CN108264515A - A kind of benzo [def] carbazole compound and its preparation method and application - Google Patents

A kind of benzo [def] carbazole compound and its preparation method and application Download PDF

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CN108264515A
CN108264515A CN201710004593.2A CN201710004593A CN108264515A CN 108264515 A CN108264515 A CN 108264515A CN 201710004593 A CN201710004593 A CN 201710004593A CN 108264515 A CN108264515 A CN 108264515A
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unsubstituted
substituted
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CN108264515B (en
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张翱
梁广
丁春勇
梁兵
陈虹锦
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Shanghai Institute of Materia Medica of CAS
Wenzhou Medical University
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Shanghai Institute of Materia Medica of CAS
Wenzhou Medical University
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    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/06—Peri-condensed systems

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

The present invention relates to a kind of benzo [def] carbazole compound with structure shown in below formula (I) or its pharmaceutically acceptable salt, preparation method, the pharmaceutical composition including the compound, and application thereof.Benzo [def] carbazole compound has the function of inside and outside anti-inflammatory activity, so as to the utilization in anti-inflammatory drug.

Description

A kind of benzo [def] carbazole compound and its preparation method and application
Technical field
The invention belongs to pharmaceutical field, it is related to benzo [def] carbazole compound of logical formula (I) and its pharmaceutically acceptable Salt, and preparation method thereof and the application in anti-inflammatory drug is prepared.
Background technology
Inflammatory reaction and generation, the development of Various Complex major disease are closely related, inhibit the reaction of early stage related inflammation, then Preventive and therapeutic action can be played to these diseases.Although at present clinically there are many anti-inflammatory drug, however, all there is differences The toxicity risk of degree.Therefore, safe and effective non-steroid antiinflammatory object of the exploitation with independent intellectual property right is used It is of great significance in the treatment and prevention of inflammation related disease.
Tanshinone IIA (Tan-IIA) is China's one important liposoluble constituent of famous salviamiltiorrhizabung, is had extensive important Bioactivity, including anti-inflammatory activity etc..According to the literature, tanshinone IIA has resisting acute lung injury activity, however its is poor Druggability limits its further clinical development, and its o-quinone segment may be to lead to a major reason of its druggability difference, It is therefore desirable to its further structure optimization.Natural products salviadione is for the first time from natural plants Radix Salviae Miltiorrhizae by Sun et al. Isolated one rare nitrogenous Fourth Ring condenses benzo [def] carbazoles 3,5- diketone chemical combination in the ethanol extract of root Object, structure novel is unique, does not have o-quinone segment.Since content is extremely rare, the rare report of activity research (J.Nat.Prod.2005,68,1066-1070)。
In this context, the structure of natural products salviadione and tanshinone IIA is carried out split by the present invention, is passed through The nitrogen cyclization of one pot of series connection, has obtained a kind of novel Fourth Ring and has condensed benzo [def] carbazole compound, such compound With significant inside and outside anti-inflammatory activity and good druggability.
Invention content
It is an object of the present invention to provide benzo [def] carbazole compounds and its pharmacy shown in a kind of logical formula (I) Upper acceptable salt.By the research of the anti-inflammatory activity to the benzo [def] carbazole compound, find it with inside and outside The effect of anti-inflammatory activity, so as to be used for anti-inflammatory drug.
Another object of the present invention is to provide the method for preparing above-mentioned benzo [def] carbazole compound.
Another object of the present invention be provide comprising therapeutically effective amount selected from above-mentioned benzo [def] carbazole compound and It is one or more as active component for anti-inflammatory pharmaceutical composition in its pharmaceutically acceptable salt.The medicine group Pharmaceutically acceptable carrier and/or excipient (for example, diluent etc.) can optionally be further included by closing object.
Another object of the present invention is to provide purposes of the aforementioned pharmaceutical compositions in preparing for anti-inflammatory drug.
Another object of the present invention is to provide a kind of for anti-inflammatory pharmaceutical composition, and it includes being selected from for therapeutically effective amount In above-mentioned benzo [def] carbazole compound and its pharmaceutically acceptable salt it is one or more as active constituents and its His pharmaceutically acceptable therapeutic agent, particularly other anti-inflammatory drugs.Described pharmaceutical composition can optionally further include medicine Acceptable carrier and/or excipient (for example, diluent etc.) on.
Another object of the present invention is to provide a kind of anti-inflammatory method, the method includes give need the treatment patient to One in benzo according to the present invention [def] carbazole compound and its pharmaceutically acceptable salt of medicine therapeutically effective amount Kind or it is a variety of or it is according to the present invention comprising therapeutically effective amount be selected from benzo according to the present invention [def] carbazole compound With one or more pharmaceutical compositions as active component in its pharmaceutically acceptable salt.
Inventor is reacted for the first time using tanshinone compound as raw material by " one pot of multistep ", is obtained shown in logical formula (I) Benzo [def] carbazole compound, so as to obtain a kind of structure novel and with notable inside and outside anti-inflammatory activity compound, It has thus completed the present invention.
In first aspect present invention, it is to provide a kind of benzo [def] carbazole compound having shown in following logical formula (I) Or its pharmaceutically acceptable salt：
Wherein：
R1Selected from H, hydroxyl, amino, C1-C8Alkoxy, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2- C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C3-C8Ring Alkenyl, substitution or unsubstituted C6-C10Aryl, halogen；The substituted substituent group be selected from halogen, nitro, cyano, amino, hydroxyl, Methylol, ethoxy, sulfydryl, carboxyl, ester group, C1-C6The monosubstituted amido of alkyl, C1-C6The disubstituted amido of alkyl, C1-C6Alcoxyl Base, C1-C6Alkyl carbonyl oxy, C1-C6Cycloalkyl carbonyloxy group, heterocycle carbonyloxy group, C1-C6Alkoxy carbonyl, C1-C6Cycloalkyloxy Carbonyl, heterocyclyloxycarbonyl, C1-C6Carbalkoxyl amido, C1-C6One or more in alkane sulfydryl or water soluble functional group It is a；
R2Selected from H, hydroxyl, amino, C1-C8Alkoxy, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2- C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C3-C8Ring Alkenyl, substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted C5-C10Heterocycle, substituted or unsubstituted C5-C10It is miscellaneous Aryl, halogen；The substituted substituent group is selected from halogen, nitro, cyano, amino, hydroxyl, methylol, ethoxy, sulfydryl, carboxylic Base, ester group, C1-C6The monosubstituted amido of alkyl, C1-C6The disubstituted amido of alkyl, C1-C6Alkoxy, C1-C6Alkyl carbonyl oxy, C1- C6Cycloalkyl carbonyloxy group, heterocycle carbonyloxy group, C1-C6Alkoxy carbonyl, C1-C6Cyclo alkoxy carbonyl, heterocyclyloxycarbonyl, C1- C6Carbalkoxyl amido, C1-C6One or more of alkane sulfydryl or water soluble functional group；
R3Selected from H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, it is substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C3-C8Cycloalkenyl group, substituted or unsubstituted C6- C10Aryl, substituted or unsubstituted C5-C10Heterocycle, substituted or unsubstituted C5-C10Heteroaryl；The substituted substituent group choosing From halogen, nitro, cyano, amino, hydroxyl, methylol, ethoxy, hydroxyl methoxyl group, hydroxy ethoxy, sulfydryl, carboxyl, ester group, three Methyl fluoride, C1-C6Alkyl, C1-C6The monosubstituted amido of alkyl, C1-C6The disubstituted amido of alkyl, C1-C6Alkoxy, C1-C6Alkyl oxycarbonyl Oxygroup, C1-C6Cycloalkyl carbonyloxy group, C6-C10Aryloxy, it is unsubstituted or by being selected from halogen, C1-C3Alkyl, C1-C3Alkoxy One or more of group substitution C6-C10Aryl, heterocycle carbonyloxy group, C1-C6Alkoxy carbonyl, C1-C6Cycloalkyloxy carbonyl Base, heterocyclyloxycarbonyl, C1-C6Carbalkoxyl amido, C1-C6One or more of alkane sulfydryl or water soluble functional group；
X1Selected from carbon, nitrogen, oxygen or sulphur；
X2It is not present or selected from nitrogen, oxygen or sulphur；
It is preferred that
R1Selected from methyl, isopropyl or methylol；
R2Selected from H, halogen, substituted or unsubstituted C2-C8Alkenyl or C2-C8Alkynyl, substituted or unsubstituted C1-C8Alkane Base, substitution or unsubstituted C6-C10Aryl, substitution or unsubstituted C6-C10Heteroaryl；The substituted substituent group is selected from halogen, nitre Base, cyano, amino, hydroxyl, methylol, ethoxy, C1-C6The monosubstituted amido of alkyl, C1-C6The disubstituted amido of alkyl, C1-C6Alkane One or more of oxygroup；
R3Selected from H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C6-C10Aryl；The substituted substitution Base is selected from halogen, amino, hydroxyl, methylol, ethoxy, hydroxyl methoxyl group, hydroxy ethoxy, trifluoromethyl, C1-C6Alkyl, C1-C6 The monosubstituted amido of alkyl, C1-C6The disubstituted amido of alkyl, C1-C6Alkoxy, C1-C6Alkyl carbonyl oxy, C1-C6Cycloalkyl carbonyl oxygen Base, C6-C10Aryloxy, it is unsubstituted or by being selected from halogen, C1-C3Alkyl, C1-C3One or more of alkoxy group Substituted C6-C10Aryl, C1-C6Alkoxy carbonyl, C1-C6Cyclo alkoxy carbonyl, C1-C6One or more in carbalkoxyl amido It is a；
X1Selected from nitrogen, oxygen or sulphur；
X2It is not present or selected from oxygen or sulphur；
Further preferably,
R1For methyl or methylol；
R2For H, chlorine, bromine, iodine, ethyl, vinyl, thienyl or methoxyphenyl；
R3For butyl, heptyl, phenyl, benzyl, phenethyl, chlorphenyl, bromophenyl, trifluoromethyl, aminomethyl phenyl, first Base phenyl, ethylphenyl, methoxyphenyl, ethoxyl phenenyl, acetamidophenyl, Phenoxyphenyl, acetoxyl group phenyl, 4- Bromo- 3- fluoro-phenyls, the bromo- 3- methylphenyls of 4-, the chloro- phenyl of the fluoro- 3- of 4-, 3,5-dimethylphenyl, Dimethoxyphenyl, trimethoxy Phenyl, methylbenzyl, chlorobenzyl, luorobenzyl, methoxy-benzyl, fluorophenylethyl or hydroxyethoxy ethyl；
Particularly preferably,
R1For methyl or methylol；
R2For H, chlorine, bromine, iodine, ethyl, vinyl, thiene-3-yl or 3- methoxyphenyls；
R3For butyl, heptyl, phenyl, benzyl, phenethyl, 4- chlorphenyls, 4- bromophenyls, 4- trifluoromethyls, 4- first Base phenyl, 3- aminomethyl phenyls, 4- ethylphenyls, 4- methoxyphenyls, 4- ethoxyl phenenyls, 4- Phenoxyphenyls, 2- methoxyl groups Phenyl, acetoxyl group phenyl, 4- acetamidophenyls, the bromo- 3- fluoro-phenyls of 4-, the bromo- 3- methylphenyls of 4-, the chloro- benzene of the fluoro- 3- of 4- Base, 2,4- 3,5-dimethylphenyls, 3,4- Dimethoxyphenyls, 3,4,5- trimethoxyphenyls, 3- methylbenzyls, 3- chlorobenzyls, 4- Chlorobenzyl, 4- luorobenzyls, 2- methoxy-benzyls, 2- methoxy-benzyls, 4- fluorophenylethyls or hydroxyethoxy ethyl；
In term used herein, " C1-C8Alkyl " refers to the linear chain or branch chain alkyl containing 1-8 carbon atom, packet It includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, n-pentyl etc..
“C1-C6Alkoxy " refers to the alkoxy containing 1-6 carbon atom, including methoxyl group, ethyoxyl, positive propoxy, different Propoxyl group, n-butoxy, isobutoxy, tert-butoxy.
“C2-C8Alkenyl " refers to the linear chain or branch chain alkylene containing 2-8 carbon atom, including but not limited to vinyl, alkene Propyl etc..
“C3-C8Cycloalkyl or cycloalkenyl group " refers to the hydrocarbon with 3-8 carbon atom single loop system of saturation or unsaturation ring Base, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclopropanyl, cyclohexenyl group etc..
" aryl " refers to the single carbon polycyclic aromatic group containing 6-14 carbon atom or condensed or non-condensed more homocyclic aromatic groups, In the case of more carbocyclic rings, as long as a carbocyclic ring is aromatic rings.
" heteroaryl " refers to contain aromatic group of the 1-4 hetero atom as ring members in ring.Hetero atom refer to nitrogen, Oxygen or sulphur.Heteroaryl can be the bicyclic heteroaryl with 5-7 annular atom or the bicyclic heteroaryl with 7-11 annular atom Base.As long as a ring is hetero-aromatic ring in the bicyclic heteroaryl, another can be aromatic rings or non-aromatic ring, containing miscellaneous Atom or without heteroatomic.In addition, the bicyclic heteroaryl is either simultaneously ring structure or spirane structure, Can be that two heterocycles are connected directly.The example of heteroaryl includes but not limited to pyrrole radicals, pyrazolyl, imidazole radicals, oxazolyls, pyrrole Piperidinyl, pyrimidine radicals, furyl, thienyl, isoxazolyls, indyl etc..
" heterocycle " refers to contain nonaromatic cyclic group of the 1-4 hetero atom as ring members in ring.Hetero atom refers to Nitrogen, oxygen or sulphur.Heterocycle can be the monocyclic heterocycles base or bicyclic with 7-11 annular atom for having 4-8 annular atom Heterocycle.As long as a ring is heterocycle in the bicyclic heterocyclic radical, another can be aromatic rings or non-aromatic ring, contain It is heteroatomic or without heteroatomic.In addition, the bicyclic heterocyclic radical is either simultaneously ring structure or spirane structure, Can also be that two heterocycles are connected directly.The example of heterocycle includes but is not limited to azelidinyl, pyrrolidinyl, pyrrolin Base, tetrahydrofuran base, dihydrofuran base, piperazinyl, piperidyl, morpholinyl, thio-morpholinyl, THP trtrahydropyranyl, thiophane Base etc..
" halogen " refers to fluorine, chlorine, bromine or iodine.
" the water-soluble functional group " is selected from hydroxyl, multi-hydroxy alkoxy, saccharide residue, carboxyl, sulfonic group, phosphate, Polyhydroxy C1-C6Alkoxy carbonyl, carboxyl C1-C6Alkoxy, carboxyl C1-C6Alkyl carbonyloxy.
" therapeutically effective amount " refers to：The amount of compound is enough to be obviously improved the state of an illness, and is unlikely to generate serious Side effect.Therapeutically effective amount is determined according to the age for the treatment of object, the state of an illness, course for the treatment of etc..
" pharmaceutically acceptable carrier " refers to：One or more biocompatible solids or liquid filler or gel Substance, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as group Close in object each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound. Pharmaceutically acceptable carrier part example has sugared (such as glucose, sucrose, lactose), starch (such as cornstarch, potato Starch etc.), cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, Talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive oil Deng), polyalcohol (such as propylene glycol, glycerine, mannitol, sorbierite), emulsifier (such as tween), wetting agent (such as dodecyl sulphur Sour sodium), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
In a preferred embodiment of the present invention, benzo [def] carbazoles chemical combination shown in logical formula (I) of the invention Object includes, but are not limited to following compound：
The second aspect of the present invention also provides benzo [def] carbazole compound preparation method of logical formula (I), this method Including：
Wherein, R1、R2、R3、X1And X2Definition as hereinbefore,
Tanshinone compound shown in formula A and aminated compounds R3-NH2In the presence of an oxidizer, it is anti-that oxidative condensation occurs Should, obtain benzo [def] carbazole compound of logical formula (I).The oxidant can be 2,2,6,6- tetramethyl piperidine nitrogen oxygen Compound (TEMPO), oxygen, silver oxide (AgO), silver carbonate (Ag2CO3), silver acetate (AgOAc), copper acetate (Cu (OAc)2), three Iron chloride (FeCl3), manganese dioxide (MnO2), 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), selenium dioxide (SeO2), Tert-butyl hydroperoxide (TBHP), iodobenzene acetate (PhI (OAc)2), benzoquinones (BQ), preferably 2,2,6,6- tetramethyl piperidine oxygen Compound (TEMPO)；
The oxidative dimerization can carry out in non-polar aroma solvent under heating condition,
The non-polar aroma solvent be benzene, chlorobenzene, toluene, dimethylbenzene, trimethylbenzene, preferably toluene；
The temperature of the heating is 50 to 160 DEG C, and the reaction time is 24 hours to 48 hours.
The third aspect of the present invention is to provide a kind of pharmaceutical composition, it contain therapeutically effective amount be selected from according to the present invention Benzo [def] carbazole compound of logical formula (I) is used as active constituent with one or more in its pharmaceutically acceptable salt, And optional pharmaceutically acceptable carrier and/or excipient (for example, diluent etc.).
The fourth aspect of the present invention is to provide benzo [def] carbazole compound of logical formula (I) or its is pharmaceutically acceptable Use in preparing for anti-inflammatory drug of salt and pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt On the way.Compound of the present invention or its pharmaceutically acceptable salt can be administered alone or pharmaceutically acceptable with other Therapeutic agent administration, particularly with other anti-inflammatory drug substances.The therapeutic agent includes but not limited to：It is aspirin, double Chlorine sweet smell acid, Ketoprofen, brufen, fenbufen, mefenamic acid, Meclofenamic Acid, Indomethacin, sulindac, acemetacin, benzyl reach Bright, Etodolac, naproxen, brufen etc..Each ingredient to be combined can simultaneously or sequentially be given, with unitary system dosage form Formula is given in the form of different preparations.The combination not only includes the compound of the present invention and a kind of group of other activating agents It closes, and the combination including the compound of the present invention He two or more other activating agents.
Therefore, in the fifth aspect of the present invention, a kind of pharmaceutical composition is provided, root is selected from it includes therapeutically effective amount According to one or more as active constituent in benzo [def] carbazole compound and its pharmaceutically acceptable salt of the present invention And other pharmaceutically acceptable therapeutic agents, particularly other anti-inflammatory drugs.Described pharmaceutical composition optionally can be further Include pharmaceutically acceptable carrier and/or excipient (for example, diluent etc.).
In the sixth aspect of the present invention, a kind of method for treating inflammation is provided, the method includes giving to need the treatment Patient's dosage treatment effective amount selected from benzo according to the present invention [def] carbazole compound and its is pharmaceutically acceptable In salt it is one or more or according to the present invention comprising therapeutically effective amount be selected from benzo according to the present invention [def] carbazole One or more pharmaceutical compositions as active component in class compound and its pharmaceutically acceptable salt.
In the present invention, the inflammation is selected from acute lung injury, malicious purulence disease, dermatitis and eczema, oro-maxillo-facial inflammation, acute Otitis externa and pneumonia.
Description of the drawings
The influence that Fig. 1 discharges the macrophage inflammatory factor that LPS is induced for part of compounds in embodiment, * P< 0.05, * * P<0.01, show that the group has significant difference compared with LPS groups；
Fig. 2 can dose-dependently inhibit the mouse pulmonary edema of LPS inductions, * P for compound S28<0.05, * * P< 0.01, show that the group has significant difference compared with LPS groups；
Fig. 3 is the increase that compound S28 can dose-dependently alleviate protein concentration in BALF；Compound S28 is tested Two groups of dosage 10mg/kg and 20mg/kg, * * P<0.01, show that the group has significant difference compared with LPS groups；
Fig. 4 can dose-dependently reduce the quantity of total cell in bronchoalveolar lavage fluid, * * P for compound S28<0.01, Show that the group has significant difference compared with LPS groups；
Fig. 5 can dose-dependently reduce the quantity of neutrophil leucocyte in bronchoalveolar lavage fluid, * * P for compound S28< 0.01, show that the group has significant difference compared with LPS groups.
Specific embodiment
Embodiment of the present invention is illustrated by the following example.However, embodiment of the present invention be not only restricted to it is following Specific detail in embodiment, because in view of the disclosure, other variations are to those of ordinary skill in the art Know and obviously.
Sample data is by following Instrument measuring：Nuclear magnetic resonance spectroscopy (1H-NMR) with 300 cores of Bruker Avance III Magnetic resonance device；Develop the color the smart section WFH-203B ultraviolet analysis instrument for three purposed used, and wavelength is 254nm and 365nm.Column chromatography silica gel (100-200 mesh, 300-400 mesh) is produced for Haiyang Chemical Plant, Qingdao；TLC silica gel plates are the HSGF-254 of Yantai chemical plant production Type tlc silica gel plate, the chromatography plate thickness that thin-layer chromatography uses are 0.2 ± 0.03mm, and the pre-prepared thin-layer chromatography used is pre- Plate thickness is prepared as 0.4-0.5mm；Petroleum ether (60-90 DEG C of boiling range), dichloromethane, ethyl acetate, methanol is that analysis is pure, red Join ketone IIA (No. CAS:568-72-9), Cryptotanshinone (No. CAS:35825-57-1), aniline, 2,2,6,6- tetramethyl piperidine oxygen Compound is provided by Sinopharm Chemical Reagent Co., Ltd., and agents useful for same and solvent unless otherwise indicated, are not specially treated. Other tanshinone compounds, for example, 17- hydroxyls tanshinone IIA, 15- bromines tanshinone IIA, 15- thiophene tanshinone IIA, 15- Ethylene tanshinone IIA, 15- ethyls tanshinone IIA, 15- m-methoxyphenyls tanshinone IIA refer to Journal ofNature Products, 2016,79 (10), 2514-2520 are made.All temperature represent that room temperature or environment temperature are with DEG C (degree Celsius) Refer to 20~25 DEG C.
The synthesis of embodiment 1, compound S1
Tanshinone IIA (32.2mg, 0.1mmol), aniline (10.2mg, 0.11mmol) and 2,2,6,6- tetramethyl piperidine oxygen Compound (TEMPO) (20.3mg, 0.13mmol) is added in the toluene of 1mL, 120 DEG C of reaction 48h of tube sealing.TLC detections have been reacted Bi Hou obtains solid 26.0mg, yield 85% by column chromatography for separation.
1H NMR(300MHz,CDCl3) δ 7.86 (d, J=6.9Hz, 1H), 7.58 (d, J=6Hz, 5H), 7.37 (d, J= 7.2Hz,1H),7.32(s,1H),2.92(s,2H),2.35(s,3H),1.53(s,6H).13C NMR(125MHz,CDCl3)δ 186.71,173.62,156.04,143.96,140.85,136.55,129.65,128.77(2C),128.31,126.80 (2C),126.46,126.39,125.37,123.61,122.71,121.80,120.66,116.05,57.83,40.67, 29.91(2C),9.41.
High resolution mass spectrum m/z (EI) C25H19NO3Theoretical value 381.1365, measured value 381.1366.
The synthesis of embodiment 2, compound S2
Using tanshinone IIA and parachloroanilinum as raw material, S2, yield 73% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.86 (d, J=7.2Hz, 1H), 7.53 (q, J=8.1Hz, 4H), 7.37 (d, J =7.2Hz, 1H), 7.32 (s, 1H), 2.92 (s, 2H), 2.34 (s, 3H), 1.52 (s, 6H)13C NMR(125MHz,CDCl3)δ 186.78,173.59,156.04,143.97,140.97,135.60,134.86,128.97(2C),128.40,128.22 (2C),126.32,126.23,125.31,123.67,123.01,121.76,120.90,116.03,57.76,40.66, 29.89(2C),9.38.
High resolution mass spectrum m/z (EI) C25H18ClNO3Theoretical value 415.0975, measured value 415.0978.
HPLC purity is 97.36%.
The synthesis of embodiment 3, compound S3
Using tanshinone IIA and para-bromoaniline as raw material, S3, yield 80% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.86 (d, J=6.9Hz, 1H), 7.67 (d, J=8.1Hz, 2H), 7.50 (d, J =8.1Hz, 2H), 7.37 (d, J=7.2Hz, 1H), 7.33 (s, 1H), 2.92 (s, 2H), 2.35 (s, 3H), 1.53 (s, 6H) .13C NMR(151MHz,CDCl3)δ186.74,173.57,156.02,143.96,140.96,135.37,131.93(2C), 128.50(2C),128.41,126.25,126.16,125.31,123.80,123.69,122.99,121.76,120.89, 116.04,57.76,40.66,29.89(2C)9.37.
High resolution mass spectrum m/z (EI) C25H18BrNO3Theoretical value 459.0470, measured value 459.0468.
HPLC purity is 97.18%.
The synthesis of embodiment 4, compound S4
Using tanshinone IIA and p-trifluoromethylaniline as raw material, S4, yield 38% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.88 (d, J=6.9Hz, 1H), 7.82 (d, J=7.8Hz, 2H), 7.76 (d, J =7.8Hz, 2H), 7.39 (d, J=6.9Hz, 1H), 7.34 (s, 1H), 2.93 (s, 2H), 2.35 (s, 3H), 1.54 (s, 6H) .13C NMR(125MHz,CDCl3)δ186.78,173.60,156.05,144.04,141.06,139.28,131.60, 131.38,128.56,127.60(2C),126.33,126.21,125.93,125.91,125.30,123.83,123.24, 121.76,121.10,116.12,57.75,40.70,29.89(2C),9.39.
High resolution mass spectrum m/z (EI) C26H18F3NO3Theoretical value 449.1239, measured value 449.1243.
HPLC purity is 95.51%.
The synthesis of embodiment 5, compound S5 and S41
Using tanshinone IIA and acetparaminosalol aniline as raw material, S5 and S41, yield point are prepared with reference to the synthetic method of S1 It Wei 50% and 13%.
S5：1H NMR(300MHz,CDCl3) δ 8.35 (s, 1H), 7.88 (d, J=7.2Hz, 1H), 7.66 (d, J= 8.4Hz, 2H), 7.48 (d, J=8.4Hz, 2H), 7.38 (d, J=7.2Hz, 1H), 7.32 (s, 1H), 2.92 (s, 2H), 2.34 (s,3H),2.10(s,3H),1.53(s,6H).13C NMR(125MHz,CDCl3)δ187.52,174.34,169.18, 156.86,144.83,141.62,140.51,132.30,128.94,127.71(2C),127.40,127.05,126.01, 124.30,123.68,122.37,121.41,120.20(2C),116.57,58.55,41.39,30.61(2C),25.27, 10.08.
High resolution mass spectrum m/z (EI) C27H22N2O4Theoretical value 438.1580, measured value 438.1574.
HPLC purity is 99.71%.
S41：1H NMR(300MHz,CDCl3) δ 9.59 (s, 1H), 8.05 (d, J=7.2Hz, 1H), 7.73 (d, J= 8.5Hz, 2H), 7.51 (d, J=8.5Hz, 2H), 7.37 (d, J=4.2Hz, 2H), 6.63 (d, J=9.9Hz, 1H), 6.47 (d, J=9.9Hz, 1H), 2.47 (s, 3H), 1.92 (s, 3H), 1.51 (s, 6H)13C NMR(125MHz,CDCl3)δ169.29, 169.23,154.14,151.44,145.33,140.23,140.20,138.35,131.08,126.31(2C),126.01, 124.05,123.90,121.53,121.13,120.63,120.50(2C),118.18,113.29,113.26,40.37, 29.09(2C),24.23,9.70.
High resolution mass spectrum m/z (EI) C27H22N2O3Theoretical value 422.1630, measured value 422.1628.
The synthesis of embodiment 6, compound s 6
Using tanshinone IIA and open-chain crown ether as raw material, S6, yield 70% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.85 (d, J=6.9Hz, 1H), 7.48 (d, J=8.1Hz, 2H), 7.41-7.30 (m,4H),2.91(s,2H),2.47(s,3H),2.35(s,3H),1.52(s,6H).13C NMR(151MHz,CDCl3)δ 186.72,173.60,156.02,143.91,140.79,139.67,133.97,129.52,129.43(2C),128.26, 126.45(2C),126.39,125.37,123.56,122.59,121.81,120.55,115.99,57.84,40.63,29.90 (2C),21.49,9.41.
High resolution mass spectrum m/z (EI) C26H21NO3Theoretical value 396.1521, measured value 396.1520.
The synthesis of embodiment 7, compound S7
Using tanshinone IIA and to ethyl aniline as raw material, S7, yield 71% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.85 (d, J=7.2Hz, 1H), 7.52 (d, J=7.2Hz, 2H), 7.40-7.34 (m, 3H), 7.32 (s, 1H), 2.91 (s, 2H), 2.86-2.62 (m, 3H), 2.35 (s, 3H), 1.52 (s, 6H), 1.33 (t, J= 7.5Hz,3H).13C NMR(125MHz,CDCl3)δ188.10,175.02,157.44,147.03,145.33,142.21, 135.50,129.69,129.56(2C),127.94(2C),127.80,126.78,125.01,123.98,123.22, 121.94,117.41,59.29,42.04,31.31(2C),30.09,16.42,10.84.
High resolution mass spectrum m/z (EI) C27H23NO3Theoretical value 409.1678, measured value 409.1681.
HPLC purity is 99.29%.
The synthesis of embodiment 8, compound S8
Using tanshinone IIA and P-nethoxyaniline as raw material, S8, yield 73% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.84 (d, J=7.2Hz, 1H), 7.53 (d, J=8.4Hz, 2H), 7.35 (d, J =7.2Hz, 1H), 7.32 (s, 1H), 7.05 (d, J=8.4Hz, 2H), 3.89 (s, 3H), 2.91 (s, 2H), 2.35 (s, 3H), 1.52(s,6H).13C NMR(125MHz,CDCl3)δ188.15,175.04,161.66,157.45,145.29,142.21, 130.66,129.63,129.32(2C),127.87,127.80,126.79,124.94,123.97,123.21,121.94, 117.36,115.31(2C),59.28,56.90,42.03,31.31(2C),10.83.
High resolution mass spectrum m/z (EI) C26H21NO4Theoretical value 411.1471, measured value 411.1476.
HPLC purity is:95.77%.
The synthesis of embodiment 9, compound S9
Using tanshinone IIA and p-ethoxyaniline as raw material, S9, yield 75% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.84 (d, J=6.9Hz, 1H), 7.51 (d, J=8.1Hz, 2H), 7.35 (d, J =7.2Hz, 1H), 7.31 (s, 1H), 7.03 (d, J=8.4Hz, 2H), 4.11 (q, J=6.8Hz, 2H), 2.91 (s, 2H), 2.35 (s, 3H), 1.52 (s, 6H), 1.46 (t, J=6.8Hz, 3H)13C NMR(125MHz,CDCl3)δ186.74,173.63, 159.71,156.04,143.87,140.78,129.04,128.20,127.85(2C),126.47,126.40,125.37, 123.51,122.53,121.80,120.50,115.94,114.32(2C),63.70,57.87,40.60,29.89(2C), 14.88,9.40.
High resolution mass spectrum m/z (EI) C27H23NO4Theoretical value 425.1627, measured value 425.1627.
HPLC purity is 95.13%.
The synthesis of embodiment 10, compound S10
Using tanshinone IIA and to phenoxybenzamine as raw material, S10, yield 64% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.86 (d, J=6.9Hz, 1H), 7.55 (d, J=8.7Hz, 2H), 7.43-.32 (m,4H),7.23-7.07(m,5H),2.92(s,2H),2.37(s,3H),1.53(s,6H).13C NMR(151MHz,CDCl3)δ 186.83,173.69,158.61,156.07,156.01,143.93,140.87,130.97,129.96(2C),128.29, 128.21(2C),126.50,126.39,125.35,124.23,123.59,122.74,121.78,120.67,120.24 (2C),117.69(2C),115.98,57.87,40.65,29.90(2C),9.44.
High resolution mass spectrum m/z (EI) C31H23NO4Theoretical value 473.1627, measured value 473.1629.
The synthesis of embodiment 11, compound S11
Using tanshinone IIA and o-aminoanisole as raw material, S11, yield 64% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.84 (d, J=6.9Hz, 1H), 7.51 (d, 2H), 7.43-7.28 (m, 2H), 7.12 (d, 2H), 3.75 (s, 3H), 3.01-2.80 (m, 2H), 2.35 (s, 3H), 1.52 (d, J=8.4Hz, 6H)13C NMR (125MHz,CDCl3)δ186.58,173.55,156.03,154.24,143.92,140.69,130.92,128.07, 128.01,126.85,126.32,126.19,125.31,123.41,122.45,121.75,120.49,120.32,116.09, 112.11,57.62,55.81,40.69,30.23,29.62,9.40.
High resolution mass spectrum m/z (EI) C26H21NO4Theoretical value 411.1471, measured value 411.1467.
HPLC purity is 96.63%.
The synthesis of embodiment 12, compound S12
Using tanshinone IIA and m-toluidine as raw material, S12, yield 63% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.85 (d, J=7.2Hz, 1H), 7.49-7.30 (m, 6H), 2.91 (s, 2H), 2.46(s,3H),2.35(s,3H),1.52(s,6H).13C NMR(151MHz,CDCl3)δ186.65,173.55,156.01, 143.90,140.80,138.70,136.54,130.51,128.56,128.23,127.28,126.52,126.49,125.35, 123.75,123.52,122.57,121.79,120.56,116.02,57.83,40.64,29.91(2C),21.51,9.39.
High resolution mass spectrum m/z (EI) C26H21NO3Theoretical value 395.1521, measured value 395.1529.
HPLC purity is 96.46%.
The synthesis of embodiment 13, compound S13
Using tanshinone IIA and 3- methyl -4- bromanilines as raw material, S13 is prepared with reference to the synthetic method of S1, yield is 66%.
1H NMR(300MHz,CDCl3) δ 7.85 (d, J=7.2Hz, 1H), 7.70 (d, J=8.4Hz, 1H), 7.46 (s, 1H),7.38–7.28(m,3H),2.91(s,2H),2.49(s,3H),2.35(s,3H),1.52(s,6H).13C NMR (125MHz,CDCl3)δ188.12,174.96,157.44,145.34,142.33,140.07,136.99,134.03, 130.36,129.74,127.76,127.73,127.04,126.73,125.02,124.28,123.19,122.22,117.45, 59.20,42.08,31.32(2C),24.62,10.79.
High resolution mass spectrum m/z (EI) C26H20BrNO3Theoretical value 473.0627, measured value 473.0626.
HPLC purity is 95.54%.
The synthesis of embodiment 14, compound S14
Using tanshinone IIA and to 3-, chloro- 4- fluoroanilines as raw material, prepare S14, yield is with reference to the synthetic method of S1 66%.
1H NMR(300MHz,CDCl3) δ 7.87 (d, J=7.2Hz, 1H), 7.68 (d, J=4.5Hz, 1H), 7.51 (d, 1H),7.43–7.27(m,3H),2.92(s,2H),2.35(s,3H),1.53(s,6H).13C NMR(125MHz,CDCl3)δ 188.15,174.97,161.04,159.03,157.44,145.37,142.45,134.25,130.88,129.75,128.37, 127.75,126.71,125.02,124.58,123.16,122.78,122.62,122.48,118.09,117.90,117.50, 59.11,42.10,31.31(2C),10.75.
High resolution mass spectrum m/z (EI) C25H17ClFNO3Theoretical value 433.0881, measured value 433.0879.
HPLC purity is 96.71%.
The synthesis of embodiment 15, compound S15
Using tanshinone IIA and the fluoro- 4- bromanilines of 3- as raw material, S15, yield 51% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.87 (d, J=6.9Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.43-7.29 (m,4H),2.93(s,2H),2.35(s,3H),1.53(s,6H).13C NMR(151MHz,CDCl3)δ186.69,173.50, 159.34,157.69,156.00,143.98,141.06,136.70,136.64,133.33,128.43,126.24,126.18, 125.28,123.99,123.97,123.70,123.24,121.75,121.12,116.10,116.02,115.85,110.8, 57.69,40.69,29.88(2C),9.34.
High resolution mass spectrum m/z (EI) C25H17BrFNO3Theoretical value 477.0376, measured value 477.0377.
HPLC purity is 98.39%.
The synthesis of embodiment 16, compound S16
Using tanshinone IIA and to acetoxyl group aniline as raw material, S16, yield 62% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.77 (d, J=7.2Hz, 1H), 7.64 (d, J=7.8Hz, 2H), 7.34 (d, J =6.9Hz, 1H), 7.29 (s, 1H), 7.27 (s, 1H), 4.88 (t, J=9.3Hz, 1H), 4.43-4.35 (m, 1H), 3.65- 3.53 (m, 1H), 2.90 (s, 2H), 2.34 (s, 3H), 1.51 (s, 6H), 1.35 (d, J=6.6Hz, 3H)13C NMR (125MHz,CDCl3)δ185.67,173.19,168.21,162.77,150.77,146.08,132.93,127.79,127.51 (2C),126.10,125.63,125.10,123.98,123.51,120.97(2C),119.92,115.59,80.89,57.27, 40.26,34.92,29.58,29.10,20.77,18.82.
High resolution mass spectrum m/z (EI) C27H23NO5Theoretical value 441.1576, measured value 441.1570.
HPLC purity is 97.06%.
The synthesis of embodiment 17, compound S17
Using tanshinone IIA and 2- methyl -4- methylanilines as raw material, S17 is prepared with reference to the synthetic method of S1, yield is 59%.
1H NMR(300MHz,CDCl3) δ 7.87 (d, J=7.2Hz, 1H), 7.38 (d, J=6.9Hz, 1H), 7.32 (s, 1H), 7.27 (s, 2H), 7.17 (s, 1H), 2.90 (s, 2H), 2.36 (d, J=12.9Hz, 6H), 2.01 (s, 3H), 1.53 (d, J =6.3Hz, 6H)13C NMR(126MHz,CDCl3)δ186.65,173.59,156.12,143.95,140.84,136.49, 136.35,131.00,130.69,130.67,127.99,127.05,126.54,126.41,125.32,123.29,122.60, 121.77,120.56,116.12,57.65,40.76,30.16,29.77,21.08,16.90,9.37.
High resolution mass spectrum m/z (EI) C27H23NO3Theoretical value 409.1678, measured value 409.1681.
HPLC purity is 97.70%.
The synthesis of embodiment 18, compound S18
Using tanshinone IIA and to -4 aminoanisole of 3- methoxyl groups as raw material, S18 is prepared with reference to the synthetic method of S1, is received Rate is 72%.
1H NMR(300MHz,CDCl3) δ 7.85 (d, J=6.9Hz, 1H), 7.39-7.30 (m, 2H), 7.17 (d, 1H), 7.09 (s, 1H), 7.00 (d, J=7.8Hz, 1H), 3.90 (s, 3H), 3.96 (s, 3H), 2.92 (s, 2H), 2.36 (s, 3H), 1.53(s,6H).13C NMR(125MHz,CDCl3)δ188.57,175.40,157.88,151.75,150.55,145.75, 142.69,131.23,130.09,128.44,128.39,127.25,125.38,124.46,123.69,122.46,120.99, 117.84,112.36,112.25,59.78,58.04,57.88,42.50,31.80(2C),11.30.
High resolution mass spectrum m/z (EI) C27H23NO5Theoretical value 441.1576, measured value 441.1577.
HPLC purity is 95.88%.
The synthesis of embodiment 19, compound S19 and S20
With tanshinone IIA and 3,4,5- trimethoxy-anilines are raw material, prepare S19 and S20 with reference to the synthetic method of S1, receive Rate is respectively 70% and 10%.
S19：1H NMR(300MHz,CDCl3) δ 7.84 (s, 1H), 7.30 (m, J=7.2Hz, 2H), 6.82 (s, 2H), 4.03-3.80(m,9H),2.92(s,2H),2.36(s,3H),1.53(s,6H).13C NMR(125MHz,CDCl3)δ188.47, 175.26,157.83,154.78(2C),145.75,142.73,140.70,133.88,130.12,128.49,128.40, 127.19,125.43,124.54,123.65,122.55,117.87,106.51,62.90,59.81,58.20(2C),42.50, 31.79(2C),11.31.
High resolution mass spectrum m/z (EI) C28H25NO6Theoretical value 471.1682, measured value 471.1681.
S20：1H NMR(300MHz,CDCl3) δ 8.01 (d, J=7.5Hz, 1H), 7.37-7.29 (m, J=6.5Hz, 2H), 6.87 (s, 2H), 6.67 (d, J=9.9Hz, 1H), 6.41 (d, J=9.8Hz, 1H), 3.99-3.80 (d, J=6.9Hz, 12H), 2.46(s,3H),1.50(s,6H).13C NMR(125MHz,CDCl3)δ169.58,154.00,153.32,150.11, 144.61,140.08,138.38,136.89,132.32,126.15,123.98,123.23,121.82,121.20,120.40, 117.91,113.66,113.52,104.28(2C),60.97,56.42(2C),40.19,29.34(2C),9.70.
High resolution mass spectrum m/z (EI) C28H25NO5Theoretical value 455.1733, measured value 455.1732.
The synthesis of embodiment 20, compound S21
Using tanshinone IIA and benzylamine as raw material, S21, yield 43% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.80 (d, J=7.2Hz, 1H), 7.62 (d, J=7.8Hz, 2H), 7.35-7.26 (m,5H),6.23(s,2H),2.92(s,2H),2.47(s,3H),1.48(s,6H).13C NMR(125MHz,CDCl3)δ 188.88,175.40,157.00,144.35,141.45,138.09,129.36(2C),129.17(2C),128.85, 128.72,126.47,125.94,123.89,123.11,122.34,121.03,116.44,58.29,51.81,41.35, 30.66(2C),10.17.
High resolution mass spectrum m/z (EI) C27H23NO3Theoretical value 395.1521, measured value 395.1526.
HPLC purity is 98.75%.
The synthesis of embodiment 21, compound S22
Using tanshinone IIA and phenyl ethylamine as raw material, S22, yield 45% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.82 (d, J=7.2Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=7.2Hz, 1H), 7.24-7.16 (m, 5H), 5.29-5.19 (m, 2H), 3.28 (t, J=7.4Hz, 2H), 2.77 (s, 2H), 2.46 (d, J= 14.0Hz,3H),1.59(s,1H),1.42(s,6H).13C NMR(151MHz,CDCl3)δ187.93,174.50,156.36, 143.65,140.74,137.37,129.22(2C),128.37(2C),127.42,126.66,126.12,125.53, 125.18,123.10,122.36,121.61,120.10,115.56,57.48,49.66,40.62,37.66,29.89(2C), 9.49.
High resolution mass spectrum m/z (EI) C27H23NO3Theoretical value 409.1678, measured value 409.1679.
HPLC purity is 97.85%.
The synthesis of embodiment 22, compound S23
Using tanshinone IIA and chlorobenzylamine as raw material, S23, yield 43% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.82 (d, J=7.2Hz, 1H), 7.56 (s, 1H), 7.52-7.46 (m, 1H), 7.32 (d, J=7.5Hz, 2H), 7.23 (d, J=4.5Hz, 2H), 6.20 (s, 2H), 2.92 (s, 2H), 2.45 (s, 3H), 1.49 (s,6H).13C NMR(125MHz,CDCl3)δ188.88,175.39,157.04,144.40,141.54,139.75,135.14, 130.65,129.12,129.08,128.73,127.36,126.36,125.93,123.88,123.36,122.34,121.24, 116.48,110.70,58.20,51.18,41.40,30.67(2C),10.14.
High resolution mass spectrum m/z (EI) C26H20ClNO3Theoretical value 429.1132, measured value 429.1134.
HPLC purity is 96.09%.
The synthesis of embodiment 23, compound S24
Using tanshinone IIA and methylbenzylamine as raw material, S24, yield 65% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.80 (d, J=7.2Hz, 1H), 7.42-7.28 (m, 4H), 7.17 (t, J= 7.5Hz, 1H), 7.06 (d, J=7.5Hz, 1H), 6.20 (s, 2H), 2.92 (s, 2H), 2.46 (s, 3H), 2.27 (s, 3H), 1.46(s,6H).13C NMR(125MHz,CDCl3)δ188.82,175.37,156.99,144.35,141.42,138.98, 137.96,129.64,129.60,129.23,128.71,126.50,126.02,125.95,123.89,123.07,122.36, 120.99,116.44,58.28,51.81,41.36,30.67(2C),22.19,10.17.
High resolution mass spectrum m/z (EI) C27H23NO3Theoretical value 409.1678, measured value 409.1677.
HPLC purity is 98.33%.
The synthesis of embodiment 24, compound S25
Using tanshinone IIA and 4-Fluorobenzylamine as raw material, S25, yield 48% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.80 (d, J=7.2Hz, 1H), 7.73-7.60 (m, 2H), 7.37-7.28 (m, 2H), 6.97 (t, J=8.7Hz, 2H), 6.19 (s, 2H), 2.92 (s, 2H), 2.46 (s, 3H), 1.48 (s, 6H)13C NMR (125MHz,CDCl3)δ188.97,175.43,164.36,162.40,157.04,144.38,141.51,134.02, 134.00,131.34,131.28,128.75,126.33,126.30,125.92,123.89,123.26,122.31,121.14, 116.44,116.29,116.12,58.27,50.98,41.36,30.65(2C),10.16.
High resolution mass spectrum m/z (EI) C26H20FNO3Theoretical value 413.1427, measured value 413.1419.
HPLC purity is 97.75%.
The synthesis of embodiment 25, compound S26
Using tanshinone IIA and O-methoxy benzylamine as raw material, S26, yield 53% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.83 (d, J=7.2Hz, 1H), 7.39-7.28 (m, 2H), 7.19 (t, J= 7.7Hz, 1H), 6.87 (d, J=8.1Hz, 1H), 6.74 (t, J=7.5Hz, 1H), 6.52 (d, J=7.5Hz, 1H), 6.27 (s, 2H),3.88(s,3H),2.89(s,2H),2.39(s,3H),1.50(s,6H).13C NMR(125MHz,CDCl3)δ188.29, 174.99,157.61,156.90,144.33,141.38,129.20,128.47,127.27,127.09,126.72,126.16, 125.93,123.76,122.96,122.36,121.12,120.90,116.48,110.87,58.24,56.14,48.32, 41.46,30.66(2C),10.08.
High resolution mass spectrum m/z (EI) C27H23NO4Theoretical value 425.1627, measured value 425.1627.
HPLC purity is 98.35%.
The synthesis of embodiment 26, compound S27
Using tanshinone IIA and to fluorophenethylamine as raw material, S27, yield 52% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.83 (d, J=7.2Hz, 1H), 7.36 (s, 1H), 7.31 (d, J=7.2Hz, 1H), 7.22-7.14 (m, 2H), 6.90 (t, J=8.7Hz, 2H), 5.21 (t, J=7.4Hz, 2H), 3.26 (t, J=7.4Hz, 2H),2.79(s,2H),2.47(s,3H),1.45(s,6H).13C NMR(125MHz,CDCl3)δ188.67,175.20, 163.50,161.55,157.08,144.34,141.48,133.73,131.43,131.37,128.14,126.69,126.24, 125.86,123.77,123.14,122.28,120.90,116.27,115.91,115.74,58.18,50.27,41.31, 37.45,30.56(2C),10.14.
High resolution mass spectrum m/z (EI) C27H22FNO3Theoretical value 427.1584, measured value 427.1587.
The synthesis of embodiment 27, compound S28 and S29
Using tanshinone IIA and n-butylamine as raw material, S28 and S29 is prepared with reference to the synthetic method of S1, yield is respectively 38% With 16%.
S28:1H NMR(300MHz,CDCl3) δ 7.81 (d, J=7.2Hz, 1H), 7.32 (d, J=7.5Hz, 2H), 5.02 (t, J=7.5Hz, 2H), 2.92 (s, 2H), 2.45 (s, 3H), 2.08-1.90 (m, 3H), 1.50 (s, 6H), 1.47-1.38 (m, 2H), 0.96 (t, J=7.4Hz, 3H)13C NMR(125MHz,CDCl3)δ187.55,174.03,155.82,143.05, 140.18,127.18,125.48,125.40,124.67,122.50,121.67,121.09,119.57,115.04,57.14, 48.04,40.14,33.12,29.45(2C),19.32,13.25,8.93.
High resolution mass spectrum m/z (EI) C23H23NO3Theoretical value 361.1678, measured value 361.1678.
HPLC purity is 98.25%.
S29:1H NMR(400MHz,CDCl3) δ 7.89 (d, J=7.2Hz, 1H), 7.33 (d, J=0.9Hz, 1H), 7.16 (d, J=7.2Hz, 1H), 4.63 (t, J=7.2Hz, 2H), 3.12 (t, J=6.3Hz, 2H), 2.52 (d, J=0.9Hz, 3H), 2.16 (t, J=6.2Hz, 2H), 2.09-1.92 (m, 3H), 1.43 (s, 6H), 1.03-0.93 (m, 3H)13C NMR(125MHz, CDCl3)δ169.88,154.01,145.55,139.42,125.05,123.52,122.47,121.13,119.79,119.68, 115.29,113.37,46.82,40.26,34.46,32.49,29.24,27.58(2C),20.11,19.65,13.34,9.22.
High resolution mass spectrum m/z (EI) C23H25NO2Theoretical value 347.1885, measured value 347.1891.
HPLC purity is 96.82%.
The synthesis of embodiment 28, compound S30
Using tanshinone IIA and n-hexylamine as raw material, S30, yield 35% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.82 (d, J=7.2Hz, 1H), 7.32 (d, J=7.3Hz, 2H), 5.01 (t, J =7.4Hz, 2H), 2.92 (s, 2H), 2.45 (s, 3H), 2.07-1.92 (m, 3H), 1.50 (s, 6H), 1.29 (d, J= 18.4Hz, 7H), 0.87 (d, J=6.4Hz, 3H) .13C NMR (125MHz, CDCl3)δ187.58,174.08,155.88, 143.11,140.23,127.24,125.52,125.44,124.73,122.57,121.71,121.16,119.61,115.12, 57.19,48.27,40.19,31.13,30.94,29.49(2C),29.25,25.78,22.11,13.56,8.97.
High resolution mass spectrum m/z (EI) C25H27NO3Theoretical value 389.1991, measured value 389.1992.
HPLC purity is 99.77%.
The synthesis of embodiment 29, compound S31
Using tanshinone IIA and diglycolamine as raw material, S31, yield 75% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.83 (d, J=7.2Hz, 1H), 7.33 (d, J=6.6Hz, 2H), 5.25 (t, J =5.1Hz, 2H), 4.06 (t, J=5.1Hz, 2H), 3.59 (s, 4H), 2.93 (s, 2H), 2.43 (s, 3H), 1.50 (s, 6H) .13C NMR(125MHz,CDCl3)δ189.26,175.50,157.09,144.47,141.49,128.49,127.34, 126.78,125.87,123.84,123.33,122.27,121.03,116.28,73.00,71.25,62.43,58.36, 48.61,41.41,30.63(2C),10.09.
High resolution mass spectrum m/z (EI) C23H23NO5Theoretical value 393.1576, measured value 393.1576.
The synthesis of embodiment 30, compound S32
Using Cryptotanshinone and parachloroanilinum as raw material, S32, yield 75% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.78 (d, J=7.2Hz, 1H), 7.57 (d, J=8.4Hz, 2H), 7.49 (d, J =8.4Hz, 2H), 7.35 (d, J=7.2Hz, 1H), 4.88 (t, J=9.2Hz, 1H), 4.48-4.33 (m, 1H), 3.61 (s, 1H), 2.91 (s, 2H), 1.52 (s, 6H), 1.35 (d, J=6.6Hz, 3H)13C NMR(125MHz,CDCl3)δ188.17, 175.61,165.29,148.49,137.37,136.58,130.66(2C),130.23,130.13(2C),128.46, 128.20,127.35,126.34,125.91,122.45,118.01,83.30,59.59,42.68,37.30,31.98, 31.50,21.17.
High resolution mass spectrum m/z (EI) C25H20ClNO3Theoretical value 417.1132, measured value 417.1129.
HPLC purity is 96.34%.
The synthesis of embodiment 31, compound S33 and S40
Using 17- hydroxyls tanshinone IIA and parachloroanilinum as raw material, S33 and S40, yield are prepared with reference to the synthetic method of S1 Respectively 65% and 10%.
S33:1H NMR(300MHz,CDCl3) δ 7.98 (d, J=7.2Hz, 1H), 7.56 (q, J=9.0Hz, 4H), 7.50 (s, 1H), 7.43 (d, J=7.2Hz, 1H), 4.69 (d, J=6.9Hz, 2H), 4.57 (t, J=6.9Hz, 1H), 2.95 (s, 2H),1.54(s,6H).13C NMR(125MHz,CDCl3)δ188.83,175.18,158.77,147.26,142.09, 137.79,136.45,130.95,130.11,129.45,128.07,127.69,127.52,126.42,125.89,123.01, 117.34,59.82,57.29,42.79,31.85(2C).
High resolution mass spectrum m/z (EI) C25H18ClNO4Theoretical value 431.0924, measured value 431.0933.
HPLC purity is 98.38%.
S40：1H NMR(300MHz,CDCl3) δ 8.13 (d, J=7.5Hz, 1H), 7.66 (d, J=8.4Hz, 2H), 7.59 (d, J=8.4Hz, 2H), 7.51 (s, 1H), 7.41 (d, J=7.5Hz, 1H), 6.70 (d, J=9.9Hz, 1H), 6.57 (d, J= 9.9Hz,1H),5.80(s,1H),4.74(s,2H),1.52(s,6H).13C NMR(125MHz,CDCl3)δ170.20, 156.42,154.36,147.81,140.96,140.64,137.30,136.62,131.45(2C),129.60(2C), 128.74,128.23,126.75,126.27,122.77,122.40,120.57,115.00,57.55,42.46,30.84 (2C).
High resolution mass spectrum m/z (EI) C25H18ClNO3Theoretical value 415.0975, measured value 415.0950.
The synthesis of embodiment 32, compound S34
Using 15- bromines tanshinone IIA and parachloroanilinum as raw material, S34, yield 51% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.89 (d, J=7.2Hz, 1H), 7.63-7.45 (m, 4H), 7.39 (d, J= 7.2Hz,1H),2.93(s,2H),2.31(s,3H),1.53(s,6H).13C NMR(125MHz,CDCl3)δ186.26, 171.65,155.19,144.03,135.23,134.21,128.51(2C),127.78,127.68(2C),126.18, 125.58,125.19,123.38,122.88,122.62,120.67,120.49,114.60,57.31,40.27,29.39 (2C),9.47.
High resolution mass spectrum m/z (EI) C25H17BrClNO3Theoretical value 493.0080, measured value 493.0074.
HPLC purity is 95.46%.
The synthesis of embodiment 33, compound S35
Using 15- thiophene tanshinone IIA and parachloroanilinum as raw material, S35 is prepared with reference to the synthetic method of S1, yield is 50%.
1H NMR(300MHz,CDCl3) δ 7.91 (d, J=7.2Hz, 1H), 7.63-7.49 (m, 6H), 7.46 (d, J= 2.7Hz, 1H), 7.38 (d, J=7.2Hz, 1H), 2.93 (s, 2H), 2.60 (s, 3H), 1.54 (s, 6H)13C NMR(125MHz, CDCl3)δ186.25,173.21,153.28,147.60,143.39,135.11,134.40,131.23,128.47(2C), 127.87,127.75(2C),126.06,125.90,125.77,125.68,125.08,123.04,122.45,120.82, 120.46,116.27,115.22,57.31,40.19,29.41(2C),9.52.
High resolution mass spectrum m/z (EI) C29H20ClNO3S theoretical values 497.0852, measured value 497.0847.
HPLC purity is 95.31%.
The synthesis of embodiment 34, compound S36
Using 15- ethylene tanshinone IIA and parachloroanilinum as raw material, S36 is prepared with reference to the synthetic method of S1, yield is 66%.
1H NMR(300MHz,CDCl3) δ 7.91 (d, J=7.2Hz, 1H), 7.54 (q, J=8.7Hz, 4H), 7.38 (d, J =7.2Hz, 1H), 6.70-6.57 (m, 1H), 5.87 (d, J=17.4Hz, 1H), 5.35 (s, 1H), 2.92 (s, 2H), 2.38 (s,3H),1.53(s,6H).13C NMR(125MHz,CDCl3)δ188.67,175.35,156.41,152.21,146.03, 137.51,136.73,130.87(2C),130.27,130.11(2C),128.36,128.27,128.07,125.59, 125.17,124.43,122.85,121.10,117.51,114.90,59.67,42.60,31.80(2C),11.08.
High resolution mass spectrum m/z (EI) C27H20ClNO3Theoretical value 441.1132, measured value 441.1124.
HPLC purity is 97.82%.
The synthesis of embodiment 35, compound S37
Using 15- ethyls tanshinone IIA and parachloroanilinum as raw material, S37 is prepared with reference to the synthetic method of S1, yield is 44%.
1H NMR(300MHz,CDCl3) δ 7.89 (d, J=7.2Hz, 1H), 7.63-7.45 (m, 4H), 7.39 (d, J= 7.2Hz,1H),2.93(s,2H),2.31(s,3H),1.53(s,6H).13C NMR(125MHz,CDCl3)δ186.25, 173.28,154.64,153.27,142.78,135.00,134.46,128.43(2C),127.93,127.75(2C), 125.88,125.63,122.67,121.90,120.36,115.60,114.39,57.29,40.09,29.41(2C),18.88, 12.41,8.55.
High resolution mass spectrum m/z (EI) C27H22ClNO3Theoretical value 443.1288, measured value 443.1290.
The synthesis of embodiment 36, compound S38 and S39
Using 15- m-methoxyphenyls tanshinone IIA and parachloroanilinum as raw material, with reference to S1 synthetic method prepare S38 and S39, yield are respectively 64% and 15%.
S38：1H NMR(300MHz,CDCl3) δ 7.93 (d, J=7.2Hz, 1H), 7.55 (q, J=8.7Hz, 4H), 7.44- 7.33 (m, 3H), 7.30 (s, 1H), 6.91 (d, J=7.8Hz, 1H), 3.90 (s, 3H), 2.93 (s, 2H), 2.63 (s, 3H), 1.54(s,6H).13C NMR(125MHz,CDCl3)δ186.24,173.23,159.30,153.77,150.03,143.48, 135.11,134.40,131.42,129.26,128.47(2C),127.88,127.75(2C),126.24,125.88, 125.76,123.08,122.58,120.47,118.37,117.53,115.21,112.85,111.51,57.30,54.91, 40.19,29.40(2C),9.93.
High resolution mass spectrum m/z (EI) C32H24ClNO4Theoretical value 521.1394, measured value 521.1391.
S39：1H NMR(300MHz,CDCl3) δ 8.08 (d, J=7.2Hz, 1H), 7.64 (d, J=8.1Hz, 2H), 7.56 (d, J=8.1Hz, 2H), 7.39 (d, J=3.9Hz, 2H), 7.33 (d, J=7.5Hz, 2H), 6.88 (s, 1H), 6.64 (d, J= 10.0Hz, 1H), 6.44 (d, J=9.9Hz, 1H), 3.90 (s, 3H), 2.74 (s, 3H), 1.50 (s, 6H)13C NMR (125MHz,CDCl3)δ169.37,159.26,151.86,150.20,149.05,144.28,136.27,134.59, 134.53,132.15,129.13,128.88(2C),127.37(2C),127.04,123.56,123.18,120.46, 120.11,118.37,117.94,117.74,112.82,112.62,112.49,111.33,54.89,39.81,28.79 (2C),10.18.
High resolution mass spectrum m/z (EI) C32H24ClNO3Theoretical value 505.1445, measured value 505.1453.
The synthesis of embodiment 37, compound S42
Using tanshinone IIA and to acetoxyl group aniline as raw material, S42, yield 56% are prepared with reference to the synthetic method of S1.
1H NMR(300MHz,CDCl3) δ 7.86 (d, J=7.2Hz, 1H), 7.63 (d, J=8.7Hz, 2H), 7.39-7.28 (m, 4H), 2.92 (s, 2H), 2.35 (d, J=4.2Hz, 6H), 1.52 (s, 6H)13C NMR(125MHz,CDCl3)δ187.33, 174.24,169.41,156.70,152.03,144.65,141.59,134.30,129.04,128.68,127.13(2C), 126.99,126.03,124.36,123.50,122.48,122.35,121.43(2C),116.73,58.53,41.33,30.58 (2C),21.98,10.07.
High resolution mass spectrum m/z (EI) C27H21NO5Theoretical value 439.1420, measured value 439.1412.
The measure of benzo [def] carbazole compound anti-inflammatory activity of the test case present invention
In vitro models and step：
We refer to Journal ofNutritional Biochemistry 2013,24:The side reported in 146-155 Method injects 6% starch Broth solution in mouse peritoneal, three days pneumoretroperitoneums extraction primary macrophage as external inflammatory model, Whether research drug can inhibit the proinflammatory factor tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) of LPS inductions Release.
Lipopolysaccharides (LPS) is purchased from Sigma Co., USA, product identification：L6386.
1st, addition LPS (0.5 μ g/mL) continues to cultivate cell for 24 hours after compound (10 μM) or DMSO are incubated 30min in advance Cell culture medium and total protein are collected afterwards.
2nd, with reference to Journal ofNutritional Biochemistry 2013,24:The method reported in 146-155 Enzyme-linked immunosorbent assay (ELISA) is carried out to detect the content of inflammatory factor inside culture medium and carry out standard with protein concentration Change.
3rd, our compound L 6H21 (British Journal for having delivered early period have been selected ofPharmacology,2015,172(17):4391-4405) as positive control, to exclude the error of experimental implementation.
Experimental result：
As shown in Figure 1, add in compound after pillar relative to LPS groups it is lower show cell discharge inflammatory factor amount more Less, that is, compound inhibits the ability of inflammatory factor release stronger.*P<0.05, * * P<0.01, show the group and LPS group phases Than having significant difference.As shown in Figure 1, in mouse primary macrophage, compound S2, S3, S21, S22, S26, S28 and S32 can significantly inhibit the TNF-α of LPS inductions and the release of IL-6, show that compound of the present invention has apparent anti-inflammatory work Property.
The foundation of internal acute lung injury model
27 C57BL/6 mouse (every weight about 20-22g) purchased from Wenzhou Medical University's Experimental Animal Center is random It is divided into 4 groups, respectively：Control group (CON groups, 6), LPS groups (7), S2810mg/kg groups (7) and S2820mg/kg groups (7 Only).The solution of 1mg/mL and 2mg/mL are made of the physiological saline solution compound S28 containing 20%PEG400,10% Tween 80, The 15min tail vein injections administration group before modeling, the i.e. mouse of S2810mg/kg groups and S2820mg/kg groups.Each group C57BL/6 Exposure tracheae after mouse etherization, in addition to control group, remaining each group mouse tracheal strips is slowly dropped into 5mg/kg LPS, is made Mould, control group instill physiological saline in an identical manner, sew up a wound.The hydration of 100 μ l 10% is injected intraperitoneally in 6h after modeling Chloralization mouse after collecting blood, opens breast knot and pricks left lung, and right lung carries out bronchoalveolar lavage with 200 μ L physiological saline, receives Collect bronchoalveolar lavage fluid (BALF), same operation is repeated 3 times.
The wet dry weight ratio of lung：Characterize the degree of pulmonary edema；It is an important indicator for evaluating lung injury；Below figure 2 Shown, compound S28 can dose-dependently inhibit the pulmonary edema that LPS is induced.*P<0.05, * * P<0.01, show the group with LPS groups, which are compared, has significant difference.
Total protein concentration in BALF：Characterize an important indicator of alveolar wall structural integrity；It is illustrated in fig. 3 shown below, chemical combination Object S28 can dose-dependently alleviate the increase of protein concentration in BALF.**P<0.01, show that the group has compared with LPS groups There is significant difference.
Total cell and neutrophil leucocyte quantity in BALF：Characterize the aggregation situation of inflammatory cell in lung tissue；Such as Fig. 4 and figure Shown in 5, S28 can dose-dependently reduce the quantity (Fig. 4) of total cell in bronchoalveolar lavage fluid and the number of neutrophil leucocyte It measures (Fig. 5).**P<0.01, show that the group has significant difference compared with LPS groups.

Claims (10)

1. with benzo [def] carbazole compound or its pharmaceutically acceptable salt shown in following logical formula (I)：
Wherein：
R1Selected from H, hydroxyl, amino, C1-C8Alkoxy, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkene Base, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C3-C8Cycloalkenyl group, Substitution or unsubstituted C6-C10Aryl, halogen；The substituted substituent group is selected from halogen, nitro, cyano, amino, hydroxyl, hydroxyl first Base, ethoxy, sulfydryl, carboxyl, ester group, C1-C6The monosubstituted amido of alkyl, C1-C6The disubstituted amido of alkyl, C1-C6Alkoxy, C1-C6Alkyl carbonyl oxy, C1-C6Cycloalkyl carbonyloxy group, heterocycle carbonyloxy group, C1-C6Alkoxy carbonyl, C1-C6Cycloalkyloxy carbonyl Base, heterocyclyloxycarbonyl, C1-C6Carbalkoxyl amido, C1-C6One or more of alkane sulfydryl or water soluble functional group；
R2Selected from H, hydroxyl, amino, C1-C8Alkoxy, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkene Base, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C3-C8Cycloalkenyl group, Substituted or unsubstituted C6-C10Aryl, substituted or unsubstituted C5-C10Heterocycle, substituted or unsubstituted C5-C10Heteroaryl, Halogen；The substituted substituent group is selected from halogen, nitro, cyano, amino, hydroxyl, methylol, ethoxy, sulfydryl, carboxyl, ester Base, C1-C6The monosubstituted amido of alkyl, C1-C6The disubstituted amido of alkyl, C1-C6Alkoxy, C1-C6Alkyl carbonyl oxy, C1-C6Cycloalkanes Base carbonyloxy group, heterocycle carbonyloxy group, C1-C6Alkoxy carbonyl, C1-C6Cyclo alkoxy carbonyl, heterocyclyloxycarbonyl, C1-C6Alcoxyl Formamido, C1-C6One or more of alkane sulfydryl or water soluble functional group；
R3Selected from H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8 Alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C3-C8Cycloalkenyl group, substituted or unsubstituted C6-C10Virtue Base, substituted or unsubstituted C5-C10Heterocycle, substituted or unsubstituted C5-C10Heteroaryl；The substituted substituent group is selected from halogen Element, nitro, cyano, amino, hydroxyl, methylol, ethoxy, hydroxyl methoxyl group, hydroxy ethoxy, sulfydryl, carboxyl, ester group, fluoroform Base, C1-C6Alkyl, C1-C6The monosubstituted amido of alkyl, C1-C6The disubstituted amido of alkyl, C1-C6Alkoxy, C1-C6Alkyl oxycarbonyl oxygen Base, C1-C6Cycloalkyl carbonyloxy group, C6-C10Aryloxy, it is unsubstituted or by being selected from halogen, C1-C3Alkyl, C1-C3In alkoxy One or more groups substitution C6-C10Aryl, heterocycle carbonyloxy group, C1-C6Alkoxy carbonyl, C1-C6Cycloalkyloxy carbonyl Base, heterocyclyloxycarbonyl, C1-C6Carbalkoxyl amido, C1-C6One or more of alkane sulfydryl or water soluble functional group；
X1Selected from carbon, nitrogen, oxygen or sulphur；
X2It is not present or selected from nitrogen, oxygen or sulphur.
2. benzo [def] carbazole compound as described in claim 1 or its pharmaceutically acceptable salt, wherein,
R1Selected from methyl, isopropyl, methylol；
R2Selected from H, halogen, substituted or unsubstituted C2-C8Alkenyl or C2-C8Alkynyl, substituted or unsubstituted C1-C8Alkyl, substitution Or unsubstituted C6-C10Aryl, substitution or unsubstituted C6-C10Heteroaryl；The substituted substituent group be selected from halogen, nitro, cyano, Amino, hydroxyl, methylol, ethoxy, C1-C6The monosubstituted amido of alkyl, C1-C6The disubstituted amido of alkyl, C1-C6In alkoxy It is one or more；
R3Selected from H, substituted or unsubstituted C1-C8Alkyl, substituted or unsubstituted C6-C10Aryl；The substituted substituent group choosing From halogen, amino, hydroxyl, methylol, ethoxy, hydroxyl methoxyl group, hydroxy ethoxy, trifluoromethyl, C1-C6Alkyl, C1-C6Alkyl Monosubstituted amido, C1-C6The disubstituted amido of alkyl, C1-C6Alkoxy, C1-C6Alkyl carbonyl oxy, C1-C6Cycloalkyl carbonyloxy group, C6- C10Aryloxy, it is unsubstituted or by being selected from halogen, C1-C3Alkyl, C1-C3The substitution of one or more of alkoxy group C6-C10Aryl, C1-C6Alkoxy carbonyl, C1-C6Cyclo alkoxy carbonyl, C1-C6One or more of carbalkoxyl amido；
X1Selected from nitrogen, oxygen or sulphur；
X2It is not present or selected from oxygen or sulphur.
3. benzo [def] carbazole compound as described in claim 1 or its pharmaceutically acceptable salt, wherein,
R1For methyl or methylol；
R2For H, chlorine, bromine, iodine, ethyl, vinyl, thienyl or methoxyphenyl；
R3For butyl, heptyl, phenyl, benzyl, phenethyl, chlorphenyl, bromophenyl, trifluoromethyl, aminomethyl phenyl, methylbenzene Base, ethylphenyl, methoxyphenyl, ethoxyl phenenyl, acetamidophenyl, Phenoxyphenyl, acetoxyl group phenyl, 4- are bromo- 3- fluoro-phenyls, the bromo- 3- methylphenyls of 4-, the chloro- phenyl of the fluoro- 3- of 4-, 3,5-dimethylphenyl, Dimethoxyphenyl, trimethoxy-benzene Base, methylbenzyl, chlorobenzyl, luorobenzyl, methoxy-benzyl, fluorophenylethyl or hydroxyethoxy ethyl.
4. benzo [def] carbazole compound as described in claim 1 or its pharmaceutically acceptable salt, wherein,
R2For H, chlorine, bromine, iodine, ethyl, vinyl, thiene-3-yl or 3- methoxyphenyls；
R3For butyl, heptyl, phenyl, benzyl, phenethyl, 4- chlorphenyls, 4- bromophenyls, 4- trifluoromethyls, 4- methylbenzenes Base, 3- aminomethyl phenyls, 4- ethylphenyls, 4- methoxyphenyls, 4- ethoxyl phenenyls, 4- Phenoxyphenyls, 2- methoxyphenyls, Acetoxyl group phenyl, 4- acetamidophenyls, the bromo- 3- fluoro-phenyls of 4-, the bromo- 3- methylphenyls of 4-, the chloro- phenyl of the fluoro- 3- of 4-, 2, 4- 3,5-dimethylphenyls, 3,4- Dimethoxyphenyls, 3,4,5- trimethoxyphenyls, 3- methylbenzyls, 3- chlorobenzyls, 4- benzyl chlorides Base, 4- luorobenzyls, 2- methoxy-benzyls, 2- methoxy-benzyls, 4- fluorophenylethyls or hydroxyethoxy ethyl.
5. benzo [def] carbazole compound as described in claim 1 or its pharmaceutically acceptable salt, wherein, it is described Benzo [def] carbazole compound is selected from following compounds：
6. the preparation method of benzo [def] carbazole compound described in claim 1 or its pharmaceutically acceptable salt, the party Method includes：
Wherein, R1、R2、R3、X1And X2Definition it is identical with claim 1,
Tanshinone compound shown in formula A and aminated compounds R3-NH2In the presence of an oxidizer, oxidative dimerization occurs, obtains To benzo [def] carbazole compound of logical formula (I)；
The oxidant is selected from 2,2,6,6- tetramethyl piperidine nitrogen oxides, oxygen, silver oxide, silver carbonate, silver acetate, acetic acid Copper, ferric trichloride, manganese dioxide, 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone, selenium dioxide, tert-butyl hydroperoxide, vinegar Sour iodobenzene or benzoquinones, preferably 2,2,6,6- tetramethyl piperidine oxides.
7. the preparation method described in claim 6, it is characterised in that：The oxidative dimerization is in non-polar aroma solvent In, carried out under heating condition, the non-polar aroma solvent be benzene, chlorobenzene, toluene, dimethylbenzene or trimethylbenzene, preferably Toluene；The temperature of the heating is 50 to 160 DEG C, and the reaction time is 24 hours to 48 hours.
8. a kind of pharmaceutical composition is selected from benzo according to any one of claims 1 to 5 it includes therapeutically effective amount It is one or more as active constituent and optional medicine in [def] carbazole compound and its pharmaceutically acceptable salt Acceptable carrier and/or excipient on.
9. pharmaceutical composition as claimed in claim 8 further includes other pharmaceutically acceptable therapeutic agents, particularly Other anti-inflammatory drug or combinations.
10. benzo [def] carbazole compound according to any one of claims 1 to 5 or its is pharmaceutically acceptable The purposes of salt and pharmaceutical composition according to claim 8 or claim 9 in preparing for anti-inflammatory drug.
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