CN104230760A - N-aryl substituted biguanide hydrobromide compound, preparation method and application thereof - Google Patents
N-aryl substituted biguanide hydrobromide compound, preparation method and application thereof Download PDFInfo
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- CN104230760A CN104230760A CN201410442471.8A CN201410442471A CN104230760A CN 104230760 A CN104230760 A CN 104230760A CN 201410442471 A CN201410442471 A CN 201410442471A CN 104230760 A CN104230760 A CN 104230760A
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- 229940123208 Biguanide Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- -1 biguanide hydrobromide compound Chemical class 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- FKPUYTAEIPNGRM-UHFFFAOYSA-N 1-(diaminomethylidene)guanidine;hydron;chloride Chemical compound [Cl-].N\C([NH3+])=N/C(N)=N FKPUYTAEIPNGRM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 46
- 150000004283 biguanides Chemical class 0.000 claims description 16
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 235000015320 potassium carbonate Nutrition 0.000 claims description 6
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 abstract description 8
- 208000014018 liver neoplasm Diseases 0.000 abstract description 8
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 abstract description 4
- 238000002156 mixing Methods 0.000 abstract description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 abstract 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 229910052700 potassium Inorganic materials 0.000 abstract 1
- 239000011591 potassium Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- HTDQSWDEWGSAMN-UHFFFAOYSA-N 1-bromo-2-methoxybenzene Chemical compound COC1=CC=CC=C1Br HTDQSWDEWGSAMN-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 4
- 229960003105 metformin Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 150000004982 aromatic amines Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- QVNJUFBAXGKRJY-UHFFFAOYSA-N (cyanoamino)cyanamide Chemical compound N#CNNC#N QVNJUFBAXGKRJY-UHFFFAOYSA-N 0.000 description 1
- BITDLWAQPKSXTF-UHFFFAOYSA-M 1-[(3-nitrophenyl)methoxymethyl]pyridin-1-ium;chloride Chemical compound [Cl-].[O-][N+](=O)C1=CC=CC(COC[N+]=2C=CC=CC=2)=C1 BITDLWAQPKSXTF-UHFFFAOYSA-M 0.000 description 1
- QBELEDRHMPMKHP-UHFFFAOYSA-N 1-bromo-2-chlorobenzene Chemical compound ClC1=CC=CC=C1Br QBELEDRHMPMKHP-UHFFFAOYSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- HKJCELUUIFFSIN-UHFFFAOYSA-N 5-bromo-1,2,3-trifluorobenzene Chemical compound FC1=CC(Br)=CC(F)=C1F HKJCELUUIFFSIN-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101000925662 Enterobacteria phage PRD1 Endolysin Proteins 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960002581 moroxydine hydrochloride Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an N-aryl substituted biguanide hydrobromide compound shown in a formula (II), which is prepared by the following steps: mixing an aromatic bromide shown as a formula (I) and a biguanide hydrochloride shown as a formula (III), adding the mixture into a solvent 1, 4-dioxane, and stirring and reacting for 5-30 hours at 40-150 ℃ under the catalytic action of cuprous iodide and in the presence of 2, 2' -bipyridine and potassium carbonateAfter the reaction is finished, post-treating the reaction solution to obtain the N-aryl substituted biguanide hydrobromide compound shown in the formula (II); the N-aryl substituted biguanide hydrobromide compound can be applied to the preparation of medicaments for treating liver cancer.
Description
(1) technical field
The present invention relates to biguanides hydrobromate compounds of the new N-aryl replacement of a class and preparation method thereof, and prepare the application in Hepatoma therapy medicine.
(2) background technology
Biguanide compound is important organic synthesis intermediate, has the multiple biological activitys such as hyperglycemia activity, anti-tumor activity, antibacterial activity simultaneously, causes the attention of people gradually.Wherein, biguanide compound and preparation method thereof report being replaced to N-aryl less, mainly comprises and being reacted by Dicyanodiamide and aromatic amine, N, N '-dicyano hydrazine and aromatic amine react, and dicyanodiamide and aromatic amine Reactive Synthesis.Therefore, the biguanide compound that the N-aryl that preparation is novel replaces also is studied its antineoplastic activity and is had certain value.
(3) summary of the invention
The present invention adopts following technical scheme:
The biguanides hydrobromate compounds that N-aryl shown in a kind of formula (II) replaces:
In formula (II): R
1, R
2respective is independently C1 ~ C10 alkyl, or R
1, R
2n is between the two combined to form the heterocycle of the C4 ~ C8 containing N, O; Preferred R
1, R
2respective is independently methyl, or R
1, R
2n is between the two combined to form morpholine ring;
R
3represent one or more substituting group on phenyl ring, be selected from hydrogen, C1 ~ C10 alkyl, C1 ~ C10 alkoxy or halogen, preferred R
3for hydrogen, methyl, methoxyl group, fluorine or chlorine.
Present invention also offers the preparation method of the biguanides hydrobromate compounds that N-aryl replaces shown in a kind of formula (II), described preparation method is:
Fragrant bromo-derivative formula (I) Suo Shi is mixed with biguanide hydrochloride formula (III) Suo Shi and adds solvent 1, in 4-dioxane, under the katalysis of cuprous iodide, and 2, under the existence of 2 '-dipyridyl and salt of wormwood, stirring reaction 5 ~ 30 hours at 40 ~ 150 DEG C, after reaction terminates, reaction solution aftertreatment obtains the biguanides hydrobromate compounds that shown in formula (II), N-aryl replaces;
Biguanide hydrochloride shown in fragrant bromo-derivative and formula (III) shown in described formula (I), the sub-ketone, 2 of iodate, the amount of substance of 2 '-dipyridyl, salt of wormwood is than being 1:0.7 ~ 1.3:0.05 ~ 0.15:0.1 ~ 0.3:3 ~ 9.
In formula (I): R
3represent one or more substituting group on phenyl ring, be selected from hydrogen, C1 ~ C10 alkyl, C1 ~ C10 alkoxy or halogen, preferred R
3for hydrogen, methyl, methoxyl group, fluorine or chlorine;
In formula (III): R
1, R
2respective is independently C1 ~ C10 alkyl, or R
1, R
2n is between the two combined to form the heterocycle of the C4 ~ C8 containing N, O; Preferred R
1, R
2respective is independently methyl, or R
1, R
2n is between the two combined to form morpholine ring.
In preparation method of the present invention, the volumetric usage of usual described solvent Isosorbide-5-Nitrae-dioxane with the molar amount of biguanide hydrochloride formula (III) Suo Shi for 10 ~ 50mL/mmol.
In preparation method of the present invention, described aftertreatment can be adopted with the following method: after reaction terminates, filter, filter residue methanol wash, concentrated filtrate, column chromatography (methylene dichloride: methyl alcohol=10:1, V:V), collect the elutriant containing target compound, underpressure distillation, drying obtains target compound (II).
The invention still further relates to the anti-tumor activity of the biguanides hydrobromate compounds that described N-aryl replaces, and prepare the application in Hepatoma therapy medicine.
Beneficial effect of the present invention is mainly reflected in: the new preparation method of the biguanides hydrobromate compounds that (1) N-aryl replaces, this technological reaction mild condition, easy to operate, cost is low, has prospects for commercial application widely.(2) the biguanides hydrobromate compounds that N-aryl provided by the present invention replaces demonstrates certain resisting liver cancer activity, for new medicament screen and exploitation are laid a good foundation, has good practical value.
(4) embodiment
Below will the present invention is further illustrated by embodiment, but protection scope of the present invention is not limited thereto.
Embodiment 1: the preparation of compound (II-1)
Metformin (0.165g, 1.0mmol) is added, to methoxybromobenzene (0.187g in reaction vessel, 1mmol), cuprous iodide (0.0190g, 0.10mmol), 2,2 '-dipyridyl (0.0312g, 0.20mmol), potassiumphosphate (1.27g, 6.0mmol), mixing in Isosorbide-5-Nitrae-dioxane (10mL), stirring reaction 15 hours under 110 DEG C of oil baths; After reaction terminates, filter, filter residue methanol wash, concentrated filtrate, column chromatography (methylene dichloride: methyl alcohol=10:1, V:V), collect R
fthe elutriant of value 0.25 ~ 0.30, underpressure distillation, drying obtains target compound (II-1) 0.180g, and yield is 57%.
1H?NMR(500MHz,DMSO-d
6)δ9.53(s,1H),7.52(s,2H),7.27(d,J＝8.9Hz,2H),6.87(d,J＝8.9Hz,2H),6.83(s,1H),6.74(s,1H),3.71(s,3H),2.95(s,6H).
Embodiment 2:
Temperature of reaction is reduced to 40 DEG C, other operations are with embodiment 1, and obtain target compound (II-1) 0.0158g, yield is 5%.
Embodiment 3:
Temperature of reaction is elevated to 150 DEG C, other operations are with embodiment 1, and obtain target compound (II-1) 0.136g, yield is 43%.
Embodiment 4:
To foreshorten to 5 hours the reaction times, other operations are with embodiment 1, and obtain target compound (II-1) 0.032g, yield is 10%.
Embodiment 5:
To extend to 30 hours the reaction times, other operations are with embodiment 1, and obtain target compound (II-1) 0.158g, yield is 50%.
Embodiment 6:
Change the amount of Metformin into 0.215g, 1.3mmol, other operations are with embodiment 1, and obtain target compound (II-1) 0.152g, yield is 48%.
Embodiment 7:
Change the amount of Metformin into 0.116g, 0.7mmol, other operations are with embodiment 1, and obtain target compound (II-1) 0.095g, yield is 30%.
Embodiment 8:
Change the amount of cuprous iodide into 0.010g, 0.05mmol, other operations are with embodiment 1, and obtain target compound (II-1) 0.120g, yield is 38%.
Embodiment 9:
Change the amount of cuprous iodide into 0.029g, 0.15mmol, other operations are with embodiment 1, and obtain target compound (II-1) 0.142g, yield is 45%.
Embodiment 10:
Change the amount of 2,2 '-dipyridyl into 0.016g, 0.1mmol, other operations are with embodiment 1, and obtain target compound (II-1) 0.057g, yield is 18%.
Embodiment 11:
Change the amount of 2,2 '-dipyridyl into 0.047g, 0.3mmol, other operations are with embodiment 1, and obtain target compound (II-1) 0.066g, yield is 21%.
Embodiment 12:
Change the amount of salt of wormwood into 0.415g, 3mmol, other operations are with embodiment 1, and obtain target compound (II-1) 0.063g, yield is 20%.
Embodiment 13:
Change the amount of salt of wormwood into 1.244g, 9mmol, other operations are with embodiment 1, and obtain target compound (II-1) 0.155g, yield is 49%.
Embodiment 14: the preparation of compound (II-2)
Operation, with embodiment 1, just will change into methyl bromobenzene (0.256g, 1.5mmol) to methoxybromobenzene, and obtained target compound (II-2) 0.156g, yield is 52%.
1H?NMR(500MHz,DMSO-d
6)δ9.33(s,1H),7.56(s,2H),7.26(d,J＝8.3Hz,2H),7.10(d,J＝8.3Hz,2H),6.76(s,2H),2.96(s,6H),2.25(s,3H).
Embodiment 15: the preparation of compound (II-3)
Operation, with embodiment 1, just will change bromobenzene (0.235g, 1.5mmol) into methoxybromobenzene, and obtained target compound (II-3) 0.180g, yield is 63%.
1H?NMR(500MHz,DMSO-d
6)δ9.46(s,1H),7.62(s,2H),6.98-7.44(m,5H),6.81(s,2H),2.97(s,6H).
Embodiment 16: the preparation of compound (II-4)
Operation, with embodiment 1, just will change 3,4,5-trifluorobromobenzene (0.316g, 1.5mmol) into methoxybromobenzene, and obtained target compound (II-4) 0.170g, yield is 50%.
1H?NMR(500MHz,DMSO-d
6)δ9.71(s,1H),7.79(s,2H),7.36(d,J＝6.4Hz,1H),7.34(d,J＝6.4Hz,1H),6.85(s,2H),2.98(s,6H).
Embodiment 17: the preparation of compound (II-5)
Operation, with embodiment 1, just will change para chlorobromobenzene (0.191g, 1mmol) into methoxybromobenzene, and obtained target compound (II-5) 0.109g, yield is 34%.
1H?NMR(500MHz,DMSO-d
6)δ9.79(s,1H),7.68(s,2H),7.40-7.46(m,2H),7.30-7.36(m,2H),6.87(s,2H),2.97(s,6H).
Embodiment 18: the preparation of compound (II-6)
Operation, with embodiment 1, just will change bromobenzene (0.157g, 1mmol) into methoxybromobenzene, Metformin changes Moroxydine hydrochloride (0.208g into, 1.0mmol), obtained target compound (II-6) 0.194g, yield is 59%.
1H?NMR(500MHz,DMSO-d
6)δ9.79(s,1H),7.68(s,2H),7.40-7.46(m,2H),7.30-7.36(m,2H),6.87(s,2H),2.97(s,6H).
Embodiment 19: anti-liver cancer cell BEL-7402 biological activity test
Anti-liver cancer cell BEL-7402 activity test method: mtt assay
A principle: Thiazolyl blue (MTT) is decomposed into water-fast bluish voilet crystallization by plastosome lytic enzyme and is deposited in cell by cell, crystallisate can by dmso solution, measure its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, indirectly reflect proliferative conditions and the number change of cell.
B cell: liver cancer cell BEL-7402 (purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank)
C experimental procedure:
1) preparation of sample: for solvable sample, every 1mg 20 μ L DMSO dissolve, and get 2uL 1000 μ L nutrient solutions and dilute, make concentration be 100 μ g/mL, then use nutrient solution serial dilution to working concentration.
2) cultivation of cell
2.1) preparation of substratum: containing 800,000 units of Penicillin in every 1000mL substratum, 1.0g Streptomycin sulphate, 10% inactivated fetal bovine serum.
2.2) cultivation of cell: by tumor cell inoculation in substratum, puts 37 DEG C, 5%CO
2cultivate in incubator, 3 ~ 5d goes down to posterity.
3) working sample is to the restraining effect of growth of tumour cell
By cell EDTA-trysinization liquid digestion, and be diluted to 1 × 10 with substratum
5/ mL, be added in 96 porocyte culture plates, every hole 100uL, puts 37 DEG C, 5%CO
2cultivate in incubator.After inoculation 24h, add the sample with substratum dilution, every hole 100 μ L, each concentration adds 3 holes, puts 37 DEG C, 5%CO
2cultivate in incubator, add the MTT of 5mg/mL after 72h in cell culture well, every hole 10 μ L, puts 37 DEG C and hatches 4h, add DMSO, every hole 150 μ L, and with oscillator vibrates, Shi Jia Za dissolves completely, by microplate reader colorimetric under 570nm wavelength.With similarity condition with containing sample, containing the culture medium culturing of same concentration DMSO cell in contrast, calculation sample is to the median lethal concentration (IC of growth of tumour cell
50), result is as shown in table 1.
With liver cancer cell BEL-7402 for model, be positive reference substance with cis-platinum, determine biguanide compound (the II-1) ~ external restraining effect to liver cancer cell growth of (II-6) 6 sample prepared in embodiment.Result shows, and in the sample that this experiment is tested, compound (II-4) and compound (II-5) have certain restraining effect (the results detailed in Table 1) to experiment liver cancer cell BEL-7402 used.
The each compound of table 1 is to the IC of BEL-7402
50(ug/mL)
| Test No. | Compound | IC 50 |
| 1 | (II-1) | >100 |
| 2 | (II-2) | >100 |
| 3 | (II-3) | >100 |
| 4 | (II-4) | 64.32 |
| 5 | (II-5) | 82.13 |
| 6 | (II-6) | >100 |
| 7 | Cis-platinum | 7.82 |
Claims (7)
1. the biguanides hydrobromate compounds that the N-aryl shown in a formula (II) replaces:
In formula (II): R
1, R
2respective is independently C1 ~ C10 alkyl, or R
1, R
2n is between the two combined to form the heterocycle of the C4 ~ C8 containing N, O; R
3represent one or more substituting group on phenyl ring, be selected from hydrogen, C1 ~ C10 alkyl, C1 ~ C10 alkoxy or halogen.
2. the biguanides hydrobromate compounds that shown in formula (II) as claimed in claim 1, N-aryl replaces, is characterized in that described R
1, R
2respective is independently methyl, or R
1, R
2n is between the two combined to form morpholine ring.
3. the biguanides hydrobromate compounds that shown in formula (II) as claimed in claim 1, N-aryl replaces, is characterized in that described R
3for hydrogen, methyl, methoxyl group, fluorine or chlorine.
4. the biguanides hydrobromate compounds that shown in formula (II) as claimed in claim 1, N-aryl replaces, is characterized in that described R
1, R
2respective is independently methyl, or R
1, R
2n is between the two combined to form morpholine ring; Described R
3for hydrogen, methyl, methoxyl group, fluorine or chlorine.
5. a preparation method for the biguanides hydrobromate compounds of the replacement of N-aryl shown in formula as claimed in claim 1 (II), is characterized in that described preparation method is:
Fragrant bromo-derivative formula (I) Suo Shi is mixed with biguanide hydrochloride formula (III) Suo Shi and adds solvent 1, in 4-dioxane, under the katalysis of cuprous iodide, and 2, under the existence of 2 '-dipyridyl and salt of wormwood, stirring reaction 5 ~ 30 hours at 40 ~ 150 DEG C, after reaction terminates, reaction solution aftertreatment obtains the biguanides hydrobromate compounds that shown in formula (II), N-aryl replaces;
Biguanide hydrochloride shown in fragrant bromo-derivative and formula (III) shown in described formula (I), the sub-ketone, 2 of iodate, the amount of substance of 2 '-dipyridyl, salt of wormwood is than being 1:0.7 ~ 1.3:0.05 ~ 0.15:0.1 ~ 0.3:3 ~ 9;
In formula (I): R
3represent one or more substituting group on phenyl ring, be selected from hydrogen, C1 ~ C10 alkyl, C1 ~ C10 alkoxy or halogen;
In formula (III): R
1, R
2respective is independently C1 ~ C10 alkyl, or R
1, R
2n is between the two combined to form the heterocycle of the C4 ~ C8 containing N, O.
6. the preparation method of the biguanides hydrobromate compounds that N-aryl replaces shown in formula (II) as claimed in claim 5, it is characterized in that the volumetric usage of described solvent Isosorbide-5-Nitrae-dioxane with the molar amount of biguanide hydrochloride formula (III) Suo Shi for 10 ~ 50mL/mmol.
7. the biguanides hydrobromate compounds that shown in the formula (II) as described in one of Claims 1 to 4, N-aryl replaces is preparing the application in Hepatoma therapy medicine.
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Denomination of invention: N-Aryl substituted biguanide hydrobromide compounds and their preparation methods and applications Granted publication date: 20160706 Pledgee: China Postal Savings Bank Limited by Share Ltd. Linquan branch Pledgor: Anhui Aibo Biotechnology Co.,Ltd. Registration number: Y2024980043245 |