Formulation of quinazoline based EGFR inhibitors containing a zinc binding moiety
The present invention relates to a composition comprising an inclusion complex of a cyclodextrin and quinazoline containing zinc-binding moiety based derivatives. The cyclodextrin is preferable a β-cyclodextrin or a derivative thereof. The quinazolines have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
1. A composition comprising an inclusion complex of a cyclodextrin and a compound represented by formula I:
or a pharmaceutically acceptable salt thereof, wherein
X is O, S, CH 2 , or —CONH—;
B is a C 3 to C 9 alkylene;
R 1 is selected from hydrogen, C 1 to C 4 alkoxy or substituted C 1 to C 4 alkoxy;
each R 2 is independently selected from halogen, C 1 to C 4 alkyl, C 2 to C 4 alkenyl, and C 2 to C 4 alkynyl; and
n is 1, 2 or 3.
2. The composition of claim 1 wherein B is a straight chain C 5 to C 7 alkylene.
3. The composition of claim 2 wherein B is a straight chain C 6 alkylene and X is O.
4. The composition of claim 1 wherein R 1 is selected from hydrogen and methoxy.
5. The composition of claim 1 wherein each R 2 is independently selected from Br, Cl, F and ethynyl.
6. The composition of claim 1 wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin and a derivative thereof, β-cyclodextrin and a derivative thereof and γ-cyclodextrin and a derivative thereof.
7. The composition of claim 6 wherein the cyclodextrin is β-cyclodextrin or a derivative thereof.
8. The composition of claim 7 wherein the β-cyclodextrin derivative is selected from the group consisting of a 2-hydroxypropyl-β-cyclodextrin and a sulfobutyl derivatized-β-cyclodextrin.
9. The composition of claim 8 wherein the cyclodextrin is sulfobutylether-7-β-cyclodextrin.
10. The composition of claim 8 wherein the cyclodextrin is present at a concentration from about 0.5% to about 35% weight/volume.
11. The composition of claim 10 wherein the cyclodextrin is present at a concentration of about 30% weight/volume.
12. The composition of claim 1 wherein the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride salt and a tartrate salt.
13. The composition of claim 1 wherein the composition is a liquid.
14. The composition of claim 1 wherein the composition is a dried formulation.
15. The composition of claim 1 wherein the compound of formula (I) is represented by formula (II):
16. The compound of claim 15 or a pharmaceutically acceptable salt thereof wherein B is a straight chain C 5 to C 7 alkylene.
17. The compound of claim 16 or a pharmaceutically acceptable salt thereof wherein B is a straight chain C 6 alkylene.
18. The composition of claim 15 wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or a derivative thereof.
19. The composition of claim 18 wherein the cyclodextrin is β-cyclodextrin or a derivative thereof.
20. The composition of claim 19 wherein the cyclodextrin derivative is selected from the group consisting of a 2-hydroxypropyl-β-cyclodextrin and a sulfobutyl derivatized-β-cyclodextrin.
21. The composition of claim 20 wherein the cyclodextrin is sulfobutylether-7-β-cyclodextrin.
22. The composition of claim 20 wherein the cyclodextrin is present at a concentration from about 0.5% to about 35% weight/volume.
23. The composition of claim 22 wherein the cyclodextrin is present at a concentration of about 30% weight/volume.
24. The composition of claim 15 wherein the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride salt and a tartrate salt.
25. The composition of claim 15 wherein the composition is a liquid.
26. The composition of claim 15 wherein the composition is a dried formulation.
27. The composition of claim 1 wherein the compound of formula (I) is represented by formula (III):
28. The composition of claim 27 wherein B is a straight chain C 5 to C 7 alkylene.
29. The composition of claim 28 wherein R 1 is hydrogen and B is a straight chain C 6 alkylene.
30. The composition of claim 27 wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin or a derivative thereof, β-cyclodextrin or a derivative thereof and γ-cyclodextrin or a derivative thereof.
31. The composition of claim 30 wherein the cyclodextrin is β-cyclodextrin or a derivative thereof.
32. The composition of claim 31 wherein the cyclodextrin derivative is selected from the group consisting of a 2-hydroxypropyl-β-cyclodextrin and a sulfobutyl derivatized-β-cyclodextrin.
33. The composition of claim 32 wherein the cyclodextrin is sulfobutylether-7-β-cyclodextrin.
34. The composition of claim 32 wherein the cyclodextrin is present at a concentration from about 0.5% to about 35% weight/volume.
35. The composition of claim 34 wherein the cyclodextrin is present at a concentration of about 30% weight/volume.
36. The composition of claim 35 wherein the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride salt and a tartrate salt.
37. The composition of claim 27 wherein the composition is a liquid.
38. The composition of claim 27 wherein the composition is a dried formulation.
39. The composition of claim 1 wherein the compound of formula (I) is represented by formula (IV):
40. The compound of claim 39 or a pharmaceutically acceptable salt thereof wherein B is a straight chain C 5 to C 7 alkylene.
41. The compound of claim 40 or a pharmaceutically acceptable salt thereof wherein R 1 is methoxy and B is a straight chain C 6 alkylene.
42. The composition of claim 39 wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin or a derivative thereof, β-cyclodextrin or a derivative thereof and γ-cyclodextrin or a derivative thereof.
43. The composition of claim 42 wherein the cyclodextrin is β-cyclodextrin or a derivative thereof.
44. The composition of claim 43 wherein the cyclodextrin derivative is selected from the group consisting of a 2-hydroxypropyl-β-cyclodextrin and a sulfobutyl derivatized-β-cyclodextrin.
45. The composition of claim 44 wherein the cyclodextrin is sulfobutylether-7-β-cyclodextrin.
46. The composition of claim 39 wherein the cyclodextrin is present at a concentration from about 0.5% to about 35% weight/volume.
47. The composition of claim 46 wherein the cyclodextrin is present at a concentration of about 30% weight/volume.
48. The composition of claim 47 wherein the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride salt and a tartrate salt.
49. The composition of claim 39 wherein the composition is a liquid.
50. The composition of claim 39 wherein the composition is a dried formulation.
51. The composition of claim 1 further comprising an acid or base in an amount from about 0.5 to about 1.5 mol equivalents.
52. The composition of claim 51 wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, hydrochloric acid, citric acid, L(−)-malic acid and L(+)-tartaric acid.
53. The composition of claim 52 wherein the acid is L(+)-tartaric acid.
54. The composition of claim 50 wherein the base is selected from the group consisting of sodium hydroxide and potassium hydroxide.