Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers
View Patent ↗The invention relates generally to anti-angiogenesis agents and related methods of using to anti-angiogenesis agents for biomedical applications including direct monotherapy and combination therapy for treatment of an angiogenesis related condition. In an embodiment, the invention provides a class of opioid compounds and structurally related opioid derivatives exhibiting anti-VEGF activity for use in therapeutic procedures, including phototherapy. Opioid compounds and structurally related opioid derivatives of the invention may be administered alone or in combination with administration of a phototherapy agent and/or other therapeutic agent.
1. A method for treating cancer, the method comprising:
administering to a patient in need of treatment an effective amount of a purified (+) enantiomer compound substantially free of a corresponding (−) enantiomer, the (+) enantiomer compound having the formula (FX2):
wherein:
ring A is
X is —OH, —OCH 3 , or C 2 -C 8 alkoxy;
Y is —H or —OH;
W is —(CR 10 R 11 )—, —(C═O)—, —(C═S)—, —(C═CR 12 R 13 )—, or —(CR 14 NR 15 R 16 —);
each of R 1 and R 2 is independently —H, —CH 3 , —(O − ), C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 1 -C 10 haloalkyl, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 5 -C 10 alkylaryl, C 5 -C 10 alkylheteroaryl, C 5 -C 10 carbonylalkenylaryl, or C 5 -C 10 carbonylalkenylheteroaryl;
each of R 3 -R 16 and R 50 -R 54 is independently —H, —OH, —OCH 3 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkoxy, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 5 -C 10 alkylaryl, C 5 -C 10 alkylheteroaryl, halo, nitrile, C 1 -C 8 haloalkyl, C 1 -C 10 hydroxyalkyl, or C 5 -C 10 carbonylalkenylheteroaryl; and
when n is 1, and the nitrogen to which R 2 is attached has a positive charge and optionally is associated with an anion.
2. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX12):
wherein:
A −z is independently an anion;
z is independently 1, 2 or 3; and
m is independently 0 or 1, wherein when m is 0, A −z is not present.
3. The method of claim 1 wherein said (+) enantiomer compound has the formula:
4. The method of claim 1 wherein said (+) enantiomer compound has the formula:
5. The method of claim 1 wherein said (+) enantiomer compound has the formula:
6. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX14):
7. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX16):
8. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX18):
9. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX19):
10. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX21):
11. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX23):
12. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX25):
13. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX27):
14. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX30):
15. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX32):
16. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX34):
17. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX36):
18. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX38):
19. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX39):
20. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX41):
21. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX43):
22. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX45).
23. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX47):
24. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX50):
25. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX52):
26. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX54):
27. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX56):
28. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX58):
29. The method of claim 1 wherein said (+) enantiomer compound has the formula (FX60):
30. The method for treating cancer of claim 1 , further comprising administering to said patient a mixture of two or more purified (+) enantiomer compounds each independently having a formula (FX2).
31. The method of claim 1 , comprising a method for treating pancreatic cancer.
32. The method of claim 1 , comprising a method of suppressing tumor growth or tumor metastasis.
33. The method of claim 1 , further comprising administering to said patient one or more chemotherapeutic agents.
34. The method of claim 1 , further comprising administering to said patient one or more VEGF inhibitors.
35. The method of claim 1 , further comprising administering to said patient 5-fluorouracil, floxuridine, furtulon, capecitabine, gemcitabine, taxol, doxorubicin, cisplatin, thalidomide, paclitaxel, docetaxel or bevacizumab.
36. A method for treating cancer, the method comprising:
administering to a patient in need of treatment an effective amount of a purified (+) enantiomer compound substantially free of a corresponding (−) enantiomer, the (+) enantiomer compound having the formula:
wherein:
each of R 1 and R 2 is independently —H, —CH 3 , —(O − ), C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 1 -C 10 haloalkyl, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 5 -C 10 alkylaryl, C 5 -C 10 alkylheteroaryl, C 5 -C 10 carbonylalkenylaryl, or C 5 -C 10 carbonylalkenylheteroaryl; and
n is 1, and the nitrogen to which R 2 is attached has a positive charge and optionally is associated with an anion.
37. The method for treating cancer of claim 36 , further comprising administering to said patient a mixture of two or more purified (+) enantiomer compounds each independently having a formula:
38. The method of claim 36 , comprising a method for treating pancreatic cancer.
39. The method of claim 36 , comprising a method of suppressing tumor growth or tumor metastasis.
40. The method of claim 36 , further comprising administering to said patient one or more chemotherapeutic agents.
41. The method of claim 36 , further comprising administering to said patient one or more VEGF inhibitors.
42. The method of claim 36 , further comprising administering to said patient 5-fluorouracil, floxuridine, furtulon, capecitabine, gemcitabine, taxol, doxorubicin, cisplatin, thalidomide, paclitaxel, docetaxel or bevacizumab.
43. A method for treating cancer, the method comprising:
administering to a patient in need of treatment an effective amount of a purified (+) enantiomer compound substantially free of a corresponding (−) enantiomer, the (+) enantiomer compound having the formula (FX14):
wherein:
each of R 1 and R 2 is independently —H, —CH 3 , —(O − ), C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl, C 1 -C 10 haloalkyl, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 5 -C 10 alkylaryl, C 5 -C 10 alkylheteroaryl, C 5 -C 10 carbonylalkenylaryl, or C 5 -C 10 carbonylalkenylheteroaryl; and
n is 1, and the nitrogen to which R 2 is attached has a positive charge and optionally is associated with an anion.
44. The method for treating cancer of claim 43 , further comprising administering to said patient a mixture of two or more purified (+) enantiomer compounds each independently having a formula (FX14).
45. The method of claim 43 , comprising a method for treating pancreatic cancer.
46. The method of claim 43 , comprising a method of suppressing tumor growth or tumor metastasis.
47. The method of claim 43 , further comprising administering to said patient one or more chemotherapeutic agents.
48. The method of claim 43 , further comprising administering to said patient one or more VEGF inhibitors.
49. The method of claim 43 , further comprising administering to said patient 5-fluorouracil, floxuridine, furtulon, capecitabine, gemcitabine, taxol, doxorubicin, cisplatin, thalidomide, paclitaxel, docetaxel or bevacizumab.