CARBONATES OF FENICOL ANTIBIOTICS

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates reaction Scheme 1 for the synthesis of florfenicol and florfenicol analog benzylic carbonate prodrugs using chloroformates.

FIG. 1B illustrates reaction Scheme 2 for the synthesis of benzylic carbonate prodrug esters from dihydroxy fenicols (of the chloramphenicol type).

FIG. 2A illustrates reaction Scheme 3 (dihydroxy type fenicol, method A) for the synthesis of benzylic carbonate prodrug esters from dihydroxy fenicols using less than one molar equivalent of chloroformate reagent.

FIG. 2B illustrates reaction Scheme 4 (dihydroxy type fenicol, method B) for the synthesis of benzylic mono-carbonate prodrugs of dihydroxy fenicols (of the chloramphenicol type) using protecting group strategy.

FIG. 3A illustrates reaction Scheme 5 (dihydroxy type fenicol, method C) for the synthesis of benzylic mono-carbonate prodrugs of dihydroxy fenicols (of the chloramphenicol type) using selective hydrolysis strategy.

FIG. 3B illustrates reaction Scheme 6 for the synthesis of florfenicol and florfenicol analog benzylic carbonate prodrugs using X—(O)C—O—R₄reagents other than chloroformates. The range of values for “X” is given by Table 1, below.

FIG. 4 illustrates the synthesis of fenicol carbonate compound D by reacting starting alcohol A with triethyl amine to provide chloroformate B which is reacted with fenicol C to produce compound D.

FIG. 5 illustrates the synthesis of bis carbonate fenicol compound F by reacting bis chloroformate E with substrate C to produce carbonate fenicol compound F.

FIG. 6 illustrates the synthesis of carbonate fenicol compound H by reacting ethyl chloroformate B with substrate G, and triethylamine (not shown), to produce benzylic bis carbonate fenicol compound H, benzylic carbonate 1, and a primary carbonate.

FIG. 7
a illustrates reaction scheme 7a for the synthesis of a bis carbonate wherein R₄is different than R₅.

FIG. 7
b illustrates reaction scheme 7b for an alternative synthesis of a bis carbonate wherein R₄is different than R₅.

Claims

1. A fenicol carbonate of Formula I, or a solvate thereof,
2. The fenicol carbonate of claim 1 wherein when R1 is NO2, R3 is not CH2O—C(O)O—R5.
3. The fenicol carbonate of claim 1 wherein R4 and R5 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-octadecyl, 2-methyl-butyl, 1-ethyl-propyl, 3-methyl-prop-2-enyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-propoxy-ethyl, 2-butoxy-ethyl, 1-methyl-2-methoxy-ethyl, cyclopropyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3,7-dimethyloct-6-enyl, benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-metyl-benzyl, 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, methyl-2-furyl, 2-(methoxy-ethoxy)-ethyl, 2-(ethoxy-ethoxy)-ethyl, 2-[2-(methoxy-ethoxy)-ethoxy]-ethyl, 2-[2-(ethoxy-ethoxy)-ethoxy]-ethyl, 2-(hydroxy-ethoxy)-ethyl, 2-[2-(hydroxy-ethoxy)-ethoxy]-ethyl, 2-acetoxy-ethyl, 2-(acetoxy-ethoxy)-ethyl, 3-acetoxy-propyl, 2-carboxy-ethyl, 3-carboxy-propyl, 4-carboxy-butyl, 2-methoxycarbonyl-ethyl, 3-methoxycarbonyl-propyl, 4-methoxycarbonyl-butyl, 2-methoxycarbonyl-benzyl, 3-methoxycarbonyl-benzyl, 4-methoxycarbonyl-benzyl, 1-ethoxycarbonyl-ethyl, 1-methoxycarbonyl-ethyl, phenyl, 4-metyl-phenyl, 4-methoxy-phenyl, 4-carboxy-phenyl, 2-carboxy-phenyl, 4-methoxycarbonyl-phenyl, 2-methoxycarbonyl-phenyl and 4-acetylamino-phenyl.
4. The fenicol carbonate of claim 3 wherein R4 and R5 are independently substituted with a moiety selected from the group consisting of methyl, methoxy, carboxy, carboalkoxy and acyloxy.
5. The fenicol carbonate of claim 3, wherein R1 is selected from the group consisting of
6. The fenicol carbonate of claim 1 wherein R1 is CH3SO2, R2 is CHCl2 and R3 is CH2F.
7. The florfenicol carbonate of claim 6, wherein R4 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-octadecyl, 2-methyl-butyl, 1-ethyl-propyl, 3-methyl-prop-2-enyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-propoxy-ethyl, 2-butoxy-ethyl, 1-methyl-2-methoxy-ethyl, cyclopropyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3,7-dimethyloct-6-enyl, benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-metyl-benzyl, 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, methyl-2-furyl, 2-(methoxy-ethoxy)-ethyl, 2-(ethoxy-ethoxy)-ethyl, 2-[2-(methoxy-ethoxy)-ethoxy]-ethyl, 2-[2-(ethoxy-ethoxy)-ethoxy]-ethyl, 2-(hydroxy-ethoxy)-ethyl, 2-[2-(hydroxy-ethoxy)-ethoxy]-ethyl, 2-acetoxy-ethyl, 2-(acetoxy-ethoxy)-ethyl, 3-acetoxy-propyl, 2-carboxy-ethyl, 3-carboxy-propyl, 4-carboxy-butyl, 2-methoxycarbonyl-ethyl, 3-methoxycarbonyl-propyl, 4-methoxycarbonyl-butyl, 2-methoxycarbonyl-benzyl, 3-methoxycarbonyl-benzyl, 4-methoxycarbonyl-benzyl, 1-ethoxycarbonyl-ethyl, 1-methoxycarbonyl-ethyl, phenyl, 4-metyl-phenyl, 4-methoxy-phenyl, 4-carboxy-phenyl, 2-carboxy-phenyl, 4-methoxycarbonyl-phenyl, 2-methoxycarbonyl-phenyl and 4-acetylamino-phenyl.
8. The fenicol carbonate of claim 1, wherein R3 is CH2F.
9. The fenicol carbonate of claim 1, wherein R1 is CH3SO2 or NO2, R2 is CHCl2, R3 is OH and R4 is ethyl.
10. The fenicol carbonate of claim 1, wherein R1 is CH3SO2 or NO2, R2 is CHCl2, R3 is
11. The fenicol carbonate of claim 1 that is selected from the group consisting of
12. The fenicol carbonate of claim 1 that is selected from the group consisting of the compounds listed by Table 2.
13. A fenicol carbonate comprising a compound of Formula II,
14. The compound of claim 13 wherein the sum of a, b, c, d and e ranges in value from 2 through 4.
15. The compound of claim 13 where R1 is
16. The compound of claim 13, having a structure selected from the group consisting of:
17. A pharmaceutical composition comprising an effective amount of the fenicol carbonate of claim 1, together with pharmaceutically acceptable excipients or solvents.
18. A pharmaceutical composition comprising an effective amount of the fenicol carbonate of claim 13, together with pharmaceutically acceptable excipients or solvents.
19. A pharmaceutical composition comprising an effective amount of the fenicol carbonate of claim 6, together with pharmaceutically acceptable excipients or solvents.
20. The pharmaceutical composition of claim 17 that further comprises flunixin.
21. The pharmaceutical composition of claim 20 that further comprises a corresponding fenicol, wherein the corresponding fenicol is a fenicol that is identical to the fenicol released in vivo by the fenicol carbonate.
22. The pharmaceutical composition of claim 19 that further comprises flunixin.
23. The pharmaceutical composition of claim 18 that further comprises flunixin.
24. The pharmaceutical composition of claim 23 that further comprises a corresponding fenicol, wherein the corresponding fenicol is a fenicol that is identical to the fenicol released in vivo by the fenicol carbonate.
25. A pharmaceutical composition comprising an effective amount of the fenicol carbonate of claim 1 together with pharmaceutically acceptable excipients or solvents and comprising a corresponding fenicol, wherein the corresponding fenicol is a fenicol that is identical to the fenicol released in vivo by the fenicol carbonate.
26. A pharmaceutical composition comprising an effective amount of the fenicol carbonate of claim 13 together with pharmaceutically acceptable excipients or solvents and comprising a corresponding fenicol, wherein the corresponding fenicol is a fenicol that is identical to the fenicol released in vivo by the fenicol carbonate.
27. The pharmaceutical composition of claim 17 further comprising at least one additional therapeutic agent.
28. The pharmaceutical composition of claim 18 further comprising at least one additional therapeutic agent.
29. The pharmaceutical composition of claim 17 further comprising a florfenicol.
30. The pharmaceutical composition of claim 18 further comprising a florfenicol.
31. The pharmaceutical composition of claim 27 wherein the additional therapeutic agent is an endectocidal compound.
32. The pharmaceutical composition of claim 28 wherein the additional therapeutic agent is an endectocidal compound.
33. The pharmaceutical composition of claim 31 wherein the endectocidal compound is an avermectin selected from the group consisting of Ivermectin, Doramectin, Abamectin, Selamectin, Emamectin, Eprinomectin, Moxidectin, Milbemycin and combinations thereof.
34. A pharmaceutical composition comprising the fenicol carbonate of claim 1 in combination with a fenicol compound of Formula III
35. The pharmaceutical composition of claim 17 wherein the fenicol carbonate comprises from about 80 percent to about 5 percent by weight of the composition.
36. The pharmaceutical composition of claim 33, wherein the avermectin compound is present in an amount ranging from about 0.03% w/v to about 20% w/v.
37. The pharmaceutical composition of claim 33 that further comprises a flukicide.
38. The pharmaceutical composition of claim 17 wherein the solvent comprises at least one pharmaceutically acceptable alcohol.
39. The pharmaceutical composition of claim 38 wherein the alcohol is benzyl alcohol.
40. The pharmaceutical composition of claim 38 wherein the alcohol content of the composition ranges from about 5% to about 98%, by weight, of the composition.
41. The pharmaceutical composition of claim 38 wherein the alcohol content of the composition ranges from about 20 to about 45% by weight.
42. A method of treating or preventing a disease or disorder in an animal in need thereof, comprising administering a pharmaceutically effective amount of the fenicol carbonate of claim 1.
43. A method of treating or preventing a disease or disorder in an animal in need thereof, comprising administering a pharmaceutically effective amount of the fenicol carbonate of claim 13.
44. The method of claim 42 wherein the amount of the fenicol carbonate administered ranges from about 1 to about 150 mg/kg of animal.
45. The method of claim 42 wherein the animal is a mammal, avian, fish, reptile or invertebrate.
46. The method of claim 42 wherein at least one additional therapeutic agent is administered to the animal in need thereof before, after, or simultaneously with the fenicol carbonate.
47. The method of claim 42 wherein the additional agent is an endoctocidic compound.
48. The method of claim 47 wherein the endectocidic compound is an avermectin selected from the group consisting of Ivermectin, Doramectin, Abamectin, Selamectin, Emamectin, Eprinomectin, Moxidectin and Milbemycin.
49. A method of treating or preventing a disease or disorder in an animal in need thereof, comprising administering a pharmaceutically effective amount of a compound selected from the group consisting of compounds of Examples 1-30, and combinations thereof.
50. A process for synthesizing the compound of claim 1, comprising reacting a fenicol compound with a corresponding chloroformate in a suitable solvent.
51. The process of claim 50, wherein the solvent is selected from the group consisting of chlorinated solvents, ester solvents, polyether solvents, formaldehyde acetal ethers, cyclic ethers, ketones, mixed ether-ester solvents, and diethylene glycol ether.
52. The process of claim 50, wherein the solvent comprises tetrahydrofuran.
53. The process of claim 50, wherein the reaction is conducted in the presence of a catalyst.
54. The process of claims 53, wherein the catalyst is selected from the group consisting of 4-dimethylamino-pyridine, 4-methyl pyridine, pyridine and combinations thereof.
55. The process of claim 50, wherein the reaction is conducted in the presence of an acid scavenger.
56. The process of claim 55, wherein the acid scavenger is selected from the group consisting of triethylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate and combinations thereof.
57. The process of claim 50, wherein the chloroformate is
58. The process of claim 50, wherein the fenicol compound has the structure of:
59. The process of claim 50, wherein the chloroformate is present in a molar excess, relative to the fenicol compound, during the reaction.
60. A process for synthesizing the compound of claim 13, comprising reacting a fenicol compound with a corresponding bis-chloroformate in a suitable solvent, wherein the fenicol compound is present in a molar excess, relative to the chloroformate.
61. The process of claim 60 wherein the fenicol is

Provisional Applications (2)

	Number	Date	Country
	60754967	Dec 2005	US
	60781487	Mar 2006	US

CARBONATES OF FENICOL ANTIBIOTICS

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Abstract

Description

Claims

Provisional Applications (2)