KR20010023822A - 8a-Azalides as veterinary antimicrobial agents - Google Patents

Abstract

8a-Azalides are useful for the treatment and prevention of bacterial respiratory and intestinal infections in livestock, particularly cattle and pigs.

Description

8a-Azalides as veterinary antimicrobial agents

Summary of the Invention

The present invention provides a method for treating or preventing bacterial respiratory infections or intestinal infections in livestock.

Background of the Invention

The morbidity and mortality rates associated with bacterial respiratory and intestinal infections in livestock represent major economic losses in the livestock industry. In cows, especially young animals, stress, transport, dehydration, dietary changes or deficiencies due to weaning can cause the animal to develop bacterial respiratory infections, especially if the animal is kept in a full or poorly ventilated house. You can do it easily. Bacterial pathogens responsible for bovine respiratory infections are Pasteurella haemolytica, Pasteurella multocida, Haemophilus somnus and Mycoplasma spp. to be. In pigs, respiratory infections caused by Pasteurella multocida or Actinobacillus pleuropneumoniae and mycoplasma are associated with significant loss of swine herds. The most common causes of intestinal disease in cattle and pigs are Escherichia coli, Treponema hyodysenteriae and Salmonella spp.

Antimicrobial products for the treatment of respiratory and intestinal infections in conventional livestock include a diverse group of older products that are effective against a wide range of infectious pathogens, of which mainly attention is given to the treatment of respiratory diseases of tetracycline and cattle. The recently introduced product groups indicated are, for example, quinolone (danoploxacin, enlofloxacin), cephalosporin (sephquinom, ceftiofur), macrolide (tilmycosine) and flofenicol. . Resistance to old antimicrobial agents has been shown in the art. Although resistance to new products is not a problem yet, the use of excess promotes the development of resistance over time, but the mechanism of action used by increasing the number of drug groups reduces the likelihood of developing resistance to individual compounds. It is known to be able to. Thus, there is a continuing need to find antimicrobial compounds suitable for veterinary medicine, and preferably, these compounds are present in different chemotypes from antimicrobial agents used in conventional animal or human medicine. Will belong. Other desirable properties of veterinary novel antimicrobial products include high potency against target organisms, high target tissue concentrations, and long tissue and plasma half-lives.

8a-Azalide is an antibiotic characterized by a lactone 15-membered ring containing ring nitrogen atoms. The 8a-azalide group has an antimicrobial spectrum similar to that of erythromycin. E. coli and H. It is described in EP 508,699 as being in vitro active against Gram positive and Gram negative bacteria, including H. influenzae. However, European Patent Publication No. 508,699 does not describe the use of 8a-azalide for the treatment and prevention of bacterial respiratory or intestinal infections in livestock. In addition, it is not proposed that 8a-azalides have antimicrobial activity against organisms that are a common cause of bacterial respiratory and intestinal infections in cattle and pigs.

The present invention provides a therapeutic or prophylactically effective amount of 8a-azalide to a livestock in need of treatment or prevention of a bacterial respiratory infection or intestinal infection, thereby treating a bacterial respiratory or bowel infection of the domestic animal. Or provide a method of prevention.

In a preferred embodiment, 8a-azalide is selected from the group consisting of a compound of formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable metal complex thereof, wherein the metal complex is selected from the group consisting of copper, zinc, cobalt, nickel and cadmium Is).

In Formula I above,

R ¹ is hydrogen; Hydroxy; C _1-4 alkoxy; Formyl; C _1-10 alkylcarbonyl, C _1-10 alkoxycarbonyl, aryloxycarbonyl, C _1-10 aralkoxycarbonyl, C _1-10 alkylsulfonyl or arylsulfonyl, wherein a C _1-10 alkyl group Is substituted with one to three halo (F, Cl, Br), hydroxy, amino, C _1-5 acylamino or C _1-4 alkyl groups); Or unsubstituted or substituted C _1-10 alkyl, C _2-10 alkenyl or C _2-10 alkynyl, wherein the alkyl chain is one or two oxa, thia, or a chemical formula, An aza of NR—, wherein R is hydrogen or C _1-3 alkyl, and the substituents are independently one to three halo (F, Cl, Br, I), C _1-4 alkyl, Aryl or heteroaryl optionally substituted with C _1-3 alkoxy, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino or hydroxy (a), unsubstituted or hydroxy, amino, C _1- Heterocyclyl (b), halo (F, Cl, Br or I substituted with ₄ alkylamino, di (C _1-4 alkyl) amino, C _1-4 alkylcarbonyloxy or C _1-4 alkylcarbonylamino ) (c), unacylated or group R ^a C (= 0) or R ^b S (O) ₂ , where R ^a is hydrogen, C _1-6 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl and, R ^b is C _1-6 alkyl or A reel) to the acylated hydroxy (d), C _1-10 alkoxy (e), unsubstituted or one to three halo, hydroxy, amino, or C _1-4 aryl optionally substituted by alkyl group or heterocyclic-oxy Aryloxy (f), amino not acylated or acylated with R ^a C (= 0), R ^a OC (= 0) or R ^b SO ₂ , wherein R ^a and R ^b are as defined above; or C _1-10 alkylamino (g), di (C _1-10 alkyl) amino (h), arylamino, heteroarylamino, aralkylamino or heteroarylalkylamino wherein the aryl or heteroaryl group is unsubstituted or Substituted with one to three halo, hydroxy, amino or C _1-4 alkyl groups) (i), mercapto (j), C _1-10 alkylthio, alkylsulfinyl or alkylsulfonyl, arylthio, Arylsulfinyl or arylsulfonyl, wherein the aryl group is unsubstituted or one to three halo, hydroxy, amino or C _{1 -4} is replaced with an alkyl group) (k), formyl (l), C _1-10 alkylcarbonyl (m), arylcarbonyl, heteroaryl-carbonyl, aralkyl carbonyl, or heteroarylalkyl carbonyl (where , Aryl or heteroaryl group is unsubstituted or substituted with one to three halo, hydroxy, amino or C _1-4 alkyl groups) (n), carboxy (o), C _1-10 alkoxycarbonyl (p ), Aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl or heteroarylalkoxycarbonyl, wherein the aryl or heteroaryl group is unsubstituted or one to three halo, hydroxy, amino or C _{1- 4} is replaced by an alkyl group) (q), N atom is optionally substituted with one or two C _1-6 alkyl groups or C _4-6 alkylene swaero substituted carbamoyl or sulfamoyl (r), cyano (s ), with isonitrile (t), nitro (u), azido (v), is optionally substituted with nitrogen or carbon is C _1-10 Kilos and substituted imino-methyl (w), oxo (x) and T, Ono (y) one to three of the dog],

R ² and R ³ are independently hydrogen, C _1-10 alkyl or aryl, or together oxo or thiono,

R ⁴ and R ⁵ are independently hydrogen or alkylcarbonyl, or together carbonyl,

R ⁴ and R ¹ are C _1-3 alkylene unsubstituted or substituted with oxo groups,

R ⁶ and R ⁷ are both hydrogen,

One of R ⁶ and R ⁷ is hydrogen and the other is hydroxy or an acyloxy derivative selected from the group consisting of formyloxy, C _1-10 alkylcarbonyloxy, arylcarbonyloxy and aralkylcarbonyloxy- NHR ¹² where R ¹² is hydrogen, arylsulfonyl or heteroarylsulfonyl unsubstituted or substituted with one to three halo or C _1-3 alkyl groups), alkylsulfonyl or -C (= 0) -XAR ¹³ where X is a linking bond, O or NH, A is a linking bond or C _1-3 alkylene, R ¹³ is hydrogen, C _1-10 alkyl, aryl, aralkyl, heteroaryl, heterocycle Aryl or C _3-7 cycloalkyl and the non-hydrogen group of the R ¹³ groups are one or more halogen, hydroxyl, C _1-3 alkoxy, cyano, isonitrilo, nitro, amino, mono (C _1-3 ) alkylamino, di (C _1-3) alkylamino, mercapto, C _1-3 alkylthio, C _1-3 alkylsulfinyl , C _1-3 alkylsulfonyl, arylthio, aryl sulfinyl, sulfamoyl, arylsulfonyl, carboxy, carbamoyl, C _1-3 which may be substituted with alkylcarbonyl or C _1-3 alkoxycarbonyl), and ,

R ⁶ and R ⁷ together are oxo, hydroxyimino, alkoxyimino, aralkoxyimino or aminoimino,

R ⁸ is methyl, aralkoxycarbonyl or arylsulfonyl,

R ⁹ is hydrogen, formyl, C _1-10 alkylcarbonyl, C _1-10 alkoxycarbonyl or arylalkoxycarbonyl,

R ¹⁰ is hydrogen,

R ¹⁰ and R ¹ are C _1-3 alkylene unsubstituted or substituted with oxo groups,

m and n are independently 0 or 1.

More preferably, 8a-azalid is n and m is 0 and R ¹ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or arylsulfonyl, wherein alkyl and Alkenyl is halo, hydroxy, cyano, C _1-10 alkoxycarbonyl, amino, C _1-10 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 hydroxyl, C _1-10 alkylcarbonyloxy, aralkyl carbonyl-oxy, amino, C _1-10 alkyl carbonyl amino substituted by carbonyl, arylcarbonyl, aryl C _1-10 alkylcarbonyl, C _1-10 alkoxycarbonyl, aryl C _1-10 alkoxycarbonyl, heteroaryl Is a compound of formula I selected from carbonyl, heteroarylalkylcarbonyl and arylsulfonyl, wherein R ⁸ is methyl.

n and m are 0, 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 More preferred are 8a-azides of formula I, wherein R ⁵ , R ⁹ and R ¹⁰ are hydrogen, one of R ⁶ and R ⁷ is hydrogen, the other is hydroxy or amino, and R ⁸ is methyl. Most preferred R ¹ groups are methyl, ethyl, propyl, allyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl.

In another preferred embodiment, the invention relates to a group in which an organism causing a therapeutically or prophylactically effective amount of 8a-azalide is composed of Pasteurella species, Actinobacillus species, Haemophilus somnus and Mycoplasma species. The causative organism is from a group consisting of Pasteurella species, Actinobacillus species, Haemophilus somnus and Mycoplasma species, including administration to cattle or pigs in need of treatment or prevention of bacterial respiratory infections selected from Provided are methods for treating or preventing bacterial respiratory tract infections of a selected cow or pig. More preferably, 8a-azalide is a compound of formula I, wherein 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 8a of Formula I, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ¹⁰ are hydrogen, one of R ⁶ and R ⁷ is hydrogen, the other is hydroxy or amino, and R ⁸ is methyl Azalides are particularly preferred. Most preferred R ¹ groups are methyl, ethyl, propyl, allyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl.

In another preferred embodiment, the invention is directed to a bacterium wherein the organism causing the therapeutically or prophylactically effective amount of 8a-azalide is selected from Escherichia coli, Treponema hyodicenteri and Salmonella spp. Bacterial intestine of bovine or swine, wherein the causative organism is selected from Escherichia coli, treponema hyodicenteria and Salmonella spp., Including administration to bovine or swine in need of treatment or prevention of intestinal infections Provided are methods for treating or preventing an infection. More preferably, 8a-azalide is a compound of formula I, wherein 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 8a of Formula I, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ¹⁰ are hydrogen, one of R ⁶ and R ⁷ is hydrogen, the other is hydroxy or amino, and R ⁸ is methyl Azalides are particularly preferred. Most preferred R ¹ groups are methyl, ethyl, propyl, allyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl.

As used herein, "8a-azalide" means a compound having the following core structure, where the asterisk indicates a substitution position.

8a-azalide is referred to herein as a derivative of erythromycin A, that is, a derivative of 9-deoxo-8a-aza-8a-homoerythromycin A.

The term “therapeutically or prophylactically effective amount” means an amount of 8a-azalide that provides antimicrobial activity at the target site of infection sufficient to inhibit the bacteria in a manner that allows the host animal to recover or protect from the infection. .

"Treatment or prophylaxis" means the use of 8a-azalide after or before the onset of signs and symptoms suggestive of bacterial infections to allow the host animal to recover or protect from the infection.

"Bacterial respiratory tract infection or intestinal infection" means an infection of the respiratory or digestive tract in which the causative or likely organism is sensitive to 8a-azalide. Such organisms include, but are not limited to, Pasteurella species (eg, Pasteurella haemolytica, Pasteurella multocida), Haemophilus somnus, Actinobacillus flulogneumoniae, Mycoplasma spp., E. coli. E. coli, treponema hyodicenteria and Salmonella spp. S. typhimurium, S. S. dublin].

The terms used to define various groups of formula (I) (eg alkyl, aryl, heterocyclyl, substituted, etc.) have the same meaning as provided in EP 508,699.

The term "pharmaceutically acceptable salts" is salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. These acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfuric acid Phonic acid, muxic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid are particularly preferred.

8a-Azalides are known compounds, such as those described in EP-508,699, or can be prepared using known methods from readily available starting materials. Representative 8a-azalides are as follows:

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

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

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

8a- (3-phenylpropyl) -8a-aza-9-deoxo-8a-homoerythromycin A;

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

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

9-deoxo-8a-aza-8a- (prop-1-yloxy) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a- (2-oxoeth-1-yl) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a- (2-hydroxyeth-1-yl) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a-((2,3-epoxy) prop-1-yl) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a- (11-azetidinyl) -2-eth-1-yl) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a-((1-pyrrolidinyl) -2-eth-1-yl) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a-((N-piperidinyl) -2-eth-1-yl) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a-((4-morpholinyl) -2-eth-1-yl) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a-((2-fluoroeth-1-yl) -2-aminoeth-1-yl) -8a-homoerythromycin A;

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

8a- (2-fluoroallyl) -8a-aza-9-deoxo-8a-homoerythromycin A;

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

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

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

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

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

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

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

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

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

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

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

8a- (3-benzyloxy-3-oxopropyl) -9-deoxo-8a-aza-8a-homoerythromycin A;

8a- (2-carboxyethyl) -9-deoxo-8a-aza-8a-homoerythromycin A;

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

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

9-deoxo-8a-aza-8a- (2-dimethylaminoethyl) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a- (N-L-leucil-2-aminoethyl) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a-carboxymethyl-8a-homoerythromycin A;

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

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

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

9-deoxo-8a-aza-8a- (2-fluoroeth-1-yl) -3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A;

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

9-deoxo-8a-aza-8a- (2-fluoroeth-1-yl) -8a-homoerythromycin A;

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

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

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

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

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

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

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

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

9-deoxo-8a-aza-8a- (benzyl) -8a-homoerythromycin A;

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

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

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

9-deoxo-8a-aza-8a- (2- (2-ethoxyethoxy) eth-1-yl) -3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerytro Mycin A;

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

9-deoxo-8a-aza-8a- (2,2-difluoroeth-1-yl) -3'-N-demethyl-3'-N-phenylsulfonyl-8a-homoerythromycin A;

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

9-deoxo-8a-aza-8a- (2,2-difluoroeth-1-yl) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a-hydroxy-8a-homoerythromycin A and 9-deoxo-8a-aza-8a- (prop-1-yl) -8a- (prop-1-yl ) -8a-homoerythromycin A;

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

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

9-deoxo-8a-aza-8a- (Leu-Gly) -8a-homoerythromycin A;

9-deoxo-8a-aza-8a-phenylsulfonyl-8a-homoerythromycin A;

2′-O-acetyl-9-deoxo-8a-methyl-8a-aza-8a-homoerythromycin A;

(11-O, 12-O-oxomethylene) -9-deoxo-8a-methyl-8a-aza-8a-homoerythromycin A;

4 "-O-phenylacetyl-8a-aza-8a-methyl-9-deoxo-8a-homoerythromycin A, of 8a-aza;

4 "-O- (4-methoxyphenyl) -acetyl-8a-aza-8a-methyl-9-deoxo-8a-homoerythromycin A;

2'-0-acetyl-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A;

4 "-epi-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A;

4 "-deoxy-4" -amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A;

4 "-deoxy-4"-(S) -amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A;

4 "-deoxo-4"-(R) -amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A;

4 "-deoxo-4"-(S) -acetylamino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A;

4 "-deoxo-4"-(R) -acetylamino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A;

4 "-(4-methoxyphenylacetyl) amino-4" -deoxo-8a-aza-8a-methyl-8a-homoerythromycin A;

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

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

4 "-deoxy-4"-(L-leucine) amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A;

4 "-deoxy-4"-(L-phenylalanyl) amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A;

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

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

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

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

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

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

2 "-O-acetyl-9-deoxo-8a-aza-8a-allyl-8a-homoerythromycin A;

4 "-deoxy-4-amino-9-deoxo-8a-aza-8a-allyl-8a-homoerythromycin A;

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

2 "-O-acetyl-9-deoxo-8a-aza-8a-methoxycarbonylethyl-8a-homoerythromycin A;

4 "-deoxy-4" -amino-9-deoxo-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.

8a-Azalide can be administered to a host in need of treatment or prevention of bacterial respiratory disease or intestinal disease in a manner similar to the way other antibacterial agents are used. For example, 8a-Azalide can be administered parenterally, orally, It can be administered topically or rectally. The dose administered will vary depending upon the particular compound employed, the relevant infectious organism, the particular host, the severity of the disease, the physical condition of the host and the route of administration chosen, and the suitable dose can be readily determined by one skilled in the art. When treating bacterial diseases, the oral dosage ranges from 1 mg / kg to 1000 mg / kg and the parenteral dosage ranges from 0.01 mg / kg to 500 mg / kg. For prophylactic use in animals, the oral dosage ranges from 1 mg / kg to 1000 mg / kg and the parenteral dosage ranges from 0.01 mg / kg to 500 mg / kg. The 8a-azalide of the present invention is preferably administered parenterally, at a dose of about 0.1 to about 10 mg / kg.

8a-azalide is preferably used in pharmaceutical compositions comprising the active ingredient and a pharmaceutically acceptable inert carrier. The pharmaceutical composition of the present invention may comprise 8a-azalide as the active ingredient and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The best route of administration in a given case will depend on the nature and severity of the particular host and the active ingredient being administered, but the formulation comprises a composition suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration. do. Pharmaceutical compositions may conveniently be presented in unit dosage form and are prepared by methods well known in the art of pharmacy.

In practical use, 8a-azalide may be mixed as the active ingredient in an intimate mixture with a pharmaceutically acceptable carrier according to conventional pharmaceutical formulation techniques. The carrier may take various forms depending on the form of preparation desired for administration, for example oral or parenteral (including intravenous, intramuscular and subcutaneous) administration, generally parenteral administration.

When preparing compositions for oral dosage forms, any conventional pharmaceutical medium may be used. For example, in the case of liquid preparations for oral administration such as suspensions, elixirs and solvents, water, glycols, oils, alcohols, flavors, preservatives, colorants and the like can be used or for oral administration such as powders, capsules and tablets. In the case of solid preparations, carriers such as starch, sugar, microcrystalline cellulose, diluents, granules, lubricants, binders, disintegrants and the like can be included. Tablets and capsules are the most advantageous oral dosage unit forms in which solid pharmaceutical carriers are clearly used due to their ease of administration. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. In addition to the conventional dosage forms mentioned above, 8a-azalide may also be administered by slow release means and / or delivery devices.

Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of active ingredient, as a powder or granules, or as an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or It can be represented as a solvent or suspending agent of a water-in-oil liquid emulsion. Such compositions may be prepared by any method in the pharmaceutical art, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more essential ingredients. In general, the compositions are prepared by homogeneous and intimate mixing of the active ingredient with the liquid carrier or finely divided solid carrier or both, if necessary, followed by molding the product into the desired shape. For example, tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in a free flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant with a suitable machine. Molded tablets can be made by molding a mixture of the wet powdered compound with an inert liquid diluent with a suitable machine. Preferably, each tablet contains about 1 mg to about 500 mg of active ingredient, and each case or capsule contains about 1 mg to about 500 mg of active ingredient.

Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of these active compounds in water, suitably mixed with surfactants such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for infusion include sterile aqueous solutions or dispersions for the immediate preparation of sterile injectable solutions or dispersions and sterile powders. In all cases, the form must be sterile and must be fluid to the extent that it can be easily injected. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof and vegetable oils.

Suitable topical formulations include transdermal devices, aerosols, creams, ointments, lotions, sprays and the like. These formulations can be prepared by conventional methods containing the active ingredient. For example, a cream or ointment is prepared by mixing a sufficient amount of hydrophilic material with water containing a sufficient amount of about 5 to 10% by weight of the compound to produce the desired concentration of cream or ointment.

Pharmaceutical compositions suitable for rectal administration wherein the carrier is a solid are most preferably unit dose suppositories. Suitable carriers include cocoa butter and other materials conventionally used in the art, and suppositories can be conveniently formed by mixing with softened or molten carriers, followed by cooling and molding.

In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical formulations may be used as suitable components such as diluents, buffers, flavors, binders, surfactants, thickening agents, lubricants, preservatives (including antioxidants), and the like with one or more additional carrier components. It is to be understood that it may include materials included to provide blood and isotonic formulations.

Compositions containing 8a-azalides can also be prepared in powder or liquid concentrate form. According to standard veterinary formulation practice, conventional water soluble excipients such as lactose or sucrose may be incorporated into the powder to improve its physical properties. Accordingly, particularly suitable powders of the invention comprise 50 to 100% w / w of the mixture, preferably 60 to 80% w / w and 0 to 50% w / w, preferably 20 of conventional veterinary excipients To 40% by weight / weight percent. These powders may, for example, be added to animal feed or diluted with animal beverages by intermediate premixing.

Liquid concentrates of the present invention suitably contain a water soluble compound mixture and are combined with a veterinary acceptable water miscible solvent such as polyethylene glycol, propylene glycol, glycerol, glycerol formal or up to 30 volumes / volume of ethanol. Mixed solvents may optionally be included. The liquid concentrate can be added to the drink of the animal.

Pharmaceutical compositions containing 8a-azalides may optionally contain secondary active ingredients, biological ingredients such as antigens, or dietary supplements such as minerals or vitamins. Active ingredients include immunomodulators such as interferon, interleukin and other chemokines, propionic acid derivatives (e.g. ibuprofen, ketoprofen, naproxen, benoxpropene, caprophene), acetic acid derivatives (e.g. acemethacin, alclofenac , Clidanac, diclofenac, fenclofenac, fencloxaic acid, pentiazac, purofenac, ibufenac, isoxepac, oxpinac, sulindac, thiopinac, tolmetin, zidomethacin and jomepilac) Non-steroidal anti-inflammatory drugs and cyclooxygena, such as namic acid derivatives (e.g. flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolphenamic acid), biphenylcarboxylic acids (e.g. diflufenisal, flufenical) Second (COX-2) inhibitors and antiparasitic agents such as avermectin, ivermectin, milbimicin, levamizol, benzimidazole, pyrantel / morantel. Biological agents include infectious bovin rhinotracheitis, bovine viral diarrhea, respiratory syncythial virus, parainfluenza, infectious gastrointestinal disease, porcine reproductive and respiratory syndrome, rotavirus and It is a vaccine commonly used in the livestock industry against coronaviruses. Dietary supplements may be vitamins, iron, selenium, and the like.

The following examples are provided to more fully illustrate the present invention and should not be construed as limiting the claims in any way.

In Vitro Activity of 8a-Azalides

Antimicrobial activity against a number of representative pathogens of representative 8a-azalide is determined by the minimum inhibitory concentration (MIC) method, which is well known in the art. This is done by preparing a series of culture tubes each containing a medium with sufficient concentration of antimicrobial agent and inoculating all tubes with the same organism. The minimum concentration of preparation that completely prevents clouding is recorded and this concentration is called MIC.

4 "-deoxy-4" -amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A, 4 "-deoxy-4" (R) -amino-9-deoxo- 8a-aza-8a-methyl-8a-homoerythromycin A, 4 "-deoxy-4" (S) -amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A and 4 The range of antimicrobial activity against the major number of organisms of "-deoxy-4" -amino-9-deoxo-8a-aza-8a-allyl-8a-homoerythromycin A is summarized below:

organism MIC range (µg / ml) Pasteurella Hemortica 0.125-0.5 Paste Pasteurella 0.125-0.5 Haemophilus somnus 0.125-0.250 Actinobacillus pluronomonia 0.062-0.125 this. Coli 0.5-2 Salmonella spp. 0.5-4

Claims (19)

Treating or preventing bacterial respiratory infections or intestinal infections in animals, including administering a therapeutically or prophylactically effective amount of 8a-azalide to a livestock in need of treatment or prevention of bacterial respiratory infections or intestinal infections Way. The compound of claim 1, wherein the 8a-azalide is a compound of formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable metal complex thereof, wherein the metal complex is from a group consisting of copper, zinc, cobalt, nickel and cadmium Is chosen). Formula I In Formula I above, R ¹ is hydrogen; Hydroxy; C _1-4 alkoxy; Formyl; C _1-10 alkylcarbonyl, C _1-10 alkoxycarbonyl, aryloxycarbonyl, C _1-10 aralkoxycarbonyl, C _1-10 alkylsulfonyl or arylsulfonyl, wherein a C _1-10 alkyl group Is substituted with one to three halo (F, Cl, Br), hydroxy, amino, C _1-5 acylamino or C _1-4 alkyl groups); Or unsubstituted or substituted C _1-10 alkyl, C _2-10 alkenyl or C _2-10 alkynyl, wherein the alkyl chain is one or two oxa, thia, or a chemical formula, An aza of NR—, wherein R is hydrogen or C _1-3 alkyl, and the substituents are independently one to three halo (F, Cl, Br, I), C _1-4 alkyl, Aryl or heteroaryl optionally substituted with C _1-3 alkoxy, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino or hydroxy (a), unsubstituted or hydroxy, amino, C _1- Heterocyclyl (b), halo (F, Cl, Br or I substituted with ₄ alkylamino, di (C _1-4 alkyl) amino, C _1-4 alkylcarbonyloxy or C _1-4 alkylcarbonylamino ) (c), unacylated or group R ^a C (= 0) or R ^b S (O) ₂ , where R ^a is hydrogen, C _1-6 alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl and, R ^b is C _1-6 alkyl or A reel) to the acylated hydroxy (d), C _1-10 alkoxy (e), unsubstituted or one to three halo, hydroxy, amino, or C _1-4 aryl optionally substituted by alkyl group or heterocyclic-oxy Aryloxy (f), amino not acylated or acylated with R ^a C (= 0), R ^a OC (= 0) or R ^b SO ₂ , wherein R ^a and R ^b are as defined above; or C _1-10 alkylamino (g), di (C _1-10 alkyl) amino (h), arylamino, heteroarylamino, aralkylamino or heteroarylalkylamino wherein the aryl or heteroaryl group is unsubstituted or Substituted with one to three halo, hydroxy, amino or C _1-4 alkyl groups) (i), mercapto (j), C _1-10 alkylthio, alkylsulfinyl or alkylsulfonyl, arylthio, Arylsulfinyl or arylsulfonyl, wherein the aryl group is unsubstituted or one to three halo, hydroxy, amino or C _{1 -4} is replaced with an alkyl group) (k), formyl (l), C _1-10 alkylcarbonyl (m), arylcarbonyl, heteroaryl-carbonyl, aralkyl carbonyl, or heteroarylalkyl carbonyl (where , Aryl or heteroaryl group is unsubstituted or substituted with one to three halo, hydroxy, amino or C _1-4 alkyl groups) (n), carboxy (o), C _1-10 alkoxycarbonyl (p ), Aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl or heteroarylalkoxycarbonyl, wherein the aryl or heteroaryl group is unsubstituted or one to three halo, hydroxy, amino or C _{1- 4} is replaced by an alkyl group) (q), N atom is optionally substituted with one or two C _1-6 alkyl groups or C _4-6 alkylene swaero substituted carbamoyl or sulfamoyl (r), cyano (s ), with isonitrile (t), nitro (u), azido (v), is optionally substituted with nitrogen or carbon is C _1-10 Kilos and substituted imino-methyl (w), oxo (x) and T, Ono (y) one to three of the dog], R ² and R ³ are independently hydrogen, C _1-10 alkyl or aryl, or together oxo or thiono, R ⁴ and R ⁵ are independently hydrogen or alkylcarbonyl, or together carbonyl, R ⁴ and R ¹ are C _1-3 alkylene unsubstituted or substituted with oxo groups, R ⁶ and R ⁷ are both hydrogen, One of R ⁶ and R ⁷ is hydrogen and the other is hydroxy or an acyloxy derivative selected from the group consisting of formyloxy, C _1-10 alkylcarbonyloxy, arylcarbonyloxy and aralkylcarbonyloxy or —NHR ¹² (wherein R ¹² is hydrogen, arylsulfonyl or heteroarylsulfonyl unsubstituted or substituted with one to three halo or C _1-3 alkyl groups), alkylsulfonyl or -C (= 0)- XAR ¹³ wherein X is a linking bond, O or NH, A is a linking bond or C _1-3 alkylene, R ¹³ is hydrogen, C _1-10 alkyl, aryl, aralkyl, heteroaryl, heterocyclyl Or C _3-7 cycloalkyl, the non-hydrogen group of the R ¹³ groups is one or more halogen, hydroxyl, C _1-3 alkoxy, cyano, isonitrilo, nitro, amino, mono (C _1-3 ) alkylamino, di (C _1-3) alkylamino, mercapto, C _1-3 alkylthio, C _1-3 alkylsulfinyl , C _1-3 alkylsulfonyl, arylthio, aryl sulfinyl, sulfamoyl, arylsulfonyl, carboxy, carbamoyl, C _1-3 which may be substituted with alkylcarbonyl or C _1-3 alkoxycarbonyl), and , R ⁶ and R ⁷ together are oxo, hydroxyimino, alkoxyimino, aralkoxyimino or aminoimino, R ⁸ is methyl, aralkoxycarbonyl or arylsulfonyl, R ⁹ is hydrogen, formyl, C _1-10 alkylcarbonyl, C _1-10 alkoxycarbonyl or arylalkoxycarbonyl, R ¹⁰ is hydrogen, R ¹⁰ and R ¹ are C _1-3 alkylene unsubstituted or substituted with oxo groups, m and n are independently 0 or 1. The compound of claim 2, wherein 8a-azalide is n and m is 0 and R ¹ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or arylsulfonyl, wherein Alkyl and alkenyl are optionally substituted with halo, hydroxy, cyano, C _1-10 alkoxycarbonyl, amino, C _1-10 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 hydroxyl, C _1-10 alkylcarbonyloxy, aralkyl-carbonyl-oxy, amino, C _1-10 alkyl-carbonyl amino, arylcarbonyl, aryl C _1-10 alkylcarbonyl, C _1-10 alkoxycarbonyl, aryl C _1-10 alkoxycarbonyl substituted with, Wherein the compound of formula I is selected from heteroarylcarbonyl, heteroarylalkylcarbonyl and arylsulfonyl, and R ⁸ is methyl. The compound of claim 2, wherein 8a-azalide is n and m is 0 and R ¹ is methyl, ethyl, propyl, allyl, propargyl, 2-cyanoethyl, 2-hydroxyethyl, 3-hydroxy Propyl, 2-methoxycarbonylethyl, 2-benzyloxycarbonylethyl, cyanomethyl, 2-aminoethyl, 2- (dimethylamino) ethyl, 2-fluoroethyl, 2-fluoroallyl, benzyl or oxy Is ranylmethyl, R ² , R ³ , R ⁴ , R ⁵ , R ⁹ and R ¹⁰ are hydrogen, one of R ⁶ and R ⁷ is hydrogen, the other is hydroxy or amino, and R ⁸ is methyl The method is a compound of I. The method of claim 4, wherein R ¹ is methyl, ethyl, propyl, allyl, 2-methoxycarbonylethyl or 2- (dimethylamino) ethyl. The method of claim 1, wherein the bacterial infection is a respiratory infection of cattle or pigs. The method of claim 6, wherein the respiratory infection is caused by Pasteurella spp., Actinovacillus spp., Haemophilus somnus or Mycoplasma spp. The method of claim 2, wherein the bacterial infection is a respiratory infection of cattle or pigs. The method of claim 8, wherein the respiratory infection is caused by Pasteurella spp., Actinobacillus spp., Haemophilus somnus or Mycoplasma spp. The method of claim 3, wherein the bacterial infection is a respiratory infection of cattle or pigs. The method of claim 10, wherein the respiratory infection is caused by Pasteurella spp., Actinovacillus spp., Haemophilus somnus or Mycoplasma spp. The method of claim 4, wherein the bacterial infection is a respiratory infection of cattle or pigs. The method of claim 12, wherein the respiratory infection is caused by Pasteurella spp., Actinobacillus spp., Haemophilus somnus or Mycoplasma spp. The method of claim 5, wherein the bacterial infection is a respiratory infection of cattle or pigs. The method of claim 14, wherein the respiratory infection is caused by Pasteurella spp., Actinobacillus spp., Haemophilus somnus or Mycoplasma spp. The method of claim 1, wherein the bacterial infection is enteric infection of a bovine or swine. The method of claim 16, wherein the intestinal infection is E. coli. A disease caused by E. coli, treponema hyodicenteri or Salmonella spp. The method of claim 2, wherein the bacterial infection is intestinal infection of a bovine or swine. The method of claim 18, wherein the intestinal infection is E. coli. A disease caused by E. coli, treponema hyodicenteri or Salmonella spp.