Gemcitabine prodrugs
This invention relates to a prodrug of the monophosphate nucleotide of the well-known oncology drug gemcitabine. Specifically, it relates to gemcitabine-[phenyl-benzoxy- L -alaninyl)]-phosphate when present as a single phosphate diastereoisomer and, in particular, it relates to the (S)-phosphate diastereoisomer which offers a remarkable and unexpected increase in solubility relative to the (R)-diastereoisomer. The (S)-phosphate epimer is also preferentially taken up into cyclodextrin solutions over the (R)-diastereoisomer.
1. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(S)-phosphate 3:
or a pharmaceutically acceptable salt thereof, having a diastereoisomeric purity greater than 90%, wherein the cancer is selected from pancreatic cancer, ovarian cancer, lung cancer, bladder cancer, cholangiocarcinoma, renal cancer, cervical cancer, and thymic cancer.
2. The method of claim 1 , wherein gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(S)-phosphate is not in the form of a salt.
3. The method of claim 1 , wherein the cancer is pancreatic cancer.
4. The method of claim 1 , wherein the cancer is ovarian cancer.
5. The method of claim 1 , wherein the cancer is cholangiocarcinoma.
6. The method of claim 1 , wherein gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(S)-phosphate is administered orally.
7. The method of claim 1 , wherein gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(S)-phosphate is administered intravenously.
8. The method of claim 1 , wherein the diastereoisomeric purity of gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(S)-phosphate is greater than 95%.
9. The method of claim 1 , wherein the diastereoisomeric purity of gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(S)-phosphate is greater than 98%.
10. The method of claim 1 , wherein the diastereoisomeric purity of gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(S)-phosphate is greater than 99.5%.