TW200301126A - Methods of treating bacterial infections in dogs and cats - Google Patents

Abstract

The invention described herein relates to the treatment of a range of bacterial infections in companion animals, in particular cats and dogs, with a β-lactam derivative, compound of Formula 1. The invention is also directed to pharmaceutical compositions of a compound of Formula I.

Description

20030112B ⑴ Rose, description of the invention (the description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments, and a brief description of the drawings) the scope of the invention The invention described herein relates to the use of p_limonamine Derivatives, compounds of formula I, treat a range of bacterial infections in companion animals, especially dogs and hybrids. The present invention is also directed to a pharmaceutical composition of the compound of formula 丨. NOR2

It's been a while and is the subject of many retrospective literature. See, for example, the properties and use of penicillins in the veterinary field, with special reference to skin, for Harvey, HG ·, HuiUer, and ρ · Α · penicillin. infections in dogs and cats.) Veterinary Dermatology, 10: 3, September 1999; Mason, IS ·, Kietzmann, M. Cephalosporins—Cephalosporins-pharmacological basis for clinical use in veterinary dermatology of clinical use in veterinary dermatology.) Veterinary Dermatology, 10: 3, September 1999; and references therein. 1 Already disclosed in International Patent Application Publication No. WO 92/01696 and disclosed by Bateson et al. In The Journal of Antibiotics, February 1994, Volume 47, Issue 2 'on pages 253-256 Many cephalosporin derivatives include the incorporation of several cyclic ether moieties at the 3-position. In the following pages, also -6- 200301126 _ (2) Description of the Invention Continued pages Reveal the data of various mice. In European Patent No. 1 178049 A1, a method for preparing cephalosporins is described. These publications are incorporated herein by reference in their entirety. SUMMARY OF THE INVENTION In one aspect, the present invention is directed to a pharmaceutical composition for treating periodontal disease caused by bacterial infection in a dog or cat, including a therapeutically effective amount of a compound of formula I,

Where R1 is hydrazone, a pharmaceutically acceptable cationic salt, or a hydrolyzable group in vivo, which can produce CO2H, and 112 is a Cw alkyl group, and a pharmaceutical diluent or carrier-.

In a preferred embodiment, the pharmaceutically acceptable cationic salt is Na +, K + or Li +. In a second aspect, the present invention is directed to treating, in dogs or cats, (a) a lack of resistance or a reduced immune system, (b) feline immunodeficiency virus (FIV), or (c) cancer chemotherapy. Pharmaceutical composition for opportunistic bacterial infections, including a therapeutically effective amount of a compound of formula I, NOR2

200301126 (3) Description of the invention Continuation page where R1 is hydrazone, a pharmaceutically acceptable cationic salt, or a hydrolyzable group in vivo, can produce C02H, and R2 is a CN4 alkyl group, and a pharmaceutical diluent or carrier . In a third aspect, the present invention is directed to a pharmaceutical composition for treating a disease or condition caused by a bacterial infection in a dog or cat, including a therapeutically effective amount of a compound of formula I, NOR2

Where R1 is hydrazone, a pharmaceutically acceptable cationic salt, or a hydrolyzable group in vivo, can produce C02H, and R2 is a Cw alkyl group, and a pharmaceutical diluent or carrier, the limitation is that if the The pharmaceutically acceptable cationic salt is Na, U or K, then R2 is not methyl.

In a preferred embodiment, the disease or condition is a bacterial infection of the skin, soft tissue or urinary tract. In other specific embodiments, R1 is fluorene, alkali metal, alkaline earth metal, ammonium, fluorenyl, p-methoxyfluorenyl, benzamidinemethyl, p-nitrofluorenyl, 4-pyridylmethyl, 2, 2,2-trichloroethyl, 2,2,2-tribromoethyl, tertiary-butyl, tertiary-pentyl, allyl, biphenylmethyl, trityl, adamantyl, 2-benzyloxybenzyl, 4-methylthiophenyl, tetrazine-2-yl, tetrazine citrul-2-yl, pentachlorophenyl, acetone, p-toluenesulfonyl Ethyl, methoxymethyl, silyl, stannyl, or phosphorus-containing groups, fatty groups of formula -N diCHR3, where R3 is aryl or heteroaryl, or ester group that is hydrolysable in vivo group. 200301126 Description of the invention continued (4) In a preferred embodiment, the compound of formula I is the z-isomer. In another preferred embodiment, R1 is fluorene, Na + or CH2OCOC (CH3) 3. In a more specific embodiment, R1 is fluorene or co2ch2ococ (ch3) 3, and R2 is methyl. In other specific embodiments, the pharmaceutical composition further comprises one or more agents for treating or preventing diseases, or reducing or suppressing the symptoms of such diseases.

In a preferred embodiment, one or more of the formulations are selected from antiparasitic drugs, antihistamines, antifungals, antibacterials, anti-inflammatory drugs, steroids, antipruritics, food supplements or lubricants. .

In a more specific embodiment, the antiparasitic agent is selected from the group consisting of arylpyrazoles, avermectins, milbemycins, organophosphates—or pyrethroids Pyrethroids; antihistamines selected from chlorpheniramine, trimeprazine, diphenhydramine or doxylamine; antifungal agents selected from fluconazole Fluconazole, ketoconazole, itraconazole, greoeofulvin, or amphotericin B; the antibacterial agent is selected from enroflaxacin ), Marbofloxacin, ampicillin or amoxycillin; anti-inflammatory drugs are selected from prednisolone, betamethasone, dexamethasone, card Carprofen or ketoprofen; food supplements are γ-linolenic acid. -9- 200301126 Description of the Invention Continued (5) In a fourth aspect, the present invention is directed to treating periodontal disease in dogs or cats or resulting from (a) lack of resistance or reduced immune system (b) cat immunity Method for defective virus (FIV) or (c) opportunistic bacterial infection undergoing chemotherapy for cancer, comprising administering a therapeutically effective amount of a compound of formula I, NOR2

Wherein R1 is hydrazone, a pharmaceutically acceptable cationic salt, or a hydrolyzable group in vivo, can produce CO2H, and R2 is a Cw alkyl group, which is effective in treating such conditions. In a preferred embodiment, the pharmaceutically acceptable cationic salt is Na +, K + or Li +. In a fifth aspect, the present invention is directed to a method for treating a disease or condition caused by a bacterial infection in a dog or cat, comprising administering a therapeutically effective amount of a compound of formula I, NOR2

Where R1 is hydrazone, a pharmaceutically acceptable cationic salt, or a group that can be solved in vivo, can produce C02H, and R2 is a Cw alkyl group, and a pharmaceutical diluent or carrier, the limitation is that if the The pharmaceutically acceptable cationic salt is Na, Li, or K, so R2 is not methyl, and it has the effect of treating 2003301126 in treating such conditions. In a preferred embodiment, the disease or condition is a bacterial infection of the skin, soft tissue or urinary tract. In a more preferred embodiment, the composition is administered to a dog or blessing in a single dose. In other preferred embodiments, the administration is subcutaneous.

In a preferred embodiment, the therapeutically effective content of the compound of formula I is 4 mg / kg to 12 mg / kg. In a more preferred embodiment, the method provides a period of at least 5 days of therapeutic activity against a possible pathogen. In a preferred embodiment, this period is at least 7 days. In other specific embodiments, a method for treating a disease or condition caused by a bacterial infection in a dog or a cat comprises administering a therapeutically effective amount of the above-mentioned pharmaceutical composition.

In a sixth aspect, the present invention is directed to a kit for treating or preventing a bacterial infection, or a condition caused or complicated by a bacterial infection, in a dog or a cat, comprising: a) a pharmaceutical composition as described above; and b) a description In dogs or cats, instructions for using the pharmaceutical composition to treat a bacterial infection, or a condition caused or complicated by a bacterial infection.

In a seventh aspect, the present invention is directed to a method for increasing acute or chronic injection-site tolerance in a dog or cat, comprising administering to a dog or cat in need thereof a single dose of a therapeutically effective amount of formula I

200301126 (7) Description of the invention Continuation page where R1 is hydrazone, a pharmaceutically acceptable cationic salt, or a hydrolyzable group in vivo, can produce C02H, and R2 is a Cw alkyl group, and is used to treat such conditions It is effective. The term "ammonium" as used herein means an ammonium moiety substituted with a Cw alkyl group and optionally with an OH; or C5_7 cycloalkyl group if necessary. For example, the lower carbon number alkylamine may be triethylamine, a hydroxy-low carbon number such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine, or tris (2-hydroxyethyl) _amine. Alkylamines, cycloalkylamines, such as dicyclohexylamine or procaine, difluorenylamine, N, N-difluorenyl · ethylenediamine, 1-ephenamine, N-formyl Molybdenum, N-ethylhexahydrop-pyridine, N-fluorenyl_β-phenylethylamine 'dihydroabietylamine, N, N, -didehydro-abietylamine, ethylenediamine, or p-pyridine Type tests, such as p-bidolide, collidine, or quinone 4, or other amines that have been used to form salts with known penicillins and cephalosporins. Other useful salts include lithium and silver salts. Salts within the scope of the compounds of formula I can be prepared in a conventional manner by salt exchange. The term "hydrolyzable ester group in vivo" means a pharmaceutically acceptable ester group that rapidly disintegrates in the human body, leaving the acid or salt of origin. Suitable types of ester groups include those described in Bateson et al. (European Patent 0540609B1), which is incorporated herein by reference in its entirety. In particular, examples of suitable ester groups that are hydrolysable in vivo include alkoxyalkyl groups such as ethoxymethyl, neopentyloxymethyl, α-ethoxy Ethyl, α-neopentyloxyethyl, 1- (cyclohexylcarbonyloxy-) propan-1-yl, and (1-aminoethyl) carbonyloxymethyl; alkoxycarbonyloxyalkyl Groups-like ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; dialkylaminoalkyl, especially di-lower alkane Aminoalkyl-12- 200301126 (8) Description of the invention Sequels such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2- (Alkoxycarbonyl) -2-fluorenyl groups, like 2- (isobutoxycarbonyl) pent-2-enyl and 2- (ethoxycarbonyl) but-2-enyl; lactone groups, like Are phthalo and dimethoxyphthaloyl; and esters linked to secondary beta-lactam antibiotics or beta-lactamase inhibitors. The hydrolyzable ester group in vivo is preferably neopentyloxymethyl ester. The term "pharmaceutically acceptable salts" of the carboxyl group of a compound of formula I includes metal salts, such as metal salts, metal salts, such as sodium or sodium, especially sodium, alkaline earth metal salts, Like calcium or magnesium, and ammonium or substituted ammonium salts. As used herein, the term "therapeutically effective content" means that the dose of the compound of formula I is effective in treating a bacterial infection. The dose may vary depending on the dog or cat patient, but is usually about 0.01 to 100 mg / kg of experimental animal body weight. Description of the invention It has been determined that compounds of formula I show unexpectedly long half-lives in dogs and cats, especially when compared to comparable antibiotics. For example, Table 1 lists well-known antibiotics and their respective half-lives in different mammals, such as mice, rats, dogs, and mice. -13-200301126 Description of the invention continued (9) Table 1: Half-life compounds of known antibiotics mouse ti / 2 (hour) rat ti / 2 (hour) dog 11/2 (hour) Cefpodoxime 0.68 ( P〇) 1.4 (PO) 2.4 (PO) Ampicillin 0.84 (IM) 0.64 (IM) Cefamandole 0.5 (IM) 0.82 (IV) Cefazolin 0.66 (IM) l.ll ( IV) Cefuroxime 0.32 (SC) 0.4 (IM) 0.93 (IM) Cephalordine 0.5 (IM) 0.97 (IM) Cefurothin 0.208 (IM) 0.4 (IM) 1.06 (IM) Cephadrine 0.82 (PO) 3.64 (PO) Erythromycin 0.65 (IV) 1.27 (IV) 1.72 (IV) Oleandomycin 0.7 (IV) 0.93 ( IV) 1.53 (IV) Taimycin 0.4 (IV) 1.24 (IV)

(Data for cefpod's monthly deficits are from "Abstract of the 1996 ICAAC", abstract 593. All other data are collected from "CRC Handbook of Comparative

Pharmacokinetics and Residues of Veterinary Antimicrobials '', J. Edmond Riviere; Arthur L. Craigmill, Stephen F. Sundlof CRC Press 1991; Route of administration: "IV" = intravenous; "IM" = intramuscular; "P〇" = oral Yueliang ;. "SC ,, = subcutaneous) After administration of the compound of formula I, wherein R1 is COC (CH3) 3, R2 is methyl, and the ether is Z-, the configuration is determined in rats and rats, respectively. The half-life in the medium is about 2.2 hours and about 3.9 hours after oral administration. However, another -14-200301126 description of the invention continued (1〇) L -__ People are unexpectedly in dogs and The half-life in each case increased dramatically, as set out in Table 2 below. 砉 I compounds in the dog and cat species during the plethora species pathway IV Dose [1] Formula I: Z- (methyloxime ether), R1 = half-life 1 mg / kg Na (compound ΙΑ) 6.9 days dog SC 8 mg / kg Na (compound ΙΑ) 4.7 days dog PO 1 g / kg neopentyloxymethyl (compound IB) 6.0 days cat SC ^ mg / Kg —-Na (compound ΙΑ) 6.3 days Note: [1] Expressed as the corresponding free acid Dose: That is, R1 = H. Concentration is measured relative to free acid. Actual, experimental details 1 • Pharmacokinetics> Experiment 1: An intravenously administered dog is administered with an aqueous solution of Compound I and administered intravenously to a male dog. Plasma samples were taken up to 28 days later. Plasma samples were extracted and measured, as determined by both bioassay and high pressure liquid chromatography ("HPLC") as follows: Milliliter of plasma (or standard for stabbing dog plasma) was acidified to a pH below 3 and shaken with 26 mL of ethyl acetate. The layers were separated by centrifugation. The 2 2 liter organic layer was moved to a new Into a container, add 2.0 μl of a phosphate buffer solution, pH 7.0. After shaking and centrifugation, the liquid phase is recovered and measured. After treatment, M. luteus is seeded in large On a culture plate (200 ml of Mueller Hinton agar), measure samples (and standards) by measuring mesoporous microbiological organisms. Also use Hpi: c to measure samples (pBondapk-C18 column, using acetonitrile- 0 · 5M sodium acetate pH 5 0, eluted at 15:85, (Using 256 nm UV detection). 'Get the consistency of Amami' between the two assay methods and use standard pharmacokinetic methods to calculate the half-life from the results of -15-200301126 (11) Continued Bioassay . Experiment 2: Subcutaneous administration The compound of formula I was administered to two dogs by subcutaneous injection. Plasma samples were taken up to 28 days after administration. By deproteinization, plasma samples and appropriate standards were prepared by adding an equal volume of acetonitrile and centrifugation (3000 r.p.m., 10 minutes). The concentration of the supernatant was determined by a dedicated HPLC method (pBondapk-C18 column, 1.0 ml / min, eluted with acetonitrile- 005m sodium acetate 5.0, 15: 85, and 256 nm UV Detection). The pharmacokinetic parameters were calculated using the program PCNONLIN. Experiment 3: Orally administered A compound of formula IB, neopentyloxymethyl-i, was administered orally to 6 隹 dogs, and the resulting plasma concentration was determined by both bioassay and HPLC. A sample of plasma was taken after administration ' at up to 696 hours (29 days). Hydrochloride, plasma samples and appropriate standards (1 ml) were first acidified to a pH below 3.0, and then shaken with 30 ml of ethyl acetate. The layers were separated by centrifugation, and then 25 ml of the organic layer was removed. Add 2.0 ml of 0.1 M phosphate buffer solution pH 7.0 to ethyl acetate, and shake to complete the back extraction. After separation of the layers, the liquid phase was removed and used for the determination. After the treatment, Micrococcus luteus was seeded on a large culture plate (200 ml Mueller Hinton agar), and the measurement sample (and standard) was measured by the microbiological organisms in the hole in the plate. The sample was also measured by HPLC. (PBondapk-C18 column, 1.5 ml for 7 minutes, eluting with acetonitrile-0.05M sodium acetate pH 5.0, 15: 85-, using UV detection at 256 nm). There was perfect agreement between the two assays (r = 0.9971 6); and the half-life was calculated from the bioassay data.

20030112B Continued description of the invention (12) Experiment 4: Cats administered under ancient medicine Compound I was administered subcutaneously to 4 cats at a dose of 8 mg / kg. After administration, blood samples were taken at intervals of 35 days, and plasma was measured. The corresponding free acid concentration was determined by HPLC / MS / MS. Divide the plasma sample (100 ml) into a centrifuge tube and add 400 ml of acetonitrile. After rotation (60 seconds) and centrifugation (20,80xg, 10 minutes), transfer 0.450 ml of the supernatant to a clean centrifuge tube and evaporate to dryness at approximately 50 ° C under N2 . Reconstitute the dehydrated sample with 0 · 100 ml of mobile phase (15/85 vol / vol acetonitrile / 10 mM HC02NH4, pH 3 · 0), rotate for 1 minute, centrifuge at 3,000 rpm for 2 minutes, and move to the autosampler vial. in. A single iteration of the plasma was analyzed by LC-MS / MS for the compound's degree. Sample analysis was performed on a SCIEX API 365 or 3000 HPLC / MS / MS system. The column effluent was connected to a steam-ion spray source set to 4500 volts. Set the collision gas value to 3. Positive ions' are generated in the spray source and sampled through a small hole into a four-stage filter. The mass spectrometer was adjusted to monitor precursor and product ions' as follows: m / z 454.0- > m / z 241.0. The pharmacokinetic program WINNONLIN version 2.1 ’was used to calculate the half-life and determine its 8.39 + /-0.97 days. 2. Efficacy In a model study of experimentally induced skin infection, Staphylococcus intermedius was completely cleared from 5 of 6 dogs 15 days after a single administration of 8 mg / kg of Compound I. = In a separate study, after a single administration of 8 mg / kg of Compound I to healthy dogs, the population of pathogenic staphylococci was significantly reduced compared to untreated control animals by 4 weeks. -17- 200301126

Description of the Continuation Sheet In the model study of experimentally induced abscesses in cats, 14 days after a single administration of 8 mg / kg of Compound I, pasteurella multocida, Clostridium perfringens ( Clostridium perfringens) and Bacteriodes fragilis were substantially reduced. The above semi-periodical results, along with the potency of the compound of formula I, confirm that by injection (for example intramuscularly, subcutaneously or intravenously) to a dog or cat, approximately 12 love; g / kg of compound I (that is, formula I One administration of the equivalent of the compound's Na salt) will advantageously provide effective concentrations up to 7-2 1 day. For veterinarians and cat and dog owners, this also represents a novel and extremely convenient therapeutic approach. It will be noted that the compound of formula I has 2 ^ stereochemistry in the furan moiety, also known as the z-isomer of "oxime ether." However, the invention is not limited to the use of pure 2S-enantiomers, but 2S- And 2R-enantiomers are effective mixtures, such as racemic mixtures (ie 1: 1 2S: 2R). This can be done by the typical decomposition of prostitutes already known in the art, or by stereoselective synthesis, Enantiomers are obtained. Enhanced mixtures can be obtained by partial decomposition, or partial stereoselective synthesis, or by mixing known enantiomeric purity of known content. The 23 and 2R enantiomers used according to the invention The ratio of enantiomers in any of the mixtures is preferably at least 2000/0. More preferably, the ratio is in the range of 5000/0 to 1000/0. Most preferably, the compound Exist in the form of a racemic mixture (ie i: i 2s: 2R), or a substantially pure 2 S isomer. It can be resisted by any administration; Φ 音 的 # 别 古 、 沐 ， & Xijing has been investing compounds of formula 丨 from ambassadors, and such methods are known in the art. It can be taken orally and it is known to be hot. Oral (for example, it includes hydrolysable bases-the part of the purpose of the compliance, such as the new and exhausted, the first 18-18200301126 Description of the Invention Continued (14) Drugs), or by any parenteral route, such as topical, or by injection, in the form of a medicinal product that includes the compound, as needed, in a non-toxic organic or inorganic form The compounds are administered in the form of an acid or base addition salt, or a prodrug, in a pharmaceutically acceptable dosage form. The composition can be administered in various doses and times depending on the condition and patient to be treated, and the route of administration.

Although it is possible to administer the compounds of the present invention directly without any formulation, it is best to formulate them in medicine (including veterinary medicine), including pharmaceutically acceptable (including veterinary) carriers, diluents or excipients. , And the form of a compound of formula I to use the compound. The desired route of administration and standard pharmacological / veterinary habits will be considered to select a carrier, diluent or excipient. A pharmaceutical (including veterinary) composition comprising a compound of the present invention may contain from about 0.1% to about 90.0% by weight of active ingredient.

Methods for administering compounds for veterinary use, including oral administration (eg prodrugs or salts of formula I, via capsules, boluses, lozenges, powders or veterinary medications, elixirs, solutions, pastes , Suspension, medicated feed or drinking water administration), or buccal or sublingual administration, which may contain flavors, flavors, or colorants, and can be prepared for immediate, delayed-, modified -, Sustained-, pulsed- or controlled-release forms; topical administration, such as ointments, pouring solutions, spotting solutions, infusions, sprays, mousse, shampoos, collars or powder formulations , Ear mark; by injection (subcutaneous, intramuscular or intravenous); as an implant. Such formulations can be prepared in a conventional manner in accordance with standard veterinary practice. For example, a formulation of a compound of formula I may contain physiologically acceptable preservatives (such as those of the "paraben" family), buffers, solvents (such as -19-200301126 (15) hydration water ), And the ingredients used depend on the type to be treated 'and the amount, the typical scope of the ingredients is to change the actual agent response in the broadcast, as well as the individual examples of cases, the other kind of treatment is given together-, plus Or premix can be alone or depressive symptoms include but not limited to (fipronil), | ivermectin (mibemycin) chlorpheniramine, such as fluconazole, description of the invention continued on other pages according to standard veterinary practice The species, species, etc. of the animal to be treated with the desired mode of administration, the severity of the infection, and the animal's weight depend on the reconstitution of the active compounds contained therein. For parenteral, local and oral administration, the active dose ranges from 0.01 to 100 mg / kg of animal body weight. It is preferably 1 to 20¾ g / kg ', more preferably 4 to 12 mg / kg. 'Veterinarian or skilled person' will be able to determine the suitability of the individual. Amount of disease 'which can vary with the particular patient's species, age, weight and bacterial species involved. The above doses are average, of course, there may be a range of higher or lower doses which are also within the scope of the present invention. The method of treating animals can be compounded with animal feed or drinking water and for this purpose, concentrated feed or drinking additives can be prepared for mixing with normal animal feed or drinking water. A compound of formula I is administered with one or more agents used to treat or prevent a disease, or to reduce it. Examples of such formulations are in antiparasitic drugs (e.g. arylpyrazoles, such as fluroni L, lufenuron, imidacloprid), and a class of drugs (e.g. abamectin) , Ivermectin, doramectin, and selamectin), organophosphorus and pyrethrum-like); antihistamines (such as alimazine, diphenhydramine, and docetaxel) Lamin); antifungal agents (eg ketoconazole, itraconazole, griseofulvin and amphotericin); anti-20-

(16) 20030112B Describes the continuation of bacterial agents (eg, Enfluoxin I, Mabofloxacin, Ampicillin, and _ Ampicillin); anti-inflammatory drugs such as fetuses & Carprofen and ketoprofen under working pressure) · Gascoxol, betamethasone, dexamethasone, such as r-yafu-you ... or other antipruritic agents; food supplements (example 7 with linoleic acid ); And Yuan, 典, and 丨 compounds and-or more ... Therefore, the present invention also provides the compound of formula 1 as a mixed product, so that according to the present invention, at the same time, ^^^ , The use to treat a disease or condition. Once, the compounds of — ,,, and Zan Yue can be used in a single dose or based on “as required,” a 7 σ

Account for two Α 疋 (that is, 疋 as needed or desired). The preferred route of administration is intravenous, subcutaneous or intramuscular injection, or local or oral administration. Regarding the note, it is said that 1 ^^^, ^^, the defect is an intravenous, subcutaneous, or intramuscular foot formula > Where the king is in the water, the compound of formula I is Na, such as compound IA Foot solution. Extraordinary, Subcutaneous / Wang She. With regard to oral administration, prodrugs (oral formulations are preferred, such as compounds of formula I in which R is neopentyloxymethyl, such as compound IB.) And can be used by itself to treat by other interest is : Skin is of particular interest,

Compounds of formula I are effective, broad-spectrum antibiotics, infections and conditions caused by a wide range of bacteria. Special soft tissue infections, urinary tract and periodontal infections. Conditions or infections caused or complicated by Gram-positive and / or Gram-negative bacteria, such as with Staphylococcus (Staphylococcus aureus, Staphylococcus aureus), E. coli SPP .) (P Hemolytic Streptococcus-), septic pasteurization; {= dry bacteria, Bacteriodes spp., Fusobactedum spp ·, porphyra Porphyromonas spp ·, Prevotella spp ·, Peptostreptococcus -21-200301126 (17) Description of the Invention Continued

spp.) and Clostridium spp. infection associated with canine pneumonia, feline pneumonia, canine pyoderma, feline pyoderma, pasteurosis, pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and Mastoiditis; with Staphylococcus aureus, Staphylococcus intermedius, coagulase-positive staphylococcus, s. Epidermidis, S. hemolyticus, Streptococcus, CF (Minute-colony streptococci), non-concurrent skin and soft tissue infections related to viddans streptococci infection, abscesses, osteomyelitis, and puerperal fever; related to Staphylococcus or E. coli infections Non-complicated acute urinary tract infections; odontogenic infections associated with Streptococcus aureus infections; urinary tract infections associated with E. coli infections in dogs and cats; and Staphylococcus epidermidis and Staphylococcus intermedius in dogs and cats Skin and soft tissue infections associated with coagulase-negative staphylococcus or Pasteurella septiceum infections; in dogs and cats, it is associated with AlCalige_sPP. Sp., Clostridium spp., Enterobacter spp ·), Eubacterium (Eubactedum), Peptostreptococcus, Porphyromonas sp constricted beneficial Leiwo infection related oral infections.

'twenty two-

Claims (1)

200301126 Patent application scope 1. A pharmaceutical composition for treating periodontal disease caused by bacterial infection in dogs or cats, comprising a therapeutically effective amount of a compound of formula I: NOR2 Wherein R1 is hydrazone, a pharmaceutically acceptable cationic salt, or a group that can be hydrolyzed in vivo to produce a CO2H group, and R2 is a Cw alkyl group, and a pharmaceutical diluent or carrier. 2. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the pharmaceutically acceptable cation is Na +, K + or Li +. 3. — An opportunistic bacteria used to treat dogs or cats that results from (a) lack of resistance or reduction, (b) feline immunodeficiency virus (FIV), or (c) opportunistic bacteria for cancer chemotherapy A pharmaceutical composition for infection, comprising a therapeutically effective amount of a compound of formula I, I wherein R1 is hydrazone, a pharmaceutically acceptable cationic salt, or a group that can be hydrolyzed in vivo to produce CO2H, and R2 is a Cw alkyl group, and a pharmaceutical diluent or carrier. 4. A pharmaceutical composition for treating dogs or depicting diseases or conditions caused by bacterial infections, comprising a therapeutically effective amount of a compound of formula I, 200301126 _ application for patent, continued page NOR2 Where R1 is hydrazone, a pharmaceutically acceptable cationic salt, or a group that can be hydrolyzed to produce CO2H in the living body, and R2 is a Cw alkyl group, and a pharmaceutical diluent or carrier, the limitation is that if the The pharmaceutically acceptable cationic salt is Na, Li or K, so R2 is not methyl. 5. The pharmaceutical composition according to item 4 of the application, wherein the disease or condition is a bacterial infection of the skin, soft tissue or urinary tract. 6. The pharmaceutical composition according to item 1, 2, 3, 4 or 5 of the scope of the applied patent, wherein R1 is rhenium, metal test, soil test, press, Y-based, p-methoxy-based, benzyl. Base, p-nitrophenyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, third-butyl, third-pentyl, allyl Base, biphenylmethyl, trityl, adamantyl, 2-benzyloxyphenyl, 4-methylpentyl, tetramethan-2-yl, tetrazol-2- Group, pentachlorophenyl, acetone, p-tosylsulfonylethyl, methoxymethyl, silane, tin alkyl or phosphorus-containing group, the oxime group of formula -N = CHR3, where R3 is Aryl or heteroaryl, or an ester group that is hydrolysable in vivo. 7. The pharmaceutical composition according to item 6 of the application, wherein the compound of formula I is a Z-isomer. 8. The pharmaceutical composition according to item 7 of the scope of patent application, wherein R1 is pyrene, Na + or CH2OCOC (CH3) 3. 200301126 _ Achievement page of patent application scope 9. According to the pharmaceutical composition of patent application scope item 1, 2 or 3, wherein R1 is Η or C02CH20C0C (CH3) 3, and R2 is methyl. 10. The pharmaceutical composition according to claim 1, 2, 3, 4 or 5 further includes one or more preparations for treating or preventing diseases, or reducing or suppressing the symptoms of such diseases. 11. The pharmaceutical composition according to item 10 of the application, wherein the one or more preparations are selected from the group consisting of antibiotics, antihistamines, antifungals, antibacterials, anti-inflammatory drugs, steroids, antipruritics, food Supplement or lubricant, 12. The pharmaceutical composition according to item 11 of the application, wherein the antiparasitic drug is selected from the group consisting of arylpyrazoles, avermectins, mbemycins, organophosphorus Pyrethroids or pyrethroids; antihistamines selected from chlorpheniramine, alimazine, diphenhydramine or doxylamine; antifungal agents selected from fluconazole, ketoconazole, itracon Vomit, griseofulvin or amphotericin; antibacterial agent is selected from enfloxacin, maberfloxacin, ampicillin or amoxicillin; anti-inflammatory drug is selected from dehydropilanol, beta Methasone, dexamethasone, carprofen or ketoprofen; and food supplements are 7 * -linolenic acid. 13. The pharmaceutical composition according to item 1, 2, 3, 4 or 5 of the patent application scope is administered in a single dose. 14. The pharmaceutical composition according to item 13 of the scope of patent application for subcutaneous administration. 15. The pharmaceutical composition according to item 14 of the scope of patent application, wherein the therapeutically effective amount of the compound of formula I is 4 mg / kg to 12 mg / kg. 16. A pharmaceutical composition according to item 15 of the scope of patent application, which provides a period of at least 5 days of therapeutic activity against possible pathogens. 17. The pharmaceutical composition according to item 16 of the scope of patent application, wherein the period is at least 7 days for the scope of patent application continuation 200301126. 18. —A kit for treating or preventing bacterial infections in or caused by or caused by bacterial infections in dogs or cats, including: a) medicine according to item 1, 2, 3, 4 or 5 of the scope of patent application The composition; and b) instructions indicating a method for using the pharmaceutical composition to treat a bacterial infection, or a condition caused or complicated by a bacterial infection, in a dog or a cat. 19. A pharmaceutical composition for increasing acute or chronic injection-site tolerance in dogs or cats, comprising a single dose of a therapeutically effective amount of Formula I NOR2 Hydrolysis produces a CO2H group, while 112 is a CN4 alkyl group, and is effective in treating such conditions. 200301126 Lu, (1), the designated representative of the case is: Figure _ (2), the representative symbols of the representative diagram are briefly explained: 柒, if there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: -4-