WO2016023404A1 - 双苄基异喹啉衍生物、其制备方法及其在肝病的治疗与预防中的用途 - Google Patents

双苄基异喹啉衍生物、其制备方法及其在肝病的治疗与预防中的用途 Download PDF

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WO2016023404A1
WO2016023404A1 PCT/CN2015/082626 CN2015082626W WO2016023404A1 WO 2016023404 A1 WO2016023404 A1 WO 2016023404A1 CN 2015082626 W CN2015082626 W CN 2015082626W WO 2016023404 A1 WO2016023404 A1 WO 2016023404A1
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optionally substituted
group
substituted
hydrogen
amino
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PCT/CN2015/082626
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English (en)
French (fr)
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潘卫东
冯奕斌
刘亚洲
王宁
黄兰
梁光义
张茂生
李天磊
娄华勇
胡占兴
刘晟
曹佩雪
阮婧华
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贵州省中国科学院天然产物化学重点实验室
港大科桥有限公司
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Priority to CN201580033920.6A priority Critical patent/CN107207524B/zh
Priority to US15/504,245 priority patent/US10189812B2/en
Publication of WO2016023404A1 publication Critical patent/WO2016023404A1/zh

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    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems

Definitions

  • This application relates generally to the field of organic chemistry and medicinal chemistry.
  • Dibenzylisoquinoline alkaloids have a variety of biological activities, including antibacterial, anti-inflammatory, antihypertensive, anti-tumor, anti-platelet aggregation, immune function regulation, anti-arrhythmia, anti-fibrosis.
  • the present application relates to a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof:
  • X 1 , X 2 , X 3 and X 4 are each independently selected from hydrogen, halogen, nitro, nitroso, -SO 3 H, optionally substituted amino or optionally substituted sulfonyl;
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted.
  • Aryl optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • X 1 , X 2 , X 3 and X 4 are not simultaneously hydrogen
  • X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of hydrogen, nitro, nitroso, -SO 3 H
  • Another aspect of the present application relates to a compound of the formula (Ia), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof and metabolites thereof:
  • R 1 is selected from nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted alkynylcarbonyl, optionally substituted a cycloalkylcarbonyl group, an optionally substituted arylcarbonyl group, or an optionally substituted heteroarylcarbonyl group or a substituted sulfonyl group;
  • R 2 is selected from hydrogen, optionally substituted alkyl, nitroso, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted alkynylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryl A carbonyl group, an optionally substituted heteroarylcarbonyl group or a substituted sulfonyl group.
  • a further aspect of the present application relates to a compound, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and a metabolite thereof, wherein the compound is selected from the group consisting of:
  • a further aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I), a compound of the formula (Ia), a compound of any of the compounds H-01 to H-55, a single stereoisomer thereof, and a stereoisomer thereof Mixtures of bodies, prodrugs thereof, pharmaceutically acceptable salts thereof and metabolites thereof, and pharmaceutically acceptable carriers.
  • Another aspect of the present application relates to a process for the preparation of a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof,
  • X 1 , X 2 , X 3 and X 4 are each independently a nitro group; or X 1 , X 2 , X 3 and X 4 are each independently hydrogen or a nitro group, provided that: X 1 , X 2 , X 3 When it is different from X 4, it is hydrogen;
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted.
  • Aryl optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • the method comprises performing nitrification reaction of berbamine, tetrandrine or tetrandrine, the structural formula is as follows
  • a further aspect of the present application relates to a process for the preparation of a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof,
  • X 1 , X 2 , X 3 and X 4 are each independently an amino group; or X 1 , X 2 , X 3 and X 4 are each independently hydrogen or amino, provided that: X 1 , X 2 , X 3 and X 4 is not hydrogen at the same time;
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted. a sulfonyl group, an optionally substituted heteroaryl group, an optionally substituted arylcarbonyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkenylcarbonyl group or an optionally substituted alkynylcarbonyl group;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • the method comprises performing a nitration reaction of berbamine, tetrandrine or tetrandrine, and then subjecting the obtained nitrated product to a reduction reaction.
  • a further aspect of the present application relates to a process for the preparation of a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof,
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted.
  • Aryl optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;
  • R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;
  • R 4 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally a substituted alkoxy group, an optionally substituted arylcarbonyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkenylcarbonyl group or an optionally substituted alkynylcarbonyl group;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • the method comprises subjecting the nitramine, tetrandrine or tetrandrine to a nitration reaction, subjecting the obtained nitrification product to a reduction reaction, and subjecting the obtained reduction product to an acylation reaction.
  • a further aspect of the present application relates to a process for the preparation of a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof,
  • X 1 , X 2 , X 3 and X 4 are each independently a sulfonic acid group; or X 1 , X 2 , X 3 and X 4 are each independently hydrogen or -SO 3 H, provided that: X 1 , X 2 , X 3 and X 4 are not hydrogen at the same time;
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted.
  • Aryl optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • It includes a method comprising subjecting a sulfonation reaction to berbamine, tetrandrine or tetrandrine.
  • a further aspect of the present application relates to a process for the preparation of a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof,
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted. a heteroaryl group, an optionally substituted arylcarbonyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkenylcarbonyl group or an optionally substituted alkynylcarbonyl group;
  • R 6 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic or any Substituted amino group;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • the method comprises the steps of: nitration reaction of berbamine, tetrandrine or tetrandrine with concentrated nitric acid, and then reacting with iron powder to form an amino group, and then reacting the amino group with an acid chloride under the catalysis of a base to obtain the above formula (I) a compound.
  • a further aspect of the present application relates to a method of treating or preventing liver disease comprising administering to a subject in need of such a method a therapeutically effective amount of a compound of the formula (I), a compound of the formula (Ia) and a compound H-1 to H-55 A compound, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof and a metabolite thereof, or a pharmaceutical composition as described above.
  • references to “an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” throughout this specification are meant to be included in the at least one embodiment.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • C 7 -C 12 alkyl describes an alkyl group as defined below having a total of from 7 to 12 carbon atoms
  • a C 4 -C 12 cycloalkylalkyl group describes the following definition having a total of from 4 to 12 carbon atoms Cycloalkylalkyl.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • Hydrophilicity refers to an -OH group.
  • Cyano refers to a -CN group.
  • Niro refers to a -NO 2 group.
  • Amino refers to a -NH 2 group.
  • Alkyl means a group consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having from one to twelve carbon atoms, especially having from one to eight carbon atoms or from one to six carbon atoms, and consisting of a single bond a straight or branched hydrocarbon chain group attached to the remainder of the molecule, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1, 1-dimethylethyl (tert-butyl) and the like.
  • the alkyl group can be optionally substituted, that is, substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanyl, Isothiocyanate, nitro, silyl, trihalomethanesulfony
  • C 1 -C 4 alkyl refers to an alkyl group as defined above containing one to four carbon atoms.
  • the C 1 -C 4 alkyl group can be optionally substituted as defined for the alkyl group.
  • C 1 -C 6 alkyl refers to an alkyl group as defined above containing one to six carbon atoms.
  • the C 1 -C 6 alkyl group can be optionally substituted as defined for the alkyl group.
  • C 1 -C 12 alkyl refers to an alkyl group as defined above containing one to twelve carbon atoms.
  • the C 1 -C 12 alkyl group can be optionally substituted as defined for the alkyl group.
  • the alkyl group is a C 1 -C 4 alkyl group.
  • the alkyl group is a C 1 -C 6 alkyl group.
  • the alkyl group is a C 1 -C 12 alkyl group.
  • Alkenyl means a straight or branched hydrocarbon chain radical consisting solely of carbon and a hydrogen atom, containing at least one double bond, having from two to twelve carbon atoms, especially having from two to eight carbon atoms or Two to six carbon atoms, and which are attached to the remainder of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1, 4 - a dienyl group or the like.
  • the alkenyl group of the present application can be substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanyl, Isothiocyanate, nitro, silyl, trihalomethanesulfonyl, or an amino group including mono- and di-substituted amino groups, and protected derivatives thereof
  • C 2 -C 6 alkenyl refers to an alkenyl group as defined above containing two to six carbon atoms.
  • the C 2 -C 6 alkenyl group can be optionally substituted as defined for the alkenyl group.
  • C 2 -C 8 alkenyl refers to an alkenyl group as defined above containing two to eight carbon atoms.
  • the C 2 -C 8 alkenyl group can be optionally substituted as defined for the alkenyl group.
  • C 2 -C 12 alkenyl refers to an alkenyl group as defined above containing two to twelve carbon atoms.
  • the C 2 -C 12 alkenyl group may be optionally substituted as defined for the alkenyl group.
  • the alkenyl is C 2 -C 6 alkenyl group.
  • the alkenyl is C 2 -C 8 alkenyl group.
  • the alkenyl is C 2 -C 12 alkenyl group.
  • Alkynyl means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, including Having at least one hydrazone bond having from two to twelve carbon atoms, especially having two to eight carbon atoms or two to six carbon atoms, and which is attached to the remainder of the molecule by a single bond, such as ethynyl, propyl Alkynyl, butynyl, pentynyl, hexynyl and the like.
  • the alkynyl groups of the present application may be substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanyl, Isothiocyanate, nitro, silyl, trihalomethanesulfonyl, or an amino group including mono- and di-substituted amino groups, and protected derivatives thereof
  • C 2 -C 6 alkynyl refers to an alkynyl group as defined above containing two to six carbon atoms.
  • the C 2 -C 6 alkynyl group can be optionally substituted as defined for the alkynyl group.
  • C 2 -C 8 alkynyl refers to an alkynyl group as defined above containing two to eight carbon atoms.
  • the C 2 -C 8 alkynyl group can be optionally substituted as defined for an alkynyl group.
  • C 2 -C 12 alkynyl refers to an alkynyl group as defined above containing two to twelve carbon atoms.
  • the C 2 -C 12 alkynyl group can be optionally substituted as defined for the alkynyl group.
  • the alkynyl group is a C 2 -C 6 alkynyl group.
  • the alkynyl group is a C 2 -C 8 alkynyl group.
  • the alkynyl group is a C 2 -C 12 alkynyl group.
  • halogen refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl means an alkyl radical as defined above substituted by one or more halo as defined above, eg, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
  • the alkyl moiety of the haloalkyl group can be optionally substituted as defined for the above alkyl group.
  • Alkoxy means an -OR group wherein R is alkyl as defined above.
  • Cycloalkyl means a stable non-aromatic monocyclic or polycyclic alkyl group consisting solely of carbon and hydrogen atoms, which may comprise a fused or bridged ring system having from three to eighteen carbon atoms, especially Is a gas having three to fifteen carbon atoms or three to ten carbon atoms, and is saturated A single bond is connected to the rest of the molecule.
  • Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Polycyclic groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl and the like.
  • the cycloalkyl groups of the present application may be substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanyl, Isothiocyanate, nitro, silyl, trihalomethanesulfonyl, or an amino group including mono- and di-substituted amino groups, and protected derivatives thereof
  • C 3 -C 18 cycloalkyl refers to a cycloalkyl group as defined above containing from three to eighteen carbon atoms.
  • the C 3 -C 18 cycloalkyl group can be optionally substituted as defined for the cycloalkyl group.
  • C 3 -C 15 cycloalkyl refers to a cycloalkyl group as defined above containing three to fifteen carbon atoms.
  • the C 3 -C 15 cycloalkyl group can be optionally substituted as defined for the cycloalkyl group.
  • C 3 -C 10 cycloalkyl refers to a cycloalkyl group as defined above containing three to ten carbon atoms.
  • the C 3 -C 10 cycloalkyl group can be optionally substituted as defined for the cycloalkyl group.
  • the cycloalkyl is C 3 -C 18 cycloalkyl.
  • the cycloalkyl is C 3 -C 15 cycloalkyl.
  • the cycloalkyl is C 3 -C 10 cycloalkyl.
  • Aryl means an aromatic monocyclic or polycyclic hydrocarbon ring system consisting solely of hydrogen and carbon and containing from six to eighteen carbon atoms, especially having six to twelve carbon atoms or six to ten carbons An atom wherein the ring system can be partially saturated.
  • Aryl groups include, but are not limited to, groups such as phenyl, naphthyl, and anthracenyl. The aryl group of the present application may be substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O- Carboyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanate, nitro, silyl, trihalomethanesulfonyl, or a mono- and di-substituted amino group The amino group, and its protected derivative. Whenever
  • C 6 -C 18 aryl means an aryl group as defined above containing from six to eighteen carbon atoms.
  • the C 6 -C 18 aryl group can be optionally substituted as defined for the aryl group.
  • C 6 -C 12 aryl refers to an aryl group as defined above containing six to twelve carbon atoms.
  • the C 6 -C 12 aryl group can be optionally substituted as defined for the aryl group.
  • C 6 -C 10 aryl refers to an aryl group as defined above containing six to ten carbon atoms.
  • the C 6 -C 10 aryl group can be optionally substituted as defined for the aryl group.
  • the aryl group is a C 6 -C 18 aryl group.
  • the aryl group is a C 6 -C 12 aryl group.
  • the aryl group is a C 6 -C 10 aryl group.
  • Heteroaryl means a five to eighty membered aromatic ring group consisting of a carbon atom and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may comprise a fused or bridged ring system; and the nitrogen, carbon or sulfur atom in the heteroaryl group may be optionally It is oxidized; the nitrogen atom can be arbitrarily quaternized.
  • Examples include, but are not limited to, azaftyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindenyl, benzothiadiazolyl, benzonaphthylfuranyl, benzoxazolyl, Benzodioxolyl, benzodioxin, benzopyranyl, benzopyranone, benzofuranyl, benzofuranone, benzothienyl (benzobenzene) Benzo, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, oxazolyl, porphyrinyl, dibenzofuranyl, furyl, thienyl, furanone Base, isothiazolyl, imidazolyl, fluorenyl, oxazolyl, isodecyl, indanyl, isoindoline, mesoindolyl, isoxazolyl
  • the heteroaryl group can be optionally substituted, that is, substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanyl, Isothiocyanate, nitro, silyl, trihalomethanesulfony
  • the "five- to eight-membered heteroaryl group” means a five- to eight-membered aromatic ring group composed of a carbon atom and one to five hetero atoms selected from nitrogen, oxygen and sulfur.
  • the five- to eight-membered heteroaryl group can be optionally substituted as defined for the heteroaryl group.
  • the "five- to twelve-membered heteroaryl group” means a five- to twelve-membered aromatic ring group composed of a carbon atom and one to five hetero atoms selected from nitrogen, oxygen and sulfur.
  • the five- to twelve-membered heteroaryl group can be optionally substituted as defined for the heteroaryl group.
  • the "five- to ten-membered heteroaryl group” means a five- to ten-membered aromatic ring group composed of a carbon atom and one to five hetero atoms selected from nitrogen, oxygen and sulfur.
  • the five- to ten-membered heteroaryl group can be optionally substituted as defined for the heteroaryl group.
  • the heteroaryl is a five to eight membered heteroaryl.
  • the heteroaryl is a five to twelve membered heteroaryl.
  • the heteroaryl is a five to ten membered heteroaryl.
  • Heterocyclyl means a stable 3 to 18 membered non-aromatic ring group consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may include a fused or bridged ring system; and optionally oxidizes nitrogen, carbon or sulfur atoms in the heterocyclic group.
  • the heterocyclic group may be partially or fully saturated.
  • heterocyclic groups include, but are not limited to, dioxapentane, thienyl [1,3] dithiaalkyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, hetero Oxazolidinyl, morpholinyl, octahydroindenyl, 2-oxopiperrazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazine Base, 4-piperidinone, pyrrolidine Base, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trioxoalkyl, trithiaalkyl, triazinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl , 1-oxo-thiomorpholinyl
  • the alkylcarbonyl groups of the present application may be substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanyl, Isothiocyanate, nitro, silyl, trihalomethanesulfonyl, or an amino group including mono- and di-substituted amino groups, and protected derivatives thereof
  • the alkenylcarbonyl group of the present application may be substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanyl, Isothiocyanate, nitro, silyl, trihalomethanesulfonyl, or an amino group including mono- and di-substituted amino groups, and protected derivatives thereof
  • the alkynylcarbonyl groups of the present application may be substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanyl, Isothiocyanate, nitro, silyl, trihalomethanesulfonyl, or an amino group including mono- and di-substituted amino groups, and protected derivatives thereof
  • the arylcarbonyl groups of the present application may be substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanyl, Isothiocyanate, nitro, silyl, trihalomethanesulfonyl, or an amino group including mono- and di-substituted amino groups, and protected derivatives thereof
  • heteroarylcarbonyl groups include, but are not limited to, 2-thienyl, 2-furoyl.
  • the heteroarylcarbonyl groups of the present application may be substituted or unsubstituted.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N- Amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanate, nitro, silyl, trihalo A methanesulfonyl group, or an amino group including a mono- and di-substituted amino group, and
  • R can be alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, amino, and the like, as defined above.
  • the substituent group is one or more groups selected individually and independently from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl , N-thiocarbamoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanyl, Isothiocyanate, nitro, silyl, trihalomethanesulfonyl, or an amino group including mono- and di-substituted amino groups, and protected derivatives thereof
  • Prodrug is intended to mean a compound that can be converted to a biologically active compound for application under physiological conditions or by solvolysis.
  • the term “prodrug” refers to a metabolically acceptable precursor of a compound of the present application that is pharmaceutically acceptable.
  • Prodrugs may be inactive when administered to an individual in need of a prodrug, but prodrugs in vivo may be converted to the active compound of the application.
  • Prodrugs can generally be rapidly converted in vivo to obtain the parent compound of the present application, for example by hydrolysis in the blood.
  • Prodrug compounds generally provide the advantage of solubility, histocompatibility or sustained release in mammalian organisms (see Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21- 24 (Elsevier, Amsterdam)).
  • prodrug is also intended to include any covalently bonded carrier capable of releasing the active compound of the present application in vivo when the prodrug is administered to a mammalian subject.
  • Prodrugs of the compounds of the present application can be prepared by modifying the functional groups present in the compounds of the present application in such a manner that the parent compound of the present application can be formed using conventional procedures or in vivo to modify the cleavage.
  • Prodrugs comprise a compound of the present invention wherein a hydroxy, amino or thiol group is bonded to any group, and when a prodrug of a compound of the present application is administered to a mammalian individual, the bonding group will cleave to form a free Hydroxyl group, free amino group or free sulfhydryl group.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the compounds of the present application, and the like.
  • “Arbitrary” or “arbitrarily” means that the condition described subsequently may or may not occur, and that the statement includes instances where the event or condition occurs and conditions that do not occur.
  • “optionally substituted aryl” means that the aryl group may or may not be substituted, and the description includes substituted aryl groups and unsubstituted aryl groups.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, antiseptic that has been approved by the U.S. Food and Drug Administration for use in humans or animals. Agents, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, etc., which have no side effects on the composition of the pharmaceutical composition. a.
  • “Pharmaceutically acceptable salts” include “pharmaceutically acceptable acid addition salts” and “pharmaceutically acceptable base addition salts.”
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are formed using inorganic or organic acids.
  • the inorganic acid is, for example but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, Aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexyl Alkyl sulfamic acid, dodecyl sulphate, ethane-1,2-d
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylaminoethanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine , histidine, caffeine, procaine, seabamin, choline, betaine, benzylamine, phenethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, Tromethamine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like.
  • solvate refers to an aggregate comprising one or more molecules of a compound of the present application bearing one or more solvent molecules.
  • the solvent may be water, in which case the solvate is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present application may exist in the form of hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as in the corresponding solvated forms.
  • the compounds of the present application may be true solvates, but in other instances, the compounds of the present application may retain only amorphous water or the compound is a mixture of water and some indefinite solvent.
  • Polymorph refers to a component having the same chemical formula but having a different structure.
  • “Pharmaceutical composition” refers to a formulation of a compound of the present invention and a medium which is generally accepted in the art for delivery of a biologically active compound to a mammal such as a human.
  • Such media include all pharmaceutically acceptable carriers, diluents or excipients.
  • a pharmaceutical composition comprising a compound of the formula (I) or the formula (Ia), which can be formulated and used as a tablet, capsule or elixiture for oral administration; suppository for rectal administration; for injection Sterile solutions for administration, suspensions; patches for transdermal administration, subcutaneous deposits, and the like.
  • the injection can be prepared in the following conventional forms: a solution or suspension, a solid dosage form suitable as a solution or suspension prior to injection, or an emulsion.
  • Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like.
  • the injectable pharmaceutical compositions may contain minor amounts of non-toxic adjuvants such as wetting agents, pH buffering agents and the like. Absorption enhancers (e.g., liposomes) can also be used if desired.
  • Formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form.
  • suspensions of the active compounds can be prepared in a suitable oily suspension.
  • suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean oil, pomelo or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes .
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran.
  • the suspension may contain suitable stabilizers or agents which increase the solubility of the compound such that a high concentration of solution can be prepared.
  • compositions for oral administration can be obtained by combining the active compound with a solid excipient, optionally milling the resulting mixture, and processing the mixture of granules, if necessary, after the addition of a suitable adjuvant A tablet or dragee core was obtained.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, Methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • a disintegrating agent such as cross-linked polyvinylpyrrolidone, agar or alginic acid or an alginate such as sodium alginate may be added.
  • a suitable coating is applied to the sugar coating core.
  • a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or Solvent mixture.
  • a dye or pigment may be added to the tablet or dragee coating.
  • the present application also relates to various pharmaceutical compositions known in the pharmaceutical arts for use in intraocular, intranasal, and intra-oral delivery.
  • the pharmaceutical formulation comprises an aqueous ophthalmic solution of the active compound, which may be present in a water soluble form such as an eye drop, or as a gellan gum or hydrogel; an ophthalmic ointment; an ophthalmic suspension, such as a microparticle, suspended in Small polymeric particles comprising a drug, a fat-soluble formulation, and microspheres in a liquid carrier medium; and an ophthalmic intercalator.
  • these suitable pharmaceutical preparations are most often and preferably manufactured as sterile, isotonic and buffered preparations.
  • compositions also include drops and sprays which often mimic nasal secretions in a number of ways to ensure maintenance of normal ciliary action.
  • suitable formulations are most often and preferably isotonic, are lightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and appropriate drugs. stabilizer.
  • Pharmaceutical formulations for intra-oral delivery include suspensions and ointments for topical application in the ear. Common solvents for these otic preparations include glycerin and water.
  • the compound of the formula (I), the compound of the formula (Ia) or the pharmaceutical composition comprising the compound of the formula (I) or the compound of the formula (Ia) can be administered orally or parenterally.
  • it can be administered in the form of capsules, tablets, granules, sprays, syrups or other dosage forms.
  • it can be administered as an aqueous suspension, an oily preparation, or the like, or as a drop, a suppository, an ointment, an ointment, or the like, when administered by injection, subcutaneously, intraperitoneally, intravenously, intramuscularly. Oral administration.
  • “Therapeutically effective amount” means an amount of a compound of the present application, when administered to a mammal, preferably to a human, sufficient to effectively treat (as defined below) a disease or condition in a mammal.
  • the amount of the compound of the present application which constitutes a “therapeutically effective amount” will vary depending on the compound, the state of the disease and its severity, and the age of the mammal to be treated, but those skilled in the art will be able to rely on their own knowledge and the present disclosure.
  • the formula determines the amount of the compound of the present application.
  • treating encompasses a mammal having a related disease or condition, preferably a treatment-related disease or condition in a human, and includes:
  • disease and “disease state” can be used to intersect each other. Used interchangeably, or may be different, because a particular disease or condition may not have a known causative factor (and therefore cannot be explained by etiology), so it is not recognized as a disease but is considered undesirable A disease state or condition in which a clinician has identified a more or less specific series of symptoms.
  • the compound of the present application or a pharmaceutically acceptable salt thereof may contain one or more asymmetric centers, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be based on absolute stereochemistry. It is defined as (R)- or (S)-, or (D)- or (L)- of the amino acid. This application is intended to include all such possible isomers, as well as the racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or Resolution is carried out using conventional techniques, such as HPLC using a chiral column.
  • a compound described herein contains an olefinic double bond or other geometrically asymmetric center, unless otherwise stated, it is meant that the compound includes both E and Z geometric isomers. Again, it is meant to include all tautomeric forms.
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond, but having different three-dimensional structures that are not interchangeable. This application covers various stereoisomers and mixtures thereof.
  • contacting refers to bringing two or more substances close together to allow interaction.
  • the present application relates to a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof:
  • X 1 , X 2 , X 3 and X 4 are each independently selected from hydrogen, halogen, nitro, nitroso, -SO 3 H, optionally substituted amino or optionally substituted sulfonyl;
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted.
  • Aryl optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • X 1 , X 2 , X 3 and X 4 are not simultaneously hydrogen
  • X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of hydrogen, nitro, nitroso, -SO 3 H
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted.
  • Aryl optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;
  • R 3 and R 5 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;
  • R 4 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally a substituted alkoxy group, an optionally substituted arylcarbonyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkenylcarbonyl group or an optionally substituted alkynylcarbonyl group;
  • R 6 and R 7 are each independently selected from an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, and an arbitrary substitution.
  • x is an integer from 1 to 3;
  • Y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • X 1 , X 2 , X 3 and X 4 are not simultaneously hydrogen
  • x is 1, 2 or 3.
  • y is 1, 2, 3 or 4.
  • z is 1 or 2.
  • X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of hydrogen, halogen, nitro, nitroso, —SO 3 H, optionally substituted alkylcarbonyl substituted amino, optionally Substituted alkenylcarbonyl substituted amino group, optionally substituted alkynylcarbonyl substituted amino group, optionally substituted alkoxycarbonyl substituted amino group, optionally substituted cycloalkylcarbonyl substituted amino group, optionally substituted arylcarbonyl substituted amino group Any optionally substituted heterocyclylcarbonyl substituted amino group, optionally substituted aminocarbonyl substituted amino group, optionally substituted heteroarylcarbonyl substituted amino group, optionally substituted alkoxycarbonylcarbonyl substituted amino group, optionally substituted alkyl sulfonate An acyl-substituted amino group, an optionally substituted alkenylsulfonyl-sub
  • X 1, X 2, X 3 and X 4 are each independently selected from hydrogen, halogen, nitro, nitroso, -SO 3 H, a substituted carbonyl group substituted with an amino alkyl, hydroxy alkyl Alkylcarbonyl substituted amino, ester substituted alkylcarbonyl substituted amino, alkenylcarbonyl substituted amino, alkoxycarbonyl substituted amino, aryl substituted alkoxycarbonyl substituted amino, halogen substituted arylcarbonyl Substituted amino, alkoxy substituted arylcarbonyl substituted amino, haloalkyl substituted arylcarbonyl substituted amino, alkoxycarbonylcarbonyl substituted amino, heterocyclylcarbonyl substituted amino, alkylsulfonyl substituted Amino, aralkylsulfonyl substituted amino, arylsulfonyl substituted amino, nitro substituted arylsulfony
  • R ⁇ 1> is selected from hydrogen, nitroso, alkyl, aryl substituted alkyl, aryl, alkylcarbonyl or arylcarbonyl.
  • x is 1 and X 2 is selected from the group consisting of halogen, nitro, nitroso, amino, -SO 3 H, alkylcarbonyl substituted amino, hydroxy substituted alkylcarbonyl substituted amino, ester Alkyl-substituted alkylcarbonyl-substituted amino, alkenylcarbonyl-substituted amino, aryl-substituted alkenylcarbonyl-substituted amino, alkoxycarbonyl-substituted amino, aryl-substituted alkoxycarbonyl-substituted amino, aryl a carbonyl-substituted amino group, a halogen-substituted arylcarbonyl-substituted amino group, an alkoxy-substituted arylcarbonyl-substituted amino group, a halogenated alkyl-substituted arylcarbonyl
  • y is 4, and X 3 is hydrogen.
  • z is 2, and X 4 is hydrogen.
  • X 1 is hydrogen
  • x is 2, and one of X 2 is hydrogen, and the other of X 2 is selected from the group consisting of amino, nitro, nitroso, -SO 3 H, Br, Cl, methylcarbonylamino , isopropylcarbonylamino, isobutylcarbonylamino, vinylcarbonylamino, styrylcarbonylamino, 2-methylpropenylcarbonylamino, 2-methylpropyloxycarbonylamino, hydroxymethylcarbonylamino, Methylcarbonyloxymethylcarbonylamino, methoxycarbonylcarbonylamino, furylcarbonylamino, thienylcarbonylamino, morpholinylcarbonylamino, phenylcarbonylamino, 2-chlorophenylcarbonylamino, 4-chlorobenzene Carbocarbonylamino, 4-methoxyphenylcarbonylamino, trifluoromethylphenylcarbonyla
  • R 2 is alkyl
  • R 2 is C 1 -C 6 alkyl.
  • R 2 is methyl
  • R 1 is alkyl and R 2 is alkyl.
  • R 1 is C 1 -C 6 alkyl
  • R 2 is C 1 -C 6 alkyl
  • R 1 methyl
  • R 2 is methyl
  • R 1 is alkyl and R 2 is hydrogen.
  • R 1 is C 1 -C 6 alkyl
  • R 2 is hydrogen
  • R 1 is methyl and R 2 is hydrogen.
  • X 1 is halogen
  • X 1 is halogen
  • X 2 is selected from nitro and/or sulfonic acid groups
  • X 3 and X 4 are hydrogen
  • x is 1.
  • x is 1 and X 2 is at the C-14 position.
  • x is 2 and X 2 is at the C-10 and C-14 positions, respectively.
  • X 3 and X 4 are hydrogen.
  • R 1 is selected from hydrogen, nitroso, optionally substituted C 1 -C 6 alkyl, optionally substituted phenylcarbonyl or optionally substituted C 1 -C 6 alkylcarbonyl.
  • R ⁇ 1> is selected from the group consisting of hydrogen, methyl, benzyl, benzoyl, nitroso or acetyl.
  • R 1 is selected from the group consisting of hydrogen, methyl, benzyl, benzoyl, nitroso or acetyl; and/or
  • R 2 is methyl
  • X 1 is hydrogen, nitro or halogen (halogen is preferably Br or Cl); and/or
  • x is 1 or 2
  • at least one X 2 is hydrogen, amino, nitro, nitroso, -SO 3 H, Br, Cl, methylcarbonylamino, isobutylcarbonylamino, vinylcarbonylamino, styrene Carbocarbonylamino, 2-methylpropenylcarbonylamino, 2-methylpropyloxycarbonylamino, hydroxymethylcarbonylamino, methylcarbonyloxymethylcarbonylamino, methoxycarbonylcarbonylamino, furylcarbonyl Amino, thienylcarbonylamino, morpholinylcarbonylamino, phenylcarbonylamino, 2-chlorophenylcarbonylamino, 4-chlorophenylcarbonylamino, 4-methoxyphenylcarbonylamino, trifluoromethylphenyl Carbonylamino, benzyloxycarbonylamino, methylsulfonylamino, phen
  • y is 3 and X 3 is hydrogen
  • X 1 , X 2 , X 3 and X 4 are not hydrogen at the same time
  • Another aspect of the present application relates to a compound of the formula (Ia), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof and metabolites thereof:
  • R 1 is selected from nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted alkynylcarbonyl, optionally substituted a cycloalkylcarbonyl group, an optionally substituted arylcarbonyl group, an optionally substituted heteroarylcarbonyl group or an optionally substituted sulfonyl group;
  • R 2 is selected from hydrogen, optionally substituted alkyl, nitroso, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted alkynylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted aryl A carbonyl group or an optionally substituted heteroarylcarbonyl group or an optionally substituted sulfonyl group.
  • R 1 is selected from halogen-substituted alkylcarbonyl, halogen-substituted alkenylcarbonyl, halogen-substituted alkynylcarbonyl, halogen-substituted cycloalkylcarbonyl, halogen-substituted arylcarbonyl, or halogen-substituted Heteroarylcarbonyl.
  • R 1 is selected from cyano-substituted alkylcarbonyl group, cyano-substituted alkenyl, cyano-substituted alkynyl group, cyano-substituted cycloalkyl, cyano-substituted aryl group A carbonyl or cyano substituted heteroarylcarbonyl group.
  • R 1 is selected from hydroxy-substituted alkylcarbonyl, hydroxy-substituted alkenylcarbonyl, hydroxy-substituted alkynylcarbonyl, hydroxy-substituted cycloalkylcarbonyl, hydroxy-substituted arylcarbonyl, or hydroxy-substituted Heteroarylcarbonyl.
  • R 1 is selected from the group consisting of a nitro-substituted alkylcarbonyl group, a nitro-substituted alkenylcarbonyl group, a nitro-substituted alkynylcarbonyl group, a nitro-substituted cycloalkylcarbonyl group, a nitro-substituted aryl group.
  • R 1 is selected from optionally substituted alkyl substituted alkylcarbonyl, optionally substituted alkyl substituted alkenylcarbonyl, optionally substituted alkyl substituted alkynylcarbonyl, optionally substituted alkyl substituted A cycloalkylcarbonyl group, an optionally substituted alkyl substituted arylcarbonyl group or an optionally substituted alkyl substituted heteroarylcarbonyl group.
  • R 1 is selected from an optionally substituted alkoxy-substituted alkylcarbonyl, an optionally substituted alkoxy-substituted alkenylcarbonyl, an optionally substituted alkoxy-substituted alkynylcarbonyl, optionally substituted An alkoxy-substituted cycloalkylcarbonyl group, an optionally substituted alkoxy-substituted arylcarbonyl group or an optionally substituted alkoxy-substituted heteroarylcarbonyl group.
  • R ⁇ 1> is selected from the group consisting of trifluoromethylcarbonyl, chloromethylcarbonyl, or 3-trifluoromethylphenylcarbonyl.
  • a further aspect of the present application relates to a compound, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and a metabolite thereof, wherein the compound is selected from the group consisting of:
  • a further aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I), a compound of the formula (Ia), a compound of any of the compounds H-01 to H-55, a single stereoisomer thereof, and a stereoisomer thereof Mixtures of bodies, prodrugs thereof, pharmaceutically acceptable salts thereof and metabolites thereof, and pharmaceutically acceptable carriers.
  • dosage forms that can be used in the pharmaceutical compositions of the present application include, but are not limited to, tablets, capsules, pills, suppositories, emulsions, ointments, injections, and infusions.
  • Another aspect of the present application relates to a process for the preparation of a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof,
  • X 1 , X 2 , X 3 and X 4 are each independently a nitro group; or X 1 , X 2 , X 3 and X 4 are each independently hydrogen or a nitro group, provided that: X 1 , X 2 , X 3 When it is different from X 4, it is hydrogen;
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted.
  • Aryl optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • the method comprises nitration of berbamine, tetrandrine or tetrandrine.
  • the nitration reaction is carried out using a mixed acid of acetic anhydride and nitric acid.
  • the nitration reaction is carried out using a non-polar solvent as the solvent.
  • the nitration reaction is carried out at a temperature of from about -10 °C to about 5 °C.
  • the nitration reaction is carried out at about 0 °C.
  • the nitration reaction is carried out in an inert gas atmosphere.
  • a further aspect of the present application relates to a process for the preparation of a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof,
  • X 1 , X 2 , X 3 and X 4 are each independently an amino group; or X 1 , X 2 , X 3 and X 4 are each independently hydrogen or amino, provided that: X 1 , X 2 , X 3 and X 4 is not hydrogen at the same time;
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted.
  • Aryl optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • the method comprises performing a nitration reaction of berbamine, tetrandrine or tetrandrine, and then subjecting the obtained nitrated product to a reduction reaction.
  • the reduction reaction is carried out using NiCl 2 ⁇ 6H 2 O as a catalyst.
  • the reduction reaction is carried out at a temperature of from about -15 °C to about 0 °C.
  • the reduction reaction is carried out in an ice bath.
  • the reduction reaction is carried out using a polar aprotic solvent as the solvent.
  • a further aspect of the present application relates to a process for the preparation of a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof,
  • R 1 is selected from hydrogen, optionally substituted alkyl, nitroso, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted Arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted sulfonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • the method comprises subjecting the nitramine, tetrandrine or tetrandrine to a nitration reaction, subjecting the obtained nitrification product to a reduction reaction, and subjecting the obtained reduction product to an acylation reaction.
  • the acyl halide or sulfonyl halide compound is used to carry out the acyl group Reaction.
  • the acylation reaction is carried out using a basic solvent as the solvent.
  • Illustrative examples of the basic solvent which can be used in the above acylation reaction include, but are not limited to, a solution of pyridine, a solution of diethylamine in dichloromethane, and a solution of triethylamine in dichloromethane.
  • the acylation reaction is carried out at a temperature of from about 0 °C to room temperature.
  • the acylation reaction is carried out in an ice bath.
  • the acylation reaction is carried out in an atmosphere of an inert gas.
  • a further aspect of the present application relates to a process for the preparation of a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof,
  • X 1 , X 2 , X 3 and X 4 are each independently a sulfonic acid group; or X 1 , X 2 , X 3 and X 4 are each independently hydrogen or -SO 3 H, provided that: X 1 , X 2 , X 3 and X 4 are not hydrogen at the same time;
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted. a heteroaryl group, an optionally substituted arylcarbonyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkenylcarbonyl group or an optionally substituted alkynylcarbonyl group;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • the method comprises a sulfonation reaction of berbamine, tetrandrine or tetrandrine.
  • the sulfonation reaction is carried out using a sulfate and concentrated sulfuric acid.
  • the sulfonation reaction is carried out using a non-polar solvent as the solvent.
  • non-polar solvents that can be used in the present application include, but are not limited to, dichloromethane, chloroform, and 1,2-dichloroethane.
  • the sulfonation reaction is carried out at a temperature of from about -15 °C to about 0 °C.
  • the sulfonation reaction is carried out in an ice bath.
  • a further aspect of the present application relates to a process for the preparation of a compound of formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and metabolites thereof,
  • R 1 and R 2 are each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted. a heteroaryl group, an optionally substituted arylcarbonyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkenylcarbonyl group or an optionally substituted alkynylcarbonyl group;
  • R 6 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic or any Substituted amino group;
  • x is an integer from 1 to 3;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 2;
  • the method comprises the steps of: nitration reaction of berbamine, tetrandrine or tetrandrine with concentrated nitric acid, and then reacting with iron powder to form an amino group, and then reacting the amino group with an acid chloride under the catalysis of a base to obtain the above formula (I) a compound.
  • a further aspect of the present application relates to a method of treating or preventing liver disease comprising administering to a subject in need of such a method a therapeutically effective amount of a compound of the formula (I), a compound of the formula (Ia) and a compound H-1 to H-55 A compound, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof and a metabolite thereof, or a pharmaceutical composition as described above.
  • the individual is a mammal.
  • the mammal is a human.
  • the liver disease is viral liver disease or non-viral liver disease.
  • liver diseases that can be treated or prevented using the compounds of the present application include, but are not limited to, hepatitis, alcoholic liver disease, drug or toxic liver disease, metabolic abnormal liver disease, and fatty liver disease.
  • the liver disease is liver tumor, cirrhosis, and liver fibrosis.
  • the mixed acid solution was placed at 0 ° C. Under Ar protection, 1.5 mL (CH 3 CO) 2 O was added to a 10 mL round bottom flask, and 0.6 mL of concentrated nitric acid was slowly added dropwise with stirring. After stirring for 5 minutes, the temperature was lowered to -10 ° C. A solution of 500 mg (0.8 mmol) of tetrandrine in 3 mL of anhydrous chloroform was slowly added dropwise to the mixed acid solution, and the mixture was added dropwise over 15 minutes. The reaction was completed by TLC, and the reaction was completed in 70 min.
  • Mass spectral data was obtained using an Agilent MS-5973 mass spectrometer and nuclear magnetic data was obtained using a VarianINOVA-400 NMR spectrometer.
  • H-28 (yield: 43%) was obtained in which the ratio of the mixed acid was changed, the volume was 4 mL, and the reaction time was extended to 200 min.
  • the nitration product H-39 (yield 90%) was synthesized from Compound H-32 using the same procedure as in Example 6 except that Compound H-31 was used instead of H-32.
  • Compound H-40 was prepared by the method of preparing compound H-36, except that concentrated sulfuric acid and Na 2 SO 4 were used instead of mixed acid.
  • Compound H-41 was prepared by the method of preparing compound H-36, except that 65 mg of N-bromosuccinimide was used instead of 32 mg of N-bromosuccinimide, and concentrated sulfuric acid was used instead of mixed acid.
  • Compound H-43 was prepared by the method of preparing compound H-36, except that 32 mg of N-chlorosuccinimide was used instead of 32 mg of N-bromosuccinimide.
  • Compound H-44 was prepared by the method of preparing compound H-36, except that 65 mg of N-chlorosuccinimide was used instead of 32 mg of N-bromosuccinimide.
  • Experimental method 1. Take 500mg (0.8mmol) of dried sample of tetrandrine in a 10mL round bottom flask, under Ar protection, add 10mL of anhydrous DMF, then add 70mg NaH (1.6mmol, 55%), stir evenly, drop 180 ⁇ L of benzoyl chloride (1.6 mmol) was added and reacted at room temperature for 8 h. The reaction was complete by TLC and the reaction was stopped.
  • Compound H-47 (yield 46%) was obtained by the method of preparing compound H-46, except that 50 mg of N-chlorosuccinimide was used instead of 25 mg of N-chlorosuccinimide.
  • Compound H-48 was prepared by the method of preparing compound H-46, except that acetic anhydride was used instead of benzoyl chloride, and 32 mg of N-bromosuccinimide was used instead of 25 mg of N-chlorosuccinimide (yield 63%). ).
  • Compound H-49 was prepared by the method of preparing compound H-46, except that acetic anhydride was used instead of benzoyl chloride, and 65 mg of N-bromosuccinimide was used instead of 25 mg of N-chlorosuccinimide (yield 49%). ).
  • Compound H-50 was prepared by the method of preparing compound H-46, except that acetic anhydride was used instead of benzoyl chloride, 50 mg of N-chlorosuccinimide was used instead of 25 mg of N-chlorosuccinimide (yield 41%). ).
  • Compound H-51 was prepared by the method of preparing compound H-46, except that acetic anhydride was used instead of benzoyl chloride, and 80 mg of N-chlorosuccinimide was used instead of 25 mg of N-chlorosuccinimide (yield 38%). ).
  • the mixed acid solution was placed at 2.0 ° C. Under Ar protection, 0.15 mL (CH 3 CO) 2 O was added to a 10 mL round bottom flask, and 0.06 mL of concentrated nitric acid was slowly added dropwise with stirring. After stirring for 5 minutes, the temperature was lowered to -10 ° C. 50 mg (0.08 mmol) of H-37 in 3 mL of anhydrous chloroform solution was slowly added dropwise to the mixed acid solution, and the mixture was added dropwise after 15 minutes. The reaction was completed by TLC, and the reaction was completed in 70 min.
  • Test compound Compound H-03
  • the adherent tumor cells in the logarithmic growth phase were inoculated into the 96-well culture plate at 200 ⁇ L/well, and the cells were added for 24 hours after adherent growth, and 3 wells were set for each concentration. The corresponding concentration of physiological saline vehicle control and cell-free zero-adjustment were set. Tumor cells were cultured for 72 h at 37 ° C under 5% CO 2 .
  • TCA trichloroacetic acid
  • the fixing solution was discarded, washed 5 times with distilled water, and naturally dried in the air.
  • the supernatant was removed, washed 5 times with 1% acetic acid, and air dried.
  • the OD value was measured by an enzyme-linked immunosorbent assay and zeroed with a blank control at a wavelength of 515 nm.
  • inhibition rate [(OD 515 control well- OD 515 administration well ) / OD 515 control well ] x 100%.
  • the half-inhibitory concentration IC50 was calculated by the Logit method according to the respective concentration inhibition rates. Each of the above experiments was repeated 2-3 times, and the average IC 50 value of 2-3 experiments was determined as a final index.
  • SRB Sulfonyl rhodamine protein staining
  • test results In the example concentration of 1.0 ⁇ 10 -5 mol/L, the inhibition rate was 93.61% ⁇ 0.68%, indicating that the test compound has an inhibitory effect on BEL-7402 cells.
  • Test compound Compound H-03
  • Inoculated cells A single cell suspension was prepared by using a culture solution containing 10% fetal calf serum, and seeded into a 96-well plate at a volume of 1000-10000 cells per well at a volume of 200 ⁇ L per well.
  • Cultured cells cultured for 3-5 days under the same general culture conditions (the culture time can be determined according to the purpose and requirements of the test).
  • Model principle There is a dehydrogenase associated with NADP in the mitochondria of living cells, which can reduce the yellow MTT to insoluble blue-purple onychomycosis (Formanzan). The dead cells disappear and the MTT is not reduced. This model detects the effect of the sample on tumor cells based on the degree of reduction of MTT.
  • Test compound Compound H-03
  • Inoculated cells A single cell suspension was prepared by using a culture solution containing 10% fetal calf serum, and seeded into a 96-well plate at a volume of 1000-10000 cells per well at a volume of 200 ⁇ L per well.
  • Cultured cells cultured for 3-5 days under the same general culture conditions (the culture time can be determined according to the purpose and requirements of the test).
  • Model principle There is a dehydrogenase associated with NADP in the mitochondria of living cells, which can reduce the yellow MTT to insoluble blue-purple onychomycosis (Formanzan). The dead cells disappear and the MTT is not reduced. This model detects the swelling of the sample according to the degree of reduction of MTT. The role of tumor cells.

Abstract

公开了通式（I）化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物：其中，X1、X2、X3、X4、R1、R2、x、y和z如本申请中所定义。

Description

双苄基异喹啉衍生物、其制备方法及其在肝病的治疗与预防中的用途
相关申请的引用
本申请要求于2014年8月15日向中华人民共和国国家知识产权局提交的发明名称为“双苄基异喹啉衍生物制备”的第201410403363.X号中国发明专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
领域
本申请大体上涉及有机化学与药物化学领域。
背景
双苄基异喹啉类生物碱具有多种生物活性，主要包括抗菌、抗炎、降压、抗肿瘤、抗血小板聚集、调节免疫功能、抗心律失常、抗肝纤维化等。
汉防己甲素，亦称粉防己碱，化学式为(6,6’,7,12-四甲氧基-2,2’-二甲基小檗胺)，是从中药材粉防己的块根中提取的双苄基异喹啉类生物碱，其化学结构式如下：
Figure PCTCN2015082626-appb-000001
概述
本申请一方面涉及，通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物：
Figure PCTCN2015082626-appb-000002
其中，
X1、X2、X3和X4各自独立地选自氢、卤素、硝基、亚硝基、-SO3H、任意取代的氨基或任意取代的磺酰基；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
条件是：
X1、X2、X3和X4不同时为氢；以及
当X1、X2、X3和X4中之一为卤素时，其余的X1、X2、X3和X4各自独立地选自氢、硝基、亚硝基、-SO3H、任意取代的氨基或任意取代的磺酰基，但不能同时为氢。
本申请另一方面涉及，通式(Ia)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物：
Figure PCTCN2015082626-appb-000003
其中，
R1选自亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的烷基羰基、任意取代的烯基羰基、任意取代的炔基羰基、任意取代的环烷基羰基、任意取代的芳基羰基、或任意取代的杂芳基羰基或取代的磺酰基；以及
R2选自氢、任意取代的烷基、亚硝基、任意取代的烷基羰基、任意取代的烯基羰基、任意取代的炔基羰基、任意取代的环烷基羰基、任意取代的芳基羰基、任意取代的杂芳基羰基或取代的磺酰基。
本申请再一方面涉及化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物，其中所述化合物选自：
Figure PCTCN2015082626-appb-000004
Figure PCTCN2015082626-appb-000005
Figure PCTCN2015082626-appb-000006
Figure PCTCN2015082626-appb-000007
Figure PCTCN2015082626-appb-000008
Figure PCTCN2015082626-appb-000009
Figure PCTCN2015082626-appb-000010
Figure PCTCN2015082626-appb-000011
本申请又一方面涉及药物组合物，其包含通式(I)化合物、通式(Ia)化合物、化合物H-01至H-55中任一化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物，以及药物可接受的载体。
本申请另一方面涉及制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
Figure PCTCN2015082626-appb-000012
其中，
X1、X2、X3和X4各自独立地为硝基；或者X1、X2、X3和X4各自独立地为氢或硝基，条件是：X1、X2、X3和X4不同时为氢；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行硝化反应，结构式如下
Figure PCTCN2015082626-appb-000013
本申请再一方面涉及制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
Figure PCTCN2015082626-appb-000014
其中，
X1、X2、X3和X4各自独立地为氨基；或者X1、X2、X3和X4各自独立地为氢或氨基，条件是：X1、X2、X3和X4不同时为氢；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的磺酰基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行硝化反应，然后将所得硝化产物进行还原反应。
本申请又一方面涉及制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
Figure PCTCN2015082626-appb-000015
其中，
X1、X2、X3和X4各自独立地为羰基取代的氨基；或者X1、X2、X3和X4各自独立地为氢或-NR3-C(＝O)-R4，条件是：X1、X2、X3和X4不同时为氢；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
R3选自氢、任意取代的烷基、任意取代的烯基、任意取代的炔基、 任意取代的环烷基、任意取代的芳基、任意取代的杂芳基；
R4选自任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的杂环基、任意取代的烷氧基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷氧基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行硝化反应，将所得硝化产物进行还原反应，以及将所得还原产物进行酰化反应。
本申请的再一方面涉及制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
Figure PCTCN2015082626-appb-000016
其中，
X1、X2、X3和X4各自独立地为磺酸基；或者X1、X2、X3和X4各自独立地为氢或-SO3H，条件是：X1、X2、X3和X4不同时为氢；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意 取代的炔基羰基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
其包括方法包括将小檗胺、汉防己甲素或汉防己乙素进行磺化反应。
本申请的再一方面涉及制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
Figure PCTCN2015082626-appb-000017
其中，
X1、X2、X3和X4各自独立地为氢或-NH-S(＝O)2-R6，条件是：X1、X2、X3和X4不同时为氢；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
R6选自任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的杂环基或任意取代的氨基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
其包括方法包括将小檗胺、汉防己甲素或汉防己乙素与浓硝酸进行硝化反应，再与铁粉发生还原反应生成氨基，氨基继而与酰氯在碱的催化下进行反应得到上述通式(I)化合物。
本申请其他方面涉及治疗或预防肝病的方法，其包括对需要所述方法的个体给予治疗有效量的通式(I)化合物、通式(Ia)化合物和化合物H-1至H-55中任一化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物或前述的药物组合物。
详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其它方法、部件、材料等的情况下可实现实施方案。
除非本申请中另外要求，在整个说明书和其后的权利要求书中，词语“包括(comprise)”及其英文变体例如“包括(comprises)”和“包括(comprising)”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提到的“一实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包括“催化剂”的反应包括一种催化剂，或两种或多种催化剂。还应当理解，术语“或”通常以其包括“和/或”的含义而使用，除非文中另外明确地规定。
定义
由表明在所示化学基团中找到的碳原子总数的简化符号在前面标示本文中命名的某些化学基团。例如，C7-C12烷基描述具有总数为7至12个碳原子的如下定义的烷基，并且C4-C12环烃基烷基描述具有总数为4至12个碳原子的如下定义的环烃基烷基。简化符号中碳原子总数并不包含可能存在于所述基团的取代基中的碳。
因此，除非另有相反的说明，否则说明书及所附权利要求中所用的下列术语具有以下的意思：
“羟基”指-OH基团。
“氰基”指-CN基团。
“硝基”指-NO2基团。
“亚硝基”指-N＝O基团。
“氨基”指-NH2基团。
“烷基”指仅由碳和氢原子组成的，不含不饱和键的，具有一至十二个碳原子的，尤其是具有一至八个碳原子或一至六个碳原子的，且由单键与分子的其余部分相连的直链或支链烃链基团，例如甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基、1,1-二甲基乙基(叔丁基)等。
烷基基团可以是任意取代的，亦即取代或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“C1-C4烷基”指含有一至四个碳原子的上述定义的烷基基团。C1-C4烷基基团可以如对烷基基团定义的那样被任意地取代。
“C1-C6烷基”指含有一至六个碳原子的上述定义的烷基基团。C1-C6烷基基团可以如对烷基基团定义的那样被任意地取代。
“C1-C12烷基”指含有一至十二个碳原子的上述定义的烷基基团。C1-C12烷基基团可以如对烷基基团定义的那样被任意地取代。
在某些实施方案中，烷基为C1-C4烷基。
在某些实施方案中，烷基为C1-C6烷基。
在某些实施方案中，烷基为C1-C12烷基。
“烯基”是指直链或支链的烃链基团，仅由碳与氢原子组成，含有至少一个双键，具有二至十二个碳原子，尤其是具有二至八个碳原子或二至六个碳原子，且其通过单键连接至分子的其余部份，例如乙烯基、丙-1-烯基、丁-1-烯基、戊-1-烯基、戊-1,4-二烯基等。本申请的烯基基团可以是取代的或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“C2-C6烯基”指含有二至六个碳原子的上述定义的烯基基团。C2-C6烯基基团可以如对烯基基团定义的那样被任意地取代。
“C2-C8烯基”指含有二至八个碳原子的上述定义的烯基基团。C2-C8烯基基团可以如对烯基基团定义的那样被任意地取代。
“C2-C12烯基”指含有二至十二个碳原子的上述定义的烯基基团。C2-C12烯基基团可以如对烯基基团定义的那样被任意地取代。
在某些实施方案中，烯基为C2-C6烯基。
在某些实施方案中，烯基为C2-C8烯基。
在某些实施方案中，烯基为C2-C12烯基。
“炔基”是指直链或支链的烃链基团，仅由碳与氢原子组成，含 有至少一个叁键，具有二至十二个碳原子，尤其是具有二至八个碳原子或二至六个碳原子，且其通过单键连接至分子的其余部份，例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。本申请的炔基基团可以是取代的或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“C2-C6炔基”指含有二至六个碳原子的上述定义的炔基基团。C2-C6炔基基团可以如对炔基基团定义的那样被任意地取代。
“C2-C8炔基”指含有二至八个碳原子的上述定义的炔基基团。C2-C8炔基基团可以如对炔基基团定义的那样被任意地取代。
“C2-C12炔基”指含有二至十二个碳原子的上述定义的炔基基团。C2-C12炔基基团可以如对炔基基团定义的那样被任意地取代。
在某些实施方案中，炔基为C2-C6炔基。
在某些实施方案中，炔基为C2-C8炔基。
在某些实施方案中，炔基为C2-C12炔基。
本申请所用的术语“卤素”指溴、氯、氟或碘。
“卤代烷基”指被一个或多个上述定义的卤素所取代的上述定义的烷基，例如三氟甲基、二氟甲基、三氯甲基、2,2,2-三氟乙基、1-氟甲基-2-氟乙基、3-溴-2-氟丙基、1-溴甲基-2-溴乙基等。卤代烷基的烷基部分可以如对上述烷基的定义那样被任意地取代。
“烷氧基”是指-OR基团，其中R为上述定义的烷基。
“环烷基”是指稳定的非芳族单环或多环烷基，仅由碳与氢原子组成，其可包含经稠合或桥接的环系统，具有三至十八个碳原子，尤其是具有三至十五个碳原子或三至十个碳原子，且其为饱和的，并通 过单键连接至分子的其余部份。单环基团包括例如环丙基、环丁基、环戊基、环己基、环庚基及环辛基。多环基团包括例如金刚烷基、降莰烷基、十氢萘基、7,7-二甲基-双环[2.2.1]庚烷基等。本申请的环烷基基团可以是取代的或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“C3-C18环烷基”指含有三至十八个碳原子的上述定义的环烷基基团。C3-C18环烷基基团可以如对环烷基基团定义的那样被任意地取代。
“C3-C15环烷基”指含有三至十五个碳原子的上述定义的环烷基基团。C3-C15环烷基基团可以如对环烷基基团定义的那样被任意地取代。
“C3-C10环烷基”指含有三至十个碳原子的上述定义的环烷基基团。C3-C10环烷基基团可以如对环烷基基团定义的那样被任意地取代。
在某些实施方案中，环烷基为C3-C18环烷基。
在某些实施方案中，环烷基为C3-C15环烷基。
在某些实施方案中，环烷基为C3-C10环烷基。
“芳基”是指芳族单环或多环烃环系统，仅由氢与碳组成，且含有六至十八个碳原子，尤其是具有六至十二个碳原子或六至十个碳原子，其中所述环系统可为部份饱和。芳基包括但不限于如苯基、萘基及芴基的基团。本申请的芳基基团可以是取代的或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O- 氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“C6-C18芳基”指含有六至十八个碳原子的上述定义的芳基基团。C6-C18芳基基团可以如对芳基基团定义的那样被任意地取代。
“C6-C12芳基”指含有六至十二个碳原子的上述定义的芳基基团。C6-C12芳基基团可以如对芳基基团定义的那样被任意地取代。
“C6-C10芳基”指含有六至十个碳原子的上述定义的芳基基团。C6-C10芳基基团可以如对芳基基团定义的那样被任意地取代。
在某些实施方案中，芳基为C6-C18芳基。
在某些实施方案中，芳基为C6-C12芳基。
在某些实施方案中，芳基为C6-C10芳基。
“杂芳基”指由碳原子和一至五个选自氮、氧和硫的杂原子组成的五至十八元的芳环基团。杂芳基基团可以是单环、双环、三环或四环环体系，其可以包含稠合的或桥联的环体系；并且杂芳基基团中的氮、碳或硫原子可以任意地被氧化；氮原子可以任意地季铵化。实例包括但不限于氮杂卓基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并噻二唑基、苯并萘并呋喃基、苯并噁唑基、苯并间二氧杂环戊烯基、苯并二噁英基、苯并吡喃基、苯并吡喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(苯并苯硫基)、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、噌啉基、二苯并呋喃基、呋喃基、噻吩基、呋喃酮基、异噻唑基、咪唑基、吲哚基、吲唑基、异吲哚基、二氢吲哚基、异二氢吲哚基、中氮茚基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂卓基、噁唑基、环氧乙烷基、吩嗪基、吩噻嗪基、吩噁嗪基、2,3-二氮杂萘基、喋啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、奎宁环基、异喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基以及苯硫基。
杂芳基基团可以是任意取代的，亦即取代或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“五元至十八元杂芳基”指由碳原子和一至五个选自氮、氧和硫的杂原子组成的五至十八元的芳环基团。五元至十八元杂芳基基团可以如对杂芳基基团定义的那样被任意地取代。
“五元至十二元杂芳基”指由碳原子和一至五个选自氮、氧和硫的杂原子组成的五至十二元的芳环基团。五元至十二元杂芳基基团可以如对杂芳基基团定义的那样被任意地取代。
“五元至十元杂芳基”指由碳原子和一至五个选自氮、氧和硫的杂原子组成的五至十元的芳环基团。五元至十元杂芳基基团可以如对杂芳基基团定义的那样被任意地取代。
在某些实施方案中，杂芳基为五元至十八元杂芳基。
在某些实施方案中，杂芳基为五元至十二元杂芳基。
在某些实施方案中，杂芳基为五元至十元杂芳基。
“杂环基”是指稳定的3至18元非芳环基团，其由2至12个碳原子和1至6个选自氮、氧和硫的杂原子组成。除非在说明书中另外具体规定，杂环基可为单环、双环、三环或四环体系，其可包括稠合或桥环体系；且可任意氧化杂环基中的氮、碳或硫原子；且所述杂环基可为部分或完全饱和的。这样的杂环基的实例包括但不限于二氧杂戊环、噻吩基[1,3]二噻烷基、十氢异喹啉基、咪唑啉基、咪唑烷基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、噁唑烷基、哌啶基、哌嗪基、4-哌啶酮基、吡咯烷 基、吡唑烷基、奎宁环基、噻唑烷基、四氢呋喃基、三噁烷基、三噻烷基、三嗪基、四氢吡喃基、硫代吗啉基、硫杂吗啉基、1-氧代-硫代吗啉基以及1,1-二氧代-硫代吗啉基。
“羰基”指碳原子与氧原子用双键相连的基团(即C(＝O)基团)。
“烷基羰基”指-C(＝O)R，其中R为上文定义的烷基基团。烷基羰基的实例包括但不限于-C(＝O)CH3、-C(＝O)CH2CH3、-C(＝O)CF3、-C(＝O)CCl3、-C(＝O)CClH2和-C(＝O)CH2CN。本申请的烷基羰基基团可以是取代的或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“烯基羰基”指-C(＝O)R，其中R为上文定义的烯基基团。烯基羰基的实例包括但不限于-C(＝O)CH＝CH2、-C(＝O)CH＝CHCH3、-C(＝O)CH＝CF2、-C(＝O)CH＝CCl2和-C(＝O)CH＝CHCH2CN。本申请的烯基羰基基团可以是取代的或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“炔基羰基”指-C(＝O)R，其中R为上文定义的炔基基团。炔基羰 基的实例包括但不限于-C(＝O)C≡CH、-C(＝O)CH2C≡CH、-C(＝O)C≡CF和-C(＝O)C≡CCH2CN。本申请的炔基羰基基团可以是取代的或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“芳基羰基”指-C(＝O)R，其中R为上文定义的芳基基团。芳基羰基的实例包括但不限于-C(＝O)Ph、-C(＝O)(PhCF3)、-C(＝O)(PhOMe)和-C(＝O)(PhNO2)。本申请的芳基羰基基团可以是取代的或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“杂芳基羰基”指-C(＝O)R，其中R为上文定义的杂芳基基团。杂芳基羰基的实例包括但不限于、2-噻吩甲酰基、2-呋喃甲酰基本申请的杂芳基羰基基团可以是取代的或未取代的。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N- 酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“磺酰基”指-S(＝O)2R基团，其中R可以是上文定义的烷基、环烃基、杂环基、芳基、杂芳基、羟基、氨基等基团。磺酰基的实例包括但不限于-S(＝O)2CH3(甲磺酰基)、-S(＝O)2CF3、-S(＝O)2CH2CH3和4-甲基苯磺酰基(甲苯磺酰基)。当被取代时，取代基团是单独地并且独立地选自下列的一个或多个基团：烷基、烯基、炔基、环烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、S-亚磺酰氨基、N-亚磺酰氨基、C-羧基、O-羧基、异氰酸根合、氰硫基、异硫氰酸根合、硝基、甲硅烷基、三卤代甲烷磺酰基、或包括单-和二-取代的氨基基团在内的氨基，及其被保护的衍生物。每当取代基被描述为被“任意取代的”时，取代基可被上述取代基之一取代。
“前药”旨在指可以在生理条件下或通过溶剂分解转化成本申请的生物活性化合物的化合物。因而，术语“前药”指药物可接受的本申请化合物的代谢前体。在对需要前药的个体给药时，前药可以是无活性的，但在体内前药可以转化成本申请的活性化合物。前药通常可在体内快速转化以获得本申请的母体化合物，例如通过血液中的水解。前药化合物通常在哺乳动物的有机体中提供溶解度、组织相容性或缓释的优点(参见Bundgard,H.,Design of Prodrugs(前药的设计)(1985),pp.7-9,21-24(Elsevier,Amsterdam))。
Higuchi,T.,et al,“Pro-drugs as Novel Delivery Systems(作为新颖输送系统的前药),”A.C.S.Symposium Series,(1975),Vol.14和Bioreversible Carriers in Drug Design(药物设计的生物可逆载体),ed.Edward B.Roche,American Pharmaceutical Association and Pergamon Press,1987中提供了前药的讨论，本文引入二者的全部内容作为参 考。
术语“前药”还旨在包括当将该前药对哺乳动物个体给药时，可以体内释放本申请活性化合物的任何共价键结合的载体。可以通过这样的方式修饰存在于本申请化合物中的官能团来制备本申请化合物的前药，以致使用常规操作或在体内均可以是修饰断裂而形成本申请的母体化合物。前药包含本申请化合物，其中羟基、氨基或巯基基团与任意基团成键，在对哺乳动物个体给予本申请化合物的前药时，所述的成键基团会断裂以分别形成游离的羟基、游离的氨基或游离的巯基。前药的实例包括但不限于本申请化合物中的醇或胺官能团的乙酸盐、甲酸盐和苯甲酸盐的衍生物等。
“任意的”或“任意地”指后续叙述的状况可能出现或可能不出现，并且该叙述包括所述事件或状况发生的情况和不发生的情况。例如，“任意取代的芳基”指芳基基团可能被取代或可能不被取代，并且该叙述包括取代的芳基基团和未取代的芳基基团。
“药物可接受的载体”包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。
“药物可接受的盐”包括“药物可接受的酸加合盐”和“药物可接受的碱加合盐”。
“药物可接受的酸加合盐”指保持游离碱的生物学有效性和性质的那些盐，所述酸加合盐是在生物学或其它方面合适的并且是使用无机酸或有机酸来形成的，所述无机酸例如但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等，所述有机酸例如但不限于乙酸、2,2-二氯乙酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯羧酸、4-乙酰胺基苯羧酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、甲酸、富马酸、粘酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、 乙醇酸、马尿酸、异丁酸、乳酸、乳糖醛酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲烷磺酸、黏酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
“药物可接受的碱加合盐”指保持游离酸的生物学有效性和性质的那些盐，所述碱加成盐是在生物学或其它方面合适的。向游离酸中加入无机碱或有机碱来制备这些盐。由无机碱衍生的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。优选的无机盐为铵、钠、钾、钙及镁盐。由有机碱衍生的盐包括但不限于伯、仲和叔胺的盐、包括天然存在的取代的胺在内的取代的胺、环胺和碱性离子交换树脂的盐，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、二甲氨基乙醇、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、苄胺、苯乙二胺、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。特别优选的有机碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
结晶经常会产生本申请化合物的溶剂化物。正如本文所用的那样，术语“溶剂化物”指包含带有一个或多个溶剂分子的一个或多个本申请化合物分子的聚集体。溶剂可以是水，在这种状况下，所述溶剂化物是水合物。或者，溶剂可以是有机溶剂。因此，本申请化合物可以以水合物的形式存在，包括一水合物、二水合物、半水合物、一倍半水合物、三水合物、四水合物等，以及以相应的溶剂化形式存在。本申请化合物可以是真正的溶剂化物，但在其它情况下，本申请化合物可以仅保有不定的水或该化合物是水和某些不定的溶剂的混合物。
“多晶型物”是指具有相同化学式但具有不同结构的组分。
“药物组合物”指本申请化合物与通常被本领域所接受的将生物活性化合物输送至诸如人类等哺乳动物的介质所形成的制剂。这样的介质包括所有药物可接受的载体、稀释剂或赋形剂。
含有通式(I)化合物或通式(Ia)的药物组合物，可按配方制造且作为以下剂型使用：供口服给药的片剂、胶囊或酏剂；供直肠给药的栓剂；供注射给药的无菌溶液，悬浮液；供透皮给药的贴片以及皮下沉积物等。注射剂可以下列常规形式制备：溶液或悬浮液、在注射前适合制成溶液或悬浮液的固体剂型、或乳剂。适合的赋形剂是，例如，水、盐水、葡萄糖、甘露醇、乳糖、卵磷脂、白蛋白、谷氨酸钠、半胱氨酸盐酸盐等。另外，如果需要，所述的注射用药物组合物可包含较少量的无毒性辅助物，例如湿润剂、pH缓冲剂等。如果需要，也可使用吸收增强剂(例如，脂质体)。
用于非肠道给药的制剂包括以水溶性形式存在的所述活性化合物的水溶液。另外，所述活性化合物的悬浮液可制备成合适的油状注射悬液。适合的亲脂性溶剂或载体包括诸如芝麻油的脂肪油，或其它诸如大豆油、柚油或杏仁油的有机油，或诸如油酸乙酯或甘油三酯的合成的脂肪酸酯，或脂质体。水性注射悬液可包含增加所述悬液粘度的物质，例如羧甲基纤维素钠、山梨糖醇或葡聚糖。任意地，所述的混悬液可包含适合的稳定剂或提高所述化合物的溶解性的试剂，使得可制备高浓度的溶液。
用于口服的药物制剂可通过下述方法获得：将所述的活性化合物与固体赋形剂结合，任意地碾磨所得的混合物，以及加工该颗粒混合物，如果需要，在加入适合的辅助剂后得到了片剂或糖衣剂核。适合的赋形剂是，具体而言，诸如糖的填充剂，包括乳糖、蔗糖、甘露醇或山梨糖醇；纤维素制剂例如玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、黄芪胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、和\或者聚乙烯吡咯酮(PVP)。如果需要，可加入崩解剂，例如交联聚乙烯吡咯烷酮、琼脂或藻酸或诸如藻酸钠的藻酸盐。对糖衣剂核进行适合的包被。为了这个目的，可使用浓缩的糖溶液，该溶液可任意地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚羧乙烯凝胶、聚乙二醇和\或二氧化钛、紫胶漆溶液和适合的有机溶剂或溶剂混合物。为了识别或表示活性化合物剂量的不同组合的特征，可向片剂或糖衣剂包衣中加入染料或色素。使用本领域中公知的方法可制造这些制剂。
本申请还涉及在制药领域中公知的用于包括眼内的、鼻内的和耳内的输送的各种药物组合物。药物配方包括所述活性化合物的水性眼用溶液，其可以诸如滴眼剂的水溶性形式存在，或以结冷胶或水凝胶；眼用软膏；眼用混悬液，例如微粒，悬浮在液体载体介质中的包含药物的小聚合粒子，脂溶性制剂，和微球；以及眼用嵌入剂。为了稳定性和舒适性，这些合适的药物制剂最经常和优选地制造成无菌的、等渗的和缓冲的制剂。药物组合物也包括滴剂和喷雾剂，其常在许多方面模拟鼻分泌物来确保正常纤毛作用的维持。正如本领域的技术人员公知的那样，合适的制剂最常和优选地是等渗的，保持pH值5.5到6.5的轻度缓冲的，且最经常和优选地包括抗菌性防腐剂和适当的药物稳定剂。用于耳内转运的药物制剂包括悬浮液和在耳内局部应用的软膏。用于这些耳用制剂的普通溶剂包括甘油和水。
通式(I)化合物、通式(Ia)化合物或包含通式(I)化合物或通式(Ia)化合物的药物组合物可通过口服或非口服途径给药。当口服给药时，它可以以胶囊、片剂、颗粒剂、喷雾剂、糖浆剂或其它剂型给药。当非口服给药时，它可以以水性悬浮液、油性制剂等或以滴剂、栓剂、油膏剂、软膏剂等给药，当注射给药时，通过皮下、腹膜内、静脉内、肌内等方式给药。
“治疗有效量”指当对哺乳动物，优选对人类给药时，本申请化合物足以有效治疗(如下定义)哺乳动物的的疾病或疾病状态的量。根据化合物、疾病状态及其严重性、以及待治疗哺乳动物的年龄，构成“治疗有效量”的本申请化合物的量将会不同，但是本领域的技术人员根据其自身的知识以及本公开可以依惯例确定本申请化合物的量。
本文所用的“进行治疗”或“治疗”涵盖患有相关疾病或病症的哺乳动物，优选人类中治疗相关的疾病或疾病状态，并且包括：
(i)预防疾病或疾病状态在哺乳动物中发生，尤其是当该哺乳动物易感于所述疾病状态，但尚未被诊断出患有这种疾病状态时；
(ii)抑制疾病或疾病状态，即阻止其发生；或者
(iii)缓解疾病或疾病状态，即使疾病或疾病状态消退。
正如本文所用的那样，术语“疾病”和“疾病状态”可以相互交 换使用，或者可以是不同的，因为特殊的疾病或疾病状态可能并没有已知的致病因子(因此不能用病因学解释)，因此其不被公认为是疾病，而是被认为是不期望的疾病状态或病症，其中临床医生已经鉴定出或多或少的特定系列的症状。
本申请化合物或其药物可接受性盐可以含一个或多个不对称中心，并且因此可以产生对映异构体、非对映异构体、以及其它立体异构形式，可以根据绝对立体化学将其定义为(R)-或(S)-，或氨基酸的(D)-或(L)-。本申请旨在包括所有这些可能的异构体，以及其外消旋形式和光学纯的形式。可使用手性合成子(chiral synthon)或手性试剂制备旋光的(+)和(-)、(R)-和(S)-、或(D)-和(L)-异构体，或使用常规技术进行拆分，如使用手性柱的HPLC。当本文所述的化合物含有烯双键或其它几何不对称中心时，除非另有说明，否则意味着化合物包括E和Z几何异构体。同样，还意味着包括所有的互变异构形式。
“立体异构体”指由相同的键键合的相同的原子组成的，但具有不可互换的不同三维结构的化合物。本申请涵盖各种立体异构体及其混合物。
本文中所用的“接触”指使两种或多种物质靠近至可以相互作用。
具体实施方案
本申请一方面涉及，通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物：
Figure PCTCN2015082626-appb-000018
其中，
X1、X2、X3和X4各自独立地选自氢、卤素、硝基、亚硝基、-SO3H、任意取代的氨基或任意取代的磺酰基；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
条件是：
X1、X2、X3和X4不同时为氢；以及
当X1、X2、X3和X4中之一为卤素时，其余的X1、X2、X3和X4各自独立地选自氢、硝基、亚硝基、-SO3H、任意取代的氨基或任意取代的磺酰基，但不能同时为氢。
在某些实施方案中，X1、X2、X3和X4各自独立地选自氢、卤素、硝基、亚硝基、氨基、-SO3H、-NR3-C(＝O)-R4、-NR5-S(＝O)2-R6或-S(＝O)2-R7；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
R3和R5各自独立地选自氢、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基；
R4选自任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的杂环基、任意取代的烷氧基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷氧基羰基、任意取代的烷基羰基、任意取代的 烯基羰基或任意取代的炔基羰基；
R6和R7各自独立地选自任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的杂环基或任意取代的氨基；
x为1至3的整数；
y为1至4的整数；
z为1至2的整数；以及
条件是：
X1、X2、X3和X4不同时为氢；以及
当X1、X2、X3和X4中之一为卤素时，其余的X1、X2、X3和X4各自独立地选自氢、硝基、亚硝基、氨基、-SO3H、-NR3-C(＝O)-R4、-NR5-S(＝O)2-R6或-S(＝O)2-R7，但不能同时为氢。
在某些实施方案中，x为1、2或3。
在某些实施方案中，y为1、2、3或4。
在某些实施方案中，z为1或2。
在某些实施方案中，X1、X2、X3和X4各自独立地选自氢、卤素、硝基、亚硝基、-SO3H、任意取代的烷基羰基取代的氨基、任意取代的烯基羰基取代的氨基、任意取代的炔基羰基取代的氨基、任意取代的烷氧基羰基取代的氨基、任意取代的环烷基羰基取代的氨基、任意取代的芳基羰基取代的氨基、任意取代的杂环基羰基取代的氨基、任意取代的氨基羰基取代的氨基、任意取代的杂芳基羰基取代的氨基、任意取代的烷氧基羰基羰基取代的氨基、任意取代的烷基磺酰基取代的氨基、任意取代的烯基磺酰基取代的氨基、任意取代的炔基磺酰基取代的氨基、任意取代的烷氧基磺酰基取代的氨基、任意取代的芳基磺酰基取代的氨基、任意取代的杂环基磺酰基取代的氨基、任意取代的杂芳基磺酰基取代的氨基、任意取代的氨基磺酰基取代的氨基、任意取代的芳基氨基取代的磺酰基或任意取代的烷基取代的磺酰基。
在某些实施方案中，X1、X2、X3和X4各自独立地选自氢、卤素、硝基、亚硝基、-SO3H、烷基羰基取代的氨基、羟基取代的烷基羰基取代的氨基、酯基取代的烷基羰基取代的氨基、烯基羰基取代的氨基、 烷氧基羰基取代的氨基、芳基取代的烷氧基羰基取代的氨基、卤素取代的芳基羰基取代的氨基、烷氧基取代的芳基羰基取代的氨基、卤代烷基取代的芳基羰基取代的氨基、烷氧基羰基羰基取代的氨基、杂环基羰基取代的氨基、烷基磺酰基取代的氨基、芳烷基磺酰基取代的氨基、芳基磺酰基取代的氨基、硝基取代的芳基磺酰基取代的氨基、烷基取代的芳基磺酰基取代的氨基、卤素取代的芳基磺酰基取代的氨基、烷基取代的氨基磺酰基取代的氨基、芳基氨基取代的磺酰基或烷氧基取代的烷基取代的磺酰基。
在某些实施方案中，R1选自氢、亚硝基、烷基、芳基取代的烷基、芳基、烷基羰基或芳基羰基。
在某些实施方案中，x为1，并且X2选自卤素、硝基、亚硝基、氨基、-SO3H、烷基羰基取代的氨基、羟基取代的烷基羰基取代的氨基、酯基取代的烷基羰基取代的氨基、烯基羰基取代的氨基、芳基取代的烯基羰基取代的氨基、烷氧基羰基取代的氨基、芳基取代的烷氧基羰基取代的氨基、芳基羰基取代的氨基、卤素取代的芳基羰基取代的氨基、烷氧基取代的芳基羰基取代的氨基、卤代烷基取代的芳基羰基取代的氨基、烷氧基羰基羰基取代的氨基、杂环基羰基取代的氨基、杂芳基羰基取代的氨基、烷基磺酰基取代的氨基、芳烷基磺酰基取代的氨基、芳基磺酰基取代的氨基、硝基取代的芳基磺酰基取代的氨基、烷基取代的芳基磺酰基取代的氨基、卤素取代的芳基磺酰基取代的氨基、烷基取代的氨基磺酰基取代的氨基、芳基氨基取代的磺酰基或烷氧基取代的烷基取代的磺酰基。
在某些实施方案中，y为4，并且X3为氢。
在某些实施方案中，z为2，并且X4为氢。
在某些实施方案中，X1为氢。
在某些实施方案中，x为2，并且X2中的一个为氢，X2中的另一个选自氨基、硝基、亚硝基、-SO3H、Br、Cl、甲基羰基氨基、异丙基羰基氨基、异丁基羰基氨基、乙烯基羰基氨基、苯乙烯基羰基氨基、2-甲基丙烯基羰基氨基、2-甲基丙基氧基羰基氨基、羟基甲基羰基氨基、甲基羰基氧基甲基羰基氨基、甲氧基羰基羰基氨基、呋喃基羰基 氨基、噻吩基羰基氨基、吗啉基羰基氨基、苯基羰基氨基、2-氯苯基羰基氨基、4-氯苯基羰基氨基、4-甲氧基苯基羰基氨基、三氟甲基苯基羰基氨基、苯甲基氧基羰基氨基、甲基磺酰基氨基、苯基磺酰基氨基、2-硝基苯基磺酰基氨基、4-硝基苯基磺酰基氨基、4-甲基苯基磺酰基氨基、4-氯苯基磺酰基氨基、2,4-二氯苯基磺酰基氨基、苯甲基磺酰基氨基、二甲基氨基磺酰基氨基、苯基氨基磺酰基或甲氧基甲基磺酰基。
在某些实施方案中，R2为烷基。
在某些实施方案中，R2为C1-C6烷基。
在某些实施方案中，R2为甲基。
在某些实施方案中，R1为烷基，并且R2为烷基。
在某些实施方案中，R1为C1-C6烷基，并且R2为C1-C6烷基。
在某些实施方案中，R1甲基，并且R2为甲基。
在某些实施方案中，R1为烷基，并且R2为氢。
在某些实施方案中，R1为C1-C6烷基，并且R2为氢。
在某些实施方案中，R1为甲基，并且R2为氢。
在某些实施方案中，X1为卤素，X2、X3和X4各自独立地选自硝基、亚硝基、氨基、-SO3H、-NR3-C(＝O)-R4、-NR5-S(＝O)2-R6或-S(＝O)2-R7。
在某些实施方案中，X1为卤素，X2选自硝基和/或磺酸基，X3和X4为氢，x为1。
在某些实施方案中，x为1，X2位于C-14位。
在某些实施方案中，x为2，X2分别位于C-10位和C-14位。
在某些实施方案中，X3和X4为氢。
在某些实施方案中，R1选自氢、亚硝基、任意取代的C1-C6烷基、任意取代的苯基羰基或任意取代的C1-C6烷基羰基。
在某些实施方案中，R1选自氢、甲基、苄基、苯甲酰基、亚硝基或乙酰基。
在某些实施方案中，R1选自氢、甲基、苄基、苯甲酰基、亚硝基或乙酰基；和/或
R2为甲基；和/或
X1为氢、硝基或卤素(卤素优选为Br或Cl)；和/或
x为1或2，且至少一个X2为氢、氨基、硝基、亚硝基、-SO3H、Br、Cl、甲基羰基氨基、异丁基羰基氨基、乙烯基羰基氨基、苯乙烯基羰基氨基、2-甲基丙烯基羰基氨基、2-甲基丙基氧基羰基氨基、羟基甲基羰基氨基、甲基羰基氧基甲基羰基氨基、甲氧基羰基羰基氨基、呋喃基羰基氨基、噻吩基羰基氨基、吗啉基羰基氨基、苯基羰基氨基、2-氯苯基羰基氨基、4-氯苯基羰基氨基、4-甲氧基苯基羰基氨基、三氟甲基苯基羰基氨基、苯甲基氧基羰基氨基、甲基磺酰基氨基、苯基磺酰基氨基、2-硝基苯基磺酰基氨基、4-硝基苯基磺酰基氨基、4-甲基苯基磺酰基氨基、4-氯苯基磺酰基氨基、2,4-二氯苯基磺酰基氨基、苯甲基磺酰基氨基、二甲基氨基磺酰基氨基、苯基氨基磺酰基或甲氧基甲基磺酰基；和/或
y为3，且X3为氢；和/或
z为2，且X4为氢，
条件是：
X1、X2、X3和X4不同时为氢，以及
当X1、X2、X3和X4中之一为卤素时，其余的X1、X2、X3和X4不同时为氢。
本申请另一方面涉及，通式(Ia)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物：
Figure PCTCN2015082626-appb-000019
其中，
R1选自亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的烷基羰基、任意取代的烯基羰基、任意取代的炔基羰基、任意取代的环烷基羰基、任意取代的芳基羰基、任意取代的杂芳基羰基或任意取代的磺酰基；以及
R2选自氢、任意取代的烷基、亚硝基、任意取代的烷基羰基、任意取代的烯基羰基、任意取代的炔基羰基、任意取代的环烷基羰基、任意取代的芳基羰基或任意取代的杂芳基羰基或任意取代的磺酰基。
在某些实施方案中，R1选自卤素取代的烷基羰基、卤素取代的烯基羰基、卤素取代的炔基羰基、卤素取代的环烷基羰基、卤素取代的芳基羰基或卤素取代的杂芳基羰基。
在某些实施方案中，R1选自氰基取代的烷基羰基、氰基取代的烯基羰基、氰基取代的炔基羰基、氰基取代的环烷基羰基、氰基取代的芳基羰基或氰基取代的杂芳基羰基。
在某些实施方案中，R1选自羟基取代的烷基羰基、羟基取代的烯基羰基、羟基取代的炔基羰基、羟基取代的环烷基羰基、羟基取代的芳基羰基或羟基取代的杂芳基羰基。
在某些实施方案中，R1选自硝基取代的烷基羰基、硝基取代的烯基羰基、硝基取代的炔基羰基、硝基取代的环烷基羰基、硝基取代的芳基羰基或硝基取代的杂芳基羰基。
在某些实施方案中，R1选自任意取代的烷基取代的烷基羰基、任意取代的烷基取代的烯基羰基、任意取代的烷基取代的炔基羰基、任意取代的烷基取代的环烷基羰基、任意取代的烷基取代的芳基羰基或任意取代的烷基取代的杂芳基羰基。
在某些实施方案中，R1选自任意取代的烷氧基取代的烷基羰基、任意取代的烷氧基取代的烯基羰基、任意取代的烷氧基取代的炔基羰基、任意取代的烷氧基取代的环烷基羰基、任意取代的烷氧基取代的芳基羰基或任意取代的烷氧基取代的杂芳基羰基。
在某些实施方案中，R1选自三氟甲基羰基、氯甲基羰基或3-三氟甲基苯基羰基。
以上实施方案中的各基团或取代基可以任意组合。
本申请再一方面涉及化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物，其中所述化合物选自：
Figure PCTCN2015082626-appb-000020
Figure PCTCN2015082626-appb-000021
Figure PCTCN2015082626-appb-000022
Figure PCTCN2015082626-appb-000023
Figure PCTCN2015082626-appb-000024
Figure PCTCN2015082626-appb-000025
Figure PCTCN2015082626-appb-000026
本申请又一方面涉及药物组合物，其包含通式(I)化合物、通式(Ia)化合物、化合物H-01至H-55中任一化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物，以及药物可接受的载体。
能够用于本申请的药物组合物的剂型的示例性实例包括但不限于片剂、胶囊剂、丸剂、栓剂、乳剂、膏剂、注射剂和输注剂。
本申请另一方面涉及制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
Figure PCTCN2015082626-appb-000027
其中，
X1、X2、X3和X4各自独立地为硝基；或者X1、X2、X3和X4各自独立地为氢或硝基，条件是：X1、X2、X3和X4不同时为氢；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行硝化反应。
在某些实施方案中，使用乙酸酐与硝酸的混酸进行所述硝化反应。
在某些实施方案中，使用非极性溶剂作为溶剂进行所述硝化反应。
能够用于上述硝化反应的非极性溶剂的示例性实例包括但不限于二氯甲烷、氯仿和1,2-二氯乙烷。
在某些实施方案中，在约-10℃至约5℃的温度下进行所述硝化反应。
在某些实施方案中，在约0℃下进行所述硝化反应。
在某些实施方案中，在惰性气体的氛围中进行所述硝化反应。
能够用于上述硝化反应的惰性气体的示例性实例包括但不限于氩气、氦气和氮气。
本申请再一方面涉及制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
Figure PCTCN2015082626-appb-000028
其中，
X1、X2、X3和X4各自独立地为氨基；或者X1、X2、X3和X4各自独立地为氢或氨基，条件是：X1、X2、X3和X4不同时为氢；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行硝化反应，然后将所得硝化产物进行还原反应。
在某些实施方案中，使用NaBH4进行所述还原反应。
在某些实施方案中，使用NiCl2·6H2O为催化剂进行所述还原反应。
在某些实施方案中，在约-15℃至约0℃的温度下进行所述还原反应。
在某些实施方案中，在冰浴中进行所述还原反应。
在某些实施方案中，使用极性非质子溶剂作为溶剂进行所述还原反应。
能够用于上述还原反应的非质子溶剂的示例性实例包括但不限于四氢呋喃、1,4-二氧六环和二甲基甲酰胺。
本申请又一方面涉及制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
Figure PCTCN2015082626-appb-000029
其中，
X1、X2、X3和X4各自独立地为羰基取代的氨基；或者X1、X2、X3和X4各自独立地为氢或-NR3-C(＝O)-R4，条件是：X1、X2、X3和X4不同时为氢；
R1选自氢、任意取代的烷基、亚硝基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的磺酰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行硝化反应，将所得硝化产物进行还原反应，以及将所得还原产物进行酰化反应。
在某些实施方案中，使用酰卤化合物或磺酰卤化合物进行所述酰 化反应。
在某些实施方案中，使用碱性溶剂作为溶剂进行所述酰化反应。
能够用于上述酰化反应的碱性溶剂的示例性实例包括但不限于吡啶、二乙胺的二氯甲烷溶液和三乙胺的二氯甲烷溶液。
在某些实施方案中，在约0℃至室温的温度下进行所述酰化反应。
在某些实施方案中，在冰浴中进行所述酰化反应。
在某些实施方案中，在惰性气体的氛围中进行所述酰化反应。
能够用于上述酰化反应的惰性气体的示例性实例包括但不限于氩气、氦气和氮气。
本申请的再一方面涉及制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
Figure PCTCN2015082626-appb-000030
其中，
X1、X2、X3和X4各自独立地为磺酸基；或者X1、X2、X3和X4各自独立地为氢或-SO3H，条件是：X1、X2、X3和X4不同时为氢；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行磺化反应。
在某些实施方案中，使用硫酸盐和浓硫酸进行所述磺化反应。
在某些实施方案中，使用非极性溶剂作为溶剂进行所述磺化反应。
能够用于本申请的非极性溶剂的示例性实例包括但不限于二氯甲烷作、氯仿和1,2-二氯乙烷。
在某些实施方案中，在约-15℃至约0℃的温度下进行所述磺化反应。
在某些实施方案中，在冰浴中进行所述磺化反应。
本申请的再一方面涉及制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
Figure PCTCN2015082626-appb-000031
其中，
X1、X2、X3和X4各自独立地为氢或-NH-S(＝O)2-R6，条件是：X1、X2、X3和X4不同时为氢；
R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
R6选自任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的杂环基或任意取代的氨基；
x为1至3的整数；
y为1至4的整数；以及
z为1至2的整数；
其包括方法包括将小檗胺、汉防己甲素或汉防己乙素与浓硝酸进行硝化反应，再与铁粉发生还原反应生成氨基，氨基继而与酰氯在碱的催化下进行反应得到上述通式(I)化合物。
本申请其他方面涉及治疗或预防肝病的方法，其包括对需要所述方法的个体给予治疗有效量的通式(I)化合物、通式(Ia)化合物和化合物H-1至H-55中任一化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物或前述的药物组合物。
在某些实施方案中，所述个体为哺乳动物。
在某些实施方案中，所述哺乳动物为人类。
在某些实施方案中，肝病为病毒性肝病或非病毒性肝病。
能够使用本申请化合物治疗或预防的肝病的示例性实例包括但不限于肝炎、酒精性肝病、药物或毒物性肝病、新陈代谢异常性肝病和脂肪性肝病。
在某些实施方案中，所述肝病为肝肿瘤、肝硬化和肝纤维化。
实施例
虽然任何本领域技术人员能够依据上述公开的一般技术来制备本申请化合物，但为方便起见，本说明书中的其它地方提供更加详细的本申请化合物的合成技术。另外，本领域技术人员已知合成中所使用的所有试剂及反应条件并且可以由普通的商品来源获得。
实施例1
汉防己甲素硝化衍生物H-27的制备
0℃下配置混酸溶液，Ar保护下，向10mL圆底烧瓶中加入1.5mL(CH3CO)2O，搅拌下缓慢滴加浓硝酸0.6mL，搅拌5min后将温度降至-10℃，向混酸溶液中缓慢滴加500mg(0.8mmol)汉防己甲素的3mL无水氯仿溶液，15min滴加完，TLC检测，70min反应完全，加水终 止反应。浓氨水调pH至碱性，氯仿萃取完全，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，得固体610mg。氯仿:甲醇＝50:1过柱纯化，得纯品化合物H-27(496mg，收率92％)。
Figure PCTCN2015082626-appb-000032
波谱数据
质谱数据使用Agilent MS-5973质谱仪获得，核磁数据使用VarianINOVA-400核磁共振波谱仪获得。
H-27C38H41N3O8；EI-MS:m/z667.32[M]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.42(1H,s,H-13),7.37(1H,dd,J＝2.0,8.0Hz,H-14′),7.12(1H,dd,J＝2.4,8.0Hz,H-13′),6.77(1H,dd,J＝2.8,8.4Hz,H-11′),6.54(1H,s,H-10),6.52(1H,s,H-5′),6.30(1H,s,H-5),6.28(1H,d,J＝2.0Hz,H-10′),5.98(1H,s,H-8′),3.98(3H,s,12-OCH3),3.91(1H,dd,J＝6.0,10.8Hz,H-1′),3.75(3H,s,6-OCH3),3.66(1H,m,H-1),3.38(3H,s,6′-OCH3),3.18(3H,s,7-OCH3),2.63(3H,s,2′-NCH3),2.21(3H,s,2-NCH3)。
使用与实施例1类似的方法制得H-28(收率43％)，其中加入混酸比例不变，体积为4mL，反应时间延长到200min。
Figure PCTCN2015082626-appb-000033
波谱数据
H-28C38H40N4O10；ESI-MS:m/z713.74[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.42(1H,s,H-13),7.39(1H,dd,J＝2.4,8.4Hz,H-14′),7.15(1H,dd,J＝2.8,8.4Hz,H-13′),6.77(1H,dd,J＝2.4,8.4Hz,H-11′),6.55(1H,s,H-10),6.52(1H,s,H-5′),6.30(1H,dd,J＝2.0,8.4Hz,H-10′),6.00(1H,s,H-8′),3.99(3H,s,12-OCH3),3.79(3H,s,6-OCH3),3.44(3H,s,6′-OCH3),3.21(3H,s,7-OCH3),2.66(3H,s,2′-NCH3),2.20(3H,s,2-NCH3)。
实施例2
汉防己甲素硝化还原衍生物H-29的制备
取H-27干燥样品100mg(0.15mmol)于25mL圆底烧瓶中，加入2mL四氢呋喃搅拌至样品完全溶解，0℃下，向反应体系中加入1mL甲醇溶解的10.8mg(0.046mmol)NiCl2·6H2O，搅拌，加入28.4mg(0.75mmol)NaBH4固体，冰浴下反应20min后，TLC检测反应完全，停止反应，反应物倾倒入冰水中，氯仿萃取三次，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，得固体96mg。氯仿：甲醇＝50:1过柱纯化，得H-29(78mg，收率78％)，H-30(12mg，收率12％)。
Figure PCTCN2015082626-appb-000034
波谱数据
H-29C38H43N3O6；ESI-MS:m/z638.52[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.28(1H,d,J＝9.6Hz,H-14′),7.18(1H,dd,J＝2.0,8.0Hz,H-13′),6.60(1H,dd,J＝2.0,8.4Hz,H-11′),6.50(1H,s,H-10), 6.46(1H,s,H-5′),6.31(1H,s,H-5),6.29(1H,s,H-13),6.12(1H,dd,J＝1.6,8.0Hz,H-10′),5.87(1H,s,H-8′),3.94(1H,d,J＝9.2Hz,H-1′),3.87(3H,s,12-OCH3),3.80(1H,dd,J＝5.2,11.2Hz,H-1),3.73(3H,s,6-OCH3),3.35(3H,s,6′-OCH3),3.11(3H,s,7-OCH3),2.61(3H,s,2′-NCH3),2.42(3H,s,2-NCH3)。
H-30C38H41N3O7；ESI-MS:m/z652.34[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.33(1H,dd,J＝2.4,8.4Hz,H-14′),7.21(1H,dd,J＝2.4,8.0Hz,H-13′),6.60(1H,dd,J＝2.8,8.4Hz,H-11′),6.50(1H,s,H-13),6.47(1H,s,H-10),6.32(1H,s,H-5),6.31(1H,s,H-5′),6.04(1H,dd,J＝2.4,8.4Hz,H-10′),5.89(1H,s,H-8′),3.92(1H,m,H-1′),3.88(3H,s,12-OCH3),3.80(1H,m,H-1),3.75(3H,s,6-OCH3),3.49(3H,s,6′-OCH3),3.36(3H,s,7-OCH3),2.66(3H,s,2′-NCH3),2.42(3H,s,2-NCH3)。
实施例3
汉防己甲素酰胺化和磺酰胺化衍生物的制备
取干燥H-29样品50mg(0.08mmol)于10mL圆底烧瓶中，Ar保护下，0℃加入1.5mL吡啶，搅拌溶解样品，再加入1.5倍量的酰氯，TLC检测反应，3h至4h反应完全，停止反应。将混合反应液倒入冰水中，饱和NaHCO3水溶液调节pH至碱性，氯仿萃取3次，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，所得固体氯仿：甲醇＝40:1过柱，分离得纯品。
除了使用相应的酰氯原料以外，使用与实施例3相同的方法得到甲素酰胺和磺酰胺类化合物26个(H-01至H-26,收率40％～80％不等)。
Figure PCTCN2015082626-appb-000035
Figure PCTCN2015082626-appb-000036
Figure PCTCN2015082626-appb-000037
Figure PCTCN2015082626-appb-000038
波谱数据
H-01C40H45N3O7；ESI-MS:m/z680.23[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.02(1H,s,-CONH-),7.90(1H,s,H-13),7.30(1H,dd,J＝1.6,8.0Hz,H-14′),7.22(1H,dd,J＝2.4,8.0Hz,H-13′),6.59(1H,d,J＝2.8Hz,H-11′),6.57(1H,s,H-10),6.47(1H,s,H-5′),6.32(1H,s,H-5),6.13(1H,dd,J＝2.0,8.4Hz,H-10′),5.89(1H,s,H-8′),3.99(1H,d,J＝9.2Hz,H-1′),3.94(3H,s,12-OCH3),3.82(1H,dd,J＝5.2,11.2Hz,H-1),3.75(3H,s,6-OCH3),3.37(3H,s,6′-OCH3),3.10(3H,s,7-OCH3),2.61(3H,s,2′-NCH3),2.51(3H,s,2-NCH3)。
H-02C45H47N3O7；ESI-MS:m/z742.51[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.27(1H,s,-CONH-),7.81(1H,s,H-13),7.36(1H,dd,J＝1.6,10.0Hz,H-14′),7.24(1H,dd,J＝2.4,10.4Hz,H-13′),6.63(1H,d,J＝2.4Hz,H-11′),6.62(1H,s,H-10),6.48(1H,s,H-5′),6.25(1H,s,H-5),6.15(1H,dd,J＝2.0,8.4Hz,H-10′),5.90(1H,s,H-8′),4.04(1H,d,J＝9.2Hz,H-1′),3.97(3H,s,12-OCH3),3.84(1H,d,J＝6.0Hz,H-1),3.72(3H,s,6-OCH3),3.37(3H,s,6′-OCH3),3.10(3H,s,7-OCH3),2.62(3H,s,2′-NCH3),2.47(3H,s,2-NCH3)。
H-03C45H46ClN3O7；ESI-MS:m/z776.26[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.80(1H,s,-CONH-),8.10(1H,s,H-13),7.31(1H,dd,J＝2.0,8.4Hz,H-14′),7.23(1H,dd,J＝2.4,8.0Hz,H-13′),6.60(1H,d,J＝2.4Hz,H-11′),6.59(1H,s,H-10),6.45(1H,s,H-5′),6.21(1H,s,H-5),6.14(1H,dd,J＝1.6,8.4Hz,H-10′),5.88(1H,s,H-8′),4.00(3H,s,12-OCH3),3.93(1H,d,J＝9.2Hz,H-1′),3.81(1H,dd,J＝5.2,11.2Hz,H-1),3.71(3H,s,6-OCH3),3.33(3H,s,6′-OCH3),3.07(3H,s,7-OCH3),2.60(3H,s,2′-NCH3),2.17(3H,s,2-NCH3)。
H-04C46H49N3O8；ESI-MS:m/z772.54[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.76(1H,s,H-13),7.32(1H,dd,J＝1.6,7.6Hz, H-14′),7.23(1H,dd,J＝2.8,8.0Hz,H-13′),6.63(1H,d,J＝2.8Hz,H-11′),6.61(1H,s,H-10),6.49(1H,s,H-5′),6.26(1H,s,H-5),6.15(1H,dd,J＝2.0,8.4Hz,H-10′),5.90(1H,s,H-8′),4.04(1H,d,J＝9.2Hz,H-1′),3.96(3H,s,12-OCH3),3.84(1H,dd,J＝5.2,10.4Hz,H-1),3.72(3H,s,6-OCH3),3.37(3H,s,6′-OCH3),3.10(3H,s,7-OCH3),2.63(3H,s,2′-NCH3),2.49(3H,s,2-NCH3)。
H-05C46H46N3O7F3；ESI-MS:m/z810.57[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.42(1H,s,CONH),7.80(1H,s,H-13),7.32(1H,dd,J＝2.4,8.4Hz,H-14′),7.23(1H,dd,J＝2.4,8.0Hz,H-13′),6.63(1H,s,H-10),6.61(1H,dd,J＝2.8,8.4Hz,H-11′),6.48(1H,s,H-5′),6.25(1H,s,H-5),6.15(1H,dd,J＝2.0,8.4Hz,H-10′),5.89(1H,s,H-8′),4.04(1H,d,J＝9.2Hz,H-1′),3.97(3H,s,12-OCH3),3.80(1H,dd,J＝5.6,10.8Hz,H-1),3.72(3H,s,6-OCH3),3.37(3H,s,6′-OCH3),3.08(3H,s,7-OCH3),2.60(3H,s,2′-NCH3),2.47(3H,s,2-NCH3)。
H-06C45H46N3O7Cl；ESI-MS:m/z776.32[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.30(1H,s,CONH),7.75(1H,s,H-13),7.32(1H,dd,J＝2.0,8.4Hz,H-14′),7.23(1H,dd,J＝2.4,8.0Hz,H-13′),6.62(1H,s,H-10),6.60(1H,d,J＝2.4Hz,H-11′),6.48(1H,s,H-5′),6.26(1H,s,H-5),6.15(1H,dd,J＝2.0,8.4Hz,H-10′),5.89(1H,s,H-8′),4.04(1H,d,J＝9.2Hz,H-1′),3.96(3H,s,12-OCH3),3.82(1H,dd,J＝5.6,11.2Hz,H-1),3.75(3H,s,6-OCH3),3.37(3H,s,6′-OCH3),3.09(3H,s,7-OCH3),2.61(3H,s,2′-NCH3),2.47(3H,s,2-NCH3)。
H-07C43H51N3O7；ESI-MS:m/z772.55[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):10.39(1H,s,CONH),7.82(1H,s,H-13),7.31(1H,d,J＝7.2Hz,H-14′),7.20(1H,d,J＝8.0Hz,H-13′),6.62(1H,s,H-10),6.61(1H,s,H-11′),6.47(1H,s,H-5′),6.32(1H,s,H-5),6.15(1H,d,J＝8.0Hz,H-10′),5.87(1H,s,H-8′),3.98(1H,d,J＝8.8Hz,H-1′),3.95(3H,s,12-OCH3),3.82(1H,dd,J＝5.2,10.4Hz,H-1),3.75(3H,s,6-OCH3),3.36(3H,s,6′-OCH3),3.08(3H,s,7-OCH3),2.61(3H,s,2′-NCH3),2.41(3H,s,2-NCH3)。
H-08C43H51N3O8；ESI-MS:m/z738.38[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):11.93(1H,s,CONH),7.72(1H,s,H-13),7.30(1H,dd,J＝2.0,8.4Hz,H-14′),7.21(1H,dd,J＝2.8,8.4Hz,H-13′),6.60(1H,dd,J＝2.4,8.4Hz,H-11′),6.52(1H,s,H-10),6.48(1H,s,H-5′),6.31(1H,s,H-5),6.15(1H,dd,J＝2.0,8.4Hz,H-10′),5.90(1H,s,H-8′),3.97(1H,s,H-1′),3.94(3H,s,12-OCH3),3.92(2H,m,CH2),3.83(1H,m,H-1),3.74(3H,s,6-OCH3),3.37(3H,s,6′-OCH3),3.11(3H,s,7-OCH3),2.61(3H,s,2′-NCH3),2.46(3H,s,2-NCH3)。
H-09C47H49N3O7；ESI-MS:m/z768.56[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.36(1H,s,CONH),8.11(1H,s,H-13),7.78(1H,d,J＝15.6Hz,CH＝CH),7.30(1H,dd,J＝2.0,8.4Hz,H-14′),7.23(1H,dd,J＝2.4,8.0Hz,H-13′),6.61(1H,s,H-10),6.58(1H,d,J＝2.4,8.4Hz,H-11′),6.51(1H,s,CH＝CH),6.47(1H,s,H-5′),6.33(1H,s,H-5),6.13(1H,dd,J＝2.0,8.4Hz,H-10′),5.89(1H,s,H-8′),4.06(1H,d,J＝8.8Hz,H-1′),3.98(3H,s,12-OCH3),3.80(1H,m,H-1),3.75(3H,s,6-OCH3),3.48(3H,s,6′-OCH3),3.09(3H,s,7-OCH3),2.60(3H,s,2′-NCH3),2.58(3H,s,2-NCH3)。
H-10C41H45N3O7；ESI-MS:m/z692.54[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.24(1H,s,CONH),8.05(1H,s,H-13),7.30(1H,d,J＝7.6Hz,H-14′),7.22(1H,dd,J＝2.4,8.4Hz,H-13′),6.59(1H,s,H-10),6.56(1H,s,H-11′),6.47(1H,s,H-5′),6.31(1H,s,H-5),6.13(1H,d,J＝7.6Hz,H-10′),5.89(1H,s,H-8′),4.01(1H,d,J＝9.2Hz,H-1′),3.95(3H,s,12-OCH3),3.80(1H,dd,J＝5.2,10.8Hz,H-1),3.74(3H,s,6-OCH3),3.36(3H,s,6′-OCH3),3.09(3H,s,7-OCH3),2.60(3H,s,2′-NCH3),2.51(3H,s,2-NCH3)。
H-11C43H49N3O7；ESI-MS:m/z720.5[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):11.88(1H,s,CONH),7.99(1H,s,H-13),7.29(1H,dd,J＝2.4,8.0Hz,H-14′),7.21(1H,dd,J＝2.4,8.4Hz,H-13′),6.59(1H,d,J＝2.4Hz,H-11′),6.57(1H,s,H-10),6.47(1H,s,H-5′),6.31(1H,s,H-5),6.12(1H,dd,J＝2.0,8.4Hz,H-10′),5.88(1H,s,H-8′),3.99(1H,d, J＝9.2Hz,H-1′),3.96(3H,s,12-OCH3),3.80(1H,dd,J＝5.6,11.2Hz,H-1),3.75(3H,s,6-OCH3),3.36(3H,s,6′-OCH3),3.10(3H,s,7-OCH3),2.60(3H,s,2′-NCH3),2.50(3H,s,2-NCH3)。
H-12C40H45N3O8；ESI-MS:m/z696.3[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.47(1H,s,CONH),7.88(1H,s,H-13),7.31(1H,dd,J＝2.0,8.0Hz,H-14′),7.22(1H,dd,J＝2.4,8.0Hz,H-13′),6.58(1H,dd,J＝2.4,8.4Hz,H-11′),6.57(1H,s,H-10),6.47(1H,s,H-5),6.31(1H,s,H-5′),6.14(1H,dd,J＝2.0,8.4Hz,H-10′),5.89(1H,s,H-8′),3.98(1H,s,H-1′),3.95(3H,s,12-OCH3),3.81(1H,dd,J＝5.6,11.2Hz,H-1),3.75(3H,s,6-OCH3),3.36(3H,s,6′-OCH3),3.10(3H,s,7-OCH3),2.60(3H,s,2′-NCH3),2.47(3H,s,2-NCH3)。
H-13C42H47N3O9；ESI-MS:m/z738.3[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.36(1H,s,CONH),7.86(1H,s,H-13),7.30(1H,dd,J＝2.0,8.0Hz,H-14′),7.21(1H,dd,J＝2.8,8.0Hz,H-13′),6.58(1H,dd,J＝2.8,8.4Hz,H-11′),6.57(1H,s,H-10),6.47(1H,s,H-5),6.31(1H,s,H-5′),6.13(1H,dd,J＝2.4,8.8Hz,H-10′),5.89(1H,s,H-8′),3.98(1H,m,H-1′),3.93(3H,s,12-OCH3),3.79(1H,m,H-1),3.75(3H,s,6-OCH3),3.36(3H,s,6′-OCH3),3.10(3H,s,7-OCH3),2.60(3H,s,2′-NCH3),2.50(3H,s,2-NCH3)。
H-14C41H45N3O9；ESI-MS:m/z:724.3[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):13.49(1H,s,CONH),7.90(1H,s,H-13),7.33(1H,dd,J＝2.0,8.0Hz,H-14′),7.22(1H,dd,J＝2.8,8.0Hz,H-13′),6.61(1H,dd,J＝2.8,8.4Hz,H-11′),6.60(1H,s,H-10),6.49(1H,s,H-5′),6.32(1H,s,H-5),6.14(1H,dd,J＝2.0,8.8Hz,H-10′),5.90(1H,s,H-8′),3.96(3H,s,12-OCH3),3.87(1H,dd,J＝5.6,11.2Hz,H-1′),3.75(3H,s,6-OCH3),3.37(3H,s,6′-OCH3),3.11(3H,s,7-OCH3),2.62(3H,s,2′-NCH3),2.49(3H,s,2-NCH3)。
H-15C43H45N3O8；ESI-MS:m/z732.5[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.44(1H,s,CONH),7.86(1H,s,H-13),7.31(1H,dd,J＝2.0,8.0Hz,H-14′),7.22(1H,dd,J＝3.2,8.4Hz,H-13′),6.64(1H, d,J＝2.8Hz,H-11′),6.62(1H,s,H-10),6.48(1H,s,H-5′),6.31(1H,s,H-5),6.14(1H,dd,J＝2.0,8.4Hz,H-10′),5.90(1H,s,H-8′),4.03(1H,d,J＝8.8Hz,H-1′),3.96(3H,s,12-OCH3),3.81(1H,dd,J＝5.6,11.2Hz,H-1),3.75(3H,s,6-OCH3),3.37(3H,s,6′-OCH3),3.10(3H,s,7-OCH3),2.60(3H,s,2′-NCH3),2.54(3H,s,2-NCH3)。
H-16C43H45N3O7S；ESI-MS:m/z748.3[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.07(1H,s,-CONH-),7.68(1H,s,H-13),7.31(1H,dd,J＝2.0,8.4Hz,H-14′),7.23(1H,dd,J＝3.2,8.4Hz,H-13′),6.23(1H,s,H-10),6.30(1H,d,J＝2.4Hz,H-11′),6.48(1H,s,H-5′),6.28(1H,s,H-5),6.15(1H,dd,J＝2.0,10.4Hz,H-10′),5.89(1H,s,H-8′),4.06(1H,d,J＝9.2Hz,H-1′),3.95(3H,s,12-OCH3),3.81(1H,dd,J＝5.6,11.2Hz,H-1),3.73(3H,s,6-OCH3),3.38(3H,s,6′-OCH3),3.09(3H,s,7-OCH3),2.60(3H,s,2′-NCH3),2.54(3H,s,2-NCH3)。
H-17C39H45N3O8S；ESI-MS:m/z716.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.36(1H,dd,J＝2.4,8.4Hz,H-14′),7.06(1H,dd,J＝2.4,8.0Hz,H-13′),6.96(1H,s,H-13),6.88(1H,dd,J＝2.8,8.4Hz,H-11′),6.80(1H,s,H-10),6.52(1H,s,H-5′),6.35(1H,d,J＝2.0Hz,H-10′),6.33(1H,s,H-5),5.93(1H,s,H-8′),3.96(3H,s,12-OCH3),3.85(1H,m,H-1′),3.75(3H,s,6-OCH3),3.36(3H,s,6′-OCH3),3.20(3H,s,7-OCH3),2.17(3H,s,2′-NCH3),2.07(3H,s,2-NCH3)。
H-18C44H47N3O8S；ESI-MS:m/z778.3[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.29(1H,d,J＝2.0Hz,H-14′),7.24(1H,s,H-13),7.17(1H,dd,J＝2.8,8.0Hz,H-13′),6.55(1H,dd,J＝2.4,8.4Hz,H-11′),6.46(1H,s,H-10),6.40(1H,s,H-5′),6.29(1H,s,H-5),6.12(1H,dd,J＝2.0,8.8Hz,H-10′),5.84(1H,s,H-8′),3.93(3H,s,12-OCH3),3.85(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.73(3H,s,6-OCH3),3.35(3H,s,6′-OCH3),3.07(3H,s,7-OCH3),2.58(3H,s,2′-NCH3),2.50(3H,s,2-NCH3)。
H-19C44H46N4O10S；ESI-MS:m/z823.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.30(1H,d,J＝2.0Hz,H-14′),7.28(1H,s,H-13), 7.18(1H,dd,J＝2.8,8.4Hz,H-13′),6.55(1H,dd,J＝2.8,8.8Hz,H-11′),6.46(1H,s,H-10),6.39(1H,s,H-5′),6.30(1H,s,H-5),6.13(1H,dd,J＝2.0,8.4Hz,H-10′),5.85(1H,s,H-8′),3.95(3H,s,12-OCH3),3.90(1H,d,J＝8.8Hz,H-1′),3.77(1H,dd,J＝5.6,11.2Hz,H-1),3.73(3H，s,6-OCH3),3.35(3H,s,6′-OCH3),3.07(3H,s,7-OCH3),2.57(3H,s,2′-NCH3),2.54(3H,s,2-NCH3)。
H-20C45H49N3O8S；ESI-MS:m/z792.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.28(1H,d,J＝6.8Hz,H-14′),7.25(1H,s,H-13),7.15(1H,d,J＝8.0Hz,H-13′),6.55(1H,dd,J＝1.6,8.0Hz,H-11′),6.46(1H,s,H-10),6.40(1H,s,H-5′),6.30(1H,s,H-5),6.12(1H,d,J＝7.6Hz,H-10′),5.84(1H,s,H-8′),3.93(3H,s,12-OCH3),3.84(1H,d,J＝9.2Hz,H-1′),3.79(1H,dd,J＝5.2,11.2Hz,H-1),3.73(3H,s,6-OCH3),3.35(3H,s,6′-OCH3),3.07(3H,s,7-OCH3),2.59(3H,s,2′-NCH3),2.49(3H,s,2-NCH3)。
H-21C44H46N4O10S；ESI-MS:m/z823.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.25(1H,d,J＝2.0Hz,H-14′),7.16(1H,dd,J＝2.4,8.0Hz,H-13′),6.90(1H,s,H-13),6.50(1H,dd,J＝2.4,8.4Hz,H-11′),6.48(1H,s,H-10),6.44(1H,s,H-5′),6.36(1H,s,H-5),6.11(1H,dd,J＝1.6,8.4Hz,H-10′),5.88(1H,s,H-8′),4.14(1H,d,J＝9.6Hz,H-1′),3.88(1H,m,H-1),3.79(3H,s,12-OCH3),3.77(3H,s,6-OCH3),3.38(3H,s,6′-OCH3),3.11(3H,s,7-OCH3),2.69(3H,s,2′-NCH3),2.58(3H,s,2-NCH3)。
H-22C44H45N3O8ClS；ESI-MS:m/z846.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.27(1H,dd,J＝2.0,8.0Hz,H-14′),7.16(1H,dd,J＝2.4,8.0Hz,H-13′),6.84(1H,s,H-13),6.51(1H,dd,J＝2.8,8.4Hz,H-11′),6.48(1H,s,H-10),6.45(1H,s,H-5′),6.33(1H,s,H-5),6.12(1H,dd,J＝2.0,8.4Hz,H-10′),5.88(1H,s,H-8′),4.02(1H,d,J＝9.2Hz,H-1′),3.78(3H,s,12-OCH3),3.77(1H,s,H-1),3.75(3H,s,6-OCH3),3.38(3H,s,6′-OCH3),3.10(3H,s,7-OCH3),2.61(3H,s,2′-NCH3),2.58(3H,s,2-NCH3)。
H-23C45H49N3O8S；ESI-MS:m/z792.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.33-7.29(7H,m,H-Ph,13,14′),7.22(1H,dd,J＝2.4,8.0Hz,H-13′),6.54(1H,dd,J＝2.8,8.4Hz,H-11′),6.49(1H,s,H-10),6.46(1H,s,H-5′),6.24(1H,s,H-5),6.14(1H,dd,J＝2.0,8.8Hz,H-10′),5.86(1H,s,H-8′),3.94(3H,s,12-OCH3),3.78(2H,m,H-1′,1),3.73(3H,s,6-OCH3),3.34(3H,s,6′-OCH3),3.08(3H,s,7-OCH3),2.58(3H,s,2′-NCH3),2.30(3H,s,2-NCH3)。
H-24C44H46N3O8ClS；ESI-MS:m/z812.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.29(1H,dd,J＝2.0,8.4Hz,H-14′),7.24(1H,s,H-13),7.18(1H,dd,J＝2.4,8.0Hz,H-13′),6.56(1H,dd,J＝2.8,8.4Hz,H-11′),6.46(1H,s,H-10),6.41(1H,s,H-5′),6.30(1H,s,H-5),6.13(1H,dd,J＝2.0,8.4Hz,H-10′),5.85(1H,s,H-8′),3.94(3H,s,12-OCH3),3.83(2H,m,H-1′,1),3.74(3H,s,6-OCH3),3.35(3H,s,6′-OCH3),3.08(3H,s,7-OCH3),2.58(3H,s,2′-NCH3),2.50(3H,s,2-NCH3)。
H-25C40H48N4O8S；ESI-MS:m/z745.3[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.28(1H,dd,J＝2.4,8.0Hz,H-14′),7.18(1H,dd,J＝2.4,8.0Hz,H-13′),6.61(1H,dd,J＝2.4,8.0Hz,H-11′),6.50(1H,s,H-13),6.46(1H,s,H-10),6.31(1H,s,H-5′),6.29(1H, s,H-5),6.12(1H,dd,J＝2.0,8.4Hz,H-10′),5.87(1H,s,H-8′),3.94(1H,m,H-1′),3.88(3H,s,12-OCH3),3.81(1H,m,H-1),3.74(3H,s,6-OCH3),3.35(3H,s,6′-OCH3),3.11(3H,s,7-OCH3),2.88(6H,s,CH3),2.59(3H,s,2′-NCH3),2.42(3H,s,2-NCH3)。
H-26C43H50N4O8S；ESI-MS:m/z716.3[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):10.19(1H,s,-CONH-),7.32(1H,s,H-13),7.29(1H,dd,J＝1.6,8.0Hz,H-14′),7.21(1H,dd,J＝2.4,8.0Hz,H-13′),6.59(1H,s,H-10),6.58(1H,d,J＝2.4Hz,H-11′),6.46(1H,s,H-5′),6.30(1H,s,H-5),6.12(1H,dd,J＝2.0,8.4Hz,H-10′),5.87(1H,s,H-8′),3.98(1H,d,J＝9.2Hz,H-1′),3.93(3H,s,12-OCH3),3.74(3H,s,6-OCH3),3.35(3H,s,6′-OCH3),3.09(3H,s,7-OCH3),2.60(3H,s,2′-NCH3),2.43(3H,s,2-NCH3)。
实施例4
汉防己乙素苯基和苄基衍生物的制备
实验操作：取汉防己乙素干燥样品50mg(0.08mmol)于10mL圆底烧瓶中，Ar保护下，加入2mL无水DMF，再加入7mg NaH(0.16mmol,55％)，搅拌均匀，滴加20μL BnBr(0.16mmol)，室温反应8h，TLC检测反应完全，停止反应。加入饱和NH4Cl终止反应，将混合液倾倒入冰水中，氯仿萃取3次，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，所得固体过200至300目硅胶(15g)，氯仿：甲醇＝30:1，得纯品H-31(15mg，收率21％)。
Figure PCTCN2015082626-appb-000039
波谱数据
H-31C51H53N2O6；ESI-MS:m/z790.5[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.02(1H,dd,J＝2.4,8.0Hz,H-14′),6.98(1H,d,J＝8.0Hz,H-13′),6.90(1H,d,J＝2.0Hz,H-14),6.88(1H,d,J＝4.0Hz,H-13),6.65(1H,s,H-10),6.55(1H,dd,J＝2.4,8.0Hz,H-11′),6.53(1H,s,H-5′),6.48(1H,dd,J＝2.4,8.0Hz,H-10′),6.33(1H,s,H-5),5.68(1H,s,H-8′),3.89(3H,s,12-OCH3),3.80(3H,s,6-OCH3),3.76(1H,d,J＝4.8Hz,H-1′),3.44(3H,s,6′-OCH3),2.83(3H,s,2′-NCH3),2.60(3H,s,2-NCH3)。
实施例5
汉防己乙素硝化和氧化衍生物的制备
实验操作：0℃下配置混酸溶液，Ar保护下，向10mL圆底烧瓶之后加入0.8mL(CH3CO)2O，搅拌下缓慢滴加浓硝酸0.5mL，搅拌5 min后将温度降至-10℃，向混酸溶液中缓慢滴加50mg(0.07mmol)H-31的1mL无水氯仿溶液，10min滴加完，TLC检测1.5h反应完全，加水终止反应。浓氨水调pH至碱性，氯仿萃取完全，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，得固体48mg。氯仿：甲醇：二乙胺＝40:1:0.1过柱纯化，得纯品H-38(46mg，收率92％)。
除使用化合物H-31代替H-32，使用与实施例6相同方法由化合物H-32合成得到硝化产物H-39(收率90％)。
Figure PCTCN2015082626-appb-000040
Figure PCTCN2015082626-appb-000041
波谱数据
H-32C44H45N3O8；ESI-MS:m/z744.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.42(1H,s,H-13),7.37(1H,dd,J＝2.0,8.0Hz,H-14′),7.13(1H,dd,J＝2.4,8.0Hz,H-13′),6.75(1H,dd,J＝2.4,8.0Hz,H-11′),6.52(1H,s,H-10),6.51(1H,s,H-5′),6.33(1H,s,H-5),6.29(1H,dd,J＝2.0,8.4Hz,H-10′),5.85(1H,s,H-8′),3.99(3H,s,12-OCH3),3.81(2H,m,H-1′,1),3.72(3H,s,6-OCH3),3.38(3H,s,6′-OCH3),2.49(3H,s,2′-NCH3),2.22(3H,s,2-NCH3)。
H-33C44H43N3O9；EI-MS:m/z757[M]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.42(1H,s,H-13),7.34(1H,d,J＝7.6Hz,H-14′),7.30(1H,d,J＝3.2Hz,H-13′),6.74(1H,d,J＝3.2Hz,H-11′),6.60(1H,s,H-10),6.46(1H,s,H-5′),6.40(1H,s,H-5),6.22(1H,m,H-10′),5.75(1H,s,H-8′),3.98(3H,s,12-OCH3),3.74(1H,m,H-1′),3.69(3H,s,6-OCH3),3.59 (1H,m,H-1),3.53(3H,s,6′-OCH3),2.24(3H,s,2′-NCH3),1.91(3H,s,2-NCH3)。
实施例6
汉防己乙素硝化氧化和还原衍生物的制备
实验操作：
a、取干燥样品H-33100mg(0.13mmol)于10mL圆底烧瓶中，加入2.0mL AcOH搅拌至样品完全溶解，分三次加入还原铁粉74mg(1.32mmol)，升温至60℃，TLC检测，5.5h反应完全。停止搅拌，降至室温，将反应混合溶液倾倒入冰水中，饱和Na2CO3水溶液调pH至碱性，氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，得固体79mg。氯仿：甲醇：二乙胺＝40:1:0.1过柱纯化，得纯品H-33还原产物H-34(60mg,65％)。
b、取上步反应干燥样品H-3460mg(0.08mmol)于10mL圆底烧瓶中，Ar保护下，0℃加入1.5mL吡啶，搅拌溶解样品，再加入16μL(0.12mmol)邻氯苯甲酰氯，TLC检测反应，4h反应完全，停止反应。将混合反应液倒入冰水中，饱和NaHCO3水溶液调节pH至碱性，氯仿萃取3次，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，得固体58mg，氯仿：甲醇：二乙胺＝40:1:0.1过柱，分离得纯品H-35(35mg，收率：50％)。
Figure PCTCN2015082626-appb-000042
Figure PCTCN2015082626-appb-000043
波谱数据
H-34C44H47N3O6；ESI-MS:m/z727.8[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.37(1H,d,J＝8.0Hz,H-14′),7.24(1H,s,H-13),7.17(1H,d,J＝6.8Hz,H-13′),6.56(1H,m,H-11′),6.41(1H,s,H-10),6.34(1H,s,H-5′),6.31(1H,s,H-5),6.03(1H,dd,J＝8.0,3.2Hz,H-10′),5.80(1H,s,H-8′),4.00(3H,s,12-OCH3),3.63(3H,s,6-OCH3),3.39(3H,s,6′-OCH3),2.22(3H,s,2′-NCH3),2.05(3H,s,2-NCH3)。
H-35C51H48N3O8Cl；ESI-MS:m/z866.4[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.77(1H,s,-CONH-),7.56-8.07(5H,m,H-Bz),7.37(1H,d,J＝8.0Hz,H-14′),7.24(1H,s,H-13),7.17(1H,d,J＝6.8Hz,H-13′),6.56(1H,m,H-11′),6.41(1H,s,H-10),6.34(1H,s,H-5′),6.31(1H,s,H-5),6.03(1H,dd,J＝2.0,8.4Hz,H-10′),5.80(1H,s,H-8′),4.00(3H,s,12-OCH3),3.96-3.67(3H,m,H-1′,1,3b),3.63(3H,s,6-OCH3),3.43(1H,s,H-3′b),3.39(3H,s,6′-OCH3),2.22(3H,s,2′-NCH3),2.14(2H,m,H-15b,4a),2.05(3H,s,2-NCH3)。
实施例7
硝化混合取代衍生物
实验操作：取干燥样品H-27100mg(0.15mmol)于10mL圆底烧瓶中，加入2.0mL三氟乙酸搅拌至样品完全溶解，冰浴下分两次加入N-溴代丁二酰亚胺57mg(0.32mmol)，继续冰浴反应30min后升温至室温，4h后反应完全。将反应混合液倾倒入冰水中，饱和Na2CO3水溶液调pH至10后以氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤，减压回收氯仿，得粗品102mg。以氯仿：甲醇：二乙胺＝50:1:0.1过柱纯化，得纯品H-27的还原产物H-36(83mg,收率75％)。
Figure PCTCN2015082626-appb-000044
波谱数据
H-36C38H39Br2N3O8；ESI-MS:m/z826.3[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.45(1H,s,H-13),7.43(1H,dd,J＝2.4,8.4Hz,H-14′),7.17(1H,dd,J＝2.4,8.4Hz,H-13′),6.78(1H,dd,J＝2.0,8.0Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝2.0,8.4Hz,H-10′),6.13(1H,s,H-8′),4.00(3H,s,12-OCH3),3.63(3H,s,6-OCH3),3.39(3H,s,6′-OCH3),2.22(3H,s,2′-NCH3),2.05(3H,s,2-NCH3)。
实施例8
化合物H-37、H-38和H-39的制备
取干燥样品汉防己甲素100mg(0.15mmol)于10mL圆底烧瓶中，加入2.13mg(0.015mmol)无水Na2SO4，再加入2.0mL二氯甲烷搅拌至样品完全溶解，冰浴下于15min内滴加27μL(1.5mmol)浓硫酸，继续冰浴反应1h后升温至室温，10h后反应完全。将反应混合液倾倒入冰水中，饱和Na2CO3水溶液调pH至10后以氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤，减压回收氯仿，得粗品102mg。以氯仿：甲醇：二乙胺＝50:1:0.1过柱纯化，制备得到化合物H-37(95mg,收率90％)。
Figure PCTCN2015082626-appb-000045
波谱数据
H-37C38H41N2O9S；ESI-MS:m/z703.4[M+H]+；1H-NMR(CDCl3,500MHz)δ(ppm):12.32(1H,s,H-S),7.81(1H,s,H-13),7.35(1H,dd,J＝1.6,8.2Hz,H-14′),7.18(1H,dd,J＝2.5,8.2Hz,H-13’),6.75(1H,s,H-10),6.68(1H,dd,J＝2.5,8.4Hz,H-11’),6.52(1H,s,H-5’),6.43(1H,s,H-5),6.19(1H,dd,J＝1.7,8.4Hz,H-10’),5.94(1H,s,H-8’),3.97(3H,s,12-OCH3),3.91(1H,dd,J＝5.9,10.6Hz,H-1’),3.78(3H,s,6-OCH3),3.42(1H,m,H-1),3.38(3H,s,6′-OCH3),3.18(3H,s,7-OCH3),2.84(3H,s,2′-NCH3),2.65(3H,s,2-NCH3)。
取干燥样品化合物H-37100mg(0.15mmol)于10mL圆底烧瓶中，再加入2.0mL二甲基甲酰胺搅拌至样品完全溶解，冰浴下于15min内滴加11μL(1.5mmol)二氯亚砜，继续冰浴反应1h后滴加溶解有14mg苯胺的1mL二甲基甲酰胺溶液，升温至100℃反应10h后反应完全。将反应混合液倾倒入冰水中，饱和NaHCO3水溶液调pH至7后以氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤，减压回收氯仿，得粗品102mg。以氯仿：甲醇：二乙胺＝50:1:0.1过柱纯化，制备得到化合物H-38(87mg,收率75％)。
Figure PCTCN2015082626-appb-000046
波谱数据
H-38C44H47N3O8S；ESI-MS:m/z778.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.55(2H,dd,J＝2.2,8.8Hz,H-Ph),7.35(1H,dd,J＝7.4,14.8Hz,H-Ph),7.18(2H,t,J＝8.0,15.2Hz,H-Ph),7.09(1H,d,J＝2.0Hz,H-14′),7.05(1H,s,H-13),7.01(1H,dd,J＝2.8,8.0Hz,H-13′),6.55(1H,dd,J＝2.4,8.4Hz,H-11′),6.46(1H,s,H-10),6.40(1H,s,H-5′),6.29(1H,s,H-5),6.12(1H,dd,J＝2.0,8.8Hz,H-10′),5.84(1H,s,H-8′),3.93(3H,s,12-OCH3),3.85(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.73(3H,s,6-OCH3),3.42(1H,m,H-15′b), 3.35(3H,s,6′-OCH3),3.07(3H,s,7-OCH3),＝2.58(3H,s,2′-NCH3),2.50(3H,s,2-NCH3)。
除使用溶解有9.0μL甲醇的二甲基甲酰胺溶液替代溶解有14mg苯胺的1mL二甲基甲酰胺溶液外，使用制备化合物H-38的方法制备得到化合物H-39(收率81％)。
Figure PCTCN2015082626-appb-000047
波谱数据
H-39C39H44N2O9S；ESI-MS:m/z717.4[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.78(1H,s,H-13),7.50(1H,dd,J＝2.0,8.4Hz,H-14’),7.25(1H,dd,J＝2.8,8.4Hz,H-13’),6.75(1H,dd,J＝2.8,8.4Hz,H-11’),6.66(1H,s,H-10),6.65(1H,s,H-5’),6.45(1H,s,H-5),6.24(1H,dd,J＝2.0,8.4Hz,H-10’),6.02(1H,s,H-8’),4.00(3H,s,12-OCH3),3.82(1H,dd,J＝5.7,10.6Hz,H-1′),3.79(3H,s,6-OCH3),3.48(1H,m,H-1),3.45(3H,s,14-SO2-OCH3),3.20(3H,s,6′-OCH3),3.06(3H,s,7-OCH3),2.78(3H,s,2′-NCH3),2.57(3H,s,2-NCH3)。
实施例9
化合物H-36、化合物H-40、化合物H-41、化合物H-43和化合物H-44的制备
1.取干燥样品化合物H-27100mg(0.15mmol)于10mL圆底烧瓶中，再加入2.0mL三氟乙酸搅拌至样品完全溶解，冰浴下分两批加入65mg N-溴代丁二酰亚胺，继续冰浴反应30min后恢复至室温，反应5h后反应完全。将反应混合液倾倒入冰水中，饱和NaHCO3水溶液调pH至7后以氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥， 过滤，减压回收氯仿，得粗品93mg。以氯仿：甲醇：二乙胺＝50:1:0.1过柱纯化，制备得到化合物H-36(78mg)。
除使用浓硫酸与Na2SO4代替混酸外，使用制备化合物H-36的方法制备得到化合物H-40。
除使用65mg N-溴代丁二酰亚胺代替32mg N-溴代丁二酰亚胺，使用浓硫酸代替混酸外，使用制备化合物H-36的方法制备得到化合物H-41。
除使用32mg N-氯代丁二酰亚胺代替32mg N-溴代丁二酰亚胺外，使用制备化合物H-36的方法制备得到化合物H-43。
除使用65mg N-氯代丁二酰亚胺代替32mg N-溴代丁二酰亚胺外，使用制备化合物H-36的方法制备得到化合物H-44。
Figure PCTCN2015082626-appb-000048
Figure PCTCN2015082626-appb-000049
波谱数据：
H-36C38H39Br2N3O8；ESI-MS:m/z825.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.43(1H,s,H-13),7.42(1H,dd,J＝1.6,6.4Hz,H-14′),7.16(1H,dd,J＝2.0,6.8Hz,H-13′),6.78(1H,dd,J＝2.0,6.8Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝1.6,6.8Hz,H-10′),6.04(1H,s,H-8′),4.00(3H,s,12-OCH3),3.85(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.71(3H,s,6-OCH3),3.45(1H,m,H-15′b), 3.29(3H,s,6′-OCH3),3.28(3H,s,7-OCH3),2.64(3H,s,2′-NCH3),2.21(3H,s,2-NCH3).
H-40C38H41BrN2O9S；ESI-MS:m/z782.1[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.45(1H,s,H-13),7.43(1H,dd,J＝2.0,8.4Hz,H-14′),7.11(1H,dd,J＝2.0,8.4Hz,H-13′),6.86(1H,s,H-10),6.78(1H,dd,J＝2.0,6.8Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝1.6,6.8Hz,H-10′),6.04(1H,s,H-8′),4.00(3H,s,12-OCH3),3.85(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝2.4,8.0Hz,H-1),3.71(3H,s,6-OCH3),3.45(1H,m,H-15′b),3.29(3H,s,6′-OCH3),3.28(3H,s,7-OCH3),2.64(3H,s,2′-NCH3),2.21(3H,s,2-NCH3).
H-41C38H40Br2N2O9S；ESI-MS:m/z860.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.36(1H,s,H-13),7.32(1H,dd,J＝2.0,8.4Hz,H-14′),7.21(1H,dd,J＝2.0,6.8Hz,H-13′),6.78(1H,dd,J＝1.6,6.8Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝2.4,8.4Hz,H-10′),6.04(1H,s,H-8′),4.00(3H,s,12-OCH3),3.85(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.71(3H,s,6-OCH3),3.45(1H,m,H-15′b),3.29(3H,s,6′-OCH3),3.28(3H,s,7-OCH3),2.65(3H,s,2′-NCH3),2.24(3H,s,2-NCH3).
H-43C38H40ClN3O8；ESI-MS:m/z703.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.47(1H,s,H-13),7.41(1H,dd,J＝2.0,8.0Hz,H-14′),7.35(1H,dd,J＝2.0,8.0Hz,H-13′),7.02(1H,s,H-10),6.77(1H,dd,J＝1.6,6.8Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝1.6,6.8Hz,H-10′),6.04(1H,s,H-8′),4.03(3H,s,12-OCH3),3.86(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.71(3H,s,6-OCH3),3.45(1H,m,H-15′b),3.29(3H,s,6′-OCH3),3.28(3H,s,7-OCH3),2.64(3H,s,2′-NCH3),2.25(3H,s,2-NCH3)。
H-44C38H39Cl2N3O8；ESI-MS:m/z737.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.47(1H,s,H-13),7.41(1H,dd,J＝2.0,8.0Hz,H-14′),7.35(1H,dd,J＝2.0,8.0Hz,H-13′),6.77(1H,dd,J＝1.6,6.8Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝1.6,6.8Hz,H-10′),6.04(1H, s,H-8′),4.03(3H,s,12-OCH3),3.80(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.54(3H,s,6-OCH3),3.45(1H,m,H-15′b),3.14(3H,m,6′-OCH3),2.62(3H,s,2′-NCH3),2.20(3H,s,2-NCH3)。
实施例10
化合物H-42的制备
0℃，Ar保护下，向10mL圆底烧瓶中加入2mL二氯甲烷溶解的50mg甲素样品，搅拌5min后将温度降至-10℃，向其中缓慢滴加0.6mL浓硝酸，15min滴加完，TLC检测，13h反应完全，加水终止反应。浓氨水调pH至碱性，氯仿萃取完全，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，得固体610mg。氯仿：甲醇＝50:1过柱纯化，得纯品H-42(33mg,收率65％)。
Figure PCTCN2015082626-appb-000050
波谱数据
H-42C37H39N3O7；ESI-MS:m/z638.1[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.40(1H,dd,J＝1.6,6.4Hz,H-14′),7.23(1H,dd,J＝2.0,6.4Hz,H-13′),6.86(1H,s,H-14),6.85(1H,s,H-13),6.76(1H,s,H-10),6.74(1H,dd,J＝2.0,6.8Hz,H-11′),6.51(1H,s,H-5′),6.37(1H,dd,J＝1.2,6.0Hz,H-10′),5.78(1H,s,H-5),5.42(1H,s,H-8′),3.93(3H,s,12-OCH3),3.80(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.54(3H,s,6-OCH3),3.45(1H,m,H-15′b),3.14(3H,m,6′-OCH3),2.62(3H,s,2′-NCH3),2.20(3H,s,2-NCH3)。
实施例11
化合物H-45和化合物H-52的制备
1.取汉防己乙素干燥样品500mg(0.8mmol)于10mL圆底烧瓶中， Ar保护下，加入10mL无水DMF，再加入70mg NaH(1.6mmol,55％)，搅拌均匀，滴加180μL苯甲酰氯(1.6mmol)，室温反应8h，TLC检测反应完全，停止反应。加入饱和NH4Cl终止反应，将混合液倾倒入冰水中，氯仿萃取3次，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，所得固体过200至300目硅胶(15g)，氯仿：甲醇＝30:1，得纯品(512mg)。
2.取第一步干燥样品100mg(0.15mmol)于10mL圆底烧瓶中，加入2.2mg(0.015mmol)无水Na2SO4，再加入2.0mL二氯甲烷搅拌至样品完全溶解，冰浴下于15min内滴加27μL(1.5mmol)浓硫酸，继续冰浴反应1h后升温至室温，10h后反应完全。将反应混合液倾倒入冰水中，饱和Na2CO3水溶液调pH至10后以氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤，减压回收氯仿，得粗品102mg。以氯仿：甲醇：二乙胺＝50:1:0.1过柱纯化，制备得到化合物H-45(95mg,收率80％)。
Figure PCTCN2015082626-appb-000051
波谱数据
H-45C44H44N2O10S；ESI-MS:m/z744.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.32(1H,s,14-SO3H),7.47-7.78(5H,m,H-Bz),7.34(2H,m,H-13′,14′),7.10(1H,s,H-13),6.87(1H,s,H-14),6.77(1H,m,H-11′),6.60(1H,s,H-10),6.44(1H,s,H-5′),6.39(1H,s,H-5),6.24(1H,m,H-10′),5.57(1H,s,H-8′),3.92(3H,s,12-OCH3),3.69(3H,s,6-OCH3),3.55(3H,m,H-1′,1,4b),3.48(3H,s,6′-OCH3),3.14(3H,m,6′-OCH3),2.62(3H,s,2′-NCH3),2.20(3H,s,2-NCH3)。
除使用实施例1所述混酸代替浓硫酸和Na2SO4外，使用制备化合物H-45的方法制备得到化合物H-52(收率87％)。
波谱数据
H-52C44H43N3O9；ESI-MS:m/z758.1[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.41(1H,s,H-13),7.36(1H,dd,J＝2.0,8.4Hz,H-14′),7.11(1H,dd,J＝2.4,8.0Hz,H-13′),6.75(1H,dd,J＝2.8,8.4Hz,H-11′),6.55(1H,s,H-10),6.49(1H,s,H-5′),6.35(1H,s,H-5),6.24(1H,dd,J＝1.6,8.0Hz,H-10′),6.04(1H,s,H-8′),3.98(3H,s,12-OCH3),3.85(1H,m,H-1′),3.72(3H,s,6-OCH3),3.66(1H,s,H-1),3.42(1H,m,H-15′b),3.45(3H,s,6′-OCH3),3.11(3H,s,7-CH3),2.59(3H,s,2′-NCH3),2.32(3H,s,2′-NCH3)。
实施例12
化合物H-46、化合物H-47、化合物H-48、化合物H-49、化合物H-50
和化合物H-51的制备
实验方法：1.取汉防己乙素干燥样品500mg(0.8mmol)于10mL圆底烧瓶中，Ar保护下，加入10mL无水DMF，再加入70mg NaH(1.6mmol,55％)，搅拌均匀，滴加180μL苯甲酰氯(1.6mmol)，室温反应8h，TLC检测反应完全，停止反应。加入饱和NH4Cl终止反应，将混合液倾倒入冰水中，氯仿萃取3次，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，所得固体过200至300目硅胶(15g)，氯仿：甲醇＝30:1，得纯品(512mg)。
2.取第一步干燥样品100mg(0.15mmol)于10mL圆底烧瓶中，再加入2.0mL三氟乙酸搅拌至样品完全溶解，冰浴下分两批加入25mg N-氯代丁二酰亚胺，继续冰浴反应30min后恢复至室温，反应5h后反应完全。将反应混合液倾倒入冰水中，饱和NaHCO3水溶液调pH至7后以氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤，减压回收氯仿，得粗品93mg。以氯仿：甲醇：二乙胺＝50:1:0.1过柱纯化，制备得到化合物H-46(56mg,收率51％)。
Figure PCTCN2015082626-appb-000052
Figure PCTCN2015082626-appb-000053
波谱数据
H-46C44H43ClN2O7；ESI-MS:m/z747.3[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.37-7.66(5H,m,H-Bz),7.34(2H,m,H-13′,14′),7.10(1H,s,H-13),7.06(1H,s,H-14),6.77(1H,m,H-11′),6.60(1H,s,H-10),6.44(1H,s,H-5′),6.39(1H,s,H-5),6.24(1H,m,H-10′),5.57(1H,s,H-8′),3.92(3H,s,12-OCH3),3.69(3H,s,6-OCH3),3.55(3H,m,H-1′,1,4b),3.49(3H,s,6′-OCH3),3.17(3H,s,2′-NCH3),2.68(2H,m,H-15b,4a),2.46(3H,s,2-NCH3)。
除使用50mg N-氯代丁二酰亚胺代替25mg N-氯代丁二酰亚胺外，使用制备化合物H-46的方法制备得到化合物H-47(收率46％)。
波谱数据
H-47C44H42Cl2N2O7；ESI-MS:m/z781.7[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.37-7.66(5H,m,H-Bz),7.34(2H,m,H-13′,H-14′),7.10(1H,s,H-13),6.77(1H,m,H-11′),6.60(1H,s,H-10),6.44(1H,s,H-5′),6.39(1H,s,H-5),6.24(1H,m,H-10′),5.57(1H,s,H-8′),3.92(3H,s,12-OCH3),3.69(3H,s,6-OCH3),3.55(3H,m,H-1′,1,4b),3.48(3H,s,6′-OCH3),3.20(3H,s,2′-NCH3),2.58(2H,m,H-15b,4a),2.17(3H,s,2-NCH3)。
除使用乙酸酐代替苯甲酰氯，32mg N-溴代丁二酰亚胺代替25mgN-氯代丁二酰亚胺外，使用制备化合物H-46的方法制备得到化合物H-48(收率63％)。
波谱数据
H-48C39H41BrN2O7；ESI-MS:m/z729.7[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.35(1H,dd,J＝1.6,6.4Hz,H-14′),7.14(1H,dd,J＝2.0,6.4Hz,H-13′),6.86(2H,m,H-13,H-14),6.80(1H,dd,J＝2.0,6.8Hz,H-11′),6.54(1H,s,H-10),6.45(1H,s,H-5′),6.28(1H,dd,J＝2.0,6.8Hz,H-10′),5.95(1H,s,H-8′),3.93(3H,s,12-OCH3),3.82(1H,m,H-1′),3.28(1H,dd,J＝5.6,11.2Hz,H-1),3.00(3H,s,6-OCH3),2.85(1H,m,H-15′b),2.73(3H,m,6′-OCH3),2.50(3H,m,2′-NCH3),2.15(3H,s,2-NCH3)。
除使用乙酸酐代替苯甲酰氯，65mg N-溴代丁二酰亚胺代替25mgN-氯代丁二酰亚胺外，使用制备化合物H-46的方法制备得到化合物H-49(收率49％)。
波谱数据
H-49C39H40Br2N2O7；ESI-MS:m/z808.6[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.36(1H,dd,J＝2.4,8.4Hz,H-14′),7.08(1H,m,H-13,H-14),7.02(1H,dd,J＝2.8,8.4Hz,H-13′),6.85(1H,dd,J＝2.8,8.0Hz,H-11′),6.55(1H,s,H-10),6.53(1H,s,H-5′),6.32(1H,dd,J＝2.0,8.4Hz,H-10′),5.93(1H,s,H-8′),3.85(3H,s,12-OCH3),3.50(1H, m,H-1′),3.15(1H,d,J＝3.2Hz,H-1),2.80(3H,s,6-OCH3),2.63(1H,m,H-15′b),2.48(3H,m,6′-OCH3),2.35(3H,m,2′-NCH3),2.11(3H,s,2-NCH3)。
除使用乙酸酐代替苯甲酰氯，50mg N-氯代丁二酰亚胺代替25mgN-氯代丁二酰亚胺外，使用制备化合物H-46的方法制备得到化合物H-50(收率41％)。
波谱数据
H-50C39H40Cl2N2O7；ESI-MS:m/z719.7[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.41(1H,s,H-13),7.36(1H,dd,J＝2.0,6.4Hz,H-14′),7.12(1H,dd,J＝2.0,6.4Hz,H-13′),6.75(1H,dd,J＝2.0,6.8Hz,H-11′),6.55(1H,s,H-10),6.52(1H,s,H-5′),6.28(1H,dd,J＝2.0,6.8Hz,H-10′),6.01(1H,s,H-8′),3.98(3H,s,12-OCH3),3.93(1H,m,H-1′),3.73(3H,s,6-OCH3),3.68(1H,d,J＝2.0Hz,H-1),3.45(1H,m,H-15′b),3.37(3H,m,6′-OCH3),3.19(3H,m,2′-NCH3),2.65(3H,s,2-NCH3)。
除使用乙酸酐代替苯甲酰氯，80mg N-氯代丁二酰亚胺代替25mgN-氯代丁二酰亚胺外，使用制备化合物H-46的方法制备得到化合物H-51(收率38％)。
波谱数据
H-51C39H39Cl3N2O7；ESI-MS:m/z754.1[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.43(1H,s,H-13),7.41(1H,dd,J＝2.0,6.4Hz,H-14′),7.16(1H,dd,J＝2.0,6.8Hz,H-13′),6.78(1H,dd,J＝2.0,6.4Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝1.6,6.4Hz,H-10′),6.04(1H,s,H-8′),4.00(3H,s,12-OCH3),3.92(1H,m,H-1′),3.71(3H,s,6-OCH3),3.67(1H,s,H-1),3.42(1H,m,H-15′b),3.27(3H,m,6′-OCH3),2.64(3H,m,2′-NCH3),2.21(3H,s,2-NCH3)。
实施例13
化合物H-53的制备
1.取汉防己乙素干燥样品500mg(0.8mmol)于10mL圆底烧瓶中，Ar保护下，加入10mL无水DMF，再加入70mg NaH(1.6mmol, 55％)，搅拌均匀，滴加113μL乙酰氯(1.6mmol)，室温反应9h，TLC检测反应完全，停止反应。加入饱和NH4Cl终止反应，将混合液倾倒入冰水中，氯仿萃取3次，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，所得固体过200至300目硅胶(15g)，氯仿：甲醇＝30:1，得乙酰化乙素(512mg)。
2.取第一步所得乙酰化汉防己乙素100mg(0.15mmol)于10mL圆底烧瓶中，加入2.13mg(0.015mmol)无水Na2SO4，再加入2.0mL二氯甲烷搅拌至样品完全溶解，冰浴下于15min内滴加27μL(1.5mmol)浓硫酸，继续冰浴反应1h后升温至室温，10h后反应完全。将反应混合液倾倒入冰水中，饱和Na2CO3水溶液调pH至10后以氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤，减压回收氯仿，得粗品102mg。以氯仿：甲醇：二乙胺＝50:1:0.1过柱纯化，制备得到化合物H-53(82mg,79％收率)。
Figure PCTCN2015082626-appb-000054
波谱数据
H-53C37H40N2O9S；ESI-MS:m/z688.8[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):12.31(1H,s,14-SO3H),7.83(1H,s,H-13),7.32(1H,dd,J＝2.0,8.4Hz,H-14′),7.11(1H,dd,J＝2.0,8.0Hz,H-13′),6.77(1H,s,H-10),6.67(1H,dd,J＝2.8,8.4Hz,H-11′),6.50(1H,s,H-5′),6.39(1H,s,H-5),6.24(1H,dd,J＝1.6,6.8Hz,H-10′),5.97(1H,s,H-8′),3.98(3H,s,12-OCH3),3.90(1H,m,H-1′),3.81(3H,s,6-OCH3),3.36(3H,s,6′-OCH3),3.23(1H,m,H-15′b),2.79(3H,s,2′-NCH3),2.64(3H,s,2′-NCH3)。
实施例14
化合物H-54的制备
1.取干燥样品汉防己甲素100mg(0.15mmol)于10mL圆底烧瓶中，再加入2.0mL三氟乙酸搅拌至样品完全溶解，冰浴下分两批加入25mg N-氯代丁二酰亚胺，继续冰浴反应30min后恢复至室温，反应5h后反应完全。将反应混合液倾倒入冰水中，饱和NaHCO3水溶液调pH至7后以氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤，减压回收氯仿，得粗品93mg。以氯仿：甲醇：二乙胺＝50:1:0.1过柱纯化，制备得到氯代汉防己甲素(86mg)。
2.取干燥样品氯代汉防己甲素50mg(0.08mmol)于10mL圆底烧瓶中，再加入2.0mL三氟乙酸搅拌至样品完全溶解，冰浴下分两批加入25mg N-溴代丁二酰亚胺，继续冰浴反应30min后恢复至室温，反应5h后反应完全。将反应混合液倾倒入冰水中，饱和NaHCO3水溶液调pH至7后以氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤，减压回收氯仿，得粗品41mg。以氯仿：甲醇：二乙胺＝50:1:0.1过柱纯化，制备得到化合物H-54(35mg,收率48％)。
Figure PCTCN2015082626-appb-000055
波谱数据
H-54C38H40BrClN2O6；ESI-MS:m/z736.1[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.38(1H,dd,J＝1.6,8.0Hz,H-14′),7.16(1H,dd,J＝2.0,6.8Hz,H-13′),7.08(1H,s,H-13),6.86(1H,dd,J＝2.4,8.8Hz,H-11′),6.57(1H,s,H-5′),6.56(1H,s,H-5′),6.35(1H,dd,J＝1.6,6.4Hz,H-10′),6.03(1H,s,H-8′),4.00(3H,s,12-OCH3),3.85(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.71(3H,s,6-OCH3),3.45(1H,m,H-15′b),3.29(3H,s,6′-OCH3),3.28(3H,s,7-OCH3),2.64(3H,s,2′-NCH3),2.21(3H,s,2-NCH3)。
实施例15
化合物H-55的制备
1.取汉防己甲素样品100mg(0.15mmol)于10mL圆底烧瓶中，加入2.13mg(0.015mmol)无水Na2SO4，再加入2.0mL二氯甲烷搅拌至样品完全溶解，冰浴下于15min内滴加27μL(1.5mmol)浓硫酸，继续冰浴反应1h后升温至室温，10h后反应完全。将反应混合液倾倒入冰水中，饱和Na2CO3水溶液调pH至10后以氯仿萃取，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤，减压回收氯仿，得粗品102mg。以氯仿：甲醇：二乙胺＝50:1:0.1过柱纯化，制备得到化合物H-37(95mg)。
2.0℃下配置混酸溶液，Ar保护下，向10mL圆底烧瓶中加入0.15mL(CH3CO)2O，搅拌下缓慢滴加浓硝酸0.06mL，搅拌5min后将温度降至-10℃，向混酸溶液中缓慢滴加50mg(0.08mmol)H-37的3mL无水氯仿溶液，15min滴加完，TLC检测，70min反应完全，加水终止反应。浓氨水调pH至碱性，氯仿萃取完全，饱和NaCl溶液洗涤，无水MgSO4干燥，过滤蒸干，回收氯仿溶液，得固体610mg。氯仿：甲醇＝50:1过柱纯化，得纯品H-55(39mg,收率65％)。
Figure PCTCN2015082626-appb-000056
波谱数据
H-55C38H40N3O11S；ESI-MS:m/z748.2[M+H]+；1H-NMR(CDCl3,400MHz)δ(ppm):7.41(1H,dd,J＝2.0,8.0Hz,H-14′),7.14(1H,dd,J＝2.0,6.8Hz,H-13′),7.08(1H,s,H-13),6.86(1H,dd,J＝2.4,8.8Hz,H-11′),6.57(1H,s,H-5′),6.56(1H,s,H-5′),6.35(1H,dd,J＝1.6,6.4Hz,H-10′),6.03(1H,s,H-8′),4.00(3H,s,12-OCH3),3.92(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.71(3H,s,6-OCH3),3.45(1H,m,H-15′b),3.29(3H,s,6′-OCH3),3.28(3H,s,7-OCH3),2.80(3H,s, 2′-NCH3),2.17(3H,s,2-NCH3).
实施例16
硬胶囊的制备
取化合物H-325g、药用淀粉75g、微晶纤维素20g，将药用淀粉先干燥，过120目筛，再与化合物H-32、微晶纤维素混合，过两次120目筛，填入硬胶囊中，制成1000粒本发明胶囊。每粒硬胶囊含主药成分0.5mg。
实施例17
包衣片的制备
取化合物H-285g、羟丙甲纤维素6g、羧甲淀粉钠10g，微晶纤维素8g，乳糖115g、淀粉50g，硬脂酸镁1g；将主药与辅料充分混匀后投入高速搅拌机中，喷雾加水适量，整粒，水分控制在3-4％，然后压片，制成1000片，包薄膜衣。
实施例18
溶液的制备
取化合物H-305g，加入400mL聚乙二醇200溶解，再加入适量蒸馏水进行稀释，然后再加入适量蔗糖并调整体积至1000mL，搅匀，过滤，灌装成10mL或20mL每只，灭菌包装。
生物学实施例
1.人肝癌细胞株BEL-7402模型筛选
测试化合物：化合物H-03
测试方法：磺酰罗丹明蛋白染色法(SRB法)
检测方法：
(一)给药
根据肿瘤细胞生长速率，将处于对数生长期的贴壁肿瘤细胞以200μL/孔接种于96孔培养板，贴壁生长24h后加药，每个浓度设3 复孔。并设相应浓度的生理盐水溶媒对照及无细胞调零孔。肿瘤细胞在37℃、5％CO2条件下培养72h。
(二)固定
取出培养板，每孔加入50％(m/v)的三氯乙酸(TCA)50μL固定细胞，4℃放置1h。若培养的是悬浮细胞。则加80％的冷TCA 50μL，TCA的终浓度为16％，先静置5min，再放入4℃冰箱中1h。
(三)洗涤
弃固定液，用蒸馏水洗涤5次，空气中自然干燥。
(四)染色
在空气中干燥后，每孔加SRB溶液100μL，室温下放置10-30min。
(五)洗涤
去上清液，用1％醋酸洗涤5次，空气干燥。
(六)溶解
最后加入150μL/孔的Tris溶液，在平板振荡器上振荡5min。
(七)测量
在酶联免疫检测仪测定OD值，用空白对照调零，所用波长为515nm。
(八)计算
按以下公式计算肿瘤细胞生长的抑制率：抑制率＝[(OD515对照孔－OD515给药孔)/OD515对照孔]×100％。
根据各浓度抑制率，采用Logit法计算半数抑制浓度IC50。以上每个实验重复2-3次，求出2-3次实验的平均IC50值作为最终指标。
模型原理：磺酰罗丹明蛋白染色法(SRB)是一种蛋白结合染料，可与生物大分子中的碱性氨基酸结合，其在特定波长范围内的OD值与细胞数量呈良好的线形关系。本模型根据SRB结合物的OD值，来检测样品对肿瘤细胞的作用情况。
试验结果：在实施例浓度为1.0×10-5mol/L时，抑制率为93.61％±0.68％，表明测试化合物对BEL-7402细胞具有抑制作用。
使用与上述相同的方法，测试了本申请制备得到的若干化合物以及对照化合物汉防已甲素、汉防己乙素和阿霉素对BEL-7402细胞的 抑制作用，具体结果如下表所示。
Figure PCTCN2015082626-appb-000057
2.人肝癌细胞株PLC/PRF/5模型筛选
测试化合物：化合物H-03
筛选方法：四氮唑盐还原法(MTT法)
(1)接种细胞：用含10％胎小牛血清得培养液配成单个细胞悬液，以每孔1000-10000个细胞接种到96孔板，每孔体积200μL。
(2)培养细胞：同一般培养条件，培养3-5天(可根据试验目的和要求决定培养时间)。
(3)呈色：培养3-5天后，每孔加MTT溶液(5mg/mL用PBS<pH＝7.4>配)20μL。继续孵育4小时，终止培养，小心吸弃孔内培养上清液，对于悬浮细胞需要离心后再吸弃孔内培养上清液。每孔加150μL DMSO，振荡10分钟，使结晶物充分融解。
(4)比色：选择490nm波长，在酶联免疫监测仪上测定各孔光吸收值，记录结果，以时间为横坐标，吸光值为纵坐标绘制细胞生长曲线。
模型原理：活细胞的线粒体中存在与NADP相关的脱氢酶，可将黄色的MTT还原为不溶性的蓝紫色甲瓒(Formanzan)，死细胞此酶消失，MTT不被还原。本模型根据MTT的还原程度，来检测样品对肿瘤细胞的作用情况。
实验结果：化合物H-03在PLC/PRF/5肝癌细胞株中IC50值为12.1μM，结果明显好于已上市药物索拉菲尼(PLC/PRF/5：IC50＝26.9μM)和汉防己乙素。
使用与上述相同的方法，测试了本申请制备得到的若干化合物以对PLC/PRF/5细胞的抑制作用，具体结果如下表所示。
Figure PCTCN2015082626-appb-000058
Figure PCTCN2015082626-appb-000059
Figure PCTCN2015082626-appb-000060
3.人肝癌细胞株MHCC97L模型筛选
测试化合物：化合物H-03
筛选方法：四氮唑盐还原法(MTT法)
(1)接种细胞：用含10％胎小牛血清得培养液配成单个细胞悬液，以每孔1000-10000个细胞接种到96孔板，每孔体积200μL。
(2)培养细胞：同一般培养条件，培养3-5天(可根据试验目的和要求决定培养时间)。
(3)呈色：培养3-5天后，每孔加MTT溶液(5mg/mL用PBS<pH＝7.4>配)20μL。继续孵育4小时，终止培养，小心吸弃孔内培养上清液，对于悬浮细胞需要离心后再吸弃孔内培养上清液。每孔加150μLDMSO，振荡10分钟，使结晶物充分融解。
(4)比色：选择490nm波长，在酶联免疫监测仪上测定各孔光吸收值，记录结果，以时间为横坐标，吸光值为纵坐标绘制细胞生长曲线。
模型原理：活细胞的线粒体中存在与NADP相关的脱氢酶，可将黄色的MTT还原为不溶性的蓝紫色甲瓒(Formanzan)，死细胞此酶消失，MTT不被还原。本模型根据MTT的还原程度，来检测样品对肿 瘤细胞的作用情况。
实验结果：化合物H-03在MHCC97L肝癌细胞株中IC50值为2.77μM，结果明显好于已上市药物索拉菲尼(HCC IC50＝34.42μM)和汉防己乙素。
使用与上述相同的方法，测试了本申请制备得到的若干化合物以对HCC细胞的抑制作用，具体结果如下表所示。
Figure PCTCN2015082626-appb-000061
Figure PCTCN2015082626-appb-000062
Figure PCTCN2015082626-appb-000063
从前述中可以理解，尽管为了示例性说明的目的描述了本申请的具体实施方案，但是在不偏离本申请的精神和范围的条件下，本领域所述技术人员可以作出各种变形或改进。这些变形或修改都应落入本申请所附权利要求的范围。

Claims (48)

  1. 通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物：
    Figure PCTCN2015082626-appb-100001
    其中，
    X1、X2、X3和X4各自独立地选自氢、卤素、硝基、亚硝基、-SO3H、任意取代的氨基或任意取代的磺酰基；
    R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
    x为1至3的整数；
    y为1至4的整数；以及
    z为1至2的整数；
    条件是：
    X1、X2、X3和X4不同时为氢；以及
    当X1、X2、X3和X4中之一为卤素时，其余的X1、X2、X3和X4各自独立地选自氢、硝基、亚硝基、-SO3H、任意取代的氨基或任意取代的磺酰基，但不能同时为氢。
  2. 如权利要求1所述的化合物，其中
    X1、X2、X3和X4各自独立地选自氢、卤素、硝基、亚硝基、氨基、-SO3H、-NR3-C(＝O)-R4、-NR5-S(＝O)2-R6或-S(＝O)2-R7；
    R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
    R3和R5各自独立地选自氢、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基；
    R4选自任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的杂环基、任意取代的烷氧基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷氧基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
    R6和R7各自独立地选自任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的杂环基或任意取代的氨基；
    x为1至3的整数；
    y为1至4的整数；以及
    z为1至2的整数；
    条件是：
    X1、X2、X3和X4不同时为氢；以及
    当X1、X2、X3和X4中之一为卤素时，其余的X1、X2、X3和X4各自独立地选自氢、硝基、亚硝基、氨基、-SO3H、-NR3-C(＝O)-R4、-NR5-S(＝O)2-R6或-S(＝O)2-R7，但不能同时为氢。
  3. 如权利要求1或2所述的化合物，其中X1、X2、X3和X4各自独立地选自氢、卤素、硝基、亚硝基、-SO3H、任意取代的烷基羰基取代的氨基、任意取代的烯基羰基取代的氨基、任意取代的炔基羰基取代的氨基、任意取代的烷氧基羰基取代的氨基、任意取代的环烷基羰基取代的氨基、任意取代的芳基羰基取代的氨基、任意取代的杂环 基羰基取代的氨基、任意取代的氨基羰基取代的氨基、任意取代的杂芳基羰基取代的氨基、任意取代的烷氧基羰基羰基取代的氨基、任意取代的烷基磺酰基取代的氨基、任意取代的烯基磺酰基取代的氨基、任意取代的炔基磺酰基取代的氨基、任意取代的烷氧基磺酰基取代的氨基、任意取代的芳基磺酰基取代的氨基、任意取代的杂环基磺酰基取代的氨基、任意取代的杂芳基磺酰基取代的氨基、任意取代的氨基磺酰基取代的氨基、任意取代的芳基氨基取代的磺酰基或任意取代的烷基取代的磺酰基。
  4. 如权利要求1至3中任一项所述的化合物，其中X1、X2、X3和X4各自独立地选自氢、卤素、硝基、亚硝基、-SO3H、烷基羰基取代的氨基、羟基取代的烷基羰基取代的氨基、酯基取代的烷基羰基取代的氨基、烯基羰基取代的氨基、烷氧基羰基取代的氨基、芳基取代的烷氧基羰基取代的氨基、卤素取代的芳基羰基取代的氨基、烷氧基取代的芳基羰基取代的氨基、卤代烷基取代的芳基羰基取代的氨基、烷氧基羰基羰基取代的氨基、杂环基羰基取代的氨基、烷基磺酰基取代的氨基、芳烷基磺酰基取代的氨基、芳基磺酰基取代的氨基、硝基取代的芳基磺酰基取代的氨基、烷基取代的芳基磺酰基取代的氨基、卤素取代的芳基磺酰基取代的氨基、烷基取代的氨基磺酰基取代的氨基、芳基氨基取代的磺酰基或烷氧基取代的烷基取代的磺酰基。
  5. 如权利要求1至4中任一权利要求所述的化合物，其中R1选自氢、亚硝基、烷基、芳基取代的烷基、芳基、烷基羰基或芳基羰基。
  6. 如权利要求1至5中任一权利要求所述的化合物，其中x为1，并且X2选自卤素、硝基、亚硝基、氨基、-SO3H、烷基羰基取代的氨基、羟基取代的烷基羰基取代的氨基、酯基取代的烷基羰基取代的氨基、烯基羰基取代的氨基、芳基取代的烯基羰基取代的氨基、烷氧基羰基取代的氨基、芳基取代的烷氧基羰基取代的氨基、芳基羰基取代的氨基、卤素取代的芳基羰基取代的氨基、烷氧基取代的芳基羰基取 代的氨基、卤代烷基取代的芳基羰基取代的氨基、烷氧基羰基羰基取代的氨基、杂环基羰基取代的氨基、杂芳基羰基取代的氨基、烷基磺酰基取代的氨基、芳烷基磺酰基取代的氨基、芳基磺酰基取代的氨基、硝基取代的芳基磺酰基取代的氨基、烷基取代的芳基磺酰基取代的氨基、卤素取代的芳基磺酰基取代的氨基、烷基取代的氨基磺酰基取代的氨基、芳基氨基取代的磺酰基或烷氧基取代的烷基取代的磺酰基。
  7. 如权利要求1至6中任一权利要求所述的化合物，其中y为4，并且X3为氢。
  8. 如权利要求1至7中任一权利要求所述的化合物，其中z为2，并且X4为氢。
  9. 如权利要求1至8中任一权利要求所述的化合物，其中X1为氢、硝基或卤素。
  10. 如权利要求1至9中任一权利要求所述的化合物，其中x为2，并且X2中的一个为氢，X2中的另一个选自氨基、硝基、亚硝基、-SO3H、Br、Cl、甲基羰基氨基、异丙基羰基氨基、异丁基羰基氨基、乙烯基羰基氨基、苯乙烯基羰基氨基、2-甲基丙烯基羰基氨基、2-甲基丙基氧基羰基氨基、羟基甲基羰基氨基、甲基羰基氧基甲基羰基氨基、甲氧基羰基羰基氨基、呋喃基羰基氨基、噻吩基羰基氨基、吗啉基羰基氨基、苯基羰基氨基、氯苯基羰基氨基、甲氧基苯基羰基氨基、三氟甲基苯基羰基氨基、苯甲基氧基羰基氨基、甲基磺酰基氨基、苯基磺酰基氨基、硝基苯基磺酰基氨基、甲基苯基磺酰基氨基、氯苯基磺酰基氨基、二氯苯基磺酰基氨基、苯甲基磺酰基氨基、二甲基氨基磺酰基氨基、苯基氨基磺酰基或甲氧基甲基磺酰基。
  11. 如权利要求1至10中任一权利要求所述的化合物，其中R2为烷基，优选C1-C6烷基，更优选甲基。
  12. 如权利要求1所述的化合物，其中R1为烷基，优选C1-C6烷基，更优选甲基，并且R2为烷基，优选C1-C6烷基，更优选甲基。
  13. 如权利要求1所述的化合物，其中R1为烷基，优选C1-C6烷基，更优选甲基，并且R2为氢。
  14. 如权利要求1所述的化合物，其中R1为氢，并且R2为烷基，优选C1-C6烷基，更优选甲基。
  15. 如权利要求1所述的化合物，其中X1为卤素，X2选自硝基和磺酸基，X3和X4为氢，x为1。
  16. 如权利要求1所述的化合物，其中X3和X4为氢。
  17. 如权利要求1所述的化合物，其中R1选自氢、亚硝基、任意取代的C1-C6烷基、任意取代的苯基羰基或任意取代的C1-C6烷基羰基。
  18. 如权利要求1所述的化合物，其中R1选自氢、甲基、苄基、苯甲酰基、亚硝基或乙酰基。
  19. 如权利要求1所述的化合物，其中R1选自氢、甲基、苄基、苯甲酰基、亚硝基或乙酰基；和/或
    R2为甲基；和/或
    X1为氢、硝基或卤素；和/或
    x为1或2，且至少一个X2为氢、氨基、硝基、亚硝基、-SO3H、Br、Cl、甲基羰基氨基、异丁基羰基氨基、乙烯基羰基氨基、苯乙烯基羰基氨基、2-甲基丙烯基羰基氨基、2-甲基丙基氧基羰基氨基、羟基甲基羰基氨基、甲基羰基氧基甲基羰基氨基、甲氧基羰基羰基氨基、呋喃基羰基氨基、噻吩基羰基氨基、吗啉基羰基氨基、苯基羰基氨基、 氯苯基羰基氨基、甲氧基苯基羰基氨基、三氟甲基苯基羰基氨基、苯甲基氧基羰基氨基、甲基磺酰基氨基、苯基磺酰基氨基、硝基苯基磺酰基氨基、甲基苯基磺酰基氨基、氯苯基磺酰基氨基、二氯苯基磺酰基氨基、苯甲基磺酰基氨基、二甲基氨基磺酰基氨基、苯基氨基磺酰基或甲氧基甲基磺酰基；和/或
    y为3，且X3为氢；和/或
    z为2，且X4为氢，
    条件是：
    X1、X2、X3和X4不同时为氢，以及
    当X1、X2、X3和X4中之一为卤素时，其余的X1、X2、X3和X4不同时为氢。
  20. 化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物，其中所述化合物选自：
    Figure PCTCN2015082626-appb-100002
    Figure PCTCN2015082626-appb-100003
    Figure PCTCN2015082626-appb-100004
    Figure PCTCN2015082626-appb-100005
    Figure PCTCN2015082626-appb-100006
    Figure PCTCN2015082626-appb-100007
    Figure PCTCN2015082626-appb-100008
    Figure PCTCN2015082626-appb-100009
  21. 药物组合物，其包含权利要求1至20中任一权利要求所述的化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物，以及药物可接受的载体。
  22. 如权利要求21所述的药物组合物，其为片剂、胶囊剂、丸剂、栓剂、乳剂、膏剂、注射剂或输注剂。
  23. 制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
    Figure PCTCN2015082626-appb-100010
    其中，
    X1、X2、X3和X4各自独立地为硝基；或者X1、X2、X3和X4各自独立地为氢或硝基，条件是：X1、X2、X3和X4不同时为氢；
    R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
    x为1至3的整数；
    y为1至4的整数；以及
    z为1至2的整数；
    其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行硝化反应。
  24. 如权利要求23所述的反应，其中使用乙酸酐与硝酸的混酸进行所述硝化反应。
  25. 如权利要求23或24所述的反应，其中使用非极性溶剂作为溶剂，优选二氯甲烷作、氯仿、1,2-二氯乙烷或其混合物为溶剂，进行所述硝化反应。
  26. 如权利要求23至25中任一权利要求所述的方法，其中在-10℃至5℃的温度下，优选0℃，进行所述硝化反应。
  27. 如权利要求23至26中任一权利要求所述的方法，其中在惰性气体的氛围中，优选氩气，进行所述硝化反应。
  28. 制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
    Figure PCTCN2015082626-appb-100011
    其中，
    X1、X2、X3和X4各自独立地为氨基；或者X1、X2、X3和X4各自独立地为氢或氨基，条件是：X1、X2、X3和X4不同时为氢；
    R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
    x为1至3的整数；
    y为1至4的整数；以及
    z为1至2的整数；
    其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行硝化反应，然后将所得硝化产物进行还原反应。
  29. 如权利要求28所述的反应，其中使用NaBH4进行所述还原反应。
  30. 如权利要求28或29所述的反应，其中使用NiCl2·6H2O为催化剂进行所述还原反应。
  31. 如权利要求28至30中任一权利要求所述的反应，其中在-15℃至0℃的温度下，优选在冰浴中，进行所述还原反应。
  32. 如权利要求28至31中任一权利要求所述的反应，其中使用极性非质子溶剂作为溶剂，优选四氢呋喃、1,4-二氧六环、二甲基甲酰胺或其混合物作为溶剂，进行所述还原反应。
  33. 制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
    Figure PCTCN2015082626-appb-100012
    其中，
    X1、X2、X3和X4各自独立地为羰基取代的氨基；或者X1、X2、X3和X4各自独立地为氢或-NR3-C(＝O)-R4，条件是：X1、X2、X3和X4不同时为氢；
    R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
    x为1至3的整数；
    y为1至4的整数；以及
    z为1至2的整数；
    其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行硝化反应，将所得硝化产物进行还原反应，以及将所得还原产物进行酰化反应。
  34. 如权利要求33所述的方法，其中使用酰卤化合物或磺酰卤化合物进行所述酰化反应。
  35. 如权利要求33或34所述的方法，其中使用碱性溶剂作为溶剂，优选吡啶、二乙胺的二氯甲烷溶液或三乙胺的二氯甲烷溶液作为溶剂，进行所述酰化反应。
  36. 如权利要求33至35中任一权利要求所述的方法，其中在0℃至室温的温度下，优选冰浴中，进行所述酰化反应。
  37. 如权利要求33至36中任一权利要求所述的方法，其中在惰性气体的氛围中，优选氩气，进行所述酰化反应。
  38. 制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
    Figure PCTCN2015082626-appb-100013
    其中，
    X1、X2、X3和X4各自独立地为磺酸基；或者X1、X2、X3和X4各自独立地为氢或-SO3H，条件是：X1、X2、X3和X4不同时为氢；
    R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的磺酰基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取 代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
    x为1至3的整数；
    y为1至4的整数；以及
    z为1至2的整数；
    其中所述方法包括将小檗胺、汉防己甲素或汉防己乙素进行磺化反应。
  39. 如权利要求38所述的方法，其中使用硫酸盐和浓硫酸进行所述磺化反应。
  40. 如权利要求38或39所述的方法，其中使用非极性溶剂作为溶剂，优选二氯甲烷作、氯仿、1,2-二氯乙烷或其混合物为溶剂，进行所述磺化反应。
  41. 如权利要求38至40中任一权利要求所述的方法，其中在-15℃至0℃的温度下，优选在冰浴中，进行所述磺化反应。
  42. 制备通式(I)化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物的方法，
    Figure PCTCN2015082626-appb-100014
    其中，
    X1、X2、X3和X4各自独立地为氢或-NH-S(＝O)2-R6，条件是：X1、 X2、X3和X4不同时为氢；
    R1和R2各自独立地选自氢、亚硝基、任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的芳基羰基、任意取代的杂芳基羰基、任意取代的烷基羰基、任意取代的烯基羰基或任意取代的炔基羰基；
    R6选自任意取代的烷基、任意取代的烯基、任意取代的炔基、任意取代的环烷基、任意取代的芳基、任意取代的杂芳基、任意取代的杂环基或任意取代的氨基；
    x为1至3的整数；
    y为1至4的整数；以及
    z为1至2的整数；
    其包括方法包括将小檗胺、汉防己甲素或汉防己乙素与浓硝酸进行硝化反应，再与铁粉发生还原反应生成氨基，氨基继而与酰氯在碱的催化下进行反应得到上述通式(I)化合物。
  43. 治疗或预防肝病的方法，其包括对需要所述方法的个体给予治疗有效量的权利要求1至20中任一权利要求所述的化合物、其单一立体异构体、其立体异构体的混合物、其前药、其药物可接受的盐及其代谢物或权利要求21或22所述的药物组合物。
  44. 如权利要求43所述的方法，其中所述个体为哺乳动物。
  45. 如权利要求44所述的方法，其中所述哺乳动物为人类。
  46. 如权利要求43至45中任一权利要求所述的方法，其中所述肝病为病毒性肝病或非病毒性肝病。
  47. 如权利要求43至46中任一权利要求所述的方法，其中所述肝病选自肝炎、酒精性肝病、药物或毒物性肝病、新陈代谢异常性肝病和脂肪性肝病。
  48. 如权利要求43至47中任一权利要求所述的方法，其中所述肝病为肝肿瘤、肝硬化和肝纤维化。
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CN109678872A (zh) * 2019-01-15 2019-04-26 山东师范大学 双苄基异喹啉化合物及其制备方法和应用
CN109678871A (zh) * 2019-01-15 2019-04-26 山东师范大学 一种制备双苄基异喹啉类化合物的方法
CN109776553A (zh) * 2019-01-15 2019-05-21 山东师范大学 福己素及其制备方法和应用
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