BG64765B1 - 8a-azalides as veterinary antimicrobial forms - Google Patents

Abstract

The invention relates to 8a-azalides which are used for the treatment and prevention of respiratory and enteral infections in animals, in particularly in cattle and pigs. The compounds are applied in a therapeutical and prophylactic effective quantity ensuring a level of antibacterial activity in the organism in the animals sufficient to inhibit the bacterial pathogenous agents of respiratory infections: Pasteurella haemolytica, P. multocida,Haemophilus somnus and Mycoplasma spp. in cattle, and Pasteurella multocida, Actinobacillus pheuropneumoniae and Mycoplasma spp. in pigs.

Description

The present invention relates to the use of 8α-azalides for the manufacture of a medicament for treating or preventing bacterial respiratory and enteral infections in livestock.

BACKGROUND OF THE INVENTION

The morbidity and mortality associated with bacterial respiratory and enteral infections in livestock is a major economic loss for industrial livestock. In cattle, especially in younger animals, stress as a result of weaning, transporting, dehydrating, eating changes or food deprivation may cause the animals to become highly susceptible to bacterial respiratory infection, especially if the animals are placed in crowded or poorly ventilated areas. The main bacterial pathogens that cause respiratory infections in livestock are Pasteurella haemolytica, P. multocida, Haemophilus sommus, and Mycoplasma spp. In pigs, respiratory infections caused by Pasteurella multocida or Actinobacillus pleuropneumoniae and Mycoplasma spp. Have been associated with significant losses in some herds. The most common organisms causing enteral diseases in livestock and pigs are Escherichia coli, Treponema hyodysenteriae and Salmonella spp.

The antimicrobial products used today for respiratory and enteral infections in livestock include various groups of older products effective against a wide range of infectious agents, most of which are tetracyclines; and a group of recently introduced products primarily indicated for the treatment of respiratory diseases in bovine animals such as quinolones (danofloxacin, enrofloxacin), cephalosporins (cefkin, ceftiofur), macrolides (tilmicosin) and florfenicol. The development of resistance to older antimicrobial agents is known. Although resistance to the latest products does not yet exist as a problem, it is known that overuse favors the emergence of resistance over time, but increasing the number of drug families and therefore the mechanisms of action when used may reduce the likelihood of development of resistance to each individual compound. Thus, there is an ongoing need to detect antimicrobial compounds that are suitable for use in veterinary medicine; preferably, such compounds should belong to different chemotypes of antimicrobial agents currently used in veterinary or human medicine. Other desirable features of new antimicrobial products for veterinary use include high activity against target organisms, high concentration in target tissues, and a long half-life in tissues and plasma.

8α-azalides are antibiotics characterized by a 15-atom lactone ring containing a ring nitrogen atom. A group of 8aazalides is described in EP 0508699, which have an antibacterial spectrum similar to erythromycin and have in vitro activity against gram-positive and gram-negative bacteria, including E. coli and H. influenzae. However, EP 0508699 does not describe the use of 8α-azalides for the treatment or prevention of bacterial respiratory or enteral infections in livestock. Moreover, there is no suggestion that 8α-azalides have antibacterial activity against organisms, common causes of bacterial respiratory and enteral infections in cattle and pigs.

SUMMARY OF THE INVENTION

The present invention relates to the use of 8α-azalides for the manufacture of a medicament for treating or preventing bacterial respiratory and enteral infections in livestock.

In a preferred embodiment, the 8α-azalide has the formula

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, the metal in the complex being selected from the group consisting of copper, zinc, cobalt, nickel and cadmium; wherein R ¹ is hydrogen; hydroxy; With ₁₄ alkoxy; formyl; C ₁₀ alkylcarbonyl, C] ₁₀ alkoxycarbonyl, aryloxycarbonyl, C _1-10 aralkoxycarbonyl, C _11o alkylsulfonyl or arylsulfonyl, in which _C1-10 alkyl is optionally substituted by 1-3 halo (F, C1, Br), hydroxy, amino, C] ₅ acylamino or C] ₄ alkyl groups; or unsubstituted or substituted _Cj-C10 alkyl, _{C2 -C10} alkenyl or _C2-10 alkynyl wherein said alkyl chain, if the length is more than 2 carbon atoms, can have inserted therein 1 to 2 oxa, thia or aza of the formula -NR- wherein R is hydrogen or _C13 alkyl, and where the substituents are independently 1 to 3 of (a) aryl or heteroaryl optionally substituted with 1-3 halogens (F, Cl, Br, I ), C, ₄ alkyl, C \ ₃ alkoxy, amino, C] ₄ alkylamino, di (C [alkyl) amino or hydroxy groups, (b) heterocyclyl unsubstituted or substituted by hydroxy, amino, C _{| 4} alkylamino, di (C _1-4 alkyl) amino, C _{| 4} alkylcarbonyloxy or C _{| 4} alkyl carbonylamino, (c) halogen (F, Cl, Br or I), (d) hydroxy, not acylated or acylated with the group R ^a C (= O) or R ^b S (O) 2, where R ^a is hydrogen, Ct 6 alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl and R ^b is C _{1 b} alkyl or aryl, (e) C] ₁₀ alkoxy, (f) aryloxy or heteroaryloxy unsubstituted or substituted by 1 to 3 halogen, hydroxy, amino or C ₁₄ alkyl groups, (g) amino or C ₁₁₀ alkylamino groups, unacylated or acylated with the group R ^a C (= O), ROC (= O) or R ^b SO ₂ , where R ^a and R ^b are as defined above ;

(h) di (C] _-C10 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 C _1-4 alkyl groups, (J) mercapto, (k) _C1-10 alkylthio, alkylsulfinyl or alkylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl wherein said aryl group is unsubstituted or substituted by 1-3 halo, hydroxy, amino or C ₄ alkyl groups, (l) formyl, (m) Cj ₁₀ alkylcarbonyl, (n) arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl or heteroarylalkylcarbonyl, where o aryl or heteroaryl group is unsubstituted or substituted by 1-3 halo, hydroxy, amino or C _1-4 alkyl groups, (o) carboxy, (p) Cj ₁₀ alkoxycarbonyl, (q) aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl or heteroarilalkoksikarbonil, wherein the aryl or the heteroaryl group is unsubstituted or substituted by 1-3 halo, hydroxy, amino or C ₄ alkyl groups, (r) carbamoyl or sulfamoyl wherein the nitrogen atom is unsubstituted or substituted with 1 -2 C ₆ alkyl groups or by C _{4 6} alkylene chain, (s) cyano, (t) isonitrile, (i) nitro, (v) azide v, (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, C 1-10 alkyl, aryl; or R ² and R ³ together are oxo or thione; R ⁴ and R ⁵ are independently hydrogen or alkylcarbonyl; or R ⁴ and R ⁵ are together carbonyl; or R ⁴ and R ⁵ together are C 1 -C 3 alkyl 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 a hydroxy, acyloxy derivative selected from the group consisting of formyloxy, C _1-10 alkylcarbonyloxy, arylcarbonyloxy and aralkylcarbonyloxy, or

-NHR ¹² where R ¹² is hydrogen, arylsulfonyl or heteroarylsulfonyl unsubstituted or substituted by 1-3 halogen or C 13 alkyl groups, alkylsulfonyl or -C (= O) -XAR ¹³ , where X is a bond, O or NH, A is bonding bond or C 1 -C 3 alkylene, R ¹³ is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, heteroaryl, heterocyclyl or C 3 -C 7 cycloalkyl, each of the R ¹³ groups other than hydrogen may be substituted by one or more halogen, hydroxy, C 1 -C 3 alkoxy, cyano, isonitrile, nitro, amino, mono- or di (C 1 -C ₃ ) alkylamino, mercapto, C 1 -C ₃ alkylthio, C 1 -C ₃ alkylsulfinyl, C 1-4 -C1 alkyls alkylsulfonyl, arylthio, arylsulfinyl, sulfamoyl, arylsulfonyl, carboxy, carbamoyl, _{(C 3} alkylcarbonyl or C ₃ 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, C _1-10 alkylcarbonyl, C _{1-3 10} alkoxycarbonyl or arylalkoxycarbonyl; R ¹⁰ is hydrogen; or R ¹⁰ and R ¹ together are C 1 -C 3 alkylene, unsubstituted or substituted by an oxo group; m and η are independently zero or one.

More preferably, the 8a-azalide has formula (I) in which η and m are zero;

R ¹ is hydrogen, C \ _{-C 10} alkyl, _C2-10 alkenyl, _{C2. 10} alkynyl or arylsulfonyl, wherein said alkyl and alkenyl being optionally substituted with halogen, hydroxy, cyano, C, _{| 0} alkoxy, amino, ₁₀ alkylamino, di (C _{1 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, C _{1 | 0} alkylcarbonyloxy, aralkylcarbonyloxy, amino, amino substituted by Cj ₁₀ alkylcarbonyl, arylcarbonyl, arylC ₁₀ alkylcarbonyl, C ,. ₁₀ alkoxycarbonyl, arylC1, ₀ alkoxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or arylsulfonyl;

R ⁸ is methyl

Also more preferred are 8a-azals di of formula (I) in which η 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-fluoroethyl 2-fluoroallyl, benzyl or oxiranyl methyl;

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 hydroxyl or amino;

R ⁸ is methyl.

The most preferred R ¹ groups are methyl, ethyl, propyl, allyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl.

In another preferred embodiment, the present invention relates to the use of 8a-azalides of formula I for the manufacture of a medicament for the treatment or prevention of bacterial respiratory infections in cattle or pigs, and in particular those in which the causative organism is selected from the group consisting of from Pasteurella spp., Actinobacillus spp., Haemophillus sommus and Mycoplasma spp. More preferably, the 8a-azalide is of formula (I) in which η and m are zero;

R * is hydrogen, C, _, _o alkyl, _C2-10 alkenyl, C _{2 0} alkynyl or arylsulfonyl, wherein said alkyl and alkenyl being optionally substituted with halogen, hydroxy, cyano, C,., _O alkoxycarbonyl, amino, C ,., _o alkylamino, di (C,., ₀ 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, C,., _o alkylcarbonyloxy, aralkylcarbonyloxy, amino, amino substituted by C,., _o alkylcarbonyl, arylcarbonyl, aryl, alkylcarbonyl, ₁₀ alkoxycarbonyl, arylC, ₁₀ alkoxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or arylsulfonyl;

R ⁸ is methyl.

Particularly preferred are 8a-azalides of formula (I) in which η 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-fluoroethyl 2-fluoroallyl, benzyl or oxiranyl methyl;

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 hydroxyl or amino;

R ⁸ is methyl.

The most preferred R ¹ groups are methyl, ethyl, propyl, allyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl.

In another preferred embodiment, the present invention relates to the use of 8a-azalides of formula I for the manufacture of a medicament for treating or preventing bacterial enteral infections in cattle or pigs, and in particular those in which the causative organism is selected from Escherichia coli, Treponema hyodysenteriae and Salmonella spp.

As used herein, "8a-azalide" means a compound having the following basic structure in which asterisks indicate the substitution sites:

The 8a-azalides are referred to herein as erythromycin A derivatives, and in particular as 9-deoxy-8a-aza-8a-homoerythromycin A derivatives.

The term "therapeutically or prophylactically effective amount" means that amount of 8a-azalide that provides 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 protect against infection .

"Treatment or prevention" means the use of 8a-azalide after or before the onset of signs and symptoms suggestive of bacterial infection, to allow the host animal to overcome or protect against infection.

"Bacterial respiratory or enteral infections" means respiratory or digestive tract infections for which the causative organism or similar causative organisms are sensitive to 8α-azalide. Such organisms include, but are not limited to, Pasteurella spp. (e.g. R. haemolytica, R. multocida), Haemophillus sommus, Actinobacillus pleuropneumoniae, Mycoplasma spp., E. coli, Treponema hyodysenteriae and Salmonella spp. (e.g. S. typhimurium, S. dublin).

The terms used to define the various groups of formula (I) (e.g. alkyl, aryl, heterocyclyl, substituted, etc.) have the same meanings as given in EP 508,699.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable, non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, almond, methanesulfonic, lactic, azovaphic, azovafor , tartaric acid, p-toluenesulfonic acid and the like. Citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids are particularly preferred.

The 8a-azalide compounds are either known as described in EP 508,699, or can be prepared using known methods from readily available starting materials.

Representative 8a-azalides are as follows:

9-deoxy-8a-aza-8a-homoerythromycin A;

9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

9-deoxy-8a-aza-8a-ethyl-8a-homoerythromycin A;

8a- (3-phenylpropyl) -8a-aza-9-deoxy-8ahomoerythromycin A;

9-deoxy-8a-aza-8a-allyl-8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (prop-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (prop-1-yloxy) -8ahomoerythromycin A;

9-deoxy-8a-aza-8a- (2-oxoet-1-yl) -8ahomoerythromycin A;

9-deoxy-8a-aza-8a- (2-hydroxy-1-yl) 8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((2,3-epoxy) prop-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (11-azetidinyl) -2-ethyl-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((1-pyrrolidinyl) -2et-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((N-piperidinyl) -2et-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((4-morpholinyl) -2et-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((2-fluoroet-1-yl) 2-amino-1-yl) -8a-homoerythromycin A;

8a- (2-chloroallyl) -8a-aza-9-deoxy-8a-homoerythromycin A;

α- (2-fluoroallyl) - 8 α-aza-9-deoxy-8 achamoerythromycin A;

9-deoxy-8a-aza-8a - ((2-cyano) eth-1-yl) 8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((3-amino) prop-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((((b1, N-dimethyl) -3amino) prop-1-yl) - 8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((2-cyanoethyl) -3-aminoprop-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((3,4-dihydroxybenzyl) -3-aminoprop-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (3-acetoxyprop-1-yl) -8a-homoerythromycin A;

- deoxy-8a-aza-8a- (3-hydroxyprop-1-yl) -8a-homoerythromycin A;

(3-methoxy-3-oxopropyl) -8a-homoerythromycin A;

8a- (3-octyloxy-3-oxopropyl) -9-deoxy-8a-aza-8a-homoerythromycin A;

8a- (3- (2-methoxyethoxy) -3-oxopropyl) 9-deoxy-8a-aza-8a-homoerythromycin A;

8a- (3-isopropoxy-3-oxopropyl) -9-deoxy-8a-aza-8a-homoerythromycin A;

8a- (3-benzyl oxy-3-oxopropyl) -9-deoxy-8a-aza-8a-homoerythromycin A;

8a- (2-carboxyethyl) -9-deoxy-8a-aza-8ahomoerythromycin A;

9-deoxy-8a-aza-8a-cyanomethyl-8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (2-aminoethyl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (2-dimethyl-aminoethyl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (N-L-leucyl-2-aminoethyl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a-carboxymethyl-8ahomoerythromycin A;

9-deoxy-8a-aza-8a-methoxycarbonylmethyl-8a-homoerythromycin A;

9-deoxy-8a-aza-3 '-N - demethyl-8a-homo erythromycin A;

9-deoxy-8a-aza-3 '-N-demethyl-3' -N-phenylsulfonyl-8a-homoerythromycin A;

9-deoxy-8a-aza- (2-fluoroet-1-yl) -3 'N-demethyl-3'-N-phenylsulfonyl-8a-homo rithromycin A;

9-deoxy-8a-aza-8a- (2-fluoroet-1-yl) 3'-N-demethyl-8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (2-fluoroet-1-yl) 8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (3-fluoroprop-1-yl) -3'-N-demethyl-3'-N-phenylsulfonyl-8a-moyrythromycin A;

9-deoxy-8a-aza-8a- (3-fluoroprop-1-yl) -3'-N-demethyl-8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (3-fluoroprop-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((4,4,4-trifluoro) but-1-yl) -3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((4,4,4-trifluoro) but-1-yl) -3 '-N-8a-homoerythromycin A;

9-deoxy-8a-aza-8a - ((4,4,4-trifluoro) but-1-yl) -8a-homoerythromycin A;

9-Deoxo-8a-aza-8a- (benzyl) -3'-N-demethyl-3'-L1-phenylsulfonyl-8a-homoerylromycin A

9-deoxy-8a-aza-8a- (benzyl) -3 '-N-demethyl-8a-homoerythromycin A;

9-deoxy-8 a-aza-8 a- (benzyl) - 8 a-homo rithromycin A;

9-deoxy-8a-aza-8a- (4-methoxybenzyl) 3 '-N-demethyl-3' -N-phenylsulfonyl-8a-homo rithromycin A;

9-deoxy-8a-aza-8a- (4-methoxybenzyl) 3'-N-demethyl-8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (4-methoxybenzyl) a-homoerythromycin A;

9-deoxy-8a-aza-8a- (2- (2-ethoxyethoxy) ethyl-1-yl) -3 '-N-demethyl-3' -N-phenylsulfonyl-8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (2- (2-ethoxyethoxy) eth-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (2,2-difluoro-1-yl) -3-N-demethyl-3'-1H-phenylsulfonyl-8a-moerythromycin A;

9-deoxy-8a-aza-8a- (2,2-difluoro-1-yl) -3'-N-demethyl-8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (2,2-difluoro-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a-hydroxy-8a-homoerythromycin A;

9-deoxy-8a-aza-8a- (prop-1-yl) -8a (prop-1-yl) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a-acetyl-8a-homoerythromycin A;

9-deoxy-8a-aza-8a-glycyl-8a-homoerythromycin A;

9-deoxo-8a-aza-8a- (L'ei-Cly) -8a-homoerythromycin A;

9-deoxy-8a-aza-8a-phenylsulfonyl-8ahomoerythromycin A;

2'-O-acetyl-9-deoxy-8a-methyl-8a-aza8a-homoerythromycin A;

(11-0,12-O-oxomethylene) -9-deoxy-8amethyl-8a-aza-8a-homoerythromycin A;

8-aza-4-O-phenylacetyl-8a-aza-8a-methyl-9-deoxy-8a-homoerythromycin A;

4-0- (4-methoxyphenyl) acetyl-8a-aza-8amethyl-9-deoxy-8a-homoerythromycin A;

2'-O-acetyl-9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

4-epi-9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

-deoxy-4-amino-9-deoxy-8a-aza-8 amethyl-8a-homoerythromycin A;

4-deoxy-4- (S) -amino-9-deoxy-8aaza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (R) -amino-9-deoxy-8aaza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (S) -acetylamino-9-deoxy8a-aza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (1H) acetylamino-9-deoxy8a-aza-8a-methyl-8a-homoerythromycin A;

4- (4-methoxyphenylacetyl) amino-4deoxy-8a-aza-8a-methyl-8a-homoerythromycinA;

4-deoxy-4- (L-alanyl) amino-9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (L-valyl) amino-9-deoxy8a-aza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (L-leucyl) amino-9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

- deoxy-4- (L-phenyl alanyl) amino-9deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (O-tert-butyl-L-tyrosyl) amino-9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (L-propyl) amino-9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (L-aspartyl-L-benzyl ester) amino-9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (L-aspartyl) amino-9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (L-pyroglutamyl) amino-9deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

4-deoxy-4- (L-glutamyl) amino-9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A;

-O-acetyl-9-deoxy-8a-aza-8a-allyl8a-homoerythromycin A;

4-deoxy-4-amino-9-deoxy-8a-aza-8aallyl-8a-homoerythromycin A;

4-deoxy-4-amino-9-deoxy-8a-aza-8-propyl-8a-homoerythromycin A;

-O-acetyl-9-deoxy-8a-aza-8a-methoxycarbonyl-8a-homoerythromycin A;

4-deoxy-4-amino-9-deoxy-8a-aza-8a (3-methoxy-3-oxopropyl) -8a-homoerythromycin A;

2'-O-acetyl-8a-aza-8a-homoerythromycin; and 4-deoxy-4-amino-8a-aza-8a-homoerythromycin A.

The 8a-azalide compounds may be administered to a host in need of treatment or prevention of bacterial respiratory or enteral diseases in a manner similar to that used for other antibacterial agents; for example, 8α-azalides may be administered parenterally, orally, topically, or rectally. The dose to be administered will vary according to the specific compound used, the infectious organism involved, the specific host, the severity of the disease, the physical condition of the host, and the route of administration selected; the appropriate dose can be readily determined by one of skill in the art. For the treatment of bacterial diseases, the oral dose may be in the range of 1 mg / kg to 1000 mg / kg; and the parenteral dose may be in the range of 0.01 mg / kg to 500 mg / kg. For prophylactic use in animals, the oral dose may be in the range of 1 mg / kg to 1000 mg / kg; and the parenteral dose may be from 0.01 mg / kg to 500 mg / kg. The 8α-azalides of the present invention are preferably administered parenterally at doses in the range of about 0.1 to about 10 mg / kg.

The 8a-azalides are preferably used in pharmaceutical compositions comprising the active ingredient and an inert pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention contain 8α-azalide as the active ingredient, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.

Formulations include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most appropriate route in each case will depend on the specific host and the nature and severity of the conditions for which the active agent is administered. ingredient is applied. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the field of pharmacy.

In practical use, the 8a-azalides can be combined as active ingredients in intimate mixtures with a pharmaceutical carrier according to conventional pharmaceutical techniques for formulation. The carrier may take a wide variety of forms depending on the form of the formulation desired, e.g. orally or parenterally (including intravenously, intramuscularly and subcutaneously); parenteral administration is generally preferred.

In the preparation of the compositions for oral dosage form, conventional pharmaceutical media may be used. For example, in the case of liquid oral preparations such as suspensions, elixirs and solutions, water, glycols, oils, alcohols, flavoring agents, preservatives, colorants and the like may be used; or in the case of oral solid preparations such as powders, capsules and tablets, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, and the like may be included. Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage forms in which case apparently solid pharmaceutical carriers are used. If desired, tablets may be coated by standard aqueous and involuntary techniques. In addition to the general dosage forms set forth above, the 8a-azalides may also be administered by controlled release means and / or delivery devices.

The pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, starch capsules or tablets, each containing a predetermined amount of the active ingredient as a powder or granules, or as a solution or suspension in aqueous liquid, non-aqueous. liquid, emulsion oil in water or water in oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of coupling the active ingredient to a carrier that consists of one or more of the required ingredients. Generally, the compositions are prepared by uniformly and intimately mixing the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product in the desired presentation. For example, the tablet may be prepared by compression or molding, optionally with one or more additional ingredients. The compressed tablets may be prepared by compression in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, a surfactant or a dispersing agent. Molded tablets can be prepared by molding in a suitable machine a mixture of the powder compound moistened with an inert liquid diluent. It is desirable that each tablet contains from about 1 to about 500 mg of the active ingredient and each starch or gelatin capsule contains from about 1 to about 500 mg of the active ingredient.

The pharmaceutical compositions of the present invention suitable for parenteral administration may be formulated as solutions or suspensions of these active compounds in water, suitably mixed with a surfactant such as hydroxypropylcellulose. The dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the development of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be liquid to the extent that it exists as easily injectable. It must be stable under conditions of production and storage and must be protected against the contagious effects of micro-organisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.

Suitable topical formulations include transdermal devices, aerosols, creams, ointments, lotions, powders and the like.

These formulations may be prepared by conventional methods involving the active ingredient. By way of illustration, a cream or ointment is prepared by mixing sufficient amounts of hydrophilic material and water containing from about 5-10 wt. % of the compound in sufficient quantities to obtain a cream or ointment having the desired consistency.

Pharmaceutical compositions suitable for rectal administration in which the carrier is a solid are particularly preferably presented as single dosage suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and suppositories may conveniently be prepared by mixing a combination with a softened or melted carrier (s), followed by freezing and molding.

It should be understood that in addition to the above-mentioned carriers of the pharmaceutical formulations described above, they may include, as appropriate, one or more additional carriers such as diluents, buffers, flavor enhancers, binders, surfactants, sealants, lubricants, preservatives (including antioxidants) and the like, and substances included for the purpose of making the preparations isotonic with the blood of the intended patient.

Formulations containing 8a-azalide may also be formulated as a powder or as a liquid concentrate. In accordance with standard veterinary formulation practice, conventional water-soluble excipients such as lactose or sucrose in powders may be incorporated to improve their physical properties. Thus particularly suitable powders according to the present invention contain 50 to 100 wt. and preferably 60 to 80 wt. % of the combination and 0 to 50 wt. and preferably 20 to 40 wt. % of normal veterinary excipients. These powders may be added to the animal feed, for example by way of an intermediate premix, or diluted in drinking water for the animals.

The liquid concentrates of the present invention suitably contain a water-soluble combination of the compound and may optionally include veterinarily acceptable water miscible solvents such as polyethylene glycol, propylene glycol, glycerol, glycerol per se or mixed up to 30% vol. % with ethanol. Liquid concentrates can be applied to drinking water from animals.

Pharmaceutical compositions containing 8a-azalide may optionally contain a second active ingredient, a biological component as an antigen or a dietary supplement such as minerals or vitamins. The active ingredients may include immunomodulators such as interferon, interleukins and other chemokines, non-steroidal anti-inflammatory agents such as propionic acid derivatives (eg, ibuprofen, keto profen, naproxen, benoxprofen, carprofen), acetic acid, acacenac, acacenac, acacenac, acacenac, alacecnac, acacenac, acacenac, alacetac diclofenac, fenclofenac, fencloic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, thiopinac, tolmetin, zidomethacin and zomepirac), fenamic acid derivatives (eg flufenamic acid, m elofenamic acid, mefenamic acid, niflumic acid and tolphenamic acid), biphenylcarboxylic acids (eg diflufenisal, flufenisal) and cyclooxygenase-2- (COX-2) inhibitors and antiparasitic agents such as avermectin, ivermezmethylmethizelmethylmethizelmethyl . Biological agents may be vaccines commonly used in industrial animal husbandry against infectious bovine rhinotracheitis, bovine viral diarrhea, respiratory syncytial virus, parainfluenza, transmissible gastroenteritis, porcine reproductive and respiratory viral respiratory virus.

Dietary supplements can be vitamins, iron, selenium and the like.

Examples of carrying out the invention

The following examples are given to further illustrate the present invention and are not intended to limit the scope of the claims in any way.

In vitro activity of 8α-azalides

The antibacterial activity of representative 8α-azalides against a set of veterinary pathogens is determined by the method of minimum inhibitory concentration (MIC) well known to those skilled in the art. This is done by preparing a series of tubes, each containing medium with different concentrations of antimicrobial and INO- | θ cupping of tubes with the same organisms. The lowest concentration of the agent that completely prevents the appearance of turbidity is noted, and this concentration is called MIC. U

The range of antibacterial activity of 4-deoxy-4-amino-9-deoxy-8a-aza-8a-methyl-8a-homoerythromycin A, 4-deoxy-4 (K) amino-9-deoxy-8a-aza- 8a-methyl-8a-homoerythromycin A, 4-deoxy-4 (8) -amino-9-deoxy-2θ 8a-aza-8a-methyl-8a-homoerythromycin A and 4deoxy-4-amino-9-deoxy-8a -aza- 8a-allyl-8 achamoerythromycin A against key veterinary organisms is summarized below:

Organism MIC range (g / ml) R. haemolytica 0.125 - 0.5 R. multocida 0.125 - 05 N. somnus 0.125 - 0.250 A. pleuropneumoniae 0.062 - 0.125 E. coli 0.5 - 2 Salmonella spp. 0.5-4

Claims

Claims (14)

Use of an 8a-azalide of formula 35 or a pharmaceutically acceptable salt or pharmaceutically acceptable metal complex thereof, the metal in the complex being selected from the group consisting of copper, zinc, cobalt, nickel and cadmium; in which formula R ¹ represents hydrogen; hydroxy; With ₁₄ alkoxy; formyl; C _1-10 alkylcarbonyl, C \ ₁₀ alkoxycarbonyl, aryloxycarbonyl, _C1-10 aralkoxycarbonyl, _C1-10 alkylsulfonyl, or arylsulfonyl, in which the C] ₁₀ alkyl group is substituted by 1-3 halo (F, C1, Br), hydroxy, amino, ₍₅ acylamino or C ₁₄ alkyl groups; or unsubstituted or substituted C ₍₁₀ alkyl, C ₂₁₀ alkenyl or C ₂₁₀ alkynyl, where the alkyl chain, if more than 2 carbon atoms in length, can have 1 to 2 oxa inserted into it or aza of the formula -NR-, wherein R is hydrogen or _C13 alkyl, and where the substituents are independently 1 to 3 of (a) aryl or heteroaryl optionally substituted with 1-3 halogens (F, Cl, Br, I ), C ₁₄ alkyl, C ₁₃ alkoxy, amino, C _1-4 alkylamino, di (C _{| 4} alkyl) amino or hydroxy groups, (b) heterocyclyl unsubstituted or substituted with hydroxy, amino, C, _ ₄ alkylamino, to (C ₁₄ alkyl) amino, C \ ₄ alkylcarbonyloxy or C ₄ alkylcarbonyl amino, (c) halo (F, C1, Br or I), (d) hydroxy non-acylated or acylated with the group R ^a C (= O) or R ^b S (O) 2, wherein R ^a is hydrogen, C 1-6 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl and R ^b is C ₍₆ alkyl or aryl, (e ) C ₁₀ alkoxy, (f) aryloxy or heteroaryloxy, unsubstituted or substituted with 1-3 halogen, hydroxy, amino or Cj ₄ alkyl groups, (g) amino or Cj ₁₀ alkylamino non-acylated or acylated by a group R * C (= O), ROC (= O) or R ^b SO _2, wherein R ^a and R ^b are as defined above ; (h) di (C 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 C _1-4 alkyl groups, (j) mercapto, (k) Cj ₁₀ alkylthio, alkylsulfinyl or alkylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl wherein said aryl group is unsubstituted or substituted by 1-3 halo, hydroxy, amino or _b4 alkyl groups, (1) formyl, (m) With ₁₁₀ alkylcarbonyl, (n) arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl or heteroarylalkylcarbonyl lo aryl or heteroaryl group is unsubstituted or substituted by 1-3 halo, hydroxy, amino or C _{| 4} alkyl groups, (o) carboxy, (p) _C1-10 alkoxycarbonyl, (q) aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl or heteroarilalkoksikarbonil wherein said aryl or heteroaryl group is unsubstituted or substituted by 1-3 halo, hydroxy, amino or C ₄ alkyl groups, (r) carbamoyl or sulfamoyl wherein the nitrogen atom is unsubstituted or substituted with 1-2 C ₆ alkyl groups or by C _{4 6} alkylene chain, (s) cyano, (t) isonitrilo (u) nitro, (v) i to, (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, C _10-10 alkyl, aryl; or R ² and R ³ together are oxo or thione; R ⁴ and R ⁵ are independently hydrogen or alkylcarbonyl; or R ⁴ and R ⁵ are together carbonyl; or R ⁴ and R ⁵ together are C 1 -C 6 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 a hydroxy, acyloxy derivative selected from the group consisting of formyloxy, C _1-10 alkylcarbonyloxy, arylcarbonyloxy and aralkylcarbonyloxy, or -NHR ¹² , where R ¹² is hydrogen, arylsulfonyl or heteroarylsulfonyl, unsubstituted or substituted with 1-3 halogen or C1-3 alkyl groups, alkylsulfonyl or -C (= O) -XAR ¹³ , where X is a bond, O or NH , A is a bonding bond or C 1 -C 3 alkylene, R ¹³ is hydrogen, C 1 -C ₁₀ alkyl, aryl, aralkyl, heteroaryl, heterocyclyl or C ₃ -C ₇ cycloalkyl, each of the R ¹³ groups other than hydrogen may be substituted by one or more halogen, hydroxy, C 1 -C ₃ alkoxy, cyano, isonitrile, nitro, amino, mono- or di (C 1 -C ₃ ) alkylamino, mercapto, C 1 -C ₃ alkylthio, C , -C ₃ alkylsulfinyl, C] _-C3 alkynyl sulfonyl, arylthio, arylsulfinyl, sulfamoyl, arylsulfonyl, carboxy, carbamoyl, C, -C ₃ alkylcarbonyl or C ^ -Cj 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, C ₁₁₀ alkylcarbonyl, C ₁₁₀ alkoxycarbonyl or arylalkoxycarbonyl; R ¹⁰ is hydrogen; or R ¹ 'and R ¹ together are C ¹ -C ₃ alkylene, unsubstituted or substituted by an oxo group; m and η are independently zero or one for the manufacture of a medicament for treating or preventing bacterial respiratory or enteral infection in a livestock. The use according to claim 1, wherein the 8a-azalide has formula (I) in which η and m are zero; R ¹ is hydrogen, C ₁₀ alkyl, C ₂₁₀ alkenyl, C ₂₁₀ alkynyl or arylsulfonyl, wherein said alkyl and alkenyl are optionally substituted by halogen, hydroxy, cyano, C _6-10 alkoxycarbonyl, amino, C ₁₀ alkylamino, di (C _{( 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 with C ₁₀ alkylcarbonyl, arylcarbonyl, arylC ₁₁₀ alkylcarbonyl, C _1-10 alkoxycarbonyl, aryl C ₁₁₀ alkoxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or arylsulfonyl; R ⁸ is methyl. The use according to claim 1, wherein the 8a-azalide has formula (I) in which η 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 oxiranyl methyl; 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 hydroxyl or amino; 5 R ⁸ is methyl. The use of claim 3, wherein R ¹ is methyl, ethyl, propyl, allyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl. Use according to claim 1, 10 wherein the bacterial infection is a respiratory infection in cattle or pigs. The use according to claim 5, wherein the respiratory infection is caused by Pasteurella spp., Actinobacillus spp., 15 Haemophilus somnus or Mycoplasma spp. Use according to claim 2, wherein the bacterial infection is a respiratory infection in cattle or pigs. Use according to claim 7, 20 wherein the respiratory infection is caused by Pasteurella spp., Actinobacillus spp., Haemophilus somnus or Mycoplasma spp. Use according to claim 3, wherein the bacterial infection is a respiratory infection in cattle or pigs. Use according to claim 9, wherein the respiratory infection is caused by Pasteurella spp., Actinobacillus spp., Haemophilus somnus or Mycoplasma spp. Use according to claim 4, wherein the bacterial infection is a respiratory infection in cattle or pigs. Use according to claim 11, wherein the respiratory infection is caused by Pasteurella spp., Actinobacillus spp., Haemophilus somnus or Mycoplasma spp. Use according to claim 1, wherein the bacterial infection is an enteric infection in cattle or pigs. The use of claim 13, wherein the enteral infection is caused by E. coli, Treponema hyodysenteriae or Salmonella spp. Publication of the Patent Office of the Republic of Bulgaria 1113 Sofia, 52-B Dr. GM Dimitrov Blvd.