WO2022206985A1 - 一种环状酮类化合物的新用途 - Google Patents
一种环状酮类化合物的新用途 Download PDFInfo
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- WO2022206985A1 WO2022206985A1 PCT/CN2022/084968 CN2022084968W WO2022206985A1 WO 2022206985 A1 WO2022206985 A1 WO 2022206985A1 CN 2022084968 W CN2022084968 W CN 2022084968W WO 2022206985 A1 WO2022206985 A1 WO 2022206985A1
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- Prior art keywords
- saturated
- group
- unsubstituted
- substituted
- alkyl
- Prior art date
Links
- -1 cyclic ketone compound Chemical class 0.000 title abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 69
- 229910052739 hydrogen Inorganic materials 0.000 claims description 68
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 65
- 125000000623 heterocyclic group Chemical group 0.000 claims description 65
- 229920006395 saturated elastomer Polymers 0.000 claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 63
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 61
- 229910052805 deuterium Inorganic materials 0.000 claims description 61
- 150000002431 hydrogen Chemical group 0.000 claims description 60
- 239000001257 hydrogen Substances 0.000 claims description 60
- 229910052736 halogen Inorganic materials 0.000 claims description 51
- 150000002367 halogens Chemical class 0.000 claims description 51
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 claims description 45
- 229910052722 tritium Inorganic materials 0.000 claims description 45
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 32
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 32
- 229940079593 drug Drugs 0.000 claims description 31
- 206010002091 Anaesthesia Diseases 0.000 claims description 30
- 230000037005 anaesthesia Effects 0.000 claims description 30
- 239000005557 antagonist Substances 0.000 claims description 26
- 125000002947 alkylene group Chemical group 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 20
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 20
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 20
- 239000003193 general anesthetic agent Substances 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims description 17
- 229960004134 propofol Drugs 0.000 claims description 17
- 239000000932 sedative agent Substances 0.000 claims description 17
- 230000003444 anaesthetic effect Effects 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 238000002347 injection Methods 0.000 claims description 15
- 239000007924 injection Substances 0.000 claims description 15
- 230000001624 sedative effect Effects 0.000 claims description 13
- 229910006069 SO3H Inorganic materials 0.000 claims description 12
- 229910003828 SiH3 Inorganic materials 0.000 claims description 12
- OLRJXMHANKMLTD-UHFFFAOYSA-N silyl Chemical compound [SiH3] OLRJXMHANKMLTD-UHFFFAOYSA-N 0.000 claims description 12
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 12
- 229940005494 general anesthetics Drugs 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 9
- 206010039897 Sedation Diseases 0.000 claims description 8
- 230000036280 sedation Effects 0.000 claims description 8
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 7
- 229960001690 etomidate Drugs 0.000 claims description 7
- 150000001557 benzodiazepines Chemical class 0.000 claims description 6
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical group NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 230000002441 reversible effect Effects 0.000 claims description 6
- 229940049706 benzodiazepine Drugs 0.000 claims description 5
- 239000003483 4 aminobutyric acid A receptor stimulating agent Substances 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 125000004419 alkynylene group Chemical group 0.000 claims description 4
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 4
- 239000002207 metabolite Substances 0.000 claims description 4
- 150000002989 phenols Chemical class 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 229940002612 prodrug Drugs 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 2
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 claims description 2
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 230000002860 competitive effect Effects 0.000 claims description 2
- 229960003529 diazepam Drugs 0.000 claims description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 229960004391 lorazepam Drugs 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 claims description 2
- 229960003793 midazolam Drugs 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 14
- 238000002695 general anesthesia Methods 0.000 description 16
- 238000011084 recovery Methods 0.000 description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 14
- 229940090044 injection Drugs 0.000 description 13
- 230000003042 antagnostic effect Effects 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 238000001802 infusion Methods 0.000 description 8
- 239000002960 lipid emulsion Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000002609 medium Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000028527 righting reflex Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 229940035674 anesthetics Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- OFBIFZUFASYYRE-UHFFFAOYSA-N flumazenil Chemical group C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 description 3
- 229960004381 flumazenil Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000003158 myorelaxant agent Substances 0.000 description 3
- 230000011514 reflex Effects 0.000 description 3
- 229940125723 sedative agent Drugs 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010040030 Sensory loss Diseases 0.000 description 1
- 229920002370 Sugammadex Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- DFBKLUNHFCTMDC-GKRDHZSOSA-N endrin Chemical compound C([C@@H]1[C@H]2[C@@]3(Cl)C(Cl)=C([C@]([C@H]22)(Cl)C3(Cl)Cl)Cl)[C@@H]2[C@H]2[C@@H]1O2 DFBKLUNHFCTMDC-GKRDHZSOSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940046926 etomidate injection Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- 229960002362 neostigmine Drugs 0.000 description 1
- 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 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000012501 relaxation of skeletal muscle Effects 0.000 description 1
- OYTJKRAYGYRUJK-FMCCZJBLSA-M rocuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 OYTJKRAYGYRUJK-FMCCZJBLSA-M 0.000 description 1
- 229960003682 rocuronium bromide Drugs 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- WHRODDIHRRDWEW-VTHZAVIASA-N sugammadex Chemical compound O([C@@H]([C@@H]([C@H]1O)O)O[C@H]2[C@H](O)[C@H]([C@@H](O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O3)O[C@@H]2CSCCC(O)=O)O)[C@H](CSCCC(O)=O)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H]3[C@@H](CSCCC(O)=O)O1 WHRODDIHRRDWEW-VTHZAVIASA-N 0.000 description 1
- 229960002257 sugammadex Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61K31/13—Amines
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- 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
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Definitions
- the invention belongs to the field of pharmacy, and in particular relates to a new use of a cyclic ketone compound in the field of perioperative medicine.
- General anesthesia referred to as general anesthesia
- general anesthesia is a class of drugs that can inhibit the function of the central nervous system. It can reversibly cause loss of consciousness, sensation and reflex, and relaxation of skeletal muscles. It is mainly used in surgical anesthesia.
- Postoperative anesthesia recovery time has always been one of the clinical concerns, which is closely related to many factors. Prolonged recovery time from postoperative anesthesia will increase the time of patients with endotracheal intubation, prolong the exposure time of patients to general anesthesia risk, increase the incidence of cardiovascular and pulmonary complications, and affect the prognosis of surgical patients. In addition, the prolongation of anesthesia recovery time will greatly reduce the utilization efficiency of the operating room, increase the vacancy rate of the operating room, and increase the cost of patients and medical staff. Moreover, with the update of the concept of day surgery, rapid recovery from anesthesia and good recovery quality are the cornerstones for promoting day surgery and ensuring the safety of day surgery.
- opioid antagonists naloxone such as opioid antagonist naloxone, broad-spectrum muscle relaxant antagonist neostigmine, and muscle relaxant drugs.
- the specific antagonists of rocuronium bromide such as sugammadex, can quickly reverse the anesthesia effect of opioids or muscle relaxants, which is beneficial to the recovery of patients and the reversal of anesthesia in emergency situations.
- rocuronium bromide such as sugammadex
- Flumazenil is a benzodiazepine Drug-like specific antagonists that can reverse the effects of benzodiazepines drug-induced anesthesia.
- flumazenil has no significant antagonistic effect on propofol-induced anesthesia.
- benzodiazepines Such drugs are no longer routinely used in clinical anesthesia, and it is urgent to develop a broader spectrum of general anesthesia antagonists, especially covering common general anesthesia drugs such as propofol and etomidate.
- the purpose of the present invention is to provide a new use of a cyclic ketone compound in the field of perioperative medicine.
- the present invention provides the compound represented by formula I, or its stereoisomer, or its deuterated derivative, or its tritiated derivative, or its metabolite, or its prodrug, or its salt, or its solvate Use of substances in the preparation of anesthetic and/or sedative antagonists:
- n 0 or 1
- n 0 or 1; when m is 1, R 10 is none;
- R 0 is selected from L 0 L 1 L 2 R x1 ;
- R 3 and R 10 are each independently selected from L 8 L 9 L 10 R x5 ;
- L 11 , L 12 , L 13 , L 14 , L 15 are each independently selected from unsubstituted, substituted or unsubstituted following groups: NHCO, NHCS, CO, COO, OCO, OCOO, C(SO), O, S, SO, SO 2.
- NH, CH N, CONH, NH(CS)S(CH 2 ), C 1-3 alkylene;
- R 10 is linked to R 5 to form a ring
- R 8 and R 9 are each independently selected from L 16 L 17 L 18 R x9 ;
- R 3 is selected from L 8 L 9 L 10 R x5 ;
- L 11 , L 12 , L 13 , L 14 , L 15 are each independently selected from unsubstituted, substituted or unsubstituted following groups: NHCO, NHCS, CO, COO, OCO, OCOO, C(SO), O, S, SO, SO 2.
- NH, CH N, CONH, NH(CS)S(CH 2 ), C 1-3 alkylene;
- R 8 and R 9 are each independently selected from L 16 L 17 L 18 R x9 ;
- R 0 is selected from hydrogen, deuterium, tritium, C 1-5 alkyl, C 1-5 alkyl substituted by 1-3 R a , C 1-5 alkoxy, C 1-3 R a Substituted C 1-5 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, saturated or unsaturated heterocyclic group, saturated or unsaturated cycloalkyl group, fused cycloalkyl group, fused heterocyclic group;
- Each R is independently selected from deuterium , tritium, halogen, hydroxyl;
- R e is selected from hydrogen, deuterium, tritium, C 1-5 alkyl;
- R h1 is selected From hydroxyl, C 1-5 alkyl;
- R 3 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-5 alkyl, L f COOR f , C 1-5 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, saturated or Unsaturated heterocyclic group, saturated or unsaturated cycloalkyl group, fused cycloalkyl group, fused heterocyclic group; L f is none or C 1-3 alkylene group, R f is selected from hydrogen, deuterium, tritium, C 1- 5 alkyl;
- R 5 is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, OCOR b , C 1-5 alkyl, C 1-5 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, saturated or unsaturated Heterocyclic group, saturated or unsaturated cycloalkyl group, fused cycloalkyl group, fused heterocyclic group; R b is C 1-5 alkyl;
- R 6 and R 7 are each independently selected from hydrogen, deuterium, tritium, halogen, C 1-5 alkyl, COOR g , C 1-5 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, Saturated or unsaturated heterocyclic group, saturated or unsaturated cycloalkyl group, fused cycloalkyl group, fused heterocyclic group;
- R g is selected from hydrogen, deuterium, tritium, C 1-5 alkyl;
- R 8 and R 9 are independently selected from hydrogen, deuterium, tritium, C 1-5 alkyl, C 1-6 alkyl substituted by 1-3 R c , C 1-5 alkoxy, 3 R c substituted C 1-5 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, saturated or unsaturated heterocyclic group, saturated or unsaturated cycloalkyl, fused cycloalkyl, fused Heterocyclyl; R c is independently selected from halogen, COOR d , hydroxyl, C 1-5 alkyl, deuterium, tritium; R d is selected from hydrogen, deuterium, tritium, C 1-5 alkyl.
- R e is selected from hydrogen, deuterium, C 1-3 alkyl;
- R h1 is selected from hydroxyl , C 1-3 alkyl;
- R 5 is selected from hydrogen, deuterium, halogen, hydroxyl, OCOR b ; R b is C 1-3 alkyl;
- R 6 and R 7 are each independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, and COOR g ;
- R g is selected from hydrogen, deuterium, and C 1-3 alkyl;
- R 8 and R 9 are each independently selected from hydrogen, deuterium, C 1-3 alkyl, and C 1-3 alkyl substituted by 1 to 3 R c ;
- R c is independently selected from halogen, COOR d , hydroxyl , C 1-3 alkyl, deuterium;
- R d is selected from hydrogen, deuterium, C 1-3 alkyl.
- R 0 is selected from methyl, methyl substituted by 1-3 R a ;
- R a is independently selected from deuterium, halogen, hydroxyl;
- R 3 is selected from hydrogen, hydroxyl, halogen, C 1-3 alkyl, L f COOH; L f is methylene;
- R 5 is selected from hydrogen, halogen, hydroxyl, OCOR b ; R b is methyl;
- R 6 is selected from hydrogen, halogen, methyl, COOH
- R 8 and R 9 are each independently selected from hydrogen, methyl, and methyl substituted by 1 to 3 R c ;
- R c is each independently selected from halogen, COOH, hydroxyl, methyl, and deuterium.
- the compound is selected from:
- the compound is selected from:
- anesthetic and/or sedative antagonists are antagonists of anesthetics and/or antagonists of sedatives.
- anesthetic and/or sedative antagonist can reverse the anesthetic and/or sedative state induced or maintained by the anesthetic and/or sedative.
- anesthesia and/or sedation antagonist can reduce anesthesia and/or sedation time.
- anesthetics include GABA A receptor agonists.
- anesthetic and/or sedative antagonists are GABA A receptor high-affinity ligands, which can act as competitive antagonists to antagonize GABA A receptor agonists.
- anesthetics are general anesthetics.
- the general anesthetics include benzodiazepines Drugs, substituted phenols, imidazoles, GABA-mimicking drugs.
- benzodiazepine Class drugs include diazepam, midazolam, lorazepam, remazolam;
- the substituted phenol drugs include propofol and cyclopofol;
- the imidazole drugs include etomidate or derivatives thereof;
- the GABA-mimicking drugs include ⁇ -aminobutyric acid and ⁇ -hydroxybutyric acid.
- anesthetic and/or sedative antagonist is the compound, or its stereoisomer, or its deuterated derivative, or its metabolite, or its prodrug, or its salt, or its solvent.
- the compound is the active ingredient, and the preparation is prepared by adding pharmaceutically acceptable auxiliary materials.
- the preparation is tablet, capsule, oral liquid, granule, pill, powder, injection or powder injection.
- a-b alkyl denotes any alkyl group containing "a" to "b” carbon atoms.
- a C 1-5 alkyl group refers to a straight or branched chain alkyl group containing 1 to 5 carbon atoms.
- Substituted herein refers to the replacement of 1, 2 or more hydrogen atoms in a molecule by a different atom or molecule, including 1, 2 or more substitutions on isotopic or isotopic atoms in the molecule .
- Substituted or unsubstituted group means that the group may be unsubstituted or further substituted by one or two or more substituents. Unless otherwise specified, the substituents may make the final compound structure Any substituent that remains stable.
- Fused cycloalkyl refers to a polycyclic cycloalkyl in which two rings share two adjacent carbon atoms.
- Heterofused ring group refers to a polycyclic heterocyclic group in which two rings share two adjacent carbon atoms or heteroatoms.
- Halogen is fluorine, chlorine, bromine or iodine.
- a “deuterated derivative” refers to a compound obtained by replacing one or more hydrogen atoms in a compound with deuterium.
- a "tritiated derivative” refers to a compound obtained by replacing one or two or more hydrogen atoms in a compound with tritium.
- Salt is an acid and/or base salt of a compound or its stereoisomer with inorganic and/or organic acids and/or bases, including zwitterionic salts (inner salts), as well as quaternary ammonium salts , such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing a compound, or a stereoisomer thereof, with a certain amount of acid or base as appropriate (eg, equivalent). These salts may be precipitated in solution and collected by filtration, recovered after evaporation of the solvent, or obtained by lyophilization after reaction in an aqueous medium.
- the salts described in the present invention can be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate of the compound salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
- the present invention finds for the first time that the cyclic ketone compound represented by formula I has good general anesthesia and sedation antagonism.
- the experimental results show that the compound of the present invention has a good antagonistic effect on general anesthesia induced by various general anesthesia drugs (including propofol, etomidate, remazolam, etc.)
- the recovery time of positive reflex significantly shortened the time for mice to return to normal walking.
- the compounds of the present invention can also exert an effective antagonistic effect on general anesthesia maintained by continuous infusion of the general anesthetic drug propofol.
- the present invention provides a new option for antagonists of anesthesia and/or sedatives, especially general anesthetics, and has broad application prospects.
- the raw materials and equipment used in the present invention are all known products, obtained by purchasing commercially available products.
- Embodiment 1 The antagonistic effect of each compound on different general anesthetics
- Propofol injection (batch number: 2010083, Xi'an Libang), etomidate injection (purity>98%), remazolam (purity>98%), medium and long chain fat emulsion injection.
- the preparation method is as follows: respectively weigh an appropriate amount of the compound to be tested, add an appropriate amount of medium and long-chain fat emulsion injection with a pipette, prepare a 50 mmol/L solution of the compound to be tested, filter with a 0.22 ⁇ m microporous membrane, immediately use.
- mice with a body weight of 25g ⁇ 1g were randomly divided into 8 groups, with 8 mice in each group, and were given a single injection of propofol 22.11mg/kg (1.5 times ED 50 ) and etomidate 4.48mg/kg (2 times ED 50 ) and remazolam 57.34 mg/kg (1.5 times ED 50 ) for induction of anesthesia, the injection time was 15 seconds, the mice maintained the disappearance of righting reflex for 30 seconds, and then were injected with 50 mg/kg of the test compound solution (medium and long).
- Chain fat emulsion injection as solvent) or an equal volume of medium and long chain fat emulsion injection observe and record the total time of mice anesthesia.
- the total time of anesthesia refers to the time from the disappearance of the righting reflex of the mouse to the recovery of the righting reflex of the mouse.
- Example 2 The antagonistic effect of compound on continuous infusion of general anesthetics
- Propofol injection (batch number: 2010083, Xi'an Libang), medium and long chain fat emulsion injection.
- the preparation method is as follows: the same as in Example 1.
- mice Twenty-four male SD rats with a body weight ranging from 250 to 300 g were randomly divided into 4 groups with 6 rats in each group. 22.11 mg/kg (1.5 times ED 50 ) propofol was used for continuous anesthesia induction, and 1 mg/(kg ⁇ min) to maintain anesthesia for 30 minutes, immediately after drug withdrawal, inject 10mg/kg, 20mg/kg, 50mg/kg85 and 50mg/kg of the test compound solution (medium and long chain fat emulsion injection as solvent) or an equal volume Medium and long chain fat emulsion injection, observe and record the recovery time of mice after drug withdrawal.
- the anesthesia recovery time refers to the time from the stop of propofol infusion to the recovery of the righting reflex of the mice.
- the compound 85 provided by the present invention can effectively reverse the anesthesia maintenance effect of the continuous infusion of propofol, and the compound 85 can dose-dependently shorten the recovery time of anesthesia in rats.
- the compounds listed in the table reversed the anesthesia maintenance effect of continuous infusion of propofol, as demonstrated by a reduction in the mean time to recovery in mice.
- the present invention provides the use of the cyclic ketone compounds represented by formula I in the preparation of anesthetic and/or sedative antagonists.
- the present invention finds for the first time that the cyclic ketone compound has good general anesthesia and sedation antagonism.
- the experimental results show that the compound of the present invention has a good antagonistic effect on general anesthesia induced by various general anesthesia drugs (including propofol, etomidate, remazolam, etc.)
- the recovery time of positive reflex significantly shortened the time for mice to return to normal walking.
- the compounds of the present invention can also exert an effective antagonistic effect on general anesthesia maintained by continuous infusion of the general anesthetic drug propofol.
- the present invention provides a new option for antagonists of anesthesia and/or sedatives, especially general anesthetics, and has broad application prospects.
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Abstract
提供了一种环状酮类化合物的新用途，属于制药领域。首次发现了该环状酮类化合物在围术期医学领域的制药新用途，应用前景广阔。
Description
本发明属于制药领域，具体涉及一种环状酮类化合物在围术期医学领域中的新用途。
全身麻醉药简称全麻药，是一类能抑制中枢神经系统功能的药物，其能可逆性引起意识、感觉和反射消失，骨骼肌松弛，主要应用于外科手术麻醉。术后麻醉苏醒时间一直是临床关注的问题之一，其与多种因素密切相关。术后麻醉苏醒时间延长会增加患者气管插管带管时间，延长患者暴露于的全身麻醉风险的时间，增加心血管、肺部并发症的发生率，影响手术病人的预后。此外，麻醉苏醒时间的延长会极大的降低手术室利用效率，增加手术室空置率，增加病人及医护人员的成本。而且，随着日间手术理念的更新，快速的麻醉苏醒和良好的苏醒质量是推广日间手术、保证日间手术安全性的基石。
随着对手术安全性、可控性要求的增加，目前已经出现了部分麻醉药物的拮抗剂，如阿片药物的拮抗药物纳洛酮、广谱肌肉松弛药拮抗药新斯的明，肌松药物罗库溴铵特异性拮抗剂舒更葡糖等，这些拮抗剂可快速逆转阿片药物或肌松药物的麻醉作用，利于患者苏醒和紧急情况下对麻醉作用的逆转。但是，目前对于全身麻醉药物，还缺乏解决长时间输注时的苏醒延迟、紧急情况下逆转全身麻醉药物作用的手段和方法。
目前，临床上使用的具有明确拮抗作用的药物有氟马西尼。氟马西尼是苯二氮
类药物特异性的拮抗剂，可以逆转由苯二氮
类药物诱导产生的麻醉效应。但已有研究证明，氟马西尼对于丙泊酚诱导的麻醉作用无显著的拮抗作用。考虑到苯二氮
类药物已不再常规应用于临床麻醉中，亟需开发出更广谱的，尤其是覆盖丙泊酚、依托咪酯等常见全身麻醉药物的全麻作用拮抗药。
发明内容
本发明的目的在于提供一种环状酮类化合物在围术期医学领域中的新用途。
本发明提供了式I所示化合物、或其立体异构体、或其氘代衍生物、或其氚代衍生物、或其代谢产物、或其前体药物、或其盐、或其溶剂合物在制备麻醉和/或镇静拮抗药中的用途：
其中，n为0或1；
m为0或1；当m为1时，R
10为无；
R
0选自L
0L
1L
2R
x1；
L
0、L
1、L
2各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO
2、NH、CH＝N、CONH、NH(CS)S(CH
2)、C
1～3亚烷基、C
2～4亚烯基、C
2～4亚炔基；
R
x1选自氢、氘、氚、卤素、醛基、CN、N
3、NO
2、OAc、取代或未取代的以下基团：OSiH
3、OOSiH
3、SO
3H、SiH
3、CS
2H、CSNH
2、NH
2、COOH、SH、SeO
2H、OH、N＝NH、＝O、CH＝NH、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；
R
1、R
2各自独立地选自L
3L
4L
5R
x2、＝NL
5R
x2、＝C(L
6R
x3)(L
7R
x4)；或者R
1、R
2连接成环；
L
3、L
4、L
5、L
6、L
7各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO
2、NH、CH＝N、CONH、NH(CS)S(CH
2)、C
1～3亚烷基；
R
x2、R
x3、R
x4各自独立地选自氢、氘、氚、卤素、醛基、CN、N
3、NO
2、OAc、取代或未取代的以下基团：OSiH
3、OOSiH
3、SO
3H、SiH
3、CS
2H、NH
2、COOH、SH、SeO
2H、OH、N＝NH、＝O、CH＝NH、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；
R
3、R
10各自独立地选自L
8L
9L
10R
x5；
L
8、L
9、L
10各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO
2、NH、CH＝N、CONH、NH(CS)S(CH
2)、C
1～3亚烷基；
R
x5选自氢、氘、氚、卤素、醛基、CN、N
3、NO
2、OAc、取代或未取代的以下基团：OSiH
3、OOSiH
3、SO
3H、SiH
3、CS
2H、CSNH
2、NH
2、COOH、SH、SeO
2H、OH、N＝NH、＝O、CH＝NH、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环 基；
R
4、R
5、R
6、R
7各自独立地选自L
11L
12L
13R
x6、＝NL
13R
x6、＝C(L
14R
x7)(L
15R
x8)；L
11、L
12、L
13、L
14、L
15各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO
2、NH、CH＝N、CONH、NH(CS)S(CH
2)、C
1～3亚烷基；
R
x6、R
x7、R
x8各自独立地选自氢、氘、氚、卤素、醛基、CN、N
3、NO
2、OAc、取代或未取代的以下基团：OSiH
3、OOSiH
3、SO
3H、SiH
3、CS
2H、NH
2、COOH、SH、SeO
2H、OH、N＝NH、＝O、CH＝NH、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；
或者，R
10与R
5连接成环；
R
8、R
9各自独立地选自L
16L
17L
18R
x9；
L
16、L
17、L
18各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO
2、NH、CH＝N、CONH、NH(CS)S(CH
2)、C
1～3亚烷基；
R
x9选自氢、氘、氚、卤素、醛基、CN、N
3、NO
2、OAc、取代或未取代的以下基团：OSiH
3、OOSiH
3、SO
3H、SiH
3、CS
2H、CSNH
2、NH
2、COOH、SH、SeO
2H、OH、N＝NH、＝O、CH＝NH、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基。
进一步地，所述化合物为式II所示化合物：
其中，R
0选自L
0L
1L
2R
x1；
L
0、L
1、L
2各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO
2、NH、CH＝N、CONH、NH(CS)S(CH
2)、C
1～3亚烷基、C
2～4亚烯基、C
2～4亚炔基；
R
x1选自氢、氘、氚、卤素、醛基、CN、N
3、NO
2、OAc、取代或未取代的以下基团：OSiH
3、OOSiH
3、SO
3H、SiH
3、CS
2H、CSNH
2、NH
2、COOH、SH、SeO
2H、OH、N＝NH、＝O、CH＝NH、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环 基；
R
1、R
2各自独立地选自L
3L
4L
5R
x2、＝NL
5R
x2、＝C(L
6R
x3)(L
7R
x4)；或者R
1、R
2连接成环；
L
3、L
4、L
5、L
6、L
7各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO
2、NH、CH＝N、CONH、NH(CS)S(CH
2)、C
1～3亚烷基；
R
x2、R
x3、R
x4各自独立地选自氢、氘、氚、卤素、醛基、CN、N
3、NO
2、OAc、取代或未取代的以下基团：OSiH
3、OOSiH
3、SO
3H、SiH
3、CS
2H、NH
2、COOH、SH、SeO
2H、OH、N＝NH、＝O、CH＝NH、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；
R
3选自L
8L
9L
10R
x5；
L
8、L
9、L
10各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO
2、NH、CH＝N、CONH、NH(CS)S(CH
2)、C
1～3亚烷基；
R
x5选自氢、氘、氚、卤素、醛基、CN、N
3、NO
2、OAc、取代或未取代的以下基团：OSiH
3、OOSiH
3、SO
3H、SiH
3、CS
2H、CSNH
2、NH
2、COOH、SH、SeO
2H、OH、N＝NH、＝O、CH＝NH、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；
R
4、R
5、R
6、R
7各自独立地选自L
11L
12L
13R
x6、＝NL
13R
x6、＝C(L
14R
x7)(L
15R
x8)；L
11、L
12、L
13、L
14、L
15各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO
2、NH、CH＝N、CONH、NH(CS)S(CH
2)、C
1～3亚烷基；
R
x6、R
x7、R
x8各自独立地选自氢、氘、氚、卤素、醛基、CN、N
3、NO
2、OAc、取代或未取代的以下基团：OSiH
3、OOSiH
3、SO
3H、SiH
3、CS
2H、NH
2、COOH、SH、SeO
2H、OH、N＝NH、＝O、CH＝NH、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；
R
8、R
9各自独立地选自L
16L
17L
18R
x9；
L
16、L
17、L
18各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO
2、NH、CH＝N、CONH、NH(CS)S(CH
2)、C
1～3亚烷基；
R
x9选自氢、氘、氚、卤素、醛基、CN、N
3、NO
2、OAc、取代或未取代的以下基团：OSiH
3、OOSiH
3、SO
3H、SiH
3、CS
2H、CSNH
2、NH
2、COOH、SH、SeO
2H、OH、N＝NH、＝O、CH＝NH、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基。
进一步地，所述化合物为式III所示化合物：
其中，R
0选自氢、氘、氚、C
1～5烷基、被1～3个R
a取代的C
1～5烷基、C
1～5烷氧基、被1～3个R
a取代的C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R
a各自独立地选自氘、氚、卤素、羟基；
R
2选自氢、氘、氚、卤素、COOR
e、SR
e、OR
e、C
1～5烷基、＝NR
h1、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R
e选自氢、氘、氚、C
1～5烷基；R
h1选自羟基、C
1～5烷基；
R
3选自氢、氘、氚、羟基、卤素、C
1～5烷基、L
fCOOR
f、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；L
f为无或C
1～3亚烷基，R
f选自氢、氘、氚、C
1～5烷基；
R
5选自氢、氘、氚、卤素、羟基、OCOR
b、C
1～5烷基、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R
b为C
1～5烷基；
R
6、R
7各自独立地选自氢、氘、氚、卤素、C
1～5烷基、COOR
g、C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R
g选自氢、氘、氚、C
1～5烷基；
R
8、R
9各自独立地选自氢、氘、氚、C
1～5烷基、被1～3个R
c取代的C
1～6烷基、C
1～5烷氧基、被1～3个R
c取代的C
1～5烷氧基、C
2～6烯基、C
2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R
c各自独立地选自卤素、COOR
d、羟基、C
1～5烷基、氘、氚；R
d选自氢、氘、氚、C
1～5烷基。
进一步地，R
0选自氢、氘、C
1～3烷基、被1～3个R
a取代的C
1～3烷基；R
a各自独立地选自氘、卤素、羟基；
R
2选自氢、氘、卤素、COOR
e、SR
e、OR
e、C
1～3烷基、＝NR
h1；R
e选自氢、氘、C
1～3烷基；R
h1选自羟基、C
1～3烷基；
R
3选自氢、氘、羟基、卤素、C
1～3烷基、L
fCOOR
f；L
f为无或C
1～3亚烷基，R
f选自氢、氘、C
1～3烷基；
R
5选自氢、氘、卤素、羟基、OCOR
b；R
b为C
1～3烷基；
R
6、R
7各自独立地选自氢、氘、卤素、C
1～3烷基、COOR
g；R
g选自氢、氘、C
1～3烷基；
R
8、R
9各自独立地选自氢、氘、C
1～3烷基、被1～3个R
c取代的C
1～3烷基；R
c各自独立地选自卤素、COOR
d、羟基、C
1～3烷基、氘；R
d选自氢、氘、C
1～3烷基。
进一步地，所述化合物为式IV所示化合物：
R
0选自甲基、被1～3个R
a取代的甲基；R
a各自独立地选自氘、卤素、羟基；
R
2选自氢、卤素、COOH、SCH
3、甲基、＝N-OH；
R
3选自氢、羟基、卤素、C
1～3烷基、L
fCOOH；L
f为亚甲基；
R
5选自氢、卤素、羟基、OCOR
b；R
b为甲基；
R
6选自氢、卤素、甲基、COOH；
R
8、R
9各自独立地选自氢、甲基、被1～3个R
c取代的甲基；R
c各自独立地选自卤素、COOH、羟基、甲基、氘。
进一步地，所述化合物选自：
进一步地，所述化合物选自：
进一步地，所述化合物选自：
进一步地，所述麻醉和/或镇静拮抗药为麻醉药物的拮抗剂和/或镇静药物的拮抗剂。
进一步地，所述麻醉和/或镇静拮抗药能够逆转麻醉药物和/或镇静药物诱导或维持的麻醉和/或镇静状态。
进一步地，所述麻醉和/或镇静拮抗药能够减少麻醉和/或镇静时间。
进一步地，所述麻醉药物包括GABA
A受体激动剂。
进一步地，所述麻醉和/或镇静拮抗药为GABA
A受体高亲和力配体，能够作为竞争性拮抗剂拮抗GABA
A受体激动剂。
进一步地，所述麻醉药物为全身麻醉药物。
进一步地，所述全身麻醉药物包括苯二氮
类药物，取代苯酚类药物，咪唑类药物，拟GABA药物。
进一步地，所述苯二氮
类药物包括地西泮、咪达唑仑、劳拉西泮、瑞马唑仑；
所述取代苯酚类药物包括丙泊酚、环泊酚；
所述咪唑类药物包括依托咪酯或其衍生物；
所述拟GABA药物包括γ-氨基丁酸、γ-羟基丁酸。
进一步地，所述麻醉和/或镇静拮抗药是以所述化合物、或其立体异构体、或其氘代衍生物、或其代谢产物、或其前体药物、或其盐、或其溶剂合物为活性成分，加上药学上可接受的辅料制得的制剂。
进一步地，所述制剂是片剂、胶囊剂、口服液、颗粒剂、丸剂、散剂、注射液或粉针剂。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀C
a～b烷基表示任何含“a”至“b”个碳原子的烷基。例如，C
1～5烷基是指包含1～5个碳原子的直链或支链的烷基。
本文“取代”是指分子中的1个、2个或多个氢原子被其它不同的原子或分子所替换，包括该分子中同位原子或异位原子上的1个、2个或多个取代。
“取代或未取代”的基团指该基团可是是未进一步取代的，也可以是进一步被一个或两个以上的取代基取代的，如无特别说明，该取代基可以是使最终化合物结构保持稳定的任意取代基。
“稠环烷基”指多环的环烷基，且该多环的环烷基中有两个环共用两个相邻的碳原子。
“杂稠环基”指多环的杂环基，且该多环的杂环基中有两个环共用两个相邻的碳原子或杂原子。
卤素为氟、氯、溴或碘。
“氘代衍生物”指化合物中的一个或两个以上的氢原子被氘替换后得到的化合物。
“氚代衍生物”指化合物中的一个或两个以上的氢原子被氚替换后得到的化合物。
“盐”是将化合物或其立体异构体，与无机和/或有机酸和/或碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。
本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明首次发现式I所示环状酮类化合物具有良好的全身麻醉及镇静拮抗作用。实验结果表明，本发明化合物对多种全身麻醉药物(包括丙泊酚、依托咪酯、瑞马唑仑等)诱导的全身麻醉均具有良好的拮抗作用，能够明显缩短小鼠经全身麻醉后翻正反射恢复的时间，明显缩短小鼠恢复正常行走的时间。而且，对于持续输注全身麻醉药物丙泊酚维持的全身麻醉，本发明化合物也能够发挥有效的拮抗作用。
本发明为麻醉和/或镇静药物的拮抗剂，特别时全身麻醉药物的拮抗剂提供了一种新的选择，应用前景广阔。
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。
本发明所用原料与设备均为已知产品，通过购买市售产品所得。
以下实施例采用的化合物均能通过购买市售产品所得，或者通过本领已知的方法合成。
实施例1、各化合物对不同全身麻醉药物的拮抗作用
1、主要试剂及药物
(1)主要试剂
丙泊酚注射液(批号：2010083，西安力邦)，依托咪酯注射液(纯度>98％)，瑞马唑仑(纯度>98％)，中长链脂肪乳注射液。
(2)受试药物
配制方法为：分别称取适量待测化合物，用移液器加取适量中长链脂肪乳注射液，配制为50mmol/L的待测化合物溶液，用0.22μm的微孔滤膜过滤后，即刻使用。
2、实验方法
将体重25g±1g，雄性ICR小鼠随机分为8组，每组8只，分别尾静脉单次注射丙泊酚22.11mg/kg(1.5倍ED
50)，依托咪酯4.48mg/kg(2倍ED
50)、瑞马唑仑57.34mg/kg(1.5倍ED
50)进行麻醉诱导，注射时间15秒，小鼠维持翻正反射消失30s后再分别注射50mg/kg待测化合物溶液(中长链脂肪乳注射液作为溶剂)或等体积中长链脂肪乳注射液，观察记录小鼠麻醉总时间。其中，麻醉总时间指从小鼠翻正反射消失到小鼠翻正反射恢复的时间。
3、实验结果
结果如表1所示。
表1.受试药物拮抗全身麻醉药物麻醉效应的效果
实验表明，对于全身麻醉药物丙泊酚、依托咪酯、瑞马唑仑，脂肪乳均不产生麻醉拮抗效果；但是，表中所列化合物均能发挥拮抗全身麻醉的作用，药效表现为小鼠总麻醉时间明显缩短。说明本发明提供的化合物可以拮抗全身麻醉药物的麻醉效果，提供更快的苏醒速度。
实施例2、化合物对持续输注全身麻醉药物的拮抗作用
1、主要试剂及药物
(1)主要试剂
丙泊酚注射液(批号：2010083，西安力邦)，中长链脂肪乳注射液。
(2)受试药物
配制方法为：同实施例1。
2、实验方法
将体重范围在250～300克的24只雄性SD大鼠随机分成4组，每组6只，使用22.11mg/kg(1.5倍ED
50)丙泊酚进行持续麻醉诱导，以1mg/(kg·min)的速度维持麻醉30分钟，停药后，立即分别注射10mg/kg、20mg/kg、50mg/kg85以及50mg/kg的受试化合物溶液(中长链脂肪乳注射液作为溶剂)或等体积中长链脂肪乳注射液，观察记录停药后小鼠麻醉苏醒时间。其中，麻醉苏醒时间指从停止丙泊酚输注到小鼠翻正反射恢复的时间。
3、实验结果
结果如表2所示。
表2.受试药物对持续输注丙泊酚维持全身麻醉的拮抗效果
| 受试药物剂量 | 受试药物 | 平均苏醒时间(min) |
| - | 脂肪乳 | 8.98±1.41 |
| 50mg/kg | 化合物67 | 3.04±0.18 |
| 10mg/kg | 化合物85 | 4.11±1.22 |
| 20mg/kg | 化合物85 | 3.68±1.12 |
| 50mg/kg | 化合物85 | 0.36±0.98 |
| 50mg/kg | 化合物130 | 3.41±0.52 |
| 50mg/kg | 化合物163 | 1.33±0.79 |
| 50mg/kg | 化合物171 | 0.34±0.89 |
| 50mg/kg | 化合物269 | 3.29±0.81 |
| 50mg/kg | 化合物280 | 0.40±0.92 |
| 50mg/kg | 化合物565 | 2.58±0.56 |
| 50mg/kg | 化合物580 | 2.76±0.20 |
| 50mg/kg | 化合物581 | 4.66±0.60 |
| 50mg/kg | 化合物582 | 0.96±0.23 |
| 50mg/kg | 化合物610 | 2.72±0.36 |
| 50mg/kg | 化合物631 | 2.85±0.58 |
| 50mg/kg | 化合物633 | 2.64±0.19 |
| 50mg/kg | 化合物643 | 1.01±0.29 |
| 50mg/kg | 化合物661 | 2.39±0.75 |
从实验结果可见，本发明提供的化合物85可以有效的逆转丙泊酚持续输注的麻醉维持作用，化合物85可剂量依赖性的缩短大鼠的麻醉苏醒时间。此外，表中所列的化合物均能逆转丙泊酚持续输注的麻醉维持作用，表现为小鼠平均苏醒时间缩短。
综上，本发明提供了式I所示环状酮类化合物在制备麻醉和/或镇静拮抗药中的用途。本发明首次发现该环状酮类化合物具有良好的全身麻醉及镇静拮抗作用。实验结果表明，本发明化合物对多种全身麻醉药物(包括丙泊酚、依托咪酯、瑞马唑仑等)诱导的全身麻醉均具有良好的拮抗作用，能够明显缩短小鼠经全身麻醉后翻正反射恢复的时间，明显缩短小鼠恢复正常行走的时间。而且，对于持续输注全身麻醉药物丙泊酚维持的全身麻醉，本发明化合物也能够发挥有效的拮抗作用。本发明为麻醉和/或镇静药物的拮抗剂，特别时全身麻醉药物的拮抗剂提供了一种新的选择，应用前景广阔。
Claims (17)
- 式I所示化合物、或其立体异构体、或其氘代衍生物、或其氚代衍生物、或其代谢产物、或其前体药物、或其盐、或其溶剂合物在制备麻醉和/或镇静拮抗药中的用途：
其中，n为0或1；m为0或1；当m为1时，R 10为无；R 0选自L 0L 1L 2R x1；L 0、L 1、L 2各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO 2、NH、CH＝N、CONH、NH(CS)S(CH 2)、C 1～3亚烷基、C 2～4亚烯基、C 2～4亚炔基；R x1选自氢、氘、氚、卤素、醛基、CN、N 3、NO 2、OAc、取代或未取代的以下基团：OSiH 3、OOSiH 3、SO 3H、SiH 3、CS 2H、CSNH 2、NH 2、COOH、SH、SeO 2H、OH、N＝NH、＝O、CH＝NH、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R 1、R 2各自独立地选自L 3L 4L 5R x2、＝NL 5R x2、＝C(L 6R x3)(L 7R x4)；或者R 1、R 2连接成环；L 3、L 4、L 5、L 6、L 7各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO 2、NH、CH＝N、CONH、NH(CS)S(CH 2)、C 1～3亚烷基；R x2、R x3、R x4各自独立地选自氢、氘、氚、卤素、醛基、CN、N 3、NO 2、OAc、取代或未取代的以下基团：OSiH 3、OOSiH 3、SO 3H、SiH 3、CS 2H、NH 2、COOH、SH、SeO 2H、OH、N＝NH、＝O、CH＝NH、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R 3、R 10各自独立地选自L 8L 9L 10R x5；L 8、L 9、L 10各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO 2、NH、CH＝N、CONH、NH(CS)S(CH 2)、C 1～3亚烷基；R x5选自氢、氘、氚、卤素、醛基、CN、N 3、NO 2、OAc、取代或未取代的以下基团：OSiH 3、OOSiH 3、SO 3H、SiH 3、CS 2H、CSNH 2、NH 2、COOH、SH、SeO 2H、OH、N＝NH、＝O、CH＝NH、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R 4、R 5、R 6、R 7各自独立地选自L 11L 12L 13R x6、＝NL 13R x6、＝C(L 14R x7)(L 15R x8)；L 11、L 12、L 13、L 14、L 15各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO 2、NH、CH＝N、CONH、NH(CS)S(CH 2)、C 1～3亚烷基；R x6、R x7、R x8各自独立地选自氢、氘、氚、卤素、醛基、CN、N 3、NO 2、OAc、取代或未取代的以下基团：OSiH 3、OOSiH 3、SO 3H、SiH 3、CS 2H、NH 2、COOH、SH、SeO 2H、OH、N＝NH、＝O、CH＝NH、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；或者，R 10与R 5连接成环；R 8、R 9各自独立地选自L 16L 17L 18R x9；L 16、L 17、L 18各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO 2、NH、CH＝N、CONH、NH(CS)S(CH 2)、C 1～3亚烷基；R x9选自氢、氘、氚、卤素、醛基、CN、N 3、NO 2、OAc、取代或未取代的以下基团：OSiH 3、OOSiH 3、SO 3H、SiH 3、CS 2H、CSNH 2、NH 2、COOH、SH、SeO 2H、OH、N＝NH、＝O、CH＝NH、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基。 - 根据权利要求1所述的用途，其特征在于：所述化合物为式II所示化合物：
其中，R 0选自L 0L 1L 2R x1；L 0、L 1、L 2各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO 2、NH、CH＝N、CONH、 NH(CS)S(CH 2)、C 1～3亚烷基、C 2～4亚烯基、C 2～4亚炔基；R x1选自氢、氘、氚、卤素、醛基、CN、N 3、NO 2、OAc、取代或未取代的以下基团：OSiH 3、OOSiH 3、SO 3H、SiH 3、CS 2H、CSNH 2、NH 2、COOH、SH、SeO 2H、OH、N＝NH、＝O、CH＝NH、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R 1、R 2各自独立地选自L 3L 4L 5R x2、＝NL 5R x2、＝C(L 6R x3)(L 7R x4)；或者R 1、R 2连接成环；L 3、L 4、L 5、L 6、L 7各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO 2、NH、CH＝N、CONH、NH(CS)S(CH 2)、C 1～3亚烷基；R x2、R x3、R x4各自独立地选自氢、氘、氚、卤素、醛基、CN、N 3、NO 2、OAc、取代或未取代的以下基团：OSiH 3、OOSiH 3、SO 3H、SiH 3、CS 2H、NH 2、COOH、SH、SeO 2H、OH、N＝NH、＝O、CH＝NH、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R 3选自L 8L 9L 10R x5；L 8、L 9、L 10各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO 2、NH、CH＝N、CONH、NH(CS)S(CH 2)、C 1～3亚烷基；R x5选自氢、氘、氚、卤素、醛基、CN、N 3、NO 2、OAc、取代或未取代的以下基团：OSiH 3、OOSiH 3、SO 3H、SiH 3、CS 2H、CSNH 2、NH 2、COOH、SH、SeO 2H、OH、N＝NH、＝O、CH＝NH、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R 4、R 5、R 6、R 7各自独立地选自L 11L 12L 13R x6、＝NL 13R x6、＝C(L 14R x7)(L 15R x8)；L 11、L 12、L 13、L 14、L 15各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO 2、NH、CH＝N、CONH、NH(CS)S(CH 2)、C 1～3亚烷基；R x6、R x7、R x8各自独立地选自氢、氘、氚、卤素、醛基、CN、N 3、NO 2、OAc、取代或未取代的以下基团：OSiH 3、OOSiH 3、SO 3H、SiH 3、CS 2H、NH 2、COOH、SH、SeO 2H、OH、N＝NH、＝O、CH＝NH、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R 8、R 9各自独立地选自L 16L 17L 18R x9；L 16、L 17、L 18各自独立地选自无、取代或未取代的以下基团：NHCO、NHCS、CO、COO、OCO、OCOO、C(SO)、O、S、SO、SO 2、NH、CH＝N、CONH、NH(CS)S(CH 2)、C 1～3亚烷基；R x9选自氢、氘、氚、卤素、醛基、CN、N 3、NO 2、OAc、取代或未取 代的以下基团：OSiH 3、OOSiH 3、SO 3H、SiH 3、CS 2H、CSNH 2、NH 2、COOH、SH、SeO 2H、OH、N＝NH、＝O、CH＝NH、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基。 - 根据权利要求2所述的用途，其特征在于：所述化合物为式III所示化合物：
其中，R 0选自氢、氘、氚、C 1～5烷基、被1～3个R a取代的C 1～5烷基、C 1～5烷氧基、被1～3个R a取代的C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R a各自独立地选自氘、氚、卤素、羟基；R 2选自氢、氘、氚、卤素、COOR e、SR e、OR e、C 1～5烷基、＝NR h1、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R e选自氢、氘、氚、C 1～5烷基；R h1选自羟基、C 1～5烷基；R 3选自氢、氘、氚、羟基、卤素、C 1～5烷基、L fCOOR f、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；L f为无或C 1～3亚烷基，R f选自氢、氘、氚、C 1～5烷基；R 5选自氢、氘、氚、卤素、羟基、OCOR b、C 1～5烷基、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R b为C 1～5烷基；R 6、R 7各自独立地选自氢、氘、氚、卤素、C 1～5烷基、COOR g、C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R g选自氢、氘、氚、C 1～5烷基；R 8、R 9各自独立地选自氢、氘、氚、C 1～5烷基、被1～3个R c取代的C 1～6烷基、C 1～5烷氧基、被1～3个R c取代的C 1～5烷氧基、C 2～6烯基、C 2～6炔基、饱和或不饱和杂环基、饱和或不饱和环烷基、稠环烷基、稠杂环基；R c各自独立地选自卤素、COOR d、羟基、C 1～5烷基、氘、氚；R d选自氢、氘、氚、C 1～5烷基。 - 根据权利要求3所述的用途，其特征在于：所述化合物为式IV所示 化合物：
R 0选自甲基、被1～3个R a取代的甲基；R a各自独立地选自氘、卤素、羟基；R 2选自氢、卤素、COOH、SCH 3、甲基、＝N-OH；R 3选自氢、羟基、卤素、C 1～3烷基、L fCOOH；L f为亚甲基；R 5选自氢、卤素、羟基、OCOR b；R b为甲基；R 6选自氢、卤素、甲基、COOH；R 8、R 9各自独立地选自氢、甲基、被1～3个R c取代的甲基；R c各自独立地选自卤素、COOH、羟基、甲基、氘。 - 根据权利要求1所述的用途，其特征在于：所述化合物选自：
- 根据权利要求5所述的用途，其特征在于：所述化合物选自：
- 根据权利要求6所述的用途，其特征在于：所述化合物选自：
- 根据权利要求1-7任一项所述的用途，其特征在于：所述麻醉和/或镇静拮抗药为麻醉药物的拮抗剂和/或镇静药物的拮抗剂。
- 根据权利要求8所述的用途，其特征在于：所述麻醉和/或镇静拮抗药能够逆转麻醉药物和/或镇静药物诱导或维持的麻醉和/或镇静状态。
- 根据权利要求8所述的用途，其特征在于：所述麻醉和/或镇静拮抗药能够减少麻醉和/或镇静时间。
- 根据权利要求8所述的用途，其特征在于：所述麻醉药物包括GABA A受体激动剂。
- 根据权利要求11所述的用途，其特征在于：所述麻醉和/或镇静拮抗药为GABA A受体高亲和力配体，能够作为竞争性拮抗剂拮抗GABA A受体激动剂。
- 根据权利要求8所述的用途，其特征在于：所述麻醉药物为全身麻醉药物。
- 根据权利要求13所述的用途，其特征在于：所述全身麻醉药物包括苯二氮类药物，取代苯酚类药物，咪唑类药物，拟GABA药物。
- 根据权利要求14所述的用途，其特征在于：所述苯二氮类药物包括地西泮、咪达唑仑、劳拉西泮、瑞马唑仑；
所述取代苯酚类药物包括丙泊酚、环泊酚；所述咪唑类药物包括依托咪酯或其衍生物；所述拟GABA药物包括γ-氨基丁酸、γ-羟基丁酸。 - 根据权利要求1-15任一项所述的用途，其特征在于：所述麻醉和/或镇静拮抗药是以所述化合物、或其立体异构体、或其氘代衍生物、或其代谢产物、或其前体药物、或其盐、或其溶剂合物为活性成分，加上药学上可接受的辅料制得的制剂。
- 根据权利要求16所述的用途，其特征在于：所述制剂是片剂、胶囊剂、口服液、颗粒剂、丸剂、散剂、注射液或粉针剂。
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