CN104262205B - N-aryl biguanide hydroiodide compound and preparation method and application thereof - Google Patents
N-aryl biguanide hydroiodide compound and preparation method and application thereof Download PDFInfo
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- CN104262205B CN104262205B CN201410442518.0A CN201410442518A CN104262205B CN 104262205 B CN104262205 B CN 104262205B CN 201410442518 A CN201410442518 A CN 201410442518A CN 104262205 B CN104262205 B CN 104262205B
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- 229940123208 Biguanide Drugs 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims description 32
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 229910052802 copper Inorganic materials 0.000 claims abstract description 10
- 239000010949 copper Substances 0.000 claims abstract description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 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
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000002184 metal Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 4
- 230000003197 catalytic effect Effects 0.000 claims abstract description 3
- -1 Hydrogen Chemical class 0.000 claims description 28
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 24
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 12
- 235000011009 potassium phosphates Nutrition 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 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 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 5
- 125000002346 iodo group Chemical group I* 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 150000005045 1,10-phenanthrolines Chemical class 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- 235000004279 alanine Nutrition 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 235000003704 aspartic acid Nutrition 0.000 claims description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- 229960003067 cystine Drugs 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- BCPFWSWROVXGQA-UHFFFAOYSA-N 2-(2,4,4-trimethylpentan-2-yl)guanidine Chemical compound CC(C)(C)CC(C)(C)N=C(N)N BCPFWSWROVXGQA-UHFFFAOYSA-N 0.000 claims 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims 1
- 229950000289 guanoctine Drugs 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 5
- 210000004252 chorionic villi Anatomy 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 2
- 201000011510 cancer Diseases 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 75
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 17
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 8
- 229960003105 metformin Drugs 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- RINOYHWVBUKAQE-UHFFFAOYSA-N 1-iodo-2-methylbenzene Chemical compound CC1=CC=CC=C1I RINOYHWVBUKAQE-UHFFFAOYSA-N 0.000 description 2
- 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical group C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 229960003767 alanine Drugs 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229960005261 aspartic acid Drugs 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003560 cancer drug Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000012531 culture fluid Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000000694 effects Effects 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
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical compound [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229960002898 threonine Drugs 0.000 description 2
- 235000008521 threonine Nutrition 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 229960004295 valine Drugs 0.000 description 2
- 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
- OIRHKGBNGGSCGS-UHFFFAOYSA-N 1-bromo-2-iodobenzene Chemical compound BrC1=CC=CC=C1I OIRHKGBNGGSCGS-UHFFFAOYSA-N 0.000 description 1
- JXMZUNPWVXQADG-UHFFFAOYSA-N 1-iodo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1I JXMZUNPWVXQADG-UHFFFAOYSA-N 0.000 description 1
- QFUYDAGNUJWBSM-UHFFFAOYSA-N 1-iodo-2-phenylbenzene Chemical class IC1=CC=CC=C1C1=CC=CC=C1 QFUYDAGNUJWBSM-UHFFFAOYSA-N 0.000 description 1
- VLCPISYURGTGLP-UHFFFAOYSA-N 1-iodo-3-methylbenzene Chemical class CC1=CC=CC(I)=C1 VLCPISYURGTGLP-UHFFFAOYSA-N 0.000 description 1
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- HHOXWPCTCQMHNN-UHFFFAOYSA-N C1(=CC=CC=C1)I.[F] Chemical compound C1(=CC=CC=C1)I.[F] HHOXWPCTCQMHNN-UHFFFAOYSA-N 0.000 description 1
- UDSRBTKHBHNHOM-UHFFFAOYSA-N CC(CC=C1)=CC=C1N/C(/N)=N/C(N(C)C)=N Chemical compound CC(CC=C1)=CC=C1N/C(/N)=N/C(N(C)C)=N UDSRBTKHBHNHOM-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical class SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- 108010019160 Pancreatin Proteins 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
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 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
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000007529 inorganic bases Chemical group 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 229960002581 moroxydine hydrochloride Drugs 0.000 description 1
- 229950002366 nafoxidine Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- CUQCMXFWIMOWRP-UHFFFAOYSA-N phenyl biguanide Chemical compound NC(N)=NC(N)=NC1=CC=CC=C1 CUQCMXFWIMOWRP-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- 239000000243 solution Substances 0.000 description 1
- 229940041022 streptomycins Drugs 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012549 training Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an N-aryl biguanide hydroiodide compound shown as a formula (III), which is prepared by the following steps: mixing biguanide hydrochloride shown in a formula (I) and aromatic iodide shown in a formula (II), adding into a solvent, stirring and reacting for 2-20 h at 60-100 ℃ under the catalytic action of a metal copper catalyst and in the presence of a ligand and an alkaline substance, and after the reaction is finished, carrying out post-treatment on a reaction solution to obtain an N-aryl biguanide hydroiodide compound shown in a formula (III); the N-aryl biguanide hydroiodide compound shown in the formula (III) can be applied to preparing medicines for treating placental villus cancer.
Description
(1) technical field
The present invention relates to a kind of new N- aryl biguanide hydroiodic acid salt compounds and preparation method thereof, and control in preparation
Treat the application in placental villi cancer drug.
(2) background technology
Biguanide compound is the important nitrogen-containing compound of a class, is lived with extensive biological activity, including hyperglycemia
Property, anti-tumor activity, antibacterial activity etc..And it is less to the research report of Biguanide derivative, mainly include by metformin
React with halogenated aliphatic hydrocarbon or disulfide, synthesize the biguanide compound that N- alkyl and N- alkylthio groups replace.Therefore, prepare
Novel biguanide compound simultaneously studies its antineoplastic activity with important theory significance and actual application value.
(3) content of the invention
The present invention is adopted the following technical scheme that：
A kind of N- aryl biguanide hydroiodic acid salt compounds as shown in formula (III)：
In formula (III)：R1, R2Hydrogen, C1～C10 alkyl or C6～C10 aryl, or R are stood alone as each1, R2With both it
Between N combine to be formed containing N or the C4～C8 containing N, O heterocycle；It is preferred that R1, R2Hydrogen, methyl or phenyl, or R are stood alone as each1,
R2N between the two combines to form nafoxidine ring, piperidine ring or morpholine ring；R3Hydrogen or a substituent group on phenyl ring are represented,
Described substituent group selected from C1～C10 alkyl, C1～C10 alkoxyls, C6～C10 aryl, halogen, nitrogenous electron-withdrawing substituent or
Sulfonyl, preferred R3Hydrogen or a substituent group on phenyl ring are represented, described substituent group is selected from methyl, methoxyl group, ethyoxyl, benzene
Base, cyano group, nitro, fluorine, chlorine, bromine or N- pyrroles's sulfonyl；
Present invention also offers a kind of preparation method of the N- aryl biguanide hydroiodic acid salt compounds shown in formula (III),
Described preparation method is：
Biguanide hydrochloride shown in formula (I) is mixed with the fragrant iodo thing shown in formula (II) in addition solvent, in metal
Under the catalytic action of copper catalyst, and in the presence of part and alkaline matter, in 60～100 DEG C of 2～20h of stirring reaction, instead
After should terminating, reactant liquor is post-treated to obtain N- aryl biguanide hydroiodic acid salt compounds shown in formula (III).
The solvent is water, alcohols, ethers, sulfoxide type or nitrile；The metal copper catalyst is that copper halide or halogenation are sub-
Copper；The part is aromatic nitrogen heterocycle, fatty azacyclo- or aminoacid；The alkaline matter is inorganic base or organic base；It is described
Fragrant iodo thing shown in formula (II) and biguanide hydrochloride shown in formula (I), metal copper catalyst, part, the material of alkaline matter
Amount is than being 1：0.7～1.3：0.05～0.15：0.1～0.3：3～9；
In formula (I)：R1, R2Hydrogen, C1～C10 alkyl or C6～C10 aryl, or R are stood alone as each1, R2Between the two
N combine to be formed containing N or the C4～C8 containing N, O heterocycle；It is preferred that R1, R2Hydrogen, methyl or phenyl, or R are stood alone as each1, R2
N between the two combines to form nafoxidine ring, piperidine ring or morpholine ring；
In formula (II)：R3Hydrogen or a substituent group on phenyl ring are represented, described substituent group is selected from C1～C10 alkyl, C1
～C10 alkoxyls, C6～C10 aryl, halogen, nitrogenous electron-withdrawing substituent or sulfonyl；It is preferred that R3Represent on hydrogen or phenyl ring
One substituent group, described substituent group are selected from methyl, methoxyl group, ethyoxyl, phenyl, cyano group, nitro, fluorine, chlorine, bromine or N- pyrroles
Sulfonyl.
Preparation method of the present invention, preferably described solvent are water, ethanol, isopropanol, tetrahydrofuran, Isosorbide-5-Nitrae-dioxy
Six rings, acetonitrile, DMF or dimethyl sulfoxide, particularly preferably tetrahydrofuran；The volume of the usual solvent
Consumption is calculated as 10～50mL/g with the quality of biguanide hydrochloride shown in formula (I).
It is preferred that described metal copper catalyst is Cu-lyt., cuprous bromide, Hydro-Giene (Water Science). or copper chloride, particularly preferably
Hydro-Giene (Water Science)..
It is preferred that described part is 2,2 '-bipyridyl, 1,10- phenanthrolines, triethylene diamine, glycine, lysine, paddy ammonia
Acid, cystine, alanine, aspartic acid, threonine or L-Valine, particularly preferably 2,2 '-bipyridyl.
It is preferred that described alkaline matter is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate or three
Ethamine, particularly preferably potassium phosphate.
In preparation method of the present invention, the post processing can be adopted with the following method：After reaction terminates, reacting liquid filtering,
Filtering residue is washed with methanol, concentrates filtrate, column chromatography (dichloromethane:Methanol=8:1, V:V), collect the eluting containing target compound
Liquid, vacuum distillation are dried to obtain target compound (III),
The invention further relates to the anti-tumor activity of the N- aryl biguanide hydroiodic acid salt compounds, and its preparing treatment
Application in placental villi cancer drug.
The beneficial effects are mainly as follows：(1) the new preparation side of N- aryl biguanide hydroiodic acid salt compounds
Method, the technological reaction mild condition, easy to operate, low cost have extensive prospects for commercial application.(2) it is provided by the present invention
N- aryl biguanide hydroiodic acid salt compounds show certain anti-human placental villi cancer activity, be that new medicament screen and exploitation are established
Basis is determined, with preferable practical value.
(4) specific embodiment
Below will by embodiment, the present invention is further illustrated, but protection scope of the present invention not limited to this.
Embodiment 1：The preparation of compound (III-1)
In reaction vessel add Metformin (0.165g, 1.0mmol), to methoxyl group iodobenzene (0.243g,
1.0mmol), Hydro-Giene (Water Science). (0.0190g, 0.10mmol), 2,2 '-bipyridyl (0.0312g, 0.20mmol), potassium phosphate
(1.3g, 6.0mmol), mixing, stirring reaction 12 hours in 80 DEG C of oil baths in tetrahydrofuran (5mL)；After reaction terminates, mistake
Filter, filtering residue are washed with methanol, concentrate filtrate, column chromatography (dichloromethane:Methanol=8:1, V:V), collect RfValue 0.3～0.35
Eluent, vacuum distillation are dried to obtain target compound (III-1) 0.352g, and yield is 97%.
1H NMR(500 MHz,DMSO-d6) δ 8.83 (s, 1H), 7.46 (s, 2H), 7.24 (d, J=9.0 Hz, 2H),
6.89 (d, J=9.0 Hz, 2H), 6.62 (s, 2H), 3.73 (s, 3H), 2.94 (s, 6H).
Embodiment 2：
Hydro-Giene (Water Science). is changed to into Cu-lyt. (0.0099g, 0.10mmol), other operations obtain targeted with embodiment 1
Compound (III-1) 0.131g, yield is 36%.
Embodiment 3：
Hydro-Giene (Water Science). is changed to into cuprous bromide (0.0143g, 0.10mmol), other operations obtain targeted with embodiment 1
Compound (III-1) 0.189g, yield is 52%.
Embodiment 4：
Hydro-Giene (Water Science). is changed to into copper chloride (0.134g, 0.10mmol), other operations obtain target chemical combination with embodiment 1
Thing (III-1) 0.0617g, yield is 17%.
Embodiment 5：
Solvents tetrahydrofurane is changed to into acetonitrile, other operations obtain target compound (III-1) 0.254g with embodiment 1,
Yield is 70%.
Embodiment 6：
Solvents tetrahydrofurane is changed to into Isosorbide-5-Nitrae-dioxane, other operations obtain target compound (III- with embodiment 1
1) 0.236g, yield are 65%.
Embodiment 7：
Solvents tetrahydrofurane is changed to into water, other operations obtain target compound (III-1) 0.0254g with embodiment 1,
Yield is 7%.
Embodiment 8：
Solvents tetrahydrofurane is changed to into DMF, other operations obtain target compound with embodiment 1
(III-1) 0.153g, yield are 42%.
Embodiment 9：
Solvents tetrahydrofurane is changed to into ethanol, other operations obtain target compound (III-1) 0.116g with embodiment 1,
Yield is 32%.
Embodiment 10：
Solvents tetrahydrofurane is changed to into isopropanol, other operations obtain target compound (III-1) with embodiment 1
0.222g, yield are 61%.
Embodiment 11：
Solvents tetrahydrofurane is changed to into dimethyl sulfoxide, other operations obtain target compound (III-1) with embodiment 1
0.174g, yield are 48%.
Embodiment 12：
2,2 '-bipyridyl is changed to into 1,10- phenanthrolines (0.036g, 0.20mmol), other operations are obtained with embodiment 1
Target compound (III-1) 0.145g, yield is 41%.
Embodiment 13：
2,2 '-bipyridyl is changed to into triethylene diamine (0.022g, 0.20mmol), other operations obtain mesh with embodiment 1
Mark compound (III-1) 0.240g, yield is 66%.
Embodiment 14：
2,2 '-bipyridyl is changed to into glycine (0.015g, 0.20mmol), other operations obtain targeted with embodiment 1
Compound (III-1) 0.262g, yield is 72%.
Embodiment 15：
2,2 '-bipyridyl is changed to into lysine (0.029g, 0.20mmol), other operations obtain targeted with embodiment 1
Compound (III-1) 0.276g, yield is 76%.
Embodiment 16：
2,2 '-bipyridyl is changed to into glutamic acid (0.029g, 0.20mmol), other operations obtain targeted with embodiment 1
Compound (III-1) 0.272g, yield is 75%.
Embodiment 17：
2,2 '-bipyridyl is changed to into cystine (0.048g, 0.20mmol), other operations obtain targeted with embodiment 1
Compound (III-1) 0.254g, yield is 70%.
Embodiment 18：
2,2 '-bipyridyl is changed to into alanine (0.018g, 0.20mmol), other operations obtain targeted with embodiment 1
Compound (III-1) 0.301g, yield is 83%.
Embodiment 19：
2,2 '-bipyridyl is changed to into aspartic acid (0.027g, 0.20mmol), other operations obtain target with embodiment 1
Compound (III-1) 0.251g, yield is 69%.
Embodiment 20：
2,2 '-bipyridyl is changed to into threonine (0.024g, 0.20mmol), other operations obtain targeted with embodiment 1
Compound (III-1) 0.258g, yield is 71%.
Embodiment 21：
2,2 '-bipyridyl is changed to into L-Valine (0.023g, 0.20mmol), other operations obtain targeted with embodiment 1
Compound (III-1) 0.229g, yield is 63%.
Embodiment 22：
Potassium phosphate is changed to into potassium carbonate (0.829g, 6.0mmol), other operations obtain target compound with embodiment 1
(III-1) 0.051g, yield are 14%.
Embodiment 23：
Potassium phosphate is changed to into sodium carbonate (0.636g, 6.0mmol), other operations obtain target compound with embodiment 1
(III-1) 0.058g, yield are 16%.
Embodiment 24：
Potassium phosphate is changed to into cesium carbonate (1.955g, 6.0mmol), other operations obtain target compound with embodiment 1
(III-1) 0.258g, yield are 71%.
Embodiment 25：
Potassium phosphate is changed to into sodium hydroxide (0.240g, 6.0mmol), other operations obtain target compound with embodiment 1
(III-1) 0.094g, yield are 26%.
Embodiment 26：
Potassium phosphate is changed to into potassium hydroxide (0.337g, 6.0mmol), other operations obtain target compound with embodiment 1
(III-1) 0.109g, yield are 30%.
Embodiment 27：
Potassium phosphate is changed to into triethylamine (0.607g, 6.0mmol), other operations obtain target compound with embodiment 1
(III-1) 0.011g, yield are 3%.
Embodiment 28：
Reaction temperature is reduced to into 60 DEG C, other operations obtain target compound (III-1) 0.127g with embodiment 1, receive
Rate is 35%.
Embodiment 29：
Reaction temperature is increased to into 100 DEG C, other operations obtain target compound (III-1) 0.301g with embodiment 1,
Yield is 83%.
Embodiment 30：
The amount of Hydro-Giene (Water Science). is changed to into 0.010g, 0.05mmol, other operations obtain target compound with embodiment 1
(III-1) 0.149g, yield are 41%.
Embodiment 31：
The amount of Hydro-Giene (Water Science). is changed to into 0.029g, 0.15mmol, other operations obtain target compound with embodiment 1
(III-1) 0.222g, yield are 61%.
Embodiment 32：
The amount of Metformin is changed to into 0.215g, 1.3mmol, other operations obtain target chemical combination with embodiment 1
Thing (III-1) 0.240g, yield is 66%.
Embodiment 33：
The amount of Metformin is changed to into 0.116g, 0.7mmol, other operations obtain target chemical combination with embodiment 1
Thing (III-1) 0.320g, yield is 88%.
Embodiment 34：
The amount of 2,2 '-bipyridyl is changed to into 0.0156g, 0.1mmol, other operations obtain target chemical combination with embodiment 1
Thing (III-1) 0.232g, yield is 64%.
Embodiment 35：
The amount of 2,2 '-bipyridyl is changed to into 0.047g, 0.3mmol, other operations obtain target compound with embodiment 1
(III-1) 0.272g, yield are 75%.
Embodiment 36：
The amount of potassium phosphate is changed to into 0.637g, 3mmol, other operations obtain target compound (III-1) with embodiment 1
0.174g, yield are 48%.
Embodiment 37：
The amount of potassium phosphate is changed to into 1.910g, 9mmol, other operations obtain target compound (III-1) with embodiment 1
0.309g, yield are 85%.
Embodiment 38：The preparation of compound (III-2)
Operation simply will be changed into methoxyl group iodobenzene to ethyoxyl iodobenzene (0.248g, 1mmol) with embodiment 1, and mesh is obtained
Mark compound (III-2) 0.240g, yield is 62%.
1H NMR(500 MHz,DMSO-d6) δ 8.80 (s, 1H), 7.43 (s, 2H), 7.22 (d, J=8.4 Hz, 2H),
6.87 (d, J=8.4 Hz, 2H), 6.59 (s, 2H), 3.98 (d, J=6.5 Hz, 2H), 2.94 (s, 6H), 1.30 (t, J=6.5
Hz,3H).
Embodiment 39：The preparation of compound (III-3)
Operation simply will be changed into methoxyl group iodobenzene to methyl iodobenzene (0.217g, 1mmol) with embodiment 1,
Prepared target compound (III-3) 0.3g, yield is 87%.
1H NMR(500 MHz,DMSO-d6) δ 8.88 (s, 1H), 7.51 (s, 2H), 7.22 (d, J=8.2 Hz, 2H),
7.11 (d, J=8.2 Hz, 2H), 6.61 (s, 2H), 2.95 (s, 6H), 2.25 (s, 3H).
Embodiment 40：The preparation of compound (III-4)
Operation simply will change 3- methyl iodobenzenes (0.217g, 1mmol) into embodiment 1 to methoxyl group iodobenzene, and target is obtained
Compound (III-4) 0.273g, yield is 78%.
1H NMR(500 MHz,DMSO-d6)δ8.90(s,1H),7.54(s,2H),7.14-7.19(m,3H),6.83-
6.90(m,1H),6.63(s,2H),2.96(s,6H),2.26(s,3H).
Embodiment 41：The preparation of compound (III-5)
Operation simply will change 2- methyl iodobenzenes (0.217g, 1mmol) into embodiment 1 to methoxyl group iodobenzene, and target is obtained
Compound (III-5) 0.123g, yield is 34%.
1H NMR(500 MHz,DMSO-d6)δ8.38(s,1H),7.40(s,2H),7.07-7.39(m,4H),6.73(s,
2H),2.91(s,6H),2.45(s,3H).
Embodiment 42：The preparation of compound (III-6)
Operation simply will change 2- phenyl iodobenzenes (0.280g, 1mmol) into embodiment 1 to methoxyl group iodobenzene, and target is obtained
Compound (III-6) 0.307g, yield is 75%.
1H NMR(500 MHz,DMSO-d6)δ9.09(s,1H),7.60-7.66(m,6H),7.30-7.48(m,5H),
6.69(s,2H),2.98(s,6H).
Embodiment 43：The preparation of compound (III-7)
Operation simply will change iodobenzene (0.204g, 1mmol) into embodiment 1 to methoxyl group iodobenzene, and target compound is obtained
(III-7) 0.289g, yield are 86%.
1H NMR(500 MHz,DMSO-d6)δ8.97(s,1H),7.57(s,2H),7.39-7.21(m,4H),7.05(t,J
=7.3 Hz, 1H), 6.64 (s, 2H), 2.96 (s, 6H).
Embodiment 44：The preparation of compound (III-8)
Operation simply will be changed into methoxyl group iodobenzene to fluorine iodobenzene (0.223g, 1mmol) with embodiment 1, and targeted is obtained
Compound (III-8) 0.255g, yield is 73%.
1H NMR(500 MHz,DMSO-d6)δ8.98(s,1H),7.54(s,2H),7.34-7.37(m,2H),7.11-
7.15(m,2H),6.64(s,2H),2.95(s,6H).
Embodiment 45：The preparation of compound (III-9)
Operation simply will be changed into methoxyl group iodobenzene to chloroiodobenzone (0.238g, 1mmol) with embodiment 1, and targeted is obtained
Compound (III-9) 0.3g, yield is 82%.
1H NMR(500 MHz,DMSO-d6) δ 9.07 (s, 1H), 7.63 (s, 2H), 7.39 (d, J=8.8,2H), 7.35
(d, J=8.8,2H), 6.67 (s, 2H), 2.96 (s, 6H).
Embodiment 46：The preparation of compound (III-10)
Operation simply will be changed into methoxyl group iodobenzene to bromo-iodobenzene (0.283g, 1mmol) with embodiment 1, and targeted is obtained
Compound (III-10) 0.282g, yield is 68%.
1H NMR(500 MHz,DMSO-d6) δ 9.11 (s, 1H), 7.64 (s, 2H), 7.47 (d, J=8.5 Hz, 2H),
7.34 (d, J=8.5 Hz, 2H), 6.69 (s, 2H), 2.96 (s, 6H)
Embodiment 47：The preparation of compound (III-11)
Operation simply will change 3- chloroiodobenzones (0.238g, 1mmol) into embodiment 1 to methoxyl group iodobenzene, and targeted is obtained
Compound (III-11) 0.299g, yield is 82%.
1H NMR(500 MHz,DMSO-d6)δ9.12(s,1H),7.68(s,2H),7.57(s,1H),7.29-7.34(m,
1H), 7.24 (d, J=8.0Hz, 2H), 7.08 (d, J=8.0Hz, 1H), 6.70 (s, 2H), 2.92 (s, 6H).
Embodiment 48：The preparation of compound (III-12)
Operation simply will be changed into methoxyl group iodobenzene to itrile group iodobenzene (0.229g, 1mmol) with embodiment 1, and target is obtained
Compound (III-12) 0.339g, yield is 94%.
1H NMR(500 MHz,DMSO-d6) δ 9.41 (s, 1H), 7.79 (s, 2H), 7.74 (d, J=8.7 Hz, 2H),
7.58 (d, J=8.7 Hz, 2H), 6.78 (s, 2H), 2.98 (s, 6H).
Embodiment 49：The preparation of compound (III-13)
Operation simply will change nitro iodobenzene (0.249g, 1mmol) into embodiment 1 to methoxyl group iodobenzene, and target is obtained
Compound (III-13) 0.151g, yield is 40%.
1H NMR(500 MHz,DMSO-d6) δ 9.63 (s, 1H), 8.19 (d, J=9.2Hz, 2H), 7.85 (s, 1H), 7.65
(d, J=9.2,2H), 6.84 (s, 3H), 3.00 (s, 6H).
Embodiment 50：The preparation of compound (III-14)
Operation simply will change 1- (4- iodophenyls)-benzene sulfonyl nafoxidine into embodiment 1 to methoxyl group iodobenzene
(0.334g, 1mmol), is obtained target compound (III-14) 0.407g, and yield is 88%.
1H NMR(500 MHz,DMSO-d6) δ 9.40 (s, 1H), 7.77 (s, 2H), 7.72 (d, J=8.7 Hz, 2H),
7.62 (d, J=8.7 Hz, 2H), 6.77 (s, 2H), 3.11 (t, J=6.5 Hz, 4H), 2.99 (s, 6H), 1.64 (t, J=6.5
Hz,4H).
Embodiment 51：The preparation of compound (III-15)
Operation simply will change piperidines biguanide hydrochloride (0.206g, 1mmol) into embodiment 1 to Metformin,
Prepared target compound (III-15) 0.279g, yield is 76%.
1H NMR(500 MHz,DMSO-d6)δ8.99(s,1H),7.62(s,2H),7.29-7.36(m,4H),7.03-
7.07 (m, 1H), 6.69 (s, 2H), 3.43 (t, J=5.2 Hz, 4H), 1.48-1.65 (m, 6H).
Embodiment 52：The preparation of compound (III-16)
Operation simply will change moroxydine hydrochloride (0.207g, 1mmol) into embodiment 1 to Metformin, be obtained
Target compound (III-16) 0.246g, yield is 66%.
1H NMR(500 MHz,DMSO-d6) δ 9.13 (s, 1H), 7.71 (s, 2H), 7.31 (d, J=13.5 Hz, 4H),
7.07(s,1H),6.84(s,2H),3.63(s,4H),3.44(s,4H).
Embodiment 53：The preparation of compound (III-17)
Operation with embodiment 1, simply Metformin will be changed into 1- phenyl biguanide hydrochlorates (0.214g,
1mmol), target compound (III-17) 0.042g is obtained, yield is 11%.
1H NMR(500 MHz,DMSO-d6)δ9.51(s,2H),7.75(s,2H),7.30-7.35(m,10H),7.28(s,
2H),7.11-7.14(m,2H).
Embodiment 54：The preparation of compound (III-18)
Operation simply will change pyrroles's biguanide hydrochloride (0.192g, 1mmol) into embodiment 1 to Metformin,
Prepared target compound (III-18) 0.215g, yield is 60%.
1H NMR(500 MHz,DMSO-d6)δ8.99(s,1H),7.62(s,2H),7.29-7.36(m,4H),7.03-
7.07 (m, 1H), 6.69 (s, 2H), 3.43 (t, J=5.2 Hz, 4H), 1.48-1.65 (m, 4H).
Embodiment 55：Anti-liver cancer and anti-cell BEL-7402 biological activity tests
Anti-liver cancer cell BEL-7402 activity test methods：Mtt assay
A principles：Thiazolyl blue (MTT) is decomposed into water-fast bluish violet by mitochondrion hydrolytic enzyme and crystallizes and sink by cell
In cell, crystal can be determined its light absorbs with enzyme-linked immunosorbent assay instrument by dmso solution at 490nm wavelength to product
Value, reflects the proliferative conditions and number change of cell indirectly.
B cell：Hepatoma carcinoma cell BEL-7402 (is purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank)
C experimental procedures：
1) preparation of sample：For solvable sample, dissolved with 20 μ L DMSO per 1mg, take 2uL dilute with 1000 μ L culture fluid
Release, make concentration be 100 μ g/mL, then with culture fluid serial dilution to concentration.
2) culture of cell
2.1) preparation of culture medium：Contain 800,000 units of Penicillin, 1.0g streptomycins, 10% inactivation in per 1000mL culture medium
Hyclone.
2.2) culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2Cultivate in incubator, 3～
5d is passed on.
3) inhibitory action of the determination sample to growth of tumour cell
Cell is digested with EDTA- pancreatin Digestive system, and 1 × 10 is diluted to culture medium5/ mL, is added to 96 hole cell trainings
In foster plate, per hole 100uL, 37 DEG C are put, 5%CO2Cultivate in incubator.After inoculation 24h, the sample that addition is diluted with culture medium,
Per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Cultivate in incubator, 5mg/ after 72h, is added in cell culture well
The MTT of mL, per 10 μ L of hole, puts 37 DEG C of incubation 4h, adds DMSO, per 150 μ L of hole, vibrated with agitator, and Shi Jia Za is completely dissolved,
With microplate reader under 570nm wavelength colorimetric.With similarity condition with without sample, the culture medium culturing containing same concentration DMSO it is thin
Born of the same parents calculate median lethal concentration (IC of the sample to growth of tumour cell as control50), as a result as shown in table 1.
With hepatoma carcinoma cell BEL-7402 as model, with cisplatin as positive reference substance, the biguanide prepared in determining embodiment
Class compound (the III-1)～samples of (III-18) 18 inhibitory action in vitro to liver cancer cell growth.As a result show, this experiment
In the sample tested, compound (III-6) hepatoma carcinoma cell BEL-7402 used to experiment has good inhibiting effect (result
Refer to table 1).
IC of the 1 each compound of table to BEL-740250(ug/mL)
| Test No. | Compound | IC50 | Test No. | Compound | IC50 |
| 1 | (III-1) | >100 | 11 | (III-11) | 95.22 |
| 2 | (III-2) | >100 | 12 | (III-12) | >100 |
| 3 | (III-3) | >100 | 13 | (III-13) | >100 |
| 4 | (III-4) | >100 | 14 | (III-14) | >100 |
| 5 | (III-5) | >100 | 15 | (III-15) | >100 |
| 6 | (III-6) | 8.66 | 16 | (III-16) | 86.34 |
| 7 | (III-7) | 80.21 | 17 | (III-17) | 96.71 |
| 8 | (III-8) | 75.98 | 18 | (III-18) | >100 |
| 9 | (III-9) | 90.23 | 19 | Cisplatin | 7.82 |
| 10 | (III-10) | 75.69 |
Claims (2)
1. the preparation method of the N- aryl biguanide hydroiodic acid salt compounds shown in a kind of formula (III), it is characterised in that described
Preparation method is：
Biguanide hydrochloride shown in formula (I) is mixed with the fragrant iodo thing shown in formula (II) in addition solvent, is urged in metallic copper
Under the catalytic action of agent, and in the presence of part and alkaline matter, in 60～100 DEG C of 2～20h of stirring reaction, reaction knot
Shu Hou, reactant liquor is post-treated to obtain N- aryl biguanide hydroiodic acid salt compounds shown in formula (III)；
The solvent is water, ethanol, isopropanol, tetrahydrofuran, 1,4- dioxane, acetonitrile, N,N-dimethylformamide or two
Methyl sulfoxide；The metal copper catalyst is Cu-lyt., cuprous bromide, Hydro-Giene (Water Science). or copper chloride；The part be 2,2 '-
Bipyridyl, 1,10- phenanthrolines, triethylene diamine, glycine, lysine, glutamic acid, cystine, alanine, aspartic acid, Soviet Union
Propylhomoserin or L-Valine；The alkaline matter is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate or three
Ethamine；Fragrant iodo thing shown in the formula (II) and biguanide hydrochloride, metal copper catalyst, part, alkaline matter shown in formula (I)
Material amount ratio be 1: 0.7～1.3: 0.05～0.15: 0.1～0.3: 3～9；
In formula (I), formula (II) or formula (III)：
R1, R2Hydrogen, C1～C10 alkyl or C6～C10 aryl, or R are stood alone as each1, R2N between the two is combined to be formed and is contained
The heterocycle of the C4～C8 of N, O；
R3Hydrogen or a substituent group on phenyl ring are represented, described substituent group is selected from C1～C10 alkyl, C1～C10 alkoxyls, C6
～C10 aryl, halogen, nitrogenous electron-withdrawing substituent or sulfonyl.
2. preparation method as claimed in claim 1, it is characterised in that the volumetric usage of the solvent is with Guanoctine shown in formula (I)
The quality of hydrochlorate is calculated as 10～50mL/g.
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| US3960949A (en) * | 1971-04-02 | 1976-06-01 | Schering Aktiengesellschaft | 1,2-Biguanides |
| FR2809310B1 (en) * | 2000-05-26 | 2004-02-13 | Centre Nat Rech Scient | USE OF BIGUANIDE DERIVATIVES FOR MANUFACTURING A MEDICINAL PRODUCT HAVING A HEALING EFFECT |
| US20110263901A1 (en) * | 2008-01-23 | 2011-10-27 | Dhananjay Govind Sathe | Process of Preparation of Proguanil |
| US9133110B2 (en) * | 2010-01-06 | 2015-09-15 | Hanall Biopharma Co., Ltd. | Biguanide derivative, preparation method thereof, and pharmaceutical composition containing same as an active ingredient |
| EP2742019B1 (en) * | 2011-08-08 | 2021-03-03 | Immunomet Therapeutics Inc. | N1-cyclic amine-n5-substituted phenyl biguanide derivatives and pharmaceutical composition comprising the same |
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