JP3859738B2 - Quinazolinone derivatives - Google Patents
Quinazolinone derivatives Download PDFInfo
- Publication number
- JP3859738B2 JP3859738B2 JP13358394A JP13358394A JP3859738B2 JP 3859738 B2 JP3859738 B2 JP 3859738B2 JP 13358394 A JP13358394 A JP 13358394A JP 13358394 A JP13358394 A JP 13358394A JP 3859738 B2 JP3859738 B2 JP 3859738B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- quinazolinone
- phenyl
- ring
- production example
- 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
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 title claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 125000003277 amino group Chemical group 0.000 claims description 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 14
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
- 125000004434 sulfur atom Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 362
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 216
- 238000004519 manufacturing process Methods 0.000 description 184
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 155
- 150000001875 compounds Chemical class 0.000 description 149
- 239000002904 solvent Substances 0.000 description 140
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 132
- 238000005160 1H NMR spectroscopy Methods 0.000 description 131
- 235000019441 ethanol Nutrition 0.000 description 125
- -1 methylene, dimethylene Chemical group 0.000 description 114
- 238000003786 synthesis reaction Methods 0.000 description 106
- 238000002844 melting Methods 0.000 description 104
- 230000008018 melting Effects 0.000 description 104
- 230000015572 biosynthetic process Effects 0.000 description 103
- 238000001953 recrystallisation Methods 0.000 description 101
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- 239000000203 mixture Substances 0.000 description 85
- 239000000243 solution Substances 0.000 description 80
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 75
- 229960001701 chloroform Drugs 0.000 description 66
- 230000002829 reductive effect Effects 0.000 description 60
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- 238000004440 column chromatography Methods 0.000 description 40
- 239000000741 silica gel Substances 0.000 description 39
- 229910002027 silica gel Inorganic materials 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 27
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- 238000000034 method Methods 0.000 description 20
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 description 18
- 125000001424 substituent group Chemical group 0.000 description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 16
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 16
- 229910001424 calcium ion Inorganic materials 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 14
- 239000007995 HEPES buffer Substances 0.000 description 14
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 14
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 238000009825 accumulation Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 239000012279 sodium borohydride Substances 0.000 description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- 239000011575 calcium Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 125000003282 alkyl amino group Chemical group 0.000 description 9
- 238000009835 boiling Methods 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- LPMXVESGRSUGHW-UHFFFAOYSA-N Acolongiflorosid K Natural products OC1C(O)C(O)C(C)OC1OC1CC2(O)CCC3C4(O)CCC(C=5COC(=O)C=5)C4(C)CC(O)C3C2(CO)C(O)C1 LPMXVESGRSUGHW-UHFFFAOYSA-N 0.000 description 8
- LPMXVESGRSUGHW-GHYGWZAOSA-N Ouabain Natural products O([C@@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1)[C@H]1C[C@@H](O)[C@@]2(CO)[C@@](O)(C1)CC[C@H]1[C@]3(O)[C@@](C)([C@H](C4=CC(=O)OC4)CC3)C[C@@H](O)[C@H]21 LPMXVESGRSUGHW-GHYGWZAOSA-N 0.000 description 8
- 244000166550 Strophanthus gratus Species 0.000 description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 150000002466 imines Chemical class 0.000 description 8
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 8
- 229960003343 ouabain Drugs 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 150000004985 diamines Chemical class 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 210000004413 cardiac myocyte Anatomy 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 230000001086 cytosolic effect Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000003834 intracellular effect Effects 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- DZNKOAWEHDKBEP-UHFFFAOYSA-N methyl 2-[6-[bis(2-methoxy-2-oxoethyl)amino]-5-[2-[2-[bis(2-methoxy-2-oxoethyl)amino]-5-methylphenoxy]ethoxy]-1-benzofuran-2-yl]-1,3-oxazole-5-carboxylate Chemical compound COC(=O)CN(CC(=O)OC)C1=CC=C(C)C=C1OCCOC(C(=C1)N(CC(=O)OC)CC(=O)OC)=CC2=C1OC(C=1OC(=CN=1)C(=O)OC)=C2 DZNKOAWEHDKBEP-UHFFFAOYSA-N 0.000 description 6
- 230000010412 perfusion Effects 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- YUBDLZGUSSWQSS-UHFFFAOYSA-N 1-benzylpiperidin-4-amine Chemical compound C1CC(N)CCN1CC1=CC=CC=C1 YUBDLZGUSSWQSS-UHFFFAOYSA-N 0.000 description 5
- LASBIWPGFBMFKW-UHFFFAOYSA-N 4-phenyl-3-piperidin-4-yl-1,4-dihydroquinazolin-2-one Chemical compound O=C1NC2=CC=CC=C2C(C=2C=CC=CC=2)N1C1CCNCC1 LASBIWPGFBMFKW-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 150000001925 cycloalkenes Chemical group 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 5
- 208000028867 ischemia Diseases 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- RTAZALJKFRUZRU-UHFFFAOYSA-N 4-phenyl-3-(pyrrolidin-2-ylmethyl)-1,4-dihydroquinazolin-2-one Chemical compound O=C1NC2=CC=CC=C2C(C=2C=CC=CC=2)N1CC1CCCN1 RTAZALJKFRUZRU-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 229910000085 borane Inorganic materials 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
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- 229910052740 iodine Inorganic materials 0.000 description 4
- 230000000302 ischemic effect Effects 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 230000003068 static effect Effects 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- HMAJFFISQKBYFQ-UHFFFAOYSA-N 1-methyl-3-morpholin-2-yl-4-phenyl-4h-quinazolin-2-one Chemical compound C=1C=CC=CC=1C1C2=CC=CC=C2N(C)C(=O)N1C1CNCCO1 HMAJFFISQKBYFQ-UHFFFAOYSA-N 0.000 description 3
- FAIAAUQDOXAYBM-UHFFFAOYSA-N 3-(1-benzylpiperidin-4-yl)-4-phenyl-1,4-dihydroquinazolin-2-one Chemical compound O=C1NC2=CC=CC=C2C(C=2C=CC=CC=2)N1C(CC1)CCN1CC1=CC=CC=C1 FAIAAUQDOXAYBM-UHFFFAOYSA-N 0.000 description 3
- FRXKPAZDDMLFQD-UHFFFAOYSA-N 3-[1-[(3-aminophenyl)methyl]piperidin-4-yl]-4-phenyl-1,4-dihydroquinazolin-2-one Chemical compound NC1=CC=CC(CN2CCC(CC2)N2C(NC3=CC=CC=C3C2C=2C=CC=CC=2)=O)=C1 FRXKPAZDDMLFQD-UHFFFAOYSA-N 0.000 description 3
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- YDBFVAHGTCNOGU-UHFFFAOYSA-N 4-phenyl-3-piperidin-4-yl-1,4-dihydropyrido[4,3-d]pyrimidin-2-one Chemical compound O=C1NC2=CC=NC=C2C(C=2C=CC=CC=2)N1C1CCNCC1 YDBFVAHGTCNOGU-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- YWPISBRZOWXVHJ-UHFFFAOYSA-N benzyl 3-[[4-(2-oxo-4-phenyl-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]methyl]benzoate Chemical compound C=1C=CC(CN2CCC(CC2)N2C(NC3=CC=CC=C3C2C=2C=CC=CC=2)=O)=CC=1C(=O)OCC1=CC=CC=C1 YWPISBRZOWXVHJ-UHFFFAOYSA-N 0.000 description 3
- 244000309464 bull Species 0.000 description 3
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- 239000003638 chemical reducing agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
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- 239000008103 glucose Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
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Images
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【0001】
【産業上の利用分野】
本発明は、細胞内カルシウムイオン(Ca2+)の過剰蓄積を抑制する作用を有するキナゾリノン誘導体またはその酸付加塩もしくは4級アンモニウム塩及びそれらの用途に関する。
【0002】
【従来の技術】
細胞内のカルシウムイオン(Ca2+)の過剰蓄積(カルシウムオーバーロード)は虚血あるいは血流再開通後の細胞障害機構として重要視されている(アニュアル・レビュー・オブ・フィジオロジー、Annu. Rev. Physiol., 1990, 52, 543 - 559)。虚血による細胞障害は日常よく遭遇する疾患に認められ、中でも虚血による心臓、脳あるいは腎臓の細胞障害は臨床上しばしば経験する重要な問題である。従って、カルシウムイオンの過剰蓄積を抑制する薬剤は、虚血性心疾患、虚血性脳疾患あるいは虚血性腎疾患に対して有用な予防および治療薬となりうる。
従来、心筋あるいは血管平滑筋細胞内へのカルシウムイオンの流入を抑制する薬剤としてカルシウム拮抗剤が用いられているが、虚血あるいは血流再開通後の心筋細胞内カルシウムイオンの過剰蓄積に対する効果は十分とは言えず、カルシウムイオンの過剰蓄積を抑制する薬剤は切望されている。
カルシウムイオンの過剰蓄積は、心筋あるいは血管平滑筋細胞においては虚血時以外にも収縮・弛緩機能障害、エネルギー代謝障害、形態学的障害あるいは電気生理学的異常を招き、循環器系疾患の原因となる(カルディオバスキュラー
リサーチ、Cardiovasc. Res., 1986, 20, 645 - 651 )。従って、カルシウムイオンの過剰蓄積を抑制する薬剤は、心不全、高血圧あるいは不整脈等の循環器系疾患に対しても有用な予防および治療薬となりうる。
【0003】
【発明が解決しようとする課題】
本発明の課題は、細胞内のカルシウムイオン過剰蓄積を抑制する化合物を提供することにある。
【0004】
【課題を解決するための手段】
今回本発明者らは上記課題を解決すべく鋭意検討を重ね、下記一般式(1)で表される化合物が細胞内へのカルシウムイオン過剰蓄積の発生を抑制することを見い出し、本発明を完成するに至った。即ち、本発明は一般式(1)
【化6】
[式中、Tは酸素原子または硫黄原子を表し、Yはアルキル基、シクロアルキル基、シクロアルキルアルキル基、フェニル基、置換フェニル基、アラルキル基、置換アラルキル基、ヘテロアリール基または置換ヘテロアリール基を表す。環Wはベンゼン環、5〜6員環のヘテロ芳香環または5〜10員環のシクロアルケン環もしくはシクロアルカン環を表す。R1 及びR2 は互いに独立して、水素原子、低級アルキル基、ハロゲン原子、シアノ基、トリフルオロメチル基、ニトロ基、アミノ基、置換アミノ基、水酸基、低級アルコキシ基、低級アルキルチオ基、低級アルキルスルフィニル基または低級アルキルスルホニル基を表す。Zは式
【化7】
{式中、A1 及びA2 は互いに独立して水素原子、アルキル基、置換アルキル基、シクロアルキル基、飽和ヘテロ環基、シクロアルキルアルキル基、シクロアルケニルアルキル基、アラルキル基、置換アラルキル基、ヘテロアリールアルキル基、置換ヘテロアリールアルキル基または基−CH2 R3 (式中、R3 はアルケニル基またはアルキニル基を表す)を表すか、またはA1 とA2 は互いに結合してヘテロ環を形成してもよい。Gは炭素原子数1〜6の直鎖状のアルキレンもしくは炭素原子数1〜8の分岐したアルキレンを表すか、または基
【化8】
(式中、p及びmは互いに独立して0、1又は2を表し、Dはシクロアルカン環を表す。)を表す}または式
【化9】
{式中、nは0、1または2を表し、環Eは窒素原子を含む4〜8員環の飽和ヘテロ環を表し、A3 は水素原子、アルキル基、置換アルキル基、シクロアルキル基、飽和ヘテロ環基、シクロアルキルアルキル基、シクロアルケニルアルキル基、アラルキル基、置換アラルキル基、ヘテロアリールアルキル基、置換ヘテロアリールアルキル基または基−CH2 R3 (式中、R3 はアルケニル基またはアルキニル基を表す)を表すか、または環Eと共にビシクロ環を形成する。}で表される基を表す。]で表されるキナゾリノン誘導体またはその酸付加塩もしくは4級アンモニウム塩を有効成分として含有するカルシウムイオン過剰蓄積阻害剤に関し、さらに本発明は、環Wが5〜6員環のヘテロ芳香環または5〜10員環のシクロアルケン環もしくはシクロアルカン環である一般式(1)のキナゾリノン誘導体またはその酸付加塩もしくは4級アンモニウム塩、または環Wがベンゼン環であり、Zが式
【化10】
(式中、n、環EおよびA3 は前記と同じ意味を表す。)で表される基である一般式(1)のキナゾリノン誘導体またはその酸付加塩もしくは4級アンモニウム塩に関する。
【0005】
本発明で使用できる化合物のうち環Wがベンゼン環であり、Zが式
【化11】
(式中、G、A1 及びA2 は前記と同じ意味を表す。)
で表される基である一部の化合物は中枢神経作用、抗炎症作用、鎮痛作用を有する化合物として公開特許公報昭和47年第14183号に、中枢神経系抑制作用を有する化合物として仏国特許第2027023号により既知である。本発明で使用できる一部の化合物はHIV逆転写酵素阻害剤としてWO93/04047号に開示されている。しかしながら、該特許の実施例には本特許の請求範囲の化合物はない。本発明で使用できる一部の化合物の類似化合物は、解熱作用を有する化合物として仏国特許第2012062号に、降圧作用、抗潰瘍作用、抗血小板凝集作用を有する化合物として公開特許公報昭和56年第92884号に、鎮痛作用、抗炎症作用及び中枢神経抑制作用を有する化合物として公開特許公報昭和51年第13794号に、抗炎症作用を有する化合物としてジャーナル・オブ・メディシナルケミストリー(J. Med. Chem., 1974, 17, 636 - 639)に記載されている。
【0006】
本発明における各種の基を詳細に説明すると次の通りである。
環Wに於ける5〜6員環のヘテロ芳香環として具体的には、窒素原子を0、1もしくは2個、硫黄原子を0もしくは1個、および酸素原子を0もしくは1個含有するヘテロ芳香族環があげられ、さらに具体的には以下の基が挙げられる。
【化12】
好ましくは、以下の基が挙げられる。
【化13】
環Wに於ける5〜10員環のシクロアルケン環もしくはシクロアルカン環としては、具体的には以下の基が挙げられる。
【化14】
(式中、u及びvは互いに独立して0または1〜5の整数を表し、且つ、u+vは1〜6の整数を表す。また、式中、太い実線と点線は隣接する橋頭位の炭素原子同士の相対的な立体配置を表すものであって、特定の光学異性体のみを意味するものではない。以後の構造式も同じ。)
好ましくは、以下の基が挙げられる。
【化15】
Gに於ける炭素原子数1〜6の直鎖状のアルキレンとしては具体的には例えばメチレン、ジメチレン、トリメチレンおよびテトラメチレンが挙げられ、炭素原子数1〜8の分岐したアルキレンとしては、具体的には例えば以下の基が挙げられる。
【化16】
Dに於けるシクロアルカン環としては、炭素原子数3〜8個のシクロアルカンが挙げられ、具体的には、例えばシクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタンが挙げられる。
Gに於ける好ましい基としては、例えばジメチレン、トリメチレン、テトラメチレン及び以下の基が挙げられる。
【化17】
【0007】
アルキル基としては、例えば直鎖または分枝した炭素原子数1〜8個のアルキル基が挙げられ、具体的には例えばメチル、エチル、プロピル、2−プロピル、ブチル、2−ブチル、2−メチルプロピル、1,1−ジメチルエチル、3−ペンチル、3−ヘキシル、4−ヘプチル、4−オクチル等が挙げられる。好ましい基としては、Yに於ては2−プロピル、ブチル、2−ブチル、2−メチルプロピル、3−ペンチル、3−ヘキシルが挙げられ、A1 、A2 及びA3 に於いてはメチル、エチル、プロピルまたは2−プロピルなどの直鎖または分枝した炭素原子数1〜4個のアルキル基が挙げられる。
シクロアルキル基としては、例えば炭素原子数3〜7個のシクロアルキル基が挙げられ、具体的には例えばシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル等が挙げられる。
シクロアルキルアルキル基としては、例えば炭素原子数10個以下のシクロアルキルアルキル基が挙げられ具体的には例えばシクロプロピルメチル、2−シクロペンチルエチル、シクロヘキシルメチル、3−シクロヘキシルプロピル、4−シクロヘキシルブチル等が挙げられる。
シクロアルケニルアルキル基としては、例えば炭素原子数10個以下のシクロアルケニルアルキル基が挙げられ、具体的には例えば4−シクロヘキセニルメチル、4−シクロペンテニルメチル、4−(4−シクロヘキセニル)ブチル等が挙げられる
アルケニル基としては、例えば炭素原子数2〜6個のアルケニル基が挙げられ、具体的には例えばビニル、アリル、1−プロペニル、1−ブテニル、2−ペンテニル、5−ヘキセニル等が挙げられる。好ましい基としては、ビニルまたはアリルが挙げられる。
アルキニル基としては、例えば炭素原子数2〜6個のアルキニル基が挙げられ、具体的には例えばエチニル、プロパルギル、2−ブチニル、3−ペンチニルなどが挙げられる。好ましい基としては、エチニル、プロパルギルが挙げられる。アラルキル基としては、例えば炭素原子数12個以下の基が挙げられ、具体的には例えばベンジル、1−フェニルエチル、2−フェニルエチル、2−ナフチルメチル等が挙げられる。好ましい基としては、A3 に於てはベンジル基が挙げられる。
ヘテロアリール基としては、例えば窒素原子を1〜2個含む5〜6員環の基、窒素原子を1〜2個と酸素原子を1個もしくは硫黄原子を1個を含む5〜6員環の基、酸素原子を1個もしくは硫黄原子を1個を含む5〜6員環の基等が挙げられ、具体的には、例えば2−ピリジル、3−ピリジル、4−ピリジル、2−チエニル、3−オキサジアゾリル、2−イミダゾリル、2−チアゾリル、3−イソチアゾリル、2−オキサゾリル、3−イソオキサゾリル、2−フリル、3−ピロリル等が挙げられる。
ヘテロアリールアルキル基に於けるヘテロアリール基としては、例えば窒素原子を1〜4個含む5〜6員環の基、窒素原子を1〜2個と酸素原子を1個もしくは硫黄原子を1個を含む5〜6員環の基等が挙げられ、具体的なヘテロアリールアルキル基としては、例えば2−ピリジルメチル、3−ピリジルメチル、4−ピリジルメチル、1−(2−ピリジル)エチル、2−(2−ピリジル)エチル、2−チエニルメチル、3−チエニルメチル、3−オキサジアゾリルメチル、2−イミダゾリルメチル、2−チアゾリルメチル、3−イソチアゾリルメチル、2−オキサゾリルメチル、3−イソオキサゾリルメチル、2−フリルメチル、3−フリルメチル、2−ピロリルメチル等が挙げられる。
飽和ヘテロ環基としては、例えば酸素原子、硫黄原子等のヘテロ原子1個と炭素原子3〜5個からなる飽和ヘテロ環基が挙げられ、具体的には例えばテトラヒヒドロピラン−4−イル、テトラヒドロフラン−3−イル、テトラヒドロチオフェン−3−イル等が挙げられる。
A1 とA2 が互いに結合して形成するヘテロ環としては、例えば窒素原子を1〜2個含む5〜7員環または窒素原子1個および酸素原子1個を含む飽和の5〜7員環が挙げられ、具体的にはピロリジン、ピペリジン、ホモピペリジン、ピペラジン、ホモピペラジン、モルホリン等が挙げられる。
環Eに於ける、窒素原子を含む4〜8員環の飽和ヘテロ環としては、例えば窒素原子を1または2個、および酸素原子を0または1個を含む環が挙げられ、具体的にはピロリジン−2−イル、ピロリジン−3−イル、ピペリジン−2−イル、ピペリジン−3−イル、ピペリジン−4−イル、ホモピペリジン−2−イル、ホモピペリジン−3−イル、ホモピペリジン−4−イル、モルホリン−2−イル等が挙げられる。好ましい基としてはnが0のときは、ピペリジン−4−イルが挙げられ、nが1または2のときは、ピロリジン−2−イル、ピロリジン−3−イル、ピペリジン−2−イル、ピペリジン−3−イル、モルホリン−2−イルが挙げられる。
環EとA3 とで形成するビシクロ環としては、例えばキヌクリジン−3−イル、キヌクリジン−4−イルが挙げらる。
低級アルキル基としては、例えば直鎖または分枝した炭素原子数4個以下のアルキル基が挙げられ、具体的には例えばメチル、エチル、プロピル、2−プロピル、ブチル、2−ブチル、2−メチルプロピル、1,1−ジメチルエチル等が挙げられる。
ハロゲン原子としては例えばフッ素、塩素、臭素、ヨウ素等が挙げられる。
低級アルコキシ基としては、例えば直鎖または分枝した炭素原子数4個以下のアルコキシ基が挙げられ、具体的には例えばメトキシ、エトキシ、プロポキシ、2−プロポキシ、ブトキシ、1,1−ジメチルエトキシ等が挙げられる。
低級アルキルチオ基としては、例えば直鎖または分枝した炭素原子数4個以下のアルキルチオ基が挙げられ、具体的には例えばメチルチオ、エチルチオ、2−プロピルチオ、ブチルチオ等が挙げられる。
低級アルキルスルフィニル基としては、例えば直鎖または分枝した炭素原子数4個以下のアルキルスルフィニル基が挙げられ、具体的には、例えばメチルスルフィニル、エチルスルフィニル、プロピルスルフィニル、2−プロピルスルフィニル、ブチルスルフィニル等が挙げられる。
低級アルキルスルホニル基としては、例えば直鎖または分枝した炭素原子数4個以下のアルキルスルホニル基が挙げられ、具体的には例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、2−プロピルスルホニル、ブチルスルホニル等が挙げられる。
【0008】
置換アミノ基の置換基としては、アルキル基または基−CH2 R6 (式中、R6 はアルケニル基またはアルキニル基を表す)が挙げられ、置換基は一個または同一もしくは異なって2個あってもよい。好ましい置換アミノ基としては例えば、メチルアミノ、エチルアミノ、アリルアミノ、プロパルギルアミノ、プロピルアミノ、2−プロピルアミノ、ブチルアミノ、N,N−ジメチルアミノ、N,N−ジエチルアミノ、N,N−ジプロピルアミノ、N,N−ジアリルアミノ等が挙げられる。
置換フェニル基、置換アラルキル基、置換ヘテロアリール基及び置換ヘテロアリールアルキル基の置換基としては、例えば低級アルキル基、低級アルコキシ基、メチレンジオキシ基、ハロゲン原子、シアノ基、トリフルオロメチル基、ニトロ基、水酸基、低級アルカノイルオキシ基、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、カルバモイル基、低級アルキルアミノカルボニル基、ジ低級アルキルアミノカルボニル基、カルボキシル基、低級アルコキシカルボニル基、低級アルキルチオ基、低級アルキルスルフィニル基、低級アルキルスルフォニル基、低級アルカノイルアミノ基、低級アルキルスルフォンアミド基等が挙げられる。ここで言う低級とは当該基のアルキル部分が低級アルキルであることを意味し、そのような低級アルキルとしてはメチル、エチル、プロピル、2−プロピル、ブチル等の炭素原子数が1〜4個のアルキルを挙げることができ、またジ低級アルキルアミノ基、ジ低級アルキルアミノカルボニル基の2個の低級アルキル基は同一でも異なっていてもよい。置換基は一個または同一もしくは異なって複数個あってもよい。
置換アルキル基の置換基としては、水酸基、低級アルコキシ基、シアノ基、カルボキシル基、カルバモイル基、低級アルコキシカルボニル基等が挙げられる。ここで言う低級とは当該基のアルキル部分が低級アルキルであることを意味し、そのような低級アルキルとしてはメチル、エチル、プロピル、2−プロピル、ブチル等の炭素原子数が1〜4個のアルキルを挙げることができる。
【0009】
酸付加塩を形成する酸としては、例えば塩酸、臭化水素酸、ヨウ化水素酸、硫酸などの無機酸または、例えば酢酸、シュウ酸、くえん酸、りんご酸、酒石酸、フマール酸、マレイン酸、メタンスルホン酸などの有機酸が挙げられる。
4級アンモニウム塩としては、式R4 −L1 (式中R4 は低級アルキル基を表し、L1 は脱離基を表す)で表されるアルキル化剤と反応させ、必要に応じて陰イオンを生理学的に許容可能な他の陰イオンに交換することにより生成できる4級アンモニウム塩が挙げられる。好ましい低級アルキル基としては、メチル基及びエチル基が挙げられる。生理学的に許容可能な陰イオンとしては、ハロゲンイオン、サルフェート、ホスフェート、ナイトレート、アセテート、サイトレート、フマレート、サクシネート等が挙げられる。好ましい脱離基としては、塩素原子、臭素原子及びヨウ素原子が挙げられる。
【0010】
本発明化合物は1個若しくは複数個の不斉炭素原子を含んでおり、立体異性体が存在する。本発明化合物には各異性体の混合物や単離されたものを含む。
【0011】
前記一般式(1)で表される化合物またはその酸付加塩もしくは4級アンモニウム塩は、これを虚血性心疾患、虚血性脳疾患、虚血性腎疾患等を治療または予防する薬剤として用いるにあたり、非経口的または経口的に投与することができる。すなわち溶液、乳剤、懸濁液等の液剤の型にしたものを注射剤として投与することができ、必要に応じて緩衝剤、溶解補助剤、等張剤等を添加することもできる。坐剤の型で直腸投与することもできる。このような投与剤型は通常の担体、賦型剤、結合剤、安定剤などと有効成分を配合することにより、一般的方法に従って製造することができる。また通常用いられる投与形態、例えば錠剤、カプセル剤、シロップ剤、懸濁液等の型で経口的に投与することができる。投与量、投与回数は症状、年令、体重、投与形態等によって異なるが、注射剤として投与する場合には、通常は成人に対し0.1〜100mgを1回または数回に分けて投与することができ、場合によっては点滴静注することもできる。経口投与する場合は、1日0.1〜1000mg(好ましくは0.1〜100mg)を1日1回または数回に分けて投与することができる。
【0012】
一般式(1)において環Wがベンゼン環または5〜6員環のヘテロ芳香環である本発明化合物は、文献記載の方法を参考にして合成することができる(例えばケミカル・ファーマシューティカル・ブレティン、Chem. Pharm. Bull., 1981,
29, 2135 - 2156)。
【化18】
(式中、環W1 はベンゼン環または5〜6員環のヘテロ芳香環を表す。X1 は塩素原子、臭素原子またはヨウ素原子を表し、X2 はフッソ原子、塩素原子または臭素原子を表す。Y1 はYと同様な基を表すが、その置換基としてアミノ基、アルキルアミノ基または水酸基などの反応性基を有する場合はこれらは保護基で保護されているものとする。R11はR1 と同様な基を表すが、R1 がアミノ基、アルキルアミノ基または水酸基などの反応性基である場合、これらが保護基で保護されているものを表す。R21はR2 と同様な基を表すが、R2 がアミノ基、アルキルアミノ基または水酸基などの反応性基である場合、これらが保護基で保護されているものを表す。Z1 はZと同様な基を表すが、A1 とA2 とも水素原子である基を除き、且つA1 、A2 またはA3 が置換基としてアミノ基、アルキルアミノ基または水酸基などの反応性基を有する場合はこれらは保護基で保護されているものとする。)
【0013】
一般式(2)で表される原料化合物は市販されているか、若しくは文献記載の方法で合成することができる(例えばジャーナル・オブ・オーガニック・ケミストリー、J. Org. Chem., 1991, 56, 3750 - 3752 :ジャーナル・ヘテロサイクリック・ケミストリー、J. Heterocyclic Chem., 1989, 26, 105:ケミカル・ファーマシューティカル・ブレティン、Chem. Pharm. Bull., 1978, 26, 1633 - 1651:ジャーナル・オブ・メディシナルケミストリー、J. Med. Chem., 1974, 17, 624 - 630)。アミノ基、アルキルアミノ基または水酸基等の保護基としては、有機合成化学の分野で使われる通常の一般的保護基(例えば水酸基の保護基としてはベンジル基、アセチル基等;アミノ基の保護基としてはベンジル基等)を挙げることができ、これらは通常の方法に従って導入、除去することができる(例えばプロテクティブ・グループス・イン・オーガニック・シンセシス、protective groups in organic synthesis, 2nd ed., John Wily & Sons, Inc.:New Yorkに記載)。
一般式(2)で表されるケトン誘導体を公知の方法に従って、トリハロ酢酸あるいはその酸ハライドでアシル化して、一般式(3)で表されるアミド体とする。
一般式(3)で表されるケトン誘導体と一般式(4)で表される一級アミンとを、ジメチルホルムアミド、ジメチルスルホキシド、テトロヒドロフラン等の非プロトン性極性溶媒中、0℃〜50℃程度にて反応させると一般式(5)で表されるキナゾリノン誘導体もしくは一般式(6)で表されるイミン誘導体または両者の混合物を得ることができる。一般式(5)で表されるキナゾリノン誘導体と一般式(6)で表されるイミン誘導体の生成比は、一般式(3)で表されるケトン誘導体の構造、一般式(4)で表される一級アミンの構造及び反応条件によって変化する。イミン誘導体(6)は、塩基の存在下上記溶媒中、50〜100℃または溶媒の沸点までの間で加熱することにより、一般式(5)で表されるキナゾリノン誘導体に変換できる。塩基としては、トリエチルアミンやピリジン等の三級アミンまたは芳香族アミンが適当である。
一般式(5)で表されるキナゾリノン誘導体を、ジメチルホルムアミド、テトロヒドロフラン等の非プロトン性極性溶媒中、0℃〜室温程度にて、水素化ほう素ナトリウム(NaBH4 )で処理することにより、トリハロメチル基を水素原子に置換した一般式(7)で表されるキナゾリノン誘導体を得ることができる。このとき、ボラン(BH3 )が基Z1 中の窒素原子に配位することがある。この場合、通常エタノール、メタノール等のアルコール系溶媒中、必要に応じて塩酸水溶液を加えて加熱還流することによりボランを取り除くことができる。ボランが配位していない場合はこの操作は必要ない。
【0014】
一般式(6)で表されるイミン誘導体からは、下記ルートにても一般式(7)で表されるキナゾリノン誘導体へ導くことができる。
【化19】
(式中、環W1 、Z1 、R11、R21、Y1 、及びX2 は前記と同じ意味を表す。)
イミン誘導体(6)をジメチルホルムアミド、ジメチルスルホキシド、テトロヒドロフラン等の非プロトン性極性溶媒中、0℃〜50℃程度にて水素化ほう素ナトリウムにて還元することにより、一般式(8)で表されるアミン誘導体に導くことができる。次いで、トリハロゲノアセチル基を除去して、一般式(9)で表されるジアミン誘導体を得ることができる。トリハロゲノアセチル基の除去は例えば、メタノール、エタノール等の低級アルコール中、0℃〜50℃程度にて水素化ほう素ナトリウムにて処理することにより好適に行なうことができる。また、一般式(9)で表されるジアミン誘導体は、一般式(6)で表されるイミン誘導体をメタノール、エタノール等の低級アルコール中、0℃〜50℃程度にて水素化ほう素ナトリウムにて処理することにより一段階で得ることもできる。この時、一般式(10)で表されるイミン誘導体が生成することがある。イミン誘導体(10)はジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒中室温から溶媒の沸点までの間で、水素化リチウムアルミニウム(LiAlH4 )にて還元してジアミン誘導体(9)に導くこともできる。
一般式(9)で表されるジアミン誘導体と1.0〜5倍当量の1,1′−カルボニルジイミダゾールとを、塩化メチレン、クロロホルム等のハロゲン化炭化水素、ジエチルエーテル、テトラヒドロフラン、ジオキサン、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシド等の溶媒中で室温から溶媒の沸点の範囲で反応させることにより、一般式(7)で表されるキナゾリノン誘導体を合成することができる。また一般式(7)で表されるキナゾリノン誘導体は、炭酸ハロゲン化物(例えばホスゲン、クロロ炭酸アルキル等)と一般式(9)で表されるジアミン誘導体を公知の手法に従って反応させることにより合成することもできる。
【0015】
一般式(7)で表されるキナゾリノン誘導体から必要に応じて以下の操作を行なうことにより、一般式(11)で表されるキナゾリノン誘導体を得ることができる。
【化20】
(式中、環W1 、Z、R1 、R2 、Y及びTは前記と同じ意味を表す。)
a)一般式(11)においてTが硫黄原子である化合物を得るためには、ウレアからチオウレアへの変換。
b)Z1 の変換。
c)一般式(7)においてR11もしくはR21が保護されている場合、またはY1 、もしくはZ1 が保護された置換基を有している場合には、保護基の除去。d)R1 、R2 、Y1 が有している置換基、またはZ1 が有している置換基の変換。
ウレアからチオウレアへの変換は、二硫化炭素、トルエン、キシレン等の不活性溶媒中、室温〜溶媒の沸点までの温度で五硫化リンと反応させることにより行なうことができる。
【0016】
Z1 の変換は、例えば化合物(7)が一般式(12)で表されるキナゾリノン誘導体である場合、公知の方法に従って脱ベンジル化を行なった後、還元アミノ化反応またはアルキル化反応を行なうことにより、一般式(15)または一般式(17)で表されるキナゾリノン誘導体に変換することができる。
【化21】
{式中、環W1 、環E、R11、R21、Y1 、X1 及びnは前記の意味を表す。A31は、水素原子、メチル基またはエチル基を表す。A32はアルキル基、置換アルキル基、シクロアルキル基、シクロアルケニル基、アリール基、置換アリール基、ヘテロアリール基、置換ヘテロアリール基または基−CH2 R3 (式中、R3 はアルケニル基またはアルキニル基を表す)を表すか、またはA31とA32は互いに結合してシクロペンタン環、シクロヘキサン環もしくはシクロヘプタン環を形成する。A33はアルキル基、置換アルキル基、シクロアルキル基、飽和ヘテロ環基、シクロアルキルアルキル基、シクロアルケニルアルキル基、アラルキル基、置換アラルキル基、ヘテロアリールアルキル基、置換ヘテロアリールアルキル基または基−CH2 R3 (式中、R3 はアルケニル基またはアルキニル基を表す)を表す}。
還元アミノ化反応は、一般式(13)で表される化合物と1〜5当量の一般式(14)で表されるカルボニル化合物をメタノール、エタノール等の低級アルコール中、0〜50℃にて1〜5当量の還元剤で処理することにより行なうことができる。還元剤としては、水素化ほう素ナトリウム(NaBH4 )、シアノ水素化ほう素ナトリウム(NaBH3 CN)を用いることで好適に行なうことができる。
アルキル化反応は公知の方法に従って行なうことができる。例えば、テトラヒドロフラン、ジメチルホルムアミド、ジクロロメタン、メタノール、エタノール等の溶媒中、一般式(13)で表される化合物と1〜5当量の一般式(16)で表されるハロゲン化物を必要に応じて炭酸カリウム、トリエチルアミン等の塩基の存在下、0℃から溶媒の沸点までの温度にて行なうことができる。
【0017】
また化合物(11)が一般式(18)で表されるキナゾリノン誘導体である場合も同様にして、還元アミノ化反応またはアルキル化反応を行なうことができる。一般式(18)で表されるキナゾリノン誘導体はそれ自体(18)に含まれる一般式(20)で表されるキナゾリノン誘導体から前記方法により合成でき、一般式(20)で表されるキナゾリノン誘導体は、一般式(19)で表されるキナゾリノン誘導体を公知の方法に従って脱ベンジル化することにより好適に得ることができる。
【化22】
(式中、環W1 、R11、R21、Y1 、及びGは前記の意味を表す。A21はA2 と同様な基を表すが、その置換基としてアミノ基、アルキルアミノ基または水酸基などの反応性基を有する場合はこれらは保護基で保護されているものとする。)一般式(7)においてR11もしくはR21が保護されている場合、またはY1 、もしくはZ1 が保護された置換基を有している場合における保護基の除去方法としては、有機合成化学の分野で使われる通常の一般的脱保護方法により行うことができる(例えばプロテクティブ・グループス・イン・オーガニック・シンセシス、protective groups in organic synthesis, 2nd ed., John Wily & Sons, Inc.:New Yorkに記載)。
R1 、R2 、Y1 が有している置換基、またはZ1 が有している置換基の変換としては例えば、低級アルキルチオ基を酸化することにより低級アルキルスルフィニル基もしくは低級アルキルスルホニル基へ変換することができ、ニトロ基を還元してアミノ基へ変換することができ、アミノ基をアルキル化することによりモノまたはジアルキル体を得ることもでき、あるいはアミノ基をアシル化することもできる。このような置換基の変換反応は、有機合成化学の分野で通常行なわれる一般的技術により実施することができる。
【0018】
一般式(11)で表されるキナゾリノン誘導体において、Tが硫黄原子である化合物(22)は、一般式(9)で表されるジアミン誘導体から下記の方法で合成することもできる。
【化23】
(式中、環W1 、R11、R21、Y1 、Z1 、R1 、R2 、Z及びYは前記の意味を表す。)
一般式(9)で表されるジアミン誘導体と1.0〜5倍当量の1,1′−チオカルボニルジイミダゾールとを、塩化メチレン、クロロホルム等のハロゲン化炭化水素、ジエチルエーテル、テトラヒドロフラン、ジオキサン、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシド等の溶媒中で室温から溶媒の沸点の範囲で反応させることにより、一般式(21)で表されるキナゾリノン誘導体を合成することができる。ついで、必要に応じて化合物(7)における場合と同様にして置換基の変換、脱保護等をおこなって一般式(22)で表されるキナゾリノン誘導体に導くことができる。
【0019】
前記一般式(1)において、環Wが5〜10員環のシクロアルケン環またはシクロアルカン環である化合物は以下の方法で合成できる。
【化24】
(式中、Y1 、Z1 、X1 、Y、R1 、R2 、Z及びTは前記の意味を表す。環W2 は5〜10員環のシクロアルケン環またはシクロアルカン環を表す。R12はR11の定義からハロゲン原子を除いたものを表し、R22はR21の定義からハロゲン原子を除いたものを表す。R5 は低級アルキル基を表す。また、式中、太い実線と点線は隣接する橋頭位の炭素原子同士の相対的な立体配置を表すものであって、特定の光学異性体のみを意味するものではない。以後の構造式も同じ。)
一般式(23)で表される原料化合物は文献記載の方法に従って合成できる(例えばジャーナル・オブ・オーガニック・ケミストリー、J. Org. Chem., 1992, 57, 7285 - 7295:ケミストリー・レターズ、Chem. Lett. 1990, 1817 - 1820 )。また必要に応じて、シス体の化合物(23)を一般式(24)で表されるトランス体に異性化して用いることもできる。異性化は溶媒中、室温から溶媒の沸点までの温度で、塩基で処理することにより行なうことができる。好ましくは、メタノール、エタノールまたはtert−ブタノール等のアルコール系溶媒中、ナトリウムもしくはカリウムのアルコキシドで処理することにより好適に行なうことができる。
一般式(23)もしくは一般式(24)で表されるケトン誘導体を、メタノール、エタノール等のアルコール系溶媒中、0℃〜室温程度にて水素化ほう素ナトリウム等の還元剤で処理して一般式(25)で表されるアルコール誘導体とした後、水酸基をハロゲン原子で置換して一般式(26)で表されるハロゲン化物とする。ハロゲン原子への置換は、ジクロロメタン、1,2−ジクロロエタン等のハロゲン系溶媒中、室温から溶媒の沸点までの間でトリフェニルホスフィン存在下四塩化炭素、四臭化炭素、N−クロロこはく酸イミドまたはN−ブロモこはく酸イミドと反応させることにより好適に行なうことができる。またヨウ素体は、クロル体もしくはブロモ体をアセトン、ジメチルホルムアミド等の溶媒中室温〜60℃程度にて、よう化ナトリウムで処理することにより得ることができる。
一般式(26)で表されるハロゲン化物と一般式(4)で表される一級アミンを溶媒中、室温から溶媒の沸点までの間にて塩基の存在下反応させることにより、一般式(27)で表されるキナゾリノン誘導体へ導くことができる。溶媒としてはジメチルホルムアミド、ジメチルスルホキシド、アセトニトリル等の非プロトン性極性溶媒、メタノール、エタノール等のアルコール系溶媒、ジクロロエタン等のハロゲン系溶媒を用いることができ、塩基としては炭酸カリウム、炭酸ナトリウム等の無機塩及びトリエチルアミン、N,N−ジイソプロピルエチルアミン等の三級アミンを用いることができる。好ましくは、ジメチルホルムアミド中トリエチルアミン、N,N−ジイソプロピルエチルアミン等の三級アミン存在下、50〜100℃にて反応させることにより好適に得ることができる。
化合物(27)において必要に応じて化合物(7)において行なったa)、b)、c)もしくはd)の操作またはこれらを組み合わせた操作を行なうことにより一般式(28)で表されるキナゾリノン誘導体を得ることができる。この時、R1 もしくはR2 がハロゲン原子である場合はR12もしくはR22が水酸基である化合物から合成できる。このような置換基の変換反応は、有機合成化学の分野で通常行なわれる一般的技術により実施することができる。
【0020】
4級アンモニウム塩は、例えば以下の方法により合成することができる。
【化25】
(式中、環W、環E、R1 、R2 、Y、G及びTは前記の意味を表す。A11はA1 の定義から水素原子を除いたものを表し、A22はA2 の定義から水素原子を除いたものを表し、A34はA3 の定義から水素原子を除いたものを表す。R4 は低級アルキル基を表し、L1 は脱離基を表し、L- は生理学的に許容可能な陰イオンを表す。)
4級アンモニウム塩は、一般式(29)または一般式(32)で表されるキナゾリノン誘導体と一般式(30)で表されるアルキル化剤を溶媒中、室温から溶媒の沸点までの間で混合することにより得ることができる。反応の進行が遅い時はオートクレーブ中120℃位まで加熱すると好適に進行することがある。
好ましい脱離基としては、塩素原子、臭素原子及びヨウ素原子が挙げられる。好ましい溶媒としては、メタノール、エタノール等のアルコール系溶媒、テトラヒドロフラン等のエーテル系溶媒等が挙げられる。陰イオンの交換は、所望の陰イオンを含むアルカリ金属塩、例えばナトリウム塩またはカリウム塩と反応させることによって行なうことができる。
【0021】
【実施例】
以下に製造例、製剤例及び試験例により本発明を更に詳細に説明するが、本発明はこれらの実施例に限定されるものではない。化合物の命名は下記構造式を基本骨格として行なった。
【化26】
【0022】
各製造例の化合物の構造式を以下に示す。
【化27】
【化28】
【化29】
【化30】
【化31】
【化32】
【化33】
【化34】
【化35】
【化36】
【化37】
【化38】
【0023】
製造例1
6−クロロ−3−[3−(ジメチルアミノ)プロピル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
本化合物は、ケミカル・ファーマシューティカル・ブレティン(Chem. Pharm. Bull., 1981, 29, 2135-2156 )に記載されている方法に従って合成した。
a)5−クロロ−2−トリクロロアセチルアミノベンゾフェノンの合成
2−アミノ−5−クロロベンゾフェノン 23.2 g (100 mmol)及びトリエチルアミン 11 g (110 mmol) のテトラヒドロフラン 200 mL 溶液に、5〜15℃にてトリクロロアセチルクロライド 20 g (110 mmol)を滴下した。室温にて3時間攪拌した後反応液を水に空け、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧下にて濃縮した。得られた粗結晶をエチルアルコールで再結晶化して 33.8 g (89.9 mmol) の標題化合物を得た。
b)6−クロロ−3−[3−(ジメチルアミノ)プロピル]−4−フェニル−4−(トリクロロメチル)−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
5−クロロ−2−トリクロロアセチルアミノベンゾフェノン 3.77 g (10 mmol) のジメチルスルホキシド 50 mL溶液に、3−ジメチルアミノプロピルアミン 1.23 g (12 mmol) を加え室温にて24時間攪拌した。反応液を氷水 200 mL に空け、析出した結晶を濾取した。得られた粗結晶をクロロホルムとジメチルホルムアミドの混合溶媒で再結晶化して 3.97 g (8.6 mmol)の標題化合物を得た。
c)6−クロロ−3−[3−(ジメチルアミノ)プロピル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
6−クロロ−3−[3−(ジメチルアミノ)プロピル]−4−フェニル−4−(トリクロロメチル)−3,4−ジヒドロ−2(1H)−キナゾリノン 3.69 g (8 mmol)のジメチルホルムアミド 80 mL溶液に、5〜15℃にて水素化ほう素ナトリウム 605 mg (16 mmol) を加えた。室温にて3時間攪拌した後氷水 300 mL に空け、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧下にて濃縮した。残さをエチルアルコールで結晶化して標題化合物を 2.23 g (6.5 mmol)得た。
上記フリー塩基 1.72 g (5.0 mmol)のエタノール溶液に、室温にてくえん酸一水和物 1.05 g (5 mmol)のエタノール溶液を加えた。1時間攪拌した後、溶媒を減圧下に留去し、残さをエタノールで結晶化して標題化合物のくえん酸塩を 2.55 g (4.6 mmol)得た。
融点 ; 157 - 159℃(再結晶溶媒:エタノール)
【0024】
製造例2
3−[3−(ジメチルアミノ)プロピル]−4−シクロヘキシル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、(2−アミノベンゾイル)シクロヘキサンと3−ジメチルアミノプロピルアミンから標題化合物を合成した。
1H NMR(CDCl3 ) δ ; 7.65 (1H, brs), 7.17 (1H, m), 6.94 (2H, m), 6.73 (1H, m), 4.16 (1H, d, J=5.0 Hz), 4.04 (1H, m), 3.02 (1H, m), 2.28 (2H, m), 2.17 (6H, s), 1.72 (7H, m), 1.04 (5H, m), 0.80 (1H, m).
融点 ; 124 - 125℃(再結晶溶媒:エタノール)
塩酸塩
融点 ; 183 - 184℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例3
3−[2−(ジエチルアミノ)エチル]−4−(3−ヒドロキシフェニル)−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
a)3−[2−(ジエチルアミノ)エチル]−4−(3−ベンジルオキシフェニル)−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、2−アミノ−3′−ベンジルオキシベンゾフェノンと2−(ジエチルアミノ)エチルアミンから標題化合物を合成した。
1H NMR(CDCl3 ) δ ; 7.29 〜7.43 (5H, m), 7.22 (1H, m), 7.12 (1H, m), 6.83〜6.97 (6H, m), 6.66 (1H, dd, J=7.9, 1.0 Hz), 5.63 (1H, s), 5.01 (2H, s), 3.77〜3.87 (1H, m), 2.93〜3.03 (1H, m), 2.54〜2.71 (1H, m), 2.39〜2.52 (5H, m), 0.97 (6H, t, J=7.3Hz).
融点 ; 128 - 129℃(再結晶溶媒:エタノール)
b)3−[2−(ジエチルアミノ)エチル]−4−(3−ヒドロキシフェニル)−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[2−(ジエチルアミノ)エチル]−4−(3−ベンジルオキシフェニル)−3,4−ジヒドロ−2(1H)−キナゾリノン 2.0 g (4.66 mmol)のメタノール 100 mL 溶液に5%パラジウム−炭素 200 mg を加え、水素雰囲気下、室温にて5時間攪拌した。反応液をセライト濾過し、濾液を減圧下にて濃縮した。析出した結晶をメタノールで再結晶化して標題化合物を 1.30 g (3.83 mmol) 得た。 1H NMR (DMSO- d6 ) δ ; 9.45 (1H, s, D2 O交換消失), 9.33 (1H, s), 7.04 〜7.15 (3H, m), 6.62〜6.83 (5H, m), 5.62 (1H, s), 3.68 (1H, m), 2.77 (1H, m), 2.34〜2.56 (6H, m), 0.89 (6H, t, J=7.3Hz).
融点 ; 208 - 210℃(再結晶溶媒:メタノール)
塩酸塩
融点 ; 247 - 249℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0025】
製造例4
3−[2−(1−メチルピロリジン−2−イル)エチル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、2−アミノベンゾフェノンと2−(2−アミノエチル)−1−メチルピロリジンから標題化合物を約1:1のジアステレオマーの混合物として合成した。
1H NMR(CDCl3 ) δ ; 7.23 〜7.34 (5H, m), 7.13 (1H, m), 7.00 (1H, m), 6.87 (1H, m), 6.71 (1H, m), 5.51 (0.5H, s), 5.49 (0.5H, s), 3.89〜4.00 (0.5H, m), 3.73〜3.84 (0.5H, m), 2.96〜3.07 (1H, m), 2.75〜2.86 (1H, m), 2.25 (1.5H, s), 2.23 (1.5H, s), 1.84〜2.14 (4H, m), 1.36〜1.78 (4H, m). 融点 ; 154 - 157℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例5
3−(ピペリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、2−アミノベンゾフェノンと2−アミノメチルピペリジンから標題化合物を約1:1のジアステレオマーの混合物として合成した。
1H NMR(CDCl3 ) δ ; 7.93 (1H, m), 6.74 〜7.49 (9H, m), 5.56 (0.5H, s), 5.52 (0.5H, s), 3.79〜4.00 (1H, m), 2.52〜3.09 (4H, m), 1.10〜1.80 (6H, m).
融点 ; 193 - 195℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例6
3−(1−エチルピペリジン−3−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、2−アミノベンゾフェノンと3 −(アミノメチル)−1−エチルピペリジンから標題化合物を約2:3のジアステレオマーの混合物として合成した。
1H NMR(CDCl3 ) δ ; 8.04 (1H, brs), 7.22 〜7.35 (5H, m), 6.74〜7.16 (4H, m), 5.52 (0.4H, s), 5.47 (0.6H, s), 3.94 (1H, m), 2.59〜3.01 (3H, m), 2.44 (2H, m), 1.55〜2.19 (7H, m), 1.05 (3H, m).
塩酸塩
融点 ;約 250℃(分解、再結晶溶媒:エタノール).
【0026】
製造例7
3−(モルホリン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、2−アミノベンゾフェノンと2−アミノメチルモルホリンから標題化合物を約1:1のジアステレオマーの混合物として合成した。
1H NMR(CDCl3 ) δ ; 7.80 (0.5H, brs), 7.71 (0.5H, brs), 6.68 〜7.40 (9H, m), 5.74 (0.5H, s), 5.69 (0.5H, s), 3.35〜3.96 (4H, m), 2.43〜3.03 (5H, m).
製造例8
3−(1−エチルピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、2−アミノベンゾフェノンと2−(アミノメチル)−1−エチルピロリジンから標題化合物をジアステレオマーの混合物として 1.02 g 合成した。カラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)でジアステレオマーの混合物を分離して、ジアステレオマーAを589 mg、ジアステレオマーBを 254 mg 、両者の混合物を 150 mg 得た。ジアステレオマーAは、薄層クロマトグラフィー(展開溶媒;メタノール:クロロホルム1:9)においてよりRf値の大きいジアステレオマーであり、ジアステレオマーBはよりRf値の小さいジアステレオマーである。
ジアステレオマーA
1H NMR(CDCl3 ) δ ; 9.59 (1H, brs), 6.80 〜7.35 (9H, m), 5.81 (1H, s), 4.04 (1H, dd, J=14, 3Hz), 3.18 (1H, m), 2.71〜3.02 (3H, m), 1.61〜2.39 (6H, m), 1.17 (3H, t, J=7Hz).
塩酸塩
融点 ; 250℃以上(再結晶溶媒:エタノール)
ジアステレオマーB
1H NMR(CDCl3 ) δ ; 9.02 (1H, brs), 6.81 〜7.39 (9H, m), 5.83 (1H, s), 3.94 (1H, dd, J=14, 6Hz), 3.29 (1H, m), 2.83〜3.11 (3H, m), 2.27〜2.46 (2H, m), 1.62〜1.93 (4H, m), 1.06 (3H, t, J=7Hz).
融点 ; 151 - 153℃(再結晶溶媒:エタノール)
【0027】
製造例9
3−[(2S)−1−エチルピロリジン−2−イル]メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
(S)−2−アミノメチル−1−エチルピロリジンを用い、製造例8と同様にして標題化合物をジアステレオマーの混合物として合成した。カラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)でジアステレオマーの混合物を分離して、ジアステレオマーA1を 11.8 g 、ジアステレオマーB1を 4.62 g 得た。ジアステレオマーA1は、薄層クロマトグラフィー(展開溶媒;メタノール:クロロホルム 1:9)においてよりRf値の大きいジアステレオマーであり、ジアステレオマーB1はよりRf値の小さいジアステレオマーである。ジアステレオマーA1は製造例8で合成したジアステレオマーAの光学活性体であり、ジアステレオマーB1はジアステレオマーBの光学活性体である。
ジアステレオマーA1:塩酸塩
融点 ; 299.5 - 302℃(再結晶溶媒:エタノール)
[α] D 24 +177.3 °(c 1.07,メタノール)
ジアステレオマーB1:塩酸塩
融点 ; 302.5 - 304℃(再結晶溶媒:エタノール)
[α] D 24 −204.9 °(c 0.943, メタノール)
製造例10
3−[(2R)−1−エチルピロリジン−2−イル]メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
(R)−2−アミノメチル−1−エチルピロリジンを用い、製造例8と同様にして標題化合物をジアステレオマーの混合物として合成した。カラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)でジアステレオマーの混合物を分離して、ジアステレオマーA2を 9.89 g 、ジアステレオマーB2を 4.12 g 得た。ジアステレオマーA2は、薄層クロマトグラフィー(展開溶媒;メタノール:クロロホルム 1:9)においてよりRf値の大きいジアステレオマーであり、ジアステレオマーB2はよりRf値の小さいジアステレオマーである。ジアステレオマーA2は製造例8で合成したジアステレオマーAの光学活性体であり、製造例9で合成したジアステレオマーA1の光学異性体である。同様にジアステレオマーB2はジアステレオマーBの光学活性体であり、ジアステレオマーB1の光学異性体である。
ジアステレオマーA2:塩酸塩
融点 ; 305 - 306.5℃(再結晶溶媒:エタノール)
[α] D 24 −178.2 °(c 0.995, メタノール)
ジアステレオマーB2:塩酸塩
融点 ; 305 - 307.5℃(再結晶溶媒:エタノール)
[α] D 24 +203.6 °(c 0.978, メタノール)
【0028】
製造例11
3−(1−ベンジルピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、2−アミノベンゾフェノンと2−(アミノメチル)−1−ベンジルピロリジンから標題化合物を約2:3のジアステレオマーの混合物として合成した。
塩酸塩
1H NMR(CD3 OD) δ ; 6.82 〜7.90 (14H, m), 5.66 (0.4H, s), 5.45 (0.6H, s), 3.78 〜4.87 (4H, m), 2.86〜3.63 (3H, m), 1.67〜2.69 (4H, m).
製造例12
3−(キヌクリジン−3−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、2−アミノベンゾフェノンと3−アミノメチルキヌキリジンから標題化合物を約1:1のジアステレオマーの混合物として合成した。但し、キヌクリジンの窒素原子に配位したボラン(BH3 )は、2N塩酸/テトラヒドロフラン中加熱還流することにより取り除いた。
塩酸塩
1H NMR(CDCl3 ) δ ; 8.96 (0.5H, brs), 8.87 (0.5H, brs), 7.22 〜7.36 (5H, m), 7.01〜7.16 (2H, m), 6.79〜6.90 (2H, m), 5.47 (0.5H, s), 5.42 (0.5H, s), 3.88〜4.19 (1H, m), 2.65〜3.66 (6H,m), 2.34 〜2.48 (1H, m), 2.01〜2.16 (1H, m), 1.40〜1.99 (5H, m).
製造例13
3−(キヌクリジン−4−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、2−アミノベンゾフェノンと4−アミノメチルキヌキリジンから標題化合物を合成した。
1H NMR(CDCl3 ) δ ; 7.10 〜7.47 (7H, m), 6.88〜7.00 (1H, m), 6.68〜6.77 (1H, m), 5.39 (2H, s), 3.93 (2H, d, J=14Hz), 2.89 (6H, brt, J=8Hz), 2.44 (2H, d, J=14Hz), 1.36 〜1.65 (6H, m).
【0029】
製造例14
3−(1−ベンジルピペリジン−4−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして、2−アミノベンゾフェノンと4−(アミノメチル)−1−ベンジルピペリジンから標題化合物を合成した。
1H NMR(CDCl3 ) δ ; 7.48 (1H, s), 7.20 〜7.31 (10H, m), 7.02 〜7.15 (2H, m), 6.85〜6.91 (1H, m), 6.71 (1H, d, J=7.9Hz), 5.41 (1H, s), 3.90 (1H, dd, J=14, 7.3Hz), 3.47 (2H, s), 2.85 (2H, brd, J=11Hz), 2.56 (1H, dd, J=14, 6.9Hz), 1.87 〜1.95 (2H, m), 1.66〜1.8 (3H, m), 1.24 〜1.42 (2H, m).
融点 ; 163 - 165℃(再結晶溶媒:エタノール)
製造例15
3−(ピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−(1−ベンジルピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 15.98 g (40.2 mmol)のエタノール溶液 300 mL に、ぎ酸アンモニウム 13.61 g (216 mmol) 、10%パラジウム−炭素 1.64 g を加え、5時間加熱還流した。冷却後反応液をセライト濾過し、濾液を減圧下にて濃縮した。残さに飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、アンモニア水:メタノール:クロロホルム 5:100:900)で精製して、標題化合物を約1:1のジアステレオマーの混合物として 9.32 g (30.3 mmol) 得た。
1H NMR(CDCl3 ) δ ; 8.32 (1H, m), 7.21 〜7.37 (5H, m), 6.99〜7.14 (2H, m), 6.74〜6.89 (2H, m), 5.81 (0.5H, s), 5.64 (0.5H, s), 3.89〜4.03 (1H, m), 3.41〜3.51 (1H, m), 2.67〜3.07 (3H, m), 2.02 (1H, brs), 1.64〜1.89 (3H, m), 1.31 (1H, m).
融点 ; 163 - 164℃(再結晶溶媒:酢酸エチル)
【0030】
製造例16
3−[1−(2−プロピル)ピロリジン−2−イル]メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−(ピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 554 mg (1.80 mmol) のメタノール溶液 30 mL溶液に、氷冷下10%塩酸/エタノール溶液 660 mg 、アセトン 523 mg (9.00 mmol) 、シアノ水素化ほう素ナトリウム 566 mg (9.00 mmol) を加えた。室温にて10時間攪拌した後、反応液を減圧下にて濃縮した。残さに飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)にて分離精製して、ジアステレオマーAを 279 mg 、ジアステレオマーBを 71 mg得た。ジアステレオマーAは、薄層クロマトグラフィー(展開溶媒;メタノール:クロロホルム 1:9)においてよりRf値の大きいジアステレオマーであり、ジアステレオマーBはよりRf値の小さいジアステレオマーである。
ジアステレオマーA
1H NMR(CDCl3 ) δ ; 9.80 (1H, brs), 7.19 〜7.36 (5H, m), 7.00〜7.13 (2H, m), 6.82〜6.87 (2H, m), 5.72 (1H, s), 3.86 (1H, dd, J=14, 3Hz), 3.18 (1H, m), 2.90〜2.97 (2H, m), 2.76 (1H, dd, J=14, 9Hz), 2.46〜2.52 (1H, m), 1.65〜1.82 (4H, m), 1.20 (3H, d, J=7Hz), 1.06 (3H, d, J=7Hz).
ジアステレオマーB:塩酸塩
1H NMR(CD3 OD) δ ; 7.29 〜7.40 (5H, m), 6.89〜7.23 (4H, m), 5.70 (1H, s), 3.81〜3.89 (1H, m), 3.38〜3.61 (3H, m), 3.18〜3.27 (1H, m), 1.88〜2.13 (5H, m), 1.31 (3H, d, J=7Hz), 1.14 (3H, d, J=7Hz).
融点 ; 250℃以上(再結晶溶媒:エタノール)
【0031】
製造例17
3−[1−(テトラヒドロピラン−4−イル)ピロリジン−2−イル]メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例16と同様にして、3−(ピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンとテトラヒドロ−4H−ピラン−4−オンから標題化合物をジアステレオマーの混合物として得た。ジアステレオマーAは、薄層クロマトグラフィー(展開溶媒;メタノール:クロロホルム1:9)においてよりRf値の大きいジアステレオマーであり、ジアステレオマーBはよりRf値の小さいジアステレオマーである。
ジアステレオマーA:塩酸塩
1H NMR(CD3 OD) δ ; 7.28 〜7.40 (5H, m), 7.06〜7.21 (2H, m), 6.87〜6.96 (2H, m), 5.77 (1H, s), 3.86〜4.12 (3H, m), 3.22〜3.64 (7H, m), 1.62〜2.15 (8H, m).
融点 ; 250℃以上(再結晶溶媒:エタノール)
ジアステレオマーB:塩酸塩
1H NMR(CD3 OD) δ ; 6.87 〜7.53 (9H, m), 5.80 (1H, s), 3.74〜3.96 (3H, m), 3.26〜3.71 (6H, m), 1.61〜2.15 (9H, m).
製造例18
3−(1−シクロヘキシルピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例16と同様にして、3−(ピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンとシクロヘキサノンから標題化合物をジアステレオマーの混合物として得た。ジアステレオマーAは、薄層クロマトグラフィー(展開溶媒;メタノール:クロロホルム 1:9)においてよりRf値の大きいジアステレオマーであり、ジアステレオマーBはよりRf値の小さいジアステレオマーである。
ジアステレオマーA:塩酸塩
1H NMR(CD3 OD) δ ; 6.84 〜7.37 (9H, m), 5.77 (1H, s), 3.84〜4.04 (2H, m), 3.40〜3.52 (1H, m), 3.15〜3.33 (2H, m), 1.47〜2.24 (9H, m), 1.14〜1.43 (6H, m).
ジアステレオマーB:塩酸塩
1H NMR(CD3 OD) δ ; 7.30 〜7.43 (5H, m), 7.18〜7.24 (1H, m), 7.06〜7.09 (1H, m), 6.90〜6.99 (2H, m), 5.75 (1H, s), 3.87〜3.92 (1H, m), 3.58〜3.82 (2H, m), 3.42〜3.51 (1H, m), 3.24〜3.34 (1H, m), 3.03〜3.13 (1H, m), 1.81〜2.17 (8H, m), 1.64 (1H, m), 1.13〜1.45 (5H, m).
融点 ; 250℃以上(再結晶溶媒:イソプロピルアルコール)
【0032】
製造例19
3−[1−(テトラヒドロチオフェン−3−イル)ピロリジン−2−イル]メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例16と同様にして、3−(ピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンとテトラヒドロチオフェン−3−オンから標題化合物をジアステレオマーの混合物として得た。本化合物には4種類のジアステレオマーが存在するが、薄層クロマトグラフィー(展開溶媒;メタノール:クロロホルム 1:9)でよりRf値の大きい物から順に、ジアステレオマーA、B、C、Dと命名した。カラムクロマトグラフィー(展開溶媒;メタノール:クロロホルム 1:9)でジアステレオマーの混合物を分離して、ジアステレオマーAとジアステレオマーBの混合物、及びジアステレオマーCとジアステレオマーDの混合物として単離した。
ジアステレオマーAとジアステレオマーBの混合物
1H NMR(CDCl3 ) δ ; 8.05 〜8.12 (1H, m), 6.73〜7.32 (9H, m), 5.70 (0.4H, s), 5.68 (0.6H, s), 3.68〜3.86 (2H, m), 2.45〜3.20 (10H, m), 1.74 〜2.20 (4H, m).
融点 ; 123 - 126℃(再結晶溶媒:エタノール)
ジアステレオマーCとジアステレオマーDの混合物:塩酸塩
1H NMR(CD3 OD) δ ; 7.29 〜7.39 (5H, m), 7.18〜7.24 (1H, m), 6.90〜7.09 (3H, m), 5.76 (1H, s), 3.79〜3.91 (3H, m), 3.58〜3.64 (2H, m), 3.29〜3.40 (1H, m), 2.70〜3.08 (4H, m), 1.93〜2.36 (6H, m).
融点 ; 250℃以上(再結晶溶媒:イソプロピルアルコール)
製造例20
3−(1−シアノメチルピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−(ピロリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 203 mg (0.66 mmol) 、ブロモアセトニトリル 95 mg (0.79 mmol)、トリエチルアミン 283 mg (2.8 mmol)のジメチルホルムアミド 5mL溶液を70℃にて6時間攪拌した。冷却後反応液に水を加え、クロロホルムで抽出した。有機層を水で洗浄し、炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製して標題化合物を約1:2のジアステレオマーの混合物として 226 mg (0.65 mmol) 得た。
1H NMR(CDCl3 ) δ ; 8.02 (0.4H, brs), 7.90 (0.6H, brs), 7.23 〜7.36 (5H, m), 6.75〜7.18 (4H, m), 5.70 (0.7H, s), 5.62 (0.3H, s), 3.91〜4.09 (1H, m), 3.57〜3.75 (2H, m), 2.54〜3.09 (5H, m), 1.62〜2.03 (3H, m).
【0033】
製造例21
3−(1−エチルピペリジン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例20と同様にして、4−フェニル−3−(ピペリジン−2−イル)メチル−3,4−ジヒドロ−2(1H)−キナゾリノンとヨウ化エチルから標題化合物を約1:1のジアステレオマーの混合物として合成した。
1H NMR(CDCl3 ) δ ; 8.05 (1H, brs), 7.24 〜7.36 (5H, m), 6.74〜7.16 (4H, m), 5.48 (1H, m), 4.16 (1H, m), 2.35〜2.96 (8H, m), 1.30〜1.77 (4H, m), 0.99 (3H, t , J=7Hz).
製造例22
3−(4−エチルモルホリン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例20と同様にして、3−(モルホリン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンとヨウ化エチルから標題化合物を約2:3のジアステレオマーの混合物として合成した。
1H NMR(CDCl3 ) δ ; 7.08 〜7.38 (6H, m), 6.99〜7.06 (1H, m), 6.83〜6.92 (1H, m), 6.65〜6.73 (1H, m), 5.75 (0.4H, s), 5.71 (0.6H, s), 4.22 (0.4H, dt, J=2, 11Hz), 4.17 (0.6H, dt, J=2, 11Hz), 4.12 (0.6H, dd, J=15, 2Hz), 3.94 (0.4H, dd, J=14, 4Hz), 3.70〜3.90 (2H, m), 2.96 (0.6H, dd, J=15, 3Hz), 2.60〜2.86 (2.2H, m), 2.37 (2H, q, J=7.2Hz), 2.06 (1.2H, J=12, 3Hz), 1.94 (0.6H, dd, J=12, 11Hz), 1.74 (0.4H, dd, J=12, 11Hz), 1.06 (1.8H, t, J=7.2Hz), 1.05 (1.2H, t, J=7.2Hz).
製造例23
3−(4−ベンジルモルホリン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例20と同様にして、3−(モルホリン−2−イル)メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンとベンジルブロマイドから標題化合物を約2:3のジアステレオマーの混合物として合成した。
1H NMR(CDCl3 ) δ; 7.64 (0.6H, brs), 7.57 (0.4H, brs), 7.17〜7.43 (9H, m), 7.12 (0.6H, dt, J=8, 1Hz), 7.11 (0.4H, dt, J=8, 1Hz), 7.02 (0.4H, s), 7.00 (0.6H, s), 6.88 (0.6H, dt, J=7, 1Hz), 6.87 (0.4H, dt, J=7, 1Hz), 6.72 (0.6H, dd, J=8, 1Hz), 6.70 (0.4H, dd, J=8, 1Hz), 5.77 (0.4H, s), 5.68 (0.6H, s), 4.11 (0.6H, dd, J=15, 6Hz), 3.70〜3.95 (2.4H, m), 3.30〜3.67 (3H, m), 2.95 (0.6H, dd, J=15, 4Hz), 2.48〜2.85 (2.2H, m), 2.00〜2.19 (1.6H, m), 1.83 (0.6H, dd, J=11, 10Hz).
【0034】
製造例24
3−(1−ベンジルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
a)N−(1−ベンジルピペリジン−4−イル)−2−(トリクロロアセチルアミノ)ベンゾフェノンイミン
製造例1の方法と同様にして2−アミノベンゾフェノンより得た2−トリクロロアセチルアミノベンゾフェノン 40.8 g (119 mmol)、4−アミノ−1−ベンジルピペリジン 25.0 g (131 mmol)をジメチルスルホキシド 300 mL に溶解し、約40℃にて15時間攪拌した。反応液を水に空け、析出した結晶を濾取した。得られた粗結晶を酢酸エチルで再結晶化して標題化合物を 44.8 g (86.9 mmol) 得た。 1H NMR(CDCl3 ) δ ; 8.73 (1H, m), 7.22 〜7.54 (9H, m), 7.12〜7.16 (2H, m), 6.88〜6.99 (2H, m), 3.44 (2H, s), 3.06〜3.17 (1H, m), 2.82〜2.86 (2H, m), 1.96〜2.11 (2H,m), 1.72 〜1.82 (2H, m), 1.50〜1.58 (2H, m).
融点 ; 151 - 152℃(再結晶溶媒:酢酸エチル)
b)α−(2−アミノフェニル)−N−(1−ベンジルピペリジン−4−イル)ベンジルアミンの合成
N−(1−ベンジルピペリジン−4−イル)−2−(トリクロロアセチルアミノ)ベンゾフェノンイミン 44.7 g (86.8 mmol) のエタノール 150 mL 溶液に、5〜15℃にて水素化ほう素ナトリウム 3.28 g (86.8 mmol) を加え2時間攪拌した。更に5〜15℃にて水素化ほう素ナトリウム 3.28 g (86.8 mmol) を加え、室温にて10時間攪拌した。反応液に水を加え、エタノールを減圧下に留去した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、酢酸エチル)で精製して標題化合物を 27.7 g (74.5 mmol) 得た。 1H NMR(CDCl3 ) δ ; 7.21 〜7.35 (10H, m), 7.01 〜7.07 (1H, m), 6.84〜6.88 (1H, m), 6.60〜6.65 (2H, m), 5.08 (1H, s), 4.74 (1H, br), 3.46 (2H, s), 2.79 (2H, brd, J=11Hz), 2.44 〜2.52 (1H, m), 1.86〜2.00 (4H, m), 1.65 (2H, brs), 1.46〜1.60 (2H, m).
c)3−(1−ベンジルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
α−(2−アミノフェニル)−N−(1−ベンジルピペリジン−4−イル)ベンジルアミン 27.6 g (74.4 mmol) のテトラヒドロフラン 300 mL 溶液に1,1′−カルボニルジイミダゾール 12.1 g (74.5 mmol) を加え、8時間加熱還流した。放冷後反応液を減圧下にて濃縮し、残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製した。得られた粗結晶をエタノールで再結晶化して標題化合物を 24.0 g (60.3 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.11 〜7.40 (12H, m), 6.91 (1H, dd, J=7.6, 1.0 Hz), 6.83 (1H, s), 6.66 (1H, d, J=7.6Hz), 5.56 (1H, s), 4.33〜4.45 (1H, m), 3.45 (1H, s), 2.90〜2.97 (1H, m), 2.74〜2.81 (1H, m), 1.91〜2.14 (2H, m), 1.42〜1.65 (2H, m).
融点 ; 199 - 200℃(再結晶溶媒:エタノール)
くえん酸塩
融点 ; 159 - 161.5℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0035】
製造例25
3−(キヌクリジン−3−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例24と同様にして、2−アミノベンゾフェノンと3−アミノキヌクリジンから標題化合物をジアステレオマーの混合物として合成した。カラムクロマトグラフィー(シリカゲル、アンモニア水:メタノール:クロロホルム 1:9:90)で分離して、ジアステレオマーAを 258 mg 、ジアステレオマーBを 330 mg 、両者の混合物を 480 mg 得た。ジアステレオマーAは、薄層クロマトグラフィー(展開溶媒;アンモニア水:メタノール:クロロホルム 1:9:90)においてよりRf値の大きいジアステレオマーであり、ジアステレオマーBはよりRf値の小さいジアステレオマーである。
ジアステレオマーA
1H NMR(CDCl3 ) δ ; 8.41 (1H, brs), 7.12 〜7.36 (8H, m), 6.96 (1H, m), 6.77 (1H, m), 5.75 (1H, s), 4.62 (1H, m), 2.77〜3.05 (5H, m), 2.50 (1H, m), 1.36〜1.98 (5H, m).
塩酸塩
融点 ; 250℃以上(再結晶溶媒:ジエチルエーテル/エタノール)
ジアステレオマーB
1H NMR(CDCl3 ) δ ; 8.59 (1H, m), 6.76 〜7.30 (9H, m), 5.59 (1H, s), 3.87 (1H, m), 3.67 (1H, m), 2.72〜3.04 (5H, m), 1.40〜2.06 (5H, m).
製造例26
3−(1−メチルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例24と同様にして2−アミノベンゾフェノンと4−アミノ−1−メチルピペリリジンから標題化合物を合成した。
1H NMR(CDCl3 ) δ ; 7.54 (1H, brs), 7.08 〜7.43 (7H, m), 6.90 (1H, m), 6.72 (1H, m), 5.55 (1H, s), 4.40 (1H, m), 2.91 (1H, m), 2.73 (1H, m), 3.23 (3H, s), 1.93〜2.12 (3H, m), 1.46〜1.69 (3H, m).
融点 ; 252 - 253℃(再結晶溶媒:エタノール)
【0036】
製造例27
3−(1−ベンジルピロリジン−3−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例24と同様にして、2−アミノベンゾフェノンと3−アミノ−1−ベンジルピロリジンから標題化合物をジアステレオマーの混合物として合成した。カラムクロマトグラフィー(シリカゲル、酢酸エチル:クロロホルム 1:2)で分離して、ジアステレオマーAを 520 mg (1.36 mmol) 、ジアステレオマーBとジアステレオマーAの混合物を 1.08 g (2.82 mmol) 得た。ジアステレオマーAは、薄層クロマトグラフィー(展開溶媒;酢酸エチル:クロロホルム 1:2)においてよりRf値の大きいジアステレオマーであり、ジアステレオマーBはよりRf値の小さいジアステレオマーである。
ジアステレオマーA
1H NMR(CDCl3 ) δ ; 7.50 (1H, m), 7.08 〜7.35 (12H, m), 6.69 〜6.93 (2H, m), 5.77 (1H, s), 4.83 (1H, m), 3.57 (1H, d, J=13Hz), 3.40 (1H, d, J=13Hz), 2.90 (1H, m), 2.68 (1H, m), 2.20〜2.34 (3H, m)2.16 (1H, m).
融点 ;約250 ℃(分解、再結晶溶媒:ジエチルエーテル/エタノール)
製造例28
3−(ピロリジン−3−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例15と同様にして、3−(1−ベンジルピロリジン−3−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンのジアステレオマー混合物から、標題化合物をジアステレオマー混合物として合成した。
1H NMR(CD3 OD) δ ; 7.29 〜7.41 (5H, m), 6.79〜7.15 (4H, m), 5.67 (1H, m), 4.20 (1H, m), 3.62 (1H, m), 2.88〜3.18 (3H, m), 2.14〜2.53 (2H, m).
融点 ; 250℃以上(再結晶溶媒:エタノール)
製造例29
3−(1−エチルピロリジン−3−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例20と同様にして、3−(ピロリジン−3−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンとヨウ化エチルから標題化合物を約1:2のジアステレオマーの混合物として得た。 1H NMR(CDCl3 ) δ ; 7.52 〜7.58 (1H, m), 7.08〜7.41 (7H, m), 6.90 (1H, m), 6.73 (1H, m), 5.76 (0.7H, s), 5.72 (0.3H, s), 4.72〜4.91 (1H, m), 1.70〜2.88 (9H, m), 1.07 (0.9H, t, J=7Hz), 0.97 (2.1H, t, J=7Hz).
【0037】
製造例30
3−(ピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例15と同様にして、3−(1−ベンジルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンから標題化合物を合成した。
1H NMR(CDCl3 ) δ ; 7.37 〜7.41 (2H, m), 7.09〜7.31 (5H, m), 6.90 (1H, dt, J=1, 7Hz), 6.71 (1H, d, J=8Hz), 5.56 (1H, s), 4.36 (1H, m), 3.13 (1H, m), 2.99 (1H, m), 2.55〜2.73 (2H, m), 1.87〜2.02 (1H, m), 1.56〜1.76 (2H, m), 1.29〜1.45 (1H, m).
融点 ; 213 - 215℃(再結晶溶媒:ジエチルエーテル/エタノール)
塩酸塩
融点 ; 250℃以上(再結晶溶媒:エタノール)
製造例31
3−(1−アリルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−(ピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 300 mg (0.976 mmol)のエタノール 20 mL溶液に、炭酸カリウム 202 mg (1.46 mmol) 、臭化アリル 142 mg (1.17 mmol) を順次加え、室温にて4時間攪拌した。反応液を減圧下にて濃縮した後、残さに水を加えクロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、アンモニア水:メタノール:クロロホルム 1:9:90)で精製して標題化合物を 262 mg (0.67 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.06 〜7.45 (7H, m), 6.90 (1H, brt, J=7.8Hz), 6.69 (1H, brd, J=8Hz), 5.73〜5.92 (1H, m), 5.58 (1H, s), 5.05〜5.22 (2H, m), 5.33〜5.52 (1H, m), 2.78〜3.10 (4H, m), 1.87〜2.24 (3H, m), 1.36〜1.80 (3H, m).
塩酸塩
融点 ; 190 - 195℃(再結晶溶媒:エタノール)
【0038】
製造例32
3−[1−(2−プロピニル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例31と同様にして、3−(ピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンとプロパルギルブロマイドから標題化合物を合成した。
1H NMR(CDCl3 ) δ ; 6.85 〜7.52 (6H, m), 6.68 (1H, brd, J=8Hz), 5.55 (1H, s), 4.32 〜4.50 (1H, m), 3.25 (2H, d, J=2Hz), 2.71 〜3.40 (2H, m), 1.95〜2.43 (3H, m), 2.21 (1H, t, J=2Hz), 1.40 〜1.90 (3H, m).
融点 ; 198 - 201℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例33
3−(1−エチルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例31と同様にして、3−(ピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンとヨウ化エチルから標題化合物を合成した。
塩酸塩
1H NMR (DMSO- d6 ) δ ; 9.58 〜9.76 (1H, brs), 9.54 (1H, s), 7.18〜7.45 (6H, m), 7.09 (1H, dd, J=8, 1.5Hz), 6.77 〜6.89 (2H, m), 5.64 (1H, s), 4.13〜4.30 (1H, m), 3.21〜3.50 (2H, m), 2.72〜3.09 (4H, m), 2.30〜2.59 (1H, m), 1.75〜1.99 (1H, m), 1.50〜1.72 (2H, m), 1.16 (3H, t, J=7Hz).
融点 ; 295 - 296℃(分解、再結晶溶媒:ジエチルエーテル/エタノール)
製造例34
3−[1−(2−ヒドロキシエチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例31と同様にして、3−(ピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンとエチレンブロモヒドリンから標題化合物を合成した。
1H NMR(CDCl3 ) δ ; 7.04 〜7.50 (7H, m), 6.90 (1H, dt, J=1, 7.6Hz), 6.69 (1H, d, J=8Hz), 5.53 (1H, s), 4.27〜4.45 (1H, m), 3.76〜3.89 (1H, m), 3.55 (2H, m), 2.91〜3.05 (2H, m), 2.49 (2H, m), 1.93〜2.28 (3H, m), 1.35〜1.72 (3H, m).
塩酸塩
融点 ; 261 - 265℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0039】
製造例35
3−(1−エトキシカルボニルメチルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−(ピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 1.5 g (4.88 mmol)のイソプロパノール溶液 30 mLに、ブロモ酢酸エチル 896 mg (5.37 mmol) 、炭酸カリウム 853 mg 96.18 mmol) 、ヨウ化カリウム 20 mgを加え、3時間加熱還流した。熱溶液を濾過し、固形物を熱イソプロパノール 200 mL で洗った。濾液を減圧下にて濃縮し、残さをカラムクロマトグラフィー(シリカゲル、アンモニア水:メタノール:クロロホルム 1:9:90)で精製して標題化合物を 1.88 g (4.37 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.71 〜7.83 (1H, brs), 7.05〜7.43 (1H, m), 6.90 (1H, dt, J=1, 7Hz), 6.73 (1H, d, J=8Hz), 5.57 (1H, s), 4.36〜4.54 (1H, m), 4.17 (2H, q, J=7Hz), 3.16 (2H, s), 2.95 〜3.07 (1H, m), 2.79〜2.90 (1H, m), 2.00〜2.39 (3H, m), 1.45〜1.82 (2H, m), 1.25 (3H, t, J=7Hz), 1.17 〜1.30 (1H, m).
塩酸塩
融点 ; 195 - 198℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例36
3−[1−(2−フリルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−(ピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン塩酸塩 344 mg (1.0 mmol)、フルフラール 384 mg (4.0 mmL) のメタノール 40 mL溶液に、氷冷下シアノ水素化ほう素ナトリウム 123 mg (2.0 mmol)を加えた。室温にて12時間攪拌した後、反応液を減圧下にて濃縮した。残さに水を加え、アンモニア水にてpH10とした後、クロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製して標題化合物を 329 mg (0.85 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.31 〜7.37 (3H, m), 7.08〜7.28 (5H, m), 6.88〜6.94 (1H, m), 6.60〜6.73 (2H, m), 6.29 (1H, dd, J=3, 2Hz), 6.16 (1H, d, J=3Hz), 5.56 (1H, s), 4.42 (1H, m), 3.49 (2H, s), 2.95 (1H, d, J=10Hz), 2.79 (1H, d, J=12Hz), 1.96〜2.17 (3H, m), 1.45〜1.69 (3H, m).
塩酸塩
融点 ; 205 - 206℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0040】
製造例36と同様にして、製造例37〜製造例69の化合物を合成した。
製造例37
3−[1−(3−フリルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.35 〜7.39 (3H, m), 7.08〜7.29 (7H, m), 6.87〜6.93 (1H, m), 6.68 (1H, d, J=8Hz), 6.34 (1H, d, J=1.6Hz), 5.56 (1H, s), 4.34〜4.43 (1H, m), 3.33 (2H, s), 2.96 (1H, d, J=8Hz), 2.81 (1H, d, J=11Hz), 1.91 〜2.12 (3H, m), 1.41〜1.65 (3H, m).
融点 ; 250℃以上(再結晶溶媒:エタノール)
製造例38
3−[1−(2−チエニルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.61 (1H, s), 7.38 (2H, m), 7.08 〜7.29 (6H, m), 6.86〜6.93 (3H, m), 6.72 (1H, d, J=8Hz), 5.56 (1H, s), 4.33 〜4.45 (1H, m), 3.68 (2H, s), 2.98 (1H, d, J=10Hz), 2.83 (1H, dd, J=11, 2.3Hz), 1.95〜2.18 (3H, m), 1.39〜1.67 (3H, m).
塩酸塩
融点 ; 213 - 214.5℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例39
3−[1−(3−チエニルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.66 (1H, s), 7.35 〜7.40 (2H, m), 7.07〜7.29 (7H, m), 7.02 (1H, m), 6.86〜6.92 (1H, m), 6.72 (1H, d, J=8Hz), 5.56 (1H, s), 4.34 〜4.42 (1H, m), 3.49 (2H, s), 2.95 (1H, brd, J=7Hz), 2.08 (1H, brd, J=11Hz), 1.93 〜2.17 (3H, m), 1.47〜1.65 (3H, m).
塩酸塩
融点 ; 240 - 242℃(再結晶溶媒:エタノール)
製造例40
3−[1−(2−ピリジルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 8.55 (1H, m), 7.69 (1H, s), 7.59 〜7.65 (1H, m), 7.08〜7.40 (9H, m), 6.87〜6.93 (1H, m), 6.73 (1H, d, J=8Hz), 5.57 (1H, s), 4.37 〜4.47 (1H, m), 3.61 (2H, s), 2.96 (1H, d, J=8.5Hz), 2.80 (1H, d, J=11Hz), 2.02 〜2.25 (3H, m), 1.51〜1.65 (3H, m).
塩酸塩
融点 ; 253 - 255℃(再結晶溶媒:エタノール)
【0041】
製造例41
3−[1−(3−ピリジルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 8.47 〜8.51 (2H, m), 7.53〜7.63 (2H, m), 7.37〜7.41 (2H, m), 7.08〜7.30 (6H, m), 6.87〜6.93 ( 1H, m), 6.71 (1H, d, J=8Hz), 5.55 (1H, s), 4.32〜4.44 (1H, m), 3.46 (2H, s), 2.90 (1H, brd, J=10Hz), 2.76 (1H, brd, J=11Hz), 1.95〜2.17 (3H, m), 1.38〜1.65 (3H, m).
塩酸塩
融点 ; 252 - 254℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例42
3−[1−(4−ピリジルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 8.52 (2H, dd, J=4.6, 1.6Hz), 7.37〜7.41 (2H, m), 7.07〜7.31 (8H, m), 6.88〜6.94 (1H, m), 6.69 (1H, d, J=8Hz), 5.56 (1H, s), 4.30 〜4.42 (1H, m), 3.44 (2H, s), 2.89 (1H, dd, J=10, 2Hz), 2.75 (1H, brd, J=11Hz), 1.97〜2.17 (3H, m), 1.45〜1.64 (3H, m).
融点 ; 241.5 - 243℃(再結晶溶媒:エタノール)
製造例43
3−[1−(2−イミダゾリルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 9.38 (1H, s), 8.31 (1H, s), 7.18 〜7.41 (6H, m), 7.03〜7.17 (1H, m), 6.76〜6.87 (2H, m), 5.69 (1H, s), 4.09 (1H, m), 3.41 (2H, s), 2.83 (1H, m), 2.65 (1H, m), 1.97〜2.00 (3H, m), 1.37 (3H, m).
塩酸塩
融点 ; 303 - 305℃(再結晶溶媒:エタノール)
製造例44
3−[1−(2−ピロリルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 10.59 (1H, brs), 9.38 (1H, brs), 7.15〜7.48 (6H, m), 7.05 (1H, m), 6.76〜6.83 (2H, m), 6.59 (1H, m), 5.88 (1H, m), 5.81 (1H, brs), 5.70 (1H, s), 4.06 (1H, m), 3.33 (2H, s), 2.82 (1H, m), 2.62〜2.71 (1H, m), 1.83〜2.10 (3H, m), 1.28〜1.43 (3H, m).
塩酸塩
融点 ; 201 - 204℃(再結晶溶媒:エタノール)
【0042】
製造例45
3−[1−(1−メチル−2−ピロリルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
1H NMR(CDCl3 ) δ ; 7.08 〜7.58 (7H, m), 6.90 (2H, m), 6.72 (2H, m), 5.54 (1H, s), 4.33〜4.57 (2H, m), 3.46〜3.73 (1H, m), 2.95 (1H, m), 2.79 (1H, m), 2.59 (3H, s), 1.88〜2.10 (3H, m), 1.20〜1.75 (3H, m).
製造例46
3−[1−(2−フェニルエチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.62 (1H, s), 7.37 〜7.41 (2H, m), 7.09〜7.30 (10H, m), 6.88 〜6.93 (1H, m), 6.73 (1H, d, J=7.6Hz), 5.59 (1H, s), 4.40 〜4.50 (1H, m), 3.06 (1H, d, J=10Hz), 2.93 (1H, d, J=11Hz), 2.73〜2.79 (2H, m), 2.53〜2.58 (2H, m), 1.97〜2.20 (3H, m), 1.43〜1.72 (3H, m).
塩酸塩
融点 ; 284 - 285.5℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例47
3−[1−(シクロヘキシルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.67 (1H, s), 7.36 〜7.41 (2H, m), 7.08〜7.29 (5H, m), 6.87〜6.93 (1H, m), 6.72 (1H, d, J=8Hz), 5.57 (1H, s), 4.34 〜4.44 (1H, m), 2.90 (1H, d, J=7Hz), 2.77 (1H, d, J=11Hz), 1.62 〜2.12 (11H, m), 1.35 〜1.51 (3H, m), 1.05〜1.25 (3H, m), 0.75〜0.88 (2H, m).
塩酸塩
融点 ; 194 - 197.5℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例48
3−[1−(4−シクロヘキセニルメチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
塩酸塩
1H NMR (DMSO- d6 ) δ ; 9.53 (1H, s), 9.35 〜9.53 (1H, m), 7.18〜7.45 (6H, m), 7.09 (1H, dt, J=1, 8Hz), 6.76 〜6.89 (2H, m), 5.55〜5.72 (3H, m), 4.12〜4.38 (1H, m), 3.20〜3.55 (2H, m), 2.80〜3.07 (4H, m), 2.39〜2.63 (1H, m), 1.47〜2.26 (9H, m), 1.10〜1.30 (1H, m).
融点 ; 160℃(分解、再結晶溶媒:ジエチルエーテル/エタノール)
【0043】
製造例49
3−(1−シクロヘキシルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.39 (2H, d, J=7Hz), 7.05〜7.29 (5H, m), 6.88〜6.94 (1H, m), 6.67 (1H, d, J=8Hz), 5.61 ( 1H, s), 4.45 (1H, m), 3.02 (1H, d, J=10Hz), 2.87 (1H, d, J=11Hz), 1.50〜2.46 (12H, m), 1.04 〜1.20 (5H, m).
融点 ; 213 - 215.5℃(再結晶溶媒:エタノール)
製造例50
3−[1−(テトラヒドロピラン−4−イル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.36 〜7.40 (2H, m), 7.08〜7.30 (5H, m), 6.88〜6.94 (1H, m), 6.68 (1H, dd, J=8, 1Hz), 5.58 (1H, s), 4.35 〜4.47 (1H, m), 3.97〜4.02 (2H, m), 3.36 (1H, d, J=11Hz), 3.32 (1H, d, J=12Hz), 3.01 (1H, brd, J=12Hz), 2.87 (1H, brd, J=11Hz), 2.10〜2.45 (3H, m), 1.89〜2.04 (1H, m), 1.37〜1.72 (7H, m).
融点 ; 282 - 284℃(再結晶溶媒:エタノール)
製造例51
3−[1−(1−フェニルエチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
約1:1のジアステレオマーの混合物として得た。
1H NMR(CDCl3 ) δ ; 8.53 (1H, s), 7.06 〜7.49 (10H, m), 6.75 〜6.90 (4H, m), 5.56 (0.5H, s), 5.55 (0.5H, s), 4.34 (1H, m), 3.38 (1H, m), 2.70〜3.09 (2H, m), 1.86〜2.08 (4H, m), 1.43〜1.67 (2H, m), 1.34 (1.5H, d, J=6Hz), 1.32 (1.5H, d, J=6Hz).
塩酸塩
融点 ; 282 - 285℃(再結晶溶媒:酢酸エチル/エタノール)
製造例52
3−[1−(2−メトキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.08 〜7.39 (8H, m), 6.81〜6.94 (4H, m), 6.65 (1H, d, J=8Hz), 5.58 (1H, s), 4.39 (1H, m), 3.79 (3H, s), 3.52 (2H, s), 2.97 (1H, m), 2.83 (1H, m), 1.95 〜2.17 (3H, m), 1.49〜1.65 (3H, m).
融点 ; 197 - 198.5℃(再結晶溶媒:エタノール)
【0044】
製造例53
3−[1−(3−メトキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.37 〜7.40 (2H, m), 7.08〜7.29 (6H, m), 6.76〜6.94 (5H, m), 6.66 (1H, d, J=8Hz), 5.56 (1H, s), 4.38 (1H, m), 3.80 (3H, s), 3.43 (2H, s), 2.93 (1H, m), 2.78 (1H, m), 1.93 〜2.09 (3H, m), 1.46〜1.65 (3H, m).
融点 ; 187 - 188.5℃(再結晶溶媒:エタノール)
メソ酒石酸塩
融点 ; 122 - 140℃(再結晶溶媒:イソプロパノール)
製造例54
3−[1−(4−メトキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.35 〜7.39 (2H, m), 7.08〜7.29 (6H, m), 6.77〜6.93 (4H, m), 6.65 (1H, dd, J=8, 1Hz), 5.56 (1H, s), 4.37 (1H, m), 3.79 (3H, s), 3.39 (2H, s), 2.92 (1H, m), 2.77 (1H, m), 1.90 〜2.10 (3H, m), 1.46〜1.64 (3H, m).
融点 ; 218 - 219.5℃(再結晶溶媒:エタノール)
製造例55
3−[1−(2−クロロベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.08 〜7.42 (11H, m), 6.88 〜6.94 (1H, m), 6.83 (1H, brs), 6.66 (1H, d, J=8Hz), 5.57 (1H, s), 4.33 〜4.45 (1H, m), 3.56 (2H, s), 2.95 (1H, m), 2.81 (1H, m), 1.95〜2.26 (3H, m), 1.45〜1.65 (3H, m).
融点 ; 206 - 207.5℃(再結晶溶媒:エタノール)
製造例56
3−[1−(3−クロロベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.37 〜7.41 (2H, m), 7.08〜7.29 (9H, m), 6.88〜6.94 (1H, m), 6.74 (1H, brs), 6.65 (1H, d, J=8Hz), 5.56 (1H, s), 4.33 〜4.43 (1H, m), 3.41 (2H, s), 2.88〜2.92 (1H, m), 2.72〜2.77 (1H, m), 1.94〜2.13 (3H, m), 1.46〜1.65 (3H, m).
融点 ; 204 - 205.5℃(再結晶溶媒:エタノール)
【0045】
製造例57
3−[1−(4−クロロベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.36 〜7.40 (2H, m), 7.08〜7.27 (9H, m), 6.91 (1H, m), 6.78 (1H, brs), 6.66 (1H, d, J=8Hz), 5.55 (1H, s), 3.42 〜4.42 (1H, m), 3.40 (2H, s), 2.88 (1H, m), 2.74 (1H, m), 1.92〜2.12 (3H, m), 1.38〜1.64 (3H, m).
融点 ; 233 - 234℃(再結晶溶媒:エタノール)
製造例58
3−[1−(3−ニトロベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 8.19 (1H, d, J=2Hz), 8.08 (1H, m), 7.61 (1H, d, J=8Hz), 7.39 〜7.48 (3H, m), 7.09〜7.31 (5H, m), 6.88〜6.94 (1H, m), 6.68 (1H, m), 5.57 (1H, s), 4.34〜4.45 (1H, m), 3.53 (2H, s), 2.89 (1H, m), 2.75 (1H, m), 1.96〜2.19 (3H, m), 1.44 (3H, m).
融点 ; 213 - 214.5℃(再結晶溶媒:エタノール)
製造例59
3−[1−(3−メチルベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.37 (2H, m), 7.04 〜7.28 (8H, m), 6.87〜6.96 (2H, m), 6.66 (1H, d, J = 8Hz), 5.56 (1H, s), 4.37 (1H, m), 3.41 (2H, s), 2.93 (1H, m), 2.77 (1H, m), 2.32 (3H, s), 1.92〜2.08 (3H, m), 1.39〜1.61 (3H, m).
融点 ; 190 - 191℃(再結晶溶媒:エタノール)
製造例60
3−[1−(3−ヒドロキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
塩酸塩
1H NMR (DMSO- d6 ) δ ; 9.37 (1H, brs), 9.25 (1H, brs), 7.39 〜7.43 (2H, m), 7.26〜7.31 (3H, m), 7.15〜7.21 (1H, m), 7.02〜7.09 (2H, m), 6.76〜6.84 (2H, m), 6.59〜6.66 (3H, m), 5.76 (1H, s), 4.12 (1H, m), 3.29 (2H, s), 2.82 (1H, m), 2.69 (1H, m), 1.86〜2.04 (3H, m), 1.35〜1.43 (3H, m).
融点 ; 222.5 - 224℃(再結晶溶媒:エタノール)
【0046】
製造例61
3−[1−(3−シアノベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.96 (1H, s), 7.63 (1H, s), 7.48 〜7.54 (2H, m), 7.35〜7.43 (3H, m), 7.09〜7.30 (5H, m), 6.87〜6.93 (1H, m), 6.75 (1H, d, J=8Hz), 5.57 (1H, s), 4.35 〜4.45 (1H, m), 3.46 (2H, s), 2.87 (1H, m), 2.73 (1H, m), 1.96〜2.17 (3H, m), 1.41〜1.65 (3H, m).
塩酸塩
融点 ; 226 - 227.5℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例62
3−[1−(3−エチルベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.36 〜7.39 (2H, m), 7.06〜7.29 (9H, m), 6.88〜6.94(1H, m), 6.75 (1H, s), 6.65 (1H, d, J=8Hz), 5.57 (1H, s), 4.40 (1H, m), 3.49 (2H, s), 2.94 (1H, m), 2.78 (1H, m), 2.62 (2H, q, J=7.6Hz), 1.93 〜2.08 (3H, m), 1.42〜1.64 (3H, m), 1.22 (3H, t, J=7.6Hz).
塩酸塩
融点 ; 175 - 179℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例63
3−[1−(3−メチルチオベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.39 (2H, d, J=7Hz), 7.02〜7.28 (9H, m), 6.87〜6.92 (1H, m), 6.69〜6.90 (1H, m), 5.56 (1H, s), 4.39 (1H, m), 3.42 (2H, s), 2.91 (1H, m), 2.78 (1H, m), 2.47 (3H, s), 1.95〜2.03 (3H, m), 1.51〜1.64 (3H, m).
融点 ; 188 - 189℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例64
3−[1−(3−ヒドロキシメチルベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.08 〜7.40 (11H, m), 6.91 (1H, m), 6.81 (1H, s), 6.65 (1H, d, J=7Hz), 5.56 (1H, s), 4.68 (2H, s), 4.38 (1H, m), 3.45 (2H, s), 2.92 (1H, m), 2.77 (1H, m), 1.93〜2.09 (3H, m), 1.46〜1.68 (3H, m).
塩酸塩
融点 ; 174 - 177℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0047】
製造例65
3−[1−(3−フルオロベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.58 (1H, brs), 7.38 〜7.41 (2H, m), 7.01〜7.30 (8H, m), 6.87〜6.95 (2H, m), 6.72 (1H, d, J=8Hz), 5.56 (1H, s), 4.40 (1H, m), 3.44 (2H, s), 2.91 (1H, d, J=8Hz), 2.77 (1H, m), 1.95〜2.14 (3H, m), 1.43〜1.65 (3H, m).
融点 ; 202 - 203℃(再結晶溶媒:エタノール)
製造例66
3−[1−(3,4−メチレンジオキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.36 〜7.40 (2H, m), 7.08〜7.29 (4H, m), 6.87〜6.93 (2H, m), 6.80 (1H, s), 6.65〜6.73 (3H, m), 5.93 (2H, s), 5.56 (1H, s), 4.38 (1H, m), 3.35 (2H, s), 2.91 (1H, m), 2.78 (1H, m), 1.91〜2.06 (3H, m), 1.39〜1.64 (3H, m).
融点 ; 209 - 210℃(再結晶溶媒:エタノール)
製造例67
3−[1−(3−エトキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 8.15 (1H, brs), 7.37 〜7.41 (2H, m), 7.07〜7.28 (6H, m), 6.73〜6.92 (5H, m), 5.56 (1H, s), 4.40 (1H, m), 4.01 (2H, q, J=7Hz), 3.42 (2H, s), 2.93 (1H, m), 2.79 (1H, m), 1.94 〜2.09 (3H, m), 1.48〜1.63 (3H, m), 1.40 (3H, t, J=7Hz).
塩酸塩
融点 ; 170 - 173℃(再結晶溶媒:エタノール)
製造例68
3−[1−(3−イソプロポキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.37 〜7.40 (2H, m), 7.08〜7.29 (6H, m), 6.64〜6.94 (6H, m), 5.56 (1H, s), 4.54 (1H, m), 4.38 (1H, m), 3.41 (2H, s), 2.93 (1H, m), 2.74 (1H, m), 1.94〜2.12 (3H, m), 1.49〜1.64 (3H, m), 1.33 (3H, d, J=6.3Hz), 1.32 (3H, d, J=6.3Hz). 塩酸塩
融点 ; 204 - 206℃(再結晶溶媒:エタノール)
製造例69
3−[1−(2−メトキシエチル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン
1H NMR(CDCl3 ) δ ; 7.53 (1H, brs), 7.36 〜7.39 (2H, m), 7.08〜7.29 (5H, m), 6.90 (1H, m), 6.71 (1H, m), 5.57 (1H, s), 4.39〜4.50 (1H, m), 3.40〜3.55 (4H, m), 3.32 (3H, s), 3.00〜3.06 (1H, m), 2.85〜2.90 (1H, m), 2.53 (2H, m), 1.95〜2.17 (3H, m).
塩酸塩
融点 ; 102 - 104℃(再結晶溶媒:アセトン)
【0048】
製造例70
3−[1−(3−アミノベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[1−(3−ニトロベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 540 mg (1.22 mmol) のエタノール 50 mL溶液に、塩化第一すず二水和物 826 mg (3.66 mmol) を加え、60℃にて12時間攪拌した。冷却後セライト濾過し、濾液を減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:19)で精製して標題化合物を 210 mg (0.51 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.36 〜7.40 (2H, m), 7.04〜7.29 (6H, m), 6.88〜6.94 (2H, m), 6.63〜6.67 (2H, m), 6.54〜6.58 (1H, m), 5.56 (1H, s), 4.40 (1H, m), 3.62 (2H, br), 3.37 (2H, s), 2.95 (1H, m), 2.81 (1H, m), 1.95 〜2.13 (3H, m), 1.50〜1.63 (3H, m).
塩酸塩
融点 ; 247 - 249℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例71
3−[1−(3−メタンスルホンアミドベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[1−(3−アミノベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 200 mg (0.48 mmol) のアセトニトリル 20 mL溶液に無水メタンスルホン酸 93 mg (0.53 mmol)を加え、室温にて10時間攪拌した。反応液を減圧下にて濃縮した後、残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製して標題化合物を 180 mg (0.37 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.57 (1H, s), 7.08 〜7.38 (11H, m), 6.86 〜6.92 (1H, m), 6.72 (1H, dd, J=8, 1Hz), 5.53 (1H, s), 4.31 (1H, m), 3.47 (1H, d, J=13Hz), 3.40 (1H, d, J=13Hz), 3.03 (3H, s), 2.93 (1H, m), 2.82 (1H, m), 1.98 〜2.08 (3H, m), 1.46〜1.57 (3H, m).
塩酸塩
融点 ; 219.5 - 222.5℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0049】
製造例72
3−[1−(3−アセチルアミノベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[1−(3−アミノベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 200 mg (0.48 mmol) のテトラヒドロフラン 20 mL溶液に、塩化アセチル 42 mg (0.53 mmol)、トリエチルアミン 1 mL を加え、室温にて10時間攪拌した。反応液を水に空け、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製して標題化合物を 170 mg (0.37 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.45 (1H, m), 7.36 〜7.40 (3H, m), 6.87〜7.29 (10H, m), 6.66 (1H, d, J=8Hz), 5.55 (1H, s), 4.31 (1H, s), 3.43 (2H, s), 2.91 (1H, m), 2.78 (1H, m), 2.17 (3H, s), 1.93〜2.11 (3H, m), 1.45〜1.61 (3H, m).
塩酸塩
融点 ; 192 - 195℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例73
3−[1−(3−ジメチルアミノベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[1−(3−アミノベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 200 mg (0.48 mmol) のメタノール溶液 20 mLに、5〜10℃にてホルマリン415 mg (4.85 mmol)、シアノ水素化ほう素ナトリウム 243 mg (3.88 mmol) を加えた。室温にて12時間攪拌した後、反応液を減圧下にて濃縮した。残さに水を加え、アンモニア水にてpH10とし、クロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、アンモニア水:メタノール:クロロホルム 1:9:90)で精製して標題化合物を 210 mg (0.47 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.37 〜7.40 (2H, m), 7.07〜7.29 (7H, m), 6.87〜6.93 (3H, m), 6.60〜6.69 (4H, m), 5.57 (1H, s), 4.39 (1H, m), 3.42 (2H, s), 2.90 (1H, m), 2.93 (6H, s), 2.80 (1H, m), 1.94〜2.13 (3H, m), 1.43〜1.60 (3H, m).
しゅう酸塩
融点 ; 264.5 - 266℃(再結晶溶媒:エタノール)
【0050】
製造例74
3−[1−(3−メトキシカルボニルベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
(a)3−[1−(3−ベンジルオキシカルボニルベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例36と同様にして、3−(ピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン塩酸塩 700 (2.03 mmol)と3−ベンジルオキシカルボニルベンズアルデヒドから標題化合物を 1012 mg (1.90 mmol)得た
1H NMR(CDCl3 ) δ ; 7.93 〜7.96 (2H, m), 7.08〜7.50 (14H, m), 6.87 〜6.93 (1H, m), 6.67 (1H, d, J=8Hz), 5.55 (1H, s), 5.36 (2H, s), 4.39 (1H, m), 3.48 (2H, s), 2.90 (1H, m), 2.83 (1H, m), 2.01 〜2.13 (3H, m), 1.41〜1.61 (3H, m).
(b)3−[1−(3−メトキシカルボニルベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[1−(3−ベンジルオキシカルボニルベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 300 mg (0.56 mmol) のメタノール 20 mL溶液に、炭酸カリウム 8 mg (0.06 mmol) を加え、室温にて12時間攪拌した。反応液を水に空け、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製して標題化合物を 179 mg (0.39 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.89 〜7.94 (3H, m), 7.08〜7.50 (8H, m), 6.88〜6.93 (1H, m), 6.77 (1H, m), 5.56 (1H, s), 4.40 (1H, m), 3.91 (3H, s), 3.49 (2H, s), 2.92 (1H, m), 2.78 (1H, m), 2.01〜2.12 (3H, m), 1.52〜1.65 (3H, m).
塩酸塩
融点 ; 190 - 191℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0051】
製造例75
3−[1−(3−カルボキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[1−(3−ベンジルオキシカルボニルベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 700 mg (1.32 mmol) の酢酸溶液に、10%パラジウム−炭素 50 mgを加え、水素雰囲気下、室温にて5時間攪拌した。セライト濾過し、濾液を減圧下にて濃縮した。得られた粗結晶をエタノールで再結晶化して標題化合物を 450 mg (1.02 mmol) 得た。 1H NMR (DMSO- d6 ) δ ; 9.37 (1H, s), 7.79 〜7.83 (2H, m), 7.15〜7.50 (8H, m), 7.02〜7.08 (1H, m), 6.75〜6.84 (2H, m), 5.80 (1H, s), 4.15 (1H, m), 3.46 (2H, s), 2.68〜2.84 (2H, m), 1.91〜2.09 (3H, m), 1.35〜1.43 (3H, m).
融点 ; 250℃以上(再結晶溶媒:エタノール)
製造例76
3−[1−(3−カルバモイルベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[1−(3−カルボキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 220 mg (0.50 mmol) 、トリエチルアミン 111 mg (1.1 mmol)の塩化メチレン 50 mL溶液に、塩化チオニル 65 mg (0.55 mmol)の塩化メチレン 5 mL 溶液を加え、室温にて1時間攪拌した。反応液にアンモニアガスを5分間通じた後、室温にて1時間攪拌した。反応液を減圧下にて濃縮し、残さを酢酸エチルに溶解した。水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後減圧下に溶媒を留去して標題化合物を 210 mg (0.48 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.77 (1H, s), 7.66 〜7.70 (1H, m), 7.09〜7.46 (10H, m), 6.88 〜6.94 (1H, m), 6.69 (1H, d, J=8Hz), 6.15 (1H, br), 5.80 (1H, br), 5.56 (1H, s), 4.33 (1H, m), 3.49 (2H, s), 2.90 (1H, m), 2.77 (1H, m), 1.96 〜2.14 (3H, m), 1.52〜1.62 (3H, m)
塩酸塩.
融点 ; 202 - 205℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0052】
製造例77
3−[1−(3−アセトキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[1−(3−ヒドロキシベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 207 mg (0.5 mmol)のピリジン 3 mL 溶液に、無水酢酸 61 mg (0.6 mmol) を加え、室温にて12時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製して標題化合物を 187 mg (0.41 mmol) 得た。
1H NMR(CDCl3 ) δ ; 7.37 〜7.39 (3H, m), 6.83〜7.32 (10H, m), 6.66 (1H, d, J=8Hz), 5.55 (1H, s), 4.36 (1H, m), 3.44 (2H, m), 2.88 (1H, m), 2.78 (1H, m), 2.29 (3H, s), 1.90〜2.08 (3H, m), 1.41〜1.58 (3H, m).
塩酸塩
融点 ; 171 - 173℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例78
3−[1−(3−メチルスルフィニルベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[1−(3−メチルチオベンジル)ピペリジン−4−イル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの塩酸塩 480 mg (1 mmol)を塩化メチレン 10 mLに溶解し、0〜10℃にてm−クロロ過安息香酸 190 mg (1.1 mmol)を加えた。室温にて10時間攪拌した後水を加え、アンモニア水でpH10とした後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製して標題化合物を約1:1のジアステレオマーの混合物として 440 mg (0.96 mmol) 得た。
1H NMR(CDCl3 ) δ ; 8.41 (1H, s), 7.61 (1H, s), 7.39 〜7.50 (5H, m), 7.08〜7.28 (5H, m), 6.86〜6.91 (1H, m), 6.78 (1H, d, J=8Hz), 5.56 (1H, s), 4.39 (1H, m), 3.51 (2H, s), 2.88 (1H, m), 2.73 (1H, m), 2.71 (1.5H, s), 2.72 (1.5H, s), 2.03 〜2.12 (3H, m), 1.51〜1.64 (3H, m).
塩酸塩
融点 ; 198 - 202℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0053】
製造例79
3−(1−カルボキシメチルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−(1−エトキシカルボニルメチルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの塩酸塩 191 mg (0.445 mmol)を4N塩酸 30 mLに溶解し、4時間加熱還流した。放冷後、反応液を減圧下にて濃縮し、残さにトルエン 30 mLを加え、再度減圧下にて濃縮して黄色結晶を得た。これをジエチルエーテル/エタノールで再結晶化して標題化合物の塩酸塩を 56 mg (0.14 mmol)得た。
塩酸塩
1H NMR (DMSO- d6 ) δ ; 9.83 〜10.13 (1H, brs), 9.55 (1H, s), 7.18 〜7.48 (6H, m), 7.03〜7.15 (1H, m), 6.75〜6.90 (2H, m), 5.67 (1H, s), 4.17〜4.35 (1H, m), 3.93〜4.13 (2H, brs), 2.87〜3.90 (5H, m), 1.49〜1.99 (3H, m).
融点 ; 230 - 236℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例80
3−(1−カルバモイルメチルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−(1−エトキシカルボニルメチルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 200 mg (0.508 mmol)をアンモニア/メタノール (6.09 M, 30 mL)に溶解し、オートクレーブ中にて、約150℃で6時間攪拌した。放冷後反応液を減圧下にて濃縮し、残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)にて精製して標題化合物を 167 mg (0.45 mmol) 得た。
塩酸塩
1H NMR (DMSO- d6 ) δ ; 9.40 (1H, s), 6.95 〜7.50 (7H, m), 6.73〜6.90 (2H, m), 5.74 (1H, s), 4.00〜4.20 (1H, m), 2.60〜2.90 (2H, m), 2.78 (2H, s), 1.92〜2.18 (3H, m), 1.20〜1.55 (3H, m).
融点 ; 208 - 220℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0054】
製造例81
3−[1−(3−メトキシベンジル)ピペリジン−4−イル]−4−(3−ヒドロキシフェニル)−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
(a)3−[1−(3−メトキシベンジル)ピペリジン−4−イル]−4−(3−ベンジルオキシフェニル)−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例24と同様にして、2−アミノ−3′−ベンジルオキシベンゾフェノンと4−アミノ−1−(3−メトキシベンジル)ピペリジンから標題化合物を合成した。
1H NMR(CDCl3 ) δ ; 6.60 〜7.41 (17H, m), 5.50 (1H, s), 5.01 (2H, s), 4.38 (1H, m), 3.79 (3H, s), 3.43 (2H, s), 2.92 (1H, m), 2.78 (1H, m), 1.77 〜2.12 (3H, m), 1.47〜1.63 (3H, m).
(b)3−[1−(3−メトキシベンジル)ピペリジン−4−イル]−4−(3−ヒドロキシフェニル)−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
3−[1−(3−メトキシベンジル)ピペリジン−4−イル]−4−(3−ベンジルオキシフェニル)−3,4−ジヒドロ−2(1H)−キナゾリノン 1.3 g (2.44 mmol)のメタノール 100 mL 溶液に、ぎ酸アンモニウム 504 mg (8 mmol)、10%パラジウム−炭素 50 mgを加え8時間加熱還流した。放冷後セライト濾過し、濾液を減圧下にて濃縮した。残さをメタノール 50 mLに溶解し、5〜10℃にてm−アニスアルデヒド 1.33 g (9.76 mmol) 、シアノ水素化ほう素ナトリウム 613 mg (9.76 mmol) を加え、室温にて12時間攪拌した。減圧下にて濃縮した後水を加え、アンモニア水にてpH10とし、クロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製して標題化合物を 810 mg (1.83 mmol) 得た。 1H NMR (DMSO- d6 ) δ ; 9.39 (1H, s), 9.33 (1H,s), 7.23〜7.26 (2H, m), 7.03〜7.08 (2H, m), 6.75〜6.86 (7H, m), 6.55 (1H, m), 5.65 (1H, s), 4.09 (1H, m), 3.72 (3H, s), 3.36 (2H, s), 2.83 (1H, m), 2.71 (1H, m), 1.88〜2.09 (3H, m), 1.39 (3H, br).
融点 ; 250℃以上(再結晶溶媒:エタノール)
くえん酸塩
融点 ; 130 - 132℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0055】
製造例82
3−(1−ベンジルピペリジン−4−イル)−6−クロロ−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例24と同様にして5−クロロ−2−トリクロロアセチルアミノベンゾフェノンと4−アミノ−1−ベンジルピペリジンから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.19〜7.38 (10H, m), 7.13 (1H, s), 7.11 (1H, d, J=8.3Hz), 6.62 (1H, d, J=8.3Hz), 5.50 (1H, s), 4.35 (1H, m), 3.45 (2H, s), 2.93 (1H, d, J=10.6Hz), 2.78 (1H, d, J=11.6Hz), 1.93 〜2.09 (3H, m), 1.40〜1.63 (3H, m).
融点 ; 230℃以上(再結晶溶媒:エタノール)
塩酸塩
融点 ; 162 - 165℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例83
3−[2−(ジエチルアミノ)エチル]−6−ニトロ−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例1と同様にして5−ニトロ−2−トリクロロアセチルアミノベンゾフェノンと2−(ジエチルアミノ)エチルアミンから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 8.85 (1H, brs), 8.04 (1H, dd, J=8.9, 2.3Hz), 7.90 (1H, d, J=2.3Hz), 7.34〜7.38 (5H, m), 6.85 (1H, d, J=8.9Hz), 5.85 (1H, s), 3.80 〜3.90 (5H, m), 2.96〜3.07 (1H, m), 2.68〜2.78 (1H, m), 2.44〜2.60 (5H, m), 0.99 (6H, t, J=7.3Hz).
融点 ; 161 - 163℃(再結晶溶媒:エタノール)
製造例84
6−アミノ−3−[2−(ジエチルアミノ)エチル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンの合成
製造例70と同様にして3−[2−(ジエチルアミノ)エチル]−6−ニトロ−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.24〜7.34 (5H, m), 6.54 (1H, d, J=8.3Hz), 6.48 (1H, dd, J=8.3, 2.3Hz), 6.31 (1H, d, J=2.3), 5.54 (1H, s), 3.74 〜3.84 (1H, m), 3.38 (2H, brs), 2.95〜3.05 (1H, m), 2.65〜2.75 (1H, m), 2.36〜2.58 (5H, m), 0.99 (6H, t, J=7.3Hz).
塩酸塩
融点 ; 242 - 244℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0056】
製造例85
3−[2−(ジエチルアミノ)エチル]−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−d]ピリミジンの合成
(a)3−ベンゾイル−2−トリクロロアセチルアミノピリジンの合成
2−アミノ−3−ベンゾイルピリジン 11.0 g (55 mmol) 及びトリエチルアミン 6.1 g (60 mmol)のテトラヒドロフラン 200 mL 溶液に、5〜15℃にてトリクロロアセチルクロライド 10.0 g (55 mmol) を滴下した。室温にて3時間攪拌した後、反応液を水に空け、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧下にて濃縮した。得られた粗結晶をエチルアルコールで再結晶化して 14 .0 g (40 mmol)の標題化合物を得た。
1H NMR(CDCl3 ) δ; 8.73〜8.75 (1H, m), 7.99〜8.02 (1H, m), 7.71〜7.77 (2H, m), 7.62〜7.68 (1H, m), 7.42〜7.56 (2H, m), 7.23〜7.28 (1H, m).
(b)3−[2−(ジエチルアミノ)エチル]−4−フェニル−4−トリクロロメチル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−d]ピリミジンの合成
3−ベンゾイル−2−トリクロロアセチルアミノピリジン 1.4 g (4.07 mmol)のジメチルスルホキシド 50 mL溶液に、2−(ジエチルアミノ)エチルアミン 0.52 g (4.5 mmol)を加えて室温にて24時間攪拌した。反応液を水に空け、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で分離精製して標題化合物を 240 mg (0.54 mmol) 得た。
1H NMR(CDCl3 ) δ; 9.42 (1H, brd), 8.33〜8.38 (2H, m), 7.31〜7.46 (3H, m), 7.13〜7.19 (2H, m), 6.83 (1H, dd, J=7.9, 4.9Hz), 3.89 〜4.00 (1H, m), 3.15〜3.26 (1H, m), 2.75〜2.85 (1H, m), 2.20〜2.34 (4H, m), 1.92〜2.02 (1H, m), 0.79 (6H, t, J=7.3Hz).
(c)3−[2−(ジエチルアミノ)エチル]−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−d]ピリミジンの合成
3−[2−(ジエチルアミノ)エチル]−4−フェニル−4−トリクロロメチル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−d]ピリミジン 240 mg (0.54 mmol) のジメチルホルムアミド 10 mL溶液に、5〜15℃にて水素化ほう素ナトリウム 82 mg (2.16 mmol)を加えた。室温にて3時間攪拌した後、反応液を氷水に空け、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製して標題化合物を 110 mg (0.34 mmol) 得た。
融点; 160-162.5 ℃
1H NMR(CDCl3 ) δ; 8.14 (1H, dd, J=5.0, 1.7Hz), 7.78 (1H, brs), 7.31 〜7.39 (5H, m), 7.25〜7.28 (1H, m), 6.82 (1H, dd, J=7.6, 5.0Hz), 5.75 (1H, s), 3.77 〜3.87 (1H, m), 2.99〜3.03 (1H, m), 2.69〜2.79 (1H, m), 2.42〜2.60 (5H, m), 0.99 (6H, t, J=7.3Hz).
【0057】
製造例86
3−[2−(ジエチルアミノ)エチル]−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[3,4−d]ピリミジンの合成
製造例85と同様にして、3−アミノ−4−ベンゾイルピリジンと2−(ジエチルアミノ)エチルアミンから標題化合物を合成した。
融点; 138-140.5 ℃(再結晶溶媒:酢酸エチル)
1H NMR(CDCl3 ) δ; 8.11 (1H, s), 8.11 (1H, d, J=5.0Hz), 7.68 (1H, brds), 7.30〜7.36 (5H, m), 6.86 (1H, d, J=5.0Hz), 5.76 (1H, s), 3.77 〜3.87(1H, m), 2.97 〜3.08 (1H, m), 2.66〜2.78 (1H, m), 2.41〜2.59 (5H, m), 0.99 (6H, t, J=7.3Hz).
製造例87
3−[2−(ジエチルアミノ)エチル]−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジンの合成
製造例85と同様にして、4−アミノ−3−ベンゾイルピリジンと2−(ジエチルアミノ)エチルアミンから標題化合物を合成した。
融点; 132.5-134 ℃(再結晶溶媒:ジエチルエーテル/エタノール)
1H NMR(CDCl3 ) δ; 8.26 (1H, d, J=5.3Hz), 8.16 (1H, s), 7.30 〜7.36 (5H, m), 6.63 (1H, d, J=5.3Hz), 5.80 (1H, s), 3.81 〜3.89 (1H, m), 2.97〜3.09 (1H, m), 2.73〜2.76 (1H ,m), 2.44〜2.60 (5H, m), 0.99 (6H, t, J=7.3Hz).
塩酸塩:融点; 230 ℃以上(再結晶溶媒:ジエチルエーテル/エタノール)
製造例88
3−[2−(ジエチルアミノ)エチル]−4−(3−メトキシ)フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−d]ピリミジンの合成
製造例85と同様にして、2−アミノ−3−(3−メトキシベンゾイル)ピリジンと2−(ジエチルアミノ)エチルアミンから標題化合物を合成した。
融点; 162.5-164 ℃(再結晶溶媒:ジエチルエーテル)
1H NMR(CDCl3 ) δ; 8.15 (1H, dd, J=4.9 and 1.6Hz), 7.88 (1H, brs), 7.23〜7.29 (2H, m), 6.92 (1H, dd, J=8.9, 1.0Hz), 6.80 〜6.86 (3H, m), 5.72 (1H, s), 3.78〜3.87(1H, m), 3.78 (3H, s), 2.91 〜3.02 (1H, m), 2.67〜2.77(1H, m), 2.38 〜2.60 (5H, m), 0.97 (6H, t, J=7.3Hz).
【0058】
製造例89
3−(1−ベンジルピペリジン−4−イル)−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジンの合成
(a)3−[α−{(1−ベンジルピペリジン−4−イル)イミノ}ベンジル]−4−トリクロロアセチルアミノピリジンの合成
3−ベンゾイル−4−トリクロロアセチルアミノピリジン 19.6 g (57 mmol) のジメチルスルホキシド 100 mL 溶液に、4−アミノ−1−ベンジルピペリジン 13.0 g (68 mmol) を加え、室温にて48時間攪拌した。反応液を水に空け、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧下にて濃縮した。カラムクロマトグラフィー(シリカゲル、酢酸エチル:ヘキサン 1:1)にて精製し、酢酸エチルで再結晶化を行ない標題化合物を 18.5 g (35.9 mmol) 得た。
融点; 152-154 ℃(分解)
1H NMR(CDCl3 ) δ; 8.60 (1H, d, J=5.9Hz), 8.52 (1H, d, J=5.9Hz), 8.07 (1H, s), 7.51〜7.53 (3H, m), 7.27〜7.32 (5H, m), 7.14〜7.18 (2H, m), 3.44 (2H, s), 3.14〜3.22 (1H, m), 2.87 (2H, m), 1.96〜2.08 (2H, m), 1.52〜1.83 (4H, m).
(b)3−[α−{(1−ベンジルピペリジン−4−イル)アミノ}ベンジル]−4−アミノピリジンの合成
3−[α−{(1−ベンジルピペリジン−4−イル)イミノ}ベンジル]−4−トリクロロアセチルアミノピリジン 18.0 g (34.9 mol)のエタノール 150 mL 溶液に氷冷下、水素化ほう素ナトリウム 2.65 g (70 mmol) を加え、室温にて5時間攪拌した。反応液を水に空け、エタノールを減圧下に留去後、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後減圧下にて濃縮した。カラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)にて精製して標題化合物を 4.82 g (12.9 mmol) 得、3−[α−[(1−ベンジルピペリジン−4−イル)イミノ]ベンジル]−4−アミノピリジンを 6.65 g (17.9 mmol) 得た。
水素化リチウムアルミニウム 0.68 g (17.9 mmol) のテトラヒドロフラン 100 mL の縣濁液に、加熱還流下3−[α−{(1−ベンジルピペリジン−4−イル)イミノ」ベンジル]−4−アミノピリジン 6.65 g (17.9 mmol) のテトラヒドロフラン 30 mL溶液を滴下し、1時間加熱還流した。放冷後、氷冷下、水 0.7 mL 、15%水酸化ナトリウム水溶液 0.7 mL 、水 2 mL を順次加え、室温にて1時間攪拌した後セライト濾過した。濾液を濃縮し、残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)にて精製して標題化合物を 4.2 g (11.3 mmol)得た。
1H NMR(CDCl3 ) δ; 8.06 (1H, d, J=5.6Hz), 7.98 (1H, s), 7.24 〜7.35 (10H, m), 6.42 (1H, d, J=5.6Hz), 5.59 (2H, brs), 5.08 (1H, s), 3.48 (2H, s), 2.82 (1H, m), 2.45 (1H, m), 1.86〜2.00 (4H, m), 1.36〜1.54 (2H, m).
3−[α−{(1−ベンジルピペリジン−4−イル)イミノ}ベンジル]−4−アミノピリジン
1H NMR(CDCl3 ) δ; 7.80 (1H, d, J=5.6Hz), 7.74 (1H, s), 7.43 〜7.46 (3H, m), 7.22〜7.33 (5H, m), 7.11〜7.14 (2H, m), 6.49 (1H, d, J=5.6Hz), 3.47 (2H, s), 3.15 〜3.22 (1H, m), 2.77〜2.81 (2H, m), 1.95〜2.02 (2H, m), 1.73〜1.87 (2H, m), 1.63〜1.67 (2H, m).
(c)3−(1−ベンジルピペリジン−4−イル)−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジンの合成
3−[α−{(1−ベンジルピペリジン−4−イル)アミノ}ベンジル]−4−アミノピリジン 8.0 g (21.5 mmol)のテトラヒドロフラン 100 mL 溶液に1,1′−カルボニルジイミダゾール 5.0 g (3.1 mmol) を加え、8時間加熱還流した。放冷後、反応液を減圧下にて濃縮し、残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製した。得られた粗結晶をジエチルエーテル/エタノールで再結晶化して標題化合物を 4.2 g (10.5 mmol)得た。
融点; 209-210 ℃(再結晶溶媒:ジエチルエーテル/エタノール)
1H NMR(CDCl3 ) δ; 8.35 (1H, s), 8.26 (1H, d, J=5.6Hz), 8.09 (1H, brs), 7.20 〜7.38 (10H, m), 6.65 (1H, d, J=5.6Hz), 5.64 (1H, s), 4.36 (1H, m), 2.96 (1H, m), 2.80 (1H, m), 2.00〜2.10 (3H, m), 1.50〜1.65 (3H, m).
塩酸塩:融点; 230 ℃以上(再結晶溶媒:ジエチルエーテル/エタノール)
【0059】
製造例90
3−(ピペリジン−4−イル)−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−d]ピリミジンの合成
製造例89と同様にして、3−ベンゾイル−2−トリクロロアセチルアミノピリジンと4−アミノ−1−ベンジルピペリジンから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 8.74 (1H, s), 8.19 (1H, dd, J=5.0, 1.7Hz), 7.19 〜7.46 (11H, m), 6.85 (1H, dd, J=7.6, 5.0Hz), 5.55 (1H, s), 4.40 (1H, m), 3.44 (2H, s), 2.93 (1H, d, J=8.3Hz), 2.78 (1H, d, J=11.6Hz), 1.94 〜2.08 (3H, m), 1.39〜1.75 (3H, m).
塩酸塩:融点; 186-189 ℃(再結晶溶媒:ジエチルエーテル/エタノール)
製造例91
3−(ピペリジン−4−イル)−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジンの合成
3−(1−ベンジルピペリジン−4−イル)−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン 4.13 g (10.4 mmol) のメタノール 250 mL 溶液に、ぎ酸アンモニウム 1.89 g (30 mmol) 、10%パラジウム−炭素 0.3 gを加え、5時間加熱還流した。冷却後、反応液をセライト濾過し、濾液を減圧下にて濃縮した。残さに飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、アンモニア水:メタノール:クロロホルム 10:100:900)で精製して標題化合物を 2.67 g (8.66 mmol) 得た。
1H NMR(CDCl3 ) δ; 9.53 (1H, brs), 8.31 (1H, s), 8.26 (1H, d, J=5.3Hz), 7.22 〜7.41 (5H, m), 6.76 (1H, d, J=5.3Hz), 5.65 (1H, s), 4.33 (1H, m), 3.17 (1H, d, J=12.2Hz), 3.03 (1H, d, J=12.5Hz), 2.58 〜2.74 (2H, m), 1.95〜2.04 (1H, m), 1.64 (2H, d, J=10.6Hz), 1.38〜1.54 (1H, m).
製造例92
3−(1−アリルピペリジン−4−イル)−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジンの合成
3−(ピペリジン−4−イル)−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン 500 mg (1.62 mmol) のエタノール 20 mL溶液に、炭酸カリウム 336 mg (2.43 mmol) 、臭化アリル 235 mg (1.94 mmol) を順次加え、室温にて4時間攪拌した。反応液を減圧下にて濃縮し、残さに水を加え、クロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)で精製して標題化合物を 385 mg (1.10 mmol) 得た。
1H NMR(CDCl3 ) δ; 8.44 (1H, s), 8.32 (1H, s), 8.24 (1H, d, J=5.3Hz), 7.21 〜7.38 (5H, m), 6.69 (1H, d, J=5.3Hz), 5.77 〜5.87 (1H, m), 5.64 (1H, s), 5.16 (1H, d, J=7.9Hz), 5.11 (1H, d, J=1.0Hz), 4.38 (1H, m), 2.80〜3.02 (3H, m), 1.91〜2.08 (3H, m), 1.52〜1.70 (3H, m).
塩酸塩:融点; 155-158 ℃(再結晶溶媒:ジエチルエーテル/エタノール)
【0060】
製造例93
3−[1−(3−チエニルメチル)ピペリジン−4−イル]−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジンの合成
3−(ピペリジン−4−イル)−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジン 500 mg (1.62 mmol) のメタノール 30 mL溶液に、氷冷下10%塩酸/エタノール溶液 1200 mg、3−チオフェンカルボキサアルデヒド 727 mg (6.48 mmol) 、シアノ水素化ほう素ナトリウム 407 mg (6.48 mmol) を加えた。室温にて10時間攪拌した後、反応液を減圧下にて濃縮した。残さに水を加え、アンモニア水にてpH10とした後、クロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、メタノール:クロロホルム 1:9)にて精製して標題化合物を 550 mg (1.36 mmol) 得た。
1H NMR(CDCl3 ) δ; 8.93 (1H, s), 8.34 (1H, s), 8.27 (1H, d, J=5.3Hz), 7.20 〜7.39 (6H, m), 7.07 (1H, m), 7.01 (1H, dd, J=5.0 and 1.3Hz), 6.70 (1H, d, J=5.3Hz), 5.64 (1H, s), 4.35 (1H, m), 3.50 (2H, s), 2.97 (1H, d, J=6.9Hz), 2.82 (1H, d, J=10.9Hz), 1.93〜2.14 (3H, m), 1.47〜1.66 (3H, m).
塩酸塩:融点; 230 ℃以上(再結晶溶媒:ジエチルエーテル/エタノール)
製造例94
3−[1−(3−メトキシベンジル)ピペリジン−4−イル]−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジンの合成
製造例93と同様にして、3−(ピペリジン−4−イル)−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロピリド[4,3−d]ピリミジンと3−メトキシベンズアルデヒドから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 8.40 (1H, brs), 8.35 (1H, s), 8.24 (1H, d, J=5.3Hz), 7.18 〜7.39 (6H, m), 6.76〜6.84 (3H, m), 6.67 (1H, d, J=5.3Hz), 5.64 (1H, s), 4.35 (1H, m), 3.80 (3H, s), 3.53 (2H, s), 2.96 (1H, m), 2.81 (1H, m).
塩酸塩:融点; 230 ℃以上(再結晶溶媒:ジエチルエーテル/エタノール)
【0061】
製造例95
3−[2−(ジエチルアミノ)エチル]−5−メチル−4−フェニル−2−オキソ−1,2,3,4−テトラヒドロチエノ[2,3−d]ピリミジンの合成
製造例85と同様にして、2−アミノ−3−ベンゾイル−4−メチルチオフェンと2−(ジエチルアミノ)エチルアミンから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.56 (1H, brs),7.28 〜7.34 (5H, m), 6.18 (1H, d, J=1.0Hz), 5.49 (1H, s), 3.56 〜3.66 (1H, m), 3.05〜3.15 (1H, m), 2.64〜2.74 (1H, m), 2.46〜2.60 (4H, m), 2.31〜2.41 (2H, m), 1.83 (3H, d, J=1.0Hz),
1.00 (6H, t, J=7.3Hz) .
製造例96
3−(1−ベンジルピペリジン−4−イル)−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンの合成
(a)4,5−シス−4−メトキシカルボニルアミノ−5−(α−ヒドロキシベンジル)シクロヘキセンの合成
4,5−シス−4−メトキシカルボニルアミノ−5−ベンゾイルシクロヘキセン 500 mg (1.93 mmol) のメタノール 10 mL溶液に、氷冷下水素化ほう素ナトリウム 162 mg (4.28 mmol) を加えた。室温にて3時間攪拌した後、反応液を水に空け、減圧下メタノールを留去し、クロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮し、得られた残さをカラムクロマトグラフィー(シリカゲル、ヘキサン:酢酸エチル 1:1)で精製して 487 mg (1.87 mmol) の標題化合物をジアステレオマーの混合物として得た。上記混合物 35 mgを更にカラムクロマトグラフィー(シリカゲル、ヘキサン:酢酸エチル 1:1)で分離精製して、ジアステレオマーAを 10 mg、ジアステレオマーBを 25 mg得た。ジアステレオマーAは、薄層クロマトグラフィー(展開溶媒;ヘキサン:酢酸エチル 1:1)においてよりRf値の大きいジアステレオマーであり、ジアステレオマーBはよりRf値の小さいジアステレオマーである。
ジアステレオマーA
1H NMR(CDCl3 ) δ; 7.18〜7.36 (5H, m), 5.48〜5.62 (2H, m), 5.03 (1H, dd, J=3, 3Hz), 4.73 (1H, d, J=9Hz), 4.28 (1H, d, J=3Hz), 3.91 (1H, m), 3.73 (3H, m), 2.39 〜2.50 (1H, m), 2.19〜2.32 (1H, m), 1.94〜2.07 (1H, m), 1.71〜1.82 (1H, m), 1.52〜1.60 (1H, m).
ジアステレオマーB
1H NMR(CDCl3 ) δ; 7.23〜7.36 (5H, m), 5.59 (2H, m), 5.10 (1H, d, J=9Hz), 4.48 〜4.55 (2H, m), 4.21(1H, dd, J=10, 4Hz), 3.74 (3H, s), 2.46 〜2.53 (1H, m), 2.13〜2.20 (1H, m), 1.44〜2.05 (1H, m), 1.50〜1.73 (2H, m).
(b)4,5−シス−4−メトキシカルボニルアミノ−5−(α−クロロベンジル)シクロヘキセンの合成
4,5−シス−4−メトキシカルボニルアミノ−5−(α−ヒドロキシベンジル)シクロヘキセンのジアステレオマーの混合物 415 mg (1.59 mmol) の1,2−ジクロロエタン 10 mL溶液に、室温にて四塩化炭素 0.17 mL (1.76 mmol)、トリフェニルフォスフィン512 mg (1.95 mmol)を加えた。室温にて2時間攪拌した後、2時間加熱還流した。減圧下1,2−ジクロロエタンを留去し、得られた残さをカラムクロマトグラフィー(シリカゲル、クロロホルム)で精製して 219 mg (0.78 mmol) の標題化合物をジアステレオマーの混合物として得た。
1H NMR(CDCl3 ) δ; 7.20〜7.41 (5H, m), 5.76〜5.81 (1H, m), 5.58〜5.67 (2H, m), 4.61〜5.05 (2H, m), 3.60〜3.71 (3H, m), 1.81〜2.82 (5H, m).
(c)3−(1−ベンジルピペリジン−4−イル)−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンの合成
4,5−シス−4−メトキシカルボニルアミノ−5−(α−クロロベンジル)シクロヘキセン 200 mg (0.72 mmol) のジメチルホルムアミド 10 mL溶液に、4−アミノ−1−ベンジルピペリジン 1.08 g (9.43 mmol) 、トリエチルアミン 1 mL を加え、約80℃にて20時間攪拌した。減圧下ジメチルホルムアミドを留去した後、水を加えクロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮し、得られた残さをカラムクロマトグラフィー(シリカゲル、アンモニア水:メタノール:クロロホルム 1:10:90)で分離精製して、ジアステレオマーAを 64 mg (0.16 mmol)、ジアステレオマーBを 112 mg (0.28 mmol) 得た。ジアステレオマーAは、薄層クロマトグラフィー(展開溶媒;アンモニア水:メタノール:クロロホルム 1:10:90)においてよりRf値の大きいジアステレオマーであり、ジアステレオマーBはよりRf値の小さいジアステレオマーである。
ジアステレオマーA
1H NMR(CDCl3 ) δ; 7.21〜7.36 (10H, m), 5.70 (1H, m), 5.56 (1H, m), 4.85 (1H, d, J=5Hz), 4.64 (1H, d, J=9Hz), 4.34 (1H, d, J=8Hz), 3.99 (1H, m), 3.52 (1H, m), 3.47 (2H, s), 2.78 (2H, m), 2.24〜2.34 (1H, m), 1.99〜2.12 (6H, m), 1.89 (2H, m), 1.40 (2H, m).
くえん酸塩
融点 ; 120 - 122℃(再結晶溶媒:イソプロパノール/酢酸エチル)
ジアステレオマーB
1H NMR(CDCl3 ) δ; 7.20〜7.37 (10H, m), 5.52 〜5.77 (2H, m), 4.84 (1H, d, J=5Hz), 4.76 (1H, d, J=9Hz), 4.50 (1H, d, J=8Hz), 3.81 〜4.01 (2H, m), 3.53 (1H, m), 3.48 (2H, s), 2.76〜2.87 (2H, m), 1.87〜2.33 (9H, m), 1.45 (2H, m).
【0062】
製造例97
3−(ピペリジン−4−イル)−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンの合成
製造例15と同様にして、3−(1−ベンジルピペリジン−4−イル)−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.23〜7.34 (5H, m), 5.69 (1H, m), 5.56 (1H, m), 4.94 (1H, d, J=9Hz), 4.80 (2H, m), 3.94 (1H, m), 3.61 (1H, m), 2.99 (2H, m), 2.62 (2H, m), 1.88 〜2.32 (6H, m), 1.20〜1.33 (2H, m).
製造例98
3−(1−アリルピペリジン−4−イル)−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンの合成
製造例31と同様にして3−(ピペリジン−4−イル)−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.14〜7.29 (5H, m), 5.63〜5.81 (2H, m), 5.49 (1H, m), 5.03〜5.11 (3H, m), 4.65〜4.79 (2H, m), 4.45 (1H, d, J=8Hz), 3.93 (1H, m), 3.49 (2H, m), 2.85 (2H, d, J=7Hz), 2.72 (2H, m), 1.65〜2.27 (6H, m), 1.31 (2H, m).
製造例99
3−[1−(3−チエニルメチル)ピペリジン−4−イル]−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンの合成
製造例36と同様にして3−(ピペリジン−4−イル)−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンと3−チオフェンカルボキサアルデヒドから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.25〜7.35 (6H, m), 7.12 (1H, s), 7.05 (1H, dd, J=5, 1Hz), 5.71 (1H, m), 5.57 (1H, m), 4.86 (1H, d, J=5Hz), 4.56 (1H, d, J=8.6Hz), 4.26 (1H, d, J=7.6Hz), 4.02 (1H, m), 3.54 (2H, s), 2.83 (2H, d, J=11.9Hz), 1.90〜2.36 (8H, m), 1.37〜1.50 (2H, m).
【0063】
製造例100
3−[1−(3−メトキシベンジル)ピペリジン−4−イル]−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンの合成
製造例36と同様にして3−(ピペリジン−4−イル)−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンと3−メトキシベンズアルデヒドから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.19〜7.35 (6H, m), 6.88 (1H, m), 6.78〜6.82 (1H, m), 5.74 (1H, m), 5.57 (1H, m), 4.86 (1H, d, J=5Hz), 4.61 (1H, d, J=8.9Hz), 4.33 (1H, d, J=7.3Hz), 4.02 (1H, m), 3.81 (3H, s), 3.57 (1H, m), 3.45 (2H, s), 2.80 〜2.88 (2H, m), 1.89〜2.35 (8H, m), 1.37〜1.48 (2H, m).
製造例101
3−(1−ベンジルピペリジン−4−イル)−4−フェニル−シス−オクタヒドロ−2(1H)−キナゾリノンの合成
3−(1−ベンジルピペリジン−4−イル)−4−フェニル−シス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンのジアステレオマーA 391 mg (0.97 mmol) のメタノール 15 mL溶液に30%酸化白金 90 mgを加え、水素雰囲気下室温にて6時間攪拌した。セライト濾過後減圧下メタノールを留去し、得られた残さをカラムクロマトグラフィー(シリカゲル、アンモニア水:メタノール:クロロホルム 1:10:90)で分離精製して標題化合物を 352 mg (0.87 mmol) 得た。
1H NMR(CDCl3 ) δ; 7.25〜7.36 (10H, m), 4.93 (1H, d, J=7.6Hz), 4.73 (1H, d, J=5.3Hz), 4.21 (1H, d, J=8.3Hz), 3.54〜3.62 (2H, m), 3.48 (2H, s), 2.76 (2H, m), 2.09 (2H, m), 1.74〜1.91 (8H, m), 1.15〜1.48 (9H, m).
製造例102
3−(ピペリジン−4−イル)−4−フェニル−シス−オクタヒドロ−2(1H)−キナゾリノンの合成
製造例15と同様にして、3−(1−ベンジルピペリジン−4−イル)−4−フェニル−シス−オクタヒドロ−2(1H)−キナゾリノンから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.28〜7.36 (5H, m), 5.14 (1H, d, J=7.6Hz), 4.73 (1H, d, J=5Hz), 4.37 (1H, d, J=8.3Hz), 3.56 〜3.70 (3H, m), 2.93〜3.02 (2H, m), 2.60 (2H, m), 1.73〜2.08 (5H, m), 1.18〜1.48 (6H, m).
【0064】
製造例103
3−(1−アリルピペリジン−4−イル)−4−フェニル−シス−オクタヒドロ−2(1H)−キナゾリノンの合成
製造例31と同様にして3−(ピペリジン−4−イル)−4−フェニル−シス−オクタヒドロ−2(1H)−キナゾリノンから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.22〜7.36 (5H, m), 5.73〜5.88 (1H, m), 5.06〜5.19 (3H, m), 4.74 (1H, d, J=5.3Hz), 4.35 (1H, d, J=7.9Hz), 3.51〜3.67 (2H, m), 2.80〜2.96 (5H, m), 1.73〜2.21 (7H, m), 1.15〜1.48 (6H, m).
製造例104
3−[1−(3−チエニルメチル)ピペリジン−4−イル]−4−フェニル−シス−オクタヒドロ−2(1H)−キナゾリノンの合成
製造例36と同様にして3−(ピペリジン−4−イル)−4−フェニル−シス−オクタヒドロ−2(1H)−キナゾリノンと3−チオフェンカルボキサアルデヒドから標題化合物を合成した。 1H NMR(CDCl3 ) δ; 7.20〜7.34 (6H, m), 7.11 (1H, m), 7.02 (1H, m), 5.29 (1H, d, J=7.9Hz), 4.73 (2H, d, J=5Hz), 3.51 (2H, s), 3.45〜3.68 (3H, m), 2.80 (2H, m), 1.70〜1.85 (5H, m), 1.12〜1.44 (6H, m).
製造例105
3−[1−(3−メトキシベンジル)ピペリジン−4−イル]−4−フェニル−シス−オクタヒドロ−2(1H)−キナゾリノンの合成
製造例36と同様にして3−(ピペリジン−4−イル)−4−フェニル−シス−オクタヒドロ−2(1H)−キナゾリノンと3−メトキシベンズアルデヒドから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.18〜7.34 (5H, m), 6.78〜6.89 (3H, m), 5.25 (1H, d, J=7.9Hz), 4.72 (1H, d, J=5Hz), 4.67 (1H, d, J=7.6 Hz), 3.79 (3H, s), 3.46 (2H, s), 3.52〜3.74 (3H, m), 2.77 (2H, m), 2.10 (2H, m), 1.70〜1.85 (5H, m), 1.13〜1.46 (6H, m).
【0065】
製造例106
3−(1−ベンジルピペリジン−4−イル)−4−フェニル−トランス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンの合成
(a)4,5−トランス−4−メトキシカルボニルアミノ−5−ベンゾイルシクロヘキセンの合成
4,5−シス−4−メトキシカルボニルアミノ−5−ベンゾイルシクロヘキセン 13.74 g (53.0 mmol)のメタノール 400 mL 溶液にナトリウムメトキシド 3.31 g (61.27 mmol)を加え、20時間加熱還流した。減圧下メタノールを留去した後、水を加えクロロホルムで抽出した。有機層を炭酸カリウムで乾燥した後減圧下にて濃縮し、得られた残さをカラムクロマトグラフィー(シリカゲル、クロロホルム:酢酸エチル 1:1)で精製した。得られた粗結晶を酢酸エチル/ヘキサンで再結晶化して標題化合物を 6.94 g (29.7 mmol) 得た。
融点 ; 122 - 124℃
1H NMR(CDCl3 ) δ; 8.07 (2H, m), 7.46〜7.60 (3H, m), 5.76 (1H, m), 5.65 (1H, m), 4.90 (1H, m), 4.20 (1H, m), 4.02 (1H, m), 3.63 (3H, s), 2.36 (3H, m), 2.17 (1H, m).
(b)4,5−トランス−4−メトキシカルボニルアミノ−5−(α−ヒドロキシベンジル)シクロヘキセンの合成
製造例96(a)と同様にして、4,5−トランス−4−メトキシカルボニルアミノ−5−ベンゾイルシクロヘキセンから標題化合物を約2:3のジアステレオマーの混合物として合成した。
1H NMR(CDCl3 ) δ; 7.17〜7.40 (5H, m), 5.49〜5.65 (2.6H, m), 5.24 (0.4H, m), 5.03 (0.6H, m), 4.94 (0.6H, d, J=10.2Hz), 4.59 (0.4H, m), 4.34 (0.4H, d, J=4Hz), 3.81 〜4.08 (1H, m), 3.71 (1.8H, s), 3.59 (1.2H, s), 1.57〜2.61 (5H, m).
(c)4,5−トランス−4−メトキシカルボニルアミノ−5−(α−クロロベンジル)シクロヘキセンの合成
製造例96(b)と同様にして、4,5−トランス−4−メトキシカルボニルアミノ−5−(α−ヒドロキシベンジル)シクロヘキセンから標題化合物をジアステレオマーの混合物として合成した。
1H NMR(CDCl3 ) δ; 7.20〜7.44 (5H, m), 5.56〜5.71 (2H, m), 5.02 (1H, d, J=6.9Hz), 4.76 (1H, m), 3.57 〜3.76 (4H, m), 2.49〜2.56 (2H, m), 1.93〜2.33 (3H, m).
(d)3−(1−ベンジルピペリジン−4−イル)−4−フェニル−トランス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンの合成4,5−トランス−4−メトキシカルボニルアミノ−5−(α−クロロベンジル)シクロヘキセン 202 mg (0.72mmol)のアセトニトリル 10 mL溶液に、4−アミノ−1−ベンジルピペリジン 205 mg (1.08 mmol) 、ヨウ化ナトリウム 163 mg (1.09 mmol) 、炭酸カリウム 300 mg (2.17 mmol) を加え、オートクレーブ中約120℃にて10時間攪拌した。放冷後セライト濾過し、濾液を減圧下濃縮した。残さに水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、炭酸カリウムで乾燥した後減圧下にて濃縮した。残さをカラムクロマトグラフィー(シリカゲル、アンモニア水:メタノール:クロロホルム 1:10:90)で精製して、標題化合物を 119 mg (0.30 mmol) 得た。
1H NMR(CDCl3 ) δ; 7.34 (3H, m), 7.20〜7.32 (7H, m), 5.53〜5.63 (2H, m), 5.01 (1H, d, J=10.2Hz), 3.45〜3.58 (2H, m), 3.45 (2H, m), 2.60〜2.78 (3H, m), 1.63〜2.17 (11H, m).
【0066】
製造例107
3−(1−ベンジルピペリジン−4−イル)−4−フェニル−トランス−オクタヒドロ−2(1H)−キナゾリノンの合成
製造例101と同様にして3−(1−ベンジルピペリジン−4−イル)−4−フェニル−トランス−3,4,4a,5,8,8a−ヘキサヒドロ−2(1H)−キナゾリノンから標題化合物を合成した。
1H NMR(CDCl3 ) δ; 7.40〜7.47 (3H, m), 7.19〜7.33 (7H, m), 5.05 (1H, d, J=10.6Hz), 3.51 (1H, m), 3.46 (2H, m), 3.28 (1H, m), 2.76 (2H, m), 2.26 (1H, m), 2.09 (2H, m), 1.61〜1.86 (7H, m), 0.94〜1.49 (5H, m).
製造例108
3−(1−ベンジルピペリジン−4−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリンチオンの合成
α−(2−アミノフェニル)−N−(1−ベンジルピペリジン−4−イル)ベンジルアミン 503 mg (1.35 mmol) のテトラヒドロフラン 10 mL溶液に1,1′−チオカルボニルジイミダゾール 300 mg (1.68 mmol) を加え、3時間加熱還流した。放冷後反応液を減圧下にて濃縮し、残さをカラムクロマトグラフィー(シリカゲル、酢酸エチル:クロロホルム 1:4)で精製して標題化合物を 540 mg (1.30 mmol) 得た。
塩酸塩
融点 ; 212 - 214℃(再結晶溶媒:ジエチルエーテル/エタノール)
1H NMR(CD3 OD) δ; 7.13〜7.57 (12H, m), 6.88 〜7.03 (2H, m), 5.70〜5.84 (2H, m), 4.85 (2H, s), 3.02〜3.59 (4H, m), 2.43 (1H, m), 1.74〜2.04 (3H, m).
製造例109
6−クロロ−3−[3−(トリメチルアンモニオ)プロピル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン イオダイドの合成
6−クロロ−3−[3−(ジメチルアミノ)プロピル]−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン 418 mg (1.22 mmol) のエタノール 30 mL溶液にヨウ化メチル 176 mg (1.24 mmol) を加え、室温にて4日間攪拌した。析出した結晶を濾取し、ジエチルエーテルで洗浄して標題化合物を 374 mg (0.77 mmol) 得た。
融点 ; 164 - 166℃
1H NMR(CD3 OD) δ; 7.28〜7.45 (5H, m), 7.09〜7.15 (2H, m), 6.83 (1H, m), 5.77 (1H, s), 3.61 (1H, m), 3.30 (2H, m), 3.15 (1H, m), 3.06 (9H, s), 2.00 (2H, m).
【0067】
製造例110
3−(1−メチル−3−キヌクリジニオ)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン イオダイドの合成
製造例109と同様にして3−(キヌクリジン−3−イル)−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンのジアステレオマーBから標題化合物を合成した。
融点 ; 230℃以上(再結晶溶媒:エタノール/アセトン)
1H NMR (DMSO- d6 ) δ; 9.89 (1H, s), 7.11〜7.48 (7H, m), 6.80〜6.95 (2H, m), 5.76 (1H, s), 3.80〜4.01 (2H, m), 3.27〜3.59 (5H, m), 2.92 (3H, s), 2.28〜2.33 (1H, m), 1.70〜2.08 (4H, m).
製造例111
3−[(2S)−1,1−ジエチル−2−ピロリジニオ]メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノン イオダイドの合成
3−[(2S)−1−エチルピロリジン−2−イル]メチル−4−フェニル−3,4−ジヒドロ−2(1H)−キナゾリノンのジアステレオマーA1 156 mg (0.46 mmol)のクロロホルム 10 mL溶液に、ヨウ化エチル 819 mg (5.25 mmol) を加え、4日間加熱還流した。放冷後セライト濾過し、濾液を減圧下にて濃縮した。得られた固形物をジエチルエーテル/エタノールで洗浄してアモルファス状の標題化合物を 63 mg (0.13 mmol)得た。
1H NMR(CD3 OD) δ; 7.25〜7.43 (5H, m), 7.13〜7.19 (2H, m), 6.84〜6.96 (2H, m), 5.79 (1H, s), 4.18〜4.35 (2H, m), 3.28〜3.60 (6H, m), 3.04〜3.12 (1H, m), 2.40 (1H, m), 2.08〜2.20 (3H, m).
【0068】
製剤例1
錠剤は例えば次のようにして製造できる。
【表1】
各成分を混合し、打錠して120mgの錠剤に成形することができる。
【0069】
製剤例2
注射剤は例えば次のようにして製造できる。
【表2】
上記成分の溶液を濾過滅菌し、洗浄、滅菌したバイアルビンに充填し、洗浄、滅菌したゴム栓で密封し、フリップオフキャップで巻締して注射剤を製造することができる。
【0070】
試験例1
本発明の使用目的の1つである心筋細胞内Ca2+の過剰蓄積に対する抑制の程度を評価するために、本発明の化合物を用いてウアバイン中毒抑制作用を測定した。ウアバイン中毒は心筋細胞内にCa2+が流入し、Ca2+の過剰蓄積が起こることにより引き起こされるので(アメリカン・ジャーナル・オブ・フィジオロジー、Am. J. Physiol., 1989, 256, C1273-C1276 :ベーシック・リサーチ・オブ・カルディオロジー、Basic Res. Cardiol., 1989, 84, 553-563)、ウアバインの作用を抑制する化合物は心筋細胞内のCa2+過剰蓄積を抑制すると言える。
試験方法
1)標本の作製
雄性モルモット(日本チャールズリバー)の頭部を殴打、頸椎脱臼して屠殺した後、直ちに心臓を摘出し、予め冷却したタイロード液中にて拍動を速やかに停止せしめ、左心房筋を分離した。95%O2 +5%CO2 ガスを通気し、32±0.3℃に維持したタイロード液25mLを満たしたマグヌス管内に左心房標本を懸垂し、0.45〜0.55gの負荷をかけた。標本は電気刺激装置(ダイヤメディカル DPS−160B)を用い、双極銀電極を介して矩形波刺激(刺激頻度;2Hz、持続時間;3msec、域値の50%増しの電圧)により電気的に駆動させた。張力はFDトランスデューサー(Toyo Baldwin T7−30−240)及び変換増幅ユニット(日本電気三栄 1829型)を介して等尺性に(isometorically)リニアコーダー(グラフテックWR−3101)上に記録した。標本を懸垂後1時間放置し、発生張力が充分に安定したことを確認した後実験を開始した。
2)本発明化合物のウアバイン誘発心筋障害改善作用の評価
本発明の化合物を3×10−6Mとなるように添加し、10分間放置した後、ウアバイン(メルク)を10−6Mとなるように適用した。各々、ウアバイン適用40分後に発生張力を記録し、60分後に発生張力、静止張力を記録した。発生張力および静止張力はウアバイン適用直前の値を100%として各時点での変化量(%発生張力および%静止張力)で表し、薬物無処理群との間で Studentのt検定で、危険率5%以下の差を有意差有りと判断した。なお、試験化合物は3×10-4Mになるように精製水で溶解して原液とした。
3)試験化合物
化合物 1:製造例1;くえん酸塩
化合物 2:製造例2;塩酸塩
化合物 3:製造例3;塩酸塩
化合物 4:製造例8;ジアステレオマーAの塩酸塩
化合物 5:製造例15;塩酸塩
化合物 6:製造例24;くえん酸塩
化合物 7:製造例25;ジアステレオマーAの塩酸塩
化合物 8:製造例53;メソ酒石酸塩
化合物 9:製造例84;塩酸塩
化合物10:製造例109
化合物11:製造例110
化合物12:製造例111
【0071】
試験結果
各化合物の試験結果を表3に示す。
【表3】
表3 ウアバイン(10-6M)により誘発した収縮不全、静止張力の増大に対する効果
成績は平均値±標準誤差で示す。
* 非処置群との間に5%の危険率で有意差あり。
** 非処置群との間に1%の危険率で有意差あり。
【0072】
試験例2
本発明の使用目的の1つである心筋細胞内Ca2+の過剰蓄積に対する抑制の程度を評価するために、本発明化合物の心筋細胞内へのCa2+の流入を抑制する効果を培養心筋細胞を用いて調べた。評価は文献記載の方法(モレキュラー・ファーマコロジー、Mol. Pharmacol., 1986, 30, 164-170:サーキュレイション・リサーチ、Circ. Res., 1992, 70, 804-811 )に従い、Na+ 非含有液置換による細胞質Ca2+濃度増大に対する抑制作用を指標に行なった。
試験方法
1)心筋細胞の培養
文献記載の方法(サーキュレイション・リサーチ、Circ. Res., 1993, 73, 758-770)に従って妊娠14〜15日目のICR系マウス胎児(日本チャールズリバー)より心筋細胞を単離培養した。すなわち、胎児心筋より心室筋を採取しミンス(mince)後、0.25%トリプシン(GIBCO)にて心室筋細胞を分離した。得られた心筋細胞を予めフィブロネクチン(高研)をコートしたカバーガラスに付着させ10%ウシ胎児血清(GIBCO)含有EagleMEM倍地(阪大微生物研究所)中でCO2 インキュベーター(アステック BL−160:37℃,5%CO2 +95%空気)にて培養した。
2)Na+ 非含有液置換による細胞質Ca2+濃度変化の測定
培養4〜6日目の細胞を117.4mM NaCl,5.4mM KCl,0.8mM MgCl2 ,1.8mM CaCl2 ,0.1%グルコース,5mMHEPES(ナカライテスク), pH7.4(正常HEPES液)で洗浄後、20μM Fura2−AM(同仁化学研究所),0.4%ウシ血清アルブミン(Sigma)含有正常HEPES液に(遮光下、37℃)にて20分間インキュベートすることにより、Fura2−AM を細胞内に負荷させた。正常HEPES液2mLにて2回洗浄後、37℃保温可能灌流用チャンバーに細胞の付着したカバーガラスを設置し高純度酸素ガスを通気した正常HEPES液を2mL/分の流速で灌流させた。次に、文献記載の方法(ビョーシニカ・エ・ビョウーフィジカ・アクタ、Biochimica et Biophysica Acta, 1981, 642, 158-172 )に従い 28mM NaCl,108mM choline−Cl(和光純薬),0.1mM EGTA(和光純薬), 0.1%グルコース,5mM HEPES,pH7.4(28mM Na負荷HEPES液)にて5分間灌流することによりNa+ を細胞に負荷した後、135mM choline−Cl,1.8mMCaCl2 ,0.1%グルコース,5mM HEPES,pH7.4(Na非含有HEPES液)で灌流し、細胞質Ca2+濃度を増加させた。細胞質Ca2+濃度は340nm及び380nm励起時の500nmの蛍光強度を2波長分光蛍光測定装置(日本分光CAM−230)にて測定し、その蛍光強度比(340nm/380nm)より算出した。薬物は1mMになるよう精製水で調製した後、灌流液に所定の濃度になるよう適宜希釈して用いた。
3)本発明化合物のCa2+濃度増大に対する抑制作用の評価
本発明化合物を28mM Na負荷HEPES液灌流時とNa非含有HEPES液灌流時の両方に処置し、Na非含有HEPES液灌流時のFura2−AM蛍光強度比変化(細胞内Ca2+濃度変化)を観察した。試験化合物による抑制作用は、処置群と非処置群におけるNa非含有HEPES 液灌流時のFura2−AM蛍光強度比変化を比較することにより評価した。
【0073】
【図面の簡単な説明】
【図1】化合物 6(製造例24;くえん酸塩)のNa+ 非含有液置換による細胞質Ca2+濃度増大に対する抑制作用試験結果を示すグラフである。横軸は試験化合物処置後の時間を表し、縦軸はNa非含有HEPES液灌流時のFura2−AM蛍光強度比変化を示す。
【0074】
【図2】化合物13(製造例89;塩酸塩)のNa+ 非含有液置換による細胞質Ca2+濃度増大に対する抑制作用試験結果を示すグラフである。横軸は試験化合物処置後の時間を表し、縦軸はNa非含有HEPES液灌流時のFura2−AM蛍光強度比変化を示す。[0001]
[Industrial application fields]
In the present invention, intracellular calcium ions (Ca2+) Quinazolinone derivatives or acid addition salts or quaternary ammonium salts thereof having an action of suppressing excessive accumulation of) and their uses.
[0002]
[Prior art]
Intracellular calcium ions (Ca2+) Overaccumulation (calcium overload) is regarded as an important mechanism of cell damage after ischemia or reperfusion (Annual Review of Physiology, Annu. Rev. Physiol., 1990, 52, 543 -559). Cell damage due to ischemia is recognized as a disease frequently encountered every day, and heart, brain or kidney cell damage due to ischemia is an important problem often experienced clinically. Therefore, a drug that suppresses excessive accumulation of calcium ions can be a useful preventive and therapeutic agent for ischemic heart disease, ischemic brain disease, or ischemic kidney disease.
Conventionally, calcium antagonists have been used as drugs that suppress the inflow of calcium ions into myocardial or vascular smooth muscle cells, but the effect on the excessive accumulation of calcium ions in myocardial cells after ischemia or reperfusion Drugs that suppress the excessive accumulation of calcium ions, which are not sufficient, are eagerly desired.
Excessive accumulation of calcium ions causes contraction / relaxation dysfunction, energy metabolism disorder, morphological disorder or electrophysiological abnormality in myocardium or vascular smooth muscle cells other than during ischemia, and may be a cause of cardiovascular disease. Naru (Cardiovascular
Research, Cardiovasc. Res., 1986, 20, 645-651). Therefore, a drug that suppresses excessive accumulation of calcium ions can be a useful preventive and therapeutic drug for cardiovascular diseases such as heart failure, hypertension, and arrhythmia.
[0003]
[Problems to be solved by the invention]
The subject of this invention is providing the compound which suppresses intracellular calcium ion excessive accumulation.
[0004]
[Means for Solving the Problems]
The inventors of the present invention have made extensive studies to solve the above problems, and found that a compound represented by the following general formula (1) suppresses the occurrence of excessive accumulation of calcium ions in cells, thereby completing the present invention. It came to do. That is, the present invention relates to the general formula (1)
[Chemical 6]
[Wherein T represents an oxygen atom or a sulfur atom, and Y represents an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, a phenyl group, a substituted phenyl group, an aralkyl group, a substituted aralkyl group, a heteroaryl group or a substituted heteroaryl group. Represents. Ring W represents a benzene ring, a 5- to 6-membered heteroaromatic ring, or a 5- to 10-membered cycloalkene ring or cycloalkane ring. R1And R2Are independently of each other a hydrogen atom, lower alkyl group, halogen atom, cyano group, trifluoromethyl group, nitro group, amino group, substituted amino group, hydroxyl group, lower alkoxy group, lower alkylthio group, lower alkylsulfinyl group or lower group. Represents an alkylsulfonyl group. Z is the formula
[Chemical 7]
{Where A1And A2Are independently of each other hydrogen atom, alkyl group, substituted alkyl group, cycloalkyl group, saturated heterocyclic group, cycloalkylalkyl group, cycloalkenylalkyl group, aralkyl group, substituted aralkyl group, heteroarylalkyl group, substituted heteroarylalkyl. Group or group -CH2RThree(Wherein RThreeRepresents an alkenyl group or an alkynyl group) or A1And A2May combine with each other to form a heterocycle. G represents a linear alkylene having 1 to 6 carbon atoms or a branched alkylene having 1 to 8 carbon atoms, or a group
[Chemical 8]
Wherein p and m independently represent 0, 1 or 2 and D represents a cycloalkane ring} or formula
[Chemical 9]
{Wherein n represents 0, 1 or 2; ring E represents a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom;ThreeIs a hydrogen atom, alkyl group, substituted alkyl group, cycloalkyl group, saturated heterocyclic group, cycloalkylalkyl group, cycloalkenylalkyl group, aralkyl group, substituted aralkyl group, heteroarylalkyl group, substituted heteroarylalkyl group or group- CH2RThree(Wherein RThreeRepresents an alkenyl group or an alkynyl group), or together with the ring E forms a bicyclo ring. } Is represented. And an acid addition salt or quaternary ammonium salt thereof as an active ingredient, the present invention further relates to a heteroaromatic ring having a ring W of 5 to 6 members or 5 A quinazolinone derivative of the general formula (1) which is a 10-membered cycloalkene ring or cycloalkane ring, or an acid addition salt or quaternary ammonium salt thereof, or ring W is a benzene ring and Z is a formula
[Chemical Formula 10]
(Where n, rings E and AThreeRepresents the same meaning as described above. The quinazolinone derivative of the general formula (1), or an acid addition salt or quaternary ammonium salt thereof, which is a group represented by
[0005]
Among the compounds that can be used in the present invention, ring W is a benzene ring, and Z is a formula
Embedded image
(Where G, A1And A2Represents the same meaning as described above. )
Some of the compounds represented by the formula are disclosed as a compound having a central nervous system action, an anti-inflammatory action, and an analgesic action as a compound having a central nervous system inhibitory action in French Patent No. 14183. No. 2027023. Some compounds that can be used in the present invention are disclosed in WO 93/04047 as HIV reverse transcriptase inhibitors. However, there are no compounds claimed in this patent example. Similar compounds of some of the compounds that can be used in the present invention are disclosed in French Patent No. 20122062 as compounds having antipyretic action, and published in Japanese Patent Publication No. 1986 as compounds having antihypertensive action, antiulcer action, and antiplatelet aggregation action. No. 92844 discloses a compound having an analgesic action, an anti-inflammatory action and a central nerve inhibitory action, published in Japanese Patent Publication No. 1979, No. 13794, and a compound having an anti-inflammatory action, J. Med. Chem. , 1974, 17, 636-639).
[0006]
Various groups in the present invention will be described in detail as follows.
Specific examples of the 5- or 6-membered heteroaromatic ring in ring W include heteroaromatics containing 0, 1 or 2 nitrogen atoms, 0 or 1 sulfur atoms, and 0 or 1 oxygen atoms. A group ring, and more specifically, the following groups.
Embedded image
The following groups are preferable.
Embedded image
Specific examples of the 5- to 10-membered cycloalkene ring or cycloalkane ring in the ring W include the following groups.
Embedded image
(In the formula, u and v each independently represent an integer of 0 or 1 to 5 and u + v represents an integer of 1 to 6. In the formula, a thick solid line and a dotted line represent adjacent bridgehead carbons. It represents the relative configuration of atoms and does not mean only a specific optical isomer. The following structural formulas are also the same.)
The following groups are preferable.
Embedded image
Specific examples of the linear alkylene having 1 to 6 carbon atoms in G include methylene, dimethylene, trimethylene and tetramethylene. Specific examples of the branched alkylene having 1 to 8 carbon atoms include Examples include the following groups.
Embedded image
Examples of the cycloalkane ring in D include cycloalkanes having 3 to 8 carbon atoms, and specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.
Preferable groups in G include, for example, dimethylene, trimethylene, tetramethylene and the following groups.
Embedded image
[0007]
Examples of the alkyl group include straight-chain or branched alkyl groups having 1 to 8 carbon atoms. Specific examples include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methyl. Examples include propyl, 1,1-dimethylethyl, 3-pentyl, 3-hexyl, 4-heptyl, 4-octyl and the like. Preferred groups for Y include 2-propyl, butyl, 2-butyl, 2-methylpropyl, 3-pentyl, 3-hexyl, and A1, A2And AThreeIn this, a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl or 2-propyl can be mentioned.
Examples of the cycloalkyl group include cycloalkyl groups having 3 to 7 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
Examples of the cycloalkylalkyl group include cycloalkylalkyl groups having 10 or less carbon atoms. Specific examples include cyclopropylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, and the like. Can be mentioned.
Examples of the cycloalkenylalkyl group include a cycloalkenylalkyl group having 10 or less carbon atoms. Specific examples include 4-cyclohexenylmethyl, 4-cyclopentenylmethyl, 4- (4-cyclohexenyl) butyl, and the like. Can be mentioned
Examples of the alkenyl group include alkenyl groups having 2 to 6 carbon atoms. Specific examples include vinyl, allyl, 1-propenyl, 1-butenyl, 2-pentenyl, 5-hexenyl and the like. Preferred groups include vinyl or allyl.
Examples of the alkynyl group include alkynyl groups having 2 to 6 carbon atoms, and specific examples include ethynyl, propargyl, 2-butynyl, 3-pentynyl and the like. Preferred groups include ethynyl and propargyl. Examples of the aralkyl group include groups having 12 or less carbon atoms, and specific examples include benzyl, 1-phenylethyl, 2-phenylethyl, 2-naphthylmethyl and the like. Preferred groups include AThreeIn the case, a benzyl group can be mentioned.
Examples of the heteroaryl group include a 5- to 6-membered ring group containing 1 to 2 nitrogen atoms, a 5- to 6-membered ring group containing 1 to 2 nitrogen atoms and one oxygen atom or one sulfur atom. Group, a 5- to 6-membered ring group containing one oxygen atom or one sulfur atom, and specific examples include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3 -Oxadiazolyl, 2-imidazolyl, 2-thiazolyl, 3-isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 2-furyl, 3-pyrrolyl and the like.
Examples of the heteroaryl group in the heteroarylalkyl group include a 5- to 6-membered ring group containing 1 to 4 nitrogen atoms, 1 to 2 nitrogen atoms and 1 oxygen atom or 1 sulfur atom. Specific examples of heteroarylalkyl groups include 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1- (2-pyridyl) ethyl, 2- (2-pyridyl) ethyl, 2-thienylmethyl, 3-thienylmethyl, 3-oxadiazolylmethyl, 2-imidazolylmethyl, 2-thiazolylmethyl, 3-isothiazolylmethyl, 2-oxazolylmethyl, 3-iso Examples include oxazolylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyrrolylmethyl and the like.
Examples of the saturated heterocyclic group include a saturated heterocyclic group composed of one heteroatom such as an oxygen atom and a sulfur atom and 3 to 5 carbon atoms, specifically, for example, tetrahyhydropyran-4-yl, Tetrahydrofuran-3-yl, tetrahydrothiophen-3-yl and the like can be mentioned.
A1And A2Examples of the heterocycle formed by bonding to each other include a 5- to 7-membered ring containing 1 to 2 nitrogen atoms or a saturated 5- to 7-membered ring containing 1 nitrogen atom and 1 oxygen atom. Specifically, pyrrolidine, piperidine, homopiperidine, piperazine, homopiperazine, morpholine and the like can be mentioned.
Examples of the 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom in ring E include, for example, a ring containing 1 or 2 nitrogen atoms and 0 or 1 oxygen atom. Pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl, homopiperidin-4-yl Morpholin-2-yl and the like. Preferred groups include piperidin-4-yl when n is 0, and pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3 when n is 1 or 2. -Yl, morpholin-2-yl.
Rings E and AThreeExamples of the bicyclo ring formed by and include quinuclidin-3-yl and quinuclidin-4-yl.
Examples of the lower alkyl group include linear or branched alkyl groups having 4 or less carbon atoms. Specific examples include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, and 2-methyl. And propyl and 1,1-dimethylethyl.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine.
Examples of the lower alkoxy group include linear or branched alkoxy groups having 4 or less carbon atoms, specifically, for example, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 1,1-dimethylethoxy, etc. Is mentioned.
Examples of the lower alkylthio group include linear or branched alkylthio groups having 4 or less carbon atoms, and specific examples include methylthio, ethylthio, 2-propylthio, butylthio and the like.
Examples of the lower alkylsulfinyl group include straight-chain or branched alkylsulfinyl groups having 4 or less carbon atoms. Specific examples include methylsulfinyl, ethylsulfinyl, propylsulfinyl, 2-propylsulfinyl, butylsulfinyl. Etc.
Examples of the lower alkylsulfonyl group include linear or branched alkylsulfonyl groups having 4 or less carbon atoms. Specific examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, 2-propylsulfonyl, butylsulfonyl. Etc.
[0008]
As the substituent of the substituted amino group, an alkyl group or a group —CH2R6(Wherein R6Represents an alkenyl group or an alkynyl group), and there may be one or two substituents which are the same or different. Preferred substituted amino groups include, for example, methylamino, ethylamino, allylamino, propargylamino, propylamino, 2-propylamino, butylamino, N, N-dimethylamino, N, N-diethylamino, N, N-dipropylamino , N, N-diallylamino and the like.
Examples of the substituent of the substituted phenyl group, the substituted aralkyl group, the substituted heteroaryl group and the substituted heteroarylalkyl group include a lower alkyl group, a lower alkoxy group, a methylenedioxy group, a halogen atom, a cyano group, a trifluoromethyl group, and a nitro group. Group, hydroxyl group, lower alkanoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, carbamoyl group, lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group, carboxyl group, lower alkoxycarbonyl group, lower alkylthio group A lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkanoylamino group, a lower alkylsulfonamide group, and the like. The term “lower” as used herein means that the alkyl part of the group is lower alkyl, and examples of such lower alkyl include those having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, and butyl. Alkyl can be mentioned, and the two lower alkyl groups of the di-lower alkylamino group and di-lower alkylaminocarbonyl group may be the same or different. One or more substituents may be the same or different.
Examples of the substituent of the substituted alkyl group include a hydroxyl group, a lower alkoxy group, a cyano group, a carboxyl group, a carbamoyl group, and a lower alkoxycarbonyl group. The term “lower” as used herein means that the alkyl part of the group is lower alkyl, and examples of such lower alkyl include those having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, and butyl. Mention may be made of alkyl.
[0009]
Examples of acids that form acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid, or acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid, maleic acid, Organic acids such as methanesulfonic acid can be mentioned.
Quaternary ammonium salts include those of formula RFour-L1(Where RFourRepresents a lower alkyl group, L1And a quaternary ammonium salt that can be produced by exchanging an anion with another physiologically acceptable anion as required. Preferred lower alkyl groups include methyl and ethyl groups. Physiologically acceptable anions include halogen ions, sulfates, phosphates, nitrates, acetates, citrates, fumarate, succinates and the like. Preferred leaving groups include chlorine atom, bromine atom and iodine atom.
[0010]
The compounds of the present invention contain one or more asymmetric carbon atoms and exist as stereoisomers. The compounds of the present invention include mixtures of isomers and isolated isomers.
[0011]
When the compound represented by the general formula (1) or an acid addition salt or quaternary ammonium salt thereof is used as a drug for treating or preventing ischemic heart disease, ischemic brain disease, ischemic kidney disease and the like, It can be administered parenterally or orally. That is, liquids such as solutions, emulsions, and suspensions can be administered as injections, and buffers, solubilizers, isotonic agents, and the like can be added as necessary. Rectal administration can also be performed in the form of suppositories. Such a dosage form can be produced according to a general method by blending an active ingredient with a usual carrier, excipient, binder, stabilizer and the like. In addition, it can be administered orally in a commonly used dosage form such as a tablet, capsule, syrup, suspension or the like. The dose and frequency of administration vary depending on symptoms, age, body weight, dosage form, etc., but when administered as an injection, 0.1-100 mg is usually administered to adults in one or several divided doses In some cases, an intravenous drip can also be used. In the case of oral administration, 0.1 to 1000 mg (preferably 0.1 to 100 mg) per day can be administered once or several times a day.
[0012]
The compound of the present invention in which the ring W in the general formula (1) is a benzene ring or a 5- or 6-membered heteroaromatic ring can be synthesized by referring to a method described in the literature (for example, chemical pharmaceutical bulletin , Chem. Pharm. Bull., 1981,
29, 2135-2156).
Embedded image
(Wherein ring W1Represents a benzene ring or a 5- or 6-membered heteroaromatic ring. X1Represents a chlorine atom, a bromine atom or an iodine atom, and X2Represents a fluorine atom, a chlorine atom or a bromine atom. Y1Represents the same group as Y, but when it has a reactive group such as an amino group, an alkylamino group or a hydroxyl group as a substituent, these are protected by a protecting group. R11Is R1Represents the same group as R1When is a reactive group such as an amino group, an alkylamino group or a hydroxyl group, it represents those protected by a protecting group. Rtwenty oneIs R2Represents the same group as R2When is a reactive group such as an amino group, an alkylamino group or a hydroxyl group, it represents those protected by a protecting group. Z1Represents the same group as Z, but A1And A2Except for a hydrogen atom, and A1, A2Or AThreeWhen has a reactive group such as an amino group, an alkylamino group or a hydroxyl group as a substituent, these are protected by a protecting group. )
[0013]
The raw material compound represented by the general formula (2) is commercially available or can be synthesized by a method described in the literature (for example, Journal of Organic Chemistry, J. Org. Chem., 1991, 56, 3750). -3752: Journal Heterocyclic Chemistry, J. Heterocyclic Chem., 1989, 26, 105: Chemical Pharmaceutical Bulletin, Chem. Pharm. Bull., 1978, 26, 1633-1651: Journal of Medicinal Chemistry, J. Med. Chem., 1974, 17, 624-630). As a protecting group for amino group, alkylamino group, hydroxyl group, etc., the usual general protecting group used in the field of synthetic organic chemistry (for example, benzyl group, acetyl group etc. as hydroxyl protecting group; Can be introduced and removed according to conventional methods (for example, protective groups in organic synthesis, 2nd ed., John Wily & Sons, Inc .: described in New York).
The ketone derivative represented by the general formula (2) is acylated with trihaloacetic acid or its acid halide according to a known method to obtain an amide compound represented by the general formula (3).
The ketone derivative represented by the general formula (3) and the primary amine represented by the general formula (4) are about 0 ° C. to 50 ° C. in an aprotic polar solvent such as dimethylformamide, dimethyl sulfoxide, and tetrohydrofuran. To obtain a quinazolinone derivative represented by the general formula (5), an imine derivative represented by the general formula (6), or a mixture of both. The production ratio of the quinazolinone derivative represented by the general formula (5) and the imine derivative represented by the general formula (6) is represented by the structure of the ketone derivative represented by the general formula (3), the general formula (4). It depends on the structure of the primary amine and the reaction conditions. The imine derivative (6) can be converted into the quinazolinone derivative represented by the general formula (5) by heating in the above solvent in the presence of a base at 50 to 100 ° C. or up to the boiling point of the solvent. As the base, a tertiary amine such as triethylamine or pyridine or an aromatic amine is suitable.
The quinazolinone derivative represented by the general formula (5) is dissolved in sodium borohydride (NaBH) in an aprotic polar solvent such as dimethylformamide or tetrohydrofuran at 0 ° C. to room temperature.Four), A quinazolinone derivative represented by the general formula (7) in which a trihalomethyl group is substituted with a hydrogen atom can be obtained. At this time, borane (BHThree) Is the group Z1May coordinate to the nitrogen atom inside. In this case, borane can be removed by adding an aqueous hydrochloric acid solution in an alcoholic solvent such as ethanol or methanol as necessary and heating to reflux. This operation is not necessary if the borane is not coordinated.
[0014]
From the imine derivative represented by the general formula (6), a quinazolinone derivative represented by the general formula (7) can be derived even by the following route.
Embedded image
(Wherein ring W1, Z1, R11, Rtwenty one, Y1And X2Represents the same meaning as described above. )
By reducing the imine derivative (6) with sodium borohydride at about 0 ° C. to 50 ° C. in an aprotic polar solvent such as dimethylformamide, dimethyl sulfoxide, and tetrohydrofuran, the general formula (8) To the amine derivatives represented. Subsequently, the trihalogenoacetyl group can be removed to obtain a diamine derivative represented by the general formula (9). The removal of the trihalogenoacetyl group can be suitably performed, for example, by treating with sodium borohydride at about 0 ° C. to 50 ° C. in a lower alcohol such as methanol or ethanol. Further, the diamine derivative represented by the general formula (9) is obtained by converting the imine derivative represented by the general formula (6) into sodium borohydride at about 0 ° C. to 50 ° C. in a lower alcohol such as methanol or ethanol. Can be obtained in one step. At this time, an imine derivative represented by the general formula (10) may be generated. The imine derivative (10) is a lithium aluminum hydride (LiAlH) solution in an ether solvent such as diethyl ether or tetrahydrofuran between room temperature and the boiling point of the solvent.Four) Can also be led to the diamine derivative (9).
A diamine derivative represented by the general formula (9) and 1.0 to 5 equivalents of 1,1′-carbonyldiimidazole, halogenated hydrocarbons such as methylene chloride and chloroform, diethyl ether, tetrahydrofuran, dioxane, acetonitrile , A quinazolinone derivative represented by the general formula (7) can be synthesized by reacting in a solvent such as dimethylformamide or dimethyl sulfoxide in the range of room temperature to the boiling point of the solvent. The quinazolinone derivative represented by the general formula (7) is synthesized by reacting a carbonic acid halide (for example, phosgene, alkyl chlorocarbonate, etc.) and a diamine derivative represented by the general formula (9) according to a known method. You can also.
[0015]
The quinazolinone derivative represented by the general formula (11) can be obtained by performing the following operations as necessary from the quinazolinone derivative represented by the general formula (7).
Embedded image
(Wherein ring W1, Z, R1, R2, Y and T represent the same meaning as described above. )
a) To obtain a compound in which T is a sulfur atom in the general formula (11), conversion from urea to thiourea.
b) Z1Conversion.
c) R in the general formula (7)11Or Rtwenty oneIs protected, or Y1Or Z1If has a protected substituent, removal of the protecting group. d) R1, R2, Y1Has a substituent, or Z1Conversion of substituents in
The conversion from urea to thiourea can be performed by reacting with phosphorus pentasulfide in an inert solvent such as carbon disulfide, toluene, xylene and the like at a temperature from room temperature to the boiling point of the solvent.
[0016]
Z1For example, when the compound (7) is a quinazolinone derivative represented by the general formula (12), debenzylation is performed according to a known method, followed by a reductive amination reaction or an alkylation reaction. It can be converted into a quinazolinone derivative represented by the general formula (15) or the general formula (17).
Embedded image
{Where ring W1, Ring E, R11, Rtwenty one, Y1, X1And n are as defined above. A31Represents a hydrogen atom, a methyl group or an ethyl group. A32Is an alkyl group, substituted alkyl group, cycloalkyl group, cycloalkenyl group, aryl group, substituted aryl group, heteroaryl group, substituted heteroaryl group or group —CH2RThree(Wherein RThreeRepresents an alkenyl group or an alkynyl group) or A31And A32Are bonded to each other to form a cyclopentane ring, a cyclohexane ring or a cycloheptane ring. A33Is an alkyl group, substituted alkyl group, cycloalkyl group, saturated heterocyclic group, cycloalkylalkyl group, cycloalkenylalkyl group, aralkyl group, substituted aralkyl group, heteroarylalkyl group, substituted heteroarylalkyl group or group —CH2RThree(Wherein RThreeRepresents an alkenyl group or an alkynyl group).
In the reductive amination reaction, a compound represented by the general formula (13) and 1 to 5 equivalents of a carbonyl compound represented by the general formula (14) are mixed in a lower alcohol such as methanol and ethanol at 0 to 50 ° C. It can be carried out by treating with ~ 5 equivalents of reducing agent. As a reducing agent, sodium borohydride (NaBH)Four), Sodium cyanoborohydride (NaBH)ThreeCN) can be preferably used.
The alkylation reaction can be carried out according to a known method. For example, in a solvent such as tetrahydrofuran, dimethylformamide, dichloromethane, methanol, ethanol, etc., the compound represented by the general formula (13) and 1 to 5 equivalents of the halide represented by the general formula (16) are optionally carbonated. The reaction can be performed at a temperature from 0 ° C. to the boiling point of the solvent in the presence of a base such as potassium or triethylamine.
[0017]
Similarly, when the compound (11) is a quinazolinone derivative represented by the general formula (18), a reductive amination reaction or an alkylation reaction can be performed. The quinazolinone derivative represented by the general formula (18) itself can be synthesized from the quinazolinone derivative represented by the general formula (20) contained in (18) by the above method, and the quinazolinone derivative represented by the general formula (20) is The quinazolinone derivative represented by the general formula (19) can be suitably obtained by debenzylation according to a known method.
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(Wherein ring W1, R11, Rtwenty one, Y1, And G represent the above meanings. Atwenty oneIs A2In the case where the substituent has a reactive group such as an amino group, an alkylamino group or a hydroxyl group, these are protected by a protecting group. ) R in general formula (7)11Or Rtwenty oneIs protected, or Y1Or Z1As a method for removing a protecting group in the case where the compound has a protected substituent, it can be carried out by a general deprotection method used in the field of synthetic organic chemistry (for example, Protective Groups in Organic synthesis, described in protective groups in organic synthesis, 2nd ed., John Wily & Sons, Inc .: New York).
R1, R2, Y1Has a substituent, or Z1As the conversion of the substituents possessed by, for example, a lower alkylthio group can be converted to a lower alkylsulfinyl group or a lower alkylsulfonyl group by oxidation, and a nitro group can be reduced to an amino group. The amino group can be alkylated to obtain a mono- or dialkyl compound, or the amino group can be acylated. Such a substituent conversion reaction can be carried out by a general technique usually performed in the field of organic synthetic chemistry.
[0018]
In the quinazolinone derivative represented by the general formula (11), the compound (22) in which T is a sulfur atom can also be synthesized from the diamine derivative represented by the general formula (9) by the following method.
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(Wherein ring W1, R11, Rtwenty one, Y1, Z1, R1, R2, Z and Y have the above meanings. )
A diamine derivative represented by the general formula (9) and 1.0 to 5 times equivalent of 1,1′-thiocarbonyldiimidazole, a halogenated hydrocarbon such as methylene chloride and chloroform, diethyl ether, tetrahydrofuran, dioxane, A quinazolinone derivative represented by the general formula (21) can be synthesized by reacting in a solvent such as acetonitrile, dimethylformamide, dimethyl sulfoxide and the like in the range of room temperature to the boiling point of the solvent. Then, if necessary, the substituent can be converted, deprotected and the like in the same manner as in the compound (7) to lead to a quinazolinone derivative represented by the general formula (22).
[0019]
In the general formula (1), the compound in which the ring W is a 5- to 10-membered cycloalkene ring or cycloalkane ring can be synthesized by the following method.
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(Where Y1, Z1, X1, Y, R1, R2, Z and T represent the above meanings. Ring W2Represents a 5- to 10-membered cycloalkene ring or cycloalkane ring. R12Is R11Represents a halogen atom removed from the definition of Rtwenty twoIs Rtwenty oneThe halogen atom is excluded from the definition of RFiveRepresents a lower alkyl group. In the formula, the thick solid line and the dotted line represent the relative configuration of adjacent bridgehead carbon atoms, and do not mean only a specific optical isomer. The following structural formula is the same. )
The raw material compound represented by the general formula (23) can be synthesized according to literature methods (for example, Journal of Organic Chemistry, J. Org. Chem., 1992, 57, 7285-7295: Chemistry Letters, Chem. Lett. 1990, 1817-1820). If necessary, the cis-form compound (23) can be isomerized to a trans-form represented by the general formula (24). Isomerization can be carried out in a solvent by treatment with a base at a temperature from room temperature to the boiling point of the solvent. Preferably, it can be suitably carried out by treatment with an alkoxide of sodium or potassium in an alcohol solvent such as methanol, ethanol or tert-butanol.
The ketone derivative represented by the general formula (23) or the general formula (24) is generally treated with a reducing agent such as sodium borohydride at about 0 ° C. to room temperature in an alcohol solvent such as methanol or ethanol. After the alcohol derivative represented by the formula (25) is obtained, the hydroxyl group is substituted with a halogen atom to obtain a halide represented by the general formula (26). The substitution to a halogen atom is carried out in a halogen-based solvent such as dichloromethane or 1,2-dichloroethane in the presence of triphenylphosphine in the presence of triphenylphosphine in the presence of triphenylphosphine, N-chlorosuccinimide. Or it can carry out suitably by making it react with N-bromosuccinimide. The iodine form can be obtained by treating a chloro form or a bromo form with sodium iodide in a solvent such as acetone or dimethylformamide at room temperature to about 60 ° C.
By reacting the halide represented by the general formula (26) and the primary amine represented by the general formula (4) in a solvent from room temperature to the boiling point of the solvent in the presence of a base, the general formula (27 To a quinazolinone derivative represented by: As the solvent, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and acetonitrile, alcohol solvents such as methanol and ethanol, and halogen solvents such as dichloroethane can be used. As the base, inorganic solvents such as potassium carbonate and sodium carbonate can be used. Salts and tertiary amines such as triethylamine and N, N-diisopropylethylamine can be used. Preferably, it can be suitably obtained by reacting at 50 to 100 ° C. in the presence of a tertiary amine such as triethylamine and N, N-diisopropylethylamine in dimethylformamide.
A quinazolinone derivative represented by the general formula (28) by performing the operation of a), b), c) or d) performed in the compound (7) or a combination thereof in the compound (27) as necessary. Can be obtained. At this time, R1Or R2R is a halogen atom12Or Rtwenty twoCan be synthesized from a compound in which is a hydroxyl group. Such a substituent conversion reaction can be carried out by a general technique usually performed in the field of organic synthetic chemistry.
[0020]
The quaternary ammonium salt can be synthesized, for example, by the following method.
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(Wherein ring W, ring E, R1, R2, Y, G and T represent the above meanings. A11Is A1Represents the hydrogen atom removed from the definition oftwenty twoIs A2Represents the hydrogen atom removed from the definition of34Is AThreeRepresents a hydrogen atom removed from the definition of RFourRepresents a lower alkyl group, L1Represents a leaving group, L-Represents a physiologically acceptable anion. )
A quaternary ammonium salt is a mixture of a quinazolinone derivative represented by general formula (29) or general formula (32) and an alkylating agent represented by general formula (30) in a solvent from room temperature to the boiling point of the solvent. Can be obtained. When the progress of the reaction is slow, it may proceed suitably when heated to about 120 ° C. in an autoclave.
Preferred leaving groups include chlorine atom, bromine atom and iodine atom. Preferred solvents include alcohol solvents such as methanol and ethanol, and ether solvents such as tetrahydrofuran. Anion exchange can be performed by reacting with an alkali metal salt containing the desired anion, such as a sodium or potassium salt.
[0021]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Production Examples, Formulation Examples, and Test Examples, but the present invention is not limited to these Examples. The compound was named using the following structural formula as a basic skeleton.
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[0022]
The structural formula of the compound of each production example is shown below.
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[0023]
Production Example 1
Synthesis of 6-chloro-3- [3- (dimethylamino) propyl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
This compound was synthesized according to the method described in Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull., 1981, 29, 2135-2156).
a) Synthesis of 5-chloro-2-trichloroacetylaminobenzophenone
To a 200 mL tetrahydrofuran solution of 23.2 g (100 mmol) of 2-amino-5-chlorobenzophenone and 11 g (110 mmol) of triethylamine, 20 g (110 mmol) of trichloroacetyl chloride was added dropwise at 5 to 15 ° C. After stirring at room temperature for 3 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl alcohol to obtain 33.8 g (89.9 mmol) of the title compound.
b) Synthesis of 6-chloro-3- [3- (dimethylamino) propyl] -4-phenyl-4- (trichloromethyl) -3,4-dihydro-2 (1H) -quinazolinone
To a 50 mL solution of 5-chloro-2-trichloroacetylaminobenzophenone 3.77 g (10 mmol) in dimethyl sulfoxide, 1.23 g (12 mmol) of 3-dimethylaminopropylamine was added and stirred at room temperature for 24 hours. The reaction solution was poured into 200 mL of ice water, and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized with a mixed solvent of chloroform and dimethylformamide to obtain 3.97 g (8.6 mmol) of the title compound.
c) Synthesis of 6-chloro-3- [3- (dimethylamino) propyl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
6-chloro-3- [3- (dimethylamino) propyl] -4-phenyl-4- (trichloromethyl) -3,4-dihydro-2 (1H) -quinazolinone 3.69 g (8 mmol) of
To an ethanol solution of 1.72 g (5.0 mmol) of the above free base, 1.05 g (5 mmol) of citric acid monohydrate was added at room temperature. After stirring for 1 hour, the solvent was distilled off under reduced pressure, and the residue was crystallized from ethanol to obtain 2.55 g (4.6 mmol) of the title compound citrate.
Melting point: 157-159 ° C (recrystallization solvent: ethanol)
[0024]
Production Example 2
Synthesis of 3- [3- (dimethylamino) propyl] -4-cyclohexyl-3,4-dihydro-2 (1H) -quinazolinone
The title compound was synthesized from (2-aminobenzoyl) cyclohexane and 3-dimethylaminopropylamine in the same manner as in Production Example 1.
1H NMR (CDClThree) δ; 7.65 (1H, brs), 7.17 (1H, m), 6.94 (2H, m), 6.73 (1H, m), 4.16 (1H, d, J = 5.0 Hz), 4.04 (1H, m), 3.02 (1H, m), 2.28 (2H, m), 2.17 (6H, s), 1.72 (7H, m), 1.04 (5H, m), 0.80 (1H, m).
Melting point; 124-125 ° C (recrystallization solvent: ethanol)
Hydrochloride
Melting point: 183-184 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 3
Synthesis of 3- [2- (diethylamino) ethyl] -4- (3-hydroxyphenyl) -3,4-dihydro-2 (1H) -quinazolinone
a) Synthesis of 3- [2- (diethylamino) ethyl] -4- (3-benzyloxyphenyl) -3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 1, the title compound was synthesized from 2-amino-3'-benzyloxybenzophenone and 2- (diethylamino) ethylamine.
1H NMR (CDClThree) δ; 7.29 to 7.43 (5H, m), 7.22 (1H, m), 7.12 (1H, m), 6.83 to 6.97 (6H, m), 6.66 (1H, dd, J = 7.9, 1.0 Hz), 5.63 (1H, s), 5.01 (2H, s), 3.77 to 3.87 (1H, m), 2.93 to 3.03 (1H, m), 2.54 to 2.71 (1H, m), 2.39 to 2.52 (5H, m), 0.97 (6H, t, J = 7.3Hz).
Melting point: 128-129 ° C (recrystallization solvent: ethanol)
b) Synthesis of 3- [2- (diethylamino) ethyl] -4- (3-hydroxyphenyl) -3,4-dihydro-2 (1H) -quinazolinone
To a solution of 3- [2- (diethylamino) ethyl] -4- (3-benzyloxyphenyl) -3,4-dihydro-2 (1H) -quinazolinone 2.0 g (4.66 mmol) in 100 mL of methanol, 5% palladium-carbon 200 mg was added and stirred at room temperature for 5 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The precipitated crystals were recrystallized from methanol to obtain 1.30 g (3.83 mmol) of the title compound.1H NMR (DMSO-d6) δ; 9.45 (1H, s, D2O exchange loss), 9.33 (1H, s), 7.04 to 7.15 (3H, m), 6.62 to 6.83 (5H, m), 5.62 (1H, s), 3.68 (1H, m), 2.77 (1H, m) , 2.34 ~ 2.56 (6H, m), 0.89 (6H, t, J = 7.3Hz).
Melting point: 208-210 ° C (recrystallization solvent: methanol)
Hydrochloride
Melting point: 247-249 ° C (recrystallization solvent: diethyl ether / ethanol)
[0025]
Production Example 4
Synthesis of 3- [2- (1-methylpyrrolidin-2-yl) ethyl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 1, the title compound was synthesized as a mixture of about 1: 1 diastereomers from 2-aminobenzophenone and 2- (2-aminoethyl) -1-methylpyrrolidine.
1H NMR (CDClThree) δ; 7.23 to 7.34 (5H, m), 7.13 (1H, m), 7.00 (1H, m), 6.87 (1H, m), 6.71 (1H, m), 5.51 (0.5H, s), 5.49 ( 0.5H, s), 3.89 to 4.00 (0.5H, m), 3.73 to 3.84 (0.5H, m), 2.96 to 3.07 (1H, m), 2.75 to 2.86 (1H, m), 2.25 (1.5H, s ), 2.23 (1.5H, s), 1.84 to 2.14 (4H, m), 1.36 to 1.78 (4H, m). Melting point: 154-157 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 5
Synthesis of 3- (piperidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 1, the title compound was synthesized as a mixture of about 1: 1 diastereomers from 2-aminobenzophenone and 2-aminomethylpiperidine.
1H NMR (CDClThree) δ; 7.93 (1H, m), 6.74 to 7.49 (9H, m), 5.56 (0.5H, s), 5.52 (0.5H, s), 3.79 to 4.00 (1H, m), 2.52 to 3.09 (4H, m), 1.10-1.80 (6H, m).
Melting point: 193-195 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 6
Synthesis of 3- (1-ethylpiperidin-3-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 1, the title compound was synthesized as a mixture of about 2: 3 diastereomers from 2-aminobenzophenone and 3- (aminomethyl) -1-ethylpiperidine.
1H NMR (CDClThree) δ; 8.04 (1H, brs), 7.22 to 7.35 (5H, m), 6.74 to 7.16 (4H, m), 5.52 (0.4H, s), 5.47 (0.6H, s), 3.94 (1H, m) , 2.59 to 3.01 (3H, m), 2.44 (2H, m), 1.55 to 2.19 (7H, m), 1.05 (3H, m).
Hydrochloride
Melting point: Approximately 250 ° C (decomposition, recrystallization solvent: ethanol).
[0026]
Production Example 7
Synthesis of 3- (morpholin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 1, the title compound was synthesized as a mixture of about 1: 1 diastereomers from 2-aminobenzophenone and 2-aminomethylmorpholine.
1H NMR (CDClThree) δ; 7.80 (0.5H, brs), 7.71 (0.5H, brs), 6.68 to 7.40 (9H, m), 5.74 (0.5H, s), 5.69 (0.5H, s), 3.35 to 3.96 (4H, m), 2.43-3.03 (5H, m).
Production Example 8
Synthesis of 3- (1-ethylpyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 1, 1.02 g of the title compound was synthesized as a mixture of diastereomers from 2-aminobenzophenone and 2- (aminomethyl) -1-ethylpyrrolidine. The mixture of diastereomers was separated by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 589 mg of diastereomer A, 254 mg of diastereomer B, and 150 mg of a mixture of both. Diastereomer A is a diastereomer having a larger Rf value in thin layer chromatography (developing solvent; methanol: chloroform 1: 9), and diastereomer B is a diastereomer having a smaller Rf value.
Diastereomer A
1H NMR (CDClThree) δ; 9.59 (1H, brs), 6.80 to 7.35 (9H, m), 5.81 (1H, s), 4.04 (1H, dd, J = 14, 3Hz), 3.18 (1H, m), 2.71 to 3.02 ( 3H, m), 1.61 to 2.39 (6H, m), 1.17 (3H, t, J = 7Hz).
Hydrochloride
Melting point: 250 ° C or higher (recrystallization solvent: ethanol)
Diastereomer B
1H NMR (CDClThree) δ; 9.02 (1H, brs), 6.81 to 7.39 (9H, m), 5.83 (1H, s), 3.94 (1H, dd, J = 14, 6Hz), 3.29 (1H, m), 2.83 to 3.11 ( 3H, m), 2.27 to 2.46 (2H, m), 1.62 to 1.93 (4H, m), 1.06 (3H, t, J = 7Hz).
Melting point; 151-153 ° C (recrystallization solvent: ethanol)
[0027]
Production Example 9
Synthesis of 3-[(2S) -1-ethylpyrrolidin-2-yl] methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
The title compound was synthesized as a mixture of diastereomers in the same manner as in Production Example 8 using (S) -2-aminomethyl-1-ethylpyrrolidine. The diastereomer mixture was separated by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 11.8 g of diastereomer A1 and 4.62 g of diastereomer B1. Diastereomer A1 is a diastereomer having a larger Rf value in thin layer chromatography (developing solvent; methanol: chloroform 1: 9), and diastereomer B1 is a diastereomer having a smaller Rf value. Diastereomer A1 is an optically active form of diastereomer A synthesized in Production Example 8, and diastereomer B1 is an optically active form of diastereomer B.
Diastereomer A1: Hydrochloride
Melting point; 299.5-302 ° C (recrystallization solvent: ethanol)
[α]D twenty four +177.3 ° (c 1.07, methanol)
Diastereomer B1: Hydrochloride
Melting point: 302.5-304 ° C (recrystallization solvent: ethanol)
[α]D twenty four −204.9 ° (c 0.943, methanol)
Production Example 10
Synthesis of 3-[(2R) -1-ethylpyrrolidin-2-yl] methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
The title compound was synthesized as a mixture of diastereomers using (R) -2-aminomethyl-1-ethylpyrrolidine in the same manner as in Production Example 8. The mixture of diastereomers was separated by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 9.89 g of diastereomer A2 and 4.12 g of diastereomer B2. Diastereomer A2 is a diastereomer having a larger Rf value in thin layer chromatography (developing solvent; methanol: chloroform 1: 9), and diastereomer B2 is a diastereomer having a smaller Rf value. Diastereomer A2 is an optically active form of diastereomer A synthesized in Production Example 8, and is an optical isomer of diastereomer A1 synthesized in Production Example 9. Similarly, diastereomer B2 is an optically active form of diastereomer B, and is an optical isomer of diastereomer B1.
Diastereomer A2: Hydrochloride
Melting point: 305-306.5 ℃ (recrystallization solvent: ethanol)
[α]D twenty four −178.2 ° (c 0.995, methanol)
Diastereomer B2: Hydrochloride
Melting point: 305-307.5 ° C (recrystallization solvent: ethanol)
[α]D twenty four +203.6 ° (c 0.978, methanol)
[0028]
Production Example 11
Synthesis of 3- (1-benzylpyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 1, the title compound was synthesized as a mixture of about 2: 3 diastereomer from 2-aminobenzophenone and 2- (aminomethyl) -1-benzylpyrrolidine.
Hydrochloride
1H NMR (CDThreeOD) δ; 6.82 to 7.90 (14H, m), 5.66 (0.4H, s), 5.45 (0.6H, s), 3.78 to 4.87 (4H, m), 2.86 to 3.63 (3H, m), 1.67 to 2.69 (4H, m).
Production Example 12
Synthesis of 3- (quinuclidin-3-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 1, the title compound was synthesized as a 1: 1 mixture of diastereomers from 2-aminobenzophenone and 3-aminomethylquinukilidine. However, borane coordinated to the nitrogen atom of quinuclidine (BHThree) Was removed by heating to reflux in 2N hydrochloric acid / tetrahydrofuran.
Hydrochloride
1H NMR (CDClThree) δ; 8.96 (0.5H, brs), 8.87 (0.5H, brs), 7.22 to 7.36 (5H, m), 7.01 to 7.16 (2H, m), 6.79 to 6.90 (2H, m), 5.47 (0.5H , s), 5.42 (0.5H, s), 3.88 to 4.19 (1H, m), 2.65 to 3.66 (6H, m), 2.34 to 2.48 (1H, m), 2.01 to 2.16 (1H, m), 1.40 to 1.99 (5H, m).
Production Example 13
Synthesis of 3- (quinuclidin-4-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 1, the title compound was synthesized from 2-aminobenzophenone and 4-aminomethylquinukilidine.
1H NMR (CDClThree) δ; 7.10 to 7.47 (7H, m), 6.88 to 7.00 (1H, m), 6.68 to 6.77 (1H, m), 5.39 (2H, s), 3.93 (2H, d, J = 14Hz), 2.89 ( 6H, brt, J = 8Hz), 2.44 (2H, d, J = 14Hz), 1.36 to 1.65 (6H, m).
[0029]
Production Example 14
Synthesis of 3- (1-benzylpiperidin-4-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 1, the title compound was synthesized from 2-aminobenzophenone and 4- (aminomethyl) -1-benzylpiperidine.
1H NMR (CDClThree) δ; 7.48 (1H, s), 7.20 to 7.31 (10H, m), 7.02 to 7.15 (2H, m), 6.85 to 6.91 (1H, m), 6.71 (1H, d, J = 7.9Hz), 5.41 (1H, s), 3.90 (1H, dd, J = 14, 7.3Hz), 3.47 (2H, s), 2.85 (2H, brd, J = 11Hz), 2.56 (1H, dd, J = 14, 6.9Hz ), 1.87 to 1.95 (2H, m), 1.66 to 1.8 (3H, m), 1.24 to 1.42 (2H, m).
Melting point: 163-165 ° C (recrystallization solvent: ethanol)
Production Example 15
Synthesis of 3- (pyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
3- (1-Benzylpyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 15.98 g (40.2 mmol) in 300 mL of ethanol was added to ammonium formate 13.61 g (216 mmol), 1.64 g of 10% palladium-carbon was added, and the mixture was heated to reflux for 5 hours. After cooling, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, aqueous ammonia: methanol: chloroform 5: 100: 900) to obtain 9.32 g (30.3 mmol) of the title compound as a mixture of about 1: 1 diastereomers.
1H NMR (CDClThree) δ; 8.32 (1H, m), 7.21 to 7.37 (5H, m), 6.99 to 7.14 (2H, m), 6.74 to 6.89 (2H, m), 5.81 (0.5H, s), 5.64 (0.5H, s), 3.89 to 4.03 (1H, m), 3.41 to 3.51 (1H, m), 2.67 to 3.07 (3H, m), 2.02 (1H, brs), 1.64 to 1.89 (3H, m), 1.31 (1H, m).
Melting point: 163-164 ° C (recrystallization solvent: ethyl acetate)
[0030]
Production Example 16
Synthesis of 3- [1- (2-propyl) pyrrolidin-2-yl] methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
To a 30 mL solution of 3- (pyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 554 mg (1.80 mmol) in methanol, 10% hydrochloric acid / ethanol solution under ice-cooling 660 mg, acetone 523 mg (9.00 mmol), and sodium cyanoborohydride 566 mg (9.00 mmol) were added. After stirring at room temperature for 10 hours, the reaction solution was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 279 mg of diastereomer A and 71 mg of diastereomer B. Diastereomer A is a diastereomer having a larger Rf value in thin layer chromatography (developing solvent; methanol: chloroform 1: 9), and diastereomer B is a diastereomer having a smaller Rf value.
Diastereomer A
1H NMR (CDClThree) δ; 9.80 (1H, brs), 7.19 to 7.36 (5H, m), 7.00 to 7.13 (2H, m), 6.82 to 6.87 (2H, m), 5.72 (1H, s), 3.86 (1H, dd, J = 14, 3Hz), 3.18 (1H, m), 2.90 to 2.97 (2H, m), 2.76 (1H, dd, J = 14, 9Hz), 2.46 to 2.52 (1H, m), 1.65 to 1.82 (4H , m), 1.20 (3H, d, J = 7Hz), 1.06 (3H, d, J = 7Hz).
Diastereomer B: Hydrochloride
1H NMR (CDThreeOD) δ; 7.29 to 7.40 (5H, m), 6.89 to 7.23 (4H, m), 5.70 (1H, s), 3.81 to 3.89 (1H, m), 3.38 to 3.61 (3H, m), 3.18 to 3.27 (1H, m), 1.88-2.13 (5H, m), 1.31 (3H, d, J = 7Hz), 1.14 (3H, d, J = 7Hz).
Melting point: 250 ° C or higher (recrystallization solvent: ethanol)
[0031]
Production Example 17
Synthesis of 3- [1- (tetrahydropyran-4-yl) pyrrolidin-2-yl] methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 16, the title compound was obtained from 3- (pyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone and tetrahydro-4H-pyran-4-one. Obtained as a mixture of stereomers. Diastereomer A is a diastereomer having a larger Rf value in thin layer chromatography (developing solvent; methanol: chloroform 1: 9), and diastereomer B is a diastereomer having a smaller Rf value.
Diastereomer A: Hydrochloride
1H NMR (CDThreeOD) δ; 7.28 to 7.40 (5H, m), 7.06 to 7.21 (2H, m), 6.87 to 6.96 (2H, m), 5.77 (1H, s), 3.86 to 4.12 (3H, m), 3.22 to 3.64 (7H, m), 1.62 to 2.15 (8H, m).
Melting point: 250 ° C or higher (recrystallization solvent: ethanol)
Diastereomer B: Hydrochloride
1H NMR (CDThreeOD) δ; 6.87 to 7.53 (9H, m), 5.80 (1H, s), 3.74 to 3.96 (3H, m), 3.26 to 3.71 (6H, m), 1.61 to 2.15 (9H, m).
Production Example 18
Synthesis of 3- (1-cyclohexylpyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 16, the title compound was obtained as a mixture of diastereomers from 3- (pyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone and cyclohexanone. Diastereomer A is a diastereomer having a larger Rf value in thin layer chromatography (developing solvent; methanol: chloroform 1: 9), and diastereomer B is a diastereomer having a smaller Rf value.
Diastereomer A: Hydrochloride
1H NMR (CDThreeOD) δ; 6.84 to 7.37 (9H, m), 5.77 (1H, s), 3.84 to 4.04 (2H, m), 3.40 to 3.52 (1H, m), 3.15 to 3.33 (2H, m), 1.47 to 2.24 (9H, m), 1.14 to 1.43 (6H, m).
Diastereomer B: Hydrochloride
1H NMR (CDThreeOD) δ; 7.30 to 7.43 (5H, m), 7.18 to 7.24 (1H, m), 7.06 to 7.09 (1H, m), 6.90 to 6.99 (2H, m), 5.75 (1H, s), 3.87 to 3.92 (1H, m), 3.58 to 3.82 (2H, m), 3.42 to 3.51 (1H, m), 3.24 to 3.34 (1H, m), 3.03 to 3.13 (1H, m), 1.81 to 2.17 (8H, m) , 1.64 (1H, m), 1.13 to 1.45 (5H, m).
Melting point: 250 ° C or higher (recrystallization solvent: isopropyl alcohol)
[0032]
Production Example 19
Synthesis of 3- [1- (tetrahydrothiophen-3-yl) pyrrolidin-2-yl] methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 16, the diastereomeric title compound was obtained from 3- (pyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone and tetrahydrothiophen-3-one. Obtained as a mixture. There are four types of diastereomers in this compound, but diastereomers A, B, C, D in descending order of Rf value by thin layer chromatography (developing solvent; methanol: chloroform 1: 9). Named. As a mixture of diastereomer A and diastereomer B, and as a mixture of diastereomer C and diastereomer D, the mixture of diastereomers is separated by column chromatography (developing solvent; methanol: chloroform 1: 9). Isolated.
A mixture of diastereomer A and diastereomer B
1H NMR (CDClThree) δ; 8.05 to 8.12 (1H, m), 6.73 to 7.32 (9H, m), 5.70 (0.4H, s), 5.68 (0.6H, s), 3.68 to 3.86 (2H, m), 2.45 to 3.20 ( 10H, m), 1.74 to 2.20 (4H, m).
Melting point: 123-126 ° C (recrystallization solvent: ethanol)
Mixture of diastereomer C and diastereomer D: hydrochloride
1H NMR (CDThreeOD) δ; 7.29 to 7.39 (5H, m), 7.18 to 7.24 (1H, m), 6.90 to 7.09 (3H, m), 5.76 (1H, s), 3.79 to 3.91 (3H, m), 3.58 to 3.64 (2H, m), 3.29 to 3.40 (1H, m), 2.70 to 3.08 (4H, m), 1.93 to 2.36 (6H, m).
Melting point: 250 ° C or higher (recrystallization solvent: isopropyl alcohol)
Production Example 20
Synthesis of 3- (1-cyanomethylpyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
3- (Pyrrolidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 203 mg (0.66 mmol), bromoacetonitrile 95 mg (0.79 mmol), triethylamine 283 mg (2.8 mmol) Of dimethylformamide in 5 mL was stirred at 70 ° C. for 6 hours. After cooling, water was added to the reaction solution and extracted with chloroform. The organic layer was washed with water, dried over potassium carbonate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 226 mg (0.65 mmol) of the title compound as a mixture of about 1: 2 diastereomers.
1H NMR (CDClThree) δ; 8.02 (0.4H, brs), 7.90 (0.6H, brs), 7.23 to 7.36 (5H, m), 6.75 to 7.18 (4H, m), 5.70 (0.7H, s), 5.62 (0.3H, s), 3.91 to 4.09 (1H, m), 3.57 to 3.75 (2H, m), 2.54 to 3.09 (5H, m), 1.62 to 2.03 (3H, m).
[0033]
Production Example 21
Synthesis of 3- (1-ethylpiperidin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 20, the title compound was converted from 4-phenyl-3- (piperidin-2-yl) methyl-3,4-dihydro-2 (1H) -quinazolinone and ethyl iodide to about 1: 1 diastereoisomer. Synthesized as a mixture of polymers.
1H NMR (CDClThree) δ; 8.05 (1H, brs), 7.24 to 7.36 (5H, m), 6.74 to 7.16 (4H, m), 5.48 (1H, m), 4.16 (1H, m), 2.35 to 2.96 (8H, m) , 1.30 ~ 1.77 (4H, m), 0.99 (3H, t, J = 7Hz).
Production Example 22
Synthesis of 3- (4-ethylmorpholin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 20, the title compound was converted from 3- (morpholin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone and ethyl iodide to about 2: 3 diastereoisomer. Synthesized as a mixture of polymers.
1H NMR (CDClThree) δ; 7.08 to 7.38 (6H, m), 6.99 to 7.06 (1H, m), 6.83 to 6.92 (1H, m), 6.65 to 6.73 (1H, m), 5.75 (0.4H, s), 5.71 (0.6 H, s), 4.22 (0.4H, dt, J = 2, 11Hz), 4.17 (0.6H, dt, J = 2, 11Hz), 4.12 (0.6H, dd, J = 15, 2Hz), 3.94 (0.4 H, dd, J = 14, 4Hz), 3.70-3.90 (2H, m), 2.96 (0.6H, dd, J = 15, 3Hz), 2.60-2.86 (2.2H, m), 2.37 (2H, q, J = 7.2Hz), 2.06 (1.2H, J = 12, 3Hz), 1.94 (0.6H, dd, J = 12, 11Hz), 1.74 (0.4H, dd, J = 12, 11Hz), 1.06 (1.8H , t, J = 7.2Hz), 1.05 (1.2H, t, J = 7.2Hz).
Production Example 23
Synthesis of 3- (4-benzylmorpholin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 20, the title compound was converted to about 2: 3 diastereomer from 3- (morpholin-2-yl) methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone and benzyl bromide. Was synthesized as a mixture of
1H NMR (CDClThree) δ; 7.64 (0.6H, brs), 7.57 (0.4H, brs), 7.17 to 7.43 (9H, m), 7.12 (0.6H, dt, J = 8, 1Hz), 7.11 (0.4H, dt, J = 8, 1Hz), 7.02 (0.4H, s), 7.00 (0.6H, s), 6.88 (0.6H, dt, J = 7, 1Hz), 6.87 (0.4H, dt, J = 7, 1Hz), 6.72 (0.6H, dd, J = 8, 1Hz), 6.70 (0.4H, dd, J = 8, 1Hz), 5.77 (0.4H, s), 5.68 (0.6H, s), 4.11 (0.6H, dd , J = 15, 6Hz), 3.70 to 3.95 (2.4H, m), 3.30 to 3.67 (3H, m), 2.95 (0.6H, dd, J = 15, 4Hz), 2.48 to 2.85 (2.2H, m) , 2.00-2.19 (1.6H, m), 1.83 (0.6H, dd, J = 11, 10Hz).
[0034]
Production Example 24
Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
a) N- (1-Benzylpiperidin-4-yl) -2- (trichloroacetylamino) benzophenone imine
In the same manner as in Production Example 1, 20.8 g (119 mmol) of 2-trichloroacetylaminobenzophenone and 25.0 g (131 mmol) of 4-amino-1-benzylpiperidine obtained from 2-aminobenzophenone were dissolved in 300 mL of dimethyl sulfoxide. And stirred at about 40 ° C. for 15 hours. The reaction solution was poured into water, and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from ethyl acetate to obtain 44.8 g (86.9 mmol) of the title compound.1H NMR (CDClThree) δ; 8.73 (1H, m), 7.22 to 7.54 (9H, m), 7.12 to 7.16 (2H, m), 6.88 to 6.99 (2H, m), 3.44 (2H, s), 3.06 to 3.17 (1H, m), 2.82 to 2.86 (2H, m), 1.96 to 2.11 (2H, m), 1.72 to 1.82 (2H, m), 1.50 to 1.58 (2H, m).
Melting point; 151-152 ° C (recrystallization solvent: ethyl acetate)
b) Synthesis of α- (2-aminophenyl) -N- (1-benzylpiperidin-4-yl) benzylamine
N- (1-benzylpiperidin-4-yl) -2- (trichloroacetylamino) benzophenoneimine in a solution of 44.7 g (86.8 mmol) in ethanol 150 mL at 5 to 15 ° C. 3.28 g (86.8 mmol) was added and stirred for 2 hours. Furthermore, sodium borohydride 3.28 g (86.8 mmol) was added at 5 to 15 ° C., and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction solution, and ethanol was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate) to obtain 27.7 g (74.5 mmol) of the title compound.1H NMR (CDClThree) δ; 7.21 to 7.35 (10H, m), 7.01 to 7.07 (1H, m), 6.84 to 6.88 (1H, m), 6.60 to 6.65 (2H, m), 5.08 (1H, s), 4.74 (1H, br), 3.46 (2H, s), 2.79 (2H, brd, J = 11Hz), 2.44 to 2.52 (1H, m), 1.86 to 2.00 (4H, m), 1.65 (2H, brs), 1.46 to 1.60 ( 2H, m).
c) Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
α- (2-Aminophenyl) -N- (1-benzylpiperidin-4-yl) benzylamine in a solution of 27.6 g (74.4 mmol) in tetrahydrofuran (300 mL) was mixed with 12.1 g (74.5 mmol) of 1,1′-carbonyldiimidazole. In addition, the mixture was heated to reflux for 8 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9). The obtained crude crystals were recrystallized from ethanol to obtain 24.0 g (60.3 mmol) of the title compound.
1H NMR (CDClThree) δ; 7.11 to 7.40 (12H, m), 6.91 (1H, dd, J = 7.6, 1.0 Hz), 6.83 (1H, s), 6.66 (1H, d, J = 7.6Hz), 5.56 (1H, s) ), 4.33 to 4.45 (1H, m), 3.45 (1H, s), 2.90 to 2.97 (1H, m), 2.74 to 2.81 (1H, m), 1.91 to 2.14 (2H, m), 1.42 to 1.65 (2H , m).
Melting point: 199-200 ° C (recrystallization solvent: ethanol)
Citrate
Melting point: 159-161.5 ° C (recrystallization solvent: diethyl ether / ethanol)
[0035]
Production Example 25
Synthesis of 3- (quinuclidin-3-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 24, the title compound was synthesized as a mixture of diastereomers from 2-aminobenzophenone and 3-aminoquinuclidine. Separation by column chromatography (silica gel, aqueous ammonia: methanol: chloroform 1: 9: 90) gave 258 mg of diastereomer A, 330 mg of diastereomer B, and 480 mg of a mixture of both. Diastereomer A is a diastereomer having a larger Rf value in thin layer chromatography (developing solvent; aqueous ammonia: methanol: chloroform 1: 9: 90), and diastereomer B is a diastereomer having a smaller Rf value. Ma.
Diastereomer A
1H NMR (CDClThree) δ; 8.41 (1H, brs), 7.12 to 7.36 (8H, m), 6.96 (1H, m), 6.77 (1H, m), 5.75 (1H, s), 4.62 (1H, m), 2.77 to 3.05 (5H, m), 2.50 (1H, m), 1.36 to 1.98 (5H, m).
Hydrochloride
Melting point: 250 ° C or higher (recrystallization solvent: diethyl ether / ethanol)
Diastereomer B
1H NMR (CDClThree) δ; 8.59 (1H, m), 6.76 to 7.30 (9H, m), 5.59 (1H, s), 3.87 (1H, m), 3.67 (1H, m), 2.72 to 3.04 (5H, m), 1.40 ~ 2.06 (5H, m).
Production Example 26
Synthesis of 3- (1-methylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
The title compound was synthesized from 2-aminobenzophenone and 4-amino-1-methylpiperidine in the same manner as in Production Example 24.
1H NMR (CDClThree) δ; 7.54 (1H, brs), 7.08 to 7.43 (7H, m), 6.90 (1H, m), 6.72 (1H, m), 5.55 (1H, s), 4.40 (1H, m), 2.91 (1H , m), 2.73 (1H, m), 3.23 (3H, s), 1.93 to 2.12 (3H, m), 1.46 to 1.69 (3H, m).
Melting point: 252-253 ° C (recrystallization solvent: ethanol)
[0036]
Production Example 27
Synthesis of 3- (1-benzylpyrrolidin-3-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 24, the title compound was synthesized as a mixture of diastereomers from 2-aminobenzophenone and 3-amino-1-benzylpyrrolidine. Separation by column chromatography (silica gel, ethyl acetate: chloroform 1: 2) gave 520 mg (1.36 mmol) of diastereomer A and 1.08 g (2.82 mmol) of a mixture of diastereomer B and diastereomer A. It was. Diastereomer A is a diastereomer having a larger Rf value in thin layer chromatography (developing solvent; ethyl acetate: chloroform 1: 2), and diastereomer B is a diastereomer having a smaller Rf value.
Diastereomer A
1H NMR (CDClThree) δ; 7.50 (1H, m), 7.08 to 7.35 (12H, m), 6.69 to 6.93 (2H, m), 5.77 (1H, s), 4.83 (1H, m), 3.57 (1H, d, J = 13Hz), 3.40 (1H, d, J = 13Hz), 2.90 (1H, m), 2.68 (1H, m), 2.20 to 2.34 (3H, m) 2.16 (1H, m).
Melting point: Approximately 250 ° C (decomposition, recrystallization solvent: diethyl ether / ethanol)
Production Example 28
Synthesis of 3- (pyrrolidin-3-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 15, from the diastereomeric mixture of 3- (1-benzylpyrrolidin-3-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone, the title compound is diastereomerized. Synthesized as a mixture.
1H NMR (CDThreeOD) δ; 7.29 to 7.41 (5H, m), 6.79 to 7.15 (4H, m), 5.67 (1H, m), 4.20 (1H, m), 3.62 (1H, m), 2.88 to 3.18 (3H, m ), 2.14 to 2.53 (2H, m).
Melting point: 250 ° C or higher (recrystallization solvent: ethanol)
Production Example 29
Synthesis of 3- (1-ethylpyrrolidin-3-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 20, the title compound was obtained from 3- (pyrrolidin-3-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone and ethyl iodide in about 1: 2 diastereomer. As a mixture of1H NMR (CDClThree) δ; 7.52 to 7.58 (1H, m), 7.08 to 7.41 (7H, m), 6.90 (1H, m), 6.73 (1H, m), 5.76 (0.7H, s), 5.72 (0.3H, s) , 4.72 ~ 4.91 (1H, m), 1.70 ~ 2.88 (9H, m), 1.07 (0.9H, t, J = 7Hz), 0.97 (2.1H, t, J = 7Hz).
[0037]
Production Example 30
Synthesis of 3- (piperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 15, the title compound was synthesized from 3- (1-benzylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone.
1H NMR (CDClThree) δ; 7.37 to 7.41 (2H, m), 7.09 to 7.31 (5H, m), 6.90 (1H, dt, J = 1, 7Hz), 6.71 (1H, d, J = 8Hz), 5.56 (1H, s ), 4.36 (1H, m), 3.13 (1H, m), 2.99 (1H, m), 2.55 to 2.73 (2H, m), 1.87 to 2.02 (1H, m), 1.56 to 1.76 (2H, m), 1.29 to 1.45 (1H, m).
Melting point: 213-215 ° C (recrystallization solvent: diethyl ether / ethanol)
Hydrochloride
Melting point: 250 ° C or higher (recrystallization solvent: ethanol)
Production Example 31
Synthesis of 3- (1-allylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
To a solution of 3- (piperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 300 mg (0.976 mmol) in
1H NMR (CDClThree) δ; 7.06 to 7.45 (7H, m), 6.90 (1H, brt, J = 7.8Hz), 6.69 (1H, brd, J = 8Hz), 5.73 to 5.92 (1H, m), 5.58 (1H, s) , 5.05 to 5.22 (2H, m), 5.33 to 5.52 (1H, m), 2.78 to 3.10 (4H, m), 1.87 to 2.24 (3H, m), 1.36 to 1.80 (3H, m).
Hydrochloride
Melting point: 190-195 ° C (recrystallization solvent: ethanol)
[0038]
Production Example 32
Synthesis of 3- [1- (2-propynyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 31, the title compound was synthesized from 3- (piperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone and propargyl bromide.
1H NMR (CDClThree) δ; 6.85 to 7.52 (6H, m), 6.68 (1H, brd, J = 8Hz), 5.55 (1H, s), 4.32 to 4.50 (1H, m), 3.25 (2H, d, J = 2Hz), 2.71 to 3.40 (2H, m), 1.95 to 2.43 (3H, m), 2.21 (1H, t, J = 2Hz), 1.40 to 1.90 (3H, m).
Melting point: 198-201 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 33
Synthesis of 3- (1-ethylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
The title compound was synthesized from 3- (piperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone and ethyl iodide in the same manner as in Production Example 31.
Hydrochloride
1H NMR (DMSO-d6) δ; 9.58 to 9.76 (1H, brs), 9.54 (1H, s), 7.18 to 7.45 (6H, m), 7.09 (1H, dd, J = 8, 1.5Hz), 6.77 to 6.89 (2H, m) , 5.64 (1H, s), 4.13 to 4.30 (1H, m), 3.21 to 3.50 (2H, m), 2.72 to 3.09 (4H, m), 2.30 to 2.59 (1H, m), 1.75 to 1.99 (1H, m), 1.50 to 1.72 (2H, m), 1.16 (3H, t, J = 7Hz).
Melting point: 295-296 ° C (decomposition, recrystallization solvent: diethyl ether / ethanol)
Production Example 34
Synthesis of 3- [1- (2-hydroxyethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 31, the title compound was synthesized from 3- (piperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone and ethylene bromohydrin.
1H NMR (CDClThree) δ; 7.04 to 7.50 (7H, m), 6.90 (1H, dt, J = 1, 7.6Hz), 6.69 (1H, d, J = 8Hz), 5.53 (1H, s), 4.27 to 4.45 (1H, m), 3.76 to 3.89 (1H, m), 3.55 (2H, m), 2.91 to 3.05 (2H, m), 2.49 (2H, m), 1.93 to 2.28 (3H, m), 1.35 to 1.72 (3H, m).
Hydrochloride
Melting point: 261-265 ° C (recrystallization solvent: diethyl ether / ethanol)
[0039]
Production Example 35
Synthesis of 3- (1-ethoxycarbonylmethylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
3- (piperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 1.5 g (4.88 mmol) in isopropanol solution 30 mL, ethyl bromoacetate 896 mg (5.37 mmol), carbonic acid Potassium 853 mg 96.18 mmol) and
1H NMR (CDClThree) δ; 7.71 to 7.83 (1H, brs), 7.05 to 7.43 (1H, m), 6.90 (1H, dt, J = 1, 7Hz), 6.73 (1H, d, J = 8Hz), 5.57 (1H, s ), 4.36 to 4.54 (1H, m), 4.17 (2H, q, J = 7Hz), 3.16 (2H, s), 2.95 to 3.07 (1H, m), 2.79 to 2.90 (1H, m), 2.00 to 2.39 (3H, m), 1.45 to 1.82 (2H, m), 1.25 (3H, t, J = 7Hz), 1.17 to 1.30 (1H, m).
Hydrochloride
Melting point: 195-198 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 36
Synthesis of 3- [1- (2-furylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
To a solution of 3- (piperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone hydrochloride 344 mg (1.0 mmol), furfural 384 mg (4.0 mmL) in
1H NMR (CDClThree) δ; 7.31 to 7.37 (3H, m), 7.08 to 7.28 (5H, m), 6.88 to 6.94 (1H, m), 6.60 to 6.73 (2H, m), 6.29 (1H, dd, J = 3, 2Hz ), 6.16 (1H, d, J = 3Hz), 5.56 (1H, s), 4.42 (1H, m), 3.49 (2H, s), 2.95 (1H, d, J = 10Hz), 2.79 (1H, d , J = 12Hz), 1.96 to 2.17 (3H, m), 1.45 to 1.69 (3H, m).
Hydrochloride
Melting point: 205-206 ° C (recrystallization solvent: diethyl ether / ethanol)
[0040]
In the same manner as in Production Example 36, the compounds of Production Example 37 to Production Example 69 were synthesized.
Production Example 37
3- [1- (3-Furylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.35 to 7.39 (3H, m), 7.08 to 7.29 (7H, m), 6.87 to 6.93 (1H, m), 6.68 (1H, d, J = 8Hz), 6.34 (1H, d, J = 1.6) Hz), 5.56 (1H, s), 4.34 to 4.43 (1H, m), 3.33 (2H, s), 2.96 (1H, d, J = 8Hz), 2.81 (1H, d, J = 11Hz), 1.91 to 2.12 (3H, m), 1.41-1.65 (3H, m).
Melting point: 250 ° C or higher (recrystallization solvent: ethanol)
Production Example 38
3- [1- (2-Thienylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.61 (1H, s), 7.38 (2H, m), 7.08 to 7.29 (6H, m), 6.86 to 6.93 (3H, m), 6.72 (1H, d, J = 8Hz), 5.56 (1H, s), 4.33 to 4.45 (1H, m), 3.68 (2H, s), 2.98 (1H, d, J = 10Hz), 2.83 (1H, dd, J = 11, 2.3Hz), 1.95 to 2.18 (3H, m), 1.39 to 1.67 (3H, m).
Hydrochloride
Melting point: 213-214.5 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 39
3- [1- (3-Thienylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.66 (1H, s), 7.35 to 7.40 (2H, m), 7.07 to 7.29 (7H, m), 7.02 (1H, m), 6.86 to 6.92 (1H, m), 6.72 (1H, d, J = 8Hz), 5.56 (1H, s), 4.34 to 4.42 (1H, m), 3.49 (2H, s), 2.95 (1H, brd, J = 7Hz), 2.08 (1H, brd, J = 11Hz), 1.93 to 2.17 (3H, m), 1.47 to 1.65 (3H, m).
Hydrochloride
Melting point: 240-242 ° C (recrystallization solvent: ethanol)
Production Example 40
3- [1- (2-Pyridylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 8.55 (1H, m), 7.69 (1H, s), 7.59 to 7.65 (1H, m), 7.08 to 7.40 (9H, m), 6.87 to 6.93 (1H, m), 6.73 (1H, d, J = 8Hz), 5.57 (1H, s), 4.37 to 4.47 (1H, m), 3.61 (2H, s), 2.96 (1H, d, J = 8.5Hz), 2.80 (1H, d, J = 11Hz) , 2.02 to 2.25 (3H, m), 1.51 to 1.65 (3H, m).
Hydrochloride
Melting point: 253-255 ° C (recrystallization solvent: ethanol)
[0041]
Production Example 41
3- [1- (3-Pyridylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 8.47 to 8.51 (2H, m), 7.53 to 7.63 (2H, m), 7.37 to 7.41 (2H, m), 7.08 to 7.30 (6H, m), 6.87 to 6.93 (1H, m), 6.71 ( 1H, d, J = 8Hz), 5.55 (1H, s), 4.32 to 4.44 (1H, m), 3.46 (2H, s), 2.90 (1H, brd, J = 10Hz), 2.76 (1H, brd, J = 11Hz), 1.95-2.17 (3H, m), 1.38-1.65 (3H, m).
Hydrochloride
Melting point: 252-254 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 42
3- [1- (4-Pyridylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 8.52 (2H, dd, J = 4.6, 1.6Hz), 7.37-7.41 (2H, m), 7.07-7.31 (8H, m), 6.88-6.94 (1H, m), 6.69 (1H, d, J = 8Hz), 5.56 (1H, s), 4.30 to 4.42 (1H, m), 3.44 (2H, s), 2.89 (1H, dd, J = 10, 2Hz), 2.75 (1H, brd, J = 11Hz ), 1.97-2.17 (3H, m), 1.45-1.64 (3H, m).
Melting point: 241.5-243 ° C (recrystallization solvent: ethanol)
Production Example 43
3- [1- (2-imidazolylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 9.38 (1H, s), 8.31 (1H, s), 7.18 to 7.41 (6H, m), 7.03 to 7.17 (1H, m), 6.76 to 6.87 (2H, m), 5.69 (1H, s) , 4.09 (1H, m), 3.41 (2H, s), 2.83 (1H, m), 2.65 (1H, m), 1.97 to 2.00 (3H, m), 1.37 (3H, m).
Hydrochloride
Melting point; 303-305 ° C (recrystallization solvent: ethanol)
Production Example 44
3- [1- (2-Pyrrolylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 10.59 (1H, brs), 9.38 (1H, brs), 7.15-7.48 (6H, m), 7.05 (1H, m), 6.76-6.83 (2H, m), 6.59 (1H, m), 5.88 (1H, m), 5.81 (1H, brs), 5.70 (1H, s), 4.06 (1H, m), 3.33 (2H, s), 2.82 (1H, m), 2.62 to 2.71 (1H, m), 1.83 to 2.10 (3H, m), 1.28 to 1.43 (3H, m).
Hydrochloride
Melting point: 201-204 ° C (recrystallization solvent: ethanol)
[0042]
Production Example 45
Synthesis of 3- [1- (1-methyl-2-pyrrolylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.08 to 7.58 (7H, m), 6.90 (2H, m), 6.72 (2H, m), 5.54 (1H, s), 4.33 to 4.57 (2H, m), 3.46 to 3.73 (1H, m) , 2.95 (1H, m), 2.79 (1H, m), 2.59 (3H, s), 1.88-2.10 (3H, m), 1.20-1.75 (3H, m).
Production Example 46
3- [1- (2-Phenylethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.62 (1H, s), 7.37 to 7.41 (2H, m), 7.09 to 7.30 (10H, m), 6.88 to 6.93 (1H, m), 6.73 (1H, d, J = 7.6Hz), 5.59 (1H, s), 4.40 to 4.50 (1H, m), 3.06 (1H, d, J = 10Hz), 2.93 (1H, d, J = 11Hz), 2.73 to 2.79 (2H, m), 2.53 to 2.58 ( 2H, m), 1.97-2.20 (3H, m), 1.43-1.72 (3H, m).
Hydrochloride
Melting point: 284-285.5 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 47
3- [1- (Cyclohexylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.67 (1H, s), 7.36 to 7.41 (2H, m), 7.08 to 7.29 (5H, m), 6.87 to 6.93 (1H, m), 6.72 (1H, d, J = 8Hz), 5.57 ( 1H, s), 4.34 to 4.44 (1H, m), 2.90 (1H, d, J = 7Hz), 2.77 (1H, d, J = 11Hz), 1.62 to 2.12 (11H, m), 1.35 to 1.51 (3H , m), 1.05 to 1.25 (3H, m), 0.75 to 0.88 (2H, m).
Hydrochloride
Melting point: 194-197.5 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 48
3- [1- (4-Cyclohexenylmethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
Hydrochloride
1H NMR (DMSO-d6) δ; 9.53 (1H, s), 9.35 to 9.53 (1H, m), 7.18 to 7.45 (6H, m), 7.09 (1H, dt, J = 1, 8Hz), 6.76 to 6.89 (2H, m), 5.55 to 5.72 (3H, m), 4.12 to 4.38 (1H, m), 3.20 to 3.55 (2H, m), 2.80 to 3.07 (4H, m), 2.39 to 2.63 (1H, m), 1.47 to 2.26 (9H , m), 1.10-1.30 (1H, m).
Melting point: 160 ° C (decomposition, recrystallization solvent: diethyl ether / ethanol)
[0043]
Production Example 49
3- (1-cyclohexylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.39 (2H, d, J = 7Hz), 7.05 to 7.29 (5H, m), 6.88 to 6.94 (1H, m), 6.67 (1H, d, J = 8Hz), 5.61 (1H, s), 4.45 (1H, m), 3.02 (1H, d, J = 10Hz), 2.87 (1H, d, J = 11Hz), 1.50 to 2.46 (12H, m), 1.04 to 1.20 (5H, m).
Melting point: 213-215.5 ° C (recrystallization solvent: ethanol)
Production Example 50
3- [1- (Tetrahydropyran-4-yl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.36 to 7.40 (2H, m), 7.08 to 7.30 (5H, m), 6.88 to 6.94 (1H, m), 6.68 (1H, dd, J = 8, 1Hz), 5.58 (1H, s), 4.35 to 4.47 (1H, m), 3.97 to 4.02 (2H, m), 3.36 (1H, d, J = 11Hz), 3.32 (1H, d, J = 12Hz), 3.01 (1H, brd, J = 12Hz) , 2.87 (1H, brd, J = 11Hz), 2.10 to 2.45 (3H, m), 1.89 to 2.04 (1H, m), 1.37 to 1.72 (7H, m).
Melting point: 282-284 ° C (recrystallization solvent: ethanol)
Production Example 51
3- [1- (1-Phenylethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
Obtained as a mixture of approximately 1: 1 diastereomers.
1H NMR (CDClThree) δ; 8.53 (1H, s), 7.06 to 7.49 (10H, m), 6.75 to 6.90 (4H, m), 5.56 (0.5H, s), 5.55 (0.5H, s), 4.34 (1H, m) , 3.38 (1H, m), 2.70 to 3.09 (2H, m), 1.86 to 2.08 (4H, m), 1.43 to 1.67 (2H, m), 1.34 (1.5H, d, J = 6Hz), 1.32 (1.5 (H, d, J = 6Hz).
Hydrochloride
Melting point: 282-285 ° C (recrystallization solvent: ethyl acetate / ethanol)
Production Example 52
3- [1- (2-Methoxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.08 to 7.39 (8H, m), 6.81 to 6.94 (4H, m), 6.65 (1H, d, J = 8Hz), 5.58 (1H, s), 4.39 (1H, m), 3.79 (3H, s), 3.52 (2H, s), 2.97 (1H, m), 2.83 (1H, m), 1.95 to 2.17 (3H, m), 1.49 to 1.65 (3H, m).
Melting point: 197-198.5 ° C (recrystallization solvent: ethanol)
[0044]
Production Example 53
3- [1- (3-Methoxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.37 to 7.40 (2H, m), 7.08 to 7.29 (6H, m), 6.76 to 6.94 (5H, m), 6.66 (1H, d, J = 8Hz), 5.56 (1H, s), 4.38 ( 1H, m), 3.80 (3H, s), 3.43 (2H, s), 2.93 (1H, m), 2.78 (1H, m), 1.93 to 2.09 (3H, m), 1.46 to 1.65 (3H, m) .
Melting point: 187-188.5 ° C (recrystallization solvent: ethanol)
Meso tartrate
Melting point: 122-140 ° C (recrystallization solvent: isopropanol)
Production Example 54
3- [1- (4-Methoxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.35 to 7.39 (2H, m), 7.08 to 7.29 (6H, m), 6.77 to 6.93 (4H, m), 6.65 (1H, dd, J = 8, 1Hz), 5.56 (1H, s), 4.37 (1H, m), 3.79 (3H, s), 3.39 (2H, s), 2.92 (1H, m), 2.77 (1H, m), 1.90 to 2.10 (3H, m), 1.46 to 1.64 (3H, m).
Melting point: 218-219.5 ° C (recrystallization solvent: ethanol)
Production Example 55
3- [1- (2-Chlorobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.08 to 7.42 (11H, m), 6.88 to 6.94 (1H, m), 6.83 (1H, brs), 6.66 (1H, d, J = 8Hz), 5.57 (1H, s), 4.33 to 4.45 ( 1H, m), 3.56 (2H, s), 2.95 (1H, m), 2.81 (1H, m), 1.95 to 2.26 (3H, m), 1.45 to 1.65 (3H, m).
Melting point: 206-207.5 ° C (recrystallization solvent: ethanol)
Production Example 56
3- [1- (3-Chlorobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.37 to 7.41 (2H, m), 7.08 to 7.29 (9H, m), 6.88 to 6.94 (1H, m), 6.74 (1H, brs), 6.65 (1H, d, J = 8Hz), 5.56 ( 1H, s), 4.33 to 4.43 (1H, m), 3.41 (2H, s), 2.88 to 2.92 (1H, m), 2.72 to 2.77 (1H, m), 1.94 to 2.13 (3H, m), 1.46 to 1.65 (3H, m).
Melting point; 204-205.5 ° C (recrystallization solvent: ethanol)
[0045]
Production Example 57
3- [1- (4-Chlorobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.36 to 7.40 (2H, m), 7.08 to 7.27 (9H, m), 6.91 (1H, m), 6.78 (1H, brs), 6.66 (1H, d, J = 8Hz), 5.55 (1H, s), 3.42 to 4.42 (1H, m), 3.40 (2H, s), 2.88 (1H, m), 2.74 (1H, m), 1.92 to 2.12 (3H, m), 1.38 to 1.64 (3H, m) .
Melting point: 233-234 ° C (recrystallization solvent: ethanol)
Production Example 58
3- [1- (3-Nitrobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 8.19 (1H, d, J = 2Hz), 8.08 (1H, m), 7.61 (1H, d, J = 8Hz), 7.39 to 7.48 (3H, m), 7.09 to 7.31 (5H, m), 6.88 to 6.94 (1H, m), 6.68 (1H, m), 5.57 (1H, s), 4.34 to 4.45 (1H, m), 3.53 (2H, s), 2.89 (1H, m), 2.75 (1H, m), 1.96-2.19 (3H, m), 1.44 (3H, m).
Melting point: 213-214.5 ° C (recrystallization solvent: ethanol)
Production Example 59
3- [1- (3-Methylbenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.37 (2H, m), 7.04 to 7.28 (8H, m), 6.87 to 6.96 (2H, m), 6.66 (1H, d, J = 8Hz), 5.56 (1H, s), 4.37 (1H, m), 3.41 (2H, s), 2.93 (1H, m), 2.77 (1H, m), 2.32 (3H, s), 1.92 to 2.08 (3H, m), 1.39 to 1.61 (3H, m).
Melting point: 190-191 ° C (recrystallization solvent: ethanol)
Production Example 60
3- [1- (3-Hydroxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
Hydrochloride
1H NMR (DMSO-d6) δ; 9.37 (1H, brs), 9.25 (1H, brs), 7.39 to 7.43 (2H, m), 7.26 to 7.31 (3H, m), 7.15 to 7.21 (1H, m), 7.02 to 7.09 (2H, m), 6.76-6.84 (2H, m), 6.59-6.66 (3H, m), 5.76 (1H, s), 4.12 (1H, m), 3.29 (2H, s), 2.82 (1H, m), 2.69 (1H, m), 1.86 to 2.04 (3H, m), 1.35 to 1.43 (3H, m).
Melting point; 222.5-224 ° C (recrystallization solvent: ethanol)
[0046]
Production Example 61
3- [1- (3-Cyanobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.96 (1H, s), 7.63 (1H, s), 7.48 to 7.54 (2H, m), 7.35 to 7.43 (3H, m), 7.09 to 7.30 (5H, m), 6.87 to 6.93 (1H, m), 6.75 (1H, d, J = 8Hz), 5.57 (1H, s), 4.35 to 4.45 (1H, m), 3.46 (2H, s), 2.87 (1H, m), 2.73 (1H, m) , 1.96-2.17 (3H, m), 1.41-1.65 (3H, m).
Hydrochloride
Melting point: 226-227.5 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 62
3- [1- (3-Ethylbenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.36 to 7.39 (2H, m), 7.06 to 7.29 (9H, m), 6.88 to 6.94 (1H, m), 6.75 (1H, s), 6.65 (1H, d, J = 8Hz), 5.57 ( 1H, s), 4.40 (1H, m), 3.49 (2H, s), 2.94 (1H, m), 2.78 (1H, m), 2.62 (2H, q, J = 7.6Hz), 1.93 to 2.08 (3H , m), 1.42 to 1.64 (3H, m), 1.22 (3H, t, J = 7.6Hz).
Hydrochloride
Melting point: 175-179 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 63
3- [1- (3-Methylthiobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.39 (2H, d, J = 7Hz), 7.02 to 7.28 (9H, m), 6.87 to 6.92 (1H, m), 6.69 to 6.90 (1H, m), 5.56 (1H, s), 4.39 ( 1H, m), 3.42 (2H, s), 2.91 (1H, m), 2.78 (1H, m), 2.47 (3H, s), 1.95 to 2.03 (3H, m), 1.51 to 1.64 (3H, m) .
Melting point: 188-189 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 64
3- [1- (3-Hydroxymethylbenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.08 to 7.40 (11H, m), 6.91 (1H, m), 6.81 (1H, s), 6.65 (1H, d, J = 7Hz), 5.56 (1H, s), 4.68 (2H, s) , 4.38 (1H, m), 3.45 (2H, s), 2.92 (1H, m), 2.77 (1H, m), 1.93 to 2.09 (3H, m), 1.46 to 1.68 (3H, m).
Hydrochloride
Melting point: 174-177 ° C (recrystallization solvent: diethyl ether / ethanol)
[0047]
Production Example 65
3- [1- (3-Fluorobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.58 (1H, brs), 7.38 to 7.41 (2H, m), 7.01 to 7.30 (8H, m), 6.87 to 6.95 (2H, m), 6.72 (1H, d, J = 8Hz), 5.56 ( 1H, s), 4.40 (1H, m), 3.44 (2H, s), 2.91 (1H, d, J = 8Hz), 2.77 (1H, m), 1.95 to 2.14 (3H, m), 1.43 to 1.65 ( 3H, m).
Melting point; 202-203 ° C (recrystallization solvent: ethanol)
Production Example 66
3- [1- (3,4-Methylenedioxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.36 to 7.40 (2H, m), 7.08 to 7.29 (4H, m), 6.87 to 6.93 (2H, m), 6.80 (1H, s), 6.65 to 6.73 (3H, m), 5.93 (2H, s), 5.56 (1H, s), 4.38 (1H, m), 3.35 (2H, s), 2.91 (1H, m), 2.78 (1H, m), 1.91 to 2.06 (3H, m), 1.39 to 1.64 (3H, m).
Melting point: 209-210 ° C (recrystallization solvent: ethanol)
Production Example 67
3- [1- (3-Ethoxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 8.15 (1H, brs), 7.37 to 7.41 (2H, m), 7.07 to 7.28 (6H, m), 6.73 to 6.92 (5H, m), 5.56 (1H, s), 4.40 (1H, m) , 4.01 (2H, q, J = 7Hz), 3.42 (2H, s), 2.93 (1H, m), 2.79 (1H, m), 1.94 to 2.09 (3H, m), 1.48 to 1.63 (3H, m) , 1.40 (3H, t, J = 7Hz).
Hydrochloride
Melting point: 170-173 ° C (recrystallization solvent: ethanol)
Production Example 68
3- [1- (3-Isopropoxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.37 to 7.40 (2H, m), 7.08 to 7.29 (6H, m), 6.64 to 6.94 (6H, m), 5.56 (1H, s), 4.54 (1H, m), 4.38 (1H, m) , 3.41 (2H, s), 2.93 (1H, m), 2.74 (1H, m), 1.94 to 2.12 (3H, m), 1.49 to 1.64 (3H, m), 1.33 (3H, d, J = 6.3Hz ), 1.32 (3H, d, J = 6.3Hz). Hydrochloride
Melting point; 204-206 ° C (recrystallization solvent: ethanol)
Production Example 69
3- [1- (2-Methoxyethyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
1H NMR (CDClThree) δ; 7.53 (1H, brs), 7.36 to 7.39 (2H, m), 7.08 to 7.29 (5H, m), 6.90 (1H, m), 6.71 (1H, m), 5.57 (1H, s), 4.39 ~ 4.50 (1H, m), 3.40 ~ 3.55 (4H, m), 3.32 (3H, s), 3.00 ~ 3.06 (1H, m), 2.85 ~ 2.90 (1H, m), 2.53 (2H, m), 1.95 ~ 2.17 (3H, m).
Hydrochloride
Melting point; 102-104 ° C (recrystallization solvent: acetone)
[0048]
Production Example 70
Synthesis of 3- [1- (3-aminobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
To a solution of 3- [1- (3-nitrobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 540 mg (1.22 mmol) in 50 mL of ethanol, Tin dihydrate 826 mg (3.66 mmol) was added, and the mixture was stirred at 60 ° C. for 12 hours. After cooling, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: chloroform 1:19) to obtain 210 mg (0.51 mmol) of the title compound.
1H NMR (CDClThree) δ; 7.36 to 7.40 (2H, m), 7.04 to 7.29 (6H, m), 6.88 to 6.94 (2H, m), 6.63 to 6.67 (2H, m), 6.54 to 6.58 (1H, m), 5.56 ( 1H, s), 4.40 (1H, m), 3.62 (2H, br), 3.37 (2H, s), 2.95 (1H, m), 2.81 (1H, m), 1.95 to 2.13 (3H, m), 1.50 ~ 1.63 (3H, m).
Hydrochloride
Melting point: 247-249 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 71
Synthesis of 3- [1- (3-methanesulfonamidobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
Methanesulfonic anhydride in a solution of 3- [1- (3-aminobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 200 mg (0.48 mmol) in
1H NMR (CDClThree) δ; 7.57 (1H, s), 7.08 to 7.38 (11H, m), 6.86 to 6.92 (1H, m), 6.72 (1H, dd, J = 8, 1Hz), 5.53 (1H, s), 4.31 ( 1H, m), 3.47 (1H, d, J = 13Hz), 3.40 (1H, d, J = 13Hz), 3.03 (3H, s), 2.93 (1H, m), 2.82 (1H, m), 1.98 to 2.08 (3H, m), 1.46 to 1.57 (3H, m).
Hydrochloride
Melting point: 219.5-222.5 ° C (recrystallization solvent: diethyl ether / ethanol)
[0049]
Production Example 72
Synthesis of 3- [1- (3-acetylaminobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
To a solution of 3- [1- (3-aminobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 200 mg (0.48 mmol) in
1H NMR (CDClThree) δ; 7.45 (1H, m), 7.36 to 7.40 (3H, m), 6.87 to 7.29 (10H, m), 6.66 (1H, d, J = 8Hz), 5.55 (1H, s), 4.31 (1H, s), 3.43 (2H, s), 2.91 (1H, m), 2.78 (1H, m), 2.17 (3H, s), 1.93 to 2.11 (3H, m), 1.45 to 1.61 (3H, m).
Hydrochloride
Melting point: 192-195 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 73
Synthesis of 3- [1- (3-dimethylaminobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
3- [1- (3-Aminobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 200 mg (0.48 mmol) in methanol (20 mL) Formalin 415 mg (4.85 mmol) and sodium cyanoborohydride 243 mg (3.88 mmol) were added at ° C. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure. Water was added to the residue, pH was adjusted to 10 with aqueous ammonia, and the mixture was extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, aqueous ammonia: methanol: chloroform 1: 9: 90) to obtain 210 mg (0.47 mmol) of the title compound.
1H NMR (CDClThree) δ; 7.37-7.40 (2H, m), 7.07-7.29 (7H, m), 6.87-6.93 (3H, m), 6.60-6.69 (4H, m), 5.57 (1H, s), 4.39 (1H, m), 3.42 (2H, s), 2.90 (1H, m), 2.93 (6H, s), 2.80 (1H, m), 1.94 to 2.13 (3H, m), 1.43 to 1.60 (3H, m).
Oxalate
Melting point: 264.5-266 ° C (recrystallization solvent: ethanol)
[0050]
Production Example 74
Synthesis of 3- [1- (3-methoxycarbonylbenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
(A) Synthesis of 3- [1- (3-benzyloxycarbonylbenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 36, the title was obtained from 3- (piperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone hydrochloride 700 (2.03 mmol) and 3-benzyloxycarbonylbenzaldehyde. Obtained 1012 mg (1.90 mmol) of the compound.
1H NMR (CDClThree) δ; 7.93 to 7.96 (2H, m), 7.08 to 7.50 (14H, m), 6.87 to 6.93 (1H, m), 6.67 (1H, d, J = 8Hz), 5.55 (1H, s), 5.36 ( 2H, s), 4.39 (1H, m), 3.48 (2H, s), 2.90 (1H, m), 2.83 (1H, m), 2.01 to 2.13 (3H, m), 1.41 to 1.61 (3H, m) .
(B) Synthesis of 3- [1- (3-methoxycarbonylbenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
To a solution of 3- [1- (3-benzyloxycarbonylbenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 300 mg (0.56 mmol) in
1H NMR (CDClThree) δ; 7.89 to 7.94 (3H, m), 7.08 to 7.50 (8H, m), 6.88 to 6.93 (1H, m), 6.77 (1H, m), 5.56 (1H, s), 4.40 (1H, m) , 3.91 (3H, s), 3.49 (2H, s), 2.92 (1H, m), 2.78 (1H, m), 2.01 to 2.12 (3H, m), 1.52 to 1.65 (3H, m).
Hydrochloride
Melting point: 190-191 ° C (recrystallization solvent: diethyl ether / ethanol)
[0051]
Production Example 75
Synthesis of 3- [1- (3-carboxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
To a solution of 3- [1- (3-benzyloxycarbonylbenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone in 700 mg (1.32 mmol) in acetic acid, 10% palladium -50 mg of carbon was added and stirred at room temperature for 5 hours under a hydrogen atmosphere. Celite filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol to obtain 450 mg (1.02 mmol) of the title compound.1H NMR (DMSO-d6) δ; 9.37 (1H, s), 7.79 to 7.83 (2H, m), 7.15 to 7.50 (8H, m), 7.02 to 7.08 (1H, m), 6.75 to 6.84 (2H, m), 5.80 (1H, s), 4.15 (1H, m), 3.46 (2H, s), 2.68 to 2.84 (2H, m), 1.91 to 2.09 (3H, m), 1.35 to 1.43 (3H, m).
Melting point: 250 ° C or higher (recrystallization solvent: ethanol)
Production Example 76
Synthesis of 3- [1- (3-carbamoylbenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
Chlorination of 3- [1- (3-carboxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 220 mg (0.50 mmol), triethylamine 111 mg (1.1 mmol) A solution of thionyl chloride 65 mg (0.55 mmol) in methylene chloride 5 mL was added to a methylene 50 mL solution, and the mixture was stirred at room temperature for 1 hour. Ammonia gas was passed through the reaction solution for 5 minutes and then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 210 mg (0.48 mmol) of the title compound.
1H NMR (CDClThree) δ; 7.77 (1H, s), 7.66 to 7.70 (1H, m), 7.09 to 7.46 (10H, m), 6.88 to 6.94 (1H, m), 6.69 (1H, d, J = 8Hz), 6.15 ( 1H, br), 5.80 (1H, br), 5.56 (1H, s), 4.33 (1H, m), 3.49 (2H, s), 2.90 (1H, m), 2.77 (1H, m), 1.96 to 2.14 (3H, m), 1.52-1.62 (3H, m)
Hydrochloride salt.
Melting point: 202-205 ° C (recrystallization solvent: diethyl ether / ethanol)
[0052]
Production Example 77
Synthesis of 3- [1- (3-acetoxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
3- [1- (3-hydroxybenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone In a solution of 207 mg (0.5 mmol) in pyridine 3 mL, acetic anhydride 61 mg (0.6 mmol) was added and stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 187 mg (0.41 mmol) of the title compound.
1H NMR (CDClThree) δ; 7.37 to 7.39 (3H, m), 6.83 to 7.32 (10H, m), 6.66 (1H, d, J = 8Hz), 5.55 (1H, s), 4.36 (1H, m), 3.44 (2H, m), 2.88 (1H, m), 2.78 (1H, m), 2.29 (3H, s), 1.90 to 2.08 (3H, m), 1.41 to 1.58 (3H, m).
Hydrochloride
Melting point: 171-173 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 78
Synthesis of 3- [1- (3-methylsulfinylbenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
480 mg (1 mmol) of 3- [1- (3-methylthiobenzyl) piperidin-4-yl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone hydrochloride dissolved in 10 mL of methylene chloride Then, 190 mg (1.1 mmol) of m-chloroperbenzoic acid was added at 0 to 10 ° C. After stirring at room temperature for 10 hours, water was added, and the pH was adjusted to 10 with aqueous ammonia, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 440 mg (0.96 mmol) of the title compound as a mixture of about 1: 1 diastereomers.
1H NMR (CDClThree) δ; 8.41 (1H, s), 7.61 (1H, s), 7.39 to 7.50 (5H, m), 7.08 to 7.28 (5H, m), 6.86 to 6.91 (1H, m), 6.78 (1H, d, J = 8Hz), 5.56 (1H, s), 4.39 (1H, m), 3.51 (2H, s), 2.88 (1H, m), 2.73 (1H, m), 2.71 (1.5H, s), 2.72 ( 1.5H, s), 2.03 to 2.12 (3H, m), 1.51 to 1.64 (3H, m).
Hydrochloride
Melting point: 198-202 ° C (recrystallization solvent: diethyl ether / ethanol)
[0053]
Production Example 79
Synthesis of 3- (1-carboxymethylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
3- (1-Ethoxycarbonylmethylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone hydrochloride 191 mg (0.445 mmol) was dissolved in 4N hydrochloric acid 30 mL. Heated to reflux for hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, 30 mL of toluene was added to the residue, and the mixture was again concentrated under reduced pressure to obtain yellow crystals. This was recrystallized from diethyl ether / ethanol to obtain 56 mg (0.14 mmol) of hydrochloride of the title compound.
Hydrochloride
1H NMR (DMSO-d6) δ; 9.83 to 10.13 (1H, brs), 9.55 (1H, s), 7.18 to 7.48 (6H, m), 7.03 to 7.15 (1H, m), 6.75 to 6.90 (2H, m), 5.67 (1H, s), 4.17 to 4.35 (1H, m), 3.93 to 4.13 (2H, brs), 2.87 to 3.90 (5H, m), 1.49 to 1.99 (3H, m).
Melting point; 230-236 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 80
Synthesis of 3- (1-carbamoylmethylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
3- (1-Ethoxycarbonylmethylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 200 mg (0.508 mmol) dissolved in ammonia / methanol (6.09 M, 30 mL) The mixture was stirred at about 150 ° C. for 6 hours in an autoclave. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 167 mg (0.45 mmol) of the title compound.
Hydrochloride
1H NMR (DMSO-d6) δ; 9.40 (1H, s), 6.95 to 7.50 (7H, m), 6.73 to 6.90 (2H, m), 5.74 (1H, s), 4.00 to 4.20 (1H, m), 2.60 to 2.90 (2H, m), 2.78 (2H, s), 1.92 to 2.18 (3H, m), 1.20 to 1.55 (3H, m).
Melting point: 208-220 ° C (recrystallization solvent: diethyl ether / ethanol)
[0054]
Production Example 81
Synthesis of 3- [1- (3-methoxybenzyl) piperidin-4-yl] -4- (3-hydroxyphenyl) -3,4-dihydro-2 (1H) -quinazolinone
(A) Synthesis of 3- [1- (3-methoxybenzyl) piperidin-4-yl] -4- (3-benzyloxyphenyl) -3,4-dihydro-2 (1H) -quinazolinone
In the same manner as in Production Example 24, the title compound was synthesized from 2-amino-3′-benzyloxybenzophenone and 4-amino-1- (3-methoxybenzyl) piperidine.
1H NMR (CDClThree) δ; 6.60 to 7.41 (17H, m), 5.50 (1H, s), 5.01 (2H, s), 4.38 (1H, m), 3.79 (3H, s), 3.43 (2H, s), 2.92 (1H , m), 2.78 (1H, m), 1.77 to 2.12 (3H, m), 1.47 to 1.63 (3H, m).
(B) Synthesis of 3- [1- (3-methoxybenzyl) piperidin-4-yl] -4- (3-hydroxyphenyl) -3,4-dihydro-2 (1H) -quinazolinone
3- [1- (3-methoxybenzyl) piperidin-4-yl] -4- (3-benzyloxyphenyl) -3,4-dihydro-2 (1H) -quinazolinone 1.3 g (2.44 mmol) in methanol 100 mL To the solution was added ammonium formate 504 mg (8 mmol), 10% palladium-carbon 50 mg, and the mixture was heated to reflux for 8 hours. The mixture was allowed to cool and then filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 50 mL of methanol, m-anisaldehyde 1.33 g (9.76 mmol) and sodium cyanoborohydride 613 mg (9.76 mmol) were added at 5 to 10 ° C., and the mixture was stirred at room temperature for 12 hours. After concentration under reduced pressure, water was added, the pH was adjusted to 10 with aqueous ammonia, and the mixture was extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 810 mg (1.83 mmol) of the title compound.1H NMR (DMSO-d6) δ; 9.39 (1H, s), 9.33 (1H, s), 7.23 to 7.26 (2H, m), 7.03 to 7.08 (2H, m), 6.75 to 6.86 (7H, m), 6.55 (1H, m) , 5.65 (1H, s), 4.09 (1H, m), 3.72 (3H, s), 3.36 (2H, s), 2.83 (1H, m), 2.71 (1H, m), 1.88 to 2.09 (3H, m ), 1.39 (3H, br).
Melting point: 250 ° C or higher (recrystallization solvent: ethanol)
Citrate
Melting point: 130-132 ° C (recrystallization solvent: diethyl ether / ethanol)
[0055]
Production Example 82
Synthesis of 3- (1-benzylpiperidin-4-yl) -6-chloro-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
The title compound was synthesized from 5-chloro-2-trichloroacetylaminobenzophenone and 4-amino-1-benzylpiperidine in the same manner as in Production Example 24.
1H NMR (CDClThree) δ; 7.19-7.38 (10H, m), 7.13 (1H, s), 7.11 (1H, d, J = 8.3Hz), 6.62 (1H, d, J = 8.3Hz), 5.50 (1H, s), 4.35 (1H, m), 3.45 (2H, s), 2.93 (1H, d, J = 10.6Hz), 2.78 (1H, d, J = 11.6Hz), 1.93 to 2.09 (3H, m), 1.40 to 1.63 (3H, m).
Melting point: 230 ° C or higher (recrystallization solvent: ethanol)
Hydrochloride
Melting point: 162-165 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 83
Synthesis of 3- [2- (diethylamino) ethyl] -6-nitro-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
The title compound was synthesized from 5-nitro-2-trichloroacetylaminobenzophenone and 2- (diethylamino) ethylamine in the same manner as in Production Example 1.
1H NMR (CDClThree) δ; 8.85 (1H, brs), 8.04 (1H, dd, J = 8.9, 2.3Hz), 7.90 (1H, d, J = 2.3Hz), 7.34-7.38 (5H, m), 6.85 (1H, d , J = 8.9Hz), 5.85 (1H, s), 3.80 to 3.90 (5H, m), 2.96 to 3.07 (1H, m), 2.68 to 2.78 (1H, m), 2.44 to 2.60 (5H, m), 0.99 (6H, t, J = 7.3Hz).
Melting point; 161-163 ° C (recrystallization solvent: ethanol)
Production Example 84
Synthesis of 6-amino-3- [2- (diethylamino) ethyl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone
The title compound was synthesized from 3- [2- (diethylamino) ethyl] -6-nitro-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone in the same manner as in Production Example 70.
1H NMR (CDClThree) δ; 7.24 ~ 7.34 (5H, m), 6.54 (1H, d, J = 8.3Hz), 6.48 (1H, dd, J = 8.3, 2.3Hz), 6.31 (1H, d, J = 2.3), 5.54 (1H, s), 3.74 to 3.84 (1H, m), 3.38 (2H, brs), 2.95 to 3.05 (1H, m), 2.65 to 2.75 (1H, m), 2.36 to 2.58 (5H, m), 0.99 (6H, t, J = 7.3Hz).
Hydrochloride
Melting point: 242-244 ° C (recrystallization solvent: diethyl ether / ethanol)
[0056]
Production Example 85
Synthesis of 3- [2- (diethylamino) ethyl] -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine
(A) Synthesis of 3-benzoyl-2-trichloroacetylaminopyridine
To a 200 mL tetrahydrofuran solution of 11.0 g (55 mmol) of 2-amino-3-benzoylpyridine and 6.1 g (60 mmol) of triethylamine, 10.0 g (55 mmol) of trichloroacetyl chloride was added dropwise at 5 to 15 ° C. After stirring at room temperature for 3 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl alcohol to obtain 14.0 g (40 mmol) of the title compound.
1H NMR (CDClThree) δ; 8.73 ~ 8.75 (1H, m), 7.99 ~ 8.02 (1H, m), 7.71 ~ 7.77 (2H, m), 7.62 ~ 7.68 (1H, m), 7.42 ~ 7.56 (2H, m), 7.23 ~ 7.28 (1H, m).
(B) Synthesis of 3- [2- (diethylamino) ethyl] -4-phenyl-4-trichloromethyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine
To a 50 mL solution of 3-benzoyl-2-trichloroacetylaminopyridine 1.4 g (4.07 mmol) in dimethyl sulfoxide, 0.52 g (4.5 mmol) of 2- (diethylamino) ethylamine was added and stirred at room temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 240 mg (0.54 mmol) of the title compound.
1H NMR (CDClThree) δ; 9.42 (1H, brd), 8.33 to 8.38 (2H, m), 7.31 to 7.46 (3H, m), 7.13 to 7.19 (2H, m), 6.83 (1H, dd, J = 7.9, 4.9Hz) , 3.89 to 4.00 (1H, m), 3.15 to 3.26 (1H, m), 2.75 to 2.85 (1H, m), 2.20 to 2.34 (4H, m), 1.92 to 2.02 (1H, m), 0.79 (6H, t, J = 7.3Hz).
(C) Synthesis of 3- [2- (diethylamino) ethyl] -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine
Of 240 mg (0.54 mmol) of 3- [2- (diethylamino) ethyl] -4-phenyl-4-trichloromethyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine 82 mg (2.16 mmol) of sodium borohydride was added to a dimethylformamide 10 mL solution at 5 to 15 ° C. After stirring at room temperature for 3 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 110 mg (0.34 mmol) of the title compound.
Melting point; 160-162.5 ℃
1H NMR (CDClThree) δ; 8.14 (1H, dd, J = 5.0, 1.7Hz), 7.78 (1H, brs), 7.31 to 7.39 (5H, m), 7.25 to 7.28 (1H, m), 6.82 (1H, dd, J = 7.6, 5.0Hz), 5.75 (1H, s), 3.77 to 3.87 (1H, m), 2.99 to 3.03 (1H, m), 2.69 to 2.79 (1H, m), 2.42 to 2.60 (5H, m), 0.99 (6H, t, J = 7.3Hz).
[0057]
Production Example 86
Synthesis of 3- [2- (diethylamino) ethyl] -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine
The title compound was synthesized from 3-amino-4-benzoylpyridine and 2- (diethylamino) ethylamine in the same manner as in Production Example 85.
Melting point: 138-140.5 ° C (recrystallization solvent: ethyl acetate)
1H NMR (CDClThree) δ; 8.11 (1H, s), 8.11 (1H, d, J = 5.0Hz), 7.68 (1H, brds), 7.30-7.36 (5H, m), 6.86 (1H, d, J = 5.0Hz), 5.76 (1H, s), 3.77 to 3.87 (1H, m), 2.97 to 3.08 (1H, m), 2.66 to 2.78 (1H, m), 2.41 to 2.59 (5H, m), 0.99 (6H, t, J = 7.3Hz).
Production Example 87
Synthesis of 3- [2- (diethylamino) ethyl] -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine
In the same manner as in Production Example 85, the title compound was synthesized from 4-amino-3-benzoylpyridine and 2- (diethylamino) ethylamine.
Melting point; 132.5-134 ° C (recrystallization solvent: diethyl ether / ethanol)
1H NMR (CDClThree) δ; 8.26 (1H, d, J = 5.3Hz), 8.16 (1H, s), 7.30 to 7.36 (5H, m), 6.63 (1H, d, J = 5.3Hz), 5.80 (1H, s), 3.81 to 3.89 (1H, m), 2.97 to 3.09 (1H, m), 2.73 to 2.76 (1H, m), 2.44 to 2.60 (5H, m), 0.99 (6H, t, J = 7.3Hz).
Hydrochloride: melting point; 230 ° C or higher (recrystallization solvent: diethyl ether / ethanol)
Production Example 88
Synthesis of 3- [2- (diethylamino) ethyl] -4- (3-methoxy) phenyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine
In the same manner as in Production Example 85, the title compound was synthesized from 2-amino-3- (3-methoxybenzoyl) pyridine and 2- (diethylamino) ethylamine.
Melting point; 162.5-164 ℃ (recrystallization solvent: diethyl ether)
1H NMR (CDClThree) δ; 8.15 (1H, dd, J = 4.9 and 1.6Hz), 7.88 (1H, brs), 7.23 to 7.29 (2H, m), 6.92 (1H, dd, J = 8.9, 1.0Hz), 6.80 to 6.86 (3H, m), 5.72 (1H, s), 3.78 to 3.87 (1H, m), 3.78 (3H, s), 2.91 to 3.02 (1H, m), 2.67 to 2.77 (1H, m), 2.38 to 2.60 (5H, m), 0.97 (6H, t, J = 7.3Hz).
[0058]
Production Example 89
Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine
(A) Synthesis of 3- [α-{(1-benzylpiperidin-4-yl) imino} benzyl] -4-trichloroacetylaminopyridine
4-Amino-1-benzylpiperidine (13.0 g, 68 mmol) was added to a solution of 3-benzoyl-4-trichloroacetylaminopyridine (19.6 g, 57 mmol) in dimethyl sulfoxide (100 mL), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (silica gel, ethyl acetate: hexane 1: 1) and recrystallization from ethyl acetate gave 18.5 g (35.9 mmol) of the title compound.
Melting point; 152-154 ℃ (decomposition)
1H NMR (CDClThree) δ; 8.60 (1H, d, J = 5.9Hz), 8.52 (1H, d, J = 5.9Hz), 8.07 (1H, s), 7.51 to 7.53 (3H, m), 7.27 to 7.32 (5H, m ), 7.14 to 7.18 (2H, m), 3.44 (2H, s), 3.14 to 3.22 (1H, m), 2.87 (2H, m), 1.96 to 2.08 (2H, m), 1.52 to 1.83 (4H, m ).
(B) Synthesis of 3- [α-{(1-benzylpiperidin-4-yl) amino} benzyl] -4-aminopyridine
3- [α-{(1-Benzylpiperidin-4-yl) imino} benzyl] -4-trichloroacetylaminopyridine 16.5 g (34.9 mol) in ethanol 150 mL solution under ice-cooling sodium borohydride 2.65 g (70 mmol) was added and stirred at room temperature for 5 hours. The reaction solution was poured into water, and ethanol was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (silica gel, methanol: chloroform 1: 9) gave 4.82 g (12.9 mmol) of the title compound, and 3- [α-[(1-benzylpiperidin-4-yl) imino] benzyl]- 6.65 g (17.9 mmol) of 4-aminopyridine was obtained.
A suspension of 0.68 g (17.9 mmol) of lithium aluminum hydride in 100 mL of tetrahydrofuran was heated to reflux with 3- [α-{(1-benzylpiperidin-4-yl) imino] benzyl] -4-aminopyridine 6.65 g. A 30 mL solution of (17.9 mmol) in tetrahydrofuran was added dropwise, and the mixture was heated to reflux for 1 hour. After standing to cool, 0.7 mL of water, 0.7 mL of 15% aqueous sodium hydroxide solution and 2 mL of water were sequentially added under ice-cooling, and the mixture was stirred at room temperature for 1 hour and filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 4.2 g (11.3 mmol) of the title compound.
1H NMR (CDClThree) δ; 8.06 (1H, d, J = 5.6Hz), 7.98 (1H, s), 7.24 to 7.35 (10H, m), 6.42 (1H, d, J = 5.6Hz), 5.59 (2H, brs), 5.08 (1H, s), 3.48 (2H, s), 2.82 (1H, m), 2.45 (1H, m), 1.86 to 2.00 (4H, m), 1.36 to 1.54 (2H, m).
3- [α-{(1-Benzylpiperidin-4-yl) imino} benzyl] -4-aminopyridine
1H NMR (CDClThree) δ; 7.80 (1H, d, J = 5.6Hz), 7.74 (1H, s), 7.43 to 7.46 (3H, m), 7.22 to 7.33 (5H, m), 7.11 to 7.14 (2H, m), 6.49 (1H, d, J = 5.6Hz), 3.47 (2H, s), 3.15 to 3.22 (1H, m), 2.77 to 2.81 (2H, m), 1.95 to 2.02 (2H, m), 1.73 to 1.87 (2H , m), 1.63 to 1.67 (2H, m).
(C) Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine
3- [α-{(1-Benzylpiperidin-4-yl) amino} benzyl] -4-aminopyridine 5.0 g (3.1 mmol) in a solution of 8.0 g (21.5 mmol) in 100 mL of tetrahydrofuran ) Was added and heated to reflux for 8 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9). The obtained crude crystals were recrystallized from diethyl ether / ethanol to obtain 4.2 g (10.5 mmol) of the title compound.
Melting point: 209-210 ° C (recrystallization solvent: diethyl ether / ethanol)
1H NMR (CDClThree) δ; 8.35 (1H, s), 8.26 (1H, d, J = 5.6Hz), 8.09 (1H, brs), 7.20-7.38 (10H, m), 6.65 (1H, d, J = 5.6Hz), 5.64 (1H, s), 4.36 (1H, m), 2.96 (1H, m), 2.80 (1H, m), 2.00 to 2.10 (3H, m), 1.50 to 1.65 (3H, m).
Hydrochloride: melting point; 230 ° C or higher (recrystallization solvent: diethyl ether / ethanol)
[0059]
Production Example 90
Synthesis of 3- (piperidin-4-yl) -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine
In the same manner as in Production Example 89, the title compound was synthesized from 3-benzoyl-2-trichloroacetylaminopyridine and 4-amino-1-benzylpiperidine.
1H NMR (CDClThree) δ; 8.74 (1H, s), 8.19 (1H, dd, J = 5.0, 1.7Hz), 7.19 to 7.46 (11H, m), 6.85 (1H, dd, J = 7.6, 5.0Hz), 5.55 (1H , s), 4.40 (1H, m), 3.44 (2H, s), 2.93 (1H, d, J = 8.3Hz), 2.78 (1H, d, J = 11.6Hz), 1.94 to 2.08 (3H, m) , 1.39-1.75 (3H, m).
Hydrochloride: melting point; 186-189 ° C (recrystallization solvent: diethyl ether / ethanol)
Production Example 91
Synthesis of 3- (piperidin-4-yl) -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine
3- (1-Benzylpiperidin-4-yl) -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine 4.13 g (10.4 mmol) in methanol 250 mL To the solution, 1.89 g (30 mmol) of ammonium formate and 0.3 g of 10% palladium-carbon were added and heated under reflux for 5 hours. After cooling, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, aqueous ammonia: methanol: chloroform 10: 100: 900) to obtain 2.67 g (8.66 mmol) of the title compound.
1H NMR (CDClThree) δ; 9.53 (1H, brs), 8.31 (1H, s), 8.26 (1H, d, J = 5.3Hz), 7.22 to 7.41 (5H, m), 6.76 (1H, d, J = 5.3Hz), 5.65 (1H, s), 4.33 (1H, m), 3.17 (1H, d, J = 12.2Hz), 3.03 (1H, d, J = 12.5Hz), 2.58 to 2.74 (2H, m), 1.95 to 2.04 (1H, m), 1.64 (2H, d, J = 10.6Hz), 1.38 ~ 1.54 (1H, m).
Production Example 92
Synthesis of 3- (1-allylpiperidin-4-yl) -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine
To a 20 mL ethanol solution of 500 mg (1.62 mmol) 3- (piperidin-4-yl) -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine, Potassium carbonate 336 mg (2.43 mmol) and allyl bromide 235 mg (1.94 mmol) were sequentially added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 385 mg (1.10 mmol) of the title compound.
1H NMR (CDClThree) δ; 8.44 (1H, s), 8.32 (1H, s), 8.24 (1H, d, J = 5.3Hz), 7.21 to 7.38 (5H, m), 6.69 (1H, d, J = 5.3Hz), 5.77 to 5.87 (1H, m), 5.64 (1H, s), 5.16 (1H, d, J = 7.9Hz), 5.11 (1H, d, J = 1.0Hz), 4.38 (1H, m), 2.80 to 3.02 (3H, m), 1.91 to 2.08 (3H, m), 1.52 to 1.70 (3H, m).
Hydrochloride: melting point; 155-158 ° C (recrystallization solvent: diethyl ether / ethanol)
[0060]
Production Example 93
Synthesis of 3- [1- (3-thienylmethyl) piperidin-4-yl] -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine
To a 30 mL methanol solution of 500 mg (1.62 mmol) 3- (piperidin-4-yl) -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine, Under ice cooling, 1200 mg of a 10% hydrochloric acid / ethanol solution, 727 mg (6.48 mmol) of 3-thiophenecarboxaldehyde, and 407 mg (6.48 mmol) of sodium cyanoborohydride were added. After stirring at room temperature for 10 hours, the reaction solution was concentrated under reduced pressure. Water was added to the residue, and the pH was adjusted to 10 with aqueous ammonia, followed by extraction with chloroform. The organic layer was dried over potassium carbonate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9) to obtain 550 mg (1.36 mmol) of the title compound.
1H NMR (CDClThree) δ; 8.93 (1H, s), 8.34 (1H, s), 8.27 (1H, d, J = 5.3Hz), 7.20 to 7.39 (6H, m), 7.07 (1H, m), 7.01 (1H, dd) , J = 5.0 and 1.3Hz), 6.70 (1H, d, J = 5.3Hz), 5.64 (1H, s), 4.35 (1H, m), 3.50 (2H, s), 2.97 (1H, d, J = 6.9Hz), 2.82 (1H, d, J = 10.9Hz), 1.93 to 2.14 (3H, m), 1.47 to 1.66 (3H, m).
Hydrochloride: melting point; 230 ° C or higher (recrystallization solvent: diethyl ether / ethanol)
Production Example 94
Synthesis of 3- [1- (3-methoxybenzyl) piperidin-4-yl] -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine
In the same manner as in Production Example 93, 3- (piperidin-4-yl) -4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido [4,3-d] pyrimidine and 3-methoxybenzaldehyde The title compound was synthesized from
1H NMR (CDClThree) δ; 8.40 (1H, brs), 8.35 (1H, s), 8.24 (1H, d, J = 5.3Hz), 7.18 to 7.39 (6H, m), 6.76 to 6.84 (3H, m), 6.67 (1H , d, J = 5.3Hz), 5.64 (1H, s), 4.35 (1H, m), 3.80 (3H, s), 3.53 (2H, s), 2.96 (1H, m), 2.81 (1H, m) .
Hydrochloride: melting point; 230 ° C or higher (recrystallization solvent: diethyl ether / ethanol)
[0061]
Production Example 95
Synthesis of 3- [2- (diethylamino) ethyl] -5-methyl-4-phenyl-2-oxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine
In the same manner as in Production Example 85, the title compound was synthesized from 2-amino-3-benzoyl-4-methylthiophene and 2- (diethylamino) ethylamine.
1H NMR (CDClThree) δ; 7.56 (1H, brs), 7.28 to 7.34 (5H, m), 6.18 (1H, d, J = 1.0Hz), 5.49 (1H, s), 3.56 to 3.66 (1H, m), 3.05 to 3.15 (1H, m), 2.64 to 2.74 (1H, m), 2.46 to 2.60 (4H, m), 2.31 to 2.41 (2H, m), 1.83 (3H, d, J = 1.0Hz),
1.00 (6H, t, J = 7.3Hz).
Production Example 96
Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-cis-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone
(A) Synthesis of 4,5-cis-4-methoxycarbonylamino-5- (α-hydroxybenzyl) cyclohexene
To a solution of 4,5-cis-4-methoxycarbonylamino-5-benzoylcyclohexene 500 mg (1.93 mmol) in methanol 10 mL was added sodium borohydride 162 mg (4.28 mmol) under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was poured into water, methanol was distilled off under reduced pressure, and the mixture was extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane: ethyl acetate 1: 1) to obtain 487 mg (1.87 mmol) of the title compound as dia Obtained as a mixture of stereomers. 35 mg of the above mixture was further separated and purified by column chromatography (silica gel, hexane: ethyl acetate 1: 1) to obtain 10 mg of diastereomer A and 25 mg of diastereomer B. Diastereomer A is a diastereomer having a larger Rf value in thin layer chromatography (developing solvent; hexane: ethyl acetate 1: 1), and diastereomer B is a diastereomer having a smaller Rf value.
Diastereomer A
1H NMR (CDClThree) δ; 7.18-7.36 (5H, m), 5.48-5.62 (2H, m), 5.03 (1H, dd, J = 3, 3Hz), 4.73 (1H, d, J = 9Hz), 4.28 (1H, d , J = 3Hz), 3.91 (1H, m), 3.73 (3H, m), 2.39 to 2.50 (1H, m), 2.19 to 2.32 (1H, m), 1.94 to 2.07 (1H, m), 1.71 to 1.82 (1H, m), 1.52-1.60 (1H, m).
Diastereomer B
1H NMR (CDClThree) δ; 7.23 to 7.36 (5H, m), 5.59 (2H, m), 5.10 (1H, d, J = 9Hz), 4.48 to 4.55 (2H, m), 4.21 (1H, dd, J = 10, 4Hz ), 3.74 (3H, s), 2.46 to 2.53 (1H, m), 2.13 to 2.20 (1H, m), 1.44 to 2.05 (1H, m), 1.50 to 1.73 (2H, m).
(B) Synthesis of 4,5-cis-4-methoxycarbonylamino-5- (α-chlorobenzyl) cyclohexene
Mixture of 4,5-cis-4-methoxycarbonylamino-5- (α-hydroxybenzyl) cyclohexene diastereomer in 415 mg (1.59 mmol) of 1,2-dichloroethane in 10 mL of carbon tetrachloride at room temperature 0.17 mL (1.76 mmol) and triphenylphosphine 512 mg (1.95 mmol) were added. The mixture was stirred at room temperature for 2 hours and then heated to reflux for 2 hours. 1,2-Dichloroethane was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, chloroform) to obtain 219 mg (0.78 mmol) of the title compound as a mixture of diastereomers.
1H NMR (CDClThree) δ; 7.20 ~ 7.41 (5H, m), 5.76 ~ 5.81 (1H, m), 5.58 ~ 5.67 (2H, m), 4.61 ~ 5.05 (2H, m), 3.60 ~ 3.71 (3H, m), 1.81 ~ 2.82 (5H, m).
(C) Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-cis-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone
To a solution of 4,5-cis-4-methoxycarbonylamino-5- (α-chlorobenzyl) cyclohexene 200 mg (0.72 mmol) in dimethylformamide 10 mL, 1.08 g (9.43 mmol) of 4-amino-1-benzylpiperidine, 1 mL of triethylamine was added and stirred at about 80 ° C. for 20 hours. Dimethylformamide was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was dried over potassium carbonate and then concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (silica gel, aqueous ammonia: methanol: chloroform 1:10:90) to obtain diastereomer A. 64 mg (0.16 mmol) and 112 mg (0.28 mmol) of diastereomer B were obtained. Diastereomer A is a diastereomer having a larger Rf value in thin layer chromatography (developing solvent; aqueous ammonia: methanol: chloroform 1:10:90), and diastereomer B is a diastereomer having a smaller Rf value. Ma.
Diastereomer A
1H NMR (CDClThree) δ; 7.21 ~ 7.36 (10H, m), 5.70 (1H, m), 5.56 (1H, m), 4.85 (1H, d, J = 5Hz), 4.64 (1H, d, J = 9Hz), 4.34 ( 1H, d, J = 8Hz), 3.99 (1H, m), 3.52 (1H, m), 3.47 (2H, s), 2.78 (2H, m), 2.24 to 2.34 (1H, m), 1.99 to 2.12 ( 6H, m), 1.89 (2H, m), 1.40 (2H, m).
Citrate
Melting point: 120-122 ° C (recrystallization solvent: isopropanol / ethyl acetate)
Diastereomer B
1H NMR (CDClThree) δ; 7.20-7.37 (10H, m), 5.52-5.77 (2H, m), 4.84 (1H, d, J = 5Hz), 4.76 (1H, d, J = 9Hz), 4.50 (1H, d, J = 8Hz), 3.81 to 4.01 (2H, m), 3.53 (1H, m), 3.48 (2H, s), 2.76 to 2.87 (2H, m), 1.87 to 2.33 (9H, m), 1.45 (2H, m ).
[0062]
Production Example 97
Synthesis of 3- (piperidin-4-yl) -4-phenyl-cis-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone
In the same manner as in Production Example 15, the title compound was obtained from 3- (1-benzylpiperidin-4-yl) -4-phenyl-cis-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone. Was synthesized.
1H NMR (CDClThree) δ; 7.23 ~ 7.34 (5H, m), 5.69 (1H, m), 5.56 (1H, m), 4.94 (1H, d, J = 9Hz), 4.80 (2H, m), 3.94 (1H, m) , 3.61 (1H, m), 2.99 (2H, m), 2.62 (2H, m), 1.88 to 2.32 (6H, m), 1.20 to 1.33 (2H, m).
Production Example 98
Synthesis of 3- (1-allylpiperidin-4-yl) -4-phenyl-cis-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone
In the same manner as in Production Example 31, the title compound was synthesized from 3- (piperidin-4-yl) -4-phenyl-cis-3,4,4a, 5,8,8-hexahydro-2 (1H) -quinazolinone.
1H NMR (CDClThree) δ; 7.14-7.29 (5H, m), 5.63-5.81 (2H, m), 5.49 (1H, m), 5.03-5.11 (3H, m), 4.65-4.79 (2H, m), 4.45 (1H, d, J = 8Hz), 3.93 (1H, m), 3.49 (2H, m), 2.85 (2H, d, J = 7Hz), 2.72 (2H, m), 1.65 to 2.27 (6H, m), 1.31 ( 2H, m).
Production Example 99
Synthesis of 3- [1- (3-thienylmethyl) piperidin-4-yl] -4-phenyl-cis-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone
3- (Piperidin-4-yl) -4-phenyl-cis-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone and 3-thiophenecarboxaldehyde as in Preparation Example 36 The title compound was synthesized from
1H NMR (CDClThree) δ; 7.25-7.35 (6H, m), 7.12 (1H, s), 7.05 (1H, dd, J = 5, 1Hz), 5.71 (1H, m), 5.57 (1H, m), 4.86 (1H, d, J = 5Hz), 4.56 (1H, d, J = 8.6Hz), 4.26 (1H, d, J = 7.6Hz), 4.02 (1H, m), 3.54 (2H, s), 2.83 (2H, d , J = 11.9Hz), 1.90-2.36 (8H, m), 1.37-1.50 (2H, m).
[0063]
Production Example 100
Synthesis of 3- [1- (3-methoxybenzyl) piperidin-4-yl] -4-phenyl-cis-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone
In the same manner as in Production Example 36, the title was obtained from 3- (piperidin-4-yl) -4-phenyl-cis-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone and 3-methoxybenzaldehyde. The compound was synthesized.
1H NMR (CDClThree) δ; 7.19-7.35 (6H, m), 6.88 (1H, m), 6.78-6.82 (1H, m), 5.74 (1H, m), 5.57 (1H, m), 4.86 (1H, d, J = 5Hz), 4.61 (1H, d, J = 8.9Hz), 4.33 (1H, d, J = 7.3Hz), 4.02 (1H, m), 3.81 (3H, s), 3.57 (1H, m), 3.45 ( 2H, s), 2.80 to 2.88 (2H, m), 1.89 to 2.35 (8H, m), 1.37 to 1.48 (2H, m).
Production Example 101
Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-cis-octahydro-2 (1H) -quinazolinone
3- (1-Benzylpiperidin-4-yl) -4-phenyl-cis-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone diastereomer A 391 mg (0.97 mmol) 90 mg of 30% platinum oxide was added to 15 mL of methanol and stirred for 6 hours at room temperature in a hydrogen atmosphere. After filtration through Celite, methanol was distilled off under reduced pressure, and the resulting residue was separated and purified by column chromatography (silica gel, aqueous ammonia: methanol: chloroform 1:10:90) to obtain 352 mg (0.87 mmol) of the title compound. .
1H NMR (CDClThree) δ; 7.25 ~ 7.36 (10H, m), 4.93 (1H, d, J = 7.6Hz), 4.73 (1H, d, J = 5.3Hz), 4.21 (1H, d, J = 8.3Hz), 3.54 ~ 3.62 (2H, m), 3.48 (2H, s), 2.76 (2H, m), 2.09 (2H, m), 1.74 to 1.91 (8H, m), 1.15 to 1.48 (9H, m).
Production Example 102
Synthesis of 3- (piperidin-4-yl) -4-phenyl-cis-octahydro-2 (1H) -quinazolinone
In the same manner as in Production Example 15, the title compound was synthesized from 3- (1-benzylpiperidin-4-yl) -4-phenyl-cis-octahydro-2 (1H) -quinazolinone.
1H NMR (CDClThree) δ; 7.28 to 7.36 (5H, m), 5.14 (1H, d, J = 7.6Hz), 4.73 (1H, d, J = 5Hz), 4.37 (1H, d, J = 8.3Hz), 3.56 to 3.70 (3H, m), 2.93 to 3.02 (2H, m), 2.60 (2H, m), 1.73 to 2.08 (5H, m), 1.18 to 1.48 (6H, m).
[0064]
Production Example 103
Synthesis of 3- (1-allylpiperidin-4-yl) -4-phenyl-cis-octahydro-2 (1H) -quinazolinone
The title compound was synthesized from 3- (piperidin-4-yl) -4-phenyl-cis-octahydro-2 (1H) -quinazolinone in the same manner as in Production Example 31.
1H NMR (CDClThree) δ; 7.22 to 7.36 (5H, m), 5.73 to 5.88 (1H, m), 5.06 to 5.19 (3H, m), 4.74 (1H, d, J = 5.3Hz), 4.35 (1H, d, J = 7.9Hz), 3.51 to 3.67 (2H, m), 2.80 to 2.96 (5H, m), 1.73 to 2.21 (7H, m), 1.15 to 1.48 (6H, m).
Production Example 104
Synthesis of 3- [1- (3-thienylmethyl) piperidin-4-yl] -4-phenyl-cis-octahydro-2 (1H) -quinazolinone
The title compound was synthesized from 3- (piperidin-4-yl) -4-phenyl-cis-octahydro-2 (1H) -quinazolinone and 3-thiophenecarboxaldehyde in the same manner as in Production Example 36.1H NMR (CDClThree) δ; 7.20-7.34 (6H, m), 7.11 (1H, m), 7.02 (1H, m), 5.29 (1H, d, J = 7.9Hz), 4.73 (2H, d, J = 5Hz), 3.51 (2H, s), 3.45 to 3.68 (3H, m), 2.80 (2H, m), 1.70 to 1.85 (5H, m), 1.12 to 1.44 (6H, m).
Production Example 105
Synthesis of 3- [1- (3-methoxybenzyl) piperidin-4-yl] -4-phenyl-cis-octahydro-2 (1H) -quinazolinone
The title compound was synthesized from 3- (piperidin-4-yl) -4-phenyl-cis-octahydro-2 (1H) -quinazolinone and 3-methoxybenzaldehyde in the same manner as in Production Example 36.
1H NMR (CDClThree) δ; 7.18-7.34 (5H, m), 6.78-6.89 (3H, m), 5.25 (1H, d, J = 7.9Hz), 4.72 (1H, d, J = 5Hz), 4.67 (1H, d, J = 7.6 Hz), 3.79 (3H, s), 3.46 (2H, s), 3.52 to 3.74 (3H, m), 2.77 (2H, m), 2.10 (2H, m), 1.70 to 1.85 (5H, m ), 1.13 to 1.46 (6H, m).
[0065]
Production Example 106
Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-trans-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone
(A) Synthesis of 4,5-trans-4-methoxycarbonylamino-5-benzoylcyclohexene
Sodium methoxide (3.31 g, 61.27 mmol) was added to a methanol (400 mL) solution of 4,5-cis-4-methoxycarbonylamino-5-benzoylcyclohexene (13.74 g, 53.0 mmol), and the mixture was heated to reflux for 20 hours. Methanol was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, chloroform: ethyl acetate 1: 1). The obtained crude crystals were recrystallized from ethyl acetate / hexane to obtain 6.94 g (29.7 mmol) of the title compound.
Melting point; 122-124 ° C
1H NMR (CDClThree) δ; 8.07 (2H, m), 7.46-7.60 (3H, m), 5.76 (1H, m), 5.65 (1H, m), 4.90 (1H, m), 4.20 (1H, m), 4.02 (1H , m), 3.63 (3H, s), 2.36 (3H, m), 2.17 (1H, m).
(B) Synthesis of 4,5-trans-4-methoxycarbonylamino-5- (α-hydroxybenzyl) cyclohexene
In the same manner as in Production Example 96 (a), the title compound was synthesized as a mixture of about 2: 3 diastereomers from 4,5-trans-4-methoxycarbonylamino-5-benzoylcyclohexene.
1H NMR (CDClThree) δ; 7.17-7.40 (5H, m), 5.49-5.65 (2.6H, m), 5.24 (0.4H, m), 5.03 (0.6H, m), 4.94 (0.6H, d, J = 10.2Hz) , 4.59 (0.4H, m), 4.34 (0.4H, d, J = 4Hz), 3.81 to 4.08 (1H, m), 3.71 (1.8H, s), 3.59 (1.2H, s), 1.57 to 2.61 ( 5H, m).
(C) Synthesis of 4,5-trans-4-methoxycarbonylamino-5- (α-chlorobenzyl) cyclohexene
The title compound was synthesized as a mixture of diastereomers from 4,5-trans-4-methoxycarbonylamino-5- (α-hydroxybenzyl) cyclohexene in the same manner as in Production Example 96 (b).
1H NMR (CDClThree) δ; 7.20-7.44 (5H, m), 5.56-5.71 (2H, m), 5.02 (1H, d, J = 6.9Hz), 4.76 (1H, m), 3.57-3.76 (4H, m), 2.49 ~ 2.56 (2H, m), 1.93 ~ 2.33 (3H, m).
(D) Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-trans-3,4,4a, 5,8,8a-hexahydro-2 (1H) -quinazolinone 4,5-trans- To a solution of 4-methoxycarbonylamino-5- (α-chlorobenzyl) cyclohexene 202 mg (0.72 mmol) in acetonitrile 10 mL, 4-amino-1-benzylpiperidine 205 mg (1.08 mmol), sodium iodide 163 mg (1.09 mmol) and 300 mg (2.17 mmol) of potassium carbonate were added, and the mixture was stirred in an autoclave at about 120 ° C. for 10 hours. After cooling, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with chloroform. The organic layer was washed with saturated brine, dried over potassium carbonate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, aqueous ammonia: methanol: chloroform 1:10:90) to obtain 119 mg (0.30 mmol) of the title compound.
1H NMR (CDClThree) δ; 7.34 (3H, m), 7.20 to 7.32 (7H, m), 5.53 to 5.63 (2H, m), 5.01 (1H, d, J = 10.2Hz), 3.45 to 3.58 (2H, m), 3.45 (2H, m), 2.60 to 2.78 (3H, m), 1.63 to 2.17 (11H, m).
[0066]
Production Example 107
Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-trans-octahydro-2 (1H) -quinazolinone
The title compound was obtained from 3- (1-benzylpiperidin-4-yl) -4-phenyl-trans-3,4,4a, 5,8,8-hexahydro-2 (1H) -quinazolinone in the same manner as in Production Example 101. Synthesized.
1H NMR (CDClThree) δ; 7.40-7.47 (3H, m), 7.19-7.33 (7H, m), 5.05 (1H, d, J = 10.6Hz), 3.51 (1H, m), 3.46 (2H, m), 3.28 (1H , m), 2.76 (2H, m), 2.26 (1H, m), 2.09 (2H, m), 1.61 to 1.86 (7H, m), 0.94 to 1.49 (5H, m).
Production Example 108
Synthesis of 3- (1-benzylpiperidin-4-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinethione
To a solution of α- (2-aminophenyl) -N- (1-benzylpiperidin-4-yl) benzylamine 503 mg (1.35 mmol) in tetrahydrofuran 10 mL, 1,1′-thiocarbonyldiimidazole 300 mg (1.68 mmol) And heated to reflux for 3 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate: chloroform 1: 4) to obtain 540 mg (1.30 mmol) of the title compound.
Hydrochloride
Melting point: 212-214 ° C (recrystallization solvent: diethyl ether / ethanol)
1H NMR (CDThreeOD) δ; 7.13-7.57 (12H, m), 6.88-7.03 (2H, m), 5.70-5.84 (2H, m), 4.85 (2H, s), 3.02-3.59 (4H, m), 2.43 (1H , m), 1.74 to 2.04 (3H, m).
Production Example 109
Synthesis of 6-chloro-3- [3- (trimethylammonio) propyl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone iodide
To a solution of 6-chloro-3- [3- (dimethylamino) propyl] -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone 418 mg (1.22 mmol) in ethanol 30 mL, methyl iodide 176 mg ( 1.24 mmol) was added and stirred at room temperature for 4 days. The precipitated crystals were collected by filtration and washed with diethyl ether to obtain 374 mg (0.77 mmol) of the title compound.
Melting point; 164-166 ° C
1H NMR (CDThreeOD) δ; 7.28-7.45 (5H, m), 7.09-7.15 (2H, m), 6.83 (1H, m), 5.77 (1H, s), 3.61 (1H, m), 3.30 (2H, m), 3.15 (1H, m), 3.06 (9H, s), 2.00 (2H, m).
[0067]
Production Example 110
Synthesis of 3- (1-methyl-3-quinuclidinio) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone iodide
The title compound was synthesized from diastereomer B of 3- (quinuclidin-3-yl) -4-phenyl-3,4-dihydro-2 (1H) -quinazolinone in the same manner as in Production Example 109.
Melting point: 230 ° C or higher (recrystallization solvent: ethanol / acetone)
1H NMR (DMSO-d6) δ; 9.89 (1H, s), 7.11 to 7.48 (7H, m), 6.80 to 6.95 (2H, m), 5.76 (1H, s), 3.80 to 4.01 (2H, m), 3.27 to 3.59 (5H, m), 2.92 (3H, s), 2.28 to 2.33 (1H, m), 1.70 to 2.08 (4H, m).
Production Example 111
Synthesis of 3-[(2S) -1,1-diethyl-2-pyrrolidinio] methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone iodide
3-[(2S) -1-ethylpyrrolidin-2-yl] methyl-4-phenyl-3,4-dihydro-2 (1H) -quinazolinone diastereomer A1 156 mg (0.46 mmol) in chloroform 10 mL solution To the solution, 819 mg (5.25 mmol) of ethyl iodide was added, and the mixture was heated to reflux for 4 days. The mixture was allowed to cool and then filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether / ethanol to obtain 63 mg (0.13 mmol) of the amorphous title compound.
1H NMR (CDThreeOD) δ; 7.25-7.43 (5H, m), 7.13-7.19 (2H, m), 6.84-6.96 (2H, m), 5.79 (1H, s), 4.18-4.35 (2H, m), 3.28-3.60 (6H, m), 3.04 to 3.12 (1H, m), 2.40 (1H, m), 2.08 to 2.20 (3H, m).
[0068]
Formulation Example 1
A tablet can be manufactured as follows, for example.
[Table 1]
Each component can be mixed and compressed into a 120 mg tablet.
[0069]
Formulation Example 2
An injection can be produced, for example, as follows.
[Table 2]
A solution of the above components can be sterilized by filtration, filled into a washed and sterilized vial, sealed with a washed and sterilized rubber stopper, and wound with a flip-off cap to produce an injection.
[0070]
Test example 1
Cardiomyocyte intracellular Ca which is one of the purposes of use of the present invention2+In order to evaluate the degree of inhibition of excessive accumulation of ouabain, the ouabain poisoning inhibitory action was measured using the compound of the present invention. Ouabain poisoning is caused by Ca in cardiomyocytes2+Flows in and Ca2+(American Journal of Physiology, Am. J. Physiol., 1989, 256, C1273-C1276: Basic Research of Cardiology, Basic Res. Cardiol., 1989, 84, 553-563), a compound that suppresses the action of ouabain is Ca in cardiomyocytes.2+It can be said that excessive accumulation is suppressed.
Test method
1) Preparation of specimen
The head of a male guinea pig (Nippon Charles River) was beaten, dislocated after cervical dislocation, and the heart was immediately removed. The pulsation was quickly stopped in pre-cooled Tyrode's solution, and the left atrial muscle was isolated. . 95% O2+ 5% CO2The left atrial specimen was suspended in a Magnus tube filled with 25 mL of Tyrode's solution maintained at 32 ± 0.3 ° C. by aeration of gas, and a load of 0.45 to 0.55 g was applied. The specimen is electrically driven by a rectangular wave stimulus (stimulation frequency: 2 Hz, duration: 3 msec, voltage 50% higher than the threshold value) through a bipolar silver electrode using an electrical stimulator (Diamedical DPS-160B). It was. The tension was recorded on an isometrically linear coder (Graphtech WR-3101) via an FD transducer (Toyo Baldwin T7-30-240) and a conversion amplification unit (NEC Sanei Model 1829). The specimen was allowed to stand for 1 hour after being suspended, and the experiment was started after confirming that the generated tension was sufficiently stable.
2) Evaluation of ouabain-induced myocardial injury ameliorating effect of the compounds of the present invention
The compound of the present invention was added to 3 × 10 −6 M and allowed to stand for 10 minutes, and then ouabain (Merck) was applied to 10 −6 M. In each case, the generated tension was recorded 40 minutes after the application of ouabain, and the generated tension and the static tension were recorded after 60 minutes. The generated tension and static tension are expressed as the amount of change (% generated tension and% static tension) at each time point, with the value immediately before ouabain application being 100%. % Difference was considered significant. The test compound was 3 × 10-FourDissolved with purified water to M to make a stock solution.
3) Test compound
Compound 1: Production Example 1; Citrate
Compound 2: Production Example 2 hydrochloride
Compound 3: Production Example 3; hydrochloride
Compound 4: Production Example 8; hydrochloride of diastereomer A
Compound 5: Production Example 15; hydrochloride
Compound 6: Production Example 24; Citrate
Compound 7: Preparation Example 25; hydrochloride of diastereomer A
Compound 8: Production Example 53; meso tartrate
Compound 9: Production Example 84; hydrochloride
Compound 10: Production Example 109
Compound 11: Production Example 110
Compound 12: Production Example 111
[0071]
Test results
The test results for each compound are shown in Table 3.
[Table 3]
Table 3 Uabine (10-6M) induced contraction failure, effect on increase in static tension
Results are shown as mean ± standard error.
* Significant difference with non-treated group at 5% risk rate.
** Significant difference with non-treated group at 1% risk rate.
[0072]
Test example 2
Cardiomyocyte intracellular Ca which is one of the purposes of use of the present invention2+In order to evaluate the degree of suppression of excessive accumulation of Ca,2+The effect of inhibiting the influx of erythrocytes was examined using cultured cardiomyocytes. The evaluation was performed according to the method described in the literature (Molecular Pharmacology, Mol. Pharmacol., 1986, 30, 164-170: Circulation Research, Circ. Res., 1992, 70, 804-811).+Cytoplasmic Ca by non-contained liquid replacement2+The inhibitory effect on the increase in concentration was used as an index.
Test method
1) Culture of cardiomyocytes
Cardiomyocytes were isolated and cultured from ICR mouse embryos (Nippon Charles River) on the 14th to 15th day of pregnancy according to the method described in the literature (Circulation Research, Circ. Res., 1993, 73, 758-770). That is, ventricular muscles were collected from fetal myocardium and minced, and then ventricular myocytes were separated with 0.25% trypsin (GIBCO). The obtained cardiomyocytes were attached to a cover glass previously coated with fibronectin (Koken) and CO in EagleMEM medium (Osaka Univ. Microbiological Research Institute) containing 10% fetal bovine serum (GIBCO).2Incubator (Astec BL-160: 37 ° C, 5% CO2+ 95% air).
2) Na+Cytoplasmic Ca by non-contained liquid replacement2+Measurement of concentration change
The cells on the 4th to 6th days of culture were transformed into 117.4 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl.2, 1.8 mM CaCl2, 0.1% glucose, 5 mM HEPES (Nacalai Tesque), pH 7.4 (normal HEPES solution), 20 μM Fura2-AM (Dojindo Laboratories), 0.4% bovine serum albumin (Sigma) normal HEPES solution Fura2-AM was loaded into the cells by incubating for 20 minutes at 37 ° C. under light shielding (37 ° C.). After washing twice with 2 mL of normal HEPES solution, a normal HEPES solution in which a cover glass having cells attached thereto was placed in a 37 ° C. heatable perfusion chamber and aerated with high-purity oxygen gas was perfused at a flow rate of 2 mL / min. Next, 28 mM NaCl, 108 mM choline-Cl (Wako Pure Chemicals), 0.1 mM EGTA (Wako Pure Chemicals) were applied according to the method described in the literature (Biosmica et Biophysica Acta, 1981, 642, 158-172). Drug), 0.1% glucose, 5 mM HEPES, pH 7.4 (28 mM Na-loaded HEPES solution) for 5 minutes to perfuse Na+After loading the cells with 135 mM choline-Cl, 1.8 mM CaCl2, 0.1% glucose, 5 mM HEPES, pH 7.4 (Na-free HEPES solution), and cytoplasmic Ca2+The concentration was increased. Cytoplasmic Ca2+The concentration was calculated from the fluorescence intensity ratio (340 nm / 380 nm) obtained by measuring the fluorescence intensity at 500 nm when excited at 340 nm and 380 nm with a two-wavelength spectrofluorometer (JASCO CAM-230). The drug was prepared with purified water to 1 mM, and then diluted appropriately in the perfusate to a predetermined concentration.
3) Ca of the present compound2+Evaluation of inhibitory effect on concentration increase
The compound of the present invention was treated both at the time of perfusion with 28 mM Na-loaded HEPES solution and at the time of perfusion with Na-free HEPES solution, and the change in Fura2-AM fluorescence intensity ratio (intracellular Ca2+Concentration change) was observed. The inhibitory action by the test compound was evaluated by comparing the Fura2-AM fluorescence intensity ratio change at the time of perfusion with Na-free HEPES solution in the treated group and the untreated group.
[0073]
[Brief description of the drawings]
FIG. 1 shows Na of compound 6 (Production Example 24; citrate).+Cytoplasmic Ca by non-contained liquid replacement2+It is a graph which shows the inhibitory effect test result with respect to a density | concentration increase. The horizontal axis represents the time after the test compound treatment, and the vertical axis represents the Fura2-AM fluorescence intensity ratio change during perfusion of Na-free HEPES solution.
[0074]
FIG. 2 shows Na of compound 13 (Production Example 89; hydrochloride).+Cytoplasmic Ca by non-contained liquid replacement2+It is a graph which shows the inhibitory effect test result with respect to a density | concentration increase. The horizontal axis represents the time after the test compound treatment, and the vertical axis represents the Fura2-AM fluorescence intensity ratio change during perfusion of Na-free HEPES solution.
Claims (5)
環W及びZは、
(a)環Wは5〜6員環のヘテロ芳香環または5〜10員環のシクロアルケン環もしくはシクロアルカン環であり、Zは
(a−1)式
(a−2)式
または、
(b)環Wはベンゼン環であり、Zが式
で表されるキナゾリノン誘導体またはその酸付加塩もしくは4級アンモニウム塩。 General formula (1)
Rings W and Z are
(A) the ring W is Ri cycloalkene ring or cycloalkane ring der heteroaromatic ring or 5-10 membered ring 5-6 membered ring, Z is
(A-1) Formula
(A-2) Formula
Or,
(B) Ring W is a benzene ring, and Z is a formula
In quinazolinone derivative or an acid addition salt or quaternary ammonium salt thereof represented.
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EP1122253B1 (en) * | 1998-10-16 | 2005-08-17 | Sumitomo Pharmaceuticals Company, Limited | Quinazolinone derivatives |
US7220735B2 (en) * | 2002-04-18 | 2007-05-22 | Schering Corporation | Benzimidazolone histamine H3 antagonists |
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JP4549649B2 (en) * | 2003-10-01 | 2010-09-22 | 大日本住友製薬株式会社 | Process for producing quinazolinone compounds |
JP4667789B2 (en) * | 2004-08-23 | 2011-04-13 | 大日本住友製薬株式会社 | Method for producing acid addition salt of quinazolinone compound |
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