Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-05-11
2002-01-15
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06339063
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention provides methods for the treatment or prevention of bacterial respiratory or enteric infections in livestock animals.
BACKGROUND OF THE INVENTION
The morbidity and mortality associated with bacterial respiratory and enteric infections in livestock represent a major economic loss for the animal husbandry industry. In cattle, especially in younger animals, stress as a result of weaning, transportation, dehydration, alteration or deprivation of diet can cause the animals to become highly susceptible to bacterial respiratory infection, especially if the animals are housed in crowded or poorly ventilated quarters. The principal causative bacterial pathogens of bovine respiratory infections are
Pasteurella haemolytica, P. multocida, Haemophilus somnus
and Mycoplasma spp. In pigs respiratory infections caused by
Pasteurella multocida
or
Actinobacillus pleuropneumoniae
, and Mycoplasma spp. are associated with considerable losses in some herds. The most common causative organisms for enteric diseases in cattle and swine are
Escherichia coli, Treponema hyodysenteriae
and Salmonella spp.
The current therapeutic antimicrobial products against respiratory and enteric infections in livestock include a diverse group of older products effective against a broad spectrum of infectious agents, mostly notably among this group are the tetracyclines; and a group of recently introduced products indicated primarily for treatment of bovine respiratory disease, such as quinolones (danofloxacin, enrofloxacin), cephalosporins (cefquinome, ceftiofur), macrolide (tilmicosin), and florfenicol. Resistance to the older antimicrobial agents has developed in the field. Although resistance to the newer products is not yet a problem, it is known that excessive usage favors the emergence of resistance over time, but increasing the numbers of drug families, and thereby mechanisms of action, in use may decrease the probability of resistance development to any individual compound. Thus, there exists a continuing need to discover antimicrobial compounds that are suitable for use in veterinary medicine; preferably, such compounds will belong to a different chemotype from the antimicrobial agents currently in use in animal or human medicine. Other desirable characteristics of a novel antimicrobial product for veterinary use include high potency against target organisms, high target tissue concentration, and long tissue half-life.
9a-Azalides are antibiotics characterized by a 15-membered lactone ring containing a ring nitrogen atom. 9a-Azalides are disclosed in, for example, U.S. Pat. Nos. 4,328,334, 4,517,359, 4,474,768, 4,464,527, 4,526,889, 4,465,674, 4,492,688, 4,512,982, 4,518,590, European Patent Application No. 136,831, European Patent Application No. 259,789, European Patent Application No. 316,128, European Patent Application No. 467,331, European Patent Application 606,062, and European Patent Application 657,464.
U.S. Pat. Nos. 4,474,768, 4,464,527, and 4,526,889 disclose azithromycin, N-ethyl and N-propyl homologs of azithromycin, and 4″-epi-azithromycin, respectively, which are said to be active against
Pasteurella multocida
in vitro; however, the patents also state that regarding the compounds disclosed therein their in vivo activity is more limited as regards susceptible organisms. To Applicants' best knowledge, the known 9a-azalides have not been reported as being clinically useful in the treatment and prevention of bovine or swine respiratory or enteric infections.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method for the treatment or prevention of bacterial respiratory or enteric infection in a livestock animal which comprises administering to a livestock animal in need of such treatment or prevention a therapeutically or prophylactically effective amount of an 9a-azalide.
In a preferred embodiment the 9a-azalide has the formula I:
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complexes thereof, and said metal complex is taken from the group consisting of copper, zinc, cobalt, nickel and cadmium; where
R
1
is hydrogen;
C
1-3
alkyl optionally substituted by hydroxy, C
1-3
alkoxy, cyano, C
1-3
alkoxycarbonyl, halogen, amino, C
1-3
alkylamino, or di(C
1-3
alkyl)amino;
allyl; or
propargyl; or one of R
2
and R
3
is hydrogen and the other is
hydroxy, or
—NH
2
.
The more preferred 9a-azalides are selected from azithromycin (which is 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A), 4″-epi-azithromycin, 4″-deoxy-4″-aminoazithromycin, and 4″-epi-4″-deoxy-4″-aminoazithromycin.
In another preferred embodiment, the present invention provides a method for the treatment or prevention of bovine or swine bacterial respiratory infections wherein the causative organism is selected from a group consisting of Pasteurella spp., an Actinobacillus spp.,
Haemophilus somnus
and Mycoplasma spp., which comprises administering to a cattle or swine in need of such treatment or prevention a therapeutically or prophylactically effective amount of an 9a-azalide. More preferably, the 9a-azalide is of formula I; and particularly preferred are 9a-azalides selected from azithromycin, 4″-epi-azithromycin, 4″-deoxy-4″-aminoazithromycin, and 4″-epi-4″-deoxy-4″-aminoazithromycin.
In another preferred embodiment, the present invention provides a method for the treatment or prevention of bovine or swine bacterial enteric infections wherein the causative organism is selected from
Escherichia coli, Treponema hyodysenteriae
, and Salmonella spp., which comprises administering to a cattle or swine in need of such treatment or prevention a therapeutically or prophylactically effective amount of an 9a-azalide. More preferably the 9a-azalide is of formula I; and particularly preferred are 9a-azalides selected from azithromycin, 4″-epi-azithromycin, 4″-deoxy-4″-aminoazithromycin, and 4″-epi-4″-deoxy-4″-aminoazithromycin.
As used herein “9a-azalide” means a compound having the following core structure in which the asterisks indicate sites for substitution:
The 9a-azalides are named herein as derivatives of azithromycin, which is 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A.
The term “therapeutically or prophylactically effective amount” means that amount of an 9a-azalide that will provide a level of antibacterial activity at the target site of infection that is sufficient to inhibit the bacteria in a manner that allows the host animal to overcome or be protected from the infection.
“Treatment or prevention” means use of 9a-azalide following or prior to manifestation of signs and symptoms suggestive of bacterial infection to allow the host animal to overcome or be protected from the infection.
“Bacterial respiratory or enteric infections” means infections of the respiratory or digestive tract for which the causative organism or the likely causative organism is susceptible to 9a-azalide. Such organisms include, but are not limited to, Pasteurella species (e.g.
P. haemolytica, P. multocida
),
Haemophilus somnus, Actinobacillus pleuropneumoniae
, Mycoplasma spp.,
E. coli, Treponema hyodysenteriae
, and Salmonella spp. (e.g.
S. typhimurium, S. dublin
).
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
9a-Azalides are either known compounds, such as those disclosed in the patents and published patent applications cited hereinabove, or they may be prepared
Clark Jeffrey
Farrington Daniel
Kropp Helmut
Ratcliffe Ronald
Wilkening Robert
Lee Shu M.
Merck & Co. , Inc.
Peselev Elli
Rose David L.
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