CN112939864B - Spiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3-ones - Google Patents
Spiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3-ones Download PDFInfo
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- CN112939864B CN112939864B CN202110126357.4A CN202110126357A CN112939864B CN 112939864 B CN112939864 B CN 112939864B CN 202110126357 A CN202110126357 A CN 202110126357A CN 112939864 B CN112939864 B CN 112939864B
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- China
- Prior art keywords
- benzo
- cyclohexyl
- aza
- dihydrospiro
- ketone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 125000005605 benzo group Chemical group 0.000 title claims abstract description 110
- 125000003003 spiro group Chemical group 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 9
- -1 mono-substituted fluorine atom Chemical group 0.000 claims abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 8
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000002552 dosage form Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- URDOPVIVMKFFHV-UHFFFAOYSA-N (1-azidocyclohexyl)benzene Chemical compound C=1C=CC=CC=1C1(N=[N+]=[N-])CCCCC1 URDOPVIVMKFFHV-UHFFFAOYSA-N 0.000 claims description 6
- DTTDXHDYTWQDCS-UHFFFAOYSA-N 1-phenylcyclohexan-1-ol Chemical compound C=1C=CC=CC=1C1(O)CCCCC1 DTTDXHDYTWQDCS-UHFFFAOYSA-N 0.000 claims description 6
- RGZGRPPQZUQUCR-UHFFFAOYSA-N 1-phenylcyclohexylamine Chemical compound C=1C=CC=CC=1C1(N)CCCCC1 RGZGRPPQZUQUCR-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 4
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims 16
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 3
- 238000012827 research and development Methods 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 64
- 238000000034 method Methods 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- 229960005420 etoposide Drugs 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000005918 in vitro anti-tumor Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- NLLGFYPSWCMUIV-UHFFFAOYSA-N (3-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC(B(O)O)=C1 NLLGFYPSWCMUIV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- QCSLIRFWJPOENV-UHFFFAOYSA-N (2-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1F QCSLIRFWJPOENV-UHFFFAOYSA-N 0.000 description 1
- ROEQGIFOWRQYHD-UHFFFAOYSA-N (2-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC=C1B(O)O ROEQGIFOWRQYHD-UHFFFAOYSA-N 0.000 description 1
- NSJVYHOPHZMZPN-UHFFFAOYSA-N (2-methylphenyl)boronic acid Chemical compound CC1=CC=CC=C1B(O)O NSJVYHOPHZMZPN-UHFFFAOYSA-N 0.000 description 1
- AFSSVCNPDKKSRR-UHFFFAOYSA-N (3-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Br)=C1 AFSSVCNPDKKSRR-UHFFFAOYSA-N 0.000 description 1
- SDEAGACSNFSZCU-UHFFFAOYSA-N (3-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(Cl)=C1 SDEAGACSNFSZCU-UHFFFAOYSA-N 0.000 description 1
- KNXQDJCZSVHEIW-UHFFFAOYSA-N (3-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(F)=C1 KNXQDJCZSVHEIW-UHFFFAOYSA-N 0.000 description 1
- QBLFZIBJXUQVRF-UHFFFAOYSA-N (4-bromophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Br)C=C1 QBLFZIBJXUQVRF-UHFFFAOYSA-N 0.000 description 1
- BIWQNIMLAISTBV-UHFFFAOYSA-N (4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=C1 BIWQNIMLAISTBV-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical group O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 244000195896 dadap Species 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000012938 design process Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
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- 229960005322 streptomycin Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to a medicineA compound with a specific chemical structure and anti-tumor activity, in particular to 4, 5-dihydrospiro [ benzo [ c ]]Aza-1, 1' -cyclohexyl]-3(2H) -ketone compound and preparation method and application thereof. The structural general formula of the compound is as follows:
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a compound with a specific chemical structure and antitumor activity, and particularly relates to a4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone compound and a preparation method and application thereof.
Background
Cancer is a serious public health problem worldwide. Most cancer patients are lost due to high mortality and high recurrence rates. It is characterized by uncontrolled division and spread of abnormal cells in the human body. Therefore, the synthesis of effective novel anticancer drugs is one of the most important targets of modern pharmaceutical chemistry. The existing antitumor drugs have certain curative effects, but have the problems of drug resistance, poor selection effect, great toxic and side effects and the like. Therefore, the novel anti-tumor compound is designed according to natural plant-high erythrina alkaloids, and the seven-membered ring structure is optimized by combining the structural characteristics of the anti-tumor compound designed by the previous team, so as to obtain the novel compound with better anti-tumor effect, and the report of related structures is not found in the prior art.
Disclosure of Invention
The invention aims to provide a4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone compound, a preparation method and application thereof, wherein the prepared heptatomic amide spiro-structure shows a good result in an in-vitro antitumor activity test. Pharmacological research shows that the compound provided by the invention has certain inhibitory activity on human colon cancer HCT-116 cells.
In order to achieve the above purpose, the invention adopts the following technical scheme.
A4, 5-dihydrospiro [ benzo [ c ] azepine-1, 1' -cyclohexyl ] -3(2H) -ketone compound has a structural general formula I as follows:
wherein: the R group on the benzene ring is substituted by a fluorine atom, a methyl group, a chlorine atom, a methoxyl group, a bromine atom or a hydrogen atom which is mono-substituted at the 2 position, the 3 position or the 4 position.
The 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone compound has a structure selected from any one of the following compounds shown in the general formula I or pharmaceutically acceptable salts, hydrates or solvates thereof:
7-phenyl-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 1);
7- (2-chlorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 2);
7- (3-chlorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 3);
7- (4-chlorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 4);
7- (2-fluorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 5);
7- (3-fluorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 6);
7- (4-fluorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 7);
7- (o-benzyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A8);
7- (m-benzyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 9);
7- (p-phenylmethyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 10);
7- (2-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 11);
7- (3-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 12);
7- (4-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 13);
7- (2-bromophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 14);
7- (3-bromophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a 15);
7- (4-bromophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A16).
However, the compound is not limited to the above compounds, and the compound structural formula satisfies the general formula, which is defined in the present invention.
The preparation method of the 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone compound specifically comprises the following steps:
step 1, adding bromobenzene and magnesium strips into a reaction bottle, dissolving the bromobenzene and the magnesium strips into a proper amount of ether, and reacting through a classical Grignard reagent to obtain 1-phenylcyclohexanol.
And 2, adding 1-phenylcyclohexanol and a proper amount of dichloromethane into a reaction bottle as a solvent, and carrying out an azide reaction to obtain the 1-azido 1-phenylcyclohexane.
And 3, adding 1-azido 1-phenylcyclohexane and a proper amount of tetrahydrofuran into the reaction bottle as a solvent, and carrying out reduction reaction to obtain the 1-amino 1-phenylcyclohexane.
Step 4, adding 1-amino-1-phenylcyclohexane and acetonitrile serving as a solvent into a reaction bottle, and performing alkylation reaction to obtain 3-chloro-N- (1-phenylcyclohexyl) propionamide;
and step 5, adding 3-chloro-N- (1-phenylcyclohexyl) propionamide into a reaction bottle, taking dichloromethane as a solvent, and performing Friedel-crafts alkylation reaction to obtain the 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone.
And step 6, adding 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -ketone into a reaction bottle, taking dichloromethane as a solvent, and performing bromination reaction to obtain 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone.
And 7, adding 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone into a reaction bottle, and carrying out Suzuki reaction to obtain the target compound shown in the structural general formula I.
A pharmaceutical composition comprises the 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone compound, pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier.
The 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone compound or pharmaceutically acceptable salt, hydrate or solvate thereof or the pharmaceutical composition is applied to the preparation of antitumor drugs.
Further, the tumor is colon cancer.
Further, the dosage form of the drug is a pharmaceutically therapeutically acceptable dosage form.
Further, the dose of the drug is a pharmaceutically therapeutically acceptable dose.
The anti-tumor drug is a drug for resisting human colon cancer cells (HCT-116).
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
The invention can contain 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone compounds with a general formula I, and pharmaceutically acceptable salts and solvates thereof as active ingredients, and the active ingredients are mixed with pharmaceutically acceptable carriers or excipients to prepare a pharmaceutical composition and prepare clinically acceptable dosage forms, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc.
Compared with the prior art, the invention has the following beneficial effects.
The 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone compound provided by the invention has a remarkable effect in an in vitro antitumor activity test. In the design process of the invention, the 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone compound is designed and synthesized, the anti-tumor effect is greatly improved, and the compound has good anti-proliferation capability on human colon cancer cells (HCT-116). In the synthesis process, the synthesis steps are optimized, and the possibility is provided for future industrial production.
Detailed Description
The present invention is further illustrated by the following specific examples, which are intended to be illustrative only and not to limit the scope of the invention.
A4, 5-dihydrospiro [ benzo [ c ] azepine-1, 1' -cyclohexyl ] -3(2H) -ketone compound has a structural general formula I as follows:
wherein: the R group on the benzene ring is substituted by a fluorine atom, a methyl group, a chlorine atom, a methoxyl group, a bromine atom or a hydrogen atom which is mono-substituted at the 2 position, the 3 position or the 4 position.
Example 17 preparation of phenyl-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A1).
a.1-phenylcyclohexanol.
Bromobenzene (50g, 0.31mol), magnesium strip (8.13g, 0.33mol) was added to a 1000mL three-necked flask and dissolved in the appropriate amount of ether and initiated at 35 ℃. After completion of the reaction, cyclohexanone (34.38g, 0.35mol) was added and reacted at 35 ℃ for 5 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding the reaction solution into saturated ammonium chloride aqueous solution, extracting with diethyl ether, drying the extract, and evaporating under reduced pressure to obtain a product with the yield: 97.0 percent.
b.preparation of 1-azido-1-phenylcyclohexane.
A1000 mL reaction flask was charged with 1-phenylcyclohexanol (20.00g, 0.11mol), dichloromethane 500mL, sodium azide (8.11g, 0.12mol), trifluoroacetic acid (25.88g, 0.23mol), reacted at room temperature for 15 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding a saturated sodium carbonate aqueous solution into the reaction solution, extracting with dichloromethane, drying the extract, and evaporating under reduced pressure to obtain a product with the yield: 96.7 percent.
c, preparing 1-amino-1-phenylcyclohexane.
1-azido 1-phenylcyclohexane (13g,0.064mol), tetrahydrofuran (500 mL) and lithium aluminum hydride (4.77g,0.13mol) are added into a 1000mL reaction flask, and after reacting for 4 hours under normal temperature conditions, the temperature is raised to 40-60 ℃ to continue the reaction, and the reaction progress is monitored by thin layer chromatography. After the reaction is finished, sequentially adding the aqueous solution and the sodium hydroxide solution into the reaction solution, performing suction filtration, performing reduced pressure evaporation on the filtrate, then adding a small amount of water, adjusting the pH value to acidity, extracting impurities with diethyl ether, adjusting the pH value to alkalinity after impurity extraction, performing dichloromethane extraction, drying and reduced pressure evaporation on the extract liquor to obtain a product, wherein the yield is as follows: 94.2 percent.
Preparation of 3-chloro-N- (1-phenylcyclohexyl) propionamide.
A1000 mL reaction flask was charged with 1-amino-1-phenylcyclohexane (10g, 0.057mol), potassium carbonate (15.77g, 0.114mol), 3-chloropropionyl chloride (7.24g, 0.057mol), acetonitrile 500mL, and reacted overnight at 94 ℃ with TLC monitoring of the progress of the reaction. After the reaction is finished, 300ml of water is added, ethyl acetate is used for extraction, and the extraction liquid is dried and evaporated under reduced pressure to obtain the product with the yield: 93.7 percent.
e.4, preparation of 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one.
A500 mL reaction flask was charged with 3-chloro-N- (1-phenylcyclohexyl) propionamide (10.00g, 0.038mol), anhydrous aluminum chloride (15.05g, 0.113mol), reacted for 5 hours in an ice bath, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding the reaction solution into a mixture of hydrochloric acid and ice water, extracting impurities by using diethyl ether, adjusting the pH value of a water layer to be alkaline, extracting by using ethyl acetate, drying and evaporating an extract liquor under reduced pressure, and then purifying by using column chromatography to obtain a product, wherein the yield is as follows: 50.2 percent.
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one.
A500 mL reaction flask was charged with 4, 5-dihydrospiro [ benzo [ c ] azepine-1, 1' -cyclohexyl ] -3(2H) -one (5.00g, 0.022mol), liquid bromine (4.18g, 0.026mol), a small amount of glacial acetic acid as a catalyst, reacted at room temperature for 6 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, 300ml of water is added, ethyl acetate is used for extraction, and the extraction liquid is dried and evaporated under reduced pressure to obtain the product with the yield: 70.9 percent.
g.7 preparation of phenyl-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A1).
A500 mL reaction flask was charged with 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (1g, 0.003mol), potassium carbonate (0.897g, 0.006mol) dissolved in water, dioxane and water as solvent (4: 1), phenylboronic acid (0.435g, 0.004mol), a small amount of palladium on carbon as catalyst, and reacted at 90 ℃ overnight under nitrogen protection, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, 300ml of water is added, ethyl acetate is used for extraction, and the extract liquor is dried and evaporated under reduced pressure to obtain a product, namely a white solid, with the yield: 82.9 percent.
1H NMR(600MHz,DMSO-d6)δ7.44(s,2H),7.41(d,J＝6.0Hz,1H),7.37–7.33(m,5H),5.80(s,2H),5.63(s,2H),1.99(s,1H),1.63(m,7H),1.28(m,2H)；13C NMR(150MHz,DMSO-d6)δ167.84,148.09,145.66,136.62,128.12,127.85,127.81,127.73,126.58,125.81,125.59,124.87,116.25,57.73,35.35,32.15,25.54,24.92,21.85。
Example preparation of 27- (2-chlorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A2).
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from o-chlorobenzoic acid as in example 1f, 7- (2-chlorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A2) was obtained according to the procedure of example 1g, brown solid, yield: 83.1 percent.
1H NMR(600MHz,DMSO-d6)δ7.51(d,J＝7.8Hz,3H),7.46–7.39(m,4H),4.70(d,J＝6.3Hz,2H),4.50(d,J＝3.8Hz,2H),2.20(m,2H),2.14–2.06(m,2H),1.86–1.75(m,4H),1.30–1.24(m,2H)；13C NMR(150MHz,DMSO-d6)δ165.40,144.48,140.84,138.96,137.45,131.85,131.53,129.44,128.86,126.94,126.76,126.19,125.59,57.64,35.40,32.16,25.55,24.94,21.82。
Example preparation of 37- (3-chlorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A3).
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from m-chlorobenzeneboronic acid as in example 1f, 7- (3-chlorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A3) was prepared according to the procedure of example 1g, brown solid, yield: 84.0 percent.
1H NMR(600MHz,DMSO-d6)δ7.46–7.42(m,4H),7.32(t,J＝7.3Hz,3H),5.91(s,2H),5.70(s,2H),1.68–1.59(m,9H),1.29(d,J＝5.2Hz,1H)；13C NMR(150MHz,DMSO-d6)δ167.40,148.02,144.18,138.69,132.90,129.97,127.75,127.64,126.47,125.85,125.14,124.84,57.79,35.31,28.63,26.85,24.91,21.84。
Example 47 preparation of- (4-chlorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A3).
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from p-chlorobenzoic acid as in example 1f, 7- (4-chlorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A4) was obtained according to the procedure of example 1g, brown solid, yield: 81.1 percent.
1H NMR(600MHz,DMSO-d6)δ7.49(d,J＝8.0Hz,1H),7.31(m,4H),7.19(t,J＝6.9Hz,2H),5.85(s,2H),5.68(s,2H),1.62(m,8H),1.26(m,2H)；13C NMR(150MHz,DMSO-d6)δ167.48,135.45,132.51,128.94,128.38,128.13,127.81,127.76,125.83,125.58,124.82,57.79,35.32,32.14,25.53,24.89,21.85。
Example preparation of 57- (2-fluorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A5).
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from o-fluorobenzeneboronic acid as in example 1f, following the procedure of example 1g, 7- (2-fluorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a5) was obtained as a brown solid in yield: 85.2 percent.
1H NMR(600MHz,DMSO-d6)δ7.40–7.32(m,4H),7.30(t,J＝7.5Hz,3H),6.00(s,2H),5.78(s,2H),1.61(m,9H),1.29(d,J＝5.4Hz,1H)；13C NMR(150MHz,DMSO-d6)δ166.44,147.99,141.15,130.70,130.68,129.96,129.90,127.67,125.73,124.87,124.22,124.19,121.49,115.36,115.18,57.77,35.40,29.41,27.97,24.91,21.74。
Example 67 preparation of- (3-fluorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A6).
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one as in example 1f, starting from m-fluorophenylboronic acid, according to the procedure of example 1g, 7- (3-fluorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a6) was obtained as a brown solid in yield: 84.4 percent.
1H NMR(600MHz,DMSO-d6)δ7.40(dd,J＝13.7,6.8Hz,2H),7.33(t,J＝7.0Hz,4H),7.27(d,J＝7.5Hz,1H),5.92(s,2H),5.71(s,2H),1.68–1.60(m,9H),1.30(s,1H)；13C NMR(150MHz,DMSO-d6)δ167.46,148.03,144.31,130.06,129.99,127.73,125.84,124.85,122.67,122.65,117.54,114.64,114.47,113.34,113.16,57.78,35.32,29.55,27.47,24.92,21.85。
Example 77 preparation of- (4-fluorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A7).
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one as in example 1f, starting from p-fluorobenzeneboronic acid, according to the procedure of example 1g, 7- (4-fluorophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a7) was obtained as a brown solid in yield: 82.8 percent.
1H NMR(600MHz,DMSO-d6)δ7.43(d,J＝6.9Hz,3H),7.20–7.17(m,4H),5.80(s,2H),5.64(s,2H),1.63(m,8H),1.26m,2H)；13C NMR(150MHz,DMSO-d6)δ167.69,128.71,128.64,127.75,127.72,125.81,125.72,124.98,124.83,116.46,115.04,114.87,57.75,35.32,34.45,24.89,21.85,21.67。
Example 87- (O-benzyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A8) preparation.
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one as in example 1f, starting from o-tolylboronic acid, following the procedure of example 1g, 7- (o-phenylmethyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A8) was prepared as a white-like solid in yield: 79.8 percent.
1H NMR(600MHz,DMSO-d6)δ7.30–7.19(m,3H),7.13(m,4H),5.98(m,2H),5.53(d,J＝10.4Hz,2H),2.65(s,3H),1.64(m,6H),1.40–1.15(m,4H)；13C NMR(150MHz,DMSO-d6)δ163.67,134.45,132.89,132.45,129.59,128.92,128.91,128.44,128.37,127.73,127.68,125.72,124.19,57.56,34.45,34.31,24.31,22.18,22.08,21.96。
Example 97- (m-benzyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A9) preparation.
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from m-methylbenzboronic acid as in example 1f, 7- (m-benzyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a9) was prepared according to the procedure of example 1g, as an off-white solid, yield: 77.2 percent.
1H NMR(600MHz,DMSO-d6)δ7.47(d,J＝7.7Hz,3H),7.34(t,J＝7.5Hz,3H),7.14(d,J＝6.0Hz,1H),5.77(s,2H),5.60(s,2H),2.30(s,3H),1.69–1.59(m,9H),1.30(s,1H)；13C NMR(150MHz,DMSO-d6)δ167.97,148.13,145.82,137.13,136.56,128.47,128.02,127.71,127.30,125.81,124.91,123.64,119.40,57.70,35.34,29.45,26.70,24.95,21.85,20.86。
Example 107- (para-benzyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A10) was prepared.
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from p-methylbenzeneboronic acid as in example 1f, 7- (p-phenylmethyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a10) was prepared according to the procedure of example 1g, as an off-white solid, yield: 80.1 percent.
1H NMR(600MHz,DMSO-d6)δ7.44(d,J＝7.5Hz,3H),7.21–7.16(m,4H),5.76(s,2H),5.56(s,2H),2.30(s,3H),1.68–1.59(m,9H),1.29(d,J＝4.9Hz,1H)；13C NMR(150MHz,DMSO-d6)δ167.98,148.11,145.51,137.24,133.71,128.70,127.73,126.44,125.80,124.86,115.27,57.70,35.33,30.11,27.73,24.91,21.84,20.57。
Example 117 preparation of- (2-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A11).
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from o-methoxyphenylboronic acid as in example 1f, 7- (2-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a11) was prepared according to the procedure of example 1g, as a grey solid in yield: 77.1 percent.
1H NMR(600MHz,DMSO-d6)δ7.47(d,J＝8.0Hz,3H),7.41–7.37(m,4H),5.92(s,2H),5.57(s,1H),3.73(s,3H),1.61(m,8H),1.29(s,2H)；13C NMR(150MHz,DMSO-d6)δ163.48,147.93,144.54,135.37,131.52,130.43,129.47,127.62,125.67,125.00,124.87,120.15,110.13,55.05,35.53,24.92,21.70,21.68,20.52,13.88.。
Example 127- (3-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A12) was prepared.
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from m-methoxyphenylboronic acid as in example 1f, 7- (3-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a12) was prepared according to the procedure of example 1g, as a grey solid in yield: 75.4 percent.
1H NMR(600MHz,DMSO-d6)δ7.46(d,J＝7.7Hz,3H),7.20(t,J＝7.4Hz,2H),7.07–7.03(m,2H),5.81(s,2H),5.63(s,2H),3.69(s,3H),1.67–1.61(m,8H),1.27(d,J＝13.8Hz,2H)；13C NMR(150MHz,DMSO-d6)δ167.79,129.61,129.17,127.72,125.79,124.87,118.92,116.42,113.51,112.17,107.67,104.41,101.10,57.74,35.35,24.94,21.87,21.70,20.52,13.88。
Example 137- (4-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A13) preparation.
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from m-methoxyphenylboronic acid as in example 1f, 7- (4-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a13) was prepared according to the procedure of example 1g, as a grey solid in yield: 77.7 percent.
1H NMR(600MHz,DMSO-d6)δ6.93(d,J＝8.3Hz,3H),6.77–6.71(m,4H),5.71(s,2H),5.53(s,2H),3.66(s,3H),1.65(m,9H),1.29(s,1H)；13C NMR(150MHz,DMSO-d6)δ168.13,145.18,128.95,127.85,127.72,125.79,124.87,115.57,114.44,114.19,113.54,54.95,35.36,30.59,28.67,26.50,24.94,21.88。
Example 147- (2-bromophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A14) preparation.
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from o-bromobenzboronic acid as in example 1f, 7- (2-bromophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a14) was prepared according to the procedure of example 1g, as a yellow solid in yield: 85.0 percent.
1H NMR(600MHz,DMSO-d6)δ7.44(d,J＝7.2Hz,4H),7.37(s,3H),6.17(s,2H),5.60(s,1H),1.60m,8H),1.25(m,2H)；13C NMR(150MHz,DMSO-d6)δ164.04,132.02,131.63,129.60,129.10,128.73,127.74,127.59,127.46,127.27,125.75,125.05,124.89,59.58,35.39,24.90,24.84,21.81,21.68。
Example 157- (3-bromophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A15) was prepared.
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from m-bromobenzeneboronic acid as in example 1f, 7- (3-bromophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a15) was prepared according to the procedure of example 1g, as a yellow solid in yield: 86.3 percent.
1H NMR(600MHz,DMSO-d6)δ7.79(d,J＝7.8Hz,4H),7.61(d,J＝8.4Hz,3H),5.92(m,2H),5.67(d,J＝5.1Hz,2H),1.64–1.59(m,7H),1.32–1.21(m,3H)；13C NMR(150MHz,DMSO-d6)δ170.13,130.90,130.54,130.28,128.86,128.37,127.76,127.69,126.63,126.56,125.85,125.73,124.97,59.57,35.29,24.88,22.18,20.58,13.91。
Example 167- (4-bromophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (A16) preparation.
Preparation of 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexyl ] -3(2H) -one starting from p-bromophenylboronic acid as in example 1f, 7- (4-bromophenyl) -4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -one (a16) was prepared according to the procedure of example 1g, as a yellow solid, yield: 81.9 percent.
1H NMR(600MHz,DMSO-d6)δ7.51(d,J＝8.1Hz,2H),7.44(m,5H),5.87(d,J＝13.4Hz,2H),5.67(d,J＝10.7Hz,2H),1.63(m,8H),1.28(s,2H)；13C NMR(150MHz,DMSO-d6)δ167.80,131.66,131.06,128.69,128.48,128.37,127.76,127.22,126.63,126.27,125.82,57.78,34.45,34.32,28.53,24.33,22.18。
Example 17 inhibition of tumor cell proliferation assay.
The compound of the invention is subjected to tumor cell proliferation inhibition experiments, and the test method adopts a conventional MTT method.
Culturing of tumor cells: HCT-116 (human colon cancer cells) is selected as a cell strain, and the cell strain is cultured in a culture solution of McCoy's 5A + 10% FBS + double antibody (penicillin 100 units/ml, streptomycin 100 mu g/ml).
Sample preparation: after dissolution in DMSO (Merck), media (-) is added to make a 1000. mu.g/ml solution or homogeneous suspension, which is then diluted with DMSO-containing media (-). The final concentrations were: 50. mu.M, 25. mu.M, 12.5. mu.M, 6.25. mu.M, 3.125. mu.M. Etoposide (Etoposide) was used as a control.
Test methods for inhibition of cell proliferation: the adding concentration of each hole of the 96-hole plate is 4-5 multiplied by 104Mu.l of cell suspension/ml, placed at 37 ℃ in 5% CO2In the incubator. After 24 hours, the sample and control solutions were added, 10. mu.l/well, double wells, 5% CO at 37 ℃2For 24 hours. Adding 20 μ l of 5mg/ml MTT (3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide) solution into each well, reacting for 4 hr, adding DMSO solution into each well, placing in an incubator, dissolving, measuring OD at 490nm with MK-2 full-automatic enzyme standard instrument, and calculating cell inhibitory concentration IC50The value is obtained. The results are shown in Table 1.
TABLE 1 IC of in vitro proliferation inhibitory Activity of Compounds on human tumor cells50The value is obtained.
| Sample name | HCT-116 |
| A1 | 3.43±1.57 |
| A2 | 9.83±1.23 |
| A3 | 10.54±3.21 |
| A4 | 8.35±0.87 |
| A5 | 4.25±1.65 |
| A6 | 7.84±2.98 |
| A7 | 6.98±1.92 |
| A8 | 9.99±4.13 |
| A9 | 17.90±2.67 |
| A10 | 10.88±3.06 |
| A11 | 13.71±2.10 |
| A12 | 14.34±5.51 |
| A13 | 16.70±6.70 |
| A14 | 10.51±4.01 |
| A15 | 18.83±3.61 |
| A16 | 4.64±2.15 |
| Etoposide | 34.41 |
The experimental data show that most of the compounds in the invention have better in-vitro anti-tumor activity, have more value in further research and development of new anti-tumor drugs, and provide a wider idea for research and development of new drugs. The compound provided by the invention has easily available raw materials, and experiments prove that the compound has good anticancer effect and good application prospect in the field of design and research of antitumor drugs.
Claims (8)
1. 4, 5-dihydrospiro [ benzo [ b ], [c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone compound or a pharmaceutically acceptable salt thereof, characterized in that said compound has the general structural formula I as follows:
general formula I
Wherein: the R group on the benzene ring is substituted by a fluorine atom, a methyl group, a chlorine atom, a methoxyl group, a bromine atom or a hydrogen atom which is mono-substituted at the 2 position, the 3 position or the 4 position.
2. The 4, 5-dihydrospiro [ benzo [ b ], [ of claim 1c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula i is any one of:
7-phenyl-4, 5-dihydrospiro [ benzo [ b ], [ 2 ]c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (2-chlorophenyl) -4, 5-dihydrospiro [ benzo [ b ], [ 2-chlorophenyl ] -2c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (3-chlorophenyl) -4, 5-dihydrospiro [ benzo [ b ], [ 2 ]c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (4-chlorophenyl) -4, 5-dihydrospiro [ benzo [ b ], [ 2 ]c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (2-fluorophenyl) -4, 5-dihydrospiro [ benzo [ b ], [ 2-fluorophenyl ] -saltc]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (3-fluorophenyl) -4, 5-dihydrospiro [ benzo [ b ], [c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (4-fluorophenyl) -4, 5-dihydrospiro [ benzo [ b ], [ 2 ]c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (o-tolyl) -4, 5-dihydrospiro [ benzo [ b ], [ 2 ]c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (m-tolyl) -4, 5-dihydrospiro [ benzo [ b ], [ 2 ]c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (p-tolyl) -4, 5-dihydrospiro [ benzo [ 2 ], [ solution of a salt of a phenolc]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (2-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ b ], [c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (3-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ b ], [c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (4-methoxyphenyl) -4, 5-dihydrospiro [ benzo [ b ], [c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (2-bromophenyl) -4, 5-dihydrospiro [ benzo [ b ], [c]Aza derivatives-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (3-bromophenyl) -4, 5-dihydrospiro [ benzo [ b ], [c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone;
7- (4-bromophenyl) -4, 5-dihydrospiro [ benzo [ b ], [c]Aza-1, 1' -cyclohexyl]-3(2H) -a ketone.
3. The 4, 5-dihydrospiro [ benzo [ b ], [ of claim 1c]Aza-1, 1' -cyclohexyl]-3(2H) The preparation method of the ketone compound is characterized by comprising the following steps:
step 1, adding bromobenzene and magnesium strips into a reaction bottle, dissolving the bromobenzene and the magnesium strips into a proper amount of ether, and reacting the bromobenzene and the magnesium strips with a classical format reagent to obtain the compound
To 1-phenylcyclohexanol;
step 2, adding 1-phenylcyclohexanol and a proper amount of dichloromethane serving as a solvent into a reaction bottle, and performing an azide reaction to obtain 1-azido 1-phenylcyclohexane;
step 3, adding 1-azido 1-phenylcyclohexane and a proper amount of tetrahydrofuran as solvents into a reaction bottle, and carrying out reduction reaction to obtain 1-amino 1-phenylcyclohexane;
step 4, adding 1-amino-1-phenylcyclohexane and acetonitrile serving as a solvent into a reaction bottle, and performing alkylation reaction to obtain 3-chloro-N- (1-phenylcyclohexyl) propionamide;
step 5, adding 3-chloro-N- (1-phenylcyclohexyl) propionamide into a reaction bottle, taking dichloromethane as a solvent, and performing Friedel-crafts alkylation reaction to obtain 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone;
step 6, adding 4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone into a reaction bottle, taking dichloromethane as a solvent,
obtaining 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone through bromination reaction;
and 7, adding 7-bromo-4, 5-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3(2H) -ketone into a reaction bottle, and carrying out Suzuki reaction to obtain the target compound shown in the structural general formula I.
4. A pharmaceutical composition comprising the 4, 5-dihydrospiro [ benzo [ b ] of claim 1c]Aza-1, 1' -cyclohexyl]-3(2H) -ketone compounds, pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.
5. The 4, 5-dihydrospiro [ benzo [ b ], [ of claim 1c]Aza-1, 1' -cyclohexyl]-3(2H) -use of a ketone compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the preparation of a medicament for the treatment of an antineoplastic drug.
6. The use of claim 5, wherein the tumor is colon cancer.
7. The use of claim 5, wherein the medicament is in a pharmaceutically-therapeutically acceptable dosage form.
8. The use of claim 5, wherein the dose of the medicament is a pharmacotherapeutically acceptable dose.
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