CN101591226B - 1,3-diarylpropane derivatives and application thereof - Google Patents

1,3-diarylpropane derivatives and application thereof Download PDF

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CN101591226B
CN101591226B CN200910012315.7A CN200910012315A CN101591226B CN 101591226 B CN101591226 B CN 101591226B CN 200910012315 A CN200910012315 A CN 200910012315A CN 101591226 B CN101591226 B CN 101591226B
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compound
acid
derivatives
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CN101591226A (en
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张为革
张良
马恩龙
吴岚
包凯
沈杞容
康健
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Shenyang Pharmaceutical University
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Abstract

The invention belongs to the technical field of medicaments, and relates to 1,3-diarylpropane derivatives, a preparation method and application thereof. A structure of the derivatives is shown in (I), wherein R1, R2, R3, R4, R5, R6, R7 and R8 are independently hydrogen, methoxy, hydroxy, and amino respectively; or two adjacent substituents are -OCH2O-, thereby forming a five-membered ring; or two adjacent substituents are -CH=CH-CH=CH-, thereby forming a six-membered ring; and R9, R10 and R11 are the hydrogen, and C1, C2, C3, C4, C5 and C6 are alkyl. The invention also provides pharmaceutically acceptable nontoxic salts formed by the derivatives shown in the structural formula and hydrates thereof, wherein the pharmaceutically acceptable nontoxic salts comprise salts formed by the derivatives and acids. Pharmacological activity experiment results show that the derivatives have better tumor inhibition activity, and can be used for the application of a tumor cell proliferation inhibitor in preparing antitumor medicaments.

Description

1,3-diaryl propane analog derivative and uses thereof
Technical field
The invention belongs to medical technical field, relate to a kind of 1,3-diaryl propane analog derivative and uses thereof, exactly, relate to this compounds and as tumor cell proliferation inhibitor in the application of preparing aspect anti-tumor drug.
Background technology
Malignant tumour is the serious disease that threatens human health and life, is the first lethal cause of disease in China.Find and find that treatment and the new drug of prophylaxis of tumours are the current key subjects that face.
Combretastatin A-4 (CA-4) separates the cis-stilbene class natural product obtaining from the willow of South Africa, and its chemical name is (Z)-2-methoxyl group-5-(3,4,5-trimethoxy styryl) phenol.CA-4 is tubulin polymerization inhibitor, presents very strong inhibition tumor cell proliferation activity, and its prodrug CA-4 phosphoric acid salt (CA-4P) enters the clinical study stage three phases in the U.S..Existing a large amount of report of research of designing, synthesizing new active compound for anti tumor for lead compound with CA-4, one class research concentrates on the variation that connects two phenyl ring key bridges, or former sub-connection or three former sub-connections, wherein can to form aromatic ring can be also three atom alkyl carbochains to three former sub-connections, but the most shortcomings such as active not high enough or synthetic more complicated that exist of the CA-4 analogue of synthesized.Relevant report is referring to Pettit G.R., et al.Experientia, 1989,45,209; Hamel E, et al.J.Med.Chem., 1992,35,1058; Nam N.H.Curr.Med.Chem., 2003,10,1697; Tron G.C., et al.J.Med.Chem., 2006,49,3033.
Contriver found that an easy route can high yield synthetic 1,3-diaryl propane analog derivative, and constitutional features based on Combretastatin A-4, design and synthesize 1,3-diaryl propane analog derivative, better active, can be for antitumor activity.
Summary of the invention
The object of the invention is to design, synthetic there is 1 of good anti-tumor activity, 3-diaryl propane analog derivative, prepared compound manifests good result in anti-tumor activity test in vitro.
Target product of the present invention can represent with following structural formula:
R 1～R 8be hydrogen, methoxyl group, hydroxyl, amino independently of one another, or two adjacent substituting groups are-OCH 2thereby O-forms five-ring, thereby or two adjacent substituting groups be-CH=CH-CH=CH-forms six-ring, R 9～R 11for hydrogen, C 1～C 6alkyl;
Its precondition is:
R 1～R 10when different, be hydrogen;
If R 1～R 3be all methoxyl group, R 4～R 11when different, be hydrogen;
If R 1～R 3be all methoxyl group, R 6for hydroxyl, R 4, R 5, R 7～R 11when different, be hydrogen;
If R 1～R 3, R 6be all methoxyl group, R 4, R 5, R 7～R 11when different, be hydrogen;
If R 1～R 3, R 6be all methoxyl group, R 5for hydroxyl, R 4, R 7～R 11when different, be hydrogen;
If R 1～R 3, R 6be all methoxyl group, R 7for hydroxyl, R 4, R 5, R 8～R 11when different, be hydrogen;
If R 1～R 3, R 5be all methoxyl group, R 6for isopropoxy, R 4, R 7～R 11when different, be hydrogen;
If R 1～R 3, R 7be all methoxyl group, R 6for isopropoxy, R 4, R 5, R 8～R 11when different, be hydrogen;
If R 1～R 3, R 8be all methoxyl group, R 5, R 6for-OCH 2o-forms five-ring, R 4, R 7, R 9～R 11when different, be hydrogen;
If R 1～R 3, R 5, R 6be all methoxyl group, R 4, R 7～R 11when different, be hydrogen;
If R 1～R 3, R 6, R 7be all methoxyl group, R 4, R 5, R 8～R 11when different, be hydrogen;
If R 1～R 3, R 5be all methoxyl group, R 6for hydroxyl, R 4, R 7～R 11when different, be hydrogen;
If R 1～R 3, R 7be all methoxyl group, R 6for hydroxyl, R 4, R 5, R 8～R 11when different, be hydrogen;
If R 2～R 4, R 8be all methoxyl group, R 1, R 5～R 7, R 9～R 11when different, be hydrogen;
If R 5～R 7be all methoxyl group, R 1～R 4, R 8～R 11when different, be hydrogen;
If R 5～R 7be all methoxyl group, R 2for hydroxyl, R 1, R 3, R 4, R 8～R 11when different, be hydrogen;
If R 2, R 5～R 7be all methoxyl group, R 1, R 3, R 4, R 8～R 11when different, be hydrogen;
If R 2, R 5～R 7be all methoxyl group, R 1for hydroxyl, R 3, R 4, R 8～R 11when different, be hydrogen;
If R 2, R 5～R 7be all methoxyl group, R 3for hydroxyl, R 1, R 4, R 8～R 11when different, be hydrogen;
If R 1, R 5～R 7be all methoxyl group, R 2for isopropoxy, R 3, R 4, R 8～R 11when different, be hydrogen;
If R 3, R 5～R 7be all methoxyl group, R 2for isopropoxy, R 1, R 4, R 8～R 11when different, be hydrogen;
If R 4, R 5～R 7be all methoxyl group, R 1, R 2for-OCH 2o-forms five-ring, R 3, R 8～R 11when different, be hydrogen;
If R 1, R 2, R 5～R 7be all methoxyl group, R 3, R 4, R 8～R 11when different, be hydrogen;
If R 2, R 3, R 5～R 7be all methoxyl group, R 1, R 4, R 8～R 11when different, be hydrogen;
If R 1, R 5～R 7be all methoxyl group, R 2for hydroxyl, R 3, R 4, R 8～R 11when different, be hydrogen;
If R 3, R 5～R 7be all methoxyl group, R 2for hydroxyl, R 1, R 4, R 8～R 11when different, be hydrogen;
If R 4, R 6～R 8be all methoxyl group, R 1～R 3, R 5, R 9～R 11when different, be hydrogen.
Compound of the present invention also comprises pharmaceutically acceptable non-toxic salt and the hydrate thereof that shown in said structure formula, derivative forms, and these pharmaceutically acceptable non-toxic salt comprise the salt that this derivative and acid form.Described acid can be the mineral acid of hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid or the organic acid that is selected from acetic acid, citric acid, oxalic acid, tartrate, phenylformic acid, oxysuccinic acid.The hydration number of described hydrate is any real number in 0～16.
Its representational example of compound of the present invention can be following compound:
Compound 1-1
Figure G2009100123157D00031
Compound 1-2
Figure G2009100123157D00032
Compound 1-3
Figure G2009100123157D00033
Compound 1-4
Figure G2009100123157D00034
Compound 1-5
Figure G2009100123157D00035
Compound 1-6
Figure G2009100123157D00036
Compound 1-7
Figure G2009100123157D00037
Compound 2-1
Compound 2-2
Figure G2009100123157D00042
Compound 2-3
Compound 2-4
Figure G2009100123157D00044
Compound 2-5
Figure G2009100123157D00045
Compound 2-6
Compound 3-1
Figure G2009100123157D00047
Compound 3-2
Figure G2009100123157D00048
Compound 3-3
Figure G2009100123157D00051
Compound 3-4
Figure G2009100123157D00052
Compound 3-5
Figure G2009100123157D00053
Compound 3-6
Figure G2009100123157D00054
Compound 4-1
Figure G2009100123157D00055
Compound 4-2
Figure G2009100123157D00056
Compound 4-3
Figure G2009100123157D00057
The present invention also provides the preparation method of this compounds, of the present invention 1, and 3-diaryl propane analog derivative (1) can obtain according to following reaction scheme is synthetic:
Route A:
Figure G2009100123157D00061
By cinnamophenone material dissolution in glacial acetic acid, the 10% palladium carbon that adds 0.6 equivalent, at 20-30 ℃, ultrasonic reaction is about 2 hours, after completion of the reaction, remove by filter palladium carbon, add water, be extracted with ethyl acetate, organic layer washs with saturated sodium-chloride water solution, separate organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, remove under reduced pressure after solvent, obtain product through column chromatography for separation, yield 72-94%;
Wherein, R 1～R 8for 1 of amino, 3-diaryl propane analog derivative can be by corresponding R 1～R 8for the cinnamophenone preparation of nitro;
Route B:
Figure G2009100123157D00062
By cinnamophenone material dissolution in glacial acetic acid, add 0.6 equivalent 10% palladium carbon, at 20-30 ℃, ultrasonic reaction is about 2 hours, after completion of the reaction, remove by filter palladium carbon, add water, be extracted with ethyl acetate, organic layer washs with saturated sodium-chloride water solution, separate organic layer and with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, remove under reduced pressure after solvent, obtain product through column chromatography for separation, yield 72-94%;
Wherein, R 1～R 8for 1 of amino, 3-diaryl propane analog derivative can be by corresponding R 1～R 8for the cinnamophenone preparation of nitro;
Provided by the present invention 1,3-diaryl propane analog derivative preparation method simple possible, yield is higher.
The present invention further provides the application of above-claimed cpd in the medicine of preparation treatment tumor disease.
Synthesis technique of the present invention is simple, gained 1, and 3-diaryl propane analog derivative yield is high, and has the effect of good treatment tumor disease, has good development prospect preparing in antitumor drug.
Embodiment
To contribute to understand the present invention by following example, but content of the present invention is not limited to example.
Agents useful for same of the present invention is commercially available, nuclear magnetic resonance spectrum is measured by AVANCE-400, Bruker ARX-300 fourier transform NMR spectrometer, mass spectrum is measured by Brukee Esqure 2000, ShimadzuGCMS-QP5050A type mass spectrograph, melting point apparatus adopts Tyke, Beijing X-4 type micro-meldometer, and temperature is not proofreaied and correct.
The preparation of embodiment 1:1-(3-hydroxyl-4-p-methoxy-phenyl)-3-(2,3,4-trimethoxyphenyl)-propane (compound 1-1)
By 3 '-hydroxyl-2,3,4,4 '-tetramethoxy cinnamophenone (0.66g, 2mmol) be dissolved in glacial acetic acid (10mL), add the palladium carbon (0.40g) of raw material 10%, ultrasonic reaction 2 hours under normal pressure atmosphere of hydrogen in 400W ultrasonic apparatus, temperature is controlled at 20-30 ℃.After completion of the reaction, filter, add water in filtrate, with ethyl acetate extraction, organic layer washs with saturated sodium-chloride water solution, separates organic layer and uses anhydrous sodium sulfate drying.Remove under reduced pressure after solvent, obtain crude product.Obtain product 1-1 through column chromatography for separation, yield is 84%.The structural formula of compound 1-1, fusing point and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 2:1-(3-amido-4-p-methoxy-phenyl)-3-(2,3,4-trimethoxyphenyl)-propane (compound 1-2)
Except using corresponding raw material, prepare compound 1-2 with the identical method of embodiment 1, yield is 76%; The structural formula of compound 1-2 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 3:1-(4-p-methoxy-phenyl)-3-(2,3,4-trimethoxyphenyl)-propane (compound 1-3)
Except using corresponding raw material, prepare compound 1-3 with the identical method of embodiment 1, yield is 82%; The structural formula of compound 1-3 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 4:1-(3,4,5-trimethoxyphenyl)-3-(2,3,4-trimethoxyphenyl)-propane (compound 1-4)
Except using corresponding raw material, prepare compound 1-4 with the identical method of embodiment 1, yield is 94%; The structural formula of compound 1-4 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 5:1-(3-methoxyl group-4-hydroxy phenyl)-3-(2,3,4-trimethoxyphenyl)-propane (compound 1-5)
Except using corresponding raw material, prepare compound 1-5 with the identical method of embodiment 1, yield is 78%; The structural formula of compound 1-5 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 6:1-(2-naphthyl)-3-(2,3,4-trimethoxyphenyl)-propane (compound 1-5)
Except using corresponding raw material, prepare compound 1-6 with the identical method of embodiment 1, yield is 89%; The structural formula of compound 1-6 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 7:1-(2,3-dihydroxyl-4-p-methoxy-phenyl)-3-(2,3,4-trimethoxyphenyl)-propane (compound 1-5)
Except using corresponding raw material, prepare compound 1-7 with the identical method of embodiment 1, yield is 72%; The structural formula of compound 1-7 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 8:1-(3-hydroxyl-4-p-methoxy-phenyl)-3-(2,3,4-trimethoxyphenyl)-2-methyl-propane (compound 2-1)
Except using corresponding raw material, prepare compound 2-1 with the identical method of embodiment 1, yield is 75%; The structural formula of compound 2-1 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 9:1-(3-amido-4-p-methoxy-phenyl)-3-(2,3,4-trimethoxyphenyl)-2-methyl-propane (compound 2-2)
Except using corresponding raw material, prepare compound 2-2 with the identical method of embodiment 1, yield is 76%; The structural formula of compound 2-2 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 10:1-(4-p-methoxy-phenyl)-3-(2,3,4-trimethoxyphenyl)-2-methyl-propane (compound 2-3)
Except using corresponding raw material, prepare compound 2-3 with the identical method of embodiment 1, yield is 87%; The structural formula of compound 2-3 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 11:1-(3,4,5-trimethoxyphenyl)-3-(2,3,4-trimethoxyphenyl)-2-methyl-propane (compound 2-4)
Except using corresponding raw material, prepare compound 2-4 with the identical method of embodiment 1, yield is 78%; The structural formula of compound 2-4 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 12:1-(2-naphthyl)-3-(2,3,4-trimethoxyphenyl)-2-methyl-propane (compound 2-5)
Except using corresponding raw material, prepare compound 2-5 with the identical method of embodiment 1, yield is 80%; The structural formula of compound 2-5 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 13:1-phenyl-3-(2,3,4-trimethoxyphenyl)-2-methyl-propane (compound 2-6)
Except using corresponding raw material, prepare compound 2-6 with the identical method of embodiment 1, yield is 81%; The structural formula of compound 2-6 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 14:1-(3-amido-4-p-methoxy-phenyl)-3-(3,4,5-trimethoxyphenyl)-propane (compound 3-1)
Except using corresponding raw material, prepare compound 3-1 with the identical method of embodiment 1, yield is 74%; The structural formula of compound 3-1 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 15:1-(2-naphthyl)-3-(3,4,5-trimethoxyphenyl)-propane (compound 3-2)
Except using corresponding raw material, prepare compound 3-2 with the identical method of embodiment 1, yield is 83%; The structural formula of compound 3-2 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 16:1-(2-hydroxyl-3,4-Dimethoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-propane (compound 3-3)
Except using corresponding raw material, prepare compound 3-3 with the identical method of embodiment 1, yield is 79%; The structural formula of compound 3-3 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 17:1-(2,3-dihydroxyl-4-p-methoxy-phenyl)-3-(3,4,5-trimethoxyphenyl)-propane (compound 3-4)
Except using corresponding raw material, prepare compound 3-4 with the identical method of embodiment 1, yield is 74%; The structural formula of compound 3-4 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 18:1-(3,4,5-trimethoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-propane (compound 3-5)
Except using corresponding raw material, prepare compound 3-5 with the identical method of embodiment 1, yield is 87%; The structural formula of compound 3-5 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 19:1-(3,4,5-trimethoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-1-methyl-propane (compound 3-6)
Except using corresponding raw material, prepare compound 3-6 with the identical method of embodiment 1, yield is 92%; The structural formula of compound 3-6 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 20:1-(3-hydroxyl-4-p-methoxy-phenyl)-3-(2-hydroxyl-3,4 methylenedioxy group phenyl)-propane (compound 4-1)
Except using corresponding raw material, prepare compound 4-1 with the identical method of embodiment 1, yield is 83%; The structural formula of compound 4-1 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 21:1-(3-amido-4-p-methoxy-phenyl)-3-(2-hydroxyl-3,4 methylenedioxy group phenyl)-propane (compound 4-2)
Except using corresponding raw material, prepare compound 4-2 with the identical method of embodiment 1, yield is 72%; The structural formula of compound 4-2 and 1h-NMR and MS data are listed in the table below in 1.
The preparation of embodiment 22:1-(4-p-methoxy-phenyl)-3-(2-hydroxyl-3,4 Dimethoxyphenyls)-propane (compound 4-3)
Except using corresponding raw material, prepare compound 4-3 with the identical method of embodiment 1, yield is 77%; The structural formula of compound 4-3 and 1h-NMR and MS data are listed in the table below in 1.
Table 1
Figure G2009100123157D00091
Figure G2009100123157D00101
Figure G2009100123157D00111
Embodiment 22: the pharmacologically active test of compound of the present invention
1. external activity testing method and result are as follows: wherein, and the positive control experiment group of clinical conventional antitumor drug cis-platinum.
Anti-tumor activity body outer screening test 1
Screening method: tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell strain: human leukemia cell line K562 cell line
Action time: 72h
Half-inhibition concentration (the IC of each compound to tumor growth 50, μ M) and in table 2.
Anti-tumor activity body outer screening test 2
Screening method: tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell strain: human lung adenocarcinoma cell line Anip 973 cell line
Action time: 72h
Half-inhibition concentration (the IC of each compound to tumor growth 50, μ M) and in table 2.
Anti-tumor activity body outer screening test 3
Screening method: tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell strain: human hepatoma cell strain Bel7402 cell line
Action time: 72h
Half-inhibition concentration (the IC of each compound to tumor cell proliferation 50, μ M) and in table 2.
Table 2
Figure G2009100123157D00121
2. activity in vivo testing method and result are as follows:
Select the good compound 1-2 of external activity and 3-1 to carry out anti-tumor activity test in animal body, model used is little s-180 sarcoma model, and positive control medicine is clinical conventional antitumor drug 5 FU 5 fluorouracil.
Experimental technique: select the S-180 knurl kind of 18-22 gram of female kunming mice and well-grown 7-11 days, tumor tissue is made to cell suspension, be seeded to right side of mice armpit subcutaneous, about 1.0-2.0 × 10 6cell/only, inoculate random point cage after 24 hours, continuous 7 days of intraperitoneal injection.Within after drug withdrawal 24 hours, put to death animal, weigh, knurl weight, calculate each group of average knurl weight, obtain tumor control rate and carry out t check by following formula.
Tumor control rate=[(the average knurl weight of the average knurl weight-treatment group of blank group)/(the average knurl weight of blank group)] × 100%
Experimental result is in table 3.
Table 3
3. acute toxic test:
Have no dead by 200 milligrams/per kilogram dosage small white mouse.

Claims (7)

1. there is 1 of following structure, 3-diaryl propane analog derivative and salt thereof:
Compound 1-1
Figure 797985DEST_PATH_IMAGE001
Compound 1-2
Figure 715126DEST_PATH_IMAGE002
Compound 1-7
Figure 432546DEST_PATH_IMAGE003
Compound 2-1
Figure 827755DEST_PATH_IMAGE004
Compound 2-2
Figure 579811DEST_PATH_IMAGE005
Compound 2-3
Compound 3-1
Figure 606989DEST_PATH_IMAGE007
Compound 3-2
Figure 805890DEST_PATH_IMAGE008
Compound 3-3
Compound 3-4
Figure 405815DEST_PATH_IMAGE010
Compound 4-1
Figure 94898DEST_PATH_IMAGE011
Compound 4-2
Figure 831910DEST_PATH_IMAGE012
Or compound 4-3
。
2. according to claim 11,3-diaryl propane analog derivative and salt thereof, is characterized in that: the described salt salt that to be this derivative form with acid.
3. according to claim 21,3-diaryl propane analog derivative and salt thereof, is characterized in that: wherein said acid is selected from the mineral acid of hydrochloric acid, sulfuric acid, Hydrogen bromide or phosphoric acid or is selected from the organic acid of acetic acid, citric acid, oxalic acid, tartrate, phenylformic acid or oxysuccinic acid.
4. claim 1-3 1 described in any one, 3-diaryl propane analog derivative and salt thereof are in the application of preparing in antitumor drug, and described tumour is leukemia, adenocarcinoma of lung or liver cancer.
5. the compound with following structure is treated the application in leukemia or liver-cancer medicine in preparation:
Compound 1-3 compound 1-6
Figure 722823DEST_PATH_IMAGE014
Figure 964448DEST_PATH_IMAGE015
Compound 2-6 or compound 3-6
Figure 177255DEST_PATH_IMAGE016
Figure 758409DEST_PATH_IMAGE017
。
6. the compound with following structure is in the application of preparing in Hepatoma therapy medicine:
Compound 2-5 or compound 3-5
。
7. the compound with following structure is treated the application in adenocarcinoma of lung or liver-cancer medicine in preparation:
Compound 2-4
Figure 714360DEST_PATH_IMAGE020
。
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CN102115429B (en) * 2010-01-06 2013-02-27 中国科学院上海药物研究所 (E)-1-(3,5-dimethoxyphenyl)-2-(3,5-dihydroxy-4-methoxyphenyl)ethylene, and preparation method and application thereof
CN102399137B (en) * 2011-07-29 2014-07-16 北京中融阳光投资管理有限公司 1-substituted aryl-3-(3,4,5-trimethoxyphenyl)-1,2-propanedione compound and derivative thereof
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CN110105323B (en) * 2019-04-28 2021-12-03 云南中医学院 Diaryl propane dimer derivative, pharmaceutical composition and application thereof
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