Taxane compounds, compositions and methods
The present invention provides a method for the preparation of orally available pentacyclic taxane compounds, as well as intermediates useful in their preparation.
1. A compound having the formula:
(TT) m .(HX) n .(H 2 O) y .(Sol) z
wherein TT is tesetaxel;
HX is an acid selected from benzoic acid, ortho-toluic acid, meta-toluic acid, para-toluic acid, ethane sulphonic acid, camphor sulphonic acid, (S)-(+)-mandelic acid, (R)-(−)-mandelic acid, gentisic acid, hippuric acid, glycolic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, gluconic acid, malic acid, oxalic acid, succinic acid, tartaric acid, malonic acid, adipic acid, itaconic acid, cyclohexane dicarboxylic acid, phthalic acid, edisylate, phenyl phosphonic acid, digluconic acid, dibasic natural amino acids, or phosphoric acid;
Sol is an organic solvent;
m and n are each independently an integer from about 1 to about 5; and
y and z are each independently an integer from 0 to about 5.
2. The compound of claim 1 , wherein both y and z are 0.
3. The compound of claim 1 , wherein said acid is selected from benzoic acid, ortho-toluic acid, meta-toluic acid, para-toluic acid, ethane sulphonic acid, camphor sulphonic acid, (S)-(+)-mandelic acid, (R)-(−)-mandelic acid, gentisic acid, hippuric acid, glycolic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, and gluconic acid.
4. The compound of claim 1 , wherein said acid is selected from malic acid, oxalic acid, succinic acid, tartaric acid, malonic acid, adipic acid, itaconic acid, cyclohexane dicarboxylic acid, phthalic acid, edisylate, phenyl phosphonic acid, digluconic acid, and dibasic natural amino acids.
5. The compound of claim 1 , wherein said acid is phosphoric acid.
6. The compound of claim 1 , wherein z is an integer from about 1 to about 5.
7. The compound of claim 6 , wherein said organic solvent is selected from the group consisting of acetone, methanol, ethanol, propanol, butanol, acetonitrile, tetrahydrofuran, isopropyl alcohol, toluene and N,N-dimethylformamide.
8. The compound of claim 1 , wherein m is 1 and n is 2.
9. The compound of claim 1 , wherein m is 2 and n is 1.
10. A method for treating a cancer in a mammal, comprising administering to said mammal a compound of claim 1 in an amount effective to treat said cancer.
11. The method of claim 10 wherein the compound is administered in a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.
12. A pharmaceutical composition comprising a compound of claim 1 and at least one additional pharmaceutically acceptable excipient.
13. The composition of claim 12 , which is formulated for oral administration, parenteral administration, intra-cavitary administration, or extended release.
14. The composition of claim 13 , which is in the form of a tablet or capsule.
15. A compound having the formula:
(TT) m .(HX) n .(H 2 O) y .(Sol) z
wherein TT is tesetaxel;
HX is a monobasic, dibasic, tribasic, or polybasic acid;
Sol is isopropyl alcohol;
m and n are each independently an integer from about 1 to about 5; and
y and z are each independently an integer from 0 to about 5.