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WO2013004116A1 - Dérivé de 9a-aza-9a-érythromycine c-3-substituée et 9-désoxydée - Google Patents

Dérivé de 9a-aza-9a-érythromycine c-3-substituée et 9-désoxydée Download PDF

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Publication number
WO2013004116A1
WO2013004116A1 PCT/CN2012/076470 CN2012076470W WO2013004116A1 WO 2013004116 A1 WO2013004116 A1 WO 2013004116A1 CN 2012076470 W CN2012076470 W CN 2012076470W WO 2013004116 A1 WO2013004116 A1 WO 2013004116A1
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Prior art keywords
methyl
ethyl
dimethylamino
oxy
hetero
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Chinese (zh)
Inventor
刘兴金
张许科
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LUOYANG HUIZHONG ANIMAL MEDICINE CO Ltd
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LUOYANG HUIZHONG ANIMAL MEDICINE CO Ltd
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    • 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
    • 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

Definitions

  • the present invention is in the field of medical technology and relates to novel C-3 substituted -9-deoxy-9A-aza-9A-homoerythromycin A derivatives, processes for their preparation and pharmaceutical compositions of the compounds.
  • the invention further relates to the use of the derivative for the manufacture of a medicament for the treatment and/or prevention of bacterial infections, protozoal infections.
  • Macrolides are an important class of anti-infectives. Since the discovery of erythromycin in 1952, after 60 years of development, it has become the second largest class of ⁇ -lactam antibiotics in clinical applications. Anti-infective drugs have made a huge contribution to the treatment of human and animal diseases.
  • the invention provides a
  • R 2 is a hydroxyl group
  • R 3 is a hetero atom-substituted or unsubstituted organic substance, and the hetero atom is one or more of halogen, N, 0 and S Species; is 11, benzyloxycarbonyl, benzoyl or acetyl.
  • R 2 o is an organic or inorganic group containing at least one of C, H, 0, N, S and halogen. More preferably, R 3 is -CH 2 NHR 3 o, wherein R 3 o is an organic or inorganic group containing at least one of C, H, 0, N, S and halogen.
  • R 3 o is preferably selected from the group consisting of H, amino, methyl, ethyl, allyl, n-butyl, isobutyl, 2-methoxyethyl, cyclopentyl, 3-methoxypropyl, 3-ethoxypropyl, n-propyl, isopropyl, 2-hydroxyethyl, cyclopropyl, 2,2,2-trifluoroethyl, 2-propynyl, sec-butyl, tert-butyl, Orthodecyl, vinyl, ethynyl, 1-methyl-1-propenyl, 3-methoxypropynyl, 3-dimethylamino-1-propynyl, 3-hydroxy-1-propanyl Block group, 3-hydroxy-1-propenyl, 3-hydroxypropyl, 3-methoxy-1-propenyl, 3-methoxypropyl, 1-propynyl, azidomethyl, A Acylmethyl, 6-cyan
  • R 3 is -CH 2 NH-(CH 2 ) m R4o, wherein m is an integer from 1 to 4, and 0 is at least C, H, 0, N, S and halogen An atomic organic or inorganic group. More preferably, R40 is selected from H, an organic group with or without a hetero atom, and the hetero atom is halogen, N, 0 or 8.
  • 0 is preferably selected from -C20 fluorenyl group, dC 6 decyloxy group, C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, and 5-20 with or without a hetero atom.
  • a aryl or heteroaryl group, and the aforementioned group may be optionally bonded to a carbon-containing substituent.
  • 0 is a C 6 -C 1Q aryl group having a substituent or a C 5 -C 2Q heteroaryl group, and the hetero atom in the heteroaryl group is halogen, N, 0 or 8.
  • R 3 is -CH 2 SR 5Q , wherein R 5 () is an organic substance substituted or unsubstituted with a hetero atom which is halogen, N, 0 or S.
  • R 5Q is selected from the group consisting of d- o fluorenyl with or without a hetero atom, dC 6 decyloxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and 5-20 aryl Or a heteroaryl group, and the aforementioned group may be optionally bonded to a carbon-containing substituent group.
  • R 5 o is methyl, ethyl, allyl, n-butyl, isobutyl, 2-methoxyethyl, cyclopentyl, 3-methoxypropyl , 3-ethoxypropyl, n-propyl, isopropyl, 2-hydroxyethyl, cyclopropyl, sec-butyl, tert-butyl, or n-hexyl.
  • hydroxyl group is 11.
  • the compound of formula (I) of the invention is specifically:
  • 111) (21, 33, 41, 5, 811, 1011, 111, 128, 138, 141)-1 1-[[3,4,6-Trideoxy-3-(dimethylamino)-oxime-0-hexpyran Xylose]oxy]-2-ethyl-13- ⁇ [(furan-2-yl-methyl)-amino]-methyl ⁇ -3,4,10,13-tetrahydroxy-3,5, 8,10,12,14-hexamethyloxy-hetero-6-azacyclopentadecane-15-one;
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a bacterial infection or a protozoal infection of a mammal, fish or bird; or the compound of the present invention for synthesizing other macrolide antibiotics The use of intermediates.
  • the invention also provides a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the starting compound 1 can be prepared or commercially available according to synthetic methods well known to those skilled in the art, including the synthetic methods described in U.S. Patent 4,474,768 and U.S. Patent 4,517,359.
  • the C-2' hydroxyl group in the compound 1 can be selectively protected by treating the compound 1 with an equivalent amount of acetic anhydride in methylene chloride in the absence of an external base, wherein R4 is an acetyl group. a compound of formula II.
  • the acetyl protecting group can be removed by treating the compound of formula II with methanol at 23 ⁇ 65'C for 10 to 48 hours.
  • the hydroxyl group of C-2' can also be protected using other hydroxy protecting groups well known to those skilled in the art, such as benzyloxycarbonyl (Cbz), during which the hydroxyl group of C-4" is also protected, but does not affect subsequent experiments.
  • 'Hydroxyl can be protected by treatment with a benzyl chloroformate in tetrahydrofuran and water in a compound of formula II using Cbz selectivity in one step.
  • the Cbz group can be removed using conventional catalytic hydrogenation, or it can be used in a suitable manner as is well known in the art.
  • the organic solvent can be removed by reacting for 2 to 5 days in a temperature range of about room temperature to about 100 ° C.
  • the hydroxyl groups of C-2' and C-4" are considered by those skilled in the art. The proper form is protected or deprotected.
  • step b SP: For the removal of the C-3 claratin sugar, the de-sugaring compound of the formula III is obtained by removing it with hydrochloric acid in ethanol/water using a removal method well known to those skilled in the art.
  • the hydroxyl group of C-3 of the formula III is oxidized.
  • the synthesis focus on the mother nucleus concentrates on the oxidation of the hydroxyl group at the C-3 position.
  • the C-3 hydroxyl group of formula III is oxidized to the corresponding ketone by methods well known to those skilled in the art, including one or more of the methods described in Jcrnmal of Anti-biotics, 1988, pages 1029-1047.
  • a ketone of formula IV can be prepared using dimethyl sulfoxide and a suitable activator.
  • the reaction conditions conventionally used for oxidation include: a) Corey-kim oxidation: J. Med.
  • the oxidation method in step c is preferably dimethyl sulfoxide and trifluoroacetic anhydride and triethylamine for oxidation.
  • the protected defatted material is dissolved in a suitable solvent: dichloromethyl hydrazine, acetone, ethyl acetate, isopropyl acetate
  • the ester or the like is preferably dichloromethane, and then trifluoroacetic anhydride is added, preferably dropwise, and the reaction is carried out for 0 to 3 hours.
  • Triethylamine is added dropwise, and the reaction is carried out for 0 to 3 hours.
  • step c using 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride/dimethylsulfoxide in dichloromethane with a compound of formula III, stirring, cooling To -15 ° C ⁇ 25 ° C, preferably 0 ° C, adding trifluoroacetic acid pyridinium chloride
  • the hydrocarbon generation solution has a controlled temperature of 3'C or less, and the reaction is completed to obtain the oxide of the general formula IV.
  • step d the compound of the formula 3b can be obtained in two ways.
  • a sodium base such as sodium hydride
  • a solvent such as tetrahydrofuran, an ether solvent
  • hydrazine hydrazine-dimethyl
  • the compound of the formula V can be obtained by treating the compound of the formula IV in a temperature range of from 0 Torr to about 60 ° C in a carboxamide, or dimethyl sulfoxide, or a mixture of two or more of the foregoing solvents.
  • the compound of the formula V can be converted into an organic substance in which R 2 is a hydroxyl group and R 3 is a hetero atom substituted or unsubstituted, and the hetero atom is one of halogen, N, 0 and S or More specifically; R 3 is -CH 2 R 20 , wherein R 2 o is an organic or inorganic group containing at least one of C, H, 0, N, S and halogen.
  • the formula HR 2Q can be used as a starting material, in a solvent having or without polarity such as water, methanol, tetrahydrofuran, or a mixture thereof, at about room temperature to about In the temperature range of 100 ° C, preferably 60 ⁇ , any treatment in the presence of a reagent such as potassium iodide, magnesium perchlorate, lithium tetrafluoroborate, pyridine hydrochloride or tetradecyl halogenated hinge halogenating reagent such as tetrabutylammonium bromide
  • a reagent such as potassium iodide, magnesium perchlorate, lithium tetrafluoroborate, pyridine hydrochloride or tetradecyl halogenated hinge halogenating reagent such as tetrabutylammonium bromide
  • a compound of the formula V gives a compound of the formula (I). The process is especially useful when R 3 is -CH 2 NHR
  • the general formula HSR 5 o can be used as a starting material, in the presence or absence of a polar solvent such as water, methanol, tetrahydrofuran, or a mixture thereof, at about room temperature to about In the temperature range of 100'C, preferably 60'C, in the presence of a reagent such as potassium iodide, magnesium perchlorate, lithium tetrafluoroborate, pyridine hydrochloride or tetradecyl ammonium halide halogenating reagent such as tetrabutylammonium bromide
  • a reagent such as potassium iodide, magnesium perchlorate, lithium tetrafluoroborate, pyridine hydrochloride or tetradecyl ammonium halide halogenating reagent such as tetrabutylammonium bromide
  • the compound of the formula V is treated to give a compound of the formula (I) a C-3-substitute
  • halogen in the present invention includes, unless otherwise stated, fluorine, chlorine, bromine or iodine.
  • mercapto in the present invention includes, unless otherwise stated, saturated monovalent hydrocarbon residues having a linear, cyclic or branched chain or a mixture thereof. It will be understood that when referring to the cyclic moiety, there are at least 3 carbon atoms in the hydrocarbyl group. Such cyclic moieties include, for example, cyclopropyl, cyclobutyl and cyclopentyl.
  • alkoxy in the present invention, unless otherwise specified, includes -0-alkyl, wherein alkyl is as defined above.
  • aryl in the present invention includes, unless otherwise stated, an organic residue derived from an aromatic hydrocarbon by removal of a hydrogen such as a phenyl group or a naphthyl group.
  • 5*20-membered heteroaryl in the present invention includes, unless otherwise stated, an aromatic heterocyclic group containing one or more hetero atoms each selected from 0, S and N, wherein each heterocyclic group It has 5-20 atoms in the ring system.
  • suitable 5-20 membered heteroaryl groups include pyridinyl, furyl, thienyl, pyrazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazine
  • the compounds of the invention may contain asymmetric carbon atoms and thus exist in different enantiomeric and diastereomeric forms.
  • the mixture of diastereomers can be separated into individual diastereomers according to their respective physicochemical differences using methods known in the art, for example, by chromatography or fractional crystallization. Conversion of the enantiomeric mixture to a mixture of diastereomers by reaction with a suitable optically active compound (eg, an alcohol), followed by separation of the diastereomers and conversion (eg, hydrolysis) of the individual diastereomers affords the corresponding pure Enantiomer.
  • a suitable optically active compound eg, an alcohol
  • conversion eg, hydrolysis
  • Treatment includes the use of a composition of the invention to treat or prevent a bacterial infection or a protozoal infection.
  • Bacterial infection and “protozoal infection” as used herein, unless otherwise indicated, include bacterial infections and protozoal infections that occur in mammals, birds, fish, and can be administered by the use of antibiotics such as the compounds of the invention. Treatment and prevention of bacterial infections and diseases of protozoal infections.
  • the bacterial infections and protozoal infections of the present invention and human diseases caused by diseases of these infections include: by pathogenic streptococci, Haemophilus influenzae, Moraxella, Staphylococcus aureus, Legionella, Actinobacilli, mycoplasma, chlamydia, pneumonia, bronchitis, otitis media, sinusitis, tonsillitis, pharyngitis, nephritis; fever, skin and soft tissue infections caused by pathogenic staphylococci, streptococci, coryneform bacteria, Abscess, osteomyelitis; urinary tract disease caused by pathogenic staphylococcus, enterococci, chlamydia, spirochete, mycoplasma, Neisseria infection, cervicitis, gonorrhea infection, sexually transmitted diseases, etc.; Lyme disease caused by spirochete infection; conjunctivitis caused by Chlamydia trachomati
  • the bacterial infections and protozoal infections of the animals which can be treated and prevented according to the invention and diseases involving these infections include the following diseases: from the hemolytic Pasteurella, Pasteurella multocida, M. bovis, or Bo Bovine respiratory diseases caused by Deuterium infection; bovine intestinal diseases caused by infection with Escherichia coli or protozoa (such as coccidia); by Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, lactation Cow mastitis caused by Streptococcus, Klebsiella, Corynebacterium, Enterococcus infection; Bovine and swine metritis caused by E.
  • protozoal diseases caused by protozoa such
  • the therapeutic dose of the effective dose of the present invention is 2-50 mg/kg, preferably 10 mg/kg, in a single administration.
  • the "pharmaceutically acceptable salts" of the present invention include, unless otherwise stated, salts of acids or bases which may be present in the compounds of the invention.
  • the compounds of the invention which are basic in nature can form salts with various inorganic or organic acids.
  • a pharmaceutically acceptable acid useful in the preparation of a basic compound of the invention including inorganic or organic acids, such as formate, acetate, propionate, lactate, citrate, tartrate, Oxalate, malate, hydrochloride, sulphate, nitrate, bisulfate, phosphate, acid salt, nicotinate, salicylate, pantothenate, ascorbate, succinate , maleate, gentisate, fumarate, gluconate, gluconate, sucrose, benzoate, glutamate, methanesulfonate, ethanesulfonate, Toluenesulfonate, p-toluenesulfonate and various amino acids.
  • the pharmaceutical composition for treating a mammalian, avian or fish bacterial infection or a protozoan infection of the present invention comprises a compound containing the general formula (I) or a pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier means any diluent or adjuvant which can be used in the pharmaceutical field.
  • the pharmaceutical composition of the present invention is in the form of an oral preparation, an injection, or an external preparation.
  • the oral preparation of the present invention is a powder, a tablet, a capsule, a granule, a solution, a suspension.
  • the injection is a powder injection, an emulsion, a coagulant, a solution; the external preparation is an ointment, a drop.
  • the carrier in the pharmaceutical composition of the present invention refers to an auxiliary component necessary for the formulation of the pharmaceutical composition, and includes: a diluent, a solubilizer, an antioxidant, a flavoring agent, a preservative, an excipient, and a coagulating agent.
  • the examples provided below illustrate specific embodiments of the invention, but the invention is not limited to the scope of the following examples.
  • the derivative nuclear magnetic resonance spectrum was measured by Bruker ARX-400, and the mass spectrum was determined by LCQ Series LC/MS.
  • the high performance liquid phase was detected by Waters ultra performance liquid chromatography (UPLC) ACQUITY.
  • the raw materials and reagents used were labeled with the main reagents and The rest of the batch numbers are commercially available analytically pure or chemically pure.
  • the solvent ratios used in the silica gel column and thin layer chromatography are all volume ratios as understood by those skilled in the art unless otherwise stated.
  • the purpose of this example is to prepare a compound of the above formula 3, which is named: (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-2-ethyl-3, 4, 10 ,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-2-0- [( Phenylmethoxy)-hetero]- ⁇ -hexyranopyranosyl]oxy]oxyx-6-azacyclopentadecane-15-one.
  • Example 8 The "n-butylamine (0.395 mL, 0.2938, 4 mmoL)" in Example 8 was changed to use "3,4,5-trimethoxy-benzylamine (0.395 mL)", and the rest was the same as in Example 8. 0.08 g of the title compound was obtained.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "benzylamine 5 mL", and the rest was the same as in Example 14. A crude product of 0.28 g was obtained in the middle to give the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “tetrahydropyrrole 5 mL", and the rest was the same as in Example 14. Intermediate was obtained in 0.25 g of crude product to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "aniline 5 mL", and the rest was the same as in Example 14. A crude product of 0.30 g was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "1-methoxypropylamine 5 mL", and the residue obtained in the same manner as in Example 14 was obtained.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "n-hexylamine 5 mL", and the rest was the same as in Example 14. 0.33 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-ethoxypropanamine 5 mL", and the residue was obtained in the same manner as in Example 14 to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “diethylamine 5 mL", and the rest was the same as in Example 14. 0.24 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "N-methyl-n-butylamine 5 mL", and the rest was the same as in Example 14. 0.23 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “N-methyl-n-propylamine 5 mL", and the rest was the same as in Example 14. 0.2 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use “ethylamine 5 mL", and the rest was the same as in Example 14. 0.2 g of crude product was obtained in the middle to give the title compound.
  • Replacement page (Article 26) TLC RfN).51 (dichloroformamidine: methanol 7:1)
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "N-methylethylamine 5 mL", and the rest was the same as in Example 14. 0.29 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “2-trifluoroethylamine 5 mL", and the rest was the same as in Example 14. In the middle, 0.28 g of crude product was obtained, which gave the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "1-hydroxyethylamine 5 mL", and the rest was the same as in Example 14. In the middle, 0.27 g of crude product was obtained, which gave the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “dimethylamine 5 mL", and the rest was the same as in Example 14. 0.25 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “imidazole 4g", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL” in Example 14 was changed to use "bis(2-hydroxyethyl)amine 4g", and the rest was the same as in Example 14. A crude product of 0.25 g was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use “pyrrole 4 mL", and the rest was the same as in Example 14. A crude product of 0.25 g was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "N-methyl-1-hydroxyethylamine 4 mL", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "1,2,3-triazole 4g", and the rest was the same as in Example 14. In the middle, 0.28 g of crude product was obtained, which gave the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “2-propargylamine 4 mL", and the rest was the same as in Example 14. 0.27 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-methylimidazole 4g", and the rest was the same as in Example 14. In the middle, 0.29 g of crude product was obtained, which gave the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “divinylamine 4 mL", and the rest was the same as in Example 14. In the middle, 0.28 g of crude product was obtained, which gave the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use “diethanolamine 4 mL", and the rest was the same as in Example 14. In the middle, 0,23 g of crude product was obtained, and the title compound was finally obtained.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "methylamine 4 mL", and the rest was the same as in Example 14. A crude product of 0.25 g was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “isopropylamine 4 mL", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “3-methylbutylamine 4 mL", and the rest was the same as in Example 14. In the middle, 0.24 g of crude product was obtained, which gave the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “cycloethylamine 4 mL", and the rest was the same as in Example 14. 0.23 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “diethylamine 4 mL", and the rest was the same as in Example 14. 0.21 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use “cyclopentylamine 4 mL", and the rest was the same as in Example 14. 0.22 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use “p-methoxybenzylamine 4 mL", and the rest was the same as in Example 14. 0.23 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "sodium hydrogencarbonate 2.0 g and p-nitrobenzylamine hydrochloride 4.0 g", and the rest was the same as in Example 14. 0.23 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “p-chlorobenzylamine 4 mL", and the rest was the same as in Example 14. Intermediate was obtained in 0.25 g of crude product to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "3,4-difluorobenzylamine 4 mL", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “p-methylaminopyridine 4g", and the rest was the same as in Example 14. 0.24 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2,6-difluorobenzylamine 4 mL", and the rest was the same as in Example 14. A crude product of 0.25 g was obtained in the middle to give the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “p-fluorobenzylamine 4 mL", and the rest was the same as in Example 14. Intermediate was obtained in 0.25 g of crude product to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “3-fluorobenzylamine 4 mL", and the rest was the same as in Example 14. 0.25 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “o-fluorobenzylamine 4 mL", and the rest was the same as in Example 14. Intermediate was obtained in 0.25 g of crude product to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "2,4-difluorobenzylamine 4 mL", and the rest was the same as in Example 14. A crude product of 0.25 g was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "2,5-difluorobenzylamine 4 mL", and the rest was the same as in Example 14. 0.22 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "3,5-difluorobenzylamine 4 mL", and the rest was the same as in Example 14. 0.24 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "4.0 g of NaHC0 3 and 1-(4-fluorophenyl)piperazine hydrochloride 4.0 g", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “o-trifluoromethylbenzylamine 4 mL", and the rest was the same as in Example 14. 0.27 g of crude product was obtained in the middle to give the title compound.
  • Example 60 Replacement Page (Rule 26) (2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-13-[(3-trifluoromethyl-benzyl-amino)methyl]-l l-[[3, 4,6-trideoxy - 3 - (dimethylamino) - ⁇ -D- xylopyranosyl hexyl] oxy] -2-ethyl-3,5-tetrahydroxy--3,4,10,13- , 8,10,12,14-hexamethyloxy-hetero-6-nitrohecyclopentadecane-15-one (see below for structural formula)
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “m-trifluoromethylbenzylamine 4 mL", and the rest was the same as in Example 14. 0.24 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "sodium hydrogencarbonate 2.0 g and N-(2-fluorophenyl)ethylamine hydrochloride 4.0 g", and the rest was the same as in Example 14. A crude product of 0.25 g was obtained in the middle to give the title compound.
  • Example 26 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "sodium hydrogencarbonate 2.0 g and N-(3-fluorophenyl)ethylamine hydrochloride 4.0 g", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-fluoro-6-trifluoromethylbenzylamine 4.0g", and the rest was the same as in Example 14. 0.24 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "3-(N-methylamino)pyridine 4.0g", and the rest was the same as in Example 14. A crude product of 0.25 g was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "4-hydroxy-3-methoxy-benzylamine 4.0 mL", and the rest was the same as Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “pepperamine 4 mL", and the rest was the same as in Example 14. 0.27 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use 3-methoxybenzylamine 4 mL", and the remainder was the same as in Example 14. 0.25 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-methoxybenzylamine 4 mL", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-aminopyridine 4.0g", and the rest was the same as in Example 14. In the middle, 0.24 g of crude product was obtained, which gave the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “2-methoxyethylamine 4 mL", and the rest was the same as in Example 14.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "2-hydroxy-N-methylethylamine 4 mL", and the rest was the same as in Example 14. 0.22 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-methyl-aminopyridine 4.0g", and the rest was the same as in Example 14. 0.21 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to "hydroxylamine 4.0 g", and the rest was the same as in Example 14. Get a replacement page in the middle (Article 26) 0.21 g of crude product, the title compound was obtained.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-hydroxyethylamine 4 mL", and the rest was the same as in Example 14. A 0.20 g crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "3-fluoro-N-methylaniline 4 mL", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 26 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "3-amino-6-chloropyridine 4 mL", and the rest was the same as in Example 14. 0.22 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "4-hydroxy-n-butylamine 4 mL", and the rest was the same as in Example 14. A crude product of 0.25 g was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “4-aminomethylbenzoic acid 4.0 g", and the rest was the same as in Example 14. 0.24 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "2-allylamine 4 mL", and the rest was the same as in Example 14. 0.24 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "3-amino-1,4,4-trimethyl-cyclohexyl-methylamine 4 mL", and the rest was the same as in Example 14. A crude product of 0.25 g was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "2-(2-hydroxy)ethylaminoethylamine 4 mL", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "sodium hydrogencarbonate 3.0 g and 2-chloro-4-methoxybenzylamine hydrochloride 4.0 g", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "1-methyl-3-phenylpropylamine 4 mL", and the rest was the same as in Example 14. 0.22 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “piperazine 4g", and the rest was the same as in Example 14. 0.21 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use "4-methylaminopyridine 4g", and the residue obtained in the same manner as in Example 14 was obtained to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "4-methylamino-3-chloropyridine 4g", and the rest was the same as in Example 14. 0.21 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use “trifluoroacetamide 4g", and the rest was the same as in Example 14. In the middle, 0.24 g of crude product was obtained, which gave the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "4-methylamino-6-chloropyridine 4g", and the rest was the same as in Example 14. 0.24 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use “n-pentylamine 4 mL", and the rest was the same as in Example 14. 0.22 g of crude product was obtained in the middle to give the title compound.
  • Example 26 The "t-butylamine 4.5 mL" in Example 14 was changed to use “1H-benzo-2-aminoimidazole 4g", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 "4.5 mL of tert-butylamine” to use " ⁇ , ⁇ '- dimethyl - 4 mL hydrazine", to obtain 0.23 g of crude product remaining with the intermediate of Example 14, to give the final title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “2,6-difluoro-4-methoxybenzylamine 4 mL", and the rest was the same as Example 14. 0.24 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “diethylene glycolamine 4 mL", and the rest was the same as in Example 14. A 0.20 g crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-chloroethylamine hydrochloride 4.0 g", and the residue obtained in the same manner as in Example 14 was obtained.
  • Example 14 The “tert-butylamine 4.5 mL” in Example 14 was changed to use "2-aminobutyric acid 4.0g", and the rest was the same as in Example 14. 0.22 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use " ⁇ -aminopropionic acid amine 4.0g", and the rest was the same as in Example 14. 0.24 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-nitro-4-fluoroaniline 4g", and the rest was the same as in Example 14. A crude product of 0.25 g was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-fluoro-4-bromoaniline 4g", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2-amino-5-bromo-pyrimidine 4g", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use "3,5-bistrifluoromethylaniline 4 mL", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "t-butylamine 4.5 mL" in Example 14 was changed to use “N-methylaminomorpholine 4 mL", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "3,4-diaminopyridine 4g", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use "2,4-dimethylaniline 4 mL", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.
  • Example 14 The "tert-butylamine 4.5 mL" in Example 14 was changed to use “3-chloroaniline 4 mL", and the rest was the same as in Example 14. 0.26 g of crude product was obtained in the middle to give the title compound.

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Abstract

La présente invention porte sur un composé tel que représenté par la formule générale (I) et un sel pharmaceutiquement acceptable de celui-ci, dans laquelle formule R1 représente H, le groupe hydroxyle ou le groupe méthoxy ; R2 représente le groupe hydroxyle ; R3 représente une matière organique non substituée ou substituée par un hétéroatome, l'hétéroatome étant un ou plusieurs hétéroatomes choisis parmi les atomes d'halogènes, N, O et S ; et R4 représente H, le groupe carbobenzoxy, le groupe benzoyle ou le groupe acétyle. Le composé de la présente invention tel que représenté par la formule générale (I) est un agent antibactérien et il peut être utilisé pour le traitement de diverses infections causées par des bactéries et des protozoaires. La présente invention porte également sur une utilisation du composé, sur un procédé de préparation de celui-ci et sur une composition formée avec celui-ci.
PCT/CN2012/076470 2011-07-06 2012-06-05 Dérivé de 9a-aza-9a-érythromycine c-3-substituée et 9-désoxydée Ceased WO2013004116A1 (fr)

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CN103232501A (zh) * 2013-04-11 2013-08-07 宜昌东阳光药业股份有限公司 阿奇霉素或阿奇霉素的中间体脱去克拉定糖化合物的制备工艺
CN104693251B (zh) * 2015-02-26 2018-05-01 齐鲁晟华制药有限公司 加米霉素或其前驱体13-脱克拉定糖化合物的制备方法
WO2020106627A1 (fr) * 2018-11-19 2020-05-28 Zikani Therapeutics, Inc. Macrolides à 13 chaînons à substitution alkylène en c10 et leurs utilisations

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CN85103264A (zh) * 1984-04-13 1987-01-14 美国辉瑞有限公司 9a-氮杂-9a-高红霉素衍生物
CN1229085A (zh) * 1997-12-31 1999-09-22 普利瓦药物，化学，食品，化妆品工业公司 9－去氧－9a－N－乙烯基－9a－氮杂－9a－高红霉素A的β,β－二取代衍生物
CN101691390A (zh) * 1997-06-11 2010-04-07 辉瑞产品公司 4”-取代的-9-脱氧-9a-氮杂-9a-高红霉素a衍生物

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US4512982A (en) * 1984-04-13 1985-04-23 Pfizer Inc. 9α-Aza-9α-homoerythromycin compounds, pharmaceutical composition and therapeutic method
HRP930014A2 (en) * 1993-01-08 1994-08-31 Pliva Pharm & Chem Works 9-deoxo-9a-aza-11-deoxy-9a-homoeritromycin a 9a, 11-cyclic carbamates

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CN85103264A (zh) * 1984-04-13 1987-01-14 美国辉瑞有限公司 9a-氮杂-9a-高红霉素衍生物
CN101691390A (zh) * 1997-06-11 2010-04-07 辉瑞产品公司 4”-取代的-9-脱氧-9a-氮杂-9a-高红霉素a衍生物
CN1229085A (zh) * 1997-12-31 1999-09-22 普利瓦药物，化学，食品，化妆品工业公司 9－去氧－9a－N－乙烯基－9a－氮杂－9a－高红霉素A的β,β－二取代衍生物

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