WO2023179068A1 - 药物中间体及合成方法、异喹啉类衍生物及其合成方法 - Google Patents
药物中间体及合成方法、异喹啉类衍生物及其合成方法 Download PDFInfo
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- WO2023179068A1 WO2023179068A1 PCT/CN2022/134144 CN2022134144W WO2023179068A1 WO 2023179068 A1 WO2023179068 A1 WO 2023179068A1 CN 2022134144 W CN2022134144 W CN 2022134144W WO 2023179068 A1 WO2023179068 A1 WO 2023179068A1
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- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title abstract description 17
- 239000003814 drug Substances 0.000 title abstract description 17
- 238000010189 synthetic method Methods 0.000 title abstract 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 17
- 239000000126 substance Substances 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 125000005843 halogen group Chemical group 0.000 claims abstract description 8
- 125000006239 protecting group Chemical group 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 153
- 238000006243 chemical reaction Methods 0.000 claims description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 238000000034 method Methods 0.000 claims description 42
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 41
- 230000008569 process Effects 0.000 claims description 30
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000001308 synthesis method Methods 0.000 claims description 15
- -1 DPEPhos Chemical compound 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000007810 chemical reaction solvent Substances 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical group [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- XFBOPBBQPJNTHW-UHFFFAOYSA-N N-[1-(methylamino)propyl]oxolane-2-carboxamide Chemical compound CNC(CC)NC(=O)C1OCCC1 XFBOPBBQPJNTHW-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- 101150003085 Pdcl gene Proteins 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 239000003223 protective agent Substances 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- OEBXWWBYZJNKRK-UHFFFAOYSA-N 1-methyl-2,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidine Chemical compound C1CCN=C2N(C)CCCN21 OEBXWWBYZJNKRK-UHFFFAOYSA-N 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- LCSNDSFWVKMJCT-UHFFFAOYSA-N dicyclohexyl-(2-phenylphenyl)phosphane Chemical compound C1CCCCC1P(C=1C(=CC=CC=1)C=1C=CC=CC=1)C1CCCCC1 LCSNDSFWVKMJCT-UHFFFAOYSA-N 0.000 claims description 3
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 3
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 claims description 2
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 22
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 150000002537 isoquinolines Chemical class 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
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- 229910004298 SiO 2 Inorganic materials 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 12
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 11
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 10
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- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 5
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- CJAAPVQEZPAQNI-UHFFFAOYSA-N (2-methylphenyl)methanamine Chemical compound CC1=CC=CC=C1CN CJAAPVQEZPAQNI-UHFFFAOYSA-N 0.000 description 3
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- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 2
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- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241001573498 Compacta Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 230000006677 mitochondrial metabolism Effects 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- QWLISCJHYITNQF-UHFFFAOYSA-N n-methoxy-1-phenylmethanamine Chemical group CONCC1=CC=CC=C1 QWLISCJHYITNQF-UHFFFAOYSA-N 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 238000010825 rotarod performance test Methods 0.000 description 1
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical compound [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention belongs to the field of drug synthesis technology and relates to the synthesis of drugs for preventing or treating Alzheimer's disease, Parkinson's disease and other related diseases, and specifically relates to drug intermediates and synthesis methods, isoquinoline derivatives and synthesis methods thereof.
- alfuzosin, terazosin and isoquinoline derivatives not only have the effect of treating or preventing Parkinson's disease, but also have the effect of preventing or treating Alzheimer's disease.
- the chemical structural formulas of the isoquinoline derivatives of the present invention are very similar to those of alfuzosin. The difference lies in that the main ring of the isoquinoline derivative is isoquinoline, while the main ring of alfuzosin is quinazoline.
- Route 1 is the first disclosed process route since the disclosure of alfuzosin, and it is currently a more conventional process route for the large-scale production of alfuzosin.
- the inventor of the present invention conducted the following experiments.
- the compound represented by formula I was prepared into compound a, and then when compound a was reacted with N-methyl-N'-tetrahydrofuranformylpropanediamine, the target product could not be obtained.
- the main reason is that the reaction temperature of compound a with N-methyl-N'-tetrahydrofuranoylpropanediamine is too high, causing the amino group at position 1 to be consumed, so the isoquinolines of the present invention cannot be obtained. derivative.
- the object of the present invention is to provide a pharmaceutical intermediate and a synthesis method, and a synthesis method of isoquinoline derivatives.
- the synthesis operation of the pharmaceutical intermediate of the present invention is simple, the conditions are mild, and the yield is high, and the pharmaceutical intermediate can be used to Isoquinoline derivatives were prepared.
- a drug intermediate has a chemical structure as shown in formula II:
- a method for synthesizing the above-mentioned pharmaceutical intermediate includes the steps of using a compound represented by formula I and an amino protecting agent (R-NH 2 ) according to the following reaction formula to obtain a compound represented by formula II;
- X and R are as described above, and X' is halogen, such as fluorine, chlorine, bromine, iodine, etc.
- the research of the present invention shows that when the compound represented by formula I reacts directly with ammonia, the reaction temperature requires 180°C and requires microwave heating.
- the present invention uses R-NH 2 to carry out the reaction, which can reduce the temperature of the reaction and can be achieved by conventional heating.
- the third aspect is a raw material compound with a chemical structure as shown in formula a:
- X is halogen, such as fluorine, chlorine, bromine, iodine, etc.
- a method for preparing isoquinoline derivatives includes the step of using a compound shown in Formula I as a raw material to obtain a compound shown in Formula IV (isoquinoline derivatives) according to the following reaction formula;
- the technical solution of the present invention can prepare pharmaceutical intermediates (compounds of formula II) under milder conditions.
- the present invention uses a pharmaceutical intermediate in which the 1-position amino group is protected by an amino protecting group for reaction, which can avoid side reactions of the 1-position amine, thereby finally preparing isoquinoline derivatives.
- the research of the present invention shows that the temperature to realize the amine substitution reaction at position 3 needs to be 220°C and above, and the selectivity is low, there are many by-products, and the yield of the target compound (i.e., the compound represented by Formula III) is extremely low (2 %the following).
- the addition of ligands, catalysts and bases for catalysis in the present invention can not only reduce the reaction temperature, but also significantly increase the yield of the compound represented by Formula III.
- the technical solution provided by the present invention involves fewer reactions and simpler operating steps.
- the fifth aspect of the present invention is an isoquinoline derivative
- the isoquinoline derivative is
- the pholine derivative is a compound represented by formula IV obtained by the above-mentioned synthesis method.
- the present invention provides a drug intermediate, which can be used to prepare isoquinazoline derivatives.
- the prepared isoquinazoline derivatives can improve mitochondrial metabolism, degrade various pathological protein accumulations, and improve blood vessels. The role of endothelial cell function in Alzheimer's disease and related complications.
- the method for preparing pharmaceutical intermediates of the present invention can be prepared by conventional heating, and the reaction conditions are not strict.
- the isoquinazoline derivatives prepared using the pharmaceutical intermediates provided by the invention have higher purity and yield.
- Figure 1 is a diagram showing the test results of rats in the Parkinson's disease model in which 6-OHDA was injected into a specific brain area with compound IV in Example 16 of the present invention during adhesion and standing.
- Figure 2 is a graph showing test results during exercise of rats in a Parkinson's disease model using Compound IV to inject 6-OHDA into specific brain areas in Example 16 of the present invention.
- Figure 3 is a diagram showing the test results of the grip strength and nervous system balance ability of mice in the Parkinson's disease model using compound IV to intraperitoneally inject MPTP in Example 17 of the present invention.
- Figure 4 is a graph showing the results of the survival number of dopamine neurons in mice using MPTP intraperitoneally in the Parkinson's disease model using Compound IV in Example 17 of the present invention.
- the present invention proposes a pharmaceutical intermediate and a synthesis method, and a synthesis method of isoquinoline derivatives.
- the substituted benzyl group is a benzyl group substituted by an alkoxy group, a halogen group, an alkyl group, an alkyl group, or the like.
- the substituted benzyl group is a benzyl group substituted by an alkoxy group, a halogen group, an alkyl group, an alkyl group, or the like.
- the substituted trityl group is a trityl group substituted by an alkoxy group, a halogen group, an alkyl group, an alkyl group, or the like.
- the amino protecting group is an alkoxy or alkyl substituted benzyl group, such as p-methoxybenzyl, 2-methylbenzyl, 3,4-dimethoxybenzyl base, 2,4-dimethoxybenzyl, etc.
- the second embodiment of the present invention provides a method for synthesizing the above-mentioned pharmaceutical intermediate, which includes the steps of using a compound represented by formula I and an amino protecting agent according to the following reaction formula to obtain a compound represented by formula II;
- X and R are as described above, and X' is halogen, such as fluorine, chlorine, bromine, iodine, etc.
- the present invention uses R-NH 2 to carry out the reaction, which can reduce the temperature of the reaction and can be achieved by conventional heating.
- amino protecting group affects the yield of drug intermediates.
- the amino protecting group is alkoxy or alkyl substituted benzyl (such as p-methoxybenzyl, 2-methylbenzyl, 3,4 -dimethoxybenzyl, 2,4-dimethoxybenzyl, etc.)
- the yield of drug intermediates is higher.
- the reaction solvent is one or more of N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).
- NMP N-methylpyrrolidone
- DMF N,N-dimethylformamide
- DMSO dimethyl sulfoxide
- the reaction temperature is 100-160°C, preferably 100-130°C.
- the mass/volume ratio of the compound represented by Formula I and the reaction solvent is 1:5-30g/mL, preferably 1:10g/mL.
- the molar ratio of the compound represented by formula I to the amino protecting agent is 1:2-5, preferably 1:2.5-4.
- the purification method of the drug intermediate (compound represented by formula II) is as follows: adding water to the reacted material to quench the reaction, extracting the quenched reacted material, and washing, drying, and evaporating the solvent of the extracted organic phase. , that’s it.
- X is halogen, such as fluorine, chlorine, bromine, iodine, etc.
- the fourth embodiment of the present invention provides a method for synthesizing isoquinoline derivatives, which includes using a compound represented by formula I as a raw material according to the following reaction formula to obtain a compound represented by formula IV (isoquinoline derivatives) step;
- the present invention not only has milder reaction conditions for preparing compounds represented by formula II and formula III, but also has a higher yield of the compound represented by formula III and has fewer operating steps.
- the route for preparing the compound of formula II from the compound represented by formula I may be route one or route two.
- the catalyst in the process of preparing the compound of formula III from the compound of formula II, is a palladium catalyst or a copper catalyst.
- the type of catalyst affects the yield of the compound represented by formula III. Research shows that the yield of the compound represented by formula III is higher when using a palladium catalyst.
- the palladium catalyst is PdCl 2 , Pd(PPh 3 ) 4 (tetrakis (triphenylphosphine) palladium), Pd (OAc) 2 (palladium acetate), Pd 2 (dba) 3 (tris (dibenzylidene acetone) Dipalladium), Pd(dba) 2 (palladium bis-dibenzylideneacetone), PdCl 2 (cod) ((1,5-cyclooctadiene)palladium chloride), [Pd(allyl)Cl] 2 (chlorine Allylpalladium(II) dimer), PdCl 2 ⁇ (CH 3 CN) 2 (bis (acetonitrile) palladium dichloride), Pd(acac) 2 (diacetylacetonate palladium), Pd(PPh 3 ) 2 Cl 2 (bis(triphenylphosphine)palladium(II) chloride), Pd
- the ligand is PPh 3 (triphenylphosphine), P(o-tolyl) 3 (tris(o-methyl) phenyl)phosphine), P(t-Bu) 3 (tri-tert-butylphosphine), P(t-Bu) 3 ⁇ HBF 4 (tri-tert-butylphosphine tetrafluoroborate), PCy 3 (tricyclohexyl Phosphine), n-BuP(Ad) 2 , BINAP (binaphthyl diphenylphosphine), Xantphos (4,5-bis(diphenylphosphine)-9,9-dimethylxanthene), DPEPhos (bis( 2-Diphenylphosphine)phenyl ether), Dppf (1,1'-bis(diphenylphosphine)ferrocene), Cy
- the base in the process of preparing the compound of formula III from the compound represented by formula II, is sodium tert-butoxide, cesium carbonate, potassium tert-butoxide, potassium carbonate, potassium phosphate, bistrimethyl Lithium silylamide, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or MTBD (7-methyl-1,5,7-triazabicyclo [4.4.0]dec-5-ene).
- the yield can reach 22%; using Pd(OAc) 2 +BINAP+Cs 2 CO 3 , the yield of the compound shown in formula III can reach 36%; using Pd(OAc) 2 +BINAP+t-BuONa, shown in formula III The yield of the compound can reach 37%; for Pd 2 (dba) 3 +RuPhos+t-BuONa, the yield of the compound represented by formula III can reach 53%.
- the yield is lower.
- the reaction temperature is 90-130°C, preferably 95-110°C.
- the solvent in the process of preparing the compound of formula III from the compound of formula II, is an organic solvent with a boiling point higher than 90°C.
- organic solvents with low boiling point (below 90°C) solvents such as tetrahydrofuran
- the reaction needs to be sealed and microwave heating is used.
- the research of the present invention has found that the above-mentioned catalyst, ligand and alkali are combined, and an organic solvent with a high boiling point (higher than 90°C) (such as toluene, 1,4-dioxane, N,N-dimethylformamide) is used.
- (DMF) and dimethyl sulfoxide (DMSO), etc.) the reaction can be carried out by simply heating.
- the mass/volume ratio of the compound represented by Formula II and the reaction solvent is 1:5 ⁇ 100g/mL, preferably 1:10 ⁇ 20g/mL.
- the molar ratio of the compound of formula II to N-methyl-N'-tetrahydrofuranformylpropanediamine is 1:1 ⁇ 5, preferably 1:1.5 ⁇ 3.
- the molar ratio of the compound of formula II to the catalyst is 1:0.01-0.5, preferably 1:0.05-0.2.
- the molar ratio of the compound of formula II to the ligand is 1:0.02-1.0, preferably 1:0.05-0.4.
- the molar ratio of the compound of formula II to the base is 1:1-4, preferably 1:1.2-2.
- the reaction temperature is 0-70°C, preferably 0-40°C.
- the reaction solvent is trifluoroacetic acid, triethylsilyl hydrogen, methanesulfonic acid, trifluoromethanesulfonic acid, or trifluoroacetic acid.
- the mass/volume ratio of the compound of formula III to the reaction solvent is 1:5 ⁇ 100g/mL, preferably 1:5 ⁇ 20g/mL.
- the fourth embodiment of the present invention provides an isoquinoline derivative, which is a compound represented by formula IV obtained by the above-mentioned synthesis method of isoquinoline derivatives.
- p-methoxybenzylamine can be replaced by 2-methylbenzylamine, 2,4-dimethoxybenzylamine, or 3,4-dimethoxybenzylamine.
- p-methoxybenzylamine can be replaced by 2-methylbenzylamine, 2,4-dimethoxybenzylamine, or 3,4-dimethoxybenzylamine.
- the salts that can be formed by the compound represented by formula IV are compounds represented by formula V, including hydrochloride, sulfate, phosphate, p-toluenesulfonate, methanesulfonate, hydrobromide, ethanesulfonate, ethanesulfonate, etc. salts, maleates, fumarates and succinates.
- Example 16 Effect of the compound represented by formula IV in the rat 6-OHDA Parkinson's disease model
- the motor function of rats was also evaluated using a fatigue rotarod instrument. After treatment with 6-OHDA, the time the rats maintained on the fatigue rotarod instrument was significantly reduced. After treatment with the compound of formula IV, this ability was significantly improved, as shown in As shown in Figure 2.
- Example 17 Effect of the compound represented by Formula IV in the Parkinson's disease model of mouse MPTP
- the substantia nigra compacta (SNpc) was stained with dopamine antibodies, and the results are shown in Figure 4. Compared with normal mice, the number of dopamine neurons after MPTP treatment was significantly reduced; while the number of dopamine neurons in mice treated with the compound of formula IV orally (MPTP-treated mice + compound of formula IV) was significantly increased, indicating that the number of dopamine neurons after administration of formula IV was significantly increased. There is a significant difference in the survival rate of dopamine neurons in MPTP-treated mice with the compound shown in IV (compound of formula IV) compared with MPTP-treated mice that were not given the compound shown in formula IV (p ⁇ 0.01).
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Abstract
本发明属于药物合成技术领域,涉及预防或治疗阿尔茨海默病、帕金森等相关疾病药物的合成,具体涉及一种药物中间体及合成方法、异喹啉类衍生物的合成方法。药物中间体,化学结构如式(II)所示:其中,X为卤素,R为氨基保护基。本发明药物中间体的合成操作简单、条件温和、收率较高,而且采用该药物中间体能够制备出异喹啉类衍生物。
Description
本发明要求于2022年3月21提交中国专利局、申请号为202210278645.6、发明名称为“药物中间体及合成方法、异喹啉类衍生物及其合成方法”的中国专利申请的优先权,其全部内容通过引用结合在本发明中。
本发明属于药物合成技术领域,涉及预防或治疗阿尔茨海默病、帕金森等相关疾病药物的合成,具体涉及药物中间体及合成方法、异喹啉类衍生物及其合成方法。
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
有研究表明,阿夫唑嗪、特拉唑嗪以及异喹啉类衍生物不仅具有治疗或预防帕金森病的作用,而且具有预防或治疗阿尔海默病的作用。
然而,经过发明人对目前公开的技术文献的研究,目前尚未有所述异喹啉类衍生物的化学合成方法的记载。
发明内容
本发明所述异喹啉类衍生物与阿夫唑嗪化学结构式极为类似,区别在于所述异喹啉类衍生物的主环为异喹啉,阿夫唑嗪的主环为喹唑啉。
经过发明人研究了解,目前制备阿夫唑嗪的路线主要分为3种分别如下:
路线1:
路线2:
路线3:
其中,路线1是从阿夫唑嗪公开以来最先公开的工艺路线,而且是目前阿夫唑嗪大规模生产的更为常规的工艺路线。
然而,采用上述阿夫唑嗪的路线1合成本发明所述异喹啉类衍生物时,存在的问题是需要如下结构式的原料:
但是,上述化学结构的化合物并不是现有化合物。
因而本发明只能通过以下化学结构的进行合成。
当采用上述原料合成异喹啉类衍生物时,需要分别在异喹啉的1、3位上由胺来取代异喹啉上的卤素原子(如氟、氯、溴、碘等),但是与喹唑啉环结构相比,异喹啉环结构的5位为碳,导致其电子云分布与喹唑啉的电子云分布完全不同,而异喹啉环的电子云分布不利于1、3位的胺取代,尤其是6、7位连接甲氧基,更加不利于1、3位的胺取代。
同时本发明的发明人进行以下实验,先将式I所示化合物制成化合物a,然后利用化合物a与N-甲基-N'-四氢呋喃甲酰基丙二胺进行反应时,无法获得目标产物。其主要原因是,化合物a 与N-甲基-N'-四氢呋喃甲酰基丙二胺反应的温度过高,导致1位上的氨基被消耗掉,因而不能获得本发明所述的异喹啉类衍生物。
综上,本领域根据现有技术无法获得本发明所述异喹啉类衍生物的合成方法。
本发明的目的是提供一种药物中间体及合成方法、异喹啉类衍生物的合成方法,本发明药物中间体的合成操作简单、条件温和、收率较高,而且采用该药物中间体能够制备出异喹啉类衍生物。
为了实现上述目的,本发明的技术方案为:
一方面,一种药物中间体,化学结构如式II所示:
其中,X为卤素,例如氟、氯、溴、碘等;R为氨基保护基,例如苄基、取代苄基、二苯甲基、取代二苯甲基、三苯甲基、取代三苯甲基、叔丁氧基羰基等。
另一方面,一种上述药物中间体的合成方法,包括以式I所示化合物与氨基保护剂(R-NH
2)按照如下反应式获得式II所示化合物的步骤;
其中,X、R的选择如上所述,X'为卤素,例如氟、氯、溴、碘等。
由于本发明中异喹啉的电子云分布以及6、7位的甲氧基不利于1、3位的胺取代,本发明研究表明,当式I所示化合物与氨直接反应时,反应温度需要180℃,而且需要进行微波加热。为了解决该问题,本发明利用R-NH
2进行反应,能够降低反应所述的温度,常规加热即可实现。
由于化合物a不是现有化合物,而式II所示化合物可以由化合物a通过氨基保护的反应获得,因而第三方面,一种原料化合物,化学结构如式a所示:
其中,X为卤素,例如氟、氯、溴、碘等。
第四方面,一种异喹啉类衍生物的制备方法,包括以式I所示化合物作为原料按照如下反应式获得式IV所示化合物(异喹啉类衍生物)的步骤;
其中,X、X'、R的选择如上所述;式II所示化合物制备式III所示化合物的过程中添加配体、催化剂和碱进行催化。
首先,本发明的该技术方案能够以更为温和的条件制备药物中间体(式II所示化合物)。
其次,由于3位胺取代反应的活性比1位更低,因而所需反应条件比1位胺取代反应的条件更高,当异喹啉的1位为伯氨基时,在进行3位胺取代反应,会导致1位为伯氨基产生副反应,从而导致无法制备异喹啉类衍生物。因而本发明利用1位氨基被氨基保护基保护的药物中间体进行反应,能够避免1位胺发生副反应,从而最终制备成异喹啉类衍生物。同时,本发明研究表明,实现3位的胺取代反应的温度需要220℃及以上,而且选择性较低,副产物极多,目标化合物(即式III所示化合物)的收率极低(2%以下)。本发明添加配体、催化剂和碱进行催化不仅能够降低反应温度,而且能够显著提高式III所示化合物的收率。
第三,本发明提供的该技术方案涉及的反应更少,操作步骤更简单。
通过本发明上述技术方案的说明,本领域技术人员根据现有技术的记载无法获得该异喹啉类衍生物,因而本发明的第五方面,一种异喹啉类衍生物,所述异喹啉类衍生物是由上述合成方法获得的式IV所示化合物。
本发明的有益效果为:
1.本发明提供了一种药物中间体,利用该药物中间体能够制备获得异喹唑啉衍生物,制备的异喹唑啉衍生物具有改善线粒体代谢、降解多种病理性蛋白堆积、改善血管内皮细胞功能的作用,可用于阿尔茨海默症和相关并发症。
2.本发明制备药物中间体的方法,采用常规加热即可制备,反应条件要求不苛刻。
3.利用本发明提供的药物中间体制备的异喹唑啉衍生物具有较高的纯度和收率。
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为本发明实施例16采用化合物IV在特定脑区注射6-OHDA的帕金森症模型的大鼠的贴壁站立过程中的测试结果图。
图2为本发明实施例16采用化合物IV在特定脑区注射6-OHDA的帕金森症模型的大鼠的运动过程中的测试结果图。
图3为本发明实施例17采用化合物IV在腹腔注射MPTP的帕金森症模型的小鼠的抓力和神经系统平衡能力的测试结果图。
图4为本发明实施例17采用化合物IV在在腹腔注射MPTP的帕金森症模型的小鼠的多巴胺神经元存活数量结果图。
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本发明的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
为了实现异喹啉类衍生物的合成,本发明提出了一种药物中间体及合成方法、异喹啉类衍生物的合成方法。
本发明的一种典型实施方式,提供了一种药物中间体,化学结构如式II所示:
其中,X为卤素,例如氟、氯、溴、碘等;R为氨基保护基,例如苄基、取代苄基、二苯甲基、取代二苯甲基、三苯甲基、取代三苯甲基、叔丁氧基羰基等。所述取代苄基是烷氧基、卤素、烷基、烷基等取代的苄基。所述取代二苯甲基是烷氧基、卤素、烷基、烷基等取代的二苯甲基。所述取代三苯甲基是烷氧基、卤素、烷基、烷基等取代的三苯甲基。
该实施方式的一些实施例中,所述氨基保护基为烷氧基或烷基取代的苄基,例如对甲氧基苄基、2-甲基苄基、3,4-二甲氧基苄基、2,4-二甲氧基苄基等。
本发明的第二种实施方式,提供了一种上述药物中间体的合成方法,包括以式I所示化合物与氨基保护剂按照如下反应式获得式II所示化合物的步骤;
其中,X、R的选择如上所述,X'为卤素,例如氟、氯、溴、碘等。
本发明利用R-NH
2进行反应,能够降低反应所述的温度,常规加热即可实现。
研究表明,氨基保护基的种类影响药物中间体的收率,当氨基保护基为烷氧基或烷基取代的苄基(例如对甲氧基苄基、2-甲基苄基、3,4-二甲氧基苄基、2,4-二甲氧基苄基等)时,药物中间体的得率更高。
该实施方式的一些实施例中,反应溶剂为N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)和二甲基亚砜(DMSO)中的一种或几种。
该实施方式的一些实施例中,反应温度为100~160℃,优选100~130℃。
该实施方式的一些实施例中,式I所示化合物和反应溶剂质量/体积比为1:5~30g/mL,优选为1:10g/mL。
该实施方式的一些实施例中,式I所示化合物与氨基保护剂的摩尔比为1:2~5,优选为1:2.5~4。
药物中间体(式II所示化合物)的纯化方法为:向反应后的物料中加入水淬灭反应,将淬灭反应后的物料进行萃取,将萃取后的有机相进行洗涤、干燥、蒸发溶剂,即得。
本发明的第三种实施方式,提供了一种原料化合物,化学结构如式a所示:
其中,X为卤素,例如氟、氯、溴、碘等。
本发明第四种实施方式,提供了一种异喹啉类衍生物的合成方法,包括以式I所示化合物作为原料按照如下反应式获得式IV所示化合物(异喹啉类衍生物)的步骤;
其中,式II所示化合物制备式III所示化合物的过程中添加配体、催化剂和碱进行催化。
本发明不仅制备式II、式III所示化合物反应条件更温和,获得的式III所示化合物的收率更高,而且操作步骤更少。
式I所示化合物制备式II所示化合物的路线可以为路线一,也可以为路线二。
路线一:
路线二:
当采用路线一时,式I所示化合物制备式II所示化合物的过程可以参考上述第二种实施方式。
该实施方式的一些实施例中,式II所示化合物制备式III所示化合物的过程中,所述催化剂为钯催化剂或铜催化剂。催化剂的种类影响式III所示化合物的收率,研究表明,采用钯催化剂的收率更高。所述钯催化剂为PdCl
2、Pd(PPh
3)
4(四(三苯基膦)钯)、Pd(OAc)
2(醋酸钯)、Pd
2(dba)
3(三(二亚苄基丙酮)二钯)、Pd(dba)
2(双二亚苄基丙酮钯)、PdCl
2(cod)((1,5-环辛二烯)氯化钯)、[Pd(allyl)Cl]
2(氯化烯丙基钯(II)二聚物)、PdCl
2·(CH
3CN)
2(双(乙腈)二氯化钯)、Pd(acac)
2(双乙酰丙酮钯)、Pd(PPh
3)
2Cl
2(双(三苯基膦)氯化钯(II))、Pd(Dppf)
2Cl
2(1,1'-双二苯基膦二茂铁二氯化钯)、PdCl
2[P(o-Tol)
3](反-二氯双(三-O-甲苯膦)钯)中的一种或几种混合。
该实施方式的一些实施例中,式II所示化合物制备式III所示化合物的过程中,所述配体为PPh
3(三苯基膦)、P(o-tolyl)
3(三(邻甲基苯基)磷)、P(t-Bu)
3(三叔丁基膦基)、P(t-Bu)
3·HBF
4(四氟硼酸三叔丁基膦)、PCy
3(三环己基膦)、n-BuP(Ad)
2、BINAP(联萘二苯膦)、Xantphos(4,5-双(二苯基膦)-9,9-二甲基氧杂蒽)、DPEPhos(双(2-二苯基膦)苯醚)、Dppf(1,1'-双(二苯基膦)二茂铁)、CyPFt-Bu、Dppp(1,3-双(二苯基膦)丙烷)、JohnPhos(2-(二叔丁基膦)联苯)、CyJohnPhos(2-(二环己基膦基)联苯)、DavePhos(2-双环己基膦-2'-(N,N-二甲基氨基)联苯)、RuPhos(2-双环已基膦-2',6'-二异丙氧基联苯)、SPhos(2-双环己基膦-2',6'-二甲氧基联苯)、Xphos(2-双环己基膦-2',4',6'-三异丙基联苯)、BrettPhos(2-(二环己基膦)3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)、t-BuXphos(2-二-叔丁膦基-2',4',6'-三异丙基联苯)、t-BuBrettPhos(2-(二叔丁基膦)-3,6-二甲氧基-2'-4'-6'三-1-丙基-1,1'-双苯基)、Me
4t-BuXphos(2-二叔丁基磷-3,4,5,6-四甲基-2',4',6'-三异丙基联苯)、Bippyphos(5-二叔丁基膦-1',3',5'-三苯基-1'H-[1,4']二吡唑)、MorDalPhos、IPr·HCl(1,3-双(2,6-二异丙基苯基)氯化咪唑翁)中一种或多种。
该实施方式的一些实施例中,式II所示化合物制备式III所示化合物的过程中,所述碱为叔丁醇钠、碳酸铯、叔丁醇钾、碳酸钾、磷酸钾、双三甲基硅基胺基锂、DBU(1,8-二氮杂二环[5.4.0]十一碳-7-烯)或MTBD(7-甲基-1,5,7-三氮杂二环[4.4.0]癸-5-烯)。
研究表明,采用上述催化剂、配体和碱需要进行配合使用能够更好地的达到预期效果。例 如采用Pd
2(dba)
3+Davephos+Cs
2CO
3,式III所示化合物的收率可达10%;采用Pd(OAc)
2+DPPF+Cs
2CO
3,式III所示化合物的收率可达22%;采用Pd(OAc)
2+BINAP+Cs
2CO
3,式III所示化合物的收率可达36%;采用Pd(OAc)
2+BINAP+t-BuONa,式III所示化合物的收率可达37%;Pd
2(dba)
3+RuPhos+t-BuONa,式III所示化合物的收率可达53%。而采用Brettphos-Pd-G
3/Cs
2CO
3,则收率较低。
该实施方式的一些实施例中,式II所示化合物制备式III所示化合物的过程中,反应温度的为90~130℃,优选95~110℃。
该实施方式的一些实施例中,式II所示化合物制备式III所示化合物的过程中,溶剂为沸点高于90℃的有机溶剂。研究表明,当采用低沸点(低于90℃)溶剂的有机溶剂(例如四氢呋喃)时,需要将反应密封,同时采用微波加热。本发明研究发现采用上述催化剂、配体和碱配合后采用,采用高沸点(高于90℃)的有机溶剂(例如甲苯、1,4-二氧六环、N,N-二甲基甲酰胺(DMF)和二甲基亚砜(DMSO)等),可以通过简单加热的方式即可实现反应的进行。
该实施方式的一些实施例中,式II所示化合物制备式III所示化合物的过程中,式II所示化合物和反应溶剂质量/体积比为1:5~100g/mL,优先选1:10~20g/mL。
该实施方式的一些实施例中,式II所示化合物制备式III所示化合物的过程中,式II所示化合物与N-甲基-N'-四氢呋喃甲酰基丙二胺摩尔比为1:1~5,优选1:1.5~3。
该实施方式的一些实施例中,式II所示化合物制备式III所示化合物的过程中,式II所示化合物与催化剂的摩尔比为1:0.01~0.5,优选1:0.05~0.2。
该实施方式的一些实施例中,式II所示化合物制备式III所示化合物的过程中,式II所示化合物与配体的摩尔比1:0.02~1.0,优选1:0.05~0.4。
该实施方式的一些实施例中,式II所示化合物制备式III所示化合物的过程中,式II所示化合物与碱的摩尔比1:1~4,优选1:1.2~2。
该实施方式的一些实施例中,式III所示化合物制备式IV所示化合物的过程中,反应温度为0~70℃,优选0~40℃。
该实施方式的一些实施例中,式III所示化合物制备式IV所示化合物的过程中,反应溶剂为三氟乙酸、三乙基硅氢、甲磺酸、三氟甲磺酸、三氟乙酸/二氯甲烷的混合溶剂、甲磺酸/二氯甲烷的混合溶剂、三乙基硅氢/三氟乙酸混合溶剂等。
该实施方式的一些实施例中,式III所示化合物制备式IV所示化合物的过程中,式III所示化合物与反应溶剂的质量/体积比为1:5~100g/mL,优选1:5~20g/mL。
本发明优选的步骤如下:
(1)将1,3-二氯-6,7-二甲氧基异喹啉(式I所示化合物)作为起始物料,加入反应溶剂搅拌 溶解,然后加入氨基保护剂,升温至90~160℃,反应完全后获得式II所示化合物;
(2)将式II所示化合物与和N-甲基-N'-四氢呋喃甲酰基丙二胺或其盐进行Buchwald-Hartwig偶联反应,得到式III所示化合物;
(3)将式III所示化合物加入至反应溶剂,控制温度为0~70℃进行脱氨基保护即得。
本发明的第四种实施方式,提供了一种异喹啉类衍生物,所述异喹啉类衍生物是由上述异喹啉类衍生物的合成方法获得的式IV所示化合物。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例详细说明本发明的技术方案。
实施例1:式II所示化合物的合成(本实施例中R=对甲氧基苄基)
向反应瓶中加入式I所示化合物(10g)和N-甲基吡咯烷酮(100mL),搅拌溶解,加入对甲氧基苄胺(15.9g),升温至120℃,反应4小时,点TLC板监控反应(石油醚/乙酸乙酯=2/1),反应完全,后处理加入水(300mL)淬灭反应,用二氯甲烷萃取3次(200mL×3),合并有机相,用饱和食盐水(300mL)洗涤一次,加入无水硫酸钠干燥,旋蒸溶剂后用柱层析(SiO
2)分离,得到12.8g产物,即式II所示化合物,收率92.1%。
得到式II所示化合物
1H NMR解析结果如下:
1H NMR:(400MHz,DMSO-d
6)δ8.08-7.88(m,1H),7.64(s,1H),7.32(d,J=8.8Hz,2H),7.14(s,1H),6.93-6.80(m,3H),4.62(d,J=6.0Hz,2H),3.87(d,J=3.6Hz,6H),3.79-3.61(m,3H)。
LC-MS(C
19H
19ClN
2O
3):359.1[M+H]
+。
实施例2:式II所示化合物的合成(本实施例中R=2-甲基苄基)
向反应瓶中加入式I所示化合物(1g)和N,N-二甲基甲酰胺(DMF),搅拌溶解,加入2-甲基苄胺(1.88g),升温至120℃,反应4小时,点TLC板监控反应(石油醚/乙酸乙酯=3/1),反应完全,后处理加入水(30mL)淬灭反应,用二氯甲烷萃取3次(20mL×3),合并有机相,用饱和食盐水(30mL)洗涤一次,加入无水硫酸钠干燥,旋蒸溶剂后用柱层析(SiO
2)分离,得到1.01g产物,即式II所示化合物,收率76.0%。
LC-MS(C
19H
19ClN
2O
2):343.0[M+H]
+。
实施例3:式II所示化合物的合成(本实施例中R=3,4-二甲氧基苄基)
向反应瓶中加入式I所示化合物(1g)和N-甲基吡咯烷酮(10mL),搅拌溶解,加入3,4-二甲氧基苄胺(2.58g),升温至120℃,反应4小时,点TLC板监控反应(石油醚/乙酸乙酯=2/1),反应完全,后处理加入水(50mL)淬灭反应,用二氯甲烷萃取3次(30mL×3),合并有机相,用饱和食盐水(30mL)洗涤一次,加入无水硫酸钠干燥,旋蒸溶剂后用柱层析(SiO
2)分离,得到1.29g产物,即式II所示化合物,收率85.5%。
LC-MS(C
20H
21ClN
2O
4):389.1[M+H]
+。
实施例4:式II所示化合物的合成(本实施例中R=2,4-二甲氧基苄基)
向反应瓶中加入式I所示化合物(1g)和N-甲基吡咯烷酮(10mL),搅拌溶解,加入2,4-二甲氧基苄胺(2.58g),升温至120℃,反应4小时,点TLC板监控反应(石油醚/乙酸乙酯=2/1),反应完全,后处理加入水(50mL)淬灭反应,用二氯甲烷萃取3次(30mL×3),合并有机相,用饱和食盐水(30mL)洗涤一次,加入无水硫酸钠干燥,旋蒸溶剂后用柱层析(SiO
2)分离,得到1.35g产物,即式II所示化合物,收率89.6%。
LC-MS(C
20H
21ClN
2O
4):389.1[M+H]
+。
实施例5:式II所示化合物的合成(本实施例中R=对甲氧基苄基)
向反应瓶中加入式I所示化合物(1g)和N-甲基吡咯烷酮(10mL),搅拌溶解,加入对甲氧基苄胺(1.58g),升温至120℃,反应4小时,点TLC板监控反应(石油醚/乙酸乙酯=2/1),反应完全,后处理加入水(300mL)淬灭反应,用二氯甲烷萃取3次(200mL×3),合并有机 相,用饱和食盐水(300mL)洗涤一次,加入无水硫酸钠干燥,旋蒸溶剂后用柱层析(SiO
2)分离,得到0.98g产物,即式II所示化合物,收率84.3%。
在本实施例中,对甲氧基苄胺可以用2-甲基苄胺、2,4-二甲氧基苄胺、3,4-二甲氧基苄胺来代替。
实施例6:式Ш所示化合物的合成(本实施例中R=对甲氧基苯基)
在反应瓶中加入甲苯(30mL)、式II所示化合物(2.00g)、N-甲基-N'-四氢呋喃甲酰基丙二胺(2.08g)、叔丁醇钠(1.07g)、Pd
2(dba)
3(1.02g)、RuPhos(1.04g),体系在N
2保护下加热至100℃反应3小时,反应结束后,后处理直接过滤,滤液用真空旋蒸,旋蒸溶剂后用柱层析(SiO
2)分离,用石油醚和乙酸乙酯的混合溶液洗脱,浓缩洗脱剂后得到3.00g产物,即式Ш所示化合物,收率52.9%。
当R=甲氧基苄胺时的
1H NMR解析如下:
1H NMR:(400MHz,CDCl
3)δ7.92-7.78(m,1H),7.41-7.34(m,1H),7.03(d,J=8.8Hz,2H),6.94-6.77(m,3H),4.46-4.25(m,1H),4.18-4.07(m,2H),4.04-4.00(m,1H),4.06-4.00(m,1H),3.98(s,2H),3.93-3.89(m,4H),3.83(s,2H),3.76-3.66(m,2H),3.41-3.22(m,3H),3.02-2.87(m,3H),2.00-1.97(m,1H),1.99-1.73(m,10H)。
LC-MS(C
28H
36N
4O
5):509.1[M+H]
+,531.1[M+Na]
+。
实施例7:式Ш所示化合物的合成(本实施例中R=2-甲基苄基)
在反应瓶中加入甲苯(2.5mL)、式II所示化合物(0.5g)、N-甲基-N'-四氢呋喃甲酰基丙二胺(0.68g)、叔丁醇钠(0.54g)、Pd
2(dba)
3(0.08g)、RuPhos(0.06g),体系在N
2保护下加热至100℃反应3小时,反应结束后,后处理直接过滤,滤液用真空旋蒸,旋蒸溶剂后用柱层析(SiO
2)分离,用石油醚和乙酸乙酯的混合溶液洗脱,浓缩洗脱剂后得到0.26g产物,即式Ш所示化合物,收率36.2%。
LC-MS(C
28H
36N
4O
4):493.3[M+H]
+。
实施例8:式Ш所示化合物的合成(本实施例中R=2,4-二甲氧基苄基)
在反应瓶中加入1,4-二氧六环(10mL)、式II所示化合物(1.1g)、N-甲基-N'-四氢呋喃甲酰基丙二胺(0.72g)、碳酸铯(1.85g)、Pd(OAc)
2(0.07g)、RuPhos(0.26g),体系在N
2保护下加热至100℃反应3小时,反应结束后,后处理直接过滤,滤液用真空旋蒸,旋蒸溶剂后用柱层析(SiO
2)分离,用石油醚和乙酸乙酯的混合溶液洗脱,浓缩洗脱剂后得到1.02g产物,即式Ш所示化合物,收率67.0%。
LC-MS(C
29H
38N
4O
6):539.3[M+H]
+。
实施例9:式Ш所示化合物的合成(本实施例中R=3,4-二甲氧基苄基)
在反应瓶中加入1,4-二氧六环(20mL)、式II所示化合物(1.0g)、N-甲基-N'-四氢呋喃甲酰基丙二胺(0.68g)、碳酸铯(1.77g)、Pd(OAc)
2(0.06g)、SPhos(0.21g),体系在N
2保护下加热至100℃反应3小时,反应结束后,后处理直接过滤,滤液用真空旋蒸,旋蒸溶剂后用柱层析(SiO
2)分离,用石油醚和乙酸乙酯的混合溶液洗脱,浓缩洗脱剂后得到0.91g产物,即式Ш所示化合物,收率65.7%。
LC-MS(C
29H
38N
4O
6):539.3[M+H]
+。
实施例10:式Ш所示化合物的合成(本实施例中R=对甲氧基苯基)
在反应瓶中加入甲苯(5mL)、式II所示化合物(0.56g)、N-甲基-N'-四氢呋喃甲酰基丙二胺(0.52g)、叔丁醇钠(0.27g)、Pd
2(dba)
3(0.26g)、RuPhos(0.26g),体系在N
2保护下加热至100℃反应3小时,反应结束后,后处理直接过滤,滤液用真空旋蒸,旋蒸溶剂后用柱层析(SiO
2)分离,用石油醚和乙酸乙酯的混合溶液洗脱,浓缩洗脱剂后得到0.42g产物,即式Ш所示化合物,收率59.4%。
在本实施例中,对甲氧基苄胺可以用2-甲基苄胺、2,4-二甲氧基苄胺、3,4-二甲氧基苄胺来代替。
实施例11:式IV所示化合物的合成(本实施例中R=对甲氧基苄基)
体系在N
2保护下,在反应瓶中加入二氯甲烷(20mL)和式III所示化合物(2g),控温20℃以下加入三氟乙酸(4mL),在20℃以下反应2小时,反应完全,向反应体系中加入饱和NaHCO
3溶液将pH调整为7-8,用二氯甲烷萃取3次,合并有机相,用真空旋蒸,旋蒸溶剂后加入用柱层析(SiO
2)分离,洗脱剂二氯甲烷:甲醇=50:1~5:1,得到1.03g产物,即式IV所示化合物,收率67.4%。
1H NMR:(400MHz,CDCl
3)δ8.48(br s,1H),6.85(s,1H),6.79(s,1H),5.98(s,1H),5.38(s,2H),4.49(dd,J=5.6,8.4Hz,1H),4.16-4.04(m,1H),4.01-3.93(m,6H),3.92-3.86(m,1H),3.58-3.50(m,1H),3.45-3.32(m,1H),3.04(tdd,J=4.4,9.2,13.6Hz,1H),2.92(s,3H),2.34-2.18(m,2H),1.98-1.86(m,2H),1.78(tdd,J=4.8,9.6,14.4Hz,1H)
LC-MS(C
20H
28N
4O
4):389.1[M+H]
+。
实施例12:式IV所示化合物的合成(本实施例中R=2-甲基苄基)
体系在N
2保护下,在反应瓶中加入乙醇(2mL)和式III所示化合物(0.2g),加入Pd/C(0.05g),Pd(OH)
2(0.05g),用氮气置换3次,用氧气置换3次,升温至50℃反应至少16小时,反应完全,降温至20-30℃,直接过滤(垫硅藻土),用真空旋蒸,旋蒸溶剂后加入用柱层析(SiO
2)分离,洗脱剂二氯甲烷:甲醇=50:1~5:1,得到0.09g产物,即式IV所示化合物,收率56.2%。
实施例13:式IV所示化合物的合成(本实施例中R=2,4-二甲氧基苄基)
体系在N
2保护下,在反应瓶中加入二氯甲烷(5mL)和式III所示化合物(1.0g),控温20℃以下加入三氟乙酸(1.0mL),加入三氟甲磺酸(2.0mL),在20℃以下反应2小时,反应完全,向反应体系中加入饱和NaHCO
3溶液将pH调整为7-8,用二氯甲烷萃取3次,合并有 机相,用真空旋蒸,旋蒸溶剂后加入用柱层析(SiO
2)分离,洗脱剂二氯甲烷:甲醇=50:1~5:1,得到0.47g产物,即式IV所示化合物,收率65.1%。
实施例14:式IV所示化合物的合成(本实施例中R=3,4-二甲氧基苄基)
体系在N
2保护下,在反应瓶中加入二氯甲烷(5mL)和式III所示化合物(0.5g),控温20℃以下加入三氟乙酸(1.0mL),加入三氟甲磺酸(0.5mL),在20℃以下反应2小时,反应完全,向反应体系中加入饱和NaHCO
3溶液将pH调整为7-8,用二氯甲烷萃取3次,合并有机相,用真空旋蒸,旋蒸溶剂后加入用柱层析(SiO
2)分离,洗脱剂二氯甲烷:甲醇=50:1~5:1,得到0.21g产物,即式IV所示化合物,收率58.2%。
实施例15:式IV所示化合物的盐的形式
式IV所示化合物可以形成的盐为式V所示化合物,包括盐酸盐、硫酸盐、磷酸盐、对甲苯磺酸盐、甲磺酸盐、氢溴酸盐、乙烷磺酸盐、乙酸盐、马来酸盐、富马酸盐和琥珀酸盐。
实施例16:式IV所示化合物在大鼠6-OHDA帕金森症模型中的效果
大鼠特定脑区注射6-OHDA的帕金森症模型,右侧纹状体脑区注射6-OHDA 2-3周后,给药治疗两周。使用圆筒实验,研究动物在贴壁站立过程中肢体不对称使用的情况,如图1所示。大鼠6-OHDA处理后,大鼠使用患侧前肢的比例降低,体现为前肢不对称指数=(使用健侧-使用患侧)/(使用健侧+使用患侧+使用双侧)×100%增加,式IV所示化合物(式IV化合物)处理后,前肢不对称指数显著降低。
还使用疲劳转棒仪对大鼠的运动功能进行评价,6-OHDA处理后,大鼠在疲劳转棒仪上维持的时间显著降低,给式IV所示化合物处理后,该能力显著改善,如图2所示。
实施例17:式IV所示化合物在小鼠MPTP的帕金森症模型中的效果
小鼠腹腔注射MPTP的帕金森症模型,腹腔注射20mg/Kg的MPTP七天后,使用转轮实验(Rotarod test)进行研究。这个实验可定量测量小鼠抓力和神经系统平衡能力。MPTP处理后,小鼠的该项能力显著降低,但式IV所示化合物处理后,如图3所示,该能力显著改善。每组检测了10只小鼠。
在黑质致密带(SNpc)用多巴胺抗体染色,结果见图4。与正常小鼠比较,MPTP处理后的 多巴胺神经元数量明显减少;而经口给予式IV所示化合物处理的小鼠(MPTP处理小鼠+式IV化合物)多巴胺神经元数量明显增多,说明给予式IV所示化合物(式IV化合物)的MPTP处理小鼠比未给予式IV所示化合物的MPTP处理小鼠在多巴胺神经元存活率方面存在显著差异(p<0.01)。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
- 如权利要求1所述的药物中间体,其特征是,所述氨基保护基为苄基、取代苄基、二苯甲基、取代二苯甲基、三苯甲基、取代三苯甲基、叔丁氧基羰基;优选为苄基或取代苄基;进一步优选为烷氧基取代的苄基或烷基取代的苄基。
- 如权利要求3所述的药物中间体的合成方法,其特征是,所述氨基保护基为苄基、取代苄基、二苯甲基、取代二苯甲基、三苯甲基、取代三苯甲基、叔丁氧基羰基;优选为苄基或取代苄基;进一步优选为烷氧基取代的苄基或烷基取代的苄基;或,反应溶剂为N-甲基吡咯烷酮、N,N-二甲基甲酰胺和二甲基亚砜中的一种或几种。
- 如权利要求3所述的药物中间体的合成方法,其特征是,反应温度为100~160℃,优选100~130℃;或,式I所示化合物和反应溶剂质量/体积比为1:5~30g/mL,优选为1:10g/mL;或,式I所示化合物与氨基保护剂的摩尔比为1:2~5,优选为1:2.5~4;或,纯化方法为:向反应后的物料中加入水淬灭反应,将淬灭反应后的物料进行萃取,将萃取后的有机相进行洗涤、干燥、蒸发溶剂,即得。
- 如权利要求7所述的异喹啉类衍生物的合成方法,其特征是,式II所示化合物制备式III所示化合物的过程中,所述催化剂为钯催化剂或铜催化剂;优选地,所述催化剂为钯催化剂;进一步优选地,所述钯催化剂为PdCl 2、Pd(PPh 3) 4、Pd(OAc) 2、Pd 2(dba) 3、Pd(dba) 2、PdCl 2(cod)、[Pd(allyl)Cl] 2、PdCl 2·(CH 3CN) 2、Pd(acac) 2、Pd(PPh 3) 2Cl 2、Pd(Dppf) 2Cl 2、PdCl 2[P(o-Tol) 3]中的一种或几种混合;或,式II所示化合物制备式III所示化合物的过程中,所述配体为PPh 3、P(o-tolyl) 3、P(t-Bu) 3、P(t-Bu) 3·HBF 4、PCy 3、n-BuP(Ad) 2、BINAP、Xantphos、DPEPhos、Dppf、CyPFt-Bu、Dppp、JohnPhos、CyJohnPhos、DavePhos、RuPhos、SPhos、Xphos、BrettPhos、t-BuXphos、t-BuBrettPhos、Me 4t-BuXphos、Bippyphos、MorDalPhos、IPr·HCl中一种或多种;或,式II所示化合物制备式III所示化合物的过程中,所述碱为叔丁醇钠、碳酸铯、叔丁醇钾、碳酸钾、磷酸钾、双三甲基硅基胺基锂、DBU或MTBD;或,式II所示化合物制备式III所示化合物的过程中,反应温度的为90~130℃,优选95~110℃;或,式II所示化合物制备式III所示化合物的过程中,溶剂为沸点高于90℃的有机溶剂,优选甲苯、1,4-二氧六环、N,N-二甲基甲酰胺或二甲基亚砜。
- 如权利要求7所述的异喹啉类衍生物的合成方法,其特征是,式II所示化合物和反应溶剂质量/体积比为1:5~100g/mL,优先选1:10~20g/mL;或,式II所示化合物制备式III所示化合物的过程中,式II所示化合物与N-甲基-N'-四氢呋喃甲酰基丙二胺摩尔比为1:1~5,优选1:1.5~3;或,式II所示化合物制备式III所示化合物的过程中,式II所示化合物与催化剂的摩尔比为1:0.01~0.5,优选1:0.05~0.2;或,式II所示化合物制备式III所示化合物的过程中,式II所示化合物与配体的摩尔比1:0.02~1.0,优选1:0.05~0.4;或,式II所示化合物制备式III所示化合物的过程中,式II所示化合物与碱的摩尔比1:1~4,优选1:1.2~2;或,式III所示化合物制备式IV所示化合物的过程中,反应温度为0~70℃,优选0~40℃;或,式III所示化合物制备式IV所示化合物的过程中,反应溶剂为三氟乙酸、三乙基硅氢、甲磺酸、三氟甲磺酸、三氟乙酸/二氯甲烷的混合溶剂、甲磺酸/二氯甲烷的混合溶剂或三乙基硅氢/三氟乙酸混合溶剂;或,式III所示化合物制备式IV所示化合物的过程中,式III所示化合物与反应溶剂的质量/体积比为1:5~100g/mL,优选1:5~20g/mL。
- 一种异喹啉类衍生物,其特征是,所述异喹啉类衍生物是由权利要求7~9任一所述的合成方法获得的式IV所示化合物。
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