A METHOD FOR THE TREATMENT OR PREVENTION OF BACTERIAL RESPIRATORY OR ENTERIC INFECTION IN A LIVESTOCK ANIMAL

摘要

1. 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 8a-azalide; wherein said respiratory infection is caused by a Pasteurella spp., an Actinobacillus spp., Haemophilus somnus, Mycoplasma spp., Treponema hyodysenteriae or a Salmonella spp. 2. The method of claim 1 wherein the 8a-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; wherein R<1> is hydrogen; hydroxy; C1-4 alkoxy; formyl; C1-10 alkylcarbonyl, C1-10 alkoxycarbonyl, aryloxycarbonyl, C1-10 aralkoxycarbonyl, C1-10 alkylsulfonyl, or arylsulfonyl wherein said C1-10 alkyl group is substituted by 1-3 halo (F, Cl, Br), hydroxy, amino, C1-5 acylamino or C1-4 alkyl groups; or unsubstituted or substituted C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl wherein said alkyl chain, if more than 2 carbons in length, can have inserted therein 1 to 2 of oxa, thia or aza of the formula -NR- wherein R is hydrogen or C1-3 alkyl, and wherein said substituents are independently 1-3 of (a) aryl or heteroaryl optionally substituted by 1-3 halogens, C1-4 alkyl, C1-3 alkoxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino or hydroxy, (b) heterocyclyl unsubstituted or substituted by hydroxy, amino, C1-4 alkylamino, di(C1-4 alkyl) amino, C1-4 alkylcarbonyloxy or C1-4 alkylcarbonylamino, (c) halo (F,Cl,Br or I), (d) hydroxy non-acylated or acylated by a group RC(=O) or RS(O)2 wherein R is hydrogen, C1-6 alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl and R is C1-6 alkyl or aryl, (e) C1-10 alkoxy, (f) aryloxy or heteroaryloxy unsubstituted or substituted by 1-3 halo, hydroxy, amino or C1-4 alkyl groups, (g) amino or C1-10 alkylamino non-acylated or acylated by a group RC(=O), ROC(=O), or RS(=O)2, wherein R and R are as defined above; (h) di(C1-10 alkyl)amino, (i) arylamino, heteroarylamino, aralkylamino or heteroarylalkylamino wherein said aryl or heteroaryl group is unsubstituted or substituted by 1-3 halo, hydroxy, amino or C1-C4 alkyl groups, (j) mercapto; (k) C1-10 alkylthio, alkylsulfinyl or alkylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl wherein said aryl groups are unsubstituted or substituted by 1-3 halo, hydroxy, amino or C1-4 alkyl groups, (l) formyl, (m) C1-10 alkylcarbonyl, (n) arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl or heteroarylalkylcarbonyl wherein said aryl or heteroaryl group is unsubstituted or substituted by 1-3 halo, hydroxy, amino or C1-4 alkyl groups, (o) carboxy, (p) C1-10 alkoxycarbonyl, (q) aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl or heteroarylalkoxycarbonyl wherein said aryl or heteroaryl group is unsubstituted or substituted by 1-3 halo, hydroxy, amino or C1-4 alkyl groups, (r) carbamoyl or sulfamoyl wherein the N-atom is unsubstituted or substituted by 1-2 C1-6 alkyl groups or by a C4-6 alkylene chain, (s) cyano, (t) isonitrilo, (u) nitro, (v) azido, (w) iminomethyl unsubstituted or substituted on nitrogen or carbon with C1-10 alkyl, (x) oxo or (y) thiono; R<2> and R<3> are independently hydrogen, C1-10 alkyl, aryl; or R<2> and R<3> together are oxo or thiono; R<4> and R<5> are independently hydrogen or alkylcarbonyl; or R<4> and R<5> are together carbonyl; or R<4> and R<1> together are C1-C3 alkylene unsubstituted or substituted by an oxo group; R<6> and R<7> are both hydrogen, or one of R<6> and R<7> is hydrogen and the other is hydroxy, acyloxy derivative taken from the group consisting of formyloxy, C1-10 alkylcarbonyloxy, arylcarbonyloxy and aralkylcarbonyloxy, or -NHR<12> wherein R<12> is hydrogen, arylsulfonyl or heteroarylsulfonyl unsubstituted or substituted by 1-3 halo or C1-3 alkyl groups, alkylsulfonyl or - C(=O)-X-A-R<13> where X is a connecting bond, O or NH, A is a connecting bond or C1-C3 alkylene, R<13> is hydrogen, C1-C10 alkyl, aryl, aralkyl, heteroaryl, heterocyclyl, or C3-C7 cycloalkyl, any of which R<13> groups other than hydrogen can be substituted by one or more substituents selected from halogen, hydroxyl, C1-C3 alkoxy, cyano, isonitrilo, nitro, amino, mono- or di- (C1-C3) alkylamino, mercapto, C1-C3 alkylthio, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, arylthio, arylsulfinyl, sulfamoyl, arylsulfonyl, carboxy, carbamoyl, C1-C3 alkylcarbonyl, or C1-C3 alkoxycarbonyl; or R<6> and R<7> are together oxo, hydroxyimino, alkoxyimino, aralkoxyimino or aminoimino; R<8> is methyl, aralkoxycarbonyl, or arylsulfonyl; R<9> is hydrogen, formyl, C1-10 alkylcarbonyl, C1-10 alkoxycarbonyl, or arylalkoxycarbonyl; R<10> is hydrogen; or R<10> and R<1> together are C1-C3 alkylene unsubstituted or substituted by an oxo group; m and n are independently zero or one. 3. The method of claim 2 wherein the 8a-azalide has the formula I wherein n and m are zero; R<1> is hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or arylsulfonyl, wherein said alkyl and alkenyl are optionally substituted with halo, hydroxy, cyano, C1-10 alkoxycarbonyl, amino, C1-10 alkylamino, di(C1-10 alkylamino), aryl or aralkoxycarbonyl; R<2>, R<3>, R<4>, R<5>, R<9> and R<10> are each hydrogen; one of R<6> and R<7> is hydrogen and the other is selected from hydroxyl, C1-10 alkylcarbonyloxy, aralkylcarbonyloxy, amino, amino substituted by C1-10 alkylcarbonyl, arylcarbonyl, aryl C1-10 alkylcarbonyl, C1-10 alkoxycarbonyl, aryl C1-10 alkoxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or arylsulfonyl; R<8> is methyl. 4. The method of claim 2 wherein the 8a-azalide has the formula I wherein n and m are zero; R<1> is methyl, ethyl, propyl, allyl, propargyl, 2-cyanoethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxycarbonylethyl, 2-benzyloxycarbonylethyl, cyanomethyl, 2-aminoethyl, 2-(dimethylamino)ethyl, 2-fluoroethyl, 2-fluoroallyl, benzyl or oxiranylmethyl; R<2>, R<3>, R<4>, R<5>, R<9> and R<10> are hydrogen; one of R<6> or R<7> is hydrogen and the other is hydroxy or amino; R<8> is methyl. 5. The method of claim 4 wherein R<1> is methyl, ethyl, propyl, allyl, 2-methoxycarbonylethyl or 2-(dimethylamino)ethyl. 6. The method of any of claims 1-5 wherein said bacterial infection is bovine or swine respiratory infection. 7. The method of claim 6 wherein said respiratory infection is caused by a Pasteurella spp., an Actinobacillus spp., Haemophilus somnus or Mycoplasma spp. 8. The method of claims 1 or 2 wherein said bacterial infection is enteric bovine or swine respiratory infection. 9. The method of claim 8 wherein said enteric infection is caused by Treponema hyodysenteriae or Salmonella spp.