CN102579468B - Application of 4-1H-1,2,3-triazole-beta-lactam derivative - Google Patents
Application of 4-1H-1,2,3-triazole-beta-lactam derivative Download PDFInfo
- Publication number
- CN102579468B CN102579468B CN 201210009365 CN201210009365A CN102579468B CN 102579468 B CN102579468 B CN 102579468B CN 201210009365 CN201210009365 CN 201210009365 CN 201210009365 A CN201210009365 A CN 201210009365A CN 102579468 B CN102579468 B CN 102579468B
- Authority
- CN
- China
- Prior art keywords
- nmr
- triazole
- beta
- cdcl
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 18
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims description 41
- 208000032612 Glial tumor Diseases 0.000 claims description 16
- 206010018338 Glioma Diseases 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 abstract description 2
- 201000007983 brain glioma Diseases 0.000 abstract 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
- 150000001875 compounds Chemical class 0.000 description 41
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- 238000004440 column chromatography Methods 0.000 description 34
- 239000012043 crude product Substances 0.000 description 34
- 239000003208 petroleum Substances 0.000 description 34
- 238000000746 purification Methods 0.000 description 34
- 239000007787 solid Substances 0.000 description 33
- 239000002994 raw material Substances 0.000 description 32
- 239000011734 sodium Substances 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 0 C[C@@](*1)[C@]1([C@](N1)[n]2nnc(-c(cc3)ccc3C(C)=O)c2)C1=O Chemical compound C[C@@](*1)[C@]1([C@](N1)[n]2nnc(-c(cc3)ccc3C(C)=O)c2)C1=O 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 230000002490 cerebral effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QDJZBFLFHUMZBE-UHFFFAOYSA-N acetylene;bromobenzene Chemical group C#C.BrC1=CC=CC=C1 QDJZBFLFHUMZBE-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- WMBOXQOLPKNIQE-UHFFFAOYSA-N 1-(4-bromophenyl)prop-2-yn-1-one Chemical compound BrC1=CC=C(C(=O)C#C)C=C1 WMBOXQOLPKNIQE-UHFFFAOYSA-N 0.000 description 1
- QVIBTURITHWFBC-UHFFFAOYSA-N 1-(4-methylphenyl)prop-2-yn-1-one Chemical compound CC1=CC=C(C(=O)C#C)C=C1 QVIBTURITHWFBC-UHFFFAOYSA-N 0.000 description 1
- DKFHWNGVMWFBJE-UHFFFAOYSA-N 1-ethynylcyclohexene Chemical compound C#CC1=CCCCC1 DKFHWNGVMWFBJE-UHFFFAOYSA-N 0.000 description 1
- DXUPKLNVOUTXKA-UHFFFAOYSA-N C#C.C(C)(=O)C1=CC=CC=C1 Chemical group C#C.C(C)(=O)C1=CC=CC=C1 DXUPKLNVOUTXKA-UHFFFAOYSA-N 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 208000007660 Residual Neoplasm Diseases 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- CRFJRGSTIQFTQW-UHFFFAOYSA-N acetylene fluorobenzene Chemical group C#C.FC1=CC=CC=C1 CRFJRGSTIQFTQW-UHFFFAOYSA-N 0.000 description 1
- BLJLOSJXZCESDI-UHFFFAOYSA-N acetylene toluene Chemical group C#C.CC1=CC=CC=C1 BLJLOSJXZCESDI-UHFFFAOYSA-N 0.000 description 1
- JGRZOVCPBRJDKA-UHFFFAOYSA-N acetylene;anisole Chemical group C#C.COC1=CC=CC=C1 JGRZOVCPBRJDKA-UHFFFAOYSA-N 0.000 description 1
- NEBFBVFMEJNMTO-UHFFFAOYSA-N acetylene;benzene Chemical group C#C.C1=CC=CC=C1 NEBFBVFMEJNMTO-UHFFFAOYSA-N 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- FMVJYQGSRWVMQV-UHFFFAOYSA-N ethyl propiolate Chemical compound CCOC(=O)C#C FMVJYQGSRWVMQV-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 1
- 229960001737 isopropamide Drugs 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the application of a 4-1H-1,2,3-triazole-beta-lactam derivative. The 4-1H-1,2,3-triazole-beta-lactam derivative is used for preparing a medicine for resisting human brain glioma and colon cancer. The 4-1H-1,2,3-triazole-beta-lactam derivative has better biological activity, and is proved to have stronger propagation inhibitory activity for the human brain glioma (U87mG) and colon cancer tumor (LS-174T) cells by in vitro activity test. Therefore, the 4-1H-1,2,3-triazole-beta-lactam derivative is a potential antitumor drug, and has the application of preparing antitumor pharmaceutical preparation.
Description
Technical field
The present invention relates to a kind of 4-1H-1, the purposes of 2,3-triazole-beta-lactam derivatives, and this compounds is to the cytotoxic activity of human glioma (U87mG) and colon cancer (LS-174T) tumor cell.This compounds is found to have the biological activity of certain described growth of tumour cell of inhibition, has potential antitumor drug purposes.
Background technology
Human life and health in the cancer serious threat, is one of the highest disease of mortality rate.Cancer therapy drug is the hot fields of medicament research and development always, because complexity and the particularity of cancer mechanism, the cancer therapy drug of seeking high selectivity, efficient and low toxic and side effects is to be rich in challenging problem in the life sciences, needs the common exploration of researchers and permanent effort.
Cerebral glioma is modal intracranial primary tumor, it is the infiltrative growth thing, it and normal cerebral tissue do not have obvious boundary, be difficult to excise fully, very inresponsive to radiotherapy chemotherapy, be very easy to recurrence, be grown in good, the malignant tumor of significant points such as brain, operation is difficult to excision or can perform the operation.Therefore chemotherapy is the important step of cerebral glioma treatment, can further kill the residual tumor cell, tumor to recurrence after operation plays very important effect, but the influence because of factors such as blood brain barrier, effect is not very desirable, and tumor is glioblastoma chemotherapy failure one of the main reasons to chemicals generation multidrug resistance
[1]For many years, update at the therapeutic modality of glioma, but fail to improve the overall prognosis of this disease, therefore seek and find the treatment glioblastoma more effectively chemotherapeutics become the significant challenge in this field.
Colon cancer is common malignancy equally, is fatality rate disease with high in western countries,, is only second to pulmonary carcinoma and is positioned at second because the annual death toll of colon cancer accounts for 9.0% of total death toll as the U.S.
[2,3]Along with the transformation of life style such as the raising of China's living standards of the people and diet, the sickness rate of colon cancer is continuous ascendant trend.The mortality rate of present China colon cancer has been positioned at the 5th of malignant tumor, the serious harm people's health
[4]The method of the treatment colon cancer of generally acknowledging is that to perform the operation be main, but about half patient occurs shifting and recurrence after surgery, except the part early stage patient, the patient behind late period and the excision all need accept chemotherapy, so chemotherapy plays considerable effect in the colon cancer Comprehensive Treatment.And existing medicine and few needs discovery and the how more effective chemotherapeutics of research to satisfy clinical demand.
List of references:
[1] Ren Linqiang, Jiang Zhengfang. the chemotherapy present situation of cerebral glioma and progress [J]. Chuanbei Medical College's journal, 2011,26 (1): 87-91.
[2]Jemal，A.；Siegel，R.；Xu，J.Q.；Ward，E.Cancer statistics，2010[J].CA Cancer J Clin，2010，60：277-300.
[3]Jemal，A.；Bray，F.；Melissa M.；et al.Global cancer statistics[J].CA Cancer J Clin，2011，61：69-90.
[4] Du Weihua, Chen Jian. several related gene progress [J] of colon cancer. forward position and progress, 2011,14 (2): 144-146.
Summary of the invention
The object of the present invention is to provide a kind of 4-1H-1, the purposes of 2,3-triazole-beta-lactam derivatives.
4-1H-1,2,3-triazole-beta-lactam derivatives is for the preparation of the medicine of anti-human glioma and colon cancer.
Described 4-1H-1,2,3-triazole-beta-lactam derivatives is:
4-1H-1,2,3-triazole-beta-lactam derivatives has biological activity preferably, the external activity test shows, this chemical compound has strong increment inhibition activity to human glioma (U87mG) and colon cancer tumor (LS-174T) cell, therefore be a kind of potential antitumor drug, have the purposes of preparation anti-tumor medicinal preparation.
The specific embodiment
4-1H-1,2,3-triazole-beta-lactam derivatives is for the preparation of the medicine of anti-human glioma and colon cancer.
Described 4-1H-1,2,3-triazole-beta-lactam derivatives is:
Following examples will help to understand the present invention, but be not limited to content of the present invention:
Embodiment 1 (1 ' R, 3R, 4R)-preparation of 4-(4-(2 '-bromophenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (I-1)
This example relate to a class have cytotoxic activity suc as formula 4-1H-1 shown in (I), the general synthetic method of 2,3-triazole-beta-lactam derivatives, wherein R1 is t-Butyldimethylsilyl (TBDMS).Be specifically related to (1 ' R, 3R, 4R)-preparation of 4-(4-(2 '-bromophenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (I-1).In 50mL single port bottle, add (1 ' R, 3R, 4R)-4-acetoxy-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (0.8610g, 3mmol), Hydrazoic acid,sodium salt (0.2925g, 4.5mmol), CuI (0.0573g, 0.1mmol), (0.5973g 3.3mmol) and the 10mL acetonitrile, stirs adjacent bromobenzene acetylene, be heated to 70 ℃ of reactions, about reaction 12h, stop heating, reactant liquor is cooled to room temperature.The thickening filtration reactant liquor, (petroleum ether: ethyl acetate=4: 1) purification obtains white solid to crude product through column chromatography.Mp 129.7-130.9℃；IR(KBr)：3448，3256，2950，2930，1792，1753，837，758cm
-1；
1H NMR(400MHz，CDCl
3)：δ8.45(1H，s)，8.06(1H，dd，J＝7.6，1.6Hz)，7.63(1H，d，J＝8.4Hz)，7.41-7.37(1H，m)，7.21-7.17(1H，m)，7.09(1H，br s，-NH)，6.33(1H，s，4-H)，4.34(1H，m)，3.60(1H，m，3-H)，1.28(3H，d，J＝6.0Hz)，0.89(9H，s)，0.11，0.10(total 6H，each s)；
13C NMR(100MHz，CDCl
3)：δ166.3，146.1，133.5，130.6，130.5，129.6，127.7，121.1，120.5，68.3，64.0，63.1，25.6，22.2，17.9，-4.3，-5.2；MS(ESI)：452.0[M+H
+].
The preparation of embodiment 2 compound I-2: be raw material with 4-fluorobenzene acetylene, operation is with embodiment 1, and (petroleum ether: ethyl acetate=2: 1) purification obtains white solid to the crude product column chromatography; Mp 147.8-149.0 ℃; IR (KBr): 3431,3208,2955,2930,1770,1742,1497,1232,839cm
-1 1H NMR (400MHz, CDCl
3): δ 8.05 (1H, s), 7.79-7.75 (2H, m), 7.17 (1H, br s ,-NH), and 7.12-7.08 (2H, m), 6.32 (1H, s, 4-H), 4.34 (1H, m), 3.54 (1H, m, 3-H), 1.27 (3H, d, J=6.4Hz), 0.89 (9H, s), 0.11,0.10 (total 6H, each s);
13C NMR (100MHz, CDCl
3): δ 166.5,164.0,161.5,147.7,127.5,127.4,126.1,126.0,116.8,116.0,115.8,77.3,77.0,76.6,68.4,64.0,63.1,25.6,22.1,17.8, and-4.4 ,-5.2; MS (ESI): 412.9[M+Na
+], 390.9[M+H
+].
The preparation of embodiment 3 compound I-3: be raw material with 4-bromobenzene acetylene, operation is with embodiment 1, and (petroleum ether: ethyl acetate=4: 1) purification obtains white solid to the crude product column chromatography; Mp 165.5-166.5 ℃; IR (KBr): 3211,2958,2930,1773,1743,829cm
-1 1H NMR (400MHz, CDCl
3): δ 8.05 (1H, s), 7.74-7.71 (2H, m), 7.60-7.57 (2H, m), 6.58 (1H, br s ,-NH), 6.32 (1H, d, J=0.8Hz, 4-H), 4.39 (1H, m), 3.54 (1H, t, J=2.4Hz, 3-H), 1.30 (3H, d, J=6.4Hz), 0.92 (9H, s), 0.14,0.13 (total 6H, each s);
13C NMR (125MHz, CDCl
3): δ 166.5,147.9,132.4,129.2,127.5,122.8,117.3,77.5,77.3,77.0,68.9,64.3,63.4,25.9,22.4,18.2, and-4.0 ,-4.9; MS (ESI): 452.0[M+H
+].
The preparation of embodiment 4 compound I-4: be raw material with the phenylacetylene, operation is with embodiment 1, and (petroleum ether: ethyl acetate=2: 1) purification obtains white solid to the crude product column chromatography; Mp:114.6-115.4 ℃; IR (KBr): 3315,1794,1768,1646,1555,1464cm
-1 1H NMR (CDCl
3): δ 8.04 (1H, s), 7.82 (2H m), 7.44-7.35 (3H, m), 6.89 (1H, br s, NH), 6.34 (1H, s, 4-H), 4.35 (1H, m), 3.56 (1H, m), 1.28 (3H, d, J=6.4Hz), 0.90 (9H, s), 0.12,0.11 (total 6H, each s);
13C NMR (CDCl
3): δ 166.6,148.9,130.2,129.2,128.8,125.9,117.2,68.8,64.3,63.4,25.9,22.4,18.2, and-4.0 ,-4.9; MS (ESI): 395.2[M+Na
+], 373.1[M+H
+].
The preparation of embodiment 5 compound I-5: be raw material with 4-methylbenzene acetylene, operation is with embodiment 1, and (petroleum ether: ethyl acetate=2: 1) purification obtains white solid to the crude product column chromatography; Mp 131.8-133.4 ℃; IR (KBr): 3200,2956,1770,1739,1378,830,814,775cm
-1 1H NMR (400MHz, CDCl
3): δ 8.01 (1H, d, J=1.6Hz), 7.68 (2H, m), 7.22 (2H, d, J=8.0Hz), 7.16 (1H, br s,-NH), 6.30 (1H, s, 4-H), 4.33 (1H, m), 3.53 (1H, m, 3-H), 2.37 (3H, s), 1.27 (3H, d, J=6.4Hz), 0.91 (9H, s), 0.12,0.11 (total 6H, each s);
13C NMR (100MHz, CDCl
3): δ 166.5,148.5,138.3,129.5,127.0,125.5,116.7,68.2,64.0,63.1,25.6,22.1,21.2,17.8, and-4.4 ,-5.2; MS (ESI): 409.2[M+Na
+], 387.2[M+H
+].
The preparation of embodiment 6 compound I-6: be raw material with 4-ethylo benzene acetylene, operation is with embodiment 1, and (petroleum ether: ethyl acetate=5: 1) purification obtains white solid to the crude product column chromatography; Mp 51.8-53.4 ℃; IR (KBr): 3448,2960,1786,1259,846cm
-1 1H NMR (CDCl
3): δ 7.99 (1H, s), 7.73-7.75 (2H, m), 7.26-7.27 (2H, m), 6.81 (1H, br s ,-NH), 6.34 (1H, d, J=1.13Hz, 4-H), 4.35 (1H, m), 3.56 (1H, m, 3-H), 2.69 (2H, q), and 1.25-1.29 (6H, m), 0.92 (9H, s), 0.13,0.12 (total 6H, each s);
13C NMR (CDCl
3): δ 166.6,149.1,145.1,128.7,127.6,126.0,116.8,68.8,64.4,63.4,28.9,25.9,22.5,18.2,15.7, and-4.0 ,-4.9; MS (ESI): 423.2[M+Na
+], 401.2[M+H
+].
The preparation of embodiment 7 compound I-7: be raw material with 4-methoxybenzene acetylene, operation is with embodiment 1, and (petroleum ether: ethyl acetate=4: 1) purification obtains white solid to the crude product column chromatography; Mp 147.6-148.9 ℃; IR (KBr): 3384,2958,1778,1254,830cm
-1 1H NMR (CDCl
3): δ 7.94 (1H, s), 7.71-7.73 (2H, m), 6.93-6.97 (1H, br s ,-NH), 6.31 (1H, d, J=0.9Hz, 4-H), 4.35 (1H, m), 3.83 (3H, s), 3.54 (1H, m, 3-H), 1.26 (3H, t, J=6.4Hz), 0.90 (9H, s), 0.12,0.11 (total 6H, each s);
13C NMR (CDCl
3): δ 166.6,160.1,148.8,127.3,122.9,116.4,114.6,68.7,64.3,63.3,55.5,25.9,22.4,18.2, and-4.0 ,-4.9; MS (ESI): 425.2[M+Na
+], 403.2[M+H
+].
The preparation of embodiment 8 compound I-8: be raw material with 4-acetylbenzene acetylene, operation is with embodiment 1, and (petroleum ether: ethyl acetate=2: 1) purification obtains white solid to the crude product column chromatography; Mp 175.3-176.1 ℃; IR (KBr): 3433,2958,2931,1773,1740,1612,829cm
-1 1H NMR (500MHz, CDCl
3): δ 9.16 (1H, s), 9.15 (1H, br s ,-NH), 8.05 (4H, m), 6.14 (1H, s, 4-H), 4.28 (1H, m), 3.78 (1H, m, 3-H), 2.60 (1H, s), 1.19 (3H, d, J=6.5Hz), 0.86 (9H, s), 0.10,0.08 (total 6H, each s);
13C NMR (125MHz, CDCl
3): δ 197.7,166.5,146.5,136.6,135.2,129.5,125.6,121.5,67.4,64.6,63.0,27.1,26.1,22.3,18.1, and-3.9 ,-4.8; MS (ESI): 413.0[M-H
+].
The preparation of embodiment 9 compound I-9: be raw material with 3-Isopropamide base phenylacetylene, operation is with embodiment 1, and (petroleum ether: ethyl acetate=2: 1) purification obtains white solid to the crude product column chromatography; Mp:95.1-97.2 ℃; IR (KBr): 3317,2958,2930,1775,1376,1252cm-1;
1H NMR (CDCl
3): δ 8.02 (1H, s), 8.01 (1H, s), 7.94 (1H, s), 7.79 (1H, br s ,-NH), and 7.57-7.59 (1H, m), 7.47-7.49 (1H, m), 7.27-7.32 (1H, m), 6.27 (1H, s, 4-H), 4.33-4.35 (1H, m), 3.57 (1H, m, 3-H), 2.58 (1H, m), 1.26 (3H, t, J=6.3Hz), 1.24 (6H, m, J=6.8Hz), 0.85 (9H, s), 0.10,0.09 (total 6H, each s);
13C NMR (CDCl
3): δ 176.3,166.8,148.3,139.1,130.7,129.8,121.5,120.1,117.9,117.2,68.4,64.3,63.4,36.7,25.9,22.4,19.8,18.1, and-4.0 ,-4.9; MS (ESI): 479.9[M+Na
+], 457.8[M+H
+].
The preparation of embodiment 10 compound I-10: be raw material with 4-tolyl acetenyl ketone, operation is with embodiment 1, and (petroleum ether: ethyl acetate=4: 1) purification obtains yellow solid to the crude product column chromatography; Mp 154.5-155.9 ℃; IR (KBr): 3331,2928,1770,1650,1259,837cm
-1 1H NMR (500MHz, CDCl
3): δ 8.53 (1H, s), 8.35 (1H, m), 8.33 (1H, m), 7.34 (1H, s), 7.32 (1H, s), 6.74 (1H, br s,-NH), 6.37 (1H, d, J=0.4Hz, 4-H), 4.38 (1H, m), 3.63 (1H, m, 3-H), 2.45 (3H, s), 1.30 (3H, d, J=6.5Hz), 0.91 (9H, s), 0.13,0.12 (total 6H, each s);
13CNMR (125MHz, CDCl
3): δ 185.2,166.1,149.1,144.8,133.9,131.0,129.5,126.5,69.0,64.3,63.5,25.9,22.5,22.0,18.2, and-4.0 ,-4.9; MS (ESI): 437.2[M+Na
+], 415.1[M+H
+].
The preparation of embodiment 11 compound I-11: be raw material with 4-bromophenyl acetenyl ketone, operation is with embodiment 1, and (petroleum ether: ethyl acetate=4: 1) purification obtains yellow solid to the crude product column chromatography; Mp 101.5-102.8 ℃; IR (KBr): 2954,2929,1779,1655,1586,906,830cm
-1 1H NMR (500MHz, CDCl
3): δ 8.30 (1H, s), 8.20-8.17 (2H, m), 7.69-7.67 (2H, m), 6.59 (1H, br s ,-NH), 6.28 (1H, d, J=1.5Hz, 4-H), 4.38 (1H, m), 3.97 (1H, m, 3-H), 1.26 (3H, d, J=6.0Hz), 0.90 (9H, s), 0.12 (6H, s);
13C NMR (125MHz, CDCl
3): δ 184.3,166.3,147.5,138.8,135.1,132.1,132.0,129.3,67.6,67.2,64.2,25.9,22.6,18.2, and-4.0 ,-4.9; MS (ESI): 477.7[M-H
+].
The preparation of embodiment 12 compound I-12: be raw material with 1-acetenyl-cyclohexene, operation is with embodiment 1, and (petroleum ether: ethyl acetate=4: 1) purification obtains white solid to the crude product column chromatography; Mp 106.9-108.1 ℃; IR (KBr): 3214,3129,2930,1778,1739,840,778cm
-1 1H NMR (400MHz, CDCl
3): δ 7.64 (1H, s), 6.58 (1H, m), 6.54 (1H, br s,-NH), 6.31 (1H, d, J=1.2Hz, 4-H), 4.34 (1H, m), 3.50 (1H, t, J=2.4Hz, 3-H), 2.38 (2H, m), 2.22 (2H, m), 1.78 (2H, m), 1.68 (2H, m), 1.25 (3H, d, J=6.4Hz), 0.90 (9H, s), 0.12,0.11 (total 6H, each s);
13CNMR (125MHz, CDCl
3): δ 166.7,150.5,127.0,126.1,115.8,68.5,64.3,63.2,26.5,25.9,25.5,22.6,22.4,22.3,18.1, and-4.1 ,-4.9; MS (ESI): 399.0[M+Na
+], 377.0[M+H
+].
The preparation of embodiment 13 compound I-13: be raw material with 3-crotonylene-ketone, operation is with embodiment 1, and (petroleum ether: ethyl acetate=2: 1) purification obtains white solid to the crude product column chromatography; Mp 148.1-149.2 ℃; IR (KBr): 2953,2930,1784,1693,1313,832cm
-1 1H NMR (400MHz, CDCl
3): δ 8.11 (1H, s), 6.52 (1H, br s ,-NH), 6.25 (1H, d, J=1.6Hz, 4-H), 4.37 (1H, m), 3.95 (1H, t, J=2.4Hz, 3-H), 2.63 (3H, s), 1.25 (3H, d, J=6.8Hz), 0.90 (9H, s), 0.12 (6H, s);
13C NMR (125MHz, CDCl
3): δ 192.1,166.5,148.3,136.1,67.5,67.2,64.2,27.5,25.9,22.5,18.2, and-4.1 ,-4.9; MS (ESI): 361.0[M+Na
+], 339.0[M+H
+].
The preparation of embodiment 14 compound I-14: be raw material with the propargylic acid methyl ester, operation is with embodiment 1, and (petroleum ether: ethyl acetate=2: 1) purification obtains white solid to the crude product column chromatography; Mp:139.4-140.6 ℃; IR (KBr): 2951,1788,1745,1374,1214,1042cm
-1.
1H NMR (CDCl
3): δ 8.41 (1H, s), 7.08 (1H, br s, NH), 6.35 (1H, s, 4-H), 4.35 (1H, m), 3.95 (3H, s), 3.56 (1H, m), 1.28 (3H, d, J=6.4Hz), 0.88 (9H, s), 0.11,0.10 (total 6H, each s);
13CNMR (CDCl
3): δ 166.1,161.0,140.8,125.7,68.9,64.3,63.7,52.6,25.9,22.4,18.1, and-4.0 ,-4.9; MS (ESI): 376.9[M+Na
+].
The preparation of embodiment 15 compound I-15: be raw material with the propargylic acid ethyl ester, operation is with embodiment 1, and (petroleum ether: ethyl acetate=4: 1) purification obtains white solid to the crude product column chromatography; Mp:142.1-143.9 ℃; IR (KBr): 2936,1790,1739,1209,1040cm
-1 1H NMR (CDCl
3): δ 8.39 (1H, s), 7.14 (1H, br s, NH), 6.34 (1H, s, 4-H), 4.41 (2H, q), 4.35 (1H, m), 3.54 (1H, m), 1.40 (3H, m), 1.27 (3H, d, J=6.4Hz), 0.87 (9H, s), 0.10,0.08 (total 6H, each s);
13C NMR (CDCl
3): δ 166.2,160.6,141.0,125.6,68.9,64.3,63.6,61.8,25.9,22.4,18.1,14.5, and-4.0 ,-4.9; MS (ESI): 390.9[M+Na
+].
The preparation of embodiment 16 compound I-16: be raw material with positive hexin, operation is with embodiment 1, and (petroleum ether: ethyl acetate=4: 1) purification obtains white solid to the crude product column chromatography; Mp:70.6-71.1 ℃; IR (KBr): 3209,1778,1750,1358cm
-1 1HNMR (CDCl
3): δ 7.54 (s, 1H), 6.87 (1H, br s ,-NH), 6.26 (1H, d, J=1.2Hz), 4.34 (1H, dd, J=6.35,2.9Hz), 3.51 (1H, m, 3-H), 2.73 (2H, t, J=7.7Hz), 1.64-1.67 (2H, m), 1.36-1.41 (2H, m), 1.26 (3H, d, J=6.4Hz), 0.95 (3H, t, J=7.4Hz), 0.89 (9H, s), 0.11,0.09 (total 6H, each s);
13C NMR (CDCl
3): δ 166.7,149.7,118.2,68.4,64.3,63.1,31.6,25.9,25.6,22.5,22.4,18.2,14.0, and-4.0 ,-4.9; MS (ESI): 375.2[M+Na
+], 353.0[M+H
+].
The preparation of embodiment 17 compound I-17: be raw material with 3-hydroxyl-3 methyl isophthalic acids-butine, operation is with embodiment 1, and (petroleum ether: ethyl acetate=2: 1) purification obtains white solid to the crude product column chromatography; Mp:137.3-137.9 ℃; IR (KBr): 3217,1776,1752cm
-1 1H NMR (CDCl
3): δ 7.72 (1H, s), 6.80 (1H, br s ,-NH), 6.26 (1H, d, J=0.95Hz, 4-H), 4.33-4.35 (1H, m), 3.52 (1H, dd, J=2.7,1.9Hz, 3-H), 2.69 (1H, br s ,-OH), 1.64 (6H, s), 1.27 (3H, d, J=6.3Hz), 0.90 (9H, s), 0.11,0.10 (total 6H, each s);
13C NMR (CDCl
3): δ 166.5,156.8,117.1,68.8,68.5,64.3,63.3,30.6,25.9,22.5,18.2, and-4.0 ,-4.9; MS (ESI): 377.2[M+Na
+].
The preparation of embodiment 18 compound I-18: be raw material with 3-hydroxyl-1-propine, operation is with embodiment 1, and (petroleum ether: ethyl acetate=2: 1) purification obtains white solid to the crude product column chromatography; Mp:124.0-125.8 ℃; IR (KBr): 3392,1777,1445,1142em
-1 1H NMR (CDCl
3): δ 7.82 (1H, s), 7.39 (1H, br s ,-NH), 6.22 (1H, s, 4-H), 4.73 (2H, s), 4.31-4.33 (1H, m), 3.70 (1H, br ,-OH), 3.48 (1H, s, 3-H), 1.25 (3H, d, J=6.3Hz), 0.89 (9H, s), 0.10,0.09 (total 6H, each s);
13C NMR (CDCl
3): δ 166.9,148.7,120.1,68.4,64.3,63.4,56.2,25.9,22.5,18.2, and-4.1 ,-4.9; MS (ESI): 349.2[M+Na
+], 327.2[M+H
+].
The preparation of embodiment 19 compound I-19: be raw material with 2-alkynes propoxyl group-Pentamethylene oxide., operation is with embodiment 1, and (petroleum ether: ethyl acetate=2: 1) purification obtains yellow oil to the crude product column chromatography; IR (CH
2Cl
2): 3262,2951,1788,1462,1132,832cm
-1 1H NMR (CDCl
3): δ 7.84 (1H, s), 7.31 (1H, br s ,-NH), 6.26 (1H, s, 4-H), 4.86 (1H, m), 4.73-4.74 (1H, m), 4.61 (1H, m), 4.32-4.34 (1H, m), 3.89 (1H, m), 3.53 (1H, m), 1.60-1.73 (2H, m), 1.52-1.60 (4H, m), 1.25 (3H, t, J=6.4Hz), 0.89 (9H, s), 0.11,0.10 (total 6H, each s);
13CNMR (CDCl
3): δ 166.7,146.2,120.4,98.6,68.3,64.2,63.2,62.5,60.6,30.5,25.8,25.4,22.4,19.5,18.1, and-4.1 ,-4.9; MS (ESI): 432.9[M+Na
+], 410.9[M+H
+].
The preparation of embodiment 20 compound I-20: be raw material with 3,3-dimethyl-ethyl acetylene, operation is with embodiment 1, and (petroleum ether: ethyl acetate=4: 1) purification obtains white solid to the crude product column chromatography; Mp.133.8-134.5 ℃, IR (KBr): 2961,2936,1780,1047,846cm
-1 1H NMR (CDCl
3): δ 7.55 (1H, s), 7.02 (1H, br s ,-NH), 6.24 (1H, s, 4-H), 4.35 (1H, m), 3.52 (1H, m, 3-H), 1.34 (9H, s), 1.28 (3H, d, J=6.4Hz), 0.89 (9H, s), 0.09,0.10 (total 6H, each s);
13C NMR (CDCl
3): δ 166.7,158.8,116.4,68.3,64.4,63.2,31.1,30.5,25.9,22.5,18.2, and-4.0 ,-4.9; MS (ESI): 375.2[M+Na
+], 353.2[M+H
+].
Embodiment 21 (1 ' R, 3R, 4R)-preparation of 4-(4-(2 '-bromophenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-hydroxyl) ethyl-nitrogen heterocyclic din-2-ketone (I-21)
This example relate to a class have cytotoxic activity suc as formula 4-1H-1 shown in (I), the general synthetic method of 2,3-triazole-beta-lactam derivatives, wherein R1 is H.Have and relate to (1 ' R, 3R, 4R)-preparation of 4-(4-(2 '-bromophenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-hydroxyl) ethyl-nitrogen heterocyclic din-2-ketone (I-21).In 50mL single port bottle, add 0.3382g (1 ' R, 3R, 4R)-4-(4-(2 '-bromophenyl)-1 hydrogen-1,2, the 3-triazol-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (I-21), 10mL acetonitrile and 10 hydrochloric acid, stirring at room about reaction 12h, adds saturated sodium bicarbonate solution cancellation reaction, concentrate desolventizing, add 30～60mL ethyl acetate and 30～60mL water, leave standstill behind the mix homogeneously, tell organic facies, the water ethyl acetate extraction, merge organic facies, use the saturated common salt water washing, add anhydrous Na
2SO
4Standing and drying concentrates, and crude product is through column chromatography (petroleum ether: ethyl acetate=1: 4) purification, obtain (1 ' R, 3R, 4R)-4-(4-(2 '-bromophenyl)-1 hydrogen-1,2,3-triazol-1-yl)-3-(1 '-hydroxyl) ethyl-nitrogen heterocyclic din-2-ketone (xx) white solid; Mp 174.2-175.1 ℃; IR (KBr): 3189,3129,1755,1728,1372,759cm
-1 1HNMR (400MHz, C
2D
6SO): δ 9.08 (1H, br s ,-NH), 8.89 (1H, s), 7.90 (1H, d, J=7.6Hz), 7.74 (1H, d, J=8.0Hz), 7.49 (1H, t, J=7.6Hz), 7.32 (1H, t, J=7.6Hz), 6.22 (1H, s, 4-H), 5.23 (1H, d, J=5.2Hz,-OH), and 4.07-3.99 (1H, m), 3.72 (1H, d, J=5.2Hz, 3-H), 1.17 (3H, d, J=6.0Hz);
13C NMR (100MHz, C
2D
6SO): δ 167.0,145.1, and 133.9,131.4,131.0,130.4,128.4,123.1,121.1,67.0,63.5,63.2,22.1; MS (ESI): 337.9[M+H
+].
The preparation of embodiment 22 compound I-22: be raw material with I-2, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 193.9-194.3 ℃; IR (KBr): 3512,3197,2970,1763,1723,1497,1383,1227,829cm
-1 1H NMR (400MHz, C
2D
6SO): δ 9.08 (1H, br s ,-NH), 8.94 (1H, s), 7.92 (2H, m), 7.30 (2H, m), 6.15 (1H, d, J=1.6Hz, 4-H), 5.24 (1H, d, J=5.2Hz ,-OH), 4.05 (1H, m), 3.63 (1H, dd, J=5.2,1.6Hz, 3-H), 1.16 (3H, d, J=6.4Hz);
13C NMR (125MHz, C
2D
6SO): δ 167.0,163.3, and 161.4,146.6,127.8,127.7,127.4,120.1,116.4,116.3,67.3,63.5,63.2,22.1; MS (ESI): 276.9[M+H
+].
The preparation of embodiment 23 compound I-23: be raw material with I-3, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 208.1-209.5 ℃; IR (KBr): 3504,3201,2964,1759,1721,1380,826cm
-1 1H NMR (400MHz, C
2D
6SO): δ 9.07 (1H, br s ,-NH), 8.99 (1H, s), 7.83 (2H, d, J=8.4Hz), 7.64 (2H, d, J=7.6Hz), 6.16 (1H, s, 4-H), 5.22 (1H, d, J=5.2Hz ,-OH), 4.04 (1H, m), 3.63 (1H, d, J=4.0Hz, 3-H), 1.15 (3H, d, J=6.4Hz);
13C NMR (100MHz, C
2D
6SO): δ 167.0,146.3, and 132.3,130.0,127.6,121.5,120.5,67.3,63.4,63.1,22.1; MS (ESI): 337.9[M+H
+].
The preparation of embodiment 24 compound I-24: be raw material with I-4, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 179.1-179.6 ℃; IR (KBr): 3391,3214,2971,1755,1732,1377,767cm
-1 1H NMR (400MHz, C
2D
6SO): δ 9.08 (1H, br s ,-NH), 8.93 (1H, s), 7.88 (2H, d, J=7.2Hz), 7.44 (2H, m), 7.33 (1H, t, J=7.2Hz), 6.17 (1H, s, 4-H), 5.24 (1H, d, J=5.6Hz ,-OH), 4.06 (1H, m), 3.65 (1H, d, J=4.8Hz, 3-H), 1.17 (3H, d, J=6.4Hz);
13C NMR (100MHz, C
2D
6SO): δ 167.0,147.4, and 130.8,129.3,128.5,125.6,120.1,67.2,63.4,63.1,22.0; MS (ESI): 258.9[M+H
+].
The preparation of embodiment 25 compound I-25: be raw material with I-5, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 200.5-201.8 ℃; IR (KBr): 3367,2984,2970,1767,1720,1169,812,803cm-1;
1H NMR (400MHz, C
2D
6SO): δ 9.06 (1H, br s ,-NH), 8.87 (1H, s), 7.77 (2H, d, J=8.0Hz), 7.25 (2H, d, J=8.0Hz), 6.16 (1H, s, 4-H), 5.23 (1H, d, J=5.6Hz ,-OH), 4.06 (1H, m), 3.65 (1H, d, J=4.4Hz, 3-H), 2.31 (3H, s), 1.17 (3H, d, J=6.0Hz);
13C NMR (100MHz, C
2D
6SO): δ 167.0,147.5, and 137.8,129.9,128.0,125.5,119.7,67.2,63.4,63.2,22.1,21.2; MS (ESI): 271.2[M-H
+].
The preparation of embodiment 26 compound I-26: be raw material with I-7, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 197.8-198.1 ℃; IR (KBr): 3330,1777,1499,1248cm
-1 1HNMR (400MHz, C
2D
6SO): δ 9.05 (1H, br s ,-NH), 8.80 (1H, s), 7.80 (2H, d, J=8.8Hz), 7.00 (2H, d, J=8.8Hz), 6.14 (1H, s, 4-H), 5.22 (1H, d, J=4.8Hz ,-OH), 4.05 (1H, m), 3.77 (3H, s), 3.64 (1H, d, J=5.2Hz, 3-H), 1.16 (3H, d, J=6.4Hz);
13C NMR (100MHz, C
2D
6SO): δ 167.0,159.5, and 147.3,127.0,123.4,119.1,114.7,67.1,63.3,63.1,55.5,22.0; MS (ESI): 288.9[M+H
+].
The preparation of embodiment 27 compound I-27: be raw material with I-8, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 226.7-227.1 ℃; IR (KBr): 3391,3241,2975,2930,1779,1661,1613,1366,1274,828cm
-1 1H NMR (400MHz, C
2D
6SO): δ 9.13 (1H, s), 9.12 (1H, br s ,-NH), 8.05 (4H, s), 6.22 (1H, s, 4-H), 5.28 (1H, d, J=5.2Hz ,-OH), 4.09 (1H, m), 3.69 (1H, d, J=4.8Hz, 3-H), 2.60 (3H, s), 1.20 (3H, d, J=6.0Hz);
13C NMR (100MHz, C
2D
6SO): δ 197.7,167.0, and 146.4,136.5,135.1,129.4,125.6,121.4,67.3,63.6,63.1,27.0,22.0; MS (ESI): 300.9[M+H
+].
The preparation of embodiment 28 compound I-28: be raw material with I-9, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 209.9-211.1 ℃; IR (KBr): 3423,3347,2972,2932,1777,1673,1619,1568,1540cm
-1 1H NMR (400MHz, C
2D
6SO): δ 9.96 (1H, br s ,-NH), 9.09 (1H, br s ,-NH), 8.91 (1H, s), 8.25 (1H, s), 7.60 (1H, d, J=8.0Hz), 7.52 (1H, d, J=7.6Hz), 7.38 (1H, m), 6.19 (1H, s, 4-H), 5.26 (1H, d, J=5.2Hz ,-OH), 4.08 (1H, m), 3.71 (1H, d, J=4.4Hz, 3-H), 2.66-2.58 (1H, m), 1.19 (3H, d, J=6.0Hz), 1.13,1.12 (total 6H, each s);
13C NMR (100MHz, C
2D
6SO): δ 175.7,167.0, and 147.3,140.3,131.1,129.6,120.5,120.2,119.3,116.3,67.1,63.4,63.2,35.3,22.1,19.8; MS (ESI): 366.0[M+Na
+], 344.0[M+H
+].
The preparation of embodiment 29 compound I-29: be raw material with I-10, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 150.2-151.4 ℃; IR (KBr): 3376,2966,2923,1786,1650,1606,1256,911,757cm
-1 1H NMR (400MHz, C
2D
6SO): δ 9.15 (1H, s), 9.07 (1H, br s ,-NH), 8.15 (2H, d, J=8.0Hz), 7.38 (2H, d, J=8.0Hz), 6.23 (1H, m, 4-H), 5.24 (1H, d, J=4.8Hz ,-OH), 4.06 (1H, m), 3.76 (1H, d, J=4.0Hz, 3-H), 2.39 (3H, s), 1.16 (3H, d, J=6.4Hz);
13C NMR (100MHz, C
2D
6SO): δ 184.8,166.8, and 147.3,144.3,134.2,130.5,129.5,129.1,67.1,63.7,63.0,22.0,21.6; MS (ESI): 300.8[M+H
+].
The preparation of embodiment 30 compound I-30: be raw material with I-11, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 1) purification obtains white solid to the crude product column chromatography; Mp 131.0-132.1 ℃; IR (KBr): 3475,2970,1775,1763,1650,1586,907,758cm
-1 1HNMR (400MHz, C
2D
6SO): δ 9.17 (1H, br s ,-NH), 8.54 (1H, s), 8.11-8.09 (2H, m), 7.81-7.79 (2H, m), 6.20 (1H, s, 4-H), 5.22 (1H, d, J=5.2Hz ,-OH), 4.05 (1H, m), 3.71 (1H, d, J=5.2Hz, 3-H), 1.16 (3H, d, J=6.0Hz);
13C NMR (100MHz, C
2D
6SO): δ 184.4,166.9, and 146.6,138.7,135.4,132.2,128.3,67.7,66.9,63.1,22.1; MS (ESI): 387.8[M+Na
+].
The preparation of embodiment 31 compound I-31: be raw material with I-12, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 148.1-149.5 ℃; IR (KBr): 3382,3224,2926,1759,1738,1372cm
-1 1H NMR (400MHz, C
2D
6SO): δ 8.98 (1H, br s ,-NH), 8.38 (1H, s), 6.42 (1H, m), 6.06 (1H, d, J=1.2Hz, 4-H), 5.19 (1H, d, J=5.6Hz ,-OH), 4.01 (1H, m), 3.59 (1H, dd, J=5.2,1.6Hz, 3-H), 2.30 (2H, m), 2.12 (2H, m), 1.70-1.64 (2H, m), 1.60-1.56 (2H, m), 1.11 (3H, d, J=6.4Hz);
13CNMR (100MHz, C
2D
6SO): δ 167.0,149.0, and 127.6,124.3,118.6,66.9,63.1,26.1,25.0,22.4,22.2,22.0; MS (ESI): 262.9[M+H
+].
The preparation of embodiment 32 compound I-32: be raw material with I-13, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 157.9-158.5 ℃; IR (KBr): 3386,3305,1785,1695,1303cm
-1 1H NMR (500MHz, C
2D
6SO): δ 9.15 (1H, br s ,-NH), 8.39 (1H, s), 6.15 (1H, s, 4-H), 5.21 (1H, d, J=5.5Hz ,-OH), 4.04 (1H, m), 3.67 (1H, d, J=5.5Hz, 3-H), 2.56 (1H, s), 1.15 (3H, d, J=6.0Hz);
13C NMR (125MHz, C
2D
6SO): δ 191.8,167.0, and 147.8,136.5,67.7,67.0,63.2,27.9,22.2; MS (ESI): 246.8[M+Na
+].
The preparation of embodiment 33 compound I-33: be raw material with I-14, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 156.5-157.5 ℃; IR (KBr): 3360,1774,1725,1237cm
-1 1HNMR (400MHz, C
2D
6SO): δ 9.07 (1H, s), 9.02 (1H, br s ,-NH), 6.16 (1H, s, 4-H), 5.20 (1H, d, J=4.8Hz ,-OH), 4.01 (1H, m), 3.82 (3H, s), 3.69 (1H, m, 3-H), 1.12 (3H, d, J=6.8Hz);
13C NMR (100MHz, C
2D
6SO): δ 166.8,160.9, and 139.4,128.4,67.0,63.6,63.0,52.3,22.0; MS (ESI): 240.8[M+H
+].
The preparation of embodiment 34 compound I-34: be raw material with I-16, operation is with embodiment 21, and (petroleum ether: ethyl acetate=1: 4) purification obtains white solid to the crude product column chromatography; Mp 129.6-130.2 ℃; IR (KBr): 3364,2970,2930,1769cm
-1 1HNMR (400MHz, C
2D
6SO): δ 8.96 (1H, br s ,-NH), 8.15 (1H, s), 6.04 (1H, d, J=1.6Hz, 4-H), 5.18 (1H, d, J=5.2Hz,-OH), 4.00 (1H, m), 3.56 (1H, dd, J=5.2,1.6Hz, 3-H), 2.60 (2H, t, J=7.6Hz), 1.56 (2H, m), 1.30 (2H, m), 1.11 (3H, d, J=6.0Hz), 0.87 (3H, t, J=7.6Hz);
13C NMR (100MHz, C
2D
6SO): δ 167.0,148.0, and 120.6,66.8,63.1,63.0,31.3,25.0,22.1,22.0,14.0; MS (ESI): 238.9[M+H
+].
Embodiment further specifies the present invention below by pharmacology.Pharmacology embodiment has provided representative chemical compound to the part activity data of human glioma (U87mG) and colon cancer (LS-174T) tumor cell.Mandatory declaration, following pharmacology embodiment is that essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out for explanation the present invention rather than limitation of the present invention.
Pharmacology embodiment 1:4 position-1H-1,2,3-triazole-beta-lactam derivatives detects the cytotoxic activity of human glioma (U87mG) cell
Human glioma (U87mG) cell DMEM culture medium culturing contains 10% hyclone in the culture medium.Cell is with every hole 4 * 10
3Concentration add in 96 orifice plates, contain 5%C0 at 37 ℃
2Cultivated 20 hours in the incubator of humid air.
The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 20 hours hatch, 4-the 1H-1 that will prepare respectively, 2, the dimethyl sulphoxide solution of 3-triazole-beta-lactam derivatives joins in each hole with Concentraton gradient, makes that the chemical compound ultimate density is respectively 64 μ g/mL, 32 μ g/mL, 16 μ g/mL, 8 μ g/mL, 4 μ g/mL, 2 μ g/mL, 1 μ g/mL in the hole.After 72 hours, add MTT (5mg/mL) reagent 10 μ L, continuation cultivate in 37 ℃ the incubator 4 hours after, get rid of culture fluid behind the centrifugal 10min, add the 150mL dimethyl sulphoxide solution in every hole, with the MTT crystal of dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, 630nm does reference wavelength.Cell inhibitory rate is calculated by formula (II).4-1H-1 wherein, 2,3-triazole-beta-lactam derivatives is to human glioma (U87mG) cell half suppression ratio concentration IC
50Obtained by curve fitting.
Table 1 has been listed several representative chemical compounds to the anti-tumor activity of the growth in vitro of U87mG cell line (human glioma).
| Compound number | IC50/(μg/mL) |
| I-1 | 4.9 |
| I-5 | 12.2 |
| I-12 | 10.3 |
| I-14 | 16.1 |
| 1-16 | 5.8 |
| I-30 | 42.7 |
This experiment with antitumor one line medication cisplatin (DDP) and irinotecan hydrochloride (CPT-11) as positive control.Half suppression ratio IC of the human glioma cell of DDP and CPT-11 (U87mG)
50Be respectively 5.3 μ g/mL and 8.0 μ g/mL.Compound I-1 drug effect is better than DDP and CPT-11 slightly.
This experiment shows this type of 4-1H-1, and 2,3-triazole-beta-lactam derivatives has stronger cytotoxicity to human glioma, might develop into the new medicine with anti-human glioma and related neoplasms effect.
Pharmacology embodiment 2:4 position-1H-1,2,3-triazole-beta-lactam derivatives detects the cytotoxic activity of colon cancer (LS-174T) and cell
Colon cancer (LS-174T) cell DMEM culture medium culturing contains 10% hyclone in the culture medium.Cell is with every hole 1 * 10
4Concentration add in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 20 hours in the incubator of humid air.The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 20 hours hatch, 4-the 1H-1 that will prepare respectively, the dimethyl sulphoxide solution of 2,3-triazole-beta-lactam derivatives joins in each hole with Concentraton gradient, makes that the chemical compound ultimate density is respectively 1000 μ g/mL, 100 μ g/mL, 10 μ g/mL in the hole.After 72 hours, add MTT (5mg/mL) reagent 10 μ L, continue cultivate in 37 ℃ the incubator 4 hours after, Cell sap is removed in suction, add the 150mL dimethyl sulphoxide solution in every hole, with the MTT crystal of dissolving and reducing, formed formazan microplate reader colorimetric under the 490nm wavelength.Cell inhibitory rate is calculated by formula (II).
Table 2 has been listed several representative chemical compounds to the anti-tumor activity of the growth in vitro of LS-174T cell line (colon cancer)
This experiment shows this type of 4-1H-1, and 2,3-triazole-beta-lactam derivatives has stronger cytotoxicity to colon cancer, might develop into the new medicine with resistive connection intestinal cancer and related neoplasms effect.
Claims (1)
1. 4-1H-1, the purposes of 2,3-triazole-beta-lactam derivatives is characterized in that 4-1H-1,2,3-triazole-beta-lactam derivatives is for the preparation of the medicine of anti-human glioma and colon cancer;
Described 4-1H-1,2,3-triazole-beta-lactam derivatives is:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210009365 CN102579468B (en) | 2012-01-12 | 2012-01-12 | Application of 4-1H-1,2,3-triazole-beta-lactam derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210009365 CN102579468B (en) | 2012-01-12 | 2012-01-12 | Application of 4-1H-1,2,3-triazole-beta-lactam derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102579468A CN102579468A (en) | 2012-07-18 |
| CN102579468B true CN102579468B (en) | 2013-09-04 |
Family
ID=46469073
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201210009365 Expired - Fee Related CN102579468B (en) | 2012-01-12 | 2012-01-12 | Application of 4-1H-1,2,3-triazole-beta-lactam derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102579468B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3019874B1 (en) * | 2013-07-09 | 2019-08-21 | The Translational Genomics Research Institute | Compositions and methods of screening for compounds that modulate activity at a tweak binding site on a crd of fn14 |
| US9797882B2 (en) | 2013-07-09 | 2017-10-24 | The Translational Genomics Research Institute | Method of screening for a compound for inhibitory activity of FN14-tweak interaction |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101665508A (en) * | 2009-09-18 | 2010-03-10 | 浙江大学 | Preparation method of 4-1H-1,2,3-triazole-beta-lactam derivative |
| CN101665509A (en) * | 2009-09-18 | 2010-03-10 | 浙江大学 | 4 pos-1H-1,2,3-triazole-beta-lactam derivative and preparation method thereof |
-
2012
- 2012-01-12 CN CN 201210009365 patent/CN102579468B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101665508A (en) * | 2009-09-18 | 2010-03-10 | 浙江大学 | Preparation method of 4-1H-1,2,3-triazole-beta-lactam derivative |
| CN101665509A (en) * | 2009-09-18 | 2010-03-10 | 浙江大学 | 4 pos-1H-1,2,3-triazole-beta-lactam derivative and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102579468A (en) | 2012-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2683127T3 (en) | Useful compositions for treating disorders related to KIT | |
| JP7050093B2 (en) | Substituted 5- and 6-membered heterocyclic compounds, methods of preparation thereof, combinations of agents and their use | |
| CN105461695A (en) | Pyrimidine or triazine derivative, and preparation method and use thereof | |
| CN101967105B (en) | Beta-hydroxy protected didecyl quaternary ammonium salt with anticancer activity and preparation method thereof | |
| CN104109166B (en) | Quinolines, its preparation method, intermediate, pharmaceutical composition and application | |
| JP2024505732A (en) | Pyridopyrimidinone derivatives and their production methods and uses | |
| CN108948002A (en) | Five yuan and hexa-atomic nitrogen heteroaromatic rings class compound, preparation method, Pharmaceutical composition and its application | |
| CN102971312A (en) | Pyrrolyl substituted dihydroindol-2-one derivatives, preparation methods and uses thereof | |
| ES2338060T3 (en) | ARILOXI AND ARILTOXIA-CETOPHENONE TYPE COMPONENTS FOR CANCER TREATMENT. | |
| CN109096250A (en) | 4- phenoxypyridines class compound and its application containing pyridazinone | |
| CN108137589A (en) | Carboline derivative as Bu Luomo region structural domain inhibitor | |
| CN111269104B (en) | Chalcone analogue and application thereof | |
| CN116462676A (en) | Multi-condensed ring PRMT5 inhibitor and preparation method and application thereof | |
| CN102579468B (en) | Application of 4-1H-1,2,3-triazole-beta-lactam derivative | |
| ES2607807T3 (en) | Procedure for the preparation of c-fms kinase inhibitors | |
| CN112552290B (en) | Amido bond-containing phenylfuran-2-tetrahydroisoquinoline compound and preparation method and application thereof | |
| CN107652300B (en) | The podophyllotoxin analogue of the structure of triazinone containing 1,2,4- and its application | |
| CN102153508B (en) | 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumour drugs | |
| CN102993018B (en) | A kind of 5-nitro coffeic acid Buddha's warrior attendant alcohol ester and preparing the application in antitumor drug | |
| CN111295387B (en) | Heteroaryl amide compound, preparation method thereof, medicinal composition and application thereof | |
| CN113366008A (en) | CD73 inhibitor, preparation method and application thereof | |
| CN104606197A (en) | Application of compound in tumor resistance | |
| CN102173997A (en) | Liver cancer, gastric cancer and cervical cancer-resistant archen derivative and preparation method thereof | |
| CN102276433B (en) | Longistylin C and derivative thereof and preparing the application in cancer therapy drug | |
| CN103435560A (en) | Synthesis and application of aceanthrylene [1,2-b] quinoxaline derivative with flexible side chain |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130904 Termination date: 20220112 |