CN103214486B - Beta-carboline derivatives or officinal salt, its preparation method and antineoplastic application thereof - Google Patents

Beta-carboline derivatives or officinal salt, its preparation method and antineoplastic application thereof Download PDF

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Publication number
CN103214486B
CN103214486B CN201310139090.8A CN201310139090A CN103214486B CN 103214486 B CN103214486 B CN 103214486B CN 201310139090 A CN201310139090 A CN 201310139090A CN 103214486 B CN103214486 B CN 103214486B
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compound
pyridine
naphthyl
indyl
methyl
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CN103214486A (en
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朱华结
李艳
白冰
李兴尧
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Kunming Institute of Botany of CAS
Heibei University
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Kunming Institute of Botany of CAS
Heibei University
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Abstract

The invention discloses a kind of beta-carboline derivatives or officinal salt of general formula (I) structure with antitumor activity, wherein R, R1、R2As defined in description.

Description

Beta-carboline derivatives or officinal salt, its preparation method and antineoplastic application thereof
Technical field:
The invention belongs to technical field of pharmaceuticals, more specifically say beta-carboline derivatives or officinal salt, its preparation methodAnd antineoplastic application.
Background technology:
Tumour is the cell of human organ tissue, be under the external and interior long term at adverse factor, produce onePlant the neoformation taking cell hyperproliferation as main feature. This neoformation is irrelevant with the physiological requirements of the organ of getting involved, not according to justThe rule growth of normal organ, loses Normocellular function, has destroyed original organ structure, and what have can transfer to other portionPosition, threat to life. Tumour can be divided into benign tumour and the large class of malignant tumour two, and benign tumour is less to Health Impact,Cancer belongs to malignant tumour. According to incompletely statistics, the whole world approximately has 2,000 ten thousand malignant tumour new cases every year. TumourTreatment mainly contain operative treatment, radiotherapy and medicine treatment. The sixties in last century, more new drug is put to clinical practice,And changing single drug is drug combination, has not only improved curative effect, has reduced toxic and side effect, and has expanded therapeutic domain, makesSuch as ALL, the existing possibility of curing of the tumours such as choriocarcinoma. Chemotherapeutic major advantage, is bothCan treat solid tumor, non-solid tumor, is also expected to treat metastatic tumor. Traditional antineoplastic mainly contains following a few class: 1. directAct on the medicine (as: alkylating agent, metal platinum compound, topoisomerase enzyme inhibitor) that DNA destroys its 26S Proteasome Structure and Function; 2. dryDisturb the synthetic medicine of DNA and nucleic acid (as: purine, pyrimidine, antifol); 3. antimitotic, affects protein syntheticMedicine (paclitaxel analogs); 4. other (as: hormone medicine). But due to tumor cell growth soon, easily variation, thereby produceMDR, causes chemotherapy of tumors failure, and the therapeutic index of most of antineoplastics is less simultaneously, and selectively low, is killing and woundingWhen tumour cell, also damage normal structure, especially breed histocyte rapidly, in the time of therapeutic dose, can cause moreBad reaction. Therefore, carry out the research of antineoplastic, have great importance.
Summary of the invention:
The object of the present invention is to provide beta-carboline derivatives or officinal salt, its preparation method and antineoplastic answering thereofWith, to provide more medicament selection for human treatment's tumor disease.
Beta-carboline derivatives of the present invention has the structure of general formula (I):
Wherein, the group of R representative is selected from: hydrogen, COOR3Or C (R4)2OR5, wherein R3For C1-4Alkyl; R4For hydrogen, C1-4AlkaneBase or phenyl; R5For hydrogen, C1-4Alkyl, benzyl, C2-4Alkanoyl or benzoyl;
R1The group of representative is selected from: anthryl, phenanthryl, 1-naphthyl, 2-naphthyl, and separately optionally by one or more identicalOr the replacement of different groups, substituting group is selected from halogen, hydroxyl, cyano group, nitro, ester group, straight or branched C1-6Alkyl, straight chain orSide chain C1-6Alkoxyl;
R2The group of representative is selected from: hydrogen, C1-4Alkyl, benzyl.
Described beta-carboline derivatives can be following any one compound and officinal salt thereof:
Wherein:
R1For: anthryl, phenanthryl, 1-naphthyl, 2-naphthyl, optionally got by one or more identical or different groups separatelyIn generation, substituting group is selected from halogen, hydroxyl, cyano group, nitro, ester group, straight or branched (C1-C6) alkyl, straight or branched (C1-C6）Alkoxyl;
R2For: hydrogen, methyl, ethyl, propyl group, butyl, benzyl;
R3For methyl, ethyl, propyl group, isopropyl, butyl.
Preferably, R5For hydrogen, acetyl group; R1The group of representative is selected from: anthryl, phenanthryl, 1-naphthyl, 2-naphthyl, methoxyl groupNaphthyl;
More preferably, beta-carboline derivatives is selected from following compound:
9-anthryl 2-click ripple quinoline methyl esters (2a);
6-methoxyl group-2-naphthyl click ripple ethyl morpholine (2k);
(1-(9-anthryl)-9H-pyridine [3,4-b]-3-indyl) methyl alcohol (4a);
2-(1-(1-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5b);
2-(1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5c);
(1-(6-methoxyl group 2-naphthyl)-9H-pyridine [3,4-b]-3 base) methyl alcohol (4d);
2-(1-(6-methoxyl group-2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5d);
(1-(9-phenanthryl)-9H-pyridine [3,4-b]-3 base) methyl alcohol (4e);
2-(1-(9-phenanthryl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5e);
(9-methyl isophthalic acid-(2-naphthyl)-9H-pyridine [3,4-b]-3 base) methyl alcohol (4j);
2-(9-methyl 1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5j);
(1-(6-methoxyl group 2-naphthyl)-9-methyl-9H-pyridine [3,4-b]-3 base) methyl alcohol (4l);
2-(1-(6-methoxyl group 2-naphthyl)-9 methyl-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol (5l);
(1-(6-methoxyl group 2-naphthyl)-9-ethyl-9H-pyridine [3,4-b]-3 base) methyl alcohol (4m);
(1-(9-phenanthryl)-9-methyl-9H-pyridine [3,4-b]-3 base) methyl alcohol (4n);
(1-(9-phenanthryl)-9-ethyl-9H-pyridine [3,4-b]-3 base) methyl alcohol (4o);
(1-(2-naphthyl)-9H-pyridine [3,4 ,-b] 3-indyl) methyl acetate (6g);
(1-(9-phenanthryl)-9H-pyridine [3,4 ,-b] 3-indyl) methyl acetate (6m).
Above-mentioned all compounds or officinal salt and isomers thereof, raceme, diastereoisomer, solvate form thisA part for invention.
Drug regimen of the present invention, contain the carrier of permitting in above-claimed cpd or officinal salt, pharmaceutics or withThis compounds is as the mixed combination with pharmaceutical excipient or diluent of active component.
Compound of the present invention or officinal salt are applied in the medicine of preparation treatment and prevention tumor disease.
In the described drug regimen Chinese pharmacology that is used for the treatment of tumour of the present invention, acceptable carrier refers to pharmacy neckThe pharmaceutical carrier of territory routine, for example: diluent is as water etc.; Excipient agent is as starch, sucrose etc., and adhesive is as cellulose-derivedThing, alginates, gelatin etc.; Wetting agent is as glycerine; Disintegrant is as agar, calcium carbonate, calcium bicarbonate etc.; Absorbent is as quaternary ammonium compoundsThing; Surfactant is as hexadecanol; Absorption carrier is as kaolin etc.; Lubricant is as talcum powder, calcium stearate, magnesium etc. In additionCan also in composition, add other assistant agent as flavouring agent, sweetener etc.
The compounds of this invention may composition form by oral, snuffing enters, the mode of rectum or parenteral is executedFor needing the patient of this treatment. When oral, can be made into conventional solid pharmaceutical preparation as tablet, pulvis, granula, glueCapsules etc., make liquid preparation if water or oil-suspending agent or other liquid preparations are as syrup, tincture etc.; During for parenteral,Can be made into solution, water or the oiliness suspending agent etc. of injection, preferred form is tablet, capsule and injection.
The various formulations of drug regimen of the present invention can be according to the conventional production method preparation of pharmaceutical field. For example make activityComposition mixes with one or more carriers, is then made into required formulation.
Pharmaceutical composition of the present invention preferably contains the active component that weight ratio is 0.1%-99.5%, most preferably contains proportionFor the active component of 0.5%-95%.
By test, compound provided by the present invention has than the better antitumor activity of positive control cis-platinum.
In the preparation method of formula of the present invention (I) compound, when R is COOR3Time, preparation method comprises the following steps:
A) use alcohol and thionyl chloride and formula (II) compound effects synthesis type (III) compound:
Wherein alcohol used is the one in methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol, butanols.
B) utilize Pictet-Spengler reaction, make formula (III) compound and R1CHO effect, obtains Tetrahydrocarboline, tetrahydrochyseneCarboline obtains formula (I A) compound under aromatic yl reagent-ing effect:
C) utilize alkyl halide to react the formula of obtaining (I B) compound with formula (I A) compound under alkali effect:
Wherein, R1、R2、R3Same aforementioned definitions.
In the preparation method of formula of the present invention (I) compound, when R is CH2When OH, comprise the following steps:
Utilize reducing agent reduction-type (I B) compound, then reaction obtains formula (I C) compound under sour effect:
Wherein, R1、R2、R3Same aforementioned definitions.
In the preparation method of formula of the present invention (I) compound, when R is C3H6When OH, comprise the following steps:
Utilize RMgBr or lithium alkylide to react the formula of obtaining (I D) compound with formula (I B) compound:
Wherein, R1、R2、R3Same aforementioned definitions.
In the preparation method of formula of the present invention (I) compound, when R is CH2When OAc, comprise the following steps:
Utilize acyl chlorides to react the formula of obtaining (I E) compound with formula (I C) compound under alkali effect:
Wherein, R1、R2、R3Same aforementioned definitions.
Detailed description of the invention:
The following examples are only used for that the present invention will be described, but do not limit the present invention in any way.
The raw materials used commercial goods that is in the embodiment of the present invention, the spectral data of made compound is the side of test routinelyMethod records.
Embodiment 1
Synthesizing of compound 1
Get absolute alcohol R3OH300mL, in flask, is cooled to-15 DEG C, drips 20mL thionyl chloride, and finish and stir 30min,Add tryptophan methyl ester 40g, 60 DEG C of backflow 24h, steaming desolventizes, and residue water dissolves, and uses Na2CO3Be adjusted to alkalescence, acetic acid secondEster extraction, merges organic phase, dry, steams to desolventize to obtain white solid compound 1. As shown in table 1, in the present embodiment, withR3Be selected from the difference of methyl, ethyl and isopropyl, make respectively compound 1a, compound 1b and compound 1c. Compound 1a, 1bAnd 1c spectral data is separately as shown in table 1.
Table 1
Embodiment 2
Synthesizing of compound 2
Get the made compound 1(5mmol of embodiment 1) be dissolved in anhydrous CH2Cl2(80mL), in, add aldehyde R1CHO（5mmol），After 1h, add 4A molecular sieve, normal-temperature reaction 2 days, is chilled to 0 DEG C, adds trifluoroacetic acid (570mg, 5mmol), finishes that to rise to room temperature anti-Answer 24h, add the saturated Na of 10mL2CO3Solution, suction filtration, filtrate is washed 3 times with saturated NaCl, anhydrous Na2SO4Dry. DDQ(2.28g, 10mmol) adds dry filtrate in batches, normal-temperature reaction 30min, and water washing is colourless to water layer, and organic layer is anhydrousNaSO4Dry, evaporate to dryness obtains light yellow solid shape compound 2. In the present embodiment, with R in compound 13Substituting group and aldehyde R1CHOMiddle R1Substituent difference, makes respectively compound 2a-2o as shown in table 2. In table 2, compound 2a is 9-anthryl 2-click ripple quinolineMethyl esters, compound 2k is 6-methoxyl group-2-naphthyl click ripple ethyl morpholine, the extracorporeal anti-tumor IC of compound 2a and compound 2k50ValueIn table 7.
Table 2
Embodiment 3
Synthesizing of compound 3
By made embodiment 2 compound 2a(0.25mmol) be dissolved in DMF(3mL) in, add successively anhydrous K2CO3Powder(69mg, 0.5mmol), iodomethane (106mg, 0.75mmol), normal-temperature reaction 12h. In reactant liquor impouring frozen water, be positioned over refrigeratorInterior complete to precipitation, suction filtration, dry, obtain white solid compound 3a.
Further, replace compound 2a with a certain compound being selected from series compound 2a-2o, with iodo-alkylR2I replaces iodomethane, reacts, according to substituent R in selected raw material by above-mentioned reaction condition with corresponding mol ratio3、R1AndR2Difference, can make the 3a-3ae series compound shown in table 3.
Table 3
Embodiment 4
Synthesizing of compound 4
LiAlH4(20mg, 0.5mmol) is suspended in (10mL) in anhydrous THF, drips the THF solution of compound 2 or 3(0.25mmol is dissolved in the anhydrous THF of 2mL), normal-temperature reaction 1h, adds 0.13mLH successively under ice bath2O、0.13mL15%NaOHSolution, 0.13mLH2O, reactant diatomite filtration, evaporate to dryness obtains light yellow solid shape compound 4.
In the present embodiment, according to R in the compound 2 of raw material choose or compound 31R2Substituent difference, obtained chemical combinationThing 4 is the compound 4a-4o shown in table 4. Wherein, compound 4a is (1-(9-anthryl)-9H-pyridine [3,4-b]-3-indolesBase) methyl alcohol; Compound 4d is (1-(6-methoxyl group 2-naphthyl)-9H-pyridine [3,4-b]-3 base) methyl alcohol; Compound 4e is (1-(9-phenanthryl)-9H-pyridine [3,4-b]-3 base) methyl alcohol; Compound 4j be (9-methyl isophthalic acid-(2-naphthyl)-9H-pyridine [3,4-b]-3 bases) methyl alcohol; Compound 4l is (1-(6-methoxyl group 2-naphthyl)-9-methyl-9H-pyridine [3,4-b]-3 base) methyl alcohol; Compound4m is (1-(6-methoxyl group 2-naphthyl)-9-ethyl-9H-pyridine [3,4-b]-3 base) methyl alcohol; Compound 4n be (1-(9-phenanthryl)-9-methyl-9H-pyridine [3,4-b]-3 base) methyl alcohol; Compound 4o is (1-(9-phenanthryl)-9-ethyl-9H-pyridine [3,4-b]-3Base) methyl alcohol; The extracorporeal anti-tumor IC of described compound 4a, 4d, 4e, 4j, 4l, 4m, 4n and 4o50Value is in table 7.
Table 4
Embodiment 5
Synthesizing of compound 5
Compound 2 or compound 3(0.25mmol) be dissolved in (10mL) in anhydrous THF, Ar2The lower methyl-magnesium-bromide that drips of protection(3mmol, 0.5mL), normal-temperature reaction 8h, adds saturated ammonium chloride cancellation reaction under ice bath, ethyl acetate dilution, saturated NaCl is moltenLiquid washing, anhydrous Na2SO4Dry, evaporate to dryness obtains buff powder, upper silicagel column, benzinum: ethyl ester wash-out, obtains white solidShape compound 5.
In the present embodiment, be R in compound 2 or compound 3 according to selected raw material2、R3Substituent difference, can divideDo not make compound 5a-5o as shown in table 5. In table 5, compound 5b is 2-(1-(1-naphthyl)-9H-pyridine [3,4-b] 3-YinDiindyl base)-2-propyl alcohol; Compound 5c
For 2-(1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol; Compound 5d is 2-(1-(6-methoxyBase-2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol; Compound 5e is 2-(1-(9-phenanthryl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol; Compound 5j is
2-(9-methyl 1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol; Compound 5l is 2-(1-(6-Methoxyl group 2-naphthyl)-9 methyl-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol. Compound 5b, 5c, 5d, 5e, 5j and 5l'sExtracorporeal anti-tumor IC50Value is in table 7.
Table 5
Embodiment 6
Synthesizing of compound 6
Compound 4(0.12mmol) be dissolved in anhydrous CH2Cl2In in (8mL), add successively triethylamine (13mg,0.13mmol), aceticanhydride (13mg, 0.13mmol) and catalytic amount DMAP. Normal-temperature reaction 12h, reactant liquor water washing 3 times, anhydrousNa2SO4Dry, upper silicagel column, Shi You Mi ︰ Yi Zhi ︰ carrene=10 ︰ 1 ︰ 2.5 wash-outs, obtain white solid compound 6.
In the present embodiment, be R in compound 4 according to selected raw material1、R2Substituent difference, can make respectively as tableSeries compound 6a-6o shown in 6. Compound 6g in table 6 is (1-(2-naphthyl)-9H-pyridine [3,4 ,-b] 3-indyl)Methyl acetate; Compound 6m is (1-(9-phenanthryl)-9H-pyridine [3,4 ,-b] 3-indyl) methyl acetate. Described compound 6g,The extracorporeal anti-tumor IC of 6m50Value is in table 7.
Table 6
Embodiment 7
Extracorporeal anti-tumor screening, is leukaemia strain with HL-60 respectively, and SMMC-772 is hepatoma cell strain, and A-549 lung cancer is thinBorn of the same parents' strain, MCF-7 breast carcinoma cell strain, SW480 colon cancer cell line is tested; Detection method is mtt assay.
Mtt assay: with being made into individual cells suspension containing the nutrient solution (DMEM or RMPI1640) of 10% hyclone, with oftenA 10000-20000 cell in hole is inoculated into 96 orifice plates, every pore volume 100 μ L, and attached cell shifts to an earlier date 12h inoculated and cultured. Add and treat(fixed concentration 40 μ M primary dcreening operations, near compound growth of tumour cell being suppressed at 50% in this concentration establishes 5 to survey compound solutionIndividual concentration enters gradient and sieves again), every hole final volume 200 μ L, 3 multiple holes are all established in every kind of processing. Cultivate after 48h for 37 DEG C, every hole addsMTT solution 20 μ L. Continue to hatch 4h, stop cultivating, careful suction abandoned culture supernatant 100 μ L to avoid cell loss, often in the hole inHole adds 20% SDS100 μ L, and night incubation (37 DEG C of temperature), fully melts crystal. Select 595nm wavelength, enzyme linked immunologicalDetector (Bio-Rad680) reads each hole absorbance value, records result, and taking concentration as abscissa, cell survival rate is ordinateDraw cell growth curve, application two-point method (ReedandMuench method) calculates the IC of compound50Be worth as shown in table 7.
The part of compounds extracorporeal anti-tumor IC that table 7. is involved in the present invention50Value

Claims (5)

1. compound or the officinal salt with active anticancer, is characterized in that being selected from following compound and officinal salt thereof:
2-(1-(1-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol;
2-(1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol;
2-(1-(6-methoxyl group-2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol;
2-(1-(9-phenanthryl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol;
2-(9-methyl 1-(2-naphthyl)-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol;
2-(1-(6-methoxyl group 2-naphthyl)-9 methyl-9H-pyridine [3,4-b] 3-indyl)-2-propyl alcohol;
((1-(2-naphthyl)-9H-pyridine [3,4-b] 3-Indoleacetic methyl esters;
(1-(9-phenanthryl)-9H-pyridine [3,4-b] 3-Indoleacetic methyl esters.
2. the isomers of compound claimed in claim 1 or officinal salt.
3. pharmaceutical composition, the mixing with pharmaceutical excipient as active component taking compound claimed in claim 1 or officinal saltCombination.
4. compound claimed in claim 1 or the officinal salt application in the medicine of preparation treatment and prevention tumor disease.
5. the application of the pharmaceutical composition described in claim 3 in the medicine of preparation treatment and prevention tumor disease.
CN201310139090.8A 2013-04-20 2013-04-20 Beta-carboline derivatives or officinal salt, its preparation method and antineoplastic application thereof Expired - Fee Related CN103214486B (en)

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