US20020040007A1 - Novel macrolide antibiotics - Google Patents

Novel macrolide antibiotics Download PDF

Info

Publication number
US20020040007A1
US20020040007A1 US09/969,486 US96948601A US2002040007A1 US 20020040007 A1 US20020040007 A1 US 20020040007A1 US 96948601 A US96948601 A US 96948601A US 2002040007 A1 US2002040007 A1 US 2002040007A1
Authority
US
United States
Prior art keywords
alkyl
infection
aryl
methyl
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US09/969,486
Other languages
English (en)
Inventor
Takushi Kaneko
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Products Inc
Pfizer Inc
Original Assignee
Takushi Kaneko
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takushi Kaneko filed Critical Takushi Kaneko
Priority to US09/969,486 priority Critical patent/US20020040007A1/en
Publication of US20020040007A1 publication Critical patent/US20020040007A1/en
Priority to US10/206,652 priority patent/US6835716B2/en
Priority to US10/896,293 priority patent/US7071170B2/en
Assigned to PFIZER PRODUCTS INC., PFIZER INC. reassignment PFIZER PRODUCTS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KANEKO, TAKUSHI
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to novel macrolide derivatives that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds.
  • This invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections and disorders related to bacterial infections, such as atherosclerosis and cancer, in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment.
  • Macrolide antibiotics are known to be useful in the treatment of a broad sprectrum of bacterial and protozoal infections in mammals, fish and birds.
  • Such antibiotics include various derivatives of erythromycin A such as azithromycin which is commercially available and is referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359, both of which are incorporated herein by reference in their entirety.
  • the novel macrolide compounds of the present invention are bond-spectrum macrolide antibodics that are effective against infections caused by certain gram-positive and gram-negative bacteria as well as protozoa.
  • the present invention relates to a compound of the formula
  • a is 0 or 1
  • R 1 is hydrogen or (C 1 -C 10 )alkyl optionally substituted by fluoro, cyano, R 7 , R 7 O 2 C, R 7 C(O)NH and R 7 S(O) n wherein n is 0, 1 or 2 and R 7 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 0 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, ary
  • R 2 is hydrogen or a hydroxy protecting group
  • R 3 is amino, cyano, N 3 , R 10 NH, R 10 C(O)NH, R 10 NHC(O)NH, R 10 NHC(S)NH, R 10 NHNHC(O)NH, R 10 ONHC(O)NH, R 10 O, R 10 OC(O)NH, R 10 S(O) n , R 10 phosphoramido, R 10 sulfonamido, SH, R 10 S wherein n is defined above and R 10 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 1 -
  • R 4 is hydrogen, methyl optionally substituted by one to two nitro, cyano, R 14 C(O) and R 14 OC(O); or R 4 is N 3 , R 14 O, R 14 NH, R 14 S wherein R 14 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo
  • X is oxygen or NOR 16 wherein R 16 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C
  • R 5 is hydrogen or methyl
  • R 3 and R 4 may be taken together with the carbons to which they are attached to form
  • W is C ⁇ O, C ⁇ S, SO 2 or C ⁇ NR 10 wherein R 10 is as defined above;
  • Y is oxygen, sulfur or NR 17 wherein R 17 is hydrogen, R 19 , R 19 O or R 19 NH wherein R 19 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroarly(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently
  • R 18 is hydrogen, (C 1 -C 6 )alkyl, (C 0 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 20 R 21 N, R 20 C(O), R 20 C(O)O, R 20 OC(O), R 20 C(O)NH, R 20 NHC(O), R 20 R 21 NC(O), and R 20 OCO 2 wherein R 20 and R 21 are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 6 )
  • R 6 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy(C 1 C 6 )alkyl or (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R 6 is (C 3 -C 10 )cycloalkyl or (C 5 -C 10 )cycloalkenyl optionally substituted by (C 1 -C 6 )alkyl or halo; or R 6 is (C 2 -C 8 )heterocycloalkyl or (C 2 -C 8 )heteroaryl optionally substituted by (C 1 -C 6 )alkyl, (
  • R 4 is hydrogen
  • R 1 is hydrogen
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. It is understood that for cyclic moieties at least three carbon atoms are required in said alkyl group, and for said alkyl group to include a carbon-carbon double or triple bond at least two carbon atoms are required in said alkyl group.
  • hydroxy protecting group includes benzoyl, benzyl, (C 1 -C 6 )alkanoyl, ((C 1 -C 3 )alkyl) 3 silyl, and tert-butyldimethylsilyl groups, preferably an acetyl group.
  • the alkanoyl group can be cleaved after its administration to function as a prodrug.
  • 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.
  • (C 2 -C 9 )Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
  • (C 2 -C 9 )Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7
  • acyl as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms “alkyl” or “aryl” are as defined above.
  • the compounds of this invention include all configurational isomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e g. enantiomers and diastereomers), as well as racemic, diastereomeric and other mixtures of such isomers.
  • 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 the present invention.
  • the compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of are those that form non-toxic acid addition salts, i.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 [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salt
  • Those compounds of the present invention 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 calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
  • Certain compounds of the present invention may have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms.
  • This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
  • the present invention includes the compounds of the present invention, and the pharmaceutically acceptable salts thereof, wherein one or more hydrogen, carbon or other atoms are replaced by isotopes thereof.
  • Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
  • Preferred compounds of formula I include those wherein a is 1 and R 1 is (C 1 -C 10 )alkyl.
  • R 3 is N 3 , R 10 NH, R 10 C(O), R 10 NHC(O)NH or R 10 NHNHC(O)NH.
  • More preferred compounds of formula I include those wherein a is 1; R 1 is (C 1 -C 10 )alkyl; R 2 is hydrogen; R 3 is N 3 , R 10 NH, R 10 C(O), R 10 NHC(O)NH or R 10 NHNHC(O)NH; R 4 is hydrogen, R 14 NH or R 14 S and R 6 is ethyl.
  • More preferred compounds of formula I include those wherein a is 1; R 1 is (C 1 -C 10 )alkyl; R 2 is hydrogen; R 3 and R 4 are taken together with the carbons to which they are attached to form the compound of formula II; W is C ⁇ O and Y is NR 17 .
  • the invention also relates to a pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, or disorder related to a bacterial infection or protozoal 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 disorder selected from a bacterial infection, a protozoal infection, or disorder related to a bacterial infection or protozoal 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.
  • the invention also relates to a pharmaceutical composition for the treatment of cancer, in particular non-small cell lung cancer, in a mammal, in particular a human, 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 cancer, in particular non-small cell lung cancer, in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • bacterial infection(s) include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalls, Staphylococcus aureus, or Peptostreptococcus spp., pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or
  • aureus food poisoning and toxic shock syndrome
  • Groups A, B, and C streptococci ulcers related to infection by Helicobacter pylori, systemic tebrile syndromes related to infection by Borrelia recurrent is; Lyme disease related to infection by Borrelia burgdorferi; 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.
  • Bacterial infections and protozoal infections, and disorders related to such infections, which may be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. haemolytica, 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 hyodysinteriae
  • cow footrot related to infection by Fusobacterium spp.
  • cow metritis related to infection by E.
  • cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus cow pink-eye related to infection by Moraxella bovis
  • urinary tract infection in dogs and cats related to infection by E. coli skin and soft tissue infections in dogs and cats related to infection by Staph. epidermidis, Staph. intermedius, coagulase neg. Staph. or P.
  • the present invention also relates to a compound of the formula
  • a is 0 or 1
  • R 1 is hydrogen or (C 1 -C 10 )alkyl optionally substituted by fluoro, cyano, R 7 , R 7 O 2 C, R 7 C(O)NH and R 7 S(O) n wherein n is 0, 1 or 2 and R 7 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • R 2 is hydrogen or a hydroxy protecting group
  • R 3 is N 3 , R 10 NH, R 10 C(O)NH, R 10 NHC(O)NH, R 10 NHC(S)NH, R 10 NHNHC(O)NH, R 10 ONHC(O)NH or R 10 OC(O)NH, wherein R 10 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl
  • X is oxygen or NOR 16 wherein R 16 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C
  • R 5 is hydrogen or methyl
  • R 6 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -c 6 alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R 6 is (C 3 -C 10 )cycloalkyl or (C 5 -C 10 )cycloalkenyl optionally substituted by (C 1 -C 6 )alkyl or halo; or R 6 is (C 2 -C 8 )heterocycloalkyl or (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkyl, (
  • R 1 is hydrogen
  • the present invention also relates to a compound of the formula
  • a is 0 or 1
  • R 1 is hydrogen or (C 1 -C 10 )alkyl optionally substituted by fluoro, cyano, R 7 , R 7 O 2 C, R 7 C(O)NH and R 7 S(O) n wherein n is 0, 1 or 2 and R 7 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • R 2 is hydrogen or a hydroxy protecting group
  • R 3 is NH 2 , N 3 , O ⁇ C ⁇ N or S ⁇ C ⁇ N;
  • X is oxygen or NOR 16 wherein R 16 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C
  • R 5 is hydrogen or methyl
  • R 6 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -c 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three hydroxy or halo groups; or R 6 is (C 3 -C 10 )cycloalkyl or (C 5 -C 10 )cycloalkenyl optionally substituted by (C 1 -C 6 )alkyl or halo; or R 6 is (C 2 -C 8 )heterocycloalkyl or (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkyl, (C 2 -C 8
  • the present invention also relates to an intermediate compound of the formula
  • a is 0 or 1;
  • R 1 is hydrogen or (C 1 -C 10 )alkyl optionally substituted by fluoro, cyano, R 7 , R 7 O 2 C, R 7 C(O)NH and R 7 S(O) n wherein n is 0, 1 or 2 and R 7 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 6 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
  • R 2 is hydrogen or a hydroxy protecting group
  • R 3 is NH 2 or N 3 ;
  • X is oxygen or NOR 16 wherein R 16 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C
  • R 5 is hydrogen or methyl
  • R 6 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -c 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R 6 is (C 3 -C 10 )cycloalkyl or (C 5 -C 10 )cycloalkenyl optionally substituted by (C 1 -C 6 )alkyl or halo; or R 6 is (C 2 -C 8 )heterocycloalkyl or (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkyl
  • the present invention also relates to a compound of the formula
  • a is 0 or 1;
  • R 1 is hydrogen or (C 1 -C 10 )alkyl optionally substituted by fluoro, cyano, R 7 , R 7 O 2 C, R 7 C(O)NH and R 7 S(O) n wherein n is 0, 1 or 2 and R 7 is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, ary
  • R 2 is hydrogen or a hydroxy protecting group
  • R 5 is hydrogen or methyl
  • R 6 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R 6 is (C 3 -C 10 )cycloalkyl or (C 5 -C 10 )cycloalkenyl optionally substituted by (C 1 -C 6 )alkyl or halo; or R 6 is (C 2 -C 8 )heterocycloalkyl or (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkyl
  • reaction 1 of Preparation A the compound of formula VII, wherein R 22 is a good leaving group, such as (C 1 -C 6 )alkylsulfonyloxy, (C 6 -C 10 )arylsulfonyloxy, (C 1 -C 6 )acyloxy or imidizolylcarbonyloxy, is converted to the corresponding ketene acetal compound of formula VI by treating VII with a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, ethyldiisopropylamine, triethylamine, lithium hexamethyldisilazide or potassium hexamethyldisilazide, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene, in the presence of a polar apotic solvent, such as acetonitrile, di
  • reaction 2 of Preparation A the ketene acetal compound of formula VI is converted to the corresponding azide compound of formula V by reacting VI with an azidonation reagent, such as azidotrimethylsilane, sodium azide or tributyltin azide, preferably azidotrimethylsilane, in the presence of a Lewis acid, such as tin(IV)chloride, titanium(IV)chloride, boron trifluoride diethyl etherate or aluminum trichloride, preferably tin(IV)chloride, and an aprotic solvent.
  • an azidonation reagent such as azidotrimethylsilane, sodium azide or tributyltin azide, preferably azidotrimethylsilane
  • a Lewis acid such as tin(IV)chloride, titanium(IV)chloride, boron trifluoride diethyl etherate or aluminum trichloride, preferably tin(IV)chloride
  • Suitable solvents include dichloromethane, dichloroethane, chloroform or carbontetrachloride, preferably dichloromethane.
  • the reaction is carried out at a temperature between about ⁇ 78° C. to about 25° C., preferably about 0° C., for a time period between about 3 hours to about 12 hours, preferably about 6 hours.
  • reaction 3 of Preparation A the azide compound of formula V is converted to the corresponding amino compound of formula IV by reducing V in the presence of hydrogen, a catalyst, such as palladium on carbon, palladium on calcium carbonate, platinum(IV)oxide or ruthenium on carbon, preferably palladium on calcium carbonate, and a solvent, such as ethanol, methanol or ethyl acetate, preferably ethanol.
  • a catalyst such as palladium on carbon, palladium on calcium carbonate, platinum(IV)oxide or ruthenium on carbon, preferably palladium on calcium carbonate
  • a solvent such as ethanol, methanol or ethyl acetate, preferably ethanol.
  • the reaction is carried out under a pressure of about 1 psi to about 50 psi, preferably about 20 psi, at a temperature between about 0° C. to about 50° C., preferably about 25° C., for a time period between 1 hours to about 6 hours,
  • reaction 4 of Preparation A the amino compound of formula IV is converted to the corresponding isocyanate compound of formula XXII by reacting IV with phosgene or triphosgene in the presence of a base, such as triethylamine or pyridine, and an aprotic solvent, such as tetrahydrofuran or dioxane.
  • a base such as triethylamine or pyridine
  • an aprotic solvent such as tetrahydrofuran or dioxane.
  • the reaction is carried out at a temperature between about 0° C. to about 50° C., preferably about 0° C., for a time period between 0.5 hours to about 12 hours, preferably about 2 hours.
  • reaction 5 of Preparation A the compound of formula V is converted to the corresponding compound of formula IX by heating V to a temperature between about 30° C. to about 100° C., preferably about 70° C., in ethanol, tetrahydrofuran, or dioxane for a time period between about 0.5 hours to about 6 hours, preferably about 2 hours.
  • reaction 6 of Preparation A the azide compound of formula IX is converted to the corresponding amino compound of formula VII according to the procedure described above in reaction 3 of Preparation A.
  • reaction 1 of Preparation B the amino compound of formula VIII is converted to the corresponding isocyanate compound of formula XIII according to the procedure described above in reaction 4 of Scheme A.
  • reaction 1 of Preparation C the ketene acetal compound of formula VI is converted to the corresponding compound of formula XXXIX, when R 4 is methylene substituted by one to two nitro, R 14 O 2 C or cyano groups, by reacting VI with a compound of the formula, R 4 H, in the presence of a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylamine, sodium hydride or lithium bis(trimethylsilyl)amide, preferably as 1,8-diazabicyclo[5.4.0]undec-7-ene, and an aprotic solvent, such as tetrahydrofuran, acetonitrile or dimethylformamide, preferably acetonitrile.
  • the reaction is carried out at a temperature between about ⁇ 20° C. to about 100° C., preferably about 80° C., for
  • reaction 1 of Scheme 1 the amino compound of formula IV is converted to the corresponding amide compound of formula X by reacting IV with a compound of the formula, R 10 —CO—X, wherein X is chloro, bromo or an anhydride, in the presence of a base, such as pyridine or triethylamine.
  • a base such as pyridine or triethylamine.
  • Suitable solvents include dichlormethane, dichloroethane, tetrahydrofuran or dioxane, preferably tetrahydrofuran.
  • the reaction is stirred at a temperature between about 0° C. to about 50° C., preferably about 0° C., for a time period between about 1 hours to about 24 hours, preferably about 12 hours.
  • the amide formation of the compound of formula X can also be effected by reacting IV with the carboxylic acid compound of the formula, R 10 —COOH, in the presence of a dehydrating agent, such as 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  • a dehydrating agent such as 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  • reaction 2 of Scheme 1 the amino compound of formula IV is converted to the corresponding urea compound of formula XI by reacting IV with phosgene or triphosgene in the presence of a base, such as triethylamine or pyridine, and an aprotic solvent, such as tetrahydrofuran or dioxane.
  • a base such as triethylamine or pyridine
  • an aprotic solvent such as tetrahydrofuran or dioxane.
  • An amine of the formula, R 10 NH 2 is added to the reaction mixture so formed in the presence of tetrahydrofuran, dioxane or dimethylformamide.
  • the reaction is carried out at a temperature between about 0° C. to about 100° C., preferably about 65° C., for a time period between about 0.5 hours to about 12 hours, preferably about 6 hours.
  • the urea formulation of the compound of formula XI can also be effected by reacting IV with a compound of the formula, R 10 N ⁇ C ⁇ O, in the presence of an aprotic solvent, such as tetrahydrofuran, dioxane or dimethylformamide.
  • the reaction is carried out at a temperature between about 0° C. to about 50° C., preferably about 25° C., for a time period between about 0.5 hours to about 24 hours, preferably about 12 hours.
  • reaction 3 of Scheme 1 the amino compound of formula IV is converted to the corresponding carbamate compound of formula XIl by reacting IV with a chloroformate of the formula, R 10 COCl, in the presence of a base, such as triethylamine, pyridine or ethyldiisopropylamine, and an aprotic solvent. Suitable solvents include tetrahydrofuran, dioxane or dimethylformamide. The reaction is carried out at a temperature between about 0° C. to about 50° C., preferably about 25° C., for a time period between about 0.5 hours to about 24 hours, preferably about 6 hours.
  • the compound of formula XIl can also be prepared by reacting the compound of the formula XXII with an alcohol of the formula R 10 OH.
  • reaction 4 of Scheme 1 the amino compound of formula IV is converted to the corresponding compound of formula XIII by the reductive amination of IV by use of an aldehyde of the formula, R 10 CHO, or ketone, and a reducing agent, such as sodium cyanoborohydride, sodium triacetoxyborohydride or hydrogen in the presence of a catalyst, such as palladium on carbon.
  • a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride or hydrogen in the presence of a catalyst, such as palladium on carbon.
  • Suitable solvents include ethanol or methanol.
  • the reaction mixture is stirred at a temperature between about 0° C. to about 50° C., preferably about 25° C., for a time period between about 0.5 hours to about 24 hours, preferably about 12 hours.
  • reaction 1 of Scheme 2 the ketene acetal compound of formula VI is converted to the corresponding compound of formula XIV by reacting VI with an alcohol compound of the formula, R 10 —OH, in the presence of an acid, such as tin(IV)chloride, titanium(IV)chloride, titanium(IV)isopropoxide or boron trifluoride diethyl etherate, and an aprotic solvent, such as methylene chloride and dichloroethane.
  • the reaction is carried out at a temperature between about ⁇ 78° C. to room temperature, preferably about 0° C., for a time period between about 1 hour to about 24 hours, preferably about 6 hours.
  • reaction 2 of Scheme 2 the ketene acetal compound of formula VI is converted to the corresponding compound of formula XV by reacting VI with a thiol compound of the formula, R 10 —SH, in the presence of an acid, such as tin(IV)chloride, titanium(IV)chloride, titanium(IV)isopropoxide or boron trifluoride diethyl etherate, and a polar aprotic solvent, such as methylene chloride.
  • the reaction is carried out at a temperature between about ⁇ 78° C. to room temperature, preferably about 0° C., for a time period between about 1 hour to about 24 hours, preferably about 6 hours.
  • reaction 3 of Scheme 2 the ketene acetal compound of formula VI is converted to the corresponding cyano compound of formula XVI by reacting VI with trimethylsilyl cyanide or tetrabutylammonium cyanide in the presence of an acid, such as tin(IV)chloride, and an aprotic solvent such as dichloromethane and dichloroethane.
  • the reaction is carried out at a temperature between about ⁇ 78° C. to room temperature, preferably about 0° C., for a time period between about 1 hour to about 24 hours, preferably about 6 hours.
  • reaction 4 of Scheme 2 the ketene acetal compound of formula VI is converted to the corresponding compound of formula XVII by reacting VI with trimethylsilyl isothiocyanate in the presence of an acid, such as tin(IV)chloride, and an aprotic solvent, such as methylene chloride, dichloroethane tetrahydrofuran or dioxane for a time period between about 1 hour to about 24 hours, preferably about 6 hours.
  • An amine of the formula, R 10 NH 2 is added to the reaction mixture so formed in the presence of tetrahydrofuran, dioxane or dimethylformamide.
  • the reaction is carried out at a temperature between about 0° C. to about 50° C., preferably about 25° C., for a time period between about 0.5 hours to about 24 hours, preferably about 6 hours.
  • reaction 1 of Scheme 3 the amino compound of formula VIII is converted to the corresponding amide compound of formula XVIII according to the procedure described above in reaction 1 of Scheme 1.
  • reaction 2 of Scheme 3 the amino compound of formula VIII is converted to the corresponding urea compound of formula XIX according to the procedure described above in reaction 2 of Scheme 1.
  • reaction 3 of Scheme 3 the amino compound of formula VIII is converted to the corresponding carbamate compound of formula XX according to the procedure described above in reaction 3 of Scheme 1.
  • reaction 4 of Scheme 3 the amino compound of formula VIII is converted to the corresponding compound of formula XXI according to the procedure described above in reaction 4 of Scheme 1.
  • reaction 1 of Scheme 4 the isocyanate compound of formula XXII is converted to the corresponding compound of formula XXIII by reacting XXII with a compound of the formula, R 19 ONH 2 , in the presence of an aprotic solvent, such as tetrahydrofuran, dioxane or dimethylformamide.
  • an aprotic solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • the reaction is carried out at a temperature between about 0° C. to about 100° C., preferably about 25° C., for a time period between about 0.5 hours to about 12 hours, preferably about 6 hours.
  • reaction 2 of Scheme 4 the compound of formula XXIII is converted to the corresponding cyclic urea compound of formula XIV by heating XXIII in the presence or absence of potassium hydroxide, sodium hydroxide, potassium tert-butoxide or acetic acid and a solvent, such as toluene, benzene or dimethylformamide.
  • the reaction is carried out at a temperature between about 25° C. to about 100° C., preferably about 80° C., for a time period between 0.5 hours to about 12 hours, preferably about 3 hours.
  • reaction 1 of Scheme 5 the urea compound of formula XI is converted to the corresponding cyclic urea compound of formula XXV according to the procedure described above in reaction 2 of Scheme 4.
  • reaction 1 of Scheme 6 the ketene acetal compound of formula IV is converted to the corresponding thioisocyanate compound of formula XXVI by reacting IV with trimethylsilyl isothiocyanate in the presence of a Lewis acid, such as tin(IV)chloride, titanium(IV)chloride, boron trifloride diethyl etherate or aluminum trichloride, preferably tin(IV)chloride, and an aprotic solvent. Suitable solvents include ichloromethane, dichloroethane, chloroform or carbontetrachloride, preferably dichloromethane.
  • the reaction is carried out at a temperature between about ⁇ 78° C. to about 50° C., preferably about 0° C., for a time period between about 0.5 hours to about 24 hours, preferably about 12 hours.
  • reaction 2 of Scheme 6 the thioisocyanate of formula XXVI is converted to the corresponding thiourea compound of formula XXVII according to the procedure described above in reaction 2 of Scheme 1.
  • reaction 2 of Scheme 6 the thiourea compound of formula XXVII is converted to the corresponding aminothiazoline compound of formula XXVIII according to the procedure described above in reaction 2 of Scheme 4.
  • reaction 1 of Scheme 7 the cyclic urea compound of formula XXIX is converted to the corresponding compound of formula XXX by reacting XXIX with a compound of the formula, NHOR 16 , in the presence of ethanol or pyridine.
  • the reaction is carried out at a temperature between about 25° C. to about 100° C., preferably about 80° C., for a time period between about 1 hour to about 48 hours, preferably about 24 hours.
  • reaction 2 of Scheme 7 the compound of reaction XXX is converted to the corresponding compound of formula XXXI by reacting XXX with an aldehyde compound of the formula, R 19 CHO, in the presence of sodium borohydride and a polar aprotic solvent, such as methanol or ethanol, preferably methanol.
  • the reaction is carried out at a temperature between about 0° C. to about 50° C., preferably about 25° C., for a time period between about 0.5 hours to about 24 hours, preferably about 12 hours.
  • reaction 1 of Scheme 8 the amino compound of formula XXXII is converted to the corresponding compound of formula XXXIII by reacting XXXII with sulfonyl diimidazole, sulfuryl chloride or thionyl chloride in the presence of a base, such as triethylamine or pyridine and an aprotic solvent, such as tetrahydrofuran, dioxane or methylene chloride.
  • a base such as triethylamine or pyridine
  • an aprotic solvent such as tetrahydrofuran, dioxane or methylene chloride.
  • the reaction is carried out at a temperature between about ⁇ 78° C. to about 25° C., preferably about 0° C., for a time period between about 0.5 hours to about 24 hours, preferably about 12 hours.
  • An amine of the formula, R 17 NH 2 is added to the reaction mixture so formed in the presence of a base, such as triethylamine or pyridine and an aprotic solvent, such as tetrahydrofuran, dioxane or methylene chloride.
  • a base such as triethylamine or pyridine
  • an aprotic solvent such as tetrahydrofuran, dioxane or methylene chloride.
  • the reaction is carried out at a temperature between about 0° C. to about 25° C., preferably about 0° C., for a time period between about 0.5 hours to about 24 hours, preferably about 6 hours.
  • reaction 2 of Scheme 8 the compound of formula XXXIII is converted the corresponding to the compound of formula XXXIV by heating XXXIII in tetrahydrofuran or dimethylformamide in the presence or absence of potassium tert-butoxide or acetic acid.
  • the reaction is carried out at a temperature between about 60° C. to about 100° C., preferably about 85° C., for a time period between about 0.5 hours to about 12 hours, preferably about 2 hours.
  • reaction 1 of Scheme 9 the compound of formula XIII is converted to the corresponding compound of formula XXXV according to the procedure described above in reaction 1 of Scheme 4.
  • reaction 2 of Scheme 9 the compound of formula XXXV is converted to the corresponding compound of formula XXXVII by reacting XXXV with an aldehyde of the formula, R 10 CHO, and a reducing agent, such as sodium cyanoborohydride.
  • Suitable solvents include methanol, ethanol or dichloroethane.
  • the reaction mixture is stirred at a temperature between about 0° C. to about 50° C., preferably about 25° C., for a time period between about 0.5 hours to about 24 hours, preferably about 12 hours.
  • reaction 1 of Scheme 10 the isocyanate compound of formula XIII is converted to the corresponding compound of formula XXXVI according to the procedure described above in reaction 1 of Scheme 4.
  • reaction 1 of Scheme 11 the thiourea compound of formula XXVII is converted to the corresponding cyclic thiourea compound of formula XXXVIII according to the procedure described above in reaction 2 of Scheme 4.
  • reaction 1 of Scheme 12 the compound of formula XXIX is converted to the corresponding compound of formula XXXX according to the procedure described above in reaction 2 of Scheme 9.
  • the starting compound of formula VII can be prepared as described in U.S. Pat. No. 5,543,400.
  • the starting compounds of formula VII where R 1 is various groups can be prepared as described in WO 98/09978.
  • the compounds of the present invention 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 the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the lafter 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 present invention 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. These salts are all 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 the present invention.
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
  • salts can easily 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.
  • 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.
  • msrA 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 III is utilized to test for activity against Pasteurella haemolytica.
  • 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.
  • 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 rpm). 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.
  • 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 ⁇ 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 0.1 ⁇ challenge dose and two infected with 1 ⁇ challenge dose; a 10 ⁇ X challenge data group may also be used. Generally, 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 compounds of formula I, and the pharmaceutically acceptable salts thereof 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.
  • 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. More particularly, 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 polyvinylpyrrolidone, 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 polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • 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.
  • the 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 purposes.
  • 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 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, polyhydroxypropylmethacrylamide 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, polyacetals, 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, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a compound of formula VI (a is 1; R 1 is methyl; R 2 is acetyl; C-8 methyl is ⁇ ; and R 6 is ethyl) (555 mg, 0.94 mmole) was dissolved 40 mL of ethylene and cooled to ⁇ 78°. Trimethylsilyl azide (744 ⁇ L of 1M tin(IV)chloride solution in methylene chloride) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched by addition of satrated sodium hydrogen carbonate solution, and the product was extracted with methylene chloride. The methylene chloride layer was washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was chromatographed to give 410 mg (69%) of the titled compound; MS m/e 637 (M+1).
  • Formula X (a is 1; R 1 is Methyl; R 2 is Acetyl; C-8 Methyl is ⁇ ; R 6 is Ethyl and R 7 is Methyl) and Formula XVIII (a is 1; R 1 is Methyl; R 2 is Acetyl; C-8 Methyl is ⁇ ; R 6 is Ethyl and R 7 is Methyl)
  • Formula XXIX (a is 1; R 1 is Methyl; R 2 is Acetyl; C-8 Methyl is ⁇ ; R 5 is ⁇ -Methyl and R 6 is Ethyl) and Formula XXXV (a is 1; R 1 is Methyl; R 2 is Acetyl; C-8 Methyl is ⁇ ; and R 6 is Ethyl)
  • Lindlar catalyst (137 mg) was added to a solution of a compound or formula V (a is 1; R 1 is methyl; R 2 is acetyl; C-8 methyl is ⁇ ; and R 6 is ethyl) (137 mg, 0.215 mmol) in 15 mL of ethanol.
  • the resulting solution was hydrogenated at 20 psi of hydrogen for 2 hours.
  • the solution was filtered through celite and the solvent was removed under reduced ressure. The residue was dissolved in 5 mL of tetrahydrofuran and cooled in an ice-bath.
  • Triethylamine 85 ⁇ L 0.611 mmol, 2.84 eq
  • phosgene 0.25 mL of 1.93 M solution in toluene, 0.483 mmol, 2.24 eq
  • the solution was stirred at 0° for 2 hours.
  • the reaction mixture was diluted with 25 mL of ethyl acetate and washed with a saturated sodium hydrogen carbonate solution and brine.
  • a compound of formula XXIX (a is 1; R 1 is methyl; R 2 is acetyl; C-8 methyl is ⁇ ; R 5 is methyl and R 6 is ethyl) (12 m, 0.027 mmol) and 3-(quinolin-4-yl)propionaldehyde (10 mg, 0.054 mmol) in 1 mL of toluene were heated to 90° for 14 hours. Toluene was removed under reduced pressure, and the residue was dissolved in 1 mL of methanol (MeOH).
  • Formula XI (a is 1; R 1 is Methyl; R 2 is Acetyl; C-8 Methyl is ⁇ ; R 6 is Ethyl and R 7 is 4-(3-pyridinyl)-1H-imidazol-1-butyl) and Formula XIX (a is 1; R 1 is Methyl; R 2 is Acetyl; C-8 Methyl is ⁇ ; R 6 is Ethyl and R 7 is 4-(3-pyridinyl)-1H-imidazol-1-butyl)
  • Lindlar catalyst (137 mg) was added to a solution of a compound of formula V (a is 1; R 1 is methyl; R 2 is acetyl; C-8 methyl is ⁇ ; and R 6 is ethyl) (137 mg, 0.215 mmol) in 15 mL of ethanol.
  • the resulting solution was hydrogenated at 20 psi of hydrogen for 2 hours.
  • the solution was filtered through celite and the solvent was removed under reduced pressure. The residue was dissolved in 5 mL of THF and cooled in an ice-bath.
  • Triethylamine (85 ⁇ L, 0.611 mmol, 2.84 eq) and a phosgene solution in toluene (250 ⁇ L of 1.93 M solution, 0.483 mmol, 2.24 eq) was added. The solution was stirred at 0° for 2 hours. The reaction mixture was diluted with 25 mL of ethyl acetate and washed with a saturated NaHCO 3 solution and brine. After drying over Na 2 SO 4 , the solvent was removed under reduced pressure. The residue was dissolved in 2 mL of DMF and 4-(3-pyridinyl)-1H-imidazol-1-butylamine (139 mg, 0.645 mmol) was added.
  • a compound of formula XI (a is 1; R 2 is methyl; R 2 is acetyl; C-8 methyl is ⁇ ; R 6 is ethyl and R 7 is 4-(3-pyridinyl)-1H-imidazol-1-butyl) (6 mg, 7 mmol) was warmed in methanol for 1 hour. Methanol was then evaporated and the residue was chromatographed on silica gel (TLC 10% MeOH—1% NH 4 OH—CH 2 Cl 2 ) to give 4 mg (70%) of the titled compound: MS m/e 812 (M+1).
  • Formula VI (a is 1; R 1 is methyl; R 2 is acetyl; C-8 methyl is ⁇ or ⁇ ; and R 6 is ethyl) (54 mg, 0.091 mmol) was dissolved in 5 mL of CH 2 Cl 2 and cooled in a dry ice-acetone bath. Trimethylsilyl isothiocyanate (128 ⁇ L, 0.91 mmol) and a tin(IV)chloride solution (137 ⁇ L of 1M solution in methylene chloride were added and the resulting solution was gradually warmed up to room temperature overnight. A saturated sodium hydrogen carbonate solution was then added and the products were extracted with ethyl acetate.
  • a compound of formula VI (a is 1; R 1 is methyl; R 2 is acetyl; C-8 methyl is ⁇ or ⁇ ; and R 6 is ethyl) (118 mg, 0.2 mmol) was dissolved in 10 mL of dry methylene chloride and cooled to ⁇ 78°. Propagyl alcohol (35 ⁇ L, 0.6 mmol) and a 1M tin(IV)chloride solution in methylene chloride (220 ⁇ L, 0.22 mmol) were added and the solution was gradually warmed to room temperature overnight. The reaction was quenched by addition of saturated sodium hydrogen carbonate solution and the methylene chloride solution was washed with brine and dried over sodium sulfate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
  • Communicable Diseases (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
US09/969,486 1998-11-03 2001-10-01 Novel macrolide antibiotics Abandoned US20020040007A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US09/969,486 US20020040007A1 (en) 1998-11-03 2001-10-01 Novel macrolide antibiotics
US10/206,652 US6835716B2 (en) 1998-11-03 2002-07-24 Macrolide antibiotics
US10/896,293 US7071170B2 (en) 1998-11-03 2004-07-21 Macrolide antibiotics

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US10683698P 1998-11-03 1998-11-03
US43244199A 1999-11-02 1999-11-02
US09/969,486 US20020040007A1 (en) 1998-11-03 2001-10-01 Novel macrolide antibiotics

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US43244199A Continuation 1998-11-03 1999-11-02

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/206,652 Continuation US6835716B2 (en) 1998-11-03 2002-07-24 Macrolide antibiotics

Publications (1)

Publication Number Publication Date
US20020040007A1 true US20020040007A1 (en) 2002-04-04

Family

ID=22313524

Family Applications (3)

Application Number Title Priority Date Filing Date
US09/969,486 Abandoned US20020040007A1 (en) 1998-11-03 2001-10-01 Novel macrolide antibiotics
US10/206,652 Expired - Fee Related US6835716B2 (en) 1998-11-03 2002-07-24 Macrolide antibiotics
US10/896,293 Expired - Fee Related US7071170B2 (en) 1998-11-03 2004-07-21 Macrolide antibiotics

Family Applications After (2)

Application Number Title Priority Date Filing Date
US10/206,652 Expired - Fee Related US6835716B2 (en) 1998-11-03 2002-07-24 Macrolide antibiotics
US10/896,293 Expired - Fee Related US7071170B2 (en) 1998-11-03 2004-07-21 Macrolide antibiotics

Country Status (34)

Country Link
US (3) US20020040007A1 (xx)
EP (1) EP1124837A2 (xx)
JP (1) JP4043191B2 (xx)
KR (1) KR20010083944A (xx)
CN (1) CN1376160A (xx)
AP (1) AP2001002131A0 (xx)
AU (1) AU5995299A (xx)
BG (1) BG105543A (xx)
BR (1) BR9914998A (xx)
CA (1) CA2349338C (xx)
CO (1) CO5140110A1 (xx)
CZ (1) CZ20011512A3 (xx)
EA (1) EA200100396A1 (xx)
EE (1) EE200100245A (xx)
GT (1) GT199900192A (xx)
HK (1) HK1049010A1 (xx)
HR (1) HRP20010306A2 (xx)
HU (1) HUP0104192A3 (xx)
ID (1) ID28286A (xx)
IL (1) IL142628A0 (xx)
IS (1) IS5919A (xx)
MA (1) MA26703A1 (xx)
NO (1) NO20012155L (xx)
OA (1) OA11670A (xx)
PA (1) PA8485101A1 (xx)
PE (1) PE20001289A1 (xx)
PL (1) PL348114A1 (xx)
SK (1) SK5812001A3 (xx)
SV (1) SV1999000188A (xx)
TN (1) TNSN99205A1 (xx)
TR (4) TR200101241T2 (xx)
UY (1) UY25780A1 (xx)
WO (1) WO2000026224A2 (xx)
ZA (1) ZA200103289B (xx)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6777543B2 (en) 1999-05-24 2004-08-17 Pfizer, Inc. 13-methyl erythromycin derivatives
US6833444B2 (en) 1999-01-27 2004-12-21 Pfizer, Inc. Ketolide antibiotics

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP9801420A0 (en) * 1998-01-02 1998-12-31 Pfizer Prod Inc Novel macrolides.
SK5812001A3 (en) 1998-11-03 2001-12-03 Pfizer Prod Inc Novel macrolide antibiotics
US6395710B1 (en) 1999-04-16 2002-05-28 Kosan Biosciences, Inc. Macrolide antiinfective agents
US6514944B2 (en) 1999-04-16 2003-02-04 Kosan Biosciences, Inc. Macrolide antiinfective agents
US6939861B2 (en) 1999-04-16 2005-09-06 Kosan Biosciences, Inc. Amido macrolides
US6451768B1 (en) 1999-04-16 2002-09-17 Kosan Biosciences, Inc. Macrolide antiinfective agents
MXPA01010521A (es) 1999-04-16 2003-08-19 Johnson & Johnson Antibacteriales de cetolidos.
US6590083B1 (en) 1999-04-16 2003-07-08 Ortho-Mcneil Pharmaceutical, Inc. Ketolide antibacterials
EP1114826A3 (en) * 1999-12-29 2001-10-31 Pfizer Products Inc. Novel antibacterial and prokinetic macrolides
EP1146051A3 (en) * 2000-04-10 2001-10-31 Pfizer Products Inc. Erythromycin A derivatives
ATE271062T1 (de) 2000-06-30 2004-07-15 Pfizer Prod Inc Makrolid-antibiotika
EP1794171A2 (en) * 2004-07-28 2007-06-13 Ranbaxy Laboratories, Ltd. Ketolide derivatives as antibacterial agents
WO2006046112A2 (en) * 2004-10-25 2006-05-04 Ranbaxy Laboratories Limited Ketolide derivatives as antibacterial agents
AP2007004026A0 (en) * 2004-12-21 2007-06-30 Pfizer Prod Inc Macrolides
EP1957508A2 (en) * 2005-11-23 2008-08-20 Ranbaxy Laboratories Limited Ketolide derivatives as antibacterial agents
WO2007060618A2 (en) * 2005-11-23 2007-05-31 Ranbaxy Laboratories Limited Macrolides derivatives as antibacterial agents
US7801502B2 (en) * 2006-12-18 2010-09-21 Aai Corporation Method for implementing continuous radio frequency (RF) alignment in advanced electronic warfare (EW) signal stimulation systems
US8409628B2 (en) 2010-02-04 2013-04-02 Penguin IP Holdings, Inc. Methods and compositions for oxygenation of skin to treat skin disorders
US8900601B2 (en) 2010-03-31 2014-12-02 Jennifer Bartels Permeable mixtures, methods and compositions for the skin
US9539223B2 (en) * 2013-05-01 2017-01-10 Neoculi Pty Ltd Methods for treating bacterial infections
RU2537143C1 (ru) * 2013-11-08 2014-12-27 Государственное научное учреждение Ставропольский научно-исследовательский институт животноводства и кормопроизводства РАСХН Препарат для лечения и профилактики мастита у коров
WO2018080072A2 (ko) * 2016-10-27 2018-05-03 한국생명공학연구원 신규한 매크로라이드계 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 말라리아의 예방 또는 치료용 약학적 조성물

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI8110592A8 (en) * 1981-03-06 1996-06-30 Pliva Pharm & Chem Works Process for preparing of n-methyl-11-aza-10-deoxo-10-dihydroerythromycine a and derivatives thereof
US4474768A (en) * 1982-07-19 1984-10-02 Pfizer Inc. N-Methyl 11-aza-10-deoxo-10-dihydro-erytromycin A, intermediates therefor
IL99995A (en) * 1990-11-21 1997-11-20 Roussel Uclaf Erythromycin derivatives, their preparation and pharmaceutical compositions containing them
FR2697524B1 (fr) * 1992-11-05 1994-12-23 Roussel Uclaf Nouveaux dérivés de l'érythromycine, leur procédé de préparation et leur application comme médicaments.
US5527780A (en) 1992-11-05 1996-06-18 Roussel Uclaf Erythromycin derivatives
US5332807A (en) 1993-04-14 1994-07-26 Merck & Co., Inc. Process of producing 8A- and 9A-azalide antibiotics
FR2702480B1 (fr) * 1993-03-09 1995-04-28 Roussel Uclaf Nouveaux dérivés de l'érythromycine, leur procédé de préparation et leur application comme médicaments.
HRP931480B1 (en) 1993-12-08 1997-08-31 Sour Pliva 9a-N-(N'-CARBAMONYL) and 9a-N-(N'-THIOCARBAMONYL) DERIVATES OF 9-DEOXO-9a-HOMOERYTHROMYCIN A
HRP950145A2 (en) 1995-03-27 1997-08-31 Sour Pliva New compounds of the secomacrolide and secoazalide class and a process for the preparation thereof
HN1996000101A (es) 1996-02-28 1997-06-26 Inc Pfizer Terapia combinada para la osteoporosis
EP0918783A1 (en) * 1996-05-07 1999-06-02 Abbott Laboratories 6-o-substituted erythromycins and method for making them
JP2000511063A (ja) 1996-07-05 2000-08-29 バイオティカ テクノロジー リミティド ポリケチド類及びそれらの合成
UA51730C2 (uk) * 1996-09-04 2002-12-16 Ебботт Лабораторіз 6-o-заміщені кетоліди з антибактеріальною активністю, спосіб їх одержання (варіанти), фармацевтична композиція та спосіб регулювання бактеріальної інфекції у ссавців
ATE296832T1 (de) 1996-09-04 2005-06-15 Abbott Lab 6-o-substituierte ketoliden mit antibakteriellen wirkung
HRP960497B1 (en) 1996-10-28 2003-08-31 Pliva Pharm & Chem Works 9-n-ethenyl derivatives of 9(s)-erythromycylamine
HN1998000074A (es) 1997-06-11 1999-01-08 Pfizer Prod Inc Derivados de macrolidos c-4 sustituidos
US6407074B1 (en) 1997-06-11 2002-06-18 Pfizer Inc C-4″-substituted macrolide derivatives
EP0895999A1 (en) 1997-08-06 1999-02-10 Pfizer Products Inc. C-4" substituted macrolide antibiotics
US6339063B1 (en) 1997-09-10 2002-01-15 Merck & Co., Inc. 9a-azalides as veterinary antimicrobial agents
DE69836697T2 (de) 1997-10-16 2007-10-04 Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. Neue 3,6-Hemiketale der 9a-Azalidklasse
ES2226282T3 (es) 1998-03-03 2005-03-16 Pfizer Products Inc. Antibioticos macrilidos de 3,6-cetal.
SK5812001A3 (en) 1998-11-03 2001-12-03 Pfizer Prod Inc Novel macrolide antibiotics
WO2000071557A1 (en) 1999-05-24 2000-11-30 Pfizer Products Inc. 13-methyl-erythromycin derivatives
EP1114826A3 (en) 1999-12-29 2001-10-31 Pfizer Products Inc. Novel antibacterial and prokinetic macrolides
EP1122261A3 (en) 2000-01-31 2001-09-26 Pfizer Products Inc. 13 and 14-membered antibacterial macrolides
ATE271062T1 (de) 2000-06-30 2004-07-15 Pfizer Prod Inc Makrolid-antibiotika
WO2003004509A2 (en) 2001-07-03 2003-01-16 Chiron Corporation C12 modified erythromycin macrolides and ketolides having antibacterial activity

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6833444B2 (en) 1999-01-27 2004-12-21 Pfizer, Inc. Ketolide antibiotics
US6777543B2 (en) 1999-05-24 2004-08-17 Pfizer, Inc. 13-methyl erythromycin derivatives

Also Published As

Publication number Publication date
HRP20010306A2 (en) 2002-06-30
SV1999000188A (es) 2000-10-16
CA2349338A1 (en) 2000-05-11
NO20012155L (no) 2001-07-02
EE200100245A (et) 2002-10-15
OA11670A (en) 2005-01-12
EA200100396A1 (ru) 2001-10-22
HUP0104192A2 (hu) 2002-02-28
CA2349338C (en) 2005-12-06
UY25780A1 (es) 2001-08-27
GT199900192A (es) 2001-04-26
BG105543A (en) 2001-12-29
TR200200434T2 (tr) 2002-09-23
WO2000026224A2 (en) 2000-05-11
TR200101241T2 (tr) 2001-09-21
PA8485101A1 (es) 2002-08-26
IS5919A (is) 2001-04-17
US7071170B2 (en) 2006-07-04
CZ20011512A3 (cs) 2001-09-12
CN1376160A (zh) 2002-10-23
TR200200435T2 (tr) 2002-07-22
US20050004047A1 (en) 2005-01-06
EP1124837A2 (en) 2001-08-22
SK5812001A3 (en) 2001-12-03
AU5995299A (en) 2000-05-22
ZA200103289B (en) 2002-08-28
ID28286A (id) 2001-05-10
TR200200436T2 (tr) 2002-06-21
NO20012155D0 (no) 2001-05-02
HUP0104192A3 (en) 2003-12-29
JP4043191B2 (ja) 2008-02-06
US6835716B2 (en) 2004-12-28
PE20001289A1 (es) 2000-11-22
JP2002528553A (ja) 2002-09-03
AP2001002131A0 (en) 2001-06-30
CO5140110A1 (es) 2002-03-22
BR9914998A (pt) 2001-07-10
PL348114A1 (en) 2002-05-06
US20030013665A1 (en) 2003-01-16
IL142628A0 (en) 2002-03-10
KR20010083944A (ko) 2001-09-03
WO2000026224A3 (en) 2000-11-16
TNSN99205A1 (fr) 2005-11-10
HK1049010A1 (zh) 2003-04-25
MA26703A1 (fr) 2004-12-20

Similar Documents

Publication Publication Date Title
US6835716B2 (en) Macrolide antibiotics
AU745006C (en) C-4''-substituted macrolide derivatives
US6300316B1 (en) C-4 substituted macrolide antibiotics
EP0988310B9 (en) 4"-substituted-9-deoxo-9a-aza-9a-homoerythromycin a derivatives
EP0941998B1 (en) 3,6-ketal macrolide antibiotics
WO1998056800A1 (en) 9-oxime erythromycin derivatives
US6576749B2 (en) C-4″-substituted macrolide derivatives
EP0984019B1 (en) C11 carbamates of macrolide antibacterials
EP0992509B1 (en) Novel macrolide derivatives
US6162794A (en) Erythromycin derivatives
US20020151507A1 (en) 9-oxime erythromycin derivatives
EP1115732B1 (en) Carbamate and carbazate ketolide antibiotics
US20010016574A1 (en) 9a,11b-dehydro derivatives of 9-oxime-3-keto-6-O- methylerythromycin
MXPA01004418A (en) Novel macrolide antibiotics
EP1437360A2 (en) C11 Carbamates of macrolide antibacterials

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: PFIZER PRODUCTS INC., CONNECTICUT

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:KANEKO, TAKUSHI;REEL/FRAME:014923/0158

Effective date: 20040728

Owner name: PFIZER INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:KANEKO, TAKUSHI;REEL/FRAME:014923/0158

Effective date: 20040728