Florfenicol prodrug having improved water solubility
View Patent ↗The present invention discloses phosphate esters of florfenicol (prodrugs) and florfenicol analogs having superior water solubility that are hydrolyzed to florfenicol or the respective florfenicol analog in vivo, upon administration to an animal.
1. A florfenicol phosphate ester having the chemical structure
or a salt thereof.
2. The florfenicol phosphate ester of claim 1 that is a florfenicol prodrug having the chemical structure:
wherein M 1 + and M 2 + are H + or a pharmaceutically-acceptable mono-cation, or taken together, are a pharmaceutically-acceptable di-cation.
3. The florfenicol prodrug of claim 2 , wherein M 1 + and M 2 + are independently selected from the group consisting of H + , Na + , NH 4 + , and K + .
4. The florfenicol prodrug of claim 3 , wherein M 1+ or M 2 + is H + and M 2 + or M 1 + , which is not H + , is Na + .
5. The florfenicol prodrug of claim 3 , wherein M 1 + and M 2 + are both Na + .
6. The florfenicol prodrug of claim 2 , wherein M 1 + and M 2 + are independently selected from the group consisting of H + and a protonated amine.
7. The florfenicol prodrug of claim 6 , wherein the protonated amine is NR 1 R 2 R 3 H + , and wherein R 1 , R 2 , and R 3 are independently selected to be either H, methyl, ethyl, propyl, isopropyl, —CH 2 CH 2 OH and —CH 2 C(CH 2 OH) 3 .
8. The florfenicol prodrug of claim 7 , wherein the protonated amine is selected from the group consisting of:
9. The florfenicol prodrug of claim 8 , wherein the protonated amine is:
10. The florfenicol prod rug of claim 7 ,
wherein R 1 is either H. methyl, ethyl, propyl, isopropyl, —CH 2 CH 2 OH and —CH 2 C(CH 2 OH) 3 ; and
wherein R 2 and R 3 are linked to form a five or six membered ring.
11. The florfenicol prodrug of claim 10 , wherein the five or six membered ring are selected from the group consisting of pirolidine, piperidine, or morpholine.
12. The florfenicol prodrug of claim 2 , wherein M 1 + and M 2 + comprise respectively, H + and a mono-cationic form of a dibasic aminoacid.
13. The florfenicol prodrug of claim 2 , wherein M 1 + and M 2 + are independently selected to be either H + , meglumine, benzocaine, or procaine.
14. The florfenicol prodrug of claim 2 , wherein M 1 + and M 2 + are taken together, and selected from the group consisting of Ca +2 , Mg +2 , a bis-protonated diamine, and a di-cationic form of a dibasic amino acid.
15. A pharmaceutical composition comprising the florfenicol prodrug of claim 2 in a pharmaceutically acceptable carrier.
16. The pharmaceutical composition of claim 15 , wherein the pharmaceutically acceptable carrier is an aqueous solution.
17. The pharmaceutical composition of claim 16 , which comprises a mixture of two or more salts of the florfenicol prodrug.
18. The pharmaceutical composition of claim 16 , wherein the pH of the aqueous solution is between pH 3.5 and pH 6.5.
19. The pharmaceutical composition of claim 18 , wherein the pH of the aqueous solution is between pH 4.0 and pH 6.
20. The pharmaceutical composition of claim 19 , wherein the pH of the aqueous solution is between pH 4.5 and pH 5.5.
21. The pharmaceutical composition of claim 16 , wherein the florfenicol phosphate ester is a mixture of a salt form of the florfenicol phosphate ester and an acid form of the florfenicol phosphate ester; and wherein a molar ratio of the base that is combined with the acid form of the florfenicol phosphate ester is in the range of 0.6–1.4.
22. The pharmaceutical composition of claim 21 , wherein the molar ratio is in the range of 0.8–1.2.
23. The pharmaceutical composition of claim 22 , wherein the molar ratio is in the range of 0.9–1.1.
24. A compound of the chemical formula:
or a salt thereof;
wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, (1C–4C)alkyl, halo, —CF 3 , —NH 2 , —CN and N 3 ;
wherein R 4 is selected from the group consisting of:
wherein A 1 is carbon or nitrogen, and carbon atoms in the ring are independently substituted with an entity selected from the group consisting of hydrogen, (1C–4C)alkyl, (3C–6C)cycloalkyl, (1C–4C)alkylO—, —CF 3 , —OH, —CN, halo, (1C–4C)alkylSO—, (1C–4C)alkylSO 2 —, NH 2 SO 2 —, (1C–4C)alkylNHSO 2 —, ((1C–4C)alkyl) 2 NSO 2 —, —NH 2 , (1C–4C)alkylNH—, ((1C–4C)alkyl) 2 N—, (1C–4C)alkylSO 2 NH—, (1C–4C)alkylC(O)—, (3C–6C)cycloalkylC(O)—, (1C–4C)alkylOC(O)—, (1C–4C)alkylC(O)NH—, —C(O)NH 2 , (1C–4C)alkylNHC(O)— and ((1C–4C)alkyl) 2 NC(O)—, wherein any of the alkyl groups within the substituents may be unsubstituted or substituted with a group selected from halo and hydroxy;
wherein A 2 , A 3 , A 4 , and A 5 are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur, provided that at least one of A 1 –A 5 is not carbon, that the total number of nitrogen, oxygen and sulfur atoms in the ring does not exceed 4 and that the ring is aromatic; and wherein if A 1 is carbon and the ring does not contain oxygen or sulfur, one of the nitrogen atoms may optionally be substituted with an entity selected from the group consisting of (1C–4C)alkyl, (1C–4C)alkylSO 2 — and —NH 2 ; and
wherein A 6 , A 7 , A 8 , A 9 and A 10 are independently selected from the group consisting of carbon, nitrogen and
provided that only one of A 6 –A 10 at a time can be
and that one, two, or three of the A 6 –A 10 atoms are nitrogen; and wherein the carbon atoms in the ring are independently substituted with an entity selected from the group consisting of hydrogen, (1C–4C)alkyl, (3C–6C)cycloalkyl, (1C–4C)alkylO—, —CF 3 , —OH, —CN, halo, (1C–4C)alkylSO—, (1C–4C)alkylSO 2 —, NH 2 SO 2 —, (1C–4C)alkylNHSO 2 —, ((1C–4C)alkyl) 2 NSO 2 —, —NH 2 , (1C–4C)alkylNH—, ((1C–4C)alkyl) 2 N—, (1C–4C)alkylSO 2 NH—, (1C–4C)alkylC(O)—, (3C–6C)cycloalkylC(O)—, (1C–4C)alkylOC(O)—, (1C–4C)alkylC(O)NH—, —C(O)NH 2 , (1C–4C)alkylNHC(O)—, ((1C–4C)alkyl) 2 NC(O)— and —OCH 2 O—,
wherein the oxygen atoms with the —OCH 2 O— substituent being bonded to adjacent ring carbon atoms, and wherein any of the alkyl groups within any of the substituents may be unsubstituted or substituted with a group selected from halo and hydroxy; and
wherein R 8 is hydrogen in all compounds, except when R 2 and R 3 are both F, in which case R 8 is hydrogen or F; and, the compound is either a racemate having the relative stereochemistry shown or is substantially enantiomerically pure and has the absolute stereochemistry shown.
25. A pharmaceutical composition comprising the compound of claim 24 in a pharmaceutically acceptable carrier.
26. A method for the synthesis of the acid form of a florfenicol phosphate ester having the chemical structure:
comprising the steps of:
(a) reacting florfenicol with di-tert-butylphosphoramidite in the presence of tetrazole in a first suitable solvent to yield a first intermediate;
(b) adding to the first intermediate an oxidant in a second suitable solvent to yield a second intermediate;
(c) isolating the second intermediate;
(d) dissolving the second intermediate in a third suitable solvent; and
(e) reacting the second intermediate with trifluoroacetic acid to yield the acid form of the florfenicol phosphate ester.
27. The method of claim 26 further comprising the step of isolating the acid form of the florfenicol phosphate ester.
28. A method for the synthesis of a salt form of a florfenicol phosphate ester having the chemical structure:
wherein M 1 + and M 2 + are a pharmaceutically-acceptable mono-cation, or taken together, are a pharmaceutically-acceptable di-cation,
wherein said method comprises combining the isolated acid form of the florfenicol phosphate ester of claim 27 with an aqueous solution of a base comprising a pharmaceutically-acceptable cation or di-cation to yield a form of the florfenicol phosphate ester as the salt of the cation or di-cation.
29. The method of claim 28 , wherein the pharmaceutically-acceptable cation or di-cation are a protonated amine or a bis-protonated diamine respectively.
30. The method of claim 28 , further comprising the step of isolating the salt form of the florfenicol phosphate ester.