CN102603619B - Compound with anticancer activity and preparation method thereof - Google Patents
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- DZUHNDQVGDSOQC-FNLZXBKISA-N Cc1ccc(CC(N[C@H](Cc2c[nH]c3ccccc23)C(N/N=C/c2ncccc2)=O)=O)cc1 Chemical compound Cc1ccc(CC(N[C@H](Cc2c[nH]c3ccccc23)C(N/N=C/c2ncccc2)=O)=O)cc1 DZUHNDQVGDSOQC-FNLZXBKISA-N 0.000 description 1
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Abstract
The invention discloses a compound with anticancer activity and a preparation method of the compound, wherein the compound with anticancer activity provided by the invention is selected from 2-(4-substituted phenyl) acetamido propyl acylhydrazone derivatives or 2-(4-substituted phenyl) acetamido propanamide derivatives. The compound provided by the invention has a good inhibitory activity on human non-small cell lung cancer cells A-549, human breast cancer cells MDA-MB-435 and human liver cancer cells HuH-7. The preparation method provided by the invention has the characteristics of simple synthetic route, mild reaction condition and high yield, and is suitable for industrial production.
Description
One, technical field
The present invention relates to a kind of medical compounds and preparation method thereof, exactly is a kind of compound with antitumour activity and preparation method thereof.
Two, background technology
Cancer threatens greatly human health and life security.Minister of Public Health Chen Zhu says, cancer has become first cause of the death of Chinese city and urban residents.China's cancer incidence is in the fast rise phase, annual pathogenesis of cancer number approximately 2,600,000, dead 1,800,000 people.The generation of cancer and development are extremely complicated processes, are subject to the impact of many factors.The aggravation of aging population, urbanization of villages and cities and towns process of industrialization, and human habitat pollution and destruction and the bad factors such as mode of life of people are that pathogenesis of cancer is the principal element that parabolic rises.Cancer patients's number of China will further increase along with the astogeny of population and urbanization.At present, the methods for the treatment of of cancer mainly is surgical treatment, radiotherapy and chemotherapy, and various treatment meanss all also exist some problems in actual applications.Searching has no side effect and efficient new type anticancer medicine is one of main task of pharmaceutical chemists.
Research is found, tumour and gastrin releasing peptide receptor (gastrin releasing peptide receptor, GRPR) in close relations, and all find the unconventionality expression of GRPR in the tumours such as colorectal carcinoma, cancer of the stomach, lung cancer, prostate cancer, mammary cancer, ovarian cancer, sealing GRPR signal path can effectively suppress the growth of tumour.
The GRPR inhibitor great majority of bibliographical information are the peptide class formations, are divided into six classes according to the mode of structural modification, 1. the Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 analogue; 2. [D-Phe
12] the bombesin analogue; 3. the analogue of the 26-27 of the 13-14 of bombesin or GRP being modified; 4. desMet14 or GRP27 analogue; 5. the class peptide comprises PD168368 and PD 176252; 6. non-peptide comprises kuwanon G and kuwanon H.
According to Terry W.Moody etc. (Bioorg.Med.Chem.Lett., 2003,474,21-29) report, class peptide GRPR inhibitor can suppress proliferation of lung cancer cells, wherein the IC of PD 176252 and 168368 pairs of Non-small cell lung carcinoma cells of PD NCI-H1299
50Value is respectively 5 and 30 μ M, and inhibition is better.PD 168368 and PD 176252 structural formulas are as follows:
PD 168368 PD 176252
Acylhydrazone is the schiff base compounds that is formed by hydrazides and aldehydes or ketones condensation, in its molecule owing to containing simultaneously Sauerstoffatom and nitrogen-atoms thereby can participate in the formation of hydrogen bond in the organism, increase the affinity between the acceptor, and then can suppress many plysiochemical processes in the organism, therefore be subject at aspects such as medicine, agricultural chemicals, material and analytical reagents paying close attention to widely.In recent years, the researchist finds, the multiple biological activitys such as that acylhydrazone has is antibiotic, anti-inflammatory and weeding, and some acylhydrazone also has antitumous effect.
2-(1H-imidazoles-1-yl) ethamine, be a kind of important pharmaceutical intermediate, as the Farnesyl protein transferase inhibitor that has the N-alkyl sulfamoyl class medicine that suppresses the gamma-secretase effect, has the nitrogenous fused heterocycle type of multiple pharmaceutical active and have an Antimalarial all contain this structure fragment.
Three, summary of the invention
The present invention aims to provide a kind of compound with antitumour activity and preparation method thereof, and the technical problem of required solution is to select this compound and confirm that it has anticancer activity.
The compound that the present invention selects is 2-(4-substituted-phenyl) acetamido propionyl hydrazone derivative and 2-(4-substituted-phenyl) acetamido propanamide derivative.
The present invention has the compound of antitumour activity, selects to be 2-(4-substituted-phenyl) acetamido propionyl hydrazone derivative, it is characterized in that its structure is represented by general formula (I):
R in the general formula (I)
1Be selected from-NO
2,-F or-CH
3
R
2Be selected from phenyl or 3-indyl;
R
3Be selected from
The present invention has the preparation method of anti-cancer active compound, the preparation, the isolation and purification that comprise intermediate, it is characterized in that: the preparation of described intermediate is that L-Phe or L-Trp made intermediate 1 in back flow reaction 5-6 hour in the methanol solution of sulfur oxychloride, and wherein the mol ratio of L-Phe or L-Trp and sulfur oxychloride is 1: 2; Substituted phenylacetic acid and oxalyl chloride are at CH
2Cl
2In obtained intermediate 2 in room temperature reaction 2-3 hour, wherein the mol ratio of substituted phenylacetic acid and oxalyl chloride is 1: 1.2; Subsequently intermediate 1 and intermediate 2 are placed CH
2Cl
2In obtained intermediate 3 in room temperature reaction 4-8 hour, wherein the mol ratio of intermediate 1 and intermediate 2 is 1: 1.2; Intermediate 3 and hydrazine hydrate obtained intermediate 4 in back flow reaction 6-9 hour in ethanolic soln, wherein the mol ratio of intermediate 3 and hydrazine hydrate is 1: 3; Last intermediate 4 and 2-pyridylaldehyde or paradimethy laminobenzaldehyde in ethanolic soln back flow reaction 2-3 hour, intermediate 4 is 1: 1.2 with the mol ratio of 2-pyridylaldehyde or paradimethy laminobenzaldehyde, filters, obtains target product after washing and the drying;
Described substituted phenylacetic acid is selected from paranitrophenylacetic acid, 4-fluorophenylacetic acid or 4-methylphenyl acetic acid.
The present invention has the compound of antitumour activity, selects the acetamido propanamide derivative into 2-(4-substituted-phenyl), it is characterized in that its structure is represented by general formula (II):
R in the general formula (II)
1Be selected from-NO
2,-F or-CH
3
R
2Be selected from phenyl or 3-indyl.
The present invention has the preparation method of the compound of antitumour activity, the preparation, the isolation and purification that comprise intermediate, it is characterized in that: the preparation of described intermediate is that L-Phe or L-Trp made intermediate 1 in back flow reaction 5-6 hour in the methanol solution of sulfur oxychloride, and wherein the mol ratio of L-Phe or L-Trp and sulfur oxychloride is 1: 2; Substituted phenylacetic acid and oxalyl chloride are at CH
2Cl
2In obtained intermediate 2 in room temperature reaction 2-3 hour, wherein the mol ratio of substituted phenylacetic acid and oxalyl chloride is 1: 1.2; Subsequently intermediate 1 and intermediate 2 are placed CH
2Cl
2In obtained intermediate 3 in room temperature reaction 4-8 hour, wherein the mol ratio of intermediate 1 and intermediate 2 is 1: 1.2; Intermediate 3 is at methyl alcohol, water and Na
2CO
3Mixing solutions under room temperature, obtained intermediate 5, wherein intermediate 3 and Na in hydrolysis reaction 6-10 hour
2CO
3Mol ratio be 1: 1.5, the volume ratio of first alcohol and water is about 4: 1; Intermediate 5 and 2-(1H-imidazoles-1-yl) ethamine generation amidate action, take carbonyl dimidazoles as condensing agent, the mol ratio of intermediate 5,2-(1H-imidazoles-1-yl) ethamine and carbonyl dimidazoles is 1: 1.2: 1.2, room temperature reaction 8-14 hour, namely get target product after the column chromatography for separation;
Described substituted phenylacetic acid is selected from paranitrophenylacetic acid, 4-fluorophenylacetic acid or 4-methylphenyl acetic acid.
Synthetic route of the present invention is as follows:
Compared with the prior art, beneficial effect of the present invention is embodied in:
1, synthetic route of the present invention is simple, and reaction conditions is gentle, and yield is higher, is easy to suitability for industrialized production;
2, the compounds of this invention has good inhibition active to Non-small cell lung carcinoma cell A-549, human breast cancer cell MDA-MB-435 and human liver cancer cell HuH-7.
Four, embodiment
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited to this:
Embodiment 1 2-(2-(4-nitrophenyl) kharophen)-3-phenyl-N '-(pyridine-2-methylene radical) propionyl hydrazine
Synthetic route:
1, the preparation of intermediate 1 (L-Phe methyl ester hydrochloride)
In anhydrous methanol (150mL), drip sulfur oxychloride (7.1mL under the ice bath, 100mmol), drip off rear stirring 1h, slowly add again L-Phe (8.26g, 50mmol), add rear back flow reaction 5h, solvent evaporated, add a small amount of dissolve with methanol, get the 9.60g white solid with the ether precipitating and be designated as intermediate 1, productive rate is 89.0%; Fusing point is 158-160 ℃ (literature value 158-161 ℃).
2, the preparation of intermediate 2 (4-oil of mirbane Acetyl Chloride 98Min.)
Add successively paranitrophenylacetic acid (3.26g, 18mmol), CH under the ice bath
2Cl
2(30mL) and triethylamine (TEA) (5.2mL, 36mmol), two dimethyl formamides (DMF), N
2Lower oxalyl chloride (1.84mL, 21.6mmol) and the CH of slowly dripping again of protection
2Cl
2Mixed solution (10mL) drips off the recession deicing and bathes, room temperature reaction 2h, and solvent evaporated and unreacted oxalyl chloride get the yellowish brown solid and are designated as intermediate 2, are directly used in the next step.
3, the preparation of intermediate 3 ((R)-2-(2-(4-oil of mirbane) acetamido)-3-phenylpropionic acid methyl esters)
The intermediate 2 and the CH that add successively new system under the ice bath
2Cl
2(20mL), slowly drip CH
2Cl
2(5mL), the mixture of intermediate 1 (3.24g, 15mmol) and TEA (2.17mL, 15mmol), room temperature reaction 5h, column chromatography for separation (V
Sherwood oil: V
Ethyl acetate=4: 1) get 3.75g reddish-brown solid and be designated as intermediate 3, yield is 91.2%.
1H NMR(CDCl
3)δ：6.94～8.17(m，9H)，4.88(m，1H)，3.72(s，3H)，3.66(s，2H)，3.11(m，2H)。
4, the preparation of intermediate 4 ((R)-2-(2-(4-nitrophenyl) kharophen)-3-phenylpropyl alcohol hydrazides)
Add successively intermediate 3 (3.21g, 9mmol), ethanol (30mL) and 80% hydrazine hydrate (1.44mL, 27mmol), back flow reaction 6h.Be cooled to room temperature, suction filtration, absolute ethanol washing, oven dry obtains the 2.55g faint yellow solid and is designated as intermediate 4, and yield is 82.8%, and fusing point is 206-207 ℃.
1H NMR((CD
3)
2SO-d
6)δ：9.30(s，1H)，8.54(d，J＝8.4Hz，1H)，8.06(d，J＝8.4Hz，2H)，7.31(d，J＝8.4Hz，2H)，7.19(s，5H)，4.45(m，1H)，4.25(s，2H)，3.54(m，2H)，2.74～2.95(m，2H)。
5, the preparation of target product (2-(2-(4-nitrophenyl) kharophen)-3-phenyl-N '-(pyridine-2-methylene radical) propionyl hydrazine)
Add successively intermediate 4 (2.05g, 6mmol), ethanol (20mL) and 2-pyridylaldehyde (0.771g, 7.2mmol), back flow reaction 2h.Be cooled to room temperature, suction filtration, absolute ethanol washing, oven dry obtains 2.35g faint yellow solid target product, and yield is 90.8%, and fusing point is 209-210 ℃.
1H NMR((CD
3)
2SO-d
6)δ：11.89(s，1H)，11.67(s，1H)，8.57～8.81(m，2H)，7.83～8.19(m，4H)，7.16～7.43(m，8H)，4.58～5.60(m，H)，3.59(t，J＝10.8Hz，2H)，3.08(m，1H)，2.85(m，1H)。
Embodiment 2 N-(3-(1H-indoles-3 base)-1-(2-(pyridine-2-methyl) propionyl hydrazine-2-(2-(4-nitrophenyl) acetyl ammonia
Operation steps is with embodiment 1, and different is to use L-Trp to replace L-Phe in step 1.Target product is yellow solid, and yield is 91.2%, and fusing point is 240-241 ℃,
1H NMR ((CD
3)
2SO-d
6) δ: 11.91 (s, 1H), 11.65 (s, 1H), (10.85 d, J=10.2Hz, 1H), 8.58～8.67 (m, 2H), 7.65～8.21 (m, 4H), 6.93～7.41 (m, 8H), 4.62～5.49 (m, 1H), 3.61 (t, J=3.0Hz, 2H), 3.17 (m, 1H), 2.88-3.10 (m, 1H).
Embodiment 3 2-(2-(4-fluorophenyl) kharophen)-3-phenyl-N '-(pyridine-2-methylene radical) propionyl hydrazine
Operation steps is with embodiment 1, and different is to use the 4-fluorophenylacetic acid to replace paranitrophenylacetic acid in step 2.Target product is white solid, and yield is 93.7%, and fusing point is 200-201 ℃,
1H NMR (CDCl
3) δ: 10.33 (s, 1H), 9.76 (s, 1H), (8.61 m, 1H), 8.10～7.75 (m, 3H), 6.97～7.36 (m, 9H), (6.40 m, 1H), 4.86～5.73 (m, 1H), 3.52 (d, J=9.3Hz, 2H), 3.20～3.02 (m, 2H).
Embodiment 4 N-(3-(1H-indoles-3 base)-1-(2-(pyridine-2-methyl) propionyl hydrazine-2-(2-(4-fluorophenyl) acetyl ammonia
Operation steps is with embodiment 2, and different is to use the 4-fluorophenylacetic acid to replace paranitrophenylacetic acid in step 2.Target product is white solid, and yield is 93.6%, and fusing point is 230-231 ℃,
1H NMR ((CD
3)
2SO-d
6) δ: 11.89 (s, 1H), 11.63 (s, 1H), (10.84 d, J=11.7Hz, 1H), 8.48～8.59 (m, 2H), 7.63～8.21 (m, 4H), 6.93～7.41 (m, 8H), 4.62～5.47 (m, 1H), (3.41 m, 2H), 3.17 (m, 1H), 3.00 (m, 1H).
Embodiment 5 2-(2-(4-aminomethyl phenyl) kharophen)-3-phenyl-N '-(pyridine-2-methylene radical) propionyl hydrazine
Operation steps is with embodiment 1, and different is to use the 4-methylphenyl acetic acid to replace paranitrophenylacetic acid in step 2.Target product is white solid, and yield is 94.7%, and fusing point is 175-176 ℃,
1H NMR (CDCl
3) δ: 10.26 (s, 1H), 9.76 (s, 1H), (8.60 m, 1H), 7.77～8.03 (m, 2H), 6.98～7.39 (m, 10H), 6.28 (m, 1H), 4.80～5.73 (m, 1H), 3.53 (d, J=3.9Hz, 2H), 3.00～3.18 (m, 2H), (2.33 d, J=6.0Hz, 3H).
Embodiment 6 N-(3-(1H-indoles-3 base)-1-(2-(pyridine-2-methyl) propionyl hydrazine-2-(2-(4-fluorophenyl) acetyl ammonia
Operation steps is with embodiment 2, and different is to use the 4-methylphenyl acetic acid to replace paranitrophenylacetic acid in step 2.Target product is white solid, and yield is 95.1%, and fusing point is 214-216 ℃,
1H NMR ((CD
3)
2SO-d
6) δ: 11.96 (s, 1H), 11.71 (s, 1H), (10.94 d, J=12.0Hz, 1H), 8.49～8.70 (m, 2H), 7.72～8.30 (m, 4H), 7.03～7.51 (m, 9H), 4.70～5.56 (m, 1H), 3.46 (m, 2H), 3.10～3.26 (m, 2H), (2.33 d, J=3.3Hz, 3H).
Embodiment 7 N '-(4-dimethylamino benzylidene)-2-(2-(4-nitrophenyl) kharophen)-3-phenylpropyl alcohol hydrazides
Operation steps is with embodiment 1, and different is to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde in step 5.Target product is faint yellow solid, and yield is 88.1%, and fusing point is 236-237 ℃,
1H NMR ((CD
3)
2SO-d
6) δ: 11.17～11.34 (m, 1H), 8.56～8.73 (m, 1H), 7.86～8.11 (m, 3H), 7.00～7.50 (m, 10H), (6.73 d, J=8.7Hz, 2H), 4.58～5.38 (m, 1H), 3.58 (m, 2H), 3.03～3.17 (m, 1H), 2.96 (s, 6H), 2.75～2.90 (m, 1H).
Embodiment 8 N '-(4-dimethylamino benzylidene)-2-(2-(4-nitrophenyl) kharophen)-3-(1H-indol-3-yl) propionyl hydrazine
Operation steps is with embodiment 2, and different is to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde in step 5.Target product is yellow solid, and yield is 90.9%, and fusing point is 251-252 ℃,
1H NMR ((CD
3)
2SO-d
6) δ: 11.17～11.38 (d, J=63.9Hz, 1H), 10.83 (s, 1H), 8.48～8.70 (m, 1H), 8.03～8.09 (m, 3H), 7.91 (s, 1H), 6.97～7.66 (m, 8H), 6.73 (m, 2H), 4.58～5.43 (m, 1H), 3.59 (t, 2H), 3.08～3.23 (m, 1H), 2.97 (m, 7H).
Embodiment 9 N '-(4-dimethylamino benzylidene)-2-(2-(4-fluorophenyl) kharophen)-3-phenylpropyl alcohol hydrazides
Operation steps is with embodiment 3, and different is to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde in step 5.Target product is white solid, and yield is 92.5%, and fusing point is 250-251 ℃.
1H NMR((CD
3)
2SO-d
6)δ：11.17～11.33(d，1H)，8.45～8.58(m，1H)，7.87～8.02(d，1H)，7.49(d，2H)，7.02～7.26(m，9H)，6.73(m，2H)，4.58～5.48(m，1H)，3.40(m，2H)，2.72～3.13(m，8H)。
Embodiment 10 N '-(4-dimethylamino benzylidene)-2-(2-(4-fluorophenyl) kharophen)-3-(1H-indol-3-yl) propionyl hydrazine
Operation steps is with embodiment 4, and different is to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde in step 5.Target product is white solid, and yield is 93.3%, and fusing point is 275-276 ℃,
1H NMR ((CD
3)
2SO-d
6) δ: 11.14～11.34 (d, J=60.6Hz, 1H), 10.82 (s, 1H), 8.33-8.52 (m, 1H), 7.92～8.02 (d, J=32.4Hz, 1H), 6.97～7.66 (m, 11H), (6.73 d, J=8.1Hz, 2H), 4.61～5.46 (m, 1H), 3.42 (s, 2H), 3.17 (m, 1H), 2.97 (t, J=11.1Hz, 7H).
Embodiment 11 N '-(4-dimethylamino benzylidene)-2-(2-(4-aminomethyl phenyl) kharophen)-3-phenylpropyl alcohol hydrazides
Operation steps is with embodiment 5, and different is to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde in step 5.Target product is white solid, and yield is 94.7%, and fusing point is 237-238 ℃,
1H NMR ((CD
3)
2SO-d
6) δ: 11.14～11.29 (d, J=45.3Hz, 1H), 8.25～8.49 (m, 1H), 7.86～8.00 (d, J=42.6Hz, 1H), (7.48 d, J=8.4Hz, 2H), 6.97～7.26 (m, 9H), 6.73 (m, 2H), 4.52～5.36 (m, 1H), 3.39 (m, 2H), 2.75～3.08 (m, 8H), 2.24 (s, 3H).
Embodiment 12 N '-(4-dimethylamino benzylidene)-2-(2-(4-aminomethyl phenyl) kharophen)-3-(1H-indol-3-yl) propionyl hydrazine
Operation steps is with embodiment 6, and different is to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde in step 5.Target product is white solid, and yield is 95.4%, and fusing point is 244-246 ℃,
1H NMR ((CD
3)
2SO-d
6) δ: 11.12～11.31 (d, J=57.0Hz, 1H), 10.82 (s, 1H), 8.23～8.44 (m, 1H), 7.91～8.01 (d, J=30.6Hz, 1H), 7.00～7.65 (m, 11H), 6.73 (d, J=8.4Hz, 2H), 4.59～5.43 (m, 1H), 3.37 (s, 2H), 3.14 (m, 1H), 2.97 (t, J=10.8Hz, 7H), 2.23 (s, 3H).
Embodiment 13 (R)-N-(2-(1H-imidazoles-1-yl) ethyl)-2-(2-(4-nitrophenyl) kharophen)-3-hydrocinnamamide
Synthetic route:
Step 1-3 prepares intermediate 3 with embodiment 1.
4, the preparation of intermediate 5 (R)-2-(2-(4-oil of mirbane) acetamido)-3-phenylpropionic acid
Add successively methyl alcohol (30mL), water (8mL) and Na
2CO
3(0.79g, 7.5mmol) is after the dissolving, add intermediate 3 (1.71g, 5mmol), behind the stirring at room 6h, 3mol/L HCl transfers about pH to 7, and evaporate to dryness methyl alcohol adds water (20mL), transfer pH to 5～6 with HCl, ethyl acetate extraction 3 times merges organic phase, gets 1.53g reddish-brown oily matter and is designated as intermediate 5, productive rate is 93.2%
1H NMR (CDCl
3) δ: 12.73 (s, 1H), 7.19～8.53 (m, 9H), 4.45 (m, 1H), 3.57 (s, 2H), 3.01 (m, 2H).
5, the preparation of target product ((R)-N-(2-(1H-imidazoles-1-yl) ethyl)-2-(2-(4-nitrophenyl) kharophen)-3-hydrocinnamamide)
Add successively intermediate 5 (0.76g, 2.5mmol), CH
2Cl
2(20mL), carbonyl dimidazoles (0.48g, 3.0mmol) and TEA (0.43mL, 3.0mmol) add 2-(1H-imidazoles-1-yl) ethamine (0.40g, 3.6mmol), stirring at room 10h, column chromatography for separation (V behind the stirring at room 2.5h
Methylene dichloride: V
Methyl alcohol: V
Triethylamine=70: 1: 0.7) also dry that the 0.90g yellow solid is target product, yield is 85.6%, and fusing point is 126-127 ℃.
1H NMR((CD
3)
2SO-d
6)δ：8.45(d，J＝8.4Hz，1H)，8.22(t，J＝10.5Hz，1H)，8.01(d，J＝8.7Hz，2H)，7.50(s，1H)，7.04～7.26(m，8H)，6.80(s，1H)，4.38(m，1H)，3.92(t，J＝11.1Hz，2H)，3.48(m，2H)，3.28(m，2H)，2.81(m，H)，2.62(m，H)。
Embodiment 14 (R)-N-(2-(1H-imidazoles-1-yl) ethyl)-3-(1H-indoles-3 base)-2-(2-(4-nitrophenyl) kharophen) propionic acid amide
Operation steps uses L-Trp to replace L-Phe in step 1 with embodiment 13.Target product is yellow solid, and yield is 82.0%, and fusing point is 237-238 ℃,
1H NMR ((CD
3)
2SO-d
6) δ: 10.81 (s, 1H), 8.45 (d, J=8.1Hz, 1H), 8.25 (t, J=10.8Hz, 1H), (8.05 d, J=8.7Hz, 2H), 7.58 (d, J=7.8Hz, 1H), 7.50 (s, 1H), (7.30 t, J=8.4Hz, 3H), 6.92～7.06 (m, 4H), 6.83 (s, 1H), 4.48 (m, 1H), 3.94 (d, J=5.4Hz, 2H), 3.57 (m, 2H), (3.32 m, 2H), 3.01 (m, H), 2.88 (m, H).
Embodiment 15 ((R)-N-(2-(1H-imidazoles-1-yl) ethyl)-2-(2-(4-fluorophenyl) kharophen)-3-hydrocinnamamide)
Operation steps uses the 4-fluorophenylacetic acid to replace paranitrophenylacetic acid in step 2 with embodiment 13.Target product is white solid, and yield is 86.7%, and fusing point is 146-147 ℃,
1H NMR (CDCl
3) δ: 8.37 (d, J=8.4Hz, 1H), 8.24 (t, J=10.8Hz, 1H), 7.60 (s, 1H), 6.99～7.25 (m, 10H), 6.89 (s, 1H), 4.41 (m, 1H), 4.00 (t, J=11.4Hz, 2H), (3.40 m, 2H), 3.32 (m, 2H), (2.90 m, H), 2.69 (m, H).
Embodiment 16 ((R)-N-(2-(1H-imidazoles-1-yl) ethyl)-3-(1H-indoles-3 base)-2-(2-(4-fluorophenyl) kharophen) propionic acid amide)
Operation steps uses the 4-fluorophenylacetic acid to replace paranitrophenylacetic acid in step 2 with embodiment 14.Target product is white solid, and yield is 84.9%, and fusing point is 259-260 ℃,
1H NMR ((CD
3)
2SO-d
6) δ: 10.74 (s, 1H), 8.22 (m, 1H), 8.17 (m, 1H), 7.50 (d, J=7.8Hz, 1H), 7.43 (s, 1H), 7.24 (d, J=8.1Hz, 1H), 6.86～7.04 (m, 8H), 6.76 (s, 1H), 4.36 (m, 1H), (3.87 m, 2H), 3.37 (m, 2H), 3.31 (m, 2H), 2.95 (m, H), 2.79 (m, H).
Embodiment 17 ((R)-N-(2-(1H-imidazoles-1-yl) ethyl)-2-(2-(4-aminomethyl phenyl) kharophen)-3-hydrocinnamamide)
Operation steps uses the 4-methylphenyl acetic acid to replace paranitrophenylacetic acid in step 2 with embodiment 13.Target product is white solid, and yield is 87.8%, and fusing point is 167-168 ℃,
1H NMR (CDCl
3) δ: 8.31 (d, J=8.4Hz, 1H), 8.26 (m, 1H), (7.56 s, 1H), 6.94～7.23 (m, 10H), 6.86 (s, 1H), 4.42 (m, 1H), 3.98 (t, J=11.7Hz, 2H), 3.37 (m, 2H), (3.31 m, 2H), 2.90 (m, H), (2.72 m, H), 2.23 (s, 3H).
The pharmacological research of embodiment 18 compounds
Antitumor shaker test, test with Non-small cell lung carcinoma cell A-549, human breast cancer cell MDA-MB-435 and human liver cancer cell HuH-7, (3-(4 to adopt MTT, 5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt) method is with 5-Fluorouracil and PD 176252 positive contrasts.
Collect the logarithmic phase cell, adjusting concentration of cell suspension is 5 * 10
4ML
-1Cell suspension, be inoculated in 96 orifice plates, every hole 200 μ L are in 5%CO
2, hatch for 37 ℃, be paved with the hole to cell monolayer at the bottom of, add the medicine of different concns, establish 3 multiple holes, the control wells that does not add medicine is set simultaneously, do not add the blank well of cell and medicine, in 5%CO
2, hatch 48h for 37 ℃, then discard former substratum, every hole adds the freshly prepared 0.5gL of containing of 200 μ L
-1The serum free medium of MTT is hatched 4～6h in the incubator, discard substratum, and every hole adds 150 μ L DMSO dissolving first a ceremonial jade-ladle, used in libation precipitation, measures light absorption value (OD value) with microplate reader under wavelength 492nm condition.
Inhibiting rate/%=1-(administration group average absorption degree value-blank group average absorption degree value)/(control group average absorption degree value-blank group average absorption degree value).
Calculate medicine to the inhibiting rate of tumour cell with above formula, and calculate IC with improvement bandit formula method
50
Improvement bandit formula method calculation formula: lgIC
50=Xm-I (P-(3-Pm-Pn)/4).
Xm:lg maximal dose wherein; I:lg (maximal dose/face mutually dosage); P: positive reaction rate sum; Pm: maximum positive reaction rate; Pn: minimum positive reaction rate.
The compound of table 1 embodiment of the invention 1-17 preparation is to the IC of A-549, MDA-MB-435 and HuH-7
50Value
Experimental result and conclusion: experimental result sees Table 1, embodiment 6,7,9,11 and 17 compound has good restraining effect to A-549, MDA-MB-435 and HuH-7 cell.Show that most compound of the present invention has obvious restraining effect to A-549, MDA-MB-435 and Huh-7 cell.
17 compounds of embodiment of the invention 1-17 preparation have good inhibition active to Non-small cell lung carcinoma cell A-549, human breast cancer cell MDA-MB-435 and human liver cancer cell HuH-7.Therefore, 2-(4-substituted-phenyl) acetamido propionyl hydrazone and amide derivatives merit attention as the prospect of very potential cancer therapy drug.
Claims (4)
1. compound with antitumour activity is characterized in that its structure is represented by logical formula I:
R in the logical formula I
1Be selected from-NO
2,-F or-CH
3
R
2Be selected from phenyl or 3-indyl;
2. preparation method with anti-cancer active compound claimed in claim 1, the preparation, the isolation and purification that comprise intermediate, it is characterized in that: the preparation of described intermediate is that L-Phe or L-Trp made intermediate 1 in back flow reaction 5-6 hour in the methanol solution of sulfur oxychloride, and the mol ratio of L-Phe or L-Trp and sulfur oxychloride is 1:2; Substituted phenylacetic acid and oxalyl chloride are at CH
2Cl
2In obtained intermediate 2 in room temperature reaction 2-3 hour, the mol ratio of substituted phenylacetic acid and oxalyl chloride is 1:1.2; Subsequently with intermediate 1 and intermediate 2 at CH
2Cl
2In obtained intermediate 3 in room temperature reaction 4-8 hour, the mol ratio of intermediate 1 and intermediate 2 is 1:1.2; Intermediate 3 and hydrazine hydrate obtained intermediate 4 in back flow reaction 6-9 hour in ethanolic soln, the mol ratio of intermediate 3 and hydrazine hydrate is 1:3; Described synthetic be intermediate 4 and 2-pyridylaldehyde or paradimethy laminobenzaldehyde in ethanolic soln back flow reaction 2-3 hour, intermediate 4 is 1:1.2 with the mol ratio of 2-pyridylaldehyde or paradimethy laminobenzaldehyde, obtains target product after filtration, washing and the drying;
Described substituted phenylacetic acid is selected from paranitrophenylacetic acid, 4-fluorophenylacetic acid or 4-methylphenyl acetic acid;
The general structure of described intermediate 1 is:
The general structure of described intermediate 2 is:
The general structure of described intermediate 3 is:
The general structure of described intermediate 4 is:
3. compound with antitumour activity is characterized in that its structure is represented by logical formula II:
R in the logical formula II
1Be selected from-NO
2,-F or-CH
3
R
2Be selected from phenyl or 3-indyl.
4. preparation method with compound of antitumour activity claimed in claim 3, the preparation, the isolation and purification that comprise intermediate, it is characterized in that: the preparation of described intermediate is that L-Phe or L-Trp made intermediate 1 in back flow reaction 5-6 hour in the methanol solution of sulfur oxychloride, and the mol ratio of L-Phe or L-Trp and sulfur oxychloride is 1:2; Substituted phenylacetic acid and oxalyl chloride are at CH
2Cl
2In obtained intermediate 2 in room temperature reaction 2-3 hour, the mol ratio of substituted phenylacetic acid and oxalyl chloride is 1:1.2; Subsequently intermediate 1 and intermediate 2 are placed CH
2Cl
2In obtained intermediate 3 in room temperature reaction 4-8 hour, the mol ratio of intermediate 1 and intermediate 2 is 1:1.2; Intermediate 3 is at methyl alcohol, water and Na
2CO
3Mixing solutions under room temperature, obtained intermediate 5, intermediate 3 and Na in hydrolysis reaction 6-10 hour
2CO
3Mol ratio be 1:1.5; Intermediate 5 and 2-(1H-imidazoles-1-yl) ethamine generation amidate action, take carbonyl dimidazoles as condensing agent, the mol ratio of intermediate 5,2-(1H-imidazoles-1-yl) ethamine and carbonyl dimidazoles is 1:1.2:1.2, room temperature reaction 8-14 hour, namely get target product after the column chromatography for separation;
Described substituted phenylacetic acid is selected from paranitrophenylacetic acid, 4-fluorophenylacetic acid or 4-methylphenyl acetic acid;
The general structure of described intermediate 1 is:
The general structure of described intermediate 2 is:
The general structure of described intermediate 3 is:
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