CN102146080B - Beta-carboline alkali derivative compounds and application thereof - Google Patents

Beta-carboline alkali derivative compounds and application thereof Download PDF

Info

Publication number
CN102146080B
CN102146080B CN 201010108531 CN201010108531A CN102146080B CN 102146080 B CN102146080 B CN 102146080B CN 201010108531 CN201010108531 CN 201010108531 CN 201010108531 A CN201010108531 A CN 201010108531A CN 102146080 B CN102146080 B CN 102146080B
Authority
CN
China
Prior art keywords
carboline
diethylamino
amino methyl
methyl
propyl group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN 201010108531
Other languages
Chinese (zh)
Other versions
CN102146080A (en
Inventor
王子厚
曹日晖
陈志勇
武嘉林
郭亮
马芹
范文玺
孙洁
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
XINJIANG HUASHIDAN PHARMACEUTICAL CO Ltd
Original Assignee
XINJIANG HUASHIDAN PHARMACEUTICAL CO Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by XINJIANG HUASHIDAN PHARMACEUTICAL CO Ltd filed Critical XINJIANG HUASHIDAN PHARMACEUTICAL CO Ltd
Priority to CN 201010108531 priority Critical patent/CN102146080B/en
Publication of CN102146080A publication Critical patent/CN102146080A/en
Application granted granted Critical
Publication of CN102146080B publication Critical patent/CN102146080B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention relates to beta-carboline alkali derivative compounds and application thereof. Novel beta-carboline alkali derivative compounds are synthesized by structurally modifying the first, third and ninth sites of beta-carboline parent nucleus and importantly introducing amido into the first and third sites; and the obvious anti-tumor activity of the compounds is kept, and the water solubility of the compounds is improved. A method for preparing the compounds is simple and convenient, the yield is high, and the beta-carboline alkali derivative compounds can be used for preparing medicines for treating various tumor diseases.

Description

Beta-carboline alkali derivative compounds and application thereof
Technical field
The present invention relates to medical compounds, especially alkaloid compound more specifically relates to general formula (I) beta-carboline alkali derivative compounds and application thereof.
Background technology
The β-carboline alkali cpd is the alkaloid of a large class natural origin or chemosynthesis, and this compounds has the pharmacologically active of wide spectrum, such as antitumor, antibiotic, parasiticide, antiviral etc.Before 2000, the active aspect of neuropharmacology that research report both domestic and external mainly concentrates on this compounds.Since 2000, the anti-tumor activity of β-carboline alkali cpd has caused people's interest, and domestic and foreign literature has been described the synthetic and anti-tumor activity of a large amount of β-carboline alkali cpds.Such as [Bioorg.Med.Chem.Lett.9 (1999) 3319-3324.] such as Ishida 7,9 of yageine are carried out structural modification and anti tumor activity in vitro structure activity study.Xiao etc. [Bioorg.Med.Chem.Lett.11 (2001) 437-441.] have synthesized the β-carboline alkali derivant of a series of 3-aminoalkylamide bases and the replacement of 3-alkylamino alkyl amido, and confirm that it has DNA and embeds activity and anti tumor activity in vitro.Song etc. [Bioorg.Med.Chem.Lett.12 (2002) 1129-1132] are to 1 of β-carboline parent nucleus, 4,5,6, structural modification has been carried out in the sites such as 7, confirm that beta-carboline alkaloid is the specific inhibitor with the closely-related Cyclin dependent kinase of cell division cycle (cyclin-dependent kinases, CDK).Boursereau etc. (Bioorg.Med.Chem.Lett.14 (2004) 5841-5844.) attempt with the substituted radical of 1 complexity of the beta-carboline alkaloid Manzamine A of the alternative marine source of simple substituted radical and keep its significant anti-tumor activity, and this research group designs, synthesized the beta-carboline alkaloid of a series of 1 simple amino side-chain groups replacement and estimated its anti tumor activity in vitro.Zhao etc. [Bioorg.Med.Chem.14 (2006) 6998-7010.] research finds that β-carboline-amino acid ester multipolymer has significant cytotoxicity to human tumor cell line.Formagio etc. [Bioorg.Med.Chem.16 (2008) 9660-9667.] etc. have synthesized the beta-carboline derivatives of a series of 1 substituted-phenyl, 3 oxygen nitrogen azoles base replacements and have confirmed that it has good external tumor promotion.
In recent years, we are take the most representative β-carboline alkali---and the chemical structure of yageine is the basis, 5 structural points such as 1,2,3,7 and 9 of β-carboline ring have been carried out modifying transformed and antitumor structure activity study, as having introduced fatty alkyl substituting group, aralkyl substituting group 1 of β-carboline ring; Carboxylic acid ester groups, amide group, aldehyde radical, methylol etc. have been introduced at 3, introduced fatty alkyl substituting group, aralkyl substituting group etc. at 9, and screened and found that some have the β-carboline alkali derivant of good inside and outside anti-tumor activity [Bioorg.Med.Chem.12 (2004) 4613-4623; Eur.J.Med.Chem.40 (2005) 249-257; Eur.J.Med.Chem.40 (2005) 991-1001; Eur.J.Med.Chem.44 (2009) 533-540.].But research finds that most β-carboline alkali derivants are not water-soluble bad, are exactly that anti-tumor activity is not high enough, thereby have limited its application prospect.For this reason, the application provides a class novel β-carboline bases derivative, and such novel β-carboline bases derivative not only has good water-soluble, also has simultaneously significant anti-tumor activity.
Summary of the invention
The object of the invention is to, provide a kind of water-soluble good and have a novel beta-carboline alkali derivative compounds of remarkable anti-tumor activity.
Another object of the present invention provides a kind of pharmaceutical composition that comprises above-mentioned beta-carboline alkali derivative compounds, and this pharmaceutical composition can be used to treat cancer.
A further object of the present invention provides the purposes of above-mentioned beta-carboline alkali derivative compounds aspect preparation treatment cancer drug.
Beta-carboline alkali derivative compounds of the present invention has the structure of general formula (I):
Figure GSA00000031974600031
Wherein:
R 1Be selected from hydrogen, C 1-4Alkyl, aryl C 1-6Alkyl and CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m is the arbitrary integer among the 2-6, n is the arbitrary integer among the 0-4;
R 3Be selected from hydrogen and CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m is the arbitrary integer among the 2-6, n is the arbitrary integer among the 0-4;
R 9Be selected from hydrogen, C 1-6Alkyl and aryl C 1-6Alkyl;
R 1, R 9Described in aryl be the phenyl that phenyl or substituting group replace, described substituting group is selected from: hydroxyl, nitro, halogen, amino, C 1-4Alkyl, C 1-4Alkoxyl group and C 1-4Alkylamino.And
(1) works as R 3And R 9During for hydrogen, R 1Be not hydrogen or C 1-4Alkyl or aryl C 1-6Alkyl;
(2) work as R 3Be hydrogen, R 9Be C 1-6Alkyl or aryl C 1-6During alkyl, R 1Be not hydrogen or C 1-4Alkyl or aryl C 1-6Alkyl.
Preferably, R 1Be selected from hydrogen, methyl, ethyl, aryl C 1-3Alkyl and CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m is the arbitrary integer among the 2-4, n is the arbitrary integer among the 0-3; R 3Be selected from hydrogen, CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m is the arbitrary integer among the 2-4, n is the arbitrary integer among the 0-3; R 9Be selected from hydrogen, C 1-6Alkyl or aryl C 1 -4Alkyl.
More preferably, R 1Be selected from hydrogen, methyl, 4-p-methoxy-phenyl, 3,4,5-trimethoxyphenyl and CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m=3 or 4, n=0 or 1.R 3Be selected from hydrogen, CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m=3 or 4, n=0 or 1; R 9Be selected from normal-butyl, isobutyl-, benzyl, 4-luorobenzyl, 3-chlorobenzyl and 3-phenyl propyl.
According to the present invention, most preferred compound is selected from following compounds:
1-(4-methoxyl group) phenyl-3-[N-(2-diethylamino)-ethyl]-methylamino-β-carboline;
1-(4-methoxyl group) phenyl-3-[N-(3-dimethylamino)-propyl group]-methylamino-β-carboline;
1-(4-methoxyl group) phenyl-3-[N-(3-diethylamino)-propyl group]-methylamino-β-carboline;
1-(4-methoxyl group) phenyl-3-[N (4-diethylamino)-butyl]-methylamino-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-9-methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-9-methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-9-methyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-9-methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-9-normal-butyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-9-normal-butyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-9-normal-butyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-9-normal-butyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-9-benzyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-9-benzyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-9-benzyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-9-benzyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-9-(4-fluorine) benzyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-9-(4-fluorine) benzyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-9-(4-fluorine) benzyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-9-(4-fluorine) benzyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-9-(3-chlorine) benzyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-9-(3-chlorine) benzyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-9-(3-chlorine) benzyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-9-(3-chlorine) benzyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-9-(3-phenyl propyl)-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-9-(3-phenyl propyl)-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-9-(3-phenyl propyl)-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-9-(3-phenyl propyl)-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-1-methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-1,9-dimethyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-1,9-dimethyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-1,9-dimethyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-1,9-dimethyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-9-normal-butyl-1-methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-9-normal-butyl-1-methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-9-normal-butyl-1-methyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-9-normal-butyl-1-methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-9-benzyl-1-methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-9-benzyl-1-methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-9-benzyl-1-methyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-9-benzyl-1-methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-9-(4-fluorine) benzyl-1-methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-9-(4-fluorine) benzyl-1-methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-9-(4-fluorine) benzyl-1-methyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-9-(4-fluorine) benzyl-1-methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-methylamino-9-(3-phenyl propyl)-1-methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-methylamino-9-(3-phenyl propyl)-1-methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-methylamino-9-(3-phenyl propyl)-1-methyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-methylamino-9-(3-phenyl propyl)-1-methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-methylamino-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-methylamino-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(2-diethylamino)-ethyl]-methylamino-9-methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-methylamino-9-methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-methylamino-9-methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(4-diethylamino)-butyl]-methylamino-9-methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(2-diethylamino)-ethyl]-methylamino-9-normal-butyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-methylamino-9-normal-butyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-methylamino-9-normal-butyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(4-diethylamino)-butyl]-methylamino-9-normal-butyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(2-diethylamino)-ethyl]-methylamino-9-(3-phenyl propyl)-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-methylamino-9-(3-phenyl propyl)-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-methylamino-9-(3-phenyl propyl)-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N (4-diethylamino)-butyl]-methylamino-9-(3-phenyl propyl)-β-carboline;
1-[N-(2-diethylamino)-ethyl]-methylamino-9-normal-butyl-β-carboline;
1-[N-(3-dimethylamino)-propyl group]-methylamino-9-normal-butyl-β-carboline;
1-[N-(3-diethylamino)-propyl group]-methylamino-9-normal-butyl-β-carboline;
1-[N-(4-diethylamino)-butyl]-methylamino-9-normal-butyl-β-carboline;
1-[N-(2-diethylamino)-ethyl]-methylamino-9-isobutyl--β-carboline;
1-[N-(3-dimethylamino)-propyl group]-methylamino-9-isobutyl--β-carboline;
1-[N-(3-diethylamino)-propyl group]-methylamino-9-isobutyl--β-carboline;
1-[N-(4-diethylamino)-butyl]-methylamino-9-isobutyl--β-carboline;
1-[N-(2-diethylamino)-ethyl]-methylamino-9-benzyl-β-carboline;
1-[N-(3-dimethylamino)-propyl group]-methylamino-9-benzyl-β-carboline;
1-[N-(3-diethylamino)-propyl group]-methylamino-9-benzyl-β-carboline;
1-[N-(4-diethylamino)-butyl]-methylamino-9-benzyl-β-carboline;
1-[N-(2-diethylamino)-ethyl]-methylamino-9-(4-fluorine) benzyl-β-carboline;
1-[N-(3-dimethylamino)-propyl group]-methylamino-9-(4-fluorine) benzyl-β-carboline;
1-[N-(3-diethylamino)-propyl group]-methylamino-9-(4-fluorine) benzyl-β-carboline;
1-[N-(4-diethylamino)-butyl]-methylamino-9-(4-fluorine) benzyl-β-carboline;
1-[N-(2-diethylamino)-ethyl]-methylamino-9-(3-chlorine) benzyl-β-carboline;
1-[N-(3-dimethylamino)-propyl group]-methylamino-9-(3-chlorine) benzyl-β-carboline;
1-[N-(3-diethylamino)-propyl group]-methylamino-9-(3-chlorine) benzyl-β-carboline;
1-[N-(4-diethylamino)-butyl]-methylamino-9-(3-chlorine) benzyl-β-carboline;
1-[N-(2-diethylamino)-ethyl]-methylamino-9-(3-phenyl propyl)-β-carboline;
1-[N-(3-dimethylamino)-propyl group]-methylamino-9-(3-phenyl propyl)-β-carboline;
1-[N-(3-diethylamino)-propyl group]-methylamino-9-(3-phenyl propyl)-β-carboline;
1-[N-(4-diethylamino)-butyl]-methylamino-9-(3-phenyl propyl)-β-carboline.
The formed salt of above-mentioned most preferred compound and they and pharmaceutically acceptable acid consists of the part of complete content of the present invention.
The invention still further relates to pharmaceutical composition, comprise at least a formula (I) compound as activeconstituents, separately or in conjunction with one or more pharmaceutically acceptable, inertia, nontoxic vehicle or carrier.
In according to pharmaceutical composition of the present invention, can mention especially and be applicable to oral, parenteral (intravenously, muscle or subcutaneous), through skin or transdermal, intranasal, through tongue, through mode, the especially tablet of eye or breathing, rectal administration or drageeing, Sublingual tablet, capsule, suppository, aerosol, creme, ointment, skin gel, injectable or drinkable preparation, eye drops, nasal drop etc.
Compound of the present invention has antitumour activity, contains at least a formula (I) compound can be used for various cancers as the pharmaceutical composition of activeconstituents treatment.
As medicine, effective dose because of patient age, body weight, route of administration, disease character, seriousness with and any other treatment of being accepted different.
Following embodiment sets forth and unrestricted the present invention.
Raw materials used or reagent is known product, or according to the product of known operation preparation.
The structure of compound described in embodiment and the synthesis step is that the spectroscopy technology (infrared spectra, mass spectrum, NMR (Nuclear Magnetic Resonance) spectrum etc.) according to routine is measured.
Description of drawings
Fig. 1 is the synthetic route chart of compound 1-4;
Fig. 2 is the synthetic route chart of compound 5-30;
Fig. 3 is the synthetic route chart of compound 31-51;
Fig. 4 is the synthetic route chart of compound 52-65;
Fig. 5 is the synthetic route chart of compound 66-89.
Embodiment
Embodiment 11-(4-methoxyl group) phenyl-3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-β-carboline (compound 1)
Starting raw material ethyl 1-(4-methoxyl group) phenyl-β-carboline-3-carboxylicesters is synthetic according to literature method.
The preparation of step (a): 1-(4-methoxyl group) phenyl-3-HMC:
Ethyl 1-(4-methoxyl group) phenyl-β-carboline-3-carboxylicesters (10mmol), THF (200ml), LiBH 4(30mmol) after the mixing, stirring at room reaction 12h, TLC (sherwood oil/acetone=1/1) follows the tracks of detection, reacts complete, and reaction mixture is slowly poured in the 200ml frozen water, stirring reaction 10 minutes, drip concentrated hydrochloric acid to pH 2-3, stirring at room 2h, mixture water cooling on the rocks, sodium hydroxide solution is regulated the pH value to 9-10, ethyl acetate extraction, washing, saturated common salt washing, anhydrous sodium sulfate drying, decolorizing with activated carbon filters, and is concentrated into dried, acetone recrystallization gets white or pale solid.Repeat aforesaid operations and can accumulate enough samples for next step reaction.
The preparation of step (b): 1-(4-methoxyl group) phenyl-β-carboline-3-formaldehyde:
The 3-methylol that step (a) is obtained replaces-β-carboline (10mmol), acetonitrile (250ml), active MnO 2(50mmol) mix, reflux 5 hours, TLC follows the tracks of detection.React complete, remove by filter immediately MnO 2, be evaporated to driedly, get yellow solid.Solid is dissolved in ethyl acetate, and activated carbon decolorizing filters, and concentrating under reduced pressure gets white or pale solid.Repeat aforesaid operations and can accumulate enough samples for next step reaction.
Step (c): the preparation of target compound 1:
3-carboxaldehyde radicals substitutive derivative (2mmol), N with step (b) preparation, N-diethyl ethylenediamine (2.4mmol), anhydrous methanol (12mL) and anhydrous methylene chloride (6mL) mix, the reaction of mixed solution stirring at room, TLC follows the tracks of detection.React complete, remove solvent under reduced pressure, get thick product Xi Fushi alkali.This thick product Xi Fushi alkali does not need purifying can be directly used in next step reduction reaction.
The thick product of Xi Fushi alkali of above-mentioned preparation is dissolved in anhydrous methanol (20mL) and cooling mixed liquid to 0 ℃, adds subsequently NaBH 3CN (10mmol).Reaction mixture stirring at room reaction 24 hours, TLC follows the tracks of detection.React complete, remove solvent under reduced pressure.Subsequently, residue is dissolved in methylene dichloride (100mL), then aqueous sodium carbonate (pH10,50mL) washing tells organic phase, and anhydrous sodium sulfate drying filters, and concentrating under reduced pressure steams and desolventizes, residue silica gel column chromatography (moving phase: CH 2Cl 2/ CH 3OH/NH 4OH, 95: 5: 1), be evaporated to driedly, get yellow oil, be target compound 1, yield 66%; IR (KBr, cm -1) v:2932,2674,1621,1515,1456,1378,1258,1182,1023,756; 1H NMR (500MHz, D 2O+Dioxane): δ 8.24 (s, 1H), 7.95 (d, J=8Hz, 1H), 7.65 (d, J=8.5Hz, 2H), 7.46-7.50 (m, 1H), 7.37 (d, J=8Hz, 1H), 7.16-7.20 (m, 1H), 7.05 (d, J=9Hz, 2H), 4.71 (s, 2H), 3.78 (s, 3H), (3.70-3.73 m, 2H), 3.60-3.63 (m, 2H), 3.29-3.34 (m, 4H), 1.31 (t, J=7Hz, 6H) 13CNMR (100MHz, D 2O+Dioxane): δ 161.9,143.4, and 139.1,132.7,131.8,131.5,131.0,130.8,122.5,122.0,120.9,119.3,117.0,115.1,112.4,55.6,48.2,48.1,46.8,41.8,8.2; ESI-MS m/z:403.3 (M+1) +.ESI-MS m/z:403.3 (M+1) +.
Yellow oil obtained above is dissolved in 4N hydrogenchloride/ethanolic soln (40mL), and stirring at room reaction 30 minutes removes solvent subsequently under reduced pressure, yellow solid, 100 ℃ of vacuum-drying 2 days is in order to remove residual solvent, get yellow solid, be the hydrochloride of target compound 1.
Embodiment 21-(4-methoxyl group) phenyl-3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-β-carboline (compound 2)
The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 2, yield 42%; IR (KBr, cm -1) v:2947,2744,1621,1510,1464,1378,1259,1181,1024,756; 1H NMR (500MHz, D 2O): δ 8.20 (s, 1H), 7.93 (d, J=8Hz, 1H), (7.63 d, J=9Hz, 2H), 7.44-7.48 (m, 1H), (7.35 d, J=8.5Hz, 1H), 7.15-7.18 (m, 1H), (7.03 d, J=8.5Hz, 2H), 4.64 (s, 2H), (3.77 s, 3H), 3.32-3.35 (m, 2H), 3.26-3.30 (m, 2H), 2.90 (s, 6H), 2.22-2.28 (m, 2H); 13C NMR (100MHz, D 2O+Dioxane): δ 161.9,143.4, and 139.0,132.7,131.8,131.5,131.0,130.8,122.5,122.0,120.9,119.3,117.1,115.1,112.4,55.6,54.2,47.7,44.8,42.9,21.3; ESI-MS m/z:389.3 (M+1) +.
The preparation method of compound 2 hydrochlorides is with embodiment 1.
Embodiment 31-(4-methoxyl group) phenyl-3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-β-carboline (compound 3)
The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 3, yield 50%; IR (KBr, cm -1) v:2941,2740,1628,1510,1449,1380,1257,1181,1025,756; 1H NMR (500MHz, D 2O): δ 8.34 (s, 1H), 8.11 (d, J=8.5Hz, 1H), 7.78 (d, J=9Hz, 2H), 7.62 (t, J=7Hz, 1H), 7.51 (d, J=8Hz, 1H), 7.33 (t, J=7.5Hz, 1H), 7.19 (d, J=8.5Hz, 2H), 4.75 (s, 2H), 3.92 (s, 3H), (3.43 t, J=7.5Hz, 2H), 3.29-3.36 (m, 6H), (2.28-2.34 m, 2H), 1.35 (t, J=7.5Hz, 6H); 13C NMR (125MHz, D 2O): δ 162.3,143.8, and 139.6,133.2,132.2,132.1,131.6,131.2,122.9,122.4,121.6,119.8,117.4,115.5,112.9,56.1,48.8,48.2,48.0,45.3,21.2,8.6; ESI-MS m/z:417.4 (M+1) +.
The preparation method of compound 3 hydrochlorides is with embodiment 1.
Embodiment 41-(4-methoxyl group) phenyl-3-[N-(4-diethylamino)-butyl]-preparation of methylamino-β-carboline (compound 4)
The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 4, yield 52%; IR (KBr, cm -1) v:2965,1621,1509,1461,1379,1257,1181,1028,750; 1H NMR (500MHz, D 2O): δ 8.27 (s, 1H), 8.01 (d, J=8Hz, 1H), 7.70 (d, J=8.5Hz, 2H), 7.53 (t, J=7Hz, 1H), 7.43 (d, J=8Hz, 1H), 7.24 (t, J=7Hz, 1H), 7.11 (d, J=9Hz, 2H), 4.69 (s, 2H), 3.86 (s, 3H), (3.37 t, J=5.5Hz, 2H), 3.23-3.30 (m, 6H), (1.88-1.96 m, 4H), 1.33 (t, J=7.5Hz, 6H); 13C NMR (100MHz, D 2O+Dioxane): δ 161.9,143.3,138.9,132.7,131.8,131.3 (2C), 130.8,122.4,121.9,120.9,119.2,117.0,115.0,112.4,55.6,50.9,47.5,47.4 (2C), 22.9,20.8,8.2; ESI-MS m/z:431.4 (M+1) +.
The preparation method of compound 4 hydrochlorides is with embodiment 1.
Embodiment 5 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-β-carboline (compound 5)
It is synthetic that starting raw material ethyl β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 5, yield 71%; IR (KBr, cm -1) v:2941,2748,1634,1466,1380,1342,752; 1H NMR (500MHz, D 2O): δ 8.87 (s, 1H), 8.50 (s, 1H), 8.07 (d, J=8Hz, 1H), 7.69 (t, J=7Hz, 1H), (7.52 d, J=8Hz, 1H), 7.33 (t, J=7Hz, 1H), 4.77 (s, 2H), 3.40 (t, J=8Hz, 2h), 3.34 (t, J=8Hz, 2H), (2.98 s, 6H), 2.28-2.34 (m, 2H); 13C NMR (100MHz, D 2O): δ 143.7,134.0, and 133.6,132.5,130.4,127.2,122.9,122.2,119.1,119.0,112.7,54.4,47.8,44.9,43.1,43.0,21.4; ESI-MS m/z:283.2 (M+1) +.
Compound 5 hydrochloride preparation methods are with embodiment 1.
Embodiment 6 3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-β-carboline (compound 6)
It is synthetic that starting raw material ethyl β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 6, yield 75%; IR (KBr, cm -1) v:2932,2712,1634,1509,1463,1348,1253,1214,1151,1026,762; 1H NMR (500MHz, D 2O): δ 8.82 (s, 1H), 8.46 (s, 1H), 8.00 (d, J=8Hz, 1H), 7.65 (t, J=7.5Hz, 1H), (7.47 d, J=8.5Hz, 1H), 7.29 (t, J=7.5Hz, 1H), 4.76 (s, 2H), 3.41 (t, J=8Hz, 2H), 3.28-3.34 (m, 6H), 2.26-2.32 (m, 2H), 1.33 (t, J=7Hz, 6H); 13C NMR (125MHz, D 2O): δ 143.8,134.1, and 133.7,132.7,130.5,127.2,123.0,122.3,119.3,119.1,112.9,48.8,48.0,47.9,45.3,21.1,8.6; ESI-MS m/z:311.4 (M+1) +.
The preparation method of compound 6 hydrochlorides is with embodiment 1.
Embodiment 7 3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-methyl-β-carboline (compound 7)
It is synthetic that starting raw material ethyl 9-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 7, yield 70%; IR (KBr, cm -1) v:2937,2768,1632,1466,1384,1338,1265,1136,1025,762; 1H NMR (500MHz, D 2O): δ 8.84 (s, 1H), 8.47 (s, 1H), 7.92 (d, J=8Hz, 1H), 7.53-7.57 (m, 1H), 7.30 (d, J=8.5Hz, 1H), 7.17 (t, J=7.5Hz, 1H), (4.80 s, 2H), 3.70-3.73 (m, 2H), 3.67 (s, 3H), 3.59-3.62 (m, 2H), 3.29-3.34 (m, 4H), 1.31 (t, J=7.5Hz, 6H); 13C NMR (100MHz, D 2O+Dioxane): δ 144.3,135.0, and 132.7,132.3,130.4,125.6,122.7,121.9,118.7,118.5,110.4,48.2,48.1,46.9,41.9,29.7,8.2; ESI-MS m/z:311.3 (M+1) +.
The preparation method of compound 7 hydrochlorides is with embodiment 1.
Embodiment 8 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-methyl-β-carboline (compound 8)
It is synthetic that starting raw material ethyl 9-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 8, yield 68%; IR (KBr, cm -1) v:2989,2735,1637,1520,1467,1382,1339,763; 1H NMR (400MHz, D 2O): δ 8.79 (s, 1H), 8.41 (s, 1H), 7.86 (d, J=8Hz, 1H), 7.47-7.52 (m, 1H), 7.23 (d, J=8.4Hz, 1H), 7.12 (t, J=7.2Hz, 1H), (4.71 s, 2H), 3.62 (s, 3H), 3.31 (t, J=7.6Hz, 2H), 3.23-3.27 (m, 2H), (2.87 s, 6H), 2.18-2.26 (m, 2H); 13CNMR (100MHz, D 2O): δ 144.2,134.9, and 132.7,132.3,130.3,125.5,122.8,121.9,118.8,118.4,110.3,54.2,47.6,44.8,42.9,29.7,21.3; ESI-MS m/z:297.3 (M+1) +.
The preparation method of compound 8 hydrochlorides is with embodiment 1.
Embodiment 9 3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-methyl-β-carboline (compound 9)
It is synthetic that starting raw material ethyl 9-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 9, yield 76%; IR (KBr, cm -1) v:2984,2736,1635,1518,1470,1385,1338,761; 1H NMR (500MHz, D 2O): δ 8.87 (s, 1H), 8.48 (s, 1H), 7.99 (d, J=8Hz, 1H), 7.59-7.62 (m, 1H), 7.37 (d, J=8.5Hz, 1H), 7.21-7.24 (m, 1H), 4.75 (s, 2H), 3.72 (s, 3H), 3.34 (t, J=8Hz, 2H), 3.20-3.28 (m, 6H), 2.18-2.24 (m, 2H), 1.25 (t, J=7Hz, 6H); 13CNMR (100MHz, D 2O): δ 144.4,135.1, and 132.8,132.3,130.4,125.7,122.8,122.0,118.8,118.6,110.5,48.4,47.7,47.6,44.9,29.7,20.8,8.2; ESI-MSm/z:325.3 (M+1) +.
The preparation method of compound 9 hydrochlorides is with embodiment 1.
Embodiment 10 3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-methyl-β-carboline (compound 10)
It is synthetic that starting raw material ethyl 9-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 10, yield 49%; IR (KBr, cm -1) v:2957,2717,1636,1519,1473,1384,1338,1051,756; 1H NMR (400MHz, D 2O): δ 8.90 (s, 1H), 8.50 (s, 1H), 8.05 (d, J=8Hz, 1H), 7.63-7.66 (m, 1H), 7.42 (d, J=8.5Hz, 1H), 7.27 (t, J=7.5Hz, 1H), (4.72 s, 2H), 3.77 (s, 3H), 3.28 (t, J=7Hz, 2H), 3.14-3.21 (m, 6H), 1.80-1.83 (m, 4H), 1.24 (t, J=7.5Hz, 6H); 13C NMR (100MHz, D 2O): δ 144.5,135.2, and 132.9,132.3,130.7,125.7,122.9,122.0,118.8,118.7,110.5,50.9,47.6,47.4,47.3,29.7,22.9,20.7,8.2; ESI-MS m/z:339.4 (M+1) +
The preparation method of compound 10 hydrochlorides is with embodiment 1.
Embodiment 11 3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-normal-butyl-β-carboline (compound 11)
It is synthetic that starting raw material ethyl 9-normal-butyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 11, yield 41%; IR (KBr, cm -1) v:2957,2587,1636,1581,1466,1381,1345,1271,1138,1053,756; 1H NMR (500MHz, D 2O): δ 9.16 (s, 1H), 8.72 (s, 1H), (8.32 d, J=8Hz, 1H), 7.85 (t, J=7.5Hz, 1H), 7.73 (d, J=8.5Hz, 1H), 7.48 (t, J=7.5Hz, 1H), (4.89 s, 2H), 4.48 (t, J=7Hz, 2H), 3.76-3.79 (m, 2H), 3.65-3.68 (m, 2H), 3.37-3.42 (m, 4H), 1.83-1.89 (m, 2H), 1.39 (t, J=7.5Hz, 6H), 1.25-1.32 (m, 2H), (0.88 t, J=7.5Hz, 3H); 13C NMR (100MHz, D 2O): δ 144.0,134.6, and 133.1,132.4,130.4,125.7,123.0,122.0,119.0,118.8,110.8,48.3,48.1,46.9,43.8,42.0,30.5,19.6,13.0,8.3; ESI-MS m/z:353.4 (M+1) +.
The preparation method of compound 11 hydrochlorides is with embodiment 1.
Embodiment 12 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-normal-butyl-β-carboline (compound 12)
It is synthetic that starting raw material ethyl 9-normal-butyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 12, yield 50%; IR (KBr, cm -1) v:2955,2704,1633,1508,1462,1382,1339,1063,754; 1H NMR (500MHz, D 2O): δ 8.97 (s, 1H), 8.54 (s, 1H), 8.04 (br s, 1H), (7.61 br s, 1H), 7.46 (br s, 1H), 7.24 (br s, 1H), 4.78 (s, 2H), 4.21 (br s, 2H), (3.36 t, J=10Hz, 2H), 3.27-3.31 (m, 2H), (2.91 s, 6H), 2.22-2.30 (m, 2H), 1.63 (br s, 2H), 1.13 (br s, 2H), 0.75 (br s, 3H); 13C NMR (100MHz, D 2O): δ 144.1,134.8, and 133.2,132.4,130.5,125.8,123.1,122.1,119.1,118.9,111.0,54.3,47.7,44.8,43.8,43.0,30.5,21.3,19.6,13.0; ESI-MS m/z:339.3 (M+1) +.
The preparation method of compound 12 hydrochlorides is with embodiment 1.
Embodiment 13 3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-normal-butyl-β-carboline (compound 13)
It is synthetic that starting raw material ethyl 9-normal-butyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 13, yield 45%; IR (KBr, cm -1) v:2941,2657,2019,1632,1510,1455,1379,1339,1263,1061,750; 1H NMR (400MHz, D 2O): δ 8.98 (s, 1H), 8.56 (s, 1H), (8.02 d, J=4.8Hz, 1H), 7.57-7.58 (m, 1H), 7.43-7.44 (m, 1H), 7.20-7.22 (m, 1H), 4.79 (s, 2H), 4.19-4.20 (m, 2H), 3.37 (t, J=8Hz, 2H), 3.20-3.28 (m, 6H), (2.19-2.27 m, 2H), 1.61 (br s, 2H), 1.25 (t, J=7.2Hz, 6H), 1.08-1.13 (m, 2H), (0.72 t, J=7.6Hz, 3H); 13C NMR (100MHz, D 2O): δ 144.2,134.7, and 133.3,132.5,130.2,125.5,123.1,122.1,119.2,118.8,110.0,48.5,47.6,47.5,45.0,43.9,30.5,20.9,19.6,13.0,8.3; ESI-MS m/z:367.4 (M+1) +.
The preparation method of compound 13 hydrochlorides is with embodiment 1.
Embodiment 14 3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-normal-butyl-β-carboline (compound 14)
It is synthetic that starting raw material ethyl 9-normal-butyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 14, yield 64%; IR (KBr, cm -1) v:2957,2767,1634,1515,1465,1382,1340,757; 1H NMR (500MHz, D 2O): δ 9.10 (s, 1H), 8.66 (s, 1H), (8.20 d, J=9Hz, 1H), 7.74 (t, J=7.5Hz, 1H), 7.59 (d, J=8.5Hz, 1H), 7.37 (t, J=7.5Hz, 1H), (4.83 s, 2H), 4.35 (t, J=7Hz, 2H), 3.39 (t, J=6.5Hz, 2H), (3.23-3.29 m, 6H), 1.92 (br s, 4H), (1.73-1-77 m, 2H), 1-32 (t, J=7-5Hz, 6H), 1-21-1-25 (m, 2H), (0.84 t, J=7Hz, 3H); 13C NMR (125MHz, D 2O): δ 144.5,135.2,133.6,132.8,131.1,126.1,123.5,122.4,119.3 (2C), 111.4,51.3,47.9,47.8,47.7,44.1,30.8,23.2,21.1,19.9,13.3,8.6; ESI-MS m/z:381.4 (M+1) +.
The preparation method of compound 14 hydrochlorides is with embodiment 1.
Embodiment 15 3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-benzyl-β-carboline (compound 15)
It is synthetic that starting raw material ethyl 9-benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1,, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 15, yield 56%; IR (KBr, cm -1) v:2969,2560,2014,1631,1505,1453,1383,1337,1269,1030,756; 1H NMR (500MHz, D 2O): δ 9.04 (s, 1H), 8.65 (s, 1H), 8.25 (d, J=10Hz, 1H), 7.67-7.71 (m, 1H), 7.55 (d, J=11Hz, 1H), (7.39 t, J=10Hz, 1H), 7.25-7.26 (m, 3H), (7.12-7.14 m, 2H), 5.60 (s, 2H), 4.80 (s, 2H), 3.68-3.72 (m, 2H), 3.57-3.61 (m, 2H), (3.29-3.34 m, 4H), 1.31 (t, J=9Hz, 6H); 13C NMR (125MHz, D 2O): δ 144.4,135.5, and 135.4,133.9,132.7,131.9,129.1,128.3,126.8,126.4,123.4,122.5,119.5,119.0,111.2,48.5,48.3,47.1,47.0,41.8,8.2; ESI-MS m/z:387.4 (M+1) +.
Compound 15 hydrochloride preparation methods are with embodiment 1.
Embodiment 16 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-benzyl-β-carboline (compound 16)
It is synthetic that starting raw material ethyl 9-benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 16, yield 54%; IR (KBr, cm -1) v:2970,2645,1999,1632,1508,1451,1381,1335,1270,1052,902,752; 1H NMR (500MHz, D 2O): δ 9.01 (s, 1H), 8.59 (s, 1H), 8.15 (d, J=10Hz, 1H), 7.57-7.61 (m, 1H), 7.41 (d, J=10.5Hz, 1H), (7.28 t, J=9Hz, 1H), 7.19-7.20 (m, 3H), 7.07-7.09 (m, 2H), 5.47 (s, 2H), 4.76 (s, 2H), (3.35 t, J=10Hz, 2H), 3.28 (t, J=10Hz, 2H), 2.91 (s, 6H), 2.21-2.29 (m, 2H); 13C NMR (125MHz, D 2O): δ 144.3,135.4, and 135.2,133.8,132.7,131.5,129.1,128.3,126.9,126.2,123.4,122.5,119.4,119.2,111.1,54.3,47.9,47.1,44.8,42.9,21.3; ESI-MS m/z:373.3 (M+1) +.
The preparation method of compound 16 hydrochlorides is with embodiment 1.
Embodiment 173-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-benzyl-β-carboline (compound 17)
It is synthetic that starting raw material ethyl 9-benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 17, yield 54%; IR (KBr, cm -1) v:2951,2619,1630,1531,1505,1453,1388,1336,1268,1158,1051,754; 1H NMR (500MHz, D 2O): δ 9.07 (s, 1H), 8.66 (s, 1H), 8.30 (d, J=10Hz, 1H), 7.72-7.76 (m, 1H), 7.61 (d, J=10.5Hz, 1H), (7.43 t, J=9Hz, 1H), 7.27-7.29 (m, 3H), 7.15-7.17 (m, 2H), 5.65 (s, 2H), 4.76 (s, 2H), (3.34 t, J=10Hz, 2H), 3.21-3.28 (m, 6H), (2.17-2.25 m, 2H), 1.27 (t, J=9Hz, 6H); 13C NMR (125MHz, D 2O): δ 144.4,135.6, and 135.5,133.9,132.7,131.8,129.1,128.3,126.8,126.5,123.4,122.5,119.6,119.1,111.3,48.4,48.1,47.6,47.1,44.8,20.8,8.2; ESI-MS m/z:401.4 (M+1) +.
The preparation method of compound 17 hydrochlorides is with embodiment 1.
Embodiment 183-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-benzyl-β-carboline (compound 18)
It is synthetic that starting raw material ethyl 9-benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 18, yield 60%; IR (KBr, cm -1) v:2950,2646,2017,1629,1515,1463,1386,1335,1272,1042,771; 1H NMR (500MHz, D 2O): δ 9.08 (s, 1H), 8.66 (s, 1H), (8.18 d, J=8Hz, 1H), 7.59 (t, J=7.5Hz, 1H), 7.40 (d, J=8.5Hz, 1H), 7.31 (t, J=7.5Hz, 1H), (7.20-7.24 m, 3H), 7.11-7.13 (m, 2H), 5.48 (s, 2H), (4.80 s, 2H), 3.38 (t, J=7Hz, 2H), 3.21-3.27 (m, 6H), 1.88-1.93 (m, 4H), (1.31 t, J=7Hz, 6H); 13C NMR (125MHz, D 2O): δ 144.5,135.6, and 135.4,134.2,133.0,132.0,129.3,128.8,127.3,126.4,123.7,122.8,119.7,119.5,111.4,51.3,48.0,47.8,47.7,47.5,23.3,21.1,8.6; ESI-MS m/z:415.4 (M+1) +.
The preparation method of compound 18 hydrochlorides is with embodiment 1.
Embodiment 19 3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(4-fluorine) benzyl-β-carboline (compound 19)
It is synthetic that starting raw material ethyl 9-(4-fluorine) benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 19, yield 58%; IR (KBr, cm -1) v:2916,2709,1632,1509,1464,1384,1337,1219,1162,1050,759; 1H NMR (400MHz, D 2O): δ 9.04 (s, 1H), 8.64 (s, 1H), 8.20 (br s, 1H), 7.63 (br s, 1H), 7.46 (br s, 1H), (7.33 br s, 1H), 7.07 (br s, 2H), 6.89-6.91 (m 2H), (5.49 br s, 2H), 4.81 (s, 2H), 3.69-3.73 (m, 2H), 3.58-3.62 (m, 2H), 3.28-3.34 (m, 4H), 1.31 (t, J=7.2Hz, 6H); 13C NMR (100MHz, D 2O): δ 163.3,160.9, and 144.2,135.2,132.6,131.9,131.3,128.8,128.7,126.4,123.4,122.5,119.5,119.1,115.8,115.6,111.1,48.4,48.3,47.0,46.5,41.8,8.2; ESI-MS m/z:405.3 (M+1) +.
The preparation method of compound 19 hydrochlorides is with embodiment 1.
Embodiment 20 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-(4-fluorine) benzyl-β-carboline (compound 20)
It is synthetic that starting raw material ethyl 9-(4-fluorine) benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 20, yield 57%; IR (KBr, cm -1) v:2952,2685,1635,1513,1383,1269,1167,1049,757; 1H NMR (500MHz, D 2O): δ 9.17 (s, 1H), 8.77 (s, 1H), 8.44 (d, J=8Hz, 1H), 7.86 (t, J=7.5Hz, 1H), 7.74 (d, J=8.5Hz, 1H), 7.56 (t, J=7Hz, 1H), 7.24-7.26 (m, 2H), 7.06-7.10 (m, 2H), 5.76 (s, 2H), (4.85 s, 2H), 3.40-3.43 (m, 2H), 3.33-3.36 (m, 2H), 2.98 (s, 6H), 2.28-2.35 (m, 2H); 13C NMR (100MHz, D 2O): δ 163.3,160.8, and 144.1,135.1,133.9,132.6,131.6,131.2,128.9,128.8,126.2,123.4,122.5,119.4,119.3,115.7,115.5,111.0,54.3,47.9,46.5,44.8,43.0,21.3; ESI-MS m/z:391.3 (M+1) +.
The preparation method of compound 20 hydrochlorides is with embodiment 1.
Embodiment 21 3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-(4-fluorine) benzyl-β-carboline (compound 21)
It is synthetic that starting raw material ethyl 9-(4-fluorine) benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 21, yield 55%; IR (KBr, cm -1) v:2928,2760,1631,1510,1457,1384,1337,1267,1221,1163,1052,758; 1HNMR (500MHz, D 2O): δ 9.17 (s, 1H), 8.78 (s, 1H), 8.47 (d, J=8Hz, 1H), 7.89 (t, J=7Hz, 1H), 7.78 (d, J=9Hz, 1H), 7.58 (t, J=7Hz, 1H), 7.25-7.28 (m, 2H), (7.08-7.11 m, 2H), 5.80 (s, 2H), 4.84 (s, 2H), (3.41 t, J=7.5Hz, 2H), 3.29-3.34 (m, 6H), (2.25-2.31 m, 2H), 1.35 (t, J=7Hz, 6H); 13C NMR (100MHz, D 2O): δ 163.3,160.9, and 144.2,135.2,133.9,132.7,131.7,131.2,128.9,128.8,126.2,123.4,122.5,119.5,119.3,115.8,115.6,111.1,48.4,47.9,47.6,46.5,44.9,20.8,8.3; ESI-MS m/z:419.4 (M+1) +.
The preparation method of compound 21 hydrochlorides is with embodiment 1.
Embodiment 22 3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-(4-fluorine) benzyl-β-carboline (compound 22)
It is synthetic that starting raw material ethyl 9-(4-fluorine) benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 22, yield 59%; IR (KBr, cm -1) v:2950,2579,2489,1631,1515,1461,1386,1342,1267,1227,1165,1040,771,755; 1H NMR (500MHz, D 2O): δ 9.10 (s, 1H), 8.69 (s, 1H), (8.17 d, J=8Hz, 1H), 7.57 (t, J=7Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 7.28 (t, J=7.5Hz, 1H), (7.06-7.09 m, 2H), 6.85 (t, J=8.5Hz, 2H), 5.43 (s, 2H), (4.83 s, 2H), 3.38 (t, J=7Hz, 2H), 3.21-3.27 (m, 6H), 1.87-1.95 (m, 4H), (1.31 t, J=7.5Hz, 6H); 13C NMR (125MHz, D 2O): δ 163.3,161.3, and 144.4,135.4,134.2,132.9,132.2,131.5,129.2,126.4,123.7,122.8,119.7,119.5,116.0,115.8,111.3,51.3,48.0,47.8,47.7,46.8,23.2,21.1,8.6; ESI-MS m/z:433.4 (M+1) +.
The preparation method of compound 22 hydrochlorides is with embodiment 1.
Embodiment 23 3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(3-chlorine) benzyl-β-carboline (compound 23)
It is synthetic that starting raw material ethyl 9-(3-chlorine) benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 23, yield 50%; IR (KBr, cm -1) v:2944,2663,1628,1467,1382,1335,1271,1130,1026,759; 1H NMR (500MHz, D 2O): δ 9.10 (s, 1H), 8.69 (s, 1H), (8.16 d, J=8Hz, 1H), 7.42 (t, J=7.5Hz, 1H), 7.19-7.23 (m, 2H), (7.04 t, J=7.5Hz, 1H), 7.00 (d, J=8Hz, 1H), 6.95 (d, J=7.5Hz, 1H), 6.93 (s, 1H), 5.39 (s, 2H), 4.87 (s, 2H), (3.78-3.81 m, 2H), 3.66-3.69 (m, 2H), 3.35-3.39 (m, 4H), (1.36 t, J=7.5Hz, 6H); 13C NMR (125MHz, D 2O): δ 144.2,137.7, and 135.6,134.3,134.0,132.7,132.5,130.7,128.4,126.8,126.7,125.7,123.8,122.7,119.8,119.4,111.0,48.8,48.6,47.4,46.9,42.3,8.6; ESI-MS m/z:421.4 (M+1) +.
The preparation method of compound 23 hydrochlorides is with embodiment 1.
Embodiment 24 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-(3-chlorine) benzyl-β-carboline (compound 24)
It is synthetic that starting raw material ethyl 9-(3-chlorine) benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 24, yield 58%; IR (KBr, cm -1) v:2958,2728,1633,1467,1380,1338,755; 1H NMR (500MHz, D 2O): δ 9.13 (s, 1H), 8.67 (s, 1H), 8.07 (d, J=8Hz, 1H), 7.18 (t, J=7.5Hz, 1H), 7.03 (t, J=7.5Hz, 1H), (6.97 d, J=8.5Hz, 1H), 6.94 (d, J=8Hz, 1H), 6.89 (t, J=8Hz, 1H), 6.83 (s, 1H), 6.72 (d, J=7.5Hz, 1H), 5.25 (s, 2H), (4.80 s, 2H), 3.43 (t, J=7.5Hz, 2H), 3.34 (t, J=8Hz, 2H), (2.96 s, 6H), 2.30-2.36 (m, 2H); 13C NMR (125MHz, D 2O): δ 143.5,137.1,134.9,133.6,133.5,132.0 (2C), 130.2,127.8,126.2,126.1,125.4,123.3,122.1,119.3,119.1,110.2,54.1,47.7,46.4,44.7,42.8,21.1; ESI-MS m/z:407.3 (M+1) +.
The preparation method of compound 24 hydrochlorides is with embodiment 1.
Embodiment 25 3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-(3-chlorine) benzyl-β-carboline (compound 25)
It is synthetic that starting raw material ethyl 9-(3-chlorine) benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 25, yield 46%; IR (KBr, cm -1) v:2949,2725,1629,1465,1382,1338,755; 1H NMR (500MHz, D 2O): δ 9.11 (s, 1H), 8.73 (s, 1H), 8.26 (d, J=8Hz, 1H), 7.58 (t, J=8.5Hz, 1H), (7.38 d, J=8.5Hz, 1H), 7.34 (t, J=7.5Hz, 1H), 7.14 (t, J=7.5Hz, 1H), 7.09 (d, J=8Hz, 1H), 7.05 (d, J=7.5Hz, 1H), (7.01 s, 1H), 5.51 (s, 2H); (4.84 s, 2H), 3.43 (t, J=7Hz, 2H), 3.27-3.34 (m, 6H), 2.26-2.33 (m, 2H), 1.33 (t, J=7.5Hz, 6H); 13C NMR (125MHz, D 2O): δ 143.9,137.2, and 135.1,133.8,133.7,132.3,131.9,130.2,127.9,126.2,125.1,123.3,122.3,119.3,119.0,110.7,48.3,47.8,47.5,46.3,44.7,20.6,8.1; ESI-MS m/z:435.4 (M+1) +.
The preparation method of compound 25 hydrochlorides is with embodiment 1.
Embodiment 26 3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-(3-chlorine) benzyl-β-carboline (compound 26)
It is synthetic that starting raw material ethyl 9-(3-chlorine) benzyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 26, yield 56%; IR (KBr, cm -1) v:2927,2763,2692,2556,1626,1513,1464,1391,1344,1268,1049,1004,751; 1H NMR (500MHz, D 2O): δ 9.11 (s, 1H), 8.71 (s, 1H), (8.22 d, J=8Hz, 1H), 7.52 (t, J=7.5Hz, 1H), 7.32 (d, J=8.5Hz, 1H), 7.29 (t, J=7.5Hz, 1H), (7.10 t, J=7.5Hz, 1H), 7.03-7.05 (m, 2H),, 6.98 (s, 1H), (5.47 s, 2H), 4.81 (s, 2H), (3.37 t, J=7Hz, 2H), 3.21-3.27 (m, 6H), 1.86-1.94 (m, 4H), (1.31 t, J=7Hz, 6H); 13C NMR (125MHz, D 2O): δ 144.3,137.7, and 135.5,134.3,134.2,132.8,132.6,130.8,128.4,126.7,126.6,125.7,123.8,122.8,119.8,119.5,111.1,51.3,48.1,47.8,47.7,46.9,23.2,21.1,8.6; ESI-MS m/z:449.4 (M+1) +.
The preparation method of compound 26 hydrochlorides is with embodiment 1.
Embodiment 27 3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 27)
It is synthetic that starting raw material ethyl 9-(3-phenyl propyl)-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 27, yield 58%; IR (KBr, cm -1) v:2938,2617,1633,1504,1462,1383,1341,753; 1H NMR (500MHz, D 2O): δ 8.74 (s, 1H), 8.48 (s, 1H), (8.00 d, J=10Hz, 1H), 7.52 (t, J=10Hz, 1H), 7.19-7.23 (m, 2H), (6.90-6.92 m, 3H), 6.69-6.71 (m, 2H), (4.78 s, 2H), 4.11 (t, J=7Hz, 2H), 3.71-3.74 (m, 2H), (3.60-3.64 m, 2H), 3.29-3.35 (m, 4H), 2.35 (t, J=9Hz, 2H), 1.90-1.97 (m, 2H), (1.32 t, J=9.5Hz, 6H); 13C NMR (125MHz, D 2O): δ 143.9,140.3, and 134.6,133.1,132.3,130.7,128.2,127.8,125.9,125.7,123.1,122.1,119.1,118.8,110.8,48.2,48.1,46.9,43.2,41.9,32.0,28.6,8.2; ESI-MS m/z:415.3 (M+1) +.
The preparation method of compound 27 hydrochlorides is with embodiment 1.
Embodiment 28 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 28)
It is synthetic that starting raw material ethyl 9-(3-phenyl propyl)-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 28, yield 57%; IR (KBr, cm -1) v:2952,2714,1635,1509,1474,1379,1338,1269,1059,752; 1H NMR (500MHz, D 2O): δ 8.78 (s, 1H), 8.50 (s, 1H), (8.10 d, J=10Hz, 1H), 7.61-7.65 (t, J=10Hz, 1H), 7.35 (d, J=10.5Hz, 1H), 7.29-7.33 (t, J=8Hz, 1H), (6.96-6.98 m, 3H), 6.76-6.79 (m, 2H), (4.74 s, 2H), 4.22-4.25 (t, J=8.5Hz, 2H), 3.32-3.36 (t, J=10Hz, 2H), (3.26-3.30 m, 2H), 2.92 (s, 6H), (2.43-2.46 t, J=9Hz, 2H), 2.22-2.30 (m, 2H), 2.02-2.09 (m, 2H); 13C NMR (125MHz, D 2O): δ 144.0,140.4, and 134.8,133.2,132.3,130.6,128.2,127.9,125.9,125.8,123.2,122.1,119.2,118.9,111.0,54.2,47.7,44.7,43.3,42.9,32.0,28.5,21.3; ESI-MS m/z:401.3 (M+1) +.
The preparation method of compound 28 hydrochlorides is with embodiment 1.
Embodiment 29 3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 29)
It is synthetic that starting raw material ethyl 9-(3-phenyl propyl)-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 29, yield 56%; IR (KBr, cm -1) v:2940,2626,1633,1508,1459,1378,1342,755; H NMR (500MHz, D 2O): δ 8.75 (s, 1H), 8.46 (s, 1H), (8.08 d, J=10Hz, 1H), 7.61 (t, J=9.5Hz, 1H), 7.27-7.33 (m, 2H), (6.96-6.98 m, 3H), 6.76-6.78 (m, 2H), (4.72 s, 2H), 4.19 (t, J=8.5Hz, 2H), 3.34 (t, J=10Hz, 2H), (3.32-3.28 m, 6H), 2.43 (t, J=8.5Hz, 2H), 2.19-2.27 (m, 2H), 1.98-2.05 (m, 2H), (1.27 t, J=9Hz, 6H); 13C NMR (125MHz, D 2O): δ 144.0,140.7, and 135.0,133.1,132.4,131.2,128.4,128.1,126.3,126.1,123.3,122.2,119.4,118.9,111.1,48.6,48.2,47.8,45.0,43.4,32.2,28.8,21.0,8.4; HRMS (EI) calcd forC 28H 36N 4: 428.2934.Found:428.2928.
The preparation method of compound 29 hydrochlorides is with embodiment 1.
Embodiment 30 3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 30)
It is synthetic that starting raw material ethyl 9-(3-phenyl propyl)-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 30, yield 67%; IR (KBr, cm -1) v:2939,2648,1637,1534,1507,1453,1428,1384,1366,1267,1150,1063,1040,775,753; 1H NMR (500MHz, D 2O): δ 8.91 (s, 1H), 8.61 (s, 1H), (8.22 d, J=8Hz, 1H), 7.75 (t, J=7.5Hz, 1H), 7.50 (d, J=9Hz, 1H), 7.41 (t, J=7.5Hz, 1H), (7.01-7.03 m, 3H), 6.84-6.86 (m, 2H), (4.81 s, 2H), 4.38 (t, J=6.5Hz, 2H), 3.37 (t, J=7Hz, 2H), (3.23-3.29 m, 6H), 2.55 (t, J=7Hz, 2H), 2.16-2.21 (m, 2H), 1.87-1.95 (m, 4H), 1.33 (t, J=7Hz, 6H); 13C NMR (75MHz, D 2O): δ 143.8,140.4, and 134.5,133.3,132.5,130.7,128.3,127.9,126.0,125.4,123.4,122.2,119.3,119.1,100.7,51.2,49.3,47.7,47.6,43.5,32.3,29.2,23.3,21.2,8.7; ESI-MS m/z:443.4 (M+1) +.
The preparation method of compound 30 hydrochlorides is with embodiment 1.
Embodiment 31 1-methyl-3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-β-carboline (compound 31)
It is synthetic that starting raw material ethyl 1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 31, yield 68%; IR (KBr, cm -1) v:2937,2745,1630,1473,1384,1343,1241,1050,761; 1H NMR (500MHz, D 2O): δ 8.22 (s, 1H), 7.90 (d, J=8Hz, 1H), (7.55-7.58 m, 1H), 7.36 (d, J=8.5Hz, 1H), 7.22 (t, J=7.5Hz, 1H), (4.62 s, 2H), 3.29-3.32 (m, 2H), (3.24-3.28 m, 2H), 2.89 (s, 6H), (2.75 s, 3H), 2.20-2.25 (m, 2H); 13CNMR (100MHz, D 2O+Dioxane): δ 142.8,139.6, and 133.1,131.9,131.4,129.8,122.5,121.9,119.1,117.3,112.3,54.2,47.4,44.7,42.9,21.3,15.7; ESI-MS m/z:297.4 (M+1) +.
The preparation method of compound 31 hydrochlorides is with embodiment 1.
Embodiment 32 3-[N-(2-diethylamino)-ethyl]-methylamino-1, the preparation of 9-dimethyl-β-carboline (compound 32)
It is synthetic that starting raw material ethyl 1,9-dimethyl-β-carboline-3-carboxylicesters are pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 32, yield 70%; IR (KBr, cm -1) v:2942,2685,1628,1466,1387,1341,1136,1027,770; 1H NMR (500MHz, D 2O): δ 8.31 (s, 1H), 7.81 (d, J=8Hz, 1H), (7.46-7.49 m, 1H), 7.21 (d, J=8.5Hz, 1H), (7.11 t, J=7.5Hz, 1H), 4.76 (s, 2H), 3.71-3.74 (m, 5H), 3.61-3.64 (m, 2H), 3.30-3.34 (m, 4H), 2.97 (s, 3H), 1.31 (t, J=7.5Hz, 6H); 13C NMR (100MHz, D 2O+Dioxane): δ 144.0,140.0, and 133.2,131.9,131.7,129.9,122.0,121.8,118.2,117.1,110.2,48.2,47.6,46.8,41.9,31.9,17.9,8.2; ESI-MS m/z:325.4 (M+1) +.
The preparation method of compound 32 hydrochlorides is with embodiment 1.
Embodiment 33 3-[N-(3-dimethylamino)-propyl group]-methylamino-1, the preparation of 9-methyl-β-carboline (compound 33)
It is synthetic that starting raw material ethyl 1,9-dimethyl-β-carboline-3-carboxylicesters are pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 33, yield 78%; IR (KBr, cm -1) v:2954,2733,1628,1470,1384,1344,1252,1057,773; 1H NMR (500MHz, D 2O): δ 8.29 (s, 1H), 7.82 (d, J=8Hz, 1H), (7.46-7.49 m, 1H), 7.21 (d, J=8.5Hz, 1H), (7.12 t, J=7.5Hz, 1H), 4.71 (s, 2H), (3.73 s, 3H), 3.35 (t, J=8Hz, 2H), (3.27-3.30 m, 2H), 2.97 (s, 3H), (2.91 s, 6H), 2.23-2.30 (m, 2H); 13C NMR (100MHz, D 2O+Dioxane): δ 144.0139.9,133.2,131.9,131.7,129.9,122.1,121.8,118.2,117.1,110.2,54.2,47.2,44.8,42.9,31.9,21.3,18.0; ESI-MS m/z:311.4 (M+1) +.
The preparation method of compound 33 hydrochlorides is with embodiment 1.
Embodiment 34 3-[N-(3-diethylamino)-propyl group]-methylamino-1, the preparation of 9-methyl-β-carboline (compound 34)
It is synthetic that starting raw material ethyl 1,9-dimethyl-β-carboline-3-carboxylicesters are pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 34, yield 75%; IR (KBr, cm -1) v:2951,2741,1630,1469,1386,1344,1254,1136,1045,768; 1H NMR (500MHz, D 2O): δ 8.36 (s, 1H), 7.94 (d, J=8Hz, 1H), (7.56-7.60 m, 1H), 7.34 (d, J=8.5Hz, 1H), (7.22 t, J=7.5Hz, 1H), 4.72 (s, 2H), (3.85 s, 3H), 3.35 (t, J=8Hz, 2H), (3.21-3.28 m, 6H), 3.03 (s, 3H), 2.20-2.25 (m, 2H), 1.27 (t, J=7.5Hz, 6H); 13C NMR (100MHz, D 2O+Dioxane): δ 144.2,140.1, and 133.4,132.1,131.8,129.9,122.2,121.9,118.4,117.2,110.4,48.4,47.6,47.3,44.9,32.0,20.8,18.0,8.2; ESI-MS m/z:339.4 (M+1) +.
The preparation method of compound 34 hydrochlorides is with embodiment 1.
Embodiment 353-[N-(4-diethylamino)-butyl]-methylamino-1, the preparation of 9-methyl-β-carboline (compound 35)
It is synthetic that starting raw material ethyl 1,9-dimethyl-β-carboline-3-carboxylicesters are pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 35, yield 75%; IR (KBr, cm -1) v:2952,2139,1629,1469,1386,1027,766; 1H NMR (300MHz, D 2O): δ 8.29 (s, 1H), 7.92 (d, J=7.8Hz, 1H), (7.55 t, J=7.2Hz, 1H), 7.32 (d, J=8.7Hz, 1H), 7.18 (t, J=7.2Hz, 1H), 4.61 (s, 2H), 3.84 (s, 3H), 3.21 (t, J=6.3Hz, 2H), 3.11-3.16 (m, 6H), 2.99 (s, 3H), (1.75-1.77 m, 4H), 1.18 (t, J=8Hz, 7.2H); 13C NMR (100MHz, D 2O+Dioxane): δ 144.0,139.9, and 133.2,131.9,131.7,130.2,122.1,121.8,118.2,117.1,110.2,50.9,47.4 (2C), 47.1,31.9,22.8,20.7,18.0,8.3; ESI-MS m/z:353.4 (M+1) +.
The preparation method of compound 35 hydrochlorides is with embodiment 1.
Embodiment 36 3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-normal-butyl-1-methyl-β-carboline (compound 36)
It is synthetic that starting raw material ethyl 9-normal-butyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 36, yield 55%; IR (KBr, cm -1) v:2969,2619,1629,1462,1385,1339,1253,1137,1058,1026,755; 1H NMR (500MHz, D 2O): δ 8.62 (s, 1H), 8.34 (d, J=8Hz, 1H), 7.88 (t, J=7.5Hz, 1H), (7.80 d, J=8.5Hz, 1H), 7.52 (t, J=7.5Hz, 1H), 4.84 (s, 2H), (4.64 t, J=7.5Hz, 2H), 3.74-3.77 (m, 2H), 3.65-3.68 (m, 2H), 3.37-3.42 (m, 4H), 3.27 (s, 3H), 1.82-1.88 (m, 2H), 1.43-1.46 (m, 2H), (1.40 t, J=7.5Hz, 6H), (0.95 t, J=7.5Hz, 3H); 13C NMR (100MHz, D 2O): δ 144.4,139.8, and 133.2,133.0,132.1,130.2,122.6,122.2,119.0,117.3,111.1,48.3,47.8,47.0,44.9,41.9,32.4,19.4,18.1,13.0,8.3; ESI-MS m/z:367.4 (M+1) +.
The preparation method of compound 36 hydrochlorides is with embodiment 1.
Embodiment 37 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-normal-butyl-1-methyl-β-carboline (compound 37)
It is synthetic that starting raw material ethyl 9-normal-butyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 37, yield 42%; IR (KBr, cm -1) v:2957,2727,1625,1536,1466,1382,1340,1252,1133,1058,764; 1H NMR (500MHz, D 2O): δ 8.57 (s, 1H), 8.24 (d, J=8.5Hz, 1H), 7.81 (t, J=7.5Hz, 1H), (7.70 d, J=8.5Hz, 1H), 7.45 (t, J=7.5Hz, 1H), 4.84 (s, 2H), (4.53 t, J=7.5Hz, 2H), 3.42-3.45 (m, 2H), 3.35-3.38 (m, 2H), 3.22 (s, 3H), 2.99 (s, 6H), (2.30-2.37 m, 2H), 1.75-1.81 (m, 2H), 1.37-1.41 (m, 2H), (0.93 t, J=7.5Hz, 3H); 13C NMR (100MHz, D 2O): δ 144.1,139.5, and 132.9,132.8,132.1,130.0,122.5,122.1,118.7,117.4,110.9,54.3,47.2,44.9 (2C), 43.0,32.4,21.3,19.3,18.0,13.1; ESI-MS m/z:353.4 (M+1) +.
The preparation method of compound 37 hydrochlorides is with embodiment 1.
Embodiment 38 3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-normal-butyl-1-methyl-β-carboline (compound 38)
It is synthetic that starting raw material ethyl 9-normal-butyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 38, yield 54%; IR (KBr, cm -1) v:2960,2676,1624,1570,1468,1383,1340,1254,1207,1136,1033,755; 1HNMR (500MHz, D 2O): δ 8.63 (s, 1H), 8.36 (d, J=8Hz, 1H), 7.89 (t, J=7.5Hz, 1H), (7.81 d, J=8.5Hz, 1H), 7.53 (t, J=7Hz, 1H), 4.83 (s, 2H), (4.66 t, J=7.5Hz, 2H), 3.43 (t, J=7.5Hz, 2H), 3.30-3.36 (m, 6H), (3.27 s, 3H), 2.27-2.33 (m, 2H), (1.83-1.89 m, 2H), 1.39-1.47 (m, 2H), (1.36 t, J=7Hz, 6H), (0.96 t, J=7.5Hz, 3H); 13C NMR (100MHz, D 2O): δ 144.2,139.6, and 132.9,132.8,132.1,130.1,122.5,122.1,118.8,117.4,111.0,48.5,47.7,47.3,45.0,44.9,32.4,20.9,19.4,18.0,13.1,8.3; ESI-MS m/z:381.4 (M+1) +.
The preparation method of compound 38 hydrochlorides is with embodiment 1.
Embodiment 39 3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-normal-butyl-1-methyl-β-carboline (compound 39)
It is synthetic that starting raw material ethyl 9-normal-butyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 39, yield 60%; IR (KBr, cm -1) v:2968,2777,1669,1628,1546,1452,1381,1341,1143,1038,774; 1H NMR (500MHz, D 2O): δ 8.47 (s, 1H), 8.03 (d, J=8Hz, 1H), 7.64 (t, J=7.5Hz, 1H), (7.47 d, J=8.5Hz, 1H), 7.27 (t, J=7.5Hz, 1H), 4.79 (s, 2H), (4.29 t, J=7.5Hz, 2H), 3.39 (t, J=7Hz, 2H), 3.23-3.29 (m, 6H), 3.10 (s, 3H), (1.88-1.97 m, 4H), 1.57-1.63 (m, 2H), 1.26-1.34 (m, 8H), (0.86 t, J=7Hz, 3H); 13C NMR (125MHz, D 2O): δ 144.5,139.9, and 133.2,133.1,132.4,130.7,122.9,122.4,119.1,117.6,111.2,51.4,47.9 (2C), 47.5,45.2,32.7,23.3,21.2,19.7,18.4,13.4,8.7; ESI-MS m/z:395.4 (M+1) +.
The preparation method of compound 39 hydrochlorides is with embodiment 1.
Embodiment 40 3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-benzyl-1-methyl-β-carboline (compound 40)
It is synthetic that starting raw material ethyl 9-benzyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 40, yield 48%; IR (KBr, cm -1) v:2739,1627,1462,1388,1344,1261,1203,1135,1025,765; 1H NMR (500MHz, D 2O): δ 8.66 (s, 1H), 8.15 (d, J=8Hz, 1H), 7.37 (t, J=8Hz, 1H), 7.19 (t, J=7.5Hz, 1H), 7.13 (d, J=8.5Hz, 1H), 6.98-7.00 (m, 3H), 6.70-6.72 (m, 2H), (5.52 s, 2H), 4.89 (s, 2H), 3.81-3.84 (m, 2H), 3.68-3.71 (m, 2H), 3.33-3.38 (m, 4H), (2.84 s, 3H), 1.34 (t, J=7.5Hz, 6H); 13C NMR (125MHz, D 2O): δ 144.3,139.8, and 136.1,133.3,133.1,132.1,130.6,128.8,127.6,125.1,122.8,122.3,118.9,117.5,110.5,48.1,47.7,47.4,46.8,41.8,17.6,8.1; ESI-MS m/z:401.4 (M+1) +.
The preparation method of compound 40 hydrochlorides is with embodiment 1.
Embodiment 41 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-benzyl-1-methyl-β-carboline (compound 41)
It is synthetic that starting raw material ethyl 9-benzyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 41, yield 44%; IR (KBr, cm -1) v:2952,2693,1623,1538,1465,1340,1260,1209,760; 1H NMR (500MHz, D 2O): δ 8.57 (s, 1H), 8.20 (d, J=8Hz, 1H), (7.52-7.55 m, 1H), 7.29-7.34 (m, 2H), 7.12-7.13 (m, 3H), 6.79-6.80 (m, 2H), 5.66 (s, 2H), (4.75 s, 2H), 3.34-3.37 (m, 2H), (3.26-3.29 m, 2H), 2.90 (s, 6H), (2.87 s, 3H), 2.22-2.29 (m, 2H); 13C NMR (100MHz, D 2O+1,4-Dioxane): δ 144.7,140.3, and 136.6,133.8,133.5,132.5,131.1,129.2,128.1,125.5,123.1,122.7,119.4,117.7,111.0,54.4,48.0,47.5,44.9,43.0,21.5,17.9; ESI-MS m/z:387.4 (M+1) +.
The preparation method of compound 41 hydrochlorides is with embodiment 1.
Embodiment 42 3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-benzyl-1-methyl-β-carboline (compound 42)
It is synthetic that starting raw material ethyl 9-benzyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 42, yield 52%; IR (KBr, cm -1) v:2949,2764,1627,1463,1384,1346,1135,1045,749; 1H NMR (500MHz, D 2O): δ 8.70 (s, 1H), 8.37 (d, J=8Hz, 1H), 7.73 (t, J=7.5Hz, 1H), (7.54 d, J=8.5Hz, 1H), 7.48 (t, J=7.5Hz, 1H), 7.28-7.29 (m, 3H), (6.95-6.96 m, 2H), 5.85 (s, 2H), 4.85 (s, 2H), (3.45 t, J=7.5Hz, 2H), (3.29-3.36 m, 6H), 3.01 (s, 3H), 2.28-2.35 (m, 2H), (1.35 t, J=7.5Hz, 6H); 13C NMR (125MHz, D 2O): δ 145.2,140.6, and 137.0,134.2,133.9,132.8,131.4,129.5,128.3,125.7,123.4,123.0,119.7,117.9,111.3,48.8,48.3,48.0,47.8,45.3,21.2,18.2,8.6; ESI-MS m/z:415.4 (M+1) +.
The preparation method of compound 42 hydrochlorides is with embodiment 1.
Embodiment 43 3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-benzyl-1-methyl-β-carboline (compound 43)
It is synthetic that starting raw material ethyl 9-benzyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 43, yield 40%; IR (KBr, cm -1) v:2953,2733,1627,1463,1395,1345,1039,764; 1H NMR (500MHz, D 2O): δ 8.67 (s, 1H), 8.30 (d, J=8Hz, 1H), (7.61 t, J=7Hz, 1H), 7.37-7.41 (m, 2H), (7.19-7.20 m, 3H), 6.87-6.89 (m, 2H), 5.73 (s, 2H), 4.82 (s, 2H), 3.40 (t, J=7Hz, 2H), 3.23-3.29 (m, 6H), 2.96 (s, 3H), (1.87-1.98 m, 2H), 1.32 (t, J=7Hz, 6H); 13C NMR (100MHz, D 2O+Dioxane): δ 144.6,140.0, and 136.5,133.6,133.4,132.4,131.2,129.1,127.9,125.4,123.0,122.6,119.2,117.6,110.8,50.9,47.9,47.4 (2C), 47.2,22.9,20.8,17.8,8.3; ESI-MS m/z:429.4 (M+1) +.
The preparation method of compound 43 hydrochlorides is with embodiment 1.
Embodiment 44 3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(4-fluorine) benzyl-1-methyl-β-carboline (compound 44)
It is synthetic that starting raw material ethyl 9-(4-fluorine) benzyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 44, yield 52%; IR (KBr, cm -1) v:2763,2615,1621,1505,1468,1387,1255,1217,1052,758; 1H NMR (400MHz, D 2O): δ 8.62 (s, 1H), 8.17 (d, J=8Hz, 1H), (7.53 t, J=7.2Hz, 1H), 7.27-7.32 (m, 2H), (6.74-6.82 m, 4H), 5.62 (s, 2H), 4.84 (s, 2H), 3.73-3.77 (m, 2H), 3.61-3.65 (m, 2H), 3.27-3.35 (m, 4H), 2.88 (s, 3H), 1.31 (t, J=7.2Hz, 1H); 13C NMR (100MHz, D 2O): δ 163.1,160.7, and 144.5,140.2,133.6,133.5,132.5,132.3,131.0,127.3,127.2,123.0,122.7,119.3,117.7,115.8,115.6,110.8,48.3,47.8,47.4,46.9,41.9,17.8,8.3; ESI-MS m/z:419.4 (M+1) +.
The preparation method of compound 44 hydrochlorides is with embodiment 1.
Embodiment 45 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-(4-fluorine) benzyl-1-methyl-β-carboline (compound 45)
It is synthetic that starting raw material ethyl 9-(4-fluorine) benzyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 45, yield 45%; IR (KBr, cm -1) v:2956,2652,1626,1507,1466,1384,1338,1220,1157,1056,752; 1HNMR (500MHz, D 2O): δ 8.62 (s, 1H), 8.30 (d, J=10Hz, 1H), (7.67-7.71 m, 1H), 7.49 (d, J=10.5Hz, 1H), (7.42 t, J=9Hz, 1H), 6.87-6.96 (m, 4H), (5.78 s, 2H), 4.78 (s, 2H), 3.37 (t, J=9.5Hz, 2H), 3.27-3.31 (m, 2H), 2.96 (s, 3H), 2.92 (s, 6H), 2.23-2.31 (m, 2H); 13CNMR (125MHz, D 2O): δ 163.2,160.8, and 144.8,140.3,133.9,133.7,132.5,131.1,127.3,127.2,123.1,122.7,119.5,117.6,115.9,115.7,111.0,54.3,47.5,44.8,42.9,21.3,17.9; ESI-MS m/z:405.4 (M+1) +.
The preparation method of compound 45 hydrochlorides is with embodiment 1.
Embodiment 46 3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-(4-fluorine) benzyl-1-methyl-β-carboline (compound 46)
It is synthetic that starting raw material ethyl 9-(4-fluorine) benzyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 46, yield 56%; IR (KBr, cm -1) v:2943,1624,1546,1509,1471,1383,1222,1160,1056,758; 1H NMR (400MHz, D 2O): δ 8.60 (s, 1H), 8.22 (d, J=8Hz, 1H), (7.58 t, J=7.2Hz, 1H), 7.31-7.38 (m, 2H), (6.80-6.87 m, 4H), 5.66 (s, 2H), 4.78 (s, 2H), 3.38 (t, J=8Hz, 2H), 3.21-3.30 (m, 6H), 2.90 (s, 3H), 2.21-2.29 (m, 2H), 1.27 (t, J=6.8Hz, 6H); 13C NMR (100MHz, D 2O): δ 163.1,160.7, and 144.6,140.2,133.7,133.5,132.4,131.2,127.3,127.2,123.0,122.7,119.4,117.7,115.9,115.7,110.9,48.5,47.7,47.5,47.4,45.0,20.9,17.9,8.3; ESI-MS m/z:433.4 (M+1) +.
The preparation method of compound 46 hydrochlorides is with embodiment 1.
Embodiment 47 3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-(4-fluorine) benzyl-1-methyl-β-carboline (compound 47)
It is synthetic that starting raw material ethyl 9-(4-fluorine) benzyl-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 47, yield 50%; IR (KBr, cm -1) v:2951,2772,1626,1505,1465,1385,1344,1220,1153,1045,761; 1HNMR (500MHz, D 2O): δ 8.65 (s, 1H), 8.12 (d, J=8Hz, 1H), 7.36 (t, J=7.5Hz, 1H), 7.12-7.16 (m, 2H), 6.69-6.72 (m, 2H), 6.63 (t, J=8.5Hz, 2H), 5.49 (s, 2H), 4.82 (s, 2H), 3.40 (t, J=7Hz, 2H), 3.19-3.24 (m, 6H), 2.86 (s, 3H), (1.87-1.95 m, 4H), 1.27 (t, J=7Hz, 6H); 13C NMR (100MHz, D 2O+Dioxane): δ 162.9,160.5,144.2,139.8,133.4,132.3 (2C), 131.6,127.4,127.3,123.1,122.6,119.2,117.8,115.8,115.6,110.6,51.1,47.6,47.5,47.4,47.2,23.1,21.0,17.9,8.5; ESI-MS m/z:447.4 (M+1) +.
The preparation method of compound 47 hydrochlorides is with embodiment 1.
Embodiment 48 3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(3-phenyl propyl)-1-methyl-β-carboline (compound 48)
It is synthetic that starting raw material ethyl 9-(3-phenyl propyl)-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 48, yield 64%; IR (KBr, cm -1) v:2931,2669,1621,1494,1435,1384,1337,1247,1139,1053,1024,777,753; 1H NMR (500MHz, D 2O): δ 8.52 (s, 1H), 8.27 (d, J=8Hz, 1H), 7.83 (t, J=7.5Hz, 1H), (7.59 d, J=8.5Hz, 1H), 7.49 (t, J=7Hz, 1H), 7.21-7.27 (m, 3H), (7.11 d, J=8.5Hz, 2H), 4.79 (s, 2H), 4.54 (t, J=7Hz, 2H), (3.70-3.74 m, 2H), 3.64-3.68 (m, 2H), (3.37-3.42 m, 4H), 3.02 (s, 3H), (2.73 t, J=6.5Hz, 2H), 2.15-2.21 (m, 2H), 1.40 (t, J=7.5Hz, 6H); 13C NMR (100MHz, D 2O): δ 143.7,140.5, and 139.3,132.8,132.7,132.0,130.3,128.4,128.2,126.2,122.6,122.2,118.9,117.3,110.4,48.3,47.6,46.9,44.0,42.0,31.8,31.2,17.7,8.3; ESI-MS m/z:429.4 (M+1) +.
The preparation method of compound 48 hydrochlorides is with embodiment 1.
Embodiment 49 3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-(3-phenyl propyl)-1-methyl-β-carboline (compound 49)
It is synthetic that starting raw material ethyl 9-(3-phenyl propyl)-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 49, yield 55%; IR (KBr, cm -1) v:2936,2711,2407,1632,1508,1454,1381,1336,1056,1026,751; 1HNMR (500MHz, D 2O): δ 8.68 (s, 1H), 8.31 (d, J=8Hz, 1H), 7.85 (t, J=7Hz, 1H), (7.55 t, J=7.5Hz, 1H), 7.49 (d, J=8.5Hz, 1H), 7.35-7.41 (m, 3H), (7.20-7.22 m, 2H), 5.01 (s, 2H), (4.44 t, J=7.5Hz, 2H), 3.64 (t, J=7.5Hz, 2H), 3.54-3.59 (m, 2H), (3.20 s, 6H), 3.10 (s, 3H), (2.78 t, J=7.5Hz, 2H), 2.52-2.58 (m, 2H), 2.11-2.17 (m, 2H); 13C NMR (75MHz, D 2O): δ 143.9,140.6, and 139.3,132.8,132.1,130.4,128.6,128.4,126.3,122.9,122.3,119.0,117.7,110.5,54.6,47.4,45.3,44.3,43.3,32.1,31.6,21.7,18.0; ESI-MS m/z:415.4 (M+1) +.
The preparation method of compound 49 hydrochlorides is with embodiment 1.
Embodiment 50 3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-(3-phenyl propyl)-1-methyl-β-carboline (compound 50)
It is synthetic that starting raw material ethyl 9-(3-phenyl propyl)-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 50, yield 55%; IR (KBr, cm -1) v:2943,2730,1623,1536,1498,1470,1385,1340,1304,1057,758; 1HNMR (500MHz, D 2O): δ 8.39 (s, 1H), 8.12 (d, J=8Hz, 1H), 7.66-7.69 (m, 1H), 7.40 (d, J=8.5Hz, 1H), 7.35 (t, J=7Hz, 1H), 7.12-7.19 (m, 3H), 7.02 (t, J=7Hz, 2H), 4.69 (s, 2H), (4.33 t, J=7.5Hz, 2H), 3.32 (t, J=7.5Hz, 2H), 3.21-3.27 (m, 6H), (2.86 s, 3H), 2.61 (t, J=7Hz, 2H), 2.18-2.24 (m, 2H), 1.98-2.04 (m, 2H), 1.26 (t, J=7Hz, 6H); 13C NMR (100MHz, D 2O): δ 143.9,140.6, and 139.4,132.9,132.8,132.0,130.4,128.5,128.2,126.2,122.7,122.2,119.0,117.4,110.6,48.5,47.7,47.3,45.0,44.1,31.8,31.2,20.8,17.8,8.3; ESI-MS m/z:443.4 (M+1) +.
The preparation method of compound 50 hydrochlorides is with embodiment 1.
Embodiment 51 3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-(3-phenyl propyl)-1-methyl-β-carboline (compound 51)
It is synthetic that starting raw material ethyl 9-(3-phenyl propyl)-1-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 51, yield 62%; IR (KBr, cm -1) v:2945,2733,1626,1464,1387,1345,1033,761; 1H NMR (500MHz, D 2O): δ 8.46 (s, 1H), 8.17 (d, J=8Hz, 1H), 7.73 (t, J=7.5Hz, 1H), (7.39-7.45 m, 2H), 7.19-7.24 (m, 3H), (7.05-7.07 d, J=7Hz, 2H), 4.75 (s, 2H), 4.37 (t, J=7Hz, 2H), (3.36 t, J=7Hz, 2H), 3.22-3.29 (m, 6H), 2.92 (s, 3H), 2.66 (t, J=6.5Hz, 2H), 2.02-2.08 (m, 2H), 1.89-1.93 (m, 4H), (1.33 t, J=7.5Hz, 6H); 13C NMR (300MHz, DMSO-d 6): δ 144.4,141.5,139.9,133.8,133.6,132.4,132.2,129.0 (2C), 126.7,123.3,122.5,119.8,118.2,112.1,50.5,46.7 (3C), 44.9,32.8,23.6,21.1,18.4,9.3; ESI-MS m/z:457.5 (M+1) +.
The preparation method of compound 51 hydrochlorides is with embodiment 1.
Embodiment 52 1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-β-carboline (compound 52)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 52, yield 62%; IR (KBr, cm -1) v:2942,2676,1628,1580,1504,1461,1380,1244,1123,756; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.59 (s, 1H), 8.32 (d, J=8.1Hz, 1H), 7.65-7.75 (m, 2H), 7.42 (s, 2H), 7.35-7.40 (m, 1H), 4.64 (s, 2H), 3.94 (s, 6H), 3.78 (s, 3H), 3.17-3.22 (m, 4H), 2.74 (s, 6H), 2.14-2.24 (m, 2H); 13CNMR (75MHz, DMSO-d 6+ D 2O): δ 153.8,144.3, and 144.1,140.1,139.9,135.4,132.9,132.8,132.7,131.5,127.2,123.3,122.0,120.6,118.0,113.9,108.1,61.0,57.1,54.3,48.3,44.6,42.8,21.4.ESI-MS m/z:449.4 (M+1) +.
The preparation method of compound 52 hydrochlorides is with embodiment 1.
Embodiment 53 1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-β-carboline (compound 53)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 53, yield 52%; IR (KBr, cm -1) v:2937,2725,1629,1580,1502,1462,1382,1243,1123,756; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8-63 (s, 1H), 8-33 (d, J=8-1Hz, 1H), 7-69-7-76 (m, 2H), 7-44 (s, 2H), 7-36-7-42 (m, 1H), 4-67 (s, 2H), 3-95 (s, 6H), 3-78 (s, 3H), 3-16-3-22 (m, 4H), 3-05-3.12 (m, 4H), 2.16-2.22 (m, 2H), 1.20 (t, J=7.2Hz, 6H); 13C NMR (75MHz, DMSO-d 6+ D 2O): δ 153.8,144.5, and 144.2,140.2,139.7,135.0,132.9,132.7,131.7,126.6,123.4,122.1,120.6,118.3,114.0,108.3,61.0,57.1,48.6,48.0,47.0,44.8,20.9,9.2.HRMS (EI) calcd for C 28H 36N 4O 3: 476.2787.Found:476.2790.
The preparation method of compound 53 hydrochlorides is with embodiment 1.
Embodiment 54 1-(3,4,5-trimethoxy) phenyl-3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-methyl-β-carboline (compound 54)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 54, yield 40%; IR (KBr, cm -1) v:2939,2658,2373,1622,1581,1525,1501,1457,1384,1286,1159,1124,759; 1H NMR (400MHz, D 2O): δ 8.66 (s, 1H), 8.13 (d, J=8Hz, 1H), 7.61 (t, J=6.8Hz, 1H), 7.41 (d, J=8.4Hz, 1H), 7.26 (t, J=6.8Hz, 1H), 7.09 (s, 2H), 4.90 (s, 2H), (3.90 s, 6H), 3.89 (s, 3H), 3.76-3.80 (m, 2H), 3.64-3.67 (m, 2H), 3.37 (s, 3H), (3.30-3.35 m, 4H), 1.31 (t, J=7.2Hz, 6H); 13C NMR (100MHz, D 2O): δ 152.9,145.5, and 139.5,139.2,134.3,133.3,132.2,130.7,125.6,122.8,122.0,119.1,118.2,110.9,108.5,61.3,56.7,48.3,48.2,46.9,41.9,32.6,8.3.ESI-MS m/z:477.4 (M+1) +.
The preparation method of compound 54 hydrochlorides is with embodiment 1.
Embodiment 55 1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-methyl-β-carboline (compound 55)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 55, yield 55%; IR (KBr, cm -1) v:2943,2720,1626,1583,1503,1411,1384,1281,1181,1122,761; 1H NMR (500MHz, D 2O): δ 8.73 (s, 1H), 8.40 (d, J=7.5Hz, 1H), 7.86 (t, J=7Hz, 1H), 7.68 (d, J=9Hz, 1H), 7.52 (t, J=7Hz, 1H), 7.18 (s, 2H), 4.87 (s, 2H), (3.99 s, 3H), 3.98 (s, 6H), 3.58 (m, 3H), 3.44 (t, J=7.5Hz, 2H), 3.34-3.37 (m, 2H), 2.98 (s, 6H), 2.31-2.37 (m, 2H); 13CNMR (125MHz, D 2O): δ 152.9,145.7, and 139.7,139.5,134.3,133.7,132.3,131.5,126.4,123.0,122.2,119.4,118.0,111.1,108.5,61.3,56.7,54.4,48.2,44.8,43.0,32.5,21.4.ESI-MS m/z:463.4 (M+1) +.
The preparation method of compound 55 hydrochlorides is with embodiment 1.
Embodiment 56 1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-methyl-β-carboline (compound 56)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 56, yield 44%; IR (KBr, cm -1) v:2939,2725,1627,1582,1504,1409,1384,1241,1125,761; 1HNMR (400MHz, D 2O): δ 8.68 (s, 1H), 8.19 (d, J=8Hz, 1H), 7.66 (t, J=7.2Hz, 1H), 7.47 (d, J=8Hz, 1H), (7.32 t, J=7.2Hz, 1H), 7.11 (s, 2H), (4.85 s, 2H), 3.92 (s, 6H), 3.90 (s, 3H), 3.39-3.42 (m, 5H), 3.22-3.31 (m, 6H), (2.23-2.31 m, 2H), 1.28 (t, J=7.2Hz, 6H); 13C NMR (100MHz, D 2O): δ 152.9,145.6, and 139.5,139.1,134.5,133.4,132.3,130.9,125.4,122.9,122.1,119.1,118.3,111.0,108.5,61.3,56.7,48.5,47.7,47.6,45.0,32.6,20.9,8.3.HRMS (EI) calcd for C 29H 38N 4O 3: 490.2944.Found:490.2935.
The preparation method of compound 56 hydrochlorides is with embodiment 1.
Embodiment 57 1-(3,4,5-trimethoxy) phenyl-3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-methyl-β-carboline (compound 57)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-methyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 57, yield 36%; IR (KBr, cm -1) v:2943,2735,1628,1584,1503,1463,1412,1334,1244,1123,762; 1H NMR (500MHz, D 2O): δ 8.74 (s, 1H), 8.29 (d, J=8Hz, 1H), 7.76 (t, J=7.5Hz, 1H), 7.57 (d, J=8.5Hz, 1H), 7.41 (t, J=7.5Hz, 1H), 7.18 (s, 2H), 4.89 (s, 2H), (3.99 s, 6H), 3.98 (s, 3H), 3.50 (s, 3H), (3.43 t, J=7Hz, 2H), 3.24-3.30 (m, 6H), (1.92-1.97 m, 4H), 1.34 (t, J=7Hz, 6H); 13C NMR (75MHz, D 2O): δ 152.9,145.5, and 139.7,139.0,134.5,133.2,132.2,131.3,125.4,122.9,122.1,119.1,118.4,111.0,108.7,61.5,57.0,51.3,47.8 (3C), 33.0,23.3,21.2,8.7.ESI-MS m/z:505.5 (M+1) +.
The preparation method of compound 57 hydrochlorides is with embodiment 1.
Embodiment 58 1-(3,4,5-trimethoxy) phenyl-3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-normal-butyl-β-carboline (compound 58)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 58, yield 38%; IR (KBr, cm -1) v:2958,2619,1628,1582,1506,1468,1402,1383,1364,1286,1124,761; 1H NMR (500MHz, D 2O): δ 8.79 (s, 1H), 8.47 (d, J=8Hz, 1H), 7.89 (t, J=7.5Hz, 1H), (7.76 d, J=5Hz, 1H), 7.56 (t, J=7.5Hz, 1H), 7.18 (s, 2H), (4.90 s, 2H), 4.02-4.05 (m, 2H), (3.98 br s, 9H), 3.78-3.81 (m, 2H), (3.67-3.71 m, 2H), 3.36-3.40 (m, 4H), (1.43-1.48 m, 2H), 1.38 (t, J=7.5Hz, 6H), 0.98-1.01 (m, 2H), (0.67 t, J=7.5Hz, 3H); 13C NMR (100MHz, D 2O): δ 152.9,144.9, and 139.4,139.0,134.8,132.8,132.4,130.8,125.9,123.2,122.2,119.5,118.5,111.2,108.0,61.2,56.7,48.3,48.2,46.9,44.8,41.9,30.9,19.3,12.7,8.3.ESI-MS m/z:519.5 (M+1) +.
The preparation method of compound 58 hydrochlorides is with embodiment 1.
Embodiment 59 1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-normal-butyl-β-carboline (compound 59)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 59, yield 61%; IR (KBr, cm -1) v:2964,2722,1624,1583,1504,1462,1412,1383,1367,1275,1180,1126,758; 1H NMR (500MHz, D 2O): δ 8.78 (s, 1H), 8.48 (d, J=8.5Hz, 1H), (7.90 t, J=7.5Hz, 1H), 7.76 (d, J=8.5Hz, 1H), 7.57 (t, J=7.5Hz, 1H), 7.19 (s, 2H), 4.86 (s, 2H), 4.04 (t, J=8.5Hz, 2H), (3.99 s, 6H), 3.98 (s, 3H), (3.44 t, J=7.5Hz, 2H), 3.34-3.37 (m, 2H), 2.99 (s, 6H), 2.31-2.37 (m, 2H), 1.43-1.49 (m, 2H), 0.99-1.03 (m, 2H), 0.68 (t, J=7.5Hz, 3H); 13C NMR (100MHz, D 2O): δ 152.9,144.9, and 139.4,139.0,134.8,132.8,132.4,131.2,126.0,123.2,122.3,119.5,118.4,111.2,108.0,61.2,56.7,54.3,47.9,44.9,43.0,30.9,28.3,21.4,19.3,12.7.ESI-MS m/z:505.4 (M+1) +.
The preparation method of compound 59 hydrochlorides is with embodiment 1.
Embodiment 60 1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-normal-butyl-β-carboline (compound 60)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 60, yield 57%; IR (KBr, cm -1) v:2958,2619,1628,1582,1506,1468,1402,1383,1364,1286,1258,1124,761; 1H NMR (500MHz, D 2O): δ 8.76 (s, 1H), 8.49 (d, J=8Hz, 1H), (7.91 t, J=7.5Hz, 1H), 7.79 (d, J=8.5Hz, 1H), 7.58 (t, J=7Hz, 1H), (7.19 s, 2H), 4.85 (s, 2H), (4.06 t, J=8Hz, 2H), 3.99 (s, 3H), 3.98 (s, 6H), 3.43 (t, J=7.5Hz, 2H), 3.28-3.35 (m, 6H), (2.27-2.34 m, 2H), 1.45-1.51 (m, 2H), (1.35 t, J=7.5Hz, 6H), 0.99-1.06 (m, 2H), 0.69 (t, J=7.5Hz, 3H); 13C NMR (100MHz, D 2O): δ 152.9,144.9, and 139.3,139.1,134.7,132.8,132.3,131.2,126.2,123.2,122.3,119.6,118.3,111.3,108.0,61.2,56.6,48.5,47.9,47.7,44.9,44.7,30.8,20.9,19.3,12.6,8.3.HRMS (EI) calcd for C 32H 44N 4O 3: 532.3413.Found:532.3409.
The preparation method of compound 60 hydrochlorides is with embodiment 1.
Embodiment 61 1-(3,4,5-trimethoxy) phenyl-3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-normal-butyl-β-carboline (compound 61)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-normal-butyl-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 61, yield 40%; IR (KBr, cm -1) v:2951,2730,1627,1586,1502,1461,1413,1374,1243,1126,755; 1H NMR (500MHz, D 2O): δ 8.82 (s, 1H), 8.27 (d, J=8Hz, 1H), (7.62 t, J=7.5Hz, 1H), 7.46 (d, J=8.5Hz, 1H), 7.31 (t, J=7.5Hz, 1H), (7.10 s, 2H), 4.92 (s, 2H), (3.91 s, 6H), 3.86 (s, 3H), (3.76 t, J=8Hz, 2H), 3.46 (t, J=7.5Hz, 2H), 3.24-3.28 (m, 6H), (1.93-1.99 m, 4H), 1.31 (t, J=7.5Hz, 6H), 1.18-1.22 (m, 2H), 0.82-0.86 (m, 2H), 0.53 (t, J=7.5Hz, 3H); 13C NMR (75MHz, D 2O): δ 153.0,144.8, and 139.6,138.8,134.9,132.7,132.4,131.6,125.7,123.4,122.3,119.6,118.7,111.2,108.1,61.3,57.0,51.3,47.9,47.8 (2C), 45.0,31.2,23.4,21.3,19.7,13.1,8.8.ESI-MS m/z:547.5 (M+1) +.
The preparation method of compound 61 hydrochlorides is with embodiment 1.
Embodiment 62 1-(3,4,5-trimethoxy) phenyl-3-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 62)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-(3-phenyl propyl)-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 62, yield 42%; IR (KBr, cm -1) v:2938,2617,1623,1581,1500,1460,1380,1363,1286,1242,1125,1058,785,756; 1H NMR (500MHz, D 2O): δ 8.83 (s, 1H), 8.31 (d, J=7Hz, 1H), (7.50 t, J=8Hz, 1H), 7.35 (t, J=8Hz, 1H), 7.07 (d, J=8.5Hz, 1H), 7.01 (s, 2H), 6.96 (t, J=7.5Hz, 2H), 6.91 (t, J=7.5Hz, 1H), 6.63-6.64 (d, J=7.5Hz, 2H), (5.05 s, 2H), 3.94 (t, J=6.5Hz, 2H), 3.89 (s, 6H), 3.88 (s, 3H), 3.80 (t, J=7Hz, 2H), (3.61-3.63 m, 2H), 3.43-3.47 (m, 4H), (1.84 t, J=7Hz, 2H), 1.44 (t, J=7Hz, 6H), 1.30-1.33 (m, 2H); 13C NMR (125MHz, D 2O): δ 152.5,143.7, and 139.9,139.2,139.0,134.0,132.2,131.9,131.3,127.9,127.3,126.2,125.6,123.0,121.7,119.4,117.8,109.9,107.5,60.7,56.3,48.2,48.0,46.7,44.0,41.7,31.9,29.9,8.0.ESI-MS m/z:581.5 (M+1) +.
The preparation method of compound 62 hydrochlorides is with embodiment 1.
Embodiment 63 1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 63)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-(3-phenyl propyl)-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 63, yield 36%; IR (KBr, cm -1) v:2937,2729,1625,1585,1501,1461,1412,1382,1241,1125,755; 1H NMR (500MHz, D 2O): δ 8.62 (s, 1H), 8.31 (d, J=8Hz, 1H), 7.66-7.69 (m, 1H), 7.66-7.69 (m, 2H), 7.02-7.07 (m, 3H), 6.92 (s, 2H), 6.72 (t, J=6.5Hz, 2H), (4.75 s, 2H), 3.85 (s, 3H), (3.81 s, 6H), 3.32-3.35 (m, 2H), 3.23-3.27 (m, 2H), (2.88 s, 6H), 2.20-2.27 (m, 2H), 2.01 (t, J=7.5Hz, 2H), 1.40-1.46 (m, 2H); 13C NMR (125MHz, D 2O): δ 152.3,143.7, and 139.9,139.4,139.3,138.7,133.7,132.2,131.2,127.8,127.2,127.0,125.5,122.6,121.5,119.3,117.2,110.1,107.3,60.7,56.1,56.1,53.8,48.1,44.2,43.9,42.5,31.7,29.7,20.8.ESI-MS m/z:567.5 (M+1) +.
The preparation method of compound 63 hydrochlorides is with embodiment 1.
Embodiment 64 1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 64)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-(3-phenyl propyl)-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 64, yield 58%; IR (KBr, cm -1) v:2942,2681,1623,1584,1501,1460,1413,1366,1332,1294,1181,1156,1125,999,757,724; 1H NMR (500MHz, D 2O): δ 8.66 (s, 1H), 8.11 (d, J=7.5Hz, 1H), (7.27 t, J=5.5Hz, 1H), 7.13 (t, J=7Hz, 1H), 6.82 (br s, 3H), 6.75 (t, J=7Hz, 2H), 6.69 (t, J=7Hz, 1H), 6.44 (d, J=7Hz, 2H), 4.82 (s, 2H), (3.70 s, 6H), 3.67 (s, 3H), (3.37-3.40 m, 4H), 3.24 (t, J=8Hz, 2H), 3.16-3.21 (m, 4H), 2.21-2.27 (m, 2H), 1.62 (br s, 2H), 1.22 (m, J=7Hz, 6H), 1.05-1.09 (m, 2H); 13C NMR (100MHz, D 2O): δ 152.8,143.9, and 140.2,139.4,134.3,132.3,132.2,131.6,128.1,127.6,126.1,125.8,123.4,122.0,119.6,118.4,110.1,107.7,60.9,58.6,48.5,48.0,47.6,45.1,44.2,32.2,30.4,20.9,8.3.HRMS (EI) calcd for C 37H 46N 4O 3: 594.3564.Found:594.3554.
The preparation method of compound 64 hydrochlorides is with embodiment 1.
Embodiment 65 1-(3,4,5-trimethoxy) phenyl-3-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 65)
It is synthetic that starting raw material ethyl 1-(3,4,5-trimethoxy) phenyl-9-(3-phenyl propyl)-β-carboline-3-carboxylicesters is pressed literature method.The preparation method is with embodiment 1, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 65, yield 45%; IR (KBr, cm -1) v:2944,2729,1626,1586,1500,1460,1413,1373,1240,1125,1002,754; 1H NMR (500MHz, D 2O): δ 8.70 (s, 1H), 8.29 (d, J=8Hz, 1H), 7.54 (t, J=7.5Hz, 1H), (7.35 t, J=7.5Hz, 1H), 7.16 (d, J=8.5Hz, 1H), 6.92-6.96 (m, 5H), (6.60 d, J=7Hz, 2H), 4.83 (s, 2H), 3.86 (s, 3H), 3.84 (s, 6H), 3.65 (t, J=7.5Hz, 2H), (3.40 t, J=7.5Hz, 2H), (3.21-3.28 m, 6H), 1.83-1.95 (m, 6H), 1.28-1.34 (m, 8H); 13C NMR (100MHz, D 2O+1,4-Dioxane): δ 152.7,144.0, and 140.3,139.4,139.1,134.2,132.7,132.5,131.6,128.2,127.6,126.9,125.9,123.2,121.9,119.7,117.9,110.4,107.6,61.0,56.5,50.9,48.2,47.4,47.3,44.3,32.2,30.3,22.9,20.8,8.2.ESI-MS m/z:609.6 (M+1) +.
The preparation method of compound 65 hydrochlorides is with embodiment 1.
Embodiment 66 1-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-normal-butyl-β-carboline (compound 66)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.
Step (a): the preparation of 9-normal-butyl-1-methyl-β-carboline:
1-methyl-β-carboline (10mmol), DMF (100ml) mix, and stirring at room adds NaH (20mmol) and iodo-n-butane (30mmol) subsequently successively to clarification, stirring at room, and TLC follows the tracks of detection.React complete, reaction solution is poured into water, ethyl acetate extraction merges organic phase, washing, saturated salt washing.Ethyl acetate is used the concentrated hydrochloric acid acidifying mutually, be evaporated to dried, dehydrated alcohol band water number time, the residue acetone recrystallization filters, and gets yellow solid; Yellow solid is water-soluble, sodium bicarbonate alkalization, ethyl acetate extraction, anhydrous sodium sulfate drying; Filter, filtrate decompression is concentrated, the residue silica gel column chromatography, and acetone/sherwood oil (2: 1) wash-out, elutriant is evaporated to dried, gets white solid.
Step (b): the preparation of 9-normal-butyl-β-carboline-1-formaldehyde:
With the 9-normal-butyl of step (a) preparation-1-methyl-β-carboline (10mmol), 1,4-dioxane (250ml) mixes, and heated and stirred is to clarification, and subsequently gradation adds the tin anhydride (20mmol) of distillation, reflux, TLC follows the tracks of detection.React complete, remove by filter immediately tin anhydride, filtrate decompression is concentrated into dried, residue silica gel column chromatography (chloroform/methanol=30: 1), and elutriant is evaporated to dried, gets white solid.
Step (c): the preparation of target compound 66:
1-carboxaldehyde radicals substitutive derivative (2mmol), N with step (b) preparation, N-diethyl ethylenediamine (2.4mmol), anhydrous methanol (12mL) and anhydrous methylene chloride (6mL) mix, the reaction of mixed solution stirring at room, TLC follows the tracks of detection.React complete, remove solvent under reduced pressure, get thick product Xi Fushi alkali.This thick product Xi Fushi alkali does not need purifying can be directly used in next step reduction reaction.
The thick product of Xi Fushi alkali of above-mentioned preparation is dissolved in anhydrous methanol (20mL) and cooling mixed liquid to 0 ℃, adds subsequently NaBH 3CN (10mmol).The reaction of reaction mixture stirring at room, TLC follows the tracks of detection.React complete, remove solvent under reduced pressure.Subsequently, residue is dissolved in methylene dichloride (100mL), then aqueous sodium carbonate (pH10,50mL) washing tells organic phase, and anhydrous sodium sulfate drying filters, and concentrating under reduced pressure steams and desolventizes, residue silica gel column chromatography (moving phase: CH 2Cl 2/ CH 3OH/NH 4OH, 95: 5: 1), be evaporated to driedly, get yellow oil, be target compound 66, yield 40%; IR (KBr, cm -1) v:2947,2792,2581,1623,1494,1443,1389,1292,1198,1134,1026,758; 1HNMR (300MHz, DMSO-d 6+ D 2O): δ 8.41 (d, J=5.1Hz, 1H), 8.30-8.33 (m, 2H), (7.77 d, J=8.1Hz, 1H), 7.64-7.69 (m, 1H), (7.33 t, J=7.5Hz, 1H), 4.99 (s, 2H), (4.56 t, J=7.2Hz, 2H), 3.64-3.66 (m, 4H), (3.18-3.25 m, 4H), 1.70-1.80 (m, 2H), 1.25-1.37 (m, 8H), 0.89 (t, J=7.2Hz, 3H); 13C NMR (75MHz, D 2O): δ 144.3,135.1, and 132.6,132.4,130.8,129.7,122.5,121.9,118.6,116.9,110.9,49.2,48.3,46.7,45.4,43.5,32.2,19.8,13.5,8.6; ESI-MS m/z:353.4 (M+1) +.
The preparation method of compound 66 hydrochlorides is with embodiment 1.
Embodiment 67 1-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-normal-butyl-β-carboline (compound 67)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 67, yield 48%; IR (KBr, cm -1) v:3013,2956,2869,2611,1625,1524,1462,1382,1338,1243,1170,1058,774,752; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.49 (d, J=5.4Hz, 1H), 8.42 (d, J=5.4Hz, 1H), 8.36 (d, J=8.1Hz, 1H), 7.81 (d, J=8.4Hz, 1H), (7.70 t, J=7.5Hz, 1H), 7.36 (t, J=7.2Hz, 1H), 4.95 (s, 2H), (4.60 t, J=6.6Hz, 2H), 3.32 (t, J=7.2Hz, 2H), 3.22 (t, J=7.2Hz, 2H), 2.76 (s, 6H), 2.18-2.27 (m, 2H), 1.69-1.79 (m, 2H), 1.31-1.40 (m, 2H), 0.89 (t, J=7.2Hz, 3H); 13C NMR (75MHz, D 2O): δ 144.7,136.3, and 133.4,132.7,131.1,126.1,122.7,122.0,118.7,117.7,110.9,54.5,45.9 (2C), 45.4,4313,31.8,21.8,19.8,13.5; ESI-MS m/z:339.4 (M+1) +.
The preparation method of compound 67 hydrochlorides is with embodiment 1.
Embodiment 68 1-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-normal-butyl-β-carboline (compound 68)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 68, yield 46%; IR (KBr, cm -1) v:2958,2685,1624,1496,1461,1383,1337,1201,1135,1044,758; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.48 (d, J=5.1Hz, 1H), 8.41 (d, J=5.4Hz, 1H), 8.35 (d, J=8.1Hz, 1H), 7.80 (d, J=8.4Hz, 1H), 7.70 (t, J=7.5Hz, 1H), (7.35 t, J=7.2Hz, 1H), 4.94 (s, 2H), 4.59 (t, J=6.9Hz, 2H), (3.31 t, J=6.9Hz, 2H), 3.20 (t, J=7.5Hz, 2H), 3.08-3.15 (m, 4H), (2.16-2.26 m, 2H), 1.69-1.79 (m, 2H), (1.30-1.37 m, 2H), 1.23 (t, J=7.2Hz, 6H), 0.88 (t, J=7.2Hz, 3H); 13C NMR (75MHz, DMSO-d 6+ D 2O): δ 144.2,133.9, and 133.9,133.2,131.9,131.5,123.6,122.0,120.0,117.6,111.8,48.6,47.1,46.4,45.6 (2C), 32.6,21.0,20.3,14.6,9.3; ESI-MS m/z:367.4 (M+1) +.
The preparation method of compound 68 hydrochlorides is with embodiment 1.
Embodiment 69 1-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-normal-butyl-β-carboline (compound 69)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 69, yield 50%; IR (KBr, cm -1) v:2958,2693,1625,1545,1496,1462,1337,1296,1201,1136,1040,759; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.63 (d, J=5.4Hz, 1H), 8.57 (d, J=5.4Hz, 1H), 8.38 (d, J=8.1Hz, 1H), 7.91 (t, J=7.5Hz, 1H), (7.83 d, J=8.4Hz, 1H), 7.53 (t, J=7.2Hz, 1H), 5.09 (s, 2H), (4.62 t, J=7.5Hz, 2H), 3.47 (t, J=7.5Hz, 2H), 3.23-3.31 (m, 6H), (1.91-1.97 m, 4H), 1.81-1.87 (m, 2H), (1.38-1.42 m, 2H), 1.34 (t, J=7.5Hz, 6H), 0.94 (t, J=7.5Hz, 3H); 13C NMR (75MHz, D 2O): δ 144.9,136.4, and 133.6,132.8,131.3,126.4,122.9,122.2,118.9,117.8,111.1,51.2,48.4,47.7,45.9,45.5,31.8,23.3,21.1,19.9,13.5,8.7; ESI-MS m/z:381.4 (M+1) +
The preparation method of compound 69 hydrochlorides is with embodiment 1.
Embodiment 70 1-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-isobutyl--β-carboline (compound 70)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 2-methyl isophthalic acid-N-PROPYLE BROMIDE as raw material, and step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 70, yield 55%; CH 2Cl 2/ CH 3OH, 95: 5; 2963,2672,1623,1497,1464,1384,1335,1135,1042,777; 1H NMR (300MHz, DMSO-d 6+ D 20): δ 8.44 (d, J=5.4Hz, 1H), 8.32-8.36 (m, 2H), (7.82 d, J=8.7Hz, 1H), 7.63-7.69 (m, 1H), (7.33 t, J=7.8Hz, 1H), 4.96 (s, 2H), (4.40 d, J=7.5Hz, 2H), 3.66-3.68 (m, 4H), (3.18-3.25 m, 4H), 2.11-2.20 (m, 1H), 1.28 (t, J=7.2Hz, 6H), 0.85 (d, J=6.6Hz, 6H); 13C NMR (75MHz, D 2O): δ 145.0,135.8, and 133.1,132.4,130.0,129.4,122.6,122.0,118.6,117.3,111.6,52.0,48.5,48.3,46.6,43.3,30.1,19.4,8.6; ESI-MS m/z:353.4 (M+1) +.
The preparation method of compound 70 hydrochlorides is with embodiment 1.
Embodiment 71 1-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-isobutyl--β-carboline (compound 71)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 2-methyl isophthalic acid-N-PROPYLE BROMIDE as raw material, and step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 71, yield 36%; IR (KBr, cm -1) v:3049,2957,2673,2485,1623,1459,1338,1289,1207,1139,1045,749; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.49 (d, J=5.4Hz, 1H), 8.41 (d, J=5.4Hz, 1H), 8.36 (d, J=7.8Hz, 1H), 7.85 (d, J=8.7Hz, 1H), (7.69 t, J=7.5Hz, 1H), 7.35 (t, J=7.2Hz, 1H), 4.91 (s, 2H), (4.43 d, J=7.2Hz, 2H), 3.32 (t, J=7.2Hz, 2H), 3.23 (t, J=7.5Hz, 2H), 2.77 (s, 6H), 2.20-2.28 (m, 2H), 2.11-2.18 (m, 1H), (0.86 d, J=6.6Hz, 6H); 13C NMR (75MHz, D 20): δ 145.3,136.3, and 133.8,132.5,131.6,126.7,122.9,122.1,118.9,117.8,111.8,54.5,52.1,46.3,45.9,43.3,30.0,21.8,19.6; ESI-MS m/z:339.4 (M+1) +.
The preparation method of compound 71 hydrochlorides is with embodiment 1.
Embodiment 72 1-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-isobutyl--β-carboline (compound 72)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 2-methyl isophthalic acid-N-PROPYLE BROMIDE as raw material, and step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 72, yield 39%; IR (KBr, cm -1) v:2926,2685,1624,1495,1463,1385,1335,1289,1137,1044,758; 1H NMR (300MHz, DMSO-d 6+ D 20): δ 8.48 (d, J=5.4Hz, 1H), 8.41 (d, J=5.4Hz, 1H), 8.35 (d, J=7.5Hz, 1H), 7.84 (d, J=8.4Hz, 1H), (7.65-7.71 m, 1H), 7.34 (t, J=7.2Hz, 1H), 4.90 (s, 2H), 4.42 (d, J=7.5Hz, 2H), 3.31 (t, J=7.2Hz, 2H), 3.20 (t, J=7.5Hz, 2H), (3.07-3.15 m, 4H), 2.19-2.27 (m, 2H), (2.10-2.17 m, 1H), 1.24 (t, J=7.2Hz, 6H), 0.85 (d, J=6.3Hz, 6H); 13C NMR (75MHz, DMSO-d 6+ D 2O): δ 144.5,134.1, and 133.9,133.5,132.1,131.4,123.4,121.8,120.0,117.3,112.4,52.1,48.6,47.1,46.7,45.6,30.7,21.0,20.5,9.3; ESI-MS m/z:367.4 (M+1) +.
The preparation method of compound 72 hydrochlorides is with embodiment 1.
Embodiment 73 1-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-isobutyl--β-carboline (compound 73)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 2-methyl isophthalic acid-N-PROPYLE BROMIDE as raw material, and step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 73, yield 40%; IR (KBr, cm -1) v:2928,2677,1623,1550,1461,1335,1211,1138,1041,767; 1HNMR (300MHz, DMSO-d 6+ D 20): δ 8.47 (d, J=5.4Hz, 1H), 8.39 (d, J=5.4Hz, 1H), 8.34 (d, J=7.8Hz, 1H), 7.83 (d, J=8.1Hz, 1H), (7.67 t, J=8.1Hz, 1H), 7.34 (t, J=7.2Hz, 1H), 4.87 (s, 2H), (4.41 d, J=7.5Hz, 2H), 3.22 (t, J=6Hz, 2H), 3.05-3.12 (m, 6H), (2.07-2.20 m, 1H), 1.81 (brs, 4H), (1.21 t, J=7.2Hz, 6H), (0.85-0.87 d, J=6.3Hz, 6H); 13C NMR (75MHz, D 2O): δ 145.3,136.1, and 134.0,132.4,132.1,127.4,122.9,122.2,119.2,117.7,111.9,52.2,51.2,48.3,47.8,46.5,30.1,23.4,21.2,19.5,8.7; ESI-MS m/z:381.4 (M+1) +
The preparation method of compound 73 hydrochlorides is with embodiment 1.
Embodiment 74 1-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-benzyl-β-carboline (compound 74)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take cylite as raw material, and step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 74, yield 45%; IR (KBr, cm -1) v:2977,2660,1624,1495,1460,1389,1336,1297,1134,1025,753; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.45 (d, J=5.1Hz, 1H), 8.37 (d, J=5.7Hz, 2H), 7.71 (d, J=8.4Hz, 1H), 7.63 (t, J=7.2Hz, 1H), 7.35 (t, J=7.2Hz, 1H), (7.22-7.29 m, 3H), 6.96-6.99 (m, 2H), 5.93 (s, 2H), 4.79 (s, 2H), 3.45-3.49 (m, 4H), (3.12-3.19 m, 4H), 1.23 (t, J=7.2Hz, 6H); 13CNMR (75MHz, DMSO-d 6+ D 2O): δ 143.6,138.1, and 135.6,134.2,133.3,132.4,131.1,129.7,128.3,126.3,123.2,121.9,120.6,117.0,111.7,48.7,47.8,47.5,46.9,42.1,9.4; ESI-MS m/z:387.4 (M+1) +.
The preparation method of compound 74 hydrochlorides is with embodiment 1.
Embodiment 75 1-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-benzyl-β-carboline (compound 75)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take cylite as raw material, and step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 75, yield 65%; IR (KBr, cm -1) v:2976,2661,1624,1494,1458,1336,1297,1199,1134,1027,749; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.45 (d, J=5.4Hz, 1H), 8.36-8.39 (m, 2H), (7.74 d, J=8.4Hz, 1H), 7.61-7.67 (m, 1H), (7.36 t, J=7.5Hz, 1H), 7.20-7.31 (m, 3H), (6.94-6.97 m, 2H), 5.92 (s, 2H), (4.69 s, 2H), 3.05-3.15 (m, 4H), (2.79 s, 6H), 2.02-2.12 (m, 2H); 13C NMR (75MHz, D 2O): δ 144.8,136.3, and 135.5,134.0,132.7,132.5,129.6,128.5,127.1,125.6,123.1,122.5,119.1,117.9,110.4,54.3,48.4,45.6 (2C), 43.3,21.5; ESI-MS m/z:373.4 (M+1) +.
The preparation method of compound 75 hydrochlorides is with embodiment 1.
Embodiment 76 1-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-benzyl-β-carboline (compound 76)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take cylite as raw material, and step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 76, yield 42%; IR (KBr, cm -1) v:2977,2661,1624,1495,1459,1336,1297,1199,1134,1026,751; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.44 (d, J=5.1Hz, 1H), 8.35 (m, 2H), 7.72 (d, J=8.4Hz, 1H), 7.63 (t, J=7.5Hz, 1H), 7.35 (t, J=7.5Hz, 1H), 7.22-7.30 (m, 3H), 6.93-6.95 (m, 2H), 5.91 (s, 2H), 4.68 (s, 2H), (3.04-3.13 m, 8H), 2.00-2.10 (m, 2H), 1.20 (t, J=7.5Hz, 6H), 1.15 (t, 3H, J=7.2Hz); 13C NMR (75MHz, D 2O): δ 144.0,136.2, and 134.6,134.1,133.9,131.8,129.6,129.1,128.4,125.65,122.7,122.0,119.5,117.1,110.3,48.6,48.2,47.9,46.6,45.4,21.0,8.7; ESI-MS m/z:401.4 (M+1) +.
The preparation method of compound 76 hydrochlorides is with embodiment 1.
Embodiment 77 1-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-benzyl-β-carboline (compound 77)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take cylite as raw material, and step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 77, yield 61%; IR (KBr, cm -1) v:2941,2677,1624,1459,1338,1199,1038,746; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.55 (m, 2H), 8.45 (d, J=7.8Hz, 1H), (7.79 d, J=8.4Hz, 1H), 7.70 (t, J=7.5Hz, 1H), 7.40 (t, J=7.5Hz, 1H), 7.23-7.29 (m, 3H), 7.00 (d, J=6.3Hz, 2H), 6.01 (s, 2H), 4.73 (s, 2H), 3.00-3.10 (m, 8H), (1.72 br s, 4H), 1.21 (t, J=7.2Hz, 6H); 13C NMR (75MHz, DMSO-d 6+ D 2O): δ 143.9,138.0, and 135.3,134.3,132.9,132.8,131.5,129.7,128.3,126.2,123.4,122.0,120.4,117.1,111.6,50.6,48.7,47.3,46.9,46.7,23.4,21.1,9.3; ESI-MS m/z:415.4 (M+1) +.
The preparation method of compound 77 hydrochlorides is with embodiment 1.
Embodiment 78 1-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(4-fluorine) benzyl-β-carboline (compound 78)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 4-fluorine cylite as raw material, and step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 78, yield 60%; IR (KBr, cm -1) v:2976,2662,1624,1494,1457,1337,1297,1246,1199,1134,1029,749; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.45 (d, J=5.1Hz, 1H), 8.37 (t, J=8.1Hz, 2H), 7.71 (d, J=8.4Hz, 1H), 7.63 (t, J=7.5Hz, 1H), 7.36 (t, J=7.5Hz, 1H), (7.11 t, J=8.7Hz, 2H), 6.99-7.04 (m, 2H), (5.91 s, 2H), 4.79 (s, 2H), 3.49 (m, 4H) 3.13-3.20 (m, 4H), 1.24 (t, J=7.2Hz, 1H); 13C NMR (75MHz, D 2O): δ 163.5,160.2, and 144.1,134.8,133.3,133.1,132.1,131.0,127.5,127.4,122.8,122.2,119.2,116.9,116.1,115.8,110.4,49.4,48.2,47.9,46.8,43.1,8.6; ESI-MS m/z:405.4 (M+1) +.
The preparation method of compound 78 hydrochlorides is with embodiment 1.
Embodiment 79 1-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(4-fluorine) benzyl-β-carboline (compound 79)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 4-fluorine cylite as raw material, and step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 79, yield 35%; IR (KBr, cm -1) v:2950,2692,1625,1547,1505,1466,1384,1332,1290,1222,1158,1130,1047,1019,751; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.48 (d, J=5.1Hz, 1H), 8.38-8.42 (m, 2H), (7.75 d, J=8.4Hz, 1H), 7.63-7.69 (m, 1H), (7.37 t, J=7.2Hz, 1H), 7.08-7.14 (m, 2H), (6.99-7.04 m, 2H), 5.93 (s, 2H), (4.70 s, 2H), 3.11-3.18 (m, 4H), (2.74 s, 6H), 2.06-2.16 (m, 2H); 13C NMR (75MHz, DMSO-d 6+ D 2O): δ 163.7,160.4, and 144.1,134.5,134.3,134.0,133.7,132.0,131.9,128.6,128.5,123.6,122.3,120.4,117.6,116.7,116.4,111.7,54.2,48.2,46.3,45.4,42.8,21.5; ESI-MS m/z:391.4 (M+1) +.
The preparation method of compound 79 hydrochlorides is with embodiment 1.
Embodiment 80 1-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(4-fluorine) benzyl-β-carboline (compound 80)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 4-fluorine cylite as raw material, and step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 80, yield 40%; IR (KBr, cm -1) v:2944,2683,1625,1506,1465,1385,1336,1290,1224,1159,1134,1045,754; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.44 (d, J=5.1Hz, 1H), 8.31-8.37 (m, 2H), (7.71 d, J=8.4Hz, 1H), 7.63 (t, J=7.5Hz, 1H), 7.35 (t, J=7.5Hz, 1H), 7.09-7.13 (m, 2H), 6.96-7.00 (m, 2H), 5.89 (s, 2H), (4.68 s, 2H), 3.05-3.14 (m, 8H), 2.03-2.09 (m, 2H), 1.21 (t, J=7.2Hz, 6H); 13C NMR (75MHz, D 2O): δ 163.5,160.3, and 144.3,135.6,134.0,133.3,132.3,131.7,128.0,127.6,127.5,122.9,122.3,119.4,117.6,116.3,116.0,110.4,48.7,47.9,47.6,46.1,45.7,21.1,8.7; ESI-MS m/z:419.4 (M+1) +.
The preparation method of compound 80 hydrochlorides is with embodiment 1.
Embodiment 81 1-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-(4-fluorine) benzyl-β-carboline (compound 81)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 4-fluorine cylite as raw material, and step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 81, yield 38%; IR (KBr, cm -1) v:2946,2683,1625,1504,1462,1337,1221,752; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.51 (s, 2H), 8.33 (d, J=7.8Hz, 1H), 7.63-7.74 (m, 2H), 7.36 (t, J=7.5Hz, 1H), 7.00-7.10 (m, 4H), (5.92 s, 2H), 4.71 (s, 2H), (3.00-3.10 m, 8H), 1.72 (br s, 4H), (1.81 t, J=6.9Hz, 6H); 13CNMR (75MHz, DMSO-d 6+ D 2O): δ 163.6,160.4, and 143.6,135.6,134.1,132.8,131.4,128.4,128.3,123.3,122.1,120.5,117.0,116.7,116.4,111.4,50.8,48.0,47.4,47.0 (2C), 23.4,21.1,9.3; ESI-MS m/z:433.4 (M+1) +.
The preparation method of compound 81 hydrochlorides is with embodiment 1.
Embodiment 82 1-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(3-chlorine) benzyl-β-carboline (compound 82)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 3-chlorine cylite as raw material, and step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 82, yield 47%; IR (KBr, cm -1) v:2971,2649,1623,1465,1434,1336,1195,772; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.43-8.49 (m, 2H), 8.28 (d, J=7.8Hz, 1H), 7.55-7.63 (m, 2H), 7.29-7.34 (m, 1H), 7.17-7.25 (m, 2H), 6.89-6.93 (m, 2H), 5.88 (s, 2H), 4.77 (s, 2H), 3.47-3.54 (m, 4H), 3.13-3.20 (m, 4H), 1.21 (d, J=7.2Hz, 6H); 13C NMR (75MHz, DMSO-d 6+ D 2O): δ 143.4,140.1,135.3,134.3,133.9,132.9 (2C), 131.6 (2C), 128.4,125.9,124.9,123.2,122.3,120.4,117.0,111.3,48.1,47.6,47.5,42.3,9.3; ESI-MS m/z:421.1 (M+1) +
The preparation method of compound 82 hydrochlorides is with embodiment 1.
Embodiment 83 1-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-(3-chlorine) benzyl-β-carboline (compound 83)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 3-chlorine cylite as raw material, and step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 83, yield 41%; IR (KBr, cm -1) v:2969,2648,1622,1463,1336,1196,1038,771; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.46 (d, J=5.4Hz, 1H), 8.37-8.39 (m, 2H), (7.69 d, J=8.4Hz, 1H), 7.64 (t, J=8.1Hz, 1H), 7.36 (t, J=6.9Hz, 1H), 7.28-7.29 (m, 2H), 6.98 (s, 1H), 6.83-6.87 (m, 1H), (5.92 s, 2H), 4.68 (s, 2H), 3.07-3.14 (m, 4H), 2.73 (s, 6H), 2.01-2.11 (m, 2H); 13C NMR (75MHz, DMSO-d 6+ D 2O): δ 144.2,140.1, and 134.4,134.3,134.2,133.9,132.2,131.6,131.1,128.4,126.3,125.0,123.8,122.5,120.1,118.0,111.7,54.1,48.4,45.9,45.4,42.8,21.5; ESI-MS m/z:407.4 (M+1) +.
The preparation method of compound 83 hydrochlorides is with embodiment 1.
Embodiment 84 1-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-(3-chlorine) benzyl-β-carboline (compound 84)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 3-chlorine cylite as raw material, and step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 84, yield 55%; IR (KBr, cm -1) v:2971,2927,2881,2752,2534,2447,1623,1562,1468,1432,1341,1288,1195,1137,1092,1040,772; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.66 (d, J=5.7Hz, 1H), 8.59 (d, J=5.7Hz, 1H), 8.48 (d, J=7.8Hz, 1H), 7.79 (d, J=8.4Hz, 1H), (7.71 t, J=7.8Hz, 1H), 7.41 (t, J=7.5Hz, 1H), 7.28-7.29 (m, 2H), (7.14 s, 1H), 6.93 (t, J=3.9Hz, 1H), 6.06 (s, 2H), 4.77 (s, 2H), 3.16-3.27 (m, 4H), 3.05-3.13 (m, 4H), 2.13-2.23 (m, 2H), (1.22 t, J=7.2Hz, 6H); 13C NMR (75MHz, DMSO-d 6+ D 2O): δ 144.0,140.4, and 134.8,134.4,134.3,133.5,132.3,131.8,131.6,128.3,126.3,125.0,123.6,122.3,120.4,117.5,111.7,48.5,48.3,47.1,46.4,45.5,20.9,9.3; ESI-MS m/z:435.4 (M+1) +.
The preparation method of compound 84 hydrochlorides is with embodiment 1.
Embodiment 85 1-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-(3-chlorine) benzyl-β-carboline (compound 85)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 3-chlorine cylite as raw material, and step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 85, yield 50%; IR (KBr, cm -1) v:2939,2671,1624,1464,1337,1197,1041,770; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.55 (br s, 2H), 8.42 (d, J=7.8Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.69 (t, J=6.9Hz, 1H), (7.39 t, J=7.2Hz, 1H), 7.28-7.30 (m, 2H), (7.09 s, 1H), 6.90-6.91 (m, 1H), 6.00 (s, 2H), 4.72 (s, 2H), 3.01-3.09 (m, 8H), (1.73 br s, 4H), 1.20 (t, J=6.9Hz, 6H); 13C NMR (75MHz, DMSO-d 6+ D 2O): δ 143.5,140.6, and 135.7,134.3,134.2,133.1,132.7,131.7,131.4,128.3,126.2,124.9,123.3,122.1,120.5,117.0,111.5,50.7,48.2,47.4,46.9 (2C), 23.4,21.1,9.3; ESI-MS m/z:449.4 (M+1) +.
The preparation method of compound 85 hydrochlorides is with embodiment 1.
Embodiment 86 1-[N-(2-diethylamino)-ethyl]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 86)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 1-bromo-3-phenyl-propane as raw material, and step (c) is with N, and the N-diethyl ethylenediamine is raw material.Get yellow oil, be target compound 86, yield 56%; IR (KBr, cm -1) v:2932,2615,1622,1571,1490,1451,1386,1336,1208,1135,1042,773; 1H NMR (500MHz, D 2O): δ 8.18 (d, J=7.5Hz, 1H), 8.11 (d, J=7.5Hz, 1H), 7.89 (d, J=10Hz, 1H), 7.52 (t, J=9.5Hz, 1H), (7.13-7.19 m, 5H), 6.94 (d, J=8.5Hz, 2H), 4.13 (s, 2H), 4.03 (t, J=9.5Hz, 2H), 3.37 (t, J=8.5Hz, 2H), 3.24-3.27 (m, 4H), 3.10 (t, J=8.5Hz, 2H), 2.48 (t, J=8Hz, 2H), 1.74-1.79 (m, 2H), (1.30 t, J=9Hz, 6H); 13CNMR (125MHz, D 2O): δ 143.8,140.7, and 134.5,134.1,132.1,131.9,129.0,128.7,128.5,126.4,122.6,121.9,119.1,116.3,110.7,50.1,47.8,46.6,44.3,43.2,31.7,30.6,8.1; ESI-MS m/z:415.4 (M+1) +.
Compound 86 hydrochloride preparation methods are with embodiment 1.
Embodiment 87 1-[N-(3-dimethylamino)-propyl group]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 87)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.Preparation technology is with embodiment 66, but step (a) is take 1-bromo-3-phenyl-propane as raw material, and step (c) is with N, and the N-dimethylated propyl diethylenetriamine is raw material.Get yellow oil, be target compound 87, yield 53%; IR (KBr, cm -1) v:2924,2684,1625,1458,1383,1338,1052,752; 1H NMR (500MHz, DMSO-d 6+ D 2O): δ 8.47 (d, J=5.4Hz, 1H), 8.34-8.40 (m, 2H), 7.65-7.74 (m, 2H), 7.32-7.38 (m, 1H), 7.16-7.27 (m, 5H), 4.86 (s, 2H), 4.62 (t, J=7.5Hz, 1H), (3.19-3.25 m, 4H), 2.69-2.77 (m, 8H), (2.16-2.26 m, 2H), 2.02-2.10 (m, 2H); 13C NMR (100MHz, D 2O): δ 144.5,140.5, and 136.2,133.5,132.5,131.7,128.7,128.3,126.8,126.4,123.0,122.2,119.4,117.7,111.0,54.2,46.0,45.2,44.4,42.9,31.8,29.8,21.5; ESI-MSm/z:401.4 (M+1) +.
Compound 87 hydrochloride preparation methods are with embodiment 1.
Embodiment 88 1-[N-(3-diethylamino)-propyl group]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 88)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.Preparation technology is with embodiment 66, but step (a) is take 1-bromo-3-phenyl-propane as raw material, and step (c) is with N, and the N-diethyl propyldiamine is raw material.Get yellow oil, be target compound 88, yield 55%; IR (KBr, cm -1) v:2933,2669,1624,1493,1457,1385,1337,1042,753; 1H NMR (500MHz, D 2O): δ 8.45-8.49 (m, 2H), 8.29 (d, J=8Hz, 1H), 7.84 (t, J=7Hz, 1H), (7.65 d, J=8.5Hz, 1H), 7.49 (t, J=8Hz, 1H), 7.25-7.32 (m, 3H), (7.11 d, J=6.5Hz, 2H), 4.65 (s, 2H), 4.49 (t, J=7.5Hz, 2H), (3.27-3.33 m, 6H), 3.13 (t, J=7.5Hz, 2H), 2.71 (t, J=7Hz, 2H), 2.13-2.24 (m, 4H), (1.35 t, J=7Hz, 4H); 13C NMR (125MHz, D 2O): δ 144.4,140.6, and 135.8,133.5,132.3,131.9,128.7,128.4,127.2,126.4,122.9,122.1,119.5,117.5,110.9,48.4,47.7,46.2,45.3,44.4,31.8,29.8,21.0,8.3; ESI-MS m/z:429.4 (M+1) +.
The preparation method of compound 88 hydrochlorides is with embodiment 1.
Embodiment 89 1-[N-(4-diethylamino)-butyl]-preparation of methylamino-9-(3-phenyl propyl)-β-carboline (compound 89)
It is synthetic that starting raw material 1-methyl-β-carboline is pressed literature method.The preparation method is with embodiment 66, but step (a) is take 1-bromo-3-phenyl-propane as raw material, and step (c) is with N, and N-diethyl butanediamine is raw material.Get yellow oil, be target compound 89, yield 59%; IR (KBr, cm -1) v:2938,2667,1625,1455,1337,1292,1143,1041,762; 1H NMR (300MHz, DMSO-d 6+ D 2O): δ 8.45-8.46 (d, J=1.8Hz, 2H), 8.30-8.32 (d, J=7.8Hz, 1H), 7.63-7.70 (m, 2H), 7.31-7.36 (m, 1H), (7.11-7.22 m, 5H), 4.77 (s, 2H), 4.56 (t, J=6.9Hz, 2H), 3.05-3.12 (m, 8H), 2.65 (t, J=7.2Hz, 2H), 1.97-2.06 (m, 2H), 1.77 (br s, 4H), 1.19 (t, J=7.2Hz, 6H); 13C NMR (75MHz, DMSO-d 6+ D 2O): δ 143.5,141.4, and 134.5,133.6,133.0,132.0,131.4,129.1,129.0,126.7,123.2,121.9,120.3,117.0,111.4,51.0,47.7,47.2 (2C), 45.2,32.7,31.9,23.5,21.2,9.3; ESI-MS m/z:443.5 (M+1) +.
The preparation method of compound 89 hydrochlorides is with embodiment 1.
The test of embodiment 90 In Vitro Anti cancer screenings:
Beta-carboline alkali derivative compounds of the present invention is as the pharmacological research of the purposes of preparation treatment cancer drug, and the compound of all tests all is prepared into hydrochloride form before test.The hydrochloride of all compounds has good water-soluble, with antitumor drug-cis-platinum commonly used clinically as the positive control medicine.
Select respectively 769-P (kidney), KB (oral squamous carcinoma cell), BGC-823 (stomach cancer cell), 786-0 (kidney), OS-RC-2 (kidney), HepG 2The clones such as (liver cancer cell), A375 (melanoma), HT-29 (colorectal carcinoma), 22RV1 (prostate cancer), MCF-7 (mammary cancer) adopt mtt assay to test.Concrete grammar is as follows: respectively growth conditions is good, be in the cell strain of logarithmic phase with 5 * 10 4The concentration of individual/ml is inoculated in 96 orifice plates, 160 μ l are inoculated in every hole, the incubator that subsequently 96 orifice plates are placed 37 ℃, contains 5%CO2 was cultivated 24 hours, abandon old liquid, renew bright nutrient solution, the β-carboline alkali derivant that adds sterilising treatment, continue to cultivate after 48 hours, discard nutrient solution, every hole adds the RPMI-1640 nutrient solution that 20ul contains 5mg/mlMTT, continue to cultivate 4 hours, after carefully removing supernatant, every hole adds the DMSO of 200 μ l, and about 10min dissolution precipitation vibrates, detect OD value, wavelength 490nm with microplate reader subsequently.Obtain cell survival rate under each sample concentration with following formula: the average OD value of the average OD value/control group of survival rate %=sample sets * 100%
To the mapping of drug level logarithm, obtain the IC of each sample with cell survival rate by graphing method 50Value.Test-results sees Table 1.
Table 1 β-carboline alkali derivant is to the IC of 10 kinds of human tumor cell lines 50Value (μ M)
Figure GSA00000031974600631
Embodiment 91 solubility tests
According to " Chinese pharmacopoeia (2005 editions) regulation takes by weighing each 10mg of beta-carboline alkali derivative compounds that is ground into fine powder, in the water of 25 ℃ of certain capacities, and 30 seconds of powerful jolting every 5 minutes; Observe the dissolving situation in 30 minutes, during without visual visible particles of solute, namely be considered as dissolving fully.Test compounds comprises 9-(3-phenyl propyl)-2-benzyl-β-carboline bromine salt (a), ethyl 9-benzyl-β-carboline-3-carboxylate hydrochloride (b), ethyl 9-butyl-β-carboline-3-carboxylate hydrochloride (c), ethyl 9-phenyl propyl-β-carboline-1-carboxylate hydrochloride (d), compound 11,17,26,29,34,50,64,66,79,88.
Table 2 β-carboline alkali derivant solubility table in water
Compound Solubleness (mg/ml)
a 0.36
b 0.21
c ＜0.2
d ＜0.2
11 ＞300
17 ＞300
26 ＞300
29 ＞300
34 ＞300
50 ＞300
64 ＞300
66 ＞300
79 ＞300
88 ＞300

Claims (10)

1. the beta-carboline alkali derivative compounds of general formula (I) and the salt that forms with pharmaceutically acceptable acid thereof,
Figure FSB00000946922400011
Wherein:
R 1Be selected from hydrogen, C 1-4Alkyl and CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m is the arbitrary integer among the 2-6, n is the arbitrary integer among the 0-4;
R 3Be selected from hydrogen and CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m is the arbitrary integer among the 2-6, n is the arbitrary integer among the 0-4;
R 9Be selected from hydrogen, C 1-6Alkyl and aryl C 1-6Alkyl, wherein aryl is the phenyl that phenyl or substituting group replace, described substituting group is selected from: hydroxyl and halogen; And
(1) works as R 3And R 9During for hydrogen, R 1Be not hydrogen or C 1-4Alkyl;
(2) work as R 3Be hydrogen, R 9Be C 1-6Alkyl or aryl C 1-6During alkyl, R 1Be not hydrogen or C 1-4Alkyl.
2. compound according to claim 1 and the salt that forms with pharmaceutically acceptable acid thereof is characterized in that R 1Be selected from hydrogen, methyl, ethyl and CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m is the arbitrary integer among the 2-4, n is the arbitrary integer among the 0-3.
3. compound according to claim 2 and the salt that forms with pharmaceutically acceptable acid thereof is characterized in that R 1Be selected from hydrogen, methyl and CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m=3 or 4, n=0 or 1.
4. compound according to claim 1 and the salt that forms with pharmaceutically acceptable acid thereof is characterized in that R 3Be selected from hydrogen and CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m is the arbitrary integer among the 2-4, n is the arbitrary integer among the 0-3.
5. compound according to claim 4 and the salt that forms with pharmaceutically acceptable acid thereof is characterized in that R 3Be selected from hydrogen, CH 2NH (CH 2) mN[(CH 2) nCH 3] 2, wherein m=3 or 4, n=0 or 1.
6. compound according to claim 1 and the salt that forms with pharmaceutically acceptable acid thereof is characterized in that R 9Be selected from hydrogen, C 1-6Alkyl and aryl C 1-4Alkyl.
7. compound according to claim 6 and the salt that forms with pharmaceutically acceptable acid thereof is characterized in that R 9Be selected from normal-butyl, isobutyl-, benzyl, 4-luorobenzyl, 3-chlorobenzyl and 3-phenyl propyl.
8. compound and the salt that forms with pharmaceutically acceptable acid thereof, they are selected from the formed salt of acceptable acid on following any one compound and they and the pharmacology:
1-(4-methoxyl group) phenyl-3-[N-(2-diethylamino)-ethyl]-amino methyl-β-carboline;
1-(4-methoxyl group) phenyl-3-[N-(3-dimethylamino)-propyl group]-amino methyl-β-carboline;
1-(4-methoxyl group) phenyl-3-[N-(3-diethylamino)-propyl group]-amino methyl-β-carboline;
1-(4-methoxyl group) phenyl-3-[N-(4-diethylamino)-butyl]-amino methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-amino methyl-9-methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-9-methyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-amino methyl-9-methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-amino methyl-9-normal-butyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-normal-butyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-9-normal-butyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-amino methyl-9-normal-butyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-amino methyl-9-benzyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-benzyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-9-benzyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-amino methyl-9-benzyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-amino methyl-9-(4-fluorine) benzyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-(4-fluorine) benzyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-9-(4-fluorine) benzyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-amino methyl-9-(4-fluorine) benzyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-amino methyl-9-(3-chlorine) benzyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-(3-chlorine) benzyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-9-(3-chlorine) benzyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-amino methyl-9-(3-chlorine) benzyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-amino methyl-9-(3-phenyl propyl)-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-(3-phenyl propyl)-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-9-(3-phenyl propyl)-β-carboline;
3-[N-(4-diethylamino)-butyl]-amino methyl-9-(3-phenyl propyl)-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-aminomethyl-1,2-methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-aminomethyl-1,2,9-dimethyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-aminomethyl-1,2,9-dimethyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-aminomethyl-1,2,9-dimethyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-aminomethyl-1,2,9-dimethyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-amino methyl-9-normal-butyl-1-methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-normal-butyl-1-methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-9-normal-butyl-1-methyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-amino methyl-9-normal-butyl-1-methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-amino methyl-9-benzyl-1-methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-benzyl-1-methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-9-benzyl-1-methyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-amino methyl-9-benzyl-1-methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-amino methyl-9-(4-fluorine) benzyl-1-methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-(4-fluorine) benzyl-1-methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-9-(4-fluorine) benzyl-1-methyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-amino methyl-9-(4-fluorine) benzyl-1-methyl-β-carboline;
3-[N-(2-diethylamino)-ethyl]-amino methyl-9-(3-phenyl propyl)-1-methyl-β-carboline;
3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-(3-phenyl propyl)-1-methyl-β-carboline;
3-[N-(3-diethylamino)-propyl group]-amino methyl-9-(3-phenyl propyl)-1-methyl-β-carboline;
3-[N-(4-diethylamino)-butyl]-amino Shen Ji-9-(3-phenyl propyl)-1-methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-amino methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-amino methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(2-diethylamino)-ethyl]-amino methyl-9-methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-amino methyl-9-methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(4-diethylamino)-butyl]-amino methyl-9-methyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(2-diethylamino)-ethyl]-amino methyl-9-normal-butyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-normal-butyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-amino methyl-9-normal-butyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(4-diethylamino)-butyl]-amino methyl-9-normal-butyl-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(2-diethylamino)-ethyl]-amino methyl-9-(3-phenyl propyl)-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-dimethylamino)-propyl group]-amino methyl-9-(3-phenyl propyl)-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(3-diethylamino)-propyl group]-amino methyl-9-(3-phenyl propyl)-β-carboline;
1-(3,4,5-trimethoxy) phenyl-3-[N-(4-diethylamino)-butyl]-amino methyl-9-(3-phenyl propyl)-β-carboline;
1-[N-(2-diethylamino)-ethyl]-amino methyl-9-normal-butyl-β-carboline;
1-[N-(3-dimethylamino)-propyl group]-amino methyl-9-normal-butyl-β-carboline;
1-[N-(3-diethylamino)-propyl group]-amino methyl-9-normal-butyl-β-carboline;
1-[N-(4-diethylamino)-butyl]-amino methyl-9-normal-butyl-β-carboline;
1-[N-(2-diethylamino)-ethyl]-amino methyl-9-isobutyl--β-carboline;
1-[N-(3-dimethylamino)-propyl group]-amino methyl-9-isobutyl--β-carboline;
1-[N-(3-diethylamino)-propyl group]-amino methyl-9-isobutyl--β-carboline;
1-[N-(4-diethylamino)-butyl]-amino methyl-9-isobutyl--β-carboline;
1-[N-(2-diethylamino)-ethyl]-amino methyl-9-benzyl-β-carboline;
1-[N-(3-dimethylamino)-propyl group]-amino methyl-9-benzyl-β-carboline;
1-[N-(3-diethylamino)-propyl group]-amino methyl-9-benzyl-β-carboline;
1-[N-(4-diethylamino)-butyl]-amino methyl-9-benzyl-β-carboline;
1-[N-(2-diethylamino)-ethyl]-amino methyl-9-(4-fluorine) benzyl-β-carboline;
1-[N-(3-dimethylamino)-propyl group]-amino methyl-9-(4-fluorine) benzyl-β-carboline;
1-[N-(3-diethylamino)-propyl group]-amino methyl-9-(4-fluorine) benzyl-β-carboline;
1-[N-(4-diethylamino)-butyl]-amino methyl-9-(4-fluorine) benzyl-β-carboline;
1-[N-(2-diethylamino)-ethyl]-amino methyl-9-(3-chlorine) benzyl-β-carboline;
1-[N-(3-dimethylamino)-propyl group]-amino methyl-9-(3-chlorine) benzyl-β-carboline;
1-[N-(3-diethylamino)-propyl group]-amino methyl-9-(3-chlorine) benzyl-β-carboline;
1-[N-(4-diethylamino)-butyl]-amino methyl-9-(3-chlorine) benzyl-β-carboline;
1-[N-(2-diethylamino)-ethyl]-amino methyl-9-(3-phenyl propyl)-β-carboline;
1-[N-(3-dimethylamino)-propyl group]-amino methyl-9-(3-phenyl propyl)-β-carboline;
1-[N-(3-diethylamino)-propyl group]-amino methyl-9-(3-phenyl propyl)-β-carboline;
1-[N-(4-diethylamino)-butyl]-amino methyl-9-(3-phenyl propyl)-β-carboline.
9. pharmaceutical composition, it comprises according to claim 1 salt that the compound of-8 any one or itself and pharmaceutically acceptable acid form as activeconstituents, separately or in conjunction with one or more pharmaceutically acceptable, inertia, nontoxic vehicle or carrier.
10. the purposes of salt in preparation treatment antitumor drug that form of the compound of claim 1-8 any one or itself and pharmaceutically acceptable acid.
CN 201010108531 2010-02-10 2010-02-10 Beta-carboline alkali derivative compounds and application thereof Active CN102146080B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 201010108531 CN102146080B (en) 2010-02-10 2010-02-10 Beta-carboline alkali derivative compounds and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 201010108531 CN102146080B (en) 2010-02-10 2010-02-10 Beta-carboline alkali derivative compounds and application thereof

Publications (2)

Publication Number Publication Date
CN102146080A CN102146080A (en) 2011-08-10
CN102146080B true CN102146080B (en) 2013-01-30

Family

ID=44420570

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 201010108531 Active CN102146080B (en) 2010-02-10 2010-02-10 Beta-carboline alkali derivative compounds and application thereof

Country Status (1)

Country Link
CN (1) CN102146080B (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102952151B (en) * 2011-08-31 2017-07-28 新疆华世丹药物研究有限责任公司 3 double β carbolines alkaloid compounds, its preparation method and its pharmaceutical composition and purposes
CN103450332B (en) * 2012-06-01 2016-03-30 首都医科大学 The tripeptide benzyl ester that vinylbenzene-β-carboline is modified, its preparation, anti-tumor activity and application
CN104530043B (en) * 2014-12-03 2017-06-06 西北农林科技大学 9 substituted beta carboline class compounds and its application for preparing prevention or tumor
CN105884767B (en) * 2015-11-24 2018-01-19 西华大学 Pyrido [3,4 b] indole derivatives of 9 substitutions and preparation method thereof and the purposes as SIRT protein inhibitors
EP3321264A1 (en) * 2016-11-14 2018-05-16 Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft Selective inhibitors of genotoxic stress-induced ikk/nf-kb pathways
CN111747955B (en) * 2020-06-08 2021-05-04 浙江大学 Marine anti-glioma active substance isobaric carboline alkali A, preparation and application thereof
CN116354959B (en) * 2023-03-10 2024-04-19 石河子大学 Beta-carboline derivative of N-N bridged thiazole unit, and preparation method and application thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0110814A2 (en) * 1982-10-29 1984-06-13 Schering Aktiengesellschaft Beta-carbolines, process for their preparation and pharmaceutical compositions containing them
GB2155462A (en) * 1984-03-08 1985-09-25 Shell Int Research Heterotricyclic herbicides/fungicides
DE4442097A1 (en) * 1994-11-25 1996-05-30 Gerhard Prof Dr Bringmann Use of halogenated ß-carbolines as model substances for the generation of neurodegenerative diseases
CN1358720A (en) * 2001-12-19 2002-07-17 北京大学 Three-site substituted beta-carboline novel compound having anti-HIV and anti-cancer activity
CN1552711A (en) * 2003-06-02 2004-12-08 �½�������ҩ���о��������ι�˾ Yageine derivative compounds and their uses
DE102007009264A1 (en) * 2007-02-26 2008-08-28 Ellneuroxx Ltd. New 9-alkyl-beta-carboline compounds are dopamine receptor stimulators useful to treat and/or prevent movement disorder, Alzheimer's disease, Parkinson's disease and Wilson's diseases, and as additives for accelerating cell growth

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0110814A2 (en) * 1982-10-29 1984-06-13 Schering Aktiengesellschaft Beta-carbolines, process for their preparation and pharmaceutical compositions containing them
US4731358A (en) * 1982-10-29 1988-03-15 Schering Aktiengesellschaft β-carbolines and their use as tranquilizers
GB2155462A (en) * 1984-03-08 1985-09-25 Shell Int Research Heterotricyclic herbicides/fungicides
DE4442097A1 (en) * 1994-11-25 1996-05-30 Gerhard Prof Dr Bringmann Use of halogenated ß-carbolines as model substances for the generation of neurodegenerative diseases
CN1358720A (en) * 2001-12-19 2002-07-17 北京大学 Three-site substituted beta-carboline novel compound having anti-HIV and anti-cancer activity
CN1552711A (en) * 2003-06-02 2004-12-08 �½�������ҩ���о��������ι�˾ Yageine derivative compounds and their uses
DE102007009264A1 (en) * 2007-02-26 2008-08-28 Ellneuroxx Ltd. New 9-alkyl-beta-carboline compounds are dopamine receptor stimulators useful to treat and/or prevent movement disorder, Alzheimer's disease, Parkinson's disease and Wilson's diseases, and as additives for accelerating cell growth

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
- and &amp *
- and &ccedil
acirc *
-Carbolines by the Palladium/Copper-Catalyzed Coupling and Cyclization of Terminal Acetylenes.《Journal of Organic Chemistry》.2002,第67卷7048-7056. *
ccedil *
Haiming Zhang.Synthesis of &acirc
Haiming Zhang.Synthesis of &amp *
Haiming Zhang.Synthesis of β-and γ-carbolines by the palladium/copper-catalyzed coupling and copper-catalyzed or thermal cyclization of terminal acetylenes.《Tetrahedron Letters》.2002,第43卷1359-1362. *
R. Cao.Design, synthesis and in vitro and in vivo antitumor activities of novel b-carboline derivatives.《European Journal of Medicinal Chemistry》.2005,第40卷991-1001. *
R.Cao.Design synthesis and in vitro and in vivo antitumor activities of novel b-carboline derivatives.《European Journal of Medicinal Chemistry》.2005
Radhika S. Kusurkar.Efficient one-pot synthesis of anti-HIV and anti-tumour b-carbolines.《Tetrahedron》.2004,第60卷5315-5318. *

Also Published As

Publication number Publication date
CN102146080A (en) 2011-08-10

Similar Documents

Publication Publication Date Title
CN102146080B (en) Beta-carboline alkali derivative compounds and application thereof
IL262345A (en) Inhibitors of activin receptor-like kinase
JP2021501191A (en) Macrocycles and their use as Wee1 inhibitors
AU2017366529A1 (en) Pyrimido(5,4-b)indolizine or pyrimido(5,4-b)pyrrolizine compound, preparation method and use thereof
Ma et al. Synthesis and cytotoxic evaluation of 1-carboxamide and 1-amino side chain substituted β-carbolines
CN102675323A (en) Pyrrole-(2, 1-f) (1, 2 and 4) triazine derivative (I) and antitumor effect thereof
EP3997086A1 (en) Tetrahydroisoquinoline compounds
CN110627801A (en) HDAC inhibitor and application thereof
CN115260193A (en) Compounds and methods for treating rabies
CN116323616A (en) Compounds useful as SHP2 inhibitors and uses thereof
CA3236558A1 (en) Synthesis, preparation method and use of shp2 and cdk4/6 dual-target inhibitory compound
BRPI0709220A2 (en) coupling process for preparation of quinolone intermediates
CN110804059B (en) Carbamate compound, pharmaceutical composition and application thereof
Xu et al. An improved synthesis of 2-oxa-7-azaspiro [3, 5] nonane and analogs as novel reagents in medicinal chemistry
CN112500412B (en) Penamine A alkaloid structure simplification compound and application thereof
CN106892859A (en) (H) ketone polyamines conjugate of benzo [c, d] indoles 2 and its preparation method and application
CN103864781A (en) Novel 1,9-disubstituted tetrahydrocarboline derivative preparation, and application of 1,9-disubstituted tetrahydrocarboline derivatives in anti-tumor drugs
CN104211712B (en) Artemisinin derivative containing heteroaryl piperidine, its preparation method and application
WO2016187028A1 (en) Heteroaryl compounds, synthesis thereof, and intermediates thereto
CN110016011B (en) Amide derivative and medical use thereof
CN112390781A (en) Diaryl substituted 1, 1-ethylene compound, preparation method and application
CN116283971B (en) Indoline compound containing condensed heterocyclic structure, and preparation method and application thereof
CN107814790B (en) Topsentin derivative, preparation method thereof and application thereof in resisting plant viruses and germs
CN114276328B (en) Compound as small molecule immunosuppressant, preparation method and application thereof
Witiak et al. Syntheses and proton NMR conformational analyses of diastereomeric 4, 4'-(4, 5-dihydroxy-1, 2-cyclohexanediyl) bis (2, 6-piperazinedione) s and a synthetically related tricyclic octahydro-2, 2-dimethyl-6-oxo-1, 3-dioxolo [4, 5-g] quinoxaline-5, 8-diacetic acid ester

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant