US20020115621A1 - Macrolide antibiotics - Google Patents

Macrolide antibiotics Download PDF

Info

Publication number
US20020115621A1
US20020115621A1 US09/920,141 US92014101A US2002115621A1 US 20020115621 A1 US20020115621 A1 US 20020115621A1 US 92014101 A US92014101 A US 92014101A US 2002115621 A1 US2002115621 A1 US 2002115621A1
Authority
US
United States
Prior art keywords
alkyl
together form
taken together
cyclic carbonate
ethyl
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
US09/920,141
Other languages
English (en)
Inventor
Wei-Gu Su
Yan Chen
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
Individual
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 Individual filed Critical Individual
Priority to US09/920,141 priority Critical patent/US20020115621A1/en
Publication of US20020115621A1 publication Critical patent/US20020115621A1/en
Priority to US10/454,354 priority patent/US6849608B2/en
Assigned to PFIZER INC., PFIZER PRODUCTS INC. reassignment PFIZER INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, YAN, SU, WEI-GUO
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
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • This invention relates to macrolide compounds that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds.
  • This invention also relates to methods of preparing the compounds, intermediates useful in preparation of the compounds, and pharmaceutical compositions containing the compounds.
  • the present invention includes methods of treating bacterial and protozoal infections through the administration of the compounds to mammals, fish and birds requiring such treatment.
  • the present invention relates to compounds of the formula
  • X is CR 9 R 10 , O, NR 11 , or S, or X may, together with R 2 , form a 4 to 10-membered carbocyclic or 4- to 10 membered heterocyclic group wherein said 4- to 10-membered carbocyclic or 4- to 10 membered heterocyclic group is optionally substituted by 1 to 4 R 14 groups;
  • Z is —C( ⁇ O)—, —C( ⁇ NOR 13 )—, —CH(NR 11 R 12 )—, —N(R 2 )CH 2 —, or —CH 2 N(R 2 )—;
  • R 1 is H, OR 16 , C 1 -C 6 alkyl, (4- to 10-membered heterocyclic) C 0 -C 5 alkyl, or (C 6 -C 10 aryl) C 0 -C 6 alkyl;
  • R 2 is selected from H, C 1 -C 16 alkyl, C 2 -C 16 alkenyl, C 2 -C 16 alkynyl, (4- to 10-membered heterocyclic) C 0 -C 6 alkyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkynyl, (C 6 -C 10 aryl) C 0 -C 6 alkyl, (C 6 -C 10 aryl) C 2 -C 6 alkenyl, and (C 6 -C 10 aryl) C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6 alkyl, wherein one to three carbons of said C 1 -C 16 alkyl, C 2 -C 16 alkenyl
  • R 3 is selected from C 1 -C 16 alkyl, C 2 -C 16 alkenyl, C 2 -C 16 alkynyl, (4- to 10-membered heterocyclic) C 0 -C 6 alkyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkynyl, (C 6 -C 10 aryl) 0 o-C 6 alkyl, (C 6 -C 10 aryl) C 2 -C 6 alkenyl, and (C 6 -C 10 aryl) C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6 alkyl, and further wherein the aryl and heterocyclic moieties of each of the foregoing groups and optional substituents are optionally
  • R 1 and R 3 together can form ⁇ O or ⁇ NOR 13 ;
  • R 4 is H or OR 19 ;
  • C 10 , C 8 , and C 6 indicate carbon atoms of the macrolide ring of formula I to which the group is attached;
  • V is O or NR 17 ;
  • R 5 and R 7 are OH, or together form a group of the formula
  • J is selected from O, NR 15 , NOR 15 , and N—NR 15 ;
  • R 6 is H, —C(O)C 1 -C 6 alkyl, benzyl, benzyloxycarbonyl, or (C 1 -C 6 alkyl) 3 silyl;
  • R 8 is selected from C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 1 -C 6 alkoxy) C 1 -C 6 alkyl, (C 1 -C 6 alkylthio) C 1 -C 6 alkyl, (C 5 -C 8 cycloalkyl) C 2 -C 5 alpha branched alkyl, C 3 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, (4- to 10-membered heterocyclic) C 1 -C 6 alkyl, (C 6 -C 10 aryl) C 1 -C 6 alkyl, wherein one or more carbons of R 8 may be replaced with one or more heteroatoms selected from O, S, N and R 8 is optionally substituted with from one to four R 14 groups;
  • R 9 and R 10 are independently selected from H and C 1 -C 6 alkyl
  • each R 11 and R 12 is independently selected from H, C 1 -C 6 alkyl, C 6 -C 10 aryl, and 4- to 10-membered heterocyclic;
  • each R 13 is independently selected from H, C 1 -C 6 alkyl, (4- to 10-membered heterocyclic) C 0 -C 6 alkyl and (C 6 -C 1 Q aryl) C 0 -C 6 alkyl, wherein said aryl and heterocyclic groups are optionally substituted by 1 to 4 R 14 groups;
  • each R 14 is independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R 14a , —C(O)OR 14a , —OC(O)R 14a , —NR 11 C(O)R 14a , —C(O)NR 11 R 14a , —NR 11 R 14a , hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 6 -C 10 aryl) C 0 -C 6 alkyl, (4- to 10-membered heterocyclic) C 0 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, —S(O) j (C 0 -C 6 alkyl) wherein said C 0 -C 6 alkyl is optionally substituted by 1 to 10 R 14a groups,
  • each R 14a is independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)R 12 , —C(O)NR R 12 , —NR 11 R 12 , hydroxy, C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 6 -C 10 aryl) C 0 -C 6 alkyl, (4- to 10-membered heterocyclic) C 0 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, -S(O)k(C 0 -C 6 alkyl), —S(O) k (C 2 -C 6 alkenyl) where each k is an integer from 0 to 2, and SO
  • R 15 is selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, (4- to 10-membered heterocyclic) C 1 -C 6 alkyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkynyl, (C 6 -C 10 aryl) C 1 -C 6 alkyl, (C 1 -C 10 aryl) C 2 -C 6 alkenyl, and (C 6 -C 10 aryl) C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6 alkyl, and wherein said heterocyclic moieties are optionally substituted by (4- to 10-membered heterocyclic) C 0
  • R 16 is selected from H and C 1 -C 6 alkyl, wherein one to three carbons of said alkyl are optionally replaced with a heteroatom selected from O, S, and N;
  • R 17 is H, OR 16 , NR 16 R 18 , C 1 -C 16 alkyl, (C 6 -C 10 aryl) C 0 -C 6 alkyl, or (4- to 10-membered heterocyclic) C 0 -C 6 alkyl;
  • R 18 is H, or C 1 -C 6 alkyl wherein one or more carbons of said C 1 -C 6 alkyl are optionally replaced with one or more heteroatoms selected from O, N, and S and optionally substituted by R 14 , and
  • R 19 is selected from H, C 1 -C 16 alkyl, C 2 -C 16 alkenyl, C 2 -C 16 alkynyl, (4- to 10-membered heterocyclic) C 0 -C 6 alkyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkynyl, (C 6 -C 10 aryl) C 0 -C 6 alkyl, (C 6 -C 10 aryl) C 2 -C 6 alkenyl, and (C 6 -C 10 aryl) C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6 alkyl, wherein one to three carbons of said C 1 -C 16 alkyl, C 2 -C 16 alkenyl
  • the carbon to which R 1 , R 3 and XR 2 are attached is in the R configuration.
  • the carbon to which R 1 , R 3 and XR 2 are attached is in the S configuration.
  • X is O, CR 9 R 10 or NR 11 , R 1 is H, R 2 is H or optionally substituted C 1 -C 16 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 thioalkyl, (C 6 -C 10 aryl) C 0 -C 6 alkyl, or (4 to 10 membered heterocyclic) C 0 -C 6 alkyl and R 3 is optionally substituted (4 to 10 membered heterocyclic) C 0 -C 6 alkyl or optionally substituted (C 6 -C 10 aryl) C 0 -C 6 alkyl.
  • R 6 is H
  • R 4 is OMe
  • Z is (C ⁇ O)
  • R 5 and R 7 together with the carbons to which they are attached form C 11 —NH—C( ⁇ O)—O—C 12
  • R 8 is ethyl
  • R 6 is H, R 4 and Z together form a cyclic carbonate, R 5 and R 7 together form a cyclic carbonate, and R 3 is ethyl.
  • X is CR 9 R 10 or NR 11 .
  • XR 2 forms a 4- to 10-membered heterocyclic group wherein the 4- to 10-membered heterocyclic group is optionally substituted by 1 to 4 R 14 groups.
  • XR 2 is optionally substituted pyrrolin-1-yl, piperidin-1-yl, morpholin-1-yl, piperazin-1-yl, or pyrrolidin-1-yl.
  • R 1 is H and R 3 is optionally substituted 4- to 10-membered aryl or 4- to 10-membered heterocyclic.
  • R 3 is optionally substituted phenyl.
  • X is O and R 2 is allyl, or methoxymethyl.
  • X is NH and R 2 is propyl, or optionally substituted pyrid-2-yl, pyrid-3-yl, or benzyl.
  • R 4 is OH
  • R 6 is H
  • Z is CHNH 2
  • R 5 is OH
  • R 7 is OH
  • R 8 is ethyl
  • R 4 is OH
  • R 5 is OH
  • R 6 is H
  • R 7 is OH
  • R 8 is ethyl
  • Z is —N(CH 3 )CH 2 —.
  • R 4 is OH
  • R 5 is OH
  • R 6 is H
  • R 7 is OH
  • R 8 is ethyl
  • Z is —CH(NMe 2 )—.
  • R 8 is selected from methyl, n-propyl, isopropyl, cyclopropyl, propenyl, n-butyl, sec-butyl, tert-butyl, isobutyl, and cyclobutyl.
  • the invention also relates to a compound of the formula
  • Z is —C( ⁇ O)—, —C( ⁇ NOR 13 )—, —CH(NR 11 R 12 )—, —N(R 2 )CH 2 —, or —CH 2 N(R 2 )—;
  • R 4 is H or OR 19 ;
  • C 10 , C 8 , and C 6 indicate carbon atoms of the macrolide ring of formula I to which the group is attached;
  • V is O, or NR 17 ;
  • R 5 and R 7 together form a group of the formula
  • J is selected from O, NR 15 , NOR 15 , and N—NR 15 ;
  • R 6 is H, —C(O)C 1 -C 6 alkyl, benzyl, benzyloxycarbonyl, or (C 1 -C 6 alkyl) 3 silyl;
  • R 8 is selected from methyl, C 3 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 1 -C 6 alkoxy) C 1 -C 6 alkyl, (C 1 -C 6 alkylthio) C 1 -C 6 alkyl, (C 5 -C 8 cycloalkyl) C 2 -C 5 alpha branched alkyl, C 3 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, (4- to 10-membered heterocyclic) C 1 -C 6 alkyl, (C 6 -C 10 aryl) C 1 -C 6 alkyl, wherein one or more carbons of R 8 may be replaced with one or more heteroatoms selected from O, S, N and R 8 is optionally substituted with from one or four R 14 groups provided that R 8 is not ethyl;
  • each R 11 and R 12 is independently selected from H, C 1 -C 6 alkyl, C 6 -C 10 aryl, and 4- to 10-membered heterocyclic;
  • each R 13 is independently selected from H, C 1 -C 6 alkyl, (4- to 10-membered heterocyclic) C 0 -C 6 alkyl and (C 6 -C 10 aryl) C 0 -C 6 alkyl, wherein said aryl and heterocyclic groups are optionally substituted by 1 to 4 R 14 groups;
  • each R 14 is independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R 14a , —C(O)OR 14a , —OC(O)R 14a , —NR 11 C(O)R 14a , —C(O)NR 11 R 14a , —NR 11 R 14a , hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 6 -C 10 aryl) C 0 -C 6 alkyl, (4- to 10-membered heterocyclic) C 0 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, —S(O) j (C 0 -C 6 alkyl) wherein said C 0 -C 6 alkyl is optionally substituted by 1 to 10 R 14a groups,
  • each R 14a is independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —NR 11 R 12 , hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 6 -C 10 aryl) C 0 -C 6 alkyl, (4- to 10-membered heterocyclic) C 0 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy, —S(O) k (C 0 -C 6 alkyl), —S(O) k (C 2 -C 6 alkenyl) where each k is an integer from 0 to 2,
  • R 15 is selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -1o alkynyl, (4- to 10-membered heterocyclic) C 1 -C 6 alkyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkynyl, (C 6 -C 10 aryl) C 1 -C 6 alkyl, (C 6 -C 10 aryl) C 2 -C 6 alkenyl, and (C 6 -C 10 aryl) C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6 alkyl, and wherein said heterocyclic moieties are optionally substituted by (4- to 10-membered heterocyclic) C 0 -
  • R 16 is selected from H and C 1 -C 6 alkyl, wherein one to three carbons of said alkyl are optionally replaced with a heteroatom selected from O, S, and N;
  • R 17 is H, OR 16 , NR 16 R 18 , C 1 -C 16 alkyl, (C 6 -C 10 aryl) C 0 -C 6 alkyl, or (4- to 10-membered heterocyclic) C 0 -C 6 alkyl;
  • R 18 is H, or C 1 -C 6 alkyl wherein one or more carbons of said C 1 -C 6 alkyl are optionally replaced with one or more heteroatoms selected from O, N, and S and optionally substituted by R 14 ; and
  • R 19 is selected from H, C 1 -C 16 alkyl, C 2 -C 16 alkenyl, 4i alkynyl, (4- to 10-membered heterocyclic) C 0 -C 6 alkyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6 alkynyl, (C 6 -C 10 aryl) C 2 -C 6 alkyl, (C 6 -C 10 aryl) C 2 -C 6 alkenyl, and (C 6 C 10 aryl) C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6 alkyl, wherein one to three carbons of said C 1 -C 16 alkyl, C 2 -C 16 alkenyl, and C 2 -C
  • 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, prodrug, or solvate 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, prodrug, or solvate 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) and protozoa infection(s) include 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, Clostridium 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 burgdorferi; conjunctivitis, kerajtis, 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 Chiamydia 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 present invention also relates to a method of preparing the above compound of formula I wherein R 6 is H, which comprises deprotecting a compound of the following formula
  • R 6 is a protecting group
  • hydroxy protecting group includes acetyl, benzyloxycarbonyl, and various hydroxy protecting groups familiar to those skilled in the art including the groups referred to in T. W. Greene, P. G. M. Wuts, “Protective Groups In Organic Synthesis,” (J. Wiley & Sons, 1991).
  • halo as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.
  • alkyl includes saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties, or mixtures thereof. It is to be understood that where cyclic moieties are intended, at least three carbons in said alkyl must be present. Such cyclic moieties include cyclopropyl, cyclobutyl and cyclopentyl.
  • alkenyl includes straight-chain or branched-chain mono- or poly-unsaturated aliphatic hydrocarbon radicals containing at least one carbon-carbon double bond.
  • alkenyl radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z,E- and Z,Z-hexadienyl and the like.
  • alkynyl includes straight-chain or branched-chain mono- or poly-unsaturated aliphatic hydrocarbon radicals containing at least one carbon-carbon triple bond.
  • alkynyl radicals include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, hexynyl and the like.
  • alkoxy as used herein, unless otherwise indicated, includes —O-alkyl groups wherein alkyl is as defined above.
  • aryl includes an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
  • Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxygen or nitrogen atoms.
  • the heterocyclic groups also include partially unsaturated or fully saturated 4- to 10-membered ring systems, e.g., single rings of 4 to 8 atoms in size and bi- or tricyclic ring systems, including aromatic 6-membered aryl or heteroaryl rings fused to a non-aromatic ring.
  • An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azefidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyr
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole may be C-attached or N-attached where such is possible.
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • protecting group refers to a suitable chemical group that may be attached to a functional group and removed at a later stage to reveal the intact functional group. Examples of suitable protecting groups for various functional groups are described in T. W. Greene and P. G. M Wuts, Protective Groups in Organic Synthesis. 2 d Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).
  • 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 diastereomic 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.
  • the compounds of this invention include pharmaceutically acceptable derivatives or prodrugs thereof.
  • a “pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or a metabolite or residue thereof.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood), enhance delivery of the parent compound to a given biological compartment, increase solubility to allow administration by injection, after metabolism or alter rate of excretion.
  • Compounds of formula I can be converted into prodrugs through, for example, free amino, amido, hydroxy or carboxylic groups.
  • prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of formula I.
  • amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
  • prodrugs can be derivatized as amides or alkyl esters.
  • the amide and ester moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalites.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlined in D. Fleisher et al., Advanced Drug Delivery Reviews, 19:115 (1996).
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs and sulfate esters of hydroxy groups.
  • the compounds of this invention also include pharmaceutically acceptable salts of the compounds of formula I.
  • pharmaceutically acceptable salt(s) includes salts of acidic or basic groups that may be present in the compounds of the present invention.
  • the starting materials used in preparing the compounds of the present invention may require proper functional group protection before various modifications can take place, and deprotection after desired modifications are complete.
  • Hydroxyl groups are generally protected as acetates or Cbz carbonates.
  • the relative reactivities of various hydroxyl groups in the macrolide molecules of the general type claimed in this invention have been well established. Such differences in reactivity permit selective modification of different parts of the compounds of this invention.
  • the synthesis of compounds of the invention involves a coupling reaction of an activated carboxylic acid, such as acid chloride, acid anhydride, mixed anhydride, or acid in combination with an activating agent such as dicyclohexylcarbodiimide (DCC) or 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC), with an appropriately protected macrolide C-3 alcohol 3.
  • DCC dicyclohexylcarbodiimide
  • EDC 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
  • the final compounds are prepared by acid hydrolysis of the corresponding macrolides.
  • the preparation of macrolide C-3 alcohols is also described in WO 99121869 and WO 98/13373.
  • the alpha-ethers of the present invention are prepared by direct alkylation of the commercially available corresponding hydroxy esters, as shown in Scheme 2.
  • racemic ⁇ -hydroxy phenylacetic acid ethyl esters are treated with an alkyl halide and a base such as sodium hydride in an aprotic solvent such as tetrahydrofuran (THF) to provide the corresponding ether.
  • aprotic solvent such as tetrahydrofuran (THF)
  • allyl ethers can be obtained in optically pure form by treatment of the optically pure hydroxy esters with allyl bromide and silver oxide in a non-polar solvent such as heptane (see: G. A. Krause and Y. Wu, J. Org. Chem., 57, 2922 (1992)).
  • a non-polar solvent such as heptane
  • R- or S-mandelic acid is treated with allyl bromide in the presence of silver oxide in heptane at room temperature to give the corresponding R- or S—O-allyl ether, which upon treatment with an alkali hydroxide produces the mandelic acid O-allyl ether.
  • the alpha amino analogues of the invention are prepared using alkyloxycarbonyl amide protected amino acids.
  • alkyloxycarbonyl amide protected amino acids For instance, t-butyloxycarbonyl (BOC) protected phenylalanine is coupled with a macrolide template 3 to give the C-3 ester 7.
  • BOC deprotection is effected by treatment with an acid, such as trifluoroacetic acid or hydrochloric acid to produce the ⁇ -amino analogue 8.
  • Sequential reductive alkylation of the amino group provides the N-monealkyl 9 or N-bis-alkyl 10 derivatives.
  • alpha aminoalkyl derivatives of the invention can be prepared as illustrated below (Scheme 5).
  • X 2 is a leaving group such as chlorine, bromine, or sulfonate ester.
  • the reaction can be carried out in polar organic solvents including, but not limited to, dichloromethane, dichloroethane, N,N-dimethylformamide and acetonitrile.
  • alpha thioethers of the invention are prepared as depicted in Scheme 6.
  • an alpha halo carboxylic ester is treated with a thiol in the presence of an organic or inorganic base in a variety of solvents to give the corresponding thioether (see: R. D. Schultz and F. J. McCarty, J. Org. Chem., 28 (1963)).
  • Subsequent acid hydrolysis gives the carboxylic acid, which upon coupling with a macrolide C-3 alcohol 3 provides the C-3 ester alpha thioether 11.
  • the alpha carbon-linked esters of the invention are prepared following the general procedure shown in Scheme 6, starting from dialkyl malonate.
  • a base preferably polymer-bond base
  • alkyl halides yields the alpha dialkyl-substituted malonate derivatives.
  • Base-catalyzed acid hydrolysis followed by decarboxylation under acidic conditions produces alpha-alkyl carboxylic acids.
  • coupling with a macrolide template 3 gives the C-3 esters 13 and 14.
  • alpha branched carboxylic acids can be synthesized in optically pure form by well-known procedures (see: A. G. Myers and B. H. Yang, Org. Syn. 77, 22 (1999)).
  • alpha carbonyl derivatives; of the invention 15 are prepared as illustrated in Scheme 8, where X is C 1 -C 4 alkyl.
  • X is C 1 -C 4 alkyl.
  • treatment of a macrolide template 3 with alpha-keto-carboxylic acid chloride in the presence of a base provides the corresponding ester.
  • alpha keto esters can be obtained by oxidation of the alpha alcohol using a variety of oxidizing reagents, such as Dess-Martin reagent. These keto esters can be further transformed into the corresponding oximes or oxime ethers 18 under standard conditions (see: M. Orchiai, A. Morimoto, Y. Matsushita and T. Okada, J. Antibiotics, 160 (1981)).
  • R 8 is other than ethyl
  • Compounds of the present invention wherein R 8 is other than ethyl may be prepared using starting materials obtained as described, e.g., in WO 98/01546, published Jan. 15, 1998; WO 98/01571, published Jan. 15, 1998; WO 00/0500, published Jan. 6, 2000; and WO 00/00618, published Jan. 6, 2000.
  • the compounds of the present invention may have asymmetric carbon atoms and therefore exist in different enantiomeric and diastereomeric forms. Diastereomeric 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. The use of all such isomers, including diastereomer mixtures and pure enantiomers, are considered to be part of the present invention.
  • 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 mammals, 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 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 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 cations.
  • base salts include the alkali metal or alkaline-earth metal salts and particularly the sodium, amine 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, magnesium, various amine cations, etc.
  • These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable bases with cations such as sodium, potassium, calcium, magnesium, various amine cations, etc., 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 present invention includes all isotopically labelled forms of the compounds of formula I, and pharmaceutically acceptable salts and prodrugs thereof. Such isotopically labelled compounds are useful as research or diagnostic tools.
  • the isotopically-labelled compounds and pharmaceutically acceptable salts thereof are identical to those of formula I but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Examples of isotopes that can be incorporated into compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Cl, respectively.
  • isotopically labelled compounds of the present invention such as those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • Substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Scheme(s) and/or in the Example(s) below and substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the antibacterial and antiprotozoa 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 erm(A)/erm(B)/erm(C) are resistant to macrolides, lincosamides, and streptogramin B antibiotics due to modifications (methylation) of 23S rRNA molecules by an Erm methylase, thereby generally preventing the binding of all three structural classes.
  • msr(A) encodes a component of an efflux system in staphylococci that prevents the entry of macrolides and streptogramins
  • mef(A/E) originally described in streptococcal species
  • mef(A/E) encodes a transmembrane protein that appears to efflux 14- and 15-membered macrolides only.
  • 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.
  • the assay is performed in microtiter trays and interpreted according to Performance Standards for Antimicrobial Disk Susceptibility Tests—Sixth Edition: Approved Standard, published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines; the minimum inhibitory concentration (MIC) is used to compare strains.
  • Compounds are initially dissolved in dimethylsulfoxide (DMSO) as 40 mg/ml stock solutions.
  • DMSO dimethylsulfoxide
  • Assay II is utilized to test for activity against Pasteurella multocida and Assay Ill 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 range from 200 ⁇ g/ml to 0.098 ⁇ g/ml, achieved by two-fold serial dilutions.
  • 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 iii of the overnight P. haemolytica culture 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, from an initial concentrate of 100-200 ⁇ g/ml.
  • 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 ⁇ 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. 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, compounds are delivered in a volume of 0.2 ml 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, prodrugs, tautomers, and solvates thereof may be administered through oral, parenteral, topical, or rectal routes in the treatment of bacterial and 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. 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 intranous 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 administered 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.
  • the active compounds of the invention can also be administered in combination with other anti-infective agents, including commercially available agents such as, but not limited to, amoxicillin, penicillin, clarithromycin, cefaclor, cefuroxime, cefprozil, ciprofloxacin, clindamycin, fluconazole, dicloxacillin, erythromycin, metronidazole, ofloxacin, griseofulvin, sulfisoxazole, griseofulvin, cephalexin, terbinafine, levofloxacin, loracarbef, nitrofurantoin, minocycline, clotrimazole, nystatin, ketoconazole, cefdinir, ampicillin, trimethoprimsulfamethoxazole, itraconazole, cefixime, mebendazole, doxycycline, sparfloxacin, and azithromycin.
  • agents such as, but not limited to, amo
  • Step 1 Clarithromycin-11,12-carbamate-3-alcohol (Formula 3 wherein R 8 is Ac, R 4 is OMe, X is C ⁇ O, R 5 and R 7 together are C 11 —NH—C 12 O-cyclic carbamate and R 8 is ethyl) (see WO 99/21869) (1 mmol) was treated with acetic anhydride (1 mmol) in anhydrous dichloromethane (10 ml) at 23° C. After 12 hours, 5% aqueous sodium carbonate was introduced and the mixture stirred for 20 minutes. The layers were separated and the aqueous phase extracted with dichloromethane (3 ⁇ 20 ml). Combined organic extracts were washed with brine, dried over potassium carbonate, filtered, and concentrated in vacuo to yield clarithromycin 11,12-carbamate-2′-acetyl-3alcohol (100% yield).
  • Step 2 The product of Step 1 (1 mmol) was dissolved in dichloromethane (5 ml) at 0° C. and to it were added 4-dimethylaminopyridine (DMAP, 1 mmol), 1-(3[dimethylaminopropyl]-3-ethyl)-carbodiimide (EDC, 3 mmol) (or 1,3-dicyclohexylcarbodiimide (DCC, 3 mmol)) and (a-0-methoxymethyl)phenylacetic acid (3 mmol). The resulting mixture was stirred at 23° C. for 12 hours before saturated sodium bicarbonate solution was added.
  • DMAP 4-dimethylaminopyridine
  • EDC 1-(3[dimethylaminopropyl]-3-ethyl)-carbodiimide
  • DCC 1,3-dicyclohexylcarbodiimide
  • a-0-methoxymethyl)phenylacetic acid 3 mmol
  • Step 3 The R- and S-isomers obtained from Step 2 were separately treated with methanol at 23° C. for 24 hours. Removal of all volatiles gave the final products: clarithromycin 11,12-carbamate-3-descladinose-3-(R-O-methoxymethyl)-mandelic acid ester and clarithromycin 11,12-carbamate-3-descladinose-3-(S-O-methoxymethyl)phenylacetic acid ester.
  • Clarithromycin-11,12-carbamate-3-descladinose-3-(R- ⁇ -O-allyl)phenylacetic acid ester (product of Example 2, 100 mg) was dissolved in methanol (5 ml) and treated with hydrogen at 40 psi in the presence of palladium on carbon (10% w/w, 10 mg) at 23° C. for 2 hours. Filtration and concentration of the filtrate produced the title compound.
  • Clarithromycin-11,12-carbamate-3-descladinose-3-(S- ⁇ -O-allyl)phenylacetic acid ester 100 mg was dissolved in methanol (5 ml) and treated with hydrogen at 40 psi in the presence of palladium on carbon (10% w/w, 10 mg) at 23° C. for 2 hours. Filtration and concentration of the filtrate produced the title compound.
  • Step 1 Erythromycylamine (Formula 2 wherein R 4 is OH, R 6 is H, Z is CHNH 2 , R 5 is OH, R 7 is OH and R 8 is Et, 10 g, 13.56 mmol) was treated with N-(benzyloxycarboxy)succinimide (4.1 g, 16.27 mmol) in anhydrous dichloromethane (70 ml) at 23° C. After 18 hours, 5% aqueous sodium carbonate was introduced and the mixture stirred for 20 min. The layers were separated and the aqueous phase extracted with dichloromethane (3 ⁇ 50 ml). Combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield N-cbz-erythromycylamine (yield: 11.81 g)
  • Step 2 The product of Step 1 (7.44 g) was dissolved in benzene (150 ml) and to it were added ethylene carbonate (7.44 g) and potassium carbonate (3.8 g). The resulting mixture was heated and refluxed (bath temperature 110° C.) for 3 hours equipped with a Dean-Stock apparatus. Saturated sodium bicarbonate solution was added to the reaction mixture. After stirring for 20 minutes, the layers were separated and the aqueous phase was extracted with dichloromethane (3 ⁇ 20 ml). Combined organic extracts were washed with brine, dried over potassium carbonate,. filtered, and concentrated in vacuo to afford 11,12-carbonate-N-cbz-erythromycylamine. The crude compound was purified by silica gel column chromatography (SGC) using 4.5% methanol-dichloromethane containing 0.45% concentrated ammonium hydroxide. (4.6 g, 60%).
  • SGC silica gel column chromatography
  • Step 3 4.6 g of 11,12-carbonate-N-cbz-erythromycylamine obtained from Step 2 was taken into 90 ml of ethanol-2 N HCl mixed solvent (1:1) and the resulting solution was stirred at room temperature for 5 hours before it was neutralized with sodium carbonate to pH 9. The excess ethanol was evaporated under vacuum and the aqueous phase was extracted with dichloromethane (3 ⁇ 60 ml). Combined organic extracts were washed with brine, dried over potassium carbonate, filtered, and concentrated in vacuo to afford 11,12-carbonate-3-descladinose-N-cbz-erythromycylamine. The crude compound was purified by silica gel column chromatography (SGC) using 2.0% methanol-dichloromethane containing 0.07% concentrated ammonium hydroxide. (3.14 g, 80%).
  • SGC silica gel column chromatography
  • Step 4 3.14 g of 11,12-carbonate-3-descladinose-N-cbz-erythromycylamine obtained from Step 3 was treated with 0.44 ml of acetic anhydride (1.1 eq) in 25 ml of dichloromethane at room temperature over night. The reaction mixture was taken up into 150 ml of dichloromethane and washed with saturated sodium carbonate followed by brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3.32 g of N-cbz-erythromycylamine-11,12-carbonate-3-descladinose-2′-acetate in quantitative yield.
  • Step 5 The product of Step 4 (0.5 mmol) was dissolved in dichloromethane (3 ml) at ⁇ 10° C. and to it were added 4-dimethylaminopyridine (DMAP, 0.25 mmol), 1,3-dicyclohexylcarbodiimide (DCC, 1.5 mmol)) and ( ⁇ -O-allyl)phenylacetic acid (1.5 mmol). The resulting mixture was allowed to warm up to room temperature and stirred at 23° C. for 1 hour. The urea was filtered off before saturated sodium bicarbonate solution was added to the reaction mixture. After stirring for 20 minutes, the layers were separated and the aqueous phase was extracted with dichloromethane (3 ⁇ 20 ml).
  • DMAP 4-dimethylaminopyridine
  • DCC 1,3-dicyclohexylcarbodiimide
  • ⁇ -O-allyl)phenylacetic acid 1.5 mmol
  • Step 6 200 mg of the product of Step 5 was treated with 6 ml of TFA-CH 2 Cl 2 (2:1) solution at room temperature for 2 days. Water was added and the pH adjusted to 9 with 5N sodium hydroxide solution or solid sodium carbonate. Extraction with dichloromethane, drying over potassium carbonate, filtration and concentration of the filtrate to dryness afforded erythromycylamine-11,12-carbonate-2′-acetyl-3-descladinose-3-( ⁇ -O-allyl)phenylacetic acid ester. The crude was purified by silica gel column chromatography (SGC) using 2.5% methanol-dichloromethane containing 0.08% concentrated ammonium hydroxide. The yield was about 84%.
  • SGC silica gel column chromatography
  • Step 7 90 mg of the product of Step 6 was treated with methanol at 23° C. for 48 hours. Removal of all volatiles gave the final product erythromycylamine-11,12-carbonate-3-descladinose-3-( ⁇ -O-methoxymethyl)phenylacetic acid ester in 100% yield.
  • Step 1 600 mg (0.78 mmol) of the product from Step 1, Example 29 was treated with 424 mg (1.17 mmol, 1.5 eq) Dess-Martin reagent in 7 ml of dichloromethane at room temperature, stirred overnight The resulting mixture was taken up in 100 ml of dichloromethane and washed by 5% sodium carbonate solution and brine respectively. The organic layer was separated and dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2′-acetate clarithromycin 11,12-carbamate-3-descladinose-3-( ⁇ -oxo)phenylacetic acid ester. The pure compound was obtained by SGC separation using 20% acetone-hexane as eluent.
  • Step 2 The product obtained from Step 1 was treated with methanol at 23° C. for 24 hours. Removal of all volatiles gave the final product: clarithromycin 11,12-carbamate-3-descladinose-3-( ⁇ -oxo)phenylacetic acid ester.
  • Example 33 50 mg (0.06mmol) of the product from Step 2, Example 33 was treated with benzyl hydroxyamine (10-20 eq) in 5 ml of ethanol and refluxed for 2 hours. The reaction mixture was concentrated in vacuo to afford clarithromycin 11,12-carbamate-3-descladinose-3-( ⁇ -benzyloxime)phenylacetic acid ester as a mixture of E- and Z-diastereomers. The ratio of the two isomers is about 1 to 1. The compound was purified by silica gel column chromatography (SGC) using 3% methanol-dichloromethane.
  • SGC silica gel column chromatography
  • DMAP 4-dimethylaminopyridine
  • the resulting suspension was filtered to remove the precipitates.
  • the filtrate was taken up in 100 ml of ethyl acetate and successively washed with 5% Na 2 CO 3 and brine. Drying over sodium sulfate, filtration, and evaporation of the solvent gave the crude product.
  • the crude product was purified by SGC using acetone-hexane (1:5) as eluent to afford alpha-bromo ester in diastereomeric form.
  • Step 2 The product of Step 1 (100 mg) was dissolved in 1.0 ml of dry DMF under nitrogen. To it was added propylamine (3 equivalents). After stirring at room temperature for 5 hours, the reaction mixture was taken up in 30 ml of ethyl acetate, and successively washed with 30 ml of H 2 O, 30 ml of 5% aqueous sodium carbonate and brine. Drying over sodium sulfate, filtration, evaporation of solvent and SGC purification using 5% methanol-dichloromethane containing 0.1 to 0.5% concentrated ammonium hydroxide as eluent provided the alpha-propylamino ester.
  • Step 3 The product of Step 2 was dissolved in methanol and the resulting solution heated at reflux for 3 hours. Removal of the solvent and purification by preparative TLC or HPLC yielded pure R- and S-(alpha-propylamino)phenylacetic acid esters (Mass Spec: 805, (M+1)).
  • Step 2 Following the procedures of Example 36, Step 2, the corresponding alpha-propylamino ester was obtained in comparable yields.
  • Step 3 The product of Step 2 was dissolved in TFA-CH 2 Cl 2 (2:1) solution and stirred for 5 days to remove the N-Cbz group. After aqueous work up the crude material was dissolved in methanol and refluxed for 3 hours to remove the 2′-acetate to yield the final product. The pure R- and S-isomers of the (alpha-propylamino)phenylacetic acid ester were obtained after preparative TLC or HPLC separation. Overall yields ranged between 20 to 50% (Mass Spec: 779 (M+1)).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
US09/920,141 2000-08-07 2001-08-01 Macrolide antibiotics Abandoned US20020115621A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/920,141 US20020115621A1 (en) 2000-08-07 2001-08-01 Macrolide antibiotics
US10/454,354 US6849608B2 (en) 2000-08-07 2003-06-03 Macrolide antibiotics

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22359100P 2000-08-07 2000-08-07
US09/920,141 US20020115621A1 (en) 2000-08-07 2001-08-01 Macrolide antibiotics

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/454,354 Continuation US6849608B2 (en) 2000-08-07 2003-06-03 Macrolide antibiotics

Publications (1)

Publication Number Publication Date
US20020115621A1 true US20020115621A1 (en) 2002-08-22

Family

ID=22837162

Family Applications (2)

Application Number Title Priority Date Filing Date
US09/920,141 Abandoned US20020115621A1 (en) 2000-08-07 2001-08-01 Macrolide antibiotics
US10/454,354 Expired - Fee Related US6849608B2 (en) 2000-08-07 2003-06-03 Macrolide antibiotics

Family Applications After (1)

Application Number Title Priority Date Filing Date
US10/454,354 Expired - Fee Related US6849608B2 (en) 2000-08-07 2003-06-03 Macrolide antibiotics

Country Status (17)

Country Link
US (2) US20020115621A1 (es)
EP (1) EP1307468A1 (es)
JP (1) JP2004505987A (es)
AP (1) AP2001002236A0 (es)
AR (1) AR034695A1 (es)
AU (1) AU2001272719A1 (es)
BR (1) BR0112863A (es)
CA (1) CA2419044A1 (es)
DO (1) DOP2001000228A (es)
GT (1) GT200100159A (es)
HN (1) HN2001000176A (es)
MX (1) MXPA03001148A (es)
PA (1) PA8524501A1 (es)
PE (1) PE20020468A1 (es)
TN (1) TNSN01121A1 (es)
UY (1) UY26870A1 (es)
WO (1) WO2002012260A1 (es)

Cited By (12)

* 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
US20050209172A1 (en) * 2004-03-17 2005-09-22 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US20050220871A1 (en) * 2000-03-28 2005-10-06 Schwarz Franz X Taste masking granules
US20060116336A1 (en) * 2004-03-17 2006-06-01 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US20060135447A1 (en) * 2004-12-21 2006-06-22 Chupak Louis S Macrolides
US20080287376A1 (en) * 2004-07-28 2008-11-20 Mohammad Salman Ketolide Derivatives as Antibacterial Agents
US20090005325A1 (en) * 2005-11-23 2009-01-01 Biswajit Bas Ketolide Derivatives as Antibacterial Agents
US20090130225A1 (en) * 2005-11-23 2009-05-21 Anjan Chakrabarti Macrolides derivatives as antibacterial agents
US20090170790A1 (en) * 2004-10-25 2009-07-02 Biswajit Das Ketolide derivatives as antibacterial agents
CN105616437A (zh) * 2008-10-24 2016-06-01 森普拉制药公司 使用含三唑的大环内酯的生物防御
US10131684B2 (en) 2007-10-25 2018-11-20 Cempra Pharmaceuticals, Inc. Process for the preparation of macrolide antibacterial agents
US10188674B2 (en) 2012-03-27 2019-01-29 Cempra Pharmaceuticals, Inc. Parenteral formulations for administering macrolide antibiotics

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6825172B2 (en) 2002-05-31 2004-11-30 Janssen Pharmaceutica, Nv 3-descladinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide antibacterial agents
HRP20020885B1 (en) 2002-11-11 2007-05-31 GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. SUBSTITUTED 9a-N-{N'-[4-(SULFONYL)PHENYLCARBAMOYL]}DERIVATIVES 9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERITHROMYCIN A AND 5-O-DESOZAMINYL-9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERITHRONOLIDE A
CA2529817C (en) 2003-03-10 2013-02-12 Optimer Pharmaceuticals, Inc. Novel antibacterial agents
GB0310981D0 (en) * 2003-05-13 2003-06-18 Glaxo Group Ltd Novel compounds
HRP20030381B1 (en) * 2003-05-14 2007-05-31 GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. 3-DECLADINOZYL 9a-N-CARBAMOYL AND 9a-N-THIOCARBAMOYL DERIVATIVES 9-DEOXO-9-DIHYDRO-9a-AZA-9a-HOMOERYTHROMICYNE A
US7276487B2 (en) 2003-09-23 2007-10-02 Enanta Pharmaceuticals, Inc. 9a, 11-3C-bicyclic 9a-azalide derivatives
US7402568B2 (en) 2004-09-29 2008-07-22 Enanta Pharmaceuticals, Inc. Bicyclic 9a-azalide derivatives
US7271155B2 (en) 2005-01-07 2007-09-18 Enanta Pharmaceuticals, Inc. 9A, 11-2C-bicyclic 9a-azalide derivatives
ES2317527T3 (es) 2005-01-13 2009-04-16 Glaxosmithkline Istrazivacki Centar Zagreb D.O.O. Decladinosil-macrolidos que presentan actividad anti-inflamatoria.
US20070281894A1 (en) * 2006-06-05 2007-12-06 Auspex Pharmaceuticals, Inc. Preparation and utility of substituted erythromycin analogs
US9937194B1 (en) 2009-06-12 2018-04-10 Cempra Pharmaceuticals, Inc. Compounds and methods for treating inflammatory diseases
JP5914335B2 (ja) 2009-09-10 2016-05-11 センプラ ファーマシューティカルズ，インコーポレイテッド マラリア、結核、及びｍａｃ病の治療方法
NZ602544A (en) 2010-03-22 2014-11-28 Cempra Pharmaceuticals Inc Crystalline forms of a macrolide, and uses therefor
US9051346B2 (en) 2010-05-20 2015-06-09 Cempra Pharmaceuticals, Inc. Process for preparing triazole-containing ketolide antibiotics
JP6042334B2 (ja) 2010-09-10 2016-12-14 センプラ ファーマシューティカルズ，インコーポレイテッド 疾患治療のための水素結合形成フルオロケトライド
US9861616B2 (en) 2013-03-14 2018-01-09 Cempra Pharmaceuticals, Inc. Methods for treating respiratory diseases and formulations therefor
JP6675973B2 (ja) 2013-03-15 2020-04-08 センプラ ファーマシューティカルズ，インコーポレイテッド マクロライド抗菌薬を調製するための集束的な方法

Family Cites Families (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US25937A (en) 1859-11-01 ballou
US156027A (en) 1874-10-20 Improvement in loom-shuttles
US61857A (en) 1867-02-05 Improvement in top-drivers or spinners
US100518A (en) 1870-03-08 Roland s
US61856A (en) 1867-02-05 Enos s
US40007A (en) 1863-09-22 Improvement in railroad-car brakes
US3923784A (en) * 1973-09-10 1975-12-02 Hoffmann La Roche Erythromycin a derivatives
YU43006B (en) * 1981-03-06 1989-02-28 Pliva Pharm & Chem Works Process for preparing n-methyl-11-aza-10-deoxo-10-dihydro erythromycin 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
US5141926A (en) * 1990-04-18 1992-08-25 Abbott Laboratories Erythromycin derivatives
US5523399A (en) * 1991-12-27 1996-06-04 Taisho Pharmaceutical Co., Ltd. 5-O-desosaminylerythronolide derivatives
FR2745290B1 (fr) * 1996-02-28 1998-04-03 Roussel Uclaf Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments
FR2748746B1 (fr) * 1996-05-14 1998-08-14 Hoechst Marion Roussel Inc Nouveau procede d'isomerisation du radical methyle en 10 de derives de l'erythromycine
US5804565A (en) * 1996-09-24 1998-09-08 Taisho Pharmaceutical Co., Ltd. Erythromycin A derivatives
BR9713302A (pt) * 1996-11-27 2000-03-21 Taisho Pharmaceutical Co Ltd Derivado de eritromicina a, composição farmacêutica, preparação antibacteriana, processo para o tratamento de uma doença bacteriologicamente infecciosa, e, uso do derivado de eritromicina a ou um seu sal farcamaceuticamente aceitável.
AU6932098A (en) * 1997-05-09 1998-12-08 Pfizer Products Inc. Erythromycin derivatives
EP0895999A1 (en) * 1997-08-06 1999-02-10 Pfizer Products Inc. C-4" substituted macrolide antibiotics
ZA987689B (en) * 1997-09-02 1999-02-24 Abbott Lab 3-descladinose 6-O substituted erythromycin derivatives
HN1998000159A (es) * 1997-10-29 1999-02-09 Monsanto Co Derivados de 9- amino - 3 ceto eritromicina
JP2004514643A (ja) 1997-10-29 2004-05-20 大正製薬株式会社 エリスロマイシンａ誘導体
AU9649598A (en) 1997-10-29 1999-05-17 Taisho Pharmaceutical Co., Ltd. Erythromycin a, 11,12-carbamate derivatives
PA8461401A1 (es) * 1997-10-29 2000-05-24 Pfizer Prod Inc Derivados de eritromicina triciclicos
AU1504899A (en) * 1997-12-11 1999-06-28 Hokuriku Seiyaku Co. Ltd Erythromycin derivatives
AP1060A (en) 1998-01-02 2002-04-23 Pfizer Prod Inc Novel erythromycin derivatives.
AU3439899A (en) * 1998-06-03 1999-12-20 Pfizer Products Inc. Tricyclic 3-keto derivatives of 6-o-methylerythromycin
BR9916969A (pt) 1999-01-27 2001-11-06 Pfizer Prod Inc Antibióticos cetólidos
WO2001010880A1 (fr) 1999-08-06 2001-02-15 Taisho Pharmaceutical Co., Ltd. Derives d'erythromycine a
WO2001010878A1 (fr) 1999-08-06 2001-02-15 Taisho Pharmaceutical Co., Ltd. Derives d'erythromycine a
US6498146B1 (en) * 1999-10-28 2002-12-24 Pfizer Inc Erythromycin derivatives
EP1101769A3 (en) * 1999-11-18 2001-10-24 Pfizer Products Inc. Nitrogen containing erythromycin derivatives

Cited By (15)

* 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
US20050220871A1 (en) * 2000-03-28 2005-10-06 Schwarz Franz X Taste masking granules
US7468428B2 (en) 2004-03-17 2008-12-23 App Pharmaceuticals, Llc Lyophilized azithromycin formulation
US20050209172A1 (en) * 2004-03-17 2005-09-22 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US20060116336A1 (en) * 2004-03-17 2006-06-01 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US20080287376A1 (en) * 2004-07-28 2008-11-20 Mohammad Salman Ketolide Derivatives as Antibacterial Agents
US20090170790A1 (en) * 2004-10-25 2009-07-02 Biswajit Das Ketolide derivatives as antibacterial agents
US7462600B2 (en) 2004-12-21 2008-12-09 Pfizer Inc Macrolides
US20060135447A1 (en) * 2004-12-21 2006-06-22 Chupak Louis S Macrolides
EP2233493A1 (en) 2004-12-21 2010-09-29 Pfizer Products Inc. Macrolides
US20090005325A1 (en) * 2005-11-23 2009-01-01 Biswajit Bas Ketolide Derivatives as Antibacterial Agents
US20090130225A1 (en) * 2005-11-23 2009-05-21 Anjan Chakrabarti Macrolides derivatives as antibacterial agents
US10131684B2 (en) 2007-10-25 2018-11-20 Cempra Pharmaceuticals, Inc. Process for the preparation of macrolide antibacterial agents
CN105616437A (zh) * 2008-10-24 2016-06-01 森普拉制药公司 使用含三唑的大环内酯的生物防御
US10188674B2 (en) 2012-03-27 2019-01-29 Cempra Pharmaceuticals, Inc. Parenteral formulations for administering macrolide antibiotics

Also Published As

Publication number Publication date
UY26870A1 (es) 2002-03-22
CA2419044A1 (en) 2002-02-14
EP1307468A1 (en) 2003-05-07
US6849608B2 (en) 2005-02-01
AU2001272719A1 (en) 2002-02-18
WO2002012260A1 (en) 2002-02-14
BR0112863A (pt) 2003-07-01
HN2001000176A (es) 2001-10-08
JP2004505987A (ja) 2004-02-26
PA8524501A1 (es) 2002-08-29
TNSN01121A1 (fr) 2005-11-10
AP2001002236A0 (en) 2001-09-30
MXPA03001148A (es) 2003-06-09
DOP2001000228A (es) 2002-09-30
GT200100159A (es) 2002-03-22
PE20020468A1 (es) 2002-06-14
US20040009930A1 (en) 2004-01-15
AR034695A1 (es) 2004-03-17

Similar Documents

Publication Publication Date Title
US6849608B2 (en) Macrolide antibiotics
US6833444B2 (en) Ketolide antibiotics
EP0941998B1 (en) 3,6-ketal macrolide antibiotics
EP1131331B1 (en) 13-membered azalides and their use as antibiotic agents
US6100240A (en) Macrolide derivatives
US6555524B2 (en) Ketolide antibiotics
US6518251B1 (en) Macrolides
US6262030B1 (en) Erythromycin derivatives
EP1114826A2 (en) Novel antibacterial and prokinetic macrolides
CA2332686C (en) Novel 13 and 14-membered antibacterial and prokinetic macrolides and their intermediates
US6809080B2 (en) Macrolide antibiotics
US20030100742A1 (en) Erythromycin a derivatives
EP1115732B1 (en) Carbamate and carbazate ketolide antibiotics
US20020077302A1 (en) Tricyclic erythromycin derivatives
US20020061856A1 (en) Novel tricyclic erythromycin derivatives
EP1439186A2 (en) Intermediates for novel antibacterial and prokinetic macrolides

Legal Events

Date Code Title Description
AS Assignment

Owner name: PFIZER PRODUCTS INC., CONNECTICUT

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SU, WEI-GUO;CHEN, YAN;REEL/FRAME:014200/0920;SIGNING DATES FROM 20030602 TO 20030604

Owner name: PFIZER INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SU, WEI-GUO;CHEN, YAN;REEL/FRAME:014200/0920;SIGNING DATES FROM 20030602 TO 20030604

STCB Information on status: application discontinuation

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