CN115108986A - 阿朴菲衍生物及其制备方法和应用 - Google Patents
阿朴菲衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN115108986A CN115108986A CN202210667737.3A CN202210667737A CN115108986A CN 115108986 A CN115108986 A CN 115108986A CN 202210667737 A CN202210667737 A CN 202210667737A CN 115108986 A CN115108986 A CN 115108986A
- Authority
- CN
- China
- Prior art keywords
- synthesis
- compound
- dmso
- nmr
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000008441 aporphines Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- -1 Alkoxy radical Chemical class 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 12
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 9
- 230000036506 anxiety Effects 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 206010013663 drug dependence Diseases 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 6
- 229940123838 5 Hydroxytryptamine 2A receptor agonist Drugs 0.000 claims abstract description 5
- 229940121744 5 Hydroxytryptamine 2C receptor agonist Drugs 0.000 claims abstract description 5
- 208000008589 Obesity Diseases 0.000 claims abstract description 5
- 206010015037 epilepsy Diseases 0.000 claims abstract description 5
- 235000020824 obesity Nutrition 0.000 claims abstract description 5
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 5
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims abstract description 4
- 208000002193 Pain Diseases 0.000 claims abstract description 4
- 206010046543 Urinary incontinence Diseases 0.000 claims abstract description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229940044601 receptor agonist Drugs 0.000 claims description 9
- 239000000018 receptor agonist Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
- 229910010082 LiAlH Inorganic materials 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- MHJUNMARMFAUBI-UHFFFAOYSA-N n-phenyliminobenzamide Chemical compound C=1C=CC=CC=1C(=O)N=NC1=CC=CC=C1 MHJUNMARMFAUBI-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 102000011352 5-Hydroxytryptamine 2A receptors Human genes 0.000 claims 2
- 108050001673 5-Hydroxytryptamine 2A receptors Proteins 0.000 claims 2
- 102000009394 5-Hydroxytryptamine 2C receptors Human genes 0.000 claims 2
- 108050000259 5-Hydroxytryptamine 2C receptors Proteins 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims 1
- 208000020401 Depressive disease Diseases 0.000 claims 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 9
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 154
- 150000001875 compounds Chemical class 0.000 description 93
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 90
- 230000015572 biosynthetic process Effects 0.000 description 81
- 238000003786 synthesis reaction Methods 0.000 description 81
- 238000005481 NMR spectroscopy Methods 0.000 description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 238000004949 mass spectrometry Methods 0.000 description 44
- 239000000543 intermediate Substances 0.000 description 43
- 102000005962 receptors Human genes 0.000 description 28
- 108020003175 receptors Proteins 0.000 description 28
- 239000000203 mixture Substances 0.000 description 21
- 239000002994 raw material Substances 0.000 description 21
- ZUGRYLJRHKHZLR-UHFFFAOYSA-N 1h-quinolin-2-one;hydrochloride Chemical compound Cl.C1=CC=C2NC(=O)C=CC2=C1 ZUGRYLJRHKHZLR-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 239000000460 chlorine Substances 0.000 description 18
- 230000002194 synthesizing effect Effects 0.000 description 17
- 230000000694 effects Effects 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 8
- 229910001424 calcium ion Inorganic materials 0.000 description 8
- ZPSZXWVBMOMXED-UHFFFAOYSA-N 2-(2-bromo-5-chlorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(Cl)=CC=C1Br ZPSZXWVBMOMXED-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000001270 agonistic effect Effects 0.000 description 6
- BZKUYNBAFQJRDM-UHFFFAOYSA-N aporphine Chemical compound C12=CC=CC=C2CC2N(C)CCC3=CC=CC1=C32 BZKUYNBAFQJRDM-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000556 agonist Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 102000014384 Type C Phospholipases Human genes 0.000 description 4
- 108010079194 Type C Phospholipases Proteins 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 3
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 102000003923 Protein Kinase C Human genes 0.000 description 3
- 108090000315 Protein Kinase C Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- QCMQEZNBBPGFKQ-UHFFFAOYSA-N Thalisopynine Natural products CN1CCC2=C(OC)C(OC)=C(OC)C3=C2C1CC1=C3C=C(OC)C(O)=C1 QCMQEZNBBPGFKQ-UHFFFAOYSA-N 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 208000015114 central nervous system disease Diseases 0.000 description 3
- 150000001982 diacylglycerols Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000004907 flux Effects 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- FVRABHGHBLRNNR-UHFFFAOYSA-N liriodenine Natural products O=C1C=CC=c2c1cc3nccc4cc5OCOc5c2c34 FVRABHGHBLRNNR-UHFFFAOYSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- BWWZVTBUNNJBBT-UHFFFAOYSA-N 2-(2-bromo-3-chlorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Cl)=C1Br BWWZVTBUNNJBBT-UHFFFAOYSA-N 0.000 description 2
- GQCHYZKUKPMGKK-UHFFFAOYSA-N 2-(2-bromo-3-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(F)=C1Br GQCHYZKUKPMGKK-UHFFFAOYSA-N 0.000 description 2
- BWAQWLHENYXBOQ-UHFFFAOYSA-N 2-(2-bromo-4-chlorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1Br BWAQWLHENYXBOQ-UHFFFAOYSA-N 0.000 description 2
- XEXHAKGPISSIIX-UHFFFAOYSA-N 2-(2-bromo-5-methoxyphenyl)acetic acid Chemical compound COC1=CC=C(Br)C(CC(O)=O)=C1 XEXHAKGPISSIIX-UHFFFAOYSA-N 0.000 description 2
- KTPDPINDCZGYEC-UHFFFAOYSA-N 2-(2-bromo-6-chlorophenyl)acetic acid Chemical compound OC(=O)CC1=C(Cl)C=CC=C1Br KTPDPINDCZGYEC-UHFFFAOYSA-N 0.000 description 2
- 125000004791 2-fluoroethoxy group Chemical group FCCO* 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical compound CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 125000005394 methallyl group Chemical group 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000036651 mood Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 208000028173 post-traumatic stress disease Diseases 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 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
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 102000003390 tumor necrosis factor Human genes 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- IBXMKLPFLZYRQZ-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 IBXMKLPFLZYRQZ-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- SKACEXLUFRXDJP-UHFFFAOYSA-N 1-amino-3-sulfonylurea Chemical compound NNC(=O)N=S(=O)=O SKACEXLUFRXDJP-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- CNWINRVXAYPOMW-FCNJXWMTSA-N 1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-1D-myo-inositol 4,5-biphosphate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)O[C@H](COC(=O)CCCCCCCCCCCCCCCCC)COP(O)(=O)O[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H]1O CNWINRVXAYPOMW-FCNJXWMTSA-N 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- JZMWDWZVHXNEEF-UHFFFAOYSA-N 2-(2-bromo-3-methylphenyl)acetic acid Chemical compound CC1=CC=CC(CC(O)=O)=C1Br JZMWDWZVHXNEEF-UHFFFAOYSA-N 0.000 description 1
- MJSGXOXCPKTZTK-UHFFFAOYSA-N 2-(2-bromo-4-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C=C1Br MJSGXOXCPKTZTK-UHFFFAOYSA-N 0.000 description 1
- BPNWLZNAKZSBHH-UHFFFAOYSA-N 2-(2-bromo-5-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=CC=C1Br BPNWLZNAKZSBHH-UHFFFAOYSA-N 0.000 description 1
- FXZNTVCKHGUWOP-UHFFFAOYSA-N 2-(2-bromo-6-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=C(F)C=CC=C1Br FXZNTVCKHGUWOP-UHFFFAOYSA-N 0.000 description 1
- DWXSYDKEWORWBT-UHFFFAOYSA-N 2-(2-bromophenyl)acetic acid Chemical class OC(=O)CC1=CC=CC=C1Br DWXSYDKEWORWBT-UHFFFAOYSA-N 0.000 description 1
- JGFXUYLYPITYGR-UHFFFAOYSA-N 2-(2-diphenylphosphanylphenyl)-n,n-dimethylaniline Chemical group CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 JGFXUYLYPITYGR-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- LTPVSOCPYWDIFU-UHFFFAOYSA-N 4-methoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1 LTPVSOCPYWDIFU-UHFFFAOYSA-N 0.000 description 1
- 102100024959 5-hydroxytryptamine receptor 2C Human genes 0.000 description 1
- 101710138093 5-hydroxytryptamine receptor 2C Proteins 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-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
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 201000007547 Dravet syndrome Diseases 0.000 description 1
- 208000001654 Drug Resistant Epilepsy Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- OUVXYXNWSVIOSJ-UHFFFAOYSA-N Fluo-4 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(F)C(=O)C=C3OC3=CC(O)=C(F)C=C32)N(CC(O)=O)CC(O)=O)=C1 OUVXYXNWSVIOSJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 208000036572 Myoclonic epilepsy Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 206010073677 Severe myoclonic epilepsy of infancy Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004946 alkenylalkyl group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000005256 alkoxyacyl group Chemical group 0.000 description 1
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000005038 alkynylalkyl group Chemical group 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000035045 associative learning Effects 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
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000005895 circadian behavior Effects 0.000 description 1
- 230000027288 circadian rhythm Effects 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000000982 direct dye Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 208000018578 heart valve disease Diseases 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 description 1
- 229960005060 lorcaserin Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 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
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 208000019899 phobic disease Diseases 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
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- QROGIFZRVHSFLM-UHFFFAOYSA-N prop-1-enylbenzene Chemical group CC=CC1=CC=CC=C1 QROGIFZRVHSFLM-UHFFFAOYSA-N 0.000 description 1
- GHUURDQYRGVEHX-UHFFFAOYSA-N prop-1-ynylbenzene Chemical compound CC#CC1=CC=CC=C1 GHUURDQYRGVEHX-UHFFFAOYSA-N 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Obesity (AREA)
- Addiction (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Rheumatology (AREA)
- Child & Adolescent Psychology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明医药技术领域,尤其是指一种阿朴菲衍生物及其制备方法和应用。
背景技术
5-羟色胺(5-HT)受体广泛分布于中枢神经***和外周神经***,并参与调节大量的生理反应,如认知、记忆加工、情绪、昼夜节律行为和食欲。其中,5-HT2受体包括高度同源性的三个亚型即5-HT2A,5-HT2B和5-HT2C受体,通过Gq/11蛋白激活相应的下游细胞内效应分子,比如磷脂酶C(PLC),而PLC的活性取决于磷酸肌醇和(或)胞内钙离子浓度,以及蛋白激酶C(PKC)。PLC催化4,5-二磷酸磷脂酰肌醇水解成为三磷酸肌醇(IP3)和二酰甘油(DAG)。IP3能够促进细胞内钙库释放钙离子,使细胞质内的钙离子浓度升高,钙离子与细胞质内的PKC结合并聚集至质膜。DAG、磷脂酰丝氨酸及钙离子共同激活PKC,继而引起各种相应的生物学效应。
在中枢神经***中,5-HT2A受体参与了认知状态、联想学习、情绪和昼夜节律的调节,因而5-HT2A受体激动剂的疗效正在用于调查多种神经***疾病适应症,包括绝症或创伤后应激障碍(PTSD)相关的恐惧和焦虑患者的辅助心理治疗,重度抑郁症、难治性抑郁症、成瘾、强迫症等,此外其还作为强效的肿瘤坏死因子(TNF-a)介导的炎症抑制剂可用于炎症性疾病的新治疗方法。5-羟色胺2C(5-HT2C)受体因主要集中表达在中枢神经***而产生外周副作用的风险低,因此5-HT2C受体成为了治疗中枢神经***疾病的理想靶点,如儿童难治性癫痫Dravet综合征、肥胖、焦虑、精神***症和成瘾药物等。而5-HT2B受体主要分布于心脏瓣膜等,当激动5-HT2B受体时,将可能诱发心脏瓣膜病的发生。因此,开发低5-HT2B受体活性的5-HT2A/2C或5-HT2C受体选择性激动剂对于中枢神经***疾病的治疗非常有必要。
目前不仅尚无高激动活性的5-HT2A/2C受体激动剂的报道,而且公开上市或者处于临床前研究的5-HT2C受体高选择性激动剂也很少,如仅有氯卡色林和戊卡色林曾上市或进入过临床。因此,仍然需要开发结构新颖,具有高选择性,高活性和好的成药性的化合物。
阿朴菲类衍生物既能从天然产物中分离得到,又可通过有机合成修饰得到,因其结构多变,从而生物活性广泛,如抗癌活性、抗炎活性、抗氧化活性、抗血小板聚集活性、抗帕金森病、抗病毒活性、对肾上腺素受体作用活性、抗风湿活性、抗疟活性、抗菌活性等。虽然阿朴菲类衍生物在治疗中枢神经***疾病的应用已经被研究多年,但主要是作为多巴胺D2受体、5-HT1A受体,5-HT2A和5-HT2B受体的配体,甚至有的化合物靶标不明(如CN112999225A和CN113004201A),但其作用于5-HT2C受体直到近年来才被探索。
现有技术中,靶向5-HT2C受体的阿朴菲类激动剂目前仍存在5-HT2C受体激动活性弱,如1857(ACS CentSci,2020,6,213-25)和18b(ACS Chem Neurosci,2020,11,549-59;ZL201910594756.6);以及5-HT2C受体选择性差等缺陷,如11b和11f(Bioorganic Chemistry123(2022)105795;ZL201910594756.6),从而最终限制了其进一步的临床发展。而兼具有5-HT2A和5-HT2C受体的双重激动剂尚无报道。
发明内容
为解决上述技术问题,本发明提供了一种阿朴菲衍生物及其制备方法和应用。
其中,R1为C1-C8烷氧基或氢,
R2为羟基或氢;
R3选自C1-C8烷基、C1-C8烷氧基、C2-C10炔基、C2-C10烯基、卤素、C1-C8卤烷基、氰基、硝基或芳基。
在本发明的一个实施例中,R2为羟基时,R1选自C1-C8烷氧基和氢,R3选自卤素、C1-C8烷氧基、C1-C8烷基。
在本发明的一个实施例中,R2为羟基时,R1选自氢,R3独立地选自卤素、C1-C8烷氧基、C1-C8烷基。
在本发明的一个实施例中,R2为羟基时,R1选自C1-C8烷氧基,R3独立地选自卤素、C1-C8烷氧基。
在本发明的一个实施例中,卤素为氟,氯,溴或碘。
进一步地,C1-C8卤烷基为含有卤素的1-8个碳的烷基,卤素的个数和种类不限,如三氟甲基、二氟甲基、单氟甲基或三氟乙基;
C2-C10烯基为2-10个碳的烯基,如乙烯,丙烯,丁烯,苯乙烯或苯丙烯;
C2-C10炔基为2-10个碳的炔基,如乙炔,丙炔,丁炔,苯乙炔或苯丙炔;
C1-C8烷基(R)和C1-C8烷氧基(RO-),其中烷基(R)具体包括脂肪族烷基和芳香族烷基;其中,所述脂肪族烷基优选为C1-C8烷基,可以是直链烷基,支链烷基,螺环烷基,桥环烷基,烯烷基,炔烷基,环烷基,环烯基,环炔基,烷氧烷基,烷氧酰基烷基,环烷基烷基,更优选地,脂肪族烷基非限制性地包括:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙烷基、环丁烷基、环戊烷基、环己烷基,烯丙基,炔丙基,环丁烯基,环己烯基,2,2-二氟乙基、2-氟乙基;所述芳香族烷基非限制性地包括:芳烷基或杂芳烷基,如取代芳氧基取代的或未取代的苯甲基;取代的或未取代的苯乙基;取代的或未取代的苯丙基等;
芳基指的是取代或未取代的芳基或杂芳基,芳基非限制性地包括:取代的或未取代的苯基,萘环,连苯环等;取代基选自卤素、氨基、羟基、肟、烷氧酰基、酰氧基、酰基、磺酰基、磺酰氨基、脲、硫脲和氨甲酰基中的一种或几种。
杂芳基非限制性地包括:取代的或未取代的芳香杂环基和苯并杂环取代基;非限制性地包括喹啉、异喹啉、吲哚、苯并呋喃环、呋喃环、苯并噻吩环、噻吩环、吡啶环、吡咯环等。
进一步地,异构体包括R型异构体和S型异构体。
在本发明的一个实施例中,R3选自卤素、C1-C8烷氧基或C1-C8烷基。
本发明的第二个目的在于提供所述的阿朴菲衍生物的制备方法,包括以下步骤:
在本发明的一个实施例中,步骤(1)中,所述脱水剂为五氧化二磷、三氯氧磷和五氯化磷中的一种或多种。
在本发明的一个实施例中,步骤(1)中,所述还原剂选自所述还原剂选自NaBH4(硼氢化钠)、LiAlH4(四氢铝锂)、BH3·THF(四氢呋喃硼烷)、KBH4(硼氢化钾)和SnCl2(二氯化锡)中的一种或多种。
在本发明的一个实施例中,步骤(1)中,所述保护基选自Tfa(三氟乙酰基)、Ts(对甲苯磺酰基)和Boc(叔丁氧羰基)中的一种或多种。
在本发明的一个实施例中,步骤(2)中,所述催化剂选自所述催化剂选自Pd(PPh3)4(四三苯基膦钯)、Pd(dppf)Cl2(1,1'-双二苯基膦二茂铁二氯化钯)、Pd(OAc)2(醋酸钯)和Pd2(dba)3(三二亚苄基丙酮二钯)中的一种或多种。
在本发明的一个实施例中,步骤(2)中,所述配体选自PhDavephos(2-二苯基膦-2'-(N,N-二甲氨基)联苯)、PCy3BHF4(三环己基膦四氟硼酸盐)、(t-Bu)2PMeHBF4(二叔丁基甲基膦四氟硼酸盐或四氟硼酸二叔丁基甲基膦盐)和PPh3(三苯基膦)中的一种或多种。
在本发明一具体实施例中,R1、R2、R3的其中一个或两个为氢,另外基团为非氢取代基,式M所示的化合物的制备方法如下:
步骤1:将含有取代基的苯乙胺M1,和取代或未取代的邻溴苯乙酸M2溶于无水二氯甲烷中,搅拌下加入HOBt,EDC,并将所得反应混合物在室温下搅拌反应,反应完全后得到式M3的酰胺化合物;
步骤2:将式M3的酰胺化合物和脱水剂置于溶剂中发生关环反应,然后在还原剂的作用下发生还原反应,反应完全后并引入三氟乙酰基保护基,得到式M4的化合物;
步骤3:将式M4的化合物在碱、配体和催化剂的作用下,在130℃下反应,反应完全后得到式M5的化合物;
步骤4:将式M5的化合物在还原剂的作用下脱去保护基团并成盐,得到式M的化合物。
本发明的第三个目的在于提供一种药物组合物,包括所述的阿朴菲衍生物。
本发明的第四个目的在于提供所述的阿朴菲衍生物、所述的药物组合物在制备5-羟色胺2A受体激动剂、5-羟色胺2C受体激动剂中的应用,所述5-羟色胺2A受体激动剂、5-羟色胺2C受体激动剂在制备预防和/或治疗肥胖、尿失禁、抑郁症、焦虑症、强迫症、癫痫、精神***症、疼痛、糖尿病或药物成瘾的药物中的应用。
在本发明的一个实施例中,所述5-羟色胺2A受体激动剂、5-羟色胺2C受体激动剂在制备预防和/或治疗抑郁症、焦虑症、强迫症或药物成瘾的药物中的应用。
在本发明的一个实施例中,所述药物还包括药学上或药理上可接受的载体。
在本发明的一个实施例中,所述载体选自崩解剂、稀释剂、润滑剂、粘合剂、湿润剂、矫味剂、助悬剂、表面活性剂和防腐剂中的一种或多种。
在本发明的一个实施例中,所述药物组合物的剂型为片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、乳剂、干混悬剂、干浸膏剂或注射剂。
在本发明的一个实施例中,所述药物还包括药学上或药理上可接受的盐、酯、水合物、溶剂化物、结晶形式、对映异构体、立体异构体、醚、代谢物和前药。
在本发明的一个实施例中,所述盐选自无机酸盐、有机酸盐、烷基磺酸盐和芳基磺酸盐中的一种或多种。
在本发明的一个实施例中,所述无机酸盐包括但不仅限于盐酸盐、氢溴酸盐、硝酸盐、硫酸盐和磷酸盐中的至少一种;优选地,所述有机酸盐包括但不仅限于甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐和柠檬酸盐中的至少一种;优选地,所述烷基磺酸盐包括但不仅限于甲基磺酸盐和乙基磺酸盐中的至少一种;所述芳基磺酸盐包括但不仅限于苯磺酸盐和对甲苯磺酸盐中的至少一种。
本发明的上述技术方案相比现有技术具有以下优点:
具体实施方式
下面结合具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
本发明以下实施例中,化合物的结构是通过核磁共振(NMR)或质谱(MS)确定的。NMR是用安捷伦400MHz或600MHz仪测定,测定溶剂为氘代二甲亚砜(DMSO-d6),氘代氯仿(CDCl3),内标为四甲基硅烷(TMS),MS用GCT PremierTM(CI)质谱仪测定,除注明外均为CI源(70ev)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板的规格是0.15mm-0.2mm,柱层析一般使用烟台黄海100~200目或200~300目硅胶为载体。
反应条件充氮气是指反应瓶连接一个约1L容积的氮气球。反应条件充氢气是指反应瓶连接一个约1L容积的氢气球。反应条件为室温(rt),温度范围是20-30℃。
本发明以下实施例中,所有溶剂在使用前均经过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得。
化合物S1-S9的合成路线如下所示:
中间体3a-i的合成:在冰水浴下,将苯乙酸衍生物2a-i(1.0eq)溶于无水二氯溶液(0.2M)中,搅拌下依次加入1-羟基苯并***(1.2eq),1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(1.2eq),对甲氧基苯乙胺1-1(1.2eq)。逐渐升至室温并搅拌过夜,TLC检测反应直至结束。将混合物用二氯甲烷和水萃取分离,有机相依次用1N稀盐酸,饱和碳酸氢钠和饱和氯化钠溶液洗涤,用无水硫酸钠干燥,减压浓缩。少量二氯甲烷溶解,置于冰浴下冷却,搅拌结晶,以78-92%收率得到白色固体3a-i。
中间体4a-i的合成:将酰胺3a-i(1.0eq)和五氧化二磷(5.0eq)在甲苯中回流3h,待反应体系冷却后,浓缩甲苯。混合物用饱和碳酸氢钠水溶液中和,所得混合物用二氯甲烷萃取,经无水硫酸钠干燥,过滤并浓缩,然后再溶解在甲醇中(0.2M)。在冰水浴下将硼氢化钠(3.0eq)分批加入到混合物中,将所得混合物在室温搅拌3h。浓缩甲醇,加50mL水稀释,二氯甲烷萃取分离。用饱和碳酸氢钠水溶液以及饱和氯化钠溶液对有机相进行洗涤,经无水硫酸钠干燥,过滤并浓缩。柱层析,两步以55-65%收率得到黄色油状物。
在室温下,将三乙胺(2.5eq)加入到黄色油状物(1.0eq)的二氯甲烷(0.2M)溶液中。将混合物冷却至0℃,并将三氟乙酸酐(1.2eq)滴加到混合物中,逐渐升至室温并搅拌1h。将混合物用二氯甲烷(50mL)稀释,然后将混合物用1N HCl(盐酸),饱和碳酸氢钠水溶液和饱和氯化钠溶液洗涤。有机相经无水硫酸钠干燥,过滤并浓缩。柱层析,以80-85%收率得到白色固体4a-i。
中间体5a-i的合成:将碳酸钾(2.5eq),2-二苯基膦-2'-(N,N-二甲氨基)联苯(0.2eq),醋酸钯(0.1eq)和4a-i(1.0eq)置于圆底烧瓶中,氮气保护。然后加入溶剂N,N-二甲基乙酰胺(0.2M),并将所得混合物在130℃下加热4h。浓缩N,N-二甲基乙酰胺,加水稀释,将混合物用二氯甲烷萃取分离,有机相用无水硫酸钠干燥,过滤并浓缩。柱层析,以40-45%收率得到白色固体5a-i。
化合物S1-S9的合成:向圆底烧瓶中加入中间体5a-i(1.0eq)和乙醇(0.2M)。然后在冰浴下逐次加入硼氢化钠(20eq),向圆底烧瓶中充入氮气并将反应混合物在室温下搅拌60分钟。然后,减压蒸发溶剂,混合物向残余物中加入饱和氯化钠溶液,用二氯甲烷萃取。将有机相用无水硫酸钠干燥。过滤后,减压蒸发溶剂,柱层析,用氯化氢的乙酸乙酯溶液成盐,旋干溶剂,反复三次,两步以40-56%收率得到白色固体S1-S9。
实施例1:化合物S1(8-氯-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-6-氯苯乙酸2a为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.81(s,1H),δ8.28(d,J=7.7Hz,1H),7.41–7.27(m,3H),7.19(d,J=8.6Hz,1H),4.39(dd,J=14.1,3.4Hz,1H),3.91(s,3H),3.77(dd,J=12.0,5.7Hz,1H),3.70(dd,J=14.2,4.4Hz,1H),3.45–3.37(m,1H),3.25(d,J=6.1Hz,1H),3.08(dd,J=16.9,4.1Hz,1H),2.75(t,J=14.3Hz,1H).13C NMR(151MHz,DMSO-d6)δ155.94,133.56,132.17,130.00,129.81,129.56,127.99,127.63(d,J=15.7Hz),121.83,120.69,112.81,54.96,52.82,41.22,29.21,24.14.MS(CI)calcd for C17H17Cl2NO[M+H]+:322.23.
实施例2:化合物S2(9-氯-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-5-氯苯乙酸2b为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ9.91(s,2H),8.22(d,J=8.5Hz,1H),7.51(s,1H),7.42–7.14(m,3H),4.33(d,J=13.3Hz,1H),3.86(s,3H),3.59(d,J=6.4Hz,1H),3.22–2.89(m,5H).13C NMR(101MHz,DMSO-d6)δ155.5,136.0,131.9,130.9,130.6,130.1,128.1,127.4,123.4,120.1,113.2,56.4,52.2,32.7,24.7.MS(CI)calcd for C17H17Cl2NO[M+H]+:322.23.
实施例3:化合物S3(10-氯-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-4-氯苯乙酸2c为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.81(s,1H),8.22(s,1H),7.41(d,J=7.8Hz,1H),7.33(d,J=7.6Hz,1H),7.26(d,J=8.4Hz,1H),7.18(d,J=8.5Hz,1H),4.31(d,J=12.4Hz,1H),3.88(s,3H),3.57(d,J=5.6Hz,1H),3.25–3.10(m,3H),2.94(t,J=14.3Hz,2H).13C NMR(101MHz,DMSO-d6)δ155.62,133.51,132.52,131.90,131.21,130.55,130.17,128.38,127.56,123.51,119.82,113.12,56.50,52.23,32.29,24.63.MS(CI)calcd for C17H17Cl2NO[M+H]+:322.23.
实施例4:化合物S4(11-氯-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-3-氯苯乙酸2d为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.65(s,1H),7.41(dd,J=20.2,7.0Hz,2H),7.30(s,2H),7.16(d,J=8.2Hz,1H),4.18(d,J=12.0Hz,1H),3.84(s,3H),3.57(s,1H),3.26–3.09(m,3H),2.98–2.78(m,2H).13C NMR(151MHz,DMSO-d6)δ154.99,137.37,133.18,132.75,130.68,130.44,129.77,128.82,126.66,122.52,119.05,112.51,55.50,52.43,40.54,24.14.MS(CI)calcd forC17H17Cl2NO[M+H]+:322.23.
实施例5:化合物S5(8-氟-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-6-氟苯乙酸2e为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.09(s,2H),8.09(d,J=8.0Hz,1H),7.37(dd,J=14.8,7.7Hz,1H),7.27(d,J=8.6Hz,1H),7.18(dt,J=8.5,4.4Hz,2H),4.34(dd,J=14.2,4.4Hz,1H),3.87(s,3H),3.59(t,J=9.5Hz,1H),3.43(dd,J=14.3,4.6Hz,1H),3.21(d,J=7.1Hz,2H),2.94(t,J=11.8Hz,1H),2.72(t,J=14.3Hz,1H).13C NMR(151MHz,DMSO-d6)δ159.1(d,J=241.6Hz),155.7,133.8,130.9,130.4,128.4(d,J=7.6Hz),125.1,123.4,120.3(d,J=18.1Hz),120.2,114.5(d,J=22.7Hz),113.2,56.4,51.9,40.6,24.6,24.4.MS(CI)calcd for C17H17ClFNO[M+H]+:305.78.
实施例6:化合物S6(9-氟-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-5-氟苯乙酸2f为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ9.88(s,2H),8.25(dd,J=8.3,6.3Hz,1H),7.29(d,J=8.1Hz,1H),7.19(dd,J=25.2,8.4Hz,3H),4.33(d,J=11.1Hz,1H),3.86(s,3H),3.58(d,J=6.9Hz,1H),3.23–3.10(m,3H),2.95(dd,J=26.0,13.2Hz,2H).13C NMR(151MHz,DMSO-d6)δ161.96,160.33,155.24,136.49(d,J=8.5Hz),131.04(d,J=8.1Hz),130.70,129.62,128.12,123.33,120.37,115.24,115.09,114.15,114.02,113.10,40.67,24.67.MS(CI)calcd for C17H17ClFNO[M+H]+:305.78.
实施例7:化合物S7(10-氟-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-4-氟苯乙酸2g为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.75(s,1H),7.99(d,J=10.1Hz,1H),7.41(t,J=7.1Hz,1H),7.26(d,J=8.5Hz,1H),7.17(d,J=8.6Hz,1H),7.12(t,J=7.3Hz,1H),4.31(s,1H),3.88(s,3H),3.57(s,1H),3.27–3.07(m,3H),2.92(dd,J=17.3,10.2Hz,2H).13C NMR(151MHz,DMSO-d6)δ162.21,160.62,155.65,133.42(d,J=9.1Hz),131.08,130.44,129.93(d,J=8.3Hz),129.57,123.39,120.08,115.55,115.39,114.51,114.37,113.08,56.42,52.45,40.56,32.12,24.62.MS(CI)calcd for C17H17ClFNO[M+H]+:305.78.
实施例8:化合物S8(11-氟-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-3-氟苯乙酸2h为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.67(s,1H),7.39–7.27(m,2H),7.25(d,J=6.5Hz,1H),7.17(d,J=7.3Hz,2H),4.22(d,J=11.8Hz,1H),3.83(s,3H),3.58(s,1H),3.26–2.84(m,5H).13C NMR(151MHz,DMSO-d6)δ159.4(d,J=253.7Hz),155.3,136.7,132.1,130.3,129.5(d,J=9.1Hz),123.9,122.9,119.4(d,J=15.1Hz),117.4,115.7(d,J=24.2Hz),112.9,56.3,52.4,40.6,33.3,24.3.MS(CI)calcd for C17H17ClFNO[M+H]+:305.78.
实施例9:化合物S9(1,9-二甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-5-甲氧基苯乙酸2i为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.67(s,1H),8.16(d,J=8.8Hz,1H),7.13(q,J=8.5Hz,2H),6.95(s,1H),6.90(d,J=8.8Hz,1H),4.27(d,J=11.2Hz,1H),3.84(s,3H),3.79(s,3H),3.55(s,1H),3.19(d,J=10.1Hz,2H),3.11–3.03(m,1H),2.94(dd,J=30.5,13.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ158.72,155.07,135.40,130.44,130.28,128.66,124.29,123.31,121.34,113.73,113.04,112.91,56.34,55.64,52.50,33.36,24.71.MS(CI)calcd forC18H20ClNO2[M+H]+:317.81.
化合物S10-S12的合成路线如下所示:
中间体6a-c的合成,同中间体3a-i的合成。
中间体7a-c的合成:向酰胺6a-c(1.0eq)的乙腈(0.2M)溶液中加入三氯氧磷(3.0eq),回流2h。待反应体系冷却后,浓缩乙腈,用饱和碳酸氢钠水溶液中和。将所得混合物用二氯甲烷萃取,浓缩,然后再溶解在甲醇中(0.2M)。后续步骤同中间体4a-i的合成。柱层析得到白色固体7a-c。
中间体8a-c的合成,同中间体5a-c的合成。
中间体9a-c的合成:将中间体8a-c(1.0eq)溶解在适量甲醇和二氯甲烷中,加入10%Pd/C(0.2eq),充入氢气,常温反应4h,TLC监测直至反应完成。过滤,DCM萃取,盐洗,干燥,粗品硅胶柱层析分离得到白色固体9a-c。
化合物S10-S12的合成,同化合物S1-S9的合成。
实施例10:化合物S10(9-氯-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以2-溴-5-氯苯乙酸2b为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),9.70(s,1H),9.44(s,1H),8.25(d,J=8.6Hz,1H),7.52(s,1H),7.43(d,J=8.5Hz,1H),6.76(s,1H),4.24(s,1H),3.58(d,J=15.3Hz,4H),3.23–3.06(m,3H),2.97–2.81(m,2H).13C NMR(101MHz,DMSO-d6)δ151.24,144.78,136.38,132.41,130.72,129.91,128.48,127.91,127.17,125.29,120.75,116.53,60.09,51.82,33.06,24.98.MS(CI)calcdfor C17H17Cl2NO2[M+H]+:338.23.
实施例11:化合物S11(11-氯-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以2-溴-3-氯苯乙酸2d为原料,按照上述步骤合成。1H NMR(300MHz,DMSO-d6)δ10.15(s,1H),9.63(s,1H),9.28(s,1H),7.53-7.25(m,3H),6.81(s,1H),4.08(s,1H),3.56(s,1H),3.42(s,3H),3.25(s,1H),3.09(d,J=10.5Hz,2H),2.82(dd,J=24.4,11.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ150.71,145.18,137.71,132.94,130.77,129.90,129.27,126.85,125.97,124.03,122.71,116.51,60.89,52.22,34.90,24.58.MS(CI)calcd forC17H17Cl2NO2[M+H]+:338.23.
实施例12:化合物S12(1,9-二甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以2-溴-5-甲氧基苯乙酸2i为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.55(s,1H),8.21(d,J=8.7Hz,1H),7.51(d,J=7.3Hz,2H),7.43(t,J=7.3Hz,2H),7.35(t,J=7.0Hz,1H),6.96(dd,J=14.7,7.2Hz,3H),5.17(s,2H),4.23(s,1H),3.80(s,3H),3.63(s,3H),3.56(d,J=6.6Hz,1H),3.24–3.04(m,3H),2.92(dd,J=29.4,14.5Hz,2H).13C NMR(151MHz,DMSO-d6)δ159.13,152.26,145.23,137.35,135.82,129.84,128.95,128.36,128.06,127.02,126.39,123.97,121.99,113.99,113.46,112.95,70.34,60.16,55.62,51.99,40.58,33.60,25.32.MS(CI)calcd for C18H20ClNO3[M+H]+:333.81.
化合物S13-S22的合成如下所示:
中间体10a-f的合成,同中间体3a-i的合成。
中间体11a-f的合成,同中间体7a-c的合成。
中间体12a-f的合成,同中间体5a-i的合成。
中间体13a-f的合成:将中间体12a-f(1eq)溶解DCM中,置于-78℃,氮气保护,逐滴加入三溴化硼的二氯甲烷溶液(3eq),-78℃反应0.5h后,常温反应1h。加水淬灭后,乙酸乙酯萃取,盐洗,干燥,过滤后结晶。得到中间体13a-f。
中间体14a-d的合成:在0℃下,向13a-d(1.0eq)的二氯甲烷(0.2M)溶液中加入三氟甲磺酸酐(1.2eq)和三乙胺(2.5eq)。将反应混合物搅拌30分钟,然后用水淬灭。有机相经无水硫酸钠干燥,过滤后浓缩。柱层析得到产物。在圆底烧瓶中加入三乙胺(8.0eq)和无水N,N-二甲基甲酰胺(0.2M),滴加98%甲酸(8.0eq)。然后加入上述产物(1.0eq),随后依次加入醋酸钯(0.04eq)和1,1'-双(二苯基膦)二茂铁(0.08eq),将混合物加热至60℃。15分钟后,将混合物冷却至室温,加入水稀释,并用二氯甲烷)萃取。有机相经无水硫酸钠干燥,过滤,浓缩。柱层析得到白色产物14a-d。
实施例13:化合物S13(8-氯-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以2-溴-6-氯苯乙酸2a为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.68(d,J=7.0Hz,1H),9.25(s,1H),7.77(s,1H),7.46(d,J=21.6Hz,2H),7.16(s,1H),6.69(s,1H),4.48(s,1H),3.65(s,2H),3.29(s,1H),3.13(s,1H),2.97(s,1H),2.77(d,J=9.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ158.01,135.72,133.65,133.07,130.81,129.40(d,J=42.8Hz),129.17,123.53,119.07,115.61,110.70,51.38,40.95,29.18,25.27.MS(CI)calcd for C16H15Cl2NO[M+H]+:308.20.
实施例14:化合物S14(9-氯-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以2-溴-5-氯苯乙酸2b为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),9.44(d,J=30.2Hz,1H),7.75(s,1H),7.52(s,1H),7.43(s,1H),7.13(s,1H),6.65(s,1H),4.41(d,J=13.2Hz,1H),3.59(s,1H),3.28(s,1H),3.15(d,J=14.2Hz,2H),2.93(t,J=15.0Hz,2H).13C NMR(151MHz,DMSO-d6)δ157.99,135.42,133.44,133.21,132.89,132.36,128.81,128.32,126.21,119.23,115.31,110.22,51.53,40.93,32.33,25.33.MS(CI)calcd for C16H15Cl2NO[M+H]+:308.20.
实施例15:化合物S15(10-氯-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以2-溴-4-氯苯乙酸2c为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.77(d,J=20.2Hz,1H),9.44(s,1H),7.77(s,1H),7.39(dd,J=23.3,7.9Hz,2H),7.18(s,1H),6.68(s,1H),4.39(d,J=12.1Hz,1H),3.68–3.48(m,1H),3.25(d,J=12.0Hz,1H),3.16(d,J=13.5Hz,2H),2.92(t,J=13.9Hz,2H).13C NMR(151MHz,DMSO-d6)δ158.02,135.43,133.22,133.01,132.02,130.94,128.29,124.08,119.43,115.66,110.53,51.58,40.85,32.04,25.31.MS(CI)calcd for C16H15Cl2NO[M+H]+:308.20.
实施例16:化合物S16(11-氯-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以2-溴-3-氯苯乙酸2d为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.78(s,1H),9.50(d,J=7.0Hz,1H),7.63(s,1H),7.50(d,J=7.8Hz,1H),7.40(d,J=7.1Hz,1H),7.30(t,J=7.6Hz,1H),6.69(s,1H),4.25(s,1H),3.56(s,1H),3.25–3.10(m,3H),2.89(t,J=13.8Hz,2H).13CNMR(151MHz,DMSO-d6)δ156.72,137.27,132.34,131.82,131.33,131.11,130.65,129.40,128.10,121.38-121.28(m),115.19,114.82,51.45,40.45,34.21,25.27.MS(CI)calcd for C16H15Cl2NO[M+H]+:308.20.
实施例17:化合物S17(11-氟-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以2-溴-3-氟苯乙酸2h为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.76(s,1H),9.52(s,1H),7.34(s,2H),7.29–7.18(m,2H),6.67(s,1H),4.35(d,J=12.1Hz,1H),3.58(d,J=7.2Hz,1H),3.22(t,J=18.6Hz,3H),2.94(dd,J=26.2,13.8Hz,2H).13C NMR(151MHz,DMSO-d6)δ160.66,159.01,157.38,136.39,132.79,130.16,129.88(d,J=9.4Hz),125.17,121.24(d,J=10.0Hz),120.12,116.22,116.06,115.23,114.06(d,J=15.2Hz),51.56,40.66,33.10,25.43.MS(CI)calcd for C16H15ClFNO[M+H]+:291.75.
实施例18:化合物S18(11-甲基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以2-溴-3-甲基苯乙酸2j为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.67(s,1H),9.27(d,J=9.6Hz,1H),7.25(d,J=6.8Hz,1H),7.21(q,J=7.0Hz,2H),7.11(d,J=1.9Hz,1H),6.63(d,J=1.6Hz,1H),4.19(s,1H),3.57(d,J=9.7Hz,1H),3.27–3.20(m,1H),3.14(dd,J=12.5,5.4Hz,1H),3.05(dd,J=13.8,4.1Hz,1H),2.86(dd,J=30.0,15.9Hz,2H),2.54(s,3H).MS(CI)calcd for C17H18ClNO[M+H]+:287.79.
实施例19:化合物S19(8-氯-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-5-氯苯乙酸2b为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ9.91(s,2H),7.90(d,J=7.2Hz,1H),7.80(d,J=7.3Hz,1H),7.49(d,J=7.6Hz,1H),7.44(d,J=6.7Hz,2H),7.29(d,J=7.2Hz,1H),4.57(d,J=11.6Hz,1H),3.63(d,J=16.4Hz,2H),3.27(d,J=12.7Hz,2H),3.08–2.82(m,2H).13C NMR(151MHz,DMSO-d6)δ135.66,133.04,132.39,131.82,130.59,129.57,129.34,129.02,128.39,123.75,123.65(d,J=29.4Hz),51.49,40.80,28.78,25.13.MS(CI)calcd for C16H15Cl2NO[M+H]+:292.20.
实施例20:化合物S20(9-氯-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-5-氯苯乙酸2c为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.74(s,1H),7.89(s,1H),7.77(s,1H),7.54(s,1H),7.43(s,2H),7.26(s,1H),4.53(s,1H),3.62(s,2H),3.25–3.12(m,2H),3.03(d,J=14.1Hz,2H).13C NMR(151MHz,DMSO-d6)δ135.20,133.06,132.23,131.98,128.93(d,J=28.8Hz),128.33,126.47,123.03,51.61,40.78,31.89,25.20.MS(CI)calcd for C16H15Cl2NO[M+H]+:292.20.
实施例21:化合物S21(10-氯-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-5-氯苯乙酸2d为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.69(s,1H),7.94(s,1H),7.84(d,J=7.6Hz,1H),7.48–7.34(m,3H),7.28(d,J=7.5Hz,1H),4.52(s,1H),3.63(s,1H),3.28(s,1H),3.22(d,J=14.8Hz,2H),3.00(dd,J=18.7,9.1Hz,2H).13C NMR(151MHz,DMSO-d6)δ135.35,133.14,131.94,131.72,130.91,129.45,128.99,128.75,128.40,124.34,123.42,51.70,40.70,31.59,25.17.MS(CI)calcdfor C16H15Cl2NO[M+H]+:292.20.
实施例22:化合物S22(11-氯-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐)的合成
以2-溴-5-氯苯乙酸2e为原料,按照上述步骤合成。1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),9.58(s,1H),8.13(d,J=7.7Hz,1H),7.52(d,J=7.8Hz,1H),7.43(d,J=6.3Hz,2H),7.32(dd,J=12.6,7.5Hz,2H),4.40(d,J=10.8Hz,1H),3.62(s,1H),3.28(s,2H),3.19(d,J=16.7Hz,1H),2.96(dd,J=31.0,16.3Hz,2H).13C NMR(151MHz,DMSO-d6)δ137.02,131.29,131.13,130.91,130.72,129.57,129.19,128.06,127.68,127.00,51.67,40.37,33.73,25.12.MS(CI)calcd for C16H15Cl2NO[M+H]+:292.20.
化合物S23-S30的合成路线如下所示:
中间体14的合成,同中间体3a-i的合成。
中间体15的合成,同中间体7a-c的合成。
中间体16的合成,同中间体5a-i的合成。
中间体17的合成,同中间体9a-c的合成。
中间体18的合成:在室温下,将三乙胺(1.5eq)加入到脱苄中间体17(1eq)的DCM(0.2M)溶液中。将混合物冷却至0℃,并将4-二甲氨基吡啶(0.2eq)、4-甲苯磺酰氯(1.2eq)滴加到混合物中,逐渐升至室温并搅拌1h。将混合物用二氯甲烷稀释,然后将混合物用1N盐酸,饱和碳酸氢钠水溶液和饱和氯化钠溶液洗涤。有机相再经无水硫酸钠进行干燥,过滤,蒸发浓缩。柱层析得到白色固体18。
中间体19的合成,同中间体13a-f的合成。
中间体20a-g的合成:将中间体19(1.0eq)和相应卤代烷烃置于丙酮中,加入碳酸钾(2.0eq),碘化钾(2.0eq),将混合物回流,TLC监测反应。浓缩溶剂,柱层析得到白色固体20a-g。
实施例23:化合物S23(11-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
同化合物S1-S9的合成,1HNMR(300MHz,DMSO-d6)δ9.96(s,1H),9.51(s,1H),9.26(s,1H),7.67(s,1H),7.27(t,J=7.8Hz,1H),7.08(d,J=8.4Hz,1H),6.97(d,J=7.5Hz,1H),6.57(s,1H),4.25(s,1H),3.87(s,3H),3.56(s,1H),3.18(s,1H),3.15-2.99(m,2H),2.85(t,J=14.3Hz,2H).MS(CI)calcd for C17H18ClNO2[M+H]+:303.79.
实施例24:化合物S24(11-丙氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
用10mL氢氧化钾(0.5M MeOH/H2O)溶液加入到中间体20a(1eq),80℃回流5h后降到室温。浓缩溶剂,向混合物中加入饱和氯化钠溶液,用二氯甲烷萃取。用无水硫酸钠干燥有机相,过滤,浓缩。柱层析洗脱后的产物在室温下不稳定,用氯化氢的乙酸乙酯溶液成盐三次,得到白色固体S24。1HNMR(300MHz,DMSO-d6)δ10.24(s,1H),9.50(s,2H),7.73(s,1H),7.24(t,J=7.8Hz,1H),7.05(d,J=8.2Hz,1H),6.94(d,J=7.2Hz,1H),6.59(s,1H),4.20(d,J=16.2Hz,1H),4.16-4.07(m,1H),3.88(dd,J=15.1,6.7Hz,1H),3.53(s,1H),3.19(d,J=9.9Hz,2H),3.08(dd,J=14.1,3.7Hz,1H),2.88(t,J=13.3Hz,2H),1.82(dd,J=11.8,5.7Hz,2H),1.01(t,J=7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.91,156.47,135.57,132.66,131.61,129.29,122.09,121.21,120.29,115.31,113.95,112.79,70.33,51.86,33.99,25.50,22.59,11.23.MS(CI)calcd for C19H22ClNO2[M+H]+:331.84.
实施例25:化合物S25(11-环丙甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以中间体20b为原料,同化合物S24的合成。1H NMR(300MHz,DMSO-d6)δ10.57(s,1H),9.90-9.49(m,2H),7.78(s,1H),7.21(t,J=7.7Hz,1H),7.01(d,J=8.2Hz,1H),6.92(d,J=7.2Hz,1H),6.60(s,1H),4.17(s,1H),4.06-3.95(m,1H),3.84–3.75(m,1H),3.48-3.37(m,1H),3.12(dd,J=18.2,14.2Hz,3H),2.88(dd,J=28.3,13.9Hz,2H),1.31(s,1H),0.56(d,J=7.6Hz,2H),0.35(d,J=4.0Hz,2H).MS(CI)calcd for C20H22ClNO2[M+H]+:343.85.
实施例26:化合物S26(11-烯丙基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以中间体20c为原料,同化合物S24的合成。1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),9.58(d,J=23.2Hz,2H),7.71(s,1H),7.24(t,J=7.8Hz,1H),7.06(d,J=8.3Hz,1H),6.96(d,J=7.2Hz,1H),6.59(s,1H),6.19–6.03(m,1H),5.43(d,J=17.4Hz,1H),5.27(d,J=10.6Hz,1H),4.75(d,J=9.6Hz,1H),4.65–4.51(m,1H),4.22(d,J=11.1Hz,1H),3.54(d,J=5.2Hz,1H),3.14(dd,J=30.2,11.0Hz,3H),2.87(t,J=13.1Hz,2H).13C NMR(101MHz,DMSO-d6)δ156.90,155.93,135.69,134.05,132.53,131.70,129.24,122.31,121.51,120.37,117.61,115.34,114.04,113.26,69.50,51.83,33.98,25.49.MS(CI)calcd forC19H20ClNO2[M+H]+:329.82.
实施例27:化合物S27(11-炔丙基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉盐酸盐-2-醇)的合成
以中间体20d为原料,同化合物S24的合成。1H NMR(300MHz,DMSO-d6)δ10.03(s,1H),9.54(s,1H),9.34(s,1H),7.65(s,1H),7.28(t,J=7.9Hz,1H),7.15(d,J=8.1Hz,1H),7.01(d,J=7.1Hz,1H),6.59(s,1H),4.91(s,2H),4.25(d,J=11.5Hz,1H),3.58(d,J=18.2Hz,2H),3.12(dd,J=26.1,12.8Hz,3H),2.86(t,J=13.3Hz,2H).MS(CI)calcd forC19H18ClNO2[M+H]+:327.81.
实施例28:化合物S28(11-(2-氟乙氧基)-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以中间体20e为原料,同化合物S24的合成。1H NMR(400MHz,DMSO-d6)δ10.32(d,J=8.4Hz,1H),9.55(s,2H),7.73(t,J=8.6Hz,1H),7.29-7.22(m,1H),7.07(d,J=8.3Hz,1H),6.99(d,J=7.4Hz,1H),6.60(t,J=4.5Hz,1H),4.99-4.68(m,2H),4.47-4.33(m,1H),4.27(dd,J=16.8,8.4,Hz,1H),4.21(dd,J=8.0,4.2Hz,1H),3.54(d,J=6.2Hz,1H),3.25-3.15(m,2H),3.14-3.05(m,1H),2.89(dd,J=16.2,12.5Hz,2H).MS(CI)calcd for C18H19ClNO2[M+H]+:335.80.
实施例29:化合物S29(11-(2,2-二氟乙氧基)-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以中间体20f为原料,同化合物S24的合成。1H NMR(300MHz,DMSO-d6)δ10.32(s,1H),9.56(s,2H),7.66(s,1H),7.27(t,J=7.7Hz,1H),7.11(d,J=8.2Hz,1H),7.03(d,J=7.2Hz,1H),6.71(s,1H),6.60(s,1H),6.52(s,1H),6.34(s,1H),4.48(dd,J=26.4,12.7Hz,1H),4.29(dd,J=26.8,12.7Hz,2H),3.47–3.35(m,1H),3.14(dd,J=22.4,10.0Hz,3H),2.89(t,J=13.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ157.05,155.21,132.13,131.77,129.31,122.41,120.35,115.31,114.23,113.16,67.52,51.75,33.87,25.47.MS(CI)calcdfor C18H18ClNO2[M+H]+:353.79.
实施例30:化合物S30(11-((2-甲基烯丙基)氧基)-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
以中间体20g为原料,同化合物S24的合成。1H NMR(300MHz,DMSO-d6)δ9.79(s,1H),9.50(s,1H),9.17(s,1H),7.69(s,1H),7.29–7.21(m,1H),7.06(d,J=8.2Hz,1H),6.98(d,J=7.3Hz,1H),6.59(s,1H),5.04(d,J=34.9Hz,2H),4.66(d,J=13.2Hz,1H),4.47(d,J=13.0Hz,1H),4.25(s,1H),3.57(s,1H),3.19(s,1H),3.17–2.99(m,2H),2.88(d,J=21.1Hz,2H),1.80(s,3H).MS(CI)calcd for C20H22ClNO2[M+H]+:343.85.
实施例31:化合物S31(1,11-二甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S31.1H NMR(300MHz,DMSO-d6)δ9.79(s,1H),9.50(s,1H),9.17(s,1H),7.27(s,1H),6.97(s,1H),6.90(s,1H),6.82(s,1H),4.64(s,1H),4.05(s,1H),3.89(s,3H),3.76(s,3H),3.33(s,1H),3.22(d,J=4.0Hz,2H),2.91(s,1H),2.75(d,J=19.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ156.27,151.22,146.82,137.07,132.08,130.97,129.51,127.67,120.48,119.09,115.33,112.20,60.70,56.83,54.17,43.55,35.58,29.18.MS(CI)calcd for C18H19ClNO3[M+H]+:297.35.
实施例32:化合物S32(1-甲氧基-11-丙氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S32.1H NMR(300MHz,DMSO-d6)δ10.39(s,1H),9.49(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),4.58(s,1H),4.03(s,1H),3.99(s,2H),3.92(s,3H),3.35(s,1H),3.25(d,J=1.8Hz,2H),2.96(s,1H),2.77(d,J=20.0Hz,2H),1.74(s,2H),0.99(s,3H).13C NMR(101MHz,DMSO-d6)δ156.46,151.22,146.83,135.73,132.08,130.97,128.98,127.66,122.15,121.14,115.33,114.04,72.25,60.70,54.17,43.55,35.58,29.18,21.58,10.60.MS(CI)calcd for C20H24ClNO3[M+H]+:361.87.
实施例33:化合物S33(11-(环丙基甲氧基)-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S33。1H NMR(300MHz,DMSO-d6)δ10.39(s,1H),9.49(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),5.99(s,1H),4.05(s,1H),3.94–3.90(m,5H),3.35(s,1H),3.25(s,1H),3.24(s,1H),2.96(s,1H),2.79(s,1H),2.75(s,1H),1.11(t,J=9.9Hz,1H),0.51(dd,J=3.7,2.7Hz,1H),0.49(d,J=1.3Hz,1H),0.26–0.20(m,1H),0.20–0.15(m,1H).13C NMR(101MHz,DMSO-d6)δ155.99,151.22,146.82,136.57,132.08,130.97,129.09,127.67,122.43,121.00,115.33,114.20,74.00,60.70,54.17,43.55,35.58,29.18,10.70,7.85.MS(CI)calcd for C21H24ClNO3[M+H]+:373.88.
实施例34:化合物S34(11-(烯丙氧基)-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S34.1H NMR(300MHz,DMSO-d6)δ10.39(s,1H),9.49(s,1H),9.17(s,1H),7.19(s,1H),6.95(s,1H),6.87(s,1H),6.84(s,1H),6.07(d,J=7.0Hz,2H),5.43(s,1H),5.31(s,1H),4.69(t,J=1.9Hz,1H),4.67(t,J=1.9Hz,1H),4.04(s,1H),3.92(s,3H),3.35(s,1H),3.27(s,1H),3.25(s,1H),2.98(s,1H),2.79(s,1H),2.75(s,1H).13C NMR(101MHz,DMSO-d6)δ155.99,151.22,146.83,136.57,132.93,132.08,130.97,129.08,127.66,122.42,121.00,117.23,115.33,114.20,70.87,60.70,54.17,43.55,35.58,29.18.MS(CI)calcd for C20H22ClNO3[M+H]+:359.85.
实施例35:化合物S35(11-(2-氟乙氧基)-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S35.1H NMR(300MHz,DMSO-d6)δ10.40(s,1H),9.22(s,1H),9.10(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.03(s,1H),5.10(t,J=5.1Hz,1H),4.91(t,J=5.2Hz,1H),4.20(t,J=5.1Hz,1H),4.10(t,J=5.2Hz,1H),4.04(s,1H),3.92(s,3H),3.35(s,1H),3.26(s,1H),3.25(s,1H),2.97(s,1H),2.79(s,1H),2.75(s,1H).13C NMR(101MHz,DMSO-d6)δ156.46,151.22,146.83,135.73,132.08,130.97,128.98,127.66,122.15,121.14,115.33,114.04,85.83,69.46,60.70,54.17,43.55,35.58,29.18.MS(CI)calcd for C19H21ClNO3[M+H]+:365.83.
实施例36:化合物S36(11-(2,2-二氟乙氧基)-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S36.1H NMR(300MHz,DMSO-d6)δ10.47(s,1H),9.47(s,1H),9.21(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.14(s,1H),5.96(s,1H),4.40(s,2H),4.03(s,1H),3.92(s,3H),3.35(s,1H),3.25(s,1H),3.23(s,1H),2.95(s,1H),2.79(s,1H),2.75(s,1H).13CNMR(101MHz,DMSO-d6)δ155.99,151.22,146.83,136.57,132.08,130.97,129.08,127.66,122.42,121.00,115.33,114.20,68.23,60.70,54.17,43.55,35.58,29.18.MS(CI)calcd for C19H20ClF2NO3[M+H]+:383.82.
实施例37:化合物S37(1-甲氧基-11-((2-甲基烯丙基)氧基)-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S37.1H NMR(300MHz,DMSO-d6)δ10.50(s,1H),9.44(s,1H),9.31(s,1H),7.19(s,1H),6.95(s,1H),6.87(s,1H),6.84(s,1H),6.00(s,1H),4.98(s,1H),4.82(s,1H),4.45(s,2H),4.05(s,1H),3.92(s,3H),3.35(s,1H),3.27(s,1H),3.25(s,1H),2.98(s,1H),2.79(s,1H),2.75(s,1H),1.66(s,3H).13C NMR(101MHz,DMSO-d6)δ155.54,151.22,146.83,140.25,137.40,132.08,130.97,129.14,127.66,122.76,120.96,115.33,114.39,113.66,72.94,60.70,54.17,43.55,35.58,29.18,19.21.MS(CI)calcd for C21H24ClNO3[M+H]+:373.88.
实施例38:化合物S38((S)-11-氯-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S38.1H NMR(300MHz,DMSO-d6)δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.48(s,1H),7.42(s,1H),7.15(s,1H),6.87(s,1H),4.48(s,1H),4.04(s,1H),3.92(s,3H),3.35(s,1H),3.25(s,1H),3.11(s,1H),3.03(s,1H),2.79(s,1H),2.75(s,1H).13C NMR(101MHz,DMSO-d6)δ150.54,142.01,139.03,130.57,129.64,129.41,128.19,127.88,125.87,125.57,124.93,115.98,60.70,54.76,43.49,36.31,30.35.MS(CI)calcd for C17H17Cl2NO2[M+H]+:338.23.
实施例39:化合物S39((R)-11-氯-1-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S39.1H NMR(300MHz,DMSO-d6)δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.48(s,1H),7.42(s,1H),7.15(s,1H),6.87(s,1H),4.48(s,1H),4.04(s,1H),3.92(s,3H),3.35(s,1H),3.25(s,1H),3.11(s,1H),3.03(s,1H),2.79(s,1H),2.75(s,1H).13C NMR(101MHz,DMSO-d6)δ150.54,142.01,139.03,130.57,129.64,129.41,128.19,127.88,125.87,125.57,124.93,115.98,60.70,54.76,43.49,36.31,30.35.MS(CI)calcd for C17H17Cl2NO2[M+H]+:338.23.
实施例40:化合物S40((S)-1,11-二甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S40.1H NMR(300MHz,DMSO-d6)δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.00(s,1H),4.04(s,1H),3.92(s,3H),3.79(s,3H),3.35(s,1H),3.25(s,1H),3.15(s,1H),3.07(s,1H),2.79(s,1H),2.75(s,1H).13C NMR(101MHz,DMSO-d6)δ156.50,151.51,146.82,137.13,131.39,130.11,129.62,127.39,120.55,119.38,115.30,112.27,60.70,56.83,54.76,43.49,37.44,30.35.MS(CI)calcd for C18H20ClNO3[M+H]+:333.81.
实施例41:化合物S41((R)-1,11-二甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-2-醇盐酸盐)的合成
参照S11的合成方法,合成化合物S41.1H NMR(300MHz,DMSO-d6)δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.00(s,1H),4.04(s,1H),3.92(s,3H),3.79(s,3H),3.35(s,1H),3.25(s,1H),3.15(s,1H),3.07(s,1H),2.79(s,1H),2.75(s,1H).13C NMR(101MHz,DMSO-d6)δ156.50,151.51,146.82,137.13,131.39,130.11,129.62,127.39,120.55,119.38,115.30,112.27,60.70,56.83,54.76,43.49,37.44,30.35.MS(CI)calcd for C18H20ClNO3[M+H]+:333.81.
实施例42:钙离子流的测定
选择以上实施例中的部分化合物以及作为对照的部分化合物作为实验对象,测试其对5HT受体钙离子流的活性。在钙流测定实验8小时之前,将稳定转染的5-HT2A/2B/2C受体的HEK 293T细胞以15,000个细胞/孔的密度接种在384孔板中,孔板中含有1%透析的FBS的DMEM。除去培养基后,然后将细胞(20μL/孔)在37℃下用在FLIPR缓冲液(19HBSS,2.5mmol/L丙磺舒和20mmol/L HEPES,pH 7.4))中重建的Fluo-4直接染料(Invitrogen)孵育1小时。加载染料后,将细胞置于FLIPRTETRA荧光成像板读数器(Molecular Devices)中;在FLIPR缓冲液中以3倍浓度制备的药物稀释液,并等分到384孔板中,也加入到FLIPR中。FLIPRTETRA的流体模块和平板读数器被编程为读取基线荧光10秒(1读/秒),然后加入10μL药物/孔并读取6分钟(1读/秒)。将每个孔中的荧光归一化至起始前10个度数的平均值(即,基线荧光)。然后,测定药物添加后60s内发生的最大倍数增加,超过载体或药物引起的基线荧光。
表1:部分化合物对5HT2受体钙离子流活性测定结果
其中,NA表示无活性,“-”表示没有进行活性测定
从表1中可以看出:
1、与目前已报道的阿朴菲类5-HT2C受体激动剂相比,绝大多数化合物活性比1857[EC50(Emax)=308nM(86.1%),ACS Cent Sci,2020,6,213-25]和18b[EC50(Emax)=103nM(95.9%),ACS Chem Neurosci,2020,11,549-59;ZL201910594756.6]强至少2-6倍,如化合物S11;代表性化合物S11其5-HT2C受体选择性明显优于11b[5-HT2C:EC50(Emax)=51nM(93.6%);5-HT2B:EC50(Emax)=794.3nM(25.4%);5-HT2A:EC50(Emax)=317.7nM(55.2%)]和11f[5-HT2C:EC50(Emax)=23.6nM(101.8%);5-HT2B:EC50(Emax)=278.4nM(63.5%);5-HT2A:EC50(Emax)=596.4nM(44.9%)](Bioorganic Chemistry 123(2022)105795;ZL201910594756.6),且几乎无5-HT2B受体激动活性,其他类似的三取代化合物S31-S39和S40-S41具有同样的性质。因此本发明化合物安全性更好。
2、本发明首次报道了一类兼具有5-HT2A和5-HT2C受体的双重激动剂,且其对5-HT2B受体几乎无活性。如化合物S23-S30所具有的5-HT2C受体激动活性与5-HT2A受体相当,EC50最高甚至达到4.85nM,且几乎无5-HT2B受体活性。
3、R1和R2无论为何取代基,通常R3在11-位的活性要优于有8-,9-,10-位,如化合物S4,S11、S16-18、S22-S30。
4、当R2为H时,R1无论为小基团H还是大基团OMe,R3无论为何取代基在何位置,化合物几乎丧失活性,如化合物S1-S3、S5-S9、S19-S21;而当R2为OH时,R1无论为小基团H还是大基团OMe,R3无论为何取代基,化合物对5-HT2C受体均具有较好的激动活性,如化合物S11-S13、S15-S18、S23-S30。
显然,上述实施例仅仅是为清楚地说明所作的举例,并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
2.根据权利要求1所述的阿朴菲衍生物,其特征在于,R3选自卤素、C1-C8烷氧基或C1-C8烷基。
4.根据权利要求3所述的制备方法,其特征在于,步骤(1)中,所述还原剂选自NaBH4、LiAlH4、BH3·THF、KBH4和SnCl2中的一种或多种。
5.根据权利要求3所述的制备方法,其特征在于,步骤(1)中,所述PG保护基选自三氟乙酰基、对甲苯磺酰基和叔丁氧羰基中的一种或多种。
6.根据权利要求3所述的制备方法,其特征在于,步骤(2)中,所述催化剂选自四三苯基膦钯、1,1'-双二苯基膦二茂铁二氯化钯、醋酸钯和三二亚苄基丙酮二钯中的一种或多种。
7.根据权利要求3所述的制备方法,其特征在于,步骤(2)中,所述配体选自2-二苯基膦-2'-(N,N-二甲氨基)联苯、三环己基膦四氟硼酸盐、二叔丁基甲基膦四氟硼酸盐或四氟硼酸二叔丁基甲基膦盐和三苯基膦中的一种或多种。
8.一种药物组合物,其特征在于,包括权利要求1或2所述的阿朴菲衍生物。
9.权利要求1或2所述的阿朴菲衍生物、权利要求9所述的药物组合物在制备5-羟色胺2A受体激动剂、5-羟色胺2C受体激动剂中的应用,所述5-羟色胺2A受体激动剂、5-羟色胺2C受体激动剂在制备预防和/或治疗肥胖、尿失禁、抑郁症、焦虑症、强迫症、癫痫、精神***症、疼痛、糖尿病以及药物成瘾的药物中的应用。
10.根据权利要求9中所述的应用,其特征在于,所述5-羟色胺2A受体激动剂、5-羟色胺2C受体激动剂在制备预防和/或治疗抑郁症、焦虑症、强迫症及药物成瘾的药物中的应用。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210667737.3A CN115108986A (zh) | 2022-06-14 | 2022-06-14 | 阿朴菲衍生物及其制备方法和应用 |
CN202310508659.7A CN116730918A (zh) | 2022-06-14 | 2023-05-08 | 阿朴菲衍生物及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210667737.3A CN115108986A (zh) | 2022-06-14 | 2022-06-14 | 阿朴菲衍生物及其制备方法和应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115108986A true CN115108986A (zh) | 2022-09-27 |
Family
ID=83328968
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210667737.3A Pending CN115108986A (zh) | 2022-06-14 | 2022-06-14 | 阿朴菲衍生物及其制备方法和应用 |
CN202310508659.7A Pending CN116730918A (zh) | 2022-06-14 | 2023-05-08 | 阿朴菲衍生物及其制备方法和应用 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310508659.7A Pending CN116730918A (zh) | 2022-06-14 | 2023-05-08 | 阿朴菲衍生物及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (2) | CN115108986A (zh) |
-
2022
- 2022-06-14 CN CN202210667737.3A patent/CN115108986A/zh active Pending
-
2023
- 2023-05-08 CN CN202310508659.7A patent/CN116730918A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
CN116730918A (zh) | 2023-09-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2785879B2 (ja) | 治療学的に有用な2―アミノテトラリン誘導体 | |
CN109516982B (zh) | μ-阿片受体激动剂及其制备方法和在医药领域的应用 | |
KR101623357B1 (ko) | 5-ht6 길항제로서 아릴설포닐 피라졸린 카복스아미딘 유도체 | |
WO2008092292A1 (en) | Isoquinolone compounds as subtype-selective agonists for melatonin receptors mt1 and mt2 | |
JP2017019768A (ja) | ヘキサヒドロジベンゾ[a,g]キノリジン系化合物、その製造方法、医薬品組成物およびその応用 | |
CN113429387B (zh) | 一种苯并[b]硒吩类STING调控剂、其制备方法及用途 | |
WO2021052501A1 (zh) | 杂环酰胺类化合物、其可药用的盐及其制备方法和用途 | |
UA100192C2 (en) | 1-(arylsulfonyl)-4-(piperazin-1-yl)-1h-benzimidazoles as 5-hydroxytryptamine-6 ligands | |
DK2616460T3 (en) | HETEROCYCLIC COMPOUNDS FOR TREATMENT OR PREVENTION OF DISEASES CAUSED BY decreased neurotransmission of serotonin, norepinephrine or dopamine | |
JPH06506442A (ja) | 1−(4−アシルアミノフェニル)−7,8−メチレンジオキシ−5h−2,3−ベンゾ−ジアゼピン誘導体及びその酸付加塩、それを含む製薬学的組成物及びその製造方法 | |
KR101697834B1 (ko) | Kcnq칼륨통로 작동제로 사용가능한 신규화합물, 그 제조방법과 용도 | |
WO2021208945A1 (zh) | 一种苯并氮杂环类化合物、其制备方法及用途 | |
CN112168824B (zh) | 阿朴菲类化合物的应用 | |
EP3535244A1 (en) | Spiro-compounds as s1p modulators | |
CN115108986A (zh) | 阿朴菲衍生物及其制备方法和应用 | |
JP2011509296A (ja) | イオンチャネルリガンドとしてのアミド誘導体およびそれを使用する薬学的組成物および方法 | |
JP2018515499A (ja) | Gpr55受容体の活性の選択的モジュレーター:クロメノピラゾール誘導体 | |
JP5940729B2 (ja) | ジアリロ[a,g]キノリジン系化合物、その製造方法、医薬品組成物およびその応用 | |
CA2047236C (en) | Substituted 3-amino chromans | |
KR100450313B1 (ko) | 이소인돌로인돌론 화합물, 이들의 제조 방법, 및 이들을함유하는 약제 조성물 | |
JP2004508352A (ja) | 置換縮合ピロールイミン及びピラゾールイミン | |
JP5251885B2 (ja) | 縮合インダン化合物 | |
CN113087713A (zh) | 一类苯并二氮䓬衍生物及其制备方法和用途 | |
WO2007090841A1 (en) | Compounds which potentiate glutamate receptor and uses thereof in medicine | |
WO2023092195A1 (en) | Analogues of mdma for modulating sert, dat, and / or net activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220927 |