CN112694414B - 一类取代苯酚羟基酸酯含n衍生物、制备和用途 - Google Patents
一类取代苯酚羟基酸酯含n衍生物、制备和用途 Download PDFInfo
- Publication number
- CN112694414B CN112694414B CN202011111247.2A CN202011111247A CN112694414B CN 112694414 B CN112694414 B CN 112694414B CN 202011111247 A CN202011111247 A CN 202011111247A CN 112694414 B CN112694414 B CN 112694414B
- Authority
- CN
- China
- Prior art keywords
- compound
- salt
- propofol
- cyclohexane
- ethyl acetate
- 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.)
- Active
Links
- -1 phenol hydroxy acid ester Chemical class 0.000 title claims abstract description 84
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 239000003814 drug Substances 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 229940079593 drug Drugs 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 125000002947 alkylene group Chemical group 0.000 claims description 19
- 241001465754 Metazoa Species 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 230000003444 anaesthetic effect Effects 0.000 claims description 7
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 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 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000932 sedative agent Substances 0.000 claims description 2
- 230000001624 sedative effect Effects 0.000 claims description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims 2
- 229940050410 gluconate Drugs 0.000 claims 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 claims 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 claims 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 claims 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 claims 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 claims 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical class [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 claims 1
- 229910002651 NO3 Inorganic materials 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 229920002230 Pectic acid Polymers 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 229920002253 Tannate Polymers 0.000 claims 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 claims 1
- 229940072056 alginate Drugs 0.000 claims 1
- 235000010443 alginic acid Nutrition 0.000 claims 1
- 229920000615 alginic acid Polymers 0.000 claims 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 claims 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims 1
- 229940072107 ascorbate Drugs 0.000 claims 1
- 235000010323 ascorbic acid Nutrition 0.000 claims 1
- 239000011668 ascorbic acid Substances 0.000 claims 1
- 229940009098 aspartate Drugs 0.000 claims 1
- 229940077388 benzenesulfonate Drugs 0.000 claims 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims 1
- 229940050390 benzoate Drugs 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 claims 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims 1
- 229940114081 cinnamate Drugs 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 1
- 229940109275 cyclamate Drugs 0.000 claims 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 claims 1
- BALGDZWGNCXXES-UHFFFAOYSA-N cyclopentane;propanoic acid Chemical compound CCC(O)=O.C1CCCC1 BALGDZWGNCXXES-UHFFFAOYSA-N 0.000 claims 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 claims 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-M dichloroacetate Chemical compound [O-]C(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-M 0.000 claims 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical class CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims 1
- 229940043264 dodecyl sulfate Drugs 0.000 claims 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 claims 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims 1
- 229940114119 gentisate Drugs 0.000 claims 1
- 229940097042 glucuronate Drugs 0.000 claims 1
- 229930195712 glutamate Natural products 0.000 claims 1
- 229940049906 glutamate Drugs 0.000 claims 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 1
- 125000000743 hydrocarbylene group Chemical group 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims 1
- 239000008101 lactose Substances 0.000 claims 1
- 229940070765 laurate Drugs 0.000 claims 1
- 229940049920 malate Drugs 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical class OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical class [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims 1
- XTEGVFVZDVNBPF-UHFFFAOYSA-L naphthalene-1,5-disulfonate(2-) Chemical class C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-L 0.000 claims 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical class C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 claims 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims 1
- 229940049964 oleate Drugs 0.000 claims 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 229940075930 picrate Drugs 0.000 claims 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 claims 1
- 229950010765 pivalate Drugs 0.000 claims 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims 1
- 229940043131 pyroglutamate Drugs 0.000 claims 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims 1
- 229960001860 salicylate Drugs 0.000 claims 1
- 229940116351 sebacate Drugs 0.000 claims 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 claims 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims 1
- 239000000779 smoke Chemical class 0.000 claims 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims 1
- 229940095064 tartrate Drugs 0.000 claims 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 27
- 150000002989 phenols Chemical class 0.000 abstract description 23
- 206010002091 Anaesthesia Diseases 0.000 abstract description 6
- 230000009471 action Effects 0.000 abstract description 6
- 230000037005 anaesthesia Effects 0.000 abstract description 6
- 238000001727 in vivo Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 6
- 230000000144 pharmacologic effect Effects 0.000 abstract 2
- 206010039897 Sedation Diseases 0.000 abstract 1
- 238000001949 anaesthesia Methods 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 230000036280 sedation Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- 239000007787 solid Substances 0.000 description 58
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 57
- 229960004134 propofol Drugs 0.000 description 57
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 54
- 229940002612 prodrug Drugs 0.000 description 40
- 239000000651 prodrug Substances 0.000 description 40
- 238000000967 suction filtration Methods 0.000 description 37
- 238000001035 drying Methods 0.000 description 30
- 238000003756 stirring Methods 0.000 description 29
- 239000012065 filter cake Substances 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- 230000002829 reductive effect Effects 0.000 description 26
- 239000002904 solvent Substances 0.000 description 24
- 238000001704 evaporation Methods 0.000 description 23
- 239000012043 crude product Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- 239000007789 gas Substances 0.000 description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- 229940089960 chloroacetate Drugs 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 210000002381 plasma Anatomy 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 125000004452 carbocyclyl group Chemical group 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 229910052731 fluorine Inorganic materials 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 8
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 8
- 229910052740 iodine Inorganic materials 0.000 description 8
- 238000011084 recovery Methods 0.000 description 8
- 230000008901 benefit Effects 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- QVNNONOFASOXQV-UHFFFAOYSA-N fospropofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1OCOP(O)(O)=O QVNNONOFASOXQV-UHFFFAOYSA-N 0.000 description 7
- 229960000239 fospropofol Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 231100001274 therapeutic index Toxicity 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 238000010626 work up procedure Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- VIWZVFVJPXTXPA-UHFFFAOYSA-N N-(2-Carboxymethyl)-morpholine Chemical compound OC(=O)CN1CCOCC1 VIWZVFVJPXTXPA-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 229940106681 chloroacetic acid Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 231100000636 lethal dose Toxicity 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ATVFTGTXIUDKIZ-YFKPBYRVSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-sulfanylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CS)C(O)=O ATVFTGTXIUDKIZ-YFKPBYRVSA-N 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- JQAOHGMPAAWWQO-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCCC1C(O)=O JQAOHGMPAAWWQO-UHFFFAOYSA-N 0.000 description 2
- JCXZKUZXVQKENT-UHFFFAOYSA-N 2-(4-methylpiperazin-1-ium-1-yl)acetate Chemical compound CN1CCN(CC(O)=O)CC1 JCXZKUZXVQKENT-UHFFFAOYSA-N 0.000 description 2
- VRDBIJCCXDEZJN-UHFFFAOYSA-N 2-piperidin-1-ylacetic acid Chemical compound OC(=O)CN1CCCCC1 VRDBIJCCXDEZJN-UHFFFAOYSA-N 0.000 description 2
- KVXXEKIGMOEPSA-UHFFFAOYSA-N 4-[(2-methylpropan-2-yl)oxycarbonyl]morpholine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCOCC1C(O)=O KVXXEKIGMOEPSA-UHFFFAOYSA-N 0.000 description 2
- PJCXUSBLNCTAJP-UHFFFAOYSA-N 4-methylmorpholine-3-carboxylic acid Chemical compound CN1CCOCC1C(O)=O PJCXUSBLNCTAJP-UHFFFAOYSA-N 0.000 description 2
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- BPSLZWSRHTULGU-UHFFFAOYSA-N Methylpipecolic acid Chemical compound CN1CCCCC1C(O)=O BPSLZWSRHTULGU-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000002567 autonomic effect Effects 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000003193 general anesthetic agent Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000028527 righting reflex Effects 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 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 1
- 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 1
- 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 1
- 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 1
- QVHJQCGUWFKTSE-RXMQYKEDSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-RXMQYKEDSA-N 0.000 description 1
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- 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 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 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 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006025 1-methyl-1-butenyl group Chemical group 0.000 description 1
- 125000006044 1-methyl-1-pentenyl group Chemical group 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- QCYOIFVBYZNUNW-UHFFFAOYSA-N 2-(dimethylazaniumyl)propanoate Chemical compound CN(C)C(C)C(O)=O QCYOIFVBYZNUNW-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- YRXIMPFOTQVOHG-UHFFFAOYSA-N 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]acetic acid Chemical compound OC(=O)CN(C)C(=O)OC(C)(C)C YRXIMPFOTQVOHG-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- IBZKBSXREAQDTO-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)ethanamine Chemical compound COCCNCCOC IBZKBSXREAQDTO-UHFFFAOYSA-N 0.000 description 1
- 125000006045 2-methyl-1-pentenyl group Chemical group 0.000 description 1
- YIYIZNFJAFZARX-UHFFFAOYSA-N 2-methyl-2-(methylamino)-3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoic acid Chemical compound CNC(C)(C(O)=O)C(=O)OC(C)(C)C YIYIZNFJAFZARX-UHFFFAOYSA-N 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- 125000006031 2-methyl-3-butenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- 241000282461 Canis lupus Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- QCYOIFVBYZNUNW-BYPYZUCNSA-N N,N-dimethyl-L-alanine Chemical compound CN(C)[C@@H](C)C(O)=O QCYOIFVBYZNUNW-BYPYZUCNSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 239000005844 Thymol Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 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 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- AGUWUIVKDXDKBT-UHFFFAOYSA-N phenyl 2-chloroacetate Chemical class ClCC(=O)OC1=CC=CC=C1 AGUWUIVKDXDKBT-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000002616 plasmapheresis Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- MQDVUDAZJMZQMF-UHFFFAOYSA-N pyridin-2-ylurea Chemical compound NC(=O)NC1=CC=CC=N1 MQDVUDAZJMZQMF-UHFFFAOYSA-N 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 231100000691 up-and-down procedure Toxicity 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/16—Halogenated acetic acids
- C07C53/18—Halogenated acetic acids containing fluorine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Anesthesiology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一类取代苯酚羟基酸酯含N衍生物、制备和用途。所述的化合物如式(Ⅰ)所示。式(I)化合的盐具备良好的水溶性,且在体内可迅速、完全地释放出具有药理作用的取代苯酚类物质,在改善取代苯酚类物质水溶性的同时,迅速发挥取代苯酚在体内的药理作用,安全性好。上述化合物的制备方法和它们在制备对人和动物产生麻醉和/或镇静催眠作用的药物中的应用。
Description
技术领域
本发明涉及一类取代苯酚的水溶性前药分子的化学结构,制备方法和用途,这类分子可在体内迅速分解释放出具有活性的取代苯酚,起效快,取代苯酚利用率高,药物摄入量小。
背景技术
本发明属于化学药物中前药研究领域。前药是一类没有活性,进入体内经酶促释放出具有活性的原型药物而发挥疗效的药物。与原型药物相比,前药分子因化学结构的明显变化,获得了与原型药物不同的理化性质,如水溶性的变化、脂溶性的变化、稳定性的变化等等。利用前药设计,可以改善原型药物的缺点,增加其疗效、耐受性、工业适用性等。丙泊酚是临床一线静脉全身麻醉药物,其本身难溶于水,目前临床制剂为乳剂。乳剂的制备成本高,易受细菌污染,注射疼痛发生率高,长时间使用还会导致个体的脂质代谢紊乱(Macario,A.,Weinger,M.,Truong,P.,Lee,M.,1999.Anesth.Analg.88,1085–1091;Bennett,S.N.,McNeil,M.M.,Bland,L.A.,Arduino,M.J.,Villarino,M.E.,Perrotta,D.M.,et al.,1995.N.Engl.J.Med.333(3),147–154;Kam,P.C.,Cardone,D.,2007.Anesthesia 62(7),690–701;Wolf,A.,Weir,P.,Segar,P.,Stone,J.,Shield,J.,2001.Lancet 357(9256),606–607))。因此,丙泊酚水溶性前药一直是药物研发的热点。将丙泊酚与水溶性分子经共价键连接,可以获得水溶性改善的前药分子,如丙泊酚-氨基酸偶联物(Gallop,Mark A.,Xu,Feng,Cundy,Kenneth C.,Sasikumar,Vivek,Woiwode,ThomasW.,2005.US20050004381)、丙泊酚糖基偶联物(Brian,Shull,John,Baldwin,Ramesh,Gopalaswamy,Zishan,Haroon,2012.WO2012142141)、丙泊酚磷酸偶联物(Fechner,J.,Ihmsen,H.,Hatterscheid,D.,Jeleazcov,C.,Schiessl,C.,Vornov,J.J.,Schwilden,H.,Schüttler,J.,2004.Anesthesiology 101(3),626–639)、丙泊酚有机多元酸偶联物(Hendler,Sheldon S.,2002.WO2002013810)、丙泊酚寡聚乙二醇偶联物(Tao Deng,Xianglan Mao,Yu Li,Shaowei Bo,Zhigang Yang,Zhong-Xing Jiang,2018.Bioorganic&Medicinal Chemistry Letters 28,3502–3505)等等,众多的丙泊酚水溶性衍生物被合成,并试图将它们开发为药品。2008年,第一个丙泊酚水溶性前药Fospropofol在美国上市,但随后撤市,原因不明,截止2019年,未见新的丙泊酚水溶性前药上市。
丙泊酚的最大临床优势表现在起效迅速,停药后恢复迅速,临床医生希望丙泊酚水溶性前药也能保留这种优势。如果丙泊酚水溶性前药在体内无法快速释放出丙泊酚,那么这种前药将丧失快速起效的优点;进一步地,如果前药释放原药速度缓慢,为了维持有效的原型药物血药浓度,就不得不增加前药的剂量,而体内剩余的前药将持续释放丙泊酚,导致苏醒延迟。Fospropofol的起效时间和麻醉维持时间均显著长于丙泊酚,原因正是由于其在体内释放丙泊酚缓慢。因此,已经有学者提出:加快丙泊酚前药在体内的原药释放速度,提高原药的分子利用率,是这类前药的开发关键,这不仅可以保留丙泊酚的临床优势,还可以减少前药的摄入量,有利于苏醒质量的改善,并增加安全性(Weiyi Zhang,Jun Yang,Jing Fan,Bin Wang,Yi Kang,Jin Liu,Wensheng Zhang,Tao Zhu.European Journal ofPharmaceutical Sciences,2019,9~13.)。
上述情况要求丙泊酚水溶性前药在体外要具有足够的稳定性以便能够生产、运输和储存;而进入体内后前药必须尽快释放出丙泊酚,以便快速起效并在停药后确保病人快速恢复。这种相互矛盾的要求使得丙泊酚水溶性前药的开发难度巨大,在保证安全性的情况下,目前尚未见任何一种丙泊酚前药能够同时满足上述要求,这种情况限制了这类药物的研发。
针对上述问题,本发明提供一类包括丙泊酚在内的取代苯酚的水溶性前药。这类分子在体外稳定,且具有良好的水溶性;进入体内在血浆的作用下可以迅速并完全释放出分子中携带的取代苯酚。这类分子经静脉给药,可以在注射完毕后立即产生麻醉效果;由于释放迅速,这类分子产生麻醉作用所需时间与直接使用丙泊酚引起麻醉所需的时间相当,有效剂量下前药的摩尔量与有效剂量的丙泊酚的摩尔量接近,因而不会引起因前药释放原药缓慢所致的苏醒延迟,实验中动物的苏醒速度快,苏醒质量好,且与丙泊酚对照组动物相比没有差异。本发明提供的这类分子彻底解决了丙泊酚前药释放原药缓慢的问题,最大限度降低了原型药物的摄入量,安全性好,具有良好的应用前景。综上,本发明式(Ⅰ)化合物及其药学上可接受的盐,可用于制备对动物或人产生镇静催眠和/或麻醉作用的中枢抑制性药物。
发明内容
本发明提供一类包括丙泊酚在内的取代苯酚的水溶性前体分子,制备方法和用途。这类分子在有效剂量下,在动物体内可快速分解释放出取代苯酚,迅速产生药效,无原药释放慢而引起的蓄积效应,在改善取代苯酚的水溶性的前提下,保留了取代苯酚快速起效和快速恢复的优势。
本发明所述的取代苯酚羟基酸酯含N衍生物,结构如式(Ⅰ)所示:
其中,R1~R5各自任选为H,C1~6的直链或支链或环状烃基,卤素,C1~4的烷氧基,氰基、硝基、酯基等;R6~9各自任选为H,C1~8的直链或支链或环状烃基;当R6和R7之间由共价键连接时,R6和R7还可以是C1~3的亚烃基;当R7和R8之间由共价键连接时,R7和R8还可以是C1~3的亚烃基;R1~9的骨架上的H可以被卤素、羟基、巯基、氨甲酰基、胍基、羧基、4-咪唑基、苯基、羟苯基、β-吲哚基等取代,R1~9骨架中可以含有O,S,N等杂原子。
式(Ⅰ)化合物的盐,包括但不限于:乙酸盐、己二酸盐、藻酸盐、4-氨基水杨酸盐、抗坏血酸盐、天门冬氨酸盐、谷氨酸盐、焦谷氨酸、苯磺酸盐、苯甲酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、碳酸盐、肉桂酸盐、柠檬酸盐、环己氨磺酸盐、环戊烷丙酸盐、癸酸盐、2,2-二氯乙酸盐、重葡萄糖酸盐、十二烷基硫酸盐、乙烷-1,2-二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、粘酸盐、龙胆酸盐、葡庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、甘油磷酸盐、羟乙酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、异丁酸盐、乳酸盐、乳糖醛酸盐、月桂酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、萘-1,5-二磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、辛酸盐、油酸盐、乳清酸盐、草酸盐、2-氧戊二酸盐、棕榈酸盐、扑酸盐、果胶酯酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、癸二酸盐、癸二酸氢盐、硬脂酸盐、琥珀酸盐、硫酸盐、鞣酸盐、酒石酸盐、酒石酸氢盐、硫氰酸盐、甲苯磺酸盐或十一酸盐、硫化氢盐、钠盐、铵盐。
进一步地,式(Ⅰ)所述的化合物各取代基的范围优选为:R1~R5各自任选为H,C1~6的直链或支链或环状烃基;R6~9各自任选为H,C1~8的直链或支链或环状烃基;R1~9的骨架上的H可以被羟基、巯基、氨甲酰基、胍基、羧基、4-咪唑基、苯基、羟苯基、β-吲哚基等取代,R1~9骨架中可以含有O,S,N等杂原子;
或者,式(Ⅰ)所述的化合物各取代基的范围优选为:R1~R5各自任选为H,C1~6的直链或支链或环状烃基;R6和R7之间由共价键连接,R6和R7为C1~3的亚烃基;R8和R9为H,C1~8的直链或支链或环状烃基。
或者,式(Ⅰ)所述的化合物各取代基的范围优选为:R1~R5各自任选为H,C1~6的直链或支链或环状烃基;R7和R8之间由共价键连接,R7和R8为C1~3的亚烃基;R6和R9为H,C1~8的直链或支链或环状烃基。
更进一步地,式(Ⅰ)所述的化合物各取代基的范围优选为:R1和R5为异丙基;R2~R4为H;R6~9各自任选为H,C1~8的直链或支链或环状烃基;当R6和R7之间由共价键连接时,R6和R7还可以是C1~3的亚烃基;当R7和R8之间由共价键连接时,R7和R8还可以是C1~3的亚烃基;R1~9的骨架上的H可以被卤素、羟基、巯基、氨甲酰基、胍基、羧基、4-咪唑基、苯基、羟苯基、β-吲哚基等取代,骨架中可以含有O,S,N等杂原子。这类化合物的优选具体分子有:
或者更进一步地,,式(Ⅰ)所述的化合物各取代基的范围优选为:R1为异丙基;R5为R2~R4为H;R6~9各自任选为H,C1~8的直链或支链或环状烃基;当R6和R7之间由共价键连接时,R6和R7还可以是C1~3的亚烃基;当R7和R8之间由共价键连接时,R7和R8还可以是C1~3的亚烃基;R1~9的骨架上的H可以被卤素、羟基、巯基、氨甲酰基、胍基、羧基、4-咪唑基、苯基、羟苯基、β-吲哚基等取代,R1~9骨架中可以含有O,S,N等杂原子。这类化合物的优选具体分子有:
根据本领域的常识,式(Ⅰ)化合物,及其立体异构体,同位素取代物,药学上可接受的盐,溶剂合物,药物组合物,与药学上可接受的辅料/载体/赋形剂形成的制剂等,均有可能在制备对人或动物产生中枢镇静和/或麻醉效果的药物中进行应用。
本专利所述的化合物的制备可按照如下通法制备:
首先使用氯乙酰氯与取代苯酚(a)成酯得到取代苯酚的氯乙酸酯类化合物(b),随后(b)与含氮羧酸化合物(c)在碱性条件下发生亲核取代反应生成目标化合物(Ⅰ)的游离碱,此游离碱与不同种类的酸可形成不同的盐。若(Ⅰ)的分子中含有羧基,(Ⅰ)还可与碳酸钠等碱性试剂反应得到(Ⅰ)的盐。上述合成通法中氯乙酰氯还可被活性更高的溴乙酰溴替换。
上述反应过程中,含氮羧酸化合物(c)中N原子若为伯胺或仲胺,可先使用保护基(如BOC保护)保护其氨基之后,再与(b)反应得到含有保护基的中间体,随后脱去氨基保护基得到目标化合物(Ⅰ)。
除非有相反的陈述,在说明书和权利要求中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代(即同位素取代物),其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)和氚(T,又称为超重氢),氧的同位素包括16O、17O、和18O,硫的同位素包括32S、33S、34S、和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素35Cl和37Cl,溴的同位素79Br和81Br。
“烃基”是指仅含有碳和氢原子的直链或支链或环状的一价取代基,主链包括1至10个碳原子,优选为1至8个碳原子,进一步优选为1至6个碳原子。烃基可以是直链或支链或环状的烷基/烯基/炔基。所述的烃基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR10、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-(C=O)-SR10、-(CH2)a-(C=O)-O-R10、-(CH2)a-(C=O)-NR10R10a、-(CH2)a-S(C=O)b-R10、-O-(=O)-O-R10或者-NR10R10a的取代基所取代,其中R10和R10a各自独立选自H、羟基、氨基、羧基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、3至10元碳环基、4至10元杂环基、3至10元碳环氧基或者4至10元杂环基氧基,a选自0、1、2、3、4或者5,b选自0、1或者2。本文中出现的烷基、a、b、R10和R10a,其定义如上所述。
“烷基”是指直链和支链的一价饱和烃基,主链包括1至10个碳原子,优选为1至8个碳原子,进一步优选为1至6个碳原子,更优选为1至4个碳原子的直链与支链基团,最优选为1至两个碳原子,烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、正己基、正庚基、正辛基、正壬基和正癸基;所述的烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR10、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-(C=O)-SR10、-(CH2)a-(C=O)-O-R10、-(CH2)a-(C=O)-NR10R10a、-(CH2)a-S(C=O)b-R10、-O-(=O)-O-R10或者-NR10R10a的取代基所取代,其中R10和R10a各自独立选自H、羟基、氨基、羧基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、3至10元碳环基、4至10元杂环基、3至10元碳环氧基或者4至10元杂环基氧基,a选自0、1、2、3、4或者5,b选自0、1或者2。本文中出现的烷基、a、b、R10和R10a,其定义如上所述。
“亚烃基”是指直链和支链的二价饱和或不饱和烃。其中饱和亚烃基又称为亚烷基,表示为:—(CH2)k—(k为1至10的整数)。亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基;所述的亚烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR10、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-(C=O)-SR10、-(CH2)a-(C=O)-O-R10、-(CH2)a-(C=O)-NR10R10a、-(CH2)a-S(C=O)b-R10、-O-(=O)-O-R10或者-NR10R10a的取代基所取代,当亚烷基中的取代基数量大于等于2个时,取代基可以稠和在一起形成环状结构。本文中出现的亚烷基,其定义如上所述。
“烷氧基”是指O-烷基的一价基团,其中,烷基如本文所定义,烷氧基实施例包括但不限于甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、1-戊氧基、2-戊氧基、3-戊氧基、2-甲基-2-丁氧基、3-甲基-2-丁氧基、3-甲基-1-丁氧基和2-甲基-1-丁氧基等。本文中出现的烷氧基,其定义如上所述。
“烯基”是指直链和支链的一价不饱和烃基,其具有至少一个,通常有1、2或3个碳碳双键,主链包括2至10个碳原子,进一步优选2至6个碳原子,更优选在主链上有2至4个碳原子,烯基实施例包括但不限于乙烯基、丙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和、1,4-己二烯等;所述的烯基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR10、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-(C=O)-SR10、-(CH2)a-(C=O)-O-R10、-(CH2)a-(C=O)-NR10R10a、-(CH2)a-S(C=O)b-R10、-O-(=O)-O-R10或者-NR10R10a的取代基所取代。本文中出现的烯基,其定义如上所述。
“炔基”是指直链和支链的一价不饱和烃基,其具有至少一个,通常有1、2或3个碳碳三键,主链包括但不限于乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、3-戊炔基、4-戊炔基、1-甲基-2-丁炔基、2-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基和4-壬炔基等;所述的炔基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR10、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-(C=O)-SR10、-(CH2)a-(C=O)-O-R10、-(CH2)a-(C=O)-NR10R10a、-(CH2)a-S(C=O)b-R10、-O-(=O)-O-R10或者-NR10R10a的取代基所取代。本文中出现的炔基,其定义如上所述。
“环烷基”是指一价饱和的碳环烃基,通常有3至10个碳原子,非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。所述的环烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR10、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-(C=O)-SR10、-(CH2)a-(C=O)-O-R10、-(CH2)a-(C=O)-NR10R10a、-(CH2)a-S(C=O)b-R10、-O-(=O)-O-R10或者-NR10R10a的取代基所取代。本文中出现的环烷基,其定义如上所述。
“碳环”是指饱和或者不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至10元的单环4至12元双环或者10至15元三环体系,碳环基可以连接有桥环或者螺环,非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、、环己二烯基、换庚基、环辛基、环壬基、环癸基、环十一烷基、换十二烷基、苯基、或萘基。所述的碳环基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR10、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-(C=O)-SR10、-(CH2)a-(C=O)-O-R10、-(CH2)a-(C=O)-NR10R10a、-(CH2)a-S(C=O)b-R10、-O-(=O)-O-R10或者-NR10R10a的取代基所取代。本文中出现的碳环,其定义如上所述。
“杂环”是指饱和或不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至10元的单环、4至10元双环或者10至15元三环体系,且包含1至4个选自N、O或S的杂原子,优选3至8元杂环基,杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上,杂环基可以连接有桥环或者螺环,非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1-3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、苯并咪唑基、苯并吡啶基、吡咯并吡咯基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、二氢噻吩基、吡唑烷基、咪唑啉基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR10、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-(C=O)-SR10、-(CH2)a-(C=O)-O-R10、-(CH2)a-(C=O)-NR10R10a、-(CH2)a-S(C=O)b-R10、-O-(=O)-O-R10或者-NR10R10a的取代基所取代。本文中出现的杂环,其定义如上所述。
“任选”是指随后所描述的事情或环境可以但不必须发生,该说明包括事件或环境发生或不发生的场合。
“药物组合物”表示一种或多种文本所述的化合物或其生理学/药学上可接受的盐与其它组成成分的混合物,其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“有效剂量”指引起组织、系统或受试者生理或医学翻译的化合物的量,此量是所寻求的,包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“溶剂合物”指本发明化合物或其盐,它们包括以分子间非共价力结合的化学计量或非化学计量的溶剂。当溶剂为水时,则为水合物。
以下结合由实施例的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。在不脱离本发明上述技术思想的情况下,根据本领域普通技术知识和惯用手段做出的各种替换或变更,均应包括在本发明的范围内。
具体实施方式
实施例1
将丙泊酚(178mg,1mmoL)与氯乙酰氯(124mg,1.1mmoL)溶解在10mL二氯甲烷中,冰浴下加入吡啶(237mg,3mmoL),回复至室温搅拌2小时,蒸干溶剂,残余物经硅胶柱层析(环己烷/乙酸乙酯=20/1)得无色油状物180mg,即中间体b,产率70.6%。
将中间体b(180mg,71mmoL)与BOC-甘氨酸(140mg,80mmoL)混合在10mL DMF中,加入无水碳酸钾(290mg,210mmoL),室温搅拌8小时,过滤,滤液冲入100mL水中,用50mL乙酸乙酯萃取,分出有机层,无水硫酸钠干燥过夜,次日过滤,滤液减压蒸干,残余物经柱层析(环己烷/乙酸乙酯=5/1)得白色固体粉末183mg,即中间体c,产率66%。将183mg中间体c溶解在10mL乙酸乙酯中,通入过量的干燥氯化氢气体,室温搅拌1小时,减压蒸干溶剂,得到粗产物。将粗产物用环己烷润洗3次,抽滤,滤饼在65℃下烘干得到白色固体,即得115mg目标化合物1,产率75%。
1H NMR(400MHz,DMSO-d6):δ8.52(s,3H),7.23~7.31(m,3H),5.29(s,2H),4.00(s,2H),2.94(hept,J=6.9Hz,2H),1.13(d,J=6.8Hz,12H).
实施例2
如实施例1所述方法制备中间体b。将中间体b(180mg,71mmoL)与BOC-肌氨酸(151mg,80mmoL)混合在10mL DMF中,加入无水碳酸钾(290mg,210mmoL),室温搅拌8小时,过滤,滤液冲入100mL水中,用50mL乙酸乙酯萃取,分出有机层,无水硫酸钠干燥过夜,次日过滤,滤液减压蒸干,残余物经柱层析(环己烷/乙酸乙酯=5/1)得白色固体粉末186mg,即中间体c,产率64.5%。将186mg中间体c溶解在10mL乙酸乙酯中,通入过量的干燥氯化氢气体,室温搅拌1小时,减压蒸干溶剂,得到粗产物。将粗产物用环己烷润洗3次,抽滤,滤饼在65℃下烘干得到白色固体,即得113mg目标化合物2,产率72%。
1H NMR(400MHz,DMSO-d6):δ9.46(s,2H),7.23~7.31(m,3H),5.31(s,2H),4.17(s,2H),2.94(hept,J=6.8Hz,2H),2.59(s,3H),1.13(d,J=6.8Hz,12H).
实施例3
如实施例1所述方法制备中间体b。将中间体b(180mg,71mmoL)与N,N-二甲基甘氨酸(82.4mg,80mmoL)混合在10mL DMF中,加入无水碳酸钾(290mg,210mmoL),室温搅拌8小时,过滤,滤液冲入100mL水中,用50mL乙酸乙酯萃取,分出有机层,无水硫酸钠干燥过夜,次日过滤,滤液减压蒸干,残余物经柱层析(环己烷/乙酸乙酯=30:1)化合物3的游离碱123mg。将化合物3的游离碱123mg溶于10mL乙酸乙酯,通入干燥后的氯化氢气体1小时,室温搅拌2小时,减压蒸干溶剂,得到粗产物。将粗产物用环己烷润洗3次,抽滤,滤饼在65℃下烘干得到白色固体,即得87.6mg目标化合物3,产率64%。
1H NMR(400MHz,DMSO-d6):δ10.78(s,1H),7.23~7.31(m,3H),5.32(s,2H),4.42(s,2H),2.94(hept,J=6.9Hz,2H),2.85(s,6H),1.13(d,J=6.8Hz,12H).
实施例4
将Boc-L-丙氨酸(1.49g,7.87mmol)和丙泊酚氯乙酸酯(2g,7.85mmol)溶于DMF(10mL)中并在室温下搅拌40分钟。然后将K2CO3(1.19g,8.6mmol)加入到该溶液中,并将该反应溶液在70℃下搅拌4小时,过滤,滤液用乙酸乙酯(100mL)和水(50mL)萃取产物,并将有机层用水(3×50mL)多次洗涤,并用无水硫酸钠干燥。通过柱层析(环己烷/乙酸乙酯从40:1至20:1)纯化粗产物,得到2.18g白色固体,即中间体a,收率68%。将中间体a(2.18g,5.35mmol)溶于50mL乙酸乙酯,同干燥氯化氢气体1小时,室温下搅拌反应4h。减压蒸除乙酸乙酯,得到粗品。将粗产物用环己烷润洗3次,抽滤,滤饼在65℃下烘干得到白色固体1.28g,即目标化合物4,产率为69.6%。
1H NMR(400MHz,DMSO-d6):δ8.66(s,3H),7.23~7.31(m,3H),5.29(d,J=2.4Hz,2H),4.26(q,J=7.1Hz,1H),2.93(hept,J=6.9Hz,2H),1.48(d,J=7.2Hz,3H),1.13(d,J=6.8Hz,12H).
实施例5
将Boc-D-丙氨酸(1.49g,7.87mmol)和丙泊酚氯乙酸酯(2g,7.85mmol)溶于DMF(10mL)中并在室温下搅拌40分钟。然后将K2CO3(1.19g,8.6mmol)加入到该溶液中,并将该反应溶液在70℃下搅拌4小时,过滤,滤液用乙酸乙酯(100mL)和水(50mL)萃取产物,并将有机层用水(3×50mL)多次洗涤,并用无水硫酸钠干燥。通过柱层析(环己烷/乙酸乙酯从40:1至20:1)纯化粗产物,得到2.01g白色固体,即中间体a,收率62.8%。将中间体a(2.01g,4.93mmol)溶于50mL乙酸乙酯,通干燥氯化氢气体1小时,室温下搅拌反应4小时。减压蒸除乙酸乙酯,得到粗品。将粗产物用环己烷润洗3次,抽滤,滤饼在65℃下烘干得到白色固体1.15g,即目标化合物5,产率62.5%。
1H NMR(400MHz,DMSO-d6):δ8.69(s,3H),7.21~7.30(m,3H),5.24(d,J=2.4Hz,2H),4.29(q,J=7.2Hz,1H),2.91(hept,J=6.9Hz,2H),1.44(d,J=7.2Hz,3H),1.11(d,J=6.8Hz,12H).
实施例6
将(R)-2-环丙基乙基-6-异丙基苯酚(CAS:1637741-58-2,204mg,1mmoL)与氯乙酰氯(124mg,1.1mmoL)溶解在10mL二氯甲烷中,冰浴下加入吡啶(237mg,3mmoL),回复至室温搅拌2小时,蒸干溶剂,残余物经硅胶柱层析(环己烷/乙酸乙酯=20/1)得无色油状物186mg,即中间体a,产率66%。将中间体a(186mg,0.66mmoL)与吗啉-4-基乙酸(96mg,0.66mmoL)溶于DMF(20mL)中并在室温下搅拌40分钟。然后将K2CO3(97mg,0.7mmol)加入到该溶液中,并将该反应溶液在70℃下搅拌4小时。冷却反应液,加入水(100mL),用乙酸乙酯(200mL)萃取产物,并用水洗涤有机层用(3×100mL),分出有机层,无水硫酸钠干燥。次日过滤,滤液蒸干溶剂得粗品,经硅胶柱层析(环己烷/乙酸乙酯从30:1)得到141mg无色油状物,即中间体b,收率为55%。将141mg中间体b溶于3mL三氟醋酸,室温搅拌30分钟,减压蒸干多余三氟醋酸,向残余物中加入20mL环己烷,析出固体,过滤,用环己烷润洗固体3次,抽滤,滤饼在65℃下烘干得到白色固体114.7mg,收率63%。
1H NMR(400MHz,DMSO-d6):δ11.23(s,1H),7.30~7.36(3H,m),5.36(2H,s),4.41(2H,s),3.82~3.89(m,4H),3.21~3.28(m,5H),2.55~2.58(m,1H),1.31(d,J=7.2Hz,3H),1.26(d,J=7.2Hz,6H),1.03~1.07(m,1H),0.42~0.52(m,2H),0.17~0.25(m,2H).
实施例7
将等摩尔的4-甲基-1-哌嗪乙酸(CAS:54699-92-2)与等摩尔的氯乙酸丙泊酚酯溶于DMF中,加入2倍过量的碳酸钾,40℃搅拌6小时,仿照实施例3后处理方式制备得到中间体a,以丙泊酚氯乙酸酯计产率46~68%。
将a溶解在乙酸乙酯中,通入干燥氯化氢气体,室温搅拌30分钟后蒸除乙酸乙酯,残余物用环己烷分散,抽滤,固体润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物7,收率71~84%。
1H NMR(400MHz,DMSO-d6):δ11.07(s,1H),7.20~7.27(m,3H),5.19(s,2H),3.85(s,broad,2H),3.42–3.47(m,2H),3.14~3.23(m,4H),2.89~2.98(m,4H),2.75(s,3H),1.13(d,J=6.9Hz,12H).
实施例8
将等摩尔的N,N-二甲基丙氨酸(CAS:19701-89-4)与等摩尔的氯乙酸丙泊酚酯溶于DMF中,加入2倍过量的碳酸钾,40℃搅拌6小时,仿照实施例3后处理方式制备得到中间体a,以丙泊酚氯乙酸酯计产率51~63%。
将a溶解在乙醇中,加入0.5倍摩尔量的硫酸,室温搅拌30分钟后蒸除乙醇,残余物用环己烷分散,抽滤,固体润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物8,收率61~71%。
1H NMR(400MHz,DMSO-d6):δ8.91(s,1H),7.25~7.33(m,3H),5.21(s,2H),4.27(q,J=7.2Hz,1H),2.95(hept,J=6.8Hz,2H),2.83(s,6H),1.88(d,J=7.2Hz,3H),1.13(d,J=6.8Hz,12H).
实施例9
将等摩尔的4-甲基-3-吗啉羧酸(CAS:1240518-88-0)与等摩尔的氯乙酸丙泊酚酯溶于DMF中,加入2倍过量的碳酸钾,40℃搅拌6小时,仿照实施例3后处理方式制备得到中间体a,以丙泊酚氯乙酸酯计产率52~71%。
将a溶解在乙酸乙酯中,通入过量的干燥氯化氢气体,室温搅拌30分钟后蒸除乙酸乙酯,残余物用环己烷分散,抽滤,固体润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物9,收率49~71%。
1H NMR(400MHz,DMSO-d6):δ10.91(s,1H),7.31~7.36(m,3H),5.16(s,2H),4.61~4.64(m,1H),3.91~4.13(m,4H),3.32~3.41(m,2H),2.85(s,3H),1.15(d,J=6.8Hz,12H).
实施例10
将等摩尔的1-甲基哌啶-2-羧酸(CAS:7730-87-2)与等摩尔的氯乙酸丙泊酚酯溶于DMF中,加入2倍过量的碳酸钾,40℃搅拌6小时,仿照实施例3后处理方式制备得到中间体a,产率36~61%。
将a溶解在乙酸乙酯中,通入过量的干燥氯化氢气体,室温搅拌30分钟后蒸除乙酸乙酯,残余物用环己烷分散,抽滤,固体润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物10,收率45~68%。
1H NMR(400MHz,DMSO-d6):δ11.21(s,1H),7.27~7.36(m,3H),5.28(s,1H),4.38~4.32(m,1H),3.13~3.25(m,2H),2.97(hept,J=6.8Hz,2H),2.91(s,3H),2.01~2.18(m,2H),1.71~1.75(m,2H),1.13~1.35(m,14H).
实施例11
将等摩尔的1-BOC-哌啶-2-羧酸(CAS:98303-20-9)与等摩尔的氯乙酸丙泊酚酯溶于DMF中,加入2倍过量的碳酸钾,40℃搅拌6小时,仿照实施例5后处理方式制备得到中间体a,产率56~71%。
将a溶解在过量的三氟乙酸中,室温搅拌6小时后减压蒸除三氟乙酸,残余物用环己烷分散,抽滤,固体润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物11,收率55~63%。
1H NMR(400MHz,DMSO-d6):δ10.83(s,2H),7.23~7.30(m,3H),5.23(s,1H),4.33~4.30(m,1H),3.14~3.26(m,2H),2.94(hept,J=6.8Hz,2H),2.03~2.16(m,2H),1.72~1.77(m,2H),1.12~1.34(m,14H).
实施例12
将等摩尔的4-BOC-吗啉-3-羧酸(CAS:212650-43-6)与等摩尔的氯乙酸丙泊酚酯溶于DMF中,加入2倍过量的碳酸钾,40℃搅拌6小时,仿照实施例5后处理方式制备得到中间体a,产率61~74%。
将a溶解在乙酸乙酯中,通入过量的干燥氯化氢气体,室温搅拌30分钟后蒸除乙酸乙酯,残余物用环己烷分散,抽滤,固体润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物12,收率55~78%。
1H NMR(400MHz,DMSO-d6):δ10.45(s,2H),7.29~7.34(m,3H),5.19(s,2H),4.63~4.65(m,1H),3.92~4.15(m,4H),3.30~3.39(m,2H),2.95(hept,J=6.8Hz,2H),1.13(d,J=6.8Hz,12H).
实施例13
将等摩尔的N,N-二(2-甲氧基乙基)乙酸胺(CAS:3235-71-0)与氯乙酸丙泊酚酯溶于DMF中,加入2倍过量的碳酸钾,40℃搅拌6小时,仿照实施例3后处理方式制备得到中间体a,产率41~61%。
将a溶解在乙酸乙酯中,通入过量的干燥氯化氢气体,室温搅拌30分钟后蒸除乙酸乙酯,残余物用环己烷分散,抽滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物13,收率65~69%。
1H NMR(400MHz,DMSO-d6):δ8.95(s,1H),7.32~7.37(m,3H),5.22(s,2H),4.25(s,2H),3.73~3.81(m,4H),3.42~3.47(m,4H),3.24=(s,6H),2.94(hept,J=6.8Hz,2H),1.13(d,J=6.8Hz,12H).
实施例14
将等摩尔的BOC-L-缬氨酸(CAS:13734-41-3)与等摩尔的氯乙酸丙泊酚酯溶于DMF中,加入2倍过量的碳酸钾,40℃搅拌6小时,仿照实施例5后处理方式制备得到中间体a,产率54~61%。
将a溶解在乙酸乙酯中,通入过量的干燥氯化氢气体,室温搅拌30分钟后蒸除乙酸乙酯,残余物用环己烷分散,抽滤,固体润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物14,收率51~68%。
1H NMR(400MHz,DMSO-d6):δ8.91(s,3H),7.31~7.35(m,3H),5.22(s,2H),4.16(d,J=6.8Hz,1H),2.96~3.04(m,3H),1.13(d,J=7.2Hz,12H),0.96(d,J=7.2Hz,6H).
实施例15
将等摩尔的BOC-L-半胱氨酸(CAS:20887-95-0)与等摩尔的氯乙酸丙泊酚酯溶于DMF中,加入2倍过量的碳酸钾,40℃搅拌6小时,仿照实施例5后处理方式制备得到中间体a,产率49~72%。
将a溶解在乙酸乙酯中,通入过量的干燥氯化氢气体,室温搅拌30分钟后蒸除乙酸乙酯,残余物用环己烷分散,抽滤,固体润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物15,收率67~73%。
1H NMR(400MHz,DMSO-d6):δ8.56(s,3H),7.28~7.33(m,3H),5.26(s,2H),4.70(t,J=6.8Hz,1H),3.46~3.64(m,3H),2.93(hept,J=6.8Hz,2H),1.16(d,J=7.2Hz,6H).
实施例16
将等摩尔的BOC-N-甲基2-氨基丙酸(CAS:13734-31-1)与等摩尔的氯乙酸丙泊酚酯溶于DMF中,加入2倍过量的碳酸钾,40℃搅拌6小时,仿照实施例5后处理方式制备得到中间体a,产率52~66%。
将a溶解在乙酸乙酯中,通入过量的干燥氯化氢气体,室温搅拌30分钟后蒸除乙酸乙酯,残余物用环己烷分散,抽滤,固体润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物16,收率61~69%。
1H NMR(400MHz,DMSO-d6):δ8.71(s,2H),7.26~7.32(m,3H),5.25(s,2H),4.24(q,J=7.2Hz,1H),2.95(hept,J=6.8Hz,2H),2.84(s,3H),1.88(d,J=7.2Hz,3H),1.13(d,J=6.8Hz,12H).
实施例17
将实施例6中所述的中间体b溶解在乙酸乙酯中,通入过量干燥氯化氢气体,室温搅拌30分钟,减压蒸干溶剂,残余物用环己烷分散,过滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物17,收率51~64%。
1H NMR(400MHz,DMSO-d6):δ10.91(s,1H),7.28~7.33(3H,m),5.29(2H,s),4.44(2H,s),3.78~3.85(m,4H),3.22~3.27(m,5H),2.55~2.59(m,1H),1.34(d,J=7.2Hz,3H),1.24(d,J=7.2Hz,6H),1.01~1.06(m,1H),0.41~0.51(m,2H),0.18~0.24(m,2H)。
实施例18
将实施例6中所述的中间体b溶解在无水乙醇中,加入等摩尔的苯磺酸,室温搅拌30分钟,减压蒸干溶剂,残余物用环己烷分散,过滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物18,收率70~84%。
1H NMR(400MHz,DMSO-d6):δ10.73(s,1H),7.68~7.79(m,5H),7.31~7.35(3H,m),5.29(2H,s),4.44(2H,s),3.81~3.89(m,4H),3.22~3.26(m,5H),2.57~2.59(m,1H),1.32(d,J=7.2Hz,3H),1.28(d,J=7.2Hz,6H),1.04~1.07(m,1H),0.41~0.52(m,2H),0.16~0.23(m,2H)。
实施例19
将实施例6中所述的中间体b溶解在无水乙醇中,加入0.5摩尔当量的硫酸,室温搅拌30分钟,减压蒸干溶剂,残余物用环己烷分散,过滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物19,收率80~88%。
1H NMR(400MHz,DMSO-d6):δ11.24(s,1H),7.31~7.35(3H,m),5.33(2H,s),4.43(2H,s),3.83~3.89(m,4H),3.19~3.26(m,5H),2.53~2.57(m,1H),1.29(d,J=7.2Hz,3H),1.25(d,J=7.2Hz,6H),1.02~1.07(m,1H),0.39~0.51(m,2H),0.18~0.26(m,2H)。
实施例20
将实施例6中所述的中间体b溶解在无水乙醇中,加入等摩尔的对甲苯磺酸,室温搅拌30分钟,减压蒸干溶剂,残余物用环己烷分散,过滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物20,收率75~86%。
1H NMR(400MHz,DMSO-d6):δ10.89(s,1H),7.68~7.79(m,2H),7.45~7.49(m,2H),7.28~7.32(3H,m),5.24(2H,s),4.41(2H,s),3.80~3.87(m,4H),3.19~3.23(m,5H),2.53~2.55(m,1H),2.43(s,3H),1.33(d,J=7.2Hz,3H),1.25(d,J=7.2Hz,6H),1.02~1.05(m,1H),0.40~0.51(m,2H),0.17~0.23(m,2H)。
实施例21
将实施例6中所述的中间体b溶解在无水乙醇中,加入等摩尔的甲磺酸,室温搅拌30分钟,减压蒸干溶剂,残余物用环己烷分散,过滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物21,收率75~86%。
1H NMR(400MHz,DMSO-d6):δ11.21(s,1H),7.28~7.32(3H,m),5.25(2H,s),4.43(2H,s),3.81~3.87(m,4H),3.31(s,3H),3.15~3.22(m,5H),2.54~2.58(m,1H),2.42(s,3H),1.32(d,J=7.2Hz,3H),1.26(d,J=7.2Hz,6H),1.01~1.05(m,1H),0.40~0.51(m,2H),0.18~0.23(m,2H).
实施例22
将吗啉-4-基乙酸(2.29g,15.8mmol),NaI(1.18g,15.8mmol)和丙泊酚氯乙酸酯(4g,15.8mmol)溶于DMF(20mL)中,加入K2CO3(2.25g,16.2mmol),40℃搅拌6小时,冷却反应液,用乙酸乙酯(200mL)和水(100mL)萃取产物,并将有机层用水(3×100mL)多次洗涤,分出有机层,无水硫酸钠干燥。次日过滤,滤液减压蒸干得粗品,柱层析(环己烷/乙酸乙酯30:1)纯化得到3.16g无色油状物,即中间体a,收率55.34%。
将中间体a(1.02g,2.8mmol)溶于30mL乙酸乙酯,通入干燥后的氯化氢气体30分钟,室温搅拌1小时,将乙酸乙酯减压蒸除,得到粗产物。将粗产物用环己烷多次润洗抽滤后,在65℃下烘干得到白色固体0.78g,即目标化合物22,产率为70.91%。
1H NMR(400MHz,DMSO-d6):δ11.29(s,1H),7.24~7.29(m,3H),5.32(s,2H),4.43(s,2H),3.86(s,broad,4H),3.25(s,broad,4H),2.93(hept,J=6.8Hz,2H),1.13(d,J=6.8Hz,12H).
实施例23
将实施例22中所述的中间体a溶解在无水乙醇中,加入0.5摩尔当量的硫酸,室温搅拌30分钟,减压蒸干溶剂,残余物用环己烷分散,过滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物23,收率70~85%。
1H NMR(400MHz,DMSO-d6):δ11.10(s,1H),7.25~7.31(m,3H),5.31(s,2H),4.41(s,2H),3.87(s,broad,4H),3.26(s,broad,4H),2.94(hept,J=6.8Hz,2H),1.14(d,J=6.8Hz,12H).
实施例24
将实施例22中所述的中间体a溶解在无水乙醇中,加入等摩尔的苯磺酸,室温搅拌30分钟,减压蒸干溶剂,残余物用环己烷分散,过滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物24,收率71~79%。
1H NMR(400MHz,DMSO-d6):δ11.32(s,1H),7.63~7.76(m,5H),7.28~7.32(m,3H),5.28(s,2H),4.37(s,2H),3.88(s,broad,4H),3.28(s,broad,4H),2.92(hept,J=6.8Hz,2H),1.13(d,J=6.8Hz,12H).
实施例25
将实施例22中所述的中间体a溶解在无水乙醇中,加入等摩尔的对甲苯磺酸,室温搅拌30分钟,减压蒸干溶剂,残余物用环己烷分散,过滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物25,收率75~89%。
1H NMR(400MHz,DMSO-d6):δ11.04(s,1H),7.65~7.77(m,2H),7.46~7.51(m,2H),,7.27~7.30(m,3H),5.22(s,2H),4.38(s,2H),3.85(s,broad,4H),3.23(s,broad,4H),2.93(hept,J=6.8Hz,2H),1.15(d,J=6.8Hz,12H).
实施例26
将实施例22中所述的中间体a溶解在无水乙醇中,加入等摩尔的甲磺酸,室温搅拌30分钟,减压蒸干溶剂,残余物用环己烷分散,过滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物26,收率72~88%。
1H NMR(400MHz,DMSO-d6):δ11.16(s,1H),7.29~7.31(m,3H),5.22(s,2H),4.37(s,2H),3.84(s,broad,4H),3.25~3.35(m,7H),2.95(hept,J=6.8Hz,2H),1.13(d,J=6.8Hz,12H).
实施例27
将实施例22中所述的中间体a溶解在过量的三氟醋酸中,室温搅拌30分钟,减压蒸干溶剂,残余物用环己烷分散,过滤,固体用环己烷润洗三次,抽滤,滤饼在65℃下烘干得到白色固体,即目标化合物27,收率68~79%。
1H NMR(400MHz,DMSO-d6):δ11.16(s,1H),7.27~7.33(m,3H),5.32(s,2H),4.43(s,2H),3.88(s,broad,4H),3.25(s,broad,4H),2.92(hept,J=6.8Hz,2H),1.13(d,J=6.8Hz,12H).
实施例28
将(S)-2-环丙基乙基-6-异丙基苯酚(CAS:1637741-59-3,204mg,1mmoL)与氯乙酰氯(124mg,1.1mmoL)溶解在10mL二氯甲烷中,冰浴下加入吡啶(237mg,3mmoL),回复至室温搅拌2小时,蒸干溶剂,残余物经硅胶柱层析(环己烷/乙酸乙酯=20/1)得无色油状物176mg,即中间体a。将中间体a(176mg,0.62mmoL)与吗啉-4-基乙酸(90mg,0.66mmoL)溶于DMF(20mL)中并在室温下搅拌40分钟。然后将K2CO3(97mg,0.7mmol)加入到该溶液中,并将该反应溶液在70℃下搅拌4小时。冷却反应液,加入水(100mL),用乙酸乙酯(200mL)萃取产物,并用水洗涤有机层用(3×100mL),分出有机层,无水硫酸钠干燥。次日过滤,滤液蒸干溶剂得粗品,经硅胶柱层析(环己烷/乙酸乙酯从30:1)得到138mg无色油状物,即中间体b,收率为54%。将138mg中间体b溶于3mL乙酸乙酯,通入过量氯化氢气体,室温搅拌30分钟,减压蒸干溶剂,向残余物中加入20mL环己烷,析出固体,过滤,用环己烷润洗固体3次,抽滤,滤饼在65℃下烘干得到白色固体101.2mg,收率55.6%。
1H NMR(400MHz,DMSO-d6):δ11.61(s,1H),7.31~7.38(3H,m),5.32(2H,s)4.39(2H,s),3.83~3.92(m,4H),3.20~3.26(m,5H),2.57~2.59(m,1H),1.35(d,J=7.2Hz,3H),1.28(d,J=7.2Hz,6H),1.02~1.09(m,1H),0.41~0.53(m,2H),0.17~0.26(m,2H).
实施例29
将哌啶-1-乙酸(2.26g,15.8mmol),NaI(1.18g,15.8mmol)和丙泊酚氯乙酸酯(4g,15.8mmol)溶于DMF(20mL)中,加入K2CO3(2.25g,16.2mmol),40℃搅拌6小时,冷却反应液,用乙酸乙酯(200mL)和水(100mL)萃取产物,并将有机层用水(3×100mL)多次洗涤,分出有机层,无水硫酸钠干燥。次日过滤,滤液减压蒸干得粗品,柱层析(环己烷/乙酸乙酯30:1)纯化得到3.31g无色油状物,即中间体a,收率58.1%。
将中间体a(1.01g,2.8mmol)溶于30mL乙酸乙酯,通入干燥后的氯化氢气体30分钟,室温搅拌1小时,将乙酸乙酯减压蒸除,得到粗产物。将粗产物用环己烷多次润洗抽滤后,在65℃下烘干得到白色固体0.82g,即目标化合物29,产率为73.6%。
1H NMR(400MHz,DMSO-d6):10.53(s,1H),7.2`~7.28(m,3H),5.33(s,2H),4.40(s,2H),3.45~3.48(m,2H),2.90~3.04(m,4H),1.68~1.80(m,5H),1.33~1.36(m,1H),1.13(d,J=6.9Hz,12H)
实施例30
将中间体a(176mg,0.62mmoL)与哌啶-1-乙酸(89mg,0.66mmoL)溶于DMF(20mL)中并在室温下搅拌40分钟。然后将K2CO3(97mg,0.7mmol)加入到该溶液中,并将该反应溶液在70℃下搅拌4小时。冷却反应液,加入水(100mL),用乙酸乙酯(200mL)萃取产物,并用水洗涤有机层用(3×100mL),分出有机层,无水硫酸钠干燥。次日过滤,滤液蒸干溶剂得粗品,经硅胶柱层析(环己烷/乙酸乙酯从30:1)得到145mg无色油状物,即中间体b,收率为60.4%。将145mg中间体b溶于3mL乙酸乙酯,通入过量氯化氢气体,室温搅拌30分钟,减压蒸干溶剂,向残余物中加入20mL环己烷,析出固体,过滤,用环己烷润洗固体3次,抽滤,滤饼在65℃下烘干得到白色固体110.2mg,收率69.4%。
1H NMR(400MHz,DMSO-d6):δ11.12(s,1H),7.29~7.37(3H,m),5.30(2H,s)4.35(2H,s),3.81~3.91(m,4H),3.15~3.19(m,1H),2.56~2.59(m,1H),1.55~1.71(m,6H),1.34(d,J=7.2Hz,3H),1.26(d,J=7.2Hz,6H),1.01~1.07(m,1H),0.40~0.52(m,2H),0.18~0.25(m,2H).
实施例31
根据实施例1~30所述的方法,本发明的式(Ⅰ)所述的目标化合物的通用制备方法具体为:将等摩尔的取代苯酚氯乙酸酯与N-BOC保护的氨基酸(氨基氢已被完全取代的氨基酸可不保护氨基)混合在DMF中,于室温至70℃范围搅拌反应4~12小时(可加入等摩尔的碘化钠促进反应发生),冷却反应液,加入水溶解无机盐并稀释DMF,用乙酸乙酯萃取产物,并用水洗涤有机层三次,分出有机层,使用无水硫酸钠干燥。次日过滤,滤液蒸干溶剂得粗品,经硅胶柱层析得到式(Ⅰ)所述的目标化合物的游离碱,产率15%~80%。游离碱与有机酸或无机酸在乙酸乙酯或乙醇溶液中成盐,去除溶剂后得到(Ⅰ)化合物的水溶性盐,产率35%~85%。可使用上述方法制备的式(Ⅰ)目标化合物的盐(附主要原料和产物分子离子峰)包括但不限于:
表1部分化合物的结构与质谱数据
实施例32
将待测前药配置成10mg/mL的生理盐水溶液。取10μL含药溶液加入990μL小鼠血浆中,涡旋30秒后于37℃孵育。在30s、1min、5min、10min、30min、60min、120min分别取含药血浆50μL,立即加入150μL乙腈终止酶促反应,然后于20000转/min、4℃离心10min,取上清液50μL进样,内标法测定丙泊酚浓度。根据丙泊酚或其他取代苯酚的浓度计算出前药的分解率。色谱条件为:色谱柱Agilent Zorbax XDB C18柱(150mm×4.6mm,5μm);柱温30℃;流动相为纯水:乙腈(40:60,v/v);荧光波长:激发波长(Ex):276nm,发射波长(Em):310nm;流速:1.2mL/min;保留时间:内标(麝香草酚)3.9min,丙泊酚7.4min。丙泊酚或其他取代苯酚的线性范围:50~35000ng/mL。仪器:Waters 2695型高效液相色谱仪,Waters 2475型荧光检测器。部分前药的血浆分解实验结果表2所示。
表2前药分子的血浆分解速度
体外血浆分解实验显示,本专利所述的前药分子,在小鼠血浆中具备极快的分解速度,这些前药分子与血浆共培养30秒后平均分解了51%~98%,而上市药物Fopropofol在与血浆共培养10分钟后仍检测不到明显分解,2小时后也仅分解了38%,这表明Fospropofol在血浆中分解速度缓慢。而本发明制备的前药分子在血浆中能快速分解,得到丙泊酚或其他取代苯酚。
实施例33
每种药物使用10只雄性昆明小鼠进行实验,体重20~35克,剂量为各药物在小鼠体内的2倍ED50。本专利所述化合物和Fospropofol溶于生理盐水后经小鼠尾静脉注射,丙泊酚使用市售乳剂得普利麻的葡萄糖稀释液(5mg/mL)经尾静脉注射,另一取代苯酚分子(CAS:1637741-58-2)使用30%脂肪乳剂配置成含药乳剂使用。本专利所述化合物的注射溶液浓度为10~15mg/mL,Fospropofol的注射溶液浓度为55mg/mL,另一取代苯酚分子(CAS:1637741-58-2)乳剂的注射液浓度为1mg/mL。记录动物注射药物后翻正反射消失的出现时间T1,翻正反射消失的持续时间T2(即麻醉时间)和动物苏醒后至完全恢复所需时间T3。完全恢复是指动物的自主活动恢复至给药前水平。实验中不给予动物吸氧或插管等呼吸支持。
表3药物的麻醉活性测试
T1:注射后起效时间;T2:翻正反射消失持续时间;T3:翻正反射恢复至自主活动恢复所需时间
表4其他取代苯酚及其前药分子的麻醉活性测试
T1:注射后起效时间;T2:翻正反射消失持续时间;T3:翻正反射恢复至自主活动恢复所需时间
实验结果显示,本专利所述前药由于具备了极快的血浆分解速度,其起效时间与丙泊酚相当,注射完毕后均可使动物立即麻醉。本专利所述的化合物在等效剂量下,动物摄入的丙泊酚量与直接使用丙泊酚麻醉动物的剂量相当,而上市药物Fospropofol携带的丙泊酚剂量远高于直接使用丙泊酚麻醉动物的剂量,由于本专利所述前药在有效剂量下携带的丙泊酚与Fospropofol相比大幅减少,其对动物的麻醉持续时间显著短于上市药物Fospropofol;本专利所述前药组的动物苏醒后至完全恢复的时间也显著短于Fospropofol组的动物。类似地,本专利所述的其他取代苯酚的前药分子与其携带的取代苯酚分子相比,也保留了原药快速起效和快速恢复的特点。
综上,本专利所述的水溶性前药分子,完全保持了包括丙泊酚在内的取代苯酚类麻醉药物起效快,停药后恢复快的优势。
实施例34
前药分子治疗指数的测定:参考文献方法(Dixon,W.Staircase bioassay:theup-and-down method.Neurosci.Biobehav.Rev.1991,15,47-50),以昆明小鼠为实验动物(体重25~30克,雌雄各半),测定待测分子的半数有效剂量(ED50)和半数致死剂量(LD50)。每种分子的治疗指数计算方法为:TI=LD50/ED50。结果见表5。
表5化合物的治疗指数
治疗指数反应了药物有效剂量和致死剂量之间的距离,是药物分子最基本的安全指标之一。实验结果显示,本专利所述化合物的治疗指数与丙泊酚相似,其安全性与丙泊酚相当,明显优于上市药物Fospropofol。由于全麻药物的治疗指数普遍较低(3~5),因此对于治疗窗本就不高的丙泊酚来说,其水溶性前药能够保持与之相似的治疗指数,说明这些分子的安全性良好。
Claims (5)
2.权利要求1所述的式(Ⅰ)化合物的盐,其特征在于:所述化合物的盐为乙酸盐、己二酸盐、藻酸盐、4-氨基水杨酸盐、抗坏血酸盐、天门冬氨酸盐、谷氨酸盐、焦谷氨酸盐、苯磺酸盐、苯甲酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、碳酸盐、肉桂酸盐、柠檬酸盐、环己氨磺酸盐、环戊烷丙酸盐、癸酸盐、2,2-二氯乙酸盐、重葡萄糖酸盐、十二烷基硫酸盐、乙烷-1,2-二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、粘酸盐、龙胆酸盐、葡庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、甘油磷酸盐、羟乙酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、异丁酸盐、乳酸盐、乳糖醛酸盐、月桂酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、萘-1,5-二磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、辛酸盐、油酸盐、乳清酸盐、草酸盐、2-氧戊二酸盐、棕榈酸盐、扑酸盐、果胶酯酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、癸二酸盐、癸二酸氢盐、硬脂酸盐、琥珀酸盐、硫酸盐、鞣酸盐、酒石酸盐、酒石酸氢盐、硫氰酸盐、甲苯磺酸盐或十一酸盐、硫化氢盐。
5.权利要求1所述的式(Ⅰ)化合物或其立体异构体或其药学上可接受的盐在制备对人或动物产生中枢镇静和/或麻醉效果的药物中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2019110098460 | 2019-10-22 | ||
CN201911009846 | 2019-10-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112694414A CN112694414A (zh) | 2021-04-23 |
CN112694414B true CN112694414B (zh) | 2023-02-28 |
Family
ID=75505553
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011111247.2A Active CN112694414B (zh) | 2019-10-22 | 2020-10-16 | 一类取代苯酚羟基酸酯含n衍生物、制备和用途 |
Country Status (4)
Country | Link |
---|---|
US (1) | US20220388947A1 (zh) |
JP (1) | JP2022553326A (zh) |
CN (1) | CN112694414B (zh) |
WO (1) | WO2021078073A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023083191A1 (zh) * | 2021-11-09 | 2023-05-19 | 四川大学华西医院 | 苯二氮卓类化合物及其制备方法和在医药上的用途 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102381997A (zh) * | 2011-09-08 | 2012-03-21 | 四川大学华西医院 | 带有氨基酸酯末端的丙泊酚羟基酸酯类化合物及其制备方法和应用 |
CN110256269A (zh) * | 2018-06-22 | 2019-09-20 | 江苏恩华络康药物研发有限公司 | 一类水溶性丙泊酚类衍生物及其用途 |
CN110655473A (zh) * | 2018-07-01 | 2020-01-07 | 重庆迈迪生医药科技有限公司 | 烷基取代苯酚羧酸酯化合物、制备方法及用途 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7241807B2 (en) * | 2004-07-12 | 2007-07-10 | Xenoport, Inc. | Prodrugs of propofol, compositions and uses thereof |
CN102617380B (zh) * | 2012-03-12 | 2014-04-02 | 成都一平医药科技发展有限公司 | 氨基酸与丙泊酚的碳酸二酯水溶性衍生物及其用途 |
-
2020
- 2020-10-16 WO PCT/CN2020/121527 patent/WO2021078073A1/zh active Application Filing
- 2020-10-16 CN CN202011111247.2A patent/CN112694414B/zh active Active
- 2020-10-16 US US17/755,167 patent/US20220388947A1/en active Pending
- 2020-10-16 JP JP2022523533A patent/JP2022553326A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102381997A (zh) * | 2011-09-08 | 2012-03-21 | 四川大学华西医院 | 带有氨基酸酯末端的丙泊酚羟基酸酯类化合物及其制备方法和应用 |
CN110256269A (zh) * | 2018-06-22 | 2019-09-20 | 江苏恩华络康药物研发有限公司 | 一类水溶性丙泊酚类衍生物及其用途 |
CN110655473A (zh) * | 2018-07-01 | 2020-01-07 | 重庆迈迪生医药科技有限公司 | 烷基取代苯酚羧酸酯化合物、制备方法及用途 |
Non-Patent Citations (7)
Title |
---|
Beagle犬单次静脉注射水溶性丙泊酚前药(HX0507)或与咪达唑仑、芬太尼联用时的麻醉效果;唐敏等;《四川大学学报(医学版)》;20090315(第02期);第350-352页 * |
RN:13174-64-6;ACS;《STN Registry数据库》;19841116 * |
RN:19405-46-0;ACS;《STN Registry数据库》;19841116 * |
RN:23380-11-2;ACS;《STN Registry数据库》;19841116 * |
RN:740020-72-8;ACS;《STN Registry数据库》;20040905 * |
RN:802291-27-6;ACS;《STN Registry数据库》;20041225 * |
RN:802591-45-3;ACS;《STN Registry数据库》;20041226 * |
Also Published As
Publication number | Publication date |
---|---|
US20220388947A1 (en) | 2022-12-08 |
CN112694414A (zh) | 2021-04-23 |
JP2022553326A (ja) | 2022-12-22 |
WO2021078073A1 (zh) | 2021-04-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7352587B2 (ja) | Krasg12c突然変異タンパク質阻害剤としてのピリドン-ピリミジン系誘導体 | |
EP3517538B1 (en) | Pyrazolopyridine derivative having glp-1 receptor agonist effect | |
RU2515983C2 (ru) | Новые соединения миметиков обратного действия, способ их получения и применения | |
CN112778284B (zh) | 一种嘧啶并环衍生物及其在医药上的应用 | |
CN112300153B (zh) | 一种杂环化合物、药物组合物和用途 | |
WO2012022121A1 (zh) | 作为盐皮质激素受体拮抗剂的并环类化合物 | |
EP3613420B1 (en) | Salts and prodrugs of 1-methyl-d-tryptophan | |
CN112694414B (zh) | 一类取代苯酚羟基酸酯含n衍生物、制备和用途 | |
CN112279848A (zh) | 一种泛JAKs抑制剂及其用途 | |
WO2022228576A1 (zh) | 一种靶向蛋白调节剂的化合物及其应用 | |
WO2020156189A1 (zh) | 喜树碱衍生物及其水溶性前药、包含其的药物组合物及其制备方法和用途 | |
CN107849009B (zh) | 一种八氢环戊二烯并[c]吡咯衍生物及其制备方法和在医药上的用途 | |
BR112021015951A2 (pt) | Composto de pirimidinil-3,8-diazabiciclo[3.2.1]octanilmetanona cristalina e uso do mesmo | |
CN110256405B (zh) | 5-烃基-n-取代芳基吡啶酮衍生物及其制备方法和用途 | |
CN112079783B (zh) | 一类含氮杂环化合物及其制备方法和用途 | |
JP2023502889A (ja) | Eed阻害剤、その製造方法およびその使用 | |
CN115197148B (zh) | 一种5-苄基咪唑类化合物及其制备方法和用途 | |
TWI768464B (zh) | 三環吡唑衍生物及其製備 | |
TWI768465B (zh) | 四氫吲唑衍生物及其製備 | |
WO2021233427A1 (zh) | 并环化合物及其制备方法、药物组合物和应用 | |
EP4252756A1 (en) | Therapeutic agent for pulmonary fibrosis | |
WO2022135390A1 (zh) | 己酮糖激酶抑制剂及其用途 | |
CN106554350B (zh) | 具有β2激动活性的苯并杂环衍生物及其制法和应用 | |
WO2023160672A1 (en) | Compounds and compositions for treating conditions associated with lpa receptor activity | |
WO2024032600A1 (zh) | 一种杂环衍生物及其组合物和药学上的应用 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |