CN1922171B - 嘧啶衍生物 - Google Patents
嘧啶衍生物 Download PDFInfo
- Publication number
- CN1922171B CN1922171B CN200580005603XA CN200580005603A CN1922171B CN 1922171 B CN1922171 B CN 1922171B CN 200580005603X A CN200580005603X A CN 200580005603XA CN 200580005603 A CN200580005603 A CN 200580005603A CN 1922171 B CN1922171 B CN 1922171B
- Authority
- CN
- China
- Prior art keywords
- base
- amino
- piperazine
- quinoline
- methyl
- 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
Links
- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 22
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims abstract description 224
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 91
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 66
- 208000002551 irritable bowel syndrome Diseases 0.000 claims abstract description 38
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 18
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- -1 piperazine-1-yl Chemical group 0.000 claims description 425
- 238000002360 preparation method Methods 0.000 claims description 256
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 217
- 150000001875 compounds Chemical class 0.000 claims description 168
- JEDVKUHCDPPWNR-UHFFFAOYSA-N 3h-thieno[2,3-d]pyrimidin-4-one Chemical compound O=C1NC=NC2=C1C=CS2 JEDVKUHCDPPWNR-UHFFFAOYSA-N 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- 239000012190 activator Substances 0.000 claims description 15
- 125000004494 ethyl ester group Chemical group 0.000 claims description 15
- 230000004913 activation Effects 0.000 claims description 13
- 239000005557 antagonist Substances 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 claims description 11
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 claims description 10
- 208000011580 syndromic disease Diseases 0.000 claims description 10
- JSWZEAMFRNKZNL-UHFFFAOYSA-N alosetron Chemical compound N1C=NC(CN2C(C3=C(N(C4=CC=CC=C43)C)CC2)=O)=C1C JSWZEAMFRNKZNL-UHFFFAOYSA-N 0.000 claims description 8
- 229940060963 lotronex Drugs 0.000 claims description 8
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 claims description 7
- 229960003727 granisetron Drugs 0.000 claims description 7
- 150000002469 indenes Chemical class 0.000 claims description 7
- 206010046543 Urinary incontinence Diseases 0.000 claims description 6
- NCNFDKWULDWJDS-OAHLLOKOSA-N cilansetron Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C=3N4CCCC=3C=CC=2)=C4CC1 NCNFDKWULDWJDS-OAHLLOKOSA-N 0.000 claims description 6
- 229960002099 cilansetron Drugs 0.000 claims description 6
- 230000003187 abdominal effect Effects 0.000 claims description 3
- YFOFKNGTFTVYBB-UHFFFAOYSA-N 3-amino-2-[4-[4-(5-methoxyquinolin-2-yl)piperazin-1-yl]butyl]quinazolin-4-one Chemical compound C1=CC=C2C(=O)N(N)C(CCCCN3CCN(CC3)C=3N=C4C=CC=C(C4=CC=3)OC)=NC2=C1 YFOFKNGTFTVYBB-UHFFFAOYSA-N 0.000 claims description 2
- 206010047700 Vomiting Diseases 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 230000008673 vomiting Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 19
- 230000003042 antagnostic effect Effects 0.000 abstract description 14
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 8
- 150000002431 hydrogen Chemical class 0.000 abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 5
- 230000001270 agonistic effect Effects 0.000 abstract 4
- 238000002560 therapeutic procedure Methods 0.000 abstract 2
- 125000002837 carbocyclic group Chemical group 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- 239000002585 base Substances 0.000 description 875
- 238000005160 1H NMR spectroscopy Methods 0.000 description 371
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 255
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 168
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 100
- 239000000460 chlorine Substances 0.000 description 78
- 229910052801 chlorine Inorganic materials 0.000 description 78
- 239000000243 solution Substances 0.000 description 63
- 238000010898 silica gel chromatography Methods 0.000 description 56
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 50
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 238000001035 drying Methods 0.000 description 48
- 229910052731 fluorine Inorganic materials 0.000 description 48
- 239000011737 fluorine Substances 0.000 description 48
- 230000006837 decompression Effects 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 45
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 41
- 229910052794 bromium Inorganic materials 0.000 description 40
- 239000007864 aqueous solution Substances 0.000 description 38
- 238000000034 method Methods 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 230000002194 synthesizing effect Effects 0.000 description 31
- 238000010992 reflux Methods 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 27
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 27
- 238000005406 washing Methods 0.000 description 26
- 238000001816 cooling Methods 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 230000000694 effects Effects 0.000 description 23
- 230000002829 reductive effect Effects 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000007788 liquid Substances 0.000 description 21
- 235000002639 sodium chloride Nutrition 0.000 description 21
- 238000000605 extraction Methods 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000002994 raw material Substances 0.000 description 18
- PYEZYNAHBMWJFR-UHFFFAOYSA-N thieno[3,2-c]pyridine Chemical group N1=CC=C2S[C]=CC2=C1 PYEZYNAHBMWJFR-UHFFFAOYSA-N 0.000 description 17
- 238000012360 testing method Methods 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 15
- 239000000370 acceptor Substances 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 125000003282 alkyl amino group Chemical group 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 12
- 238000003810 ethyl acetate extraction Methods 0.000 description 12
- 230000009471 action Effects 0.000 description 11
- 125000001118 alkylidene group Chemical group 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- ZYXBIOIYWUIXSM-UHFFFAOYSA-N furo[2,3-c]pyridine Chemical compound C1=NC=C2OC=CC2=C1 ZYXBIOIYWUIXSM-UHFFFAOYSA-N 0.000 description 10
- WJDMEHCIRPKRRQ-UHFFFAOYSA-N furo[3,2-c]pyridine Chemical compound N1=CC=C2OC=CC2=C1 WJDMEHCIRPKRRQ-UHFFFAOYSA-N 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 238000011534 incubation Methods 0.000 description 10
- 238000002386 leaching Methods 0.000 description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 10
- GDQBPBMIAFIRIU-UHFFFAOYSA-N thieno[2,3-c]pyridine Chemical compound C1=NC=C2SC=CC2=C1 GDQBPBMIAFIRIU-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 9
- 229910052700 potassium Inorganic materials 0.000 description 9
- 239000011591 potassium Substances 0.000 description 9
- 229910001948 sodium oxide Inorganic materials 0.000 description 9
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 230000003139 buffering effect Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 0 *C*C(*)N1CCN(*)CC1 Chemical compound *C*C(*)N1CCN(*)CC1 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 description 7
- 230000036471 bradycardia Effects 0.000 description 7
- 208000006218 bradycardia Diseases 0.000 description 7
- 230000013872 defecation Effects 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 150000002240 furans Chemical class 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 6
- IYRMNDOLPONSCJ-UHFFFAOYSA-N isoquinolin-2-ium;chloride Chemical compound Cl.C1=NC=CC2=CC=CC=C21 IYRMNDOLPONSCJ-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- NUKZAGXMHTUAFE-UHFFFAOYSA-N methyl hexanoate Chemical compound CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 6
- 229960003688 tropisetron Drugs 0.000 description 6
- MMVSOHZQZLHWNH-UHFFFAOYSA-N 1,7-dihydrocyclopenta[d]pyrimidin-4-one Chemical compound O=C1NC=NC2=C1C=CC2 MMVSOHZQZLHWNH-UHFFFAOYSA-N 0.000 description 5
- ASXGJMSKWNBENU-UHFFFAOYSA-N 8-OH-DPAT Chemical compound C1=CC(O)=C2CC(N(CCC)CCC)CCC2=C1 ASXGJMSKWNBENU-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 238000006386 neutralization reaction Methods 0.000 description 5
- 125000003386 piperidinyl group Chemical group 0.000 description 5
- 235000010288 sodium nitrite Nutrition 0.000 description 5
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 4
- SODQFLRLAOALCF-UHFFFAOYSA-N 1lambda3-bromacyclohexa-1,3,5-triene Chemical compound Br1=CC=CC=C1 SODQFLRLAOALCF-UHFFFAOYSA-N 0.000 description 4
- SABCCZAHTZTCNO-UHFFFAOYSA-N 2-[4-(3-chloropropyl)piperazin-1-yl]quinoline Chemical compound C1CN(CCCCl)CCN1C1=CC=C(C=CC=C2)C2=N1 SABCCZAHTZTCNO-UHFFFAOYSA-N 0.000 description 4
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 4
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 4
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 235000015165 citric acid Nutrition 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229940076279 serotonin Drugs 0.000 description 4
- 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 4
- 239000007787 solid Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- GKTQKQTXHNUFSP-UHFFFAOYSA-N thieno[3,4-c]pyrrole-4,6-dione Chemical compound S1C=C2C(=O)NC(=O)C2=C1 GKTQKQTXHNUFSP-UHFFFAOYSA-N 0.000 description 4
- 229930192474 thiophene Natural products 0.000 description 4
- 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 3
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 3
- MFWNKCLOYSRHCJ-UHFFFAOYSA-N 1-Methyl-N-{9-methyl-9-azabicyclo[3.3.1]nonan-3-yl}-1H-indazole-3-carboxamide Chemical compound C1=CC=C2C(C(=O)NC3CC4CCCC(C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-UHFFFAOYSA-N 0.000 description 3
- UFCCTPREKSTTIX-UHFFFAOYSA-N 2-bromo-4-(4-methylpiperazin-1-yl)thieno[3,2-c]pyridine Chemical compound C1CN(C)CCN1C1=NC=CC2=C1C=C(Br)S2 UFCCTPREKSTTIX-UHFFFAOYSA-N 0.000 description 3
- UNVYSECOIMWWKM-UHFFFAOYSA-N 3,6-dihydro-2h-thiopyran Chemical compound C1CC=CCS1 UNVYSECOIMWWKM-UHFFFAOYSA-N 0.000 description 3
- IPNFHINMZIGBIH-UHFFFAOYSA-N 3-(4-quinolin-2-ylpiperazin-1-yl)propan-1-amine Chemical compound C1CN(CCCN)CCN1C1=CC=C(C=CC=C2)C2=N1 IPNFHINMZIGBIH-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
本发明提供式(I)所示嘧啶衍生物或其盐,该嘧啶衍生物兼有5-HT1A激活作用和5-HT3拮抗作用的两种作用,对IBS等疾病的治疗、处置等有效。本发明还提供IBS的治疗方法,其特征在于:通过给予对5-HT1A具有激活作用的5-HT3拮抗剂,或者同时、依次或间隔给予5-HT1A激活剂和5-HT3拮抗剂,使5-HT1A激活作用和5-HT3拮抗作用在机体内同时协同作用。所述式(I)中,A环表示碳环基或杂环基;X1表示氢原子、低级烷基、氨基等;X2表示氢原子或低级烷基;Y表示直接键合或者硫原子或氮原子;n为0-4的整数;Ar为下式的基团。
Description
技术领域
本发明涉及嘧啶衍生物及其盐,该嘧啶衍生物及其盐兼有5-羟色胺受体亚型1A(下面,简称5-HT1A)激活作用和5-羟色胺受体亚型3(下面,简称5-HT3)拮抗作用的两种作用,可用作过敏性肠综合征(IBS:Irritable Bowel Syndrome;下面,简称“IBS”)等的处置剂。
本发明还涉及IBS等的治疗方法,其特征在于:使5-HT1A激活作用和5-HT3拮抗作用在机体内同时协同作用。
背景技术
IBS是以腹泻或便秘等排便异常或者腹痛为主要症状的机能性疾病,未发现肠道的器质性病变。该疾病因肠道运动异常、内脏知觉过敏和心理、社会的因素等相互作用而发病。
肠道中的5-HT3参与肠道收缩、肠液分泌、蠕动运动、内容物输送等,因此通过给予5-HT3拮抗药可以改善IBS的腹泻症状。美国已批准5-HT3拮抗药阿洛司琼作为IBS治疗药。此外,在WO99/17755小册子和美国专利第6,284,770号说明书中,还公开了其它的5-HT3拮抗药,例如昂丹司琼、阿洛司琼、托烷司琼(、格拉司琼等,这些文献中记载了5-HT3拮抗药作为IBS治疗剂有效。
另一方面,IBS的病因之一是例如心理、社会的因素,因此在IBS治疗中尝试了给予苯并二氮杂类抗焦虑药。最近,开发了新型5-羟色胺激活性的抗焦虑药,例如副作用更小的非苯并二氮杂类化合物等,这些化合物在IBS治疗上可望得到应用。
在J.Med.Chem.,40,574-585(1997)和Eur.J.Med.Chem.,35,677-689(2000)中,公开了对5-HT1A具有选择性亲和性的嘧啶酮衍生物。这些文献中相对于α1受体,探讨了对5-HT1A的选择性。在欧洲专利第343,050号说明书、WO01/32659小册子、日本2001-97978A和J.Med.Chem.,32,1147-1156(1989)中,还公开了对5-HT1A等具有亲和性的哌嗪基异喹啉衍生物、哌嗪基噻吩并吡啶衍生物和哌嗪基呋吡啶衍生物。这些文献中记载了基于5-HT1A激活作用的精神上的作用,但没有关于5-HT3的记载,也没有任何基于对两受体的作用而应用于IBS等的记载或启示。
在J.Med.Chem.,42,4362-4379(1999)中,记载了对5-HT3具有选择性亲和性的哌嗪基吡嗪衍生物,但其作用为激活性的作用。
在日本,5-HT1A激活药坦度螺酮以应激性消化性溃疡等为适应症已经上市。所述适应症缘于通过坦度螺酮的抗焦虑作用解除应激反应,IBS并未被列为适应症。
如上所述,现在已经开发或上市了多种5-HT3拮抗药和5-HT1A激活药。只是,5-HT3拮抗药和5-HT1A激活药的作用都是单向性的,而IBS是多原因疾病,因此这些化合物对IBS的疗效不充分。
最近,在Bioorg.Med.Chem.Lett.,13,3177-3180(2003)中,公开了对5-HT3和5-HT1A两种受体具有亲和性的化合物。但是,该化合物为苯并咪唑-烯丙基哌嗪衍生物,而且,该文献中仅记载了上述化合物对神经系统的作用,对IBS的5-HT3拮抗作用和5-HT1A激活作用的组合及其效果没有任何记载或启示。
本发明人进行了反复深入的研究,结果发现:为了处置与5-HT3的过度活化或表达增强和5-HT1A的活性低下的两者相关的疾病,特别是处置IBS,使5-HT3拮抗作用和5-HT1A激活作用在机体内同时表达是极为有效的。
发明内容
于是,本发明提供兼有5-HT1A激活作用和5-HT3拮抗作用的两种作用的下式(I)所示新型嘧啶衍生物或其药学上可接受的盐:
式中,
A环表示烃环基或杂环基;
X1表示氢原子、氨基、低级烷基氨基、二低级烷基氨基、低级亚烷基氨基、低级烷基、苯基低级烷基或者取代或未取代的苯基;
X2表示氢原子或低级烷基;
Y表示直接键合或者硫原子或氮原子;
n为0或1-4的整数;
Ar表示未取代或者被选自卤素原子、低级烷基、羟基、低级烷氧基和苯基的取代基取代的下式的基团:
其中,Z表示碳原子、氧原子或硫原子,B表示可与上式基团的剩余部分一起形成稠合环的、形成单环或多环式含氮杂环基所需的其余部分,虚线表示那里可以存在键。
本发明还提供IBS的治疗方法,其特征在于:对需要治疗IBS的人或其他哺乳动物,通过给予兼具5-HT1A激活作用的5-HT3拮抗剂,或者同时、依次或间隔给予5-HT1A激活剂和5-HT3拮抗剂,使5-HT1A激活作用和5-HT3拮抗作用在机体内同时协同作用。
下面,对本发明进行更具体的说明。
在本说明书中,术语“低级”表示带有该术语的基团的碳原子数为6个以下,优选为4个以下。
因此,“低级烷基”为直链状或支链状,例如可以是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等,其中,优选甲基、乙基、正丙基、异丙基和正丁基等C1-C4烷基。“低级烷氧基”例如可以是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、正戊氧基、正己氧基等,其中,优选甲氧基、乙氧基、正丙氧基、异丙氧基和正丁氧基等C1-C4烷氧基。
X1定义中的“苯基低级烷基”是指被苯基取代的如上所述的低级烷基,例如可以是苄基、苯基乙基、苯基丙基、苯基丁基等。其中特别优选苄基。X1定义中的“取代或未取代的苯基”的苯基上的取代基例如有卤素原子、低级烷基、低级烷氧基等,其中优选低级烷氧基。
X1定义中的“低级烷基氨基”是指被如上所述的低级烷基一取代的氨基,具体例子有:N-甲基氨基、N-乙基氨基、N-正丙基氨基、N-异丙基氨基、N-正丁基氨基、N-异丁基氨基、N-仲丁基氨基、N-叔丁基氨基、N-正戊基氨基、N-正己基氨基等。其中特别优选N-甲基氨基、N-乙基氨基、N-正丙基氨基、N-异丙基氨基和N-正丁基氨基等C1-C4烷基氨基。X1定义中的“二低级烷基氨基”是指被相同或不同的如上所述低级烷基二取代的氨基,具体例子有:N,N-二甲基氨基、N,N-二乙基氨基、N,N-二正丙基氨基、N,N-二异丙基氨基、N-甲基-N-乙基氨基、N-甲基-N-正丙基氨基、N-乙基-N-异丙基氨基、N-甲基-N-正丁基氨基、N-乙基-N-异丁基氨基、N-异丙基-N-仲丁基氨基、N-正丙基-N-正戊基氨基、N-甲基-N-正己基氨基等。其中特别优选N,N-二甲基氨基、N-甲基-N-乙基氨基、N-乙基-N-异丙基氨基和N-甲基-N-正丁基氨基等二C1-C4烷基氨基。X1定义中的“低级亚烷基氨基”是指被低级亚烷基取代的氨基,具体例子有N-亚异丙基氨基等。
“卤素原子”包含氟、氯、溴或碘原子,其中优选氟、氯和溴原子。
上述式(I)中,A环表示碳环基时,作为该碳环基,可优选例如下述式i)-iv)等基团:
式中,
R1表示氢原子、卤素原子、低级烷基、卤代低级烷基、低级烷氧基、羧基、低级烷氧基羰基、苯基、氨基、肼基或硝基;
R2、R3和R4各自独立表示氢原子、卤素原子、低级烷基、低级烷氧基、苯基或羟基,或者R2、R3和R4中的两个一起表示氧代基或低级亚烷二氧基;
m是1-3的整数。
上述式(I)中,A环表示杂环基时,该杂环基可以是单环或者与其它环稠合形成稠合环,其优选的基团可以是例如下式v)-xv)等基团:
式中,
R5表示氢原子、低级烷基、羧基或低级烷氧基羰基,
R6表示氢原子或低级烷基,
R7表示氢原子、低级烷基、低级烷酰基、低级烷氧基羰基或苯基低级烷氧基羰基。
作为A环,其中,优选式i)或ii)的基团,特别优选式ii)的基团。
在上述A环的定义中,“卤代低级烷基”是指低级烷基的至少一个氢原子被卤素原子取代后的基团,例如可以是氯甲基、2-溴乙基、3-氟丙基、4-碘异戊基、二氯甲基、1,2-二溴乙基、三氟甲基、2,2,2-三氯乙基等。其中特别优选氯甲基和三氟甲基。
A环定义中的“低级烷氧基羰基”是低级烷氧基-CO-基,例如可以是甲氧基羰基、乙氧基羰基、异丙氧基羰基、叔丁氧基羰基等,其中,特别优选甲氧基羰基和乙氧基羰基。
A环定义中的“低级亚烷二氧基”例如可以是亚甲二氧基、亚乙二氧基、亚丙二氧基等,特别优选亚乙二氧基。
A环定义中的“低级烷酰基”为低级烷基-CO-基,例如可以是乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基等,其中优选乙酰基和丙酰基。
A环定义中的“苯基低级烷氧基羰基”是被苯基取代的如上所述的低级烷氧基羰基,例如可以是苄氧基羰基、1-苯基乙氧基羰基、2-苯基乙氧基羰基、3-苯基丙氧基羰基、1-苄基乙氧基羰基、1-苄基-1-甲基乙氧基羰基等,其中特别优选苄氧基羰基、2-苯基乙氧基羰基和3-苯基丙氧基羰基。
上述式(I)中,对Ar定义的下式基团:
式中Z和B如上定义,
可以包含例如未取代或者被选自卤素原子、低级烷基、羟基、低级烷氧基和苯基的取代基取代的单环或多环含氮杂环基等。其中,该含氮杂环基的骨架部分例如可以是下述式等所示的基团:
其中,特别优选下述式所示的基团:
本说明书中,“兼有5-HT1A激活作用的5-HT3拮抗剂”,除了具有5-HT1A激活作用和5-HT3拮抗作用的两种作用之外,还可具有其它的药理作用。所述拮抗剂,具体来说例如可以是上述式(I)所示的嘧啶衍生物或其药学上可接受的盐和下述式(II)所示的哌嗪基吡啶衍生物或其药学上可接受的盐:
式中,
C环表示未取代的苯环或选自吡啶、呋喃和噻吩的未取代杂环基;被选自卤素原子、低级烷基、苯基、羟基、低级烷氧基、苯基低级烷氧基(该基团的苯基部分为未取代或可被卤素原子取代)、氨基、低级烷基氨基、二低级烷基氨基、低级烷基硫基、低级烷基亚硫酰基和氨基磺酰氧基的取代基取代的苯环;或者选自被卤素原子或低级烷基取代的吡啶、呋喃和噻吩的杂环基;
R8表示氢原子、卤素原子或低级烷基,
R9表示氢原子、低级烷基、苯基低级烷基(该基团的苯基部分为未取代或可被选自卤素原子、低级烷基和低级烷氧基的取代基取代)、氨基低级烷基(该基团的氨基部分为未取代或者可被低级烷基一或二取代或者形成环状亚胺基)或苯基环烷基(该基团的苯基部分为未取代或可被选自卤素原子、低级烷基和低级烷氧基的取代基取代);
而
R10表示氢原子或低级烷基,或者
R9和R10可一起形成吡咯烷环或哌啶环(该吡咯烷环和哌啶环为未取代或可被选自羟基、低级烷氧基和苯基低级烷氧基的取代基取代)的其余部分;
R11表示氢原子或低级烷基。
在上述式(II)的C环定义中,“苯基低级烷氧基(该基团的苯基部分为未取代或可被卤素原子取代)”是指被未取代的或经卤素原子取代的苯基取代的低级烷氧基,例如可以是苄氧基、苯基乙氧基、苯基丙氧基、苯基丁氧基、2-氯苄氧基、2-溴苄氧基、2-氟苄氧基、3-溴苄氧基、4-氟苄氧基、2,4-二氯苄氧基、1-(4-氟苯基甲基)乙氧基等。其中特别优选未取代或被一个卤素原子取代的苄氧基。
在上述式(II)的C环定义中,“低级烷基氨基”是被低级烷基一取代的氨基,例如可以是N-甲基氨基、N-乙基氨基、N-正丙基氨基、N-仲丁基氨基等,特别优选N-甲基氨基和N-乙基氨基。另外,C环定义中的“二低级烷基氨基”是被相同或不同的低级烷基二取代的氨基,例如可以是N,N-二甲基氨基、N,N-二乙基氨基、N,N-二异丙基氨基、N-甲基-N-乙基氨基、N-甲基-N-叔丁基氨基等,特别优选N,N-二甲基氨基和N,N-二乙基氨基。
在上述式(II)的C环定义中,“低级烷基硫基”是低级烷基-S-基,
例如可以是甲硫基、乙硫基、异丁硫基等,其中特别优选甲硫基。
另外,C环定义中的“低级烷基亚硫酰基”是低级烷基-SO-基,例如可以是甲基亚硫酰基、乙基亚硫酰基、异丙基亚硫酰基等,其中特别优选甲基亚硫酰基。
上述式(II)中,当C环表示“选自吡啶、呋喃和噻吩的未取代杂环基”或“选自吡啶、呋喃和噻吩的杂环基”时,所述基团与式(II)中的吡啶环稠合形成的杂环例如可以是1,6-二氮杂萘、2,6-二氮杂萘、2,7-二氮杂萘、1,7-二氮杂萘、呋喃并[3,2-c]吡啶、呋喃并[3,4-c]吡啶、呋喃并[2,3-c]吡啶、噻吩并[3,2-c]吡啶、噻吩并[3,4-c]吡啶、噻吩并[2,3-c]吡啶等。其中,优选1,6-二氮杂萘、2,6-二氮杂萘、2,7-二氮杂萘、1,7-二氮杂萘、呋喃并[3,2-c]吡啶、呋喃并[2,3-c]吡啶、噻吩并[3,2-c]吡啶和噻吩并[2,3-c]吡啶,特别优选1,6-二氮杂萘、1,7-二氮杂萘、呋喃并[2,3-c]吡啶和噻吩并[2,3-c]吡啶。
上述式(II)的R9定义中所用的“苯基低级烷基(该基团的苯基部分为未取代或可被选自卤素原子、低级烷基和低级烷氧基的取代基取代)”是被取代或未取代的苯基取代的低级烷基,其中苯基上的取代基例如可以是2-氟、3-氟、4-氟、2-氯、4-氯、3-溴、4-溴、4-碘、2-甲基、3-甲基、4-甲基、2-乙基、3-乙基、3-正丙基、4-异丙基、2-甲氧基、3-甲氧基、4-甲氧基、3-乙氧基、4-异丙氧基等,其中优选4-氟、4-氯、4-溴、3-甲基、3-乙基、3-甲氧基和3-乙氧基。而且,上述低级烷基优选为例如甲基、乙基、正丙基和正丁基。因此,“苯基低级烷基(该基团的苯基部分为未取代或可被选自卤素原子、低级烷基和低级烷氧基的取代基取代)”的优选具体例子可以是苄基、4-氟苄基、2-(4-氯苯基)乙基、3-(4-溴苯基)-正丙基、3-甲基苄基、3-(3-乙基苯基)丁基、3-甲氧基苄基和4-(3-甲氧基苯基)丁基。
上述式(II)的R9定义中所用的“氨基低级烷基(该基团的氨基部分为未取代或者可被低级烷基一或二取代或者形成环状亚胺基)”是被氨基取代的低级烷基,其中,“氨基”不仅包含未取代的氨基也包含被一个或两个低级烷基取代的氨基和形成了环状亚胺基的氨基。可取代所述氨基的低级烷基优选甲基、乙基、正丙基和正丁基。因此,“氨基低级烷基(该基团的氨基部分为未取代或者可被低级烷基一或二取代或者形成环状亚胺基)”的优选具体例子可以是氨基甲基、2-氨基乙基、3-氨基丙基、4-氨基丁基、2-(N-甲基氨基)乙基、3-(N,N-二甲基氨基)丙基和3-邻苯二甲酰亚氨基丙基。
上述式(II)的R9定义中所用的“苯基环烷基(该基团的苯基部分为未取代或可被卤素原子、低级烷基或低级烷氧基取代)”是被未取代的或经选自卤素原子、低级烷基和低级烷氧基的取代基取代的苯基取代的环烷基,其中,苯基上取代基的例子可与上述R9定义中的“苯基低级烷基”的苯基上的取代基中所述的取代基相同。另外,该环烷基可以是环戊基、环己基、环庚基、环辛基等,其中,优选环己基。而且,在“苯基环烷基”中苯基的取代位置,优选在环戊基的情况下为3位,在环己基和环庚基的情况下为4位,在环辛基的情况下为5位。因此,“苯基环烷基(该基团的苯基部分为未取代或可被选自卤素原子、低级烷基和低级烷氧基的取代基取代)”的优选具体例子可以是4-(4-氟苯基)环己基、4-(4-氯苯基)环己基、4-(4-溴苯基)环己基、4-(3-甲基苯基)环己基、4-(3-乙基苯基)环己基、4-(3-甲氧基苯基)环己基和4-(3-乙氧基苯基)环己基。
在上述式(II)中,在C环表示苯环情况下所形成的异喹啉环中的苯环上的取代基,例子有:5-氯、6-氯、7-氯、8-氯、5-氟、7-氟、5-溴、7-溴、5-碘、5-甲基、6-甲基、7-甲基、8-甲基、5-乙基、5-正丙基、5-仲丁基、5-苯基、6-苯基、7-苯基、8-苯基、5-羟基、6-羟基、7-羟基、8-羟基、5-甲氧基、6-甲氧基、7-甲氧基、8-甲氧基、5-乙氧基、7-乙氧基、5-异丙氧基、5-叔丁氧基、5-苄氧基、7-苄氧基、5-(2-苯基)乙氧基、5-(4-氟苯基)甲氧基、7-(4-氟苯基)甲氧基、5-(2-氯苯基)甲氧基、5-(3-溴苯基)甲氧基、5-(2-氟-4-氯苯基)甲氧基、6-(2,4-二氯苯基)乙氧基、5-氨基、6-氨基、7-氨基、8-氨基、5-(N-甲基氨基)、7-(N-甲基氨基)、5-(N-乙基氨基)、5-(N-异丁基氨基)、6-(N-叔丁基氨基)、5-(N,N-二甲基氨基)、7-(N,N-二甲基氨基)、5-(N,N-二异丙基氨基)、6-(N-甲基-N-正丁基氨基)、5-甲硫基、6-甲硫基、7-甲硫基、8-甲硫基、5-乙硫基、5-正丙硫基、5-异丁硫基、6-异丙硫基、5-甲基亚硫酰基、6-甲基亚硫酰基、7-甲基亚硫酰基、8-甲基亚硫酰基、5-乙基亚硫酰基、6-异丙基亚硫酰基、7-叔丁基亚硫酰基、8-正戊基亚硫酰基、5-氨基磺酰氧基、6-氨基磺酰氧基、7-氨基磺酰氧基、8-氨基磺酰氧基等,其中,优选5-氯、6-氯、7-氯、7-氟、7-溴、7-甲基、7-苯基、7-羟基、5-甲氧基、6-甲氧基、7-甲氧基、7-乙氧基、7-苄氧基、7-(4-氟苯基)甲氧基、7-(N-甲基氨基)、7-(N,N-二甲基氨基)、7-甲硫基、7-甲基亚硫酰基和7-氨基磺酰氧基,特别优选6-氯、7-氯、7-氟、7-溴、7-甲基、7-羟基、7-甲氧基、7-乙氧基、7-苄氧基、7-(4-氟苯基)甲氧基、7-(N,N-二甲基氨基)和7-甲硫基。
在上述式(II)中,在C环表示苯环情况下所形成的异喹啉环中的吡啶环上的取代基,即上述式(II)中R8所示的基团,例子有:3-氟、4-氟、3-氯、4-氯、3-溴、4-溴、3-碘、4-碘、3-甲基、4-甲基、3-乙基、4-乙基、3-正丙基、4-异丙基、3-叔丁基、4-正丁基、3-异戊基、4-(1,2-二甲基丁基)等,其中优选3-氯、4-氯、3-甲基和4-甲基。因此,上述式(II)中当C环表示苯环时所形成的异喹啉环上的优选取代基,例如可以是5-氯、6-氯、7-氯、7-氟、7-溴、7-甲基、7-苯基、7-羟基、5-甲氧基、6-甲氧基、7-甲氧基、7-乙氧基、7-苄氧基、7-(4-氟苯基)甲氧基、7-(N-甲基氨基)、7-(N,N-二甲基氨基)、7-甲硫基、7-甲基亚硫酰基、7-氨基磺酰氧基、3-甲基-5-氯、4-甲基-6-氯、3-甲基-7-氯、3-甲基-7-氟、3,7-二甲基、3-甲基-7-羟基、4-氯-7-甲氧基、4-甲基-7-苄氧基、3-氯-7-(4-氟苯基)甲氧基、3-氯-7-(N-甲基氨基)、4-氯-7-(N,N-二甲基氨基)、3-甲基-7-甲氧基、4-甲基-7-甲氧基和3-氯-7-甲基。
在上述式(II)中,在C环表示吡啶环情况下所形成的杂环为1,6-二氮杂萘环时,所述1,6-二氮杂萘环上的取代基例如可以是2-氯、3-氯、4-氯、2-氟、3-氟、2-溴、3-溴、2-碘、2-甲基、3-甲基、4-甲基、2-乙基、2-正丙基、2-仲丁基、2,7-二氯、2,8-二氯、3,7-二氯、3,8-二氯、4,7-二氯、4,8-二氯、8-氯-4-氟、2,7-二甲基、2,8-二甲基、3,7-二甲基、3,8-二甲基、4,7-二甲基、4,8-二甲基、2-甲基-7-乙基、2-氯-7-甲基、3-氯-7-甲基、7-氯-2-甲基、7-氯-3-甲基等,其中,优选2-氯、3-氯、3-氟、3-溴、3-甲基和3-氯-7-甲基。
在上述式(II)中,在C环表示吡啶环情况下所形成的杂环为2,6-二氮杂萘环时,所述2,6-二氮杂萘环上的取代基例如可以是5-氯、7-氯、8-氯、5-氟、7-氟、5-溴、7-溴、5-碘、5-甲基、7-甲基、8-甲基、5-乙基、7-正丙基、8-仲丁基、3,5-二氯、3,7-二氯、3,8-二氯、4,5-二氯、4,7-二氯、4,8-二氯、4-氯-8-氟、3,5-二甲基、3,7-二甲基、3,8-二甲基、4,5-二甲基、4,7-二甲基、4,8-二甲基、3-氯-5-甲基、3-氯-7-甲基、3-氯-8-甲基、4-氯-5-甲基、4-氯-7-甲基、4-氯-8-甲基、5-氯-3-甲基、5-氯-4-甲基、7-氯-3-甲基、7-氯-4-甲基、8-氯-3-甲基、8-氯-4-甲基等,其中,优选5-氯、7-氯、7-氟、7-溴、7-甲基和3,7-二氯基。
在上述式(II)中,在C环表示吡啶环情况下所形成的杂环为2,7-二氮杂萘环时,所述2,7-二氮杂萘环上的取代基例如可以是5-氯、6-氯、8-氯、5-氟、6-氟、5-溴、6-溴、5-碘、5-甲基、6-甲基、8-甲基、5-乙基、6-正丙基、8-仲丁基、3,5-二氯、3,6-二氯、3,8-二氯、4,5-二氯、4,6-二氯、4,8-二氯、4-氯-8-氟、3,5-二甲基、3,6-二甲基、3,8-二甲基、4,5-二甲基、4,6-二甲基、4,8-二甲基、5-氯-3-甲基、5-氯-4-甲基、6-氯-3-甲基、6-氯-4-甲基、8-氯-3-甲基、8-氯-4-甲基、3-氯-5-甲基、3-氯-6-甲基、3-氯-8-甲基、4-氯-5-甲基、4-氯-6-甲基、4-氯-8-甲基等,其中,优选5-氯、6-氯、6-氟、6-溴、6-甲基、3,6-二氯和3,6-二甲基。
在上述式(II)中,在C环表示吡啶环情况下所形成的杂环为1,7-二氮杂萘环时,所述1,7-二氮杂萘环上的取代基例如可以是2-氯、3-氯、4-氯、2-氟、4-氟、2-溴、4-溴、4-碘、2-甲基、3-甲基、4-甲基、4-乙基、3-正丙基、2-仲丁基、2,5-二氯、2,6-二氯、3,5-二氯、3,6-二氯、4,5-二氯、4,6-二氯、5-氯-2-氟、2,5-二甲基、2,6-二甲基、3,5-二甲基、3,6-二甲基、4,5-二甲基、4,6-二甲基、2-氯-5-甲基、2-氯-6-甲基、3-氯-5-甲基、3-氯-6-甲基、4-氯-5-甲基、4-氯-6-甲基、5-氯-2-甲基、6-氯-2-甲基、5-氯-3-甲基、6-氯-3-甲基、5-氯-4-甲基、6-氯-4-甲基等,其中,优选2-氯、4-氯、2-氟、2-溴、2-甲基和2,6-二氯基。
在上述式(II)中,在C环表示呋喃环情况下所形成的杂环为呋喃并[3,2-c]吡啶时,所述呋喃并[3,2-c]吡啶上的取代基除了与上述“C环表示苯环时的异喹啉环中吡啶环上的取代基”中所述同样的取代基之外,还可以是例如2-氯、3-氯、2-氟、2-溴、2-碘、2-甲基、3-甲基、2-乙基、3-正丙基、2,6-二氯、2,7-二氯、3,6-二氯、3,7-二氯、2,6-二甲基、2,7-二甲基、3,6-二甲基、3,7-二甲基、7-氯-3-氟、2-氯-6-甲基、3-氯-6-甲基、2-氯-7-甲基、3-氯-7-甲基、6-氯-2-甲基、6-氯-3-甲基、7-氯-2-甲基、7-氯-3-甲基等,其中,优选2-氯、3-氯、2-溴、2-甲基、3-甲基、6-氯-2-甲基、6-氯-3-甲基、2,6-二甲基、3,6-二甲基和7-氯-3-甲基。
在上述式(II)中,在C环表示呋喃环情况下所形成的杂环为呋喃并[3,4-c]吡啶时,所述呋喃并[3,4-c]吡啶上的取代基例如可以是1-氯、3-氯、1-氟、1-溴、1-碘、1-甲基、3-甲基、1-乙基、3-正丙基、1,6-二氯、3,6-二氯、1,7-二氯、3,7-二氯、7-氯-3-氟、1,6-二甲基、1,7-二甲基、3,6-二甲基、3,7-二甲基、1-氯-6-甲基、1-氯-7-甲基、3-氯-6-甲基、3-氯-7-甲基、6-氯-1-甲基、6-氯-3-甲基、7-氯-1-甲基、7-氯-3-甲基等,其中优选1-氯、3-氯、1-溴、1-甲基、3-甲基、6-氯-1-甲基、3-氯-6-甲基和6-氯-3-甲基。
在上述式(II)中,在C环表示呋喃环情况下所形成的杂环为呋喃并[2,3-c]吡啶时,所述呋喃并[2,3-c]吡啶上的取代基例如可以是2-氯、3-氯、3-氟、3-溴、3-碘、2-甲基、3-甲基、3-乙基、2-正丙基、2,4-二氯、2,5-二氯、3,4-二氯、3,5-二氯、4-氯-2-氟、2,4-二甲基、2,5-二甲基、3,4-二甲基、3,5-二甲基、2-氯-4-甲基、2-氯-5-甲基、3-氯-4-甲基、3-氯-5-甲基、4-氯-2-甲基、4-氯-3-甲基、5-氯-2-甲基、5-氯-3-甲基等,其中优选2-氯、3-氯、3-溴、3-甲基、2-甲基、2-氯-5-甲基、5-氯-2-甲基和5-氯-3-甲基。
在上述式(II)中,在C环表示噻吩环情况下所形成的杂环为噻吩并[3,2-c]吡啶时,所述噻吩并[3,2-c]吡啶上的取代基例如可以是2-氯、3-氯、2-氟、2-溴、2-碘、2-甲基、3-甲基、2-乙基、3-正丙基、2,6-二氯、2,7-二氯、3,6-二氯、3,7-二氯、2,6-二甲基、2,7-二甲基、3,6-二甲基、3,7-二甲基、7-氯-3-氟、2-氯-6-甲基、3-氯-6-甲基、2-氯-7-甲基、3-氯-7-甲基、6-氯-2-甲基、6-氯-3-甲基、7-氯-2-甲基、7-氯-3-甲基等,其中优选2-氯、3-氯、2-溴、2-甲基、3-甲基、6-氯-2-甲基、6-氯-3-甲基、2,6-二甲基、3,6-二甲基和7-氯-3-甲基。
在上述式(II)中,在C环表示噻吩环情况下所形成的杂环为噻吩并[3,4-c]吡啶时,所述噻吩并[3,4-c]吡啶上的取代基例如可以是1-氯、3-氯、1-氟、1-溴、1-碘、1-甲基、3-甲基、1-乙基、3-正丙基、1,6-二氯、3,6-二氯、1,7-二氯、3,7-二氯、7-氯-3-氟、1,6-二甲基、1,7-二甲基、3,6-二甲基、3,7-二甲基、1-氯-6-甲基、1-氯-7-甲基、3-氯-6-甲基、3-氯-7-甲基、6-氯-1-甲基、6-氯-3-甲基、7-氯-1-甲基、7-氯-3-甲基等,其中优选1-氯、3-氯、1-溴、1-甲基、3-甲基、6-氯-1-甲基、3-氯-6-甲基和6-氯-3-甲基。
在上述式(II)中,在C环表示噻吩环情况下所形成的杂环为噻吩并[2,3-c]吡啶时,所述噻吩并[2,3-c]吡啶上的取代基例如可以是2-氯、3-氯、3-氟、3-溴、3-碘、2-甲基、3-甲基、3-乙基、2-正丙基、2,4-二氯、2,5-二氯、3,4-二氯、3,5-二氯、4-氯-2-氟、2,4-二甲基、2,5-二甲基、3,4-二甲基、3,5-二甲基、2-氯-4-甲基、2-氯-5-甲基、3-氯-4-甲基、3-氯-5-甲基、4-氯-2-甲基、4-氯-3-甲基、5-氯-2-甲基、5-氯-3-甲基等,其中优选2-氯、3-氯、3-溴、3-甲基、2-甲基、2-氯-5-甲基、5-氯-2-甲基和5-氯-3-甲基。
在上述式(II)中,“R9和R10一起形成吡咯烷环或哌啶环(该吡咯烷环和哌啶环为未取代或可被选自羟基、低级烷氧基和苯基低级烷氧基的取代基取代)的其余部分”时优选的环可以是吡咯烷环,所述吡咯烷环或哌啶环上的取代基例如可以是羟基、甲氧基、乙氧基、正丙氧基、苄氧基、(2-苯基)乙氧基等,其中优选羟基、甲氧基和苄氧基。
在本发明提供的IBS治疗方法中,对同时、依次或间隔给予5-HT1A激活剂和5-HT3拮抗剂时可使用的“5-HT1A激活剂”没有特别限定,只要具有5-HT1A激活作用即可使用,可以是已知的化合物或新型的化合物,具体地说例如可以是坦度螺酮。另外,在本发明中,作为5-HT1A激活剂,除了只具有5-HT1A激活作用的化合物之外,也可使用具有5-HT1A激活作用以外的药理作用的化合物。
按照本发明的IBS治疗方法,对与5-HT1A激活剂组合使用的“5-HT3拮抗剂”也没有特别限定,只要具有5-HT3拮抗作用即可使用,可以是已知的化合物或新型的化合物。具体地说例如可以是阿洛司琼、格拉司琼、阿扎司琼、托烷司琼、雷莫司琼、昂丹司琼、来立司琼、西兰司琼、伊他司琼、吲地司琼、多拉司琼或(R)-扎考必利等,其中特别优选阿洛司琼和西兰司琼。另外,在本发明中,作为5-HT3拮抗剂,除了只具有5-HT3拮抗作用的化合物之外,也可同样使用具有5-HT3拮抗作用以外的药理作用的化合物。
5-HT1A激活剂和5-HT3拮抗剂在机体内表达其作用的时期,因有效成分化合物的种类或制剂形态等而异,但其作用表达时期可通过检测各药剂给予后的血中浓度推移和药物动态等容易地获悉。对本发明的治疗方法而言,优选给予5-HT1A激活剂和5-HT3拮抗剂,使其在机体内实质上同时表达5-HT1A激活作用和5-HT3拮抗作用的两种作用。当使用给药后的作用表达时期大致相同的5-HT1A激活剂和5-HT3拮抗剂时,可以将两种药剂同时或依次给药。而当使用作用表达时期有差异的5-HT1A激活剂和5-HT3拮抗剂时,可以仅其相差的部分间隔给药,这样,可使两种药剂的作用在机体内同时表达。
本发明中上述式(I)所示优选的一组化合物为A环表示上述式i)或ii)基团时的式(I)化合物,其中更优选A环表示式ii)基团时的式(I)化合物,而且,特别优选A环表示式ii)基团且m为2时和/或R2、R3和R4均表示氢原子时的式(I)化合物。
本发明中上述式(I)所示优选的其它的一组化合物为X1表示氢原子、氨基或低级烷基时的式(I)化合物,其中更优选X1表示氨基或低级烷基时的式(I)化合物,而且,特别优选X1表示氨基、甲基或乙基时的式(I)化合物。另外,本发明中上述式(I)所示优选的其它的一组化合物为X2表示氢原子时的式(I)化合物。
本发明中上述式(I)所示优选的更其它的一组化合物为Y表示直接键合或硫原子时的式(I)化合物。
本发明中上述式(I)所示优选的更其它的一组化合物是n为2或3时的式(I)化合物。
本发明中上述式(I)所示优选的更其它的一组化合物是Ar表示未取代或被选自卤素原子、低级烷基、羟基、低级烷氧基和苯基的取代基取代的喹啉基时的式(I)化合物,其中特别优选Ar表示未取代或被选自卤素原子、低级烷基、羟基、低级烷氧基和苯基的取代基取代的喹啉-2-基时的式(I)化合物。
在本发明提供的IBS治疗方法中,当给予兼有对5-HT1A的激活作用的5-HT3拮抗剂时,优选的一组化合物为上述式(I)所示嘧啶衍生物或其药学上可接受的盐或者上述式(II)所示哌嗪基吡啶衍生物或其药学上可接受的盐。其中,上述式(I)所示嘧啶衍生物或其药学上可接受的盐中优选的化合物可与上述的“本发明中优选的一组化合物”、“本发明中优选的其它的一组化合物”和“本发明中优选的更其它的一组化合物”中所述的同样。另外,上述式(II)所示哌嗪基吡啶衍生物或其药学上可接受的盐中优选的化合物,例如可以是以下的化合物:
7-哌嗪-1-基呋喃并[2,3-c]吡啶、
6-甲基-7-哌嗪-1-基呋喃并[2,3-c]吡啶、
7-(3-甲基哌嗪-1-基)呋喃并[2,3-c]吡啶、
7-(4-甲基哌嗪-1-基)呋喃并[2,3-c]吡啶、
4-哌嗪-1-基呋喃并[3,2-c]吡啶、
4-(3-甲基哌嗪-1-基)呋喃并[3,2-c]吡啶、
3-氯-4-(3-甲基哌嗪-1-基)呋喃并[3,2-c]吡啶、
4-(4-甲基哌嗪-1-基)呋喃并[3,2-c]吡啶、
4-哌嗪-1-基呋喃并[3,4-c]吡啶、
7-哌嗪-1-基噻吩并[2,3-c]吡啶、
7-(3-甲基哌嗪-1-基)噻吩并[2,3-c]吡啶、
3-氯-7-(3-甲基哌嗪-1-基)噻吩并[2,3-c]吡啶、
7-(4-甲基哌嗪-1-基)噻吩并[2,3-c]吡啶、
4-哌嗪-1-基噻吩并[3,2-c]吡啶、
4-哌嗪-1-基噻吩并[3,4-c]吡啶、
4-(3-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶、
6-氯-4-(3-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶、
4-(4-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶、
2-溴-4-哌嗪-1-基噻吩并[3,2-c]吡啶二盐酸盐、
2-溴-4-(3-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶、
2-溴-6-甲基-4-(3-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶、
2-溴-4-(4-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶、
2-甲基-4-哌嗪-1-基噻吩并[3,2-c]吡啶二盐酸盐、
2-甲基-4-(3-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶二盐酸盐、
2-甲基-4-(4-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶二盐酸盐、
3-溴-4-哌嗪-1-基噻吩并[3,2-c]吡啶二盐酸盐、
3-溴-4-(3-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶、
3-溴-4-(4-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶、
7-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[2,3-c]吡啶、
7-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)呋喃并[2,3-c]吡啶、
2-甲基-4-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[3,2-c]吡啶、
2-甲基-哌嗪-1-基呋喃并[3,2-c]吡啶、
7-(4-乙基哌嗪-1-基)噻吩并[2,3-c]吡啶、
4-(4-乙基哌嗪-1-基)噻吩并[3,2-c]吡啶、
5-哌嗪-1-基-1,6-二氮杂萘、
7-氯-5-哌嗪-1-基-1,6-二氮杂萘、
5-(4-乙基哌嗪-1-基)-1,6-二氮杂萘、
8-哌嗪-1-基-1,7-二氮杂萘、
8-(4-乙基哌嗪-1-基)-1,7-二氮杂萘、
1-哌嗪-1-基-2,6-二氮杂萘、
1-哌嗪-1-基-2,7-二氮杂萘、
3-氯-1-哌嗪-1-基异喹啉二盐酸盐、
3-氯-7-甲氧基-1-哌嗪-1-基异喹啉、
3-氯-1-(4-甲基哌嗪-1-基)异喹啉二盐酸盐、
7-甲氧基-3-甲基-1-哌嗪-1-基异喹啉、
7-甲氧基-3,4-二甲基-1-(4-甲基哌嗪-1-基)异喹啉、
7-甲氧基-4-甲基-1-哌嗪-1-基异喹啉、
7-甲氧基-4-甲基-1-(4-甲基哌嗪-1-基)异喹啉、
7-溴-1-哌嗪-1-基异喹啉、
7-溴-1-(4-甲基哌嗪-1-基)异喹啉、
7-甲氧基-1-(4-甲基哌嗪-1-基)异喹啉、
1-(4-乙基哌嗪-1-基)-7-甲氧基异喹啉、
7-甲氧基-1-哌嗪-1-基异喹啉、
1-哌嗪-1-基异喹啉、
1-(4-甲基哌嗪-1-基)异喹啉、
1-(4-乙基哌嗪-1-基)异喹啉、
7-甲氧基-1-(3-甲基哌嗪-1-基)异喹啉、
1-(3,5-二甲基哌嗪-1-基)-7-甲氧基异喹啉、
6-甲氧基-1-哌嗪-1-基异喹啉、
6-甲氧基-1-(4-甲基哌嗪-1-基)异喹啉、
1-(4-乙基哌嗪-1-基)-6-甲氧基异喹啉、
5-甲氧基-1-哌嗪-1-基异喹啉、
5-甲氧基-1-(4-甲基哌嗪-1-基)异喹啉、
1-(4-乙基哌嗪-1-基)-5-甲氧基异喹啉、
7-甲基-1-哌嗪-1-基异喹啉、
7-甲基-1-(4-甲基哌嗪-1-基)异喹啉、
1-(4-乙基哌嗪-1-基)-7-甲基异喹啉、
7-氯-1-哌嗪-1-基异喹啉、
7-氯-1-(4-甲基哌嗪-1-基)异喹啉、
7-氯-1-(4-乙基哌嗪-1-基)异喹啉、
7-氟-1-(4-甲基哌嗪-1-基)异喹啉、
1-(4-乙基哌嗪-1-基)-7-氟异喹啉、
1-(4-甲基哌嗪-1-基)-7-苯基异喹啉、
1-(4-乙基哌嗪-1-基)-7-苯基异喹啉、
7-苯基-1-哌嗪-1-基异喹啉、
6-氯-1-哌嗪-1-基异喹啉、
6-氯-1-(4-甲基哌嗪-1-基)异喹啉、
6-氯-1-(4-乙基哌嗪-1-基)异喹啉、
5-氯-1-哌嗪-1-基异喹啉、
5-氯-1-(4-甲基哌嗪-1-基)异喹啉、
5-氯-1-(4-乙基哌嗪-1-基)异喹啉、
7-氟-1-哌嗪-1-基异喹啉、
7-氯-1-[4-[4-(3-甲氧基苯基)丁基]哌嗪-1-基]异喹啉、
7-甲氧基-1-[4-[4-(3-甲氧基苯基)丁基]哌嗪-1-基]异喹啉、
7-氯-1-[4-[反式-4-(3-甲氧基苯基)环己烷-1-基]哌嗪-1-基]异喹啉、
7-甲氧基-1-[4-[反式-4-(3-甲氧基苯基)环己烷-1-基]哌嗪-1-基]异喹啉、
1-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)-7-甲氧基异喹啉、
7-氯-1-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)异喹啉、
8-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)-1,7-二氮杂萘、
5-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)-1,6-二氮杂萘、
7-氯-1-((8aR)-八氢吡咯并[1,2-a]吡嗪-2-基)异喹啉、
1-((8aR)-八氢吡咯并[1,2-a]吡嗪-2-基)-7-甲氧基异喹啉、
3-氯-1-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)异喹啉、
3-氯-1-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)-7-甲基异喹啉、
7-氯-1-八氢吡啶并[1,2-a]吡嗪-2-基异喹啉、
7-甲氧基-1-八氢吡啶并[1,2-a]吡嗪-2-基异喹啉、
7-甲硫基-1-(S)-八氢吡啶并[1,2-a]吡喃-2-基异喹啉、
7-甲基亚硫酰基-1-(S)-八氢吡啶并[1,2-a]吡喃-2-基异喹啉、
7-羟基-1-八氢吡啶并[1,2-a]吡嗪-2-基异喹啉、
1-(S)-八氢吡啶并[1,2-a]吡喃-2-基-7-羟基异喹啉、
1-八氢吡啶并[1,2-a]吡嗪-2-基-7-氨磺酰氧基异喹啉、
1-(S)-八氢吡啶并[1,2-a]吡喃-2-基-7-氨磺酰氧基异喹啉、
1-(4-苄基哌嗪-1-基)-7-氯异喹啉、
1-(4-苄基哌嗪-1-基)-7-二甲基氨基异喹啉、
7-甲基氨基-1-哌嗪-1-基异喹啉、
7-乙基氨基-1-哌嗪-1-基异喹啉、
7-二甲基氨基-1-哌嗪-1-基异喹啉、
7-二甲基氨基-1-(4-甲基哌嗪-1-基)异喹啉、
7-甲基氨基-1-(4-甲基哌嗪-1-基)异喹啉、
1-[4-(4-氟苄基)哌嗪-1-基]-7-甲氧基异喹啉、
1-[4-(4-氟苄基)哌嗪-1-基]异喹啉、
7-羟基-1-哌嗪-1-基异喹啉盐酸盐、
7-羟基-1-(4-甲基哌嗪-1-基)异喹啉、
7-乙氧基-1-哌嗪-1-基异喹啉、
7-(4-氟苄氧基)-1-哌嗪-1-基异喹啉、
7-苄氧基-1-哌嗪-1-基异喹啉和
7-氨磺酰氧基-1-哌嗪-1-基异喹啉盐酸盐,其中特别优选以下化合物:
7-氯-1-(4-甲基哌嗪-1-基)异喹啉、
7-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[2,3-c]吡啶、
7-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)呋喃并[2,3-c]吡啶、
2-甲基-4-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[3,2-c]吡啶、
7-甲氧基-1-((8aR)-八氢吡咯并[1,2-a]吡嗪-2-基)异喹啉和
2-溴-4-(4-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶。
在本发明提供的IBS治疗方法中,同时、依次或间隔给予5-HT1A激活剂和5-HT3拮抗剂时,优选的5-HT1A激活剂是坦度螺酮,优选的5-HT3拮抗剂是阿洛司琼、格拉司琼、阿扎司琼、托烷司琼、雷莫司琼、昂丹司琼、来立司琼、西兰司琼、伊他司琼、吲地司琼、多拉司琼和(R)-扎考必利。其中特别优选的5-HT3拮抗剂是阿洛司琼和西兰司琼。
本发明提供的上述式(I)化合物的代表例可以是后述实施例中揭示的化合物和如下所述化合物:
3-氨基-6-苄基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4,3-d]嘧啶-4-酮、
3-氨基-6-苄基-8-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4,3-d]嘧啶-4-酮、
3-氨基-6-苯甲酰基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4,3-d]嘧啶-4-酮、
3-氨基-6-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4,3-d]嘧啶-4-酮、
3-氨基-7-苄基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[3,4-d]嘧啶-4-酮、
3-氨基-7-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[3,4-d]嘧啶-4-酮、
3-氨基-5-氯-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-氯-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-7-氯-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-8-氯-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-氟-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-7-氟-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-溴-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-7-溴-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-5-甲氧基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-甲氧基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-环己基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-7-三氯甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-苄基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-苯乙基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-丙基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-7,8-二氢-3H,6H-噻喃并[3,2-d]嘧啶-4-酮、
3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-7,8-二氢-3H,5H-噻喃并[4,3-d]嘧啶-4-酮、
3-氨基-6,6-二氧代-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-7,8-二氢-3H,5H-噻喃并[4,3-d]吡啶-4-酮、
3-氨基-6-氧代-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-7,8-二氢-3H,5H-噻喃并[4,3-d]吡啶-4-酮、
3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,8-二氢-3H,6H-噻喃并[3,4-d]嘧啶-4-酮、
3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-7,8-二氢-3H,5H-吡喃并[4,3-d]嘧啶-4-酮、
3-氨基-4-氧代-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4,5,6,7,8-六氢喹唑啉酮-6-羧酸、
3-氨基-4-氧代-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4,5,6,7,8-六氢喹唑啉酮-6-羧酸乙酯、
3-氨基-4-氧代-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4,5,6,7,8-六氢喹唑啉酮-6-甲腈、
3-氨基-4-氧代-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4,5,6,7,8-六氢喹唑啉酮-7-甲腈、
3,6-二氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-甲基氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6,6-二甲基氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-硝基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-氨基-6-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6-二氢-3H,7H-环戊二烯并[d]嘧啶-4-酮、
3-氨基-6-氯-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6-二氢-3H,7H-环戊二烯并[d]嘧啶-4-酮、
3-氨基-6-羟基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6-二氢-3H,7H-环戊二烯并[d]嘧啶-4-酮、
3-氨基-5-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6-二氢-3H,7H-环戊二烯并[d]嘧啶-4-酮、
3-氨基-6-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H,9H-芳庚并[d]嘧啶-4-酮、
3-氨基-6-苯基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6-二氢-3H,7H-环戊二烯并[d]嘧啶-4-酮、
3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H,7H-吡咯并[2,3-d]嘧啶-4-酮、
3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H,5H-吡咯并[3,2-d]嘧啶-4-酮、
3-氨基-6-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H,5H-吡咯并[3,2-d]嘧啶-4-酮、
3-氨基-6-乙基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H,5H-吡咯并[3,2-d]嘧啶-4-酮、
3-氨基-6,7-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H,5H-吡咯并[3,2-d]嘧啶-4-酮、
3,5-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3,7-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3,8-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-甲基-2-[4-[4-(5-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-甲基-2-[4-[4-(6-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-甲基-2-[4-[4-(7-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
2-[4-[4-(6-溴喹啉-2-基)哌嗪-1-基]丁基]-3-甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮、
2-[4-[4-(6-氯喹啉-2-基)哌嗪-1-基]丁基]-3-甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮、
2-[4-[4-(6-羟基喹啉-2-基)哌嗪-1-基]丁基]-3-甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮、
2-[4-[4-(3-羟基喹啉-2-基)哌嗪-1-基]丁基]-3-甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮、
6-甲氧基-3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
6-甲氧基-3-甲基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-3H-喹唑啉-4-酮、
2-[4-[4-(4-氯喹啉-2-基)哌嗪-1-基]丁基]-6-甲氧基-3-甲基-3H-喹唑啉-4-酮、
3-乙基-6-甲氧基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
3,6-二甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-乙基-6-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3-乙基-6-甲基-2-[3-[4-(5-甲基喹啉-2-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
2-[3-[4-(4-氯喹啉-2-基)哌嗪-1-基]丙硫基]-3,6-二甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3,6-二甲基-2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁硫基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3,6-二甲基-2-[3-(4-喹啉-2-基)丙基氨基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3,6-二甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丁基氨基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
2-[3-[4-(4-氯喹啉-2-基)哌嗪-1-基]丁基氨基]-3,6-二甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮、
3,6-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
2-[4-[4-(4-氯喹啉-2-基)哌嗪-1-基]丁基]-3-乙基-6-甲基-3H-喹唑啉-4-酮、
3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)戊基]-3H-喹唑啉-4-酮、
6-甲氧基-3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-喹唑啉-4-酮、
3-乙基-6-甲氧基-2-[3-(4-喹啉-2-基哌嗪-1-基)丁硫基]-3H-喹唑啉-4-酮、
3-苄基-2-[3-(4-喹啉-2-基哌嗪-1-基)丁基氨基]-3H-喹唑啉-4-酮、
6,7-二氯-3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丁基氨基]-3H-喹唑啉-4-酮、
3,5,6-三甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丁基氨基]-3H-噻吩并[2,3-d]嘧啶-4-酮、
3-乙基-5,6-二甲基-2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮、
2-[4-(4-苯并噻唑-2-基哌嗪-1-基)戊基]-3-甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮、
2-[4-(4-苯并噻唑-2-基哌嗪-1-基)戊基]-3-乙基-6-甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮、
2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丁硫基]-3-乙基-5,6,7,8-四氢-3H-喹唑啉-4-酮、
2-[4-(4-苯并噻唑-2-基哌嗪-1-基)丁基]-6-氯-3-甲基-3H-喹唑啉-4-酮、
2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丁硫基]-3-甲基-3H-喹唑啉-4-酮等。
本发明所提供的式(I)化合物和本发明IBS治疗方法中所用的化合物还可以根据情况以盐的形式存在,其盐例如可以是与盐酸、氢溴酸、硫酸、硝酸、磷酸等无机酸形成的盐;与乙酸、草酸、枸橼酸、乳酸、酒石酸、对甲苯磺酸等有机酸形成的盐等,其中优选药学上可接受的盐。
本发明可根据X1和Y的种类,通过例如以下的(a)-(e)所述任一种方法制备上述式(I)的化合物。
方法(a):X1表示氨基、低级烷基、苯基低级烷基或者取代或未取代的苯基,Y为直接键合时的式(I)化合物,即下述式所示嘧啶衍生物:
式中A环、n、X2和Ar如上定义,X1a表示氨基、低级烷基、
苯基低级烷基或者取代或未取代的苯基,
可通过下述方法制备:例如用乙酸酐处理式(III)的化合物:
式中A环、n、X2和Ar如上定义,
然后反应产物不经分离,使其继续与式(IV)的化合物反应,
H2N-X1a (IV)
式中X1a如上定义。
方法(b):X1表示低级烷基氨基、二低级烷基氨基或低级亚烷基氨基,Y为直接键合时的式(I)化合物,即下述式所示嘧啶衍生物:
式中A环、n、X2和Ar如上定义,X1b表示低级烷基氨基、二低级烷基氨基或低级亚烷基氨基,
例如可通过下述方法制备:将通过方法(a)制备的式(I-1)化合物中X1a表示氨基时的化合物N-烷基化、N,N-二烷基化或N-亚烷基化,或者将生成的式(I-2)化合物中X1b表示低级烷基氨基时的化合物进一步N-烷基化。
方法(c):X1表示氢原子,Y为直接键合时的式(I)化合物,即下述式所示嘧啶衍生物:
式中A环、n、X2和Ar如上定义,
例如可通过下述方法制备:对通过方法(a)制备的式(I-1)化合物中X1a表示氨基时的化合物用亚硝酸钠进行处理。
其它方法(c-1):在上述方法(c)的式(I-3)中,当X2表示氢原子时的化合物,即下述式所示嘧啶衍生物:
式中A环、n和Ar如上定义,
可通过下述方法制备:使式(V)的化合物:
式中A环和n如上定义,Hal表示卤素原子,
与式(VI)的化合物反应,
Ar如上定义。
方法(d):当Y表示硫原子时的式(I)化合物,即下述式所示嘧啶衍生物:
式中A环、X1、n、X2和Ar如上定义,
例如可通过下述方法制备:使式(VII)的化合物:
式中A环和X1如上定义,M表示碱金属或碱土金属,SM表示硫原子形成所述金属盐,
与式(VIII)的化合物反应,
式中n、X2、Ar和Hal如上定义。
方法(e):当Y表示氮原子时的式(I)化合物,即下述式所示嘧啶衍生物:
式中A环、X1、n、X2和Ar如上定义,
例如可通过下述方法制备:使式(IX)的化合物:
式中A环和X1如上定义,
与式(X)的化合物反应,
式中n、X2和Ar如上定义。
上述方法(a)中用乙酸酐对式(III)化合物所进行的处理,通常可在下述条件下进行:相对于每1摩尔式(III)化合物使用1-10摩尔乙酸酐、优选1.3-5摩尔左右,在惰性有机溶剂中,例如在N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等酰胺类;甲醇、乙醇、异丙醇等醇类;四氢呋喃、二噁烷等醚类等中,在0℃至反应混合物的回流温度、优选室温至反应混合物的回流温度范围内的温度下。
随后通过向反应混合物中加入式(IV)化合物,使其在0℃至反应混合物的回流温度范围内的温度下反应,可以得到目标式(I-1)化合物。
对式(IV)化合物相对于式(III)化合物的使用比例没有特别限定,通常相对于每一摩尔式(III)化合物,除剩余的乙酸酐摩尔数,即从所用乙酸酐摩尔数减去式(III)化合物摩尔数后所得的摩尔数外,最好至少使用1摩尔、优选1.2-10摩尔、更优选1.3-5摩尔的式(IV)化合物。
上述方法(b)中的式(I-1)化合物的N-烷基化反应可通过使用卤化烷基等的亲核取代反应、使用醛类等的还原烷基化反应等进行,另外,N-亚烷基化反应可通过使用醛类等的脱水反应等进行。这些反应,通常在惰性有机溶剂中,例如在N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等酰胺类;甲醇、乙醇、异丙醇等醇类;四氢呋喃、二噁烷等醚类等中,在0℃至反应混合物的回流温度、优选室温至反应混合物的回流温度范围内的温度下进行。
对式(I-1)化合物的N-烷基化或N-亚烷基化所用的卤化烷基或醛类等烷基化剂或亚烷基化剂的使用比例没有特别限定,通常在将式(I-1)中X1a表示氨基的化合物转换成式(I-2)中X1b表示低级烷基氨基或低级亚烷基氨基的化合物时,或者在将式(I-2)中X1b表示低级烷基氨基的化合物转换成式(I-2)中X1b表示二低级烷基氨基(其中低级烷基可相同或可分别不同)的化合物时,相对于每一摩尔式(I-1)中X1a表示氨基的化合物或式(I-2)中X1b表示低级烷基氨基的化合物,可使用至少1摩尔、优选1.2-10摩尔、更优选1.3-5摩尔的烷基化剂或亚烷基化剂。另外,在将式(I-1)中X1a表示氨基的化合物转换成式(I-2)中X1b表示含有同一低级烷基的二低级烷基氨基的化合物时,相对于每一摩尔式(I-1)中X1a表示氨基的化合物,可使用至少2摩尔、优选2.2-10摩尔、更优选3-5摩尔的烷基化剂或亚烷基化剂。
在上述方法(c)中,用亚硝酸钠处理式(I-1)中X1a表示氨基时的化合物的反应,通常在乙酸和水的混合溶剂中,在0℃至反应混合物的回流温度、优选室温至反应混合物的回流温度范围内的温度下进行。
对亚硝酸钠相对于式(I-1)中X1a表示氨基时的化合物的使用比例没有特别限定,通常相对于每一摩尔式(I-1)中X1a表示氨基时的化合物,可使用至少1摩尔、优选1.5-10摩尔、更优选2-5摩尔的亚硝酸钠。
在上述其它方法(c-1)中,式(V)化合物与式(VI)化合物的反应通常可在下述条件下进行:在惰性有机溶剂中,例如在N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等酰胺类;甲醇、乙醇、异丙醇等醇类;四氢呋喃、二噁烷等醚类;丙酮、二乙基酮等酮类;苯、甲苯等芳烃类等中,根据需要在氢化钠、甲醇钠、丁醇钾、碳酸钾、氢氧化钾等碱类,或三乙胺、2,6-二叔丁基-4-甲基吡啶等有机碱类的存在下,在-20℃至反应混合物的回流温度、优选0℃至60℃范围内的温度下。
对式(VI)化合物相对于式(V)化合物的使用比例没有特别限定,通常相对于每一摩尔式(V)化合物,可使用至少1摩尔、优选1.05-4摩尔、更优选1.2-2摩尔的式(VI)化合物。
在上述方法(d)中,式(VII)化合物与式(VIII)化合物的反应通常可在下述条件下进行:在惰性有机溶剂中,例如在N,N-二甲基甲酰胺、N,N-二甲基乙酰胺等酰胺类;甲醇、乙醇、异丙醇等醇类;四氢呋喃、二噁烷等醚类;吡啶等有机碱类等中,根据需要在氢化钠、甲醇钠、丁醇钾、碳酸钾、氢氧化钾等碱类,或三乙胺、2,6-二叔丁基-4-甲基吡啶等有机碱类的存在下,在-20℃至反应混合物的回流温度、优选0℃至60℃范围内的温度下。
对式(VIII)化合物相对于式(VII)化合物的使用比例没有特别限定,通常相对于每一摩尔式(VII)化合物,可使用至少1摩尔、优选1.1-5摩尔、更优选1.2-2摩尔的式(VIII)化合物。而且,相对于每一摩尔式(VII)化合物,优选使用1.2-10摩尔的上述碱类或有机碱类。
在上述方法(e)中,式(IX)化合物与式(X)化合物的反应通常在吡啶中,可通过加热至反应混合物的回流温度来进行。
对式(X)化合物相对于式(IX)化合物的使用比例没有特别限定,通常相对于每一摩尔式(IX)化合物,可使用至少1摩尔、优选1.1-5摩尔、更优选1.2-2摩尔的式(X)化合物。
由此形成本发明目标的上述式(I-1)、(I-2)、(I-3)、(I-4)或(I-5)的化合物,即式(I)的化合物。
在上述方法(a)中,作为起始原料使用的上述式(III)化合物可通过其自身已知的合成方法,例如可按照下述反应式1所示途径容易地合成。有关反应式1中的反应条件等的详细说明,请参照后述实施例7-1的步骤7-1-A~D。
反应式1:
上述各式中,A环、n、X2、Ar、Ha1和R如上定义,R表示低级烷基。
在上述方法(a)中,作为起始原料使用的上述式(III)化合物还可按照下述反应式2所示途径合成。有关反应式2中的反应条件等的详细说明,请参照后述实施例7-14。
反应式2:
上述各式中,A环、n、X2、Ar和R如上定义。
在上述其它方法(c-1)中,作为起始原料使用的上述式(V)化合物可基于其自身已知的合成方法,例如可按照下述反应式3所示途径合成。有关反应式3中的反应条件等的详细说明,请参照后述实施例3-1的步骤3-1-A。
反应式3:
上述各式中,A环、n、Hal和R如上定义。
在上述方法(d)中,作为起始原料使用的上述式(VII)化合物可基于其自身已知的合成方法,例如基于参考文献J.Med.Che m.,40,574-585(1997)中记载的方法,可按照下述反应式4所示途径合成。
反应式4:
上述各式中,A环、X1、R和M如上定义。
在上述方法(e)中,作为起始原料使用的上述式(IX)化合物可按照例如下述反应式5所示途径,可通过将上述式(VII)化合物甲基化来合成。有关反应式中的反应条件等的详细说明,请参照后述实施例7-29的步骤7-29-A。
反应式5:
上述各式中,A环、X1和M如上定义。
按照以上所述方法制备的本发明的式(I)化合物,可通过其自身已知的方法,例如重结晶、柱色谱法、薄层色谱法等方法,从反应混合物中分离、纯化。
本发明的IBS治疗方法中使用的上述式(II)化合物大部分是文献(例如,J.Med.Chem.,42,4362-4379(1999)等)中记载的已知化合物,即使是新型化合物也可按照文献等中记载的合成方法或后述制备例容易地合成。
本发明的式(I)所示嘧啶衍生物或其药学上可接受的盐兼有5-HT1A激活作用和5-HT3拮抗作用的两种作用,可用于治疗、处置人、其他哺乳动物与5-HT1A和/或5-HT3受体相关的各种疾病,所述与5-HT1A和/或5-HT3受体相关的各种疾病例如有:IBS、机能性胃肠症(FD)、不安、腹压性尿失禁、先兆性尿失禁、抑郁症、前列腺癌、综合失调症、尿频、精神分裂症、过动性膀胱综合征、精神病、下泌尿系疾病、老年性痴呆症、伴随前列腺肥大的排尿障碍、早老性痴呆、间质性膀胱炎、上瘾/脱瘾症状、慢性前列腺炎、认知障碍、因急性脑中风产生的缺血、亨廷顿舞蹈病、一时性脑缺血发作、帕金森综合征、头部或脊髓的外伤、肌萎缩性侧索硬化症、胎儿低氧症、AIDS痴呆症、非溃疡性消化不良、视网膜疾病等慢性神经变性疾病、回流性食管炎、酒精或可卡因成瘾、刺激反应性肠综合征、锥体外束障碍、呼吸暂停或呼吸暂停症、恐慌综合征、震颤、短期记忆障碍、恶心或呕吐、酒精中毒、癫痫、烟碱依赖症、睡眠障碍、药物成瘾、疼痛、摄食障碍、性功能不全、外伤性应激症、肥胖、幼年期孤独症、咳嗽、因神经压迫引起的综合征、筋膜综合征、神经障碍、テンドミォシス(tendomyosis)、疼痛性营养不良、テンディノ-シス(tendinosis)、兴奋症状、插入テンドパシ-(tendopathy)、攻击性(敌意)、滑液囊疾病、强迫性障碍、关节周围症(periarthropathy)、智力促进、肌内超负荷综合征、月经前紧张综合征、植物神经失调症、原发性高血压病、身心病、痉挛、消化性溃疡、躁狂、胃炎、偏头痛、半月损伤、慢性多发性关节炎、关节外伤、副肿瘤性症状、局部分离性骨软骨炎、肿瘤诱导性炎症性疾病、骨坏死、白浊性渗出、关节软骨肿症、胶原病、慢性阻塞性肺疾患(COPD)、感染后关节炎、成人呼吸困难综合征(ARDS)、血清反应阴性脊髓关节炎、支气管炎、血管炎、尘肺、类肉瘤性关节病、喉头痉挛、肺血管炎、肺肉芽肿、外原性过敏性肺泡炎、慢性疲劳性综合征、接触性过敏、青光眼等,其中,对于通过5-HT1A激活作用和5-HT3拮抗作用的两种作用产生疗效的疾病,例如IBS、FD、回流性食管炎、不安、身心病、呕吐、疼痛、腹压性尿失禁、先兆性尿失禁、尿频等的治疗、处置特别有效。
本发明的式(I)化合物和本发明IBS治疗方法中使用的式(II)化合物所具有的5-HT1A激活作用和5-HT3拮抗作用,可通过以下所述实验显示。
(1)测定化合物对人5-HT1A受体的亲和性(体外):
将0.25mL(约50单位)表达人5-HT1A受体的CHO细胞膜标本(购于Packard Bioscience公司)加入到24.75mL的温育缓冲液-A液(使用1N-氢氧化钠水溶液,在27℃的条件下,将50mmol/L Tris-盐酸、10mmol/L硫酸镁、0.5mmol/L EDTA和0.1%抗坏血酸的混合物的水溶液调节至pH为7.4后的溶液)中,以此液作为膜标本悬浮液A液。另外,将各被测化合物调节为270μmol/L的DMSO(二甲基亚砜)溶液,然后使用温育缓冲液-A液稀释至规定的浓度,作为化合物溶液。
往聚丙烯制的管中加入20μL[3H]8-OH-DPAT(8-羟基-2-(二正丙基氨基)四氢化萘;购于第一化学药品株式会社)的温育缓冲液-A溶液(调节[3H]8-OH-DPAT的浓度,以使反应混合物中的[3H]8-OH-DPAT浓度达到0.25nmol/L)和20μL的化合物溶液,再加入500μL膜标本悬浮液A液,在27℃下温育60分钟。使用Brandel.细胞收集器,通过用GF/C滤纸急速过滤使反应终止,所述GF/C滤纸在向温育缓冲液-A液中加入聚乙烯亚胺并使其浓度达到0.3%而得到的溶液中预先浸渍过,然后使用约5ml冷却至4℃的50mmol/L Tris-盐酸洗涤滤纸,再次通过同样的操作洗涤滤纸。
用液体闪烁计数器(Aloka公司制造,LSC-5100)测定滤纸上残存的放射活性。各被测化合物对0.25nmol/L浓度的[3H]8-OH-DPAT与5-HT1A受体结合的抑制率(%),即各被测化合物对5-HT1A受体的亲和性,可通过下式计算。测定使用10μmol/L浓度的8-OH-DPAT时的放射活性,由此算出非特异结合的比例,以此来修正各被测化合物的测定值。
(2)测定化合物对人5-HT3受体的亲和性(体外):
将0.05mL(约50微测定)表达人5-HT3受体的HEK-293细胞膜标本(购于バィォリンクス株式会社)加入到24.95mL的温育缓冲液-B液(使用1N-氢氧化钠水溶液,在25℃的条件下,将50mmol/L Tris-盐酸、5mmol/L氯化镁和1mmol/L EDTA的混合物的水溶液调节至pH为7.5后的溶液)中并使其均化,以此液作为膜标本悬浮液B液。另外,将各被测化合物调节为270μmol/L的DMSO溶液,然后用温育缓冲液-B液稀释至规定的浓度,作为化合物溶液。
往聚丙烯制的管中加入20μL[3H]BRL-43694(购于第一化学药品株式会社)的温育缓冲液-B液(预先调节[3H]BRL-43694的浓度,以使反应混合物中的[3H]BRL-43694浓度为0.5nmol/L)和20μL的化合物溶液,再加入500μL膜标本悬浮液B液,在25℃下温育60分钟。使用Brandel细胞收集器,通过用GF/B滤纸急速过滤使反应终止,所述GF/B滤纸在向温育缓冲液-B液中加入聚乙烯亚胺并使其浓度达到0.5%而得到的溶液中预先浸渍过,然后使用约5mL冷却至4℃的50mmol/L Tris-盐酸洗涤滤纸,再次通过同样的操作洗涤滤纸。
用液体闪烁计数器(Aloka公司制造,LSC-5100)测定滤纸上残存的放射活性。各被测化合物对0.5nmol/L浓度的[3H]BRL-43694与5-HT3受体结合的抑制率(%),即各被测化合物对5-HT3受体的亲和性,可通过下式算出。测定使用10μmol/L浓度的托烷司琼(ICS205-930)时的放射活性,由此算出非特异结合的比例,以此来修正各被测化合物的测定值。
在100nmol/L的浓度下,各被测化合物对5-HT1A受体和5-HT3受体的亲和性如下表A-1和A-2所示。测定化合物对5-HT3受体的亲和性所用的BRL-43694和托烷司琼(ICS205-930)如以下的结构式所示。
BRL-43694 托烷司琼
表A-1
表A-2
(3)测定对大鼠的5-HT1A受体激活作用(体内):
将7周龄的SD系雄性大鼠按每组4-5只分组。将其在实验环境中二次驯化,在第二次驯化的一周后装入塑料盒中,腹腔内给予10mg/kg被测化合物(溶解于1N-盐酸,然后用适量盐水稀释)。在化合物临给予前和给予5、10、20和30分钟后,进行对下唇缩进(lowerlip retraction,LLR)和flat body posture(FBP)的行动观察,按四级(0:无反应、1:微反应、2:中度反应、3:最大反应)进行评价。由此,求出各测定点的各组评价的最大值。其结果如下表B-1和B-2所示。
表B-1
表B-2
(4)测定对大鼠的5-HT3受体拮抗作用(体内):
向270-410g的SD系雄性大鼠的腹腔内给予1.25g/kg的尿烷(溶解于蒸馏水)进行麻醉后,分别在左颈动脉、右颈静脉处插入导管,左颈动脉处导管用于测定血压和心率、右颈静脉处导管用于给予化合物。血压和心率稳定后,快速静脉内给予300μg/kg的5-羟色胺肌酸酐硫酸盐(以下简称为5-羟色胺),观察一时性表现的心动徐缓反应(BC1)。随后,在给予5-羟色胺后血压和心率再次稳定时,静脉内给予被测化合物,给予10分钟后再次快速静脉内给予300μg/kg的5-羟色胺,观察此时表现的一时性心动徐缓(BC2)。各被测化合物的心动徐缓表现抑制率,即BJ反射抑制率可通过下式算出。
各被测化合物的心动徐缓表现抑制率如下表C-1和C-2所示。
表C-1
化合物 | 投药量(mg/kg) | 心动徐缓抑制率(%) |
实施例4-1 | 0.1 | 70.4 |
实施例4-3 | 1.0 | 90.1 |
实施例4-4 | 0.1 | 68.7 |
实施例4-18 | 0.1 | 35.6 |
实施例4-25 | 0.1 | 49.1 |
实施例7-1 | 0.1 | 90.3 |
实施例7-6 | 0.01 | 58.5 |
实施例7-7 | 1.0 | 85.4 |
实施例7-20 | 0.01 | 64.7 |
表C-2
化合物 | 投药量(mg/kg) | 心动徐缓抑制率(%) |
制备例34 | 1.0 | 92.0 |
制备例35 | 1.0 | 94.6 |
制备例38 | 1.0 | 82.9 |
制备例46 | 1.0 | 94.4 |
制备例47 | 1.0 | 89.9 |
制备例49 | 1.0 | 96.8 |
制备例50 | 1.0 | 86.8 |
制备例72 | 0.3 | 72.5 |
制备例73 | 0.01 | 52.2 |
制备例95 | 1.0 | 96.0 |
制备例102 | 3.0 | 61.5 |
制备例103 | 3.0 | 57.6 |
制备例104 | 10.0 | 46.1 |
(5)测定大鼠在束缚压力下的排便亢进:
将6周龄的SD系雄性大鼠按每组6-8只分组,将其在实验前日用5连笼子个别喂养,并使其驯服于环境。到实验当日的早晨为止使其自由摄取饲料和饮料。实验当日,分别经口给予被测化合物,腹腔内给予阳性对照药溶液(将化合物溶解于1N-盐酸后用适量生理盐水稀释而得到的溶液),给予5分钟后,在轻度乙醚麻醉下,通过将包括上肢在内的上半身用橡胶胶带固定,使其承受束缚压力。进行1小时束缚压力负荷,测定该期间排泄的大便次数。
在下表D中,将本发明化合物对压力排便的作用在各组中的平均值与各种5-HT1A激活剂和5-HT3拮抗剂对压力排便的组合作用在各组中的平均值进行比较。其中,将给予生理盐水、未负荷束缚压力的动物组作为正常组,将给予生理盐水、负荷束缚压力的动物组作为对照组。此外,在大鼠的束缚压力下排便亢进的测定中作为阳性对照药使用的各化合物,由以下的结构式表示。
坦度螺酮 丁螺环酮
阿洛司琼 格拉司琼
西兰司琼
表D:本发明化合物对压力排便的作用
因此,本发明的式(I)所示嘧啶衍生物或其药学上可接受的盐,作为具有5-HT1A激活作用的5-HT3拮抗剂,用于人或其它哺乳动物的治疗、处置等,可经口给药或胃肠外给药(例如,肌肉注射、静脉注射、腹腔内给药、直肠给药、经皮给药等)。在本发明的IBS治疗方法中,为了在人或其它哺乳动物的机体内使5-HT1A激活作用和5-HT3拮抗作用的两种作用协同作用,可采用经口给药或胃肠外给药(例如,肌肉注射、静脉注射、腹腔内给药、直肠给药、经皮给药等)的方式,给予兼有5-HT1A激活作用的5-HT3拮抗剂,或者同时、依次或间隔给予5-HT1A激活剂和5-HT3拮抗剂。
本发明的化合物和本发明的IBS治疗方法中使用的活性化合物作为药剂使用时,根据其用途,可与无毒性的添加剂一起调制成固体形态(例如,片剂、硬胶囊剂、软胶囊剂、颗粒剂、粉剂、细粒剂、丸剂、糖锭剂等)、半固体形态(例如,栓剂、软膏等)或者液体形态(例如,注射剂、乳剂、悬浮液、洗液、喷雾剂等)中任一种制剂形态使用。可用于上述制剂的无毒性添加剂例如可以是淀粉、明胶、葡萄糖、乳糖、果糖、麦芽糖、碳酸镁、滑石、硬脂酸镁、甲基纤维素、羟甲基纤维素或其盐、阿拉伯树胶、聚乙二醇、对羟基苯甲酸烷基酯、糖浆、乙醇、丙二醇、凡士林、碳蜡、甘油、氯化钠、亚硫酸钠、磷酸钠、柠檬酸等。该药剂还可含有治疗学上有效的其它药剂。
本发明化合物或本发明IBS治疗方法中所用的活性化合物在该药剂中的含量,根据其剂型而异,通常,在固体或半固体形态时优选0.1-50%重量的浓度,而液体形态时优选0.05-10%重量的浓度。
本发明的化合物或本发明的IBS治疗方法中使用的活性化合物的给药量,可因以人为首的温血动物对象的种类、给药途径、症状的轻重、医师的诊断等而大范围地变化,通常,可按照每日在0.01-5mg/kg、优选0.02-2mg/kg的范围内给药。但是,如上所述的根据病人症状的轻重、医师的诊断等,当然可以给予比上述范围的下限少的量或比上限多的量。上述给药量可一日一次或分数次给药。
实施例
以下,通过实施例和制剂例进一步具体地说明本发明。
实施例1:在上述式(I)中,X1表示氨基、低级烷基氨基、二低级烷基氨基或低级亚烷基氨基,Y表示硫原子时的化合物的合成
实施例1-1
步骤1-1-A:将4.31g无水哌嗪溶解于30ml乙二醇中,加入818mg 2-氯喹啉,在140℃下搅拌2小时。冷却后,加入饱和碳酸氢钠水溶液,通过氯仿萃取,用无水硫酸镁干燥有机层,减压下馏去溶剂。用硅胶柱色谱法(氯仿∶甲醇=2∶1)纯化残余物,得到1.09g(100%)的2-哌嗪-1-基喹啉。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H),7.59(dd,J=1.5Hz,8.0Hz,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.26~7.22(m,1H),6.97(d,J=9.2Hz,1H),3.70(t,J=5.0Hz,4H),3.01(t,J=5.0Hz,4H)
Mass,m/e:213(M+),145(base)
步骤1-1-B:将上述步骤1-1-A中制备的853mg 2-哌嗪-1-基喹啉溶解于5ml丙酮中,加入将160mg氢氧化钠溶解于5ml水中所得的溶液,进一步滴加0.5ml 1-溴-3-氯丙烷,在室温下搅拌过夜。往其中加入二乙醚,用饱和碳酸氢钠水溶液洗涤,用无水硫酸镁干燥有机层,减压下馏去溶剂。用硅胶柱色谱法(氯仿∶甲醇=50∶1)纯化残余物,得到1.10g(95%)的2-[4-(3-氯丙基)哌嗪-1-基]喹啉。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H),7.59(dd,J=1.4Hz,8.0Hz,1H),7.53(ddd,J=1.5Hz,7.1Hz,8.5Hz,1H),7.22(ddd,J=1.1Hz,6.9Hz,8.0Hz,1H),6.98(d,J=9.2Hz,1H),3.75(t,J=5.1Hz,4H),3.61(t,J=6.5Hz,2H),2.63~2.43(m,6H),2.04~1.97(m,2H)
Mass,m/e:289(M+),157(base)
步骤1-1-C:将由2-氨基-4,5-二甲基噻吩-3-羧酸乙酯制备的80mg 3-氨基-5,6-二甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-2-硫醇钾、上述步骤1-1-B中制备的104mg 2-[4-(3-氯丙基)哌嗪-1-基]喹啉和5ml乙醇的混合物加热回流4.5小时。冷却后,加入氯仿,用饱和食盐水洗涤,用无水硫酸镁干燥有机层,减压下馏去溶剂。用硅胶柱色谱法(氯仿∶甲醇=100∶1)纯化残余物,得到72mg(50%)的3-氨基-5,6-二甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=8.7Hz,1H),7.70(d,J=8.4Hz,1H),7.59(d,J=8.1Hz,1H),7.54~7.52(m,1H),7.23~7.20(m,1H),6.99(d,J=9.2Hz,1H),4.77(s,2H),3.79(t,J=5.1Hz,4H),3.19(t,J=7.3Hz,2H),2.62(t,J=5.1Hz,4H),2.56(t,J=7.0Hz,2H),2.45(s,3H),2.36(s,3H),2.00(q,J=7.3Hz,2H)IR(KBr)vmax:3308,2916,1668,1604,1506cm-1Mass,m/e:480(M+),157(base)
实施例1-2
与实施例1-1同样地操作,得到3-氨基-5,6-二甲基-2-[3-(4-吡啶-2-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
熔点:183.1-184.8℃
1H-NMR(CDCl3)δ:8.19(ddd,J=0.6Hz,1.9Hz,4.9Hz,1H),7.48(ddd,J=1.9Hz,7.2Hz,8.9Hz,1H),6.65(d,J=8.5Hz,1H),6.62(ddd,J=0.8Hz,4.9Hz,7.1Hz,1H),4.77(s,2H),3.57(t,J=5.0Hz,4H),3.18(t,J=7.1Hz,2H),2.59(t,J=5.1Hz,4H),2.54(t,J=7.0Hz,2H),2.44(s,3H),2.36(s,3H),1.98(q,J=7.2Hz,2H)
IR(KBr)vmax:3500,2920,1660,1592,1504cm-1Mass,m/e:430(M+),107(base)
实施例1-3
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-吡啶-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.19(ddd,J=0.8Hz,2.1Hz,4.9Hz,1H),7.49~7.47(m,1H),6.65(d,J=8.8Hz,1H),6.63~6.61(m,1H),4.77(s,2H),3.57(t,J=5.2Hz,4H),3.17~3.15(m,2H),2.97~2.94(m,2H),2.77~2.73(m,2H),2.59(t,J=4.9Hz,4H),1.98(q,J=7.2Hz,2H),1.89~1.78(m,4H)
IR(KBr)vmax:3104,2940,1594,1506cm-1Mass,m/e:456(M+),107(base)
实施例1-4
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.7Hz,1H),7.70(d,J=7.8Hz,1H),7.59(dd,J=1.3Hz,8.0Hz,1H),7.53(m,1H),7.24~7.20(m,1H),6.99(d,J=9.2Hz,1H),4.77(s,2H),3.79(t,J=5.1Hz,4H),3.21~3.17(m,2H),2.99~2.95(m,2H),2.75~2.71(m,2H),2.62(t,J=5.1Hz,4H),2.56(t,J=7.0Hz,2H),1.99(q,J=7.3Hz,2H),1.91~1.80(m,4H)
Mass,m/e:506(M+),157(base)
实施例1-5
与实施例1-1同样地操作,得到3-氨基-5,6-二甲基-2-[3-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.82~7.81(m,1H),7.73(dd,J=1.5Hz,8.0Hz,1H),7.67(dd,J=1.5Hz,8.0Hz,1H),7.34~7.25(m,2H),6.80(dd,J=1.3Hz,3.9Hz,1H),6.77~6.75(m,1H),4.78(s,2H),3.85(t,J=4.9Hz,4H),3.20(t,J=7.2Hz,2H),2.68(t,J=4.9Hz,4H),2.68(t,J=7.2Hz,2H),2.44(s,3H),2.36(s,3H),2.04~1.96(m,2H)
IR(KBr)vmax:3468,1662,1510cm-1Mass,m/e:519(M+),196(base)
实施例1-6
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-5,6-二甲基-3H-噻吩并[2,3-d]嘧啶-4-酮。
熔点:200.5-201.2℃
1H-NMR(CDCl3)δ:7.61~7.59(m,1H),7.57~7.55(m,1H),7.29(ddd,J=1.4Hz,7.5Hz,7.9Hz,1H),7.08(ddd,J=1.2Hz,7.5Hz,7.9Hz,1H),4.77(s,2H),3.68(t,J=5.1Hz,4H),3.18(t,J=7.4Hz,2H),2.62(t,J=5.1Hz,4H),2.56~2.54(m,2H),2.44(d,J=0.7Hz,3H),2.36(d,J=0.9Hz,3H),2.00~1.94(m,2H)IR(KBr)vmax:3200,2920,1666,1512cm-1Mass,m/e:486(M+),128(base)
实施例1-7
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-噻吩并[3,2-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.90(d,J=5.1Hz,1H),7.70(d,J=8.4Hz,1H),7.61~7.58(m,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.23~7.21(m,1H),7.20(d,J=5.1Hz,1H),6.98(d,J=9.1Hz,1H),4.83(s,2H),3.79(t,J=4.9Hz,4H),3.22(t,J=7.3Hz,2H),2.63(t,J=4.9Hz,4H),2.59(t,J=7.3Hz,2H),2.03(q,J=7.3Hz,2H)
Mass,m/e:452(M+),157(base)
实施例1-8
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.22~8.19(m,1H),7.89(d,J=9.2Hz,1H),7.73~7.69(m,1H),7.61~7.51(m,3H),7.41~7.36(m,1H),7.24~7.20(m,1H),6.99(d,J=9.2Hz,1H),4.82(s,2H),3.79(t,J=4.8H z,4H),3.26(t,J=7.3Hz,2H),2.65~2.58(m,6H),2.05(q,J=7.0Hz,2H)
Mass,m/e:446(M+),157(base)
实施例1-9
与实施例1-1同样地操作,得到3-氨基-5,6-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁-2-烯基硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.69(d,J=8.3Hz,1H),7.61~7.56(m,1H),7.55~7.50(m,1H),7.23~7.20(m,1H),6.95(d,J=9.2Hz,1H),5.92~5.85(m,1H),5.83~5.76(m,1H),4.76(s,2H),3.78(d,J=6.7Hz,2H),3.74(t,J=5.1Hz,4H),3.06(d,J=6.4Hz,2H),2.57(t,J=5.1Hz,4H),2.44(s,3H),2.35(s,3H)
Mass,m/e:492(M+),157(base)
实施例1-10
与实施例1-1同样地操作,得到3-氨基-4-氧代-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4-二氢喹唑啉-7-羧酸乙酯。
1H-NMR(CDCl3)δ:8.25(d,J=5.5Hz,1H),8.24(d,J=0.7Hz,1H),7.99(dd,J=1.5Hz,8.4Hz,1H),7.88(d,J=9.2Hz,1H),7.70(d,J=8.1Hz,1H),7.61~7.58(m,1H),7.53(ddd,J=1.8Hz,7.0Hz,8.8Hz,1H),7.22(ddd,J=1.1Hz,7.0Hz,8.1Hz,1H),7.00(d,J=4.2Hz,1H),4.84(s,2H),4.44(q,J=7.3Hz,2H),3.80(t,J=5.1Hz,4H),3.28(t,J=7.0Hz,2H),2.65(t,J=5.1Hz,4H),2.60(t,J=7.0Hz,2H),2.08~2.01(m,2H),1.43(t,J=7.3Hz,3H)
Mass,m/e:518(M+),157(base)
实施例1-11
与实施例1-1同样地操作,得到3-氨基-5,6-二甲基-2-[3-(4-菲啶-6-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.55(d,J=8.4Hz,1H),8.42(dd,J=1.1Hz,8.1Hz,1H),8.21(d,J=7.3Hz,1H),7.92(dd,J=1.1Hz,8.1Hz,1H),7.79~7.75(m,1H),7.63~7.60(m,2H),7.50~7.46(m,1H),3.56(brs,4H),3.21(t,J=7.0Hz,2H),2.79(brs,4H),2.64(t,J=7.0Hz,2H),2.44(s,3H),2.35(s,3H)
Mass,m/e:530(M+),207(base)
实施例1-12
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4,7-二氧杂-9-硫杂-1,3-二氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.89(d,J=9.1Hz,1H),7.70(d,J=8.1Hz,1H),7.69(d,J=7.9Hz,1H),7.53(ddd,J=1.3Hz,6.9Hz,8.2Hz,1H),7.24~7.20(m,1H),4.78(s,4H),4.02~4.00(m,2H),3.79(t,J=5.0Hz,4H),3.22~3.07(m,2H),2.62(t,J=5.0Hz,4H),2.57(t,J=6.8Hz,2H),2.04~1.96(m,2H)
Mass,m/e:508(M+),157(base)
实施例1-13
与实施例1-1同样地操作,得到3-氨基-7-叔丁氧基羰基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H),7.61~7.58(m,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.24~7.20(m,1H),6.99(d,J=9.2Hz,1H),4.78(s,2H),4.60(brs,2H),3.79(t,J=5.1Hz,4H),3.73~3.70(m,2H),3.22~3.18(m,2H),3.06(brs,2H),2.62(t,J=5.1Hz,4H),2.58~2.54(m,2H),2.00(q,J=7.3Hz,2H)
Mass,m/e:607(M+),157(base)
实施例1-14
与实施例1-1同样地操作,得到3-氨基-5-甲基-4-氧代-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸乙酯。
1H-NMR(CDCl3)δ:7.89(d,J=8.8Hz,1H),7.70(d,J=8.4Hz,1H),7.61~7.55(m,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.22(ddd,J=1.1Hz,7.0Hz,8.1Hz,1H),6.99(d,J=9.2Hz,1H),4.78(s,2H),4.36(q,J=7.3Hz,2H),3.79(t,J=5.1Hz,4H),3.23~3.19(m,2H),2.91(s,3H),2.66~2.63(m,4H),2.61~2.57(m,2H),2.05~1.98(m,2H),1.40(t,J=7.3Hz,3H)
Mass,m/e:538(M+),157(base)
实施例1-15
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.59(dd,J=1.2Hz,7.7Hz,1H),7.54(dd,J=1.2Hz,8.1Hz,1H),7.29~7,27(m,1H),7.07~7.05(m,1H),4.76(s,2H),3.68~3.66(m,4H),3.19~3.15(m,2H),2.97~2.94(m,2H),2.73(t,J=5.8Hz,2H),2.60(t,J=5.1Hz,4H),2.55(t,J=6.9Hz,2H),1.96(q,J=7.0Hz,2H),1.90~1.83(m,4H)Mass,m/e:512(M+),163(base)
实施例1-16
与实施例1-1同样地操作,得到3-氨基-7-硝基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-喹唑啉-4-酮。
1H-NMR(DMSO-d6)δ:8.29(d,J=8.9Hz,1H),8.23(d,J=2.2Hz,1H),8.12(dd,J=2.2Hz,8.9Hz,1H),8.02(d,J=9.2Hz,1H),7.67(d,J=7.2Hz,1H),7.56~7.40(m,2H),7.23~7.18(m,2H),5.84(s,2H),3.72(t,J=4.8Hz,4H),3.17(t,J=7.3Hz,2H),2.55~2.48(rn,6H),1.93(t,J=7.3Hz,2H)
Mass,m/e:491(M+),157(base)
实施例1-17
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-7-硝基-3H-喹唑啉-4-酮。
1H-NMR(DMSO-d6)δ:8.30(d,J=8.5Hz,1H),8.23(d,J=2.2Hz,1H),8.14(dd,J=2.2Hz,8.8Hz,1H),7.75(d,J=6.9Hz,1H),7.45(d,J=7.5Hz,1H),7.29~7.25(m,1H),7.08~7.04(m,1H),5.85(s,2H),3.62~3.59(m,4H),3.19~3.15(m,2H),2.51~2.49(m,6H),1.93(t,J=7.3Hz,2H)
Mass,m/e:497(M+),163(base)
实施例1-18
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4,7-二氧杂-9-硫杂-1,3-二氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.65~7.51(m,2H),7.38~7.13(m,2H),4.78(s,2H),4.00(t,J=5.5Hz,2H),3.74~3.54(m,4H),3.27~3.02(m,4H),2.67~2.49(m,6H),2.13~1.88(m,2H),1.62(m,2H),
Mass,m/e:514(M+),163(base)
实施例1-19
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-吡啶并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.77(dd,J=1.5Hz,4.4Hz,1H),7.92(dd,J=1.5Hz,8.4Hz,1H),7.89(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H),7.64~7.59(m,2H),7.54(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.25~7.21(m,1H),6.99(d,J=9.2Hz,1H),4.94(s,2H),3.79(t,J=5.1Hz,4H),3.27(t,J=7.3Hz,2H),2.64(t,J=5.1Hz,4H),2.60(t,J=7.3Hz,2H),2.05(q,J=7.3Hz,2H)
Mass,m/e:447(M+),157(base)
实施例1-20
与实施例1-1同样地操作,得到3-氨基-7-叔丁氧基羰基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.60(dd,J=0.7Hz,7.7Hz,1H),7.56(d,J=8.1Hz,1H),7.31~7.29(m,1H),7.10~7.06(m,1H),4.78~4.76(m,2H),4.61~4.59(m,2H),3.73~3.68(m,6H),3.21~3.18(m,2H),3.06(brs,2H),2.63~2.61(m,4H),2.57(t,J=7.0Hz,2H),2.05~1.96(m,2H),1.50(s,9H)
Mass,m/e:613(M+),56(base)
实施例1-21
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-吡啶并[3,2-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.92(dd,J=1.8Hz,4.4Hz,1H),8.55(dd,J=1.8Hz,8.1Hz,1H),7.88(d,J=8.8Hz,1H),7.70(d,J=8.4Hz,1H),7.59(dd,J=1.1Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.37~7.34(m,1H),7.24~7.20(m,1H),6.98(d,J=9.1Hz,1H),4.84(s,2H),3.78(t,J=5.1Hz,4H),3.38(t,J=7.3Hz,2H),2.64~2.59(m,6H),2.07(q,J=7.3Hz,2H)
Mass,m/e:447(M+),157(base)
实施例1-22
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-3H-吡啶并[2,3-d]嘧啶-4-酮。
1H-NMR(DMSO-d6)δ:8.69(dd,J=1.5Hz,4.4Hz,1H),7.95~7.92(m,1H),7.76~7.71(m,2H),7.44~7.42(m,2H),7.28~7.24(m,2H),7.07~7.03(m,2H),5.81(s,2H),3.57(t,J=5.1Hz,4H),3.15~3.11(m,2H),2.55~2.52(m,4H),2.50~2.44(m,2H),1.92~1.89(m,2H)
Mass,m/e:453(M+),163(base)
实施例1-23
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-3H-吡啶并[3,2-d]嘧啶-4-酮。
1H-NMR(DMSO-d6)δ:8.87(dd,J=1.8Hz,5.3Hz,1H),8.45(dd,J=1.8Hz,8.1Hz,1H),7.73(d,J=8.1Hz,1H),7.45~7.42(m,2H),7.28~7.24(m,1H),7.07~7.03(m,1H),5.76(s,2H),3.59~3.57(m,4H),3.17~3.14(m,2H),2.56(brs,4H),2.53~2.48(m,2H),1.94~1.90(m,2H)
Mass,m/e:453(M+),163(base)
实施例1-24
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8,9,10-八氢-4-氧杂-11-硫杂-1,3-二氮杂-11H-芳辛并[a]茚。
1H-NMR(CDCl3)δ:7.99(d,J=9.0Hz,1H),7.70(d,J=9.0Hz,1H),7.69(d,J=8.0Hz,1H),7.54~7.53(m,1H),7.24~7.22(m,1H),6.99(d,J=9.2Hz,1H),4.78(s,2H),3.79(t,J=5.1Hz,4H),3.21~3.18(m,2H),3.09(t,J=6.4Hz,2H),2.64~2.62(m,2H),2.63(t,J=5.1Hz,4H),2.59~2.55(m,2H),2.04~1.99(m,2H),1.72~1.69(m,4H),1.57~1.47(m,2H),1.34~1.26(m,2H)
Mass,m/e:534(M+),157(base)
实施例1-25
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8,9,10-八氢-4-氧杂-11-硫杂-1,3-二氮杂-11H-芳辛并[a]茚。
1H-NMR(CDCl3)δ:7.58(d,J=0.7Hz,1H),7.56(d,J=2.1Hz,1H),7.32~7.28(m,1H),7.10~7.08(m,1H),4.79(s,2H),3.73(brs,4H),3.20~3.17(m,2H),3.08~3.04(m,2H),2.85~2.82(m,2H),2.68(brs,4H),2.62(brs,2H),2.04~2.02(m,2H),1.72~1.69(m,4H),1.47~1.43(m,2H),1.36~1.37(m,2H)
Mass,m/e:540(M+),163(base)
实施例1-26
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7-五氢-4-氧杂-8-硫杂-1,3-二氮杂-8H-环戊二烯并[a]茚。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.1Hz,1H),7.59(d,J=8.1Hz,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.24~7.20(m,1H),6.99(d,J=9.2Hz,1H),4.80(s,2H),3.78(t,J=5.1Hz,4H),3.22~3.18(m,2H),3.04(t,J=7.3Hz,2H),2.94(t,J=7.3Hz,2H),2.62(t,J=5.1Hz,4H),2.59~2.55(m,2H),2.46(q,J=7.0H z,2H),2.00(q,J=7.3Hz,2H)
Mass,m/e:492(M+),157(base)
实施例1-27
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丙硫基]-3,4,5,6,7-五氢-4-氧杂-8-硫杂-1,3-二氮杂-8H-环戊二烯并[a]茚。
1H-NMR(CDCl3)δ:7.77(dd,J=1.3Hz,8.2Hz,1H),7.72~7.70(m,1H),7.53(ddd,J=1.3Hz,3.0Hz,8.2Hz,1H),7.25~7.22(m,1H),6.85(s,1H),4.80(s,2H),3.78(t,=5.1Hz,4H),3.22~3.18(m,2H),3.04(t,J=7.3Hz,2H),2.94(t,J=7.3Hz,2H),2.61(t,J=5.1Hz,4H),2.60(s,3H),2.56(t,J=7.3Hz,2H),2.50~2.42(m,2H),2.00(q,J=7.3Hz,2H)
Mass,m/e:506(M+),171(base)
实施例1-28
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7-五氢-4-氧杂-8-硫杂-1,3-二氮杂-8H-环戊二烯并[a]茚。
1H-NMR(CDCl3)δ:7.60(dd,J=0.7Hz,7.7Hz,1H),7.56(d,J =1.3Hz,1H),7.32~7.28(m,1H),7.10~7.06(m,1H),4.80(s,2H),3.69(t,J=5.1Hz,4H),3.21~3.17(m,2H),3.06~3.02(m,2H),2.94(t,J=7.3Hz,2H),2.62(t,J=5.1Hz,4H),2.56(t,J=6.1Hz,4H),2.46(q,J=7.3Hz,2H),1.98(q,J=7.0Hz,2H)Mass,m/e:498(M+),128(base)
实施例1-29
与实施例1-1同样地操作,得到3-氨基-5-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H),7.59(d,J=8.1Hz,1H),7.55~7.51(m,1H),7.24~7.22(m,1H),6.99(d,J=9.2Hz,1H),4.79(s,2H),3.79(t,J=5.1Hz,4H),3.22~3.17(m,2H),2.80~2.69(m,1H),2.62(t,J=5.1Hz,4H),2.56(t,J=7.0Hz,2H),2.01~1.57(m,6H),1.30(d,J=6.0Hz,3H)
Mass,m/e:520(M+),157(base)
实施例1-30
与实施例1-1同样地操作,得到3-氨基-6-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H),7.60~7.58(m,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.22(ddd,J=1.1Hz,7.0Hz,8.1Hz,1H),6.99(d,J=9.2Hz,1H),4.77(s,2H),3.79(t,J=5.1Hz,4H),3.19(t,J=7.3Hz,2H),2.63~2.62(m,1H),2.62~2.60(m,4H),2.56(t,=7.0Hz,2H),2.04~1.92(m,6H),1.00(d,J=6.6Hz,3H)
Mass,m/e:520(M+),157(base)
实施例1-31
与实施例1-1同样地操作,得到3-氨基-7-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7,89(d,J=9.2Hz,1H),7.69(m,1H),7.59(d,J=7.9Hz,1H),7.53(d,J=7.9Hz,1H),7.53(m,1H),7.22(m,1H),6.99(d,J=9.2Hz,1H),4.77(s,2H),3.78(t,J=5.1Hz,4H),3.21~3.18(m,3H),2.90~2.80(m,2H),2.62(t,J=5.1Hz,4H),2.56(t,J=7.0Hz,2H),2.41~2.35(m,2H),2.04~1.98(m,4H),1.10(d,J=6.6H z,3H)
Mass,m/e:520(M+),157(base)
实施例1-32
与实施例1-1同样地操作,得到3-氨基-5,6-二甲基-2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.77(dd,J=1.1Hz,8.1Hz,1H),7.71(d,J=7.7Hz,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.25~7.22(m,1H),6.84(d,J=3.7Hz,1H),4.78(s,2H),3.78(t,J=5.1Hz,4H),3.20~3.17(m,2H),2.62~2.60(m,4H),2.60(s,3H),2.58~2.54(m,2H),2.44(d,J=0.7H z,3H),2.36(d,J=0.7Hz,3H),1.99(q,J=7.3Hz,2H)
Mass,m/e:494(M+),171(base)
实施例1-33
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.77(dd,J=1.1Hz,8.4Hz,1H),7.71(d,J=8.4Hz,1H),7.52(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.25~7.22(m,1H),6.85(s,1H),4.77(s,2H),3.78(t,J=5.1Hz,4H),3.19(t,J=7.3Hz,2H),2.98~2.95(m,2H),2.75(t,J=5.9,2H),2.62~2.60(m,4H),2.60(s,3H),2.56(t,J=7.3Hz,2H),2.44(d,J=0.7Hz,3H),2.36(d,J=0.7Hz,3H),1.99(q,J=7.3Hz,2H),1.89~1.83(m,4H)
Mass,m/e:520(M+),171(base)
实施例1-34
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丙硫基]-3,4,5,6,7,8-六氢-4,7-二氧杂-9-硫杂-1,3-二氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.77(dd,J=1.1Hz,8.0Hz,1H),7.70(d,J=8.4Hz,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.25~7.23(m,1H),6.84(s,1H),4.78(brs,4H),4.13~3.99(m,2H),3.78(t,J=5.1Hz,4H),3.22~3.18(m,2H),3.10~3.07(m,2H),2.63~2.55(m,6H),2.60(s,3H),2,04~1.97(m,2H)
Mass,m/e:522(M+),171(base)
实施例1-35
与实施例1-1同样地操作,得到3-氨基-5,6-二甲基-2-[3-[4-(5,6,7,8-四氢喹啉-2-基)哌嗪-1-基]丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.17(d,J=8.4Hz,1H),6.43(d,J=8.4Hz,1H),4.77(s,2H),3.50(t,J=5.1Hz,4H),3.17(t,J=7.3Hz,2H),2.75(t,J=5.6Hz,2H),2.63~2.52(m,8H),2.44(s,3H),2.35(d,J=7.0Hz,3H),1.97(q,J=7.3Hz,1H),1.86~1.80(m,2H),1.78~1.75(m,2H)
Mass,m/e:484(M+),161(base)
实施例1-36
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(5,6,7,8-四氢喹啉-2-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.17(d,J=8.4Hz,1H),6.44(d,J=8.4Hz,1H),4.77(s,2H),3.51(t,J=5.1Hz,4H),3.17(t,J=7.3Hz,2H),2.98~2.95(m,2H),2.75~2.73(m,2H),2.62~2.52(m,8H),1.98(q,J=7.3Hz,1H),1.89~1.72(m,8H)
Mass,m/e:510(M+),161(base)
实施例1-37
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(5,6,7,8-四氢喹啉-2-基)哌嗪-1-基]丙硫基]-3,4,5,6,7-五氢-4-氧杂-8-硫杂-1,3-二氮杂-8H-环戊二烯并[a]茚。
1H-NMR(CDCl3)δ:7.18(d,J=8.4Hz,1H),6.44(d,J=8.4Hz,1H),4.81(s,2H),3.52(t,J=5.1Hz,4H),3.18(t,J=7.3Hz,2H),2.95~2.91(m,2H),2.76~2.57(m,6H),2.46(q,J=7.3Hz,2H),2.01(q,J=7.3Hz,2H),1.86~1.68(m,8H)
Mass,m/e:496(M+),161(base)
实施例1-38
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(7-甲氧基异喹啉-1-基)哌嗪-1-基]丙硫基]-5,6-二甲基-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.07(d,J=5.8Hz,1H),7.68(d,J=8.0Hz,1H),7.40(d,J=2.3Hz,1H),7.30~7.27(m,1H),7.21(d,J=5.8Hz,1H),4.78(s,2H),3.94(s,3H),3.44(brs,4H),3.20(t,J=7.3Hz,2H),2.78(brs,4H),2.64(t,J=7.3Hz,2H),2.44(s,3H),2.35(s,3H),2.02(q,J=7.3Hz,2H)
Mass,m/e:510(M+),187(base)
实施例1-39
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(7-甲氧基异喹啉-1-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.07(d,J=5.8Hz,1H),7.68(d,J=8.9Hz,1H),7.40(d,J=2.3Hz,1H),7.30~7.27(m,1H),7.21(d,J=5.4Hz,1H),4.78(s,2H),3.94(s,3H),3.45(brs,4H),3.20(t,J=7.0Hz,2H),2.98~2.96(m,2H),2.79(brs,4H),2.73~2.71(m,2H),2.65(t,J=7.0Hz,2H),2.03(q,J=7.3Hz,2H),1.86~1.82(m,4H)
Mass,m/e:536(M+),187(base)
实施例1-40
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(7-甲氧基异喹啉-1-基)哌嗪-1-基]丙硫基]-3H-吡啶并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.70(dd,J=1.5Hz,4.6Hz,1H),7.92~7.91(m,1H),7.69~7.66(m,1H),7.63~7.57(m,1H),7.40~7.34(m,1H),7.30~7.20(m,2H),4.93(s,2H),3.91(s,3H),3.48~3.44(m,4H),3.30~3.26(m,2H)
Mass,m/e:477(M+),187(base)
实施例1-41
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(7-甲氧基异喹啉-1-基)哌嗪-1-基]丙硫基]-3H-吡啶并[3,2-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.99~8.90(m,1H),8.56~8.54(m,1H),8.06(d,J=5.4Hz,1H),7.69~7.67(m,2H),7.40~7.21(m,3H),4.84(s,2H),3.94(s,3H),3.45~3.38(m,6H),2.79(brs,4H),2.78~2.70(m,2H),2.10~2.05(m,2H)
Mass,m/e:477(M+),187(base)
实施例1-42
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(7-甲氧基-3-甲基异喹啉-1-基)哌嗪-1-基]丙硫基]-5,6-二甲基-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.58(d,J=8.9Hz,1H),7.34(brs,1H),7.23(dd,J=2.7Hz,8.9Hz,1H),7.04(s,1H),4.77(s,2H),3.92(s,3H),3.46(brs,4H),3.21(t,J=7.3Hz,2H),2.78(brs,4H),2.65~2.63(m,2H),2.53(s,3H),2.44(s,3H),2.35(s,3H),2.04(brs,2H)
Mass,m/e:524(M+),188(base)
实施例1-43
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(7-甲氧基-3-甲基异喹啉-1-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.57(d,J=8.7Hz,1H),7.34(d,J=1.5Hz,1H),7.22(dd,J=2.3Hz,8.9Hz,1H),7.04(s,1H),4.77(s,2H),3.92(s,3H),3.46(brs,4H),3.20(t,J=7.3Hz,2H),2.96(m,2H),2.77(brs,4H),2.74~2.71(m,2H),2.62~2.53(m,2H),2.53(s,3H),2.10(brs,2H),1.86~1.85(m,2H)
Mass,m/e:550(M+),188(base)
实施例1-44
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(5-甲氧基异喹啉-1-基)哌嗪-1-基]丙硫基]-5,6-二甲基-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.17(d,J=5.8Hz,1H),7.68~7.63(m,2H),7.42(d,J=8.1Hz,1H),6.95(d,J=7.7Hz,1H),4.79(s,2H),4.00(s,3H),3.47(brs,4H),3.21(t,J=6.9Hz,2H),2.77(brs,4H),2.64(t,J=7.3Hz,2H),2.46(s,3H),2.36(s,3H),2.03(q,J=7.3Hz,1H)
Mass,m/e:510(M+),187(base)
实施例1-45
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(5-甲氧基异喹啉-1-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.17(d,J=5.8Hz,1H),7.68~7.63(m,2H),7.44~7.40(m,1H),6.95(d,J=7.7Hz,1H),4.78(s,2H),4.00(s,3H),3.47(brs,4H),3.21(t,J=7.3Hz,2H),2.99~2.96(m,2H),2.76~2.74(m,6H),2.64(t,J=7.3Hz,2H),2.06~2.00(m,2H)Mass,m/e:536(M+),187(base)
实施例1-46
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-呋喃并[2,3-c]吡啶-7-基哌嗪-1-基)丙硫基]-5,6-二甲基-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.95(d,J=5.4Hz,1H),7.60(d,J=2.3Hz,1H),6.96(d,J=5.4Hz,1H),6.72(d,J=1.9Hz,1H),4.77(s,2H),3.19(t,J=7.3Hz,4H),2.65(t,J=5.0Hz,4H),2.57(t,J=0.8Hz,3H),2.36(d,J=0.8Hz,3H),2.00(q,J=7.3Hz,1H)
Mass,m/e:470(M+),147(base)
实施例1-47
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-呋喃并[3,2-c]吡啶-4-基哌嗪-1-基)丙硫基]-5,6-二甲基-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.04(d,J=5.8Hz,1H),7.53(d,J=2.3Hz,1H),6.94(dd,J=0.8Hz,5.8Hz,1H),6.82(dd,J=1.2Hz,2.3Hz,1H),4.77(s,2H),3.76(t,J=5.0Hz,4H),3.19(t,J=7.3Hz,2H),2.65(t,J=5.0Hz,4H),2.57(t,J=7.3Hz,2H),2.45(s,3H),2.36(s,3H),2.05~1.96(m,2H)
Mass,m/e:470(M+),147(base)
实施例1-48
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(6-甲氧基异喹啉-1-基)哌嗪-1-基]丙硫基]-5,6-二甲基-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.09(d,J=5.8Hz,1H),8.00(d,J=9.3Hz,1H),7.16~7.10(m,2H),7.02(d,J=2.3Hz,1H),4.78(s,2H),3.93(s,3H),3.45(brs,4H),3.20(t,J=7.3Hz,2H),2.76(brs,4H),2.63(t,J=6.9Hz,2H),2.44(s,3H),2.35(s,3H),2.03~2.00(m,1H)
Mass,m/e:510(M+),187(base)
实施例1-49
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(6-甲氧基异喹啉-1-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.09(d,J=6.0Hz,1H),7.99(d,J=9.3Hz,1H),7.16(d,J=5.7Hz,1H),7.12(dd,J=2.7Hz,9.3Hz,1H),7.02(d,J=2.3Hz,1H),4.78(s,2H),3.93(s,3H),3.45(brs,4H),3.22~3.18(m,2H),2.98~2.96(m,2H),2.77(brs,4H),2.73(t,J=5.8Hz,2H),2.66~2.62(m,2H),2.05~2.00(m,2H),1.88~1.75(m,4H)
Mass,m/e:536(M+),187(base)
实施例1-50
与实施例1-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.0Hz,1H),7.70(d,J=8.3Hz.1H).7.59(d,J=7.9Hz,1H),7.53(ddd,J=1.6Hz,7.0Hz,8.7Hz,1H),7.24~7.20(m,1H),6.98(d,J=8.3Hz,1H),4.80(s,2H),3.77(t,J=4.8Hz,4H),3.14(t,J=7.4Hz,4H),2.62~2.60(m,4H),2.58~2.45(m,6H),1.99~1.95(m,2H),1.80~1.72(m,4H)
Mass,m/e:450(M+),157(base)
实施例1-51
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.77(m,1H),7.70(d,J=8.1Hz,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.27~7.23(m,1H),6.84(d,J=0.7Hz,1H),4.80(s,2H),3.76(t,J=5.1Hz,4H),3.16~3.12(m,2H),2.64~2.61(m,4H),2.60~2.49(m,6H),1.97(q,J=7.3Hz,2H),1.81~1.63(m,4H)
Mass,m/e:464(M+),171(base)
实施例1-52
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(3-氯异喹啉-1-基)哌嗪-1-基]丙硫基]-5,6-二甲基-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.01(d,J=8.1Hz,1H),7.65(d,J=8.1Hz,1H),7.58(dt,J=0.8Hz,6.6Hz,1H),7.45(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.25~7.23(m,1H),4.78(s,2H),3.53(brs,4H),3.18(t,J=7.3Hz,2H),2.75(brs,4H),2.63(t,J=7.3Hz,2H),2.43(s,3H),2.34(s,3H),2.00(q,J=7.3Hz,2H)
Mass,m/e:514(M+),128(base)
实施例1-53
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(3-氯异喹啉-1-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.99(d,J =8.5Hz,1H),7.65(d,J=7.0Hz,1H),7.59(dt,J=1.2Hz,6.9Hz,1H),7.45(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.24~7.22(m,1H),4.78(s,2H),3.59(brs,4H),3.19(t,J=7.3Hz,2H),2.97~2.90(m,2H),2.81(brs,4H),2.72~2.69(m,2H),2.06~2.03(m,2H),1.87~1.82(m,2H)
Mass,m/e:128(base)
实施例1-54
与实施例1-1同样地操作,得到3-氨基-5,6-二甲基-2-[3-[4-(3-甲基喹喔啉-2-基)哌嗪-1-基]丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(dd,J=1.1Hz,8.4Hz,2H),7.82(dd,J=1.1Hz,8.4Hz,2H),7.57(ddd,J=1.1Hz,6.9Hz,8.4Hz,1H),7.50(ddd,J=1.1Hz,6.9Hz,8.4Hz,1H),4.78(s,2H),3.39~3.48(m,4H),3.20(t,J=7.0Hz,2H),2.71(s,3H),2.68~2.73(m,4H),2.57~2.63(m,2H),2.45(s,3H),2.36(s,3H),1.94~2.08(m,2H)
Mass,m/e:495(M+),268(base),128
实施例1-55
与实施例1-1同样地操作,得到3-氨基-2-[3-[4-(3-甲基喹喔啉-2-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶酮-4-酮。
1H-NMR(CDCl3)δ:7.88(dd,J=1.1Hz,8.1Hz,1H),7.82(dd,J=1.1Hz,8.1Hz,1H),7.58(ddd,J=1.1Hz,6.9Hz,8.1Hz,1H),7.51(ddd,J=1.1Hz,6.9Hz,8.1Hz,1H),4.77(s,2H),3.38~3.49(m,4H),3.20(t,J=7.1Hz,2H),2.93~2.99(m,8H),2.00(q,J=7.1Hz,2H),1.79~1.93(m,4H)
Mass,m/e:521(M+),349,294,128(base)
实施例1-56
与实施例1-1同样地操作,得到3-氨基-5,6-二甲基-2-[3-[4-(3-苯基喹喔啉-2-基)哌嗪-1-基]丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.96~8.01(m,2H),7.84(dd,J=1.5Hz,8.4Hz,1H),7.60(ddd,J=1.1Hz,6.9Hz,8.1Hz,1H),7.41~7.52(m,5H),4.75(s,2H),3.29~3.37(m,4H),3.14(t,J=7.0Hz,2H),2.47~2.53(m,4H),2.43(s,3H),2.35(s,3H),1.91(q,J=7.0Hz,2H),1.24(t,J=7.0Hz,2H)
Mass,m/e:557(M+),128(base)
实施例1-57
与实施例1-1同样地操作,得到3-氨基-4-氧代-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4-二氢喹唑啉-7-羧酸。
1H-NMR(DMSO-d6)δ:8.05~7.99(m,2H),7.72~7.66(m,2H),7.57~7.47(m,3H),7.24~7.18(m,2H),5.79(brs,2H),3.68(brs,4H),3.17~3.13(m,2H),2.81~2.77(m,2H),2.54~2.52(m,4H),1.90~1.83(m,2H)
Mass,m/e:490(M+),157(base)
实施例1-58
将实施例1-57中合成的250mg 3-氨基-4-氧代-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4-二氢喹唑啉-7-羧酸溶解于10ml叔丁醇中,往其中加入52mg三乙胺,再加入147mg DPPA,然后将该混合物加热回流过夜。减压下馏去溶剂,用硅胶柱色谱法(氯仿∶甲醇=50∶1)纯化残余物。将其加入8ml 4当量盐酸二噁烷溶液中,搅拌1小时后,加入过量的三乙胺,减压下馏去溶剂。用硅胶柱色谱法(氯仿∶甲醇=50∶1)纯化残余物,得到20mg(8%)的3,7-二氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.02(d,J=9.2Hz,1H),7.72~7.67(m,2H),7.56~7.49(m,2H),7.25~7.19(m,2H),6.65~6.62(m,1H),6.50(d,J=2.2Hz,1H),6.03(brs,2H),5.51(brs,2H),3.70(brs,2H),3.05(t,J=7.0Hz,2H),2.53~2.45(m,6H),1.98~1.87(m,2H)
Mass,m/e:461(M+),157(base)
实施例1-59
将实施例1-13中合成的100mg 3-氨基-7-叔丁氧基羰基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴加入到6ml 4当量盐酸二噁烷溶液中,搅拌2.5小时。减压下馏去溶剂,得到105mg(100%)的3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴三盐酸盐。
1H-NMR(DMSO-d6)δ:9.82(brs,1H),8.46(d,J=9.5Hz,1H),8.32(brs,1H),7.93(d,J=7.7Hz,1H),7.78(m,1H),7.58(d,J=9.2Hz,1H),7.50(m,1H),4.87(d,J=8.2Hz,2H),4.33(brs,2H),4.20~3.85(m,4H),3.70(d,J=5.4Hz,2H),3.39(brs,2H),3.26(brs,2H),3.17~3.13(m,4H),2.23~2.16(m,2H)
Mass,m/e:507(M+),157(base)
实施例1-60
与实施例1-59同样地操作,使用实施例1-20中合成的3-氨基-7-叔丁氧基羰基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴,得到3-氨基-2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.60(dd,J=1.0Hz,7.9Hz,1H),7.56(d,J=7.6Hz,1H),7.32~7.28(m,1H),7.10~7.06(m,1H),4.79(s,2H),4.03~4.02(m,2H),3.70~3.67(m,4H),3.21~3.12(m,4H),3.02~3.00(m,2H),2.62(t,J=5.1Hz,4H),2.57(t,J=7.0Hz,2H),1.98(q,J=7.3Hz,2H)
Mass,m/e:513(M+),163(base)
实施例1-61
首先,与实施例1-1同样地操作,得到3-氨基-7-叔丁氧基羰基-2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。随后,与实施例1-59同样地操作,得到3-氨基-2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴三盐酸盐。
1H-NMR(DMSO-d6)δ:8.05~7.05(m,5H),4.34(brs,4H),3.71~3.15(m,6H),2.69(m,4H),2.51~2.46(m,7H),2.20(m,2H)
Mass,m/e:521(M+),171(base)
实施例1-62
将实施例1-59中合成的203mg 3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴三盐酸盐加入到10ml四氢呋喃中,往其中滴入133mg三乙胺,在冰冷却下往该混合物中加入乙酰氯。搅拌30分钟后,减压下馏去,用硅胶柱色谱法(氯仿∶甲醇=25∶1)纯化残余物,得到150mg(83%)的7-乙酰基-3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.99(d,J=8.9Hz,1H),7.70(d,J=8.5Hz,1H),7.59(d,J=7.7Hz,1H),7.55~7.51(m,1H),7.24~7.21(m,1H),6.99(d,J=9.2Hz,1H),4.78(brs,4H),3.79(t,J=4.6Hz,4H),3.75(d,J=5,8Hz,2H),3.22~3.19(m,2H),3.15~3.07(m,2H),2.67(t,J=4.6Hz,4H),2.58~2.55(m,2H),2.21(s,3H),2.04~1.96(m,2H)
Mass,m/e:549(M+),157(base)
实施例1-63
将实施例1-59中合成的310mg 3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴三盐酸盐加入到10ml四氢呋喃中,再加入50mg乙基碘,往该混合物中滴入200mg三乙胺。室温下搅拌3天,然后减压下馏去。用硅胶柱色谱法(氯仿∶甲醇=10∶1)进行纯化,得到100mg(37%)的3-氨基-7-乙基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.87(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.59~7.57(m,1H),7.54~7.50(m,1H),7.21(ddd,J=1.2Hz,7.0Hz,8.5Hz,1H),6.97(d,J=9.3Hz,1H),4.87(s,2H),3.79~3.76(m,4H),3.65(brs,2H),3.18(t,J=7.3Hz,2H),3.08(t,J=5.8Hz,2H),2.81(t,J=5.8Hz,2H),2.67~2.60(m,6H),2.55(t,J=7.0Hz,2H),2.02~1.95(m,2H),1.20(t,J=7.3Hz,3H)
Mass,m/e:535(M+),157(base)
实施例2:在上述式(I)中,X1表示氢原子,Y表示硫原子时的化合物的合成
实施例2-1
将由2-氨基-4,5-二甲基噻吩-3-羧酸乙酯制备的75mg 5,6-二甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-2-硫醇钾与87mg 2-[4-(3-氯丙基)哌嗪-1-基]吡啶在3ml乙醇中,加热回流5小时。冷却后,加入氯仿,用饱和食盐水洗涤,用无水硫酸镁干燥有机层并在减压下馏去溶剂。用硅胶柱色谱法(氯仿∶甲醇=100∶1)纯化残余物,得到93mg(75%)的5,6-二甲基-2-[3-(4-吡啶-2-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
熔点:209.0-209.4℃
1H-NMR(CDCl3)δ:8.20~8.18(m,1H),7.47(ddd,J=1.9Hz,7.1Hz,8.8Hz,1H),6.65(d,J=8.6Hz,1H),6.61(dd,J=5.0Hz,7.1Hz,1H),3.63(t,J=5.1Hz,4H),3.28(t,J=6.9Hz,2H),2.63(t,J=5.1Hz,4H),2.59(d,J=6.7Hz,2H),2.43(s,3H),2.35(s,3H),2.01(q,J=6.8Hz,2H)
IR(KBr)vmax:3468,1650,1590cm-1
Mass,m/e:415(M+),107(base)
实施例2-2
与实施例2-1同样地操作,得到2-[3-(4-吡啶-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
熔点:190.2-191.6℃
1H-NMR(CDCl3)δ:8.19(ddd,J=0.8Hz,2.0Hz,4.9Hz,1H),7.47(ddd,J=2.0Hz,7.1Hz,8.6Hz,1H),6.65(d,J=8.6Hz,1H),6.61(ddd,J=0.8Hz,4.9Hz,7.1Hz,1H),3.64(t,J=6.9Hz,4H),3.29(t,J=6.9Hz,2H),2.99~2.95(m,2H),2.76~2.72(m,2H),2.63(t,J=5.0Hz,4H),2.59(d,J=6.8Hz,2H),1.90~1.79(m,4H)
IR(KBr)vmax:2932,1666,1594cm-1
Mass,m/e:441(M+),107(base)
实施例2-3
与实施例2-1同样地操作,得到5-甲基-4-氧代-2-[3-(4-吡啶-2-基哌嗪-1-基)丙硫基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸乙酯。
熔点:160.1-161.8℃
1H-NMR(CDCl3)δ:8.19~8.17(m,1H),7.48~7.45(m,1H),6.65(d,J=8.6Hz,1H),6.62(dd,J=4.9Hz,7.1Hz,1H),4.34(q,J=7.1Hz,2H),3.66~3.63(m,4H),3.27~3.20(m,2H),2.84(s,3H),2.73(t,J=5.1H z,4H),2.68(t,J=7.0Hz,2H),2.12~2.06(m,2H),1.39(t,J=7.1Hz,3H)
IR(KBr)vmax:3452,2928,1710,1656,1594cm-1
Mass,m/e:473(M+),107(base)
实施例2-4
与实施例2-1同样地操作,得到5,6-二甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
熔点:224.8-225.9℃
1H-NMR(CDCl3)δ:7.88(d,J=8.8Hz,1H),7.70(d,J=8.6Hz,1H),7.59(dd,J=1.2Hz,8.0Hz,1H),7.54~7.50(m,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.0Hz,1H),6.98(d,J=9.2Hz,1H),3.89~3.80(m,4H),3.29(t,J=6.9Hz,2H),2.67(t,J=4.9Hz,4H),2.62(t,J=6.8Hz,2H),2.43(d,J=0.8Hz,3H),2.43(d,J=0.8Hz,3H),2.08~1.98(m,2H)
IR(KBr)vmax:3056,2916,1678,1616,1552cm-1Mass,m/e:465(M+),157(base)
实施例2-5
与实施例2-1同样地操作,得到2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.0Hz,1H),7.70(d,J=8.0Hz,1H),7.60(d,J=7.8Hz,1H),7.55~7.51(m,1H),7.24~7.18(m,1H),6.99(d,J=9.0Hz,1H),3.89(brs,4H),3.30(t,J=6.8Hz,2H),3.01~2.92(m,2H),2.78~2.70(m,2H),2.66(brs,4H),2.68~2.58(m,2H),1.89~1.78(m,2H),1.59~1.50(m,2H)IR(KBr)vmax:3056,2932,1678,1616,1604,1550,1504cm-1
Mass,m/e:491(M+),157(base)
实施例2-6
与实施例2-1同样地操作,得到5-甲基-4-氧代-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸乙酯。
熔点:200.1-201.4℃
1H-NMR(CDCl3)δ:7.89(d,J=9.1Hz,1H),7.69(d,J=7.8Hz,1H),7.59(dd,J=1.1Hz,7.9Hz,1H).7.53~7.51(m,1H),7.23~7.21(m,1H),6.98(dd,J=2.7Hz,9.2Hz,1H),4.34(q,J=7.1Hz,2H),3.86~3.85(m,4H),3.27(t,J=6.2Hz,2H),2.84(s,3H),2.78~2.76(m,4H),2.70(t,J=7.0Hz,2H),2.12~2.11(m,2H),1.39(t,J=7.1Hz,3H)
IR(KBr)vmax:3464,3048,2936,1712,1662,1604cm-1
Mass,m/e:523(M+),157(base)
实施例2-7
与实施例2-1同样地操作,得到2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-3H-喹唑啉-4-酮。
1H-NMR(DMSO-d6)δ:8.04(dd,J=1.5Hz,8.1Hz,1H),7.78~7.74(m,1H),7.51(d,J=8.1H z,1H),7.45(d,J=8.1Hz,1H),7.43~7.39(m,1H),7.29~7.27(m,1H),7.08~7.05(m,1H),3.59(t,J=5.0Hz,4H),3.27~3.25(m,2H),2.54(t,J=5.0H z,4H),2.51~2.49(m,2H),1.95~1.88(m,2H)
Mass,m/e:437(M+),163,109(base)
实施例2-8
与实施例2-1同样地操作,得到2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.16(dd,J=1.5Hz,8.5Hz,1H),7.88(d,J=8.1Hz,1H),7.70~7.66(m,2H),7.60~7.50(m,3H),7.35(ddd,J=1.1Hz,6.9Hz,8.1Hz,1H),7.21(ddd,J=0.8Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),3.88(t,J=5.0Hz,4H),3.34(t,J=7.0Hz,2H),2.68~2.63(m,6H),2.07~2.04(m,2H)
Mass,m/e:431(M+),157(base)
实施例2-9
与实施例2-1同样地操作,得到5,6-二甲基-2-[3-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.87(dd,J=1.4Hz,2.8Hz,1H),7.79~7.76(m,1H),7.70~7.69(m,2H),7.36~7.28(m,2H),6.82(dd,J=1.4Hz,3.9Hz,1H),6.79~6.78(m,1H),3.85(t,J=4.9Hz,4H),3.29(t,J=7.2Hz,2H),2.72(t,J=4.9Hz,4H),2.63~2.60(m,2H),2.42(s,3H),2.37(s,3H),2.05~2.01(m,2H)
IR(KBr)vmax:2920,2824,1668,1518cm-1
Mass,m/e:504(M+),196(base)
实施例2-10
与实施例2-1同样地操作,得到2-[3-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.87(dd,J=1.2Hz,2.0Hz,1H),7.79~7.76(m,1H),7.69~7.67(m,1H),7.35~7.28(m,1H),6.83~6.82(m,1H),6.78(dd,J=2.8Hz,4.0Hz,1H),3.86~3.84(m,4H),3.29(t,J=7.3Hz,2H),2.94(J=5.9Hz,2H),2.76~2.71(m,6H),2.63~2.60(m,2H),1.89~1.82(m,2H)
IR(KBr)vmax:2936,1664,1518cm-1
Mass,m/e:530(M+),196(base)
实施例2-11
与实施例2-1同样地操作,得到2-[3-(4-苯并噻唑-2-基哌嗪-1-基)丙硫基]-5,6-二甲基-3H-噻吩并[2,3-d]嘧啶-4-酮。
Mass,m/e:471(M+),163(base)
实施例2-12
与实施例2-1同样地操作,得到2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-噻吩并[3,2-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.73(d,J=5.1Hz,1H),7.70(d,J=8.1Hz,1H),7.59(d,J=7.7Hz,1H),7.55~7.51(m,1H),7.26~7.20(m,1H),6.98(d,J=9.2Hz,1H),3.91(t,J=4.8Hz,4H),3.34~3.31(m,2H),2.71~2.65(m,6H),2.08~2.02(m,2H)
Mass,m/e:437(M+),157(base)
实施例2-13
与实施例2-1同样地操作,得到5,6-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁-2-烯基硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.87(d,J=9.2Hz,1H),7.69(d,J=8.6Hz,1H),7.60~7.57(m,1H),7.54~7.50(m,1H),7.23~7.20(m,1H),6.94(d,J=8.9Hz,1H),5.88(q,J=6.4Hz,1H),5.78(q,J=6.7Hz,1H),3.89(d,J=6.7Hz,1H),3.71(t,J=5.1Hz,4H),3.05(d,J=6.4Hz,1H),2.54(t,J=5.1Hz,4H),2.46(s,3H),2.35(s,3H)
Mass,m/e:477(M+),157(base)
实施例2-14
与实施例2-1同样地操作,得到6-丙基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.69(d,J=9.4Hz,1H),7.59(d,J=8.1Hz,1H),7.55~7.51(m,1H),7.24~7.20(m,1H),6.98(d,J=9.2Hz,1H),6.01(s,1H),3.83(t,J=4.8Hz,4H),3.25(t,J=7.0Hz,2H),2.62(t,J=4.8Hz,4H),2.59~2.56(m,2H),1.99(q,J=6.9Hz,2H),1.68(q,J=7.3Hz,2H),0.97(t,J=7.3Hz,3H)
Mass,m/e:423(M+),157(base)
实施例2-15
与实施例2-1同样地操作,得到5,6-二甲基-2-[3-[4-(3-甲基喹喔啉-2-基)哌嗪-1-基]丙基硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(dd,J=1.1Hz,8.1Hz,1H),7.81(dd,J=1.1Hz,8.1Hz,1H),7.57(ddd,J=1.1Hz,6.9Hz,8.1Hz,1H),7.51(ddd,J=1.1Hz,6.9Hz,8.1Hz,1H),3.49(t,J=4.4Hz,4H),3.29(t,J=7.0Hz,2H),2.75(t,J=4.4Hz,4H),2.71(s,3H),2.65(t,J=7.0Hz,2H),2.42(s,3H),2.33(s,3H),2.04(q,J=7.0Hz,2H)
Mass,m/e:480(M+),321,253(base)
实施例2-16
将实施例2-6中合成的105mg 5-甲基-4-氧代-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸乙酯加入到1当量氢氧化钠水溶液中,在70℃-100℃下搅拌1小时。冷却后,用氯仿洗涤,用2当量盐酸中和水层,滤取沉淀物质并干燥,得到100mg(100%)的5-甲基-4-氧代-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸。
1H-NMR(DMSO-d6)δ:8.16(d,J=8.1Hz,1H),7.76(d,J=8.1Hz,1H),7.66~7.75(m,1H),7.60~7.59(m,1H),7.36~7.29(m,2H),4.65~4.64(m,4H),3.64~3.62(m,4H),3.39~3.27(m,7H),2.19~2.16(m,2H)
IR(KBr)vmax:3432,1648,1536cm-1
Mass,m/e:451(M+),157(base)
实施例2-17
与实施例2-16同样地操作,使用实施例2-3中合成的5-甲基-4-氧代-2-[3-(4-吡啶-2-基哌嗪-1-基)丙硫基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸乙酯,得到5-甲基-4-氧代-2-[3-(4-吡啶-2-基哌嗪-1-基)丙硫基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸。
1H-NMR(DMSO-d6)δ:8.11~8.09(m,1H),7.52(ddd,J=1.8Hz,7.0Hz,8.8Hz,1H),6.81(d,J=8.4Hz,1H),6.64~6.61(m,1H),3.53~5.49(m,4H),3.21~3.20(m,2H),2.76(s,3H),2.66~2.54(m,4H),2.52~2.47(m,4H),1.92~1.85(m,2H)
IR(KBr)vmax:3464,2928,1664,1534cm-1
Mass,m/e:445(M+),107(base)
实施例2-18
将实施例2-17中合成的470mg 5-甲基-4-氧代-2-[3-(4-吡啶-2-基哌嗪-1-基)丙硫基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸溶解于20ml叔丁醇中,往其中加入107mg三乙胺,加入305mg DPPA,然后加热回流9小时。减压下馏去溶剂,用硅胶柱色谱法(氯仿∶甲醇=50∶1)纯化残余物。将其加入到6ml 4当量盐酸二噁烷溶液中,搅拌过夜,然后减压下馏去溶剂。再往其中加入氯仿,用饱和碳酸氢钠水溶液洗涤后,用无水硫酸镁干燥并在减压下馏去溶剂。用硅胶柱色谱法(氯仿∶甲醇=25∶1)纯化残余物,得到78mg(18%)的6-氨基-5-甲基-2-[3-(4-吡啶-2-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
实施例2-19
与实施例2-18同样地操作,使用实施例2-16中合成的5-甲基-4-氧代-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸,得到6-氨基-5-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CD3OD)δ:8.02(d,J=9.0Hz,1H),7.69(d,J=8.1Hz,1H),7.57~7.50(m,2H),7.24~7.21(m,2H),5.45(brs,1H)3,34~3.28(m,6H),2.53~2.48(m,4H),2.44(t,J=6.6Hz,2H),1.89~1.81(m,2H)
Mass,m/e:466(M+),157(base)
实施例2-20
与实施例2-1同样地操作,得到2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丙硫基]-3,4,5,6,7,8-六氢-4-氧代-9-硫杂-1,3,7-三氮杂-9H-芴三盐酸盐。
1H-NMR(DMSO-d6)δ:9.62(brs,1H),8.13(d,J=8.1Hz,1H),7.78~7.76(m,1H),7.54~7.51(m,3H),4.83(brs,2H),4.33(s,2H),3.71~3.68(m,4H),3.25~3.24(m,2H),3.13~3.12(m,2H),2.69(s,7H),2.24~2.19(m,2H)
Mass,m/e:506(M+),171(base)
实施例2-21
与实施例2-1同样地操作,得到2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴三盐酸盐。
1H-NMR(DMSO-d6)δ:11.86(brs,1H),9.89(brs,1H),8.50(d,J=9.6Hz,1H),8.42(d,J=8.9Hz,1H),7.95(d,J=8.1Hz,1H),7.80(t,J=7.3Hz,1H),7.61(d,J=9.6Hz,1H),7.53(t,J=7.3Hz,1H),4.91(brs,2H),4.32(brs,2H),3.93~3.87(m,2H),3.36~3.24(m,6H),3.17~3.13(m,2H),2.51~2.49(m,2H),2.21(q,J=7.3Hz,2H)
Mass,m/e:492(M+),157(base)
实施例3:在上述式(I)中,X1表示氢原子,Y为直接键合时的化合物的合成
实施例3-1
步骤3-1-A:将996mg 2-氨基-4,5-二甲基噻吩-3-羧酸乙酯加入到10ml4当量盐酸二噁烷溶液中,往其中滴加972mg 5-溴戊腈。室温下搅拌6小时,然后移到冰水中,用25%氨水中和,滤取沉淀物。用氯仿-乙醇混合溶剂洗涤沉淀物并干燥,得到750mg(48%)的2-(4-溴丁基)-5,6-二甲基-3H-噻吩并[2,3-c]嘧啶-4-酮。
1H-NMR(CDCl3):3.45(t,J=6.3Hz,2H),2.77(t,J=6.3Hz,2H),2.45(d,J=0.6Hz,3H),2.01(s,3H),2.00~1.98(m,4H)
Mass,m/e:314(M+),235(base)
步骤3-1-B:将步骤3-1-A中制备的124mg 2-(4-溴丁基)-5,6-二甲基-3H-噻吩并[2,3-c]嘧啶-4-酮和168mg 2-哌嗪-1基喹啉加入到10ml四氢呋喃中,加热回流2小时。减压下馏去溶剂,用硅胶柱色谱法(氯仿∶甲醇=50∶1)纯化残余物,得到74mg(42%)的5,6-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.69(d,J=8.3Hz,1H),7.59(dd,J=1.3Hz,8.1Hz,1H),7.53(ddd,1.5Hz,6.9Hz,9.9Hz,1H),7.24~7.20(m,1H),6.98(d,J=9.2Hz,1H),3.86~3.84(m,4H),2.75(t,J=7.2Hz,2H),2.63(t,J=5.0Hz,4H),2.51~2.48(m,2H),2.47(d,J=0.6Hz,3H),2.38(d,J=0.6Hz,3H),1.91~1.87(m,2H),1.72~1.64(m,2H)
IR(KBr)vmax:2924,1664,1594cm-1
Mass,m/e:447(M+),157(base)
实施例3-2
与实施例3-1同样地操作,得到5,6-二甲基-2-(4-吡啶-2-基哌嗪-1-基甲基)-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:9.88(brs,1H),8.23(dd,J=1.8Hz,5.4Hz,1H),7.53~7.48(m,1H),6.68~6.62(m,2H),3.62(t,J=4.9Hz,4H),3.59(s,2H),2.69(t,J=5.1Hz,4H),2.49(d,J=0.7Hz,3H),2.39(s,3H)
Mass,m/e:355(M+),107(base)
实施例3-3
与实施例3-1同样地操作,得到5,6-二甲基-2-(4-喹啉-2-基哌嗪-1-基甲基)-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:9.88(brs,1H),7.92(d,J=9.1Hz,1H),7.71(d,J=8.3Hz,1H),7.61(d,J=8.0Hz,1H),7.56~7.53(m,1H),7.26~7.20(m,1H),6.99(d,J=9.1Hz,1H),3.83(t,J=5.0Hz,4H),3.60(s,2H),2.72(t,J=5.0Hz,4H),2.50(d,J=0.6Hz,3H),2.39(s,3H)
Mass,m/e:405(M+),157(base)
实施例3-4
与实施例3-1同样地操作,得到5,6-二甲基-2-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基甲基)-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:9.88(brs,1H),7.83~7.82(m,1H),7.74~7,72(m,1H),7.36~7.28(m,2H),6.78~6.75(m,2H),3.87(t,J=4.9Hz,4H),3.63(s,2H),2.79(t,4.9Hz,4H),2.50(d,J=0.8Hz,3H),2.40(s,3H)
Mass,m/e:444(M+),196(base)
实施例3-5
与实施例3-1同样地操作,得到2-(4-吡啶-2-基哌嗪-1-基甲基)-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:9.86(brs,1H),8.20~8.19(m,1H),7.50(ddd,J=1.8Hz,7.0Hz,8.4Hz,1H),6.67~6.64(m,2H),3.64~3.62(m,4H),3.59(s,2H),3.02~3.01(m,2H),2.78(t,J=5.9Hz,2H),2.69(t,J=5.1Hz,4H),1.92~1.81(m,4H)
Mass,m/e:381(M+),107(base)
实施例3-6
与实施例3-1同样地操作,得到2-(4-喹啉-2-基哌嗪-1-基甲基)-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:9.91(brs,1H),7.92(d,J=9.0Hz,1H),7.71(d,J=8.5Hz,1H),7.61~7.60(m,1H),7.55(ddd,J=1.4Hz,7.1Hz,8.5Hz,1H),7.27~7.23(m,1H),6.99(d,J=9.3Hz,1H),3.38(t,J=4.9Hz,4H),3.62(s,2H),3.03~3.02(m,2H),2.78~2.76(m,2H),2.72(t,J=4.9Hz,4H),1.92~1.82(m,4H)
Mass,m/e:431(M+),157(base)
实施例3-7
与实施例3-1同样地操作,得到2-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基甲基)-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.84~7.83(m,1H),7.74(dd,J=1.7Hz,8.0Hz,1H),7.69(dd,J=1.7Hz,7.7Hz,1H),7.36~7.25(m,2H),6.78~6.76(m,2H),3.03(s,2H),3.03~3.02(m,2H),2.80~2.78(m,6H),1.90~1.85(m,4H)
Mass,m/e:470(M+),196(base)
实施例3-8
与实施例3-1同样地操作,得到2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.69(d,J=8.6Hz,1H),7.56(d,J=7.3Hz,1H),7.54~7.53(m,1H),7.23~7.21(m,1H),6.97(d,J=9.2Hz,1H),3.85~3.83(m,4H),2.78~2.74(m,2H),2.64~2.63(m,4H),2.51~2.47(m,2H),1.99~1.64(m,8H)
Mass,m/e:473(M+),157(base)
实施例3-9
与实施例3-1同样地操作,得到5,6-二甲基-2-[4-(4-吡啶-2-基哌嗪-1-基)丁基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.18(dd,J=1.2Hz,4.9Hz,1H),7.47(ddd,J=1.8Hz,7.3Hz,9.1Hz,1H),6.64(d,J=8.8Hz,1H),6.62~6.60(m,1H),3.63~3.61(m,4H),2.75~2.74(m,4H),2.49~2.45(m,5H),2.38(s,3H),1.92~1.84(m,2H),1.70~1.62(m,2H)
IR(KBr)vmax:2836,1664,1594cm-1
Mass,m/e:397(M+),107(base)
实施例3-10
与实施例3-1同样地操作,得到2-[4-(4-吡啶-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
熔点:192.6-194.4℃
1H-NMR(CDCl3)δ:11.20(brs,1H),8.18(dd,J=1.2Hz,4.9Hz,1H),7.49~7.45(m,1H),6.64(d,J=8.8Hz,1H),6.63~6.60(m,1H),3.62(t,J=5.5Hz,4H),3.01~2.98(m,2H),2.78~2.73(m,4H),2.59(t,J=5.2Hz,4H),2.47(t,J=7.0Hz,2H),1.92~1.82(m,4H),1.69~1.59(m,4H)
IR(KBr)vmax:2928,1664,1954,1482cm-1
Mass,m/e:423(M+),107(base)
实施例3-11
与实施例3-1同样地操作,得到5,6-二甲基-2-[4-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基)丁基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:11.30(brs,1H),7.81(dd,J=1.2Hz,2.7Hz,1H),7.72(dd,J=1.5Hz,8.1Hz,1H),7.67~7.65(m,1H),7.34~7.24(m,2H),6.79~6.74(m,2H),3.90(t,J=4.8Hz,4H),2.76(t,J=7.2Hz,2H),2.67(t,J=4.8Hz,4H),2.51(t,J=6.9Hz,2H),2.48(s,3H),2.38(s,3H),1.94~1.86(m,2H),1.72~1.65(m,2H)
Mass,m/e:486(M+),196(base)
实施例3-12
与实施例3-1同样地操作,得到5,6-二甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:12.92(brs,1H),7.99(d,J=9.3Hz,1H),7.69(d,J=8.1Hz,1H),7.60(dd,J=1.5Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.25~7.21(m,1H),6.99(d,J=9.3Hz,1H),4.02(t,J=5.0Hz,4H),2.89(t,J=6.2Hz,2H),2.74(t,J=5.0Hz,4H),2.60~2.57(m,2H),2.45(s,3H),2.37(d,J=0.8Hz,3H),2.01(t,J=6.2Hz,2H)
Mass,m/e:433(M+),153(base)
实施例3-13
与实施例3-1同样地操作,得到7-乙氧基羰基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.87(d,J=8.9Hz,1H),7.68(d,J=8.5Hz,1H),7.58(dd,J=1.2Hz,8.1Hz,1H),7.51(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.21(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.96(d,J=9.2Hz,1H),4.67(brs,2H),4.18(q,J=6.9Hz,2H),3.81(t,J=5.0Hz,4H),3.76~3.72(m,2H),3.10(brs,2H),2.78(t,J=7.3Hz,2H),2.60(t,J=5.0Hz,4H),2.47(t,J=6.9Hz,2H),1.98~1.86(m,2H),1.70~1.63(m,4H)
Mass,m/e:546(M+),157(base)
实施例3-14
与实施例3-1同样地操作,得到7-苄氧基羰基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.87(d,J=8.9Hz,1H),7.68(d,J=8.5Hz,1H),7.58(d,J=8.1Hz,1H),7.53~7.49(m,1H),7.36~7.29(m,5H),7.23~7.19(m,1H),6.96(d,J=9.2Hz,1H),5.17(s,2H),4.69(s,2H),3.82(t,J=5.0Hz,4H),3.79~3.75(m,2H),3.11(brs,2H),2.76(t,J=6.9Hz,2H),2.61(t,J=5.1Hz,4H),2.49~2.46(m,2H),1.87(q,J=7.3Hz,2H),1.70~1.64(m,4H)
Mass,m/e:395,304(base),91
实施例3-15
将60mg 3-氨基-7-叔丁氧基羰基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮溶解于5ml乙酸和2ml水的混合液中,在冰冷却下,往其中滴加10mg亚硝酸钠在2ml水中的溶液。搅拌30分钟后,用饱和碳酸氢钠水溶液中和,用氯仿萃取所得沉淀物并水洗,用无水硫酸镁干燥,然后减压下馏去溶剂。用硅胶柱色谱法纯化残余物,得到52mg(99%)的7-乙酰基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:11.54(brs,1H),7.88(d,J=9.2Hz,1H),7.68(d,J=8.5Hz,1H),7.58(dd,J=1.5Hz,8.5Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.21(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),6.97(d,J=9.2Hz,1H),4.79(brs,2H),3.83~3.81(m,4H),3.73(t,J=7.0Hz,2H),3.17~3.12(m,2H),2.81~2.73(m,2H),2.65~2.60(m,4H),2.49(t,J=6.4Hz,2H),2.19(s,3H),1.89(q,J=7.0Hz,2H),1.67(q,J=7.0Hz,2H)
Mass,m/e:516(M+),372,157(base)
实施例3-16
往实施例3-14中合成的100mg 7-苄氧基羰基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴中加入5ml溴化氢乙酸溶液,在室温下进行搅拌。用饱和碳酸氢钠水溶液中和后,用氯仿萃取,用无水硫酸镁干燥后浓缩,得到78mg(100%)的2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。
1H-NMR(DMSO-d6)δ:8.01(d,J=9.2Hz,1H),7.68(d,J=8.5Hz,1H),7.54~7.49(m,2H),7.35~7.32(m,1H),7.29~7.20(m,1H),4.03(brs,2H),3.77~3.66(m,4H),3.12~3.10(m,2H),2.93(brs,2H),2.67~2.64(m,2H),2.49~2.46(m,4H),2.36(t,J=7.0Hz,2H),1.76~1.70(m,2H),1.55~1.50(m,2H)
Mass,m/e:157(base),128
实施例3-17
首先,与实施例3-1同样地操作,得到7-苄氧基羰基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。其次,使用该化合物,与实施例3-16同样地操作,合成2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴三氢溴酸盐。
1H-NMR(DMSO-d6)δ:12.47(s,1H),10.16(s,1H),9.20(s,2H),8.12(d,J=8.1Hz,1H),8.05(d,J=8.5Hz,1H),7.86~7.82(m,1H),7.63(brs,1H),7.60~7.56(m,1H),4.77~4.74(m,2H),4.62~4.21(m,6H),3.79~3.74(m,4H),3.16~3.13(m,2H),2.72(s,3H),2.59~2.49(m,4H)
Mass,m/e:488(M+),171(base)
实施例3-18
与实施例1-62同样地操作,使用实施例3-17中合成的2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴,得到7-乙酰基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴。
1H-NMR(CDCl3)δ:7.75(d,J=7.7Hz,1H),7.70(d,J=8.5Hz,1H),7.54~7.50(m,1H),7.23~7.22(m,2H),6.83(s,1H),4.77(brs,4H),3.78~3.72(m,6H),3.19(t,J=7.3Hz,2H),3.13~3.04(m,2H),2.61~2.53(m,6H),2.59(s,3H),2.20(s,3H),1.98(q,J=6.9Hz,2H)
Mass,m/e:225,171(base),142
实施例4:在上述式(I)中,X1表示氨基、低级烷基氨基、二低级烷基氨基或低级亚烷基氨基,Y为直接键合时的化合物的合成
实施例4-1
步骤4-1-A:往7当量氨甲醇溶液中加入170g 2-氧代环己烷羧酸乙酯,在室温下搅拌过夜。将减压下馏去溶剂而得到的粗结晶在乙酸乙酯-正己烷中重结晶,得到152g(90%)的2-氨基-环己-1-烯羧酸乙酯。
1H-NMR(CDCl3):4.14(q,J=7.3Hz,2H),2.25(d,J=5.9Hz,2H),2.20(d,J=5.9Hz,2H),1.67~1.56(m,4H)
Mass,m/e:169(M+),96(base)
步骤4-1-B:将上述步骤4-1-A中合成的42.3g 2-氨基环己-1-烯羧酸乙酯溶解于150ml四氢呋喃中,加入40g吡啶,冰冷却下,往其中滴加5-溴戊酰氯。在室温下搅拌过夜,再往其中加入乙酸乙酯,用饱和碳酸氢钠水溶液、10%柠檬酸水溶液和饱和食盐水洗涤,然后用无水硫酸镁干燥并在减压下馏去溶剂。用硅胶柱色谱法(正己烷∶乙酸乙酯=8∶1)纯化残余物,得到76.6g(92%)的2-(5-溴戊酰基氨基)环己-1-烯羧酸乙酯。
1H-NMR(CDCl3):11.62(brs,1H),4.22~4.09(m,2H),3.42(t,J=6.9Hz,2H),2.97~2.94(m,2H),2.34(t,J=7.0Hz,2H),2.32~2.23(m,2H),1.94~1.88(m,2H),1.85~1.79(m,2H),1.65~1.56(m,4H),1.30(t,J=7.0Hz,3H)
Mass,m/e:333(M+),55(base)
步骤4-1-C:将上述步骤4-1-B中合成的66.5g2-(5-溴戊酰基氨基)环己-1-烯羧酸乙酯、46.9g 2-哌嗪-1-基喹啉和22.3g三乙胺溶解于350ml甲苯中并加热回流过夜。减压下馏去溶剂,往其中加入乙酸乙酯,用饱和碳酸氢钠水溶液洗涤。用无水硫酸镁干燥有机层,然后在减压下馏去溶剂。用硅胶柱色谱法(正己烷∶乙酸乙酯∶甲醇=1∶6∶0.2)纯化残余物,得到79.8g(86%)的2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]环己-1-烯羧酸乙酯。
1H-NMR(CDCl3):11.61(brs,1H),7.87(d,J=9.2Hz,1H),7.69(d,J=8.5Hz,1H),7.58~7.56(m,1H),7.51(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.20(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.97(d,J=9.2Hz,1H),4.16(q,J=6.9Hz,2H),3.74(t,J=5.0Hz,4H),2.97(t,J=5.0Hz,2H),2.56(t,J=5.0Hz,4H),2.43~2.90(m,6H),1.74~1.70(m,2H),1.68(m,4H),1.28(t,J=6.9Hz,2H)
Mass,m/e:464(M+),157(base)
步骤4-1-D:将上述步骤4-1-C中合成的8.0g2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]环己-1-烯羧酸乙酯溶解于120ml乙醇中,加入60ml一水合肼,加热回流4小时。减压下馏去溶剂,将其溶解于氯仿中,用饱和碳酸氢钠水溶液和饱和食盐水洗涤,用无水硫酸镁干燥。减压下馏去溶剂,用硅胶柱色谱法(氯仿∶甲醇∶=50∶1)纯化残余物,得到3.8g(51%)的3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.87(d,J=9.3Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=7.7Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,7.5Hz,1H),7.25~7.19(m,1H),6.97(d,J=8.9Hz,1H),4.93(s,2H),3.74(t,J=5.0Hz,4H),2.92(t,J=7.7Hz,2H),2.58~2.55(m,6H),2.52~2.49(m,2H),2.44(t,J=7.3Hz,2H),1.81~1.63(m,8H)
Mass,m/e:432(M+),157(base)
实施例4-2
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.74(d,J=8.5Hz,1H),7.69(d,J=8.5Hz,1H),7.51(ddd,J=1.2Hz,7.0Hz,8.1Hz,1H),7.22(d,J=8.1Hz,1H),6.82(s,1H),4.94(s,2H),3.74(t,J=5.0Hz,4H),2.92(t,J=7.3Hz,2H),2.57(s,3H),2.56~2.54(m,6H),2.53~2.50(m,2H),2.44(t,J=7.3Hz,2H),1.82~1.62(m,8H)
Mass,m/e:446(M+),171(base)
实施例4-3
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.24(dd,J=1.2Hz,8.1Hz,1H),7.88(d,J=8.9Hz,1H),7.73(ddd,J=1.6Hz,6.9Hz,8.5Hz,1H),7.71~7.65(m,2H),7.59(dd,J=1.2Hz,7.9Hz,1H),7.52(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.44(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.21(ddd,J=1.2Hz,6.4Hz,8.1Hz,1H),6.97(d,J=9.2Hz,1H),4.91(s,2H),3.75(t,J=4.8Hz,4H),3.07(t,J=7.7Hz,2H),2.58(t,J=5.0Hz,4H),2.48(t,J=7.3Hz,2H),1.95~1.87(m,2H),1.76~1.69(m,2H)
Mass,m/e:428(M+),157(base)
实施例4-4
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.24(dd,J=1.5Hz,8.1Hz,1H),7.77~7.65(m,4H),7.51(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.47~7.42(m,1H),7.23~7.21(m,1H),6.83(s,1H),4.91(s,2H),3.74(t,J=5.0Hz,4H),3.07(t,J=7.3Hz,2H),2.58(t,J=5.4Hz,4H),2.48(t,J=7.3Hz,2H),1.91(q,J=7.7Hz,2H),1.74(q,J=7.7Hz,2H)
Mass,m/e:428(M+),157(base)
实施例4-5
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(3-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.83(d,J=8.5Hz,1H),7.77(s,1H),7.60(d,J=8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.31(ddd,J=1.1Hz,6.9Hz,8.1Hz,1H),4.98(s,2H),3.35~3.33(m,4H),2.93(t,J=7.3Hz,2H),2.64(brs,4H),2.59(t,J=6.2Hz,2H),2.53~2.50(m,2H),2.47(t,J=7.3Hz,2H),2.42(d,J=0.8Hz,3H),1.83~1.65(m,8H)
Mass,m/e:446(M+),171(base)
实施例4-6
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(3,4-二甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.87(d,J=7.3Hz,1H),7.83(d,J=7.3Hz,1H),7.53(t,J=8.1Hz,1H),7.37~7.35(m,1H),4.99(s,2H),3.27(brs,4H),2.93(t,J=7.7Hz,2H),2.64(brs,4H),2.59(t,J=5.8Hz,2H),2.55(s,3H),2.52(t,J=6.2Hz,2H),2.47~2.46(m,2H),2.37(s,3H),1.81~1.67(m,8H)
Mass,m/e:460(M+),185(base)
实施例4-7
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(2,3-二氢-1H-环戊二烯并[c]喹啉-4-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.80(d,J=8.5Hz,1H),7.64(d,J=8.1Hz,1H),7.53~7.49(m,1H),7.30~7.26(m,1H),4.96(s,2H),3.57(brs,4H),3.17(t,J=7.3Hz,2H),3.04(t,J=7.3Hz,2H),2.93(t,J=7.7Hz,2H),2.60~2.57(m,6H),2.52(t,J=6.2Hz,2H),2.47~2.44(m,2H),2.22(q,J=7.3Hz,2H),1.82~1.65(m,8H)
Mass,m/e:472(M+),197(base)
实施例4-8
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(7,8,9,10-四氢菲啶-6-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.84~7.80(m,2H),7.53(t,J=8.1Hz,1H),7.37~7.33(m,1H),4.99(s,2H),3.31(brs,4H),3.10(t,J=6.6Hz,2H),2.95~2.91(m,2H),2.76(t,J=5.8Hz,2H),2.62(brs,4H),2.60~2.57(m,2H),2.52(t,J=6.2Hz,2H),2.49~2.45(m,2H),1.98~1.93(m,2H),1.82~1.65(m,10H)
Mass,m/e:486(M+),211(base)
实施例4-9
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(3,4-二甲基喹啉-2-基)哌嗪-1-基]丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.25~8.23(m,1H),7.87(dd,J=1.2Hz,8.5Hz,1H),7.85~7.82(m,1H),7.66(d,J=7.7Hz,1H),7.53(ddd,J=1.2Hz,6.9Hz,8.5Hz,1H),7.44(ddd,J=1.2Hz,6.9Hz,8.0Hz,1H),7.35(ddd,J=1.2Hz,6.9Hz,8.0Hz,1H),7.33(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),4.95(s,2H),3.28(brs,4H),3.10~3.06(m,2H),2.65(brs,4H),2.55(s,3H),2.53~2.49(m,2H),2.37(s,3H),1.95~1.88(m,2H),1.77~1.69(m,2H)
Mass,m/e:456(M+),185(base)
实施例4-10
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(2,3-二氢-1H-环戊二烯并[c]喹啉-4-基)哌嗪-1-基]丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.24(dd,J=1.2Hz,8.1Hz,1H),7.80(d,J=8.1Hz,1H),7.73(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.67~7.63(m,2H),7.51(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.47~7.42(m,2H),7.28(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),4.93(s,2H),3.58(brs,4H),3.19~3.15(m,2H),3.10~3.03(m,4H),2.62(brs,4H),2.49(t,J=7.3Hz,2H),2.23(q,J=7.3Hz,2H),1.91(q,J=7.7Hz,2H),1.75~1.71(m,2H)
Mass,m/e:468(M+),197(base)
实施例4-11
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(7,8,9,10-四氢菲啶-6-基)哌嗪-1-基]丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.24(dd,J=1.5Hz,8.5Hz,1H),7.84~7.80(m,2H),7.73(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.67(d,J=8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.44(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.35(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),4.95(s,2H),3.32(brs,4H),3.11~3.06(m,4H),2.76(t,J=5.8Hz,2H),2.64(brs,4H),2.51(t,J=7.3Hz,2H),2.00~1.88(m,2H),1.79~1.71(m,2H)
Mass,m/e:482(M+),211(base)
实施例4-12
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-吡啶并[3,2-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.83(dd,J=1.5Hz,4.2Hz,1H),8.01(dd,J=1.5Hz,8.5Hz,1H),7.88(d,J=9.2Hz,1H),7.70~7.64(m,2H),7.58(d,J=2.1Hz,1H),7.54~7.50(m,1H),7.23~7.19(m,1H),6.97(d,J=8.9Hz,1H),5.03(s,2H),3.76(t,J=5.0Hz,4H),3.10(t,J=7.3Hz,2H),2.59(t,J =5.0Hz,4H),2.48(t,J=7.3Hz,2H),1.92(q,J=7.7Hz,2H),1.76~1.71(m,2H)
Mass,m/e:429(M+),157(base)
实施例4-13
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.24(dd,J=1.2Hz,7.7Hz,1H),7.80(m,1H),7.75~7.73(m,1H),7.72(dd,J=1.5Hz,5.4Hz,1H),7.67~7.66(m,1H),7.65~7.64(m,1H),7.46~7.43(m,1H),7.33~7.28(m,1H),7.27~7.23(m,1H),6.77(dd,J=1.2Hz,3.9Hz,1H),6.75~6.73(m,1H),4.91(s,2H),3.82(t,J=5.0Hz,4H),3.08(t,J=7.7Hz,2H),2.65(t,J=5.0H z,4H),2.50(t,J=7.3Hz,2H),1.91(q,J=7.7Hz,2H),1.77~1.69(m,2H)
Mass,m/e:429(M+),157(base)
实施例4-14
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基)丁基]-3H-吡啶并[3,2-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.84(dd,J=1.5Hz,4.2Hz,1H),8.00(dd,J=1.5Hz,6.1Hz,1H),7.80(dd,J=1.5Hz,2.7Hz,1H),7.71(dd,J=1.5Hz,8.1Hz,1H),7.66(dd,J=1.5Hz,3.1Hz,1H),7.65~7.64(m,1H),7.33~7.22(m,2H),6.77~6.73(m,2H),5.04(s,2H),3.82(t,J=5.0Hz,4H),3.10(t,J=7.7Hz,2H),2.65(t,J=5.0Hz,4H),2.51(t,J=7.3Hz,2H),1.92(q,J=7.3Hz,2H),1.73(q,J=7.3Hz,2H)
Mass,m/e:468(M+),196(base)
实施例4-15
与实施例4-1同样地操作,得到3-氨基-7-氯-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.16(d,J=8.5Hz,1H),7.88(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.67(d,J=1.9Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.1Hz,1H),7.43(d,J=1.9Hz,1H),7.38(d,J=2.3Hz,1H),7.21(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.97(d,J=9.2Hz,1H),4.89(s,2H),3.76(t,J=5.0Hz,4H),3.06(t,J=7.3Hz,2H),2.58(t,J=5.0Hz,4H),2.48(t,J=7.3Hz,2H),1.90(q,J=7.7Hz,2H),1.71(q,J=7.3Hz,2H)
Mass,m/e:462(M+),157(base)
实施例4-16
与实施例4-1同样地操作,得到3-氨基-6-溴-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.37(d,J=2.3Hz,1H),7.88(d,J=9.3Hz,1H),7.80(dd,J=2.3Hz,8.9Hz,1H),7.79(d,J=8.5Hz,1H),7.58(d,J=7.7Hz,1H),7.54~7.50(m,2H),7.23~7.19(m,1H),6.97(d,J=9.2Hz,1H),4.91(s,2H),3.75(t,J=5.0Hz,4H),3.06(t,J=7.7Hz,2H),2.58(t,J=5.0Hz,4H),2.48(t,J=7.3Hz,2H),1.90(t,J=7.3Hz,2H),1.71(t,J=7.7Hz,2H)
Mass,m/e:506(M+),157(base)
实施例4-17
与实施例4-1同样地操作,得到3-氨基-6,7,8-三甲氧基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.87(d,J=9.2Hz,1H),7.69(d,J=8.5Hz,1H),7.58(dd,J=1.2Hz,8.5Hz,1H),7.58(ddd,J=1.5Hz,7.0Hz,8.5Hz,1H),7.38(s,1H),7.21(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.97(d,J=9.2Hz,1H),4.91(s,2H),4.08(s,3H),4.02(s,3H),3.96(s,3H),3.75(t,J=5.0Hz,4H),3.07(t,J=7.7Hz,2H),2.58(t,J=5.0Hz,4H),2.47(t,J=7.7Hz,2H),1.92(q,J=7.7Hz,2H),1.72(q,J=7.7Hz,2H)
Mass,m/e:157(base)
实施例4-18
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-噻吩并[3,2-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.76(d,J=5.0Hz,1H),7.69(d,J=7.3Hz,1H),7.58(dd,J=1.5Hz,8.0Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.1Hz,1H),7.27(d,J=5.4Hz,1H),7.21(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.97(d,J=9.2Hz,1H),4.94(s,2H),3.75(t,J=5.0Hz,4H),3.08(t,J=7.7Hz,2H),2.58(t,J=5.0Hz,4H),2.47(t,J=7.7Hz,2H),1.89(q,J=7.7Hz,2H),1.71(q,J=7.7Hz,2H)
Mass,m/e:434(M+),157(base)
实施例4-19
与实施例4-1同样地操作,得到3-氨基-8-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.08(dd,J=0.8Hz,8.1Hz,1H),7.88(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.58(ddd,J=1.5Hz,6.2Hz,7.7Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.32(t,J=7.7Hz,1H),7.23~7.19(m,1H),6.97(d,J=9.2Hz,1H),4.88(s,2H),3.76(t,J=5.0Hz,4H),3.07(t,J=7.7Hz,2H),2.59(t,J=5.4Hz,4H),2.50(t,J=7.7Hz,2H),1.95(q,J=7.3Hz,2H),1.77~1.73(m,2H)
Mass,m/e:442(M+),157(base)
实施例4-20
与实施例4-1同样地操作,得到3-氨基-6-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.02(s,1H),7.88(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.59~7.50(m,4H),7.23~7.19(m,1H),6.97(d,J=9.2Hz,1H),4.90(s,2H),3.75(t,J=5.0Hz,4H),3.06(t,J=1.7Hz,2H),2.58(t,J=5.0Hz,4H),2.49~2.44(m,2H),2.48(s,3H),1.90(q,J=7.7Hz,2H),1.72(q,J=7.7Hz,2H)
Mass,m/e:442(M+),157(base)
实施例4-21
与实施例4-1同样地操作,得到3-氨基-5-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.08(d,J=8.1Hz,1H),7.88(d,J=9.2Hz,1H),7.69(d,J=8.1Hz,1H),7.59~7.54(m,2H),7.54~7.50(m,1H),7.32(t,J=7.7Hz,1H),7.23~7.20(m,1H),6.97(d,J=9.2Hz,1H),4.89(s,2H),3.75(t,J=5.0Hz,4H),3.07(t,J=7.3Hz,2H),2.61(s,3H),2.58(t,J=5.0Hz,4H),2.49(t,J=7.7Hz,2H),1.93(q,J=7.7Hz,2H),1.77~1.70(m,2H)
Mass,m/e:442(M+),157(base)
实施例4-22
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(5-甲氧基喹啉-2-基)哌嗪-1-基]丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.28(d,J=10.0Hz,1H),8.25~8.23(m,1H),7.66(d,J=8.1Hz,1H),7.47~7.40(m,2H),7.32(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.29(d,J=8.5Hz,1H),6.91(d,J=9.2Hz,1H),6.56(d,J=6.9Hz,1H),4.91(s,2H),3.94(s,3H),3.75(t,J=5.0Hz,4H),3.07(t,J=7.7Hz,2H),2.58(t,J=5.1Hz,4H),2.48(t,J=7.7Hz,2H),1.91(q,J=7.7Hz,2H),1.76~1.69(m,2H)
Mass,m/e:458(M+),187(base)
实施例4-23
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.79(d,J=8.4Hz,1H),7.58(d,J=8.1Hz,1H),7.52(m,1H),7.42(d,J=5.8,1H),7.23~7.18(m,2H),6.97(d,J=9.2Hz,1H),6.56(d,J=6.9Hz,1H),4.93(s,2H),3.75(t,J=5.0Hz,4H),3.07(t,J=7.7H z,2H),2.58(t,J=5.0Hz,4H),2.48(t,J=7.7H z,2H),1.89~1.87(m,2H),1.72~1.70(m,2H)
Mass,m/e:434(M+),157(base)
实施例4-24
与实施例4-1同样地操作,得到3-氨基-8-氯-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.16(dd,J=1.5Hz,8.1Hz,1H),7.88(d,J=9.2Hz,1H),7.81(dd,J=1.5Hz,8.1Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=7.7Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.38~7.34(m,1H),7.23~7.19(m,1H),6.97(d,J=9.2Hz,1H),4.93(s,2H),3.76(t,J=5.0Hz,4H),3.12(t,J=7.7Hz,2H),2.60(t,J=5.0Hz,4H),2.50(t,J=7.7Hz,2H),1.95(q,J=7.7Hz,2H),1.75(q,J=7.7Hz,2H)
Mass,m/e:462(M+),157(base)
实施例4-25
与实施例4-1同样地操作,得到3-氨基-5-氯-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.69(d,J=8.5Hz,1H),7.59~7.50(m,4H),7.44(dd,J=2.7Hz,6.6Hz,1H),7.23~7.19(m,1H),6.97(d,J=8.9Hz,1H),4.86(s,2H),3.76(t,J=5.0Hz,4H),3.05(t,J=7.7Hz,2H),2.59(t,J=5.0Hz,4H),2.48(t,J=7.7Hz,2H),1.89(q,J=7.7Hz,2H),1.75~1.69(m,2H)
Mass,m/e:462(M+),157(base)
实施例4-26
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-苯并[g]喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.87(s,1H),8.17(s,1H),8.05(d,J=7.7Hz,1H),7.97(d,J=8.1Hz,1H),7.88(d,J=8.3Hz,1H),7.69(d,J=8.5Hz,1H),7.62~7.58(m,2H),7.55~7.51(m,2H),7.24~7.20(m,1H),6.98(d,J=9.2Hz,1H),4.87(s,2H),3.77(t,J=5.0Hz,4H),3.11(t,J=7.7Hz,2H),2.60(t,J=5.0Hz,4H),2.51(t,J=7.7Hz,2H),1.96(q,J=7.7Hz,2H),1.76(q,J=7.7Hz,2H)
Mass,m/e:478(M+),157(base)
实施例4-27
与实施例4-1同样地操作,得到3-氨基-8-氟-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.69(d,J=8.9Hz,1H),7.66~7.62(m,1H),7.59(d,J=8.1Hz,1H),7.54~7.51(m,1H),7.45(d,J=8.5Hz,1H),7.23~7.19(m,1H),7.11~7.06(m,1H),6.97(d,J=8.9Hz,1H),4.86(s,2H),3.76(brs,4H),3.06(t,J=7.7Hz,2H),2.59(brs,4H),2.50~2.46(m,2H),1.92~1.87(m,2H),1.72~1.70(m,2H)
Mass,m/e:446(M+),157(base)
实施例4-28
与实施例4-1同样地操作,得到3-氨基-5-肼基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:9.15(s,2H),7.88(d,J=9.2Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=8.5Hz,1H),7.55~7.50(m,2H),7.23~7.19(m,1H),7.00(d,J=7.3Hz,1H),6.97(d,J=8.9Hz,1H),6.87~6.85(m,1H),4.73(s,2H),3.76~3.74(m,4H),3.63(s,2H),3.00(t,J=7.7Hz,2H),2.58(t,J=5.0Hz,4H),2.47(t,J=7.3Hz,2H),1.87(q,2H),1.72~1.68(m,2H)
Mass,m/e:446(M+),157(base)
实施例4-29
与实施例4-1同样地操作,得到3-氨基-7-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.11(d,J=8.5Hz,1H),7.88(d,J=9.2Hz,1H),7.69(d,J=8.1Hz,1H),7.58(d,J=7.0Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.27(m,1H),7.23~7.19(m,2H),6.97(d,J=9.2Hz,1H),4.88(s,2H),3.76(t,J=5.0Hz,4H),3.07~3.04(m,2H),2.61(s,3H),2.58(t,J=5.0Hz,4H),2.49~2.46(m,2H),2.48(s,3H),1.90(q,J=7.7Hz,2H),1.72(q,J=7.7Hz,2H)
Mass,m/e:442(M+),157(base)
实施例4-30
与实施例4-1同样地操作,得到3-氨基-5-甲基-4-氧代-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸乙酯。
1H-NMR(CDCl3)δ:7.88(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=8.1Hz,1H),7.54~7.52(m,1H),7.23~7.21(m,1H),6.97(d,J=9.2Hz,1H),4.88(s,2H),3.75(t,J=5.0Hz,4H),3.06(t,J=5.0Hz,2H),2.93(s,3H),2.58(t,J=5.0Hz,4H),2.48~2.45(m,2H),1.88~1.86(m,2H),1.71~1.69(m,2H),1.39(t,J=6.9Hz,3H)
Mass,m/e:520(M+),157(base)
实施例4-31
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(5-甲氧基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.28(d,J=9.6Hz,1H),7.44~7.40(m,1H),7.28(d,J=7.7Hz,1H),6.92(d,J=9.2Hz,1H),6.58(d,J=7.3Hz,1H),4.94(s,2H),3.98(s,3H),3.75(t,J=5.0Hz,4H),2.94~2.90(s,3H),2.60~2.55(m,6H),2.44(t,J=7.7Hz,2H),1.83~1.60(m,8H)
Mass,m/e:462(M+),187(base)
实施例4-32
与实施例4-1同样地操作,得到3-氨基-6-苯基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.8Hz,1H),7.79(d,J=8.4Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.34~7.19(m,6H),6.98(d,J=9.2Hz,1H),4.96(s,2H),3.76(t,J=5.0Hz,4H),2.95(t,J=7.7Hz,2H),2.75(m,2H),2.58(t,J=5.0Hz,4H),2.46(t,J=7.3Hz,2H),2.16~2.12(m,1H),1.96~1.61(m,8H)
Mass,m/e:508(M+),157(base)
实施例4-33
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(4,8-二甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.63(d,J=8.1Hz,1H),7.40(d,J=6.9Hz,1H),7.15~7.12(m,1H),6.82(s,1H),4.95(s,2H),3.75(t,J=5.0Hz,4H),2.93(t,J=7.7Hz,2H),2.64(s,3H),2.60~2.56(m,6H),2.58(s,3H),2.53~2.50(m,2H),2.44(t,J=7.3Hz,2H),1.84~1.61(m,8H)
Mass,m/e:460(M+),185(base)
实施例4-34
与实施例4-1同样地操作,得到3-氨基-2-[4-[4-(4,8-二甲基喹啉-2-基)哌嗪-1-基]丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.24(dd,J=1.2Hz,8.1Hz,1H),7.76~7.71(m,1H),7.66(d,J=7.7Hz,1H),7.62(d,J=7.7Hz,1H),7.47~7.43(m,1H),7.40(d,J=6.9Hz,1H),7.15~7.12(m,1H),6.82(s,1H),4.92(s,2H),3.75(t,J=5.0Hz,4H),3.08(t,J=7.7Hz,2H),2.64(s,3H),2.60~2.58(m,4H),2.58(s,3H),2.48(t,J=7.7Hz,2H),1.93~1.87(m,2H),1.75~1.71(m,2H)
Mass,m/e:456(M+),185(base)
实施例4-35
与实施例4-1同样地操作,得到3-氨基-5,6-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.79(d,J=8.1Hz,1H),7.58(dd,J=1.2Hz,8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.23~7.19(m,1H),6.97(d,J=9.2Hz,1H),4.88(s,2H),3.76(t,J=5.0Hz,4H),3.04(t,J=7.7Hz,2H),2.57(t,J=5.0Hz,4H),2.46~2.44(m,2H),2.46(d,J=0.8Hz,3H),2.37(d,J=0.8Hz,3H),1.88~1.82(m,2H),1.72~1.66(m,2H)
Mass,m/e:462(M+),157(base)
实施例4-36
与实施例4-1同样地操作,得到3-氨基-8-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.9Hz,1H),7.69(d,J=7.7Hz,1H),7.58(d,J=8.1Hz,1H),7.54~7.50(m,1H),7.23~7.19(m,1H),6.97(d,J=9.0Hz,1H),4.92(s,2H),3.75(t,J=5.0Hz,4H),2.92(t,J=7.7Hz,2H),2.66~2.65(m,1H),2.57(t,J=5.0Hz,4H),2.56~2.40(m,4H),1.87~1.57(m,11H)
Mass,m/e:446(M+),157(base)
实施例4-37
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,5a,6,7,8,9,9a,10-八氢-3H-苯并[g]喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.9Hz,1H),7.69(d,J=8.9Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.23~7.19(m,1H),6.97(d,J=9.2Hz,1H),4.93(s,2H),3.75(t,J=5.0Hz,4H),2.95~2.90(m,2H),2.64~2.57(m,8H),2.45(t,J=7.7Hz,2H),2.04~1.98(m,2H),1.83~1.40(m,14H)
Mass,m/e:486(M+),157(base)
实施例4-38
与实施例4-1同样地操作,得到3-氨基-5,7-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.69(d,J=8.1Hz,1H),7.58(d,J=7.7Hz,1H),7.54~7.50(m,1H),7.23~7.19(m,1H),6.97(d,J=9.2Hz,1H),4.93(s,2H),3.75(t,J=5.0Hz,4H),2.91(t,J=7.7Hz,2H),2.57(m,6H),2.44(t,J=7.7Hz,2H),2.27~2.22(m,1H),2.03~1.98(m,1H),1.84~1.63(m,6H),1.30(d,J=6.6Hz,3H),1.03(d,J=6.6Hz,3H)
Mass,m/e:460(M+),157(base)
实施例4-39
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7-三氢-3H-环戊二烯并[d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.3Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=7.7Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.21(ddd,J=1.2Hz,7.0Hz,8.1Hz,1H),6.97(d,J=9.2Hz,1H),4.97(s,2H),3.75(t,J=5.0Hz,4H),2.97(t,J=7.7Hz,2H),2.86~2.80(m,4H),2.57(t,J=5.0Hz,4H),2.45(t,J=7.5Hz,2H),2.08(t,J=7.7Hz,2H),1.84~1.78(m,2H),1.70~1.61(m,2H)
Mass,m/e:418(M+),402,157(base)
实施例4-40
与实施例4-1同样地操作,得到3-氨基-8-甲氧基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.87(d,J=9.2Hz,1H),7.81(dd,J=0.8Hz,8.1Hz,1H),7.69(d,J=8.4Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.39~7.36(m,1H),7.22~7.20(m,1H),7.17(d,J=6.9Hz,1H),6.97(d,J=9.2Hz,1H),4.96(s,2H),4.00(s,3H),3.75(t,J=4.6Hz,4H),3.12(t,J=8.1Hz,2H),2.58(t,J=5.0Hz,4H),2.47(t,J=7.3Hz,2H),1.94~1.86(m,2H),1.75~1.68(m,2H)
Mass,m/e:458(M+),442,157(base)
实施例4-41
与实施例4-1同样地操作,得到3-氨基-6,7-二甲氧基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.3Hz,1H),7.69(d,J=8.1Hz,1H),7.59(d,J=8.1Hz,1H),7.53(s,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.06(s,1H),6.97(d,J=9.2Hz,1H),4.90(s,2H),3.99(brs,6H),3.75(m,4H),3.05(t,J=7.7Hz,2H),2.63(m,4H),2.51(t,J=6.9Hz,2H),1.92~1.86(m,2H),1.78~1.71(m,2H)
Mass,m/e:488(M+),472,157(base)
实施例4-42
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8,9-五氢-3H-芳庚并[d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.3Hz,1H),7.69(d,J=8.1Hz,1H),7.58(d,J=9.1Hz,1H),7.52(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.22~7.20(m,1H),6.97(d,J=9.3Hz,1H),5.00(s,2H),3.75(t,J=5.0Hz,4H),2.91(t,J=7.3Hz,2H),2.75(t,J=8.5Hz,2H),2.58(t,J=5.0Hz,4H),2.45(t,J=7.3Hz,2H),1.83~1.78(m,4H),1.70~1.60(m,6H)
Mass,m/e:446(M+),430,157(base)
实施例4-43
与实施例4-1同样地操作,得到4-氨基-12-甲基-5-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-4,6,12-三氮杂-三环[7.2.1.0*2,7*]十二碳-2(7),5-二烯-3-酮。
1H-NMR(CDCl3)δ:7.87(d,J=9.2Hz,1H),7.69(d,J=7.5Hz,1H),7.58(d,J=8.1Hz,1H),7.53~7.50(m,1H),7.23~7.21(m,1H),6.95(d,J=9.2Hz,1H),5.00(s,2H),3.74(t,J=5.0Hz,4H),3.11(s,3H),2.87(t,J=5.3Hz,4H),2.56~2.53(m,4H),2.45~2.37(m,4H),2.06~1.54(m,8H)
Mass,m/e:281,255,171,157(base),145,128
实施例4-44
步骤4-44-A:与实施例4-1同样地操作,得到3-氨基-6-叔丁氧基羰基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.3Hz,1H),7.69(d,J=8.1Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.21(ddd,J=1.2Hz,7.0Hz,8.1Hz,1H),6.97(d,J=8.8Hz,1H),4.96(s,2H),4.35(s,2H),3.75(t,J=5.0Hz,4H),3.65(t,J=5.7Hz,2H),2.95(t,J=7.7Hz,2H),2.57(t,J=5.0Hz,4H),2.45(t,J=7.4Hz,2H),1.84~1.77(m,2H),1.70~1.64(m,2H),1.48(s,9H)
Mass,m/e:533(M+),433,157(base)
步骤4-44-B:将上述步骤4-44-A中合成的53mg3-氨基-6-叔丁氧基羰基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4,3-d]嘧啶-4-酮加入到10ml 4当量盐酸二噁烷溶液中,在室温下搅拌18小时。用饱和碳酸氢钠水溶液中和反应溶液,用乙酸乙酯萃取,用无水硫酸镁干燥,并在减压下馏去溶剂。用硅胶柱色谱法(氯仿∶甲醇=9∶1)纯化残余物,得到39mg(90%)的3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.7Hz,1H),7.69(d,J=8.1Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.23~7.17(m,1H),6.97(d,J=9.3Hz,1H),4.95(s,2H),3.80(s,2H),3.75(t,J=4.6Hz,4H),3.10(t,J=5.8Hz,2H),2.95(t,J=7.7Hz,2H),2.62(t,J=5.8Hz,2H),2.58(t,J=5.2Hz,4H),2.45(t,J=7.4Hz,2H),2.35(s,1H),1.83~1.79(m,2H),1.69~1.64(m,2H)
Mass,m/e:433(M+,base),417,157
实施例4-45
与实施例4-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.69(d,J=8.1Hz,1H),7.58(d,J=7.7Hz,1H),7.54~7.50(m,1H),7.24~7.20(m,1H),6.95(d,J=9.2Hz,1H),5.57(s,2H),3.70(t,J=5.0Hz,4H),3.01~2.98(m,2H),2.61~2.50(m,8H),2.47~2.44(m,2H),2.05(q,J=6.9Hz,2H),1.82~1.70(m,4H)
Mass,m/e:418(M+),157(base)
实施例4-46
与实施例4-1同样地操作,得到3-氨基-2-[2-(4-喹啉-2-基哌嗪-1-基)乙基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.69(d,J=8.5Hz,1H),7.69(d,J=8.9Hz,1H),7,52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.24~7.20(m,1H),6.96(d,J=9.2Hz,1H),5.71(s,2H),3.72(t,J=5.0Hz,4H),3.14(t,J=6.5Hz,2H),2.86(t,J=6.5Hz,2H),2.69(t,J=5.0Hz,4H),2.59(t,J=6.2Hz,2H),2.53(t,J=6.2Hz,2H),1.81~1.72(m,4H)
Mass,m/e:404(M+),157(base)
实施例4-47
与实施例4-1同样地操作,得到3-氨基-2-[5-(4-喹啉-2-基哌嗪-1-基)戊基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.87(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=8.2Hz,1H),7,54~7.50(m,1H),7,23~7.19(m,1H),6.97(d,J=8.9Hz,1H),4.86(s,2H),3.75(t,J=5.0Hz,4H),2.89(t,J=7.7Hz,2H),2.60~2.55(m,6H),2.53~2.50(m,2H),2.40(t,J=7.7Hz,2H),1.81~1.71(m,6H),1.64~1.57(m,2H),1.50~1.44(m,2H)
Mass,m/e:446(M+),157(base)
实施例4-48
与实施例4-1同样地操作,得到3-氨基-7-叔丁氧基羰基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.69(d,J=8.5Hz,1H),7.56~7.60(m,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.21(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),6.97(d,J=9.3Hz,1H),4.88(s,2H),4.60(brs,2H),3.68~3.78(m,6H),3.00~3.12(m,4H),2.55~2.60(m,4H),2.46(t,J=7.0Hz,2H),1.82~1.91(m,2H),1.66~1.73(m,2H),1.48(s,9H)
Mass,m/e:589(M+),489,445,157(base)
实施例4-49
与实施例4-1同样地操作,得到7-乙酰基-3-氨基-2-[4-(4-喹啉-2-基)丁基]-5,6,7,8-四氢-3H-吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.69(d,J=8.5Hz,1H),7.58(dd,J=1.1Hz,8.5Hz,1H),7.52(ddd,J=1.1Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.1Hz,6.9Hz,8.5Hz,1H),6.97(d,J=9.2Hz,1H),4.90(brs,2H),4.79(s,2H),3.72~3.80(m,6H),3.13~3.18(m,2H),3.04(t,J=7.0Hz,4H),2.60(t,J=5.0Hz,4H),2.48(t,J=7.0Hz,2H),2.20(s,3H),1.87(q,J=7.0Hz,2H),1.70(q,J=7.0Hz,2H)
Mass,m/e:531(M+),387,157(base)
实施例4-50
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.69(d,J=8.5Hz,1H),7.58(dd,J=1.5Hz,8.5Hz,1H),7.51(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.21(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),6.97(d,J=9.2Hz,1H),4.87(s,2H),3.73~3.79(m,4H),2.96~3.05(m,4H),2.75(t,J=5.9Hz,2H),2.58(brs,4H),2.46(t,J=7.3Hz,2H),1.81~1.92(m,6H),1.65~1.74(m,2H)
Mass,m/e:488(M+),472,344,157(base)
实施例4-51
与实施例4-1同样地操作,得到7-乙酰基-3-氨基-2-[4-[4-(4-苯基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-吡啶并[4’,3’:4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.75~7.77(m,2H),7.70(dd,J=3.1Hz,5.2Hz,1H),7.61(dd,J=1.1Hz,8.5Hz,2),7.45~7.56(m,4H),7.16(ddd,J=1.1Hz,6.9Hz,8.5Hz,1H),4.90(s,2H),3.71~3.83(m,6H),3.15(t,J=5.7Hz,2H),3.04(t,J=7.7Hz,4H)2.58(t,J=5.0H,4H),2.46(t,J=7.7Hz,2H),2.20(s,3H),1.87(q,J=7.7Hz,2H),1.62~1.74(m,2H)
Mass,m/e:607(M+),279,149(base)
实施例4-52
与实施例4-1同样地操作,得到3-氨基-6-氯-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.19(d,J=2.3Hz,1H),7.87(d,J=9.2Hz,1H),7.68(d,J=9.2Hz,1H),7.66(dd,J=2.3Hz,8.4Hz,1H),7.60(d,J=8.4Hz,1H),7.56~7.59(m,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.21(ddd,J=1.5Hz ,6.9Hz,8.5Hz,1H),6.96(d,J=9.2Hz,1H),4.90(brs,2H),3.75(t,J=5.0Hz,4H),3.05(t,J=7.4Hz,2H),2.58(t,J=5.0Hz,4H),2.47(t,J=7.4Hz,2H),1.89(q,J=7.4Hz,2H),1.71(q,J=7.4Hz,2H)
Mass,m/e:462(M+),446,157(base)
实施例4-53
与实施例4-1同样地操作,得到3-氨基-6-甲氧基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.59~7.61(m,1H),7.58(d,J=2.7Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.34(d,J=3.0Hz,1H),7.32(d,J=2.7Hz,1H),7.21(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),6.97(d,J=1.5Hz,1H),4.92(s,2H),3.19(s,3H),3.73~3.77(4H,m),3.05(t,J=7.7Hz,2H),2.58(t,J=7.7Hz,1H),1.89(q,J=7.7Hz,1H),1.71(q,J=7.7Hz,1H)
Mass,m/e:458(M+),442,157(base)
实施例4-54
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-7-三氟甲基-3H-喹唑啉酮-4-酮。
1H-NMR(CDCl3)δ:8.35(d,J=8.9Hz,1H),7.96(s,1H),7.87(d,J=9.2Hz,1H),7.67(d,J=8.5Hz,1H),7.65(dd,J=1.5Hz,8.5Hz,1H),7.58(dd,J=0.8Hz,7.7Hz,1H),7.52(ddd,J=1.5Hz,7.0Hz,8.5Hz,1H),7.21(ddd,J=1.5Hz,7.0Hz,8.5Hz,1H),6.96(d,J=9.2Hz,1H),4.95(s,2H),3.75(t,J=5.0Hz,4H),3.09(t,J=7.7Hz,2H),2.59(t,J=5.0Hz,4H),2.49(t,J=7.7Hz,2H),1.92(q,J=7.7Hz,2H),1.72(q,J=7.7Hz,2H)
Mass,m/e:496(M+),480,157
实施例4-55
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-吡啶并[3’,2’:4,5]噻吩并[3,2-d]吡啶-4-酮。
1H-NMR(CDCl3)δ:8.75(dd,J=1.5Hz,4.5Hz,1H),8.54(dd,J=1.5Hz,8.1Hz,1H),7.87(d,J=8.9Hz,1H),7.67(d,J=8.5Hz,1H),7.56~7.60(m,1H),7.52(ddd,J=1.5Hz,7.0H,8.5Hz,1H),7.45(dd,J=4.6Hz,8.1Hz,1H),7.21(ddd,J=1.5Hz,7.0Hz,8.5Hz,1H),6.96(d,J=8.9Hz,1H),5.09(s,2H),3.71~3.79(m,4H),3.14(t,J=7.7Hz,2H),2.59(t,J=5.0Hz,4H),2.50(t,J=7.7Hz,2H),1.95(q,J=7.7Hz,2H),1.74(q,J=7.7Hz,2H)
Mass,m/e:485(M+),470,341,157(base)
实施例4-56
与实施例4-1同样地操作,得到3-氨基-6-氟-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.87(dd,J=2.7Hz,8.5Hz,1H),7.72~7.65(m,2H),7.59(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.46(dt,J=2.7Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.92(s,2H),3.76(t,J=5.0Hz,4H),3.07(t,J=7.7Hz,2H),2.59(t,J=5.0Hz,4H),2.49(t,J=7.7Hz,2H),1.91(q,J=7.7Hz,2H),1.73(q,J=7.7Hz,2H)
Mass,m/e:446(M+),157(base)
实施例4-57
与实施例4-1同样地操作,得到3-氨基-7-氟-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.25(dd,J=6.2Hz,8.9Hz,1H),7.89(d,J=9.2Hz,1H),7.70(d,J=8.1Hz,1H),7.59(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.31(dd,J=2.7Hz,9.6Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.16(dt,J=2.3Hz,8.9Hz,1H),6.98(d,J=9.2Hz,1H),4.89(s,2H),3.76(t,J=5.0Hz,4H),3.07(t,J=7.7Hz,2H),2.59(t,J=5.0Hz,4H),2.49(t,J=7.7Hz,2H),1.91(q,J=7.7Hz,2H),1.73(q,J=7.7Hz,2H)
Mass,m/e:446(M+),157(base)
实施例4-58
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-噻吩并[3,4-d]嘧啶-4-酮。
1H-NMR(DMSO-d6)δ:8.02(d,J=9.2Hz,1H),7.69(d,J=8.1Hz,1H),7.58~7.48(m,2H),7.35~7.28(m,2H),7.25~7.18(m,2H),5.51(brs,2H),3.68(brs,4H),3.27(brs,2H),2.53~2.24(m,6H),1.68~1.49(m,4H)
Mass,m/e:434(M+),157(base)
实施例4-59
与实施例4-1同样地操作,得到3-氨基-7-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.59(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.95(s,2H),3.76(t,J=5.0Hz,4H),2.93(t,J=6.9Hz,2H),2.74~2.63(m,2H),2.58(t,J=5.0Hz,4H),2.49~2.37(m,3H),2.28~2.18(m,1H),1.92~1.75(m,4H),1.72~1.59(m,2H),1.34~1.22(m,1H),1.06(d,J=6.6Hz,3H)
Mass,m/e:446(M+),157(base)
实施例4-60
与实施例4-1同样地操作,得到3-氨基-6-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.1Hz,1H),7.59(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.95(s,2H),3.76(t,J=5.0Hz,4H),2.93(t,J=7.7Hz,2H),2.77~2.69(m,1H),2.67~2.60(m,2H),2.58(t,J=5.0Hz,4H),2.45(t,J=7.3Hz,2H),2.09~1.98(m,1H),1.92~1.62(m,6H),1.45~1.32(m,1H),1.08(d,J=6.6Hz,3H)
Mass,m/e:446(M+),157(base)
实施例4-61
与实施例4-1同样地操作,得到3-氨基-6-乙基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.59(d,J=8.1Hz,1H),7.53(t,J=8.1Hz,1H),7.22(t,J=8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.95(s,2H),3.76(t,J=5.0Hz,4H),2.93(t,J=7.3Hz,2H),2.80~2.72(m,1H),2.66~2.53(m,6H),2.45(t,J=7.3Hz,2H),2.09~1.98(m,1H),1.98~1.89(m,1H),1.81(q,J=7.3Hz,2H),1.72~1.30(m,6H),0.98(t,J=7.3Hz,3H)
Mass,m/e:460(M+),157(base)
实施例4-62
与实施例4-1同样地操作,得到3-氨基-6,7-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.59(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.1Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.95(s,2H),3.76(t,J=5.0Hz,4H),3.00~2.86(m,2H),2.73~2.52(m,6H),2.45(t,J=7.3Hz,2H),2.40~2.25(m,2H),2.04~1.90(m,2H),1.86~1.76(m,2H),1.73~1.59(m,2H),0.95~0.89(m,6H)
Mass,m/e:460(M+),157(base)
实施例4-63
与实施例4-1同样地操作,得到3-氨基-6-叔丁基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.59(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.96(s,2H),3.76(t,J=5.0Hz,4H),2.94(t,J=7.7Hz,2H),2.76~2.54(m,7H),2.45(t,J=7.3Hz,2H),2.20~2.10(m,1H),2.04~1.96(m,1H),1.86~1.76(m,2H),1.72~1.57(m,2H),1.39~1.23(m,2H),0.96(s,9H)
Mass,m/e:488(M+),157(base)
实施例4-64
与实施例4-1同样地操作,得到3-氨基-5,7,7-三甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.59(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.94(s,2H),3.76(t,J=5.0Hz,4H),3.00~2.80(m,3H),2.58(t,J=5.0Hz,4H),2.52~2.42(m,3H),2.32~2.25(m,1H),1.87~1.62(m,5H),1.33(d,J=6.6Hz,3H),1.23~1.15(m,1H),1.06(s,3H),0.85(s,3H)
Mass,m/e:474(M+),157(base)
实施例4-65
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-苯并噻唑-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.60(d,J=8.5Hz,1H),7.55(d,J=8.1Hz,1H),7.32~7.27(m,1H),7.10~7.04(m,1H),4.90(s,2H),3.65(t,J=5.0Hz,4H),2.92(t,J=7.7Hz,2H),2.62~2.49(m,8H),2.45(t,J=7.3Hz,2H),1.85~1.60(m,8H)
Mass,m/e:438(M+),422(base)
实施例4-66
与实施例4-1同样地操作,得到3-氨基-6,6-亚乙二氧基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.1Hz,1H),7.59(dd,J=1.2Hz,7.7Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.1Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.94(s,2H),4.07~3.98(m,4H),3.76(t,J=5.0Hz,4H),2.94(t,J=7.7Hz,2H),2.85(t,J=6.9Hz,2H),2.75(s,2H),2.58(t,J=5.0Hz,4H),2.45(t,J=7.3Hz,2H),1.96(t,J=6.9Hz,2H),1.80(q,J=7.7Hz,2H),1.72~1.59(m,2H)
Mass,m/e:490(M+),157(base)
实施例4-67
将实施例4-66中合成的229mg 3-氨基-6,6-亚乙二氧基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮和59mg对甲苯磺酸吡啶鎓加入到29ml丙酮和1ml水的混合溶液中,加热回流112小时。冷却后,用二氯甲烷萃取,水洗并用无水硫酸镁干燥,减压下馏去溶剂。用硅胶柱色谱法(甲醇∶二氯甲烷=1∶9)纯化残余物,得到194mg(78%)的6,6-亚乙二氧基-3-亚异丙基氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.59(dd,J=1.2Hz,8.5Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.08~3.99(m,4H),3.76(t,J=5.0Hz,4H),2.86(t,J=6.6Hz,2H),2.75(brs,2H),2.63(t,J=7.3Hz,2H),2.57(t,J=5.0Hz,4H),2.45~2.37(m,2H),1.97(t,J=6.9Hz,2H),1.66~1.57(m,2H),1.59(s,6H),1.31~1.24(m,2H)
Mass,m/e:530(M+),157(base)
实施例4-68
将300mg硼氢化钠加入到10ml甲醇中,在冰冷却下,往该混合物中滴加实施例4-67中合成的145mg 6,6-亚乙二氧基-3-亚异丙基氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮的10ml甲醇溶液,使温度返回至室温后搅拌1小时。减压下馏去溶剂后,加水,用二氯甲烷萃取,水洗并用无水硫酸镁干燥,减压下馏去溶剂。用硅胶柱色谱法(甲醇∶二氯甲烷=2∶23)纯化残余物,得到89mg(61%)的6,6-亚乙二氧基-3-异丙基氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.59(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),5.33(d,J=4.6Hz,1H),4.09~3.99(m,4H),3.76(t,J=5.0Hz,4H),3.41~3.32(m,1H),2.84(t,J=6.6Hz,2H),2.74(s,2H),2.58(t,J=5.0Hz,4H),2.43(t,J=7.3Hz,2H),1.96(t,J=6.6Hz,2H),1.82~1.72(m,2H),1.67~1.56(m,4H),1.16~1.01(m,6H)
Mass,m/e:532(M+),157(base)
实施例4-69
将实施例4-66中合成的2.72g 3-氨基-6,6-亚乙二氧基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮加入到40ml 6当量盐酸中,加热回流1小时。冷却后,用饱和碳酸氢钠水溶液中和所得反应溶液,用二氯甲烷萃取,用无水硫酸镁干燥,并在减压下馏去溶剂。用硅胶柱色谱法(甲醇∶二氯甲烷=2∶23)纯化残余物,得到1.77g(71%)的3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4,5,6,7,8-六氢-4,6-二氧杂喹唑啉。
1H-NM R(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.60(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.23(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),5.01(s,2H),3.76(t,J=5.0Hz,4H),3.39(s,2H),3.06~2.95(m,4H),2.66(t,J=7.3Hz,2H),2.59(t,J=5.0Hz,4H),2.47(t,J=7.3Hz,2H),1.89~1.79(m,2H),1.74~1.64(m,2H)
Mass,m/e:446(M+),157(base)
实施例4-70
将500mg硼氢化钠加入到25ml甲醇中,在冰冷却下,往该混合物中滴加实施例4-69中合成的1.00g 3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,4,5,6,7,8-六氢-4,6-二氧杂喹唑啉的25ml甲醇溶液,使温度返回至室温后搅拌3小时。减压下馏去溶剂后,加水,用二氯甲烷萃取,水洗并用无水硫酸镁干燥,减压下馏去溶剂。用硅胶柱色谱法(甲醇∶二氯甲烷=1∶9)纯化残余物,得到520mg(52%)的3-氨基-6-羟基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.59(d,J=8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.97(d,J=9.2Hz,1H),4.97(s,2H),4.24~4.16(m,1H),3.75(t,J=5.0Hz,4H),2.93(t,J=7.7Hz,2H),2.88~2.76(m,2H),2.69~2.49(m,6H),2.45(t,J=7.3Hz,2H),2.01~1.61(m,6H)
Mass,m/e:448(M+),157(base)
实施例4-71
与实施例4-1同样地操作,得到3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-6-三氟甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.59(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.23(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.97(s,2H),3.79~3.74(m,4H),2.98~2.90(m,3H),2.82~2.32(m,10H),2.23~2.15(m,1H),1.86~1.62(m,5H)
Mass,m/e:500(M+),157(base)
实施例5:在上述式(I)中,X1表示氢原子,Y表示氮原子时的化合物的合成
实施例5-1
步骤5-1-A:在室温搅拌下,将256mg钠加入到14ml甲醇中,随后往其中加入1.04g硝基胍,加热回流45分钟,随后加入1.70g 2-环己酮羧酸乙酯,加热回流9小时。冷却后,减压下馏去溶剂。往残余物中加水,加入乙酸使其呈酸性后,滤取沉淀物并干燥,得到1.76g(84%)的2-硝基氨基-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(DMSO-d6)δ:2.56~2.45(m,2H)2.30~2.19(m,2H),1.74~1.58(m,4H)
Mass,m/e:210((M+1)+),122(base)
步骤5-1-B:往1.52g 2-[3-(4-喹啉-2-基哌嗪-1-基)丙基]异吲哚-1,3-二酮的30ml乙醇溶液中加入1.50g一水合肼的10ml乙醇溶液,加热回流7小时。冷却后,过滤去除不溶物质,减压馏去溶剂。加入5当量氢氧化钠使所得溶液呈碱性后,用氯仿萃取,用饱和食盐水洗涤,用无水硫酸钠干燥并在减压下馏去溶剂,得到0.99g(96%)的3-(4-喹啉-2-基哌嗪-1-基)丙胺。
1H-NMR(CDCl3)δ:7.87(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.23(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.97(d,J=8.9Hz,1H),3.75(t,J=5.4Hz,4H),2.78(t,J=6.9Hz,2H),2.58(t,J=5.4Hz,4H),2.46(t,J=7.3Hz,2H),1.78~1.63(m,2H)
Mass,m/e:270(M+),157(base)
步骤5-1-C:往3ml吡啶中加入上述步骤5-1-A中得到的210mg 2-硝基氨基-5,6,7,8-四氢-3H-喹唑啉-4-酮和上述步骤5-1-B中得到的270mg3-(4-喹啉-2-基哌嗪-1-基)丙胺,加热回流16小时。冷却后,减压下馏去溶剂。用硅胶柱色谱法(25%氨水∶甲醇∶氯仿=0.5∶5∶45)纯化残余物,得到301mg(72%)的2-[3-(4-喹啉-2-基哌嗪-1-基)丙基氨基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.87(d,J=8.9Hz,1H),7.68(d,J=8.1Hz,1H),7.58(d,J=7.8Hz,1H),7.52(t,J=7.0Hz,1H),7.21(t,J=7.0Hz,1H),6.97(d,J=9.2Hz,1H),5.73(brs,1H),3.91(brs,4H),3.39(brs,2H),2.62(t,J=5.0Hz,4H),2.51(t,J=6.2Hz,2H),2.42(t,J=6.2Hz,2H),2.37(t,J=6.2Hz,2H),1.98~1.53(m,6H)
Mass,m/e:418(M+),157(base)
实施例5-2
与实施例5-1同样地操作,得到2-[4-(4-喹啉-2-基哌嗪-1-基)丁基氨基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.87(d,J=9.2Hz,1H),7.68(d,J=8.5Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.21(t,J=8.1Hz,1H),6.96(d,J=9.2Hz,1H),6.05(brs,1H),3.76(t,J=5.0Hz,4H),3.38(brs,2H),2.58(t,J=5.0Hz,4H),2.52~2.28(m,6H),1.95~1.51(m,8H)
Mass,m/e:432(M+),157(base)
实施例5-3
与实施例5-1同样地操作,得到2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丙基氨基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.77(d,J=8.5Hz,1H),7.69(d,J=7.7Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.24(t,J=7.7Hz,1H),6.84(s,1H),3.95(brs,4H),3.39(brs,2H),2.62(t,J=5.0Hz,4H),2.59(s,3H),2.52(t,J=6.2Hz,2H),2.46~2.36(m,4H),1.87~1.64(m,6H)
Mass,m/e:432(M+),171(base)
实施例5-4
与实施例5-1同样地操作,得到2-[3-[4-(7-甲氧基异喹啉-1-基)哌嗪-1-基]丙基氨基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.04(d,J=5.8Hz,1H),7.66(d,J=8.9Hz,1H),7.37(d,J=2.7Hz,1H),7.27(dd,J=2.7Hz,8.9Hz,1H),7.20(d,J=5.8Hz,1H),6.00(brs,1H),3.93(s,3H),3.56(brs,4H),3.41(brs,2H),2.77(brs,4H),2.59(t,J=6.2Hz,2H),2.48~2.41(m,2H),2.40~2.33(m,2H),1.91~1.80(m,2H),1.78~1.63(m,4H)
Mass,m/e:448(M+),187(base)
实施例5-5
与实施例5-1同样地操作,得到2-[3-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基)丙基氨基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.81(dd,J=1.2Hz,2.7Hz,1H),7.72(dd,J=1.5Hz,8.1Hz,1H),7.65(dd,J=1.5Hz,7.7Hz,1H),7.35~7.23(m,2H),6.80~6.73(m,2H),4.01(brs,4H),3.40(brs,2H),3.69(t,J=5.0Hz,4H),2.54(t,J=6.2Hz,2H),2.44(t,J=5.7Hz,2H),2.39(t,J=5.7Hz,2H),1.88~1.63(m,6H)
Mass,m/e:457(M+),196(base)
实施例5-6
与实施例5-1同样地操作,得到2-[3-(4-喹啉-2-基哌嗪-1-基)丙基氨基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.09(brs,1H),7.90(d,J=9.2Hz,1H),7.71(d,J=8.5Hz,1H),7.61(d,J=8.1Hz,1H),7.58~7.51(m,2H),7.38~7.19(m,2H),7.15(brs,1H),6.99(d,J=9.2Hz,1H),3.92(t,J=5.0Hz,4H),3.55(brs,2H),2.67(brs,4H),2.60(t,J=6.2Hz,2H),1.95(brs,2H)
Mass,m/e:414(M+),157(base)
实施例5-7
与实施例5-1同样地操作,得到2-[3-[4-(7-甲氧基异喹啉-1-基)哌嗪-1-基]丙基氨基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.13~8.03(m,2H),7.69(d,J=8.9Hz,1H),7.55(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.39(d,J=2.3Hz,1H),7.35(d,J=8.1Hz,1H),7.29(dd,J=2.3Hz,8.1Hz,1H),7.27~7.21(m,1H),7.14(brs,1H),3.93(s,3H),3.62~3.53(m,6H),2.83(brs,4H),2.69(t,J=6.2Hz,2H),2.07~1.94(m,2H)
Mass,m/e:444(M+),187(base)
实施例5-8
与实施例5-1同样地操作,得到2-[3-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基)丙基氨基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.09(brs,1H),7.82(s,1H),7.74(d,J=7.7Hz,1H),7.68(d,J=7.7Hz,1H),7.56(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.38~7.24(m,3H),7.12(brs,1H),6.81~6.73(m,2H),3.99(brs,4H),3.56(brs,2H),2.73(brs,4H),2.62(t,J=6.2Hz,2H),1.95(brs,2H)
Mass,m/e:453(M+),196(base)
实施例6:在上述式(I)中,X1表示氨基、低级烷基氨基、二低级烷基氨基或低级亚烷基氨基,Y表示氮原子时的化合物的合成
实施例6-1
步骤6-1-A:往209mg 3-氨基-3H-喹唑啉-4-酮-2-硫醇钾的5ml二甲基甲酰胺溶液中加入141mg甲基碘,在室温下搅拌20分钟。往反应溶液中加水,用乙酸乙酯萃取,用无水硫酸镁干燥并在减压下馏去溶剂,得到161mg(86%)的3-氨基-2-甲硫基-3H-喹唑啉-4-酮。
步骤6-1-B:将上述步骤6-1-A中合成的131mg 3-氨基-2-甲硫基-3H-喹唑啉-4-酮和172mg 3-(4-喹啉-2-基哌嗪-1-基)丙胺的混合物在145℃下加热搅拌5小时。将反应混合物冷却后,用硅胶柱色谱法(甲醇∶二氯甲烷=1∶19)进行纯化,得到198mg(73%)的3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基氨基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.06(dd,J=1.5Hz,8.1Hz,1H),7.90(d,J=9.2Hz,1H),7.71(d,J=8.1Hz,1H),7.62~7.51(m,3H),7.50~7.45(m,1H),7.37(d,J=8.1Hz,1H),7.23(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.13(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.99(d,J=9.2Hz,1H),4.51(s,2H),3.81(t,J=5.0Hz,4H),3.64(q,J=6.2Hz,2H),2.65(t,J=5.0H z,4H),2.60(t,J=6.2Hz,2H),1.91(q,J=6.2Hz,2H)
Mass,m/e:429(M+),157(base)
实施例6-2
与实施例6-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基氨基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.90(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.60(dd,J=1.2Hz,8.1Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.23(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),4.42(brs,2H),3.80(t,J=5.0Hz,4H),3.52(q,J=6.2Hz,2H),2.63(t,J=5.0Hz,4H),2.56(t,J=6.2Hz,2H),2.50~2.40(m,4H),1.89~1.80(m,2H),1.78~1.66(m,4H)
Mass,m/e:433(M+),157(base)
实施例6-3
与实施例6-1同样地操作,得到3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基氨基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.90(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.60(d,J=7.7Hz,1H),7.54(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.46~7.41(m,1H),7.23(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.99(d,J=9.2Hz,1H),4.41(s,2H),3.81(t,J=5.0Hz,4H),3.57(q,J=5.8Hz,2H),2.93~2.88(m,2H),2.69~2.55(m,8H),1.92~1.76(m,6H)
Mass,m/e:489(M+),157(base)
实施例7-1
步骤7-1-A:2-哌嗪-1-基喹啉的合成
将4.31g无水哌嗪溶解于30ml乙二醇中,往其中加入818mg 2-氯喹啉,在140℃下搅拌2小时。冷却后,加入饱和碳酸氢钠水溶液,用氯仿萃取,用无水硫酸镁干燥有机层,然后进行减压浓缩。用硅胶柱色谱法(氯仿∶甲醇=2∶1)纯化残余物,得到1.09g(100%)的2-哌嗪-1-基喹啉。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H),7.59(dd,J=1.5Hz,8.0Hz,1H),7.53(ddd,J=1.5Hz,7.0Hz,8.4Hz,1H),7.26~7.22(m,1H),6.97(d,J=9.2Hz,1H),3.70(t,J=5.0Hz,4H),3.01(t,J=5.0Hz,4H)
Mass,m/e:213(M+),145(base)
步骤7-1-B:2-氨基环己-1-烯羧酸乙酯的合成
往7当量氨-甲醇溶液中加入170g 2-氧代环己烷羧酸乙酯,在室温下搅拌过夜。将溶剂进行减压浓缩,得到粗结晶。将所得粗结晶在乙酸乙酯-正己烷中重结晶,得到152g(90%)的2-氨基-环己-1-烯羧酸乙酯。
1H-NMR(CDCl3)δ:4.14(q,J=7.3Hz,2H),2.25(d,J=5.9Hz,2H),2.20(d,J=5.9Hz,2H),1.67~1.56(m,4H)
Mass,m/e:169(M+),96(base)
步骤7-1-C:2-(5-溴戊酰基氨基)环己-1-烯羧酸乙酯的合成
将上述步骤7-1-B中合成的42.3g 2-氨基环己-1-烯羧酸乙酯溶解于150ml四氢呋喃中,加入40g吡啶,在冰冷却下,往其中滴加5-溴戊酰氯。在室温下搅拌过夜,再加入乙酸乙酯,用饱和碳酸氢钠水溶液、10%柠檬酸水溶液和饱和盐水洗涤,然后用无水硫酸镁干燥,将溶剂进行减压浓缩。用硅胶柱色谱法(正己烷∶乙酸乙酯=8∶1)纯化残余物,得到76.6g(92%)的2-(5-溴戊酰基氨基)环己-1-烯羧酸乙酯。
1H-NMR(CDCl3)δ:11.62(brs,1H),4.22~4.09(m,2H),3.42(t,J=6.9Hz,2H),2.97~2.94(m,2H),2.34(t,J=7.0Hz,2H),2.32~2.23(m,2H),1.94~1.88(m,2H),1.85~1.79(m,2H),1.65~1.56(m,4H),1.30(t,J=7.0Hz,3H)
Mass,m/e:333(M+),55(base)
步骤7-1-D:2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]环己-1-烯羧酸乙
酯的合成
将上述步骤7-1-C中合成的66.5g 2-(5-溴戊酰基氨基)环己-1-烯羧酸乙酯、上述步骤7-1-A中合成的46.9g 2-哌嗪-1-基喹啉、22.3g三乙胺和350ml甲苯的混合物加热回流过夜。减压下浓缩溶剂,加入乙酸乙酯,用饱和碳酸氢钠水溶液洗涤。用无水硫酸镁干燥有机层,然后在减压下浓缩溶剂。用硅胶柱色谱法(正己烷∶乙酸乙酯∶甲醇=1∶6∶0.2)纯化残余物,得到79.8g(86%)的2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]环己-1-烯羧酸乙酯。
1H-NMR(CDCl3)δ:11.61(brs,1H),7.87(d,J=9.2Hz,1H),7.69(d,J=8.5Hz,1H),7.58~7.56(m,1H),7.51(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.20(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.97(d,J=9.2Hz,1H),4.16(q,J=6.9Hz,2H),3.74(t,J=5.0Hz,4H),2.97(t,J=5.0Hz,2H),2.56(t,J=5.0Hz,4H),2.43~2.90(m,6H),1.74~1.70(m,2H),1.68(m,4H),1.28(t,J=6.9Hz,2H)
Mass,m/e:464(M+),157(base)
步骤7-1-E:2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]环己-1-烯羧酸的
合成
将上述步骤7-1-D中合成的168.0g 2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]环己-1-烯羧酸乙酯悬浮在725ml2-丙醇和365ml蒸馏水中,往其中加入580ml 1当量氢氧化钠水溶液,加热回流1.5小时。冷却后,加入2当量盐酸进行中和。滤取沉淀的结晶并进行干燥,得到131.8g(83.4%)的2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]环己-1-烯羧酸。
1H-NMR(CDCl3)δ:12.29(brs,1H),7.92(d,J=9.2Hz,1H),7.70(d,J=8.5Hz,1H),7.61(d,J=8.1Hz,1H),7.57~7.53(m,1H),7.18~7.15(m,1H),6.96(d,J=8.9Hz,1H),3.89(brs,4H),2.92~2.91(m,6H),2.72~2.69(m,2H),2.37~2.35(m,2H),2.32~2.31(m,2H),1.73~1.67(m,4H),1.61~1.55(m,4H)
Mass,m/e:418(M+-18),392(M+-44),157(base)
步骤77-1-F:3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-
喹唑啉-4-酮的合成
将上述步骤7-1-E中合成的10.0g 2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]环己-1-烯羧酸悬浮于30ml四氢呋喃中,往其中加入7.0g 3当量的乙酸酐,加热回流1小时。使反应溶液在冰冷却下,往其中缓慢加入35.6ml过剩的40%甲胺-甲醇溶液。加热搅拌约10分钟后,使温度返回至室温后进行减压浓缩。加入80ml蒸馏水,搅拌30分钟后,滤取沉淀的结晶并干燥,得到8.83g(89.3%)的3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.1Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=8.1Hz,1H),7.52(dd,J=8.5Hz,J=1.5Hz,1H),7.23~7.20(m,1H),6.97(d,J=9.2Hz,1H),3.75(brs,4H),3.53(s,3H),2.74(t,J=7.7Hz,2H),2.57~2.54(m,6H),2.50~2.43(m,4H),1.83~1.66(m,8H)
Mass,m/e:431(M+),157(base)
实施例7-2
与实施例7-1同样地操作,合成3-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=8.1Hz,1H),7.54~7.50(m,1H),7.23~7.19(m,1H),6.97(d,J=9.2Hz,1H),4.11~4.06(m,2H),3.75(t,J=5.0Hz,4H),2.76~2.72(m,2H),2.58~2.53(m,6H),2.49~2.43(m,4H),1.83~1.65(m,8H),1.33~1.30(m,3H)
Mass,m/e:445(M+),157(base)
实施例7-3
与实施例7-1同样地操作,合成3-丙基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.89(d,J=9.2Hz,1H),7.70(d,J=8.1Hz,1H),7.59(dd,J=1.2Hz,7.7Hz,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.2Hz,1H),6.98(d,J=9.2Hz,1H),3.95(t,J=7.7Hz,2H),3.76(t,J=4.6Hz,4H),2.74(t,J=7.7Hz,2H),2.59(t,J=4.6Hz,4H),2.56~2.53(m,2H),2.51~2.42(m,4H),1.86~1.58(m,11H)
Mass,m/e:459(M+),157(base)
实施例7-4
与实施例7-1同样地操作,合成3-苄基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.23~7.20(m,1H),6.97(d,J=9.2Hz,1H),7.87(d,J=8.9Hz,1H),7.69(d,J=8.9Hz,1H),7.58(dd,J=8.1Hz,1.2Hz,1H)7.57~7.50(m,1H),7.33~7.27(m,3H),7.23~7.19(m,1H),7.15(d,J=6.9Hz,2H),6.96(d,J=8.9Hz,1H),5.31(s,2H),3.73~3.71(m,4H),2.60~2.54(m,2H),2.52~2.50(m,6H),2.33(t,J=7.3Hz,2H),1.82~1.66(m,6H),1.56~1.52(m,4H)
Mass,m/e:507(M+),157(base)
实施例7-5
与实施例7-1同样地操作,合成3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.59(dd,J=1.1Hz,8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,6.9Hz,1H),7.22(ddd,J=1.1Hz,6.9Hz,6.9Hz,1H),6.96(d,J=9.1Hz,1H),3.75~3.70(m,4H),3.55(s,3H),2.77(t,J=8.0Hz,2H),2.62~2.56(m,10H),1.99(q,J=7.3Hz,2H),1.81~1.68(m,4H)
Mass,m/e:417(M+),240,178,157(base)
实施例7-6
与实施例7-1同样地操作,合成3-甲基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.76(dd,J=8.1Hz,1.2Hz,1H),7.69(d,J=8.5Hz,1H),7.54~7.50(m,1H),7.25~7.22(m,1H),6.83(s,1H),3.75(t,J=5.0Hz,4H),3.53(s,3H),2.74(t,J=8.1Hz,2H),2.59~2.54(m,9H),2.50~2.43(m,4H),1.81~1.68(m,8H)
Mass,m/e:445(M+),171(base)
实施例7-7
与实施例7-1同样地操作,合成3-乙基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.76(d,J=6.9Hz,1H),7.69(d,J=8.5Hz,1H),7.54~7.50(m,1H),7.26~7.22(m,1H),6.83(s,1H),4.12~4.05(m,2H),3.77~3.74(m,4H),2.74(t,J=7.7Hz,2H),2.62~2.59(m,4H),2.59(s,3H),2.56~2.53(m,2H),2.49~2.45(m,4H),1.83~1.67(m,8H),1.33~1.29(m,3H)
Mass,m/e:459(M+),171(base)
实施例7-8
与实施例7-1同样地操作,合成3-苄基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.76(dd,J=8.1Hz,J=1.2Hz,1H),7.79(d,J=7.7Hz,1H),7.54~7.49(m,1H),7.33~7.21(m,4H),7.16(s,1H),7.15(s,1H),6.81(s,1H),5.31(s,2H),3.72~3.70(m,4H),2.67~2.64(m,2H),2.60~2.52(m,2H),2.59(s,3H),2.50(t,J=5.0Hz,4H),2.34~2.30(m,2H),2.04~1.73(m,4H),1.71~1.65(m,2H),1.58~1.50(m,2H)
Mass,m/e:521(M+),171(base)
实施例7-9
与实施例7-1同样地操作,合成2-[4-(4-苯并噻唑-2-基哌嗪-1-基)丁基]-3-甲基-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.59(d,J=7.3Hz,1H),7.54(d,J=8.1Hz,1H),7.31~7.27(m,1H),7.09~7.05(m,1H),3.65~3.63(m,4H),3.52(s,3H),2.75~2.71(m,2H),2.58~2.54(m,6H),2.50~2.43(m,4H),1.81~1.63(m,8H)
Mass,m/e:437(M+),96(base)
实施例7-10
与实施例7-1同样地操作,合成2-[4-(4-苯并噻唑-2-基哌嗪-1-基)丁基]-3-乙基-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.61~7.54(m,2H),7.32~7.28(m,1H),7.10~7.06(m,1H),3.66~3.63(m,4H),3.31~3.24(m,2H),2.73~2.71(m,2H),2.59(t,J=5.0Hz,4H),2.54~2.53(m,2H),2.47~2.44(m,4H),1.85~1.65(m,8H),1.12(t,J=7.3Hz,3H)
Mass,m/e:451(M+),96(base)
实施例7-11
与实施例7-1同样地操作,合成2-[4-(4-苯并噻唑-2-基哌嗪-1-基)丁基]-3-苄基-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.59(d,J=6.9Hz,1H),7.54(d,7.3Hz,1H),7.33~7.27(m,6H),7.09~7.05(m,1H),4.43(d,J=5.8Hz,2H),3.61~3.59(m,4H),2.65(t,J=7.7Hz,2H),2.58(t,J=5.8Hz,2H),2.55~2.52(m,2H),2.51~2.48(m,4H),2.32(t,J=7.3Hz,2H),1.81~1.64(m,6H),1.55~1.49(m,2H)
Mass,m/e:513(M+),91(base)
实施例7-12
以5-甲基-2-氧代-环己烷羧酸乙酯(文献:J.Am.Chem.Soc.,85,207-222(1963)中记载的化合物)为起始原料,采用与实施例7-1同样的方法,合成3,6-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=7.7Hz,1H),7.54~7.50(m,1H),7.23~7.19(m,1H),6.97(d,J=9.2Hz,1H),3.75(t,J=5.0Hz,4H),3.53(s,3H),2.74~2.68(m,3H),2.60~2.56(m,7H),2.45(t,J=7.3Hz,2H),2.03~1.96(m,1H),1.88~1.76(m,3H),1.71~1.65(m,2H),1.40~1.34(m,1H),1.06(d,J=6.6Hz,3H)
Mass,m/e:445(M+),157(base)
实施例7-13
与实施例7-12同样地操作,合成3-乙基-6-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.0Hz,1H),7.69(d,J=8.5Hz,1H),7.58(dd,J=7.7Hz,1.2Hz,1H),7.52(ddd,J=8.5Hz,6.9Hz,1.5Hz,1H),7.21(ddd,J=8.1Hz,6.9Hz,1.2Hz,1H),6.97(d,J=9.2Hz,1H),4.08(q,J=7.3Hz,2H),3.75(t,J=5.0Hz,4H),2.76~2.67(m,3H),2.60~2.56(m,7H),2.44(t,J=7.3Hz,2H),1.99(dd,J=17.3Hz,10.0Hz,1H),1.87~1.72(m,3H),1.71~1.65(m,2H),1.39~1.35(m,1H),1.31(t,J=6.9Hz,3H),1.06(d,J=6.7Hz,3H)
Mass,m/e:459(M+),157(base)
实施例7-14
步骤7-14-A:5-氧代-己酸甲酯的合成
在冰冷却搅拌下,用20分钟将2.06g N-甲基-N-亚硝基脲加入到30ml4当量氢氧化钠水溶液和30ml二乙醚的混合液中,随后搅拌20分钟。分取二乙醚层,往其中加入1.30g 5-氧代-己酸,在室温下搅拌2小时。用饱和碳酸氢钠水溶液洗涤反应溶液,用无水硫酸镁干燥,减压浓缩溶剂。用硅胶柱色谱法(乙酸乙酯∶正己烷=1∶3)纯化残余物,得到1.15g(80%)的5-氧代-己酸甲酯。
1H-NMR(CDCl3)δ:3.66(s,3H),2.49(t,J=7.3Hz,2H),2.33(t,J=7.3Hz,2H),2.13(s,3H),1.89~1.84(m,2H)
Mass,m/e:145,59(base)
步骤7-14-B:5-(4-喹啉-2-哌嗪-1-基)己酸甲酯的合成
将上述步骤7-14-A中合成的1.10g 5-氧代-己酸甲酯、1.36g 2-哌嗪-1-基喹啉、20mg对甲苯磺酸和50ml甲苯的混合物加热回流16小时,通过共沸除去生成的水。对溶剂进行减压浓缩,将残余物溶解于50ml四氢呋喃中,一边导入盐酸气体一边在室温下搅拌1小时。往其中加入溶解于10ml甲醇的380mg氰基三氢硼酸钠并搅拌2小时。往反应溶液中加入30ml 0.1当量氢氧化钾水溶液,用乙酸乙酯萃取。用无水硫酸镁干燥有机层,对溶剂进行减压浓缩,用硅胶柱色谱法(乙酸乙酯∶正己烷=1∶1)纯化残余物,得到977mg(45%)的5-(4-喹啉-2-哌嗪-1-基)己酸甲酯。
1H-NMR(CDCl3)δ:7.86(d,J=9.3Hz,1H),7.68(d,J=8.1Hz,1H),7.57(d,J=8.1Hz,1H),7.51(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.20(ddd,J=1.5Hz,6.9Hz,8.1Hz,1H),6.96(d,J=8.9Hz,1H),3.74~3.71(m,4H),3.67(s,3H),2.70~2.62(m,3H),2.60~2.55(m,2H),2.34(t,J=7.3Hz,2H),1.75~1.64(m,4H),1.00(d,J=6.6Hz,3H)
Mass,m/e:341(M+),157(base)
步骤7-14-C:5-(4-喹啉-2-哌嗪-1-基)己酸的合成
往10ml1当量氢氧化钠∶乙醇=1∶1的溶液中加入上述步骤7-14-B中合成的850mg 5-(4-喹啉-2-哌嗪-1-基)己酸甲酯,加热回流1小时。冷却后,往其中加入2当量盐酸将pH调节为7,滤取沉淀的结晶并干燥,得到728mg(89%)的5-(4-喹啉-2-哌嗪-1-基)己酸。
1H-NMR(CDl3)δ:7.91(d,J=9.3Hz,1H),7.70(d,J=8.5Hz,1H),7.60(d,J=8.1Hz,1H),7.54(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.27~7.23(m,1H),6.95(d,J=9.2Hz,1H),4.05~3.95(m,4H),3.06~3.00(m,3H),2.98~2.94(m,2H),2.34(t,J=7.3Hz,2H),1.98~1.93(m,1H),1.75~1.64(m,2H),1.54~1.49(m,1H),1.16(d,J=6.9Hz,3H)
Mass,m/e:327(M+),157(base)
步骤7-14-D:2-[5-(4-喹啉-2-基-哌嗪-1-基)己酰基氨基]-环己-1-烯羧
酸乙酯的合成
在冰冷却下,往上述步骤7-1-B中合成的170mg 2-氨基-环己-1-烯羧酸乙酯的5ml吡啶溶液中加入70mg三氯化磷,搅拌15分钟。使温度返回至室温,往其中加入上述步骤7-14-C中合成的327mg 5-(4-喹啉-2-哌嗪-1-基)己酸并搅拌3小时,然后减压馏去吡啶,用乙酸乙酯萃取。水洗后,用无水硫酸镁干燥有机层,将溶剂进行减压浓缩。用硅胶柱色谱法(乙酸乙酯)纯化残余物,得到182mg(38%)的2-[5-(4-喹啉-2-基-哌嗪-1-基)己酰基氨基]-环己-1-烯羧酸乙酯。
1H-NMR(CDCl3)δ:11.61(br-s,1H),7.86(d,J=8.9Hz,1H),7.68(d,J=8.5Hz,1H),7.57(d,J=7.7Hz,1H),7.51(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.22~7.18(m,1H),6.96(d,J=9.3Hz,1H),4.14(q,J=6.9Hz,2H),3.80~3.70(m,4H),2.98~2.95(m,2H),2.75~2.65(m,3H),2.64~2.56(m,2H),2.34(t,J=7.3Hz,2H),2.31~2.28(m,2H),1.81~1.70(m,2H),1.69~1.56(m,6H),1.26(t,J=6.9Hz,3H),1.01(d,J=6.6Hz,3H)
Mass,m/e:478(M+),157(base)
步骤7-14-E:2-[5-(4-喹啉-2-基-哌嗪-1-基)己酰基氨基]-环己-1-烯羧
酸的合成
使用步骤7-14-D中合成的2-[5-(4-喹啉-2-基-哌嗪-1-基)己酰基氨基]-环己-1-烯羧酸乙酯,与上述步骤7-1-E同样地操作,合成2-[5-(4-喹啉-2-基-哌嗪-1-基)己酰基氨基]-环己-1-烯羧酸。
1H-NMR(CDCl3)δ:12.32(br-s,1H),7.91(d,J=9.3H z,1H),7.70(d,J=8.5Hz,1H),7.61(d,J=8.1Hz,1H),7.55(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.28~7.23(m,1H),6.95(d,J=8.9Hz,1H),4.05~3.97(m,4H),3.04~2.96(m,3H),2.95~2.90(m,2H),2.43~2.26(m,6H),1.93~1.71(m,2H),1.61~1.41(m,6H),1.19(d,J=6.9Hz,3H)
Mass,m/e:406,157(base)
步骤7-14-F:3-甲基-2-[4-(4-喹啉-2-基-哌嗪-1-基)-戊基]-5,6,7,8-四氢-
3H-喹唑啉-4-酮的合成
使用上述步骤7-14-E中合成的2-[5-(4-喹啉-2-基-哌嗪-1-基)己酰基氨基]-环己-1-烯羧酸,与上述步骤7-1-F同样地操作,合成3-甲基-2-[4-(4-喹啉-2-基-哌嗪-1-基)-戊基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.87(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.23~7.19(m,1H),6.96(d,J=9.2Hz,1H),3.77~3.71(m,4H),3.54(s,3H),2.74~2.68(m,5H),2.59~2.54(m,4H),2.50~2.47(m,2H),1.83~1.68(m,8H),1.01(d,J=6.6Hz,3H)
Mass,m/e:445,157(base)
实施例7-15
步骤7-15-A:2-[4-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]苯甲酸的合成
以邻氨基苯甲酸乙酯为起始原料,与上述步骤7-1-C至7-1-E同样地操作,合成2-[4-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]苯甲酸。
因难溶没有1H-NMR
Mass,m/e:432(M+),414,157(base)
步骤7-15-B:2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,1-苯并噁嗪-4-酮的
合成
在80℃下,将上述步骤7-15-A中合成的4.32g 2-[4-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]苯甲酸和3.06g乙酸酐的混合物搅拌1小时,然后减压馏去溶剂,得到4.17g(100%)的2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,1-苯并噁嗪-4-酮。
1H-NMR(CDCl3)δ:8.19(dd,J=1.5Hz,8.1Hz,1H),7.87(d,J=9.3Hz,1H),7.79(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.69(d,J=8.1Hz,1H),7.61~7.54(m,2H),7.55~7.48(m,2H),7.21(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.97(d,J=9.2Hz,1H),3.75(t,J=5.0Hz,4H),2.74(t,J=7.7Hz,2H),2.58(t,J=5.0Hz,4H),2.46(t,J=7.3Hz,2H),1.90(q,J=7.7Hz,2H),1.74~1.65(m,2H)
Mass,m/e:414(M+),157(base)
步骤7-15-C:N-异丙基-2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]苯甲
酰胺的合成
将上述步骤7-15-B中合成的414mg 2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,1-苯并噁嗪-4-酮、590mg异丙胺和5ml四氢呋喃密封在玻璃管内,在外温80℃下搅拌1小时。冷却后,减压馏去溶剂,用硅胶柱色谱法(二氯甲烷∶甲醇=10∶1)纯化所得残余物,得到275mg(58%)的N-异丙基-2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]苯甲酰胺。
1H-NMR(CDCl3)δ:11.11(brs,1H),8.61(dd,J=0.8Hz,8.5Hz,1H),7.87(d,J=9.3Hz,1H),7.68(d,J=8.5Hz,1H),7.58(dd,J=1.2Hz,8.1Hz,1H),7.51(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.45(ddd,J=1.5Hz,6.9Hz,8.9Hz,1H),7.41(dd,J=1.5Hz,8.1Hz,1H),7.20(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.05(ddd,J=1.2Hz,7.3Hz,8.5Hz,1H),6.96(d,J=9.3Hz,1H),5.99~5.97(m,1H),4.26~4.21(m,1H),3.74(t,J=5.0Hz,4H),2.61~2.57(m,4H),2.45(t,J=7.3Hz,2H),1.81~1.75(m,2H),1.69~1.59(m,2H),1.26(d,J=6.6Hz,6H)
Mass,m/e:473(M+),157(base)
步骤7-15-D:3-异丙基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-
4-酮的合成
将上述步骤7-15-C中合成的200mg N-异丙基-2-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]苯甲酰胺在250℃下搅拌1小时。冷却后,用硅胶柱色谱法(二氯甲烷∶甲醇=15∶1)纯化残余物,得到25mg(13%)的3-异丙基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.21(dd,J=1.2Hz,8.1Hz,1H),7.88(d,J=9.3Hz,1H),7.70~7.66(m,2H),7.64~7.62(m,1H),7.60~7.57(m,2H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.40(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.24~7.19(m,1H),6.97(d,J=9.3Hz,1H),4.64~4.56(m,1H),3.78~3.74(m,4H),2.90(t,J=7.7Hz,2H),2.61~2.57(m,4H),2.50(t,J=7.7Hz,2H),1.93~1.85(m,2H),1.79~1.69(m,2H),1.68(d,J=6.6Hz,6H)
Mass,m/e:455(M+),157(base)
实施例7-16
将上述步骤7-15-B中合成的207mg 2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,1-苯并噁嗪-4-酮和150mg苄基胺的混合物在250℃下搅拌1小时。冷却后,用硅胶柱色谱法(二氯甲烷∶甲醇=15∶1)纯化残余物,得到163mg(65%)的3-苄基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.30(dd,J=1.2Hz,8.1Hz,1H),7.88(d,J=8.9Hz,1H),7.74(ddd,J=1.2Hz,6.9Hz,8.5Hz,1H),7.72~7.57(m,2H),7.53(dd,J=1.1Hz,6.9Hz,1H),7.35~7.16(m,7H),7.46(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.96(d,J=8.9Hz,1H),5.43(s,3H),3.74~3.70(m,4H),2.79(t,J=7.7Hz,2H),2.54~2.50(m,4H),2.38(t,J=7.3Hz,2H),1.86~1.79(m,2H),1.63~1.55(m,2H)
Mass,m/e:503(M+),157(base),91
实施例7-17
与实施例7-16同样地操作,合成3-(4-甲氧基苯基)-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.26(dd,J=1.5Hz,8.1Hz,1H),7.87(d,J=9.2Hz,1H),7.78~7.76(m,1H),7.73(d,J=1.5Hz,1H),7.69(d,J=8.1Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.45(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.23~7.19(m,1H),7.16(dd,J=2.3Hz,6.5Hz,2H),7.05(dd,J=2.3Hz,6.5Hz,2H),6.96(d,J=9.2Hz,1H),3.86(s,3H),3.72~3.70(m,4H),2.52~2.48(m,6H),2.32(t,J=7.3Hz,2H),1.80~1.71(m,2H),1.53~1.49(m,2H)
Mass,m/e:519(M+),307,157(base)
实施例7-18
步骤7-18-A:2-氨基-6-氯-苯甲酸甲酯的合成
在冰冷却下,往20ml 4当量氢氧化钠、50ml二乙醚的混合溶液中加入2.7g N-甲基-N-亚硝基脲并搅拌30分钟。分取有机层,将其加入到915mg 2-氨基-6-氯-苯甲酸的20ml二乙醚溶液中,在室温下搅拌1小时。用饱和碳酸氢钠水溶液洗涤反应溶液,用无水硫酸镁干燥,减压馏去溶剂。用硅胶柱色谱法(正己烷∶乙酸乙酯=3∶1)纯化所得残余物,得到790mg(80%)的2-氨基-6-氯-苯甲酸甲酯。
1H-NMR(CDCl3)δ:7.07(t,J=8.1Hz,1H),6.74(dd,J=0.8Hz,7.7Hz,1H),6.57(dd,J=0.8Hz,8.1Hz,1H),4.86(brs,2H),3.93(s,3H)
Mass,m/e:185(M+),153(base),126,90
步骤7-18-B:2-(5-溴-戊酰基氨基)-6-氯-苯甲酸甲酯的合成
在冰冷却下,往上述步骤7-18-A中合成的750mg 2-氨基-6-氯-苯甲酸甲酯的10ml四氢呋喃溶液中加入700mg吡啶,随后加入800mg5-溴戊酰氯。使反应溶液在室温下搅拌1小时,然后减压馏去溶剂。用乙酸乙酯萃取残余物,用饱和碳酸氢钠水溶液、1当量盐酸、饱和食盐水洗涤,用无水硫酸镁干燥,减压馏去溶剂,得到1.34g(96%)的2-(5-溴-戊酰基氨基)-6-氯-苯甲酸甲酯。
1H-NMR(CDCl3)δ:9.07(brs,1H),8.27(d,J=8.1Hz,1H),7.35(t,J=8.1Hz,1H),7.17(dd,J=0.8Hz,8.1Hz,1H),3.98(s,3H),3.44(t,J=6.6Hz,4H),2.41(t,J=7.3Hz,2H),1.99~1.91(m,2H),1.90~1.83(m,2H)
Mass,m/e:347(M+),185,55(base)
步骤7-18-C:2-氯-6-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]苯甲酸甲
酯的合成
将上述步骤7-18-B中合成的1.29g 2-(5-溴-戊酰基氨基)-6-氯-苯甲酸甲酯、上述步骤7-1-A中合成的800mg 2-哌嗪-1-基喹啉、400mg三乙胺和200ml甲苯的混合物加热回流3小时。冷却后,水洗反应溶液,用无水硫酸镁干燥,减压馏去溶剂,用硅胶柱色谱法(乙酸乙酯∶甲醇=15∶1)纯化所得残余物,得到1.13g(64%)的2-氯-6-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]苯甲酸甲酯。
1H-NMR(CDCl3)δ:9.08(brs,1H),8.28(d,J=8.5Hz,1H),7.87(d,J=8.9Hz,1H),7.69(d,J=8.1Hz,1H),7.58(d,J=6.5Hz,1H),7.56(d,J=8.3Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.35(t,J=8.5Hz,1H),7.23~7.15(m,2H),6.97(d,J=9.2Hz,1H),3.97(s,3H),3.74(t,J=5.0Hz,4H),2.57(t,J=5.0Hz,4H),2.45~2.40(m,4H),1.81~1.73(m,2H),1.66~1.59(m,2H)
Mass,m/e:480(M+),157(base)
步骤7-18-D:5-氯-3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑
啉-4-酮
将上述步骤7-18-C中合成的250mg 2-氯-6-[5-(4-喹啉-2-基哌嗪-1-基)戊酰基氨基]苯甲酸甲酯和5ml 40%甲胺甲醇溶液的混合物密封在玻璃管内,在外温100℃下搅拌18小时。冷却后,减压馏去溶剂,用硅胶柱色谱法(二氯甲烷∶甲醇=15∶1)纯化所得残余物,得到96mg(40%)的5-氯-3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.9Hz,1H),7.70(d,J=8.5Hz,1H),7.59(dd,J=1.2Hz,8.1Hz,1H),7.56~7.50(m,3H),7.43(d,J=2.3Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.97(d,J=9.2Hz,1H),3.76(t,J=5.0Hz,4H),3.59(s,3H),2.85(t,J=7.7Hz,2H),2.59(t,J=5.0Hz,4H),2.49(t,J=7.3Hz,2H),1.95~1.86(m,2H),1.75~1.68(m,2H)
Mass,m/e:461(M+),157(base)
实施例7-19
使用5-氨基-1-甲基-1H-吡唑-4-羧酸乙酯作为起始原料,与实施例7-18同样地操作,合成1,5-二甲基-6-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-1,5-二氢-吡唑并[3,4-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:8.01(s,1H),7.89(d,J=8.9Hz,1H),7.70(d,J=8.5Hz,1H),7.62~7.58(m,1H),7.54(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.23(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=8.9Hz,1H),3.77(t,J=5.0Hz,4H),3.61(s,3H),3.59(s,3H),2.86(t,J=7.3Hz,2H),2.60(t,J=4.6Hz,4H),2.50(t,J=7.3Hz,2H),1.94~1.86(m,2H),1.75~1.70(m,2H)
Mass,m/e:431(M+),157(base)
实施例7-20
在起始原料中使用邻氨基苯甲酸乙酯,与实施例7-18同样地操作,合成3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.26(dd,J=1.2Hz,8.1Hz,1H),7.89(d,J=9.3Hz,1H),7.72(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.71~7.69(m,1H),7.64~7.62(m,1H),7.62~7.58(m,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.44(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=9.2Hz,1H),3.76(t,J=5.1Hz,4H),3.64(s,3H),2.89(t,J=8.1Hz,2H),2.59(t,J=5.0Hz,4H),2.49(t,J=7.3Hz,2H),1.93(q,J=7.7Hz,2H),1.79~1.70(m,2H)
Mass,m/e:427(M+),157(base)
实施例7-21
使用邻氨基苯甲酸乙酯作为起始原料,与实施例7-18同样地操作,合成3-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.25(dd,J=1.5Hz,8.1Hz,1H),7.89(d,J=9.2Hz,1H),7.71(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.70(dd,J=1.2Hz,8.5Hz,1H),7.64~7.58(m,2H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.43(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.98(d,J=8.9Hz,1H),4.19(q,J=6.9Hz,3H),3.77(t,J=5.0Hz,4H),2.88(t,J=7.7Hz,2H),2.60(t,J=5.0Hz,4H),2.50(t,J=7.3Hz,2H),1.95(q,J=7.7Hz,2H),1.80~1.70(m,2H),1.37(t,J=6.9Hz,3H)
Mass,m/e:441(M+),157(base)
实施例7-22
使用2-氨基-4,5-二甲氧基苯甲酸作为起始原料,与实施例7-18同样地操作,合成6,7-二甲氧基-3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.58(dd,J=1.2Hz,8.1Hz,1H),7.57(s,1H),7.53(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.22(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.03(s,1H),6.97(d,J=9.2Hz,1H),3.99(s,3H),3.98(s,3H),3.76(t,J=5.0Hz,4H),3.64(s,3H),2.86(t,J=7.3Hz,2H),2.59(t,J=5.0Hz,4H),2.49(t,J=7.3Hz,2H),1.93~1.85(m,2H),1.75~1.56(m,2H)
Mass,m/e:487(M+),157(base)
实施例7-23
使用2-氨基-4,5-二甲基噻吩-3-羧酸乙酯作为起始原料,与实施例7-18同样地操作,合成3,5,6-三甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-噻吩并[2,3-d]嘧啶-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.3Hz,1H),7.69(d,J=8.1Hz,1H),7.58(d,J=8.1Hz,1H),7.54~7.50(m,1H),7.23~7.19(m,1H),6.97(d,J=8.2Hz,1H),3.76(t,J=5.0Hz,4H),3.58(s,3H),2.83~2.79(m,2H),2.59(t,J=5.0Hz,4H),2.50~2.38(m,2H),2.46(s,3H),2.36(s,3H),1.89~1.83(m,2H),1.73~1.68(m,2H)
Mass,m/e:461(M+),157(base)
实施例7-24
使用2-氨基-4-甲基苯甲酸乙酯作为起始原料,与实施例7-18同样地操作,合成3,7-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.13(d,J=8.1Hz,1H),7.88(d,J=8.9Hz,1H),7.69(d,J=8.1Hz,1H),7.59(d,J=8.1Hz,1H),7.54~7.50(m,1H),7.42(s,1H),7.24~7.19(m,2H),6.97(d,J=9.2Hz,1H),3.76~3.75(m,4H),3.63(s,3H),2.88~2.84(m,2H),2.60~2.58(m,4H),2.51~2.48(m,5H),1.93~1.89(m,2H),1.74~1.71(m,2H)
Mass,m/e:441(M+),157(base)
实施例7-25
使用2-氨基-5-氯苯甲酸乙酯作为起始原料,与实施例7-18同样地操作,合成6-氯-3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.21(d,J=2.3Hz,1H),7.89(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.65~7.62(m,1H),7.60~7.51(m,3H),7.24~7.20(m,1H),6.98(d,J=8.9Hz,1H),3.76(brs,4H),3.64(s,3H),2.87(t,J=7.7Hz,2H),2.59(brs,4H),2.51~2.47(m,2H),1.94~1.88(m,2H),1.75~1.71(m,2H)
Mass,m/e:461(M+),157(base)
实施例7-26
使用2-氨基-5-溴苯甲酸乙酯作为起始原料,与实施例7-18同样地操作,合成6-溴-3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.38(d,J=2.3Hz,1H),7.88(d,J=9.2Hz,1H),7.78(dd,J=8.5Hz,J=2.3Hz,1H),7.69(d,J=8.5Hz,1H),7.60~7.58(m,1H),7.55~7.49(m,2H),7.24~7.20(m,1H),6.97(d,J=9.2Hz,1H),3.76(t,J=5.0Hz,4H),3.63(s,3H),2.86(t,J=7.7Hz,2H),2.59(t,J=5.0Hz,4H),2.51~2.47(m,2H),1.97~1.87(m,2H),1.77~1.64(m,2H)
Mass,m/e:505(M+),157(base)
实施例7-27
步骤7-27-A:2-[4-(3-氯丙基)哌嗪-1-基]喹啉的合成
将上述步骤7-1-A中合成的853mg 2-哌嗪-1-基喹啉溶解于5ml丙酮中,加入160mg氢氧化钠的5ml水溶液。往其中滴加0.5ml 1-溴-3-氯丙烷,在室温下搅拌过夜。往其中加入二乙醚,用饱和碳酸氢钠水溶液洗涤,用无水硫酸镁干燥有机层,减压馏去溶剂。用硅胶柱色谱法(氯仿∶甲醇=50∶1)纯化残余物,得到1.10g(95%)的2-[4-(3-氯丙基)哌嗪-1-基]喹啉。
1H-NMR(CDCl3):7.89(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H),7.59(dd,J=1.4Hz,8.0Hz,1H),7.53(ddd,J=1.5Hz,7.1Hz,8.5Hz,1H),7.22(ddd,J=1.1Hz,6.9Hz,8.0Hz,1H),6.98(d,J=9.2Hz,1H),3.75(t,J=5.1Hz,4H),3.61(t,J=6.5Hz,2H),2.63~2.43(m,6H),2.04~1.97(m,2H)
Mass,m/e:289(M+),157(base)
步骤7-27-B:3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢
-3H-喹唑啉-4-酮
将234mg 3-甲基-4-氧代-3,4,5,6,7,8-六氢喹唑啉-2-硫醇钾(文献:J.Med.Chem.,40,574-585(1997)中记载的化合物)、上述步骤7-27-A中合成的290mg 2-[4-(3-氯丙基)哌嗪-1-基]喹啉和5ml2-丙醇的混合物加热回流过夜。用硅胶柱色谱法(氯仿∶甲醇=10∶1)纯化残余物,得到467mg(定量)的3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.88(d,J=9.3Hz,1H),7.69(d,J=8.5Hz,1H),7.59(dd,J=8.1Hz,1.2Hz,1H),7.55~7.51(m,1H),7.23~7.20(m,1H),6.97(d,J=9.3Hz,1H),3.76(t,J=5.0Hz,4H),3.48(s,3H),3.23(t,J=7.3Hz,2H),2.60(t,J=5.0Hz,4H),2.56~2.51(m,4H),2.49~2.46(m,2H),2.01~1.93(m,2H),1.78~1.70(m,4H)
Mass,m/e:449(M+),157(base)
实施例7-28
使用3-甲基-4-氧代-3,4-二氢喹唑啉-2-硫醇钾作为起始原料,与实施例7-27同样地操作,合成3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.21(dd,J=8.1Hz,1.5Hz,1H),7.88(d,J=9.2Hz,1H),7.71~7.66(m,2H),7.59(d,J=7.7Hz,1H),7.55~7.51(m,2H),7.39~7.35(m,1H),7.24~7.20(m,1H),6.98(d,J=9.2Hz,1H),3.79~3.77(m,4H),3.65(s,3H),3.39~3.35(m,2H),2.64~2.57(m,6H),2.09~2.02(m,2H)
Mass,m/e:445(M+),157(base)
实施例7-29
步骤7-29-A:3-甲基-2-甲硫基-5,6,7,8-四氢-3H-喹唑啉-4-酮的合成
往10ml四氢呋喃、5ml二甲基甲酰胺的混合液中加入340mg 3-甲基-4-氧代-3,4,5,6,7,8-六氢喹唑啉-2-硫醇钾,往其中加入210mg甲基碘,在室温下搅拌过夜。将反应溶液进行浓缩,加入氯仿,用饱和食盐水洗涤,然后用无水硫酸镁干燥。减压馏去溶剂,得到310mg(定量)的3-甲基-2-甲硫基-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:3.49(s,3H),2.56~2.54(m,2H),2.54(s,3H),2.49~2.46(m,2H),1.77~1.70(m,4H)
Mass,m/e:210(M+),165(base)
步骤7-29-B:2-[4-(3-氨基丙基)哌嗪-1-基]喹啉的合成
往30ml乙醇中加入1.52g 2-[3-(4-喹啉-2-基哌嗪-1-基)丙基]异吲哚-1,3-二酮(文献:Pol.J.Chem.,75,71-78(2001)中记载的化合物),随后加入溶解于10ml乙醇的1.50g一水合肼,加热回流7小时。冷却后,过滤去除不溶物质,减压馏去溶剂。用5当量氢氧化钠使所得溶液呈碱性后,用氯仿萃取,用饱和食盐水洗涤,用无水硫酸钠干燥,减压馏去溶剂,得到0.99g(96%)的2-[4-(3-氨基丙基)哌嗪-1-基]喹啉。
1H-NMR(CDCl3)δ:7.87(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=8.1Hz,1H),7.52(ddd,J=1.5Hz,6.9Hz,8.5Hz,1H),7.23(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),6.97(d,J=8.9Hz,1H),3.75(t,J=5.4Hz,4H),2.78(t,J=6.9Hz,2H),2.58(t,J=5.4Hz,4H),2.46(t,J=7.3Hz,2H),1.78~1.63(m,2H)
Mass,m/e:270(M+),157(base)
步骤7-29-C:3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基氨基]-5,6,7,8-四
氢-3H-喹唑啉-4-酮的合成
将上述步骤7-29-A中合成的420mg 3-甲基-2-甲硫基-5,6,7,8-四氢-3H-喹唑啉-4-酮和上述步骤7-29-B中合成的540mg 2-[4-(3-氨基丙基)哌嗪-1-基]喹啉的混合物在140℃下过热搅拌6小时。用硅胶柱色谱法(氯仿∶甲醇=10∶1)纯化残余物,得到420mg(48%)的3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基氨基]-5,6,7,8-四氢-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:7.91(d,J=9.3Hz,1H),7.70(d,J=8.5Hz,1H),7.60(d,J=8.1Hz,1H),7.54(ddd,J=8.5Hz,6.9Hz,1.5Hz,1H),7.26~7.22(m,1H),6.98(d,J=8.9Hz,1H),6.69(brs,1H),3.77(brs,4H),3.56~3.52(m,2H),3.48(s,3H),2.67(brs,4H),2.64~2.61(m,2H),2.54(s,3H),2.49~2.40(m,4H),1.88~1.87(m,2H),1.77~1.70(m,4H)
Mass,m/e:432(M+),157(base)
实施例7-30
步骤7-30-A:3-甲基-2-甲硫基-3H-喹唑啉-4-酮的合成
使用3-甲基-4-氧代-3,4-二氢喹唑啉-2-硫醇钾作为起始原料,与上述步骤7-29-A同样地操作,得到3-甲基-2-甲硫基-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.22~8.20(m,1H),7.70~7.65(m,1H),7.57~7.55(m,1H),7.36(ddd,J=8.1Hz,J=6.9Hz,J=1.2Hz,1H),3.61(s,3H),2.66(s,3H)
Mass,m/e:206(M+),161(base)
步骤7-30-B:3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基氨基]-3H-喹唑
啉-4-酮的合成
使用上述步骤7-30-A中合成的3-甲基-2-甲硫基-3H-喹唑啉-4-酮作为起始原料,与上述步骤7-29-B同样地操作,得到3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基氨基]-3H-喹唑啉-4-酮。
1H-NMR(CDCl3)δ:8.10(dd,J=8.1Hz,1.2Hz,1H),7.92(d,J=9.2Hz,1H),7.72(d,J=8.5Hz,1H),7.62(dd,J=8.1Hz,1.2Hz,1H),7.58~7.53(m,2H),7.36(d,J=7.7Hz,1H),7.27~7.23(m,1H),7.15~7.11(m,1H),6.99(d,J=8.9Hz,1H),6.94(brs,1H),3.79(t,J=5.0Hz,4H),3.69~3.65(m,2H),3.51(s,3H),2.70(t,J=5.0Hz,4H),2.68~2.65(m,2H),1.95~1.92(m,2H)
Mass,m/e:428(M+),157(base)
制备例1
将8.6g无水哌嗪溶解于100ml乙二醇中,往其中加入7-氯呋喃并[2,3-c]吡啶,在140℃下搅拌过夜。冷却后,加入饱和碳酸氢钠水溶液,用氯仿萃取,用无水硫酸镁干燥有机层,减压下馏去溶剂。用硅胶柱色谱法纯化残余物,得到1.52g(75%)的7-哌嗪-1-基呋喃并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:7.96(d,J=5.5Hz,1H),7.63(d,J=2.3Hz,1H),6.97(d,J=5.4Hz,1H),6.72(d,J=1.9Hz,1H),3.83~3.80(m,4H),3.06(t,J=5.0Hz,4H)
Mass,m/e:203(M+),135(base)
制备例2
与制备例1同样地操作,得到7-(4-甲基哌嗪-1-基)呋喃并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:7.95(d,J=5.3Hz,1H),7.62(d,J=1.9Hz,1H),6.96(d,J=5.4Hz,1H),6.72(d,J=1.9Hz,1H),3.88(t,J=5.0Hz,4H),2.59(t,J=5.0Hz,4H),2.38(s,3H)
Mass,m/e:217(M+),147(base)
制备例3
与制备例1同样地操作,得到4-哌嗪-1-基呋喃并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.05(d,J=5.8Hz,1H),7.53(d,J=2.0Hz,1H),6.94(dd,J=0.8Hz,5.8Hz,1H),6.81(dd,J=1.2Hz,2.3Hz,1H),3.67(t,J=5.0Hz,4H),3.05(t,J=5.0Hz,4H)
Mass,m/e:203(M+),135(base)
制备例4
与制备例1同样地操作,得到4-(4-甲基哌嗪-1-基)呋喃并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:8.05(d,J=5.8Hz,1H),7.53(d,J=2.3Hz,1H),6.94(dd,J=1.2Hz,5.8Hz,1H),6.81(dd,J=1.2Hz,2.3Hz,1H),3.74(t,J=5.0Hz,4H),2.59(t,J=5.0Hz,4H),2.37(s,3H)
Mass,m/e:217(M+),147(base)
制备例5
与制备例1同样地操作,得到7-哌嗪-1-基噻吩并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:8.14(d,J=5.8Hz,1H),7.58(d,J=5.4Hz,1H),7.32(d,J=5.4Hz,1H),7.25(d,J=5.4Hz,1H),3.64(t,J=5.0Hz,4H),3.09(t,J=5.0Hz,4H)
Mass,m/e:219(M+),151(base)
制备例6
与制备例1同样地操作,得到7-(4-甲基哌嗪-1-基)噻吩并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:8.13(d,J=5.8Hz,1H),7.57(d,J=5.4Hz,1H),7.31(d,J=5.4Hz,1H),7.24(d,J=5.4Hz,1H),3.71(t,J=5.0Hz,4H),2.63(t,J=5.0Hz,4H),2.38(s,3H)
Mass,m/e:233(M+),163(base)
制备例7
与制备例1同样地操作,得到4-哌嗪-1-基噻吩并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.09(d,J=5.8Hz,1H),7.42~7.35(m,3H),3.50(t,J=5.0Hz,4H),3.11(t,J=5.0Hz,4H)
Mass,m/e:219(M+),151(base)
制备例8
与制备例1同样地操作,得到4-(4-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.08(d,J=5.8Hz,1H),7.41~7.33(m,3H),3.57(t,J=5.0Hz,4H),2.64(t,J=5.0Hz,4H),2.39(s,3H)
Mass,m/e:233(M+),163(base)
制备例9
与制备例1同样地操作,得到2-溴-4-哌嗪-1-基噻吩并[3,2-c]吡啶二盐酸盐。
1H-NMR(DMSO-d6)δ:8.03(d,J=5.8Hz,1H),7.90(s,1H),7.67(d,J=5.8Hz,1H),3.72(brs,4H),2.59(brs,4H)
Mass,m/e:297(M+),229(base)
制备例10
与制备例1同样地操作,得到2-溴-4-(4-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.05(d,J=5.4Hz,1H),7.36(d,J=0.8Hz,1H),7.19(dd,J=0.8Hz,5.8Hz,1H),3.53(t,J=5.0Hz,4H),2.63(t,J=5.0Hz,4H),2.39(s,3H)
Mass,m/e:311(M+),83(base)
制备例11
与制备例1同样地操作,得到2-甲基-4-哌嗪-1-基噻吩并[3,2-c]吡啶二盐酸盐。
1H-NMR(DMSO-d6)δ:7.94(d,J=6.2Hz,1H),7.76(d,J=6.2Hz,1H),7.55(s,1H),3.91(brs,4H),2.59(brs,4H),2.64(s,3H)
Mass,m/e:233(M+),177(base)
制备例12
与制备例1同样地操作,得到2-甲基-4-(4-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶二盐酸盐。
1H-NMR(DMSO-d6)δ:7.96(d,J=6.2Hz,1H),7.73(d,J=5.8Hz,1H),7.50(s,1H),4.20(d,J=5.9Hz,3H),3.57(brs,4H),3.30~3.27(m,4H),2.84(d,J=4.3Hz,3H)
Mass,m/e:247(M+),177(base)
制备例13
与制备例1同样地操作,得到3-溴-4-哌嗪-1-基噻吩并[3,2-c]吡啶二盐酸盐。
1H-NMR(DMSO-d6)δ:8.17(d,J=5.4Hz,1H),8.02(s,1H),7.83(d,J=5.8Hz,1H),3.56~3.32(m,8H)
Mass,m/e:297(M+),229(base)
制备例14
与制备例1同样地操作,得到3-溴-4-(4-甲基哌嗪-1-基)噻吩并[3,2-c]吡啶。
1H-NMR(DMSO-d6)δ:8.17(d,J=5.4Hz,1H),8.03(s,1H),7.84(d,J=5.4Hz,1H),3.59~3.51(m,4H),3.37~3.27(m,4H),2.87(m,3H)
Mass,m/e:311(M+),83(base)
制备例15
与制备例1同样地操作,得到3-氯-1-哌嗪-1-基异喹啉二盐酸盐。
1H-NMR(DMSO-d6)δ:8.08(d,J=8.5Hz,1H),7.90(d,J=8.1Hz,1H),7.78~7.75(m,1H),7.64~7.62(m,1H),7.60(s,1H),3.60~3.57(m,4H),3.29(brs,4H)
Mass,m/e:247(M+),179(base)
制备例16
与制备例1同样地操作,得到3-氯-1-(4-甲基哌嗪-1-基)异喹啉二盐酸盐。
1H-NMR(CDCl3)δ:8.02(d,J=8.1Hz,1H),7.90(d,J=8.1Hz,1H),7.79~7.75(m,1H),7.64(d,J=7.3Hz,1H),7.61(s,1H),3.98~3.52(m,4H),3.52~3.32(m,4H),2.86(m,3H)
Mass,m/e:261(M+),83(base)
制备例17
与制备例1同样地操作,得到7-(4-乙基哌嗪-1-基)-噻吩并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:8.12(d,J=5.8Hz,1H),7.57(d,J=5.4Hz,1H),7.31(d,J=5.4Hz,1H),7.23(d,J=5.8Hz,1H),3.73(t,J=5.0Hz,4H),2.67(t,J=5.0Hz,4H),2.52(q,J=7.3Hz,2H),1.53(t,J=7.3Hz,3H)
Mass,m/e:247(M+),163(base)
制备例18
与制备例1同样地操作,得到4-(4-乙基哌嗪-1-基)-噻吩并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.08(d,J=5.8Hz,1H),7.41~7.33(m,3H),3.59(t,J=5.0Hz,4H),2.68(t,J=5.0Hz,4H),2.52(q,J=7.3Hz,2H),1.15(t,J=7.3Hz,3H)
Mass,m/e:247(M+),163(base)
制备例19
与制备例1同样地操作,得到5-哌嗪-1-基-[1,6]二氮杂萘。
1H-NMR(CDCl3)δ:8.99(dd,J=1.9Hz,4.2Hz,1H),8.39(dd,J=1.2Hz,8.5Hz,1H),8.34(d,J=6.2Hz,1H),7.48(d,J=6.2Hz,1H),7.42(dd,J=4.2Hz,8.5Hz,1H),3.42~3.39(m,4H),3.16~3.14(m,4H)
Mass,m/e:214(M+),146(base)
制备例20
与制备例1同样地操作,得到5-(4-甲基哌嗪-1-基)-[1,6]二氮杂萘。
1H-NMR(CDCl3)δ:8.98(dd,J=1.9Hz,4.2Hz,1H),8.39~8.36(m,1H),8.33(d,J=6.2Hz,1H),7.48(dd,J=0.8Hz,5.8Hz,1H),7.41(dd,J=4.3Hz,5.8Hz,1H),3.49(t,J=5.0Hz,4H),2.69(t,J=5.0Hz,4H),2.41(s,3H)
Mass,m/e:228(M+),158(base)
制备例21
与制备例1同样地操作,得到5-(4-乙基哌嗪-1-基)-[1,6]二氮杂萘。
1H-NMR(CDCl3)δ:8.97(dd,J=1.9Hz,4.2Hz,1H),8.38~8.35(m,1H),8.32(d,J=5.8Hz,1H),7.46~7.45(m,1H),7.40(dd,J=4.2Hz,8.5Hz,1H),3.49(t,J=5.0Hz,4H),2.71(t,J=5.0Hz,4H),2.54(q,J=7.3Hz,2H),1.15(t,J=7.3Hz,3H)
Mass,m/e:242(M+),158(base)
制备例22
与制备例1同样地操作,得到8-哌嗪-1-基-[1,7]二氮杂萘。
1H-NMR(CDCl3)δ:8.82(dd,J=1.9Hz,4.3Hz,1H),8.13(d,J=5.4Hz,1H),8.00(dd,J=1.9Hz,8.5Hz,1H),7.47(dd,J=4.2Hz,8.5Hz,1H),7.04(d,J=5.8Hz,1H),3.93(t,J=5.0Hz,4H),3.13(t,J=5.0Hz,4H)
Mass,m/e:214(M+),146(base)
制备例23
与制备例1同样地操作,得到8-(4-甲基哌嗪-1-基)-[1,7]二氮杂萘。
1H-NMR(CDCl3)δ:8.82(dd,J=1.9Hz,4.3Hz,1H),8.12(d,J=5.8Hz,1H),7.80(dd,J=1.9Hz,8.5Hz,1H),7.47(dd,J=4.2Hz,8.5Hz,1H),7.04(d,J=5.4Hz,1H),4.01(brs,4H),2.67(t,J=5.0Hz,4H),2.38(s,3H)
Mass,m/e:228(M+),158(base)
制备例24
与制备例1同样地操作,得到8-(4-乙基哌嗪-1-基)-[1,7]二氮杂萘。
1H-NMR(CDCl3)δ:8.81(dd,J=1.9Hz,4.2Hz,1H),8.16(d,J=5.4Hz,1H),7.99(dd,J=1.9Hz,8.5Hz,1H),7.47(dd,J=4.2Hz,8.5Hz,1H),7.03(d,J=5.4Hz,1H),4.03(t,J=4.6Hz,4H),2.71(t,J=4.6Hz,4H),2.51(q,J=7.3Hz,2H),1.15(t,J=7.3Hz,3H)
Mass,m/e:242(M+),158(base)
制备例25
与制备例1同样地操作,得到2-甲基-哌嗪-1-基呋喃并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:7.93(d,J=5.8Hz,1H),6.86(dd,J=1.2Hz,5.8Hz,1H),6.38(s,1H),3.60(t,J=5.0Hz,4H),3.03(t,J=5.0Hz,4H),2.43(d,J=1.2Hz,3H)
Mass,m/e:217(M+),161(base)
制备例26
与制备例1同样地操作,得到7-甲氧基-3-甲基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:7.58(d,J=8.9Hz,1H),7.36(d,J=2.3Hz,1H),7.23(dd,J=2.3Hz,8.9Hz,1H),7.05(s,1H),3.92(s,3H),3.36~3.32(m,4H),3.18~3.14(m,4H),2.54(s,3H)
Mass,m/e:257(M+),188(Base)
制备例27
与制备例1同样地操作,得到7-甲氧基-3,4-二甲基-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:7.82(d,J=9.2Hz,1H),7.41(d,J=2.7Hz,1H),7.27(dd,J=2.7Hz,9.2Hz,1H),3.93(s,3H),3.41~3.34(m,4H),2.73~2.68(m,4H),2.56(s,3H),2.46(s,3H),2.41(s,3H)
Mass,m/e:285(M+),215(base),202
制备例28
与制备例1同样地操作,得到7-甲氧基-4-甲基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:7.92(d,J=0.7Hz,1H),7.81(d,J=9.2Hz,1H),7.49(d,J=2.7Hz,1H),7.40(dd,J=2.7Hz,9.2Hz,1H),3.95(s,3H),3.31~3.26(m,4H),3.18~3.14(m,4H),2.49(d,J=0.7Hz,3H)
Mass,m/e:257(M+),201,188(base)
制备例29
与制备例1同样地操作,得到7-甲氧基-4-甲基-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:7.90(s,1H),7.80(d,J=9.3Hz,1H),7.45(d,J=2.7Hz,1H),7.33(dd,J=2.7Hz,9.3Hz,1H),3.95,(s,3H),3.48~3.39(m,4H),2.75~2.66(m,4H),2.49(s,3H),2.41(s,3H)
Mass,m/e:305(M+),235,83(base)
制备例30
与制备例1同样地操作,得到7-溴-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.24~8.22(m,1H),8.16(d,J=5.8Hz,1H),7.67(dd,J=1.9Hz,8.5Hz,1H),7.61(d,J=8.9Hz,1H),7.26~7.19(m,1H),3.36~3.32(m,4H),3.16~3.12(m,4H)
Mass,m/e:292(M+),235,223(base)
制备例31
与制备例1同样地操作,得到7-溴-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.23~8.21(m,1H),8.16(d,J=5.8Hz,1H),7.67(dd,J=1.9Hz,8.5Hz,1H),7.61(d,J=8.5Hz,1H),7.20(dd,J=0.8Hz,5.8Hz),3.47~3.39(m,4H),2.76~2.26(m,4H),2.41(s,3H)
Mass,m/e:305(M+),235,83(base)
制备例32
与制备例1同样地操作,得到7-甲氧基-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.07(d,J=5.8Hz,1H),7.68(d,J=8.9Hz,1H),7.39(d,J=2.7Hz,1H),7.29(dd,J=2.7Hz,8.9Hz,1H),7.22(d,J=5.8Hz,1H),3.94(s,3H),3.48~3.40(m,4H),2.77~2.69(m,4H)
Mass,m/e:257(M+),187(base)
制备例33
与制备例1同样地操作,得到1-(4-乙基哌嗪-1-基)-7-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.07(d,J=5.8Hz,1H),7.68(d,J=8.7Hz,1H),7.40(d,J=2.5Hz,1H),7.31~7.25(m,1H),7.21(d,J=5.8Hz,1H),3.48~3.39(m,4H),2.79~2.69(m,4H),2.55(q,J=7.2Hz,2H),1.17(t,J=7.2Hz,3H)
Mass,m/e:271(M+),187(base)
制备例34
与制备例1同样地操作,得到7-甲氧基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.08(d,J=5.5Hz,1H),7.68(d,J=9.2Hz,1H),7.42(d,J=2.6Hz,1H),7.29(dd,J=2.6Hz,9.2Hz,1H),7.23(d,J=5.5Hz,1H),3.94(s,3H),3.37~3.30(m,4H),3.20~3.13(m,4H)
Mass,m/e:243(M+),174(base)
制备例35
与制备例1同样地操作,得到1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.15(d,J=5.9Hz,1H),8.11(d,J=8.4Hz,1H),7.75(d,J=8.1Hz,1H),7.61(ddd,J=1.1Hz,7.0Hz,8.1Hz,1H),7.51(ddd,1.1Hz,7.0Hz,8.4Hz,1H),7.25(d,J=5.9Hz,1H),3.41~3.34(m,4H),3.18~3.13(m,4H)
Mass,m/e:213(M+),145(base)
制备例36
与制备例1同样地操作,得到1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.15(d,J=5.9Hz,1H),8.09(d,J=8.4Hz,1H),7.75(d,J=8.1Hz,1H),7.60(ddd,J=1.1Hz,7.0Hz,8.1Hz,1H),7.50(ddd,1.1Hz,7.0Hz,8.4Hz,1H),7.24(d,J=5.9Hz,1H),3.51~3.41(m,4H),2.74~2.66(m,4H),2.42(s,3H)
Mass,m/e:227(M+),157(base)
制备例37
与制备例1同样地操作,得到1-(4-乙基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.14(d,J=5.9Hz,1H),8.09(d,J=8.4Hz,1H),7.74(d,J=8.1Hz,1H),7.60(ddd,J=1.1Hz,7.0Hz,8.1Hz,1H),7.50(ddd,1.1Hz,7.0Hz,8.4Hz,1H),7.23(d,J=5.9Hz,1H),3.51~3.44(m,4H),2.77~2.69(m,4H),2.55(q,J=7.3Hz,2H),1.17(t,J=7.3Hz,3H)
Mass,m/e:241(M+),157(base)
制备例38
与制备例1同样地操作,得到7-甲氧基-1-(3-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.07(d,J=5.8Hz,1H),7.68(d,J=8.9Hz,1H),7.40(d,J=2.7Hz,1H),7.29(dd,J=2.7Hz,8.9Hz,1H),7.23(d,J=5.8Hz,1H),3.94(s,3H),3.70~3.62(m,2H),3.30~3.17(m,3H),3.08~2.99(m,1H),2.80~2.71(m,1H),1.20(d,J=6.6Hz,3H)
Mass,m/e:257(M+),175(base)
制备例39
与制备例1同样地操作,得到1-(3,5-二甲基哌嗪-1-基)-7-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.07(d,J=5.8Hz,1H),7.68(d,J=8.9Hz,1H),7.40(d,J=2.7Hz,1H),7.29(dd,J=2.7Hz,8.9Hz,1H),7.21(d,J=5.8Hz,1H),3.93(s,3H),3.70~3.62(m,2H),3.33~3.23(m,2H),2.66~2.57(m,2H),1.17(d,J=6.6Hz,6H)
Mass,m/e:271(M+),187(base)
制备例40
与制备例1同样地操作,得到6-甲氧基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.10(d,J=5.9Hz,1H),8.01(d,J=9.2Hz,1H),7.16(d,J=5.9Hz,1H),7.13(dd,J=2.6Hz,9.2Hz,1H),7.02(d,J=2.6Hz,1H),3.93(s,3H),3.38~3.32(m,4H),3.18~3.12(m,4H)
Mass,m/e:243(M+),187(base)
制备例41
与制备例1同样地操作,得到6-甲氧基-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.09(d,J=5.9Hz,1H),7.99(d,J=9.2Hz,1H),7.15(d,J=5.9Hz,1H),7.12(dd,J=2.6Hz,9.2Hz,1H),7.02(d,J=2.6Hz,1H),3.93(s,3H),3.48~3.38(m,4H),2.74~2.64(m,4H),2.41(s,3H)
Mass,m/e:257(M+),187(base)
制备例42
与制备例1同样地操作,得到1-(4-乙基哌嗪-1-基)-6-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.09(d,J=5.9H z,1H),7.99(d,J=9.2Hz,1H),7.14(d,J=5.9Hz,1H),7.11(dd,J=2.6Hz,9.2Hz,1H),7.01(d,J=2.6Hz,1H),3.93(s,3H),3.48~3.38(m,4H),2.76~2.67(m,4H),2.55(q,J=7.3Hz,2H),1.16(t,J=7.3Hz,3H)
Mass,m/e:271(M+),187(base)
制备例43
与制备例1同样地操作,得到5-甲氧基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.16(d,J=6.2Hz,1H),7.67(d,J=8.5Hz,1H),7.63(dd,J=0.8Hz,5.8Hz,1H),7.41(t,J=7.7Hz,1H),6.94(d,J=7.7Hz,1H),3.99(s,3H),3.39~3.31(m,4H),3.18~3.11(m,4H)
Mass,m/e:243(M+),174(base)
制备例44
与制备例1同样地操作,得到5-甲氧基-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.16(d,J=5.8Hz,1H),7.65(dd,J=0.8Hz,8.5Hz,1H),7.62(dd,J=0.8Hz,5.8Hz,1H),7.41(t,J=7.7Hz,1H),6.94(d,J=7.7Hz,1H),3.98(s,3H),3.50~3.38(m,4H),2.74~2.63(m,4H),2.41(s,3H)
Mass,m/e:257(M+),187(base)
制备例45
与制备例1同样地操作,得到1-(4-乙基哌嗪-1-基)-5-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.15(d,J=5.8Hz,1H),7.65(d,J=8.5Hz,1H),7.62(d,J=5.8Hz,1H),7.40(t,J=7.7Hz,1H),6.93(d,J=7.7Hz,1H),3.98(s,3H),3.50~3.40(m,4H),2.77~2.68(m,4H),2.55(q,J=7.3Hz,2H),1.16(t,J=7.3Hz,3H)
Mass,m/e:271(M+),187(base)
制备例46
与制备例1同样地操作,得到7-甲基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.10(d,J=5.8Hz,1H),7.88(s,1H),7.66(d,J=8.1Hz,1H),7.45(dd,J=1.5Hz,8.1Hz,1H),7.22(d,J=5.8Hz,1H),3.39~3.32(m,4H),3.20~3.13(m,4H)
Mass,m/e:227(M+),159(base)
制备例47
与制备例1同样地操作,得到7-甲基-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.09(d,J=5.8Hz,1H),7.85(s,1H),7.65(d,J=8.5Hz,1H),7.44(dd,J=1.5Hz,8.5Hz,1H),7.21(d,J=5.8Hz,1H),3.51~3.38(m,4H),2.77~2.64(m,4H),2.54(s,3H),2.42(s,3H)
Mass,m/e:241(M+),171(base)
制备例48
与制备例1同样地操作,得到1-(4-乙基哌嗪-1-基)-7-甲基异喹啉。
1H-NMR(CDCl3)δ:8.09(d,J=5.8Hz,1H),7.85(s,1H),7.65(d,J=8.5Hz,1H),7.44(dd,J=1.5Hz,8.5Hz,1H),7.20(d,J=5.8Hz,1H),3.50~3.40(m,4H),2.80~2.69(m,4H),2.59~2.52(m,5H),1.17(t,J=7.3Hz,3H)
Mass,m/e:255(M+),171(base)
制备例49
与制备例1同样地操作,得到7-氯-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.16(d,J=5.8Hz,1H),8.07(d,J=1.9Hz,1H),7.70(d,J=8.5Hz,1H),7.55(dd,J=1.9Hz,8.5Hz,1H),7.23(d,J=5.8Hz,1H),3.41~3.33(m,4H),3.20~3.14(m,4H)
Mass,m/e:247(M+),179(base)
制备例50
与制备例1同样地操作,得到7-氯-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.15(d,J=5.8Hz,1H),8.05(d,J=1.9Hz,1H),7.70(d,J=8.5Hz,1H),7.55(dd,J=1.9Hz,8.5Hz,1H),7.22(d,J=5.8Hz,1H),3.48~3.40(m,4H),2.77~2.70(m,4H),2.42(s,3H)
Mass,m/e:261(M+),83(base)
制备例51
与制备例1同样地操作,得到7-氯-1-(4-乙基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.15(d,J=5.8Hz,1H),8.05(d,J=1.9Hz,1H),7.70(d,J=8.5Hz,1H),7.55(dd,J=1.9Hz,8.5Hz,1H),7.21(d,J=5.8Hz,1H),3.49~3.40(m,4H),2.79~2.69(m,4H),2.56(q,J=7.3Hz,2H),1.17(t,J=7.3Hz,3H)
Mass,m/e:275(M+),97(base)
制备例52
与制备例1同样地操作,得到7-氟-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.14(d,J=5.8Hz,1H),7.78~7.73(m,1H),7.73~7.66(m,1H),7.42~7.35(m,1H),7.24(d,J=5.8Hz,1H),3.48~3.37(m,4H),2.76~2.64(m,4H),2.42(s,3H)
4Mass,m/e:245(M+),175(base)
制备例53
4与制备例1同样地操作,得到1-(4-乙基哌嗪-1-基)-7-氟异喹啉。
1H-NMR(CDCl3)δ:8.14(d,J=5.8Hz,1H),7.78~7.73(m,1H),7.73~7.67(m,1H),7.42~7.36(m,1H),7.24(d,J=5.8Hz,1H),3.49~3.39(m,4H),2.79~2.70(m,4H),2.56(q,J=7.3Hz,2H),1.17(t,J=7.3Hz,3H)
4Mass,m/e:259(M+),175(base)
制备例54
与制备例1同样地操作,得到1-(4-甲基哌嗪-1-基)-7-苯基异喹啉。
1H-NMR(CDCl3)δ:8.30~8.27(m,1H),8.16(d,J=5.8Hz,1H),7.90~7.80(m,2H),7.72~7.67(m,2H),7.55~7.48(m,2H),7.44~7.39(m,1H),7.29~7.25(m,1H),3.55~3.49(m,4H),2.76~2.66(m,4H),2.42(s,3H)
4Mass,m/e:303(M+),233(base)
制备例55
与制备例1同样地操作,得到1-(4-乙基哌嗪-1-基)-7-苯基异喹啉。
1H-NMR(CDCl3)δ:8.30~8.27(m,1H),8.16(d,J=5.8Hz,1H),7.89~7.80(m,2H),7.72~7.67(m,2H),7.55~7.49(m,2H),7.44~7.39(m,1H),7.28~7.24(m,1H),3.58~3.48(m,4H),2.81~2.72(m,4H),2.56(q,J=7.3Hz,2H),1.17(t,J=7.3Hz,3H)
Mass,m/e:317(M+),233(base)
制备例56
与制备例1同样地操作,得到7-苯基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.30(s,1H),8.16(d,J=5.8Hz,1H),7.90~7.80(m,2H),7.72~7.67(m,2H),7.54~7.48(m,2H),7.44~7.39(m,1H),7.28(d,J=5.8H z,1H),3.47~3.38(m,4H),3.21~3.14(m,4H)
Mass,m/e:289(M+),220(base)
制备例57
与制备例1同样地操作,得到6-氯-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.16(d,J=5.8Hz,1H),8.03(d,J=8.9Hz,1H),7.73(d,J=1.9Hz,1H),7.44(dd,J=1.9Hz,8.9Hz,1H),7.16(d,J=5.8Hz,1H),3.40~3.34(m,4H),3.17~3.12(m,4H)
Mass,m/e:247(M+),179(base)
制备例58
与制备例1同样地操作,得到6-氯-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.15(d,J=5.8Hz,1H),8.01(d,J=8.9Hz,1H),7.72(d,J=1.9Hz,1H),7.43(dd,J=1.9Hz,8.9Hz,1H),7.14(d,J=5.8Hz,1H),3.45(t,J=4.6Hz,4H),2.69(t,J=4.6Hz,4H),2.41(s,3H)
Mass,m/e:261(M+),83(base)
制备例59
与制备例1同样地操作,得到6-氯-1-(4-乙基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.15(d,J=5.8Hz,1H),8.01(d,J=8.9Hz,1H),7.72(d,J=1.9Hz,1H),7.42(dd,J=1.9Hz,8.9Hz,1H),7.14(d,J=5.8Hz,1H),3.46(t,J=4.6Hz,4H),2.72(t,J=4.6Hz,4H),2.55(q,J=7.3Hz,2H),1.16(t,J=7.3Hz,3H)
Mass,m/e:275(M+),83(base)
制备例60
与制备例1同样地操作,得到5-氯-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.25(d,J=5.8Hz,1H),8.04(td,J=1.2Hz,8.5Hz,1H),7.69(dd,J=1.2Hz,7.3Hz,1H),7.64(dd,J=1.2Hz,5.8Hz,1H),7.42(dd,J=7.3Hz,8.5Hz,1H),3.41~3.35(m,4H),3.18~3.13(m,4H)
Mass,m/e:247(M+),179(base)
制备例61
与制备例1同样地操作,得到5-氯-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.24(d,J=5.8Hz,1H),8.02(d,J=8.5Hz,1H),7.68(dd,J=1.2Hz,7.3Hz,1H),7.62(dd,J=1.2Hz,5.8Hz,1H),7.41(dd,J=7.3Hz,8.5Hz,1H),3.45(t,J=4.6Hz,4H),2.69(t,J=4.6Hz,4H),2.41(s,3H)
Mass,m/e:261(M+),83(base)
制备例62
与制备例1同样地操作,得到5-氯-1-(4-乙基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.24(d,J=5.8Hz,1H),8.02(d,J=8.5Hz,1H),7.68(dd,J=0.8Hz,7.3Hz,1H),7.61(d,J=6.2Hz,1H),7.40(t,J=8.1Hz,1H),3.47(t,J=4.6Hz,4H),2.73(t,J=4.6Hz,4H),2.55(q,J=7.3Hz,2H),1.16(t,J=7.3Hz,3H)
Mass,m/e:275(M+),97(base)
制备例63
与制备例1同样地操作,得到7-氟-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.14(d,J=5.8Hz,1H),7.79~7.69(m,2H),7.43~7.37(m,1H),7.27~7.24(m,1H),3.38~3.32(m,4H),3.19~3.14(m,4H)
Mass,m/e:231(M+),163(base)
制备例64
与制备例1同样地操作,得到1-(2,5-二氮杂双环[2.2.2]辛烷-1-基)-7-甲氧基异喹啉。
1H-NMR(DMSO-d6)δ:7.97(d,J=8.9Hz,1H),7.79(d,J=6.2Hz,1H),7.59(d,J=8.9Hz,1H),7.48(s,1H),7.42(d,J=6.2Hz,1H),4.63(brs,1H),4.42~4.31(m,1H),4.10~3.98(m,1H),3.96(s,3H),3.96~3.27(m,3H),2.48~2.37(m,1H),2.28~2.13(m,1H),2.08~1.92(m,2H)
Mass,m/e:269(M+),175(base)
制备例65
与制备例1同样地操作,得到7-氯-1-[4-[4-(3-甲氧基苯基)丁基]哌嗪-1-基]异喹啉。
1H-NMR(CDCl3)δ:8.15(d,J=5.8Hz,1H),8.06(m,1H),7.67(d,J=8.9Hz,1H),7.56(d,J=1.9Hz,1H),7.52(d,J=2.3Hz,1H),7.26(t,J=3.9Hz,1H),6.82(d,J=7.7Hz,1H),6.75~6.69(m,2H),3.86(s,3H),3.39(t,J=5.0Hz,4H),2.69(t,J=4.8Hz,4H),2.59(t,J=7.0Hz,2H),2.41(t,J=7.5Hz,2H),1.75~1.50(m,4H)
Mass,m/e:409(M+),191(base),121,107
制备例66
与制备例1同样地操作,得到7-甲氧基-1-[4-[4-(3-甲氧基苯基)丁基]哌嗪-1-基]异喹啉。
1H-NMR(CDCl3)δ:8.17(d,J=5.9Hz,1H),8.08(s,1H),7.20(d,J=8.9Hz,1H),7.13(d,J=1.9Hz,1H),7.10(d,J=2.3Hz,1H),7.04(t,J=3.9Hz,1H),6.80(d,J=7.6Hz,1H),6.79~6.65(m,2H)3.96(s,3H),3.89(s,3H),3.42(t,J=4.8Hz,4H),2.73(t,J=4.8Hz,4H),2.63(t,J=6.9Hz,2H),2.43(t,J=7.5Hz,2H),1.78~1.47(m,4H)
Mass,m/e:405(M+),187(base),121,107
制备例67
与制备例1同样地操作,得到7-氯-1-[4-[反式-4-(3-甲氧基苯基)环己烷-1-基]哌嗪-1-基]异喹啉。
1H-NMR(CDCl3)δ:8.14(d,J=5.8Hz,1H),8.03(m,1H),7.69(d,J=8.9Hz,1H),7.55(d,J=1.9Hz,1H),7.53(d,J=1.9Hz,1H),7.22(d,J=5.9Hz,1H),6.81(d,J=7.7Hz,1H),6.76~6.72(m,2H),3.80(s,3H),3.59(t,J=5.0Hz,4H),2.97(t,J=4.8Hz,4H),2.53~2.47(m,2H),2.21~2.10(m,4H),2.09~2.00(m,4H)
Mass,m/e:435(M+),420,191(base),121,107
制备例68
与制备例1同样地操作,得到7-甲氧基-1-[4-[反式-4-(3-甲氧基苯基)环己烷-1-基]哌嗪-1-基]异喹啉。
1H-NMR(CDCl3)δ:8.08(d,J=5.7Hz,1H),8.00(d,J=9.3Hz,1H),7.20(d,J=5.7Hz,1H),7.14(d,J=5.7Hz,1H),7.11(dd,J =2.7Hz,9.3Hz,1H),7.01(d,J=2.7Hz,1H),6.82(d,J=7.3Hz,1H),6.78~6.72(m,2H),3.92(s,3H),3.80(s,3H),3.43(m,4H),2.87(t,J=4.4Hz,4H),2.50~2.47(m,2H),2.16~2.10(m,4H),2.06~1.98(m,4H)
Mass,m/e:431(M+),416,187(base),121
制备例69
与制备例1同样地操作,得到1-[4-(2,3-二氢-苯并[1,4]二噁烯-2-基甲基)-哌嗪-1-基]-7-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.06(d,J=5.7Hz,1H),7.66(d,J=9.0Hz,1H),7.39(d,J=2.3Hz,1H),7.22(d,J=5.4Hz,1H),7.28(dd,J=2.3Hz,8.8Hz,1H),6.89(dd,J=4.6Hz,9.6Hz,1H),6.84(dd,J=3.4Hz,5.8Hz,1H),4.41~4.35(m,2H),4.05(dd,J=7.4Hz,11.2Hz,1H),3.94(s,3H),3.41(t,J=4.5Hz,4H),2.92~2.85(m,2H),2.83~2.73(m,4H)
Mass,m/e:391(M+),376,282,187(base),174
制备例70
与制备例1同样地操作,得到1-[1,4]二氮杂环庚烷-1-基-7-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.02~7.99(m,2H),7.11~7.09(m,2H),7.00(d,J=2.3Hz,1H),3.92(s,3H),3.76(t,J=5.4Hz,2H),3.72(t,J=5.8Hz,2H),3.27(t,J=5.4Hz,2H),3.16(t,J=5.7Hz,2H),2.75(brs,1H),2.00~1.95(m,2H)
Mass,m/e:257(M+),242,201,187(base)
制备例71
与制备例1同样地操作,得到1-(4-苯并[1,3]二氧杂环戊烯-5-基甲基哌嗪-1-基)-7-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.07(d,J=5.8Hz,1H),7.97(d,J=9.3Hz,1H),7.13(d,J=5.8Hz,1H),7.09(dd,J=2.7Hz,9.3Hz,1H),7.00(d,J=2.7Hz,1H),6.91(s,1H),6.77(t,J=7.2Hz,2H),5.94(s,2H),3.91(s,3H),3.53(s,2H),3.39(m,4H),2.69(t,J=4.5Hz,4H)
Mass,m/e:377(M+),187(base),174,135
制备例72
与制备例1同样地操作,得到1-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)-7-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.07(d,J=5.4Hz,1H),7.68(d,J=8.9Hz,1H),7.40(d,J=2.7Hz,1H),7.29(dd,J=2.3Hz,8.9Hz,1H),7.21(d,J=5.4Hz,1H),3.94(s,3H),3.87~3.84(m,1H),3.79~3.75(m,2H),3.22~3.16(m,2H),2.93~2.88(m,1H),2.64~2.58(m,1H),2.40~2.38(m,1H),2.29(q,J=8.5Hz,1H),1.94~1.76(m,3H),1.65~1.52(m,1H)
Mass,m/e:283(M+),96(base)
制备例73
与制备例1同样地操作,得到7-氯-1-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)异喹啉。
1H-NMR(CDCl3)δ:8.14(d,J=5.8Hz,1H),8.04(d,J=2.3Hz,1H),7.68(d,J=8.9Hz,1H),7.55~7.52(m,1H),7.19(d,J=5.4Hz,1H),3.87~3.83(m,1H),3.78~3.73(m,1H),3.24~3.16(m,3H),2.93~2.87(m,1H),2.63~2.60(m,1H),2.38~2.25(m,2H),1.93~1.83(m,3H),1.63~1.51(m,1H)
Mass,m/e:287(M+),96(base)
制备例74
与制备例1同样地操作,得到8-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)-1,7-二氮杂萘。
1H-NMR(CDCl3)δ:8.83(dd,J=1.9Hz,4.2Hz,1H),8.13(d,J=5.4Hz,1H),8.01(dd,J=1.9Hz,8.5Hz,1H),7.48(dd,J=4.3Hz,8.5Hz,1H),7.04(d,J=5.4Hz,1H),4.96~4.90(m,2H),3.32~3.25(m,1H),3.19~3.15(m,2H),2.97~2.92(m,1H),2.62~2.56(m,1H),2.34~2.33(m,1H),2.25(q,J=8.9Hz,1H),1.96~1.85(m,2H),1.82~1.75(m,1H),1.56~1.50(m,1H)
Mass,m/e:254(M+),96(base)
制备例75
与制备例1同样地操作,得到5-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)-1,6-二氮杂萘。
1H-NMR(CDCl3)δ:8.98(dd,J=1.9Hz,4.2Hz,1H),8.40~8.37(m,1H),8.33(d,J=5.8Hz,1H),7.47~7.40(m,2H),3.93(td,J=2.3Hz,8.3Hz,1H),3.82(dd,J=2.7Hz,11.8Hz,1H),3.32~3.25(m,1H),3.21~3.16(m,2H),2.97~2.93(m,1H),2.59(dt,J=2.7Hz,11.2Hz,1H),2.37~2.25(m,2H),1.94~1.75(m,3H),1.55~1.50(m,1H)
Mass,m/e:254(M+),96(base)
制备例76
与制备例1同样地操作,得到7-氯-1-((8aR)-八氢吡咯并[1,2-a]吡嗪-2-基)异喹啉。
1H-NMR(CDCl3)δ:8.15(d,J=5.8Hz,1H),8.06(d,J=1.9Hz,1H),7.69(d,J=8.9Hz,1H),7.55(dd,J=1.9Hz,8.9Hz,1H),7.21(d ,J=5.8Hz,1H),3.86(td,J=2.3Hz,11.6Hz,1H),3.80~3.75(m,1H),3.25~3.17(m,3H),2.94~2.88(m,1H),2.65~2.59(m,1H),2.39~2.34(m,1H),2.28(t,J=8.9Hz,1H),1.95~1.84(m,2H),1.84~1.75(m,1H),1.55~1.48(m,1H)
Mass,m/e:287(M+),96(base)
制备例77
与制备例1同样地操作,得到1-((8aR)-八氢吡咯并[1,2-a]吡嗪-2-基)-7-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.06(d,J=5.8Hz,1H),7.66(dd,J=3.4Hz,8.9Hz,1H),7.39(d,J=2.3Hz,1H),7.27(dd,J=2.3Hz,8.9Hz,1H),7.19(d,J=5.4Hz,1H),3.93(s,3H),3.85(td,J=2.3Hz,12.0Hz,1H),3.77~3.74(m,1H),3.20~3.15(m,3H),2.89(t,J=10.8Hz,1H),2.60(t,J=11.2Hz,1H),2.39~2.37(m,1H),2.32~2.25(m,1H),1.93~1.83(m,2H),1.80~1.76(m,1H),1.59~1.51(m,1H)
Mass,m/e:283(M+),96(base)
制备例78
与制备例1同样地操作,得到3-氯-1-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)异喹啉。
1H-NMR(CDCl3)δ:8.00(d,J=8.5Hz,1H),7.64(d,J=7.7Hz,1H),7.60~7.56(m,1H),7.46~7.42(m,1H),7.22(s,1H),3.99(td,J=2.3Hz,12.3Hz,1H),3.93~3.89(m,1H),3.24(dt,J=2.7Hz,12.0Hz,1H),3.18~3.13(m,2H),2.95~2.90(m,1H),2.61~2.23(m,2H),1.93~1.83(m,1H),1.81~1.74(m,2H),1.53~1.47(m,1H)
Mass,m/e:287(M+),96(base)
制备例79
与制备例1同样地操作,得到3-氯-1-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)-7-甲基异喹啉。
1H-NMR(CDCl3)δ:7.55(d,J=8.5Hz,1H),7.42(dd,J=1.5Hz,8.5Hz,1H),7.19(s,1H),3.95(td,J=2.3Hz,12.3Hz,1H),3.90~3.86(m,1H),3.25~3.13(m,2H),2.95~2.89(m,1H),2.62~2.57(m,1H),2.51(s,3H),2.35~2.24(m,2H),1.91~1.83(m,2H),1.79~1.76(m,1H),1.56~1.51(m,1H)
Mass,m/e:301(M+),96(base)
制备例80
与制备例1同样地操作,得到7-氯-1-八氢吡啶并[1,2-a]吡嗪-2-基异喹啉。
1H-NMR(CDCl3)δ:8.15(d,J=5.8Hz,1H),8.05(d,J=1.9Hz,1H),7.69(d,J=8.9Hz,1H),7.55(dd,J=1.9Hz,8.9Hz,1H),7.21(d,J=5.8Hz,1H),3.72(qd,J=2.7Hz,12.3Hz,1H),3.56(td,J=2.7Hz,12.3Hz,1H),3.23(dt,J=2.7Hz,12.3Hz,1H),2.97~2.84(m,3H),2.63(dt,J=2.7Hz,11.6Hz,1H),2.33~2.16(m,2H),1.87~1.78(m,1H),1.75~1.57(m,3H),1.45~1.28(m,2H)
Mass,m/e:301(M+),110(base)
制备例81
与制备例1同样地操作,得到7-甲氧基-1-八氢吡啶并[1,2-a]吡嗪-2-基异喹啉。
1H-NMR(CDCl3)δ:8.07(d,J=5.4Hz,1H),7.67(d,J=8.9Hz,1H),7.40(d,J=2.7Hz,1H),7.28(dd,J=2.7Hz,8.9Hz,1H),7.20(d,J=5.8Hz,1H),3.94(s,3H),3.72(qd,J=2.7Hz,12.3Hz,1H),3.57(td,J=2.7Hz,12.3Hz,1H),3.26~3.16(m,1H),2.98~2.84(m,3H),2.63(dt,J=2.7Hz,11.6Hz,1H),2.35~2.25(m,1H),2.25~2.15(m,1H),1.84~1.54(m,4H),1.42~1.32(m,2H)
Mass,m/e:297(M+),110(base)
制备例82
与制备例1同样地操作,得到7-甲硫基-1-(S)-八氢吡啶并[1,2-a]吡喃-2-基异喹啉。
1H-NMR(CDCl3)δ:8.10(d,J=5.8H z,1H),7.85(d,J=1.9Hz,1H),7.65(d,J=8.5Hz,1H),7.50(dd,J=1.9Hz,8.5Hz,1H),7.18(d,J=5.8Hz,1H),3.91~3.84(m,1H),3.82~3.75(m,1H),3.25~3.15(m,3H),2.94~2.85(m,1H),2.59(s,3H),2.43~2.24(m,2H),1.97~1.73(m,3H),1.66~1.47(m,2H)
Mass,m/e:299(M+),96(base)
制备例83
首先,与制备例1同样地操作,得到285mg 7-甲硫基-1-(S)-八氢吡啶并[1,2-a]吡喃-2-基异喹啉。向其中加入1ml 30%过氧化氢水和0.5ml乙酸,在室温下搅拌15分钟,然后用氨水使其碱性化并用二氯甲烷萃取,用无水硫酸镁干燥,减压下馏去溶剂。用硅胶柱色谱法(甲醇∶二氯甲烷=1∶4)纯化残余物,得到235mg(78%)的7-甲基亚硫酰基-1-(S)-八氢吡啶并[1,2-a]吡喃-2-基异喹啉。
1H-NMR(CDCl3)δ:8.43~8.40(m,1H),8.23(d,J=5.8Hz,1H),7.89(d,J=8.5Hz,1H),7.77~7.73(m,1H),7.28~7.25(m,1H),3.94(d,J=12.0Hz,1H),3.89~3.81(m,1H),3.33~3.23(m,1H),3.23~3.14(m,2H),3.02~2.91(m,1H),2.79(d,J=1.5Hz,3H),2.70~2.60(m,1H),2.46~2.25(m,2H),1.97~1.75(m,3H),1.62~1.46(m,1H)
Mass,m/e:315(M+),96(base)
制备例84
首先,与制备例1同样地操作,得到610mg 7-甲氧基-1-八氢吡啶并[1,2-a]吡嗪-2-基异喹啉。向其中加入8ml 47%氢溴酸水溶液并加热回流2小时。冷却后,使用5当量氢氧化钠水溶液进行中和,用氯仿萃取,用无水硫酸镁干燥并在减压下馏去溶剂。用硅胶柱色谱法(饱和氨水∶甲醇∶氯仿=0.5∶5∶45)纯化残余物,得到500mg(86%)的7-羟基-1-八氢吡啶并[1,2-a]吡嗪-2-基异喹啉。
1H-NMR(CDCl3)δ:8.03(dd,J=1.2Hz,5.8Hz,1H),7.67(d,J=8.9Hz,1H),7.41(d,J=2.3Hz,1H),7.27~7.21(m,1H),7.20(d,J=5.8Hz,1H),3.71~3.63(m,1H),3.58~3.51(m,1H),3.27~3.17(m,1H),2.95~2.83(m,3H),2.60~2.50(m,1H),2.31~2.07(m,2H),1.82~1.54(m,4H),1.39~1.26(m,2H)
Mass,m/e:283(M+),110(base)
制备例85
与制备例84同样地操作,得到1-(S)-八氢吡啶并[1,2-a]吡喃-2-基-7-羟基异喹啉。
1H-NMR(CDCl3)δ:8.02(d,J=5.4Hz,1H),7.68(d,J=8.9Hz,1H),7.42(d,J=2.3Hz,1H),7.29~7.25(m,1H),7.23(d,J=5.4Hz,1H),3.71~3.58(m,2H),3.32~3.23(m,1H),3.21~3.13(m,2H),3.01~2.85(m,3H),2.55~2.46(m,1H),1.98~1.79(m,3H),1.59~1.49(m,1H)
Mass,m/e:269(M+),96(base)
制备例86
将制备例84中合成的105mg 7-羟基-1-八氢吡啶并[1,2-a]吡嗪-2-基异喹啉溶解于3ml N-甲基吡咯烷酮中,向其中加入1.00g氨磺酰氯,在室温下搅拌1小时。用饱和氢氧化钠水溶液进行中和,用氯仿萃取,用无水硫酸镁干燥并在减压下馏去溶剂。用硅胶柱色谱法(25%氨水∶甲醇∶氯仿=1∶10∶90)纯化残余物,得到85mg(75%)的1-八氢吡啶并[1,2-a]吡嗪-2-基-7-氨磺酰基异喹啉。
1H-NMR(CDCl3)δ:8.05(d,J=5.8Hz,1H),7.97(d,J=2.7Hz,1H),7.75(d,J=8.9Hz,1H),7.57(dd,J=2.7Hz,8.9Hz,1H),7.14(d,J=5.8Hz,1H),3.62~3.49(m,2H),3.05(dt,J=2.7Hz,12.3Hz,1H),2.94~2.72(m,3H),2.54(dt,J=3.1Hz,11.6Hz,1H),2.27(t,J=10.8Hz,1H),2.21~2.12(m,1H),1.83~1.54(m,4H),1.43~1.21(m,2H)
Mass,m/e:362(M+),110(base)
制备例87
与制备例86同样地操作,得到1-(S)-八氢吡啶并[1,2-a]吡喃-2-基-7-氨磺酰基异喹啉。
1H-NMR(CDCl3)δ:8.08(d,J=5.8Hz,1H),7.98(d,J=2.3Hz,1H),7.77(d,J=8.9Hz,1H),7.57(dd,J=2.3Hz,8.9Hz,1H),7.17(d,J=5.8Hz,1H),3.85~3.78(m,1H),3.73~3.65(m,1H),3.18~3.05(m,3H),2.86~2.78(m,1H),2.63~2.54(m,1H),2.43~2.24(m,2H),1.95~1.74(m,3H),1.53~1.41(m,1H)
Mass,m/e:348(M+),96(base)
制备例88
步骤1:1-(4-苄基哌嗪-1-基)-7-氯异喹啉的合成
将3.96g 1,7-二氯异喹啉和10.50g苄基哌嗪的混合物在150℃下搅拌3小时。往残余物中加水,用氯仿萃取,用饱和碳酸氢钠水溶液洗涤,用无水硫酸镁干燥并在减压下馏去溶剂。用硅胶柱色谱法(乙酸乙酯)纯化残余物,得到4.78g(71%)的1-(4-苄基哌嗪-1-基)-7-氯异喹啉。
1H-NMR(CDCl3)δ:8.14(d,J=5.4Hz,1H),8.04(d,J=1.9Hz,1H),7.68(d,J=8.5Hz,1H),7.53(dd,J=2.3Hz,8.8Hz,1H),7.39~7.23(m,5H),7.20(d,J=5.8Hz,1H),3.64(s,2H),3.41(t,J=5.6Hz,4H),2.73(t,J=4.8Hz,4H)
Mass,m/e:337(M+),191,159,91(base)
步骤2:1-(4-苄基哌嗪-1-基)-7-二甲基氨基异喹啉的合成
将上述步骤1中合成的1.01g 1-(4-苄基哌嗪-1-基)-7-氯异喹啉溶解于30ml四氢呋喃中,然后向其中加入20mg乙酸钯、48mg 2-(二叔丁基膦基)联苯、450mg叔丁醇钠和5ml 2.0M二甲胺四氢呋喃溶液并封管,将该混合物在80℃下搅拌16小时。过滤去除不溶物质后,减压馏去溶剂,用硅胶柱色谱法(甲醇∶氯仿=1∶19)纯化残余物,得到261mg(25%)的1-(4-苄基哌嗪-1-基)-7-二甲基氨基异喹啉。
1H-NMR(CDCl3)δ:7.94(d,J=5.7Hz,1H),7.63(d,J=9.0Hz,1H),7.45~7.20(m,6H),7.18(d,J=5.4Hz,1H),7.12(d,J=2.3Hz,1H),3.69(s,2H),3.49(t,J=4.8Hz,4H),3.06(s,6H),2.77(t,J=5.0Hz,4H)
Mass,m/e:346(M+),330,200(base),187,91
步骤3:7-二甲基氨基-1-哌嗪-1-基异喹啉的合成
将上述步骤2中合成的250mg 1-(4-苄基哌嗪-1-基)-7-二甲基氨基异喹啉溶解于20ml乙醇中,往其中加入50mg 10%披钯碳,将该混合物在氢气氛下在室温下搅拌16小时。过滤去除不溶物质,减压下馏去溶剂。用硅胶柱色谱法(甲醇∶氯仿=1∶9)纯化残余物,得到46mg(25%)的7-二甲基氨基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:7.95(d,J=5.4Hz,1H),7.64(d,J=8.9Hz,1H),7.27(dd,J=2.3Hz,8.9Hz,1H),7.16(d,J=5.4Hz,1H),7.12(d,J=2.3Hz,1H),3.39(t,J=5.0Hz,4H),3.19(t,J=5.0Hz,4H),3.07(s,6H)
Mass,m/e:256(M+),200,187(base)
制备例89
通过常规方法将制备例88所得化合物甲基化,得到7-二甲基氨基-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:7.95(d,J=5.7Hz,1H),7.63(d,J=9.0Hz,1H),7.32(dd,J=2.8Hz,9.0Hz,1H),7.21(d,J=5.4Hz,1H),7.12(d,J=2.8Hz,1H),3.45(t,J=5.0Hz,4H),3.07(s,6H),2.71(t,J=5.0Hz,4H),2.42(s,3H)
Mass,m/e:270(M+),200,187(base)
制备例90
与制备例88同样地操作,得到7-甲基氨基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:7.93(d,J=5.8Hz,1H),7.57(d,J=8.9Hz,1H),7.17(d,J=5.4Hz,1H),7.01(dd,J=1.3Hz,8.9Hz,1H),6.90(d,J=1.9Hz,1H),3.56(t,J=5.0Hz,4H),3.33(t,J=5.0Hz,4H),2.94(s,3H)
Mass,m/e:242(M+),198,186,173(base)
制备例91
与制备例89同样地操作,得到7-甲基氨基-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:7.94(d,J=5.7Hz,1H),7.55(d,J=9.5Hz,1H),7.21(d,J=9.2Hz,1H),7.07(dd,J=2.6Hz,5.1Hz,1H),6.97(d,J=2.0Hz,1H),3.44(t,J=4.8Hz,4H),2.95(s,3H),2.72(t,J=5.0Hz,4H),2.42(s,3H)
Mass,m/e:256(M+),186(base),173,157
制备例92
步骤1:2-苯并[1,3]二氧杂环戊烯-5-基甲基-1-叔丁氧基羰基-3-氧代
哌嗪的合成
在氩气氛下,在冰冷却下,往25ml四氢呋喃和2.78g二异丙胺的混合物中滴加17.5ml 1.58M的正丁基锂-正己烷溶液,原样搅拌30分钟。在冰冷却下,往其中滴加2.50g 1-叔丁氧基羰基-3-氧代哌嗪(参照Tetrahedron Lett,1980,21,3019-3020制备的化合物)的60ml四氢呋喃溶液,原样搅拌3小时后,在冰冷却下,往其中滴加2.30g 5-氯甲基-苯并[1,3]二氧杂环戊烯的20ml四氢呋喃溶液,原样搅拌1小时。使反应溶液的温度返回至室温后搅拌18小时,然后加入饱和氯化铵水溶液,用乙酸乙酯萃取,用无水硫酸镁干燥,减压下馏去溶剂。用硅胶柱色谱法(乙酸乙酯)纯化残余物,得到2.84g(68%)的2-苯并[1,3]二氧杂环戊烯-5-基甲基-1-叔丁氧基羰基-3-氧代哌嗪。
1H-NMR(CDCl3)δ:6.67(s,1H),6.65(d,J=1.3Hz,2H),5.90(s,2H),4.52~4.43(m,1H),4.12(d,J=7.2Hz,2H),3.23(t,J=5.1Hz,2H),2.57(t,J=5.8Hz,2H),1.45(s,9H)
Mass,m/e:334(M+),278,144,57(base)
步骤2:2-苯并[1,3]二氧杂环戊烯-5-基甲基-1-叔丁氧基羰基哌嗪的合
成
将上述步骤中合成的2.00g 2-苯并[1,3]二氧杂环戊烯-5-基甲基-1-叔丁氧基羰基-3-氧代哌嗪溶解于50ml四氢呋喃中,往所得溶液中加入1.00g氢化铝锂,加热回流16小时。向其中加入10%氢氧化锂水溶液,过滤去除不溶物质,用乙酸乙酯萃取,用无水硫酸镁干燥,减压下馏去溶剂。用硅胶柱色谱法(甲醇∶氯仿=1∶19)纯化残余物,得到1.27g(66%)的2-苯并[1,3]二氧杂环戊烯-5-基甲基-1-叔丁氧基羰基哌嗪。
1H-NMR(CDCl3)δ:6.68(s,1H),6.65(d,J=0.5Hz,2H),5.90(s,2H),4.02~3.87(m,3H),3.78~3.54(m,2H),2.96~2.77(m,2H),2.65~2.51(m,2H),1.45(s,9H)
Mass,m/e:320(M+),219,57(base)
步骤3:1-(2-苯并[1,3]二氧杂环戊烯-5-基甲基-1-叔丁氧基羰基哌嗪-4-
基)-7-甲氧基异喹啉的合成
在150℃下,将上述步骤中合成的320mg 2-苯并[1,3]二氧杂环戊烯-5-基甲基-1-叔丁氧基羰基哌嗪、200mg 1-氯-7-甲氧基异喹啉和110mg三乙胺的混合物在2ml乙二醇中搅拌18小时。往反应溶液中加入水,用乙酸乙酯萃取,用无水硫酸镁干燥,减压下馏去溶剂。用硅胶柱色谱法(乙酸乙酯∶正己烷=1∶1)纯化残余物,得到210mg(44%)的1-(2-苯并[1,3]二氧杂环戊烯-5-基甲基-1-叔丁氧基羰基哌嗪-4-基)-7-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.05(d,J=5.5Hz,1H),7.64(d,J=9.1Hz,1H),7.26(dd,J=2.1Hz,9.1Hz,1H),7.22(d,J=5.4Hz,1H),7.08(d,J=2.1Hz,1H),6.92(s,1H),6.79(d,J=1.3Hz,1H),5.94(s,2H),3.93(s,3H),3.33~3.26(m,2H),3.21~3.14(m,2H),2.80~2.66(m,3H),1.45(s,9H)
Mass,m/e:477(M+),342(base),187,135
步骤4:1-(3-苯并[1,3]二氧杂环戊烯-5-基甲基哌嗪-1-基)-7-甲氧基异
喹啉的合成
将上述步骤中合成的150mg 1-(2-苯并[1,3]二氧杂环戊烯-5-基甲基-1-叔丁氧基羰基哌嗪-4-基)-7-甲氧基异喹啉在10ml 4当量盐酸二噁烷溶液中搅拌18小时。用饱和碳酸氢钠水溶液中和反应溶液,用乙酸乙酯萃取,用无水硫酸镁干燥,减压下馏去溶剂。用硅胶柱色谱法(甲醇∶氯仿=1∶9)纯化残余物,得到69mg(58%)的1-(3-苯并[1,3]二氧杂环戊烯-5-基甲基哌嗪-1-基)-7-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.07(d,J=5.5Hz,1H),7.66(d,J=9.2Hz,1H),7.33~7.30(m,1H),7.25~7.18(m,2H),6.74(s,1H),6.72(d,J=0.8Hz,1H),5.93(s,2H),3.84(s,3H),3.66~3.59(m,2H),3.30~3.18(m,2H),3.15~3.10(m,2H),2.80~2.64(m,3H)
Mass,m/e:377(M+),242(base),187,135
制备例93
往10ml丙酮中加入50mg 7-甲氧基-1-哌嗪-1-基异喹啉、100mg 4-氟苄基溴和100mg三乙胺,加热回流5小时。减压下馏去溶剂,用硅胶柱色谱法(甲醇∶氯仿=1∶19)纯化残余物,得到52mg(79%)的1-[4-(4-氟苄基)哌嗪-1-基]-7-甲氧基异喹啉。
1H-NMR(CDCl3)δ:8.07(d,J=5.5Hz,1H),7.68(d,J=9.2Hz,1H),7.41~7.32(m,3H),7.30~7.26(m,1H),7.21(d,J=5.5Hz,1H),7.06~6.99(m,2H),3.93(s,3H),3.61(s,2H),3.45~3.35(m,4H),2.77~2.67(m,4H)
Mass,m/e:351(M+),187(base)
制备例94
与制备例93同样地操作,得到1-[4-(4-氟苄基)哌嗪-1-基]异喹啉。
1H-NMR(CDCl3)δ:8.14(d,J=5.8Hz,1H),8.08(d,J=8.5Hz,1H),7.74(d,J=8.1Hz,1H),7.59(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.49(ddd,1.2Hz,6.9Hz,8.5Hz,1H),7.38~7.32(m,2H),7.23(d,J=5.8Hz,1H),7.06~6.99(m,2H),3.61(s,2H),3.47~3.40(m,4H),2.75~2.68(m,4H)
Mass,m/e:321(M+),157(base)
制备例95
步骤1:1-(4-叔丁氧基羰基哌嗪-1-基)-7-羟基异喹啉的合成
将4.00g 7-甲氧基-1-哌嗪-1-基异喹啉和40ml 47%氢溴酸水溶液的混合物加热回流2小时。冷却后,利用5当量氢氧化钠水溶液使所得溶液呈碱性,随后往其中加入30ml 1,4-二噁烷、3.94g二碳酸二叔丁酯,在室温下搅拌1小时。用乙酸乙酯萃取,用饱和食盐水洗涤,用无水硫酸镁干燥并在减压下馏去溶剂。用硅胶柱色谱法(甲醇∶氯仿=1∶19)纯化残余物,得到4.63g(85%)的1-(4-叔丁氧基羰基哌嗪-1-基)-7-羟基异喹啉。
1H-NMR(CDCl3)δ:8.03(d,J=5.5Hz,1H),7.70(d,J=8.8Hz,1H),7.43(d,J=2.6Hz,1H),7.30~7.23(m,2H),3.72~3.64(m,4H),3.34~3.26(m,4H),1.51(s,9H)
Mass,m/e:329(M+),173(base)
步骤2:7-羟基-1-哌嗪-1-基异喹啉盐酸盐的合成
将上述步骤中合成的70mg 1-(4-叔丁氧基羰基哌嗪-1-基)-7-羟基异喹啉和3ml 4当量盐酸乙酸乙酯溶液的混合物在室温下搅拌1小时。滤取结晶并用乙酸乙酯洗涤,得到43mg(产率78%)的7-羟基-1-哌嗪-1-基异喹啉盐酸盐。
1H-NMR(CD3OD)δ:8.02(d,J=8.5Hz,1H),7.78(d,J=6.6Hz,1H),7.72(d,J=6.6Hz,1H),7.64~7.56(m,2H),4.06~3.98(m,4H),3.68~3.59(m,4H)
Mass,m/e:229(M+),173(base)
制备例96
将795mg 7-甲氧基-(4-甲基哌嗪-1-基)异喹啉和8ml 47%氢溴酸水溶液的混合物加热回流2.5小时。冷却后,用20%氢氧化钠水溶液中和,用氯仿萃取,用无水硫酸镁干燥并在减压下馏去溶剂。用硅胶柱色谱法(饱和氨水∶甲醇∶氯仿=1∶10∶90)纯化残余物,得到673mg(80%)的7-羟基-1-(4-甲基哌嗪-1-基)异喹啉。
1H-NMR(CDCl3)δ:8.01(d,J=5.8Hz,1H),7.66(d,J=8.5Hz,1H),7.36(d,J=2.7Hz,1H),7.26~7.19(m,2H),3.48~3.35(m,4H),2.70~2.55(m,4H),2.33(s,3H)
Mass,m/e:243(M+),173(base)
制备例97
将105mg 1-(4-叔丁氧基羰基哌嗪-1-基)-7-羟基异喹啉溶解于10ml丙酮中,然后往其中加入93mg碳酸钾和55mg乙基碘,加热回流2小时。追加55mg乙基碘回流2小时,然后追加48mg碳酸钾和55mg乙基碘,进一步回流过夜。冷却后,往其中加水并用乙酸乙酯萃取,用饱和食盐水洗涤,用无水硫酸镁干燥并在减压下馏去溶剂。用硅胶柱色谱法(乙酸乙酯∶正己烷=1∶4)纯化残余物,得到102mg(90%)的1-(4-叔丁氧基羰基哌嗪-1-基)-7-乙氧基异喹啉。随后将其在3ml 4当量盐酸二噁烷溶液中,在室温下搅拌30分钟。用10%氢氧化钠水溶液使所得溶液呈碱性,用乙酸乙酯萃取,减压下馏去溶剂。用硅胶柱色谱法(甲醇∶氯仿=1∶4)纯化残余物,得到67mg(93%)的7-乙氧基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.07(d,J=5.8Hz,1H),7.67(d,J=8.9Hz,1H),7.40(d,J=2.3Hz,1H),7.28(dd,J=2.3Hz,8.9Hz,1H),7.22(d,J=5.8Hz,1H),4.17(q,J=6.9Hz,2H),3.38~3.32(m,4H),3.20~3.14(m,4H),1.51(t,J=6.9Hz,3H)
Mass,m/e:257(M+),188(base)
制备例98
与制备例97同样地操作,得到7-(4-氟苄氧基)-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.08(d,J=5.8Hz,1H),7.70(d,J=8.8Hz,1H),7.49~7.42(m,2H),7.41~7.38(m,1H),7.38~7.33(m,1H),7.22(d,J=5.8Hz,1H),7.12~7.06(m,2H),5.20(s,2H),3.29~3.22(m,4H),3.13~3.06(m,4H)
Mass,m/e:337(M+),109(base)
制备例99
与制备例97同样地操作,得到7-苄氧基-1-哌嗪-1-基异喹啉。
1H-NMR(CDCl3)δ:8.06(d,J=5.8Hz,1H),7.69(d,J=8.9Hz,1H),7.50~7.29(m,7H),7.21(d,J=5.8Hz,1H),5.25(s,2H),3.24~3.18(m,4H),3.08~3.02(m,4H)
Mass,m/e:319(M+),91(base)
制备例100
与制备例97同样地操作,得到7-[4-(1,3-二氧代-1,3-二氢异吲哚-2-基)丁氧基]-1-哌嗪-1-基异喹啉盐酸盐。
1H-NMR(DMSO-d6)δ:7.97~7.91(m,2H),7.89~7.80(m,4H),7.57~7.48(m,2H),7.38(d,J=2.3Hz,1H),4.25~4.16(m,4H),3.79~3.63(m,8H),1.87~1.77(m,4H)
Mass,m/e:430(M+),160(base)
制备例101
与制备例97同样地操作,得到7-氨磺酰氧基-1-哌嗪-1-基异喹啉盐酸盐。
1H-NMR(DMSO-d6)δ:8.19~8.11(m,3H),8.07(d,J=8.9Hz,1H),7.98(d,J=2.3Hz,1H),7.69(dd,J=2.3Hz,8.9Hz,1H),7.57(d,J=5.8Hz,1H),3.65~3.57(m,4H),3.40~3.31(m,4H)
制备例102
步骤102-A
往12ml吡啶中加入10.0g 3-呋喃醛和15.0g丙二酸,在80℃-90℃下加热搅拌2小时。将反应溶液移到冰水中,用1当量盐酸使反应溶液呈弱酸性,滤取沉淀的结晶,将其溶解于乙酸乙酯中,然后用1当量盐酸洗涤。用无水硫酸镁干燥有机层并浓缩。使残余物在乙酸乙酯-正己烷中重结晶,得到11.78g(82%)的3-呋喃-3-基丙烯酸(ァリリックァシッド)。
1H-NMR(CDCl3):7.70~7.67(m,2H),7.45(s,1H),6.62~6.61(m,1H),6.16(d,J=15.8Hz,1H)
Mass,m/e:138(M+,base)
步骤102-B
将上述步骤102-A中得到的5.0g 3-呋喃-3-基丙烯酸和4.3g三乙胺溶解于50ml丙酮中,在冰冷却下,用10分钟往所得溶液中滴加5.2g氯代碳酸乙酯。在冰冷却下搅拌30分钟,然后往其中滴加迭氮化钠水溶液(将3.5g迭氮化钠溶解于15ml纯净水中所得的溶液),进一步在冰冷却下搅拌1小时。往其中加入150ml冰水,用苯萃取,用无水硫酸镁干燥后,使液温保持在30℃以下减压下浓缩至约20ml。用1.5小时,一边馏去苯一边将该溶液滴加到加热至220℃的40ml二苯基甲烷、7ml三丁胺中,并使液温保持在220℃。滴加结束后,进行冷却,往其中加入正己烷,滤取沉淀的结晶,用乙酸乙酯洗涤并干燥,得到3.15g(64%)的6H-呋喃并[2,3-c]吡啶-7-酮。
1H-NMR(DMSO-d6):11.50(brs,1H),8.07(d,J=1.9Hz,1H),6.86(d,J=1.9Hz,1H),6.50(d,J=6.9Hz,1H)
Mass,m/e:135(M+,base)
步骤102-C
将上述步骤102-B中得到的3.1g 6H-呋喃并[2,3-c]吡啶-7-酮在16.0g磷酰氯中加热回流1.5小时,然后将反应溶液移到冰中,用饱和碳酸氢钠水溶液中和。利用氯仿萃取后,用无水硫酸镁干燥,减压下馏去溶剂。用硅胶柱色谱法(正己烷∶乙酸乙酯=1∶1)纯化残余物,得到2.36g(67%)的7-氯呋喃并[2,3-c]吡啶。
1H-NMR(CDCl3):8.19(d,J=5.4Hz,1H),7.81(d,J=1.9Hz,1H),7.49(d,J=5.4Hz,1H),6.87(d,J=2.3Hz,1H)
Mass,m/e:153(M+,base)
步骤102-D
将12.5g N-苄氧基羰基-L-脯氨酸和8.9g羰基二咪唑溶解于150ml四氢呋喃中,搅拌30分钟。往其中加入6.9g甘氨酸甲酯盐酸盐和5.6g三乙胺,在室温下搅拌过夜。浓缩反应溶液,往其中加入乙酸乙酯,用饱和碳酸氢钠水溶液、10%柠檬酸水溶液和饱和食盐水洗涤,然后用无水硫酸镁干燥、浓缩。将残余物溶解于100ml甲醇中,往其中加入2.0g 10%披钯碳,在氢气流下搅拌过夜,过滤去除催化剂并浓缩。将该残余物溶解于100ml甲醇中,往其中加入三乙胺,加热回流14小时。浓缩并加入适量2-丙醇,滤取沉淀的结晶并干燥,得到6.48g(84%)的(8aS)-2-苄氧基羰基六氢吡咯并[1,2-a]吡嗪-1,4-二酮。将4.0g该(8aS)-2-苄氧基羰基六氢吡咯并[1,2-a]吡嗪-1,4-二酮在40ml四氢呋喃中溶解,滴加到5.9g氢化铝锂的60ml四氢呋喃溶液中,然后加热回流14小时。将反应溶液进行冰冷却,往其中加入饱和碳酸氢钠水溶液用于分解过剩的氢化铝锂,然后加入苄氧基碳酰氯,在冰冷却下搅拌1小时,继续在室温下搅拌2小时。用氯仿萃取,用饱和食盐水洗涤,用无水硫酸镁干燥,然后进行浓缩。用硅胶柱色谱法(氯仿∶甲醇=25∶1)进行纯化,得到2.77g(41%)的(8aS)-2-苄氧基羰基八氢吡咯并[1,2-a]吡嗪。
1H-NMR(CDCl3):7.36~7.35(m,5H),5.13(s,2H),4.28~4.10(m,2H),3.10~3.05(m,1H),2.98(brs,2H),2.61(brs,1H),2.15~2.09(m,2H),1.88~1.66(m,5H)
Mass,m/e:260(M+),91(base)
步骤102-E
将上述步骤102-D中得到的5.2g(8aS)-2-苄氧基羰基八氢吡咯并[1,2-a]吡嗪溶解于100ml甲醇中,往其中加入2.0g 20%氢氧化钯碳,在氢气流下搅拌1小时,然后过滤去除催化剂,浓缩反应溶液得到4.65g(100%)的(8aS)-八氢吡咯并[1,2-a]吡嗪。
步骤102-F
将上述步骤102-E中得到的380mg(8aS)-八氢吡咯并[1,2-a]吡嗪溶解于10ml乙二醇中,往其中加入上述步骤102-C中得到的270mg 7-氯呋喃并[2,3-c]吡啶、202mg三乙胺,在140℃下搅拌过夜。冷却后,加入饱和碳酸氢钠水溶液,用氯仿萃取,用无水硫酸镁干燥有机层,减压下馏去溶剂。用硅胶柱色谱法(氯仿∶甲醇=20∶1)纯化残余物,得到190mg(39%)的7-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)呋喃并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:7.95(d,J=5.4Hz,1H),7.63(d,J=2.3Hz,1H),6.95(d,J=5.4Hz,1H),6.72(d,J=1.9Hz,1H),4.80~4.76(m,1H),4.71~4.66(m,1H),3.325~3.14(m,3H),2.87~2.81(m,1H),2.44-2.40(m,1H),2.38~2.13(m,2H),1.96~1.84(m,2H),1.82~1.74(m,1H),1.56~1.51(m,1H)
Mass,m/e:243(M+),147(base)
制备例103
与制备例102同样地操作,得到7-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:8.12(d,J=5.4Hz,1H),7.57(d,J=5.4Hz,1H),7.31(d,J=5.4Hz,1H),7.23(d,J=5.4Hz,1H),4.44~4.40(m,1H),4.34~4.31(m,1H),3.27~3.26(m,1H),3.23~3.11(m,2H),2.92~2.86(m,1H),2.50~2.45(m,1H),2.27~2.21(m,2H),1.95~1.86(m,2H),1.83~1.76(m,1H),1.59~1.51(m,1H)
Mass,m/e:259(M+),163(base)
制备例104
与制备例102同样地操作,得到4-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.04(d,J=5.4Hz,1H),7.43~7.29(m,3H),4.17~4.12(m,1H),4.07~4.02(m,1H),3.28~3.22(m,1H),3.19~3.14(m,2H),2.94~2.88(m,1H),2.51(dt,J=2.7Hz,7.2Hz,1H),2.29~2.22(m,2H),1.94~1.85(m,2H),1.85~1.75(m,1H),1.56~1.50(m,1H)
Mass,m/e:259(M+),107(base)
制备例105
与制备例102同样地操作,得到4-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)呋喃并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.04(d,J=5.8Hz,1H),7.53(d,J=2.3Hz,1H),6.93(d,J=5.8Hz,1H),6.83(dd,J=0.8Hz,2.3Hz,1H),4.48(ddd,J=1.9Hz,2.7Hz,12.3Hz,1H),4.35~4.31(m,1H),3.30~3.23(m,1H),3.18~3.13(m,2H),2.91~2.85(m,1H),2.44~2.38(m,1H),2.25~2.13(m,2H),1.95~1.84(m,2H),1.82~1.50(m,2H)
Mass,m/e:243(M+),147(base)
制备例106
与制备例102同样地操作,得到2-溴-4-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.05(d,J=5.3Hz,1H),7.38(s,1H),7.17(d,J=5.8Hz,1H),4.06(td,J=2.3Hz,12.3Hz,1H),3.98~3.94(m,1H),3.25~3.14(m,3H),2.91~2.85(m,1H),2.51~2.47(m,1H),2.27~2.19(m,2H),1.94~1.82(m,2H),1.81~1.75(m,1H),1.54~1.49(m,1H)
Mass,m/e:337(M+),96(base)
制备例107
与制备例102同样地操作,得到4-((8aS)-八氢吡咯并[1,2-a]吡嗪-2-基)-2-甲基噻吩并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.01(d,J=5.4Hz,1H),7.23~7.22(m,1H),7.03(d,J=1.2Hz,1H),4.07(td,J=2.3Hz,12.0Hz,1H),3.98(d,J=11.8Hz,1H),3.23~3.08(m,3H),2.90~2.84(m,1H),2.58(dd,J=1.2Hz,4.3Hz,3H),2.53~2.47(m,2H),2.37~2.27(m,2H),1.93~1.85(m,2H),1.81~1.75(m,1H),1.54~1.50(m,1H)
Mass,m/e:273(M+),177(base)
制备例108
与制备例102同样地操作,得到7-((8aR)-八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:8.13(d,J=5.4Hz,1H),7.57(d,J=5.4Hz,1H),7.31(d,J=5.4Hz,1H),7.24(d,J=5.4Hz,1H),4.41(td,J=2.3Hz,12.0Hz,1H),4.35~4.31(m,1H),3.24~3.15(m,3H),2.93~2.87(m,1H),2.51~2.45(m,1H),2.28~2.22(m,2H),1.94~1.87(m,2H),1.81~1.73(m,1H),1.56~1.52(m,1H)
Mass,m/e:259(M+),163(base)
制备例109
与制备例102同样地操作,得到4-((8aR)-八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[3,2-c]吡啶。
1H-NMR(CDC13)δ:8.07(d,J=5.4Hz,1H),7.43~7.41(m,1H),7.37(d,J=5.4Hz,1H),7.33(dd,J=0.8Hz,5.8Hz,1H),4.17~4.13(m,1H),4.05(ddd,J=1.9Hz,5.0Hz,12.7Hz,1H),3.26(dt,J=2.7Hz,12.3Hz,1H),3.19~3.15(m,2H),2.95~2.89(m,1H),2.52(dt,J=2.7Hz ,11.2Hz,1H),2.30~2.23(m,2H),1.94~1.87(m,2H),1.82~1.76(m,1H),1.56~1.49(m,1H)
Mass,m/e:259(M+),163(base)
制备例110
与制备例102同样地操作,得到7-((8aR)-八氢吡咯并[1,2-a]吡嗪-2-基)呋喃并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:7.93(d,J=5.0Hz,1H),7.62(d,J=1.9Hz,1H),6.94(d,J=5.4Hz,1H),6.70(d,J=2.3Hz,1H),4.79~4.74(m,1H),4.69~4.65(m,1H),3.324~3.12(m,3H),2.86~2.80(m,1H),2.43~2.39(m,1H),2.37~2.12(m,2H),1.95~1.83(m,2H),1.81~1.70(m,1H),1.56~1.49(m,1H)
Mass,m/e:243(M+),147(base)
制备例111
与制备例102同样地操作,得到7-((7R,8aS)-7-羟基八氢吡咯并[1,2-a]吡嗪-2-基)呋喃并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:7.93(d,J=5.4Hz,1H),7.62(d,J=2.3Hz,1H),6.95(d,J=5.4Hz,1H),6.71(d,J=2.3Hz,1H),4.76~4.72(m,1H),4.68~4.63(m,1H),4.56~4.52(m,1H),3.60~3.56(m,1H),3.19~3.07(m,2H),2.78(dt,J=1.9Hz,10.4Hz,1H),2.61~2.49(m,2H),2.23~2.19(m,1H),1.92~1.81(m,2H)
Mass,m/e:259(M+),147(base)
制备例112
与制备例102同样地操作,得到7-((7R,8aS)-7-羟基八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:8.11(d,J=5.4Hz,1H),7.57(d,J=5.4Hz,1H),7.30(d,J=5.4Hz,1H),7.23(d,J=5.4Hz,1H),4.57~4.52(m,1H),4.38~4.34(m,1H),4.30~4.25(m,1H),3.61~3.56(m,1H),3.18(dt,J=3.1Hz,12.7Hz,1H),3.10(dt,J=2.7Hz,11.2Hz,1H),2.86~2.81(m,1H),2.72~2.59(m,2H),2.28~2.24(m,1H),1.93~1.81(m,2H)
Mass,m/e:275(M+),163(base)
制备例113
与制备例102同样地操作,得到4-((8aR)-八氢吡咯并[1,2-a]吡嗪-2-基)呋喃并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.04(d,J=5.8Hz,1H),7.53(d,J=2.3Hz,1H),6.93(dd,J=0.8Hz,5.8Hz,1H),6.83~6.82(m,1H),4.50~4.46(m,1H),4.35~4.31(m,1H),3.27(dt,J=3.1Hz,12.3Hz,1H),3.18~3.14(m,2H),2.92~2.86(m,1H),2.41(dt,J=3.4Hz,11.2Hz,1H),2.25~2.15(m,2H),1.95~1.85(m,2H),1.82~1.75(m,1H),1.56~1.48(m,1H)
Mass,m/e:243(M+),147(base)
制备例114
与制备例102同样地操作,得到4-((7R,8aS)-7-羟基八氢吡咯并[1,2-a]吡嗪-2-基)呋喃并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.04(d,J=5.8Hz,1H),7.54(d,J=2.3Hz,1H),6.92(dd,J=1.2Hz,5.8Hz,1H),6.82(dd,J=0.8Hz,2.3Hz,1H),4.57~4.53(m,1H),4.43(ddd,J=1.9Hz,2.7Hz,11.9Hz,1H),4.32~4.27(m,1H),3.60~3.56(m,1H),3.25~3.20(m,1H),3.11~3.07(m,1H),2.86~2.81(m,1H),2.66~2.52(m,2H),2.26~2.23(m,1H),1.89~1.82(m,2H)
Mass,m/e:259(M+),147(base)
制备例115
与制备例102同样地操作,得到4-((8aR)-八氢吡咯并[1,2-a]吡嗪-2-基)-2-甲基呋喃并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:7.97(d,J=5.8Hz,1H),6.84(dd,J=0.8Hz,5.8Hz,1H),6.40(s,1H),4.42~4.38(m,1H),4.28~4.21(m,1H),3.24~3.12(m,3H),2.86~2.80(m,1H),2.43(d,J=1.2Hz,3H),2.42~2.35(m,1H),2,26~2.13(m,2H),1.93~1.85(m,2H),1.80~1.73(m,1H),1.55~1.48(m,1H)
Mass,m/e:257(M+),161(base)
制备例116
与制备例102同样地操作,得到7-((7R,8aS)-7-苄氧基八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:8.11(d,J=5.8Hz,1H),7.56(d,J=5.4Hz,1H),7.34~7.22(m,7H),4.49(dd,J=1.6Hz,3.5Hz,2H),4.39~4.35(m,1H),4.30~4.26(m,1H),3.56~3.52(m,1H),3.20~3.08(m,2H),2.85~2.80(m,1H),2.62~2.53(m,2H),2.38~2.34(m,1H),1.99(ddd,J=1.5Hz,7.2Hz,13.1Hz,1H),1.81~1.75(m,1H)
Mass,m/e:365(M+),91(base)
制备例117
与制备例102同样地操作,得到4-((7R,8aS)-7-苄氧基八氢吡咯并[1,2-a]吡嗪-2-基)噻吩并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.06(d,J=5.8Hz,1H),7.41~7.26(m,8H),4.53~4.4(m,2H),4.25~4.22(m,1H),4.10(t d,J=2.3Hz,11.9Hz,1H),4.00(dd,J=2.7Hz,12.7Hz,1H),3.56~3.52(m,1H),3.21~3.14(m,1H),3.11~3.07(m,1H),2.85~2.80(m,1H),2.66~2.56(m,2H),2.37(dd,J=5.4Hz,9.6Hz,1H),1.97(ddd,J=1.5Hz,6.2Hz,13.1Hz,1H),1.79~1.71(m,1H)
Mass,m/e:365(M+),163(base)
制备例118
与制备例102同样地操作,得到7-八氢吡啶并[1,2-a]吡嗪-2-基呋喃并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:7.95(d,J=5.4Hz,1H),7.62(d,J=2.3Hz,1H),6.95(d,J=5.4Hz,1H),6.71(d,J=2.3Hz,1H),4.65~4.58(m,1H),4.49~4.43(m,1H),3.30~3.20(m,1H),2.94~2.77(m,3H),2.47~2.38(m,1H),2.15~2.04(m,2H),1.87~1.77(m,1H),1.73~1.64(m,3H),1.40~1.29(m,2H)
Mass,m/e:257(M+),110(base)
制备例119
与制备例102同样地操作,得到4-八氢吡啶并[1,2-a]吡嗪-2-基呋喃并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.04(d,J=5.8Hz,1H),7.53(d,J=2.3Hz,1H),6.92(dd,J=0.7Hz,5.8Hz,1H),6.80(dd,J=1.2Hz,2.3Hz,1H),4.30~4.22(m,1H),4.20~4.13(m,1H),3.29(dt,J=2.7Hz,12.3Hz,1H),2.94~2.81(m,3H),2.46~2.37(m,1H),2.15~2.04(m,2H),1.88~1.75(m,1H),1.75~1.57(m,3H),1.42~1.24(m,2H)
Mass,m/e:257(M+),110(base)
制备例120
与制备例102同样地操作,得到7-八氢吡啶并[1,2-a]吡嗪-2-基噻吩并[2,3-c]吡啶。
1H-NMR(CDCl3)δ:8.12(d,J=5.4Hz,1H),7.57(d,J=5.4Hz,1H),7.31(d,J=5.4Hz,1H),7.23(d,J=5.4Hz,1H),4.32~4.24(m,1H),4.16~4.09(m,1H),3.26(dt,J=2.7Hz,12.3Hz,1H),2.95~2.82(m,3H),2.49(dt,J=3.1Hz,12.0Hz,1H),2.20~2.09(m,2H),1.86~1.78(m,1H),1.74~1.60(m,3H),1.40~1.31(m,2H)
Mass,m/e:273(M+),110(base)
制备例121
与制备例102同样地操作,得到4-八氢吡啶并[1,2-a]吡嗪-2-基噻吩并[3,2-c]吡啶。
1H-NMR(CDCl3)δ:8.07(d,J=5.4Hz,1H),7.41(d,J=5.4Hz,1H),7.37(d,J=5.4Hz,1H),7.33(d,J=5.4Hz,1H),4.01~3.94(m,1H),3.87~3.81(m,1H),3.26(dt,J=2.7Hz,12.3Hz,1H),2.95~2.83(m,3H),2.52(dt,J=3.0Hz,11.6Hz,1H),2.24~2.10(m,2H),1.87~1.75(m,1H),1.73~1.56(m,3H),1.42~1.29(m,2H)
Mass,m/e:273(M+),110(base)
制造例:片剂:
mg/片
活性成分 5.0
淀粉 10.0
乳糖 73.0
羧甲基纤维素钙 10.0
滑石粉 1.0
硬脂酸镁 1.0
100.0
将活性成分粉碎成70μm以下的粒度,往其中加入淀粉、乳糖和羧甲基纤维素钙并充分混合。往上述混合粉末中加入10%的淀粉糊浆并搅拌混和,制备颗粒。将其整理成干燥后粒径为1000μm左右,往其中混合滑石粉和硬脂酸镁,制成片剂。
Claims (7)
2.选自以下化合物的嘧啶衍生物或其药学上可接受的盐:
1)3-氨基-5,6-二甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮、
2)3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮、
3)3-氨基-5,6-二甲基-2-[3-(4-吡咯并[1,2-a]喹喔啉-4-基哌嗪-1-基)丙硫基]-3H-噻吩并[2,3-d]嘧啶-4-酮、
4)3-氨基-5-甲基-4-氧代-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸乙酯、
5)3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8,9,10-八氢-4-氧杂-11-硫杂-1,3-二氮杂-11H-芳辛并[a]茚、
6)3-氨基-7-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮、
7)3-氨基-2-[3-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丙硫基]-5,6,7,8-四氢-3H-苯并[4,5]噻吩并[2,3-d]嘧啶-4-酮、
8)3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3,4,5,6,7,8-六氢-4-氧杂-9-硫杂-1,3,7-三氮杂-9H-芴、
9)3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
10)3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
11)3-氨基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-3H-喹唑啉-4-酮、
12)3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-噻吩并[3,2-d]嘧啶-4-酮、
13)3-氨基-6-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
14)3-氨基-2-[4-[4-(5-甲氧基喹啉-2-基)哌嗪-1-基]丁基]-3H-喹唑啉-4-酮、
15)3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-噻吩并[2,3-d]嘧啶-4-酮、
16)3-氨基-5-氯-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
17)3-氨基-5-肼基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
18)3-氨基-5,6-二甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-噻吩并[2,3-d]嘧啶-4-酮、
19)3-氨基-8-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
20)3-氨基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3,5,6,7,8,9-六氢-芳庚并[d]嘧啶-4-酮、
21)3-氨基-6-氟-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
22)3-氨基-6-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
23)3-氨基-6-乙基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
24)3-氨基-6-羟基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
25)3-氨基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙基氨基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
26)3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
27)3-乙基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
28)3-甲基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
29)3-乙基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
30)3-苄基-2-[4-[4-(4-甲基喹啉-2-基)哌嗪-1-基]丁基]-5,6,7,8-四氢-3H-喹唑啉-4-酮、
31)3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
32)3-乙基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
33)6-氯-3-甲基-2-[4-(4-喹啉-2-基哌嗪-1-基)丁基]-3H-喹唑啉-4-酮、
34)3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-5,6,7,8-四氢-3H-喹唑啉-4-酮和
35)3-甲基-2-[3-(4-喹啉-2-基哌嗪-1-基)丙硫基]-3H-喹唑啉4-酮。
3.一种兼有对5-HT1A的激活作用的5-HT3拮抗剂,其特征在于含有权利要求1-2中任一项的嘧啶衍生物或其药学上可接受的盐。
4.一种医药组合物,该组合物含有权利要求1-2中任一项的嘧啶衍生物或其药学上可接受的盐和药学上可接受的载体。
5.一种下述疾病的处置剂,其特征在于含有权利要求1-2中任一项的嘧啶衍生物或其药学上可接受的盐,所述疾病为:过敏性肠综合征、不安、腹压性尿失禁、先兆性尿失禁、过动性膀胱综合征、呕吐。
6.权利要求1的嘧啶衍生物或其药学上可接受的盐在制备用于治疗过敏性肠综合征的药物中的应用。
7.一种用于治疗过敏性肠综合征的联合药物,该联合药物含有5-HT1A激活剂和5-HT3拮抗剂,其中5-HT1A激活剂为坦度螺酮,5-HT3拮抗剂为选自以下的化合物:阿洛司琼、格拉司琼和西兰司琼。
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