CN104230760B - The biguanide hydrobromate compounds of N-aryl replacement and preparation method and application - Google Patents
The biguanide hydrobromate compounds of N-aryl replacement and preparation method and application Download PDFInfo
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Abstract
The invention discloses the biguanide hydrobromate compounds that the N-aryl shown in a kind of formula (II) replaces, its preparation method is: fragrance bromo-derivative formula (I) Suo Shi mixes addition solvent 1 with biguanide hydrochloride shown in formula (III), in 4-dioxane, under the catalytic action of Hydro-Giene (Water Science)., and 2, under the existence of 2 '-bipyridyl and potassium carbonate, stirring reaction 5～30 hours at 40～150 DEG C, after reaction terminates, reactant liquor post processing prepares the biguanide hydrobromate compounds that N-aryl shown in formula (II) replaces；The biguanide hydrobromate compounds that N-aryl of the present invention replaces can be applicable to the medicine of preparation treatment hepatocarcinoma；
Description
(1) technical field
The present invention relates to new biguanide hydrobromate compounds of N-aryl replacement of a class and preparation method thereof and the application in preparation treatment liver-cancer 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, N-aryl replacing biguanide compound and preparation method thereof report less, mainly include being reacted with aromatic amine by dicyanodiamine, N, N '-dicyano hydrazine reacts with aromatic amine, and cyanoguanidines and aromatic amine are synthesized.Therefore, 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 the following technical scheme that
The biguanide hydrobromate compounds that N-aryl shown in a kind of formula (II) replaces:
In formula (II): R1, R2Each stand alone as C1～C10 alkyl or R1, R2N combination between the two forms the heterocycle of the C4～C8 containing N, O；Preferred R1, R2Each stand alone as methyl or R1, R2N combination between the two forms morpholine ring；
R3Represent one or more substituent group on phenyl ring, selected from hydrogen, C1～C10 alkyl, C1～C10 alkoxy or halogen, it is preferable that R3For hydrogen, methyl, methoxyl group, fluorine or chlorine.
The preparation method that present invention also offers the biguanide hydrobromate compounds that N-aryl shown in a kind of formula (II) replaces, described preparation method is:
Fragrance bromo-derivative formula (I) Suo Shi is mixed with biguanide hydrochloride shown in formula (III) addition solvent 1, in 4-dioxane, under the catalytic action of Hydro-Giene (Water Science)., and 2, under the existence of 2 '-bipyridyl and potassium carbonate, stirring reaction 5～30 hours at 40～150 DEG C, after reaction terminates, reactant liquor post processing prepares the biguanide hydrobromate compounds that N-aryl shown in formula (II) replaces；
Fragrance bromo-derivative shown in described formula (I) and biguanide hydrochloride shown in formula (III), iodate Asia ketone, 2,2 '-bipyridyl, potassium carbonate amount of substance ratio for 1:0.7～1.3:0.05～0.15:0.1～0.3:3～9.
In formula (I): R3Represent one or more substituent group on phenyl ring, selected from hydrogen, C1～C10 alkyl, C1～C10 alkoxy or halogen, it is preferable that R3For hydrogen, methyl, methoxyl group, fluorine or chlorine；
In formula (III): R1, R2Each stand alone as C1～C10 alkyl or R1, R2N combination between the two forms the heterocycle of the C4～C8 containing N, O；Preferred R1, R2Each stand alone as methyl or R1, R2N combination between the two forms morpholine ring.
In preparation method of the present invention, the volumetric usage of usual described solvent Isosorbide-5-Nitrae-dioxane is with the molar amount of biguanide hydrochloride shown in formula (III) for 10～50mL/mmol.
In preparation method of the present invention, described post processing can be adopted with the following method: after reaction terminates, filter, filtering residue methanol washs, concentrated filtrate, column chromatography (dichloromethane: methanol=10:1, V:V), collect the eluent containing target compound, decompression distillation, dry and obtain target compound (II).
The invention still further relates to the anti-tumor activity of the biguanide hydrobromate compounds that described N-aryl replaces and the application in preparation treatment liver-cancer medicine.
The beneficial effects are mainly as follows: the new preparation method of the biguanide 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 biguanide hydrobromate compounds that N-aryl provided by the present invention replaces demonstrates certain resisting liver cancer activity, lays a good foundation for new medicament screen and exploitation, has good practical value.
(4) detailed description of the invention
Following by embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited to this.
Embodiment 1: the preparation of compound (II-1)
Reaction vessel adds Metformin (0.165g, 1.0mmol), to methoxybromobenzene (0.187g, 1mmol), Hydro-Giene (Water Science). (0.0190g, 0.10mmol), 2,2 '-bipyridyl (0.0312g, 0.20mmol), potassium phosphate (1.27g, 6.0mmol), mixing, stirring reaction 15 hours under 110 DEG C of oil baths in Isosorbide-5-Nitrae-dioxane (10mL)；After reaction terminates, filtering, filtering residue methanol washs, concentrated filtrate, and column chromatography (dichloromethane: methanol=10:1, V:V) collects RfThe eluent of value 0.25～0.30, decompression distillation, dry and obtain target compound (II-1) 0.180g, yield is 57%.
1HNMR(500MHz,DMSO-d6) δ 9.53 (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:
Reaction temperature is reduced to 40 DEG C, and other operations, with embodiment 1, obtain target compound (II-1) 0.0158g, and yield is 5%.
Embodiment 3:
Reaction temperature is increased to 150 DEG C, and other operations, with embodiment 1, obtain target compound (II-1) 0.136g, and yield is 43%.
Embodiment 4:
To foreshorten in the response time 5 hours, other operations, with embodiment 1, obtain target compound (II-1) 0.032g, and yield is 10%.
Embodiment 5:
To extend to 30 hours the response time, other operations, with embodiment 1, obtain target compound (II-1) 0.158g, and yield is 50%.
Embodiment 6:
Changing the amount of Metformin into 0.215g, 1.3mmol, other operations, with embodiment 1, obtain target compound (II-1) 0.152g, and yield is 48%.
Embodiment 7:
Changing the amount of Metformin into 0.116g, 0.7mmol, other operations, with embodiment 1, obtain target compound (II-1) 0.095g, and yield is 30%.
Embodiment 8:
Changing the amount of Hydro-Giene (Water Science). into 0.010g, 0.05mmol, other operations, with embodiment 1, obtain target compound (II-1) 0.120g, and yield is 38%.
Embodiment 9:
Changing the amount of Hydro-Giene (Water Science). into 0.029g, 0.15mmol, other operations, with embodiment 1, obtain target compound (II-1) 0.142g, and yield is 45%.
Embodiment 10:
Changing the amount of 2,2 '-bipyridyl into 0.016g, 0.1mmol, other operations, with embodiment 1, obtain target compound (II-1) 0.057g, and yield is 18%.
Embodiment 11:
Changing the amount of 2,2 '-bipyridyl into 0.047g, 0.3mmol, other operations, with embodiment 1, obtain target compound (II-1) 0.066g, and yield is 21%.
Embodiment 12:
Changing the amount of potassium carbonate into 0.415g, 3mmol, other operations, with embodiment 1, obtain target compound (II-1) 0.063g, and yield is 20%.
Embodiment 13:
Changing the amount of potassium carbonate into 1.244g, 9mmol, other operations, with embodiment 1, obtain target compound (II-1) 0.155g, and yield is 49%.
Embodiment 14: the preparation of compound (II-2)
Methoxybromobenzene, with embodiment 1, simply will be changed into methyl bromobenzene (0.256g, 1.5mmol) by operation, prepare target compound (II-2) 0.156g, and yield is 52%.
1HNMR(500MHz,DMSO-d6) δ 9.33 (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)
Methoxybromobenzene, with embodiment 1, simply will be changed into bromobenzene (0.235g, 1.5mmol) by operation, prepare target compound (II-3) 0.180g, and yield is 63%.
1HNMR(500MHz,DMSO-d6)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)
Methoxybromobenzene, with embodiment 1, simply will be changed into 3,4,5-trifluorobromobenzenes (0.316g, 1.5mmol) by operation, prepare target compound (II-4) 0.170g, and yield is 50%.
1HNMR(500MHz,DMSO-d6) δ 9.71 (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)
Methoxybromobenzene, with embodiment 1, simply will be changed into para chlorobromobenzene (0.191g, 1mmol) by operation, prepare target compound (II-5) 0.109g, and yield is 34%.
1HNMR(500MHz,DMSO-d6)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)
Methoxybromobenzene, with embodiment 1, simply will be changed into bromobenzene (0.157g, 1mmol) by operation, Metformin changes Moroxydine hydrochlorate (0.208g into, 1.0mmol), preparing target compound (II-6) 0.194g, yield is 59%.
1HNMR(500MHz,DMSO-d6)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-hepatoma carcinoma 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 violet crystallization by mitochondrion hydrolytic enzyme and is deposited in cell by cell, crystal 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: hepatoma carcinoma 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 dissolves with 20 μ LDMSO, takes 2uL and dilutes with 1000 μ L culture fluid, and making concentration is 100 μ g/mL, then with culture fluid serial dilution to working concentration.
2) cultivation of cell
2.1) preparation of culture medium: containing 800,000 units of Penicillin, 1.0g streptomycin, 10% inactivated fetal bovine serum in every 1000mL culture medium.
2.2) cultivation of cell: by tumor cell inoculation in culture medium, puts 37 DEG C, 5%CO2Cultivating in incubator, 3～5d goes down to posterity.
3) sample inhibitory action to growth of tumour cell is measured
Cell EDTA-trypsinization liquid is digested, and is diluted to 1 × 10 by culture medium5/ mL, is added in 96 porocyte culture plates, and every hole 100uL puts 37 DEG C, 5%CO2Incubator is cultivated.After inoculation 24h, the sample that addition is diluted by culture medium, every hole 100 μ L, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Incubator is cultivated, in cell culture well, after 72h, adds the MTT of 5mg/mL, every hole 10 μ L, put 37 DEG C and hatch 4h, add DMSO, every hole 150 μ L, vibrate with agitator, make first be completely dissolved, by microplate reader colorimetric under 570nm wavelength.With similarity condition with without sample, the cell of the culture medium culturing containing same concentration DMSO, as comparison, calculates the sample median lethal concentration (IC to growth of tumour cell50), result is as shown in table 1.
With hepatoma carcinoma cell BEL-7402 for model, with cisplatin for positive reference substance, determine biguanide compound (the II-1)～external inhibitory action to liver cancer cell growth of (II-6) 6 sample of preparation in embodiment.Result shows, in the sample that this experiment is tested, the hepatoma carcinoma cell BEL-7402 that experiment is used is had certain inhibitory action (the results detailed in Table 1) by compound (II-4) and compound (II-5).
The table 1 each compound IC to BEL-740250(ug/mL)
| Test No. | Compound | IC50 |
| 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 | Cisplatin | 7.82 |
Claims (2)
1. the preparation method of the biguanide hydrobromate compounds that N-aryl shown in a formula (II) replaces, it is characterised in that described preparation method is:
Fragrance bromo-derivative formula (I) Suo Shi is mixed with biguanide hydrochloride shown in formula (III) addition solvent 1, in 4-dioxane, under the catalytic action of Hydro-Giene (Water Science)., and 2, under the existence of 2 '-bipyridyl and potassium carbonate, stirring reaction 5～30 hours at 40～150 DEG C, after reaction terminates, reactant liquor post processing prepares the biguanide hydrobromate compounds that N-aryl shown in formula (II) replaces；
Fragrance bromo-derivative shown in described formula (I) and biguanide hydrochloride shown in formula (III), iodate Asia ketone, 2,2 '-bipyridyl, potassium carbonate amount of substance ratio for 1:0.7～1.3:0.05～0.15:0.1～0.3:3～9；
In formula (I), formula (II) or formula (III):
R3Represent one or more substituent group on phenyl ring, selected from hydrogen, C1～C10 alkyl, C1～C10 alkoxy or halogen；
R1, R2Each stand alone as C1～C10 alkyl or R1, R2N combination between the two forms the heterocycle of the C4～C8 containing N, O.
2. the preparation method of the biguanide hydrobromate compounds that N-aryl shown in formula (II) as claimed in claim 1 replaces, it is characterized in that the volumetric usage of described solvent Isosorbide-5-Nitrae-dioxane is with the molar amount of biguanide hydrochloride shown in formula (III) for 10～50mL/mmol.
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Effective date of registration: 20200930 Address after: No. 351, Renmin East Road, economic development zone, Linquan County, Fuyang City, Anhui Province Patentee after: Anhui Aibo Biotechnology Co.,Ltd. Address before: Unit 2414-2416, main building, no.371, Wushan Road, Tianhe District, Guangzhou City, Guangdong Province Patentee before: GUANGDONG GAOHANG INTELLECTUAL PROPERTY OPERATION Co.,Ltd. Effective date of registration: 20200930 Address after: Unit 2414-2416, main building, no.371, Wushan Road, Tianhe District, Guangzhou City, Guangdong Province Patentee after: GUANGDONG GAOHANG INTELLECTUAL PROPERTY OPERATION Co.,Ltd. Address before: 310014 Department of science and technology, Zhejiang University of Technology, No. 18 Chao Wang Road, Xiacheng District, Zhejiang, Hangzhou Patentee before: ZHEJIANG University OF TECHNOLOGY |