WO2015096611A1 - 一种喹啉衍生物、其制备方法和应用 - Google Patents

一种喹啉衍生物、其制备方法和应用 Download PDF

Info

Publication number
WO2015096611A1
WO2015096611A1 PCT/CN2014/093258 CN2014093258W WO2015096611A1 WO 2015096611 A1 WO2015096611 A1 WO 2015096611A1 CN 2014093258 W CN2014093258 W CN 2014093258W WO 2015096611 A1 WO2015096611 A1 WO 2015096611A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
substituted
alkyl
formula
Prior art date
Application number
PCT/CN2014/093258
Other languages
English (en)
French (fr)
Inventor
邓杰
雷皇书
王为波
刘才平
叶文润
徐立炎
周昌兵
张国尧
邹艳冶
何志琴
Original Assignee
重庆医药工业研究院有限责任公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 重庆医药工业研究院有限责任公司 filed Critical 重庆医药工业研究院有限责任公司
Publication of WO2015096611A1 publication Critical patent/WO2015096611A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a quinoline derivative, a preparation method and application thereof.
  • tuberculosis is the second leading cause of infectious diseases after AIDS.
  • first-line anti-tuberculosis drugs have been used for decades of isoniazid, rifampicin (rifamycin), pyrazinamide and ethambutol.
  • ATP synthase inhibitors are the most important anti-tuberculosis drugs with a new mechanism of action.
  • a class of diarylquinoline derivatives, compounds of the general formula (Ia) or formula (Ib), which have good antituberculosis activity, are disclosed in the patent application filed by the Japanese Society of the United States, in the patent application No. WO2004011436A1. ;
  • TMC-207 is a diarylquinoline derivative having the structure shown by formula IX;
  • the drug has good anti-tuberculosis activity, has a good killing effect on drug-resistant and multi-drug resistant Mycobacterium tuberculosis, and was approved for marketing at the end of 2012.
  • the drug is the first anti-tuberculosis drug with a novel mechanism of action in the past 40 years. It targets the inhibition of ATP synthase of Mycobacterium tuberculosis and exerts the efficacy of killing Mycobacterium tuberculosis by cutting off the energy source of Mycobacterium tuberculosis.
  • anti-tuberculosis drugs there are still relatively few new types of anti-tuberculosis drugs, and it is urgent to develop more new anti-tuberculosis drugs to facilitate the prevention and treatment of tuberculosis.
  • an object of the present invention is to provide a quinoline derivative, a process for the preparation thereof and use thereof, or a compound thereof or an optical isomer, a racemate, a diastereomer thereof, a pharmaceutically acceptable salt Or the solvate has a significant killing effect on Mycobacterium tuberculosis and can be applied to the preparation of a medicament for treating or preventing a disease or a disease caused by Mycobacterium tuberculosis infection.
  • the present invention adopts the following technical solutions:
  • the present invention provides a compound of formula I or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof,
  • R 1 is hydrogen, halogen, hydroxy, alkoxy, alkyl, cyano, amino or nitro;
  • R 2 is a phenyl group, a naphthyl group, a heterocyclic group, a substituted phenyl group, a substituted naphthyl group or a substituted heterocyclic group, and the substituent of the substituted phenyl group, substituted naphthyl group or substituted heterocyclic group is one Or a plurality of substituents of the substituted phenyl, substituted naphthyl or substituted heterocyclic group are selected from the group consisting of halogen, hydroxy, acyl, alkyl, haloalkyl, alkoxy, cyano, nitro and amino;
  • R 3 and R 4 are a group which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, and the saturated or unsaturated heterocyclic ring contains a ring. Or a plurality of nitrogen atoms and the nitrogen atom of the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, hydroxy, alkyl, acyl, Ar, Ar-alkyl, Het, and Het-alkyl;
  • n 0, 1, 2, 3 or 4.
  • the saturated or unsaturated heterocyclic ring contains a nitrogen atom.
  • the present invention provides a compound of formula I or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof,
  • R 1 is hydrogen, halogen or alkyl
  • R 2 is phenyl, naphthyl, substituted phenyl or substituted naphthyl, the substituted phenyl, substituted naphthyl substituent is one or more, the substituted phenyl, substituted naphthyl Substituents are selected from the group consisting of halogen, alkyl, haloalkyl and alkoxy;
  • R 3 and R 4 are a group which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, and the saturated or unsaturated heterocyclic ring contains a ring. Or a plurality of nitrogen atoms and the nitrogen atom of the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, alkyl, acyl, Ar, and Ar-alkyl;
  • n 0, 1, or 2.
  • the present invention provides a compound, or an optical isomer, a racemate, a diastereomer, a pharmaceutically acceptable salt or a solvate thereof, a saturated or unsaturated heterocyclic ring.
  • the nitrogen atom in the middle is substituted with a group selected from the group consisting of methyl, ethyl, propyl, isopropyl and diphenyl. methyl.
  • R 1 is bromine
  • the compound provided by the present invention or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof, substituted phenyl, substituted naphthyl or substituted hetero
  • the substituent of the cyclic group is fluorine.
  • the number of substituents of the naphthyl or substituted heterocyclic group is two.
  • n 0, 1, or 2.
  • n is 0 or 1.
  • the compound provided by the present invention or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof includes hydrochloride, hydrogen Bromate, sulfate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, mandelate, citrate or tartrate.
  • the compounds provided herein, or optical isomers, racemates, diastereomers, pharmaceutically acceptable salts or solvates thereof are specifically:
  • Example 14 1-(1-Diphenylmethylazetidin-3-yl)-2-(6-bromo-2-methoxyquinolin-3-yl)-1,2-diphenylethanol, and
  • the compound I (A) obtained in Example 14 is a mixed body containing 4 isomers;
  • the invention also provides a process for the preparation of a compound of formula I, or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof, comprising:
  • the compound of the formula II is deprotonated with a strong base in anhydrous tetrahydrofuran under the protection of nitrogen, and then reacted with the compound of the formula III;
  • R 1 is hydrogen, halogen, hydroxy, alkoxy, alkyl, cyano, amino or nitro;
  • R 2 is a phenyl group, a naphthyl group, a heterocyclic group, a substituted phenyl group, a substituted naphthyl group or a substituted heterocyclic group, and the substituent of the substituted phenyl group, substituted naphthyl group or substituted heterocyclic group is one Or a plurality of substituents of the substituted phenyl, substituted naphthyl or substituted heterocyclic group are selected from the group consisting of halogen, hydroxy, acyl, alkyl, haloalkyl, alkoxy, cyano, nitro and amino;
  • R 3 and R 4 are a group which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, and the saturated or unsaturated heterocyclic ring contains a ring. Or a plurality of nitrogen atoms and the nitrogen atom of the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, hydroxy, alkyl, acyl, Ar, Ar-alkyl, Het, and Het-alkyl;
  • n 0, 1, 2, 3 or 4.
  • the strong base used is lithium diisopropylamide.
  • the preparation method of the compound of Formula III in the preparation method provided by the present invention is specifically as follows:
  • the compound of the formula IV is hydrolyzed in an anhydrous tetrahydrofuran with a compound of the formula V to be hydrolyzed;
  • R 2 is phenyl, naphthyl, heterocyclic, substituted phenyl, substituted naphthyl or substituted heterocyclic, substituted phenyl, substituted naphthyl or substituted heterocyclic substituent
  • the substituent of the substituted phenyl, substituted naphthyl or substituted heterocyclic group is selected from the group consisting of halogen, hydroxy, acyl, alkyl, haloalkyl, alkoxy, cyano, nitro and amino ;
  • R 3 and R 4 are a group which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, and the saturated or unsaturated heterocyclic ring contains a ring. Or a plurality of nitrogen atoms and the nitrogen atom of the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, hydroxy, alkyl, acyl, Ar, Ar-alkyl, Het, and Het-alkyl;
  • X is a halogen
  • n 0, 1, 2, 3 or 4.
  • the preparation method of the compound of Formula IV in the preparation method provided by the present invention comprises:
  • the compound of the formula XI is reacted with methanesulfonyl chloride in an organic solvent in the presence of triethylamine, and after the reaction is completed, the obtained reaction product is subjected to a substitution reaction with sodium cyanide;
  • R 3 and R 4 are groups which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, said saturated or unsaturated heterocyclic ring Containing one or more nitrogen atoms and the nitrogen atom in the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, hydroxy, alkyl, acyl, Ar, Ar-alkyl, Het, and Het-alkane base;
  • n 0, 1, 2, 3 or 4.
  • the preparation method of the compound of Formula III in the preparation method provided by the present invention is specifically as follows:
  • the acylation reaction is carried out by reacting a compound of the formula VII with a compound of the formula VIII under the action of a Lewis acid;
  • R 2 is phenyl, naphthyl, heterocyclic, substituted phenyl, substituted naphthyl or substituted heterocyclic, substituted phenyl, substituted naphthyl or substituted heterocyclic substituent
  • the substituent of the substituted phenyl, substituted naphthyl or substituted heterocyclic group is selected from the group consisting of halogen, hydroxy, acyl, alkyl, haloalkyl, alkoxy, cyano, nitro and amino ;
  • R 3 and R 4 are a group which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, and the saturated or unsaturated heterocyclic ring contains a ring. Or a plurality of nitrogen atoms and the nitrogen atom of the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, hydroxy, alkyl, acyl, Ar, Ar-alkyl, Het, and Het-alkyl;
  • n 0, 1, 2, 3 or 4.
  • the compound of formula VI in the preparation method provided by the present invention may be represented by the formula IV
  • R 3 and R 4 are groups which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, said saturated or unsaturated heterocyclic ring Containing one or more nitrogen atoms and the nitrogen atom in the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, hydroxy, alkyl, acyl, Ar, Ar-alkyl, Het, and Het-alkane base;
  • n 0, 1, 2, 3 or 4.
  • the preparation method of the compound represented by Formula III is specifically as follows:
  • the compound of the formula VI is condensed with N,O-dimethylhydroxylamine under the action of a condensing agent to form a compound of the formula X;
  • the compound represented by the formula X is hydrolyzed and reacted with a compound of the formula V to be hydrolyzed;
  • R 2 is phenyl, naphthyl, heterocyclic, substituted phenyl, substituted naphthyl or substituted heterocyclic, substituted phenyl, substituted naphthyl or substituted heterocyclic substituent
  • the substituent of the substituted phenyl, substituted naphthyl or substituted heterocyclic group is selected from the group consisting of halogen, hydroxy, acyl, alkyl, haloalkyl, alkoxy, cyano, nitro and amino ;
  • R 3 and R 4 are a group which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, and the saturated or unsaturated heterocyclic ring contains a ring. Or a plurality of nitrogen atoms and the nitrogen atom of the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, hydroxy, alkyl, acyl, Ar, Ar-alkyl, Het, and Het-alkyl;
  • X is a halogen
  • n 0, 1, 2, 3 or 4.
  • the condensing agent used in the preparation method of the compound of the formula III is carboxydiimidazole or 1-ethyl-(3-dimethylaminopropane). Carbo diimine hydrochloride (EDCI.HCl).
  • the compound of the formula II in the preparation method provided by the present invention, can be obtained commercially or can be obtained, and the specific preparation method is disclosed in the patent application filed as WO2004011436A1. Preparation method.
  • the preparation method of the compound of the formula II, and the preparation method of the compound of the formula III include, but are not limited to, the preparation method provided by the present invention.
  • a method for preparing a pharmaceutically acceptable salt of a compound of formula I comprising:
  • R 1 is hydrogen, halogen, hydroxy, alkoxy, alkyl, cyano, amino or nitro;
  • R 2 is a phenyl group, a naphthyl group, a heterocyclic group, a substituted phenyl group, a substituted naphthyl group or a substituted heterocyclic group, and the substituent of the substituted phenyl group, substituted naphthyl group or substituted heterocyclic group is one Or a plurality of substituents of the substituted phenyl, substituted naphthyl or substituted heterocyclic group are selected from the group consisting of halogen, hydroxy, acyl, alkyl, haloalkyl, alkoxy, cyano, nitro and amino;
  • R 3 and R 4 are a group which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, and the saturated or unsaturated heterocyclic ring contains a ring. Or a plurality of nitrogen atoms and the nitrogen atom of the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, hydroxy, alkyl, acyl, Ar, Ar-alkyl, Het, and Het-alkyl;
  • n 0, 1, 2, 3 or 4;
  • Pharmaceutically acceptable salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, mandelate, citrate or tartaric acid salt.
  • the present invention also provides a compound of the formula I or an optical isomer, a racemate, a diastereomer, a pharmaceutically acceptable salt or a solvate thereof for use in the treatment or prevention of Mycobacterium tuberculosis infection.
  • a drug for a disease or condition a compound of the formula I or an optical isomer, a racemate, a diastereomer, a pharmaceutically acceptable salt or a solvate thereof for use in the treatment or prevention of Mycobacterium tuberculosis infection.
  • R 1 is hydrogen, halogen, hydroxy, alkoxy, alkyl, cyano, amino or nitro;
  • R 2 is a phenyl group, a naphthyl group, a heterocyclic group, a substituted phenyl group, a substituted naphthyl group or a substituted heterocyclic group, and the substituent of the substituted phenyl group, substituted naphthyl group or substituted heterocyclic group is one Or a plurality of substituents of the substituted phenyl, substituted naphthyl or substituted heterocyclic group are selected from the group consisting of halogen, hydroxy, acyl, alkyl, haloalkyl, alkoxy, cyano, nitro and amino;
  • R 3 and R 4 are a group which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, and the saturated or unsaturated heterocyclic ring contains a ring. Or a plurality of nitrogen atoms and the nitrogen atom of the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, hydroxy, alkyl, acyl, Ar, Ar-alkyl, Het, and Het-alkyl;
  • n 0, 1, 2, 3 or 4.
  • the Mycobacterium tuberculosis is selected from the group consisting of a standard strain of Mycobacterium tuberculosis, a clinically sensitive strain of Mycobacterium tuberculosis or a clinically resistant strain of Mycobacterium tuberculosis.
  • the standard susceptible strain of Mycobacterium tuberculosis in the application provided by the present invention is the H37RV strain.
  • the clinically susceptible strain of Mycobacterium tuberculosis in the application provided by the present invention is 741 strain, 753 strain, 758 strain, 760 strain or 821 strain.
  • the clinically resistant strain of Mycobacterium tuberculosis in the application provided by the invention is 930 strain, 1237 strain, 1256 strain, 1259 strain or 1288 strain.
  • the disease caused by Mycobacterium tuberculosis infection in the application provided by the present invention is tuberculosis.
  • the use of the invention described above also includes a method of treating and preventing a disease caused by infection with Mycobacterium tuberculosis comprising administering to a mammal and a human infected with a Mycobacterium tuberculosis a therapeutically effective amount of a compound of formula I.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or an optical isomer, a racemate, a diastereomer, a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable Acceptable excipients.
  • the pharmaceutically acceptable excipients in the pharmaceutical compositions provided by the present invention include pharmacy An acceptable carrier and/or a pharmaceutically acceptable excipient.
  • the compound of the formula I of the present invention or an optical isomer, a racemate, a diastereomer, a pharmaceutically acceptable salt or a solvate thereof may be used singly or in a pharmaceutically acceptable carrier. And/or a pharmaceutically acceptable excipient is used after preparation into a pharmaceutical composition.
  • a pharmaceutically acceptable carrier and/or pharmaceutically acceptable excipient are combined in a suitable form or dosage form, which comprises mixing, granulating, compressing or compressing the components by suitable methods. Dissolved.
  • compositions provided by the present invention may be administered by any of the following methods: oral, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration (such as subcutaneous, intravenous, muscular, Intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or input; or by means of an external reservoir), preferably oral, intramuscular, intraperitoneal or intravenous.
  • the compounds of formula I provided herein, or optical isomers, racemates, diastereomers, pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, may be administered in unit dosage form.
  • the dosage form can be a liquid dosage form or a non-liquid dosage form.
  • the liquid dosage form can be a true solution, a colloidal, a microparticulate form, an emulsion dosage form or a mixed dosage form.
  • the non-liquid dosage form may be a tablet, a capsule, a dropping pill, an aerosol, a pill, a powder, a solution, a mixed agent, an emulsion, a granule, a suppository, a lyophilized powder, a clathrate, an implant, a patch. Or liniment.
  • the pharmaceutically acceptable carrier of the pharmaceutical composition provided by the present invention includes, but is not limited to, an ion exchanger, alumina, aluminum stearate, lecithin, serum protein (such as human serum albumin), Buffer substances (such as phosphate, glycerin, sorbic acid, potassium sorbate), partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride) , zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax or lanolin).
  • the above pharmaceutically acceptable carrier is contained in the pharmaceutical composition in an amount of from 1% to 98% by weight, usually 80% by mass.
  • the local anesthetic, preservative or buffer may be dissolved directly in the vehicle.
  • Oral tablets and capsules may contain pharmaceutically acceptable excipients including binders, fillers, lubricants or disintegrating or emollients.
  • the binder comprises syrup, gum arabic, sorbitol, tragacanth or polyvinylpyrrolidone;
  • the filler comprises lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine;
  • the lubricant comprises magnesium stearate, talc Polyethylene glycol or silica;
  • the disintegrant comprises potato starch;
  • the humectant comprises sodium lauryl sulfate. Tablets can be prepared by methods known in the pharmacy.
  • Oral solutions can be prepared as suspensions of water and oil, solutions, emulsions, syrups or elixirs, or as dry products, supplemented with water or other suitable medium before use.
  • Such liquid preparations may contain conventional additives including suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the suspending agent includes sorbitol, cellulose methyl ether, glucose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fat;
  • the emulsifier includes lecithin, sorbus Monosaccharide monooleate or gum arabic;
  • the non-aqueous carrier (which may contain edible oils) includes almond oil, oils such as glycerol, ethylene glycol or ethanol;
  • the preservative includes methylparaben, p-hydroxybenzoic acid Propyl ester, sorbic acid. Flavoring or coloring agents can be added as needed.
  • liquid dosage forms are generally provided by the present invention as a compound of formula I or light thereof.
  • the carrier is preferred water.
  • the compounds of formula I provided herein, or optical isomers, racemates, diastereomers, pharmaceutically acceptable salts or solvates thereof may be used. It can also be stably dispersed in a carrier to form a suspension in a solution prepared by dissolving the carrier; in the preparation of the solution for injection, the compound is dissolved in water, filtered and sterilized, and then placed in a sealing bottle or an ampoule.
  • the present invention provides a compound of formula I or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof, which can be formulated into a suitable ointment.
  • a suitable ointment In the form of a lotion or cream, wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Pharmaceutically acceptable carriers in which the ointment formulation can be used include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax or water.
  • Pharmaceutically acceptable carriers for use in lotions and creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2- Octyl dodecanol, benzyl alcohol or water.
  • the suppository can comprise a conventional suppository base such as cocoa butter or other glycerides.
  • the concentration of the compound of the formula I, or an optical isomer, a racemate, a diastereomer, a pharmaceutically acceptable salt or a solvate thereof, in the above pharmaceutical preparation should be the percentage by mass of the drug.
  • the total weight of the composition is from 0.1% to 99.5%, preferably from 0.5% to 95%.
  • the above pharmaceutical preparation may further comprise other pharmaceutically active compounds in addition to the compound of formula I or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof. .
  • the invention has proven to be advantageous, whether in human medicine or in veterinary medicine, the invention
  • the total amount of the compound of the formula I, or an optical isomer, racemate, diastereomer, pharmaceutically acceptable salt or solvate thereof is from 0.5 mg to 500 mg per 24 hours.
  • the amount of the active compound contained in a single dose is preferably from 1 mg to 80 mg, more preferably from 1 mg to 50 mg per kg of body weight, but may not be in accordance with the above-mentioned dosage, depending on the type and weight of the subject, the nature and severity of the disease. , the type of formulation and the mode of administration of the drug, as well as the dosing cycle or time interval.
  • a certain atomic group may be attached to several hydrogen atoms such that the atomic group can satisfy the chemical valence requirement, although the hydrogen atom on the corresponding atomic group is in the structural formula. Not drawn.
  • a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a saturated cyclic group having 3 to 6 carbon atoms, a linear or branched chain having 1 to 6 carbon atoms, and containing A group of a saturated ring of 3 to 6 carbon atoms, and the hydrogen on the alkyl group may be substituted with a hydroxyl group or a halogen.
  • Alkoxy means alkyl-O- wherein alkyl is as defined above for alkyl.
  • Halogen is a substituent selected from fluorine, chlorine, bromine, and iodine.
  • the haloalkyl group is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, wherein hydrogen at one or more carbon atoms is substituted, and the hydrogen atom is substituted
  • the number is one or more, and the substituent of the hydrogen atom is a halogen.
  • Ar is a carbocyclic ring selected from the group consisting of phenyl, naphthyl and tetrahydronaphthyl, each carbocyclic ring optionally being substituted by 1, 2 or 3 substituents, each substituent being independently selected from the group consisting of a hydroxyl group, a halogen, a cyano group, and a nitrate Alkyl, amino, mono or dialkylamino, alkyl, haloalkyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, morpholinyl and mono or dialkylaminocarbonyl.
  • Het is selected from the group consisting of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazole, isoxazole, pyridyl, pyrimidinyl, pyrazinyl and a monocyclic heterocyclic ring of a pyridazinyl group; or a quinolyl group, a quinazolinyl group, a fluorenyl group, a benzimidazolyl group, a benzoxazolyl group, a benzisoxazole group, a benzothiazole, a benzo Isothiazolyl, benzofuran, benzothienyl; each monocyclic or bicyclic heterocyclic ring is optionally substituted by 1, 2 or 3 substituents selected from halogen, hydroxy, alkyl, alkoxy or Ar-carbonyl .
  • a subject can refer to a patient or receive a compound provided by the present invention or an optical isomer, a racemate, a diastereomer, a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof for treatment and/or Or an animal, particularly a mammal, such as a human, a dog, a monkey, a cow, or a mouse, which prevents the disease or condition mentioned in the present invention.
  • a disease and/or condition refers to a physical condition of a subject described above that is associated with a disease and/or condition in an application provided by the present invention.
  • % means weight/weight percentage, that is, mass percentage, unless otherwise specified, particularly in the case of describing a solid matter.
  • the "%” may mean a weight/volume percentage (in the case where the solid is dissolved in a liquid), or may refer to a volume/volume percentage (in the case where the liquid is dissolved in a liquid).
  • room temperature means 15 ° C to 30 ° C unless otherwise specified.
  • pharmaceutically acceptable or “pharmaceutically acceptable” as used interchangeably, is not only physiologically acceptable to the subject, such as “pharmaceutically acceptable salts,” but may also mean A pharmaceutically useful synthetic substance such as "a salt formed as an intermediate in chiral resolution", although a salt of such an intermediate cannot be directly administered to a subject, the salt may be in the present invention The end product works.
  • the present invention provides a quinoline derivative, a process for its preparation and an application.
  • the compound provided by the present invention is a compound of the formula I or an optical isomer, a racemate, a diastereomer, a pharmaceutically acceptable salt or a solvate thereof.
  • R 1 is hydrogen, halogen, hydroxy, alkoxy, alkyl, cyano, amino or nitro;
  • R 2 is a phenyl group, a naphthyl group, a heterocyclic group, a substituted phenyl group, a substituted naphthyl group or a substituted heterocyclic group, and the substituent of the substituted phenyl group, substituted naphthyl group or substituted heterocyclic group is one Or a plurality of substituents of the substituted phenyl, substituted naphthyl or substituted heterocyclic group are selected from the group consisting of halogen, hydroxy, acyl, alkyl, haloalkyl, alkoxy, cyano, nitro and amino;
  • R 3 and R 4 are a group which can be joined together to form a saturated or unsaturated heterocyclic ring which is a 4-, 5- or 6-membered ring, and the saturated or unsaturated heterocyclic ring contains a ring. Or a plurality of nitrogen atoms and the nitrogen atom of the saturated or unsaturated heterocyclic ring is substituted with a group selected from the group consisting of hydrogen, hydroxy, alkyl, acyl, Ar, Ar-alkyl, Het, and Het-alkyl;
  • n 0, 1, 2, 3 or 4.
  • the compound has a remarkable killing effect against Mycobacterium tuberculosis and can be applied to the preparation of a medicament for treating or preventing a disease or a disease caused by Mycobacterium tuberculosis infection.
  • the invention discloses a quinoline derivative, a preparation method and application thereof.
  • Those skilled in the art can refer to the content herein to obtain the quinoline derivative and realize its application. It is particularly noted that all similar substitutions and modifications will be apparent to those skilled in the art, and they are all considered to be included in the present disclosure.
  • the preparation method and application of the present invention have been described in the preferred embodiments, and it is obvious that those skilled in the art can make modifications or appropriate changes and combinations to the preparation methods and applications herein without departing from the scope of the invention. The technique of the present invention is applied.
  • the reagents and starting materials used in the quinoline derivative, the preparation method and the application thereof provided by the present invention are commercially available.
  • N-methyl-3-pyrrolidinecarboxylic acid 2.3g (17.9mmol) was dissolved in 50mL of dichloromethane, 12mL (174mmol) of thionyl chloride was added, then 0.1mL of DMF was added, refluxed for 7 hours, cooled to room temperature, decompression After concentration to dryness, it was dissolved in 50 mL of dichloromethane, and 2.5 g (19 mmol) of naphthalene was added thereto, and 3.5 g (26.3 mmol) of anhydrous aluminum trichloride was added in three portions at room temperature, and stirred at room temperature overnight.
  • the reaction solution was poured into a mixture of 50 mL of concentrated hydrochloric acid and 50 mL of ice water, stirred for 30 min, dichloromethane was separated, and the aqueous layer was extracted once again with 50 mL of dichloromethane, and the methylene chloride layer was combined and washed with 50 mL of brine. Drying with anhydrous sodium sulfate, concentrating and purifying by column chromatography (developing agent: a mixed solution of methanol and ethyl acetate in a volume ratio of 2:1), and drying to obtain a light yellow oily compound of formula III (D) 1.0 g The yield is 24%. MS (ESI) m / z: 240 (M + +1).
  • the reaction solution was poured into a mixture of 50 mL of concentrated hydrochloric acid and 50 mL of ice water, stirred for 30 min, dichloromethane was separated, and the aqueous layer was extracted once again with 50 mL of dichloromethane, and the methylene chloride layer was combined and washed with 50 mL of brine. Drying with anhydrous sodium sulfate, concentrating and separating and purifying by column chromatography (developing agent: a molar ratio of methanol to ethyl acetate is 2:1 mixed solution), and drying to obtain 10 g of a pale solid compound of pale III (E). The rate is 86%.
  • the mixture was stirred at room temperature for 2 hours, 100 mL of cold water was added to the reaction mixture, and the dichloromethane layer was separated by stirring, washed once with 50 mL of 10% sodium hydroxide solution, once with saturated brine, dried over anhydrous sodium sulfate and evaporated.
  • Step 4 is a compound of formula XV
  • the solid was added to 200 mL of dichloromethane, and 6.3 g (49.1 mmol) of naphthalene was added thereto, and the mixture was stirred and dissolved.
  • the mixture was cooled to 0 ° C, and anhydrous AlCl 38.0 g (60 mmol) was added in four portions, and the reaction was kept at 0 ° C for 2 hours.
  • the reaction solution was poured into a mixed solution of 100 mL of concentrated hydrochloric acid and 100 g of crushed ice, stirred at room temperature for 30 min, and the methylene chloride layer was separated. The aqueous layer was extracted once with 150 mL of dichloromethane.
  • the NMR data of the compound I(A) are: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 8.64 (s, 1H), 7.82 (s, 1H), 7.63 - 6.92 (m, 20H), 4.90 (s, 1H), 4.53 (s, H), 3.85 (s, 3H), 3.51 - 2.19 (m, 5H). It is a mixed race containing 4 isomers.
  • test tube Under a nitrogen atmosphere, 15 mL of the test tube was charged with 0.21 mL of diisopropylamine (1.5 mmol) and 1.5 mL of water tetrahydrofuran, and stirred at -78 ° C for 0.5 h to give 0.68 mL of 2.5 mol/L n-butyllithium (1.7 mmol). The reaction solution was added dropwise, and stirring was continued at -78 ° C for 0.5 h.
  • Example 4 After dissolving 328 mg of the compound of the formula II obtained in Example 1 in 1 mL of anhydrous tetrahydrofuran at -78 ° C, the reaction solution was slowly added dropwise, and after completion of the dropwise addition, stirring was continued at -78 ° C for 1 hour. 100 mg of the preparation of Example 4 The compound of the formula III (C) was dissolved in 1 mL of anhydrous tetrahydrofuran, and the reaction mixture was slowly added dropwise thereto, and the mixture was stirred at -78 ° C for 4 hours.
  • the reaction was quenched by the addition of 1 mL of a saturated aqueous solution of ammonium chloride, and the mixture was warmed to room temperature, and 10 mL of water was added, and ethyl acetate was extracted three times each time, and the organic layer was combined.
  • the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated, and purified by column chromatography (developing solvent: mixture of ethyl acetate and methanol in a volume ratio of 10:1). The fractions were separately collected and dried to obtain two products, 40 mg each.
  • the first component was labeled as Compound I (B), melting point 199 ° C; the latter component was labeled as Compound I (C) melting point, 220 ° C, Rate: 7.9%.
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • Compound I(C) 1 H NMR (400MHz, CDCl 3 ) ⁇ 7.81 (s, 1H), 7.65 - 6.64 (m, 13H), 4.78 (s, 1H), 3.91 (s, 3H), 3.67–3.09 (m, 5H), 2.55 (s, 3H).
  • Compound I (B) and Compound I (C) are each a diastereomer.
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the two components are separated and purified by column chromatography (developing agent: mixed solution of methanol and ethyl acetate in a volume ratio of 1:20), separately collected and dried to obtain two components, and the first component is marked as Compound I (F), a total of 86 mg, melting point: 197 ° C, yield: 10%; the resulting component was labeled as Compound I (G), a total of 80 mg, melting point: 175 ° C, yield: 9%.
  • developing agent mixed solution of methanol and ethyl acetate in a volume ratio of 1:20
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the first component was labeled as Compound I (P), 95 mg in total, melting point: 195 ° C, yield: 8.1%; the component which was later labeled was Compound I (Q), total 88 mg. , melting point: 197 ° C, yield: 7.5%.
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the first component is labeled as compound I (R), a total of 90 mg, melting point: 201 ° C, yield: 7.5%; the component that is later labeled is compound I (S), a total of 70 mg, Melting point: 210 ° C, yield: 5.8%.
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and then purified by column chromatography (developing solvent: mixture of methanol and ethyl acetate in a ratio of 1:10) to obtain two components, respectively.
  • the first component is labeled as compound I (V), 110 mg after drying, melting point: 73 ° C, yield: 9.0%; the component after the component is labeled as compound I (W), and after drying, 95 mg melting point: 75 °C, yield: 7.8%.
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the obtained product was detected by nuclear magnetic resonance spectroscopy, and the obtained nuclear magnetic resonance spectrum data were as follows:
  • the materials used include:
  • the strain used was:
  • H37RV strain Mycobacterium tuberculosis standard sensitive strain: H37RV strain, from the US Centers for Disease Control and Prevention;
  • Clinically resistant strains of Mycobacterium tuberculosis 930 strain, 1237 strain, 1256 strain, 1259 strain, and 1288 strain; all from Chongqing Public Health Medical Treatment Center;
  • the strain culture was operated according to the Standardized Operation and Quality Assurance Manual for Tuberculosis Culture.
  • tuberculosis standard sensitive strain, clinically sensitive strain of Mycobacterium tuberculosis and clinically resistant strain of Mycobacterium tuberculosis were cultured, labeled one by one, and after 2 weeks of passage in the modified Roche medium, the strains with good growth were selected to pick the appropriate amount, and the grinding bacteria were used.
  • the device was ground into a bacterial suspension, adjusted to a concentration of 1 mg/mL by turbidimetry, and then diluted to 1 ⁇ 10 -1 mg/mL, 1 ⁇ 10 -2 mg/mL with a general enrichment medium, and then 1
  • the bacterial concentration of ⁇ 10 -2 mg/mL was diluted with the modified Roche medium to a working concentration of 1 ⁇ 10 -3 mg / mL.
  • the compound No. 1 to Compound 23 obtained by the present invention was dissolved in DMSO and prepared into a sample stock solution of the compound prepared by the present invention at 5 mg/mL, and the stock solution was separately used according to the final concentration of each sample.
  • DMSO was prepared as a 100 ⁇ L dilution, and further diluted with DMSO to prepare a serial concentration gradient of each sample DMSO solution.
  • the DMSO solution of each sample was diluted 140 times with the modified Roche medium to obtain the sample working solution.
  • the concentration gradient of each sample was 0.125 ⁇ g/mL, 0.25 ⁇ g/mL, 0.5 ⁇ g/mL, from low to high.
  • Compound TMC207A was used as a comparative solution to obtain a stock solution of the sample according to the same formulation method.
  • the compounds of the present invention were numbered as Compounds 1 to 23; the positive control group: TMC207A; the negative control group: the general enrichment medium experiment was carried out in a 96-well culture plate, first by 10 ⁇ L/ The wells are added to the above prepared concentrations of the drug (ie, all the samples obtained in the preparation of the sample stock solution), the growth control wells containing no antibacterial agent are added to the general enrichment medium, and the prepared bacterial liquid concentration is further prepared. The bacterial strains of each strain of 1 ⁇ 10 -3 mg/mL were inoculated into each well at 200 ⁇ L/well, and the bacterial species and bacterial concentration in each well of the same plate were the same, and one complex plate was set. After the addition, the 96-well plate lid was sealed with tape and incubated at 37 °C.
  • the minimum inhibitory concentration of the compound provided by the present invention and the positive control compound for each strain is shown in Table 1.
  • the quinoline derivative provided by the invention has good antibacterial activity against the standard sensitive strain of Mycobacterium tuberculosis; some compounds have good antibacterial activity against the clinically sensitive strain of Mycobacterium tuberculosis and the clinically resistant strain of Mycobacterium tuberculosis, and can be used.
  • a medicament for treating or preventing a disease or condition caused by Mycobacterium tuberculosis infection For the preparation of a medicament for treating or preventing a disease or condition caused by Mycobacterium tuberculosis infection.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明属于药物化学技术领域，公开了一种喹啉衍生物、其制备方法和应用。本发明提供的化合物为如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物。该化合物对结核杆菌具有显著的杀灭效果，能够应用于制备用于治疗或预防结核杆菌感染所引起的疾病或病症的药物。

Description

一种喹啉衍生物、其制备方法和应用
本申请要求于2013年12月25日提交中国专利局、申请号为201310726353.5、发明名称为“一种喹啉衍生物、其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物化学技术领域，特别涉及一种喹啉衍生物、其制备方法和应用。
背景技术
在全球传染病统计中，结核病是仅次于艾滋病的第二致死传染病。尽管目前临床应用的抗结核治疗药物众多，但一线抗结核药物仍为应用了数十年的异烟肼、利福平(利福霉素类)、吡嗪酰胺和乙胺丁醇。这些药物在结核病治疗中存在明显的不足：(1)耐药性严重，导致出现了多药耐药性、甚至广泛耐药性结核菌株；(2)治疗周期太长，最少都需要规律服药半年以上，患者难以坚持；(3)具有肝药酶抑制或诱导作用，容易导致联合用药时产生相互作用，因此常不能与抗病毒药(例如，治疗艾滋病的药物)联合用药；(4)副作用较多，例如胃肠道功能障碍及肝功损害。
由于现有治疗药物的长期应用，以及患者的不规律用药，导致患者体内的结核杆菌对现有治疗药物产生了明显的耐药性，甚至出现了对多种一线抗结核药物耐药的多药耐药性结核菌株和对所有抗结核药物耐药的广泛耐药性结核菌株。一方面，这些耐药结核病患者因无有效的药物治疗而造成较高的死亡率，另一方面，由于结核病的传染性，导致了耐药性结核菌的流行。耐药性结核病的发生与流行，使结核病重新成为不治之症。据 WHO有关人士称，今后10年内肺结核患者将增至3,000万人以上，而使用现有的药物只能减少1,500万人的死亡，另一半人的生命则完全取决于能否开发出抗结核的新药。因此，寻找新的结核药物作用靶点，开发新型抗结核药物已迫在眉睫。
目前，处于研究阶段的抗结核药物中，ATP合成酶抑制剂是最受瞩目的一类全新作用机制的抗结核药物。美国强生旗下Tibotec公司在公开号为WO2004011436A1的专利申请文件中公开了一类二芳基喹啉类衍生物，通式(Ia)或通式(Ib)化合物，其具有较好的抗结核杆菌活性；
Figure PCTCN2014093258-appb-000001
经研究，已成功开发出了一种新型抗结核杆菌药物，命名TMC-207，即具有式IX所示结构的二芳基喹啉衍生物；
Figure PCTCN2014093258-appb-000002
研究证实，该药物具有良好的抗结核杆菌活性，对耐药性和多药耐药性的结核杆菌具有很好的杀灭效果，已经于2012年底被批准上市。该药物是40年来第一种具有新型作用机理的抗结核药物，靶向抑制结核杆菌的ATP合成酶，通过切断结核杆菌的能量来源发挥杀灭结核杆菌的疗效。但是目前新型抗结核药物的种类还比较少，急需要研发更多的新型抗结核药物以便于结核病的防治。
发明内容
有鉴于此，本发明的发明目的在于提供一种喹啉衍生物、其制备方法和应用，该化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物对结核杆菌具有显著的杀灭效果，能够应用于制备用于治疗或预防结核杆菌感染所引起的疾病或病症的药物。
为了实现本发明的发明目的，本发明采用如下的技术方案：
本发明提供了一种如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物，
Figure PCTCN2014093258-appb-000003
其中，R1为氢、卤素、羟基、烷氧基、烷基、氰基、氨基或硝基；
R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，该取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，该取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
n为0、1、2、3或4。
优选地，本发明提供的式I化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物中，饱和或不饱和杂环含一个氮原子。
优选地，本发明提供的式I化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物中，
R1为氢、卤素或烷基；
R2为苯基、萘基、取代的苯基或取代的萘基，所述取代的苯基、取代的萘基的取代基为一个或多个，所述取代的苯基、取代的萘基的取代基选自卤素、烷基、卤代烷基和烷氧基；
R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、烷基、酰基、Ar和Ar-烷基；
n为0、1或2。
在本发明的一些实施例中，本发明提供的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物中，饱和或不饱和杂环中的氮原子被选自下列的基团取代：甲基、乙基、丙基、异丙基和二苯 甲基。
优选地，本发明提供的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物中，R1为溴。
优选地，本发明提供的化合物或其光学异构体、消旋体、非对应异构体、药学上可接受的盐或溶剂合物中，取代的苯基、取代的萘基或取代的杂环基的取代基为氟。
在本发明的一些实施例中，本发明提供的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物中，取代的苯基、取代的萘基或取代的杂环基的取代基个数为两个。
优选地，本发明提供的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物中，n为0、1或2。
在本发明的一些实施例中，本发明提供的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物中，n为0或1。
优选地，本发明提供的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物中，药学上可接受的盐包括盐酸盐、氢溴酸盐、硫酸盐、甲磺酸盐、对甲苯磺酸盐、马来酸盐、富马酸盐、扁桃酸盐、枸橼酸盐或酒石酸盐。
在本发明的一些实施例中，本发明提供的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物具体为：
1-(1-二苯甲基氮杂环丁烷-3-基)-2-(6-溴-2-甲氧基喹啉-3-基)-1,2-二苯基乙醇，与实施例14制得的化合物I(A)相对，为含有4个异构体的混旋体；
2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-甲基氮杂环丁烷-3-基)-1,2-二苯基乙醇，与实施例15制得的化合物I(B)和化合物I(C)相对应，化合物I(B)和化合物I(C)互为非对映异构体；
1-(1-二苯甲基氮杂环丁烷-3-基)-2-(6-溴-2-甲氧基喹啉-3-基)-1-(3,5-二氟苯基)-2-苯乙醇，与实施例16制得的化合物I(D)和化合物I(E)相对应，化合物I(D)和化合物I(E)互为非对映异构体；
2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-甲基吡咯烷-3-基)-1-(萘-1-基)-2-苯乙醇，与实施例17制得的化合物I(F)和化合物I(G)相对应，化合物I(F)和化合物I(G)互为非对映异构体；
1-(6-溴代-2-甲氧基喹啉-3-基)-3-(1-甲基氮杂环丁烷-2-基)-2-(萘-1-基)-1-苯基-2-丙醇，与实施例18制得的化合物I(H)和化合物I(I)相对应，化合物I(H)和化合物I(I)互为非对映异构体；
2-(6-溴代-2-甲氧基喹啉-3-基)-1-(萘-1-基)-2-苯基-1-(吡啶-3-基)乙醇碘甲烷鎓盐，与实施例19制得的化合物I(L)和化合物I(M)相对应，化合物I(L)和化合物I(M)互为非对映异构体；
2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-甲基-1,2,5,6-四氢吡啶-3-基)-1-(萘-1-基)-2-苯乙醇，与实施例20制得的化合物I(N)和化合物I(O)相对应，化合物I(N)和化合物I(O)互为非对映异构体；
2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-甲基哌啶-4-基)-1-(萘-1-基)-2-苯乙醇，与实施例21制得的化合物I(P)和化合物I(Q)相对应，化合物I(P)和化合物I(Q)互为非对映异构体；
2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-乙基哌啶-4-基)-1-(萘-1-基) -2-苯乙醇，与实施例22制得的化合物I(R)和化合物I(S)相对应，化合物I(R)和化合物I(S)互为非对映异构体；
2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-异丙基哌啶-4-基)-1-(萘-1-基)-2-苯乙醇，与实施例23制得的化合物I(T)和化合物I(U)相对应，化合物I(T)和化合物I(U)互为非对映异构体；
2-(6-溴代-2-甲氧基喹啉-3-基)-1-(萘-1-基)-2-苯基-1-(1-丙基哌啶-4-基)-乙醇，与实施例24制得的化合物I(V)和化合物I(W)相对应，化合物I(V)和化合物I(W)互为非对映异构体；
2-(6-溴代-2-甲氧基喹啉-3-基)-1-(3,5二氟苯基)-1-(1-甲基哌啶-4-基)-2-苯基乙醇，与实施例25制得的化合物I(X)相对，为含有4个异构体的混旋体；
2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-甲基哌啶-4-基)-1,2-二苯基乙醇,与实施例26制得的化合物I(Y)相对，为含有4个异构体的混旋体。
本发明还提供了一种如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物的制备方法，包括：
在氮气保护下，将式II所示化合物在无水四氢呋喃中与强碱发生去质子化反应，再与式III所示化合物反应即得；
Figure PCTCN2014093258-appb-000004
其中，R1为氢、卤素、羟基、烷氧基、烷基、氰基、氨基或硝基；
R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，该取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，该取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
n为0、1、2、3或4。
优选地，本发明提供的制备方法中，所用的强碱为二异丙胺基锂。
在本发明的一些实施例中，本发明提供的制备方法中如式III所示化合物的制备方法具体为：
在氮气保护下，将如式IV所示化合物在无水四氢呋喃中与如式V所示化合物发生亲核加成反应后水解即得；
Figure PCTCN2014093258-appb-000005
其中，R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，该取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，该取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
X为卤素；
n为0、1、2、3或4。
在本发明的另外一些实施例中，本发明提供的制备方法中如式IV所示化合物的制备方法包括：
如式XI所示化合物在有机溶剂中，在三乙胺存下，与甲磺酰氯反应，反应完后，将所得反应产物与氰化钠发生取代反应，即得；
Figure PCTCN2014093258-appb-000006
其中，R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
n为0、1、2、3或4。
在本发明的另外一些实施例中，本发明提供的制备方法中如式III所示化合物的制备方法具体为：
将如式VI所示化合物与氯化亚砜发生取代反应生成如式VII所示化 合物；
将如式VII所示化合物与如式VIII所示化合物在路易斯酸作用下，发生酰化反应，即得；
Figure PCTCN2014093258-appb-000007
其中，R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，该取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，该取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
n为0、1、2、3或4。
本发明提供的制备方法中如式VI所示化合物可以由如式IV所示化
Figure PCTCN2014093258-appb-000008
其中，R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱 和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
n为0、1、2、3或4。
在本发明的另外一些实施例中，本发明提供的制备方法中，如式III所示化合物的制备方法具体为：
将如式VI所示化合物与N,O-二甲基羟胺在缩合剂作用下发生缩合反应生成如式X所示化合物；
将如式X所示化合物与如式V所示化合物亲核加成反应后水解即得；
Figure PCTCN2014093258-appb-000009
其中，R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，该取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，该取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个 氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
X为卤素；
n为0、1、2、3或4。
在本发明的另外一些实施例中，本发明提供的制备方法中，如式III所示化合物的制备方法中所用的缩合剂为羧基二咪唑或1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI.HCl)。
在本发明的另外一些实施例中，本发明提供的制备方法中，如式II所示化合物可以由商业途径获得，也可制备获得，其具体制备方法参见公开号为WO2004011436A1的专利申请文件中公开的制备方法。
本发明提供的制备方法中，如式II所示化合物的制备方法、如式III所示化合物的制备方法包括但不仅限于本发明提供的制备方法。
在本发明的另外一些实施例中，本发明提供的制备方法中，如式I所示化合物的药学上可接受的盐的制备方法，包括：
取如式I所示化合物，与药学上可接受的无机或有机酸反应，即得；
Figure PCTCN2014093258-appb-000010
其中，R1为氢、卤素、羟基、烷氧基、烷基、氰基、氨基或硝基；
R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环 基，该取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，该取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
n为0、1、2、3或4；
药学上可接受的盐包括盐酸盐、氢溴酸盐、硫酸盐、甲磺酸盐、对甲苯磺酸盐、马来酸盐、富马酸盐、扁桃酸盐、枸橼酸盐或酒石酸盐。
本发明还提供了如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物在制备用于治疗或预防结核杆菌感染所引起的疾病或病症的药物中的应用，
Figure PCTCN2014093258-appb-000011
其中，R1为氢、卤素、羟基、烷氧基、烷基、氰基、氨基或硝基；
R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，该取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，该取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
n为0、1、2、3或4。
在本发明的一些实施例中，本发明提供的应用中，结核杆菌选自结核杆菌标准敏感株、结核杆菌临床敏感株或结核杆菌临床耐药株。
在本发明的一些实施例中，本发明提供的应用中的结核杆菌标准敏感株为H37RV菌株。
在本发明的另外一些实施例中，本发明提供的应用中的结核杆菌临床敏感株为741菌株、753菌株、758菌株、760菌株或821菌株。
在本发明的另外一些实施例中，本发明提供的应用中的结核杆菌临床耐药株为930菌株、1237菌株、1256菌株、1259菌株或1288菌株。
在本发明的另外一些实施例中，本发明提供的应用中结核杆菌感染所引起的疾病为肺结核。
上述本发明提供的应用，还包括一种治疗和预防由结核杆菌感染所引起的疾病的方法，包括给感染上结核杆菌的动物和人服用有效治疗量的如式I所示化合物。
本发明还提供了一种药物组合物，其包括如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物和药学上可接受的辅料。
优选地，本发明提供的药物组合物中的药学上可接受的辅料包括药学 上可接受的载体和/或药学上可接受的赋形剂。
本发明的如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物可以单独使用，也可以与药学上可接受的载体和/或药学上可接受的赋形剂制备成药物组合物之后使用。当以药物组合物的形式使用时，通常将有效计量的本发明的如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物以及药学上可接受的载体和/或药学上可接受的赋形剂结合制成适当的施用形式或剂量形式，这一程序包括通过适合的方法将各个组分混合、粒化、压缩或溶解。
本发明提供的药物组合物可以选自以下任何方式给药：口服、喷雾吸入、直肠给药、鼻腔给药、阴道给药、局部给药、非肠道给药(如皮下、静脉、肌肉、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入；或借助一种外置的储器用药)，其中优选为口服、肌肉、腹膜内或静脉内用药方式。
本发明提供的如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物或药物组合物可以以单位剂量形式给药。给药剂型可以是液体剂型、非液体剂型。液体剂型可以是真溶液、胶体类、微粒剂型、乳剂剂型或混旋剂型。非液体剂型可以是片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混旋剂、乳剂、颗粒剂、栓剂、冻干粉针、包合物、埋植剂、贴剂或擦剂。
本发明提供的药物组合物中药学上可接受的载体，包括但不局限于：离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人血清蛋白)， 缓冲物质(如磷酸盐，甘油，山梨酸，山梨酸钾)、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜂蜡或羊毛酯)。上述药学上可接受的载体在药物组合物中的含量以质量百分比计为1％～98％重量，通常为80％。为使用方便起见，局部麻醉剂，防腐剂或缓冲剂可直接溶于载体中。
口服片剂和胶囊可以含有药学上可接受的赋形剂，该药学上可接受的赋形剂包括粘合剂、填充剂、润滑剂或崩解剂或增润剂。该粘合剂包括糖浆、阿拉伯胶、山梨醇、黄芪胶或聚乙烯吡咯烷酮；该填充剂包括乳糖、蔗糖、玉米淀粉、磷酸钙、山梨醇或氨基乙酸；该润滑剂包括硬脂酸镁、滑石、聚乙二醇或硅土；该崩解剂包括马铃薯淀粉；该增润剂包括月桂醇钠硫酸盐。片剂可以用药学上公知的方法制备。
口服液可以制成水和油的悬浮液，溶液，乳浊液，糖浆或酏剂，也可以制成干品，用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂，该添加剂包括悬浮剂、乳化剂、非水载体或防腐剂。该悬浮剂包括山梨醇、纤维素甲醚、葡萄糖糖浆、凝胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化的食用油脂；该乳化剂包括卵磷脂、山梨聚醣单油酸盐或阿拉伯胶；该非水载体(可能包含可食用油)包括杏仁油、油脂如甘油、乙二醇或乙醇；该防腐剂包括对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、山梨酸。如需要可添加调味剂或着色剂。
对胃外投药，液态剂型通常由本发明提供的如式I所示化合物或其光 学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物和一种消毒的载体制成。载体首选水。依照所选载体和药物浓度的不同，本发明提供的如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物既可溶于载体制成溶液中也可稳定分散在载体中制成悬浮液；在制成注射用溶液时先将化合物溶于水中，过滤消毒后装入封口瓶或安瓿中。
当皮肤局部施用时，本发明提供的如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物可以制成适当的软膏，洗剂或霜剂的形式，其中活性成分悬浮或溶解于一种或多种的载体中。其中软膏制剂可以使用的药学上可接受的载体包括但不局限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡或水。洗剂和霜剂可使用的药学上可接受的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇或水。
栓剂可包含常规的栓剂基质，如可可黄油或其它甘油酯。
在上述药物制剂中如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物的存在浓度以质量百分比计应为该药物组合物总重量的0.1％～99.5％，优选0.5％～95％。
上述药物制剂除了包含如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物外，还可进一步包含其它的药物活性化合物。
—般而言，已经证明有利的无论在人体医药还是在兽医药中，本发明 提供的如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物的给药总量每24小时为0.5mg～500mg，优选每千克体重给药lmg～100mg，如果有需要，分多次单剂量给药，以达到所要求的效果。单剂量中含活性化合物的量优选为lmg～80mg，更优选为每千克体重给药lmg～50mg，但也可以不按照上述的剂量，而根据治疗对象的种类和体重、疾病的性质和严重程度、制剂的类型和药物的给药方式，以及给药周期或时间间隔。
本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本发明仍再次对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本发明所表达的含义为准。下面是某些术语的定义，这些定义适用于本发明整个申请文件中所用的术语，除非在具体情况中另作说明。
在本发明上下文中，例如在通式化合物或具体化合物中所描绘的，某个原子团可以连接若干个氢原子，使该原子团可以满足化学价的要求，尽管相应的原子团上的氢原子在结构式中没有绘出。
烷基为1-6个碳原子的直链或支链的碳氢基团、含有3-6个碳原子的饱和环状基团、含1-6个碳原子的直链或支链并含有3-6个碳原子的饱和环的基团，该烷基上的氢可以被羟基或卤素取代。
烷氧基是指烷基-O-，其中烷基如上述烷基中所定义。
卤素为选自氟、氯、溴、碘的取代基。
卤代烷基为具有1-6个碳原子的直链或支链饱和烃基或具有3-6个碳原子的环状饱和烃基，其中一个或多个碳原子上的氢被取代，该氢原子个 数为一个或多个，该氢原子的取代基为卤素。
Ar为选自苯基、萘基、四氢萘基的碳环，每个碳环任选被1、2或3个取代基取代，各个取代基独立地选择自羟基、卤素、氰基、硝基、氨基、单或二烷基氨基、烷基、卤代烷基、烷氧基、卤代烷氧基、羧基、烷氧基羰基、氨基羰基、吗啉基和单或二烷基氨基羰基。
Het为选自N-苯氧基哌啶基、哌啶基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑、异噁唑、吡啶基、嘧啶基、吡嗪基和哒嗪基的单环杂环；或为选自喹啉基、喹唑啉基、吲哚基、苯并咪唑基、苯丙恶唑基、苯并异恶唑基、苯并噻唑，苯并异噻唑基、苯并呋喃、苯并噻吩基；每个单环或双环杂环任选被1、2或3个选自卤素、羟基、烷基、烷氧基或Ar-羰基的取代基取代。
受试者可以指患者或者接受本发明提供的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物或其药物组合物以治疗和/或预防本发明提到的疾病或病症的动物，特别是哺乳动物，例如人、狗、猴、牛、鼠。
疾病和/或病症是指上述受试者的一种身体状态，该身体状态与本发明提供的应用中的疾病和/或病症有关。
如本文描述，如无特别指明，“％”是指重量/重量百分比，即质量百分比，特别是在描述固体物质的情况下。当然，在描述液体物质时，该“％”可以指重量/体积百分比(对于固体溶于液体的情形)，或者可以指体积/体积百分比(液体溶于液体的情形)。
如本文描述，如无特别指明，“室温”指15℃～30℃。
如本文描述，“药学上可接受的”或者与其可互换使用的“可药用的”，不但是受试者生理上可接受，例如“药学上可接受的盐”，而且还可指在药学上有使用价值的合成物质，例如“在进行手性拆分时所形成的作为中间体的盐”，虽然这种中间体的盐并不能直接给予受试者，但该盐可在本发明的终产物中起作用。
本发明提供了一种喹啉衍生物、其制备方法和应用。本发明提供的化合物为如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物。实验数据表明，本发明提供的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物对结核杆菌具有显著的杀灭效果，与阳性对照化合物相比较，某些本发明提供的化合物对结核杆菌的抑制作用与阳性对照相同或者更优，说明本发明提供的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物能够应用于制备用于治疗或预防结核杆菌感染所引起的疾病或病症的药物。
Figure PCTCN2014093258-appb-000012
其中，R1为氢、卤素、羟基、烷氧基、烷基、氰基、氨基或硝基；
R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，该取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，该取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰 基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
n为0、1、2、3或4。
该化合物对结核杆菌具有显著的杀灭效果，能够应用于制备用于治疗或预防结核杆菌感染所引起的疾病或病症的药物。
具体实施方式
本发明公开了一种喹啉衍生物、其制备方法和应用。本领域技术人员可以参考本文内容，获得该喹啉衍生物，实现其应用，特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。本发明的制备方法及应用已经通过较佳的实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文制备方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明提供的一种喹啉衍生物、其制备方法和应用中所用到的试剂和原料均可由市场购得。
为了使本技术领域的技术人员能够更好地理解本发明的技术方案，下面结合实施例，进一步阐述本发明：
实施例1如式II所示化合物的制备
步骤1如式XII所示化合物的制备
取苯丙酸220g(1.47mol)加入到400mL二氯甲烷中，室温搅拌下加入氯化亚砜165mL，随后加入DMF 2mL，室温搅拌1小时后，回流反应2小时，减压浓缩干，用300mL二氯甲烷溶解，室温下滴加入含有230g(1.34mol)对溴苯胺、250mL三乙胺的500mL二氯甲烷溶液中。滴加完毕后室温下搅拌过夜。向反应液中加入20％碳酸钾溶液400mL，剧烈搅拌10分钟分出有机层，水层用二氯甲烷400mL提取，合并二氯甲烷提取液后，用20％碳酸钾溶液400mL洗涤，无水硫酸钠干燥，浓缩后加石油醚析出固体，过滤收集，干燥，经检测，其中含有如式XII所示化合物369g，收率83％。
Figure PCTCN2014093258-appb-000013
步骤2如式XIII所示化合物的制备
三氯氧磷72mL冷却到5℃，保持该温度下滴加入DMF 28mL，加完后，拆除冰水浴，室温搅拌20分钟后，30g(0.1mol)步骤1制得的如式XII所示化合物加入该搅拌液中，搅拌均匀后升温到80℃反应过夜。冷却至室温，缓缓倒入700g冰水中，搅拌半个小时，乙酸乙酯500mL提取三次。合并乙酸乙酯层，500mL 20％碳酸钾水溶液洗涤一次，饱和食盐水洗涤一次,无水硫酸钠干燥，浓缩，剩余物用乙醇重结晶，干燥，经检测，其中含有如式XIII所示化合物7.2g，收率20％。
Figure PCTCN2014093258-appb-000014
步骤3如式II所示化合物的制备
室温下，金属钠4.0g(168mmol)溶解于50mL干燥后的无水甲醇中，7.0g(21mmol)步骤2制得的式XIII所示化合物加入该甲醇钠溶液中回 流过夜。将该反应液浓缩，用100mL冷水稀释，过滤析出的固体，用冷水洗涤抽干，得到的滤饼，减压干燥，经检测，其中含有如式II所示化合物7.0g，收率100％。
Figure PCTCN2014093258-appb-000015
实施例2如式III所示化合物的制备
步骤1如式XI(A)所示化合物的制备
取二苯甲胺36.6g(0.2mol)和环氧氯丙烷26g(0.2mol)于200mL异丙醇中，室温搅拌反应16小时。将该反应液浓缩，加入100mL乙腈和30mL三乙胺，加热至65℃搅拌反应24小时。浓缩后用400mL 2N盐酸溶解，所得溶液用200mL乙酸乙酯洗涤一次后，氢氧化钠水溶液调节pH＝10，再用乙酸乙酯500mL提取三次，该乙酸乙酯提取液用饱和食盐水洗涤，无水硫酸钠干燥后浓缩，当剩余物为粘稠状时，加入250mL石油醚强力搅拌。过滤收集洗出的固体，干燥，得式XI(A)的固体化合物26g，收率55％。MS(ESI)m/z:240(M++1)。
Figure PCTCN2014093258-appb-000016
步骤2如式XIV所示化合物的制备
4.2g(17.5mmol)步骤1制得的如式XI(A)所示化合物，溶解于30mL二氯甲烷中，加入14mL(105mmol)三乙胺，冷却至0℃；2.7mL(35.1mmol)甲磺酰氯溶解于20mL二氯甲烷中，缓缓滴加入该反应液。滴加完毕后室温反应2.5小时，减压蒸除二氯甲烷，剩余物用100mL乙 酸乙酯溶解，10％氢氧化钠溶液50mL洗涤该乙酸乙酯溶液，再用饱和食盐水洗涤，无水硫酸钠干燥后，浓缩后经硅胶柱层析分离纯化(展开剂：乙酸乙酯与石油醚的体积比为1:2的混合溶液)，干燥，得如式XIV所示化合物4.0g，收率71.4％。MS(ESI)m/z:286(M++1)。
Figure PCTCN2014093258-appb-000017
步骤3如式IV所示化合物的制备
3.0g(9.5mmol)步骤2制得的如式XIV所示化合物，1.4g(28.6mmol)氰化钠，加入到含DMF 20mL和水3mL的混合液液中，加热到65℃，搅拌反应10小时。将反应液倒入120mL冷水中，乙酸乙酯每次50mL，提取三次，合并乙酸乙酯层先后用50mL水，50mL饱和食盐水洗涤一次后，无水硫酸钠干燥，浓缩后经硅胶柱层析分离纯化(展开剂：乙酸乙酯与石油醚的体积比为1:2的混合溶液)，干燥，得如式IV(A)所示化合物1.4g，收率60％。MS(ESI)m/z:249(M++1)。
Figure PCTCN2014093258-appb-000018
步骤4如式III所示化合物的制备
氮气保护下，250mL三颈瓶中，将6g(24.19mmol)步骤3所得的如式IV(A)所示化合物溶于50mL无水四氢呋喃，室温搅拌下将该溶液滴加入由19.0g溴苯和4.0g镁屑于100mL四氢呋喃中制备的格式试剂中，滴完后升温至50℃搅拌2.5h。冷却至室温，加入100mL饱和氯化铵水溶液终止反应，乙酸乙酯每次50mL萃取3次，合并有机层。先后用水和饱和食盐水各洗涤一次，无水硫酸钠干燥，浓缩，经柱层析(展开剂：石油醚与 二氯甲烷的体积比为1:1的混合溶液)分离纯化，干燥，得式III(A)的白色固体化合物3.95g，收率52％。
MS(ESI)m/z:328(M++1)。
Figure PCTCN2014093258-appb-000019
实施例3如式III所示化合物的制备
氮气保护下，250mL三颈瓶中，将6g(24.19mmol)实施例2步骤3所得的如式IV(A)所示化合物溶于50mL无水四氢呋喃，室温搅拌下将该溶液滴加入由3,5二氟溴苯23g(178mmol)和4.0g镁屑于100mL四氢呋喃中制备的格式试剂中，滴完后升温至50℃搅拌2.5h。冷却至室温，加入100mL饱和氯化铵水溶液终止反应，乙酸乙酯每次50mL萃取3次，合并有机层。先后用水和饱和食盐水各洗涤一次，无水硫酸钠干燥，浓缩，经柱层析(展开剂：石油醚与二氯甲烷的体积比为1:1混合溶液)分离纯化，干燥，得式III(B)的白色固体化合物4.0g，收率50％。MS(ESI)m/z:364(M++1)。
Figure PCTCN2014093258-appb-000020
实施例4如式III所示化合物的制备
50mL圆底烧瓶中，加入910mg(2.78mmol)实施例2步骤4制得的如 式III(A)所示化合物以及10mL二氯甲烷，搅拌溶解，室温搅拌下滴入0.91mL氯甲酰1-氯乙酯(8.35mmol)，反应4h。加入甲醇20mL，回流搅拌0.5h后减压浓缩，得黄色固体。将该黄色固体溶于28mL甲醇后，加入3.45mL甲醛水溶液(37％，体积百分比计)(42.51mmol)室温搅拌5min，然后加入醋酸钠680mg(8.29mmol)和氰基硼氢化钠552mg(8.78mmol)，室温搅拌反应45min。向反应液中加入2N盐酸水溶液，搅拌均匀，用乙酸乙酯萃取2次洗去杂质，水层加氢氧化钠水溶液调至pH>10，二氯甲烷萃取3次，合并有机层。有机层先后用水和饱和食盐水洗涤一次后，无水硫酸钠干燥，浓缩，经柱层析分离纯化(展开剂：二氯甲烷与甲醇的体积比为10:1混合溶液)分离得到式III(C)的黄色油状物120mg，收率25％。MS(ESI)m/z:176(M++1)。
Figure PCTCN2014093258-appb-000021
实施例5如式III所示化合物的制备
N-甲基-3-吡咯烷甲酸2.3g(17.9mmol)溶于50mL二氯甲烷中，加入12mL(174mmol)氯化亚砜，再加入0.1mL DMF，回流7小时，冷却到室温，减压浓缩至干，加入50mL二氯甲烷溶解，2.5g(19mmol)萘加入其中，室温下分三次共加入无水三氯化铝3.5g(26.3mmol)，室温搅拌过夜。将该反应液倒入50mL浓盐酸和50mL冰水的混合液中，搅拌30min，分出二氯甲烷，水层用50mL二氯甲烷再提取一次，合并二氯甲烷层，50mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经柱层析分离纯化(展开剂：甲醇与乙酸乙酯的体积比为2:1的混合溶液)，干燥，得式III(D)的淡黄色油状化合物1.0g，收率24％。MS(ESI)m/z:240(M++1)。
Figure PCTCN2014093258-appb-000022
实施例6如式III所示化合物的制备
异烟酸6.2g(50mmol)溶于50mL二氯甲烷中，加入12mL(174mmol)氯化亚砜，再加入0.1mL DMF，回流7小时，冷却到室温，减压浓缩至干，加入50mL二氯甲烷溶解，6.4g(50mmol)萘加入其中，室温下分三次加入无水三氯化铝8.6g(65mmol)，室温搅拌过夜。将该反应液倒入50mL浓盐酸和50mL冰水的混合液中，搅拌30min，分出二氯甲烷，水层用50mL二氯甲烷再提取一次，合并二氯甲烷层，50mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经柱层析分离纯化(展开剂：甲醇与乙酸乙酯的体积比为2:1混合溶液)，干燥，得淡式III(E)的黄色固体化合物10g，收率86％。
MS(ESI)m/z:234(M++1)。
Figure PCTCN2014093258-appb-000023
实施例7如式III所示化合物的制备
步骤1如式XV所示化合物的制备
取18.3g(100mmol)二苯甲胺，1,3-二溴丁酸甲酯26g(100mmol)溶于150mL乙腈，加入30g(300mmol)碳酸钾和30mL水，加热回流24小时。将反应液冷却至室温，浓缩，剩余物用250mL冷水稀释，乙酸乙酯每次150mL提取三次，合并有机相，饱和食盐水洗涤，经无水硫酸钠干燥，浓缩，柱层析分离纯化(展开剂：乙酸乙酯与石油醚的体积比为2:10混合溶液)，干燥，得如式XV(A)所示化合物28g，收率98％。 MS(ESI)m/z:282(M++1)。
Figure PCTCN2014093258-appb-000024
步骤2如式XI所示化合物的制备
取LiAlH42.8g分散于30mL THF中，冷却至0℃，向该溶液滴加含14.0g(50mmol)本实施例步骤1所得的如式XV(A)所示化合物的30mLTHF溶液，滴加完毕后，室温继续反应1小时，加入氢氧化钾溶液(15％)2.8mL和水8.0mL，低温搅拌40min，用硅藻土过滤，乙酸乙酯洗涤，滤液浓缩干燥，得如式XI(B)所示化合物10.0g，收率85％。MS(ESI)m/z:254(M++1)。
Figure PCTCN2014093258-appb-000025
步骤3如式IV所示化合物的制备
取本实施例步骤2制得的如式XI(B)所示化合物10.0g(39.5mmol)溶于70mL二氯甲烷中后，加入27.5mL(200mmol)三乙胺。滴加含有甲磺酰氯4.3mL(55mmol)的300mL二氯甲烷溶液。滴加完毕后室温搅拌2小时，向反应液中加入100mL冷水，搅拌分出二氯甲烷层，用10％氢氧化钠溶液50mL洗涤一次，饱和食盐水洗涤一次，无水硫酸钠干燥，减压浓缩至干，得固体10.5g，将该固体溶于70mL DMF中，加入3.2g氰化钠，70℃反应过夜，冷却至室温，将该反应液倒入300mL冷水中，乙酸乙酯每次150mL提取三次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，经柱层析分离纯化(展开剂：乙酸乙酯：石油醚为1:4的混合溶液)，干燥，得如式IV(B)所示化合物6.0g，收率74％。MS(ESI)m/z:263(M++1)。
Figure PCTCN2014093258-appb-000026
步骤4如式XV所示化合物
取6.0g(23.6mmol)本实施例步骤3所得如式IV(B)所示化合物溶于20mL 1,2-二氯乙烷中，加入5.0mL 1-氯甲酸氯乙酯，80℃反应2小时，冷却至室温，浓缩后加入30mL甲醇回流过夜，将反应液浓缩干，加入150mL 20％碳酸钾水溶液，二氯甲烷每次100mL提取三次，合并有机相，饱和食盐水洗涤一次，无水硫酸干燥，减压浓缩。将所得浓缩的剩余物溶于50mL甲醇中，加入6mL甲醛水溶液(30％)，随后在搅拌下分三次共加入2.0g氰基硼氢化钠，室温下搅拌3小时，减压浓缩反应液，加入100mL2N盐酸水溶液溶解，异丙醚每次50mL洗涤该酸水溶液两次，去除有机层。水层用40％氢氧化钠溶液调节pH＝11，乙酸乙酯每次100mL提取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩至干，得如式XV(B)所示化合物3.0g，收率，90％。MS(ESI)m/z:144(M++1)。
Figure PCTCN2014093258-appb-000027
步骤5如式VI所示化合物的制备
取3.0g(24.4mmol)本实施例步骤4制得的如式XV(B)所示化合物，溶于35mL甲醇中，加入氢氧化锂1.2g(29.3mmol)、水35mL，室温下搅拌过夜，浓缩除去大部分甲醇，水层用20mL水稀释，甲基叔丁基醚每次20mL洗涤水层三次，水层用盐酸调节pH＝1，浓缩至干，得如式VI(A)所示化合物1.5g。MS(ESI)m/z:128(M+-1)。
Figure PCTCN2014093258-appb-000028
步骤6如式III所示化合物的制备
取本实施例步骤5制得的如式VI(A)所示化合物1.5g(11.6mmol)溶于50mL二氯甲烷中，加入12mL(174mmol)氯化亚砜，再加入0.1mL DMF后，回流7小时，冷却到室温，减压浓缩至干，加入50mL二氯甲烷溶解，取1.5g(11.7mmol)萘加入其中，室温下分三次共加入无水三氯化铝2.3gg(17.5mmol)，室温搅拌过夜。将该反应液倒入50mL浓盐酸和50mL冰水的混合液中，搅拌30min，分出二氯甲烷，水层用50mL二氯甲烷再提取一次，合并二氯甲烷层后，50mL饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经柱层析分离纯化(展开剂：甲醇与乙酸乙酯的体积比为2:1的混合溶液)，干燥，得式III(F)的无色油状化合物500mg，收率18.5％。MS(ESI)m/z:240(M++1)。
Figure PCTCN2014093258-appb-000029
实施例8如式III所示化合物的制备
步骤1如式XVI所示化合物的制备
取乙酰基4-哌啶甲酸8.4g(49.1mmol)加入100mL二氯甲烷中，加入35mL(490mmol)氯化亚砜和0.1mL DMF室温搅拌1小时后加热回流1小时，冷却到室温，减压浓缩，向浓缩液中加入石油醚200mL，搅拌30min，过滤，滤渣用100mL石油醚洗涤，干燥后得固体9.2g。将该固体加入200mL二氯甲烷中，加入萘6.3g(49.1mmol)，搅拌溶解，冷却到0℃，分四次共加入无水AlCl38.0g(60mmol)，保持0℃下反应2小时，将该反应液倒入100mL浓盐酸和100g碎冰的混合溶液中，室温搅拌30min， 分出二氯甲烷层，水层用150mL二氯甲烷提取一次，合并二氯甲烷液，先后用20％碳酸钾水溶液每次100mL洗涤2次，100mL饱和食盐水洗涤一次，无水硫酸钠干燥后减压浓缩，向浓缩液中加入石油醚300mL搅拌30min，过滤，收集析出的固体，用石油醚洗涤该固体，得式XVI的固体化合物11.5g，收率81％。MS(ESI)m/z:282(M++1)。
Figure PCTCN2014093258-appb-000030
步骤2如式XVII所示化合物的制备
取11.0g本实施例步骤1制得的如式XVI所示化合物，于200mL 6N盐酸水溶液里回流6小时后浓缩，加入丙酮300mL析出固体，抽滤，烘干，得式XVII的固体化合物11.5g，收率91％。MS(ESI)m/z:240(M++1)。
Figure PCTCN2014093258-appb-000031
步骤3如式III所示化合物的制备
50mL圆底烧瓶中，加入830mg(3mmol)本实施例步骤2所得如式XVII所示化合物，360mg(9mmol)多聚甲醛和552mg(6mmol)醋酸钠，于10mL甲醇中搅拌均匀后，再加入377mg氰基硼氢化钠(6mmol)，室温搅拌过夜。反应液直接浓缩，加15mL水稀释，用10mL二氯甲烷萃取3次，合并有机层。有机层用饱和食盐水洗，无水硫酸钠干燥。减压浓缩得粗品，经柱层析分离纯化(展开剂：乙酸乙酯与甲醇的体积比为20:1的混合液)，干燥，式III(G)的得淡黄色油状化合物610mg，收率80％。 MS(ESI)m/z:254(M++1)。
Figure PCTCN2014093258-appb-000032
实施例9如式III所示化合物的制备
50mL圆底烧瓶中，加入830mg(3mmol)实施例8步骤2制得的如式XVII所示化合物，1.65mL乙醛水溶液(40％)和860μL醋酸(15mmol)，搅拌均匀，加入377mg氰基硼氢化钠(6mmol)，室温搅拌过夜。反应液浓缩，加15mL水稀释，二氯甲烷萃取3次，每次10mL二氯甲烷，合并有机层。有机层用饱和食盐水洗，无水硫酸钠干燥，浓缩，经柱层析分离纯化(展开剂：乙酸乙酯与甲醇的体积百分比为20:1的混合液)，干燥，得式III(H)的淡黄色油状化合物635mg，产率79.3％。MS(ESI)m/z:268(M++1)。
Figure PCTCN2014093258-appb-000033
实施例10如式III所示化合物的制备
50mL圆底烧瓶中，加入830mg(3mmol)实施例8步骤2制得的如式XVII所示化合物，1.12mL丙酮(15mmol)和860μL醋酸(15mmol)，搅拌均匀，加入377mg氰基硼氢化钠(6mmol)，室温搅拌过夜。反应液浓缩，加20mL水稀释，二氯甲烷萃取3次，每次15mL二氯甲烷，合并有机层。有机层用饱和食盐水洗，无水硫酸钠干燥，浓缩，经柱层析分离纯化(展开剂：乙酸乙酯与甲醇的体积百分比为20:1混合溶液)，干燥，得如式III(I)的淡黄色油状化合物540mg，产率63.8％。MS(ESI)m/z:282(M++1)
Figure PCTCN2014093258-appb-000034
实施例11如式III所示化合物的制备
50mL圆底烧瓶中，加入830mg(3mmol)实施例8步骤2制得的如式XVII所示化合物，2.18mL丙醛(30mmol)和860μL醋酸(15mmol)，搅拌均匀，加入377mg氰基硼氢化钠(6mmol)，室温搅拌过夜。反应液浓缩，加20mL水稀释，二氯甲烷萃取3次，每次15mL二氯甲烷，合并有机层。有机层用饱和食盐水洗，无水硫酸钠干燥，浓缩，经柱层析分离纯化(展开剂：乙酸乙酯与甲醇的体积百分比为20:1混合溶液)，干燥，得如式III(J)的淡黄色油状化合物445mg，产率52.5％。MS(ESI)m/z:282(M++1)
Figure PCTCN2014093258-appb-000035
实施例12如式III所示化合物的制备
步骤1如式X所示化合物的制备
取N-甲基-4-哌啶甲酸8.0g(55.9mmol)溶于100mL二氯甲烷中，加入9.5g(58.4mmol)羰基二咪唑(CDI)，室温下搅拌2小时，加入N,O-二甲基羟胺盐酸盐5.7g(58.4mmol)，室温搅拌过夜，加入12mL 4N的二氧六环氯化氢溶液，室温搅拌30min，过滤除去固体，滤液用碳酸钾溶液和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，干燥，得如式X所示化合物6.18g，收率60％；MS(ESI)m/z:187(M++1)
Figure PCTCN2014093258-appb-000036
步骤2如式III所示化合物的制备
取3,5-二氟溴苯4.64mL(40.3mmol)与1.0g镁屑于无水四氢呋喃中，室温制备成格式试剂，加入2.5g(13.4mmol)本实施例步骤1制得的如式X所示化合物，室温搅拌过夜，加入饱和氯化铵溶液终止反应，乙酸乙酯提取柱层析分离纯化(展开剂：二氯甲烷与丙酮的体积比为3:1混合溶液)，干燥，得如式III(K)的淡黄色油状化合物1.15g，收率40％。MS(ESI)m/z:240(M++1)；
Figure PCTCN2014093258-appb-000037
实施例13如式III所示化合物的制备
取溴苯10.5g(67mmol)与1.6g镁屑于无水四氢呋喃中，室温下制备成格式试剂，加入2.5g(13.4mmol)实施例12步骤1制得的如式X所示化合物，室温搅拌过夜，加入饱和氯化铵溶液终止反应，乙酸乙酯提取柱层析分离纯化(展开剂：二氯甲烷与丙酮的体积比为3:1混合溶液)，干燥，得如式III(L)的淡黄色油状化合物1.83g，收率67.1％。MS(ESI)m/z:204(M++1)
Figure PCTCN2014093258-appb-000038
实施例14如式I所示化合物的制备
氮气保护下，15mL反应试管中，加入0.21mL二异丙基胺(1.5mmol)以及1mL无水四氢呋喃，-78℃搅拌0.5h，将0.68mL 2.5mol/L的正丁基锂(1.7mmol)滴加入反应液，-78℃继续搅拌0.5h。将328mg实施例1制得的如式II所示化合物溶于1mL无水四氢呋喃后，慢慢滴加入到上述反应液中，滴完后-78℃下继续搅拌1h。将327mg实施例2制得的如式III(A)所示化合物溶于1mL无水四氢呋喃，慢慢滴加入反应液中，滴完后在-78℃下搅拌4h。加入1mL饱和氯化铵水溶液终止反应，升温至室温，加入10mL水，乙酸乙酯每次5mL萃取3次，合并有机层。有机层先后用水和饱和食盐水洗后，无水硫酸钠干燥，浓缩，经柱层析分离纯化(展开剂：石油醚与二氯甲烷的体积比为2:1的混合溶液)，得到一个组分，标记为化合物I(A)，干燥后得55mg熔点95℃，收率8.3％。
化合物I(A)核磁共振氢谱数据为：1H NMR(400MHz,CDCl3)δ8.64(s,1H),7.82(s,1H),7.63–6.92(m,20H),4.90(s,1H),4.53(s,H),3.85(s,3H),3.51–2.19(m,5H)。为含4个异构体的混旋体。
Figure PCTCN2014093258-appb-000039
实施例15如式I所示化合物的制备
氮气保护下，15mL应试管中，加入0.21mL二异丙基胺(1.5mmol)以及1.5mL水四氢呋喃，在-78℃搅拌0.5h，将0.68mL 2.5mol/L正丁基锂(1.7mmol)滴加入反应液，-78℃继续搅拌0.5h。在-78℃下，将328mg实施例1制得的如式II所示化合物溶于1mL无水四氢呋喃后，慢慢滴加入反应液，滴完后，-78℃下继续搅拌1小时。将100mg实施例4制得的如 式III(C)所示化合物溶于1mL无水四氢呋喃，慢慢滴加入反应液，滴完后在-78℃下搅拌4h。加入1mL饱和氯化铵水溶液终止反应，升温至室温，加入10mL水，乙酸乙酯每次5mL萃取3次，合并有机层。有机层先后用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经柱层析分离纯化(展开剂：乙酸乙酯与甲醇的体积比为10:1的混合溶液)，先后得到两个组分，分别收集，干燥，得到两个产物，各40mg，先出的组分标记为化合物I(B)，熔点199℃；后出的组分标记为化合物I(C)熔点,220℃，收率：7.9％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(B)：1H NMR(400MHz,CDCl3)δ8.23(s,1H),7.85(s,1H),7.67(d,J＝8.8Hz,1H),7.62(d,J＝8.8Hz,1H),7.48–6.83(m,10H),5.10(s,1H),4.45(s,1H),4.15(s,3H),3.18(s,1H),3.00–2.58(m,4H),2.09(s,3H)。化合物I(C)：1H NMR(400MHz,CDCl3)δ7.81(s,1H),7.65–6.64(m,13H),4.78(s,1H),3.91(s,3H),3.67–3.09(m,5H),2.55(s,3H)。化合物I(B)和化合物I(C)互为非对映异构体。
Figure PCTCN2014093258-appb-000040
实施例16如式I所示化合物的制备
氮气保护下，30mL反应试管中，0.42mL二异丙基胺(3.0mmol)溶于5.0mL无水四氢呋喃，-78℃搅拌0.5小时，缓缓滴加入1.25mL(2.5mol/L)正丁基锂(3.1mmol)，-78℃继续搅拌0.5h。将650mg(2.0mmol)实施例1制得的如式II所示化合物溶于3mL无水四氢呋喃后，慢慢滴入 该反应液中，滴完后，-78℃下继续搅拌1小时。将720mg(2.0mmol)实施例3制得的如式III(B)所示化合物溶于4mL无水四氢呋喃，慢慢滴加入反应液，滴完后，在-78℃下搅拌反应4h。加入10mL饱和氯化铵水溶液终止反应，升温至室温，加入10mL水，乙酸乙酯每次15mL萃取3次，合并有机层。有机层先后用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经柱层析(展开剂：乙酸乙酯与石油醚的体积比为0.5:1的混合溶液)分离，先后得到两个组分，分别收集，先出的组分标记为化合物I(D)，干燥后得65mg，熔点：115℃，收率10％；后出的组分标记为化合物I(E)，干燥后得45mg，熔点：115℃，收率7％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(D)：1H NMR(400MHz,CDCl3)δ8.71(s,1H),7.88(s,1H),7.60–6.94(m,19H),6.54–6.42(m,1H),5.11(s,1H),4.83(s,1H),3.90(s,3H),3.76–0.71(m,5H)。
化合物I(E)1H NMR(400MHz,CDCl3)δ8.29(s,1H),7.85(s,1H),7.60–6.94(m,19H),6.54–6.42(m,1H),5.30(s,1H),5.03(s,1H),4.10(s,3H),3.76–0.71(m,5H)。化合物I(D)和化合物I(E)互为非对映异构体。
Figure PCTCN2014093258-appb-000041
实施例17如式I所示化合物的制备
取二异丙胺316μL(2.25mmol)溶于5mL无水四氢呋喃中，氮气保护下，冷却到-78℃，滴加入1.0mL(2.5mol/L)正丁基锂，搅拌40min；取494mg(1.5mmol)实施例1制得的如式II所示化合物溶于3mL THF(四氢呋喃)，-78℃下缓缓加入该溶液中，滴加完毕后保温反应1小时，滴加入含360mg(1.5mmol)实施例5制得的如式III(D)所示化合物的3mL四氢呋喃溶液，滴加完毕，保持-78℃下反应4小时。20mL饱和氯化铵溶液加入该反应液中，升温到室温，加入10mL乙酸乙酯搅拌5min，分出有机层，水层用乙酸乙酯每次5mL提取两次，合并有机相，饱和食盐水洗涤一次，无水硫酸钠干燥。经柱层析(展开剂:甲醇与乙酸乙酯体积比为1:20的混合溶液)分离纯化得到先后两个组分，分别收集，干燥，得到两个组分，先出来的组分标记为化合物I(F)，共86mg，熔点：197℃，收率：10％；后出来的组分标记为化合物I(G)，共80mg，熔点：175℃，收率：9％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(F)：1H NMR(400MHz,CDCl3)δ8.17–6.87(m,16H),5.35(s,1H),4.13(s,3H),3.05(broad s,1H),2.81–2.54(m,2H),2.29–2.19(m,1H),2.09(s,3H),2.00–0.75(m,4H)。化合物I(G)：1H NMR(400MHz,CDCl3)δ8.66(s,1H),8.08–7.05(m,15H),5.10(s,1H),3.88(s,3H),2.93–0.67(m,12H)。化合物I(F)与化合物I(G)互为非对映异构体。
Figure PCTCN2014093258-appb-000042
实施例18如式I所示化合物的制备
取二异丙胺326μL(2.32mmol)溶于5mL无水四氢呋喃中，氮气保护下，冷却到-78℃，滴加入1.05mL(2.5mol/L)正丁基锂，搅拌40min；取500mg(1.55mmol)实施例1制得的如式II所示化合物溶于5mL THF，-78℃下缓缓加入该反应液中，滴加完毕后保温反应1小时，滴加入含370mg(1.55mmol)实施例7制得的如式III(F)所示化合物的3mL四氢呋喃溶液，滴加完毕，保持-78℃下反应4小时。20mL饱和氯化铵水溶液加入该反应液中淬灭反应，升温到室温，加入10mL乙酸乙酯搅拌5min，分出有机层，水层用乙酸乙酯每次5mL提取两次，合并有机相，饱和食盐水洗涤一次，无水硫酸钠干燥。经柱层析(展开剂：甲醇与乙酸乙酯的体积比为1:20的混合溶液)分离纯化，先后得到两个组分，分别收集，干燥，先出来的组分标记为化合物I(H)，共68mg，熔点：187℃，收率：4％；后出来的组分标记为化合物I(I)，共11mg，熔点：170℃，收率：3.5％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(H)：1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.87–6.88(m,15H),5.32(s,1H),4.16(s,3H),3.07(broad s,1H),2.81–0.71(m,10H)。化合物I(I)：1H NMR(400MHz,CDCl3)δ7.84–6.80(m,16H),5.06(s,1H),3.87(s,3H),3.43–0.67(m,11H)。化合物I(H)和化合物I(I)互为非对映异构体。
Figure PCTCN2014093258-appb-000043
实施例19如式I所示化合物的制备
氮气保护下，1.14mL二异丙基胺(10.3mmol)溶于10mL无水四氢呋喃，冷却至-78℃，滴加4.6mL(2.5mol/L)正丁基锂，搅拌0.5h。在-78℃下，将2.25g(6.87mmol)实施例1制得的如式I所示化合物溶于10mL无水四氢呋喃，慢慢滴加入反应液，保持-78℃下继续搅拌1h。将1.6g(6.87mmol)实施例6制得的如式III(E)所示化合物溶于8mL无水四氢呋喃中，慢慢滴加入反应液，保持-78℃下搅拌4h。加入50mL饱和氯化铵水溶液终止反应，升温至室温，乙酸乙酯每次5mL萃取3次，合并有机层。有机层用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经柱层析(展开剂：乙酸乙酯与石油醚的体积比为1:3的混合物)分离，先后得到两个组分，分别收集，干燥，先出来的组分标记为化合物I(J)，共220mg，熔点：125℃，收率：5.8％；后出来的组分标记为化合物I(K)，共210mg，熔点：115℃，收率：5.5％。
取200mg(0.356mmol)本实施例所制得的化合物I(J)，溶于2mL丙酮，加入碘甲烷1mL，加热回流1小时，冷却到室温，过滤析出固体，该固体用丙酮洗涤，收集得到黄色固体，干燥后得到化合物I(L)198mg，熔点：170℃，收率：79％。
用200mg(0.356mmol)本实施例制得的化合物I(K)，溶于2mL丙酮，加入碘甲烷1mL，加热回流1小时，冷却到室温，过滤析出固体，用丙酮洗涤，收集得到黄色固体，干燥后得化合物I(M)200mg，熔点：173℃，收率：80％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(L)：1H NMR(400MHz,DMSO)δ9.13(s,1H),8.68(d,J＝6.0Hz,1H),8.64(d,J＝8.3Hz,1H),8.61(s,1H),8.14(s,1H),8.04(s,1H),7.95–6.99(m,14H),5.81(s,1H),4.24(s,3H),3.87(s,3H)。
化合物I(M)：1H NMR(400MHz,DMSO)δ9.17(s,1H),8.89–7.02(m,18H),6.95(s,1H),5.77(s,1H),4.22(s,3H),3.88(s,3H)。化合物I(L)和化合物I(M)互为非对映异构体。
Figure PCTCN2014093258-appb-000044
实施例20如式I所示化合物的制备
取150mg(0.213mmol)实施例19制得的化合物I(L)，即化合物10，溶于1mL甲醇中，50mg(1.315mmol)硼氢化钠加入其中，室温下搅拌反应40min，该反应液用10mL饱和氯化铵水溶液稀释，二氯甲烷每次5mL提取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。浓缩后经柱层析(乙酸乙酯：100％)分离纯化，得到一个组分，标记为化合物I(N)干燥后得100mg，熔点：210℃，收率：81％。
取150mg(0.213mmol)实施例19制得的化合物I(M)，即化合物11，溶于1mL甲醇中，50mg(1.315mmol)硼氢化钠加入其中，室温下搅拌反应40min，该反应液用10mL饱和氯化铵水溶液稀释，二氯甲烷每次5mL提取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。浓缩后经柱层析(乙酸乙酯：100％)分离纯化，得到一个组分，标记为化合物I(O)，干燥后得106mg，熔点：206℃，收率：82％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(N)：1H NMR(600MHz,CDCl3)δ8.58(s,1H),7.82–6.80(m, 15H),5.60(s,1H),5.48(s,1H),5.33(s,1H),4.12(s,3H),3.19(d,J＝16.8Hz,1H),2.85(s,1H),2.48(d,J＝16.5Hz,1H),2.38–1.87(m,5H)。化合物I(O)：1H NMR(400MHz,CDCl3)δ8.52(s,1H),7.99(s,1H),7.85–7.12(m,14H),5.45(d,J＝9.3Hz,1H),5.26(s,1H),5.21(s,1H),3.89(s,3H),3.20(d,J＝15.6Hz,1H),2.79(s,1H),2.48(d,J＝16.4Hz,1H),2.27(d,J＝11.2Hz,1H),2.05(s,3H),1.96(d,J＝11.2Hz,1H),1.51(s,1H)。化合物I(N)和化合物I(O)互为非对映异构体。
Figure PCTCN2014093258-appb-000045
实施例21如式I所示化合物的制备
氮气保护下，0.42mL(3.0mmol)二异丙基胺以及1.5mL无水四氢呋喃，搅拌下冷却至-78℃，滴加入1.36mL 2.5mol/L正丁基锂，-78℃继续搅拌0.5h。在-78℃下，将656mg(2.0mmol)实施例1制得的如式II所示化合物溶于5mL无水四氢呋喃，慢慢滴加入到反应液中，-78℃下继续搅拌1小时。将506mg(2.0mmol)实施例8制得的如式III(G)所示化合物溶于4mL无水四氢呋喃，慢慢滴加到反应液中，滴完后在-78℃下搅拌4h。加入20mL饱和氯化铵水溶液终止反应，升温至室温，乙酸乙酯每次10mL萃取3次，合并有机层。有机层用饱和食盐水洗后，无水硫酸钠干燥，浓缩，经柱层析(展开剂：甲醇与乙酸乙酯体积比为1:10混合溶液)分离，先后得到两个组分，分别收集，干燥后得到两个组分，先出来的组分标记为化合物I(P)，共95mg，熔点：195℃，收率：8.1％；后出来的组分标记为化合物I(Q)，共88mg，熔点：197℃，收率：7.5％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(P)：1H NMR(400MHz,CDCl3)δ8.44(s,1H),8.00–7.21(m,15H),5.60(s,1H),3.99(s,3H),2.88(d,J＝8.4Hz,1H),2.73(d,J＝8.4Hz,1H),2.60–2.38(broad s,1H),2.26(d,J＝8.8Hz,1H),2.11(s,3H),1.91–1.22(m,5H),1.02–0.82(m,1H)。化合物I(Q)：1H NMR(400MHz,CDCl3)δ8.72(s,1H),7.98(s,1H),7.82(s,1H),7.78–7.64(m,5H),7.59(d,J＝6.8Hz,1H),7.48–7.37(m,2H),7.24–7.18(m,2H),7.03–6.87(m,3H),5.62(s,1H),4.12(s,3H),2.81–2.69(m,2H),2.08(s,3H),1.90–1.43(m,6H),0.88–0.74(m,1H)。化合物I(P)与化合物I(Q)互为非对映异构体。
Figure PCTCN2014093258-appb-000046
实施例22如式I所示化合物的制备
氮气保护下，0.42mL(3.0mmol)二异丙基胺以及1.5mL无水四氢呋喃，搅拌下冷却至-78℃，滴加入1.36mL 2.5mol/L正丁基锂，-78℃继续搅拌0.5h。在-78℃下，将656mg(2.0mmol)实施例1制得的如式II所示化合物溶于5mL无水四氢呋喃，慢慢滴加入到反应液中，-78℃下继续搅拌1小时。将535mg(2.0mmol)实施例9制得的如式III(H)所示化合物溶于4mL无水四氢呋喃，慢慢滴加到反应液中，滴完后在-78℃下搅拌4h。加入20mL饱和氯化铵水溶液终止反应，升温至室温，乙酸乙酯每次10mL萃取3次，合并有机层。有机层用饱和食盐水洗后，无水硫酸钠干燥，浓缩，经柱层析(展开剂：甲醇与乙酸乙酯体积比为1:10混合溶液)分离，先后得到两个组分，分别收集，先出来的组分标记为化合物I(R)，共90mg，熔点：201℃，收率：7.5％；后出来的组分标记为化合物I(S)，共70mg， 熔点：210℃，收率：5.8％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(R)：1H NMR(600MHz,CDCl3)δ8.70(s,1H),7.98(s,1H),7.84(s,1H),7.81–7.63(m,5H),7.59(d,J＝8.5Hz,1H),7.46–7.39(m,2H),7.24(d,J＝7.7Hz,2H),7.01–6.88(m,3H),5.64(s,1H),4.14(s,3H),2.89–2.77(m,2H),2.40(s,1H),2.19(dd,J＝13.9,6.8Hz,2H),1.91–1.79(m,3H),1.69(t,J＝11.3Hz,1H),1.54–1.38(m,2H),0.90(t,J＝7.0Hz,3H),0.86–0.75(m,1H)。化合物I(S)：1H NMR(400MHz,CDCl3)δ8.44(s,1H),8.04–7.11(m,15H),5.61(s,1H),3.99(s,3H),2.99(d,J＝10.9Hz,1H),2.85(d,J＝10.9Hz,1H),2.38–1.18(m,9H),0.94(t,J＝7.0Hz,3H)。化合物I(R)和化合物I(S)互为非对映异构体。
Figure PCTCN2014093258-appb-000047
实施例23如式I所示化合物的制备
氮气保护下，0.42mL(3.0mmol)二异丙基胺以及1.5mL无水四氢呋喃，搅拌下冷却至-78℃，滴加入1.36mL 2.5mol/L正丁基锂，-78℃继续搅拌0.5h。在-78℃下，将656mg(2.0mmol)实施例1步骤3制得的如式II所示化合物溶于5mL无水四氢呋喃，慢慢滴加入到反应液中，-78℃下继续搅拌1小时。将562mg(2.0mmol)实施例10制得的如式III(I)所示化合物溶于4mL无水四氢呋喃，慢慢滴加到反应液中，滴完后在-78℃下搅拌4h。加入20mL饱和氯化铵水溶液终止反应，升温至室温，乙酸乙酯每次10mL萃取3次，合并有机层。有机层用饱和食盐水洗后，无水硫酸 钠干燥，浓缩，经柱层析(展开剂：甲醇与乙酸乙酯体积比为1:10的混合溶液)分离，先后得到两个组分，分别收集，先出来的组分标记为化合物I(T)，干燥后得101mg，熔点：212℃，收率：8.2％；后出来的组分标记为化合物I(U)，干燥后得82mg，熔点：222℃，收率：6.7％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(T)，：1H NMR(600MHz,CDCl3)δ8.70(s,1H),7.98(s,1H),7.82(s,1H),7.80–7.63(m,5H),7.59(d,J＝8.4Hz,1H),7.47–7.38(m,2H),7.23(d,J＝7.5Hz,2H),7.01–6.88(m,3H),5.63(s,1H),4.13(s,3H),2.87–0.59(m,16H)。化合物I(U)：1H NMR(400MHz,CDCl3)δ8.43(s,1H),7.84–7.18(m,15H),5.61(s,1H),3.99(s,3H),2.92(d,J＝10.4Hz,1H),2.78(d,J＝10.2Hz,1H),2.69–1.18(m,8H),0.90(d,J＝6.3Hz,6H)。化合物I(T)和化合物I(U)互为非对映异构体。
Figure PCTCN2014093258-appb-000048
实施例24如式I所示化合物的制备
氮气保护下，0.42mL(3.0mmol)二异丙基胺以及1.5mL无水四氢呋喃，搅拌下冷却至-78℃，滴加入1.36mL 2.5mol/L正丁基锂，-78℃继续搅拌0.5h。在-78℃下，将656mg(2.0mmol)实施例1制得的如式II所示化合物溶于5mL无水四氢呋喃，慢慢滴加入到反应液中，-78℃下继续搅拌1小时。将562mg(2.0mmol)实施例11制得的如式III(J)所示化合物溶于4mL无水四氢呋喃，慢慢滴加到反应液中，滴完后在-78℃下搅拌4h。加入20mL饱和氯化铵水溶液终止反应，升温至室温，乙酸乙酯每次10mL 萃取3次，合并有机层。有机层用饱和食盐水洗后，无水硫酸钠干燥，浓缩，经柱层析(展开剂：甲醇与乙酸乙酯体积比为1:10的混合溶液)分离，先后得到两个组分，分别收集，先出来的组分标记为化合物I(V)，干燥后得110mg，熔点：73℃，收率：9.0％；后出来的组分标记为化合物I(W)，干燥后得95mg熔点：75℃，收率：7.8％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(V)：1H NMR(600MHz,CDCl3)δ8.69(s,1H),7.98(s,1H),7.83(s,1H),7.80–7.64(m,5H),7.58(d,J＝8.5Hz,1H),7.47–7.36(m,2H),7.22(d,J＝7.8Hz,2H),6.98(t,J＝7.4Hz,2H),6.92(t,J＝7.0Hz,1H),5.63(s,1H),4.13(s,3H),2.94–2.76(m,2H),2.21–0.70(m,14H)。化合物I(W)：1HNMR(400MHz,CDCl3)δ8.42(s,1H),7.88–7.20(m,15H),5.59(s,1H),3.99(s,3H),3.03(d,J＝10.5Hz,1H),2.88(d,J＝10.9Hz,1H),2.35–0.68(m,14H)。化合物I(V)与化合物I(W)互为非对映异构体。
Figure PCTCN2014093258-appb-000049
实施例25如式I所示化合物的制备
氮气保护下，0.42mL(3.0mmol)二异丙基胺以及1.5mL无水四氢呋喃，搅拌下冷却至-78℃，滴加入1.36mL 2.5mol/L正丁基锂，-78℃继续搅拌0.5h。在-78℃下，将1.1g(3.35mmol)实施例1制得的如式II所示化合物溶于9mL无水四氢呋喃，慢慢滴加入到反应液中，-78℃下继续搅拌1小时。将800mg(3.35mmol)实施例12制得的如式III(K)所示化合物溶 于4mL无水四氢呋喃，慢慢滴加到反应液中，滴完后在-78℃下搅拌4h。加入20mL饱和氯化铵水溶液终止反应，升温至室温，乙酸乙酯每次10mL萃取3次，合并有机层。有机层用饱和食盐水洗后，无水硫酸钠干燥，浓缩，经柱层析(展开剂：甲醇与乙酸乙酯体积比为1:10的混合溶液)分离，得到一个组分，收集，，标记为化合物I(X)，干燥后得300mg，熔点：162℃，收率：17％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(X)：1H NMR(400MHz,CDCl3)δ8.38(s,1H),7.79–6.90(m,10H),6.47(t,J＝8.6Hz,1H),5.34(s,1H),3.97(s,3H),2.97–2.65(m,2H),2.24–0.59(m,10H)。为含有4个异构体的混旋体。
Figure PCTCN2014093258-appb-000050
实施例26如式I所示化合物的制备
氮气保护下，0.42mL(3.0mmol)二异丙基胺以及1.5mL无水四氢呋喃，搅拌下冷却至-78℃，滴加入1.36mL 2.5mol/L正丁基锂，-78℃继续搅拌0.5h。在-78℃下，将620mg(1.89mmol)实施例1制得的如式II所示化合物溶于9mL无水四氢呋喃，慢慢滴加入到反应液中，-78℃下继续搅拌1小时。将384mg(1.89mmol)实施例13制得的如式III(L)所示化合物溶于4mL无水四氢呋喃，慢慢滴加到反应液中，滴完后在-78℃下搅拌4h。加入20mL饱和氯化铵水溶液终止反应，升温至室温，乙酸乙酯每次10mL萃取3次，合并有机层。有机层用饱和食盐水洗后，无水硫酸钠干燥，浓缩，经柱层析(展开剂：甲醇与乙酸乙酯体积比为1:10的混合溶液)分离，得到一个组分，收集，标记为化合物I(Y)，干燥后得到290mg，熔点：182℃， 收率：28％。
用核磁共振氢谱检测所得产物，所得核磁共振氢谱谱图数据如下：
化合物I(Y)：1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.66(s,1H),7.56–6.89(m,12H),5.45(s,1H),3.95(s,3H),2.95–2.69(m,2H),2.33–0.81(m,10H)。为含有4个异构体的混旋体。
Figure PCTCN2014093258-appb-000051
实施例27药理实验
采用Alamar Blue微量快速显色药敏检测法对本发明制得的如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物的化合物进行体外筛选，
Figure PCTCN2014093258-appb-000052
所用材料包括：
通用增菌培养基：批号120301，上海积彩医疗器械有限公司，9mL/瓶；TWEEN 80：CAS9005-65-6，Sigma P1754，≥70％；二甲亚砜(DMSO)：分析纯、Alamar blue检测试剂和改良罗氏固体培养基均为市售。培养管、96孔板、磨菌器为市售；化合物1～化合物23为本发明制备获得；如式XVIII所示化合物按照专利WO2004011436A1中化合物14(该化合物为混旋体)的制备方法制得，将该化合物命名为TMC207A，
Figure PCTCN2014093258-appb-000053
所用菌株为：
结核杆菌标准敏感株：H37RV菌株，来自美国疾病控制与预防中心；
结核杆菌临床敏感株：741菌株、753菌株、758菌株、760菌株、821菌株；全部来自重庆市公共卫生医疗救治中心；
结核杆菌临床耐药株：930菌株、1237菌株、1256菌株、1259菌株、1288菌株；全部来自重庆市公共卫生医疗救治中心；
菌株培养按《结核菌培养标准化操作及质量保证手册》操作。
实验方法：
1、菌株菌液工作浓度的获得：
取上述结核杆菌标准敏感株、结核杆菌临床敏感株和结核杆菌临床耐药株进行培养，一一标记，在改良罗氏培养基中传代2周后，选生长良好的菌株挑取适量，用磨菌器研磨成菌悬液，应用比浊法调节浓度为1mg/mL，再用通用增菌培养基逐级稀释为1×10-1mg/mL、1×10-2mg/mL，再将1×10-2mg/mL的菌浓度用改良罗氏培养基稀释为1×10-3mg/mL的菌液工作浓度。
2、样品储备液的配制：
取本发明制得的编号为化合物1～化合物23的化合物，分别用DMSO溶解并配制为5mg/mL的本发明制得的化合物的样品储备液，根据各样品的终浓度，分别将储备液用DMSO配制为100μL的稀释液，再进一步用DMSO作倍比稀释，配制为各样品DMSO溶液的系列浓度梯度。用改良罗氏培养基分别对各样品的DMSO液稀释140倍，即得到样品工作液，各样品的浓度梯度由低到高依次0.125μg/mL、0.25μg/mL、0.5μg/mL、 1.0μg/mL、2.0μg/mL、4.0μg/mL、8.0μg/mL。化合物TMC207A作为对比例，按照相同的配制方法获得该样品的储备液。
3、实验设实验组：本发明制得的编号为化合物1～化合物23的化合物；阳性对照组：TMC207A；阴性对照组：通用增菌培养基实验在96孔培养板中进行，先按10μL/孔加入上述配制好的各浓度的药物(即“样品储备液的配制”中获得的所有样品)，不含抗菌药的生长对照孔加入通用增菌培养基，再将上述配制好的菌液浓度为1×10-3mg/mL的各个菌株菌液分别以200μL/孔接种到各孔中，同一块板的各孔中的菌种类及菌浓度相同，并设1块复板。加完后用胶带将96孔板盖密封，于37℃孵育。
4、结果判定：
孵育约14天后，生长对照孔有大量菌生长，且阳性对照药抑菌梯度明显，则每孔加入20μL Alamar blue溶液和50μL无菌5％Tween 80的混合液，37℃孵育24h。记录各孔的颜色，蓝色孔为无生长；粉红色孔为有生长；紫红色孔再继续37℃培养24小时，不变为粉红色，其相连的蓝色孔仍为蓝色，则记录为有生长。最低抑菌浓度(MIC)定义为阻止颜色变化(从蓝色变为粉红色)的最低药物浓度。
本发明提供的化合物以及阳性对照组化合物对各个菌株的最低抑菌浓度见表1。
表1各个化合物对不同结核杆菌的最低抑菌浓度(MIC)
Figure PCTCN2014093258-appb-000054
Figure PCTCN2014093258-appb-000055
从表1中数据可以发明，相比阳性对照TMC207A而言，本发明提供的化合物大部分能够很好地抑制结核杆菌标准株敏感株，这些化合物的抑菌作用与阳性对照化合物相当或更优；本发明提供的化合物对结核杆菌临床敏感株和结核杆菌临床耐药株也表现了一定程度的抑菌作用，其中有70％的化合物对结核杆菌临床敏感株和结核杆菌临床耐药菌株的抑菌作用与阳性对照化合物相当或更优。说明本发明提供的喹啉衍生物对结核杆菌标准敏感株具有很好地抑菌活性；某些化合物对结核杆菌临床敏感株和结核杆菌临床耐药株也具有较好地抑菌活性，可以用于制备用于治疗或预防结核杆菌感染所引起的疾病或病症的药物。
以上对本发明所提供的一种喹啉衍生物、其制备方法和应用进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (11)

  1. 一种如式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物，
    Figure PCTCN2014093258-appb-100001
    其中，R1为氢、卤素、羟基、烷氧基、烷基、氰基、氨基或硝基；
    R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，所述取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，所述取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
    R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
    n为0、1、2、3或4。
  2. 根据权利要求1所述的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物，其特征在于，所述饱和或不饱和杂环含一个氮原子。
  3. 根据权利要求1所述的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物，其中
    R1为氢、卤素或烷基；
    R2为苯基、萘基、取代的苯基或取代的萘基，所述取代的苯基、取代的萘基的取代基为一个或多个，所述取代的苯基、取代的萘基的取代基选自卤素、烷基、卤代烷基和烷氧基；
    R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、烷基、酰基、Ar和Ar-烷基；
    n为0、1或2。
  4. 根据权利要求1所述的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物，其特征在于，具体为：
    1-(1-二苯甲基氮杂环丁烷-3-基)-2-(6-溴-2-甲氧基喹啉-3-基)-1,2-二苯基乙醇；
    2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-甲基氮杂环丁烷-3-基)-1,2-二苯基乙醇；
    1-(1-二苯甲基氮杂环丁烷-3-基)-2-(6-溴-2-甲氧基喹啉-3-基)-1-(3,5-二氟苯基)-2-苯乙醇；
    2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-甲基吡咯烷-3-基)-1-(萘-1-基)-2-苯乙醇；
    1-(6-溴代-2-甲氧基喹啉-3-基)-3-(1-甲基氮杂环丁烷-2-基)-2-(萘-1-基)-1-苯基-2-丙醇；
    2-(6-溴代-2-甲氧基喹啉-3-基)-1-(萘-1-基)-2-苯基-1-(吡啶-3- 基)乙醇碘甲烷鎓盐；
    2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-甲基-1,2,5,6-四氢吡啶-3-基)-1-(萘-1-基)-2-苯乙醇；
    2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-甲基哌啶-4-基)-1-(萘-1-基)-2-苯乙醇；
    2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-乙基哌啶-4-基)-1-(萘-1-基)-2-苯乙醇；
    2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-异丙基哌啶-4-基)-1-(萘-1-基)-2-苯乙醇；
    2-(6-溴代-2-甲氧基喹啉-3-基)-1-(萘-1-基)-2-苯基-1-(1-丙基哌啶-4-基)-乙醇；
    2-(6-溴代-2-甲氧基喹啉-3-基)-1-(3,5二氟苯基)-1-(1-甲基哌啶-4-基)-2-苯基乙醇；
    2-(6-溴代-2-甲氧基喹啉-3-基)-1-(1-甲基哌啶-4-基)-1,2-二苯基乙醇。
  5. 一种式I所示化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物的制备方法，包括：
    在氮气保护下，将式II所示化合物在无水四氢呋喃中与强碱发生去质子化反应，再与式III所示化合物反应即得；
    Figure PCTCN2014093258-appb-100002
    其中，R1为氢、卤素、羟基、烷氧基、烷基、氰基、氨基或硝基；
    R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，所述取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，所述取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
    R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
    n为0、1、2、3或4。
  6. 根据权利要求5所述的制备方法，进一步包括式III所示化合物的制备，其方法包括：
    在氮气保护下，将如式IV所示化合物在无水四氢呋喃中与如式V所
    Figure PCTCN2014093258-appb-100003
    其中，R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，所述取代的苯基、取代的萘基或取代的杂环基的取代基为一个 或多个，所述取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
    R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
    X为卤素；
    n为0、1、2、3或4。
  7. 根据权利要求5所述的制备方法，进一步包括式III所示化合物的制备，其方法包括：
    将如式VI所示化合物与氯化亚砜发生取代反应生成如式VII所示化合物；
    将如式VII所示化合物与如式VIII所示化合物在路易斯酸作用下，发生酰化反应，即得；
    Figure PCTCN2014093258-appb-100004
    其中，R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，所述取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，所述取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
    R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个 氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
    n为0、1、2、3或4。
  8. 根据权利要求5所述的制备方法，进一步包括式III所示化合物的制备，其方法包括：
    将如式VI所示化合物与N,O-二甲基羟胺在缩合剂作用下发生缩合反应生成如式X所示化合物；
    将如式X所示化合物与如式V所示化合物亲核加成反应后水解即得；
    Figure PCTCN2014093258-appb-100005
    其中，R2为苯基、萘基、杂环基、取代的苯基、取代的萘基或取代的杂环基，所述取代的苯基、取代的萘基或取代的杂环基的取代基为一个或多个，所述取代的苯基、取代的萘基或取代的杂环基的取代基选自卤素、羟基、酰基、烷基、卤代烷基、烷氧基、氰基、硝基和氨基；
    R3、R4为能连在一起形成饱和或不饱和杂环的基团，所述饱和或不饱和杂环为4元、5元或6元环，所述饱和或不饱和杂环含有一个或多个氮原子且所述饱和或不饱和杂环中的氮原子被选自下列的基团取代：氢、羟基、烷基、酰基、Ar、Ar-烷基、Het和Het-烷基；
    X为卤素；
    n为0、1、2、3或4。
  9. 如权利要求1至4任意一所述的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物在制备用于治疗或预防结核杆菌感染所引起的疾病或病症的药物中的应用。
  10. 根据权利要求9所述的应用，其特征在于，所述结核杆菌感染所引起的疾病为肺结核。
  11. 一种药物组合物，包括权利要求1至4任意一所述的化合物或其光学异构体、消旋体、非对映异构体、药学上可接受的盐或溶剂合物和药学上可接受的辅料。
PCT/CN2014/093258 2013-12-25 2014-12-08 一种喹啉衍生物、其制备方法和应用 WO2015096611A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310726353.5 2013-12-25
CN201310726353.5A CN103664877A (zh) 2013-12-25 2013-12-25 一种喹啉衍生物、其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2015096611A1 true WO2015096611A1 (zh) 2015-07-02

Family

ID=50303748

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/093258 WO2015096611A1 (zh) 2013-12-25 2014-12-08 一种喹啉衍生物、其制备方法和应用

Country Status (2)

Country Link
CN (1) CN103664877A (zh)
WO (1) WO2015096611A1 (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10584131B2 (en) 2018-08-03 2020-03-10 Cadent Therapeutics, Inc. Heteroaromatic NMDA receptor modulators and uses thereof
US10626122B2 (en) 2015-12-09 2020-04-21 Cadent Therapeutics, Inc. Heteroaromatic NMDA receptor modulators and uses thereof
US10973825B2 (en) 2015-12-09 2021-04-13 Cadent Therapeutics, Inc. Thienopyrimidinone NMDA receptor modulators and uses thereof
US11274107B2 (en) 2016-12-22 2022-03-15 Cadent Therapeutics, Inc. NMDA receptor modulators and uses thereof
CN115094573A (zh) * 2022-07-18 2022-09-23 南通大学 一种抗菌纳米敷料及其制备方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664877A (zh) * 2013-12-25 2014-03-26 重庆医药工业研究院有限责任公司 一种喹啉衍生物、其制备方法和应用
CN105440051B (zh) * 2014-09-19 2019-07-05 重庆医药工业研究院有限责任公司 一种抗结核的噻吩吡啶衍生物
WO2021057190A1 (zh) * 2019-09-29 2021-04-01 上海阳帆医药科技有限公司 喹啉类化合物、其制备方法和用途
CN110804016B (zh) * 2019-12-05 2022-11-04 福建省微生物研究所 抗结核分枝杆菌的二芳基喹啉衍生物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101087608A (zh) * 2004-12-24 2007-12-12 詹森药业有限公司 用于治疗潜伏性结核的喹啉衍生物
CN103664877A (zh) * 2013-12-25 2014-03-26 重庆医药工业研究院有限责任公司 一种喹啉衍生物、其制备方法和应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101087608A (zh) * 2004-12-24 2007-12-12 詹森药业有限公司 用于治疗潜伏性结核的喹啉衍生物
CN103664877A (zh) * 2013-12-25 2014-03-26 重庆医药工业研究院有限责任公司 一种喹啉衍生物、其制备方法和应用

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10626122B2 (en) 2015-12-09 2020-04-21 Cadent Therapeutics, Inc. Heteroaromatic NMDA receptor modulators and uses thereof
US10973825B2 (en) 2015-12-09 2021-04-13 Cadent Therapeutics, Inc. Thienopyrimidinone NMDA receptor modulators and uses thereof
US11236104B2 (en) 2015-12-09 2022-02-01 Cadent Therapeutics, Inc. Heteroaromatic NMDA receptor modulators and uses thereof
US11541057B2 (en) 2015-12-09 2023-01-03 Cadent Therapeutics, Inc. Thienopyrimidinone NMDA receptor modulators and uses thereof
US11648253B2 (en) 2015-12-09 2023-05-16 Novartis Ag Thienopyrimidinone NMDA receptor modulators and uses thereof
US11274107B2 (en) 2016-12-22 2022-03-15 Cadent Therapeutics, Inc. NMDA receptor modulators and uses thereof
US11807650B2 (en) 2016-12-22 2023-11-07 Novartis Ag NMDA receptor modulators and uses thereof
US10584131B2 (en) 2018-08-03 2020-03-10 Cadent Therapeutics, Inc. Heteroaromatic NMDA receptor modulators and uses thereof
US10752633B2 (en) 2018-08-03 2020-08-25 Cadent Therapeutics, Inc. Heteroaromatic NMDA receptor modulators and uses thereof
US11542264B2 (en) 2018-08-03 2023-01-03 Cadent Therapeutics, Inc. Heteroaromatic NMDA receptor modulators and uses thereof
CN115094573A (zh) * 2022-07-18 2022-09-23 南通大学 一种抗菌纳米敷料及其制备方法
CN115094573B (zh) * 2022-07-18 2024-03-22 南通大学 一种抗菌纳米敷料及其制备方法

Also Published As

Publication number Publication date
CN103664877A (zh) 2014-03-26

Similar Documents

Publication Publication Date Title
WO2015096611A1 (zh) 一种喹啉衍生物、其制备方法和应用
AU2005254095B2 (en) Treatment or prevention of skin conditions or tissue conditions in animals using boryloxypyridylmethanones
EP2215049B1 (en) P2x3, receptor antagonists for treatment of pain
JP2021038263A (ja) 治療上活性な化合物およびそれらの使用方法
TWI823845B (zh) 用於治療癌症的組合療法
TW201408661A (zh) 抗病毒性化合物之固體形式
JPH0641475B2 (ja) 置換アルファアミノ酸、その製法および医薬
JPH01139565A (ja) フェネタノールアミン誘導体
EP2064192A2 (en) Compounds and methods for inhibiting the interaction of bcl proteins with binding partners
JP2011516564A (ja) 脂肪酸アミド加水分解酵素の阻害剤
EA022165B1 (ru) Производное 1,2,3,4-тетрагидрохинолина, подходящее для лечения диабета
KR980008228A (ko) N-(4-아릴-티아졸-2-일)-설폰아미드 유도체 및 이를 함유하는 약제학적 조성물
CN111410661A (zh) 帽依赖性内切核酸酶抑制剂及其用途
WO2018157842A1 (zh) 2-(取代苯氨基)苯甲酸类fto抑制剂治疗白血病的用途
CN107108598A (zh) 作为Rorγt调节剂的噻唑
US20230286904A1 (en) Inhibitors of yap/taz-tead oncoproteins, synthesis and use thereof
CN102746291B (zh) 13-取代小檗碱衍生物及其制备方法和作为抗结核病药物的用途
JPS636058B2 (zh)
US5750524A (en) Remedy for hyperlipidemia
WO2019101045A1 (zh) 鞘氨醇-1-磷酸受体调节剂化合物及其制备方法与应用
TWI824251B (zh) 吡啶嗎啉類化合物、其製備方法及其應用
CN107531613B (zh) 苯并脂肪环取代烷基胺类化合物及其用途
US4301167A (en) 2-Amino thiazoline derivatives
CA2933556A1 (en) Solid forms of an alpha, omega di-substituted dihydroxy cyclopentyl compound and methods for the preparation and use thereof
CN114450288A (zh) 4-喹啉酮抗细菌化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14875693

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14875693

Country of ref document: EP

Kind code of ref document: A1