the method comprising administering an oral formulation of claim 1 to a subject in need thereof.
24. An oral formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and edetic acid (EDTA) or an ionized salt thereof, wherein the compound of Formula (I) has the structure:
wherein,
W is selected from the group consisting of CR e and N;
X is selected from the group consisting of O, CH 2 , and S;
each of Y and Z is independently selected from the group consisting of CH and N:
R g is H or the two R g groups are combined to form an acetonide;
R a is selected from the group consisting of NH 2 , NHR 1 , and NR 1 R 2 ;
R c is selected from the group consisting of H, halogen, haloalkyl, NH 2 , NHR 3 , NR 3 R 4 , R 3 , OH, OR 3 , SR 3 , SO 2 R 3 , —X 1 —NH 2 , —X 1 —NHR 3 , —X 1 —NR 3 R 4 , —X 1 —OH, —X 1 —OR 3 , —X 1 —SR 3 , and —X 1 —SO 2 R 3 ;
R e is selected from the group consisting of H, halogen, and optionally substituted C 1 -C 6 alkyl;
each X 1 is C 1 -C 4 alkylene; and
each R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 7 cycloalkylC 1 -C 4 alkyl-, optionally substituted 4-7 membered heterocycloalkyl, optionally substituted 4-7 membered heterocycloalkylC 1 -C 4 alkyl-, optionally substituted aryl, optionally substituted arylC 1 -C 4 alkyl-, optionally substituted heteroaryl, and optionally substituted heteroarylC 1 -C 4 alkyl-, or when R 1 and R 2 or R 3 and R 4 are attached to the same nitrogen, they combine to form a 4- to 7-membered heterocyclic ring.