CN102307867A - 二氢喹啉酮衍生物 - Google Patents
二氢喹啉酮衍生物 Download PDFInfo
- Publication number
- CN102307867A CN102307867A CN2010800069350A CN201080006935A CN102307867A CN 102307867 A CN102307867 A CN 102307867A CN 2010800069350 A CN2010800069350 A CN 2010800069350A CN 201080006935 A CN201080006935 A CN 201080006935A CN 102307867 A CN102307867 A CN 102307867A
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- CN
- China
- Prior art keywords
- compound
- alkyl
- reaction
- carbonyl
- dihydroquinoline
- 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.)
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- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical class C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims abstract description 6
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims abstract description 6
- 206010012289 Dementia Diseases 0.000 claims abstract description 6
- 208000030814 Eating disease Diseases 0.000 claims abstract description 6
- 208000019454 Feeding and Eating disease Diseases 0.000 claims abstract description 6
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 6
- 208000008589 Obesity Diseases 0.000 claims abstract description 6
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims abstract description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 6
- 235000014632 disordered eating Nutrition 0.000 claims abstract description 6
- 201000003631 narcolepsy Diseases 0.000 claims abstract description 6
- 235000020824 obesity Nutrition 0.000 claims abstract description 6
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 6
- 201000002859 sleep apnea Diseases 0.000 claims abstract description 6
- -1 dihydroquinoline ketone Chemical class 0.000 claims description 147
- 229910052760 oxygen Inorganic materials 0.000 claims description 52
- 239000001301 oxygen Substances 0.000 claims description 52
- 125000005843 halogen group Chemical group 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 21
- 125000004076 pyridyl group Chemical group 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000003368 amide group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000006828 (C2-C7) alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000004761 (C2-C7) alkylaminocarbonyl group Chemical group 0.000 claims description 8
- 125000004763 (C3-C13) dialkylaminocarbonyl group Chemical group 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000001041 indolyl group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- TVPRCLHSULCNLV-UHFFFAOYSA-N pyridazin-3-one Chemical compound O=C1C=CC=N[N]1 TVPRCLHSULCNLV-UHFFFAOYSA-N 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 230000033764 rhythmic process Effects 0.000 claims description 6
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 5
- NSGCECVNIHAAIE-UHFFFAOYSA-N 2,3-dihydro-1h-1,4-benzodiazepine Chemical compound N1CCN=CC2=CC=CC=C21 NSGCECVNIHAAIE-UHFFFAOYSA-N 0.000 claims description 5
- 206010010904 Convulsion Diseases 0.000 claims description 5
- 230000036461 convulsion Effects 0.000 claims description 5
- 208000024732 dysthymic disease Diseases 0.000 claims description 5
- 206010015037 epilepsy Diseases 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 230000003449 preventive effect Effects 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 9
- 208000024827 Alzheimer disease Diseases 0.000 abstract 1
- 208000017164 Chronobiology disease Diseases 0.000 abstract 1
- 206010039085 Rhinitis allergic Diseases 0.000 abstract 1
- 201000010105 allergic rhinitis Diseases 0.000 abstract 1
- 230000000069 prophylactic effect Effects 0.000 abstract 1
- 208000019116 sleep disease Diseases 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 129
- 238000006243 chemical reaction Methods 0.000 description 122
- 239000002585 base Substances 0.000 description 91
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 79
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- 238000002360 preparation method Methods 0.000 description 49
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- 239000002904 solvent Substances 0.000 description 36
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- 238000000034 method Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 21
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
- 239000002253 acid Substances 0.000 description 20
- 229960001340 histamine Drugs 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000003513 alkali Substances 0.000 description 17
- 238000009833 condensation Methods 0.000 description 17
- 230000005494 condensation Effects 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 150000008282 halocarbons Chemical class 0.000 description 14
- 239000012046 mixed solvent Substances 0.000 description 14
- 230000035484 reaction time Effects 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 150000002170 ethers Chemical class 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000007810 chemical reaction solvent Substances 0.000 description 12
- 229930195733 hydrocarbon Natural products 0.000 description 12
- 150000002430 hydrocarbons Chemical class 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 150000001408 amides Chemical class 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 11
- 235000015320 potassium carbonate Nutrition 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 10
- 150000002576 ketones Chemical class 0.000 description 10
- 238000010561 standard procedure Methods 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000003395 histamine H3 receptor antagonist Substances 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
- 102000004384 Histamine H3 receptors Human genes 0.000 description 7
- 108090000981 Histamine H3 receptors Proteins 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 229940125425 inverse agonist Drugs 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 6
- XNQIOISZPFVUFG-RXMQYKEDSA-N (R)-alpha-methylhistamine Chemical compound C[C@@H](N)CC1=CN=CN1 XNQIOISZPFVUFG-RXMQYKEDSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 235000010755 mineral Nutrition 0.000 description 5
- 239000011707 mineral Substances 0.000 description 5
- 235000011118 potassium hydroxide Nutrition 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 102000000543 Histamine Receptors Human genes 0.000 description 4
- 108010002059 Histamine Receptors Proteins 0.000 description 4
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910052759 nickel Inorganic materials 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- 230000009871 nonspecific binding Effects 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000002469 receptor inverse agonist Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- 235000005074 zinc chloride Nutrition 0.000 description 4
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 3
- QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 description 3
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
- 239000012964 benzotriazole Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229940126540 compound 41 Drugs 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 210000004188 enterochromaffin-like cell Anatomy 0.000 description 3
- 210000003630 histaminocyte Anatomy 0.000 description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 1
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- QQJLHRRUATVHED-UHFFFAOYSA-N tramazoline Chemical compound N1CCN=C1NC1=CC=CC2=C1CCCC2 QQJLHRRUATVHED-UHFFFAOYSA-N 0.000 description 1
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- 230000009466 transformation Effects 0.000 description 1
- 229910021381 transition metal chloride Inorganic materials 0.000 description 1
- HILRAMQWKMIWCB-UHFFFAOYSA-N tributyl(cyanomethyl)phosphanium Chemical compound CCCC[P+](CCCC)(CCCC)CC#N HILRAMQWKMIWCB-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/24—Antidepressants
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- 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
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Abstract
Description
背景技术
组胺通常储存在肥大细胞、肺、肝和胃粘膜等的细胞内颗粒体中。作为对外界刺激例如抗原与细胞表面抗体结合的反应,组胺释放到细胞外环境中。例如,当肥大细胞受到由外界进入的抗原的刺激时,肥大细胞释放组胺,组胺刺激位于血管或平滑肌上的组胺H1(H1)受体以引起变态反应。同样地,胃粘膜上的ECL细胞(肠嗜铬样细胞, enterochromaffin-like cells)释放的组胺刺激壁细胞上的组胺H2(H2)受体以促进胃酸分泌。基于这些事实,H1和H2受体拮抗剂已经分别被开发为变应性疾病和胃溃疡的治疗剂,二者现已广泛地用作药物。
此外,已经阐明组胺可以用作神经递质,并且作用于中枢和外周神经上的组胺受体(组胺H3(H3)受体)从而发挥各种生理学作用。该受体于1999年被克隆并且测定了其基因序列和氨基酸序列。然而,其与H1受体和H2受体的氨基酸序列同源性分别低至22%和21.4%(参见非专利文献1)。H3受体存在于突触前膜中,并被证实可以用作控制组胺合成和释放的自身受体(参见非专利文献2)。此外,H3受体还被证实不仅控制组胺的释放,还控制其它神经递质包括乙酰胆碱、羟色胺、多巴胺和去甲肾上腺素的释放(参见非专利文献3)。这些事实表明选择性H3受体调节剂可以用作与神经中神经递质的异常释放相关的各种疾病的治疗剂。
事实上,使用合成化合物的动物模型研究的结果表明H3受体拮抗剂或反相激动剂可以用作痴呆、阿尔茨海默氏病(参见非专利文献4和5)、注意缺陷多动障碍(参见非专利文献6)、精神分裂症(参见非专利文献7)、癫痫、中枢性惊厥等的治疗剂的可能性。
此外,已经证实H3受体与进食行为有关(参见非专利文献8);因此H3受体拮抗剂或反相激动剂可能的目标疾病还包括代谢性疾病,例如进食障碍、肥胖症、糖尿病、高脂血症等。
此外,已经证实组胺调节脑中的昼夜节律并且负责维持觉醒和睡眠状态的平衡(参见非专利文献9和10);因此H3受体拮抗剂或反相激动剂可能的目标疾病还包括睡眠障碍和与睡眠障碍相关的疾病,例如发作性睡病、睡眠呼吸暂停综合征、昼夜节律障碍、抑郁症等。
此外,已经证实H3受体存在于鼻粘膜上的交感神经中,有报道表明H3和H1受体拮抗剂的组合使用显著改善鼻充血(参见非专利文献11)。这表明H3受体拮抗剂或反相激动剂单独或与H1受体拮抗剂组合用于治疗变应性鼻炎或其他疾病的可能性。
H3受体拮抗剂或反相激动剂已经概述于一些综述中(参见非专利文献12-15),并且可以参考这些综述。早些年间,发表了许多有关由组胺自身起始作为先导化合物的咪唑化合物的报道。然而,这些化合物尚未被开发作为药物,因为担心它们具有负面作用,例如药物代谢酶,细胞色素P450(CYP)的抑制。
近年来,许多文献和专利已经报道了非咪唑H3受体拮抗剂或反相激动剂(参见专利文献1-10) 。
此外,还已报道了具有二氢喹啉酮结构的组胺H3受体拮抗剂(参见专利文献 11)。然而,没有关于具有本发明披露的结构的化合物的报道。对于具有二氢喹啉酮骨架的化合物,已经报道了缺氧改善剂、血小板粘附抑制剂和抗心律不齐剂(参见专利文献12-14)。然而,没有披露它们对H3受体的亲和性或者它们对组胺受体亚型的选择性。
引文列表
专利文献
[专利文献1] 国际专利公开号WO2005/097751
[专利文献2] 国际专利公开号WO2005/097778
[专利文献3] 国际专利公开号WO2005/118547
[专利文献4] 国际专利公开号WO2006/014136
[专利文献5] 国际专利公开号WO2006/045416
[专利文献6] 国际专利公开号WO2006/046131
[专利文献7] 国际专利公开号WO2006/059778
[专利文献8] 国际专利公开号WO2006/061193
[专利文献9] 国际专利公开号WO2006/107661
[专利文献10] 国际专利公开号WO2006/103057
[专利文献11] 国际专利公开号WO2004/026837
[专利文献12] JP 62-135423 A
[专利文献13] JP 63-045220 A
[专利文献14] JP 63-290821 A
非专利文献
[非专利文献1] Lovenberg T.W等,Molecular pharmacology, 55, 1101-1107, 1999
[非专利文献2] Arrang J-M等,Nature, 302, 832-837, 1983
[非专利文献3] Brown R.E等,Progress in Neurobiology, 63, 637-672, 2001
[非专利文献4] Huang Y-W等,Behavioural Brain Research, 151, 287-293, 2004
[非专利文献5] Komater V.A等,Behavioural Brain Research, 159, 295-300, 2005
[非专利文献6] Passani M.B等,Neuroscience and Biobehavioral Reviews, 24, 107-113, 2000
[非专利文献7] Fox G.B等,J. Pharmacol. Exp. Ther., 313, 176-190, 2005
[非专利文献8] Hancock A.A等,Curr. Opin. Investig. Drug, 4, 1190-1197
[非专利文献9] Huang Z-L等,Prog. Natr. Acad. Sci., 103, 4687-4692, 2006
[非专利文献10] Babier A.J等,Br. J. Pharmacol., 143, 649-661, 2004
[非专利文献11] McLeod R.L等,Am. J. Rhinol., 13, 391-399, 1999
[非专利文献12] Schwartz J.C等,Trends in Pharmacol. Sci., 7, 24-28, 1986
[非专利文献13] Passani M.B等,Trends in Pharmacol. Sci., 25, 618-625, 2004
[非专利文献14] Leurs R等,Nature Drug Discovery, 4, 107-122, 2005
[非专利文献15] Leurs R等,Drug Discovery Today, 10, 1613-1627, 2005。
发明概述
本发明的目的是寻找用于组胺H3受体-介导的障碍的预防剂或治疗剂,所述障碍例如痴呆、阿尔茨海默氏病、注意缺陷多动障碍、精神分裂症、癫痫、中枢性惊厥、进食障碍、肥胖症、糖尿病、高脂血症、睡眠障碍、发作性睡病、睡眠呼吸暂停综合征、昼夜节律障碍、抑郁症、变应性鼻炎或其他疾病,其中预防剂或治疗剂对组胺与组胺H3受体的结合具有强的抑制作用。
作为为了实现上述目的而作出的广泛而深入努力的结果,本发明的发明人发现二氢喹啉酮衍生物对组胺与组胺H3受体的结合具有强的抑制活性。该发现导致了本发明的完成。
即,本发明涉及下列内容。
(I) 式(1)表示的二氢喹啉酮衍生物或其药学可接受的盐:
[式1]
[其中Q表示下列式(A)或(B):
[式2]
R1表示氢原子、卤素原子或C1-C6烷基,
R2表示氢原子或C1-C6烷基,
n表示1或2,
R3和R4可以相同或不同,各自表示C1-C6烷基或C3-C7环烷基,或者
R3和R4与它们邻近的氮原子相互连接一起形成3-至7-元饱和杂环(其中所述饱和杂环可以被一个或两个C1-C6烷基取代),
R5表示C1-C6烷基(其中所述C1-C6烷基可以被一个或两个C3-C7环烷基取代)或C3-C7环烷基(其中所述C3-C7环烷基可以被一个或两个C1-C6 烷基取代),以及
P表示芳基、杂芳基或杂环基{其中所述芳基、杂芳基或杂环基可以被相同或不同的1至3个选自下列的取代基取代:
卤素原子,
C1-C6烷基(其中所述C1-C6烷基可以被1至3个卤素原子、羟基、C1-C6烷氧基或C2-C12二烷基氨基取代),
C1-C6烷氧基(其中所述C1-C6烷氧基可以被1至3个卤素原子取代),
氨基,
C1-C6 烷基氨基,
C2-C12二烷基氨基,
C2-C7烷酰基,
C4-C8环烷基羰基,
氰基,
C2-C7烷氧基羰基,
C2-C7烷基氨基羰基,
C3-C13二烷基氨基羰基,
与在环中含有一个或多个氮原子并且可以进一步含有氧或硫原子的单环饱和杂环相连的羰基,
氨基甲酰基,
杂芳基,
杂环基(其中所述杂环基可以被一个或两个C1-C6烷基取代),或者
杂芳基氧基(其中所述杂芳基氧基可以被一个或两个C1-C6烷基取代)}]。
(II) 根据上文(I)的二氢喹啉酮衍生物或其药学可接受的盐,其中式(1)由式(2)表示:
[式3]
(III) 根据上文(I)或(II)的二氢喹啉酮衍生物或其药学可接受的盐,其中P表示苯基、吡啶基、嘧啶基、喹啉基、萘啶基、吲哚基、2,3-二氢[1,4]苯并二烯基(benzodioxinyl)、苯并[1,3]间二氧杂环戊烯基、2,3-二氢苯并呋喃基或2-氧-1,2-二氢吡啶基{其中所述苯基、吡啶基、嘧啶基、喹啉基、萘啶基、吲哚基、2,3-二氢[1,4]苯并二烯基、苯并[1,3]间二氧杂环戊烯基、2,3-二氢苯并呋喃基或2-氧-1,2-二氢吡啶基可以被相同或不同的1至3个选自下列的取代基取代:
卤素原子,
C1-C6烷基(其中所述C1-C6烷基可以被1至3个卤素原子、羟基、C1-C6烷氧基或C2-C12二烷基氨基取代),
C1-C6烷氧基(其中所述C1-C6烷氧基可以被1至3个卤素原子取代),
C2-C7烷酰基,
C4-C8环烷基羰基,
氰基,
C2-C7烷氧基羰基,
C2-C7烷基氨基羰基,
C3-C13二烷基氨基羰基,
吡咯烷-1-基羰基,
氨基甲酰基,
吗啉-4-基或2-氧吡咯烷-1-基(其中所述吗啉-4-基或2-氧吡咯烷-1-基可以被一个或两个C1-C6烷基取代),或者
哒嗪基氧基(其中所述哒嗪基氧基可以被一个或两个C1-C6烷基取代)}。
(IV) 药物制剂,其包含根据上文(I)-(III)任一所述的作为活性成分的二氢喹啉酮衍生物或其药学可接受的盐。
(V) 用于痴呆、阿尔茨海默氏病、注意缺陷多动障碍、精神分裂症、癫痫、中枢性惊厥、进食障碍、肥胖症、糖尿病、高脂血症、睡眠障碍、发作性睡病、睡眠呼吸暂停综合征、昼夜节律障碍、抑郁症或变应性鼻炎的预防剂或治疗剂,其包含根据上文(I)-(III)任一所述的作为活性成分的二氢喹啉酮衍生物或其药学可接受的盐。
发现本发明的化合物具有优异的组胺H3受体拮抗作用。
实施方案的描述
本文所用的术语和表述如下文所定义。
如本文所用,术语“卤素原子” 是指氟原子、氯原子、溴原子和碘原子。
术语“C1-C6烷基” 是指含有1-6个碳原子的线性或支链烷基。实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基和正己基。
术语“C3-C7环烷基” 是指环丙基、环丁基、环戊基、环己基或环庚基。
术语“C1-C6烷氧基” 是指含有1-6个碳原子的线性或支链烷氧基。实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基、新戊氧基和正己氧基。
术语“C2-C7烷氧基羰基” 是指与含有1-6个碳原子的线性或支链烷氧基相连的羰基。实例包括甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、正丁氧基羰基、异丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、正戊氧基羰基、异戊氧基羰基、新戊氧基羰基和正己氧基羰基。
术语“C1-C6烷基氨基” 是指被含有1-6个碳原子的线性或支链烷基取代的氨基。实例包括甲基氨基、乙基氨基、正丙基氨基、异丙基氨基、正丁基氨基、异丁基氨基、仲丁基氨基、叔丁基氨基、正戊基氨基、异戊基氨基、新戊基氨基和正己基氨基。
术语“C2-C12二烷基氨基” 是指被两个含有1-6个碳原子的线性或支链烷基取代的氨基。实例包括二甲基氨基、二乙基氨基、二正丙基氨基、N,N-异丙基甲基氨基、二正丁基氨基,二异丁基氨基、N,N-仲丁基乙基氨基、N,N-叔丁基甲基氨基、二正戊基氨基、N,N-异戊基甲基氨基、N,N-新戊基甲基氨基和二正己基氨基。
术语“C2-C7烷酰基” 是指与含有1-6个碳原子的烷基相连的羰基。实例包括乙酰基、丙酰基、丁酰基、异丁酰基、特戊酰基、戊酰基、3-甲基丁酰基、4,4-二甲基戊酰基和庚酰基。
术语“C4-C8环烷基羰基” 是指环丙基羰基、环丁基羰基、环戊基羰基、环己基羰基或环庚基羰基。
术语“C2-C7烷基氨基羰基” 是指与含有1-6个碳原子的线性或支链烷基氨基相连的羰基。实例包括甲基氨基羰基、乙基氨基羰基、正丙基氨基羰基、异丙基氨基羰基、正丁基氨基羰基、异丁基氨基羰基、仲丁基氨基羰基、叔丁基氨基羰基、正戊基氨基羰基、异戊基氨基羰基、新戊基氨基羰基和正己基氨基羰基。
术语“C3-C13二烷基氨基羰基” 是指与含有2-12个碳原子的二烷基氨基相连的羰基。实例包括二甲基氨基羰基、二乙基氨基羰基、二正丙基氨基羰基、N,N-异丙基甲基氨基羰基、二正丁基氨基羰基、二异丁基氨基羰基、N,N-仲丁基乙基氨基羰基、N,N-叔丁基甲基氨基羰基、二正戊基氨基羰基、N,N-异戊基甲基氨基羰基、N,N-新戊基甲基氨基羰基和二正己基氨基羰基。
表述“与在环中含有一个或多个氮原子并且可以进一步含有氧或硫原子的单环饱和杂环相连的羰基”意在表示与饱和的3-至7-元单环杂环相连的羰基,所述杂环在环中含有一个或多个氮原子并且可以进一步含有一个或多个选自氮、氧或硫原子的另外的杂原子。实例包括吖丙啶-1-基羰基、氮杂环丁-1-基羰基、吡咯烷-1-基羰基、哌啶-1-基羰基、氮杂环庚-1-基羰基、咪唑烷-1-基羰基、吡唑烷-1-基羰基、哌嗪-1-基羰基、唑烷-1-基羰基、吗啉-1-基羰基和硫代吗啉-1-基羰基。
表述“与它们邻近的氮原子相互连接一起形成3-至7-元饱和杂环”意在表示1-吖丙啶基、1-氮杂环丁基、1-吡咯烷基、哌啶子基或1-氮杂环庚基。
术语“芳基” 是指由6-18个碳原子组成的单环至四环芳香碳环基团。实例包括苯基、萘基、蒽基、菲基、并四苯基和芘基。
术语“杂芳基” 是指由5-或6-元单环或9-或10-元双环芳香杂环组成的基团。实例包括吡啶基、哒嗪基、嘧啶基、吡嗪基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、萘啶基(naphthylizinyl)、吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、唑基、异唑基, 噻唑基、异噻唑基、三唑基、吲哚基、苯并呋喃基、苯并噻吩基、苯并咪唑基、吲唑基、苯并唑基、苯并噻唑基和苯并三唑基。更具体的实例包括2-吡啶基、3-吡啶基、4-吡啶基、哒嗪-3-基、哒嗪-4-基、嘧啶-2-基、嘧啶-4-基、嘧啶-5-基、吡嗪-2-基、喹啉-2-基、喹啉-3-基、喹啉-4-基、喹啉-6-基、喹啉-8-基、异喹啉-1-基、异喹啉-6-基、喹唑啉-2-基、喹唑啉-5-基、喹喔啉-2-基、喹喔啉-6-基、1,5-萘啶-3-基、1,6-萘啶-8-基、吡咯-3-基、呋喃-2-基、呋喃-3-基、噻吩-2-基、噻吩-3-基、吡唑-3-基、吡唑-4-基、咪唑-2-基、唑-2-基、唑-4-基、唑-5-基、异唑-3-基、噻唑-2-基、噻唑-5-基、异噻唑-4-基、1,2,4-三唑-3-基、吲哚-2-基、吲哚-3-基、吲哚-5-基、吲哚-7-基、苯并呋喃-3-基、苯并噻吩-3-基、苯并咪唑-2-基、吲唑-5-基、苯并唑-2-基、苯并噻唑-2-基和苯并三唑-4-基。
术语“杂环基” 是指由5-或6-元单环或9-或10-元双环饱和杂环组成的基团,所述杂环在环中含有一个或多个氮、氧和硫原子并且可以含有不饱和键作为环的一部分。杂环基可以被一个或两个氧代基取代。实例包括1-吡咯烷基、1-哌啶基、1-哌嗪基、吗啉-4-基、硫代吗啉-4-基、2-氧吡咯烷-1-基、2,5-二氧吡咯烷-1-基、2-四氢呋喃基、3-四氢呋喃基、4-四氢吡喃基、1,4,5,6-四氢哒嗪-3-基、2-氧-1,2-二氢吡啶-4-基、吲哚啉-4-基、吲哚啉-6-基、异吲哚啉-4-基、1,2,3,4-四氢喹啉-7-基、1,2,3,4-四氢异喹啉-6-基、2,3-二氢苯并呋喃-5-基、2,3-二氢苯并呋喃-6-基、苯并[1,3]间二氧杂环戊烯-5-基、2,3-二氢[1,4]苯并二烯-5-基、2,3-二氢[1,4]苯并二烯-6-基和3,4-二氢[1,4]苯并嗪-7-基。
术语“杂芳基氧基” 是指其中上文定义的“杂芳基”通过氧原子相连的基团。实例包括吡啶基氧基、哒嗪基氧基、嘧啶基氧基、吡嗪基氧基、喹啉基氧基、异喹啉基氧基、喹唑啉基氧基、喹喔啉基氧基、萘啶基氧基、吡咯基氧基、呋喃基氧基、噻吩基氧基、吡唑基氧基、咪唑基氧基、唑基氧基、异唑基氧基、噻唑基氧基、异噻唑基氧基、三唑基氧基、吲哚基氧基、苯并呋喃基氧基、苯并噻吩基氧基、苯并咪唑基氧基、吲唑基氧基、苯并唑基氧基、苯并噻唑基氧基和苯并三唑基氧基。更具体的实例包括吡啶-2-基氧基、吡啶-3-基氧基、吡啶-4-基氧基和哒嗪-3-基氧基。
本发明一个优选的实施方案是式(2)表示的二氢喹啉酮衍生物或其药学可接受的盐:
[式4]
[其中Q表示下列式(A)或(B):
[式5]
R1表示氢原子、卤素原子或C1-C6烷基,
R3和R4可以相同或不同,各自表示C1-C6烷基或C3-C7环烷基,或者
R3和R4与它们邻近的氮原子相互连接一起形成3-至7-元饱和杂环(其中所述饱和杂环可以被一个或两个C1-C6烷基取代),
R5表示C1-C6烷基(其中所述C1-C6烷基可以被一个或两个C3-C7环烷基取代)或C3-C7环烷基(其中所述C3-C7环烷基可以被一个或两个C1-C6烷基取代),以及
P表示苯基、吡啶基、嘧啶基、喹啉基、萘啶基、吲哚基、2,3-二氢[1,4]苯并二烯基、苯并[1,3]间二氧杂环戊烯基、2,3-二氢苯并呋喃基或2-氧-1,2-二氢吡啶基{其中所述苯基、吡啶基、嘧啶基、喹啉基、萘啶基、吲哚基、2,3-二氢[1,4]苯并二烯基、苯并[1,3]间二氧杂环戊烯基、2,3-二氢苯并呋喃基或2-氧-1,2-二氢吡啶基可以被相同或不同的1至3个选自下列的取代基取代:
卤素原子,
C1-C6烷基(其中所述C1-C6烷基可以被1至3个卤素原子、羟基、C1-C6烷氧基或C2-C12二烷基氨基取代),
C1-C6烷氧基(其中所述C1-C6烷氧基可以被1至3个卤素原子取代),
C2-C7烷酰基,
C4-C8环烷基羰基,
氰基,
C2-C7烷氧基羰基,
C2-C7烷基氨基羰基,
C3-C13二烷基氨基羰基,
吡咯烷-1-基羰基,
氨基甲酰基,
吗啉-4-基或2-氧吡咯烷-1-基(其中所述吗啉-4-基或2-氧吡咯烷-1-基可以被一个或两个C1-C6烷基取代),或者
哒嗪基氧基(其中所述哒嗪基氧基可以被一个或两个C1-C6 烷基取代)}]。
在这种情况下,R1优选为氢原子。
在式(A)中,R3和R4优选与它们邻近的氮原子相互连接一起形成3-至7-元饱和杂环(其中所述饱和杂环可以被一个或两个C1-C6烷基取代),更优选为1-吡咯烷基(其中所述1-吡咯烷基可以被一个或两个C1-C6 烷基取代)。
P优选为苯基或吡啶基{其中所述苯基或吡啶基可以被相同或不同的1至3个选自下列的取代基取代:
卤素原子,
C1-C6烷基(其中所述C1-C6 烷基可以被1至3个卤素原子、羟基、C1-C6烷氧基或C2-C12二烷基氨基取代),
C1-C6烷氧基(其中所述C1-C6烷氧基可以被1至3个卤素原子取代),
C2-C7烷酰基,
C4-C8环烷基羰基,
氰基,
C2-C7烷氧基羰基,
C2-C7烷基氨基羰基,
C3-C13二烷基氨基羰基,
吡咯烷-1-基羰基,
氨基甲酰基,
吗啉-4-基或2-氧吡咯烷-1-基(其中所述吗啉-4-基或2-氧吡咯烷-1-基可以被一个或两个C1-C6烷基取代),或者
哒嗪基氧基(其中所述哒嗪基氧基可以被一个或两个C1-C6烷基取代)}。
P更优选为苯基或吡啶基{其中所述苯基或吡啶基可以被相同或不同的1至2个选自下列的取代基取代:
卤素原子,
C1-C6烷基(其中所述C1-C6烷基可以被1至3个卤素原子、羟基、C1-C6烷氧基或C2-C12二烷基氨基取代),
C1-C6 烷氧基(其中所述C1-C6烷氧基可以被1至3个卤素原子取代),
C2-C7烷酰基,
C4-C8环烷基羰基,
氰基,
C2-C7烷氧基羰基,
C2-C7烷基氨基羰基,
C3-C13二烷基氨基羰基,或
吡咯烷-1-基羰基}。
如本文所用,术语“药学可接受的盐”意在包括与无机酸例如硫酸、盐酸、氢溴酸、磷酸或硝酸的盐;与有机酸例如乙酸、草酸、乳酸、酒石酸、富马酸、马来酸、柠檬酸、苯磺酸、甲磺酸、对甲苯磺酸、苯甲酸、樟脑磺酸、乙磺酸、葡庚糖酸、葡糖酸、谷氨酸、羟乙酸、苹果酸、丙二酸、扁桃酸、粘酸或萘-2-磺酸的盐;与一个或多个金属离子例如锂离子、钠离子、钾离子、钙离子、镁离子、锌离子和/或铝离子的盐;以及与氨或胺例如精氨酸、赖氨酸、哌嗪、胆碱、二乙胺、4-苯基环己胺、2-氨基乙醇或苄星青霉素的盐。
本发明化合物可以各种溶剂化物形式存在。就作为药物制剂的实用性而言,它们还可以为水合物形式。
本发明化合物包括以下所有:对映异构体、非对映异构体、平衡化合物、其任意比例的混合物、外消旋化合物等。
本发明化合物还包括其中一个或多个氢原子、碳原子、氮原子、氧原子或硫原子被它们的放射性同位素或稳定的同位素替换的化合物。这些标记化合物可以用于代谢和/或药代动力学研究、作为受体配体的生物学分析或者其它目的。
本发明化合物可以与一种或多种药学可接受的载体、赋形剂或稀释剂组合配制成药物制剂。这类载体、赋形剂或稀释剂的实例包括水、乳糖、葡萄糖、果糖、蔗糖、山梨醇、甘露醇、聚乙二醇、丙二醇、淀粉、树胶、明胶、藻酸盐、硅酸钙、磷酸钙、纤维素、水糖浆、甲基纤维素、聚乙烯吡咯烷酮、烷基对羟基苯甲酸酯、滑石、硬脂酸镁、硬脂酸、甘油以及各种油,例如芝麻油、橄榄油、大豆油等。
此外,上述载体、赋形剂或稀释剂可以任选与常用的添加剂例如增充剂、粘合剂、崩解剂、pH调节剂、增溶剂等混合,然后使用标准技术配制成口服或非肠道剂型,包括片剂、丸剂、胶囊剂、颗粒剂、粉剂、溶液剂、乳剂、混悬剂、软膏剂、注射剂、皮肤硬膏剂等。本发明化合物可以通过口服或非肠道途径以每次给药0.001-500 mg给予成年患者,一日一次或数次。可以增加或减少该剂量以适应所治疗的疾病类型、患者的年龄、体重和症状等。
本发明化合物所需的性质包括优异的功效、良好的体内动力学(良好的口服吸收、非组织特异性蓄积)、优异的物理性质、低毒性等。预期优选的本发明化合物具有优异的渗透入脑的能力。
本发明化合物可以下列方式制备。
本发明化合物可以通过已知的有机化学方法制备,例如,根据下列反应方案。在下文所示的反应方案1-4中,R1、R2、R3、R4、R5、n和P如上文所定义。R6表示氢原子或通常用作羟基保护基的基团(例如,乙酰基、苯甲酰基、苄基、苯甲氧基羰基、叔丁氧基羰基、甲氧基甲基、四氢吡喃基或叔丁基二甲基硅烷基),R7和R8 各自表示氢原子、烷基或环烷基,或者可选择地,R7和R8可以与它们邻近的碳原子一起形成环烷基,X1和X2可以相同或不同,各自表示离去基团例如卤素原子(例如,氯原子、溴原子、碘原子)或有机磺酰基氧基(例如,甲磺酰基氧基、苯磺酰基氧基、对甲苯磺酰基氧基、三氟甲磺酰基氧基),Y1、Y2、Y3和Y4可以相同或不同,各自表示离去基团(例如,卤素原子或有机磺酰基氧基)或羟基,虚线表示单键或双键。
下文将对用于制备本发明化合物的反应方案1中所示的方法进行说明。该方法用于由化合物(2)制备本发明化合物(1-2)。
(反应方案1)
[式6]
(步骤1)
步骤1用于通过偶联反应缩合化合物(2)和(3)得到化合物(4)。化合物(2)和(3)是已知的或者可以容易地由已知化合物合成。
在Y1为羟基的情况下,反应可以通过羧酸酰胺化的标准方法完成,例如,通过将羧酸转化为羧酰卤(例如,羧酰氯、羧酰溴)并随后与胺反应,通过混合酸酐(例如,由羧酸和氯代碳酸酯得到)与胺的反应,通过将羧酸转化为活性酯(例如,1-苯并三唑基酯、琥珀酰亚胺酯)并随后与胺反应,或者通过在脱水缩合剂存在下羧酸与胺反应。所有这些反应可以在溶剂中在碱存在或不存在下完成。可以用于该反应中的脱水缩合剂的实例包括3-(3-二甲基氨基丙基)-1-乙基碳二亚胺盐酸盐、二环己基碳二亚胺、二苯基磷酰基叠氮化物和羰二咪唑。如果需要,可以使用活化剂例如1-羟基苯并三唑或羟基琥珀酰亚胺。可以用于该反应中的碱的实例包括吡啶、三乙胺、二异丙基乙胺、碳酸钾、碳酸钠和碳酸氢钠。可以用于该反应中的溶剂的实例包括醚(例如,四氢呋喃、1,2-二甲氧基乙烷、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮);酮(例如,丙酮、2-丁酮);二甲亚砜;乙腈;水;或其混合溶剂。该反应的反应温度通常范围为0℃-120℃,优选15℃-40℃,反应时间通常范围为1-48小时,优选1-16小时。
在Y1为卤素原子的情况下,反应可以在具有或不具有溶剂的情况下,在碱存在或不存在下通过化合物(2)和(3)之间的反应完成。可以用于该反应中的碱的实例包括吡啶、三乙胺、二异丙基乙胺、碳酸钾、碳酸氢钠和氢氧化钠。可以用于该反应中的溶剂的实例包括醚(例如,四氢呋喃、1,2-二甲氧基乙烷, 1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮);或其混合溶剂。该反应的反应温度通常范围为0℃-120℃,优选15℃-40℃,反应时间通常范围为1-48小时,优选1-16小时。
(步骤2)
步骤2用于通过化合物(4)的分子内环化得到化合物(5)。
在Y2为羟基的情况下,反应可以在具有或不具有溶剂的情况下,在酸的存在下通过化合物(4)的反应完成,例如,根据Journal of Heterocyclic Chemistry,1991,第28卷,第919页中描述的方法或其等同方法。可以用于该反应中的酸的实例包括路易斯酸,例如三氯化铝、二氯化锌、三氟化硼和四氯化钛;以及无机酸例如硫酸、磷酸和多磷酸。可以用于该反应中的溶剂的实例包括醚(例如,乙醚、1,4-二烷);芳香烃(例如,甲苯、苯、硝基苯、氯苯);卤代烃(例如,氯仿、二氯甲烷、1,2-二氯乙烷);二硫化碳;或其混合溶剂。该反应的反应温度通常范围为0℃-200℃,优选15℃-150℃,反应时间通常范围为1-48小时,优选1-16小时。
在Y2为卤素原子的情况下,反应可以在具有或不具有溶剂的情况下,在酸的存在下通过化合物(4)的反应完成,例如,根据Journal of American Chemical Society,1973,第95卷,第546页中描述的方法或其等同方法。可以用于该反应中的酸的实例包括路易斯酸,例如三氯化铝、二氯化锌、三氟化硼和四氯化钛;以及无机酸例如硫酸、磷酸、和多磷酸。可以用于该反应中的溶剂的实例包括醚(例如,乙醚、1,4-二烷);芳香烃(例如,甲苯、苯、硝基苯、氯苯);卤代烃(例如,氯仿、二氯甲烷、1,2-二氯乙烷);二硫化碳;或其混合溶剂。该反应的反应温度通常范围为0℃-200℃,优选15℃-150℃,反应时间通常范围为1-48小时,优选1-16小时。
(步骤3)
步骤3用于在化合物(5)中的R6为通常用作羟基保护基的基团的情况下通过脱保护得到化合物(6)。如果R6为氢原子,则不需要该步骤。该反应可以通过适合保护基类型的标准脱保护反应完成,例如根据T.W. Greene和P.G.M. Wuts主编,Protective Groups in Organic Synthesis,第3版,John Wiley and Sons, Inc中描述的方法或其等同方法。
(步骤4a)
步骤4a用于通过化合物(6)和已知的化合物(7)的偶联反应得到化合物(8)。该反应可以在具有或不具有溶剂的情况下,在碱的存在下通过用于苯酚和烷基卤反应的标准方法完成。如果需要,例如,可以加入添加剂例如碘化钾或溴化钠。可以用于该反应的碱的实例包括吡啶、三乙胺、二异丙基乙胺、叔丁醇钾、碳酸钾、碳酸铯、碳酸氢钠、氢氧化钠、氢氧化钾和氢化钠。可以用于该反应的溶剂的实例包括醇(例如,甲醇、乙醇、异丙醇);醚(例如,四氢呋喃、1,2-二甲氧基乙烷、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮);酮(例如,丙酮、2-丁酮);二甲亚砜;乙腈;水;或其混合溶剂。该反应的反应温度通常范围为0℃-200℃,优选15℃-100℃,反应时间通常范围为1-48小时,优选1-16小时。
(步骤5a)
步骤5a用于通过偶联反应将化合物(8)和(9)缩合得到化合物(10)。化合物(9)是已知的或者可以容易地由已知化合物合成。该反应可以在具有或不具有溶剂的情况下,在碱的存在或不存在下通过用于胺和烷基卤反应的标准方法完成。如果需要,例如,可以加入添加剂例如碘化钾或溴化钠。可以用于该反应的碱的实例包括吡啶、三乙胺、二异丙基乙胺、叔丁醇钾、碳酸钾、碳酸铯、碳酸氢钠、氢氧化钠、氢氧化钾和氢化钠。可以用于该反应的溶剂的实例包括醇(例如,甲醇、乙醇、异丙醇);醚(例如,四氢呋喃、1,2-二甲氧基乙烷、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮);酮(例如,丙酮、2-丁酮);二甲亚砜;乙腈;水;或其混合溶剂。该反应的反应温度通常范围为0℃-200℃,优选15℃-100℃,反应时间通常范围为1-48小时,优选1-16小时。
(步骤6a)
步骤6a 用于通过交叉-偶联反应将化合物(10)和(11)缩合得到本发明化合物(1-2)。化合物(11)是已知的或者可以容易地由已知化合物合成。该反应可以在溶剂中在催化剂及其配体的存在下通过标准方法完成,例如,根据Kunz等,Synlett, 2003,第15卷,第2428-2439页中描述的方法或其等同方法。该反应优选在碱的存在下进行。可以用于该反应的催化剂的实例包括通常用于交叉-偶联反应的过渡金属催化剂,其例证为铜、镍和钯。更具体的实例包括铜(0)、碘化铜(I)、氯化铜(I)、氧化铜(I)、溴化铜(I)三(三苯基膦)络合物、三氟甲磺酸铜(I)苯络合物、醋酸钯(II)、四(三苯基膦)钯(0)、双(三苯基膦)氯化钯(II)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)、三(二亚苄基丙酮)二钯(0)和双(乙酰丙酮)镍(II)。可以用于该反应的配体的实例包括在金属催化剂的存在下通常用于缩合反应的配体,其例证为N,N’-二甲基乙二胺、N,N’-二甲基环己基-1,2-二胺、2-氨基吡啶、1,10-菲咯啉、2-羟基苯甲醛肟、乙二醇、三苯基膦和三叔丁基膦。可以用于该反应的碱的实例包括碳酸钾、磷酸钾、氢氧化钾、叔丁醇钾、叔丁醇钠、碳酸铯、碳酸钠、碳酸氢钠、醋酸钠、甲醇钠和四丁基氢氧化铵。可以用于该反应的溶剂的实例包括醇(例如,甲醇、乙醇、异丙醇);醚(例如,四氢呋喃、1,2-二甲氧基乙烷、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮);酮(例如,丙酮、2-丁酮);二甲亚砜;乙腈;水;或其混合溶剂。该反应的反应温度通常范围为0℃-200℃,优选40℃-150℃,反应时间通常范围为1-48小时,优选1-16小时。
可选择地,化合物(5)还可以根据反应方案2中所示的方法制备。
(反应方案2)
[式7]
(步骤7)
步骤7用于由化合物(12)得到化合物(5)。化合物(12)是已知的或者可以容易地由已知化合物合成,例如,根据Journal of Heterocyclic Chemistry,1979,第16卷,第221页或Synthesis,1984,第10卷,第862页中描述的方法或其等同方法。该反应可以在用于还原反应的条件下通过化合物(12)在溶剂中反应完成,例如,根据 Journal of American Chemical Society,1944,第66卷,第1442页中描述的方法或其等同方法。可以用于该反应的还原反应的条件包括在氢气氛下在催化剂(例如,拉尼镍或钯碳)的存在下在正常或升高压力下反应的条件、与金属氢络合物化合物(例如,氢化铝锂、硼氢化钠)反应的条件、在酸(例如,乙酸)或氯化铵存在下与铁(0)、氯化锌(II)或氯化锡(II)反应的条件,以及这些条件的组合。可以用于该反应的溶剂的实例包括醇(例如,甲醇, 乙醇);醚(例如,四氢呋喃、1,2-二甲氧基乙烷、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺, N-甲基-2-吡咯烷酮);酮(例如,丙酮、2-丁酮);二甲亚砜;乙腈;或其混合溶剂。该反应的反应温度通常范围为0℃-200℃,优选15℃-150℃,反应时间通常范围为1-48小时,优选1-16小时。
此外,化合物(13),作为该步骤中的反应中间体,可以通过分子内环化进一步转化为化合物(5)。反应可以通过用于将苯胺和羧酸或酯缩合得到酰苯胺的标准方法完成,例如,通过将羧酸转化为羧酰卤(例如,羧酰氯、羧酰溴)并随后与苯胺反应,通过与氯代碳酸酯等将羧酸转化为混合酸酐并随后与苯胺反应,通过将羧酸转化为活性酯(例如,1-苯并三唑基酯、琥珀酰亚胺酯)并随后与苯胺反应,或者通过在脱水缩合剂存在下反应。所有这些反应可以在具有或不具有溶剂的情况下,在酸或碱存在或不存在下完成。可以用于该反应的脱水缩合剂的实例包括3-(3-二甲基氨基丙基)-1-乙基碳二亚胺盐酸盐、二环己基碳二亚胺、二苯基磷酰基叠氮化物和羰二咪唑。如果需要,可以使用活化剂例如1-羟基苯并三唑或羟基琥珀酰亚胺。可以用于该反应的碱的实例包括吡啶、三乙胺、二异丙基乙胺、碳酸钾、碳酸钠和碳酸氢钠。可以用于该反应中的溶剂的实例包括醚(例如,四氢呋喃、1,2-二甲氧基乙烷、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮);酮(例如,丙酮、2-丁酮);二甲亚砜;乙腈;水;或其混合溶剂。该反应的反应温度通常范围为0℃-200℃,优选15℃-150℃,反应时间通常范围为1-48小时,优选1-16小时。
在化合物(13)中的虚线为双键的情况下,上述分子内环化后进行将双键转化为单键的还原反应从而得到化合物(5)。该反应可以通过用于α,β-不饱和酯或α,β-不饱和羧酸的1,4-还原的标准方法完成,例如,通过在氢气氛下使用过渡金属催化剂(例如,钯碳、氧化铂、拉尼镍)的反应,通过在甲酸或三乙基硅烷存在下使用过渡金属催化剂的反应,或通过在质子溶剂(例如,醇)中使用还原剂(例如,硼氢化钠)的反应。在这种情况下,如果需要,可以加入过渡金属氯化物例如氯化铜(II)或氯化镍(II)。此外,例如,如果需要,可以加入添加剂例如盐酸或乙酸。这些反应可以在溶剂中进行。可以使用的溶剂的实例包括醇(例如,甲醇、乙醇);醚(例如,四氢呋喃、1,2-二甲氧基乙烷、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮);酮(例如,丙酮、2-丁酮);二甲亚砜;乙腈;水;或其混合溶剂。该反应的反应温度通常范围为0℃-200℃,优选15℃-150℃,反应时间通常范围为1-48小时,优选1-16小时。
或者,化合物(10)可以根据反应方案3中所示的方法制备。
(反应方案3)
[式8]
(步骤5b)
步骤5b用于通过偶联反应将化合物(9)和(7)缩合得到化合物(14)。该反应可以通过与步骤5a中所示的相同方式完成。
(步骤4b)
步骤4b用于通过偶联反应将化合物(14)和(6)缩合得到化合物(10)。该反应可以通过与步骤4a中所示的相同方式完成。
下文将对用于制备本发明化合物的反应方案4中所示的方法进行说明。该方法用于由化合物(6)制备本发明化合物(1-3)。
(反应方案4)
[式9]
(步骤8a)
步骤8a用于通过偶联反应将化合物(6)和(15)缩合得到化合物(16)。化合物(15)是已知的或者可以容易地由已知化合物合成。
在Y3为离去基团例如卤素原子或有机磺酰基氧基的情况下,反应可以在具有或不具有溶剂的情况下,在碱的存在或不存在下通过用于苯酚中的羟基烷基化的标准方法完成。如果需要,例如,可以加入添加剂例如碘化钾或溴化钠。可以用于该反应的碱的实例包括有机碱例如吡啶、三乙胺和二异丙基乙胺;以及无机碱例如叔丁醇钾、碳酸钾、碳酸铯、碳酸氢钠、氢氧化钠、氢氧化钾和氢化钠。可以用于该反应的溶剂的实例包括醇(例如,甲醇、乙醇、异丙醇);醚(例如,四氢呋喃、1,2-二甲氧基乙烷、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮);酮(例如,丙酮、2-丁酮);二甲亚砜;乙腈;水;或其混合溶剂。该反应的反应温度通常范围为0℃-200℃,优选15℃-150℃,反应时间通常范围为1-48小时,优选1-16小时。
在Y3为羟基的情况下,反应可以是Mitsunobu反应,例如,其可以在溶剂中
在包含有机磷化合物(例如,三苯基膦、三丁基膦)和偶氮化合物(例如,偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、偶氮二甲酸二叔丁酯)的试剂存在下或者在磷叶立德试剂(例如,氰基甲基三丁基正膦)存在下完成。可以用于该反应中的溶剂的实例包括醚(例如,四氢呋喃、1,2-二甲氧基乙烷、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮);酮(例如,丙酮、2-丁酮);二甲亚砜;乙腈;或其混合溶剂。该反应的反应温度通常范围为0℃-150℃,优选15℃-100℃,反应时间通常范围为1-48小时,优选1-16小时。
(步骤6b)
步骤6b用于通过交叉-偶联反应将化合物(16)和(11)缩合得到本发明化合物(1-3)。该反应可以通过与步骤6a中所示的相同方式完成。
下文将对用于制备本发明化合物的反应方案5中所示的方法进行说明。该方法用于由化合物(6)制备本发明化合物(1-3)。
(反应方案5)
[式10]
(步骤8b)
步骤8b用于通过偶联反应将化合物(6)和(17)缩合得到化合物(18)。化合物(17)是已知的或者可以容易地由已知化合物合成。该反应可以通过与步骤8a中所示的相同方式完成。
(步骤6c)
步骤6c用于通过偶联反应将化合物(18)和(11)缩合得到化合物(19)。该反应可以通过与步骤6a中所示的相同方式完成。
(步骤9)
步骤9用于通过除去化合物(19)中的叔丁氧基羰基得到化合物(20)。该反应可以通过用于叔丁氧基羰基脱保护的标准方法完成,例如,在具有或不具有溶剂的情况下,在强酸存在下,或者可选择地,在溶剂中在碱存在下,根据T.W. Greene和P.G.M. Wuts, Protective Groups in Organic Synthesis中描述的方法或其等同方法。可以用于该反应中的酸的实例包括盐酸、硫酸、三氟乙酸和三氟甲磺酸。可以用于该反应的碱的实例包括氢氧化钠和氢氧化钾。可以用于该反应的溶剂的实例包括醇(例如,甲醇、乙醇、异丙醇);醚(例如,四氢呋喃、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);酰胺(例如,N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮);酮(例如,丙酮、2-丁酮);二甲亚砜;乙腈;水;或其混合溶剂。该反应的反应温度通常范围为0℃-150℃,优选15℃-40℃,反应时间通常范围为1-48小时,优选1-12小时。
(步骤10)
步骤10用于通过偶联反应将化合物(20)和(21)缩合得到本发明化合物(1-3)。化合物(21)是已知的或者可以容易地由已知化合物合成。该反应可以通过与步骤5a中所示的相同方式完成。
可选择地,本发明化合物(1-3)可以根据反应方案6中所示的方法制备。
(反应方案6)
[式11]
(步骤11)
步骤11用于通过还原缩合反应将化合物(20)和(22)缩合得到本发明化合物(1-3)。反应通过用于还原胺化的标准方法通过羰基化合物和胺的缩合完成,例如,通过在具有或不具有溶剂的情况下,在酸存在或不存在下向化合物(20)和(22)的混合物中加入还原剂。作为另一个实例,可以使用通过氢化的催化还原,所述氢化使用催化剂例如钯碳、铂、拉尼镍或铑-氧化铝。用于该反应的还原剂的实例包括硼氢化钠、三乙酰氧基硼氢化钠、氰基硼氢化钠、二硼烷和氢化铝锂。可以用于该反应中的酸的实例包括有机酸(例如,乙酸、甲酸);无机酸(例如,盐酸、硫酸);以及路易斯酸(例如,氯化钛、氯化锌、三氟甲磺酸镱(III))。可以用于该反应的溶剂的实例包括醇(例如,甲醇、乙醇、异丙醇);醚(例如,四氢呋喃、1,4-二烷);烃(例如,甲苯、苯);卤代烃(例如,氯仿、二氯甲烷);乙腈;水;或其混合溶剂。该反应的反应温度通常范围为0℃-150℃,优选15℃-40℃,反应时间通常范围为1-48小时,优选1-12小时。
本发明进一步通过下列实施例和试验实施例更详细地进行描述,其不用于限制本发明的范围。
实施例
(实施例1)
4-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]苄腈(化合物1)的制备
(1) (2R)-1-(3-氯丙基)-2-甲基吡咯烷的制备
[式12]
在冰浴中向(R)-2-甲基吡咯烷(18.0 g)和1-溴-3-氯丙烷(100.0 g)的丙酮(360 mL)溶液中,逐滴加入5M 氢氧化钠水溶液(50 mL),并在80℃下搅拌4小时。将反应混合物冷却至室温并使用乙醚萃取。使用盐水洗涤有机层,通过无水硫酸钠干燥并减压浓缩,通过NH-型硅胶柱色谱(洗脱溶剂:正己烷/乙酸乙酯 = 4/1-1/1)和硅胶柱色谱法(洗脱溶剂:氯仿/甲醇 = 9/1)纯化得到的残留物,得到标题化合物(17.8 g, 52%),为黄色的油。
(2) (2R)-6-[3-(2-甲基吡咯烷-1-基)丙氧基]-3,4-二氢喹啉-2(1H)-酮的制备
[式13]
向6-羟基-3,4-二氢喹啉-2(1H)-酮(0.55 g)的乙腈(10 mL)溶液中,加入碳酸铯(2.0 g)和实施例1-(1)中制备的(2R)-1-(3-氯丙基)-2-甲基吡咯烷(0.50 g),在100℃下搅拌1小时。使用水稀释反应混合物并使用乙酸乙酯萃取。通过无水硫酸镁干燥有机层 并减压浓缩,通过NH-型硅胶柱色谱法(洗脱溶剂:正己烷/乙酸乙酯 = 1/1)纯化得到的残留物。将得到的固体从正己烷中重结晶,得到标题化合物(0.33 g, 37%),为无色粉末。
(3) 4-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]苄腈(化合物1)的制备
[式14]
将实施例1-(2)中制备的(2R)-6-[3-(2-甲基吡咯烷-1-基)丙氧基]-3,4-二氢喹啉-2(1H)-酮(0.20 g)、4-碘苄腈(0.18 g)、rac-反式-N,N’-二甲基环己基-1,2-二胺(0.041 g)、碘化铜(0.013 g)和碳酸铯(0.45 g)的N,N-二甲基甲酰胺(2 mL)悬浮液在100℃下搅拌16小时。使用水稀释反应混合物并使用氯仿萃取。通过无水硫酸钠干燥有机层并减压浓缩。通过制备型TLC(在一块2 mm厚的板上,展开剂:氯仿/甲醇 = 9/1)和NH-型制备型TLC(在两块0.25 mm厚的板上,展开剂:正己烷/乙酸乙酯= 1/1)纯化得到的残留物,得到标题化合物(0.062 g, 23%),为浅棕色无定形物质。
重复与实施例1所示相同的步骤以制备下文所列的化合物:
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-苯基-3,4-二氢喹啉-2(1H)-酮(化合物2);
1-(4-甲基苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物3);
1-(4-甲氧基苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物4);
1-(4-乙氧基苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物5);
1-(4-氟苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物6);
1-(4-氯苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物7);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-[4-(三氟甲基)苯基]-3,4-二氢喹啉-2(1H)-酮(化合物8);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-[4-(三氟甲氧基)苯基]-3,4-二氢喹啉-2(1H)-酮(化合物9);
1-[4-(羟基甲基)苯基]-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物10);
1-[4-(甲氧基甲基)苯基]-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物11);
1-{4-[(二甲基氨基)甲基]苯基}-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物12);
N,N-二甲基-4-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]苯甲酰胺(化合物13);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-[4-(吡咯烷-1-基羰基)苯基]-3,4-二氢喹啉-2(1H)-酮(化合物14);
1-(4-乙酰基苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物15);
1-[4-(环丙基羰基)苯基]-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物16);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-[4-(吗啉-4-基)苯基]-3,4-二氢喹啉-2(1H)-酮(化合物17);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-[4-(2-氧吡咯烷-1-基)苯基]-3,4-二氢喹啉-2(1H)-酮(化合物18);
1-{4-[(6-甲基哒嗪-3-基)氧基]苯基}-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物20);
N,N-二甲基-3-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]苯甲酰胺(化合物21);
1-(3-甲氧基苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物22);
1-(2-甲氧基苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物23);
1-(3-氟苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物24);
1-(2,4-二甲氧基苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物25);
1-(3-氟-5-甲氧基苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物26);
1-(3,5-二氟苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物27);
1-(3,4-二氟苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物28);
1-(2,4-二氟苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物29);
1-(4-氯-2-氟苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物30);
3-氯-5-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]苄腈(化合物31);
2-甲基-5-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]苄腈(化合物32);
2-甲氧基-5-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]苄腈(化合物33);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-(吡啶-2-基)-3,4-二氢喹啉-2(1H)-酮(化合物34);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-(吡啶-3-基)-3,4-二氢喹啉-2(1H)-酮(化合物35);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-(嘧啶-5-基)-3,4-二氢喹啉-2(1H)-酮(化合物36);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢-2H-1,3’-二喹啉-2-酮(化合物37);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢-2H-1,6’-二喹啉-2-酮(化合物38);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-(1,5-萘啶-3-基)-3,4-二氢喹啉-2(1H)-酮(化合物39);
6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-1-(1,6-萘啶-8-基)-3,4-二氢喹啉-2(1H)-酮(化合物40);
5-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]-1H-吲哚-1-羧酸叔丁酯(化合物41);
3-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]-1H-吲哚-1-羧酸叔丁酯(化合物42);
1-(1,3-苯并间二氧杂环戊烯-5-基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物44);
1-(2,3-二氢-1-苯并呋喃-6-基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物45);
6-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]吡啶-3-甲腈(化合物46);
1-(6-甲基吡啶-3-基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物47);
1-(6-甲氧基吡啶-3-基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物48);
1-(5-氯吡啶-2-基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物49);
5-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]吡啶-3-甲腈(化合物50);
2-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]吡啶-3-甲腈(化合物51);
1-(5-氟吡啶-3-基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物52);
1-(3-甲基吡啶-2-基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物53);
1-(1-甲基-2-氧-1,2-二氢吡啶-4-基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物54);和
6’-甲氧基-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢-2H-1,3’-二喹啉-2-酮(化合物55)。
化合物2-55的结构式以及物理和化学数据显示于表1中。
[表1-1]
[表1-2]
[表1-3]
[表1-4]
[表1-5]
[表1-6]
[表1-7]
[表1-8]
(实施例2)
1-(1H-吲哚-5-基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物56)的制备
[式15]
向以实施例1所示的相同方式制备的5-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]-1H-吲哚-1-羧酸叔丁酯(化合物41)(0.050 g)的甲醇(0.19 mL)溶液中,加入水(0.3 mL)和碳酸钾(0.041 g)并在80℃下搅拌2小时。减压浓缩反应混合物,通过NH-型制备型TLC(在三块0.25 mm厚的板上,展开剂:乙酸乙酯)纯化得到的残留物,得到标题化合物(0.0090 g, 2.2%),为无色无定形物质。
(实施例3)
1-(1H-吲哚-3-基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物57)的制备
[式16]
重复与实施例2所示的相同步骤得到标题化合物,除了采用3-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]-1H-吲哚-1-羧酸叔丁酯(化合物42)代替5-[6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-2-氧-3,4-二氢喹啉-1(2H)-基]-1H-吲哚-1-羧酸叔丁酯(化合物41)。
(实施例4)
6-[(1-环丁基哌啶-4-基)氧基]-3,4-二氢-2H-1,3’-二喹啉-2-酮(化合物58)的制备
(1) 6-(1-环丁基哌啶-4-基氧基)-3,4-二氢喹啉-2(1H)-酮的制备
[式17]
在氮气氛下,在冰冷却下向6-羟基-3,4-二氢喹啉-2(1H)-酮(5.00 g)和N-环丁基-4-羟基哌啶(其可以根据WO2005/108384的描述合成)(7.10 g)的四氢呋喃(50 mL)溶液中,逐滴加入偶氮二甲酸二乙酯(40%在甲苯中, 16.7 mL)。完成滴加后,将反应混合物加热至室温并搅拌40小时。减压浓缩反应混合物,通过硅胶柱色谱法(洗脱溶剂:氯仿/甲醇 = 95/5)纯化得到的残留物,得到标题化合物(2.30 g, 25%),为无色粉末。
(2) 6-[(1-环丁基哌啶-4-基)氧基]-3,4-二氢-2H-1,3’-二喹啉-2-酮(化合物58)的制备
[式18]
将实施例4-(1)中合成的6-(1-环丁基哌啶-4-基氧基)-3,4-二氢喹啉-2(1H)-酮(0.10 g)、3-溴异喹啉(0.10 g)、rac-反式-N,N’-二甲基环己基-1,2-二胺(0.047 g)、碘化铜(0.016 g)和碳酸铯(0.22 g)的甲苯(1 mL)悬浮液在110℃下搅拌3小时。将反应混合物冷却至室温,使用氯仿稀释并过滤除去不溶性物质。减压浓缩滤液,通过NH-型硅胶柱色谱法(洗脱溶剂:己烷/乙酸乙酯 = 4/1-1/4)和OH-型制备型TLC(在两块1 mm厚的板上, 展开剂:氯仿/甲醇 = 4/1)纯化得到的残留物,得到标题化合物(0.061 g, 44%),为无色无定形物质。
(实施例5)
6-[(1-叔丁基哌啶-4-基)氧基]-3,4-二氢-2H-1,3’-二喹啉-2-酮(化合物59)的制备
[式19]
重复与实施例4所示的相同步骤以得到标题化合物,除了采用1-叔丁基-4-羟基哌啶(其可以根据Journal of Organic Chemistry, 2005, 第70卷, 第1930-1933页的描述合成)代替N-环丁基-4-羟基哌啶。
(实施例6)
6-[(1-环丁基哌啶-4-基)氧基]-1-(4-氟苯基)-3,4-二氢喹啉-2(1H)-酮(化合物60)的制备
[式20]
重复与实施例4所示的相同步骤以得到标题化合物,除了采用4-氟碘苯代替3-溴喹啉。
(实施例6-2)
6-[(1-环丁基哌啶-4-基)氧基]-1-(4-氟苯基)-3,4-二氢喹啉-2(1H)-酮盐酸化物(化合物60的盐酸盐)的制备
向实施例6中制备的6-[(1-环丁基哌啶-4-基)氧基]-1-(4-氟苯基)-3,4-二氢喹啉-2(1H)-酮(化合物60) (0.90 g)在乙酸乙酯(10 mL)和乙醇(2 mL)混合物中的溶液中,加入4N在乙酸乙酯中的盐酸(1.14 mL),在室温下搅拌3小时。减压浓缩反应混合物,随后向残留物中加入异丙醇(7 mL)和乙醇(2 mL)。在油浴中(110℃)加热的同时将混合物搅拌5分钟,然后在冷却至室温的同时进行搅拌。过滤收集沉淀物并干燥,得到标题化合物(0.93 g, 95%),为无色晶体。
熔点 >250℃
重复与实施例4-6中所示相同的步骤以制备下文所列的化合物:
6-[(1-叔丁基哌啶-4-基)氧基]-1-苯基-3,4-二氢喹啉-2(1H)-酮(化合物61);
4-{6-[(1-叔丁基哌啶-4-基)氧基]-2-氧-3,4-二氢喹啉-1(2H)-基}苄腈(化合物62);
3-{6-[(1-叔丁基哌啶-4-基)氧基]-2-氧-3,4-二氢喹啉-1(2H)-基}苄腈(化合物63);
6-[(1-叔丁基哌啶-4-基)氧基]-1-(5-氟吡啶-3-基)-3,4-二氢喹啉-2(1H)-酮(化合物64);
6-[(1-叔丁基哌啶-4-基)氧基]-1-(6-甲氧基吡啶-3-基)-3,4-二氢喹啉-2(1H)-酮(化合物65);
6-[(1-叔丁基哌啶-4-基)氧基]-1-(4-氟苯基)-3,4-二氢喹啉-2(1H)-酮(化合物66);
6-[(1-环丁基哌啶-4-基)氧基]-1-(6-甲氧基吡啶-3-基)-3,4-二氢喹啉-2(1H)-酮(化合物67);
6-[(1-环丁基哌啶-4-基)氧基]-1-(3,5-二氟苯基)-3,4-二氢喹啉-2(1H)-酮(化合物68);
6-[(1-环丁基哌啶-4-基)氧基]-1-(3-氟苯基)-3,4-二氢喹啉-2(1H)-酮(化合物69);
1-(4-氯苯基)-6-[(1-环丁基哌啶-4-基)氧基]-3,4-二氢喹啉-2(1H)-酮(化合物70);
6-[(1-环丁基哌啶-4-基)氧基]-1-(5-氟吡啶-3-基)-3,4-二氢喹啉-2(1H)-酮(化合物71);
6-[(1-环丁基哌啶-4-基)氧基]-1-苯基-3,4-二氢喹啉-2(1H)-酮(化合物72);
4-{6-[(1-环丁基哌啶-4-基)氧基]-2-氧-3,4-二氢喹啉-1(2H)-基}苄腈(化合物73);和
3-{6-[(1-环丁基哌啶-4-基)氧基]-2-氧-3,4-二氢喹啉-1(2H)-基}苄腈(化合物74)。
化合物61-74的结构式以及物理和化学数据显示于表2中。
[表2-1]
[表2-2]
[表2-3]
(实施例7)
1-(4-氟苯基)-6-{[1-(丙-2-基)哌啶-4-基]氧基}-3,4-二氢喹啉-2(1H)-酮(化合物75)的制备
(1) 4-(2-氧-1,2,3,4-四氢喹啉-6-基氧基)哌啶-1-羧酸叔丁酯的制备
[式21]
将6-羟基-3,4-二氢喹啉-2(1H)-酮(5.0 g)、4-(甲烷磺酰氧基)哌啶-1-羧酸叔丁酯(13 g)和碳酸钾(5.1 g)的N,N-二甲基甲酰胺(30 mL)悬浮液在100℃下搅拌20小时。将反应混合物冷却至室温,使用水稀释并使用氯仿萃取。使用盐水洗涤有机层并减压浓缩。通过NH-型硅胶柱色谱法(洗脱溶剂:氯仿/己烷 = 4/1)纯化得到的残留物,得到标题化合物(6.9 g, 65%),为无色固体。
(2) 4-(1-(4-氟苯基)-2-氧-1,2,3,4-四氢喹啉-6-基氧基)哌啶-1-羧酸叔丁酯的制备
[式22]
将实施例7-(1)中制备的4-(2-氧-1,2,3,4-四氢喹啉-6-基氧基)哌啶-1-羧酸叔丁酯 (3.0 g)、1-氟-4-碘苯(2.9 g)、rac-反式-N,N’-二甲基环己基-1,2-二胺(1.2 g)、碘化铜(0.41 g)和碳酸铯(5.6 g)的甲苯(8.0 mL)悬浮液在100℃下搅拌4小时。将反应混合物冷却至室温,使用甲苯稀释并过滤除去不溶性物质。减压浓缩滤液。通过硅胶柱色谱法(洗脱溶剂:己烷/乙酸乙酯 = 7/3-1/4)纯化得到的残留物,得到标题化合物(3.8 g, 99%),为无色无定形物质。
(3) 1-(4-氟苯基)-6-(哌啶-4-基氧基)-3,4-二氢喹啉-2(1H)-酮盐酸化物的制备
[式23]
在室温下向实施例7-(2)中制备的4-(1-(4-氟苯基)-2-氧-1,2,3,4-四氢喹啉-6-基氧基)哌啶-1-羧酸叔丁酯(6.0 g)在乙酸乙酯(12 mL)和乙醇(4 mL)混合物中的溶液中,逐滴加入4M在乙酸乙酯中的盐酸(10 mL),搅拌16小时。减压浓缩反应混合物,使用乙酸乙酯稀释并在室温下搅拌1小时。过滤收集沉淀物并干燥,得到标题化合物(5.1 g, 99%),为无色固体。
(4) 1-(4-氟苯基)-6-{[1-(丙-2-基)哌啶-4-基]氧基}-3,4-二氢喹啉-2(1H)-酮(化合物75)的制备
[式24]
将实施例7-(3)中制备的1-(4-氟苯基)-6-(哌啶-4-基氧基)-3,4-二氢喹啉-2(1H)-酮盐酸化物(0.30 g)、碳酸钾(0.55 g)和2-碘丙烷(0.68 g)的N,N-二甲基甲酰胺(10 mL)悬浮液在100℃下搅拌1小时。将反应混合物冷却至室温,使用水稀释并使用氯仿萃取。使用盐水洗涤有机层,通过无水硫酸钠干燥并减压浓缩。通过硅胶柱色谱法(洗脱溶剂:氯仿 → 氯仿/甲醇 = 4/1)纯化得到的残留物,得到标题化合物(0.16 g, 52%),为无色固体。
(实施例8)
6-{[1-(环丙基甲基)哌啶-4-基]氧基}-1-(4-氟苯基)-3,4-二氢喹啉-2(1H)-酮(化合物76)的制备
[式25]
将实施例7-(3)中制备的1-(4-氟苯基)-6-(哌啶-4-基氧基)-3,4-二氢喹啉-2(1H)-酮盐酸化物(0.30 g)、碳酸钾(0.55 g)和(溴甲基)环丙基(0.32 g)的N,N-二甲基甲酰胺(10 mL)悬浮液在100℃下搅拌6小时。将反应混合物冷却至室温,使用水稀释并使用氯仿萃取。使用盐水洗涤有机层,通过无水硫酸钠干燥并减压浓缩。通过硅胶柱色谱法(洗脱溶剂:氯仿 → 氯仿/甲醇 = 4/1)和制备型TLC(在一块2 mm厚的板上,展开剂:氯仿/甲醇 = 9/1)纯化得到的残留物,得到标题化合物(0.11 g, 35%),为无色无定形物质。
(实施例9)
6-[(1-环丙基哌啶-4-基)氧基]-1-(4-氟苯基)-3,4-二氢喹啉-2(1H)-酮(化合物77)的制备
[式26]
将实施例7-(3)中制备的1-(4-氟苯基)-6-(哌啶-4-基氧基)-3,4-二氢喹啉-2(1H)-酮盐酸化物(0.30 g)、三乙胺(0.080 g)、[(1-乙氧基环丙基)-氧基]三甲基硅烷(0.69 g)、乙酸(0.48 g)和分子筛3A(1.0 g)的甲醇(10 mL)悬浮液在室温下搅拌1小时,随后加入氰基硼氢化钠(0.25 g),并在相同温度下搅拌16小时。将反应混合物加热到95℃,加热回流7小时,然后冷却至室温,随后过滤除去不溶性物质。减压浓缩滤液,通过硅胶柱色谱法(洗脱溶剂:氯仿 → 氯仿/甲醇 = 4/1)和制备型TLC(在一块2 mm厚的板上,展开剂:氯仿/甲醇 = 9/1) 纯化得到的残留物,得到标题化合物(0.11 g, 37%),为无色无定形物质。
(实施例10)
1-(4-氟苯基)-6-[3-(吡咯烷-1-基)丙氧基]-3,4-二氢喹啉-2(1H)-酮(化合物78)的制备
(1) 6-(3-氯丙氧基)-3,4-二氢喹啉-2(1H)-酮的制备
[式27]
将6-羟基-3,4-二氢喹啉-2(1H)-酮(50 g)、碳酸铯(150 g)和1-溴-3-氯丙烷(58 g)的乙腈(300 mL)悬浮液在110℃下搅拌4小时。将反应混合物冷却至室温,使用氯仿稀释并过滤除去不溶性物质。减压浓缩滤液。通过硅胶柱色谱法(洗脱溶剂:氯仿 → 氯仿/甲醇 = 4/1)纯化得到的残留物,得到的固体从乙醇中重结晶,得到标题化合物(42 g, 68%),为无色固体。
(2) 6-[3-(吡咯烷-1-基)丙氧基]-3,4-二氢喹啉-2(1H)-酮的制备
[式28]
将实施例10-(1)中制备的6-(3-氯丙氧基)-3,4-二氢喹啉-2(1H)-酮(10 g)和吡咯烷(15 g)的2-丙醇(15 mL)溶液在90℃下搅拌2天。将反应混合物冷却至室温,使用水稀释并使用氯仿萃取。使用盐水洗涤有机层,通过无水硫酸钠干燥并减压浓缩。通过硅胶柱色谱法(洗脱溶剂:氯仿 → 氯仿/甲醇 = 4/1)纯化得到的残留物,得到的固体从乙酸乙酯中重结晶,得到标题化合物(7.5 g, 65%),为无色固体。
(3) 1-(4-氟苯基)-6-[3-(吡咯烷-1-基)丙氧基]-3,4-二氢喹啉-2(1H)-酮(化合物78)的制备
[式29]
将实施例10-(2)中制备的6-[3-(吡咯烷-1-基)丙氧基]-3,4-二氢喹啉-2(1H)-酮(0.20 g)、1-氟-4-碘苯(0.24 g)、rac-反式-N,N’-二甲基环己基-1,2-二胺(0.10 g)、碘化铜(0.035 g)和碳酸铯(0.48 g)的甲苯(1.0 mL)悬浮液在105℃下搅拌60小时。将反应混合物冷却至室温,使用氯仿稀释并过滤除去不溶性物质。减压浓缩滤液。通过NH-型硅胶柱色谱法(洗脱溶剂:己烷/乙酸乙酯 = 1/1)纯化得到的残留物,得到的固体从二异丙基醚和乙酸乙酯的混合物中重结晶,得到标题化合物(0.10 g, 37%),为无色固体。
重复与实施例10所示相同的步骤以制备下文所列的化合物:
1-(3-氟苯基)-6-[3-(吡咯烷-1-基)丙氧基]-3,4-二氢喹啉-2(1H)-酮(化合物79);
1-(3,5-二氟苯基)-6-[3-(吡咯烷-1-基)丙氧基]-3,4-二氢喹啉-2(1H)-酮(化合物80);
1-(3,4-二氟苯基)-6-[3-(吡咯烷-1-基)丙氧基]-3,4-二氢喹啉-2(1H)-酮(化合物81);
1-(4-氟苯基)-6-[3-(哌啶-1-基)丙氧基]-3,4-二氢喹啉-2(1H)-酮(化合物82);
6-[3-(二乙基氨基)丙氧基]-1-(4-氟苯基)-3,4-二氢喹啉-2(1H)-酮(化合物83);和
6-{3-[(2R,5R)-2,5-二甲基吡咯烷-1-基]丙氧基}-1-(4-氟苯基)-3,4-二氢喹啉-2(1H)-酮(化合物84)。
化合物79-84的结构式以及物理和化学数据显示于表3中。
[表3]
(实施例11)
8-氯-1-(4-氟苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物85)的制备
(1) 8-氯-6-羟基-3,4-二氢喹啉-2(1H)-酮的制备
[式30]
将3-氯-N-(2-氟-4-甲氧基苯基)丙酰胺(1.0 g, 由3-氯丁酰氯和2-氟-4-甲氧基苯胺合成)和氯化铝(5.0 g)的正庚烷(2.0 mL)悬浮液在110℃下搅拌3天。使用氯仿稀释反应混合物,随后在冰冷却下加入冰水。在室温下搅拌2小时后,分离有机层和水层。使用氯仿萃取水层,合并有机层,通过无水硫酸镁干燥并减压浓缩。通过硅胶柱色谱法(洗脱溶剂:己烷/乙酸乙酯 = 3/2)和NH-型硅胶柱色谱法(洗脱溶剂:氯仿/甲醇 = 99/1-9/1)纯化得到的残留物,得到标题化合物(0.059 g, 7%),为浅黄色固体。
(2) 8-氯-1-(4-氟苯基)-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物85)的制备
[式31]
重复与实施例1所示的相同步骤以得到标题化合物,除了采用实施例11-(1)中制备的8-氯-6-羟基-3,4-二氢喹啉-2(1H)-酮代替6-羟基-3,4-二氢喹啉-2(1H)-酮,采用4-氟碘苯代替4-碘苄腈。
(实施例12)
1-(4-氟苯基)-8-甲基-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物86)的制备
(1) 6-羟基-8-甲基-3,4-二氢喹啉-2(1H)-酮的制备
[式32]
将3-氯-N-(4-甲氧基-2-甲基苯基)丙酰胺(0.50 g, 由3-氯丁酰氯和4-甲氧基-2-甲基苯胺合成)和氯化铝(1.4 g)的正庚烷(4.0 mL)悬浮液在110℃下搅拌4天。使用氯仿稀释反应混合物,随后在冰冷却下加入冰水。在室温下搅拌1小时后,分离有机层和水层。使用乙酸乙酯萃取水层,合并有机层,通过无水硫酸镁干燥并减压浓缩。通过硅胶柱色谱法(洗脱溶剂:氯仿/甲醇 = 10/0-97/3) 纯化得到的残留物,得到标题化合物(0.166 g, 39%),为浅棕色固体。
(2) 1-(4-氟苯基)-8-甲基-6-{3-[(2R)-2-甲基吡咯烷-1-基]丙氧基}-3,4-二氢喹啉-2(1H)-酮(化合物86)的制备
[式33]
重复与实施例1所示的相同步骤以得到标题化合物,除了采用实施例12-(1)中制备的6-羟基-8-甲基-3,4-二氢喹啉-2(1H)-酮代替6-羟基-3,4-二氢喹啉-2(1H)-酮, 采用4-氟碘苯代替4-碘苄腈。
试验实施例1:H3受体结合试验
人H3受体-表达CHO-K1细胞(Perkin Elmer, ES-392-M400UA, 15 μg 蛋白质/200 μl)的膜制品、R(-)-α-甲基[3H]组胺(Amersham, TRK-1017, 比活性:1.74 TBq/mmol, 1 nM)和测试药物在室温下反应1小时。反应完成后,反应混合物通过0.3%聚乙烯亚胺-处理的玻璃滤器(GF/C)进行抽滤。使用含有5 mM EDTA的50 mM Tris-HCl洗液(pH 7.4)洗涤玻璃滤器5次。洗涤后,干燥玻璃滤器并向其中加入闪烁剂,随后使用液体闪烁计数器在滤器上测定放射性。
将R(-)-α-甲基[3H]组胺在10 μM R(-)-α-甲基组胺存在下的结合定义为非特异性结合,R(-)-α-甲基[3H]组胺的总的结合与非特异性结合之间的差被定义为R(-)-α-甲基[3H]组胺的特异性结合。固定浓度(1 nM)的R(-)-α-甲基[3H]组胺在上述条件下与不同浓度的各种测试药物反应以获得抑制曲线。抑制曲线用于测定抑制50%的R(-)-α-甲基[3H]组胺结合所需的各种测试药物的浓度(IC50)。实施例制备的化合物的IC50值显示于表4中。
[表4]
表4
试验实施例2:[35S]GTP-γ-S结合试验
试验实施例1中所用的相同的人H3受体膜制品(7.5 μg 蛋白质/200 μl)、3 μM GDP、10 nM R(-)-α-甲基组胺和测试化合物在30℃下反应20分钟。反应完成后,加入[35S]GTP-γ-S(0.2 nM)并再反应30分钟。反应完成后,反应混合物通过玻璃滤器(GF/C)进行抽滤。使用20 mM HEPES洗液(pH 7.4)洗涤玻璃滤器三次,所述洗液含有100 mM 氯化钠和3 mM 氯化镁。洗涤后,干燥玻璃滤器,向其中加入闪烁剂,随后使用液体闪烁计数器在滤器上测定放射性。
将[35S]GTP-γ-S在R(-)-α-甲基组胺不存在下的结合定义为非特异性结合,在R(-)-α-甲基组胺存在下的总的结合与非特异性结合之间的差被定义为[35S]GTP-γ-S的特异性结合。固定浓度的[35S]GTP-γ-S(0.2 nM)和R(-)-α-甲基组胺(10 nM)在上述条件下与不同浓度的各种测试药物反应以获得抑制曲线。抑制曲线用于测定抑制50%的[35S]GTP-γ-S结合所需的各种测试药物的浓度(IC50)。结果,发现化合物6的IC50值为0.28 nM,发现化合物12的IC50值为0.21nM,发现化合物13的IC50值为0.62 nM,发现化合物58的IC50值为0.40 nM,发现化合物60的IC50值为0.23 nM,发现化合物69的IC50值为0.20 nM,发现化合物71的IC50值为0.26 nM,发现化合物72的IC50值为0.16 nM,以及发现化合物73的IC50值为0.23 nM。
工业实用性
本发明能够提供对组胺H3受体结合具有强的抑制作用并且可以用于预防或治疗组胺H3受体-介导的障碍的药物制剂,所述障碍例如痴呆、阿尔茨海默氏病、注意缺陷多动障碍、精神分裂症、癫痫、中枢性惊厥、进食障碍、肥胖症、糖尿病、高脂血症、睡眠障碍、发作性睡病、睡眠呼吸暂停综合征、昼夜节律障碍、抑郁症、变应性鼻炎或其他疾病。预期本发明会对医药工业的发展作出巨大的贡献。
Claims (5)
1. 式(1)表示的二氢喹啉酮衍生物或其药学可接受的盐:
[式1]
[其中Q表示下列式(A)或(B):
[式2]
R1表示氢原子、卤素原子或C1-C6烷基,
R2表示氢原子或C1-C6烷基,
n表示1或2,
R3和R4可以相同或不同,各自表示C1-C6烷基或C3-C7环烷基,或者
R3和R4与它们邻近的氮原子相互连接一起形成3-至7-元饱和杂环(其中所述饱和杂环可以被一个或两个C1-C6烷基取代),
R5表示C1-C6烷基(其中所述C1-C6烷基可以被一个或两个C3-C7环烷基取代) 或C3-C7环烷基(其中所述C3-C7环烷基可以被一个或两个C1-C6烷基取代),以及
P表示芳基、杂芳基或杂环基{其中所述芳基、杂芳基或杂环基可以被相同或不同的1至3个选自下列的取代基取代:
卤素原子,
C1-C6烷基(其中所述C1-C6烷基可以被1至3个卤素原子、羟基、C1-C6烷氧基或C2-C12二烷基氨基取代),
C1-C6烷氧基(其中所述C1-C6烷氧基可以被1至3个卤素原子取代),
氨基,
C1-C6烷基氨基,
C2-C12二烷基氨基,
C2-C7烷酰基,
C4-C8环烷基羰基,
氰基,
C2-C7烷氧基羰基,
C2-C7烷基氨基羰基,
C3-C13二烷基氨基羰基,
与在环中含有一个或多个氮原子并且可以进一步含有氧或硫原子的单环饱和杂环相连的羰基,
氨基甲酰基,
杂芳基,
杂环基(其中所述杂环基可以被一个或两个C1-C6 烷基取代),或者
杂芳基氧基(其中所述杂芳基氧基可以被一个或两个C1-C6 烷基取代)}]。
3. 根据权利要求1或2所述的二氢喹啉酮衍生物或其药学可接受的盐,其中P表示苯基、吡啶基、嘧啶基、喹啉基、萘啶基、吲哚基、2,3-二氢[1,4]苯并二烯基、苯并[1,3]间二氧杂环戊烯基、2,3-二氢苯并呋喃基或2-氧-1,2-二氢吡啶基{其中所述苯基、吡啶基、嘧啶基、喹啉基、萘啶基、吲哚基、2,3-二氢[1,4]苯并二烯基、苯并[1,3]间二氧杂环戊烯基、2,3-二氢苯并呋喃基或2-氧-1,2-二氢吡啶基可以被相同或不同的1至3个选自下列的取代基取代:
卤素原子,
C1-C6烷基(其中所述C1-C6烷基可以被1至3个卤素原子、羟基、C1-C6烷氧基或C2-C12二烷基氨基取代),
C1-C6烷氧基(其中所述C1-C6 烷氧基可以被1至3个卤素原子取代),
C2-C7烷酰基,
C4-C8环烷基羰基,
氰基,
C2-C7烷氧基羰基,
C2-C7烷基氨基羰基,
C3-C13二烷基氨基羰基,
吡咯烷-1-基羰基,
氨基甲酰基,
吗啉-4-基或2-氧吡咯烷-1-基(其中所述吗啉-4-基或2-氧吡咯烷-1-基可以被一个或两个C1-C6 烷基取代),或者
哒嗪基氧基(其中所述哒嗪基氧基可以被一个或两个C1-C6 烷基取代)}。
4. 药物制剂,其包含根据权利要求1-3任一所述的作为活性成分的二氢喹啉酮衍生物或其药学可接受的盐。
5. 用于痴呆、阿尔茨海默氏病、注意缺陷多动障碍、精神分裂症、癫痫、中枢性惊厥、进食障碍、肥胖症、糖尿病、高脂血症、睡眠障碍、发作性睡病、睡眠呼吸暂停综合征、昼夜节律障碍、抑郁症或变应性鼻炎的预防剂或治疗剂,其包含根据权利要求1-3任一所述的作为活性成分的二氢喹啉酮衍生物或其药学可接受的盐。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104130187A (zh) * | 2014-05-27 | 2014-11-05 | 浙江工业大学 | 一种手性二氢喹啉酮类化合物的不对称合成方法 |
CN110156676A (zh) * | 2019-06-26 | 2019-08-23 | 绍兴文理学院 | 一种3,4-二氢喹啉-2(1h)-酮类衍生物及其制备方法与应用 |
CN114702428A (zh) * | 2019-12-09 | 2022-07-05 | 苏州恩华生物医药科技有限公司 | 连双环结构sigma-1受体抑制剂 |
CN115784983A (zh) * | 2022-12-05 | 2023-03-14 | 井冈山大学 | 6-胺烷氧基-3,4-二氢喹啉酮衍生物及制备方法和应用 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8946260B2 (en) | 2010-09-16 | 2015-02-03 | Novartis Ag | 17α-hydroxylase/C17,20-lyase inhibitors |
JP6218366B2 (ja) * | 2012-09-04 | 2017-10-25 | 大正製薬株式会社 | H3受容体の放射性標識リガンド |
HUP1300139A2 (en) | 2013-03-06 | 2014-09-29 | Richter Gedeon Nyrt | Phenoxypiperidine h3 antagonists |
IN2014MU00197A (zh) * | 2014-01-21 | 2015-08-28 | Wanbury Ltd | |
US9145388B2 (en) | 2014-02-19 | 2015-09-29 | King Fahd University Of Petroleum And Minerals | 6-piperazinyl-3,4-dihydroquinazolin-2(1H)-ones |
US10428030B2 (en) * | 2015-10-30 | 2019-10-01 | Trillium Therapeutics | Heterocycle derivatives and their use for the treatment of CNS disorders |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004026837A2 (en) * | 2002-09-18 | 2004-04-01 | Eli Lilly And Company | Histamine h3 receptor antagonists, preparaton and therapeutic uses |
CN1918128A (zh) * | 2004-02-13 | 2007-02-21 | 万有制药株式会社 | 稠环4-氧代-嘧啶衍生物 |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK588486A (da) | 1985-12-09 | 1987-06-10 | Otsuka Pharma Co Ltd | Anvendelse af en forbindelse til behandling af hypoxi |
JPS62135423A (ja) | 1985-12-09 | 1987-06-18 | Otsuka Pharmaceut Co Ltd | 低酸素症改善剤 |
KR940000785B1 (ko) | 1986-04-02 | 1994-01-31 | 오오쓰까세이야꾸 가부시끼가이샤 | 카르보스티릴 유도체 및 그의 염의 제조 방법 |
DK167187A (da) | 1986-04-02 | 1987-10-03 | Otsuka Pharma Co Ltd | Carbostyrilderivater og salte deraf, fremgangsmaade til fremstilling af saadanne forbindelser og laegemiddel indeholdende disse |
JPH0681727B2 (ja) | 1986-04-02 | 1994-10-19 | 大塚製薬株式会社 | 血小板粘着抑制剤 |
JPS63290821A (ja) | 1987-05-25 | 1988-11-28 | Otsuka Pharmaceut Co Ltd | 抗不整脈剤 |
TW448161B (en) * | 1994-07-14 | 2001-08-01 | Otsuka Pharma Co Ltd | Cyclic amide derivatives |
CN1972914A (zh) | 2004-03-31 | 2007-05-30 | 詹森药业有限公司 | 作为组胺h3受体配合体的非咪唑杂环化合物 |
GB0408083D0 (en) | 2004-04-08 | 2004-05-12 | Glaxo Group Ltd | Novel compounds |
ES2346665T3 (es) | 2004-05-07 | 2010-10-19 | Warner-Lambert Company Llc | Derivados de fenol y tiofenol 3- o 4-monosustituidos utiles como ligandos de h3. |
FR2870846B1 (fr) | 2004-05-25 | 2006-08-04 | Sanofi Synthelabo | Derives de tetrahydroisoquinolylsulfonamides, leur preparation et leur utilisation en therapeutique |
SE0401971D0 (sv) | 2004-08-02 | 2004-08-02 | Astrazeneca Ab | Piperidne derivatives |
KR100867071B1 (ko) | 2004-10-19 | 2008-11-04 | 에프. 호프만-라 로슈 아게 | 퀴놀린 유도체 |
WO2006046131A1 (en) | 2004-10-29 | 2006-05-04 | Pfizer Products Inc. | Tetralin histamine-3 receptor antagonists |
EP1820797A4 (en) | 2004-12-01 | 2009-10-28 | Banyu Pharma Co Ltd | SUBSTITUTED PYRIDONE DERIVATIVE |
BRPI0518841A2 (pt) | 2004-12-07 | 2008-12-09 | Glaxo Group Ltd | derivados de indenila e uso destes para o tratamento de transtornos neurolàgicos |
US7790720B2 (en) | 2005-03-31 | 2010-09-07 | Ucb Pharma, S.A. | Compounds comprising an oxazole or thiazole moiety, processes for making them, and their uses |
CN101151244B (zh) | 2005-04-01 | 2014-09-03 | 伊莱利利公司 | 组胺h3受体活性剂、制备和治疗用途 |
JP4315393B2 (ja) * | 2005-04-14 | 2009-08-19 | 大塚製薬株式会社 | 複素環化合物 |
JP2007001944A (ja) * | 2005-06-24 | 2007-01-11 | Sankyo Agro Kk | 3,4−ジヒドロ−1,3’−ビキノリン−2−オン誘導体 |
-
2010
- 2010-01-28 TW TW099102463A patent/TW201039822A/zh unknown
- 2010-02-03 AR ARP100100292A patent/AR075229A1/es not_active Application Discontinuation
- 2010-02-05 SG SG2011056413A patent/SG173555A1/en unknown
- 2010-02-05 US US13/144,591 patent/US8609847B2/en active Active
- 2010-02-05 WO PCT/JP2010/052114 patent/WO2010090347A1/en active Application Filing
- 2010-02-05 RU RU2011136821/04A patent/RU2011136821A/ru not_active Application Discontinuation
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-
2011
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- 2011-07-26 IL IL214293A patent/IL214293A0/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004026837A2 (en) * | 2002-09-18 | 2004-04-01 | Eli Lilly And Company | Histamine h3 receptor antagonists, preparaton and therapeutic uses |
CN1918128A (zh) * | 2004-02-13 | 2007-02-21 | 万有制药株式会社 | 稠环4-氧代-嘧啶衍生物 |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104130187A (zh) * | 2014-05-27 | 2014-11-05 | 浙江工业大学 | 一种手性二氢喹啉酮类化合物的不对称合成方法 |
CN110156676A (zh) * | 2019-06-26 | 2019-08-23 | 绍兴文理学院 | 一种3,4-二氢喹啉-2(1h)-酮类衍生物及其制备方法与应用 |
CN110156676B (zh) * | 2019-06-26 | 2020-11-03 | 绍兴文理学院 | 一种3,4-二氢喹啉-2(1h)-酮类衍生物及其制备方法与应用 |
CN114702428A (zh) * | 2019-12-09 | 2022-07-05 | 苏州恩华生物医药科技有限公司 | 连双环结构sigma-1受体抑制剂 |
CN114702428B (zh) * | 2019-12-09 | 2023-11-28 | 苏州恩华生物医药科技有限公司 | 连双环结构sigma-1受体抑制剂 |
CN115784983A (zh) * | 2022-12-05 | 2023-03-14 | 井冈山大学 | 6-胺烷氧基-3,4-二氢喹啉酮衍生物及制备方法和应用 |
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