CN1358720A - Three-site substituted beta-carboline novel compound having anti-HIV and anti-cancer activity - Google Patents
Three-site substituted beta-carboline novel compound having anti-HIV and anti-cancer activity Download PDFInfo
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Abstract
The persent invention relates to a 3-bustituted beta-carboline compound with activity for resisting HIV and resisting cancers. Said invention also provides its chemical structural formula, and provides the medicines made up said compound.
Description
The present invention relates to the β-Ka Lin new compound that the 3-position replaces.Such new compound has keying action to HIV-1 genome TAR RNA, can suppress combining of HIV-1 Tat albumen and TAR RNA, thereby duplicating of viral interference produces antiviral activity.Suppress the outer experimental result of HIV-1 replisome and show, do not showing under the toxic dosage, such compound exhibits good antiviral activity, the experimental result of this and in-vitro transcription matches.This compounds has antitumor action and anti-OH simultaneously
*Antioxygenation to dna break.
HIV-1 TAR RNA is a fragment gene group that is present on the HIV-1 virus mRNA, when HIV-1 Tat protein binding during in TAR RNA, has activated transcribing of virus, and transcript is prolonged, and virus is duplicated.The anti-HIV-1 medicine is primarily aimed at virus replication and the key enzyme of transcribing two stages at present: proteolytic enzyme and reversed transcriptive enzyme.But these two kinds of enzymes are because the variation and the genetic heterogeneity and very easily produce resistance of virus itself.Therefore, the investigator gets back in the fundamental research of HIV-1 virus once more, has found the proteic vital role that is combined in the viral life of TAR RNA and Tat.HIV-TAR RNA becomes the focus of Recent study thus.At present, just there are being some research institutions to be engaged in the anti-AIDS drug research that TAR RAN is a target abroad; The domestic still unmanned research of this target being carried out medicinal design except that this group.Therefore,, find a kind of medicine of new anti-HIV-1, so just can reach treatment AIDS patient's purpose as serving as the research target with TAR RNA.
A large amount of 'Beta '-carboline compounds has been described in the document.Especially for its HT
2cThe report of the strong affinity of acceptor.Japan carried out Anticancer Activities to 'Beta '-carboline compound, German Patent GP19502753, claimed 'Beta '-carboline compound with external antagonism cel l proliferation.European patent application EP 373986 claimed 'Beta '-carboline compound Fravopereirine, it has intensive antitumour activity and antiviral (comprising HIV) activity.
Except The compounds of this invention was novel, they also were proved to be anti-HIV-1, anticancer and anti-OH effectively
*Material to the dna break effect.Therefore they can be used for the antioxidant in acquired immune deficiency syndrome (AIDS), cancer therapy and dietetic food, the disease treatment.
The present invention more properly relates to (I) compound.
Wherein:
R
1The group of representative is selected from:
COR
4, R wherein
4Represent hydrogen atom, straight or branched (C
1-C
6) alkyl, aryl, cycloalkyl, heterocycle, list-(C
1-C
6) alkylamino, list-(C
1-C
6) alkyl guanidine radicals, two-(C
1-C
6) the alkyl guanidine radicals, the moieties of each group can be a straight or branched,
CONHR
4R wherein
4Be as defined above,
R
2The group of representative is selected from:
Hydrogen,
Straight or branched (C
1-C
6) alkyl,
COR
4R wherein
4Be as defined above,
R
3Represent hydrogen atom, straight or branched (C
1-C
6) alkyl or aryl-(C
1-C
6) alkyl, the latter's moieties can be a straight or branched,
Ra, Rb, Rc and Rd can be identical or different, and the group of representative is selected from hydrogen, halogen, straight or branched (C independently of one another
1-C
6) alkyl, hydroxyl, straight or branched (C
1-C
6) alkoxyl group.---wherein each moieties can be a straight or branched;---the alkyl-carbonyl oxygen base of hydroxyl, straight or branched, straight or branched (C
1-C
6) acyl group, aryloxy and aryl---(C
1-C
6) alkoxyl group;---wherein the alkoxyl group part can be a straight or branched ...
All compounds and at pharmaceutically acceptable acid or the formed additive salt of alkali,
Undoubtedly:
--" aryl " is understood that phenyl, naphthyl, tetralyl, dihydro naphthyl, indenyl or 2, and 3-dihydro indenyl is randomly replaced by one or more identical or different groups separately, and substituting group is selected from halogen, hydroxyl, cyano group, nitro, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, amino, straight or branched (C
1-C
6) alkylamino;--wherein each alkoxyl group part can be a straight or branched--, straight or branched (C
1-C
6) acyl group, straight or branched (C
1-C
6) alkoxy carbonyl, straight or branched (C
1-C
6) alkyl amino-carbonyl and oxo.
--" heterocycle " is understood that saturated or undersaturated list-or two-cyclic group, have aromatics and non-aromatic character, have 5 to 12 annular atomses, contain one, heteroatoms that two or three are identical or different, heteroatoms is selected from oxygen, nitrogen and sulphur, heterocycle is understood that and can be randomly replaced by one or more identical or different substituting groups that substituting group is selected from halogen, hydroxyl, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, nitro, oxo and amino is (arbitrarily by one or two straight or branched (C
1-C
6) the alkyl replacement).
In heterocycle, can be symbolic and do not add any pyridyl, thienyl, furyl, imidazolyl, 4-H-pyrans-4-ketone, pyrazinyl, pyrimidyl, isoxazolyl, tetrazyl, pyrryl, pyrazolyl, quinolyl, isoquinolyl, quinazolyl, pyrrolidyl, piperidyl, piperazinyl, 1 restrictedly mentioned, 2, the 3-thiadiazolyl group ...
In pharmaceutically acceptable acid, can not add any hydrochloric acid, cyanogen bromic acid, sulfuric acid, phosphonic acids, acetate, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, oxalic acid, methylsulfonic acid, dextrocamphoric acid etc. restrictedly mentioned.
In pharmaceutically acceptable alkali, can not add any sodium hydroxide, potassium hydroxide, triethylamine, TERTIARY BUTYL AMINE etc. restrictedly mentioned.
According to a kind of favourable change example, preferably The compounds of this invention is, wherein, and R
1Be COR
4R wherein
4Define suc as formula (I).According to a kind of favourable change example, preferred substituted R
1Be CONR
4aR
4bWherein work as R
4bWhen representing hydrogen atom, R
4aRepresent strand (C
1-C
6) alkylamino, strand (C
1-C
6) the alkyl guanidine radicals; R
4aAnd R
4bWhen linking to each other, represent piperazine.
According to the present invention, preferred substituted R
2And R
3Be hydrogen atom and single straight chain (C
1-C
6) alkyl.Especially advantageously R
2And R
3Represent hydrogen atom and methyl.
According to the present invention, preferred compound is:
3-ethylamino-β-Ka Lin-3-methane amide
3-third amino-beta--carboline-3-methane amide
Own amino-beta--the carboline of 3--3-methane amide
9-methyl-3-third amino-beta--carboline-3-methane amide
1-methyl-3-ethylamino-β-Ka Lin-3-methane amide
1-methyl-3-third amino-beta--carboline-3-methane amide
1-methyl-3-piperazinyl-β-Ka Lin-3-methane amide
Own amino-beta--the carboline of 1-methyl-3--3-methane amide
1,9-dimethyl-3-third amino-beta--carboline-3-methane amide
3-(2-guanidine radicals)-ethyl-β-Ka Lin-3-methane amide
3-(3-guanidine radicals)-propyl group-β-Ka Lin-3-methane amide
3-(6-guanidine radicals)-hexyl-β-Ka Lin-3-methane amide
3-(12-guanidine radicals)-dodecyl-β-Ka Lin-3-methane amide
1-methyl-3-(2-guanidine radicals)-ethyl-β-Ka Lin-3-methane amide
1-methyl-3-(3-guanidine radicals)-propyl group-β-Ka Lin-3-methane amide
1-methyl-3-(6-guanidine radicals)-hexyl-β-Ka Lin-3-methane amide
Preferred compound and they and pharmaceutically acceptable acid or the formed additive salt of alkali constitute the part of complete content of the present invention.
The invention still further relates to the preparation method of formula (I) compound, it is characterized in that using (II) compound as raw material:
Wherein Ra, Rb, Rc, Rd and R
3Be as defined above.
According to conventional one-tenth ester condition in the organic synthesis, obtain formula (III) compound with methyl alcohol.
Wherein Ra, Rb, Rc, Rd and R
3Be as defined above.
According to the Pictet-Spengler reaction conditions in the organic synthesis, make this formula (III) compound and (IV) compound reaction:
R
2CHO (IV)
Wherein, R
2Define suc as formula (I).
Obtain the formula V compound:
Wherein Ra, Rb, Rc, Rd, R
2And R
3Be as defined above.
Be subjected to the effect of oxygenant commonly used in the organic synthesis, obtain formula (VI) compound
Wherein Ra, Rb, Rc, Rd, R
2And R
3Be as defined above.
According to the amidation condition of routine, use formula (VII) compound treatment:
R
4aNHR
4b (VII)
R wherein
4aAnd R
4bBe as defined above.
Obtain formula (I/a) compound, i.e. a specific examples of formula (I) compound:
Wherein Ra, Rb, Rc, Rd, R
2, R
3, R
4aAnd R
4bBe as defined above.
This formula compound is placed under the effect of formula (VIII) compound:
[H
2N-C(-SCH
3)＝NH]
2·H
2SO
4 (VIII)
Obtain formula (I/b) compound, i.e. a specific examples of formula (I) compound:
Wherein Ra, Rb, Rc, Rd, R
2, R
3And R
4aBe as defined above.
Compound (I/a) and (I/b) constitute the integral body of this compound.If necessary, these compounds carry out purifying according to the purifying process of routine, if necessary, can randomly be converted into additive salt with pharmaceutically acceptable acid or alkali.
Formula (II), (IV), (VII), (VIII) compound are commercial available compounds, or the compound that obtains according to the currently known methods of organic synthesis.
The invention still further relates to pharmaceutical composition, comprise at least a formula (I) compound or with pharmaceutically acceptable acid or the formed additive salt of alkali as activeconstituents, independent or pharmaceutically acceptable, inert, nontoxic vehicle or carrier in conjunction with one or more.
In according to drug regimen of the present invention, can mention especially and be applicable to oral, parenteral (intravenously, muscle or subcutaneous), through skin or transdermal, intranasal, rectum, through tongue, through those of eye or respiratory administration, especially tablet or drageeing, Sublingual tablet, cachet, capsule, lozenge, suppository, creme, ointment, skin gel, can be injected into drinkable preparation, aerosol, eye drops or nasal drop etc.
The compounds of this invention has anti-HIV-1 activity, antitumour activity and anti-OH
*The anti-oxidant activity of dna breakage.Therefore the drug regimen that contains at least a formula (I) compound can be used for the treatment of HIV-1, the antioxidant in cancer therapy and disease, food, the pharmaceuticals.
As medicine, useful dosage is different because of patient age and body weight, route of administration, disease character and seriousness and any other treatment of being accepted.
The following example is set forth and is limited the present invention absolutely not:
Raw materials used and/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 be according to routine spectroscopic techniques (infrared, NMR, TOF-mass spectrum ...) measure.
Embodiment 1 3-ethylamino-β-Ka Lin-3-methane amide
Steps A: hydrochloric acid tryptophan methyl ester
1.0ml sulfur oxychloride splashes under-4 ℃ in the suspension of 1.0g L-tryptophane and 20ml anhydrous methanol, finishes, and removes ice-water bath, stirring at room is after 6 hours, and 70 ℃-80 ℃ were refluxed 6 hours, and the pressure reducing and steaming solvent obtains expecting product.
Step B:1,2,3,4-tetrahydrochysene-β-Ka Lin-3-methyl-formiate
The product that obtains in the 1.25g steps A is dissolved in the 75ml methyl alcohol, add 37% formaldehyde 0.95ml, after vapor bath refluxed 2 hours, the pressure reducing and steaming solvent, transfer PH8 to 9 with 14% strong aqua, add the 40ml chloroform extraction, use 3 * 20ml chloroform wash water layer again, the combined chloroform layer, anhydrous sodium sulfate drying spends the night, filtering sodium sulfate, the filtrate decompression evaporate to dryness obtains expecting product.
Step C: β-Ka Lin-3-methyl-formiate
The product that obtains among the 0.5g step B is dissolved in the 10ml Glacial acetic acid, in the cooling bath, stirs adding lead tetra-acetate 2.25g down fast, finish, stirred 20 minutes, add 2.5g oxalic acid, stirred 1 hour, and filtered, precipitation is suspended in the mixing solutions of 25ml water and 50ml chloroform, transfer pH to neutral with sodium bicarbonate, it is two-layer to filter branch, collects chloroform layer, wash chloroform layer with saturated common salt, tell chloroform layer, anhydrous sodium sulfate drying spends the night, remove by filter sodium sulfate, the filtrate decompression evaporate to dryness obtains expecting product.
Step D:3-ethylamino-β-Ka Lin-3-methane amide
The product that obtains among the 0.1g step C is dissolved in 4ml chloroform and 5 methyl alcohol, this solution was splashed into the 1ml 1 that is heated to 80 ℃-85 ℃ in 3 hours, in the 2-quadrol, finish, after the reflux 6 hours, concentrating under reduced pressure, the mixed solution of adding 5ml chloroform and 3ml water in the residue fully stirs the back standing over night.Separate out solid next day, filter, wash solid respectively with less water and methyl alcohol, the collection solid is in vacuum-drying, obtains expecting product.
Fusing point: 234-237 ℃
EI-MS：255
1H-NMR：12.26，9.08，8.92，8.87，8.45，7.69，7.61，3.63，3.03
Embodiment 2:3-third amino-beta--carboline-3-methane amide
Operation uses 1 with embodiment 1 in step D, the 3-propylene diamine is as reactant.
Fusing point: 218-222 ℃
EI-MS：269
1H-NMR：8.917，8.889，8.835，8.395，7.673，7.591，7.297，3.420，
2.614，1.638
Own amino-beta--the carboline of embodiment 3:3--3-methane amide
Operation uses 1 with embodiment 1 in step D, the 6-hexanediamine is as reactant
Fusing point: 189-193 ℃
EI-MS：311
1H-NMR：8.93，8.84，8.37，7.67，7.58，7.25，3.42，3.28，2.78，1.82
Embodiment 4:9-methyl-3-third amino-beta--carboline-3-methane amide
Operation uses 1-methyl-L-tryptophane as reactant in steps A with embodiment 2.
Fusing point: 116-118 ℃
EI-MS：282
Embodiment 5:1-methyl-3-ethylamino-β-Ka Lin-3-methane amide
Step e: 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-β-Ka Lin-3-methyl-formiate
Get 0.5g L-tryptophane, add the mixed solution of 1N sulfuric acid 2.5ml and 8ml water, stir adding 40% acetaldehyde 3.6ml down, 40 ℃ of heating in water bath 30 minutes, stirring at room 2 hours, reflux is 1.5 hours in vapor bath, be chilled to room temperature, with dense ammonia thermal transfer pH to 8, filter, precipitate with cold water washing, collecting precipitation, room temperature is dried, with the precipitation that obtains set by step B carry out esterification, obtain expecting product.
Step F: 1-methyl-β-Ka Lin-3-methyl-formiate
Get the product that the 1.5g step e obtains, add 4.2g sulphur, the 100ml dry xylene refluxed 4.5 hours, reaction solution is chilled to 5 ℃ spends the night, filter next day, with 40ml cold xylene and the washing precipitation successively of lower boiling sherwood oil, collecting precipitation, vacuum-drying obtains the re-set target compound.
Compound D reaction set by step with step F obtains obtains expected compound.
Fusing point: butter shape
EI-MS：268
1H-NMR：11.15，8.72，8.34，7.64，7.58，6.8，3.1-3,67，2.83
Embodiment 6:1-methyl-3-third amino-beta--carboline-3-methane amide
Operation is with embodiment 5, and with 1, the 3-propylene diamine is as reactant in step D.
Fusing point: 175-177 ℃
EI-MS：292
1H-NMR：12.03，8.77，8.35，7.67，7.59，7.30，3.56，3.33，2.83，1.9
Own amino-beta--the carboline of embodiment 7:1-methyl-3--3-methane amide
Operation is with embodiment 5, and with 1, the 6-hexanediamine is as reactant in step D
Fusing point: 243 ℃ (carbonization)
EI-MS：324
Embodiment 8:1-methyl-3-piperazinyl-β-Ka Lin-3-methane amide
Operation uses piperazine as reactant in step D with embodiment 5.
Fusing point: 192-194 ℃
EI-MS：294
Embodiment 9:1,9-dimethyl-3-third amino-beta--carboline-3-methane amide
Operation is with embodiment 5, in step e with 1-methyl-L-tryptophane as reactant, in step D with 1,3 propylene diamine as reactant.
Fusing point: 149-151 ℃
EI-MS：296
Embodiment 10:3-(2-guanidine radicals)-ethyl-β-Ka Lin-3-methane amide
Step G: take by weighing S-first isothiourea vitriol 0.021g, add 0.03ml water and 0.03ml 2M sodium hydroxide, drip the compound 0.1g that obtains among the embodiment 1 under stirring fast and be suspended in 2ml H
2The mixed solution of O finishes, stirring at room two days, and 4 ℃ of placements are spent the night, and filter, and precipitation is used a spot of water and methanol wash respectively, collecting precipitation, vacuum-drying obtains expecting compound.
Fusing point: 312-313 ℃
TOF-MS：297.0486
Embodiment 11 3-(3-guanidine radicals)-propyl group-β-Ka Lin-3-methane amide
Operation is with embodiment 10, and the compound that use embodiment 2 obtains in step G is as reactant.
Fusing point: 199-201 ℃
TOF-MS：311.0407
1H-NMR：8.92，8.81，8.37，7.64，7.58，7.27，3.41，3.11，1.75
13C-NMR：165.08，157.12，141.10，139.61，137.23，132.47，128.38，
128.00，122.07，120.96，119.75，113.73，112.30，38.39，36.23，28.84
Embodiment 13 3-(12-guanidine radicals)-dodecyl-β-Ka Lin-3-methane amide
Operation is with embodiment 10, usefulness in step D, 1,12-diamino-dodecane is as reactant, this product in step G as reactant.
Fusing point: 199-201 ℃
TOF-MS：437.1623
Embodiment 14:1-methyl-3-(2-guanidine radicals)-ethyl-β-Ka Lin-3-methane amide
Operation uses compound that embodiment 5 obtains as reactant in step G with embodiment 10.
Fusing point: 242-245 ℃
TOF-MS：297.0486
Embodiment 15 1-methyl-3-(3-guanidine radicals)-propyl group-β-Ka Lin-3-methane amide
Operation is with embodiment 10, and the compound that use embodiment 6 obtains in step G is as reactant.
Fusing point: 270-272 ℃
TOF-MS：325.0608
1H-NMR：12.03，8.66，8.28，7.64，7.53，7.23，3.36，3.12，2.82，1.69
13C-NMR：165.12，157.13，140.94，140.84，138.99，135.85，128.13，
127.31，122.03，121.42，119.77，112.27，111.99，36.30，29.06，20.41(2C)
Embodiment 16 1-methyl-3-(6-guanidine radicals) hexyl-β-Ka Lin-3-methane amide.
Operation is with embodiment 10, and the compound that use embodiment 7 obtains in step G is as reactant.
Fusing point: 196-198 ℃
TOF-MS：367.0860
The pharmacological research of The compounds of this invention.
Embodiment 17 anticancer shaker tests are tested with KB, Hela, HL-60, BGC and BEL-7402 tumour cell respectively, with mtt assay or srb assay.
Mtt assay: respectively with growth conditions HL-60 good, that be in logarithmic phase, Bel-7402, KB and Hela cell with 1 * 10
4Individual/mL concentration is inoculated in 96 orifice plates, 37 ℃ of 5%CO
2Cultivated 24 hours in the incubator.Abandon old liquid, renew nutrient solution, add the compound of sterilising treatment, continue to cultivate after 48 hours, discard nutrient solution, every hole adds RPMI 1640 (the containing 10% calf serum) nutrient solution that 20mL contains 5mg/mL MTT, continues to cultivate 4 hours.Centrifugal, 2500rpm, 20min, the sucking-off supernatant, room temperature is dried.Add a certain amount of dmso solution purple residue, on 570nm place microplate reader, measure absorption value.
Srb assay: the same with mtt assay.
Respectively with growth conditions HL-60 good, that be in logarithmic phase, Bel-7402, KB and Hela cell with 1 * 10
4Individual/mL concentration is inoculated in 96 orifice plates, 37 ℃ of 5%CO
2Cultivated 24 hours in the incubator.Abandon old liquid, renew nutrient solution, add the compound of sterilising treatment, continue to cultivate after 48 hours, get supernatant, add 100 μ l 10%TCA (Tricholroacetic Acid) in each aperture, leave standstill 5 minutes after, in 4 ℃ place 1 hour fixing.Outwell stationary liquid then, each aperture washes with water 5 times.After the drying at room temperature, every hole adds 0.4%SRB100 μ l, and room temperature was placed after 10 minutes, washes 5 times with 1%HOAc (acetic acid), and dry air adds the every hole of 10mMTris 200 μ l/, the vibration dissolving, and the place measures the OD value in the single wavelength of 540nm
Embodiment 18: anxious poison test
Medication preparation is become hydrochloride, standby with physiological saline solution.At first carry out trial test, find out 0% and 100% and estimate lethal quantity; According to this result, set five dosage groups then, the dosage spacing is 1: 0.8.(body weight 20 ± 2g) is divided into five groups to Kunming mouse at random, and 10 every group, male and female half and half are observed animal toxicity response situation and death condition in 14 days continuously after the administration.Add up dead animal number in 14 days, the input computer calculates its LD with Bliss method statistics program
50Value and 95% average fiducial limit.Record compound 3-third amino-beta--carboline-3-methane amide to the medium lethal dose (LD of mouse according to aforesaid method through intraperitoneal administration
50) be 170mg/Kg.
Embodiment 19: the combination of transcriptional level antagonism HIV-1 Tat/TAR RNA
We have successfully made up two plasmids.One is Tat gene expression plasmid (plasmid I), and another is to be promotor with HIV-1 LTR fragment, contains the plasmid (plasmid II) of E.C. 2.3.1.28 (CAT) reporter gene.Behind the transformed into escherichia coli, cut evaluation through enzyme and obtain positive colony.Utilize calcium phosphate to mediate this two kinds of plasmid cotransfection 293 cells, add 3 kinds of samples after 24 hours, concentration is 30 μ mol/L.Collect 48 hours culture supernatant, under the 405/490nm wavelength, detect CAT activity in the cell conditioned medium liquid with CAT ELISA test kit.Investigate sample to the interactional influence of Tat-TAR.
With the plasmid I that does not add sample, the CAT activity of II cotransfection system is 100%, represents the CAT activity of application of sample cotransfection system with relative reactivity.
Embodiment 20: suppress HIV-1 and duplicate in vitro tests.
Adopt MT
4Cell and HIV IIIB strain are tested, and the virus quantity of use is divided into 100TCID
50And 1000TCID
50(tissue cultured infection dose).MT
4Medicine under cell and HIV IIIB strain and the various dose was cultivated after 5 days, examined under a microscope CPE (cytopathy---cavity, swelling, fusion etc.).Set up five groups of experiments:
Contrast: medicine+MT
4Cell
Blank: MT
4Cell+HIV IIIB
Negative control: water+MT
4Cell+HIV IIIB
Positive control: AZT+MT
4Cell+HIV IIIB
Experimental group: medicine+MT
4Cell+HIV IIIB
Embodiment 21: anti-OH
*To the anti-oxidant activity of dna break, adopt plasmid pBR322 to test, with the reaction induced OH of Fenton
*Generation.
This test is widely used in estimating medicine antagonism OH
*Protective capability to dna break.
Steps A:
With compound (5/0.5mM) 2 μ l and tetraacethyl disodium (3mm), potassium phosphate buffer (50mm, pH7.4), hydrogen peroxide (3mm), ferrous sulfate (1.6mm) and each 2ul of pBR322 plasmid DNA, be mixed in the 1.5ml Eppendorf pipe, the ratio that guarantees ferrous sulfate/tetraacethyl disodium is 0.53, and cumulative volume is 12ul (insufficient water replenishes), 37 ℃ hatch 30 minutes after, every pipe adds 2ul bromine Fen indigo plant, agarose gel electrophoresis (0.8% agar powder, 1XTAE, pH7.4,600mv, about 1 hour) observations under the ultraviolet transilluminator.
Blank: plasmid DNA
Negative control: do not add any anti-oxidation active substance
Positive control: V
E(5mM)
Claims (21)
1, formula (I) compound: wherein:
R
1The group of representative is selected from: COR
4, R wherein
4Represent hydrogen atom, straight or branched (C
1-C
6) alkyl, aryl, cycloalkyl, heterocycle, list-(C
1-C
6) alkylamino, list-(C
1-C
6) alkyl guanidine radicals, two-(C
1-C
6) the alkyl guanidine radicals, the moieties of each group can be a straight or branched.
CONHR
4R wherein
4Be as defined above.
R
2The group of representative is selected from:
Hydrogen,
Straight or branched (C
1-C
6) alkyl,
COR
4Middle R
4Be as defined above,
R
3Represent hydrogen atom, straight or branched (C
1-C
6) alkyl or aryl-(C
1-C
6) alkyl, the latter's moieties can be a straight or branched.
Ra, Rb, Rc and Rd can be identical or different, and the group of representative is selected from hydrogen, halogen, straight or branched (C independently of one another
1-C
6) alkyl, hydroxyl, straight or branched (C
1-C
6) alkoxyl group.---wherein each moieties can be a straight or branched;---the alkyl-carbonyl oxygen base of hydroxyl, straight or branched, straight or branched (C
1-C
6) acyl group, aryloxy and aryl---(C
1-C
6) alkoxyl group;---wherein the alkoxyl group part can be a straight or branched ...All compounds and at pharmaceutically acceptable acid or the formed additive salt of alkali,
Undoubtedly:
-" aryl " is understood that phenyl, naphthyl, tetralyl, dihydro naphthyl, indenyl or 2, and 3-dihydro indenyl is randomly replaced by one or more identical or different groups separately, and substituting group is selected from halogen, hydroxyl, cyano group, nitro, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, amino, straight or branched (C
1-C
6) alkylamino;---wherein each alkoxyl group part can be a straight or branched---, straight or branched (C
1-C
6) acyl group, straight or branched (C
1-C
6) alkoxy carbonyl, straight or branched (C
1-C
6) alkyl amino-carbonyl and oxo.
-" heterocycle " is understood that saturated or undersaturated single or two-cyclic group, have aromatics and non-aromatic character, have 5 to 12 annular atomses, contain one, heteroatoms that two or three are identical or different, heteroatoms is selected from oxygen, nitrogen and sulphur, heterocycle is understood that and can be randomly replaced by one or more identical or different substituting groups that substituting group is selected from halogen, hydroxyl, straight or branched (C
1-C
6) alkyl, straight or branched (C
1-C
6) alkoxyl group, nitro, oxo and amino is (arbitrarily by one or two straight or branched (C
1-C
6) the alkyl replacement.In heterocycle, can be symbolic and do not add any pyridyl, thienyl, furyl, imidazolyl, 4-H-pyrans-4-ketone, pyrazinyl, pyrimidyl, isoxazolyl, tetrazyl, pyrryl, pyrazolyl, quinolyl, isoquinolyl, quinazolyl, pyrrolidyl, piperidyl, piperazinyl, 1 restrictedly mentioned, 2, the 3-thiadiazolyl group ...
2, according to formula (I) compound of claim 1, it is characterized in that R
1Represent COR
4Base, wherein R
4Define suc as formula (I).
They and with pharmaceutically acceptable acid or the formed additive salt of alkali.
3, according to formula (I) compound of claim 1 or 2, it is characterized in that R
1Represent CONHR
4a, R
4aRepresent strand (C
1-C
6) alkylamino, strand (C
1-C
6) the alkyl guanidine radicals.
They and with pharmaceutically acceptable acid or the formed additive salt of alkali.
4, according to formula (I) compound of claim 1, it is characterized in that R
2The group of representative is selected from: hydrogen, straight or branched (C
1-C
6) alkyl, COR
4, R wherein
4Be as defined above.
They and with pharmaceutically acceptable acid or the formed additive salt of alkali.
5, according to formula (I) compound of claim 1 or 4, it is characterized in that R
2Represent hydrogen or methyl.
They and with pharmaceutically acceptable acid or the formed additive salt of alkali.
6, according to formula (I) compound of claim 1, it is characterized in that R
3Represent (the C of hydrogen atom, straight or branched
1-C
6) alkyl or aryl (C
1-C
6) alkyl, the latter's moieties can be a straight or branched.
They and with pharmaceutically acceptable acid or the formed additive salt of alkali.
7, according to formula (I) compound of claim 1 or 6, it is characterized in that R
3Represent hydrogen atom or methyl.
They and with pharmaceutically acceptable acid or the formed additive salt of alkali.
8, according to formula (I) compound of claim 1, it is 3-third amino-beta--carboline-3-methane amide.
It and with pharmaceutically acceptable acid or the formed additive salt of alkali.
9, according to formula (I) compound of claim 1, it is 1-methyl-3-ethylamino-β-Ka Lin-3-methane amide.
It and with pharmaceutically acceptable acid or the formed additive salt of alkali.
10, according to formula (I) compound of claim 1, it is 1-methyl-3-third amino-beta--carboline-3-methane amide.
It and with pharmaceutically acceptable acid or the formed additive salt of alkali.
11, according to formula (I) compound of claim 1, it is 3-(2-guanidine radicals)-ethyl-β-Ka Lin-3-methane amide.
It and with pharmaceutically acceptable acid or the formed additive salt of alkali.
12, according to formula (I) compound of claim 1, it is 3-(3-guanidine radicals)-propyl group-β-Ka Lin-3-methane amide.
It and with pharmaceutically acceptable acid or the formed additive salt of alkali.
13, according to formula (I) compound of claim 1, it is 3-(6-guanidine radicals)-hexyl-β-Ka Lin-3-methane amide.
It and with pharmaceutically acceptable acid or the formed additive salt of alkali.
14, according to formula (I) compound of claim 1, it is 3-(12-guanidine radicals)-dodecyl-β-Ka Lin-3-methane amide.
It and with pharmaceutically acceptable acid or the formed additive salt of alkali.
15, according to formula (I) compound of claim 1, it is 1-methyl-3-(2-guanidine radicals)-ethyl-β-Ka Lin-3-methane amide.
It and with pharmaceutically acceptable acid or the formed additive salt of alkali.
16, according to formula (I) compound of claim 1, it is 1-methyl-3-(3-guanidine radicals)-propyl group-β-Ka Lin-3-methane amide.
It and with pharmaceutically acceptable acid or the formed additive salt of alkali.
17, according to formula (I) compound of claim 1, it is 1-methyl-3-(6-guanidine radicals)-hexyl-β-Ka Lin-3-methane amide.
It and with pharmaceutically acceptable acid or the formed additive salt of alkali.
18, the preparation method of formula (I) compound is characterized in that using (II) compound as raw material:
Wherein Ra, Rb, Rc, Rd and R
3Be as defined above.
According to conventional one-tenth ester condition in the organic synthesis, obtain formula (III) compound with methyl alcohol.
According to the Pictet-Spengler reaction conditions in the organic synthesis, make this formula (III) compound and (IV) compound reaction:
R
2CHO (IV) wherein, R
2Define suc as formula (I).Obtain the formula V compound:
Wherein Ra, Rb, Rc, Rd, R
2And R
3Be as defined above.
Be subjected to the effect of oxygenant commonly used in the organic synthesis, obtain formula (VI) compound
Wherein Ra, Rb, Rc, Rd, R
2And R
3Be as defined above.
According to the amidation condition of routine, use formula (VII) compound treatment:
R
4aNHR
4b(VII) R wherein
4aAnd R
4bBe as defined above.Obtain formula (I/a) compound, i.e. a specific examples of formula (I) compound:
Wherein Ra, Rb, Rc, Rd, R
2, R
3, R
4aAnd R
4bBe as defined above.
This formula compound is placed under the effect of formula (VIII) compound:
[H
2N-C (SCH
3)=NH]
2H
2SO
4(VIII) obtain formula (I/b) compound, i.e. a specific examples of formula (I) compound:
Wherein Ra, Rb, Rc, Rd, R
2, R
3And R
4bBe as defined above.
19, pharmaceutical composition comprises at least a formula any according to claim 1 to 17 (I) compound as activeconstituents, independent or pharmaceutically acceptable in conjunction with one or more, inert, nontoxic vehicle or carrier.
20, according to the pharmaceutical composition of claim 19, comprise at least a activeconstituents any according to claim 1 to 18, be used for anti-AIDS, anticancer therapy.
21, according to the pharmaceutical composition of claim 19, comprise at least a activeconstituents any according to claim 1 to 18, be used for the antioxidant of food or medicine and the anti-oxidant treatment in the disease.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011445319A CN1160352C (en) | 2001-12-19 | 2001-12-19 | Three-site substituted beta-carboline novel compound having anti-HIV and anti-cancer activity |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011445319A CN1160352C (en) | 2001-12-19 | 2001-12-19 | Three-site substituted beta-carboline novel compound having anti-HIV and anti-cancer activity |
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| Publication Number | Publication Date |
|---|---|
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| CN1160352C CN1160352C (en) | 2004-08-04 |
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ID=4677649
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|---|---|---|---|
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2211295A1 (en) * | 2002-07-19 | 2004-07-01 | Consejo Sup. De Investig. Cientificas | Tetrahydro-beta-phenolate carbolins are used as anti-oxidants for termination of lipidic peroxidation |
| WO2004106335A1 (en) * | 2003-06-02 | 2004-12-09 | Xinjiang Huashidan Pharmaceutical Research Co., Ltd | Harmine derivatives, intermediates used in their preparation, preparation processes and use thereof |
| 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 |
| CN102146080A (en) * | 2010-02-10 | 2011-08-10 | 新疆华世丹药业股份有限公司 | Beta-carboline alkali derivative compounds and application thereof |
| CN101423517B (en) * | 2008-11-28 | 2011-09-14 | 浙江大学 | Gamma-carbolines derivates as well as preparation method and application thereof |
| CN103214486A (en) * | 2013-04-20 | 2013-07-24 | 河北大学 | Beta-carboline derivative or medicinal salt as well as preparation method and anti-tumour application thereof |
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| CN113387963A (en) * | 2021-05-12 | 2021-09-14 | 南方海洋科学与工程广东省实验室(湛江) | Beta-carboline compound and preparation method and application thereof |
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2001
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2211295A1 (en) * | 2002-07-19 | 2004-07-01 | Consejo Sup. De Investig. Cientificas | Tetrahydro-beta-phenolate carbolins are used as anti-oxidants for termination of lipidic peroxidation |
| US8772311B2 (en) | 2003-06-02 | 2014-07-08 | Xinjiang Huashidan Pharmaceutical Research Co., Ltd. | Harmine derivatives, intermediates used in their preparations, preparation processes and use thereof |
| WO2004106335A1 (en) * | 2003-06-02 | 2004-12-09 | Xinjiang Huashidan Pharmaceutical Research Co., Ltd | Harmine derivatives, intermediates used in their preparation, preparation processes and use thereof |
| 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 |
| CN101423517B (en) * | 2008-11-28 | 2011-09-14 | 浙江大学 | Gamma-carbolines derivates as well as preparation method and application thereof |
| CN102146080A (en) * | 2010-02-10 | 2011-08-10 | 新疆华世丹药业股份有限公司 | Beta-carboline alkali derivative compounds and application thereof |
| CN102146080B (en) * | 2010-02-10 | 2013-01-30 | 新疆华世丹药业股份有限公司 | Beta-carboline alkali derivative compounds and application thereof |
| CN103214486A (en) * | 2013-04-20 | 2013-07-24 | 河北大学 | Beta-carboline derivative or medicinal salt as well as preparation method and anti-tumour application thereof |
| CN103214486B (en) * | 2013-04-20 | 2016-05-11 | 河北大学 | Beta-carboline derivatives or officinal salt, its preparation method and antineoplastic application thereof |
| CN104744460A (en) * | 2013-12-30 | 2015-07-01 | 南开大学 | B-carboline, dihydro-B-carboline and tetrahydro-B-carboline alkaloid derivative as well as preparation method and application in aspects of plant virus prevention and cure, sterilization and insecticide |
| WO2015101206A1 (en) * | 2013-12-30 | 2015-07-09 | 南开大学 | Β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives and method for preparing same and use in aspects of preventing and treating plant viruses, fungicides and insecticides |
| US10208033B2 (en) | 2013-12-30 | 2019-02-19 | Nankai University | β-carboline, dihydro-β-carboline and tetrahydro-β-carboline alkaloid derivatives and preparation methods same and use in aspects of preventing and treating plant viruses, fungicides and insecticides |
| CN113387963A (en) * | 2021-05-12 | 2021-09-14 | 南方海洋科学与工程广东省实验室(湛江) | Beta-carboline compound and preparation method and application thereof |
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|---|---|
| CN1160352C (en) | 2004-08-04 |
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