CN102503888A - 2-aryl-1,3-isoquinoline diketone anti-tumor compound and synthesis method and application thereof - Google Patents
2-aryl-1,3-isoquinoline diketone anti-tumor compound and synthesis method and application thereof Download PDFInfo
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Abstract
The invention relates to 2-aryl-1,3-isoquinoline diketone anti-tumor compound and a synthesis method and application thereof. The 2-aryl-1,3-isoquinoline diketone anti-tumor compound has the chemical structural formula I and the chemical structural formula II, wherein R represents the hydrogen, the hydroxy or the methoxyl, and Ar is phenyl, one or more of the halogen-atom substituted phenyl, the trifluoromethylphenyl, the 3-acetylenyl phenyl, the 6-benzothiazolyl, the 2-acetylamino pyridine and the like. The 2-aryl-1,3-isoquinoline diketone anti-tumor compound has a novel structure, and the synthesis method of the 2-aryl-1,3-isoquinoline diketone anti-tumor compound is easy to implement. The antiproliferative activity assay shows that most compounds have significant functions of inhibiting the growth of human prostate cancer cells PC3 and human kidney cancer cells 786-0, and the in vivo anti-S180 tumor activity test shows that the activity of the compound 21 is significantly stronger than that of Gefitinib.
Description
Technical field
The invention belongs to field of antineoplastic medicaments, relate to a kind of antineoplastic compound, particularly one type of 2-aryl-1,3-isoquinoline 99.9 two ketones have the compound of anti-tumor activity, the purposes of compound method and preparation anti-tumor medicinal preparation thereof.
Background technology
Malignant tumour serious threat human health.Over nearly 20 years, the M & M of China's malignant tumour constantly rises, and tumor incidence is about 2,00/,100,000 people, and annual new cases reach more than 2,200,000 people, is controlling more than patient 6,000,000 people.
The tumor treatment means remain conventional surgical treatment, radiotherapy and pharmacological agent at present, are main but be still to a great extent with pharmacological agent.Therefore, the new antitumor drug of research and development is significant.
Antitumor drug can roughly be divided three classes according to action principle: (1) directly acts on DNA, destroys the medicine of its 26S Proteasome Structure and Function; (2) disturb DNA and nucleic acid synthetic medicine; (3) influence the medicine of protein synthesis.
In recent years; Along with the oncomolecularbiology progress of research; Tumor invasion mechanism there has been more understanding; Found the novel targets of many antitumor drug effects, made the development of antitumor drug obtain many new achievements, like topoisomerase enzyme inhibitor, anti-microtubule medicine, protein tyrosine kinase inhibitor etc.
In the most tumors cell, protein tyrosine kinase presents high expression level.To these characteristics, developed ZD1939, imatinib, dust Lip river small molecules antitumor drug for targeting proteins Tyrosylprotein kinases such as Buddhist nun, Xarelto, Sutent and lapatinibditosylates.These medicinal applications are in clinical treatment tumour, and some clinical effective rate is not high, and some has also produced resistance.Need the new antitumor drug of development.
Adopt the method for SARS drug design; The 2-aryl-1 that the present invention designs and synthesizes; 3 (2H, 4H)-the isoquinoline 99.9 cyclohexadione compounds has identical pharmacophore with 4-aryl amine quinazoline ditosylate salt tyrosine kinase inhibitor (ZD1939 etc.), thereby has anti-tumor activity.
Summary of the invention
The objective of the invention is to overcome the shortcoming of above-mentioned prior art; A kind of 2-aryl-1 is provided; 3-isoquinoline 99.9 diketone anti-tumor compounds and preparation method and use thereof; Such compound structure is novel, simple, compound method realizes easily, and its biological activity test can grow with human renal carcinoma cell 786-0 to Human Prostate Cancer Cells PC3 restraining effect arranged, and its effect is superior to or approaches ZD1939.The anti-tumor in vivo activity test shows that the activity of compound 21 obviously is better than ZD1939.
The objective of the invention is to solve through following technical scheme:
Such 2-aryl-1, the chemical structural formula of 3-isoquinoline 99.9 diketone anti-tumor compounds is following:
Structural formula I
Among the structural formula I: R representes hydrogen, hydroxyl or methoxyl group; Ar is phenyl, the substituted phenyl of one or more halogen atom, 3-trifluoromethyl, 3-ethynyl phenyl, the substituted phenyl of 3-substituted amido formyl radical, 3-pyridyl or 6-benzothiazolyl etc.
The further prioritization scheme of the present invention has: in said structure formula I, R is 6,8-dimethoxy, 6-methoxyl group-8-hydroxyl or 6-methoxyl group.
The present invention also proposes a kind of above-mentioned compound method with compound of anti-tumor activity, and this compound method refluxes synthetic in the acetic acid organic solvent with substituted high Tetra hydro Phthalic anhydride and substituted aromatic amine.
Further, above-mentioned compound method, specifically synthetic according to following steps:
Above building-up process is under nitrogen protection, and high Tetra hydro Phthalic anhydride class and substituted aromatic amine reflux to synthesize in acetic acid and have the compound shown in the structural formula I; Wherein, the volume of the acetic acid of 1 mole high Tetra hydro Phthalic anhydride adding is 1L-5L; The mol ratio of high Tetra hydro Phthalic anhydride and substituted aromatic amine is 1: 1.
In addition, the present invention also proposes a kind of above-mentioned application of compound in the preparation anti-tumor medicinal preparation with anti-tumor activity.
The present invention has following beneficial effect:
(1) compound in structural formula I that has that proposes of the present invention has antitumor action, and its novel structure, compound method are realized easily.The antitumor cell activity test shows that the compound shown in the structural formula I all has a significant restrained action to Human Prostate Cancer Cells PC3 and human renal carcinoma cell 786-0, and the activity of most compounds approaches or be better than ZD1939.The anti-tumor in vivo activity test shows that the activity of compound 21 obviously is better than ZD1939.
(2) the present invention provides has the activity that compound in structural formula I has the obvious suppression tumor cell proliferation, and wherein the activity of part of compounds is superior to the marketed drug ZD1939.And the compound in structural formula I that has that the present invention provides can be used in the preparation anti-tumor medicinal preparation, when pharmaceutical formulations, can process various ways such as tablet, capsule, soft capsule or injection, and is very easy to use.
Embodiment
It is following that the present invention proposes the chemical structural formula of one type of compound with anti-tumor activity:
Structural formula I
Among the structural formula I: R representes hydrogen, hydroxyl or methoxyl group (as 6,8-dimethoxy, 6-methoxyl group-8-hydroxyl or 6-methoxyl group); Ar is phenyl, the substituted phenyl of one or more halogen atom, 3-trifluoromethyl, 3-ethynyl phenyl, the substituted phenyl of 3-substituted amido formyl radical, 3-pyridyl or 6-benzothiazolyl.
In addition, the present invention also proposes a kind of above-mentioned compound method with compound of anti-tumor activity, and this compound method is to reflux in the acetic acid organic solvent with substituted high Tetra hydro Phthalic anhydride and substituted aromatic amine to synthesize.Its concrete compound method is carried out according to following steps:
Under nitrogen protection, high Tetra hydro Phthalic anhydride class and substituted aromatic amine reflux to synthesize in acetic acid and have the compound shown in the structural formula I in above building-up process, and wherein, the volume of the acetic acid of 1 mole high Tetra hydro Phthalic anhydride adding is 1L-5L; The mol ratio of high Tetra hydro Phthalic anhydride and substituted aromatic amine is 1: 1.
Below be representative compound numbering, structure and MS, like table 1 with structural formula I.
Some representative compound numberings of table 1., structure and MS data
The compound in structural formula I that has that above the present invention provides can be used in the preparation anti-tumor medicinal preparation, wherein every or this pharmaceutical prepn in contain the compound in structural formula I that has of 10-500mg.And, when the active compound that utilizes the present invention to provide prepares anti-tumor medicinal preparation, can this medicine be processed tablet, capsule, soft capsule or injection.These pharmaceutical prepns can be processed according to the conventional preparation technology of various preparations.For tablet or capsule, preferred content is 50-150mg.And can contain pharmaceutical excipient in the oral prepns that the present invention relates to; Comprise additive, stablizer, solubilizing agent, lubricant, disintegrating agent etc., like starch, dextrin, glucose, lactose, Mierocrystalline cellulose, Vinylpyrrolidone polymer, cross-linked polyvinylpyrrolidone, pectin, Schardinger dextrins, soil temperature-80, Z 150PH, Magnesium Stearate, talcum powder etc.
Below in conjunction with embodiment the present invention is explained further details:
Embodiment 1
6,8-dimethoxy-2-phenyl-1, the preparation of 3-isoquinoline 99.9 diketone (1):
3, the high Tetra hydro Phthalic anhydride of 5-dimethoxy (reference J.Org.Chem.2003,68; The 5967-5973 preparation) 2.42g (10.89mmol), aniline 1.01g (10.89mmol) and glacial acetic acid (20mL) add in the 100mL round-bottomed flask, and mixture is stirring and refluxing 5h under nitrogen protection; Cool to room temperature; Slowly pour in the water hold over night, suction filtration into.Bullion is used recrystallizing methanol, gets product 1.70g.Yield 52.6%.mp：190-192℃。
Embodiment 2
6,8-one methoxyl group-2-(4-aminomethyl phenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (2):
With embodiment 1, difference is: replace aniline with the 4-monomethylaniline.Yield 64.8%.mp：160-163℃。
Embodiment 3
6,8-dimethoxy-2-(4-p-methoxy-phenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (3):
With embodiment 1, difference is: replace aniline with the 4-anisidine.Yield 84.8%.mp：211-213℃。
Embodiment 4
6,8-dimethoxy-2-(2-methyl 3-chloro-phenyl-)-1, the preparation of 3-isoquinoline 99.9 diketone (4):
With embodiment 1, difference is: replace aniline with 2-methyl-3-chloroaniline.Yield 52.2%.mp：163-167℃。
Embodiment 5
6,8-dimethoxy-2-(3-trifluoromethyl)-1, the preparation of 3-isoquinoline 99.9 diketone (5):
With embodiment 1, difference is: replace aniline with the 3-5-trifluoromethylaniline.Yield 36.5%.mp：175-176℃。
Embodiment 6
6,8-dimethoxy-2-(4-trifluoromethyl)-1, the preparation of 3-isoquinoline 99.9 diketone (6):
With embodiment 1, difference is: replace aniline with the 4-5-trifluoromethylaniline.Yield 54.8%.mp：183-185℃。
Embodiment 7
6,8-dimethoxy-2-(3, the 5-Dimethoxyphenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (7):
With embodiment 1, difference is: with 3, the 5-dimethoxyaniline replaces aniline.Yield 59.0%.mp：179-181℃。
Embodiment 8
6,8-dimethoxy-2-(2-methoxyl group-5-methoxycarbonyl phenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (8):
With embodiment 1, difference is: replace aniline with 2-methoxyl group-5-methoxycarbonyl aniline.Yield 57.7%.mp：168-170℃。
Embodiment 9
6,8-dimethoxy-2-(3, the 4-dichlorophenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (9):
With embodiment 1, difference is: with 3, the 4-dichlorphenamide bulk powder replaces aniline.Yield 60.7%.mp：211-213℃。
Embodiment 10
6,8-dimethoxy-2-(3-chloro-4-fluorophenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (10):
With embodiment 1, difference is: replace aniline with 3-chloro-4-fluoroaniline.Yield 63.6%.mp：189-191℃。
Embodiment 11
6,8-dimethoxy-2-(3-fluorophenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (11):
With embodiment 1, difference is: replace aniline with the 3-fluoroaniline.Yield 70.5%.mp：194-196℃。
Embodiment 12
6,8-dimethoxy-2-(2-fluorophenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (12):
With embodiment 1, difference is: replace aniline with the 2-fluoroaniline.Yield 46.9%.mp：189-191℃。
Embodiment 13
6,8-dimethoxy-2-(4-bromophenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (13):
With embodiment 1, difference is: replace aniline with the 4-bromaniline.Yield 70.9%.mp：197-199℃。
Embodiment 14
6,8-dimethoxy-2-(3, the 4-difluorophenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (14):
With embodiment 1, difference is: with 3, the 4-difluoroaniline replaces aniline.Yield 53.4%.mp：215-217℃。
Embodiment 15
6,8-dimethoxy-2-(3-ethynyl phenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (15):
With embodiment 1, difference is: replace aniline with 3-ethynyl aniline.Yield 70.2%.mp：197-199℃。
Embodiment 16
6-methoxyl group-8-hydroxyl-2-(3-ethynyl phenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (16):
Compound 15 (0.3g), the mixture of DMAC N,N (12mL) and lithium chloride (1.12g) stir 9h, removal of solvent under reduced pressure, residue acidifying, column chromatography separation (sherwood oil: ETHYLE ACETATE=5: 1), get product 30mg in 130 ℃ under nitrogen protection.Yield 10.3%.mp：197-199℃。
Embodiment 17
6-methoxyl group-2-(3-ethynyl phenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (17):
With embodiment 1, difference is: replace 3, the high Tetra hydro Phthalic anhydride of 5-dimethoxy with the high Tetra hydro Phthalic anhydride of 3-methoxyl group; Replace aniline with 3-ethynyl aniline.Yield 66.0%.mp：186-187℃。
Embodiment 18
6-methoxyl group-2-(3-chloro-4-fluorophenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (18):
With embodiment 17, difference is: replace 3-ethynyl aniline with 3-chloro-4-fluoroaniline.Yield 54.1%.mp：173-175℃。
Embodiment 19
6,8-dimethoxy-2-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl)-1, the preparation of 3-isoquinoline 99.9 diketone (19):
With embodiment 1, difference is: replace aniline with 2-acetylaminohydroxyphenylarsonic acid 6-aminobenzothiazole.Yield 49.8%.mp：243-245℃。
Embodiment 20
6,8-dimethoxy-2-(2-acetylaminohydroxyphenylarsonic acid 5-pyridyl)-1, the preparation of 3-isoquinoline 99.9 diketone (20):
With embodiment 1, difference is: replace aniline with 2-acetylaminohydroxyphenylarsonic acid 5-EL-970.Yield 75.1%.mp：255-257℃。
Embodiment 21
6,8-dimethoxy-2-(2-cyclopropyl formamido group-6-benzothiazolyl)-1, the preparation of 3-isoquinoline 99.9 diketone (21):
With embodiment 1, difference is: replace aniline with 2-cyclopropyl formamido group-6-aminobenzothiazole.Yield 75.2%.mp：252-254℃。
Embodiment 22
2-(3-ethynyl phenyl)-1, the preparation of 3-isoquinoline 99.9 diketone (22):
With embodiment 1, difference is: replace 3 with high Tetra hydro Phthalic anhydride, the high Tetra hydro Phthalic anhydride of 5-dimethoxy; Replace aniline with 3-ethynyl aniline.Yield 82.9%.mp：192-193℃。
Should be noted that, above embodiment be used for explanation of the present invention and and unrestricted the present invention.Although with preferred embodiment the present invention has been carried out detailed explanation, those of ordinary skill in the art should be appreciated that and under not departing from the scope of the present invention, can make amendment, be out of shape the present invention or be equal to replacement, all belongs to protection scope of the present invention.
In order to prove validity of the present invention, the applicant adopts external mtt assay to measure compound 1-22 to Human Prostate Cancer Cells PC3 with the positive control drug of ZD1939, and the growth-inhibiting effect of people's kidney cancer cells 786-0 is specific as follows said:
Method: PC3 or 786-0 cell cultures in the RPMI that contains 10% calf serum 1640 substratum, are included mould and have 100UmL
-1, Streptomycin sulphate 100 μ gmL
-1, in 37 ℃, 5%CO
2The cultivation of going down to posterity in the incubator.
Get the adherent tumour cell of 0.3% trysinization, contain the RPMI RPMI-1640 preparation cell suspension of 10% calf serum, concentration is 6 * 10
3Individual cell/mL.200 μ L (containing 1000 tumour cells approximately) are inoculated in every hole in 96 well culture plates, cultivate 24h for 37 ℃.The administration group adds different pharmaceutical, and every medicine final concentration is 1 μ mol/L, establishes 3 parallel holes for every group.Control group adds and the isopyknic solvent of administration group, places 37 ℃, 5%CO
2Discard nutrient solution after cultivating 48h in the incubator, every hole adds 20 μ l 5mgmL
-1MTT solution, hatch 4h after, abandoning supernatant, every hole adds DMSO 150 μ L, under 570nm, measures OD value (OD) with ELIASA behind the gentle agitation.Every medicine repeats said process once, calculates average inhibiting rate.The result sees following table 2:
Compound was to two kinds of tumor cell proliferation inhibition rates (%) when table 2. was 1 μ mol/L in concentration
(n=6, standard deviation is omitted)
In order to prove the anti-tumor activity with structural formula I compound that provides of the present invention, the applicant adopts Kunming kind lotus S180 knurl mouse, has observed the anti-tumor in vivo effect of compound 21.
Positive drug: ZD1939; Dosage 50mg/kg.
Receive reagent: compound 21; Dosage 5mg/kg.
Administering mode: irritate stomach.
Method: 30 of Kunming mouses, body weight 20-24 gram, male.Before right limb armpit subcutaneous vaccination S180 oncocyte diluent 0.2mL.Raised 4 days, and be divided into 3 groups immediately, i.e. solvent control group, ZD1939 positive drug 50mg/kg group is organized by reagent 5mg/kg.Group of solvents and positive drug group, administration every day 1 time; Receive the reagent group, the next day administration 1 time.The 12nd day, put to death mouse, peel off tumour, weigh, calculate inhibition rate of tumor growth.
Inhibiting rate (%)=(group of solvents tumor weight-administration group tumor weight) ÷ group of solvents tumor weight * 100%
The result: the inhibition rate of tumor growth of ZD1939 positive drug is 50.4%; The inhibition rate of tumor growth that receives reagent compound 21 is 56.8%.
Claims (5)
1. 2-aryl-1,3-isoquinoline 99.9 diketone anti-tumor compounds is characterized in that the chemical structural formula of this compounds is following:
Structural formula I
Among the structural formula I: R representes hydrogen, hydroxyl or methoxyl group; Ar representes phenyl, the substituted phenyl of one or more halogen atom, 3-trifluoromethyl, 3-ethynyl phenyl, the substituted phenyl of 3-substituted amido formyl radical, 3-pyridyl or 6-benzothiazolyl.
2. 2-aryl-1 according to claim 1,3-isoquinoline 99.9 diketone anti-tumor compounds is characterized in that said R is 6,8-dimethoxy, 6-methoxyl group-8-hydroxyl or 6-methoxyl group.
3. the said compound method with compound of anti-tumor activity of claim 1 is characterized in that, this compound method refluxes synthetic in the acetic acid organic solvent with substituted high Tetra hydro Phthalic anhydride and substituted aromatic amine.
4. compound method according to claim 3 is characterized in that, and is specifically synthetic according to following steps:
Under nitrogen protection, high Tetra hydro Phthalic anhydride and substituted aromatic amine reflux to synthesize in acetic acid and have the compound shown in the structural formula I;
Wherein, the volume of the acetic acid of 1 mole high Tetra hydro Phthalic anhydride adding is 1L-5L; The mol ratio of high Tetra hydro Phthalic anhydride and substituted aromatic amine is 1: 1.
5. said 2-aryl-1 of claim 1, the application of 3-isoquinoline 99.9 diketone anti-tumor compounds in the preparation anti-tumor medicinal preparation.
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| CN104693205A (en) * | 2014-12-12 | 2015-06-10 | 西安交通大学 | Total synthesis method of amides alkaloid |
| CN105153030A (en) * | 2015-10-14 | 2015-12-16 | 吉首大学 | Perfluoro group substituted isoquinoline-1,3(2H,4H)-diketone as well as preparation method and application thereof |
| CN105579447A (en) * | 2013-09-25 | 2016-05-11 | 豪夫迈·罗氏有限公司 | Ethynyl derivatives |
| CN107805220A (en) * | 2017-10-24 | 2018-03-16 | 贵州医科大学 | The preparation method of 4 aryl isoquinolines 1,3 (2H, 4H) cyclohexadione compounds |
| CN110408011A (en) * | 2019-08-23 | 2019-11-05 | 中国科学院化学研究所 | A kind of two isoquinolin of second y-bend, four ketone polymer and the preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105579447A (en) * | 2013-09-25 | 2016-05-11 | 豪夫迈·罗氏有限公司 | Ethynyl derivatives |
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| CN110408011A (en) * | 2019-08-23 | 2019-11-05 | 中国科学院化学研究所 | A kind of two isoquinolin of second y-bend, four ketone polymer and the preparation method and application thereof |
| CN110408011B (en) * | 2019-08-23 | 2021-08-24 | 中国科学院化学研究所 | Binary diisoquinoline tetrone polymer and preparation method and application thereof |
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Application publication date: 20120620 |