CN111662230A - 一类苄基异喹啉化合物、制备方法和用途 - Google Patents
一类苄基异喹啉化合物、制备方法和用途 Download PDFInfo
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- CN111662230A CN111662230A CN201910173822.2A CN201910173822A CN111662230A CN 111662230 A CN111662230 A CN 111662230A CN 201910173822 A CN201910173822 A CN 201910173822A CN 111662230 A CN111662230 A CN 111662230A
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- -1 Benzyl isoquinoline compound Chemical class 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 239000003814 drug Substances 0.000 claims abstract description 43
- 206010021118 Hypotonia Diseases 0.000 claims abstract description 34
- 230000036640 muscle relaxation Effects 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 210000000715 neuromuscular junction Anatomy 0.000 claims abstract description 6
- 239000003937 drug carrier Substances 0.000 claims abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 239000012453 solvate Substances 0.000 claims abstract 2
- 238000006467 substitution reaction Methods 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 150000001450 anions Chemical class 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229940006460 bromide ion Drugs 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 150000005516 benzylisoquinolines Chemical class 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 230000000903 blocking effect Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
- 239000012634 fragment Substances 0.000 description 40
- 238000004440 column chromatography Methods 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000003158 myorelaxant agent Substances 0.000 description 17
- 230000000694 effects Effects 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- AXOIZCJOOAYSMI-UHFFFAOYSA-N succinylcholine Chemical compound C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C AXOIZCJOOAYSMI-UHFFFAOYSA-N 0.000 description 13
- 229940032712 succinylcholine Drugs 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 11
- 239000012043 crude product Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 8
- 210000003205 muscle Anatomy 0.000 description 8
- 230000002999 depolarising effect Effects 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- KGPAYJZAMGEDIQ-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinoline Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCN1C KGPAYJZAMGEDIQ-UHFFFAOYSA-N 0.000 description 4
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 4
- KRGXWTOLFOPIKV-UHFFFAOYSA-N 3-(methylamino)propan-1-ol Chemical compound CNCCCO KRGXWTOLFOPIKV-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 230000002040 relaxant effect Effects 0.000 description 4
- LMBUJNXYGGNSAH-UHFFFAOYSA-N 1-(4-chlorophenyl)-n-methylmethanamine Chemical compound CNCC1=CC=C(Cl)C=C1 LMBUJNXYGGNSAH-UHFFFAOYSA-N 0.000 description 3
- KQNBRMUBPRGXSL-UHFFFAOYSA-N 1-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1 KQNBRMUBPRGXSL-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000003301 hydrolyzing effect Effects 0.000 description 3
- QAWFLJGZSZIZHO-UHFFFAOYSA-N methyl 4-bromobutanoate Chemical compound COC(=O)CCCBr QAWFLJGZSZIZHO-UHFFFAOYSA-N 0.000 description 3
- 229940035363 muscle relaxants Drugs 0.000 description 3
- 239000003156 neuromuscular nondepolarizing agent Substances 0.000 description 3
- 230000002980 postoperative effect Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 2
- DBKSSENEKWOVKL-UHFFFAOYSA-N 4-(methylamino)butan-1-ol Chemical compound CNCCCCO DBKSSENEKWOVKL-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108010009685 Cholinergic Receptors Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- NDDAQHROMJDMKS-XFYXLWKMSA-N [(2s,3s,5s,8r,9s,10s,13s,14s)-2-hydroxy-10,13-dimethyl-17-oxo-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-3-yl]azanium;chloride Chemical compound Cl.C1[C@H](N)[C@@H](O)C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 NDDAQHROMJDMKS-XFYXLWKMSA-N 0.000 description 2
- 102000034337 acetylcholine receptors Human genes 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 2
- KQEVIFKPZOGBMZ-UHFFFAOYSA-N methyl 3-bromopropanoate Chemical compound COC(=O)CCBr KQEVIFKPZOGBMZ-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229960002362 neostigmine Drugs 0.000 description 2
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 2
- 229960004134 propofol Drugs 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000012313 reversal agent Substances 0.000 description 2
- 238000002627 tracheal intubation Methods 0.000 description 2
- IKSNDOVDVVPSMA-UHFFFAOYSA-N 1-(bromomethyl)-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(CBr)C=C1 IKSNDOVDVVPSMA-UHFFFAOYSA-N 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
- SIOJFYRPBYGHOO-UHFFFAOYSA-N 2-(4-fluorophenyl)acetyl chloride Chemical compound FC1=CC=C(CC(Cl)=O)C=C1 SIOJFYRPBYGHOO-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- SIJLYRDVTMMSIP-UHFFFAOYSA-N 4-Bromo-1-butanol Chemical compound OCCCCBr SIJLYRDVTMMSIP-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- 241001535291 Analges Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 208000002682 Hyperkalemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020844 Hyperthermia malignant Diseases 0.000 description 1
- KGPAYJZAMGEDIQ-KRWDZBQOSA-N Laudanosine Chemical compound C1=C(OC)C(OC)=CC=C1C[C@H]1C2=CC(OC)=C(OC)C=C2CCN1C KGPAYJZAMGEDIQ-KRWDZBQOSA-N 0.000 description 1
- 208000018717 Malignant hyperthermia of anesthesia Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- IZTUINVRJSCOIR-UHFFFAOYSA-N benzylisoquinoline Chemical compound N=1C=CC2=CC=CC=C2C=1CC1=CC=CC=C1 IZTUINVRJSCOIR-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 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
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000000816 effect on animals Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000002389 essential drug Substances 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 201000007004 malignant hyperthermia Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- QQHNGZNHRRLNKI-UHFFFAOYSA-N methyl carbonobromidate Chemical compound COC(Br)=O QQHNGZNHRRLNKI-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000003019 respiratory muscle Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- OYTJKRAYGYRUJK-FMCCZJBLSA-M rocuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 OYTJKRAYGYRUJK-FMCCZJBLSA-M 0.000 description 1
- 229960003682 rocuronium bromide Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- KVCGISUBCHHTDD-UHFFFAOYSA-M sodium;4-methylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1 KVCGISUBCHHTDD-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一类苄基异喹啉化合物,制备方法和用途。这类化合物的结构如式Ⅰ所示:
Description
技术领域
本发明涉及一类苄基异喹啉化合物、制备方法和用途。
背景技术
神经肌肉接头阻滞剂又称为肌松药物,是外科手术时的必须药物。这类药物使手术期间病人的骨骼肌松弛,便于进行气管插管,肌层切开等手术操作。在肌肉松弛度不佳的情况下上述操作是难以进行的。神经肌肉接头阻滞剂的使用历史悠久,从第一个临床使用的筒箭毒开始,各种结构各异的化合物在临床被使用和淘汰。目前,按照药物的结构类型分类,临床使用的肌松药物主要有三类:琥珀胆碱,氨基甾体类和苄基异喹啉类。若按照作用机制分类,琥珀胆碱属于去极化型肌松药物,而氨基甾体类和苄基异喹啉类属于非去极化型。由于广泛地激动全身的乙酰胆碱受体,琥珀胆碱的副作用明显,包括高钾血症,恶性高热、心率失常等。与之相反的是,非去极化肌松药物通过拮抗乙酰胆碱受体而发挥肌松作用,从而避免引起琥珀胆碱那样的副作用,成为临床使用的主流肌松药物。
尽管非去极化肌松药物具有很多优势,但在超短效方面仍不如琥珀胆碱,这也是琥珀胆碱仍保留在临床的主要原因。目前临床上单次给药能够实现超短效肌松作用的药物只有琥珀胆碱(小于10分钟),而作用时间最短的非去极化肌松药物米库氯铵的作用也只能达到短效标准(约15分钟),其余非去极化肌松药物的作用时间更可长达20~60分钟。
由于不具备超短效作用特点,非去极化肌松药物的肌松残留作用明显。肌松残留是导致患者术后死亡或持续昏迷最重要的危险因素。大约40%的术后监护病房病人被认为有肌松残留(Murphy GS,Anesth Analg.2008;107(1):130-137)。肌松残留的危害主要表现在残留的肌松药物引起的呼吸肌抑制,咽喉食管功能瘫痪导致误吸等,在监护不力的情况下诱发严重的呼吸事件(Berg H,Acta Anaesthesiol Scand.1997;41(9):1095-1103;Sundman E,Anesthesiology.2000;92(4):977-984)。目前对肌松残留的应对措施是使用胆碱酯酶抑制剂,如新斯的明,通过增加内源性乙酰胆碱的浓度来对抗残留的肌松药物,但这种措施仅适合在肌力恢复至一定程度后方可使用(Tajaate N,Eur JAnaesthesiol.2017);此外,高剂量的新斯的明还会增加术后呼吸***疾病的发生(SasakiN,Anesthesiology.2014;121(5):959-68)。对于程度较深的肌松残留,除了耗费较多的医疗资源加强监护,等待肌松药物在病人体内缓慢代谢外,临床对肌松残留这一问题仍没有更好的解决方式。针对上述情况,国际上出现了一些肌肉松弛逆转技术。如针对氨基甾体类化合物的特殊结构,开发了特异性的拮抗剂sugammadex,这类环糊精分子可以在血液中包裹如罗库溴铵等氨基甾体类肌松药物分子,形成的复合物可经肾排除,实现快速清除体内的氨基甾体类肌松药(Stefan Josef Schaller&Heidrun Lewald,Expert Opinion onDrug Metabolism&Toxicology,2016,12(9),1097-1108)。又如有一类葫芦脲化合物Calabdions,可以清除氨基甾体类和苄基异喹啉类的肌松药物,实现肌松效果的逆转,但对于氨基甾体类肌松药物的逆转效果更明显(Friederike Haerter,Anesthesiology 2015;123:1337-49)。还有一种肌松逆转技术,是在苄基异喹啉类肌松药物分子中引入一个对巯基氨基酸敏感的结构片段,而具有该片段的肌松药物与半胱氨酸反应后生成的分子没有肌松活性,因此可以在需要时外给较大剂量(一般是肌松药物剂量的100~200倍)的半胱氨酸,在2~5分钟内对肌松作用予以解除(Paul M.Heerdt.Curr Opin Anaesthesiol.2015;28(4):403-10)。
可见,目前的肌松药物逆转技术都需要外给大量与治疗作用无关的分子来解除肌松作用,这些较大剂量的解救剂有的已经被报道对机体具有一定副作用,如严重过敏(LMenéndez-Ozcoidi,Anaesthesia,2011,66(3):217-9)。因此,如果能够获得一种在机体内生物消除半衰期本身就很短的非去极化肌松药物,具备与琥珀胆碱相似或更优的超短效特点,就能够实现停药后机体对药物的快速清除,从而不需要再外给任何解救剂来逆转肌松作用,这样的肌松药物无疑会更安全,并显著减轻肌松残留,极大地增加药物的安全性,降低监护成本,减轻病人经济负担。
发明内容
鉴于上述情况,本发明公开一种肌松作用超短效的苄基异喹啉类化合物,以及它们的制备方法和用途。这类化合物单次静脉注射后可以产生快速的肌肉松弛效应,并在很短时间后,不依赖任何解救剂实现肌松作用消退。在动物实验中具有比目前临床上的超短效肌松药琥珀胆碱作用时间更短效的特点,使用本申请所述化合物的动物,其肌松作用可快速消退。
本发所述的肌松超短效苄基异喹啉类化合物,结构如式(Ⅰ)所示:
式中,Ar1,Ar2为无取代或有取代的芳基,所述的取代可以是单取代也可以是多取代,所述的取代基可为硝基,氰基,烷氧基,卤原子,烷氧羰基,烃基,三氟甲基;R1,R2,R3各自可以为C1~6的烃基、芳环上无取代或有取代的苄基,所述的取代基包括硝基,氰基,烷氧基,卤原子,烷氧羰基,烃基,三氟甲基;B1为C1~8的取代或无取代,饱和或不饱和的亚烃基,B1的骨架中可以含有O等杂原子;B2为C1~8的取代或无取代,饱和或不饱和的亚烃基,B2的骨架中可以含有O等杂原子;Y选自Z为药学上可接受的阴离子,如氯离子、溴离子,磺酸根离子等。
上述化合物根据Y的不同,可初步分为两个亚类:
第一亚类:式(Ⅰ)中Y为其余结构特征为:Ar1,Ar2为有取代的芳基,所述的取代可以是单取代也可以是多取代,所述的取代基可为硝基,氰基,烷氧基,卤原子,三氟甲基;R1,R2,R3各自可以为C1~6的烃基、芳环上无取代或有取代的苄基,所述的取代基包括硝基,氰基,烷氧基,卤原子,三氟甲基;B1为C1~6的亚烷基,B1的骨架中可以含有O等杂原子;B2为C1~6的亚烷基,B2的骨架中可以含有O等杂原子;Z为药学上可接受的阴离子,如氯离子、溴离子,磺酸根离子等。代表化合物有:
第二亚类:(Ⅰ)中Y为其余结构特征为:Ar1,Ar2为有取代的芳基,所述的取代可以是单取代也可以是多取代,所述的取代基可为硝基,氰基,烷氧基,卤原子,三氟甲基;R1,R2,R3各自可以为C1~6的烃基、芳环上无取代或有取代的苄基,所述的取代基包括硝基,氰基,烷氧基,卤原子,三氟甲基;B1为C1~6的亚烷基,B1的骨架中可以含有O等杂原子;B2为C1~6的亚烷基,B2的骨架中可以含有O等杂原子;Z为药学上可接受的阴离子,如氯离子、溴离子,磺酸根离子等其余代表的化合物有:
上述各亚类化合物的制备方法不同,但所有具体化合物均是由片段a和片段b经Y偶联而得到式(I)结构的化合物:
其中,第一亚类化合物的制备方法的特征是:先将芳香乙胺与芳香乙酸缩合成酰胺a1,然后在三氯氧磷作用下得到a2,经还原后得到a3,a3取代溴代羧酸甲酯的溴原子后得到a4,a4经氮烷基化后得到a5,a5经水解后得到羧酸钠盐衍生物a6:
随后,按照常规叔胺的烷基化方法制备得到中间体b1,随后b1中羟基
与氯甲酸氯甲酯成酯后得到中间体b2:
最后,b2与a6发生取代反应得到式(I)化合物:
第二亚类化合物的制备方法特征是:先制备出中间体a3,其分子中的叔胺后与末端含溴的醇进行烷基化反应,得到季铵盐中间体a8,其羟基与氯甲酸氯甲酯成酯后得到中间体a9。
随后,使用仲胺与末端溴化的羧酸甲酯进行烷基化,得到叔胺中间体b3,b3再进行一次烷基化得到季铵盐中间体b4,随后水解甲酯,得含有羧酸钠结构的季铵盐中间体b5:
中间体b5与a9经取代反应偶联得到目标分子(Ⅰ):
本发明所述的化合物由于可能具有不对称因素,因此可具立体异体。这些异构体大多数可经过拆分试剂对异构体混合物进行拆分,得到各立体异构体的纯品,所使用的的拆分方法的特征是使用手性拆分试剂,如手性酒石酸或其衍生物,与式(I)化合物成盐,在不同重结晶条件下不同立体异构体与拆分试剂形成的盐会分别析出,经过滤分离得到立体异构体的纯品。也可以使用具有手性的原料构建a片段和b片段的立体异构体,最后经偶联得到式(I)化合物的异构体纯品。
动物实验结果显示,上述式(Ⅰ)结构的苄基异喹啉类化合物能够产生快速、可逆的肌肉松弛作用,与现有的临床短效肌松药物相比,本发明所述的化合物单次给药后肌松持续时间更短,在增加给药剂量后肌力恢复比等效剂量的琥珀胆碱更快。在体外分解实验中,本申请所述化合物在动物的肝匀浆和血浆中均能快速分解,这提示本发明所述的化合物可以依赖机体本身的酶***迅速代谢,从而不需要外给任何解救剂来实现肌松作用迅速消退。因而,本发明上述式(Ⅰ)结构的化合物在制备作为对动物或人产生肌肉松弛作用的手术用药中的应用方面,具有明显的优势和良好的前景。综上,上述式(I)结构的化合物,包括其消旋体、立体异构体、立体异构体混合物以及它们药学上可接受的盐,以及上述物质与药学上可接受的载体形成的药物组合物,可产生神经肌肉接头阻滞作用,在制备肌肉松弛药物领域中应用。
以下实施例所提供的内容,是对本发明的内容作进一步的详细说明,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情况下,根据本领域公知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
将劳丹素(CAS:1699-51-0)715mg与3-溴丙酸甲酯334mg于30mL乙腈中,55℃搅拌24小时,减压蒸干乙腈,经柱层析(二氯甲烷/甲醇=10/1)得N-甲基-N-丙酸甲酯劳丹素季铵盐590mg,加入2N氢氧化钠水溶液20mL,室温水解2小时,用氢溴酸水溶液调Ph值至9,减压蒸干溶剂,粗品经柱层析(二氯甲烷/甲醇=10/1)得溴化N-甲基-N-丙酸基劳丹素季铵盐钠盐280mg,即片段a。
将3-(甲氨基)-1-丙醇(CAS:42055-15-2)178mg与4-硝基苄溴(CAS:100-11-8)648mg于30mL乙腈中,55℃搅拌24小时,减压蒸干乙腈,经柱层析(二氯甲烷/甲醇=10/1)得溴化N-甲基-N-羟丙基-N,N-二对硝基苄基季铵盐480mg,加入20mL二氯甲烷,200mg氯甲酸氯甲酯以及350mg吡啶,室温搅拌5小时,经柱层析得溴化N-甲基-N-氯甲基碳酸丙基-N,N-二对硝基苄基季铵盐479mg,即片段b。
将265mg片段b与265mg片段a溶于20mL DMF中,室温搅拌反应36小时,减压蒸干DMF,经柱层析(二氯甲烷/甲醇=10/1)得式(I)结构目标化合物152mg。
HNMR(d-DMSO,400MHz):1.19~1.22(2H,m),2.65(2H,m),2.95~3.75(28H,m),4.22(2H,t,J=8Hz),4.52(4H,s),4.91~4.97(1H,m),5.75(2H,s),6.08~6.81(5H,m),7.39~7.43(4H,m),8.09~8.12(4H,m).
实施例2
按照实施例1所述的方法,制备片段a。
将3-(甲氨基)-1-丙醇(CAS:42055-15-2)178mg与4-氯苄溴410mg于30mL乙腈中,50℃搅拌3小时,随后加入450mg 4-硝基苄溴,55℃搅拌24小时,减压蒸干乙腈,经柱层析(二氯甲烷/甲醇=10/1)得溴化N-甲基-N-羟丙基-N-对氯苄基-N-对硝苄基季铵盐435mg,加入20mL二氯甲烷,200mg氯甲酸氯甲酯以及350mg吡啶,室温搅拌5小时,经柱层析得溴化N-甲基-N-氯甲基碳酸丙基-N-对氯苄基-N-对硝基苄基季铵盐415mg,即片段b。
将261mg片段b与266mg片段a溶于20mL DMF中,室温搅拌反应36小时,减压蒸干DMF,经柱层析(二氯甲烷/甲醇=10/1)得式(I)结构目标化合物132mg。
HNMR(d-DMSO,400MHz):1.19~1.22(2H,m),2.65(2H,m),2.95~3.75(32H,m),4.22(2H,t,J=8Hz),4.52(4H,s),4.91~4.97(1H,m),5.75(2H,s),6.08~6.81(5H,m),7.12~7.43(6H,m),8.09~8.12(2H,m).
实施例3
将劳丹素(CAS:1699-51-0)715mg与2-溴乙酸甲酯304mg于30mL乙腈中,55℃搅拌24小时,减压蒸干乙腈,经柱层析(二氯甲烷/甲醇=10/1)得N-甲基-N-乙酸甲酯劳丹素季铵盐510mg,加入2N氢氧化钠水溶液20mL,室温水解2小时,用氢溴酸水溶液调Ph值至9,减压蒸干溶剂,粗品经柱层析(二氯甲烷/甲醇=10/1)得溴化N-甲基-N-乙酸基劳丹素季铵盐钠盐280mg,即片段a。
将2-(甲氨基)-乙醇(CAS:109-83-1)150mg与4-氯苄溴410mg于30mL乙腈中,50℃搅拌3小时,随后加入378mg 4-氟苄溴,55℃搅拌24小时,减压蒸干乙腈,经柱层析(二氯甲烷/甲醇=10/1)得溴化N-甲基-N-羟乙基-N-对氯苄基-N-对氟基季铵盐402mg,加入20mL二氯甲烷,200mg氯甲酸氯甲酯以及350mg吡啶,室温搅拌5小时,经柱层析得溴化N-甲基-N-氯甲基碳酸乙基-N-对氯苄基-N-对溴苄基季铵盐385mg,即片段b。
将240mg片段b与260mg片段a溶于20mL DMF中,室温搅拌反应36小时,减压蒸干DMF,经柱层析(二氯甲烷/甲醇=10/1)得式(I)结构目标化合物102mg。
HNMR(d-DMSO,400MHz):2.98~3.77(26H,m),4.22(2H,s),4.50~4.63(6H,m),4.95~4.99(1H,m),5.72(2H,s),6.09~6.82(5H,m),7.13~7.44(8H,m).
实施例4
将劳丹素(CAS:1699-51-0)715mg与4-溴丁酸甲酯360mg于30mL乙腈中,55℃搅拌24小时,减压蒸干乙腈,经柱层析(二氯甲烷/甲醇=10/1)得N-甲基-N-丁酸甲酯劳丹素季铵盐500mg,加入2N氢氧化钠水溶液20mL,室温水解2小时,用氢溴酸水溶液调Ph值至9,减压蒸干溶剂,粗品经柱层析(二氯甲烷/甲醇=10/1)得溴化N-甲基-N-丁酸基劳丹素季铵盐钠盐293mg,即片段a。
将4-(甲氨基)-丁醇(CAS:42042-68-2)180mg与4-氯苄溴850mg于30mL乙腈中,55℃搅拌24小时,减压蒸干乙腈,经柱层析(二氯甲烷/甲醇=10/1)得溴化N-甲基-N-羟丁基-N,N-二对氯苄基季铵盐421mg,加入20mL二氯甲烷,200mg氯甲酸氯甲酯以及350mg吡啶,室温搅拌5小时,经柱层析得溴化N-甲基-N-氯甲基碳酸丁基-N,N-二对氯苄基季铵盐395mg,即片段b。
将240mg片段b与260mg片段a溶于20mL DMF中,室温搅拌反应36小时,减压蒸干DMF,经柱层析(二氯甲烷/甲醇=10/1)得式(I)结构目标化合物112mg。
HNMR(d-DMSO,400MHz):1.62~1.71(4H,m),2.11~2.31(4H,m),2.95~3.89(28H,m),4.21~4.25(2H,m),4.50(4H,s),4.93~4.99(1H,m),5.77(2H,s),6.08~6.81(5H,m),7.15~7.33(8H,m).
实施例5
将(S)-劳丹素(CAS:2688-77-9)715mg与4-溴丁酸甲酯360mg于30mL乙腈中,55℃搅拌24小时,减压蒸干乙腈,经柱层析(二氯甲烷/甲醇=10/1)得(S)-N-甲基-N-丁酸甲酯劳丹素季铵盐500mg,加入2N氢氧化钠水溶液20mL,室温水解2小时,用氢溴酸水溶液调Ph值至9,减压蒸干溶剂,粗品经柱层析(二氯甲烷/甲醇=10/1)得(S)-溴化N-甲基-N-丁酸基劳丹素季铵盐钠盐283mg,即片段a。
将2-(甲氨基)-乙醇(CAS:109-83-1)150mg与苄溴340mg于30mL乙腈中,50℃搅拌3小时,随后加入280mg 4-硝基苄溴,55℃搅拌24小时,减压蒸干乙腈,经柱层析(二氯甲烷/甲醇=10/1)得溴化N-甲基-N-羟乙基-N-苄基-N-对硝基苄基季铵盐380mg,加入20mL二氯甲烷,200mg氯甲酸氯甲酯以及350mg吡啶,室温搅拌5小时,经柱层析得溴化N-甲基-N-氯甲基碳酸乙基-N-苄基-N-对硝基苄基季铵盐305mg,即片段b。
将260mg片段b与273mg片段a溶于20mL DMF中,室温搅拌反应36小时,减压蒸干DMF,经柱层析(二氯甲烷/甲醇=10/1)得式(I)结构目标化合物126mg。
HNMR(d-DMSO,400MHz):2.11~2.31(4H,m),2.95~3.89(26H,m),4.21~4.25(2H,m),4.50~4.61(6H,m),4.93~4.98(1H,m),5.74(2H,s),6.10~6.82(5H,m),7.15~7.43(7H,m),8.11~8.13(2H,m).
实施例6
以4-硝基苯乙酰氯和3,4-二甲氧基苯乙胺为原料,按照文献(Chin.J.Chem.2014,32,1039—1048)方法制备得到中间体a3。将656mg a3和250mg溴乙醇溶于25mL乙腈中,加热至60℃搅拌3小时,随后加入300mg碘甲烷封管50℃搅拌24小时,减压蒸干乙腈,粗品经柱层析(二氯甲烷/甲醇=10/1)得溴化2-(2-羟乙基)-6,7-二甲氧基-2甲基-1-(4-硝基苯基)-1,2,3,4-四氢异喹啉-2-季铵盐(a fragment)470mg,加入20mL二氯甲烷,200mg氯甲酸氯甲酯以及350mg吡啶,室温搅拌5小时,经柱层析得片段a 380mg。
将对氯苄基甲基胺(CAS:104-11-0)310mg与360mg 4-溴丁酸甲酯溶于25mL乙腈中,于60℃搅拌3小时,再加入4-三氟甲基苄溴480mg,回流搅拌反应24小时。蒸干溶剂,粗品经柱层析(二氯甲烷/甲醇=10/1)得580mg溴化N-(3-甲氧羰基-丙基)-N-甲基-N-对三氟甲基苄基-N-对氯苄基季铵盐,加入2N氢氧化钠水溶液20mL,室温水解2小时,用氢溴酸水溶液调Ph值至9,减压蒸干溶剂,粗品经柱层析(二氯甲烷/甲醇=10/1)得溴化N-(4-羧基-丙基)-N-甲基-N-对三氟甲基苄基-N-对氯苄基季铵盐钠盐370mg,即片段b。
将280mg片段a与250mg片段b溶于20mL DMF中,室温搅拌反应24小时,减压蒸干DMF,经柱层析(二氯甲烷/甲醇=10/1)得式(I)结构目标化合物131mg。
HNMR(d-DMSO,400MHz):2.12~2.31(4H,m),2.96~3.88(24H,m),4.51~4.63(4H,m),4.92~4.99(1H,m),5.72(2H,s),6.70~6.81(2H,m),7.16~7.55(10H,m),8.12~8.14(2H,m).
实施例7
以4-氟苯乙酰氯和3,4-二甲氧基苯乙胺为原料,按照文献(Chin.J.Chem.2014,32,1039—1048)方法制备得到中间体a3。将602mg a3和306mg 4-溴丁醇溶于25mL乙腈中,加热至60℃搅拌3小时,随后加入300mg碘甲烷封管50℃搅拌24小时,减压蒸干乙腈,粗品经柱层析(二氯甲烷/甲醇=10/1)得溴化2-(4-羟丁基)-6,7-二甲氧基-2甲基-1-(4-氟苯基)-1,2,3,4-四氢异喹啉-2-季铵盐(a fragment)480mg,加入20mL二氯甲烷,200mg氯甲酸氯甲酯以及350mg吡啶,室温搅拌5小时,经柱层析得片段a 350mg。
将对氯苄基甲基胺(CAS:104-11-0)310mg与304mg 2-溴乙酸甲酯溶于25mL乙腈中,于60℃搅拌3小时,再加入4-氟苄溴380mg,回流搅拌反应24小时。蒸干溶剂,粗品经柱层析(二氯甲烷/甲醇=10/1)得510mg溴化N-(2-甲氧羰基-甲基)-N-甲基-N-对氟苄基-N-对氯苄基季铵盐,加入2N氢氧化钠水溶液20mL,室温水解2小时,用氢溴酸水溶液调Ph值至9,减压蒸干溶剂,粗品经柱层析(二氯甲烷/甲醇=10/1)得溴化N-(羧甲基)-N-甲基-N-对氟苄基-N-对氯苄基季铵盐钠盐330mg,即片段b。
将280mg片段a与212mg片段b溶于20mL DMF中,室温搅拌反应24小时,减压蒸干DMF,经柱层析(二氯甲烷/甲醇=10/1)得式(I)结构目标化合物141mg。
HNMR(d-DMSO,400MHz):1.65~1.72(4H,m),2.99~3.89(20H,m),4.21~4.33(4H,m),4.54(2H,s),4.59(2H,s),4.92~4.99(1H,m),5.70(2H,s),6.71~6.82(2H,m),7.12~7.35(12H,m).
实施例8
以劳丹素(CAS:1699-51-0)为原料,以如实施例7所述的合成方法制备片段a。以如实施例7所示的合成方法,使用对氯苄基甲基胺、3-溴丙酸甲酯和对硝基苄溴为原料,合成片段b。
将301mg片段a与233mg片段b溶于20mL DMF中,室温搅拌反应24小时,减压蒸干DMF,经柱层析(二氯甲烷/甲醇=10/1)得式(I)结构目标化合物133mg。
HNMR(d-DMSO,400MHz):1.65~1.72(4H,m),2.65~2.69(2H,m),2.99~3.89(28H,m),4.21~4.33(2H,m),4.55(2H,s),4.58(2H,s),5.01~5.04(1H,m),5.71(2H,s),6.71~6.82(5H,m),7.12~7.45(6H,m),8.09~8.12(2H,m).
实施例9
将300mg化合物16溶于50mL二氯甲烷,加入含有2g对甲苯磺酸钠盐的水溶液50mL,充分振摇5分钟,静置分层后分出有机层,蒸干溶剂,残余物经柱层析纯化得目标化合物210mg。
HNMR(d-DMSO,400MHz):2.11~2.30(4H,m),2.56(6H,s),2.95~3.89(24H,m),4.50~4.62(4H,m),4.91~4.98(1H,m),5.71(2H,s),6.72~6.85(2H,m),7.14~7.56(14H,m),7.75~7.78(4H,m),8.11~8.13(2H,m).
实施例10
本专利所述的化合物,均可参照本专利说明书披露的合成通法,并结合实施例1~9所述的具体反应条件制备得到,他们的质谱数据如表1所示(荷质比不含阴离子)。
表1目标化合物的质谱
实施例11
部分实施例所述的化合物,进行兔血浆体外分解实验。将含有200μg药物的DMSO溶液(10μL)加入到4mL兔血浆中,使血浆药物浓度为50μg/mL,混匀后立即于37℃孵育,并在2min,5min,10min,20min分别取200μL含药血浆,加入600μL甲醇,离心后取上层清液测定,以HPLC测定药物含量,具体测定条件为:4.6X50mm,5μm C18柱,0.04%三氟醋酸水溶液为A流动相,0.02%三氟醋酸乙腈溶液为B流动相,流速1.5mL/min,柱温45℃,梯度洗脱(B:10%/2.5min→80%/1.5min→10%/2min),二极管阵列检测器。测定得到的药物浓度,与进样时的初始药物浓度进行比对,计算出药物在各时间点的剩余百分比。结果显示,实施例中的化合物在血浆中,大多可在5分钟内完全分解(表2)。上述实验血浆替换为20%兔肝匀浆后,分解更快,具体分解情况见表3。
表2药物在兔血浆中的分解
-:检测不到原型药物。
表3药物在兔肝匀浆中的分解
-:检测不到原型药物。
上述实验说明本专利所述的化合物可以在血浆和肝脏迅速分解,这种特点有利于机体对原型药物的迅速清除,从而不借助任何其他手段或药物使肌松作用迅速消退。
实施例12
体重2~3kg的成年雄性新西兰大白兔,使用丙泊酚按5mg/kg经静脉进行麻醉诱导,实施气管插管,呼吸机通气,并用丙泊酚以0.6mg/kg/min静脉输注维持麻醉。随后,按体重经静脉给予各药物在兔体内的3倍ED95剂量(使肌张力降低95%的最小剂量),随后记录肌张力完全恢复所需时间并使用TOF肌松监测仪检测神经肌肉接头功能(每次给予1组连续四次的成串刺激,并记录各刺激引起的肌肉反应,分别记录为T1,T2,T3,T4)。将部分实施例所述化合物,以琥珀胆碱为对照进行上述实验,结果见表4。
表4 3倍ED95药物引起的肌松时间(N=6)
实验结果显示,在等效剂量下,实施例中化合物具有比琥珀胆碱还短的肌松持续时间,这种用药后肌力的快速恢复不需要任何逆转试剂来实现,依靠机体本身的代谢***即可实现肌松作用的快速消退。此外,本发明实施例中的化合物在TOF检测下均可实现T1~T4依次逐步降低并消失的情况,提示本申请所述化合物均为非去极化肌松药物,而琥珀胆碱在有效剂量下,在T1~T4等比例同步降低并消失,显示出去极化肌松药物的特点。因此,本申请所述的化合物,不依赖任何逆转试剂,具备非去极化肌松药物和超短效的特点。
Claims (7)
6.如权利要求1~5中所述的化合物,可经过拆分试剂对其立体异构体混合物进行拆分,得到各立体异构体,所使用的的拆分方法的特征是使用拆分试剂,如手性酒石酸及其衍生物,与式(I)化合物成盐,在不同重结晶条件下不同立体异构体的盐会析出,经过滤分离得到立体异构体的纯品。
7.如权利要求1~5所述的化合物,包括其立体异构体、立体异构体混合物以及其药学上可接受的盐,溶剂合物,以及它们与药学上可接受的载体形成的药物组合物,可产生神经肌肉接头阻滞作用,在制备肌肉松弛药物领域中应用。
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