CN1210265C - 酞嗪衍生物和***障碍的治疗剂 - Google Patents
酞嗪衍生物和***障碍的治疗剂 Download PDFInfo
- Publication number
- CN1210265C CN1210265C CNB998014729A CN99801472A CN1210265C CN 1210265 C CN1210265 C CN 1210265C CN B998014729 A CNB998014729 A CN B998014729A CN 99801472 A CN99801472 A CN 99801472A CN 1210265 C CN1210265 C CN 1210265C
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- Prior art keywords
- group
- amino
- phthalazines
- chloro
- benzyl
- 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.)
- Expired - Fee Related
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- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 title claims description 91
- 201000001881 impotence Diseases 0.000 title abstract description 5
- 208000010228 Erectile Dysfunction Diseases 0.000 title abstract description 3
- -1 phthalazine compound Chemical class 0.000 claims abstract description 255
- 150000003839 salts Chemical class 0.000 claims abstract description 102
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 94
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 78
- 125000005843 halogen group Chemical group 0.000 claims abstract description 77
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 45
- 150000001412 amines Chemical group 0.000 claims abstract description 35
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 17
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 15
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 14
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 9
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 5
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 381
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 240
- 150000001875 compounds Chemical class 0.000 claims description 135
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 107
- 238000006243 chemical reaction Methods 0.000 claims description 98
- 238000002360 preparation method Methods 0.000 claims description 89
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 71
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 125000006239 protecting group Chemical group 0.000 claims description 34
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 28
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 230000001225 therapeutic effect Effects 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 16
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 15
- 230000002265 prevention Effects 0.000 claims description 14
- 125000002541 furyl group Chemical group 0.000 claims description 11
- 125000001544 thienyl group Chemical group 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000001118 alkylidene group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 150000003851 azoles Chemical class 0.000 claims description 8
- 208000012201 sexual and gender identity disease Diseases 0.000 claims description 8
- 208000015891 sexual disease Diseases 0.000 claims description 8
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims 4
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 claims 2
- 208000005171 Dysmenorrhea Diseases 0.000 claims 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 1
- DYDNPESBYVVLBO-UHFFFAOYSA-N formanilide Chemical compound O=CNC1=CC=CC=C1 DYDNPESBYVVLBO-UHFFFAOYSA-N 0.000 claims 1
- WTYSCLHDMXBMKM-UHFFFAOYSA-N phthalazin-1-amine Chemical class C1=CC=C2C(N)=NN=CC2=C1 WTYSCLHDMXBMKM-UHFFFAOYSA-N 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
- 150000003413 spiro compounds Chemical class 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 304
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 228
- 238000005160 1H NMR spectroscopy Methods 0.000 description 144
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 128
- 239000000203 mixture Substances 0.000 description 118
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 111
- 239000000243 solution Substances 0.000 description 81
- 235000019439 ethyl acetate Nutrition 0.000 description 76
- 235000002639 sodium chloride Nutrition 0.000 description 69
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 65
- 238000010898 silica gel chromatography Methods 0.000 description 59
- 238000005406 washing Methods 0.000 description 58
- 238000001704 evaporation Methods 0.000 description 57
- 238000001035 drying Methods 0.000 description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
- 239000000706 filtrate Substances 0.000 description 47
- 239000002904 solvent Substances 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- 238000003810 ethyl acetate extraction Methods 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 238000003756 stirring Methods 0.000 description 32
- 230000008020 evaporation Effects 0.000 description 30
- 238000001816 cooling Methods 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 239000013078 crystal Substances 0.000 description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 238000001914 filtration Methods 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 238000010438 heat treatment Methods 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 15
- 210000003899 penis Anatomy 0.000 description 15
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- 239000001301 oxygen Substances 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 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 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 11
- 238000001556 precipitation Methods 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 10
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 229910052731 fluorine Inorganic materials 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- VLECDMDGMKPUSK-NUBCRITNSA-N (3r)-piperidin-3-ol;hydrochloride Chemical compound Cl.O[C@@H]1CCCNC1 VLECDMDGMKPUSK-NUBCRITNSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 229960002460 nitroprusside Drugs 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- 210000005226 corpus cavernosum Anatomy 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
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- 230000002829 reductive effect Effects 0.000 description 7
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- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 6
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- 125000001153 fluoro group Chemical group F* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
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- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 5
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- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 5
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- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 101150098694 PDE5A gene Proteins 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
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- 230000031709 bromination Effects 0.000 description 4
- 238000005893 bromination reaction Methods 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
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- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 3
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
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- 125000004423 acyloxy group Chemical group 0.000 description 3
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- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 3
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- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclo-pentanone Natural products O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 3
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
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- 230000005764 inhibitory process Effects 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000001050 pharmacotherapy Methods 0.000 description 3
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 3
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- VUNPWIPIOOMCPT-UHFFFAOYSA-N piperidin-3-ylmethanol Chemical compound OCC1CCCNC1 VUNPWIPIOOMCPT-UHFFFAOYSA-N 0.000 description 3
- 230000001568 sexual effect Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
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- 239000007983 Tris buffer Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- UDEGSYXELBQAAG-UHFFFAOYSA-N azanium;methanol;chloride Chemical class [NH4+].[Cl-].OC UDEGSYXELBQAAG-UHFFFAOYSA-N 0.000 description 1
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- SQMPZGSUNNMVKE-UHFFFAOYSA-N benzyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate Chemical compound C1CC(CO)(F)CCN1C(=O)OCC1=CC=CC=C1 SQMPZGSUNNMVKE-UHFFFAOYSA-N 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229930188620 butyrolactone Natural products 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- IRDLUHRVLVEUHA-UHFFFAOYSA-N diethyl dithiophosphate Chemical compound CCOP(S)(=S)OCC IRDLUHRVLVEUHA-UHFFFAOYSA-N 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- RCFKEIREOSXLET-UHFFFAOYSA-N disulfamide Chemical compound CC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O RCFKEIREOSXLET-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000005799 fluoromethylation reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
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- 239000012442 inert solvent Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 229960004269 methoxamine hydrochloride Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 230000004220 muscle function Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960002841 oxypertine Drugs 0.000 description 1
- 235000020636 oyster Nutrition 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 210000005164 penile vein Anatomy 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- REPWBKQJAMXHFL-UHFFFAOYSA-N phenylphosphane;hydrobromide Chemical class [Br-].[PH3+]C1=CC=CC=C1 REPWBKQJAMXHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- XBXHCBLBYQEYTI-UHFFFAOYSA-N piperidin-4-ylmethanol Chemical compound OCC1CCNCC1 XBXHCBLBYQEYTI-UHFFFAOYSA-N 0.000 description 1
- KCDIWATZOVCVKI-UHFFFAOYSA-N piperidin-4-ylurea Chemical compound NC(=O)NC1CCNCC1 KCDIWATZOVCVKI-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 201000011264 priapism Diseases 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical class O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- MDUSUFIKBUMDTJ-UHFFFAOYSA-N sodium;1h-1,2,4-triazole Chemical compound [Na].C=1N=CNN=1 MDUSUFIKBUMDTJ-UHFFFAOYSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- SSTZGACKDAVIGZ-UHFFFAOYSA-N sulfanium;bromide Chemical compound [SH3+].[Br-] SSTZGACKDAVIGZ-UHFFFAOYSA-N 0.000 description 1
- SNHOURMNEXCAJV-UHFFFAOYSA-N sulfuryl dichloride;toluene Chemical class ClS(Cl)(=O)=O.CC1=CC=CC=C1 SNHOURMNEXCAJV-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- HCDWHGFENXBNSC-UHFFFAOYSA-N tert-butyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11OCC(O)C1 HCDWHGFENXBNSC-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000003527 tetrahydropyrans Chemical class 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- REZGGXNDEMKIQB-UHFFFAOYSA-N zaprinast Chemical compound CCCOC1=CC=CC=C1C1=NC(=O)C2=NNNC2=N1 REZGGXNDEMKIQB-UHFFFAOYSA-N 0.000 description 1
- 229950005371 zaprinast Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
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Abstract
本发明提供了由下式表示的酞嗪衍生物、其药学上可接受的盐或其水合物,作为***障碍的治疗剂,其中R1和R2彼此相同或不同,表示卤原子、可以被卤原子取代的C1至C4烷基、可以被卤原子取代的C1至C4烷氧基、或氰基;X表示氰基、硝基、卤原子、可以被取代的肟基、或可以被取代的杂芳基;Y表示杂芳基、可以被取代的芳基、可以被取代的炔基、烯基、烷基、可选被取代的饱和或不饱和4至8元胺环,该胺环化合物是单环化合物、二环化合物或螺环化合物;l是1至3的整数;其条件是排除下列情况:l是1或2,X是氰基、硝基或氯原子,R1是氯原子,R2是甲氧基,Y是被羟基取代的5或6元胺环。
Description
发明领域
本发明涉及酞嗪衍生物。确切地说,本发明涉及用于男性***障碍的预防与治疗剂和用于女性性机能障碍或痛经的预防与治疗剂。
现有技术
据说在日本,***障碍的潜在患者数量达到大约300万。据报道在美国,***障碍患者的数量达到了2000万,15%五十多岁男性和1/3六十多岁男性患有该疾病。在这个老龄化社会,***被看作一种愉快和情感上的行为。由于有提高生活质量的需要,***障碍预期未来不仅会引发医学问题,而且会引发社会问题。该疾病分为由***本身的神经、血管或肌肉机能紊乱或性激素失调导致的器质性阳萎和由精神或心理障碍导致的机能性(精神性)阳萎两类。有三个因素是***所必需的,即,***动脉血流的增加、自***静脉血液漏出的抑制和海绵体组织的舒张。当这些条件中有任何一种被抑制时,则发生***障碍。
今天所进行的用于***障碍的泌尿学治疗涉及药物疗法和利用***修复器进行的***修复手术。
可行的药物疗法是向******组织内注射盐酸罂粟碱或***素E1。不过,这种治疗在今天几乎已经不再进行了,因为日本不允许患者给自己注射,而且实际上也不可能在每次***时都去医生那里接受注射。另外,注射盐酸罂粟碱可能导致疼痛症状,称为茎异常***,尽管只是例外情况。用现有药物进行治疗在实际上是不可用的。因此,迫切需要开发出临床实践上有效的药物疗法。
Bowman和Drummond于1984年报道,选择性环GMP磷酸二酯酶抑制剂M&B22948(扎普司特)增加组织中的环GMP,舒张牛***缩肌(环GMP介导牛***缩肌的神经源性舒张作用,《英国药理学杂志》Br.J.Pharmacol.81,665-674,1984)。后来,其他研究人员相继报道了由组织中环GMP增加所引起的***海绵体的舒张作用(《国际阳萎研究杂志》Int.J.Impotence Res.;4,85-93,1992;《泌尿科学杂志》J.Urol.,147,1650-1655,1992;《新英格兰医学杂志》N.Engl.J.Med.,326,90-94,1992)。不过,这些研究所利用的化合物都不能令人满意地应用于临床,原因在于功效较差等。
V型(5型)磷酸二酯酶抑制剂对女性性机能障碍也是有效的。
WO 9605176(JP-A 8-225541)公开了对V型磷酸二酯酶具有抑制作用的酞嗪衍生物,但是其中既没有公开含有氮原子的螺环化合物或双环和6元杂环化合物,也没有任何关于***障碍的预防和治疗的内容。
发明的公开
本发明人进行了各种研究,从而发现,由式(I)表示的酞嗪衍生物对降解环GMP的V型磷酸二酯酶显示出高度选择性和有力的抑制作用,对***海绵体表现出强烈舒张作用,具有较高的生物利用度和安全性,于是完成了本发明。
本发明涉及JP-A 8-225541中没有明确公开的酞嗪衍生物,涉及其中完全没有暗示的酞嗪衍生物,进一步涉及用于制备一些该化合物的方法。
本发明涉及由式(I)表示的酞嗪衍生物、其药学上可接受的盐或其水合物:
其中R1和R2彼此相同或不同,表示卤原子、可以被卤原子取代的C1至C4烷基、羟基、可以被卤原子取代的C1至C4烷氧基、或氰基;
X表示氰基,硝基,卤原子,硫代氨基甲酰基,可以被C1至C4烷基、芳基C1至C4烷基或羧基C1至C4烷基取代的肟基,或可以被1至3个取代基取代的杂芳基,取代基选自下列取代基A;
Y表示:
i)由式(II)表示的基团:
其中环A表示可以被甲基取代的4至8元胺环,可以具有双键;D表示单键或氧原子;R3表示氢原子、C1至C4烷基或卤原子;m表示0或1至3的整数;W表示氨基、羟基、氰基、可以具有保护基的羧基、或C1至C4烷氧基;
ii)由式(III)表示的基团:
其中环B表示可以具有双键的4至8元胺环;n和p彼此相同或不同,表示0或1至3的整数;
iii)由式(IV)表示的基团:
其中环G表示可以具有双键的4至8元胺环,E表示羟基、卤原子、C1至C4烷基或C1至C4烷氧基,J是式-(CHR4)q-Q(其中R4表示氢原子或C1至C4烷基,Q表示羟基、卤原子、可以具有保护基的羧基、氨基甲酰基或不含有除氮原子以外杂原子的唑系基团,q是0或1至4的整数),或者E和J可以与它们所结合的碳原子一起构成3至6元环,该环可选地具有杂原子,可选地具有取代基;
iv)由式(V)表示的基团:
其中M表示单键或可以被羟基、羧基、C1至C4烷基或C1至C4烷氧基取代的C1至C4亚烷基,环K表示与M一起构成的5至8元胺环,环L表示可以具有取代基且可以具有氧原子的5至8元烷基环;
v)由式(VI)表示的基团:
其中环P表示5至7元胺环,R5表示氢原子或可以被卤原子、羟基或羧基取代的C1至C4烷基;
vi)炔基、烯基或烷基,所有这些都可以具有取代基;
vii)可以被1至3个取代基取代的苯基,取代基选自下列取代基A;或
viii)吡啶基、嘧啶基、噻吩基、噻唑基或呋喃基,所有这些都可以被1至3个取代基取代,取代基选自下列取代基A;
取代基A是:可以被卤原子、氰基、硝基或羟基取代的C1至C4烷基;可以被卤原子、氰基、硝基或羟基取代的C1至C4烷氧基;氰基;硝基;可以具有保护基的羧基;可以具有保护基的羟基;可以被低级烷基取代的氨基甲酰基;卤原子;和可以被C1至C4酰基、C1至C4烷基磺酰基或芳基磺酰基取代的氨基,该芳基磺酰基可以具有取代基;
l是1至3的整数;
其条件是排除下列情况:l是1或2,X是氰基、硝基或氯原子,R1是氯原子,R2是甲氧基,环A是5或6元胺环,D是单键,m是0,W是可以具有保护基的羧基或C1至C4烷氧基;l是1,R1是氯原子,R2是甲氧基,环A是饱和的5或6元胺环,D是单键,W是羟基;l是1,环B是5或6元胺环,n和p都是0;l是1,E和Q是羟基,q是0;l是1,X是氯原子,Y是被甲氧基取代的苯基。
本发明人进一步发现,下式(VII)化合物也对***海绵体表现出强烈舒张作用,具有较高的生物利用度和安全性。于是完成了本发明。
***障碍治疗剂,包含由式(VII)表示的酞嗪衍生物、其药学上可接受的盐或其水合物作为活性成分:
其中l’是1至3的整数;R6表示卤原子、可以被卤原子取代的C1至C4烷基或氰基;
X1表示氰基、硝基或卤原子;
Y1表示:
i)由式(VIII)表示的基团:
其中环A1表示5或6元胺环;m1表示0或1至3的整数;Z表示氨基、可以具有保护基的羟基、可以具有保护基的羧基、C1至C4烷氧基或氰基;
ii)由式(IX)表示的基团:
其中环B1表示5或6元胺环,n1和p1是0或1至3的整数;
iii)吗啉代基或硫原子可以被氧化的硫代吗啉代基;
iv)可以被1至3个取代基取代的苯基,取代基选自下列取代基A1;
v)杂芳基,它是吡啶基、嘧啶基、噻吩基或呋喃基,所有这些都可以被1至3个取代基取代,取代基选自下列取代基A1;或
vi)式-N(R7)-(CH2)s-Het基团,其中R7表示低级烷基,Het表示吡啶基或嘧啶基,所有这些都可以被1至3个取代基取代,取代基选自下列取代基A1,s是0或1至3的整数;
取代基A1是:可以被卤原子、氰基、硝基或羟基取代的低级烷基;可以被卤原子、氰基、硝基或羟基取代的低级烷氧基;氰基;硝基;可以具有保护基的羧基;可以具有保护基的羟基;可以被低级烷基取代的氨基甲酰基;卤原子;和可以被烷基、烷氧基、卤原子或氨基取代的苯基。
本发明提供了包括使由式(X)表示的化合物
(其中Hal表示卤原子;R1、R2、l和X定义同上)与式Y3-B(OH)2化合物(其中Y3表示苯基、吡啶基、嘧啶基、噻吩基或呋喃基,所有这些都可以具有选自上述取代基A1的取代基)反应的步骤,用于制备由式(XI)表示的化合物的方法,
(其中X、Y3、R1、R2和l定义同上)。
本发明提供了用于***障碍的预防和治疗剂,包含由上式(I)表示的酞嗪衍生物、其药学上可接受的盐或其水合物作为活性成分。本发明进一步提供了用于女性性机能障碍或痛经的预防和治疗剂,包含由上式(I)或(VII)表示的酞嗪衍生物、其药学上可接受的盐或其水合物作为活性成分。
本发明提供了药物组合物,包含药学上或临床上有效量的由上式(I)或(XI)表示的酞嗪衍生物、其药学上可接受的盐或其水合物和药学上可接受的载体。
本发明提供了用于预防或治疗***障碍、女性性机能障碍或痛经的方法或用途,包括将药学上或临床上有效量的由上式(I)或(VII)表示的酞嗪衍生物、其药学上可接受的盐或其水合物对***障碍患者、女性性机能障碍或痛经患者给药。
在本发明所列举的定义中,X、R1、R2、R3、R4、R5、E、Q、取代基A和A1中所定义的卤原子指的是氟原子、氯原子、溴原子和碘原子。
R1、R2、R3、R4、R5、R6、R7、取代基A和A1中所定义的C1至C4烷基指的是具有1至4个碳原子的直链或支链烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、1-甲基丙基和叔丁基。R1、R2、取代基A和A1中所定义的C1至C4烷氧基指的是从上述C1至C4烷基衍生的基团,例如包括甲氧基、乙氧基、丙氧基等。
Q、W、取代基A和A1中所定义的可以具有保护基的羧基中的保护基团例如指的是低级烷基,如甲基、乙基和叔丁基等;被可以具有取代基的苯基取代的低级烷基,如对甲氧基苄基、对硝基苄基、3,4-二甲氧基苄基、二苯甲基、三苯甲基和苯乙基;卤代低级烷基,如2,2,2-三氯乙基和2-碘乙基;低级烷酰氧基低级烷基,如新戊酰氧基甲基、乙酰氧基甲基、丙酰氧基甲基、丁酰氧基甲基、戊酰氧基甲基、1-乙酰氧基乙基、2-乙酰氧基乙基、1-新戊酰氧基乙基和2-新戊酰氧基乙基;高级烷酰氧基低级烷基,如棕榈酰氧基乙基、十七烷酰氧基甲基和1-棕榈酰氧基乙基;低级烷氧基碳酰氧基低级烷基,如甲氧基碳酰氧基甲基、1-丁氧基碳酰氧基乙基和1-(异丙氧基碳酰氧基)乙基;羧基低级烷基,如羧甲基和2-羧乙基;杂芳基,如3-酞基;可选具有取代基的苯甲酰氧基低级烷基,如4-甘氨酰氧基苯甲酰氧基甲基;(取代的二氧杂环戊烯)低级烷基,如(5-甲基-2-氧-1,3-二氧杂环戊烯-4-基)甲基;环烷基取代的低级烷酰氧基低级烷基,如1-环己基乙酰氧基乙基;和环烷氧基碳酰氧基低级烷基,如1-环己氧基碳酰氧基乙基。简而言之,任何可以被体内任意方式降解生成羧酸的基团都能充当羧基保护基团。
取代基A和A1中所定义的可以具有保护基的羟基中的保护基团例如指的是酰基,如甲酰基、乙酰基和苯甲酰基;和低级烷氧基甲基,如2-甲氧基乙氧基甲基。简而言之,任何可以被体内任意方式降解生成羟基的基团都能充当羟基保护基团。
Q中所定义的不含有除氮原子以外杂原子的唑系基团指的是从吡咯、吡唑、咪唑、***、四唑、吲唑、苯并咪唑和苯并***衍生的基团。
式(IV)中,从E与J以及它们所结合的碳原子构成的环和环G制得的化合物是螺环化合物。E与J以及它们所结合的碳原子构成的环包括环丁烷、环戊烷、环己烷、环氧乙烷、四氢呋喃、四氢吡喃、丁内酯和丁内酰胺。进一步地,这些环上的取代基包括羟基,可以具有上述保护基的羧基,可以被羟基取代的C1至C4烷基、例如羟甲基和羟乙基等,羰基,卤原子、例如氟原子和氯原子等。
式(V)中,当M是C1至C4亚烷基时,由环K和L构成的双环指的是桥联的环。环L上的取代基包括羟基,可以具有上述保护基的羧基,可以被羟基取代的C1至C4烷基、例如羟甲基和羟乙基等,可以被羧基取代的C1至C4烷基羰基、例如羧甲基和羧乙基,卤原子、例如氟原子和氯原子,乙烯基等。
Y中所定义的可以具有取代基的炔基、烯基或烷基中的取代基包括C1至C4烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基;从环烷衍生的基团,例如环丙烷、环丁烷、环戊烷和环己烷;从上述C1至C4烷基衍生的C1至C4烷氧基,例如甲氧基、乙氧基和丙氧基等;羟基;可以被C1至C4烷基取代的氨基;可以被羟基取代的环胺,例如环乙亚胺、氮杂环丁烷、吡咯烷和哌啶;羟基C1至C4烷基;羟基C1至C4烷氧基;羧基烷氧基;和卤原子,例如氟原子和氯原子。
X中,杂芳基包括从下列化合物衍生的基团:吡咯、吡唑、咪唑、***、四唑、吲唑、苯并咪唑、苯并***、噻唑、异噻唑、噻二唑、苯并噻二唑、吡啶、嘧啶、三嗪、喹啉、异喹啉、萘啶(naphthyridine)、酞嗪等。
本发明中,药学上可接受的盐例如包括无机酸盐,如盐酸盐、硫酸盐、氢溴酸盐和磷酸盐,以及有机酸盐,如甲酸盐、乙酸盐、马来酸盐、富马酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐和甲苯磺酸盐。
不言而喻,在本发明化合物具有一个不对称原子的情况下,它们的旋光活性化合物也包括在本发明的范围内。
而且,体内代谢生成本发明化合物的化合物和本发明化合物通过代谢作用生成的化合物也包括在本发明的范围内。
上述酞嗪衍生物、其药学上可接受的盐或其水合物由于具有优异的口服可吸收性和长效作用,在治疗时可以经皮、静脉内或口服给药,无需直接注射到***海绵体或***内,这对用于***障碍的预防和治疗剂和用于女性性机能障碍或痛经的预防和治疗剂来说是可取的。
对本发明化合物的给药剂量没有特别的限制,不过一般来说,在静脉内给药的情况下,成人给药剂量为5μg至100mg,优选为10至1000μg,或者在口服给药的情况下,剂量为1至1000mg,优选为5至100mg。
制备方法1
WO 9605176(JP-A 8-225541)描述了用于制备类似于本发明化合物的化合物或其药学上可接受的盐的方法,本发明的酞嗪衍生物是以如下相同方式制备的:
其中,Y2是:
其中的环A、D、R3、m和W定义同上;
其中的环B、n和p定义同上;
其中的环G、E和J定义同上;
其中的环K、环L和M定义同上;
其中的环P和R5定义同上;
Hal指卤原子;R1、R2、l和X定义同上。
该反应是,由式(X)表示的化合物与HY2在溶剂中反应,得到由式(XII)表示的化合物。作为反应溶剂,N-甲基-2-吡咯烷酮是优选的,但是可以使用任意的溶剂,只要它是反应惰性的。使用过量于化合物(X)的HY2,或者使用二异丙基乙胺等有机碱或碳酸钾、碳酸钠或碳酸氢钠等盐,可以得到良好结果。反应温度在室温至溶剂沸点的范围内,优选为100℃或以上。
WO96 05176(JP-A 8-225541)中没有记载的W是氰基的化合物的制备中所必需的HY2的合成如下:
上述申请没有明确记载其中W是氨基的情况,在这种情况下,如下合成其中氨基被保护的HY2,然后脱保护:
式(I)中,利用WO 9806720公开的化合物或其中公开的方法,可以制备其中Y是由式(IV)和(V)表示的HY2。
1)例如,某些由式(IV)表示的化合物是用下列方法制备的。
其中G1表示4至8元胺环;Q1表示吡咯基、吡唑基、咪唑基、***基、四唑基、吲唑基、苯并咪唑基、苯并***基或氟原子;Pro表示氮原子的保护基团。
在甲苯、二甲苯或四氢呋喃等溶剂中,将甲基三苯基溴化锍用碱如叔丁醇钾或丁基锂处理,再与由式(a)表示的酮化合物反应,由此可以得到由式(b)表示的化合物。反应温度优选为-78℃至室温。
在二***、二甲氧基乙烷或四氢呋喃等溶剂中,使化合物(b)与三氯乙酰氯反应,得到二氯环丁酮化合物(f)(或者,与二乙酰氯反应,得到一氯化合物。该一氯化合物与三氯乙酰氯反应、再用乙酸处理,也可以得到),然后将产物用锌粉等还原剂处理,由此可以得到由式(g)表示的环丁酮化合物。该反应温度优选为10至50℃。在碳酸氢钠的存在下,在二氯甲烷等溶剂中,将化合物(g)用3-氯过苯甲酸等过氧化物处理,可以得到由式(h)表示的内酯化合物。反应温度优选在室温至40℃的范围内。若将化合物(b)用二氯乙烯酮和重氮甲烷处理,则得到式(f)中的环戊酮化合物,若将化合物(g)用重氮甲烷处理,则得到式(g)中的环戊酮化合物。若将该环戊酮化合物进一步用重氮甲烷处理,则得到环己酮化合物。
若将化合物(b)用单过氧邻苯二甲酸镁等过酸处理,则得到由式(c)表示的环氧化物。若在二甲基甲酰胺等溶剂中,使环氧化物(c)与仅含有氮原子作为杂原子的唑系的钠盐反应,则得到由式(d)(Q1是1-咪唑基、1-***基等)表示的相应化合物。在Bu4N·H2F3的存在下,在100至150℃下用氟化氢钾处理,得到由式(d)表示的氟甲基化合物,其中Q1是氟原子。
另一方面,在-10至10℃下,在二氯甲烷等溶剂中,将化合物(c)用氟化氢吡啶处理,得到由式(e)表示的氟化物。
2)在由式(V)表示的化合物中,其中的M是被羟基取代的亚甲基者例如是用下列方法制备的。
其中环L含有氧原子的化合物也可以以相同方式制备。
制备方法2
其中Y是炔基、烯基或烷基的式(I)化合物可以用下列方法制备,所有这些Y都可以具有取代基。
其中Hal是卤原子;R8是可选被取代的C1至C4烷基,或可选被取代的环烷基或环烷基烷基;R1、R2、l和X定义同上。
式(X)化合物与炔化合物的反应条件是在催化量的二氯双三苯基膦合钯(II)、碘化亚铜和叔胺的存在下,在室温或加热下进行。所用溶剂包括二甲基甲酰胺或1-甲基吡咯烷酮。所用的叔胺包括三乙胺、二异丙基乙胺、DBU和二甲基苯胺等。反应温度优选为0至150℃。
在林德勒催化剂或Pd-C催化剂的存在下,利用催化还原等反应,将由式(XIII)表示的炔化合物转化为由式(XIV)表示的烯化合物或由式(XV)表示的烷化合物。
制备方法3
进一步地,其中Y是Y3的酞嗪衍生物是如下制备的,Y3是可选被取代的芳基或杂芳基:
其中Y3是苯基、吡啶基、嘧啶基、噻吩基或呋喃基,所有这些都可以具有一个1至3个选自上述取代基A的取代基;Hal是卤原子;R1、R2、l和X定义同上。
该反应是如下进行的,通过一种零价或二价钯配合物,将由式(X)表示的1-卤代喹唑啉衍生物与具有相应芳基或杂芳基的硼酸、二烷氧基硼烷或三烷基锡化合物偶合。将具有芳基或杂芳基的硼酸、二烷氧基硼烷或三烷基锡化合物和钯配合物溶解或悬浮在两相溶剂中,该两相溶剂由有机溶剂和碳酸钠水溶液组成。在氮气流中,使该混合物在室温至溶剂沸点范围内的温度下反应约1至24小时。作为钯配合物,可以任意使用允许反应进行的钯配合物,四(三苯基膦)合钯等是优选的。作为有机溶剂,可以任意使用反应惰性溶剂,二甲苯、甲苯、四氢呋喃或它们的混合溶剂是优选的。
制备方法4
式(I)中,使用其中X是氰基的化合物(XVII),结合已知反应可以制备下列反应流程所示化合物。
其中R9是氢原子、可以被卤原子取代的C1至C4烷基、芳基C1至C4烷基或羧基C1至C4烷基;R10是C1至C4烷基;R1、R2、l和Y定义同上。
制备方法5
某些其中X是杂芳基的式(I)化合物可以以制备方法3相同的方式制备。
其中Hal是卤原子;Het1是杂芳基;R1、R2、l和Y定义同上。
卤原子优选为溴原子或碘原子。
而且,在预先制得由式(X)表示的相应化合物后,按照上述制备方法1制备具有不含有除氮原子以外杂原子的唑系基团的式(I)化合物。式(X)的相应化合物例如可以按照如下方法制备:将4-氟邻苯二甲酸二甲酯用不含有除氮原子以外杂原子的唑系处理,得到4-唑系基团邻苯二甲酸二甲酯,然后用肼处理,得到6-唑系基团-2,3-二氢-1,4-酞嗪二酮,然后按照WO 9605176公开的方法制备。
制备方法6
用已知方法将由下式(XXIV)表示的化合物转化为肟,可以制备其中Y是由式(VI)表示的式(I)化合物:
其中R1、R2、R5、l和X定义同上。
下面,参照实验例描述本发明化合物的作用。
1)对来自猪血小板的cGMP-PDE的酶抑制作用
如下测定供试化合物对来自猪血小板的cGMP-PDE酶的抑制活性:按照Tompson等的方法,在1mM EGTA的存在下,向反应溶液中加入供试化合物的DMSO溶液,其中使用1μM cGMP作为酶底物。DMSO在反应溶液中的最终浓度是1%或以下。如下进行cGMP-PDE的制备。向缓冲液A(20mM Tris/HCl,2mM乙酸镁,10mM 2-巯基乙醇,0.1mM EGTA;pH7.4)中加入猪血小板,然后超声处理。所得混悬液以100000×g离心60分钟,所得上清液上柱(DEAE-Toyopearl 650S,日本东京Tosoh制造)。柱子用缓冲液A洗涤后,酶用缓冲液A中的0.075至0.25M NaCl梯度洗脱,得到cGMP-PDE部分。将所得部分透析、浓缩、贮藏。
表1:对PDE5的抑制作用
供试化合物 | PDE5 IC50(nM) | 供试化合物 | PDE5 IC50(nM) | ||
12345678910111213141516 | 制备例1制备例3制备例4制备例5制备例6制备例7制备例8制备例11实施例1实施例2实施例3实施例4实施例5实施例6实施例9实施例11 | 0.090.720.190.230.50.030.470.240.780.301.10.510.0510.980.540.68 | 171819202122232425262728293031 | 实施例12实施例25实施例36实施例43实施例50实施例52实施例76实施例77实施例79实施例83实施例84实施例85实施例88实施例105实施例110 | 0.540.160.250.230.240.200.130.230.270.50.930.120.890.100.66 |
2)PDE5抑制剂增强硝普盐(nitroprusside)所致取自兔子的***海绵体标本的舒张作用
通过静脉内注射戊巴比妥(50mg/kg)杀死NZW系家兔(约3kg),摘出***。然后除去白膜等周围组织,暴露海绵体,得到标本(约10×1.5×1.5mm)。将该标本悬吊在Magnus试管内,试管内盛有37℃的10ml Krebs-Henseleit营养溶液(118.4mM NaCl,4.7mM KCl,2.5mMCaCl2,1.3mM MgSO4,1.2mM KH2PO4,25.0mM NaHCO3,11.0mM葡萄糖,0.026mM EDTA和0.001mM消炎痛),向其中通入混合气体(95%氧+5%二氧化碳)。然后,在2g负荷下记录等长张力。为了使收缩稳定,因加入氯化钾溶液(最终浓度:100mM)和洗涤而导致的收缩重复两次,而且,也进行因加入苯福林(最终浓度:10μM)和洗涤而导致的收缩。
再装入10ml Krebs-Henseleit溶液,加入L-NG-硝基精氨酸甲酯(最终浓度:100μM),以抑制内源性一氧化氮的生成。加入苯福林(最终浓度:10μM)导致收缩,向其中加入最终浓度为3、30或300nM的化合物溶液。在该反应中使用二甲基亚砜作为介质。加入化合物15分钟后,加入硝普盐(最终浓度:300μM)以舒张标本。进一步加入罂粟碱(最终浓度:100μM)以测定最大舒张。
实验后,以因加入罂粟碱而产生的张力为基线,利用DEGIMATICCALIPER在图表上记录因加入硝普盐而引起的标本舒张,以测定舒张的程度。
表2:PDE5抑制剂增强硝普盐所致取自兔子的***海绵体标本的舒张作用
供试 舒张比例(%) EC50
化合物 3nM 30nM 300nM (nM)
实施例9 56.6 77.7 79.6 2.0
实施例36 35.0 60.8 54.8 3.5
实施例37 33.4 50.1 56.0 29.3
实施例77 58.8 71.7 80.6 0.7
实施例83 50.6 67.3 69.9 2.8
实施例86 50.2 70.2 71.5 3.0
实施例88 50.0 67.5 75.0 3.0
表中数值指示在向预先用3、30和300nM化合物处理过的标本中加入硝普盐后的舒张比例(%),以两次重复实验的平均值表示。而且,EC50值表示由苯福林导致的收缩被舒张50%的化合物浓度,该值是经过对两次重复实验中的舒张曲线进行回归分析而计算的。
由硝普盐生成的一氧化氮活化鸟苷酸环化酶,促进从GTP生成cGMP,由此舒张***海绵体。PDE5抑制剂通过抑制cGMP的降解,增强了该舒张作用。
如上所述,本发明化合物证明对PDE5具有抑制作用,剂量依赖性地增加硝普盐对兔***海绵体样本的舒张作用。
也就是说,本发明作为用于***障碍的预防和治疗剂是有用的。
给出制备例和实施例以助于理解本发明,但是不言而喻,本发明不限于这些化合物。下文中,“盐水”指饱和食盐水,“MASS”指质谱。
制备例1
盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-[(3R)-3-羟基哌啶子基]酞嗪
将1.0g 1-氯-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪、1.92g盐酸(R)-(+)-3-羟基哌啶、1.80g二异丙基乙胺和12ml 1-甲基-2-吡咯烷酮的混合物在170℃下搅拌1小时又15分钟。冷却后,向反应溶液中加入乙酸乙酯,然后用水和盐水洗涤。经无水硫酸钠干燥,蒸发溶剂,所得残余物用硅胶柱层析法纯化。将所得游离化合物悬浮在乙酸/乙醇/水中,向其中加入1N盐酸水溶液,加热使其溶解。冷却后,过滤收集所得晶体,得到860mg标题化合物,为黄色粉末。
MASS(ESI):424.1(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.39-1.50(1H,m),1.65-1.78(1H,m),1.75-1.98(2H,m),2.82-2.91(1H,m),2.93-3.02(1H,m),3.33-3.48(2H,m),3.79-3.88(1H,m),3.85(3H,s),4.72(2H,br),7.16(1H,d,J=8.4Hz),7.47(1H,dd,J=8.4,1.6Hz),7.62(1H,d,J=1.6Hz),8.31(1H,d,J=8.4Hz),8.48(1H,d,J=8.4Hz),9.38-9.46(1H,m),10.27(1H,br).
制备例2
盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-[(3S)-3-羟基吡咯烷基]酞嗪
用(S)-3-羟基吡咯烷代替制备例1中的盐酸(R)-(+)-3-羟基哌啶,得到标题化合物。
MASS(ESI);410.0(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.94-2.10(2H,m),3.50-3.62(1H,m),3.42-3.68(1H,m),3.83(3H,s),3.93-4.10(2H,m),4.43-4.50(1H,m),4.50-4.64(2H,m),5.30(1H,br),7.13(1H,d,J=8.4Hz),7.34-7.44(1H,m),7.48-7.56(1H,m),8.38-8.46(1H,m),8.62-8.74(1H,m),9.10-9.32(1H,m).
制备例3
盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-[(2S)-2-羟甲基吡咯烷基]酞嗪
用(S)-2-羟甲基吡咯烷代替制备例1中的盐酸(R)-(+)-3-羟基哌啶,得到标题化合物。
MASS(ESI);424.1(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.60-2.39(4H,m),3.44-3.53(1H,m),3.83(3H,s),3.89-3.99(1H,m),4.34-4.70(3H,m),7.12-7.16(1H,m),7.38-7.46(1H,m),7.52-7.59(1H,m),8.40-8.43(1H,m),8.43-8.60(1H,m),9.23-9.30(1H,m).
制备例4
盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(3-羟甲基哌啶子基)酞嗪
用3-羟甲基哌啶代替制备例1中的盐酸(R)-(+)-3-羟基哌啶,得到标题化合物。
MASS(ESI);438.2(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.13-1.28(1H,m),1.70-1.86(3H,m),1.87-1.99(1H,m),2.67-2.75(1H,m),2.86-2.95(1H,m),3.33-3.50(3H,m),3.51-3.60(1H,m),3.16(3H,s),3.85(3H,s),4.71(2H,br-s),7.16(1H,d,J=8.4Hz),7.44(1H,dd,J=8.4,0.8Hz),7.59(1H,d,J=0.8Hz),8.23(1H,d,J=8.8Hz),8.45(1H,dd,J=8.8,0.4Hz),9.28-9.35(1H,m),9.95(1H,br),14.00(1H,br).
制备例5
盐酸4-(3-氯-4-甲氧基苯乙基)氨基-6-氰基-1-(3-羟甲基哌啶子基)酞嗪
用1-氯-4-(3-氯-4-甲氧基苯乙基)氨基-6-氰基酞嗪代替制备例4中的1-氯-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪,得到标题化合物。
MASS(ESI);452.3(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.70-1.90(2H,m),1.90-2.05(2H,m),2.70(1H,br-t),2.88(1H,br-t),2.95-3.08(2H,m),3.25-3.63(2H,m),3.78(2H,m),3.83(3H,s),7.09(1H,d,J=8.6Hz),7.29(1H,d,J=8.6Hz),7.47(1H,s),8.25(1H,d,J=8.6Hz),8.49(1H,d,J=8.6Hz),9.48(1H,s).
制备例6
4-(3-氯-4-甲氧基苯乙基)氨基-6-氰基-1-(4-羟甲基哌啶子基)酞嗪
用4-羟甲基哌啶代替制备例5中的3-羟甲基哌啶,得到标题化合物。
MASS(ESI);452.3(MH+)
1H-NMR(400MHz,CDCl3)δ;1.51-1.65(2H,m),1.79-1.85(1H,m),1.93(2H,m),2.99-3.09(4H,m),3.56-3.68(4H,m),3.90(3H,s),3.85-3.99(2H,m),4.94(1H,br-t),6.88(1H,d,J=8.4Hz),7.13(1H,dd,J=2.2,8.4Hz),7.28(1H,d,J=2.2Hz),7.94(1H,d,J=8.4Hz),7.98(1H,s),8.13(1H,d,J=8.4Hz).
制备例7
二盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-[甲基-(2-吡啶甲基)氨基]酞嗪
除了用N-甲基-[(2-吡啶基)甲基]胺代替盐酸(R)-(+)-3-羟基哌啶以外,经过与制备例1相同的处理得到标题化合物。
MASS(ESI);445.3(MH+)
1H-NMR(400MHz,DMSO-d6)δ;2.95(3H,s),3.85(3H,s),4.73-4.79(4H,m),7.16(1H,d,J=8.4Hz),7.49(1H,dd,J=8.4,2.0Hz),7.64(1H,d,J=2.0Hz),7.65-7.72(1H,m),7.83-7.87(1H,m),8.18-8.26(1H,m),8.52(1H,dd,J=8.4,1.2Hz),8.60(1H,d,J=8.4Hz),8.74(1H,d,J=4.8Hz),9.53-9.55(1H,m),10.64(1H,br).
制备例8
二盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-{N-甲基-[2-(2-吡啶基)乙基]氨基}酞嗪
除了用N-甲基-[2-(2-吡啶基)乙基]胺代替N-甲基-[(2-吡啶基)甲基]胺以外,经过与制备例7相同的处理得到标题化合物。
MASS(ESI);459.2(MH+)
1H-NMR(400MHz,DMSO-d6)δ;3.00(3H,s),3.35(2H,t,J=6.4Hz),3.76(2H,t,J=6.4Hz),3.85(3H,s),4.73-4.77(2H,m),7.18(1H,d,J=8.4Hz),7.50(1H,d,J=8.4Hz),7.53-7.64(1H,m),7.65(1H,s),7.68-7.77(1H,m),8.10-8.30(1H,m),8.16(1H,d,J=8.6Hz),8.44(1H,d,J=8.6Hz),8.55-8.61(1H,m),9.45-9.51(1H,m),10.53(1H,br).
制备例9
盐酸4-(3-氯-4-甲氧基苯乙基)氨基-6-氰基-1-(4-甲氧基哌啶子基)酞嗪
除了用盐酸4-甲氧基哌啶代替3-羟甲基哌啶以外,经过与制备例5相同的处理得到标题化合物。
MASS(ESI);452.2(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.66-1.76(2H,m),2.00-2.08(2H,m),2.91-2.97(2H,m),2.99-3.07(2H,m),3.29(3H,s),3.37-3.49(3H,m),3.70-3.77(2H,m),3.81(3H,s),7.07(1H,d,J=8.6Hz),7.26(1H,dd,J=8.6,2.0Hz),7.43(1H,d,J=2.0Hz),8.24(1H,d,J=8.3Hz),8.45(1H,dd,J=8.3,1.6Hz),9.22(1H,d,J=1.6Hz).
制备例10
盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(4-甲氧基苯基)酞嗪
在氮气中,向1.0g 1-氯-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪、423mg 4-甲氧基苯基硼酸、30ml甲苯、30ml四氢呋喃和30ml 2M碳酸钠水溶液的混合物中加入423mg四(三苯基膦)合钯(O)。混合物在80℃下搅拌2小时,进一步在10℃下搅拌15.5小时。反应溶液恢复至室温,加入氯化铵水溶液,用乙酸乙酯萃取。有机层用氨水、水和盐水洗涤,经无水硫酸钠干燥。蒸发溶剂,所得残余物用硅胶柱层析法纯化。将所得偶合的化合物溶于乙酸乙酯/乙醇,向其中加入4N盐酸/乙酸乙酯溶液,过滤收集所得晶体,得到460mg标题化合物,为黄色粉末。
MASS(ESI);431.2(MH+)
1H-NMR(400MHz,DMSO-d6)δ;3.85(3H,s),3.87(3H,s),4.82-4.85(2H,m),7.16-7.21(3H,m),7.49(1H,dd,J=8.6,2.2Hz),7.60-7.63(3H,m),8.08(1H,d,J=8.4Hz),8.45(1H,dd,J=8.4,1.4Hz),9.45-9.49(1H,m),10.39(1H,br).
制备例11
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基-3-甲基哌啶子基)-6-酞嗪甲腈(carbonitrile)
除了用4-羟基-3-甲基哌啶代替盐酸(R)-(+)-3-羟基哌啶以外,经过与制备例1相同的处理得到标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;0.94(3H,t,J=8.0Hz),1.59-2.03(3H,m),2.74-3.96(5H,m),3.83(3H,s),4.68(2H,d,J=5.2Hz),7.15(1H,d,J=8.4Hz),7.43(1H,d,J=8.0Hz),7.58(1H,s),8.23(1H,t,J=8.0Hz),8.45(1H,d,J=8.4Hz),9.29(1H,s).
制备例12
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基-3,3,5,5-四甲基哌啶子基)-6-酞嗪甲腈
除了用4-羟基-3,3,5,5-四甲基哌啶代替盐酸(R)-(+)-3-羟基哌啶以外,经过与制备例1相同的处理得到标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;0.91(6H,s),1.15(6H,s),2.57(1H,d,J=12.4Hz),2.95(1H,s),3.21(2H,d,J=12.0Hz),3.83(3H,s),4.47(2H,d,J=5.6Hz),7.14(1H,d,J=8.4Hz),7.47(1H,d,J=8.8Hz),7.63(1H,s),8.29(1H,d,J=8.4Hz),8.55(1H,d,J=8.4Hz),9.52(1H,s),10.63(1H,br-s).
中间体制备例1
1-氯-4-{[(4-甲氧基-3-三氟甲基)苄基]氨基}-6-酞嗪甲腈
将10g 2-三氟甲基苯酚、17g碳酸钾、150ml丙酮和7.7ml碘代甲烷的混合物加热回流2小时。冷却后,过滤除去不溶物,蒸发滤液。将所得残余物溶于乙酸乙酯,用水和盐水洗涤。经无水硫酸镁干燥,过滤,减压浓缩,得到12.15g 2-三氟甲基茴香醚。
将8.5g 2-三氟甲基茴香醚和7.0g六亚甲基四胺在80ml三氟乙酸中的混合物在90℃下搅拌1.5小时。反应溶液减压浓缩。将所得残余物溶于乙酸乙酯,滴加到冰冷却的饱和碳酸氢钠水溶液中。回收乙酸乙酯层,用盐水洗涤。经无水硫酸镁干燥,过滤,减压浓缩。所得残余物用硅胶柱层析法纯化,得到5.8g 3-三氟甲基-p-茴香醛。
将5.8g 3-三氟甲基-p-茴香醛、8.6ml甲酰胺和13.6ml甲酸的混合物在130℃下搅拌9小时。冷却后,向其中加入水和乙酸乙酯。回收乙酸乙酯层,用盐水洗涤。经无水硫酸镁干燥,过滤,减压浓缩。所得残余物用硅胶柱层析法纯化,得到3.8g N-[4-甲氧基-3-(三氟甲基)苄基]甲酰胺。
将3.8g N-[4-甲氧基-3-(三氟甲基)苄基]甲酰胺溶于20ml乙醇,向其中加入2ml浓盐酸,混合物加热回流3小时。冷却后,向其中加入二***,过滤收集所得晶体,得到2.5g盐酸4-甲氧基-3-(三氟甲基)苄胺。
向2.2g 1,4-二氯酞嗪-6-甲腈、2.5g盐酸4-甲氧基-3-(三氟甲基)苄胺和25ml 1-甲基-2-吡咯烷酮的混合物中加入3.7g DBU,混合物在室温下搅拌1.25小时。向反应溶液中加入乙酸乙酯,然后用水和盐水洗涤。经无水硫酸钠干燥,过滤,蒸发。所得残余物用硅胶柱层析法纯化,得到1.66g标题化合物,为弱极性化合物。
1H-NMR(400MHz,DMSO-d6)δ;3.86(3H,s),4.74(2H,d,J=5.2Hz),7.22(1H,d,J=9.6Hz),7.67-7.71(2H,m),8.20(1H,d,J=8.4Hz),8.35(1H,dd,J=8.4,1.4Hz),8.50(1H,t,J=5,2Hz),8.99(1H,d,J=1.4Hz).
以相同方式,从市售2-碘茴香醚得到1-氯-4-[(3-碘-4-甲氧基苄基)氨基]-6-酞嗪甲腈;从3-溴-p-茴香醛得到4-[(3-溴-4-甲氧基苄基)氨基]-1-氯-6-酞嗪甲腈;从3-氟-p-茴香醛得到1-氯-4-[(3-氟-4-甲氧基苄基)氨基]-6-酞嗪甲腈;从3-甲基-p-茴香醛得到1-氯-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈。
中间体制备例2
1-氯-4-[(3-碘-4-甲氧基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.80(3H,s),4.67(2H,d,J=5.2Hz),6.96(1H,d,J=8.4Hz),7.42(1H,dd,J=8.4,2.0Hz),7.83(1H,d,J=2.0Hz),8.18(1H,d,J=8.4Hz),8.34(1H,dd,J=8.4,1.2Hz),8.45(1H,t,J=5.2Hz),8.99(1H,d,J=1.2Hz).
中间体制备例3
4-[(3-溴-4-甲氧基苄基)氨基]-1-氯-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.82(3H,s),4.70(2H,d,J=5.2Hz),7.07(1H,d,J=8.4Hz),7.41(1H,dd,J=8.4,2.0Hz),7.63(1H,d,J=2.0Hz),8.20(1H,d,J=8.4Hz),8.34(1H,dd,J=8.4,1.2Hz),8.47(1H,t,J=5.2Hz),8.99(1H,d,J=1.2Hz).
中间体制备例4
1-氯-4-[(3-氟-4-甲氧基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.81(3H,s),4.70(2H,d,J=5.4Hz),7.11(1H,t,J=8.8Hz),7.19(1H,d,J=8.8Hz),7.26(1H,dd,J=12.8,2.0Hz),8.20(1H,d,J=8.4Hz),8.35(1H,dd,J=8.4,0.8Hz),8.46(1H,t,J=5.4Hz),9.01(1H,d,J=0.8Hz).
中间体制备例5
1-氯-4-[(3-氰基-4-甲氧基苄基)氨基]-6-酞嗪甲腈
将20g 4-甲氧基苄基氯、26g邻苯二甲酰亚胺钾和100ml二甲基甲酰胺的混合物在50℃下搅拌5小时。冷却后,将反应溶液倒入冰水中,过滤收集所得沉淀。沉淀用水洗涤,干燥,得到31g N-(4-甲氧基苄基)邻苯二甲酰亚胺。
向31g N-(4-甲氧基苄基)邻苯二甲酰亚胺和100ml三氟乙酸的混合物中一点一点地加入18g六亚甲基四胺,在室温下搅拌1小时,然后加热回流4小时。反应溶液冷却至0℃,向其中加入水。向其中加入碳酸钾,过滤收集所得晶体。干燥晶体,得到20g N-(3-甲酰基-4-甲氧基苄基)邻苯二甲酰亚胺。
向20g N-(3-甲酰基-4-甲氧基苄基)邻苯二甲酰亚胺和200ml四氢呋喃的混合物中加入5.2g盐酸羟胺、12.2g乙酸钠和50ml水,在室温下搅拌1小时。在60℃下搅拌1小时,然后蒸发。向所得残余物中加入水,过滤收集不溶物。用二***洗涤,得到20g N-(3-肟基-4-甲氧基苄基)邻苯二甲酰亚胺。
向20g N-(3-肟基-4-甲氧基苄基)邻苯二甲酰亚胺和200ml二甲苯的混合物中加入6.7ml乙酸酐,混合物加热回流10小时。恢复至室温,过滤收集所得晶体,用二甲苯洗涤,得到15g N-(3-氰基-4-甲氧基苄基)邻苯二甲酰亚胺。
向15g N-(3-氰基-4-甲氧基苄基)邻苯二甲酰亚胺和200ml乙醇的混合物中加入3.9g一水合肼,混合物加热回流3小时。冷却后,过滤除去不溶物。蒸发滤液,向所得残余物中加入1N氢氧化钠水溶液,然后用二氯甲烷萃取。萃取液经无水硫酸镁干燥,过滤。蒸发滤液,得到8.0g 3-氰基-4-甲氧基苄胺。
在DBU的存在下,将1,4-二氯酞嗪-6-甲腈和3-氰基-4-甲氧基苄胺在室温的1-甲基-2-吡咯烷酮中搅拌,由此得到1-氯-4-[(3-氰基-4-甲氧基苄基)氨基]-6-酞嗪甲腈,为弱极性产物。
1H-NMR(400MHz,DMSO-d6)δ;3.87(3H,s),4.70(2H,d,J=5.6Hz),7.20(1H,d,J=8.4Hz),7.70(1H,dd,J=2.4,8.4Hz),7.75(1H,d,J=2.4Hz),8.19(1H,d,J=8.4Hz),8.34(1H,dd,J=1.2,8.4Hz),8.48(1H,t,J=5.6Hz),8.97(1H,s).
中间体制备例6
1-氯-4-[(3-乙基-4-甲氧基苄基)氨基]-6-酞嗪甲腈
在0℃下,向12.7g甲基三苯基溴化鏻的80ml四氢呋喃溶液中加入3.99g叔丁醇钾,向其中加入7g N-(3-甲酰基-4-甲氧基苄基)邻苯二甲酰亚胺,混合物在室温下搅拌1小时。使反应溶液通过硅藻土过滤,然后蒸发。所得残余物用硅胶柱层析法纯化,得到2.75g N-(4-甲氧基-3-乙烯基苄基)邻苯二甲酰亚胺。
将2.75g N-(4-甲氧基-3-乙烯基苄基)邻苯二甲酰亚胺溶于50ml四氢呋喃,向其中加入0.1g 10%Pd-C,混合物在氢气中搅拌40分钟。使反应溶液通过硅藻土过滤,蒸发滤液。所得残余物用硅胶柱层析法纯化,得到2.55g N-(3-乙基-4-甲氧基苄基)邻苯二甲酰亚胺。
向2.55g N-(3-乙基-4-甲氧基苄基)邻苯二甲酰亚胺和60ml乙醇的混合物中加入0.84ml一水合肼,混合物加热回流1小时。冷却后蒸发,向所得残余物中加入2N氢氧化钠水溶液,然后用二氯甲烷萃取。萃取液经无水硫酸镁干燥,过滤。蒸发滤液,向其中加入乙酸乙酯,然后过滤不溶物。向其中加入4N盐酸(乙酸乙酯溶液),过滤收集所得晶体,得到1.75g盐酸3-乙基-4-甲氧基苄胺。
在DBU的存在下,将1,4-二氯酞嗪-6-甲腈和盐酸3-乙基-4-甲氧基苄胺在室温的1-甲基-2-吡咯烷酮中搅拌,由此得到1-氯-4-[(3-乙基-4-甲氧基苄基)氨基]-6-酞嗪甲腈,为弱极性化合物。
1H-NMR(400MHz,CDCl3)δ;1.14(3H,t,J=7.5Hz),2.60(2H,q,J=7.5Hz),3.81(3H,s),4.84(2H,s),6.80(1H,d,J=8.2Hz),7.25(1H,d,J=2.0Hz),7.30(1H,dd,J=2.0,8.2Hz),8.06(1H,d,J=9.0Hz),8.27(1H,d,J=9.0Hz),8.42(1H,m).
中间体制备例7
1-氯-4-[(3-氯-4-甲基苄基)氨基]-6-酞嗪甲腈
在氮气中,将2.0g 3-氯-4-甲基苄腈的15ml四氢呋喃溶液滴加到453mg氢化锂铝的40ml四氢呋喃溶液中。混合物加热回流2小时又10分钟。混合物用冰冷却,使溶液保持在10℃或以下,向其中滴加0.45ml水、0.45ml 15%氢氧化钠水溶液和1.35ml水。使溶液通过硅藻土过滤,向所得滤液中加入无水硫酸钠进行干燥。使其通过NH型硅胶,蒸发滤液,得到1.74g 3-氯-4-甲基苄胺。
在DBU的存在下,将1,4-二氯酞嗪-6-甲腈和3-氯-4-甲基苄胺在室温的1-甲基-2-吡咯烷酮中搅拌,由此得到1-氯-4-[(3-氯-4-甲基苄基)氨基]-6-酞嗪甲腈,为弱极性化合物。
1H-NMR(400MHz,DMSO-d6)δ;2.29(3H,s),4.73(2H,d,J=5.2Hz),7.28-7.32(2H,m),7.45(1H,d,J=0.8Hz),8.20(1H,dd,J=8.4,0.4Hz),8.34(1H,d,J=8.4,1.6Hz),8.52(1H,t,J=5.2Hz),9.00(1H,m).
中间体制备例8
1-氯-4-[(4-氯-3-甲氧基苄基)氨基]-6-酞嗪甲腈
在DBU的存在下,将按照WO 9518097所述方法合成的盐酸4-氯-3-甲氧基苄胺和1,4-二氯酞嗪-6-甲腈在室温的1-甲基-2-吡咯烷酮中搅拌,由此得到1-氯-4-[(4-氯-3-甲氧基苄基)氨基]-6-酞嗪甲腈,为弱极性产物。
1H-NMR(400MHz,DMSO-d6)δ;3.86(3H,s),4.76(2H,d,J=5.5Hz),4.74(1H,d,J=4.2Hz),6.99(1H,dd,J=1.8,8.1Hz),7.22(1H,d,J=1.8Hz),7.35(1H,d,J=8.1Hz),8.21(1H,d,J=8.6Hz),8.36(1H,d,J=8.6Hz),8.52(1H,t,J=5.5Hz),9.03(1H,s).
中间体制备例9
1-氯-4-[(3,4-二氯苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;4.76(2H,d,J=5.4Hz),7.40(1H,dd,J=8.4,1.8Hz),7.58(1H,d,J=8.4Hz),7.68(1H,d,J=1.8Hz),8.21(1H,dd,J=8.4,0.4Hz),8.36(1H,dd,J=8.4,1.6Hz),8.57(1H,t,J=5.4Hz),8.99(1H,d,J=1.6Hz).
中间体制备例10
4-氟-4-羟甲基-1-哌啶羧酸苄酯
向16.1g叔丁醇钾和500ml四氢呋喃的混合物中加入51.1g甲基甲苯基溴化鏻,然后在室温下搅拌1小时又20分钟。向其中加入16.1g4-氧-1-哌啶羧酸苄酯,混合物在室温下搅拌2小时又40分钟。蒸发反应溶液,向其中加入二***,然后通过硅藻土过滤。滤液用水和盐水洗涤,经无水硫酸镁干燥,然后过滤。蒸发滤液,所得残余物用硅胶柱层析法纯化,得到25.5g 4-亚甲基-1-哌啶羧酸苄酯。
将14.7g 4-亚甲基-1-哌啶羧酸苄酯溶于300ml甲醇,向其中加入20.4g单过氧邻苯二甲酸镁盐和13.3g碳酸氢钠,混合物在室温下搅拌7.5小时。蒸发反应溶液。向所得残余物中加入乙酸乙酯,然后用水和盐水洗涤,经无水硫酸镁干燥,然后过滤。蒸发滤液,然后用硅胶柱层析法纯化,得到11.3g 1-氧杂-6-氮杂螺[2.5]辛烷-6-羧酸苄酯。
将5ml氟化氢吡啶和20ml二氯甲烷的混合物冷却,历时25分钟向其中滴加4.95g 1-氧杂-6-氮杂螺[2.5]辛烷-6-羧酸苄酯的10ml二氯甲烷溶液,同时使内温为0℃或以下。混合物在冰冷却下搅拌35分钟。将反应溶液倒入饱和碳酸氢钠与冰的混合物中。回收有机层,经无水硫酸镁干燥,过滤。蒸发滤液,然后用硅胶柱层析法纯化,得到2.84g标题化合物。
中间体制备例11
4-羟基-4-(1H-1-咪唑甲基)-1-哌啶羧酸叔丁酯
将13.5g 4-亚甲基-1-哌啶羧酸叔丁酯溶于300ml甲醇,向其中加入28.3g单过氧邻苯二甲酸镁盐和8.62g碳酸氢钠,混合物在室温下搅拌1天。使反应溶液通过硅藻土过滤,蒸发所得滤液。向所得残余物中加入乙酸乙酯,然后用水和盐水洗涤,经无水硫酸镁干燥,然后过滤。蒸发滤液,然后用硅胶柱层析法纯化,得到12.2g 1-氧杂-6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯。
将4.25g 1-氧杂-6-氮杂螺[2.5]辛烷-6-羧酸叔丁酯溶于30ml二甲基甲酰胺,向其中加入5.38g咪唑钠,混合物在60℃下搅拌3小时又40分钟。冷却后,向反应溶液中加入乙酸乙酯,用水洗涤3次,然后用盐水洗涤,经无水硫酸镁干燥,过滤。蒸发滤液,然后用硅胶柱层析法纯化,得到4.93g 4-羟基-4-(1H-1-咪唑甲基)-1-哌啶羧酸叔丁酯。
中间体制备例12
4-羟基-4-(1H-1,2,4-***-1-基甲基)-1-哌啶羧酸叔丁酯
用1,2,4-***钠代替中间体制备例11中的咪唑钠,得到标题化合物。
中间体制备例13
4-氟甲基-4-羟基-1-哌啶羧酸苄酯
向5g 1-氧杂-6-氮杂螺[2.5]辛烷-6-羧酸苄酯中加入3.2g氟化氢钾和610mg四正丁基三氟化二氢铵,在120℃下搅拌7小时。冷却后,向其中加入二氯甲烷,通过硅藻土过滤。蒸发滤液,所得残余物用硅胶柱层析法纯化,得到4.7g标题化合物。
中间体制备例14
盐酸4-羟基-4-哌啶甲酰胺(carboxamide)
将18ml浓硫酸和1.8ml水的混合溶液冷却至0℃,向其中一点一点地加入5g盐酸1-苄基-4-羟基-4-哌啶甲腈。向其中加入25ml浓硫酸和2.5ml水的混合溶液,在室温下搅拌2小时。在冰箱中放置过夜。将反应溶液倒在冰上,向其中一点一点地加入47g氢氧化钠。用四氢呋喃和乙酸乙酯的混合溶剂(1∶1)萃取3次。萃取液用盐水洗涤,经无水硫酸镁干燥,然后过滤。蒸发滤液,用硅胶柱层析法纯化,得到3.19g1-苄基-4-羟基-4-哌啶甲酰胺。
将3.19g 1-苄基-4-羟基-4-哌啶甲酰胺溶于150ml甲醇,向其中加入1.5g 20%氢氧化钯水溶液。混合物在4大气压的氢气中摇动4小时。使反应溶液通过硅藻土过滤,向滤液中加入5ml 4N HCl-二噁烷,然后蒸发。所得结晶状残余物用二异丙醚洗涤,过滤收集,得到1.96g标题化合物。
中间体制备例15
N-(3-氯-4-甲氧基苄基)-N-[4-氯-7-(1H-1-吡唑基)-1-酞嗪基]胺
历时30分钟向100g 4-氟邻苯二甲酸酐和1500ml甲醇的混合物中滴加110ml二氯亚砜。混合物加热回流8小时,蒸发。向所得残余物中加入冰水,然后用乙酸乙酯萃取。萃取液用盐水洗涤,经无水硫酸镁干燥,过滤。蒸发滤液,得到125g 4-氟邻苯二甲酸二甲酯。
历时40分钟向44g吡唑的200ml 1-甲基-2-吡咯烷酮溶液中加入26g油状氢化钠。历时30分钟向其中加入125g 4-氟邻苯二甲酸二甲酯,在室温下搅拌2小时。反应溶液冷却至0℃,加入冰水中。用乙酸乙酯萃取,用饱和碳酸氢钠和盐水洗涤。经无水硫酸镁干燥,过滤。蒸发滤液,向所得结晶状残余物中加入二***,然后过滤收集之,得到77g 4-(1H-1-吡唑基)邻苯二甲酸二甲酯。
向77g 4-(1H-1-吡唑基)邻苯二甲酸二甲酯和500ml乙醇的混合物中加入22ml一水合肼,混合物加热回流6小时。冷却后,过滤收集所得沉淀,得到36g 6-(1H-1-吡唑基)-1,4-酞嗪二酮。
向5.0g 6-(1H-1-吡唑基)-1,4-酞嗪二酮和20ml三氯氧磷的混合物中加入15ml二异丙基乙胺,混合物在110℃下搅拌0.5小时。反应溶液冷却至0℃,向其中加入乙酸乙酯,进一步向其中一点一点地加入冰和水。反应溶液在0℃下搅拌0.5小时,过滤除去不溶物。回收乙酸乙酯层,用盐水洗涤,经无水硫酸镁干燥,过滤。蒸发滤液,向所得结晶状残余物中加入乙酸乙酯,然后过滤收集之,得到3.8g 1,4-二氯-6-(1H-1-吡唑基)酞嗪。
向8g 1,4-二氯-6-(1H-1-吡唑基)酞嗪、9.5g盐酸3-氯-4-甲氧基苄胺和30ml 1-甲基-2-吡咯烷酮的混合物中加入14ml DBU,混合物在室温下搅拌1小时。进一步在60℃下搅拌3小时。反应溶液冷却至0℃,向其中加入乙酸乙酯,然后用水和盐水洗涤。经无水硫酸镁干燥,过滤,蒸发滤液。所得残余物用硅胶柱层析法纯化,由此得到2.6g标题化合物,为弱极性化合物。
1H-NMR(400MHz,DMSO-d6)δ;3.80(3H,s),4.68(2H,d,J=6.0Hz),6.70(1H,t,J=2.0Hz),7.09(1H,d,J=8.8Hz),7.35(1H,dd,J=2.0,8.4Hz),7.47(1H,d,J=2.0Hz),7.91(1H,d,J=2.0Hz),8.18(1H,d,J=9.2Hz),8.32(1H,t,J=5.6Hz),8.50(1H,dd,J=2.0,8.8Hz),8.68(1H,d,J=2.4Hz),8.78(1H,d,J=2.0Hz).
中间体制备例16
N-(3-氯-4-甲氧基苄基)-N-[4-氯-7-(1H-1,2,3-***-1-基)-1-酞嗪基]胺
除了用1,2,3-***代替吡唑以外,以中间体制备例15相同方式得到标题化合物。
1H-NMR(400MHz,CD3OD)δ;3.82(3H,s),4.72(2H,s),6.97(1H,d,J=8.4Hz),7.34(1H,dd,J=1.6,8.4Hz),7.44(1H,d,J=1.6Hz),7.99(1H,d,J=1.2Hz),8.34(1H,d,J=8.8Hz),8.52(1H,dd,J=1.6,8.8Hz),8.72(1H,d,J=1.2Hz),8.81(1H,d,J=2Hz).
中间体制备例17
6-溴-1-氯-4-[(3-氯-4-甲氧基苄基)氨基]酞嗪
向20g 4-溴邻苯二甲酸酐和400ml乙醇的混合物中加入96.9ml一水合肼,混合物加热回流8小时。冷却后,过滤收集所得沉淀,得到28g 6-溴-1,4-酞嗪二酮。
向6.8g 6-溴-1,4-酞嗪二酮和15ml三氯氧磷的混合物中加入15ml二异丙基乙胺,混合物加热回流1.5小时。冷却后,将反应溶液倒入冰水中,充分搅拌,用二氯甲烷萃取。含水层用乙酸乙酯萃取。合并了的萃取液经无水硫酸镁干燥,过滤。蒸发滤液,所得残余物用硅胶柱层析法纯化,得到4.3g 6-溴-1,4-二氯酞嗪。
向3.8g 6-溴-1,4-二氯酞嗪、3.5g盐酸3-氯-4-甲氧基苄胺和30ml1-甲基-2-吡咯烷酮的混合物中加入5.2ml DBU,混合物在100℃下搅拌3小时。冷却后,向反应溶液中加入水,然后用乙酸乙酯萃取。萃取液用盐水洗涤。经无水硫酸镁干燥,过滤,蒸发滤液。所得残余物用硅胶柱层析法纯化,由此得到1.8g标题化合物,为弱极性化合物。
中间体制备例18
1-(1,1-二甲基-2-丙炔基)-4-哌啶醇
在氮气中,向7.3g 4-羟基哌啶的5ml二***溶液和水(2.5ml)的混合溶液中加入24mg氯化亚铜和15mg铜粉。混合物用冰冷却,在内温为17至22℃下,向其中滴加2.7ml 3-氯-3-甲基-1-丁炔的2.5ml二***溶液。然后,在室温下搅拌过夜。向其中加入水,所得混合物用二***萃取5次。有机层合并,经碳酸钾干燥,然后经氢氧化钾干燥,过滤。滤液在常压下浓缩。向其中加入乙酸乙酯/己烷,过滤收集所得结晶状残余物,得到2.54g标题化合物。
中间体制备例19
1-(1,1-二甲基-2-丙炔基)吡咯烷
以中间体制备例18相同的方式,从吡咯烷和3-氯-3-甲基-1-丁炔得到标题化合物。
中间体制备例20
(2R)-1-氧杂-8-氮杂螺[4.5]癸-2-基甲醇
将105.5g(5S)-5-(羟甲基)四氢-2-呋喃酮溶于1.2L吡啶,在室温下向其中加入380g三苯甲基氯,混合物在80℃下搅拌过夜。反应完全后,混合物冷却,向其中加入水,用乙酸乙酯萃取,然后用盐水洗涤除去溶剂,将所得残余物溶于300ml氯仿,向其中加入600ml硅胶后,除去溶剂。所得残余物用硅胶柱层析法纯化,得到149.3g(5S)-5-[(三苯甲氧基)甲基]四氢-2-呋喃酮。
将26.9g(5S)-5-[(三苯甲氧基)甲基]四氢-2-呋喃酮溶于200mlTHF,在室温下向其中加入1M乙烯基溴化镁的300ml THF溶液,在加热回流下搅拌1.5小时。反应完全后,在冰冷却下向其中加入饱和氯化铵水溶液,用乙酸乙酯萃取,然后用盐水洗涤两次。除去溶剂,所得残余物用硅胶柱层析法纯化,得到13.0g(2S)-1-(三苯甲氧基)-5-乙烯基-6-庚烯-2,5-二醇。
将13.0g(2S)-1-(三苯甲氧基)-5-乙烯基-6-庚烯-2,5-二醇和57.2g甲苯磺酰氯溶于200ml吡啶,在80℃下搅拌过夜。反应完全后,向其中加入水,在室温下搅拌10分钟。用乙酸乙酯萃取两次后,用盐水洗涤,经硫酸镁干燥。除去溶剂,将所得残余物溶于甲苯。再次除去溶剂后,所得残余物用硅胶柱层析法纯化,得到5.88g(5R)-5-[(三苯甲氧基)甲基]-2,2-二乙烯基四氢呋喃。
将4.68g(5R)-5-[(三苯甲氧基)甲基]-2,2-二乙烯基四氢呋喃、100ml 0.5M 9-BBN和6.1g 9-BBN二聚物悬浮在100ml THF中,在加热回流下搅拌30小时。冷却后,在冰冷却下向其中加入50ml 30%过氧化氢和50ml 3N氢氧化钠,在50℃下搅拌20小时。反应完全后,使反应溶液恢复至室温,用乙酸乙酯萃取,用盐水洗涤,用硫酸镁干燥。除去溶剂所得残余物用硅胶柱层析法纯化,得到2.68g 2-(5R)-2-(羟乙基)-5-[(三苯甲氧基)甲基]四氢-2-呋喃基-1-乙醇。
将2.68g 2-(5R)-2-(羟乙基)-5-[(三苯甲氧基)甲基]四氢-2-呋喃基-1-乙醇和12ml吡啶溶于30ml二氯甲烷,在冰冷却下向其中加入11.82g甲苯磺酰氯,搅拌2.5小时。反应完全后,向其中加入30ml吡啶,然后浓缩。在冰冷却下再次向其中加入吡啶和水后,混合物搅拌15分钟。用乙酸乙酯萃取,用盐水洗涤,然后经硫酸镁干燥。蒸馏除去溶剂,向其中加入甲苯,再次蒸馏除去溶剂,然后将所得残余物用硅胶柱层析法纯化,得到4.17g 2-(5R)-[2-[(4-甲基苯基)磺酰]氧乙基]-5-[(三苯甲氧基)甲基]四氢-2-呋喃乙基4-甲基-1-苯磺酸酯。
将4.17g 2-(5R)-[2-[(4-甲基苯基)磺酰]氧乙基]-5-[(三苯甲氧基)甲基]四氢-2-呋喃乙基4-甲基-1-苯磺酸酯和5.36g苄胺溶于80mlDMF,在110℃下搅拌11.5小时。反应完全后,向其中加入水,用乙酸乙酯萃取,用盐水和饱和碳酸氢钠水溶液洗涤两次。经硫酸镁干燥后,除去溶剂,所得残余物用硅胶柱层析法纯化,得到2.1g(2R)-8-苄基-2-[(三苯甲氧基)甲基]-1-氧杂-8-氮杂螺[4.5]癸烷。
将2.10g(2R)-8-苄基-2-[(三苯甲氧基)甲基]-1-氧杂-8-氮杂螺[4.5]癸烷溶于20ml THF,在冰冷却下向其中加入4N盐酸的8ml二噁烷溶液,然后搅拌1小时。反应完全后,向其中加入水和饱和碳酸氢钠水溶液,用乙酸乙酯萃取两次,用饱和碳酸氢钠水溶液和盐水洗涤,然后经硫酸镁干燥。除去溶剂,所得残余物用硅胶柱层析法纯化,得到1.03g[(2R)-8-苄基-1-氧杂-8-氮杂螺[4.5]癸-2-基]甲醇。
将1.03g[(2R)-8-苄基-1-氧杂-8-氮杂螺[4.5]癸-2-基]甲醇和0.45g 10%钯碳悬浮在30ml乙醇中,在1大气压氢气氛下、在室温下搅拌18小时。过滤除去不溶物,除去溶剂,干燥,得到0.76g标题化合物。
中间例21
将25.0g 4-氧-1-哌啶羧酸叔丁酯的800ml二***溶液在冰/甲醇中冷却,向其中滴加烯丙基溴化镁的138ml溶液(1M二***溶液)。反应混合物搅拌3小时又10分钟。将反应溶液倒入饱和氯化铵水溶液与冰的混合物中。回收二***层,用盐水洗涤。经无水硫酸镁干燥,然后过滤。蒸发滤液,所得残余物用硅胶柱层析法纯化,得到15.9g 4烯丙基-4-羟基-1-哌啶羧酸叔丁酯。
将9.83g 4-烯丙基-4-羟基-1-哌啶羧酸叔丁酯溶于60ml四氢呋喃/水(9∶1),向其中加入四氧化锇的叔丁醇溶液(2.5wt%,2ml)和6.68gN-甲基吗啉-N-氧化物,混合物在室温下搅拌过夜。蒸发反应溶液,使所得残余物在乙酸乙酯和水中分布,用盐水洗涤,经硫酸镁干燥。过滤后,蒸发溶剂,所得残余物用硅胶柱层析法纯化(乙酸乙酯/甲醇),得到9.11g 4-(2,3-二羟丙基)-4-羟基-1-哌啶羧酸叔丁酯。
将9.11g 4-(2,3-二羟丙基)-4-羟基-1-哌啶羧酸叔丁酯溶于40ml吡啶,向其中加入10.0g氯代三苯甲烷,混合物在室温下搅拌过夜。使反应溶液在乙酸乙酯和水中分布,用2N盐酸、水、饱和碳酸氢钠水溶液和盐水洗涤,经硫酸镁干燥。过滤后,蒸发溶剂,所得残余物用硅胶柱层析法纯化(己烷/乙酸乙酯),得到10.3g 4-[3-(叔丁氧基)-2-羟丙基]-4-羟基-1-哌啶羧酸叔丁酯。
将2.59g 4-[3-(叔丁氧基)-2-羟丙基]-4-羟基-1-哌啶羧酸叔丁酯溶于10ml二甲基甲酰胺,向其中加入400mg氢化钠和823mg苄基氯,混合物在室温下搅拌20分钟。将反应溶液倒入冰水,用乙酸乙酯萃取,用水和盐水洗涤,经硫酸镁干燥。过滤后,蒸发溶剂,所得残余物用硅胶柱层析法纯化(己烷/乙酸乙酯),得到2.66g 4-[2-(苄氧基)-3-(叔丁氧基)丙基]-4-羟基-1-哌啶羧酸叔丁酯。
将2.36g 4-[2-(苄氧基)-3-(叔丁氧基)丙基]-4-羟基-1-哌啶羧酸叔丁酯溶于40ml乙腈,向其中加入426mg硝酸铈铵,混合物在室温下搅拌过夜。向反应溶液中加入硅胶,然后蒸发。用未吸附的硅胶柱纯化吸附的硅胶,用己烷-乙酸乙酯洗脱,得到547mg 4-[2-(苄氧基)-3-羟丙基]-4-羟基-1-哌啶羧酸叔丁酯。
将4.81g 4-[2-(苄氧基)-3-羟丙基]-4-羟基-1-哌啶羧酸叔丁酯溶于20ml吡啶,向其中加入2.76g甲苯磺酰氯,混合物在室温下搅拌2小时。进一步向其中加入1.00g甲苯磺酰氯,混合物在室温下搅拌30分钟,在50℃下搅拌35分钟。使反应溶液在乙酸乙酯和水中分布,用1N盐酸、饱和碳酸氢钠水溶液和盐水洗涤,经硫酸镁干燥。过滤后,蒸发溶剂,所得残余物用硅胶柱层析法纯化(己烷/乙酸乙酯),得到3.72g 3-(苄氧基)-1-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯。
将6.47g 3-(苄氧基)-1-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯溶于100ml四氢呋喃,向其中加入1.3g钯碳,混合物在氢气中搅拌过夜。从反应溶液中滤出催化剂,向其中加入1.3g钯碳,溶液在氢气中搅拌过夜。从反应溶液中滤出催化剂,向其中加入2.6g钯碳,溶液在4.2大气压氢气中搅拌过夜。从反应溶液中滤出催化剂,蒸发溶剂,所得残余物用硅胶柱层析法纯化(乙酸乙酯/甲醇),得到4.27g 3-羟基-1-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯。
中间体制备例22
盐酸(反式)-3-氧杂-9-氮杂二环[3.3.1]壬-7-醇
将2.0g氢化锂铝悬浮在200ml四氢呋喃中,在冰冷却下向其中滴加14.17g 9-甲基-3-氧杂-9-氮杂二环[3.3.1]壬-7-酮的20ml四氢呋喃溶液。搅拌35分钟后,按顺序向反应溶液中加入2.0ml水、2.0ml 15%氢氧化钠水溶液和6.0ml水,混合物在室温下搅拌。反应溶液过滤,蒸发溶剂。将所得残余物溶于乙酸乙酯,通过氧化铝过滤。蒸发溶剂,得到10.00g(反式)-9-甲基-3-氧杂-9-氮杂二环[3.3.1]壬-7-醇,为黄色蜡状物。
将10.0g(反式)-9-甲基-3-氧杂-9-氮杂二环[3.3.1]壬-7-醇溶于100ml四氢呋喃,向其中加入10.7ml三乙胺、7.2ml乙酸酐和0.77g4-二甲氨基吡啶,混合物在50℃下搅拌过夜。蒸发反应溶液,将所得残余物溶于乙酸乙酯,通过氧化铝过滤。浓缩滤液,用氧化铝柱层析法纯化(溶剂:正己烷/乙酸乙酯),得到8.68g(反式)-3-氧杂-9-氮杂二环[3.3.1]壬-7-基乙酸酯,为淡黄色油。
将8.68g(反式)-3-氧杂-9-氮杂二环[3.3.1]壬-7-基乙酸酯溶于40ml 1,2-二氯乙烷,向其中加入7.0ml氯甲酸乙烯酯。混合物在室温下搅拌30分钟,然后加热回流2小时又35分钟。蒸发反应溶液,用硅胶柱层析法纯化(溶剂:正己烷/乙酸乙酯),得到8.96g(反式)-3-氧杂-9-乙烯氧基羰基-9-氮杂二环[3.3.1]壬-7-基乙酸酯,为淡黄色油。
将8.96g(反式)-3-氧杂-9-乙烯氧基羰基-9-氮杂二环[3.3.1]壬-7-基乙酸酯溶于45ml甲醇,向其中加入30ml水和7.3g碳酸钾。混合物在室温下搅拌1小时又30分钟,再在50℃下搅拌30分钟。蒸发反应溶液,向其中加入盐水,用乙酸乙酯萃取。经无水硫酸镁干燥后,蒸发溶剂,由此得到7.37g(反式)-3-氧杂-9-乙烯氧基羰基-9-氮杂二环[3.3.1]壬-7-醇,为淡黄色油。
向7.37g(反式)-3-氧杂-9-乙烯氧基羰基-9-氮杂二环[3.3.1]壬-7-醇中加入4N氯化氢的17ml二噁烷溶液,混合物在室温下搅拌30分钟。向反应溶液中加入40ml乙醇,混合物加热回流1小时。蒸发溶剂,向所得残余物中加入乙酸乙酯,过滤收集所得沉淀,由此得到5.55g标题化合物,为白色针状晶体。
中间体制备例23
盐酸(顺式)-3-氮杂二环[3.2.1]辛-8-醇
以中间体制备例22相同的方式,从3-甲基-3-氮杂二环[3.2.1]辛-8-酮得到标题化合物。
中间体制备例24
盐酸(反式)-3-氧杂-7-氮杂二环[3.3.1]壬-9-醇
以中间体制备例22相同的方式,从7-甲基-3-氧杂-7-氮杂二环[3.3.1]壬-9-酮得到标题化合物。
中间体制备例25
盐酸(反式)-9-氮杂二环[3.3.1]壬-3-醇
以中间体制备例22相同的方式,从9-甲基-9-氮杂二环[3.3.1]壬-3-酮得到标题化合物。
中间体制备例26
盐酸(外)-8-氮杂二环[3.2.1]辛-3-醇
以中间体制备例22相同的方式,在(外)-8-甲基-8-氮杂二环[3.2.1]辛-3-醇的乙酰化作用后得到标题化合物。
中间体制备例27
盐酸(内)-8-氮杂二环[3.2.1]辛-3-醇
以中间体制备例22相同的方式,在(内)-8-甲基-8-氮杂二环[3.2.1]辛-3-醇的乙酰化作用后得到标题化合物。
中间体制备例28
盐酸(反式)-3-氮杂二环[3.3.1]壬-9-醇
将1.0g氢化锂铝悬浮在100ml四氢呋喃中,在冰冷却下向其中滴加7.00g 3-甲基-3-氮杂二环[3.3.1]壬-9-酮的20ml四氢呋喃溶液。搅拌50分钟后,按顺序向反应溶液中加入1.0ml水、1.0ml 15%氢氧化钠水溶液和3.0ml水,混合物在室温下搅拌。反应溶液过滤后,蒸发溶剂,由此得到7.08g淡黄色油。将该油溶于90ml四氢呋喃,向其中加入9.55ml三乙胺混合物然后在冰冷却下搅拌。向其中加入6.46ml乙酸酐和0.56g 4-二甲氨基吡啶,混合物在室温下搅拌14小时。向其中加入约20ml甲醇,然后蒸发反应溶液。向残余物中加入碳酸钾水溶液,然后用乙酸乙酯萃取。有机层用水和盐水洗涤,然后经无水硫酸钠干燥。蒸发溶剂,所得残余物用硅胶柱层析法纯化(溶剂:正己烷/乙酸乙酯),得到3.33g(反式)-3-甲基-3-氮杂二环[3.3.1]壬-9-基乙酸酯(无色的油),为极性较小的化合物。进一步得到2.06g(顺式)-3-甲基-3-氮杂二环[3.3.1]壬-9-基乙酸酯(淡橙色油),为极性较大的化合物。
将2.06g(反式)-3-甲基-3-氮杂二环[3.3.1]壬-9-基乙酸酯溶于10ml 1,2-二氯乙烷,向其中加入2.07ml氯甲酸乙烯酯。混合物在室温下搅拌50分钟,然后加热回流5小时又25分钟。蒸发反应溶液,向残余物中加入水,用乙酸乙酯萃取。有机层用1N盐酸、饱和碳酸氢钠水溶液和盐水洗涤,经无水硫酸镁干燥。蒸发溶剂,得到2.51g(反式)-3-乙烯氧基羰基-3-氮杂二环[3.3.1]壬-9-基乙酸酯,为淡橙色油。
将4.02g(反式)-3-乙烯氧基羰基-3-氮杂二环[3.3.1]壬-9-基乙酸酯溶于36ml乙醇,向其中加入18ml 1N氢氧化钠水溶液。混合物在室温下搅拌1小时又50分钟。蒸发反应溶液,向所得残余物中加入水,然后用乙酸乙酯萃取。有机层用水、饱和碳酸氢钠水溶液和盐水洗涤,经无水硫酸镁干燥。蒸发溶剂,然后将所得残余物用硅胶柱层析法纯化(溶剂:正己烷/乙酸乙酯),得到3.09g(反式)-3-乙烯氧基羰基-3-氮杂二环[3.3.1]壬-9-醇,为浅黄色油。
向3.09g(反式)-3-乙烯氧基羰基-3-氮杂二环[3.3.1]壬-9-醇中加入4N氯化氢/二噁烷的7ml溶液,混合物在室温下搅拌50分钟。蒸发反应溶液,向所得残余物中加入30ml乙醇,然后加热回流50分钟。蒸发溶剂,向所得残余物中加入乙酸乙酯,过滤收集所得沉淀,得到2.41g标题化合物,为浅乳白色细粉。
中间体制备例29
(顺式)-3-氮杂二环[3.3.1]壬-9-醇酸盐
以中间体制备例28相同的方式,从(顺式)-3-甲基-3-氮杂二环[3.3.1]壬-9-基乙酸酯得到标题化合物。
中间体制备例30
盐酸(反式)-2-(3-氮杂二环[3.3.1]壬-9-基)-1-乙醇
将1.0g氢化锂铝悬浮在30ml四氢呋喃中,在冰冷却下向其中滴加3.24g(反式)-甲基-(3-氮杂二环[3.3.1]壬-9-基)乙酸酯的25ml四氢呋喃混悬液。搅拌35分钟后,按顺序向反应溶液中加入1.0ml水、1.0ml 15%氢氧化钠水溶液和3.0ml水,在室温下搅拌。加入硅藻土和无水硫酸钠过滤反应混合物,蒸发溶剂。将残余物溶于乙酸乙酯,向其中加入5ml 4N盐酸/乙酸乙酯,过滤收集所得沉淀,得到2.29g标题化合物,为白色粉末。
中间体制备例31
1-氯-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;2.10(3H,s),3.73(3H,s),4.64(2H,d,J=5.4Hz),6.85(1H,d,J=8.0Hz),7.17-7.21(2H,m),8.15(1H,d,J=8.6Hz),8.31(1H,dd,J=8.6,1.2Hz),8.35(1H,t,J=5.4Hz),9.00(1H,d,J=1.2Hz).
实施例1
二盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(3-吡啶基)酞嗪
在-70℃以下,向2.53g 3-溴吡啶的50ml无水二***溶液中滴加10ml正丁基锂的己烷溶液(1.6M),搅拌30分钟。向所得混合物中加入5.21g三正丁基氯化锡的10ml无水二***溶液。经过1小时,反应溶液恢复至室温。将反应溶液倒入盐水,有机层用盐水洗涤。经无水硫酸镁干燥,然后蒸发,得到3-(1,1,1-三正丁基甲锡烷基)吡啶,为黄色的油。
将1-氯-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪、579mg四(三苯基膦)合钯、25ml二甲苯和3ml 1-甲基-2-吡咯烷酮的混合物剧烈搅拌并加热回流,历时1小时向其中滴加上面得到的3-(1,1,1-三正丁基甲锡烷基)吡啶的25ml二甲苯溶液。反应溶液进一步加热回流15分钟。反应溶液恢复至室温,用水洗涤三次,用盐水洗涤一次。用硅胶柱层析法纯化,得到偶联产物。将其悬浮在四氢呋喃与甲醇的混合溶剂中,然后向其中加入4N盐酸/乙酸乙酯溶液,蒸发混合物。所得产物用乙酸乙酯/甲醇重结晶,得到1.80g标题化合物,为无色粉末。
MASS(ESI);402.0(MH+)
1H-NMR(400MHz,DMSO-d6)δ;3.85(3H,s),4.06(2H,br),4.89(2H,br),7.18(1H,d,J=8.0Hz),7.53(1H,dd,J=8.0,1.2Hz),7.67(1H,d,J=1.2Hz),7.81-7.90(1H,m),8.07(1H,dd,J=8.8,0.4Hz),8.38-8.45(1H,m),8.46(1H,dd,J=8.8,1.4Hz),8.90-9.00(2H,m),9.57(1H,dd,J=1.4,0.4Hz),10.76(1H,br).
实施例2
二盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(2-吡啶基)酞嗪
除了用2-溴吡啶代替3-溴吡啶以外,以实施例1相同方式得到标题化合物。
MASS(ESI);402.0(MH+)
1H-NMR(400MHz,DMSO-d6)δ;3.83(3H,s),4.86-4.90(2H,m),7.16(1H,d,J=8.6Hz),7.52(1H,dd,J=8.6,2.1Hz),7.63-7.69(2H,m),7.97(1H,d,J=8.5Hz),8.08-8.13(1H,m),8.47(1H,dd,J=8.5,1.4Hz),8.72-8.83(2H,m),9.56(1H,d,J=1.4Hz),10.82-10.92(1H,m).
实施例3
盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(4-氰基哌啶子基)酞嗪
将15g 4-哌啶甲酰胺、16.3g苄基氯、32.3g碳酸钾和200ml N,N-二甲基甲酰胺的混合物在80℃下搅拌4小时。反应溶液恢复至室温,向其中加入氢氧化钠水溶液,然后用乙酸乙酯萃取。有机层用盐水洗涤,经无水硫酸钠干燥,然后蒸发。所得结晶状残余物用己烷/乙酸乙酯洗涤,过滤收集之。得到12.7g 1-苄基-4-哌啶甲酰胺,为白色鳞片状晶体。
在冰冷却下,向12.7g 1-苄基-4-哌啶甲酰胺和60ml三氯氧磷的混合物中加入5ml N,N-二甲基甲酰胺,在室温下搅拌1.5小时。蒸发,将所得残余物溶于乙酸乙酯,用氢氧化钠水溶液和盐水洗涤。经无水硫酸钠干燥后,蒸发,所得残余物用硅胶柱层析法纯化,得到11.0g 1-苄基-4-哌啶甲腈。
将11.0g 1-苄基-4-哌啶甲腈溶于100ml 1,2-二氯乙烷,在冰冷却下向其中加入7.1ml氯甲酸1-氯乙基酯。混合物在室温下搅拌15分钟,然后加热回流1小时又20分钟。蒸发后,向其中加入50ml乙醇,加热回流1小时。蒸发反应溶液,结晶状残余物用乙酸乙酯洗涤,过滤收集,得到8.0g盐酸4-哌啶甲腈,为白色晶体。
将1.2g所得盐酸4-哌啶甲腈、1.0g 1-氯-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪、1.8g二异丙基乙胺和10ml 1-甲基-2-吡咯烷酮的混合物在170℃下搅拌2小时又30分钟。冷却后,向反应溶液中加入乙酸乙酯,然后用水和盐水洗涤。经无水硫酸钠干燥后,蒸发溶剂,所得残余物用硅胶柱层析法纯化。将所得游离化合物溶于乙酸乙酯,然后向其中加入4N盐酸/乙酸乙酯溶液,过滤收集所得晶体,得到880mg标题化合物,为黄色粉末。
MASS(ESI);433.2(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.98-2.17(4H,m),3.10-3.33(5H,m),3.86(3H,s),4.70-4.74(2H,m),7.17(1H,d,J=8.4Hz),7.45(1H,dd,J=8.4,2.0Hz),7.61(1H,d,J=2,0Hz),8.27(1H,d,J=8.4Hz),8.47(1H,dd,J=8.4,0.8Hz),9.34-9.38(1H,m),10.28(1H,br).
实施例4
盐酸4-(3-氯-4-甲氧基苯乙基)氨基-6-氰基-1-(4-氰基哌啶子基)酞嗪
用1-氯-4-(3-氯-4-甲氧基苯乙基)氨基-6-氰基酞嗪代替实施例3中的1-氯-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪,得到标题化合物。
MASS(ESI);447.1(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.97-2.18(4H,m),2.94-3.00(2H,m),3.11-3.23(3H,m),3.33-3.40(2H,m),3.72-3.80(2H,m),3.82(3H,s),7.09(1H,d,J=8.4Hz),7.27(1H,dd,J=8.4,2.0Hz),7.44(1H,d,J=2.0Hz),8.28(1H,d,J=8.4Hz),8.47(1H,dd,J=8.4,0.8Hz),9.23-9.28(1H,m),9.85(1H,br).
实施例5
二盐酸1-(4-氨基哌啶子基)-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪
将10.0g 1-氯-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪溶于50ml1-甲基-2-吡咯烷酮,然后向其中加入43.32g 4-羟基哌啶和10ml二异丙基乙胺,混合物在170℃下加热8小时。冷却后,向其中加入乙酸乙酯,混合物用水洗涤三次,用盐水洗涤一次。经无水硫酸镁干燥后,蒸发溶剂。所得残余物用硅胶柱层析法纯化,得到10.1g 1-(4-羟基哌啶子基)-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪,为黄色晶体。
然后在冰冷却下,历时30分钟向4.2g 1-(4-羟基哌啶子基)-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪、2.94g邻苯二甲酰亚胺和5.24g三苯膦的100ml四氢呋喃溶液中滴加3.48g偶氮二羧酸二乙酯的30ml四氢呋喃溶液,然后在4℃下搅拌24小时。蒸发反应溶液,向其中加入水和乙酸乙酯,然后过滤除去不溶物。有机层浓缩,所得残余物用硅胶柱层析法纯化,得到4.85g 4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(4-邻苯二酰亚胺基哌啶子基)酞嗪。
将4.85g所得4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(4-邻苯二酰亚胺基哌啶子基)酞嗪、4ml一水合肼和40ml乙醇的混合物加热回流1小时。蒸发反应溶液,溶于乙酸乙酯,向其中加入1N盐酸,调其pH至3,过滤除去不溶物。滤液中的含水层用1N氢氧化钠调pH至11,然后用乙酸乙酯萃取。有机层用盐水洗涤,经无水硫酸钠干燥,蒸发,然后用硅胶柱层析法纯化。将所得产物悬浮在乙醇/水中,然后向其中加入1N盐酸水溶液,加热使其溶解。冷却后,过滤收集所得晶体,得到440mg标题化合物,为黄色粉末。
MASS(FAB);423(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.78-1.92(2H,m),2.03-2.11(2H,m),2.90-3.0(2H,m),3.20-3.34(1H,m),3.54-3.63(2H,m),3.82(3H,s),4.70(2H,d,J=5.6Hz),7.13(1H,d,J=8.4Hz),7.47(1H,dd,J=8.4,2.0Hz),7.62(1H,d,J=2.0Hz),8.17(1H,d,J=8.4Hz),8.35-8.45(2H,m),8.47(1H,dd,J=8.4,1.0Hz),9.54(1H,d,J=1.0Hz),10.63(1H,br).
实施例6
盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-[4-羟基-4-(羟甲基)哌啶子基]酞嗪
将7.9g 60%氢化钠用己烷洗涤,然后在减压下干燥。向其中加入100ml二甲基亚砜,在氮气中80至100℃下搅拌30分钟。用冰冷却,向其中加入180ml四氢呋喃。向其中滴加4.37g三甲基碘化锍的150ml二甲基亚砜溶液。混合物在冰冷却下搅拌30分钟后,向其中加入15g 1-苄基-4-哌啶酮,在冰冷却下搅拌30分钟,然后在室温下搅拌6小时。向反应溶液中加入水,然后用乙酸乙酯萃取。有机层用盐水洗涤,然后经无水硫酸钠干燥。用硅胶柱层析法纯化,得到6.8g 6-苄基-1-氧-6-氮杂螺[2.5]辛烷。
向6.8g该6-苄基-1-氧-6-氮杂螺[2.5]辛烷的100ml四氢呋喃溶液中加入100ml水和10ml高氯酸,混合物在室温下搅拌7小时。混合物用冰冷却,向其中加入碳酸钠水溶液,以调其pH至7,然后蒸发混合物。向残余物中加入乙酸乙酯,过滤除去不溶物。蒸发滤液,然后用硅胶柱层析法纯化,得到4g 1-苄基-4-(羟甲基)-4-哌啶醇。
然后,将1.46g 1-苄基-4-(羟甲基)-4-哌啶醇溶于30ml甲醇,向其中加入10ml乙酸和10%Pd-C,然后在4大气压下氢化。使反应溶液通过硅藻土过滤,蒸发滤液,将残余物溶于甲醇。向其中加入4N盐酸/乙酸乙酯,然后浓缩。过滤收集用甲醇/乙酸乙酯结晶所得晶体,得到880mg盐酸4-(羟甲基)-4-哌啶醇。
以实施例4相同方式,使所得4-(羟甲基)-4-哌啶醇与1-氯-4-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪反应,得到标题化合物。
MASS(FAB);454.2(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.46-1.54(2H,m),1.82-1.94(2H,m),3.16-3.30(6H,m),3.84(3H,s),4.68-4.72(2H,m),7.15(1H,d,J=8.6Hz),7.44(1H,dd,J=8.6,2.0Hz),7.59(1H,d,J=2.0Hz),8.22(1H,d,J=8.6Hz),8.45(1H,dd,J=8.6,1.0Hz),9.36(1H,d,J=1.0Hz).
实施例7
盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-[(2S)-2-(甲氧甲基)吡咯烷基]酞嗪
用(S)-2-甲氧甲基吡咯烷代替制备例1中的盐酸(R)-(+)-3-羟基哌啶,得到标题化合物。
MASS(ESI);438.1(MH+)
1H-NMR(400MHz,DMSO-d6)δ;1.81-1.89(2H,m),1.95-2.03(1H,m),2.15-2.24(1H,m),3.16(3H,s),3.28-3.37(1H,m),3.46-3.58(2H,m),3.84(3H,s),3.87-3.98(1H,m),4.44-4.57(1H,m),4.62-4.78(2H,m),7.15(1H,d,J=8.6Hz),7.47(1H,dd,J=8.6,0.4Hz),7.61(1H,d,J=0.4Hz),8.41-8.51(2H,m),9.42-9.60(1H,m),10.50(1H,br),13.79(1H,br).
实施例8
盐酸4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-苯基酞嗪
除了用苯基硼酸代替甲氧基苯基硼酸以外,以制备例10相同方式得到标题化合物。
MASS(ESI);401.1(MH+)
1H-NMR(400MHz,DMSO-d6)δ;3.84(3H,s),4.81-4.85(2H,m),7.15(1H,d,J=8.6Hz),7.48(1H,dd,J=8.6,2.1Hz),7.60-7.66(6H,m),8.00(1H,d,J=8.6Hz),8.41(1H,dd,J=8.6,0.9Hz),9.42(1H,d,J=0.9Hz).
实施例9
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈
向14.8g叔丁醇钾和300ml四氢呋喃的混合物中加入47.2g甲基甲苯基溴化鏻和21.9g 4-氧-1-哌啶羧酸叔丁酯,在室温下搅拌40分钟。蒸发反应溶液,向其中加入二***,然后通过硅藻土过滤。滤液用水和盐水洗涤,经无水硫酸镁干燥,然后过滤。蒸发滤液,所得残余物用硅胶柱层析法纯化,得到20.8g 4-亚甲基-1-哌啶羧酸叔丁酯。
向157.2g锌铜合金和500ml二***的混合物中加入49.3g 4-亚甲基-1-哌啶羧酸叔丁酯,历时5.5小时向其中滴加181.8g三氯乙酰氯的900ml二甲氧基乙烷溶液。搅拌30分钟后,反应溶液冷却,在0℃或以下向其中加入饱和碳酸氢钠水溶液。混合物通过硅藻土过滤,蒸发。所得残余物用乙酸乙酯萃取。萃取液用盐水洗涤,经无水硫酸镁干燥,过滤。蒸发滤液,所得残余物用硅胶柱层析法纯化,得到62.5g1,1-二氯-2-氧-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯。
向62.5g 1,1-二氯-2-氧-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯和500ml饱和氯化铵甲醇溶液的混合物中加入106.1g锌粉。混合物在室温下搅拌1小时又20分钟,通过硅藻土过滤。蒸发滤液,向其中加入1N盐酸/乙酸乙酯,回收有机层。萃取液用水、饱和碳酸氢钠和盐水洗涤,经无水硫酸镁干燥,过滤。蒸发滤液,所得残余物用硅胶柱层析法纯化,得到38.9g 2-氧-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯。
将300ml乙醇用冰冷却,在其中溶解6.13g硼氢化钠。历时25分钟向其中滴加38.9g 2-氧-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯的100ml乙醇溶液。反应溶液用饱和氯化铵水溶液处理,蒸发。使所得残余物在乙酸乙酯和水中分布,乙酸乙酯层用盐水洗涤,经硫酸镁干燥。过滤后,蒸发溶剂,所得残余物用硅胶柱层析法纯化(己烷/乙酸乙酯),得到36.6g 2-羟基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯。
1H-NMR(400MHz,CDCl3)δ;1.45(9H,s),1.43-1.57(4H,m),1.65-1.72(2H,m),3.27-3.35(4H,m),4.32(1H,quint,J=7.2Hz).
将6.22g 2-羟基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯溶于20ml四氢呋喃,向所得溶液中加入80ml 4N氯化氢/二噁烷溶液,然后在室温下搅拌1小时。蒸发反应溶液,将所得残余物溶于20ml 1-甲基-2-吡咯烷酮,向其中加入4.67g 1-氯-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈和6.72g二异丙基乙胺,然后在160℃下搅拌9小时。反应溶液恢复至室温,使其在乙酸乙酯和水中分布,含水层用乙酸乙酯萃取。乙酸乙酯层合并,按顺序用水(5次)和盐水洗涤,经硫酸镁干燥。过滤后,蒸发溶剂,所得残余物用硅胶柱层析法纯化(乙酸乙酯/甲醇),将所得粗晶体粉碎,在二***中洗涤,得到4.86g黄色晶体。将所得产物溶于150ml乙醇,向其中加入15ml 4N氯化氢/二噁烷溶液,蒸发溶剂。将所得残余物溶于150ml乙醇,加热至80℃,接种分别在含水乙醇中合成的晶体,当开始结晶时,停止加热。冷却至室温后,过滤收集之,用乙醇洗涤,得到4.35g标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;1.58-1.66(2H,m),1.68-1.76(4H,m),2.14-2.22(2H,m),3.05-3.16(4H,m),3.83(3H,s),4.12(1H,t,J=7.2Hz),4.72(2H,d,J=5.6Hz),7.14(1H,d,J=8.8Hz),7.45(1H,dd,J=8.8,2.0Hz),7.60(1H,d,J=2.0Hz),8.20(1H,d,J= 8.4Hz),8.44(1H,dd,J=8.4,1.2Hz),9.46(1H,s).
实施例10
4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-吡啶基)-6-酞嗪甲腈
以实施例1相同方式得到标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;3.80(3H,s),4.76(2H,d,J=5.5Hz),7.10(1H,d,J=8.8Hz),7.38(1H,dd,J=8.8,2.4Hz),7.50(1H,d,J=2.4Hz),7.64(2H,d,J=5.6Hz),7.94(1H,d,J=8.8Hz),8.20(1H,d,J=8.8Hz),8.52(1H,dd,J=5.5,5.5Hz),8.73(2H,d,J=5.6Hz),9.02(1H,s).
实施例11
4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-氧-2-氧杂-8-氮杂螺[4.5]癸-8-基)-6-酞嗪甲腈
将37.8g 2-氧-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯的567ml甲醇溶液用冰水冷却,向其中滴加43g 30%过氧化氢水溶液。向其中滴加63ml1N氢氧化钠水溶液,混合物在室温下搅拌2小时。向其中加入1000ml乙酸乙酯、600ml水和100ml饱和硫代硫酸钠五水合物水溶液,回收有机层。萃取过的溶液用盐水洗涤,经无水硫酸镁干燥,然后过滤。蒸发滤液,得到28.4g 3-氧-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯。
将1.16g 3-氧-2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯溶于2.3ml甲醇,向其中加入4.6ml 4N盐酸/乙酸乙酯,混合物在室温下搅拌1小时。向其中加入5ml乙酸乙酯,过滤收集所得晶体,得到700mg盐酸3-氧-2-氧杂-8-氮杂螺[4.5]癸烷。
将657mg 1-氯-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈、700mg盐酸3-氧-2-氧杂-8-氮杂螺[4.5]癸烷、0.44ml二乙基苯胺、137mg碘化钠和1.7ml 1-甲基-2-吡咯烷酮的混合物在130℃下搅拌15小时又40分钟。冷却后,反应溶液用40ml四氢呋喃、100ml乙酸乙酯和15ml1-甲基-2-吡咯烷酮稀释,然后用饱和碳酸氢钠水溶液和盐水洗涤。经无水硫酸镁干燥,然后过滤。蒸发滤液,所得残余物用硅胶柱层析法纯化,得到713mg 4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-氧-2-氧杂-8-氮杂螺[4.5]癸-8-基)-6-酞嗪甲腈。
1H-NMR(400MHz,CDCl3)δ;1.88-2.01(4H,m),2.53(2H,s),3.22-3.40(4H,m),3.90(3H,s),4.20(2H,s),4.77(2H,d,J=5.2Hz),5.20(1H,t,J=5.2Hz),6.92(1H,d,J=8.4Hz),7.32(1H,dd,J=8.4,2.0Hz),7.46(1H,d,J=2.0Hz),7.96(1H,dd,J=8.4,2.0Hz),8.11(1H,d,J=8.4Hz),8.14(1H,d,J=0.8Hz).
实施例12
4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-氧-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈
将500mg 4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈悬浮在20ml二氯甲烷和10ml四氢呋喃中,然后向其中加入690mg 1,1,1-三乙酰氧基-1,1-二氢-1,2-benziodoxsol-3(1H)-酮,混合物在室温下搅拌15分钟。向其中加入乙酸乙酯、30ml饱和碳酸氢钠水溶液和2ml饱和硫代硫酸钠5水合物水溶液。回收有机层,含水层用乙酸乙酯萃取。合并萃取过的溶液,用盐水洗涤,经无水硫酸镁干燥,然后过滤。蒸发滤液,所得残余物用硅胶柱层析法纯化,用乙醇结晶,向其中加入己烷,过滤收集所得晶体,得到420mg 4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-氧-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈。
1H-NMR(400MHz,DMSO-d6)δ;1.90(4H,m),2.86(4H,m),3.09(4H,s),3.80(3H,s),4.62(2H,d,J=5.6Hz),7.07(1H,d,J=8.5Hz),7.33(1H,d,J=8.5Hz),7.44(1H,s),7.89(1H,t,J=5.6Hz),8.09(1H,d,J=8.0Hz),8.19(1H,d,J=8.0Hz),8.88(1H,s).
实施例13
二盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-羟基-4-(1H-1-咪唑甲基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.49(2H,d,J=12.4Hz),1.82-1.93(2H,m),3.13(2H,t,J=10.8Hz),3.37(2H,d,J=12.4Hz),3.82(3H,s),4.30(2H,s),4.74(2H,d,J=5.6Hz),7.13(1H,d,J=8.8Hz),7.48(1H,dd,J=2.0,8.4Hz),7.63(1H,d,J=2.0Hz),7.66-7.71(2H,m),8.18(1H,d,J=8.4Hz),8.48(1H,d,J=8.4Hz),9.10(1H,s),9.60(1H,s).
实施例14
二盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-羟基-4-(1H-1,2,4-***-1-基甲基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.54(2H,d,J=12.8Hz),1.82-1.92(2H,m),3.15(2H,t,J=11.2Hz),3.35(2H,d,J=12.8Hz),3.82(3H,s),4.29(2H,s),4.73(2H,d,J=6.0Hz),7.13(1H,d,J=8.4Hz),7.48(1H,dd,J=2.0,8.4Hz),7.62(1H,d,J=2.0Hz),8.20(1H,d,J=8.4Hz),8.21(1H,s),8.45(1H,dd,J=1.2,8.4Hz),8.79(1H,s),9.56(1H,s),10.75(1H,br-s).
实施例15
1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-(1H-1,2,3,4-四唑-5-基)-1-酞嗪基]-4-哌啶醇
向1.0g 4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈、1.2g盐酸三乙胺和20ml 1-甲基-2-吡咯烷酮的混合物中加入0.55g叠氮化钠,在100℃下搅拌8小时。反应溶液恢复至室温,向其中加入水,过滤收集所得晶体,得到1.0g标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;1.58-1.7(2H,m),1.8-1.97(2H,m),2.8-2.98(2H,m),3.3-3.43(2H,m),3.6-3.7(1H,m),3.79(3H,s),4.6(2H,s),7.06(1H,d,J=8Hz),7.34(1H,d,J=8Hz),7.45(1H,s),7.95(1H,d,J=8Hz),8.45(1H,d,J=8Hz),8.89(1H,s).
实施例16
1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-(1-甲基-1H-1,2,3,4-四唑-5-基)-1-酞嗪基]-4-哌啶醇
向0.25g 1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-(1H-1,2,3,4-四唑-5-基)-1-酞嗪基]-4-哌啶醇、1.2g碳酸钾和5ml二甲基甲酰胺的混合物中加入0.037ml碘甲烷,在室温下搅拌3小时。向反应溶液中加入水,过滤收集沉淀出来的不溶物。然后,用硅胶柱层析法纯化,得到50mg标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;1.6-1.7(2H,m),1.85-1.95(2H,m),2.85-2.95(2H,m),3.25-3.45(2H,m),3.6-3.7(1H,m),3.80(3H,s),4.48(3H,s),4.61(2H,d,J=5.6Hz),4.73(1H,d,J=4.0Hz),7.07(1H,d,J=8.4Hz),7.34(1H,dd,J=2.0,8.4Hz),7.44(1H,d,J=2.0Hz),8.07(1H,t,J=5.6Hz),8.10(1H,d,J=8.4Hz),8.47(1H,d,J=8.8Hz),9.00(1H,s).
实施例17
4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪硫代甲酰胺
向2.0g 4-[(3-氯-4-甲氧基苄基)氨基]-1-(羟基哌啶子基)-6-酞嗪甲腈、1ml水和2ml并丙醇的混合物中加入3.7ml二硫代磷酸二乙酯,混合物加热回流1小时。冷却后,向反应溶液中加入水,过滤收集所得晶体。滤液用乙酸乙酯萃取,用盐水洗涤。经无水硫酸钠干燥,过滤。蒸发滤液,将所得结晶状残余物与上面过滤收集的晶体合并,由此得到1.5g标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;1.6-1.7(2H,m),1.85-2.00(2H,m),2.90-3.1(2H,m),3.3-3.5(2H,m),3.6-3.8(1H,m),3.81(3H,s),4.68(2H,d,J=4Hz),7.13(1H,d,J=8Hz),7.40(1H,d,J=8Hz),7.54(1H,s),8.08(1H,d,J=8Hz),8.3-8.4(1H,m),8.9-9.1(1H,m),9.88(1H,s),10.33(1H,s).
实施例18
1-[4-[(3-溴-4-甲氧基苄基)氨基]-6-(4-甲基-1,3-噻唑-2-基)-1-酞嗪基]-4-哌啶醇
将1.5g 4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪硫代甲酰胺溶于50ml二甲基甲酰胺,向其中加入1.1ml氯丙酮,混合物在100℃下搅拌4小时。冷却后,向反应溶液中加入水,用滗析法除去含水层。残余物在减压下干燥,然后用硅胶色谱法纯化,得到200mg标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;1.6-1.7(2H,m),1.85-1.95(2H,m),2.47(3H,s),2.83-2.94(2H,m),3.3-3.4(2H,m),3.6-3.7(1H,m),3.80(3H,s),4.63(2H,d,J=5.6Hz),4.72(1H,d,J=4.0Hz),7.07(1H,d,J=8.4Hz),7.34(1H,dd,J=2.0,8.4Hz),7.44(1H,d,J=2.0Hz),7.48(1H,s),7.96-8.04(1H,m),8.01(1H,d,J=8.4Hz),8.36(1H,dd,J=1.6,8.4Hz),8.76(1H,d,J=1.6Hz).
实施例19
盐酸1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-(2-噻吩基)-1-酞嗪基]-4-哌啶醇
向200mg 1-[6-溴-4-[(3-溴-4-甲氧基苄基)氨基]-1-酞嗪基]-4-哌啶醇和2ml甲苯的混合物中加入24mg四(三苯基膦)合钯(O)和1.4ml2-(三丁基甲锡烷基)噻吩。混合物加热回流2小时。冷却后,将反应溶液倒入冰水中,用乙酸乙酯萃取。萃取过的溶液经无水硫酸镁干燥,然后过滤。蒸发滤液,残余物用硅胶色谱法纯化。用4N盐酸/乙酸乙酯将所得产物转化为盐酸盐,得到73mg标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;1.67(2H,m),1.92(2H,m),3.00(2H,m),3.45(2H,m),3.74(1H,m),3.82(3H,s),4.73(2H,m),7.13(1H,d,J=7.2Hz),7.27(1H,s),7.46(1H,d,J=7.2Hz),7.61(1H,s),7.79(1H,d,J=5.6Hz),8.03(1H,d,J=5.6Hz),8.09(1H,d,J=8.8Hz),8.34(1H,d,J=8.8Hz),9.20(1H,br-s).
实施例20
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲醛(carbaldehyde)肟
将10.0g 4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈和5.3g叔丁基二甲基氯硅烷溶于80ml二甲基甲酰胺,向其中加入4.8g咪唑。混合物在室温下搅拌过夜。向反应溶液中加入乙酸乙酯,然后用水洗涤一次,用盐水洗涤两次。混合物经无水硫酸镁干燥,过滤。蒸发滤液,得到11.7g 1-[4-[[1-(叔丁基)-1,1-二甲基甲硅烷基]氧]哌啶子基]-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈。
将11.7g 1-[4-[[1-(叔丁基)-1,1-二甲基甲硅烷基]氧]哌啶子基]-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈溶于150ml二氯甲烷,冷却。在-78℃下,向其中加入1M氢化二异丁基铝的44ml甲苯溶液。恢复至室温后,混合物搅拌过夜。向其中加入100ml饱和氯化铵水溶液,混合物在室温下搅拌0.5小时。向其中加入40ml 10%硫酸后,用乙酸乙酯萃取。萃取过的溶液用盐水洗涤,经无水硫酸镁干燥,然后过滤。蒸发滤液,残余物用硅胶柱层析法纯化,得到5.3g 1-[4-[[1-(叔丁基)-1,1-二甲基甲硅烷基]氧]哌啶子基]-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲醛。
将1.5g 1-[4-[[1-(叔丁基)-1,1-二甲基甲硅烷基]氧]哌啶子基]-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲醛和0.35g盐酸羟胺溶于50ml甲醇,混合物加热回流2小时。冷却后,向其中加入水,然后用乙酸乙酯萃取。萃取过的溶液用盐水洗涤,经无水硫酸镁干燥,然后过滤。蒸发滤液,残余物用硅胶柱层析法纯化,得到1.18g 1-[4-[[1-(叔丁基)-1,1-二甲基甲硅烷基]氧]哌啶子基]-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲醛肟。
向1.18g 1-[4-[[1-(叔丁基)-1,1-二甲基甲硅烷基]氧]哌啶子基]-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲醛肟的30ml四氢呋喃溶液中加入1M四丁基氟化铵的四氢呋喃溶液。混合物在室温下搅拌过夜。向反应溶液中加入水,然后用乙酸乙酯萃取。萃取过的溶液用盐水洗涤,经无水硫酸镁干燥,然后过滤。蒸发滤液,所得结晶状残余物用乙酸乙酯洗涤,过滤收集之,得到0.34g标题化合物。将该产物以常规方法转化为盐酸盐。
1H-NMR(400MHz,DMSO-d6)δ;1.58-1.70(2H,m),1.86-1.95(2H,m),2.92-3.02(2H,m),3.08-3.22(2H,m),3.64-3.73(1H,m),3.82(3H,s),4.61-4.68(2H,m),4.77-4.79(1H,m),7.10(1H,d,J=8Hz),7.38(1H,d,J=8Hz),7.51(1H,s),8.06(1H,d,J=8Hz),8.23(1H,d,J=8Hz),8.28(1H,s),8.69-8.76(1H,m).
实施例21
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[(2R)-2-(羟甲基)-1-氧杂-8-氮杂螺[4.5]癸-8-基]-6-酞嗪甲腈
将1.08g 1-氯-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈和0.76g(2R)-1-氧杂-8-氮杂螺[4.5]癸-2-基甲醇溶于20ml N-甲基-2-吡咯烷酮,在160℃下搅拌5小时。反应完全后,反应溶液恢复至室温,向其中加入水和饱和碳酸氢钠水溶液,用乙酸乙酯萃取,用盐水洗涤三次。经硫酸镁干燥后,除去溶剂,残余物用硅胶柱层析法纯化,得到0.60g结晶状化合物。
将所得化合物溶于20ml乙醇,在室温下向其中加入1.40ml 1N盐酸/乙醇,混合物搅拌10分钟。除去溶剂后,残余物用二异丙醚处理,然后干燥,得到555mg标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;1.67-1.98(8H,m),3.15-3.40(6H,m),3.82(3H,s),3.90-3.98(1H,m),4.68-4.77(2H,m),7.14(1H,d,J=9Hz),7.46(1H,dd,J=2,9Hz),7.62(1H,d,J=2Hz),8.23(1H,d,J=9Hz),8.45(1H,d,J=9Hz),9.50(1H,s).
实施例22
盐酸(反式)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(7-羟基-3-氧杂-9-氮杂二环[3.3.1]壬-9-基)-6-酞嗪甲腈
向8ml N-甲基-2-吡咯烷酮中加入1.5g 1-氯-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈、1.13g盐酸(反式)-3-氧杂-9-氮杂二环[3.3.1]壬-7-醇和2.16ml二异丙基乙胺,混合物在170℃下搅拌9小时又15分钟。向反应溶液中加入水,然后用乙酸乙酯萃取,有机层用水和盐水洗涤。混合物经无水硫酸镁干燥后,蒸发溶剂。残余物用硅胶柱层析法纯化(溶剂:二氯甲烷/甲醇),得到0.085g黄色的油。
将所得油溶于乙酸乙酯,然后向其中加入0.05ml 4N氯化氢/乙酸乙酯,混合物在室温下搅拌。过滤收集所得沉淀,得到0.075g标题化合物。
1H-NMR(400MHz,DMSO-d6)δ;1.69-1.78(2H,m),2.46-2.56(2H,m),3.77-3.84(2H,m),3.86(3H,s),3.86-3.95(3H,m),4.04-4.12(2H,m),4.74(2H,s),7.17(1H,d,J=8.4Hz),7.46(1H,dd,J=2.2,8.4Hz),7.61(1H,d,J=2.2Hz),8.13(1H,d,J=8.4Hz),8.45(1H,d,J=8.4Hz),9.39(1H,m).
实施例23
盐酸(反式)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(9-羟基-3-氮杂二环[3.3.1]壬-3-基)-6-酞嗪甲腈
向8ml N-甲基-2-吡咯烷酮中加入1.5g 1-氯-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈、1.12g盐酸(反式)-3-氮杂二环[3.3.1]壬-9-醇和2.18ml二异丙基乙胺,混合物在170℃下搅拌9小时。向反应溶液中加入水,然后用乙酸乙酯萃取,有机层用水和盐水洗涤。经无水硫酸镁干燥,然后蒸发溶剂。向其中加入二氯甲烷,过滤收集不溶物,得到1.23g淡黄色粉末。将所得粉末悬浮在乙酸乙酯中,向其中加入0.7ml 4N氯化氢/乙酸乙酯,混合物在室温下搅拌。过滤收集所得沉淀,得到1.28g标题化合物,为浅色粉末。
1H-NMR(400MHz,DMSO-d6)δ;1.54(1H,m),1.66-1.75(2H,m),1.86-1.93(2H,m),2.11-2.23(2H,m),2.38(1H,m),3.15-3.24(2H,m),3.62-3.70(2H,m),3.75(1H,m),3.85(3H,s),4.74(2H,s),7.16(1H,d,J=8.4Hz),7.47(1H,dd,J=1.8,8.4Hz),7.62(1H,d,J=1.8Hz),8.23(1H,d,J=8.4Hz),8.56(1H,dd,J=1.3,8.4Hz),9.49(1H,m).
实施例24
盐酸(反式)-4-[(3-氯-4-甲氧基苄基)氨基]-1-[9-(2-羟乙基)-3-氮杂二环[3.3.1]壬-3-基]-6-酞嗪甲腈
向8ml N-甲基-2-吡咯烷酮中加入1.5g 1-氯-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈、1.29g盐酸(反式)-2-(3-氮杂二环[3.3.1]壬-9-基)-1-乙醇和2.18ml二异丙基乙胺,混合物在170℃下搅拌8小时又40分钟。向反应溶液中加入水,然后用乙酸乙酯萃取,有机层用水和盐水洗涤。反应溶液经无水硫酸镁干燥,然后蒸发溶剂。残余物用硅胶柱层析法纯化(溶剂:二氯甲烷/甲醇),用二氯甲烷-乙酸乙酯-***结晶,得到1.12g淡黄色粉末。将所得粉末悬浮在丙酮中,向其中加入2ml 4N氯化氢/乙酸乙酯和乙酸乙酯,混合物在室温下搅拌。过滤收集所得沉淀,得到0.98g标题化合物,为淡黄色粉末。
1H-NMR(400MHz,DMSO-d6)δ;1.61(1H,m),1.66-1.73(2H,m),1.73-1.87(5H,m),1.88-2.00(2H,m),2.42(1H,m),3.14-3.23(2H,m),3.49(2H,t,J=6.4Hz),3.67-3.76(2H,m),3.85(3H,s),4.73(2H,s),7.16(1H,d,J=8.6Hz),7.47(1H,dd,J=1.6,8.6Hz),7.62(1H,d,J=1.6Hz),8.24(1H,d,J=8.4Hz),8.55(1H,dd,J=1.3,8.4Hz),9.46(1H,m).
实施例25
盐酸1-(3-氨基-3-甲基-1-丁炔基)-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈
向500mg 1-氯-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈、53mg碘化亚铜、98mg二氯双(三苯基膦)合钯(II)、347mg 3-氨基-3-甲基-1-丁炔和10ml二甲基甲酰胺的混合物中加入0.39ml三乙胺,混合物在80℃氮气氛下搅拌3小时。冷却后,向反应溶液中加入乙酸乙酯,然后向其中加入水和浓氨水,回收有机层。有机层用稀氨水和盐水洗涤,经无水硫酸钠干燥。过滤,蒸发滤液。所得残余物用NH型硅胶柱层析法纯化,得到446mg标题化合物。以常规方法将产物转化为盐酸盐。
1H-NMR(400MHz,DMSO-d6)δ;1.75(6H,s),3.82(3H,s),4.76(2H,d,J=5.6Hz),7.10(1H,d,J=8.4Hz),7.37(1H,dd,J=8.4,2.2Hz),7.50(1H,d,J=2.2Hz),8.31(1H,dd,J=8.4,1.4Hz),8.35(1H,d,J=8.4Hz),8.83(1H,t,J=5.6Hz),8.92-9.05(3H,m),9.07(1H,br).
实施例26
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(甲氧基亚氨基)哌啶子基]-6-酞嗪甲腈
将1.19g 4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-氧哌啶子基)-6-酞嗪甲腈、354mg盐酸甲氧胺、1.2g碳酸钠和10ml乙醇加热回流2小时。冷却后,向反应溶液中加入盐水,然后用乙酸乙酯萃取。经无水硫酸钠干燥,过滤。蒸发滤液,所得残余物用硅胶柱层析法纯化,得到620mg 4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(甲氧基亚氨基)哌啶子基]-6-酞嗪甲腈。将该产物溶于甲醇与乙醇的混合溶剂,加入0.35ml4N盐酸/乙酸乙酯重结晶,得到388mg盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(甲氧基亚氨基)哌啶子基]-6-酞嗪甲腈。
1H-NMR(400MHz,DMSO-d6)δ;2.50-2.55(2H,m),2.74-2.80(2H,m),3.29-3.35(4H,m),3.77(3H,s),3.85(3H,s),4.72(2H,br),7.16(1H,d,J=8.4Hz),7.45(1H,dd,J=8.4,2.0Hz),7.60(1H,d,J=2.0Hz),8.33(1H,d,J=8.8Hz),8.48(1H,dd,J=8.8,0.8Hz),9.35(1H,d,J=0.8Hz),10.19(1H,br).
使用相应的原料,以制备例或实施例相同的方式合成下列化合物。
实施例27
盐酸4-[(3-氯-4-甲基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.62-1.73(2H,m),1.90-1.99(2H,m),2.32(3H,s),2.98-3.08(2H,m),3.42-3.50(2H,m),3.72-3.80(1H,m),4.76(2H,d,J=5.6Hz),7.36(2H,s),7.57(1H,s),8.23(1H,d,J=8.4Hz),8.47(1H,dd,J=8.4,1.2Hz),9.37(1H,d,J=1.2Hz),10.21(1H,br).
实施例28
4-[(3-氯-4-甲氧基苄基)氨基]-1-(5-羟基全氢环戊烷并[c]吡咯-2-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.40-1.49(2H,m),2.02-2.12(2H,m),2.55-2.64(2H,m),3.24(4H,d,J=4.0Hz),3.80(3H,s),3.94-4.04(1H,m),4.61(2H,d,J=5.2Hz),4.72(1H,d,J=5.6Hz),7.07(1H,d,J=8.4Hz),7.32(1H,dd,J=2.0,8.4Hz),7.77-7.83(1H,m),8.14-8.23(2H,m),8.66(1H,d,J=0.8Hz).
实施例29
4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(2-羟乙基)-1,2,3,6-四氢-1-吡啶基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;2.15-2.22(2H,m),2.27-2.39(2H,m),3.20(2H,t,J=5.6Hz),3.48-3.60(2H,m),3.69(2H,s),3.80(3H,s),4.47(1H,t,J=5.6Hz),4.61(2H,d,J=5.6Hz),5.55(1H,d,J=0.4Hz),7.08(1H,d,J=8.4Hz),7.33(1H,dd,J=2.0,8.4Hz),7.44(1H,d,J=2.0Hz),7.83-7.89(1H,m),8.04(1H,d,J=8.4Hz),8.08(1H,dd,J=1.2,8.4Hz),8.87(1H,t,J=0.4Hz).
实施例30
4-[(3-氯-4-甲氧基苄基)氨基]-1-[3-(羟甲基)四氢-1H-1-吡咯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.59-1.70(1H,m),1.83-2.02(2H,m),2.31-2.41(1H,m),3.34-3.60(5H,m),4.58(2H,J=5.6Hz),4.67(1H,t,J=5.6Hz),7.07(1H,d,J=8.4Hz),7.32(1H,dd,J=2.0,8.4Hz),7.43(1H,d,J=2.0Hz),7.56-7.62(1H,m),8.14(1H,dd,J=1.6,8.8Hz),8.23(1H,d,J=8.8Hz),8.820(1H,d,J=1.2Hz).
实施例31
4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(羟甲基)-1,2,3,6-四氢-1-吡啶基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;2.28(2H,br-s),3.19-3.26(2H,m),3.73(2H,br-s),3.80(3H,s),3.89(2H,d,J=4.4Hz),4.62(2H,d,J=5.6Hz),4.78(1H,t,J=5.6Hz),5.72(1H,br-s),7.08(1H,d,J=8.4Hz),7.33(1H,dd,J=2.0,8.4Hz),7.44(1H,d,J=2.0Hz),7.87(1H,t,J=5.6Hz),8.05(1H,d,J=8.4Hz),8.18(1H,dd,J=1.2,8.4Hz),8.87(1H,d,J=1.2Hz).
实施例32
盐酸2-[1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]-4-哌啶基]丙酸
1H-NMR(400MHz,DMSO-d6)δ;1.08(3H,d,J=6.8Hz),1.46-1.64(2H,m),1.66-1.83(3H,m),2.22-2.32(1H,m),2.78-2.90(2H,m),3.54-3.64(2H,m),3.83(3H,s),4.72(2H,d,J=6.0Hz),7.14(1H,d,J=8.4Hz),7.46(1H,dd,J=2.0,8.4Hz),7.61(1H,d,J=2.0Hz),8.22(1H,d,J=8.4Hz),8.45(1H,dd,J=1.6,8.4Hz),9.49(1H,s).
实施例33
盐酸2-[1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]-1,2,3,6-四氢-4-吡啶基]乙酸
1H-NMR(400MHz,DMSO-d6)δ;2.38-2.44(2H,m),3.04(2H,s),3.79-3.83(2H,m),3.83(3H,s),4.72(2H,t,J=2.8Hz),5.63-5.68(1H,m),7.15(1H,d,J=8.8Hz),7.46(1H,dd,J=2.4,8.4Hz),7.61(1H,d,J=2.4Hz),8.21(1H,d,J=8.8Hz),8.46(1H,dd,J=1.2,8.4Hz),9.45(1H,s).
实施例34
盐酸2-[1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]-4-哌啶基]-2-氟乙酸
1H-NMR(400MHz,DMSO-d6)δ;1.60-1.90(4H,m),2.03-2.20(1H,m),2.83-2.98(2H,m),3.58-3.65(2H,m),3.83(3H,s),4.73(2H,t,J=2.8Hz),4.98(1H,dd,J=4.0,48.4Hz),7.14(1H,d,J=8.4Hz),7.46(1H,dd,J=2.0,8.4Hz),7.61(1H,d,J=2.4Hz),8.23(1H,d,J=8.4Hz),8.44(1H,dd,J=1.2,8.4Hz),8.46(1H,s).
实施例35
盐酸2-[1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]-4-哌啶基]乙酸
1H-NMR(400MHz,DMSO-d6)δ;1.44-1.57(2H,m),1.79-1.84(2H,m),1.85-1.96(1H,m),2.25(2H,d,J=6.8Hz),2.89(2H,t,J=12.0Hz),3.55(2H,d,J=12.0Hz),3.84(3H,s),4.70(2H,d,J=6.0Hz),7.15(1H,d,J=8.8Hz),7.44(1H,dd,J=2.0,8.4Hz),7.94(1H,d,J=2.0Hz),8.21(1H,d,J=8.4Hz),8.46(1H,dd,J=1.6,8.8Hz),9.37(1H,s).
实施例36
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(1-氟-2-羟乙基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.56-1.78(3H,m),1.83-1.99(2H,m),2.80-2.91(2H,m),3.51-3.69(4H,m),3.83(3H,s),4.25-4.31(1/2H,m),4.37-4.43(1/2H,m),4.73(2H,d,J=5.6Hz),7.14(1H,d,J=8.4Hz),7.47(1H,dd,J=2.0,8.4Hz),7.62(1H,d,J=2.0Hz),8.22(1H,d,J=8.4Hz),8.45(1H,dd,J=1.2,8.4Hz),9.52(1H,s),10.58(1H,s).
实施例37
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(2-羟基乙氧基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.68-1.77(4H,m),1.98-2.07(2H,m),2.98-3.07(2H,m),3.44-3.52(2H,m),3.56-3.62(3H,m),3.83(3H,s),4.74(2H,d,J=5.6Hz),7.13(1H,d,J=8.4Hz),7.48(1H,dd,J=2.0,8.4Hz),7.627(1H,d,J=2.0Hz),8.23(1H,d,J=8.4Hz),8.45(1H,dd,J=1.6,8.4Hz),9.57(1H,s),10.68(1H,br-s).
实施例38
盐酸2-[[1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]-4-哌啶基]氧]乙酸
1H-NMR(400MHz,DMSO-d6)δ;1.69-1.82(2H,m),1.99-2.10(2H,m),2.98-3.09(2H,m),3.60-3.68(1H,m),3.83(3H,s),4.08(2H,s),4.72(2H,d,J=5.6Hz),7.14(1H,d,J=8.4Hz),7.46(1H,dd,J=2.4,8.4Hz),7.61(1H,d,J=2.0Hz),8.24(1H,d,J=8.4Hz),8.46(1H,dd,J=1.2,8.4Hz),9.46(1H,s),10.46(1H,br-s).
实施例39
4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(2-羟基-1-甲基乙基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;0.85(3H,d,J=6.4Hz),1.40-1.59(4H,m),1.64-1.73(2H,m),2.68-2.79(2H,m),3.33-3.47(4H,m),3.78(3H,m),4.40(1H,t,J=5.2Hz),4.60(2H,d,J=5.6Hz),7.06(1H,d,J=8.4Hz),7.31(1H,dd,J=2.0,8.4Hz),7.42(1H,d,J=2.0Hz),7.85(1H,t,J=6.0Hz),8.03(1H,d,J=8.4Hz),8.16(1H,dd,J=1.6,8.4Hz),8.85(1H,d,J=0.8Hz).
实施例40
盐酸2-[7-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]-7-氮杂螺[3.5]壬-2-基]乙酸
1H-NMR(400MHz,DMSO-d6)δ;1.45-1.53(2H,m),1.66-1.73(2H,m),1.77-1.84(2H,m),1.96-2.04(2H,m),2.34(2H,d,J=7.6Hz),3.02(2H,br-s),3.11(2H,br-s),3.82(3H,s),4.67(2H,s),7.11(1H,d,J=8.4Hz),7.40(1H,dd,J=2.0,8.4Hz),7.54(1H,d,J=2.0Hz),8.15(1H,d,J=8.8Hz),8.34(1H,d,J=8.8Hz),9.24(1H,s).
实施例41
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[2-(羟甲基)全氢[1,3]二氧杂环戊烷并[4,5-c]吡咯-5-基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.54-3.67(2H,m),3.80-3.92(2H,m),4.16(2/3H,br-s),4.29(4/3H,br-s),4.54(1H,t,J=5.2Hz),4.54-4.62(1H,m),5.16-5.32(2H,m),7.11(1H,d,J=8.4Hz),7.34-7.40(1H,m),7.50(1H,s),8.37(1H,d,J=8.4Hz),8.48-8.58(1H,m),9.12-9.21(1H,m).
实施例42
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(1-羟乙基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.07(3H,d,J=6.0Hz),1.34-1.60(3H,m),1.65-1.76(2H,m),1.86-1.94(2H,m),2.75-2.86(2H,m),3.55-3.63(2H,m),3.82(3H,s),4.73(2H,d,J=5.6Hz),7.13(1H,d,J=8.8Hz),7.48(1H,dd,J=2.0,8.8Hz),7.63(1H,d,J=2.0Hz),8.20(1H,d,J=8.4Hz),8.45(1H,dd,J=1.2,8.4Hz),9.56(1H,s),10.69(1H,br-s).
实施例43
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-氟-4-(羟甲基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.69-1.77(2H,m),1.83-2.08(2H,m),3.05-3.16(2H,m),3.48(2H,d,J=20.0Hz),3.82(3H,s),4.74(2H,d,J=5.6Hz),7.14(1H,d,J=8.8Hz),7.48(1H,dd,J=2.0,8.8Hz),7.63(1H,d,J=2.0Hz),8.26(1H,d,J=8.4Hz),8.46(1H,dd,J=1.2,8.4Hz),9.57(1H,s),10.73(1H,br-s).
实施例44
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(羟甲基)-4-甲氧基哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.71-1.86(4H,m),3.04-3.16(2H,m),3.16(3H,s),3.41(2H,s),3.83(3H,s),4.72(2H,d,J=5.6Hz),7.14(1H,d,J=8.4Hz),7.46(1H,dd,J=2.0,8.4Hz),7.61(1H,d,J=2.0Hz),8.23(1H,d,J=8.8Hz),8.44(1H,dd,J=1.2,8.8Hz),9.48(1H,s),10.46(1H,br-s).
实施例45
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-羟基-6-氮杂螺[3.4]辛-6-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.00-1.08(2H,m),1.82-2.04(4H,m),2.19-2.35(2H,m),3.32-3.45(2H,m),3.55-3.60(2H,m),3.80(3H,s),4.04-4.19(1H,m),4.56(2H,br-s),7.10(1H,d,J=8.4Hz),7.37(1H,br-s),7.50(1H,br-s),8.38(1H,d,J=8.4Hz),8.45-8.73(1H,m).
实施例46
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[3-(羟甲基)-2,5-二氢-1H-1-吡咯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.82(3H,s),4.12(2H,s),4.45-4.83(6H,m),5.84(1H,br-s),7.11(1H,d,J=9Hz),7.33-7.56(2H,m),8.45(1H,d,J=9Hz),8.66-9.14(2H,m).
实施例47
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[(3R,4S)-3,4-二(羟甲基)四氢-1H-1-吡咯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;2.50-2.57(2H,m),3.38-3.49(2H,m),3.56-3.60(2H,m),3.76-3.87(4H,m),3.81(3H,s),4.55(2H,br-s),7.10(1H,d,J=8.4Hz),7.36(1H,d,J=7.6Hz),7.49(1H,s),8.41(1H,d,J=8.4Hz),8.68(1H,d,J=8.4Hz),9.13(1H,s).
实施例48
盐酸1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]-4-羟基-4-哌啶甲酰胺
1H-NMR(400MHz,DMSO-d6)δ;1.56-1.64(2H,m),2.16-2.28(2H,m),3.12-3.24(2H,m),3.32-3.48(2H,m),3.54(1H,brs),3.83(3H,s),4.10-4.30(1H,m),4.74(2H,s),7.13(1H,d,J=8.4Hz),7.15(1H,br-s),7.31(1H,br-s),7.48(1H,d,J=8.4Hz),7.64(1H,s),8.26(1H,d,J=8.4Hz),8.44(1H,d,J=8.4Hz),9.52-9.60(1H,m).
实施例49
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(氟甲基)-4-羟基哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.54-1.64(2H,m),1.80-1.92(2H,m),3.18-3.26(2H,m),3.32-3.44(4H,m),3.83(3H,s),4.22(2H,d,J=7.6Hz),4.72(1H,d,J=6.0Hz),7.14(1H,d,J=8.4Hz),7.48(1H,dd,J=8.4,1.6Hz),7.62(1H,d,J=1.6Hz),8.23(1H,d,J=8.4Hz),8.45(1H,d,J=8.4Hz),9.45(1H,br-s).
实施例50
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-肟基哌啶子基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;2.50-2.52(2H,m),2.74-2.80(2H,m),3.26-3.35(4H,m),3.85(3H,s),4.71(2H,br),7.17(1H,d,J=8.8Hz),7.45(1H,dd,J= 8.8,2.0Hz),7.60(1H,d,J=2.0Hz),8.34(1H,d,J=8.4Hz),8.49(1H,dd,J=8.4,0.4Hz),9.34(1H,d,J=0.4Hz),10.53(1H,br).
实施例51
盐酸(反式)-2-[3-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]-3-氮杂二环[3.3.1]壬-9-基]乙酸
1H-NMR(400MHz,DMSO-d6)δ;1.62(1H,m),1.75-2.00(4H,m),2.12(1H,m),2.52(2H,d,J=8.1Hz),3.16-3.24(2H,m),3.68-3.76(2H,m),3.85(3H,s),4.74(2H,s),7.16(1H,d,J=8.6Hz),7.48(1H,dd,J=1.8,8.6Hz),7.62(1H,d,J=1.8Hz),8.23(1H,d,J=8.4Hz),8.55(1H,dd,J=1.3,8.4Hz),9.48(1H,m).
实施例52
盐酸(内)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-8-氮杂二环[3.2.1]辛-8-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.81-1.88(2H,m),1.90-1.98(2H,m),2.19-2.30(4H,m),3.85(3H,s),4.04(1H,m),4.16-4.26(2H,m),4.71(2H,s),7.16(1H,d,J=8.6Hz),7.46(1H,d,J=8.6Hz),7.61(1H,s),8.29(1H,d,J=8.4Hz),8.47(1H,dd,J=1.3,8.4Hz),9.44(1H,m).
实施例53
盐酸(顺式)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(9-羟基-3-氮杂二环[3.3.1]壬-3-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.53(1H,m),1.74-1.86(2H,m),1.87-1.93(2H,m),2.05-2.14(2H,m),2.37(1H,m),3.28-3.44(2H,m),3.41-3.61(2H,m),3.68(1H,m),3.85(3H,s),4.73(2H,s),7.15(1H,d,J=8.6Hz),7.47(1H,d,J=8.6Hz),7.62(1H,s),8.22(1H,d,J=8.6Hz),8.54(1H,d,J=8.6Hz),9.48(1H,m).
实施例54
盐酸(顺式)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(8-羟基-3-氨杂二环[3.2.1]辛-3-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.75-1.96(4H,m),2.02-2.09(2H,m),3.06-3.18(2H,m),3.50-3.60(2H,m),3.86(3H,s),3.91(1H,t,J=4.8Hz),4.73(2H,s),7.16(1H,d,J=8.6Hz),7.47(1H,d,J=8.6Hz),7.61(1H,s),8.36(1H,d,J=8.6Hz),8.48(1H,dd,J=1.5,8.6Hz),9.43(1H,m).
实施例55
盐酸(外)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-8-氮杂二环[3.2.1]辛-8-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.68-1.83(2H,m),1.90-2.02(4H,m),3.85(3H,s),3.97(1H,m),4.18-4.28(2H,m),4.70(2H,s),7.15(1H,d,J=8.6Hz),7.44(1H,d,J=8.6Hz),7.59(1H,s),8.29(1H,d,J=8.6Hz),8.45(1H,d,J=8.6Hz),9.36(1H,m).
实施例56
盐酸(反式)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(9-羟基-3-氧杂-7-氮杂二环[3.3.1]壬-7-基)-6-酞嗪甲腈
1H NMR(DMSO-d6)δ;1.69-1.76(2H,m),3.24-3.38(2H,m),3.73-3.83(2H,m),3.85(3H,s) 3.85-3.93(2H,m),4.11-4.20(2H,m),4.73(2H,s),7.16(1H,d,J=8.6Hz),7.47(1H,d,J=8.6Hz),7.62(1H,s),8.36(1H,d,J=8.4Hz),8.52(1H,d,J=8.4Hz),9.43(1H,m).
实施例57
盐酸(反式)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-9-氮杂二环[3.3.1]壬-9-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.38-1.54(4H,m),1.59(1H,m),1.90-2.02(2H,m),2.22-2.45(3H,m),3.86(3H,s),3.87(1H,m),4.08-4.17(2H,m),4.69(2H,s),7.16(1H,d,J=8.6Hz),7.44(1H,d,J=8.6Hz),7.58(1H,s),8.07(1H,d,J=8.6Hz),8.44(1H,d,J=8.6Hz),9.29(1H,m).
实施例58
N1-[3-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]苯基]乙酰胺
1H-NMR(400MHz,DMSO-d6)δ;2.05(3H,s),3.81(3H,s),4.76(2H,d,J=6.0Hz),7.09(1H,d,J=8.4Hz),7.24(1H,d,J=8.0Hz),7.38(1H,dd,J=8.0,1.6Hz),7.45(1H,dd,J=8.4,8.0Hz),7.50(1H,d,J=1.6Hz),7.67(1H,d,J=8.0Hz),7.86(1H,m),7.92(1H,d,J=8.4Hz),8.17(1H,dd,J=8.4,1.6Hz),8.35(1H,dd,J=6.0,6.0Hz),9.00(1H,s),10.09(1H,s).
实施例59
二盐酸1-(3-氨基苯基)-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.83(3H,s),4.89(2H,br-s),7.16(1H,d,J=8.6Hz),7.38-7.44(3H,m),7.53(1H,dd,J=8.6,2.0Hz),7.58-7.62(2H,m),7.68(1H,d,J=2.0Hz),8.02(1H,d,J=8.4Hz),8.45(1H,d,J=8.4Hz),9.65(1H,s).
实施例60
盐酸N-[3-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]苯基]甲磺酰胺
1H-NMR(400MHz,DMSO-d6)δ;3.06(3H,s),3.84(3H,s),4.86(2H,d,J=5.6Hz),7.15(1H,d,J=8.4Hz),7.35(1H,d,J=7.6Hz),7.43(1H,d,J=7.6Hz),7.50(1H,br-s),7.53(1H,dd,J=8.4,2.0Hz),7.55(1H,dd,J=7.6,7.6Hz),7.66(1H,d,J=2.0Hz),8.03(1H,d,J=8.8Hz),8.44(1H,d,J=8.8Hz),9.60(1H,br-s),10.14(1H,br-s).
实施例61
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(甲亚磺酰)苯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;2.84(3H,s),3.83(3H,s),4.87(2H,br-s),7.16(1H,d,J=8.4Hz),7.51(1H,d,J=8.4Hz),7.66(1H,br-s),7.83(2H,d,J=8.4Hz),7.92(2H,d,J=8.4Hz),8.00(1H,d,J=8.4Hz),8.43(1H,d,J=8.4Hz).9.52-9.60(1H,m).
实施例62
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(甲磺酰)苯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.31(3H,s),3.82(3H,s),4.80(2H,br-s),7.12(1H,d,J=8.8Hz),7.43(1H,dd,J=8.8,2.0Hz),7.56(1H,d,J=2.0Hz),7.90(2H,d,J=8.0Hz),7.93(1H,d,J=8.4Hz),8.11(2H,d,J=8.0Hz),8.28(1H,d,J=8.4Hz),9.19-9.22(1H,m).
实施例63
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-甲酰苯基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.84(3H,s),4.86(2H,br-s),7.16(1H,d,J=8.4Hz),7.51(1H,d,J=8.4Hz),7.66(1H,br-s),7.86(2H,d,J=8.0Hz),7.99(1H,d,J=8.8Hz),8,13(2H,d,J=8.0Hz),8.42(1H,d,J=8.8Hz),9.48-9.53(1H,m),10.15(1H,s).
实施例64
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[(4-羟甲基)苯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.84(3H,s),4.62(2H,s),4.84(2H,br-s),7.16(1H,d,J=8.4Hz),7.49(1H,dd,J=8.4,2.0Hz),7.55(2H,d,J=8.0Hz),7.60(2H,d,J=8.0Hz),7.65(1H,d,J=2.0Hz),8.02(1H,d,J=8.4Hz),8.43(1H,d,J=8.4Hz),9.50-9.58(1H,m).
实施例65
4-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]苯甲酸
1H-NMR(400MHz,DMSO-d6)δ;3.84(3H,s),4.76(2H,d,J=6.0Hz),7.10(1H,d,J=8.8Hz),7.38(1H,dd,J=8.8,2.0Hz),7.50(1H,d,J=2.0Hz),7.72(2H,d,J=8.4Hz),7.91(1H,d,J=8.8Hz),8.08(2H,d,J=8.4Hz),8.19(1H,dd,J=8.4,1.6Hz),8.44(1H,dd,J=6.0,6.0Hz),9.01(1H,d,J=1.6Hz).
实施例66
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(1,3-噻唑-2-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.80(3H,s),4.82(2H,s),7.13(1H,d,J=8.4Hz),7.42(1H,d,J=8.4Hz),7.57(1H,s),7.94(1H,d,J=3.6Hz),8.11(1H,d,J=3.6Hz),8.46(1H,d,J=8.4Hz),9.20-9.26(1H,m),9.70(1H,d,J=8.4Hz).
实施例67
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-3-甲基-1-丁炔基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.57(6H,s),3.84(3H,s),4.84(2H,s),7.15(1H,d,J=8.8Hz),7.46(1H,dd,J=8.8,2.0Hz),7.61(1H,d,J=2.0Hz),8.34(1H,d,J=8.4Hz),8.52(1H,dd,J=8.4,0.4Hz),9.04(1H,d,J=0.4Hz),10.36(1H,br).
实施例68
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-1-丙炔基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.84(3H,s),4.49(2H,s),4.81(2H,d,J=4.0Hz),7.14(1H,d,J=8.4Hz),7.43(1H,dd,J=8.4,2.4Hz),7.58(1H,d,J=2.4Hz),8.35(1H,d,J=8.8Hz),8.48(1H,dd,J=8.8,0.8Hz),9.28(1H,d,J=0.8Hz),9.92(1H,br).
实施例69
4-[(3-氯-4-甲氧基苄基)氨基]-1-[3,4-二羟基-3-(羟甲基)-1-丁炔基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;3.54-3.66(4H,m),3.82(3H,s),4.76(2H,d,J=5.2Hz),4.98(2H,t,J=5.2Hz),5.62(1H,s),7.10(1H,d,J=8.8Hz),7.36(1H,dd,J=8.8,2.0Hz),7.49(1H,d,J=2.0Hz),8.29-8.34(1H,m),8.51(1H,t,J=5.2Hz),8.96(1H,s).
实施例70
二盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[3-(二甲氨基)-1-丙炔基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;2.91(6H,s),3.83(3H,s),4.52(2H,s),4.83(2H,d,J=4.8Hz),7.13(1H,d,J=8.8Hz),7.42(1H,dd,J=8.8,2.0Hz),7.56(1H,d,J=2.0Hz),8.40(1H,dd,J=8.4,1.4Hz),8.46(1H,d,J=8.4Hz),9.27(1H,d,J=1.4Hz),9.76(1H,br),11.39(1H,br).
实施例71
盐酸2-[[3-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基-1-酞嗪基]-1,1-二甲基-2-丙炔基]氧]乙酸
1H-NMR(400MHz,DMSO-d6)δ;1.62(6H,s),3.84(3H,s),4.21-4.24(2H,m),4.77-4.82(2H,br),7.11-7.15(1H,m),7.38-7.42(1H,m),7.51-7.55(1H,m),8.19-8.24(1H,m),8.38-8.42(1H,m),9.12-9.16(1H,m).
实施例72
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[3-(2-羟基乙氧基)-3-甲基-1-丁炔基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.61(6H,s),3.55(2H,t,J=5.6Hz),3.65(2H,t,J=5.6Hz),3.84(3H,s),4.85(2H,d,J=4.8Hz),7.14(1H,d,J=8.6Hz),7.46(1H,dd,J=8.6,2.2Hz),7.61(1H,d,J=2.2Hz),8.30(1H,d,J=8.4Hz),8.48(1H,dd,J=8.4,1.6Hz),9.42(1H,d,J=1.6Hz),10.41(1H,br).
实施例73
二盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[3-(4-羟基哌啶子基)-3-甲基-1-丁炔基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.79-2.04(10H,m),2.12-2.23(1H,m),3.04-3.19(1H,m),3.26-3.37(2H,m),3.54-3.77(1H,m),3.82(3H,s),4.83(2H,d,J=5.6Hz),7.12(1H,d,J=8.4Hz),7.43(1H,dd,J=8.4,1.2Hz),7.56(1H,d,J=1.2Hz),8.38(1H,dd,J=8.4,0.8Hz),8.43(1H,d,J=8.4Hz),9.30(1H,d,J=0.8Hz),9.91(1H,br),11.40-11.66(1H,m).
实施例74
二盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-甲基-3-四氢-1H-1-吡咯基-1-丁炔基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.85(6H,s),1.90-2.08(4H,m),3.30-3.42(2H,m),3.60-3.72(2H,m),3.83(3H,s),4.80(2H,d,J=5.2Hz),7.11(1H,d,J=8.4Hz),7.39(1H,dd,J=8.4,2.0Hz),7.52(1H,d,J=2.0Hz),8.28(1H,d,J=8.4Hz),8.36(1H,dd,J=8.4,0.8Hz),9.14(1H,d,J=0.8Hz),9.33(1H,br),11.89(1H,m).
实施例75
盐酸1-(4-羟基哌啶子基)-4-[[4-甲氧基-3-(三氟甲基)苄基]氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.62-1.73(2H,m),1.90-1.99(2H,m),2.97-3.07(2H,m),3.40-3.52(2H,m),3.72-3.80(1H,m),3.89(3H,s),4.80(2H,d,J=5.6Hz),7.28(1H,d,J=8.4Hz),7.81-7.85(2H,m),8.24(1H,d,J=8.4Hz),8.47(1H,dd,J=8.4,1.2Hz),9.53(1H,d,J=1.2Hz),10.29(1H,br),14.02(1H,br).
实施例76
盐酸1-(4-羟基哌啶子基)-4-[(3-碘-4-甲氧基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.62-1.73(2H,m),1.90-2.00(2H,m),2.98-3.08(2H,m),3.40-3.50(2H,m),3.72-3.80(1H,m),3.82(3H,s),4.68(2H,d,J=4.8Hz),7.02(1H,d,J=8.8Hz),7.50(1H,dd,J=8.8,2.2Hz),7.93(1H,d,J=2.2Hz),8.24(1H,d,J=8.6Hz),8.46(1H,dd,J=8.6,0.8Hz),9.32(1H,d,J=0.8Hz),10.05(1H,br).
实施例77
盐酸4-[(3-溴-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.62-1.73(2H,m),1.90-1.99(2H,m),2.98-3.07(2H,m),3.39-3.50(2H,m),3.72-3.80(1H,m),3.84(3H,s),4.71(2H,d,J=4.8Hz),7.13(1H,d,J=8.6Hz),7.49(1H,dd,J=8.6,2.2Hz),7.75(1H,d,J=2.2Hz),8.24(1H,d,J=8.4Hz),8.46(1H,dd,J=8.4,0.8Hz),9.34(1H,d,J=0.8Hz),10.11(1H,br).
实施例78
盐酸4-[(3-溴-4-甲氧基苄基)氨基]-1-[3-(羟甲基)四氢-1H-1-吡咯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.72-1.86(1H,m),1.99-2.12(1H,m),2.39-2.51(1H,m),3.42(1H,dd,J=7.2,10.8Hz),3.48(1H,dd,J=6.0,10.8Hz),3.60-3.90(4H,m),3.80(3H,s),7.06(1H,d,J=8.4Hz),7.38-7.46(1H,m),7.64(1H,s),8.40(1H,dd,J=1.6,8.8Hz),8.65(1H,d,J=8.0Hz),9.18(1H,s).
实施例79
盐酸4-[(3-溴-4-甲氧基苄基)氨基]-1-[(3S)-3-(羟甲基)四氢-1H-1-吡咯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.58-1.76(3H,m),1.92-2.02(2H,m),2.29-2.42(2H,m),3.42-3.60(2H,m),3.78(3H,s),4.58(2H,J=6.0Hz),4.69(1H,t,J=5.6Hz),7.03(1H,d,J=8.4Hz),7.36(1H,dd,J=2.0,8.4Hz),7.57(1H,d,J=2.0Hz),7.59(1H,d,J=6.0Hz),8.13(1H,dd,J=1.2,8.8Hz),8.22(1H,d,J=8.8Hz),8.81(1H,d,J=0.8Hz).
实施例80
盐酸4-[(3-溴-4-甲氧基苄基)氨基]-1-[(3R)-3-(羟甲基)四氢-1H-1-吡咯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.72-1.86(1H,m),1.99-2.12(1H,m),2.39-2.51(1H,m),3.42(1H,dd,J=7.2,10.8Hz),3.48(1H,dd,J=6.0,10.8Hz),3.60-3.90(4H,m),3.80(3H,s),7.06(1H,d,J=8.8Hz),7.38-7.46(1H,m),7.65(1H,s),8.40(1H,d,J=8.8Hz),8.59-8.68(1H,m),9.26(1H,s).
实施例81
盐酸4-[(3-溴-4-甲氧基苄基)氨基]-1-[4-(2-羟乙基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.68-1.77(2H,m),1.96-2.07(2H,m),3.02(2H,t,J=12.0Hz),3.38-3.59(6H,m),3.80(3H,s),3.81-3.99(3H,m),4.72(2H,d,J=6.0Hz),7.10(1H,d,J=8.6Hz),7.49(1H,d,J=8.6Hz),7.76(1H,s),8.22(1H,d,J=8.6Hz),8.45(1H,d,J=8.6Hz),9.50(1H,s).
实施例82
盐酸4-[(3-溴-4-甲氧基苄基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.58-1.66(2H,m),1.68-1.76(4H,m),2.14-2.23(2H,m),3.08(2H,br-s),3.13(2H,br-s),4.08-4.17(1H,m),4.73(1H,d,J=5.6Hz),7.10(1H,d,J=8.4Hz),7.52(1H,dd,J=2.0,8.4Hz),7.70(1H,d,J=2.0Hz),8.20(1H,d,J=8.4Hz),8.44(1H,dd,J=1.6,8.4Hz),9.55(1H,s).
实施例83
盐酸4-[(3-溴-4-甲氧基苄基)氨基]-1-[4-氟-4-(羟甲基)哌啶子基]-6-酞嗪甲腈
1H NMR(DMSO-d6)δ1.87-2.10(4H,m),3.08-3.17(2H,m),3.40-3.49(2H,m),3.55(2H,d,J=12Hz),3.84(3H,s),4.74(2H,d,J=5.2Hz),7.13(1H,d,J=8.6Hz),7.52(1H,dd,J=8.6,2.2Hz),7.78(1H,d,J=2.2Hz),8.28(1H,d,J=8.4Hz),8.48(1H,dd,J=8.4,1.2Hz),9.47(1H,br),10.43(1H,br),14.00(1H,br)
实施例84
盐酸4-[(3-溴-4-甲氧基苄基)氨基]-1-[4-(羟甲基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.41-1.52(2H,m),1.58-1.69(1H,m),1.79-1.86(2H,m),2.85-2.94(2H,m),3.35-3.40(2H,m),3.59(2H,d,J=12.8Hz),3.84(3H,s),4.71(2H,d,J=5.2Hz),7.13(1H,d,J=8.4Hz),7.50(1H,dd,J=8.4,2.0Hz),7.76(1H,d,J=2.0Hz),8.22(1H,d,J=8.4Hz),8.47(1H,dd,J=8.4,0.8Hz),9.38(1H,br),10.21(1H,br).
实施例85
(内)-4-[(3-溴-4-甲氧基苄基)氨基]-1-(3-羟基-8-氮杂二环[3.2.1]辛-8-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.70-1.95(4H,m),2.14-2.28(4H,m),3.82(3H,s),4.15(1H,m),4.09(2H,m),4.49(1H,d,J=2.2Hz),4.62(2H,d,J=5.5Hz),7.05(1H,d,J=8.6Hz),7.38(1H,dd,J=2.2,8.6Hz),7.60(1H,d,J=2.2Hz),7.72(1H,t,J=5.5Hz),8.11(1H,d,J=8.6Hz),8.18(1H,dd,J=1.5,8.6Hz),8.87(1H,d,J=1.5Hz).
实施例86
盐酸1-(4-羟基哌啶子基)-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.62-1.73(2H,m),1.90-1.99(2H,m),2.15(3H,s),2.98-3.07(2H,m),3.42-3.50(2H,m),3.72-3.80(1H,m),3.78(3H,s),4.67-4.70(2H,m),6.94(1H,d,J=8.2Hz),7.28(1H,d,J=2.0Hz),7.31(1H,dd,J=8.2,2.0Hz),8.23(1H,d,J=8.4Hz),8.47(1H,dd,J=8.4,1.2Hz),9.45(1H,d,J=1.2Hz),10.39(1H,br).
实施例87
盐酸1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.57-1.66(2H,m),1.67-1.8(4H,m),2.11(3H,s),2.14-2.23(2H,m),3.07(2H,br-s),3.12(2H,br-s),3.55-3.61(1H,m),4.07-4.17(1H,m),4.69(1H,d,J=5.2Hz),6.91(1H,d,J=8.4Hz),7.29(1H,s),7.31(1H,dd,J=2.0,8.4Hz),8.19(1H,d,J=8.4Hz),8.44(1H,dd,J=1.2,8.4Hz),9.56(1H,s),10.59(1H,br-s).
实施例88
盐酸1-[4-氟-4-(羟甲基)哌啶子基]-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.88-2.10(4H,m),2.15(3H,s),3.08-3.17(2H,m),3.40-3.50(2H,m),3.51(2H,d,J=19.6Hz),3.78(3H,s),4.68(2H,d,J=5.2Hz),6.94(1H,d,J=8.0Hz),7.28-7.33(2H,m),8.28(1H,d,J=8.4Hz),8.47(1H,dd,J=8.4,1.4Hz),9.42(1H,dd,J=1.4Hz),10.26(1H,br),13.96(1H,br).
实施例89
盐酸1-[4-(羟甲基)哌啶子基]-4-[(3-甲氧基-4-甲基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.41-1.52(2H,m),1.58-1.68(1H,m),1.79-1.87(2H,m),2.15(3H,s),2.82-2.93(2H,m),3.30-3.40(2H,m),3.58(2H,d,J=12.8Hz),3.78(3H,s),4.67(2H,d,J=5.2Hz),6.94(1H,d,J=8.8Hz),7.26-7.32(2H,m),8.22(1H,d,J=8.4Hz),8.47(1H,dd,J=8.4,0.8Hz),9.36(1H,br),10.09(1H,br).
实施例90
(内)-1-(3-羟基-8-氮杂二环[3.2.1]辛-8-基)-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.79-1.93(4H,m),2.13(3H,s),2.13-2.27(4H,m),3.75(3H,s),4.03(1H,m),4.08(2H,m),4.49(1H,d,J=2.2Hz),4.59(2H,d,J=5.3Hz),6.87(1H,d,J=7.9Hz),7.16-7.22(2H,m),7.61(1H,t,J=5.3Hz),8.11(1H,d,J=8.4Hz),8.17(1H,dd,J=1.5,8.4Hz),8.90(1H,d,J=1.5Hz).
实施例91
1-[3-(羟甲基)四氢-1H-1-吡咯基]-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.67(1H,m),2.00(1H,m),2.16(3H,s),2.38(1H,m),3.36-3.61(6H,m),3.75(3H,s),4.58(2H,d,J=5.5Hz),4.68(1H,t,J=5.5Hz),6.86(1H,d,J=8.1Hz),7.16-7.22(2H,m),7.50(1H,t,J=5.3Hz),8.15(1H,dd,J=1.5,8.6Hz),8.24(1H,dd,J=8.6Hz),8.88(1H,d,J=1.5Hz).
实施例92
4-[(3-氟-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.60-1.73(2H,m),1.88-1.97(2H,m),2.86-2.94(2H,m),3.42-3.50(2H,m),3.64-3.71(1H,m),3.80(3H,s),4.62(2H,d,J=5.4Hz),4.77(1H,d,J=2.0Hz),7.09(1H,t,J=8.2Hz),7.18(1H,d,J=8.2Hz),7.23(1H,dd,J=12.0,2.0Hz),7.84(1H,t,J=5.4Hz),8.04(1H,d,J=8.4Hz),8.20(1H,dd,J=8.4,1.2Hz),8.89(1H,d,J=1.2Hz).
实施例93
4-[(4-氯-3-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.60-1.72(2H,m),1.87-1.96(2H,m),2.86-2.95(2H,m),3.31-3.39(2H,m),3.68(1H,m),3.84(3H,s),4.72(2H,d,J=5.5Hz),4.74(1H,d,J=4.2Hz),6.98(1H,dd,J=1.8,8.1Hz),7.20(1H,d,J=1.8Hz),7.34(1H,d,J=8.1Hz),7.92(1H,t,J=5.5Hz),8.07(1H,d,J=8.6Hz),8.21(1H,dd,J=1.5,8.6Hz),8.92(1H,d,J=1.5Hz).
实施例94
盐酸4-[(3-氰基-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.6-1.73(2H,m),1.88-2.0(2H,m),2.95-3.08(2H,m),3.4-3.7(2H,m),3.7-3.8(1H,m),3.90(3H,s),4.74(2H,d,J=5.6Hz),7.27(1H,d,J=9.2Hz),7.79(1H,dd,J=2.0,8.8Hz),7.87(1H,d,J=2.0Hz),8.24(1H,d,J=8.4Hz),8.47(1H,dd,J=1.2,8.4Hz),9.38(1H,s).
实施例95
盐酸(内)-4-[(3-氰基-4-甲氧基苄基)氨基]-1-(3-羟基-8-氮杂二环[3.2.1]辛-8-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.9-1.96(4H,m),2.17-2.29(4H,m),3.91(3H,s),4.04(1H,m),4.15(2H,m),4.68(2H,s),7.25(1H,d,J=8.6Hz),7.74(1H,d,J=8.6Hz),7.80(1H,s),8.21(1H,d,J=8.6Hz),8.34(1H,m),9.07(1H,m).
实施例96
盐酸4-[(3-氰基-4-甲氧基苄基)氨基]-1-[3-(羟甲基)四氢-1H-1-吡咯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.84(1H,m),2.09(1H,m),2.48(1H,m),3.40-3.55(2H,m),3.64-3.90(4H,m),3.91(3H,s),4.59(2H,m),7.24(1H,d,J=8.8Hz),7.74(1H,d,J=8.8Hz),7.79(1H,s),8.42(1H,d,J=9.3Hz),8.70(1H,m),9.15(1H,m).
实施例97
盐酸4-[(3-乙基-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.14(3H,t,J=7.5Hz),1.63-1.74(2H,m),1.90-2.01(2H,m),2.57(2H,q,J=7.5Hz),2.97-3.08(2H,m),3.40-3.54(2H,m),3.75(1H,m),3.79(3H,s),4.69(2H,s),6.95(1H,d,J=8.2Hz),7.26-7.35(2H,m),8.25(1H,d,J=8.6Hz),8.48(1H,dd,J=1.3,8.6Hz),9.44(1H,m).
实施例98
盐酸4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.58-1.66(2H,m),1.67-1.78(4H,m),2.14-2.23(2H,m),2.92-3.01(2H,m),3.07(2H,s),3.11(2H,s),3.70-3.82(3H,m),3.80(3H,s),4.08-4.18(1H,m),7.06(1H,d,J=8.4Hz),7.26(1H,dd,J=2.0,8.4Hz),7.43(1H,d,J=2.0Hz),8.19(1H,d,J=8.4Hz),8.44(1H,dd,J=1.2,8.4Hz),9.55(1H,s),10.47(1H,br-s),13.9(1H,br-s).
实施例99
盐酸4-[(3-氯-4-甲氧基苯乙基)氨基]-1-[4-(2-羟基乙氧基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.68-1.77(2H,m),2.00-2.06(2H,m),2.76(2H,t,J=8.0Hz),3.03(2H,t,J=12.0Hz),3.32(10H,m),3.75(2H,d,J=8.0Hz),3.81(3H,s),7.07(1H,d,J=8.6Hz),7.25(1H,d,J=8.6Hz),7.43(1H,s),8.24(1H,d,J=8.6Hz),8.45(1H,d,J=8.6Hz),9.32(1H,s).
实施例100
4-[(3-氯-4-甲氧基苯乙基)氨基]-1-[4-氟-4-(羟甲基)哌啶子基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.82-2.06(4H,m),2.83-2.94(2H,m),3.04-3.14(2H,m),3.24-3.30(1H,m),3.49(2H,dd,J=10.2,6.0Hz),3.54-3.60(1H,m),3.64-3.70(2H,m),3.80(3H,s),5.03(1H,dd,J=6.0,6.0Hz),7.05(1H,d,J=12.6Hz),7.19(1H,dd,J=12.6,2.0Hz),7.32(1H,d,J=2.0Hz),7.40-7.45(1H,m),8.08(1H,d,J=8.4Hz),8.18(1H,d,J=8.4Hz),8.82(1H,brs).
实施例101
(内)-4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(3-羟基-8-氮杂二环[3.2.1]辛-8-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.78-1.94(4H,m),2.14-2.28(4H,m),2.92(2H,t,J=7.0Hz),3.67(2H,q,J=7.0Hz),3.82(3H,s),4.04(1H,m),4.09(2H,m),4.49(1H,d,J=1.8Hz),7.06(1H,d,J=8.4Hz),7.20(1H,dd,J=2.2,8.4Hz),7.27(1H,m),7.33(1H,d,J=2.2Hz),8.11(1H,d,J=8.6Hz),8.17(1H,dd,J=1.5,8.6Hz),8.80(1H,d,J=1.5Hz).
实施例102
4-[(3-氯-4-甲氧基苯乙基)氨基]-1-[3-(羟甲基)四氢-1H-1-吡咯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.68(1H,m),2.00(1H,m),2.40(1H,m),2.92(2H,t,J=7.5Hz),3.37-3.70(8H,m),3.82(3H,s),4.69(1H,d,J=5.3Hz),7.06(1H,d,J=8.6Hz),7.16(1H,m),7.20(1H,dd,J=2.0,8.6Hz),7.33(1H,d,J=2.0Hz),8.15(1H,dd,J=1.3,8.6Hz),8.25(1H,d,J=8.6Hz),8.78(1H,m).
实施例103
盐酸4-[(3,4-二氯苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.61-1.72(2H,m),1.90-2.00(2H,m),3.01-3.18(2H,m),3.40-3.52(2H,m),3.72-3.80(1H,m),4.75(2H,d,J=5.2Hz),7.49(1H,dd,J=8.6,2.0Hz),7.66(1H,d,J=8.6Hz),7.79(1H,d,J=2.0Hz),8.25(1H,d,J=8.6Hz),8.47(1H,dd,J=8.6,1.0Hz),9.36(1H,d,J=1.0Hz),10.24(1H,br).
实施例104
盐酸1-[6-溴-4-[(3-氯-4-甲氧基苄基)氨基]-1-酞嗪基]-4-哌啶醇
1H-NMR(400MHz,DMSO-d6)δ;1.59-1.68(2H,m),1.85-1.94(2H,m),2.94-3.08(2H,m),3.45-3.55(2H,m),3.70-3.76(1H,m),3.83(3H,s),4.69(2H,d,J=4.8Hz),7.14(1H,d,J=8.4Hz),7.44(1H,d,J=8.4Hz),7.59(1H,s),8.01(1H,d,J=8.8Hz),8.26(1H,d,J=8.8Hz),9.18(1H,s).
实施例105
盐酸1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-(1H-1-吡唑基)-1-酞嗪基]-4-哌啶醇
1H-NMR(400MHz,DMSO-d6)δ;1.6-1.75(2H,m),1.85-2.0(2H,m),2.95-3.1(2H,m),3.3-3.55(2H,m),3.7-3.8(1H,m),3.82(3H,s),4.68-4.77(2H,m),6.72(1H,m),7.14(1H,d,J=8.4Hz),7.48(1H,d,J=7.6Hz),7.63(1H,s),7.93(1H,d,J=1.6Hz),8.22(1H,d,J=8.8Hz),8.61(1H,dd,J=1.6,8.8Hz),8.97(1H,s),9.46(1H,m).
实施例106
盐酸7-[4-[(3-氯-4-甲氧基苄基)氨基]-6-(1H-1-吡唑基)-1-酞嗪基]-7-氮杂螺[3.5]壬-2-醇
1H-NMR(400MHz,DMSO-d6)δ;1.55-1.68(2H,m),1.68-1.80(4H,m),2.14-2.25(2H,m),3.0-3.2(4H,m),3.82(3H,s),4.14(1H,hep,J=7.2Hz),4.72(2H,m),6.72(1H,t,J=2Hz),7.14(1H,d,J=8.4Hz),7.47(1H,d,J=8.4Hz),7.62(1H,s),7.93(1H,d,J=1.6Hz),8.20(1H,d,J=9.2Hz),8.60(1H,dd,J=2.0,9.2Hz),8.94(1H,d,J=2.4Hz),9.43(1H,s).
实施例107
盐酸[1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-(1H-1-吡唑基)-1-酞嗪基]-4-氟-4-哌啶基]甲醇
1H-NMR(400MHz,DMSO-d6)δ;1.85-2.0(2H,m),1.95-2.1(2H,m),3.05-3.2(2H,m),3.4-3.6(2H,m),3.51(2H,d,J=20Hz),3.83(3H,s),4.74(2H,d,J=5.2Hz),6.72(1H,t,J=1.6Hz),7.14(1H,d,J=8.8Hz),7.48(1H,d,J=8.4Hz),7.64(1H,s),7.93(1H,d,J=1.6Hz),8.25(1H,d,J=9.2Hz),8.61(1H,dd,J=2.0,9.2Hz),8.95(1H,s),9.44(1H,s).
实施例108
盐酸1-[4-[(3-溴-4-甲氧基苄基)氨基]-6-(1H-1-吡唑基)-1-酞嗪基]-4-哌啶醇
1H-NMR(400MHz,DMSO-d6)δ;1.6-1.74(2H,m),1.87-2.0(2H,m),2.9-3.1(2H,m),3.4-3.55(2H,m),3.7-3.8(1H,m),3.81(3H,s),4.65-4.8(2H,m),6.72(1H,m),7.10(1H,d,J=8.8Hz),7.53(1H,d,J=8.0Hz),7.79(1H,s),7.93(1H,d,J=1.2Hz),8.21(1H,d,J=8.8Hz),8.61(1H,d,J=8.8Hz),9.00(1H,d,J=2.8Hz),9.51(1H,s).
实施例109
盐酸1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-(1H-1,2,3-***-1-基)-1-酞嗪基]-4-哌啶醇
1H-NMR(400MHz,DMSO-d6)δ;1.62-1.75(2H,m),1.9-2.0(2H,m),3.0-3.1(2H,m),3.3-3.58(2H,m),3.7-3.8(1H,m),3.83(3H,s),4.73(2H,d,J=5.6Hz),7.15(1H,d,J=8.8Hz),7.46(1H,d,J=8.4Hz),7.62(1H,s),8.13(1H,m),8.32(1H,d,J=8.8Hz),8.68(1H,d,J=9.2Hz),9.17(1H,s),9.56(1H,s).
实施例110
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲醛06-甲基肟
1H-NMR(400MHz,DMSO-d6)δ;1.60-1.70(2H,m),1.87-1.70(2H,m),2.96-3.05(2H,m),3.30-3.50(2H,m),3.68-3.78(1H,m),3.83(3H,s),3.99(3H,s),4.66-4.73(2H,m),7.14(1H,d,J=8Hz),7.42(1H,dd,J=2,8Hz),7.57(1H,d,J=2Hz),8.13(1H,d,J=8Hz),8.28(1H,d,J=8Hz),8.39(1H,s),8.94(1H,br-s).
实施例111
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲醛06-乙基肟
1H-NMR(400MHz,DMSO-d6)δ;1.28(3H,t,J=6Hz),1.60-1.73(2H,m),1.87-1.98(2H,m),2.94-3.06(2H,m),3.39-3.52(2H,m),3.68-3.78(1H,m),3.83(3H,s),4.25(2H,q,J=6Hz),4.67-4.74(2H,m),7.13(1H,d,J=9Hz),7.42(1H,d,J=9Hz),7.58(1H,s),8.13(1H,d,J=8Hz),8.30(1H,d,J=8Hz),8.39(1H,s),8.97(1H,s).
实施例112
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲醛06-苄基肟
1H-NMR(400MHz,DMSO-d6)δ;1.59-1.71(2H,m),1.87-1.96(2H,m),2.94-3.05(2H,m),3.37-3.51(2H,m),3.68-3.78(1H,m),3.82(3H,s),4.67-4.76(2H,m),5.27(2H,s),7.13(1H,d,J=9Hz),7.29-7.48(6H,m),7.59(1H,s),8.12(1H,d,J=9Hz),8.29(1H,d,J=9Hz),8.45(1H,s),9.04(1H,br-s).
实施例113
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[3-氟-3-(羟甲基)四氢-1H-1-吡咯基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;2.09-2.28(2H,m),3.50-4.05(6H,m),3.81(3H,s),4.66(2H,s),7.11(1H,d,J=8.0Hz),7.43(1H,d,J=8.0Hz),7.58(1H,s),8.43(1H,d,J=8.4Hz),8.53(1H,s),9.45(1H,s).
实施例114
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-1-氧杂-8-氮杂螺[4.5]癸-8-基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.65-1.85(3H,m),1.87-2.01(2H,m),3.16-3.63(8H,m),3.82(3H,s),4.32(1H,s),4.73(2H,d,J=4.8Hz),7.13(1H,d,J=8.4Hz),7.48(1H,d,J=8.0Hz),7.62(1H,s),8.23(1H,d,J=8.0Hz),8.44(1H,d,J=8.0Hz),9.57(1H,s),10.78(1H,s).
实施例115
4-[(3-氯-4-甲氧基苄基)氨基]-1-[2-(1-羟基环戊基)-1-乙炔基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.69-1.86(4H,m),1.97-2.04(4H,m),3.82(3H,s),4.75(2H,d,J=5.4Hz),5.60(1H,s),7.10(1H,d,J=8.8Hz),7.36(1H,dd,J=8.8,1.2Hz),7.49(1H,d,J=1.2Hz),8.19(1H,d,J=8.8Hz),8.31(1H,dd,J=8.8,0.6Hz),8.52(1H,t,J=5.4Hz),8.97(1H,d,J=0.6Hz).
实施例116
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[2-(1-羟基环戊基)乙基]-6-酞嗪甲腈
将690mg 4-[(3-氯-4-甲氧基苄基)氨基]-1-[2-(1-羟基环戊基)-1-乙炔基]-6-酞嗪甲腈溶于200ml四氢呋喃,向其中加入50mg 10%Pd-C,混合物在氢气中搅拌0.5小时。使反应溶液通过硅藻土过滤,蒸发滤液。所得残余物用硅胶柱层析法纯化,得到400mg 4-[(3-氯-4-甲氧基苄基)氨基]-1-[2-(1-羟基环戊基)乙基]-6-酞嗪甲腈。以常规方法将该产物转化为盐酸盐。
1H-NMR(400MHz,DMSO-d6)δ;1.47-1.78(8H,m),1.89-1.94(2H,m),3.24-3.33(2H,m),3.84(3H,s),4.74(2H,d,J=4.4Hz),7.15(1H,d,J=8.4Hz),7.45(1H,dd,J=8.4,2.0Hz),7.60(1H,d,J=2.0Hz),8.46(1H,d,J=8.8Hz),8.55(1H,dd,J=8.8,1.2Hz),9.40(1H,br).
以相同方式得到下列化合物。
实施例117
盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-3-甲基丁基)-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.17(6H,s),1.73-1.80(2H,m),3.17-3.24(2H,m),3.80(3H,s),4.78(2H,d,J=4.4Hz),7.10(1H,d,J=8.4Hz),7.48(1H,dd,J=8.4,1.8Hz),7.62(1H,d,J=1.8Hz),8.43(1H,d,J=8.6Hz),8.51(1H,dd,J=8.6,1.2Hz),9.63(1H,br),10.30(1H,br).
实施例118
二盐酸1-(3-氨基-3-甲基丁基)-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;1.37(6H,s),2.00-2.19(2H,m),3.21-3.56(2H,m),3.84(3H,s),4.78(2H,d,J=4.4Hz),7.15(1H,d,J=8.4Hz),7.46(1H,d,J=8.4Hz),7.61(1H,s),8.15-8.29(4H,m),8.48(1H,d,J=8.8Hz),8.56(1H,d,J=8.8Hz),9.38(1H,br).
实施例119
二盐酸4-[(3-氯-4-甲氧基苄基)氨基]-1-[3-(二甲氨基)丙基]-6-酞嗪甲腈
1H-NMR(400MHz,DMSO-d6)δ;2.11-2.19(2H,m),2.74(3H,s),2.75(3H,s),3.16-3.29(4H,m),3.85(3H,s),4.80(2H,d,J=5.2Hz),7.16(1H,d,J=8.4Hz),7.48(1H,dd,J=8.4,2.0Hz),7.63(1H,d,J=2.0Hz),8.49(1H,d,J=8.4Hz),8.56(1H,dd,J=8.4,1.4Hz),9.47(1H,d,J=1.4Hz),10.56(2H,br).
Claims (38)
1、由式(I)表示的酞嗪衍生物或其药学上可接受的盐:
其中R1和R2彼此相同或不同,表示卤原子、可以被卤原子取代的C1至C4烷基、羟基、可以被卤原子取代的C1至C4烷氧基、或氰基;
X表示氰基,硝基,卤原子,硫代氨基甲酰基,可以被C1至C4烷基或羧基C1至C4烷基取代的肟基,或可以被C1至C4烷基取代的杂芳基;
Y表示:
i)由式(II)表示的基团:
其中环A表示可以被甲基取代的4至8元胺环,其中可以具有双键;D表示单键或氧原子;R3表示氢原子、C1至C4烷基或卤原子;m表示0或1至3的整数;W表示氨基、羟基、氰基、可以具有保护基的羧基、或C1至C4烷氧基;
ii)由式(III)表示的基团:
其中环B表示可以具有双键的4至8元胺环;n和p彼此相同或不同,表示0或1至3的整数;
iii)由式(IV)表示的基团:
其中环G表示可以具有双键的4至8元胺环,E表示羟基、卤原子、C1至C4烷基或C1至C4烷氧基,J是式-(CHR4)q-Q-其中R4表示氢原子或C1至C4烷基,Q表示羟基、卤原子、可以具有保护基的羧基、氨基甲酰基或不含有除氮原子以外杂原子的唑系基团,q是0或1至4的整数;或者E和J可以与它们所结合的碳原子一起构成3至6元环,该环任选地具有氧原子,任选地具有羟基、氧代或被羟基或羧基取代的C1至C4烷基;
iv)由式(V)表示的基团:
其中M代表单键或可以被羟基、羧基、C1至C4烷基或C1至C4烷氧基取代的C1至C4亚烷基,环K表示与M一起构成的5至8元胺环,环L表示可以具有取代基且可以具有氧原子的5至8元烷基环;
v)由式(VI)表示的基团:
其中环P表示5至7元胺环,R5表示氢原子或可以被卤原子、羟基或羧基取代的C1至C4烷基;
vi)可以具有取代基的炔基、烯基或烷基,取代基选自C1至C4烷基;C3~C6环烷基;C1至C4烷氧基;羟基;可以被C1至C4烷基取代的氨基;可以被羟基取代的3至6元环胺;羟基C1至C4烷基;羟基C1至C4烷氧基;羧基烷氧基;和卤原子;
vii)可以被1至3个取代基取代的苯基,取代基选自下列取代基A;或
viii)吡啶基、嘧啶基、噻吩基、噻唑基或呋喃基,所有这些都可以被1至3个取代基取代,取代基选自下列取代基A;
取代基A是:可以被卤原子、氰基、硝基或羟基取代的C1至C4烷基;可以被卤原子、氰基、硝基或羟基取代的C1至C4烷氧基;氰基;硝基;可以具有保护基的羧基;可以具有保护基的羟基;可以被低级烷基取代的氨基甲酰基;卤原子;和可以被C1至C4酰基、C1至C4烷基磺酰基或芳基磺酰基取代的氨基,该芳基磺酰基可以具有取代基;
l是1至3的整数;
其条件是排除下列情况:l是1或2,X是氰基、硝基或氯原子,R1是氯原子,R2是甲氧基,环A是饱和的5或6元胺环,D是单键,m是0,W是可以具有保护基的羧基或C1至C4烷氧基;
l是1,R1是氯原子,R2是甲氧基,环A是饱和的5或6元胺环,D是单键,W是羟基;
l是1,环B是5或6元胺环,n和p都是0;
l是1,E和Q是羟基,q是0;
l是1,X是氯原子,Y是被甲氧基取代的苯基。
2、如权利要求1的酞嗪衍生物或其药学上可接受的盐,其中R1是卤原子、可以被卤原子取代的C1至C4烷基、或氰基,R2是卤原子、羟基或C1至C4烷氧基。
6、如权利要求1或2的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(V)表示的:
其中M、环K和环L定义同上。
8、如权利要求1或2的酞嗪衍生物或其药学上可接受的盐,其中Y是可以具有取代基的炔基、烯基或烷基,取代基选自C1至C4烷基;C3~C6环烷基;C1至C4烷氧基;羟基;可以被C1至C4烷基取代的氨基;可以被羟基取代的3至6元环胺;羟基C1至C4烷基;羟基C1至C4烷氧基;羧基烷氧基;和卤原子。
9、如权利要求1或2的酞嗪衍生物或其药学上可接受的盐,其中Y是可以被下列取代基取代的苯基:可以被羟基取代的C1至C4烷基;可以具有保护基的羧基;甲酰基;可以被C1至C4酰基、C1至C4烷基磺酰基或C1至C4烷基亚磺酰基取代的氨基。
10、如权利要求1或2的酞嗪衍生物或其药学上可接受的盐,其中Y是可以被取代基A取代的吡啶基、嘧啶基、噻吩基、噻唑基或呋喃基,其中取代基A定义同权利要求1。
11、如权利要求1或2的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(II)表示的基团;环A是可以具有双键的4至8元胺环;W是羟基;m是0或1至3的整数;而且,
i)D是单键,R3是卤原子,或
ii)D是氧原子,R3是氢原子。
12、如权利要求3的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(II)表示的基团;环A是可以具有双键的4至8元胺环;W是羟基;m是0或1至3的整数;而且,
i)D是单键,R3是卤原子,或
ii)D是氧原子,R3是氢原子。
13、如权利要求1或2的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(III)表示的基团,环B是6元氨基环,n是0或1,p是1。
14、如权利要求4的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(III)表示的基团,环B是6元氨基环,n是0或1,p是1。
15、如权利要求1或2的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(IV)表示的基团,E和J与它们所结合的碳原子一起构成3至6元环,该环任选地具有氧原子,任选地具有羟基、氧代或被羟基或羧基取代的C1至C4烷基,环G是可以具有双键的4至8元胺环。
16、如权利要求5的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(IV)表示的基团,E和J与它们所结合的碳原子一起构成3至6元环,该环任选地具有氧原子,任选地具有羟基、氧代或被羟基或羧基取代的C1至C4烷基,环G是可以具有双键的4至8元胺环。
17、如权利要求1或2的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(IV)表示的基团,E是羟基、卤原子、C1至C4烷基或C1至C4烷氧基,J是式-(CHR4)q-Q,其中R4是氢原子或C1至C4烷基,Q是羟基、卤原子、可以具有保护基的羧基、氨基甲酰基或不含有除氮原子以外杂原子的唑系基团,q是0或1至4的整数,环G是可以具有双键的4至8元胺环。
18、如权利要求5的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(IV)表示的基团,E是羟基、卤原子、C1至C4烷基或C1至C4烷氧基,J是式-(CHR4)q-Q,其中R4是氢原子或C1至C4烷基,Q是羟基、卤原子、可以具有保护基的羧基、氨基甲酰基或不含有除氮原子以外杂原子的唑系基团,q是0或1至4的整数,环G是可以具有双键的4至8元胺环。
19、如权利要求1或2的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(V)表示的基团,环K和L定义同上,M是C1至C4亚烷基,且被羟基、羧基、羟基C1至C4亚烷基或羧基C1至C4亚烷基取代。
20、如权利要求6的酞嗪衍生物或其药学上可接受的盐,其中Y是由式(V)表示的基团,环K和L定义同上,M是C1至C4亚烷基,且被羟基、羧基、羟基C1至C4亚烷基或羧基C1至C4亚烷基取代。
21、如权利要求1或2的酞嗪衍生物或其药学上可接受的盐,其中Y是具有一个叁键的炔基,任选具有选自可以被羟基取代的C1至C4烷基;4-羟基哌啶;吡咯烷;可以被低级烷基取代的氨基、可以被羟基、羧基烷氧基和环戊醇基的取代基。
22、如权利要求8的酞嗪衍生物或其药学上可接受的盐,其中Y是具有一个叁键的炔基,任选具有选自可以被羟基取代的C1至C4烷基;4-羟基哌啶;吡咯烷;可以被低级烷基取代的氨基、可以被羟基、羧基烷氧基和环戊醇基的取代基。
23、如权利要求1的稠合酞嗪衍生物或其药学上可接受的盐,其中该化合物选自下组:
1)1-(4-氨基哌啶子基)-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈;
2)4-[(3-氯-4-甲氧基苄基)氨基]-1-[(4-羟基-4-羟甲基)哌啶子基]-6-酞嗪甲腈;
3)4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-氰基哌啶子基)-6-酞嗪甲腈;
4)4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-氰基苯基)-6-酞嗪甲腈;
5)4-[4-[(3-氯-4-甲氧基苄基)氨基]-6-氰基酞嗪-1-基]苯基甲酰胺;
6)4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(4-氰基哌啶子基)-6-酞嗪甲腈;
7)4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-吡啶基)-6-酞嗪甲腈;
8)4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-吡啶基)-6-酞嗪甲腈;
9)4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-吡啶基)-6-酞嗪甲腈;
10)4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(2-吡啶基)-6-酞嗪甲腈;
11)4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(3-吡啶基)-6-酞嗪甲腈;
12)4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(4-吡啶基)-6-酞嗪甲腈;
13)4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈;
14)4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈;
15)4-[(3-溴-4-甲氧基苄基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈;
16)4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-羟基-6-氮杂螺[3.4]辛-6-基)-6-酞嗪甲腈;
17)4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(1-氟-2-羟乙基)哌啶子基]-6-酞嗪甲腈;
18)4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-氟-4-(羟甲基)哌啶子基]-6-酞嗪甲腈;
19)4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(羟甲基)-4-甲氧基哌啶子基]-6-酞嗪甲腈;
20)4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(羟基乙氧基)哌啶子基]-6-酞嗪甲腈;
21)4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-3-甲基-1-丁炔基)-6-酞嗪甲腈;
22)1-(3-氨基-3-甲基-1-丁炔基)-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈;
23)4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-3-甲基丁基)-6-酞嗪甲腈;
24)4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-肟基哌啶子基)-6-酞嗪甲腈;
25)4-[(3-溴-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈;
26)1-(4-羟基哌啶子基)-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈;
27)1-(4-羟基哌啶子基)-4-[[4-甲氧基-3-(三氟甲基)苄基]氨基]-6-酞嗪甲腈;
28)1-(4-羟基哌啶子基)-4-[(3-碘-4-甲氧基苄基)氨基]-6-酞嗪甲腈;
29)1-[4-氟-4-(羟甲基)哌啶子基]-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈;
30)4-[(3-溴-4-甲氧基苄基)氨基]-1-[4-(羟甲基)哌啶子基]-6-酞嗪甲腈;
31)4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(氟甲基)-4-羟基哌啶子基]-6-酞嗪甲腈;
32)4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲醛O6-甲基肟;
33)1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-(1H-1-吡唑基)-1-酞嗪基]-4-哌啶醇;
34)4-[(3-氰基-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈;
35)(内)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-8-氮杂二环[3.2.1]辛-8-基)-6-酞嗪甲腈;和
36)(顺式)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(9-羟基-3-氮杂二环[3.3.1]壬-3-基)-6-酞嗪甲腈。
24、如权利要求1的稠合酞嗪衍生物或其药学上可接受的盐,其中该化合物选自下组:
1)4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-吡啶基)-6-酞嗪甲腈;
2)4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-吡啶基)-6-酞嗪甲腈;
3)4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-吡啶基)-6-酞嗪甲腈;
4)4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(2-吡啶基)-6-酞嗪甲腈;
5)4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(3-吡啶基)-6-酞嗪甲腈;
6)4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(4-吡啶基)-6-酞嗪甲腈;
7)4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈;
8)4-[(3-氯-4-甲氧基苯乙基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈;
9)4-[(3-溴-4-甲氧基苄基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈;
10)4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-羟基-6-氮杂螺[3.4]辛-6-基)-6-酞嗪甲腈;
11)4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(1-氟-2-羟乙基)哌啶子基]-6-酞嗪甲腈;
12)4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-氟-4-(羟甲基)哌啶子基]-6-酞嗪甲腈;
13)4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(羟甲基)-4-甲氧基哌啶子基]-6-酞嗪甲腈;
14)4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(羟基乙氧基)哌啶子基]-6-酞嗪甲腈;
15)4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-3-甲基-1-丁炔基)-6-酞嗪甲腈;
16)1-(3-氨基-3-甲基-1-丁炔基)-4-[(3-氯-4-甲氧基苄基)氨基]-6-酞嗪甲腈;
17)4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-3-甲基丁基)-6-酞嗪甲腈;
18)4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-肟基哌啶子基)-6-酞嗪甲腈;
19)4-[(3-溴-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈;
20)1-(4-羟基哌啶子基)-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈;
21)1-[4-氟-4-(羟甲基)哌啶子基]-4-[(4-甲氧基-3-甲基苄基)氨基]-6-酞嗪甲腈;
22)4-[(3-氯-4-甲氧基苄基)氨基]-1-[4-(氟甲基)-4-羟基哌啶子基]-6-酞嗪甲腈;
23)4-[(3-氯-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲醛O6-甲基肟;
24)1-[4-[(3-氯-4-甲氧基苄基)氨基]-6-(1H-1-吡唑基)-1-酞嗪基]-4-哌啶醇;
25)4-[(3-氰基-4-甲氧基苄基)氨基]-1-(4-羟基哌啶子基)-6-酞嗪甲腈;
26)(内)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(3-羟基-8-氮杂二环[3.2.1]辛-8-基)-6-酞嗪甲腈;和
27)(顺式)-4-[(3-氯-4-甲氧基苄基)氨基]-1-(9-羟基-3-氮杂二环[3.3.1]壬-3-基)-6-酞嗪甲腈。
25、如权利要求1的稠合酞嗪衍生物或其药学上可接受的盐,为:
4-[(3-氯-4-甲氧基苄基)氨基]-1-(2-羟基-7-氮杂螺[3.5]壬-7-基)-6-酞嗪甲腈。
26、***障碍的预防或治疗剂,包含如权利要求1至25中任一项的化合物、其药学上可接受的盐或其水合物作为活性成分。
27、权利要求26的治疗剂,包含由式(VII)表示的酞嗪衍生物或其药学上可接受的盐作为活性成分:
其中l’表示1至3的整数;R6表示卤原子、可以被卤原子取代的C1至C4烷基或氰基;
X1表示氰基、硝基或卤原子;
Y1表示:
i)由式(VIII)表示的基团:
其中环A1表示5或6元胺环;m1是0或1至3的整数;Z表示氨基、可以具有保护基的羟基、可以具有保护基的羧基、C1至C4烷氧基或氰基;
ii)由式(IX)表示的基团:
其中环B1表示5或6元胺环,n1和p1是0或1至3的整数;
iii)吗啉基或硫原子可以被氧化的硫代吗啉基;
iv)可以被1至3个取代基取代的苯基,取代基选自下列取代基A1;
v)杂芳基,是吡啶基、嘧啶基、噻吩基或呋喃基,且可以被1至3个取代基取代,取代基选自下列取代基A1;或
vi)式-N(R7)-(CH2)s-Het基团,其中R7表示C1至C4烷基,Het表示吡啶基或嘧啶基,所有这些都可以被1至3个取代基取代,取代基选自下列取代基A1,s是0或1至3的整数;
取代基A1是:可以被卤原子、氰基、硝基或羟基取代的低级烷基;可以被卤原子、氰基、硝基或羟基取代的低级烷氧基;氰基;硝基;可以具有保护基的羧基;可以具有保护基的羟基;可以被低级烷基取代的氨基甲酰基;卤原子;和可以被烷基、烷氧基、卤原子或氨基取代的苯基。
29、如权利要求27的预防或治疗剂,包含如下酞嗪衍生物或其药学上可接受的盐作为活性成分,其中Y1是苯基或杂芳基,该杂芳基是吡啶基、嘧啶基、噻吩基或呋喃基,所有这些都可以被1至3个选自上述取代基A1的取代基取代。
30、如权利要求27的***障碍的预防或治疗剂,包含该酞嗪衍生物或其药学上可接受的盐作为活性成分,其中Y1是式-N(R7)-(CH2)s-Het基团,其中Het表示可以被1至3个选自上述取代基A1的取代基取代的吡啶基,R7和s定义同上。
31、如权利要求27的***障碍的治疗剂,包含该酞嗪衍生物或其药学上可接受的盐作为活性成分,其中该化合物选自下组:
1)4-(3-氯-4-甲氧基苄基)氯基-6-氰基-1-(3-羟甲基哌啶子基)酞嗪;
2)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(3,4-二羟基哌啶子基)酞嗪;
3)4-(4-氨基哌啶子基)-1-(3-氯-4-甲氧基苄基)氨基-6-氰基酞嗪;
4)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(4-甲氧基哌啶子基)酞嗪;
5)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(4-羟基-4-羟甲基哌啶子基)酞嗪;
6)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(4,4-二羟甲基哌啶子基)酞嗪;
7)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(4-氰基哌啶子基)酞嗪;
8)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-[(3R)-羟基吡咯烷基]酞嗪;
9)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(3-羟甲基吡咯烷基)酞嗪;
10)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(3,4-二羟基吡咯烷基)酞嗪;
11)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(2-甲氧基甲基吡咯烷基)酞嗪;
12)4-[4-(3-氯-4-甲氧基苄基氨基)-6-氰基酞嗪-1-基]硫代吗啉1-氧化物;
13)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(4-甲氧基苯基)酞嗪;
14)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(4-氰基苯基)酞嗪;
15)4-[4-(3-氯-4-甲氧基苄基氨基)-6-氰基酞嗪-1-基]苯基-1-甲酰胺;
16)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-(2-吡啶甲基)氨基酞嗪;
17)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-[N-甲基-N-(2-吡啶甲基)氨基]酞嗪;
18)4-(3-氯-4-甲氧基苯乙基)氨基-6-氰基-1-(4-氰基哌啶子基)酞嗪;
19)4-(3-氯-4-甲氧基苯乙基)氨基-6-氰基-1-(3-羟甲基哌啶子基)酞嗪;
20)4-(3-氯-4-甲氧基苯乙基)氨基-6-氰基-1-(4-羟甲基哌啶子基)酞嗪;
21)4-(3-氯-4-甲氧基苄基)氨基-6-氰基-1-苯基酞嗪;
22)4-(3-氯-4-甲氧基苄基)-6-氰基-1-(2-吡啶基)酞嗪;
23)4-(3-氯-4-甲氧基苄基)-6-氰基-1-(3-吡啶基)酞嗪;
24)4-(3-氯-4-甲氧基苄基)-6-氰基-1-(4-吡啶基)酞嗪;
25)4-(3-氯-4-甲氧基苯乙基)-6-氰基-1-(2-吡啶基)酞嗪;
26)4-(3-氯-4-甲氧基苯乙基)-6-氰基-1-(3-吡啶基)酞嗪;和
27)4-(3-氯-4-甲氧基苯乙基)-6-氰基-1-(4-吡啶基)酞嗪;
32、女性性机能障碍或痛经的预防和治疗剂,包含如权利要求1至25中任一项的化合物、其药学上可接受的盐或其水合物作为活性成分。
33、如权利要求1至25中任一项的酞嗪衍生物或其药学上可接受的盐在制备***障碍治疗剂中的应用。
34、如权利要求33所述的应用,所述化合物是由式(VII)表示的酞嗪衍生物或其药学上可接受的盐:
其中l’表示1至3的整数;R6表示卤原子、可以被卤原子取代的C1至C4烷基或氰基;
X1表示氰基、硝基或卤原子;
Y1表示:
i)由式(VIII)表示的基团:
其中环A1表示5或6元胺环;m1是0或1至3的整数;Z表示氨基、可以具有保护基的羟基、可以具有保护基的羧基、C1至C4烷氧基或氰基;
ii)由式(IX)表示的基团:
其中环B1表示5或6元胺环,n1和p1是0或1至3的整数;
iii)吗啉基或硫原子可以被氧化的硫代吗啉基;
iv)可以被1至3个取代基取代的苯基,取代基选自下列取代基A1;
v)杂芳基,是吡啶基、嘧啶基、噻吩基或呋喃基,且可以被1至3个取代基取代,取代基选自下列取代基A1;或
vi)式-N(R7)-(CH2)s-Het基团,其中R7表示C1至C4烷基,Het表示吡啶基或嘧啶基,所有这些都可以被1至3个取代基取代,取代基选自下列取代基A1,s是0或1至3的整数;
取代基A1是:可以被卤原子、氰基、硝基或羟基取代的低级烷基;可以被卤原子、氰基、硝基或羟基取代的低级烷氧基;氰基;硝基;可以具有保护基的羧基;可以具有保护基的羟基;可以被低级烷基取代的氨基甲酰基;卤原子;和可以被烷基、烷氧基、卤原子或氨基取代的苯基。
35、如权利要求1至25中任一项的酞嗪衍生物或其药学上可接受的盐在制备女性性机能障碍或痛经治疗剂中的应用。
36、如权利要求35所述的应用,所述化合物是由式(VII)表示的酞嗪衍生物或其药学上可接受的盐:
其中l’表示1至3的整数;R6表示卤原子、可以被卤原子取代的C1至C4烷基或氰基;
X1表示氰基、硝基或卤原子;
Y1表示:
i)由式(VIII)表示的基团:
其中环A1表示5或6元胺环;m1是0或1至3的整数;Z表示氨基、可以具有保护基的羟基、可以具有保护基的羧基、C1至C4烷氧基或氰基;
ii)由式(IX)表示的基团:
其中环B1表示5或6元胺环,n1和p1是0或1至3的整数;
iii)吗啉基或硫原子可以被氧化的硫代吗啉基;
iv)可以被1至3个取代基取代的苯基,取代基选自下列取代基A1;
v)杂芳基,是吡啶基、嘧啶基、噻吩基或呋喃基,且可以被1至3个取代基取代,取代基选自下列取代基A1;或
vi)式-N(R7)-(CH2)s-Het基团,其中R7表示C1至C4烷基,Het表示吡啶基或嘧啶基,所有这些都可以被1至3个取代基取代,取代基选自下列取代基A1,s是0或1至3的整数;
取代基A1是:可以被卤原子、氰基、硝基或羟基取代的低级烷基;可以被卤原子、氰基、硝基或羟基取代的低级烷氧基;氰基;硝基;可以具有保护基的羧基;可以具有保护基的羟基;可以被低级烷基取代的氨基甲酰基;卤原子;和可以被烷基、烷氧基、卤原子或氨基取代的苯基。
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JP3702098 | 1998-02-19 | ||
JP37020/1998 | 1998-02-19 | ||
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JP319540/1998 | 1998-11-10 |
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US (2) | US6498159B1 (zh) |
EP (1) | EP1057819A4 (zh) |
KR (1) | KR20010023724A (zh) |
CN (1) | CN1210265C (zh) |
AU (1) | AU755361B2 (zh) |
BR (1) | BR9909369A (zh) |
CA (1) | CA2302943C (zh) |
HU (1) | HUP0003219A3 (zh) |
NO (1) | NO317877B1 (zh) |
NZ (1) | NZ503399A (zh) |
PL (1) | PL339836A1 (zh) |
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CN108395377A (zh) * | 2018-01-16 | 2018-08-14 | 吴江信凯医药科技有限公司 | 一种3-氯-4-甲氧基苄胺盐酸盐的制备方法 |
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JP2004500425A (ja) | 2000-04-19 | 2004-01-08 | リリー アイコス リミテッド ライアビリティ カンパニー | パーキンソン病の処置に対する環状gmp特異的ホスホジエステラーゼインヒビターの使用 |
US6803906B1 (en) * | 2000-07-05 | 2004-10-12 | Smart Technologies, Inc. | Passive touch system and method of detecting user input |
US6821978B2 (en) | 2000-09-19 | 2004-11-23 | Schering Corporation | Xanthine phosphodiesterase V inhibitors |
EP1442042A1 (en) | 2001-11-09 | 2004-08-04 | Schering Corporation | Polycyclic guanine derivative phosphodiesterase v inhibitors |
WO2005075423A1 (fr) * | 2004-01-30 | 2005-08-18 | Beijing Tuolin Medicine Science And Technology Co., Ltd | Extraits de marasmines androsaceus l.es, derives de piperdinone et utilisations de ceux-ci en tant qu'agents hypertensifs |
CA2577442A1 (en) | 2004-08-17 | 2006-03-02 | The Johns Hopkins University | Pde5 inhibitor compositions and methods for treating cardiac indications |
CA2593005A1 (en) * | 2005-01-03 | 2006-07-13 | Myriad Genetics Inc. | Pharmaceutical compounds as activators of caspases and inducers of apoptosis and the use thereof |
US7759337B2 (en) | 2005-03-03 | 2010-07-20 | Amgen Inc. | Phthalazine compounds and methods of use |
WO2010042649A2 (en) | 2008-10-10 | 2010-04-15 | Amgen Inc. | PHTHALAZINE COMPOUNDS AS p38 MAP KINASE MODULATORS AND METHODS OF USE THEREOF |
WO2010042646A1 (en) | 2008-10-10 | 2010-04-15 | Amgen Inc. | Aza- and diaza-phthalazine compounds as p38 map kinase modulators and methods of use thereof |
FR2941696B1 (fr) | 2009-02-05 | 2011-04-15 | Sanofi Aventis | Derives d'azaspiranyl-alkylcarbamates d'heterocycles a 5 chainons, leur preparation et leur application en therapeutique |
CN102060749B (zh) * | 2009-11-12 | 2013-07-10 | 上海药明康德新药开发有限公司 | 2-氰基-7-氮杂-螺[3,5]壬烷衍生物的制备方法 |
EP2938343B1 (en) | 2012-12-21 | 2018-09-12 | Mayo Foundation For Medical Education And Research | Methods and materials for treating calcific aortic valve stenosis |
CN105492442A (zh) * | 2013-09-06 | 2016-04-13 | 日本曹达株式会社 | 内型-9-氮杂双环[3.3.1]壬烷-3-醇衍生物的制造方法 |
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US4754091A (en) * | 1985-02-28 | 1988-06-28 | Amoco Corporation | Conversion of a lower alkane |
MY104343A (en) | 1987-11-23 | 1994-03-31 | Janssen Pharmaceutica Nv | Novel pyridizinamine deravatives |
TW279162B (zh) * | 1991-09-26 | 1996-06-21 | Mitsubishi Chem Corp | |
US5849741A (en) | 1994-08-09 | 1998-12-15 | Eisai Co., Ltd. | Fused pyridazine compounds |
JP3919835B2 (ja) | 1994-08-09 | 2007-05-30 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 縮合ピリダジン系化合物 |
JPH09135938A (ja) | 1995-11-16 | 1997-05-27 | Toyota Motor Corp | 水陸両用ボ−ト |
CA2258079A1 (en) | 1996-08-20 | 1998-02-26 | Mayu Shibazaki | Remedy for erection failure comprising fused pyridazine compound |
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CA2302943C (en) | 2007-08-07 |
HUP0003219A2 (hu) | 2001-05-28 |
US20030105074A1 (en) | 2003-06-05 |
EP1057819A1 (en) | 2000-12-06 |
BR9909369A (pt) | 2000-11-28 |
NZ503399A (en) | 2003-01-31 |
AU2547099A (en) | 1999-09-06 |
CA2302943A1 (en) | 1999-08-26 |
KR20010023724A (ko) | 2001-03-26 |
AU755361B2 (en) | 2002-12-12 |
NO317877B1 (no) | 2004-12-27 |
EP1057819A4 (en) | 2003-02-05 |
CN1275124A (zh) | 2000-11-29 |
US6699870B2 (en) | 2004-03-02 |
HUP0003219A3 (en) | 2001-07-30 |
NO20000969L (no) | 2000-08-11 |
WO1999042452A1 (fr) | 1999-08-26 |
PL339836A1 (en) | 2001-01-02 |
RU2229476C2 (ru) | 2004-05-27 |
NO20000969D0 (no) | 2000-02-25 |
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