Synthesis of combretastatin A-4 prodrugs and trans-isomers thereof
Combretastatin A-4 has been previously selected for pre-clinical development as antineoplastic agent. However, it is essentially insoluble in water. New water soluble derivatives of combretastatin A-4 and its qualified analogs have been discovered and synthesized through a multistage process using other derivatives of combretastatin A-4 as intermediates. These water soluble derivatives are herein denominated as “Combretastatin A-4 Prodrugs”.
1. A compound of Formula I:
wherein:
one of —OR 1 or —OR 2 is O − Na + , and the other is hydroxyl.
2. A composition comprising the compound of claim 1 .
3. The composition of claim 2 , further comprising a compound of Formula I:
wherein:
—OR 1 and —OR 2 are both O − Na + .
4. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier thereof.
5. A pharmaceutical unit dosage form comprising the compound of claim 1 .
6. The dosage form of claim 5 , wherein the dosage form is selected from the group consisting of a tablet, a capsule, an oral suspension, an intranasal suspension, an insufflation, a troche, a suppository, a powder packet, a wafer, a cachet, an ampule, and a vial.
7. The dosage form of claim 5 , which is a topical dosage form.
8. A method of modulating tumor growth or metastasis in an animal suffering from a neoplastic disease comprising administering to the animal an effective amount of a compound having a general structure of Formula I:
wherein:
one of —OR 1 or —OR 2 is O − Na + , and the other is hydroxyl.
9. The method of claim 8 , wherein the neoplastic disease is selected from the group consisting of acute myelocytic leukemia, acute lymphocytic leukemia, malignant melanoma, adenocarcinoma of the lung, neuroblastoma, small cell carcinoma of the lung, breast carcinoma, colon carcinoma, ovarian carcinoma, and bladder carcinoma.
10. The method of claim 8 , wherein the compound is administered intravenously.
11. The method of claim 10 , wherein the effective amount is from about 0.1 mg/kg to about 20 mg/kg.
12. The method of claim 8 , wherein the compound is administered intramuscularly.
13. The method of claim 12 , wherein the effective amount is from about 1 mg/kg to about 50 mg/kg.
14. The method of claim 8 , wherein the compound is administered orally.
15. The method of claim 14 , wherein the effective amount is from about 5 mg/kg to about 100 mg/kg.
16. The method of claim 8 , wherein the compound is administered topically.
17. The method of claim 16 , wherein the effective amount is from about 0.01% w/w to about 50% w/w.
18. The method of claim 8 , wherein the animal is a human.