WO2017036128A1 - 一种生物碱类化合物及其制备方法与作为抗单纯疱疹ⅰ型病毒剂的应用 - Google Patents

一种生物碱类化合物及其制备方法与作为抗单纯疱疹ⅰ型病毒剂的应用 Download PDF

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WO2017036128A1
WO2017036128A1 PCT/CN2016/077649 CN2016077649W WO2017036128A1 WO 2017036128 A1 WO2017036128 A1 WO 2017036128A1 CN 2016077649 W CN2016077649 W CN 2016077649W WO 2017036128 A1 WO2017036128 A1 WO 2017036128A1
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compound
formula
group
pharmaceutically acceptable
alkaloid
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邵长伦
王长云
牟晓凤
胥汝芳
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中国海洋大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16061—Methods of inactivation or attenuation
    • C12N2710/16063—Methods of inactivation or attenuation by chemical treatment
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi

Definitions

  • the present invention relates to a novel class of alkaloid compounds and methods for preparing the same, which have anti-herpes simplex virus type 1 (HSV-1, Herpes Simplex Virus 1) activity and can be developed to be resistant to herpes simplex type I A viral agent for the treatment of neuroinflammation and other diseases caused by herpes simplex type I virus.
  • HSV-1 Herpes Simplex virus 1
  • Herpes Simplex Virus 1 Herpes Simplex Virus 1
  • Herpes simplex type I virus (HSV-1) is a wrapped DNA virus with high morbidity, long incubation period, characteristic of neurotropic tissue, lurking in the peripheral nervous system, mainly infected children, immunocompromised individuals and organ transplants. If it is properly stimulated by the outside world, it will erupt on a large scale, causing encephalitis and keratitis. In severe cases, it can cause death.
  • antiviral drugs are mainly nucleoside antibiotics, such as acyclovir, but in recent years, the number of drug-resistant infections has increased rapidly. Therefore, the search for new antiviral drugs, especially novel antiviral drugs, has become an urgent problem to be solved.
  • the virus has an inhibitory effect and can be used for the treatment of diseases such as neuroinflammation and other complications caused by herpes simplex type I virus.
  • Species collection information Name of the depositary: General Microbiology Center of China Microbial Culture Collection Management Committee; Depository Address: Institute of Microbiology, Chinese Academy of Sciences, No. 3, Beichen West Road, Chaoyang District, Beijing; Date of deposit: December 17, 2012 Day; preservation number: CGMCC6959; classification nomenclature: Scopulariopsis sp.
  • the present invention provides a compound of Formula I, Formula II, Formula III, Formula IV, and Formula V, or a pharmaceutically acceptable salt thereof:
  • R is X is OH or a C1-C4 alkoxy group, Y is OH or a C1-C4 alkoxy group, Z is an OH or a C1-C4 alkoxy group, and W is an OH or a C1-C4 alkoxy group;
  • R is X is OH or C1-C4 alkanoyloxy group, Y is OH or C1-C4 alkanoyloxy group, Z is OH or C1-C4 alkanoyloxy group, W is OH or C1-C4 alkanoyloxy group base;
  • R is X is OH, a C1-C4 alkoxy group or a C1-C4 alkanoyloxy group
  • Y is a halogen (Cl, Br, F) or OH
  • Z is an OH, OCH 3 , C1-C4 alkoxy group or C1 Alkanoyloxy group of -C4
  • W is OH or a C1-C4 alkoxy group or a C1-C4 alkanoyloxy group;
  • R is X is OH, a C1-C4 alkoxy group or a C1-C4 alkanoyloxy group
  • Y is H, OH, a halogen, a C1-C4 alkoxy group or a C1-C4 alkanoyloxy group
  • Z is OH, OCH 3 , a C1-C4 alkoxy group or a C1-C4 alkanoyloxy group
  • W is an OH or a C1-C4 alkoxy group or a C1-C4 alkanoyloxy group.
  • the compounds of the invention include all stereoisomers, whether in the form of a mixture or in the form of a pure isomer, the compounds of the invention may form asymmetric centers on any chiral carbon atom.
  • Formula I, Formula II, Formula III, Formula IV, and Formula The V compound may exist in the form of an enantiomer or a diastereomer or a mixture thereof.
  • the preparation method can use a racemate, an enantiomer or a diastereomer as a raw material. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods such as chromatography, chemical resolution or fractional crystallization.
  • the present invention provides a process for the preparation of a compound of formula I, formula II, formula III, formula IV and formula V, characterized in that the endophytic fungus Scopulariopsis sp. (TA01- isolated from Carijoa sp. 33)
  • the culture is carried out, and the fungus is fermented in a fermentation medium, and then the obtained fermentation liquid is extracted with ethyl acetate; the extract is concentrated and subjected to normal phase silica gel column chromatography, Sephadex LH-20 gel.
  • the culture medium in the above preparation method preferably contains glucose 0.1% - 5.0% (% by weight, the same below), yeast extract 0.01% - 1%, peptone 0.01% - 1%, agar 0.1% - 3.0%, sodium chloride 0.05% - 5%, the rest of the medium is water, the culture temperature is preferably 0 - 30 ° C, the culture time is preferably 3 - 15 days; the fermentation medium preferably contains glucose 0.1% - 5.0% (% by weight, the same below), Yeast extract 0.01% - 1%, peptone 0.01% - 1%, sodium chloride 0.05% - 5%, the rest is water, the culture temperature is preferably 0 - 30 ° C, and the culture time is preferably 10 - 60 days;
  • the stationary phase used for phase silica gel column chromatography is preferably 200-300 mesh silica gel, and the mobile phase is preferably 5%-95% by volume of ethyl acetate-petroleum ether mixed solvent; the
  • the chromatographic column used in the HPLC high performance liquid chromatography is a conventional ODS C18 column, preferably Kromasil 10 ⁇ 250 mm. 7 ⁇ m, the flow rate is preferably 1.0–5.0 mL/min, and the mobile phase preferably has a volume ratio of 5 -95% methanol - water mixed solvent.
  • the compound of the formula I, the formula II, the formula III, the formula IV and the formula V or a pharmaceutically acceptable salt thereof in the present invention includes an intramolecular salt, a solvate or a hydrate thereof.
  • the alkaloid compounds and derivatives thereof obtained from marine fungi have strong inhibitory activity against herpes simplex type I virus, and can be used for developing anti-herpes simplex type I virus agents, and have broad application prospects.
  • Another embodiment of the invention provides a compound of Formula I, Formula II, Formula III, Formula IV, and Formula V, or a pharmaceutically acceptable compound thereof
  • pharmaceutically acceptable salt in the present invention means an addition salt of a non-toxic inorganic or organic acid and/or base. See “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.
  • the culture medium used for the culture of the strain contains glucose 1.0% (% by weight, the same below), yeast extract 0.2%, peptone 0.2%, agar 1.0%, sodium chloride 3.0%, and the rest is water. When used, the test tube is beveled, fungus The strain was cultured at 30 ° C for 5 days.
  • the medium used for the fermentation culture contained glucose 1.0% (% by weight, the same below), yeast extract 0.2%, peptone 0.2%, sodium chloride 3.0%, and the balance was water; the fungal strain was cultured at 28 ° C for 60 days.
  • the culture medium used for strain culture contains glucose 0.1%–5.0% (% by weight, the same below), yeast extract 0.01%–1%, peptone 0.01%–1%, agar 0.1%–3.0%, sodium chloride 0.05% – 5%, the rest is water, used to make test tube bevel, fungal strains cultured at 0–30 ° C for 3–15 days.
  • the medium used for fermentation culture contains glucose 0.1% - 5.0% (% by weight, the same below), yeast extract 0.01% - 1%, peptone 0.01% - 1%, sodium chloride 0.05% - 5%, and the rest is water, fungi
  • the strain was cultured for 10–60 days at 0–30 °C.
  • the compound of the formula I is obtained by the production method of the embodiment 1-2, and the compound of the formula II, the formula III, the formula IV and the formula V is obtained by a hydrogenation addition reaction, a substitution reaction, an acylation reaction or the like.
  • [ ⁇ ] 24 D +95 (c 0.014, MeOH); infrared IR (KBr) ⁇ max 3350, 2900, 1630, 1450 and 1135 cm -1 ; UV UV (MeOH) ⁇ max (log ⁇ ): 200.8 (0.69), 215.2 (0.64), 250.5 (0.13), 282 (0.05) nm; mass spectrum EIMS m/z 422 [M] ⁇ + .
  • [ ⁇ ] 24 D +130 (c 0.014, MeOH); infrared IR (KBr) ⁇ max 3360, 2929, 1650, 1410 and 1105 cm -1 ; UV UV (MeOH) ⁇ max (log ⁇ ): 204.8 (0.69), 211.2 (0.64), 254 (0.13) , 270 (0.05) nm; mass spectrum EIMS m / z 423 [m] ⁇ +.
  • [ ⁇ ] 24 D +130 (c 0.014, MeOH); infrared IR (KBr) ⁇ max 3360, 2929, 1650, 1410 and 1105 cm -1 ; UV UV (MeOH) ⁇ max (log ⁇ ): 204.8 (0.69), 211.2 (0.64), 254 (0.13), 270 (0.05) nm; mass spectrum EIMS m/z 471.6 [M] ⁇ + .
  • [ ⁇ ] 24 D +100.2 (c 0.020, MeOH); infrared IR (KBr) ⁇ max 3330, 2900, 1620, 1415 and 1105 cm -1 ; UV UV (MeOH) ⁇ max (log ⁇ ): 206.3 (0.69), 210.2 (0.64), 254.3 (0.13), 270 (0.05) nm; mass spectrum EIMS m/z 472.5 [M] ⁇ + .
  • [ ⁇ ] 24 D +140 (c 0.016, MeOH); IR (KBr) ⁇ max 3340, 2929, 1650, 1410 and 1105 cm -1 ; UV UV (MeOH) ⁇ max (log ⁇ ): 206.8 (0.69), 215.2 (0.64), 250 (0.13), 272 (0.05) nm; mass spectrum EIMS m/z 452 [M] ⁇ + .
  • [ ⁇ ] 24 D +142 (c 0.012, MeOH); infrared IR (KBr) ⁇ max 3345, 2900, 1650, 1400 and 1125 cm -1 ; UV UV (MeOH) ⁇ max (log ⁇ ): 210.4 (0.69), 211.5 (0.64), 254 (0.13), 270 (0.05) nm; mass spectrum EIMS m/z 453.6 [M] ⁇ +
  • the dried compound of formula I, formula II, formula III or formula IV (0.1 mol) is dissolved in dehydrated methanol and placed in a reaction flask filled with hydrogen. Under normal temperature conditions, an appropriate amount of Pd/C is added with sufficient stirring. After the reaction mixture was allowed to react overnight, the palladium carbon was removed by filtration, and the reaction mixture was concentrated.
  • HSV-1 herpes simplex virus type 1
  • CPE cytopathic inhibition
  • the Hep-2 cells cultured in a single layer were trypsinized, seeded in a 96-well plate, and grown into a single layer for use.
  • the HSV-1 virus was inoculated into Hep-2 cells, and 2% serum 1640 medium was added and cultured at 37 ° C and 5% CO 2 . After more than 90% of the lesions were present, the cells were repeatedly frozen and thawed and then centrifuged. Quantitative dispensing, frozen in a refrigerator at –80 °C. After each tube was dissolved in 10 ⁇ L of DMSO, 200 ⁇ L of 2% 1640 medium was added and serially diluted 10 times for 10 dilutions, and then laterally seeded on monolayer cells in 96 wells.
  • 11 columns were virus control, 12 columns were cell control, cultured at 37 ° C, 5% CO 2 , and the lesions were observed every hour for 24 hours (HSV-1). After more than 90% of the lesions in the virus control, the liquid in the well was aspirated, stained with 1% neutral red, the OD value was measured at 540 nm, and the half effective concentration (IC 50 ) of the drug was calculated by Reed-Muench method. The effect of killing the virus.
  • test results show that the compounds of the formula I, the formula II, the formula III, the formula IV and the formula V prepared by the invention have different degrees of inhibition on the HSV-1 virus, and the IC 50 values are between 0.07-100 ⁇ M, wherein the compound of the formula I
  • the anti-HSV-1 virus activity is most prominent, far stronger than the activity of the positive drug ribavirin (see Table 1). More importantly, the compounds of formula I prepared according to the invention are extremely toxic.
  • alkaloid compounds of the present invention have strong inhibitory activity against HSV-1 infection, and can be made into an antiviral drug, and have broad application prospects.

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Abstract

一种生物碱类化合物及其制备方法与作为抗单纯疱疹Ⅰ型病毒剂的应用，制备时先对真菌Scopulariopsis sp.（TA01-33）进行菌种发酵培养，发酵液提取浓缩后，依次进行正相硅胶柱层析、Sephadex LH-20凝胶柱层析、HPLC高效液相色谱，即得式I化合物，式I化合物经过一系列常规化学反应制备得到式II-式V化合物。本发明还提供一种抗单纯疱疹Ⅰ型病毒剂，是以本发明的式I-式V化合物或其药学上可接受的盐，用于治疗单纯疱疹I型病毒引起的疾病。

Description

一种生物碱类化合物及其制备方法与作为抗单纯疱疹Ⅰ型病毒剂的应用 技术领域
本发明涉及一类新的生物碱(Alkaloid)化合物及其制备方法与应用，所述化合物具有抗单纯疱疹Ⅰ型病毒(HSV-1,Herpes Simplex Virus 1)活性，可开发为抗单纯疱疹Ⅰ型病毒剂，用于治疗由单纯疱疹Ⅰ型病毒引起的神经炎症及其他疾病。
背景技术
单纯疱疹Ⅰ型病毒(HSV-1)是一种包裹着的DNA病毒，具有高发病率，潜伏期长，嗜神经组织的特点，潜伏于周围神经系统，主要感染儿童，免疫力低下者以及器官移植者，一旦受到外界适当刺激就会大规模爆发，引发脑炎和角膜炎，严重者能致人死亡。目前临床上抗病毒药物主要是核苷类抗生素，如阿昔洛韦，但近年来耐药性感染人群迅速增加。因此，寻找新的抗病毒药物尤其是结构新颖的抗病毒药物已成为亟待解决的课题。海洋微生物独特的生存环境(高压、高盐、缺氧、避光等)，促使海洋微生物产生大量结构新颖、具有抗病毒活性的化合物，为寻找潜在的抗病毒药物提供了重要来源。但是关于海洋微生物来源的具有抗HSV-1活性的化合物的报道还相当少，尤其是具有潜在开发成为手性药物的海洋来源化合物的报道。(Newman,D.J.；Cragg,G.M.J.Nat.Prod.2012,75,311–335；Blunt,J.W.；Copp,B.R.；Keyzers,R.A.；Munro,M.H.G.；Prinsep,M.R.Nat.Prod.Rep.2014,31,160–258,and previous annual reports.)
发明内容
本发明的目的在于提供一类新的生物碱类化合物如式I、式II、式III、式IV及式V所示，其制备方法以及制备药物组合物的应用，所述化合物对抗单纯疱疹I型病毒具有抑制作用，可用于治疗由单纯疱疹I型病毒引起的神经炎症及其他并发症等疾病。
菌种保藏信息：保藏单位名称：中国微生物菌种保藏管理委员会普通微生物中心；保藏单位地址：北京市朝阳区北辰西路1号院3号中国科学院微生物研究所；保藏日期：2012年12月17日；保藏编号：CGMCC6959；分类命名：Scopulariopsis sp.。
本发明提供式I、式II、式III、式IV及式V化合物或其药学上可接受的盐：
Figure PCTCN2016077649-appb-000001
R为
Figure PCTCN2016077649-appb-000002
Figure PCTCN2016077649-appb-000003
R为
Figure PCTCN2016077649-appb-000004
X为OH或C1-C4的烷氧基,Y为OH或C1-C4的烷氧基,Z为OH或C1-C4的烷氧基,W为OH或C1-C4的烷氧基；
Figure PCTCN2016077649-appb-000005
R为
Figure PCTCN2016077649-appb-000006
X为OH或C1-C4的烷酰氧基，Y为OH或C1-C4的烷酰氧基，Z为OH或C1-C4的烷酰氧基,W为OH或C1-C4的烷酰氧基；
Figure PCTCN2016077649-appb-000007
R为
Figure PCTCN2016077649-appb-000008
X为OH、C1-C4的烷氧基或C1-C4的烷酰氧基，Y为卤素(Cl、Br、F)或OH，Z为OH、OCH3、C1-C4的烷氧基或C1-C4的烷酰氧基,W为OH或C1-C4的烷氧基或C1-C4的烷酰氧基；
Figure PCTCN2016077649-appb-000009
R为
Figure PCTCN2016077649-appb-000010
X为OH、C1-C4的烷氧基或C1-C4的烷酰氧基，Y为H、OH、卤素、C1-C4的烷氧基或C1-C4的烷酰氧基，Z为OH、OCH3、C1-C4的烷氧基或C1-C4的烷酰氧基,W为OH或C1-C4的烷氧基或C1-C4的烷酰氧基。
本发明化合物包括所有立体异构体，无论是混合物形式或是纯异构体的形式，本发明化合物可以在任何手性碳原子上形成不对称中心。这样，式I、式II、式III、式IV及式 V化合物可以以对映体或非对映体形式或其混合物的形式存在。制备方法可以使用外消旋体、对映体或非对映体作为原料。当制备非对映体或对映体产物时，它们可以通过常规方法，例如层析、化学拆分或分级结晶分离。
本发明提供式I、式II、式III、式IV及式V化合物的制备方法，其特征在于先在菌种培养基中对分离自柳珊瑚Carijoa sp.的内生真菌Scopulariopsis sp.(TA01-33)进行菌种培养，再在发酵培养基中对该真菌进行发酵培养，然后将所得发酵液用乙酸乙酯萃取；萃取液浓缩后分别进行正相硅胶柱层析、Sephadex LH-20凝胶柱层析，再经HPLC高效液相制备色谱，将所得洗脱液浓缩，即可获得式I化合物；在溶有式I化合物的甲醇溶液中加入Pd/C催化氢化或溶有式I化合物的丙酮溶液中加入碳酸钾和卤代烷烃或酰氯等反应物，反应后得到式II、式III、式IV及式V化合物。
上述制备方法中菌种培养基优选为含有葡萄糖0.1％–5.0％(重量百分比，下同)、酵母膏0.01％–1％、蛋白胨0.01％–1％、琼脂0.1％–3.0％、氯化钠0.05％–5％，其余为水的培养基，培养温度优选为0–30℃，培养时间优选为3–15天；发酵培养基优选含有葡萄糖0.1％–5.0％(重量百分比，下同)、酵母膏0.01％–1％、蛋白胨0.01％–1％、氯化钠0.05％–5％，其余为水，培养温度优选为0–30℃，培养时间优选为10–60天；所述的正相硅胶柱层析采用的固定相优选200–300目硅胶，流动相优选体积比为5％–95％的乙酸乙酯-石油醚混合溶剂；所述Sephadex LH-20凝胶柱层析采用的流动相优选体积比为石油醚:氯仿:甲醇＝2:1:1的混合溶剂；所述HPLC高效液相制备色谱中采用的色谱柱为本领域常规ODS C18柱，优选为Kromasil 10×250mm,7μm，流速优选为1.0–5.0mL/min，流动相优选体积比为5％–95％的甲醇-水混合溶剂。
本发明中式I、式II、式III、式IV及式V化合物或其药学上可接受的盐包括其分子内盐、其溶剂化物或水合物。
本发明从海洋真菌中获得的生物碱类化合物及其衍生物对单纯疱疹Ⅰ型病毒具有极强的抑制活性，可用于开发抗单纯疱疹Ⅰ型病毒剂，应用前景广阔。
本发明的另一实施方案提供式I、式II、式III、式IV及式V化合物或其药学上可 接受的盐在制备抗单纯疱疹Ⅰ型病毒剂中的应用。
本发明中术语“药学上可接受的盐”是指非毒性的无机或有机酸和/或碱的加成盐。可参见“Salt selection for basic drugs”,Int.J.Pharm.(1986),33,201–217。
具体实施方式
为了便于对本发明的进一步理解，下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则，本发明的实施方式不限于以下内容。
实施例1
(1)柳珊瑚内生真菌Scopulariopsis sp.(TA01-33)的菌种培养
菌种培养所用的培养基含有葡萄糖1.0％(重量百分比，下同)、酵母膏0.2％、蛋白胨0.2％、琼脂1.0％、氯化钠3.0％，其余为水，使用时制成试管斜面，真菌菌株在30℃下培养5天。
(2)柳珊瑚内生真菌Scopulariopsis sp.(TA01-33)的发酵
发酵培养所用的培养基含有葡萄糖1.0％(重量百分比，下同)、酵母膏0.2％、蛋白胨0.2％、氯化钠3.0％，其余为水；真菌菌株于28℃培养60天。
(3)式I化合物的获得
取10L步骤(2)得到的发酵液过滤，除去菌体，将滤液浓缩后，用等体积的乙酸乙酯萃取5次；萃取液浓缩后分别进行正相硅胶柱层析(固定相为200–300目硅胶；流动相为40％-60％乙酸乙酯/石油醚混合溶剂，体积比)、Sephadex LH-20凝胶柱层析(石油醚：氯仿：甲醇＝2：1：1的混合溶剂，体积比)后，再经HPLC高效液相制备色谱分离(色谱柱为Kromasil10×250mm，7μm，流动相为70％或80％(体积比)的甲醇-水混合溶剂，流速为2.0mL/min)，将所得洗脱液浓缩，得到式I化合物。
式I化合物的结构确证数据:
Figure PCTCN2016077649-appb-000011
无色结晶,[α]24 D＝+133.5(c 0.017,MeOH)；1H NMR(acetone-d6,400MHz,TMS)δH 3.67(1H,s,H-3),7.42(1H,d,J＝8.0Hz,H-8),6.57(1H,d,J＝8.0Hz,H-9),7.34(5H,m,overlap,H-12,13,14,15,16),6.87(1H,d,J＝16.4Hz,H-17),6.35(1H,d,J＝16.4Hz,H-18),4.42(1H,t,J＝7.2Hz,H-20),2.08(1H,m,H-21a),1.75(1H,m,H-21b),1.98(1H,q,J＝4.4Hz,H-22a),1.89(1H,m,H-22b),5.05(1H,m,H-24a),4.75(1H,m,H-24b),1.73(3H,s,H-25),1.35(3H,s,H-26),3.51(3H,s,H-27)；13C NMR(acetone-d6,100MHz,TMS)δC166.3(C-2),85.6(C-3),79.9(C-4),112.0(C-5),156.9(C-6),121.5(C-7),127.9(C-8),107.7(C-9),137.1(C-10),140.1(C-11),129.5(C-12,16),127.4(C-13,15),129.7(C-14),121.6(C-17),135.9(C-18),83.6(C-19),82.7(C-20),31.8(C-21),39.3(C-22),147.2(C-23),110.2(C-24),18.6(C-25),27.3(C-26),58.9(C-27)；红外(溴化钾)νmax 3288,2970,1721,1689,1618,1379and 1082cm–1；紫外(甲醇)λmax(logε):211(0.41),233.6(0.26),280.9(0.20),287.4(0.19),322(0.21)nm；质谱EIMS m/z 435[M]·+；高分辨质谱HREEIMS m/z 436.2114[M+H]+(calcd for C26H29NO5,436.2118)。
Figure PCTCN2016077649-appb-000012
无色结晶；[α]24 D＝+133.5(c 0.017,MeOH)；1H NMR(acetone-d6,400MHz,TMS)δH 3.66(1H,d,J＝1.2Hz,H-3),7.43(1H,d,J＝8.0Hz,H-8),6.57(1H,d,J＝8.0Hz,H-9),7.35(5H,m,overlap,H-12,13,14,15,16),6.63(1H,d,J＝16.4Hz,H-17),6.20(1H,d,J＝16.4Hz,H-18),1.07(1H,t,J＝12.8Hz,H-20a),1.74(1H,m,H-20b),1.54(1H,m,H-21),3.02(1H,m,H-22),1.71(1H,m,H-23a),1.49(1H,m,H-23b),1.78(1H,m H-24a),1.39(1H,qd,J＝13.6,3.2Hz,H-24b),1.01(3H,s,H-25),0.96(3H,d,J＝6.8Hz,H-26),3.52(3H,s,H-27)；13C NMR(acetone-d6,100MHz,TMS)δC 166.3(C-2),85.7(C-3),80.0(C-4),112.1(C-5),155.9(C-6),122.3(C-7),127.4(C-8),107.7(C-9),136.8(C-10),140.2(C-11),129.5 (C-12,16),127.4(C-13,15),129.6(C-14),122.5(C-17),137.5(C-18),37.7(C-19),46.9(C-20),36.9(C-21),76.7(C-22),33.0(C-23),37.7(C-24),31.8(C-25),19.3(C-26),58.9(C-27)；红外IR(KBr)νmax 3366,2926,1687,1600,1421 and 1107cm–1；紫外UV(MeOH)λmax(logε):204.8(0.69),211.2(0.64),252.8(0.13),281.6(0.05)nm；质谱EIMS m/z 437[M]·+；高分辨质谱HREIMS m/z 437.2200[M]·+(calcd for C26H31NO5,437.2197)。
实施例2
(1)柳珊瑚内生真菌Scopulariopsis sp.(TA01-33)的菌种培养
菌种培养所用的培养基含有葡萄糖0.1％–5.0％(重量百分比，下同)、酵母膏0.01％–1％、蛋白胨0.01％–1％、琼脂0.1％–3.0％、氯化钠0.05％–5％，其余为水，使用时制成试管斜面，真菌菌株在0–30℃下培养3–15天。
(2)柳珊瑚内生真菌Scopulariopsis sp.(TA01-33)的发酵
发酵培养所用的培养基含有葡萄糖0.1％–5.0％(重量百分比，下同)、酵母膏0.01％–1％、蛋白胨0.01％–1％、氯化钠0.05％–5％，其余为水，真菌菌株于0–30℃培养10–60天。
(3)式I化合物的提取分离
取5–50L步骤(2)所得的发酵液过滤，除去菌体，将滤液浓缩后，用1–3倍体积的乙酸乙酯萃取2–5次；萃取液浓缩后分别进行正相硅胶柱层析(固定相为本领域常规正相硅胶，流动相为5％–95％的乙酸乙酯-石油醚混合溶剂，体积比)、Sephadex LH-20凝胶柱层析(流动相为石油醚:氯仿:甲醇＝2:1:1的混合溶剂，体积比)后，再经HPLC高效液相制备色谱(色谱柱为本领域常规ODS C18柱，流速为1.0–5.0mL/min，流动相为5％–95％的甲醇-水混合溶剂，体积比)，将所得洗脱液浓缩，得无色结晶，即为式I化合物。其中化合物的结构确证数据与实施例1中相应数据一致。
实施例1–2中未具体指明的其他菌种培养、发酵条件，以及正相硅胶柱色谱分离、Sephadex LH-20凝胶柱层析分离、高效液相色谱分离等其他实验操作条件均为本领域常规的实验操作条件，本领域的技术人员可以根据实际需要，进行合理的选择。
实施例3
如实施例1-2的制备方法，得到式I化合物，通过氢化加成反应，取代反应，酰化反应等获得式II、式III、式IV及式V化合物。
式II化合物的制备：
1)称取上述干燥后的式I化合物(0.1mol)溶于DMF中，加入无水碳酸钾，常温条件下，在充分搅拌下向反应体系中加入碘甲烷，反应1-5h后，向反应体系中加水终止反应，用乙酸乙酯(500mL)进行萃取，将萃取液浓缩后，进行柱层析，用乙酸乙酯洗脱，洗脱液浓缩，重结晶后得到式I化合物的甲基化产物。
Figure PCTCN2016077649-appb-000013
相关化合物的结构确证数据：
Figure PCTCN2016077649-appb-000014
白色粉末,[α]24 D＝+102.5(c 0.017,MeOH)；红外(溴化钾)νmax2970,1730,1689,1618,1400and 1080cm–1；紫外(甲醇)λmax(logε):211(0.41),233.6(0.26),280.9(0.20),285.4(0.19),325(0.21)nm；质谱EIMS m/z 464[M]·+。
Figure PCTCN2016077649-appb-000015
白色粉末,[α]24 D＝+103.5(c 0.017,MeOH)；红外(溴化钾)νmax2970,1721,1690,1618,1375and 1082cm–1；紫外(甲醇)λmax(logε):211(0.41),233.6(0.26),280.9(0.20),287.4(0.19),320(0.21)nm；质谱EIMS m/z 494[M]·+。
Figure PCTCN2016077649-appb-000016
无色结晶；[α]24 D＝+123(c 0.012,MeOH)；红外IR(KBr)νmax 2926, 1687,1620,1421and 1102cm–1；紫外UV(MeOH)λmax(logε):202.8(0.69),211.2(0.64),255.8(0.13),284.6(0.05)nm；质谱EIMS m/z 479[M]·+。
Figure PCTCN2016077649-appb-000017
无色结晶；[α]24 D＝+104.5(c 0.014,MeOH)；红外IR(KBr)νmax 2926,1687,1600,1421and 1107cm–1；紫外UV(MeOH)λmax(logε):202.8(0.69),211.2(0.64),255.8(0.13),284.4(0.05)nm；质谱EIMS m/z 509[M]·+。
2)称取上述干燥后的式I化合物(0.1mol)溶于硫醇中，加入BBr3，在-70℃丙酮干冰浴中充分搅拌，反应过夜后，终止反应，反应产物进行柱层析，洗脱液浓缩后得到式I化合物的的脱甲基衍生物。
Figure PCTCN2016077649-appb-000018
相关化合物的结构确证数据：
Figure PCTCN2016077649-appb-000019
[α]24 D＝+95(c 0.014,MeOH)；红外IR(KBr)νmax 3350,2900,1630,1450and 1135cm–1；紫外UV(MeOH)λmax(logε):200.8(0.69),215.2(0.64),250.5(0.13),282(0.05)nm；质谱EIMS m/z 422[M]·+。
Figure PCTCN2016077649-appb-000020
[α]24 D＝+130(c 0.014,MeOH)；红外IR(KBr)νmax 3360,2929,1650,1410and 1105cm–1；紫外UV(MeOH)λmax(logε):204.8(0.69),211.2(0.64),254(0.13),270(0.05)nm；质谱EIMS m/z 423[M]·+。
式III化合物的制备：
称取上述干燥后的式I化合物(0.1mol)溶于无水丙酮中，加入无水碳酸钾，常温条件下，在充分搅拌下向反应体系中加入乙酸酐，反应1-5h后，向反应体系中加水终止反应，用乙酸乙酯(500mL)进行萃取，将萃取液浓缩后，进行柱层析，用乙酸乙酯洗脱，洗脱液浓缩，重结晶后得到式I化合物的乙酰化产物。
Figure PCTCN2016077649-appb-000021
相关化合物的结构确证数据：
Figure PCTCN2016077649-appb-000022
白色粉末；[α]24 D＝+130.5(c 0.022,MeOH)；红外(溴化钾)νmax2970,1720,1618,1379and 1085cm–1；紫外(甲醇)λmax(logε):211(0.41),233.6(0.26),280.9(0.20),285(0.19),325(0.21)nm；质谱EIMS m/z 520[M]·+。
Figure PCTCN2016077649-appb-000023
白色粉末；[α]24 D＝+130(c 0.015,MeOH)；红外(溴化钾)νmax 2970,1721,1618,1380and 1082cm–1；紫外(甲醇)λmax(logε):211(0.41),234(0.26),282.4(0.20),285(0.19),325(0.21)nm；质谱EIMS m/z 606[M]·+。
Figure PCTCN2016077649-appb-000024
白色粉末；[α]24 D＝+123.5(c 0.014,MeOH)；红外IR(KBr)νmax2926,1675,1600,1420and 1100cm–1；紫外UV(MeOH)λmax(logε):202.8(0.69),211.2(0.64),255(0.13),281.6(0.05)nm；质谱EIMS m/z 564[M]·+。
Figure PCTCN2016077649-appb-000025
白色粉末；[α]24 D＝+100.5(c 0.016,MeOH)；红外IR(KBr)νmax2926,1687,1620,1421and 1110cm–1；紫外UV(MeOH)λmax(logε):204.8(0.69),215.2(0.64), 252.8(0.13),285.6(0.05)nm；质谱EIMS m/z 650[M]·+。
式IV化合物的制备
1)称取上述干燥后的式I、式II或式III化合物(0.1mol)溶于无水二氯甲烷中，加入1N磺酰氯，在冰水浴中充分搅拌，反应3-5h后，向反应体系中加氯化铵溶液终止反应，用乙酸乙酯(500mL)进行萃取，将萃取液浓缩后，进行柱层析，用乙酸乙酯洗脱，洗脱液浓缩，重结晶后得到式I化合物的卤代产物。
Figure PCTCN2016077649-appb-000026
相关化合物的结构确证数据：
Figure PCTCN2016077649-appb-000027
[α]24 D＝+130(c 0.014,MeOH)；红外IR(KBr)νmax 3360,2929,1650,1410and 1105cm–1；紫外UV(MeOH)λmax(logε):204.8(0.69),211.2(0.64),254(0.13),270(0.05)nm；质谱EIMS m/z 471.6[M]·+。
Figure PCTCN2016077649-appb-000028
[α]24 D＝+100.2(c 0.020,MeOH)；红外IR(KBr)νmax 3330,2900,1620,1415and 1105cm–1；紫外UV(MeOH)λmax(logε):206.3(0.69),210.2(0.64),254.3(0.13),270(0.05)nm；质谱EIMS m/z 472.5[M]·+。
2)称取上述干燥后的式I的卤代产物(0.1mol)，加入1N氢氧化钠固体以及适量硝酸银和蒙脱石混合催化剂，96℃反应3-5h后，反应产物先后通过氯仿以及甲醇萃取，萃取液浓缩进行柱层析，洗脱液重结晶后得到式IV化合物。
Figure PCTCN2016077649-appb-000029
相关化合物的结构确证数据：
Figure PCTCN2016077649-appb-000030
[α]24 D＝+140(c 0.016,MeOH)；红外IR(KBr)νmax 3340,2929,1650,1410and 1105cm–1；紫外UV(MeOH)λmax(logε):206.8(0.69),215.2(0.64),250(0.13),272(0.05)nm；质谱EIMS m/z 452[M]·+。
Figure PCTCN2016077649-appb-000031
[α]24 D＝+142(c 0.012,MeOH)；红外IR(KBr)νmax 3345,2900,1650,1400and 1125cm–1；紫外UV(MeOH)λmax(logε):210.4(0.69),211.5(0.64),254(0.13),270(0.05)nm；质谱EIMS m/z 453.6[M]·+
式V化合物的制备：
称取上述干燥后的式I、式II、式III或式IV化合物(0.1mol)溶于脱水甲醇后置于充满氢气的反应瓶中，常温条件下，在充分搅拌下将适量Pd/C加到反应溶液中，反应过夜后，过滤除去钯碳，终止反应，将反应液浓缩后，进行柱层析，用乙酸乙酯洗脱，洗脱液浓缩，重结晶后得到式V化合物。
Figure PCTCN2016077649-appb-000032
相关化合物的结构确证数据：
Figure PCTCN2016077649-appb-000033
无色结晶；[α]24 D＝+133.5(c 0.017,MeOH)；红外(溴化钾)νmax 3288,2970,1721,1618,1379and 1082cm–1；紫外(甲醇)λmax(logε):211(0.41),233.6(0.26),280.9(0.20),285(0.19),322(0.21)nm；质谱EIMS m/z 440.2[M]·+。
Figure PCTCN2016077649-appb-000034
白色粉末；[α]24 D＝+133.5(c 0.017,MeOH)；红外IR(KBr)νmax 3366,2926,1600,1421and 1105cm–1；紫外UV(MeOH)λmax(logε):204.8(0.69),211.2(0.64),253(0.13),280(0.05)nm；质谱EIMS m/z 440[M]·+。
实施例3中未具体指明的其他有机化学反应条件，以及正相硅胶柱色谱分离等其他实验操作条件均为本领域常规的实验操作条件，本领域的技术人员可以根据实际需要，进行合理的选择。
实施例4
本发明式Ⅰ化合物的抗病毒活性
(1)抗病毒活性测试
采用细胞病变抑制作用(CPE)对单纯疱疹Ⅰ型病毒(HSV-1)的体外抗病毒活性进行测试。
(2)活性测试方法
将培养成单层的Hep-2细胞用胰酶消化后，接种于96孔板中，长成单层备用。将HSV-1病毒接种于Hep-2细胞上，加2％血清1640培养液后置37℃、5％CO2条件下培养，出现90％以上的病变后，反复冻融3次后吹打离心，定量分装，–80℃冰箱冻存备用。受试样品每管以10μL DMSO溶解后，加入200μL的2％1640培养液，并连续10次2倍比稀释，共10个稀释度，然后横向接种于96板孔中的单层细胞上，11列为病毒对照、12列为细胞对照，37℃、5％CO2培养，每小时观察病变，连续观察24h(HSV-1)。病毒对照出现90％以上的病变后， 将板孔内液体吸弃，加1％中性红染色，在540nm波长测定OD值，用Reed-Muench方法计算药物半数有效浓度(IC50)，观察药物抑杀病毒的效果。
(3)活性测试结果
试验结果显示，本发明制备的式I、式II、式III、式IV及式V化合物对HSV-1病毒具有不同程度的抑制作用，IC50值均在0.07-100μM之间，其中式I化合物的抗HSV-1病毒活性最为突出，远远强于阳性药利巴韦林的活性(见表1)。更为重要的是本发明制备的式I化合物的毒性极低。
表1式I化合物的抗HSV-1病毒活性
Figure PCTCN2016077649-appb-000035
实验表明，本发明的生物碱类化合物对HSV-1感染具有很强的抑制活性，可将其制成抗病毒药物，具有广阔的应用前景。

Claims (10)

  1. 一种生物碱类化合物或其药学上可接受的盐:
    Figure PCTCN2016077649-appb-100001
    式中，R为二萜侧链或其含氧衍生物,X、Z、W为羟基或其衍生物，Y为H或卤素或羟基衍生物。
  2. 根据权利要求1所述的生物碱类化合物或其药学上可接受的盐，其特征在于，所述生物碱类化合物为
    Figure PCTCN2016077649-appb-100002
    R为
    Figure PCTCN2016077649-appb-100003
  3. 根据权利要求1所述的生物碱类化合物或其药学上可接受的盐，其特征在于，所述生物碱类化合物为：
    Figure PCTCN2016077649-appb-100004
    R为
    Figure PCTCN2016077649-appb-100005
    X为OH或C1-C4的烷氧基,Y为OH或C1-C4的烷氧基,Z为OH或C1-C4的烷氧基,W为OH或C1-C4的烷氧基。
  4. 根据权利要求1所述的生物碱类化合物或其药学上可接受的盐，其特征在于，所述生物碱类化合物为：
    Figure PCTCN2016077649-appb-100006
    R为
    Figure PCTCN2016077649-appb-100007
    X为OH或C1-C4的烷酰氧基，Y为OH或C1-C4的烷酰氧基，Z为OH或C1-C4的烷酰氧基,W为OH或C1-C4的烷酰氧基。
  5. 根据权利要求1所述的生物碱类化合物或其药学上可接受的盐，其特征在于，所述生物 碱类化合物为：
    Figure PCTCN2016077649-appb-100008
    R为
    Figure PCTCN2016077649-appb-100009
    X为OH、C1-C4的烷氧基或C1-C4的烷酰氧基，Y为卤素(Cl、Br、F)或OH，Z为OH、C1-C4的烷氧基或C1-C4的烷酰氧基,W为OH或C1-C4的烷氧基或C1-C4的烷酰氧基。
  6. 根据权利要求1所述的生物碱类化合物或其药学上可接受的盐，其特征在于，所述生物碱类化合物为：
    Figure PCTCN2016077649-appb-100010
    R为
    Figure PCTCN2016077649-appb-100011
    X为OH、C1-C4的烷氧基或C1-C4的烷酰氧基，Y为H、OH、卤素、C1-C4的烷氧基或C1-C4的烷酰氧基，Z为OH、C1-C4的烷氧基或C1-C4的烷酰氧基,W为OH或C1-C4的烷氧基或C1-C4的烷酰氧基。
  7. 权利要求1所述的化合物的制备方法，其特征包括以下一个或几个步骤：
    (1)对真菌Scopulariopsis sp.(TA01-33)进行进行发酵培养，发酵液提取浓缩后分别进行正相硅胶柱层析、Sephadex LH-20凝胶柱层析后，再经HPLC高效液相制备色谱，得到式I喹啉酮生物碱结晶化合物；
    (2)式I化合物溶于DMF、丙酮、氯仿等非质子性溶剂中，在碳酸钾催化下，分别与卤代烷烃或酰氯常温下反应，得到生物碱的卤素取代或烷氧基取代或烷酰氧基取代衍生物；
    (3)式I化合物溶于硫醇中，与BBr3低温下反应，得到生物碱化合物的脱甲基衍生物；
    (4)式I化合物溶于甲醇溶剂中，在Pd/C催化下与氢气加成，得到生物碱化合物的氢化衍生物。
  8. 一种抗单纯疱疹Ⅰ型病毒(HSV-1,Herpes Simplex Virus 1)剂，其特征在于其含有权利要求1所述的化合物或其药学上可接受的盐作为有效成分。
  9. 权利要求1所述的化合物或其药学上可接受的盐在制备抗单纯疱疹Ⅰ型病毒剂中的应用。
  10. 一种药物组合物，其特征在于其含有权利要求1所述的化合物或其药学上可接受的盐以及药学上可接受的载体、稀释剂、赋形剂。
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