Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-08-29
2003-02-04
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007100
Reexamination Certificate
active
06514946
ABSTRACT:
TECHNICAL FIELD
This invention relates to 16-membered ring macrolide antibiotics and the treatment or prophylaxis of pasteurellosis of mammalian livestock or poultry using the same as an active ingredient.
BACKGROUND ART
Some 16-membered ring macrolide antibiotics including tylosin are antibiotic:s which have been used from long ago in treating infectious diseases of humans and livestock. Thereafter, comprehensive derivatives have been proposed aiming to enhance their antibacterial activity and heighten the selectivity of the antibacterial activity. However, the greater part of the various derivatives which have thus been proposed are left alone without attaining their purpose.
Taking infectious diseases with Pasteurella as an example among these infectious diseases, various derivatives showing antibacterial activity against Pasteurella are known, but the derivative being put to practical use is only tilmicosin (or Micotil®), as stated thereinafter.
On the other hand, among the derivatives of tylosin or mycaminosyltylonolide represented by the following formula (A)
(hereinafter, sometimes abbreviated as MT), compounds showing antibacterial activity against
Pasteurella haemolytica
as a main causal bacterium of pasteurellosis are also known, although they are not put to practical use [see Japanese. Laid-open Patent Publication No. 59-167598 (claim of priority: Feb. 28, 1983, U.S. Ser. No. 06/470,833, now abandoned, Japanese Laid-open Patent Publication No. 59-44398 (claim of priority: Aug. 2, 1982, U.S Ser. No. 404024, now U.S. Pat. No. 4,454,314,)]. There is a disclosure in the former publication “Some of the derivatives have activity against certain Gram-negative bacteria of the genus Pasteurella”, and it is disclosed that compounds of the formula (A) wherein the aldehyde group at the 20-position and the hydroxyl group at the 23-position are replaced with (i) methyl and octahydroazocin-1-yl and (ii) methylol and octahydroazocin-1-yl, respectively, show an MIC of 0.78 &mgr;g/ml against a certain strain of Pasteurella haemolytica. Further, the former publication discloses compounds of the formula (A) wherein the aldehyde group at the 20-position and the hydroxyl group at the 23-position are replaced with pyrrolidin-1-yl and hydroxyl; piperidin-1-yl and hydroxyl; and octahydroazocin-1-yl and octahydroazocin-1-yl, respectively, but there is no specific disclosure on whether these compounds have antibacterial activity against Pasteurella.
Further, as publications describing interesting derivatives proposed by part of the present inventors, although there is no disclosure about antibacterial activity against Pasteurella, Japanese Laid-open Patent Publication Nos. 59-181299, 59-51299 and 59-225199 are mentioned. These publications disclose, for example, compounds of the formula (A) wherein the aldehyde group at the 20-position and the hydroxyl group at the 23-position are replaced with a di-lower alkyl-substituted amino group and inclusively a 5- to 13-membered alkylene-imino group, respectively. Antibacterial activities against Micrococcus, Staphylococcus, Streptococcus, Klebsiella, Shigella and Salmonella of part of these compounds are shown, and it is also described that these compounds have excellent antibacterial activity against Gram-positive and Gram-negative bacteria and are useful as an antibacterial agent.
Bovine respiratory disease as a typical disease among pasteurellosis is a disease from which cattle of all ages may suffer and young animals may generally suffer more easily. Above all, pneumonic pasteurellosis or shippin fever is a disease from which young, stressed cattle suffer in a higher probability. As stated above, tilmicosin is used in the treatment of such diseases, but needs for safely usable and effective drugs still exist. Especially when it is taken into account that such a drug is administered to cattle directed to milking or meat, the provision of a drug which not only has only low general toxicity, but also has antibacterial activity as low as possible against bacteria other than bacteria to be controlled (thereby frequency in the emergence of drug-resistant bacteria will be lowered) but strong antibacterial activity against objective bacteria (namely, Pasteurella) will be desired in view of safe use.
DISCLOSURE OF INVENTION
It is known that a compound of the formula (A) wherein the aldehyde group at the 20-position and the hydroxyl group at the 23-position were replaced with alkyleneimino groups, respectively, the compound being inclusively described in the Japanese Laid-open Patent Publication No. 59-181299, generally has excellent antibacterial activity against Gram-negative bacteria. However, it has now been found that compounds represented by the following formula (I) as a result of novel combined selection of the above both groups have, on the one hand, ant bacterial activity against Pasteurella significantly higher than those of tilmicosin and other compounds having structure similar thereto, but have, on the other hand, significantly lower antibacterial activity against other
Staphylococcus aureus, Escherichia coli, Serratia marcescens,
etc.
Therefore, according to the invention, a compound represented by the following formula (I) or a physiologically acceptable acid addition salt thereof having selectively higher antibacterial activity against Pasteurella is provided:
wherein
R
1
and R
2
are the same and represent a group of the
As other embodiments of the invention are also provided a method and a composition for the treatment or prophylaxis of pasteurellosis, especially of livestock and poultry, and further use of a compound represented by the formula (I) or a physiologically acceptable acid addition salt thereof for preparing a composition for the treatment or prophylaxis of pasteurellosis.
The compounds of the formula (I) not only have significantly higher antibacterial activity against Pasteurella than tilmicosin, but also show significant behavior also in in vivo absorption and excretion, and thus have better efficacy against pasteurellosis.
REFERENCES:
patent: 4454314 (1984-06-01), Nagel
patent: 4629786 (1986-12-01), Debono et al.
patent: 59-44398 (1984-03-01), None
patent: 59-51299 (1984-03-01), None
patent: 59-167598 (1984-09-01), None
patent: 59-181299 (1984-10-01), None
patent: 59-225199 (1984-12-01), None
Hamada Masa
Miyake Toshiaki
Takeuchi Tomio
Takita Tomohisa
Umezawa Sumio
Wadachi Asako
Wilson James O.
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
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