CN1439001A - 四氢吡啶基或哌啶基杂环衍生物 - Google Patents
四氢吡啶基或哌啶基杂环衍生物 Download PDFInfo
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- CN1439001A CN1439001A CN01812001A CN01812001A CN1439001A CN 1439001 A CN1439001 A CN 1439001A CN 01812001 A CN01812001 A CN 01812001A CN 01812001 A CN01812001 A CN 01812001A CN 1439001 A CN1439001 A CN 1439001A
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- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 134
- -1 C 1-5Alkyl Chemical group 0.000 claims description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000006625 (C3-C8) cycloalkyloxy group Chemical group 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000005942 tetrahydropyridyl group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000002769 corticotropin releasing factor antagonist Substances 0.000 claims 2
- 102100021752 Corticoliberin Human genes 0.000 abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 17
- 201000010099 disease Diseases 0.000 abstract description 14
- 108010056643 Corticotropin-Releasing Hormone Receptors Proteins 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 100
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 50
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 45
- 239000002585 base Substances 0.000 description 43
- 239000000203 mixture Substances 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 41
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 38
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
- 239000012442 inert solvent Substances 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 30
- 239000003513 alkali Substances 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 238000001914 filtration Methods 0.000 description 25
- 238000001035 drying Methods 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000000034 method Methods 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000003480 eluent Substances 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 239000000499 gel Substances 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 239000004215 Carbon black (E152) Substances 0.000 description 14
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 14
- 238000003810 ethyl acetate extraction Methods 0.000 description 14
- 229930195733 hydrocarbon Natural products 0.000 description 14
- 150000002430 hydrocarbons Chemical class 0.000 description 14
- 239000012312 sodium hydride Substances 0.000 description 14
- 229910000104 sodium hydride Inorganic materials 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 13
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 10
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 10
- 229910052500 inorganic mineral Inorganic materials 0.000 description 10
- 235000010755 mineral Nutrition 0.000 description 10
- 239000011707 mineral Substances 0.000 description 10
- 235000017550 sodium carbonate Nutrition 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- 239000004533 oil dispersion Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 235000015320 potassium carbonate Nutrition 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 206010008118 cerebral infarction Diseases 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 7
- 230000006103 sulfonylation Effects 0.000 description 7
- 238000005694 sulfonylation reaction Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 6
- RMLHVYNAGVXKKC-UHFFFAOYSA-N [SH2]=N.C(F)(F)F Chemical compound [SH2]=N.C(F)(F)F RMLHVYNAGVXKKC-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 230000026030 halogenation Effects 0.000 description 6
- 238000005658 halogenation reaction Methods 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 6
- 229910000105 potassium hydride Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 208000019901 Anxiety disease Diseases 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 208000030814 Eating disease Diseases 0.000 description 4
- 208000019454 Feeding and Eating disease Diseases 0.000 description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000009435 amidation Effects 0.000 description 4
- 238000007112 amidation reaction Methods 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
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- 208000010643 digestive system disease Diseases 0.000 description 4
- 235000014632 disordered eating Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 208000018685 gastrointestinal system disease Diseases 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000011877 solvent mixture Substances 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- VZEQVJZHDYRCBZ-UHFFFAOYSA-N 8-bromo-2-methyl-1h-quinolin-4-one Chemical compound C1=CC(Br)=C2NC(C)=CC(=O)C2=C1 VZEQVJZHDYRCBZ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 201000004384 Alopecia Diseases 0.000 description 3
- 201000006474 Brain Ischemia Diseases 0.000 description 3
- 206010048962 Brain oedema Diseases 0.000 description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- BYWBCSRCPLBDFU-CYBMUJFWSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3R)-3-aminopyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@@H](CC1)N BYWBCSRCPLBDFU-CYBMUJFWSA-N 0.000 description 3
- 231100000360 alopecia Toxicity 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 208000006752 brain edema Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000013016 damping Methods 0.000 description 3
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- 206010015037 epilepsy Diseases 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- YAQWKLISPINTJM-UHFFFAOYSA-N (2,4-dichlorophenoxy)boronic acid Chemical compound OB(O)OC1=CC=C(Cl)C=C1Cl YAQWKLISPINTJM-UHFFFAOYSA-N 0.000 description 2
- HAKSOKWVNPZVNM-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine;hydrochloride Chemical compound Cl.C1CNC=CC1 HAKSOKWVNPZVNM-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000173347 Tonsilla Species 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
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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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- 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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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
- A61P25/12—Antiepileptics; Anticonvulsants for grand-mal
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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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
- A61P25/22—Anxiolytics
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Abstract
式[I]:A-Het[I]代表的四氢吡啶基或哌啶基杂环衍生物对CRF受体具有高度亲合性,可有效治疗被认为与CRF有关的疾病。
Description
技术领域
本发明涉及治疗促肾上腺皮质激素释放因子(CRF)相关疾病如下列疾病的治疗剂:抑郁症、焦虑症、阿尔茨海默氏病、帕金森氏病、杭廷顿氏舞蹈病、饮食障碍、高血压、胃肠病、药物依赖、脑梗塞、脑缺血、脑水肿、头部外伤、炎症、免疫相关性疾病、脱发等。
背景技术
CRF是包含41个氨基酸的激素(Science,213,1394-1397,1981;和J.Neurosci.,7,88-100,1987),并且显示CRF在对抗紧张的生物反应中起核心作用(Cell.Mol.Neurobiol.,14,579-588,1994;Endocrinol.,132,723-728,1994;和Neuroendocrinol.61,445-452,1995)。对于CRF,有下列两条途径:CRF经由下丘脑-垂体-肾上腺系统作用于外周免疫系统或交感神经系统的途径,和CRF作为中枢神经系统中的神经递质起作用的途径(Corticotropin ReleasingFactor:Basic and Clinical Studies of a Neuropeptide,pp.29-52,1990)。将CRF对垂体切除大鼠和正常大鼠心室内给药都引起焦虑样症状(Pharmacol.Rev.,43,425-473,1991;和Brain Res.Rev.,15,71-100,1990)。因此,文献提示了CRF参与下丘脑-垂体-肾上腺系统以及CRF作为中枢神经系统中的神经递质起作用的途径。
Owens和Nemeroff于1991年在综述中总结了涉及CRF的疾病(Pharmacol.Rev.,43,425-473,1991),其中指出CRF参与抑郁症、焦虑症、阿尔茨海默氏病、帕金森氏病、亨廷顿氏舞蹈病、饮食障碍、高血压、胃肠病、药物依赖、炎症、免疫相关疾病等。最近有人报道CRF还与癫痫、脑梗塞、脑缺血、脑水肿、和头外伤有关(Brain Res.545,339-342,1991;Ann.Neuro.31,48-498,1992;Dev.Brain Res.91,245-251,1996;和Brain Res.744,166-170,1997)。因此,CRF受体的拮抗剂可用作治疗上述疾病的治疗药。
本发明的目的是提供CRF受体的拮抗剂,所述拮抗剂能有效地用作CRF相关疾病例如下列疾病的治疗剂或预防剂:抑郁症、焦虑症、阿尔茨海默氏病、帕金森氏病、亨廷顿氏舞蹈病、饮食障碍、高血压、胃肠病、药物依赖、癫痫、脑梗塞、脑缺血、脑水肿、头部外伤、炎症、免疫相关疾病、脱发等。
发明内容
本发明的发明人认真地研究了四氢吡啶基或哌啶基杂环衍生物,并发现了对CRF受体有高亲和力的新的四氢吡啶基或哌啶基杂环衍生物,从而完成了本发明。
下文解释本发明。
本发明是下式[I]所代表的四氢吡啶基或哌啶基杂环衍生物或其可药用盐或水合物:
A-Het [I]
R0是氢原子、C1-5烷基、C3-8环烷基或C3-8环烷基-C1-5烷基,
n是0-5的整数,且
Y是氰基、式-CONR1(R2)所代表的基团(其中R1和R2可相同或不同,各自是氢原子、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、C1-5烷氧基-C1-5烷基、C3-8环烷氧基-C1-5烷基或苯基,或者R1和R2与相邻氮原子一起代表下式所示的5到8元饱和杂环基团:(其中B是CH2,NH、N-C1-5烷基、N-C3-8环烷基、N-C1-5烷基-C3-8环烷基、O或S))或式-CO2R3所代表的基团(其中R3是氢原子、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、C1-5烷氧基-C1-5烷基、C3-8环烷氧基-C1-5烷基或苯基),且
式(05) 式(06) 式(07) 式(08)
式(17) 式(18) 式(19) 式(20)其中E是CH或N,
R4是氢原子、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、羟基、C1-5烷氧基、C3-8环烷氧基、或式-N(R10)R11所代表的基团(其中R10和R11可相同或不同,各自是氢原子、C1-5烷基、C3-8环烷基、或C3-8环烷基-C1-5烷基),
R5、R6、R7和R8可相同或不同,各自是氢原子、卤素原子、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、羟基、C1-5烷氧基、C3-8环烷氧基、式-N(R12)R13所代表的基团(其中R12和R13可相同或不同,各自是氢原子、C1-5烷基、C3-8环烷基、或C3-8环烷基-C1-5烷基)、式-CO2R14所代表的基团(其中R14是氢原子、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、C1-5烷氧基-C1-5烷基、C3-8环烷氧基-C1-5烷基或苯基)、氰基、硝基、C1-5烷硫基、三氟甲基或三氟甲氧基,
R9是氢原子、C1-5烷基、C2-5链烯基、C2-5炔基、C3-8环烷基或C3-8环烷基-C1-5烷基,且
Ar是未取代的或者被1-3个相同或不同的选自下列的取代基取代的芳基或杂芳基:卤素原子、C1-5烷基、C1-5烷氧基、C1-5烷硫基、三氟甲基、三氟甲氧基和式-N(R15)R16所代表的基团(其中R15和R16可相同或不同,各自是氢原子或C1-5烷基)。
本说明书中所用术语的含义如下所述。
术语“C1-5烷基”是指具有1-5个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基等。术语“C2-5链烯基”是指具有2-5个碳原子的直链或支链链烯基,例如乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基等。术语“C2-5炔基”是指具有2-5个碳原子的直链或支链炔基,例如乙炔基、2-丙炔基等。术语“C3-8环烷基”是指具有3-8个碳原子的环烷基,例如环丙基、环丁基、环戊基、环己基、环庚基等。术语“C3-8环烷基-C1-5烷基”是指具有上述C3-8环烷基作为取代基的取代的C1-5烷基,例如环丙基甲基、环丙基乙基、环戊基乙基等。
对于B,术语“N-C1-5烷基”是指在氮原子上具有C1-5烷基作为取代基的基团。术语“N-C3-8环烷基”是指在氮原子上具有C3-8环烷基作为取代基的基团。术语“N-C1-5烷基-C3-8环烷基”是指在氮原子上具有C3-8环烷基-C1-5烷基作为取代基的基团。
术语“卤素原子”是指氟原子、氯原子、溴原子或碘原子。术语“C1-5烷氧基”是指具有1-5个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、戊氧基、异戊氧基等。术语“C3-8环烷氧基”是指具有3-8个碳原子的环烷氧基,例如环丙氧基、环丁氧基、环戊氧基等。术语“C1-5烷氧基-C1-5烷基”是指具有C1-5烷氧基作为取代基的取代的C1-5烷基,例如甲氧基甲基、2-乙氧基乙基等。术语“C3-8环烷氧基-C1-5烷基”是指具有C3-8环烷氧基作为取代基的取代的C1-5烷基,例如环丙氧基甲基、2-环丙氧基乙基等。术语“C1-5烷硫基”是指具有1-5个碳原子的直链或支链烷硫基,例如甲硫基、乙硫基、丙硫基等。
术语“芳基”是指苯基、萘基等。术语“杂芳基”是指在其环中具有1-4个可相同或不同的选自氮、氧和硫的原子的杂环基,例如吡啶基、喹啉基、吲哚基、苯并呋喃基、苯并噻二唑基、苯并呋咱基、喹喔啉基等。因此,取代的芳基或杂芳基包括例如2,4,6-三甲基苯基、2,4,6-三溴苯基、2,4-二溴-6-氯苯基、2,4-二氯苯基、2,4,6-三氯苯基、2-甲基-4-甲氧基苯基、2,4-二溴-6-氟苯基、2,4-二溴-6-甲基苯基、2,4-二溴-6-甲氧基苯基、2,4-二溴-6-甲硫基苯基、2,6-二溴-4-异丙基苯基、2,6-二溴-4-三氟甲基苯基、2-氯-4-三氟甲基苯基、2-氯-4-三氟甲氧基苯基、6-二甲基氨基-4-甲基吡啶-3-基、2-氯-6-三氟甲基吡啶-3-基、2-氯-6-三氟甲氧基吡啶-3-基、2-氯-6-甲氧基吡啶-3-基、2-三氟甲基-6-甲氧基吡啶-3-基、2-氯-6-二氟甲基吡啶-3-基、2-甲基-6-甲氧基吡啶-3-基、2,6-二甲氧基吡啶-3-基、5,7-二甲基-2,1,3-苯并噻二唑-4-基、5,7-二甲基苯并呋咱-4-基、6,8-二甲基喹喔啉-5-基、5,7-二氯-2,1,3-苯并噻二唑-4-基、5,7-二氯苯并呋咱-4-基和6,8-二氯喹喔啉-5-基。
本发明中的可药用盐包括例如与无机酸例如硫酸、盐酸、磷酸等形成的盐;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、对甲苯磺酸等形成的盐;和与金属离子例如锂离子、钠离子、钾离子、钙离子、镁离子、锌离子等形成的盐。
本发明化合物的优选实例如下。
即,其中A是式[II]所代表的基团的式[I]化合物是优选的。其中A是式[II]所代表的基团,Y是氨基甲酰基,且n是0或1的式[I]化合物是更优选的。此外,其中Het是式(01)或式(12)所代表的杂环基的式[I]化合物也是优选的。定义如下的式[I]化合物是更优选的:Het是式(01)或式(12)所代表的杂环基,且Ar是具有2或3个取代基的苯基,所述取代基可相同或不同,并选自卤素原子、C1-5烷基、C1-5烷氧基、C1-5烷硫基、三氟甲基和三氟甲氧基。定义如下的式[I]化合物是更优选的:Het是式(01)或式(12)所代表的杂环基,且Ar是具有2或3个相同或不同的选自氯原子、三氟甲基和三氟甲氧基的取代基的苯基。
式[I]化合物可通过例如下述反应方案1-7中所示的任一方法制得(在下述反应方案中,A、Het、R1、R2、R3、R4、R5、R6和R7如上所定义,R17是C1-5烷基或苯基,且X4是氯原子、溴原子、碘原子、甲磺酰氧基、苯磺酰氧基、甲苯磺酰氧基或三氟甲磺酰氧基)。
反应方案1
步骤1:
化合物(2)可通过将化合物(1)的羟基卤化或磺酰化而获得。在此,卤化是指,在有或没有例如N,N-二甲基苯胺或N,N-二乙基苯胺存在下,不用溶剂或者在惰性溶剂例如烃(例如苯和甲苯)或含卤溶剂(例如氯仿和二氯甲烷)中,与卤化剂例如三氯氧化磷、五氯化磷、硫酰氯、亚硫酰氯、亚硫酰溴、草酰氯等的反应。磺酰化是指,在有或没有碱存在下,在惰性溶剂例如醚(例如乙醚、四氢呋喃、1,4-二氧杂环己烷和1,2-二甲氧基乙烷)、烃(例如苯和甲苯)、酰胺(例如N,N-二甲基甲酰胺和N-甲基吡咯烷酮)、乙腈、二甲亚砜、吡啶、或选自这些惰性溶剂的溶剂混合物中,与磺酰化试剂例如甲磺酰氯、对甲苯磺酰氯、三氟甲磺酸酐、N-苯基二(三氟甲磺酰亚胺)等的反应。此处所述的碱包括,例如,有机碱如三乙胺、二异丙基乙基胺、吡啶、1,8-二氮杂二环[5.4.0]-7-十一碳烯等;和无机碱例如氢化钠、氢化钾、碳酸钠、碳酸钾、碳酸氢钠、氨基钠等。
步骤2:
本发明化合物(3)可通过有或没有碱存在下将化合物(2)与化合物(4)在惰性溶剂中反应而制得。此处所述的碱包括,例如,胺如三乙胺、二异丙基乙基胺、吡啶等;无机碱如碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钡、氢化钠等;金属醇化物如甲醇钠、乙醇钠、叔丁醇钾等;氨基金属如氨基钠、二异丙基氨基锂等;和格氏试剂如甲基溴化镁等。惰性溶剂包括,例如,醇如甲醇、乙醇、异丙醇、乙二醇等;醚如乙醚、四氢呋喃、1,4-二氧杂环己烷、1,2-二甲氧基乙烷等;烃如苯、甲苯等;酰胺如N,N-二甲基甲酰胺、N-甲基吡咯烷酮等;乙腈;二甲亚砜;吡啶;水;和选自这些惰性溶剂的溶剂混合物。
本发明化合物(9)可依据下述反应方案2合成。
反应方案2
步骤3:
化合物(6)可通过在有或没有碱存在下将化合物(2)与化合物(5)在惰性溶剂中反应而制得。此处所述的碱包括,例如,胺如三乙胺、二异丙基乙基胺、吡啶等;无机碱如碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钡、氢化钠等;金属醇化物如甲醇钠、乙醇钠、叔丁醇钾等;氨基金属如氨基钠、二异丙基氨基锂等;和格氏试剂如甲基溴化镁等。惰性溶剂包括,例如,醇如甲醇、乙醇、异丙醇、乙二醇等;醚如乙醚、四氢呋喃、1,4-二氧杂环己烷、1,2-二甲氧基乙烷等;烃如苯、甲苯等;酰胺如N,N-二甲基甲酰胺、N-甲基吡咯烷酮等;乙腈;二甲亚砜;吡啶;水;和选自这些惰性溶剂的溶剂的混合物。
步骤4:
可通过在酸性条件下进行常规水解除去化合物(6)的醛缩醇保护基来将化合物(6)转化成化合物(7)(参见Theodora W.Green和PeterG.W.Wtus“Protective Groups in Organic Synthesis”)。
步骤5:
可通过下述方法将化合物(7)转化成化合物(8):在惰性溶剂如醇(例如甲醇、乙醇、异丙醇和乙二醇)、醚(例如乙醚、四氢呋喃、1,4-二氧杂环己烷和1,2-二甲氧基乙烷)、乙腈、乙酸、水、或选自这些惰性溶剂的溶剂混合物中,化合物(7)在氰化剂例如氰化钠、氰化钾、三甲基甲硅烷基氰等存在下反应;然后在有或没有有机碱如吡啶、三乙胺或二异丙基乙基胺存在下,在惰性溶剂如含卤溶剂(例如二氯甲烷和氯仿)、醚(例如乙醚、四氢呋喃、1,4-二氧杂环己烷和1,2-二甲氧基乙烷)、烃(例如苯和甲苯)等中,将所得氰化产物与例如三氯氧磷、亚硫酰氯、甲磺酰氯、对甲苯磺酰氯或三氟乙酸酐反应。
步骤6:
可通过下述方法将化合物(8)转化成本发明化合物(9):在惰性溶剂如含卤溶剂(例如二氯甲烷和氯仿)、醚(例如乙醚、四氢呋喃、1,4-二氧杂环己烷和1,2-二甲氧基乙烷)、烃(例如苯和甲苯)、水或选自这些惰性溶剂的溶剂混合物中,用例如硫酸、盐酸和甲酸(它们单独使用或者两种或更多种组合使用)与化合物(8)的氰基反应。
此外,本发明化合物(10)和化合物(17)可依据下述反应方案3获得。
反应方案3
步骤7:
可通过在碱存在或不存在下,在惰性溶剂中将化合物(7)与化合物(11)或化合物(12)反应来将化合物(7)转化成化合物(13)。在此,所述的碱包括例如氢化钠、氢化钾、甲醇钠、叔丁醇钾、正丁基锂、二(三甲基甲硅烷基)氨基锂、氨基钠和碳酸钾。如果需要的话,可使用18-冠-6醚、15-冠-5醚、四甲基乙二胺、六甲基磷酰胺等作为添加剂。惰性溶剂包括,例如,醚如乙醚、四氢呋喃、1,2-二甲氧基乙烷等;烃如苯、甲苯等;醇如乙醇、甲醇等;酰胺如N,N-二甲基甲酰胺、N-甲基吡咯烷酮等;四甲基脲;二甲亚砜;水;和选自这些惰性溶剂的溶剂的混合物。
步骤8:
当化合物(13)的R不是氢原子时,可通过在酸性或碱性条件下将酯部分常规水解来将化合物(13)转化成化合物(14)(参见Theodora W.Green和Peter G.W.Wtus,“Protective Groups inOrganic Synthesis”)。
步骤9:
本发明化合物(10)可通过将化合物(14)酰胺化来制得。在此,酰胺化是指羧基的一般酰胺化,指任何下述反应:在碱例如N-甲基吗啉、三乙胺等存在下,将化合物(15)与通过化合物(14)与卤代甲酸酯(例如氯甲酸乙酯和氯甲酸异丁酯)或酰卤(例如苯甲酰氯和新戊酰氯)反应而获得的混合酸酐反应;在缩合剂如N,N′-二环己基碳二亚胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC)、羰基二咪唑(CDI)、二苯基磷酰基叠氮(DPPA)、氰基磷酸二乙酯等存在下,以及任选在添加剂例如1-羟基苯并三唑(HOBt)、N-羟基琥珀酰亚胺、4-二甲基氨基吡啶等存在下,将化合物(14)与化合物(15)反应;将化合物(15)与通过化合物(14)与卤化试剂如亚硫酰氯、草酰氯、四溴化碳-三苯基膦等反应而获得的酰卤反应。
步骤10:
可通过在酸或碱存在下在惰性溶剂中使化合物(13)反应来将化合物(13)转化成化合物(16)。在此,所述的酸包括,例如,无机酸如盐酸、氢溴酸、硫酸等;和有机酸例如乙酸、三氟乙酸、对甲苯磺酸等。所述碱包括无机碱如氢氧化钠、氢氧化钾、碳酸钾等。惰性溶剂包括,例如,醚如乙醚、四氢呋喃、1,2-二甲氧基乙烷等;烃如苯、甲苯等;醇如乙醇、甲醇等;酰胺如N,N-二甲基甲酰胺、N-甲基吡咯烷酮等;四甲基脲;二甲亚砜;水;丙酮;和选自这些惰性溶剂的溶剂的混合物。当R3是非氢原子的基团时,使用仅由水构成或由水与一种或多种其它溶剂的混合物构成的反应溶剂,使得能够同时将R3转化成氢原子和将化合物(13)转化成化合物(16)。
步骤11:
当R3是非氢原子的基团时,可通过与步骤8相同的方法将R3转化成氢原子,然后可通过与步骤9相同的反应获得本发明化合物(17)。
化合物(22)、(23)和(24)可依据下述反应方案4获得。
步骤12:
化合物(20)可通过在碱存在下将化合物(18)与化合物(19)在惰性溶剂中反应而获得。在此,所述的惰性溶剂包括,例如,醚如乙醚、四氢呋喃、1,2-二甲氧基乙烷等;烃如苯、甲苯等;醇如乙醇、甲醇等;酰胺如N,N-二甲基甲酰胺、N-甲基吡咯烷酮等;四甲基脲;二甲亚砜;和选自这些惰性溶剂的溶剂的混合物。碱包括,例如,胺如三乙胺、二异丙基乙基胺、吡啶等;无机碱如氢化钠、氢化钾、碳酸钠等;金属醇化物如甲醇钠、乙醇钠、叔丁醇钾等;烷基金属如正丁基锂、叔丁基锂、苯基锂等;和氨基金属如二异丙基氨基锂、二(三甲基甲硅烷基)氨基锂、氨基钠等。
步骤13:
通过例如使用硼氢化钠的氢化物还原和氢化(参见Ahmed F.Abdel-Magid“有机合成中的还原”)将酮部分还原,从而将化合物(20)转化成化合物(21)。
步骤14:
可通过下述方法将化合物(21)转化成化合物(22):在惰性溶剂如含卤溶剂(例如二氯甲烷和氯仿)、醚(例如乙醚、四氢呋喃、1,4-二氧杂环己烷和1,2-二甲氧基乙烷)、烃(例如苯和甲苯)等中,在有或没有有机碱如吡啶、4-二甲基氨基吡啶、三乙胺、二异丙基乙基胺、1,8-二氮杂二环[5.4.0]-7-十一碳烯等存在下,将化合物(21)与例如三氯氧磷、亚硫酰氯、甲磺酰氯、对甲苯磺酰氯或三氟乙酸酐反应,或者将化合物(21)与例如硫酸、三氟乙酸或甲酸在惰性溶剂如含卤溶剂(例如二氯甲烷和氯仿)、醚(例如乙醚、四氢呋喃、1,4-二氧杂环己烷和1,2-二甲氧基乙烷)、烃(例如苯和甲苯)等中反应。
步骤15:
通过按照与步骤8相同的方法将化合物(22)的酯部分转化成羧基,可将化合物(22)转化成本发明化合物(23)。
步骤16:
通过按照与步骤9相同的方法将化合物(23)与化合物(15)反应,可将化合物(23)转化成化合物(24)。
本发明化合物(29)可依据下述反应方案5合成。
反应方案5
步骤17:
化合物(26)可这样获得:按照与步骤1相同的方法将化合物(25)的羟基卤化或磺酰化,然后在有或没有碱存在下将卤化或磺酰化产物与化合物(5)在惰性溶剂中反应。此处,所述的碱包括,例如,有机碱如三乙胺、二异丙基乙基胺、吡啶、1,8-二氮杂二环[5.4.0]-7-十一碳烯等;和无机碱如氢化钠、氢化钾、碳酸钠、碳酸钾、碳酸氢钠、氨基钠等。惰性溶剂包括,例如,醚如乙醚、四氢呋喃、1,4-二氧杂环己烷、1,2-二甲氧基乙烷等;烃如苯、甲苯等;酰胺如N,N-二甲基甲酰胺、N-甲基吡咯烷酮等;乙腈;二甲亚砜;吡啶;和选自这些惰性溶剂的溶剂的混合物。
步骤18:
可通过下述方法将化合物(26)转化成化合物(28):在碱、零价钯络合物(例如四(三苯基膦)钯和四(三丁基膦)钯)或二价钯复合物(例如乙酸钯和氯化钯)以及任选在膦(例如三苯基膦或三丁基膦)存在下,在惰性溶剂中将化合物(26)与芳基硼酸衍生物(27)反应。在此,所述的碱包括,例如,无机碱如碳酸钠、碳酸氢钠、碳酸钾、氢氧化钡、氢氧化钠等;和有机碱如三乙胺、二异丙基乙基胺、吡啶、4-二甲基氨基吡啶等。所述惰性溶剂包括,例如,含卤溶剂例如二氯甲烷、氯仿等;醚如乙醚、四氢呋喃、1,4-二氧杂环己烷、1,2-二甲氧基乙烷等;烃如苯、甲苯等;醇如甲醇、乙醇等;水;和选自这些惰性溶剂的溶剂的混合物。
步骤19、步骤20和步骤21:
本发明化合物(29)可通过按照分别与步骤4、步骤5和步骤6相同的方法进行步骤19、步骤20和步骤21而获得。
本发明化合物(32)可依据下述反应方案6合成。
反应方案6
步骤22:
化合物(31)可这样获得:按照与步骤1相同的方法将化合物(25)的羟基卤化或磺酰化,然后在有或没有碱存在下将卤化或磺酰化产物与化合物(4)在惰性溶剂中反应。此处,所述的碱包括,例如,有机碱如三乙胺、二异丙基乙基胺、吡啶、1,8-二氮杂二环[5.4.0]-7-十一碳烯等;和无机碱如氢化钠、氢化钾、碳酸钠、碳酸钾、碳酸氢钠、氨基钠等。惰性溶剂包括,例如,醚如乙醚、四氢呋喃、1,4-二氧杂环己烷、1,2-二甲氧基乙烷等;烃如苯、甲苯等;酰胺如N,N-二甲基甲酰胺、N-甲基吡咯烷酮等;乙腈;二甲亚砜;吡啶;和选自这些惰性溶剂的溶剂的混合物。
步骤23:
本发明化合物(32)可通过与步骤18相同的方法制得。
本发明化合物(33)、(34)和(35)可通过下述反应方案7合成。
反应方案7
步骤24:
本发明化合物(33)和(34)可通过将酯部分和羧酸部分进行常规保护和脱保护来彼此转化(参见Theodora W.Green和Peter G.W.Wtus“Protective Groups in Organic Synthesis”)。
步骤25:
可通过按照与步骤9相同的方式进行常规酰胺化来将本发明化合物(34)转化成本发明化合物(35)。可通过常规水解将化合物(35)的酰胺部分转化成羧酸来将化合物(35)转化成化合物(34)(参见Theodora W.Green和Peter G.W.Wtus“Protective Groups in OrganicSynthesis”)。
本发明化合物可用作CRF相关疾病的治疗或预防药物。为此,本发明的化合物可采用常规制剂技术,通过加入常规填充剂、粘合剂、崩解剂、pH调节剂、溶剂等,配制成片剂、丸剂、胶囊、颗粒剂、粉末、溶液、乳液、悬浮剂、注射剂等。
本发明化合物可以以每天0.1-500mg的剂量经口服或非胃肠途径、一次性地或分数次对成年患者给药。根据疾病的类型以及患者的年龄、体重和症状,剂量可适当增减。
发明的最佳实施方式
使用下列实施例和试验实施例具体解释本发明,但不限制本发明。
实施例1
8-(2,4-二氯苯基)-4-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2-甲基喹啉的合成(化合物1-01)
将60%氢化钠(油分散体)(79mg)用己烷洗涤后,悬浮于N,N-二甲基甲酰胺(3ml),该悬浮液用冰冷却。一次性往该冷却的悬浮液中加入8-(2,4-二氯苯基)-2-甲基-4-羟基喹啉(500mg)并将所得混合物在冰冷却下搅拌10分钟,然后在室温再搅拌30分钟。往如此获得的溶液中一次加入N-苯基二(三氟甲磺酰亚胺)(703mg),并将所得混合物在室温搅拌30分钟。
往所得反应混合物中加入碳酸氢钠(413mg)和4-氨基甲酰基-1,2,3,6-四氢吡啶盐酸盐(533mg),并将所得混合物在120℃剧烈搅拌1小时。
使如此获得的反应混合物冷却到室温,然后用氯仿和水分离。水层用氯仿萃取,合并的有机层经无水硫酸钠干燥,之后滤除干燥剂,并将滤液减压浓缩。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:氯仿-甲醇=10∶1),然后将如此获得的结晶用甲醇洗涤,再用四氢呋喃洗涤,获得标题化合物(156mg)。
m.p.263.5-265.5℃。
表1、表2、表7、表17和表18列出了实施例1获得的化合物以及采用与实施例1相同的方法获得的化合物。
实施例2
8-(2,4-二氯苯基)-4-(5-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2-甲基喹啉的合成(化合物1-15)
(1)在三氯氧化磷(5ml)中,将8-(2,4-二氯苯基)-2-甲基-4-羟基喹啉(2.0mg)加热回流1小时。使该反应混合物冷却到室温并小心地倾入冰水中,并用饱和碳酸氢钠溶液和乙酸乙酯分离该所得混合物。有机层经无水硫酸钠干燥,之后滤除干燥剂并减压浓缩滤液,得到固体(2.1g)。
(2)使(1)中获得的固体(200mg)、5-氨基甲酰基-1,2,3,6-四氢吡啶盐酸盐(121mg)、二异丙基乙基胺(240mg)和乙醇(1ml)-水(0.075ml)的混合物在密封试管中于80℃反应10天。使该反应混合物冷却到室温,倾入饱和碳酸氢钠水溶液,然后用氯仿萃取三次。合并的有机层经无水硫酸钠干燥,之后滤除干燥剂并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:氯仿-甲醇=10∶1),然后将如此获得的结晶用乙酸乙酯洗涤,获得标题化合物(159mg)。
m.p.230.0-232.0℃。
表1、表2、表3-11、表13、表16、表19和表20列出了实施例2获得的化合物以及采用与实施例2相同的方法获得的化合物。
实施例3
8-(2,4-二氯苯基)-4-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2-甲基喹啉的合成(化合物1-01)
(1)在N,N-二甲基甲酰胺(50ml)中,将采用与实施例2(1)相同的方法获得的4-氯-8-(2,4-二氯苯基)-2-甲基喹啉(3.3g)和4-哌啶酮缩乙二醇(7.5g)在120℃搅拌2小时,然后在150℃搅拌2小时,并将所得混合物加热回流3.5小时。减压蒸除溶剂,之后往残余物中加入水和饱和碳酸氢钠水溶液并过滤收集沉淀的固体。所得固体经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:氯仿-甲醇=10∶1),获得8-(2,4-二氯苯基)-4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-2-甲基喹啉(3.2g)。
m.p.179.5-181.5℃。
(2)在1M盐酸(30ml)和四氢呋喃(15ml)中,将8-(2,4-二氯苯基)-4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-2-甲基喹啉(3.2g)在室温搅拌2小时,然后在70℃搅拌5.5小时。减压蒸除四氢呋喃,在冰冷却下用41%氢氧化钠水溶液使残余物呈碱性并用乙酸乙酯萃取三次。合并的有机层经无水硫酸钠干燥,之后滤除干燥剂并减压浓缩滤液。
将所得残余物溶于(12.5ml)-氯仿(6ml),并往其中加入氰化钾(5.4g)。在冰冷却下,在10分钟内往如此获得的混合物中加入乙酸(4.4ml),并将所得混合物在室温搅拌6小时。用乙酸乙酯和饱和碳酸氢钠水溶液分离该反应混合物,有机层经无水硫酸钠干燥,之后滤除干燥剂并减压浓缩滤液。
将所得残余物溶于吡啶(15ml),并在冰冷却下往其中加入三氯氧化磷(7.5ml)。将该反应混合物在室温搅拌24小时后,小心地倾入冰水中。如此获得的反应混合物用氯仿和甲醇的混合溶剂萃取三次,合并的有机层经无水硫酸钠干燥,之后滤除干燥剂并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:己烷-乙酸乙酯=5∶1),然后在二异丙基醚中结晶,获得8-(2,4-二氯苯基)-2-甲基-4-(4-氰基-1,2,3,6-四氢吡啶-1-基)喹啉(1.0g)。
m.p.177.5-179.5℃。
(3)在96%甲酸(5ml)中溶解8-(2,4-二氯苯基)-2-甲基-4-(4-氰基-1,2,3,6-四氢吡啶-1-基)喹啉(1.0g),并在冰冷却下往该溶液中通入氯化氢气,使该溶液饱和。将该反应混合物在室温搅拌4小时后,减压蒸馏除去溶剂。用氯仿和饱和碳酸氢钠水溶液分离该残余物,有机层经无水硫酸钠干燥。滤除干燥剂并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:氯仿-甲醇=10∶1),然后在四氢呋喃中重结晶,获得标题化合物(174mg)。
m.p.263.5-265.5℃。
表1和表14列出了实施例3获得的化合物以及采用与实施例3相同的方法获得的化合物。
实施例4
4-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-1-(2,4-二氯苯基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(化合物12-01)
(1)将60%氢化钠(油分散体)(0.97g)用己烷洗涤后,悬浮于N,N-二甲基甲酰胺(10ml),往其中滴加1-(2,4-二氯苯基)-4-羟基-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(6.50g)的N,N-二甲基甲酰胺(90ml)溶液。将所得混合物在40℃搅拌30分钟,然后往其中一次加入N-苯基二(三氟甲磺酰亚胺)(8.65g),然后在室温搅拌30分钟。往如此获得的溶液中加入4-哌啶酮缩乙二醇(16.4g),使反应在90℃进行2小时,在100℃进行1.5小时,然后在120℃进行2.5小时。待反应混合物冷却到室温后,往其中倾入饱和氯化铵溶液,然后用乙酸乙酯萃取,有机层经无水硫酸钠干燥。滤除干燥剂,之后减压浓缩滤液,残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:己烷-乙酸乙酯=3∶1),获得1-(2,4-二氯苯基)-4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(5.23g)。
(2)将1-(2,4-二氯苯基)-4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(5.21g)在4M盐酸(60ml)和四氢呋喃(60ml)的混合液中在室温搅拌2.5小时后,往其中加入6M盐酸(30ml)并将所得混合物搅拌过夜。待反应完全后,将反应混合物倾入饱和碳酸氢钠水溶液并用乙酸乙酯萃取三次。合并的有机层经无水硫酸钠干燥,之后滤除干燥剂并减压浓缩滤液。如此获得的结晶用乙酸乙酯洗涤,得到1-(2,4-二氯苯基)-4-(4-氧代哌啶-1-基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(3.83g)。
(3)在乙醇(10ml)-氯仿(4ml)中溶解1-(2,4-二氯苯基)-4-(4-氧代哌啶-1-基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(0.55g),并往其中加入氰化钾(0.91g)。在冰冷却下,15分钟内往该所得混合物中加入乙酸(0.75ml),然后在室温搅拌2小时。用乙酸乙酯和饱和碳酸氢钠水溶液分离该反应混合物,有机层经无水硫酸钠干燥,之后滤除干燥剂并减压浓缩滤液。
将所得残余物溶于吡啶(6.4ml),并在冰冷却下,往其中加入三氯氧化磷(1.3ml)。将反应混合物在室温搅拌1小时后,在60℃搅拌1小时。将该反应混合物小心地倾入冰水中并用乙酸乙酯萃取三次。合并的有机层经无水硫酸钠干燥并滤除干燥剂,减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:己烷-乙酸乙酯=4∶1),获得4-(4-氰基-1,2,3,6-四氢吡啶-1-基)-1-(2,4-二氯苯基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(0.33g)。
(4)在二氯甲烷(2.0ml)中溶解4-(4-氰基-1,2,3,6-四氢吡啶-1-基)-1-(2,4-二氯苯基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(0.19g),然后在冰冷却下,往其中加入浓硫酸(0.5ml),并将所得化合物缓慢加热至室温后,搅拌过夜。用乙酸乙酯和饱和碳酸氢钠水溶液分离该反应混合物,水层用乙酸乙酯萃取两次。合并的有机层经无水硫酸钠干燥并滤除干燥剂,之后减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:氯仿-甲醇=30∶1),沉淀的结晶用乙酸乙酯洗涤,获得标题化合物(0.10g)。
m.p.265.0-167.0℃。
表11和表12列出了实施例4获得的化合物和采用与实施例4相同的方法获得的化合物。
实施例5
4-(5-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-1-(2,4-二氯苯基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(化合物12-09)的合成
(1)将60%氢化钠(油分散体)(79mg)和少量35%氢化钾(油分散体)用己烷洗涤,往其中加入四氢呋喃(2.0ml)和碳酸二乙酯(0.21g)并将所得混合物在80℃加热。然后,用10分钟往其中滴加采用与实施例4相同的方法合成的1-(2,4-二氯苯基)-4-(4-氧代哌啶-1-基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(0.29g)的四氢呋喃(2.0ml)溶液,并将所得混合物加热回流1.5小时。待反应混合物冷却至室温后,将饱和氯化铵水溶液倾入该反应混合物中,然后用乙酸乙酯萃取三次。合并的有机层经无水硫酸钠干燥。滤除干燥剂并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:己烷-乙酸乙酯=4∶1),获得1-(2,4-二氯苯基)-4-(3-乙氧羰基-4-氧代哌啶-1-基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(0.14g)。
(2)在乙醇(3.0ml)中溶解1-(2,4-二氯苯基)-4-(3-乙氧羰基-4-氧代哌啶-1-基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(0.13g),并将该溶液冷却至-15℃。然后,往其中加入硼氢化钠并将所得混合物搅拌过夜,这期间使其缓慢地加热至0℃。将饱和氯化铵水溶液倾入该反应混合物中,用乙酸乙酯萃取三次。合并的有机层经无水硫酸钠干燥。滤除干燥剂并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:氯仿-甲醇=50∶1),获得1-(2,4-二氯苯基)-4-(3-乙氧羰基-4-羟基-哌啶-1-基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(35mg)。
(3)在二氯甲烷(1.5mL)中溶解1-(2,4-二氯苯基)-4-(3-乙氧羰基-4-羟基哌啶-1-基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(53mg)、三乙胺(34mg)和少量4-二甲氨基吡啶。往其中加入甲磺酰氯(25mg)并将所得混合物在室温搅拌2小时。将饱和碳酸氢钠水溶液倾入该反应混合物中,然后用氯仿萃取三次。合并的有机层经无水硫酸钠干燥。滤除干燥剂并减压浓缩滤液。将残余物溶于苯(1.0ml),然后往其中加入1,8-二氮杂双环[5.4.0]-7-十一碳烯(17mg),并将所得混合物加热回流1小时。将饱和氯化铵水溶液倾入该反应混合物中,然后用乙酸乙酯萃取三次。合并的有机层经无水硫酸钠干燥剂,之后滤除干燥剂并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:WakoGel(C200),洗脱剂:己烷-乙酸乙酯=5∶1),获得4-(5-乙氧羰基-1,2,3,6-四氢吡啶-1-基)-1-(2,4-二氯苯基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(27mg)。
(4)在乙醇(1.0ml)中溶解4-(5-乙氧羰基-1,2,3,6-四氢吡啶-1-基)-1-(2,4-二氯苯基)-2,3,6-三甲基-1H-吡咯并[2,3-b]吡啶(27mg),然后往其中加入1M氢氧化钠水溶液(1.0ml),并将所得混合物在室温搅拌8.5小时。将饱和氯化铵水溶液倾入该反应混合物中,然后用氯仿萃取三次。合并的有机层经无水硫酸钠干燥。滤除干燥剂并减压浓缩滤液。
将所得残余物悬浮于N,N-二甲基甲酰胺(0.8ml)和氯仿(0.2ml)的混合溶剂中,并往其中加入1-羟基苯并三唑一水合物(18mg)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(23mg)。所得混合物在室温搅拌40分钟后,往其中加入数滴28%氨水溶液,并将如此获得的混合物在室温搅拌1.5小时。将饱和碳酸氢钠水溶液倾入该反应混合物中,然后用乙酸乙酯萃取三次。合并的有机层经无水硫酸钠干燥。滤除干燥剂并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:己烷-乙酸乙酯=1∶2),在二异丙基醚和乙酸乙酯的混合溶剂中结晶,得到标题化合物(6.0mg)。
表12列出了实施例5获得的化合物。
实施例6
5-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2-(N-乙基-2,4-二氯苯氨基)-4-甲基噻唑(化合物15-01)的合成
(1)将2-(N-乙基-2,4-二氯苯氨基)-4-甲基噻唑盐酸盐(6.0g)和碳酸钙(4.6g)悬浮于氯仿(90ml)和甲醇(36ml)的混合溶剂中后,少量多次地往其中加入苄基-三甲基三溴化铵(7.2g)。滤除反应混合物中的固体并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:己烷-乙酸乙酯=9∶1),获得5-溴-2-(N-乙基-2,4-二氯苯氨基)-4-甲基噻唑(4.5g)。
(2)使5-溴-2-(N-乙基-2,4-二氯苯氨基)-4-甲基噻唑(0.20g)、5-氨基甲酰基-1,2,3,6-四氢吡啶盐酸盐(178mg)、碳酸氢钠(94mg)和乙醇(1.5ml)的混合物在密封试管中于120℃反应3天。用水和氯仿分离反应混合物,水层用氯仿萃取,之后合并的有机层经无水硫酸钠干燥。滤除干燥剂并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:氯仿-甲醇=20∶1),然后在二异丙基醚中结晶,获得标题化合物(34mg)。
m.p.148.0-150.0℃。
表15列出了实施例6中获得的化合物。
实施例7
2-{1-[8-(2,4-二氯苯基)-2-甲基喹啉-4-基]-哌啶-4-亚基}-乙酰胺(化合物1-22)和2-{1-[8-(2,4-二氯苯基)-2-甲基喹啉-4-基]-1,2,3,6-四氢吡啶-4-基}-乙酰胺(化合物1-05)的合成
(1)在1M盐酸(26ml)和四氢呋喃(13ml)的混合液中,将采用与实施例3(1)的相同方法获得的8-(2,4-二氯苯基)-4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-2-甲基喹啉(2.6g)在室温搅拌2小时,然后在70℃搅拌5.5小时。减压蒸除四氢呋喃,在冰冷却下,用41%氢氧化钠水溶液使残余物呈碱性并用乙酸乙酯萃取三次。合并的有机层经无水硫酸钠干燥,滤除干燥剂并减压浓缩滤液。
将所得残余物溶于四氢呋喃(10ml),在冰冷却下用20分钟将所得溶液滴加到Horner-Emmons试剂的溶液中,该溶液预先从二乙基膦酰乙酸乙酯(2.05g)和60%氢化钠(油分散体)(293mg)在四氢呋喃(10ml)中制备。移走冰浴,将反应混合物在室温搅拌30分钟,用饱和氯化铵水溶液处理,然后用乙酸乙酯萃取两次。合并的有机层经无水硫酸钠干燥,滤除干燥剂后并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:己烷-乙酸乙酯=9∶1),然后在二异丙基醚中结晶,获得8-(2,4-二氯苯基)-2-甲基-4-(4-乙氧羰基-亚甲基哌啶-1-基)喹啉(2.4g)。
(2)在85%氢氧化钾(1.3g)和水(1.4ml)-乙醇(8ml)的混合溶剂中,将8-(2,4-二氯苯基)-2-甲基-4-(4-乙氧羰基-亚甲基哌啶-1-基)喹啉(2.3g)在80℃搅拌1小时。在冰冷却下,该反应混合物用3M盐酸中和并在冰冷却下搅拌2小时,然后在室温搅拌30分钟。过滤收集沉淀的固体,获得2-{1-[8-(2,4-二氯苯基)-2-甲基喹啉-4-基]-哌啶-4-亚基}-乙酸和2-{1-[8-(2,4-二氯苯基)-2-甲基喹啉-4-基]-1,2,3,6-四氢吡啶-4-基}-乙酸的混合物(1.5g)。
(3)将2-{1-[8-(2,4-二氯苯基)-2-甲基喹啉-4-基]-哌啶-4-亚基}-乙酸和2-{1-[8-(2,4-二氯苯基)-2-甲基喹啉-4-基]-1,2,3,6-四氢吡啶-4-基}-乙酸的混合物(400mg)、1-羟基苯并三唑一水合物(215mg)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(215mg)在N,N-二甲基甲酰胺(2ml)中、在室温搅拌20分钟。然后往其中加入28%氨水溶液(0.075ml)并将所得混合物在室温搅拌3天。用氯仿和水分离反应混合物,有机层经无水硫酸钠干燥。滤除干燥剂并减压浓缩滤液。分离残余物,并经两次硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:氯仿-乙醇=50∶1),之后使纯化的产物分别在乙醚和二异丙基醚中结晶,分别获得标题化合物1-22(109mg)和标题化合物1-05(43mg)。
化合物1-22:m.p.225.0-227.0℃。
化合物1-05:m.p.160.0-162.0℃。
表1和表16列出了实施例7的化合物和采用与实施例7的相同方法获得的化合物。
实施例8
8-(2,4-二氯苯基)-4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-2-甲基喹啉的合成
(1)将60%氢化钠(油分散体)(1.68g)用己烷洗涤后,悬浮于N,N-二甲基甲酰胺(20ml)中。在室温下,用10分钟往所得的悬浮液中加入8-溴-4-羟基-2-甲基喹啉(10.0g)在N,N-二甲基甲酰胺(35ml)中的溶液,然后在室温搅拌30分钟。往所得溶液中一次加入N-苯基二(三氟甲磺酰亚胺)(15.0g),然后在室温搅拌1小时。
往所得反应混合物中加入4-哌啶酮缩乙二醇(11.0g),并将所得混合物在室温搅拌24小时,然后在60℃加热回流4小时,然后2.5小时。往其中加入4-哌啶酮缩乙二醇(5.5g)后,将如此获得的混合物加热回流3小时。使反应混合物冷却到室温,倾入水(200ml)中,然后搅拌24小时。过滤收集沉淀的固体,并经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:己烷-乙酸乙酯=5∶1-3∶1),获得8-溴-4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-2-甲基喹啉(10.3g),m.p.156.0-158.0℃。
(2)在氮气氛下,将8-溴-4-(1,4-二氧杂-8-氮杂螺[4.5]癸-8-基)-2-甲基喹啉(10.2g)、2,4-二氯苯基硼酸(6.0g)和碳酸钠(8.93g)悬浮于脱气的水(24ml)、甲苯(12ml)和乙醇(12ml)的混合溶剂中,然后往其中加入四(三苯基膦)钯(1.6g),并将所得混合物加热回流16小时。使反应混合物冷却到室温并用乙酸乙酯和饱和氯化铵水溶液分离。水相用乙酸乙酯萃取,合并的有机相经无水硫酸钠干燥。滤除干燥剂,之后减压浓缩滤液,所得残余物在二异丙基醚中结晶。过滤收集结晶,并用少量二异丙基醚洗涤,得到标题化合物(10.5g)。
m.p.179.5-181.5℃
实施例9
8-(2,4-二氯苯基)-4-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2-甲基喹啉(化合物1-01)的合成
(1)用己烷洗涤后,将60%氢化钠(油分散体)(1.0g)悬浮于N-甲基吡咯烷酮(40ml)中。在室温下往该悬浮液中一次加入8-溴-4-羟基-2-甲基喹啉(5.0g),然后在室温搅拌1小时。往所得溶液中一次加入N-苯基二(三氟甲磺酰亚胺)(15.0g),然后在室温搅拌1小时。
往所得反应混合物中加入碳酸氢钠(5.3g)和4-氨基甲酰基-1,2,3,6-四氢吡啶盐酸盐(6.8g),并将所得混合物在130℃搅拌30分钟。该反应混合物冷却到室温后,往其中加入水(100ml),然后在室温搅拌2小时。过滤收集沉淀的固体,然后用水洗涤,得到8-溴-4-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2-甲基喹啉(4.8g)。
m.p.225.0-227.0℃。
(2)在氮气氛下,将8-溴-2-甲基-4-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)喹啉(4.7g)、2,4-二氯苯基硼酸(2.9g)和碳酸钠(4.5g)悬浮于脱气水(14ml)、甲苯(7ml)和乙醇(7ml)的混合溶剂中,然后往其中加入四(三苯基膦)钯(0.81g),并将该所得混合物加热回流5小时。使反应混合物冷却到室温,然后在室温搅拌3小时。过滤收集沉淀的固体并用水-乙醇(2∶1)的混合溶剂(30ml)洗涤,然后用乙醇(30ml)洗涤,获得标题化合物(4.7g)。
表1列出了实施例9的化合物。
实施例10
8-(2,4-二氯苯基)-4-(4-异丙氧羰基-1,2,3,6-四氢吡啶-1-基)-2-甲基喹啉(化合物1-14)的合成
(1)用己烷洗涤后,将60%氢化钠(油分散体)(1.0g)悬浮于N-甲基吡咯烷酮(30ml)中。在室温下往该悬浮液中一次加入8-溴-4-羟基-2-甲基喹啉(5.0g),然后在室温搅拌1小时。立即往所得溶液中加入N-苯基二(三氟甲磺酰亚胺)(9.0g),然后在室温搅拌1小时。
往所得反应混合物中加入4-异丙氧羰基-1,2,3,6-四氢吡啶(8.5g),并将所得混合物在室温搅拌过夜。将该反应混合物倾入水和乙酸乙酯中进行分离。水相用乙酸乙酯萃取,合并的有机相经无水硫酸钠干燥。过滤除去干燥剂并减压浓缩滤液。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:己烷-乙酸乙酯=9∶1),并且如此获得的固体用二异丙基醚和己烷洗涤,获得8-溴-4-(4-异丙氧羰基-1,2,3,6-四氢吡啶-1-基)-2-甲基喹啉(6.0g)。
m.p.130.0-131.0℃。
(2)在氮气氛下,将8-溴-4-(4-异丙氧羰基-1,2,3,6-四氢吡啶-1-基)-2-甲基喹啉(5.9g)、2,4-二氯苯基硼酸(3.2g)和碳酸钠(4.8g)悬浮于脱气水(15ml)、甲苯(7.5ml)和乙醇(7.5ml)的混合溶剂中,然后往其中加入四(三苯基膦)钯(0.88g),并将该所得混合物加热回流5小时。使反应混合物冷却到室温进行分离。水相用乙酸乙酯萃取,合并的有机相经无水硫酸钠干燥。滤除干燥剂并减压浓缩滤液,所得残余物在二异丙基醚中结晶。过滤收集所得固体并用少量二异丙基醚洗涤,得到标题化合物(5.3g)。
m.p.131.0-133.0℃。
表1列出了实施例10的化合物。
实施例11
8-(2,4-二氯苯基)-4-(4-羧基-1,2,3,6-四氢吡啶-1-基)-2-甲基喹啉(化合物1-11)的合成
在浓盐酸(10ml)中悬浮8-(2,4-二氯苯基)-4-(4-氨基甲酰基-1,2,3,6-四氢吡啶-1-基)-2-甲基喹啉(0.10g),并将该悬浮液加热回流1小时。将反应混合物减压浓缩后,往其中加入28%氨水(2ml),然后减压浓缩。残余物经硅胶柱色谱纯化(硅胶:Wako Gel(C200),洗脱剂:氯仿-甲醇=20∶1-10∶1),沉淀的固体用乙酸乙酯洗涤,得到标题化合物(74mg)。
m.p.218.0-220.0℃。
表1列出了实施例11中制备的化合物。表1*1 表1*1(续) 表1*1(续) 表1*1(续) 表2*1 表3*1 表4*1 表5*1 表6*1 表7*1 表8*1 表9*1 表10*1 表11*1 表12*1 表12(续)*1:Com.No.=化合物号,Ex.No.=实施例号,结晶溶剂;
AcOEt=乙酸乙酯,IPE=二异丙基醚*2:1H NMR(200MHz,CDCl3);δ2.06(3H,s),2.40(3H,s),2.45(3H,br.s),2.48-2.60(2H,m),
3.21-3.43(2H,m),3.86-3.96(2H,m),6.54(1H,s),6.70-6.77(1H,m),7.29(1H,d,J=8.5Hz),
-续-表16(续)*1:Com.No.=化合物号,Ex.No.=实施例号,结晶溶剂;
AcOEt=乙酸乙酯,Et2O=乙醚,IPE=二异丙基醚*2:1H NMR(200MHz,CDCl3);δ1.20(3H,t,J=7.0Hz),1.29(6H,d,J=6.8Hz),2.12-2.34(2H,m),2.20(3H,s),2.36(3H,s),2.80-3.04(3H,m),3.30-4.39(6H,m),3.69(3H,s),5.70(1H,s),5.81(1H,s),6.95-7.18(3H,m).MS(ES,Pos);455(M+1)+*3:1H NMR(200MHz,CDCl3);δ1.02-1.38(12H,m),2.03-2.43(2H,m),2.21(3H,s),2.37(3H,s),2.72-3.08(3H,m),3.17-4.35(6H,m),4.15(2H,q,J=7.0Hz),5.69(1H,s),5.81(1H,s),6.94-7.17(3H,m).MS(ES,Pos);469(M+1)+*4:1H NMR(200MHz,CDCl3);δ0.03-0.48(4H,m),1.04-1.39(10H,m),2.08-2.34(2H,m),2.19(3H,s),2.33(3H,s),2.80-3.07(3H,m),3.15-3.74(5H,m),4.02-4.33(1H,m),4.15(2H,q,J=7.0Hz),5.69(1H,s),5.80(1H,s),6.96-7.22(3H,m).MS(SIMS,Pos);495(M+1)+*5:1H NMR(200MHz,CDCl3);δ1.20-1.35(9H,m),2.10-2.33(2H,m),2.19(3H,s),2.36(3H,s),2.78-3.06(3H,m),3.30-3.74(4H,m),3.90-4.30(1H,m),4.15(2H,q,J=7.0Hz),4.65-5.20(3H,m),5.70(1H,s),5.82(1H,s),5.92-6.20(1H,m),6.94-7.17(3H,m).MS(SIMS,Pos);481(M+1)+*6:1H NMR(200MHz,CDCl3);δ1.19-1.36(9H,m),2.08-2.38(3H,m),2.22(3H,s),2.38(3H,s),2.80-3.05(3H,m),3.35-3.77(4H,m),4.00-4.30(1H,m),4.16(2H,q,J=7.0Hz),5.00-5.37(1H,m),5.71(1H,s),5.87(1H,s),6.98-7.33(3H,m).MS(SIMS,Pos);479(M+1)+ *7:1H NMR(200MHz,CDCl3):δ1.13-1.38(12H,m),1.87(3H,s),2.18(3H,s),2.26-2.77(4H,m)2.36(3H,s),2.95(1H,sept,J=7.0Hz),3.33-4.32(6H,m),4.19(2H,q,J=7.0Hz),5.74(1H,s)6.96-7.17(3H,m).MS(ES,Pos);483(M+1)+*8:1H NMR(200MHz,CDCl3);δ1.21(3H,t,J=7.0Hz),1.28(6H,d,J=7.0Hz),2.04-2.41(2H,m),2.21(3H,s),2.36(3H,s),2.80-3.06(3H,m),3.23-4.39(6H,m),5.60(1H,s),5.81(1H,s),6.01(1H br.s),6.93-7.15(3H,m).MS(FAB,Pos);441(M+1)+*9:1H NMR(200MHz,CDCl3);δ1.21(3H,t,J=7.0Hz),1.29(6H,d,J=7.0Hz),2.10-2.35(2H,m),2.23(3H,s),2.37(3H,s),2.41-2.59(2H,m),2.94(1H,sept,J=7.0Hz),3.31-4.38(6H,m),5.14(1H,s),5.83(1H,s),6.98-7.18(3H,m).MS(ES,Pos);422(M+1)+*10:1H NMR(200MHz,CDCl3);δ1.20(3H,t,J=7.0Hz),1.27(6H,d,J=7.0Hz),2.00-2.32(2H,m),2.19(3H,s),2.35(3H,s),2.80-3.05(3H,m),3.36-4.38(6H,m),5.36-5.71(3H,m),5.73(1H,s),6.96-7.18(3H,m).MS(FAB,Pos);440(M+1)+*11:1H NMR(200MHz,CDCl3);δ1.20(3H,t,J=7.0Hz),1.27(6H,d,J=7.0Hz),2.06-2.32(2H,m),2.19(3H,s),2.35(3H,s),2.72-3.06(3H,m),2.81(3H,d,J=5.0Hz),3.23-4.35(6H,m),5.35-5.60(1H,m),5.55(1H,s),5.80(1H,s),6.92-7.16(3H,m).MS(FAB,Pos);454(M+1)+*12:1H NMR(200MHz,CDCl3);δ1.20(3H,t,J=7.0Hz),1.26(6H,d,J=7.0Hz),2.06-2.30(2H,m),2.20(3H,s),2.36(3H,s),2.46-2.61(2H,m),2.80-3.10(1H,m),2.97(3H,s),3.01(3H,s),3.31-4.39(6H,m),5.80(1H,s),6.94-7.17(3H,m). MS(FAB,Pos);468(M+1)+*13:HCl salt,1H NMR(200MHz,CDCl3);δ1.03-1.53(9H,m),1.60-4.88(14H,m),2.41(3H,s),4.45(2H,d,J=5.0Hz),5.56-6.62(3H,m),6.84-7.59(8H,m),13.37(1H,br s).MS(FAB,Pos);530(M+1)+*14:1H NMR(200MHz,CDCl3);δ1.20(3H,t,J=7.0Hz),1.28(6H,d,J=7.0Hz),1.75-2.03(4H,m),2.09-2.32(2H,s),2.20(3H,s),2.35(3H,s),2.70-2.90(2H,m),2.95(1H,sept,J=7.0Hz),3.33-4.33(10H,m),5.81(1H,s),5.83(1H,s),6.96-7.15(3H,m).MS(FAB,Pos);494(M+1)+*15:1H NMR(200MHz,CDCl3);δ1.20(3H,t,J=7.0Hz),1.27(6H,d,J=7.0Hz),2.10-2.30(2H,m),2.20(3H,s),2.36(3H,s),2.41-2.60(2H,m),2.96(1H,sept,J=7.0Hz),3.27-4.40(14H,m),5.81(1H,s),6.95-7.16(3H,m).MS(FAB,Pos);510(M+1)+表17*1 表18*1 表19*1 表20*1 试验实施例[CRF受体结合试验]
使用大鼠额皮质膜或猴子扁桃体膜作为受体制品。
使用125I-CRF作为125I-标记的配体。
按照The Journal of Neuroscience,7,88(1987)中描述的方法,使用125I-标记的配体进行结合反应。受体膜的制备:
将大鼠额皮质或猴子扁桃体在含有10mM MgCl2和2mMEDTA的50mM Tris-HCl缓冲液(pH7.0)中匀化,并在48,000×g下离心,沉淀用Tris-HCl缓冲液洗涤一次。将洗涤过的沉淀悬浮于含有10mM MgCl2、2mM EDTA、0.1%牛血清白蛋白和100激肽释放酶单位/ml抑肽酶的50mM Tris-HCl缓冲液(pH7.0)中,获得膜制品。CRF受体结合试验:
使该膜制品(0.3mg蛋白/ml)、125I-CRF(0.2nM)和试验药物在25℃反应2小时。反应结束后,将反应混合物吸滤过用0.3%聚乙烯-亚胺处理过的玻璃漏斗(GF/C),并将该玻璃漏斗用含0.01%Triton X-100的磷酸缓冲盐溶液洗涤三次。洗涤后,在γ-计数器中测定滤纸的放射性。
以在1μM CRF存在下进行反应时结合的125I-CRF的量作为125I-CRF的非特异性结合度,以125I-CRF的总结合度与125I-CRF的非特异性结合度之间的差作为125I-CRF的特异性结合度。在上述条件下,通过将确定浓度(0.2nM)的125I-CRF与不同浓度的各种试验药物进行反应获得抑制曲线。根据该抑制曲线,确定125I-CRF的结合被抑制50%的试验药物的浓度(IC50)。
结果发现,例如化合物1-01,1-02,1-05,1-06,1-07,1-09,1-10,1-12,1-15,1-16,12-01至12-09,16-05,16-06和16-12作为代表性化合物,它们的IC50为500nM或更低。
工业实用性
本发明提供了对CRF受体具有高度亲和力的化合物。这些化合物可有效对抗被认为与CRF有关的疾病,例如抑郁症、焦虑症、阿尔茨海默氏病、帕金森氏病、杭廷顿氏舞蹈病、饮食障碍、高血压、胃肠病、药物依赖、癫痫、脑梗塞、脑缺血、脑水肿、头部外伤、炎症、免疫相关性疾病、脱发等。
Claims (13)
1.式[I]所代表的四氢吡啶基或哌啶基杂环衍生物或者其可药用盐或其水合物:
A-Het [I]其中A是下式[II]或[III]所代表的基团:其中式[II]所代表的基团中Y-(CH2)n-基团的取代位置是4-位或5-位,式[III]所代表的基团中Y-C(R0)=基团的取代位置是3-位或4-位,
R0是氢原子、C1-5烷基、C3-8环烷基或C3-8环烷基-C1-5烷基,
n是0-5的整数,且
Y是氰基、式-CONR1(R2)所代表的基团(其中R1和R2可相同或不同,各自是氢原子、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、C1-5烷氧基-C1-5烷基、C3-8环烷氧基-C1-5烷基或苯基,或者R1和R2与相邻氮原子一起代表下式所示基团代表的5到8元饱和杂环:(其中B是CH2,NH、N-C1-5烷基、N-C3-8环烷基、N-C1-5烷基-C3-8环烷基、O或S))或式-CO2R3所代表的基团(其中R3是氢原子、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、C1-5烷氧基-C1-5烷基、C3-8环烷氧基-C1-5烷基或苯基),且
Het是下式(01)-式(20)所代表的杂环基团:式(01) 式(02) 式(03) 式(04)式(05) 式(06) 式(07) 式(08)式(09) 式(10) 式(11) 式(12)式(13) 式(14) 式(15) 式(16)式(17) 式(18) 式(19) 式(20)其中E是CH或N,
R4是氢原子、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、羟基、C1-5烷氧基、C3-8环烷氧基、或式-N(R10)R11所代表的基团(其中R10和R11可相同或不同,各自是氢原子、C1-5烷基、C3-8环烷基、或C3-8环烷基-C1-5烷基),
R5、R6、R7和R8可相同或不同,各自是氢原子、卤素原子、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、羟基、C1-5烷氧基、C3-8环烷氧基、式-N(R12)R13所代表的基团(其中R12和R13可相同或不同,各自是氢原子、C1-5烷基、C3-8环烷基、或C3-8环烷基-C1-5烷基)、式-CO2R14所代表的基团(其中R14是氢原子、C1-5烷基、C3-8环烷基、C3-8环烷基-C1-5烷基、C1-5烷氧基-C1-5烷基、C3-8环烷氧基-C1-5烷基或苯基)、氰基、硝基、C1-5烷硫基、三氟甲基或三氟甲氧基,
R9是氢原子、C1-5烷基、C2-5链烯基、C2-5炔基、C3-8环烷基或C3-8环烷基-C1-5烷基,且
Ar是未取代或者被1-3个相同或不同的选自下列的取代基取代的芳基或杂芳基:卤素原子、C1-5烷基、C1-5烷氧基、C1-5烷硫基、三氟甲基、三氟甲氧基和式-N(R15)R16所代表的基团(其中R15和R16相同或不同,各自是氢原子或C1-5烷基)。
4.根据权利要求3的四氢吡啶基杂环衍生物或者其可药用盐或其水合物,其中式[V]中的m是0。
6.根据权利要求5的四氢吡啶基杂环衍生物或者其可药用盐或其水合物,它是式[VII]所代表的化合物:
其中R18、R19和R20如上所定义;X8和X9可以相同或不同,各自是氯原子、三氟甲基或三氟甲氧基。
7.根据权利要求6的四氢吡啶基杂环衍生物或者其可药用盐或其水合物,它是式[VIII]所代表的化合物:
其中X9如上所定义;并且R21是氢原子、氯原子或甲基。
9.根据权利要求8的四氢吡啶基杂环衍生物或者其可药用盐或其水合物,其中式[IX]中的m是0。
12.一种CRF受体拮抗剂,其包含权利要求1-11任一项的四氢吡啶基杂环衍生物或者其可药用盐或其水合物作为活性成分。
13.权利要求1-11任一项的四氢吡啶基杂环衍生物或者其可药用盐或其水合物作为CRF受体拮抗剂的应用。
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CN1972940B (zh) * | 2004-06-25 | 2011-08-10 | 大正制药株式会社 | 环氨基取代的吡咯并嘧啶和吡咯并吡啶衍生物作为crf受体拮抗剂 |
CN103313970A (zh) * | 2011-01-07 | 2013-09-18 | 大鹏药品工业株式会社 | 新型二环式化合物或其盐 |
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