WO2022078483A1 - Composé stéroïde d'ammonium quaternaire, son procédé de préparation, sa préparation et son utilisation - Google Patents
Composé stéroïde d'ammonium quaternaire, son procédé de préparation, sa préparation et son utilisation Download PDFInfo
- Publication number
- WO2022078483A1 WO2022078483A1 PCT/CN2021/123999 CN2021123999W WO2022078483A1 WO 2022078483 A1 WO2022078483 A1 WO 2022078483A1 CN 2021123999 W CN2021123999 W CN 2021123999W WO 2022078483 A1 WO2022078483 A1 WO 2022078483A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- rocuronium
- sodium
- chloride
- acetate
- solution
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 104
- -1 Quaternary ammonium steroid compound Chemical class 0.000 title claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 16
- 239000012453 solvate Substances 0.000 claims abstract description 16
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 120
- 229960000491 rocuronium Drugs 0.000 claims description 115
- YXRDKMPIGHSVRX-OOJCLDBCSA-N rocuronium Chemical compound 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 YXRDKMPIGHSVRX-OOJCLDBCSA-N 0.000 claims description 111
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 107
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 105
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 103
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 96
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 70
- 238000000034 method Methods 0.000 claims description 62
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 60
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 59
- 229960003682 rocuronium bromide Drugs 0.000 claims description 53
- 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 claims description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 50
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 46
- 239000000706 filtrate Substances 0.000 claims description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- 239000003960 organic solvent Substances 0.000 claims description 41
- 235000002639 sodium chloride Nutrition 0.000 claims description 33
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 32
- 238000002347 injection Methods 0.000 claims description 31
- 239000007924 injection Substances 0.000 claims description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 30
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 30
- 239000012065 filter cake Substances 0.000 claims description 29
- 229940090044 injection Drugs 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 26
- 239000007787 solid Substances 0.000 claims description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 23
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 22
- 229940079593 drug Drugs 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- 230000003637 steroidlike Effects 0.000 claims description 22
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 21
- 239000012141 concentrate Substances 0.000 claims description 21
- 150000002148 esters Chemical class 0.000 claims description 21
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 21
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 20
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 20
- 229940011051 isopropyl acetate Drugs 0.000 claims description 20
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 238000004108 freeze drying Methods 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 17
- 125000001033 ether group Chemical group 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- 150000002170 ethers Chemical class 0.000 claims description 16
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 16
- 229940090181 propyl acetate Drugs 0.000 claims description 16
- VEPSYABRBFXYIB-PWXDFCLTSA-M vecuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](OC(C)=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(C)CCCCC2)CCCCC1 VEPSYABRBFXYIB-PWXDFCLTSA-M 0.000 claims description 16
- 229960004298 vecuronium bromide Drugs 0.000 claims description 16
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 15
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 15
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 15
- 150000002576 ketones Chemical class 0.000 claims description 15
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 14
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 14
- 229960003819 vecuronium Drugs 0.000 claims description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 13
- 239000012071 phase Substances 0.000 claims description 13
- BGSZAXLLHYERSY-XQIGCQGXSA-N vecuronium Chemical compound N1([C@@H]2[C@@H](OC(C)=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(C)CCCCC2)CCCCC1 BGSZAXLLHYERSY-XQIGCQGXSA-N 0.000 claims description 13
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 238000012805 post-processing Methods 0.000 claims description 12
- 239000004471 Glycine Substances 0.000 claims description 11
- 239000008346 aqueous phase Substances 0.000 claims description 11
- 239000000284 extract Substances 0.000 claims description 11
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 235000011054 acetic acid Nutrition 0.000 claims description 10
- 238000010828 elution Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 235000017550 sodium carbonate Nutrition 0.000 claims description 10
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 claims description 9
- 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 claims description 9
- 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 description 9
- 239000008101 lactose Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 235000011181 potassium carbonates Nutrition 0.000 claims description 9
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 8
- 229940043232 butyl acetate Drugs 0.000 claims description 8
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 8
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 8
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 7
- 235000010216 calcium carbonate Nutrition 0.000 claims description 7
- 238000001990 intravenous administration Methods 0.000 claims description 7
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 6
- 239000005695 Ammonium acetate Substances 0.000 claims description 6
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 229930003268 Vitamin C Natural products 0.000 claims description 6
- 235000019257 ammonium acetate Nutrition 0.000 claims description 6
- 229940043376 ammonium acetate Drugs 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 235000006708 antioxidants Nutrition 0.000 claims description 6
- 239000008139 complexing agent Substances 0.000 claims description 6
- 238000004042 decolorization Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 229910021645 metal ion Inorganic materials 0.000 claims description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 6
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 239000013557 residual solvent Substances 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 6
- 235000019154 vitamin C Nutrition 0.000 claims description 6
- 239000011718 vitamin C Substances 0.000 claims description 6
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims description 5
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 5
- 230000003078 antioxidant effect Effects 0.000 claims description 5
- 239000000022 bacteriostatic agent Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 239000012931 lyophilized formulation Substances 0.000 claims description 5
- 239000001630 malic acid Substances 0.000 claims description 5
- 235000011090 malic acid Nutrition 0.000 claims description 5
- 229940017219 methyl propionate Drugs 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 238000004366 reverse phase liquid chromatography Methods 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 235000015424 sodium Nutrition 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 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 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229940035676 analgesics Drugs 0.000 claims description 4
- 239000000730 antalgic agent Substances 0.000 claims description 4
- NHJPVZLSLOHJDM-UHFFFAOYSA-N azane;butanedioic acid Chemical compound [NH4+].[NH4+].[O-]C(=O)CCC([O-])=O NHJPVZLSLOHJDM-UHFFFAOYSA-N 0.000 claims description 4
- 238000010009 beating Methods 0.000 claims description 4
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 4
- 239000000920 calcium hydroxide Substances 0.000 claims description 4
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 229960004926 chlorobutanol Drugs 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 4
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- CVOQYKPWIVSMDC-UHFFFAOYSA-L dipotassium;butanedioate Chemical compound [K+].[K+].[O-]C(=O)CCC([O-])=O CVOQYKPWIVSMDC-UHFFFAOYSA-L 0.000 claims description 4
- 230000002496 gastric effect Effects 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims description 4
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
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- YPSNMKHPDJVGEX-UHFFFAOYSA-L potassium;sodium;3-carboxy-3-hydroxypentanedioate Chemical compound [Na+].[K+].OC(=O)CC(O)(C([O-])=O)CC([O-])=O YPSNMKHPDJVGEX-UHFFFAOYSA-L 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000275 quality assurance Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000001034 respiratory center Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000010825 rotarod performance test Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229960004258 umeclidinium Drugs 0.000 description 1
- PEJHHXHHNGORMP-AVADPIKZSA-M umeclidinium bromide Chemical compound [Br-].C=1C=CC=CC=1C([C@@]12CC[N@@+](CCOCC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 PEJHHXHHNGORMP-AVADPIKZSA-M 0.000 description 1
- 229960004541 umeclidinium bromide Drugs 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
Images
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
Definitions
- the present invention relates to steroidal quaternary ammonium compounds, their preparation methods, preparations and their uses in the related medical treatment fields.
- R 1 , R 2 , R 3 , R 4 are optionally non-hydrogen hydrocarbon groups or substituted hydrocarbon groups, wherein any two or three groups can be linked by chemical bonds, and X - is a negative ion.
- bromide ions are slowly eliminated, and it is easy to accumulate poisoning in the body. Patients with hypertension and edema should not take bromide. Patients with epilepsy should not use ammonium bromide. Patients with severe pulmonary insufficiency, bronchial asthma and respiratory center depression caused by craniocerebral injury It should be avoided, and it should be used with caution in patients with liver and renal insufficiency.
- bromide anion is less stable than chloride anion, and is easily oxidized to bromine or hypobromous acid, and hypobromous acid is further decomposed into bromic acid and elemental bromine or decomposed into bromous acid and hydrobromic acid.
- Elemental bromine is toxic and irritating. Inhalation of low concentrations of bromine can cause coughing, chest tightness, increased mucosal secretions, headache, dizziness, general discomfort, etc. Some people can cause gastrointestinal symptoms and even some people can develop allergic dermatitis (Cutaneous drug reactions: Pathogenesis and clinical classification. Journal of the American Academy of Dermatology. Bruce U. Wintroub, M.D., and Robert Stem, M.D. San Francisco and Boston. 1985.13(2):167-179). Hydrogen bromide is irritating, toxic, and easily soluble in water. Its aqueous solution is called hydrobromic acid, which is a strong acid.
- bromine affects the metabolism of iodine in the body and affects thyroid function (Metabolism of Bromide and Its Interference with the Metabolism of Iodine, S. Pavelka, Physiol. Res. 2004, 53 (Suppl. 1): S81-S90). Excessive intake of bromide will affect human health. From the results of toxicity studies, the allowable daily intake of bromine (ADI) is 0.12mg/kg body weight (Toxicity of sodium bromide in rats: effects on endocrine system and reproduction, Van Leeuwen FX, Den Tonkelaar EM, Van Logten MJ, Food Chem Toxicol. 1983, 21(4):383-9)
- bromide has poorer biocompatibility, higher toxicity and lower safety than chloride.
- Rocuronium bromide is a medium-time-acting non-depolarizing muscle relaxant currently used clinically. It has the advantages of rapid onset of action, no release of histamine, and no significant effect on autonomic nerves and cardiovascular disease. Tracheal intubation and intraoperative muscle relaxation were maintained during routine induction of anesthesia.
- rocuronium bromide The 17-position of rocuronium bromide is substituted with an acetoxy group, and its ester bond is chemically unstable and prone to hydrolysis.
- Both rocuronium bromide and pancuronium bromide currently used clinically are injections. In order to maintain their stability and reduce the generation of impurities and potency due to hydrolysis side reactions, the pH value of the injections must be kept at about 4 or lower. Even so, existing clinical drugs are still unstable and require refrigerated storage at 2-8 degrees Celsius. Others, such as vecuronium bromide, pipecuronium bromide and recuronium bromide, also require a pH of about 4 or lower for clinical use solutions.
- the intake of bromide ions is likely to exceed the safe limit, which poses a safety risk to patients.
- the safe dose limit of rocuronium bromide is 0.92mg/kg body weight/day. If this dose is exceeded, the intake of bromide ions will exceed the ADI limit, resulting in safety risks.
- the recommended induction dose of tracheal intubation is 0.6 mg/kg body weight, and its muscle relaxation time is about 30 minutes, followed by 2) intravenous infusion of 10-12 ⁇ g/kg body weight at the recommended dose /min to maintain the muscle relaxation effect, the bromine intake safety dose limit is reached when the intravenous infusion is maintained for 27-32 minutes; in the case of rapid sequence intubation (Rapid sequence intubation), the recommended induction dose is 0.6-1.2 mg/kg body weight, the bromide ion introduced by the upper limit dose has exceeded the ADI value, so patients face a very high risk of excess bromine intake in clinical muscle relaxant therapy practice.
- bromine can affect the metabolism of iodine in the body and affect thyroid function (Metabolism of Bromide and Its Interference with the Metabolism of Iodine., S. Pavelka, Physiol. Res. 2004, 53 (Suppl. 1): S81-S90). Excessive intake of bromide will affect human health. From the results of toxicity studies, the allowable daily intake of bromine (ADI) is 0.12mg/kg body weight (Toxicity of sodium bromide in rats: effects on endocrine system and reproduction., Van Leeuwen FX , Den Tonkelaar EM, Van Logten MJ, Food Chem Toxicol.
- a first aspect of the present invention provides a steroidal quaternary ammonium compound of formula I or an addition salt or a solvate thereof:
- A is CH2 or O
- R 1 is H or CH 3 CO
- X is Cl, Br or CH 3 COO
- Y is Cl, Br or CH 3 COO
- the steroidal quaternary ammonium compound or its addition salt is preferably selected from the group consisting of:
- the solvent in the solvate is water, alcohol, acid, ester, ether, ketone or halogenated hydrocarbon, and the amount of solvent may be present in a stoichiometric or non-stoichiometric ratio.
- the solvent is water, C 1-6 alcohol, C 1-6 acid, C 3 -C 6 ester, C 4-6 ether, C 3-6 ketone or C 1-6 halogenated hydrocarbon; preferably in the following group One or more of: water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, acetic acid, propionic acid, butyric acid, ethyl acetate, methyl acetate, isopropyl acetate, propyl acetate Methyl acid, ethyl propionate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, methyl e
- a method A1 for preparing the rocuronium chloride of the structure of the formula I-1 which is prepared as follows: the rocuronium bromide is dissolved in water to prepare a solution, and then enters a reversed-phase liquid chromatography , carry out gradient elution with a solution containing hydrochloric acid, collect fractions, the obtained fractions are concentrated under reduced pressure and dried to obtain rocuronium chloride hydrochloride of formula I-2 structure; the obtained rocuronium chloride salt of formula I-2 structure The acid salt is added into organic solvent A and inorganic base, stirred at room temperature, filtered, and the filtrate is concentrated to obtain the rocuronium chloride compound of formula I-1, wherein the organic solvent A includes ethyl acetate, methyl acetate, isopropyl acetate At least one or a combination of ester, methyl propionate, ethyl propionate, diethyl ether
- compound M8 is reacted with allyl chloride at a temperature of 0-80° C., preferably 20-60° C., more preferably 30-50° C., for 12-168 hours, and the reaction solution undergoes a post-treatment procedure to obtain rocuronium chloride.
- the post-processing procedure includes the following steps: concentrating the reaction solution to obtain crude rocuronium chloride, preparing by reversed-phase liquid chromatography, using aqueous ammonium acetate and methanol as mobile phases, The acetate fraction was obtained by the first elution and purification, and then entered into reversed-phase liquid chromatography for preparation. Hydrochloric acid solution and methanol were used as mobile phases, and the rocuronium chloride hydrochloride fraction was obtained after the second elution and purification.
- organic solvent A and inorganic base are added to the residue, stirred at room temperature, filtered, and the filtrate is concentrated to obtain the rocuronium chloride compound of formula I-1, wherein the organic solvent A is selected from the following group: acetic acid Ethyl ester, methyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, methyl ethyl ketone, dichloromethane, chloroform and acetonitrile or combinations thereof, preferably is selected from the group consisting of tetrahydrofuran, acetone, dichloromethane, chloroform, acetonitrile, and methyl tert-butyl ether or a combination thereof, and the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide,
- the post-processing procedure includes the following steps: concentrating the reaction solution, adding water to dissolve, adding dichloromethane or ethyl acetate for extraction, adjusting the pH of the water phase to 1-6, adding activated carbon for decolorization , filter, neutralize the pH of the filtrate to 7 ⁇ 9, the temperature of the filtrate during the neutralization process is less than or equal to 10 ° C, filter, add sodium chloride to the filtrate until a saturated solution of sodium chloride is formed, add dichloromethane for extraction, and the organic phase is dried.
- the solvent was dried, filtered, and the filtrate was concentrated, and the concentrate was added to an anhydrous solvent
- the anhydrous solvent included acetonitrile, propionitrile, methanol, ethanol, isopropanol, propanol, butanol, sec-butanol, tert-butanol, dichloromethane
- the organic solvent B includes ethers such as diethyl ether , isopropyl ether, methyl tertiary ether, tetrahydrofuran, tetrahydropyran, dioxane, or ketones such as acetone, butanone, cyclohexanone, cyclopentanone, or esters such as ethyl acetate, methyl acetate,
- the organic solvent B includes ethers such as diethyl ether , isopropyl ether, methyl tertiary ether, tetrahydrofuran, tetrahydro
- the present invention provides a preparation method B1 of the hydrochloride of rocuronium chloride or vecuronium chloride: dissolve the rocuronium chloride or vecuronium chloride compound with an organic solution of hydrogen chloride, wherein the organic solution of hydrogen chloride comprises methanol, ethanol, isomeric Hydrogen chloride solution of at least one of propanol, acetonitrile, propionitrile or a combination thereof, drop an organic solvent B into the solution, the organic solvent B includes ethers such as diethyl ether, isopropyl ether, methyl tertiary ether, tetrahydrofuran, tetrahydrofuran Pyran, dioxane, or ketones such as acetone, butanone, cyclohexanone, cyclopentanone or esters such as ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isopropyl acetate At least one
- the present invention also provides another method B2 for preparing rocuronium chloride hydrochloride with the structure of formula I-2, which comprises preparing rocuronium chloride according to the method of route 1 of the present invention, and then performing post-processing including the following steps on it Procedure: Concentrate the reaction solution, add the organic solvent B including ethers such as diethyl ether, isopropyl ether, methyl tertiary ether, tetrahydrofuran, tetrahydropyran, dioxane, or ketones such as acetone, butanone, cyclohexane Ketone, cyclopentanone, or esters such as at least one of ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isopropyl acetate, or a combination thereof, separate out the crude product, filter, dissolve the solid in water, and dissolve the water layer Extract with dichloromethane or ethyl acetate,
- Another embodiment of the preparation method B2 of the present invention includes, after preparing rocuronium chloride according to the method of route 1 of the present invention, adding an organic solvent B therein, and the organic solvent B includes ethers such as diethyl ether, isopropyl ether, methyl ether Tertiary ether, tetrahydrofuran, tetrahydropyran, dioxane, or ketones such as acetone, butanone, cyclohexanone, cyclopentanone, or esters such as ethyl acetate, methyl acetate, propyl acetate, butyl acetate At least one of ester, isopropyl acetate or its combination, after dispersing and beating, filtering step, also comprises the following steps: filter cake adds organic solvent C again, and described organic solvent C comprises pentane, hexane, heptane , at least one of petroleum ether, acetone, butanone, cyclo
- Yet another embodiment of the preparation method B2 of the present invention includes, after preparing rocuronium chloride according to the method of route 1 of the present invention, performing a post-processing procedure including the following steps: concentrating the reaction solution, adding the organic solvent B, including Ethers such as diethyl ether, isopropyl ether, methyl tertiary ether, tetrahydrofuran, tetrahydropyran, dioxane, or ketones such as acetone, butanone, cyclohexanone, cyclopentanone, or esters such as ethyl acetate, At least one of methyl acetate, propyl acetate, butyl acetate, and isopropyl acetate or its combination, separate out the crude product, filter, dissolve the solid in water, extract the aqueous layer with dichloromethane or ethyl acetate, and adjust the pH of the aqueous phase To 1-6, add activated carbon to de
- the organic solvent B includes ethers such as diethyl ether, isopropyl ether, methyl tertiary ether, tetrahydrofuran , tetrahydropyran, dioxane, or ketones such as acetone, butanone, cyclohexanone, cyclopentanone, or esters such as ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isoacetate At least one of the propyl esters or a combination thereof, crystallize, filter, and dry the filter cake under reduced pressure at a temperature of less than or equal to 40°C to obtain the rocuronium chloride hydrochloride of the structure of formula I-2.
- ethers such as diethyl ether, isopropyl ether, methyl tertiary ether, tetrahydrofuran , tetrahydropyran, dioxane, or ketones such as
- Another embodiment of the preparation method B2 of the present invention includes, after preparing rocuronium chloride according to the method of route 1 of the present invention, performing a post-processing procedure including the following steps: concentrating the reaction solution, adding an organic solvent B, the
- the organic solvent B includes ethers such as diethyl ether, isopropyl ether, methyl tertiary ether, tetrahydrofuran, tetrahydropyran, dioxane, or ketones such as acetone, butanone, cyclohexanone, cyclopentanone, or esters such as At least one of ethyl acetate, methyl acetate, propyl acetate, butyl acetate, and isopropyl acetate or a combination thereof, the crude product was separated out, filtered, the solid was dissolved in water, and the aqueous layer was extracted with dichloromethane or ethyl acetate, The water phase is adjusted to pH
- the present invention provides a method for preparing a hydrate of rocuronium chloride hydrochloride having a structure of formula I-2, which comprises the following steps after preparing rocuronium chloride according to the method of route 1 of the present invention Treatment procedure: Concentrate the reaction solution, add organic solvent B, and the organic solvent B includes ethers such as diethyl ether, isopropyl ether, methyl tertiary ether, tetrahydrofuran, tetrahydropyran, dioxane, or ketones such as acetone, Butanone, cyclohexanone, cyclopentanone or esters such as at least one of ethyl acetate, methyl acetate, propyl acetate, butyl acetate, isopropyl acetate or its combination, separate out the crude product, filter, add water to the solid Dissolve, extract the aqueous layer with dichloromethane or ethyl acetate, adjust the
- a third aspect of the present invention provides a lyophilized formulation comprising a steroidal quaternary ammonium compound or an addition salt or a solvate thereof or rocuronium or vecuronium bromide according to the present invention, and one or A variety of pharmaceutically acceptable excipients.
- the freeze-dried preparation contains any one or more pharmaceutically acceptable excipients
- the adjuvants include freeze-drying support agents and/or protective agents, or powder inhalation supplements, such as mannitol, sorbitan Alcohol, xylitol, sucrose, lactose, glucose, dextran, dextrin, maltose, maltitol, maltodextrin, erythritol, trehalose, calcium gluconate, calcium sulfate, sodium chloride, glycine, hydrolysis At least one of gelatin, human albumin, or a combination thereof.
- the freeze-dried preparation contains one or more pharmaceutically acceptable excipients
- the excipients include pH adjusters, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sodium dihydrogen phosphate, diphosphate dibasic Potassium hydrogen phosphate, ammonium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, diammonium hydrogen phosphate, sodium phosphate, potassium phosphate, ammonium phosphate, sodium hydrogen sulfate, potassium hydrogen sulfate, ammonium hydrogen sulfate, sodium hydrogen carbonate, hydrogen carbonate Potassium, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, ammonia water, citric acid, sodium dihydrogen citrate, potassium dihydrogen citrate, ammonium dihydrogen citrate, disodium hydrogen citrate, Dipotassium citrate, diammonium citrate, sodium potassium citrate, sodium citrate, sodium citrate, sodium cit
- the freeze-dried preparation contains one or more pharmaceutically acceptable excipients
- the excipients include a stabilizer
- the stabilizer includes at least one of an antioxidant or a metal ion complexing agent or a combination thereof
- the antioxidant comprises at least one of sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium thiosulfate, vitamin C, sodium thioglycolate, glycine, cysteine or a combination thereof
- the metal ion complexing agent Including at least one of disodium EDTA, calcium sodium EDTA, or a combination thereof.
- the freeze-dried preparation contains one or more pharmaceutically acceptable excipients
- the excipients include analgesics and local anesthetics, such as benzyl alcohol, chlorobutanol, Procaine, Cocaine, Tetracaine, Proparacaine, Orbucaine, Benzocaine, Lidocaine, Cincocaine, Prilocaine, Trimethaine, Bupivacaine, Levobupiva At least one of mepivacaine, ropivacaine, dyclonine, chloroprocaine, articaine, eticaine or a combination thereof.
- analgesics and local anesthetics such as benzyl alcohol, chlorobutanol, Procaine, Cocaine, Tetracaine, Proparacaine, Orbucaine, Benzocaine, Lidocaine, Cincocaine, Prilocaine, Trimethaine, Bupivacaine, Levobupiva At least one of mepivacaine, ropivacaine,
- the freeze-dried preparation contains one or more pharmaceutically acceptable excipients
- the excipients include bacteriostatic agents, such as benzyl alcohol, chlorobutanol, benzoic acid and the like. At least one of salts, sorbic acid and its salts, and parabens, or a combination thereof.
- kits comprising said steroidal quaternary ammonium compound or an addition salt or solvate thereof, or a lyophilized preparation thereof or comprising rocuronium bromide or vecuronium bromide Lyophilized preparation of ammonium.
- the steroidal quaternary ammonium compound or its addition salt or its solvate or its freeze-dried preparation or the freeze-dried preparation comprising rocuronium or vecuronium is used for the preparation of bone Muscle relaxants.
- the drug is administered by gastrointestinal and parenteral routes.
- the gastrointestinal route is the oral route;
- the parenteral route is the inhalation, intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, mucosal and deep tissue or ocular, transdermal, topical and other external routes.
- a method of treating a disease or condition in a subject comprising administering to the subject a therapeutically effective amount of a compound according to the invention or an addition salt or a solvate thereof or a lyophilized preparation thereof.
- a preparation method of a freeze-dried preparation comprising the steps of: wherein a drug, an auxiliary material and a corresponding solvent are mixed to form a solution, and the pH of the solution is adjusted to 1-7, preferably pH 2-6, and more Preferably, the pH is 3.5 to 5.5, and the filtrate is filtered, and the filtrate is freeze-dried to obtain a freeze-dried preparation.
- the solvent is water.
- the preparation method of the steroidal quaternary ammonium compound freeze-dried preparation wherein the prepared solution, wherein the steroidal quaternary ammonium compound or rocuronium bromide or vecuronium bromide concentration is 100 ⁇ g/ml-300mg/ml ,
- concentration of pharmaceutical excipients lyophilized support agent and/or protective agent, pH adjuster, antioxidant and metal ion complexing agent and other stabilizers, analgesic, bacteriostatic agent
- the preparation method of the described steroidal quaternary ammonium compound freeze-dried preparation adopts freeze-drying, and the process includes:
- the temperature of the frozen solution system is increased to a temperature in the range of -30°C to -5°C, wherein the temperature in the range of about -30°C to -5°C makes the frozen solution system Keep the frozen state; cool the frozen solution system to below -30°C again, and this process can be repeated;
- step (3) the primary drying stage, including the sublimation step, by removing the solvent in the frozen solution system in the frozen state described in step (1) or step (2) under reduced pressure, to obtain a partially dried product;
- the residual solvent in the partially dried product in the non-frozen state is removed under reduced pressure to obtain a freeze-dried product, and this stage is usually accompanied by further temperature rise.
- the above freeze-dried preparation is used to prepare a muscle relaxant drug.
- a multi-part combination kit comprising a first container and a second container, the first container containing the lyophilized preparation of the steroidal quaternary ammonium compound, the second container
- the container contains a physiologically acceptable solution for formulating the lyophilized formulation.
- the acceptable solutions include, but are not limited to, 5% dextrose solution, 0.9% sodium chloride solution, sodium lactated Ringer's solution, 5% dextrose in physiological saline solution.
- the multi-part combination kit is used for preparing clinical medicine for muscle relaxation.
- a clinical method of skeletal muscle relaxation comprising administering to a subject in need thereof an effective dose of a lyophilized formulation according to the present invention.
- the present invention also provides a solution for injection prepared from a freeze-dried preparation of a steroidal quaternary ammonium compound, the pH of the solution for injection is not lower than 4, preferably 4-8, more preferably 5-7, wherein acid-containing solution
- the concentration is 0 to 0.15M, preferably 0 to 0.1M, and more preferably 0 to 0.03M.
- the freeze-dried preparation involved in the present invention has outstanding advantages, and it is formulated into a solution for injection, the pH of the solution for injection is not lower than 4, and the pH is preferably 4-8, more preferably 5-7, wherein acid-containing solution
- the concentration is 0 to 0.15M, preferably 0 to 0.1M, and more preferably 0 to 0.03M.
- the pH of the solution for injection prepared by the freeze-dried preparation is 4.5-6.
- a solution for injection prepared from a freeze-dried preparation of rocuronium bromide, the pH of the solution for injection is 4.5-6.
- a solution for injection prepared from a freeze-dried preparation of vecuronium bromide, the pH of the solution for injection is 4.5-6.
- the quaternary ammonium chloride compound provided by the present invention has lower cost.
- the quaternary ammonium chloride compound provided by the present invention does not form genotoxic impurities, and the chloride ion in the body is better and safer than the bromide ion biocompatibility, so the safety and quality of its pharmaceutical product More controllability.
- the existing clinically used rocuronium bromide is a solution preparation with low stability and needs to be transported and stored at a low temperature of 2-8°C.
- the freeze-dried preparation of rocuronium chloride provided by the present invention is solid, has high stability compared with the above-mentioned rocuronium bromide solution preparation product, does not require low temperature, is more convenient for production, transportation, storage and use of the product, and greatly improves the performance of the drug in each Link quality assurance, thereby improving the safety of medication.
- the freeze-dried preparation of rocuronium bromide, the freeze-dried preparation of vecuronium bromide, the freeze-dried preparation of rocuronium bromide or its hydrochloride and its solvent provided by the present invention.
- the dry product completely eliminates the excess acid such as acetic acid required to maintain the pH of the solution at 4 or lower, and completely eliminates the lower pH and free acid and acid radicals in the current clinical formulations of rocuronium and vecuronium.
- the disadvantage of high total concentration leads to obvious irritation during intravenous injection, which makes the patient feel pain at the injection site. The advantages of painless injection and clinical practical value.
- Vecuronium bromide hydrobromide, vecuronium chloride and vecuronium chloride hydrochloride provided by the present invention also have rocuronium bromide hydrobromide, rocuronium chloride or its hydrochloride provided by the present invention Same advantages.
- the present invention overcomes the above-mentioned safety shortcomings of existing bromide-containing anion-containing quaternary ammonium drugs and preparations thereof, and provides a new type of quaternary ammonium compound, a preparation method and preparation thereof, which have higher safety, fewer side effects and better quality. control advantages.
- FIG. 1 EMG signals before and after administration of Solution A in Experimental Example 2.
- Figure 4 Plot of the ratio of the post-dose response plateau signal integral (8 sec duration) to the pre-dose baseline plateau signal integral (8 sec duration) in each EMG of Solutions A-C.
- Fig. 5 EMG signals before and after administration of solution D in Experimental Example 3.
- Fig. 7 EMG signals before and after administration of Solution F in Experimental Example 3.
- Figure 8 Plot of the ratio of the post-dose response plateau signal integral (8 seconds duration) to the pre-dose baseline plateau signal integration (8 seconds duration) in each EMG of solutions D-F.
- the obtained fractions were concentrated under reduced pressure not higher than 35° C. and dried in vacuo to obtain 73 mg of rocuronium hydrochloride with a yield of 37%.
- Filter cool the filtrate to 0°C, adjust the pH to 7.88 with 1 mol/L NaOH solution, filter, add sodium chloride to the filtrate to saturation. Extract with dichloromethane 10ml ⁇ 3, combine the extracts, add anhydrous sodium sulfate and dry overnight. Filter, concentrate, add 3 ml of anhydrous acetonitrile to the concentrate. Dissolve, filter, drop the filtrate into 18 ml of ether for crystallization for 2.0 hours, stir, filter, and dry the filter cake until the residual solvent is qualified, 510 mg of rocuronium chloride, with a purity greater than 99.0% .
- Filter, concentrate add 3 ml of anhydrous ethanol to the concentrate. Dissolve, filter, drop the filtrate into 18 ml of ethyl acetate for crystallization for 2.0 hours, stir, filter, and dry the filter cake until the residual solvent is qualified. 99.0%.
- Dissolve 510 mg of rocuronium chloride prepared according to the method in Example 2-5 dissolve it in 3 ml of ethanolic hydrogen chloride solution, and then add 18 ml of ether dropwise, a solid is precipitated, stir at room temperature for 2-3 hours, filter, and dry the filter cake under reduced pressure to The residual solvent is qualified, and the white solid of rocuronium chloride hydrochloride is 450 mg, and the purity is more than 99.0%.
- Example 1 Using vecuronium bromide as a raw material, referring to the operation of Example 1, 6 or 7, and using a mixture of hydrobromic acid and hydrochloric acid in different proportions instead of hydrochloric acid, the title compound was prepared.
- Example 1 Using vecuronium bromide as a raw material, referring to the operation of Example 1, 6 or 7, and using a mixture of acetic acid and hydrochloric acid in different proportions instead of hydrochloric acid, the title compound was prepared.
- Rocuronium chloride and mannitol were dissolved in water for injection into 1# 2mg/mL containing 5% mannitol, 2# 4mg/mL containing 10% mannitol, 3# 6mg/mL containing 15% mannitol solution, adjusted with hydrochloric acid.
- Rocuronium chloride and glycine were dissolved in water for injection into 4# 2mg/mL containing 2% glycine, 5# 4mg/mL containing 4% glycine, 6# 6mg/mL containing 6% glycine, 7# 8mg/mL containing 8% glycine Glycine solution, adjusted to pH 4.0-5.0 with hydrochloric acid, filtered, the filtrate was pre-frozen at -70°C for 2.5h, lyophilized by Xinzhi SCIENTZ-12N lyophilizer for 20h, the end point of lyophilization, the vacuum degree of the system was about 2.7Pa, the temperature At about 20° C., the obtained four freeze-dried substances are all white and slightly glossy lumps with smooth structure, and the above-mentioned four freeze-dried substances are rapidly reconstituted with water for injection.
- the 5# lyophilisate was reconstituted to 2mg/mL, pH 4.72, and placed at room temperature (20-25°C), the stability is as follows:
- Rocuronium chloride and dextran 40 were dissolved in water for injection into 8# 2mg/mL containing 2% dextran 40, 9# 4mg/mL containing 4% dextran 40, 10# 6mg/mL containing 6% dextran Polysaccharide 40, 11# 8mg/mL solution containing 8% dextran 40, adjusted to pH 4.0-5.0 with hydrochloric acid, filtered, the filtrate was pre-frozen at -70°C for 2.5h, and freeze-dried with Xinzhi SCIENTZ-12N type freeze dryer After drying for 20h, the freeze-drying end point, the vacuum degree of the system is about 2.7Pa, and the temperature is about 20°C, the obtained four kinds of freeze-dried products are all white and smooth in structure, and the above four kinds of freeze-dried products are rapidly reconstituted with water for injection.
- Rocuronium chloride and lactose were dissolved in water for injection into 12#3mg/mL containing 2% lactose, 13#5mg/mL containing 4% lactose, 14#7mg/mL containing 6% lactose, 15#9mg/mL containing 8% lactose, respectively
- the lactose solution was adjusted to pH 4.0-5.0 with hydrochloric acid, filtered, the filtrate was pre-frozen at -70°C for 2.5 hours, and then lyophilized by Xinzhi SCIENTZ-12N freeze-drying machine for 20 hours.
- the obtained four freeze-dried substances are all white and smooth in structure, and the above-mentioned four freeze-dried substances are rapidly reconstituted with water for injection.
- the 20#-23# lyophilisates were prepared with reference to the method in Example 27, all of which were white lumps and smooth in structure, and the above four lyophilisates were rapidly reconstituted with water for injection.
- the 27#-30# lyophilisates were prepared with reference to the method in Example 29, all of which were white lumps and smooth in structure, and the above four lyophilisates were rapidly reconstituted with water for injection.
- Neostigmine 0.02 mg/kg
- atropine 0.04 mg/kg
- mice in group A were given 1ml/mouse of rocuronium chloride freeze-dried reconstituted solution (10mg/ml) via the marginal ear vein
- animals in group B were given 1ml/mouse of the commercial preparation of rocuronium bromide (10mg/ml) via the marginal ear vein
- the liquid is injected at a constant speed in about 15-20 seconds, and the performance of the animals during and after injection is observed.
- the results are recorded in the following table:
- ⁇ Solution A 5 mg/ml rocuronium chloride in physiological saline solution
- ⁇ Solution B commercial preparation of rocuronium bromide, diluted to 5 mg/ml with normal saline;
- the solution is prepared as follows:
- 30% urethane solution Weigh 6.01 g of urethane, add 20 mL of purified water, and vortex to dissolve.
- the rats were intraperitoneally injected with 30% urethane solution. After anesthesia, they were fixed on the operation board. The surface hair of the operation site was cut off. The superficial abdominal artery on one side was found and separated with a thread. A single-use injection needle was inserted into the isolated superficial epigastric artery for drug injection, and the injection needle was replaced with the drug.
- the blank control group was injected with 5% glucose (ie, solution D) 60uL, and the above test substances, namely solution E and solution F, were injected through the superficial epigastric artery, 40ul each, and the EMG signals were recorded as shown in Figures 5 to 7 (arrows in the figure). is the start time of dosing).
- FIG. 8 is a graph of the ratio of the post-dose response plateau signal integral (8 sec duration) to the pre-dose baseline plateau signal integral (8 sec duration) in each EMG of solutions D-F.
- the rocuronium chloride compound of the present invention has less stimulation intensity and less injection pain on rats, and is basically equivalent to the 5% glucose group.
- solution E commercially available formulation of rocuronium bromide
- solution D and solution F did not have this phenomenon, indicating that rocuronium bromide was administered in the market.
- the commercially available preparations are irritating to a certain extent and have the side effect of injection pain.
- mice Three days before the experiment, the rotarod was initially screened, and the rotating speed of the mouse rotarod was set to a constant speed of 20 rpm/min.
- Five mice were placed on a rotarod with a diameter of 3 cm, the rotarod was activated, and if the mouse fell during the experiment, it was placed on the rod again.
- Each training is 4 minutes, a total of 5 times, and the interval between two trainings is more than 20 minutes as the fatigue recovery time.
- the dwell time (time from placing to dropping) of the mouse on the rotarod was recorded on the 3rd, 4th and 5th times. Mice with two dwell times of less than 4 min, immobile axes, poor jumping and physical coordination were excluded. Eligible mice were regrouped after screening. Experiments were carried out under the condition of 20-24°C air-conditioned room temperature.
- mice were placed on the rotating rod, and the time (s) from placing the mice to falling down was recorded.
- the ED50 was calculated by a linear fit using GraphPad Prism 5 software.
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Abstract
L'invention concerne un composé stéroïde d'ammonium quaternaire représenté par la formule I, ou un sel d'addition ou un solvate du composé stéroïde d'ammonium quaternaire : dans la formule, R 1 représente H ou CH 3CO ; R 2 représente CH 3 ou -CH 2CH=CH 2, et t vaut 2 ou 3 ; X représente Cl, Br ou CH 3COO ; Y représente Cl, Br ou CH 3COO ; les valeurs de m et n sont toutes les deux ≥ 0, et m + n = 1 ou 2 ; et la condition est : lorsque l'un quelconque de X et Y représente Br, m + n = 2. La présente invention concerne en outre un procédé de préparation du composé, une préparation et une utilisation.
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CN117986204A (zh) * | 2024-04-02 | 2024-05-07 | 华泰民康(沈阳)科技有限公司 | 一种盐酸达克罗宁的合成方法 |
CN117986204B (zh) * | 2024-04-02 | 2024-06-04 | 华泰民康(沈阳)科技有限公司 | 一种盐酸达克罗宁的合成方法 |
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US4297351A (en) * | 1978-09-05 | 1981-10-27 | Akzona Incorporated | Method of manufacture and use of improved 2β, 16β-piperidino androstanes |
CN1864667A (zh) * | 2006-06-02 | 2006-11-22 | 重庆医药工业研究院有限责任公司 | 一种稳定的罗库溴铵冻干制剂及其制备方法 |
CN102481195A (zh) * | 2009-04-01 | 2012-05-30 | 米歇尔技术公司 | 涂覆支架 |
CN103520121A (zh) * | 2013-10-16 | 2014-01-22 | 海南斯达制药有限公司 | 注射用维库溴铵冻干粉针剂及其制备方法 |
CN104519872A (zh) * | 2012-09-27 | 2015-04-15 | B·布郎梅尔松根股份公司 | 神经肌肉阻断剂的稳定水性组合物 |
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US4297351A (en) * | 1978-09-05 | 1981-10-27 | Akzona Incorporated | Method of manufacture and use of improved 2β, 16β-piperidino androstanes |
CN1864667A (zh) * | 2006-06-02 | 2006-11-22 | 重庆医药工业研究院有限责任公司 | 一种稳定的罗库溴铵冻干制剂及其制备方法 |
CN102481195A (zh) * | 2009-04-01 | 2012-05-30 | 米歇尔技术公司 | 涂覆支架 |
CN104519872A (zh) * | 2012-09-27 | 2015-04-15 | B·布郎梅尔松根股份公司 | 神经肌肉阻断剂的稳定水性组合物 |
CN103520121A (zh) * | 2013-10-16 | 2014-01-22 | 海南斯达制药有限公司 | 注射用维库溴铵冻干粉针剂及其制备方法 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN117986204A (zh) * | 2024-04-02 | 2024-05-07 | 华泰民康(沈阳)科技有限公司 | 一种盐酸达克罗宁的合成方法 |
CN117986204B (zh) * | 2024-04-02 | 2024-06-04 | 华泰民康(沈阳)科技有限公司 | 一种盐酸达克罗宁的合成方法 |
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