CN102746255A - Compound having anti-tumor activity, and preparation method and application thereof - Google Patents

Compound having anti-tumor activity, and preparation method and application thereof Download PDF

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CN102746255A
CN102746255A CN2012102563596A CN201210256359A CN102746255A CN 102746255 A CN102746255 A CN 102746255A CN 2012102563596 A CN2012102563596 A CN 2012102563596A CN 201210256359 A CN201210256359 A CN 201210256359A CN 102746255 A CN102746255 A CN 102746255A
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arh
compound
nch
nmr
propoxy
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李家明
何广卫
周鹏
袁明
胡敏华
王杰
吴强
钟国珅
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HEFEI YIGONG MEDICINE CO Ltd
Anhui University of Traditional Chinese Medicine AHUTCM
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HEFEI YIGONG MEDICINE CO Ltd
Anhui University of Traditional Chinese Medicine AHUTCM
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Abstract

The invention relates to the field of medicinal chemistry, in particular to a compound (I) having anti-tumor activity, a preparation method and an application of the compound (1), and a medicinal composition containing the compound (1), wherein the definitions of R and X are shown in the specifications. As proved by pharmacological testing, the compound provided by the invention has superior anti-tumor activity.

Description

Compound, preparation method and application with anti-tumor activity
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to one type of compound, preparation method, purposes with anti-tumor activity, and the pharmaceutical composition that contains them.
Background technology
The treatment of malignant tumour is a global difficult problem for a long time; Along with the fast development of subjects such as oncomolecularbiology, people recognize that gradually the essence of cell carcinogenesis possibly be the cell infinite multiplication that the intracellular signal transduction pathway imbalance causes, and great change has also taken place the theory of antitumor drug research and development thereupon; (mainly act on DNA from the research of conventional cell poison type medicine; RNA and tubulin) turn to the new type antineoplastic medicine sought to the intracellular signal transduction path (referring to Peng Yao, Zhang Yixuan, Zheng Gengxin. the progress of novel protein tyrosine kinase inhibitor series antineoplastic medicament. Shenyang Pharmaceutical University's journal; 2007,24 (7): 451-456).Characteristics are different with conventional cell cytotoxic drug poor selectivity, toxic side effect be strong etc.; Targeting anti-tumor medicine based on the intracellular signal transduction path can reach highly selective, hypotoxic result of treatment (referring to Aggarwal B B; Sethi G; Baladandayuthapani V, et al.Targeting cell signaling pathways for drug discovery:an old lock needs a new key.J.Cell.Biochem.2007,102:580-592; Zhu Yijing, Jiang Fengchao. with the conduction of regulation and control Ras signal is the antitumor drug progress of target. Acta Pharmaceutica Sinica, 2009,44 (1): 1-10; Huambo, Liu Yu. act on the angiogenesis inhibitor of VEGF signal path. pharmacy progress, 34 (6): 256-263).In molecular targeted antitumor drug; The exploitation of protein tyrosine kinase inhibitor is particularly noticeable; Imatinib (Gleevec), ZD1939 (Gefitinib), lapatinibditosylate medicines such as (Lapatinib) successively go through to go on the market; Smooth degree for medicines such as Buddhist nun (Tandutinib), Neratinib etc. just in the clinical study stage, fully proved protein tyrosine kinase be a prospect as rich as Croesus the antitumor drug target (referring to the brave army of cogongrass, Li Haihong; Li Jianfeng. etc. protein tyrosine kinase signal transduction pathway and antitumor drug. Acta Pharmaceutica Sinica .2008,43 (4): 323-334; The Tanghai great waves, Chen Guoguang, Founder, etc. the progress of many target spots receptor tyrosine kinase inhibitors. Chinese Journal of New Drugs .2009,18 (6): 502-506).
Summary of the invention
The invention discloses class formation formula (I) compound, pharmacological evaluation proves that compound of the present invention has good anti-tumor activity.
Compound of the present invention (I) structural formula is following:
Wherein R chooses wantonly and represents halogen, methyl, trifluoromethyl or nitro; X represents O, CH 2, NH, CH 3CON, HOCH 2CH 2N or CH 3N.
X preferably represents O.
The preferred F of said halogen, Cl or Br.
The available following method of compound of the present invention (I) prepares:
Figure BDA00001922788200022
Wherein the definition of R and X is the same.
Its pharmacy acceptable salt of compound of the present invention (I) has same effect.Hydrochloride, vitriol, phosphoric acid salt, PHENRAMINE MALEATE, fumarate, citrate, mesylate, tosilate, tartrate or the acetate of described pharmacy acceptable salt preferred formula (I) compound.
Compound (I) or its pharmacy acceptable salt can be processed various preparations through adding pharmaceutically acceptable carrier.Be used for oral, injection etc. clinical.
The clinical used dosage of compound of the present invention (I) is 0.01mg～1000mg/ days, also can depart from this scope according to the weight of the state of an illness or the difference of formulation.
The preferred following part of compounds of the present invention:
Figure BDA00001922788200023
Figure BDA00001922788200031
Figure BDA00001922788200041
Be the pharmacodynamic experiment and the result of part of compounds of the present invention below, the structure of compound code name is the same in the test:
Measuring method and experimental result
(1) mtt assay
1. adopt cell strain: the human leukemia HL-60 cell;
2. the cell of logarithmic phase is blown and beaten into single cell suspension, be inoculated in 96 well culture plates; 5 * 10 3Cells/well, every hole substratum 100 microlitres, 37 ℃, 5%CO 2Overnight cultures in the incubator;
3. the test-compound that adds gradient concentration was cultivated in incubator 3 days again.
4. the MTT liquid (20 microlitres/hole) that adds 5 mg/ml; Continue to cultivate 4 hours.
5. in the sucking-off hole behind the nutrient solution, add DMSO liquid (100 microlitres/hole), culture plate was placed microwell plate to pull to swing on the device vibration 10 minutes, make the crystallisate dissolving.
6. ELIASA detects each hole OD value (detection wavelength: 570nm); The record result; Calculate inhibiting rate by following formula: inhibiting rate (%)=(OD contrast-OD administration)/OD contrast * 100%, adopt Logit method calculation of half inhibitory concentration IC 50
(2) srb assay
1. adopt cell strain: people's lung cancer A549 cell, people's epidermal carcinoma A431 cell and human breast carcinoma MDA-MB-468 cell;
2. behind the cell dissociation with logarithmic phase, blow and beat into single cell suspension, be inoculated in 96 well culture plates; 5 * 10 3Cells/well, every hole substratum 200 microlitres, 37 ℃, 5%CO 2Overnight cultures in the incubator;
3. the test-compound and the positive control drug that add gradient concentration were cultivated in incubator 3 days again.
4. 10% Tricholroacetic Acid is fixing 1 hour.
5. with the distilled water washing, after the drying, every hole adds 70 microlitre SRB solution (4mg/mL), room temperature dyeing 20 minutes, the washing of 1% acetic acid, drying.
6. every hole adds 100 microlitre 10mM Tris-Base solution makes the SRB dissolving.
7. ELIASA detects each hole OD value (detection wavelength: 515nm); The record result; Calculate inhibiting rate by following formula: inhibiting rate (%)=(OD contrast-OD administration)/OD contrast * 100%, and calculate IC 50If tried the IC of thing 50IC less than the positive control medicine 50, then be regarded as to do the compound that effect is superior to positive control drug.
Table 1 given the test agent is to the 72h inhibited proliferation of four kinds of human tumor cells
Figure BDA00001922788200051
Visible by table 1, for the human leukemia HL-60 cell, compound H SA 1～HSA 3, HSA 5Effect all is superior to the positive drug ZD1939; For people's epidermal carcinoma A431 cell and people's lung cancer A549 cell, compound H SA 1～HSA 5, HSA 9～HSA 10Effect all is superior to the positive drug ZD1939; For human breast carcinoma MDA-MB-468 cell, compound H SA 1～HSA 7Effect all is superior to the positive drug ZD1939.
Embodiment
Embodiment 1
Synthesizing of 4-(3-morpholine propoxy-)-2-hydroxy-n-(3-bromophenyl) BM
1.1 2,4-methyl dihydroxy benzoate synthetic
Figure BDA00001922788200052
In three-necked bottle, add 2, the 4-resorcylic acid (10g, 0.065mol), sodium hydrogencarbonate (6.5g, 0.077mol), DMF (100mL); Behind stirring at room 10min, and the adding methyl iodide (13.8g, 0.097mol), behind 40 ℃ of reaction 10h; TLC [V (sherwood oil): V (ETHYLE ACETATE)=be developping agent at 3: 1] detects and shows that reaction is complete basically, and cooling is crossed and filtered filtrating, adds water 100mL; (3 * 100mL) extractions, the combined ethyl acetate layer is used 5%NaHCO with ETHYLE ACETATE 3(3 * 50mL), (after 3 * 50mL) washings, through anhydrous sodium sulfate drying, get white solid 9.2g behind the reclaim under reduced pressure ETHYLE ACETATE, yield is 84.4% to the 5%NaCl aqueous solution to the aqueous solution, m.p.110.9-112.2 ℃.
1.2 4-(3-bromine propoxy-)-2 hydroxybenzoic acid methyl esters is synthetic
In three-necked bottle, add 2 successively, the 4-methyl dihydroxy benzoate (8.0g, 0.047mol), salt of wormwood (6.5g, 0.047mol), acetone (80mL), TEBAC (0.1g); Behind 60 ℃ of reaction 0.5h, add 1 under stirring, and the 3-dibromopropane (19.0g, 0.095mol); After keeping 60 ℃ of stirring reaction 8h, TLC [V (sherwood oil): V (ETHYLE ACETATE)=be developping agent at 10: 1] detects and shows that reaction is complete basically, and cooling is crossed and filtered filtrating; Get faint yellow oily thing behind the decompression and solvent recovery, separate through silica gel column chromatography, sherwood oil-chloroform (2: 1) is an eluent; Get white solid 7.6g, yield is 55.5%, m.p.72.8-74.5 ℃; 1HNMR (CDCl 3, 400MHz) δ: 10.97 (s, 1H, OH), 7.77 (d, J=8.8Hz, 1H, ArH), 6.48 (d, J=2.4Hz, 1H, ArH), 6.46 (dd, J=8.8,2.4Hz, 1H, ArH), 4.16 (t, J=5.6Hz, 2H, BrCH 2CH 2 CH 2 O), 3.93 (s, 3H, COOCH 3), 3.62 (t, J=6.4Hz, 2H, Br CH 2 CH 2CH 2O), 2.37～2.31 (m, 2H, BrCH 2 CH 2 CH 2O); 13C NMR (CDCl 3, 100MHz) δ: 170.3,164.6,163.7,161.4,131.3,107.7,101.3,65.5,52.0,32.0,29.7; IR (KBr, cm -1) υ: 3016.8,2949.9,1673.2,1623.1,1585.1,1509.6,1467.1,1438.3,1351.3,1256.9,1222.7,1187.0,1138.9,1022.5,986.7,952.8,917.4,832.7; ESI-MS for C 11H 13BrO 4: m/z (M +-H): 286.97.
1.3 4-(3-morpholine propoxy-)-2 hydroxybenzoic acid methyl esters is synthetic
Figure BDA00001922788200062
In three-necked bottle, add 2-hydroxyl-4-(3-bromine propoxy-)-oil of Niobe (7.0g, 0.024mol), morpholine (3.1g, 0.036mol), sodium hydrogencarbonate (3.1g, 0.037mol) and Virahol (50mL); In 85 ℃ of reaction 6h, (developping agent: ETHYLE ACETATE) extremely reaction is complete basically, cools off in the TLC detection under stirring; Cross and filter filtrating, the reclaim under reduced pressure Virahol gets faint yellow oily thing; Through silica gel column chromatography (eluent: ETHYLE ACETATE) separate 4.8g, pale yellow oily liquid body, yield 67.6%; 1H NMR (CDCl3,400MHz) δ: 10.95 (s, 1H, OH), 7.73 (d, J=8.8Hz, 1H, ArH), 6.45 (d, J=2.4Hz, 1H, ArH), 6.44 (dd, J=8.8,2.4Hz, 1H, ArH), 4.07 (t, J=6.4Hz, 2H, NCH 2CH 2 CH 2 O), 3.91 (s, 3H, COOCH 3), 3.73 (t, J=4.8Hz, 4H, morpholine ring C H 2 O CH 2 ), 2.52～2.46 (m, 6H, morpholine rings CH 2 N CH 2 And N CH 2 CH 2CH 2O), 2.00～1.93 (m, 2H, NCH 2 CH 2 CH 2O); 13C NMR (CDCl3,100MHz) δ: 170.4,165.0,163.7,131.2,107.8,105.3,101.2,67.0,66.3,55.3,53.7,51.9,26.2; IR (KBr, cm -1) υ: 3416.7,3066.7,2956.4,2861.6,2824.8,2782.8,1663.9; 1626.2,1582.0,1508.2,1470.3,1436.9,1402.8,1354.0; 1306.9,1259.8,1222.4,1191.1,1144.4,1113.7,1028.4; 999.4,973.8,951.4,915.0,860.4,832.7,779.9; ESI-MS for C 15H 21NO 5: m/z (M +-H): 294.26
1.4 4-(3-morpholine propoxy-)-2 hydroxybenzoic acid is synthetic
Figure BDA00001922788200071
In round-bottomed flask, add 2-hydroxyl-4-(3-morpholine propoxy-)-oil of Niobe (4.0g successively; 0.014mol), NaOH (0.8g; 0.020mmol), methyl alcohol (20mL), pure water (10mL), stirring at room 6h, TLC [V (chloroform): V (methyl alcohol)=be developping agent at 5: 1] detection reaction is complete; Decompression and solvent recovery is used 3molL after the cooling -1Hydrochloric acid is regulated pH to 5～6, and the adularescent deposition is separated out immediately, suction filtration, washing, exsiccant white solid 3.1g, yield 81.6%, m.p.199.8-201.1 ℃; 1H NMR (DMSO-d 6, 400MHz) δ: 7.65 (d, J=8.8Hz, 1H, ArH), 6.38～6.41 (m, 2H, ArH), 4.08 (t, J=5.6Hz, 2H, NCH 2CH 2 CH 2 O), 3.78 (br s, 4H, morpholine rings CH 2 O CH 2 ), 2.98 (br s, 6H, morpholine rings CH 2 N CH 2 AndN CH 2 CH 2CH 2O), 2.07 (br s, 2H, NCH 2CH 2CH 2O); 13C NMR (DMSO-d 6, 100MHz) δ: 172.4,0164.0,163.8,131.9,106.8,106.7,101.5,65.7,64.6,54.2,52.1,24.2; IR (KBr, cm -1) υ: 2949.8,2872.5,1591.6,1504.4,1436.1,1369.4,1263.1,1184.6,1112.7,1083.4,983.1,932.0,866.4,830.3,779.9; ESI-MS for C 14H 19NO 5: m/z (M +-H): 280.19.
1.5 4-(3-morpholine propoxy-)-2-hydroxy-n-(3-bromophenyl) BM is synthetic
(2g 7.1mmol), thionyl chloride (15mL), DMF 3d, stirs down in 50 ℃ of reaction 3h, and it is dried that reaction soln is concentrated into, and adds exsiccant CH in flask at the bottom of the garden, to add 2-hydroxyl-4-(3-morpholine propoxy-)-phenylformic acid 2Cl 2(10mL) solution A subsequent use.
Solution A is moved into tap funnel, splash into contain m-bromoaniline (1.3g, 7.6mmol), triethylamine (2mL, 14.4mmol), CH 2Cl 2(20mL) in the three-necked bottle, 30min drips off under the condition of ice bath, continues reaction 20min, and TLC [V (chloroform): V (methyl alcohol)=be developping agent at 10: 1] detects and shows and react complete basically; Add water 20mL, obtain organic layer, water layer is used CH 2Cl 2(20mL * 2) extraction merges organic layer, and after water (40mL) washing, through anhydrous sodium sulfate drying, decompression and solvent recovery gets tawny oily matter; Separate through silica gel column chromatography, chloroform: methyl alcohol (20: 1) be eluent, must white solid 1.0g, and yield is 36.7%, m.p.167.3～168.4 ℃; 1H NMR (DMSO-d 6, 400MHz) δ: 12.15 (s, 1H, NH), 10.39 (s, 1H, OH), 8.04 (s; 1H, ArH), 7.95 (d, J=8.8Hz, 1H, ArH), 7.65 (d, J=6.4Hz; 1H, ArH), 7.32～7.31 (m, 2H, ArH), 6.55 (d, J=8.8Hz, 1H; ArH), 6.49 (s, 1H, ArH), 4.06 (t, J=6.4Hz, 2H, NCH 2CH 2 CH 2 O), 3.57 (br s, 4H, morpholine rings CH 2 O CH 2 ), 2.44～2.38 (m, 6H, morpholine rings CH 2 N CH 2 AndN CH 2 CH 2CH 2O), 1.91～1.84 (m, 2H, NCH 2 CH 2 CH 2O); 13C NMR (DMSO-d 6, 100MHz) δ: 167.5,163.7,162.0,140.3,131.1,130.8,126.9,123.6,121.8,120.1,109.5,107.1,102.2,66.6,66.5,55.1,53.7,26.1; IR (KB r, cm -1) υ: 3438.2,2923.5,2867.0,1648.2,1588.9,1530.4,1470.6,1439.4,1234.2,1211.6,1113.0,1058.1,988.8,781.6; ESI-MS for C 20H 23BrN 2O 4: m/z (M +-H): 433.39.
Embodiment 2
Synthesizing of 4-(3-morpholine propoxy-)-2-hydroxy-n-(3-trifluorophenyl) BM
Figure BDA00001922788200081
Press among the embodiment 1 operation of 1.5 methods, 4-(3-morpholine propoxy-)-2-hydroxy-n-(3-trifluorophenyl) BM white crystal, yield 38.9%, m.p.159.2～160.8 ℃; 1H NMR (DMSO-d 6, 400MHz) δ: 12.07 (s, 1H, NH), 10.48 (s, 1H, OH), 8.17 (s; 1H, ArH), 7.97～7.94 (m, 2H, ArH), 7.62 (t, J=8.0Hz, 1H; ArH), 7.48 (d, J=7.6Hz, 1H, ArH), 6.58 (d, J=8.8Hz, 1H; ArH), 6.50 (s, 1H, ArH), 4.07 (t, J=6.0Hz, 2H, NCH 2CH 2 CH 2 O), 3.58 (br s, 4H, morpholine rings CH 2 O CH 2 ), 2.45～2.39 (m, 6H, morpholine rings CH 2 N CH 2 AndN CH 2 CH 2CH 2O), 1.90～1.87 (m, 2H, NCH 2 CH 2 CH 2O); 13C NMR (DMSO-d 6, 100MHz) δ: 167.7,163.8,162.0,139.5,130.8,130.3,124.9,123.2,120.8,120.7,117.5,109.4,107.2,102.2,66.6,66.5,55.1,53.7,26.1; IR (KBr, cm -1) υ: 3298.5,2963.7,2862.3,1662.4,1601.6,1558.7,1508.4,1446.3,1332.5,1289.9,1244.1,1192.7,1161.5,1120.5,1068.6,998.8,759.4,705.0; ESI-MS forC 21H 23F 3N 2O 4: m/z (M +-H) 423.37.
Embodiment 3
The building-up reactions formula of 4-(3-morpholine propoxy-)-2-hydroxy-n-(3-aminomethyl phenyl) BM
Figure BDA00001922788200091
Press among the embodiment 1 operation of 1.5 methods, 4-(3-morpholine propoxy-)-2-hydroxy-n-(3-aminomethyl phenyl) BM white crystal, yield 37.9%, m.p.166.8～168.7 ℃; 1H NMR (DMSO-d 6, 400MHz) δ: 12.41 (s, 1H, NH), 10.17 (s, 1H, OH), 7.99 (d, J=8.8Hz, 1H; ArH), 7.51 (s, 1H, ArH), 7.48 (d, J=8.0Hz, 1H, ArH), 7.26 (t, J=7.6Hz; 1H, ArH), 6.96 (d, J=7.6Hz, 1H, ArH), 6.55 (d, J=8.8Hz, 1H; ArH), 6.48 (d, J=1.6Hz, 1H, ArH), 4.07 (t, J=6.0Hz, 2H, NCH 2CH 2 CH 2 O), 3.58 (br s, 4H, morpholine ring CH2OCH2), 2.45～2.39 (m, 6H, morpholine ring CH2NCH2 and NCH2CH2CH2O), 2.31 (s, 3H, CH3), 1.93～1.85 (m, 2H, NCH2CH2CH2O); 13C NMR (DMSO-d6,100MHz) δ: 167.5,163.5,162.1,138.4,138.3,130.5,128.9,125.2,122.1,118.8,109.4,107.0,102.2,66.6,66.5,55.1,53.7,26.1,21.6; IR (KBr) υ: 3423.9,2921.9,2871.1,1649.4,1592.4,1555.1,1489.9,1439.7,1240.9,1216.9,1169.7,1110.2,1056.0,986.6,900.6,840.6,782.0; ESI-Mass (c+) for C21H26N2O4:m/z (M+-H) 369.37.
Embodiment 4
The building-up reactions formula of 4-(3-morpholine propoxy-)-2-hydroxy-n-(3-chloro-phenyl-) BM
Figure BDA00001922788200092
Press among the embodiment 1 operation of 1.5 methods, 4-(3-morpholine propoxy-)-2-hydroxy-n-(3-chloro-phenyl-) BM white crystal, yield 36.5%, m.p.178.3～179.2 ℃; 1H NMR (DMSO-d 6, 400MHz) δ: 12.15 (s, 1H, NH), 10.36 (s, 1H, OH), 7.95 (d, J=8.8Hz, 1H; ArH), 7.90 (s, 1H, ArH), 7.62 (t, J=7.6Hz, 1H, ArH), 7.41 (t, J=8.4Hz; 1H, ArH), 7.19 (d, J=7.6Hz, 1H, ArH), 6.57 (dd, J=8.8,1.6Hz, 1H; ArH), 6.49 (d, J=1.6Hz, 1H, ArH), 4.07 (t, J=6.4Hz, 2H, NCH 2CH 2 CH 2 O), 3.58 (br s, 4H, morpholine ring CH 2OCH 2), 2.45～2.39 (m, 6H, morpholine ring CH 2NCH 2And NCH 2CH 2CH 2O), 1.93～1.85 (m, 2H, NCH 2CH 2CH 2O); 13C NMR (DMSO-d 6, 100MHz) δ: 167.5,163.7,161.9,140.2,133.4,130.8,124.1,120.8,119.7,119.6,109.5,107.2,102.2,66.5,55.1,55.0,53.7,26.0; IR (KBr, cm -1) υ: 3422.6,2867.2,1650.1,1588.4,1534.3,1469.4,1432.6,1236.6,1112.7,1056.8,990.0,689.0; ESI-MS for C 20H 23ClN 2O 4: m/z (M +-H) 389.23.
Embodiment 5
The building-up reactions formula of 4-(3-morpholine propoxy-)-2-hydroxy-n-(2-chloro-4-nitrophenyl) BM
Figure BDA00001922788200101
Press among the embodiment 1 operation of 1.5 methods, 4-(3-morpholine propoxy-)-2-hydroxy-n-(2-chloro-4-nitrophenyl) BM yellow crystals, yield 39.2%, m.p.176.9～178.2 ℃; 1H NMR (DMSO-d 6, 400MHz) δ: 11.65 (s, 1H, NH), 8.87 (d, J=9.2Hz, 1H, ArH); 8.41 (d, J=2.0Hz, 1H, ArH), 8.28 (dd, J=9.2,2.0Hz, 1H; ArH), 7.96 (d, J=9.2Hz, 1H, ArH), 6.58 (d, J=8.8Hz, 1H; ArH), 6.52 (s, 1H, ArH), 4.04 (t, J=6.4Hz, 2H, NCH 2CH 2CH 2O), 3.58 (t, J=4.4Hz, 4H, morpholine ring CH 2OCH 2), 2.47～2.43 (m, 6H, morpholine ring CH 2NCH 2And NCH 2CH 2CH 2O), 1.92～1.86 (m, 2H, NCH 2CH 2CH 2O); 13C NMR (DMSO-d 6, 100MHz) δ: 164.4,163.8,159.6,142.5,142.3,133.1,125.2,124.3,122.4,120.8,111.4,107.3,102.3,66.4,66.3,55.0,53.6,25.8; IR (KBr, cm -1) υ: 3408.4,3288.5,2918.8,1678.6,1607.5,1546.0,1503.8,1468.7,1397.3,1337.5,1236.6,1114.6; ESI-MS for C 20H 22ClN 3O 6: m/z (M +-H) 434.22.
Embodiment 6
The building-up reactions formula of 4-(3-morpholine propoxy-)-2-hydroxy-n-(3-chloro-4-fluorophenyl) BM
Figure BDA00001922788200102
Press among the embodiment 1 operation of 1.5 methods, 4-(3-morpholine propoxy-)-2-hydroxy-n-(3-chloro-4-fluorophenyl) BM white crystal, yield 37.2%, m.p.168.3～170.1 ℃; 1H NMR (DMSO-d 6, 400MHz) δ: 12.14 (s, 1H, NH), 10.39 (s, 1H, OH), 8.01 (dd, J=6.8; 2.0Hz, 1H, ArH), 7.94 (d, J=9.2Hz, 1H, ArH), 7.65～7.61 (m, 1H; ArH), 7.44 (t, J=8.8Hz, 1H, ArH), 6.56 (dd, J=9.2,2.0Hz, 1H; ArH), 6.49 (d, J=2.0Hz, 1H, ArH), 4.06 (t, J=6.4Hz, 2H, NCH 2CH 2CH 2O), 3.57 (s, 4H, morpholine ring CH 2OCH 2), 2.44～2.38 (m, 6H, morpholine ring CH 2NCH 2And NCH 2CH 2CH 2O), 1.91～1.84 (m, 2H, NCH 2CH 2CH 2O); 13C NMR (DMSO-d 6, 100MHz) δ: 167.5,163.7,162.0,135.9,130.7,129.7,123.0,121.9,121.8,117.4,117.1,107.2,102.2,66.5,55.1,55.0,53.7,26.0; IR (KBr, cm -1) υ: 3413.7,2955.7,2862.1,1658.0,1600.8,1546.9,1502.7,1460.9,1433.1,1393.8,1325.3,1238.0,1115.6,1052.8,997.7,817.3; ESI-MS forC 20H 22ClFN 2O 4: m/z (M +-H) 407.33.
Embodiment 7
Synthesizing of 4-(3-piperidines propoxy-)-2-hydroxy-n-(3-bromophenyl) BM
7.14-(3-piperidines propoxy-)-2 hydroxybenzoic acid methyl esters is synthetic
In three-necked bottle, add 2-hydroxyl-4-(3-bromine propoxy-)-oil of Niobe (7.0g, 0.024mol), piperidines (3.0g, 0.036mol), sodium hydrogencarbonate (3.1g, 0.037mol) and Virahol (50mL); Stir down and react 6h with 85 ℃, and the TLC detection (developping agent: ETHYLE ACETATE) complete basically to reaction, cooling; Cross and filter filtrating, the reclaim under reduced pressure Virahol gets faint yellow oily thing; Through silica gel column chromatography (eluent: ETHYLE ACETATE) separate 4.9g, pale yellow oily liquid body, yield 70.5%. 1H NMR (CDCl 3, 400MHz) δ: 10.93 (s, 1H, OH), 7.71 (d, J=8.8Hz, 1H, ArH), 6.42 (d, J=9.2Hz, 1H, ArH), 4.03 (t, J=6.4Hz, 2H, NCH 2CH 2CH 2O), 3.89 (s, 3H, COOCH 3), 2.51～2.43 (m, 6H, piperidine ring CH 2NCH 2And NCH 2CH 2CH 2O), 2.02～1.96 (m, 2H, NCH 2CH 2CH 2O), 1.64～1.58 (m, 4H, piperidine ring CH 2), 1.46～1.44 (m, 2H, piperidine ring CH 2); 13C NMR (CDCl 3, 100MHz) δ: 170.3,165.0,163.7,131.1,107.7,105.3,101.2,66.6,55.6,54.5,51.8,26.4,25.7,24.2; IR (KBr, cm -1) υ: 3430.7,2955.8,2874.6,2647.6,1627.5,1587.7,1502.9,1439.3,1364.6,1227.3,1188.2,1149.1,1089.1,975.4,905.3,865.0; ESI-MS for C 16H 23NO 4: m/z (M ++ H) 294.19.
7.24-(3-piperidines propoxy-)-2 hydroxybenzoic acid is synthetic
Figure BDA00001922788200112
In round-bottomed flask, add successively 2-hydroxyl-4-(3-piperidines propoxy-)-oil of Niobe (4.1g, 0.014mol), NaOH (0.8g, 0.020mmol), methyl alcohol (20mL), pure water (10mL); Stirring at room 6h, TLC [V (chloroform): V (methyl alcohol)=be developping agent at 5: 1] detection reaction is complete, decompression and solvent recovery; PH to 5～6 are regulated with 3M hydrochloric acid in the cooling back, and the adularescent deposition is separated out suction filtration immediately; Washing; Dry 2-hydroxyl-4-(3-piperidines propoxy-)-phenylformic acid white solid 3.2g, yield 82.1%, m.p.180.5-182.2 ℃ of getting. 1H NMR (DMSO-d 6, 300MHz) δ: 12.89 (s, 1H, COOH), 10.87 (s, 1H, OH), 7.71 (d, J=9.6Hz, 1H, ArH), 6.47 (d, J=9.6Hz, 2H, ArH), 4.12 (t, J=6.0Hz, 2H, NCH 2CH 2CH 2O), 3.42 (brs, 2H, NCH 2CH 2CH 2O), 3.17 (t, J=7.8Hz, 2H, piperidine ring CH 2N), 2.87 (br s, 2H, piperidine ring CH 2N), 2.23～2.18 (m, 2H, NCH 2CH 2CH 2O), 1.79 (br s, 4H, piperidine ring CH 2), 1.69～1.40 (m, 2H, piperidine ring CH 2); 13C-NMR (DMSO-d 6, 100MHz) δ: 172.4,164.2,163.9,132.1,107.3,101.7,65.9,53.7,52.4,23.6,22.8,21.9; IR (KBr, cm -1) υ: 3373.0,2954.0,2873.0,1591.5,1505.1,1438.9,1363.0,1265.3,1185.1,1089.0,1049.2,978.8,907.3,830.9,786.9; ESI-MS for C 14H 19NO 5: m/z (M +-H) 278.40.
The building-up reactions formula of (7.44-3-piperidines propoxy-)-2-hydroxy-n-(3-bromophenyl) BM
(2g 7.1mmol), thionyl chloride (15mL), DMF 3d, stirs down in 50 ℃ of reaction 3h, and it is dried that reaction solution is concentrated into, and adds exsiccant CH in flask at the bottom of the garden, to add 2-hydroxyl-4-(3-piperidines propoxy-)-phenylformic acid 2Cl 2(10mL) 4-(3-piperidines propoxy-)-2-hydroxybenzoyl chloride solution A (solution A) is subsequent use.
Solution A is moved into tap funnel, splash into contain m-bromoaniline (1.3g, 7.6mmol), triethylamine (2mL, 14.4mmol), CH 2Cl 2In the three-necked bottle (20mL), 30min drips off under the condition of ice bath, continues reaction 20min, and TLC [V (chloroform): V (methyl alcohol)=be developping agent at 10: 1] detects and shows and react complete basically; Add water 20mL, after the jolting, obtain organic layer, water layer is used CH 2Cl 2(20mL * 2) extraction merges organic layer, after water (40mL) washing; Through anhydrous sodium sulfate drying, reclaim under reduced pressure gets tawny oily matter, separates through silica gel column chromatography; Chloroform: methyl alcohol (20: 1) is eluent; 4-(3-piperidines propoxy-)-2-hydroxy-n-(3-bromophenyl) BM white solid 1.0g, yield is 32.7%, m.p.220.5～222.3 ℃. 1H NMR (DMSO-d 6, 400MHz) δ: 10.77 (s, 1H, OH), 8.03 (s, 1H, ArH), 7.93 (t; J=9.2Hz, 1H, ArH), 7.64～7.62 (m, 1H, ArH), 7.32～7.28 (m, 2H; ArH), 6.51 (dd, J=8.4,2.4Hz, 1H, ArH), 6.45 (d; J=2.4Hz, 1H, ArH), 4.05 (t, J=5.6Hz, 2H, NCH 2CH 2CH 2O), 3.38 (m, 6H, piperidine ring CH 2NCH 2And NCH 2CH 2CH 2O), 1.92～1.88 (m, 2H, NCH 2CH 2CH 2O), 1.57～1.52 (m, 4H, piperidine ring CH 2), 1.42 (br s, 2H, piperidine ring CH 2); 13C NMR (DMSO-d 6, 100MHz) δ: 166.9,163.0,162.1,138.1,137.8,130.1,128.4,124.5,121.4,118.1,109.2,106.1,101.8,65.8,55.3,44.8,26.4,21.1; IR (KBr, cm -1) υ: 2947.4,1647.4,1578.2,1528.3,1473.6,1435.1,1225.8,986.0,779.7; ESI-MS for C 21H 25BrN 2O 3: m/z (M +-H) 431.37.
Embodiment 8
Synthesizing of 4-(3-piperidines propoxy-)-2-hydroxy-n-(3-trifluorophenyl) BM
Figure BDA00001922788200131
Press among the embodiment 7 operation of 7.4 methods, 4-(3-piperidines propoxy-)-2-hydroxy-n-(3-trifluorophenyl) BM white crystal, yield 37.5%, m.p.196.7～198.0 ℃; 1H NMR (DMSO-d 6, 400MHz) δ: 11.31 (s, 1H, NH), 10.61 (s, 1H, OH), 8.20 (s, 1H; ArH), 8.05 (d, J=8.4Hz, 1H, ArH), 7.97 (d, J=8.4Hz, 1H, ArH); 7.62 (t, J=7.6Hz, 1H, ArH), 7.48 (d, J=7.6Hz, 1H, ArH); 6.58 (d, J=9.2Hz, 2H, ArH), 4.12 (t, J=5.6Hz, 2H, NCH 2CH 2CH 2O), 3.08～3.05 (m, 6H, piperidine ring CH 2NCH 2And NCH 2CH 2CH 2O), 2.18～2.14 (m, 2H, NCH 2CH 2CH 2O), 1.77～1.74 (m, 4H, piperidine ring CH 2), 1.52 (br s, 2H, piperidine ring CH2); 13C NMR (DMSO-d 6, 100MHz) δ: 167.7,163.4,161.9,139.5,131.0,130.3,130.0,129.7,125.9,125.0,123.2,120.8,120.7,117.5,109.8,107.0,102.4,65.8,53.8,52.7,23.9,23.1,22.1; IR (KB r, cm -1) υ: 3283.4,2947.6,2635.9,1648.2,1598.4,1554.3,1494.3,1447.4,1379.5,1332.4,1249.7,1154.5,1122.6,1071.6,801.2; ESI-MS for C 22H 25F 3N 2O 3: m/z (M +-H) 421.38.
Embodiment 9
The building-up reactions formula of 4-(3-piperidines propoxy-)-2-hydroxy-n-(3-trifluorophenyl) BM
Figure BDA00001922788200132
Press among the embodiment 7 operation of 7.4 methods, 4-(3-piperidines propoxy-)-2-hydroxy-n-(3-aminomethyl phenyl) BM white crystal, yield 35.6%, m.p.169.8～171.6 ℃; 1H NMR (DMSO-d 6, 300MHz) δ: 11.48 (s, 1H, NH), 10.26 (s, 1H, OH), 8.02 (d, J=8.7Hz, 1H; ArH), 7.51 (t, J=8.7Hz, 2H, ArH), 7.27 (t, J=7.5Hz, 1H, ArH), 6.96 (d; J=7.5Hz, 1H, ArH), 6.56 (m, 2H, ArH), 4.07 (t, J=5.7Hz, 2H, NCH 2CH 2CH 2O), 2.83 (br s, 6H, piperidine ring CH 2NCH 2And NCH 2CH 2CH 2O), 2.31 (s, 3H, CH 3), 2.09～2.03 (m, 2H, NCH 2CH 2CH 2O), 1.66～1.64 (m, 4H, piperidine ring CH 2), 1.47 (brs, 2H, piperidine ring CH 2); 13C NMR (DMSO-d 6, 75MHz) δ: 167.4,163.2,162.1,138.4,138.3,130.7,129.0,125.3,122.1,118.8,109.7,106.9,102.3,65.8,54.0,52.8,24.1,23.4,22.2,21.6; IR (KBr, cm -1) υ: 2945.6,1645.8,1597.4,01549.4,1488.2,1438.1,1380.1,1330.6,1244.0,1145.2,1093.2,982.1,850.7,788.0,694.6; ESI-MS for C 22H 28N 2O 3: m/z (M +-H) 367.33.
Embodiment 10
The building-up reactions formula of 4-(3-piperidines propoxy-)-2-hydroxy-n-(3-chloro-phenyl-) BM
Figure BDA00001922788200141
Press among the embodiment 7 operation of 7.4 methods, 4-(3-piperidines propoxy-)-2-hydroxy-n-(3-chloro-phenyl-) BM, white solid, yield 36.8%, m.p.215.4～217.3 ℃; 1H NMR (DMSO-d 6, 300MHz) δ: 11.59 (s, 1H, NH), 10.75 (s, 1H, OH), 7.93～7.91 (m, 2H; ArH), 7.59 (d, J=8.1Hz, 1H, ArH), 7.38 (t, J=8.1Hz, 1H, ArH); 7.18 (d, J=7.5Hz, 1H, ArH), 6.52 (dd, J=9.0,2.4Hz, 1H, ArH); 6.45 (d, J=2.1Hz, 1H, ArH), 4.05 (t, J=6.3Hz, 2H, NCH 2CH 2CH 2O), 3.34 (brs, 6H, piperidine ring CH 2NCH 2And NCH 2CH 2CH 2O), 1.92～1.87 (m, 2H, NCH 2CH 2CH 2O), 1.54～1.51 (m, 4H, piperidine ring CH 2), 1.41 (br s, 2H, piperidine ring CH 2); 13C-NMR (DMSO-d 6, 75MHz) δ: 167.6,163.6,162.4,160.1,136.5,133.4,132.1,130.8,124.0,120.8,119.7,106.9,102.4,66.4,55.0,54.1,25.8,25.3,23.8; IR (KBr, cm -1) υ: 3412.6,2945.9,1646.8,1588.4,1532.4,1475.3,1433.8,1327.4,1230.5,1135.0,1096.4,986.8,871.0,690.9; ESI-MS for C 21H 25ClN 2O 3: m/z (M +-H) 387.29.
Embodiment 11
Synthesizing of 4-(3-piperidines propoxy-)-2-hydroxy-n-(2-chloro-4-nitrophenyl) BM
Figure BDA00001922788200142
Press 7.4 methods operation among the embodiment 7, get 4-(3-piperidines propoxy-)-2-hydroxy-n-(2-chloro-4-nitrophenyl) BM yellow crystals, yield 37.2%, m.p.231.5-232.7 ℃; 1H NMR (DMSO-d 6, 400MHz) δ: 8.90 (d, J=9.2Hz, 1H, ArH), 8.38 (d, J=2.8Hz, 1H, ArH), 8.26 (dd, J=9.2,2.4Hz, 1H, ArH), 7.93 (d, J=9.2Hz, 1H, ArH), 6.47～6.45 (m, 2H, ArH), 4.04 (t, J=6.0Hz, 2H, NCH 2CH 2CH 2O), 2.96 (br s, 6H, piperidine ring CH 2NCH 2And NCH 2CH 2CH 2O), 2.06～2.02 (m, 2H, NCH 2CH 2CH 2O), 1.69～1.65 (m, 4H, piperidine ring CH 2), 1.49 (br s, 2H, piperidine ring CH 2); 13C-NMR (DMSO-d 6, 100MHz) δ: 170.0,168.2,148.1,146.7,137.5,129.9,129.0,127.1,125.5,116.6,115.9,110.6,107.5,70.3,59.0,57.8,29.2,28.5,27.2; IR (KBr, cm -1) υ: 2966.0,2703.8,1658.8,1618.5,1587.3,1513.6,1470.3,1413.1,1344.6,1296.3,1220.8,1155.9,1098.0,981.5,846.6; ESI-MS for C 21H 24ClN 3O 5: m/z (M ++ H) 434.11.
Embodiment 12
Synthesizing of 4-(3-piperidines propoxy-)-2-hydroxy-n-(3-chloro-4-fluorophenyl) BM
Figure BDA00001922788200151
Press among the embodiment 7 operation of 7.4 methods, 4-(3-piperidines propoxy-)-2-hydroxy-n-(3-chloro-4-fluorophenyl) BM, white solid, yield 37.2%, m.p.214.4～215.7 ℃; 1H NMR (DMSO-d 6, 300MHz) δ: 10.81 (s, 1H, OH), 8.03 (m, 1H, ArH), 7.91 (d, J=8.7Hz, 1H; ArH), 7.63～7.58 (m, 1H, ArH), 7.44 (t, J=8.7Hz, 1H, ArH), 6.51 (dd, J=8.7; 2.1Hz, 1H, ArH), 6.45 (s, 1H, ArH), 4.05 (t, J=6.0Hz, 2H, NCH 2CH 2CH 2O), 3.36 (br s, 6H, piperidine ring CH 2NCH 2And NCH 2CH 2CH 2O), 1.94～1.85 (m, 2H, NCH 2CH 2CH 2O), 1.54～1.51 (m, 4H, piperidine ring CH 2), 1.42～1.40 (m, 2H, piperidine ring CH 2); 13C-NMR (DMSO-d 6, 75MHz) δ: 180.6,169.4,167.5,163.6,136.1,130.7,125.4,122.8,121.7,117.4,117.1,106.7,102.4,66.4,55.1,54.2,26.1,25.5,24.0; IR (KBr, cm -1) υ: 3416.7,2944.2,2867.7,1646.3,1594.9,1546.9,1498.6,1436.1,1324.9,1243.7,1212.3,1140.8,1051.7,982.6,859.8; ESI-MS for C 21H 24ClFN 2O 3: m/z (M +-H) 405.39.

Claims (6)

1. the compound of general formula (I) or its pharmacy acceptable salt:
Figure FDA00001922788100011
Wherein R chooses wantonly and represents halogen, methyl, trifluoromethyl or nitro; X represents O, CH 2, NH, CH 3CON, HOCH 2CH 2N or CH 3N.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein X represents O.
3. the compound of claim 1 or its pharmacy acceptable salt, wherein halogen is F, Cl or Br.
4. the compound of claim 1 or its pharmacy acceptable salt, wherein pharmacy acceptable salt is hydrochloride, vitriol, phosphoric acid salt, PHENRAMINE MALEATE, fumarate, citrate, mesylate, tosilate, tartrate or the acetate of general formula (I) compound.
5. anti-tumor composition wherein contains in the claim 1 to 4 each compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
6. each compound or its pharmacy acceptable salt are used to prepare the purposes of antitumor drug in the claim 1 to 4.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030149015A1 (en) * 1997-07-01 2003-08-07 Barrett Stephen Douglas 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives
US20030212068A1 (en) * 1998-05-15 2003-11-13 Astrazeneca Ab Benzamide derivatives for the treatment of diseases mediated by cytokines
CN101184734A (en) * 2004-12-28 2008-05-21 金克斯医药品有限公司 Compositions and methods of treating cell proliferation disorders
CN101506175A (en) * 2006-06-15 2009-08-12 贝林格尔·英格海姆国际有限公司 2-anilino-4-(heterocyclic)amino-pyrimidines as inhibitors of protein kinase C-alpha
CN102531949A (en) * 2010-12-29 2012-07-04 中国医学科学院药物研究所 Substituted benzamide compounds and preparation method and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030149015A1 (en) * 1997-07-01 2003-08-07 Barrett Stephen Douglas 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives
US20030212068A1 (en) * 1998-05-15 2003-11-13 Astrazeneca Ab Benzamide derivatives for the treatment of diseases mediated by cytokines
CN101184734A (en) * 2004-12-28 2008-05-21 金克斯医药品有限公司 Compositions and methods of treating cell proliferation disorders
CN101506175A (en) * 2006-06-15 2009-08-12 贝林格尔·英格海姆国际有限公司 2-anilino-4-(heterocyclic)amino-pyrimidines as inhibitors of protein kinase C-alpha
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