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A Phosphate Ester Of Florfenicol Having Superior Water Solubility

Abstract: 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.

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Patent Information

Application #
Filing Date
22 June 2006
Publication Number
23/2007
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2009-05-25
Renewal Date

Applicants

SCHERING-PLOUGH LTD.
Weystrasse 20, P.O. Box, CH-6000 Lucerne 6

Inventors

1. HECKER, Scott, J.
4802 Rancho Viejo Drive, Del Mar, California 92014
2. PANSARE, Sunil, V.
48 Greenspond Drive, St. Johns, Newfoundland & Labrador A1E 5Z8

Specification

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a non-provisional application that claims priority under 35 U.S.C. § 119(e) of provisional application U.S. Serial No. 60/532,227 filed December 23, 2003, the contents of which are hereby incorporated by reference in their entireties. FIELD OF THE INVENTION The present invention is directed to phosphate esters of florfenicol, including a florfenicol prodrug having superior water solubility, and phosphate esters of florfenicol analogs. BACKGROUND OF THE INVENTION Florfenicol is a structural analog of thiamphenlcol, which in turn is a derivative of chloramphenicol [see, e.g., U.S. 4,235,892, U.S. 5,352,832, the contents of which are hereby incorporated by reference in their entireties]. Florfenicol is a broad spectrum antibiotic with activity against many gram-negative and gram-positive bacteria, including utility in the prevention and treatment of bacterial infections due to susceptible pathogens in birds, reptiles, fish, shellfish and mammals. One of florfenicol's primary uses is in the treatment of pneumonia and associated respiratory infections in cattle (often referred to generically as Bovine Respiratory Disease or BRD) caused by Mannhemia haemolyiica, Pasturella muliocida and/or Haemophilus somnus, also known as Histophilus somni. It is also . indicated in the treatment of: pododermatitis in cattle caused by Fusobacterium necrophorum and Bacterioides melaninogenicus; swine respiratory disease caused by Pasteurella multocida, Actinobacillus pleuropneumoniae. Streptococcus suis, Salmonella cholerasuis and/or Mycoplasma spp.; colibacillosis In chickens caused by Escherichia coli; enteric septicemia in catfish caused by Edwardsiella ictaluri; and furunculosis In salmon caused by Aeromonas salmonicida. Other genera of bacteria that have exhibited susceptibility to florfenicoj include Enterobacter, Klebsiella, Staphylococcus, Enterococcus, Bordetella, Proteus and Shigella. In particular, chloramphenicol-resistant strains of organisms, such as K. pneumorjiae, E. cloacae, S. typhus and E. coli, are susceptible to florfenicol. Florfenicol Is most often administered to subjects which can benefit from Its advantages either orally or parenterally, the latter being primarily intramuscular or intravenous. Due to its very low water solubility (approximately one mg/mL), organic solvents must be added to achieve the desired product concentration In a commercial formulation. For example, In NUFLOR® (veterinary-labeled florfenicol formulation in the United States and Canada), the organic solvents N-methylpyrrolldinone, propylene glycol and/or polyethylene glycol are used to afford florfenicol solubility of 300 mg/mL. Unfortunately, when administered parenterally, these solvents often cause significant localized irritation. Therefore, there is a need for a more water-soluble form of florfenicol. SUMMARY OF THE INVENTION The present invention therefore, provides a water-soluble form of florfenicol that has substantially greater aqueous solubility than florfenicol itself. Preferably a water-soluble form of florfenicol of the present invention Is also a prodrug that rapidly and efficiently converts to florfenicol in vivo. One aspect of the present invention therefore provides a florfenicol phosphate ester {e.g., a florfenicol prodrug) having the chemical structure: The present invention further provides salts of this florfenicol phosphate ester. Such salts may be useful in t!ie stable storage of the florfenicol phosphate esters. Preferably, the florfenicol phosphate ester salts comprise pharmaceutically-acceptable counterions. In a particular embodiment, the acids and pharmaceutically-acceptable florfenicol phosphate ester salts of the present invention may be depicted as: wherein Mi"^ and M2'^ are independently selected to be either H"^ or a pharmaceutically-acceptable mono-cation, or alternatively, M/ and Ma"*" can be taken together as a pharmaceutically-acceptable di-cation. In one embodiment of the present invention, Mi* and Ma"^ are independently selected to be H^ Na"*", NH4"^, or K"*^. In a particular embodiment of this type, Mi"^ and M2* are respectively, H* and Na*. In another particular embodiment of this type. Mi* and M2* are both Na*. In yet another embodiment, Mi* and M2* taken together are Ca*^. In still another embodiment, Mi* and M2* taken together are Mg*^. In yet another embodiment of the present invention. Mi* and M2* are independently selected to be either H* or a protonated amine. 1n another embodiment of the present invention, Mi* and M2'*' are respectively, H*and a protonated amine comprising the chemical formula NR^R^R^H*. In still another embodiment. Mi* and M2* are both a protonated amine comprising the chemical formula NR''R^R®H*. With regard to the protonated amine comprising the chemical formula NR^R^R^H*: R\ R^, and R^ are independently selected to be either H, methyl, ethyl, propyl, isopropyl, -CH2CH2OH and -CH2C(CH20H)3. Alternatively, R^ is as provided above, but R^ and R^are linked to form a five or six membered ring, in a specific ennbodiment of this type, the ring is pirolidine, piperidine or morphoiine. Examples of amine cations of the present invention include, but are not limited to: « In still another embodiment M/ and 1^2"^ taken together form a bis-protonated diamine. Examples of bis-protonated diamines of the present invention include: In yet another embodiment Mi"^ and Mz* comprise respectively, H"^ and a mono-cationic form of a dibasic aminoacid. In a particular embodiment of this type, the mono-cationic form of the dibasic aminoacid comprises one of the following two chemical formulas: In still another embodiment Mi"*^ and M2'^ taken together comprise a di-cationic form of a dibasic aminoacid. In a particular embodiment of this type, the di-cationic form of the dibasic aminoacid comprises one of the two following chemical formulas: In yet another embodiment of the present invention, Mi"*" and M2* are independently selected to be either H^ meglumine, benzocaine, or procaine. In a particular embodiment of this type, either Mi"*^ and Mz^ are H"^, while the other is either meglumine, benzocaine or procaine. In still another embodiment, the present invention provides a formulation that comprises Formula I as a mixture of two or more salts. In a particular embodiment of this type, for one salt, Mi'^or M2'^ is H"^, whereas the other is a specific counterion, wherein for the second salt, both Mi* and Mz^ are that specific counterion. In a related embodiment, Mi"^ and M2* of the first salt are identical counterions, but not H"*", whereas Mi"*" and M2'^of the second salt are also identical counterions, but are neither H"*^, nor the specific counterion of the first salt. In yet another embodiment, the formulation comprises Formula I as a mixture of two or more salts, and all of the counterions of the different salts are selected independently. In a preferred embodiment, the counterions in these formulations are disclosed herein. The present invention further provides phosphate esters of flqrfenicoljnalogs (including phosphate esters of chloramphenicol and thiamphenicol) that also can be useful as antibiotics and/or prodrugs of antibiotics. The present invention further ' provides salts of these phosphate esters of the fiorfenicol analogs, preferably salts comprising the counterions provided herein. One appropriate family of fiorfenicol analogs has recently been synthesized and chara£terizedJU.S. 20040082553, WO03/077828, the contents of which are hereby incorporated by reference in their entireties]. The phosphate esters of these fiorfenicol analogs and salts thereof, can! be prepared and then employed as antibiotics and/or prodrugs of antibiotics througn the teachings provided herein, in view of the teachings'of IJ."S: 20640082553 and / WO03/077828. ' In a particular embodiment, a phosphate esterjaf a fterfenrcol analog of the present invention comprises-tbe-Gbemical structure of: wherein R^ and R^ are independently selected from the group consisting of hydrogen, (1C - 4C)alkyl, halo, -CF3, -NH2, -CN and N3; wherein R** is selected from the group consisting of: wherein A^ 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)cycloaIkyl, (1C - 4C)alkylO-, -CF3, -OH, -CN, halo, (1C - 4C)aIkylS0-, (1C - 4C)alkylS02-, NH2SO2-, (1C - 4C)alkylNHS02-, ((1C -4C)alkyI)2NS02-, -NH2, (1C - 4C)alkylNH-, ((1C - 4C)alkyl)2N-, (1C - 4C)alkylS02NH-, (IC - 4C)alkylC(0)-, (3C - 6C)cycloalkylC{0)-, (1C - 4C)alkylOC(0)., (1C -4C)alkylC(0)NH-, -C(0)NH2, (IC - 4C)alkylNHC(0)- and ((IC - 4C)alkyl)2NC(0)-, wherein any of the alkyl groups within the substltuents may be unsubstituted or substituted with a group selected from halo and hydroxy; wherein A^, A^, A"*, and A^ are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur, provided that at least one of A^ - A^ 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"" 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)a!kyl, (1C -4C)all

Documents

Application Documents

# Name Date
1 2264-CHENP-2006 CORRESPONDENCE OTHERS 03-12-2012.pdf 2012-12-03
1 abs 2264-chenp-2006 abstract.jpg 2011-09-04
2 2264-CHENP-2006 FORM-13 03-12-2012.pdf 2012-12-03
2 2264-chenp-2006.tif 2011-09-04
3 2264-chenp-2006-pct.pdf 2011-09-04
3 2264-CHENP-2006 POWER OF ATTORNEY 03-12-2012.pdf 2012-12-03
4 2264-chenp-2006-form 5.pdf 2011-09-04
4 2264-CHENP-2006 CORRESPONDENCE OTHERS.pdf 2011-12-01
5 2264-chenp-2006-form 3.pdf 2011-09-04
5 2264-CHENP-2006 CORRESPONDENCE PO.pdf 2011-12-01
6 2264-chenp-2006-form 18.pdf 2011-09-04
6 2264-CHENP-2006 FORM 3.pdf 2011-12-01
7 2264-chenp-2006-form 1.pdf 2011-09-04
7 2264-CHENP-2006 FORM 5.pdf 2011-12-01
8 2264-chenp-2006-drawings.pdf 2011-09-04
8 2264-CHENP-2006 PETITIONS.pdf 2011-12-01
9 2264-CHENP-2006 POWER OF ATTORNEY.pdf 2011-12-01
9 2264-chenp-2006-description(complete).pdf 2011-09-04
10 2264-chenp-2006 complete specification as granted.pdf 2011-09-04
10 2264-chenp-2006-correspondnece-others.pdf 2011-09-04
11 2264-chenp-2006 drawings.pdf 2011-09-04
11 2264-chenp-2006-claims.pdf 2011-09-04
12 2264-chenp-2006-abstract.jpg 2011-09-04
12 2264-chenp-2006-assignement.pdf 2011-09-04
13 2264-chenp-2006-abstract.pdf 2011-09-04
14 2264-chenp-2006-abstract.jpg 2011-09-04
14 2264-chenp-2006-assignement.pdf 2011-09-04
15 2264-chenp-2006 drawings.pdf 2011-09-04
15 2264-chenp-2006-claims.pdf 2011-09-04
16 2264-chenp-2006 complete specification as granted.pdf 2011-09-04
16 2264-chenp-2006-correspondnece-others.pdf 2011-09-04
17 2264-chenp-2006-description(complete).pdf 2011-09-04
17 2264-CHENP-2006 POWER OF ATTORNEY.pdf 2011-12-01
18 2264-CHENP-2006 PETITIONS.pdf 2011-12-01
18 2264-chenp-2006-drawings.pdf 2011-09-04
19 2264-chenp-2006-form 1.pdf 2011-09-04
19 2264-CHENP-2006 FORM 5.pdf 2011-12-01
20 2264-chenp-2006-form 18.pdf 2011-09-04
20 2264-CHENP-2006 FORM 3.pdf 2011-12-01
21 2264-chenp-2006-form 3.pdf 2011-09-04
21 2264-CHENP-2006 CORRESPONDENCE PO.pdf 2011-12-01
22 2264-chenp-2006-form 5.pdf 2011-09-04
22 2264-CHENP-2006 CORRESPONDENCE OTHERS.pdf 2011-12-01
23 2264-chenp-2006-pct.pdf 2011-09-04
23 2264-CHENP-2006 POWER OF ATTORNEY 03-12-2012.pdf 2012-12-03
24 2264-CHENP-2006 FORM-13 03-12-2012.pdf 2012-12-03
25 abs 2264-chenp-2006 abstract.jpg 2011-09-04
25 2264-CHENP-2006 CORRESPONDENCE OTHERS 03-12-2012.pdf 2012-12-03

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