CN112876408A - 一类短效双季铵化合物及其制备方法和用途 - Google Patents
一类短效双季铵化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN112876408A CN112876408A CN202011323173.9A CN202011323173A CN112876408A CN 112876408 A CN112876408 A CN 112876408A CN 202011323173 A CN202011323173 A CN 202011323173A CN 112876408 A CN112876408 A CN 112876408A
- Authority
- CN
- China
- Prior art keywords
- substituted
- unsubstituted
- halogen
- alkyl
- substituent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 239000003158 myorelaxant agent Substances 0.000 claims abstract description 42
- 206010021118 Hypotonia Diseases 0.000 claims abstract description 21
- 230000036640 muscle relaxation Effects 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 40
- 150000002367 halogens Chemical class 0.000 claims description 40
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 125000002947 alkylene group Chemical group 0.000 claims description 28
- 230000002999 depolarising effect Effects 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 18
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 16
- 150000002430 hydrocarbons Chemical group 0.000 claims description 16
- 125000000743 hydrocarbylene group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 230000000155 isotopic effect Effects 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 150000001450 anions Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- 239000004215 Carbon black (E152) Substances 0.000 claims description 8
- 229930195733 hydrocarbon Natural products 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical group [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- -1 sulfonate ion Chemical group 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical group [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229940006460 bromide ion Drugs 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000008177 pharmaceutical agent Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 29
- 229940079593 drug Drugs 0.000 abstract description 13
- 210000003205 muscle Anatomy 0.000 abstract description 8
- YXSLJKQTIDHPOT-LJCJQEJUSA-N cisatracurium Chemical compound C1=C(OC)C(OC)=CC=C1C[C@H]1[N@+](CCC(=O)OCCCCCOC(=O)CC[N@+]2(C)[C@@H](C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 YXSLJKQTIDHPOT-LJCJQEJUSA-N 0.000 abstract description 7
- 229960000358 cisatracurium Drugs 0.000 abstract description 7
- 230000004044 response Effects 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 210000002027 skeletal muscle Anatomy 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 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 9
- 230000009471 action Effects 0.000 description 8
- 229940035363 muscle relaxants Drugs 0.000 description 8
- 229940032712 succinylcholine Drugs 0.000 description 8
- 238000011084 recovery Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 238000004237 preparative chromatography Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000002441 reversible effect Effects 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000002040 relaxant effect Effects 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 229940125904 compound 1 Drugs 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
- 238000001914 filtration Methods 0.000 description 3
- 229960002362 neostigmine Drugs 0.000 description 3
- 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 3
- 238000002627 tracheal intubation Methods 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
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 2
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000002695 general anesthesia Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000028161 membrane depolarization Effects 0.000 description 2
- 210000001611 motor endplate Anatomy 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000003156 neuromuscular nondepolarizing agent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 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
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 229940124326 anaesthetic agent Drugs 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 238000009835 boiling Methods 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 230000036540 impulse transmission Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- RZVWBASHHLFBJF-UHFFFAOYSA-N methyl piperidine-4-carboxylate Chemical compound COC(=O)C1CCNCC1 RZVWBASHHLFBJF-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000002715 neuromuscular depolarizing agent Substances 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- NPIJXCQZLFKBMV-YTGGZNJNSA-L pancuronium bromide Chemical compound [Br-].[Br-].C[N+]1([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 NPIJXCQZLFKBMV-YTGGZNJNSA-L 0.000 description 1
- 229960003379 pancuronium bromide Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 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 description 1
- 229960000491 rocuronium Drugs 0.000 description 1
- 229940125706 skeletal muscle relaxant agent Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- JFJZZMVDLULRGK-URLMMPGGSA-O tubocurarine Chemical compound C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CCN3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 JFJZZMVDLULRGK-URLMMPGGSA-O 0.000 description 1
- 229960001844 tubocurarine Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- 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
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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
本发明提供了一类短效双季铵化合物及其制备方法和用途,该双季铵化合物如式(I)所示。本发明化合物具备快速起效且超短效的非去极化肌松分子活性,在低给药剂量下,起效快,能产生完全的肌肉松弛作用,且肌力完全恢复所需时间短,明显短于阳性药顺阿曲库铵和去极化肌松药琥珀胆碱,有效克服了现有技术中非去极化肌松药存在的问题,可用于制备效果优良的非去极化肌松药物,具有良好的前景。
Description
技术领域
本发明属于化学药物合成领域,具体涉及一种双季铵盐化合物及其制备方法和用途。
背景技术
N2胆碱受体阻滞药又称骨骼肌松弛药(简称肌松药,skeletal muscularrelaxants),是一种重要麻醉手术药物。肌松药能选择性地作用于运动神经终板膜上的N2受体,阻断神经冲动向骨骼肌传递,导致骨骼肌松弛,主要用于外科手术过程中和气管插管时产生肌肉松弛作用。肌松药按其作用机制不同,主要可以分为去极化型(depolarizingmuscular relaxants)和非去极化型(nondepolarizing muscular relaxants)两大类。肌松药按其肌松作用时间长度,可分为超短效、短效、中效和长效肌松药。
去极化肌松药与运动神经终板膜上的N2受体结合,使肌细胞膜产生持久去极化作用,对ACh的反应减弱或消失,从而导致骨骼肌松弛。目前临床正在使用的去极化肌松药物有琥珀胆碱(succinylcholine,司可林,scoline)。使用琥珀胆碱后,由于不同部位的骨骼肌在药物作用下去极化出现的时间先后不同,首先出现不协调的肌束颤动,然后迅速转为肌松,以颈部、四肢和腹部肌松最明显,作用快而短暂。既可用于气管插管、气管镜、食管镜等短时的小手术,也可作全麻手术时的辅助用药,使在较浅麻醉下的骨骼肌完全松弛,减少全麻药的用量,以提高外科手术的安全性。由于琥珀胆碱作用时间短,人体持续时间为10分钟左右且起效迅速,因此在临床中常作为超短效肌松药物使用,尤其适合应用于急诊病人,从而避免了使用作用时间较长的肌松药物,在急症情况下导致的严重脑损伤甚至死亡。因此,目前去极化肌松药物琥珀胆碱是最适合用于急诊的肌松药物。但由于去极化肌松药特殊的作用机制,在使用时会产生严重的副作用,诸如血钾升高、恶心高热、心率失常、眼内压增加和胃紧张等,从而大大限制了其在临床的应用。
非去极化肌松药又称竞争型肌松药(competitive muscular relaxants),能与ACh竞争骨骼肌运动终板膜上的N2胆碱受体,本身无内在活性,但可通过阻断ACh与N2胆碱受体结合,使终板膜不能去极化,导致骨骼肌松弛。抗胆碱酯酶药如新斯的明能拮抗其骨骼肌肌松作用,过量时可用适量新斯的明解救。吸入性全麻药如麻醉乙醚和氨基苷类抗生素如链霉素能增强和延长该类药物的作用。该类药物的代表药物为筒箭毒碱。非去极化肌松药没有去极化肌松药的众多副作用,因此被公认为是临床上更安全的肌松药,但其肌松作用时间过长同样也被认为是其一大弊端。目前已经上市的所有非去极化肌松药,单次给药后骨骼肌松弛持续时间均超过10分钟,都不具有满足临床恢复快的需求。例如:已上市的临床肌松药中,米库氯铵单次给药后的肌松持续时间约为15~20分钟,顺阿曲库铵和罗库溴铵单次使用后的肌松持续时间约为40~60分钟,而泮库溴铵单次使用后肌松持续时间甚至超过60分钟,无法实现肌肉松弛的快速恢复。因此,目前临床急需起效快、恢复快的非去极化肌松药。
发明内容
为了解决上述问题,本发明提供了一类短效双季铵化合物及其制备方法和用途。
本发明提供了式(I)所示的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物:
其中,
R1、R2、R3、R4分别独立选自取代或未取代的C1~C20饱和烃基、取代或未取代的C2~C20不饱和烃基;所述饱和烃基或不饱和烃基骨架中0~5个碳原子被杂原子取代,所述杂原子为O、S;所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基;所述芳基的取代基为C1~C10饱和烃基、C1~C10烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基骨架中0~5个碳原子被杂原子取代,所述杂原子为O、S;所述亚烃基的取代基为C1~C20烷基、卤素;
R5选自氢、C1~C6烷基、3~8元环烷基;
n、m、a、b分别为0~3的整数,且n+m大于等于3,a+b大于等于3;
k=0或1;
L2为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基骨架中0~5个碳原子被杂原子取代,所述杂原子为O、S;所述亚烃基的取代基为C1~C20烷基、卤素;
M为药学上可接受的阴离子。
进一步地,
R1、R2、R3、R4分别独立选自取代或未取代的C1~C10饱和烃基、取代或未取代的C2~C10不饱和烃基;所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基;所述芳基的取代基为C1~C6饱和烃基、C1~C6烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
R5选自氢、C1~C6烷基、3~6元环烷基;
n、m、a、b分别为0~3的整数,且n+m大于等于3,a+b大于等于3;
k=0或1;
L2为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
M为药学上可接受的阴离子。
进一步地,所述化合物为式(II)所示化合物:
其中,
R1、R2、R3、R4分别独立选自取代或未取代的C1~C10饱和烃基、取代或未取代的C2~C10不饱和烃基;所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基;所述芳基的取代基为C1~C6饱和烃基、C1~C6烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
R5选自氢、C1~C6烷基、3~6元环烷基;
n、m、a、b分别为0~3的整数,且n+m大于等于3,a+b大于等于3;
L2为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
M为药学上可接受的阴离子。
进一步地,
R1、R2、R3、R4分别独立选自取代或未取代的C1~C3烷基、未取代的C2~C3烯基;所述烷基的取代基选自卤素、取代的芳基;所述芳基的取代基为C1~C3烷基、C1~C3烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、未取代的C1~C2亚烷基;
R5选自氢、C1~C3烷基;
n、m、a、b分别为0~3的整数,且n+m等于3或4,a+b等于3或4;
L2为不存在、未取代的C1~C2亚烷基;
M为溴离子,氯离子,磺酸根离子。
进一步地,所述化合物为式(III)所示化合物:
其中,
R1、R2、R3、R4分别独立选自取代或未取代的C1~C10饱和烃基、取代或未取代的C2~C10不饱和烃基;所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基;所述芳基的取代基为C1~C6饱和烃基、C1~C6烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
n、m、a、b分别为0~3的整数,且n+m大于等于3,a+b大于等于3;
L2为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
M为药学上可接受的阴离子。
进一步地,
R1、R2、R3、R4分别独立选自取代或未取代的C1~C3烷基;所述烷基的取代基选自卤素、取代的芳基;所述芳基的取代基为C1~C3烷基、C1~C3烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、未取代的C1~C2亚烷基;
n、m、a、b分别为0~3的整数,且n+m等于3或4,a+b等于3或4;
L2为不存在、未取代的C1~C2亚烷基;
M为溴离子,氯离子,磺酸根离子。
进一步地,所述化合物为如下化合物之一:
本发明还提供了前述的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物在制备肌肉松弛药物中的用途。
进一步地,所述肌肉松弛药物为非去极化肌肉松弛药物。
本发明还提供了一种药物,它是由前述的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物为活性成分,加上药学上可接受的载体或其他活性成分制备而成的混合物或组合物。
上述化合物均由两个季铵盐结构片段经某些偶联片段连接而得,因此其制备方法的一般路线为先合成目标化合物一端的季铵盐片段分子,再合成另一端季铵结构片段分子,最后将两个片段偶联后得到目标物。本发明中所述的大部分化合物的合成路线如下所示:
本发明中所述的其余部分化合物因季铵片段和偶联片段不同而有所不同,具体合成情况见相关实施例。
式(Ⅰ)所述的化合物,单次用药具有起效快,并提供2~10分钟的彻底的肌肉松弛作用,这些化合物只需依赖机体本身的代谢就可以实现超短效非去极化肌松作用,在大剂量和持续用药后仍表现出肌松作用的快速消退,同时可使用新斯的明等传统非去极化肌松药物解救剂来加快药物作用的消退,适合急诊和各类手术使用。
鉴于上述特点,具有式(Ⅰ)结构的化合物,其立体异构体或异构体混合物,其药学上可接受的盐与溶剂化物,上述物质与药学上可接受的载体和赋形剂组成的混合物,可在制备肌肉松弛药物领域中的应用,提供符合临床需求的快速和超短效肌松作用,并在持续用药后依然保持肌松作用的快速消退。
综上,本发明化合物具备快速起效且超短效的非去极化肌松分子活性,在低给药剂量下,起效快,能产生完全的肌肉松弛作用,且肌力完全恢复所需时间短,明显短于阳性药顺阿曲库铵和去极化肌松药琥珀胆碱,有效克服了现有技术中非去极化肌松药存在的问题,可用于制备效果优良的非去极化肌松药物,具有良好的前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例1、本发明化合物1的制备
1、中间体1-1的制备
将1.01克4-羟基哌啶溶于30毫升乙腈,加入1.89克4-氟苄溴和1.38克无水碳酸钾,50℃搅拌10小时,随后加入2.16克对硝基苄溴,55℃搅拌6小时,过滤,减压蒸干溶剂,得黄色固体3.6克,加入30毫升二氯甲烷,随后加入1.3克氯甲酸氯甲酯,冷水冷却下滴入1.6克吡啶,搅拌5小时。减压蒸干溶剂,残余物经柱层析得2.0克中间体1-1。
2、中间体1-2的制备
将1.43克4-哌啶甲酸甲酯和1.89克4-氟苄溴溶解在30毫升乙腈中,加入1.4克无水碳酸钾,于55℃搅拌8小时,随后加入2.16克对硝基苄溴,55℃搅拌6小时,过滤,减压蒸干溶剂,向剩余物中加入2N氢氧化钠水溶液40毫升,室温搅拌2小时,用氢溴酸水溶液调节pH值至9,减压蒸干溶剂,向残余物中加入50毫升二氯甲烷,加热至微沸,趁热过滤,滤液蒸干得1.78克亮黄色中间体1-2。
3、化合物1的制备
将0.52克中间体1-1与0.48克中间体1-2溶解在50毫升乙腈中,50℃搅拌12小时,减压蒸干溶剂,残余物经反相制备色谱分离,得白色粉末0.21克,即化合物1,产率22.5%。
1HNMR(DMSO-d6,400MHz)δ:2.07~2.28(m,2H),2.33~2.40(m,6H),2.67~2.73(m,1H),2.09~3.15(m,2H),3.34(s,broad,6H),4.58~5.02(m,9H),5.63~5.65(m,2H),7.34~7.39(m,4H),7.65~7.68(m,4H),7.91~7.93(m,4H),8.32~8.40(m,4H).
实施例2、本发明化合物2的制备
参照实施例1的方法制备出中间体2-1和中间体2-2。将0.40克中间体2-1与0.50克中间体2-2溶解在50毫升乙腈中,50℃搅拌12小时,减压蒸干溶剂,残余物经反相制备色谱分离,得白色粉末0.17克,即化合物2,产率20.3%。
1HNMR(DMSO-d6,400MHz)δ:2.07~2.11(m,3H),2.29~2.41(m,4H),2.84~2.98(m,1H),3.02(s,3H),3.16~3.22(m,2H),3.38~3.41(m,3H),3.56~3.59(m,4H),4.61(s,2H),4.71(s,2H),4.84~4.92(m,1H),5.00(s,2H),5.75(s,2H),7.32~7.40(m,4H),7.64~7.87(m,7H).
实施例3、本发明化合物3的制备
参照实施例1的方法制备出中间体3-1和中间体1-2。将0.53克中间体3-1与0.47克中间体1-2溶解在50毫升乙腈中,50℃搅拌12小时,减压蒸干溶剂,残余物经反相制备色谱分离,得白色粉末0.18克,即化合物3,产率19.0%。
1HNMR(DMSO-d6,400MHz)δ:1.82~1.84(m,1H),2.07~2.24(m,2H),2.34~2.41(m,6H),2.65~2.71(m,1H),2.08~3.15(m,2H),3.35(s,broad,6H),4.20~4.24(m,2H),4.55~5.02(m,8H),5.62~5.65(m,2H),7.33~7.39(m,4H),7.64~7.69(m,4H),7.90~7.93(m,4H),8.33~8.41(m,4H).
实施例4、本发明化合物4的制备
参照实施例1的方法制备出中间体4-1和中间体4-2。将0.52克中间体4-1与0.46克中间体4-2溶解在50毫升乙腈中,50℃搅拌12小时,减压蒸干溶剂,残余物经反相制备色谱分离,得白色粉末0.15克,即化合物4,产率20.5%。
1HNMR(DMSO-d6,400MHz)δ:1.79~1.82(m,1H),2.06~2.20(m,2H),2.32~2.44(m,6H),2.62~2.75(m,1H),2.03~3.16(m,2H),3.38(s,broad,6H),4.21~4.25(m,2H),4.50~5.01(m,8H),5.61~5.68(m,2H),7.56~7.65(m,8H),7.88~7.95(m,8H).
实施例5、本发明化合物5的制备
参照实施例1的方法制备出中间体5-1和中间体1-2。按照实施例1~6的方法,将中间体5-1与中间体1-2溶解在50毫升乙腈中,50℃搅拌12小时,减压蒸干溶剂,残余物经反相制备色谱分离,得化合物5。
1HNMR(DMSO-d6,400MHz)δ:2.06~2.26(m,2H),2.31~2.38(m,6H),2.65~2.74(m,1H),2.08~3.16(m,2H),3.37(s,broad,6H),4.59~5.04(m,9H),5.61~5.64(m,2H),7.32~7.39(m,6H),7.63~7.69(m,6H),7.90~7.95(m,2H),8.31~8.42(m,2H).
实施例6、本发明化合物6~35的制备
本发明所述的其他具体化合物6~35,均可通过本发明合成路线制备得到,本发明合成路线如下:
其制备通法参考实施例1~5:将等摩尔(1mmol)的中间体1和中间体2溶于50毫升乙腈中,50℃搅拌12小时,减压蒸干溶剂,残余物经反相制备色谱分离得到化合物Ⅰ,产率9~22%。比如,对于化合物6,其中间体1中R1、R2分别为对硝基苄基、对氟苄基,m与n的和为4,L1为亚甲基,R5为氢,中间体2中L2不存在,a与b的和为4,R3、R4为对硝基苄基、对氟苄基。若需要变换化合物Ⅰ中的阴离子,可以使用离子交换的常见方式实现。其他具体化合物及其质谱数据见表1。
表1.具体化合物及其质谱数据
实施例7、本发明化合物作为肌肉松弛剂的效果
体重2~3kg的成年雄性大白兔,使用丙泊酚按5mg/kg剂量经静脉进行麻醉诱导,实施气管插管,呼吸机供氧,丙泊酚以0.6mg/kg/min静脉输注速度维持麻醉。随后,按体重经静脉给予含一定剂量本发明所述化合物、阳性对照药顺阿曲库铵和琥珀胆碱的生理盐水溶液,使用TOF肌松监测仪检测肌力变化,记录起效(T1≤5%)所需时间和肌张力完全恢复(TOF>90%)所需时间,每组6只动物。本发明化合物与对照药物琥珀胆碱、顺阿曲库铵均使用各自的两倍ED95作为给药剂量,作为肌肉松弛剂的效果如表2所示。
表2.各化合物肌松活性测试数据
上述实验结果显示:本发明化合物给药剂量小,起效快,能产生完全的肌肉松弛作用,且肌力完全恢复(TOF>90%)所需时间远比顺阿曲库铵和去极化肌松药琥珀胆碱短。此外,本发明化合物起效时T1~4的比例逐步消失,恢复时T1~4的比例也是逐步恢复,这种TOF的变化特征属于非去极化肌松药物所特有。上述实验证明,本发明化合物具备快速起效且超短效的非去极化肌松分子活性。
综上,本发明化合物具备快速起效且超短效的非去极化肌松分子活性,在低给药剂量下,起效快,能产生完全的肌肉松弛作用,且肌力完全恢复所需时间短,明显短于阳性药顺阿曲库铵和去极化肌松药琥珀胆碱,有效克服了现有技术中非去极化肌松药存在的问题,可用于制备效果优良的非去极化肌松药物,具有良好的前景。
Claims (10)
1.式(I)所示的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物:
其中,
R1、R2、R3、R4分别独立选自取代或未取代的C1~C20饱和烃基、取代或未取代的C2~C20不饱和烃基;所述饱和烃基或不饱和烃基骨架中0~5个碳原子被杂原子取代,所述杂原子为O、S;所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基;所述芳基的取代基为C1~C10饱和烃基、C1~C10烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基骨架中0~5个碳原子被杂原子取代,所述杂原子为O、S;所述亚烃基的取代基为C1~C20烷基、卤素;
R5选自氢、C1~C6烷基、3~8元环烷基;
n、m、a、b分别为0~3的整数,且n+m大于等于3,a+b大于等于3;
k=0或1;
L2为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基骨架中0~5个碳原子被杂原子取代,所述杂原子为O、S;所述亚烃基的取代基为C1~C20烷基、卤素;
M为药学上可接受的阴离子。
2.根据权利要求1所述的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物,其特征在于:
R1、R2、R3、R4分别独立选自取代或未取代的C1~C10饱和烃基、取代或未取代的C2~C10不饱和烃基;所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基;所述芳基的取代基为C1~C6饱和烃基、C1~C6烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
R5选自氢、C1~C6烷基、3~6元环烷基;
n、m、a、b分别为0~3的整数,且n+m大于等于3,a+b大于等于3;
k=0或1;
L2为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
M为药学上可接受的阴离子。
3.根据权利要求2所述的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物,其特征在于:所述化合物为式(II)所示化合物:
其中,
R1、R2、R3、R4分别独立选自取代或未取代的C1~C10饱和烃基、取代或未取代的C2~C10不饱和烃基;所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基;所述芳基的取代基为C1~C6饱和烃基、C1~C6烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
R5选自氢、C1~C6烷基、3~6元环烷基;
n、m、a、b分别为0~3的整数,且n+m大于等于3,a+b大于等于3;
L2为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
M为药学上可接受的阴离子。
4.根据权利要求3所述的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物,其特征在于:
R1、R2、R3、R4分别独立选自取代或未取代的C1~C3烷基、未取代的C2~C3烯基;所述烷基的取代基选自卤素、取代的芳基;所述芳基的取代基为C1~C3烷基、C1~C3烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、未取代的C1~C2亚烷基;
R5选自氢、C1~C3烷基;
n、m、a、b分别为0~3的整数,且n+m等于3或4,a+b等于3或4;
L2为不存在、未取代的C1~C2亚烷基;
M为溴离子,氯离子,磺酸根离子。
5.根据权利要求2所述的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物,其特征在于:所述化合物为式(III)所示化合物:
其中,
R1、R2、R3、R4分别独立选自取代或未取代的C1~C10饱和烃基、取代或未取代的C2~C10不饱和烃基;所述饱和烷烃、不饱和烷烃的取代基分别独立选自卤素、取代或未取代的芳基;所述芳基的取代基为C1~C6饱和烃基、C1~C6烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
n、m、a、b分别为0~3的整数,且n+m大于等于3,a+b大于等于3;
L2为不存在、取代或未取代的C1~C5亚烃基;所述亚烃基的取代基为C1~C10烷基、卤素;
M为药学上可接受的阴离子。
6.根据权利要求5所述的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物,其特征在于:
R1、R2、R3、R4分别独立选自取代或未取代的C1~C3烷基;所述烷基的取代基选自卤素、取代的芳基;所述芳基的取代基为C1~C3烷基、C1~C3烷氧基、卤素、氰基、硝基、三氟甲基、羟基、酯基、烷氧羰基;
L1为不存在、未取代的C1~C2亚烷基;
n、m、a、b分别为0~3的整数,且n+m等于3或4,a+b等于3或4;
L2为不存在、未取代的C1~C2亚烷基;
M为溴离子,氯离子,磺酸根离子。
8.权利要求1~7任一项所述的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物在制备肌肉松弛药物中的用途。
9.根据权利要求8所述的用途,其特征在于:所述肌肉松弛药物为非去极化肌肉松弛药物。
10.一种药物,它是由权利要求1~7任一项所述的化合物,或其盐,或其立体异构体、或其立体异构体混合物、或其同位素标记物、或其溶剂化物为活性成分,加上药学上可接受的载体或其他活性成分制备而成的混合物或组合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2019112068027 | 2019-11-29 | ||
CN201911206802 | 2019-11-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112876408A true CN112876408A (zh) | 2021-06-01 |
CN112876408B CN112876408B (zh) | 2022-05-17 |
Family
ID=76043061
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011323173.9A Active CN112876408B (zh) | 2019-11-29 | 2020-11-23 | 一类短效双季铵化合物及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112876408B (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5827881A (en) * | 1994-02-28 | 1998-10-27 | Italfarmaco S.P.A. | Diesters of carbonic acid endowed with antiviral and anti-inflammatory activity |
US5990124A (en) * | 1997-10-24 | 1999-11-23 | Gyermek; Laszlo | Neuromuscular relaxants |
CN108727248A (zh) * | 2018-07-25 | 2018-11-02 | 四川大学华西医院 | 一类双季铵化合物及其制备方法和用途 |
CN110156666A (zh) * | 2018-02-11 | 2019-08-23 | 四川大学华西医院 | 一种阳离子类化合物及其制备方法与用途 |
CN112939896A (zh) * | 2019-11-26 | 2021-06-11 | 四川大学华西医院 | 一种双季铵化合物及其制备方法和用途 |
-
2020
- 2020-11-23 CN CN202011323173.9A patent/CN112876408B/zh active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5827881A (en) * | 1994-02-28 | 1998-10-27 | Italfarmaco S.P.A. | Diesters of carbonic acid endowed with antiviral and anti-inflammatory activity |
US5990124A (en) * | 1997-10-24 | 1999-11-23 | Gyermek; Laszlo | Neuromuscular relaxants |
CN1280578A (zh) * | 1997-10-24 | 2001-01-17 | 纽莱克森特有限责任公司 | 用作神经肌肉松弛药的双季铵衍生物 |
CN110156666A (zh) * | 2018-02-11 | 2019-08-23 | 四川大学华西医院 | 一种阳离子类化合物及其制备方法与用途 |
CN110156665A (zh) * | 2018-02-11 | 2019-08-23 | 四川大学华西医院 | 一种季铵盐类化合物及其制备方法与用途 |
CN108727248A (zh) * | 2018-07-25 | 2018-11-02 | 四川大学华西医院 | 一类双季铵化合物及其制备方法和用途 |
CN112939896A (zh) * | 2019-11-26 | 2021-06-11 | 四川大学华西医院 | 一种双季铵化合物及其制备方法和用途 |
Non-Patent Citations (1)
Title |
---|
闻大翔等: "肌肉松弛药及其拮抗剂的研究进展", 《药学进展》 * |
Also Published As
Publication number | Publication date |
---|---|
CN112876408B (zh) | 2022-05-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108727248B (zh) | 一类双季铵化合物及其制备方法和用途 | |
EP0222191B1 (de) | 4-Benzyl-1-(2H)-phthalazinon-Derivate | |
EP0181055B1 (en) | Bis-dimethoxymethyl (trimethoxybenzyl)isoquinolinium salts, their preparation and pharmaceutical compositions containing them | |
DE69830157T2 (de) | Substituierte isochinoline als ultrakurz wirkende neuromuskuläre blocker | |
CN103739553B (zh) | 含有醚侧链的n-取代咪唑羧酸酯手性化合物、制备方法和用途 | |
CN110776481A (zh) | 一类双阳离子化合物及其制备方法和用途 | |
TW202102480A (zh) | 6-側氧基-1,6-二氫噠嗪類前藥衍生物、其製備方法及其在醫藥上的應用 | |
JPH05508648A (ja) | 神経筋遮断剤 | |
CN113698345A (zh) | 作为钾通道调节剂的化合物及其制备和应用 | |
EP3517537B1 (en) | Deuterated derivative of l-tetrahydropalmatine and medical use thereof | |
CN112939896B (zh) | 一种双季铵化合物及其制备方法和用途 | |
EP0125636A1 (de) | Pyridazinone, ihre Herstellung und Verwendung, Pyridazinone enthaltende Arzneimittel | |
CN112876408B (zh) | 一类短效双季铵化合物及其制备方法和用途 | |
EP0170861B1 (de) | 3-Aminocarbonylmethoxy-5-phenylpyrazol-Verbindungen sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel | |
JP7096559B2 (ja) | トリプトリド誘導体およびその製造方法と使用 | |
CN112876373A (zh) | 一种双季铵化合物及其制备方法和用途 | |
WO2020249120A9 (zh) | 氨基硫醇类化合物作为脑神经或心脏保护剂的用途 | |
WO2021150697A1 (en) | N-substituted-3-tricyclyl piperidine derivatives as anticancer and neuroprotective agents | |
CN112851599A (zh) | 一种具有双阳离子季铵盐结构的化合物及其制备方法和用途 | |
CN113087686B (zh) | 一类含氰基的双季铵类化合物及其制备方法和用途 | |
CN111662230A (zh) | 一类苄基异喹啉化合物、制备方法和用途 | |
CN115785094B (zh) | 苄基取代α-咔啉化合物或其药用盐、其药物组合物及其制备方法和用途 | |
DE69602248T4 (de) | 4a-aryldecahydroisochinolin-verbindungen und ihre medizinische verwendungen | |
WO2021150700A1 (en) | N-substituted-3-tricyclyl piperidine derivatives as anticancer and neuroprotective agents | |
DE2843328A1 (de) | Phenylacetamidverbindungen und sie enthaltende zusammensetzung |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
EE01 | Entry into force of recordation of patent licensing contract | ||
EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20210601 Assignee: YICHANG HUMANWELL PHARMACEUTICAL Co.,Ltd. Assignor: WEST CHINA HOSPITAL OF SICHUAN University Contract record no.: X2022990000253 Denomination of invention: A class of short acting double quaternary ammonium compounds and their preparation methods and uses Granted publication date: 20220517 License type: Exclusive License Record date: 20220610 |