Classifications

• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • 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
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
  • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

• This invention relates to novel 3-keto-9-oxime-11 ,12-carbazate or carbamate derivatives of 6-O-methyl-erythromycin A.
• the compounds of this invention are useful as antibiotic agents in mammals, including man, as well as in fish and birds.
• the compounds of the present invention are broad-spectrum macrolide antibiotics that are effective against infections caused by certain gram-positive and gram-negative bacteria as well as protozoa.
• R 1 is H or C 1 -C 10 alkyl, wherein 1 to 3 carbons of said alkyi are optionally replaced by a heteroatom selected from O, S and N, and said alkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(O)O(CrC 10 alkyl), C ⁇ -C 10 alkoxy, C1-C 10 alkanoyi, halo, nitro, cyano, 5-10 membered heterocyclyl, C 1 -C 10 alkyl, -NR 7 R 8 ,
• R 2 is (i) H, R ⁇ -C(0)R 4 , -C(0)OR 4 or -(CR 7 R 8 ) m R 3 when X is -NR 7 -, or (ii) H, R 4 , or -(CR 7 R 8 ) m R 3 when X is -CR 7 R 8 -, wherein for both (i) and (ii) m is an integer ranging from 0 to 6 and both R 7 and R 8 may vary for each iteration where m is greater than 1 ; each R 3 is independently C 6 -C 10 aryl or 5-10 membered heterocyclyl, wherein said aryl and heterocyclyl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of -C(O)O(C ⁇ -C 10 alkyl), C1-C1 0 alkoxy, C 1 -C 10 alkanoyi, halo, nitro, cyano, 5-10 membered heterocyclyl, C ⁇
• R 6 is H, -C(0)R 3 or C C 18 alkanoyi, wherein in the alkyl portion of said alkanoyi one or two carbons optionally may be replaced by a heteroatom selected from O, S and N; and, each R 7 and R 8 is independently H or C C 6 alkyl.
• More specific embodiments of this invention include compounds of formula I wherein R 6 is H.
• R 1 is H, benzyl or C C 3 alkyl or -CH 2 0(CH 2 ) 2 OCH 3 .
• R 2 is -(CH 2 ) m R 3 wherein m is an integer ranging from 0 to 6 and R 3 is 5-10 membered heterocyclyl or C ⁇ -C-io aryl.
• R 3 include quinolin-4-yl, 4-phenyI-imidazol- 1-yl, imidazo(4,5-b)pyridin-3-yl, 4-pyridin-3-ylimidazol-1-yl and pyridin-3-yl. Examples of preferred compounds of this invention include:
• the invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the invention also relates to a method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
• treatment includes the treatment or prevention of a bacterial infection or protozoa infection as provided in the method of the present invention.
• bacterial infection(s) or “protozoa infection” includes bacterial infections and protozoa infections that occur in mammals, fish and birds as well as disorders related to bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compounds of the present invention.
• Such bacterial infections and protozoa infections and disorders related to such infections include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clost dium diptheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related
• aureus food poisoning and Toxic shock syndrome
• Groups A, B, and C streptococci ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorfe ; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H.
• MAC Mycobacterium avium complex
• gastroenteritis related to infection by Campylobacter jejuni
• intestinal protozoa related to infection by Cryptosporidium spp.
• odontogenic infection related to infection by viridans streptococci
• persistent cough related to infection by Bordetella pertussis
• gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.
• atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae.
• Bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. haem., P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by E. coli or protozoa (i.e., coccidia, cryptosporidia, etc.); dairy cow mastitis related to infection by Staph. aureus, Strep, uberis, Strep, agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by A.
• pleuro., P. multocida, or Mycoplasma spp. swine enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae
• cow footrot related to infection by Fusobacterium spp.
• cow metritis related to infection by E. coli
• cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus
• cow pink-eye related to infection by Moraxella bovis cow premature abortion related to infection by protozoa (i.e. neosporium); urinary tract infection in dogs and cats related to infection by E.
• the invention also relates to a process of preparing the compound of formula I, and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 6 and X are as defined above, which comprises treating a compound of the formula
• X and R 2 are as defined above, with a compound of the formula R 1 ONH 2 « HCI or R 1 ONH 2 , wherein R 1 is as defined for said compound of formula I, in the presence of an acid, in a polar solvent such as methanol, ethanol, or isopropyl alcohol.
• said acid is PyHCI, wherein Py denotes pyridine, or Et 3 N « HCI.
• a wavy line indicates that the stereochemistry at the chiral center to which the wavy line is connected is either an R or S configuration where the wavy line is connected to a carbon atom.
• the wavy line at position 10 of the macrolide ring indicates that the methyl group can be either R or S configuration at that position.
• the wavy line connected to the oxime nitrogen at position 9 of the macrolide ring indicates that the -OR 1 moiety is in an E or Z configuration.
• halo means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
• alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties, or mixtures thereof. Said alkyl group may include one or two double or triple bonds. It is understood that for cyclic moieties at least three carbon atoms are required in said alkyl group.
• alkanoyi as used herein, unless otherwise indicated, includes -C(0)-alkyl groups wherein “alkyl” is as defined above.
• aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
• 5-10 membered heterocyclyl as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyciic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyciic group has from 5-10 atoms in its ring system.
• heterocyciic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties.
• An example of a 5 membered heterocyciic group is thiazolyl, and an example of a 10 membered heterocyciic group is quinolinyl.
• Examples of non-aromatic heterocyciic groups are pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl.
• aromatic heterocyciic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl and thiazolyl.
• Heterocyciic groups having a fused benzene ring include benzimidazolyl.
• phrases "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula I.
• the compounds of formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula I are those that form non-toxic acid addition salts, e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [Le., 1 ,1'-methylene-bis-(2- hydroxy-3-naphthoate)
• the present invention also includes all radiolabelled forms of the compounds of formula I, and pharmaceutically acceptable salts thereof, wherein the radiolabel is selected from 3 H, 11 C and 4 C.
• radiolabelled compounds are useful as research or diagnostic tools.
• Certain compounds of formula I may have asymmetric centers and therefore exist in different enantiomeric forms.
• This invention relates to the use of ail optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.
• the invention includes both the R and S configurations of the methyl group at C-10 of the macrolide ring of formula I, and both the E and Z configurations of the -OR 1 group connected to the nitrogen of the oxime moiety at C-9 of the macrolide ring of formula I.
• the compounds of formula I may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
• step 1 of Scheme 1 compounds of the formula 111, wherein X is -CR 7 R 8 - and R 2 is as defined above, can be prepared by treating a compound of the formula ll with a compound of the formula H 2 N-X-R 2 , wherein X and R 2 are as indicated for said compound of formula 111, in a solvent such as acetonitrile, dimethyiformamide (DMF), tetrahydrofuran (THF), dimethoxy ethane or dimethylsulfoxide (DMSO), at a temperature within the range of about 50°C to 90°C for a period of about 4 to 10 hours.
• a solvent such as acetonitrile, dimethyiformamide (DMF), tetrahydrofuran (THF), dimethoxy ethane or dimethylsulfoxide (DMSO)
• step 2 of Scheme 1 compounds of the formula I can be prepared by treating a compound of the formula III with a compound of the formula R 1 ONH 2 « HCI or R ONH 2 , wherein R 1 is as defined above, in the presence of an acid, such as PyHCl, wherein Py denotes pyridine, or Et 3 N « HCI, in a polar solvent, preferably methanol, ethanol, or isopropyl alcohol, at a temperature within the range of about 65°C to 95°C for a period of about 10 hours to 6 days.
• a polar solvent preferably methanol, ethanol, or isopropyl alcohol
• Scheme 2 illustrates an alternative method of preparing compounds of the formula I wherein X is -NH-.
• the compound of formula IV can be prepared according to the procedures described in Baker et al., Journal of Organic Chemistry, 53, 2340 (1988).
• the compound of formula V can be prepared by treating the compound of formula IV with hydrazine according to the procedure described above for the preparation of the compound of formula 111 wherein X is -NH-.
• the compound of formula V is prepared by treating a compound of formula IV with anhydrous hydrazine in a solvent such as MeCN or DMF at a temperature of from about 60°C to 90°C for about 12 hours.
• the compound of formula VI can be prepared by treating a compound of formula V with an acid, such as hydrochloric acid, in a solvent such as methanol or ethanol.
• the compound of formula VII can be prepared by treating a compound of formula VI with a compound of the formula R 3 -(CH 2 ) m - ⁇ -C(0)H, wherein m is 1 to 7 and R 3 is as defined above, in an anhydrous solvent, such as anhydrous ethanol or isopropanol, at a temperature within the range of about 80°C to 90°C.
• the hydroxy group at position C-2' of the compound of formula VII is protected as an acetate by treating the compound with acetic anhydride to form the compound of formula VIII, followed by oxidation of the hydroxy group at position 3 to provide a carbonyl group.
• this is done by treating the compound of formula VII with acetic anhydride in a solvent such as CH 2 CI 2 at ambient temperature to provide the compound of formula VIII.
• the compound of formula IX can be prepared by treating a compound of formula VIII, in a solvent such as CH 2 Cl 2 , with DMSO, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC) and pyridinium trifluoroacetate (PyTFA) at ambient temperature.
• the compound of formula X can be prepared by treating the compound of formula IX with a reducing agent such as NaBH 3 CN in a solvent such as methanol at ambient temperature.
• the compound of formula XI can be prepared as described above for step 2 of Scheme 1.
• Scheme 3 illustrates an additional method of preparing compounds of the formula I wherein X is -NH-.
• the compound of formula XII can be prepared according to the procedures described in Griesgraber et al., Journal of Antibiotics, 49(5), 465-477 (1966).
• step 1 of Scheme 3 the compound of formula XII can be prepared by treating the compound of formula XII with a compound of the formula R 1 ONH 2 « HCI or R ONH 2 in the presence of an acid such as PyHCl, wherein Py denotes pyridine, or Et 3 N*HCI, in a polar solvent, preferably ethanol, methanol, or isopropyl alcohol, at a temperature within the range of about 65°C to 95°C for a period of about 10 hours to 4 days.
• step 2 of Scheme 3 the compound of formula XIII can be converted to the compound of formula XIV according to the procedure of step 3 of Scheme 2.
• step 3 of Scheme 3 the compound of formula XIV can be converted to the compound of formula XV according to the procedure of step 6 of Scheme 2.
• the compounds of the present invention may have asymmetric carbon atoms.
• Such diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
• Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomer mixtures and pure enantiomers are considered as part of the invention.
• the compounds of formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
• the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
• the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
• Those compounds of the formula I that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts.
• salts may be prepared by conventional techniques.
• the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I.
• Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
• These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
• they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
• stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
• the activity of the compounds of the present invention against bacterial and protozoa pathogens is demonstrated by the compound's ability to inhibit growth of defined strains of human (Assay I) or animal (Assays II and III) pathogens.
• Assay I employs conventional methodology and interpretation criteria and is designed to provide direction for chemical modifications that may lead to compounds that circumvent defined mechanisms of macrolide resistance.
• Assay I a panel of bacterial strains is assembled to include a variety of target pathogenic species, including representatives of macrolide resistance mechanisms that have been characterized. Use of this panel enables the chemical structure/activity relationship to be determined with respect to potency, spectrum of activity, and structural elements or modifications that may be necessary to obviate resistance mechanisms.
• Bacterial pathogens that comprise the screening panel are shown in the table below.
• both the macrolide-susceptible parent strain and the macrolide-resistant strain derived from it are available to provide a more accurate assessment of the compound's ability to circumvent the resistance mechanism.
• Strains that contain the gene with the designation of ermA/ermB/ermC are resistant to macrolides, lincosamides, and streptogramin B antibiotics due to modifications (methylation) of 23S rRNA molecules by an Erm methylase, thereby generally prevent the binding of all three structural classes.
• srA encodes a component of an efflux system in staphylococci that prevents the entry of macrolides and streptogramins while mefA/E encodes a transmembrane protein that appears to efflux only macrolides.
• Inactivation of macrolide antibiotics can occur and can be mediated by either a phosphorylation of the 2'-hydroxyl (mph) or by cleavage of the macrocyclic lactone (esterase).
• the strains may be characterized using conventional polymerase chain reaction (PCR) technology and/or by sequencing the resistance determinant. The use of PCR technology in this application is described in J.
• Assay II is utilized to test for activity against Pasteurella multocida and Assay ill is utilized to test for activity against Pasteurella haemolytica.
• Assay II This assay is based on the liquid dilution method in microliter format. A single colony of
• P. multocida (strain 59A067) is inoculated into 5 ml of brain heart infusion (BHI) broth.
• the test compounds are prepared by solubilizing 1 mg of the compound in 125 ⁇ l of dimethylsulfoxide (DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth. The concentrations of the test compound used range from 200 ⁇ g/ml to 0.098 ⁇ g/ml by two-fold serial dilutions.
• the P. multocida inoculated BHI is diluted with uninoculated BHI broth to make a 10 4 cell suspension per 200 ⁇ l.
• the BHI cell suspensions are mixed with respective serial dilutions of the test compound, and incubated at 37°C for 18 hours.
• the minimum inhibitory concentration (MIC) is equal to the concentration of the compound exhibiting 100% inhibition of growth of P. multocida as determined by comparison with an uninoculated control.
• Assay 111 is equal to the concentration of the compound exhibiting 100% inhibition of growth of P. multocida as determined by comparison with an uninoculated control.
• This assay is based on the agar dilution method using a Steers Replicator. Two to five colonies isolated from an agar plate are inoculated into BHI broth and incubated overnight at 37°C with shaking (200 rpm). The next morning, 300 ⁇ l of the fully grown P. haemolytica preculture is inoculated into 3 ml of fresh BHI broth and is incubated at 37°C with shaking (200 ⁇ m). The appropriate amounts of the test compounds are dissolved in ethanol and a series of two-fold serial dilutions are prepared. Two ml of the respective serial dilution is mixed with 18 ml of molten BHI agar and solidified. When the inoculated P.
• haemolytica culture reaches 0.5 McFarland standard density, about 5 ⁇ l of the P. haemolytica culture is inoculated onto BHI agar plates containing the various concentrations of the test compound using a Steers Replicator and incubated for 18 hours at 37°C. Initial concentrations of the test compound range from 100-200 ⁇ g/ml. The MIC is equal to the concentration of the test compound exhibiting 100% inhibition of growth of P. haemolytica as determined by comparison with an uninoculated control.
• the in vivo activity of the compounds of formula (I) can be determined by conventional animal protection studies well known to those skilled in the art, usually carried out in mice.
• mice are allotted to cages (10 per cage) upon their arrival, and allowed to acclimate for a minimum of 48 hours before being used.
• Animals are inoculated with 0.5 ml of a 3 x 10 3 CFU/ml bacterial suspension (P. multocida strain 59A006) intraperitoneally.
• Each experiment has at least 3 non-medicated control groups including one infected with 0.1X challenge dose and two infected with 1X challenge dose; a 10X challenge data group may also be used.
• all mice in a given study can be challenged within 30-90 minutes, especially if a repeating syringe (such as a Cornwall® syringe) is used to administer the challenge.
• a repeating syringe such as a Cornwall® syringe
• the first compound treatment is given. It may be necessary for a second person to begin compound dosing if all of the animals have not been challenged at the end of 30 minutes.
• the routes of administration are subcutaneous or oral doses. Subcutaneous doses are administered into the loose skin in the back of the neck whereas oral doses are given by means of a feeding needle. In both cases, a volume of 0.2 ml is used per mouse. Compounds are administered 30 minutes, 4 hours, and 24 hours after challenge. A control compound of known efficacy administered by the same route is included in each test. Animals are observed daily, and the number of survivors in each group is recorded. The P. multocida model monitoring continues for 96 hours (four days) post challenge.
• the PD 50 is a calculated dose at which the compound tested protects 50% of a group of mice from mortality due to the bacterial infection which would be lethal in the absence of drug treatment.
• the active compounds may be adminstered through oral, parenteral, topical, or rectal routes in the treatment or prevention of bacterial or protozoa infections.
• these compounds are most desirably administered in dosages ranging from about 0.2 mg per kg body weight per day (mg/kg/day) to about 200 mg/kg/day in single or divided doses (i.e., from 1 to 4 doses per day), although variations will necessarily occur depending upon the species, weight and condition of the subject being treated and the particular route of administration chosen.
• a dosage level that is in the range of about 4 mg/kg/day to about 50 mg/kg/day is most desirably employed. Variations may nevertheless occur depending upon the species of mammal, fish or bird being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
• the active compounds may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the routes previously indicated, and such administration may be carried out in single or multiple doses.
• the active compounds may be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
• Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
• oral pharmaceutical compositions can be suitably sweetened and/or flavored.
• the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
• tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvi ⁇ ylpyrrolidone, sucrose, gelatin and acacia.
• disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvi ⁇ ylpyrrolidone, sucrose, gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting pu ⁇ oses.
• compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
• the active compound may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
• solutions of an active compound in either sesame or peanut oil or in aqueous propylene glycol may be employed.
• aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection pu ⁇ oses.
• the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques will known to those skilled in the art.
• the active compounds of the present invention may be administered topically and this may be done by way of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with standard pharmaceutical practice.
• the active compounds may be administered in the feed of the animals or orally as a drench composition.
• the active compounds may also be adminstered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
• Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
• the active compounds may also be coupled with soluble polymers as targetable drug carriers.
• soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylam.de phenyl, polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoylresidues.
• the active compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, poiyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
• a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, poiyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
• Example 1 4"-Acetyl-11-deoxy-11-hvdrazo-6-0-methylervthromvcin A, 11.12-carbamate
• 1011-anhydro-2',4'-di-0-acetyl-12-0-imidazolylcarbonyl-6-0- methylerythromycin A (460 mg, 0.51 mmol) (which was prepared following the procedures of Baker et al., J. Org. Chem., 1988, 53, 2340), in MeCN at room temperature was added anhydrous NH 2 NH 2 (0.16 mL, 5.1 mmol) and the resulting solution was heated at 60°C for 12 hours.
• 11-Deoxy-5-Q-desosaminyl-11-hvdrazo-6-0-methylervthronolide A 11.12-carbamate A solution of 4"-acetyl-11-deoxy-11-hydrazo-6-0-methylerythromycin A, 11,12- carbamate (40 mg, 0.048 mmol) in E 5H-2N HCI (1 : 2) was stirred at room temperature overnight and the reaction mixture was poured into a cold solution of saturated NaHC0 3 . The aqueous layer was extracted with CHCI 3 (3 times). The combined organic layers were washed with brine, dried over anhydrous MgS0 4 , and concentrated in vacuo.
• Example 6 11-Deoxy-5-0-desosaminyl-11-f3-quinolin-4-yl-propyl))hydrazo-6-0-methyl-3- oxoervthronolide A. 11.12-carbamate;
• 11 ,12-carbamate To a solution of 9-Deoxo-11-deoxy-5-0-desosaminyl-11-hydrazo-9-methoxyimino-6-0- methyl-3-oxoerythronolide A, 11 ,12-carbamate (2.0 g, 3.05 mmol) in toluene (30 mL) was added 3-(imidazo(4,5-b)pyridin-3-yl)-propioaldehyde (910 mg, 4.26 mmol, 1.4 eq) and the reaction mixture was heated at 90°C for 18 hours. Toluene was removed in vacuo and the residue was dissolved in MeOH (30 mL).
• Example 14 9-Deoxo-11 -deoxy-5-Q-desosaminyl-10-ep/-11 -hvdrazo-9-benzoxyimino-6-Q-methyl-3- oxoervthro ⁇ olide A. 11.12-carbamate
• 11 ,12-carbamate (20 g, 31.8 mmol) in EtOH (210 mL) was added NH 2 OH-HCI (33.1g, 477 mmol, 15 eq) and pyridine (38.4 mL, 477 mmol, 15 eq), and the resulting solution at 80°C for 38 h.
• EtOH was removed in vacuo and the residue was dissolved in CH 2 CI 2 .
• Example 21 9-Deoxo-11-deoxy-5-0-desosaminyl-11-(3-benzotrizol-1-yl-propyl1hvdrazo-9- hvdroxyimino-6-Q-methyl-3-oxoervthronolide A. 11 ,12-carbamate 1 H NMR (400 MHz, CDCI 3 ) ⁇ : 9.02 (1H, br. s), 6.23 (1H, br. s), 2.58 (3H, s), 2.32 (6H, s),
• Example 23 9-Deoxo-11-deoxy-5-0-desosaminyl-11-(3-(4-hvdro ⁇ yphenyl)-propyl)hvdrazo-9- hvdroxyimino-6-0-methyl-3-oxoervthronol.de A. 11.12-carbamate H NMR (400 MHz, CDCI 3 ) ⁇ : 6.91 (2H), 6.68 (2H), 6.43 (1 H, br. s), 2.67 (3H, s), 2.30
• Example 25 9-Deoxo-11-deoxy-5-0-desosaminyl-11-(3-(2-methoxyphenyl)-propyl)hvdrazo-9- . hvdroxyimino-6-Q-methyl-3-oxoervthronolide A. 11.12-carbamate H NMR (400 MHz, CDCI 3 ) ⁇ : 8.66 (1H, br. s), 7.13 (2H), 6.82 (2H). 3.80 (3H, s), 2.68 (3H, s), 2.30 (6H, s), 1.45 (3H, s). 1.43 (3H, s), 1.32 (3H.
• the following compounds can be prepared from 9-deoxo-11-deoxy-5-0-desosaminyl-11- hydrazo-9-hydroxyimino-6-0-methyl-3-oxoerythronolide A, 11 ,12-carbamate and appropriate aldehydes by using the procedures as described as above.

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