CN103058959A - N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amide compound and application thereof - Google Patents
N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amide compound and application thereof Download PDFInfo
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Abstract
The invention relates to an application of a new N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amide compound in prevention and treatment of various cancers; the general formula of the N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amide compound is as shown in (I), wherein L represents C1-4 lower alkyl, C1-4 lower alkoxyl, C1-4 lower alkylamino, O or OR2, S or SR2 and NH or NR2, and R2 represents C1-4 lower alkyl, C1-4 lower alkoxyl or C1-4 lower monoalkylamino; and R1 represents C1-18 hydrocarbyl, C1-9 alkoxyl or C1-9 monoalkylamino, substituted 3-9-membered alicyclic ring, alicyclic heterocyclic ring, phenyl, substituted phenyl, substituted aromatic ring, substituted aromatic heterocyclic ring or substituted aromatic heterocyclic bicyclic ring, halogen, SH, OH or NO2. The cancer cell inhibition experiment validates that the amide compound can inhibit SW480, HeLa, A549, HCT-8 and other cancer cells, has better curative effect and preventive effect on cancer, and can be used as a new broad-spectrum anti-cancer drug.
Description
[technical field]
The present invention relates to the cancer drug technical field, be specially the new N-of a class (2-(4-methylpiperazine-1-yl)-5-formylphenyl) amides and application thereof.
[background technology]
Cancer is that body is under various carcinogenic factor effects, some cells of local organization or a plurality of cell lose normal regulation to its growth at gene level, the abnormality that causes its clonal abnormality hyperplasia and form, the cell of propagation form lump and then are called tumour.Malignant tumour is greatly threatening human healthy living, has become the first killer of one of maximum public health security in the whole world and new millennium threat human life.The sickness rate of malignant tumour is improving year by year.From world wide, be 1,010 ten thousand in the number of global new tumour in 2000, dead 6,200,000, just cancered number is 22,400,000 now.In 2008, cancer number and death toll rose to respectively 1,266 ten thousand and 7,560,000, and wherein developing country's cancer number will reach 56%.Develop down according to this situation, 2015, will there be 1,500 ten thousand new cancer patientss in the whole world, and developing country approximately will have 9,000,000 people to die from cancer.
The methods for the treatment of of tumour is divided into operative treatment, radiotherapy and three kinds of methods of pharmacological agent.Wherein operative treatment and radiotherapy are large to Normocellular infringement, and substantially can't eradicate for malignant tumour.Enter 21 century, along with scientific and technical fast development, increasing effect is being brought into play in pharmacological agent in oncotherapy.Its small molecular target therapeutic agent is more and more active in the treatment of tumour, in order obviously to improve result for the treatment of, seeks some and has specific small molecules targeted drug and become the task of top priority.
The objective of the invention is to utilize N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amides to come anticancer propagation as the small molecules targeted drug, reach the effect for the treatment of and prophylaxis of tumours.
[summary of the invention]
The object of the present invention is to provide a kind of new N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amides and application thereof.
The objective of the invention is to be achieved through the following technical solutions:
A kind of new inhibitor of EGF-R ELISA, its chemical structural formula is:
Wherein
L is C
1-4Low alkyl group, C
1-4Lower alkoxy, C
1-4Lower alkyl amino, O or OR
2, S or SR
2, NH or NR
2, R
2Be C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4A kind of in the rudimentary alkyl monosubstituted amino;
L is preferably O or OR
2, S or SR
2, NH or NR
2, R
2Be C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino;
R
1For phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus, replace 5-9 membered aromatic heterocycle or the assorted dicyclo of substituted aroma and (contain 1-3 heteroatoms that is selected from oxygen, sulphur, nitrogen, can and close by phenyl and aromatic heterocycle, or by one or more halogen, C of being selected from
1-C
6Straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4Acyl group, 5-9 unit's aromatic base or fragrant heterocyclic radical Ar replace);
Aromatic base or fragrant heterocyclic radical Ar can be that (substituting group can be 1-4 and be selected from halogen, C for phenyl, substituted-phenyl, substituted benzyl, substituted benzyloxy, replacement benzyl amino, replacement 5-9 unit's aromatic base or fragrant heterocyclic radical
1-C
6Straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4The group of acyl group), Nai Ji, Lian Naiji;
R
1For being preferably phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus;
A kind of pharmaceutical composition, it is characterized in that, contain compound or the combination of formula I, the pharmaceutically acceptable salt that perhaps contains the compound of formula I such as the salt of receiving of the compound that contains formula I, contains the sylvite of the compound of formula I, the hydrochloride that contains the compound of formula I, the vitriol that contains the compound of formula I contains the calcium salt of the compound of formula I, contains the hydrochloride of the compound of formula I.
A kind of route of administration of pharmaceutical composition comprises oral, nasal cavity suction, Transdermal absorption, pulmonary administration and parenteral drug administration by injection.
Contain medicine or the medicinal application of pharmaceutical composition in prevention and treatment cancer of formula I structural formula.
Cancer can be lung cancer, mammary cancer, head and neck cancer, the rectum cancer etc.
Compared with prior art, positively effect of the present invention is:
The present invention by the computer virtual screening design obtain, this compounds of inhibition of cancer cell experiment confirm has preferably curative effect and prophylactic effect for cancer.
The present invention is a kind of new texture, has certain antitumour activity, can become a kind of novel antitumor and anticancer agent.
[description of drawings]
Fig. 1 is that N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-phenoxy acetamide is to the inhibition curve of SW480 cell;
Fig. 2 is that N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-phenoxy acetamide is to the inhibition curve of HCT-8 cell;
Fig. 3 is that N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) pyrazine-2-methane amide is to the inhibition curve of A549 cell;
Fig. 4 is that N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) pyrazine-2-methane amide is to the inhibition curve of HeLa cell;
Fig. 5 is that N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(thiophene-2-yl) ethanamide is to the inhibition curve of A549 cell;
Fig. 6 is that N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(thiophene-2-yl) ethanamide is to the inhibition curve of SW480 cell;
Fig. 7 is that N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(pyridine-4-sulfo-) ethanamide is to the inhibition curve of A549 cell;
Fig. 8 is the structural formula of a kind of novel N-of the present invention (2-(4-methylpiperazine-1-yl)-5-formylphenyl) amides anticancer compound.
[embodiment]
The embodiment of a kind of N-of the present invention (2-(4-methylpiperazine-1-yl)-5-formylphenyl) amides and application thereof below is provided.
Embodiment 1
3-nitro-4-(4-methylpiperazine-1-yl) phenyl aldehyde
In the 100mL there-necked flask, add 3-nitro-4-fluorobenzaldehyde (6.76g, 39.97mmol), Anhydrous potassium carbonate (6.08g, 43.97mmol), dry DMF 15mL is at N
2The lower heated and stirred of protection when temperature rises to 100 ℃, is slowly injected N methyl piperazine (4.88mL, 43.97mmol) with syringe, continues to stir the TLC tracking monitor.
After reaction finishes, pressure reducing and steaming solvent and excessive N methyl piperazine, be transferred in the 250mL separating funnel after adding 100mL ethyl acetate mixing, (3 * 50mL), (3 * 50mL) wash respectively the organic phase anhydrous magnesium sulfate drying three times to saturated nacl aqueous solution with distilled water, suction filtration, collect filtrate, revolve the steaming desolventizing, obtain yellow crude product.
Crude product separates (developping agent: ethyl acetate/methanol, 3: 1) through 200-300 order silica gel column chromatography and obtains yellow solid compound 3-nitro-4-(4-methylpiperazine-1-yl) phenyl aldehyde (8.97g, 35.98mmol), productive rate 90%.
MS(EI)m/z：[M]
+＝249.0；
1H?NMR(400MHz，CDCl
3)：δ9.85(s，1H)，8.26(d，J＝4Hz，1H)，7.92-7.94(q，1H)，7.14(d，J＝8Hz，1H)，3.24-3.32(m，4H)，2.51-2.66(m，4H)，2.37(s，3H)；IR(KBr)v(cm
-1)：3015(v?CH
2)，2852，2810(v?CH＝O)，1686(v?C＝O)，1606，1532，1505，1458(v?C＝C)，1347，813(vNO
2)。
Embodiment 2
3-amino-4-(4-methylpiperazine-1-yl) phenyl aldehyde
In the 250mL there-necked flask, add 3-nitro-4-(4-methylpiperazine-1-yl) phenyl aldehyde (7.48g, 30mmol), reduced iron powder (11.76g, 0.21mol) and the mixture of dehydrated alcohol, Glacial acetic acid and water (2: 2: 1,200mL), under mechanical stirring behind the backflow 15min, stirring at room 30min.
After reaction finishes, be cooled to room temperature, suction filtration falls iron powder, is spin-dried for solvent, with in the saturated sodium bicarbonate solution and Glacial acetic acid to weakly alkaline, with methylene dichloride (3 * 100mL) extractions, organic phase saturated nacl aqueous solution (3 * 100mL) washings, anhydrous magnesium sulfate drying, suction filtration, collect filtrate, revolve the steaming desolventizing, obtain yellow crude product.
Crude product separates (developping agent: methylene chloride/methanol, 40: 1) through 200-300 order silica gel column chromatography and obtains faint yellow compound 3-amino-4-(4-methylpiperazine-1-yl) phenyl aldehyde (4.60g, 20.98mmol), productive rate 69.9%.
MS(EI)m/z：[M]+＝219.1；1H?NMR(500MHz，CDCl3)：δ9.83(s，1H)，7.25-7.27(m，1H)，7.23(d，J＝1.5Hz，1H)，7.08(d，J＝8Hz，1H)，3.99(s，1H)，3.05(m，4H)，2.82(m，4H)，2.62(s，3H)；IR(KBr)v(cm-1)：3364(v?N-H)，2826，2739(v?CH＝O)，1684(v?C＝O)，1633(v?N-H)，1590，1572，1508，1446(v?C＝C)。
Embodiment 3
The carboxylic acid cpd that adds 1.37mmol in the 50mL round-bottomed flask slowly drips thionyl chloride 5mL under ice-water bath, stir behind the 30min reflux 4h in oil bath, revolves excessive thionyl chloride with Rotary Evaporators, need not purifying and is directly used in next step.
With compound 3-amino-4-(4-methylpiperazine-1-yl) phenyl aldehyde (200mg, 0.91mmol) be dissolved in the 15mL anhydrous methylene chloride, add the 0.5mL pyridine, under ice-water bath, dropwise add freshly prepd acyl chlorides in the dichloromethane solution, stir 15min, remove ice-water bath, stirring at room 24h adds saturated sodium bicarbonate solution after reaction finishes, tell organic phase after the extraction, organic phase distilled water, saturated sodium bicarbonate solution, saturated nacl aqueous solution respectively washs three times, anhydrous sodium sulfate drying, suction filtration, collect filtrate, revolve the steaming desolventizing, obtain crude product, crude product silicagel column purifying.
Embodiment 4
N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-phenoxy acetamide
In the 50mL round-bottomed flask, add phenoxy acetic acid (168mg, 1.10mmol), under ice-water bath, slowly drip excessive thionyl chloride, reflux 4h steams thionyl chloride with Rotary Evaporators, obtains the phenoxy acetic acid acyl chlorides, need not purifying, directly drop into next step.
In the 50mL round-bottomed flask with 3-amino-4-(4-methylpiperazine-1-yl) phenyl aldehyde (200mg, 0.91mmol) be dissolved in the 15mL methylene dichloride, drip again the 0.5mL pyridine, under ice-water bath, slowly drip the phenoxy acetic acid acyl chlorides, dropwise and stir 30min, then at room temperature stir and spend the night, reaction finishes, and is spin-dried for solvent, uses dichloromethane extraction, organic phase distilled water (3 * 50mL), saturated sodium bicarbonate solution (3 * 50mL) and saturated nacl aqueous solution (3 * 50mL) washing, use anhydrous magnesium sulfate drying, suction filtration is collected filtrate again, revolve the steaming desolventizing, obtain yellow crude product.Crude product separates (developping agent: methylene chloride/methanol, 40: 1) through 200-300 order silica gel column chromatography and obtains whitening compound 224mg, yield 69.7%.
m.p.127-129℃；
1H?NMR(500MHz，CDCl
3)；δ9.97(s，1H)，9.47(s，1H)，8.97(d，J＝2Hz，1H)，7.68(dd，J
1＝2Hz，J
2＝8Hz，1H)，7.37-7.39(t，2H)，7.28(d，J＝8Hz，1H)，7.06-7.09(m，3H)，4.69(s，2H)，2.93-2.95(m，4H)，2.45-2.85(m，4H)，2.36(s，3H)；
13C?NMR(100MHz，CDCl
3)：δ191.54，166.31，157.23，144.30，129.91，129.10，125.85，123.90，122.35，120.95，116.03，114.74，67.90，55.49，51.92，46.16；IR(KBr)v(cm
-1)：3222(v?N-H)，2845，2795，2768(v?CH＝O)，1705(v?O＝C-H)，1690(v?O＝C-NH)，1597，1575，1527，1496，1460(v?C＝C)；HRMS(EI)Calcd?for?C
20H
23N
3O
3[M+H]
+353.1741，Found：353.1739。
Embodiment 5
3-(4-fluorophenyl)-N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) acrylamide
With reference to the preparation method of embodiment 3, get yellow solid 3-(4-fluorophenyl)-N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) acrylamide 233mg, yield 69.8%.m.p.149-151℃；
1H?NMR(400MHz，CDCl
3)；δ9.97(s，1H)，8.96(s，1H)，8.36(s，1H)，7.76(d，J＝1.6Hz，1H)，7.67(d，J＝8Hz，1H)，7.58(t，2H)，7.26-7.30(t，1H)，7.09-7.13(t，2H)，6.47(d，J＝1.6Hz，1H)，3.02(m，4H)，2.69(m，4H)，2.44(s，3H)；
13C?NMR(100MHz，CDCl
3)：δ191.61，165.07，162.57，146.90，141.64，130.68，129.98，124.60，122.67，120.57，120.30，116.20，115.98，55.62，51.64，46.13；IR(KBr)v(cm-1)：3326(v?N-H)，2942，2842，2794(v?CH＝O)，1695(v?C＝O)，1633(v?N-H)，1599，1579，1526，1510，1441(v?C＝C)；HRMS(EI)Calcd?for?C
21H
22FN
3O
2[M+H]
+367.1694，Found：367.1696。
Embodiment 6
N-(2-(4-methylpiperazine-1-yl-5-formylphenyl) biphenyl-4-methane amide
With reference to the preparation method of embodiment 3, get white solid N-(2-(4-methylpiperazine-1-yl-5-formylphenyl) biphenyl-4-methane amide 236mg, yield 65.0%.m.p.181-183℃；
1H?NMR(400MHz，CDCl
3)：δ10.01(s，1H)，9.21(s，1H)，9.08(s，1H)，8.02(d，J＝8Hz，2H)，7.78(d，J＝8Hz，2H)，7.60-7.74(m，3H)，7.50(t，2H)，7.43(d，J＝8Hz，1H)，7.35(d，J＝8Hz，1H)，3.07(m，4H)，2.71(m，4H)，2.44(s，3H)；
13C?NMR(100MHz，CDCl
3)：δ191.70，164.67，146.75，145.02，139.71，133.81，133.58，133.12，129.03，128.28，127.64，127.50，127.25，124.47，122.34，120.88，55.73，51.58，46.02；IR(KBr)v(cm-1)：3382(v?N-H)，2847，2770(v?CH＝O)，1689(v?O＝C-H)，1668(v?O＝C-NH)，1599，1576，1526，1488，1458，1437(v?C＝C)；HRMS(EI)Calcd?for?C
25H
25N
3O
2[M+H]
+399.1948，Found：399.1947。
Embodiment 7
N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) pyrazine-2-methane amide
With reference to the preparation method of embodiment 3, get faint yellow solid N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) pyrazine-2-methane amide 213mg, yield 72%.m.p.166-168℃；
1H?NMR(400MHz，CDCl
3)：δ10.62(s，1H)，10.00(s，1H)，9.55(s，1H)，9.06(s，1H)，8.85(s，1H)，8.65(s，1H)，7.71(d，J＝8Hz，1H)，7.30(d，J＝8Hz，1H)，3.08(m，4H)，2.74(m，4H)，2.45(s，3H)；
13C?NMR(100MHz，CDCl
3)：δ191.47，160.75，147.68，144.81，144.65，142.64，132.98，132.55，125.32，122.10，120.41，55.44，51.56，46.24；IR(KBr)v(cm-1)：3292(v?N-H)，2931，2829，2795(v?CH＝O)，1691(v?C＝O)，1598，1577，1531，1494，1463，1440(v?C＝C)；HRMS(EI)Calcdfor?C
17H
19N
5O
2[M+H]
+325.1533，Found：325.1539。
Embodiment 8
N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(naphthyl-2-yl) ethanamide
With reference to the preparation method of embodiment 3, get white solid N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(naphthyl-2-yl) ethanamide 264mg, yield 75%.m.p.136-138℃；
1H?NMR(400MHz，CDCl
3)：δ9.95(s，1H)，9.00(s，1H)，8.32(s，1H)，7.89(dd，J
1＝8Hz，J
2＝20Hz，4H)，7.57(dd，J
1＝8Hz，J
2＝16Hz，3H)，7.47(d，J＝8Hz，1H)，7.13(d，J＝8Hz，1H)，4.01(s，2H)，2.45-2.74(m，4H)，1.85-2.35(m，4H)，1.73(s，3H)；
13C?NMR(100MHz，CDCl
3)：δ191.71，169.27，146.56，133.91，133.62，133.30，132.93，131.62，129.39，128.99，127.91，127.77，127.34，126.90，126.56，124.34，121.79，120.76，54.34，51.45，45.66，45.18；IR(KBr)v(cm-1)：3293(v?N-H)，2945，2842(v?CH＝O)，1691(v?O＝C-H)，1668(v?O＝C-NH)，1597，1578，1524，1460，1437(v?C＝C)；HRMS(EI)Calcd?for?C
24H
25N
3O
2[M+H]
+387.1948，Found：387.1947。
Embodiment 9
N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2,2-phenylbenzene ethanamide
With reference to the preparation method of embodiment 3, obtain white solid N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2,2-phenylbenzene ethanamide 300mg, yield 80%.m.p.164-166℃；
1H?NMR(400MHz，CDCl
3)：δ9.92(s，1H)，8.98(s，1H)，8.49(s，1H)，7.63(d，J＝8Hz，1H)，7.32-7.40(m，10H)，7.20(d，J＝8Hz，1H)，5.16(s，1H)，2.65-2.83(m，4H)，2.24-2.42(m，4H)，2.17(s，3H).；
13C?NMR(100MHz，CDCl
3)：δ191.62，170.38，146.72，138.90，133.53，133.29，129.09，129.08，127.72，124.33，122.28，120.76，60.56，54.75，51.61，45.85；IR(KBr)v(cm-1)：3330(v?N-H)，2944，2847，2802，2772(v?CH＝O)，1690(v?C＝O)，1597，1575，1520，1492，1461，1448，1433(v?C＝C)；HRMS(EI)Calcd?for?C
26H
27N
3O
2[M+H]
+413.2101，Found：413.2103。
Embodiment 10
N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(thiophene-2-yl) ethanamide
With reference to the preparation method of embodiment 3, obtain faint yellow solid N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(thiophene-2-yl) ethanamide 194mg, yield 62%.m.p.80-82℃；
1H?NMR(400MHz，CDCl
3)：δ9.94(s，1H)，8.94(s，1H)，8.61(s，1H)，7.62(d，J＝8Hz，1H)，7.35(d，J＝4Hz，1H)，7.22(d，J＝8Hz，1H)，7.1-7.13(m，2H)，4.04(s，2H)，2.7-2.89(m，4H)，2.35-2.52(m，4H)，2.33(s，3H)；
13C?NMR(100MHz，CDCl
3)：δ191.65，168.08，146.67，135.50，133.55，133.36，128.37，128.01，126.48，124.63，121.77，120.99，54.79，51.53，45.84，38.92；IR(KBr)v(cm-1)：3420(v?N-H)，2851，2740(v?CH＝O)，1636(v?C＝O)，1521，1461，1399(v?C＝C)；HRMS(EI)Calcd?for?C
18H
21N
3O
2S[M+H]
+343.1356，Found：343.1354。
Embodiment 11
N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(pyridine-4-sulfo-) ethanamide
3-amino-4-(4-methylpiperazine-1-yl) phenyl aldehyde (200mg, 0.91mmol) be dissolved in the 15mL dichloromethane solution, add successively 4-(pyrimidine phosphorothioate) acetic acid (230mg, 1.36mmol), EDCI (391mg, 2.04mmol) and HOBT (276mg, 2.04mmol), add at last the 1mL triethylamine, at room temperature stir and spend the night, after reaction finishes, be spin-dried for solvent, add the 30mL dichloromethane solution, use successively distilled water (3 * 30mL), saturated sodium bicarbonate solution (3 * 30mL) and saturated nacl aqueous solution (3 * 30mL) washing, use again anhydrous magnesium sulfate drying, suction filtration, collect filtrate, revolve the steaming desolventizing, obtain yellow crude product.Crude product separates (developping agent: methylene chloride/methanol, 40: 1) through 200-300 order silica gel column chromatography and obtains faint yellow compound 195mg, yield 58%.
Ethanamide m.p.72-74 ℃ of N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(pyridine-4-sulfo-);
1H NMR (400MHz, CDCl3): δ 9.95 (s, 1H), 9.58 (s, 1H), 8.91 (d, J=4Hz, 2H), 8.46 (d, J=4Hz, 2H), 7.65 (dd, J
1=2Hz, J
2=8.4Hz, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 7.16 (dd, J
1=1.6Hz, J
2=4.8Hz, 2H), 3.92 (s, 2H), 2.75-2.94 (m, 4H), 2.42-1.65 (m, 4H), 2.37 (s, 3H);
13C NMR (100MHz, CDCl
3): δ 186.15,159.80, and 144.71,128.20,127.69,120.16,116.23,115.83,114.78,49.91,46.31,40.72,30.42; IR (KBr) v (cm-1): 3331 (v N-H), 2922,2849,2801 (v CH=O), 1690 (v C=O), 1600,1577,1523,1460,1437 (v C=C); HRMS (EI) Calcd forC
19H
22N
4O
2S[M+H]
+371.1541, Found:370.1463.
Embodiment 12
In the moist incubator that carbonic acid gas 5% is 37 ℃, (add 10% foetal calf serum with the DMEM nutrient solution, the glutamine of 2mM, the Streptomycin sulphate of the penicillin of 50U/mL and 50 μ g/mL) cellar culture Non-small cell lung carcinoma cell line A549, human colon cancer cell SW480, human cervical carcinoma cell strain HeLa and ileocecum JEG-3 HCT-8 etc.The cancer cells of taking the logarithm vegetative period adds respectively in 96 orifice plates, 10000 cells in every hole, 200 μ L/ holes.After 24 hours, add among the embodiment and prepare compound, concentration is 0-100 μ M, and each concentration arranges 3 parallel holes, puts 37 ℃ of cultivations.After 72 hours, discard nutrient solution, every hole adds the DMEM nutrient solution 200 μ L of 10%MTT, cultivated again 4 hours, and discarded nutrient solution, add the DMSO of 200 μ L, after first is collected together dissolution of crystals, detect the OD value in every hole under 492nm on the microplate reader and 570nm wavelength, more by formula: cell survival rate=administration group OD value/control group OD value * 100%, inhibiting rate=(1-administration group OD value/control group OD value) * 100% calculates the half inhibiting rate of each compound.Take logC (logarithm of concentration) as X-coordinate, cell survival rate as ordinate zou mapping obtain respectively embodiment 4 N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl)-the 2-phenoxy acetamide is 33.14 μ mol/L for the half inhibiting rate of SW480 cell, be 25.31 μ mol/L for the half inhibiting rate of HCT-8 cell.The N-of embodiment 7 (2-(4-methylpiperazine-1-yl)-5-formylphenyl) pyrazine-2-methane amide is 33.80 μ mol/L and 33.85 μ mol/L for the half inhibiting rate of A549 cell and HeLa cell.The N-of embodiment 10 (2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(thiophene-2-yl) ethanamide is 25.12 μ mol/L and 45.97 μ mol/L for the half inhibiting rate of A549 and SW480 cell.The N-of embodiment 11 (2-(4-methylpiperazine-1-yl)-5-formylphenyl)-2-(pyridine-4-sulfo-) ethanamide is 30.19 μ mol/L for the inhibiting rate of A549.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, without departing from the inventive concept of the premise; can also make some improvements and modifications, these improvements and modifications also should be considered within the scope of protection of the present invention.
Claims (7)
1. a N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amides is characterized in that, its chemical structural formula is:
Wherein
L is C
1-4Low alkyl group, C
1-4Lower alkoxy, C
1-4Lower alkyl amino, O or OR
2, S or SR
2, NH or NR
2, R
2Be C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino;
R
1For phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus, replace 5-9 membered aromatic heterocycle or the assorted dicyclo of substituted aroma and (contain 1-3 heteroatoms that is selected from oxygen, sulphur, nitrogen, can and close by phenyl and aromatic heterocycle, or by one or more halogen, C of being selected from
1-C
18Straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4Acyl group, 5-9 unit's aromatic base or fragrant heterocyclic radical Ar replace);
Aromatic base or fragrant heterocyclic radical Ar can be that (substituting group can be 1-4 and be selected from halogen, C for phenyl, substituted-phenyl, substituted benzyl, substituted benzyloxy, replacement benzyl amino, replacement 5-9 unit's aromatic base or fragrant heterocyclic radical
1-C
6Straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4The group of acyl group), Nai Ji, Lian Naiji.
2. a kind of N-as claimed in claim 1 (2-(4-methylpiperazine-1-yl)-5-formylphenyl) amides is characterized in that, L is preferably O or OR
2, S or SR
2, NH or NR
2, R
2Be C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino.
3. a kind of N-as claimed in claim 1 (2-(4-methylpiperazine-1-yl)-5-formylphenyl) amides is characterized in that R
1For being preferably phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus.
4. a pharmaceutical composition is characterized in that, contains compound or the combination of formula I, perhaps contains the pharmacy acceptable salt of the compound of formula I.
5. the route of administration of a kind of pharmaceutical composition as claimed in claim 4 is characterized in that, comprises oral, nasal cavity suction, Transdermal absorption, pulmonary administration and parenteral drug administration by injection.
6. the medicinal application of N-as claimed in claim 1 (2-(4-methylpiperazine-1-yl)-5-formylphenyl) amides in prevention and treatment cancer.
7. a kind of medicine as claimed in claim 4 or pharmaceutical composition are in the medicinal application of prevention and treatment cancer.
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|---|---|---|---|---|
| WO2010059239A2 (en) * | 2008-11-21 | 2010-05-27 | Millennium Pharmaceuticals, Inc | Lactate salt of 4-(6-methoxy-7-(3-piperidin-1-yl-propoxy)quinazolin-4-yl]piperazine-1-carboxylic acid(4-isopropoxyphenyl)-amide and pharmaceutical compositions thereof for the treatment of cancer and other diseases or disorders |
| CN101774976A (en) * | 2010-01-26 | 2010-07-14 | 天津药物研究院 | Sulfonyl isoxazoline derivative and anti-tumor application |
| CN102363618A (en) * | 2011-07-04 | 2012-02-29 | 华东理工大学 | Novel inhibitor of epidermal growth factor receptor (EGFR) and application thereof |
| CN102503945A (en) * | 2011-11-28 | 2012-06-20 | 华东理工大学 | Compound capable of inhibiting epidermal growth factor receptor and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010059239A2 (en) * | 2008-11-21 | 2010-05-27 | Millennium Pharmaceuticals, Inc | Lactate salt of 4-(6-methoxy-7-(3-piperidin-1-yl-propoxy)quinazolin-4-yl]piperazine-1-carboxylic acid(4-isopropoxyphenyl)-amide and pharmaceutical compositions thereof for the treatment of cancer and other diseases or disorders |
| CN101774976A (en) * | 2010-01-26 | 2010-07-14 | 天津药物研究院 | Sulfonyl isoxazoline derivative and anti-tumor application |
| CN102363618A (en) * | 2011-07-04 | 2012-02-29 | 华东理工大学 | Novel inhibitor of epidermal growth factor receptor (EGFR) and application thereof |
| CN102503945A (en) * | 2011-11-28 | 2012-06-20 | 华东理工大学 | Compound capable of inhibiting epidermal growth factor receptor and application thereof |
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