CN115677675A - Salt of 6-oxaspiro [4,5] decane compound, preparation method and application - Google Patents
Salt of 6-oxaspiro [4,5] decane compound, preparation method and application Download PDFInfo
- Publication number
- CN115677675A CN115677675A CN202210627814.2A CN202210627814A CN115677675A CN 115677675 A CN115677675 A CN 115677675A CN 202210627814 A CN202210627814 A CN 202210627814A CN 115677675 A CN115677675 A CN 115677675A
- Authority
- CN
- China
- Prior art keywords
- oxaspiro
- fluorophenyl
- benzyl
- decan
- pyridin
- 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.)
- Pending
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- -1 6-oxaspiro [4,5] decane compound Chemical class 0.000 title claims description 38
- UTYPARUARYGOQR-MUUNZHRXSA-N 2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]-N-[(2-pyridin-4-ylphenyl)methyl]ethanamine Chemical compound FC1=CC=C([C@@]2(CCNCC(C=CC=C3)=C3C3=CC=NC=C3)CC3(CCCC3)OCC2)C=C1 UTYPARUARYGOQR-MUUNZHRXSA-N 0.000 claims abstract description 29
- 208000002193 Pain Diseases 0.000 claims abstract description 10
- 230000036407 pain Effects 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 24
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 17
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 16
- 230000000202 analgesic effect Effects 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- 239000001530 fumaric acid Substances 0.000 claims description 10
- 235000015165 citric acid Nutrition 0.000 claims description 9
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 239000005711 Benzoic acid Substances 0.000 claims description 7
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 7
- 229960000583 acetic acid Drugs 0.000 claims description 7
- 235000010233 benzoic acid Nutrition 0.000 claims description 7
- 235000006408 oxalic acid Nutrition 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 6
- 229960002989 glutamic acid Drugs 0.000 claims description 6
- 239000011976 maleic acid Substances 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 229940116315 oxalic acid Drugs 0.000 claims description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 5
- 229930195714 L-glutamate Natural products 0.000 claims description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 5
- 229940001468 citrate Drugs 0.000 claims description 5
- 229940049906 glutamate Drugs 0.000 claims description 5
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical class OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 5
- 150000002688 maleic acid derivatives Chemical class 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 235000019260 propionic acid Nutrition 0.000 claims description 5
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical group NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- 229960005261 aspartic acid Drugs 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 4
- 229960001270 d- tartaric acid Drugs 0.000 claims description 4
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 4
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 229940013688 formic acid Drugs 0.000 claims description 4
- 229930195712 glutamate Natural products 0.000 claims description 4
- 239000004220 glutamic acid Substances 0.000 claims description 4
- 235000013922 glutamic acid Nutrition 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960004838 phosphoric acid Drugs 0.000 claims description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 229940032330 sulfuric acid Drugs 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 229940077388 benzenesulfonate Drugs 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 3
- 229960004106 citric acid Drugs 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 2
- 229930195713 D-glutamate Natural products 0.000 claims description 2
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 229960004909 aminosalicylic acid Drugs 0.000 claims description 2
- 229940072107 ascorbate Drugs 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 229940009098 aspartate Drugs 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 2
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 claims description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 2
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 2
- 229940114081 cinnamate Drugs 0.000 claims description 2
- 229930016911 cinnamic acid Natural products 0.000 claims description 2
- 235000013985 cinnamic acid Nutrition 0.000 claims description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-M dichloroacetate Chemical compound [O-]C(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-M 0.000 claims description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical class OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 claims description 2
- 229960000443 hydrochloric acid Drugs 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 229940074355 nitric acid Drugs 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 229940086735 succinate Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 235000011044 succinic acid Nutrition 0.000 claims description 2
- 229960005137 succinic acid Drugs 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 229960001367 tartaric acid Drugs 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 235000021317 phosphate Nutrition 0.000 claims 2
- CKLJMWTZIZZHCS-REOHCLBHSA-L L-aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 claims 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L L-glutamate group Chemical class N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 claims 1
- 150000001242 acetic acid derivatives Chemical class 0.000 claims 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims 1
- 150000001860 citric acid derivatives Chemical class 0.000 claims 1
- 150000004675 formic acid derivatives Chemical class 0.000 claims 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 claims 1
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- 239000002756 mu opiate receptor agonist Substances 0.000 claims 1
- 150000003891 oxalate salts Chemical class 0.000 claims 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims 1
- WFFUVYLIAPPPGM-UHFFFAOYSA-N 6-oxaspiro[4.5]decane Chemical class C1CCCC21OCCCC2 WFFUVYLIAPPPGM-UHFFFAOYSA-N 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 208000035475 disorder Diseases 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 49
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- 238000011160 research Methods 0.000 description 20
- 238000004949 mass spectrometry Methods 0.000 description 19
- 229960000074 biopharmaceutical Drugs 0.000 description 18
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 15
- 208000000114 Pain Threshold Diseases 0.000 description 11
- DMNOVGJWPASQDL-OAQYLSRUSA-N n-[(3-methoxythiophen-2-yl)methyl]-2-[(9r)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine Chemical compound C1=CSC(CNCC[C@@]2(CC3(CCCC3)OCC2)C=2N=CC=CC=2)=C1OC DMNOVGJWPASQDL-OAQYLSRUSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000004448 titration Methods 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 230000037040 pain threshold Effects 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 5
- 238000010812 external standard method Methods 0.000 description 5
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- 102000051367 mu Opioid Receptors Human genes 0.000 description 4
- 108020001612 μ-opioid receptors Proteins 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- 229940124636 opioid drug Drugs 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YSGJMABZOCFSFD-MRXNPFEDSA-N 2-[(9r)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]ethanamine Chemical compound C([C@@](C1)(CCN)C=2C=CC(F)=CC=2)COC21CCCC2 YSGJMABZOCFSFD-MRXNPFEDSA-N 0.000 description 1
- HPSCYFZOYJSYGZ-UHFFFAOYSA-N 2-pyridin-4-ylbenzaldehyde Chemical compound O=CC1=CC=CC=C1C1=CC=NC=C1 HPSCYFZOYJSYGZ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- COTNUBDHGSIOTA-YPAXDSTQSA-N CO[2H].CO Chemical class CO[2H].CO COTNUBDHGSIOTA-YPAXDSTQSA-N 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
Classifications
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutical chemical synthesis, in particular to 6-oxaspiro [4,5] decane derivatives, and more particularly relates to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine pharmaceutically acceptable salts and a preparation method thereof, which are used for treating pain and pain-related disorders.
Description
Technical Field
The invention relates to the field of pharmaceutical chemical synthesis, in particular to 6-oxaspiro [4,5] decane derivatives, and more particularly relates to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine pharmaceutically acceptable salts and a preparation method thereof, which are used for treating pain and pain-related disorders.
Background
Until now, opioids (opioid drugs) represented by morphine are still effective drugs mainly for treating severe pain, and these drugs have good analgesic activity, but have great limitation on clinical application due to serious adverse reactions of the central nervous system, especially side effects such as respiratory depression, constipation, tolerance and addiction. Therefore, people are always dedicated to searching for ideal opioid with good analgesic effect and small addiction, and in the process of continuously exploring the structure-activity relationship of opioid, people have deeper understanding on the in vivo specific substance group of the opioid.
Three molecularly and pharmacologically distinct classes of Opioid Receptors (ORs) have been shown: δ, κ, and μ. Opioids are primarily conducted through opioid μ receptors. The mu receptor is a classical GPCR, and a large number of researches show that the biased agonist of the mu receptor has better analgesic effect and can reduce related side effects. This opens the possibility for the development of ideal opioid drugs. Currently, trevena TRV130 (oligoridine) is marketed for postoperative analgesia by FDA approval at 8 months of 2020. TRV130 phase iii clinical results show: under the dosage of achieving the same analgesic effect, the TRV130 has lower toxic and side effects than morphine, but has no significant difference and large toxic and side effects, the daily cumulative dosage of the TRV130 is not more than 27mg, and the safety window is narrow.
Therefore, on the basis of the existing domestic and foreign research, the invention strives to develop the mu receptor bias agonist with better drug effect, wide safety window and lower side effect, and provides a better choice for clinical application. The (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine is a pharmaceutically acceptable salt which is solid at normal temperature, improves the solubility, and has good pharmacokinetic property, long half-life period, good analgesic effect and good drug forming property.
Disclosure of Invention
The invention aims to disclose a compound (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine pharmaceutically acceptable salt shown as a formula I, a preparation method thereof and application thereof in preparing analgesic drugs, in particular application in preparing moderate to severe pain drugs.
The pharmaceutically acceptable salt is an acid salt, a zwitterion salt (inner salt) or a quaternary ammonium salt formed by inorganic and/or organic acid.
Preferably, the pharmaceutically acceptable salt is specifically acetate, oxalate, 4-aminosalicylate, ascorbate, benzenesulfonate, p-toluenesulfonate, benzoate, phthalate, butyrate, camphorsulfonate, camphorate, cinnamate, 2,2-dichloroacetate, formate, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, citrate, fumarate, hydrochloride, hippurate, glycolate, hydrobromide, hydroiodide, lactate, maleate, propionate, malonate, glutamate, nitrate, phosphate, salicylate, perchlorate, trifluoroacetate, sulfate, glutamate, aspartate, citrate, succinate or tartrate.
Further, the pharmaceutically acceptable salt specifically refers to oxalate, p-toluenesulfonate, D-tartrate, maleate, fumarate, L-glutamate, L-aspartate, acetate, benzoate, citrate, hydrobromide, phosphate, formate, benzenesulfonate, hydrochloride or sulfate.
Further, the pharmaceutically acceptable salts of the compound of formula I of the present invention, which is (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine, include, but are not limited to:
the diacetate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
(ii) the monoacetate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the bisulphate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono maleate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a dimaleate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monobenzoate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a dibenzoate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono L-aspartate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-L-aspartate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono D-aspartate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-D-aspartate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono-oxalate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the di-oxalate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a mono-citrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the dicitrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono D-tartrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the di-D-tartrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono L-tartrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-L-tartrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono L-glutamate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-L-glutamate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono D-glutamate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-D-glutamate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono-p-toluenesulfonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-p-toluenesulfonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the monofumarate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the difumarate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a dihydrobromide salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monohydrobromide salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monophosphate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a diphosphate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a diformate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
monopropionate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
dipropionate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine
A monomalonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a dimalonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a diphenylsulfonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
(iv) the monosulfate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monohydrochloride salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the dihydrochloride salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine.
Still further, pharmaceutically acceptable salts of the compound of formula I of the present invention (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine include, but are not limited to:
the diacetate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the bisulphate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono maleate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monobenzoate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono L-aspartate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono-oxalate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a mono-citrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono D-tartrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono L-glutamate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono-p-toluenesulfonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono-fumarate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the difumarate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a dihydrobromide salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monophosphate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a diformate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
monopropionate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a diphenylsulfonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
(iv) the monosulfate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monohydrochloride salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the dihydrochloride salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the hemifumarate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine.
In another aspect of the present invention, there is disclosed a process for the preparation of a pharmaceutically acceptable salt of a compound of formula I (formula II) comprising the steps of:
wherein: n =1 to 2, preferably n is 1 or 2.
(1) Adding a solvent into the compound of the formula I under the condition of stirring at room temperature until the compound is completely dissolved;
the solvent is selected from formamide, acetonitrile, methanol, ethanol, propanol, n-butanol, acetone, dioxane, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, bromoethane, benzene, chloropropane, toluene, carbon tetrachloride, carbon disulfide, cyclohexane, hexane or heptane.
(2) Slowly dripping acid or organic solvent solution of the acid, and fully stirring;
the acid or the organic solvent solution of the acid is acetic acid, oxalic acid, 4-aminosalicylic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, phthalic acid, butyric acid, camphorsulfonic acid, camphoric acid, cinnamic acid, 2,2-dichloroacetic acid, formic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, citric acid, fumaric acid, hydrogen chloride dioxane solution, hippuric acid, glycolic acid, hydrobromic acid, hydroiodic acid, lactic acid, maleic acid, propionic acid, malonic acid, glutamic acid, nitric acid, phosphoric acid, salicylic acid, perchloric acid, trifluoroacetic acid, sulfuric acid, glutamic acid, aspartic acid, citric acid, succinic acid or tartaric acid.
(3) Filtering and vacuum drying to obtain the pharmaceutically acceptable salt of the compound of the formula I.
Wherein, the solvent in the step (1) further specifically refers to acetonitrile, methanol, ethanol, propanol, n-butanol, dioxane, tetrahydrofuran, ethyl acetate, dichloromethane or chloroform. Furthermore, the solvent in the step (1) specifically refers to tetrahydrofuran or ethyl acetate.
The molar ratio of the compound of formula I to the acid in step (1) is 1: (0.5 to 2);
further, the molar ratio of the compound of formula I to the acid in step (1) is 1: (1-2);
the acid or the organic solvent solution of the acid in the step (2) is further specifically oxalic acid, p-toluenesulfonic acid, D-tartaric acid, maleic acid, fumaric acid, L-glutamic acid, L-aspartic acid, acetic acid, benzoic acid, citric acid, hydrobromic acid, phosphoric acid, formic acid, benzenesulfonic acid, hydrochloric acid or sulfuric acid.
Through the test of the solubility of the pharmaceutically acceptable salt of the compound shown in the formula I in water, the compound shown in the invention has obviously improved solubility after being salified compared with the compound shown in the formula I ((R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine) per se, such as the disulfate, monomaleate, monocitric acid, mono D-tartrate, mono-p-toluenesulfonate, monofumarate, difumarate, dihydrobromate, monosulfate, monohydrochloride and dihydrochloride of the compound shown in the invention shown in the formula I (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine, and the solubility of the compound shown in the invention is over 10mg/ml, and the solubility of the monohydrochloride and the compound shown in the invention is improved by more than 100 times.
Through research and test on pharmacokinetics of normal rats, the pharmaceutically acceptable salt of the compound shown as the formula I shows excellent pharmacokinetic characteristics; through a pharmacodynamic test on the influence of a mouse hot plate model, the pharmaceutically acceptable salt of the compound shown in the formula I still can show a good analgesic effect 1h after administration, and is suitable for preparing analgesic drugs, in particular for preparing moderate to severe pain drugs.
In the present invention, "the compound of the present invention" and "the salt of the present invention" are used interchangeably and refer to pharmaceutically acceptable salts of the compound of formula I (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine.
Detailed Description
The present invention is described in further detail with reference to the following examples, but the present invention is not limited thereto, and any equivalent replacement in the field made in accordance with the present disclosure is included in the scope of the present invention.
The structure of the compound is determined by Mass Spectrometry (MS) or nuclear magnetic resonance (M) 1 H NMR). Nuclear magnetic resonance ( 1 H NMR) shifts (δ) are given in parts per million (ppm), nuclear magnetic resonance ( 1 H NMR) was measured using a BrukeraVANCE-400 nuclear magnetic spectrometerIn the following, the solvent used for the determination is tetradeuterated Methanol (Methanol-d) 4 ) Internal standard is Tetramethylsilane (TMS).
Mass Spectrometry (MS) measurements were performed using a FINNIGAN LCQad (ESI) mass spectrometer (manufacturer: therm, model: finnigan LCQ advantage MAX).
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
In the examples, room temperature means an ambient temperature of 10 to 25 ℃.
HPLC test conditions: a chromatographic column: YMC-Triart C18250X 4.6mm I.D.S-5 um.
EXAMPLE 1 preparation of the Compound 1 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine
The preparation scheme is shown in the following scheme:
(R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) ethylamine (6.66g, 24mmol) was dissolved in methylene chloride (70 mL), and 2- (4-pyridyl) benzaldehyde (4.4 g, 24mmol) and anhydrous sodium sulfate (14g, 96mmol) were added thereto, followed by reaction at room temperature. After the reaction is carried out for 12 hours, dichloromethane in the reaction system is concentrated, then methanol (70 mL) is added to dissolve the dichloromethane, sodium borohydride (1.82g, 48mmol) is added in batches in ice water bath, after the reaction is finished, the methanol in the reaction system is concentrated, then water and ethyl acetate are added to dissolve the methanol, liquid separation is carried out, the water phase is extracted for 2 times by ethyl acetate, the organic phase is combined, then water washing and saturated saline water washing are carried out for 1 time, after anhydrous sodium sulfate is dried, suction filtration is carried out, and the filtrate is concentrated to obtain yellow oily matter. The yellow oil was purified by column chromatography (dichloromethane/methanol = 25/1) to give compound 1 (4.6 g, yellow oil) in 42.7% yield, purity: 98.18 percent.
MS m/z(ES)：445.3[M+1] +
1 H NMR(400MHz,CDCl 3 )δ8.62–8.60(m,2H),7.35–7.30(m,3H),7.27–7.25(m,2H), 7.21–7.17(m,3H),7.01–6.97(m,2H),3.74–3.68(m,2H),3.51(s,2H),2.32–2.25(m,1H), 2.17–2.13(m,1H),2.03–1.96(m,2H),1.87(d,J＝13.9Hz,1H),1.78–1.57(m,6H),1.50– 1.40(m,4H),0.85–0.77(m,1H).
EXAMPLE 2 preparation of the Compound 2 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine diacetate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (86 mg, 0.193 mmol) was added ethyl acetate (3 ml) until it was dissolved, then acetic acid (23.2mg, 0.387mmol) was slowly added dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give the compound 2R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine diacetate (98 mg, light yellow solid), yield: 89.9 percent; HPLC:98.23 percent. The acetic acid content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine diacetate was 21.21% (theoretical 21.27%) calculated by HPLC external standard method using glacial acetic acid as a control.
MS m/z(ES):445.3[M+H] +
1HNMR(400MHz,Methanol-d4)δ8.62–8.59(m,2H),7.56–7.52(m,1H), 7.50-7.47(m,2H),7.36–7.29(m,5H),7.07(t,J＝8.72Hz,2H),3.96(s,2H),3.70–3.67(m,2H), 2.63–2.56(m,1H),2.22-2.06(m,3H),1.93(s，6H),1.89–1.82(m,2H),1.77–1.68(m,2H), 1.64-1.57(m,2H),1.53–1.39(m,4H),1.20–1.15(m,1H),0.87–0.79(m,1H).
EXAMPLE 3 preparation of the Compound 3 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine disulfate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (244 mg, 0.549 mmol) was added ethyl acetate (5 ml) until it dissolved, then sulfuric acid (108mg, 1.1 mmol) was slowly added dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give the compound 3R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine disulfate (318 mg, white solid) yield: 90.4 percent; HPLC:98.35 percent. The sulfuric acid content of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine disulfate was determined by titration to be 30.46% (theoretical 30.61%).
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.91(d,J＝6.8Hz,2H),8.06(d,J＝6.8Hz,2H),7.70–7.58(m, 3H),7.48(dd,J＝7.4,1.7Hz,1H),7.41–7.36(m,2H),7.10–7.05(m,2H),4.14(d，J＝6.2Hz, 2H),3.72–3.69(m,2H),2.87(td,J＝12.5,4.4Hz,1H),2.35–2.26(m,2H),2.18(dd,J＝13.9, 2.1Hz,1H),1.99–1.82(m,3H),1.76–1.68(m,2H),1.62–1.41(m,5H)，1.18–1.15(m,1H), 0.86–0.78(m,1H).
EXAMPLE 4 preparation of the Compound 4 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monomaleate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5)]Decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (310 mg, 0.697 mmol) tetrahydrofuran (5 ml) was added until it dissolved, then maleic acid (81 mg, 0.697 mmol) was added slowly dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5]Decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monomaleate compound 4 (237 mg, white solid), yield: 60.6 percent; HPLC:98.48 percent. (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5) was determined by titration]The maleic acid content of decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monomaleate was 20.59% (theoretical 20.71%). MS m/z (ES) 445.3[ m ] +H] +
1 H NMR(400MHz,Methanol-d4)δ8.62(dt,J＝4.5,1.3Hz,2H),7.58–7.51(m,3H),7.37– 7.31(m,5H),7.07(td,J＝8.8,1.1Hz,2H),6.23(d,J＝0.9Hz,2H),4.08(s,2H),3.73–3.67(m, 2H),2.74–2.67(m,1H),2.24–2.12(m,3H),1.89–1.84(m,2H),1.77–1.69(m,2H), 1.66-1.57(m,2H),154-1.40(m,4H),1.23–1.17(m,1H),0.86-0.78m,1H).
EXAMPLE 5 preparation of the Compound 5 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine monobenzoate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (75 mg, 0.169 mmol) was added tetrahydrofuran (5 ml) until it was dissolved, then benzoic acid (20.6 mg, 0.169 mmol) was added slowly dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monobenzoate compound 5 (95 mg, light yellow solid), yield: 99.3 percent; HPLC:98.21 percent. The benzoic acid content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monobenzoate was calculated to be 21.79% (theoretical 21.55%) using HPLC external standard method with benzoic acid as a control.
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.60(d,J＝5.4Hz,2H),7.98–7.93(m,2H),7.59–7.56 (m,1H),7.50–7.46(m,3H),7.42–7.37(m,3H),7.36–7.34(m,2H),7.33–7.27(m,2H),7.07 –7.01(m,2H),3.98(s,2H),3.68–3.65(m,2H),2.64–2.57(m,1H),2.20–2.08(m,3H),1.94 –1.81(m,2H),1.77–1.69(m,2H),1.63–1.56(m,2H),1.51–1.39(m,4H),1.19–1.16(m, 1H),0.85–0.77(m,1H).
EXAMPLE 6 preparation of the Compound 6 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine mono oxalate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (73mg, 0.164mmol) was added tetrahydrofuran (5 ml) until it was dissolved, then oxalic acid (14.8mg, 0.164mmol) was slowly added dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine mono oxalate compound 6 (75 mg, white solid) yield: 85.4 percent; HPLC:98.51%. Oxalic acid was used as a control, and the oxalic acid content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine mono-oxalate was 16.81% (theoretical 16.84%) calculated by HPLC external standard method.
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.62(d,J＝5.0Hz,2H),7.60–7.58(m,1H),7.53-7.50(m, 2H),7.37-7.30(m,5H),7.07(t,J＝8.5Hz,2H),4.12–4.05(s，2H),3.73-3.71(m,2H),2.72– 2.65(m,1H),2.21–2.10(m,3H),1.92–1.83(m,2H),1.78–1.70(m,2H),1.64–1.57m,2H), 1.53–1.41(m,4H),1.18–1.15(m,1H),0.86-0.78(m,1H).
EXAMPLE 7 preparation of the Compound 7 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine Monocitrate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (67 mg, 0.151 mmol) was added tetrahydrofuran (5 ml) until it was dissolved, then citric acid (28.9 mg, 0.151 mmol) was added slowly dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine mono citrate compound 7 (75 mg, light yellow solid), yield: 99 percent; HPLC:98.11 percent. The citric acid content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine monocitrate was 30.21% (theoretical 30.17%) calculated by HPLC external standard method using citric acid as a control.
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.62(d,J＝5.0Hz,2H),7.62–7.59(m,1H),7.54-7.49(m, 2H),7.37–7.29(m,5H),7.07(t,J＝8.7Hz,2H),4.08–4.06(d,J＝3.8Hz,2H),3.70–3.67(m, 2H),2.88–2.74(m,4H),2.70-2.63(m,1H),2.21–2.11(m,3H),1.93-1.84(m 2H),1.78-1.70 (m,2H),1.65-1.58(m,2H),1.51–1.341(m,4H),1.19–1.17(m,1H),0.85-0.77(m,1H).
EXAMPLE 8 preparation of the Compound 8 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine mono D-tartrate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (65 mg, 0.146 mmol) was added tetrahydrofuran (5 ml) until it dissolved, then D-tartaric acid (21.9 mg, 0.146 mmol) was slowly added dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) mono D-tartrate compound 8 (73 mg, white solid) yield: 84%; HPLC:98.46 percent. The D-tartaric acid content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine mono D-tartrate was determined by titration to be 25.34% (theoretical 25.24%).
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.62(d,J＝5.7Hz,2H),7.64–7.61(m,1H),7.53–7.48(m, 2H),7.36–7.29(m,5H),7.07(t,J＝8.7Hz,2H),4.40(s,2H),4.07(s,2H),3.70–3.67(m,2H), 2.67-2.60(m,1H),2.20–2.06(m,3H),1.92–1.83(m,2H),1.79–1.69(m,2H),1.66-1.56(m, 2H),1.53–1.39(m,4H),1.22-1.16(m,1H),0.84-0.77(m,1H).
EXAMPLE 9 preparation of the Compound 9 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine mono-p-toluenesulfonate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (63 mg, 0.142 mmol) was added tetrahydrofuran (5 ml) until it dissolved, then p-toluenesulfonic acid (24.4 mg, 0.142 mmol) was slowly added dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine mono p-toluenesulfonate compound 9 (45 mg, white solid) yield: 51.5 percent; HPLC:98.42 percent. The p-toluenesulfonic acid content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine mono-p-toluenesulfonate was determined by titration to be 28.11% (theoretical 27.92%).
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.61(d,J＝6.0Hz,2H),7.67(d,J＝8.2Hz,2H),7.59–7.56(m,1H),7.53–7.50(m,2H),7.36–7.28(m,5H),7.23(d,J＝7.9Hz,2H),7.08–7.04(m, 2H),4.06(s,2H),3.68–3.63(m,2H),2.72–2.65(m,1H),2.37(s,3H),2.20–2.08(m,3H), 1.91-1.81(m,2H),1.76–1.68(m,2H),1.66-1.56(m,2H),1.54–1.36(m,4H),1.21-1.16(m, 1H),0.83–0.75(m,1H).
EXAMPLE 10 preparation of the Compound 10 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monofumarate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5)]Decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (99 mg,0.223 mmol) tetrahydrofuran (5 ml) was added until it dissolved, then fumaric acid (25.8mg, 0.223mmol) was added slowly dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5]Decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monofumarate compound 10 (120 mg, white solid), yield: 96.1 percent; HPLC:98.45 percent. (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5) was measured by titration]The fumaric acid content of decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monofumarate was 20.84% (theoretical 20.71%). MS m/z (ES) 445.3[ m ] +H] +
1 H NMR(400MHz,Methanol-d4)δ8.62(d，J＝5.96Hz,2H),7.60–7.57(m,1H),7.54-7.49(m, 2H),7.37–7.29(m,5H),7.10–7.05(m,2H),6.68(d,J＝1.5Hz,2H),4.06(s,2H),3.70–3.67 (m,2H),2.71–2.64(m,1H),2.21–2.10(m,3H),1.88-1.83(m,2H),1.79-1.70(m,2H), 1.66-1.57(m,2H),1.53-1.39(m,4H),1.23–1.17(m,1H),0.86–0.78(m,1H).
EXAMPLE 11 preparation of the Compound 11 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine difumarate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (49mg, 0.11 mmol) was added tetrahydrofuran (5 ml) until it was dissolved, then fumaric acid (25.6 mg, 0.22mmol) was slowly added dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine difumarate compound 11 (70 mg, white solid) yield: 93.8 percent; HPLC:98.39%. The fumaric acid content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine difumarate was determined by titration to be 34.44% (theoretical 34.30%).
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.64–8.62(m,2H),7.60–7.51(m,3H),7.39–7.30(m, 5H),7.10–7.06(m,2H),6.73(s,4H),4.08(s,2H),3.71–3.68(m,2H),2.73–2.66(m,1H)， 2.23–2.12(m，3H)，1.92–1.84(m，2H)，1.79–1.70(m，2H)，1.65–1.58(m，2H)，1.54– 1.40(m，4H)，1.20–1.18(m,1H)，0.86–0.78(m,1H).
EXAMPLE 12 preparation of the Compound 12 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrobromide
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5]Decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (75 mg, 0.169 mmol) was added tetrahydrofuran (2 ml) until it was dissolved, and then hydrobromic acid (27.3 mg,0.337 mmol) until a white solid precipitates, stirring thoroughly for 3 hours, filtering and drying in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5]Decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrobromide compound 12 (72 mg, white solid), yield: 70.4 percent; HPLC:98.38 percent. (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5) was measured by titration]The hydrobromic acid content of decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrobromide was 26.74% (theoretical 26.68%). MS m/z (ES) 445.3[ m ] +H] +
1 H NMR(400MHz,Methanol-d4)δ8.94(d,J＝6.7Hz,2H),8.08(d,J＝6.8Hz,2H),7.73–7.70(m, 1H),7.68–7.59(m,2H),7.50–7.47(m,1H),7.42–7.35(m,2H),7.11–7.05(m,2H),4.22– 4.14(m,2H),3.76–3.66(m,2H),2.95–2.88(m,1H),2.38–2.27(m,2H),2.21–2.17(m,1H), 2.05–1.97(m,1H),1.93–1.84(m,2H),1.77–1.40(m,7H),1.24–1.18(m,1H),0.87–0.79 (m,1H).
EXAMPLE 13 preparation of the Compound 13 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine monopropionate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine (68mg, 0.153mmol) was added ethyl acetate (2 ml) until it dissolved, then propionic acid (11.3mg, 0.153mmol) was slowly added dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine monopropionate compound 13 (78 mg, light yellow solid), yield: 98.4 percent; HPLC:98.22 percent. The content of propionic acid in (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethanamine monopropionate was calculated to be 14.41% (theoretical 14.29%) using HPLC external standard method with propionic acid as a control.
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.61–8.59(m,2H),7.56–7.54(m,1H),7.50–7.47(m, 2H),7.36–7.30(m,5H),7.08–7.04(m,2H),3.95(s,2H),3.70–3.67(m,2H),2.62–2.55(m, 1H),2.26–2.20(m,2H),2.21–2.06(m,3H),1.89–1.82(m,2H),1.75–1.68(m,2H), 1.64-1.57(m,2H),1.53–1.40(m,4H),1.25–1.18(m,1H),1.10–1.06(m,3H),0.87–0.78(m, 1H).
EXAMPLE 14 preparation of the Compound 14 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monosulfate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (40mg, 0.09 mmol) was added ethyl acetate (5 ml) until it was dissolved, then sulfuric acid (8.8mg, 0.09mmol) was slowly added dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monosulfate compound 14 (35 mg, white solid), yield: 71.7 percent; HPLC:98.35 percent. The sulfuric acid content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monosulfate was determined by titration to be 18.20% (theoretical 18.08%).
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.79(s,2H),7.76–7.66(m,3H),7.61–7.53(m,2H),7.42 –7.35(m,3H),7.09–7.05(m，2H),4.12–4.11(m,2H),3.71–3.68(m,2H),2.82–2.75(m, 1H),2.27–2.13(m,3H),1.98–1.81(m,3H),1.75–1.58(m,3H),1.55–1.39(m,4H),1.19– 1.15(m,1H),0.84–0.77(m,1H).
EXAMPLE 15 preparation of the Compound 15 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (314 mg, 0.706 mmol) was added ethyl acetate (5 ml) until it was dissolved, then 3.0M hydrogen chloride dioxane solution (0.24ml, 0.706mmol) was slowly added dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride compound 15 (263 mg, white solid) yield: 77.4 percent; HPLC:98.44 percent. The hydrogen chloride content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride, determined by titration, was 7.78% (theoretical 7.59%).
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.93(d,J＝6.6Hz,2H),8.09(d,J＝6.1Hz,2H),7.73–7.71 (m,1H),7.68–7.59(m,2H),7.50–7.47(m,1H),7.40–7.35(m,2H),7.10–7.06(m,2H),4.18 –4.10(m,2H),3.75–3.67(m,2H),2.90–2.83(m,1H),2.34–2.26(m,2H),2.20–2.16(m, 1H),2.04–1.97(m,2H),1.93–1.84(m,2H),1.77–1.60(m,2H),1.57–1.41(m,4H),1.24-1.17 (m,1H),0.86–0.78(m,1H).
EXAMPLE 16 preparation of the Compound 16 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrochloride
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (314 mg, 0.706 mmol) was added ethyl acetate (5 ml) until it dissolved, then 3.0M hydrogen chloride dioxane solution (0.47ml, 1.412mmol) was slowly added dropwise until a white solid precipitated, stirred well for 3 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrochloride compound 16 (268 mg, white solid) in yield: 73.3 percent; HPLC:98.49 percent. The hydrogen chloride content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine dihydrochloride was determined by titration to be 14.18% (theoretical 14.09%).
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,Methanol-d4)δ8.96(d,J＝6.1Hz,2H),8.12(d,J＝6.4Hz,2H),7.77(dd,J＝7.5,1.5Hz,1H),7.68–7.50(m,2H),7.50(dd,J＝7.4,1.6Hz,1H),7.42–7.39(m,2H),7.09(t, J＝8.5Hz,2H),4.20–4.12(m，2H)，3.76–3.68(m，2H)，2.92–2.85(m,1H)，2.36–2.27(m, 2H)，2.21–2.17(m,1H)，2.10–1.99(m，2H),1.95–1.88(m，2H)，1.78–1.67(m,2H)，1.65 –1.42(m，4H)，1.25–1.18(m，1H)，0.88–0.80(m,1H).
EXAMPLE 17 preparation of the Compound 17 (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine hemifumarate
The preparation scheme is shown in the following scheme:
to (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (1280 mg, 2.879 mmol) was added acetonitrile (15 mL) until it was dissolved, and a solution of fumaric acid (167mg, 1.439mmol) in tetrahydrofuran (3 mL) was added to the above solution at 65 deg.C, stirred well for 3 hours, then allowed to cool to room temperature and stirred for 2 hours, filtered and dried in vacuo to give R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine hemi-fumarate compound 17 (1149 mg, white solid) yield: 79.4 percent; HPLC:99.87 percent. The fumaric acid content of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine hemifumarate was determined by titration to be 11.68% (theoretical 11.55%).
MS m/z(ES):445.3[M+H] +
1 H NMR(400MHz,DMSO)δ8.60–8.58(m,2H),7.49–7.47(m,1H),7.41–7.36(m,4H), 7.34–7.30(m,2H),7.25–7.22(dd,J＝7.2,1.7Hz,1H),7.10(t,J＝8.8Hz,2H),6.50(s,1H), 3.62–3.58(m,2H),3.52–3.48(m,2H),2.30–2.23(m,1H),2.10–2.00(m,2H),1.94–1.87(m, 1H),1.79–1.62(m,4H),1.59–1.50(m,2H),1.46–1.34(m,4H),1.16–1.10(m,1H),0.85– 0.77(m,1H).
Pharmacological toxicological evaluation
The test drugs are:
positive control drug: TRV130 (fumarate), supplied by gengduangdong biopharmaceutical gmbh, white solid, purity: 99.90 percent;
the compound of example 1: example 1 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, yellow oil, purity: 98.18 percent;
the compound of example 2: example 2 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, light yellow solid, purity: 98.23 percent;
the compound of example 3: example 3 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 98.35 percent;
the compound of example 4: example 4 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 98.48 percent;
the compound of example 5: example 5 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, light yellow solid, purity: 98.21 percent;
the compound of example 6: example 6 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 98.51%;
the compound of example 7: example 7 preparation, provided by the synthetic research laboratory of bonded bio-pharmaceutical corporation, dongdong, inc, as a pale yellow solid, purity: 98.11 percent;
the compound of example 8: example 8 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 98.46 percent;
the compound of example 9: example 9 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 98.42 percent;
the compound of example 10: example 10 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 98.45 percent;
the compound of example 11: example 11 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 98.39%;
the compound of example 12: example 12 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 98.38 percent;
the compound of example 13: example 13 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, light yellow solid, purity: 98.22 percent;
the compound of example 14: example 14 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 98.35 percent;
the compound of example 15: example 15 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 98.44 percent;
the compound of example 16: example 16 preparation, provided by the synthetic research laboratory of bonded bio-pharmaceutical corporation, dongdong, white solid, purity: 98.49 percent.
The compound of example 17: example 17 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 99.87 percent.
Test example 1 solubility test
In order to examine the solubility of the salified and non-salified samples of examples 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 according to the invention, example 1, the solubility of the above salts was determined in water at 37 ℃ and the results are shown in table 1 below:
table 1 solubility test results
| Sample(s) | Water (mg/mL) |
| Example 1 | <0.1 |
| Example 2 | 8.5 |
| Example 3 | >10 |
| Example 4 | >10 |
| Example 5 | 4.8 |
| Example 6 | 2.5 |
| Example 7 | >10 |
| Example 8 | >10 |
| Example 9 | 0.7 |
| Example 10 | >10 |
| Example 11 | >10 |
| Example 12 | >10 |
| Example 13 | 3.8 |
| Example 14 | >10 |
| Example 15 | >10 |
| Example 16 | >10 |
| Example 17 | 3 |
The above test results show that the solubility of each salt of compound 1 prepared in examples 2 to 17 of the present invention is significantly improved as compared to compound 1 not formed as a salt, and the solubility of the salts prepared in examples 3, 4, 7, 8, 10, 11, 12, 14, 15, and 16 in water is more than 10mg/ml, and the solubility is improved by 100 times or more.
Test example 2 pharmacokinetic testing of Compounds of formula I after a single intravenous injection
1. The purpose of the test is as follows: pharmacokinetic parameters were examined for each compound of the experimental examples after a single intravenous administration.
2. Test method
(1) Test animals and drug administration
SD rats, SPF grade, half male and female, weighing 180-220g, were provided by Woodsville Biotech, inc. Approximately 5mg of each compound was weighed, dissolved in 100. Mu.L of DMSO, and then a solution of 0.25mg/mL was prepared by adding physiological saline. The administration mode is single tail vein injection administration, the administration volume is 4mL/kg, the administration concentration is 0.25mg/mL, and the administration dosage is 1mg/kg.
(2) Designing a blood sampling point:
before administration, 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 6h, 8h, 24h after administration, blood was taken from jugular vein, 200. Mu.L of whole blood was taken at each time point, and placed in a container containing EDTA-K 2 In the anticoagulation tube, the plasma is separated after the centrifugation of 2000 g at the low temperature of 4 ℃, transferred into a microcentrifuge tube and stored in a refrigerator at the temperature of 80 ℃ below zero for standby.
(3) Sample detection
By establishing a reliable LC/MS/MS analysis method, the blood concentration of each sample is detected, and the pharmacokinetic parameters of each compound are calculated.
3. Test results
Table 2 single tail vein administration major pharmacokinetic parameters (n = 3)
| Parameter(s) | T 1/2 (h) | C 5min (ng·mL -1 ) | AUC last (h·ng·mL -1 ) |
| TRV130 | 0.72±0.01 | 249.7±25.3 | 322.1±23.4 |
| Example 6 | 1.46±0.31* | 520.3±32.2** | 752.3±18.2** |
| Example 8 | 2.10±0.38** | 485.0±24.2** | 560.8±31.22** |
| Example 9 | 2.10±0.27** | 499.0±12.5** | 596.1±24.3** |
| Example 10 | 2.44±0.52** | 498.3±27.0** | 617.8±26.9** |
| Example 11 | 1.81±0.44* | 481.3±18.5** | 554.7±24.8** |
| Example 12 | 1.95±0.31** | 463.7±27.2** | 573.1±25.5** |
| Example 14 | 1.99±0.38** | 482.3±28.4** | 587.2±17.8** |
| Example 15 | 2.48±0.47** | 465.7±21.2** | 592.6±28.3** |
| Example 16 | 1.54±0.16** | 499.3±26.3** | 568.5±17.3** |
Note: p <0.05, P <0.01 compared to the positive compound TRV 130.
Example 6, example 8, example 9, example 10, example 11, example 12, example 14, example 15, example 16 in vivo rat T compared to the positive compound TRV130 1/2 Elongation of more than one time, C 5min The blood concentration is obviously increased, AUC last The compound is obviously increased and has statistical difference, which indicates that the compound of the embodiments has longer duration of analgesic effect, lower effective dose and better absorption.
Test example 3 Effect of a Single intravenous injection of a Compound of formula I on the pain-like response of mice to Heat conduction in mice
1. The purpose of the test is as follows: test of the effect of test compounds on the pain-like response of mice to heat conduction in mice, the pharmacodynamic effects of examples 10 and 16 were investigated.
2. Test method
(1) Test animal and test article preparation
KM mice, SPF grade, all females, weighing 18-22g, were supplied by Dow-Coulter Biotech. TRV130, example 10, and example 16 were weighed out to about 5mg and dissolved in 100. Mu.L DMSO, and then a solution of an appropriate concentration was prepared by adding physiological saline.
(2) Test procedure
Taking 18-22g of KM full-female mice, measuring a basic pain threshold value on a hot plate at 55 +/-0.5 ℃, and selecting 32 mice with the pain threshold value of 5-30s for experiments. The pain threshold of 32 qualified mice is measured 2 times before administration at an interval of 5min, and the average value is taken as the basic pain threshold. The mice were randomly divided into 4 groups, i.e., vehicle control group, TRV130 group (1 mg/kg), example 10 group (1 mg/kg) and example 16 (1 mg/kg), 8 mice in each group were administered into the tail vein (the control group was administered with an equal amount of 0.9% physiological saline), the pain threshold of the mice was measured 30 and 60min after administration, and the difference between the pain threshold of each drug group and the pain threshold of the control group was statistically compared in 60s for those with the pain threshold exceeding 60 s.
(3) And (3) calculating test results:
the analgesic rate of the example compound was calculated according to the following calculation formula:
analgesic rate = (post-administration pain threshold-pre-administration pain threshold)/pre-administration pain threshold × 100%;
3. test results
Table 3 analgesic rate of each example compound (n = 8)
Note: p <0.05, P <0.01, compared to vehicle control group; compared with the positive compound TRV130, the delta-P is less than 0.05 and the delta-P is less than 0.01.
Compared with the vehicle control group, after administration for 30min and 60min, the positive compound TRV130 group, the example 10 group and the example 16 group all have significant analgesic effect; compared with the positive compound TRV130 group, the analgesic effect of the example 10 group and the analgesic effect of the example 16 group after 30min and 60min of administration are significantly different, which indicates that the compound has better analgesic effect.
It will be apparent to those skilled in the art from the foregoing that the compounds of the present embodiments exhibit analgesic effects, and that various modifications and variations can be made in the compounds, compositions and methods of the present invention without departing from the spirit or scope of the invention, and therefore, the invention includes modifications and variations to the invention provided they come within the scope of the appended claims and their equivalents.
Claims (10)
1. A pharmaceutically acceptable salt of compound (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine having the structure shown in formula I:
wherein the salt is acid salt, zwitterion salt (inner salt) and quaternary ammonium salt formed by inorganic and/or organic acid.
2. The pharmaceutically acceptable salt of the compound of formula I according to claim 1, wherein the salt is an acid addition salt, in particular acetate, oxalate, 4-aminosalicylate, ascorbate, benzenesulfonate, p-toluenesulfonate, benzoate, phthalate, butyrate, camphorsulfonate, camphorate, cinnamate, 2,2-dichloroacetate, formate, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, citrate, fumarate, hydrochloride, hippurate, glycolate, hydrobromide, hydroiodide, lactate, maleate, propionate, malonate, glutamate, nitrate, phosphate, salicylate, perchlorate, trifluoroacetate, sulfate, glutamate, aspartate, citrate, succinate or tartrate.
3. Pharmaceutically acceptable salts of the compounds of formula I according to claim 1, wherein said salts are in particular oxalates, p-toluenesulphonates, D-tartrates, maleates, fumarates, L-glutamates, L-aspartates, acetates, benzoates, citrates, hydrobromides, phosphates, formates, benzenesulphonates, hydrochlorides or sulphates.
4. A pharmaceutically acceptable salt of a compound of formula I according to claim 2 or 3, wherein said salt is in particular:
the diacetate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
(iii) the monoacetate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the bisulphate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono maleate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a dimaleate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monobenzoate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a dibenzoate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono L-aspartate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the di-L-aspartate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono D-aspartate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-D-aspartate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono-oxalate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the di-oxalate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a mono-citrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the dicitrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono D-tartrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the di-D-tartrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono L-tartrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-L-tartrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono L-glutamate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-L-glutamate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono D-glutamate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-glutamate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono-p-toluenesulfonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
di-p-toluenesulfonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the monofumarate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the difumarate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a dihydrobromide salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monohydrobromide salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monophosphate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a diphosphate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the diformate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
monopropionate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
dipropionate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine
A monomalonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a dimalonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a diphenylsulfonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
(ii) the monosulfate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monohydrochloride salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the dihydrochloride salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine.
5. The pharmaceutically acceptable salt of the compound of formula I according to claim 4, wherein said salt is in particular:
the diacetate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the bisulphate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono maleate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monobenzoate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono L-aspartate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono-oxalate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a mono-citrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the mono D-tartrate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono L-glutamate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono-p-toluenesulfonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
mono-fumarate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the difumarate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a dihydrobromide salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the monophosphate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a diformate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
monopropionate of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a diphenylsulfonate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
(iv) the monosulfate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
a monohydrochloride salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the dihydrochloride salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine;
the hemifumarate salt of R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine.
6. A process for preparing a pharmaceutically acceptable salt of a compound of formula I as claimed in any one of claims 1 to 3 or 5, comprising the steps of:
(1) Adding a solvent into the compound of the formula I under the condition of stirring at room temperature until the compound is completely dissolved;
the solvent is selected from formamide, acetonitrile, methanol, ethanol, propanol, n-butanol, acetone, dioxane, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, bromoethane, benzene, chloropropane, toluene, carbon tetrachloride, carbon disulfide, cyclohexane, hexane and heptane;
(2) Slowly dripping acid or organic solvent solution of the acid, and fully stirring;
the acid or the organic solvent solution of the acid is acetic acid, oxalic acid, 4-aminosalicylic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, phthalic acid, butyric acid, camphorsulfonic acid, camphoric acid, cinnamic acid, 2,2-dichloroacetic acid, formic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, citric acid, fumaric acid, hydrogen chloride dioxane solution, hippuric acid, glycolic acid, hydrobromic acid, hydroiodic acid, lactic acid, maleic acid, propionic acid, malonic acid, glutamic acid, nitric acid, phosphoric acid, salicylic acid, perchloric acid, trifluoroacetic acid, sulfuric acid, glutamic acid, aspartic acid, citric acid, succinic acid or tartaric acid;
(3) Filtering and vacuum drying to obtain the pharmaceutically acceptable salt of the compound of the formula I.
7. The preparation method according to claim 6, wherein the solvent in step (1) is acetonitrile, methanol, ethanol, propanol, n-butanol, dioxane, tetrahydrofuran, ethyl acetate, dichloromethane or chloroform; preferably, the solvent in step (1) specifically refers to tetrahydrofuran or ethyl acetate.
8. The process according to claim 6, wherein the acid in the step (2) is oxalic acid, p-toluenesulfonic acid, D-tartaric acid, maleic acid, fumaric acid, L-glutamic acid, L-aspartic acid, acetic acid, benzoic acid, citric acid, hydrobromic acid, phosphoric acid, formic acid, benzenesulfonic acid, hydrochloric acid or sulfuric acid.
9. The process according to claim 6, wherein the molar ratio of the compound of formula I to the acid in step (1) is 1: (0.5-2); preferably, in step (1), the molar ratio of compound of formula I to acid is 1: (1-2).
10. The use of a pharmaceutically acceptable salt of a compound of formula I according to any one of claims 1 to 3 for the manufacture of a mu receptor agonist medicament; preferably, the use is in the preparation of an analgesic medicament; more preferably, the use is in the manufacture of a medicament for moderate to severe pain.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110821803 | 2021-07-21 | ||
| CN2021108218033 | 2021-07-21 | ||
| CN2021111063540 | 2021-09-22 | ||
| CN202111106354 | 2021-09-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115677675A true CN115677675A (en) | 2023-02-03 |
Family
ID=85060363
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210627814.2A Pending CN115677675A (en) | 2021-07-21 | 2022-06-06 | Salt of 6-oxaspiro [4,5] decane compound, preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115677675A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114269738A (en) * | 2020-08-10 | 2022-04-01 | 成都苑东生物制药股份有限公司 | MOR receptor agonist compound, preparation method and application thereof |
| CN116041336A (en) * | 2022-01-21 | 2023-05-02 | 成都苑东生物制药股份有限公司 | New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound |
| CN116589451A (en) * | 2022-02-11 | 2023-08-15 | 成都苑东生物制药股份有限公司 | New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound |
-
2022
- 2022-06-06 CN CN202210627814.2A patent/CN115677675A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114269738A (en) * | 2020-08-10 | 2022-04-01 | 成都苑东生物制药股份有限公司 | MOR receptor agonist compound, preparation method and application thereof |
| CN114269738B (en) * | 2020-08-10 | 2023-09-29 | 成都苑东生物制药股份有限公司 | MOR receptor agonist compound, preparation method and application thereof |
| CN116041336A (en) * | 2022-01-21 | 2023-05-02 | 成都苑东生物制药股份有限公司 | New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound |
| CN116589451A (en) * | 2022-02-11 | 2023-08-15 | 成都苑东生物制药股份有限公司 | New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN115677675A (en) | Salt of 6-oxaspiro [4,5] decane compound, preparation method and application | |
| EP1392307B1 (en) | Tartrate salts of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene | |
| EP3610875A1 (en) | Opioid receptor (mor) agonist salt, fumarate salt i crystal form thereof and preparation method thereof | |
| CN111233737B (en) | Salts of heteroaromatic derivatives and use thereof | |
| AU2020222083B2 (en) | Crystalline pyrimidinyl-3,8-diazabicyclo(3.2.1)octanylmethanone compound and use thereof | |
| EP3722286B1 (en) | Salt of a phenylpropionamide derivative and preparation method therefor | |
| TW202140466A (en) | Salts and crystalline forms of a taar1 agonist | |
| JP2022543924A (en) | Benzopyrazole Compounds as RHO Kinase Inhibitors, Salt Forms, Crystal Forms and Methods of Making Same | |
| AU2003248910B2 (en) | Naphthalimide synthesis including amonafide synthesis and pharmaceutical preparations thereof | |
| US9409857B2 (en) | Agomelatine sulfuric acid complex, and preparation method and application thereof | |
| CN114853762A (en) | Solid form of imidazotriazine compound and preparation method and application thereof | |
| EP4310080A1 (en) | Polymorphic forms of compound and preparation method therefor and application thereof | |
| EP2922838B1 (en) | Solid forms of {s-3-(4-amino-1-oxo-isoindolin-2-yl)(piperidine-3,4,4,5,5-d5)-2,6-dione} . | |
| JP2011503146A (en) | Novel 1,4-diaza-bicyclo [3.2.2] nonylpyrimidine derivatives and their medical use | |
| EP3988560A1 (en) | Small-molecule compound having a2a adenosine receptor antagonism | |
| US11225462B2 (en) | Crystal forms of oxypyridine amide derivative and preparation method therefor | |
| WO2024009977A1 (en) | 5h-pyrrolo[2,3-d]pyrimidin-6(7h)-one and crystal of salt thereof | |
| CN111362859B (en) | Salts of heteroaromatic derivatives and use thereof | |
| EP4177257A1 (en) | Succinate of octahydrothienoquinoline compound, and crystals thereof | |
| JP4469280B2 (en) | Muscarinic agonist | |
| US20210253576A1 (en) | Pyrazolopyrimidine derivative, use thereof and pharmaceutical composition | |
| CN117480153A (en) | Azabicyclo [3.1.0] hexane compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |