WO2023011634A1 - 含苯并环类衍生物及其制备方法和应用 - Google Patents
含苯并环类衍生物及其制备方法和应用 Download PDFInfo
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- WO2023011634A1 WO2023011634A1 PCT/CN2022/110558 CN2022110558W WO2023011634A1 WO 2023011634 A1 WO2023011634 A1 WO 2023011634A1 CN 2022110558 W CN2022110558 W CN 2022110558W WO 2023011634 A1 WO2023011634 A1 WO 2023011634A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- cycloalkyl
- methyl
- hydrogen
- pharmaceutically acceptable
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 125000005605 benzo group Chemical group 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 241000124008 Mammalia Species 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 206010002091 Anaesthesia Diseases 0.000 claims abstract description 9
- 230000037005 anaesthesia Effects 0.000 claims abstract description 9
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 5
- -1 cyano, amino Chemical group 0.000 claims description 135
- 125000000217 alkyl group Chemical group 0.000 claims description 97
- 229910052739 hydrogen Inorganic materials 0.000 claims description 95
- 239000001257 hydrogen Substances 0.000 claims description 95
- 150000002431 hydrogen Chemical class 0.000 claims description 78
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 229910052805 deuterium Inorganic materials 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 26
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 24
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 23
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 22
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 16
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 16
- 239000011734 sodium Chemical group 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- 230000036506 anxiety Effects 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 206010015037 epilepsy Diseases 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 4
- 206010010904 Convulsion Diseases 0.000 claims description 4
- 208000019695 Migraine disease Diseases 0.000 claims description 4
- 206010028813 Nausea Diseases 0.000 claims description 4
- 206010039897 Sedation Diseases 0.000 claims description 4
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 4
- 206010047700 Vomiting Diseases 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 230000036461 convulsion Effects 0.000 claims description 4
- 230000000147 hypnotic effect Effects 0.000 claims description 4
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- 206010027599 migraine Diseases 0.000 claims description 4
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- 239000003483 4 aminobutyric acid A receptor stimulating agent Substances 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 229940031098 ethanolamine Drugs 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Chemical group 0.000 claims description 2
- 229940086542 triethylamine Drugs 0.000 claims description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical group OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 2
- 229960004418 trolamine Drugs 0.000 claims description 2
- 229960000281 trometamol Drugs 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims 1
- 150000001342 alkaline earth metals Chemical class 0.000 claims 1
- 150000002500 ions Chemical class 0.000 claims 1
- 230000001939 inductive effect Effects 0.000 abstract description 3
- 239000003477 4 aminobutyric acid receptor stimulating agent Substances 0.000 abstract 1
- 229940121909 GABA receptor agonist Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- 239000000047 product Substances 0.000 description 41
- 125000001424 substituent group Chemical group 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 125000000753 cycloalkyl group Chemical group 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 229910052799 carbon Inorganic materials 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 239000000243 solution Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
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- 239000011541 reaction mixture Substances 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
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- 125000001072 heteroaryl group Chemical group 0.000 description 18
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 125000003367 polycyclic group Chemical group 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
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- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 3
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- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
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- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
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- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
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- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
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- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
- C07C39/04—Phenol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
Definitions
- the invention belongs to the field of medicinal chemistry, in particular to derivatives containing benzo rings and their preparation methods and applications.
- GABA A receptors are the major inhibitory neurotransmitter receptors in the central nervous system.
- the GABA A receptor is composed of a pentamer of transmembrane polypeptide subunits, and 19 different subunits make up a variety of different GABA A receptor subtypes.
- GABA A receptors are involved in the pathogenesis, diagnosis and treatment of various diseases such as anesthesia, depression, anxiety, epilepsy, memory impairment, and drug dependence. Therefore, GABA A receptors are pharmacologically and clinically important drug targets. Propofol and its derivatives are an important class of compounds targeting GABA A.
- Propofol can activate a variety of GABA A receptor subtypes. It is a short-acting intravenous general anesthetic with the advantages of rapid onset, no obvious accumulation, and quick and complete recovery. Its injection is clinically used for general anesthesia. induce and maintain.
- propofol is a clinically mature intravenous anesthetic and is widely used, there are also obvious limitations and shortcomings. Due to its poor water solubility, it is difficult to make suitable preparations, and it has to be used clinically. It is given by injection in the form of an emulsion. This makes the existing propofol medicine have the following disadvantages: 1, poor physical stability; 2, may cause vascular embolism due to the larger oil droplet size; 4.
- the emulsion is easy to breed bacteria; 6. It is easy to cause toxic side effects on the heart; 7. It can reduce systolic blood pressure, diastolic blood pressure and average blood pressure. Arterial blood pressure, so it will cause hypotension clinically; 8. It is easy to cause adverse reactions such as respiratory depression.
- the technical problem to be solved by the present invention is to provide a derivative containing benzo rings and its preparation method and application.
- the object of the present invention is to provide a kind of compound shown in general formula (Ia), its stereoisomer or its pharmaceutically acceptable salt:
- Ring A is a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group
- R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
- R is hydrogen , deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 deuterated alkyl or C 1-6 haloalkyl;
- R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
- Y is hydrogen, sodium, potassium, C 1-6 alkyl or
- R AA and R BB are each independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, alkali metal ion, alkaline earth metal ion, protonated amine or protonated Amino acid, the alkali metal ion is Na + , K + or Li + , the alkaline earth metal ion is Be 2+ , Mg 2+ or Ca 2+ , and the protonated amine is tromethamine, tri Ethanolamine, ethanolamine, triethylamine or N-methylglucamine, the amino acid being arginine or lysine; and
- x is an integer of 0-5.
- ring A is a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing 1-3 N, O or S atoms.
- Ring A is preferably
- M is CR aa R bb , NR aa , O or S, preferably CR aa R bb or O, more preferably CH 2 or O;
- R aa and R bb are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 deuterated alkyl or C 1-6 Haloalkyl, preferably hydrogen or C 1-6 alkyl, more preferably hydrogen or C 1-3 alkyl.
- each R a is independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, preferably hydrogen, C 1-3 alkyl or C 3-5 cycloalkyl, more Preferable is hydrogen, methyl, ethyl, propyl or cyclopropyl, more preferably hydrogen, methyl, ethyl or cyclopropyl.
- R 1 is hydrogen or halogen, preferably hydrogen, fluorine, chlorine or bromine, more preferably hydrogen, fluorine or chlorine.
- R and R are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, preferably hydrogen, C 1-3 alkyl or C 3-5 cycloalkane group, more preferably hydrogen, methyl, ethyl, propyl or cyclopropyl, further preferably methyl or cyclopropyl.
- Y is hydrogen or
- R AA and R BB are each independently hydrogen, C 1-6 alkyl, alkali metal ion or alkaline earth metal ion, and the alkali metal ion is Na + , K + or Li + ,
- the alkaline earth metal ions are Be 2+ , Mg 2+ or Ca 2+ .
- R AA and R BB are preferably alkali metal ions, more preferably Na + .
- x is 0, 1 or 2.
- the present invention further provides a compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:
- Ring A is a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group
- R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
- R is hydrogen , deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 deuterated alkyl or C 1-6 haloalkyl;
- R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; and
- x is an integer of 0-5.
- ring A is a C 5-6 cycloalkyl group or a 5-6 membered heterocyclic group containing 1-3 atoms that are N, O or S.
- Ring A is preferably
- M is CR aa R bb , NR aa , O or S, preferably CR aa R bb or O, more preferably CH 2 or O;
- R aa and R bb are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 deuterated alkyl or C 1-6 Haloalkyl, preferably hydrogen or C 1-6 alkyl, more preferably hydrogen or C 1-3 alkyl.
- each R a is independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, preferably hydrogen, C 1-3 alkyl or C 3-5 cycloalkyl , more preferably hydrogen, methyl, ethyl, propyl or cyclopropyl, further preferably hydrogen, methyl, ethyl or cyclopropyl.
- R 1 is hydrogen or halogen, preferably hydrogen, fluorine, chlorine or bromine, more preferably hydrogen, fluorine or chlorine.
- R 2 and R 3 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, preferably hydrogen, C 1-3 alkyl or C 3-5 Cycloalkyl, more preferably hydrogen, methyl, ethyl, propyl or cyclopropyl, further preferably methyl or cyclopropyl.
- x is 0, 1 or 2.
- R 4 , R 4 ', R 5 and R 5 ' are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, preferably hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, more preferably hydrogen, C 1-3 alkyl or C 3-5 cycloalkyl, further preferably hydrogen, methyl, ethyl, propyl or cyclopropyl, particularly preferably hydrogen, methyl, ethyl or cyclopropyl;
- R 1 , R 2 , R 3 and Y are the same as those described above in general formula (Ia).
- R4 and R4 ' are each independently hydrogen, methyl, ethyl or cyclopropyl.
- R5 and R5 ' are each independently hydrogen or methyl.
- R 4 , R 4 ', R 5 and R 5 ' are each independently hydrogen, deuterium, halogen, hydroxyl, cyano , amino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, preferably hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, more preferably hydrogen, C 1-3 alkyl or C 3-5 cycloalkyl, further preferably hydrogen, methyl, ethyl, propyl or cyclopropyl, particularly preferably hydrogen, methyl, ethyl or cyclopropyl;
- R 1 , R 2 and R 3 are respectively the same as those described above in general formula (I).
- R4 and R4 ' are each independently hydrogen, methyl, ethyl or cyclopropyl.
- R5 and R5 ' are each independently hydrogen or methyl.
- R 1 is hydrogen or halogen, preferably hydrogen, fluorine, chlorine or bromine, more preferably hydrogen, fluorine or chlorine.
- R 2 and R 3 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, preferably hydrogen, C 1-3 alkyl or C 3-5 Cycloalkyl, further preferably hydrogen, methyl, ethyl, propyl or cyclopropyl, particularly preferably methyl or cyclopropyl.
- the compounds described in the above general formula (Ia), general formula (I), general formula (IIa) or general formula (II) do not include the following compounds:
- the compound is any of the following structures:
- the compound can be any of the following structures:
- the present invention further provides a compound, which is any of the following compounds (wherein -OBn is -oxybenzyl):
- the present invention further provides a compound, which is any one of the following compounds:
- the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer.
- compound 10A1 It is prepared by the debenzylation reaction of the above chiral intermediate A1, Pd/C and Na 2 CO 3 , wherein the carbon atom with "*" is a chiral carbon atom, in the form of (R) or (S) single enantiomer exist.
- compound 10A2 It is prepared by the debenzylation reaction of the above chiral intermediate A2, Pd/C and Na 2 CO 3 , wherein the carbon atom with "*" is a chiral carbon atom, in the form of (R) or (S) single enantiomer exist.
- compound 10B1 It is prepared by the debenzylation reaction of the above chiral intermediate B1, Pd/C and Na 2 CO 3 , wherein the carbon atom with "*" is a chiral carbon atom, in the form of (R) or (S) single enantiomer exist.
- compound 10B2 It is prepared by the debenzylation reaction of the above chiral intermediate B2, Pd/C and Na 2 CO 3 , wherein the carbon atom with "*" is a chiral carbon atom, in the form of (R) or (S) single enantiomer exist.
- compound 11A1 It is prepared by the protonation reaction of the above-mentioned chiral intermediate A1 and hydrochloric acid, wherein the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer.
- compound 11A2 It is prepared by the protonation reaction of the above-mentioned chiral intermediate A2 and hydrochloric acid, wherein the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer.
- compound 11B1 It is prepared by the protonation reaction of the above-mentioned chiral intermediate B1 and hydrochloric acid, wherein the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer.
- compound 11B2 It is prepared by the protonation reaction of the above-mentioned chiral intermediate B2 and hydrochloric acid, wherein the carbon atom with "*" is a chiral carbon atom, and exists in the form of (R) or (S) single enantiomer.
- the present invention further provides a preparation method of the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof.
- the preparation method can be synthesized by known methods using commercially available raw materials.
- the preparation method preferably includes the following steps: in a solvent, the compound represented by formula I-1 undergoes a dehydroxylation reaction in the presence of a dehydroxylation reagent and an acid to obtain a compound represented by formula I ;
- ring A, R 1 , R 2 and R 3 , R a and x are all as defined above.
- the conditions of the dehydroxylation reaction can be conventional conditions of this type of reaction in the art.
- the solvent may be a conventional solvent for this type of reaction in the art, such as a halogenated hydrocarbon solvent, preferably dichloromethane.
- the dehydroxylation reagent may be a conventional dehydroxylation reagent of this type of reaction in the art, for example, a silane dehydroxylation reagent, preferably triethylsilane.
- the acid may be a conventional acid for this type of reaction in the art, such as a strong organic acid, preferably trifluoroacetic acid.
- the preparation method may further include the following steps: in a solvent, the compound represented by formula I-2 undergoes a substitution reaction in the presence of Grignard reagent R 3 -MgX 1 to obtain formula I Compounds indicated in -1;
- R 3 is defined as above, and X 1 is halogen.
- the conditions of the substitution reaction can be conventional conditions of this type of reaction in the art.
- the halogen can be a conventional halogen in Grignard reagents, such as Cl, Br or I, preferably Br.
- the solvent can be a conventional solvent for this type of reaction in the art, such as an ether solvent, preferably tetrahydrofuran.
- the present invention further provides a preparation method of the compound represented by the general formula (Ia), its stereoisomer or a pharmaceutically acceptable salt thereof.
- the preparation method can be synthesized by known methods using commercially available raw materials.
- the preparation method is preferably any of the following methods:
- Method 1 comprises the following steps: in a solvent, the compound represented by formula Ia-1 undergoes a dehydroxylation reaction in the presence of a dehydroxylation reagent and an acid to obtain a compound represented by formula Ia;
- ring A, R 1 , R 2 and R 3 , R a , Y and x are all as defined above;
- Method 2 includes the following steps: in a solvent, the compound represented by formula I undergoes a substitution reaction in the presence of X 2 -Y and a base to obtain the compound represented by formula Ia;
- ring A, R 1 , R 2 and R 3 , Ra , Y and x are all defined as above, and the definition of Y does not include H; X 2 is halogen.
- the conditions of the dehydroxylation reaction can be conventional conditions of this type of reaction in the art.
- the solvent in the first method, can be a conventional solvent for this type of reaction in the art, such as a halogenated hydrocarbon solvent, preferably dichloromethane.
- the dehydroxylation reagent in the first method, can be a conventional dehydroxylation reagent for this type of reaction in the art, for example, a silane dehydroxylation reagent, preferably triethylsilane.
- the acid in the first method, can be a conventional acid for this type of reaction in the art, such as a strong organic acid, preferably trifluoroacetic acid.
- the conditions of the substitution reaction can be conventional conditions for this type of reaction in the art.
- the halogen in the second method, can be a conventional halogen for this type of reaction in the art, such as F, Cl, Br or I, preferably Cl.
- the solvent in the second method, can be a conventional solvent for this type of reaction in the art, such as an amide solvent, preferably N,N-dimethylformamide.
- the base in the second method, can be a conventional base for this type of reaction in the art, such as an alkali metal hydride, preferably NaH.
- the first method may further include the following steps: in a solvent, the compound represented by formula Ia-2 undergoes a substitution reaction in the presence of Grignard reagent R 3 -MgX 1 to obtain formula Ia Compounds indicated in -1;
- R 3 is defined as above, and X 1 is halogen.
- the conditions of the substitution reaction can be conventional conditions of this type of reaction in the art.
- the halogen can be a conventional halogen in Grignard reagents, such as Cl, Br or I, preferably Br.
- the solvent can be a conventional solvent for this type of reaction in the art, such as an ether solvent, preferably tetrahydrofuran.
- the present invention further relates to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds shown, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients Forming agent.
- the present invention further relates to the application of any one of the shown compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of GABA A receptor agonist drugs.
- the present invention further relates to the application of any one of the shown compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of drugs in the field of central nervous system.
- the central nervous system drugs are used to induce and maintain anesthesia in mammals, promote sedation and hypnosis in mammals, treat and/or prevent anxiety, depression, insomnia, nausea, vomiting, migraine , schizophrenia, convulsions or epilepsy drugs.
- the present invention further relates to any one of the shown compounds, its stereoisomers or pharmaceutically acceptable salts thereof, or its pharmaceutical composition in the preparation for inducing and maintaining anesthesia in mammals, promoting sedation and hypnosis in mammals, treating And/or the use of drugs to prevent anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, or epilepsy.
- the present invention also relates to a method for inducing and maintaining anesthesia in mammals, promoting sedation and hypnosis in mammals, treating and/or preventing diseases such as anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions or epilepsy, It includes administering to said mammal a therapeutically effective dose of any one of the indicated compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
- alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms attached to the rest of the molecule by a single bond.
- Alkyl can have 1-8 or more carbon atoms, that is, “C 1 -C 8 alkyl", such as C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 3 alkyl, C 4 alkyl, C 1-6 alkyl, C 3-6 alkyl.
- Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc., or their iso Construct.
- Alkyl groups may be optionally substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl base. When the alkyl group is substituted by a substituent, the substituent is not further substituted.
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl group contains 3 to 20 carbon atoms, preferably contains 3 to 12 carbon atoms, more preferably contains 3 to 6 Carbon atoms, most preferably comprise 3 to 5 carbon atoms or 5 to 6 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
- spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation
- the ⁇ -electron system Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the spirocycloalkyl group is divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl or double spirocycloalkyl , more preferably 3/6, 3/5, 4/4, 4/5, 4/6, 5/5 or 5/6 monospirocycloalkyl . Also included are spiroheterocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl.
- fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
- it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic fused cycloalkyl groups, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups .
- bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which contain one or more double bonds, but none of the rings has a complete shared bond.
- the ⁇ -electron system of the yoke Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups.
- cycloalkyl groups described above can all be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring bonded to the parent structure is a cycloalkyl group.
- Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or hetero Aryl. When the cycloalkyl is substituted by a substituent, the substituent is not further substituted.
- heterocyclyl refers to a saturated or unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen and S(O) m (wherein m is an integer of 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
- ring atoms Preferably comprising 3 to 12 ring atoms, including 1-4 heteroatoms, more preferably comprising 3 to 6 ring atoms, including 1-3 heteroatoms, further preferably comprising 1-3 atoms selected from the group consisting of N, O and 5-6 membered heterocyclic group of S atom.
- Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, Dihydrofuryl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolyl, 2,2-difluoro-1,3-dioxolyl or Azepanyl et al.
- Non-limiting examples of polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls, wherein the spiro, fused and bridged heterocyclyls are optionally bonded to other groups via a single bond.
- spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the spiroheterocyclyl is divided into a single spiroheterocyclyl, a double spiroheterocyclyl or a polyspiroheterocyclyl, preferably a single spiroheterocyclyl or a double spiroheterocyclyl , more preferably 3/6, 3/5, 4/4, 4/5, 4/6, 5/5 or 5/6 monospiroheterocyclyl .
- fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, wherein one or more ring atoms are selected from nitrogen , oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon, one or more rings may contain one or more double bonds, but none of the rings has a complete consensus
- the ⁇ -electron system of the yoke Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups Ring base.
- bridged heterocyclic group refers to a polyheterocyclic group of 5 to 20 members, any two rings share two atoms not directly connected, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms are carbon, which contains one or more double bonds, but none of the rings has a fully conjugated ⁇ -electron system.
- m is an integer from 0 to 2
- it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups.
- the heterocyclyl groups described above can all be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring bonded to the parent structure is a heterocyclyl group.
- the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably one or more of the following groups, which are independently Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl base. When the heterocyclic group is substituted by a substituent, the substituent is not further substituted.
- aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic group with a conjugated ⁇ electron system, preferably 6 to 12 members, such as phenyl or naphthyl, more preferably phenyl.
- the aryl group can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered heterocyclic group, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heterocyclic group.
- Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably one or more of the following groups, which are independently alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl . When the aryl is substituted by a substituent, the substituent is not further substituted.
- heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, and the like.
- Heteroaryl is preferably 5 to 12 membered, more preferably 5 to 6 membered, such as pyrrolyl, imidazolyl, furyl, pyryl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, oxazolyl, Diazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, etc.
- the heteroaryl group may be fused to an aryl, cycloalkyl or heterocyclyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
- Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, which are independently Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl base. When the heteroaryl is substituted with a substituent, the substituent is not further substituted.
- alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
- alkoxy include: methoxy, ethoxy, propoxy, butoxy, and the like.
- Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, which are independently Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl base. When the alkoxy group is substituted by a substituent, the substituent is not further substituted.
- alkylthio refers to -S-(alkyl), wherein alkyl is as defined above.
- alkylthio include: methylthio, ethylthio, propylthio, butylthio, and the like.
- Alkylthio can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, which are independently Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl base. When the alkylthio group is substituted by a substituent, the substituent is not further substituted.
- halo or "halogen” or “halo” is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine, bromine atom.
- deuteroalkyl refers to an alkyl group substituted with one or more deuteriums, wherein alkyl is as defined above.
- haloalkyl refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.
- haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
- alkenyl refers to an alkenyl group, also known as an alkene group, wherein the alkene can be further substituted by other related groups.
- alkynyl refers to (CH ⁇ C-), wherein said alkynyl group may be further substituted by other related groups.
- Amino refers to -NH2 .
- Cyano refers to -CN.
- Niro refers to -NO2 .
- Carbonyl refers to -C(O)-.
- Carboxy refers to -C(O)OH.
- NBS N-bromosuccinimide
- DCM dichloromethane
- Pd(dppf) Cl2 refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
- NCS N-chlorosuccinimide
- DMF N,N-dimethylformamide
- DIEA refers to N,N-diisopropylethylamine.
- THF tetrahydrofuran
- TFA trifluoroacetic acid
- AIBN means azobisisobutyronitrile
- PE petroleum ether
- EA means ethyl acetate
- one (species) or more (species) may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) or more (species).
- mn refers to the range from m to n and the subranges and individual point values therein.
- C 2 -C 8 or “C 2-8” covers the range of 2-8 carbon atoms and should be understood to also cover any subrange therein as well as every point value, such as C 2 -C 5 , C 3 -C 4 , C 2 -C 6 , C 3 -C 6 , C 4 -C 6 , C 5 -C 6 , C 4 -C 7 , C 4 -C 8 etc., and C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 and so on.
- C 3 -C 10 or “C 3-10” should also be understood in a similar manner, for example to cover any sub-ranges and point values contained therein, such as C 3 -C 9 , C 6 -C 9 , C 6 -C 8 , C 6 -C 7 , C 7 -C 10 , C 7 -C 9 , C 7 -C 8 , C 8 -C 9 etc. and C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 etc.
- C 1 -C 6 or "C 1-6” covers the range of 1-6 carbon atoms, and should be understood as also covering any sub-range and each point value, such as C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 etc., and C 1 , C 2 , C 3 , C 4 , C 5 , C 6 etc.
- the expression "three to ten” should be understood as covering any sub-range and every point value therein, such as three to five, three to six, three to seven, three to eight , four yuan to five yuan, four yuan to six yuan, four yuan to seven yuan, four yuan to eight yuan, five yuan to six yuan, five yuan to seven yuan, five yuan to eight yuan, six yuan to seven yuan, six Yuan to eight yuan, nine yuan to ten yuan, etc., and three, four, five, six, seven, eight, nine, ten yuan, etc.
- Other similar expressions herein should also be read in a similar manner.
- X is selected from A, B or C
- X is selected from A, B and C
- X is A, B or C
- X is A, B and C
- etc. expresses The same meaning means that X can be any one or several of A, B, and C.
- cycloalkyl optionally (optionally) substituted with alkyl means that an alkyl group may but need not be present, and the description includes cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group .
- substituted and “substituted” mean that one or more (e.g., one, two, three or four) hydrogens on the indicated atom are replaced by a selection from the indicated group, provided that no more than the indicated Atoms are indicated at their normal valences at the present situation and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. When the absence of a substituent is described, it is understood that the substituent may be one or more hydrogen atoms, provided that the described structure renders the compound in a stable state. When it is described that each carbon atom in a group may optionally be replaced by a heteroatom, provided that the normal valences of all atoms in the group are not exceeded under the circumstances and that a stable compound is formed.
- variable such as R
- labeled variables such as R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , etc.
- substituted means that one or more hydrogen atoms on a compound or group are replaced by other atoms or groups. The condition is that a stable valence state or compound is formed.
- non-substituted can be understood as “unsubstituted”. It should be understood that when a substituent is hydrogen, this can also mean that the corresponding group is “unsubstituted” or “unsubstituted”.
- the compounds of the invention may exist in particular geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- preferred compounds are those isomeric compounds that exhibit superior biological activity.
- Purified or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. Purification and isolation of such materials can be achieved by standard techniques known in the art.
- the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by a deuterium atom.
- pharmaceutically acceptable means a substance which, within the scope of normal medical judgment, is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic reaction, etc., with a reasonable ratio of benefit to harm, and can be effectively used for its intended purpose.
- pharmaceutically acceptable salt refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
- pharmaceutical composition refers to a mixture containing one or more compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiologically/pharmaceutical Pharmaceutical carrier or excipient.
- the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
- pharmaceutically acceptable carrier refers to those substances that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound.
- “Pharmaceutically acceptable carrier” includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, Stabilizer, solvent or emulsifier.
- administering or “administering” and the like refer to methods that enable the delivery of a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. Especially by injection or by mouth.
- the term "treating” includes alleviating, alleviating or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing underlying metabolic factors of a symptom, inhibiting a disease or symptom, e.g. Amelioration of a disease or condition, or cessation of symptoms of a disease or condition, and extends to include prophylaxis.
- “Treatment” also includes achieving therapeutic benefit and/or prophylactic benefit.
- Therapeutic benefit refers to eradication or amelioration of the condition being treated.
- therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, whereby improvement in the patient's disease is observed although the patient may still suffer from the underlying disease.
- Prophylactic benefit means that the patient uses the composition to prevent the risk of a certain disease, or takes it when the patient has one or more physiological symptoms of the disease, although the disease has not yet been diagnosed.
- active ingredient refers to a chemical entity that is effective in the treatment or prevention of the disorder, disease or condition of interest.
- neuropsychiatric disease refers to a general term for neurological diseases and mental diseases, including neurological diseases and/or mental diseases.
- the term "effective amount”, “therapeutically effective amount” or “prophylactically effective amount” refers to a sufficient amount of the drug or agent that has acceptable side effects but can achieve the desired effect.
- the determination of the effective amount varies from person to person, depending on the age and general condition of the individual, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine tests.
- “Individual” as used herein includes a human or non-human animal.
- Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
- Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
- the compound of the present invention has a novel structure, relatively stable chemical properties, can produce better anesthesia effect, better drug effect, is safer, has a larger safety window, and has less side effects.
- the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS).
- NMR chemical shifts are given in parts per million (ppm).
- the determination of NMR is to use AVANCE III 600 nuclear magnetic instrument or Bruker Avance III 400MHz nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) or deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).
- DMSO-d 6 dimethyl sulfoxide
- CD 3 OD deuterated methanol
- CDCl 3 deuterated chloroform
- TMS tetramethylsilane
- LC-MS Liquid chromatography-mass chromatography
- the thin-layer chromatography silica gel plate uses Yantai Jiangyou silica gel plate, the specification used by TLC is 0.2mm ⁇ 0.03mm, and the specification used for thin-layer chromatography separation and purification products is 0.4mm-0.5mm.
- the first step preparation of ethyl 2-(2-acetyl-3-hydroxyphenoxy)acetate
- the second step the preparation of 2-(2-acetyl-3-hydroxyphenoxy)acetic acid
- the third step the preparation of 3-methylbenzofuran-4-ol
- the fourth step the preparation of 3-methyl-2,3-dihydrobenzofuran-4-ol
- the first step the preparation of 4-chloro-7-hydroxy-2,3-dihydro-1H-inden-1-one
- the second step the preparation of 6-bromo-4-chloro-7-hydroxyl-2,3-dihydro-1H-inden-1-one
- the third step the preparation of 6-bromo-4-chloro-7-(methoxymethoxy)-2,3-dihydro-1H-inden-1-one
- the fifth step 4-chloro-7-(methoxymethoxy)-1-methylene-6-(prop-1-en-2-yl)-2,3-dihydro-1H-indene preparation
- the sixth step 6-isopropyl-7-(methoxymethoxy)-1-methyl-2,3-dihydro-1H-indene
- the seventh step 5-isopropyl-3-methyl-2,3-dihydro-1H-inden-4-ol
- the first step the preparation of 5-bromo-3-methyl-2,3-dihydrobenzofuran-4-ol
- the second step the preparation of 5-bromo-4-(methoxymethoxy)-3-methyl-2,3-dihydrobenzofuran
- the third step the preparation of 5-(1-ethoxyvinyl)-4-(methoxymethoxy)-3-methyl-2,3-dihydrobenzofuran
- the second step the preparation of 1-(3-bromo-5-fluoro-2,4-dihydroxyphenyl)ethan-1-one
- Step 5 Preparation of 5-(1-cyclopropyl-1-hydroxyethyl)-7-fluoro-3-methyl-2,3-dihydrobenzofuran-4-ol
- Example 1 5-isopropyl-3-methyl-2,3-dihydrobenzofuran-4-ol (400 mg, 2.08 mmol) was dissolved in CHCl 3 (10 mL), and NCS (556 mg , 4.16mmol), reflux reaction for 2 hours. After the reaction was completed, the crude product was obtained by cooling and concentrating, and the target product Example 5 (19.5 mg, yield 4%) was obtained by preparative HPLC.
- the first step chiral resolution of 1-(7-fluoro-4-hydroxy-3-methyl-2,3-dihydrobenzofuran-5-yl)ethan-1-one
- the second step the synthesis of 5-(1-cyclopropyl-1-hydroxyethyl)-7-fluoro-3-methyl-2,3-dihydrobenzofuran-4-ol
- the third step the synthesis of 5-(1-cyclopropylethyl)-7-fluoro-3-methyl-2,3-dihydrobenzofuran-4-ol
- Step 4 Dibenzyl[(5-(1-cyclopropylethyl)-7-fluoro-3-methyl-2,3-dihydro-1-benzofuran-4-yl)oxy]phosphoric acid Synthesis of methyl esters
- Step 5 Dibenzyl[(5-(1-cyclopropylethyl)-7-fluoro-3-methyl-2,3-dihydro-1-benzofuran-4-yl)oxy]phosphoric acid Chiral resolution of methyl esters
- Step 6 Sodium (5-(1-cyclopropyl)-7-fluoro-3-methyl-2,3-dihydrobenzofuran-4-yl)oxymethylphosphate (optical isomer 10A1 and 10A2) synthesis
- the first step chiral resolution of 1-(7-fluoro-4-hydroxy-3-methyl-2,3-dihydrobenzofuran-5-yl)ethan-1-one
- the second step the synthesis of 5-(1-cyclopropyl-1-hydroxyethyl)-7-fluoro-3-methyl-2,3-dihydrobenzofuran-4-ol
- the target product 5-(1-cyclopropyl-1-hydroxyethyl)-7-fluoro-3-methyl- 2,3-Dihydrobenzofuran-4-ol (32.6 g).
- the third step the synthesis of 5-(1-cyclopropylethyl)-7-fluoro-3-methyl-2,3-dihydrobenzofuran-4-ol
- Step 4 Dibenzyl[(5-(1-cyclopropylethyl)-7-fluoro-3-methyl-2,3-dihydro-1-benzofuran-4-yl)oxy]phosphoric acid Synthesis of methyl esters
- Step 5 Dibenzyl[(5-(1-cyclopropylethyl)-7-fluoro-3-methyl-2,3-dihydro-1-benzofuran-4-yl)oxy]phosphoric acid Chiral resolution of methyl esters
- Step 6 Sodium (5-(1-cyclopropyl)-7-fluoro-3-methyl-2,3-dihydrobenzofuran-4-yl)oxymethylphosphate (optical isomer 10B1 and 10B2) synthesis
- Example 4 For the synthesis method of Example 12, refer to Example 4.
- Example 14 For the synthesis method of Example 13, refer to Example 4.
- Example 14 For the synthesis method of Example 14, refer to Example 4.
- Example 4 For the synthesis method of Example 15, refer to Example 4.
- Test Example 1 Mouse righting reflex test and LD 50 test
- the ED50 value and LD50 value of the compound of the present invention were measured by sequential method, the TI (therapeutic index) of the drug was calculated, and the animal symptoms during the experiment were observed to investigate the drug efficacy, safety and side effects of the compound of the present invention.
- mice SPF grade ICR mice (Pizhou Dongfang Breeding Co., Ltd.), 22-28 grams, 15/group. All mice received 3 days of quarantine and adaptive feeding, and were transferred from the breeding room to the laboratory to adapt to the environment 1 hour before the experiment.
- test compound was dissolved in 20% fat emulsion or purified water to prepare a 5 mg/mL liquid medicine.
- mice were injected with the drug of the previous dose (i.e. 1.25 times the first dose); When the anesthesia effect or death occurs, the next mice are injected with the drug at the next concentration (ie 0.8 times the first dose); and so on, until the test is repeated 6 times or 15 mice are completed.
- ED 50 test anesthesia effect
- LD 50 test death
- ED 50 half effective dose: the dose required to cause 50% of mice to lose the righting reflex by passing the test
- LD 50 half lethal dose: the dose required to cause 50% of mice to die by passing the test
- TI therapeutic index
- the compound of the present invention has better anesthetic effect, is safer, has a larger safety window, and has fewer side effects.
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Abstract
Description
Claims (15)
- 一种通式(Ia)所示的化合物、其立体异构体或其药学上可接受的盐:其中:环A为C 5-6环烷基或5~6元杂环基;R a各自独立地为氢、氘、卤素、羟基、氰基、氨基、C 1-6烷氧基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-6环烷基或3~6元杂环基;R 1为氢、氘、卤素、羟基、氰基、氨基、C 1-6烷氧基、C 1-6烷基、C 1-6氘代烷基或C 1- 6卤代烷基;R 2和R 3各自独立地为氢、氘、卤素、羟基、氰基、氨基、C 1-6烷氧基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-6环烷基或3~6元杂环基;R AA和R BB各自独立地为氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、碱金属离子、碱土金属离子、质子化胺或质子化氨基酸,所述的碱金属离子为Na +、K +或Li +,所述的碱土金属离子为Be 2+、Mg 2+或Ca 2+,所述的质子化胺为氨丁三醇、三乙醇胺、乙醇胺、三乙胺或者N-甲基葡萄糖胺,所述的氨基酸为精氨酸或者赖氨酸;且x为0~5的整数。
- 根据权利要求1或2所述的化合物、其立体异构体或其药学上可接受的盐,其特征在于,满足以下条件中的一种或多种:(1)环A为C 5-6环烷基或含1~3个为N、O或S原子的5~6元杂环基,优选 其中,M为CR aaR bb、NR aa、O或S,优选CR aaR bb或O,更优选CH 2或O;其中,R aa和R bb各自独立地为氢、氘、卤素、羟基、氰基、氨基、C 1-6烷氧基、C 1-6烷基、C 1-6氘代烷基或C 1-6卤代烷基,优选氢或C 1-6烷基,更优选氢或C 1-3烷基;(3)R AA和R BB各自独立地为氢、C 1-6烷基、碱金属离子或碱土金属离子,所述的碱金属离子为Na +、K +或Li +,所述的碱土金属离子为Be 2+、Mg 2+或Ca 2+,优选碱金属离子Na +、K +或Li +,更优选Na +;(4)R a各自独立地为氢、C 1-6烷基或C 3-6环烷基,优选氢、C 1-3烷基或C 3-5环烷基,更优选氢、甲基、乙基、丙基或环丙基,进一步优选氢、甲基、乙基或环丙基;(5)R 1为氢或卤素,优选氢、氟、氯或溴,更优选氢、氟或氯;(6)R 2和R 3各自独立地为氢、C 1-6烷基或C 3-6环烷基,优选氢、C 1-3烷基或C 3-5环烷基,更优选氢、甲基、乙基、丙基或环丙基,进一步优选甲基或环丙基;(7)x为0、1或2。
- 根据权利要求5或6所述的化合物、其立体异构体或其药学上可接受的盐,其特征在于,满足以下条件中的一种或多种:(1)R 4和R 4’各自独立地为氢、甲基、乙基或环丙基;(2)R 5和R 5’各自独立地为氢或甲基。
- 一种药物组合物,其包含治疗有效剂量的权利要求1~9中任一项所述的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
- 根据权利要求1~9中任一项所述的化合物、其立体异构体或其药学上可接受的盐,或权利要求12所述的药物组合物在制备GABA A受体激动剂药物中的应用。
- 根据权利要求1~9中任一项所述的化合物、其立体异构体或其药学上可接受的盐,或权利要求12所述的药物组合物在制备中枢神经系统领域药物中的应用。
- 根据权利要求14所述的应用,其特征在于,所述中枢神经系统领域药物为用于诱导和维持哺乳动物的麻醉,促进哺乳动物的镇静催眠,治疗和/或预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥或癫痫的药物。
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CN114249652A (zh) * | 2020-09-25 | 2022-03-29 | 天地恒一制药股份有限公司 | 苯酚衍生物及其在医药上的应用 |
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2022
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CN101268062A (zh) * | 2005-07-28 | 2008-09-17 | 弗·哈夫曼-拉罗切有限公司 | 对gaba-b-受体具有亲合性的2-羟基-丙酸衍生物和3-羟基-苯并呋喃-2-酮衍生物 |
CN114249652A (zh) * | 2020-09-25 | 2022-03-29 | 天地恒一制药股份有限公司 | 苯酚衍生物及其在医药上的应用 |
Non-Patent Citations (2)
Title |
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DATABASE REGISTRY ANONYMOUS : "1H-Inden-4-ol, 3-amino-2,3-dihydro-2,2,7-trimethyl-5-(1-methylpropyl)- (CA INDEX NAME) RENCES IN FILE CA (1907 TO DATE) 1 REFERENCES IN FILE CAPLUS (1907 TO DATE)", XP093032342, retrieved from STN * |
DATABASE REGISTRY ANONYMOUS : "1H-Inden-4-ol, 3-amino-7-ethyl-2,3-dihydro-5-(1-methylpropyl)- (CA INDEX NAME) ", XP093032344, retrieved from STN * |
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