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
  • A61P31/04—Antibacterial agents

Definitions

• United States Patent 5,444,051 and United States Patent 5,770,579 disclose 6-O- substituted-3-oxoerythromycin derivatives in which the substituents are selected from alkyl, -CONH2, -CONHC(O)alkyl and -CONHSO2alkyl.
• PCT application WO 97/10251, published March 20, 1997 discloses 6-O-methyl 3-descladinose erythromycin derivatives.
• R is selected from the group consisting of: .
• step (c) reacting the compound obtained in step (b) with an amine of the formula H 2 N- W-R , wherein W and R are as defined above, anhydrous ammonia, or ammonium hydroxide; (d) optionally removing the cladinose sugar and oxidizing the resulting hydroxy group; and
• Ci-C ⁇ alkynyl refers to straight- or branched-chain hydrocarbon radicals comprising one to six carbon atoms, respectively, which contain one or more carbon-carbon triple bonds. Compounds of the invention have either a known configuration or exist as a mixture of isomers.
• aryl refers to a mono-, fused bicyclic or fused tricyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl. naphthyl, indanyl, indenyl. tetrahydronaphthyl, anthracenyl, phenanthrenyl, biphenylenyl, fluorenyl, and the like.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• pharmaceutically acceptable solvate represents an aggregate that comprises one or more molecules of the solute, such as a compound of the invention, with one or more molecules of solvent.
• compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers.
• pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
• the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
• treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of a compounds of the invention per day in a single or multiple doses.
• AIBN for azobisisobutyronitrile
• Bu3SnH for tributyltin hydride
• CDI carbonyldiimidazole
• DBU for l,8-diazabicyclo[5.4.0]undec-7-ene
• DEAD for diethylazodi-carboxylate
• DMF for dimethylformamide
• DMSO for dimethylsulfoxide
• DPPA diphenylphosphoryl azide
• Et3N for triethylamine
• EtOAc for ethyl acetate
• Et2 ⁇ for diethyl ether
• EtOH for ethanol
• HO Ac for acetic acid
• MeOH for methanol
• NaN(TMS) 2 for sodium bis(trimethylsilyl)amide
• NCS for N- chlorosuccinimide
• NMMO for N-methylmorpholine N-oxide
• Me 2 S for dimethyl sulfide
• Exemplary conditions for converting the protected oxime N-O-C(R y )(R z )-O-R x , wherein R x , R y , and R z are as defined above, to the oxime (N-OH) involve treating compound 2 or 3 with aqueous acid in acetonitrile.
• Aqueous acids suitable for the reaction include, but are not limited to, aqueous acetic acid, hydrochloric acid, and sulfuric acid.
• the 2'- and 4"-hydroxy protecting groups R p and R p
• a thorough discussion of the procedures, reagents and conditions for removing protecting groups is discussed by T. W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Son, Inc., (1991), which is herein incorporated by reference.
• the 2 '-hydroxy group of the macrolide is optionally protected as previously described using a hydroxy protecting reagent in an aprotic solvent.
• Preferred hydroxy protecting reagents are acetic anhydride, benzoyl anhydride, benzyl chloroformate or trialkylsilyl chloride.
• the aprotic solvent is dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof.
• a particularly preferred protecting group RP is acetate or benzoate. Protection of the hydroxy group can be accomplished before or after the descladinozation reaction.
• Compound 8 is reacted with a primary amine R 4 -W-NH2 , wherein R 4 and W are as previously defined.
• the reaction is carried out in a suitable solvent from room temperature to reflux temperature for about 4 to about 48 hours.
• exemplary solvents are acetonitrile, tetrahydrofuran, dimethyl formamide, dimethylsulfoxide, dimethyl ether, N- methyl pyrrolidinone, water, or a mixture thereof.
• Preferred solvents are aqueous acetonitrile, and aqueous DMF.
• Step 3(h): Compound of formula (II-A): wherein A is -O-; X is N-OH; -M- is -CH7- CH CH-; R 2 is 3-quinolyl; and R p is benzoyl.
• NCS 1.7 eq.
• Me 2 S 2.5 eq.
• White precipitate is formed.
• the compound obtained from step 3(g) (1 eq.) in of CH 2 CI 2 is added slowly to the mixture over a 15 minutes period. The mixture is stirred for 40 minutes at -10°C and Et 3 N was added.
• Step 4(a): Compound 2 from Scheme 1. wherein V is N-O-(l-isopropoxycvclohexyl); R is -M-R 1 , wherein -M- is -CH Z -CH CH- and R 1 is hydrogen; R p is benzoyl: and R p2 is benzoyl.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Oncology (AREA)
• Animal Behavior & Ethology (AREA)
• Communicable Diseases (AREA)
• Public Health (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biochemistry (AREA)
• Biotechnology (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Cephalosporin Compounds (AREA)

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• 2000
  • 2000-05-31 CA CA002378671A patent/CA2378671C/en not_active Expired - Fee Related
  • 2000-05-31 JP JP2001502437A patent/JP2003501439A/ja active Pending
  • 2000-05-31 DE DE60005334T patent/DE60005334T2/de not_active Expired - Fee Related
  • 2000-05-31 DK DK00936424T patent/DK1181300T3/da active
  • 2000-05-31 WO PCT/US2000/014923 patent/WO2000075156A1/en not_active Ceased
  • 2000-05-31 AT AT00936424T patent/ATE250076T1/de not_active IP Right Cessation
  • 2000-05-31 PT PT00936424T patent/PT1181300E/pt unknown
  • 2000-05-31 EP EP00936424A patent/EP1181300B1/en not_active Expired - Lifetime
  • 2000-05-31 MX MXPA01012661A patent/MXPA01012661A/es active IP Right Grant
  • 2000-05-31 ES ES00936424T patent/ES2208334T3/es not_active Expired - Lifetime

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