PT1011689E - Use of 9a-azalides as veterinary antimicrobial agents - Google Patents

Description

9A-AZALIDES AS ANTIMICROBIAL AGENTS "

SUMMARY OF THE INVENTION The present invention provides the use of 9a-azalides for the manufacture of a medicament for the treatment or prevention of respiratory or enteral bacterial infections in farmed animals.

BACKGROUND OF THE INVENTION Morbidity and mortality associated with respiratory or enteral bacterial infections in farm animals represent a significant economic loss for the livestock industry. In the case of livestock, especially in young animals, stress due to weaning, transport, dehydration, dietary alteration or deprivation of food can cause a high susceptibility of the animals to respiratory bacterial infection, especially if the animals are housed in crowded or weak facilities ventilated The bacterial pathogens that are the main cause of bovine respiratory infections are Pasteurella Haemolytica, P. multocida, Haemophilus somnus and Mycoplasma spp. In pigs the respiratory infections caused by Pasteurella multocida or Actlnobaclllus 2 ΡΕ1011689 pleuropneumoniae, and Mycoplasma spp. are associated with considerable losses in some rods. The most common organisms that cause enteric diseases in cattle and pigs are Escherichia coli, Treponema Hyodysenteriae and Sal-monella spp.

Current antimicrobial therapeutics against respiratory and enteric infections in farm animals include a diverse group of older products effective against a broad spectrum of infectious agents, notably tetracyclines in this group; and a recently introduced group of products indicated primarily for the treatment of respiratory diseases in cattle, such as quinolones (danofloxacin, enrofloxacin), cephalosporins (cefquinoma, ceftiofur), macrolides (tilmicosin), and florfenicol. Resistance to older antimicrobial agents has developed in the field. Although resistance to newer products is not yet a problem, it is known that excessive use favors the emergence of resistance over time, but the increase in the number of families of drugs, and hence their mechanisms of action, in may decrease the likelihood of developing resistance to an individual compound. Thus, there is a continuing need for the discovery of antimicrobial compounds that are suitable for use in veterinary medicine; preferably, such a compound will belong to a different chemotype of the antimicrobial agents currently in use in animal or human medicine. Other desirable features of a novel antimicrobial veterinary product include high potency against target organisms, high concentration in target tissue, and high tissue half-life.

9a-azalides are antibiotics which are characterized by having a 15-membered lactone ring containing one nitrogen atom in the ring. 9a-azalides are shown, for example, in U.S. Patent 4,328,334, U.S. Patent 4,517,359, U.S. Patent 4,474,768, U.S. Patent 4,464,527, U.S. 4,526,889, U.S. Patent 4,465,674, U.S. Patent 4,492,688, U.S. Patent 4,512,982, U.S. Patent 4,518,590, U.S.

European Patent No. 136,831, European Patent Application No. 259,789, European Patent Application No. 316,128, European Patent Application No. 467,331, European Patent Application No. 606,062, and European Patent Application No. 657,464.

US Patents 4,464,768, 4,464,527 and 4,526,889, respectively, have azithromycin and N-ethyl and N-propyl homologs of azithromycin, and 4 "-epi-azithromycin which are said to be active against Pasteurella multocida in vitro; however, the patents also state that in relation to compounds disclosed therein, their in vivo activities are more limited in relation to susceptible organisms. To the knowledge of the Applicant, known 9a-azalides have not been reported to be chemically useful in the treatment and prevention of respiratory or enteral infections of cattle or swine. 4 ΡΕ1011689

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention relates to the use of a therapeutically or prophylactically effective amount of a 9a-azalide for the manufacture of a medicament for the treatment or prevention of a bacterial respiratory infection in cattle or pigs caused by Actinobacillus spp., Haemophilus somnus or Mycoplasma spp. or an enteric infection caused by Treponema hyodysenteriae in farm animals, wherein 9a-azalide has the formula I:

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, wherein said metal is selected from the group consisting of copper, zinc, cobalt, nickel and cadmium; Wherein R 1 is: hydrogen; C1-3 alkyl optionally substituted by hydroxy, C1-3 alkoxy, cyano, C1-3 alkoxycarbonyl, halogen, amino, C1-3 alkylamino, or di (C1-3 alkyl) amino; or allyl; or propargyl; and one of R2 and R3 is hydrogen and the other is hydroxy, or -NH2.

In a preferred embodiment, the 9a-azalide is selected from azithromycin, 4 "-epi-azithromycin, 4" -deoxy-4 "-aminoazithromycin, and 4" -epi-4 "-deoxy-4 ' '-aminoazithromycin.

In another preferred embodiment, the use is for treatment.

In yet another preferred embodiment, the use is for prevention.

In another preferred embodiment, said bacterial infection is a respiratory infection of cattle or swine.

In a particularly preferred embodiment, Actinobacillus spp. is Actinobacillus plueropneu-moniae.

In yet another preferred embodiment, said bacterial infection is an enteric infection of cattle or swine.

In another preferred embodiment, the infections are bovine.

In yet another preferred embodiment, the infections are swine.

In another preferred embodiment, the medicament is for parenteral administration.

In a particularly preferred embodiment, the dosage range is from 0.01 mg / kg to 500 mg / kg.

In another particularly preferred embodiment, the dosage range is from 0.1 mg / kg to 10 mg / kg.

9a-azalides are referred to herein as azithromycin derivatives, which is 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A. The term " therapeutically or prophylactically effective amount " means an amount of a 9a-azalide which provides a level of antibacterial activity at the target site of the infection which is sufficient to inhibit the bacterium in a manner that allows the host animal to overcome or protect itself from infection. " Treatment or prevention " means the use of 9a-azalide after or before the onset of two signs and symptoms that suggest a bacterial infection that allows the host animal to overcome or protect itself from infection. " Bacterial respiratory or enteric infections " means infections of the respiratory or digestive tract for which the causative organism or probable causative organism is susceptible to 9a-azalide. Such organisms include, but are not limited to, Haemophilus somnus, Actinobacillus pleuropneumoniae, Mycoplasma spp., Treponema hyodysenteriae. The term " pharmaceutically acceptable salts " refers to salts prepared from non-toxic pharmaceutically acceptable acids including inorganic acids and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, galactaric, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acids. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. 8 ΡΕ1011689

9a-azalides are either known compounds, such as those disclosed in the patents or the published patent applications cited above, or may be prepared from readily available starting materials using conventional chemical synthesis methods.

9a-azalides may be administered to a host in need of treatment, or prevention of bacterial respiratory or enteral disease in a manner similar to that used for other antibacterial agents; for example, 9a-azalides may be administered parenterally, orally, topically or rectally. The dosage to be administered varies according to the particular compound used, the infectious organism involved, the particular host, the severity of the disease, the physical state of the host, and the selected route of administration; the particular dosage can be readily determined by one skilled in the art. For the treatment of bacterial diseases, the oral dosage may range from 1 mg / kg to 1000 mg / kg; and the parenteral dosage may range from 0.01 mg / kg to 500 mg / kg. The 9α-azalides of the present invention are preferably administered parenterally at a dosage in the range of about 0.1 to about 10 mg / kg.

9a-azalides are preferably used in a pharmaceutical composition comprising the active ingredient ΡΕ 1011689 and a pharmaceutically acceptable inert carrier. The pharmaceutical compositions of the present invention comprise a 9a-azalide as the active ingredient, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The formulations include compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular, and intravenous) administrations, although the most suitable route in a particular case depends on the particular host, and the nature and severity of the condition for which the active ingredient is being administered. The pharmaceutical compositions may conveniently be presented in single dose form and prepared by any of the methods well known in the pharmaceutical art.

In practical use, 9a-azalide may be combined as an active ingredient in an intimate admixture with a pharmaceutical carrier according to standard pharmaceutical formulation techniques. The carrier may take a wide variety of forms depending on the form of the preparation desired for administration, for example, oral or parenteral (including intravenous, intramuscular, and subcutaneous); parenteral administration is generally preferred.

In preparing the compositions for oral dosage form, any of the conventional pharmaceutical media may be used. For example, in the case of oral liquid preparations such as suspensions, elixirs and solutions, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents may be used; or in the case of solid oral preparations such as powders, capsules and tablets, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents may be 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 obviously used. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. In addition to the common dosage forms presented above, 9a-azalides may also be administered by controlled release methods and / or by delivery devices.

Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, pills or tablets each containing a predetermined amount of the active ingredient in the form of a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an emulsion of an oil in water. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of combining the active ingredient with the carrier which constitutes a necessary ingredient (s). In general, the compositions are prepared by adding even and intimate admixture of the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, preparing the product in the desired embodiment. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. The tablets may be prepared by compression in a suitable machine of the active ingredient in a free form such as in powder or granules, optionally mixed with a binder, lubricant, inert diluent, dispersing agent or surfactant. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 1 mg to about 500 mg of the active ingredient and each pill or capsule contains from about 1 to about 500 mg of the active ingredient.

Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of these active compounds in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions may also be made in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under conventional conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. 12 ΡΕ1011689

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 under the conditions of manufacture and storage and must be protected from the contaminating action of micro-organisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a 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 and powder powders. These formulations may be prepared by conventional methods containing the active ingredient. For illustration, a cream or ointment is prepared by mixing sufficient amounts of hydrophilic material and water containing about 5-10% by weight of the compound in amounts sufficient to produce a cream or ointment of the desired consistency.

Pharmaceutical compositions suitable for rectal administration in which the carrier is a solid are most preferably presented in the form of unit doses in suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may conveniently be formed by adding and mixing the combination with the softened or melted carrier (s) 13 ΡΕ1011689 followed by the cooling and molding.

It will be understood that in addition to the above-mentioned carrier ingredients, the pharmaceutical formulations described above may include, if appropriate, one or more carrier ingredients such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants and preservatives (including antioxidants), and substances included for the purpose of rendering the formulation isotonic relative to the patient's blood.

Compositions containing a 9a-azalide in powder or liquid concentrate form may also be prepared. In accordance with the practice of conventional veterinary formulation, conventional water soluble excipients, such as lactose or sucrose, may be incorporated into the powders in order to improve their physical properties. Thus, particularly acceptable powders of this invention comprise 50 to 100% w / w, and preferably 60 to 80% w / w of the combination and 0 to 50% w / w and preferably 20 to 40% w / w of conventional veterinary excipients. These powders may be either added to animal feed, for example by means of an intermediate premix, or diluted in drinking water from the animal.

The liquid concentrates of the invention suitably contain a water-soluble compound combination and may optionally include a water miscible solvent in veterinary acceptable, for example, polyethylene glycol, propylene glycol, glycerol, glycerol formal or one of these solvents mixed with up to 30% v / v ethanol. The liquid concentrates may be administered to drinking water of the animal. The pharmaceutical composition containing 9a-azalide may optionally contain a second active ingredient, a biological component such 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-inflammatories such as propionic acid derivatives (e.g., ibuprofen, ketoprofen, naproxene, benoxaprofen, carprofen), acetic acid derivatives , acemetacin, alclofenac, clidanac, diclo-fenac, fenclofenac, phenolic acid, furofenac, ibufenac, isoxepac, oxepinac, sulindac, thiopinac, tolmetin, zidometacine, and zomepirac), phenamic acid derivatives (for example flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acids (e.g., diflufenisal, flufenisal), and cyclooxygenase 2 (COX-2) inhibitors, and antiparasitic agents such as avermectin, ivermethins, milbemycins, levamisole, benzimidazoles, pyran-tel / morantel. Biological agents may be vaccines commonly used in the livestock industry 15 ΡΕ1011689 against infectious bovine rhinotracheitis, bovine diarrhea virus, respiratory syncytial virus, parainfluenza, transmissible gastroenteritis, swine reproductive and respiratory syndrome, rotavirus and coronavirus.

Dietary supplements can be vitamins, iron and selenium.

The following examples are presented to more fully illustrate the present invention. IN VITRO ACTIVITY OF 9a-azalides

The antibacterial activity of representative 9a-azalides against a set of veterinary pathogens was determined by the Minimum Inhibitory Concentration (MIC) method well known in the art. This is accomplished by preparing a series of culture tubes, each containing a medium with a different concentration of antimicrobial agent, and inoculating all tubes with the same organism. The lowest concentration of agent that completely prevents the onset of turbidity is noted, and at this concentration is called the MIC. The range of antibacterial activity of azithromycin and 4 "-deoxy-4" -aminoazithromycin against key veterinary organisms is summarized below: ΡΕ1011689

Organism CIM Range (g / ml) P. haemolytica 0.125-0.5 P. multocida 0.125-2 H. somnus 0.062-0.25 A. pleuropneumoniae 0.062-0.5 E. coli 0.5-16 Salmonella spp. 1-16

Lisbon, March 2, 2007

Claims (12)

Use of a therapeutically or prophylactically effective amount of a 9a-azalide for the manufacture of a medicament for the treatment or prevention of a bacterial respiratory infection in cattle or pigs caused by Actinobacillus spp., Haemophilus somnus or Mycoplasma spp. or an enteric infection caused by Treponema hyodysenteriae in farm animals, wherein 9a-azalide has the formula I: or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable metal complex thereof, wherein said metal is selected from the group consisting of copper, zinc, cobalt, nickel and cadmium; wherein R 2 is hydrogen; C1-3 alkyl optionally substituted by hydroxy, C1-3 alkoxy, cyano, C1-3 alkoxycarbonyl, halogen, amino, C1-3 alkylamino, or di (C1-3 alkyl) amino; or allyl; or propargyl; and one of R2 and R3 is hydrogen and the other is hydroxy, or -NH2. The use according to claim 1, wherein the 9a-azalide is selected from azithromycin, 4 "-epi-azithromycin, 4" -deoxy-4 "-aminoazithromycin, and 4" -epi-4 ' '-deoxy-4 " -aminoazithromycin. Use according to claim 1 or 2 for treatment. Use according to claim 1 or 2 for prevention. Use according to any preceding claim, wherein said bacterial infection is a respiratory infection of bovine or swine. Use according to claim 5, wherein Actinobacillus spp. is Actinobacillus pluero-pneumoniae. 3 ΡΕ1011689 Use according to any one of claims 1 to 4, wherein said bacterial infection is an enteric infection of cattle or swine. Use according to any preceding claim, wherein the infections are bovine. Use according to any one of claims 1 to 7, wherein the infections are porcine. Use according to any preceding claim, wherein the medicament is for parenteral administration. Use according to claim 10, wherein the dosage range is from 0.01 mg / kg to 500 mg / kg. Use according to claim 11, wherein the dosage range is from 0.1 mg / kg to 10 mg / kg. Lisbon, March 2, 2007