NO312746B1 - Use of an 8a-azalide for the manufacture of a medicament for the treatment or prevention of infections in domestic animals - Google Patents

Abstract

α-azalides are useful in the treatment and prevention of bacterial respiratory and enteric infections in domestic animals, in particular in cattle and pigs.

Description

Summary of the invention

The present invention relates to the use of an 8a-azalide for the production of a drug for the treatment or prevention of bacterial respiratory or enteric infections in livestock.

Background for the invention

The morbidity and mortality associated with bacterial respiratory and enteric infections in livestock represent an extensive economic loss within the agricultural industry. In cattle, especially in younger animals, stress as a result of weaning, transport, dehydration, change or deprivation of diet can make the animals very susceptible to bacterial respiratory infection, especially if the animals are kept in overcrowded or poorly ventilated stalls. The principal causative bacterial pathogens for bovine respiratory infections are Pasteurella haemolytica, P. multocida, Haemophilus somnus and Mycoplasma spp. In pigs, respiratory infections are caused by Pasteurella multocida or Actinobacillus pleuropneumoniae, and Mycoplasma spp. are associated with significant losses in some herds. The most common causative organisms for enteric diseases in cattle and pigs are Escherichia coli, Treponema hyodysenteriae and Salmonella spp.

The current therapeutic antimicrobial products against respiratory and enteric infections in livestock include a disparate group of older products that are effective against a wide range of infectious agents, and most prominent among this group are the tetracyclines; and a group of newly introduced products primarily indicated for the treatment of respiratory disease in cattle, such as quinolones (danofloxacin, enrofloxacin), cephalosporins (cefkinome, ceftiofur), macrolide (tilmicosin) and florfenicol. Resistance to the older antimicrobial agents has developed in the area. Although resistance to newer products is not a problem so far, it is known that excessive use favors the appearance of resistance over time, but increasing the number of drug families, and thus the mechanisms of action, in use may reduce the likelihood of developing resistance to any individual compound. There is thus a continuous need to find new antimicrobial compounds suitable for use in veterinary medicine, and preferably such compounds will belong to a different chemotype from the antimicrobial agents currently in use in animal or human medicine. Other desirable characteristics of a new antimicrobial product for veterinary use include high potency against the target organisms, high target tissue concentration, and long tissue and plasma half-lives.

8a-azalides are antibiotics that are characterized by a 15-membered lactone ring containing a ring nitrogen atom. A group of 8a-azalides is described in European patent application 508 699 as having an antibacterial spectrum similar to that of erythromycin, and which is active in vitro against gram-positive and gram-negative bacteria, including E. coli and H. influenzae. However, EP 508 699 does not describe the use of 8a-azalides for the treatment and prevention of bacterial respiratory or enteric infections in livestock. Furthermore, there is no assumption that the 8a-azalides should have antibacterial activity against the usual causative organisms for cattle and bacterial respiratory and enteric infections in pigs.

Detailed description of the invention

The present invention provides the use of 8a-azalides for the treatment or prevention of bacterial respiratory or enteric infections in a domestic animal, which comprises administering to a domestic animal in need of such treatment or prevention, a therapeutically or prophylactically effective amount of an 8a-azalide.

The 8a-azalide is characterized by formula I:

or a pharmaceutically acceptable salt thereof,

R<1> is methyl, ethyl, propyl, allyl, propargyl;

R<2>, R<3>, R<4,><R5,><R9> and R<10> are hydrogen;

one of R<6> and R<7> is hydrogen and the other is hydroxy or amino;

R<8> is methyl, for the preparation of a medicament for the treatment or prevention of bacterial respiratory or enteric infection in a domestic animal, in which the infection is caused by Pasteurella haemolytica, P. multocida, Haemophilus somnus, Actinobacillus pleuropneumoniae and Salmonella spp.

It is preferred that 8a-azalides are used in which Ri is methyl, ethyl, propyl or allyl. Furthermore, it is preferred that the drug produced according to the present application is used in the treatment or prevention of respiratory infection in cattle or pigs.

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

The 8a-azalides are here named as derivatives of erythromycin A, namely as derivatives of 9-deoxo-8a-aza-8a-homoerythromycin A.

The term "therapeutically or prophylactically effective amount" means that amount of an 8a-azalide which will provide a level of antibacterial activity at the target site of infection sufficient to inhibit the bacteria in a manner that enables the host animal to overcome or be protected against the infection. .

"Treatment or prevention" means the application of 8a-azalide after or before the manifestation of signs and symptoms indicative of bacterial infection to enable the host animal to overcome or be protected from the infection.

"Bacterial respiratory or enteric infections" means infections of the respiratory or digestive tract for which the causative organism or probable causative organism is sensitive to 8a-azalide. Such organisms include, but are not limited to, Pasteurella species (e.g., P. haeolytica, P. multocida), Haemophilus somnus, Actinobacillus pleuropneumoniae, Mycoplasma spp., E. coli, Treponema hyodysenteriae, and Salmonella spp. (e.g. eg S. typhimurium, S. dublin).

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable, non-toxic acids including inorganic acids and organic acids. Such 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, methanesulfonic acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid , tartaric acid, p-toluenesulfonic acid and the like. In particular, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid can be used.

8a-azalides are either known compounds such as those described in European application 508 699, or they can be prepared using known methods from readily available starting materials.

Examples of 8a-azalides are as follows: 4"-deoxy-4"-amino-9-deoxo-8a-aza-8a-methyl-8a-homoerythromyein

A; 4 11 -deoxy-4"-(S)-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-amino-9-deoxo-8a-aza-8a-allyl-8a-homoerythromycin

A;

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

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

A

8a-azalides can be administered to a host in need of treatment or prevention of bacterial respiratory or enteric diseases in a similar manner to that used for other antibacterial agents, for example 8a-azalides can be administered parenterally, orally, topically or rectally. The dose administered will vary according to the particular compound employed, the infectious organism involved, the particular host, the severity of the disease, the physical condition of the host and the chosen route of administration, and the appropriate dose can be readily determined by one skilled in the art. For the treatment of bacterial diseases, the oral dose may vary from 1 mg/kg to 1,000 mg/kg, and the parenteral dose may vary from 0.01 mg/kg to 500 mg/kg. For prophylactic use in animals can

the oral dose can vary from 1 mg/kg to 1,000 mg/kg, and the parenteral dose can vary from 0.01 mg/kg to 500 mg/kg. The 8a-azalides according to the present application can preferably be administered parenterally in a dose range of approx. 0.1 to approx. 10 mg/kg.

The 8a-azalides are preferably used in a pharmaceutical preparation comprising the active ingredient and an inert pharmaceutically acceptable carrier. According to the present invention, an 8a-azalide is used as an active ingredient for the production of a drug which can also contain a pharmaceutically acceptable carrier and possibly other therapeutic ingredients. The formulations include preparations suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the particular host, the nature and severity of the conditions for which the active ingredient is administered. The pharmaceutical preparations can conveniently be presented in unit dosage form and prepared by any of the methods that are well known in the pharmaceutical field.

In practical use, the 8a-azalide can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can assume a large number of forms depending on the form of the desired preparation for administration, e.g. oral or parenteral (including intravenous, intramuscular and subcutaneous), and generally parenteral administration is preferred.

When preparing the preparations for oral dosage form, any of the usual pharmaceutical agents can be used. By e.g. oral, liquid preparations such as suspensions, elixirs and solutions, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes and the like can be used, and in the case of oral, solid preparations such as powders, capsules and tablets, carriers such as such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, breaking agents and the like, are included. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are of course used. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. In addition to the usual dosage forms as indicated above, 8a-azalides can also be administered in controlled release agents and/or with delivery devices.

According to the present application, a medicament suitable for oral administration can be prepared which can be presented as separate units such as capsules, powder capsules or tablets, each containing a predetermined amount of active ingredient, as a powder or granules or as a solution or suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil-liquid emulsion. Such preparations may be prepared by any of the methods in the pharmaceutical art, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In general, the preparations are prepared by uniform and intimate mixing of the active ingredient with liquid carriers or finely divided solid carriers or both, after which, if necessary, the product is shaped into the desired presentation. For example, a tablet can be produced by compression or molding, possibly with one or more auxiliary ingredients. Compressed tablets can be prepared by compression, in a suitable machine, of the active ingredient in a free-flowing form such as powder or granules, possibly mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets may be prepared by molding in a suitable machine, from a mixture of the powdered compound moistened with an inert liquid diluent. Advantageously, each tablet contains from approx. 1 mg to approx. 500 mg of the active ingredient, and each powder capsule or capsule contains from approx. 1 to approx. 500 mg of the active ingredient.

According to the present application, a drug suitable for parenteral administration can be prepared and which can be prepared as solutions or suspensions of these active compounds in water appropriately mixed with a surfactant such as hydroxypropyl cellulose. 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 growth of microorganisms.

The 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 stable and fluid to the extent that easy sprayability exists. It must be stable under the manufacturing and storage conditions and must be preserved against the contaminating effect of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing e.g. 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 can be prepared via conventional methods containing the active ingredient. By way of illustration, a cream or ointment is prepared by mixing sufficient amounts of hydrophilic material and water, containing from 5-10% by weight of the compound, in sufficient amounts to provide a cream or ointment having the desired consistency.

Pharmaceutical preparations suitable for rectal administration in which the carrier is solid are most advantageously presented as unit suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may conveniently be formed by mixing the combination with the softened or molten carrier, followed by cooling and forming into molds.

It should be understood that in addition to the above

carrier components, the pharmaceutical formulations described above, can appropriately include one or more additional carrier components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including

antioxidants) and the like, and substances included for the purpose of making the formulation isotonic with the blood of the intended recipient.

Preparations containing an 8a-azalide can also be produced 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 powders to improve their physical properties. A particularly suitable powder thus comprises 50 to 100% by weight, and preferably 60 to 80% by weight of the combination and 0 to 50% by weight and preferably 20 to 40% by weight of conventional veterinary excipients. These powders can either be added to animal feed, e.g. using an intermediate premix, or diluted in the animal's drinking water.

Liquid concentrates suitably contain a water-soluble compound combination and may optionally include a veterinary acceptable water-miscible solvent, e.g. polyethylene glycol, propylene glycol, glycerol, glycerol formal or such a solvent mixed with up to 30% v/v ethanol. The liquid concentrates can be administered to the animals' drinking water.

A pharmaceutical preparation containing 8a-azalide may optionally contain a second active ingredient, a biological component such as an antigen, or a dietary supplement such as minerals or vitamins. Active ingredients may include immunomodulators such as interferon, interleukins and other chemokines, non-steroidal anti-inflammatory agents such as propionic acid derivatives (eg ibuprofen, ketoprofen, naproxen, benoxprofen, carprofen), acetic acid derivatives (eg acemetacin, alclofenac, clidanac , diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, thiopinac, tolmetin, zidomethacin and zome-pirac), phenamic acid derivatives (e.g. flufenamic acid, meclo-fenamic acid, mefenamic acid, nuflumic acid and tolfenamic acid), biphenylcarboxylic acids (eg, diflufenisal, flufenisal), and cyclooxygenase-2 (COX-2) inhibitors, and antiparasitic agents such as avermectin, ivermectins, milbemycins, leva-misol, benzimidazoles, pyrantel/morantel. Biological agents can be vaccines commonly used in the agricultural industry against infectious bovine rhinotracheitis, bovine viral diarrhoea, respiratory syncytial virus, parainfluenza, transmissible gastroenteritis, porcine reproductive and respiratory syndrome, rotavirus and coronavirus. Dietary supplements can be vitamins, iron, selenium and the like.

In vitro activity of 8a-azalides

The antibacterial activity of representative 8a-azalides against a selection of veterinary pathogens was determined by the minimum inhibitory concentration (MIC) method well known in the art. This was done by preparing a series of culture tubes, each containing a medium with a different concentration of the antimicrobial agent, and inoculating all the tubes with the same organism. The lowest concentration of agent which completely prevents the appearance of turbidity is recorded, and this concentration is called the MIC.

The range of antibacterial activity of 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"-deoxy-4"- amino-9-deoxo-8a-aza-8a-allyl-8a-homoerythromycin A against key organisms in veterinary medicine is summarized below:

Claims (3)

1. Use of an 8a-azalide of formula I: or a pharmaceutically acceptable salt thereof, wherein n and m are zero; R<1> is methyl, ethyl, propyl, allyl, propargyl; R<2>, R<3>, R<4,><R5,><R9> and R<10> are hydrogen; one of R6 or R<7> is hydrogen and the other is hydroxy or amino; R is methyl, for the manufacture of a medicament for the treatment or prevention of bacterial respiratory or enteric infection in a domestic animal, wherein the infection is caused by Pasteurella haemolytica, P. multocida, Haemophilus somnus, Actinobacillus pleuropneumoniae and Salmonella spp. 2. Use according to claim 1, in which R<1> is methyl, ethyl, propyl, allyl. 3. Use according to claims 1-2, in which the specified bacterial infection is a respiratory infection in cattle or pigs.