Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention described herein relates to the treatment of a range of bacterial infections in companion animals, in particular cats and dogs, with a ⁇ -lactam derivative, compound of Formula I.
• the invention is also directed to pharmaceutical compositions of a compound of Formula I.
• ⁇ -Lactam antibiotics such as penicillins and cephalosporins
• penicillins and cephalosporins have been known for some time and are the subject of many review articles. See, for example, Harvey, R.G., Hunter, P.A. The properties and use of penicillins in the veterinary field, with special reference to skin infections in dogs and cats.
• cephalosporin derivatives including several incorporating a cyclic ether moiety at the 3-position, were disclosed in International Patent Application publication number WO 92/01696 and by Bateson et al in The Journal of Antibiotics, Feb.1994, vol.47, no.2, at pages 253-256. Various mouse data are also disclosed in the latter paper. A process for preparing the cephalosporins is described in EP1178049A1. These publications are herein incorporated in their entirety.
• the invention is directed to a pharmaceutical composition for treating periodontal diseases in a dog or cat caused by bacterial infections comprising a therapeutically effective amount of a compound of Formula I,
• R 1 is H, a pharmaceutically acceptable cation salt, or an in vivo hydrolysable group capable of generating CO 2 H, and R 2 is C ⁇ alkyl, and a pharmaceutical diluent or carrier.
• the pharmaceutically acceptable cation salt is
• the invention is directed to a pharmaceutical composition for treating opportunistic bacterial infections resulting from (a) a compromised or diminished immunological system, (b) Feline Immunodeficiency Virus (FIV) or (c) cancer chemotherapy in or on a dog or cat comprising a therapeutically effective amount of a compound of Formula I,
• R 1 is H, a pharmaceutically acceptable cation salt, or an in vivo hydrolysable group capable of generating CO 2 H, and R 2 is C ⁇ alkyl, and a pharmaceutical diluent or carrier.
• the invention is directed to a pharmaceutical composition for treating a disease or condition caused by a bacterial infection in a dog or cat comprising a therapeutically effective amount of a compound of Formula I,
• R 1 is H, a pharmaceutically acceptable cation salt, or an in vivo hydrolysable group capable of generating CO 2 H, and R 2 is C ⁇ alkyl, and a pharmaceutical diluent or carrier, with the proviso that if the pharmaceutically acceptable cation salt is Na, Li or K, R 2 is not methyl.
• the disease or condition is a skin, soft tissue or urinary tract bacterial infection.
• the compound of formula I is the Z-isomer.
• R 1 is H, Na + or CH 2 OCOC(CH 3 ) 3 ).
• R 1 is H or CO 2 CH 2 OCOC(CH 3 ) 3 ) and R 2 is methyl.
• the pharmaceutical composition further comprises one or more agents used in the treatment or prophylaxis of disease or in the reduction or suppression of symptoms of such disease.
• one or more of the agents are selected from antiparasitics, antihistamines, antifungals, antibacterials, anti-inflammatories, steroids, antipruritic agents, dietary supplements or emollients.
• the antiparasitics are selected from arylpyrazoles, avermectins, milbemycins, organophosphates or pyrethroids;
• the antihistamines are selected from chlorpheniramine, trimeprazine, diphenhydramine or doxylamine;
• the antifungals are selected from fluconazole, ketoconazole, itraconazole, griseofulvin or amphotericin B;
• the antibacterials are selected from enroflaxacin, marbofloxacin, ampicillin or amoxycillin;
• the anti-inflammatories are selected from prednisolone, betamethasone, dexamethasone, carprofen or ketoprofen; and the dietary supplement is gamma-linoleic acid.
• the invention is directed to a method of treating periodontal disease or an opportunistic bacterial infection in or on a dog or cat, resulting from (a) a compromised or diminished immunological system, (b) Feline Immunodeficiency Virus (FIV) or (c) cancer chemotherapy in or on a comprising administrating a therapeutically effective amount of a compound of Formula I
• R 1 is H, a pharmaceutically acceptable cation salt, or an in vivo hydrolysable group capable of generating CO 2 H, and R 2 is C ⁇ alkyl, effective in treating such a condition.
• the pharmaceutically acceptable cation salt is Na + , K + or Li + .
• the invention is directed to a method of treating a disease or condition caused by a bacterial infection in or on a dog or cat comprising administrating a therapeutically effective amount of a compound of Formula I,
• R 1 is H, a pharmaceutically acceptable cation salt, or an in vivo hydrolysable group capable of generating CO 2 H, and R 2 is C h alky], and a pharmaceutical diluent or carrier, with the proviso that if the pharmaceutically acceptable cation salt is Na, Li or K, R 2 is not methyl, effective in treating such a condition.
• the disease or condition is a skin, soft tissue or urinary tract bacterial infection.
• composition is administered to the dog or cat in a single dose.
• the administration is subcutaneous.
• the therapeutically effective amount of the compound of Formula I is 4mg/kg to 12mg/kg.
• the method provides a duration of treatment activity of at least five days against susceptible pathogens.
• the duration is at least 7 days.
• the method of treating a disease or condition caused by a bacterial infection in or on a dog or cat comprises administrating a therapeutically effective amount of the pharmaceutical composition described above.
• the invention is directed to a kit for treatment or prevention of a bacterial infection or a condition caused or complicated by a bacterial infection, in or on a dog or cat, comprising : a) a pharmaceutical composition as described above; and b) instructions describing a method of using the pharmaceutical composition to treat a bacterial infection or a condition caused or complicated by a bacterial infection, in or on a dog or cat.
• the invention is directed to a method for increasing acute or chronic injection-site toleration in a dog or a cat, comprising administering to a dog or a cat in need thereof a single dose of a therapeutically effective amount of a Formula I
• R 1 is H, a pharmaceutically acceptable cation salt, or an in vivo hydrolysable group capable of generating CO 2 H, and R 2 is d- 4 alkyl, effective in treating such a condition.
• ammonium as used herein means an ammonium moiety optionally substituted with d-e alkyl, optionally substituted by OH; or C 5 . 7 cycloalkyl groups.
• lower alkylamines may be triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl) amine or tris(2-hydroxyethyl)-amine, cycloalkylamines such as dicyclohexylamine or with procaine, dibenzylamine, N,N- dibenzylethylene-diamine, 1-ephenamine, ⁇ /-methylmorpholine, ⁇ /-ethylpiperidine, N- benyzl- ⁇ -phenethylamine, dehydroabietylamine, ⁇ /, ⁇ /-bisdehydro-abietylamine, ethylenediamine, or bases of the pyridine type such as pyridine, collidine, or
• in vivo hydrolysable ester group means a pharmaceutically acceptable ester group that readily breaks down in the human body to leave the parent acid or its salt.
• Suitable ester groups of the type include those described in Bateson et al. (EP0540609B1), hereby incorporated by reference in its entirety.
• suitable in vivo hydrolysable ester groups include acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl, 1 -(cyclohexylcarbonyloxy)prop-l -yl, and (1 -aminoethyl)carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, ⁇ - ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; dialkylaminoalkyl, especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(alkoxycarbonyl)-2-alkenyl groups such as 2-(isobutoxycarbonyl)pent-2-eny
• salts of the carboxy group of the compound of Formula I include metal salts, e.g. aluminum, alkali metal salts such as sodium or potassium, especially sodium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts.
• terapéuticaally effective amount means the dose of a compound of Formula I effective in treating bacterial infections.
• the dose may vary depending upon the dog or cat patient, but generally is about 0.01 to 100 mg/kg of the subject animal's weight.
• a male dog was dosed intravenously with an aqueous solution of Compound I.
• Blood plasma was sampled at times up to 28 days post dosing. Plasma samples were extracted and assayed to determine the concentration by both bioassay and High Pressure Liquid Chromatography ("HPLC") as follows: 1 mL of plasma (or standards of spiked dog plasma) were acidified to a pH of less than 3 with hydrochloric acid, then shaken with 26 mL of ethyl acetate. The layers were separated by centrifugation. 22 mL of the organic layer was transferred into a fresh container and 2.0 mL of 0.1 M phosphate buffer, pH of 7.0, was added. After shaking and centrifugation, the aqueous phase was recovered and assayed.
• HPLC High Pressure Liquid Chromatography
• Plasma samples and appropriate standards were prepared by deproteination by the addition of an equal volume of acetonitrile and centrifugation (3000 r.p.m. for 10 minutes). Supernatant was assayed by a specific HPLC method to determine the concentration ( ⁇ Bondapk -C18 column eluted with acetonitrile- 0.05M sodium acetate pH 5.0, 15:85, at 1.0 mL/min with UV detection at 256nm). Pharmacokinetic parameters were calculated using the program PCNONLIN.
• aqueous phase was removed and used for the assays.
• samples (and standards) were assayed by hole-in-the-plate microbiological bioassay on large plates (200 mL Mueller Hinton agar) seeded with M. luteus.
• Plasma samples were taken at intervals to 35 days post-dosing and the plasma assayed to determine the concentration of the corresponding free acid by HPLC/MS/MS.
• Plasma samples 100 mL were aliquoted into centrifuge tubes, then 400 mL of acetonitrile was added. Following vortexing (60 sec.) and centrifugation (20,800 x g for 10 minutes), 0.450 mL of the supernatant was transferred into clean centrifuge tubes, and evaporated to dryness at approximately 50°C under N 2 .
• Dried samples were reconstituted in 0.100 mL of mobile phase (15/85 v/v acetonitrile/10 mM HCO 2 NH 4 , pH 3.0), vortexed for 1 minute, centrifuged at 3,000 rpm for 2 minutes, and transferred to an autosampler vial. Single replicates of plasma were analyzed by LC-MS/MS for concentration of compound. Sample analysis was performed on a SCI EX API 365 or 3000 HPLC/MS/MS system. The column effluent was connected to a Turbo-ionspray source set at 4500 V. The collision gas was set to a value of 3. Positive ions were generated in the source and sampled through an orifice into the quadrupole mass filter.
• the mass spectrometer was adjusted to monitor the precursor and product ions as follows: m/z 454.0 -> m/z 241.0. Half-life was calculated using pharmacokinetic program WINNONLIN v2.1 and determined to be 8.39 +/- 0.97 days.
• Formula I demonstrates that one administration of an equivalent of about 4-12 mg/kg of Compound I, (e.g. Na salt of compound of Formula I), given by injection ⁇ e.g. intramuscularly, subcutaneously or intravenously), to a cat or dog would advantageously provide an efficacious concentration for 7-21 days.
• Compound I e.g. Na salt of compound of Formula I
• injection e.g. intramuscularly, subcutaneously or intravenously
• the compounds of Formula I have the 2S-stereochemistry in the furan moiety, also referred to as the Z isomer of the "oxime ether".
• the invention is not, however, limited to uses of the pure 2S-enantiomer, and can be effected with efficacious mixtures of the 2S- and 2R-enantiomer, for example, as a racemic mixture (i.e. 1:1 2S:2R).
• the enantiomers may be obtained by classical resolution techniques well-known in the art, or by stereoselective synthesis. Enriched mixtures may be obtained by partial resolution, or partially stereoselective synthesis, or by admixing known amounts of known enantiomeric purity.
• the proportion of 2S-enantiomer in any mixture of 2S and 2R enantiomers, used in accordance with this invention is at least 20%. More preferably the proportion is in the range 50%-100%. Most preferably, the compound is present as a racemic mixture (i.e. 1 :1 2S:2R), or as the substantially pure 2S isomer.
• the compounds of Formula I may be administered by any convenient means for administering an antibiotic, such means being well-known in the art.
• the compounds could be administered orally (e.g. as a prodrug comprising a hydrolysable carboxy-protected ester moiety such as a pivaloyloxymethyl ester moiety) or by any parenteral route such as topically or by injection, in the form of pharmaceutical preparations comprising the compound, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, or prodrug, in a pharmaceutically acceptable dosage form.
• the compositions may be administered at varying doses and times.
• the compounds are preferably employed in the form of a pharmaceutical (including veterinary) formulation comprising a pharmaceutically (including veterinary) acceptable carrier, diluent or excipient and a compound of Formula I.
• a pharmaceutical (including veterinary) formulation comprising a pharmaceutically (including veterinary) acceptable carrier, diluent or excipient and a compound of Formula I.
• the carrier, diluent or excipient may be selected with due regard to the intended route of administration and standard pharmaceutical/veterinary practice.
• Pharmaceutical (including veterinary) compositions comprising the compounds of the invention may contain from about 0.1 percent by weight to about 90.0 percent by weight of the active ingredient.
• the methods by which the compounds may be administered for veterinary use include oral administration (for example of a prodrug or salt of formula I by capsule, bolus, tablet, powder or drench, elixir, solution, paste, suspension, medicated feed or drinking water, or buccally, or sublingually, that may contain flavouring, palatable or colouring agents, and which may be prepared for immediate, delayed-, modified-, sustained-, pulsed-, or controlled-release; topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation, ear tags; by injection (e.g., subcutaneously, intramuscularly or intravenously); as an implant.
• Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice.
• formulations of the compounds of Formula I may contain physiologically-acceptable preservatives (such as those of the "paraben” family, buffering agents, solvents (such as water), and other ingredients used in accordance with standard veterinary practice and with the intended mode of administration.
• physiologically-acceptable preservatives such as those of the "paraben” family, buffering agents, solvents (such as water), and other ingredients used in accordance with standard veterinary practice and with the intended mode of administration.
• the formulations will vary with regard to the weight of active compound contained therein, depending on the species, variety, etc. of animal to be treated, the severity and type of infection and the body weight of the animal.
• typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal.
• the range is 1 to 20 mg per kg, more preferably 4 to 12 mg per kg.
• the veterinary practitioner or the skilled person, will be able to determine the actual dosage which will be suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient, as well as the bacterial species involved.
• the above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
• the compounds may be administered with the animal feedstuff or drink, and for this purpose a concentrated feed or drink additive or premix may be prepared for mixing with the normal animal feed or drink.
• Compounds of Formula I may be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of disease or in the reduction or suppression of symptoms. Examples of such agents, include but are not limited to, antiparasitics, (e.g., antiparasitics, (e.g.
• arylpyrazoles such as fipronil, lufenuron, imidacloprid, avermectins (e.g.abamectin, ivermectin, doramectin and selamectin), milbemycins, organophosphates and pyrethroids); antihistamines (e.g. chlorpheniramine, trimeprazine, diphenhydramine and doxylamine); antifungals (e.g.fluconazole, ketoconazole, itraconazole, griseofulvin and amphotericin B); antibacterials (e.g.
• the invention further provides for uses, etc., of compounds of Formula I and one or more selected compounds from the above list as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases or conditions according to the invention.
• Preferred administration routes are intravenous, subcutaneous or intramuscular injection or topical or oral administration.
• a solution of a compound of Formula I where R 2 is Na, e.g. the compound IA, in water is injected either intravenously, subcutaneously or intramuscularly.
• an oral formulation of a prodrug is preferred, such as a formulation of a compound of formula I where R 2 is pivaloyloxymethyl, such as the compound IB.
• the compounds of Formula I are potent broad spectrum antibiotics, and as such can be used to treat infections and conditions caused by a wide range of bacteria. Particularly of interest are: skin and soft tissue infections, urinary tract and periodontal infections.
• Gram positive and/or Gram negative bacteria such as canine pneumonia, feline pneumonia, canine pyoderma, feline pyoderma, pasteurellosis, pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis associated with infection by Staphylococcus spp. (Staphylococcus intermedius, Staphyloccus aureus), Escherichia coli, Streptococcus spp.
• multocida infections of the oral cavity in dogs and cats associated with infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Immunology (AREA)
• Communicable Diseases (AREA)
• Virology (AREA)
• Oncology (AREA)
• Epidemiology (AREA)
• Molecular Biology (AREA)
• Tropical Medicine & Parasitology (AREA)
• AIDS & HIV (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Cephalosporin Compounds (AREA)

Priority Applications (8)

Applications Claiming Priority (6)

Publications (1)

Family

ID=27256361

Family Applications (1)

Country Status (12)

Cited By (1)

Citations (3)

• 2002
  • 2002-11-13 PL PL02370624A patent/PL370624A1/pl not_active Application Discontinuation
  • 2002-11-13 CA CA002470995A patent/CA2470995A1/en not_active Abandoned
  • 2002-11-13 JP JP2003554278A patent/JP2005524611A/ja active Pending
  • 2002-11-13 EP EP02781498A patent/EP1455900A1/en not_active Withdrawn
  • 2002-11-13 CN CNA028256506A patent/CN1606463A/zh active Pending
  • 2002-11-13 AU AU2002348985A patent/AU2002348985A1/en not_active Abandoned
  • 2002-11-13 IL IL16210302A patent/IL162103A0/xx unknown
  • 2002-11-13 WO PCT/IB2002/004741 patent/WO2003053522A1/en not_active Application Discontinuation
  • 2002-11-13 BR BR0215070-0A patent/BR0215070A/pt not_active IP Right Cessation
  • 2002-11-19 TW TW091133726A patent/TW200301126A/zh unknown
  • 2002-11-28 AR ARP020104593A patent/AR037594A1/es unknown
• 2004
  • 2004-07-15 NO NO20043008A patent/NO20043008L/no not_active Application Discontinuation

Patent Citations (3)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events