Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-11-06
2001-12-11
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S226000, C540S205000, C540S301000
Reexamination Certificate
active
06329363
ABSTRACT:
BRIEF SUMMARY OF THE INVENTION
This invention relates to new fluorinated cephalosporin antibiotics and to formulations comprising, and methods of using, these antibiotics to control susceptible pathogens. The invention particularly relates to veterinary formulations and to methods for preventing or treating mastitis in a mammal with a fluorinated cephalosporin of this invention.
Mastitis is a serious problem, especially in the dairy industry. It is an inflammation of the udder caused by a number of different pathogens, including Staphylococcus species and Streptococcus species. There are, however, difficulties in treating mastitis effectively while still meeting the needs of the dairy industry. The agent used must be effective against the pathogen or pathogens causing the mastitis, must not adversely affect the animal being treated, and must be quickly cleared from the animal's system so that the milk it produces may be safe for subsequent use.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a new group of fluorinated cephalosporin compounds of formula I:
wherein
R
a
, R
b
, R
c
, R
d
and R
f
, independently, are H, F or a C
1
-C
6
alkyl-(Z)
n
- group having at least one fluorine substituent;
X is O or S;
Y is S, O, or —CH
2
—;
Z is O, S, —SO—, or —SO
2
—;
m and n independently are 0 or 1;
and
R
1
is H, C
1
-C
6
-alkyl, phenyl or benzyl, each of which may optionally have up to three substitute selected from halo, C
1
-C
4
-alkoxy, phenyl, NO
2
, C
1
-C
6
-alkanoyl, benzoyl, or C
1
-C
6
-alkanoyloxy;
or a physiologically acceptable salt thereof; provided that:
1) at least one of R
a
, R
b
, R
c
, R
d
or R
f
is other than hydrogen; and
2) when X and Y are S and R
b
or R
c
is F, one of the remaining R
a
, R
b
, R
c
R
d
or R
f
is other than hydrogen.
The term “C
1
-C
n
-alkyl” refers to a straight or branched chain alkyl group having the designated number of carbon atoms. Examples include methyl, ethyl, isopropyl, n-pentyl, and the like.
The term “halo” refers to chloro, iodo, bromo or fluoro.
The formula I esters, i.e. those compounds wherein R
1
is other than hydrogen or a salt form, act as pro-drugs. Thus, these compounds are converted in vivo to the corresponding free acid that has the desired activity. Certain Formula I esters are preferred. These esters include the pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl, 1-(acetyloxy)ethyl and phenacyl.
Physiologically acceptable salts of the formula I compounds are also part of this invention. These salts include alkali-metal salts, e.g., sodium, potassium, etc., alkaline-earth metal salts, e.g., calcium, magnesium, etc., and salts with organic bases, such as organic amines, e.g., benzathine, pyridine, triethylamine, tripropylamine and triisopropylamine, etc. The triethylamine and sodium salts are particularly preferred salts.
The formula I compounds are active both in vitro and in vivo against various pathogenic organisms. In one aspect, they are active against certain pathogens that cause mastitis in mammals, particularly in ruminants. A special benefit of the formula I compounds is that they are active at levels such that they may provide improved control of mastitis over products currently used in the dairy industry.
This invention provides, therefore, a method of preventing or treating mastitis in a mammal that comprises administering to the mammal an amount of a formula I compound that effectively prevents or treats the mastitis. This method is particularly useful for preventing or treating mastitis in a ruminant.
The formula I compounds are especially useful for preventing or treating mastitis in cattle, goats and sheep. In one embodiment of this invention, the formula I compound is administered as the animal is lactating (“wet cow” therapy). In this embodiment the milk will be discarded until the mastitis has been successfully treated and the drug has cleared the animal, i.e., the drug is no longer present in the milk. The compounds of this invention may also be used for “dry cow” therapy, that is when administration occurs after lactation, and the animal will thereafter be managed as a dry cow with no further milking until the next parturition. In still another aspect, the formula I compound can be used prophylactically by administering it to a non-lactating animal, such as a nulliparous heifer, in the period prior to parturition.
The formula I compounds can be administered by a variety of methods, such as intramuscularly, subcutaneously, intravenously, intranasally, orally or by intramammary infusion. When used for preventing or treating mastitis, they are preferably administered by intramammary infusion.
It is understood in the art that the amount of formula I compound administered should be the amount that is effective to control the particular pathogen or pathogens in question. In addition, the type, size and condition of the host being treated must be taken into consideration. For example, when controlling a pathogen responsible for mastitis, the dose will vary depending on the type and size of the ruminant being treated.
As an illustration, when treating mastitis in cows, amounts of from about 10 to about 1000 milligrams per quarter are generally effective to control the mastitis. Doses of about 50 to 300 mg per quarter are preferable; and doses of about 100 to 200 mg per quarter are most effective. In goats, on the other hand, amounts of from about 10 to about 100 milligrams per half are generally sufficient; doses of about 10 to 30 mg per half are preferred; and a dose of 20 mg per half is most preferred. An effective amount may also be achieved by multiple dosings.
This invention also provides a veterinary formulation comprising a formula I compound and one or more physiologically acceptable carriers. The veterinary formulations of this invention are particularly useful for preventing or treating mastitis in a mammal, especially a ruminant. Preferred ruminants are cattle and goats.
A pharmaceutical formulation comprising a formula I compound and a pharmaceutically acceptable carrier is another aspect of the invention. These pharmaceutical formulations are useful for treating a bacterial infection in a mammal, especially a human.
The formula I compounds can be formulated for veterinary or pharmaceutical administration according to methods understood in the art. When the compound is to be used in a veterinary formulation for preventing or treating mastitis, the formulation is preferably one that can be administered by intramammary infusion. For this type of infusion, the compound may be formulated in an oily base, e.g., a vegetable oil such as peanut oil or a non-vegetable oil such as mineral oil. The formulation may include a thickening agent and optionally also a surfactant.
When a formula I compound is to be administered to a mammal for the treatment of other types of infections, it may be preferable to administer it in a pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients. The preparation of such formulations is also understood in the art. See, for example,
Remington the Science and Practice of Pharmacy,
(Mack Publishing Co., Easton, Pa., 1995).
In preparing a pharmaceutical formulation or a veterinary formulation other than for intramammary infusion, the formula I compound is usually mixed with an excipient, diluted by an excipient or enclosed within a carrier that can be in the form of a capsule, sachet, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
During the preparation of the formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combi
Berch Mark L.
Demeter John C.
Eli Lilly and Company
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