CN106798739A - A kind of medicine for treating tumor disease - Google Patents
A kind of medicine for treating tumor disease Download PDFInfo
- Publication number
- CN106798739A CN106798739A CN201510881550.3A CN201510881550A CN106798739A CN 106798739 A CN106798739 A CN 106798739A CN 201510881550 A CN201510881550 A CN 201510881550A CN 106798739 A CN106798739 A CN 106798739A
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- CN
- China
- Prior art keywords
- amino
- alkyl
- acid
- base
- medicine
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- 239000003814 drug Substances 0.000 title claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 21
- -1 benzimidazole ketone compound Chemical class 0.000 claims abstract description 67
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 238000006467 substitution reaction Methods 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000004193 piperazinyl group Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-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
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000005936 piperidyl group Chemical group 0.000 claims description 4
- TZMHSWLDPZJUAJ-UHFFFAOYSA-N (2-amino-3-phenylphenyl)-phenylmethanone Chemical compound C(C1=CC=CC=C1)(=O)C=1C(=C(C=CC1)C1=CC=CC=C1)N TZMHSWLDPZJUAJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 claims description 3
- 235000010338 boric acid Nutrition 0.000 claims description 3
- JQPDCKOQOOQUSC-OOZYFLPDSA-N dihydrokainic acid Chemical compound CC(C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O JQPDCKOQOOQUSC-OOZYFLPDSA-N 0.000 claims description 3
- 229960001484 edetic acid Drugs 0.000 claims description 3
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 235000011087 fumaric acid Nutrition 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 239000004334 sorbic acid Substances 0.000 claims description 3
- 235000010199 sorbic acid Nutrition 0.000 claims description 3
- 229940075582 sorbic acid Drugs 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 claims description 3
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- AYCBYZKNYLHNLC-UHFFFAOYSA-N CC=1C=C(C=C(C=1)C)N(N)C1=CC=CC=C1 Chemical compound CC=1C=C(C=C(C=1)C)N(N)C1=CC=CC=C1 AYCBYZKNYLHNLC-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Chemical group 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 230000037429 base substitution Effects 0.000 claims description 2
- 229960002645 boric acid Drugs 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229960000448 lactic acid Drugs 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 150000003214 pyranose derivatives Chemical class 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- DRSFOJYINWZTOS-UHFFFAOYSA-N CC(C)NC1(CCN(C(C1(NC2CCCCC2)NC3CC3)(N)N4CCCCC4)C)N Chemical compound CC(C)NC1(CCN(C(C1(NC2CCCCC2)NC3CC3)(N)N4CCCCC4)C)N DRSFOJYINWZTOS-UHFFFAOYSA-N 0.000 claims 1
- KCECGOSWTJWBKL-UHFFFAOYSA-N CN1CCCCC1(N)N2CCCCC2 Chemical compound CN1CCCCC1(N)N2CCCCC2 KCECGOSWTJWBKL-UHFFFAOYSA-N 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims 1
- 239000012965 benzophenone Substances 0.000 claims 1
- ZPFKRQXYKULZKP-UHFFFAOYSA-N butylidene Chemical group [CH2+]CC[CH-] ZPFKRQXYKULZKP-UHFFFAOYSA-N 0.000 claims 1
- 125000005392 carboxamide group Chemical class NC(=O)* 0.000 claims 1
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 1
- FUXUNHNJKWQHTO-UHFFFAOYSA-N formamide 1-methylpiperidine Chemical class C(=O)N.CN1CCCCC1 FUXUNHNJKWQHTO-UHFFFAOYSA-N 0.000 claims 1
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- 125000005942 tetrahydropyridyl group Chemical group 0.000 claims 1
- 230000012010 growth Effects 0.000 abstract description 4
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 94
- 238000006243 chemical reaction Methods 0.000 description 55
- 238000004440 column chromatography Methods 0.000 description 34
- 238000000926 separation method Methods 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
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- 239000000243 solution Substances 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
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- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 21
- 235000002639 sodium chloride Nutrition 0.000 description 19
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 description 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- JNRLEMMIVRBKJE-UHFFFAOYSA-N 4,4'-Methylenebis(N,N-dimethylaniline) Chemical group C1=CC(N(C)C)=CC=C1CC1=CC=C(N(C)C)C=C1 JNRLEMMIVRBKJE-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- SJFHBBDJHAJCFP-UHFFFAOYSA-N CC(C)NC1CCN(C(C1(NC2CCCCC2)NC3CC3)(N)N4CCCCC4)C Chemical compound CC(C)NC1CCN(C(C1(NC2CCCCC2)NC3CC3)(N)N4CCCCC4)C SJFHBBDJHAJCFP-UHFFFAOYSA-N 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000248349 Citrus limon Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- QFHMNFAUXJAINK-UHFFFAOYSA-N [1-(carbamoylamino)-2-methylpropyl]urea Chemical group NC(=O)NC(C(C)C)NC(N)=O QFHMNFAUXJAINK-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- HXHWSAZORRCQMX-UHFFFAOYSA-N albendazole Chemical compound CCCSC1=CC=C2NC(NC(=O)OC)=NC2=C1 HXHWSAZORRCQMX-UHFFFAOYSA-N 0.000 description 1
- 229960002669 albendazole Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MYONAGGJKCJOBT-UHFFFAOYSA-N benzimidazol-2-one Chemical compound C1=CC=CC2=NC(=O)N=C21 MYONAGGJKCJOBT-UHFFFAOYSA-N 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- KFDKSWDECHPONU-UHFFFAOYSA-N bis(trichloromethyl) carbonate Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl.ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl KFDKSWDECHPONU-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000000006 cell growth inhibition assay Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- LAYPMCGIWDGYKX-UHFFFAOYSA-N trichloromethyl hydrogen carbonate Chemical compound OC(=O)OC(Cl)(Cl)Cl LAYPMCGIWDGYKX-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of medicine for treating tumor disease, the medicine contains the acceptable salt of the biology of benzimidazole ketone compound or type I compound with structural formula shown in formula I as active component.The present invention is good for suppressing the growth of tumour cell for treating the medicine of tumor disease.
Description
Technical field
The present invention relates to a kind of medicine for treating tumor disease, more particularly to a kind of benzimidazole ketone compound is made
It is the medicine for treating tumor disease of active component, belongs to biomedicine technical field.
Background technology
Modern society's life rhythm is fast, and people's routine work pressure is big, is chronically at sub-health state.Autoimmunity
Deficiency, causes various exogenous germ invasions and endogenic abnormal growth of cells ratio persistently to increase, and seriously threatens the mankind
Life.The mankind are increasingly turned to organic chemical synthesis for the research of medicine since 20th century, and wherein heterocyclic compound is unique with it
Stereoeffect, electronics distribution, the spatial arrangement of active group the features such as, given play to protrusion in various disease treatments
Effect.
Benzimidazole ring is the aromatic heterocycles containing two nitrogen-atoms, this special structure can with the enzyme in organism and
Acceptor etc. forms hydrogen bond.Numerous medicines containing benzimidazole structure fragment are applied to the clinical treatment of various diseases, such as Ah
Department's imidazoles, Omeprazole, albendazole etc..
The content of the invention
Object of the present invention is to provide a kind of benzimidazole ketone compound with structure shown in formula I, while of the invention
Additionally provide the method for preparing the compound.
It is a further object of the present invention to provide a kind of medical compounds or composition for treating bacterium infection, the medicine
Compound or composition contain the benzimidazole ketone compound of formula I or the acceptable salt of its biology, used as being active component.
In order to realize foregoing invention purpose, the invention provides following technical scheme：
A kind of medicine for treating tumor disease, the medicine contains the benzimidazole ketone with structural formula shown in formula I
The acceptable salt of biology of compound or type I compound is used as active component.
Wherein, X is oxygen or sulphur；
Y is the subunit of C1-C5, can be the subunit of the C1-C5 of straight chain, or the subunit of the C1-C5 containing side chain.
In other words, Y isM=1-5, thereon atom can be replaced by C1-C3 alkyl.It is preferred that Y is methylene
Base, ethylidene, propylidene, isopropylidene, butylidene or isobutylidene.
R1Selected from the following group of unsubstituted or substituted base substitution：Aryl, alkylaryl or azepine aryl.Its
In, the substitution base is selected from：Hydrogen, halogen, cyano group, amino, hydroxyl, C3-C7 cycloalkyl, C1-C3 alkyl, halo C1-C3 alkyl,
In C1-C3 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C3 alkyl) amino, haloalkyl, alkoxy and nitros one
It is individual.
Wherein, R5 is
R2、R3Can be respective independent substitution base, or the loop configuration being interconnected to form.
When it is each independent substitution base, R2, R3 are independently selected from：Hydrogen, halogen, cyano group, C1-C7 alkyl,
C1-C6 alkoxies, C3-C7 cycloalkyl, C1-C6 alkoxy carbonyls, C1-C6 alkyl-carbonyls, amino carbonyl, C1-C6 alkyl aminos
Carbonyl, nitro, amino, substituted-amino, oxazolyl, thiazolyl, piperidyl, hexahydro piperidyl, pyridine radicals, dihydropyridine base, four
Pyridinium hydroxide base, thiazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, pyrimidine radicals, piperazinyl, morpholinyl, substituted piperazinyl, furyl,
Pyranose, the heterocyclic radical for being optionally substituted base Z substitutions, are optionally substituted the aryl of base Z substitutions, are optionally substituted base Z
Substituted heteroaryl；
The substitution base Z is hydrogen atom, C1-C6 alkyl, halo C1-C6 alkyl, halogen, hydroxyl, aryl, amino, C1-C6
Alkyl amino, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, cyano group or C3-C7 cycloalkyl；
The substituted-amino include phenyl amino, phenylmethyl amino, substituted-phenyl amino, methylamino, ethylamino,
Propylcarbamic, isopropylamino, cyclopropylamino, Cyclohexylamino, piperidyl amino, methyl piperidine base amino, pyridine radicals ammonia
Base, piperazinyl amino.
Substituted-phenyl amino refers to MethYlphenylamino, ethylphenyl amino, propyl group phenyl amino, 3,5-dimethylphenyl ammonia
Base, methyl (ethyl) phenyl amino, halogen substituted-phenyl amino, nitro-phenylamino, phenylsulfone base phenyl amino, Benzophenone base
One in phenyl amino, benzophenone base amino.
The substituted piperazinyl refers to methyl piperazine base, ethyl piperazidine base, propylpiperazinyl, lupetazin base, methyl
(ethyl) piperazinyl, isopropyl piperazinyl, halogen substituted piperazinyl；Halogen includes fluorine, chlorine, bromine, iodine in halogen substituted piperazinyl.
R2、R3Formed together with their annular atom is connected with the 3-8 ring of annular atom.Work as R2And R3It is collectively forming ring
No longer it is single substituent structure during shape structure.
N=0-3.
R4 is to be independently selected from：Fluorine, chlorine, bromine, nitro, amino, C1-C4 alkyl, C3-C7 cycloalkyl, halo C1-C6
Alkyl, C2-C6 alkenyls, hydroxyl-C1-C6 alkyl, (two-C1-C6 alkyl aminos)-C1-C6 alkyl, amino, C1-C6 alkyl ammonia
Base, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, amino-C1-C6 alkyl aminos, C1-C6 alkoxies, C1-C6 alkyl
Amino, C1-C6 alkoxy carbonyl C1-C6 alkyl aminos, two (C1-C6 alkoxy -C 1-C6 alkyl) amino, amino carbonyl, C1-
C6 alkyl amino-carbonyls, two (C1-C6 alkyl) amino carbonyls, C3-C7 cycloalkyl amino carbonyls, C1-C6 alkoxies, C3-C7 rings
Alkoxy, hydroxyl-C1-C6 alkoxies, halo C1-C6 alkoxies, amino C1-C6 alkyl, amino C1-C6 alkoxies, C1-C6 alkane
Base sulfone, C2-6 alkenyls sulfone, C3-C7 cycloalkyl sulfone, C3-C7 cycloalkyl, halo C3-C7 cycloalkyl, heterocyclic oxy group, piperidyl ammonia
Base, N- methyl piperidine -4- carbonyls, piperazine-C1-C6 alkyl, pyrrolylcarbonyl amido, N- methyl piperidines formamido or heterocycle C1-
C6 alkyl oxies.Each substituent R4Can be identical, it is also possible to different.
The pharmaceutical salts of the type I compound be type I compound and acetic acid, dihydrokainic acid, benzoic acid, citric acid, sorbic acid,
Propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid,
The salt of the formation such as boric acid, lactic acid, ethylenediamine tetra-acetic acid.At least one above-mentioned sour composition and type I compound into salt.Can be single
The pharmaceutical salts that one organic acid, inorganic acids, or various organic acids or inorganic acids are obtained.
Further, R1It is phenyl, benzyl or their derivative.The derivative of the phenyl or benzyl refers to by C1-C3
The phenyl or benzyl of any one or a few substitution in alkyl, halogen, nitro and amino.
Further, R2、R3One of them is hydrogen.
Further, preferred R5 is selected from：Oxazolyl, In one.The evil of the oxazolyl
Word is one, mouthful side evil of evil.
Further, for more specifically, benzimidazolone compound of the present invention is one of following compound.
The present invention additionally provides a kind of method for preparing above-mentioned type I compound simultaneously, whereinIt is R5.
The method for synthesizing above-mentioned benzimidazolone compound, comprises the following steps：
(1) to cylite or its analog is added in ortho-nitrophenyl amine aqueous solution, reaction obtains the compound of formula V；
(2) compound of formula V and chlorosulfonic acid reaction are obtained into the compound of formula IV；
(3) reacted with amine and the compound of formula IV and obtain the compound of formula III；
(4) compound of reduction-type III obtains the compound of formula II；
(5) compound of formula II and BTC (triphosgene) reactions are obtained into type I compound.
Reaction process is as follows：
Another aspect of the present invention additionally provides medical compounds, the composition for treating tumor disease, the pharmaceutical compound
Thing or composition contain benzimidazole ketone compound or the acceptable salt of its biology with structure shown in formula I, as activity into
Point.
Further, the acceptable salt of the biology refers to type I compound and acetic acid, dihydrokainic acid, benzoic acid, lemon
Acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid,
The salt of the formation such as ascorbic acid, boric acid, lactic acid, ethylenediamine tetra-acetic acid.Certainly can also be other it is well known in the prior art can
For the organic acid or inorganic acid of field of medicaments.
Another goal of the invention of the present invention is to provide the application using type I compound in antineoplastic is prepared.
Further, type I compound or its medicine are used to treat the application in the medicines such as adenocarcinoma of lung, breast cancer, breast ductal cancer.
Compared with prior art, beneficial effects of the present invention：
The invention provides a kind of novel compounds with structure shown in formula I, can effectively suppress the growth of tumour cell,
It is applied to the treatment and prevention of tumor disease caused by various human body own cells misgrowths.What the present invention was provided simultaneously has
The novel compounds of structure shown in formula I, can effectively suppress the growth of various malignant bacterias and with the potentiality killed, can be with
It is applied to the treatment and prevention of various bacteria infectious disease.
Specific embodiment
Part technical term is explained as follows in the present invention：" triphosgene ", english abbreviation BTC, i.e., double (trichloromethyl) carbonic acid
Ester, is commonly called as solid phosgene, and chemical formula is C3Cl6O3.Low alkyl group include methyl, ethyl, propyl group, isopropyl, cyclopropyl, butyl,
Isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, hexyl, heptyl.
C1-C5 alkyl includes：Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, n-amyl, iso- penta
Base, neopentyl, sec-amyl, tertiary pentyl etc..C1-C7 alkyl includes：Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, uncle
Butyl, n-amyl, iso- amyl group, neopentyl, sec-amyl, tertiary pentyl, hexyl, heptyl etc..Low-grade alkenyl includes：Vinyl, third
Alkenyl, cyclobutenyl, pentenyl, hexenyl, heptenyl, octenyl etc..
With reference to test example and specific embodiment, the present invention is described in further detail.But this should not be understood
For the scope of above-mentioned theme of the invention is only limitted to following embodiment, all technologies realized based on present invention belong to this
The scope of invention.
The compound of 1 formula of embodiment V
Scheme 1Z：A is that acetone is solvent, sodium hydroxide catalyzed, and cylite or the reaction of its analog is added dropwise；Product acetic acid
Ethyl ester is extracted, and anhydrous magnesium sulfate is dried, column chromatography for separation；Preferably, separating liquid is hexamethylene：Ethyl acetate=6~10：1.
1 mM of ortho-nitraniline is dissolved in 3~5 milliliters of acetone, 1~2 times of NaOH is added 60~70
DEG C stirring 3~5 minutes, is slowly added dropwise 1.2~1.5 mMs of cylite or its analog, reacts 5~60 minutes, thin layer color
Spectrum tracking and monitoring, after completion of the reaction add 5~10 times of water, be extracted with ethyl acetate (10 milliliters × 2), be associated with it is several layers of and with satisfy
With saline solution backwash (20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (hexamethylene：Acetic acid
Ethyl ester=6~10：1), yield 35~95%.
Scheme 1A：A is acetone as solvent, potassium tert-butoxide catalysis, dropwise addition cylite or the reaction of its analog；Product second
Acetoacetic ester is extracted, and anhydrous magnesium sulfate is dried, column chromatography for separation；Preferably, separating liquid is hexamethylene：Ethyl acetate=6~10：1.
1 mM of ortho-nitraniline is dissolved in 3~5 milliliters of acetone, 1~2 times of potassium tert-butoxide is added 60~70
DEG C stirring 3~5 minutes, be slowly added dropwise 1.2~1.5 mMs cylite and or its analog, react 5~60 minutes, thin layer
Chromatogram tracking is monitored, and 5~10 times of water are added after completion of the reaction, is extracted with ethyl acetate (10 milliliters × 2), is associated with several layers of being used in combination
Saturated aqueous common salt backwash (20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (hexamethylene：Second
Acetoacetic ester=6~10：1), yield 60~85%.
Scheme 1B：A is acetone as solvent, sodium hydride catalysis, dropwise addition cylite or the reaction of its analog；Product acetic acid
Ethyl ester is extracted, and anhydrous magnesium sulfate is dried, column chromatography for separation；Preferably, separating liquid is hexamethylene：Ethyl acetate=6~10：1.
1 mM of ortho-nitraniline is dissolved in 3~5 milliliters of acetone, 1~2 times of sodium hydride is added at 60~70 DEG C
Stirring 3~5 minutes, is slowly added dropwise 1.2~1.5 mMs cylite and the like, reacts 5~60 minutes, thin-layer chromatography
Tracking and monitoring, adds 5~10 times of water after completion of the reaction, is extracted with ethyl acetate (10 milliliters × 2), is associated with several layers of and uses saturation
Saline solution backwash (20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (hexamethylene：Acetic acid second
Ester=6~10：1), yield 30~70%.
Scheme 1C：A be dichloromethane as solvent, it is sodium methoxide catalyzed, be added dropwise cylite or its analog reaction；Product is used
Ethyl acetate is extracted, and anhydrous magnesium sulfate is dried, column chromatography for separation；Preferably, separating liquid is hexamethylene：Ethyl acetate=6~10：
1。
1 mM of ortho-nitraniline is dissolved in 3~5 milliliters of dichloromethane, add 1~2 times of sodium methoxide 60~
70 DEG C of stirring a few minutes, 1.2~1.5 mMs of cylite or its analog are slowly added dropwise, reacted 5~60 minutes, thin layer color
Spectrum tracking and monitoring, after completion of the reaction add 5~10 times of water, be extracted with ethyl acetate (10 milliliters × 2), be associated with it is several layers of and with satisfy
With saline solution backwash (20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (hexamethylene：Acetic acid
Ethyl ester=6~10：1), yield 30~95%
Scheme 1D：A be tetrahydrofuran as solvent, it is sodium methoxide catalyzed, be added dropwise cylite or its analog reaction；Product is used
Ethyl acetate is extracted, and anhydrous magnesium sulfate is dried, column chromatography for separation；Preferably, separating liquid is hexamethylene：Ethyl acetate=6~10：
1。
1 mM of ortho-nitraniline is dissolved in 3~5 milliliters of tetrahydrofuran, add 1~2 times of sodium methoxide 60~
70 DEG C are stirred 3~5 minutes, are slowly added dropwise 1.2~1.5 mMs cylite and the like, are reacted 5~60 minutes, thin layer
Chromatogram tracking is monitored, and 5~10 times of water are added after completion of the reaction, is extracted with ethyl acetate (10 milliliters × 2), is associated with several layers of being used in combination
Saturated aqueous common salt backwash (20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (hexamethylene：Second
Acetoacetic ester=6~10：1), yield 20~75%
The compound of 2 formula of embodiment IV
Scheme 2Z：B is reacted for the compound of formula V is added in chlorosulfonic acid in batches, and reaction is finished, ice bath, ethyl acetate
Extraction, anhydrous magnesium sulfate is dried, column chromatography for separation；Preferably, separating liquid is hexamethylene：Ethyl acetate=4~6：1.
The chlorosulfonic acid for taking 5~10 mMs is stirred 5~10 minutes at 0 DEG C, and 1 mM of raw material is added in batches, is finished, will
Temperature is slowly increased to room temperature (20~35 DEG C), reacts 0.5~3h, thin-layer chromatography tracking and monitoring, after completion of the reaction, reaction solution pole
It is slow to pour into ice-water bath (with a large amount of ice cubes, volume is 10~20 times of reaction solution) and be stirred continuously with glass bar, use second
Acetoacetic ester extract (20 milliliters × 2), be associated with it is several layers of and use saturated aqueous common salt backwash (20 milliliters × 2), anhydrous magnesium sulfate drying
Half an hour, recycling design, column chromatography for separation (hexamethylene：Ethyl acetate=4~6：1), yield 40~95%.
Scheme 2A：b：To phosphorus pentoxide is added in chlorosulfonic acid, the compound of formula V is then added to chlorosulfonic acid in batches
Middle reaction, reaction is finished, ice bath, ethyl acetate extraction, is satisfied and is closed saline solution backwash, and anhydrous magnesium sulfate is dried, column chromatography for separation；It is excellent
Choosing, separating liquid is hexamethylene：Ethyl acetate=4~6：1.
The chlorosulfonic acid for taking 5~10 mMs is stirred 5~10 minutes at 0 DEG C, adds 1 mM of phosphorus pentoxide to continue to stir
Mix 5~10 minutes, 1 mM of raw material is added in batches, finish, temperature is slowly increased to room temperature (20~35 DEG C), reaction 0.5~
3h, thin-layer chromatography tracking and monitoring, after completion of the reaction, (with a large amount of ice cubes, volume is reaction solution extremely slowly to be poured into ice-water bath
10~20 times of reaction solution) in and be stirred continuously with glass bar, be extracted with ethyl acetate (20 milliliters × 2), be associated with several layers of being used in combination
Saturated aqueous common salt backwash (20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (hexamethylene：Second
Acetoacetic ester=4~6：1), yield 50~95%.
Scheme 2B：b：With chloroform as solvent, the compound of formula V is dissolved in wherein, is subsequently adding chlorosulfonic acid reaction, reaction
Finish, ice bath, ethyl acetate extraction is satisfied and closes saline solution backwash, and anhydrous magnesium sulfate is dried, column chromatography for separation；Preferably, separating liquid
It is hexamethylene：Ethyl acetate=4~6：1.
Take 1 mM of raw material and be dissolved in 3~5 milliliters of chloroforms, stirred at 0 DEG C 10 minutes or so, disposably add 5~10 mmoles
Your chlorosulfonic acid, room temperature (20~35 DEG C) is slowly increased to by temperature, reacts 0.5~3h, and thin-layer chromatography tracking and monitoring, reaction is finished
Afterwards, reaction solution is extremely slowly poured into ice-water bath (with a large amount of ice cubes, volume is 10~20 times of reaction solution) and used glass bar
It is stirred continuously, is extracted with ethyl acetate (20 milliliters × 2), is associated with several layers of and with saturated aqueous common salt backwash (20 milliliters × 2), nothing
Water magnesium sulfate dries half an hour, recycling design, column chromatography for separation (hexamethylene：Ethyl acetate=4~6：1), yield 40~90%.
Scheme 2C：b：In to the compound of formula V, chlorosulfonic acid reaction is slowly added to, reaction is finished, ice bath, ethyl acetate extraction
Take, satisfy and close saline solution backwash, anhydrous magnesium sulfate is dried, column chromatography for separation；Preferably, separating liquid is hexamethylene：Ethyl acetate=4
~6：1.
1 mM of raw material is placed in 0 DEG C and is incubated 10 minutes, be slowly added to 5~10 mMs of chlorosulfonic acid, finished temperature
Degree is slowly increased to room temperature (20~35 DEG C), reacts 0.5~3h, and thin-layer chromatography tracking and monitoring after completion of the reaction, extremely delays reaction solution
Slow pours into ice-water bath (with a large amount of ice cubes, volume is 10~20 times of reaction solution) and is stirred continuously with glass bar, uses acetic acid
Ethyl ester extract (20 milliliters × 2), be associated with it is several layers of and use saturated aqueous common salt backwash (20 milliliters × 2), anhydrous magnesium sulfate dry partly
Hour, recycling design, column chromatography for separation (hexamethylene：Ethyl acetate=4~6：1), yield 35~85%.
The compound of 3 formula of embodiment III
Concrete scheme：c：The compound of modus ponens IV and amine, react in organic solvent, and reaction finishes extract and separate and obtains formula III
Compound.
Take 1 mM of raw material, 1 mM of ammonia is dissolved in 3~5 milliliters of tetrahydrofurans, (20~35 DEG C) stirrings 0.5 of room temperature~
2h, thin-layer chromatography tracking and monitoring adds proper amount of methanol after reaction completely, add appropriate 300~400 mesh silica gel, recycling design,
Column chromatography for separation (hexamethylene：Ethyl acetate=2~4：1) yield is 60~95%.
The compound of 4 formula of embodiment II
Scheme 4Z reaction conditions d：In ethanol solution, pH=3~5 are reacted, instead under conditions of 80 ± 5 DEG C for iron powder, silica gel
Should finish, filter, with regulation pH=8~9, filtrate be collected by filtration, ethyl acetate extraction, column chromatography for separation obtains product.It is preferred that
, column chromatography for separation liquid is hexamethylene：Ethyl acetate=1~2：1.
The iron powder and appropriate 300~400 mesh silica gel that take 2.5~3 mMs add 10~15 milliliter 50~90% of ethanol
Solution, modulates 4 or so, 80 DEG C and stirs 5~10 minutes or so with watery hydrochloric acid by ethanol solution pH, and by raw material, 1 mM adds in batches
Enter mixed liquor, react 2~5h, thin-layer chromatography tracking and monitoring, reaction is finished, filtering (is equipped with appropriate 300~400 mesh silicon in funnel
Glue), to appropriate 300~400 mesh silica gel is added in filtrate, pH value of solution is modulated 8~9 with saturated sodium bicarbonate, filter (in funnel
Equipped with proper silica gel), to 5~10 times of water are added in filtrate, (20 milliliters × 2) are extracted with ethyl acetate, it is associated with several layers of being used in combination
Saturated aqueous common salt backwash (20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (hexamethylene：Second
Acetoacetic ester=1~2：1), yield 60~90%.
The compound of scheme 4A hydrazine hydrate reductions formula III, does not as a result react.
The compound of scheme 4B hydrogen reducings formula III, does not as a result react.
(document：Benzimidazole derivatives as novel nonpeptide luteinizing
hormone-releasing hormone(LHRH)antagonists.Part 1:Benzimidazole-5-
H is used in sulfonamides2, 10%Pd/C, THF, rt, 99%；)
Embodiment 5 prepares type I compound
Scheme 5Z reaction conditions e：With tetrahydrofuran as solvent, by the compound of formula II and BTC reaction generation type I compounds.
Reaction finishes regulation pH=8~9, and ethyl acetate extraction, column chromatography for separation obtains type I compound.Preferably, column chromatography for separation liquid
It is dichloromethane：Methyl alcohol=15~30:1.
Take 1 mM of raw material and be dissolved in 3~5 milliliters of anhydrous tetrahydro furans, stirred 5~10 minutes at 0 DEG C, take 0.6 mM
BTC (Triphosgene) (Triphosgene) dissolved with 1~2 milliliter of anhydrous tetrahydro furan, be slowly dropped into constant pressure funnel
State and (drip off within 3~5 minutes) in solution, react 0.2h~3h, thin-layer chromatography tracking and monitoring, reaction is finished, to adding 3 in reaction solution
~5 times of water, 8~9 are modulated with saturated sodium bicarbonate by pH value of solution, then are extracted with ethyl acetate (20 milliliters × 2), are associated with several layers of
And with saturated aqueous common salt backwash (20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (dichloromethane
Alkane：Methyl alcohol=15~30:1), yield 60~95%.
Scheme 5A reaction conditions e：The compound of formula II is dissolved in tetrahydrofuran, the tetrahydrofuran solution of BTC is slowly added dropwise,
Reaction is finished, and adjusts pH=8~9, and ethyl acetate extraction, column chromatography for separation obtains type I compound.Preferably, column chromatography for separation
Liquid is dichloromethane：Methyl alcohol=15~30:1.
Take 1 mM of raw material and be dissolved in tetrahydrofuran, stirred 5~10 minutes or so at 0 DEG C, take 0.6 mM of BTC (three
Surpalite) dissolved with 3~5 milliliters of tetrahydrofurans, it is slowly dropped into above-mentioned solution with constant pressure funnel and (is dripped off within 3~5 minutes),
0.5~3h of reaction, thin-layer chromatography tracking and monitoring reacts incomplete and more miscellaneous, to 3~5 times of water are added in reaction solution, uses saturated carbon
PH value of solution is modulated 8~9 by sour hydrogen sodium, then is extracted with ethyl acetate (20 milliliters × 2), is associated with several layers of and anti-with saturated aqueous common salt
Wash (20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (dichloromethane：Methyl alcohol=15~30:
1), yield is 10~50%.
Scheme 5B reaction conditions e：The compound of formula II is dissolved in tetrahydrofuran, the tetrahydrofuran solution of BTC is slowly added dropwise,
Reaction is finished, and adjusts pH=8~9, and ethyl acetate extraction, column chromatography for separation obtains type I compound.Preferably, column chromatography for separation
Liquid is dichloromethane：Methyl alcohol=15~30:1.
Take 1 mM of raw material and be dissolved in anhydrous tetrahydro furan, stirred 5~10 minutes at 0 DEG C, take 0.3 mM of BTC (three
Surpalite) dissolved with 3~5 milliliters of anhydrous tetrahydro furans, it is slowly dropped into above-mentioned solution with constant pressure funnel and (is dripped within 3~5 minutes
It is complete), 0.5~3h is reacted, thin-layer chromatography tracking and monitoring, reaction is not finished, and to 3~5 times of water are added in reaction solution, uses unsaturated carbonate
PH value of solution is modulated 8~9 by hydrogen sodium, then is extracted with ethyl acetate (20 milliliters × 2), is associated with several layers of and is used saturated aqueous common salt backwash
(20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (dichloromethane：Methyl alcohol=15~30:
1), yield 60~75%.
Scheme 5C reaction conditions e：The compound of formula II is dissolved in tetrahydrofuran, the tetrahydrofuran solution of BTC is slowly added dropwise,
Reaction is finished, and adjusts pH=8~9, and ethyl acetate extraction, column chromatography for separation obtains type I compound.Preferably, column chromatography for separation
Liquid is dichloromethane：Methyl alcohol=15~30:1.
Take 1 mM of raw material and be dissolved in 3~5 milliliters of anhydrous tetrahydro furans, in (20~35 DEG C) stirrings of room temperature, take 0.6 mmoles
Your BTC (Triphosgene) is dissolved with 3~5 milliliters of anhydrous tetrahydro furans, is slowly dropped into above-mentioned solution with constant pressure funnel
(dripping off within 3~5 minutes), reacts 0.5~3h, and thin-layer chromatography tracking and monitoring, reaction is not finished, to adding excessive water in reaction solution,
PH value of solution is modulated 8~9 with saturated sodium bicarbonate, then is extracted with ethyl acetate (20 milliliters × 2), be associated with several layers of and use saturation
Saline solution backwash (20 milliliters × 2), anhydrous magnesium sulfate dries half an hour, recycling design, column chromatography for separation (dichloromethane：Methyl alcohol
=15~30:1), yield 60~85%.
Embodiment 6-N
According to the processing step of embodiment 1-5, multi-stage synthesis obtain in Tables 1 and 2 compound (Coupounds) and by its
For related bacteriostatic activity and Anti-tumor angiogenesis experiment.
The antibacterial activity experiment of benzimidazole ketone compound：
And the antibacterial activity of the compound obtained using the synthesis of in vitro test measurement of test method, as a result show present invention conjunction
Into compound be respectively provided with different degrees of antibacterial activity for S. aureus L-forms, Pseudomonas aeruginosa, hemolytic streptococcus etc..
The Anti-tumor angiogenesis experiment of benzimidazolone
By the compound of above-mentioned synthesis using in vitro culture measurement of test method its for A549, HCC1937 and MDA-
The IC of MB-48 tumour cells50Concentration (MIC) is as a result as follows.
Cell growth inhibition assay
Using mtt assay：It is tri- kinds of cells of HCC1937, A549, MDA-MB-48 to adjust cell line with complete culture solution respectively
Cell concentration is 2 × 104/ ml, is inoculated in 96 orifice plates, per the μ L of hole 200, overnight incubation, next day respectively with various dose wait sieve
Compound (final concentration is respectively 10,5,2.5,1.25,0.625,0.312,0.16 μ g/ml) is selected to process cell, while in equal volume
Solvent control group, DMSO concentration be 0.1% (0.1% DMSO cell proliferations do not influence).Each sets 5 multiple holes, 37
DEG C, 5%CO2After culture 48 hours, the μ L of 5mg/ml MTT reagents 20 are added per hole, continue to cultivate 2~4h, abandon supernatant, then add
The μ L of DMSO 150, vibration mixes 15min, and with ELIASA (λ=570nm) mensuration absorbance (A) value, (A values are with viable count into just
Than), take its average value.Relative cell proliferation inhibiting rate (%)=(control group A 570- experimental group A570)/control group A 570 ×
100%, inhibiting rate is the IC of the 50% compound concentration as compound50Value.Experiment is at least repeated 3 times.Positive control is adopted
Use adriamycin.
It is good that above-mentioned result of the test shows that there is the compound on tumor cell of the structure shown in formula I of the present invention preparation growth to have
Inhibitory action, can be used for the treatment of various human tumor diseases.
Claims (8)
1. a kind of medicine for treating tumor disease, the medicine contains the benzimidazole ketone with structural formula shown in formula I
The acceptable salt of biology of compound or type I compound as active component,
Wherein, X is oxygen or sulphur；
Y isM=1-5；Also it is the subunit of substituted C1-C5 including Y, the hydrogen atom on the subunit of C1-C5 can
Replace with by C1-C3 alkyl；
R1 is selected from the following group of unsubstituted or substituted base substitution：Aryl, alkylaryl or azepine aryl；Wherein, institute
State substitution base and be selected from hydrogen, halogen, cyano group, amino, hydroxyl, C3-C7 cycloalkyl, C1-C3 alkyl, halo C1-C3 alkyl, C1-C3
One in alkyl amino, C3-C7 cycloalkyl aminos, two (C1-C3 alkyl) amino, haloalkyl, alkoxy and nitros；
Wherein, R5It is
R2, R3 are independently selected from：Hydrogen, halogen, cyano group, C1-C7 alkyl, C1-C6 alkoxies, C3-C7 cycloalkyl, C1-C6
Alkoxy carbonyl, C1-C6 alkyl-carbonyls, amino carbonyl, C1-C6 alkyl amino-carbonyls, nitro, amino, substituted-amino, oxazole
Base, thiazolyl, piperidyl, hexahydro piperidyl, pyridine radicals, dihydropyridine base, tetrahydro pyridyl, thiazinyl, pyrrole radicals, imidazoles
Base, pyrazolyl, pyrimidine radicals, piperazinyl, morpholinyl, substituted piperazinyl, furyl, pyranose, be optionally substituted base Z substitution
Heterocyclic radical, is optionally substituted the aryl of base Z substitutions, is optionally substituted the heteroaryl of base Z substitutions；
The substitution base Z is hydrogen atom, C1-C6 alkyl, halo C1-C6 alkyl, halogen, hydroxyl, aryl, amino, C1-C6 alkyl
Amino, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, cyano group or C3-C7 cycloalkyl；
The substituted-amino includes phenyl amino, phenylmethyl amino, substituted-phenyl amino, methylamino, ethylamino, propyl group
Amino, isopropylamino, cyclopropylamino, Cyclohexylamino, piperidyl amino, methyl piperidine base amino, pyridinylamino, piperazine
Piperazine base amino；
The substituted-phenyl amino refers to MethYlphenylamino, ethylphenyl amino, propyl group phenyl amino, 3,5-dimethylphenyl ammonia
Base, methyl (ethyl) phenyl amino, halogen substituted-phenyl amino, nitro-phenylamino, phenylsulfone base phenyl amino, Benzophenone base
One in phenyl amino and benzophenone base amino；
The substituted piperazinyl refers to methyl piperazine base, ethyl piperazidine base, propylpiperazinyl, lupetazin base, methyl (second
Base) piperazinyl, isopropyl piperazinyl, halogen substituted piperazinyl；Halogen includes fluorine, chlorine, bromine, iodine in halogen substituted piperazinyl；Or,
Formed together with R2, R3 and the annular atom for being connected them with the 3-8 ring of annular atom；
N=0-3；
R4 is to be independently selected from：Fluorine, chlorine, bromine, nitro, amino, C1-C4 alkyl, C1-C3 alkoxies, C3-C7 cycloalkyl,
Halo C1-C6 alkyl, C2-6 alkenyls, hydroxyl substitution C1-C6 alkyl, (two-C1-C6 alkyl aminos)-C1-C6 alkyl, amino,
C1-C6 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C6 alkyl) amino, amino-C1-C6 alkyl aminos, C1-C6 alcoxyls
Base C1-C6 alkyl aminos, C1-C6 alkoxy carbonyls, C1-C6 alkyl aminos, two (C1-C6 alkoxy -C 1-C6 alkyl) amino,
Amino carbonyl, C1-C6 alkyl amino-carbonyls, two (C1-C6 alkyl) amino carbonyls, C3-C7 cycloalkyl amino carbonyls, C1-C6 alkane
Epoxide, C3-C7 cycloalkyloxies, hydroxyl-C1-C6 alkoxies, halo C1-C6 alkoxies, amino C1-C6 alkyl, amino C1-C6 alkane
Epoxide, C1-C6 alkyl sulfone, C2-6 alkenyls sulfone, C3-C7 cycloalkyl sulfone, C3-C7 cycloalkyl, halo C3-C7 cycloalkyl, heterocycle oxygen
Base, piperidyl amino, N- methyl piperidine -4- carbonyls, piperazine-C1-C6 alkyl, pyrrolylcarbonyl amido, N- methyl piperidine formamides
Base or heterocycle C1-C6 alkyl oxies.
2. the medicine for treating tumor disease according to claim 1, it is characterised in that X is oxygen.
3. the medicine for treating tumor disease according to claim 1, it is characterised in that Y be methylene, ethylidene,
Propylidene, isopropylidene or butylidene.
4. the medicine for treating tumor disease according to claim 1, it is characterised in that R1 be phenyl, benzyl or it
Derivative；The derivative of the phenyl or benzyl refers to by any one in C1-C3 alkyl, halogen, nitro and amino
Or several substituted phenyl or benzyl.
5. the medicine for treating tumor disease according to claim 1, it is characterised in that R2, R3 one of them be hydrogen.
6. the medicine for treating tumor disease according to claim 1, it is characterised in that R5 is selected from：Oxazolyl, In one.
7. the medicine for treating tumor disease according to claim 1, the pharmaceutical salts refer to type I compound and second
Acid, dihydrokainic acid, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, Asia
The salt of at least one formation in sulfuric acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid and ethylenediamine tetra-acetic acid.
8. the medicine for treating tumor disease according to claim 1, it is characterised in that be for treat adenocarcinoma of lung,
The medicine of breast cancer or breast ductal cancer.
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| WO2012020725A1 (en) * | 2010-08-10 | 2012-02-16 | 塩野義製薬株式会社 | Heterocyclic derivative having npy y5 receptor antagonism |
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| WO2012020725A1 (en) * | 2010-08-10 | 2012-02-16 | 塩野義製薬株式会社 | Heterocyclic derivative having npy y5 receptor antagonism |
| CN107257791A (en) * | 2014-12-19 | 2017-10-17 | 盖尔德马研究及发展公司 | It is used as the benzimidazole sulfonamides derivative of the orphan receptor γ ROR γ (t) related to biostearin inverse agonist |
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