WO2013182070A1 - Médicament pour la prévention ou le traitement de maladies mycobactériennes - Google Patents

Médicament pour la prévention ou le traitement de maladies mycobactériennes Download PDF

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WO2013182070A1
WO2013182070A1 PCT/CN2013/076872 CN2013076872W WO2013182070A1 WO 2013182070 A1 WO2013182070 A1 WO 2013182070A1 CN 2013076872 W CN2013076872 W CN 2013076872W WO 2013182070 A1 WO2013182070 A1 WO 2013182070A1
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compound
oxo
phenyl
fluoro
oxazolidinyl
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PCT/CN2013/076872
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English (en)
Chinese (zh)
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阙峰
王莹
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四川贝力克生物技术有限责任公司
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Priority to CN201380029863.5A priority Critical patent/CN104364240B/zh
Publication of WO2013182070A1 publication Critical patent/WO2013182070A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • A61P31/08—Antibacterial agents for leprosy
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention pertains to the field of medicine and relates to a compound for preventing or treating mycobacterial diseases, and in particular, the compound of the present invention is useful for preventing or treating tuberculosis.
  • Mycobacteria are quite diverse, and they are pathogenic and non-pathogenic. Causes of human diseases are: (1) infections caused by human and Bovine Mycobacterium tuberculosis and several atypical mycobacteria; (2) leprosy. Most of these infections are chronic infections, long-term prolongation, and destructive tissue lesions.
  • Tuberculosis is a chronic infectious disease caused by the Mycobacterium tuberculosis complex (Mycobacterium tuberculosis complex, M. tuberculosis or tuberculosis), which can affect the multiple organ system of the whole body.
  • Mycobacterium tuberculosis complex M. tuberculosis or tuberculosis
  • the most common diseased part is the lung, which accounts for tuberculosis in various organs. 80-90% of the total; can also involve organs such as liver, kidney, brain, lymph nodes.
  • the main transmission routes are the respiratory tract, the digestive tract, the skin and the uterus, but mainly through the respiratory tract. After the sputum of the sterilized tuberculosis patient is dried, the bacteria fly with the dust and are inhaled by others to cause infection.
  • Tuberculosis is a chronic infectious disease that seriously endangers people's health. At present, about 2 billion people are infected worldwide, and the incidence of tuberculosis carriers can account for 80%. The number of new tuberculosis patients is about 8-10 million per year, and 3 million people are caused. death.
  • CN1155585 discloses that the compound represented by the following formula has potent anti-Gram-positive bacteria activity
  • R1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom or a halogenated alkyl group, and the haloalkyl group is an alkyl group having 1 to 6 carbon atoms substituted by one or more halogen atoms;
  • R3 represents diimide, five a heterocyclic heterocyclic group, wherein the five-membered heterocyclic group is an imidazolyl group, a thiadiazolyl group, a triazolyl group, a tetrazolyl group or a benzotriazole group.
  • this document does not mention that these compounds can be used to treat mycobacterial diseases, especially tuberculosis. Summary of the invention
  • the present invention provides the use of a compound represented by the following formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof for the preparation of a medicament for preventing or treating mycobacteria.
  • the present invention also provides a pharmaceutical composition for preventing or treating tuberculosis, which comprises, as an active ingredient, a compound represented by the above formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof, a complex or prodrug, or any combination thereof, and a pharmaceutically acceptable adjuvant.
  • the invention also provides a method of preventing or treating tuberculosis comprising administering to a patient a therapeutically effective amount of a compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex thereof or Prodrug, or any combination thereof, or a pharmaceutical composition as described.
  • the compound represented by the formula I of the present invention has a remarkable effect in the treatment or prevention of mycobacterial infection, particularly Mycobacterium tuberculosis infection, particularly drug-resistant Mycobacterium tuberculosis.
  • the compound represented by the above formula I of the present invention represents a hydroxyl group, an amino group, or a substituted or unsubstituted group: a C1-C10 amine group, a di(C1-C10) an imido group, a C1-C10 amide group, and C1- a C10 acyl imido group, a di(C1-C10 acyl)imido group, a C1-C10 sulfonylamino group, a C1-C10 sulfonyloxy group, a C1-C10 alkanoyloxy group, a five- or six-membered heterocyclic group, a five- or six-membered heterocyclic fluorenyl group, a benzoheterocyclyl fluorenyl group, a benzoheterocyclic group; R 2 represents a substituted or unsubstituted five- or six-membered heterocyclic group; a substituted or
  • R 3 and R 5 each independently represent 11, a halogen atom or a halogenated alkyl group
  • R4 represents a substituted or unsubstituted group: a five- or six-membered heterocyclic ring, a five- or six-membered heterocyclic oxy group, an alkoxy group, an aralkyloxy group, a five- or six-membered heterocyclic fluorenyl group, Benzoheterocyclyl fluorenyl, 5- or 6-membered heterocyclylamino, benzoheterocyclylamino.
  • the formula I represents a hydroxy group, an amino group, a C1-C10 alkylamino group, a C1-C10 arylalkylamino group, a C1-C10 arylamino group, a bis(C1-C10 alkyl)imide.
  • the formula I represents a hydroxy group, an amino group, an acetamido group, a chloroacetamido group, a methanesulfonylamino group, a methanesulfonyloxy group, an ethylsulfonyloxy group, an o-phenylene group.
  • R 2 in the formula I represents a substituted or unsubstituted group: pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyridyl An oxazolidinyl, pyrazolinyl, 4-morpholinyl, piperazinyl, piperidinyl, pyrimidinyl, oxazolyl, pyridyl; or C1-C4 acyl; or a group of the formula:
  • R 3 and R 5 each independently represent 15, a halogen atom or a halogenated alkyl group
  • R4 represents a substituted or unsubstituted group: a five- or six-membered heterocyclic ring, a five- or six-membered heterocyclic oxy group, an alkoxy group, an aralkyloxy group, a five- or six-membered heterocyclic fluorenyl group, Benzoheterocyclyl fluorenyl.
  • R 2 in the formula I represents an acetyl group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted oxa substituted pyridyl group, or a formula below group:
  • R 3 and R 5 each independently represent 15, a halogen atom or a halogenated alkyl group
  • R4 represents a substituted or unsubstituted group: a five- or six-membered heterocyclic ring, a five- or six-membered heterocyclic oxy group, an alkoxy group, an aralkyloxy group, a five- or six-membered heterocyclic fluorenyl group, Benzoheterocyclyl fluorenyl.
  • R 2 in formula I represents acetyl, 2-phenylpiperidinyl, 2-hydroxypyrimidinyl, 6-chloro-4-cyano-2-pyridyl, 4-oxazolyl Or 2-acetoxypyrimidinyl.
  • R 3 and R 5 each independently represent 11, F, C1 or CF 3 ;
  • R4 represents a substituted or unsubstituted group: a five- or six-membered heterocyclic ring, a five- or six-membered heterocyclic oxy group, an alkoxy group, an aralkyloxy group, a five- or six-membered heterocyclic fluorenyl group, Benzoheterocyclyl fluorenyl.
  • the R4 represents a substituted or unsubstituted group: pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, pyrrolyl, dihydropyrrolyl, pyrrolinyl, imidazolidinyl, imidazole Polinyl, pyrazolidinyl, imidazolylhydrazino, pyrazolinyl, thiadiazolyl, thiadiazolylamino, thiadiazolylhydrazino, morpholinyl, piperazinyl, triazinyl, pyrimidinyl, six Hydropyrimidine, pyridyl, chromanyl, quinolyl, benzofuranyl, pyrazinyl, pyrazinyloxy or piperidinyl.
  • R4 represents morpholinyl, 4-phenylpiperazinyl, 1-methyl-5,6-dihydro-1,2,4-triazin-4C1H)-yl, 2-chloromethyl -piperidinyl, 2-chloromethyl-4-methyl-piperidinyl, 4,6-dimethoxy-2-hexahydropyrimidinyl, 4,6-dimethoxy- 5 -methyl 2-hexahydropyrimidinyl, 6 -chloro-4-cyano-2-pyridyl, 6-chloro-4-cyano-5-methyl-2-pyridyl, 4-oxo-2- Chromatidine, 5-fluoro-4-oxo-1,2,3,4-tetrahydro-2-quinolyl, benzofuranyl, 3-chloropropionyl-1-piperazine, 5-(nitrogen Heterocyclobutane-1-carbonyl)-2-oxopyrazinyl, 1-methyl-1-H-2-imidazol
  • the R 4 may represent a group of the formula:
  • R4 can also:
  • R4 can also be
  • R 7 represents a hydrogen atom, a C1-10 alkyl group or a C1-C10 halogenated alkyl group
  • R 8 represents a hydrogen atom, a C1-C10 alkyl group or a C1-C10 phenylalkyl group; preferably R 7 represents a hydrogen atom, a methyl group or a chloro group.
  • Methyl represents a hydrogen atom, a methyl group or a benzyl group.
  • R 4 of the formula ⁇ may represent a group of the formula:
  • R 9 represents a hydrogen atom, a C1-C10 alkoxy group or a C1-C10 alkylthio group;
  • R u represents a hydrogen atom or a C1-C10 alkyl group; preferably R 9 represents a hydrogen atom, a methoxy group or a methyl group;
  • Ru indicating a hydrogen atom or a methyl group.
  • the compound represented by the formula I is a compound represented by the following formula III:
  • R 3 , R 5 are as defined above;
  • the following groups are represented by a substituted or unsubstituted group: a phenyl group, an aralkyl group, an alkyl acyl group, a five- or six-membered heterocyclic group.
  • a substituted or unsubstituted group a phenyl group, an aralkyl group, an alkyl acyl group, a five- or six-membered heterocyclic group.
  • it represents a phenyl group, a substituted phenyl group, a phenylalkyl group, an alkyl acyl group, or a halogenated alkyl acyl group.
  • the substituted or unsubstituted group phenyl, benzyl, C1-C10 alkyl acyl, five- or six-membered heterocyclic group; preferred represents phenyl, substituted phenyl, benzyl, C1-C10 An alkyl acyl group, or a halogenated C1-C10 alkyl acyl group. Specifically, it means a phenyl group, a p-methoxyphenyl group, a benzyl group, or a chloropropionyl group.
  • C1-C10 and the like means that the modified group has a number of carbon atoms
  • a C1-C10 alkyl group means a linear alkyl group having 1 to 10 carbon atoms
  • a branched alkyl group or a cycloalkyl group includes, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a t-butyl group, a n-hexyl group, a cyclopropyl group and the like.
  • halogen means fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • Substituted means that the hydrogen atom on the defined group is substituted by another atom or group, for example by one or more halogen atoms.
  • the five- or six-membered heterocyclic group in the present invention means a saturated, partially saturated or unsaturated five- or six-membered ring system in which at least one carbon atom is substituted by N, 0, S, SO, S0 2 , such as imidazole , thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, piperidinyl, pyrimidinyl, piperazinyl, morpholinyl, furyl, tetrahydrofuranyl, pyrazinyl, pyrrolyl, pyrrolidine A pyrazole group, a pyrazolyl group, an oxazolyl group, an oxazolidinyl group, a chromanyl group, a quinolyl group, a dihydropyrrolyl group, or a hexahydropyrimidinyl group.
  • the benzo five-membered heterocyclic ring or the benzo six-membered heterocyclic ring in the present invention means quinoline, benzofuran, benzimidazole, or benzotriazole or the like.
  • the sulfonyloxy group of the present invention includes, but is not limited to, a methylsulfonyloxy group, a benzenesulfonyloxy group, an ethylsulfonyloxy group, a p-toluenesulfonyloxy group, preferably a methanesulfonyloxy group or a p-toluenesulfonyloxy group.
  • the mycobacterial disease referred to in the present invention refers to a bacterium of the genus Mycobacterium as a pathogen or any disease, disorder, pathology, symptom, clinical disease or syndrome associated with, detecting or designing a mycobacterial infection.
  • the mycobacterial disease includes Mycobacterium tuberculosis, non-tuberculous mycobacterial infection or mycobacterial diseases associated therewith, such as various forms of tuberculosis, leprosy, and the like.
  • the compound represented by the above formula I of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof can be used for preventing or treating tuberculosis or leprosy, preferably for preventing or treating tuberculosis .
  • the pharmaceutical composition for preventing or treating tuberculosis of the present invention contains, as an active ingredient, the compound represented by the above formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or any thereof Combinations, as well as medicinal adjuvants.
  • the active ingredient is usually administered in a dose of 0.01 to 2000 mg/day, preferably, the dose is 0.01 to 1800 mg, more preferably 0.1 to 1500 mg, still more preferably 1 to 1200 mg. Further, the active ingredient is from 0.05 to 100% by weight of the composition.
  • the method for preventing or treating tuberculosis of the present invention comprises applying a therapeutically effective amount of a compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof to a patient in need of treatment.
  • “Therapeutically effective amount” in the present invention means an effective amount, such as a human or a non-human, when administered to a subject in need thereof to alleviate symptoms or to prevent further mycobacterial infection.
  • the pharmaceutically acceptable salts of the compounds of the above formula I in the present invention include sodium, potassium, calcium, aluminum, magnesium, zinc or other metal salts and ammonium salts.
  • a salt of an organic acid such as acetate, lactate, citrate, tartrate, maleate, malate, fumarate, benzoate, methanesulfonate, benzenesulfonic acid salt. It may also be an inorganic acid salt such as a hydrochloride, a sulfate, a hydrobromide, a phosphate or a sulfonate.
  • the hydrate of the compound represented by the formula I includes a hemihydrate, a 3/4 hydrate, a 2/7 hydrate, a 2/5 hydrate, and a 1/12 hydrate.
  • the pharmaceutically acceptable salts, hydrates, complexes, and solvates can also be used as intermediates or prodrugs.
  • the "prodrug” as used in the present invention means a substance which can be converted into a compound represented by the formula I or a pharmaceutically acceptable salt thereof in vivo to have the same pharmacological action as the compound represented by the formula I.
  • the compound of the formula I of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof is as follows:
  • the compound represented by the formula I of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof may be used singly or in any combination.
  • the mycobacterial disease in the present invention is an infectious disease caused by infection of the human or animal body by mycobacteria, including but not limited to tuberculosis and leprosy.
  • the mycobacteria are Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium marinum, Mycobacterium lactis, Mycobacterium fulvum, Mycobacterium phlei, Mycobacterium tuberculosis, Mycobacterium lactis, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium tuberculosis, Mycobacterium phlei, Mycobacterium phlei, Mycobacterium faecalis, Mycobacterium erythropolis, Mycobacterium smegmatis, Mycobacterium faecalis, Mycobacterium phlei, or Mycobacterium tuberculosis.
  • the present invention provides the use of a compound represented by Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, for the manufacture of a medicament for preventing or treating tuberculosis.
  • Tuberculosis bacteria inhibited by the compounds of the invention include, but are not limited to, human, bovine, avian, African-type Mycobacterium tuberculosis, and Mycobacterium tuberculosis.
  • the compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof can also be used for the prevention or treatment of a mixed infection caused by different types of Mycobacterium tuberculosis.
  • Tuberculosis which is prevented or treated by the pharmaceutically active ingredient of the present invention includes primary pulmonary tuberculosis, hematogenous disseminated pulmonary nucleus, secondary pulmonary tuberculosis, tuberculous pleurisy, bone and joint tuberculosis, tuberculous meningitis, renal tuberculosis, and intestinal tuberculosis.
  • a method of treating an individual having a mycobacterial infection comprises administering to the individual a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex thereof, or Prodrug.
  • a method of treating an individual having a mycobacterial infection comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or administration thereof. Any combination of the compounds.
  • a method of treating an individual having a mycobacterial infection comprises administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.
  • a pharmaceutical composition comprising:
  • a compound represented by Formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or any combination of at least one compound, and a pharmaceutically acceptable adjuvant, such as at least one pharmaceutically acceptable excipient.
  • the effective amount of the compound represented by Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, to achieve the desired biological effect may depend on a number of factors, such as the intended use, mode of administration. And the patient's clinical.
  • the medicament of the present invention may be any of oral or parenteral dosage forms such as injections, respiratory administration, dermal administration, mucosal administration and the like.
  • the drug is an oral agent such as a tablet, a capsule, a dry suspension, or an injection, from the viewpoint of convenience for the patient.
  • the medicament of the present invention is usually administered at a dose of 0.01 to 2000 mg/day; the daily dose may be divided into multiple administrations.
  • the daily dose may be 0.01-1800 mg, or 0.1-1500 mg, or 1-1200 mg, administered in two, three or four doses.
  • the dosage can be adjusted according to the patient's condition, gender, age, and weight.
  • the pharmaceutical composition of the compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof as an active ingredient can be prepared into a slow release, a controlled release, and a slow release. Release, pulse release and sustained release dosage forms.
  • the compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof may be used in the form of a compound, or may be combined with a pharmaceutically acceptable auxiliary agent, for example.
  • a pharmaceutically acceptable carrier is used in the form of a pharmaceutical composition.
  • the carrier should conform to the compatibility test with the other ingredients of the composition and be harmless to the health of the patient.
  • the carrier may be a solid or a liquid or a combination of the two, and can be prepared as a single dosage form with the compound of the formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.
  • a tablet may be prepared in an amount of from 0.05% to 100% by weight of the compound represented by the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.
  • the pharmaceutical composition should have at least one active ingredient comprising a compound of the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or any combination thereof.
  • the pharmaceutical composition can be prepared by a known method such as mixing the active ingredient with a pharmaceutically acceptable carrier such as a carrier and/or an excipient.
  • the excipient includes, but is not limited to, microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine, a disintegrant (such as starch, croscarmellose sodium, Composite silicates and high molecular weight polyethylene glycols), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants (such as magnesium stearate, glycerin and talc).
  • a disintegrant such as starch, croscarmellose sodium, Composite silicates and high molecular weight polyethylene glycols
  • granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic
  • lubricants such as magnesium stearate, glycerin and talc
  • the at least one compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof may also be used with a sweetener, a flavoring agent, a pigment, a dye. Or an emulsifier and a mixture thereof.
  • the compound of the formula I of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof may also be used in combination with other anti-tuberculosis drugs such as isoniazid and rifampin.
  • the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of acetonitrile.
  • the oil bath was heated, condensed and refluxed, and after dissolution, an appropriate amount of water was added to precipitate at least a solid amount, and the liquid was poured into a beaker. Cooling and crystallization in the freezer for 2h. Filter by suction and wash the solids three times with water.
  • the solid is added to the reaction flask for secondary recrystallization: it is refined by acetonitrile, heated in an oil bath, and condensed and refluxed.
  • Step 2 Add 500ml of THF to the distillation reaction bottle, stir, pass nitrogen protection, and export the tail gas.
  • the tail gas is bubbled with a conical flask filled with liquid paraffin.
  • the oil bath is heated and the external temperature of the oil bath is 95 °C. Condensation reflux. 5 g of LiAlH4 powder was added, and the THF was collected after 1 hour of dehydration with timed stirring, and the former fraction was discarded (about 50 ml).
  • reaction solution was washed once with 100 ml of a saturated aqueous NH 4 C1 solution, and the reaction mixture was washed three times with saturated aqueous NaCl solution (100 ml each time).
  • the upper organic phase was separated and collected, distilled under reduced pressure (-0.08 MPa, 60 °C) to a certain amount, poured into a beaker and placed in a freezer for cooling and crystallization for 2 h. After suction filtration, the solid matter was added to the reaction flask, and purified by adding 100 ml of THF: the oil bath was heated, and the mixture was condensed and refluxed.
  • the third step 15g of the second step reaction product and 200ml of dichloromethane were added to the reaction flask, and placed in a low temperature coolant circulation pump to cool down to -8 ° C, the device was installed, and stirred.
  • the internal temperature is 0 ° C
  • 7 g of triethylamine is added, and 6 g of methanesulfonyl chloride is added dropwise at an internal temperature of -5 ° C, and the internal temperature is controlled to be 0.5 ° or less for 0.5 h, and the reaction at room temperature is taken for 2 h.
  • Step 4 Add 10 g of the third step reaction product, 150 ml of DMF to the reaction flask, install the device, stir, add 3.6 g of phthalimide, 4 g of anhydrous K 2 C0 3 in turn , heat in oil bath, set oil The outside temperature of the bath was 82 ° C, and the reaction was stirred overnight.
  • the white solid was stirred out in 300 ml, cooled in a freezer for 30 min, and suction filtered, and washed with solid water three times (100 ml).
  • the solid matter was added to the reaction flask, and refined by adding 150 ml of DMF: the oil bath was heated, and the mixture was condensed and refluxed. After the solution was dissolved, at least a solid amount of the solid was precipitated by adding an appropriate amount of water, poured into a beaker, cooled in a freezer for 2 hours, and suction filtered. The obtained solid was recrystallized twice by the same operation method. After suction filtration, the obtained solid was washed with water and dried in vacuo. Used in the next step of the reaction.
  • Step 5 Add 5 g of the fourth step reaction product, 500 ml of absolute ethanol to the reaction flask, secure the device, and stir.
  • the oil bath is heated, and the oil bath is set to an external temperature of 82 ° C, and condensed and refluxed.
  • Step 6 Add 2 g of the reaction product of the fifth step, 100 ml of THF to the reaction flask, install in a low temperature coolant circulation pump, and stir to cool to -8 °C. Add lg triethylamine at an internal temperature of 0 ° C, add 0.7 g of acetic anhydride at an internal temperature of -5 ° C, and control the internal temperature to below -5 ° C. After the dropwise addition, react at -5 ° C for 0.5 h, take out, and react at room temperature for 2 h. .
  • the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of acetonitrile.
  • the oil bath was heated, condensed and refluxed, and after dissolution, an appropriate amount of water was added to precipitate at least a solid amount, and the liquid was poured into a beaker. Cooling and crystallization in the freezer for 2h. Filter by suction and wash the solids three times with water.
  • the solid is added to the reaction flask for secondary recrystallization: it is refined by adding acetonitrile, heated in an oil bath, and condensed and refluxed.
  • a suitable amount of water is added to precipitate at least a solid, which is poured into a beaker and cooled to crystallize for 2 hours. After suction filtration, the solid was washed with water and dried under vacuum for the next step.
  • Step 2 Add 500ml of THF to the distillation reaction bottle, stir, pass nitrogen protection, and export the tail gas.
  • the tail gas is bubbled with a conical flask filled with liquid paraffin.
  • the oil bath is heated and the external temperature of the oil bath is 95 °C. , condensed reflux.
  • LiAlH4 powder dehydrated by timed stirring, collected THF after lh, and the former fraction was discarded (50 ml).
  • reaction solution was washed once with 100 ml of a saturated aqueous NH 4 C1 solution, and the reaction mixture was washed three times with saturated aqueous NaCl solution (100 ml each time).
  • the upper organic phase was separated and collected, distilled under reduced pressure (-0.08 MPa, 60 °C) to a certain amount, poured into a beaker and placed in a freezer for cooling and crystallization for 2 h. After suction filtration, the solid matter was added to the reaction flask, and purified by adding 100 ml of THF: the oil bath was heated, and the mixture was condensed and refluxed.
  • the third step 15g of the second step reaction product and 200ml of dichloromethane were added to the reaction flask, placed in a low temperature coolant circulation pump to cool down to -8 ° C, the device was installed, and stirred.
  • the internal temperature was 0 ° C
  • 7 g of triethylamine was added, and 5.8 g of methanesulfonyl chloride was added dropwise at an internal temperature of -5 ° C.
  • the internal temperature was controlled at 0 ° C for 0.5 h, and the reaction was carried out for 2 h at room temperature.
  • the fourth step 10g of the third step reaction product, 150ml of DMF into the reaction bottle, the device is installed, stirred, and then added 3.5g phthalimide, 3.8g anhydrous K 2 C0 3 , heated in oil bath, set The external temperature of the oil bath was 82 ° C, and the reaction was stirred overnight.
  • the solid matter was added to the reaction flask, and refined by adding 150 ml of DMF: the oil bath was heated, and the mixture was condensed and refluxed. After the solution was dissolved, at least a solid amount of the solid was precipitated by adding an appropriate amount of water, poured into a beaker, cooled in a freezer for 2 hours, and suction filtered. The obtained solid was recrystallized twice by the same operation method. After suction filtration, the obtained solid was washed with water and dried in vacuo. Used in the next step of the reaction.
  • Step 5 Add 5 g of the fourth step reaction product, 500 ml of absolute ethanol to the reaction flask, secure the device, and stir.
  • the oil bath is heated, and the oil bath is set to an external temperature of 82 ° C, and condensed and refluxed.
  • the methylamine gas was stopped and the reaction was continued for 2 h. After the reaction was completed, suction filtration was carried out, and the filtrate was poured into a beaker and placed in a freezer to be crystallized overnight.
  • the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of ethyl acetate: the oil bath was heated, condensed and refluxed, and the solid was completely dissolved by adding an appropriate amount of DMF, and then a small amount of water was added dropwise, and a small amount of solid was precipitated.
  • the liquid When pouring the liquid into the beaker, put it into a freezer and cool it for 2 hours, and filter it by suction.
  • the obtained solid was recrystallized twice by the same operation method. Filter by suction, wash with water and dry in vacuum. Used in the next step of the reaction.
  • Step 6 Add 2 g of the reaction product of the fifth step, 100 ml of THF to the reaction flask, install in a low temperature coolant circulation pump, and stir to cool to -8 °C. Add lg triethylamine at an internal temperature of 0 ° C, add 0.6 g of acetic anhydride at an internal temperature of -5 ° C, and control the internal temperature to below -5 ° C. After the dropwise addition, the reaction at -5 ° C for 0.5 h, take out, and react at room temperature for 2 h. .
  • the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of acetonitrile.
  • the oil bath was heated, condensed and refluxed, and after dissolution, an appropriate amount of water was added to precipitate at least a solid amount, and the liquid was poured into a beaker. Cooling and crystallization in the freezer for 2h. Filter by suction and wash the solids three times with water.
  • the solid is added to the reaction flask for secondary recrystallization: it is refined by adding acetonitrile, heated in an oil bath, and condensed and refluxed.
  • a suitable amount of water is added to precipitate at least a solid, which is poured into a beaker and cooled to crystallize for 2 hours. After suction filtration, the solid was washed with water and dried under vacuum for the next step.
  • Step 2 Add 500ml THF to the distillation reaction bottle, stir, pass nitrogen protection, and export the tail gas.
  • the tail gas is bubbled with a conical flask filled with liquid paraffin.
  • the oil bath is heated and the external temperature of the oil bath is 95 °C. , condensed reflux. 5 g of LiAlH4 powder was added, and the mixture was dehydrated for 1 hour, and then THF was collected, and the former fraction was discarded (50 ml).
  • reaction solution was washed once with 100 ml of a saturated aqueous NH 4 C1 solution, and the reaction mixture was washed three times with saturated aqueous NaCl solution (100 ml each time).
  • the upper organic phase was separated and collected, distilled under reduced pressure (-0.08 MPa, 60 °C) to a certain amount, poured into a beaker and placed in a freezer for cooling and crystallization for 2 h. After suction filtration, the solid matter was added to the reaction flask, and purified by adding 100 ml of THF: the oil bath was heated, and the mixture was condensed and refluxed.
  • the third step 15g of the second step reaction product and 200ml of dichloromethane were added to the reaction flask, and placed in a low temperature coolant circulation pump to cool down to -8 ° C, the device was installed, and stirred.
  • the internal temperature is 0 ° C
  • 6.5 g of triethylamine is added
  • 5.6 g of methanesulfonyl chloride is added dropwise at an internal temperature of -5 ° C, and the internal temperature is controlled to be 0.5 ° or less for 0.5 h, and the reaction at room temperature is taken for 2 h.
  • the fourth step 10 g of the third step reaction product, 150 ml of DMF was added to the reaction flask, the device was set up, stirred, and 3.4 g of phthalimide, 3.6 g of anhydrous K 2 C0 3 were added in sequence, and heated in an oil bath. The oil bath was set to an external temperature of 82 ° C, and the reaction was stirred overnight.
  • the white solid was stirred out in 300 ml, cooled in a freezer for 30 min, and suction filtered, washed three times with solid water. (100ml).
  • the solid matter was added to the reaction flask, and refined by adding 150 ml of DMF: the oil bath was heated, and the mixture was condensed and refluxed. After the solution was dissolved, at least a solid amount of the solid was precipitated by adding an appropriate amount of water, poured into a beaker, cooled in a freezer for 2 hours, and suction filtered. The obtained solid was recrystallized twice by the same operation method. After suction filtration, the obtained solid was washed with water and dried in vacuo. Used in the next step of the reaction.
  • Step 5 Add 5 g of the fourth step reaction product, 500 ml of absolute ethanol to the reaction flask, secure the device, and stir.
  • the oil bath is heated, and the oil bath is set to an external temperature of 82 ° C, and condensed and refluxed.
  • the methylamine gas was stopped and the reaction was continued for 2 h. After the reaction was completed, suction filtration was carried out, and the filtrate was poured into a beaker and placed in a freezer to be crystallized overnight.
  • the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of ethyl acetate: the oil bath was heated, condensed and refluxed, and the solid was completely dissolved by adding an appropriate amount of DMF, and then a small amount of water was added dropwise, and a small amount of solid was precipitated.
  • the liquid When pouring the liquid into the beaker, put it into a freezer and cool it for 2 hours, and filter it by suction.
  • the obtained solid was recrystallized twice by the same operation method. Filter by suction, wash with water and dry in vacuum. Used in the next step of the reaction.
  • Step 6 Add 2 g of the reaction product of the fifth step, 100 ml of THF to the reaction flask, install in a low temperature coolant circulation pump, and stir to cool to -8 °C. Add 0.8g of triethylamine at an internal temperature of 0 ° C, add 0.6 g of acetic anhydride at an internal temperature of -5 ° C, and control the internal temperature to below -5 ° C. After the dropwise addition, react at -5 ° C for 0.5 h, take out, and react at room temperature. 2h.
  • N-benzyloxycarbonyl-3-fluoro-4-(4'-phenylpiperazinyl)aniline obtained in step (3) was added to a 100 ml three-necked flask (baked at 120 °C for more than 2 hours), 3.4 g, Water tetrahydrofuran 50 ml. 6.60 ml of a 1.6 M butyl lithium solution was added dropwise at -78 °C under N 2 protection. Stir at -78 °C for 80 minutes and gradually turn into a yellow-green solution. The solution was added dropwise at 1.78 ml of CR)-butyl glycerol and 5 ml of anhydrous tetrahydrofuran, and the solution quickly became clear.
  • the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of acetonitrile.
  • the oil bath was heated, condensed and refluxed, and after dissolution, an appropriate amount of water was added to precipitate at least a solid amount, and the liquid was poured into a beaker. Cooling and crystallization in the freezer for 2h. Filter by suction and wash the solids three times with water.
  • the solid is added to the reaction flask for secondary recrystallization: it is refined by adding acetonitrile, heated in an oil bath, and condensed and refluxed.
  • a suitable amount of water is added to precipitate at least a solid, which is poured into a beaker and cooled to crystallize for 2 hours. After suction filtration, the solid was washed with water and dried under vacuum for the next step.
  • Step 2 Add 500ml of THF to the distillation reaction bottle, stir, pass nitrogen protection, and export the tail gas.
  • the tail gas is bubbled with a conical flask filled with liquid paraffin.
  • the oil bath is heated and the external temperature of the oil bath is 95 °C. , condensed reflux. 5 g of LiAlH4 powder was added, and the mixture was dehydrated for 1 hour, and then THF was collected, and the former fraction was discarded (50 ml).
  • reaction solution was washed once with 100 ml of a saturated aqueous NH 4 C1 solution, and the reaction mixture was washed three times with saturated aqueous NaCl solution (100 ml each time).
  • the upper organic phase was separated and collected, distilled under reduced pressure (-0.08 MPa, 60 °C) to a certain amount, poured into a beaker and placed in a freezer for cooling and crystallization for 2 h. After suction filtration, the solid matter was added to the reaction flask, and purified by adding 100 ml of THF: the oil bath was heated, and the mixture was condensed and refluxed.
  • the third step 15g of the second step reaction product and 200ml of dichloromethane were added to the reaction flask, and placed in a low temperature coolant circulation pump to cool down to -8 ° C, the device was installed, and stirred.
  • the internal temperature is 0 ° C
  • 6.5 g of triethylamine is added, and 5.5 g of methanesulfonyl chloride is added dropwise at an internal temperature of -5 ° C, and the internal temperature is controlled to be 0.5 ° or less for 0.5 h, and the reaction at room temperature is taken for 2 h.
  • the fourth step 10g of the third step reaction product, 150ml of DMF into the reaction bottle, the device is installed, stirred, and then added 3.3g phthalimide, 3.6g anhydrous K 2 C0 3 , heated in oil bath, set The external temperature of the oil bath was 82 ° C, and the reaction was stirred overnight.
  • the solid matter was added to the reaction flask, and refined by adding 150 ml of DMF: the oil bath was heated, and the mixture was condensed and refluxed. After the solution was dissolved, at least a solid amount of the solid was precipitated by adding an appropriate amount of water, poured into a beaker, cooled in a freezer for 2 hours, and suction filtered. The obtained solid was recrystallized twice by the same operation method. After suction filtration, the obtained solid was washed with water and dried in vacuo. Used in the next step of the reaction.
  • Step 5 Add 5 g of the fourth step reaction product, 500 ml of absolute ethanol to the reaction flask, secure the device, and stir.
  • the oil bath is heated, and the oil bath is set to an external temperature of 82 ° C, and condensed and refluxed.
  • the methylamine gas was stopped and the reaction was continued for 2 h. After the reaction was completed, suction filtration was carried out, and the filtrate was poured into a beaker and placed in a freezer to be crystallized overnight.
  • the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of ethyl acetate: the oil bath was heated, condensed and refluxed, and the solid was completely dissolved by adding an appropriate amount of DMF, and then a small amount of water was added dropwise, and a small amount of solid was precipitated.
  • the liquid When pouring the liquid into the beaker, put it into a freezer and cool it for 2 hours, and filter it by suction.
  • the obtained solid was recrystallized twice by the same operation method. Filter by suction, wash with water and dry in vacuum. Used in the next step of the reaction.
  • Step 6 2 g of the fifth step reaction product, 100 ml of THF was added to the reaction flask, and the device was placed in a low temperature coolant circulation pump, and the mixture was cooled to -8 ° C with stirring. Add lg triethylamine at an internal temperature of 0 ° C, add 0.6 g of acetic anhydride at an internal temperature of -5 ° C, and control the internal temperature to below -5 ° C. After the dropwise addition, the reaction at -5 ° C for 0.5 h, take out, and react at room temperature for 2 h. .
  • the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of acetonitrile.
  • the oil bath was heated, condensed and refluxed, and after dissolution, an appropriate amount of water was added to precipitate at least a solid amount, and the liquid was poured into a beaker. Cooling and crystallization in the freezer for 2h. Filter by suction and wash the solids three times with water.
  • the solid is added to the reaction flask for secondary recrystallization: it is refined by adding acetonitrile, heated in an oil bath, and condensed and refluxed.
  • a suitable amount of water is added to precipitate at least a solid, which is poured into a beaker and cooled to crystallize for 2 hours. After suction filtration, the solid was washed with water and dried under vacuum for the next step.
  • Step 2 Add 500ml THF to the distillation reaction bottle, stir, pass nitrogen protection, and export the tail gas.
  • the tail gas is bubbled with a conical flask filled with liquid paraffin.
  • the oil bath is heated and the external temperature of the oil bath is 95 °C. , condensed reflux. 5 g of LiAlH4 powder was added, and the mixture was dehydrated for 1 hour, and then THF was collected, and the former fraction was discarded (50 ml).
  • reaction solution was washed once with 100 ml of a saturated aqueous NH 4 C1 solution, and the reaction mixture was washed three times with saturated aqueous NaCl solution (100 ml each time).
  • the upper organic phase was separated and collected, distilled under reduced pressure (-0.08 MPa, 60 °C) to a certain amount, poured into a beaker and placed in a freezer for cooling and crystallization for 2 h. After suction filtration, the solid matter was added to the reaction flask, and purified by adding 100 ml of THF: the oil bath was heated, and the mixture was condensed and refluxed.
  • the third step 15g of the second step reaction product and 200ml of dichloromethane were added to the reaction flask, and placed in a low temperature coolant circulation pump to cool down to -8 ° C, the device was installed, and stirred.
  • the internal temperature is 0 ° C
  • 7 g of triethylamine is added, and 6 g of methanesulfonyl chloride is added dropwise at an internal temperature of -5 ° C, and the internal temperature is controlled to be 0.5 ° or less for 0.5 h, and the reaction at room temperature is taken for 2 h.
  • Step 4 Add 10 g of the third step reaction product, 150 ml of DMF to the reaction flask, install the device, stir, add 3.6 g of phthalimide, 4 g of anhydrous K 2 C0 3 in turn , heat in oil bath, set oil The outside temperature of the bath was 82 ° C, and the reaction was stirred overnight.
  • the white solid was stirred out in 300 ml, cooled in a freezer for 30 min, and suction filtered, and washed with solid water three times (100 ml).
  • the solid matter was added to the reaction flask, and refined by adding 150 ml of DMF: the oil bath was heated, and the mixture was condensed and refluxed. After the solution was dissolved, at least a solid amount of the solid was precipitated by adding an appropriate amount of water, poured into a beaker, cooled in a freezer for 2 hours, and suction filtered. The obtained solid was recrystallized twice by the same operation method. After suction filtration, the obtained solid was washed with water and dried in vacuo. Used in the next step of the reaction.
  • Step 5 Add 5 g of the fourth step reaction product, 500 ml of absolute ethanol to the reaction flask, secure the device, and stir.
  • the oil bath is heated, and the oil bath is set to an external temperature of 82 ° C, and condensed and refluxed.
  • the methylamine gas was stopped and the reaction was continued for 2 h. After the reaction was completed, suction filtration was carried out, and the filtrate was poured into a beaker and placed in a freezer to be crystallized overnight.
  • the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of ethyl acetate: the oil bath was heated, condensed and refluxed, and the solid was completely dissolved by adding an appropriate amount of DMF, and then a small amount of water was added dropwise, and a small amount of solid was precipitated.
  • the liquid When pouring the liquid into the beaker, put it into a freezer and cool it for 2 hours, and filter it by suction.
  • the obtained solid was recrystallized twice by the same operation method. Filter by suction, wash with water and dry in vacuum. Used in the next step of the reaction.
  • Step 6 Add 2 g of the fifth step reaction product, 100 ml of THF to the reaction flask, install in a low temperature coolant circulation pump, and stir to cool to -8 °C. Add lg triethylamine at an internal temperature of 0 ° C, add 0.7 g of acetic anhydride at an internal temperature of -5 ° C, and control the internal temperature to below -5 ° C. After the dropwise addition, react at -5 ° C for 0.5 h, take out, and react at room temperature for 2 h. .
  • the second step 600 ml of tetrahydrofuran and 30 g of the first reaction product were added to the reaction flask, and the temperature was lowered to -70 ° C using liquid nitrogen, and 36 ml of butyl lithium was added to the dropping port, followed by dropwise addition of 13.5 g of R-glycidyl butyrate (98%). After the completion of the dropwise addition, the mixture was kept at a low temperature - 70 ° C for 1 hour, and then reacted at room temperature for 16 hours. After the completion of the reaction, the mixture was filtered, and the mother liquid was distilled to dryness (-0.08 MPa, 60 ° C), and the obtained solid was used for the next step.
  • Step 1 Add 4-methylimidazole 41g and absolute ethanol 1000ml into the reaction flask, stir, add 40g of triethylamine and 80g of 3, 4-difluoronitrobenzene in turn, heat in oil bath, set the temperature of oil bath At 82 ° C, condensed reflux, timed reaction for 3 days.
  • reaction solution was frozen, and a large amount of a yellow solid was precipitated in the reaction mixture, and the mixture was directly cooled and crystallized for 2 hours.
  • the solid was purified by using anhydrous ethanol (1000 ml): the oil bath was warmed and refluxed. After dissolving, pour into a beaker to cool and crystallize for 2-3 h, suction filtration, vacuum drying: 80 ° C, -0.08 Mpa. Used in the next step of the reaction.
  • Step 2 Add 22g of the first reaction product and 400ml of acetone to the reaction flask, stir, add 20g of formic acid amine, 10% Pb/C5g, heat in oil bath, set the external temperature of oil bath 82 °C, condense reflux, time Reaction for 5 h.
  • the filtrate was placed in a low-temperature coolant circulating pump to cool, stirred, and 12 g of pyridine was added at 5 ° C. 19 g of benzyl chloroformate (mixed acetone solvent) was added dropwise at 0 ° C. After lh, the reaction was carried out for 30 min at low temperature, and the reaction was carried out overnight at room temperature. .
  • a red liquid is obtained, concentrated to a certain volume, poured into a saturated aqueous solution of NaCl, stirred, and a white solid is precipitated, suction filtration, 30 g of solid is added to the reaction flask, and 500 ml of acetonitrile is added for purification: the oil bath is heated, condensed and refluxed, and dissolved. After that, add a proper amount of water to precipitate at least a solid, pour it into a beaker and put it into a freezer to cool and crystallize. The mother liquor is distilled under reduced pressure.
  • mother liquor When a small amount of mother liquor remains, it is poured into a beaker and placed in a freezer for cooling and crystallization, suction filtration, water washing, and solid use. Mother liquor recovery The solid matter is added to the reaction flask, and refined by adding acetonitrile: the oil bath is heated, and the mixture is condensed and refluxed. After the solution is dissolved, at least a solid amount of the solid is precipitated by adding an appropriate amount of water, poured into a beaker, cooled in a freezer, filtered, and washed with water.
  • the third step 1000ml of THF is added to the distillation reactor, stirred, and protected by nitrogen gas.
  • the tail gas is exported.
  • the tail gas is bubbled with a conical flask containing liquid paraffin, heated in an oil bath, and the external temperature of the oil bath is 95 °C. Condensation reflux. Turn off the small nitrogen, add 5g of LiAlH 4 powder, time the reaction for 1h, start collecting THF, and discard the previous part.
  • the collected second step of the reaction product was added to the collected 600 ml of THF, and the apparatus was set up, purged with nitrogen, and cooled with a mixture of dry ice and acetone.
  • the upper mother liquor is distilled under reduced pressure, and a small amount of the solution is poured into a beaker and placed in a freezer for cooling and crystallization for 2 hours.
  • the upper mother liquor is filtered, and the solid is added to the reaction flask and refined by adding THF.
  • the oil bath is heated, condensed and refluxed. After the solution is dissolved, an appropriate amount of water is added to precipitate at least a solid, which is poured into a beaker and cooled to crystallize.
  • a large amount of white solids in the lower supernatant is precipitated, suction filtered, solids are added to the reaction flask, and refined by adding THF: the oil bath is heated, condensed and refluxed, and after dissolution, an appropriate amount of water is added to precipitate at least a solid, which is poured into a beaker and placed in a freezer. Medium cooling and crystallization.
  • the filtrate was light yellow transparent liquid, distilled under reduced pressure (-0.08 MPa, 80 ° C), when a small amount of mother liquor remained Pour into saturated NaCl aqueous solution for crystallization, cool in a freezer for 30 min, remove the suction filtration, and wash the solids obtained by washing three times into the reaction flask, and add 200 ml of DMF to refine: heat up the oil bath, condense and reflux, dissolve, and add at least the right amount of water. The solid matter was precipitated, poured into a beaker and placed in a freezer for cooling and crystallization for 2 h, suction filtration, and washing with water. The same operation method was used for secondary recrystallization. Filtered, washed with water and vacuum dried: 110 ° C, -0.08 Mpa. Compound 42 was obtained.
  • the product was a yellow powdery solid, mp: 220-222 ° C, and the three experimental yields were: 100,903 batches of 27.7%, 101,001 batches of 41.4%, and 101,101 batches of 12.5%.
  • Example 21 The same preparation method as in Example 21 except that in the first step, the (R)-[3-(3-fluoro-4-(4-methyl) group of Example 21 was replaced with the materials listed in Table 4 below, respectively. -1H-imidazol-1-yl)phenyl)-2-oxo-5-oxazolidinyl]methyl methanesulfonate and phthalimide, the corresponding compound was obtained.
  • the product was a white powdery solid, mp: 181-182 ° C.
  • the total yield of the two experiments was: 101101 batches +101102 batches 23.2%, content: 99.6% (HPLC).
  • Example 23 In the same manner as in Example 23, the (S)-5-(aminomethyl)-3-[3-fluoro-4-(4-methyl) group of Example 23 was replaced with the starting materials listed in Table 6 below. -1H-imidazol-1-yl)phenyl]oxazolidin-2-one and acetic anhydride afforded the corresponding compound.
  • Step 1 Add 10g of NaOH and 400ml of absolute ethanol to the reaction flask, install the device, heat in the oil bath, set the oil bath to an external temperature of 82 ° C, condense and reflux, stir for 30 min, and dissolve the NaOH, then add 19 g of succinimide. , all dissolved, began to add 3, 4-difluoronitrobenzene 16g, drip, timed reaction 24h. After the reaction, a large amount of yellow solid matter was precipitated in the red reaction solution, and the crystal was directly cooled and crystallized for 2 hours.
  • the mixture was suction filtered, and the solid was washed three times with water, and dried in vacuo: 80 ° C, -0.08 MPa, for the next step.
  • the reaction product of the first step was a yellow powdery solid, mp: 81-83 ° C, and the yields of the three experiments were: 101201 batches 62.5%, 101202 batches 64.6%, 101203 batches 64.0%.
  • the second step 30 g of the first reaction product and 400 ml of acetone were added to the reaction flask, stirred, and then 25 g of formic acid amine, 10% Pb/C 5 g were sequentially added, and heated in an oil bath, and the external temperature of the oil bath was set to 50 ° C, and condensed and refluxed. The internal temperature was 48 ° C, and the reaction time was 5 h.
  • the third step the filtrate obtained in the second step is placed in a low temperature coolant circulating pump to cool, stir, add pyridine llg at 5 ° C, start adding 20 g of benzyl chloroformate at 0 ° C, lh drop, low temperature reaction for 30 min, take out normal temperature The reaction was overnight.
  • Recrystallization was repeated twice by the same procedure. After suction filtration, vacuum drying after washing: 85 ° C, -0.08 Mpa. Used for the next step.
  • the reaction product of the third step was a white powdery solid, mp: 100-lOrC.
  • the yields of the three experiments were: 101201 batches of 85.3%, 101,202 batches of 84.8%, and 101,203 batches of 86.1%.
  • THF is added to the distillation reactor, stirred, and protected by nitrogen gas.
  • the tail gas is led out.
  • the tail gas is bubbled with a conical flask filled with liquid paraffin.
  • the oil bath is heated, and the external temperature of the oil bath is 95 ° C. Reflux. Turn off the small nitrogen, add 5g of LiAlH ⁇ ij at the end, time the reaction for 1h, start collecting THF, and discard the previous part.
  • Example 39 The product was a pale yellow powdery solid, mp: 120-122 ° C, and the experimental yield was: 110101 batches 73.0%.
  • Examples 39, 46, 52, 58, 64, and 70 In the same manner as in Example 25, the 3,4-difluoronitrobenzene of Example 25 was replaced with the starting materials listed below, to obtain the corresponding compounds.
  • the minimum inhibitory concentration (MIC) of the compound against M. tuberculosis standard strain H37Rv was determined by Microplate Alamar Blue Assay (MABA) method.
  • MABA Microplate Alamar Blue Assay
  • the experimental strain according to the present invention Mycobacterium tuberculosis standard strain H37Rv, which is provided by the Beijing Institute of Tuberculosis and Thoracic Oncology.
  • Mycobacterium tuberculosis sensitive clinical isolates 9102, 3215, 1105,
  • Mycobacterium tuberculosis drug-resistant clinical isolates 20161, 6233, 16543, 5116, 3328, 3289, 3303, 7153, 31251, 30129 are all provided by the Beijing Tuberculosis Thoracic Tumor Institute.
  • Test compound
  • Isoniazid (INH) and rifampicin (RFP) are products of Sigma.
  • Isoniazid was dissolved in sterile distilled water, and rifampicin and the test compound were dissolved in dimethyl sulfoxide to prepare an initial solution having a concentration of 6.4 mg/ml.
  • a sterile 96-well plate (Falcon3072; Becton Dickinson, Lincoln Park, NJ), add the highest concentration well to the 198 ⁇ 1 7 ⁇ 9 medium, 2 ⁇ 1 compound initial solution, mix well, and then dilute to the remaining wells twice, the final concentration of the compound is : 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03 g/ml.
  • the final concentrations of INH were: 0.2, 0.1, 0.05, 0.025, 0.0125 g/ml.
  • Mycobacterium tuberculosis H37RV was selected and cultured for 2 to 3 weeks to prepare a bacterial suspension, inoculated into 7H9 medium containing 0.05% Tween 80 and 10% ADC, and cultured at 37 ° C for 1 to 2 weeks.
  • the turbidity is McFarland 1 (equivalent to 10 7 CFU/ml)
  • 100 ⁇ l of each well is added, and the final concentration of the bacterial solution is 106 CFU/ml.
  • Two anti-bacterial growth control wells were placed on each plate and 96-well plates were incubated at 37 °C.
  • a growth control well of 20 ⁇ l 1 O Alamar Blue (product of Setotec) and 5% Tween 80 50 ⁇ l was added, and incubation was carried out for 24 hours for 37 hours. If the color changed from blue to pink, the above amount was added to the wells of each experimental drug.
  • the mixture of Alamar Blue and Tween80 was incubated at 37 ° C for 24 hours to record the color of each well, and the fluorescence values at 530 nm and 590 nm were measured using a microplate reader to calculate the MIC90.
  • the minimum inhibitory concentration (MIC) determined by the MABA method is shown in Table 1.
  • Table 1 MIC of test compound against M. tuberculosis standard strain H37Rv
  • Test compound Compound 1-143; Control drug isoniazid (INH), rifampicin (RFP) are produced by Sigma
  • tuberculosis sensitive clinical isolates and 10 strains of drug-resistant clinical isolates were selected, and the cultures were cultured for 2 ⁇ 3 weeks to prepare bacterial suspensions, which were inoculated into 7H9 containing 0.05% Tween 80 and 10% ADC.
  • culture at 37 ° C for 1 to 2 weeks grow to a turbidity of McFarland 1 (equivalent to 10 7 CFU / ml), after 1: 20 dilution, add 100 ⁇ 1 of each well, the final concentration of the bacterial solution is 10 6 CFU/ ml.
  • Two growth control wells containing no antibacterial agents were placed on each plate, and 96-well plates were incubated at 37 °C.
  • the minimum inhibitory concentration (MIC) determined by the MABA method is shown in Table 2.
  • the MIC range of most compounds for single isolates of isoniazid, rifampicin or isoniazid-resistant rifampicin (MDR-TB) is 1-32 ⁇ ⁇ /ml , a considerable part of the compound is in 1-16 ⁇ ⁇ /ml, and some compounds are in 1-8 ⁇ ⁇ /ml, so the compound of the present invention has in vitro antibacterial activity against sensitive and drug-resistant clinical isolates of Mycobacterium tuberculosis, especially It has a significant effect on drug-resistant Mycobacterium tuberculosis.
  • the compounds of the present invention are capable of shortening and simplifying the course of treatment, overcoming multidrug resistance, and treating tuberculosis and AIDS co-infections, particularly for the treatment of latent tuberculosis infections. At the same time, it has improved the efficacy of multi-drug resistant tuberculosis, and can be specially developed into a drug for the treatment of multidrug-resistant tuberculosis, which will provide a safe and effective drug for tuberculosis patients.

Abstract

La présente invention concerne un médicament pour la prévention ou le traitement de maladies mycobactériennes. En particulier, l'invention concerne l'utilisation d'un composé représenté par la formule générale suivante (I) ou des sels, hydrates, solvates, complexes ou promédicaments pharmaceutiquement acceptables de ceux-ci dans la préparation de médicaments pour la prévention ou le traitement de maladies mycobactériennes, fournissant une nouvelle façon pour la prévention et le traitement de la tuberculose et similaires.
PCT/CN2013/076872 2012-06-08 2013-06-06 Médicament pour la prévention ou le traitement de maladies mycobactériennes WO2013182070A1 (fr)

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WO2017066964A1 (fr) * 2015-10-22 2017-04-27 Merck Sharp & Dohme Corp. Composés oxazolidinone et procédés d'utilisation de ces derniers en tant qu'agents antibactériens
CN107286111A (zh) * 2016-03-30 2017-10-24 四川赛卓药业股份有限公司 一种噁唑烷酮化合物的制备方法
CN107400126A (zh) * 2016-05-19 2017-11-28 陕西合成药业股份有限公司 新型噁唑烷酮类化合物及其制备方法和在医学上的应用
WO2020039088A3 (fr) * 2018-08-24 2020-04-02 Xeniopro GmbH Nouveaux composés
CN111925343A (zh) * 2020-08-12 2020-11-13 石家庄四药有限公司 一种利奈唑胺降解杂质的合成方法

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WO2017066964A1 (fr) * 2015-10-22 2017-04-27 Merck Sharp & Dohme Corp. Composés oxazolidinone et procédés d'utilisation de ces derniers en tant qu'agents antibactériens
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CN107286111A (zh) * 2016-03-30 2017-10-24 四川赛卓药业股份有限公司 一种噁唑烷酮化合物的制备方法
CN107286111B (zh) * 2016-03-30 2020-06-19 广东赛法洛药业有限公司 一种噁唑烷酮化合物的制备方法
CN107400126A (zh) * 2016-05-19 2017-11-28 陕西合成药业股份有限公司 新型噁唑烷酮类化合物及其制备方法和在医学上的应用
WO2020039088A3 (fr) * 2018-08-24 2020-04-02 Xeniopro GmbH Nouveaux composés
CN111925343A (zh) * 2020-08-12 2020-11-13 石家庄四药有限公司 一种利奈唑胺降解杂质的合成方法
CN111925343B (zh) * 2020-08-12 2021-11-23 石家庄四药有限公司 一种利奈唑胺降解杂质的合成方法

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