Anticancer and antiprotozoal dihydroartemisinene and dihydroartemisitene dimers with desirable chemical functionalities
View Patent ↗This invention comprises compositions containing dihydroartemisinin- and dihydroartemisitene-dimers with activity as anticancer or anticancer metastasis agents and anti-protozal, including anti-malarial and anti-leishmanial properties. This invention also describes methods of preparation of these compositions and methods of use of such compositions for the treatment of cancer or prevention of cancer metastasis, and protozoal infections, including malaria, or leishmaniasis. The compounds of this invention represent a potential new class of anti-tumor or anti-metastasis agents, one that has shown promising activity against solid tumors.
1. A method of treating cancer or inhibiting cancer metastasis comprising administering to a subject suffering from cancer an effective amount of at least one compound of the formula:
Where R is:
where R 1 is H or alkyl, cycloalkyl or aryl moiety, free or containing one of a variety of functional groups such as COOH, OH, NH or derivatives thereof;
where R 2 is H or alkyl, cycloalkyl or aryl moiety, free or containing one of a variety of functional groups such as COOH, OH, NH or derivatives thereof;
or a compound of the formula
where R 5 is selected from one of the substituents described above for R.
2. A method of treating a protozoal infection comprising administering to a subject suffering from an infection an effective amount of at least one compound of the formula:
where R is
where R 1 is H or alkyl, cycloalkyl or aryl moiety, free or containing one of a variety of functional groups such as COOH, OH, NH or derivatives thereof;
where R 2 is H or alkyl, cycloalkyl or aryl moiety, free or containing one of a variety of functional groups such as COOH, OH, NH or derivatives thereof;
or a compound of the formula:
where R 5 is selected from one of the substituents described above for R.
3. A compound of the formula
where R is
Where R 1 is H or alkyl, cycloalkyl or aryl moiety, free or containing one of a variety of functional groups such as COOH, OH, NH or derivatives thereof;
where R 2 is H or alkyl, cycloalkyl or aryl moiety, free or containing one of a variety of functional groups such as COOH, OH, NH or derivatives thereof;
or a compound of the formula
where R 5 is selected from one of the substituents described above for R.
4. A pharmaceutical composition comprising at least of one compound according to claim 3 and a pharmaceutically acceptable carrier and/or excipient.
5. A method of preparing compounds of the formulas of claim 3 , comprising reacting dihydroartemisinin or dihydroartemisitene with dihydroxy acetone under acidic conditions such as borontrifluoride etherate followed by additional functionalization of the resulting ketone dimer.
6. The method of claim 5 where R is
residue and R 1 is selected from H, or alkyl, cycloalkyl or aryl groups free or containing one of a variety of functional groups such as COOH, OH or NH or derivatives thereof comprising reacting the ketone dimer of claim 5 with NH 2 —O—R 1 (where R 1 is the appropriate substituent) under basic conditions followed by purification of the reaction mixture to separate the purified oxime.
7. The method of claim 5 where R is
residue and R 2 is selected from H, or alkyl, cycloalkyl or aryl groups free or containing one of a variety of functional groups such as COOH, OH or NH or derivatives thereof comprising reacting the ketone dimer of claim 5 with NH 2 —R 2 (where R 2 is the appropriate substituent) and sodium cyanoborohydride or sodium triacetoxyborohydride, followed by purification of the reaction mixture to separate the purified amine.
8. The method of claim 5 where R5 is
residue and R 1 is selected from H, or alkyl, cycloalkyl or aryl groups free or containing one of a variety of functional groups such as COOH, OH or NH or derivatives thereof comprising reacting the ketone dimer of claim 5 with NH 2 —O—R 1 , (where R 1 is the appropriate substituent) under basic conditions followed by purification of the reaction mixture to separate the purified oxime.
9. The method of claim 5 where R5 is
residue and R 2 is selected from H, or alkyl, cycloalkyl or aryl groups free or containing one of a variety of functional groups such as COOH, OH or NH or derivatives thereof comprising reacting the ketone dimer of claim 5 with NH 2 —R 2 (where R 2 is the appropriate substituent) and sodium cyanoborohydride or sodium triacetoxyborohydride, followed by purification of the reaction mixture to separate the purified amine.
10. A compound of claim 3 where R and R 1 are as depicted in structure 6.
11. A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier and/or excipient.
12. A method of treating Cancer or inhibiting cancer metastasis comprising administering to a subject suffering from Cancer an effective dosage of a composition of claim 11 .
13. A method of treating a protozoal infection comprising administering to a subject suffering from an infection with an effective dosage of a composition of claim 11 .
14. A method of preparing a compound of claim 10 comprising reaction of the ketone dimer 4 with aminoxy-acetic acid in the presence of sodium acetate followed by workup and purification of the reaction mixture.
15. A compound of claim 3 where R and R 1 are as depicted in structure 7.
16. A pharmaceutical composition comprising the compound of claim 15 and a pharmaceutically acceptable carrier and/or excipient.
17. A method of treating Cancer or inhibiting cancer metastasis comprising administering to a subject suffering from Cancer an effective dosage of a composition of claim 16 .
18. A method of treating a protozoal infection comprising administering to a subject suffering from an infection with an effective dosage of a composition of claim 16 .
19. A method of preparing a compound of claim 15 comprising reaction of the ketone dimer 4 with hydroxylamine hydrochloride in the presence of sodium acetate followed by workup and purification of the reaction mixture.
20. A compound of claim 3 where R and R 1 are as depicted in structure 8.
21. A pharmaceutical composition comprising the compound of claim 20 and a pharmaceutically acceptable carrier and/or excipient.
22. A method of treating Cancer or inhibiting cancer metastasis comprising administering to a subject suffering from Cancer an effective dosage of a composition of claim 21 .
23. A method of treating a protozoal infection comprising administering to a subject suffering from an infection with an effective dosage of a composition of claim 21 .
24. A method of preparing a compound of claim 20 comprising reaction of the ketone dimer 4 with O-benzyl hydroxylamine hydrochloride in the presence of sodium acetate followed by workup and purification of the reaction mixture.
25. A compound of claim 3 where R and R 1 are as depicted in structure 9.
26. A pharmaceutical composition comprising the compound of claim 25 and a pharmaceutically acceptable carrier and/or excipient.
27. A method of treating Cancer or inhibiting cancer metastasis comprising administering to a subject suffering from Cancer an effective dosage of a composition of claim 26 .
28. A method of treating a protozoal infection comprising administering to a subject suffering from an infection with an effective dosage of a composition of claim 26 .
29. A method of preparing a compound of claim 25 comprising reaction of the ketone dimer 4 with O-ethyl hydroxylamine hydrochloride in the presence of sodium acetate followed by workup and purification of the reaction mixture.
30. A compound as depicted in structure 10.
31. A pharmaceutical composition comprising the compound of claim 30 and a pharmaceutically acceptable carrier and/or excipient.
32. A method of treating Cancer or inhibiting cancer metastasis comprising administering to a subject suffering from Cancer an effective dosage of a composition of claim 31 .
33. A method of treating a protozoal infection comprising administering to a subject suffering from an infection with an effective dosage of a composition of claim 31 .
34. A method of preparing a compound of claim 30 comprising reaction of the glycerol dimer 5 with chlorosulphonic acid in the presence of pyridine followed by workup and purification of the reaction mixture.
35. A compound of claim 3 where R and R 1 are as depicted in structure 11.
36. A pharmaceutical composition comprising the compound of claim 35 and a pharmaceutically acceptable carrier and/or excipient.
37. A method of treating Cancer or inhibiting cancer metastasis comprising administering to a subject suffering from Cancer an effective dosage of a composition of claim 36 .
38. A method of treating a protozoal infection comprising administering to a subject suffering from an infection with an effective dosage of a composition of claim 36 .
39. A method of preparing a compound of claim 35 comprising reaction of the glycerol dimer 5 with 4-phenyl chloroformate and then adding 4-amino butyric acid allyl ester followed by deprotection of the resulting carbamate, workup and purification of the reaction mixture.
40. A compound of claim 3 where R and R 1 are as depicted in structure 12.
41. A pharmaceutical composition comprising the compound of claim 40 and a pharmaceutically acceptable carrier and/or excipient.
42. A method of treating Cancer or inhibiting cancer metastasis comprising administering to a subject suffering from Cancer an effective dosage of a composition of claim 41 .
43. A method of treating a protozoal infection comprising administering to a subject suffering from an infection with an effective dosage of a composition of claim 41 .
44. A method of preparing a compound of claim 40 comprising reaction of the ketone dimer 4 with benzyl amine, sodium triacetoxy borohydride and acetic acid followed by, workup and purification of the reaction mixture.
45. A compound of claim 3 where R and R 1 are as depicted in structure 13.
46. A pharmaceutical composition comprising the compound of claim 45 and a pharmaceutically acceptable carrier and/or excipient.
47. A method of treating Cancer or inhibiting cancer metastasis comprising administering to a subject suffering from Cancer an effective dosage of a composition of claim 46 .
48. A method of treating a protozoal infection comprising administering to a subject suffering from an infection with an effective dosage of a composition of claim 46 .
49. A method of preparing a compound of claim 45 comprising reaction of the ketone dimer 4 with 6-amino hexanoic acid, sodium triacetoxy borohydride and acetic acid followed by workup and purification of the reaction mixture.