CN102603619A - Compound with anticancer activity and preparation method thereof - Google Patents

Compound with anticancer activity and preparation method thereof Download PDF

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CN102603619A
CN102603619A CN2012100345224A CN201210034522A CN102603619A CN 102603619 A CN102603619 A CN 102603619A CN 2012100345224 A CN2012100345224 A CN 2012100345224A CN 201210034522 A CN201210034522 A CN 201210034522A CN 102603619 A CN102603619 A CN 102603619A
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CN102603619B (en
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姚日生
李婷婷
阮班锋
邓胜松
何红波
陆小琴
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Hefei University of Technology
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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

A kind of compound and preparation method thereof with antitumour activity
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 that cancer has become first cause of the death of Chinese city and urban residents.China's cancer incidence is in the fast rise phase, and annual pathogenesis of cancer number is about 2,600,000, dead 1,800,000 people.The generation of cancer and development are extremely complicated processes, receive influence of various 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 treatment for cancer method mainly is surgical treatment, radiotherapy and chemotherapy, and various treatment meanss all also exist some problems in practical application.Searching have no side effect and efficiently the new type anticancer medicine be one of main task of pharmaceutical chemists.
Discover; Tumour and gastrin releasing peptide receptor (gastrin releasing peptide receptor; GRPR) in close relations; And in tumours such as colorectal carcinoma, cancer of the stomach, lung cancer, prostate cancer, mammary cancer, ovarian cancer, all find the unconventionality expression of GRPR, sealing GRPR signal path can effectively suppress growth of tumor.
The GRPR suppressor factor great majority of bibliographical information are the peptide class formations, are divided into six types according to the mode of structural modification, 1. P material 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. type 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, a type peptide GRPR suppressor factor can suppress proliferation of lung cancer cells, wherein the IC of PD 176252 and 168368 pairs of people's non-small cell lung cancer cells of PD NCI-H1299 50Value is respectively 5 and 30 μ M, and it is better to suppress effect.PD 168368 is following with PD 176252 structural formulas:
Figure BDA0000135920610000011
PD?168368 PD?176252
The acylhydrazone compounds is the schiff base compounds that is formed by hydrazides and aldehydes or ketones condensation; In its molecule owing to contain Sauerstoffatom and nitrogen-atoms thereby can participate in the formation of hydrogen bond in the organism simultaneously; Increase the affinity between the acceptor; And then can suppress many plysiochemical processes in the organism, therefore received at aspects such as medicine, agricultural chemicals, material and analytical reagents widely and having paid close attention to.In recent years, the researchist finds, multiple biological activitys such as that the acylhydrazone compounds 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 effect 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 represented by general formula (I):
Figure BDA0000135920610000021
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
Figure BDA0000135920610000022
The present invention has the preparation method of anti-cancer active compound; The preparation, the isolation and purification that comprise midbody; It is characterized in that: the preparation of said midbody is that L-phenylalanine(Phe) or L-tryptophane made midbody 1 in back flow reaction 5-6 hour in the methanol solution of sulfur oxychloride, and wherein the mol ratio of L-phenylalanine(Phe) or L-tryptophane and sulfur oxychloride is 1: 2; Substituted phenylacetic acid and oxalyl chloride are at CH 2Cl 2In obtained midbody 2 in room temperature reaction 2-3 hour, wherein the mol ratio of substituted phenylacetic acid and oxalyl chloride is 1: 1.2; Subsequently midbody 1 and midbody 2 are placed CH 2Cl 2In obtained midbody 3 in room temperature reaction 4-8 hour, wherein the mol ratio of midbody 1 and midbody 2 is 1: 1.2; Midbody 3 and Hydrazine Hydrate 80 obtained midbody 4 in back flow reaction 6-9 hour in ethanolic soln, wherein the mol ratio of midbody 3 and Hydrazine Hydrate 80 is 1: 3; Last midbody 4 and 2-pyridylaldehyde or paradimethy laminobenzaldehyde in ethanolic soln back flow reaction 2-3 hour, midbody 4 is 1: 1.2 with the mol ratio of 2-pyridylaldehyde or paradimethy laminobenzaldehyde, filters, obtains title product after washing and the drying;
Said 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 represented by general formula (II):
Figure BDA0000135920610000031
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 midbody; It is characterized in that: the preparation of said midbody is that L-phenylalanine(Phe) or L-tryptophane made midbody 1 in back flow reaction 5-6 hour in the methanol solution of sulfur oxychloride, and wherein the mol ratio of L-phenylalanine(Phe) or L-tryptophane and sulfur oxychloride is 1: 2; Substituted phenylacetic acid and oxalyl chloride are at CH 2Cl 2In obtained midbody 2 in room temperature reaction 2-3 hour, wherein the mol ratio of substituted phenylacetic acid and oxalyl chloride is 1: 1.2; Subsequently midbody 1 and midbody 2 are placed CH 2Cl 2In obtained midbody 3 in room temperature reaction 4-8 hour, wherein the mol ratio of midbody 1 and midbody 2 is 1: 1.2; Midbody 3 is at methyl alcohol, water and Na 2CO 3Mixing solutions under room temperature, obtained midbody 5, wherein midbody 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; Midbody 5 and 2-(1H-imidazoles-1-yl) ethamine generation amidate action; With the carbonyl dimidazoles is condensing agent; The mol ratio of midbody 5,2-(1H-imidazoles-1-yl) ethamine and carbonyl dimidazoles is 1: 1.2: 1.2, room temperature reaction 8-14 hour, promptly gets title product after the column chromatography for separation;
Said substituted phenylacetic acid is selected from paranitrophenylacetic acid, 4-fluorophenylacetic acid or 4-methylphenyl acetic acid.
Synthetic route of the present invention is following:
Figure BDA0000135920610000041
Compared with present technology, 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 restraining active to people's non-small cell lung cancer 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 thereto:
Embodiment 1 2-(2-(4-nitrophenyl) kharophen)-3-phenyl-N '-(pyridine-2-methylene radical) propionyl hydrazine
Synthetic route:
Figure BDA0000135920610000051
1, the preparation of midbody 1 (L-phenylalanine methyl ester hydrochloride)
Under the ice bath in anhydrous methanol (150mL) dripping thionyl chloride (7.1mL 100mmol), drips off the back and stirs 1h; (8.26g 50mmol), adds back back flow reaction 5h slowly to add the L-phenylalanine(Phe) again; Solvent evaporated; Add the small amount of methanol dissolving, get the 9.60g white solid with the ether precipitating and be designated as midbody 1, productive rate is 89.0%; Fusing point is 158-160 ℃ (literature value 158-161 a ℃).
2, the preparation of midbody 2 (4-oil of mirbane Acetyl Chloride 98Min.)
Add successively under the ice bath paranitrophenylacetic acid (3.26g, 18mmol), CH 2Cl 2(30mL) and triethylamine (TEA) (5.2mL, 36mmol), two Ns (DMF), N 2Protection slowly drip again down oxalyl chloride (1.84mL, 21.6mmol) and CH 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 midbody 2, directly are used for step reaction down.
3, the preparation of midbody 3 ((R)-2-(2-(4-oil of mirbane) acetamido)-3-phenylpropionic acid methyl esters)
The midbody 2 and the CH that add new system under the ice bath successively 2Cl 2(20mL), slowly drip CH 2Cl 2(5mL), midbody 1 (3.24g, 15mmol) and TEA (2.17mL, mixture 15mmol), room temperature reaction 5h, column chromatography for separation (V Sherwood oil: V ETHYLE ACETATE=4: 1) get 3.75g reddish-brown solid and be designated as midbody 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 midbody 4 ((R)-2-(2-(4-nitrophenyl) kharophen)-3-phenylpropyl alcohol hydrazides)
Add successively midbody 3 (3.21g, 9mmol), ethanol (30mL) and 80% Hydrazine Hydrate 80 (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 midbody 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 title product (2-(2-(4-nitrophenyl) kharophen)-3-phenyl-N '-(pyridine-2-methylene radical) propionyl hydrazine)
Add successively midbody 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 title 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 in step 1, to use the L-tryptophane to replace the L-phenylalanine(Phe).Title product is a 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 in step 2, to use the 4-fluorophenylacetic acid to replace paranitrophenylacetic acid.Title product is a 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
Figure BDA0000135920610000071
Operation steps is with embodiment 2, and different is in step 2, to use the 4-fluorophenylacetic acid to replace paranitrophenylacetic acid.Title product is a 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
Figure BDA0000135920610000072
Operation steps is with embodiment 1, and different is in step 2, to use the 4-methylphenyl acetic acid to replace paranitrophenylacetic acid.Title product is a 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
Figure BDA0000135920610000073
Operation steps is with embodiment 2, and different is in step 2, to use the 4-methylphenyl acetic acid to replace paranitrophenylacetic acid.Title product is a 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 tolylene)-2-(2-(4-nitrophenyl) kharophen)-3-phenylpropyl alcohol hydrazides
Operation steps is with embodiment 1, and different is in step 5, to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde.Title product is a 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 tolylene)-2-(2-(4-nitrophenyl) kharophen)-3-(1H-indol-3-yl) propionyl hydrazine
Figure BDA0000135920610000082
Operation steps is with embodiment 2, and different is in step 5, to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde.Title product is a 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 tolylene)-2-(2-(4-fluorophenyl) kharophen)-3-phenylpropyl alcohol hydrazides
Figure BDA0000135920610000083
Operation steps is with embodiment 3, and different is in step 5, to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde.Title product is a 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 tolylene)-2-(2-(4-fluorophenyl) kharophen)-3-(1H-indol-3-yl) propionyl hydrazine
Figure BDA0000135920610000091
Operation steps is with embodiment 4, and different is in step 5, to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde.Title product is a 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 tolylene)-2-(2-(4-aminomethyl phenyl) kharophen)-3-phenylpropyl alcohol hydrazides
Figure BDA0000135920610000092
Operation steps is with embodiment 5, and different is in step 5, to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde.Title product is a 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 tolylene)-2-(2-(4-aminomethyl phenyl) kharophen)-3-(1H-indol-3-yl) propionyl hydrazine
Figure BDA0000135920610000101
Operation steps is with embodiment 6, and different is in step 5, to use paradimethy laminobenzaldehyde to replace the 2-pyridylaldehyde.Title product is a 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:
Figure BDA0000135920610000103
Step 1-3 prepares midbody 3 with embodiment 1.
4, the preparation of midbody 5 (R)-2-(2-(4-oil of mirbane) acetamido)-3-phenylpropionic acid
Add methyl alcohol (30mL), water (8mL) and Na successively 2CO 3(0.79g 7.5mmol), after the dissolving, adds midbody 3 (1.71g; 5mmol), behind the stirring at room 6h, 3mol/L HCl transfers about pH to 7, evaporate to dryness methyl alcohol; Add water (20mL), transfer pH to 5～6 with HCl, ethyl acetate extraction 3 times merges organic phase; Get 1.53g reddish-brown oily matter and be designated as midbody 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 title product ((R)-N-(2-(1H-imidazoles-1-yl) ethyl)-2-(2-(4-nitrophenyl) kharophen)-3-hydrocinnamamide)
Add successively midbody 5 (0.76g, 2.5mmol), CH 2Cl 2(20mL), carbonyl dimidazoles (0.48g, 3.0mmol) and TEA (0.43mL, 3.0mmol), add behind the stirring at room 2.5h 2-(1H-imidazoles-1-yl) ethamine (0.40g, 3.6mmol), stirring at room 10h, column chromatography for separation (V Methylene dichloride: V Methyl alcohol: V Triethylamine=70: 1: 0.7) also dry that the 0.90g yellow solid is title 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
Figure BDA0000135920610000111
Operation steps uses the L-tryptophane to replace the L-phenylalanine(Phe) in step 1 with embodiment 13.Title product is a 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)
Figure BDA0000135920610000112
Operation steps uses the 4-fluorophenylacetic acid to replace paranitrophenylacetic acid in step 2 with embodiment 13.Title product is a 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)
Figure BDA0000135920610000121
Operation steps uses the 4-fluorophenylacetic acid to replace paranitrophenylacetic acid in step 2 with embodiment 14.Title product is a 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)
Figure BDA0000135920610000122
Operation steps uses the 4-methylphenyl acetic acid to replace paranitrophenylacetic acid in step 2 with embodiment 13.Title product is a 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; Experimentize with people's non-small cell lung cancer 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, with 5-Fluorouracil and PD 176252 positive contrasts.
Collect the logarithmic phase cell, the adjustment 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 ℃, discard former substratum then, 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 deposition, under wavelength 492nm condition, measures light absorption value (OD value) with ELIASA.
Inhibiting rate/%=1-(administration group average absorption degree value-blank control group average absorption degree value)/(control group average absorption degree value-blank control group average absorption degree value).
Calculate the inhibiting rate of medicine with above formula, and calculate IC with improvement bandit formula method to tumour cell 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
Figure BDA0000135920610000131
Experimental result and conclusion: experimental result is seen table 1, and embodiment 6,7,9,11 and 17 compound have the good restraining effect to A-549, MDA-MB-435 and HuH-7 cell.Show that most compound of the present invention has the obvious suppression effect to A-549, MDA-MB-435 and Huh-7 cell.
17 compounds of embodiment of the invention 1-17 preparation have good restraining active to people's non-small cell lung cancer 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 represented by general formula (I):
Figure FDA0000135920600000011
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
Figure FDA0000135920600000012
2. described preparation method of claim 1 with anti-cancer active compound; The preparation, the isolation and purification that comprise midbody; It is characterized in that: the preparation of said midbody is that L-phenylalanine(Phe) or L-tryptophane made midbody 1 in back flow reaction 5-6 hour in the methanol solution of sulfur oxychloride, and the mol ratio of L-phenylalanine(Phe) or L-tryptophane and sulfur oxychloride is 1: 2; Substituted phenylacetic acid and oxalyl chloride are at CH 2Cl 2In obtained midbody 2 in room temperature reaction 2-3 hour, the mol ratio of substituted phenylacetic acid and oxalyl chloride is 1: 1.2; Subsequently with midbody 1 and midbody 2 at CH 2Cl 2In obtained midbody 3 in room temperature reaction 4-8 hour, the mol ratio of midbody 1 and midbody 2 is 1: 1.2; Midbody 3 and Hydrazine Hydrate 80 obtained midbody 4 in back flow reaction 6-9 hour in ethanolic soln, the mol ratio of midbody 3 and Hydrazine Hydrate 80 is 1: 3; Described synthetic be midbody 4 and 2-pyridylaldehyde or paradimethy laminobenzaldehyde in ethanolic soln back flow reaction 2-3 hour; Midbody 4 is 1: 1.2 with the mol ratio of 2-pyridylaldehyde or paradimethy laminobenzaldehyde, obtains title product after filtration, washing and the drying;
Said substituted phenylacetic acid is selected from paranitrophenylacetic acid, 4-fluorophenylacetic acid or 4-methylphenyl acetic acid.
3. compound with antitumour activity is characterized in that its structure represented by general formula (II):
Figure FDA0000135920600000013
R in the general formula (II) 1Be selected from-NO 2,-F or-CH 3
R 2Be selected from phenyl or 3-indyl.
4. described preparation method of claim 3 with compound of antitumour activity; The preparation, the isolation and purification that comprise midbody; It is characterized in that: the preparation of said midbody is that L-phenylalanine(Phe) or L-tryptophane made midbody 1 in back flow reaction 5-6 hour in the methanol solution of sulfur oxychloride, and the mol ratio of L-phenylalanine(Phe) or L-tryptophane and sulfur oxychloride is 1: 2; Substituted phenylacetic acid and oxalyl chloride are at CH 2Cl 2In obtained midbody 2 in room temperature reaction 2-3 hour, the mol ratio of substituted phenylacetic acid and oxalyl chloride is 1: 1.2; Subsequently midbody 1 and midbody 2 are placed CH 2Cl 2In obtained midbody 3 in room temperature reaction 4-8 hour, the mol ratio of midbody 1 and midbody 2 is 1: 1.2; Midbody 3 is at methyl alcohol, water and Na 2CO 3Mixing solutions under room temperature, obtained midbody 5, midbody 3 and Na in hydrolysis reaction 6-10 hour 2CO 3Mol ratio be 1: 1.5; Midbody 5 and 2-(1H-imidazoles-1-yl) ethamine generation amidate action; With the carbonyl dimidazoles is condensing agent; The mol ratio of midbody 5,2-(1H-imidazoles-1-yl) ethamine and carbonyl dimidazoles is 1: 1.2: 1.2, room temperature reaction 8-14 hour, promptly gets title product after the column chromatography for separation;
Said substituted phenylacetic acid is selected from paranitrophenylacetic acid, 4-fluorophenylacetic acid or 4-methylphenyl acetic acid.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108440504A (en) * 2018-03-28 2018-08-24 合肥工业大学 Quasi- peptides with anti-inflammatory activity and preparation method thereof and medicinal usage
CN110577521A (en) * 2019-09-30 2019-12-17 齐鲁工业大学 Structure, preparation and application of 2-thiazole formaldehyde-2-pyridine Schiff base

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008036643A2 (en) * 2006-09-19 2008-03-27 Incyte Corporation Amidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
WO2008082692A2 (en) * 2006-07-06 2008-07-10 University Of Medicine And Dentistry Of New Jersey Isothiocyanate compounds, pharmaceutical compositions, and uses thereof
US7411003B1 (en) * 2007-07-09 2008-08-12 Golden Biotechnology Corporation Inhibition of Hepatitis B virus by cyclohexenone compounds from Antrodia camphorata
CN101786990A (en) * 2010-03-04 2010-07-28 合肥工业大学 Compound having anti-itching activity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008082692A2 (en) * 2006-07-06 2008-07-10 University Of Medicine And Dentistry Of New Jersey Isothiocyanate compounds, pharmaceutical compositions, and uses thereof
WO2008036643A2 (en) * 2006-09-19 2008-03-27 Incyte Corporation Amidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
US7411003B1 (en) * 2007-07-09 2008-08-12 Golden Biotechnology Corporation Inhibition of Hepatitis B virus by cyclohexenone compounds from Antrodia camphorata
CN101786990A (en) * 2010-03-04 2010-07-28 合肥工业大学 Compound having anti-itching activity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
姚日生，等: "氨基丙酸乙酯类GRPR抑制剂的设计、合成与抗痒活性研究", 《中国药学大会暨第十届中国药师周》, 30 November 2010 (2010-11-30) *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108440504A (en) * 2018-03-28 2018-08-24 合肥工业大学 Quasi- peptides with anti-inflammatory activity and preparation method thereof and medicinal usage
CN110577521A (en) * 2019-09-30 2019-12-17 齐鲁工业大学 Structure, preparation and application of 2-thiazole formaldehyde-2-pyridine Schiff base
CN110577521B (en) * 2019-09-30 2022-09-30 齐鲁工业大学 Structure, preparation and application of 2-thiazole formaldehyde-2-pyridine Schiff base

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