Carbonates of fenicol antibiotics
View Patent ↗Novel fenicol compounds having useful properties as antibiotic prodrugs, are provided, together with methods of making and using these new compounds.
1. A fenicol carbonate of Formula I, or a solvate thereof,
wherein R 1 is selected from the group consisting of
R 2 is selected from a group consisting of dichloromethyl, difluoromethyl, chlorfluoromethyl, chloromethyl and methyl,
R 3 is selected from a group consisting of hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl and CH 2 O—C(O)O—R 5 ,
R 4 and R 5 are independently selected from the group consisting of substituted or unsubstituted C 1-10 straight, branched or cyclo alkyl, substituted or unsubstituted C 1-10 alkoxyalkyl, C 1-10 aryl, C 1-10 arylalkyl, substituted or unsubstituted C 1-10 straight, branched or cycloalkenyl.
2. The fenicol carbonate of claim 1 wherein R 4 and R 5 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-methyl-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-methyl-phenyl, 4-methoxy-phenyl, 4-carboxy-phenyl, 2-carboxy-phenyl, 4-methoxycarbonyl-phenyl, 2-methoxycarbonyl-phenyl and 4-acetylamino-phenyl.
3. The fenicol carbonate of claim 2 wherein R 4 and R 5 are independently substituted with a moiety selected from the group consisting of methyl, methoxy, carboxy, carboalkoxy and acyloxy.
4. The fenicol carbonate of claim 2 , wherein R 1 is selected from the group consisting of
R 2 is dichloromethyl or difluoromethyl, and R 3 is selected from the group consisting of hydroxymethyl, fluoromethyl and CH 2 O—C(O)O—R 5 .
5. The fenicol carbonate of claim 1 wherein R 1 is CH 3 SO 2 , R 2 is CHCl 2 and R 3 is CH 2 F.
6. The florfenicol carbonate of claim 5 , wherein R 4 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-methyl-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-methyl-phenyl, 4-methoxy-phenyl, 4-carboxy-phenyl, 2-carboxy-phenyl, 4-methoxycarbonyl-phenyl, 2-methoxycarbonyl-phenyl and 4-acetylamino-phenyl.
7. The fenicol carbonate of claim 1 , wherein R 3 is CH 2 F.
8. The fenicol carbonate of claim 1 , wherein R 1 is CH 3 SO 2 R 2 is CHCl 2 , R 3 is OH and R 4 is ethyl.
9. The fenicol carbonate of claim 1 , wherein R 1 is CH 3 SO 2 , R 2 is CHCl 2 , R 3 is
and R 4 is ethyl.
10. The fenicol carbonate of claim 1 that is selected from the group consisting of
11. The fenicol carbonate of claim 1 that is selected from the group consisting of the following compounds
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl) propyl methyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl ethyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl propyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl isopropyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl isobutyl carbonate;
cyclopropylmethyl (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 3-methylbut-2-enyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl isopentyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl pentan-3-yl carbonate;
cyclohexyl (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-methoxyethyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-ethoxyethyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-butoxyethyl carbonate;
benzyl (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 4-methylbenzyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 4-methoxybenzyl carbonate;
(S)-ethyl 2-(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propoxy)carbonyloxy)propanoate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl dodecyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl octadecyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-(3R,S)-3,7-dimethyloct-6-enyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(2-methoxyethoxy)ethyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl octyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl 2-(2-(2-methoxyethoxy)ethoxy)ethyl carbonate;
(1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-fluoromethylsulfonyl)phenyl)propyl ethyl carbonate; and
bis((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl) ethane-1,2-diyl dicarbonate.
12. A fenicol carbonate compound of Formula II,
wherein R 1 is selected from the group consisting of
wherein a, c and e are integers that independently range in value from 0 through 4, b and d are integers that independently range in value from 0 through 2, provided that the sum of integers a, b, c, d and e range in value from 2 to 8,
R 51 and R 52 are independently selected from the group consisting of H, methyl, hydroxyl, methoxy, and acetoxy.
13. The compound of claim 12 wherein the sum of a, b, c, d and e ranges in value from 2 through 4.
14. The compound of claim 12 where R 1 is
15. The compound of claim 12 , having a structure selected from the group consisting of:
16. The compound of claim 1 , having the following structure
17. The compound of claim 15 , having the following structure